Risk-factors and strategies for control of carcinoma cervix in India: hospital based cytological screening experience of 35 years.

PURPOSE: Role of risk factors in cervical carcinogenesis and strategies for control of the disease have been assessed from the accumulated cytological data, derived from 35 years of hospital-based screening in Lucknow, North India. MATERIALS AND METHODS: A total of 36,484 women have been cytologically screened during a span of 35 years (April 1971 - June 2005) in the Gynaecology out patient department (OPD) of Queen Mary's Hospital. RESULTS: The frequency of Squamous Intraepithelial Lesion (SIL) and carcinoma was found to be 7.2% and 0.6%, respectively, in the present study. The study revealed high age and parity as a predominant factor in cervical carcinogenesis, while viral sexually transmitted disease (STDs) -human papilloma virus (HPV) and Herpes simplex virus (HSV) were also largely associated with SIL cases. The study emphasized great value of clinically downstaging the cervical cancer by detecting cervical cancer in the early stage. The study also revealed a significant difference in the frequency of SIL in symptomatic and asymptomatic women. CONCLUSION: Based on the analyzed data, it was felt that single lifetime screening, which appears to be the most feasible and affordable mode for control of carcinoma cervix in developing countries like India, should be carried out in all women of high parity irrespective of age (with three or more children) and in older women above the age of 40 years irrespective of parity.

MIB-1 and PCNA immunostaining as a diagnostic adjunct to cervical Pap smear.

The present study was done to determine the role of MIB-1 (Molecular Immunology Borstel) and proliferating cell nuclear antigen (PCNA) proliferative index as a diagnostic adjunct to cervical Papanicolaou (Pap) smear for the identification of ascending grades of cervical intraepithelial neoplasia (CIN) developing into cancer in the human uterine cervix. A total of 49 adequate Pap smears with consensus diagnosis were destained for immunocytochemical staining (MIB-1 and PC10). Staining was done by streptavidin-biotin method after antigen retrieval. MIB-1 and PC10 labeling index (LI) were calculated in each case and divided into three groups, i.e., <10%, 10-20%, and >20%, respectively. Statistical analysis was done by using the SPSS 10.0 package. The comparisons were made using analysis of variance (ANOVA) and independent sample t-test. Bivariate and Pearson's correlation coefficient were used to obtain correlations between different groups. Out of 49 cases, 40 cases (81.6%) showed positive immunostaining with MIB-1 and PCNA. Proliferative LI of MIB-1 and PCNA increased with the ascending grades of CIN lesions to carcinoma. The highest proliferative index (mean +/- SD) for PCNA and MIB-1 were observed for the carcinoma group (PCNA LI, 39.200 +/- 1.6865; MIB-1LI, 35.300 +/- 1.8886). A significant positive correlation between ascending grades of squamous intraepithelial lesion (SIL) and labeling indices of markers (r = 0.87 for MIB-1 and r = 0.88 for PCNA) suggests that MIB-1/PCNA proliferative markers can be used as an adjunct to cytomorphological interpretation of conventional cervical Pap smear.

Results of clinically downstaging cervical cancer in a cytological screening programme.

The study was aimed at clinically downstaging cancer of the cervix during a cytological Screening Programme to find out whether such a strategy may help in yielding a large number of early cases of cancer. A cohort of 6,178 women with different cervical lesions were cytologically examined from April 1971 at Queen Mary's Hospital, Lucknow, India. The 8,718 asymptomatic women with healthy cervices were taken as controls. The incidence of cervical dysplasia and malignancy in the study group was found to be 11.2% and 1.9%, which was statistically highly significant compared to control values of 3.3% and 0.02%, respectively. Dysplastic smears were seen maximally in women whose cervix bled to the touch, and the rate of cervical cancer was high in women with suspicious cervix. Dysplastic smears were seen frequently in all age and parity groups, but malignancy was common in women of high age (over 30 years) and high parity (two and above). The incidence of three sexually transmitted diseases, namely Trichomonas vaginalis, Herpes simplex, and condyloma revealed highly significant values, especially in women whose cervix bled to the touch. The study highlights the strategy of clinically downstaging cervical cancer, which is very useful in detecting a large number of dysplasia and frank malignancy cases and also the presence of any associated sexually transmitted pathogens whose treatment would aid in restricting the rising incidence of the dreaded disease in this country.

Cervical cytology associated with levonorgestrel contraception.

