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Currently, there are about 13,000 women diagnosed with invasive cancers in the United States each year, and about 4,500 who die from this disease. Thus, while the scourge of cervical cancer has greatly declined, we are still a long way from eradication. There are two main histologic types of cervical cancers: squamous cell carcinomas (85-90%) and adenocarcinomas (10-15%). Identifiable premalignant lesions in the squamous and glandular epithelium respectively, precede both histologic types. For example, squamous cell cancers are preceded for many years by a stage of low-grade dysplasia, progressing eventually to high-grade dysplasia and carcinoma-in-situ, before culminating into invasive cancer. Both squamous and glandular dysplastic cells can be identified in Pap smears, resulting in early intervention and treatment.
The risk factors associated with cervical cancers include increasing age, low socioeconomic status, smoking, and human papilloma virus (HPV) infections. The last is possibly the most important risk factor and the one whose causal role has been best studied. HPV can infect squamous epithelium at numerous sites in the body, resulting in the formation of raised or flat warts ("condyloma"). Condyloma associated with "low-risk" HPV (types 6,11) rarely progress to malignancy, while those associated with "high-risk" HPV (types 16, 18, 33 and 35) are linked to cervical, vulvar and vaginal cancers. HPV is a sexually transmittable disease, and thus initiation of sexual activity at an early age or multiple sexual partners are associated with an increased incidence of cervical cancer. It is possible to genotype the HPV from cervical smears, and this can be used to risk-stratify patients for progression to cancer. While HPV is most commonly implicated in squamous cell carcinogenesis, adenocarcinomas are also associated with the presence of HPV, particularly type 18. HPV produces two proteins E-6 and E-7, which bind to and inactivate p53 and pRB respectively, thus disrupting normal cell cycle control mechanisms. E-7 also binds to and inactivates p21WAF1 - the "universal" cyclin dependent kinase inhibitor - also resulting in disruption of cell cycle checkpoints. In addition to HPV, human immunodeficiency virus (HIV) infection is associated with an increased risk for cervical cancer, possibly through greater susceptibility to HPV infections and lack of effective host tumor surveillance mechanisms.
The genetic changes in cervical cancers are manifold, and their spectrum reflects the ubiquitous influence of HPV on carcinogenesis. As an example, mutations of p53, otherwise extremely common in most human cancers, are uncommon in cervical cancers. This has been explained on the basis of the fact that p53 is inactivated by binding with E-6 protein, thereby preempting the need for p53 mutations. On the contrary, abnormalities of the short arm of chromosome 3 (including the FHIT gene) are very common and occur early, even at the stage of dysplasia. This has been attributed to the existence of putative "HPV integration sites" on chromosome 3p, leading to strand breaks. Stage retains its primal importance as the most important predictor of prognosis and survival. Several novel parameters have been suggested as prognostic indicators including expression of the pro- and anti -apoptotic proteins Bax and Bcl-2, the metastasis suppressor gene KAI-1, and several cell cycle proteins such as p21WAF1 and p27KIP1. Recent studies have shown that methylation of tumor suppressor genes is a widespread phenomenon in cervical neoplasia, including premalignant cervical epithelium, and therefore, immunohistochemistry for protein expression becomes of paramount to detect downregulation of the specified product.
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