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Although in developed countries the incidence of cervical cancer seems to be declining, it remains a serious health problem. One major concern is the absence of prognostic factors which reliably predict the evolution of early cancers. It is believed that human papillomaviruses are important aetiological factors and their detection in precancerous lesions is a risk factor for malignant transformation. If these viruses seem to have a role in the initiation of cervical cancer, other factors may be necessary to the malignant transformation. Among those, certain proto-oncogenes (c-myc and c-Ha-ras) seem to be involved in the development and progression of cancer. Detection of gene alterations (mutation, deletion, amplification) and gene overexpression in early invasive cancers could be useful to establish a more reliable prognosis. A better surveillance of these high risk patients and a more appropriate treatment could then be selected.

The use of deoxyribonucleic acid probes to examine the type of the human papillomavirus genome found in penile lesions is described at a technical level and in a clinical application. At least 40 different types of human papillomavirus have been identified and these types vary not only in their deoxyribonucleic acid base sequences but also in their clinical manifestations. Although deoxyribonucleic acid probes currently have a role only in a research setting, this study delineates the possible role of this technology in a clinical setting to detect subclinical intraurethral human papillomavirus. The results have widespread implications regarding the treatment of condyloma and the associated cervical dysplasia. In this series 25 grossly visible lesions were typed and 85 per cent contained human papillomavirus types 6 and 11. In contrast, microscopic lesions identified in the male partners of women with cervical dysplasia were shown to contain human papillomavirus types 16, 18 or 31 in 60 per cent of the cases. In addition, urethral brushings were obtained and were positive for human papillomavirus in 50 per cent of the cases despite normal urethroscopy. Human papillomavirus types 16, 18 or 31 accounted for 70 per cent of the positive urethral brushings.

Plasma concentrations of vitamin C were determined in a case-control study of women (n = 80) who had sought a Papanicolaou test in the Bronx Municipal Hospital Center. Controls (n = 34) were women having negative cytologic tests, negative colposcopic findings, and no known gynecologic dysfunction. Cases (n = 46) were defined as women who had either one positive or two consecutive suspicious Papanicolaou smears in a 12-month period. The mean concentration of vitamin C in the plasma was significantly lower in the cases than in the controls (0.36 versus 0.75 mg/dl, p less than 0.0001). Cases were further stratified according to the histopathologic diagnosis. The data direct attention to a possible etiologic association of vitamin C in human cervical epithelial abnormalities. A clinical trial with vitamin C intervention is suggested.

We conducted a case-control study of cigarette smoking and dysplasia and carcinoma in situ of the uterine cervix. Cases were black women 17 to 55 years of age who were attending a dysplasia clinic and had biopsy-confirmed cervical pathologic conditions. Controls were women who were attending the family planning clinic at the same hospital and who had at least two normal Papanicolaou smears. Results were adjusted for age, number of sexual partners, age at first intercourse, socioeconomic status, and oral contraceptive use. Cigarette smoking was significantly associated with carcinoma in situ, severe dysplasia, and mild-moderate dysplasia (relative risks, 3.6, 3.3, and 2.4, respectively). Cumulative exposure to cigarette smoking (as measured by pack-years smoked) was strongly related to the risk of these conditions; women with 12 or more pack-years of exposure had relative risks of 12.7, 10.2, and 4.3, respectively, for the three conditions. There was some evidence that the risk was greatest in women who began smoking in their early teenage years. A reduction in the risk of cervical cancer appears to be another inducement for young women not to smoke.

A review of 5,752 cervical smears done on college students at a medium-sized midwestern university in a 24-month period showed 496 cytologic diagnoses of inflammatory atypia and 132 of dysplasia (cervical intraepithelial neoplasia: CIN). Further retrospective review of a nonselected cohort (178 cases) of the 496 patients with inflammatory atypia showed that their subsequent cytologic smears were more likely to show CIN than could be explained by chance alone. Only ten cases accounted for this difference, and a case-controlled blind review of the original cytologic smears of these ten patients resulted in the reclassification to CIN (mild dysplasia) of seven who had subsequently "progressed" from inflammatory atypia to dysplasia. Only one control smear was reclassified. In this population, underreading of a small number of cervical smears explained a strong statistical apparent correlation between inflammatory atypia and the subsequent development of CIN.

