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NEOPLASIA
I. Definitions and nomenclature.
There are several conditions, when there is increased growth of cells and
tissues/ In a number of instances, exceptions to the following definitions have been
established by long use; the most common of these are mentioned here.
1. Hypertrophy is an enlargement in individual cell size, causing a corresponding increase in
mass.
3. Metaplasia is the replacement of one adult tissue type by another; usually the replacement
Classification of neoplasms
According to clinical and morphological features:
1. BENIGN TUMORS. In general these are designated by attaching the suffix "oma" to the cell
of origin: fibroma, chondroma, osteoma, etc.
2. MALIGNANT TUMORS The nomenclature of the MALIGNANT TUMORS essentially
follows the same scheme used for benign neoplasms, with certain additions. Thus malignant
tumors arising in mesenchymal tissue are usually called sarcomas: fibrosarcoma, liposarcoma,
leiomyosarcoma, etc.
On the other hand malignant neoplasms of epithelial cell origin, derived from the three
germ layers, are called carcinomas: adenocarcinoma or squamous cell carcinoma.
Classification of neoplasms
According to histogenesis:
TISSUE
Epithelial
tissues:
Stratified
Simple
and
glandular
Tissues
mesenchymal (or
mesodermal) in
origin:
Fibrous
connective tissue
Vascular tissue
Adipose tissue
Smooth muscular
tissue
Skeletal striated
muscular tissue
Cartilage
Bone
Hemopoietic
tissue
Lymphoid tissue
BENIGN TUMORS
MALIGNANT TUMORS
Papilloma
Adenoma
Fibroma
Fibrosarcoma
Hemagioma
Lipoma
Leiomyoma
Hemagiosarcoma
Liposarcoma
Leiomyosarcoma
Rhabdomyoma
Rhabdomyosarcoma
Chondroma
Osteoma
Chondrosarcoma
Osteosarcoma
Leukemia
Lymphoma
TISSUE
BENIGN TUMORS
Tissues neural in
origin:
Neural tissue of Glyomas
(biologically
CNS
malignant):
Astrocytoma
Oligodendroglyoma
Neural tissue of Neurilemmoma
PNS
Melaninproducing
tissue
Different tissues:
Epithelial
and Fibroadenoma
connective
(mixed tumor)
tissues
Different
germ Teratoma
layers
MALIGNANT TUMORS
Glyoblastoma
Medullablastoma
Malignant neurilemmoma
Melanoma
Malignant fibroadenoma
(mixed tumor)
Malignant teratoma
Besides there are mixed tumors, which contain epithelial components scattered within the
myxoid stroma that sometimes contains islands of apparent cartilage or even bone.
And finally there are teratomas. This tumor is made up of a variety of parenchymal cell
types representative of more than one germ layer, usually all three.
Epidemiology
1. In the United States, cancer is the second leading cause of death, accounting for 20% of deaths
compared to 38% from cardiac causes, 10% from cerebrovascular disease, and 5% from
accidents of various types.
2. For perspective, however, one should recognize that cancer is less significant worldwide: In
underdeveloped countries, malnutrition and parasitic infections (e.g., malaria) still account for
more deaths than cancer does.
3. Risk factors. Four important factors believed to be associated with the increasing incidence of
cancer are age, diet, environment, and genetic makeup.
a. Age
(1)
With the population increasing in age, carcinogens are thought to have more time to
exert their effects; additionally, the immunologic defenses of the elderly may be less
effective than those of young people.
(2)
However, it is crucial to remember that cancer can occur at any age. There are
congenital neoplasms, and in the 1- to 14-year-old age-group, cancer accounts for 11% of
deaths, second only to accidents as a cause of death.
b. Diet
(1) Geographic differences in cancer rates can be explained partially by dietary differences.
(a)The smoking of foods is known to produce chemical carcinogens. Icelandic people, who
have an exceedingly high rate of esophageal cancer, eat large amounts of smoked fish.
(b)A diet rich in fiber and low in animal fat and refined carbohydrates seems to discourage
colorectal cancer. The African Bantus, on such a diet, have almost no incidence of
colorectal cancer.
(c) Japanese people who live in Japan have a high rate of cancer of the stomach, twice the
rate of Japanese who have migrated to Hawaii and have adopted a Western diet.
However, diet alone cannot be the total answer, since Japanese in Hawaii still have a
higher rate of gastric cancer than do non-Japanese in the same environment.
(2) Alcoholic beverages affect carcinogenesis when consumed frequently and excessively over
long periods.
(a) Although the alcohol per se appears not to be carcinogenic, it may potentiate the effects of
other substances in alcoholic beverages or may allow for the increased absorption of
carcinogens.
(b) The carcinogenic impact of alcohol is especially pronounced on hepatic cells and,
especially when combined with tobacco use, on the mucosa of the esophagus, pharynx,
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and oral cavity. Coexisting (multiple primary) cancers occur twice as often among
cirrhotic persons as among the noncirrhotic.
c. Environment. The environmental agents associated with a high incidence of cancer
include radiation and chemical pollution. Industrialization and development, along with the
conquest of infection and malnutrition, bring an increase in cancer incidence.
(1) An urban setting, with its greater air and water pollution than in a rural environment, leads to
higher cancer rates, especially for lung cancer.
