CL. PATHOLOGY (Q.

1-90)

1) The subject of pathology.

Pathology is the study of suffering. It is a discipline that bridges clinical practice and basic
science and it involves the investigation of the causes (etiology) of disease as well as the
underlying mechanisms (pathogenesis) that result in the presenting signs and symptoms of the
patient. Pathologists use a variety of molecular, microbiologic and immunologic techniques to
understand the biochemical, structural and functional changes that occur in cells, tissues and
organs. To render diagnoses and guide therapy, pathologists identify changes in the gross or
microscopic appearance (morphology) of cells and tissues and biochemical alterations in body
fluids (such as blood and urine). The discipline is divided into general pathology (focuses on the
fundamental cellular and tissue responses to pathologic stimuli) and systemic pathology
(examines the particular responses of specialized organs).

2) Congenital heart disease.

Congenital heart disease (CHD) is a defect in the structure of the heart and great vessels which
is present at birth. Many types of heart defects exist, most of which either obstruct blood flow
in the heart or vessels near it, or cause blood to flow through the heart in an abnormal pattern.
Etiology: the cause may be either genetic or environmental, but is usually a combination of
both. In few patients, a specific cause can be identified, such as transplacental infection of the
fetus by rubeola virus (1st trimester). Chromosomal abnormalities may be associated with CHD,
high incidence of defects of the atrioventricular valves in Down syndrome. Some drugs, such as
thalidomide were shown to cause severe defects in the fetus including cardiac anomalies.. Fetal
alcohol syndrome is another cause due to high amounts of alcohol used during early
pregnancy.
Classification:
Congenital heart anomalies are of two major types: shunts and obstructions.
Shunts: abnormal communications between heart chambers, between large vessels or
between chambers and vessels.
Common defects are classified according to:
1- which side of the heart is involved,

2- whether there is a communication (shunt) between both sides,

3- in the defect with shunt, if there is a cyanosis (a bluish color of the skin and mucous
membranes caused by increased amount of reduced hemoglobin in arterial blood).
Obstruction: typically coarctation, valvular stenoses (partial occlusion) and atresias
(complete occlusion). These do not cause cyanosis.
CHD with left-to-right shunts (CHD with late cyanosis)
These include atrial (abnormal opening in the atrial septum that allows free communication of
blood) and ventricular septal defects (abnormal opening in the ventricular septum that allows
free communication between left and right ventricles) and patent ductus arteriosus (in the
fetus, the ductus arteriosus is a normal fetal vascular channel that connects the pulmonary
artery and the aorta permitting to by-pass the inactive fetal lungs; after the birth, the ductus
closes spontaneously by muscle spasm within 1 to 2 days of life). At early stage these
anomalies are without cyanosis, but the increased blood pressure in right side induces chronic
right heart overload with pulmonary hypertension and right ventricle hypertrophy, this results
in reversal of the direction of blood flow, leads to a development of right-to-left shunt and that
means that unoxygenated blood is then shunted to the left heart which causes late cyanosis.
CHD with right-to-left shunts (CHD with early cyanosis)
These include tetralogy of Fallot (it is characterized by large ventricular septal defects,,
dextroposed aorta overriding the ventricular septal defect,, stenosis of the pulmonary tract with
RV outflow obstruction,, hypertrophy of the right ventricle)), truncus arteriosus and
transpositions of large heart arteries. Secondary finding in long-standing cyanotic HD induce
clubbing of the fingers and toes, hypertrophic osteopathy and polycythemia. Cyanosis is
present from birth because the stenosis of pulmonary artery causes right-to-left shunt from the
very beginning, early cyanosis (blue babies).
CHD with obstruction of blood flow without cyanosis
These include coarctation of the aorta (narrowing or stenosis of the aorta), aortic valvular
stenosis and pulmonary valvular stenosis. Two types of the coarctation of the aorta:
preductal type manifests early in life and may cause rapid death; survival depends on
the ability of the ductus arteriosus to sustain blood flow to the distal aorta and to the
lower body adequately- even then- severe lower body cyanosis often associated with
fetal RV hypertrophy and early right heart failure.
postductal type the adult type because this type of anomaly is generally
asymptomatic until adult life. It usually leads to hypertension in the upper extremity,

but weak pulses and low blood pressure in the lower extremities causes arterial
insufficiency, often claudications and coldness of the lower extremity.. Collateral flow
around stenosis of the aorta develops with mammary and axillary arteries dilatation.

3) Atherosclerosis epidemiology, risk factors, pathogenesis.

Atherosclerosis is a condition in which an artery wall thickens as a result of the accumulation of
fatty materials such as cholesterol and triglyceride. An atheromatous plaque consists of a raised
lesion with a soft, yellow, grumous core of lipid (mainly cholesterol and cholesterol esters)
covered by a firm, white fibrous cap . Besides obstructing blood flow, atherosclerotic plaques
weaken the underlying media and can themselves rupture, causing acute catastrophic vessel
thrombosis. Atheromatous plaques (also called fibrous or fibrofatty plaques) impinge on the
lumen of the artery and grossly appear white to yellow; thrombosis superimposed over the
surface of ulcerated plaques is red-brown in color. Plaques vary from 0.3 to 1.5 cm in diameter
but can coalesce to form larger masses.
Epidemiology: Although atherosclerosis usually manifests in later life, its early phases are
present in teenagers and young adults. The clinical manifestations of atherosclerosis, such as
CVD cardiovascular diseases, are common in Western and urban populations and are an
important and common cause of death and disease.
Risk factors:
-Hyperlipidemia: more specifically hypercholesterolemia. The major component of serum
cholesterol associated with increased risk is low-density lipoprotein (LDL) cholesterol ("bad
cholesterol"). LDL cholesterol has an essential physiologic role delivering cholesterol to
peripheral tissues. In contrast, high-density lipoprotein (HDL, "good cholesterol") mobilizes
cholesterol from developing and existing atheromas and transports it to the liver for excretion
in the bile.
-Hypertension: both systolic and diastolic levels are important.
-Cigarette Smoking
-Diabetes mellitus: induces hypercholesterolemia as well as a markedly increased
predisposition to atherosclerosis.
Pathogenesis: The first stage of atherosclerosis is endothelial damage and dysfunction, which
stimulates the accumulation and oxidation of LDL-C in the vessel wall. Monocytes migrate from
the blood into the subendothelial intima and transform into macrophages, which accumulate
lipids to form the lipid core of the atherosclerotic plaque. Thrombotic and inflammatory
processes are central to atherosclerotic lesion formation. Production of inflammatory

mediators and cytokines stimulate migration and proliferation of smooth muscle cells of the
vascular intima, and deposition of extracellular matrix molecules such as elastin and collagen,
which leads to plaque expansion and the formation of the fibrous cap. Eventually the fibrous
cap may weaken and rupture, exposing the underlying thrombogenic tissues. Plaque rupture
can cause continued development of the atherosclerotic lesion by inducing further thrombus
formation and release of more inflammatory mediators, resulting in continued luminal
narrowing. A more drastic outcome of plaque rupture is arterial occlusion, which can result in
myocardial infarction, ischemic stroke, or critical ischemia in peripheral tissues.

4) Atherosclerosis types of atherosclerotic changes. Organs involvement in

atherosclerosis. Complications.
Atherosclerosis is a condition in which an artery wall thickens as a result of the accumulation of
fatty materials such as cholesterol and triglyceride. An atheromatous plaque consists of a raised
lesion with a soft, yellow, grumous core of lipid (mainly cholesterol and cholesterol esters)
covered by a firm, white fibrous cap . Besides obstructing blood flow, atherosclerotic plaques
weaken the underlying media and can themselves rupture, causing acute catastrophic vessel
thrombosis. Atheromatous plaques (also called fibrous or fibrofatty plaques) impinge on the
lumen of the artery and grossly appear white to yellow; thrombosis superimposed over the
surface of ulcerated plaques is red-brown in color. Plaques vary from 0.3 to 1.5 cm in diameter
but can coalesce to form larger masses.
Types of atherosclerotic changes and organs involvement in atherosclerosis:
Chronic endothelial injury, with resultant endothelial dysfunction, causing increased
permeability, leukocyte adhesion, and thrombosis. Accumulation of lipoproteins: mainly LDL
("bad cholesterol") and its oxidized forms in the vessel wall. Monocyte adhesion to the
endothelium: followed by migration into the intima and transformation into macrophages and
foam cells. Endothelial Injury: early human lesions begin at sites of morphologically intact
endothelium. Non-denuding endothelial dysfunction underlies human atherosclerosis. In the
setting of intact but dysfunctional ECs (=endothelial cells) there is increased endothelial
permeability, enhanced leukocyte adhesion, and altered gene expression. Two most important
causes of endothelial dysfunction are hemodynamic disturbances and hypercholesterolemia.
Hemodynamic Disturbance: the importance of hemodynamic turbulence in atherogenesis is
illustrated by the observation that plaques tend to occur at ostia of exiting vessels, branch
points and along the posterior wall of the abdominal aorta, where there are disturbed flow
patterns. Lipids: are typically transported in the bloodstream bound to specific apoproteins
(forming lipoprotein complexes). Chronic hyperlipidemia, particularly hypercholesterolemia,
can directly impair EC function by increasing local production of reactive oxygen species. With

chronic hyperlipidemia, lipoproteins accumulate within the intima. These lipids are oxidized
through the action of oxygen free radicals locally generated by macrophages or ECs. Oxidized
LDL is ingested by macrophages through a scavenger receptor, distinct from the LDL receptor,
resulting in foam-cell formation. In addition, oxidized LDL stimulates the release of growth
factors, cytokines, and chemokines by ECs and macrophages that increase monocyte
recruitment into lesions. Monocytes transform into macrophages and avidly engulf
lipoproteins, including oxidized LDL. Monocyte recruitment and differentiation into
macrophages is protective, since these cells remove potentially harmful lipid particles. In
humans, the abdominal aorta is typically much more frequently involved than the thoracic
aorta. In descending order, the most extensively involved vessels are the lower abdominal
aorta, the coronary arteries, the popliteal arteries, the internal carotid arteries.
Complications:
-Rupture, ulceration, or erosion: of the luminal surface of atheromatous plaques exposes the
bloodstream to highly thrombogenic substances and induces thrombus formation. Such
thrombi can partially or completely occlude the lumen and lead to downstream ischemia.
-Hemorrhage into a plaque: rupture of the overlying fibrous cap or of the thin-walled vessels in
the areas of neovascularization can cause intra-plaque hemorrhage; a contained hematoma
may expand the plaque or induce plaque rupture.
-Atheroembolism: plaque rupture can discharge debris into the bloodstream, producing
microemboli composed of plaque contents.
-Aneurysm formation: atherosclerosis-induced pressure or ischemic atrophy of the underlying
media, with loss of elastic tissue, causes weakness of the vessel wall and development of
aneurysms that may rupture.

5) Ischemic heart disease. Categories.

Ischemic heart disease is caused by plaque building up along the inner walls of the arteries of
the heart, which narrows the arteries and reduces blood flow to the heart.
Angina (stable and unstable): chest pain due to inadequate blood supply to the heart itself

from the coronary arteries. Pain results for too little blood reaching the heart muscle. Stable
angina: It can likely predict when it will happen. It happens when the heart is working harder
and needs more oxygen, such as during exercise. It also may occur during exposure to cold or
during times of emotional stress. The pain goes away when you rest or take nitroglycerin. It
may continue without much change for years. Unstable angina: Unstable angina is unexpected.
It happens when blood flow to the heart is suddenly slowed by narrowed vessels or small blood

clots that form in the coronary arteries. Unstable angina is a warning sign for a heart attack. It is
an emergency and may happen at rest.
Myocardial Infarction: a disease characterized by ischemia (reduced blood supply) of the
heart muscle causing the heart cells to be damaged or die (necrosis), usually due to occlusion
(blockage) of coronary artery due to an unstable buildup of white blood cells, cholesterol and
fat.

6) Ischemic heart disease myocardial infarction.

Ischemic heart disease is caused by plaque building up along the inner walls of the arteries of
the heart, which narrows the arteries and reduces blood flow to the heart.
Myocardial infarction (MI): is a disease characterized by ischemia (reduced blood supply) of the
heart muscle causing the heart cells to be damaged or die (necrosis), usually due to occlusion
(blockage) of coronary artery due to an unstable buildup of white blood cells, cholesterol and
fat.
Morphology: The gross and microscopic appearance of an MI depends on the interval of time
since the original injury. MIs less than 12 hours old are usually not grossly apparent. However,
infarcts more than 3 hours old can be visualized by exposing heart slices to vital stains (ex.
triphenyl tetrazolium chloride). Because dehydrogenases are depleted in the area of ischemic
necrosis an infarcted area is revealed as an unstained pale zone. By 12 to 24 hours after MI, an
infarct can usually be grossly identified by a reddish blue discoloration caused by stagnant,
trapped blood. Progressively thereafter, an infarct becomes more sharply delineated as a
yellow-tan, softened area; by 10 to 14 days infarcts become rimmed by hyperemic granulation
tissue. Over the succeeding weeks the MI evolves to a fibrous scar. Typical features of
coagulative necrosis become detectable within 4 to 12 hours of infarction. Necrotic
myocardium elicits acute inflammation (typically most prominent 1-3 days after MI), followed
by a wave of macrophages to remove necrotic myocytes and neutrophil fragments (most
pronounced 5-10 days after MI). The infarcted zone is progressively replaced by granulation
tissue (most prominent 2-3 weeks after MI), which in turn forms the provisional scaffolding
upon which dense collagenous scar is formed.
Etiology: risk increases with age, smoking, hypercholesterolemia (high cholesterol levels),
diabetes and hypertension and is more common in men and those who have close relatives
with ischemic heart disease.
Pathogenesis: it results from the partial interruption of blood supply to a part of the heart
muscle, causing the heart cells to be damaged or die. This is most commonly due to occlusion
(blockage) of a coronary artery following the rupture of a vulnerable atherosclerotic plaque,

which is an unstable collection of cholesterol and fatty acids and white blood cells in the wall of
an artery. The resulting ischemia (restriction in blood supply) and ensuing oxygen shortage, if
left untreated for a sufficient period of time, can cause damage or death (infarction) of heart
muscle tissue (myocardium).
Symptoms: include sudden retrosternal chest pain (typically radiating to the left arm or left side
of the neck), shortness of breath, nausea, vomiting, palpitations, sweating and anxiety.
Clinical forms: according to the assumed proximate cause of the myocardial infarction:
Type 1: MI consequent to a pathologic process in the wall of the coronary artery (e.g. plaque
erosion/rupture, fissuring, or dissection)
Type 2: MI consequent to increased oxygen demand or decreased supply (e.g. coronary artery
spasm, coronary artery embolus, anemia, arrhythmias, hypertension or hypotension)
Type 3: Sudden unexpected cardiac death before blood samples for biomarkers could be drawn
or before their appearance in the blood
Type 4a: MI associated with percutaneous coronary intervention
Type 4b: MI associated with stent thrombosis
Type 5: MI associated with coronary artery bypass graft surgery
Diagnosis: Diagnosis of IHD is with X-ray of the chest, an electrocardiogram (elevated ST), blood
tests (cardiac markers like creatine kinase-MB), cardiac stress testing or a coronary angiogram.

7) Chronic ischemic heart disease.

Ischemic heart disease is caused by plaque building up along the inner walls of the arteries of
the heart, which narrows the arteries and reduces blood flow to the heart.
Chronic ischemic heart disease: stable angina pectoris.
Acute ischemic heart disease: unstable angina pectoris, myocardium infarction.
Angina (stable): chest pain due to inadequate blood supply to the heart itself from the
coronary arteries. Pain results for too little blood reaching the heart muscle. It can likely predict
when it will happen. It happens when the heart is working harder and needs more oxygen, such
as during exercise. It also may occur during exposure to cold or during times of emotional
stress. The pain goes away when you rest or take nitroglycerin. It may continue without much
change for years.
The anatomic causes of angina pectoris may be divided according to anatomic sites as follows:
(1) the major coronary arterial trunks and their epicardial branches, (2) the coronary ostia at
the aorta and (3) the intramyocardial "small" arteries.

Morphology: In coronary angiography there is constriction of one or more of the coronary

arteries and their branches, occasionaly artherosclerotic plaque calcifications can be seen in the
cardiac shadow on a chest radiograph. At gross examination, the heart varies in size: normal,
small (atrophic) or large (compensatory hypertrophy), dilated (in patients with congestive heart
failure). Endocardium and pericardium are normal or with white plaques, corresponding to
fibrosis. On section surface, the myocardium has a "tiger-spotted" aspect, due to intermingled
normal myocardium (red) and fibrosis (white). Large areas of scarring might be visible if the
patient had a previous infarct. Microscopically, one can see small fibrous scars (with collagen
fibers) surrounding viable myocardial cells (fibers), normal, with atrophy or with hypertrophy
("tiger-spotted" aspect). Also, might be present focal myocytolisis: isolated "empty" myocardial
cells (no nuclei, no striations, eosinophilic cytoplasm).
Symptoms: pain in chest, neck, arms or abdomen, shortness of breath, nausea, vomiting,
irregular heartbeat, fatigue.
Diagnosis: ECG (ST depression, T wave inversion), lab tests (increased cardiac biomarkers
cardiac specific troponins), coronary angiogram.
Treatment: nitroglycerin vasodilator that makes more oxygen available to the heart. Beta
blockers and calcium channel blockers decrease hearts workload.

8) Systemic arterial hypertension heart and vascular pathology.

Arterial hypertension: is a chronic medical condition in which the blood pressure in the arteries
is elevated.
Heart pathology in hypertension:
Systemic hypertensive heart disease is diagnosed when there is (1) left ventricular hypertrophy
(usually concentric) in the absence of other causal cardiovascular pathology (ex. valvular
stenosis) and (2) a history or pathologic evidence of hypertension. Even mild hypertension
(levels only slightly above 140/90 mm Hg), if sufficiently prolonged, induces left ventricular
hypertrophy.
Morphology:
The essential feature of hypertensive heart disease is left ventricular hypertrophy, typically
without ventricular dilation. The left ventricular wall thickness may exceed 2.0 cm and the heart
weight may exceed 500 gm. The increased thickness of the left ventricular wall imparts a
stiffness that impairs diastolic filling. This often induces left atrial enlargement. Microscopically,
myocyte diameter increases, typically associated with prominent, somewhat irregular nuclear
enlargement and hyperchromasia ("box-car nuclei"); there is also increased interstitial fibrosis.

Vascular pathology in hypertension:

In addition to accelerating atherogenesis, hypertension-associated degenerative changes in the
walls of large and medium arteries can potentiate both aortic dissection and cerebrovascular
hemorrhage. Hypertension is also associated with two forms of small blood vessel disease:
hyaline arteriolosclerosis and hyperplastic arteriolosclerosis.
Morphology:
-Hyaline Arteriolosclerosis: this vascular lesion consists of a homogeneous pink hyaline
thickening of the walls of arterioles with loss of underlying structural detail and with narrowing
of the lumen. Encountered frequently in elderly patients, whether normotensive or
hypertensive, hyaline arteriolosclerosis is more generalized and more severe in patients with
hypertension. It is also common as part of the characteristic microangiography in diabetes.
-Hyperplastic Arteriolosclerosis: related to more acute or severe elevations of blood pressure,
hyperplastic arteriolosclerosis is characteristic of (but not limited to) malignant hypertension
(typically, diastolic pressures over 120 mm Hg associated with acute cerebral and/or renal
injury). Hyperplastic arteriolosclerosis is associated with "onion-skin," concentric, laminated
thickening of the walls of arterioles with luminal narrowing. In malignant hypertension, the
hyperplastic changes are accompanied by fibrinoid deposits and vessel wall necrosis
(necrotizing arteriolitis), particularly prominent in the kidney.

9) Pulmonary hypertension.
Pulmonary hypertension (PH): is an increase of blood pressure in the pulmonary artery,
pulmonary vein, or pulmonary capillaries. Pulmonary hypertension is most often secondary to
a decrease in the cross-sectional area of the pulmonary vascular bed, or to increased
pulmonary vascular blood flow. It affects the right side of the heart. Pulmonary hypertension
begins when tiny arteries in the lungs, called pulmonary arteries and capillaries become
narrowed, blocked or destroyed. This makes it harder for blood to flow through thelungs and
raises pressure within lungs' arteries. As the pressure builds, the right ventricle must work
harder to pump blood through the lungs, eventually causing the heart muscle to weaken and
eventually fail.
PH: is arterial, venous, hypoxic, thromboembolic, or miscellaneous.
Etiology: Chronic obstructive or interstitial lung disease causes increased pulmonary arterial
resistance and secondarily, elevated arterial pressure. Recurrent pulmonary emboli leads to
increased vascular resistance. Antecedent heart disease (ex. mitral stenosis), which increases
left atrial pressure, leading to higher pulmonary venous pressures, and ultimately pulmonary

arterial hypertension. Congenital left-to-right shunts are another cause of pulmonary

hypertension.
Morphology: vascular alterations in all forms of pulmonary hypertension (primary and
secondary) involve the entire arterial tree and include: (1) in the main elastic arteries,
atheromas similar to those in systemic atherosclerosis; (2) in medium-sized muscular arteries,
proliferation of myointimal cells and smooth muscle cells, causing thickening of the intima and
media with narrowing of the lumina; and (3) in smaller arteries and arterioles, thickening,
medial hypertrophy, and reduplication of the internal and external elastic membranes. In these
vessels, the wall thickness may exceed the diameter of the lumen, which is sometimes
narrowed to the point of near-obliteration. Individuals with severe, long-standing primary
pulmonary hypertension may develop plexogenic pulmonary arteriopathy, so called because a
tuft of capillary formations is present, producing a network, or web, that spans the lumens of
dilated thin-walled, small arteries.
Pathogenesis: pulmonary arterial hypertension involves the vasoconstriction of blood vessels
connected to and within the lungs. This makes it harder for the heart to pump blood through
the lungs. Over time, the affected blood vessels become both stiffer and thicker, in a process
known as fibrosis. This further increases the blood pressure within the lungs and impairs their
blood flow. In addition, the increased workload of the heart causes hypertrophy of the right
ventricle, making the heart less able to pump blood through the lungs, ultimately causing right
heart failure. As the blood flowing through the lungs decreases, the left side of the heart
receives less blood. This blood may also carry less oxygen than normal.
Symptoms: shortness of breath, fatigue, non-productive cough, angina pectoris, peripheral
edema (swelling around the ankles and feet), and rarely hemoptysis (coughing up blood).

10) Rheumatic heart disease.

Rheumatic fever (rheumatic heart disease)
Inflammatory disease that occurs following a Streptococcus pyogenes infection, such as scarlet
fever.
Morphologic Features:
-ASCHOFF BODIES OR NODULES:

Classic lesions of rheumatic fever

Spheroidal or fusiform. 1-2mm in size. May be visible to the naked eye

Found in the vicinity of small vessels in the myocardium, endocardium, occasionally the
pericardium and adventitia of proximal part of aorta.

Its an area of focal interstitial myocardial inflammation characterized by fragmented

collagen and fibroid material.

Large cells (anitschkow myocytes)

And occasionally multinucleated giant cells (aschoff cells)

Etiology: caused by antibody cross-reactivity that can involve the heart, joints, skin and brain. It
develops two to three weeks after the infection.
Pathogenesis: the valves most affected: mitral, aortic, tricuspid and pulmonary valves. In acute
disease, small thrombi form along the lines of valve closure. In chronic disease, there is
thickening and fibrosis of the valve resulting in stenosis or regurgitation. T-cells that are
responsive to the Streptococcal M-protein infiltrate the valve through the valvular
endothelium, activated by the binding of antistreptococcal carbohydrates with release or tumor
necrosis factor (TNF) and interleukins.
Symptoms: abdominal pain, nose bleeds, fever.
Diagnosis: history of an infection (with group A streptococcal bacteria) either by laboratory
documentation (rapid strep test) or positive strep culture and must have two major or one
major and two minor criteria findings. Major: polyarthritis, carditis, congestive heart failure
with shortness of breath, pericarditis with new heart murmur. Minor: leukocytosis, ECG
showing heart block such as a prolonged PR interval, orthralgia, fever.
Treatment: anti-inflammatory medications such as aspirin or corticosteroids.

11) Endocarditis classification. Infective endocarditis acute and subacute.

Endocarditis is an inflammation of the inner layer of the heart, the endocardium. It usually
involves the heart valves (native or prosthetic valves). Endocarditis is characterized by a
prototypic lesion, the vegetation, which is a mass of platelets, fibrin, microcolonies of
microorganisms, and scant inammatory cells.
Classification is based on etiology: either infective (acute and subacute) or non-infective,
depending on whether a microorganism is the source of the inflammation or not. Infective
endocarditis (IE) is classified into acute and subacute forms, mostly on the basis of clinical
tempo and severity; the distinctions are attributable to the intrinsic microbial virulence and
whether underlying cardiac disease is present.

Acute: most often occurs when an aggressive species of skin bacteria, especially a
staphylococcus aureus, enters the bloodstream and attacks a normal, undamaged heart valve.
Once staph bacteria begin to multiply inside the heart, they may send small clumps of bacteria
called septic emboli into the bloodstream to spread the infection to other organs, especially to
the kidneys, lungs and brain. If lesft untreated, this form of endocarditis can be fatal in less than
six weeks.
Subacute: is caused by one of the viridans group of streptococci (Streptococcus sanguis,
mutans, mitis or milleri) that normally live in the mouth and throat. Subacute endocarditis
tends to involve heart valves that already are damaged in some way, and it usually is less likely
to cause septic emboli than acute endocarditis. If untreated, subacute bacterial endocarditis
can worsen for as long as one year before it is fatal.
Morphology: In both acute and subacute forms of the disease, friable, bulky, and potentially
destructive vegetations containing fibrin, inflammatory cells, and microorganisms are present
on the heart valves.The aortic and mitral valves are the most common sites of infection,
although the tricuspid valve is a frequent target in the setting of intravenous drug abuse.
Vegetations may be single or multiple and may involve more than one valve; they can erode
into the underlying myocardium to produce an abscess cavity (ring abscess) . The appearance of
vegetations is influenced by the infecting organism, the degree of host response, and antibiotic
therapy. Fungal endocarditis, for example, tends to cause larger vegetations than does bacterial
infection. Systemic emboli may occur at any time because of the friable nature of the
vegetations. Because the embolic fragments contain large numbers of virulent organisms,
abscesses often develop at the sites of such infarcts (septic infarcts). Subacute endocarditis is
typically associated with less valvular destruction than is acute endocarditis. Microscopically, in
subacute IE vegetations often have granulation tissue at their bases, suggesting chronicity. As
time passes, fibrosis, calcification, and a chronic inflammatory infiltrate may develop.
Symptoms: fever of unknown origin, malaise and endurance fatigue, a new or changing heart
murmur, weight loss, and coughing. Other signs may include: night sweats, rigors, anemia,
splenomegaly, clubbing.

12) Valvular heart disease types.

Valve pathology can lead to occlusion (stenosis) and/or to regurgitation (insufficiency). Valve
disease can be congenital (present at birth) or may be acquired later in life.
Types:

-Aortic stenosis, aortic valve is narrowed; the aortic valve is the valve between the left ventricle
of the heart and the aorta.
-Aortic regurgitation, abnormal leaking of the aortic valve of the heart that causes blood to
flow in the reverse direction during ventricular diastole, from the aorta into the left ventricle.
-Mitral stenosis, narrowing of the mitral valve; almost all cases of mitral stenosis are due to
disease in the heart secondary to rheumatic fever and the consequent rheumatic heart disease.
-Mitral regurgitation, abnormal leaking of blood from the left ventricle, through the mitral
valve, and into the left atrium, when the left ventricle contracts, i.e. there is regurgitation of
blood back into the left atrium.
-Pulmonary valve stenosis
-Pulmonary valve regurgitation
-Tricuspid valve stenosis
-Tricuspid valve regurgitation
Calcification (calcific aortic stenosis is heaped-up calcified masses on the outflow side of the
cusps) of valve substance typically results in stenosis; abnormal extracellular matrix synthesis
and turnover can result in myxomatous degeneration (mitral valve prolapse is a primary form of
myxomatous mitral degeneration and causes the tissues of the valve to become abnormal and
stretchy, causing the valve to leak.) and insufficiency. Pulmonary and tricuspid valve diseases
are right-side heart diseases: rheumatic heart disease, dysplasia. Rheumatic heart disease
results from formation of anti-streptococcal antibodies that cross-react with cardiac tissue.
Pericardium, myocardium, and the valves are involved by acute inflammation; healing is
associated with mitral and less commonly, aortic valve disease. Infective endocarditis can be
aggressive and rapidly destroy normal valves (acute IE) or can be indolent and minimally
destructive of previously abnormal valves (subacute IE). It occurs when germs (especially
bacteria) enter the blood stream and attach to the surface of your heart valves. Systemic
embolization may produce septic infarcts. Nonbacterial thrombotic endocarditis (NBTE) gives
rise to sterile vegetations on previously normal valves in states of general debility. Embolic
complications can occur.

13) Myocarditis.
Myocarditis is inflammation of heart muscle (myocardium), with an inflammatory infiltrate, and
damage to the heart muscle, without the blockage of coronary arteries that define a heart
attack (myocardial infarction) or other common non-infectious causes.
Morphology: During active myocarditis the heart may appear normal or dilated. The ventricular
myocardium is typically flabby and often mottled by patchy or diffuse foci of pallor and/or
hemorrhage. Mural thrombi can be present. Microscopically, active myocarditis shows an
interstitial inflammatory infiltrate, with focal necrosis of myocytes adjacent to the inflammatory
cells. Lymphocytic myocarditis is most common. Hypersensitivity myocarditis has interstitial
and perivascular infiltrates composed of lymphocytes, macrophages, and a high proportion of
eosinophils. Giant-cell myocarditis is a morphologically distinctive entity characterized by

widespread inflammatory cellular infiltrates containing multinucleate giant cells (formed by

macrophage fusion) interspersed with lymphocytes, eosinophils, and plasma cells. Giant-cell
myocarditis probably represents the aggressive end of the spectrum of lymphocytic
myocarditis, and there is at least focal-and frequently extensive-necrosis. Chagas myocarditis is
distinctive by virtue of the parasitization of scattered myofibers by trypanosomes accompanied
by an inflammatory infiltrate of neutrophils, lymphocytes, macrophages, and occasional
eosinophils.
Symptoms: chest pain, Congestive heart failure (leading to edema, breathlessness and hepatic
congestion), Palpitations (due to arrhythmias), Fever (especially when infectious, ex. in
rheumatic fever).

14) Cardiomyopathies.
The cardiomyopathies are a group of diseases that affect the heart muscle itself and are not the
result of hypertension or congenital or acquired valvular, coronary, or pericardial abnormalities. When
the cardiomyopathies are classified on an etiologic basis two forms are recognized: 1) a primary type,
consisting of heart muscle disease of unknown cause, and (2) a secondary type, consisting of myocardial
disease of known cause or associated with a disease involving other organ systems. It is often more
desirable to classify the cardiomyopathies into one of three types (dilated, hypertrophic, restrictive).

1-Dilated Cardiomyopathy (DCM): is characterized by progressive cardiac dilation and

contractile (systolic) dysfunction, usually with concurrent hypertrophy. It is sometimes called
congestive cardiomyopathy. Approximately 25% to 35% have genetic basis.
Morphology: The heart in DCM is characteristically enlarged (two to three times its normal
weight) and flabby, with dilation of all chambers. Because of the wall thinning that accompanies
dilation, the ventricular thickness may be less than, equal to, or greater than normal. Mural
thrombi are common and may be a source of thromboemboli. There is no primary valve
pathology; any valvular insufficiency is a secondary consequence of ventricular chamber
dilation. The coronary arteries are usually free of significant atherosclerotic stenosis.
Microscopically most myocytes are hypertrophied with enlarged nuclei, but many are
attenuated, stretched, and irregular. There is variable interstitial and endocardial fibrosis;
scattered scars are also often present, probably marking previous myocyte ischemic necrosis
caused by reduced perfusion (due to poor contractile function) and increased demand (due to
myocyte hypertrophy).
2-Hypertrophic Cardiomyopathy (HCM): is characterized by myocardial hypertrophy, abnormal
diastolic filling, and-in a third of cases-ventricular outflow obstruction. The obstruction, in some
cases, is dynamic, caused by the anterior leaflet of the mitral valve. The heart is thick-walled,
heavy, and hypercontracting, in striking contrast to the flabby, poorly contractile heart in DCM.

