ROBBIN’S PATHOLOGY SUMMARIES

CHAPTER 1
Cellular Adaptations, Cell Injury, Cell Death

The four aspects of the disease process that form the core of pathology are its cause (etiology), the mechanisms
of development (pathogenesis), the structural alterations induced in the cells and organs of the body (morphologic
changes), and the functional consequences of the morphologic changes (clinical significance)

CELLULAR RESPONSE TO INJURY

Nature and Severity of Injurious Stimuli Cellular Response

Altered Physiological Stimuli: Cellular Adaptations:
-inc. demand, inc. trophic stimulation -hyperplasia, hypertrophy(e.g. growth factors, hormones)
-dec. nutrients, stimulation -atrophy
-chronic irritation (chemical/physical) -metaplasia
Reduced Oxygen Supply; Chemical Injury; Microbial Cell injury:
Infection -acute reversible injury
-acute and self-limited -irreversible injury--->cell death
-progressive and severe (including DNA damage) *Necrosis, *Apoptosis
-mild chronic injury -subcellular alterations in various organelles
Metabolic Alterations, Genetic or Acquired Intracellular Accumulations;Calcifications
Prolonged life span with cumulative sublethal injury Cellular Aging

FEATURES OF NECROSIS AND APOPTOSIS

Feature Necrosis Apoptosis

Cell size Enlarged (swelling) Reduced (shrinkage)
Nucleus Pyknosis-> Karyorrhexis> Karyolysis Fragmentation into nucleosome size
fragments
Plasma Membrane Disrupted Intact; altered structure, especially
orientation of lipids
Cellular Contents Enzymatic digestion, may leak out of Intact; may be released in apoptotic
cells bodies

Adjacent Inflammation Frequent No

Physiologic/Pathologic Role Invariably pathologic (culmination of Often physiologic, means of
irreversible cell injury) eliminating unwanted cells; may be
pathologic after some forms of cell
injury, esp. DNA damage

Facts and Terms:

Hyperplasia - increase in the number of cells in an organ or tissue
*ex. Physiologic hyperplasia - hormonal hyperplasia and compensatory hyperplasia
Hypertrophy - increase in the size of cells, resulting in an increase in the size of an organ
Atrophy - shrinkage in the size of the cell by loss of cell substance
*Causes: decreased workload(atrophy of disuse), loss of innervation (denervation atrophy), diminished blood supply,
inadequate nutrition, loss of endocrine stimulation, aging (senile atrophy), pressure
Metaplasia - reversible change in which one adult cell type (epithelial or mesenchymal) is replaced by another adult cell
type
Apoptosis - programmed cell death; its biochemical features are protein cleavage, DNA breakdown and phagocytic
recognition
Pyknosis - shrinkage and increased basophilia of the nucleus due to DNA condensation
Karyorrhexis - fragmentation and breakdown of the nucleus
Karyolysis - dissolution of the nucleus

Overview of Cell Death and Injury

Causes of Cell Injury:
-oxygen deprivation (hypoxia)
-physical agents

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-chemical agents and drugs
-infectious agents
-immunologic reactions
-genetic derangements
-nutritional imbalances

Mechanisms of Cell Injury:

*BIOCHEMICAL MECHANISMS
1. The cellular response to injurious stimuli depends on the type of injury, its duration and its severity.
2. The consequences of cell injury depend on the type, state and adaptability of the injured cell.
3. Cell injury results from functional and biochemical abnormalities in one or more of several essential cellular
components.
*DEPLETION OF ATP
*MITOCHONDRIAL DAMAGE
*INFLUX OF INTRACELLULAR CALCIUM AND LOSS OF CALCIUM HOMEOSTASIS
*ACCUMULATION OD OXYGEN-DERIVED FREE RADICALS (OXIDATIVE STRESS)
*DEFECTS IN MEMBRANE PERMEABILITY

OTHER CELLULAR RESPONSES:

Intracellular Storage
-normal cellular constituent of accumulating excess like water, protein, carbohydrates, etc.
-abnormal substance, either exogenous or endogenous
-pigment, either exogenous or endogenous

Increased Production, inadequate metabolism

ex. fatty liver
hemochromatosis
local hemosiderosis

Accumulation due to abnormal metabolism

ex. lipofuscin
endogenous pigments like melanin

Abnormal exogenous pigments

ex. carbon or coal in anthracosis
tattoo

Pathologic Calcification
ex. Dystrophic - deposition in injured tissue (TB valve stenosis)
Metastatic - deranged calcium metabolism (chronic renal failure, vitamin D intoxication, hyperparathyroidism)

CHAPTER 2
Acute and Chronic Inflammation

Selectins and Integrins: Adhesion Molecules Involved in the Inflammatory Response

- the specific adhesion of cells to other cells/ECM is a basic component of cell migration and underlies many biologic
processes (embryogenesis, tissue repair, immune and inflammation)
- 2 families of adhesive proteins especially important in inflammation are selectins and integrins

Selectins
- family of 3 closely-related proteins
- all function in adhesion of leukocytes to endothelial cells
- all are single-chain transmembrane glycoproteins with an amino terminus related to C-type lectins
- ligand binding is calcium dependent
- has fast on rate but fast off rate and is of low affinity
o this allows them to mediate initial attachment and subsequent rolling of leukocytes in the face of
flowing blood
1) L-selectin (CD62L) – expressed on lymphocytes and other leukocytes
- binds neutrophils to cytokine-activated endothelial cells at sites of inflammation
- at least 3 endotheliai cell ligands can bind:
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 o GlyCAM-1 – HEVs of lymph node
o MadCAM-1 – GALT
o CD34 – proteoglycan on endothelial cells (and bone marrow)
2) E-selectin (CD62E) – previously known as endothelial leukocyte adhesion molecule (ELAM-1)
- expressed only on cytokine0activated endothelial cells
- recognizes complex sialylated carbohydrate group on granulocytes, monocytes and previously activated
effector and memory T-cells
- important in homing of effector and memory T-cells to peripheral sites of inflammation (e.g. skin)
- endothelial expression is hallmark of acute cytokine-mediated inflammation
- antibodies can block leukocyte accumulation
3) P-selectin (CD62P) – first identified on secretory granules of platelets
- found in secretory granules of endothelial cells (Weibel-Palade bodies)
- mediates binding of neutrophil, T-lymphocytes, monocytes
 experiments show that E-selectin and P-selectin are functionally redundant
 LAD-2 – Leukocyte Adhesion deficiency 2
o Syndrome in humans who lack one of the enzymes needed to express carbohydrate ligands for E- and P-
selectins

Integrins
- superfamily consists of about 30 structurally homologous proteins that promote cell-cell or cell-
matrixinteractions
- all are heterodimeric cell surface proteins composed of non-covalently linked α and β chains
- 3 subfamilies defined on the basis of the β–subunits used
- more recently, 5 additional β chains have been identified
1) VLA molecules (“very late activation”) – β1-containing
- α1β1 and α2β2 – expressed on T-cells 2-4 weeks after repetitive stimulation
- others are constitutively expressed in leukocytes and rapidly induced on others
- aka CD49a-hCD29:
o CD49a-h: different alpha chains (α1 to α8)
o CD29: common β1 subunit
- most are expressed on leukocytes; mediate attachment of cells to ECM
- VLA-4 (α4β1) – only in leukocytes and interacts with VCAM-1 (vascular CAM)
- surface protein that mediate homing of leukocytes at peripheral sites of inflammation

2) LFA-1 (Leukocyte Function-Associated Antigen-1) – β2 – CD11a-c CD18

- LFA-1 (CD11aCD18) – important role in adhesion of leukocytes and lymphocytes with other cells, such as AP
cells and vascular endothelium
- CD11bCD18 (Mac-1 or CR3) – fibrinogen receptor and complement receptor on phagocytic cells
- CD11cCD18 (p150,95 or CR4) – mediate leukocyte attachment to endothelial cells and subsequent
extravasation
*other integrins – expressed on platelets and bind to ECM proteins; protein involved in coagulation

The Complement System in Health and Disease

- activation of complement cascade: early – 3 different pathways; late steps – all 3 pathways converge

The Early Steps of Complement Activation

The Late Steps of Complement Activation
- polymerized C9 forms a channel on lipid membranes (membrane attack complex)  fluids enter  cell lysis
Regulation of Complement Activation
- mammals – have regulatory proteins that are absent in microbes and can thus function against them
1) regulation of C3 and C5 convertases – regulatory proteins enhance dissociation (decay accelearation) of the
convertase complement or proteolytically cleaves C3b
2) binding of active complement components – by specific proteins in plasma
o C1 inhibitor (C1INH) – blocks C1 from binding to an immune complex
o Inhibit MAC formation – CD59, membrane inhibitor of reactive lysis
Disorders of the Complement System – defects may result in increased susceptibility to infections, or to pathologic
activation
- deficiency in C3 – increased susceptibility; fatal unless treated
- deficiency in alternative pathway proteins – defective resistance to infections
- deficiency in C2 and C4 – associated with autoimmune diseases (SLE)
o failure to clear immune complexes formed
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 - deficiency in late components – defective MAC formation; sugger only from Neisseria organism infections
- genetic deficiencies of regulatory proteins
o paroxysmal nocturnal hemoglobinuria – mutations in gene encoding enzyme that synthesizes
phosphoinositol linkages
 defective phosphoinositol-linked membrane proteins, DAF and CD59  uncontrolled
complement activation
 recurrent intravascular hemolysis  chronic hemolytic anemia
o hereditary angioneurotic edema – deficiency of C1INH
 episodic edema accumulation in the skin and extremities as well as laryngeal and intestinal
mucosa, provoked by emotional stress/ trauma
 increased breakdown of C2 and C4
 C2 kinin and bradykinin – mediators of edema formation
 C1INH also inhibits kallikrein and coagulation of factor XII both of which when activated 
increased bradykinin

CHAPTER 3
Tissue Renewal and Repair: Regeneration, Healing, and Fibrosis
* no purple boxes to summarize

CHAPTER 4
Hemodynamic Disorders, Thromboembolic Diseases, and Shock

EDEMA

Edema- easily recognized grossly and most easily encountered in subcutaneous tissues , the lungs, and the brain

Edema Fluid- generally manifests only as a subtle swelling, with clearing and separation of the extracellular matrix
elements

Edema of the dependent parts of the body is a prominent feature of congestive failure, particularly of the right ventricle

Edema as a result of renal dysfunction or nephritic syndrome is generally more severe than cardiac edema and affects
all parts of the body easily.

Pulmonary edema- a common clinical problem most typically seen in the setting of left ventricular failure but also
occurring in renal failure, acute respiratory distress syndrome, pulmonary infections, and hypersensitivity reactions

Edema of the brain- may be localized or generalized, as in encephalitis, hypertensive crises, or obstruction to the brain’s
venous outflow

HYPEREMIA AND CONGESTION

Acute pulmonary congestion- characterized by alveolar capillaries engorged with blood

Chronic pulmonary congestion- the septa are thickened and fibrotic, and the alveolar spaces may contain numerous
hemosiderin-laden macrophages (heart failure cells)

Acute hepatic congestion- the central vein and the sinusoids are distended with blood, and there may even be central
hepatocyte degeneration.

Chronic passive congestion of the liver- the central regions of the hepatic lobules are grossly red-brown and slightly
depressed and are accentuated against the surrounding zones of uncongested tan liver.

THROMBOSIS

Thrombi- may develop anywhere in the cardiovascular system

Arterial thrombi- tend to grow in a retrograde direction from the point of attachment
-usually occlusive
-commonly found in the coronary, cerebral, and femoral arteries

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Venous thrombi- extend in the direction of the blood flow
- almost invariably occlusive
- also known as phlebothrombosis
- affects the lower extremities in 90% of the cases

INFARCTION

Red (Hemorrhagic) infarcts occur

1. with venous occlusions
2. in loose tissues (such as lung), which allow blood to collect in the infracted zone
3. in tissues with dual circulations
4. in tissues that were previously congested because of sluggish venous outflow
5. when flow is re-established

White (Anemic) infarcts occur with arterial occlusions in solid organs with end-arterial circulation (such as heart, spleen,
and kidney).

SHOCK

Shock is characterized by failure of multiple organ systems. The cellular changes may appear in any tissue.
Nevertheless, they are particularly evident in brain, heart, lungs, kidneys, adrenals, and gastrointestinal tract.

Brain- may develop ischemic encephalopathy

Heart- may undergo focal or widespread coagulation necrosis
Kidneys- typically exhibit extensive tubular ischemic injury
Lungs- seldom affected in pure hypovolemic shock because they are resistant to hypoxic injury
Adrenals- may have cortical cell lipid depletion
Gastrointestinal tract- may suffer patchy mucosal hemorrhages and necroses, referred to as hemorrhagic enteropathy
Liver- may develop fatty change, and with severe perfusion deficits, central hemorrhagic necrosis

CHAPTER 5
Genetic Disorders

MARFAN SYNDROME

Morphology.

I. Skeletal Abnormalities
- Bones: appearance: unusually tall, with long extremities (fingers, toes)
i. Upper segment of body (head to pubis) and lower segment of body (pubis to floor) ratio is
significantly lower than norm for age, race, and gender. Due to  lower segment.
- Joints: Double-jointed
i. Joint ligaments in hands and feet are lax; thumb hyper extended to wrist
- Head: Dolichocephalic, bossing of frontal eminences and supraorbital
ridges.
- Other abnormalities: kyphosis, scoliosis, slipping/rotation of lumbar
vertebrae

Trivia: Abraham Lincoln has most of above characteristics, thus suspected of having Marfan Syndrome

II. Ocular Changes

- Bilateral subluxation/dislocation of lens “ectopia lentis”

III. Cardiovascular Lesions

- 2 common lesions: (1) Mitral valve prolapse – more frequent (2) dilatation of ascending aorta due to cystic
medionecrosis.
- Note: Loss of medial support results in progressive dilation of aortic valve ring and root of aorta leading to
severe aortic incompetence.
- Most life – threatening feature of this disorder.

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TAY_SACHS DISEASE

Morphology.

- Involvement of neurons in the central and autonomic nervous systems and retina dominates clinical picture.
- In time, progressive destruction of neurons, proliferation of microglia, accumulation of complex lipids in
phagocytes w/in brain substance.
- Cherry red spot in macula and storage disorders affecting neurons-  characteristic of Tay Sachs
disease.

NIEMANN-PICK Disease: Types A & B

Morphology.

Type A variant – missense mutation – results to deficiency of sphingomyelinase. W/o the enzyme, results to undegraded
lipids accumulating w/in lysosomes. Cells  size. In addition, small vacuoles are created, imparting foaminess to
cytoplasm.

Lipid laden phyocyteic foam cells -  in spleen, liver, lymph nodes, bone marrow, tonsils, GI tract, lungs. Involvement of
spleen generally produces massive enlargement.

In brain: gyri shrunken, sulci widened. Neuronal involvement is diffuse, affecting all parts of Nervous system.

Retinal cherry red spot like in Taysachs is seen in 1/3- ½ of affected individuals where accumulated metabolite is
sphingomyelin.

GAUCHER DISEASE

Morphology.

Gaucher Disease: Characteristic: glucocerebrosides accumulate in  amounts w/in phagocytic cells. Distended cells “
gaucher cells” are found in spleen, liver, bone marrow, lymph nodes, tonsils, thymus, peyer patches, alveolar septa, and
air spaces in lungs.

- rarely vacuolated, have fibrillary type of cytoplasm instead.

PAS staining – intensely positive.

Using electron microscope, fibrillary cytoplasm seen as elongated, distended lysosomes containing stored lipid in stacks
of bilayers.

- Spleen enlarged in type 1 variant. (sometimes up to 10 kg), surface appears pale, mottled due to focal
accumulations.

Can cause skeletal deformities and fractures.

Neurons shriveled and destroyed.

MUCOPOLYSACCHARIDOSES

 in mononuclear phagocytic cells, endothelial cells, initial smooth muscle cells, fibroblast throughout body.

Common sites of involvement: spleen, liver, bone marrow, lymph nodes, blood vessels, heart.

Affected cells: distended, clearing of cytoplasm creating “balloon cells”

Note: Hepatosplenomegaly, skeletal deformities, valvular lesions, subendothelial arterial deposits, particularly in the
coronary arteries, and lesions in the brain, are common threads that run through all of the MPS.

May lead to MI thus leading to death.

ALKAPTONURIA (Ochronosis)

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Morphology

Ochronosis (blue black pigmentation) evident in ears, nose & cheeks due to retained homogentisic acid that binds to
collagen in connective tissues, tendons, and cartilage.

- Most serious consequence of ochronosis: deposits in the articular cartilages of the joints – lost of normal
resiliency and cartilages become brittle& fibrillated.

Most attacked places: vertebral column, intervertebral disc, knees, shoulders, and hips. (Small joints in hands and feet are
spared.)

NEUROFIBROMATOSIS: Types 1 & 2

Morphology.
3 types
(1) Cutaneous/dermal
- Soft, sessile, pedunculated lesions that vary in #.
(2) Subcutaneous neurofibromas
- grows beneath skin, firm, round masses often painful.
- Less than 1 cm in diameter; moderate-sized pedunculated lesions, 20 cm or more in diameter.
(3) Plexiform neurofibroma
- Diffusely involves subcutaneous tissue and contains numerous tortuous, thickened nerves. May cause
enlargement of limbs and other parts.

Another component of this disease are cutaneous pigmentations. – light brown café au lait macules, w/ smooth borders.
If 6 spots found with size greater than 1.5 cm in diameter, patient  in Neurofibromatosis type 1.
Lish nodules (pigmented hamartomas in the iris)
- present in 94% age 6 yrs .

CHAPTER 6
Diseases of Immunity

Toll-like Receptors
TLRs – membrane proteins that recognize microbe-derived molecules and stimulate innate immune responses
- 10 have been identified (TLR1 to 10)
- all contain leusine-rich repeats flanked by characteristic cysteine-rich motifs
- Toll/IL-1 receptor (TIR) domain – conserved signaling domain also found in cytoplasmic tails of IL1 and 8
receptors
 expressed on cells of the innate immune responses—macrophages, dendritic cells, neutrophils,
NK cells, mucosal epithelial cells, and endothelial cells
 involved in divergent types of molecules expressed by microbial cells: Gram-negative bacterial
lipopolysaccharide(LPS), Gram-positive bacterial peptidoglycan, bacterial lipoproteins, flagellin,
heat shock protein 60, unmethylated CpG DNA motifs, double-stranded RNa
 specificity is dependent on associations between TLRs and non-TLR adapter molecules
- activates transcription factors, notably NF-κB
- TRAF-6 – TNF-receptor (TNF-R) associated factor 6
 Activates I-κB cascade   NF-κB transcription factor
- MAP kinase cascade   AP-1 TF
- Genes expressed in response to TLR signaling encode components of innate immune responses
 Inflammatory cytokines: TNF, IL-1, IL-12
 Endothelial adhesion molecules: E-selectin
 Proteins involved in microbial killing mechanisms (inducible nitric oxide synthase)
- Depend on responding cell type

Systemic Immune Complex Disease

- morphology: dominated by acute necrotizing vasculitis with necrosis of the vessel wall and intense
meutrophilic infiltration
- fibroid necrosis: appearance of smudgy eosinophilic deposit produced by necrotic tissue and deposits of
immune complexes, complement and plasma proteins
- in kidney glomeruli – hypercellular (due to swelling and proliferation of endothelial and mesangial cells)
accompanied by neutrophilic and monocytic infiltration
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 - immunofluorescence microscopy: granular lumpy deposits of immunoglobulins and complement
- electron microscopy: electron-dense deposits along glomerular basement membrane

Rejection Reactions
1. Hyperacute rejection – occurs within minutes or hours after transplantation
- morphology (kidney graft): becomes cyanotic, mottled and flaccid and may excrete few drops of bloody
urine
2. Acute rejection – may occur within days of transplantation in the untreated patient, or months/years later after
immunosuppression has been employed and terminated
- histologically: humoral rejection is associated with vasculitis, cellular rejection with interstitial mononuclear
cell infiltrate
a. Acute cellular rejection - within initial months after transplantation
 elevated serum creatinine levels and renal failure
 histologically, extensive interstitial mononuclear cell infiltration and edema; mild interstitial
hemorrhage
 immunoperoxidase staining revelas activated T-cell lymphocytes
 focal tubular necrosis of glomerular and peritubular capillaries
 endothelitis – due to CD8+ cells injuring the vascular endothelium
 recognition is important because in the absence of accompanying arthritis, patients respond to
immunosuppressive therapy (cyclosporine – nephrotoxic)
b. Acute humoral rejection (rejection vasculitis) - mediated by antidonor antibodies and manifests
mainly as damage to the blood vessels
 necrotizing vasculitis with endothelial cell necrosis, neutrophilic infiltration, deposition of
immunoglobulins, complement and fibrin, and thrombosis
 marked thickening of the intima by proliferating fibroblasts, myocytes, and foamy macrophages
 resulting narrowing of arterioles may cause infarction or renal cortical atrophy
 the proliferative vascular lesions are believed to be caused by cytokines that cause growth of
vascular smooth muscles
3. Chronic rejection – progressive rise in serum creatinine over a period of 4-6 months
- dominated by vascular changes, interstitial fibrosis and tubular atrophy with loss of renal parenchyma
- vascular changes: dense, obliterative intimal fibrosis, principally in the cortical arteries
- result in renal ischemia (glomerular loss, instertitial fibrosis and tubular atrophy)
- chronic transplant glomerulopathy – glomeruli show duplication of basement membranes
- interstitial mononuclear cell infiltrates  plasma cells and eosinophils

Systemic Lupus Erythematosus

CHAPTER 7
Neoplasia

Gene expression profiles of Human Cancers, Microarrays and Proteomics

The most common method for large-scale analysis of gene expression in use today is based on DNA microarray
technology. In this method, DNA gragments, either cDNA (complementary DNA) or oligonucleotides, are spotted on a
glass slide or on some other solid support. These arrays are known as “gene chips”. The gene chips are hybridized to
“probes” (w/c are initially labeled w/ flurochromes that emit different colors) prepared from tumor and control samples.
After hybridization, the chip is read using a laser scanner. Sophisticated software has been developed to measure the
intensity of the fluorescence for each spot and produce data sets in which genes with wimilar expression patterns are
clustered. This is known as hierarchical clustering. This allows for appropriate gene identification and comparison
between expression profiles from various sources. Some problems encountered include: heterogeneity, variable amounts
of stromal connective tissue, inflammatory infiltrates and normal tissue cells. One wat to overcome this problem is to
obtain nearly pure tumor cells or small tumors free from associated tissues using the laser capture microdissection.
Gene expression analysis can be used to classify tumors; to predict metastatical potential, prognosis and
response to therapy; to reveal gene expression patterns that are dependent on the mutations of a single oncogene and
analyze the effects of hormones and environmental agents on cancer development.
The work that has received highest publicity involves gene expression profiling of breast cancers, in addition to
this, a 70 gene prognosis profile was also established. Using this type of profile, it has been reported that; (1) the profile
was a powerful predictor of disease prognosis for young patients; (2) it was particularly accurate for predicting metastasis
during the first 5 years after diagnosis; and (3) prognosis determined by gene expression profiles correlated highly with
histologic grade and estrogen receptor status but not with lymphatic spread of the tumor. Now the issue is whether this
technology is ready for day to day clinical application, but first other issues also need to be settled like larger trials to

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prove the reliability and accuracy of the analysis, also the procedures for handling samples, performing analysis and
reporting data which all need to be standardized.
Next on the horizon for the global analysis of gene expression in cancers is proteomics, a technique used to
obtain expression profiles of proteins contained in tissues, serum, or other body fluids. The more recent technique called
ICAT (isotype coding infinity tags) does not rely on electrophoresis for protein separation. In ICAT, proteins in the test and
control samples are labeled with light and heavy isotopes. The differently labeled proteins are then identified and
quantified by mass spectrometry. A variation of proteomic analysis has been used to obtain protein profiles in the blood of
cancer patients without identification of individual proteins. Indeed, it is hard to escape the excitement generated by the
development of new and powerful methods of molecular analysis.

CHAPTER 8
Infectious Disease

CHAPTER 9
Environmental and Nutritional Pathology

ENVIRONMENT AND DISEASE

Recognition of Occupational and Environmental Diseases
Mechanisms of Toxicity

COMMON ENVIRONMENTAL AND OCCUPATIONAL EXPOSURES

Personal Exposures
Therapeutic Drugs
Outdoor Air Pollution
Indoor Air Pollution
Industrial Exposures
Agricultural Hazards
Natural Toxins
Radiation Injury
Physical Environment

NUTRITION AND DISEASE

Food Safety: Additives and Contaminants
Nutritional Deficiencies
Obesity
Diet and Systemic Diseases
Chemoprevention of Cancer

RADIATION INJURY

IONIZING RADIATION

Clinical Manifestations:
BLOOD VESSELS
- show subintimal fibrosis, fibrosis of the muscle wall, degeneration of the internal elastic lamina, and severe
narrowing of the lumen after an initial inflammatory reaction, accompanied by endothelial cell death
- show capillaries that are thrombosed and obliterated or ectatic
- have organs supplied showing ischemic changes, atrophy and fibrosis
SKIN
- sensitive to acute radiation-induced injury
- desquamation: replacement of the normal epidermis by atrophic epidermis characterized by hyperkeratosis,
hyperpigmentation and hypopigmentation
- has subcutaneous vessels weakened and dilated, surrounded by dense bands of collagen in the dermis
- radiation dermatitis = impaired healing + increased susceptibility to infection + ulceration
- has increased risk for basal cell and squamous skin carcinomas even 20 years after exposure
HEART
- occurs after radiotherapy delivered to chest after malignant lymphoma, lung cancer or breast cancer
- constrictive pericarditis: caused by fibrosis of the pericardium
- less commonly, injury to capillaries and coronary arteries cause myocardial ischemia and fibrosis
LUNGS

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 - highly-susceptible to radiation-induced injury, leading to acute lung injury and delayed radiation pneumonitis
- dyspnea + chronic cough + diminished lung function = delayed injury, caused by intra-alveolar and interstitial
fibrosis
- risk of lung cancer is increased by both internal and external radiation, since it is synergistic with smoking;
cigarette smoke contains two radionuclides: lead 210 and polonium 210
- underground miners exposed to radon 222 are at risk for lung CA with a characteristic mutation (GT) at codon
249 of the p53 tumor-suppressor gene
KIDNEYS AND URINARY BLADDER
- kidneys
o moderately susceptible to injury
o delayed peritubular fibrosis, vascular damage and hyalinization of glomeruli may lead to hypertension and
atrophy
- urinary bladder
o sensitive to radiation injury
o has acute necrosis of the epithelium followed by submucosal fibrosis, contracture, bleeding and ulceration
- tumors found in these organs were reported in Japanese atomic bomb survivors and in women treated for cervical
CA
GASTROINTESTINAL TRACT
- esophagitis, gastritis, enteritis, colitis, and proctitis
- associated with exfoliation of the epithelial mucosa, susceptibility to infection, and loss of electrolytes and fluid
- delayed injury to small blood vessels  causes chronic ischemia, ulceration, and atrophy of the mucosa
- fibrosis  cause strictures and obstruction
BREAST
- diagnostic doses administered during adolescence increases incidence of breast CA after 15 to 20 years
- causes a dense, fibrotic reaction with extreme pleomorphism of epithelial cells
OVARY AND TESTIS
- spermatogonia
o extremely sensitive to radiation
o even with low doses, suppression of meiosis and infertility can occur
- blood vessels may be obliterated
- seminiferous tubules may be fibrotic
- Sertoli cells and Leydig cells however still intact
- Ovarian follicles
o degenerate acutely
o leaving usually a few primordial oocytes and their follicular epithelium scattered in the fibrous stroma
EYES AND CENTRAL NERVOUS SYSTEM
- lens
o sensitive to ionizing radiation, giving rise to cataracts and damaged retinal and ciliary arteries
- brain
o may show focal necrosis and demyelination of white matter
- spinal cord
o may damage small blood vessels leading to necrosis, demyelination and paraplegia (called transverse
myelitis)

PHYSICAL ENVIRONMENT

THERMAL INJURIES

THERMAL BURNS
Morphology
Gross inspection:
- Full-thickness burns = white or charred, dry and anesthetic (due to nerve ending destruction)
- Partial-thickness burns (depending on the depth) = pink or mottled, with blisters and are painful
Histologic examination:
- Devitalized tissue = demonstrates coagulative necrosis
- Adjacent vital tissues = quickly acquires inflammatory changes with an accumulation of inflammatory cells and
marked exudation

NUTRITIONAL DEFICIENCIES

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PROTEIN ENERGY MALNUTRITION

Morphology
Central anatomic changes in PEM:
1) growth failure
2) peripheral edema in Kwashiorkor
3) loss of body fat and atrophy of muscle, more marked in marasmus

Kwashiorkor Marasmus
Liver - enlarged and fatty - none
- (rare) superimposed cirrhosis
Small bowel -  in the mitotic index in the crypts of glands, - (rare)  in the mitotic index in the crypts of
associated with mucosal atrophy and loss of villi glands, associated with mucosal atrophy and
and microvilli loss of villi & microvilli
- disaccharidase deficiency can occur in such
cases, hence infants may not respond well to a
full-strength, milk-based diet
- reversible
Bone marrow - may be hypoplastic, mainly because of  numbers of red cell precursors (whether due to a
deficiency in protein and folates or to reduced synthesis of transferring and ceruloplasmin is
uncertain)
- anemia is usually present, often hypochromic, microcytic anemia, but a concurrent deficiency of
folates may lead to a mixed microcytic-macrocytic anemia
Brain - found in infants born to malnourished mothers and thus suffering PEM during the first 1 or 2 years
of life: cerebral atrophy, reduced number of neurons, and impaired myelinization of white white
matter
- however, no universal agreement of validity of these findings
Other changes - thymic and lymphoid changes more marked in kwashiorkor
- anatomic alterations induced by intercurrent infections, particularly with all manner of endemic
worms and other parasites
- deficiencies of other required nutrients, such as iodine and vitamins

VITAMIN DEFICIENCIES

VITAMIN D
Excess of unmineralized matrix = basic derangement in both rickets and osteomalacia

CHAPTER 10
Diseases of Infancy and Childhood

I. Congenital Anomalies
a. Definitions
i. Malformations – primary errors of morphogenesis; intrinsically abnormal developmental process
ii. Disruptions – secondary destruction of an organ or body region that was previously normal in
development; extrinsic disturbance in morphogenesis
iii. Deformations – extrinsic disturbance of development; localized or generalized compression of the
growing fetus by abnormal biomechanical forces, leading to structural abnormalities
iv. Sequence – pattern of cascade anomalies; single, localized aberration in organogenesis may
lead to secondary effects in other organs
v. Syndrome – constellation of congenital anomalies believed to be pathologically related, that
cannot be explained on the basis of a single, localized, initiating defect

b. Causes
i. Genetic – karyotypic aberrations or single gene mutations
ii. Environmental – viruses (ex. Rubella virus and cytomegalovirus), drugs and other chemicals,
radiation, maternal diabetes
iii. Multifactorial

c. Pathogenesis

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 i. Timing of the prenatal teratogenic insult – important impact on the occurrence and type of
anomaly produced
1. Early embryonic period (first 3 weeks) – injurious agent either damages enough cells to
cause death and abortion, or only a few cells to allow the embryo to recover without
defects
2. 3rd week to ninth week (Organogenesis) – embryo is extremely susceptible to
teratogenesis (peak during the 4th to 5th week)
3. Fetal period – fetus is susceptible to growth retardation or injury to already formed organs
ii. Teratogens and genetic defects may act at several steps in normal morphogenesis (Cell
migration, Cell proliferation, Cellular interactions, Cell-matrix associations, Programmed Cell
death, Hormonal influences and mechanical forces)
iii. Homeobox (HOX) and PAX genes
1. HOX genes – implicated in the patterning of limbs, vertebrae and craniofacial structures
2. PAX genes

II. Birth Weight and Gestational Age

a. Prematurity and Fetal Growth Restriction
i. Prematurity – gestational age less than 37 weeks
ii. Risk Factors for Prematurity
1. Preterm premature rupture of placental membranes (PPROM) – spontaneous rupture
prior to 37 weeks’ gestation; associated with maternal smoking, prior history of preterm
delivery, vaginal bleeding during the index pregnancy
- outcome depends on gestational age of fetus, effective prophylaxis of infections in
the exposed amniotic cavity
2. Intrauterine infections – the earlier the gestational age at delivery, the higher the
frequency of intra-amniotic infection; histologic correlates are chorioamnionitis and
funisitis
3. Uterine, cervical and placental structural abnormalities (uterine distortions, compromised
cervical structural support, placenta previae, abruptio placentae)
4. Multiple gestation
iii. Fetal Growth Restriction - commonly underlies SGA (Small for Gestational Age); can be detected
before delivery by ultrasonographic measurement of various fetal dimensions
- Factors that result in FGR
1. Fetal – intrinsically reduce growth potential of the fetus despite an adequate supply of
nutrients from the mother (ex. Chromosomal disorders, congenital anomalies, congenital
infections)
2. Placental – esp. important in the 3rd trimester, when vigorous fetal growth places heavy
demands on the uteroplacental supply line
- insufficiency may be due to umbilical-placental vascular anomalies, placenta abruptio,
placenta previa, placental thrombosis and infarction, placental infection, multiple gestations,
confined placental mosaicism
3. Maternal- many conditions affecting the mother’s health may result in decreased
placental blood flow (ex. vascular diseases like preeclampsia and chronic hypertension,
narcotic abuse, alcohol intake, heavy cigarette smoking, maternal malnutrition)
b. Immaturity of Organ Systems – a major problem for preterm infants is the functional, and sometimes
structural, immaturity of various organs
i. Lungs – immature lungs are grossly unexpanded, red and meaty; their alveolar spaces are
incompletely expanded and often lined by cuboidal epithelium, they usually contain pink
proteinaceous precipitate and occasional squamous epithelial cells
ii. Kidneys – glomerulus formation is incomplete in the preterm infant; these primitive glomeruli are
seen in the subcapsular zone, however the deeper glomeruli are well formed and have adequate
renal function for survival
iii. Brain – the brain is incompletely developed in the preterm, however the vital brain centers are
sufficiently developed to sustain normal central nervous system function; homeostasis is not
perfect, though
iv. Liver – the liver suffers from lack of physiologic maturity, and many of its functions are marginally
adequate to carry out the demands placed on them; thus almost all newborns, particularly those
with low birth weight, will have physiologic jaundice in the first post-natal week
c. APGAR Score –a clinically useful method of evaluating the physiologic condition and responsiveness of
newborn infants and, hence, their chance for survival
III. Birth Injuries
12
 a. important causes of illness or death in infants as well as children during their first years
b. most commonly involve the head, skeletal system, adrenals, liver, peripheral nerves
c. may be acute or the result of late-appearing sequelae (LGA infants are at greater risk for birth injury)
d. Intracranial hemorrhages – the most common important birth injury; excessive molding of the head or
sudden pressure changes in its shape as it is subjected to pressure from forceps or to sudden precipitate
expulsion
IV. Perinatal Infections
a. Transcervical (Ascending) Infections
i. May be acquired in utero or around the time of birth
ii. Fetus acquires the infection either by inhaling infected amniotic fluid into the lungs shortly before
birth or by passing through an infected birth canal during delivery
iii. Preterm birth is often an unfortunate consequence
b. Transplacental (Hematologic)
i. Parasitic, viral, and bacterial infections gain access to the fetal bloodstream via the chorionic villi
ii. Some infections (parvovirus B19)-spontaneous abortion, stillbirth, hydrops fetalis, congenital
anemia
iii. TORCH infections – fever, encephalitis, chorioretinitis, hepatosplenomegaly, pneumonitis,
myocarditis, myocarditis, hemolytic anemia, vesicular or hemorrhagic skin lesions
c. Onset of sepsis
i. Early-onset (within the first 7 days of life) – usually acquired at or shortly before birth
ii. Late-onset (from 7 days to 3 months)
V. Neonatal Respiratory Distress Syndrome
Morphology- distinctive lungs on gross exam (normal size, but they are solid, airless and reddish purple)
- microscopically: poorly developed or collapsed alveoli
- necrotic cellular debris in the terminal bronchioles and alveolar ducts (in infants who have
died early in the course of the disease); the necrotic material is incorporated within eosinophilic
hyaline membranes lining the respiratory bronchioles, alveolar ducts and random alveoli; no
lesions are seen in the lungs of stillborn infants
- eosinophilic hyaline membrane - paucity of neutrophilic inflammatory reaction; largely made up
of fibrinogen and fibrin admixed with cell debris
- Infants who survive more than 48 hours – reparative changes in the lungs; alveolar epithelium
proliferates under the membrane surface (may undergo partial digestion or phagocytosis by
macrophages)

VI. Necrotizing Enterocolitis

a. Most commonly occurs in premature infants; high perinatal mortality
b. Most likely multifactorial
c. Intestinal ischemia – appears to be a prerequisite; generalized hypoperfusion or selective reduction of
blood flow to the intestines to divert oxygen to vital organs
d. Inflammatory mediators –implicated in increasing mucosal permeability
e. Clinical course: bloody stools, abdominal distention and circulatory collapse
f. Abdominal radiographs: gas within the intestinal wall
g. Typically involves the terminal ileum, cecum, and right colon; involved segment is distended, friable,
congested, or it can be frankly gangrenous
h. Microscopically: mucosal or transmural coagulative necrosis, ulceration, bacterial colonization,
submucosal gas bubbles; reparative changes like fibrosis may be seen after an acute episode
VII. Germinal Matrix – Intraventricular Hemorrhage
Subependymal hemorrhage, with secondary bleeding into the ventricles; particularly prone to occur in
preterm infants
VIII. Fetal Hydrops
Morphology of Hydrops Fetalis:
a. anatomic findings vary with disease severity and underlying etiology
b. hydrops fetalis is the most severe and generalized manifestation of intrauterine fluid accumulation; lesser
degrees of edema can occur
c. dysmorphic figures: suggests a constitutional chromosomal abnormality
d. hydrops with fetal anemia: fetus and anemia are pale
e. enlarged liver and spleen (from cardiac failure and congestion); bone marrow demonstrates
compensatory hyperplasia of erythroid precursors; extramedullary hematopoesis in the liver, spleen, and
other tissues; increased hematopoietic activity accounts for large numbers of immature red cells in the
peripheral circulation