(2) Smokers get lung cancer much more frequently than do nonsmokers. Smoking has also been
linked to oral, pharyngeal, laryngeal, and bladder carcinoma.
(3) Industrial workers exposed to certain agents (e.g., asbestos or vinyl chloride) develop cancer
more often than do nonexposed groups.
(4) Sexual activity may be related to cancer.
(a) Possible carcinogens or cocarcinogens (e.g., certain viruses) may be venereally
transmitted.
(b) In the female reproductive tract, the uterine cervix has the highest association with
malignant disease and its precursors.
(i) The cervix shows an increased vulnerability to neoplasia after it is exposed to
infection, particularly herpes simplex virus type 2 infection.
(ii) Since squamous cervical neoplasia begins in the squamocolumnar junction,
hyperplasia in this area as a result of the irritation of infection may play a causative
role.
(iii) Only herpes simplex virus type 2 and human papilloma virus appear to be able to
reprogram the nuclei of growing cells and perhaps lead to cervical cancer.
d. Genetic makeup. In some families, predisposition to cancer appears to be hereditary.
Nonhereditary chromosomal abnormalities also increase the risk of certain cancers.
(1)Clinical observations indicate that some forms of cancer have a mendelian basis of
a. The cancerous phenotype itself is unstable. In time, with continued cell division and
progression of the neoplastic process, a variety of subclones may appear as the progeny of a
single cancer.
b. This clonal heterogeneity may be manifested morphologically or biochemically. Each of
the subclones can show differences in morphology, special product elaboration, and
antigenicity.
c. Cancer cells display a type of clonal evolution that allows for the insidious selection of the
most aggressive, rapidly growing, and invasive clones. It is this feature that gives rise to
subclones that are fiercely resistant to all known modes of therapy and eventually prove
lethal.
3.The mutation hypothesis
a. Most neoplasms are associated with a heritable alteration in the involved cells. That is, the
transformation of a normal to a neoplastic cell involves changes within the genetic
apparatus of the cell (mutation). Heredity, chemicals, physical agents, radiation, and
viruses may be involved in this change.
b.Most investigators feel that neoplasia involves a multifactorial, multistage process of
progressive mutation in the genetic makeup of cells. The mutation hypothesis is favored
by several arguments.
(1) All carcinogens (including chemicals, radiation, and viruses) are mutagenic.
(2) Defective DNA repair mechanisms, as occur in xeroderma pigmentosa, are associated
with an increased risk of neoplasia.
(3) Neoplasia is a clonal disease.
B. Role of carcinogens
1. A constant feature of all agents that are known carcinogens is their demonstrated interaction
with DNA. This interaction is obvious for the three major classes of carcinogens, namely
chemicals, viruses, and ionizing radiation. Each of these classes can intercalate with nuclear
DNA and induce miscoding of genetic information.
2. Many carcinogens (often chemicals by nature) must be metabolically activated by cellular
enzymes. In the absence of the appropriate enzymes, transformation cannot occur.
3. Neoplasia is at least a two-stage process (at least in experimental settings): initiation
(primary insult) and promotion (requiring other agents for full expression of the neoplasm).
a. An initiator causes alterations in DNA structure and is mutagenic.
b.A promoter stimulates replication of the mutant cells, apparently by acting on cell
membranes. Alone, promoters are not carcinogens, and they must act after the initiator to
produce cancer.
c. Two or more initiators, acting in combination, can induce transformation
(cocarcinogenesis).
C. Role of viruses
1.General concepts
a.Functionally speaking, viruses are blocks of genetic material. Thus, once inside a cell, a virus
can change the genetic information that the cell transmits to all its progeny.
b.Neoplastic transformation can be caused by viruses of either the DNA or RNA type, and in
some experimental systems, the viral genes seem necessary to maintain the transformed
state. The neoplastic change involves the integration of new genetic information from the
virusin the form of DNA nucleotide sequencesinto the host's cellular genome.
2.Retroviruses and oncogenes
a. Retroviruses are RNA viruses. They replicate by forming a proviral DNA that integrates into
host-cell DNA. The integrated provirus then acts just like host-cell genes, transmitting
genetic information to the cell's progeny.
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malignant transformation. These sequences are called viral oncogenes (v-oncs). Several voncs have proved to induce cancers in experimental systems; none is definitely known to
produce cancer in humans, although for some viruses there is strong evidence that this is
so in humans.
(2)Eukaryote cells contain genes with nucleotide sequences that are identical or closely
similar (homologous) to v-oncs. These proto-oncogenes, or cellular oncogenes (concs), are thought to be the precursors of v-oncs, picked up by retroviruses in the course
of evolution.
b. Oncogenes probably confer a selective growth advantage on the transformed cell, since many
v-oncs are genes that code for protein kinase enzyme systems, which appear to bind to cell
membranes and serve as growth factor receptors.
c. The proto-oncogene (c-onc) sequences found in the DNA of normal cells may be
involved in normal cellular differentiation and in growth control, since their evolutionary
conservation suggests an important natural function.
d. Retrovirus genomes (even those without v-oncs) also contain long repeated nucleotide
sequences at both ends of the integrated DNA. These long terminal repeat (LTR)
sequences regulate transcription. LTRs may be capable of activating nearby c-oncs,
converting them to oncogenes and causing the breakdown of control mechanisms. (Gene
amplification, gene rearrangements, and chromosomal translocations are suggested
mechanisms of oncogene activation.)
e. Possibly, other etiologic (perhaps exogenous) factors also act by activating c-oncs.
