The causal role of human papillomavirus infections in cervical cancer has been documented beyond reasonable doubt. The association is present in virtually all cervical cancer cases worldwide. It is the right time for medical societies and public health regulators to consider this evidence and to define its preventive and clinical implications. A comprehensive review of key studies and results is presented.

https://jcp.bmj.com/content/jclinpath/55/4/244.full.pdf

The causal relation between human papillomavirus and cervical cancer

Papillomavirus infections — a major cause of human cancers

The epidemiology of human papillomavirus infections.

The identification of high-risk human papillomavirus (HPV) types as a necessary cause of cervical cancer offers the prospect of effective primary prevention and the possibility of improving the efficiency of cervical screening programmes. However, for these opportunities to be realized, a more complete understanding of the natural history of HPV infection, and its relationship to the development of epithelial abnormalities of the cervix, is required. We discuss areas of uncertainty, and their possible effect on disease prevention strategies.

The natural history of cervical HPV infection: unresolved issues.

Background. Infant and under-5 childhood mortality rates in developing countries have declined significantly in the past 2 to 3 decades. However, 2 critical indicators, maternal and newborn mortality, have hardly changed. World leaders at the United Nations Millennium Summit in September 2000 agreed on a critical goal to reduce deaths of children Objective. This review of community-based antenatal, intrapartum, and postnatal intervention trials in developing countries aimed to identify (1) key behaviors and interventions for which the weight of evidence is sufficient to recommend their inclusion in community-based neonatal care programs and (2) key gaps in knowledge and priority areas for future research and program learning. Methods. Available published and unpublished data on the impact of community-based strategies and interventions on perinatal and neonatal health status outcomes were reviewed. Evidence was summarized systematically and categorized into 4 levels of evidence based on study size, location, design, and reported impact, particularly on perinatal or neonatal mortality. The evidence was placed in the context of biological plausibility of the intervention; evidence from relevant developed-country studies; health care program experience in implementation; and recommendations from the World Health Organization and other leading agencies. Results. A paucity of community-based data was found from developing-country studies on health status impact for many interventions currently being considered for inclusion in neonatal health programs. However, review of the evidence and consideration of the broader context of knowledge, experience, and recommendations regarding these interventions enabled us to categorize them according to the strength of the evidence base and confidence regarding their inclusion now in programs. This article identifies a package of priority interventions to include in programs and formulates research priorities for advancing the state of the art in neonatal health care. Conclusions. This review emphasizes some new findings while recommending an integrated approach to safe motherhood and newborn health. The results of this study provide a foundation for policies and programs related to maternal and newborn health and emphasizes the importance of health systems research and evaluation of interventions. The review offers compelling support for using research to identify the most effective measures to save newborn lives. It also may facilitate dialogue with policy makers about the importance of investing in neonatal health.

/pdf/community-based-interventions-for-improving-perinatal-and-17rlant020.pdf

Community-Based Interventions for Improving Perinatal and Neonatal Health Outcomes in Developing Countries: A Review of the Evidence

To identify the genetic events which may play a role in the development of cervical carcinoma, we performed a detailed allelotype analysis utilizing DNA from 53 primary tumors and corresponding normal cells and 57 polymorphic probes mapped to each of the chromosomal arms, excluding the short arms of the acrocentric chromosomes. Loss of heterozygosity (LOH) of >25% was observed at sites on 11 chromosomal arms, which included 1q (26%), 3p (35%), 3q (31%), 4q (46%), 5p (53%), 5q (38%), 6p (28%), 10q (28%), 11p (42%), 18p (38%), and Xq (26%). The most frequent LOH was noted on 4q ( ADH3 ) and 5p ( D5S19 ), suggesting that loss of candidate tumor suppressor genes on these chromosomal arms may play a role in the development of cervical carcinoma. The two sites of deletions identified on 5p and Xq represent novel candidate tumor suppressor gene sites which have so far not been reported in any other tumor type. Human papilloma virus status did not correlate with any of the sites which showed frequent LOH. TP53 mutation analysis by single-strand conformation polymorphism analysis was performed in 17 tumors that either showed 17p deletions ( TP53, D17S5 , or D17S28 ) or were human papilloma virus negative. One of the 7 human papilloma virus-negative tumors, which also showed LOH at the D17S28 locus, had a mutation in exon 5. This study represents the first comprehensive genetic analysis of this cancer and identifies several novel features of significance to genetic etiology of cervical carcinoma.

Allelotype Analysis of Cervical Carcinoma

Integration of human papillomavirus (HPV) DNA into the host cell genome is believed to be essential for malignant progression. However unambiguous detection of the physical state of HPV is a difficult and time-consuming procedure. To resolve this issue a simple, rapid and highly sensitive technique of polymerase chain reaction (PCR) has been utilized for detecting the physical state of HPV-16 DNA. Investigations were carried out in 122 cervical specimens comprising the whole spectrum of cervical lesions starting from cervical dysplasia to invasive carcinoma including HPV-16-positive normal controls. A pair of oligonucleotide primers specific to the E2 open reading frame, which is often deleted or disrupted following HPV integration, was used for the study. Distinction between episomal and integrated forms of viral DNA was accomplished by detecting amplification of the E2-specific fragment (1139 bp) in the PCR product. The PCR results were compared with those obtained by the conventional methods of Southern blotting, two-dimensional gel electrophoresis and chromosomal in situ hybridization; a high degree of agreement was observed between the methods. The findings indicate that although integrated forms of HPV-16 DNA were detected in more than 70% of cervical cancer specimens, integration was less frequent (23%) in severe dysplasia and carcinoma in situ. Only 2.5% of cases showed both episomal and integrated forms of HPV-16 DNA. The difference between episomal and integrated forms was statistically significant (P < 0.01). The absence of integration in about 30% of cancer cases suggests that integration of HPV may not be necessary for malignant progression and alternative mechanism(s) of malignant transformation may occur without HPV integration. The PCR test thus provides an effective complement to Southern blotting and two-dimensional gel electrophoresis for accurate detection of the integration of HPV DNA.