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 f. Kernicterus – most serious threat in fetal hydrops; central nervous damage; affected brain is enlarged;
when sectioned, the brain is found to have a bright yellow pigmentation (kernicterus)
IX. Inborn Errors of Metabolism and Other Genetic Disorders
Morphology:
a. anatomic changes are highly variable – depend on which glands are affected and on the severity of
involvement
b. Cystic fibrosis – may be compatible with long life or may cause death in infancy
i. Pancreatic abnormalities – in majority of patients with cystic fibrosis
- milder cases (may only have mucus accumulation in the small duct with
some exocrine gland dilation)
- advanced cases (older children and adolescents; ducts are totally
plugged, causing atrophy of exocrine glands and progressive fibrosis; total
atrophy of the exocrine portion of the pancreas may occur; total loss of
pancreatic exocrine secretion impairs fat absorption; may cause
avitaminosis A)
ii. Liver involvement – bile canaliculi are plugged by mucinous material, with ductular proliferation
and portal inflammation
- focal biliary cirrhosis develops over time, eventually involving the entire liver, resulting in diffuse
hepatic nodularity
iii. Salivary glands – histologic changes include progressive dilation of ducts, squamous metaplasia
of the lining epithelium, glandular atrophy followed by fibrosis
iv. Pulmonary changes – most serious complications of the disease
- stem from the viscous mucus secretions of the submucosal glands of the respiratory tree, with
secondary obstruction and infection of the air passages
- bronchioles are often distended with thick mucus associated with marked hyperplasia and
hypertrophy of the mucus-secreting cells
- superimposed infections – severe chronic bronchitis and bronchiectasis; lung abscesses may
develop
v. Azoospermia and infertility – in 95% of the males who survive to
adulthood; congenital bilateral absence of the vas deferens (CBAVD) is
frequently in these patients

X. Sudden Infant Death Syndrome (SIDS)

Morphology:
a. A variety of findings have been reported at autopsy; usually subtle, of uncertain significance, and are not
present in all cases
b. Multiple petechiae – most common; usually present on the thymus, viscera, parietal pleura and
epicardium
c. Lungs – grossly appear congested; vascular engorgement with or without pulmonary edema
demonstrable microscopically; possibly demonstrate agonal events
d. CNS – astrogliosis of the brain stem and cerebellum; hypoplasia of the arcuate nucleus or a subtle
decrease in brainstem neural populations
e. Nonspecific findings – frequent hepatic extramedullary hematopoiesis and periadrenal brown fat

XI. Tumors and Tumor-Like Lesions of Infancy and Childhood

a. Benign tumors and tumor-like lesions
i. Hemangioma – most common tumors of infancy; usually located in the skin, particularly on the
face and scalp; spontaneously regress in many cases
ii. Lymphatic tumors – lymphangiomas (hamartomatous or neoplastic in origin;cystic and cavernous
spaces) and lymphangiectasis (abnormal dilations of preexisting lymph channels; presents as a
diffuse swelling of part or all of an extremity)
iii. Fibrous tumors – fibromatosis, fibrosarcomas, myofibromatoses
iv. Teratomas – may be benign, well-differentiated cystic lesions, lesions of indeterminate potential,
or maybe unequivocally malignant
b. Malignant tumors
i. Neuroblastic tumors
1. Range in size from minute nodules to large masses; majority arise in the adrenal medulla
2. Majority spontaneously regress, leaving a focus of fibrosis or calcification in the adult
3. Histologically: small, primitive-appearing cells with dark nuclei, scant cytoplasm, poorly
defined cell borders growing in solid sheets; mitotic activity, nuclear breakdown and
14
 pleomorphism may be prominent; faintly eosinophilic fibrillary material in the background
(neuropil)
4. Homer-Wright pseudorosettes – tumor cells concentrically arranged about a central
space filled with neuropil
5. Maturation of neuroblasts into ganglion cells is usually accompanied by the appearance
of Schwann cells (schwannian stroma); associated with a favorable histology
6. Follows the international neuroblastoma staging system
ii. Wilms tumor
1. Grossly: large, solitary, well-circumscribed mass
2. Cut section: soft, homogeneous, tan to gray with occasional foci of hemorrhage, cyst
formation, and necrosis
3. Microscopically: recognizable attempts to recapitulate different phases of nephrogenesis
(triphasic combination: blastemal, stromal, epithelial cell types)
: sheets of small blue cells with little distinctive features
: epithelial differentiation – abortive tubules or glomeruli
: fibrocytic or myxoid stromal cells
: sometimes other heterologous elements may be identified, as well as anaplasia
(correlates with p53 mutations and resistance to chemotherapy)

CHAPTER 11
Blood Vessels
I. ATHEROSCLEROSIS
A. Key processes
 Intimal thickening
 Lipid accumulation
 ATHEROMA- aka “atheromatous plaque”
- Raised focal lesions from the intimal layer with a soft, yellow, grumous core of lipid, covered by a firm,
white fibous cap
- Impinge on the arterial lumen and can coalesce to form large masses
- Initially focal and sparsely distributed and become numerous and diffuse in later stage of disease
 Usual sites (from the most common to the least common)
- Abdominal aorta > thoracic aorta > coronary arteries > popliteal arteries > internal carotid arteries >
Circle of Willis
B. Morphology
 Components of plaques:
- Cells (SMC, macrophages, leukocytes)
- ECM (collagen, elastic fibers, proteoglycans)
- Intracellular and extracellular lipid
 Arrangement of typical well-developed plaque
- Fibrous cap (Cells + ECM + neovascularization)
- Necrotic Center (Cell debris, cholesterol crystals, foam cells, calcium)
- Tunica media
 Calcification and advanced atherosclerotic lesions
- Plaques enlarge through cell death and degeneration thrombus calcification
- Advanced lesions are at risk for:
i. Focal rupture, ulceration, erosion, emboli
ii. Hemorrhage
iii. Superimposed thrombosis
iv. Aneurismal dilatation

II. HYPERTENSION
A. Hyaline Arteriolosclerosis
 Major morphologic characteristic of benign nephrosclerosis
 Homogenous, pink, hyaline thickening of arteriole wall, with loss of underlying structural detail and narrowing
of lumen
 Reflects leakage of plasma components across vascular endothelium and excessive extracellular matrix
production
 More generalized and frequent in the elderly, and more severe in hypertensive patients and diabetics

B. Hyperplastic Arteriolosclerosis

15
  Characteristic but NOT limited to malignant hypertension
 Onionskin, concentric, laminated thickening of arteriole wall with progressive narrowing of the lumina
composed of SMC and thickened BM
 Seen in more acute or severe elevation of BP
 In malignant hypertension, accompanied by fibrinoid deposits and acute necrosis  necrotizing arteriolitis

III. ANEURYSMS
A. Abdominal Aortic Aneursyms/AAA
 Usually seen in renal arteries and above bifurcation of the aorta
 Saccular or fusiform (up to 15 cm in diameter)
 Weakening of the wall occurs in areas of severe atherosclerosis
 Often contain atheromatous ulcers and granular mural thrombi which lodge in the kidneys or lower extremities
 Inflammatory abdominal aortic aneurysms
- Dense periaortic fibrosis with abundant, inflammatory reaction rich in lymphocytes and plasma cells
with macrophages and giant cells
 Mycotic abdominal aortic aneurysms
- Atherosclerotic AAAs that have become infected by lodgment of circulating organisms in the wall
(Salmonella gastroenteritis)
B. Syphilitic/ Luetic Aneurysms
 Inflammatory involvement begins in aortic adventitia (vasa vasorum) inducing obliterative endarteritis rimmed
by infiltrate of lymphocytes and plasma cells (syphilitic aortitis)
 Narrow lumen causes ischemic injury  loss of medial fibers and muscle cells inflammation scarring
dilation aneurysm
 Tree barking (wrinkling of intervening segments of aortic intima due to contraction of fibrous scars )
 Luetic involvement development of superimposed aortic root atheromatosis occlude coronary ostia
valvular insufficiency LVH cor bovinium or “cow’s heart”

C. Aortic Dissection/Dissecting Hematoma

 Spontaneous dissection from intimal tear which extends into media of ascending aorta
 Transverse or oblique, with sharp but jagged edges
 Often ruptures out massive hemorrhage
 Can sometimes re-rupture into aortic lumen  double barreled aorta
 Medial degeneration/Cystic medial necrosis: most common preexisting histologically detectable lesion
- Elastic tissue fragmentation and separation of the elastic and fibromuscular elements of the tunica
media by small cleftlike spaces filled with amorphous ECM of CT (“cystic”)
- Large scale loss of elastic laminae

IV. VASCULITIDES
A. Giant Cell Arteritis
 Nodular thickenings with reduction of lumen which become thrombosed
 Commonly with granular inflammation of the inner half of the media with multinucleate giant cells and
fragmentation of internal elastic lamina
 Less common: rare granuloma and giant cells, but with nonspecific panarteritis with a mixed inflammatory
infiltrate of lymphocytes, macropahges, neutrophils, eosinophils
 Healed stage: collagenous thickening of vessel wall; organization of luminal thrombus transforms artery into
a fibrous cord

B. Takayasu Arteritis
 Classically involves aortic arch
 Irregular thickening of the aortic or branch vessel wall with intimal wrinkling
 Orifices of major arteries to the upper portion of the body may be markedly narrowed or even obliterated by
intimal thickening when aortic arch, coronary and renal arteries are involved
 Histological changes: adventitial mononuclear infiltrate with perivascular cuffing of the vasa vasorum to
intense mononuclear inflammation in the media
 Distinctions among active giant cell lesions of the aorta are based largely on the age of the patient, and most
giant cell lesions of the aorta in young patients are designated as Takayasu Arteritis

C. Polyarteritis Nodosa/PAN

16
  Segmental transmural necrotizing inflammation of arteries of medium to small size in any organ (most
common: kidney, heart, liver, GI; least common: lungs)
 Histologic picture:
- Acute phase: transmural inflammation of the arterial wall (with neutrophils, eosinophils, and
mononuclear cells, with fibrinoid necrosis)
- Chronic: fibrous thickening of vessel wall that extends into the adventitia with firm nodularity of lesions
- All stages of activity may coexist in different vessels or even within the same vessel

D. Kawasaki Disease
 Vasculitis is PAN-like with necrosis and pronounced inflammation affecting entire thickness of the vessel wall
but is LESS PROMINENT in Kawasaki
 Acute vasculitis subsides spontaneously or in response to treatment
 Complicated by aneurysm formation, thrombosis, MI and obstructive intimal thickening

E. Microscopic Polyangiitis
 Histologically similar to those of PAN
 Muscular and large arteries are usually spared
 Macroscopic infarcts are uncommon
 Histologic picture:
- No granulomatous inflammation
- Segmental fibrinoid necrosis of the media may be present, but in some lesions the change is limited
to infiltration with neutrophils ( leukocytoclasia/ leukocytoclastic angiitis) which is commonly found in
postcapillary venules
 Pauci-immune injury unless patients are examined within 24 hours of development

F. Wegener’s Granulomatosis
 Upper respiratory tract lesions range from inflammatory sinusitis resulting from mucosal granulomas to
ulcerative lesions of the nose, palate, or pharynx, rimmed by necrotizing granulomas and accompanying
vasculitis
 Histologic picture:
- Granulomas: geographic pattern of necrosis surrounded by lymphocytes, plasma cells, macrophages,
and giant cells
- Necrotizing or granulomatous vasculitis
 Radiographic resemblance to tubercle, so mycobacterial or fungal infection should be R/O
 Advanced lesions: diffuse necrosis, proliferation, and crescent formation

G. Thromboangiitis Obliterans/ Buerger Disease

 Sharply segmental acute and chronic vasculitis of medium-sized and small arteries mostly of the upper and
lower extremities
 Histologic picture:
- Acute and chronic inflammation permeates arterial walls
- Thrombosis of lumen which may have organization and recanalization
- Small microabscesses with central focus of neutrophils surrounded by granulomatous inflammation
 Veins and nerves also become encased in fibrous tissue

V. VEINS AND LYMPHATICS

 Varicose veins
- Dilated, tortuous and scarred with thinning at points of maximal dilation
- Intraluminal thrombosis and valvular deformities seen upon opening of vessels
- Histologic picture: variations in thickness of vein wall, phlebosclerosis (elastic tissue degeneration
and spotty calcifications)

VI. TUMORS
A. Benign
 Capillary Hemangioma
- Bright red to blue, level with the surface of the skin or slightly elevated, with intact covering epithelium
- Can be pedunculated
- Histologic picture:
i. lobulated but unencapsulated aggregates of closely packed, thin-walled capillaries, usually
blood-filled and lined by a flattened endothelium, separated by scant CT stroma
17
 ii. lumina partially or completely thrombosed and organized
iii. rupture of vessels causes scarring and accounts for the hemosiderin pigment occasionally
found

 Cavernous Hemangioma
- Red-blue, soft, spongy mass 1 to 2 cm in diameter
- Giant forms occur affect large subcutaneous areas of the face, extremities or other regions of the
body
- Histologic picture:
i. Sharply, defined, not encapsulated
ii. Made up of large, cavernous vascular spaces
iii. Partly or completely filled with blood separated by scant CT stroma
iv. Intravascular thrombosis with associated dystrophic calcification is common

 Glomangioma/Glomus Tumor
- Lesions are usually small (<1 cm), slightly elevated, rounded, red-blue,and firm nodules, minute foci
of fresh hemorrhage under the anil
- Histologic picture:
i. Branching vascular channels separated by CT stroma
ii. CT stroma contains aggregates, nests, and masses of the specialized glomus cells typically
arranged around vessels
iii. Usually small, regular size, round or cuboidal, with scant cytoplasm and features very similar
to smooth muscle cells on EM

 Bacillary Angiomatosis
- One to numerous red papules and nodules or rounded subcutaneous masses
- Histologic picture:
i. Tumor-like growth pattern involving proliferation of capillaries that exhibit protuberant
epithelioid endothelial cells with nuclear atypia and mitoses.
ii. Numerous stromal neutrophils, nuclear dust, purplish granular material (distinguishes this
from pyogenic granuloma, Kaposi sarcoma, or angiosarcoma)
- Domestic cat: principal reservoir of B. henselae
- Cat flea: vector
- Human body louse: important role in infection due to B. quintana
- Infections are cured by macrolides

B. Intermediate, Low-grade malignant

 Kaposi Sarcoma
- Patches: pink to red to purple solitary or multiple macules that in the classic disease are usually
confined to the distal lower extremities or feet
- Histologic picture:
i. Dilated, irregular, angulated blood vessels lined by endothelial cells with an interspersed
infiltrate of lymphocytes, plasma cells, and macrophages
ii. Lesions difficult to distinguish from granulation tissue
- Lesions spread proximally and usually convert into larger, violaceous, raised plaques
- Histologic picture:
i. Dermal, dilated, jagged vascular channels lined by plump spindle cells accompanied by
perivascular aggregates of similar spindled cells
ii. Between vascular channels are red cells, hemosiderin-laden macrophages, lymphocytes, and
plasma cells
iii. Pink, hyaline, globules found in spindle cells and macrophages
- Later stage: nodular and neoplastic lesions
- Histologic picture:
i. Plump, proliferating spindle cells in dermis or subcutaneous tissues
ii. Scattered small vessels and slit-like spaces in the cellular background with rows of red cells
and hyaline droplets
iii. Marked hemorrhage, hemosiderin, lymphocytes, and macrophages
iv. Mitotic figures, and round, pink cytoplasmic globules common

18
 C. Malignant
 Angiosarcoma
- Deceptively small, sharply, demarcated, asymptomatic, multiple red nodules, but eventually most
such tumors become large, fleshy masses of pale, gray-white, soft tissue
- Margins blend imperceptibly with surrounding structures
- Central softening and areas of necrosis and hemorrhage are frequent
- Histologic picture:
i. All degrees of differentiation of these tumors may be found
- largely vascular with plump, anaplastic but recognizable endothelial cells producing vascular
channels
-tumors that are undifferentiated, produce no definite blood vessels, are markedly atypical,
solid spindle cell appearance

CHAPTER 12
The Heart

LEFT-SIDED HEART FAILURE

Morphology. Findings vary depending on the cause of the disease. Myocardial infarction or a valvular deformity may be
present. Left ventricle is usually hypertrophied and dilated. Resultant atrial fibrillation may either compromise stroke
volume or cause blood stasis and possible thrombus formation. The extracardiac effects are manifested most prominently
in the lungs.

Lungs. Pressure in pulmonary veins increase resulting to pulmonary congestion, edema, with heavy, wet lungs. Changes
include (1) a perivascular and interstitial transudate, particularly in the interlobular septa, responsible for Kerley’s B lines
on x-ray; (2) progressive edematous widening of alveolar septa; and (3) accumulation of edema fluid in the alveolar
spaces. Iron-containing proteins in edema fluid and hemoglobin from erythrocytes, are phagocytosed by macrophages
and converted to hemosiderin (called siderophages or heart failure cells). Clinical manifestations include dyspnea,
orthopnea, paroxysmal nocturnal dyspnea and cough.

Kidneys. Decrease cardiac output causes reduction in renal perfusion, which activates the renin-angiotensin-aldosterone
system, inducing retention of salt and water with consequent expansion of the interstitial fluid and blood volumes. If
perfusion deficit becomes severe, excretion of nitrogenous products may cause prerenal azotemia.

Brain. In far-advanced CHF, cerebral hypoxia may give rise to hypoxic encephalopathy.

RIGHT-SIDED HEART FAILURE

Liver and Portal System. The liver is usually increased in size and weight (congestive hepatomegaly), and a cut
section displays prominent passive congestion. When severe, central areas can become fibrotic, creating so-called
cardiac sclerosis or cardiac cirrhosis. Right-sided heart failure also leads to elevated pressure in the portal vein and its
tributaries. Congestion produces a tense, enlarged spleen (congestive splenomegaly). Accumulations of transudate in
the peritoneal cavity may give rise to ascites.

Kidneys. In right-sided heart failure there is greater fluid retention, peripheral edema, and more pronounced azotemia as
compared to left-sided heart failure.

Brain. Identical to those described in left-sided heart failure.

Pleural and Pericardial Spaces. Accumulation of fluid in the pleural space (particularly right) and pericardial space
(effusions) may appear. Pleural effusions (100 ml-1 L) can cause partial atelectasis of the corresponding lung.

Subcutaneous Tissues. Peripheral edema of the dependent portions of the body, especially ankle (pedal) and pretibial
edema.

ATRIAL SEPTAL DEFECT

Morphology. There are three major types: (1) secundum ASD (90% of ASDs), is a defect located at and resulting from a
deficient or fenestrated oval fossa; (2) primum (5% of ASDs) occur adjacent to the AV valves; (3) sinus venosus (5%)
are located near the entrance of the superion vena cava. ASDs result in left-to-right shunt, largely because pulmonary
vascular resistance is considerably less than systemic vascular resistance and because compliance of the right ventricle
19
is much greater than that of the left. A murmur is often present as a result of excessive flow through the pulmonary valve.
Eventually, volume hypertrophy of the right atrium and right ventricle develops.

TETRALOGY OF FALLOT

Morphology. The heart is often enlarged and may be “boot-shaped” owing to the marked right ventricular hypertrophy,
particularly of the apical region. The VSD is usually large. The aortic valve forms the superior border of the VSD, thereby
overriding the defect and both ventricular chambers.

MYOCARDIAL INFARCTION

Morphology. The frequencies of critical narrowing of each of the three main arterial trunks and the corresponding sites of
myocardial lesions resulting in infarction are as follows:
o Left anterior descending coronary artery (40% to 50%): infarct involves anterior wall of left ventricle near apex;
anterior portion of ventricular septum; apex circumferentially
o Right coronary artery (30% to 40%): infarct involves inferior/posterior wall of left ventricle; posterior portion of
ventricular septum; inferior/posterior right ventricular free wall in some case
o Left circumflex coronary artery (15% to 20%): infarct involves lateral wall of left ventricle except at apex

CHRONIC ISCHEMIC HEART DISEASE

Morphology. Hearts are usually enlarged and heavy, secondary to left ventricular hypertrophy and dilation. There is
moderate to severe stenosing atherosclerosis of the coronary arteries. Major microscopic findings include myocardial
hypertrophy, diffuse subendocardial vacuolization, and scars of previously healed infarcts.

SUDDEN CARDIAC DEATH

Morphology. Marked coronary atherosclerosis with critical (>75%) stenosis involving one or more of the three major
vessels is present in 80% to 90% of SCD victims. Subendocardial myocyte vacuolization indicative of severe chronic
ischemia is common.

SYSTEMIC (LEFT-SIDED) HYPERTENSIVE HEART DISEASE

Morphology. Hypertension induces left ventricular pressure overload hypertrophy without dilation of the left ventricle. In
time, thickness of the left ventricular wall imparts a stiffness that impairs diastolic filling.

PULMONARY (RIGHT-SIDED) HYPERTENSIVE HEART DISEASE (COR PULMONALE)

Morphology. In acute cor pulmonale, there is marked dilation of the right ventricle without hypertrophy. In chronic cor
pulmonale, the right ventricular wall thickens.

CALCIFIC AORTIC STENOSIS

Morphology. The morphologic hallmark of non-rheumatic, calcific aortic stenosis (with either tricuspid or bicuspid valves)
is heaped-up calcified masses within the aortic cusps that ultimately protrude through the outflow surfaces into the
sinuses of Valsalva, preventing the opening of the cusps. An earlier, hemodynamically inconsequential stage of the
calcification process is called aortic valve sclerosis.

MYXOMATOUS DEGENERATION OF THE MITRAL VALVE (MITRAL VALVE PROLAPSE)

Morphology. The characteristic anatomic change is intercordal ballooning (hooding) of the mitral leaflets or portions
thereof. The affected leaflets are often enlarged, redundant, thick and rubbery. Frequently involved, the tendinous cords
are elongated, thinned and occasionally ruptured. Annular dilation is characteristic, a finding that is rare in other causes of
mitral insufficiency.

RHEUMATIC FEVER AND RHEUMATIC HEART DISEASE

Morphology. During acute RF, focal inflammatory lesions are found in various tissues. They are most distinctive in the
heart, where they are called Aschoff bodies. They consist of foci of swollen eosinophilic collagen surrounded by
lymphocytes (primarily T cells), occasional plasma cells, and plump macrophages called Anitschkow cells
(pathognomonic for RF). Chronic RHD is characterized by organization of the acute inflammation and subsequent fibrosis.
20
In particular, the valvular leaflets become thickened and retracted, causing permanent deformity. The cardinal anatomic
changes of the mitral (or tricuspid ) valve are leaflet thickening, commissural fusion and shortening, and thickening
and fusion of the tendinous cords.

INFECTIVE ENDOCARDITIS (IE)

Morphology. In both the subacute and acute forms of the disease, friable, bulky, and potentially destructive vegetations
containing fibrin, inflammatory cells, and bacteria or other organisms are present on the heart valves. The aortic and mitral
valves are the most common sites of infection. Vegetations sometimes erode into the underlying myocardium to produce
an abscess cavity (ring abscess). Systemic emboli may occur at any time because of the friable nature of the
vegetations, and they may cause infarcts in the brain, kidneys, myocardium, and other tissues.
NONBACTERIAL THROMBOTIC ENDOCARDITIS (NBTE)

Morphology. Vegetations of the NBTE are sterile, nondestructive, and small (1 to 5 mm), and occur singly or multiply
along the line of closure of the leaflets or cusps.

ENDOCARDITIS OF SLE (LIBMAN-SACKS DISEASE)

Morphology. The lesions are small single or multiple, sterile, granular pink vegetations ranging from 1 to 4 mm in
diameter. The lesions may be located on the undersurfaces of the AV valves, on the valvular endocardium, on the cords,
or on the mural endocardium of atria or ventricles. Histologically the verrucae consists of a finely granular, fibrous
eosinophilic material that may contain hematoxylin bodies.

CARCINOID HEART DISEASE

Morphology. Consists of fibrous intimal thickenings on the inside surfaces of the cardiac chambers and valvular leaflets.
They are located mainly in the right ventricle, tricuspid and pulmonic valves, and occasionally in the major blood vessels.
The endocardial plaquelike thickenings are predominantly smooth muscle cells and sparse collagen fibers embedded in
an acid mucopolysaccharide-rich matrix material.

DILATED CARDIOMYOPATHY

Morphology. The heart is usually heavy, often weighing two to three times normal, and large and flabby, with dilation of
all chambers. Mural thrombi are common and may be a source of thromboemboli. The histologic abnormalities in
idiopathic DCM also are nonspecific and usually do not reflect a specific etiologic agent.

HYPERTROPHIC CARDIOMYOPATHY

Morphology. Essential feature is the massive myocardial hypertrophy without ventricular dilation. Classic pattern is
disproportionate thickening of the ventricular septum as compared with the free wall of the left ventricle (ration greater
than 1:3). Often present are endocardial thickening or mural plaque formation in the left ventricular outflow tract and
thickening of the anterior mitral leaflet. Most important histologic features: (1) extensive myocyte hypertrophy; (2)
haphazard disarray of bundles of myocytes; and (3) interstitial and replacement fibrosis.

RESTRICTIVE CARDIOMYOPATHY

Morphology. The ventricles are of approximately normal size or slightly enlarged, the cavities are not dilated, and the
myocardium is firm. Biatrial dilation is common. Microscopically, there is often only patchy or diffuse interstitial fibrosis.

MYOCARDITIS

Morphology. During active phase, the heart may appear normal or dilated; some hypertrophy may be present.
Myocarditis is most frequently characterized by an interstitial inflammatory infiltrate and focal necrosis of myocytes
adjacent to the inflammatory cells. Lesions may be focal or patchy. Hypersensitivity myocarditis has interstitial
infiltrates, principally perivascular, composed of lymphocytes, macrophages, and a high proportion of eosinophils. Giant
cell myocarditis is characterized by a widespread inflammatory cellular infiltrates containing mononucleate giant cells
interspersed with lymphocytes, eosinophils, plasma cells, and macrophages and having at least focal but frequently
extensive necrosis. This carries a poor prognosis. The myocarditis of Chagas disease is rendered distinctive by
parasitization of myofibers by trypanosomes.

ACUTE PERICARDITIS
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Morphology. There is an inflammatory reaction in the epicardial and pericardial surfaces with scant numbers of
polymorphonuclear leukocytes, lymphocytes, and macrophages. Usually fluid volume is not large (50 to 200 mL) and
accumulates slowly. Organization into fibrous adhesions rarely occurs.

FIBRINOUS AND SEROFIBRINOUS PERICARDITIS

Morphology. The surface is dry, with a fine granular roughening. As with all inflammatory exudates, fibrin may be
digested with resolution of the exudates or it may be organized.

PURULENT OR SUPPURATIVE PERICARDITIS

Morphology. The exudates ranges from a thin to a creamy pus of up to 400 to 500 mL in volume. The serosal surfaces
are reddened, granular, and coated with the exudates. Sometimes the acute inflammatory process extends into the
surrounding structures to induce mediastinopericarditis. Organization is the usual outcome frequently producing
constrictive pericarditis.

MYXOMA

Morphology. The tumors are almost always single, but rarely several occur simultaneously. The region of the fossa ovalis
in the atrial septum is the favored site of origin. Myxomas range from less than 1 up to 10 cm in size, sessile or
pedunculated masses that vary from globular hard masses mottled with hemorrhage to soft, translucent, papillary, or
villous lesions having a gelatinous appearance. Histologically, myxomas are composed of stellate or globular myxoma
(“lepidic”) cells, endothelial cells, smooth muscle cells, and undifferentiated cells embedded within an abundant acid
mucopolysaccharide ground substance and covered on the surface by endothelium.

PAPILLARY FIBROELASTOMA

Morphology. Generally located on valves, particularly the ventricular surfaces of semilunar valves and the atrial surfaces
of AV valves. They constitute a distinctive cluster of hair-like projections up to 1 cm in diameter, covering up to several
centimeters in diameter of the endocardial surface.

RHABDOMYOMA

Morphology. They are generally small, gray-white myocardial masses up to several centimeters in diameter located on
either the left or the right side of the heart and protruding into the ventricular chambers. Histologically they are composed
of a mixed population of cells, the most characteristic of which are large, rounded, or polygonal cells containing numerous
glycogen-laden vacuoles separated by strands of cytoplasm running from the plasma membrane to the more or less
centrally located nucleus, the so-called spider cells.

CHAPTER 13
Red Blood Cell and Bleeding Disorder

Morphology of Hematopoietic Cells

 Best studied in smears of marrow aspirates.
 Additional complementary information is obtained from bone marrow biopsy specimens
 (i.e. by examining the ratio of fat cells to hematopoietic elements in bone marrow biopsy samples, a
reasonable estimate of marrow activity could be obtained)
 also applicable to certain diseases (such as metastatic cancers and granulomatous diseases) that induce
local marrow fibrosis, rendering the lesional cells “inaspirable”
 limitation: tissue fixation and decalcification alter the appearance of marrow cells, making them less
recognizable than in air-dried aspirate smears
 It is not always possible to differentiate the various “blast” forms morphologically.
 Tentative identification is based on “the company they keep”.
 A primitive cell found within a focus of maturing granulocytes is likely a myeloblast.
 Pluripotent and multipotent stems cells are morphologically inconspicuous lymphocyte-like cells constituting less than
0.1% of the marrow cellularity.
 Stem cells are identified and purified away from other cell types using antibodies against discriminating markers (i.e.
CD34)
 Normal relative proportion of hematopoietic precursors:
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  65% granulocytes and their precursors
 25% erythroid precursors
 10% lymphocytes and monocytes and their precursors
 normal myeloid to erythroid ratio is 2 to 3:1
 Prevalent cell types in the myeloid compartment: myelocytes, metamyelocytes, granulocytes
 Erythroid compartment: polychromatophilic and orthochromic normoblasts

Morphology Hemolytic Anemia

 Appearance of increased numbers of erythroid precursors (normoblasts) in the marrow (due to increased production
of erythropoietin resulting from anemia and lowered tissue oxygen tension).
 If anemia is severe, extramedullary hematopoiesis can appear in the liver, spleen, and lymph nodes.
 The accelerated erythropoiesis leads to a prominent reticulocytosis in the peripheral blood.
 Elevated biliary excretion of bilirubin promotes the formation of pigment gallstones (cholethiasis).
 If chronic, phagocytosis of red cells leads to hemosiderosis, usually confined to the mononuclear phagocyte system.

Morphology of Hereditary Spherocytosis (HS)

 Most outstanding morphologic finding in this disease are spherocytes, seen on smears as abnormally small, dark-
staining (hyperchromic) red cells lacking the normal central zone of pallor.
 Distinctive but not pathognomonic (also seen in autoimmune hemolytic anemias)
 The following characteristics are also observed: reticulocytosis, marrow hyperplasia due to increased erythropoiesis,
hemosiderosis, and mild jaundice.
 Cholelithiasis (pigment stones) occurs in 40 to 50% of affected adults.
 Other alterations fairly distinctive.
 Moderate splenic enlargement (500 to 1000 gm)
 In few other hemolytic anemias: spleen is enlarged as much or as often. (results from congestion of the cords
of Billroth and “work hyperplasia” due to markedly increased erythrophagocytosis).

Morphology of Sickle Cell Disease

 Anatomic alterations caused by:
 Chronic hemolysis
 Increased formation of bilirubin
 Small vessel stasis
 Thrombosis
 Bone marrow hyperplastic due to a compensatory hyperplasia of erythroid progenitors.
 Expansion of marrow  bone resorption and secondary new bone formation  prominent cheekbones and changes
in the skull (resemble crew-cut in roentgenograms)
 Extramedullary hematopoiesis can also appear.
 In children, spleen commonly enlarged up to 500 gm in the early phase
 Marked congestion of red pulp upon histologic examination (due to trapping of sickled red cells in splenic cords and
sinuses)
 Erythrostasis in the spleen leads to marked tissue hypoxia, thrombosis, infarction, and fibrosis.
 Continued scarring causes progressive shrinkage of spleen so that by adolescence or early adulthood, only a small
nubbin of fibrous tissue is left (autosplenectomy).
 Infarction (secondary to vascular occlusions and anoxia) can occur in the bones, brain, kidney, liver, retina, other
tissues and pulmonary vessels, the latter sometimes producing cor pulmonale.
 Vascular stagnation in subcutaneous tissues often leads to ulcers in adult patients (rare in children).
 Increased breakdown of hemoglobin can cause pigment gallstones.
 Hyperbilirubinemia develop in all patients during periods of active hemolysis.

Morphology of -Thalassemia
 Major morphologic alterations involve bone marrow and spleen (in addition to those found in hemolytic anemias).
 Striking expansion of hematopoietically active marrow particularly in facial bones (00000in untransfused patients).
 Erodes existing cortical bone
 Induces new bone formation  “crew-cut” appearance on X-rays
 Spleen enlarges and weighs up to 1500 gm (due to mononuclear phagocytic cell hyperplasia and extramedullary
hematopoiesis).
 Hemosiderosis and secondary hemochromatosis (manifestation of iron overload) occurs in almost all patients.
 Due to numerous blood transfusions and increased absorption of dietary iron.
 Several organs are damaged (including heart, liver and pancreas) due to iron deposition.

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Morphology of Megaloblastic Anemias
 Peripheral blood examination usually reveals pancytopenia (all myeloid lineages are affected).
 Marked variation in size and shape of red cells (anisocytosis), which are however normochromic.
 Many red cells are macrocytic and oval (macroovalocytes).
 Mean corpuscular (cell) volumes above 100 fl (normal, 82-98)
 Most macrocytes lack the central pallor of normal red cells and can appear “hyperchromic” (they are thicker than
normal and well-hemoglobinized).
 MCHC is not elevated.
 Reticulocyte count is low; nucleated red cells occasionally appear in the circulating blood with severe anemia.
 Neutrophils larger than normal (macropolymorphonuclear) and hypersegmented (have 5-6 or more nuclear lobules).
 Marrow usually markedly hypercellular (due to increased numbers of all myeloid precursor types, which may
completely replace fatty marrow).
 Marrow hyperplasia is a response to increased levels of GFs such as erythropoietin.
 However, most myeloid precursors undergo apoptosis in the marrow due to derangement in DNA synthesis
(pancytopenia).
 Megaloblastic change detected in all stages of red cell dev’t.
 Promegaloblasts are large, with a deeply basophilic cytoplasm, prominent nucleoli, and a distinctive fine nuclear
chromatin pattern.
 During differentiation, their nuclei retain their finely distributed chromatin, thus failing to undergo chromatin
clumping typical of a normoblast.
 E.g. orthochromatic megaloblasts have a large amount of pink, well-henoglobinized cytoplasm, but the
nucleus remains relatively large and immature instead of becoming pyknotic.
 Granulocytic precursors display nuclear-cytoplasmic asynchrony in the form of giant metamyelocytes and band forms
(DNA synthesis is impaired).
 Megakaryocytes can be abnormally large and have bizarre, multilobate nuclei.
 Anemia further exacerbated by increased hemolytic destruction of red cells in the periphery.
 Basis for hemolysis not entirely clear; suggestions include an acquired intracorpuscular defect and a poorly
characterized plasma factor.
 Enhanced uptake of iron in the gut (when the deficiency persists) can lead to anatomic signs of mild to moderate iron
overload after several years.

Morphology of Pernicious Anemia

 Major specific changes found in the bone marrow, alimentary tract and central nervous system.
 Changes in the bone marrow and blood similar to those described for all megaloblastic anemias.
 Changes in the alimentary system:
 Abnormalities are regularly found in the tongue and stomach.
 Tongue is shiny, glazed, and “beefy” (atrophic glossitis).
 Changes in the stomach are those of diffuse chronic gastritis.
 Most characteristic histologic alteration: atrophy of the fundic glands, affecting both chief cells and parietal
cells, the latter being virtually absent.
 Glandular lining epithelium is replaced by mucus-secreting goblet cells that resemble those lining the large
intestine (intestinalization).
 Some cells as well as their nuclei may increase to double their normal size.
 Patients with pernicious anemia have a higher incidence of gastric cancer.
 Gastric and atrophic changes due to autoimmunity and not vitamin B12 deficiency.
 Central Nervous System:
 Lesions are found in approximately ¾ of all cases of fulminant pernicious anemia but in some instances,
neuronal involvement is seen in the absence of overt megaloblastic anemia.
 Principal alterations involve the spinal cord  degeneration of myelin in the dorsal and lateral tracts,
sometimes followed by loss of axons.
 Give rise to spastic paraparesis, sensory ataxia, and severe paresthesias in the lower limbs.
 Less frequently, degenerative changes occur in the ganglia of the posterior roots and in peripheral nerves.
 Because both motor and sensory pathways are involved, neurologic changes associated with vit B12
deficiency is described as “subacute combined degeneration” or “combined system disease”

Morphology of Iron Deficiency Anemia

 Bone marrow reveals a mild to moderate increase in erythroid progenitors (normoblasts).
 Disappearance of stainable iron from mononuclear phagocytic cells in the bone marrow (diagnostically significant).
 Assessed by performing Prussian blue stains on aspirated or sectioned bone marrow.
24
 In peripheral blood smear, red cells are small (microcytic) and pale (hyperchromic).
 Normal well-hemoglobinized red cells have a zone of central pallor measuring about 1/3 of the cell diameter.
 In established iron deficiency, zone of pallor is enlarged; hemoglobin may be seen only in a narrow peripheral rim.
 Poikilocytosis in the form of small, elongated red cell (pencil cells) is also characteristic.

Morphology of Aplastic Anemia

 The markedly hypercellular bone marrow is largely devoid of hematopoietic cells; often, only fat cells, fibrous stroma
and scattered or clustered foci of lymphocytes and plasma cells remain.
 A marrow aspirate often yields little material (a “dry tap”).
 Marrow aplasia best appreciated in a bone marrow biopsy.
 Some additional pathologic changes are related to granulocytopenia and thrombocytopenia, such as mucocutaneous
bacterial infections and abnormal bleeding, respectively.
 Toxic drug or agent can injure other tissues.
 i.e. Benzene can cause fatty changes in the liver and kidneys.
 Systemic hemosiderosis can appear if anemia necessitates multiple transfusions.

Morphology of Immune Thrombocytopenic Purpura (ITP)

 Principal morphologic lesions are found in the spleen and bone marrow but are not diagnostic.
 Secondary changes related to the bleeding diasthesis may be found in any tissue or structure in the body.
 Characteristics of the spleen:
 Normal in size.
 Upon histologic examination, there is congestion of the sinusoids and hyperactivity and enlargement of the
splenic follicles, manifested by the formation of prominent germinal centers.
 In many instances, scattered megakaryocytes are found within the sinuses and sinusoidal walls  may
represent a very mild form of extramedullary hematopoiesis (driven by elevated levels of thrombopoietin).
 These findings are not sufficiently distinctive to be diagnostic.
 Characteristics of the bone marrow:
 Reveals a moderately increased number of megakaryocytes. Some apparently immature, with large,
nonlobulated, single nuclei.
 Not specific for ITP.
 Merely reflect accelerated thrombopoiesis (found in most forms of thrombocytopenia resulting from
increased platelet destruction).
 Importance of bone marrow examination is to rule out thrombocytopenias resulting from bone marrow failure.
 Decrease in megakaryocytes argues against ITP diagnosis.