Systolic function is usually preserved in HCM, but the myocardium does not relax and therefore
shows primary diastolic dysfunction.
Morphology: The essential gross feature of HCM is massive myocardial hypertrophy without
ventricular dilation. The classic pattern of HCM involves disproportionate thickening of the
ventricular septum relative to the left ventricle free wall (called asymmetrical septal
hypertrophy). In about 10% of cases there is concentric hypertrophy. On longitudinal
sectioning, the ventricular cavity loses its usual round-to-ovoid shape and is compressed into a
"banana-like" configuration. Often present is an endocardial plaque in the left ventricular
outflow tract, as well as a thickening of the anterior mitral leaflet. Both findings reflect contact
of the anterior mitral leaflet with the septum during ventricular systole and correlate with
functional left ventricular outflow tract obstruction.The characteristic histologic features in
HCM are severe myocyte hypertrophy, myocyte (and myofiber) disarray, and interstitial and
replacement fibrosis.
3-Restrictive Cardiomyopathy: is characterized by a primary decrease in ventricular
compliance, resulting in impaired ventricular filling during diastole (simply put, the wall is
stiffer). The contractile (systolic) function of the left ventricle is usually unaffected.
Morphology: In idiopathic restrictive cardiomyopathy the ventricles are of approximately
normal size or slightly enlarged, the cavities are not dilated, and the myocardium is firm. Biatrial
dilation is commonly observed. Microscopically there is interstitial fibrosis, varying from
minimal and patchy to extensive and diffuse. Restrictive cardiomyopathy of disparate causes
may have similar gross morphology. However, endomyocardial biopsy can reveal diseasespecific features (e.g., amyloid, iron overload, sarcoid granulomas).

15) Pericarditis. Vasculitis. Aneurysms.

Pericarditis: is an inflammation of the pericardium (the fibrous sac surrounding the heart).
Depending on the time of presentation and duration, pericarditis is divided into "acute" and
"chronic" forms. Acute pericarditis is more common than chronic pericarditis, and can occur as
a complication of infections, immunologic conditions, or even as a result of a heart attack
(myocardial infarction). Chronic pericarditis however is less common, a form of which is
constrictive pericarditis.
Morphology: The appearance of acute pericarditis varies slightly depending on its cause. In
patients with viral pericarditis or uremia, the exudate is typically fibrinous, imparting an
irregular (even shaggy) appearance to the pericardial surface (so-called bread-and-butter
pericarditis). In acute bacterial pericarditis the exudate is fibrinopurulent (suppurative), often
with areas of frank pus; tuberculous pericarditis can show areas of caseation. Pericarditis due to

malignancy is often associated with an exuberantly shaggy fibrinous exudate and a bloody
effusion; metastases can be grossly evident as irregular excrescences or may be relatively
inapparent, especially in the case of leukemia. In most cases, acute fibrinous or fibrinopurulent
pericarditis resolves without any sequelae. However, when there is extensive suppuration or
caseation, healing can result in fibrosis (chronic pericarditis). The appearance of chronic
pericarditis ranges from delicate adhesions to dense, fibrotic scars that obliterate the
pericardial space. In extreme cases the heart is so completely encased by dense fibrosis that it
cannot expand normally during diastole, so-called constrictive pericarditis.
Vasculitis is a group of disorders that destroy blood vessels by inflammation. According to the
size of the vessel affected, vasculitis can be classified into:
-Large vessel: ex. Takayasu's arteritis, temporal arteritis
-Medium vessel: ex. Kawasaki disease, polyarteritis nodosa
-Small vessel: ex. cutaneous vasculitis
Takayasus arteritis morphology: involves the aortic arch but in a lot of cases also affects the
remainder of the aorta and its branches. Gross changes include intimal hyperplasia and
irregular thickening of the vessel wall; when the aortic arch is involved, the origin for the great
vessels can be markedly narrowed or even obliterated. Such narrowing explains the weakness
of the peripheral pulses; coronary and renal arteries may be similarly affected. Histologically,
the changes range from adventitial mononuclear infiltrates with perivascular cuffing of the vasa
vasorum, to intense mononuclear inflammation in the media, to granulomatous inflammation,
replete with giant cells and patchy medial necrosis. As the disease progresses, collagenous
scarring, with admixed chronic inflammatory infiltrates, occurs in all three layers of the vessel
wall. Prominent intimal involvement causes the luminal narrowing and obliteration.
Occasionally, aortic root involvement causes dilation and aortic valve insufficiency.
Temporal arteritis morphology: a chronic, typically granulomatous inflammation of large to
small-sized arteries. Involved arterial segments in giant-cell arteritis develop nodular intimal
thickening with reduction of the lumen and occasional thrombosis. Classical lesions show
granulomatous inflammation within the inner media centered on the internal elastic
membrane; there is a lymphocyte and macrophage infiltrate, with multinucleated giant cells,
and fragmentation of the internal elastic lamina . Occasionally, granulomas and giant cells are
rare or absent, and lesions show only a nonspecific panarteritis with a mixed infiltrate
composed predominantly of lymphocytes and macrophages with scattered neutrophils and
eosinophils.

Polyarteritis nodosa (PAN) morphology: a systemic vasculitis of small or medium-sized

muscular arteries (but not arterioles, capillaries, or venules), typically involving renal and
visceral vessels but sparing the pulmonary circulation. During the acute phase there is
transmural inflammation of the arterial wall with a mixed infiltrate of neutrophils, eosinophils,
and mononuclear cells, frequently accompanied by fibrinoid necrosis. Luminal thrombosis can
occur. Later, the acute inflammatory infiltrate is replaced by fibrous (occasionally nodular)
thickening of the vessel wall that can extend into the adventitia. Characteristically, all stages of
activity (from early to late) may coexist in different vessels or even within the same vessel,
suggesting ongoing and recurrent pathogenic insults.
Kawasaki Disease the vasculitis of Kawasaki disease is PAN-like, with pronounced
inflammation affecting the entire thickness of the vessel wall; nevertheless, the fibrinoid
necrosis is usually less prominent in Kawasaki disease than in PAN. Although the acute vasculitis
subsides spontaneously or in response to treatment, aneurysm formation, or thrombosis and
myocardial infarction, can supervene. As with other causes of arteritis, healed lesions may have
obstructive intimal thickening.
Aneurysms: is a localized, blood-filled balloon-like bulge in the wall of a blood vessel. Types:
Aortic aneurysms abdominal aortic and thoracic aortic aneurysms, Cerebral aneurysms,
Peripheral aneurysms. An aneurysm occurs when part of a blood vessel (artery) or cardiac
chamber swells, - either the blood vessel is damaged or there is a weakness in the wall of the
blood vessel. As blood pressure builds up it balloons out at its weakest point. The swelling can
be quite small or very large - when large it tends to extend along the blood vessel. As the
aneurysm grows there is a greater risk of rupture - this can lead to severe hemorrhage, and
other complications, including sudden death. Atherosclerosis, the most common cause of
aneurysms, causes thinning and weakening of the media secondary to intimal plaques. Such
plaques compress the underlying media and also compromise nutrient and waste diffusion
from the vascular lumen into the arterial wall. The media consequently undergoes
degeneration and necrosis, thus allowing the dilation of the vessel. Atherosclerotic aneurysms
occur most frequently in the abdominal aorta but the common iliac arteries, the arch, and
descending parts of the thoracic aorta can also be involved.

16) Heart failure left-sided, right-sided, total.

Heart failure: inability of the heart to supply sufficient blood flow to meet the needs of the
body. Heart failure is caused by any condition which reduces the efficiency of the myocardium,
or heart muscle, through damage or overloading.
Left-sided: The most common causes of left-sided cardiac failure are (1) Ischemic Heart
Disease, (2) systemic hypertension, (3) mitral or aortic valve disease, and (4) primary diseases of

the myocardium. Backward failure of the left ventricle causes congestion of the pulmonary
vasculature, and so the symptoms are respiratory in nature. Backward failure can be subdivided
into failure of the left atrium, the left ventricle or both within the left circuit. The patient will
have dyspnea on exertion and in severe cases, dyspnea at rest.
Morphology: Findings in the heart depend on the underlying disease process; for example,
myocardial infarction or valvular deformities may be present. Except in cases of mitral valve
stenosis (or other processes that restrict left ventricular size), the left ventricle is usually
hypertrophied and often dilated, sometimes quite massively. There are usually nonspecific
changes of hypertrophy and fibrosis in the myocardium. Secondary enlargement of the left
atrium with resultant atrial fibrillation can reduce stroke volume or lead to blood stasis and
thrombus formation; a fibrillating left atrium carries a substantially increased risk of embolic
stroke. The extracardiac effects of left-sided heart failure are manifested most prominently in
the lungs. Rising pressure in the pulmonary veins is ultimately transmitted retrogradely to the
capillaries, resulting in pulmonary congestion and edema. The lungs are heavy and boggy, and
histologically there are perivascular and interstitial transudate, alveolar septal edema, and
intra-alveolar edema. Moreover, capillary leakiness leads to the accumulation of erythrocytes
(containing hemoglobin) that are phagocytosed by macrophages. Within macrophages,
hemoglobin is converted to hemosiderin and hence hemosiderin-containing macrophages in
the alveoli (called heart failure cells) are evidence of prior of pulmonary edema.
Right sided: Right-sided heart failure is usually the consequence of left-sided heart failure.
Backward failure of the right ventricle leads to congestion of systemic capillaries. This generates
excess fluid accumulation in the body.
Morphology: The liver is usually increased in size and weight (congestive hepatomegaly), and a
cut section displays prominent passive congestion, a pattern referred to as nutmeg liver;
congested red centers of the liver lobules are surrounded by paler, sometimes fatty, peripheral
regions. In some instances, especially when left-sided heart failure is also present, severe
central hypoxia produces centrilobular necrosis along with the sinusoidal congestion. With
long-standing severe right-sided heart failure, the central areas can become fibrotic, creating
so-called cardiac cirrhosis. Fluid may accumulate in the pleural space (particularly right) and
pericardial space (effusions). While pulmonary edema indicates left-sided heart failure, pleural
effusions accompany both right-sided and left-sided heart failure. Pleural effusions (typically
serous) can range from 100 mL to well over 1 L and can cause partial atelectasis of the affected
lung. Unlike inflammatory edema, the edema fluid in CHF has a low protein content. Peripheral
edema of dependent portions of the body, especially ankle (pedal) and pretibial edema, is a
hallmark of right-sided heart failure. In chronically bedridden patients, the edema may be
primarily presacral. Generalized massive edema is called anasarca.

17) Veins pathology varicous veins, phlebothrombosis, thrombophlebitis.

Varicose veins varices: are veins that have become enlarged and tortuous. The term
commonly refers to the veins on the leg, although varicose veins can occur elsewhere. Veins
have leaflet valves to prevent blood from flowing backwards. . When veins become varicose,
the leaflets of the valves no longer meet properly, and the valves do not work (valvular
incompetence). This allows blood to flow backwards and they enlarge even more. Varicose
veins are more common in women than in men, and are linked with heredity. Other related
factors arepregnancy, obesity, menopause, aging, prolonged standing, leg injury, and
abdominal straining.
Morphology: Varicose veins show wall thinning at the points of maximal dilation with smooth
muscle hypertrophy and intimal fibrosis in adjacent segments. Elastic tissue degeneration and
spotty medial calcifications (phlebosclerosis) also occur. Focal intraluminal thrombosis (due to
stasis) and venous valve deformities (rolling and shortening) are common. Esophageal varices:
Liver cirrhosis (less frequently, portal vein obstruction or hepatic vein thrombosis) causes portal
vein hypertension. Portal hypertension leads to the opening of porto-systemic shunts,
increasing blood flow into veins at the gastroesophageal junction (forming esophageal varices),
the rectum (forming hemorrhoids) and periumbilical veins of the abdominal wall (forming a
caput medusa). Esophageal varices are the most important, since their rupture can lead to
massive (even fatal) upper GI hemorrhage.
Symptoms: heavy legs, ankle swelling (especially in evening), brownish-yellow shiny skin
discoloration near the affected veins, redness, dryness, itchiness of areas of skin, cramps may
develop, minor injuries to the area may bleed more than normal or take a long time to heal.
Treatment: elevating the legs often provides temporary symptomatic relief, anti-inflammatory
medication such as ibuprofen or aspirin.
Phlebothrombosis: occurs when a blood clot in a vein (venous thrombosis) forms
independently from the presence of inflammation of the vein (phlebitis).
Symptoms: are tenderness and pain in the area of the affected vein, redness and/or swelling
can also be seen. In superficial phlebothrombosis, the location of the clot may sometimes be
seen by the unaided eye.
Treatment: Taking nutritional supplements; supplements which help prevent blood clots and
keep veins healthy include B-complex vitamins, especially folic acid, vitamin B6 and vitamin
B12, vitamin C and vitamin E. Limiting fat intake; saturated and hydrogenated fats are related
to increased risk of thrombosis and poor blood circulation.

Thrombophlebitis: is phlebitis (vein inflammation) related to a thrombus (blood

clot). Thrombophlebitis is when a venous thrombosis does result from phlebitis.
Symptoms: pain in the part of the body affected, skin redness or inflammation (not always
present), swelling (edema) of the extremities (ankle and foot), palpable cord-like veins.
Diagnosis: Doppler ultrasound, Extremity arteriography, Blood clotting tests.
Treatment: analgesics (pain medications), anticoagulants e.g. warfarin or heparin to prevent
new clot formation, thrombolytics to dissolve an existing clot such as intravenous
streptokinase, nonsteroidal anti-inflammatory medications (NSAIDS) such as ibuprofen to
reduce pain and inflammation.

18) Connective tissue diseases Systemic lupus erythematodes.

Dermatomyositis.
Systemic lupus erythematosus (SLE): is a multisystem autoimmune disease of protean
manifestations and variable behavior. Clinically, it is an unpredictable, remitting and relapsing
disease of acute or insidious onset that may involve virtually any organ in the body; however, it
affects principally the skin, kidneys, serosal membranes, joints, and heart. Immunologically, the
disease is associated with an enormous array of autoantibodies, classically including antinuclear
antibodies (ANAs).
Morphology: The morphologic changes in SLE are extremely variable and depend on the nature
of the autoantibodies, the tissue in which immune complexes deposit and the course and
duration of disease. The most characteristic morphologic changes result from the deposition of
immune complexes in a variety of tissues. An acute necrotizing vasculitis affecting small arteries
and arterioles may be present in any tissue. The arteritis is characterized by necrosis and by
fibrinoid deposits within vessel walls containing antibody, DNA, complement fragments, and
fibrinogen; a transmural and perivascular leukocytic infiltrate is also frequently present. In
chronic stages, vessels show fibrous thickening with luminal narrowing. Kidney involvement is
one of the most important clinical features of SLE, with renal failure being the most common
cause of death. The focus here is on glomerular pathology, although interstitial and tubular
lesions are also seen in SLE. These evoke an inflammatory response that may cause
proliferation of the endothelial, mesangial, and/or epithelial cells and, in severe cases, necrosis
of the glomeruli. The spleen may be moderately enlarged. Capsular fibrous thickening is
common, as is follicular hyperplasia with numerous plasma cells in the red pulp. Central
penicilliary arteries characteristically show thickening and perivascular fibrosis, producing
onion-skin lesions. Pericardium and pleura, in particular, are serosal membranes that show a
variety of inflammatory changes in SLE ranging (in the acute phase) from serous effusions to

fibrinous exudates and progressing to fibrous opacification in the chronic stage. Involvement of
the heart is manifested primarily in the form of pericarditis. Myocarditis, in the form of a
nonspecific mononuclear cell infiltrate, and valvular lesions, called Libman-Sacks endocarditis,
also occur but are less common in the current era of aggressive corticosteroid therapy.
Treatment can include corticosteroids and anti-malarial drugs.
Dermatomyositis (DM): is a connective-tissue disease related to polymyositis that is
characterized by inflammation of the muscles and the skin. While DM most frequently affects
the skin and muscles, it is a systemic disorder that may also affect the joints, the esophagus, the
lungs, and, less commonly, the heart. It may result from either a viral infection or an
autoimmune reaction.
Morphology: Dermatomyositis occurs more commonly in female patients. It presents as a
proximal symmetrical muscle weakness with vasculitis affecting the skin, muscles and internal
organs. Patients find it hard to raise their arms to comb their hair or walk up the stairs due to
the proximal muscle weakness. It can be severe enough to affect the muscles needed for
speech and swallowing and is also known to cause respiratory compromise. Calcinosis can occur
in the skin, joints and tissues. "Gottron's papules" (pink patches on the knuckles and other
extensor surfaces) and priapism are associated with this disorder. Other skin manifestations
involve periungual telangiectasias and a heliotropic (purple) rash over the upper eyelids. The
rash also may come and go, and may not be dependent on the severity of the muscle
involvement at the time. Cross sections of muscle reveal muscle fascicles with small, shrunken
polygonal muscle fibers on the periphery of a fascicle surrounding central muscle fibers of
normal, uniform size. Aggregates of mature lymphocytes with small, dark nuclei and scant
cytoplasm are seen surrounding vessels. Both B- and T-cells are present in approximately equal
numbers.

19) Connective tissue diseases Polyarteritis nodosa, Sclerodermia. Rheumatoid

arthritis.
Polyarteritis nodosa (PAN): is a systemic vasculitis of small or medium-sized muscular arteries
(but not arterioles, capillaries, or venules), typically involving renal and visceral vessels but
sparing the pulmonary circulation.
Morphology: Classic PAN is characterized by segmental transmural necrotizing inflammation of
small to medium-sized arteries. Vessels of the kidneys, heart, liver, and GI tract are involved in
descending order of frequency. Lesions usually involve only part of the vessel circumference,
with a predilection for branch points. The inflammatory process weakens the arterial wall and
can lead to aneurysms or even rupture. Impaired perfusion with ulcerations, infarcts, ischemic

atrophy, or hemorrhages in the distribution of affected vessels may be the first sign of disease.
During the acute phase there is transmural inflammation of the arterial wall with a mixed
infiltrate of neutrophils, eosinophils, and mononuclear cells, frequently accompanied by
fibrinoid necrosis. Luminal thrombosis can occur. Later, the acute inflammatory infiltrate is
replaced by fibrous (occasionally nodular) thickening of the vessel wall that can extend into the
adventitia. Characteristically, all stages of activity (from early to late) may coexist in different
vessels or even within the same vessel, suggesting ongoing and recurrent pathogenic insults.
Sclerodermia: It is characterized by excessive fibrosis throughout the body and not just the
skin.
-Skin. The vast majority of patients have diffuse, sclerotic atrophy of the skin, usually beginning
in the fingers and distal regions of the upper extremities and extending proximally to involve
the upper arms, shoulders, neck, and face. In the early stages, affected skin areas are
somewhat edematous and have a doughy consistency. Histologically, there are edema and
perivascular infiltrates containing CD4+ T cells. Capillaries and small arteries (as large as 500 m
in diameter) may show thickening of the basal lamina, endothelial cell damage, and partial
occlusion. With progression, the edematous phase is replaced by progressive fibrosis of the
dermis, which becomes tightly bound to the subcutaneous structures. There is marked increase
of compact collagen in the dermis along with thinning of the epidermis, atrophy of the dermal
appendages, and hyaline thickening of the walls of dermal arterioles and capillaries.
-Gastrointestinal Tract. The gastrointestinal tract is affected in approximately 90% of patients.
Progressive atrophy and collagenous fibrous replacement of the muscularis may develop at any
level of the gut but are most severe in the esophagus, with the lower two-thirds often
developing an inflexibility not unlike a rubber hose. The associated dysfunction of the lower
esophageal sphincter gives rise to gastroesophageal reflux and its complications, including
Barrett metaplasia and strictures. The mucosa is thinned and may be ulcerated, and there is
excessive collagenization of the lamina propria and submucosa. Loss of villi and microvilli in the
small bowel is the anatomic basis for the malabsorption syndrome sometimes encountered.
-Musculoskeletal System. Synovial hyperplasia and inflammation is common in the early
stages; fibrosis later ensues. Although these changes are reminiscent of Rheumatoid Arthritis,
joint destruction is not common in Sjgren Syndrome. In a small subset of patients
inflammatory myositis indistinguishable from polymyositis may develop.
Rheumatoid arthritis (RA): is a systemic, chronic inflammatory disease affecting many tissues
but principally attacking the joints to produce a nonsuppurative proliferative synovitis that
frequently progresses to destroy articular cartilage and underlying bone with resulting disabling
arthritis.

Morphology: A broad spectrum of morphologic alterations is seen in RA; the most severe occur
in the joints. RA typically presents as symmetric arthritis, principally affecting the small joints of
the hands and feet, ankles, knees, wrists, elbows, and shoulders. Typically, the proximal
interphalangeal and metacarpophalangeal joints are affected, but distal interphalangeal joints
are spared. Axial involvement, when it occurs, is limited to the upper cervical spine; similarly,
hip joint involvement is extremely uncommon. Histologically, the affected joints show chronic
synovitis, characterized by (1) synovial cell hyperplasia and proliferation; (2) dense perivascular
inflammatory cell infiltrates (frequently forming lymphoid follicles) in the synovium composed
of CD4+ T cells, plasma cells, and macrophages; (3) increased vascularity due to angiogenesis;
(4) neutrophils and aggregates of organizing fibrin on the synovial surface and in the joint
space; and (5) increased osteoclast activity in the underlying bone, leading to synovial
penetration and bone erosion. The classic appearance is that of a pannus, formed by
proliferating synovial-lining cells admixed with inflammatory cells, granulation tissue and
fibrous connective tissue; the overgrowth of this tissue is so exuberant that the usually thin,
smooth synovial membrane is transformed into lush, edematous, frondlike (villous) projections.

20) Adult respiratory distress syndrome ARDS.

ARDS is a clinical syndrome caused by diffuse alveolar capillary and epithelial damage. There is
usually rapid onset of life-threatening respiratory insufficiency, cyanosi and severe arterial
hypoxemia that is refractory to oxygen therapy and that may progress to multisystem organ
failure. The histologic manifestation of ARDS in the lungs is known as diffuse alveolar damage.
Pathogenesis: Neutrophils are thought to have an important role in the pathogenesis of ARDS.
Histologic examination of lungs early in the disease process shows increased numbers of
neutrophils within the vascular space, the interstitium, and the alveoli. Activated neutrophils
release a variety of products (ex. oxidants, proteases, platelet-activating factor and
leukotrienes) that cause damage to the alveolar epithelium and maintain the inflammatory
cascade. Combined assault on the endothelium and epithelium perpetuate vascular leakiness
and loss of surfactant that render the alveolar unit unable to expand.
Morhology: In the acute phase of ARDS the lungs are dark red, firm, airless, and heavy.
Microscopically, there is capillary congestion, necrosis of alveolar epithelial cells, interstitial and
intra-alveolar edema and hemorrhage, and (particularly with sepsis) collections of neutrophils
in capillaries. The most characteristic finding is the presence of hyaline membranes, particularly
lining the distended alveolar ducts. Such membranes consist of fibrin-rich edema fluid admixed
with remnants of necrotic epithelial cells. Overall, the picture is remarkably similar to that seen
in respiratory distress syndrome in the newborn. In the organizing stage there is marked
proliferation of type II pneumocytes in an attempt to regenerate the alveolar lining. Resolution
is unusual; more commonly there is organization of the fibrin exudates, with resultant intra-

alveolar fibrosis. Marked thickening of the alveolar septa ensues, caused by proliferation of
interstitial cells and deposition of collagen.

21) Bronchitis acute and chronic. Bronchiolitis.

Bronchitis: inflammation of the bronchi.
Acute Bronchitis: is an inflammation of the large bronchi (medium-size airways) in the lungs
that is usually caused by viruses or bacteria and may last several days or weeks. Characteristic
symptoms include cough, sputum (phlegm) production and shortness of breath and wheezing
related to the obstruction of the inflamed airways. Diagnosis is by clinical examination and
sometimes microbiological examination of the phlegm. Treatment for acute bronchitis is
typically symptomatic. As viruses cause most cases of acute bronchitis, antibiotics should not be
used unless microscopic examination of gram-stained sputum reveals large numbers of
bacteria.
Chronic Bronchitis: is common among cigarette smokers; some studies of men in the 40- to 65year age group indicate that 20% to 25% have the disease. The diagnosis of chronic bronchitis is
made on clinical grounds: it is defined as a persistent productive cough for at least 3
consecutive months in at least 2 consecutive years.
Pathogenesis: The distinctive feature of chronic bronchitis is hypersecretion of mucus,
beginning in the large airways. Although the single most important cause is cigarette smoking,
other air pollutants, such as sulfur dioxide and nitrogen dioxide, may contribute. These
environmental irritants induce hypertrophy of mucous glands in the trachea and main-stem
bronchi and lead to a marked increase in mucin-secreting goblet cells in the surface epithelium
of smaller bronchi and bronchioles. In addition, these irritants cause inflammation with
infiltration of CD8+ T cells, macrophages, and neutrophils.
Morphology: Grossly, the mucosal lining of the larger airways is usually hyperemic and swollen
by edema fluid. It is often covered by a layer of mucinous or mucopurulent secretions. The
smaller bronchi and bronchioles may also be filled with similar secretions. Histologically, the
diagnostic feature of chronic bronchitis in the trachea and larger bronchi is enlargement of the
mucus-secreting glands. The magnitude of the increase in size is assessed by the ratio of the
thickness of the submucosal gland layer to that of the bronchial wall (normally 0.4). A variable
density of inflammatory cells, largely mononuclear but sometimes admixed with neutrophils, is
frequently present in the bronchial mucosa. The tissue neutrophilia increases markedly during
bronchitic exacerbations.
Bronchiolitis: is inflammation of the bronchioles, the smallest air passages of the lungs
characterized by goblet cell metaplasia, mucus plugging, inflammation, and fibrosis, is also

present. In the most severe cases, there may be complete obliteration of the lumen due to
fibrosis (bronchiolitis obliterans). It is the peribronchiolar fibrosis and luminal narrowing that
results in airway obstruction.

22) Bronchiectasis congenital and acquired. Complications.

Bronchiectasis is a disease state defined by localized, irreversible dilation of part of the
bronchial tree caused by destruction of the muscle and elastic tissue resulting from or
associated with chronic necrotizing infections. In bronchiectasis, the airways slowly lose their
ability to clear out mucus. The mucus builds up, and bacteria begin to grow. This leads to
repeated, serious lung infections.
Congenital: Bronchiectasis may result from congenital infections that affect cilia motility or ion
transport. A common cause is cystic fibrosis, which affects chloride ion transport, in which a
small number of patients develop severe localized bronchiectasis. Patients with alpha 1antitrypsin deficiency have been found to be particularly susceptible to bronchiectasis.
Acquired: Tuberculosis, pneumonia, inhaled foreign bodies, allergic bronchopulmonary
aspergillosis and bronchiol tumours are the major acquired causes of Bronchiectasis. Infective
causes associated with Bronchiectasis include infections caused by the Staphylococcus,
Klebsiella, or Bordetella pertussis, the causative agent of whooping cough. Also: aspiration of
ammonia and other toxic gases, pulmonary aspiration, alcoholism, heroin (drug use), various
allergies.
Pathogenesis: Two processes are crucial and intertwined in the pathogenesis of bronchiectasis:
obstruction and chronic persistent infection. Normal clearance mechanisms are hampered by
obstruction, so secondary infection soon follows; conversely, chronic infection in time causes
damage to bronchial walls, leading to weakening and dilation. The resultant inflammatory
damage to the bronchial wall and the accumulating exudate further distend the airways,
leading to irreversible dilation. Conversely, a persistent necrotizing inflammation in the bronchi
or bronchioles may cause obstructive secretions, inflammation throughout the wall (with
peribronchial fibrosis and traction on the walls), and eventually the train of events already
described.
Morphology: Bronchiectatic involvement of the lungs usually affects the lower lobes bilaterally,
particularly those air passages that are most vertical. When tumors or aspiration of foreign
bodies lead to bronchiectasis, involvement may be sharply localized to a single segment of the
lungs. Usually, the most severe involvement is found in the more distal bronchi and
bronchioles. The airways may be dilated to as much as four times their usual diameter and on
gross examination of the lung can be followed almost to the pleural surfaces. (By contrast, in

normal lungs, the bronchioles cannot be followed by ordinary gross examination beyond a
point 2-3 cm from the pleural surfaces). The histologic findings vary with the activity and
chronicity of the disease. In the full-blown active case, an intense acute and chronic
inflammatory exudate within the walls of the bronchi and bronchioles and the desquamation of
lining epithelium cause extensive areas of ulceration. When healing occurs, the lining
epithelium may regenerate completely; however, usually so much injury has occurred that
abnormal dilation and scarring persist. Fibrosis of the bronchial and bronchiolar walls and
peribronchiolar fibrosis develop in more chronic cases. In some instances, the necrosis destroys
the bronchial or bronchiolar walls and forms a lung abscess.
Complications: Bronchiectasis can complicate atopic asthma, pulmonary hypertension and
chronic bronchitis. A rare but serious complication of bronchiectasis is coughing up large
amount of blood (massive haemoptysis). This can occur when a section of one of the blood
vessels supplying the lungs suddenly splits open.

23) Pulmonary infections general features, classification.

1. Upper Respiratory Infections: common cold, sinusitis, pharyngitis,epiglottitis and
laryngotracheitis.
Etiology: Most upper respiratory infections are of viral etiology. Epiglottitis and
laryngotracheitis are exceptions with severe cases likely caused by Haemophilus influenzae type
b. Bacterial pharyngitis is often caused by Streptococcus pyogenes.
Pathogenesis: Organisms gain entry to the respiratory tract by inhalation of droplets and
invade the mucosa. Epithelial destruction may ensue, along with redness, edema, hemorrhage
and sometimes an exudate.
Clinical Manifestations: Initial symptoms of a cold are runny, stuffy nose and sneezing, usually
without fever. Other upper respiratory infections may have fever. Children with epiglottitis may
have difficulty in breathing, muffled speech, drooling and stridor. Children with serious
laryngotracheitis (croup) may also have tachypnea, stridor and cyanosis.
Microbiologic Diagnosis: Common colds can usually be recognized clinically. Bacterial and viral
cultures of throat swab specimens are used for pharyngitis, epiglottitis and laryngotracheitis.
Blood cultures are also obtained in cases of epiglottitis.
Treatment: Viral infections are treated symptomatically. Streptococcal pharyngitis and
epiglottitis caused by H influenzae are treated with antibacterials. Haemophilus influenzae type
b vaccine is commercially available and is now a basic component of childhood immunization
program.

2. Lower Respiratory Infections: bronchitis, bronchiolitis and pneumonia.

Lower respiratory tract infections are generally more serious than upper respiratory infections.
LRIs are the leading cause of death among all infectious diseases. The two most common LRIs
are bronchitis and pneumonia. Influenza affects both the upper and lower respiratory tracts,
but more dangerous strains such as the highly pernicious H5N1 tend to bind to receptors deep
in the lungs.
Etiology: Causative agents of lower respiratory infections are viral or bacterial. Viruses cause
most cases of bronchitis and bronchiolitis. In community-acquired pneumonias, the most
common bacterial agent is Streptococcus pneumoniae. Atypical pneumonias are cause by such
agents as Mycoplasma pneumoniae, Chlamydia spp, Legionella, Coxiella burnetti and viruses.
Nosocomial pneumonias and pneumonias in immunosuppressed patients have protean etiology
with gram-negative organisms and staphylococci as predominant organisms.
Pathogenesis: Organisms enter the distal airway by inhalation, aspiration or by hematogenous
seeding. The pathogen multiplies in or on the epithelium, causing inflammation, increased
mucus secretion, and impaired mucociliary function; other lung functions may also be affected.
In severe bronchiolitis, inflammation and necrosis of the epithelium may block small airways
leading to airway obstruction.
Clinical Manifestations: Symptoms include cough, fever, chest pain, tachypnea and sputum
production. Patients with pneumonia may also exhibit non-respiratory symptoms such as
confusion, headache, myalgia, abdominal pain, nausea, vomiting and diarrhea.
Microbiologic Diagnosis: Sputum specimens are cultured for bacteria, fungi and viruses. Culture
of nasal washings is usually sufficient in infants with bronchiolitis. Fluorescent staining technic
can be used for legionellosis. Blood cultures and/or serologic methods are used for viruses,
rickettsiae, fungi and many bacteria. Enzyme-linked immunoassay methods can be used for
detections of microbial antigens as well as antibodies. Detection of nucleotide fragments
specific for the microbial antigen in question by DNA probe or polymerase chain reaction can
offer a rapid diagnosis.
Treatment: Symptomatic treatment is used for most viral infections. Bacterial pneumonias are
treated with antibacterials. A polysaccharide vaccine against 23 serotypes of Streptococcus
pneumoniae is recommended for individuals at high risk.

24) Lobar pneumonia /crouposa/. Stages. Complications.

Lobar (croupous) pneumonia is a form of lung infection that involves a contagious

inflammation across one of the lobes on the lung. The infection follows a viral upper respiratory
tract infection. The onset is usually abrupt, with high fever, shaking chills, pleuritic chest pain,
and a productive mucopurulent cough; occasional patients may have hemoptysis. S.
Pneumoniae is the most common cause of community-acquired acute pneumonia.
Stages: congestion, red hepatization, gray hepatization, and resolution. Early antibiotic therapy
alters or halts this typical progression, so if the person dies, the anatomic changes seen at
autopsy may not conform to the classic stages.
-Congestion, the affected lobe(s) is (are) heavy, red, and boggy; histologically, vascular
congestion can be seen, with proteinaceous fluid, scattered neutrophils, and many bacteria in
the alveoli.
-Red hepatization (Within a few days, the stage of)ensues, in which the lung lobe has a liverlike consistency; the alveolar spaces are packed with neutrophils, red cells, and fibrin.
-Gray hepatization, the lung is dry, gray, and firm, because the red cells are lysed, while the
fibrinosuppurative exudate persists within the alveoli.
-Resolution follows in uncomplicated cases, as exudates within the alveoli are enzymatically
digested to produce granular, semifluid debris that is resorbed, ingested by macrophages,
coughed up, or organized by fibroblasts growing into it. The pleural reaction (fibrinous or
fibrinopurulent pleuritis) may similarly resolve or undergo organization, leaving fibrous
thickening or permanent adhesions.
Complications:
(1) tissue destruction and necrosis may lead to abscess formation;
(2) suppurative material may accumulate in the pleural cavity, producing an empyema;
(3) organization of the intra-alveolar exudate may convert areas of the lung into solid fibrous
tissue;
(4) bacteremic dissemination may lead to meningitis, arthritis, or infective endocarditis.