Whether an etiologic factor influences anything more than the first step of transformation is
not known. Perhaps the etiologic agent starts the process and then the inevitable
consequence of neoplastic independence occurs without further exogenous stimulation.
f. Certain c-oncs have been found in patients with specific human cancers, although causation
has not been proved.
(1)The oncogene c-myc is associated with a translocation between chromosomes 8 and 14 in
Burkitt's lymphoma.
(2)The oncogene c-ras is associated with loss of the small arm of chromosome 11 in
Wilms' tumor.
3. DNA viruses. Less is known about the role of DNA viruses in tumorigenesis.
a. Carcinogenic DNA viruses code for certain proteins that are prerequisites for the transformation
of cells, such as the SV40 virus T antigens. These substances, like the protein products of voncs, are membrane-associated and have protein kinase activity.
b. Moreover, the SV40 virus genome also has repeat sequences like the LTRs of retroviruses; these
sequences are required for the transcription of T antigens.
D. Role of endogenous factors
1. The
It is possible that all tumors pass through stages when they are still dependent upon physiologic
factors, but this has only been documented in cases of the endocrine-dependent tissues, such as
the female breast. With time, due to tumor progression, a tumor loses its endocrine dependency,
and hormonal manipulation ceases to influence its growth.
III. CHARACTERISTICS OF NEOPLASMS. Groups of abnormally proliferating cells can
arise in any part of the body. Certain characteristics are shared by these neoplasms, both in vitro
and in vivo. Besides the major components found in all neoplasms, important properties
include clon-ality, autonomy, a blood supply, and, in malignant neoplasms, the capacity to
metastasize.
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form a fibrous capsule which separates them from the host tissue.
Local invasion. The growth of cancers is accompanied by progressive infiltration,
invasion and destruction of the surrounding tissue. In general, they are poorly demarcated from
the surrounding normal tissue, and thus they are obviously invasive and can be expected to
penetrate the wall of colon or uterus, for example, or fungate through the surface of the skin.
Metastases. The development of metastases is the most reliable feature that
differentiates malignant from benign tumors.
Metastases are tumors implants discontinuous with the primary tumor. Metastasis marks
tumor as malignant because benign neoplasms do not metastasize. The invasiveness of cancers
permits them to penetrate into blood vessels, lymphatics, and body cavities, producing the
opportunity of spread. With few exceptions, all cancers can metastasize.
animal studies, tumor antigens have been identified that are capable of stimulating
resistance to a tumor implant in normal animals. These are called tumor-specific or tumorassociated transplantation antigens (TSTA or TATA), depending on whether they are found
only on tumor cells or also on normal cells.
common.
(b) Cell nuclei also tend to be large, so that the
seen.
(c) Mitotic figures are numerous and often abnormal. Karyotypic analysis shows that many,
although not all, malignant tumors are aneuploid, with an abnormal number of
chromosomes.
B.Identification of precancerous lesions
1.In many if not all systems (e.g., cervix, lung, colon), clinicopathologic studies have
demonstrated that initial neoplastic change can be recognized in a preinvasive stage. Such
changes can progress over a prolonged time span.
a. Whether all malignant neoplasms arise as benign lesions, which then undergo progression, or
whether some are highly malignant from the start is debatable.
b. However, it seems probable that all neoplasms go through a benign preinvasive phase, even if
this phase is often not recognized clinically.
2.The morphologic alterations of cancer allow the trained eye to recognize not only the invasive
malignant process, but also the preinvasive lesions (carcinoma in situ).
a. In situ carcinomas are usually recognized in epithelial malignancies (not in sarcomas or
lymphomas). They show the various morphologic changes of malignancy, but remain
confined to the epithelial or mucosal surface.
b. Developments in histopathology and cytopathology have allowed for the screening of
preinvasive (usually asymptomatic) cancer; once such a lesion is recognized, it can be
effectively treated.
C.
Grading and staging of malignancies. These prognostic measures attempt to express the
degree of malignancy and aggressiveness of a tumor, as a guide to its clinical behavior and the
probable outcome of therapy.
1. The grade of a tumor describes its histologic degree of anaplasia and extent of invasion.
Grade levels of I to IV are often used.
2. The stage of a tumor describes its size, the extent of regional lymph node spread, and the
presence or absence of metastases. Several systems for staging are in use.
a. The TNM system assigns a T level of 1 to 4 for tumor size; an N level of 0 to 3 for nodal
involvement; and an M level of 0 or 1 for metastases.
b. A simpler system incorporates this information into stages 0 to IV.
