Human papillomavirus (HPV) infection, HIV infection and cervical cancer in Tanzania, east Africa.

The presence of HPV-DNA was determined in tumor biopsies of cervical-cancer patients and in cervical swabs of non-cancer patients from Tanzania, East Africa, by Southern blot hybridization and/or PCR. HPV types 16 and 18 were detected in 38% and 32%, respectively, of 50 cervical-carcinoma biopsies. A consensus primer PCR capable of detecting a broad spectrum of HPV types revealed the presence of HPV-DNA in 59% of 359 cervical swabs of non-cancer patients. Type-specific PCR showed that types 16 and 18 accounted for 13.2% and 17.5%, respectively, of all HPV infections. Therefore we concluded that HPV 18 is more prevalent in Tanzania than in any other geographical location so far reported. The strongest risk factors for the presence of any HPV-DNA in the 359 female non-cancer patients were young age and HIV infection. The epidemiology of HPV types 16 and 18 was found to differ from that of other HPV types, being associated in univariate analysis with trichomonas vaginalis infection, martial status (single/divorced), age at first intercourse, and young age at menarche. However, young age at menarche accounted for most of the effects of all other, variables in multivariate analysis. Of the non-cancer patients, 12.8% had antibodies against HIV I (no patient being severely symptomatic), and HIV infection was highly correlated with the presence of HPV-DNA, especially types 16 and 18. While HPV-DNA of any type was detectable 1.4-fold more often in HIV-positive patients than in HIV-negative patients, evidence of an infection with HPV types 16 or 18 was found 2.2-fold more often in the HIV-positive patients. The HIV-positive women did not show an increased rate of cervical cytological abnormalities as assessed by PAP staining of a single cervical smear, the overall rate of abnormalities being 2.8%. Furthermore, the age-adjusted prevalence of HIV antibodies was found to be considerably lower in 270 cervical-carcinoma patients (3% HIV-positive) in comparison with non-cancer patients. Thus there was no association observable between the prevalence of HIV infections and the frequency of cervical cytological abnormalities or cervical cancer in the setting of this cross-sectional study.

PIP: Southern blot hybridization and/or PCR was used to examine tumor biopsies of 53 women with cervical or vaginal cancer at Ocean Road Hospital in Dar es Salaam, Tanzania, and the cervical swabs of 359 women with no cancer at the gynecologic clinic at Muhimbili University College of Health Sciences in Dar es Salaam. Tanzanian and German scientists wanted to determine whether an association existed between human papillomavirus (HPV) infections and HIV, and whether the high prevalence of HIV infection was matched by a high prevalence of HPV infections, cervical dysplasias, and cervical cancer in HIV-positive cases. 59% of the noncancerous women had HPV-DNA. Young age and HIV infection were the greatest risk factors for HPV-DNA in these women (p .0001 for age and HPV-16/18; p = .08 for other HPVs; and p = .03 for HIV). 13.2% and 17.5% of all HPV infections were HPV types 16 and 18, respectively. Tanzania had the highest prevalence of HPV 18 ever reported. HPV-16/18 risk factors included: Trichomonas vaginalis infection (odds ratio [OR] = 2.23; p = .04), single status (OR = 2.55; p = .01), 16 years old or less at first intercourse (OR = 2.1; p = .03), and young age at menarche (OR = 6 for or=12 years old; p = .02 and OR = 3.25 for or=13 years old and or=16 years old; p = .05). Yet, the multivariate analysis revealed young age at menarche had the greatest effect (OR = 6.2 for or= 12 years old, p = .03; OR = 3.73 for or=16 years old, p = .08). 12.8% of noncancerous women tested positive for HIV-1, but none of them were obviously symptomatic. These HIV-positive women had a higher OR if they had HPV-16/18 than if they had other HPV types (4.25 vs. 2.02). Further, they did not have more cervical cytological abnormalities than did the HIV-negative women (overall cervical cytological abnormality rate - 2.8%). The HIV-positive rate for cancerous patients was only 3%. In conclusion, no association existed between HIV infection and cervical cytological abnormalities or cervical cancer.

Most clinicians feel DES exposure does not contraindicate OC use.

PIP: Although concerns about a possible association between exposure to diethylstilbestrol (DES) in utero, use of combined oral contraceptives (OCs), and cervical/vaginal carcinoma have been largely allayed, many physicians remain cautious with DES daughters. Over 80% of the 621 physician respondents in a 1987 Contraceptive Technology Update survey indicated they would prescribe combined OCs for DES offspring, but half of them would require more frequent or more thorough follow-up than with their other OC patients. There are indications that areas of metaplasia in the vagina convert into a malignancy faster in DES-exposed women than in nonexposed patients. Of the 16% of physicians who said they would not prescribe OCs for a DES daughter, the majority indicated they would refer the patient to a specialist who would probably prescribe OCs. Only 1.5% said they considered DES exposure to be an absolute contraindication to OC use. Physicians generally indicated that they would move more quickly to perform a colposcopy on DES-exposed patients in the event of abnormal Pap findings. Others noted that more extensive follow-up on DES daughters may not be clinically essential but good policy from a medicolegal standpoint.^ieng

Development of DES-associated clear-cell carcinoma: the importance of regular screening.