25) Lobular pneumonia etiology, pathogenesis. Morphology.

Lobular pneumonia (bronchopneumonia) is acute inflammation of the walls of the bronchioles.
It is a type of pneumonia affecting one or more pulmonary lobules. It is one of two types
of bacterial pneumonia as classified by gross anatomic distribution of consolidation
(solidification), the other being lobar pneumonia.

Etiology: a result of the spread of infection from the upper to the lower respiratory tract. It is
an infection, but asthma and smoking will make it more severe.
Pathogenesis:
Bacteria infect pulmonary lobesproduction of mucusfill alveolar sacsdecrease air
spacedifficulty in breathing.

Morphology: In the bronchopneumonic pattern, foci of inflammatory consolidation are

distributed in patches throughout one or several lobes, most frequently bilateral and basal.
Well-developed lesions up to 3 or 4 cm in diameter are slightly elevated and are gray-red to
yellow; confluence of these foci may occur in severe cases, producing the appearance of a lobar
consolidation. The lung substance immediately surrounding areas of consolidation is usually
hyperemic and edematous, but the large intervening areas are generally normal. Pleural
involvement is less common than in lobar pneumonia. Histologically, the reaction consists of
focal suppurative exudate that fills the bronchi, bronchioles, and adjacent alveolar spaces.
Complications:
(1) tissue destruction and necrosis may lead to abscess formation;
(2) suppurative material may accumulate in the pleural cavity, producing an empyema;
(3) organization of the intra-alveolar exudate may convert areas of the lung into solid fibrous
tissue;
(4) bacteremic dissemination may lead to meningitis, arthritis, or infective endocarditis.

26) Lung abscess and gangrene.

Lung abscess: It is a localized area of suppurative necrosis within the pulmonary parenchyma,
resulting in the formation of one or more large cavities.
Pathogenesis: Aspiration of infective material from carious teeth or infected sinuses or tonsils,
particularly likely during oral surgery, anesthesia, coma, or alcoholic intoxication and in
debilitated patients with depressed cough reflexes.Aspiration of gastric contents, usually
accompanied by infectious organisms from the oropharynx.As a complication of necrotizing
bacterial pneumonias, particularly those caused by S. aureus, Streptococcus pyogenes, K.
pneumoniae, Pseudomonas spp., and rarely, type 3 pneumococci. Mycotic infections and
bronchiectasis may also lead to lung abscesses.Bronchial obstruction, particularly with

bronchogenic carcinoma obstructing a bronchus or bronchiole. Impaired drainage, distal

atelectasis and aspiration of blood and tumor fragments all contribute to the development of
abscesses.
Morphology: Abscesses vary in diameter from a few millimeters to large cavities of 5 to 6 cm.
The localization and number of abscesses depend on their mode of development. Pulmonary
abscesses resulting from aspiration of infective material are much more common on the right
side (more vertical airways) than on the left, and most are single. On the right side, they tend to
occur in the posterior segment of the upper lobe and in the apical segments of the lower lobe,
because these locations reflect the probable course of aspirated material when the patient is
recumbent. Abscesses that develop in the course of pneumonia or bronchiectasis are
commonly multiple, basal, and diffusely scattered. Septic emboli and abscesses arising from
hematogenous seeding are commonly multiple and may affect any region of the lungs.
Gangrene: is a serious and potentially life-threatening condition that arises when a
considerable mass of body tissue dies (necrosis). This may occur after an injury or infection, or
in people suffering from any chronic health problem affecting blood circulation. The primary
cause of gangrene is reduced blood supply to the affected tissues, which results in cell death.
Diabetes and long-term smoking increase the risk of suffering from gangrene.
Wet gangrene: occurs in moist tissue and organs such as the mouth, bowel, lungs, cervix, and
vulva. Bedsores occurring on body parts such as the sacrum, buttocks, and heels although
not necessarily moist areas are also categorized as wet gangrene infections. It is
characterized by numerous bacteria and has a poor prognosis (compared to dry gangrene) due
to septicemia. In wet gangrene, the tissue is infected by saprogenic microorganisms
(Clostridium perfringens or Bacillus fusiformis, for example), which cause tissue to swell and
emit a fetid smell. Wet gangrene usually develops rapidly due to blockage of venous and/or
arterial blood flow. Wet gangrene is coagulative necrosis progressing to liquefactive necrosis.
Dry gangrene: begins at the distal part of the limb due to ischemia, and often occurs in the toes
and feet of elderly patients due to arteriosclerosis. Dry gangrene is mainly due to arterial
occlusion. There is limited putrefaction and bacteria fail to survive. Dry gangrene spreads slowly
until it reaches the point where the blood supply is adequate to keep tissue viable. The affected
part is dry, shrunken and dark reddish-black, resembling mummified flesh. The dark coloration
is due to liberation of hemoglobin from hemolyzed red blood cells, which is acted upon by
hydrogen sulfide (H2S) produced by the bacteria, resulting in formation of black iron sulfide
that remains in the tissues. The line of separation usually brings about complete separation,
with eventual falling off of the gangrenous tissue if it is not removed surgically, also called
autoamputation.

27) Interstitial pneumonitis. Morphology.

Interstitial lung disease involves an inflammation of this supportive tissue between the air sacs
rather than inflammation in the air sacs themselves.
Classification:
-INTERSTITIAL PNEUMONIA,
-IDIOPATHIC PULMONARY FIBROSIS (fibrosis of the interstitium),
-NONSPECIFIC INTERSTITIAL PNEUMONIA (present with autoimmune conditions),
-DESQUAMATIVE INTERTITIAL PNEUMONIA (partially caused by smoking),
-HYPERSENSITIVITY PNEUMONITIS (caused by ongoing inhalation of dust, mold, or other
irritants).
-Interstitial pneumonitis: is often categorized as both an interstitial lung disease and a form
of acute respiratory distress syndrome (ARDS) but it is distinguished from the chronic forms of
interstitial pneumonia such as idiopathic pulmonary fibrosis. The most common symptoms of
acute interstitial pneumonitis are cough, fever, and difficulties breathing. These often occur
over a period of one to two weeks before medical attention is sought. Difficulties breathing can
quickly progress to an inability to breathe without support (respiratory failure). A biopsy of the
lung that shows organizing diffuse alveolar damage is required for diagnosis. Other diagnostic
tests are useful in excluding other similar conditions, but history, x-ray, and biopsy are
essential. These other tests may include basic blood work, blood cultures, and bronchoalveolar
lavage. The clinical picture is similar to ARDS, but AIP differs from ARDS in that the cause for AIP
is not known. Treatment: therapy with corticosteroids is generally attempted but the only
treatment that has met with success to date is a lung transplant.
-Usual Intersitial Pneumonitis: the clinical term for UIP of unknown cause is idiopathic
pulmonary fibrosis (IPF). Examples of known causes of UIP include systemic
sclerosis/scleroderma, rheumatoid arthritis, asbestosis and chronic nitrofurantoin toxicity. The
typical symptoms of UIP are progressive shortness of breath and cough for a period of months.
In some patients, UIP is diagnosed only when a more acute disease supervenes and brings the
patient to medical attention. UIP may be diagnosed by a radiologist using a computed
tomogram of the chest (CT scan of the chest), or by a pathologist using tissue obtained by a
lung biopsy. Radiologically, the main feature required for a confident diagnosis of UIP is
honeycomb change in the periphery and the lower portions (bases) of the lungs.

28) Viral and mycoplasmal pneumonia. Morphology.

Viral pneumonia is a pneumonia caused by a virus. Viruses are one of the two major causes of
pneumonia, the other being bacteria; less common causes are fungi and parasites. Viruses are
the most common cause of pneumonia in children, while in adults bacteria are a more common
cause. Viruses must invade cells in order to reproduce. Typically, a virus will reach the lungs by
traveling in droplets through the mouth and nose with inhalation. There, the virus invades the
cells lining the airways and the alveoli. This invasion often leads to cell death either through
direct killing by the virus or by self-destruction through apoptosis. Further damage to the lungs
occurs when the immune system responds to the infection. White blood cells, in particular
lymphocytes, are responsible for activating a variety of chemicals (cytokines) which cause
leaking of fluid into the alveoli. The combination of cellular destruction and fluid-filled alveoli
interrupts the transportation of oxygen into the bloodstream. In addition to the effects on the
lungs, many viruses affect other organs and can lead to illness affecting many different bodily
functions. Viruses also make the body more susceptible to bacterial infection; for this reason,
bacterial pneumonia often complicates viral pneumonia.
Atypical pneumonia is caused by a variety of organisms, Mycoplasma pneumoniae being the
most common. Mycoplasma infections are particularly common among children and young
adults. Etiologic agents are viruses, including influenza types A and B, the respiratory syncytial
viruses, adenovirus, rhinoviruses, rubeola, and varicella viruses; Chlamydia pneumoniae and
Coxiella burnetti (Q fever) Nearly all of these agents can also cause a primarily upper
respiratory tract infection ("common cold").
Pathogenesis: The common pathogenetic mechanism is attachment of the organisms to the
respiratory epithelium followed by necrosis of the cells and an inflammatory response. When
the process extends to alveoli there is usually interstitial inflammation, but there may also be
some outpouring of fluid into alveolar spaces so that on chest films the changes may mimic
bacterial pneumonia. Damage to and denudation of the respiratory epithelium inhibits
mucociliary clearance and predisposes to secondary bacterial infections.
Morphology: Regardless of cause, the morphologic patterns in atypical pneumonias are
similar. The process may be patchy, or it may involve whole lobes bilaterally or unilaterally.
Macroscopically, the affected areas are red-blue, congested, and subcrepitant. Histologically
the inflammatory reaction is largely confined within the walls of the alveoli. The septa are
widened and edematous; they usually contain a mononuclear inflammatory infiltrate of
lymphocytes, histiocytes, and, occasionally, plasma cells. In contrast to bacterial pneumonias,
alveolar spaces in atypical pneumonias are remarkably free of cellular exudate. In severe cases,
however, full-blown diffuse alveolar damage with hyaline membranes may develop. In less
severe, uncomplicated cases, subsidence of the disease is followed by reconstitution of the

native architecture. Superimposed bacterial infection, as expected, results in a mixed histologic

picture.

29) Chronic pneumonia. Pneumosclerosis types.

Chronic pneumonia is an inflammation of the lungs that persists for an extended period of
time, without a sudden onset. In contrast, acute pneumonia develops quickly and usually lasts
less than three weeks. Chronic pneumonia is most often a localized lesion in an
immunocompetent person, with or without regional lymph node involvement. There is typically
granulomatous inflammation, which may be due to bacteria (ex. M. tuberculosis) or fungi. In
the immunocompromised, such as those with debilitating illness, on immunosuppressive agents
or with human immune deficiency virus (HIV) infection, there is usually systemic dissemination
of the causative organism, accompanied by widespread disease. Tuberculosis is by far the most
important entity within the spectrum of chronic pneumonias.
Tuberculosis: is a communicable chronic granulomatous disease caused by Mycobacterium
tuberculosis. It usually involves the lungs but may affect any organ or tissue in the body.
Typically, the centers of tubercular granulomas undergo caseous necrosis.
Primary Tuberculosis: is the form of disease that develops in a previously unexposed and
therefore unsensitized, person.
Morphology: the inhaled bacilli implant in the distal airspaces of the lower part of the upper
lobe or the upper part of the lower lobe, usually close to the pleura. As sensitization develops, a
1- to 1.5-cm area of gray-white inflammatory consolidation emerges, the Ghon focus. In most
cases the center of this focus undergoes caseous necrosis. Tubercle bacilli, either free or within
phagocytes, drain to the regional nodes, which also often caseate. This combination of
parenchymal lesion and nodal involvement is referred to as the Ghon complex. Histologically,
sites of active involvement are marked by a characteristic granulomatous inflammatory
reaction that forms both caseating and noncaseating tubercles.
Secondary Tuberculosis: is the pattern of disease that arises in a previously sensitized host.
Morphology: The initial lesion is usually a small focus of consolidation, less than 2 cm in
diameter, within 1 to 2 cm of the apical pleura. Such foci are sharply circumscribed, firm, graywhite to yellow areas that have a variable amount of central caseation and peripheral fibrosis.
In favorable cases, the initial parenchymal focus undergoes progressive fibrous encapsulation,
leaving only fibrocalcific scars. Histologically, the active lesions show characteristic coalescent
tubercles with central caseation. Although tubercle bacilli can be demonstrated by appropriate
methods in early exudative and caseous phases of granuloma formation, it is usually impossible
to find them in the late, fibrocalcific stages. Localized, apical, secondary pulmonary tuberculosis

may heal with fibrosis either spontaneously or after therapy, or the disease may progress and
extend along several different pathways. Progressive pulmonary tuberculosis may ensue. The
apical lesion enlarges with expansion of the area of caseation. Erosion into a bronchus
evacuates the caseous center, creating a ragged, irregular cavity lined by caseous material that
is poorly walled off by fibrous tissue. Endobronchial, endotracheal, and laryngeal tuberculosis
may develop when infective material is spread either through lymphatic channels or from
expectorated infectious material.
Pneumosclerosis pathological connective tissue replacement of the pulmonary, as a
consequence of inflammatory or degenerative processes in the lungs, accompanied by a breach
of the elasticity and gas exchange in the affected areas. Overgrowth of connective tissue in the
lungs causes deformation of the bronchi, the sharp compression and shrinkage of lung tissue.
Lungs become airless and reduced in size. Pneumosclerosis can develop at any age, this
pathology is more easily observed in men.
Types:
The prevalence of lung pneumosclerosis may be limited (local, focal), and diffuse. Limited
pneumosclerosis is fine and macrofocal. Limited pneumosclerosis macroscopically represents
plot thickened lung parenchyma with a decline in this part of the lung. A special form of focal
pneumosclerosis is carnification (postpnevmonichesky sclerosis, in which the inflammation in
the lung tissue to form and texture resembles raw meat). Microscopic examination in the lung
may be determined sclerosal suppurative foci fibroatelektaz, fibrinous exudate, etc. Diffuse
pneumosclerosis affects the whole lung and sometimes both lungs. Lung tissue is sealed, the
amount of light is reduced and their normal structure is lost. Limited pneumosclerosis has no
significant effect on gas exchange function and the elasticity of the lungs. In diffuse lung
pneumosclerosis observed pattern of rigid lung and reduce its ventilation.

30) Pulmonary emphysema types and pathogenesis. Chronic diffuse

obstructive pulmonary emphysema.
Emphysema is characterized by abnormal permanent enlargement of the airspaces distal to the
terminal bronchioles, accompanied by destruction of their walls without obvious fibrosis.
Centriacinar (Centrilobular) Emphysema: The distinctive feature of this type of emphysema is
the pattern of involvement of the lobules: the central or proximal parts of the acini, formed by
respiratory bronchioles, are affected, while distal alveoli are spared. Both emphysematous and
normal airspaces exist within the same acinus and lobule. The lesions are more common and
severe in the upper lobes, particularly in the apical segments. It is most commonly seen as a
consequence of cigarette smoking in people who do not have congenital deficiency of 1antitrypsin.

Panacinar (Panlobular) Emphysema: In this type of emphysema, the acini are uniformly
enlarged from the level of the respiratory bronchiole to the terminal blind alveoli. In contrast to
centriacinar emphysema, panacinar emphysema tends to occur more commonly in the lower
lung zones and is the type of emphysema that occurs in 1-antitrypsin deficiency.
Distal Acinar (Paraseptal) Emphysema: In this form, the proximal portion of the acinus is
normal but the distal part is primarily involved. The emphysema is more striking adjacent to the
pleura, along the lobular connective tissue septa, and at the margins of the lobules. It occurs
adjacent to areas of fibrosis, scarring, or atelectasis and is usually more severe in the upper half
of the lungs.
Irregular Emphysema: Irregular emphysema, so named because the acinus is irregularly
involved, is almost invariably associated with scarring, such as resulting from healed
inflammatory diseases.
Morphology: The diagnosis and classification of emphysema depend largely on the macroscopic
appearance of the lung. Panacinar emphysema, when well developed, produces pale,
voluminous lungs that often obscure the heart when the anterior chest wall is removed at
autopsy. The macroscopic features of centriacinar emphysema are less impressive. The lungs
are a deeper pink than in panacinar emphysema and less voluminous, unless the disease is well
advanced. Generally, in centriacinar emphysema the upper two-thirds of the lungs is more
severely affected than the lower lungs. Histologically there is thinning and destruction of
alveolar walls. With advanced disease, adjacent alveoli become confluent, creating large
airspaces. Terminal and respiratory bronchioles may be deformed because of the loss of septa
that help tether these structures in the parenchyma. With the loss of elastic tissue in the
surrounding alveolar septa, there is reduced radial traction on the small airways. As a result,
they tend to collapse during expiration-an important cause of chronic airflow obstruction in
severe emphysema. In addition to alveolar loss, the number of alveolar capillaries is diminished.

31) Compensatory emphysema: senile emphysema, obstructive over inflation,

bullous emphysema, interstitial emphysema.
Compensatory emphysema is a term used to designate the compensatory dilation of alveoli in
response to loss of lung substance elsewhere, such as occurs in residual lung parenchyma after
surgical removal of a diseased lung or lobe.
Obstructive overinflation refers to the condition in which the lung expands because air is
trapped within it. A common cause is subtotal obstruction by a tumor or foreign object.
Obstructive overinflation can be a life-threatening emergency if the affected portion extends
sufficiently to compress the remaining normal lung.

Bullous emphysema refers merely to any form of emphysema that produces large subpleural
blebs or bullae (spaces >1 cm in diameter in the distended state). They represent localized
accentuations of one of the four forms of emphysema, are most often subpleural, and on
occasion, rupture leading to pneumothorax.
Mediastinal (interstitial) emphysema designates the entrance of air into the connective tissue
stroma of the lung, mediastinum, and subcutaneous tissue. This may occur spontaneously with
a sudden increase in intra-alveolar pressure (as with vomiting or violent coughing) that causes a
tear, with dissection of air into the interstitium. Sometimes it occurs in children with whooping
cough. It is particularly likely to occur in patients on respirators who have partial bronchiolar
obstruction or in persons who suffer a perforating injury (ex. a fractured rib). When the
interstitial air enters the subcutaneous tissue, the patient may literally blow up like a balloon,
with marked swelling of the head and neck and crackling crepitation all over the chest. In most
instances, the air is resorbed spontaneously when the site of entry is sealed.

32) Chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease refers to a long term narrowing of the airways, causing
obstruction to airflow through the lung, which leads to shortness of breath. It consists of
chronic bronchitis and emphysema.
Chronic bronchitis: is common among cigarette smokers; some studies of men in the 40- to 65year age group indicate that 20% to 25% have the disease. The diagnosis of chronic bronchitis is
made on clinical grounds: it is defined as a persistent productive cough for at least 3
consecutive months in at least 2 consecutive years.
Pathogenesis: The distinctive feature of chronic bronchitis is hypersecretion of mucus,
beginning in the large airways. Although the single most important cause is cigarette smoking,
other air pollutants, such as sulfur dioxide and nitrogen dioxide, may contribute. These
environmental irritants induce hypertrophy of mucous glands in the trachea and main-stem
bronchi and lead to a marked increase in mucin-secreting goblet cells in the surface epithelium
of smaller bronchi and bronchioles. In addition, these irritants cause inflammation with
infiltration of CD8+ T cells, macrophages, and neutrophils.
Morphology: Grossly, the mucosal lining of the larger airways is usually hyperemic and swollen
by edema fluid. It is often covered by a layer of mucinous or mucopurulent secretions. The
smaller bronchi and bronchioles may also be filled with similar secretions. Histologically, the
diagnostic feature of chronic bronchitis in the trachea and larger bronchi is enlargement of the
mucus-secreting glands. The magnitude of the increase in size is assessed by the ratio of the
thickness of the submucosal gland layer to that of the bronchial wall (normally 0.4). A variable

density of inflammatory cells, largely mononuclear but sometimes admixed with neutrophils, is
frequently present in the bronchial mucosa. The tissue neutrophilia increases markedly during
bronchitic exacerbations.
Emphysema: is characterized by abnormal permanent enlargement of the airspaces distal to
the terminal bronchioles, accompanied by destruction of their walls without obvious fibrosis.
Morphology: The diagnosis and classification of emphysema depend largely on the macroscopic
appearance of the lung. Panacinar emphysema, when well developed, produces pale,
voluminous lungs that often obscure the heart when the anterior chest wall is removed at
autopsy. The macroscopic features of centriacinar emphysema are less impressive. The lungs
are a deeper pink than in panacinar emphysema and less voluminous, unless the disease is well
advanced. Generally, in centriacinar emphysema the upper two-thirds of the lungs is more
severely affected than the lower lungs. Histologically there is thinning and destruction of
alveolar walls. With advanced disease, adjacent alveoli become confluent, creating large
airspaces. Terminal and respiratory bronchioles may be deformed because of the loss of septa
that help tether these structures in the parenchyma. With the loss of elastic tissue in the
surrounding alveolar septa, there is reduced radial traction on the small airways. As a result,
they tend to collapse during expiration-an important cause of chronic airflow obstruction in
severe emphysema. In addition to alveolar loss, the number of alveolar capillaries is diminished.

33) Athelectasis types, morphology.

Atelectasis, also known as collapse, is loss of lung volume caused by inadequate expansion of
airspaces. It results in shunting of inadequately oxygenated blood from pulmonary arteries into
veins, thus giving rise to a ventilation-perfusion imbalance and hypoxia. On the basis of the
underlying mechanism or the distribution of alveolar collapse, atelectasis is classified into three
forms.
Resorption Atelectasis: Resorption atelectasis occurs when an obstruction prevents air from
reaching distal airways. The air already present gradually becomes absorbed, and alveolar
collapse follows. Depending on the level of airway obstruction, an entire lung, a complete lobe,
or one or more segments may be involved. The most common cause of resorption collapse is
obstruction of a bronchus by a mucous or mucopurulent plug. This frequently occurs
postoperatively but may also complicate bronchial asthma, bronchiectasis, chronic bronchitis,
or the aspiration of foreign bodies, particularly in children.
Compression Atelectasis: Compression atelectasis (sometimes called passive or relaxation
atelectasis) is usually associated with accumulations of fluid, blood, or air within the pleural
cavity, which mechanically collapse the adjacent lung. This is a frequent occurrence with pleural

effusions, caused most commonly by congestive heart failure (CHF). Leakage of air into the
pleural cavity (pneumothorax) also leads to compression atelectasis. Basal atelectasis resulting
from the elevated position of the diaphragm commonly occurs in bedridden patients, in
patients with ascites, and in patients during and after surgery.
Contraction Atelectasis: Contraction (or cicatrization) atelectasis occurs when either local or
generalized fibrotic changes in the lung or pleura hamper expansion and increase elastic recoil
during expiration.

34) Hypersensitive pulmonary diseases. Bronchial asthma. Pulmonary

eosinophilia.
Bronchial asthma: asthma is a chronic inflammatory disorder of the airways that causes
recurrent episodes of wheezing, breathlessness, chest tightness, and cough, particularly at
night and/or early in the morning. This clinical picture is caused by repeated immediate
hypersensitivity and late-phase reactions in the lung that give rise to the triad of intermittent
and reversible airway obstruction, chronic bronchial inflammation with eosinophils and
bronchial smooth muscle cell hypertrophy and hyperreactivity.The disease is triggered by
environmental antigens, such as dusts, pollen, animal dander and foods, but potentially any
antigen is implicated.
Pathogenesis: mast cells also release additional cytokines that cause the influx of other
leukocytes, including neutrophils and mononuclear cells, and particularly eosinophils. These
inflammatory cells set the stage for the late-phase reaction, which starts 4 to 8 hours later and
may persist for 12 to 24 hours. Eosinophils are particularly important in the late phase. As
mentioned, their accumulation at sites of allergic inflammation is favored by several mast cellderived chemotactic factors, as well as chemokines (ex. eotaxin) produced by activated
bronchial epithelial cells themselves. The accumulated eosinophils exert a variety of effects.
Their armamentarium of mediators is as extensive as that of mast cells and includes major basic
protein and eosinophil cationic protein, which are directly toxic to airway epithelial cells.
Eosinophil peroxidase causes tissue damage through oxidative stress. Activated eosinophils are
also a rich source of leukotrienes, especially leukotriene C4, which contribute to
bronchoconstriction.
Morphology: The morphologic changes in asthma have been described in persons who die of
prolonged severe attacks (status asthmaticus) and in mucosal biopsy specimens of persons
challenged with allergens. In fatal cases, grossly, the lungs are overdistended because of
overinflation, and there may be small areas of atelectasis. The most striking macroscopic
finding is occlusion of bronchi and bronchioles by thick, tenacious mucus plugs. Histologically,
the mucus plugs contain whorls of shed epithelium (Curschmann spirals). Numerous eosinophils

and Charcot-Leyden crystals (collections of crystalloids made up of eosinophil proteins) are also
present.
"Airway remodeling" include: Thickening of the basement membrane of the bronchial
epithelium. Edema and inflammatory infiltrate in the bronchial walls, with a prominence of
eosinophils and mast cells. An increase in the size of the submucosal glands. Hypertrophy of the
bronchial muscle walls.
Symptoms: an attack of asthma is characterized by severe dyspnea with wheezing; the chief
difficulty lies in expiration. The victim labors to get air into the lungs and then cannot get it out,
so that there is progressive hyperinflation of the lungs with air trapped distal to the bronchi,
which are constricted and filled with mucus and debris. In the usual case, attacks last from 1 to
several hours and subside either spontaneously or with therapy, usually bronchodilators and
corticosteroids.
Pulmonary eosinophilia: A majority of simple pulmonary eosinophilia syndrome cases result
from an allergic reaction that may be triggered by a variety of allergy triggers such as (but not
limited to) certain drugs (sulfonamide, etc.), or a parasitic infection (ex. Ascaris lumbricoides
worm) caused by various parasites. It must be noted, however, it is not always possible to
determine the exact underlying cause of this rare disorder.

35) Idiopathic pulmonary hemoiderosis.

Idiopathic pulmonary haemosiderosis (IPH) is a lung disease of unknown cause that is
characterized by alveolar capillary bleeding and accumulation of haemosiderin in the lungs.
Clinically, IPH manifests as a triad of haemoptysis, diffuse parenchymal infiltrates on chest
radiographs, and iron deficiency anaemia. It is common in females. The clinical course of IPH is
exceedingly variable and most of the patients continue to have episodes of pulmonary
haemorrhage despite therapy. Death may occur suddenly from acute pulmonary haemorrhage
or after progressive pulmonary insufficiency resulting in chronic respiratory failure.
Treatment: Corticosteroids are the mainstay of treatment of IPH, though they are controversial
and lack clear evidence in their favour. They are thought to decrease the frequency of
haemorrhage, while other studies suggest that they do not have any effect on the course or
prognosis of this disease. In either case, steroid therapy has significant side effects. Small trials
have investigated the use of other medications, but none has emerged as a clear standard of
care. This includes immune modulators such as hydroxychloroquine,
azathioprine and cyclophosphamide 6-mercaptopurine as a long-term therapy may prevent
pulmonary haemorrhage.

Prognosis: Death may occur rapidly with acute, massive pulmonary bleeding or over longer
periods as the result of continued pulmonary failure and left heart failure. Historically, patients
had an average survival of 2.5 years after diagnosis, but today 86% may survive beyond five
years.

36) Pneumoconiosis types, general pathology.

Pneumoconiosis is a term originally coined to describe the non-neoplastic lung reaction to
inhalation of mineral dusts. The term has been broadened to include diseases induced by
organic as well as inorganic particulates and some experts also regard chemical fume-and
vapor-induced non-neoplastic lung diseases as pneumoconioses.
Types:
-Coal Workers' Pneumoconiosis
-Silicosis
-Asbestosis and Asbestos-Related Diseases
Pathogenesis: The reaction of the lung to mineral dusts depends on many variables, including
size, shape, solubility, and reactivity of the particles. For example, particles greater than 5 to 10
m are unlikely to reach distal airways, whereas particles smaller than 0.5 m tend to act like
gases and move into and out of alveoli, often without substantial deposition and injury.
Particles that are 1 to 5 m are the most dangerous, because they get lodged at the bifurcation
of the distal airways.
-Coal dust is relatively inert and large amounts must be deposited in the lungs before lung
disease is clinically detectable. Silica, asbestos and beryllium are more reactive than coal dust,
resulting in fibrotic reactions at lower concentrations. Most inhaled dust is entrapped in the
mucus blanket and rapidly removed from the lung by ciliary movement. However, some of the
particles become impacted at alveolar duct bifurcations, where macrophages accumulate and
endocytose the trapped particulates. The pulmonary alveolar macrophage is a key cellular
element in the initiation and perpetuation of lung injury and fibrosis. The more reactive
particles trigger the macrophages to release a number of products that mediate an
inflammatory response and initiate fibroblast proliferation and collagen deposition. Some of
the inhaled particles may reach the lymphatics either by direct drainage or within migrating
macrophages and thereby initiate an immune response to components of the particulates
and/or to self-proteins that are modified by the particles. This then leads to an amplification
and extension of the local reaction. Tobacco smoking worsens the effects of all inhaled mineral
dusts, more so with asbestos than with any other particle.

37) Silicosis pathogenesis, morphology.

Silicosis is caused by inhalation of crystalline silica, mostly in occupational settings. Silica occurs
in both crystalline and amorphous forms, but crystalline forms (including quartz, cristobalite,
and tridymite) are by far the most toxic and fibrogenic. Of these, quartz is most commonly
implicated in silicosis. After inhalation the particles interact with epithelial cells and
macrophages. Ingested silica particles cause activation and release of mediators by pulmonary
macrophages, including IL-1, TNF, fibronectin, lipid mediators, oxygen-derived free radicals and
fibrogenic cytokines.
Morphology: Silicotic nodules are characterized grossly in their early stages by tiny, barely
palpable, discrete, pale-to-blackened (if coal dust is also present) nodules in the upper zones of
the lungs. Microscopically, the silicotic nodule demonstrates concentrically arranged hyalinized
collagen fibers surrounding an amorphous center. The "whorled" appearance of the collagen
fibers is quite distinctive for silicosis. Examination of the nodules by polarized microscopy
reveals weakly birefringent silica particles, primarily in the center of the nodules. As the disease
progresses, the individual nodules may coalesce into hard, collagenous scars, with eventual
progression to PMF-primary myelofibrosis. The intervening lung parenchyma may be
compressed or overexpanded, and a honeycomb pattern may develop. Fibrotic lesions may also
occur in the hilar lymph nodes and pleura. Sometimes, thin sheets of calcification occur in the
lymph nodes and are appreciated radiographically as "eggshell" calcificatio.
Clinical course: Silicosis is usually detected in routine chest radiographs performed on
asymptomatic workers. The radiographs typically show a fine nodularity in the upper zones of
the lung, but pulmonary function is either normal or only moderately affected. Most individuals
do not develop shortness of breath until late in the course, after PMF is present. At this time,
the disease may be progressive, even if the person is no longer exposed. Many individuals with
PMF develop pulmonary hypertension and cor pulmonale, as a result of chronic hypoxiainduced vasoconstriction and parenchymal destruction. The disease is slow to kill, but impaired
pulmonary function may severely limit activity. Silicosis is associated with an increased
susceptibility to tuberculosis.

38) Asbestos-related diseases. Talcosis. Pneumoconiosis from metal polluted

dust berylliosis, siderosis, aluminosis.
Asbestos is a family of crystalline hydrated silicates with a fibrous geometry. On the basis of
epidemiologic studies, occupational exposure to asbestos is linked to:
(1) parenchymal interstitial fibrosis (asbestosis);

(2) localized fibrous plaques or, rarely, diffuse fibrosis in the pleura;
(3) pleural effusions;
(4) bronchogenic carcinoma;
(5) malignant pleural and peritoneal mesotheliomas;
(6) laryngeal carcinoma.
Concentration, size, shape, and solubility of the different forms of asbestos dictate whether
disease will occur. There are two distinct forms of asbestos: serpentine (in which the fiber is
curly and flexible) and amphibole (in which the fiber is straight, stiff, and brittle). There are
several subtypes of curly and straight asbestos fibers. Amphiboles, even though less prevalent,
are more pathogenic than the serpentine chrysotile, but both types can produce asbestosis,
lung cancer, and mesothelioma.
Asbestosis is marked by diffuse pulmonary interstitial fibrosis. These changes are
indistinguishable from those resulting from other causes of diffuse interstitial fibrosis, except
for the presence of asbestos bodies, which are seen as golden brown, fusiform or beaded rods
with a translucent center. They consist of asbestos fibers coated with an iron-containing
proteinaceous material. Asbestos bodies apparently arise when macrophages attempt to
phagocytose asbestos fibers; the iron is derived from phagocyte ferritin. Asbestos bodies can
sometimes be found in the lungs of normal persons, but usually in much lower concentrations
and without an accompanying interstitial fibrosis. In contrast to CWP-coal-workers'
pneumoconiosis and silicosis, asbestosis begins in the lower lobes and subpleurally, but the
middle and upper lobes of the lungs become affected as fibrosis progresses. Contraction of the
fibrous tissue distorts the native architecture, creating enlarged airspaces enclosed within thick
fibrous walls. In this way the affected regions become honeycombed. Simultaneously, the
visceral pleura undergoes fibrous thickening and sometimes binds the lungs to the chest wall.
The scarring may trap and narrow pulmonary arteries and arterioles, causing pulmonary
hypertension and cor pulmonale. Pleural plaques are the most common manifestation of
asbestos exposure and are well-circumscribed plaques of dense collagen, often containing
calcium. They develop most frequently on the anterior and posterolateral aspects of the
parietal pleura and over the domes of the diaphragm. They do not contain asbestos bodies, and
only rarely do they occur in persons who have no history or evidence of asbestos exposure.
Uncommonly, asbestos exposure induces pleural effusions, which are usually serous but may be
bloody. Rarely, diffuse visceral pleural fibrosis may occur and, in advanced cases, bind the lung
to the thoracic cavity wall.