3. Staging has proved to be more useful clinically than grading.
D. Tumor markers
1. In some forms of cancer, a particular protein or other substance is found consistently
enough in patients' serum that the substance can be used to screen for the cancer and to monitor
cancer patients for recurrences. The substance may be an abnormal counterpart of a known body
component, an excess of a normal component, or the re-expression of a fetal or embryonic
substance. Two examples follow.
a. In 40% to 90% of primary liver cancers, there is an associated elaboration of
alphafetoprotein, a substance regularly made by developing embryonic liver cells but not by
normal adult tissue.
b. The hormone calcitonin, normally produced by thyroid parafollicular cells, is elevated in the
serum of patients with medullary thyroid cancer.
2.Finding cancer-specific oncogenes or chromosomal abnormalities could provide invaluable
additional tumor markers. Besides serving a diagnostic or post-therapeutic use like the tumor
markers described above, these markers could be useful for identifying cancer-prone patients.
like a malignant lymphoma of the small intestine, can occupy the lumen and obstruct it.
can cause bleeding. Benign neoplasms usually produce bleeding by expansive
growth and erosion of the overlying surface. Cancers are more likely to invade the overlying
surface tissues and ulcerate, as in adenocarcinoma of the stomach, or to infiltrate vessels and
rupture them.
5. They can produce abnormal function.
a. In endocrine organs, for example, either a benign or malignant neoplasm can produce an
excess of a specific hormone, since the neoplasm is not bound by normal feedback control
mechanisms.
b. Symptoms will be those of hormonal excess. Examples include hypercalcemia from a
parathyroid adenoma and Cushing's syndrome from an adrenal adenoma.
6.They can interfere with function. A benign pituitary adenoma, for example, can replace the
normal gland and lead to pituitary hormonal deficiencies. Similarly, a histologically benign
glioma in the thalamic region of the brain can expand and lead to brain edema, herniation,
and death.
4. They
normal tissue.
4. Paraneoplastic syndromes. These are symptom complexes seen in cancer patients that are not
caused by the tumor, by its metastases, or by hormones secreted by the tumor's tissue of
origin. The following are two of the most common.
a. Ectopic hormone production
(1)
Peptide hormones such as adrenocorticotropic hormone (ACTH) and antidiuretic
hormone (ADH) may be increased in some forms of lung cancer. The consequent
symptoms of hormonal excess (e.g., Cushing's syndrome, hyponatremia) may become a
life-threatening clinical problem.
(2)
These syndromes suggest that the regulation of cell differentiation tends to be
deranged in bizarre and unexpected ways. These changes are not completely random,
however, since particular types of tumors show particular patterns of aberrant
differentiation.
b.Hypercoagulability. This can result in nonbacterial thrombotic endocarditis or venous
thrombosis.
5. Infections are common in patients who have cancer and may occur for several reasons.
a. An obstructive neoplasm (e.g., of a bronchus) can lead to postobstructive infection (e.g.,
pneumonia).
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b. Altered host resistance may permit relatively avirulent organisms (e.g., normal
bacterial bowel flora) as well as common fungi, parasites, or viruses to cause
infection and death.
(1)Serologic factors. In lymphomas and leukemias, normal immunoglobulins are
decreased, resulting in an increased susceptibility to and severity of infection.
(2) Cellular factors
(a) Decreased
projection above a mucosal surface and projects, for example, into a gastric or colonic lumen, it
is termed as polyp. The term "polyp" is preferably restricted to benign tumors. Malignant polyps
are better designated as polypoid cancers.
Malignant neoplasms of epithelial cell origin are called carcinomas. Carcinomas may be
further qualified. One within glandular growth pattern microscopically is termed as
adenocarcinoma and one producing recognizable squamous cell arising in any epithelium of the
body would be termed a squamous cell carcinoma. It is further common practice to specify, when
possible, the organ of origin (renal cell adenocarcinoma, or bronchogenic squamous cell
carcinoma, etc.). Not infrequently, however, a cancer is composed of undifferentiated cells and
must be designated merely as a poorly differentiated or undifferentiated malignant tumor.
The term: Simple and Malignant Connective Tissue Tumors.
As you know, the connective tissue, vessels, muscle, bones and ligaments, serosa and
blood production system are developed of mesenchymal tissue. The tumors of mesenchyma are
called mesenchymal tumors. The benign tumors are marked by suffix "oma", the malignant
tumors are marked by suffix "sarcoma".
The Simple Connective Tissue Tumors.
These tumors are composed of differentiated connective tissues of the body - fibrous
tissue, cartilage, bone, muscle, fatty tissue. They all tend to be rounded or lobulated, wellencapsulated and merely compress the surrounding tissues.
Tumors of Fibrous Tissue.
So-called FIBROMAS are extremely rare in soft tissues. They occur in the ovary and
kidney, in the skin, uterine and other organs. Fibroma looks like a node of a well-differentiated
connective tissue, the bands of fibers lay in different directions, the vessels are distributed
irregular. There are two types of fibroma. There are soft and hard fibromas.
Neurofibroma and Schwannoma.
These are derived from the connective tissues of the peripheral nerves. They may be
single or multiple and cause compression effects.
DESMOID is a variety of fibroma. It often locates in the front of the abdominal wall. Desmoid
has a structure of hard fibroma, but sometimes it may grow by invasive type. After resection this
tumor may grow again. Desmoid takes place more often in female than male. The growth of
tumor may be more rapid in pregnancy.
