Trends in squamous cell carcinoma of the vulva: the influence of vulvar intraepithelial neoplasia

OBJECTIVE: To determine trends in the clinicopathology of vulvar squamous cell carcinoma over the past 2 decades, with particular reference to the possible effects of the increasing incidence of vulvar intraepithelial neoplasia (VIN) during this time. METHODS: Two cohorts of 56 and 57 women with squamous cell carcinoma of the vulva and separated by at least 2 decades were reviewed retrospectively. Pathologic specimens were analyzed concurrently. RESULTS: In the 1965-1974 cohort, only one of 56 patients was younger than 50 years of age at the time of presentation, whereas in the 1990-1994 cohort, 12 of 57 (21%) were younger than 50 years of age (P = .001). Ten of 13 women younger than 50 years of age, compared with 13 of 100 of women 50 years of age or older, had warty or basaloid VIN associated with their invasive carcinoma (P < .001). Cigarette smoking and multiple lower genital tract neoplasia were both significantly more common in women younger than 50 years of age (P < .001). CONCLUSION: Over the past 2 decades, a subset of women younger than 50 years of age with squamous cell carcinoma of the vulva has emerged. Most of these carcinomas appear to arise in a field of warty or basaloid VIN. This suggests that the increasing incidence of VIN seen in young women during the past 2 decades is being reflected now in VIN-associated squamous cell carcinoma of the vulva in younger women.     

Descriptive epidemiology of vulvar and vaginal cancers in Vaud, Switzerland, 1974-1994

BACKGROUND: To analyse trends in incidence, survival and risk of second neoplasms following vaginal and vulvar cancers using data collected by the Swiss Cancer Registry of Vaud over the 21-year period 1974-1994. MATERIALS AND METHODS: Subjects were 257 vulvo-vaginal cancers. Of these, 69 were vaginal, 153 vulvar cancers, and 35 non-specified lower genital tract neoplasms; 94 in situ neoplasms were also registered (85 for the vulva). RESULTS: Invasive vaginal cancer incidence decreased from 0.8 in 1974-1984 to 0.4/100,000 women in 1985-1994, while invasive vulvar cancer incidence remained approximately stable around 1.2/100,000 (world standard); incidence of in situ vulvar cancer increased from 0.8 to 1.3/100,000, the rise being larger in younger women. Significant excesses for second primary neoplasms were observed for pro-pharyngeal and lung cancer, and for non-melanomatous skin neoplasms, as well as for invasive vulvar cancers following in situ cancers. CONCLUSIONS: This population-based dataset confirms that the incidence of in situ vulvar (but not invasive vulvar or vaginal cancer) has been increasing over the last 20 years. The excess second primary neoplasms supports the hypotheses that human papillomavirus and cigarette smoking are related to vulvo-vaginal neoplasms.     

Survival, fecundity, and development of Dermatophagoides farinae (Acari: Pyroglyphidae) at fluctuating relative humidity

OBJECTIVE: To determine the impact of margin status on disease recurrence and the incidence of occult cancer in women diagnosed with vulvar intraepithelial neoplasia (VIN) III and treated with surgical excision. METHODS: Between 1989 and 1995, 73 women were diagnosed preoperatively with VIN III by vulvar biopsy and were treated with surgical resection. Patients were examined postoperatively, and recurrence was diagnosed when a biopsy of suspicious lesions confirmed VIN III. RESULTS: The mean age was 45 years; 81% of the patients were white, and 18% were black. Eighty-two percent of the women had used tobacco, 56% had prior cervical dysplasia, and 37% had prior genital warts. An underlying squamous vulvar cancer was found in 22% of patients at initial treatment for VIN III. Fifty-nine women had follow-up of at least 7 months. Of these, 66% (39 of 59) had positive surgical margins, 31% (18 of 59) had negative margins and 3% had unknown margins (two of 59). With positive margins, 46% (18 of 39) suffered recurrent disease; with negative margins, only 17% (three of 18) had recurrent disease (P = .03). Multifocal disease and a history of genital warts also correlated with VIN III recurrence (P = .03 for both). CONCLUSION: A significant number of women diagnosed initially with VIN III on a vulvar biopsy harbored occult vulvar cancer. Recurrences were almost threefold higher when margins were positive for residual VIN III. We conclude that surgical resection is an appropriate method of treatment of VIN III for both diagnostic and therapeutic purposes.     