Talcosis: Talc consists of magnesium silicates that are used in a number of industries for their
lubricant properties, and in cosmetics and pharmaceuticals. Occupational exposure to talc
occurs among workers engaged in mining and milling the mineral and in the leather, rubber,
paper, and textile industries. Industrial talc is usually mixed with other minerals such as
asbestos or silica. Cosmetic talc is more than 90% pure and rarely causes lung disease. On gross
examination, talcosis lesions vary from minute nodules to severe fibrosis. Microscopically,
foreign-body granulomas associated with birefringent platelike talc particles are scattered
throughout the parenchyma, which displays fibrotic nodules and interstitial fibrosis. Associated
minerals, such as silica or asbestos, may contribute to the fibrotic changes. Intravenous drug
abusers who use talc as a carrier for illicit drugs may develop vascular and interstitial
granulomas in the lung and variable degrees of fibrosis. Arterial changes of pulmonary
hypertension are common. Persons with these changes may initially present with cor
pulmonale.
Berylliosis occurs as an acute chemical pneumonitis or a chronic pneumoconiosis. In the acute
form, symptoms begin within hours or days after inhalation of metal particles and mainfest
pathologically as diffuse alveolar damage. Of all persons with acute beryllium pneumonitis, 10%
progress to chronic disease, although chronic berylliosis is often encountered in workers
without any history of an acute illness. Chronic berylliosis differs from other pneumoconioses in
that the amount and duration of exposure may be small. The lesion is thus suspected to be a
hypersensitivity reaction. Pathologically, the pulmonary lesions are indistinguishable from those
of sarcoidosis. Multiple noncaseating granulomas are distributed along the pleura, septa, and
bronchovascular bundles. The beryllium lymphocyte proliferation test may aid in separating
these two entities. Disease progression can lead to end-stage fibrosis and honeycomb lung.
Patients with chronic berylliosis have an insidious onset of dyspnea 15 or more years after the
initial exposure. The disease appears to be associated with an increased risk of lung cancer.
Siderosis is the deposition of iron in tissue; it usually refers to an environmental disease of the
lung. Similar to asbestosis.
Aluminosis: a lung disease caused by the inhalation of dusts of certain aluminum compounds.

39) Lung cancer. Classification macroscopical, histological. Spreading of

metastasis. Complications.
Lung cancer: Carcinomas of the lung begin as small mucosal lesions that are usually firm and
gray-white. They may form intraluminal masses, invade the bronchial mucosa, or form large
bulky masses pushing into adjacent lung parenchyma. Some large masses undergo cavitation
caused by central necrosis or develop focal areas of hemorrhage. Finally, these tumors may
extend to the pleura, invade the pleural cavity and chest wall, and spread to adjacent

intrathoracic structures. More distant spread can occur via the lymphatics or the
hematogenous route.
-Squamous cell carcinomas are more common in men than in women and are closely
correlated with a smoking history; they tend to arise centrally in major bronchi and eventually
spread to local hilar nodes, but they disseminate outside the thorax later than other histologic
types. Large lesions may undergo central necrosis, giving rise to cavitation. The preneoplastic
lesions that antedate, and usually accompany, invasive squamous cell carcinoma are well
characterized. Squamous cell carcinomas are often preceded for years by squamous metaplasia
or dysplasia in the bronchial epithelium, which then transforms to carcinoma in situ, a phase
that may last for several years. By this time, atypical cells may be identified in cytologic smears
of sputum or in bronchial lavage fluids or brushings, although the lesion is asymptomatic and
undetectable on radiographs. Eventually, the small neoplasm reaches a symptomatic stage,
when a well-defined tumor mass begins to obstruct the lumen of a major bronchus, often
producing distal atelectasis and infection. Simultaneously, the lesion invades surrounding
pulmonary substance. Histologically, these tumors range from well-differentiated squamous
cell neoplasms showing keratin pearls and intercellular bridges to poorly differentiated
neoplasms having only minimal residual squamous cell features.
-Adenocarcinomas may occur as central lesions like the squamous cell variant but are usually
more peripherally located, many arising in relation to peripheral lung scars ("scar carcinomas").
The etiologic basis for this association is not clear, although the current thinking is that the
scarring probably occurred secondary to the tumor, rather than being contributory.
Adenocarcinomas are the most common type of lung cancer in women and nonsmokers. In
general, adenocarcinomas grow slowly and form smaller masses than do the other subtypes,
but they tend to metastasize widely at an early stage. Histologically, they assume a variety of
forms, including acinar (gland forming), papillary, and solid types. The solid variant often
requires demonstration of intracellular mucin production by special stains to establish its
adenocarcinomatous lineage. Although foci of squamous metaplasia and dysplasia may be
present in the epithelium proximal to resected adenocarcinomas, these are not the precursor
lesions for this tumor. The putative precursor of peripheral adenocarcinomas has been
described as atypical adenomatous hyperplasia (AAH). Microscopically, AAH is recognized as a
well-demarcated focus of epithelial proliferation composed of cuboidal to low-columnar cells
resembling Clara cells or type 2 alveolar pneumocytes, which demonstrate various degrees of
cytologic atypia (nuclear hyperchromasia, pleomorphism, prominent nucleoli), but not to the
extent seen in frank adenocarcinomas.
-Bronchioloalveolar carcinomas (BACs): The key feature of BACs is their growth along
preexisting structures and preservation of alveolar architecture. The tumor cells grow in a

monolayer on top of the alveolar septa, which serves as a scaffold. By definition, BACs do not
demonstrate destruction of alveolar architecture or stromal invasion with desmoplasia,
features that would merit their classification as frank adenocarcinomas. The two subtypes of
BACs are mucinous and nonmucinous, with the former comprising tall, columnar cells with
prominent cytoplasmic and intra-alveolar mucin. Analogous to the adenoma-carcinoma
sequence in the colon, it is proposed that some invasive adenocarcinomas of the lung may arise
through an atypical adenomatous hyperplasia-bronchioloalveolar carcinoma-invasive
adenocarcinoma sequence. It is important to stress, however, that not all adenocarcinomas
arise in this manner, nor do all BACs become invasive if left untreated. While the cell types
giving rise to the centrally located squamous cell carcinoma (metaplastic squamous cells in the
main stem bronchi) and small cell lung carcinoma (native neuroendocrine cells, see below)
were recognized for a while, the "cell of origin" for peripheral adenocarcinomas remained
unclear until recently.
-Large-cell carcinomas are undifferentiated malignant epithelial tumors that lack the cytologic
features of small-cell carcinoma and glandular or squamous differentiation. The cells typically
have large nuclei, prominent nucleoli, and a moderate amount of cytoplasm. Large-cell
carcinomas probably represent squamous cell or adenocarcinomas that are so undifferentiated
that they can no longer be recognized by light microscopy. Ultrastructurally, however, minimal
glandular or squamous differentiation is common.
-Small-cell lung carcinomas generally appear as pale gray, centrally located masses with
extension into the lung parenchyma and early involvement of the hilar and mediastinal nodes.
These cancers are composed of tumor cells with a round to fusiform shape, scant cytoplasm,
and finely granular chromatin. Mitotic figures are frequently seen. Despite the appellation of
"small," the neoplastic cells are usually twice the size of resting lymphocytes. Necrosis is
invariably present and may be extensive. The tumor cells are markedly fragile and often show
fragmentation and "crush artifact" in small biopsy specimens. Another feature of small-cell
carcinomas, best appreciated in cytologic specimens, is nuclear molding resulting from close
apposition of tumor cells that have scant cytoplasm. These tumors are derived from
neuroendocrine cells of the lung, and hence they express a variety of neuroendocrine markers
in addition to a host of polypeptide hormones that may result in paraneoplastic syndromes.
Complications: shortness of breath, coughing up blood, Pain (advanced lung cancer that
spreads to the lining of a lung or to another area of the body, such as a bone, can cause pain),
fluid in the chest (pleural effusion) and cancer that spreads to other parts of the body
(metastasis).

40) Pleura pathology. Pleural tumors.

Pleural effusion and Pleuritis: Pleural effusion, the presence of fluid in the pleural space, can be
either a transudate or an exudate. A pleural effusion that is a transudate is termed
hydrothorax. Hydrothorax from CHF is probably the most common cause of fluid in the pleural
cavity. An exudate, characterized by protein content >2.9gm/dL and, often, inflammatory cells,
suggests pleuritis. The four principal causes of pleural exudate are (1) microbial invasion
through either direct extension of a pulmonary infection or blood-borne seeding (suppurative
pleuritis or empyema); (2) cancer (bronchogenic carcinoma, metastatic neoplasms to the lung
or pleural surface, mesothelioma); (3) pulmonary infarction; and (4) viral pleuritis. Other, less
common causes of exudative pleural effusions are systemic lupus erythematosus, rheumatoid
arthritis, or uremia and previous thoracic surgery. Cancer should be suspected as the underlying
cause of an exudative effusion in any patient older than the age of 40, particularly when there
is no febrile illness, no pain, and a negative tuberculin test result. These effusions
characteristically are large and frequently are bloody (hemorrhagic pleuritis). Cytologic
examination may reveal malignant and inflammatory cells. Whatever the cause, transudates
and serous exudates are usually resorbed without residual effects if the inciting cause is
controlled or remits. In contrast, fibrinous, hemorrhagic, and suppurative exudates may lead to
fibrous organization, yielding adhesions or fibrous pleural thickening, and sometimes minimal
to massive calcifications.
Pneumothorax, Hemothorax, Chylothorax: Pneumothorax refers to air or other gas in the
pleural sac. It may occur in young, apparently healthy adults, usually men without any known
pulmonary disease (simple or spontaneous pneumothorax), or as a result of some thoracic or
lung disorder (secondary pneumothorax), such as emphysema or a fractured rib. Secondary
pneumothorax occurs with rupture of any pulmonary lesion situated close to the pleural
surface that allows inspired air to gain access to the pleural cavity. Such pulmonary lesions
include emphysema, lung abscess, tuberculosis, carcinoma, and many other, less common,
processes. Mechanical ventilatory support with high pressure may also trigger secondary
pneumothorax. There are several possible complications of pneumothorax. A ball-valve leak
may create a tension pneumothorax that shifts the mediastinum. Compromise of the
pulmonary circulation may follow and may even be fatal. If the leak seals and the lung is not reexpanded within a few weeks (either spontaneously or through medical or surgical
intervention), so much scarring may occur that it can never be fully re-expanded. In these cases,
serous fluid collects in the pleural cavity and creates hydropneumothorax. With prolonged
collapse, the lung becomes vulnerable to infection, as does the pleural cavity when
communication between it and the lung persists. Empysema is an important complication of
pneumothorax (pyopneumothorax). Secondary pneumothorax tends to be recurrent if the
predisposing condition remains. What is less well recognized is that simple pneumothorax is
also recurrent. Hemothorax, the collection of whole blood (in contrast to bloody effusion) in
the pleural cavity, is a complication of a ruptured intrathoracic aortic aneurysm that is almost

always fatal. With Chylothorax is a pleural collection of a milky lymphatic fluid containing
microglobules of lipid. The total volume of fluid may not be large, but chylothorax is always
significant because it implies obstruction of the major lymph ducts, usually by an intrathoracic
cancer (ex. a primary or secondary mediastinal neoplasm, such as a lymphoma).
Malignant mesothelioma: is a rare cancer of mesothelial cells, usually arising in the parietal or
visceral pleura, although it also occurs, much less commonly, in the peritoneum and
pericardium. It has assumed great importance because it is related to occupational exposure to
asbestos in the air. Approximately 50% of individuals with this cancer have a history of
exposure to asbestos. Those who work directly with asbestos are at greatest risk, but malignant
mesotheliomas have appeared in persons whose only exposure was living in proximity to an
asbestos factory or being a relative of an asbestos worker. The latent period for developing
malignant mesotheliomas is long, often 25 to 40 years after initial asbestos exposure,
suggesting that multiple somatic genetic events are required for tumorigenic conversion of a
mesothelial cell. Malignant mesotheliomas are often preceded by extensive pleural fibrosis and
plaque formation, readily seen in computed tomographic scans. These tumors begin in a
localized area and in the course of time spread widely, either by contiguous growth or by
diffusely seeding the pleural surfaces. At autopsy, the affected lung is typically ensheathed by a
yellow-white, firm, sometimes gelatinous layer of tumor that obliterates the pleural space.
Distant metastases are rare. The neoplasm may directly invade the thoracic wall or the
subpleural lung tissue. Normal mesothelial cells are biphasic, giving rise to pleural lining cells as
well as the underlying fibrous tissue. Therefore, histologically, mesotheliomas conform to one
of three patterns: (1) epithelial, in which cuboidal cells line tubular and microcystic spaces, into
which small papillary buds project; this is the most common pattern and also the one most
likely to be confused with a pulmonary adenocarcinoma; (2) sarcomatoid, in which spindled and
sometimes fibroblastic-appearing cells grow in nondistinctive sheets; and (3) biphasic, having
both sarcomatoid and epithelioid areas.

41) Tumors of the upper airways: nose, sinuses, nasopharynx and larynx.
Nasopharyngeal carcinoma: This rare neoplasm merits comment because of (1) the strong
epidemiologic links to EBV infection and (2) the high frequency of this form of cancer in the
Chinese, which raises the possibility of viral oncogenesis on a background of genetic
susceptibility. EBV infects the host by first replicating in the nasopharyngeal epithelium and
then infecting nearby tonsillar B lymphocytes. In some persons this leads to transformation of
the epithelial cells. Unlike the case with Burkitt lymphoma, another EBV-associated tumor, the
EBV genome is found in virtually all nasopharyngeal carcinomas. The three histologic variants
are keratinizing squamous cell carcinoma, nonkeratinizing squamous cell carcinoma, and
undifferentiated carcinoma; the last-mentioned is the most common and the one most closely

linked with EBV. The undifferentiated neoplasm is characterized by large epithelial cells having
indistinct cell borders ("syncytial" growth) and prominent eosinophilic nucleoli. It should be
recalled that in infectious mononucleosis, EBV directly infects B lymphocytes, after which a
marked proliferation of reactive T lymphocytes causes atypical lymphocytosis, seen in the
peripheral blood, and enlarged lymph nodes. Similarly, in nasopharyngeal carcinomas a striking
influx of mature lymphocytes can often be seen. These neoplasms are therefore referred to as
"lymphoepitheliomas," a misnomer because the lymphocytes are not part of the neoplastic
process, nor are the tumors benign. The presence of large neoplastic cells in a background of
reactive lymphocytes may give rise to an appearance similar to non-Hodgkin lymphomas, and
immunohistochemical stains may be required to prove the epithelial nature of the malignant
cells. Nasopharyngeal carcinomas invade locally, spread to cervical lymph nodes, and then
metastasize to distant sites. They tend to be radiosensitive, and 5-year survival rates of 50% are
reported for even advanced cancers.
Laryngeal tumors:
Nonmalignant Lesions Vocal cord nodules ("polyps") are smooth, hemispherical protrusions
(usually less than 0.5 cm in diameter) located, most often, on the true vocal cords. The nodules
are composed of fibrous tissue and covered by stratified squamous mucosa that is usually intact
but can be ulcerated by contact trauma with the other vocal cord. These lesions occur chiefly in
heavy smokers or singers (singer's nodes), suggesting that they are the result of chronic
irritation or abuse. Laryngeal papilloma or squamous papilloma of the larynx is a benign
neoplasm, usually on the true vocal cords, that forms a soft, raspberry-like excrescence rarely
more than 1 cm in diameter. Histologically, it consists of multiple, slender, finger-like
projections supported by central fibrovascular cores and covered by an orderly, typical,
stratified squamous epithelium. When the papilloma is on the free edge of the vocal cord,
trauma may lead to ulceration that can be accompanied by hemoptysis.
Carcinoma of Larynx: represents only 2% of all cancers. It most commonly occurs after age 40
years and is more common in men (7 : 1) than in women. Environmental influences are very
important in its causation; nearly all cases occur in smokers, and alcohol and asbestos exposure
may also play roles. About 95% of laryngeal carcinomas are typical squamous cell lesions.
Rarely, adenocarcinomas are seen, presumably arising from mucous glands. The tumor
develops directly on the vocal cords (glottic tumors) in 60% to 75% of cases, but it may arise
above the cords (supraglottic; 25% to 40%) or below the cords (subglottic; less then 5%). The
major etiologic factors associated with laryngeal squmaous carcinomas include most
importantly smoking, but also alcohol and previous radiation exposure. Human papillomavirus
sequences have been detected in a minority of cases. Squmaous cell carcinomas of the larynx
follow the growth pattern of all squamous cell carcinomas. They begin as in situ lesions that

later appear as pearly gray, wrinkled plaques on the mucosal surface, ultimately ulcerating. The
glottic tumors are usually keratinizing, well- to moderately differentiated squamous cell
carcinomas, although neonkeratinizing, poorly differentiated carcinomas may also be seen. As
expected with lesions arising from recurrent exposure to environmental carcinogens, adjacent
mucosa may demonstrate squamous cell hyperplasia with foci of dysplasia.

42) Dental caries. Pulpitis.

Dental caries: is an infection usually bacterial in origin that causes demineralization of the hard
tissues (enamel, dentin and cementum) and destruction of the organic matter of the tooth,
usually by production of acid by hydrolysis of the food debris accumulated on the tooth surface.
If demineralization exceeds saliva and other remineralization factors such as from calcium and
fluoridated toothpastes, these tissues progressively break down, producing dental caries
(cavities, holes in the teeth). Two groups of bacteria are responsible for initiating caries:
Streptococcus mutans and Lactobacillus. If left untreated, the disease can lead to pain, tooth
loss and infection. Initially it may appear as a small chalky area (smooth surface caries), which
may eventually develop into a large cavitation. Sometimes caries may be visible direct.
However other methods of detection such as radiographs are used for less visible areas of teeth
and to judge the extent of destruction. Tooth decay is caused by specific types of acidproducing bacteria that cause damage in the presence of fermentable carbohydrates such as
sucrose, fructose, and glucose. The mineral content of teeth is sensitive to increases in acidity
from the production of lactic acid. To be specific, a tooth (which is primarily mineral in content)
is in a constant state of back-and-forth demineralization and remineralization between the
tooth and surrounding saliva. For people with little saliva, especially due to radiation therapies
that may destroy the salivary glands, there also exists remineralization gel. These patients are
particularly susceptible to dental caries. When the pH at the surface of the tooth drops below
5.5, demineralization proceeds faster than remineralization (meaning that there is a net loss of
mineral structure on the tooth's surface).
Pulpitis: is medical symptom in which the dental pulp becomes inflamed. Increased sensitivity
to stimuli, specifically hot and cold, is a common symptom of pulpitis. A prolonged throbbing
pain may be associated with the disease. However, pulpitis can also occur without any pain at
all. In the pulp, just as in other areas of the body, inflammation can be present. Inflammation of
the pulp does not take place only when the bacteria in the decay have reached the pulp.
Bacterial products may reach the pulp much earlier and begin the inflammatory response. The
inflammation may be acute or chronic because just like other tissues in the body, the pulp will
react to irritants with innate and/or adaptive immune responses. Innate immunity in the pulp is
not specific but uses receptors to recognize molecular patterns common to microbes to initiate
bacterial killing (phagocytosis). The components of the innate response of the dentin/pulp

complex to caries include at least the following six: (1) outward flow of dentinal fluid; (2)
odontoblasts; (3) neuropeptides and neurogenic inflammation; (4) innate immune cells,
including immature dendritic cells (DCs), natural killer (NK) cells, and T cells, as well as (5) their
cytokines and (6) chemokines. Although the first two items are not classic components of
innate immunity, they are uniquely involved in the initial inflammatory response to caries.
Odontoblasts, (the cells that form dentin) have cellular processes that extend into dentinal
tubules and are the first to encounter the caries bacterial antigens. They express low levels of
interleukin-8 (IL-8) and genes related to chemokines and chemokine receptors. The
ondontoblasts have been shown to attract immature Dendritic Cells. Dendritic cells (DCs) are a
heterogeneous leukocyte (white blood cell) population. DCs in healthy peripheral tissues
(steady state) are in an immature state. The cells are capable of sensing microbes as well as
antigen capture and processing capabilities. A rapid accumulation of pulpal DCs has been
observed beneath cavity preparations, and an increased number of DCs accumulated under
caries. Immature DCs are therefore considered to be part of the innate phase of pulpal immune
response.

43) Inflammatory disease of oral mucosa. Diseases or salivary glands

sialadenitis.
Herpesvirus Infection: Herpetic stomatitis is an extremely common infection caused by herpes
simplex virus (HSV) type 1. The pathogen is transmitted from person to person, most often by
kissing; by middle life over three-fourths of the population have been infected. In most adults
the primary infection is asymptomatic, but the virus persists in a dormant state within ganglia
about the mouth (e.g., trigeminal ganglia). With reactivation of the virus (which may be caused
by fever, sun or cold exposure, respiratory tract infection, trauma), solitary or multiple small (<5
mm in diameter) vesicles containing clear fluid appear. They occur most often on the lips or
about the nasal orifices and are well known as cold sores or fever blisters. They soon rupture,
leaving shallow, painful ulcers that heal within a few weeks, but recurrences are common.
Morphology: The vesicles begin as an intraepithelial focus of intercellular and intracellular
edema. The infected cells become ballooned and develop intranuclear acidophilic viral
inclusions. Sometimes adjacent cells fuse to form giant cells known as multinucleated
polykaryons. Necrosis of the infected cells and the focal collections of edema fluid account for
the intraepithelial vesicles detected clinically.
Oral Candidiasis: Candida albicans is a normal inhabitant of the oral cavity found in 30% to 40%
of the population; it causes disease only when there is some impairment of the usual protective
mechanisms. Pseudomembranous candidiasis (thrush, moniliasis) is the most common fungal
infection of the oral cavity and is particularly common among persons rendered vulnerable by

diabetes mellitus, anemia, antibiotic or glucocorticoid therapy, immunodeficiency, or

debilitating illnesses such as disseminated cancer. Persons with the acquired immunodeficiency
syndrome (AIDS) are at particular risk. Typically, oral candidiasis takes the form of an adherent
white, curdlike, circumscribed plaque anywhere within the oral cavity. The pseudomembrane
can be scraped off to reveal an underlying granular erythematous inflammatory base.
Histologically, the pseudomembrane is composed of a myriad of fungal organisms superficially
attached to the underlying mucosa. In milder infections there is minimal ulceration, but in
severe cases the entire mucosa may be denuded. The fungi can be identified within these
pseudomembranes as boxcar-like chains of tubular cells producing pseudohyphae from which
bud ovoid yeast forms, typically 2 to 4 m in greatest diameter.
Sialadenitis: Inflammation of the major salivary glands may be of traumatic, viral, bacterial, or
autoimmune origin. The most common lesion of the salivary glands is mucocele, resulting from
blockage or rupture of a salivary gland duct, with consequent leakage of saliva into the
surrounding tissues. Mucoceles are most often found in the lower lip, as a consequence of
trauma. Dominant among other causations of sialadenitis is the infectious viral disease mumps,
which may produce enlargement of all the major salivary glands but predominantly the
parotids. Although several viruses may cause mumps, the most important cause is a
paramyxovirus, an RNA virus related to the influenza and parainfluenza viruses. It usually
produces a diffuse, interstitial inflammation marked by edema and a mononuclear cell
infiltration and, sometimes, by focal necrosis. Although childhood mumps is self-limited and
rarely creates residual problems, mumps in adults may be accompanied by pancreatitis or
orchitis; the latter sometimes causes permanent sterility. Bacterial sialadenitis most often
occurs secondary to ductal obstruction resulting from stone formation (sialolithiasis), but it may
also arise after retrograde entry of oral cavity bacteria under conditions of severe systemic
dehydration such as the postoperative state. The most common bacteria causing the infection
are Staphylococcus aureus and Streptococcus viridans. Persons with chronic, debilitating
medical conditions, compromised immune function, or on medications contributing to oral or
systemic dehydration are at increased risk for acute bacterial sialadenitis. The sialadenitis may
be largely interstitial, or it may cause focal areas of suppurative necrosis or even abscess
formation.

44) Tumors of lips, tongue, salivary glands and tonsils.

Tumors of salivary glands:
Pleomorphic Adenoma (Mixed Tumor of Salivary Glands)
This tumor accounts for more than 90% of benign tumors of the salivary glands. It is a slowgrowing, well-demarcated, apparently encapsulated lesion rarely exceeding 6 cm in greatest

dimension. Most often arising in the superficial parotid, it usually causes painless swelling at the
angle of the jaw and can be readily palpated as a discrete mass. It is nonetheless often present
for years before being brought to medical attention. Despite the tumor's encapsulation,
histologic examination often reveals multiple sites where the tumor penetrates the capsule.
Adequate margins of resection are thus necessary to prevent recurrences. This may require
sacrifice of the facial nerve, which courses through the parotid gland. On average, about 10% of
excisions are followed by recurrence.
Morphology: The characteristic histologic feature of pleomorphic adenoma is heterogeneity.
The tumor cells form ducts, acini, tubules, strands, or sheets of cells. The epithelial cells are
small and dark and range from cuboidal to spindle forms. These epithelial elements are
intermingled with a loose, often myxoid connective tissue stroma sometimes containing islands
of apparent cartilage or, rarely, bone. Immunohistochemical evidence suggests that all of the
diverse cell types within pleomorphic adenoma, including those within the stroma, are of
myoepithelial derivation.
Warthin Tumor (Papillary Cystadenoma Lymphomatosum, Cystadenolymphoma)
This infrequent benign tumor occurs virtually only in the region of the parotid gland and is
thought to arise from heterotopic salivary tissue trapped within a regional lymph node during
embryogenesis. This tumor is generally a small, well-encapsulated, round to ovoid mass that on
transection often reveals mucin-containing cleftlike or cystic spaces within a soft gray
background. Microscopically, it exhibits two characteristic features: (1) a two-tiered epithelial
layer lining the branching, cystic, or cleftlike spaces; and (2) an immediately subjacent, welldeveloped lymphoid tissue sometimes forming germinal centers. A recurrence rate of about
10% is attributed to incomplete excision, multicentricity, or a second primary tumor. Malignant
transformation is rare; about half of reported cases have had prior radiation exposure.
Tumors of oral cavity and tongue:
These lesions may cause local pain or difficulty in chewing, but many are relatively
asymptomatic and so the lesion (very familiar to the exploring tongue) is ignored. As a result, a
significant number are not discovered until beyond cure. The overall 5-year survival rates after
surgery and adjuvant radiation and chemotherapy are about 40% for cancers of the base of the
tongue, pharynx, and floor of the mouth without lymph node metastasis, compared with less
than 20% for those with lymph node metastasis. When these cancers are discovered at an early
stage, 5-year survival can exceed 90%.
Morphology: The three predominant sites of origin of oral cavity carcinomas are (in order of
frequency) the (1) vermilion border of the lateral margins of the lower lip, (2) floor of the
mouth, and (3) lateral borders of the mobile tongue. Early lesions appear as pearly white to

gray, circumscribed thickenings of the mucosa closely resembling leukoplakic patches. They
then may grow in an exophytic fashion to produce readily visible and palpable nodular and
eventually fungating lesions, or they may assume an endophytic, invasive pattern with central
necrosis to create a cancerous ulcer. The squamous cell carcinomas are usually moderately to
well-differentiated keratinizing tumors. Before the lesions become advanced it may be possible
to identify epithelial atypia, dysplasia, or carcinoma in situ in the margins, suggesting origin
from leukoplakia or erythroplakia. Spread to regional nodes is present at the time of initial
diagnosis only rarely with lip cancer, in about 50% of cases of tongue cancer, and in more than
60% of those with cancer of the floor of the mouth. More remote spread to tissues or organs in
the thorax or abdomen is less common than extensive regional spread.

45) Larynx inflammation and tumors.

Laryngitis: is an inflammation of the larynx. It causes hoarse voice or the complete loss of the
voice because of irritation to the vocal cords. Dysphonia is the medical term for a vocal
disorder, of which laryngitis is one cause. Laryngitis is categorized as acute if it lasts less than a
few days. Otherwise it is categorized as chronic, and may last over 3 weeks. The chronic form of
disease occurs mostly in middle age and is much more common in men than women.
Causes: acid reflux disease, allergies, bacterial or fungal infection, excessive coughing, smoking,
or alcohol consumption, inflammation due to overuse of the vocal cords, use of inhaled
corticosteroids for asthma treatment, viral infection.
Symptoms: hoarseness or no voice at all, dry, sore, burning throat, coughing, which can be a
symptom of, or a factor in causing laryngitis, difficulty swallowing, sensation of swelling in the
area of the larynx, cold or flu-like symptoms (which, like a cough, may also be the causal factor
for laryngitis), swollen lymph nodes in the throat, chest, or face, fever, coughing out blood.
Carcinoma of larynx: represents only 2% of all cancers. It most commonly occurs after age 40
years and is more common in men (7:1) than in women. Environmental influences are very
important in its causation; nearly all cases occur in smokers and alcohol and asbestos exposure
may also play roles. About 95% of laryngeal carcinomas are typical squamous cell lesions.
Rarely, adenocarcinomas are seen, presumably arising from mucous glands. The tumor
develops directly on the vocal cords (glottic tumors) in 60% to 75% of cases, but it may arise
above the cords (supraglottic; 25% to 40%) or below the cords (subglottic; less then 5%). The
major etiologic factors associated with laryngeal squmaous carcinomas include most
importantly smoking, but also alcohol and previous radiation exposure. Human papillomavirus
sequences have been detected in a minority of cases. Squmaous cell carcinomas of the larynx
follow the growth pattern of all squamous cell carcinomas. They begin as in situ lesions that
later appear as pearly gray, wrinkled plaques on the mucosal surface, ultimately ulcerating and

fungating. The glottic tumors are usually keratinizing, well- to moderately differentiated
squamous cell carcinomas, although neonkeratinizing, poorly differentiated carcinomas may
also be seen. As expected with lesions arising from recurrent exposure to environmental
carcinogens, adjacent mucosa may demonstrate squamous cell hyperplasia with foci of
dysplasia, or even carcinoma in situ.

46) Ear inflammatory lesions and tumors.

Otitis externa: is an inflammation of the outer ear and ear canal. Along with otitis media,
external otitis is one of the two human conditions commonly called "earache". Inflammation of
the skin of the ear canal is the essence of this disorder. The inflammation can be secondary to
dermatitis (eczema) only, with no microbial infection, or it can be caused by active bacterial or
fungal infection. In either case, but more often with infection, the ear canal skin swells and may
become painful and tender to touch.
Symptoms: pain is the predominant complaint and the only symptom directly related to the
severity of acute external otitis.
The bacterial pathogens at the top of the list are Pseudomonas aeruginosa and Staphylococcus
aureus, followed by a great number of other gram-positive and gram-negative species. Candida
albicans and Aspergillus species are the most common fungal pathogens responsible for the
condition.
Otitis media: is inflammation of the middle ear, or a middle ear infection. It occurs in the area
between the tympanic membrane and the inner ear, including a duct known as the eustachian
tube. It is one of the two categories of ear inflammation that can underlie what is commonly
called an earache, the other being otitis externa. Diseases other than ear infections can also
cause ear pain, including cancers of any structure that shares nerve supply with the ear and
shingles which can lead to herpes zoster oticus. Though painful, otitis media is not threatening
and usually heals on its own within 26 weeks.
Symptoms: when the middle ear becomes acutely infected, pressure builds up behind the
tympanic membrane, frequently causing intense pain. The tympanic membrane is blistered and
inflamed. In severe or untreated cases, the tympanic membrane may rupture, allowing the pus
in the middle ear space to drain into the ear canal. If there is enough of it, this drainage may be
obvious. Even though the rupture of the tympanic membrane suggests a highly painful and
traumatic process, it is almost always associated with the dramatic relief of pressure and pain.
Benign Tumors: Cholesteatoma, Osteoma, Exostosis, Chemodectoma, Acoustic Neuroma
(Schwannoma)

Malignant tumors:
1-External Ear Squamous Cell Carcinoma, Basal Cell Carcinoma
2-Middle Ear Squamous Cell Carcinoma

47) Pharyngitis and tonsilitis types, sequence.

