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					                                  LECTURE. NEOPLASIA
        I. Definitions and nomenclature.
       Neoplasia is the autonomous proliferation of cells without response to the
normal control mechanisms governing their growth. As used by investigators,
clinicians, and the laity alike, neoplasia is often equated with cancer. However,
neoplasia may be benign or malignant.
       Neoplasia literally means "new growth" and the new growth is a
"neoplasm". The term "tumor" is, literally, any swelling, including an
inflammatory mass (e.g., an abscess), but the term has become a synonym for
neoplasm, to the point of being equated often with the term/
        Now oncology is the study of rumors or neoplasm. At the same time cancer is the
common term for all malignant tumors.
But what does" neoplasm" mean?
        "A neoplasm is an abnormal mass of tissue, the growth of which exceeds and is
uncontrolled with the normal tissue and persists in the same excessive manner after cessation of
the stimuli which evoked the change".
       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
    tissue mass. Cellular proliferation is controlled.
  2.Hyperplasia is an increase in the number of cells, causing a corresponding increase in tissue
    mass.
  3.Metaplasia is the replacement of one adult tissue type by another; usually the replacement
    (i.e., the metaplastic tissue) is simpler in form.
  4.Dysplasia literally means any abnormal growth. However, the term has come to have several
    more restricted meanings.
    a. It is applied to certain congenital defects such as dysplastic (malformed) kidneys.
    b. More commonly, however, dysplasia connotes cytologic abnormalities that are believed to be
       precursors of malignant neoplastic changes. These include disorderly architectural changes
       and pleomorphism (a multiplicity of sizes and shapes); frequent mitoses, often in odd
       locations; and unusually large, hyperchromatic (deeply staining) nuclei.
  5. Anaplasia is a loss of the cell's normal morphologic and functional characteristics. In practice,
     anaplasia is equated with malignancy (i.e., with cancer).
     a. Anaplastic cells resemble more primitive cells of similar tissue. The more primitive
        (embryonic) the cells appear, the more anaplastic they are said to be.
     b. Anaplasia literally means "backward formation." However, the anaplastic process is a failure
        to develop into a differentiated cell, and not a progressive loss, or dedifferentiation, of cellular
        specialization. Hence the earlier concept of malignancy as being due to dedifferentiation has
        been abandoned.

       All tumors have two basic components: proliferating neoplasmic cells that constitute their
parenchyma and supportive stroma made up of connective tissue and blood vessels. The
nomenclature of tumors is based on the parenchymal component.
       Types of tumor growth are the following:
       - expansive - the tumor grows "from its own" moving aside the surrounding tissues;

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       - appositional - the growth at the expense of neoplastic transformation of normal cells in
the tumor cells;
       - infiltrative (invasive) -- tumor cells grow into surrounding tissues and destroy them;
       - endophytic - infiltrative growth; tumor penetrates deep into the wall of the hollow
organ;
       - exophytic - expansive growth into the cavity of the hollow organ;
       -unicentric - the growth of the tumor from one focus;
       -multicentric - the growth of the tumor from plural foci;
       -systemic growth is typical for tumors of the blood.
       There are two principle types of tumors: benign and malignant.
                                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               BENIGN TUMORS                      MALIGNANT TUMORS
           Epithelial
           tissues:
           Stratified           Papilloma                          Squamous cell carcinoma
           Simple         and   Adenoma                            Adenocarcinoma
           glandular
           Tissues
           mesenchymal (or
           mesodermal) in
           origin:
           Fibrous              Fibroma                            Fibrosarcoma
           connective tissue
           Vascular tissue      Hemagioma                          Hemagiosarcoma
           Adipose tissue       Lipoma                             Liposarcoma
           Smooth muscular      Leiomyoma                          Leiomyosarcoma
           tissue
           Skeletal striated    Rhabdomyoma                        Rhabdomyosarcoma
           muscular tissue
           Cartilage            Chondroma                          Chondrosarcoma
           Bone                 Osteoma                            Osteosarcoma
           Hemopoietic                                             Leukemia
           tissue
           Lymphoid tissue                                         Lymphoma



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           TISSUE             BENIGN TUMORS                          MALIGNANT TUMORS
           Tissues neural in
           origin:
           Neural tissue of Glyomas             (biologically        Glyoblastoma
           CNS                malignant):                            Medullablastoma
                                 Astrocytoma
                                 Oligodendroglyoma
           Neural tissue of Neurilemmoma                             Malignant neurilemmoma
           PNS
           Melaninproducing                                          Melanoma
           tissue
           Different tissues:
           Epithelial     and Fibroadenoma                           Malignant fibroadenoma
           connective         (mixed tumor)                          (mixed tumor)
           tissues
           Different    germ Teratoma                                Malignant teratoma
           layers



        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.