LIPOMA. Circumscribed masses of fat cells are commonly found in the subcutaneous tissue of
the arms, shoulders and buttocks. They may also be found in the peritoneal cavity in relation to
the kidney, omentum or mesentery, but very rarely in solid organs. Lipoma may be single or
multiple. This tumor looks like a node. Sometimes lipomas may have projections into the
surrounding tissues which make complete removal difficult. The node of lipoma may be painful
(Dercum's disease).
CHONDROMA. Two types are sometimes described:
1. Solitary enchondroma. This type is found in the tubular bones of the hands and feet
and also in the long bones. It is formed in the substance or at the surface of the bone and
destruction of the bone by expansion and pressure. Growth occurs by the proliferation and
metaplastic transformation of the capsular fibrocytes.
2. Multiple enchondromatosis. These are cartilaginous masses which appear in children,
in hands and feet but also important in the long bones where deformities may result. They
usually cease to grow when adulthood is reached and ossify or regress; therefore they are
probably in the nature of developmental abnormalities rather than true neoplasms. Occasionally
they may continue to grow, and may even become malignant.
OSTEOMA. As with chondromas, two types are described:
3. Ivory osteoma. This is a true tumor and is mainly found in
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4. the long bones of the scull, although it may occur in the long bones. Osteomas are
usually relatively small but may produce severe symptoms because of their situation. (Osteoma
on floor of orbit causing protrusion of eyeball)
5. Cancellous bony growths. They are found at the end of long and the ossified remains
of cartilaginous exostoses. They are formed developmentally displacing epiphyseal of cartilage.
Growth continues until epiphyses unite. A cap of cartilage covers the mass and growth takes
place by proliferation of the cartilage and transformation into bone.
LEIOMYOMA. Simple tumors of muscle are derived from smooth muscle, and the majority
occur in the uterus where they are extremely common. They are firm, rounded masses which
usually begin in the myometrium. Subsequently, they may move inward to the uterine cavity
forming polyps, or towards the serous surface.
RHUBDOMYOMA is composed of large cells that have abundant cytoplasm. These cells
resemble striated muscle cells. The tumors are most frequently primary tumor of the heart in
infants and children and are frequently discovered in the first years of life because it leads to
obstruction of valve orifice or cardiac chamber.
Malignant Connective Tissue Tumors.
Sarcomas are less common than carcinomas. Next to leukemia, they are the most
common malignant rumors in children and young adults. In older age groups, 90 % of malignant
tumors are carcinomas. Sarcomas are large fleshy tumors. Arising from and within connective
tissues means that infiltration between normal cells is not a feature. The malignant cells advance
on a broad front destroying and replacing normal cells. The result is a rounded growth with fairly
definite margins. The neoplastic process is associated with the formation of many large, new,
thin-walled blood vessels.
As a result, hemorrhage and necrosis are frequently in sarcomas. Sarcoma cells, like all
connective tissue cells, are strongly motile. They easily invade the veins and early lung
metastases are common.
LECTURE. THE MOST IMPORTANT HUMAN TUMORS
Here the tumors of lungs, stomach, cervix, uterus and breast will be discussed.
LUNG. A variety of benign and malignant tumors may arise in the lung, but the vast majority
(90 - 95 %) are bronchogenic carcinomas, that in industrial countries are called "public enemy
number one" among all cancers.
There are some factors that play an important role in etiology and pathogenesis of this
tumor: tobacco smoking, industrial hazards (radiation, asbestosis, nickel, etc.), air pollution,
genetic factors, etc. Role of Tobacco Smoking. The evidence provided by statistical and clinical
observations establishing a positive relationship between tobacco smoking and lung cancer is
incontrovertible. Experimental data have also been pursued, but this approach is limited by
species differences.
Role of Industrial Hazards.
Certain industrial exposures increase the risk of developing lung cancer. All types of
radiation may be cancerogenic. The risk of cancer is increased with asbestos. Among asbestos
workers, one death in five is due to bronchogenic carcinoma, one in ten to pleural or peritoneal
mesotheliomas, and one in ten to gastrointestinal carcinomas.
There is also an increased risk of respiratory cancer among persons who work with
nickel, chromates, coal, mustard gas, arsenic, beryllium, and iron and in newspaper workers,
African gold miners, and haloether workers.
Role of Air Pollution. Unquestionably, we all "swim" in a sea of carcinogens, and it is
conceivable that atmospheric pollutants may play some role in the increased incidence of
bronchogenic carcinoma today. Recent attention has been drawn to the potential problem of
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its site of origin is usually more rapid than that of other types. Squamous metaplasia, epithelial
dysplasia, and foci of frank carcinoma in situ are sometimes present in bronchial epithelium
adjacent to the tumor mass.
Adenocarcinoma. Histologic classifications of adenocarcinomas include at least two
forms: 1) the usual bronchial-derived adenocarcinoma and 2) a somewhat distinctive type termed
bronchioloalveolar carcinoma, which probably arises from terminal bronchioles or alveolar
walls. There may be overlap between these two forms, but the bronchioloalveolar carcinoma has
sufficiently distinctive gross, microscopic and epidemiologic features.
Adenocarcinoma is the most common type of lung cancer in women and nonsmokers.