Pharyngitis: is inflammation of throat. In most cases it is quite painful and is the most common
cause of a sore throat. Like many types of inflammation, pharyngitis can be acute
characterized by a rapid onset and typically a relatively short course or chronic. Pharyngitis
can result in very large tonsils which cause trouble swallowing and breathing. Pharyngitis can be
accompanied by a cough or fever, for example, if caused by a systemic infection. Most acute
cases are caused by viral infections with the remainder caused by bacterial infections, fungal
infections, or irritants such as pollutants or chemical substances. Treatment of viral causes are
mainly symptomatic while bacterial or fungal causes may be amenable to antibiotics and antifungal respectively. If the inflammation includes tonsillitis, it is called pharyngotonsillitis.
Another sub classification is nasopharyngitis.
--Acute pharyngitis may be catarrhal, purulent or ulcerative, depending on the virulence of the
causative agent and the immune capacity of the affected individual. Chronic pharyngitis is the
most common otolaringologic disease and may be catarrhal, hypertrophic or atrophic.
Tonsilitis: is inflammation of the tonsils most commonly caused by a viral or bacterial infection.
Symptoms of tonsillitis include sore throat and fever. While no treatment has been found to
shorten the duration of viral tonsillitis otherwise known as the common cold, bacterial causes
such as streptococcal pharyngitis are treatable with antibiotics. It usually takes one to three
weeks to recover. The most common causes of tonsillitis are the (adenovirus, rhinovirus,
influenza, coronavirus, respiratory syncytial virus). It can also be caused by Epstein-Barr virus,
herpes simplex virus, cytomegalovirus, or HIV. The second most common causes are bacterial.
The most common bacterial cause is Group A -hemolytic streptococcus (GABHS), which causes
strep throat. Less common bacterial causes include: Staphylococcus aureus, Streptococcus
pneumoniae, Mycoplasma pneumoniae, Chlamydia pneumoniae, pertussis, Fusobacterium,
diphtheria, syphilis, and gonorrhea.
Symptoms: red and/or swollen tonsils, white or yellow patches on the tonsils, tender, stiff,
and/or swollen neck , swollen lymph nodes , sore throat , cough, headache.
Complications: include dehydration and kidney failure due to difficulty swallowing, blocked
airways due to inflammation and pharyngitis due to the spread of infection. An abscess may
develop lateral to the tonsil during an infection, typically several days after the onset of

tonsillitis. This is termed a peritonsillar abscess. Rarely, the infection may spread beyond the
tonsil resulting in inflammation and infection of the internal jugular vein giving rise to a
spreading septicaemia infection (Lemierre's syndrome).
Treatment: In chronic/recurrent cases or in acute cases where the palatine tonsils become so
swollen that swallowing is impaired, a tonsillectomy can be performed to remove the tonsils.
Patients whose tonsils have been removed are still protected from infection by the rest of their
immune system.

48) Esophagus: -lesions associated with motor dysfunction, esophagitis,

esophageal varices.
Achalasia: "failure to relax," and in the present context, denotes incomplete relaxation of the
lower esophageal sphincter in response to swallowing. This produces functional obstruction of
the esophagus, with consequent dilation of the more proximal esophagus. Manometric studies
show three major abnormalities in achalasia: (1) aperistalsis, (2) partial or incomplete relaxation
of the lower esophageal sphincter with swallowing, and (3) increased resting tone of the lower
esophageal sphincter. In primary achalasia there is progressive dilation of the esophagus above
the level of the lower esophageal sphincter. The wall of the esophagus may be of normal
thickness, thicker than normal because of hypertrophy of the muscularis, or markedly thinned
by dilation. The myenteric ganglia are usually absent from the body of the esophagus but may
or may not be reduced in number in the region of the lower esophageal sphincter.
Inflammation in the location of the esophageal myenteric plexus is pathognomonic of the
disease. Although achalasia is not a mucosal disease, stasis of food may produce mucosal
inflammation and ulceration proximal to the lower esophageal sphincter. Achalasia is
characterized clinically by progressive dysphagia and inability to completely convey food to the
stomach. Nocturnal regurgitation and aspiration of undigested food may occur. It usually
becomes manifest in young adulthood, but it may appear in infancy or childhood. The most
serious aspect of this condition is the hazard of developing esophageal squamous cell
carcinoma, reported to occur in about 5% of patients and typically at an earlier age than in
those without achalasia.
Hiatal hernia: separation of the diaphragmatic crura and widening of the space between the
muscular crura and the esophageal wall permits a dilated segment of the stomach to protrude
above the diaphragm. Two anatomic patterns are recognizing: the axial, or sliding, hernia and
the nonaxial, or paraesophageal, hernia. The sliding hernia constitutes 95% of cases; protrusion
of the stomach above the diaphragm creates a bell-shaped dilation, bounded below by the
diaphragmatic narrowing. In paraesophageal hernias, a separate portion of the stomach,
usually along the greater curvature, enters the thorax through the widened foramen.

Symptoms more likely result from incompetence of the lower esophageal sphincter than from
the hiatal hernia and are accentuated by positions favoring reflux (bending forward, lying
supine) and obesity.
Lacerations (Mallory-Weiss Syndrome): Longitudinal tears in the esophagus at the
esophagogastric junction are termed Mallory-Weiss tears. They are encountered in chronic
alcoholics after a bout of severe retching or vomiting, but they may also occur during acute
illnesses with severe vomiting. The presumed pathogenesis is inadequate relaxation of the
musculature of the lower esophageal sphincter during vomiting, with stretching and tearing of
the esophagogastric junction at the moment of propulsive expulsion of gastric contents.
Notably, almost half of individuals presenting with upper gastrointestinal bleeding attributable
to a Mallory-Weiss tear have no antecedent history of nausea, retching, abdominal pain, or
vomiting. One must hypothesize that normal variability in intra-abdominal pressure can be
transduced through a hiatal hernia, occasionally leading to a Mallory-Weiss tear. Tears may
involve only the mucosa or may penetrate the wall. Infection of the defect may lead to an
inflammatory ulcer or to mediastinitis.
Esophagitis: Injury to the esophageal mucosa with subsequent inflammation is a common
condition worldwide. The inflammation may have many origins: prolonged gastric intubation,
uremia, ingestion of corrosive or irritant substances, and radiation or chemotherapy, among
others.Heartburn dominant symptom.The anatomic changes depend on the causative agent
and on the duration and severity of the exposure. Mild esophagitis may appear macroscopically
as simple hyperemia, with virtually no histologic abnormality. In contrast, the mucosa in severe
esophagitis shows confluent epithelial erosions or total ulceration into the submucosa. Three
histologic features are characteristic of uncomplicated reflux esophagitis although only one or
two may be present: (1) eosinophils, with or without neutrophils, in the epithelial layer; (2)
basal zone hyperplasia; and (3) elongation of lamina propria papillae. Intraepithelial neutrophils
are markers of more severe injury.
Varices: they appear as tortuous dilated veins lying primarily within the submucosa of the distal
esophagus and proximal stomach. The net effect is irregular protrusion of the overlying mucosa
into the lumen, although varices are collapsed in surgical or postmortem specimens. When the
varix is unruptured, the mucosa may be normal, but often it is eroded and inflamed because of
its exposed position, further weakening the tissue support of the dilated veins. Variceal rupture
produces massive hemorrhage into the lumen, as well as suffusion of blood into the esophageal
wall. Varices produce no symptoms until they rupture. Among persons with advanced cirrhosis
of the liver, half the deaths result from rupture of a varix, either as a direct consequence of the
hemorrhage or from the hepatic coma triggered by the hemorrhage. However, even when
varices are present, they account for less than half of all episodes of hematemesis. Bleeding

from concomitant gastritis, peptic ulcer, or esophageal laceration accounts for most of the
remainder.

49) Esophagus tumors.

Squamous cell carcinoma: An important contributing variable is retarded passage of food
through the esophagus, prolonging mucosal exposure to potential carcinogens such as those
contained in tobacco and alcoholic beverage. There is a well-defined predisposing role for
chronic esophagitis, which is often the consequence of alcohol and tobacco use. Squamous cell
carcinomas are usually preceded by a long prodrome of mucosal epithelial dysplasia followed
by carcinoma in situ and, ultimately, by the emergence of invasive cancer. Early overt lesions
appear as small, gray-white, plaquelike thickenings or elevations of the mucosa. In months to
years, these lesions become tumorous, taking one of three forms: (1) polypoid exophytic
masses that protrude into the lumen; (2) necrotizing cancerous ulcerations that extend deeply
and sometimes erode into the respiratory tree, aorta, or elsewhere; and (3) diffuse infiltrative
neoplasms that cause thickening and rigidity of the wall and narrowing of the lumen.
Whichever the pattern, about 20% arise in the cervical and upper thoracic esophagus, 50% in
the middle third, and 30% in the lower third.
Adenocarcinoma: Barrett esophagus is the only recognized precursor of esophageal
adenocarcinoma. The development of adenocarcinomas from Barrett esophagus is a multistep
process that unfolds over many years. The degree of dysplasia is the strongest predictor of the
progression to cancer. Individuals with low-grade dysplasia have very low rates of progression
to adenocarcinomas but the progression to cancer may be 10% or more per year in individuals
with high-grade dysplasia. Adenocarcinomas seem to arise from dysplastic mucosa in the
setting of Barrett esophagus. Unlike squamous cell carcinomas, they are usually in the distal
one-third of the esophagus and may invade the subjacent gastric cardia. Initially appearing as
flat or raised patches on an otherwise intact mucosa, they may develop into large nodular
masses or show deeply ulcerative or diffusely infiltrative features. Microscopically, most tumors
are mucin-producing glandular tumors showing intestinal-type features, in keeping with the
morphology of the preexisting metaplastic mucosa. Esophageal carcinoma is insidious in onset
and produces dysphagia and obstruction gradually and late. Weight loss, anorexia, fatigue, and
weakness appear, followed by pain, usually related to swallowing. Diagnosis is usually made by
imaging techniques and endoscopic biopsy.

50) Acute gastritis.

Gastritis: inflammation of the stomach lining.

Acute gastritis: sudden, caused by excessive alcohol intake, or by the use of non- steroidal antiinflammatory drug (NSAIDs- aspirin), which reduce the production of mucus by the stomach
lining cells. Acute gastritis is frequently associated with: heavy use of nonsteroidal antiinflammatory drugs (NSAIDs), particularly aspirin, excessive alcohol consumption, heavy
smoking.Treatment with cancer chemotherapeutic drugs.
Morphology: Acute gastritis ranges from extremely localized (as occurs in NSAID-induced
injury) to diffuse, and from superficial inflammation to involvement of the entire mucosal
thickness with hemorrhage and focal erosions. Concurrent erosion and hemorrhage are readily
visible by endoscopy and termed acute erosive gastritis. All variants are marked by mucosal
edema and an inflammatory infiltrate of neutrophils and possibly by chronic inflammatory cells.
Regenerative replication of epithelial cells in the gastric pits is usually prominent. Provided that
the noxious event is short lived, acute gastritis may disappear within days with complete
restitution of the normal mucosa.
Clinical Features: Depending on the severity of the anatomic changes, acute gastritis may be
entirely asymptomatic, may cause variable epigastric pain with nausea and vomiting, or may
present as overt hematemesis, melena, and potentially fatal blood loss. Overall, it is one of the
major causes of hematemesis, particularly in alcoholics. The risk of gastric bleeding from NSAIDinduced gastritis is dose related, increasing the likelihood of this complication in persons
requiring long-term use of such drugs.

51) Chronic gastritis types, evolution.

Gastritis: inflammation of the stomach lining.
Chronic gastritis: long- term, due to infection of the stomach lining by the bacterium
Helicobacter pylori, which weakens the protective mucus barrier. H. pylori is a noninvasive,
non-spore-forming, S-shaped gram-negative rod measuring approximately 3.5 m 0.5 m.
Suffice it to say that gastritis develops as a result of the combined influence of bacterial
enzymes and toxins and release of noxious chemicals by the recruited neutrophils. After initial
exposure to H. pylori, gastritis may develop in two patterns: (1) an antral-type with high acid
production and higher risk for the development of duodenal ulcer, and (2) a pangastritis with
multifocal mucosal atrophy, with low acid secretion and increased risk for adenocarcinoma.
Persons with chronic gastritis and H. pylori usually improve symptomatically when treated with
antibiotics and proton pump inhibitors. Improvement in the underlying chronic gastritis may
take much longer. Relapses are associated with reappearance of this organism.
Morphology: Regardless of the cause or histologic distribution of chronic gastritis, the
inflammatory changes consist of a lymphocytic and plasma cell infiltrate in the lamina propria,

occasionally accompanied by neutrophilic inflammation of the neck region of the mucosal pits.
The inflammation may be accompanied by variable gland loss and mucosal atrophy. When
present, H. pylori organisms are found nestled within the mucus layer overlying the superficial
mucosal epithelium. In the autoimmune variant, loss of parietal cells is particularly prominent.
Two additional features are of note. Intestinal metaplasia refers to the replacement of gastric
epithelium with columnar and goblet cells of intestinal variety. This is significant, because
gastrointestinal-type carcinomas seem to arise from dysplasia of this metaplastic epithelium.
Second, H. pylori-induced proliferation of lymphoid tissue within the gastric mucosa has been
implicated as a precursor of gastric lymphoma.
Clinical Features: Chronic gastritis usually causes few or no symptoms; upper abdominal
discomfort and nausea and vomiting can occur. When severe parietal cell loss occurs in the
setting of autoimmune gastritis, hypochlorhydria or achlorhydria (referring to concentrations of
gastric luminal hydrochloric acid) and hypergastrinemia are characteristically present.
Individuals with chronic gastritis from other causes may be hypochlorhydric, but because
parietal cells are never completely destroyed, these persons do not develop achlorhydria or
pernicious anemia. Serum gastrin levels are either normal or only modestly elevated. Most
important is the relationship of chronic gastritis to the development of peptic ulcer and gastric
carcinoma. Most individuals with a peptic ulcer, whether duodenal or gastric, have H. pylori
infection.

52) Peptic ulcer disease morphology, sequence, complications.

Morphology: All peptic ulcers, whether gastric or duodenal, have an identical gross and
microscopic appearance. By definition, they are defects in the mucosa that penetrate at least
into the submucosa and often into the muscularis propria or deeper. Most are round, sharply
punched-out craters 2 to 4 cm in diameter ; those in the duodenum tend to be smaller, and
occasional gastric lesions are significantly larger. Favored sites are the anterior and posterior
walls of the first portion of the duodenum and the lesser curvature of the stomach. The
location within the stomach is dictated by the extent of the associated gastritis: antral gastritis
is most common and the ulcer is often along the lesser curvature at the margin of the inflamed
area and the upstream acid-secreting mucosa of the corpus. Occasional gastric ulcers occur on
the greater curvature or anterior or posterior walls of the stomach, the very same locations of
most ulcerative cancers. Classically, the margins of the crater are perpendicular and there is
some mild edema of the immediately adjacent mucosa, but unlike ulcerated cancers there is no
significant elevation or beading of the edges. The surrounding mucosal folds may radiate like
wheel spokes. The base of the crater appears remarkably clean, as a result of peptic digestion
of the inflammatory exudate and necrotic tissue. Infrequently, an eroded artery is visible in the
Ulcer. If the ulcer crater penetrates through the duodenal or gastric wall, a localized or

generalized peritonitis may develop. Alternatively, the perforation is sealed by an adjacent

structure such as adherent omentum, liver, or pancreas.
The histologic appearance varies with the activity, chronicity, and degree of healing. In a
chronic, open ulcer, four zones can be distinguished : (1) the base and margins have a thin layer
of necrotic fibrinoid debris underlain by (2) a zone of active nonspecific inflammatory
infiltration with neutrophils predominating, underlain by (3) granulation tissue, deep to which is
(4) fibrous, collagenous scar that fans out widely from the margins of the ulcer. Vessels trapped
within the scarred area are characteristically thickened and occasionally thrombosed, but in
some instances they are widely patent. With healing, the crater fills with granulation tissue,
followed by re-epithelialization from the margins and more or less restoration of the normal
architecture (hence the prolonged healing times). Extensive fibrous scarring remains.
Clinical Features: Most peptic ulcers cause epigastric pain, often described as gnawing, burning,
or boring, but a significant minority first come to light with complications such as hemorrhage
or perforation. The pain tends to be worse at night and occurs usually 1 to 3 hours after meals
during the day. Classically, the pain is relieved by alkalis or food, but there are many exceptions.
Nausea, vomiting, bloating, belching and significant weight loss (raising the specter of some
hidden malignancy) are additional manifestations.
Complications: Bleeding is the chief complication, occurring in as many as one-third of patients,
and may be life-threatening. Perforation occurs in about 5% of patients but accounts for twothirds of deaths from this disease in the United States. Obstruction of the pyloric channel is
rare. Malignant transformation occurs in about 2% of patients, generally from ulcers in the
pyloric channel, and is very rare with gastric ulcers. In the latter event, it is often difficult to
exclude the possibility that carcinoma was present from the outset.

53) Acute gastric ulceration.

Gastric ulcer: a localized area of erosion in the stomach lining, resulting in abdominal pain,
possible bleeding, and other gastrointestinal symptoms.The most common cause of gastric
ulcer is a stomach infection associated with the Helicobacter pylori (H pylori) bacteria. Focal,
acutely developing gastric mucosal defects that may appear after severe physiologic stress are
called stress ulcers. Generally, there are many lesions located mainly in the stomach and
occasionally in the duodenum. The pathogenesis of these lesions is uncertain and may vary with
the setting. NSAID-induced ulcers are linked to decreased prostaglandin production. The
systemic acidosis that can accompany severe trauma and burns may contribute to mucosal
injury presumably by lowering the intracellular pH of mucosal cells already rendered hypoxic by
impaired mucosal blood flow. With cranial lesions, direct stimulation of vagal nuclei by

increased intracranial pressure may cause gastric acid hypersecretion, which is common in
these patients.
Morphology: Acute stress ulcers are usually circular and small (<1 cm in diameter). The ulcer
base is frequently stained dark brown by the acid digestion of extruded blood. Unlike chronic
peptic ulcers, acute stress ulcers are found anywhere in the stomach. They may occur singly,
but more often there are several, located throughout the stomach and duodenum.
Microscopically, acute stress ulcers are abrupt lesions, with essentially unremarkable adjacent
mucosa. They range in depth from very superficial lesions (erosion) to deeper lesions that
involve the entire mucosal thickness (true ulceration). The shallow erosions are, in essence, an
extension of acute erosive gastritis. The deeper lesions comprise well-defined ulcerations but
are not precursors of chronic peptic ulcers. Even the deeper lesions do not penetrate the
muscularis propria.
Clinical Features: A high percentage of persons admitted to hospital intensive care units with
sepsis, severe burns, or trauma develop superficial gastric erosions or ulcers. These may be of
limited clinical consequence or may be life-threatening. Although prophylactic antacid regimens
and blood transfusions may blunt the impact of stress ulceration, the single most important
determinant of clinical outcome is the ability to correct the underlying condition. The gastric
mucosa can recover completely if the person does not die from the primary disease.

54) Stomach benign tumors.

Gastric polyps: The term polyp is applied to any nodule or mass that projects above the level of
the surrounding mucosa. Occasionally, a lipoma or leiomyoma arising in the wall of the stomach
may protrude from under the mucosa to produce an apparent polypoid lesion. However, the
use of the term polyp in the gastrointestinal tract is generally restricted to mass lesions arising
in the mucosa. Gastric polyps are uncommon and are found in about 0.4% of adult autopsies, as
compared with colonic polyps, which are seen in 25% to 50% of older persons. In the stomach,
these lesions are most frequently (1) hyperplastic polyps (80% to 85%), (2) fundic gland polyps
(10%), and (3) adenomatous polyps (5%). All three types arise in the setting of chronic
gastritis and so are seen in the same patient populations. Hyperplastic and fundic gland polyps
are essentially innocuous. In contrast, there is a definite risk of an adenomatous polyp
harboring adenocarcinoma, which increases with polyp size. Because the different types of
gastric polyps cannot be reliably distinguished by endoscopy, histologic examination is
mandatory.
Morphology: Hyperplastic polyps arise from an exuberant reparative response to chronic
mucosal damage and are composed of a hyperplastic mucosal epithelium and an inflamed
edematous stroma. They are not true neoplasms. Fundic gland polyps are small collections of

dilated corpus-type glands thought to be small hamartomas. On the other hand, the less
common adenomas contain dysplastic epithelium. As with colonic adenomas, adenomas are
true neoplasms.

55) Gastric carcinoma. Early diagnostics.

More than 90% of gastric tumors are carcinomas; lymphomas, carcinoids and stromal tumors
are relatively infrequent.The two main types of gastric adenocarcinomas are the intestinal and
diffuse types; macroscopic patterns of both types may be exophytic, flat or depressed, or
excavating.Intestinal type of adenocarcinoma is associated with chronic gastritis caused by H.
pylori infection, with gastric atrophy and intestinal metaplasia; composed of malignant cells
forming intestinal glands.Diffuse type of adenocarcinoma is not associated with H. pylori
infection; composed of gastric type of mucous cells (signet ring cells) that permeate the mucosa
without forming glands.
Morphology: The location of gastric carcinomas within the stomach is as follows: pylorus and
antrum, 50% to 60%; cardia, 25%; and the remainder in the body and fundus. The lesser
curvature is involved in about 40% and the greater curvature in 12%. Thus, a favored location is
the lesser curvature of the antropyloric region. Though less frequent, an ulcerative lesion on
the greater curvature is more likely to be malignant than benign. Gastric carcinoma is classified
on the basis of depth of invasion, macroscopic growth pattern, and histologic subtype. The
morphologic feature having the greatest impact on clinical outcome is the depth of invasion.
Early gastric carcinoma is defined as a lesion confined to the mucosa and submucosa,
regardless of the presence or absence of perigastric lymph node metastases. Advanced gastric
carcinoma is a neoplasm that has extended below the submucosa into the muscular wall and
has perhaps spread more widely. Gastric mucosal dysplasia is the presumed precursor lesion of
early gastric cancer, which then in turn progresses to "advanced" lesions. The three
macroscopic growth patterns of gastric carcinoma, which may be evident at both the early and
advanced stages, are (1) exophytic, with protrusion of a tumor mass into the lumen; (2) flat or
depressed, in which there is no obvious tumor mass within the mucosa; and (3) excavated,
whereby a shallow or deeply erosive crater is present in the wall of the stomach. Exophytic
tumors may contain portions of an adenoma. Flat or depressed malignancy presents only as
regional effacement of the normal surface mucosal pattern. Excavated cancers may mimic, in
size and appearance, chronic peptic ulcers, although more advanced cases show heaped-up
margins. Uncommonly, a broad region of the gastric wall, or the entire stomach, is extensively
infiltrated by malignancy. The rigid and thickened stomach is termed a leather bottle stomach,
or linitis plastica; metastatic carcinoma from the breast and lung may generate a similar
picture.

--Whatever the histologic variant, all gastric carcinomas eventually penetrate the wall to involve
the serosa, spread to regional and more distant lymph nodes, and metastasize widely. For
obscure reasons, the earliest lymph node metastasis may sometimes involve a supraclavicular
lymph node (Virchow node). Another somewhat unusual mode of intraperitoneal spread in
females is to both the ovaries, giving rise to the so-called Krukenberg tumor.

56) Precancerous lesions in stomach morphologic diagnosis.

Gastric dysplasia: Over the past 25 years it has become clear that the malignancy is the final
step of progressive phenotypic changes. Such changes modify the original cellular morphology,
eventually generating a biologically new cell characterised by uncontrolled growth and the
potential to migrate and implant in locations beyond its original fixed site. This biological
process has been called multistep or stepwise oncogenesis. A collection of (mostly unknown)
genetic alterations underlies the neoplastic changes of the original cellular phenotype. They
vary from cancer to cancer and from subject to subject in quality, number, and timing. The
phenotypic counterpart of such genomic alterations consists of a continuum of morphological
lesions characterised by progressive dedifferentiation of the histological and cytological
structure of the original tissue. In the intestinal district, such a model has been originally
studied in the mucosa of the large bowel. In this context, three main categories of lesions have
been distinguished:
(a) true normal,
(b) atypical lesions, mostly polypoid, associated with high risk of cancer evolution,
(c) cancer.
The definition of dysplasia was successfully applied to the intermediate category, also
emphasising the increasing cancer risk associated with the increasing degree of atypical
phenotypes. On the basis of the large bowel model, similar aberrant epithelia have also been
described in the stomach mucosa, where they were formerly considered as coexisting with
gastric malignancies.
From gastritis to cancer: In this model, chronic gastritis progressively evolves to atrophy and
intestinal metaplasia. In some subjects the metaplastic epithelium undergoes further genomic
and phenotypic disarrangements (dysplasia) and may progress to invasive neoplasia. Recently,
the paradigm has been modified to insert H pylori at the beginning of the sequence. Although
this model is validated and widely accepted, there is still a wide discordance in the
histopathological recognition of two of its crucial steps: atrophy and dysplasia.

57) Small intestine inflammation.

Inflammatory bowel disease: a group of inflammatory conditions of the colon and small
intestine. The major types of IBD are Crohn's disease and ulcerative colitis. Cause: H. pylori
infection is caused by the Helicobacter pylori bacterium. H. pylori is primarily passed from
person to person through direct contact with saliva or stool. It may also be spread through
untreated water. H. pylori infection infects the stomach or the first section of the small
intestine and is the cause of most ulcers and many cases of gastritis or stomach inflammation.
Symptoms: Most patients with H. pylori infection have no symptoms. When symptoms are
present, they can include an ache or burning pain in the abdomen, nausea and vomiting,
frequent burping, bloating or weight loss. Patients should seek immediate medical attention if
they experience severe or persistent abdominal pain, difficulty swallowing, bloody or black
tarry stools, bloody or black vomit, or vomit that looks like coffee grounds.
Complications: may include ulcers in the stomach or small intestine, inflammation of the
stomach lining or stomach cancer.
Diagnosis: H. pylori infection can be done by testing the patient's blood, breath and stool.
Endoscopy -- a test that examines the esophagus, stomach and duodenum through a tiny
camera on the end of a long, flexible tube -- is used if the patient has symptoms of an ulcer.
Treatment: treatment for H. pylori may include a combination of medications, including
antibiotics such as amoxicillin, tetracycline or metronidazole, and proton-pump inhibitors such
as omeprazole. Treatment with medications lasts for 10 to 14 days.

58) Mesenterial thrombosis sequence.

Mesenteric artery thrombosis: Thrombosis of the superior mesenteric or celiac arteries is most
often associated with a preexisting atherosclerotic lesion that already compromises flow. The
most common preexisting pathology found in patients with acute mesenteric thrombosis is
atherosclerosis. Many patients present with histories consistent with chronic mesenteric
ischemia. Wasting, postprandial pain and phagophobia (fear of eating) are all common.
Typically, the atherosclerotic lesion gradually compromises flow to the gut, causing a
progressive worsening of symptoms. During a period of low flow, the artery thromboses, and
flow to the gut is compromised. The atherosclerotic plaque, usually at the origin of the superior
mesenteric artery (SMA) or celiac artery grows over time. The SMA is the most common visceral
branch to thrombose. A thrombus forms during a state of low flow, resulting in acute cessation
of flow to the gut. Bloody stools develop as the more sensitive mucosa dies first. The bowel
gradually becomes necrotic; subsequently, bacterial overgrowth develops, and the resulting
bowel perforation causes sepsis and finally death. Gross specimens of dead bowels are shown
in the images below.

Mesenteric venous thrombosis: The risk of acute mesenteric venous thrombosis increases in
patients with hypercoagulable states (ex. polycythemia vera, protein C and S deficiencies)
visceral infection, portal hypertension, perforated viscus, blunt abdominal trauma, malignancy,
previous abdominal surgery (open or laparoscopic), or pancreatitis and in patients who smoke.
Women taking oral contraceptives are also at increased risk of venous thrombosis. While the
mesenteric arterial system may carry 25-40% of the cardiac output at one time, the venous
system typically carries 30%. The mechanism that causes ischemia is a massive influx of fluid
into the bowel wall and lumen, resulting in systemic hypovolemia and hemoconcentration.
Resulting bowel edema and decreased outflow of blood secondary to venous thrombosis
impede the inflow of arterial blood, which leads to bowel ischemia. While bowel ischemia is
detrimental to the patient, the resulting multiple organ system failure actually accounts for the
increased mortality rate. Lack of anticoagulation also may have been a factor. Five-year
mortality, according to the investigators, was primarily related to short-bowel syndrome.
Indications for surgery in patients with acute mesenteric venous thrombosis include signs of
peritonitis, possible bowel infarction and hemodynamic instability.

59) Crohn disease. Wipple disease.

Crohn's disease is a type of inflammatory bowel disease that may affect any part of the
gastrointestinal tract from mouth to anus, causing a wide variety of symptoms. It primarily
causes abdominal pain, diarrhea (which may be bloody if inflammation is severe), vomiting, or
weight loss, but may also cause complications outside the gastrointestinal tract such as anemia,
skin rashes, arthritis, inflammation of the eye, tiredness, and lack of concentration. Crohn's
disease is caused by interactions between environmental, immunological and bacterial factors
in genetically susceptible individuals. This result in a chronic inflammatory disorder, in which
the body's immune system attacks the gastrointestinal tract possibly directed at microbial
antigens. While Crohn's is an immune related disease, it does not appear to be an autoimmune
disease (in that the immune system is not being triggered by the body itself). The exact
underlying immune problem is not clear; however it may be an immune deficiency state.
Morphology: By microscopic examination, the mucosa shows several characteristic features: (1)
inflammation, with neutrophilic infiltration into the epithelial layer and accumulation within
crypts to form crypt abscesses; (2) ulceration, which is the usual outcome of active disease; and
(3) chronic mucosal damage in the form of architectural distortion, atrophy, and metaplasia
(including rudimentary gastric metaplasia in the intestine). Granulomas may be present anywhere in the alimentary tract, even in individuals with Crohn disease limited to one bowel
segment. However, the absence of granulomas does not preclude a diagnosis of Crohn disease.
In diseased segments, the muscularis mucosae and muscularis propria are usually markedly

thickened, and fibrosis affects all tissue layers. Lymphoid aggregates scattered through the
various tissue layers and in the extramural fat also are characteristic.
Whipple's disease is a rare, systemic infectious disease caused by the bacterium Tropheryma
whipplei. Whipple's disease primarily causes malabsorption but may affect any part of the body
including the heart, lungs, brain, joints, skin, and the eyes. Weight loss, diarrhea, joint pain, and
arthritis are common presenting symptoms, but the presentation can be highly variable and
approximately 15% of patients do not have these classic signs and symptoms. Whipple's disease
is significantly more common in men, with 87% of the patients being male. When recognized
and treated, Whipple's disease can usually be cured with long-term antibiotic therapy;
untreated, the disease is ultimately fatal.
Morphology: These macrophages can be easily observed infiltrating the tissues using
conventional light microscopy. The macrophages are easily observed when periodic acid-Schiff
stain is used for the histologic sections. However, positive periodic acid-Schiffstained
macrophages infiltrating body tissues are not pathognomonic for Whipple disease. These
microphages also can be detected in infection due to Mycobacterium avium intracellulare,
cryptococcosis, or other parasitic organisms (usually observed in patients who are
immunosuppressed with HIV disease). Stains for fungal organisms and acid-fast bacilli are
helpful in ruling out Whipple disease.

60) Chronic enteritis. Melabsorption syndromes.