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         (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,
            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
           inheritance. For example, in families affected with xeroderma pigmentosum, familial
           polyposis of the colon, or multiple endocrine neoplasia syndromes, neoplasms are
           common, multiple, and often found at an early age.
        (2)Children with primary immunodeficiency disorders have an extremely high rate of
           lymphoid malignancies.
        (3)Persons with Down's syndrome (which affects chromosome 21) have an incidence of
           acute leukemia that is 4 to 30 times higher than in the normal population.
        (4)Translocation of chromosomes 8 and 14 is associated with Burkitt's lymphoma.
II. MECHANISMS OF CARCINOGENESIS. A variable number of steps occur during the
  change from the normal to the fully malignant cell. The first step apparently occurs in a single
  cell (i.e., cancer is a monoclonal disease). The change (mutation) in the first neoplastic cell is a
  random process. Any given etiologic factor simply increases the probability that any particular
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 cell will be transformed, but how this is done is still not known.
 A.Role of genetic instability
   1. Role in initial transformation
      a. Because of genetic instability (apparently greater in the neoplastic state), mutant cells are
         produced. Some of these are destroyed by either metabolic disadvantage or immune
         mechanisms, but an occasional cell will express a selective advantage over the original
         neoplastic cells and will give rise to the predominant subpopulation.
      b. In time, this selection process leads to increasingly abnormal cells with the acquired
         properties of the fully developed cancer.
   2. Subsequent role
      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
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     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
        virus—in the form of DNA nucleotide sequences—into 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.
        (1)Some retroviruses contain one or more nucleotide sequences capable of inducing
           malignant transformation. These sequences are called viral oncogenes (v-oncs). Several v-
           oncs 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 (c-
           oncs), 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 v-oncs,
       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 change from normality to malignancy is associated with increasing inflexibility of
    enzyme patterns. The reasons for this are unknown but may be related to the fact that
    malignant cells often have many more free ribosomes than normal cells.

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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.
   A.Components. All neoplasms have a parenchyma and a stroma.
     1.The parenchyma comprises the neoplastic proliferating cells. Parenchymal morphology
       underlies the name assigned to a neoplasm, and parenchymal behavior determines whether a
       neoplasm is benign or malignant.
     2.The stroma comprises the supporting connective tissue and blood supply that allows the
       neoplasm to grow.
   B. Clonality. In theory, a neoplasm represents the progeny of one cell, a clone, and in many
      neoplasms all cells show the same abnormal karyotype. Even when several chromosome
      patterns are present, marker chromosomes in each cell suggest that the different
      subpopulations derive from a common stemline. The following are examples.
      1.Immunoglobulins from a myeloma (a plasma cell neoplasm) display a homogeneity that is
        characteristic of a single clone.
      2.Human females have two types of cells: In one, the active X chromosome is maternally
        derived; in the other, it is paternally derived. If a woman who is heterozygous for an X-
        linked gene should develop cancer, all the cancer cells will be homozygous for that gene,
        strongly suggesting descent from a common precursor.
   C.Autonomy. Neoplastic cells exhibit uncontrolled proliferation; that is, they are autonomous.
     1.Normally, inhibitory influences control cell growth and proliferation; this accounts for the
       stoppage of cell movement that occurs when two cells growing in tissue culture collide.
       Neoplastic cells, in contrast, tend to grow over one another.
     2.The property of autonomy is probably related to the fact that neoplastic cells show changes
       in morphology and membrane composition and, hence, in receptor sites.
   D. Blood supply. Solid neoplastic growth requires the development of a blood supply to the
     neoplasm; that is, neovascularization. Without such a blood supply, solid neoplasms cannot
     grow beyond 2 to 3 mm in diameter.
     1.Various experiments have shown that neovascularization does not require direct cell-to-
       cell contact either between neoplastic cells or between these cells and endothelial cells in
       blood vessels near the lesion.
     2.A protein called tumor angiogenesis factor that stimulates endothelial cell mitosis and new
       vessel growth has been discovered.
   E. Metastasis. The major characteristic of cancer is the capacity to metastasize.
      1.As the neoplastic clone undergoes mutation, the more aggressive subpopulations selected
        tend to be those with metastasizing potential.
      2.Not only can such subpopulations travel, via the bloodstream or lymphatics, away from the
        initial focus of cancer, but they can also transfer to organs other than those of their origin
        (e.g., liver or lung). Reasons for this ability remain unknown. However, such cell groups
        must attain the capacity to blind the body's defense mechanisms in addition to having the
        ability to penetrate lymphatic and vascular channels.
      3.Each neoplasm tends to have certain sites of predilection for metastasis.
        a. Some of these patterns are determined by purely anatomic considerations; for example,