Analysis by polymerase chain reaction of the physical state of human papillomavirus type 16 DNA in cervical preneoplastic and neoplastic lesions

Background. The role of male behavior in the genesis of cervical cancer was examined. In India, where the incidence of cervical cancer is among the highest in the world, promiscuity among women is virtually unknown. In this study, the authors investigated the role of male behavior in cervical carcinogenesis among Indian women who had one lifetime sexual partner.



Methods. A case-control study was used.



Results. Premarital sexual relationships (relative risk [RR], 1.9; confidence interval, 1.2–3.2) and extramarital sexual relationships (RR, 2.7; confidence interval, 1.5–4.9) of husbands were risk factors. When husbands had sexual relationships both before and during the marriage, their wives' risk of getting cervical cancer increased by 6.9 (CI, 2.3–20.7). Risk also increased with husbands having three or more extramarital sexual partners (RR, 3.05; CI, 1.25–12.6). Sexual contact with prostitutes before or after marriage, however, did not increase the risk. History of sexually transmitted disease before marriage (RR, 2.9) or after marriage (RR, 5.9) was an important risk factor, which persisted after controlling for other factors. Sexual abstinence for 40 or more days after a wife's giving birth or having an abortion provided protection. Sex with uncircumcised men or men circumcised after age 1 year increased the risk of cervical cancer (RR, 4.1).



Bidi smoking (bidi is a cheap smoking stick of 4–8 cm, consisting of a rolled piece of dried temburni leaf [Diospyres melanoxylon] containing 0.15–0.25 g of coarsely ground tobacco) for more than 20 years was a significant risk factor (RR = 2.4), whereas cigarette smoking was not a risk factor.



Conclusions. Male sexual partners play a role in cervical carcinogenesis.

https://acsjournals.onlinelibrary.wiley.com/doi/pdf/10.1002/1097-0142%2819930901%2972%3A5%3C1666%3A%3AAID-CNCR2820720528%3E3.0.CO%3B2-M

Role of male behavior in cervical carcinogenesis among women with one lifetime sexual partner

Ninety-six colposcopical ly directed biopsies from squamous epithelial carcinoma of the uterine cervix and 22 age-matched normal control biopsy specimens were examined by both Southern blot hybridization and polymerase chain reaction (PCR) for the presence of different human papillomavirus (HPV) DNA types. Cancer of the uterine cervix, which is the most common malignant disease in Indian women, showed a high frequency (98%) of HPV as compared to those reported from other parts of the world. HPV type 16 was found to be the dominant (64%) type while the frequency of HPV type 18 was verylow (3%). On individual typing of HPV, no biopsy was found to contain any other known HPV types under stringent conditions of hybridization except a single case of HPV type 11. Only one case of double infection with HPV types 16 and 18 was recorded. Under low stringency conditions of hybridization with a mixed probe of HPV types 16 and 18, 29 additional biopsies were found to be positive. Southern blot hybridization alone detected HPV DNA in 92% of the cases but none in the controls. By PCR, six (6.25%) more cases and four (18.18%) healthy women were found to be positive for HPVs. Analysis of the physical state of HPV 16 indicated integration in about 70% of carcinoma cases while 30% of them were in episomal form. The findings suggest that infection with HPV is an important etiologic factor for the development of cervical cancer, that a number of such tumours may arise without HPV infection, and that integration of the viral DNA into host genome is not always essential for malignant progression. Furthermore, the use of PCR provides an effective complementation of Southern blot hybridization for meaningful epidemiological studies of HPV infection.

A high frequency of human papillomavirus DNA sequences in cervical carcinomas of Indian women as revealed by Southern blot hybridization and polymerase chain reaction.

OBJECTIVE--To assess the efficacy of visual screening for cervical cancer in the maternal and child health setting. DESIGN--Clinical and cytological screening. SETTING--Maternal and child health centres, Delhi. SUBJECTS--44,970 women attending the centres from May 1988 to March 1991. RESULTS--238 cancers in early stages (0-IIa) were detected cytologically and proved through biopsy. Prevalence of cancer in women defined as high risk through examination by speculum was 29/1000 as compared to 1.53/1000 among women with a normal looking cervix. Though only 11.4% women belonged to the high risk category, 63% had early stage cancer. If all women with bleeding symptoms were included in the high risk category, the yield of cancer would be 71.4% (170/238) by referring only 15.6% of women attending maternal and child health centres for further evaluation through cytology or colposcopy. CONCLUSION--Though visual screening is a suboptimal strategy in comparison to the cytological screening, it may be useful where there is a heavy load of prevalent cancer and where cytological screening may not be available for years to come.

https://www.bmj.com/content/bmj/304/6826/534.full.pdf

Usha K. Luthra

Papers

Allelotype Analysis of Cervical Carcinoma

Analysis by polymerase chain reaction of the physical state of human papillomavirus type 16 DNA in cervical preneoplastic and neoplastic lesions

Role of male behavior in cervical carcinogenesis among women with one lifetime sexual partner

A high frequency of human papillomavirus DNA sequences in cervical carcinomas of Indian women as revealed by Southern blot hybridization and polymerase chain reaction.

Screening for cervical cancer by direct inspection.