Neoplasia

Definition

Neoplasia is new, uncontrolled growth; a "tumor" or "mass lesion" is simply a "growth" or "enlargement" which may not be neoplastic (such as a granuloma). The term "cancer" implies malignancy, but neoplasms can be subclassified as either benign or malignant.

Benign Neoplasms

Characteristics include slow growth, resemblance to tissue of origin (well differentiated), circumscription, lack of invasion or metastases.

Usually solitary (e.g., lipoma of colon, meningioma of dura), but may be multiple (e.g., leiomyomata of uterus, intradermal nevi on skin). May cause problems through mass effect, particularly in tight quarters (pituitary adenoma in sella turcica).

A hamartoma is a peculiar benign neoplasm which is a localized but haphazard growth of tissues normally found at a given site (pulmonary hamartoma has jumbled cartilage, bronchial epithelium, and connective tissue)

A choristoma is a benign neoplasm consisting of tissue that is not normal to the site of origin (e.g., salivary gland choristoma of the middle ear).

Malignant Neoplasms

Characteristics include more rapid increase in size, lack of differentiation (anaplasia), and tendency to spread by invasion or metastases.

Cytologic features of malignant neoplasms include:

• increased nuclear size (with increased nuclear/cytoplasmic ratio--N/C ratio).
• variation in nuclear or cell size (pleomorphism).
• lack of differentiation (anaplasia).
• increased nuclear DNA content with subsequent dark staining on H and E slides (hyperchromatism).
• prominent nucleoli within the nuclei.
• mitoses (especially irregular or bizarre mitoses).

All of these features are "atypical". Atypia implies a change for the worse from normal.

Spread of Malignant Neoplasms

• By direct extension (invasion) into surrounding tissues.
• Through lymph channels to lymph nodes (lymphatic spread)--typical of carcinomas.
• Via the bloodstream (hematogenous spread)--typical of carcinomas or sarcomas.
• Within body cavities (seeding)--typical of neoplasms in peritoneal cavity.

The spread of malignant neoplasms determines the stage

• In-situ (refers to epithelial malignancies confined to just the epithelium without going throug the basement membrane).
• Microinvasion (spread of epithelial malignancies just beyond the point of origin through the basement membrane).

• Local invasion (spread within the organ of origin or to contiguous structures).
• Local metastases (non-contiguous spread of the neoplasm within the organ of origin or to the lymph nodes closest to the organ of origin).
• Distant metastases (spread to other organs or to far away lymph nodes)

The indicators that a neoplasm is malignant are:

• Metastases (best indicator) and
• Invasion (next best indicator)

Grading of neoplasms

Based upon: differentiation (the degree to which the neoplasm resembles the tissue of origin) along with the degree of atypia.

• well-differentiated--looks very similar to normal tissue
• moderately differentiated--looks something like normal
• poorly differentiated--hardly looks like normal tissue
• anaplastic--virtually no similarity to normal tissue

Both staging and grading schemes are devised to classify malignant neoplasms for determining appropriate treatment and to try and determine the prognosis. In general, the higher the stage or the higher the grade, the worse the prognosis.

Appearances of Neoplasms

Desmoplasia refers to the proliferation of non-neoplastic connective tissue in association with neoplasia (gives tumors a firm, fibrous, "scirrhous" appearance) and may distort surrounding tissues.

Neoplasms may mimic the tissue of origin, but not always. Larger masses tend to undergo central necrosis. Metastases usually look similar to the primary, but not always.

The primary site is ususally a single large mass in an organ, while multiple masses in an organ usually indicate metastases.

It is not always possible to tell benign from malignant based upon histologic or cytologic criteria alone. The biologic behavior of a neoplasm may not always correlate with the appearance, making choice of treatment more difficult.

Oncogenesis

The process of neoplasia is represented symbolically below:

Nomenclature of Neoplasia

Based upon origin:

• Maligant neoplasms arising from tissue embryologically derived from ectoderm or endoderm are usually carcinomas. Examples include:
• Squamous cell carcinoma of cervix
• Adenocarcinoma of stomach
• Hepatocellular carcinoma
• Renal cell carcinoma
• Malignancies arising from mesoderm are usually sarcomas. Examples include:
• Leiomyosarcoma
• Chondrosarcoma
• Osteosarcoma
• Liposarcoma
• Neoplasms with more than one cell type but arising from only one germ layer are called "mixed tumors". The best example is the benign mixed tumor (also called pleomorphic adenoma) of salivary gland.
• Neoplasms with more than one cell type and arising from more than one germ layer are called teratomas. Such neoplasms are common in the ovary.
• Neoplasms ending in "-blastoma" resemble primitive embryonic tissues. Examples include:
• Retinoblastoma
• Neuroblastoma
• Hepatoblastoma
• Medulloblastoma
• Not all malignant neoplasms have benign counterparts:
• Hematopoietic and lymphoid cells (as in bone marrow and lymph node) give rise to leukemias and lymphomas. They have no benign counterpart.
• Gliomas (astrocytomas, oligodengrogliomas, glioblastoma multiforme, etc) arise from glial cells in the CNS. They have no benign counterpart.