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            the lung capillary bed is the first vascular sieve that "catches" intravenous tumor cells.
         b. However, some patterns of tumor metastasis are explained only on the basis of more
            favorable sites for that particular neoplasm.
      4. The biochemical basis of invasion and metastasis has several factors.
         a. Cells of a malignant neoplasm are less tightly adherent than are normal cells.
            (1)The calcium content in the malignant cell wall is lower than that in normal cells.
            (2)The negative surface charge of malignant cells tends to be high, and the cells tend to
               repel one another.
         b. Some neoplasms have been shown to produce hyaluronidase, which may facilitate
            invasion through tissue ground substance.

       The differences between benign and malignant tumors can be discussed
under the following headings:
       - differentiation and anaplasia,
       - rate of growth,
       - local invasion (throw basement membrane, into blood or lymph vessels and
into the capsule);
       - metastasis.
       Differentiation and anaplasia. The terms "differentiation" and "anaplasia" apply to
the parenchyma cells of neoplasms. Differentiation refers to the extent to which parenchymal
cells resemble comparable cells, both morphologically and functionally. Well-differentiated
tumors are thus composed of the cells resembling the nature normal cells of the tissue of origin
of the neoplasm. Poorly differentiated or undifferentiated tumors have primitive applying,
unspecialized cells. In general, malignant neoplasms range from well-differentiated to
undifferentiated. In contrast, benign tumors are well-differentiated.
        Lack of differentiation, or anaplasia, is marked by a number of morphologic and
functional changes. Both the cells and nuclei characteristically display pleomorphism - variation
in size and shape. Cells may be found that are many times larger than their neighbors, and other
cells may be extremely small and primitive appearing. Characteristically the nuclei contain an
abundance of DNA and are extremely dark staining - hyperchromatic. Besides, the nuclear-
cytoplasmic ratio may approach 1:1 instead of the normal 1:4 or 1:6.
        Rate of growth. Undifferentiated tumors usually possess large number of mitosis, but
it should be noted, however, that the presence of mitosis does not necessarily indicate that a
tumor is malignant or that the tissue is neoplasmic. More important as a morphologic feature of
malignant neoplasia are atypical mitotic figures sometimes producing tripolar, quadripolar or
multipolar spindles. Another feature of anaplasia is the formation of tumor giant cells, some
possessing only a single huge polymorphic nucleus, when others have two or more nuclei. And
what is more, orientation of anaplastic cells is markedly disturbed. Sheets or large masses of
tumor cells grow in an anarchic, disorganized fashion.
        Before we leave the subject of differentiation and anaplasia we should discuss dysplasia,
a term used to describe disorderly, but non-neoplastic proliferation. Displasia is encountered
principally in the epithelia. It is a loss in the uniformity of the individual cells as well as a loss of
their architectural orientation. Dysplastic cells exhibit considerable pleomorphism and often
possess deeply stained nuclei, which are abnormally large size for the size of the cell. Mitotic
figures are more abundant than usual. Frequently the mitoses appear in abnormal locations
within the epithelium. Thus in dysplastic stratified squamous epithelium mitoses are not confined
to the basal layers and may appear at all levels and even in surface cells. When dysplastic
changes are marked and involve the entire thickness of the epithelium, the lesions are considered
a preinvasive neoplasm and are referred to as carcinoma in situ. But dysplasia does not
necessarily progress to cancer.
        The generalization can be made that most benign tumors grow slowly over period of
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years, whereas most cancers grow rapidly, sometimes at an erratic pace, and eventually spread
and kill their hosts.
        In general, once again, the growth rate of tumors correlates with their level of
differentiation, and thus most malignant tumors grow more rapidly than benign lesions do.
        But the rate of growth of benign as well as malignant neoplasms may not be constant
over time. Factors such as hormone dependence, adequacy of blood supply and likely unknown
influences may affect their growth. Nearly all benign tumors grow as cohesive expansive masses
that remain localized to their site of origin and do not have capacity to infiltrate, invade or
metastasize to distant sites as malignant tumors do. Sometimes the benign tumors are able to
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.
       Dissemination of cancers may occur through one of four pathways:
       - direct seeding of body cavities or surfaces,
       - lymphatic spread,
       - hematogenous spread and
       - mixed pathway.
         1. Seeding of the body cavities and surfaces may occur whenever a malignant neoplasm
penetrates into a natural "open field". Most often involved in the peritoneal cavity, but any other
cavity -pleural, pericardial, subarachnoid, and joint spaces -may be affected.
         2. Lymphatic spread. Transport through lymphatics is the most common pathway for the
initial dissemination of carcinomas. In many cases, the regional nodes serve as an effective
barriers to the further dissemination of the tumor, at least for a time. The cells after arrest within
the lymphatic nodes may be destroyed. A tumor specific immune response may participate in
this cell destruction. Drainage of tumor cells debris or tumor antigens, or both, also induces
reactive changes within nodes. So enlargement of nodes may be caused by 1) the spread and
growth of cancer, 2) reactive hyperplasia.
         3. Hematogenous spread. This pathway is typical for sarcomas but is also used by
carcinomas. Arteries with their thicker walls, are less readily penetrated than veins are. The liver
and lungs are most frequently involved secondary in venous invasion or in this kind of
hematogenous dissemination.
  IV. IMMUNE HOST RESPONSES TO MALIGNANT NEOPLASMS. At least in animal
      studies, autoimmune reactions to cancer cells are common. However, the ability of cancer cells
      to stimulate the immune mechanism in humans is usually quite small and is probably
      inconsequential as a defense mechanism.
    A.Tumor antigens
      1.Some antigens on the surface of cancer cells are much the same as those on normal cells
        (e.g., organ-specific antigens and histocompatibility antigens).
      2.Most cancer cells also appear to possess antigenic specificities that are nonexistent in normal
        cells. Some of these, such as carcinoembryonic antigen (CEA) and alpha-fetoprotein, may
        result from derepression of parts of the genome that normally function only in embryonic
        life.