Morphology of Disseminated Intravascular Coagulation (DIC)

 In general, thrombi are found in the following sites (decreasing order of frequency): brain, heart, lungs, kidneys,
adrenals, spleen, and liver.
 However, no tissue is spared; thrombi are occasionally found in only one or several organs without affecting others.
 i.e. In giant hemangiomas, thrombi are localized to neoplasm, where they are believed to form due to local
stasis and recurrent trauma to fragile blood vessels.
 Affected kidneys can reveal small thrombi in the glomeruli  may evoke only reactive swelling of endothelial cells or
in severe cases, microinfarcts or even bilateral renal cortical necrosis.
 Numerous fibrin thrombi may be found in alveolar capillaries, sometimes associated with pulmonary edema and fibrin
exudation, creating “hyaline membranes” reminiscent of acute respiratory distress syndrome.
 In the CNS, fibrin thrombi can cause microinfarcts, occasionally complicated by simultaneous hemorrhage  basis for
the bizarre neurologic signs and symptoms sometimes observed in DIC.
 In meningococcemia, fibrin thrombi within the microcirculation of the adrenal cortex are the likely basis for the massive
adrenal hemorrhages seen in Waterhouse-Friderichsen syndrome.
 Sheehan postpartum pituitary necrosis is a form of DIC complicating labor and delivery.
 In toxemia of pregnancy, placenta exhibits widespread microthrombi  plausible explanation for the premature
atrophy of the cytotrophoblast and syncytiotrophoblast observed in this condition.

CHAPTER 14
Diseases of White Blood Cells, Lymph Nodes, Spleen, and Thymus

Hereditary Spherocytosis
MORPHOLOGY
- On smears, RBCs lack the central zone of pallor because of its spheroidal shape.

25
 - Splenomegaly is greater and more common in HS than in any other form of hemolytic anemia- from congestion of the
cords of Billroth and increased numbers of mononuclear phagocytes.
- Phagocytosed RBCs are frequently seen within hypertrophic macrophages lining the sinusoids and within the cords.
- In long-standing cases, there is prominent systemic hemosiderosis.

Sickle Cell Anemia

MORPHOLOGY
- The anatomic alterations stem from: (1) hemolysis, with resultant anemia; (2) increased breakdown of Hb, with bilirubin
formation; and (3) capillary stasis, leading to tissue ischemia and infarction.
- In peripheral smears, irreversibly sickled RBCs are elongated, spindled, or boat-shaped structures.
- Severe anemia and the vascular stasis lead to fatty changes in the heart, liver, and renal tubules.
- Erythropoiesis is activated in the bone marrow. Expansion of marrow may lead to resorption of bone with appositional
new bone formation on the external aspect of the skull, leading to a "crew-cut" appearance on radiographs.
- Extramedullary hematopoiesis may appear in the spleen and liver.
- In children there is moderate splenomegaly caused by congestion of the red pulp with masses of sickled RBCs.
Eventually this splenic erythrostasis leads to enough hypoxic tissue damage, sometimes with frank infarction, to create
a shrunken, fibrotic spleen – autosplenectomy – seen in all long-standing adult cases.
- Vascular congestion, thrombosis, and infarction may affect any organ.
- As with the other hemolytic anemias, hemosiderosis and gallstones are common.

Thalassemia
MORPHOLOGY
Only the morphologic changes in β-thalassemia are described.
- Peripheral blood RBCs in thalassemia major are small (microcytic) and pale (hypochromic). Cells also have a large
surface area to volume ratio.
- Target-like appearance (target cells) when RBC’s spread on slide.
- severe poikilocytosis, anisocytosis, and reticulocytosis.
- In β-thalassemia major, the anatomic changes are those common to all hemolytic anemias but extreme in degree. The
combination of ineffective erythropoiesis and hemolysis results in a striking hyperplasia of erythroid progenitors, with a
shift toward primitive forms. The burgeoning erythropoietic marrow may completely fill the intramedullary space of the
skeleton, invade the bony cortex, impair bone growth, and produce skeletal deformities.
- Extramedullary hematopoiesis and hyperplasia of the mononuclear phagocytes produces prominent splenomegaly,
hepatomegaly, and lymphadenopathy.
- The expanded mass of ineffective erythropoietic tissue consumes nutrients, producing growth retardation and a
degree of cachexia reminiscent of that seen in cancer patients.

Iron Deficiency Anemia

MORPHOLOGY
- Iron deficiency anemia is relatively mild.
- The RBCs are microcytic and hypochromic, reflecting the reduced MCV and MCHC
- Often accompanied by an increase in the platelet count.
- In some cases, atrophic glossitis is present, giving the tongue a smooth, glazed appearance.
When accompanied by dysphagia and esophageal webs, it constitutes the Plummer-Vinson syndrome.

Megaloblastic Anemia
MORPHOLOGY
Certain morphologic features are common to all forms of megaloblastic anemias.
- The bone marrow is markedly hypercellular, owing to increased numbers of megaloblasts. These cells are larger than
normoblasts and have a delicate, finely reticulated nuclear chromatin (suggestive of nuclear immaturity) and an
abundant, strikingly basophilic cytoplasm.
- As the megaloblasts differentiate and begin to acquire Hb, the nucleus retains its finely distributed chromatin and fails
to undergo the chromatin clumping typical of an orthochromatic normoblast. Similarly, the granulocytic precursors also
demonstrate nuclear-cytoplasmic asynchrony, yielding giant metamyelocytes. Megakaryocytes, too, may be abnormally
large, with bizarre multilobed nuclei.

Aplastic Anemia
MORPHOLOGY
- The bone marrow is markedly hypocellular, with >90% of the intertrabecular space occupied by fat. These changes are
better appreciated in a bone marrow biopsy specimen than in marrow aspirates.
- A number of secondary changes may accompany marrow failure. Hepatic fatty change may result from anemia, and
thrombocytopenia and granulocytopenia may give rise to hemorrhages and bacterial infections, respectively.
26
Neutropenia
MORPHOLOGY
- Anatomic alterations in bone marrow depend on the underlying basis of the neutropenia.
- Marrow hypercellularity caused by increased numbers of immature granulocytic precursors is seen when the
neutropenia results from excessive destruction of mature neutrophils or in ineffective granulopoiesis.
- Agents that suppress granulocytopoiesis are associated with a marked decrease in maturing granulocytic
precursors in the marrow.
- Erythropoiesis and megakaryopoiesis may remain at normal levels (if the agent specifically affects granulocytes).

Infectious Mononucleosis
MORPHOLOGY
- The major alterations mainly involve the blood, lymph nodes, spleen, liver & central nervous system.
- The peripheral blood shows absolute lymphocytosis with a total white cell count between 12,000 and 18,000/μL,
more than 60% of which are lymphocytes. Many of these are large, atypical lymphocytes, 12 to 16 μm in diameter,
characterized by an abundant cytoplasm containing multiple clear vacuolations and an oval, indented, or folded
nucleus.
- The lymph nodes are typically discrete and enlarged throughout the body, principally in the posterior cervical, axillary,
and groin regions.
- Histologically, the lymphoid tissue is flooded by atypical lymphocytes, which occupy the paracortical (T-cell) areas.
- Cells resembling Reed-Sternberg cells, hallmark of Hodgkin lymphoma, may be found in the nodes.
- The spleen is enlarged in most cases. The rapid increase in splenic size and the infiltration of the trabeculae and
capsule by the lymphocytes together contribute to making such spleens fragile.
- Liver function is almost always transiently impaired to some degree.

Acute Nonspecific Lymphadenitis

MORPHOLOGY
- Macroscopically, acutely inflamed nodes are swollen, gray-red, and engorged.
- Histologically, there are large germinal centers containing numerous mitotic figures. When the condition is caused by
pyogenic organisms, a neutrophilic infiltrate is seen about the follicles and within the lymphoid sinuses. With severe
infections, the centers of follicles may undergo necrosis, resulting in the formation of an abscess.
- Affected nodes are tender and, when abscess formation is extensive, become fluctuant. The overlying skin is
frequently red, and penetration of the infection to the skin may produce draining sinuses.

Chronic Nonspecific Lymphadenitis

MORPHOLOGY
FOLLICULAR HYPERPLASIA.
- This pattern is associated with processes that activate B cells. B cells accumulate within large round germinal centers
(secondary follicles). These aggregates also feature scattered phagocytic macrophages containing nuclear debris and
an inconspicuous meshwork of dendritic cells that function in antigen presentation.
- Some causes of follicular hyperplasia are rheumatoid arthritis, toxoplasmosis, and the early stages of HIV infection.
PARACORTICAL LYMPHOID HYPERPLASIA.
- This pattern is characterized by reactive changes within the T-cell regions of the lymph node. Parafollicular T cells
undergo proliferation and transformation to immunoblasts that may efface the germinal follicles.
- Paracortical lymphoid hyperplasia is encountered, particularly, in viral infections or after smallpox vaccination, and in
immune reactions induced by certain drugs.
SINUS HISTIOCYTOSIS.
- This reactive pattern is characterized by distention and prominence of the lymphatic sinusoids, owing to marked
hypertrophy of lining endothelial cells and infiltration with histiocytes.
- Sinus histiocytosis is often encountered in lymph nodes draining cancers and may represent an immune response to
the tumor or its products.

Cat-Scratch Disease
MORPHOLOGY
- The anatomic changes in the lymph node are quite characteristic; initially, sarcoid-like granulomas are formed that
develop central necrosis with accumulation of neutrophils.
- The microbe is extracellular and can be visualized only with silver stains or electron microscopy. Diagnosis is based on
a history of exposure to cats, clinical findings, positive skin test to the microbial antigen, and the distinctive morphologic
changes in the lymph nodes.

Acute Leukemias
27
MORPHOLOGY
- Because of differing responses to therapy, it is of great practical importance to differentiate ALL from AML.
The nuclei of lymphoblasts in Wright-Giemsa-stained preparations have coarse and clumped chromatin and one or two
nucleoli; myeloblasts tend to have finer chromatin and more cytoplasm, which may contain granules.
- Commonly, the cytoplasm of lymphoblasts contains large aggregates of periodic acid-Schiff (PAS)-positive material,
whereas myeloblasts are often peroxidase positive.

Small Lymphocytic Lymphoma/Chronic Lymphocytic Leukemia

MORPHOLOGY
- Sheets of small round lymphocytes and scattered ill-defined foci of larger cells termed prolymphocytes diffusely
efface involved lymph nodes. The predominant cells are compact, small, apparently unstimulated lymphocytes with
dark-staining round nuclei, scanty cytoplasm, and little variation in size. The foci of mitotically active prolymphocytes
are called proliferation centers; their presence is pathognomonic for CLL/SLL. Mitotic figures are rare except in the
proliferation centers, and there is little or no cytologic atypia.
- In addition to the lymph nodes, the bone marrow, spleen, and liver are involved in almost all cases.
- In most patients, there is an absolute lymphocytosis of small, mature-looking lymphocytes.

Follicular Lymphoma
MORPHOLOGY
- Lymph nodes are effaced by proliferations that usually have a distinctly nodular appearance under low power. The
tumor cells resemble normal germinal center B cells.
- Most commonly, the predominant neoplastic cells are "centrocyte-like." These cells are slightly larger than resting
lymphocytes, with an angular "cleaved" nuclear contour characterized by prominent indentations and linear infoldings.
Nuclear chromatin is coarse and condensed, and nucleoli are indistinct. These small cleaved cells are mixed with
variable numbers of larger "centroblast-like" cells that are three to four times the size of resting lymphocytes. This
second cell type has vesicular chromatin, several nucleoli, and modest amounts of cytoplasm, and it resembles the
mitotically active cells found within normal germinal centers.

Mantle Cell Lymphoma

MORPHOLOGY
- Mantle cell lymphomas show a diffuse or vaguely nodular pattern of lymph node involvement. In most cases, the tumor
cells are slightly larger than normal lymphocytes and have an irregular cleaved nucleus and inconspicuous nucleoli.
- The bone marrow is involved in the majority of cases, with about 20% of cases being "leukemic" at presentation. One
unexplained but characteristic tendency is the frequent involvement of the gastrointestinal tract, sometimes in the form
of multifocal submucosal nodules that grossly resemble polyps (lymphomatoid polyposis).

Diffuse Large B-Cell Lymphoma

MORPHOLOGY
- The nuclei of the neoplastic B cells are large (at least three to four times the size of resting lymphocytes) and can take
a variety of forms. In many tumors, large cells with round, irregular, or cleaved nuclear contours, dispersed chromatin,
and several distinct nucleoli predominate. The cytoplasm in such tumors tends to be pale and modest in volume. Such
cells resemble "centroblasts," the large cells seen in reactive germinal centers.
- In other tumors, the cells have a round or multilobulated large vesicular nucleus with one or two centrally placed
prominent nucleoli. They have abundant cytoplasm that can be either deeply staining and pyroninophilic or clear.
These cells resemble "immunoblasts," normal antigen-activated interfollicular lymphoid cells.

Burkitt Lymphoma
MORPHOLOGY
- The tumor cells are monotonous, are intermediate in size between small lymphocytes and large noncleaved cells, and
have round or oval nuclei containing two to five prominent nucleoli. The nuclear size approximates that of benign
macrophages within the tumor. There is a moderate amount of faintly basophilic or amphophilic cytoplasm, which is
intensely pyroninophilic and often contains small, lipid-filled vacuoles.
- A high mitotic rate is very characteristic of this tumor, as is cell death, accounting for the presence of numerous tissue
macrophages with ingested nuclear debris. Because these benign macrophages are often surrounded by a clear
space, they create a "starry sky" pattern.

Multiple Myeloma
MORPHOLOGY
- Multiple myeloma presents most often as multifocal destructive bone lesions throughout the skeletal system.
Although any bone may be affected, the following distribution was found in a large series of cases: vertebral column,

28
 66%; ribs, 44%; skull, 41%; pelvis, 28%; femur, 24%; clavicle, 10%; and scapula, 10%. These focal lesions generally
begin in the medullary cavity, erode the cancellous bone, and progressively destroy the cortical bone.
- Plasma cell lesions often produce pathologic fractures; they are most common in the vertebral column but may affect
any of the numerous bones suffering erosion and destruction of their cortical substances. Microscopic examination of
the marrow reveals an increased number of plasma cells, constituting 10% to 90% of all cells in the marrow. The
neoplastic plasma cells may resemble normal mature plasma cells but more often show abnormal features, such as
prominent nucleoli or abnormal cytoplasmic inclusions containing immunoglobulin.
- With progressive disease, plasma cell infiltrations of soft tissues may be encountered in the spleen, liver, kidneys,
lungs, and lymph nodes, or, more widely and terminally, a leukemic picture may emerge.
- Renal involvement, generally called myeloma nephrosis, is one of the more distinctive features of multiple myeloma.
Microscopically, interstitial infiltrates of abnormal plasma cells may be encountered. Proteinaceous casts are prominent
in the distal convoluted tubules and collecting ducts. Most of these casts are made up of Bence Jones proteins, but
they may also contain complete immunoglobulins, Tamm-Horsfall protein, and albumin. Multinucleate giant cells
created by the fusion of infiltrating macrophages usually surround the casts. Very often the cells that line tubules
containing casts become necrotic or atrophic because of the toxic actions of free light chains (Bence Jones proteins).
- In contrast to multiple myeloma, lymphoplasmacytic lymphoma is not associated with lytic skeletal lesions.
Instead, the neoplastic cells diffusely infiltrate the bone marrow, lymph nodes, spleen, and sometimes the liver.

Hodgkin Lymphoma
MORPHOLOGY
- The sine qua non for the histologic diagnosis of Hodgkin lymphoma is the RS cell. The RS cell has abundant, usually
slightly eosinophilic, cytoplasm and ranges in diameter from 15 to 45 μm. It is distinguished principally either by having
a multilobate nucleus or being multinucleate with large, round, prominent nucleoli. Particularly characteristic are two
mirror-image nuclei or nuclear lobes, each containing a large (inclusion-like) acidophilic nucleolus surrounded
by a distinctive clear zone; together they impart an owl-eyed appearance.
- "Classic" RS cells are common in the mixed cellularity subtype, uncommon in the nodular sclerosis subtype, and rare in
the lymphocyte-predominance subtype; in these latter two subtypes, other characteristic RS cell variants predominate.

NODULAR SCLEROSIS HODGKIN LYMPHOMA.

- This is by far the most common histologic form. It is distinct from the other forms both clinically and histologically and is
characterized morphologically by two features:
 The presence of a particular variant of the RS cell, the lacunar cell. This cell is large and has a single
hyperlobate nucleus with multiple small nucleoli and an abundant, pale-staining cytoplasm. In formalin-fixed
tissue, the cytoplasm often retracts, giving rise to the appearance of cells lying in clear spaces, or lacunae.
 The presence in most cases of collagen bands that divide the lymphoid tissue into circumscribed nodules. The
fibrosis may be scant or abundant, and the cellular infiltrate may show varying proportions of lymphocytes,
eosinophils, histiocytes, and lacunar cells. Classic RS cells are infrequent.

MIXED-CELLULARITY HODGKIN LYMPHOMA.

- This is the most common form of Hodgkin lymphoma in patients older than the age of 50 and overall comprises about
25% of cases. There is a male predominance. Typical RS cells are plentiful within a distinctive heterogeneous cellular
infiltrate, which includes small lymphocytes, eosinophils, plasma cells, and benign histiocytes.

LYMPHOCYTE PREDOMINANCE HODGKIN LYMPHOMA.

- This subgroup, comprising about 5% of Hodgkin lymphoma, is characterized by a large number of small, mature-
looking reactive lymphocytes admixed with a variable number of benign histiocytes, often within large, poorly defined
nodules. Other types of reactive cells, such as eosinophils, neutrophils, and plasma cells, are scanty or absent, and
typical RS cells are extremely difficult to find. More common are L&H variant cells that have a delicate multilobed, puffy
nucleus that has been likened in appearance to popcorn ("popcorn cell").
- Clinically, nodular sclerosis Hodgkin lymphoma is the only form more common in women, and it has a striking
propensity to involve the lower cervical, supraclavicular, and mediastinal lymph nodes. Most of the patients are
adolescents or young adults, and they have an excellent prognosis, especially when their disease is in clinical stages I
and II.
- It is apparent that Hodgkin lymphoma spans a wide range of histologic patterns and that certain forms, with their
characteristic fibrosis, eosinophils, neutrophils, and plasma cells, come deceptively close to simulating an inflammatory
reactive process. The histologic diagnosis, then, of Hodgkin lymphoma rests on the unmistakable identification
of RS cells or their variants in the appropriate background of reactive cells.
- In all forms, involvement of the spleen, liver, bone marrow, and other organs and tissues may appear in due course
and take the form of tumor-like nodules of tissue resembling that present in the nodes.

Acute Myeloblastic Leukemia

29
MORPHOLOGY
- In most cases, myeloblasts can be distinguished from lymphoblasts with routine Wright-Giemsa stains. The blasts have
delicate nuclear chromatin; three to five nucleoli; and fine, azurophilic granules in the cytoplasm.
- Distinctive red-staining rodlike structures (Auer rods) are present in some cases, more often in the promyelocytic
variant. Auer rods are found only in neoplastic myeloblasts and are thus a helpful diagnostic clue when present.

Polycythemia Vera
MORPHOLOGY
- The major anatomic changes stem from the increase in blood volume and viscosity brought about by the
erythrocytosis. Plethoric congestion of all tissues and organs is characteristic of polycythemia vera.
- The liver is enlarged and frequently contains foci of extramedullary hematopoiesis. The spleen is slightly enlarged in
about 75% of patients owing to the presence of extramedullary hematopoiesis and vascular congestion.
- Consequent to the increased viscosity and vascular stasis, thromboses and infarctions are common; they
affect most often the heart, spleen, and kidneys. Hemorrhages occur in about a third of these patients, probably
owing to excessive distention of blood vessels and abnormal platelet function.

Myeloid Metaplasia with Myelofibrosis

MORPHOLOGY
- The principal site of the extramedullary hematopoiesis is the spleen, which is usually markedly enlarged, sometimes
up to 4000 g. Multiple subcapsular infarcts may be present.
- Histologically, there is trilineage proliferation affecting normoblasts, granulocyte precursors, and megakaryocytes;
however, megakaryocytes are usually prominent, owing to increased numbers and bizarre morphology.
- The liver may be moderately enlarged, with foci of extramedullary hematopoiesis.
- Microscopically, the lymph nodes also contain foci of extramedullary hematopoiesis, but these are insufficient to cause
appreciable enlargement.
- The bone marrow in a typical case is hypocellular and shows diffuse fibrosis. However, the marrow is
hypercellular in early cases, with equal representation of the three major cell lines. Megakaryocytes are often
prominent and may show dysplastic changes.

DIC (Disseminated Intravascular Coagulation)

MORPHOLOGY
- Microthrombi are found principally in the arterioles and capillaries of the kidneys, adrenals, brain, and heart, but no
organ is spared, and the lungs, liver, and gastrointestinal mucosa may also be prominently involved.
- The glomeruli contain small fibrin thrombi, which may evoke only a reactive swelling of the endothelial cells or may be
surrounded by a florid focal glomerulitis. The resultant ischemia leads to microinfarcts in the renal cortex. In severe
cases, the ischemia may even extend to destroy the entire cortex and cause bilateral renal cortical necrosis.
- Microinfarcts are also commonly encountered in the brain, surrounded by microscopic or gross foci of hemorrhage.
These may give rise to bizarre neurologic signs. Similar changes are seen in the heart and often in the anterior
pituitary.
- The bleeding tendency associated with DIC is manifested not only by larger than expected hemorrhages near foci of
infarction but also by diffuse petechiae and ecchymoses, which may be found on the skin, serosal linings of the body
cavities, epicardium, endocardium, lungs, and mucosal lining of the urinary tract.

Thymoma
MORPHOLOGY
- Macroscopically, thymomas are lobulated, firm, gray-white masses up to 15 to 20 cm in longest dimension. Most
appear encapsulated, but in 20% to 25% there is apparent penetration of the capsule and infiltration of perithymic
tissues and structures.
- Microscopically, virtually all thymomas are made up of a mixture of epithelial cells and a variable infiltrate of non-
neoplastic lymphocytes. In benign thymomas, the epithelial cells tend to resemble those of the medulla and are often
elongated or spindle shaped, producing what is called a medullary thymoma. Frequently, there is an admixture of the
plumper, rounder, cortical-type epithelial cells, and some are composed largely of such cells. Some experts would call
this pattern a mixed thymoma. The medullary and mixed patterns account for 60% to 70% of all thymomas.
- The designation malignant thymoma type I implies a cytologically benign tumor that is locally invasive and sometimes
has the capacity for widespread metastasis. These tumors account for 20% to 25% of all thymomas. They are
composed of varying proportions of epithelial cells and lymphocytes; the epithelial cells, however, tend to be of the
cortical variety, with abundant cytoplasm and rounded vesicular nuclei. The critical distinguishing feature of these
neoplasms is penetration of the capsule with invasion into surrounding structures.
- Malignant thymoma type II is better designated thymic carcinoma. These represent about 5% of thymomas. In
contrast to the type I malignant thymomas, these are cytologically malignant. Macroscopically, they are usually fleshy,
obviously invasive masses sometimes accompanied by metastases to such sites as the lungs. Most are squamous
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 cell carcinomas, either well or poorly differentiated. The next most common malignant pattern is the so-called
lymphoepithelioma, composed of cytologically anaplastic cortical-type epithelial cells scattered against a dense
background of benign-appearing lymphocytes. Some of these tumors contain the EBV genome and hence resemble
nasopharyngeal carcinomas.

CHAPTER 15
The Lung

Morphology
ARDS (Diffuse Alveolar damage)
Acute Stage
 heavy, firm, red, boggy
 exhibit congestion, interstitial and intra-alveolar edema, inflammation, fibrin deposition
 hyaline membranes- lines alveolar walls
Organizing stage
 Type II epithelial cells undergo proliferation in an attempt to regenerate alveolar lining
 Organization of transudate, intra-alveolar fibrosis
 Thickening of alveolar septa
 In fatal cases: bronchopneumonia

Emphysema
 In well-developed panacinar emphysema cases: Voluminous lungs, overlaps heart and hides it when the anterior
chest wall is removed
 Macroscopic features
o Centriacinar emphysema: Lungs will not appear pale& voluminous until disease is well advanced
o upper 2/3 are more severely affected
o Large apical blebs/bullae are more characteristic of irregular emphysema secondary to scarring and of
distal acinar emphysema
 Microscopic features
o Abnormally large alveoli separated by thin septa with only focal centriacinar fibrosis
o Enlargement of pores of Kohn
o Larger abnormal airspaces , blebs and bullae in advanced cases leads to deformed and compressed
bronchioles and vessels , chronic bronchitis/bronchiolitis

Chronic Bronchitis
 Gross morphology: hyperemia, swelling, edema of mucous membranes, excessive epithelial mucinous to
mucopurulent secretions
 Characteristic histologic features: chronic inflammation of airways (predominantly lymphocytes), hypertrophy and
slight hyperplasia of mucus-secreting glands of trachea and bronchi
 Increased Reid Index (ratio of thickness of the mucous gland layer to the thickness of the wall between the
epithelium and cartilage); normal: 0.4
 Bronchial epithelium may exhibit squamous metaplasia and dysplasia
 Marked narrowing of bronchioles ( due to goblet cell metaplasia, mucus plugging, inflammation, fibrosis)
 Brionchiolitis obliterans: obliteration of lumen due to fibrosis, found in severe bronchitis
Asthma
 Gross morphology: lungs are overdistended because of overinflation, may have atelactasis in small areas,
occlusion of bronchi and bronchioles by thick, tenacious mucous plugs
 Histological findings
o presence of whorls of shed epithelium in mucous plugs gives rise to Curschmann spirals
o Presence of numerous eosinophils and Charcot-Leyden crystals (crystalloid consisting of eosinophil
membrane protein)
o “Airway remodeling”
 Thickening of basement membrane of the bronchial epithelium
 Edema and an inflammatory infiltrate in the bronchial walls, with a prominence of eosinophils and
mast cells
 Hypertrophy of submucosal glands and bronchial wall muscle

Bronchiectasis
 Usually affects lower lobes bilaterally, especially vertical passages and more distal bronchi and bronchioles
 Airways are dilated, up to 4x the normal size; may cause: Cylindrical / Fusiform/ Saccular bronchiectasis

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  Gross morphology: in contrast to the normal lung, the bronchi and bronchioles are dilated sufficiently that one can
follow these airways directly to the pleural surfaces
 Histologic findings
o Active cases
 intense acute and chronic inflammatory exudation within walls of the bronchi and bronchioles
 may have pseudostratification of the columnar cells or squamous metaplasia of epithelium
 lung abscess due to necrotic bronchial/bronchiolar walls in some cases
 in more chronic cases: Fibrosis may develop into subtotal or total obliteration of bronchiolar
lumina
 The ff can be cultured from involved bronchi: staphylococci, streptococci, pneumococci, enteric organisms,
anaerobic and microaerophilic bacteria, Haemophilus influenzae and Pseudomonas aeruginosa. Fungus may
also infiltrate bronchial wall in late stages.

Diffuse Interstitial (Infiltrative, Restrictive) Diseases

Fibrosing Diseases
Idiopathic Pulmonary Fibrosis
 Gross morphology: cobblestoned appearance of pleural surface  due to retraction of scars along
interlobular septa
 Fibrosis predominates in the lower lobes, with distinct distribution in subpleural regions and interlobular
sepata leads to collapsed alveolar walls, cystic spaces (honeycomb fibrosis)
 Microscopic findings: Hallmark of Usual Interstitial Pneumoniae is patchy interstitial fibrosis; fibroblastic
foci (earliest lesions)
 Mild to moderate inflammation within fibrotic areascontains lymphocytes, plasma cells, neutrophils,
eosinophils, mast cells
 Secondary pulmonary hypertensive changes present: intimal fibrosis, medial thickening of pulmonary
arteries
Nonspecific Interstitial Pneumonia (NSIP)
 Divided into 2 patterns:
o Cellular: mild to moderate chronic interstitial inflammation, with lymphocytes and plasma cells in
patchy distribution
o Fibrosing: diffuse, patchy interstitial fibrosis without temporal heterogeneity, no fibroblastic foci
(suggests that NSIP is not caused by recurrent sequential bouts of alveolitis)
 Mild to moderate chronic inflammation and lymphoid aggregates may be present
Pneumoconioses: Anthracosis
 Most innocuous coal induced pulmonary lesion in coalminers, urban dwellers, tobacco smokers.
 Linear streaks and aggregates of anthracotic piment identify pulmonary lymphatics at autopsy
 Simple Coal Worker’s Pneumoconiosis (CWP) is characterized by coal macules (1 to 2mm in diameter,
consists of carbon-laden macrophages) and larger coal nodules (also includes collagen fibers). These are
scattered throughout the lungs but the upper lobes and upper zones of the lower lobe are more involved.
o Centrilobular emphysema occurs when initial dust accumulation in the respiratory bronchioles
results in dilation of adjacent alveoli
 Complex CWP(PMF) takes many years to develop from simple CWP; characterized by multiple intensely
blackened scars 2-10cm in diameter.
o Lesions consist of dense collagen and pigment, with necrotic centers resulting from local
ischemia
Pneumoconioses: Silicosis
 Gross morphology: Tiny, barely palpable, discrete pale to blackened (if coal is present) nodules in upper
zone of lungs in its early stages then progress into hard, collagenous scars in later stages.
o Softening and cavitation may occur in nodules, which may be due to superimposed TB or
ischemia
o Fibrotic lesions in hilar lymph nodes and pleura, Eggshell calcification in lymph nodes may be
present and are seen radiographically
o Expansion and coalescence of lesions may lead to PMF
 Histological findings: hyalinized collagen surrounded by a dense capsule of more condensed collagen
make up the nodular lesions; Bipolarized microscopy reveals birefringent silica particles
Pneumoconioses: Abestosis
 Marked by diffuse pulmonary interstitial fibrosis with asbestos bodies
o Asbestos bodies: golden brown, fusiform or beaded rods with a translucent center and consist of
asbestos fibers coated with an iron-containing proteinaceous material
 Arise when macs attempt to phagocytose asbestos fibers
 Can be found in lungs of normal persons, but in much lower amounts
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  Begins as fibrosis around respiratory bronchioles and alveolar ducts and extends to involve adjacent
alveolar sacs and alveoli
 In contrast to CWP and silicosis, asbestosis begins in the lower lobes and subpleurally
 Pleural plaques – most common manifestation of asbestos exposure; well-circumscribed plaques of
dense collagen, often containing Calcium.
o Frequently develop on anterior and posterolateral aspects of parietal pleura and over domes of
diaphragm
 Asbestos exposure may uncommonly induce pleural effusions, which are usually serous but may be
bloody
 Diffuse visceral pleural fibrosis may rarely occur and, in advanced cases, bind the lung to the thoracic
cavity wall.
 Lung carcinomas and mesotheliomas(pleural and peritoneal) may develop from asbestos exposure
Granulomatous Diseases
Sarcoidosis
 Histological findings: all involved tissues show non caseating granulomas, often with Langhans or foreign
body type giant cells. Central necrosis is unusual.
o Granulomas may be replaced by hyaline fibrous scars as disease progresses
o 2 other microscopic features present in 60% of granulomas (characteristic but not
pathognomonic of Sarcodosis:
 Schaumann bodies(Laminated concretions composed of calcium and proteins)
 asteroid bodies (Stellate inclusions)
 LUNGS
o Coalescence of granulomas may at times produce palpable or visible 1-2cm nodules which are
non-caseating, noncavitated consolidations.
o Histological findings: Lesions distributed along lymphatics, around bronchi and blood vessels.
 LYMPH NODES
o Enlarged, discrete, and sometimes calcified
o Tonsils may be affected in ¼ to 1/3 of cases
 SPLEEN
o Ganulomas may coalesce to form small nodules that are barely visible macroscopically
 LIVER
o May be moderately enlarged and may contain scattered granulomas
 BONE MARROW
o Radiologically visible bone lesions have the tendency to involve phalangeal bones of hands and
feet
 SKIN LESIONS
o Assume a variety of macroscopic appearances
o May appear on mucous membranes of oral cavity, larynx, upper respiratory tract
 Sarcoid granulomas occasionally occur in the heart, kidneys, CNS, endocrine glands.
Hypersensitivity Pneumonitis
 Histological changes of Subacute and chronic forms are centered on bronchioles:
o Interstitial pneumonitis (primarily lymphocytes, plasma cells, macrophages)
o Noncaseating granulomas in 2/3 of patients
o Interstitial fibrosis and obliterative bronchiolitis (late stages)
Smoking-related interstitial diseases
Desquamative Interstitial Pneumonia (DIP)
 Histological Findings
o Most striking: accumulation of large number of macrophages with abundant cytoplasm with dusty
brown pigment n airspaces (smoker’s macrophages)
o Cytoplasm of macropages may contain finely granular iron
o Some macs contain lamellar bodies (surfactant) within phagocytic vacuoles
o Alveolar septa are thickened by inflammatory infiltrate
 Ephysema often present
Respiratory Bronchiolitis-Associated Interstitial Lung Disease
 Respiratory bronchioles, alveolar ducts, peribronchiolar spaces contain smoker’s macrophages similar in
DIP
 Patchy submucosal peribronchiolar infiltrate of lymphocytes and histiocytes
 Mild peribronchiolar fibrosis as also seen
 Centrilobular emphysema is common but not severe
Pulmonary Alveolar Proteinosis

33
  Characterized by a peculiar homogeneous, granular precipitate within the alveoli, causing focal-to-
confluent consolidation of large areas of the lungs with minimal inflammatory reaction
 Marked increase in size and weight of lungs due to turbid fluid exudates in alveoli
 Precipitates are PAS positive and contains cholesterol clefts
Diseases of Vascular Origin
Pulmonary Embolism, Hemorrhage, and Infarction
 Morphologic consequences of embolic occlusion depend on size of embolic mass and the general state
of circulation
 Acute cor pulmonale – acute failure of the right side of the heart which may lead to death
 Only 10% if emboli actually cause infarction
 Pulmonary embolism usually causes infarction only when the circulation is already inadequate, as in heart
or lung disease
 ¾ of all infarcts affect lower lobes, and in ore than half, multiple lesions occur. These may extend to lung
periphery as a wedge with apex pointing to the hilus of lung. The occluded vessel may be identified near
the apex of infarct.
 classically hemorrhagic and appears as raised, red-blue areas in early stages. Apposed
pleural surface is covered by fibrinous exudates. In later stages, fibrous replacement
begins at the margins as a gray-white peripheral zone and converts infarct to scar.
 Septic Infarcts – caused by infected embolus with more intense neutrophilic exudation and inflammatory
reaction
Pulmonary Hypertension
 Chronic hypoxiaPresence of many organizing or recanalized thrombi--> recurrent pulmonary emboli
and diffuse pulmonary fibrosis
 Involves the entire arterial tree, but the most prominently affected, with striking medial hypertrophy, intimal
fibrosis and sometimes narrowing the lumina to pinpoint channels.
 Plexogenic pulmonary arteriopathy- formation of a web or network of capillaries that spans the lumens of
dilated thin-walled, small arteries
Diffuse Pulmonary Hemorrhage Syndromes
Goodpasture Syndrome
 Lungs are heavy, with areas of red-brown consolidation
 Histological findings: focal necrosis of alveolar with associated with intra-alveolar hemorrhages, often
contain hemosiderin-laden macrophages. In later stages, thickening of septae, hypertrophy of type II
pneumocytes and organization of blood in alveolar spaces may occur
 Kidneys may have focal proliferative glomerulonephritis in early cases or crescenteric glomerulonephritis
with rapidly progressive glomerulonephritis.
Idiopathic Pulmonary Hemosiderosis
 Lungs are moderately increased in weight, with areas of consolidation usually colored red brown to red
 Cardinal histologic feature: hemorrhage into alveolar spaces, hemosiderosis within alveolar septa and in
macrophages lying free within the pulmonary alveoli. There may be hyperplasia of type II pneumocytes
and varying degrees of interstitial fibrosis
Pulmonary Infections
Community Acquired Acute Pneumonias
 Bacterial pneumonia has 2 gross patterns of anatomic distribution
o Lobular bronchopneumonia
 Patchy consolidation is the dominant characteristic
o Lobar pneumonia
 Acute bacterial infection resulting in fibrinosuppurative consolidation of a large potion or
an entire a lobe
 4 stages of inflammatory response :
 Congestion – lungs are heavy, boggy, red with vascular engorgement,
intraalveolar fluid with few neutrophils, and often numerous bacteria
 Red hepatization – massive confluent exudation with red cells (congestion),
neutrophils, and fibrin filling the alveolar spaces.. Lobe appears red distinctly red,
firm, airless, with liver-like consistency
 Gray hepatization – progressive disintegration of red cells and the persistence of
a fibrinosuppurative exudates, giving appearance of grayish brown, dry surface
 Resolution – consolidated exudates within the alveolar spaces undergoes
progressive enzymatic digestion to produce a granular, semifluid, debris that is
resorbed, ingested by macs, coughed up or organized by fibroblasts growing into
it.
o Pleuritis consolidation extending to surface
34
  Effective present-day antibiotic slows/halts progression
o Foci of Bronchopneumonia are consolidated areas of acute suppurative inflammation.
Histologically, reaction elicits a suppurative neutrophil-rich exudates that fills the bronchi,
bronchioles, and adjacent alveolar spaces
o Complications of pneumonia include:
 Tissue destruction and necrosis causing abscess formation (common with type3
pneumococci or Kleibsiella infections)
 Spread of infection to pleural cavity causing empyema ( intrapleural fibrinosuppurative
reaction)
 Organization of exudates, which may convert part of lung to solid tissue
 Bacteremic dissemination to heart valves, pericardium, brain, kidneys, spleen, joints,
causing metastatic abscesses, endocarditis, meningitis or suppurative arthritis.
Community Acquired Atypical (Viral and Mycoplasmal) Pneumonias
 All causal agents produce similar morphologic patterns – may be patchy or may involve white lobes
bilaterally or unilaterally. Affected areas are red-blue, congested, and subcrepitant. Pleura is smooth,
pleuritis or pleural effusions are infrequent.
o Predominant is the interstitial nature of the inflammatory reaction, virtually localized within the
walls of the alveoli
o Alveolar damage similar to that seen diffusely in ARDS
 Superimposed bacterial infection modifies the histologic picture causing ulcerative bronchitis and
bronchiolitis.
 Some viruses such as herpes simplex, varicella, and adenovirus may be associated with necrosis of
bronchial and alveolar epithelium and acute inflammation
Influenza Infections
 Viral upper respiratory tract infections are marked by mucosal hyperemia and swelling with a
predominantly lymphomonocytic and plasmacytic infiltration of the submucosa with overproduction of
mucus secretions.
 Laryngotracheobronchitis and bronchiolitis – there is vocal cord swelling and abundant mucous
exudation. Plugged airways may lead to focal alectasis. Organization and fibrosis may occur when airway
obstruction becomes severe and prolonged.
Lung Abscess
 May vary in size, affected part of lung; may be single or multiple
 Pulmonary abscesses due to aspiration are more common on the right and most often single (right main
bronchus is vertical)
 Those that develop in the course of pneumoniaor bronchiectasis are usually multiple, basal and diffusely
scattered.
 Septic emboli and pyemic abscesses are multiple and may affect any lung region
 Abscess cavity may or may not be filled with suppurative debris. When the affected area has
communication with an air passage, exudates may be partially drained.
 Gangrene of the Lung – continued infection leads to this.
 Cardinal histologic change in all abscesses is suppurative destruction of the lung parenchyma within
central area of cavitation
Chronic Pneumonia
Histoplasmosis
 Produce epitheloid granulomas, which usually undergo coagulative necrosis and coalesce to produce
large areas of consolidation but also may liquefy to form cavities.
 Histo differentiation from TB, sarcoidosis, coccidiodomycosis requires identification of 3- to 5- microm
thin-walled yeast forms that may persist in years.
 Chronic histoplasosis – graywhite granuloas are usually present in lung apices with retraction and
thickening of pleura and in hilar nodes.
 Fulminant disseminated histoplasmosis – occurs in immunosuppressed individuals; no epitheid cell
granulomas but instead are focal accumulations of mononuclear phagocytes filled with fungal yeasts
throughout the tissues and organs
Blastomycosis
 Lung lesions are suppurative granulomas
 Macs have limited ability to ingest and kill B. dermatidis and its persistence leads to continued recruitment
of neutrophils
 Involvement of skin and larynx is associated with marked epithelial hyperasia
Coccidioidomycosis
 Primary and secondary lesions of C. immitis are similar to that of HIstoplama.
 Box-car like arthrospores produced in culture are easily detached and disseminated by air
35
  Involves lungs, meninges, skin, bones, adrenals, lymph nodes, spleen or liver and inflammatory response
for these sites may be purely granulomatous, pyogenic or mixed.
 Purulent lesions dominate in patients with low resistance
Lung Transplantation
 Transplanted lung is subject to 2 major complications:
o Infection – common in immunocompromised hosts; may include bacterial and viral pneumonias,
Pneumonia carinii pneumonia and fungal infections (Candida and aspergillus species)
 Most cases occur in 3rd to 12th month after transplant
o Rejection –
 Acute- often occurs during early weeks to months after surgery , may occur years later
when immunosuppression is decreased.
 Patients present with fever, dyspnea, cough, and radiologic infiltrates. Diagnosis
relies on transbronchial biopsy
 Morphologic features: inflammatory infiltrates either around small vessels ,
submucosa of airways or both
 Chronic – significant in ½ of all lung transplants after 3-5 years.
 Manifested by cough, dyspnea, and irreversible decrease in lung fxn tests
 Major morphologic correlate is bronchiolitis obliterans
Tumors
Carcinomas
 Often found in and about of lung hilus
 Extension may occur in pleural surface and then within pleural cavity ad into pericardium. Spread to
tracheal, bronchial, mediastinal nodes can be found.
 Distant spread occurs through both lymphatic and hematogenouspathways.
o Adrenals, Liver, brain and bone are favored sites of metastases
Squamous cell carcinoma
 Found in men and is closely correlated with a smoking history
 Histo feature: presence of keratinization and/or intercellular bridges
 Show highest frequency of p53 mutations of all histologic lung carcinomas
Adenocarcinoma
 Malignant epithelial tumor with glandular differentiation or mucin production by tumor cells.
May show patterns such as acinar, papillary, bronchioalveolar, solid with mucin formation.
 Most common in women and nonsmokers.
 As compared to squamous cells, lesions are more peripherally located and smaller; it grows
slower but tend to metastasize widely and earlier
Small cell carcinoma
 Epithelia cells are small, with scant cytoplasm, ill defined cell bordersm finely granular nuclear
chromatin, and absent or inconspicuous nucleoli
 Cells are round, oval and spindle shaped and nuclear molding is prominent.
 Necrosis is common and often extensive
 all small cell carcinomas are high grade
 combined small cell carcinoma: mixture of small cell carcinoma and any other non small cell
component, including large cell neuroendocrine carcinoma and sarcoma
Large cell carcinoma
 lacks cytoloic features of small cell carcinoma andglandular or squamous differentiation
 cells typically have large nuclei, prominent nucleoli, and a moderate amount of cytoplasm
Combined carcinoma
 10% of all lung carcinomas have combined histology
Secondary pathology
 Lung carcinomas cause related anatomic changes in lung substance distal to the point of bronchial
involvement.
 Partial obstruction may cause marked focal emphysema, total obstruction may lead to atelectasis.
 Severe suppurative or ulcerative bronchitis or bronchiectasis
 Pulmonary abscesses
 Superior vena cava syndrome
 Pericarditis or pleuritis
Neuroendocrine Proliferations and Tumors
 Carcinoids may arise centrally or at the peripheral.
 Grow as finger-like, or spherical polypoid masses that project into the lumen of bronchus and covered by
intact mucosa. Mostly confined to the man stem bronchi
o Others have Collar button lesion
36
  Peripheral tumors are solid and nodular.
 Spread to local lymph nodes at resection is more likely with atypical carcinoid.
 Histological finding: organoid, trabecular, palisading, ribbon, or rosette like arrangement of cells
separated by a delicate fibrovascular stroma.
 Atypical carcinoids tend to show more cellular atypia, increased cellularity, nucleoli, lymphatic invasion
and disorganized structure
Metastatic Tumors
 Variable growth pattern, but usually have cannonball lesions scattered throughout all lobes.
o Occurs in the periphery rather than in the central locations
 May be confined to peribronchiolar and perivascular tissue spaces, when tumor has extended to the lung
through lymphatics
 Lymphangitis carcinomatosa – gross appearance referring to subpleural lymphatics outlined by
contained tumor
Pleura
Pleural Tumors
Malignant Mesothelioma
 Diffuse lesion that spread widely in pleural surface and is associated with extensive pleural effusion and
direct invasion of thoracic structures
 Affected lung gets ensheathed by thick layer of soft, gelatinous, grayish pink tumor tissue
 Microscopically, malignant mesothelioas consist of a mixture of 2 cell types:
o Epitheloid type – cuboidal, columnar, flattened cells forming tubular or papillary structures
resembling adenocacinoma. Features include:
 Positive staining foracid mucopolysaccharide
 Lack of staining for carcoembryonic antigen
 Strong staining for keratin proteins
 Positive staining for calretinin
 Presence of long mocrovilli and abundant tonofilaments in EM (gold standard of
diagnosis is electron microscopy)
o Sarcomatoid type – spindle cell, resembling fibrosacrcoma