Carcinomas

Arise from epithelial surfaces (in gastrointestinal tract, in respiratory tract, in urogenital tract, in biliary tract, in skin) and in organs with epithelial-lined ducts (breast, pancreas, salivary gland, liver). Endocrine glands, including testis and ovary, may also give rise to carcinomas. In general, carcinomas are composed of polygonal-shaped cells.

• Carcinomas that form glandular configurations are called adenocarcinomas.
• Carcinomas that form solid nests of cells with distinct borders, intercellular bridges, and pink keratinized cytoplasm are called squamous cell carcinomas.

Sarcomas

Arise from soft tissues (connective tissues such as cartilage, bone, or fascia, smooth or skeletal muscle, blood vessels, lymph vessels, coverings of organs such as mesothelium). In general, sarcomas are composed of very pleomorphic spindle-shaped cells. Sarcomas are generally big and bad.

Biology of Neoplasia

This subject attempts to determine what gives rise to neoplasms and what controls their growth.

Causes of Neoplasia

The origin for many neoplasms is obscure. However, there are several theories of origin:

Environmental causes:

• Chemicals that are man-made (such as aniline dyes and bladder cancer), drugs (cigarette smoke and lung cancer), and natural compounds (aflatoxins and liver cancer) which are carcinogenic.
• Oncogenic viruses such as human papillomavirus (HPV) implicated in most squamous cell carcinomas of cervix and anogenital squamous papillomas, Epstein-Barr virus (EBV) implicated in African Burkitt's lymphoma, and hepatitis B virus (HBV) implicated in development of hepatocellular carcinomas.
• Radiation (such as ultraviolet light and skin cancers; gamma radiation and leukemia, thyroid, lung, colon, and breast cancers). Ultraviolet light induces pyrimidine dimers in DNA. Ionizing radiation induces mutations in DNA.

Hereditary causes:

• Chromosomes which have absent or defective anti-oncogenes that control growth (retinoblastoma results from defective chromosome 13)
• Obscure defects: racial predilections (American women have breast cancer more often than Japanese women; Japanese men have stomach cancer far more often than American men).

Age: older persons have a greater propensity to develop neoplasms from lack of effective control mechanisms.

Altered DNA:

• All of the above are probably mediated by the cause, whatever it is, producing a mutation in, or damage to, cell DNA
• There can be mutations involving tumor suppressor genes (such as p53), which then fail to exert a controlling influence upon growth activation. The majority of human neoplasms probably arise via this mechanism.
• In some cases these mutations are probably mediated by proto-oncogenes (genes which control cellular growth) that undergo mutation to oncogenes which give rise to neoplasia. Proto-oncogenes can be activated by point mutations, translocations, and by gene amplification.
  • An example of this is chronic myelogenous leukemia (CML) which is a neoplastic proliferation of white blood cells. All cases of CML have the "Philadelphia chromosome" which is a translocation between chromosomes 9 and 22. This translocation juxtaposes the proto-oncogene ABL with the breakpoint cluster region (BCR) on chromosome 22. The chimeric ABL-BCR gene leads to production of a mutant protein with enhanced tyrosine kinase activity. This protein may play a role in regulation of cell growth in CML.
• About 15 to 20% of human cancers have been linked to oncogenic activity. The ras oncogene is the transforming gene found most frequently in human cancers.
• Oncogenic viruses may bring oncogenes with them, so-called viral oncogenes (typical of RNA containing "retroviruses" such as human T-lymphotropic viruses (HTLV's).
• Growth factors such as epidermal growth factor (EGF), platelet-derived growth factor (PDGF) and colony-stimulating factor-1 (CSF-1) assist oncogene activity. Transforming growth factor (TGF-alpha) also promotes tumor growth.

Tissue evidence of carcinogenic factors at work

• Metaplasia: an initial change from normal cells to a different cell type (such as chronic irritation of cigarette smoke causing ciliated pseudostratified epithelium to be replaced by squamous epithelium more able to withstand the insult).
• Dysplasia: an increasing degree of disordered growth or maturation of the tissue (often thought to precede neoplasia) such as cervical dysplasia as a result of human papillomavirus infection. Dysplasia is still a reversible process. However, once the transformation to neoplasia has been made, the process is not reversible.
• Thus, there is a natural history from metaplasia to dysplasia to neoplasia. This is best evidenced in development of uterine cervix and respiratory tract neoplasms.