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      3.In 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 tumor-
        associated transplantation antigens (TSTA or TATA), depending on whether they are found
        only on tumor cells or also on normal cells.
   B. Cellular and humoral defenses
      1. Because immunodeficient persons are prone to develop malignancies, a normal immuno-
        logic defense system against malignancy would seem likely. In vitro and animal studies
        have produced the following data in support of this assumption.
        a. Cells that seem to destroy tumor cells include:
           (1)Cytotoxic T cells that become sensitized by specific tumor antigens
           (2)Killer (K) cells that also recognize specific antigens
           (3)Natural killer (NK) cells that are not specifically sensitized
           (4)Macrophages, some activated by gamma-interferon, and some nonspecifically
              activated
        b. Immunoglobulins aroused by tumor antigens seem to aid in tumor destruction by:
           (1)Activating complement
           (2)Coating tumor cells and thereby enhancing their destruction by NK cells and
              macrophages
     2. Several findings argue against the concept of immunosurveillance against tumors.
       a. The malignancies found in immunodeficient persons are mostly lymphomas, not the
          common epithelial cancers with high incidence rates.
       b. Immunologic mechanisms can also promote tumor growth, as well as fight it, through the
          actions of suppressor T cells and of unidentified humoral blocking factors, which appear
          to act via antigen-antibody complexes.
   C. The possibility of immunotherapy
     1.Although immunologic surveillance may be weak to the point of nonexistent,
       immunotherapy for cancer may become possible, especially in certain tumors with strong in
       vitro evidence of an immune response to tumor cells.
     2.Since most and perhaps all tumors probably have TSTAs, it may be possible to activate the
       important immune defense mechanism to greater effectiveness. Clinical trials have been
       started with interferon and with interleukin 2, which both activate NK cells, and with NK
       cells themselves.
V. THE DIAGNOSIS OF CANCER. Many of the techniques being used in the diagnosis of
  malignant neoplasms are described in Chapter 2.
  A. Identification of malignancy. Once a lesion has been identified as neoplastic, a prime duty of
    the pathologist is to determine whether the neoplasm is benign or malignant.
    1. The gross appearance of a lesion may be suggestive of the degree of malignancy.
       a. Benign lesions usually tend to grow by expansion, compress surrounding structures, and
          often produce a well-defined capsule.
       b. Malignant lesions, in contrast, tend to infiltrate the surrounding tissues so that the
          borders of the lesions are not discrete, and no capsule is formed.
    2. The histologic appearance is of major diagnostic importance.
       a. The edges of malignant lesions are usually poorly demarcated, and individual neoplastic
          cells infiltrate the surrounding normal tissue.
   b. There is invasion into lymphatic channels and blood vessels.
   c. Anaplasia, or the lack of differentiation, is a major indicator of malignancy.
      (1)In principle, the prime feature of neoplastic progression to malignancy is the stepwise
         loss of characteristics of the tissue of origin. Clinicopathologic studies have shown that
         in many types of cancer the better the differentiation, the better the prognosis.