A study of 80 cases of dysplasia of the uterine cervix showed the coexistence of HPV infections in 52 cases. This association (65%) shows the important role played by the human papilloma virus in the genesis of cancer of the cervix.

Since genital infection with Chlamydia trachomatis may be associated with cervical abnormalities 160 patients with grandular ectopia attending a gynaecological outpatient clinic were examined for antibodies against C trachomatis, the presence of C trachomatis infection, and cytological and histopathological abnormalities of the cervix.A significantly higher incidence of histological dysplasia was found in women with glandular ectopia who had antichlamydial antibodies than in those without.

Human cytomegalovirus (HCMV) DNA sequence and HCMV antigen were detected by dot blot hybridization and PAP staining in biopsy specimens from cervical lesions. The results showed that the positive rate of HCMV DNA sequence was 73% in cervical cancer and 73% in cervical dysplasia which were higher than that in chronic cervicitis (44%) (P less than 0.05). HCMV antigen could be detected in all kinds of cervical lesions. But there was no significant difference in the positive rates. The detection rate of HCMV DNA sequence was not always in accordance with that of HCMV antigen. The results indicate that HCMV may be another high risk factor of cervical cancer.

The authors examined the interaction of exposure to various numbers of sex partners and evidence of antibodies to herpes simplex virus type 2 (HSV-2) in cervical neoplasia in 181 cases of cervical dysplasia, carcinoma in situ and cancer of the cervix and 130 control patients in Los Angeles County, California hospitals, in 1974-1979. Studies by the authors and other investigators have found that risk of cancer of the cervix was enhanced with numbers of sex partners, frequency and duration of using the vaginal douche, early age at first pregnancy, and antibodies to HSV-2 as measured by radioimmunoassay. In this study, it was found that for women with only one or no sex partner in their history, risk was elevated if evidence of antibodies to HSV-2 were present. The same was true for women with two or more sex partners. The risk associated with two or more sex partners was not higher than that for women with one sex partner among those positive for HSV-2, and among those negative for HSV-2. Thus, although this inquiry needs replication on larger numbers of women, whatever the other microorganisms or carcinogens patients were exposed to with multiple sex partners, there was no apparent effect beyond the fact that HSV-2 raises the risk of cancer of the cervix. This may strengthen credence in the hypothesis that HSV-2 is an etiologic factor in cervical cancer.

The epidemiological and clinical evidence for various forms of exogenous estrogens altering the risk of neoplasms of the female genital system, breast, and liver are reviewed and evaluated. It is virtually certain that in utero exposure to diethylstilbestrol can cause clear cell adenocarcinomas of the vagina and cervix. There is strong evidence that various estrogens given for treatment of menopausal symptoms can cause endometrial carcinoma and that sequential oral contraceptives probably also do so. Oral contraceptives very probably reduce the risk of both cystic disease and fibroadenoma of the breast and increase the risk of liver cell adenomas. Studies to date do not provide consistent and convincing evidence that any form of exogenous estrogen alters the risk of cancers of the breast or ovary or that oral contraceptives alter the risk of cervical neoplasia or focal nodular hyperplasia of the liver, although recent reports suggest that continued vigilance is warranted. Specific topics requiring further epidemiological investigation are suggested.

Serum specimens from 75 women with cervical carcinoma in situ, 84 with squamous dysplasia, and 132 controls, who had previously been interviewed and tested for complement fixing antibodies against a number of organisms, were analyzed for HSV-2 antibodies. Carcinoma in situ and severe dysplasia were associated with HSV-2 antibodies. Mild dysplasia was related to evidence of prior infection by Trichomonas vaginalis, adenoviruses, and Mycoplasma pneumoniae, plus a history of vaginal discharge. Severe dysplasia was less strongly related to these variables. The relative risk of dysplasia increased with the number of different pathogens by which a woman had been infected. It is concluded that HSV-2 may be a cause of carcinoma in situ; that much dysplasia is a nonspecific reaction of the cervical epithelium to chronic inflammation; and that dysplastic lesions that are caused by HSV-2, and hence may be a precursor to carcinoma in situ, tend to be distinguished by their severity.

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.

