Neoplasia

Definition of Neoplasia

Neoplasia is new, uncontrolled growth of cells that is not under physiologic control. 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.

There is no single mechanism by which a neoplasm arises. Many different mechanisms give rise to neoplasms, and that is what makes diagnosis and treatment so challenging.

Nomenclature of Neoplasia

Based upon origin:

• Malignant 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 (connective tissues) 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, which are often pediatric neoplasms. 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.

Causes of Neoplasia

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

Environmental causes:

• Chemicals: including those 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: including ultraviolet light that induces pyrimidine dimers in DNA and promotes skin cancers. Ionizing radiation (such as gamma radiation) induces mutations in DNA and promotes malignancies such as leukemia, thyroid, lung, colon, and breast cancers.

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 diethylstilbesterol, and chemicals such as cyclamates used as sweeteners.

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).
• DNA repair mechanisms may be affected. There are DNA excision repair genes that can be mutated, introducing genomic instability and a greater likelihood that mutations in other genes will occur to drive oncogenesis. Examples include:
  
  • DNA mismatch repair genes: defective nucleotide "spell checker" introducing "microsatellite instability" of tandem repeat sequences in DNA. Seen in hereditary non-polyposis colon cancer (HNPCC)
  • Nucleotide excision repair genes: defective function in xeroderma pigmentosa, allowing DNA damage from pyrimidine dimer formation induced by ultraviolet light
• 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.

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Familial and Sporadic Neoplasia

Most human cancers are "sporadic" because there is no identifiable inherited gene involved, but the cancers developed as a result of environmental factors (carcinogens such as cigarette smoke) that randomly induced mutations in cells that led to uncontrolled growth. Such factors are encountered throughout life and act over a long period of time; hence, most sporadic cancers occur in adults. Most affected persons have one primary site, and that site is where you would expect most cancers to be (breast, lung, prostate, colon, etc.)

Familial cancers tend to occur at a younger age than sporadic cancers. There is a specific gene with a defined inheritance pattern. Thus, one is born with "one strike" and it is a matter of years before another event triggers the cancer growth. One form of classic familial cancer syndrome involves a tumor suppressor gene, with the "two hit" hypothesis. A person inherits a bad p53 gene, for example, (first hit), but still has another functional copy of this gene on the other chromosome. Sometime later, a mutation wipes out the good gene (second hit) and growth control is lost, allowing a clone of neoplastic cells to arise. Multiple organs can be affected. Thus, familial cancers often involve more than one organ, and affected individuals can have more than one cancer, and malignancies other than epithelial are more likely (soft tissue sarcomas, leukemias/lymphomas, nervous system tumors).

The rare Li Fraumeni Syndrome illustrates the difference between "familial" and "sporadic" cancers. In Li Fraumeni syndrome there is an inherited mutation in the p53 gene, and a variety of cancers arise in persons with this mutation. However, it should be noted that p53 mutations are the most common mutations in sporadic cancers, too.

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). However, in some cases such as adenomas of the colon, the appearance of the benign neoplasm is a step toward possible malignancy, because oncogenic forces are at work producing additonal abnormalities in DNA in existing lesions.
• 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, and oral leukoplakia. In these cases, there is ongoing cellular proliferation for repair of damaged tissue, often from ongoing inflammation. Abnormal cell proliferation leads to a greater likelihood for mutation to occur.

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. The subclones may arise from acquisition of additional mutations.

Tumor Genetics

Neoplasms have a greater tendency to demonstrate karyotypic abnormalities such as translocations, deletions, and gene amplifications (which are also activators of proto-oncogenes). Leukemias and lymphomas are famous with chronic myelogenous leukemia, and the t(8:14) translocation in Burkitt lymphoma.

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.
• 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.
• Neoplastic cells may attain "immortality" or the ability to keep dividing indefinitely.
  
  
  

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