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      (2)In practice, malignant neoplasms range in histologic appearance from well differentiated to
         markedly anaplastic. Whereas a well-differentiated appearance may be seen in either a
         benign or a malignant neoplasm, anaplasia usually signifies malignancy.
      (3)The following are features of anaplasia.

         (a) Cells tend to be pleomorphic, that is, to vary in size and shape. Giant cells are
             common.
         (b)Cell nuclei also tend to be large, so that the nucleancytoplasmic ratio is higher than
             normal. Multiple and prominent nucleoli may be present, and chromatin clumping is
             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

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      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.
VI. CLINICAL ASPECTS
  A. Both benign and malignant neoplasms can produce the following manifestations.
   1.They can be asymptomatic and be noticed incidentally at physical examination, at unrelated
      surgery, or at autopsy.
   2.They can produce a lump.
   3.They can cause obstruction. A benign tumor, such as a leiomyoma of the small bowel, just
      like a malignant lymphoma of the small intestine, can occupy the lumen and obstruct it.
   4.They 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.
 B. Problems more likely to occur with malignancies include the following.
  1. Anemia
     a. As a consequence of chronic low-grade blood loss (usually associated with gastrointestinal
        or genitourinary neoplasms), an iron deficiency anemia may be responsible for the initial
        symptoms (weakness and fatigue) of a cancer.
     b. Anemia also may result from poor nutrition, especially in oral and esophageal cancers, or
        from metastatic replacement of the red cell-producing bone marrow.
  2. Malnutrition
     a. This is most often noted in patients who have cancer of the head and neck or the upper
        gastrointestinal tract. However, many other cancer patients also exhibit poor nutrition.
     b. Sometimes malnutrition is associated with the gastric distress, nausea, and vomiting
        resulting from radiotherapy and chemotherapy.
     c. Carcinomas also may produce substances that interfere with intestinal absorption or produce
        anorexia. Although poorly characterized, such substances are strongly suspected to exist.
  3.Loss of function can result from the mass effect of a cancer or from the replacement of
    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

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          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).
   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 total mature granulocyte counts are found in patients with acute
         leukemia or with other neoplasms involving the bone marrow and also often
         follow intensive chemotherapy. Neutrophil function, as well as total count, is
         critical, since immature granulocytes phagocytize and kill bacteria less
         efficiently than mature leukocytes. Quantitative and qualitative abnormalities
         of neutrophil function include defects in chemotaxis, phagocytosis, and
         bactericidal capacity.
      (b)Patients with lymphoid malignancies (especially Hodgkin's disease) have
         alterations of cell-mediated immunity.

     (3)Cytotoxic chemotherapy has significant adverse effects on both B- and T-cell
     functions, resulting in diminished opsonization, inadequate lysis of bacteria, and
     defective neutralization of bacterial toxins.
     (4)Integumentary and mucosal barriers can be disrupted by a tumor or by its
     treatment (surgery, radiation), providing a nidus for microbial colonization and a
     portal for invasion. Breakdown of mucous membranes may lead to sepsis from
     normal bowel flora.
  c. Malnutrition promotes infection by contributing to the loss of integrity of the skin
     and mucosal barriers, impairing phagocytosis, and depressing lymphocyte function.
  d. Microbial flora. Some 80% of infections that occur in cancer patients arise from
     endogenous flora. The flora can be altered by antibiotic and cancer chemotherapy
     agents; when such microbial changes occur in conjunction with other host
     defects, lifethreatening infection can result.
6. Associated disorders may be of clinical or epidemiologic importance. For example,
  in medullary carcinoma of the thyroid, the finding of multiple nodules of tumor or
  hyperplastic parafollicular cells strongly suggests the presence of multiple endocrine
  neoplasia syndrome; since family members of an affected patient may also be affected,
  they should also be evaluated.