Chronic enteritis polietiolohichne disease, based on a dystrophic process in the small
intestine that leads to destruction ing barrier function, digesting and absorption, settling its
upper large number of microorganisms are recycled metabolic and immune disorders,
disorders function of the nervous system.
The basis of virulence of pathogens enteritis is a combination of pathogens and intestinal
enterocytes, resulting in forming pilus bacteria, increasing contact with the epithelial
membrane. Bacterial for adhesion which is on the surface of microorganisms interact with
specific binding of carbon places epithelial cells on the principle of ligand-receptor interaction.
This mechanism is typical for E. Coli. An important role is temperature-stable toxin. Inhibition of
growth of normal flora under the influence of antibiotics on subsequent reproduction and
allocating them toxin and underlies the development of pseudomembranous enteritis. In the
development of infectious diarrhea, but these toxins, taking an active part endogenous
stimulants water and electrolyte secretion in the small intestine. This is particularly serotonin
(5-HT). It connects to the 5-NT3-receptor neurons afferent intramural nervous arc, which
controls water and electrolyte secretion. As a result of this process increases water and
electrolyte flow. Another endogenous stimulator of this secretion is intestinal Vasoactive

peptide (V1P). He interacts with VIP receptors bazolateral membrane of intestinal epithelial
cells, induces water and electrolyte secretion and inhibited intestinal absorption of electrolytes
and neurotransmitters. Strengthen an important role in intestinal secretion of prostaglandins
play, in which hyperproduction invasion causes shortening of intestinal villi, crypt deepening,
inhibition of sodium and fluid absorption.
Malabsorption syndrome: is an alteration in the ability of the intestine to absorb nutrients
adequately into the bloodstream. It may refer to malabsorption of one specific nutrient or for
specific carbohydrates, fats, or trace elements (micronutrients).
The most common symptoms of malabsorption include: anemia, with weakness and fatigue
due to inadequate absorption of vitamin B12, iron, and folic acid, diarrhea, steatorrhea
(excessive amount of fat in the stool), and abdominal distention with cramps, bloating, and gas
due to impaired water and carbohydrate absorption, and irritation from unabsorbed fatty acids.
The individual may also report explosive diarrhea with greasy, foul-smelling stools, edema (fluid
retention in the body's tissues) due to decreased protein absorption, malnutrition and weight
loss due to decreased fat, carbohydrate, and protein absorption, muscle cramping due to
decreased vitamin D, calcium, and potassium levels,muscle wasting and atrophy due to
decreased protein absorption and metabolism, perianal skin burning, itching, or soreness due
to frequent loose stools, irregular heart rhythms may also result from inadequate levels of
potassium and other electrolytes, blood clotting disorders may occur due to a vitamin K
deficiency. Children with malabsorption syndrome often exhibit a failure to grow and thrive.
Several disorders can lead to malabsorption syndrome, including cystic fibrosis, chronic
pancreatitis, lactose intolerance, and gluten enteropathy (nontropical sprue).
Diagnosis: The first phase involves a thorough medical history. A 72-hour stool collection may
be ordered for fecal fat measurement; increased fecal fat in the stool collected indicates
malabsorption. A biopsy of the small intestine may be done to assist in differentiating between
malabsorption syndrome and small bowel disease. Ultrasound, computed tomography scan (CT
scan), magnetic resonance imaging (MRI), or other x rays to identify abnormalities of the
gastrointestinal tract and pancreas may also be ordered.

61) Intestinal obstruction.

Intestinal obstruction: Although any part of the gut may be involved, because of its narrow
lumen, the small bowel is most commonly affected. Four entities-hernias, intestinal adhesions,
intussusception, and volvulus-account for at least 80% of the cases. Hernias, a weakness or
defect in the wall of the peritoneal cavity, may permit protrusion of a pouchlike, serosa-lined
sac of peritoneum, called a hernial sac. The usual sites of weakness are anteriorly at the

inguinal and femoral canals, at the umbilicus, and in surgical scars. Rarely, retroperitoneal
hernias may occur, chiefly about the ligament of Treitz. Hernias are of concern because
segments of viscera frequently intrude and become trapped in them (external herniation). This
is particularly true with inguinal hernias, which have narrow orifices and large sacs. The most
frequent intruders are small bowel loops, but portions of omentum or large bowel also may
become trapped. Pressure at the neck of the pouch may impair venous drainage of the trapped
viscus. The ensuing stasis and edema increase the bulk of the herniated loop, leading to
permanent trapping (incarceration). Further compromise of its blood supply and drainage leads
to infarction of the trapped segment (strangulation).
Intussusception denotes telescoping of a proximal segment of bowel into the immediately
distal segment. In children, intussusception sometimes occurs without apparent anatomic
basis, perhaps related to excessive peristaltic activity. In adults, such telescoping often points to
an intraluminal mass (e.g., tumor) that becomes trapped by a peristaltic wave and pulls its point
of attachment along with it into the distal segment. Not only does intestinal obstruction ensue,
but the vascular supply may be so compromised as to cause infarction of the trapped segment.
Volvulus refers to twisting of a loop of bowel or other structure (e.g., ovary) about its base of
attachment, constricting the venous outflow and sometimes the arterial supply as well.
Volvulus affects the small bowel most often and rarely the redundant sigmoid. Intestinal
obstruction and infarction may follow.
Surgical procedures, infection, and even endometriosis often cause localized or general
peritoneal inflammation (peritonitis). With healing, adhesions may develop between bowel
segments or the abdominal wall and the operative site. These fibrous bridges can create closed
loops through which the intestines may slide and become trapped (internal herniation). The
sequence of events is much the same as with external hernias.

62) Tumors of small intestine.

Small intestine tumors: Whereas the small bowel represents 75% of the length of the
alimentary tract, its tumors account for only 3% to 6% of gastrointestinal tumors, with a slight
preponderance of benign tumors. The number of deaths in the United States annually is under
1000, representing only about 1% of gastrointestinal malignancies. The most frequent benign
tumors in the small intestine are stromal tumors of predominantly smooth muscle origin,
adenomas, and lipomas, followed by various neurogenic, vascular, and hamartomatous
epithelial lesions. Small intestinal adenocarcinomas and carcinoids have a roughly equal
incidence. Gastrointestinal stromal tumors (GISTs) have received much attention recently,
because they have an activating mutation affecting KIT, a tyrosine kinase receptor that is the
target of new therapeutic agents (discussed in the next section).

Adenocarcinoma of the small intestine:These tumors grow in a napkin-ring encircling pattern

or as polypoid fungating masses, in a manner similar to colonic cancers. Most small bowel
carcinomas arise in the duodenum (including the ampulla of Vater). Cramping pain, nausea,
vomiting, and weight loss are the common presenting signs and symptoms, but such
manifestations generally appear late in the course of these cancers. By the time of diagnosis,
most have already penetrated the bowel wall, invaded the mesentery or other segments of the
gut, spread to regional nodes, and sometimes metastasized to the liver and more widely.
Despite these problems, wide en bloc excision of these cancers yields a 5-year survival rate of
about 70%. Adenomas of the small intestine may present with anemia or rarely intussusception
or obstruction. Adenomas in the immediate vicinity of the ampulla of Vater may produce biliary
obstruction causing jaundice.

63) Appendicitis. Complications.

Appendicitis is a condition characterized by inflammation of the appendix. It is classified as a
medical emergency and many cases require removal of the inflamed appendix, either by
laparotomy or laparoscopy. Untreated, mortality is high, mainly because of the risk of rupture
leading to peritonitis and shock. The histologic findings of appendicits are neutrophils in the
muscularis propria. Periappendicits, inflammation of tissues around the appendix, is often
found in conjunction with other abdominal pathology.
Symptoms: Pain first, vomiting next and fever last has been described as the classic
presentation of acute appendicitis. Pain starts mid-abdomen, and except in children below 3
years, tends to localize in the right iliac fossa in a few hours. This pain can be elicited through
various signs and can be severe. Signs include localized findings in the right iliac fossa. The
abdominal wall becomes very sensitive to gentle pressure (palpation). Also, there is severe pain
on sudden release of deep pressure in the lower abdomen (rebound tenderness). In case of a
retrocecal appendix, however, even deep pressure in the right lower quadrant may fail to elicit
tenderness (silent appendix), the reason being that the cecum, distended with gas, prevents the
pressure exerted by the palpating hand from reaching the inflamed appendix.
Complications: The most serious complication of appendicitis is rupture. The appendix bursts or
tears if appendicitis is not diagnosed quickly and goes untreated. Infants, young children, and
older adults are at highest risk. A ruptured appendix can lead to peritonitis and abscess.
Peritonitis is a dangerous infection that happens when bacteria and other contents of the torn
appendix leak into the abdomen. In people with appendicitis, an abscess usually takes the form
of a swollen mass filled with fluid and bacteria. In a few patients, complications of appendicitis
can lead to organ failure and death.

64) Large intestine inflammation.

Crohn disease and ulcerative colitis are chronic relapsing inflammatory disorders known as
idiopathic inflammatory bowel disease (IBD). They result from an abnormal local immune
response against the normal flora of the gut, and probably against some self antigens, in
genetically susceptible individuals. Crohn disease may affect any portion of the gastrointestinal
tract from esophagus to anus but most often involves the ileum; about half of cases exhibit
noncaseating granulomatous inflammation. Ulcerative colitis is a nongranulomatous disease
limited to the colon.
Etiology and pathogenesis: The normal intestine is in a steady state of "physiologic"
inflammation, representing a dynamic balance between (1) factors that activate the host
immune system, such as luminal microbes, dietary antigens, and endogenous inflammatory
stimuli; and (2) host defenses that down-regulate inflammation and maintain the integrity of
the mucosa. The search for the causes of loss of this balance in Crohn disease and ulcerative
colitis has revealed many parallels, but the origins of both diseases remain unexplained (thus
their designation as idiopathic). The pathogenesis of IBD involves genetic susceptibility, failure
of immune regulation, and triggering by microbial flora.
Immunological factors: It is not known whether the immune responses in IBD are directed
against self-antigens of the intestinal epithelium or to bacterial antigens. In both Crohn disease
and ulcerative colitis the primary damaging agents appear to be CD4+ cells. Antineutrophil
cytoplasmic antibodies and antitropomyosin antibodies detected in persons with ulcerative
colitis do not seem to play a pathogenetic role.It has long been thought that Crohn disease is
the result of a chronic delayed-type hypersensitivity reaction induced by interferon -producing
TH1 cells. However, recent results from mouse models of IBD suggest that the tissue
inflammation may be the result of secretion of the cytokine IL-17 by a recently discovered
subset of CD4+ T cells that is being called the "TH17" subset.Although in animal models
ulcerative colitis may be caused by activation of TH2 cells, IL-4, the signature cytokine for this
kind of response, has not been found, suggesting that in ulcerative colitis there may not be a
predominant class of T-cell response.The inflammatory cytokine TNF may play an important
pathogenic role in Crohn disease. This is suggested by the effectiveness of treatment with TNF
antagonists in this disorder.

65) Ulcerative colitis.

Ulcerative colitis involves the rectum and sigmoid and may involve the entire colon.
Presentation with an even higher proximal extension (pancolitis) occurs much less frequently.
Colonic involvement is continuous from the distal colon, so that skip lesions are not
encountered. Active disease denotes ongoing inflammatory destruction of the mucosa, with
macroscopic hyperemia, edema, and granularity with friability and easy bleeding. With severe
active disease, there is extensive and broad-based ulceration of the mucosa in the distal colon

or throughout its length. Isolated islands of regenerating mucosa bulge upward to create
pseudopolyps. Often the undermined edges of adjacent ulcers interconnect to create tunnels
covered by tenuous mucosal bridges. As with Crohn disease, the ulcers of ulcerative colitis are
frequently aligned along the axis of the colon, but rarely do they replicate the linear serpentine
ulcers of Crohn disease. In rare cases, the muscularis propria is so compromised as to permit
perforation and pericolonic abscess formation. Exposure of the muscularis propria and neural
plexus to fecal material also may lead to complete shutdown of neuromuscular function. When
this occurs, the colon progressively swells and becomes gangrenous (toxic megacolon). With
indolent chronic disease or with healing of active disease, progressive mucosal atrophy leads to
a flattened and attenuated mucosal surface.
Morphology: The pathologic features of ulcerative colitis are those of mucosal inflammation,
ulceration, and chronic mucosal damage. A diffuse, predominantly mononuclear inflammatory
infiltrate in the lamina propria is almost universally present, even at the time of clinical
presentation. Neutrophilic infiltration of the epithelial layer may produce collections of
neutrophils in crypt lumina (crypt abscesses). These are not specific for ulcerative colitis and
may be observed in Crohn disease or any active inflammatory colitis. Unlike Crohn disease,
there are no granulomas, although rupture of crypt abscesses may incite a foreign body
reaction in the lamina propria. Further destruction of the mucosa leads to outright ulceration,
extending into the submucosa and sometimes leaving only the raw, exposed muscularis
propria. With remission of active disease, granulation tissue fills in the ulcer craters, followed
by regeneration of the mucosal epithelium. Submucosal fibrosis and mucosal architectural
disarray and atrophy remain as residua of healed disease.
Symptoms: a chronic relapsing disorder marked by attacks of bloody mucoid diarrhea that may
persist for days, weeks, or months and then subside, only to recur after an asymptomatic
interval of months to years or even decades. Presentation is usually insidious, with cramps,
tenesmus, and colicky lower abdominal pain that is relieved by defecation. Some people
manifest fever and weight loss. Grossly bloody stools are more common with ulcerative colitis
than with Crohn disease, and the blood loss may be considerable.
Complications: Uncommon but life-threatening complications include severe diarrhea and
electrolyte derangements, massive hemorrhage, severe colonic dilation (toxic megacolon) with
potential rupture, and perforation with peritonitis. Inflammatory strictures of the colorectum,
while uncommon, must be differentiated from cancer. Diagnosis can usually be made by
endoscopic examination and biopsy. The most feared long-term complication of ulcerative
colitis is cancer.

66) Adenomas in large intestine. Malignant risk. Morphologic diagnosis.

Adenomas are neoplastic polyps that range from small, often pedunculated, tumors to large
lesions that are usually sessile. The prevalence of colonic adenomas is 20% to 30% before age
40, rising to 40% to 50% after age 60. Males and females are affected equally. There is a welldefined familial predisposition to sporadic adenomas, accounting for about a fourfold greater
risk for adenomas among first-degree relatives, and also a fourfold greater risk of colorectal
carcinoma in any person with adenomas. All adenomatous lesions arise as the result of
epithelial proliferation and dysplasia, which may range from mild to so severe as to represent
transformation to carcinoma. Furthermore, there is strong evidence that most sporadic invasive
colorectal adenocarcinomas arise in preexisting adenomatous lesions. Adenomatous polyps are
segregated into four subtypes on the basis of the epithelial architecture: 1) Tubular adenomasmostly tubular glands, 2) Villous adenomas-villous projections, 3) Tubulovillous adenomas-a
mixture of the above, 4) Sessile serrated adenomas-serrated epithelium lining the crypts.
Morphology: Most tubular adenomas are small and pedunculated. Tubular adenomas may
arise anywhere in the colon, but about half are found in the rectosigmoid, the proportion
increasing with age. In about half of the instances they occur singly, but in the remainder two or
more lesions are distributed at random. The smallest adenomas are sessile; lesions 0.3 cm in
size can be identified at endoscopy. Among the larger tubular adenomas up to 2.5 cm in
diameter, most have slender stalks 1 to 2 cm long and raspberry-like heads. Histologically the
stalk is covered by normal colonic mucosa, but the head is composed of neoplastic epithelium,
forming branching glands lined by tall, hyperchromatic, somewhat disorderly cells, which may
or may not show mucin secretion. In some instances there are small foci of villous architecture.
In the clearly benign lesion, the branching glands are well separated by lamina propria, and the
level of dysplasia or cytologic atypia is slight. However, all degrees of dysplasia may be
encountered, ranging up to cancer confined to the mucosa (intramucosal carcinoma) or
invasive carcinoma extending into the submucosa of the stalk. A frequent finding in any
adenoma is superficial erosion of the epithelium, the result of mechanical trauma.Villous
adenomas are the larger and more ominous of the epithelial polyps. They tend to occur in older
persons, most commonly in the rectum and rectosigmoid, but they may be located elsewhere.
They generally are sessile, up to 10 cm in diameter, velvety or cauliflower-like masses
projecting 1 to 3 cm above the surrounding normal mucosa. The histology is that of frondlike
villiform extensions of the mucosa covered by dysplastic, sometimes very disorderly,
sometimes piled-up, columnar epithelium. All degrees of dysplasia may be encountered, and
invasive carcinoma is found in as many as 40% of these lesions, the frequency being correlated
with the size of the polyp. Tubulovillous adenomas are composed of a broad mix of tubular and
villous areas. They are intermediate between the tubular and the villous lesions in their
frequency of having a stalk or being sessile, their size, the degree of dysplasia, and the risk of
harboring intramucosal or invasive carcinoma.

Symptoms: The smaller adenomas are usually asymptomatic, until such time that occult
bleeding leads to clinically significant anemia. Villous adenomas are much more frequently
symptomatic because of overt or occult rectal bleeding. The most distal villous adenomas may
secrete sufficient amounts of mucoid material rich in protein and potassium to produce
hypoproteinemia or hypokalemia. On discovery, all adenomas, regardless of their location in
the alimentary tract, are to be considered potentially malignant; in practical terms, prompt and
adequate excision is mandated.

67) Colorectal carcinoma.

Colorectal carcinoma: is a cancer from uncontrolled cell growth in the colon, rectum, or
appendix. Symptoms typically include rectal bleeding and anemia which are sometimes
associated with weight loss and changes in bowel habits.
Causes: People with inflammatory bowel disease (ulcerative colitis and Crohn's disease) are at
increased risk of colon cancer. The risk is greater the longer a person has had the disease and
the worse the severity of inflammation.
Symptoms: depend on the location of tumor in the bowel and whether it has spread elsewhere
in the body (metastasis). The classic ones include: worsening constipation, blood in the stool,
weight loss, fever, loss of appetite, and nausea or vomiting in someone over 50 years old. While
rectal bleeding or anemia are high risk features in those over the age of 50.
The pathology of the tumor is usually reported from the analysis of tissue taken from a biopsy
or surgery. A pathology report will usually contain a description of cell type and grade. The
most common colon cancer cell type is adenocarcinoma which accounts for 95% of cases.
Other, rarer types include lymphoma and squamous cell carcinoma. Cancers on the right side
(ascending colon and cecum) tend to be exophytic, that is, the tumour grows outwards from
one location in the bowel wall. This very rarely causes obstruction of feces, and presents with
symptoms such as anemia. Left-sided tumours tend to be circumferential, and can obstruct the
bowel much like a napkin ring.
--Colon Adenocarcinoma is a malignant epithelial tumor, originating from glandular epithelium
of the colorectal mucosa. It invades the wall, infiltrating the muscularis mucosae, the
submucosa and thence the muscularis propria. Tumor cells describe irregular tubular
structures, harboring pluristratification, multiple lumens, reduced stroma ("back to back"
aspect). Sometimes, tumor cells are discohesive and secrete mucus, which invades the
interstitium producing large pools of mucus/colloid (optically "empty" spaces) - mucinous
(colloid) adenocarcinoma, poorly differentiated. If the mucus remains inside the tumor cell, it
pushes the nucleus at the periphery - "signet-ring cell."

68) Peritoneum inflammation.

Peritonitis: is an inflammation (irritation) of the peritoneum, the thin tissue that lines the inner
wall of the abdomen and covers most of the abdominal organs. Peritonitis may be localised or
generalised, and may result from infection (often due to rupture of a hollow organ as may occur
in abdominal trauma or appendicitis) or from a non-infectious process.
Symptoms: The main manifestations of peritonitis are acute abdominal pain, abdominal
tenderness and abdominal guarding, which are exacerbated by moving the peritoneum, ex.
coughing (forced cough may be used as a test), flexing one's hips, or eliciting the Blumberg sign
(rebound tenderness, meaning that pressing a hand on the abdomen elicits less pain than
releasing the hand abruptly, which will aggravate the pain, as the peritoneum snaps back into
place). The presence of these signs in a patient is sometimes referred to as peritonism. The
localization of these manifestations depends on whether peritonitis is localized (ex. appendicitis
or diverticulitis before perforation), or generalized to the whole abdomen.
Pathology: In normal conditions, the peritoneum appears greyish and glistening; it becomes
dull 24 hours after the onset of peritonitis, initially with scarce serous or slightly turbid fluid.
Later on, the exudate becomes creamy and evidently suppurative; in dehydrated patients, it
also becomes very inspissated. The quantity of accumulated exudate varies widely. It may be
spread to the whole peritoneum, or be walled off by the omentum and viscera. Inflammation
features infiltration by neutrophils with fibrino-purulent exudation.
Complications: Sequestration of fluid and electrolytes, as revealed by decreased central venous
pressure, may cause electrolyte disturbances, as well as significant hypovolemia, possibly
leading to shock and acute renal failure. A peritoneal abscess may form (ex. above or below the
liver, or in the lesser omentum). Sepsis may develop, so blood cultures should be obtained. The
fluid may push on the diaphragm, causing splinting and subsequent breathing difficulties.
Diagnosis: is based primarily on the clinical manifestations described above. If peritonitis is
strongly suspected, then surgery is performed without further delay for other investigations.
Leukocytosis, hypokalemia, hypernatremia and acidosis may be present, but they are not
specific findings. Abdominal X-rays may reveal dilated, edematous intestines, although such Xrays are mainly useful to look for pneumoperitoneum, an indicator of gastrointestinal
perforation. The role of whole-abdomen ultrasound examination is under study and is likely to
expand in the future. Computed tomography (CT or CAT scanning) may be useful in
differentiating causes of abdominal pain.

69) Peritoneum primary and secondary tumors.

Primary peritoneal tumors are lesions that arise from the mesothelial or submesothelial layers
of the peritoneum. Primary malignant mesothelioma, multicystic mesothelioma, primary
peritoneal serous carcinoma, leiomyomatosis peritonealis disseminata, and desmoplastic small
round cell tumor are the most prominent of these rare lesions.
Peritoneal Malignant mesothelioma: is a malignant neoplasm that arises from mesothelial cells
or multipotential subserosal mesenchymal cells of the pleura, peritoneum, pericardium, or
tunica vaginalis of the testis. The majority of malignant mesotheliomas originate in the pleura.
At inspection of gross specimens, diffuse peritoneal malignant mesothelioma is often
indistinguishable from peritoneal carcinomatosis. It is characterized by multiple, firm, gray or
white nodules scattered along the peritoneal surfaces of the mesenteries, omenta, and serosal
surfaces of the viscera. The tumor may spread along the parietal and visceral peritoneal
surfaces and form a continuous tumor rind that encases the peritoneal cavity and
intraperitoneal organs. The small bowel may become fixed, rigid, and immobile, which are signs
of advanced disease. Morphologically, malignant mesothelioma can be divided into three
forms: epithelial, sarcomatous, and mixed. The mixed form is often referred to as biphasic or
bimorphic. Mixed tumors consist of both epithelial and sarcomatous components. Epithelial
malignant mesotheliomas are composed of cells that resemble normal mesothelial cells.
Multicystic mesothelioma: is an unusual, multilocular cystic tumor that most commonly arises
from the pelvic surfaces of the peritoneum. It has benign or indolent biologic behavior in the
majority of patients. Multicystic mesothelioma is composed of multiple, translucent, fluid-filled
cysts that grow along the pelvic peritoneum in grapelike clusters. It is usually large at the time
of diagnosis (mean diameter, 13 cm). In women, the tumor is typically located in the cul-de-sac
and along the peritoneal surfaces of the uterus and rectum. In men, it most commonly arises
along the peritoneal surface of the bladder and rectum. When large, multicystic mesothelioma
extends into the upper portions of the peritoneal cavity.
Primary Peritoneal Serous Carcinoma: is indistinguishable from metastatic serous ovarian
carcinoma at gross, histopathologic, and immunohistochemical examination. The primary gross
characteristic is multiple nodules on the peritoneal surface and omentum. Omental caking may
occur with confluent and large masses. Large masses may also have a papillary appearance
grossly. The tumors are histologically composed of irregular, interconnecting clusters of
malignant cells that show solid, cribiform, or cystic architecture. Papillary formation and
glandlike areas may be present. The cells are atypical with large nuclei, prominent nucleoli, and
frequent mitoses.
Secondary peritoneal tumors:

Carcinomatosis: carcinomas from the gastrointestinal tract (stomach, colon, appendix,

gallbladder, and pancreas), ovary, breast, lung, and uterus may metastasize to the peritoneal
surface. In the largest studies of peritoneal carcinomatosis from nongynecologic malignancies,
55% of cases were reported synchronously with the diagnosis of a primary cancer and 45%
were documented in follow up. Patients with peritoneal carcinomatosis may be asymptomatic
at the onset of the lesions, but progressive involvement of the peritoneum will cause them to
complain of abdominal enlargement from ascites or nausea, vomiting, and abdominal pain from
bowel obstruction. Bowel obstruction is most frequently reported in patients with peritoneal
carcinomatosis from colorectal carcinoma. Tumor nodules studding the peritoneal surfaces
typify peritoneal carcinomatosis. A fibrotic response may occur as the tumor grows along the
peritoneal surface or invades into the subperitoneal tissues. Consequently, omental fat may be
replaced with tumor and fibrosis, producing the classic gross appearance often referred to as
omental caking. Transperitoneal spread of tumor may also result in ovarian metastasis
(Krukenberg tumors). The histologic characteristics of peritoneal carcinomatosis vary depending
on the primary tumor. Adenocarcinomas with abundant mucin and signet ring cell morphology
are the most frequent types. On occasion, carcinomas may histologically resemble malignant
mesothelioma.
Lymphomatosis: Lymphomas may involve the peritoneal surfaces as a primary or secondary
process. Nodal or extranodal non-Hodgkin lymphomas, such as small B-cell lymphoma, diffuse
large B-cell lymphoma, and Burkitt lymphoma, may have secondary peritoneal involvement.
Secondary peritoneal involvement may occur in the general population of patients with
lymphoma as well as in immunocompromised patients. Primary lymphomas of the peritoneum,
also called body cavitybased lymphomas or primary effusion lymphomas, are uncommon and
nearly exclusively found in immunocompromised patients, most of whom are infected with the
human immunodeficiency virus. These lymphomas are associated with two viruses in the
herpes virus family: human herpes virus 8 (HHV-8), which is also associated with Kaposi
sarcoma, and Epstein-Barr virus. Lymphomas that secondarily involve the peritoneum have the
same histologic characteristics and immunophenotypic expression as lymphomas in any other
location. Primary effusion lymphoma usually does not form a discrete lesion. Ascites containing
numerous atypical lymphoid cells is the most common finding. The tumor cells are large to
pleomorphic, with large round to irregular nuclei, prominent nucleoli, and a modest amount of
basophilic cytoplasm. Some cells can have plasma-cytoid appearance with a distinct area of
pallor directly adjacent to the nucleus, a finding that is often referred to as a perinuclear hoff.
The lymphoma cells are of B-cell origin.

70) Cholangitis and cholangiohepatitis.

Cholangitis: it is an infection of the bile duct (cholangitis), usually caused by bacteria ascending
from its junction with the duodenum (first part of the small intestine). It tends to occur if the
bile duct is already partially obstructed by gallstones. Cholangitis can be life-threatening, and is
regarded as a medical emergency. Characteristic symptoms include jaundice, fever, abdominal
pain, and in severe cases, low blood pressure and confusion. Initial treatment is with
intravenous fluids and antibiotics, but there is often an underlying problem (such as gallstones
or narrowing in the bile duct) for which further tests and treatments may be necessary, usually
in the form of endoscopy to relieve obstruction of the bile duct.
Causes: Bile duct obstruction, which is usually present in acute cholangitis, is generally due to
gallstones. 1030% of cases, however, are due to other causes such as benign stricturing
(narrowing of the bile duct without an underlying tumor), postoperative damage or an altered
structure of the bile ducts such as narrowing at the site of an anastomosis (surgical connection)
and various tumors (cancer of the bile duct, gallbladder cancer, cancer of the ampulla of Vater,
pancreatic cancer or cancer of the duodenum).
Symptoms: abdominal pain (particularly in the right upper quadrant of the abdomen), fever,
rigors (uncontrollable shaking) and a feeling of uneasiness (malaise). Some may report jaundice
(yellow discoloration of the skin and the whites of the eyes).
Pathogenesis: The main factors in the pathogenesis of acute cholangitis are biliary tract
obstruction, elevated intraluminal pressure, and infection of bile. A biliary system that is
colonized by bacteria but is unobstructed, typically does not result in cholangitis. It is believed
that biliary obstruction diminishes host antibacterial defenses, causes immune dysfunction, and
subsequently increases small bowel bacterial colonization. Although the exact mechanism is
unclear, it is believed that bacteria gain access to the biliary tree by retrograde ascent from the
duodenum or from portal venous blood. As a result, infection ascends into the hepatic ducts,
causing serious infection. Increased biliary pressure pushes the infection into the biliary
canaliculi, hepatic veins, and perihepatic lymphatics, leading to bacteremia (25-40%). The
infection can be suppurative in the biliary tract. The bile is normally sterile. In the presence of
gallbladder or common duct stones (CBD), however, the incidence of bactibilia increases. The
most common organisms isolated in bile are Escherichia coli, Klebsiella species, Enterococcus
species.
Cholangiohepatitis: inflammation of the biliary system and, by extension, of the periportal
hepatic parenchyma. This form of hepatitis centers on structures that convey bile, produced in
the liver, into the gall bladder and on out into the small intestine. Words that begin with
chole all relate to bile. When the normal flow of bile is blocked by inflammation of these
structures, severe consequences ensue. Bile has several functions. It emulsifies the fat in our
diets so that we can absorb it into our bodies. It also serves as a medium to dump toxins that

the liver has removed from our bodies and processed so they cannot be reabsorbed. This is a
fine system but problems can occur when the bacteria that live in the small intestine venture
up the bile duct and invade the liver, which is normally sterile (free of bacteria). Inflammation
results and the liver can fail.

71) Liver abscesses.

In developing countries liver abscesses are common; most result from parasitic infections, such
as amebic, echinococcal, and (less commonly) other protozoal and helminthic organisms. In
developed countries parasitic liver abscesses are rare, and many occur in immigrants. Bacterial
abscesses are more common, representing a complication of an infection elsewhere. The
organisms reach the liver through one of the following pathways: (1) ascending infection in the
biliary tract (ascending cholangitis); (2) vascular seeding, either portal or arterial, predominantly
from the gastrointestinal tract (3) direct invasion of the liver from a nearby source; or (4) a
penetrating injury. Debilitating disease with immune deficiency is a common setting-for
example, extreme old age, immunosuppression, or cancer chemotherapy with marrow failure.
Pyogenic (bacterial) hepatic abscesses may occur as solitary or multiple lesions, ranging from
millimeters to massive lesions, many centimeters in diameter. They are generally produced by
gram-negative bacteria such as Escherichia coli and Klebsiella sp. Bacteremic spread through
the arterial or portal system tends to produce multiple small abscesses, whereas direct
extension and trauma usually cause solitary large abscesses. Gross and microscopic features are
those of any pyogenic abscess, consisting of necrotic tissue with abundant neutrophils.
Occasionally, fungi or parasites rather than bacteria can be identified. Liver abscesses are
associated with fever and, in many instances, with right upper quadrant pain and tender
hepatomegaly. Jaundice is often the result of extrahepatic biliary obstruction. Although
antibiotic therapy may control smaller lesions, surgical drainage is often necessary. Because
diagnosis is frequently delayed, particularly in persons with serious coexistent disease, the
mortality rate with large liver abscesses ranges from 30% to 90%. With early recognition and
management, as many as 80% of patients may survive.

72) Biliary cirrhosis primary and secondary.

Primary biliary cirrhosis (PBC): is a chronic, progressive, and often fatal cholestatic liver
disease, characterized by the destruction of intrahepatic bile ducts, portal inflammation and
scarring, and the eventual development of cirrhosis and liver failure over years to decades. The
primary feature of this disease is a nonsuppurative destruction of small and medium-sized
intrahepatic bile ducts; cirrhosis appears only late in the course. In the early lesions there is a
dense lymphocyte/plasma cell infiltrate around small bile ducts in portal tracts, and
granulomatous lesions may also appear. The onset of primary biliary cirrhosis is insidious,

usually presenting as pruritus; jaundice develops late. Over a period of two or more decades,
the individuals develop hepatic decompensation, including portal hypertension with variceal
bleeding and hepatic encephalopathy. Serum alkaline phosphatase and cholesterol levels are
almost always elevated; hyperbilirubinemia is a late development and usually signifies incipient
hepatic decompensation. Associated extrahepatic conditions include the sicca complex of dry
eyes and mouth (Sjgren syndrome), scleroderma, thyroiditis, rheumatoid arthritis, Raynaud
phenomenon, membranous glomerulonephritis and celiac disease.
Morphology: PBC is the prototype of conditions leading to small-duct biliary fibrosis and
cirrhosis. PBC is a focal and variable disease, showing different degrees of severity in different
portions of the liver. During the pre-cirrhotic stage portal tracts are infiltrated by a dense
accumulation of lymphocytes, macrophages, plasma cells, and occasional eosinophils.
Interlobular bile ducts are infiltrated by lymphocytes and may show noncaseating
granulomatous inflammation and undergo progressive destruction. With time the obstruction
to intrahepatic bile flow leads to progressive secondary hepatic damage. Portal tracts upstream
from damaged bile ducts show bile ductular proliferation, inflammation, and necrosis of the
adjacent periportal hepatic parenchyma. The parenchyma develops generalized cholestasis.
Over years to decades, relentless portal tract scarring and bridging fibrosis lead to cirrhosis.
Macroscopically, the liver does not at first appear abnormal, but as the disease progresses bile
stasis stains the liver green. The capsule remains smooth and glistening until a fine granularity
appears, representing deposition of fibrous septa. This process culminates in a well-developed,
uniform micronodular cirrhosis. Liver weight is at first normal to increased (because of
inflammation) but is ultimately decreased. In most cases the end-stage picture is
indistinguishable from secondary biliary cirrhosis or the cirrhosis that follows chronic hepatitis
from other causes.
Secondary biliary cirrhosis: Prolonged obstruction of the extrahepatic biliary tree results in
profound damage to the liver itself. The most common cause of obstruction is extrahepatic
cholelithiasis. Other obstructive conditions include biliary atresia, malignancies of the biliary
tree and head of the pancreas and strictures resulting from previous surgical procedures.
Secondary inflammation resulting from biliary obstruction initiates periportal fibrogenesis,
which eventually leads to scarring and nodule formation, generating secondary biliary cirrhosis.
Subtotal obstruction may promote secondary bacterial infection of the biliary tree (ascending
cholangitis), which further contributes to the damage. Enteric organisms such as coliforms and
enterococci are common culprits.
Morphology: The end-stage obstructed liver shows yellow-green pigmentation that is
accompanied by marked icteric discoloration of body tissues and fluids. On cut surface the liver
is hard, with a finely granular appearance. The histology is characterized by coarse fibrous septa

that subdivide the liver in a jigsaw-like pattern. Embedded in the septa are distended small and
large bile ducts, which frequently contain inspissated pigmented material. There is extensive
proliferation of smaller bile ductules, particularly at the interface between septa in former
portal tracts and the parenchyma. Cholestatic features in the parenchyma may be severe, with
extensive feathery degeneration and formation of bile lakes. However, once regenerative
nodules have formed, bile stasis may become less conspicuous. Ascending bacterial infection
incites a robust neutrophilic infiltration of bile ducts; severe pylephlebitis and cholangitic
abscesses may develop.