The lesions are usually more peripherally located, tend to be smaller, and vary histologically
from well-differentiated tumors with obvious glandular elements to papillary lesions resembling
other papillary carcinomas, to solid masses with only occasional mucin-producing glands and
cells. About 80 % contain mucin. Adenocarcinomas grow more slowly than squamous cell
carcinomas. Peripheral adenocarcinomas are sometimes associated with areas of scarring.
Adenocarcinomas, including bronchioloalveolar carcinomas, are less frequently associated with
a history of smoking than are squamous or small cell carcinomas.
Small Cell Carcinoma. This highly malignant tumor has a distinctive cell type. The
epithelial cells are generally small, have little cytoplasm and are round or oval and, occasionally,
lymphocyte-like (although they are about twice the size of a lymphocyte). This is the classic "oat
cell". Other small cell carcinomas have spindle-shaped or polygonal cells and may be thus
classified (spindle or polygonal small cell carcinoma). The cells grow in clusters that exhibit
neither glandular nor squamous organization.
Electron microscopic studies show dense-core neurosecretory granules in some of these
tumor cells. The granules are similar to those found in the neuroendocrine argentaffln
(Kulchitsky's) cells present along the bronchial epithelium, particularly in the fetus and neonate.
The occurrence of neurosecretory granules, the ability of some of these tumors to secrete
polypeptide hormones, and the presence (ascertained by immunohistochemical stains) of
neuroendocrine markers such as neuron-specific enolase and parathormone-like and other
hormonally active products suggests derivation of this tumor from neuroendocrine cells of the
lining bronchial epithelium.
Small cell carcinomas have a strong relationship to cigarette smoking; only about 1 %
occur in nonsmokers. Most often hilar or central, they are the most aggressive of lung tumors,
metastasize widely, and are virtually incurable by surgical means. They are the most common
pattern associated with ectopic hormone production.
Large Cell Carcinoma. This anaplastic carcinoma has larger, more polygonal cells and
vesicular nuclei. Large cell carcinomas probably represent those squamous cell carcinomas and
adenocarcinomas that are so undifferentiated that they can no longer be recognized. Some of
these large cell carcinomas contain intracellular mucin, some exhibit larger numbers of
multinuclear cells (giant cell carcinoma), some have cleared cells and are termed clear cell
carcinoma, and some have a distinctly spindly histologic appearance (spindle cell carcinoma).
Secondary Pathology. Bronchogenic carcinomas cause related anatomic changes in the lung
substance distal to the point of bronchial involvement. Partial obstruction may cause marked
focal emphysema; total obstruction may lead to atelectasis. The impaired drainage of the airways
is a common cause for severe suppurative or ulcerative bronchitis or bronchiectasis. Pulmonary
abscesses sometimes call attention to a silent carcinoma that has initiated the chronic
suppuration. Compression or invasion of the superior vena cava can cause venous congestion,
dusky head and arm edema, and, ultimately, circulatory compromise, the superior vena cava
syndrome. Extension to the pericardial or pleural sacs may cause pericarditis or pleuritis with
significant effusions.
GASTRIC TUMORS
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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 beneath the mucosa to produce an apparent polypoid lesion. The use of the term
"polyp" in the gastrointestinal tract, however, is generally restricted to mass lesions arising in the
mucosa. Gastric polyps are uncommon and are found in about 0.4 % of adult autopsies and 3 to 5
% of Japanese adults. Although gastric polyps are usually found incidentally, dyspepsia or
anemia resulting from blood loss may prompt the search for a gastrointestinal lesion.
The adenoma of the stomach is a true neoplasm, representing 5 to 10 % of the polypoid
lesions in the stomach. By definition, an adenoma contains proliferative dysplastic epithelium
and thereby has malignant potential. Adenomatous polyps are much more common in the colon.
Gastric adenomas may be sessile (without a stalk) or pedunculated (stalked). The most common
location is the distal portion of the stomach, particularly the antrum. These lesions are usually
single and may grow up to 3 to 4 cm in size before detection. In contrast to the colon,
adenomatous change may carpet a large region of flat gastric mucosa without forming a mass
lesion.
Among the malignant tumors that occur in the stomach, carcinoma is overwhelmingly the
most important and the most common (90 to 95 %). Next in order of frequency are lymphomas
(4 %), carcinoids (3 %), and malignant spindle cell tumors (2 %).
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 22 %. Thus a favored
location is the lesser curvature of the antropyloric region. Although less frequent, an ulceratlve
lesion on the greater curvature is more likely to be malignant.
Gastric carcinoma is classified basing on: 1) depth of invasion, 2) macroscopic growth
pattern, and 3) histologic subtype. The morphologic feature having the greatest impact on
clinical outcome is the depth of invasion. Early gastric carcinoma is denned 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. All cancers presumably begin as
"early" lesions, which precede the development of "advanced" lesions.
The three macroscopic growth patterns of gastric carcinoma, which may be evident at
both the early and the advanced stages, are 1) exophytic, with protrusion of a tumor mass into the
lumen, 2) flat or depressed, in which no tumor mass is visibly obvious, and 3) excavated, when a
shallow or deeply erosive crater is present. Excavated cancers may closely mimic, in size and
appearance, chronic peptic ulcers. In advanced cases, cancerous craters can be identified by their
heaped-up, beaded margins and shaggy, necrotic bases as well as the overt neoplastic tissue
extending into the surrounding mucosa and wall. Uncommonly a broad region of the gastric wall
or the entire stomach is extensively infiltrated by malignancy, creating a rigid, thickened "leather
bottle", termed linitis plastica. Metastatic carcinoma, from the breast and lung, may generate a
similar picture.