Because the rate of malignancies in young women exposed in utero to diethylstilbesterol (DES) is low, appropriate population screening methods have not been established. A case is presented that is believed to represent the first reported instance of a DES-exposed daughter who developed clear cell adenocarcinoma of the vagina after initially negative examinations. The patient was followed with Papanicolaou smears, pelvic examinations, and colposcopy every 6 months for 2 years prior to the discovery of malignancy. Initially negative, Papanicolaou smears successfully predicted the presence of an early adenocarcinoma. Palpation aided by colposcopy allowed directed biopsy of the small asymptomatic lesion. This case underscores the necessity for frequent vaginal cytologic smears and pelvic examinations at intervals no greater than 6 months. Colposcopy is indicated to direct biopsies when an abnormal cytologic smears is reported or when abnormal bleeding or discharge occurs. Biopsy of any palpable lesion is mandatory.

PIP: The value of frequent routine screening of in utero diethylstilbestrol-exposed women has not been established because of lack of documented reports of patients with initially negative examinations who later developed malignancy. LB, a 19-year-old nulligravida with a history of drug exposure in utero, was 1st evaluated for vaginal adenosis at age 15. The patient was followed with Papanicolaou (Pap) smears, pelvic examination, and colposcopy every 6 months for 2 years before malignancy was discovered. After initially negative Pap smears, the patient's smears were classified as Class III 2 years later, and she was referred to the hospital where colposcopy revealed a cervical collar and extensive columnar ectopy covering the entire cervix. A transformation zone, extending onto the upper third of the vagina, showed epithelial and vascular changes characteristic of immature squamous metaplasia. A directed biopsy (aided by palpation) of the area uncovered a clear cell carcinoma. Reactive hyperplasia was present in multiple lymph nodes, and surgery (radical hysterectomy, total vaginectomy, and vaginal reconstruction) was performed. At 24 weeks postoperation, the patient was sexually active and orgasmic, and 1 year postoperation was clinically free of disease, asymptommatic, and enrolled in college, where follow-up continues. This case underscores the necessity for frequent vaginal cytologic smears and pelvic examinations at intervals no greater than 6 months. Biopsy of any palpable lesion is mandatory.

Colposcopic aspects of management of vaginal adenosis in DES children.

PIP: This report presents evidence from clinical experience of the etiological role of in utero exposure to diethylstilbestrol (DES) in vaginal adenosis of children and adolescents. Figures depict the histological pattern of adenosis lesions, and a brief history of research and serendipity leading to the causal hypothesis is reviewed. This research included 2 retrospective studies of pediatric vaginal carcinoma (circa 1927 and 1963) as well as current studies. The study summarized here was prompted by the author's extensive use of DES for high-risk pregnancy management and his resultant attempt to locate patients exposed in utero during his practice. Office records since 1948 were reviewed, comprising 10,051 charts. Using colposcopy, 20 respondents to a questionnaire have been examined, and 17 had varying degrees of vaginal or cervical abnormalities. The mothers of all cases with severe adenosis (n=9) received more than 100 mg daily during the first trimester of pregnancy. All 20 mothers had received from 15-600 mg daily. In the 3 patients without adenosis, 1 mother was treated daily with 15 mg, starting Day 78; the second was treated with 15-25 mg daily, starting on Day 28; and the third was treated with 100 mg daily for only 5 days on Day 67-72 of gestation. 2 case reports are published. The treatment method recommended is to remove all abnormal epithelium from the top of the vagina under colposcopic guidance in the operating room under general anesthesia or in the office with local anesthesia; a small Eppendorfer biopsy instrument should be used to "weed the garden."^ieng

Clear-cell adenocarcinoma of the vagina in a girl whose mother had taken diethylstilbestrol.

PIP: This case study illustrates the delayed association of administration of synthetic nonsteroidal estrogen to mothers in early pregnancy with the postmenarchial onset of vaginal adenocarcinoma in their offspring. An 18-year-old-patient, whose mother had received 25 mg of diethylstilbestrol (DES) 4 times/day during the 1st 4 months of pregnancy, presented with irregular vaginal bleeding. Pelvic examination revealed circumferential thickening and induration of the posterior vaginal wall. The area was nodular to granular and discolored by irregular hemorrhages. 1 month after biopsy confirmation, a Wertheim hysterectomy with right salpingo-oophorectomy, vaginectomy, resection of the anterior rectal segment and including pelvic lymphadenectomy, was preformed. The left oviduct and ovary were preserved, and vaginal reconstruction was also carried out. Microscopical examination of the vaginal tumor revealed clear-cell adenocarcinoma confined to the vaginal wall (Stage 1). The patient progressed normally, and was discharged on the 16th postoperative day. She remains well.^ieng

Transplacental carcinogenesis by stilbestrol.

PIP: This editorial argues the cause-and-effect relationship between in utero exposure to diethylstilbestrol (DES) and incidence of vaginal adenocarcinoma among young women. It is conjectured that the mechanism by which DES induces tumors is a result of transplacental carcinogenesis; i.e., DES causes a malignant change in any fetal cell of future vaginal tissue, resulting in a genetic defect which may not be realized until puberty, when endogenous hormone production acts as a promoter of the malignancy initiated by DES exposure during gestation. If this theory is correct, local progestational therapy may arrest future adenocarcinoma cases. Though it is obvious that DES therapy must be avoided in the future in the population of pregnant women, of more concern is the presence of residual DES in foodstuffs, particularly livestock meat. A ban of such diet supplementation of human foodstuffs is called for.^ieng