73) Acute viral hepatitis.

Systemic viral infections can involve the liver as in (1) infectious mononucleosis (Epstein-Barr
virus), which may cause a mild hepatitis during the acute phase; (2) cytomegalovirus infection,
particularly in the newborn or immunosuppressed patient; and (3) yellow fever (yellow fever
virus), which has been a major and serious cause of hepatitis in tropical countries. Infrequently,
in children and immunosuppressed patients, the liver is affected in the course of rubella,
adenovirus, herpesvirus, or enterovirus infections. However, unless otherwise specified, the
term viral hepatitis is applied for hepatic infections caused by a group of viruses known as
hepatotropic virus (hepatitis viruses A, B, C, D, and E) that have a particular affinity for the liver.
Hepatitis A Virus: The receptor for HAV is HAVcr-1, a 451amino acid class I integralmembrane
mucin-like glycoprotein of unknown normal function. HAV is spread by ingestion of
contaminated water and foods and is shed in the stool for 2 to 3 weeks before and 1 week after
the onset of jaundice. Close personal contact with an infected individual or fecal-oral
contamination during this period accounts for most cases and explains the outbreaks in
institutional settings such as schools and nurseries and the water-borne epidemics in places
where people live in overcrowded, unsanitary conditions. HAV can also be detected in serum
and saliva. Because HAV viremia is transient, blood-borne transmission of HAV occurs only
rarely; therefore, donated blood is not specifically screened for this virus. Cellular immunity,
particularly CD8+ T cells, plays a key role in hepatocellular injury during HAV infection.
Acute Hepatitis: With acute hepatitis hepatocyte injury takes the form of diffuse swelling
(ballooning degeneration), so the cytoplasm looks empty and contains only scattered
eosinophilic remnants of cytoplasmic organelles. An inconstant finding is cholestasis, with bile
plugs in canaliculi and brown pigmentation of hepatocytes. The canalicular bile plugs result
from cessation of the contractile activity of the hepatocyte pericanalicular actin microfilament
web. Several patterns of hepatocyte cell death are seen. Rupture of the cell membrane leads to
cell death and focal loss of hepatocytes. The sinusoidal collagen reticulin framework collapses
where the cells have disappeared, and scavenger macrophage aggregates mark sites of
hepatocyte loss. Apoptosis, caused by anti-viral cytotoxic (effector) T cells. Apoptotic

hepatocytes shrink, become intensely eosinophilic, and have fragmented nuclei; effector T cells
may still be present in the immediate vicinity. Apoptotic cells are rapidly phagocytosed by
macrophages and hence might be difficult to find, despite a brisk rate of hepatocyte injury. In
severe cases of acute hepatitis, confluent necrosis of hepatocytes may lead to bridging necrosis
connecting portal-to-portal, central-to-central, or portal-to-central regions of adjacent lobules.
Hepatocyte swelling and regeneration compress sinusoids, and the more or less radial array of
hepatocyte plates around terminal hepatic veins is lost. Inflammation is a characteristic and
usually prominent feature of acute hepatitis. Kupffer cells undergo hypertrophy and
hyperplasia and are often laden with lipofuscin pigment as a result of phagocytosis of
hepatocellular debris. The portal tracts are usually infiltrated with a mixture of inflammatory
cells. The inflammatory infiltrate may spill over into the adjacent parenchyma, causing
apoptosis of periportal hepatocytes. This is known as interface hepatitis, which can occur in
acute and chronic hepatitis. Cells in the canals of Hering proliferate, forming ductular structures
at the parenchymal interface (ductular reaction).

74) Chronic hepatitis types, etiology, clinical course, complications.

Chronic hepatitis is defined as symptomatic, biochemical, or serologic evidence of continuing or
relapsing hepatic disease for more than 6 months. As mentioned earlier, HCV infection causes
chronic hepatitis at a high frequency while only a small number of patients with HBV infection
develop chronic disease. The clinical features of chronic hepatitis are extremely variable and
are not predictive of outcome. In some patients the only signs of chronic disease are persistent
elevations of serum transaminases. The most common symptom is fatigue; less common
symptoms are malaise, loss of appetite, and occasional bouts of mild jaundice. Physical findings
are few, the most common being spider angiomas, palmar erythema, mild hepatomegaly,
hepatic tenderness, and mild splenomegaly. Laboratory studies may reveal prolongation of the
prothrombin time and, in some instances, hyperglobulinemia, hyperbilirubinemia, and mild
elevations in alkaline phosphatase levels. Occasionally, in cases of HBV and HCV, immune
complex disease may develop secondary to the presence of circulating antibody-antigen
complexes, in the form of vasculitis (subcutaneous or visceral) and glomerulonephritis.
Cryoglobulinemia is found in about 35% of individuals with chronic hepatitis C. HCV is by far the
most common cause of chronic viral hepatitis. The clinical diagnosis may not be apparent
because patients with chronic HCV infection often have mild or no symptoms. However, even
patients with normal transaminases are at high risk of developing permanent liver damage.
Therefore, any individual with detectable HCV RNA in the serum needs medical attention. HCV
infection is potentially curable. Treatment is currently based on combination of pegylated IFN-
and ribavirin. The response to therapy depends on the viral genotype; patients with genotype 2
or 3 infection generally have the best responses. Several new drugs targeting viral protease and
polymerase are under investigation. The clinical course of viral hepatitis is unpredictable.

Patients may experience spontaneous remission or may have indolent disease without
progression for many years. Conversely, some patients have rapidly progressive disease and
develop cirrhosis within a few years. The major causes of death from cirrhosis are: liver failure
and hepatic encephalopathy, massive hematemesis from esophageal varices, and HCC in those
with long-standing HBV (particularly neonatal) or HCV infection.
Morphology: The histologic features of chronic hepatitis range from exceedingly mild to severe.
In the mildest forms, inflammation is limited to portal tracts and consists of lymphocytes,
macrophages, occasional plasma cells, and rare neutrophils or eosinophils. Liver architecture is
usually well preserved, but smoldering hepatocyte apoptosis throughout the lobule may occur
in all forms of chronic hepatitis. In chronic HCV infection, common findings (occurring in 55% of
HCV infections) are lymphoid aggregates and bile duct reactive changes in the portal tracts, and
focal mild to moderate macrovesicular steatosis. The steatosis is more prevalent and prominent
in HCV genotype 3 infections. In all forms of chronic hepatitis, continued interface hepatitis and
bridging necrosis between portal tracts and portal tracts-to-terminal hepatic veins, are
harbingers of progressive liver damage.
The hallmark of chronic liver damage is the deposition of fibrous tissue. At first, only portal
tracts show increased fibrosis, but with time periportal septal fibrosis occurs, followed by
linking of fibrous septa (bridging fibrosis), especially between portal tracts. In clinical practice,
several systems have been used to score the severity and progression of liver damage due to
HBV and HCV infection. In each system the key elements are inflammation and hepatocyte
destruction (grade), and the severity of fibrosis (stage).
Continued loss of hepatocytes and fibrosis results in cirrhosis. It is characterized by irregularly
sized nodules separated by variable but mostly broad scars, and is often referred to as postnecrotic cirrhosis. However, this term is not specific to viral etiology, and is applied to all forms
of cirrhosis in which the liver shows large, irregular-sized nodules with broad scars. In addition
to viral hepatitis, autoimmune hepatitis, hepatotoxins (carbon tetrachloride, mushroom
poisoning), pharmaceutical drugs (acetaminophen, -methyldopa) and even alcohol (discussed
later) can give rise to cirrhotic livers with irregular-sized large nodules. In about 20% of cases
the inciting cause of the cirrhosis cannot be determined, and these are labeled as cryptogenic
cirrhosis. The morphology of the end-stage cirrhotic liver is often not helpful in determining the
basis of the liver injury.

75) Drug and toxin induced liver disease.

Injury may result (1) from direct toxicity to hepatocytes or biliary epithelial cells, causing
necrosis, apoptosis, or disruption of cellular function; (2) through hepatic conversion of a
xenobiotic to an active toxin; or (3) through immune mechanisms, usually by a drug or a

metabolite acting as a hapten to convert a cellular protein into an immunogen. Predictable drug
reactions can occur in anyone who receives a sufficient dose of an agent. Unpredictable
reactions depend on idiosyncracies of the host, particularly the rate at which the host
metabolizes the agent, and the intensity of the immune response. Idiosyncratic drug reaction
should be considered in any patient receiving a therapeutic drug who develops evidence of liver
damage. Generally, adults are more susceptible than children and women are affected more
than men. Important examples include chlorpromazine, an agent that causes cholestasis in
patients who are slow to metabolize it to an innocuous byproduct, and halothane, which can
cause a fatal immune-mediated hepatitis in some patients who are exposed to this anesthetic
on multiple occasions. It should be noted that the injury may be immediate or may take weeks
to months to develop, presenting only after severe liver damage has developed. It may take the
form of hepatocyte necrosis, cholestasis, or insidious onset of liver dysfunction. Drug-induced
chronic hepatitis is clinically and histologically indistinguishable from chronic viral hepatitis;
hence, serologic markers of viral infection are critical for making the distinction. Hepatic injury
is considered predictable with overdoses of acetaminophen, exposure to Amanita phalloides
toxin, carbon tetrachloride, and, to a certain extent, alcohol. However, individual genetic
differences in the hepatic metabolism of xenobiotics through activating and detoxification
pathways play a major role in individual susceptibility to even predictable hepatotoxins. Many
other xenobiotics, such as sulfonamides, -methyldopa, and allopurinol, cause idiosyncratic
reactions. Acetaminophen is the leading cause of drug-induced acute liver failure. The most
common prescription drugs causing idiosyncratic injury that is, drug toxicity unrelated to drug
dosage include antibiotics and, in particular, isonazid, nonsteroidal analgesics, and anti-seizure
medications. Idiosyncratic reactions evolve with a subacute course and are usually
characterized by high bilirubin levels. Herbal preparations can be responsible for both
predictable and idiosyncratic liver damage. Reye syndrome, a rare and potentially fatal
syndrome of mitochondrial dysfunction in liver, brain, and elsewhere, occurs predominantly in
children and is characterized morphologically by extensive accumulation of fat droplets within
hepatocytes (microvesicular steatosis). Its development has been associated with the
administration of acetylsalicylic acid (aspirin) for the relief of fever, but a causal relationship
between aspirin and Reye syndrome has not been established. Nevertheless, aspirin should be
avoided in children with febrile illness. Long-term methotrexate administration, an effective
treatment for moderate to severe psoriasis, can cause liver injury, including hepatic steatosis
and fibrosis. Drug-induced liver disease is usually followed by recovery upon removal of the
drug. Exposure to a toxin or therapeutic agent should always be included in the differential
diagnosis of liver disease. There are three distinctive forms of alcoholic liver disease: (1) hepatic
steatosis (fatty liver disease), (2) alcoholic hepatitis, and (3) cirrhosis.

76) Cirrhosis hepatis characteristics, classification, etiology, pathogenesis,

clinical course, cpomplications.
Cirrhosis is the twelfth most common cause of death in the United States, accounting for most
liver-related deaths. The chief worldwide causes of cirrhosis are alcohol abuse, viral hepatitis,
and non-alcoholic steatohepatitis (NASH). Other etiologies include biliary disease and iron
overload. The ultimate mechanism of deaths in most cirrhotic patients is (1) progressive liver
failure, (2) a complication related to portal hypertension, or (3) the development of
hepatocellular carcinoma. Cirrhosis, as the end stage of chronic liver disease, is defined by
three main morphologic characteristics:

Bridging fibrous septa in the form of delicate bands or broad scars linking portal tracts
with one another and portal tracts with terminal hepatic veins. Fibrosis is the key
feature of progressive damage to the liver. Fibrosis is a dynamic process of collagen
deposition and remodeling.
Parenchymal nodules containing hepatocytes encircled by fibrosis, with diameters
varying from very small (<0.3 cm, micronodules) to large (several centimeters,
macronodules). Nodularity results from cycles of hepatocyte regeneration and scarring.
Disruption of the architecture of the entire liver. The parenchymal injury and
consequent fibrosis are diffuse, extending throughout the liver. Focal injury with
scarring does not constitute cirrhosis, nor does diffuse nodular transformation without
fibrosis.

Pathogenesis: The central pathogenic processes in cirrhosis are death of hepatocytes,

extracellular matrix (ECM) deposition and vascular reorganization. In the normal liver,
interstitial collagens (types I and III) are concentrated in portal tracts and around central veins,
and thin strands of type IV collagen are present in the space of Disse. In cirrhosis, types I and III
collagen are deposited in the space of Disse, creating fibrotic septal tracts. The vascular
architecture of the liver is disrupted by the parenchymal damage and scarring, with the
formation of new vascular channels in the fibrotic septa that connect the vessels in the portal
region (hepatic arteries and portal veins) to terminal hepatic veins, shunting blood from the
parenchyma. The deposition of collagen in the space of Disse is accompanied by the loss of
fenestrations of sinusoidal endothelial cells (capillarization of sinusoids), impairing the function
of sinusoids as channels that permit the exchange of solutes between hepatocytes and plasma.
The predominant mechanism of fibrosis is the proliferation of hepatic stellate cells and their
activation into highly fibrogenic cells, but other cell types, such as portal fibroblasts, fibrocytes,
and cells derived from epithelium-mesenchymal transitions may also produce collagen.
Proliferation of hepatic stellate cells and their activation into myofibroblasts is initiated by a
series of changes that include an increase in the expression of platelet-derived growth factor

receptor (PDGFR-) in the stellate cells. At the same time, Kupffer cells and lymphocytes
release cytokines and chemokines that modulate the expression of genes in stellate cells that
are involved in fibrogenesis. These include transforming growth factor (TGF-) and its
receptors, metalloproteinase 2 (MMP-2), and tissue inhibitors of metalloproteinases 1 and 2
(TIMP-1 and -2). As they are converted into myofibroblasts, the cells release chemotactic and
vasoactive factors, cytokines, and growth factors. Myofibroblasts are contractile cells, capable
of constricting sinusoidal vascular channels and increasing vascular resistance within the liver
parenchyma; their contraction is stimulated by endothelin-1 (ET-1). The stimuli for stellate cell
activation may originate from several sources: (a) chronic inflammation, with production of
inflammatory cytokines such as tumor necrosis factor (TNF), lymphotoxin, and interleukin 1
(IL-1), and lipid peroxidation products; (b) cytokine and chemokine production by Kupffer
cells, endothelial cells, hepatocytes, and bile duct epithelial cells; in response to (c) disruption
of the ECM; and (d) direct stimulation of stellate cells by toxins.
Throughout the process of liver damage and fibrosis in the development of cirrhosis, the
surviving hepatocytes are stimulated to regenerate and proliferate as spherical nodules within
the confines of the fibrous septa. The net outcome is a fibrotic, nodular liver in which delivery
of blood to hepatocytes is severely compromised, as is the ability of hepatocytes to secrete
substances into plasma. Disruption of the interface between the parenchyma and portal tracts
may also obliterate biliary channels, leading to the development of jaundice.
Symptoms: About 40% of individuals with cirrhosis are asymptomatic until late in the course of
the disease. When symptomatic, they present with nonspecific clinical manifestations:
anorexia, weight loss, weakness, and, in advanced disease, symptoms and signs of hepatic
failure discussed earlier. Incipient or overt hepatic failure may develop, usually precipitated by
a superimposed metabolic load on the liver, usually from systemic infection or gastrointestinal
hemorrhage. Imbalances of pulmonary blood flow may lead to severely impaired oxygenation
(hepatopulmonary syndrome, already discussed under liver failure), further stressing the
patient.

77) Portal hypertension.

Portal hypertension: Increased resistance to portal blood flow may develop in a variety of
circumstances, which can be divided into prehepatic, intrahepatic, and posthepatic causes. The
major prehepatic conditions are obstructive thrombosis, narrowing of the portal vein before it
ramifies within the liver, or massive splenomegaly with increased splenic vein blood flow. The
main post-hepatic causes are severe right-sided heart failure, constrictive pericarditis, and
hepatic vein outflow obstruction. The dominant intrahepatic cause is cirrhosis, accounting for
most cases of portal hypertension. Far less frequent intrahepatic causes are schistosomiasis,

massive fatty change, diffuse fibrosing granulomatous disease such as sarcoidosis, and diseases
affecting the portal microcirculation such as nodular regenerative hyperplasia.
-The increased resistance to portal flow at the level of the sinusoids is caused by contraction of
vascular smooth muscle cells and myofibroblasts, and disruption of blood flow by scarring and
the formation of parenchymal nodules. Sinusoidal endothelial cells contribute to intrahepatic
vasoconstriction associated with portal hypertension through a decrease in nitric oxide
production, the release of endothelin-1 (ET-1), angiotensinogen, and eicosanoids. Sinusoidal
remodeling and anastomosis between the arterial and portal system in the fibrous septa
contribute to portal hypertension by imposing arterial pressures on the low pressure portal
venous system. Sinusoidal remodeling and intrahepatic shunts also interfere with the metabolic
exchange between sinusoidal blood and hepatocytes.
-Another major factor in the development of portal hypertension is an increase in portal venous
blood flow resulting from a hyperdynamic circulation. This is caused by arterial vasodilation,
primarily in the splanchnic circulation. The increased splanchnic arterial blood flow in turn leads
to increased venous efflux into the portal venous system. While various mediators such as
prostacyclin and TNF have been implicated in the causation of the splanchnic arterial
vasodilation, NO has emerged as the most significant one. It is thought that NO production is
stimulated by reduced clearance of bacterial DNA absorbed from the gut, due to decreased
function of the mononuclear phagocyte system and shunting of blood from the portal to
systemic circulation, thereby bypassing the vast pool of Kupffer cells in the liver. In keeping with
this hypothesis, treatment with antibiotics appears to be beneficial in experimental models of
portal hypertension.
The four major clinical consequences of portal hypertension are (1) ascites, (2) the formation
of portosystemic venous shunts, (3) congestive splenomegaly, and (4) hepatic encephalopathy.

78) Inborn errors of metabolism and liver disease Hemochromatosis and

Wilson disease.
Hemochromatosis is characterized by the excessive accumulation of body iron, most of which is
deposited in parenchymal organs such as the liver and pancreas. Iron can also accumulate in
the heart, joints, or endocrine organs. Hemochromatosis (also known as primary or hereditary
hemochromatosis) is a homozygous-recessive inherited disorder that is caused by excessive
iron absorption. Accumulation of iron in tissues, which may occur as a consequence of
parenteral administration of iron, usually in the form of transfusions, or other causes is variably
known as secondary hemochromatosis, acquired hemochromatosis, or hemosiderosis. We will
use the terms hemochromatosis for the hereditary disease and hemosiderosis for the acquired
deposition of iron in some tissues. The most common causes of hemosiderosis (secondary or

acquired hemochromatosis) are disorders associated with ineffective erythropoiesis, such as severe
forms of thalassemia and myelodysplastic syndromes. Alcoholic cirrhosis is often associated with a
modest increase in stainable iron within liver cells.
Classification of Iron Overload
I.

HEREDITARY HEMOCHROMATOSIS
Mutations of genes encoding HFE, transferrin receptor 2 (TfR2), or hepcidin
Mutations of genes encoding HJV (hemojuvelin: juvenile hemochromatosis)
(Neonatal hemochromatosis)[*]

II.

HEMOSIDEROSIS (SECONDARY HEMOCHROMATOSIS)

A.

Parenteral iron overload

Transfusions
Long-term hemodialysis
Aplastic anemia
Sickle cell disease
Myelodysplastic syndromes
Leukemias
Iron-dextran injections

B.

Ineffective erythropoiesis with increased erythroid activity

-Thalassemia
Sideroblastic anemia
Pyruvate kinase deficiency

C.

Increased oral intake of iron

African iron overload (Bantu siderosis)

D.

Congenital atransferrinemia

E.

Chronic liver disease

Chronic alcoholic liver disease
Porphyria cutanea tarda

F.

Neonatal hemochromatosis

The following features characterize this disease:

-Fully developed cases exhibit (1) micronodular cirrhosis in all patients; (2) diabetes mellitus in
75% to 80% of patients; and (3) skin pigmentation in 75% to 80% of patients.
-Iron accumulation is lifelong but the injury caused by excessive iron is slow and progressive;
hence symptoms usually first appear in the fifth to sixth decades of life.
-Males predominate (5 to 7:1) with slightly earlier clinical presentation, partly because
physiologic iron loss (menstruation, pregnancy) delays iron accumulation in women.
Morphology: The morphologic changes in hereditary hemochromatosis are characterized
principally by: (1) deposition of hemosiderin in the following organs (in decreasing order of
severity): liver, pancreas, myocardium, pituitary gland, adrenal gland, thyroid and parathyroid
glands, joints, and skin (detected by the Prussian blue histologic reaction or by atomic
absorption analysis of tissue); (2) cirrhosis; and (3) pancreatic fibrosis. In the liver, iron
becomes evident first as golden-yellow hemosiderin granules in the cytoplasm of periportal
hepatocytes, which stain blue with the Prussian blue stain. With increasing iron load, there is
progressive involvement of the rest of the lobule, along with bile duct epithelium and Kupffer
cell pigmentation. Iron is a direct hepatotoxin, and inflammation is characteristically absent. At
this stage, the liver is typically slightly larger than normal, dense, and chocolate brown. Fibrous
septa develop slowly, leading ultimately to a micronodular pattern of cirrhosis in an intensely
pigmented liver.

Symptoms: hepatomegaly, abdominal pain, skin pigmentation (particularly in sun-exposed

areas), deranged glucose homeostasis or frank diabetes mellitus due to destruction of
pancreatic islets, cardiac dysfunction (arrhythmias, cardiomyopathy), and atypical arthritis.
Wilson disease: is an autosomal recessive disorder caused by mutation of the ATP7B gene,
resulting in impaired copper excretion into bile and a failure to incorporate copper into
ceruloplasmin. This disorder is marked by the accumulation of toxic levels of copper in many
tissues and organs, principally the liver, brain, and eye. Normally, 40% to 60% of ingested
copper (2 to 5 mg/day) is absorbed in the duodenum and proximal small intestine, and is
transported to the portal circulation complexed with albumin and histidine. Free copper
dissociates and is taken up by hepatocytes. Copper is incorporated into enzymes and also binds
to a 2-globulin (apoceruloplasmin) to form ceruloplasmin, which is secreted into the blood.
Excess copper is transported into the bile. Ceruloplasmin accounts for 90% to 95% of plasma
copper. Circulating ceruloplasmin is eventually desialylated, endocytosed by the liver, and
degraded within lysosomes, after which the released copper is excreted into bile. This
degradation/excretion pathway is the primary route for copper elimination. The estimated total
body copper is only 50 to 150 mg. In the brain, toxic injury primarily affects the basal ganglia,
particularly the putamen, which shows atrophy and even cavitation. Nearly all patients with
neurologic involvement develop eye lesions called Kayser-Fleischer rings, green to brown
deposits of copper in Desemet's membrane in the limbus of the cornea.
Morphology: The liver often bears the brunt of injury, but the disease may also present as a
neurologic disorder. The hepatic changes are variable, ranging from relatively minor to massive
damage. Fatty change (steatosis) may be mild to moderate, with vacuolated nuclei (glycogen or
water) and occasionally, focal hepatocyte necrosis. An acute hepatitis can show features
mimicking acute viral hepatitis, except possibly for the accompanying fatty change. The chronic
hepatitis of Wilson disease exhibits moderate to severe inflammation and hepatocyte necrosis,
with the particular features of macrovesicular steatosis, vacuolated hepatocellular nuclei, and
Mallory bodies. With progression of chronic hepatitis, cirrhosis will develop. Massive liver
necrosis is a rare manifestation that is indistinguishable from that caused by viruses or drugs.
Excess copper deposition can often be demonstrated by special stains (rhodamine stain for
copper, orcein stain for copper-associated protein). Because copper also accumulates in chronic
obstructive cholestasis and because histology cannot reliably distinguish Wilson disease from
viral- and drug-induced hepatitis, demonstration of hepatic copper content in excess of 250 g
per gram dry weight is most helpful for making a diagnosis.

79) Primary carcinoma of the liver. Benign tumors and tumorous conditions.
Metastatic carcinomas.

Benign neoplasms developing from hepatocytes are called hepatic adenomas or liver cell
adenomas. Although they may occur in men, hepatic adenomas most frequently occur in young
women who have used oral contraceptives; tumors generally regress if contraceptive use is
terminated. Hepatic adenomas have clinical significance for three reasons: (1) when they
present as an intrahepatic mass they may be mistaken for the more ominous hepatocellular
carcinomas; (2) subcapsular adenomas have a tendency to rupture, particularly during
pregnancy (under estrogen stimulation), causing life-threatening intraperitoneal hemorrhage;
(3) rarely, they may transform into carcinomas, particularly, when the adenoma arises in an
individual with glycogen storage disease, and adenomas in which mutations of the -catenin
gene are present. Although hormonal stimulation is clearly associated with the development of
solitary hepatic adenoma, the causal events are unknown.
Morphology: Liver cell adenomas are pale, yellowtan and frequently bile-stained nodules,
found anywhere in the hepatic substance but often beneath the capsule. They may reach 30 cm
in diameter. Although they are usually well demarcated, encapsulation might not be present.
The tumor commonly presents as a solitary lesion, but multiple lesions (adenomatosis) can
occur. Histologically, liver cell adenomas are composed of sheets and cords of cells that may
resemble normal hepatocytes or have some variation in cell and nuclear size. Abundant
glycogen may generate large hepatocytes with a clear cytoplasm. Steatosis is commonly
present. Portal tracts are absent; instead, prominent solitary arterial vessels and draining veins
are distributed through the substance of the tumor.
Malignant tumors occurring in the liver can be primary or metastatic. Most primary liver
cancers arise from hepatocytes and are termed hepatocellular carcinoma (HCC). Much less
common are carcinomas of bile duct origin, cholangiocarcinomas. Two rare forms of primary
liver cancer deserve brief mention: hepatoblastomas and angiosarcomas. Angiosarcoma of the
liver resembles those occurring elsewhere. The primary liver form is of interest because of its
association with exposure to vinyl chloride, arsenic, or Thorotrast. The latency period after
exposure to the putative carcinogen may be several decades. These highly aggressive
neoplasms metastasize widely and generally kill within a year. The major features of
hepatoblastoma are discussed next.
Hepatoblastoma is the most common liver tumor of young childhood. The tumor is usually fatal
within a few years if not treated. This tumor has two anatomic variants:
-The epithelial type, composed of small polygonal fetal cells or smaller embryonal cells forming
acini, tubules, or papillary structures vaguely recapitulating liver development.
-The mixed epithelial and mesenchymal type, which contains foci of mesenchymal
differentiation that may consist of primitive mesenchyme, osteoid, cartilage, or striated muscle.

Hepatocellular Carcinoma (HCC): Four major etiologic factors associated with HCC have been
established: chronic viral infection (HBV, HCV), chronic alcoholism, non-alcoholic
steatohepatitis (NASH), and food contaminants (primarily aflatoxins). Other conditions include
tyrosinemia, glycogen storage disease, hereditary hemochromatosis, non-alcoholic fatty liver
disease, and 1-antitrypsin deficiency. Many factors, including genetic factors, age, gender,
chemicals, hormones, and nutrition, interact in the development of HCC. The disease that is
most likely to give rise to HCC is the extremely rare hereditary tyrosinemia, in which almost
40% of patients develop the tumor despite adequate dietary control.
Morphology: HCC may appear grossly as (1) a unifocal (usually large) mass; (2) multifocal,
widely distributed nodules of variable size; or (3) a diffusely infiltrative cancer, permeating
widely and sometimes involving the entire liver. All three patterns may cause liver enlargement,
particularly the large unifocal and multinodular patterns. The diffusely infiltrative tumor may
blend imperceptibly into a cirrhotic liver background. HCCs are usually paler than the
surrounding liver and sometimes take on a green hue when composed of well-differentiated
hepatocytes capable of secreting bile. All patterns of HCCs have a strong propensity for invasion
of vascular structures. Extensive intrahepatic metastases ensue, and occasionally, long,
snakelike masses of tumor invade the portal vein (with occlusion of the portal circulation) or
inferior vena cava, extending even into the right side of the heart. HCC spreads extensively
within the liver by obvious contiguous growth and by the development of satellite nodules,
which can be shown by molecular methods to be derived from the parent tumor. Metastasis
outside the liver is primarily via vascular invasion, especially into the hepatic vein system, but
hematogenous metastases, especially to the lung, tend to occur late in the disease. Lymph node
metastases to the perihilar, peripancreatic and para-aortic nodes above and below the
diaphragm are found in fewer than half of HCCs that spread beyond the liver. If HCC with
venous invasion is identified in explanted livers at the time of liver transplantation, tumor
recurrence is likely to occur in the transplanted donor liver.
Cholangiocarcinoma (CCA): the second most common hepatic malignant tumor after HCC. The
risk factors for development of CCA include primary sclerosing cholangitis (PSC), congenital
fibropolycystic diseases of the biliary system (particularly Caroli disease and choledochal cysts
that will be discussed later), HCV infection, and previous exposure to Thorotrast (formerly used
in radiography of the biliary tract). According to their localization, CCAs are classified into
intrahepatic and extrahepatic forms. Eighty to 90% of the tumors are extrahepatic. The
extrahepatic forms include perihilar tumors known as Klatskin tumors, which are located at the
junction of the right and left hepatic ducts forming the common hepatic duct, and distal bile
duct tumors. A subgroup of distal tumors arise in the immediate vicinity of the ampulla of
Vater. Tumors of this region also include adenocarcinoma of the duodenal mucosa and
pancreatic carcinoma and are collectively referred to as periampullary carcinomas.

Morphology:
Extrahepatic CCAs are generally small lesions at the time of diagnosis. Most tumors appear as
firm, gray nodules within the bile duct wall; some may be diffusely infiltrative lesions; others
are papillary, polypoid lesions. Most are adenocarcinomas that may or may not secrete mucin.
Uncommonly, squamous features are present. For the most part, an abundant fibrous stroma
accompanies the epithelial proliferation. Klatskin tumors generally have slower growth than
other CCAs, show prominent fibrosis, and infrequently involve distal metastases.
Intrahepatic CCAs occur in the noncirrhotic liver and may track along the intrahepatic portal
tract system to create a treelike tumorous mass within a portion of the liver. Alternatively, a
massive tumor nodule may develop. By microscopy, CCAs resemble adenocarcinomas arising in
other parts of the body, and they may show the full range of morphologic variation. Most are
well- to moderately differentiated sclerosing adenocarcinomas with clearly defined glandular
and tubular structures lined by cuboidal to low columnar epithelial cells. These neoplasms are
usually markedly desmoplastic, with dense collagenous stroma separating the glandular
elements. As a result, the tumor substance is extremely firm and gritty. Lymph node metastasis
and hematogenous metastases to the lungs, bones, adrenals, brain, or elsewhere are present at
autopsy in about 50% of cases. Mixed variants occur, in which elements of both HCC and CCA
are present. Three forms are recognized: (1) separate tumor masses of HCC and CCA within the
same liver; (2) collision tumors, in which tumorous masses of HCC and CCA commingle at an
identifiable interface; and (3) tumors in which elements of HCC and CCA are intimately mixed at
the microscopic level. These mixed tumors are infrequent, but careful microscopic
examination of CCAs can often reveal small foci of hepatocellular differentiation.
Metastatic tumors: Involvement of the liver by metastatic malignancy is far more common than
primary hepatic neoplasia. The liver and lungs share the dubious distinction of being the
visceral organs that are most often involved in the metastatic spread of cancers. Although the
most common primary sources producing hepatic metastases are those of the colon, breast,
lung, and pancreas, any cancer in any site of the body may spread to the liver, including
leukemias, melanomas, and lymphomas. Typically, multiple nodular metastases are found that
often cause striking hepatomegaly and may replace over 80% of existent hepatic parenchyma.
The liver weight can exceed several kilograms. Metastasis may also appear as a single nodule, in
which case it may be resected surgically. There is a tendency for metastatic nodules to outgrow
their blood supply, producing central necrosis and umbilication when viewed from the surface
of the liver. Always surprising is the amount of metastatic involvement that may be present in
the absence of clinical or laboratory evidence of hepatic functional insufficiency. Often the only
telltale clinical sign is hepatomegaly, sometimes with nodularity of the free edge. However,

with massive destruction of liver substance or direct obstruction of major bile ducts, jaundice
and abnormal elevations of liver enzymes may appear.