CHAPTER 16
Head and Neck

HSV Infections
- vesicular lesions filled with clear, serous fluid often ruptures to yield extremely painful, red-rimmed and
shallow ulcerations
- individual epidermal cells in the margins of the vesicle or lying free within the fluid sometimes develop
eosinophilic intracellular viral inclusion
- several cells may fuse to produce giant cells (multinucleate polykaryons)
- diagnosis: Tzanck test/smear (of the vesicle fluid under the microscope)
- lesions disappear in 3-4 weeks, but virus still persists in the regional nerves and becomes dormant in the local
ganglia

Leukoplakia &Erythroplakia
- may occur anywhere in the oral cavity (favoring the buccal mucosa, floor of the mouth, ventral surface of
tongue, palate and gingiva)
- solitary/multiple white patches or plagues with indistinct or sharply demarcated borders
- Histologic exam: epithelial changes ranging from hyperkeratosis overlying a thickened, acanthotic but orderly
mucosla epithelium to lesions with markedly dysplastic changes sometimes merging into Cis
- In erythroplakia: rarely consists of epidermal thickening; (approx. 90%) superficial erosions with dysplasia,
Cis, or already developed CA in surrounding margins; intense subepithelial inflammatory reaction with
vascular dilation accounts for the red appearance of the lesion

Squamous Cell CA
- can arise anywhere favoring the ventral surface of tongue, floor of the mouth, lower lip, soft palate and
gingival
- usu preceeded by a premalignant lesion that can be very heterogenous in presentation
- Histologic Exam: CA begin as dysplastic lesions which may or may not progress to full-thickness dysplasia
prior to invading the underlying connective tissue stroma unlike in cervical CA (full-thickness dysplasia occurs
prior to invasion)

37
 - These tumors tend to infiltrate locally before they metastasize to other sites (routes of extension depends on
the primary site)
- Preferred site of metastasis are the cervical lymph nodes; most common sites are mediastinal lymph nodes,
lung, liver and bone

Nasopharyngeal CA
- Histologic Exam: keratinizing and non-keratinizing squamous cell lesions more or less resemble usual well-
differentiated and poorly differentiated squamous cell CA arising in other locations
- Undifferentiated variant: large epithelial cells with oval or round vesicular nuclei, prominent nucleoli, and
indistinct cell borders disposed in a syncytium-like array; together with epithelial cells are abundant normal-
appearing lymphocytes

Carcinomaof the Larynx

- 95% of which are typical squamous cell tumors
- Us develops on the vocal cords, but may arise above or below the cords
- Confined within the larynx proper are termed intrinsic those that arise outside extrinsic
- Squamous cell CA of the larynx follow the growth pattern of all squamous cell carcinomas
- Lesions arising from recurrent exposure to environmental carcinogens, adjacent mucosa may demonstrate
squamous cell hyperplasia with foci of dysplasia or even Cis

Paraganglioma (Carotid Body Tumor)

- prototype of parasymphatetic paraganglioma
- arise close to or envelops the bifurcation of the common carotid artery
- microscopic feature of all parangangliomas are remarkably uniform, composed of nests “zellballen” of
polygonal chief cells enclosed by trabeculae of fibrous and sustentacular elongated cells.

Pleomorphic adenoma
- most present as rounded, well-demarcated masses rarely exceeding 6 cm in greatest dimension
- although encapsulated, in some locations capsule is not fully developed and expansile growth produces
tongue like protrusions into the surrounding gland, rendering tumor enucleation hazardous
- dominant histologic feature is the great heterogeneity
- most cases, no epithelial dysplasia or evident mitotic activity
- no difference in biologic behavior between the tumors composed largely of epithelial cells and those
composed only of seemingly mesenchymal elements

Warthin Tumor (Papillary Cystadenoma Lymphomatosum)

- round to oval, encapsulated masses arising in most cases in the suyperficial parotid gland where they are
readily palpable
- microscopic examination: spaces are lined by a double layer of neoplastic epithelial cells resting on a dense
lymphoid stroma sometimes bearing germinal centers
- double layer of lining cells is distinctive, with a surface palisade of columnar cells having an abundant, finely
granular, eosinophilic cytoplasm resting on a layer of cuboidal to polygonal cells
- secretory cells are dispersed in the columnar cell layer, accounting for the secretion within the lumens

Mucoepidermoid Carcinoma
- lack well-defined capsules and are often infiltrative at the margins
- frequently reveal small, mucin-containing cysts
- subclassified into low, intermediate or high grade

Adenoid Cystic Carcinoma

- generally small, poorly encapsulated, infiltrative, gray-pink lesions
- Histologically: small cells having dark, compact nuclei and scant cytoplasm
- Tend to be disposed in tubular, solid, or cribriform patterns reminiscent of cyclindromas arising in skin adnexa
- Spaces between tumor cells often filled with a hyaline material thought to represent excess basement
membrane

CHAPTER 17
The Gastrointestinal Tract

38
Achalasia – progressive dilation of the esophagus above the level of the LES; wall is thicker because of hypertrophy and
muscularis is thinned by dilation; ganglia are absent; mucosal lining is unaffected but with inflammation, ulceration or
fibrotic thickening at just above the LES at times

Lacerations (Mallory-weiss syndrome) – lacerations are mm to cm in length from mucosa to wall; usually found astride the
esophagogastric junction or in the proximal gastric mucosa; there is hemorrhage and an inflammatory response which
may lead to mediastinitis

Esophageal varices – appear as dilated veins within submucosa of distal esophagus and proximal stomach; effect is
irregular protrusion of mucosa into lumen; often eroded and inflamed with hemorrhage and suffusion of the esophageal
wall with blood; overlying mucosa is ulcerated and necrotic

Barrett esophagus – red, velvety mucosa between pink squamous mucosa and brown gastric mucosa; patches; displaces
squamocolumnar junction;replaced by metaplastic columnar epithelium which contains only gastric surface and glandular
mucus secreting cells making a distinction from hiatal hernia; definitive diagnosis when columnar mucosa has intestinal
goblet cells; has low grade or high grade dysplasia; high grade requires clinical intervention

Esophagitis – different causes with own characteristic features; commonality is sever acute inflammation, necrosis and
ulceration with formation of granulationtissue and eventual fibrosis

Sqaumous cell carcinomas – begin as insitu lesions 50 percent of which is in the middle third; start as gray white plaque
like thickenings then become tumorous masses; moderately to well differentiated; metastasize to cervical, mediastianl,
paratracheal, tracheobronchial, gastric and celiac nodes

Adenocarcinomas – usually located in distal esophagus, invades adjacent gastric cardia, starts as flator raised patches
and develops into large nodular masses; has mucin producing glandular tumors; requires multisite biopsy

Acute gastritis – lamina propria has moderate edema and vascular congestion; surface epithelium is intact with scattered
neutrophils; has erosion generating a defect in the mucosa that does not cross the muscularis mucosa; concurrent
erosion and hemorrhage is termed acute erosive hemorrhagic gastritis

Chronic gastritis – affects different regions of the stomach with varying degrees of mucosal damage; mucosa is reddened
with coarser texture; thickened rugal folds; histologic changes – regenerative changes, intestinal metaplasia, atrophy,
dysplasia; lymphocytes in lamina propria; lymphoid aggregates in mucosa; active inflammation may be present or absent

Peptic ulcer – in first portion of duodenum or in stomach; usually the anterior wall and in the lesser curvature; size and
location do not differentiate a malignant from a benign tumor; oval, sharply punched out defects with straight walls;depth
varies; perforation ay occur; base is smooth and clean due to peptic digestion; gastic mucosa surrounding in edematous
and reddened; histologic appearance has active necrosis and chronic inflammation; has chronic gastric as well

Acute gastric ulceration – less than 1 cm, circular and small with dark brown base; often multiple with unremarkable
adjacent mucosa; healing with complete epithelialization occurs after the causative factors are removed.

Benign tumors – majority are non-neoplastic and appear to be hyperplastic; surface epithelium maybe regenerative;
dysplasia not present; small and sessile; located in anrtum; adenomatous polyps are common in the colon; gastric
adenomas maybe sessile or pedunculated; usually single; other polyps, fundic polyps, Peutz-Jeghers polyps; juvenile
polyps and inflammatory fibroid polyps

Gastric Carcinoma – located in pylorus and antrum in the lesser curvature; greater curvature more likely to be malignat;
greatest impact on clinical outcome is the depth of invasion; advanced gastric carcinoma extends below the submocusa
into the muscular wall; has 3 macroscopic growth factors; exophytic, flat or depressed and excavated

Less Common Gastric Tumors (Gastric Lymphoma) – occurs in the mucosa or the superficial submucosa; infiltrated with
atypical lymphocytes

Less Common Gastric Tumors (Gastrointestinal Stromal Tumor) – solitary or multiple; can protrude into the lumen; firm to
soft, hemorrhagic; has necrosis or cystic changes; can exhibit spindle cells, mitotic activity is variable

Congenital Aganglionic Megacolon or HIRSCHSPRUNG disease – absence of ganglion cells; rectum always affected with
involvement of proximal colon; thickening and hypertrophy of non myelinated fibers; progressive dilation and hypertrophy
of colon; may rupture near the cecum; stercoral ulcers may appear
39
Viral Gastroenteritis – small intestinal mucosa has shortened villi; lamina propira is infiltrated with lymphocytes; loss of
microvillus brush border; crypts become hypertrophied

Antibiotic Associated Colitis – non-specific pattern of damage; decreased epithelial cell maturation; increased mitotic rate;
hyperemia of lamina propria; variable neutrophilic infiltration; with recovery, epithelial damage and neutrophilic
inflammation subside, however progressive destruction leads to ulceration, erosion, and severe submocusal inflammation

Amebiasis – cecum, ascending colon, followed by sigmoid, rectum and appendix; amoeba mimics macrophages; invade
the crypts and burrow into the mucosa, eliciting neutrophilic interaction; surface mucosa deprived of its blood supply and
sloughs

Giardiasis – with sickle shaped trophozoites; small intestinal morphology is normal; mixed inflammatory infiltrate in the
lamina propria; brush borders of the absorptive epithelial cells are irregular; resembles atrophic stage of celiac disease

Celiac Disease – small intestine is flat or scalloped; diffuse enteritis with marked atrophy or total loss of villi; vacuolar
degeneration; loss of brush border; increase in lymphocytes; increase mitotic activity; lamina propria; increase in plasma
cells; lymphocytes, macrophages, eosinophils and mast cells; marked in proximal small intestine; condition reverts to
normal following diet with gluten exclusion.

Tropical Sprue (Postinfectious Sprue) – seen in all levels of the small intestine, with folate or vit B12 deficiency; atypical
enlargement of the nuclei of epithelial cells

Whipple Disease – small intestinal mucosa has distended macrophages in the lamina propria; involvement of mesenteric
lymph nodes; lymphatic dilation and obstruction; lipid deposition in villi (intestinal lipodystrophy)

Crohn Disease – intestinal wall is rubbery and thick with edema, inflammation, fibrosis, and hypertrophy of the muscularis
propria; sharp demarcation of disease bowel segments from adjacent uninvolved bowel; with narrow fissures in the folds
of the mucosa, leading to fistula or sinus tract formation; histologic features are mucosal inflammation, chronic mucosal
damage, ulceration, transmural inflammation, nocaseating granuloma

Ulcerative Colitis – involves the rectum; ulceration of the mucosa in the distal colon; has pseudo polyps; mucosal damage
is continuous from the rectum and extends proximally; epithelial changes signifying dysplasia and the progression to frank
carcinoma

Ischemic Bowel Disease – due to transmural infarction (small intestinal infarction following sudden and total occlusion of
mesenteric arterial blood flow), mucosal and mural infarction; chronic ischemia

Hemorrhoids – varicosities in the inferior hemorrhoidal plexus below the anorectal line or from dilation of superior
hemorrhoidal plexus; both plexus affected produce combined hemorrhoids

Diverticular Disease – Descending colon or entire colon affected; occurs alongside taenia coli, easily emptied of fecal
contents; atrophic mucosa, compressed submucosa, absend muscularis propria; obstruction leads to inflammatory
changes, which leads to fibrotic thickening,

non neoplastic polyps – such as hyperplastic polyps which are small and have no malignant potential; hamartomatous
polyps which are malformations of the mucosal epithelium and the lamina propria; Peutz-Jeghers polyps involve the
mucosal epithelium, lamina propria; patients with these polyps have increased risk of developing carcinomas of the
pancreas, breast lung ovary and uterus

ADENOMAS - (1) Tubular adenomas – found in the colon; low graded dysplasia (2) villous adenomas occur in older
persons in rectum and rectosigmoid colon (3) tubulo villous adenomas – intermediate between tubular and villous lesions

Colorectal carcinoma – begins as in situ lesions; evolves into different morphologic patterns; produce mucin which
worsens the prognosis

Carcinoid Tumors – Most common in the appendix; solid yellow tan appearance on transaction; almost never
metastasized

Gastrointestinal lymphoma – full thickness mural thickening, effacement of the overlying mucosal folds, tumor infiltration
destroys muscle fibers; with atypical lymphoid cells infiltrating the mucosa
40
Mesenchymal Tumors – well demarcated, firm modules, in submucosa or muscularis propria; large sized and high mitotic
rate

Acute appendicits – subserosal vessels are congested, with modest perivascular, neutrophilic infiltrate; neutrophilic
infiltration of the muscularis propria; muscular wall inflammation

Mucocele and pseudomyxoma peritonei – with appendiceal dilation secondary to mucinous secretions; produces atrophy
of the mucosal cells; usually asymptomatic

Peritoneal infection – loss of the gray; accumulation of serous or slightly turbid fluid; localized by the omentum and the
viscera; produces plastic exudates studded with minute pale granulomas

CHAPTER 18
Liver and Biliary Tract

HEPATIC INJURY MORPHOLOGY

Inflammation.
Hepatitis
- injury to hepatocytes associated with an influx of acute or chronic inflammatory cells into the liver
- hepatocyte necrosis may precede onset of inflammation and vice versa
- common cause of liver damage: attack of viable antigen-exressing liver cells by sensitized T-cells
- inflammation- portal tracts or may spill over into parenchyma
- scavenger macrophages engulf dead hepatocytes and this generates clumps of inflammatory cells
- granulomatous reaction: foreign bodies, organisms, and a variety of drugs
Degeneration
- ballooning degenaration – edematous appearance due to damage from toxic or immunologic insult
- foamy degenaration – retained biliary material may impart diffuse, foamy and swollen hepatocytes
- iron, copper and retained biliary material may accumulate in viable hepatocytes
- steatosis- accumulation of fat droplets within hepatocytes = alcoholic liver disease, Reye syndrome,
acute fatty liver of pregnancy
- macrovesicular steatosis- single large droplet that displaces nucleus = alcoholic liver or in livers of
obese or diabetic individuals
Cell Death
- coagulative necrosis as a result of ischaemia = poorly stained hepatocytes
- apoptosis due to cell death that is toxic or immunologically mediated = isolated hepatocytes become
shrunken, pyknotic, intensely eosinophilic
- hydropic degeneration or lytic necrsis- osmotic swelling and rupture of hepatocyes
- centrolobular necrosis – hepatocyte necrosis distributed immediately around central vein = ischaemia
and a number of drug and toxic reactions
- pure midzonal and periportal necrosis is rare
- interface hepatitis – immunologically mediated hepatocyte death that limits apoptosis to scattered
cells within hepatic parenchyma or interface between the periportal parenchyma and inflamed portal
tracts.
- Bridging necrosis – apoptosis or necrosis of contiguous hepatocytes may span adjacent lobule in a
portal-to-portal, portal-to-central, central-to-central fashion
- Submassive necrosis – destruction of entire lobules
- Massive necrosis – destruction of most of the liver parenchyma; usually accompanied by liver failure
Fibrosis
- fibrous tissue is formed due to inflammation or direct toxic insult to liver
- deposition of collagen has lasting effects on hepatic patterns of blood flow and perfusion of
hepatocytes
- initially, fiborsis may develop within or around portal tracts or the central vein may be deposited
directly withiin the sinusouds
- bridging fibrosis- liking of regions of the liver by fibrous strands (portal-to-portal, portal-to-central,
central-to-central)
Cirrhosis
- cirrhosis - subdivision of the liver into nodule of regenerating hepatocytes surrounded by scar tissue
due to continuing fibrosis and parenchymal injury

CHOLESTASIS MORPHOLOGY
41
 - common for both nonobstructive and obstructive conditions :
o elongated green-brown plugs of bile are visible in dilated canaliculi, droplets of bile pigment
also accumulate within hepatocytes taking on a wispy appearance (foamy degenaration)
- obstructive conditions: obstruction to biliary tree either intrahepatic or extrahepatic induces distention
of upstream bile ducts by bile
o bile ductular proliferation – proliferation of epithelial cells and looping and
reduplication of the ductulre connecting bile ducts to parenchyma due to bile stasis and back-
pressure
- portal tract findings: edema, periductal infiltrates of neutrophils
- prolonged obstructive cholestasis_ foamy change of hepatocyes and focal destruction of parenchyma
= bile lakes
- portal tract fibrosis = due to unrelieved obstruction = extends into and subdivied the parenchyma with
relative preservatoin of hepatic architecture; end-stage is biliary cirrhosis

HEPATITIS MORPHOLOGY
Acute Hepatitis
- ballooning degeneration
- cholestasis (not constant) with bile plugs in canaliculi and brown pigmentation of hepatocytes
- fatty change is mild and unsusual except with HCV infection
- Kuppfer cells indergo hypertrophy and hyperplasia
- Laden with lipofuscin due to phagocytosis of pepatocellular debris
- Portal tracts are infiltrated with a mixture of inflammatory cells
- Interface hepatitis – inflammatory infiltrate may spill over into the parenchyma to cause necrosis of
periportal hepatocytes
- Bile duct epithelium- may become reactice and proliferate = poorly defined ductular structures in the
midst of portal tract inflammation
- Bile duct destruciton doesn’t occur
Chronic Hepatitis
- smoldering hepatocyte necrosis throughout the lobule may occur in all forms of chronic hepatitis
- midlest forms- significan inflammation limited to portal tracts (lymphocytes, macrophages, occasional
plasma cells and neutrophils or eosinophils)
- lymphoid aggregates in portal tract = HCV infection
- liver arthitecture is usually well preserved
- continued periportal necrosis and bridging necrosis
- irreversible liver damage = deposition of fibrous tisssue – portal tracts, periportal tracts, bridging
fibrosis
- cirrhosis- continued loss of hepatocytes and fibrosis = irregulartly sized nodule separated by variable
but mostly broad scars

HBV Infection (both acute and choric)

- ground-glass hepatocytes- finely granular,eosinophilic cytoplasm that contain massive quantitis of
HbsAg in the form of sphere and tubules
- sanded nuclei

Hepatocyte Necrosis
2 Patterns
1. cytolysis; necrotic cells appear to have dropped out; scavenger macrophages aggregate
2. apoptosis. More distinctive. Eosinophilic hepatocytes with fragmented nuclei.
3. in severe cases, confluent necrosis of hepatocytes may lead to bridging necrosis connecting
portal-to-portal, central-to-central, or portal-to-central regoins of adjacent lobules

MASSIVE HEPATIC NECROSIS MORPHOLOGY

- distribution of liver destruction is extremely capricious
- entire liver may be involved or only random areas are affected
- liver may shrink to as litte as 500-700g
- necrotic areas have a muddy red, mushy appearnce with blotchy bile staining
- complete destruction of hepatocytes in contiguous lobues - collapsed reticulin framework and
preserved portal tracts
- little inflammatory reaction
- px survival for more than a week permits regeneration of surviving hepatocytes
- regeneration- initially in the form of string of ductular structures which mature into hepatocytes
42
 - regeneartion is orgerly and native liver architecture is restored if parenchyml framework is preserved
- massive destruction of confluent lobules= regeneration is disorderly, yielding nodular masses of liver
cells
- scaring may occur

ALCOHOL LIVER DISEASE MORPHOLOGY

Fatty Liver (Hepatic Steatosis)
- chronic alcohol intake- lipi accumulatees to the point of creatly large, clear macrovesivular globules
that compress and displace the nucleus to the periphery of hepatocyte
- initially centrilobular but in severe cases may involve entire lobule
- fatty liver is large, soft, yellow, greasy
- little or no fibrosis at the outset, with continued alcohol intake, fibrous tissue develps around the
central veins and extends into the adjacent sinusoids
- completely reversible unless fibrosis starts
Alcohol Hepatitis
- Hepatocyte swelling and necrosis – ballooning and necrosis
- Mallory bodies – scattered hepatocytes accumulate tangle skeins of cytokeratin intermediate
filaments and other protiens visible as eosinophilic cytoplasmic inclusions
- Neutrophili reaction
- Fibrosis – almost always accompanies alcoholic hepatitis
- Cholestasis and mild deposition of hmosiderin in hepatocyes and Kupffer cells
Alcoholic Cirrhosis
- final and irreversible form of alcoholic liver disease
- liver is yellow-tan, enlarged, weighing over 2kg
- may develop more rapidly in the setting of alcoholic hepatitis within 1-2 years
- regenerative activity of entrapped parenchymal hepatocytes generates fairly uniformly sized nodules
= micronodular cirrhosis
- nodularity becomes more prominent with time
- “hobnail” appearance- prominent nodules
- liver becomes more fibrotic, loses fat, shrinks progressively as fibrous septa dissect and surround
nodules
- liver is converted into a mixed micronodular and macronodular pattern
- end-stage alcoholic cirrhosis eventually resemnbles both macroscopically and microscopically the
cirrhosis developing from viral hepatitis

HEMOCHROMATOSIS MORPHOLOGY
- deposition of hemosiderin in the liver, pancreas, myocardium, pituitary, adrenal, thyroid and
parathyroid gralds, joints and skin (decreasing severity)
- cirrhosis
- pancreatic fibrosis
- in the liver – iron becomes evident as hemosiderin granules of periportal hepatocytes which stain blue
with the prussian blue stain
- increasing iron load – progressive involvement of the rest of the lobue along with bile duct epithelium
and Kupffer cell pigmentation
- iron is a direct hepatotoxin
- inflammation is characteristically absent
- liver is sligtly larger than normal, dense, chocolate brown
- micronodular pattern of cirrhosis in intensely pigmented liver due to development of fibrous septa
- 10000microgram/g dry wt of iron
- pancreas: intensely pigmented, diffuse interstitial fibrosis, parenchymal atrophy, hemosiderin in acinar
and islet cells
- heart: enlarged with hemosiderin within myocardial fibers, brown myocardium
- acute synovitis due to hemosiderin deposition in the joint synovial linings, pseudogout due to
excessive deposition of Calcium pyrophosphate
- testes: may be small and atrophic but not discolored

Wilson Disease Morphology

- Fatty change may be mild to moderate with vacuolated nuclei (glycogen or water)
- Occasional hepatocyt focal necrosis
- Acute hepatitis can mimic acute viral hepatitis except for accompanying fatty change

43
 - Chronic hepatitis resemble viral, drug, or alcoholic chronic hepatitis but with distinguishing features
like fatty change, vacuolated nuclei and Mallory bodies
- Cirrhosis develops with progression
- Massive liver necrosis is a rare manifestatoin
- Excess copper deposition (rhodanine stain, orcein stain)
- Demonstration of hepatic copper content in excess of 250microgram/g dry wt is most helpful for
making dx
- Brain: toxic injury affects basal ganglia (putamen), eye lesions (Kayser-Fleischer rings) –green to
brown deposits of copper in Descemet membrane in limbus of cornea

Alpha-Antitrypsin Deficiency
- hepatocytes contain roind to oval cytoplasmic globular inclusions of retained AAT

Reye Syndrome Morphology

- microvesicular steatosis
- electron microscopy of hepatocellular mitochondria reveals pleomorphic enlargement and elctron
lucency of matrices with disruption of cristae and loss of dense bodies
- brain: cerebral edema, swollen astrocytes, similar mitochondrial changes
- inflammation is absent
- skeletal muscles, kidneys and heart may also reveal microvesicular fatty change and mitochondrial
alterations

BILIARY CIRHOSSIS MORPHOLOGY

- primary and secondary biliary cirrhosis and primary sclerosing cholangitis- end0stage liver exhibits
extraordinary yello0green pigmentation associated with mareked icteric discoloration of body tissues
and fluids
- on cut surface, liver is hard, finely granular appearnce
Secondary Biliary Cirrhosis
- coarse fibrous septa that subdivide the liver ina jigsaw-lke pattern
- distended large and small bile ducts which contain inspissated pigmented mateiral are embedded in
the septa
- extensive proliferation of smaller bile ductures
- edema at the interface between septa and the parenchyma
- bacterial infection can cause a robust neutrophilic infiltration of bile ducts
- severe pylephlebitis (vein inflammation) and cholangitic abscesses may develop
Primary Biliary Cirhossis
- interlobular bile ducts are absent
- precirrhotic stage reveals most morphologic changes: interlobular bile ducts are destroyed by
inflammation with intraephithelial infiltration of lymphocytes, granulomatous inflammation, dense
portal tract infiltrate of lymphocytes, macrophages and plasma cells, upstream bile ductular
proliferation due to obstruction to intrahepatic bile flow, inflammation and necrosis of adjacent
periportal hepatic parenchyma and generalized cholestasis
Primary Sclerosing Cholangitis
- fibrosing cholangitis of bile ducts
- affected portal tracts have concentric periductal onion0skin fiborisis and modest lymphocytic infiltrate
- progressive atrophy of bile duct epithelium = lumen obliteration
- bile ductes become ectatic and inflamed due to downstream obstruction
- entire liver becomes markedly cholestatic and fibrotic as dusease origresses

HEPATIC VEIN THROMBOSIS (BUDD-CHIARI SYNDROME) MORPHOLOGY

- swollen liver
- red-purple
- tense capsule
- hepatic parenchyma reveals severe centrolobular congestion and necrosis
- centrolobular fibrosis develops when thrombosis is more slowly developing
- major vein contain totally occlusis fresh thrombi, subtotal occlusion or organized adherent thrombi in
chronic cases

CARCINOMA OF THE LIVER MORPHOLOGY

Hepatocellular Carcinoma (HCC)
- Primary Liver Carcinoma may appear grossly as:
44
 o a unifocal, usually massive tumor
o multifocal malignancy with widely distributed nodule of variable size
o diffusely infiltrative cancer, can sometimes involve whole liver, blending imperceptibly into the
cirrhotic liver background
- discrete tumor masses are usually yellow-white, punctuated by bile staining and areas of hemorrhage
or necrosis
- discrete tumor masses are usually yellow-whit with bile staining and hemorrhagic or necrotic areas
- strong propensity for invasion of vasular channels
- extensive intrahepatic metastases ensues
- occasionally snakelike masses of tumore invade the portal vein or inferiour vena cava
- HCC – well-differentiated lesions that reproduce hepatocytes arranged in cords or small nests to
poorly differentiated lesions often made up of large multinucleate anaplastic tumor giant cells
- In better differentiated variants, globules of bile may be found withn the cytoplasm of cells and in
pseudocanaliculi between cells
- Acidophilic hyalin inclusions within cytoplasm may be present, resembling Mallory bodies
- Scant stroma
- Fibrolamellar carcinoma- clinicopathologic variant of HCC; occurs in young male and female adults
(20-40 yo); single larte, hard “scirrhous” tumor with fibrous bands coursing through it, vaguely
resembling focal nodular hyperplasia; composed of well-differentiated polygonal cells growing in
nests or cords and separated by parallel lamellae of dense collagen bundles

Cholangiocarcinomas
- well-differentiated adenocarcinomas
- abundant fibrous stroma- desmoplasia = firm, gritty consistency
- defined glandular and tubular structures line by somewhat anaplastic cuboidal-to-low columnar
epithelial cells
- bile pigment and hyaline inclusions are not found within the cells

DISORDERS OF TEH GALLBLADDER

Cholelithiasis (Gallstones) Morphology
- pure cholesterol stones are pale yellow
- increasing proportions of calcium carbonate, phosphates and bilirubin impart gray-white to black
discoloration
- stones are ovoid and firm
- may be single but most often are multiple and have faceted surfaces
- most cholesterol stones are radiolucent, some have sufficient calcium carbonoate to render tehm
radiopaque
- pigment stones may arise anywhere in teh biliary tree and are trivially classifiead as black and as
brown:
o black- sterile gallbladder bile; small and present in great number, crumble easily
o brown- infected intrahepatic or extrahepatic ducts, single or few in number, soft, greasy,
soap-like consistency due to retained fatty acid salts
- stones contain calcium salts of unconjugated bilirubin and lesser amounts of other calcium salts,
mucin, glycoprotiens and cholesterol

Cholecystitis Morphology
-Acute
- enlarged gallbladder (2x-3x), tense, assumes a bright red or blotchy, violaceous to green-black
discoloration
- serosal covering is layerd by fibrin and in severe cases, by a suppurative exudate
- stones are present 90% of the time, often obstructs the nect of the gallbladder or the cystic duct
- gallbladder lumen is filled with a cloudy or turbid bile that may contain fibrin, hemorrhage, and frank
pus
- empyema of the gallbladder- contained exudate is virtually pure pus
- gangrenous cholecystitis – gall ladder wall is thickened and edematous and hyperemic, and in severe
cases, it is transformed into a green-black necrotic organ
- inflammatory reactions are not distinctive and consist of usual patterns of acute inflammation
-Chronic
- morphologic changes are variable
- mere presence of stones within the bladder even in the absence of acute inflammation is often taken as
sufficient justification for the dx
45
 - bladder may be contracted, of normal size or enlarged
- mucosal ulcerations aren’t frequent
- submucosa and subserosa are often thickened from fibrosis

CARCINOMA OF THE GALLBLADDER MORPHOLOGY

- Infiltrating patterns:
- More common and usually apperars as apoorly defined area of diffues thickeining and induration of
teh gallbladder wall
- Tumors are scirrhous and very firm
- Exophytic patterns:
- Growns into the lumen as an irregular cauliflower mass but at the same time it invade the underlying
wall
- Most carcinomas of the gallbladder are adenocarcinomas
- Some are papillary
- Others are poorly differentiated to undifferentiated infiltrating tumors
- 5% are squamous cell carcinomasor have adenoaquamous differentiation
- few are carcinoid tumors
- by the time gallbladder cancers are discovered, most have invaded the liver directly and many have
extended to the cystic duct and adjacent bile ducts and portahepatic lymph nodes
- peritoneum, git, lungs are less common sites of seeding

CARCINOMA OF EXTRAHEPATIC BILE DUCTS INCLUDING AMPULLA OF VATER MORPHOLOGY

- partial or complete obstruction of bile duct leads to jaundice
- tumors are firm, gray nodules within the bile duct wall
- some may be diffusely infiltrative lesions = ill-defined thickening of the wall
- papillary, polypoid lesions
- most bile duct tumors are adenocarcinomas that may or may not secrete mucin
- abundant fibrous stroma accompanies the epithelial proliferation
- squamous features are seldom present

CHAPTER 19
The Pancreas

PANCREATITIS
Acute Pancreatitis
 morphology ranges from trivial inflammation and edema to severe extensive necrosis and hemorrhage
o acute interstitial pancreatitis – milder form; alterations limited to interstitial edema and focal areas of fat
necrosis
o acute necrotizing pancreatitis – more severe form; with necrosis of acinar and ductal tissues as well as
islets of Langerhans; appears macroscopically as areas of red-black hemorrhage interspersed with foci of
yellow-white, chalky fat necrosis
o hemorrhagic pancreatitis – most severe form; extensive parenchymal necrosis with diffuse hemorrhage
 basic alterations:
o microvascular leaking causing edema
o necrosis of fat by lipolytic enzymes
o an acute inflammatory reaction
o proteolytic destruction of pancreatic parenchyma
o destruction of blood vessels with subsequent interstitial hemorrhage

Chronic Pancreatitis
 characterized by parenchymal fibrosis, reduced number and size of acini with relative sparing of the islets of
Langerhans, and variable dilatation of the pancreatic ducts
 grossly, the gland is hard, sometimes, with extremely dilated ducts and visible calcified secretions

NON-NEOPLASTIC CYSTS
Pseudocysts
 usually solitary; may be within the substance of the pancreas but more commonly attached to the surface of
the gland and involve peripancreatic tissues
 composed usually of central-hemorrhagic material rich in pancreatic enzymes surrounded by nonepithelial
lined fibrous walls of granulation tissue

46
NEOPLASMS
Pancreatic Carcinoma
 60% in the head of the gland – usually obstructs the distal common bile duct causing marked distention of
the biliary tree
 15% in the body, 5% in the tail – do not impinge on the biliary tract and hence remains silent for some time;
may be quite large and disseminated by the time they are discovered
 20% diffusely involves the entire gland
 majority are ductal adenocarcinomas
o microscopically: moderately to poorly differentiated adenocarcinoma forming abortive tubular structures
or cell clusters and exhibiting an aggressive, deeply infiltrative growth pattern
o macroscopically: usually hard, stellate, gray-white, poorly defined masses
 less common variants:
o acinar cell carcinomas
o adenosquamos carcinomas
o undifferentiated carcinomas with osteoclast-like giant cells
 2 characteristic feature of pancreatic cancer:
o highly invasive
o elicits an intense non-neoplastic host reaction composed of fibroblasts, lymphocytes and extracellular
matrix (called a “desmoplactic response”)