The histologic subtypes of gastric cancer have been variously subclassified, but the two
most important types, as noted earlier, are the intestinal type and diffuse type. The intestinal
variant is composed of neoplastic intestinal glands resembling those of colonic adenocarcinoma,
which permeate the gastric wall but tend to grow along broad cohesive fronts in the "expanding"
growth pattern. The neoplastic cells often contain apical mucin vacuoles, and abundant mucin
may be present in gland: lumina. The diffuse variant is composed of gastric-type mucous cells,
which generally do not form glands but rather permeate the mucosa and wall as scattered
individual cells or small clusters in an "infiltrative" growth pattern. In this variant, mucin
formation expands the malignant cells and pushes the nucleus to the periphery, creating a
"signet-ring" conformation. Regardless of cell type, the amount of mucin formation varies and in
poorly differentiated portions of the tumor may be absent. Conversely, excessive mucin
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production may generate large mucinous lakes that dissect tissue planes; isolated tumor cells or
glands may be difficult to identify in such areas. Infiltrative tumors often evoke a strong mural
desmoplastic reaction, in which the malignant cells are embedded; the ensuing fibrosis creates
local rigidity of the wall, which provides a valuable clue to the presence of an infiltrative lesion.
Whatever the variant is, all gastric carcinomas eventually penetrate the wall to involve
the serosa and spread to regional and more distant lymph nodes. For obscure reasons, gastric
carcinomas may metastasize to the supraclavicular sentinel (Virchow's) node as the first clinical
manifestation of an occult neoplasm. Local invasion into the duodenum, pancreas, and
retroperitoneum is characteristic. At the time of death, widespread peritoneal seedings and
metastases to the liver and lungs are common. A notable site of visceral metastasis is to one or
both ovaries. Although uncommon, metastatic adenocarcinoma to the ovaries (from stomach,
breast, pancreas, and even gallbladder) is so distinctive as to be called Krukenberg tumor.
BREAST
A great variety of tumors may occur in the female breast. Only the more common tumors
specialized to the breast will be discussed.
The most common benign tumor of the female breast is fibrosarcoma - a new growth
composed of both fibrinous and glandular tissue. Occurring at any age within the reproductive
period of life, it is somewhat more common by the age of 30. Multiple small areas closely
resembling a fibroadenoma are sometimes found in cases of cystic disease, termed
fibroadenomatosis.
MORPHOLOGY. The fibroadenoma grows as a spherical nodule that is usually sharply
circumscribed and freely movable from surrounding breast tissue. They vary in size from under 1
cm to giant forms 10 to 15 cm in diameter.
The histologic pattern is essentially one of delicate, cellular, fibroblastic stroma resembling
intralobular stroma, enclosing glandular and cystic spaces lined by epithelium. Intact, round-tooval gland spaces may be present, lined by single or multiple layers of cells. In other areas the
connective tissue stroma appears to have undergone more active proliferation with compression
of the gland spaces.
CARCINOMA. Breast cancer causes some 20 % of cancer deaths among females and has been
called the "foremost cancer" in women. The incidence has been increasing steadily over the past
80 years so that currently one of every nine women in the U.S. will develop cancer in their
lifetime.
Classification and distribution. Among breast carcinomas small enough for their general
areas of origin to be identified approximately 50 % arise in the upper quadrant; 10 % in each of
remaining quadrants; and about 20 % in the central or subareolar region. The WHO classification
of this tumor is as follows:
A) Noninvasive (inrtaductal carcinoma, intraductal carcinoma with Paget's disease;
lobular carcinoma in situ);
B) Invasive (infiltrating) - invasive ductal carcinoma; invasive ductal carcinoma with
Paget's disease; invasive lobular carcinoma; tubular carcinoma; adenoid cystic carcinoma;
apocrine carcinoma; invasive papillary carcinoma.
Only the more common types will be discussed.
Noninvasive (in situ) carcinoma - intraductal carcinoma is defined as a malignant
population of cells that lack the capacity to invade through the basement membrane and
therefore are incapable of distant metastasis. But these cells can spread throughout a ductal
system and produce extensive lesions involving an entire sector of a breast. Movement of these
cells up the main duct and into the nipple skin results in the clinical appearance of Paget's disease
of the nipple.
Paget's disease is a form of ductal carcinoma, that arises in the main excretory ducts of
the breast and extends intraepithelially to involve the skin of the nipple and areola. The skin
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lesions are invariably associated with an underlying ductal carcinoma in situ, or less common by
invasive ductal carcinoma, arising deeper within the breast. The histologic hallmark of this entity
is the involvement of the epidermis by malignant cells. That's why the skin of the nipple and
areola is frequently fissured, ulcerated and oozing with surrounding inflammatory hyperemia and
edema. The prognosis is dependent on the underlying carcinoma.