Chemical carcinogenesis

There are two steps: initiation and promotion

An initiating carcinogenic agent irreversibly damages cell DNA (it is mutagenic) to start the process. Examples of carcinogenic initiators include: alkylating agents like cyclophosphamide, polycyclic aromatic hydrocarbons like epoxides found in smoked foods, aromatic amines or azo dyes used in food coloring, aflatoxins in moldy peanuts, nitrosamines in pickled foods.

A promoting agent (which may be the same as the carcinogen) then acts (reversibly) to cause proliferation of a neoplastic cell clone, but there appears to be a "dose-threshold" concentration of promoter below which neoplasia will not occur. Examples of promoters include: hormones such as estrogen, drugs such as diethylstibesterol, and chemicals such as cyclamates used as sweeteners.

Cellular Transformation

• Some factor, as discussed above, causes a cell to be transformed to a neoplastic cell that is not controlled by normal body processes. Probably most transformed cells die because they are too abnormal to function or are abnormal enough for the body's immune system to destroy them. However, if the factors promoting neoplasia persist, a transformed cell may some day give rise to a clone that does continue to grow.

• Malignant neoplasms do not tend to arise from benign neoplasms (e.g., malignant melanomas do not come from benign nevi) though in some cases such as adenomas of the colon, the appearance of the benign neoplasm is a step toward possible malignancy.
• There are "pre-cancerous" conditions in which malignant neoplasia is more likely to occur (but not in every case): liver cirrhosis, chronic ulcerative colitis, atrophic gastritis, epidermal actinic keratosis, oral leukoplakia.

Clonality

• Neoplastic cells tend to be monoclonal, or similar in genetic makeup, indicating origin from a transformed cell. Non-neoplastic proliferations (such as reactions to inflammation) have cells that are polyclonal in origin.
• The concept of "tumor progression" holds that subclones may arise over time from the original malignant clone. These subclones may differ from the original clone in characteristics such as invasiveness, metastatic potential, and response to therapy.

Tumor Genetics

Neoplasms have a greater tendency to karyotypic abnormalities such as translocations, deletions, and gene amplifications (which are also activators of proto-oncogenes). Leukemias and lymphomas are famous for this, as with the Philadelphia (Ph1) chromosome of chronic myelogenous leukemia and the t(8:14) translocation in Burkitt's lymphomas.

Tumor growth

• In general, the less differentiated a neoplasm, the faster it grows. The cell cycle of neoplastic cells is not shortened, rather the growth fraction of cells proliferating is increased. This is offset by neoplastic cell death. Tumor growth is expressed as a "doubling time" or the time to increase twice in volume (e.g., from 1 to 1.3 cm diameter). An aggressive malignant neoplasm doubles in 1 to 3 months, while benign neoplasms double in years.
• Some neoplastic growth is influenced by host factors. Estrogenic hormones aid growth of breast fibroadenomas or carcinomas and uterine leiomyomas because the tumor cells have hormone receptors.
• Growth is also dependent upon the ability of the tumor to develop a blood supply. Factors secreted by neoplastic cells promote angiogenesis and fibroblast proliferation.

Characteristics of Transformed (Neoplastic) Cells

• Neoplastic cell growth is not inhibited by contact with surrounding cells and is not dependent on anchorage to a solid surface.
• Neoplastic cells may attain "immortality" or the ability to keep dividing indefinitely.
• They are discohesive and transplantable--favoring invasion and metastasis.
• Tumor cells can bind to laminin and fibronectin in connective tissues, then secrete collagenases or proteases, and then invade.

Epidemiology of Neoplasia

Neoplasms can be characterized by:

• Their incidence (how often they occur).
• Their death rate (how many deaths are caused by them).

A neoplasm such as basal cell carcinoma of the skin can be quite common, yet it almost never kills the patient. On the other hand, gliomas of the brain are uncommon but virtually always kill the patient. One in 5 Americans dies of cancer.

These data indicate that some cancers such as prostate and breast are more amenable to therapy than lung or pancreas. Another measure of therapeutic effectiveness is the so-called "5-year survival". Treatments can be compared based upon who survived the longest.

The incidence of some tumors in the U.S. is increasing (lung) while others are decreasing (stomach). Environmental factors influence incidences from location to location and race to race.