CHAPTER 20
The Kidney

1. Autosomal Dominant ( Adult) Polycystic Kidney Disease

 Gross appearance:
- Usually bilaterally enlarged and can reach enormous size
- External surface composed solely of mass of cysts with no intervening parenchyma
 Histologic picture:
i. Functioning nephrons dispersed between cysts
ii. Cysts filled with clear, serous fluid or with turbid, red to brown, sometimes hemorrhagic fluid
 Enlarged cysts encroach on calyces and pelvis  pressure defects
 Cysts arise from tubules throughout nephron and have variable lining epithelia
 Papillary epithelial formations and polyps project into lumen
 Bowman’s capsule occasionally involved in cyst formation and glomerular tufts seen within cystic space

2. Autosomal Recessive (Childhood) Polycystic Kidney Disease

 Gross appearance:
- Enlarged kidneys with smooth external appearance
- Cut section: numerous small cysts in cortex and medulla (sponge-like)
- Dilated elongated channels at right angles to cortical surface, completely replacing medulla and
cortex
 Histologic picture:
- Cylindrical or saccular dilatation of all collecting tubules
- Uniform lining of cuboidal cells due to origin in collecting tubules
 Bilateral involvement
 Most cases : liver has cysts with portal fibrosis as well as proliferation of portal bile ducts

3. Nephronophthisis-Medullary Cystic Disease Complex

 Gross appearance:
- Small contracted granular surfaces
- Medullary cysts , most prominent at corticomedullary junction
- Small cysts also in cortex
 Histologic picture:
- Cysts lined by flattened or cuboidal epithelium and usually surroundd by inflammatory cells or fibrous
tissue
- Cortex shows widespread atrophy and thickening of BM of proximal and distal tubules with interstitial
fibrosis
- Some glomeruli hyalinized, but most of the glomerular structure is preserved

4. Acute Glomerulonephritis (HUMPS)

47
  Enlarged, hypercellular glomeruli
 Hypercellularity due to
- Diffuse infiltration by leukocytes (all lobules of all glomeruli)
- Proliferation of endothelial and mesangial cells with swelling
- Crescent formation
 Obliteration of capillary lumen, interstitial edema and inflammation
 Tubules contain red cell casts
 Immunofluorescence microscopy:
- Granular deposits of IgG, IgM, and C3 in mesangium and BM
 EM findings:
- Discrete, amorphous, electron-dense deposits  HUMPS
- HUMPS: on epithelial side representing antigen-antibody complexes
- Subendothelial and intramembranous deposits commonly seen
- Mesangial deposits present
- Swelling of endothelial and mesangial cells

5. Rapidly Progressive (Crescentic) Glomerulonephritis (CRESCENT)

 Gross appearance:
- Enlarged and pale kidneys with petechial hemorrhages on the cortical surfaces
- Glomeruli shows focal necrosis, diffuse or focal endothelial proliferation and mesangial proliferation
 Histologic picture:
- Dominated by crescents due to proliferation of parietal cells and migration of monocytes and
macrophages into the urinary space
- Neutrophils and lymphocytes present
- Crescents obliterate Bowman space and compress glomerular tuft
- Fibrin strands prominent between cellular layers in crescents
 EM findings:
- Ruptures in GBM, allowing leukocytes, proteins and inflammatory mediators into urinary space which
trigger the crescent formation
 Immunofluorescence microscopy:
- Postinfectious cases exhibit granular immune deposits
- Goodpasture syndrome cases show linear fluorescence for immunoglobulin

6. Membranous Glomerulopathy/Membranous Nephropathy (SPIKES)

 Uniform, diffuse thickening of glomerular capillary wall
 Caused by irregular dense deposits between BM and overlying epithelial cells, with effaced foot processes
 Irregular spikes protruding from GBM via electron microscopy using silver stain
 Granular deposits with immunoglobulins and complement seen in immunofluorescence microscopy
 Advanced disease: membrane thickening progressively encroaches on capillary lumen, sclerosis of
mesangium
 Glomeruli may become totally sclerosed over time

7. Minimal Change Disease (FUSION FOOT PROCESS)

 Normal glomeruli by light microscopy
 EM findings:
- BM appears normal
- No electron dense material deposited
- Lesion in visceral epithelial cells: uniform and diffuse effacement of foot processes/ “fusion” of foot
processes
 Diagnosis of MCD: Normal glomeruli by light microscopy + fusion of foot processes by EM
 Completely reversible viscerable epithelial changes after corticosteroid therapy
 Cells of proximal tubules with lipid and protein
 No immunoglobulin or complement in immunofluorescence

8. Focal Segmental Glomerulosclerosis (JUXTAMEDULLARY)

 Segmental lesions involve only minority of the glomeruli and may be missed if insufficient glomeruli in biopsy
 Involve juxtamedullary glomeruli
 Collapse of BM, increase in matrix, and segmental insudation of plasma proteins along capillary wall
 Lipid droplets and foam cells present

48
  Glomeruli can be normal or show increased mesangial matrix and mesangial proliferation
 EM findings:
- Sclerotic and nonsclerotic areas show diffuse effacement of foot processes and focal detachment of
epithelial cells with denudation of underlying GBM
 Immunofluorescence:
- IgM and C3 present in sclerotic areas and mesangium
- Focal sclerosis
- Hyalinosis and thickening of afferent arterioles
 In time can have total sclerosis of glomeruli with pronounced tubular atrophy and interstitial fibrosis
 Collapsing glomerulopathy
- Collapse and sclerosis of entire glomerular tuft in addition to usual FSGS lesions
- Most characteristic lesion in HIV_associated nephropathy
- Prominent tubular injury with formation of microcysts
- Poor prognosis

9. Membranoproliferative Glomerulonephritis (TRAM TRACK)

 Large glomeruli and hypercellular
 Hypercellular: produced by proliferation of cells in mesangium and so-called endocapillary cell proliferation
involving capillary endothelium and infiltrating leukocytes
 Parietal epithelial crescents commonly present
 Glomeruli have lobular appearance due to proliferating mesangial cells and increased mesangial matrix
 GBM thickened focally, most evident in peripheral capillary loops
 TRAM-TRACK appearance in silver or PAS stains (due to duplication of BM)
 TYPE I MPGN
- Common
- Subendothelial electron-dense deposists
- Mesangial and occasional subepithelial deposits
- Immunofluorescence: C3, IgG, early complement
 TYPE II MPGN
- Dense-deposit disease
- Rare
- Lamina densa of GBM becomes irregular, ribbon-like, extremely electron-dense structure because of
deposisiton of dense material
- Immunofluorescence: C3 present, no IgG

10. IgA Nephropathy/ Berger Disease (IgA)

 Glomeruli normal or have mesangial widening and proliferation, segmental proliferation confined to some
glomeruli or overt crescentic GN (rare)
 Immunofluorescence: mesangial deposition of IgA often with C3, no early complement components
 EM findings: electron dense deposists in mesangium

11.Alport Syndrome (BASKET WEAVE)

 Glomeruli always involved
 Early lesion detected only by EM: diffuse glomerular BM thinning
 Interstitial cells accumulate fat foam cells
 Development of focal segmental and global glomerulosclerosis , vascular sclerosis, tubular atrophy, and
interstitial fibrosis in later stages
 EM findings in fully developed disease:
- Irregular foci of thickening alternating with attenuation/thinning
- Pronounced splitting and lamination of the lamina densa BASKET WEAVE appearance

12. Chronic Glomerulonephritis

 Gross appearance:
- Symmetrically contracted
- Diffusely granular, cortical surfaces
- Section: cortex is thinned, increase in peripelvic fat
 Histologic picture:
- Depends on stage
- Early: primary disease or MPGN

49
 - Late stage: hyaline obliteration of glomeruli acellular eosinophilic masses
- Hyaline: combination of trapped plasma proteins, increased mesangial matrix, BM membrane like
material and collagen
- Arterial and arteriolar sclerosis conspicuous (because patients usually have HPN)
- Marked atrophy of associated tubules
 Dialysis changes:
- Arterial intimal thickening
- Extensive deposition of CaOx crystals
- Acquired cystic disease
 Uremic complications:
- Uremic pericarditis, gastroenteritis
- Secondary hyperparathyroidism with nephrocalcinosis
- Renal osteodystrophy
- Left ventricular hypertrophy

13.Henoch-Schonlein Purpura
 Deposition of IgA, sometimes with IgG and C3 in mesangial region
 Skin lesions: subepidermal hemorrhages and necrotizing vasculitis involving small vessels of dermis
14.Diabetic Glomerulosclerosis
 Capillary Basement Membrane Thickening
- Widespread thickening of GBM
- Thickening continues progressively and usually concurrently with mesangial widening
- Thickening of tubular BM
 Diffuse Mesangial Sclerosis
- Diffuse increase in mesangial matrix
- Mild proliferation of mesangial cells early in disease
 Nodular glomerulosclerosis
- Intercapillary glomerulosclerosis/ Kimmelstiel-Wilson disease
- Ovoid or spherical, often laminated,nodules of matrix situated in the periphery of glomerulus (PAS-
positivie)
- Within mesangial core of glomerula lobules and can be surrounded by patent peripheral capillary
loops or markedly dilated ones
- Mesangiolysis with fraying of mesangial lumen
- Disruption of sites at which capillaries anchored into mesangial stalks
- Resultant capillary microaneurysm formation
- Late stage: FIBRIN CAPS CAPSULAR DROPS

15. Acute Tubular Necrosis

 Ischemic ATN
- Focal tubular epithelial necorsis at multiple points along nephron with large skip areas in between
often accompanied by rupture of BM and occlusion of tubular lumen by casts
- Vulnerable areas: PCT (straight part), Ascending thick limb in renal mdulla, distal tubule (Focal
lesions
- Attenuation or loss of proximal tubule brush borders
- Simplification of cell structure
- Cell swelling and vacuolization
- Sloughing of non-necrotic tubular cells into tubular lumina
- Eosinophilic hyaline casts are common
- Contain Tamm-Horsfall protein
- Interstitial edema and accumulation of leukocytes within dilated vasa recta
- Evidence of epithelial regeneration
 Toxic ATN
- Acute tubular injury most obvious in PCT
- Distinctive in poisoning with certain agents (ex. Mercuric chloride, ethylene glycol)

16. Acute Pyelonephritis

 Patchy interstitial suppurative inflammation, intratubular aggregates of neutrophils, and tubular necrosis
 Complications:
i. Papillary necrosis : diabetics, urinary tract obstruction
- Usually bilateral but can unilateral
50
 - Cut section: tips or distal 2/3 of pyramids have areas of gray-white to yellow necrosis
- Histo: coagulative necrosis with preservation of outlines of tubules
ii. Pyonephrosis: total or complete obstruction in urinary tract
- Suppurative exudate unable to drain fills renal pelvis, calyces and ureter
iii. Perinephric abscess
- Extension of suppurative inflammation through renal capsule into perinephric tissue
 Pyelonephritic scar always associated with inflammation, fibrosis, and deformation of underlying calyx and
pelvis

17. Chronic Pyelonephritis and Reflux Nephropathy

 Gross appearance:
- Irregularly scarred kidneys
- If bilateral, involvement is asymmetric (vs. Chronic GN)
- Coarse, discrete, corticomedullary scar overlying dilated, blunted or deformed calyx
 Histologic picture:
- Tubules show atrophy in some areas and hypertrophy or dilation in others
- Thyroidization
- Active infection: neutrophils in interstitium and pus casts in tubules
- Arcuate and interlobular vessels demonstrate obliterative intimal sclerosis in scarred areas
- HPN: hyaline arteriosclerosis in ENTIRE kidney
- Fibrosis around calyceal epithelium

18. Acute Drug-Induced Interstitial Nephritis

 Abnormalities in interstitium
 Variable, frequently pronounced edema and infiltration by mononuclear cells (lymphos, macrophages)
 Eosinophils and neutrophils predominant
 Plasma cells and basophils smaller in numbers
 Methicillin, Thinazides: interstitial granulomas with giant cells
 Glomeruli normal except in NSAIDS (develop MCD and Nephrotic syndrome)

19. Analgesic Nephropathy

 Gross appearance:
- Kidneys normal or slightly smaller
- Cortex has depressed (cortical atrophy overlying necrotic papillae) and raised areas
 Histologic picture:
- Early stage: patchy necrosis
- Advanced stage: entire papilla necrotic

20. Multiple Myeloma

 Bence Jones tubular casts present as pink to blue amorphous masses, sometimes concentrically laminated,
often with fractured appearance, filling and distending tubular lumen
 Some casts surrounded by multinucleate giant cells
 Adjacent interstitial tissue shows nonspecific inflammatory response and fibrosis
21. Benign Nephrosclerosis
 Gross appearance:
- Normal or moderately reduced
- Cortical surface have a fine evenly granular texture
- Loss of mass due to cortical scarring and shrinking
 Histologic picture:
- Narrowing of lumen of arterioles and small arteries caused by thickening and hyalinization of wall
- Medial hypertrophy, reduplication of elastic lamina and increased myofibroblastic tissue in intima, with
consequent narrowing of lumen (fibroelastic hyperplasia)
- Patchy ischemic atrophy
i. Foci of tubular atrophy and intersititial fibrosis
ii. Variety of glomerula alterations

22. Malignant Hypertension and Accelerated Nephrosclerosis

 Gross appearance:
- Size depends on duration and severity of hypertensive disase
- Small, pinpoint, petechial hemorrhages
51
  Fibrinoid necrosis of arterioles
- Eosinophilic granular change in the blood vessel wall
- Acute event
- Not accompanied by prominent inflammation
 Onion-skinning
- Intimal thickening caused by proliferation of elongated, concentrically arranged SMC

23. Renal Artery Stenosis

 Most common cause: occlusion by an atheromatous plaque at origin of renal artery
 More frequent in men
 Incidence increases with advancing age and DM
 Plaque concentric and superimposed thrombosis
 Fibromuscular dysplasia of renal artery leads to stenosis
 Ischemic kidney:
- Reduced in size
- Signs of diffuse ischemic atrophy
- Crowded glomeruli
- Atrophic tubules
- Interstitial fibrosis and focal inflammatory infiltrates
- Arterioles in ischemic kidney protected from effects of high BP

24. Classic (Childhood) Hemolytic-Uremic Syndrome

 Gross appearance:
- Patchy or diffuse renal cortical necrosis
 Histologic Picture:
- Glomeruli shjow thickening and splitting of capillary walls due to endothelial and subendothelial
swelling and deposits of fibrin related material in capillary lumen, subendothelially, and in mesangium
- Mesangiolysis common
- Fibrinoid necrosis and intimal hyperplasia

25. Diffuse Cortical Necrosis

 Limited to CORTEX
 Histologic picture:
- Acute ischemic infarction
- Patchy lesions, with coagulative necrosis and better preserved cortex
- Intravascular and inrtaglomerular thromboses prominent but are usually focal
- Hemorrhages present in glomeruli

26.Renal Infarcts
 Mostly of “white” anemic type
 Solitary or multiple or bilateral
 Within 24 hrs: become sharply demarcated, pale, yellow-white areas that may contain small irregular foci of
hemorrhage discoloration
 Ringed by a zone of intense hyperemia
 Cut section:
- Wedge-shaped infarcts with base against cortical surface and apex pointing toward medulla
- Narrow rim of preserved subcortical tissue spared by collateral capsular circulation
- Undergo progressive fibrous scarring giving rise to depressed pale, gray-white scars (V-shaped)

27. Obstructive Uropathy

 Sudden, complete obstruction: mild dilation of pelvis and calyces but sometimes atrophy of renal parenchyma
 Subtotal/ intermittent obstruction: glomerular filtration not suppressed, progressive dilation ensues
 Gross appeareance:
- Slight to massive enlargement
- Acute phase: Simple dilation of pelvis and calyces
- Chronic pahse: cortical tubular atrophy with marked diffuse interstitial fibrosis
- Progressive blunting of apices of pyramids
-
28. Urolithiasis

52
  Unilateral
 Favored sites:
- Renal calyces
- Renal pelvis
- Bladder
 Smooth contours
 Irregular, jagged mass of spicules

29. Renal Papillary Adenoma

 Small tumors < 5mm
 Gross appearance:
- Pale-yellow to gray, discrete, well-circumscribed nodules
 Histologic picture:
- Composed of complex branching, papillomatous structures with numerous complex fronds
- Cells may grow as tubules, glands, cords, and sheets of cells
- Cells cuboidal to polygonal in shape
- Regular small central nuclei, scanty cytoplasm, no atypia

30. Renal Cell Carcinoma

 Gross appearance:
- Spherical masses, variable in size
- Bright yellow-gray to white tissue that distorts renal outline
- Yellow: lipid accumulation
- Gray-white: necrosis
- Sharply defined margins and confined within renal capsule
 Papillary tumors:
- Arise from DCT
- Hemorrhagic and cystic
- Most common type of renal cancer in patient with dialysis-associated cystic disease
 Can invade renal vein and grow as solid column in vessel can extend into IVC and R side of heart
 Clear cell carcinoma
- Growth pattern: variable
- Rounded or polygonal tumor cells with abundant clear or granulated plasm
- Delicate, branching vasculature
- Cystic or solid
- Well differentiated
 Papillary carcinoma
- Cuboidal or low columnar cells arranged in papillary formation
- With interstitial foam cells in core
- Psammoma bodies may be present
- Scanty stroma, highly vascularized
 Chromophobe renal carcinoma
- Pale, eosinophilic cells, with perinuclear halo
- Arranged in solid sheets with concentration of largest cells around blood vessels
 Collecting duct carcinoma
- Rare variant
- Irregular channels lined by highly atypical epithelium w/ hobnail pattern

CHAPTER 21
Lower Unirinary Tract Infection and Male Genital System

CHAPTER 22
Female Genital Tract

Box 1: 2-7 days after inoculation, gonococcal disease is characterized by an acute suppurative reaction with
inflammation largely confined to the superficial mucosa and underlying submucosa.
These Gram negative diplococci need culture for absolute confirmation. If spread occurs, the endometrium is
usually spared. Once inside the tubes, an acute suppurative salphingitis ensues. Involved are tubal serosa (hyperemic,
fibrillar), tubular fimbriae and lumen (filled with purulent exudate). In days or wks, fimbriae may seal or become plastered
53
against the ovary to create a salphingo-oophoritis. Collection of pus within ovary and tube (tubulo-ovarian abscesses) or
tubal lumen (pyosalpinx) may occur. The pus eventually undergo proteolysis to a thin, serous fluid to produce a
hydrosalphinx

VULVA
Box 2: HPV-associated squamous cell CA begin as classic VIN lesions (discrete, flesh-colored or pigmented,
slightly raised). Carcinomas associated with lichen sclerosus, lichen simplex chronicus and differentiated VIN may
develop quickly as nodules in a bachground of vulvar inflammation. Clinical manifestations are often non-specific (local
discomfort, itching, and exudation). On histologic exam, tumors associated with HPV or VIN frequently exhibit invasive
growth patterns that mimic intraepithelial neoplasia.

Box 3: The diagnostic microscopic feature of this lesion is the presence of large tumor cells lying singly or in
small clusters within the epidermis and its appendages, distinguished by a clear separation (halo) from surrounding
epithelial cells and a finely granular cytoplasm with mucopolysaccharide that stains with Periodic Acid Schiff, Alcian blue
or mucicarmine. Paget cells display aprocrine, eccrine and keratinocyte differentiation.

VAGINA
Box 4: Vaginal Intraepithelial Neoplasia and squamous cell carcinoma. Most often the tumor affects the
upper posterior vagina at junction with endocervix. From a focus of epithelial lining, it progresses to a plaquelike mass
extending centrifugally and invades the cervix and perivaginal structures. Lower lesion metastasize to inguinal nodes
while upper ones involve iliac nodes.

Box 5: Adenocarcinoma. Tumors are most often on the anterior wall, upper third, 0.2 to 2 cm in diameter. It is
composed of vacuolated, glycogen-containing cells. A probably precursor is vaginal adenosis which presents clinically as
red, granular foci contrasting with the normal pale pink, opaque vaginal mucosa. On microscopy, the granular epithelium
may be either mucus secreting, resembling endocervical mucosa (tubuloendometrial) often containing cilia.

Box 6. the pathologic correlates of acute and chronic cervicitis include epithelial spongiosis, submucosal edema
and epithelial and stromal changes. Acute – acute inflammatory cells, erosion and reactive epithelial changes. Chronic –
inflammation, mononuclear usually, lymphocytic, w/ macrophages and plasma cells. HSV associated with epithelial ulcers,
C. Trachomatis and plasmacytic infiltrate. Epithelial spongosis is associated with T. Vaginalis infection.

Box 6. See Figures 22-19 and 22-20 p. 1075

Box 7. Morphology Invasive cervical carcinoma. Fungating, ulcerating, and infiltrative. Stage 0. in situ
1. confined to cervix
2. beyond cervix not onto pelvic wall, involves vagina not lower third.
3. Carcinoma extended into pelvic wall, involves vagina lower third
4. beyond true pelvis and involved mucosa of bladder or rectum

Endometrial Hyperplasia.

Simple: cystic/mild. With architechtural changes in glands; frequently evolve to atrophy

Complex atypical hyperplasia: increase in number and size of endometrial glands, complexity of lining epithelium w/
scalloped/tufted surface. Glands remain distinct and non-confluent. With mitotic figures.
A shift in gland morphology from benign to precancerous is often highlighted by a loss of PTEN gene expression.

Endometrial Carcinoma. Localized polypoid tumor or as a diffuse tumor. Dissemination to regional lymph nodes
eventually occur. Microscopically with well defined patterns from grade 1-3 see figure 22-32A.

Stromal Nodule is a well circumscribed aggregate of endometrial stromal cells in the myometrium that doesn’t
penetrate myometrium.

Stromal Sarcoma. Of neoplastic bundles of the myometrium and is distinguished from nodules by either diffuse
infiltration of myometrial tissue of penetration of lymphatic channels.

Leiomyomas. Sharply circumscribed, discrete, round, firm, gray-white tumors varying in size from small, barely
visible nodules to massive tumors that fill the pelvis. Characteristic whorled pattern of smooth muscle bundles on cut
section makes them readily identifiable on gross inspection. Large tumors develop areas of yellow-brown to red softening
(red degeneration)
Variants include benign metastasizing leiomyomas and disseminated peritoneal leiomyomatosis.
54
 Follicular Luteal Cysts. Multiple, filled with serous fluid, lined by gray, glistening membrane.

Serous Tumors. either cystic lesion where papillary epitherlium is contained within a few fibrous walled cysts or
projecting from the ovarian surface. See Figure 22-39

Mucinous Tumors. more cysts of variable size and a rarity of surface involvement. Less frequently bilateral; tend
to produce larger cystic masses and some have been recorded with weights of >25 kg. Benign ones are characterized by
lining of tall columnar epithelium with apical mucin and no cilia.

Brenner Tumor. Solid to cystic; usually unilateral and vary in size from small lesions less than 1 cm to massive
20 to 30 cm ones. With fibrous stroma marked by sharply demarcated nests.

Teratomas. Unilocular cysts with hair and cheesy sebaceous material (Fig. 22-48)

Immature Malignant tumors. bulky with external surface; predominantly solid structure; With areas of necrosis
and hemorrhage; Varying amounts of immature tissue.

Dysgerminoma. Yellow-white to gray-pink appearance and often soft and fleshy.

Granulosa Thecal cell tumor. See fig 22-53.

CHAPTER 23
The Breast

FEMALE BREAST

I. INFLAMMATIONS

A. Acute Mastitis
- Staphylococcal Infections  cause localized area of acute inflammation; may progress to form sinlge or
multiple abscesses
- Streptococcal Infections  cause diffuse spreading infection; eventually involves entire breast, usually
necrotic and infiltrated by neutrophils

B. Periductal Mastitis
- Main Histological Feature: KERATINIZING SQUAMOUS EPITHELIUM WITH ABNORMAL DEPTH INTO
ORIFICES OF NIPPLE DUCTS
- Keratin in ductal system  causes dilation and rupture of duct
- Keratin spilled in periductal tissue  causes intense chronic and granulomatous inflammatory response
- Secondary infection with skin bacteria + anaerobes  causes acute inflammation

C. Mammary Duct Ectasia

- characterized by:
1. dilation of ducts
(dilated ducts filled with granular debris containing mainly LIPID-LADEN MACROPHAGES)
2. inspissation of breast secretions
3. marked periductal and interstitial granulomatous inflammatory reaction
(periductal and interductal inflammation manifested by heavy infiltration of lymphocytes and macrophages,
WITH striking PREDOMINANCE of PLASMA CELLS in some cases)
- + SKIN and NIPPLE retraction due to fibrosis
- Granulomatous inflammation form around cholesterol deposits
- Squamous metaplasia NOT a feature of this disorder

D. Fat Necrosis
GROSS APPEARANCE
- Early Stages: Hemorrhage
- Later: Central liquefactive Necrosis of Fat
- Still Later  : Ill-defined nodule of gray-white firm tissue with small foci of chalky white or hemorrhagic debris
- At first central focus of necrotic fat surrounded

55
 MACROPHAGES + NEUTROPHILS, then next few
days 
 Progressive Fibroblastic proliferation
 Increased vascularization
 Lymphocytic and histiocytic infiltration
 ALL wall off the focus
- Then Foreign body, giant cells, calcification and hemosderin appear
- Then focus is replaced by scar tissue
- OR may be encysted and walled off by collagenous tissue

E. Nonproliferative Breast changes (Fibrocystic changes)

THREE PRINCIPAL PATTERNS:
1. CYSTS
- small cysts  when lobules dilate and unfold
- large cysts  cystic lobules coalesce
- unopened cysts  or blue-dome cysts contain semitranslucent turbid fluid.
- LINING of cysts: flattened atrophic epithelium or cells altered by apocrine metaplasia (Metaplastic cells have
abundant granular cytoplasm, eosinophilic cytoplasm, round nuclei a in aprocrine epithelium of sweat glands)
- May have Papillary projections and calcifications
- MILK OF CALCIUM  in radiology describes calcifications in LARGE CYSTS that look as if they are lining the
bottom of a rounded cyst on mammography

2. FIBROSIS
- cysts rupture often  release secretory material into adjacent stroma  cause chronic inflammation and fibrous
scarring
- CLINICAL MANIFESTATION: palpable firmness of breast

3. ADENOSIS
- increase in number of acini per lobule
- also occurs among PREGNANT WOMEN PHYSIOLOGIC (NORMAL)
- May occur as focal change in NONPREGNANT WOMEN
- BLUNT DUCT ADENOSIS: acini enlarged and not distorted
- SCLEROSING ADENOSIS: acini distorted
- Calcification occasionally present within lumen

LACTATIONAL ADENOMAS
- CLINICAL M: palpable mass in pregnant or lactating women
- Formed by normal appearing breast tissue with physiologic adenosis and epithelial lactational changes
- NOT TRUE NEOPLASMS but EXAGGERATED FOCAL RESPONSE to hormonal influences
-
F. Proliferative Breast Disease Without Atypia

1. Epithelial Hyperplasia
- NORMAL HISTO: above basement membrane are myoepithelial cells and SINGLE layer luminal cells
- ABNORMAL: MORE THAN TWO CELL LAYERs above basement membrane
- MODERATE TO FLORID EPITH HYPERPLASIA: if more than 4 cells layers
- Proliferating myoepithelial and luminal cells fill and distend ducts and lobules
- FENESTRATIONS/IRREGULAR LUMENS – may be discerned at periphery of cellular mass

2. Sclerosis Adenosis
- number of acini per terminal duct is increased to at least twice the number found in uninvolved lobules  thus
acini COMPRESSED and DISTORTED in CENTRAL part of lesion but DILATED at the PERIPHERY
- normal lobular arrangement is maintained
- Prominent myoepithelial cells
- SIMILARITY WITH INVASIVE CARCINOMA: occasionally, stromal fibrosis completely compresses lumens to
create appearance of solid cords or double strands of cells lysing within dense stroma
- FREQUENT FINDING: calcifications within lumen of acini

3. Complex Sclerosing Lesion (Radial Scar)

56
 - are STELLATE lesions characterized by central nidus of entrapped glands in a hyalinized stroma
- resemble IRREGULAR INVASIVE CARCINOMA mammographically or grossly
- “SCAR” refers to MORPHOLOGIC APPEARANCE since these are NOT associated with prior trauma or injury
- “COMPLEX SCLEROSING LESION”: so named since it includes NOT ONLY radial scars but ALSO related
lesions with components of:
 Sclerosing adenosis
 Papilloma formation
 Epithelial hyperplasia

4. Papillomas
- composed of MULTIPLE BRANCHING FIBROVASCULAR CORES each with CONNECTIVE TISSUE AXIS with
LUMINAL and MYOEPITHELIAL CELLS
- Growth occurs within a dilated duct
- Frequently has:
 Epithelial hyperplasia
 Apocrine metaplasia
- LARGE DUCT PAPILLOMAS:
Are usually SOLITARY
Located in lactiferous sinuses of nipple
Unsure if this increases risk for development of carcinomas
- SMALL DUCT PAPILLOMA:
Are usually MULTIPLE
Located DEEPER in ductal system
A component of Proliferative breast
disease and increases risk for subsequent
carcinomas

G. Proliferative Breast Disease With Atypia

Atypical Hyperplasia (General)

- cellular proliferation resembling ductal carcinoma in situ (DCIS) or lobular carcinoma in situ (LCIS) BUT
- LACKS sufficicent qualitative and quantitative features for a diagnostic carcinoma in situ
- Has two types described below:

1. Atypical DUCTAL Hyperplasia (ADH)

- SIMILARITY with DCIS:
 Monomorphic cell population
 Regular cell placement
 Round lumina
- DIFFERENCE WITH DCIS:
 Lesion characteristically limited in extent
 Cells NOT COMPLETELY monomorphic in type OR
 They FAIL TO COMPLETELY fill ductal spaces

2. Atypical LOBULAR HYPERPLASIA (ALH)

- proliferation of cells identical to LCIS but cells DO NOT fill or distend more than 50% of acini within a lobule
- can also extend into ducts and this is associated with increased risk of developing invasive carcinomas

II. BREAST CARCINOMAS

A. In Situ Carcinomas
i. Ductal Carcinoma In Situ (DCIS) or Intraductal Carcinoma
- divided into 5 ARCHITECTURAL SUBtypes:
1. Comedocarcinoma
- characterized by solid sheets of pleomorphic cells with high-grade nuclei and central necrosis
- MAMMOGRAPHIC FINDINGS: detected as clusters or linear and branching calcifications (necrotic cell
membranes calcify)
- Common features:
 Periductal concentric fibrosis

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  Chronic inflammation
 Extensive lesions sometimes palpable as area of vague nodularity

Noncomedo DCIS
- consist of monomorphic population of cells with nuclear grades ranging from low to high
- includes the remaining 4 architectural subtypes described below: Solid, Cribriform Papillary and Micropapillary
DCIS
- NOTE: CALCIFICATIONS may be associated with central necrosis but more commonly form in intraluminal
secretions

2. Solid
- completely fills involved spaces

3. Cribriform
- “COOKIE CUTTER-LIKE” because
Intraepithelial cells are evenly distributed and regular in shape

4. Papillary
- grows into spaces and lines fibrovascular cores typically lacking the normal myoepithelial cell layer

5. Micropapillary
- BULBOUS PROTRUSIONS without a fibrovascular core often forming complex intraductal patterns

Paget Disease of the Nipple

- a RARE manifestation of breast cancer (1-2% of cases)
- presents as UNITLATERAL ERYTHEMATOUS ERUPTION with a SCALE CRUST
- PATHOPHYSIO:

Malignant cells or Paget cells extend from DCIS within ductal system into nipple skin without crossing basement
membrane.

Tumor cells disrupt normal epithelial barrier, allowing extracellular fluid to seep out onto nipple surface.

Paget cells easily detected by NIPPLE BIOPSY or cytologoc preparations of exudates.

Carcinomas are usually poorly differentiated and overexpress HER2/neu

Production of heregulin-α (which acts via HER/neu receptor) may be involved in the pathogenesis of the disease

- CLINICAL MANIFESTATIONS:
 Pruritis (common)
 Lesion may be mistaken for eczema
 Palpable mass present in 50-60% of women with Paget disease, almost all of whom have underlying invasic
carcinoma
 Fewer than half of women WITHOUT Palpable Mass will have invasive carcinoma
- PROGNOSIS: depends on
 Extent of underlying carcinoma
 Not affected by presence or absence of DCIS involving skin when matched for age, tumor size, grade,
HER2/neu status and nodal status.

DCIS with microinvasion

- defined by foci of tumor cells < 0.1cm in diameter invading stroma

- most commonly seen in association with COMEDOCARCINOMA

ii. Lobular In Situ Carcinoma (LCIS)

- HISTOPATH: consists of small cells that have oval or round nuclei with small nucleoli that do not adhere to one
another
- seen in LCIS, Atypical Lobular Hyperplasia (ALH) and Invasive Lobular carcinoma
- Presence of signet-ring cells with mucin are common
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 - Rarely distorts underlying architecture
- Involved acini remain recognizable as lobules
- Almost always expresses estrogen and progesterone receptors
- Overexpression of HER2/neu NOT observed

B. Invasive Carcinomas

- most carcinomas firm to hard and have irregular border

- small pinpoint foci or streaks of chalky white elastotic stroma at center of carcinoma
- occasionally small foci of calcification
- characteristic GRATING sound (like cutting a water chestnut) when cut or scraped
- less frequent finding: carcinoma having well-circumscribed border and may be soft to firm in consistency
- [1] Well differentiated tumors have tubules lined by minimally atypical cells and can occasionally be difficult to
distinguish from benign sclerosing lesions; more likely to express hormone receptors but not overexpress
HER2/neu
- [2] Others are composed of anastomosing sheets of pleomorphic cells; more likely to overexpress HER2/neu
- Other types fall in between the two
- Most carcinomas induce marked increase in dense, fibrous desmoplastic stroma, giving tumor a hard
consistency on palpation and replace fat, resulting in mammographic density (SCIRRHOUS CARCINOMA)

i. No Special Type
- accompanied by varying amount of DCIS, the grade of which correlates with grade of invasive carcinoma
- Example:

Comedo DCIS usually associated with poorly differentiated carcinomas

Low-grade DCIS  associated with well-differentiated carcinomas

- Carcinomas with large amount of DCIS require large excisions with wide margins to reduce local occurrences

ii. Invasive Lobular Carcinoma

- GROSS: most tumors firm to hard with irregular margin
- Tissue may occasionally feel diffusely thickened; a discrete tumor mass cannot be defined
- Histological Hallmark:

SINGLE INFILTRATING TUMOR CELLS, often only one cell width (in form or single file) or in loose clusters or
sheets

Desmoplastic response minimal or absent

Cells have same cytological features as LCIS, lack cohesion without formation of tubules or papillae

Signet-ring cells common

Tumor cells frequently arranged in concentric rings surrounding normal ducts

Variants  tumors with large nests of cells and high degree of pleomorphism

iii. MEdullary Carcinoma

- DO NOT HAVE striking desmoplasia; thus MORE YIELDING on external palpation and on cut section
- TUMOR  has soft, fleshy consistency ( “medulla” Latin for marrow); well-circumscribed
- Characterized by:
 solid syncytium-like sheets (occupying > 75% of tumor)
 pleomorphic nuclei with PROMINENT NUCLEOLI and frequent mitoses
 MODERATE to MARKED lymphoplasmacytic infiltrate surrounding and within tumor
 Pushing (noninfiltrative) border
- ALL medullary carcinomas POORLY DIFFERENTIATED
- DCIS is MINIMAl or ABSENT

59
 - NO lymphatic or vascular invasion

iv. Mucinous or Colloid Carcinoma

- tumor EXTREMELY SOFT
- has consistency and appearance of PALE GRAY-BLUE GELATIN
- Tumor cells seen as CLUSTERS and small islands of cells within large lake of mucin that push into adjacent
stroma

v. Tubular Carcinoma
- consists exclusively of WELL-FORMED TUBULES
- sometimes mistaken for BENIGN SCLEROSING LESIONS
- NO myoepithelial cell layer
- Tumor cells in direct contact with stroma
- Cribriform spaces may be present
- APOCRINE SNOUT typical
- CALCIFICATIONS may be present within lumen
- LCIS frequent present, though this association has not been explained
-
III. STROMAL TUMORS

A. Fibroadenoma
- GROSS:
 Well-circumscribed tumors
 rubbery
 grayish white nodules bulging above surrounding tissue
 often with slitlike spaces
- grow as spherical nodules usually SHARPLY CIRCUMSCRIBED and FREELY MOVABLE in surrounding breast
substance
- vary in size from <1cm in diameter to large tumors that can REPLACE most of the breast
- Stroma usually delicate, cellular, often myxoid, resembling intralobular stroma, enclosing glandular and cystic
spcaces lined by epithelium
- Epithelium may be surrounded by STROMA or COMPRESSED or DISTORTED by it
- OLDER WOMEN  stroma typically becomes DENSELY HYALINIZED and epithelium atrophic.