Cytologic monitoring of cervical smears was carried out in 686 women receiving two modes of levonorgestrel contraception, one in the form of a subdermal implant and the other as an intrauterine device. The period of contraception with both delivery systems ranged from six months to five years. No case of malignant neoplasia was seen in any of the 44 subjects even after five years of continued levonorgestrel contraception. Preinsertion cytology revealed eight dysplastic smears (seven mild and one moderate); the lesions reverted to normal six months later and remained normal after one to four years of hormone use. A total of 19 dysplastic smears (18 mild and 1 moderate) were detected in the postinsertion smears collected after one to five years of contraception, giving an incidence of 2.8%, which was nonsignificant when compared with the control figure of 1.3%. Regression of the lesion to normal was observed in all 19 dysplasias on follow-up and in none did the dysplasia progress to a higher grade or frank malignancy. The incidence of dysplasia was more than twice as high with the intrauterine device as with the implant (4.9% vs. 2.1%). Hence, the implant appeared to be safe during five years of contraceptive use in terms of cervical pathology. However, longer follow-up of a large number of women is needed to reach a definitive conclusion.

PIP: Physicians performed cervical smears before insertion and every 6 or 12 months thereafter on 686 fertile women who had received either a subdermal levonorgestrel implant (524) or a levonorgestrel-releasing IUD (162) since October 1983 at eight human reproduction centers of the Indian Council of Medical Research throughout India. There were a total of 1503 smears among implant users and 359 smears for IUD users. Researchers aimed to determine the oncogenic potential of levonorgestrel in long-term users of these contraceptives. The period of contraceptive use ranged from 6 months to 5 years. 21.5% of the women had inflammatory smears at preinsertion. 5.6% of them had trichomonal infection. The incidence of inflammation increased with duration of contraceptive use among women with initially normal smears (e.g., IUD, 12.1-40%), while it fluctuated among those with initially inflammatory smears. Physicians should conduct early cytologic monitoring 1-2 months after treatment for infection, since inflammation can lead to cytopathologic changes in epithelial cells. There were 19 new cases (1 moderate and 18 mild cases) of squamous intraepithelial lesions (SIL) (dysplasia). 4 of the 19 women had inflammatory smears. The postinsertion incidence of SIL was more than twice that of the preinsertion incidence (2.8% vs. 1.3%), but the increase was not significant. The postinsertion SIL incidence was more than two times as high for IUD users than implant users (4.9% vs. 2.1%). Neither incidence was significantly greater than the preinsertion incidence. The dysplasia did not advance to a higher grade or malignant neoplasia on subsequent follow-up. In fact, in all 19 cases, the lesion regressed to normal on subsequent follow-up. These findings suggest that the levonorgestrel implant can be used safely for as long as 5 years. A long-term follow-up study with a large sample size is needed to confirm that levonorgestrel contraceptives do not induce cervical cancer.

Cervical carcinogenesis and contraception.

Cytologic evaluation of cervical smears has been carried out in 3,374 women who used different modes of contraception (Lippes loop, copper T200, copper T220, copper devices containing higher copper content than the copper T200, CuT380 Ag, levonorgestrel IUD, injections of noresthisterone oenanthate, and subdermal implants of levonorgestrel) under the Contraceptive Testing Programme of Indian Council of Medical Research for periods ranging from 6 months to 15 yr. While no case of severe dysplasia or malignancy was noticed with any type of contraceptive, 113 dysplastic smears (99 mild and 14 moderate) were encountered on follow-up, giving an incidence of 3.3%, which was statistically insignificant compared with the pretreatment incidence of 1.4% (47 of 3,374). The highest incidence of dysplasia was seen with devices containing a high copper content (9.2%), followed by CuT200 (6.1%) and levonorgestrel implants (4.2%), and was lowest with Lippes loop (1.8%), injection of noresthisterone oenanthate (1.7%), and CuT380 Ag (1.5%), but statistics higher than the pretreatment incidence of 1.4% were seen only with CuT200 and devices containing high copper content. Retrogression of dysplasia was seen in 85 of the 94 posttreatment dysplasia cases and in all 47 pretreatment dysplasia cases, whereas in the remaining nine posttreatment cases of dysplasia the lesion persisted for 6-12 mo, necessitating discontinuation of contraception. The accumulated follow-up data indicate that the CuT380 Ag device is a promising IUD for the future in view of its low incidence of dysplasia determined during its use up to 5 yr. However, more prolonged follow-up in larger numbers of subjects is required to confirm its innocuousness on long-term retention.

