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Cervical Cancer: Etilogy, Screening and Clinical Staging

Cervical cancer is considered as third most common cancer in women worldwide, next to breast and lung cancer. Although accurate statistics are not available from India, but it is perhaps the leading cause of death in women. With the introduction of an effective program in developed countries, the incidence of invasive cervical cancer has declined greatly.

Etiopathogenesis of cervical cancer

Several epidemiologic, virologic, molecular, immunologic and ultrastructural studies have  helped to understand the carcinoma of the cervix:

1. Epidemiologic studies– based on epidemiology of a large population of women with cervical cancer, several risk factors have been identified which include-

  • Women having early age of sexual activity.
  • Women having multiple sexual partners.
  • Women with a persistent HPV infection with high-risk types of oncogenic virus.
  • Potential role of high-risk male sexual partners such as promiscuous males having previous multiple sexual partners, having a history of penile condyloma, or males who had a previous spouse with cervical cancer.
  • Miscellaneous risk factors include – a high incidence of cervical cancer is also observed in lower socioeconomic strata, in multiparous women, cigarette smoking women, users of oral contraceptives, HIV infection and immunosuppression while low incidence is noted in virgins and nuns.

2. Virologic studiesHuman Papillomavirus (HPV) infection is strongly implicated in the etiology of cervical cancer. By recombinant DNA hybridisation techniques, the following observations have been documented:

  • High risk type HPV, most commonly of types 16 and 18 in 70% cases of cervical cancer.
  • Low-risk type HPV, types 6 and 11 are found most frequently in condylomas.
  • Mixed high and low risk types HPV may be found in dysplasias.

3. Molecular studies– high risk HPV types are integrated into the nucleus of cervical epithelial cells whereas low risk HPV types do not integrate in the host cell genome.

4. Immunologic studies– circulating tumour specific antibodies and antigens are detected in patients of cervical cancer. Antibodies to virus specific antigens are identified on tumour cells and in sera of such patient.

5. Ultrastructural studies– it reveals that increased mitochondria and free ribosomesseen in cells of cervical intraepithelial neoplasia and depletion of normally accumulated glycogen in the surface cells. The latter change forms the basis of Schiller’s test in which the suspended cervix is painted with the solution of iodine and potassium iodide. The cancerous focus, if present, fails to stain because of lack of glycogen in the surface cells.

Cervical screening and the Bethesda system

NATIONAL CANCER INSTITUTE (NCI) of the US proposed the Bethesda system (TBS) for reporting cervical cytopathology.

According to the Bethesda system, based on cytomorphologic features and HPV types implicated in their etiology, the three grades of cervical intraepithelial lesions (CIN) are readjusted into two grades of squamous intraepithelial lesions (SIL) –LOW GRADE SIL and HIGH GRADE SIL as under:

  1. L-SIL corresponds to CIN-1 and is a flat condyloma, having koliocytic atypia related to HPV 6 and 11 infection (i.e. includes mild dysplasia and HPV infection). About 10% cases of L-SIL may progress to H-SIL.
  2. H-SIL corresponds to CIN-2 and 3 has abnormal pleomorphic atypical squamous cells. HPV 16 and 18 are implicated in the etiology of H-SIL Approximately, 10% cases of H-SIL may progress to invasive cervical cancer over a period of about two years.

Cervical screening recommendations include annual cervical smear in all sexually active women having any risk factors listed above. However, if three consecutive pap smears are negative in ‘high risk women’ or satisfactory in ‘low risk women’ frequency of Pap smear is reduced. There is no upper age limit for cervical screening.

In the pap screening programme, patients having abnormal Pap smear are appropriately followed up and therefore it requires understanding of the Bethesda system by the clinician as regards value and limitations of cytology reports prepared by the cytologist/cytotechnician.

The Bethesda system

The broad principles of the Bethesda system of cytologic evaluation are as under:

  1. Pap smears are evaluated as regards adequacy of specimen i.e. satisfactory for evaluation, satisfactory but limited or unsatisfactory for evaluating giving reasons.
  2. General diagnosis is given in the form of normal or abnormal smear.
  3. Descriptive diagnosis is given in abnormal smears that includes: benign cellular changes, reactive cellular changes, and abnormalities of epithelial cells.
  4. Cellular abnormalities include: ASCUS, L-SIL , H-SIL and squamous cell carcinoma.

The incidence of cervical cancer has shown a declining trend in developed countries in the last half of the century due to increased use of Pap smear technique for early detection and diagnosis but the incidence remains high in developing countries with low living standards.

Clinical staging

Classification of cervical cancer described by the cancer committee of the international federation of gynaecology and obstetrics (FIGO Classification) is widely adopted by the clinicians and pathologists,

Stage 0 – carcinoma in situ

Stage 1 – carcinoma strictly confined to the cervix

1A – preclinical carcinoma diagnosed only by microscopy. Maximum size 5cm deep and 7mm across measured from the base of epithelium.

1A1– stromal invasion of less than 3mm in depth and 7mm or less,micro-invasive.

1A2 – stromal invasion of 3 to 5 mm depth and horizontal 7mm or less micro-invasive.

1B – clinical lesion confined to the cervix or preclinical lesions greater than stage1A

1B1 – clinical lesions no greater than 4cm in size

1B2 – clinical lesions greater than 4cm in size

Stage 2– carcinoma extends beyond the cervix but has not extended to the pelvic wall. Involvement of the vagina limited to upper two-thirds.

2A– no obvious parametrial involvement

2B – obvious parametrial involvement

Stage 3– the carcinoma has extended to the pelvic wall. The tumour invades the lower third of vagina.

3A –no extension to the pelvic wall.

3B – extension to the pelvic wall and/or hydro-nephrosis or non-functioning kidney

Stage 4– the carcinoma has extended beyond the true pelvis or has clinically involved the mucosa of the bladder or rectum

4A– spread of the growth to adjacent organs.

 4B – spread to distant organs.

Author

 Yash Batra

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