B. Phyllodes Tumor
- tumors vary in size: FEW centimeters  massive lesions involving ENTIRE BREAST (lesions often with
BULBOUS PROTRUSION or “phyllodes” in Greek which means leaflike since it involves the presence of nodules
of proliferating stroma covered by epithelium)
- some phyllodes extend into cystic spaces; also occasionally seen in larger fibroadenomas; NOT an indication of
malignancy
- distinguished from the more common cellular fibroadenoma by:
 cellularity
 mitotic rate
 nuclear pleomorphism
 stromal overgrowth
 infiltrative borders
- Lowgrade lesions  resemble fibroadenomas but WITH increased cellular and mitotic figures
- High Grade Lesions  hard to distinguish from other types of soft tissue sarcoma; may have foci of
mesenchymal differentiation (RHABDOMYOSARCOMA or LIPOSARCOMA)
- Tumors not uncommonly recur with higher grade

C. Sarcoma

MALE BREAST

Gynecomastia

- proliferation of dense collagenous connective tissue

- Marked micropapillary hyperplasia of ductal linings
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 - Individual cells fairly regular, columnar to cuboidal with regular nuclei
- Lobule formation RARE

CHAPTER 24
The Endocrine System

1. Pituitary Adenomas and Hyperpituitarism

 Common Pituitary Adenoma
- soft, well-circumscribed,
- larger ones compress optic chiasm and other adjacent structures
- *invasive adenoma
– up to 30% of cases
– not grossly encapsulated;
– do not demonstrate the ability for distant metastasis
– foci of hemorrhage and necrosis common (larger adenomas)
- histologically:
- relatively uniform, polygonal cells in sheets or cords
- reticulin is sparse – soft,gelatinous consistency of many of the lesions
- nuclei of neoplastic cells may be uniform or pleomorphic
- modest mitotic activity
- acidophilic, basophilic, or chromophobic cytoplasm depending on the type and amount of secretory product
within the cells but is generally uniform throughout the cytoplasm
- the cellular monomorphism and the absence of a significant reticulin network distinguish pituitary adenomas
from non-neoplastic anterior pituitary parenchyma
2. Hypothalamic Suprasellar Tumors
 Craniopharyngiomas
- ave diameter: 3-4cm
- may be encapsulated and solid
- more common: cystic,sometimes multiloculated
- 2 distinct pathologic variants:
a.Adamantinomatous craniopharyngioma
- frequently contains radiologically demonstrable dystrophic calcifications
- nests or cords of stratified squamous epithelium embedded in a spongy “reticulum” – becomes more
prominent in internal layers
- peripherally: palisade resting on basement membrane
- “wet keratin”– diagnostic feature
- Additional features: cyst formation (often contain “machinery oil” cholesterol-rich thick brownish yellow
fluid), fibrosis, chronic inflammatory reaction
- Extend fingerlets of epithelium into adjacent brain, where they elicit a brisk glial reaction
b.Papillary Craniopharyngioma
- rarely calcified
- solid sheets and papillae lined by well-differentiated squamous epithelium
- usually lack keratin, calcification, and cysts
- squamous cells of solid sections of the tumor do not have the peripheral palisading
- do not typically generate a spongy reticulum in the internal layers
3. Hashimoto Thyroiditis
- often diffusely enlarged
- intact capsule
- gland is well demarcated from adjacent structures
- cut surface is pale, yellow-tan, firm and somewhat nodular
- extensive infiltration of parenchyma - mononuclear inflammatory infiltrate containing small lymphocytes, plasma
cells, and well-developed germinal centers
- atrophic thyroid follicles lined in many areas by Hürthle cells - its presence in conjunction with a heterogenous
population of lymphocytes in fine-needle aspiration biopsies is characteristic of Hashimoto thyroiditis
- in “classic” Hashimoto thyroiditis, interstitial connective tissue is increased and may be abundant
- fibrous variant: severe thyroid follicular atrophy and dense “keloid-like” fibrosis, with broad bands of acellular
collagen encompassing residual thyroid tissue; fibrosis does not extend beyond the capsule of the gland
- remnant thyroid parenchyma demonstrates features of chronic lymphocytic thyroiditis
4. Subacute (Granulomatous) Thyroiditis
- may be unilaterally or bilaterally enlarged and firm with intact capsule
- may be slightly adherent to surrounding structures
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 - cut section: involved areas firm and yellow-white and stand out from the more rubbery, normal brown thyroid
substance
- histologically:
- changes are patchy and depend on stage of disease
- early active inflammatory phase: scattered follicles may be entirely disrupted and replaced by neutrophils
forming microabscesses
- later the more characteristic features appear in the form of aggregations of lymphocytes, histiocytes, and
plasma cells about collapsed and damaged thyroid follicles
- multinucleate giant cells enclose naked pools or fragments of colloid
- later stages” chronic inflammatory infiltrate and fibrosis may replace the foci of injury
- waves of destruction over a period of time – different histologic stages found in the same gland
5. Subacute Lymphocytic (Painless) Thyroiditis
- appears normal on gross inspection except for possible mild symmetric enlargement
- lymphocytic infiltration with hyperplastic germinal centers within the thyroid parenchyma
- patch disruption
- collapse of thyroid follicles
- fibrosis and Hürthle cell metaplasia not commonly seen
6. Graves Disease
- symmetrically enlarged thyroid: diffuse hypertrophy and hyperplasia of thyroid follicular epithelial cells
- not uncommon: increases in weight to over 80 g
- usually smooth and soft with capsule intact
- cut section: soft and meaty parenchyma resembling normal muscles
- histologically:
- dominant: too many cells –often resulting in the formation of small papillae
- pale colloid with scalloped margins within follicular lumen
- lymphoid infliltrates (predominantly T cells, fewer B cells and mature plasma cells) present throughout
interstitium
- germinal centers common
- preoperative therapy: alters morphology of thyroid
- preoperative administration of iodine: causes involution of epithelium and accumulation of colloid by blocking
thyroglobulin secretion
- treatment with propylthiouracil (antithyroid drug) exaggerates epithelial hypertrophy and hyperplasia by
stimulating TSH secretion
- in pre-treated patients: impossible from histological examination of surgical specimens to evaluate the functional
activity of the gland
- changes in extrathyroidal tissue:
- generalized lymphoid hyperplasia
- hypertrophied heart
- ischemic changes particularly in patients with preexisting coronary artery disease
- patients with ophthalmopathy:
- edematous tissues of the orbit due to the presence of hydrophilic mucopolysaccharides
- infiltration of lymphocytes and fibrosis
- orbital muscles initially edematous but may undergo fibrosis late in the course of the disease
- dermopathy, if present: thickening of dermis due to deposition of glycosaminoglycans and lymphocyte infiltration
7. Diffuse Nontoxic (Simple) Goiter
- 2 phases:
a. hyperplastic phase
- diffusely and symmetrically enlarged thyroid with only moderate increase (rarely exceeding 100-150g)
- follicles lined by crowded columnar cells (may pile up and form projections similar to those seen in Graves
disease)
- accumulation dissimilar throughout gland: some follicles hugely distended, others remaining small
b. colloid involution
- stimulated follicular epithelium involutes to form an enlarged, colloid-rich gland if dietary iodine subsequently
increases or if demand for thyroid hormone decrease
- cut surface: usually brown, somewhat glassy, translucent
- histologically: flattened and cuboidal follicular epithelium, abundant colloid during periods of involution
8. Multinodular Goiter
- multilobulated
- asymmetrically enlarged
- can achieve a weight of more than 2000 g
- unpredictable pattern of enlargement
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 - may involve one lobe far more than the other – produce lateral pressure on midline structures (trachea and
esophagus)
- may grow behind sternum and clavicles: intrathoracic or plunging goiter
- occasionally,most of it hidden behind the trachea and esophagus, other instances: one nodule may so stand out
as to impart the clinical appearance of a solitary nodule
- cut section: irregular nodules containing variable amounts of brown, gelatinous colloid
- regressive changes frequently, particularly in older lesions, include areas of hemorrhage, fibrosis, calcification,
cystic change
- microscopic appearance: colloid-rich follicles lined by flattened, inactive epithelium and areas of follicular epithelial
hypertrophy and hyperplasia, accompanied by degenerative changes
9. Thyroid Adenomas
- solitary, spherical, encapsulated, well demarcated from the surrounding thyroid parenchyma
- microscopically:
- constituent cells often form uniform-appearing follicles that contain colloid
- follicular adenomas: average about 3 cm in diameter, up to 10 cm in diameter
- freshly resected: bulges from the cut surface and compresses the adjacent thyroid
- color: gray-white to red-brown depending on cellularity of adenoma and its colloid content
- areas of hemorrhage, fibrosis, calcification, cystic change are common particularly within larger lesions
- neoplastic cells: demarcated from the adjacent parenchyma by a well-defined, intact capsule; occasionally
acquire brightly eosinophilic granular cytoplasm (oxyphil or Hürthle cell change)
- follicular growth pattern within the adenoma is usually quite distinct from the adjacent non-neoplastic thyroid
- epithelial cells reveal little variation in cell and nuclear morphology
- mitotic figures are rare
- extensive mitotic activity warrants careful examination of the capsule to exclude follicular carcinoma
- papillary change is not a typical feature and if extensive, should raise the suspicion of an encapsulated
papillary carcinoma
- Hürthle cell adenoma (follicular adenoma with oxyphilia) – clinical presentation and behavior is no different
from that of a conventional adenoma
- Other variants: clear cell follicular adenoma - extensive clear cell change of the cytoplasm; signet-ring cell
follicular adenoma – adenomas with “signet-ring” features
- Similar to endocrine tumors at other anatomic sites, even benign follicular adenomas may, on occasion,
exhibit focal nuclear pleomorphism, atypia, and prominent nucleoli (endocrine atypia) but by itself does not
constitute a feature of malignancy
- Infrequently can demonstrate increased cellularity, more extensive variation in cellular size and nuclear
morphology, and even mitotic activity; warrant careful examination of the tumor capsule to exclude capsular
and/or vascular invasion – atypical follicular adenomas
- Hallmark: the presence of an intact, well-formed capsule encircling the tumor. Careful evaluation of the
integrity of the capsule is therefore critical in distinguishing follicular adenomas from follicular carcinomas,
which demonstrate capsular and/or vascular invasion
- multinodular goiters
– contain multiple nodules on cut surface (even though the patient may present clinically with a solitary
dominant module)
– produce less compression of adjacent thyroid parenchyma, lack a well-formed capsule
– Areas of hemorrhage, fibrosis, calcification, cystic change
– Nodular and uninvolved thyroid parenchyma may have similar growth patterns
10. Papillary Carcinoma
- solitary or multifocal lesions; some tumors may be well-circumscribed and even encapsulated; others may
infiltrate the adjacent parenchyma with ill-defined margins
- lesions may contain areas of fibrosis and calcification and are often cystic
- on cut surface lesions may appear granular and may sometimes contain grossly discernible papillary foci
- definitive diagnosis can be made only after microscopic examination
- characteristic landmarks:
- can contain branching papillae
– fibrovascular stalk covered by a single to multiple layers of cuboidal epithelial cells
– in most neoplasms, covering epithelium consists of well-differentiated, uniform, orderly, cuboidal cells, but
at the other extreme are those with fairly anaplastic epithelium showing considerable variation in cell
and nuclear morphology
– when present, papillae differ from those seen in areas of hyperplasia
– neoplastic papillae are more complex and have dense fibrovascular cores in contrast to hyperplastic
papillary lesions
- ground glass or Orphan Annie eye nuclei
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 - finely dispersed chromatin in nuclei of cells imparting an optically clear or empty appearance giving rise to
the abovementioned designation
- invaginations of cytoplasm may in cross-sections give the appearance of intranuclear inclusions
(“pseudo-inclusions”) or intranuclear grooves – diagnosis is based on these nuclear features even in
the absence of papillary architecture
- psammoma bodies
- concentrically calcified structures often present within the lesion, usually within the cores of papillae
- almost never found in follicular and medullary carcinomas, thus when present, strongly indicate that the
lesion is a papillary carcinoma
- it is said that whenever a psammoma body is found within a lymph node or perithyroidal tissues, a hidden
papillary carcinoma must be considered
- foci of lymphatic invasion by tumor often present
- involvement of blood vessels is relatively uncommon, particularly in smaller lesions
- metastases to adjacent cervical lymph nodes are estimated to occur in up to half the cases
- variant forms (important to recognize because they can resemble other lesions and have unique clinical
features):
- encapsulated variant
– 10% of all papillary neoplasms
– usually confined to the thyroid gland, well encapsulated
– rarely presents with vascular or lymph node dissemination and so can easily be confused with a
benign adenoma
– in most cases, this variant has an excellent prognosis
- follicular variant
– characteristic nuclei of papillary carcinoma but has an almost totally follicular architecture
– grossly, tumor may be encapsulated
– focally, psammoma bodies may be seen
– still behave biologically as usual papillary carcinomas as long as they meet the nuclear criteria for
diagnosis of papillary cancers
– true follicular carcinoma, in contrast lacks these nuclear features
– frequently demonstrates capsular and vascular invasion
– less favorable prognosis
- tall cell variant
– tall columnar cells with intensely eosinophilic cytoplasm lining the papillary structures
– typically the cells are at least twice as tall as they are wide
– tumors tend to occur in older individuals and are usually large with prominent vascular invasion,
extrathyroidal extension, and cervical and distant metastases
– has been recently demonstrated that more than half the tall cell variants harbor a ret/PTC
translocation that confers greater mitogenic potential than the ret/PTC observed in usual papillary
thyroid cancers
– presence of this genetic abnormality might result in more aggressive behavior
- diffuse sclerosing variant
– unusual
– occurs in younger individuals, including children
– do not present with a mass, but rather with a bilateral goiter
– a characteristic “gritty” sensation to the cut surface of the lesion due to the presence of abundant
psammoma bodies
– demonstrates a prominent papillary growth pattern intermixed with solid areas containing nests of
squamous cells (squamous morules)
– neoplastic cells exhibit classic nuclear features of a papillary neoplasm
– there is extensive, diffuse fibrosis throughout the thyroid gland, often associated with a prominent
lymphocytic infiltrate, simulating Hashimoto thyroiditis
– neoplastic cells have a peculiar propensity to invade intrathyroidal lymphatic channels, hence, nodal
metastases are present in almost all cases
- hyalinizing trabecular tumors
- includes both adenomas and carcinomas
- have recently been reconsidered as a variant of papillary carcinomas, based on the presence
of ret/PTC gene rearrangements in 30% to 60% of these tumors
- characterized by an “organoid” growth pattern, with nests and trabeculae of elongated tumor
cells within a fibrovascular stroma
- at first glance, tumor may resemble an extra-adrenal paraganglioma

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 - both intracellular and extracellular hyalinization are prominent and confer a pink hue on the
tumor on low-power microscopic examination
- nuclear features resemble those seen in classic papillary carcinomas, and psammoma bodies
may be present
- well incapsulated, while carcinomas demonstrate capsular and/or vascular invasion
11. Follicular Carcinoma
- single nodules that may be well circumscribed or widely infiltrative
- sharply demarcated lesions may be exceedingly difficult to distinguish from follicular adenomas by gross
examination
- larger lesions may penetrate the capsule and infiltrate well beyond the thyroid capsule into the adjacent neck
- gray tan to pink on cut section and on occasion are somewhat translucent when large, colloid-filled follicles are
present
- degenerative changes, such as central fibrosis and foci of calcification, are sometimes present
- microscopically: most are composed of fairly uniform cells forming small follicles containing colloid, quite
reminiscent of normal thyroid; in other cases follicular differentiation may be less apparent, and there may be
nests or sheets of cells without colloid
- occasional tumors are dominated by Hürthle cells
- whatever the pattern, nuclei lack the features typical of papillary carcinoma, and psammoma bodies are not
present – important to note the absence of these details because some papillary carcinomas may appear
almost entirely follicular
- follicular lesions, in which the nuclear features are helpful in distinguishing papillary from follicular neoplasm, are
of little value in distinguishing follicular adenomas from minimally invasive follicular carcinomas – this distinction
requires extensive histological sampling of tumor-capsule-thyroid interface to exclude capsular and/or vascular
invasion
- criterion for vascular invasion is applicable only to capsular vessels and vascular spaces beyond the capsule;
presence of tumor plugs within intratumoral blood vessels has little prognostic significance
- lymphatic spread is distinctly uncommon in follicular cancers
- extensive invasion of adjacent thyroid parenchyma or extrathyroidal tissues makes the diagnosis of carcinoma
obvious in widely invasive follicular carcinomas
- histologically: tend to have a greater proportion of solid or trabecular growth pattern, less evidence of follicular
differentiation, and increased mitotic activity
12. Medullary Carcinoma
- solitary nodule or may present as multiple lesions involving both lobes of the thyroid
- sporadic neoplasms tend to originate in one lobe, in contrast, bilaterality and multicentricity are common in familial
cases
- larger lesions often contain areas of necrosis and hemorrhage and may extend through the capsule of the thyroid
- tumor tissue: firm, pale gray to tan, infiltrative
- may be foci of hemorrhage and necrosis in the larger lesions
- microscopically: composed of polygonal to spindle-shaped cells (may form nests, trabeculae, and even follicles);
small, more anaplastic cells are present in some tumors and may be the predominant cell type
- acellular amyloid deposits, derived from altered calcitonin molecules, are present in the adjacent stroma in many
cases
- calcitonin is readily demonstrable within the cytoplasm of the tumor cells as well as in the stromal amyloid by
immunohistochemical methods
- electron microscopy: reveals variable numbers of membrane-bound electron-dense granules within the cytoplasm
of the neoplastic cells
- one peculiar feature of familial medullary cancers is the presence of multicentric C-cell hyperplasia in the
surrounding thyroid parenchyma, a feature that is usually absent in sporadic lesions
- presence of multiple prominent clusters of C cells scattered throughout the parenchyma should raise the specter
of a familial tumor, even if that history is not explicitly present
- foci of C-cell hyperplasia are believed to represent the precursor lesions from which medullary carcinomas arise
13. Anaplastic Carcinoma
- microscopically: neoplasms are composed of highly anaplastic cells, which may take one of several histologic
patterns:
- large pleomorphic giant cells, including occasional osteoclast-like multinucleate giant cells
- spindle cells with a sarcomatous appearance
- mixed spindle and giant cells
- small cells resembling those seen in small cell carcinomas arising at other sites
- unlikely that a true small cell carcinoma exists in the thyroid, and a significant number of such “small cell” tumors
have ultimately proven to be medullary carcinomas or malignant lymphomas, which may also occur in the
thyroid but have much better prognosis
65
 - foci of papillary or follicular differentiation may be present in some tumors, suggesting origin from a better
differentiated carcinoma
14. Primary Hyperparathyroidism
- morphologic changes include those in the parathyroid glands as well as those in other organs affected by
elevated levels of calcium
- parathyroid adenomas
- almost solitary and may lie in close proximity to the thyroid gland or in an ectopic site
- 0.5-5 g
- well-circumscribed, soft, tan to reddish-brown nodule
- invested by a delicate capsule
- in contrast to primary hyperplasia, glands outside adenomas are usually normal in size or somewhat
shrunken because of feedback inhibition by elevations in serum calcium
- microscopically:
- often composed predominantly of fairly uniform, polygonal chief cells with small, centrally placed nuclei
- most cases – at least a few nests of larger cells containing oxyphil cells are present as well; uncommonly,
entire adenomas may be composed of this cell type (oxyphil adenomas)
- chief cells arranged in a variety of patterns; follicles reminiscent of those seen in the thyroid are present in
some cases; mitotic figures are rare
- a rim of compressed, non-neoplastic parathyroid tissue, generally separated by a fibrous capsule, is often
visible at the edge of the adenoma
- not uncommon: bizarre and pleomorphic nuclei even within adenomas (endocrine atypia) that should not
be used as a criterion for defining malignancy
- in contrast to the normal parathyroid parenchyma, adipose tissue is inconspicuous within the adenoma
- primary hyperplasia
- may occur sporadically or as a component of MEN syndrome
- there is frequently asymmetry with apparent sparing of one or two glands, although classically all four glands
are involved, making the distinction between hyperplasia and adenoma difficult; combined weight of all
glands rarely exceeds 1 g and is often less
- microscopically – most common pattern seen is that of chief cell hyperplasia, which may involve the glands in
a diffuse or multinodular pattern; less commonly, the constituent cells contain abundant water-clear cells
(“water-clear cell hyperplasia”); in many instances, there are islands of oxyphils, and poorly developed,
delicate fibrous strands may envelop the nodules; as in the case of adenomas, stromal fat is inconspicuous
within the foci of hyperplasia
- parathyroid carcinomas
- may be fairly circumscribed lesions that are difficult to distinguish from adenomas, or they may be clearly
invasive neoplasms
- these tumors enlarge one parathyroid gland and consist of gray-white, irregular masses that sometimes
exceed 10 g in weight
- cells are usually uniform and resemble normal parathyroid cells arrayed in nodular or trabecular patterns with
a dense, fibrous capsule enclosing the mass
- general agreement: a diagnosis of carcinoma based on cytologic detail is unreliable, and invasion of
surrounding tissues and metastasis are the only reliable criteria of malignancy
- local recurrence occurs in one third of cases, and more distant dissemination occurs in another third
- morphologic changes in other organs deserving special mention include skeletal and renal lesions:
- skeletal changes
- prominence of osteoclasts, which, in turn, erode bone matrix and mobilize calcium salts, particularly in
metaphyses of long tubular bones
- bone resorption is accompanied by increased osteoblastic activity and the formation of new bone trabeculae;
- in many cases, the resultant bone contains widely spaced, delicate trabeculae reminiscent of those seen in
osteoporosis; in more severe cases, the cortex is grossly thinned, and the marrow contains increased
amounts of fibrous tissue accompanied by foci of hemorrhage and cyst formation (osteitis fibrosa cystica)
- aggregates of osteoclasts, reactive giant cells, and hemorrhagic debris occasionally form masses that may be
mistaken for neoplasms (brown tumors of hyperparathyroidism)
- renal changes:
- PTH-induced hypercalcemia favors formation of urinary tract stones (nephrolithiasis) as well as calcification of
the renal interstitium and tubules (nephrocalcinosis); metastatic calcification secondary to hypercalcemia
may also be seen in other sites, including the stomach, lungs, myocardium, and blood vessels
15. Secondary Hyperparathyroidism
- hyperplastic parathyroid glands
- as in primary hyperplasia, degree of glandular enlargement is not necessarily symmetric
- microscopically:
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 - hyperplastic glands contain an increased number of chief cells, or cells with more abundant, clear cytoplasm
(so-called water-clear cells) in a diffuse or multinodular distribution
- fat cells decreased in number
- bone changes similar to those seen in primary hyperthyroidism may also be present
- metastatic calcification may be seen in many tissues, including lungs, heart, stomach, and blood vessels
16. Morphology of Diabetes and its Late Complications
- Pancreas
- lesions are inconsistent and rarely of diagnostic value
- distinctive changes are more commonly associated with type 1 than with type 2 diabetes
- one or more of the following alterations may be present:
- reduction in the number and size of islets
- most often seen in type 1 diabetes, particularly with rapidly advancing disease
- most of the islets are small and inconspicuous, and not easily detected
- insulitis
- leukocytic infiltration of the islets principally composed of T lymphocytes similar to that in animal
models of autoimmune diabetes
- may be seen in type 1 diabetes at the time of clinical presentation
- distribution may be strikingly uneven
- eosinophilic infiltrates may also be found, particularly in diabetic infants who fail to survive the
immediate postnatal period
- ß-cell degranulation
- may be observed by electron microscopy, reflecting depletion of stored insulin in already damaged ß
cells
- more commonly seen in patients with newly diagnosed type 1 disease, when some ß cells are still
present
- in type 2 diabetes, there may be a subtle reduction in islet cell mass – demonstrated only by special
morphometric studies
- amyloid replacement of islets in type 2 diabetes
- appears as deposition of pink, amorphous material beginning in and around capillaries and between
cells
- at advanced stages, may be virtually obliterated
- fibrosis may also be observed often seen in long-standing cases of type 2 diabetes – similar lesions
may be found in elderly nondiabetics, apparently as part of normal aging
- increase in the number and size of islets
- especially characteristic of nondiabetic newborns of diabetic mothers
- presumably, fetal islets undergo hyperplasia in response to the maternal hyperglycemia
- Diabetic Macrovascular Disease
- hallmark: accelerated atherosclerosis involving the aorta and large- and medium-sized arteries – except for its
greater severity and earlier age at onset, atherosclerosis in diabetics is indistinguishable from that in
nondiabetics
- myocardial infarction
- caused by atherosclerosis of the coronary arteries, is the most common cause of death in diabetics –
almost as common in diabetic women as in diabetic men
- in contrast, myocardial infarction is uncommon in nondiabetic women of reproductive age
- gangrene of the lower extremities
- as a result of advanced vascular disease, is about 100 times more common in diabetics than in the general
population
- larger renal arteries are also subject to severe atherosclerosis, but the most damaging effect of diabetes on
the kidneys is exerted at the level of glomeruli and the microcirculation
- hyaline arteriosclerosis
- vascular lesion association with hypertension
- more prevalent and more severe in diabetics than in nondiabetics, but is not specific for diabetes and may
be seen in elderly nondiabetics without hypertension
- takes the form of an amorphous, hyaline thickening of the wall of the arterioles, which causes narrowing of
the lumen
- related not only to the duration of the disease but also to the level of blood pressure
- Diabetic Microangiopathy
- diffuse thickening of basement membranes
- one of the most consistent morphologic features of diabetes
- most evident in capillaries of the skin, skeletal muscle, retina, renal glomeruli, and renal medulla

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 - may also be seen in such nonvascular structures as renal tubules, the Bowman capsule, peripheral nerves,
and placenta
- by light and electron microscopy: basal lamina separating parenchymal or endothelial cells from the
surrounding tissue is markedly thickened by concentric layers of hyaline material composed
predominantly of type IV collagen
- despite the increase in the thickness of basement membranes, diabetic capillaries are more leaky than
normal to plasma proteins
- microangiopathy underlies the development of diabetic nephropathy, retinopathy, and some forms of
neuropathy; an indistinguishable microangiopathy can be found in aged nondiabetic patients but rarely to
the extent seen in patients with long-standing diabetes
- Diabetic Nephropathy
- kidneys are prime targets of diabetes
- renal failure is second only to myocardial infarction as a cause of death from this disease
- 3 lesions are encountered:
1. glomerular lesions
- most important are:
a. capillary basement membrane thickening
- thickened throughout their entire length
- can be detected by electron microscopy within a few years of the onset of diabetes, sometimes
without any associated change in renal function
b. diffuse mesangial sclerosis
- diffuse increase in mesangial matrix and is always associated with basement membrane
thickening
- found in most patients with disease of more than 10 years’ duration
- when glomerulosclerosis becomes marked, patients manifest the nephritic syndrome
characterized by proteinuria, hypoalbuminemia, and edema
c. nodular glomerulosclerosis
- glomerular lesion made distinctive by ball-like deposits of a laminated matrix situated in the
periphery of the glomerulus
- nodules are PAS positive and usually contain trapped mesangial cells – Kimmelstiel-Wilson
lesion – after pathologists who described it
- encountered in approximately 15% - 30% of long-term diabetics and is a major cause of morbidity
and mortality
- nodular form of glomerulosclerosis, once certain unusual forms of nephropathies have been
excluded is essentially pathognomonic of diabetes (in contrast to diffuse mesangial sclerosis,
which may also be seen in association with old age and hypertension)
- both diffuse and nodular forms induce sufficient ischemia to cause overall fine scarring of the
kidneys, marked by a finely granular cortical surface
2. renal vascular lesions, principally arteriolosclerosis
- renal atherosclerosis and arteriosclerosis constitute part of the macrovascular disease in diabetics
- kidney is one of the most frequently and severely affected organs
- changes in arteries and arterioles are similar to those found throughout the body
- hyaline arteriosclerosis affects not only afferent but also efferent arterioles, but rarle, if ever, encountered
in individuals who do not have diabetes
3. pyelonephritis, including necrotizing papillitis
- an acute or chronic inflammation of the kidneys that usually begins in the interstitial tissue and then
spreads to affect the tubules
- both acute and chronic forms occur in non-diabetics as well as in diabetics but are more common in
diabetics than in the general population
- diabetics tend to have more severe involvement
- necrotizing papillitis = papillary necrosis – special pattern of acute pyelonephritis that is much more
prevalent in diabetics than in nondiabetics
- Diabetic Ocular Complications
- may take the form of retinopathy, cataract formation, or glaucoma
- Diabetic Neuropathy
- central and peripheral NS are not spared by diabetes
- described further in chapters 27 and 28
17. Hyperinsulinism (Insulinoma)
- most often found within the pancreas and are generally benign
- most are solitary lesions, although multiple tumors or tumors ectopic to the pancreas may be encountered
- bona fide carcinomas, making up only about 10 % of cases, are diagnosed on the basis of criteria for malignancy
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 - rarely, may arise in ectopic pancreatic tissue
- solitary tumors are usually small (often less than 2 cm in diameter) and are encapsulated, pale to red-brown
nodules located anywhere in the pancreas
- histologically: these benign tumors look remarkably like giant islets, with preservation of the regular cords of
monotonous cells and their orientation to the vasculature
- not even the malignant lesions present much evidence of anaplasia and may be deceptively encapsulated
- by immunocytochemistry, insulin can be localized in the tumor cells
- under electron microscope, neoplastic ß cells, like their normal counterparts, display distinctive round granules
that contain polygonal or rectangular dense crystals separated from the enclosing membrane by a distinct halo
- it should be cautioned that granules may be present in the absence of clinically significant hormone activity
18. Zollinger-Ellison Syndrome (Gastrinomas)
- may arise in the pancreas, the peripancreatic region, or the wall of the duodenum
- over half of the gastrin-producing tumors are locally invasive or have already metastasized at the time of
diagnosis
- in approximately 25% of patients, gastrinomas arise in conjunction with other endocrine tumors, thus conforming
to the MEN-1 syndrome
- MEN-1 associated gastrinomas are usually single
- As with insulin-secreting tumors of the pancreas, gastrin-producing tumors are histologically bland and rarely
exhibit marked anaplasia
19. Hypercortisolism (Cushing Syndrome)
- main lesions found in the pituitary and adrenal glands
- pituitary
- shows changes regardless of the cause
- most common alteration, Crooke hyaline change, results from high levels of endogenous or exogenous
glucocorticoids – normal granular, basophilic cytoplasm of ACTH- producing cells in the anterior pituitary is
replaced by homogenous, lightly basophilic material and is the result of the accumulation of intermediate
keratin filaments in the cytoplasm
- adrenal glands
- morphology depends on the cause of hypercorticolism
- have one of the following abnormalities:
1. cortical atrophy
- bilateral cortical atrophy is a result in patients in whom the syndrome results from exogenous
glucocorticoids, suppression of endogenous ACTH due to a lack of stimulation of the zonae fasciculate
and reticularis by ACTH
- zona glomerulosa is of normal thickness in such cases because this portion of the cortex functions
independently of ACTH
- in contrast, in cases of endogenous hypercorticolism, the adrenals either are hyperplastic or contain a
cortical neoplasm
2. diffuse hyperplasia
- found in 60% - 70% of cases of Cushing syndrome
- both glands are enlarged, either subtly or markedly weighing up to 25 to 40 g
- adrenal cortex is diffusely thickened and yellow, owing to an increase in the size and number of lipid-rich
cells in the zonae fasciculata and reticularis
3. nodular hyperplasia
- some degree of nodularity is common but pronounced
- takes the form of bilateral, 0.5-2.0 cm, yellow nodules scattered throughout the cortex, separated by
intervening areas of widened cortex
- uninvolved cortex and nodules are composed of a mixture of lipid-laden clear cells and lipid-poor compact
cells showing some variability in cell and nuclear size with occasional binucleate forms
- combined adrenals may weigh up to 30-50g
- most cases of hyperplasia are associated with elevated serum levels of ACTH, whether of pituitary or
ectopic origin
- PRIMARY ADRENOCORTICAL NEOPLASMS causing Cushing syndrome may be malignant or benign
4. adenoma – rarely a carcinoma
- adenomas or carcinomas of the adrenal cortex as the source of cortisol secretion are not macroscopically
distinctive from nonfunctioning adrenal neoplasms
- both benign and malignant lesions are more common in women in their thirties to fifties
- adrenocortical adenomas
- yellow tumors surrounded by thin or well-developed capsules
- most weigh less than 30 g
- microscopically: composed of cells that are similar to those encountered in the normal zona fasciculata
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 - morphology: identical to that of nonfunctional adenomas and of adenomas associated with
hyperaldosteronism
- carcinomas associated with Cushing syndrome, in contrast, tend to be larger than the adenomas –
unencapsulated masses frequently exceeding 200 – 300 g in weight, havng all of the anaplastic
characteristics of cancer
- with functioning tumors, both benign and malignant, the adjacent adrenal cortex and that of the contralateral
adrenal gland are atrophic, owing to suppression of endogenous ACTH by high cortisol levels
20. Primary Hyperaldosteronism
- aldosterone-producing adenomas
- almost always solitary, small (< 2 cm in diameter), well-circumscribed lesions, more often found on the left
than on the right
- tend to occur in the thirties and forties and in women more often than in men
- often buried within the gland and do not produce visible enlargement, a point to be remembered in
interpreting sonographic or scanning imagees
- bright yellow on cut section and surprisingly are composed of lipid-laden cortical cells that more closely
resembles fasciculate cells than glomerulosa cells (the normal source of aldosterone)
- generally, cells tend to be uniform in size and shape and resemble mature cortical cells
- occasionally there is some nuclear and cellular pleomorphism but no evidence of anaplasia
- characteristic feature: presence of spironolactone bodies (eosinophilic, laminated cytoplasmic inclusions
found after treatment with anti-hypertensive drug spironolactone)
- cortical adenomas associated with hyperaldosteronism do not usually suppress ACTH secretion
- adjacent adrenal cortex and that of the contralateral gland are not atrophic
- bilateral idiopathic hyperplasia
- marked by diffuse and focal hyperplasia of cells resembling those of the normal zona glomerulosa
- hyperplasia often wedge-shaped, extending from the periphery toward the center of the gland
- bilateral enlargement can be subtle
- as a rule, an adrenocortical adenoma should be carefully excluded as the cause for hyperaldosteronism
21. Adrenogenital Syndromes
- in all cases of Congenital Adrenal Hyperplasia (CAH), the adrenals are bilaterally hyperplastic, sometimes
expanding to 10 to 15 times their normal weights because of the sustained elevation in ACTH
- adrenal cortex is thickened and nodular, and on cut section, the widened cortex appears brown, owing to total
depletion of all lipid
- proliferating cells are mostly compact, eosinophilic, lipid depleted cells, intermixed with lipid-laden clear cells
- hyperplasia of corticotroph (ACTH-producing) cells is present in the anterior pituitary in most CAH patients
22. Primary Chronic Adrenocortical Insufficiency (Addison Disease)
- anatomic changes in the adrenal glands depend on the underlying disease:
- Primary autoimmune adrenalitis – characterized by irregularly shrunken glands, which may be difficult to
identify within the suprarenal adipose tissue
- Histologically: cortex contains only scattered residual cortical cells in a collapsed network of connective tissue
- Variable lymphoid infiltrate is present in the cortex and may extend into the subjacent medulla, although the
medulla is otherwise preserved
- Tuberculous and fungal disease: adrenal architecture is effaced by a granulomatous inflammatory reaction
identical to that encountered in other sites of infection
- When hypoadrenalism is caused by metastatic carcinoma, the adrenals are enlarged, and their normal
architecture is obscured by the infiltrating neoplasm
23. Secondary Adrenocortical Insufficiency
- secondary hypoadrenalism (hypoadrenalsim secondary to hypothalamic or pituitary disease): depending on the
extent of ACTH lack, the adrenals may be moderately to markedly reduced in size
- to small, flattened structures that usually retain thir yellow color owing to a small amount of residual lipid
-cortex may be reduced to a thin ribbon composed largely of zona glomerulosa
- Medulla is unaffected
24. Adrenocortical Neoplasms
- adrenocortical adenomas
- most are clinically silent and are usually encountered as incidental findings at the time of autopsy or during
abdominal imaging for an unrelated cause
- some experts believe that all adrenal adenomas should, by definition, demonstrate clinical or biochemical
evidence of hyperfunction and that the incidentally discovered “tumors” are best classified as hyperplastic
nodules
- typical cortical adenoma is a well-circumscribed, nodular lesion up to 2.5 cm in diameter that expands the
adrenal

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 - presence of lipid within the tumor cells makes the cortex adjacent to non-functional adenomas yellow to
yellow-brown, in contrast to functional adenomas, which are associated with atrophy of the adjacent cortex
- cortex adjacent to non-functional adenomas is of normal thickness, in contrast to functional adenomas, which
are associated with atrophy of the adjacent cortex
- on cut surface, are usually yellow to yellow-brown because of the presence of lipid within the tumor cells
- microscopically:
- composed of cells similar to those populating the normal adrenal cortex
- nuclei tend to be small, although some degree of pleomorphism may be encountered even in benign
lesions (“endocrine atypia”)
- cytoplasm of neoplastic cells ranges from eosinophilic to vacuolated, depending on their lipid content
- mitotic activity is generally inconscpicuous
- adrenocortical carcinomas
- rare neoplasms that can occur at any age, including childhood
- more likely to be functional than adenomas are and are therefore often associated with virilism or other
clinical manifestations of hyperadrenalism
- two rare inherited causes: Li-Fraumeni syndrome and Beckwith-Wiedemann syndrome
- in most cases: large, invasive lesions, many exceeding 20 cm in diameter, that efface the native adrenal
gland
- less common, smaller, and better-circumscribed lesions may be difficult to distinguish from an adenoma
- on cut surface are typically variegated, poorly demarcated lesions containing areas of necrosis, hemorrhage,
and cystic change
- invasion of contiguous structures, including the adrenal vein and inferior vena cava, is common
- microscopically: may be composed of well-differentiated cells resembling those seen in cortical adenomas or
bizarre, monstrous giant cells, which may be difficult to distinguish from those of an undifferentiated
carcinoma metastatic to the adrenal
- between these extremes are found cancers with moderate degrees of anaplasia, some composed
predominantly of spindle cells
- carcinomas, particularly those of bronchogenic origin, may metastasize to the adrenals, and they may be
extremely difficult to differentiate from primary cortical carcinomas
- adrenal cancers have a strong tendency to invade the adrenal vein, vena cava, and lymphatics
- metastases to regional and periaortic nodes are common, as is distant hematogenous spread to the lungs
and other viscera
- bone metastases are unusual
- median patient survival is about 2 years
25. Pheochromocytoma
- range from small, circumscribed lesions confined to the adrenal to large hemorrhagic masses weighing kilograms
- average weight is 100 g, but variations form just over 1 g to almost 4000 g have been reported
- larger tumors are well demarcated by either connective tissue or compressed cortical of medullary tissue
- richly vacularized fibrous trabeculae pass into the tumor and produce a lobular pattern
- in many tumors, remnants of the adrenal gland can be seen, stretched over the surface or attached at one pole
- on section, cut surfaces of smaller pheochromocytomas are yellow-tan
- larger lesions tend to be hemorrhagic, necrotic, and cystic and typically efface the adrenal gland
- incubation of fresh tissue with a potassium dichromate solution turns the tumor a dark brown color owing to
oxidation of stored catecholamines, thus the term chromaffin
- histologic pattern is quite variable
- tumors are composed of polygonal to spindle-shaped chromaffin cells or chief cells, clustered with the
sustentacular cells into small nests or alveoli (zellballen) by a rich vascular network
- uncommonly, the dominant cell type is a spindle or small cell
- various patterns can be found in any one tumor
- cytoplasm has a finely granular appearance, best demonstrated with silver stains, owing to the appearance of
granules containing catecholamines
- nuclei are usually round to ovoid, with a stippled “salt and pepper” chromatin that is characteristic of most
neuroendocrine tumors
- electron microscopy reveals variable numbers of membrane-bound, electron-dense granules, representing
catecholamines and sometimes other peptides
- immunoreactivity for neuroendocrine markers (chromogranin and synaptophysin) is present in the chief cells,
while the peripheral sustentacular cells label with S-100, a calcium-binding protein expressed by a variety of
mesenchymal cell types
- criteria for determining malignancy can be a vexing issue: there is no histologic feature that can reliably predict
clinical behavior in pheochromocytomas