PIP: Cytologic evaluation of cervical smears was carried out in 3374 women who used different modes of contraception (Lippes loop, Copper T2000, Copper T2200, copper devices containing higher copper content than the Copper T2000, CuT380 Ag, levonorgestrel IUD, norethisterone enanthate injections, and subdermal implants of levonorgestrel) under the Contraceptive Testing Program of the Indian Council or Medical Research for periods ranging from 6 months-15 years. While no case of severe dysplasia or malignancy was seen with any contraceptive, 113 dysplastic smears (99 mild and 14 moderate) were seen on followup, which gave an incidence of 3.3%, statistically insignificant compared to pretreatment incidence of 1.4% (47 of 3374). The highest incidence of dysplasia was seen with devices containing a high copper content (9.2%), followed by the CuT200 (6.1%, and levonorgestrel implants (4.2%), and was lowest with the Lippes loop (1.8%), norethisterone enanthate injection (1.7%), and the CuT380 Ag (1.5%). However, statistics higher than the pretreatment incidence of 1.4% were seen only with the CuT200 and devices containing higher copper contents. Retrogression of dysplasia was seen in 85 of 94 posttreatment dysplasia cases and in all 47 pretreatment dysplasia cases, whereas in the remaining 9 posttreatment cases of dysplasia, the lesions persisted for 6-12 months, necessitating discontinuation of contraception. The accumulated followup data indicate that the Cut380 Ag device is a promising IUD for future use in light of its low incidence of dysplasia determined during its use up to 5 years. More prolonged followup in larger numbers of subjects is necessary to confirm its efficacy on longterm retention.

Cytopathological changes in human cervix and endometrium following prolonged retention of copper-bearing intrauterine contraceptive devices.

Since 1971, cytological evaluation of cervical smears and endometrial aspirates was carried out in 604 women wearing CuT200 intrauterine contraceptive devices (IUDs) for periods ranging from 6 mo to 15 yr. No cases of cervical neoplasia or endometrial carcinoma were encountered, even after continuous use of the device for 15 years. Dysplastic cervical smears were, however, found in 45 postinsertional smears, and endometrial hyperplasia was detected in seven aspirates; in no cases was the dysplasia or hyperplasia higher than of moderate degree. Thirty-nine of the 45 women with postinsertional dysplastic smears were followed for 3-4 yr; in no case did the lesion progress to a higher grade or to frank malignancy. However, persistence and recurrence of dysplasia were seen in 10 women, necessitating removal of the IUDs. The incidence of cervical dysplasia and endometrial hyperplasia was found to be much higher when the IUDs had been changed than when the original devices were worn continuously. The rate of removal of IUDs because of persistent or recurring dysplasia was also much higher in the former group. Since no pregnancies were reported in any of the women wearing the original device for as long as 15 yr, we do not advocate the practice of changing the device at the end of 3 yr for maintaining contraceptive efficacy as recommended by the manufacturers; instead, we recommend the uninterrupted retention of the original device for periods not longer than 5 yr in view of occurrence of endometrial hyperplasia in two 6-yr wearers.

The role of routine outpatient cytological screening for early detection of carcinoma of the cervix in India.

Cytological evaluation of cervical smears has been carried out in 4,338 women attending the Gynecology and Obstetrics Department and Family Planning Clinic of Queen Mary's Hospital, Lucknow, India, since April 1971. The incidence of cervical dysplasia was found to be 4.6% (205 out of 4,338) in the series, while malignant smears were detected in 54 patients (1.2%). In five cases, malignant smears were encountered in women with apparently normal cervices, highlighting the advantage of exfoliative cytology in screening subjects without cervical pathology. The remaining 49 cases with malignant smears had lesions on the cervix that had been clinically diagnosed as carcinoma. The diagnosis of malignancy was confirmed by biopsy in all 54 cases showing malignant smears; however, in 10 cases clinically diagnosed as carcinoma of the cervix, and subsequently confirmed histologically, the diagnosis was missed by cytology, the smears being reported as inflammatory in seven and inadequate in three. Cytological evidence of herpes simplex infection was seen in the smears in 23 out of 54 cases of carcinoma, and trichomonal infection was present in 15, indicating some relationship of these infections with the development of neoplastic changes in the cervical epithelium. Eleven of the total 54 cases of carcinoma of the cervix were in the age group of 26-35 yr, and four were in subjects with only two children. This emphasizes the need for the routine cytologic screening of all child-bearing women with parities of two and above, regardless of their age, if any meaningful results are to be obtained in a cancer-screening program in India in view of the prevailing custom of early marriage.