80) Cholelithiasis.
Gallstones: The vast majority of gallstones (>80%) are silent, and most individuals remain free
of biliary pain or other complications for decades. There are two main types of gallstones:
cholesterol stones, containing more than 50% of crystalline cholesterol monohydrate; The rest
are pigment stones composed predominantly of bilirubin calcium salts.
The risk factors most commonly associated with the development of cholesterol stones are:
--Age and Sex.
--Environmental Factors.
--Acquired Disorders. Gallbladder stasis, either neurogenic or hormonal, fosters a local
environment that is favorable for both cholesterol and pigment gallstone formation.
--Hereditary Factors.
Pathogenesis: Cholesterol is rendered soluble in bile by aggregation with water-soluble bile
salts and water-insoluble lecithins, both of which act as detergents. When cholesterol
concentrations exceed the solubilizing capacity of bile (supersaturation), cholesterol can no
longer remain dispersed and nucleates into solid cholesterol monohydrate crystals. Cholesterol
gallstone formation involves four simultaneous conditions: (1) The bile must be supersaturated
with cholesterol; (2) hypomotility of the gallbladder promotes nucleation; (3) cholesterol
nucleation in the bile is accelerated; (4) hypersecretion of mucus in the gallbladder traps the
nucleated crystals, leading to their aggregation into stones.
Pathogenesis: Pigment gallstones are complex mixtures of abnormal insoluble calcium salts of
unconjugated bilirubin along with inorganic calcium salts. Disorders that are associated with
elevated levels of unconjugated bilirubin in bile such as hemolytic syndromes, severe ileal
dysfunction (or bypass), and bacterial contamination of the biliary tree, increase the risk of
developing pigment stones. Unconjugated bilirubin is normally a minor component of bile, but
it increases when infection of the biliary tract leads to release of microbial -glucuronidases,
which hydrolyze bilirubin glucuronides. However, because about 1% of bilirubin glucuronides
are deconjugated in the biliary tree, the large amounts of unconjugated bilirubin produced may
exceed its solubility.
Morphology: Cholesterol stones arise exclusively in the gallbladder and are composed of
cholesterol. Pure cholesterol stones are pale yellow, round to ovoid, and have a finely granular,

hard external surface which on transection reveals a glistening radiating crystalline palisade.
With increasing proportions of calcium carbonate, phosphates, and bilirubin, the stones show
discoloration and may be lamellated and gray-white to black. Most often, multiple stones are
present that range up to several centimeters in diameter. Rarely, there is a single much larger
stone that may virtually fill the fundus. Surfaces of multiple stones may be rounded or faceted,
because of tight apposition.
Morphology: Pigment gallstones are trivially classified as black and brown. In general,
black pigment stones are found in sterile gallbladder bile, and brown stones are found in
infected intrahepatic or extrahepatic ducts. Black pigment stones contain oxidized polymers
of the calcium salts of unconjugated bilirubin, small amounts of calcium carbonate, calcium
phosphate, and mucin glycoprotein, and some cholesterol monohydrate crystals. Brown
pigment stones contain pure calcium salts of unconjugated bilirubin, mucin glycoprotein, a
substantial cholesterol fraction, and calcium salts of palmitate and stearate. The black stones
are rarely greater than 1.5 cm in diameter, are almost invariably present in great number with
an inverse relationship between size and number; and may crumble to the touch. Their
contours are usually spiculated and molded. Brown stones tend to be laminated and soft and
may have a soaplike or greasy consistency. Brown stones, which contain calcium soaps, are
radiolucent. Mucin glycoproteins constitute the scaffolding and interparticle cement of all
stones, whether pigment or cholesterol.

81) Acute and chronic cholecystitis. Complications.

Acute cholecystitis is an acute inflammation of the gallbladder, precipitated 90% of the time by
obstruction of the neck or cystic duct. It is the primary complication of gallstones and the most
common reason for emergency cholecystectomy. Cholecystitis without gallstones called
acalculous cholecystitis may occur in severely ill patients and accounts for about 10% of
patients with cholecystitis. Acute calculous cholecystitis frequently develops in diabetic patients
who have symptomatic gallstones and results from chemical irritation and inflammation of the
obstructed gallbladder. Acute acalculous cholecystitis is thought to result from ischemia.
Morphology: In acute cholecystitis the gallbladder is usually enlarged and tense, and it may
assume a bright red or blotchy, violaceous to green-black discoloration, imparted by subserosal
hemorrhages. The serosal covering is frequently layered by fibrin and, in severe cases, by a
definite suppurative, coagulated exudate. There are no specific morphologic differences
between acute acalculous and calculous cholecystitis, except for the absence of macroscopic
stones in the acalculous form. In calculous cholecystitis, an obstructing stone is usually present
in the neck of the gallbladder or the cystic duct. The gallbladder lumen may contain one or
more stones and is filled with cloudy or turbid bile that may contain large amounts of fibrin,
pus, and hemorrhage. When the contained exudate is virtually pure pus, the condition is

referred to as empyema of the gallbladder. In mild cases the gallbladder wall is thickened,
edematous, and hyperemic. In more severe cases it is transformed into a green-black necrotic
organ, termed gangrenous cholecystitis, with small-to-large perforations. The invasion of gasforming organisms, notably clostridia and coliforms, may cause an acute emphysematous
cholecystitis. The inflammatory reactions are not histologically distinctive and consist of the
usual patterns of acute inflammation.
Chronic cholecystitis may be a sequel to repeated bouts of mild to severe acute cholecystitis,
but in many instances it develops in the apparent absence of antecedent attacks. Since it is
associated with cholelithiasis in more than 90% of cases, the patient populations are the same
as those for gallstones. The evolution of chronic cholecystitis is obscure, in that it is not clear
that gallstones play a direct role in the initiation of inflammation or the development of pain,
particularly since chronic acalculous cholecystitis shows symptoms and histology similar to
those of the calculous form. Rather, supersaturation of bile predisposes to both chronic
inflammation and, in most instances, stone formation. Unlike acute calculous cholecystitis,
obstruction of gallbladder outflow is not a requisite. Nevertheless, the symptoms of calculous
chronic cholecystitis are similar to those of the acute form and range from biliary colic to
indolent right upper quadrant pain and epigastric distress.
Morphology: The serosa is usually smooth and glistening but may be dulled by subserosal
fibrosis. Dense fibrous adhesions may remain as sequelae of preexistent acute inflammation.
On sectioning, the wall is variably thickened and has an opaque gray-white appearance. In the
uncomplicated case the lumen contains fairly clear, green-yellow, mucoid bile and usually
stones. On histologic examination: In the mildest cases, only scattered lymphocytes, plasma
cells, and macrophages are found in the mucosa and in the subserosal fibrous tissue. In more
advanced cases there is marked subepithelial and subserosal fibrosis, accompanied by
mononuclear cell infiltration. Reactive proliferation of the mucosa and fusion of the mucosal
folds may give rise to buried crypts of epithelium within the gallbladder wall. Outpouchings of
the mucosal epithelium through the wall (Rokitansky-Aschoff sinuses) may be quite prominent.
Superimposition of acute inflammatory changes implies acute exacerbation of an already
chronically injured gallbladder.
In rare instances extensive dystrophic calcification within the gallbladder wall may yield a
porcelain gallbladder, notable for a markedly increased incidence of associated cancer.
Xanthogranulomatous cholecystitis is also a rare condition in which the gallbladder has a
massively thickened wall, is shrunken, nodular, and chronically inflamed with foci of necrosis
and hemorrhage. Finally, an atrophic, chronically obstructed gallbladder may contain only clear
secretions, a condition known as hydrops of the gallbladder.
Complications:

-Bacterial superinfection with cholangitis or sepsis

-Gallbladder perforation and local abscess formation
-Gallbladder rupture with diffuse peritonitis
-Biliary enteric (cholecystenteric) fistula, with drainage of bile into adjacent organs, entry of air
and bacteria into the biliary tree, and potentially, gallstone-induced intestinal obstruction
(ileus)
-Aggravation of preexisting medical illness, with cardiac, pulmonary, renal, or liver
decompensation
-Porcelain gallbladder, with increased risk of cancer, although surveys of this risk have yielded
widely discrepant frequencies.

82) Carcinoma of the gallbladder and the extrahepatic bile ducts.

Carcinoma of the gallbladder is the most common malignancy of the extrahepatic biliary tract.
It is slightly more common in women and occurs most frequently in the seventh decade of life.
Only rarely is it discovered at a resectable stage, and the mean 5-year survival rate has
remained for many years at about 5% to 12% despite surgical intervention. The most important
risk factor associated with gallbladder carcinoma is gallstones (cholelithiasis), which are present
in 95% of cases. However, it should be noted that only 0.5% of patients with gallstones develop
gallbladder cancer after twenty or more years. Presumably, gallbladders containing stones or
infectious agents develop cancer as a result of irritative trauma and chronic inflammation. Most
carcinomas of the gallbladder are adenocarcinomas.
Morphology: Carcinomas of the gallbladder show two patterns of growth: infiltrating and
exophytic. The infiltrating pattern is more common and usually appears as a poorly defined
area of diffuse thickening and induration of the gallbladder wall that may cover several square
centimeters or may involve the entire gallbladder. Deep ulceration can cause direct penetration
of the gallbladder wall or fistula formation to adjacent viscera into which the neoplasm has
grown. These tumors are scirrhous and have a very firm consistency. The exophytic pattern
grows into the lumen as an irregular, cauliflower mass but at the same time invades the
underlying wall. The luminal portion may be necrotic, hemorrhagic, and ulcerated. The most
common sites of involvement are the fundus and the neck; about 20% involve the lateral walls.
Symptoms: are insidious and typically indistinguishable from those associated with
cholelithiasis: abdominal pain, jaundice, anorexia, and nausea and vomiting. Early detection of
the tumor may be possible in patients who develop a palpable gallbladder and acute

cholecystitis before extension of the tumor into adjacent structures, or when the carcinoma is
an incidental finding during a cholecystectomy for symptomatic gallstones.

83) Acute pancreatitis.

Pancreatitis is inflammation in the pancreas associated with injury to the exocrine parenchyma.
The clinical manifestations range in severity from a mild, self-limited disease to a lifethreatening acute inflammatory process, and the duration of the disease can range from a
transient attack to a permanent loss of function. In acute pancreatitis the gland can return to
normal if the underlying cause of the pancreatitis is removed. By contrast, chronic pancreatitis
is defined by the irreversible loss of exocrine pancreatic parenchyma.
The acute pancreatitis (acute hemorrhagic pancreatic necrosis) is characterized by acute
inflammation and necrosis of pancreas parenchyma, focal enzymic necrosis of pancreatic fat
and vessel necrosis (hemorrhage). These are produced by intrapancreatic activation of
pancreatic enzymes. Lipase activation produces the necrosis of fat tissue in pancreatic
interstitium and peripancreatic spaces as well as vessel damage. Necrotic fat cells appear as
shadows, contours of cells, lacking the nucleus, pink, finely granular cytoplasm. It is possible to
find calcium precipitates (hematoxylinophilic). Digestion of vascular walls results in thrombosis
and hemorrhage. Inflammatory infiltrate is rich in neutrophils. Due to the pancreas lacking a
capsule, the inflammation and necrosis can extend to include fascial layers in the immediate
vicinity of the pancreas.
Etiologic Factors in Acute Pancreatitis
METABOLIC
Alcoholism
Hyperlipoproteinemia
Hypercalcemia
Drugs (e.g., azathioprine)
GENETIC
Mutations in the cationic trypsinogen (PRSS1) and trypsin inhibitor (SPINK1) genes

MECHANICAL
Gallstones
Trauma
Iatrogenic injury
Operative injury
Endoscopic procedures with dye injection

VASCULAR
Shock
Atheroembolism
Vasculitis
INFECTIOUS
Mumps

84) Chronic pancreatitis.

Pancreatitis is inflammation in the pancreas associated with injury to the exocrine parenchyma.
The clinical manifestations range in severity from a mild, self-limited disease to a lifethreatening acute inflammatory process, and the duration of the disease can range from a
transient attack to a permanent loss of function. In acute pancreatitis the gland can return to
normal if the underlying cause of the pancreatitis is removed. By contrast, chronic pancreatitis
is defined by the irreversible loss of exocrine pancreatic parenchyma.
Chronic pancreatitis is defined as inflammation of the pancreas with irreversible destruction of
exocrine parenchyma, fibrosis, and, in the late stages, the destruction of endocrine
parenchyma. Although chronic pancreatitis may present as repeated bouts of acute
pancreatitis, the chief distinction between acute and chronic pancreatitis is the irreversible

impairment in pancreatic function that is characteristic of chronic pancreatitis. There is

significant overlap in the causes of acute and chronic pancreatitis. By far the most common
cause of chronic pancreatitis is long-term alcohol abuse, and these patients are usually middleaged males.
Morphology: Chronic pancreatitis is characterized by parenchymal fibrosis, reduced number
and size of acini with relative sparing of the islets of Langerhans and variable dilation of the
pancreatic ducts. These changes are usually accompanied by a chronic inflammatory infiltrate
around lobules and ducts. The interlobular and intralobular ducts are frequently dilated and
contain protein plugs in their lumens. The ductal epithelium may be atrophied or hyperplastic
or may show squamous metaplasia and ductal concretions may be evident. The remaining islets
of Langerhans become embedded in the sclerotic tissue and may fuse and appear enlarged.
Eventually, they disappear. Grossly, the gland is hard, sometimes with extremely dilated ducts
and visible calcified concretions. Lymphoplasmacytic sclerosing pancreatitis (autoimmune
pancreatitis) is a distinct form of chronic pancreatitis characterized by a duct-centric mixed
inflammatory cell infiltrate, venulitis, and increased numbers of IgG4-producing plasma cells.
Symptoms: it may present in many different forms. It may be associated with repeated attacks
of moderately severe abdominal pain, recurrent attacks of mild pain, or persistent abdominal
and back pain. The disease may be entirely silent until pancreatic insufficiency and diabetes
mellitus develop, the latter from associated destruction of islets of Langerhans. In still other
instances, recurrent attacks of jaundice or vague attacks of indigestion may hint at pancreatic
disease.

85) Tumors of the exocrine pancreas.

Pancreatic carcinoma: Pancreatic cancer has one of the highest mortality rates of any cancer.
Just as there is a progression in the colorectum from non-neoplastic epithelium to adenoma to
invasive carcinoma there is a progression in the pancreas from non-neoplastic epithelium to
histologically well-defined noninvasive lesions in small ducts and ductules to invasive
carcinoma. These precursor lesions are called pancreatic intraepithelial neoplasias (PanINs).
The genetic and epigenetic alterations identified in PanINs are similar to those present in
invasive cancers. The epithelial cells in PanINs show dramatic telomere shortening. A critical
shortening of telomere length in PanINs may predispose these lesions to accumulate
progressive chromosomal abnormalities and to develop invasive carcinoma
Morphology: Approximately 60% of cancers of the pancreas arise in the head of the gland, 15%
in the body, and 5% in the tail; in 20% the neoplasm diffusely involves the entire gland.
Carcinomas of the pancreas are usually hard, stellate, gray-white, poorly defined masses. The
vast majority of carcinomas are ductal adenocarcinomas that recapitulate to some degree

normal ductal epithelium by forming glands and secreting mucin. Two features are
characteristic of pancreatic cancer: It is highly invasive (even early invasive pancreatic cancers
extensively invade peripancreatic tissues), and elicits an intense non-neoplastic host reaction
composed of fibroblasts, lymphocytes, and extracellular matrix (called a desmoplastic
response). Microscopically, there is no difference between carcinomas of the head of the
pancreas and those of the body and tail of the pancreas. The appearance is usually that of a
moderately to poorly differentiated adenocarcinoma forming abortive tubular structures or cell
clusters and showing an aggressive, deeply infiltrative growth pattern. Dense stromal fibrosis
accompanies the invasive cancer, and there is a proclivity for perineural invasion within and
beyond the organ. Lymphatic and large vessel invasion are also commonly seen. The malignant
glands are poorly formed and are usually lined by pleomorphic cuboidal-to-columnar epithelial
cells. Well-differentiated carcinomas are the exception.
Less common variants of pancreatic cancer include adenosquamous carcinomas, colloid
carcinoma, hepatoid carcinoma, medullary carcinoma, signet-ring cell carcinoma,
undifferentiated carcinoma, and undifferentiated carcinomas with osteoclast-like giant cells.
Adenosquamous carcinomas have focal squamous differentiation in addition to glandular
differentiation, and undifferentiated carcinomas may contain large multinucleated osteoclastlike giant cells. Carcinomas of the pancreas remain silent until they invade into adjacent
structures. Pain is usually the first symptom, but by the time pain appears these cancers are
usually beyond cure.
Acinar cell carcinoma: show prominent acinar cell differentiation, including the formation of
zymogen granules and the production of exocrine enzymes including trypsin and lipase. Fifteen
percent of individuals with acinar cell carcinoma develop the syndrome of metastatic fat
necrosis caused by the release of lipase into the circulation.
Pancreatoblastomas: are rare neoplasms that occur primarily in children aged 1 to 15 years.
They have a distinct microscopic appearance with squamous islands admixed with acinar cells.
These are fully malignant neoplasms, although survival may be better than that for pancreatic
ductal adenocarcinomas.

86) Primary glomerular diseases Glomerulonephritis. Classification. Acute

nephritic and nephrotic syndromes.
Nephritic syndrome: Glomerular diseases presenting with a nephritic syndrome are often
characterized by inflammation in the glomeruli. The nephritic patient usually presents with
hematuria, red cell casts in the urine, azotemia, oliguria, and mild to moderate hypertension.
Proteinuria and edema are common, but these are not as severe as those encountered in the
nephrotic syndrome. The acute nephritic syndrome may occur in such multisystem diseases as

SLE and microscopic polyangiitis. Typically, however, it is characteristic of acute proliferative

glomerulonephritis and is an important component of crescentic glomerulonephritis.
Acute Proliferative (Poststreptococcal, Postinfectious) Glomerulonephritis: As the name
implies, this cluster of diseases is characterized histologically by diffuse proliferation of
glomerular cells, associated with influx of leukocytes. These lesions are typically caused by
immune complexes. The inciting antigen may be exogenous or endogenous. The prototypic
exogenous antigen-induced disease pattern is postinfectious glomerulonephritis, whereas an
example of an endogenous antigen-induced disease is the nephritis of SLE. The most common
underlying infections are streptococcal, but the disorder also has been associated with other
infections.
Poststreptococcal Glomerulonephritis: It usually appears 1 to 4 weeks after a streptococcal
infection of the pharynx or skin (impetigo). Skin infections are commonly associated with
overcrowding and poor hygiene. Poststreptococcal glomerulonephritis occurs most frequently
in children 6 to 10 years of age, but adults of any age can also be affected.
Morphology: The classic diagnostic picture is one of enlarged, hypercellular glomeruli. The
hypercellularity is caused by (1) infiltration by leukocytes, both neutrophils and monocytes; (2)
proliferation of endothelial and mesangial cells; and (3) in severe cases by crescent formation.
The proliferation and leukocyte infiltration are diffuse, that is, involving all lobules of all
glomeruli. There is also swelling of endothelial cells, and the combination of proliferation,
swelling, and leukocyte infiltration obliterates the capillary lumens. There may be interstitial
edema and inflammation, and the tubules often contain red cell casts. Subendothelial and
intramembranous deposits are also commonly seen and mesangial deposits may be present.
Nephrotic syndrome: Certain glomerular diseases virtually always produce the nephrotic syndrome.
The manifestations of the nephrotic syndrome include:
1.

Massive proteinuria, with the daily loss of 3.5 gm or more of protein (less in children)

2.

Hypoalbuminemia, with plasma albumin levels less than 3 gm/dL

3.

Generalized edema

4.

Hyperlipidemia and lipiduria

Nephrotic patients are particularly vulnerable to infection, especially staphylococcal and

pneumococcal, probably related to loss of immunoglobulins in the urine. Thrombotic and

thromboembolic complications are also common in nephrotic syndrome, due in part to loss of
endogenous anticoagulants (ex. antithrombin III) and antiplasmins in the urine. Renal vein
thrombosis, once thought to be a cause of nephrotic syndrome, is most often a consequence of
this hypercoagulable state, particularly in patients with membranous nephropathy.

87) Tubulo-interstitial nephritis Acute and chronic pyelonephritis.

Tubulointerstitial nephritis can be acute or chronic. Acute tubulointerstitial nephritis has a
rapid clinical onset and is characterized histologically by interstitial edema, often accompanied
by leukocytic infiltration of the interstitium and tubules, and focal tubular necrosis. In chronic
interstitial nephritis there is infiltration with predominantly mononuclear leukocytes,
prominent interstitial fibrosis, and widespread tubular atrophy. Morphologic features that are
helpful in separating acute from chronic tubulointerstitial nephritis include edema and, when
present, eosinophils and neutrophils in the acute form, while fibrosis and tubular atrophy
characterize the chronic form. These conditions are distinguished clinically from the glomerular
diseases by the absence, in early stages, of such hallmarks of glomerular injury as nephritic or
nephrotic syndrome and by the presence of defects in tubular function. The latter may be
subtle and include impaired ability to concentrate urine, evidenced clinically by polyuria or
nocturia; salt wasting; diminished ability to excrete acids (metabolic acidosis); and isolated
defects in tubular reabsorption or secretion. The advanced forms, however, may be difficult to
distinguish clinically from other causes of renal insufficiency.
Pyelonephritis and Urinary Tract Infection: Pyelonephritis is a renal disorder affecting the
tubules, interstitium, and renal pelvis and is one of the most common diseases of the kidney. It
occurs in two forms. Acute pyelonephritis is caused by bacterial infection and is the renal lesion
associated with urinary tract infection. Chronic pyelonephritis is a more complex disorder;
bacterial infection plays a dominant role, but other factors (vesicoureteral reflux, obstruction)
are involved in its pathogenesis. Pyelonephritis is a serious complication of urinary tract
infections that affect the bladder (cystitis), the kidneys and their collecting systems
(pyelonephritis), or both. Bacterial infection of the lower urinary tract may be completely
asymptomatic (asymptomatic bacteriuria) and most often remains localized to the bladder
without the development of renal infection. However, lower urinary tract infection always
carries the potential of spread to the kidney.
Morphology: The hallmarks of acute pyelonephritis are patchy interstitial suppurative
inflammation, intratubular aggregates of neutrophils, and tubular necrosis. The suppuration
may occur as discrete focal abscesses involving one or both kidneys, which can extend to large
wedge-shaped areas of suppuration. The distribution of these lesions is unpredictable and
haphazard, but in pyelonephritis associated with reflux, damage occurs most commonly in the
lower and upper poles. In the early stages, the neutrophilic infiltration is limited to the

interstitial tissue. Soon, however, the reaction involves tubules and produces a characteristic
abscess with the destruction of the engulfed tubules. Since the tubular lumens present a ready
pathway for the extension of the infection, large masses of intraluminal neutrophils frequently
extend along the involved nephron into the collecting tubules. Characteristically, glomeruli
seem to be relatively resistant to the infection. Large areas of severe necrosis, however,
eventually destroy the glomeruli, and fungal pyelonephritis (ex. Candida) often affects
glomeruli.
Three complications of acute pyelonephritis are encountered in special circumstances.

Papillary necrosis is seen mainly in diabetics and in those with urinary tract obstruction. Papillary
necrosis is usually bilateral but may be unilateral. One or all of the pyramids of the affected
kidney may be involved. On cut section, the tips or distal two thirds of the pyramids have areas of
gray-white to yellow necrosis ( Fig. 20-30 ). On microscopic examination the necrotic tissue shows
characteristic coagulative necrosis, with preservation of outlines of tubules. The leukocytic
response is limited to the junctions between preserved and destroyed tissue.

Pyonephrosis is seen when there is total or almost complete obstruction, particularly when it is
high in the urinary tract. The suppurative exudate is unable to drain and thus fills the renal pelvis,
calyces, and ureter with pus.

Perinephric abscess is an extension of suppurative inflammation through the renal capsule into
the perinephric tissue.

Chronic Pyelonephritis and Reflux Nephropathy: is a disorder in which chronic

tubulointerstitial inflammation and renal scarring are associated with pathologic involvement of
the calyces and pelvis. Pelvocalyceal damage is important in that virtually all the disease
etiologies listed in Table 20-8 produce chronic tubulointerstitial alterations, but with the
exception of chronic pyelonephritis and analgesic nephropathy, none affect the calyces. Chronic
pyelonephritis is an important cause of end-stage kidney disease; at one time it accounted for
as many as 10% to 20% of patients in renal transplant or dialysis units, until predisposing
conditions such as reflux became better recognized. This condition remains an important cause
of kidney destruction in children with severe lower urinary tract abnormalities.
Morphology: The characteristic changes of chronic pyelonephritis are seen on gross
examination. The kidneys usually are irregularly scarred; if bilateral, the involvement is
asymmetric. This contrasts with chronic glomerulonephritis, in which both kidneys are diffusely
and symmetrically scarred. The hallmarks of chronic pyelonephritis are coarse, discrete,
corticomedullary scars overlying dilated, blunted, or deformed calyces, and flattening of the
papillae. The scars can vary from one to several in number and may affect one or both kidneys.

Most are in the upper and lower poles, consistent with the frequency of reflux in these sites.
The microscopic changes involve predominantly tubules and interstitium. The tubules show
atrophy in some areas and hypertrophy or dilation in others. Dilated tubules with flattened
epithelium may be filled with colloid casts (thyroidization). There are varying degrees of chronic
interstitial inflammation and fibrosis in the cortex and medulla. In the presence of active
infection there may be neutrophils in the interstitium and pus casts in the tubules. Arcuate and
interlobular vessels demonstrate obliterative intimal sclerosis in the scarred areas; and in the
presence of hypertension, hyaline arteriosclerosis is seen in the entire kidney. There is often
fibrosis around the calyceal epithelium as well as a marked chronic inflammatory infiltrate.
Glomeruli may appear normal except for periglomerular fibrosis, or exhibit a variety of changes,
including ischemic fibrous obliteration and secondary changes related to hypertension.
Individuals with chronic pyelonephritis and reflux nephropathy who develop proteinuria in
advanced stages show secondary focal segmental glomerulosclerosis, as described later.
Xanthogranulomatous pyelonephritis is an unusual and relatively rare form of chronic
pyelonephritis characterized by accumulation of foamy macrophages intermingled with plasma
cells, lymphocytes, polymorphonuclear leukocytes, and occasional giant cells. Often associated
with Proteus infections and obstruction, the lesions sometimes produce large, yellowish orange
nodules that may be grossly confused with renal cell carcinoma.

88) Tubulo-interstitial nephritis induced by drugs and toxins.

Acute Drug-Induced Interstitial Nephritis: This is a well-recognized adverse reaction to a
constantly increasing number of drugs. First reported after the use of sulfonamides, acute
tubulointerstitial nephritis most frequently occurs with synthetic penicillins (methicillin,
ampicillin), other synthetic antibiotics (rifampin), diuretics (thiazides), NSAIDs, and
miscellaneous drugs (allopurinol, cimetidine). The disease begins about 15 days (range: 240)
after exposure to the drug and is characterized by fever, eosinophilia (which may be transient),
a rash in about 25% of patients, and renal abnormalities. The latter take the form of hematuria,
mild proteinuria, and leukocyturia (often including eosinophils). A rising serum creatinine level
or acute renal failure with oliguria develops in about 50% of cases, particularly in older patients.
Morphology: On histologic examination the abnormalities are in the interstitium, which shows
variable but frequently pronounced edema and infiltration by mononuclear cells, principally
lymphocytes and macrophages. Eosinophils and neutrophils may be present often in clusters
and large numbers, and plasma cells and basophils are sometimes found in small numbers.
With some drugs (ex. methicillin, thiazides), interstitial non-necrotizing granulomas containing
giant cells may be seen. Tubulitis, the infiltration of tubules by lymphocytes, is common.
Variable degrees of tubular necrosis and regeneration are present. The glomeruli are normal

except in some cases caused by NSAIDs, when minimal-change disease and the nephrotic
syndrome develop concurrently (see the discussion of NSAIDs later in the chapter).
Analgesic Nephropathy: This is a form of chronic renal disease caused by excessive intake of
analgesic mixtures and characterized morphologically by chronic tubulointerstitial nephritis and
renal papillary necrosis. It is clear that in the sequence of events leading to renal damage,
papillary necrosis occurs first, and cortical tubulointerstitial nephritis follows as a consequence
of impeded urine outflow.
Morphology: In gross appearance the kidneys are either normal or slightly reduced in size, and
the cortex shows depressed areas representing cortical atrophy overlying necrotic papillae. The
papillae show various stages of necrosis, calcification, fragmentation, and sloughing. This gross
appearance contrasts with the papillary necrosis seen in diabetic patients, in which all papillae
are at the same stage of injury. On microscopic examination the papillary changes may take one
of several forms. In early cases there is patchy necrosis, but in the advanced form the entire
papilla is necrotic, often remaining in place as a structureless mass containing ghosts of
tubules and foci of dystrophic calcification. Segments of entire portions of the papilla may then
be sloughed and excreted in the urine. The cortical changes consist of loss and atrophy of
tubules and interstitial fibrosis and inflammation. These changes are mainly due to obstructive
atrophy caused by the tubular damage in the papillae.
Nephropathy Associated with NSAIDs: include:

Hemodynamically induced acute renal failure, due to the decreased synthesis of

vasodilatory prostaglandins. This is particularly likely to occur in the setting of other
renal diseases or conditions causing volume depletion.

Acute hypersensitivity interstitial nephritis, resulting in acute renal failure, as

described earlier.

Acute interstitial nephritis and minimal-change disease. This curious association of

two diverse renal conditions, one leading to renal failure and the other to nephrotic
syndrome, suggests a hypersensitivity reaction affecting the interstitium and possibly
the glomeruli, but also is consistent with injury to podocytes mediated by cytokines
released as part of the inflammatory process.

Membranous nephropathy, with the nephrotic syndrome, is a recently appreciated

association, also of unclear pathogenesis.

Urate Nephropathy: three types of nephropathy can occur in persons with hyperuricemic
disorders:

Acute uric acid nephropathy is caused by the precipitation of uric acid crystals in the
renal tubules, principally in collecting ducts, leading to obstruction of nephrons and the
development of acute renal failure. This type is particularly likely to occur in individuals
with leukemias and lymphomas who are undergoing chemotherapy; the drugs increase
the death of tumor cells, and uric acid is produced as released nucleic acids are broken
down. Precipitation of uric acid is favored by the acidic pH in collecting tubules.

Chronic urate nephropathy, or gouty nephropathy, occurs in patients with more

protracted forms of hyperuricemia. The lesions are ascribed to the deposition of
monosodium urate crystals in the acidic milieu of the distal tubules and collecting ducts
as well as in the interstitium. These deposits have a distinct histologic appearance and
may form variably birefringent needle-like crystals either in the tubular lumens or in the
interstitium. The urates induce a tophus consisting of foreign-body giant cells, other
mononuclear cells, and a fibrotic reaction. Tubular obstruction by the urates causes
cortical atrophy and scarring. Renal arterial and arteriolar thickening is common as a
result of the relatively high frequency of hypertension in patients with gout.

The third renal syndrome in hyperuricemia is nephrolithiasis; uric acid stones are present
in 22% of individuals with gout and 42% of those with secondary hyperuricemia.

89) Endemic nephropathy.

Nephropathy refers to damage to or disease of the kidney. An older term for this is nephrosis.
Causes of nephropathy include deposition of the IgA antibodies in the glomerulus,
administration of analgesics, xanthine oxidase deficiency, and long-term exposure to lead or its
salts. Chronic conditions that can produce nephropathy include systemic lupus erythematosus,
diabetes mellitus and high blood pressure (hypertension), which lead to diabetic nephropathy
and hypertensive nephropathy, respectively. Another possible cause of nephropathy is due to
decreased function of xanthine oxidase in the purine degradation pathway. Xanthine oxidase
will degrade hypoxanthine to xanthine and then to uric acid. Xanthine is not very soluble in
water; therefore, an increase in xanthine forms crystals (which can lead to kidney stones) and
result in damage of the kidney. Drugs like allopurinol that are used to inhibit xanthine oxidase
can therefore cause possible nephropathy. Additional possible cause of nephropathy is due to
the formation of cysts or pockets containing fluid within the kidneys. These cysts get enlarged

with the progression of aging causing renal failure. Cysts may also form in other organs
including the Liver, Brain and Ovaries. Polycystic Disease is a genetic disease caused by
Mutations in the PKD1, PKD2, and PKHD1 genes. This disease affects about half a million people
in the US. Polycystic kidneys are susceptible to infections and cancer other factors contributing
to renal failure.
IgA nephropathy
IgA nephropathy is the most common glomerulonephritis throughout the world. Primary IgA
nephropathy is characterized by deposition of the IgA antibody in the glomerulus. The classic
presentation (in 40-50% of the cases) is episodic frank hematuria which usually starts within a
day or two of a non-specific upper respiratory tract infection (hence synpharyngitic) as opposed
to post-streptococcal glomerulonephritis which occurs some time (weeks) after initial infection.
Less commonly gastrointestinal or urinary infection can be the inciting agent. All of these
infections have in common the activation of mucosal defenses and hence IgA antibody
production.