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 - tumors with “benign” histologic features may metastasize, while bizarrely pleomorphic tumors may remain
confined to the adrenal gland
- in fact, cellular and nuclear pleomorphism, including the presence of giant cells, and mitotic figures are often seen
in benign pheochromocytomas, while cellular monotony is paradoxically associated with an aggressive behavior
- even capsular and vascular invasion may be encountered in benign lesions
- definitive diagnosis of malignancy in pheochromatomas is based exclusively on the presence of metastases: may
involve regional lymph nodes as well as more distant sites, including liver, lung, and bone
- several histologic features, such as numbers of mitoses, confluent tumor necrosis, and spindle cell morphology,
have been associated with an aggressive behavior and increased risk of metastasis, but in and of itself, not
single criterion is entirely reliable
26. Pinealomas
- Pineoblastomas
- encountered mostly in the first two decades of life and appear as soft, friable, gray masses punctuated with
areas of hemorrhage and necrosis
- typically invade surrounding structures, such as the hypothalamus, midbrain, and lumen of the third ventricle
- histologically:
- composed of masses of pleomorphic cells two to four times the diameter of an erythrocyte
- large hyperchromatic nuclei appear to occupy almost the entire cell, and mitoses are frequent
- cytology: primitive embryonal tumor (“small blue cell neoplasm”) similar to medulloblastoma or retinoblastoma
- like medulloblastomas, tend to spread via the cerebrospinal fluid, enlarging mass may compress the aqueduct
of Sylvius, giving rise to internal hydrocephalus and all its consequences
- survival beyond 1 to 2 years is rare
- pineocytomas
- occur mostly in adults and are much slower-growing than pineoblastomas
- tend to be well-circumscribed, gray, or hemorrhagic masses that compress but do not infiltrate surrounding
structures
- histologically: tumors may be pure pineocytomas or exhibit divergent glial, neuronal, and retinal differentiation;
tumors are composed largely of pineocytes having darkly staining, round-to-oval, fairly regular nuclei;
necrosis is unusual, mitosis virtually absent
- neoplastic cells resemble normal pineocytes in their strong immunoreactivity for neuro-specific enolase and
synaptophysin
- pineocytomatous pseudorosettes – rimmed by rows of pineocytes; centers of these rosettes are filled with
eosinophioic cytoplasmic material representing tumor cell processes; set against a background of thin,
fibrovascular, anastomosing sepat, which confer a lobular growth pattern to the tumor
- glial and retinal differentiation is detectable immunoreactivity for glial fibrillary acidic protein and retinal S-
antigen, respectively

CHAPTER 25
The Skin

A. Disorders of Pigmentation and Melanocytes

 Vitiligo
 usually indistinguishable from normal skin histologically
 under EM, characterized by loss of melanocytes
 diagnosed by immunohistochemistry for melanocyte-associated proteins
 ex. tyrosinase or Melan-A, S-100
 albinism - melanocytes are present but melanin pigment is not produced due to lack of or defect in
tyrosinase
 some causes of hypopigmentation are unrelated to lack of melanin or melanocytes (ex. post-
inflammatory hypopigmentation is due to redistribution of existing pigment within skin)

 Freckle (Ephelis)
 Due to increased amounts of melanin pigment within basal keratinocytes
 melanocytes are relatively normal in number but may be slightly enlarged
 unclear whether it is a focal abnormality in pigment production, enhanced pigment donation to adjacent basal
keratinocytes, or both
 café au lait spots
 seen in neurofibromatosis
 histologically indistinguishable from freckles
 evolve independent from sun exposure
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  often contain aggregated melanosomes (macromelanosomes) within the cytoplasm of melanocytes
 Melasma
 3 histologic patterns:
 epidermal type
- increased melanin deposition in basal layers
 dermal type
- characterized by macrophages in the superficial (papillary) dermis that have phagocytosed melanin
from the adjacent epidermal layer (process called melanin pigment incontinence)
 mixed type
- combination of epidermal and dermal type changes
 the 3 types may be distinguished by Wood’s light (black light)
 permits distinction between epidermal and dermal pigmentation on clinical inspection
 important as epidermal type and mixed type (partially) may respond to hydroquinone, a topical bleaching
agent

 Lentigo
 Essential histologic feature: linear (non-nested) melaocytic hyperplasia
 Elongation and thinning of rete ridges also common
 solar / actinic lentigo
 occurs in sun-damaged skin in older adults
 associated w/ subtle alteration in keratinocyte maturation

 Melanocyte Nevus (Pigmented Nevus, Mole)

 Initially formed by melanocyte that have been from highly dendritic single cells interspersed among basal
keratinocytes to round cells that grow in aggregates (“nests”) along the dermoepidermal junction
 Nuclei: uniform and rounded contour, inconspicuous nucleoli, little or no mitotic activity
 junctional nevi
 early developmental stage in melanocytic activity
 most grow into the dermis as nests or cords of cells (compound nevi)
 older lesions: epidermal nests may be lost entirely to form pure intradermal nevi
 clinically, compound and dermal nevi are more elevated than junctional nevi
 growth accompanied by maturation
 less mature nevus cells:
- more superficial, larger, produce melanin, grow in nests
 more mature nevus cells:
- deeper, smaller, produce little or no pigment, grow in cords
- most mature cells found at deepest extension of lesions, where they often acquire fusiform contours
and grow in fascicles resembling neural tissue
 correlates with enzymatic changes
 sequence of maturation important in diagnosing and distinguishing some benign nevi from melanomas
(which usually show little or no maturation)

 Dysplastic Nevi
 Histologically, consist of compound nevi with evidence of abnormal growth (both architectural and cytologic)
 Nevus cells nests within epidermis may be enlarged and exhibit abnormal fusion or coalesce w/ adjacent
nests
 Single nevus cells begin to replace normal basal cell layer along the dermoepidermal junction; results in
lentiginous hyperplasia
 Cytologic atypia frequently observed (irregular, angulated, nuclear contours; hyperchromasia)
 Alterations also occur in superficial dermis
 Sparse lymphocytic infiltrate
 Loss of melanin
 Phagocytosis of pigment by dermal macrophages (melanin pigment incontinence)
 Linear fibrosis surrounding epidermal rete ridges that are involved by the nevus

 Malignant Melanoma
 2 concepts: Radial growth & Vertical growth
 Radial growth
 Tendency of melanoma to grow horizontally within epidermal and superficial dermal layers often for a
prolonged time
 Melanoma cells don’t have capacity to metastasize
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  Ex. Lentigo maligna, superficial spreading, acral/mucosal lentiginous
- defined on basis of biologic behavior & architectural and cytologic features of growth within epidermal
layer
 Vertical growth
 With time, melanoma grows downward into deeper dermal layers
 Melanoma as an expensile mass lacking cellular maturation
 Cells do not become smaller as they descend into reticular dermis
 Nature and extent determine biologic behavior of malignant melanoma
 Heralded clinically by development of a nodule in the relatively flat radial growth phase; correlates with
emergence of clone cells with true metastatic potential
 Melanoma cells larger than nevus cells
 With large nuclei (w/ irregular contours); chromatin clumped at periphery of nuclear membrane; prominent
eosinophilic (red) nucleoli

B. Benign Epithelial Tumors

 Seborrheic Keratoses
 Exophytic; demarcated sharply from adjacent epidermis
 Composed of sheets of small cells resembling basal cells of normal epidermis
 Variable melanin pigmentation present (hence brown coloration)
 Characteristic features: Hyperkeratosis, horn cysts, invagination cysts
 When irritated & inflamed: whirling squamous cells present
 Inverted follicular keratoses
 Involve hair follicle epithelium
 Endophytic (downward) growth
 Show effects of inflammation

 Acanthosis Nigricans
 All forms have similar histologic features
 Epidermis & dermal papillae form repeating peaks and valleys
 Features: variable hyperplasia, hyperkeratosis, slight basal layer hyperpigmentation

 Fibroepithelial Polyp
 Histologically: fibrovascular cores covered by benign squamous epithelium; ischemic necrosis

 Epithelial Cyst (Wen)

 Different histologic types based on wall components:
 Epidermal inclusion cyst
- wall identical to epidermis
- filled with laminated strands of keratin
 Pilar or trichilemmal cyst
- wall resembles follicular epithelium
- no granular cell layer
- filled by homogenous mixture of keratin and lipid
 Dermoid cyst
- similar to epidermal inclusion cyst
- with multiple appendages budding outward from wall
 Steatocystoma multiplex
- wall resembles sebaceous gland duct
- can be inherited

 Adnexal (Appendage) Tumors

 Cylindroma
 Composed of islands of cells fitting together within a fibrous dermal matrix
 Trichoepithelioma
 Proliferation of basaloid cells forming primitive structures resembling hair follicles
 Mixed tumor (chondroid syringoma)
 Composed of variably dilated sweat gland-like ducts surrounded by blue-gray matrix with features of true
cartilage
 Trichilemmoma
 Localized proliferation of pale pink, glassy cells
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  Hidradenoma papilliferum
 Composed of ducts lined by apocrine-type cells that show characteristic decapitation secretion and a
fibrous stroma

 Keratoacanthoma
 Histologic features: central keratin-filled crater surrounded by proliferating epithelial cells that extend upward
and downward
 With enlarged cells showing evidence of cytologic atypia
 with glassy eosinophilic cytoplasm
 produce keratin abruptly

C. Premalignant and Malignant Epidermal Tumors

 Actinic Keratosis
 Cytologic atypia in lowermost epidermal layers
 Atypical basal cells have evidence of dyskeratosis with pink or reddish cytoplasm
 Intercellular bridges present
 Dermis contains thickened, blue-gray elastic fibers (elastosis)
 Stratum corneum thickened; cell nuclei often retained (parakeratosis)

 Squamous Cell Carcinoma

 In situ carcinoma
 hasn’t invaded through basement membrane of dermoepidermal junction
 appear as sharply defined, red, scaling plaques
 more advanced, invasive lesions are nodular, has variable keratin production (hyperkeratosis), and may
ulcerate
 well-differentiated lesions indistinguishable from keratoacanthoma
 leukoplakia
 oral mucosa involved
 presence of zone of white thickening
 caused by a variety of disorders
 cells have atypical nuclei at all levels of epidermis
 invasive squamous cell carcinoma
 exhibits variable differentiation

 Basal Cell Carcinoma

 Histologically, tumor cells resemble those in normal basal cell layer of epidermis
 2 patterns:
 multifocal growths
- originates from epidermis, extends over several square cms or more of skin surface
 nodular lesions
- downward growth into dermis as cords and islands of variably basophilic cells w/ hyperchromatic nuclei,
embedded in mucinous matrix, surrounded by fibroblasts and lymphocytes
- cells at the periphery arranged radially in parallel alignment (palisading)

 Merkel Cell Carcinoma

D. Tumors of the Dermis

 Benign Fibrous Histiocytoma (Dermatofibroma)

 Most common form of fibrous histiocytoma
 Formed by benign, spindle-shaped fibroblasts arranged in well-defined, nonencapsulated mass within the mid-
dermis; extension into subcutaneous fat observed
 Majority of cases demonstrate “dirty fingers” pattern (downward elongation of hyperpigmented rete ridges

 Dermatofibrosarcoma Protuberans
 Cellular, composed of fibroblasts arranged radially like a pinwheel (storiform pattern)
 Overlying epidermis generally thinned
 Deep extension from dermis into subcutaneous fat, producing “honeycomb” pattern frequently present,
hindering attempts at complete surgical removal

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 Xanthomas
 All types characterized by dermal accumulation of benign-appearing histiocytes (macrophages) with abundant,
finely vacuolated (foamy) cytoplasm
 Cholesterol, phospholipids, and triglycerides present within cells

 Dermal Vascular Tumors

 Capillary and cutaneous hemangiomas
 Represented histologically by well-formed, blood-filled vascular spaces lined by benign endothelial cells within
dermis

E. Tumors of Cellular Immigrants to the Skin

 Langerhans Cell Histiocytosis

 Several histologic patterns:
 1st pattern: Diffuse dermal infiltrate of large, round to ovoid cells w/ pale pink cytoplasm containing indented,
often bland nuclei
 2nd pattern: Clustering of similar cells into granuloma-resembling small aggregates
 3rd pattern: dermal infiltrate of cells w/ foamy, xanthoma-like cytoplasm
 eosinophils observed, especially with the 1st pattern
 special immunohistochemical methods necessary for histologic diagnosis
 ultrastructural identification of specific organelles (Birbeck granules), characteristic of epidermal Langerhans
cells, also helpful

 Mycosis Fungoides (Cutaneous T-Cell Lymphoma)

 Histologic hallmark is presence of Sezary-Lutzer cells
 T-helper cells (CD4 positive)
 Form bandlike aggregates within superficial dermis
 Invade epidermis as single cells and small clusters (Pautrier microabscesses)
 patches and plaques show pronounced epidermal infiltration (epidermotropism)

 Mastocytosis
 Histologic picture varies from subtle increase of spindle-shaped and stellate mast cells around superficial
dermal blood vessels, to large numbers of tightly packed, round to oval mast cells in the upper to mid-dermis
 Fibrosis, edema, few eosinophils may also be present
 Mast cells difficult to differentiate from lymphocytes in H&E sections

F. Disorders of Epidermal Maturation

 Ichtyosis
 Histology: subtle build-up of compacted stratum corneum (also, loss of normal weave pattern in hair-bearing
skin)
 Little or no inflammation
 Subtle associated variations in thickness of epidermis and stratum granulosum

G. Acute Inflammatory Dermatoses

 Urticaria
 Histologic features very subtle
 Sparse superficial perivenular infiltrate consisting of mononuclear cells and rare neutrophils
 Eosinophils present
 Collagen bundles more widely spaced than in normal skin
 Suoerficial lymphatic channels dilated
 Epidermal changes typically not present

 Acute Eczematous Dermatitis

 Spongiosis
 Accumulation of edema fluid within intercellular spaces of epidermis
 Characterizes acute eczematous dermatitis
 Intercellular bridges prominent, hence spongy appearance of epidermis
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 Erythema Multiforme
 Early lesions show superficial perivascular, lymphocytic infiltrate associated with dermal edema and
accumulation of lymphocytes along dermoepidermal junction
 Eventually, there is upward migration of lymphocytes into epidermis
 Blister formation results in occurrence of discrete and confluent zones of epidermal necrosis
 Target lesion exhibits central necrosis surrounded by rim of perivenular inflammation

H. Chronic Inflammatory Dermatoses

 Psoriasis
 Characterized histologically by increased epidermal cell turnover resulting in marked epidermal thickening
(acanthosis), with regular downward elongation of rete ridges
 Stratum granulosum thinned or absent
 Extensive overlying parakeratotic scale seen
 Changes result in abnormal proximity of dermal vessels within dermal papillae to overlying parakeratotic;
accounts for characteristic clinical phenomenon of multiple, minute, bleeding points when scale is lifted from
plaques (Auspitz sign)
 Presence of spongiform pustules and Munro microabscesses

 Seborrheic Dermatitis
 Histologically similar to spongiotic dermatitis and psoriasis
 Mounds of parakeratosis containing neutrophils and serum present at ostia of hair follicles (follicular lipping)
 With HIV infection, apoptotic keratinocytes and plasma cells may also be present

 Lichen Planus
 Characterized histologically by a dense, continuous infiltrate of lymphocytes along dermoepidermal junction
 “saw-toothing” of dermoepidermal interface due to destructive lymphocyte infiltration
 anucleate, necrotic basal cells may be incorporated into inflamed papillary dermis (referred to as colloid or
Civatte bodies)
 epidermal hyperplasia and thickening of granular cell layer and stratum corneum observed
 lichen planus affecting hair follicle epithelium is referred to as lichen planopilaris

 Lupus Erythematosus
 Characterized histologically by an infiltrate of lymphocytes along the dermoepidermal or dermal-follicular
epithelial junction, or both
 Deep perivascular and periappendageal infiltrates also observed
 Preferential infiltration of subcutaneous fat referred to as lupus profundus
 Basal cell layer shows diffuse vacuolization
 Epidermal layer thinned or atrophied, with loss of rete ridge pattern; variable hyperkeratosis present
 Direct immunofluorescence shows characteristic granular band of immunoglobulin and complement along
dermoepidermal and dermal-follicular junction (lupus band test)

I. Blistering (Bullous) Diseases

 Pemphigus
 Acantholysis
 Histologic common denominator in all forms of pemphigus
 Implies dissolution or lysis of intercellular adhesion sites within squamous epithelial surface
 Cells no longer attached to other epithelial cells lose their polyhedral shape and become rounded
 Suprabasal acantholytic blister
 Characteristic of pemphigus vulgaris
 Single layer of intact basal cells forming the blister base likened to a row of tomstones
 Variable superficial dermal infiltration by lymphocytes, histiocytes, and eosinophils accompanies all forms of
pemphigus

 Bullous Pemphigoid
 Separation from pemphigus was based on observation that pemphigoid resulted from a subepidermal,
nonacantholytic blister

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  Early lesion show superficial and sometimes deep perivascular infiltrate of lymphocytes and eosinophils,
occasional neutrophils, superficial dermal edema, and associated basal cell layer vacuolization
 Eosinophils show degranulation
 Vacuolated basal cell layer gives rise to fluid-filled blister

 Dermatitis Herpetiformis
 Fibrin and neutrophils accumulate selectively at the tips of dermal papillae, forming small microabscesses
 Basal cells overlying abscesses show vacuolization
 Minute zones of dermoepidermal separation (microscopic blisters) may occur at tips of involved papillae; zones
coalesce to form a true subepidermal blister
 shows granular deposits of IgA selectively localized in tips of dermal paipllae

J. Disorders of Epidermal Appendages

 Acne Vulgaris
 4 key components contributing to acne development:
 changes in keratinization of lower portion of follicular infudibulum w/ development of a keratin plug blocking
outflow of sebum to skin surface
 increase in size of sebaceous glands (puberty) or increased activity due to hormonal stimulation
 lipase-synthesizing bacteria (Propionibacterium acnes) colonizing upper and midportion of hair follicle,
converting lipids within sebum to pro-inflammatory fatty acids
 induction of inflammation in the follicle associated with release of cytotoxic and chemotactic factors

K. Panniculitis

 Erythema Nodosum
 Histopathology: widening of connective tissue septa due to edema, fibrin exudation, and neutrophilic infiltration
 Also, infiltration by lymphocytes, histiocytes, multinucleated giant cells, and occasional eosinophils
 Vasculitis not present

 Erythema Induratum
 Granulomatous inflammation and zones of caseous necrosis involve the fat lobule
 Show necrotizing vasculitis affecting small to medium-sized arteries and veins in deep dermis and subcutis

L. Infection and Infestation

 Verrucae (Warts)
 Histologic features: epidermal hyperplasia (often undulant in character; referred to as verrucous or
papillomatous epidermal hyperplasia) & cytoplasmic vacuolization involving superficial epidermal layers,
producing halos of pallor surrounding infected nuclei
 viral particles within nuclei
 infected cells show keratohyaline granules and jagged eosinophilic intracytoplasmic keratin aggregates

 Molluscum Contagiosum
 Characterized by cuplike verrucous epidermal hyperplasia
 Diagnostically specific structure is the molluscum body
 Large, ellipsoid, homogenous, cytoplasmic inclusion in cells of stratum granulosum and stratum corneum
 Numerous virions present

 Impetigo
 Characteristic feature: accumulation of neutrophils beneath stratum corneum (often with subcorneal pustule
formation)
 Bacteria present
 Accompanied by non-specific, reactive epidermal alterations and superficial dermal inflammation

 Superficial Fungal Infections

 Histologic features variable, depending on antigenic properties of organism, host response, and degree of
bacterial superinfection; may take form of a mild eczematous dermatitis

 Arthropod Bites, Stings, and Infestations

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  Classic lesion shows wedge-shaped perivascular infiltrate of lymphocytes, histiocytes, and eosinophils within
dermis
 Presence of a central zone of exceedingly focal epidermal necrosis (birefringement insect mouthparts may be
found underneath)
 Site of bite is called punctum
 Urticarial reaction, dense and florid inflammatory infiltratem seen in some bites
 May superficially resemble cutaneous lymphoma
 Spongiosis present in some biopsy specimens
 Some insect bites resemble bullous pemphigoid

CHAPTER 26
Bones, Joints, and Soft Tissue Tumors

Morphology of Achondroplasia
 Histologic abnormalities can be found in growth plates.
 Zones of proliferation and hypertrophy are narrowed and disorganized and contain clusters of large chondrocytes
instead of well-formed columns.
 There is premature deposition of horizontal struts of bone at the base of the growth plate  seals plate and prevents
future growth.
 Appositional intramembranous bone formation is not disrupted  cortices form normally and appear thickened in
relation to the short length of the bone.

Morphology of Osteopetrosis
 Morphologic changes explained by deficient osteoclast activity.
 Grossly, bones lack a medullary canal and the ends of long bones are bulbous (Erlenmeyer flask deformity) and
misshapen.
 Neural foramina are small thereby compressing exiting nerves.
 Primary spongiosa (normally removed during growth) persists and fills the medullary cavity, leaving no room for the
hematopoietic marrow and preventing the formation of premature trabeculae.
 Bone formed is not remodeled and tends to be woven in architecture  bone becomes brittle.
 Histologically, the number of osteoclasts may be normal, increased, or decreased depending on the underlying
mechanism of the disease.

Morphology of Osteoporosis
 Entire skeleton is affected in post-menopausal and senile osteoporosis but certain regions tend to be more severely
involved than others.
 In postmenopausal osteoporosis:
 Increase in osteoclast activity mainly affects bones or portions of bones that have increased surface area (i.e.
cancellous compartment of vertebral bodies).
 Osteoporotic trabeculae are thinned and lose their interconnections, leading to progressive microfractures
and eventual vertebral collapse.
 In senile osteoporosis:
 Osteoporotic cortex is thinned by subperiosteal and endosteal resorption and the haversian systems widened.
 In severe cases, haversian systems are so enlarged that the cortex mimics cancellous bone. The bone that
remains is of normal composition.

Morphology of Paget Disease

 The histologic hallmark is the mosaic pattern of lamellar bone.
 Likened to a jigsaw puzzle.
 Produced by prominent cement lines that anneal haphazardly oriented units of lamellar bone.
 In the initial lytic phase, there are waves of osteoclastic activity and numerous resorption pits. Osteoclasts are
abnormally large and have many more than normal 10 to 12 nuclei; sometimes 100 nuclei are present.
 In the mixed phase, osteoclasts persist but now many of the bone surfaces are line by prominent osteoblasts.
 The marrow adjacent to the bone-forming surface is replaced by loose CT that contains osteoprogenitor cells and
numerous blood vessels, which transport nutrients and catabolites to and from these metabolically active sites.
 Newly formed bone maybe woven or lamellar, but all of it will eventually be remodeled into lamellar bone.
 As mosaic pattern unfolds and cell activity decreases, periosseous fibrovascular tissue recedes and is replaced by
normal marrow.

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 In the end, bone becomes a caricature of itself: larger than normal and composed of coarsely thickened trabeculae
and cortices that are soft and porous and lack structural stability  bone is vulnerable to deformation under stress; it
fractures easily.

Morphology of Hyperparathyroidism
 Increased osteoclast activity in hyperparathyroidism affects cortical bone (subperiosteal, osteonal, and endosteal
surfaces) more severely than cancellous bone.
 Subperiosteal resorption produces thinned cortices and the loss of the lamina dura around the teeth.
 X-ray pattern (diagnostic of hyperparathyroidism) is most frequently identified along the radial aspect of the middle
phalanges of the index and middle fingers.
 Cortical cutting cones composed of a spearhead arrangement of osteoclasts that bore along and enlarge haversian
and Volkman canals.
 In cancellous bone, osteoclasts tunnel into and dissect centrally along the length of the trabeculae, creating the
appearance of railroad tracks (dissecting osteitis).
 Decrease in bone density (osteopenia).
 Increased osteoblast activity.
 In regions of bone cell activity, the marrow spaces around the affected surfaces are replaced by fibrovascular tissue.
 Bone loss predisposes to microfractures and secondary hemorrhages that elicit an influx of multinucleated
macrophages and an ingrowth of reparative fibrous tissue, creating a brown tumor (a mass of reactive tissue).
 Brown color result of vascularity, hemorrhage, and hemosiderin deposition.
 Uncommon for the lesions to undergo cystic degeneration.
 Hallmark of severe hyperparathyroidism: generalized osteitis fibrosa cystica (von Recklinghausen disease of
bone)  combined picture of increased bone cell activity, peritrabecular fibrosis, and cystic brown tumors.

Morphology of Osteonecrosis
 Pathologic features are the same regardless of the cause.
 In medullary infarcts, necrosis is geographic and involves the cancellous bone and marrow. Cortex is not usually
affected because of its collateral blood flow.
 In subchondral infarcts, necrosis involves a triangular or wedge-shaped segment of tissue that has the subchondral
plate as its base and the center of the epiphysis as its apex. The overlying articular cartilage remains viable because it
receives nutrition from the synovial fluid.
 The dead bone (recognized by its empty lacunae): surrounded by necrotic adipocytes that frequently rupture  fatty
acids are released  may bind with calcium  form insoluble calcium soaps that may remain for life.
 In the healing response, osteoclasts resorb the necrotic trabeculae. Those that remain act as scaffolding for the
deposition of new living bone (creeping substitution).
 In subchondral infarcts, the pace of creeping substitution is too slow to be effective  eventual collapse of the
necrotic cancellous bone and distortion, fracture, and even sloughing of the articular cartilage.

Morphology of Osteogenic Osteomyelitis

 Morphologic changes depend on stage (acute, subacute, or chronic) and location of infection.
 Once localized in bone, bacteria proliferate and induce an acute inflammatory reaction and cause cell death.
 Entrapped bone undergoes necrosis within the first 48 hours  bacteria and inflammation spread within the shaft of
the bone and may percolate throughout the haversian systems to reach the periosteum.
 In children, sizable subperiosteal abscesses may form (as periosteum is loosely attached to the cortex), which can
trek for long distances along the bone surface.
 Lifting of periosteum further impairs blood supply of affected region; both suppurative and ischemic injury may cause
segmental bone necrosis (sequestrum  dead piece of bone).
 Rupture of periosteum leads to an abscess in the surrounding soft tissue and eventual formation of a draining sinus.
 Sometimes sequestrum crumbles and forms free foreign bodies that pass through the sinus tract.
 In infants, epiphyseal infection spreads through the articular surface or along capsular and tendoligamentous
insertions into a joint, producing septic or suppurative arthritis.
 Sometimes causes extensive destruction of articular cartilage and permanent disability.
 Analogous process: in the vertebrae, the infection destroys the hyaline cartilage and plate and vertebral discs
and spreads into adjacent vertebrae.
 Over time, host response develops. After one week of infection, chronic inflammatory cells become more numerous.
 Release of cytokines from leukocytes stimulates osteoclastic bone resorption, ingrowth of fibrous tissue, and
deposition of reactive bone in the periphery.
 Reactive woven or lamellar bone may be deposited and may form an involucrum (a sleeve of living tissue
around a segment of devitalized bone).

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 Other morphologic variants of osteomyelitis:
 Brodie abscess – small intraosseous abscess that frequently involves the cortex and is walled off by reactive
bone.
 Sclerosing osteomyelitis of Garre – typically develops in the jaw. Is associated with extensive new bone
formation that obscures much of the underlying osseous structure.

Morphology of Tuberculous Osteomyelitis

 Organisms are usually blood borne and originate from a focus of active visceral disease.
 Direct extension (i.e. from pulmonary focus into a rib or from tracheobronchial nodes into adjacent vertebrae) or
spread via draining lymphatics may also occur.
 Bony infection usually solitary; in some cases, may be the only manifestation of tuberculosis.
 May fester for years before being recognized. It tends to be more destructive and resistant to control than pyogenic
osteomyelitis.
 In patients with acquired immunodeficiency syndrome, bone infection is usually multifocal.
 Spine (esp. thoracic and lumbar vertebrae) is the most common site of skeletal involvement followed by knees and
hips.
 Infection spreads through large areas of medullary cavity and causes extensive necrosis.
 In the spine (Pott disease), infection breaks through intervertebral discs to involve multiple vertebrae and extends
into the soft tissues, forming abscesses.

Morphology of Skeletal Syphilis

 Histology of congenital syphilitic bone infection is characterized by edematous granulation tissue containing numerous
plasma cells and necrotic bone.
 Also seen in acquired syphilis.
 Gummata also occur.
 Using special silver stains, spirochetes can be demonstrated in the inflammatory tissue.

Morphology of Osteoid Osteoma and Osteoblastoma

 Grossly, both are round to oval masses of hemorrhagic gritty tan tissue
 Histologically, they are well circumscribed and composed of a morass of randomly interconnecting trabeculae of
woven bone prominently rimmed by osteoblasts.
 Stroma surrounding the tumor bone consists of loose CT that contains many dilated and congested capillaries.
 The relatively small size and well-defined margins of the tumors plus the benign cytologic features of neoplastic
osteoblasts help distinguish them from osteosarcoma.
 Osteoid osteomas (esp. those that arise beneath periosteum) usually elicit tremendous amount of bone formation that
encircles the lesion.
 The nidus (actual tumor) manifests radiographically as a small round lucencythat is variably mineralized.

Morphology of Osteosarcoma
 Subtypes of osteosarcoma are recognized and grouped accdg to:
 Anatomic portion of the bone from which they arise (intramedullary, intracortical or surface).
 Degree of differentiation.
 Multicentricity (synchronous, metachronous).
 Primary (underlying bone is unremarkable) or secondary (e.g., osteosarcoma associated with pre-existing
disorders such as benign tumors, Paget disease, bone infarcts, previous irradiation).
 Histologic variants (osteoblastic, chondroblastic, fibroblastic, telangiectatic, small cell, and giant cell).
 Most common subtype: osteosarcoma that arises in the metaphysic of long bones.
 Primary, solitary, intramedullary and poorly differentiated.
 Produces a predominantly bony matrix.
 Grossly, osteosarcomas are bulky tumors that are gritty, gray-white, and often contain areas of hemorrhage and cystic
degeneration.
 Tumors frequently destroy surrounding cortices and produce soft tissue masses. They spread extensively in the
medullary canal, infiltrating and replacing the marrow surrounding the pre-existing bone trabeculae.
 Infrequently, tumors penetrate the epiphyseal plate or enter the joint. When joint invasion occurs, tumor grows into it
along tendinoligamentous structures or through the attachment site of the joint capsule.
 Tumor cells vary in size and shape and frequently have large hyperchromatic nuclei.
 Bizarre tumor giant cells and mitoses are common.
 Formation of bone by tumor cells (primary characteristic).
 Neoplastic bone has a coarse, lacelike architecture.

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  Also deposited in broad sheets or as primitive trabeculae..
 Other matrices (including cartilage or fibrous tissue) may be present in varying amounts.
 Chondroblastic osteosarcoma – tumor when malignant cartilage is abundant.
 Vascular invasion usually inconspicuous.
 Up to 50% to 60% of an individual tumor may demonstrate spontaneous necrosis.

Morphology of Osteochondroma
 Mushroom-shaped
 Size ranges from 1-20 cm
 Cap is composed of benign hyaline cartilage varying in thickness and is covered peripherally by perichondrium.
 Cartilage has appearance of disorganized growth plate and undergoes enchondral ossification, with the newly made
bone forming the inner portion of the head and stalk.
 Cortex of stalk merges with the cortex of the host bone so that the medullary cavity of the osteochondroma and bone
are in continuity.

Morphology of Chondroma
 Enchondromas are usually smaller than 3 cm.
 Gray-blue, translucent, and have nodular configuration.
 Microscopically, the nodules of cartilage are well-circumscribed and have a hyaline matrix; the neoplastic
chondrocytes that reside in lacunae are cytologically benign.
 At the periphery of the nodules, cartilage undergoes enchondral ossification; the center frequently calcifies and dies.
 Chondromas in Ollier disease and Maffucci syndrome may demonstrate a greater degree of cellularity and cytologic
atypia and may be difficult to distinguish from chondrosarcoma.

Morphology of Chondroblastoma
 Tumor is cellular and is composed of sheets of compact polyhedral chondroblasts that have well-defined cytoplasmic
borders, moderate amounts of pink cytoplasm, and nuclei that are hyperlobulated with longitudinal grooves.
 Mitotic activity and necrosis frequently present.
 Tumor cells surrounded by scant amounts of hyaline matrix that is deposited in a lacelike configuration; nodules of
well-formed hyaline cartilage are distinctly uncommon.
 A calcified matrix produces a characteristic chicken-wire pattern of mineralization.
 Scattered through the lesion are non-neoplastic osteoclast-type giant cells.
 Occasionally, tumors undergo prominent hemorrhagic cystic degeneration.

Morphology of Chondromyxoid Fibroma

 Tumors range from 3-8 cm in greatest dimension and are well-circumscribed, solid, and glistening tan-gray.
 Microscopically, there are nodules of poorly formed hyaline cartilage and myxoid tissue delineated by fibrous septae.
 Cellularity varies; areas of greatest cellularity are at the periphery of the nodules.
 In cartilaginous regions, tumor cells are situated in lacunae.
 In myxoid areas, cells are stellate, and their delicate cell processes extend through the mucinous ground substance
and approach or contact neighboring cells.
 Neoplastic cells show varying degrees of cytologic atypia, including the presence of large hyperchromatic nuclei.
 Other findings: small foci of calcification of the cartilaginous matrix and scattered, non-neoplastic, osteoclast-type
giant cells.

Morphology of Chondrosarcoma
 Conventional chondrosarcoma is composed of malignant hyaline and myxoid cartilage.
 Large bulky tumors are made up of nodules of gray-white, somewhat translucent glistening tissue.
 In predominantly myxoid variants, tumors are viscous and gelatinous and the matrix oozes from the cut surface.
 Spotty calcifications typically present; central necrosis may create cystic spaces.
 Adjacent cortex is thickened or eroded. The tumor grows with broad pushing fronts into the surrounding tissue.
 Malignant cartilage infiltrates the marrow space and surrounds pre-existing bony trabeculae.
 Tumors vary in degree of cellularity, cytologic atypia, and mitotic activity.
 Low-grade (Grade 1) lesions demonstrate mild hypercellularity, and the chondrocytes have plump vesicular nuclei
with small nucleoli. Binucleate cells are sparse, and mitotic figures are difficult to find. Portions of matrix frequently
mineralize, and cartilage may undergo enchondral ossification.
 Grade 3 chondrosarcomas are characterized by marked hypercellularity and extreme pleomorphism with bizarre
tumor giant cells and mitoses. Pure grade 3 chondrosarcomas are uncommon (such cartilage is more frequently a
component of chondroblastic osteosarcoma).
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 ~ 10% of conventional low-grade chondrosarcomas have a second high-grade component that has the morphology of
a poorly differentiated sarcoma (i.e. malignant fibrous histiocytoma, fibrosarcoma, osteosarcoma).
 Defines dedifferentiated chondrosarcomas.
 Hallmark of clear cell chondrosarcoma:
 Sheets of large malignant chondrocytes that have abundant clear cytoplasm.
 Numerous osteoclast-type giant cells.
 Intralesial reactive bone formation  causes confusion with osteosarcoma.
 Mesenchymal chondrosarcoma – composed of islands of well-differentiated hyaline cartilage surrounded by sheets
of small round cells, which can mimic Ewing sarcoma.

Morphology of Fibrous Cortical Defect and Nonossifying Fibroma

 Both produce elongated, sharply demarcated radiolucencies that are surrounded by a thin zone of sclerosis.
 Consist of gray and yellow-brown tissue and are cellular lesions composed of fibroblasts and histiocytes
(activated macrophages).
 The cytologically benign fibroblasts are frequently arranged in a storiform (pinwheel) pattern.
 Histiocytes are either multinucleated giant cells or clusters of foamy macrophages.

Morphology of Fibrous Dysplasia

 Grossly, lesions are well-circumscribed, are intramedullary, and vary greatly in size.
 Larger lesions expand and distort bone.
 Lesional tissue is tan-white and gritty and is composed of curvilinear trabeculae of woven bone surrounded by a
moderately cellular fibroblastic proliferation.
 Shapes of trabeculae mimic Chinese characters.
 Bone lacks osteoblastic rimming.
 Nodules of hyaline cartilage with the appearance of disorganized growth plate are also present in ~ 20% of cases.
 Other common findings: cystic degeneration, hemorrhage, and foamy macrophages.

Morphology of Fibrosarcoma and Malignant Fibrous Histiocytoma

 Grossly, these tumors are large, hemorrhagic, tan-white masses that destroy the underlying bone and frequently
extend into the soft tissues.
 Fibrosarcoma is composed of malignant fibroblasts arranged in a herringbone pattern.
 Level of differentiation determines the amount of collagen produced and the degree of cytologic atypia.
 Bizarre multinucleated cells are not common.
 Most have the appearance of low- to intermediate-grade malignancy.
 Malignant fibrous histiocytoma consists of a background of spindled fibroblasts arranged in a storiform pattern
admixed with large, ovoid, bizarre multinucleated tumor giant cells.
 Morphologically, some tumor cells resemble neoplastic histiocytes. However, they are actually fibroblasts.
 Is generally a high-grade pleomorphic tumor.

Morphology of Ewing Sarcoma and Primitive Neuroectodermal Tumor (PNET)

 Usually invade the cortex and periosteum (they arise from the medullary cavity), producing a soft tissue mass.
 Tumor is tan-white and frequently contains areas of hemorrhage and necrosis.
 Composed of sheets of uniform, small, round cells that are slightly larger than lymphocytes.
 Have scant cytoplasm, which may appear clear because it is rich in glycogen.
 Presence of Homer-Wright rosettes (where tumor cells are arranged in a circle about a central fibrillary space)
is indicative of neural differentiation.
 There is generally little stroma though it contains fibrous septae.
 Necrosis may be prominent. There are relatively few mitotic figures in relation to the dense cellularity of the tumor.

Morphology of the Giant Cell Tumor

 Tumors are large and red-brown and frequently undergo cystic degeneration.
 Composed of uniform oval mononuclear cells that have indistinct cell membranes.
 Appear to grow in syncytium.
 Mononuclear cells are the proliferating component; mitoses are frequent.
 Scattered are numerous osteoclast-type giant cells having 100 or more nuclei (they have identical features to
mononuclear cells).
 Common secondary features: necrosis, hemorrhage, hemosiderin deposition, reactive bone formation.
 Histologic differential diagnosis includes other giant cells lesions such as brown tumor seen in hyperparathyroidism,
giant cell reparative granuloma, chondroblastoma, and pigmented villonodular synovitis.

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 Morphologic identity between nuclei of the stromal cells and those of giant tumor cells helps distinguish giant cell
tumor from other lesions.

Morphology of Osteoarthritis
 In the early stages, chondrocytes proliferate  accompanied by biochemical changes (water content of matrix
increases and concentration of proteoglycans decreases).
 Vertical and horizontal fibrillation and cracking of the matrix occur as superficial layers of cartilage are
degraded.
 Gross examination reveals a granular articular surface that is softer than normal.
 Eventually, full-thickness portions of cartilage are sloughed; exposed subchondral bone plate becomes new articular
surface.
 Friction smoothes and burnishes exposed bone, giving it the bone eburnation appearance (polished ivory).
Concurrently, rebuttressing and sclerosis of underlying cancellous bone occurs.
 Small fractures through the articulating bone are common; dislodged pieces of cartilage and subchondral bone tumble
into the joint, forming loose bodies (joint mice).
 Fracture gaps allow synovial fluid to be forced into the subchondral regions (one-way, ball-valve-like mechanism).
Loculated fluid collection increases in size  form fibrous walled cysts.
 Mushroom-shaped osteophytes (bony outgrowths) develop at the margins of the articular surface and are capped by
fibrocartilage and hyaline cartilage that gradually ossify.
 Synovium shows minor alterations in comparison to destruction of articular surface and is congested and fibrotic, and
may have scattered chronic inflammatory cells.
 In severe disease, a fibrous synovial pannus covers the peripheral portions of the articular surface.