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              LECTURE. EPITHELIAL AND MESENCHYMAL TUMORS

        Epithelial tumors are divided in two groups: benign and malignant.
        Benign neoplasms.
        Adenoma - this is the epithelial tumor forming glandular patterns as well as the tumors
derived from the glands but not necessarily reproducing glandular patterns.
        Benign epithelial neoplasms producing microscopically or macroscopically visible
finger-like or warty projections from the epithelial surfaces are referred to as papillomas.
        Those which form large cystic masses, as in the ovary, are referred to as cystadenomas.
Some rumors produce papillary patterns that protrude into cystic spaces and are called papillary
cystadenoma. When a neoplasm, benign or malignant produces a macroscopically visible
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, well-
encapsulated 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:

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        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
        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.

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        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
"indoor" air pollution.
        Role of Genetic Factors. Occasional familial clustering has suggested a genetic
predisposition to lung cancer, as has the variable risk even among very heavy smokers. However,
attempts at defining markers of genetic susceptibility have proved elusive.

CLASSIFICATION. Numerous histologic classifications of bronchogenic carcinoma have been
proposed, but the currently popular ones, based on classifications of the World Health
Organization, divide these tumors into four major categories: squamous cell carcinoma, and
adenocarcinoma of approximately equal frequency, 25 to 40 % each; small cell carcinoma, 20 to
25 %; and large cell carcinoma, 10 to 15%. There may be mixtures of histologic patterns, even in
the same cancer. Thus combined types of squamous cell carcinoma and adenocarcinoma or of
small cell and squamous cell carcinoma are not infrequent. Another classification in common
clinical use is based on response to available therapies: small cell carcinomas (high initial
response to chemotherapy) versus non-small cell carcinomas (less responsive). The strongest
relationship to smoking is with squamous cell and small cell carcinoma.
From a histogenetic point of view, it seems most likely that all histologic variants of
bronchogenic carcinoma, including small cell carcinoma as well as the bronchial carcinoid are
derived from endoderm or a derivative - a view consistent with the frequency of rumors with
mixed histologic patterns.
        MORPHOLOGY. Bronchogenic carcinomas arise most often in and about the hilus of
the lung. About three-fourths of the lesions take origin from first-, second-, and third-order
bronchi. A small number of primary carcinomas of the lung arise in the periphery of the lung
substance from the alveolar septal cells or terminal bronchioles. These are predominantly
adenocarcinomas, including those of the bronchioloalveolar type, to be discussed separately.
Carcinoma of the lung begins as an area of in situ cytologic atypia that, over an unknown
interval of time, yields a small area of thickening or piling up of bronchial mucosa. With
progression, this small focus, usually less than 1 cm in area, assumes the appearance of an
irregular, warty excrescence that elevates or erodes the lining epithelium. The tumor may then
follow variety of paths. It may continue to fungate in to the bronchial lumen to produce an
intraluminal mass. It can also rapidly penetrate the wall of the bronchus to infiltrate along the
peribronchial tissue into the adjacent region of the carina or mediastinum. In other instances, the
tumor grows along a broad front to produce cauliflower-like intraparenchymal mass that appears
to push lung substance ahead of it. In almost all patterns, the neoplastic tissue is gray-white one,
firm to hard. Especially when the rumors are bulky focal areas of hemorrhage or necrosis may
appear to produce yellow-white mottling and softening. Sometimes these necrotic foci cavitate.
        Extension may occur to the pleural surface and then within the pleural cavity or into the
pericardium. Spread to the tracheal, bronchial, and mediastinal nodes can be found in most cases.
The frequency of nodal involvement varies slightly within the histologic pattern but averages
over 50 %.
        More distant spread of bronchogenic carcinoma occurs through both lymphatic and
hematogenous pathways. These tumors have a distressing habit of spreading widely throughout

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the body and at an early stage in their evolution. Often the metastasis presents as the first
manifestation of the underlying occult bronchogenic lesion. No organ or tissue is spared in the
spread of these lesions, but the adrenals, for obscure reasons, are involved in more than half the
cases. The liver (30 to 50 %), brain (20 %), and bone (20 %) are additional favored sites of
metastases.
         Squamous Cell Carcinoma. This type is most commonly found in men and is closely
correlated with a smoking history. The microscopic features are familiar in the form of
production of keratin and intercellular bridges in the well-differentiated forms, but many less
well-differentiated squamous cell tumors are encountered that begin to merge with the
undifferentiated large cell pattern. This tumor arises in the larger, more central bronchi, tends to
spread locally, and metastasizes somewhat later than the other patterns, but its rate of growth in
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

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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

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.

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        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
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-to-
oval 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

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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
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 (well-
differentiated) 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.

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        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, gray-
white 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
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-year-
old 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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