The incidence of biopsy-proven cervical neoplasia during a 10-year follow-up was determined in 6838 parous women who entered the Oxford-Family Planning Association contraceptive study while using oral contraceptives and 3154 parous women who entered the study while using an intrauterine device (IUD). Risk factors for cervical neoplasia, continuation of attendance at family planning clinics, and frequency of examination by cervical cytology were similar in the two groups. All 13 cases of invasive cancer occurred in women in the oral contraceptive group; 9 had more than 6 years' use of the pill. Both carcinoma-in-situ and dysplasia also occurred more frequently in the oral contraceptive group than in the IUD group, and when the two conditions were considered together there was a trend in incidence with duration of oral contraceptive use. The incidence for all three forms of neoplasia combined rose from 0.9 per 1000 woman-years in those with up to 2 years' pill use to 2.2 per 1000 woman-years in those with more than 8 years' pill use. Amongst IUD users, there was no such trend in incidence with duration of use: the rate fluctuated around 1.0 per 1000 woman-years. The great majority of cases of invasive cancer were detected by means of cervical smears and were treated while the disease was still curable. Long-term users of oral contraceptives should have regular cervical cytological examination.

Human papillomavirus (HPV) DNA is present in adenocarcinoma of the cervix as frequently as in squamous cell carcinoma of the cervix. Recent molecular biologic studies strongly suggested that HPV acts at least as a cocarcinogen in the female genital organs. Thus, a study of the presence of HPV DNA in adenocarcinoma in situ, endocervical glandular dysplasia and microglandular endocervical hyperplasia, three lesions suggested as possible precursor lesions of adenocarcinoma of the cervix, would clarify some aspects of the histogenesis of adenocarcinoma of the cervix. The presence of HPV-6, HPV-16 and HPV-18 in those precursor lesions was studied with highly sensitive in situ DNA hybridization. Fourteen of 21 cases of adenocarcinoma in situ (67%) contained HPV DNA; approximately the same proportion of HPV DNA was seen in invasive adenocarcinoma. Two of 36 cases of endocervical glandular dysplasia contained HPV DNA; both of them were lesions coexisting with adenocarcinoma in situ and thus might have been well-differentiated lesions of adenocarcinoma in situ. HPV DNA was not present in 16 cases of microglandular endocervical hyperplasia. Adenocarcinoma in situ may be the earliest event in HPV infection of the endocervical cells to lead to the development of adenocarcinoma of the cervix.

Cytomegalovirus and Chlamydia trachomatis are prevalent sexually transmissible pathogens. They produce persistent infections of the cervix and have been associated with cervical neoplasia. Cytomegalovirus has also been shown to induce transformation of cells in culture. Because of the high prevalence of genital infections with these pathogens and evidence that they may have oncogenic effects on the cervix, cytomegalovirus (strain AD-169) and C. trachomatis (serovar LGV-2) were tested for oncogenicity in a mouse model in which induction of cervical neoplasia by repeated exposure to inactivated herpes simplex viruses has been demonstrated previously. Cotton tampons, saturated with UV-inactivated cytomegalovirus, C. trachomatis, or corresponding control fluids, were inserted into the vaginas of virgin C57 mice 3 times a week. Smears of vaginal aspirates for cytological examination were obtained every 5 weeks. After 75-90 weeks of exposure, the mice were sacrificed and serial sections of their reproductive tracts were examined. Cervical dysplasia was detected by histological examination in 51% and cervical carcinoma in 10% of mice exposed to cytomegalovirus. In control mice, in contrast, dysplasia developed in 3% and carcinoma in none. The progression from normal cervical epithelium to dysplasia to carcinoma observed with cytomegalovirus exposure was similar to that observed previously in this model after exposure of mice to herpes simplex virus types 1 and 2. The frequencies of cervical abnormalities in mice exposed to C. trachomatis or corresponding control fluid were low, and differences between the two groups were not statistically significant. These data indicate that strain AD-169 of cytomegalovirus is oncogenic for the mouse cervix and suggest that the LGV-2 serovar of C. trachomatis is not.

The New Zealand contraception and health study is investigating the potential health risks associated with oral contraceptives, intrauterine contraceptive devices and injectable medroxy-progesterone acetate. This prospective observational study, begun as a pilot study in 1980, will record for at least six years the health of approximately 7500 women divided into three groups of equal size according to contraceptive method at entry. A major objective is to compare the incidence of dysplasia, carcinoma in situ and invasive carcinoma of the cervix in each group. This paper describes the design of the study and reports its progress.