Morphology of Rheumatoid Arthritis

 Joints
 Most severe morphologic alterations.
 Initially, synovium becomes grossly edematous, thickened, and hyperplastic (smooth contour transformed into
one that’s covered by delicate and bulbous fronds)
 Characteristic histologic features:
 Infiltration of synovial stroma by dense perivascular inflammatory cells, consisting of B cells and
CD4+ helper T cells (often forming lymphoid follicles), plasma cells, and macrophages.
 Increased vascularity owing to vasodilation and angiogenesis, with superficial hemosiderin deposits.
 Aggregation of organizing fibrin covering portions of the synovium and floating in the joint space as
rice bodies.
 Accumulation of neutrophils in the synovial fluid and along the surface of synovium but usually not
deep in the synovial stroma.
 Osteoclastic activity in underlying bone (synovium is able to penetrate into the bone thereby forming
juxta-articular erosions, subchondral cysts, and osteoporosis)
 Pannus formation.
 Mass of synovium and synovial stroma consisting of inflammatory cells, granulation tissue, and
fibroblasts. It grows over the articular cartilage and causes its erosion.
 In time, after the cartilage has been destroyed, the pannus bridges the apposing bones, forming a
fibrous ankylosis, which eventually ossifies resulting in bony ankylosis.
 Arthritis is frequently accompanied by inflammation in tendons, ligaments, and occasionally the adjacent
skeletal muscle.
 Skin
 Rheumatoid nodules
 Most common cutaneous lesions.
 Occur in ~ 25% of patients, usually those with severe disease.
 Arise in regions of the skin subjected to pressure (ulnar aspect of forearm, elbows, occiput,
lumbosacral area). Less commonly, they form in the lungs, spleen, pericardium, myocardium, heart
valves, aorta, and other viscera.
 Firm, nontender, and round to oval.
 Arise in the subcutaneous tissue in the skin.
 Microscopically, they have a central zone of fibrinoid necrosis surrounded by a prominent rim of
epithelioid histiocytes and numerous lymphocytes and plasma cells.
 Blood vessels
 Patients with severe erosive disease, rheumatoid nodules, and high titers of rheumatoid factor are at risk for
developing vasculitic syndromes.
 Rheumatoid vasculitis is a potentially catastrophic complication of RA esp when it affects vital organs.

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  Involvement of medium to small arteries is similar to that occurring in polyarteritis nodosa except that in RA,
kidneys are not involved.
 Segments of small arteries (such as vasa nervorum and digital arteries) are obstructed by an obliterating
endarteritis  peripheral neuropathy, ulcers and gangrene.
 Leukocytoclastic venulitis produces purpura, cutaneous ulcers, and nail bed infarction.

Morphology of Gout
 Distinct morphologic changes:
 Acute arthritis
 Chronic tophaceous arthritis
 Tophi in various sites
 Sometimes, gouty nephropathy.
 Acute arthritis
 Characterized by a dense neutrophilic infiltrate that permeates the synovium and synovial fluid.
 Monosodium urate crystals frequently found in the cytoplasm of the neutrophils and arranged in small clusters
in the synovium. They are long, slender, and needle-shaped and are negatively birefringent.
 Synovium is edematous and congested, and also contains scattered lymphocytes, plasma cells, and
macrophages.
 When episode of crystallization abates and the crystals are resolubilized, the acute attack remits.
 Chronic tophaceous arthritis
 Evolves from the repetitive precipitation of urate crystals during acute attacks.
 Urates may heavily encrust the articular surfaces and form visible deposits in the synovium.
 Synovium becomes hyperplastic, fibrotic, and thickened by inflammatory cells and forms a pannus that
destroys the underlying cartilage, leading to juxta-articular bone erosions.
 In sever cases, fibrous or bony ankylosis ensues  partial to complete loss of joint function.
 Tophi
 Pathognomonic hallmark of gout.
 Formed by large aggregations of urate crystals surrounded by an intense inflammatory reaction of
macrophages, lymphocytes and large foreign body giant cells, which may have partially or completely
engulfed masses of crystals.
 May appear in the articular cartilage of joints and in periarticular ligaments, tendons, and soft tissues including
the olecranon and patellar bursae, Achilles tendons, and ear lobes.
 May occur less frequently in the kidneys, nasal cartilages, skin of the fingertips, palms, or soles as well as
elsewhere.
 Superficial tophi can lead to large ulcerations of the overlying skin.
 Gouty neuropathy
 Refers to the renal disorder associated with deposition of monosodium urate crystals in the renal medullary
interstitium, sometimes forming tophi, intratubular precipitations, or free uric acid crystals, and the production
of uric acid renal stones.
 Secondary complications (i.e. pyelonephritis) may ensue particularly when the urates induce some urinary
obstruction.

Morphology of Calcium Pyrophosphate Crystal Deposition Disease (PSEUDOGOUT)

 Crystals first develop in the articular matrix, menisci, and intervertebral discs. As deposits enlarge, they may rupture
and seed the joint.  once released into the joint, they elicit production of chemokines such as IL-8, which helps
produce an inflammatory infiltrate rich in neutrophils.
 Neutrophils are thought to produce damage through release of oxygen metabolites, catabolic enzymes, and
cytokines.  more chronic reactions associated with macrophages and fibrosis.
 Crystals form chalky white friable deposits  seen histologically as oval blue-purple aggregates.
 Individual crystals generally 0.5 to 5 µm in greatest dimension, are weakly birefringent and have geometric shapes.
 Rarely, crystals are deposited in masslike aggregates stimulating tophi.

Morphology of Pigmented Villonodular Synovitis and Giant Cell Tumor of Tendon Sheath
 Grossly, lesions of PVNS and GCT are both red-brown to mottled orange-yellow.
 In PVNS, the normally smooth joint synovium (of usually the knee) is converted into a tangled mat by red-brown folds,
finger-like projections, and nodules.
 GCT is localized and well-circumscribed, and resembles a small walnut.
 Tumor cells in both lesions are polyhedral, moderately sized, and resemble synoviocytes.
 In PVNS, they spread along the surface and infiltrate the subsynovial compartment.
 In GCT, cells grow in a solid nodular aggregate that may be attached to the synovium by a pedicle.

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 Other frequent findings: hemosiderin deposits, foamy macrophages, multinucleated giant cells, and zones of
sclerosis.

Morphology of Fatty Tumors

 The conventional lipoma (most common subtype) is a well-encapsulated mass of mature adipocytes that varies
considerably in size.
 Arises in the subcutis of proximal extremities and trunk, most frequently during mid-adulthood.
 Consist of mature white fat cells with no pleomorphism.
 Infrequently, lipomas are large, intramuscular, and poorly circumscribed.

Morphology of Liposarcoma
 Can be divided histologically into well-differentiated, myxoid, round cell, and pleomorphic variants.
 Cells in well-differentiated liposarcomas are readily recognized as lipocytes.
 In other variants, most of tumor cells are not obviously adipogenic, but some cells indicative of fatty differentiation
(lipoblasts) are almost always present.
 Lipoblasts mimic fetal fat cells and contain round clear cytoplasmic vacuoles of lipid that scallop the nucleus.
 Myxoid and round cell variant has a t(12;16) chromosomal abnormality in most cases.

Morphology of Nodular Fasciitis

 Lesions arise in the deep dermis, subcutis, or muscle.
 Grossly, lesion is several cm in greatest dimension, is nodular, and has poorly defined margins.
 Is richly cellular and consists of plump, immature-appearing fibroblasts arranged randomly or in short intersecting
fascicles.
 Cells vary in size and shape (spindle to stellate) and have conspicuous nucleoli and abundant mitotic figures.
 Frequently, stroma is myxoid and contains lymphocytes and extravasated RBCs.
 Histologic differential is extensive; should exclude fibromatosis and spindle cell sarcomas.
 Lesion rarely recurs after excision.

Morphology of Myositis Ossificans

 Grossly, usual lesions are 3-6 cm in greatest dimension.
 Most lesions are well delineated and have soft, glistening centers and a firm, gritty periphery.
 Microscopic findings vary according to age of lesion.
 Earliest phase: lesion is most cellular and consists of plump, elongated fibroblast-like cells (simulates nodular
fasciitis).
 Morphologic zonation begins within 3 weeks.
 Center retains its population of fibroblasts; however, it merges with an adjacent intermediate zone
that contains osteoblasts, which deposit ill-defined trabeculae of woven bone.
 Most peripheral zone contains well-formed, mineralized trabeculae that closely resemble cancellous bone.
Frequently, skeletal muscle fibers and regenerating muscle giant cells are trapped within the margins. 
eventually, entire lesion ossifies  intertrabecular spaces become filled with bone marrow  mature lesion
completely ossified.

Morphology of Deep-Seated Fibromatosis (Desmoid Tumors)

 Tumors occur as gray-white, firm, poorly demarcated masses varying from 1-15 cm in greatest diameter. They are
rubbery and tough and infiltrate surrounding tissues.
 (Histologically) Composed of plump fibroblasts arranged in broad sweeping fascicles that infiltrate to the adjacent
tissue.
 Mitoses usually infrequent.
 When trapped within these lesions, regenerating muscle cells may take on the appearance of multinucleated giant
cells.

Morphology of Benign Fibrous Histiocytoma (Dermatofibroma)

 Most consist of a proliferation of bland spindle cells arranged in a storiform pattern.
 Have infiltrative margins.
 Common secondary findings: presence of foam cells, hemosiderin deposits, multinucleated giant cells, and
hyperplasia of overlying epidermis.
 Most frequently arise in the dermis (they’re called dermatofibromas).
 Other types of benign fibrohistiocytic tumors: juvenile xanthogranuloma, epithelioid histiocytoma, and
reticulohistiocytoma.

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 Adequate treatment: simple excision.

Morphology of Malignant Fibrous Histiocytoma

 Tumors are usually large (5-20 cm), gray-white and unencapsulated. However, they often appear deceptively
circumscribed.
 Based on histologic features, they have been categorized into:
 Storiform-pleomorphic – most common; composed of malignant spindle cells oriented in a storiform pattern
with scattered, large round pleomorphic cells.
 Myxoid
 Inflammatory
 Giant cell
 Angiomatoid

Morphology of Rhabdomyosarcoma
 Histologically subclassified into the ff variants:
 Embryonal
 Alveolar
 Pleomorphic
 Rhabdomyoblast
 Diagnostic cell type in all variants
 Contains eccentric eosinophilic granular cytoplasm rich in thick and thin filaments.
 May be round or elongate (tadpole or strap cells).
 May contain cross-striations visible by light microscopy.
 Contains sarcomeres.
 Stain with antibodies to the myogenic markers desmin, MYOD1, and myogenin.
 Embryonal rhabdomyosarcoma
 Most common (~66% of cases)
 Includes sarcoma botryoides and spindle cell variants.
 Tumor occurs in children under age 10 years and typically arises in the nasal cavity, orbit, middle ear,
prostate, and paratesticular region.
 Commonly has allelic loss of chromosome 11p15.5 (its major genetic abnormality).
 Sarcoma botryoides subtype develops in the walls of hollow, mucosa-lined structures (i.e. nasopharynx,
common bile duct, bladder, and vagina).
 Grows in a polypoid fashion, producing the appearance of a cluster of grapes protruding into a hollow
structure such as the bladder or vagina.
 Most are present as a soft gray infiltrative mass.
 Tumor cells mimic skeletal muscle cells at various stages of embryogenesis and consist of sheets of both
malignant round and spindled cells in a variably myxoid stroma.  forms a submucosal zone of
hypercellularity (cambium layer) when the tumor abuts the mucosa of an organ.
 Rhabdomyoblasts with visible cross-striations may be present.
 Alveolar rhabdomyosarcoma
 Most common in early to mid-adolescence.
 Usually arises in the deep musculature of extremities.
 Tumor is traversed by a network of fibrous septae that divide the cells into clusters or aggregates; as the
central cells degenerate and drop out, a crude resemblance to pulmonary alveolae is created.
 Tumor cells moderate in size; many have little cytoplasm. Those in center of aggregates are discohesive
while those at periphery adhere to the septae.
 Cells with cross-striations are identified in ~25% of cases.
 Cytogenetic studies showed that this variant has a t(2;13) or t(1;13) chromosomal translocation.
 Pleomorphic rhabdomyosarcoma
 Characterized by numerous large, sometimes multinucleated, bizarre eosinophilic tumor cells.
 This variant is rare and has a tendency to arise in the deep soft tissue of adults.
 Can resemble malignant fibrous histiocytoma histologically.

Morphology of Leiomyosarcoma
 Present in painless firm masses.
 Retroperitoneal tumors may be large and bulky and cause abdominal symptoms.
 Characterized by malignant spindle cells that have cigar-shaped nuclei arranged in interweaving fascicles.
 Morphologic variants include tumors with prominent myxoid stroma and others with epithelioid cells.

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 Malignant smooth muscle cells contain bundles of thin filaments with dense bodies and pinocytotic vesicles, and
individual cells are surrounded by basal lamina. They stain with antibodies to vimentin, actin, smooth muscle actin,
and desmin immunohistochemically.

Morphology of Synovial Sarcoma

 Histologic hallmark of biphasic synovial sarcoma: dual line of differentiation of tumor cells (i.e. epithelial-like and
spindle cells).
 Despite mimicry of synovium, tumor cells do not have the features of synoviocytes.
 Epithelial cells cuboidal to columnar, and form glands or grow in solid cords or aggregates.
 Spindle cells are arranged in densely cellular fascicles that surround the epithelial cells.
 Most synovial sarcomas are monophasic  composed of only spindle cells or, rarely, epithelial cells.
 Lesions composed solely of spindled cells are easily mistaken for fibrosarcomas or malignant peripheral nerve sheath
tumors.
 Characteristic feature when present: calcified concretions (can sometimes be detected radiographically).
Immunochemistry is helpful in identifying these tumors  tumor cells yield positive reactions for keratin and epithelial
membrane antigen (differentiates them from most other sarcomas

CHAPTER 27
Peripheral Nerve and Skeletal Muscle

Dominant histopathologic finding:

Inflammation of peripheral nerve manifested as perivenular and endoneurial infiltration by lymphocytes, macrophages
and a few plasma cells.

 invading inflammatory cells vary in number from sparse seeding of the perivenous spaces to large collections of
mononuclear cells disseminated throughout the entire nerve
 segmental demyelination – primary lesion
 damage to axons is also characteristic, particularly in severe cases
o early effect on myelin sheaths easily identifiable by electron microscopy
o cytoplasmic processes of macrophages penetrate the basement membranes of Schwann cells
(particularly in the vicinity of the nodes of Ranvier), and extend between the myelin lamellae, stripping
away the myelin from the axon
o macrophages engulf myelin sheath remnants
o remyelination follows demyelination
 inflammatory foci and demyelination are widely distributes throughout the PNS (although intensity is variable)
 most intense inflammatory reaction – localized in spinal and cranial motor roots and adjacent parts of the spinal
and cranial nerves

Hereditary Motor and Sensory Neuropathy Type I (HSMN I)

 also called the Charcot-Marie-Tooth (CMT) disease, hypertrophic type

 usually presents in childhood or early adulthood
 a demyelinating neuropathy, both by nerve conduction velocity studies, and pathologically
 histologic examination shows the consequences of repeated demyelination and remyelination
o multiple onion bulbs – more pronounced in distal nerves than in proximal nerves
o axon is often present in the center of the onion bulb, with the myelin sheath usually thin or absent
o redundant layers of Schwann cell hyperplasia surrounding individual axons - associated with
enlargement of individual peripheral nerves which may be palpable (hence the term hypertrophic
neuropathy)
 in the longitudinal plane, individual segments may show evidence of segmental demyelination
 autopsy studies of individuals have shown degeneration of the posterior columns of the spinal cord

Patients may be asymptomatic, but common presenting symptoms are:

 distal muscle weakness
 atrophy of the calf
 secondary orthopedic problems of the foot (such as pes cavus)

Peripheral Neuropathy in Adult-Onset Diabetes Mellitus

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Distinct clinicopathologic patterns of diabetes-related periopheral nerve abnormalities have been identified:

1. Distal symmetric sensory/ sensorimotor neuropathy (most common)

a. Predominant pathologic finding is an axonal neuropathy
i. often some segmental demyelination
ii. there is relative loss of small myelinated fibers and of unmyelinated fibers, but large fibers are
also affected
b. Endoneurial arterioles show thickening, hyalinization, and intense PAS positivity in their walls, and also
extensive reduplication of the basement membrane
2. autonomic neuropathy
3. focal or multifocal asymmetric neuropathy

Spinal Muscular Atrophy (Infanitle Motor Neuron Disease)

Typical histologic finding in muscle: large numbers of atrophic fibers

 only a few micrometers in diameter, unlike the groups of angulated atrophic fibers seen in denervation atrophy of
muscles in adults
 muscle fiber atrophy often involves an entire fascicle (panfascicular atrophy)

There are also scattered large fibers that are two to four times the normal size.

X-linked Muscular Dystrophy (Duchenne Muscular Dystrohy and Becker Muscular Dystrophy)

DMD – absence of dystrophin

BMD – altered dystrophin size

Histopathologic abnormalities common to DMD and BMD:

1. Variation in fiber size (diameter) due to the presence of both small and enlarged fibers, sometimes with fiber
splitting
2. Increased numbers of internalized nuclei (beyond the normal range of 3-5%)
3. Degeneration, necrosis and phagocytosis of muscle fibers
4. Regeneration of muscle fibers
5. Proliferation of endomysial connective tissue

 DMD cases also show enlarged, rounded, hyaline fibers that have lost their normal cross – striations, believed to
be hypercontracted fibers (rare in BMD)
o Both type 1 and type 2 fibers are involved, and no alterations in the proportion or distribution of fiber types
are evident.
o Histochemical reactions sometimesfail to identify distinct fiber types in DMD
 In later stages, the muscles eventually become almost totally replaced by fat and connective tissue
 Cardiac involvement (when present) consists of interstitial fibrosis, more prominent in the subendocardial layers
 Despite clinical evidence of CNS dysfunction in DMD, no consistent neuropathologic findings have been
described

Myotonic Dystrophy

 skeletal muscle may show variation in fiber size

 striking increase in the number of internal nuclei (form conspicuous chains in longitudinal section)
 ring fiber – well-recognized abnormality; a subsarcolemmal band of cytoplasm that appears distinct from the
center of the fiber
o rim contains myofibrils oriented circumferentially around the longitudinally oriented fibrils in the rest of the
fiber
o may be associated with an irregular mass of cytoplasm (sarcoplasmic mass) extending outward from the
ring which stain:
 BLUE – hematoxylin and eosin
 RED – Gomori trichrome
 INTENSELY BLUE – NADH-TR reaction [nicotinamide adenine dinucleotide tetrazolium
reductase]

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  histochemical techniques have demonstrated a relative atrophy of Type I fibers early in the course of disease of
some cases
 the ONLY dystrophy that shows pathologic changes in the intrafusal fibers of muscle spindles, with fiber splitting,
necrosis and regeneration

Lipid Myopathies

Principal morphologic characteristic: accumulation of lipids within myocytes

 myofibrils are separated by vacuoles that stain with oil red O or sudan black and have the typical appearance of
lipid by EM
 vacuoles occur predominantly in Type 1 fibers, and are dispersed diffusely throughout the fiber

Mitochondrial Myopathies

Most consistent mitochondrial finding: aggregates of abnormal mitochondria that are demonstrable only by special
techniques
 occur under the subsarcolemma in early stages
 with severe involvement, may extend through out the fiber
 abnormal mitochondria impart a blotchy red appearance on the modified Gomori trichrome stain
 myofibrils are distorted, muscle fiber contour becomes irregular on cross-section (hence, “ragged, red fibers”)
 EM appearance:
o Increased numbers of, and abnormalities in the shape and size of mitochondria
o Paracrystalline parking lot intrusions/ alterations in the structure of cristae
 cytochrome oxidase activity – determined in muscle biopsy specimens using histochemistry
o cytochrome oxidase negative fibers may be present

Non-infectious Inflammatory Myopathies

Dermatomyositis
 inflammatory infiltrates located predominantly around small blood vessels and in the perimysial connective tissue
 groups of atrophic fibers are particularly prominent at the periphery of fascicles (perifascicular atrophy- sufficient
for diagnosis even if inflammation is mild or absent)
o most likely related to a relative state of hypoperfusion of the periphery of muscular fascicles
 dramatic reduction in intramuscular capillaries (result of vascular endothelial injury and fibrosis)
 necrotic muscle fibers and regeneration may also be seen throughout the fascicles

Polymyositis
 inflammatory cells are found in the endomysium
 CD8+ lymphocytes and other lymphoid cells surround and invade healthy muscle fibers
 necrotic and regenerating fibers seen throughout the fascicles, but without perifascicular atrophy
 no evidence of vascular injury

Inclusion Body Myositis

 presence of rimmed vacuoles
o within myocytes
o highlighted by basophilic granules at their periphery
 vacuolated fibers may also contain amyloid deposits that reveal typical staining with Congo Red
 under EM, tubular and filamentous inclusions are seen in the cytoplasm and nucleus
o composed of beta-amyloid or hyperphosphorylated tau
 pattern of inflammatory cell infiltrate is similar to that of polymyositis

Myasthenia Gravis
 specimens unrevealing under LM
 in severe cases, disuse changes with type 2 fiber atrophy may be found
o postsynaptic membrane is simplified, with loss of AChRs from the region of the synapse
o immune complexes as well as the membrane attack complex of the complement cascade (C5-C9) can
also be found along the postsynaptic membrane

CHAPTER 28
The Central Nervous System
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CEREBRAL EDEMA

- edematous brain softer than normal.

- Appears to ‘overfill cranial vault.
- (1) generalized edema: gyri flattened, intervening sulci narrowed, ventricular cavities compressed.
- As brain expands, herniation may occur.

PERENCYMAL INJURIES

Contusions seen on cross section are wedge-shaped,

- appearance independent on type of trauma

early stages – edema and hemorrhage. ( pericapillary)

next few hours – extravasations of blood to tissues, cerebral cortex, white matter and subarachnoid space.

Old trauma appearance: depressed, retracted, yellowish brown patches.

DIFFUSE AXONAL INJURY

Histopathology: wide, asymmetric distribution of axonal swellings.

Demonstrated with silver impregnation and immunoperoxidase stains.
-  # of microglia in related areas of cerebral cortex, and subsequently, degeneration of involved fiber
tracts.
-
SUBDURAL HEMATOMA

- appears as freshly clotted blood along contour of brain surface, w/o extension into depths of sulci.

- Underlying brain flattened, subarachnoid space often clear.

Sequence of subdural hematoma

(1) lysis of clot (about 1 week)

(2) Growth of fibroblast from dural surface into hematoma (2 weeks)
(3) Early development of hyalines connective tissue (1 – 3 months)

- Macroscopic view: lesion attached to fibrous tissue only to inner surface of dura.

-  Occurrence of multiple episodes of rebleeding “chronic subdural hematoma” due to thin walled vessels
of granulation tissue.

Subarachnoid and intraparenchymal hemorrhages most often occur with superficial contusions and lacerations.

Spat-apoplexie (Delayed posttraumatic hemorrhage) syndrome of sudden, deep intracerebral hemorrhage.

SPINAL CORD TRAUMA

- Hemorrhage, necrosis, axonal swelling in surround white matter.

- Lesion tapers above and below level of injury
- Central necrotic lesion becomes cystic and gliotic.
- Cord sections above and below lesion show secondary ascending and descending wallerian
degeneration.

HYPOTENSION, HYPOPERFUSION, LOW-FLOW STATES (Global Cerebral Ischemia)

- brain swollen, gyri widened, sulci narrowed.

- Cut surface shows poor demarcation between gray and white matter.

3 categories

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 (1) Early changes: 12-24 hours after insult, include acute neuronal cell change characterized
by microvacuolation, eosinophilia of neuronal cytoplasm, nuclear pyknosis and
karyortrhexis.

Pyramidal cells, sommer sector (CA1) of hippocampus, purkinje cells of cerebellum, pyramidal neurons in neocrotex –
most susceptible to global ischeimia of short duration.

(2) Subacute changes: 24 hrs – 2 wks

Necrosis of tissue, influx of macrophages, vascular proliferation, reactive gliosis.

(3) Repair: 2 wks.

Removal of all necrotic tissue, loss of organized CNS structure, gliosis. In cerebral cortex “
pseudolaminar necrosis”

Border zone “Watershed infarcts”.

Wedge shaped areas of infarct that occur in brain, spinal cord.

Often seen after hypotensive episodes.

Infarction from obstruction of local blood supply (Focal Cerebral Ischemia)

Non-hemorrhagic infarct

6 hrs of irreversible injury – little can be observed

48 hours – tissue: pale, soft, swollen, corticomedullary junction indistinct
2-10 days – brain becomes gelatinous, friable, more distinct boundaries between normal and abnormal.
10 – 3 wks – tissue liquefies.

In 12 hours – ischemic neuronal change

48 hrs – neutrophilic emigration progressively increases and falls off.
Several months – astrocytic nuclear and cytoplasmic enlargement recedes.

Incomplete infarction – occurs in focal cerebral ischemia

Spinal cord infarction – in hypoperfusion/consequence of interaction of feeding tributaries derived from aorta.

Intracerebral Hemorrhage /intraparenchymal

- may originate in putamen (50-60% of cases), thalamus, pons, cerebellar hemispheres.

“Ganglionic hemorrhages” – if it occurred in basal ganglia of thalamus

“Lobar Hemorrhages” – if it occurred in lobes of cerebral hemispheres.

I. Acute hemorrhage.
- extravasation of blood, w/ compression of adjacent parenchyma.

SACCULAR ANEURYSMS

Unruptured saccular aneurysm – thin walled outpouching at an arterial branch point along circle of Willis/or major vessel
just beyond.

Saccular aneurysms

- few mm to 2-3 cm in diameter.

- Bright red, shiny surface, thin, translucent wall.

Vascular Malformations

Arteriovenous malformations
- vessels in the subarachnoid space.or may occur exclusively within brain.
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Cavernous Hemangiomas
- loosely organized vascular channels with thin, collagenized wall, devoid of intervening nervous tissue.
- Occur most often in cerebellum, pons, subcortical regions decreasing order of frequency, low flow w/o
arteriovenous shunting.

Capillary telagiectasias
- microscopic foci of dilated, thin walled vascular channels separated by relatively normal brain
parenchyma occurring most frequently in pons.

Venous angiomas.
- aggregates of venous channels

Foix alajouanine disease – venous angiomatous malformation of spinal cord and overlying meninges

Acute pyogenic Meningitis

Normally clear CSF is cloudy, and purulent.

In Acute meningitis, exudates evident w/in leptomeninges over surface of brain.

Meningeal vessels are engorged and stand out prominently.

On microscopic exam: neutrophils fill entire subarachnoid space.

Acute Aseptic Viral Meningitis

- brain swelling.
- On microscopic exam: either no abnormality or a mild to moderate infiltration of leptomeninges with
lymphocytes.

Brain Abscess

on examination:
- Discrete lesions with central liquefactive necrosis, surrounding fibrous capsule, & edema
- exuberant granulation tissue with neovascularization around necrosis, responsible for marked vasogenic
edema.

Most common brain regions affected: frontal lobe, parietal lobe, cerebellum.

Chronic Bacterial Meningoencepalitis

- on examination:
- Subarachnoid space contains gelationous/fibrinous exudate, most often at base of brain.
- Mixtures of lymphocytes, plasma cells, macrophages.

Neurosyphilis
- Chronic meningitis involving base of brain.
1. Paretic neurosyphilis – caused by invasion of brain by treponema pallidum
- Causes progressive loss of mental and physical functions with alterations, and severe dementia.
On examination
- Inflammatory lesions associated with parenchymal damage in cerebral cortex.

Arthropod-Borne Viral Encephalitis

Characteristically: lymphocytic meningoencephalitis with tendency for inflammatory cells to accumulate perivasculary.
- Multiple foci of necrosis of gray & white matter found.

Herpes Simplex Virus Type 1 (HSV1)

- Starts & involves inferior and medial regions of temporal lobes and orbital gyri of frontal lobe.
- Infection necrotizing, often hemorrhagic.

Cytomegalovirus
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CMV can infect any type of cell w/in CNS (neurons, glia, ependma, endothelium).
- can attack lower spinal cord and roots – radiculoneuritis.

Poliomyelitis
Inflammation reaction -  contained to anterior horns but may extend to posterior horns, with damage sever to produce
cavation.

Rabies
On Examination
- brain with intense edema & vascular congestion
- neuronal degeneration and inflammatory reaction (severe in rhombencephalon)

HIV
On examination:
- meninges clear, ventricular dilation with sulcal widening, normal orticla thickness.

Progressive multifocal leukoencephalopathy (PML)

- patches of irregular, ill-defined destruction of white matter.

Fungal Meningoencephalitis

Other infectious diseases of the NS.

In toxoplasmosis of CNS

Transmissible Spongiform Encephalopathies (Prion Diseases)

Fatal Familial Insomnia

- neuronal loss and relative gliosis in anterior ventral and dorsomedial nuclei of thalamus.

Multiple Schlerosis

ADEM – acute disseminated encephalomyelitis and acute necrotizing hemorrhagic encephalomyelitis.

On examination:

- Grayish discoloration around white matter vessels.

- Myelin loss with preservation of axons.

Alzheimer Disease
-  cortical atrophy, wideing of cerebral sulci.
- Due to  atrophy, compensatory ventricular enlargement.
On examination
- has neuritic (senile) plaques, neurofibrillary tangles, and amyloid angiopathy.

Frontotemporal Dementia with Parkinsonism Linked to Chromosome 17 (FTD (P) – 17).

Pick disease

Progressive Supranuclear Palsy (PSP)

Corticobasal Degeneration CBD

Parkinson Disease
On Examination
- pallor of substantia nigra & locus ceruleus.
- Loss of pigmented, catecolaminergic neuron.

Lewy bodies found in remaining neurons.

: Single or multiple, cytopasmic, eosinophilic, round/elongated inclusion.
: Fine filaments, densely packed at center, loose at rim.
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Multiple System Atrophy
On examination
- atrophy of cerebellum, cerebellar peduncles, pons, medulla, substantia nigra, striatum.

Huntington Disease
On examination
- brain small, shows striking atrophy of caudate nucleus, and putamen
- globus pallidus may atrophy, lateral and third ventricles dilate.
- Note: Atrophy also seen in frontal lobe, parietal lobe, and cortex.
- Severe loss of striated neurons.

Spinocerebellar Ataxias –
Friedrich Ataxia
- degeneration of neurons in spinal cord, brainstem, cerebellum, and Betz cells of motor cortex.

Ataxia Telangiectasia
Abnormalities in:
 cerebellum, loss of purkinje and granule cells, degeneration of dorsal columns, spinocerebellar tracts, anterior horn cells
and peripheral neuropathy.

Amyotrophic Lateral Schlerosis (Motor Neuron Disease)

On examination
- anterior roots of spinal cord thin.
- Precentral gyrus atrophic
- Reduction in # of anterior horn neurons thoughout length of spinal cord.

Vitamin Deficiencies

Wernicke encephalopathy
Characterized by: Foci of hemorrhage and necrosis in mammilary bodies, adjacent to 3 rd & 4th ventricles.
- early lesion –dilated capillaries with prominent endothelial cells.

Fibrillary (Diffuse) Astrocytomas and Glioblastoma

On examination:
- Poorly defined, gray, infiltrative tumor that expands and distorts brain.
- Few cm to entire hemisphere.
- Firm/soft, gelatinous.
- Mild to moderate  in # of glial cell nuclei,

Anaplastic astroctyomas
- More densely cellular and have greater nuclear pleomorphism from well differentiated fibrillary
astrocytoma
- With mitotically active cells

Gemistocytic astocytoma – tumors in w/c predominant neoplastic astrocyte shows brightly esosinophilic cell body from w/c
emanate abundant, stout processes.

Glioblastoma
-siliar to amaplastic astrocytoma. But w/ necrosis and vascular or endothelial cell proliferation.

Pilocytic Astrocytoma
On examination
- cystic with mural nodule in wall of cyst.
- Solid: well circumscribed or sometimes, infiltrative.
- Tumor composed of bipolar cells with long, thin processes that are GFAP +.
- Have narrow infiltrative border w/ the surrounding brain.

Oligodendroglioma
I. On examination
- well circumscribed, gelatinous, gray masses, with cysts, focal hemorrhage and calcification.
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 - Composed of sheets of regular cells with spherical nuclei containing finely granular chromatin.
- Calcification present in 90% of tumors.
- Oligodendrogliomas – grade II/IV lesion of WHO

II. Anaplastic Oligodendrogliomas – grade iii/iv of Who

-  cell density, nuclear anaplasia,  mitotic activity and necrosis.

Ependymoma and Related Paraventricular Mass Lesions

Gangliocytomas
- Well-circumscribed masses with focal calcification and small cysts in floor of third ventricle,
hypothalamus, or temporal lobe.
- neoplastic ganglion cell present as clumps of cells
- -  in temporal lobe.

Neoplastic ganglion cells

- Irregularly clustered
- Graded as I to II/IV lesions.

Anaplastic gangliomas – grade III/IV lesions.

Papillary glioneuronal tumor.

- low grade lesion, glial cells

Glial-neuronal tumor
- small, round cells
- forms multiple discrete intracortical nodules what have myxoid background.

Medulloblastoma
- in children, located in midline of cerebellum. In adults, lateral.
- May lead to hydrocephalus
- Tumor often well circumscribed, gray, friable.
- On examination, extremely cellular, w/ sheets of anaplastic cells.

Atypical Teratoid/Rhabdoid Tumar (AT/RT)

- large with soft consistency and spread along surface of brain.
- Rhabdoid cells – eosinophilic cytoplasm, sharp cell borders, eccentrical nuclei.

Primary CNS Lymphoma

- involves cortex, deep gray matter and white matter.
-  grade lymphomas
- malignant cells infiltrate parenchyma of brain and accumulate around blood vessels

Meningiomas
- rounded masses, with well-defined dural base, compresses underlying brain.

Metastatic Tumors
ON examination
- intraparenchymal metastases form sharply demarcated masses.
- (Exception to rule: melanoma)

Schwannoma
- well circumscribed, encapsulated masses attached to nerve.
- - firm, gray masses, with cystic and xanthomatous change
- 2 growth patterns
- (1) antoni A – elongated cells with cytoplasmic processes are arranged in fascicles.
- (2) antoni B – less densely cellular with loose meshwork of cells among mucrocysts and myxoid changes.

Neurofibroma
I. Cutaneous neurofibroma
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 - present in dermis and subcutaneous fat.
- Not invasive.
-  clagenized
-  myxoid material

II. Plexiform neurofibroma

- may arise anywhere along a nerve. ( large nerve trunk)
-  multiple
- at lesion, nerve irregularly expanded

Malignant Peripheral Nerve Sheath Tumor (PNST, Malignant Schwannoma)

- poorly defined tumor masses
-  infiltrating along axis of parant nerve.
- Necrosis  present.
- May resemble schwann cells with elongated nuclei and prominent bipolar processes.

Tuberous Schlerosis
- likened to potatoes. Ü

Von Hippel-Lindau Disease.

On examination

- lesion consists of a mixture of variable proportions of capillary size or somewhat larger thin-walled vessels with
intervening stromal cells of uncertain histogenesis characterized by vacuolated, lightly PAS-positive, lipid-rich cytoplasm
and indefinite immunohistochemical phenotype.

CHAPTER 29
The Eye

I. Orbit

Idiopathic orbital inflammation

1. characterized histologically by chronic inflammation and variable degrees of fibrosis

i. inflammatory infiltrate – lymphocytes, plasma cells and eosinophils
2. typically confined to orbit but may develop concomitantly with sclerosing inflammation in the retroperitoneum,
mediastinum and thyroid
3. Presence of germinal centers – raise suspicion of a reactive lymphoid hyperplasia
4. Presence of elements of vasculitis – suggestive of underlying systemic vasculitis
5. Presence of necrotic collagen with vasculitis – raise suspicion of Wegener’s granulomatosis

II. Neoplasms

Sebaceous carcinoma (moderately differentiated/well differentiated)

1. vacuolization of the cytoplasm

-helps in the diagnosis
2. can mimic a variety of other malignancies histologically
3. may spread through the:
a. conjunctival epithelium
b. epidermis to the lacrimal drainage system
c. nasopharynx
d. lacrimal gland ductules of the lacrimal gland

III. Corneal Degenerations and Dystrophies

Keratoconus

1. thinning of the cornea with breaks in the Bowman’s layer

2. Corneal hydrops
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 a. sudden effusion of aqueous humor in the corneal stroma from the anterior chamber
b. may cause vision to worsen suddenly
c. may be followed by corneal scarring that can contribute to visual loss
d. can complicate Descemet’s membrane ruptures that develop:
i. secondary to extraordinary elevations of intraocular pressure in infantile glaucoma
ii. following obstetrical forceps injury to the eye

IV. Uvea

Uveitis

1. characterized by diffuse granulomatous inflammation of the uvea

2. plasma cells typically absent
3. eosiniophils present

Uveal Melanomas

1. contain two types of cells

a. spindle – fusiform in shape and have little atypia
b. epitheliod cells – spherical and have greater cytologic atypicality
2. location affects clinical course
a. exclusively in iris – relatively indolent course
b. ciliary body and choroid – more aggressive
-prognosis is classically related to size, cell type (epitheloid-worse prognosis) and
proliferative index
3. Other Prognostic factors
a. extraocular extension – poor prognosis
b. monosomy 3 and trisomy 8 – poor prognosis
c. presence of histologically looping patterns rich in laminin that surround packets of tumor cells-poor
i. connect to blood vessels and serve as extravascular conduits for transport of plasma
and blood
ii. patterns formed by vasculogenic mimicry

V. Retinal Neoplasms

Retinoblastoma

1. may contain both undifferentiated and differentiated elements

a. undifferentiated type – collections of small, round cells with hyperchromatic nuclei
b. well-differentiated type – Flexner-Wintersteiner rosettes and fleurettes reflecting
photoreceptors
2. degree of tumor differentiation not associated with prognosis
3. viable tumor cells encircling tumor blood vessels with zones of necrosis in relatively avascular areas
4. also characterized by focal zones of dystrophic calcification

VI. Optic Nerve

Glaucomatous Optic Nerve Damage

1. diffuse loss of ganglion cells and thinning of retinal nerve fiber layer
2. optic nerve is cupped and atrophic in advanced cases
3. elevated intraocular pressure in infants and children can lead to:
a. buphthalmos – diffuse enlargement of the eye
b. megalocornea – enlargement of the cornea
4. after reaching adult size Prolonged elevation of IOP may lead to:
a. focal thinning of sclera
b. staphyloma – lining of uveal tissue with ectatic sclera
5. cornea may become edematous
6. formation of degenerative pannus

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