Neoplasia 3

Epidemiology
Esophageal CA is common in North Iraq, North Iran and central Asia. Other examples of environmental factors as cancer inducers include:
• Occupational exposure to asbestos (lung CA, pleural and peritoneal mesotheliomas), aniline dyes (bladder), polyvinyl chloride monomers (liver angiosarcoma).
• Cigarette smoking (CA lung, larynx and oropharynx).
• Air pollution (CA lung).

Age: Cancer is most common in those over 55 years of age, a fact pointing that cancer evolution require multiple independent events apparently taking place over a long time. However, certain tumors are particularly common in children under age of 15 years e.g. leukemias, lymphomas, neuroblastoma, Wilm s tumor, Ewing s and osteo-sarcomas, rhabdomyosarcoma and retinoblastoma.

Hereditary: It plays a role in development of cancer even in presence of a clearly defined environmental factor. It can be divided into 3 categories:

1. Inherited cancer syndromes:
They are characterized by inheritance of a single mutant gene that greatly increase risk of developing a tumor. It is an autosomal dominant trait associated with inheritance of single mutant allel of cancer suppressor gene as in familial retinoblastoma and familial adenomatosous polyposis coli (FAPC).
In these syndromes, only specific tissues are affected and usually there is an associated marker phenotype e.g. colonic adenomatous polyps.

2. Familial cancer syndromes:
They are characterized by familial clustering of specific forms of cancers, but the transmission pattern isn t clear in every individual case.
Familial forms of CA breast, colon, brain and ovary are reported, and unlike inherited syndromes there is no marker phenotype i.e. CA colon doesn t arise on a pre-existing polyps.
3. Autosomal recessive syndromes of defective DNA repair:
They are characterized by chromosomal and DNA instability that greatly increase predisposition to environmental carcinogens e.g. xeroderma pigmentosa.

Acquired Pre-neoplastic disorders
Certain clinical conditions are associated with an increased risk of developing cancer e.g. :
• Liver cirrhosis: Hepatocellular CA.
• Atrophic gastritis: Gastric CA.
• Chronic idiopathic ulcerative colitis: Colonic CA.
• Leukoplakia of oral and genital mucosa: Squamous cell CA.
The subsequent development of malignancy in a benign tumor is quite uncommon as almost all malignant tumors arise de novo. However few exceptions are seen e.g. villous adenoma of colon progress to CA colon.

Genetic bases of cancer
• Non lethal genetic damage lies at the heart of carcinogenesis. This damage (mutation) may be acquired by environmental factors such as radiation, chemical substances or viruses or it may be inherited in the germ line.
The tumor mass results from clonal expansion of a single progenitor cell that have the genetic damage.
• Normal regulator genes: They are the principal targets of genetic damage (mutation). They are 3 classes:
1. Growth promoting genes (proto-oncogens).
2. Growth inhibiting/cancer suppressor genes (anti-oncogens).
3. Programmed cell death (apoptosis) genes.
• 4th category of genes that regulate repair of damaged DNA.
• Carcinogenesis: It is a multi-step process at both phenotypic and molecular or genetic levels.
At phenotypic level; excessive growth, local invasion and distant metastasis are acquired in a step-wise fashion, a phenomenon called tumor progression.
At genetic (molecular) level; these features are due to accumulation of genetic lesions that are favored by defect in DNA repair.

Chemicals can induce cancers by 2 mechanisms: complete carcinogenesis with both initiation and promotion effects and incomplete carcinogenesis with only initiation effect.

Initiators are of 2 types:
1. Direct acting: They don t require chemical transformation (metabolism) for their carcinogenesis.
2. Indirect acting (procarcinogens): They need metabolic conversion in vivo by cytochrome P-450 in the liver to form ultimate carcinogen.

Promoters don t induce DNA damage, but they alter expression of genetic information in the cell, mainly by binding or activation of protein kinases that catalyze phosphorylation of proteins causing changes in the intracellular PH and increase growth and activity. By this mechanism, promoters induce clonal proliferation program by activating enzymes that are part of physiologic signal transduction pathways.

Examples of chemical carcinogens:
1. Direct acting alkylating agents e.g. cyclophosphamide, chlorambucil and busulfan.
2. poly-cyclic aromatic hydrocarbons.
3. Aromatic amines e.g. in rubber industries.
4. Naturally occurring carcinogens e.g. aflatoxin B produced by some strains of Aspergillus may induce hepatocellular CA.
5. Nitrosamine: GIT tumors.
6. Miscellaneous agents e.g. occupational exposure to asbestos increases risk of pleural, bronchial and GIT cancers, cigarettes smoking increases risk of bronchogenic CA.