Cervical biopsies and explant cultures from patients with squamous metaplasia, various grades of dysplasia, carcinoma in situ (CIS), and invasive squamous cell carcinoma were screened for VP143, an early nonstructural polypeptide of herpes simplex virus type 2 (HSV-2), VP143 was identified in 31% of biopsies exhibiting severe dysplasia, 29% with CIS, and 41% with invasive squamous cell carcinoma. Similar results were obtained when explants derived from these biopsies were examined for VP143. The expression of the protein persisted in passaged subcultures in four of five invasive carcinomas which originally contained VP143. Staining for VP157, the major capsid protein of HSV-2, was absent. Furthermore, virus structures were not seen by electron microscopy and infectious virus was not isolated from cell cultures inoculated with biopsy extracts. These results suggest that VP143 was expressed in the premalignant and malignant cervical cells in the absence of productive viral infection. Thus, a fragment of the HSV-2 genome was retained within the cells, the expression of which resulted in the production of VP143.

Vulvar condylomata acuminata are the commonest clinical expression of human papilloma virus infection of the female genital tract. Various epidemiological factors were examined in a group of patients with vulvar warts in whom the incidence of biopsy proven human papilloma virus infection of the cervix was 39.7% and the incidence of biopsy proven cervical intraepithelial neoplasia was increased significantly (16.2%).

Recent data on the role of human papillomaviruses in the arising and development of cervical neoplasia are reviewed. Cervical dysplasia is characterized, its natural history and the role of papillomaviruses in arising of dysplasia and cervical cancer are described. Modern results on identification of the capsid antigen and DNA of human papillomaviruses in different cervical lesions are presented. Several types of papillomaviruses with different oncogenic potential, as well as molecular aspects of the virus gene expression and cellular differentiation are discussed.

Numerous studies have suggested that patients with oral cancer have an increased immune response to herpes simplex virus. However, the number of cases has always been small, and essential controls have not always been included. Laboratory experiments have shown that herpes simplex virus can be carcinogenic or cocarcinogenic under certain circumstances and so must be considered as a possible etiologic agent in oral cancer. This article reviews past research and suggests priorities for future investigations.

A study of 318 patients with tubal infertility and a control group of 200 unselected infertile women yielded 14 (4.4%) and 1 (0.5%), respectively, with precancerous lesions of the cervix uteri. The one patient in the control group with severe dysplasia was later shown to have tubal infertility. The overall incidence of premalignant lesions of the cervix uteri as reported to the National Cancer Registry of Norway was 0.1% for the age group and period studied. Women with tubal infertility represent a small but comparatively high risk group for the development of precancerous lesions of the cervix uteri.

The studies associating infections by herpes simplex virus type 2 (HSV-2) with carcinoma of the human uterine cervix are reviewed within the context of three possible interpretations. Extensive seroepidemiologic evidence indicates that the virus does not grow preferentially in neoplastic tissue, nor is the association of HSV-2 with cervical carcinoma a reflection of their independent relationship to promiscuity. While a number of infectious agents, including other viruses, are associated with cervical atypia, only HSV-2 is a significant risk factor for CIS. In vitro transformation data supporting the oncogenic potential of the virus are summarized, and evidence is presented that an antigen designated ICP 10/AG-4 is a valid candidate for the role of a virus-encoded protein involved in the maintenance of a transformed phenotype. Antibody to AG-4 is IgM, and it is detected by microquantitative complement fixation. With this assay, it is demonstrated that conversion to anti-AG-4 occurs during primary infection with HSV-2; however, it is transient. In testing 1325 patients, a correlation was observed between antibody to AG-4 and cervical carcinoma. Thus, whereas only 11.7% of controls and 7.7% of patients with cancer at other sites are AG-4 seropositive, as many as 49.6% of patients with dysplasia, 63% of those with CIS, and 72.7% of those with invasive cancer are positive for the antibody. Antibody to AG-4 is related to tumor growth. This is evidence by 1) retrospective analyses demonstrating that the proportion of AG-4 seropositive individuals is directly correlated to the state of the disease and 2) prospective study of 209 patients demonstrating loss of antibody in patients with a successfully removed tumor mass and reappearance of AG-4 antibody in cancer recurrence. The possible use of AG-4 (or its antibody) in the diagnosis and monitoring of cervical carcinoma and its treatment is discussed.