Important to remember: the incidence of cancer varies greatly with age. Testicular cancers and Hodgkin's disease are seen mostly in young adult males, while prostate cancers are more frequent in older men. Of malignant neoplasms in children, leukemias and brain tumors are most frequent.

Effects of neoplasia on the body

• Mass effect: impinging on a vital area (airway, nerve, blood vessel, hollow viscus) to obstruct or destroy it, or lead to infarction or infection.
• Local destruction: invasion or lysis of epithelial surfaces or vascular channels, leading to ulceration, bleeding, and infection.
• Cachexia: either caloric intake is decreased (lack of appetite or inability to eat) or the neoplasm alters normal metabolism (tumor necrosis factor); cancers do not "eat" the calories themselves.
• Functional activity: production of a hormone or substance that has an untoward effect. Many of these are so-called "paraneoplastic" syndromes (such as an oat cell lung cancer secreting ACTH or a renal cell carcinoma secreting erythropoietin or an islet cell tumor producing insulin).
• Hypercalcemia often accompanies cancers and is due either to: (1) osteolysis from metastases to bone or (2) production of parathormone-like substance (often in squamous cell carcinomas).

Immunology of Neoplasia

• Persons with congenital immunodeficiencies have increased risk (200 times normal) for malignancies, so immune surveillance must play some role in preventing neoplasia.
• Viral and chemical-induced cancers in animals are associated with "tumor-specific antigens" but this is equivocal in humans. Such antigens could evoke host defenses in the form of sensitized cytotoxic T lymphcytes, natural killer (NK) cells, and macrophages. Such antigens could also evoke humoral immunity (antibody formation), but such antibodies could "block" antigens and prevent recognition and attack through cellular immunity.

Diagnosis of Neoplasia

• Cytology: these procedures are the fastest and simplest with the least morbidtity, but yield few cells. Techniques include fine needle aspiration, brushings through an endoscope, tapping of fluid collections through a needle, and direct scrapings such as a pap smear.
• Biopsy: these procedures take a bite of tissue, either as a small piece through an endoscope or a larger piece as an excision. There is more preparation and skill required, and the potential for complications is greater, but more diagnostic tissue can be obtained.
• Autopsy: some neoplasms are discovered only at autopsy, either because they had not yet manifested an effect, because diagnostic techniques did not work, or because the patient died before a diagnosis could be obtained.

Limitations of diagnosis:

• Sampling error: not all neoplasms are uniform, and the material obtained may be the desmoplastic reaction, an area of necrosis, inflammation around the neoplasm, or not be representative of the majority of the neoplasm.
• Improper handling: allowing the sample to dry, crushing the material, using the wrong fixative, delay in sending to laboratory.
• Lack of correlation between histologic appearance and actual biologic behavior of the neoplasm.

Adjuncts to histologic diagnosis:

• Flow cytometry: in general, more aneuploid tumors have a worse prognosis, but this is still an experimental technique for most tumors.
• DNA probes may recognize oncogenes or clonal gene rearrangements.
• Immunohistochemistry may identify tumor-specific products or markers (such as prostate specific antigen, common leukocyte antigen, keratin).
• Tumor markers in serum such as carcinoembryonic antigen (CEA), alpha-fetoprotein (AFP), human chorionic gonadotropin (HCG), or prostatic acid phosphatase (PAP). Unfortunately, they are not all that specific or sensitive, particularly when applied as screening tests to a general population.

Treatment for Neoplasia

• Surgery: cutting out the neoplasm is still the most effective method, but not all primary sites are accessible or resectable with a clear margin. Once metastasis has occurred, surgery is no longer primary curative therapy.
• Radiation: effectiveness depends upon the radiosensitivity of the tumor and the body's ability to tolerate the dose without serious sequelae from necrosis, fibrosis, or radiation sickness.
• Chemotherapy: effectiveness depends upon the ability of the drug to selectively poison the neoplastic cells and not normal cells. Combination chemotherapy (multiple drugs) allows lower doses of each drug with potentially less tumor resistance. Some neoplasms can be influenced by hormonal therapy (estrogens inhibit prostatic adenocarcinoma, antiestrogen therapy inhibits breast adenocarcinoma).
• Immunotherapy: either tries to promote the body's own immune surveillance (activating T lymphocytes) or tries to direct antibodies against tumor antigens.
• Physical agents: hyperthermia and cryotherapy attempt to selectively kill more thermally sensitive neoplastic cells.

The problem with all treatments other than surgery is that they are never 100% selective for the neoplastic cells, and normal cells are injured.

Patients with a positive attitude or who have something to live for and have emotional support from family, friends, or a caring physician will tend to do better with treatment and/or live longer.