Long-term cytologic studies of copper-IUD users.

Cytologic evaluation was carried out in 198 women using copper T-200-mm intrauterine devices (IUDs) for periods ranging from four to eight years. Preinsertional cytology revealed one mild dysplasia; the lesion reverted to normal six months later and has remained normal after five years of copper T contraception. A total of 18 dysplasias (16 mild and 2 moderate) were found in post-IUD-insertion smears during follow-ups after one to eight years of IUD use. Regression of the lesion was noticed in 14 of the 18 within 6 to 12 months with the device in situ. Persistence of the lesion was found in one case and a waxing and waning pattern in two, necessitating removal of the device in all three. In the remaining case, the device was removed due to menopausal menstrual irregularity.

PIP: In 1971, a preliminary study of 293 women using Copper T 200 was started at the Contraceptive Clinic, Queen Mary's Hospital, Lucknow. A follow-up study of 38 cases for 5 years showed a low incidence of cervical dysplasia and no case of cervical carcinoma. This paper presents the results of a cytologic follow-up for an additional 36 months for 198 of the 293 women. The 198 women were aged 21 to 42 years with parity ranging from 1 to 8. Annual follow up rate ranged from 66.1% to 100%. Preinsertional smears were available in all 198 women and were collected from 3 sites: ectocervix-squamo-columnar junction, endocervical canal and endometrium. Smears from the first 2 sites were repeated at 6-month intervals and evaluated using the nomenclature of World Health Organization (WHO) study group. 125 had their IUDs changed after 3 to 6 years (group 2), while 73 had worn the same devices continuously for periods ranging from 3 to 8 years (group 1). Preinsertional cytology of the 198 women revealed 118 negative smears (59.7%); 70 exhibited evidence of inflammation (39.8%), and 1 had dysplasia of a mild degree (0.5%). 18 (9.06%) dysplastic smears were seen during follow-up of the 198 women over the 8-year period. 11 were found in group 1 and 7 in group 2. Regression of the lesion occurred in 14 of the 18 women within 6 to 12 months with the IUD in situ. IUD was removed in 1 case due to menopausal menstrual irregularity and in 3 patients with persistent lesion, and a waxing and waning pattern. These 3 patients should be considered a risk for cervical carcinoma and need observation for at least another 5 years. The incidence of dysplasia increased progressively with increasing duration of device use, regardless of whether the devices had been changed. In women with unchanged IUDs, the maximum incidence of dysplasia was observed after 5 years of use (5.0%), while in those whose IUDs have been changed, a higher incidence was seen 2 to 3 years after the device has been changed (6.2% and 8.0%, respectively). The findings suggest that uninterrupted use of a copper IUD should not exceed 5 years. Thereafter, another mode of contraception should be offered to the patient.

Cytological studies in women using different types of hormonal contraceptives.

PIP: 116 women aged 19 to 40 years and with parities ranging from 1 to 12 were assigned to 4 different hormonal contraceptives: 1) pill-a-month, a combination of 2 mg quinestrol and 2.5 mg quinestrol acetate; 2) DMPA (depo medroxyprogesterone acetate injections); 3) norethisterone enanthate injections, and; 4) subdermal silastic implants of norethindrone acetate embedded in the anterolateral aspect of the thigh. The hormonal preparation contained either estrogen-progestogen combination (group A) and progestogen alone (group B). Socioeconomic status and previous mode of contraception were analyzed to determine their effects on pretreatment cytology. The results show a higher number of inflammatory smears associated with clinical pathology in group A cases than in group B. 11 inflammatory smears showed up on follow-up in 37 cases of group A (29.7%) of which 10 were associated with clinical pathology while 16 inflammatory smears were observed on follow-up in 79 cases in group B (20.2%), of which only 3 were associated with clinical abnormality. The findings suggest that abnormal clinical findings are often found in women taking estrogen-progestogen combination contraceptives than in women using products containing progestogen alone. Socioeconomic status had a significant contributory role to the inflammatory changes in the genital tract as most of the inflammatory smears observed on follow-up belonged to low income women.^ieng