There are some types of invasive (infiltrating) carcinoma of the breast: invasive ductal
carcinoma, medullary carcinoma, colloid or mucinous carcinoma, invasive lobular carcinoma.
Features common to all invasive cancers: as focal lesions, they extend progressively in all
directions. In the course of time, they may become adherent to the deep fascia of the chest wall
and thus become fixed in position. When the tumor involves the main excretory ducts,
particularly in the intraduct variety, retraction of the nipple may develop. Spread of the tumor
eventually occurs through the lymphohematogenous routes. The pattern of nodal spread is
heavily influenced by the location of the cancer in the breast. Distant metastases via the
bloodstream may affect virtually any organ of the body.
CERVIX - is both a sentinel for potentially serious upper genital tract infections and a target for
viral or chemical cancerogens, which may lead to invasive carcinoma. Squamous cell carcinoma
may occur in any age from the second decade of life to senility.
MORPHOLOGY. Invasive cervical carcinoma manifests in three somewhat distinctive
patterns: fungating (or exophytic), ulcerating, and infiltrative cancer. Histologically, about 95 %
of squamous cell carcinomas are composed of relatively large cells either keratinizing (welldifferentiated) or non-keratinizing (moderately differentiated) patterns.
Cervical cancer is staged as follows: Stage O. Carcinoma in situ. Stage 1. Carcinoma confined to
the cervix:
1A. Preclinical carcinoma diagnosed only microscopically but showing. Stage 2.
Carcinoma extends beyond the cervix but not onto the pelvic wall. Carcinoma involves the
vagina, but not to the lower third. Stage 3. Carcinoma has extended onto the pelvic wall. The
tumor involves the lower third of the vagina. Stage 4. Carcinoma has extended beyond the true
pelvis or has involved the mucosa of the bladder or rectum. This stage obviously includes those
with metastatic dissemination. Ten to twenty-five per cent of cervical carcinoma constitute
adenocarcinoma, adenosquamous carcinoma and undifferentiated carcinoma.
With current methods of treatment, there is 5 year survival rate about 80 to 90 % with
stage 1, 75 % with stage 2, 35 % with stage 3 and 10 to 15 % with stage 4 disease.
BODY OF UTERUS AND ENDOMETRIUM
The uterine corpus including its endometrium and myometrium is affected by a great
variety of neoplastic growth. These can be benign or malignant and can arise from 1) the
endometrium glands (endometrial polyps and endometrial carcinomas), 2) the endometrial
stroma (stromal nodule and stromal sarcoma), 3) mixed mesodermal tumors or 4) the smooth
muscle of the myometrium (leiomyoma, leiomyosarcoma). The most common of these tumors
are the endometrial polyps, leiomyomas, and endometrial carcinomas.
Endomterial polyps are sessile masses of variable size that project into the endometrial
cavity. They may be single or multiple, asymptomatic or may cause abnormal bleeding if they
ulcerate or undergo necrosis. Histologically, they are generally of two types, made up of 1)
functional endometrium or 2) more commonly hyperplastic endometrium, mostly of the cystic
variety. Rarely, adenocarcinomas may arise within endometrial polyps.
Leiomyomas are the most common tumors in women and are referred to in colloquial
usage as "fibrosis". These tumors are found in at least 25 % of women in active reproductive life
and are estrogen responsive.
MORPHOLOGY. Leiomyomas are sharply circumscribed, discrete, round, firm, graywhite tumors varying in size from small to the massive tumors that fill the pelvis. They can occur
within the myometrium (intramural), just beneath the endometrium (submucosal) or beneath the
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serosa (subserosal).
Histologically, the leiomyoma is composed of whorled bundles of smooth muscle cells
that resemble the architecture of the involved myometrium. Mitotic figures are scarce. Benign
variants of leiomyoma include atypical bizarre (symplastic) tumors with nuclear atypia and giant
cells and cellular leiomyomas.
CARCINOMA of endometrium is the most common invasive cancer of the female genital tract.
It is uncommon in women younger than 40 years of age. The peak incidence is in 55 to 65-yearold women. In terms of potential pathogenesis, two general groups of endometrium cancer can
be identified. The first and the most well-studied develops on a background of prolonged
estrogen stimulation and endometrial hyperplasia.
MORPHOLOGY. Grossly, endometrial carcinoma presents as a localized polypoid tumor
or as a diffuse tumor involving the entire endometrial surface. Eventually dissemination to the
regional lymph nodes occurs, and in the late stages, the tumor may be hematogenously borne to
the lungs, bones and other organs.
Histologically, most endometrial carcinomas are adenocarcinomas characterized by more or less
well-differentiated gland patterns lined by malignant stratified columnar epithelial cells. The
more well-differentiated tumors tend to be those of endometrial differentiation. Two to twenty
per cent of endometrial carcinomas contain foci of squamous differentiation. Squamous elements
most commonly are histologically benign in appearance (called adenocarcinoma with squamous
metaplasia or more traditionally, adenoacantoma) when associated with well-differentiated
adenocarcinomas.
Although classification as a poorly differentiated adenocarcinoma typically requires less
of glandular differentiation and the presence of solid growth, two histologic patterns behave as
poorly differentiated regardless of their degree of differentiation and include papillary serous
carcinoma of clear cell carcinoma.
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