Intraepithelial neoplasia of the vulva

Intraepithelial neoplasia of the vulva is being seen with increasing frequency. Awareness of this should prompt the clinician to carefully inspect the vulva on all patients. Reports strongly suggest a relationship between infection with human papillomavirus and vulvar intraepithelial neoplasia. The frequency with which this disease progresses to invasive carcinoma is unknown at present. However, it is obvious that it does occur. Both the warty and basaloid types of vulvar intraepithelial neoplasia are associated with HPV infection and are often associated with invasive squamous cell carcinoma of the vulva demonstrating similar morphologic characteristics. These changes are seen more often in younger women who smoke than in the older nonsmoking woman whose lesions do not appear to be HPV related. Both local excision and the carbon dioxide laser are effective for treating vulvar intraepithelial neoplasia. The choice of which approach to take depends upon the location and size of the lesion or lesions. Whichever approach is utilized, preservation of the normal vulvar anatomy and function are of paramount importance.     

Ano-genital neoplasia in renal transplant patients

Ano-genital neoplasia is about 20 x more common in renal transplant patients than the general population. Neoplasms in the immunosuppressed are more morbid and mortal because: patients are younger; tumors are more undifferentiated; they have more and larger foci; more sites are involved; neoplasms tend to persist, recur and progress; and there are more complications from treatments. Intraepithelial neoplasia engenders some morbidity. Invasion is rarer, but when it occurs, it is always morbid, and all too often mortal. Invasive ano-genital cancer is primarily preventable because the lower genital and anal tracts are accessible to inspection, cytologic screening, endoscopy and biopsy. Prime prevention is avoiding infection with the Human Papilloma Virus (HPV). Next best is detecting HPV/intraepithelial neoplasia early with frequent inspection, cytology and liberal biopsies; and then removing any condylomas or intraepithelial neoplasia that develop.     

Failure of isotretinoin and interferon-alpha combination therapy for HPV-linked severe vulvar dysplasia. A report of two cases

BACKGROUND: Retinoids (RA) and interferon (IFN) have been reported to be active against a variety of tumors and human papillomavirus (HPV)-related lesions. Because chronic and recurrent HPV-linked vulvar intraepithelial neoplasia 3 (VIN 3) have a high risk of invasion, we evaluated combined therapy of IFN-alpha with 13-cis-retinoic acid (13 cRA) in the treatment of two VIN 3 cases of this type. CASE: Two patients with chronic and recurrent VIN 3 were treated with combined therapy of IFN-alpha (4.5 x 10(6) five times a week) and 13 cRA (1 mg/kg/d) for six months. Clinical regression was observed at the end of treatment in both cases, but histologic features of VIN 3 were still present. CONCLUSION: These data demonstrate the ineffectiveness of the combined regimen of IFN-alpha and 13 cRA with this schedule for a period of six months in recurrent and chronic VIN 3.     

Breast cancer risk: protective effect of an early first full-term pregnancy versus increased risk of induced abortion

PURPOSE/OBJECTIVES: To examine the question of whether an early first full-term pregnancy (FFTP) protects against breast cancer and whether interruption of the pregnancy with an induced abortion increases breast cancer risk. DATA SOURCES: Published medical and epidemiology journal articles, books, scientific reports, news interviews of researchers, scientific journals. DATA SYNTHESIS: Continually increasing breast cancer rates cannot be explained by the American Cancer Society risk factors, which account for only 25% of cases. Induced abortion is a newly recognized risk factor and has been prevalent in our society since it was legalized in 1973. CONCLUSIONS: Early FFTP confers protection, while induced abortion confers risk. Most specific and controlled variables studies indicate 150% risk for abortions performed on women younger than 18 years of age. Studies have yet to discover the full impact of induced abortion because women who underwent legalized abortion in 1973 are just reaching ages of highest breast cancer incidence. IMPLICATIONS FOR NURSES: Awareness of a controversial risk factor and its relevance to women allows nurses to include this information when educating and supporting patients. Specifically, nurses need to include questions on this reproductive risk when eliciting a patient's reproductive history. Nurses should further be aware of the emotional impact disclosure may have.     

Patterns of allelic loss (LOH) in vulvar squamous carcinomas and adjacent noninvasive epithelia

The pathogenesis of carcinoma of the vulva is diverse and includes both human papilloma virus (HPV)-positive and HPV-negative pathways. The objective of this study was to correlate the morphology with patterns of loss of heterozygosity (LOH) within four vulvar carcinomas and in adjacent vulvar epithelia. Tumors were categorized as HPV positive or negative by polymerase chain reaction (PCR) analysis. Forty-one different sites of normal squamous mucosa, hyperplasia, vulvar intraepithelial neoplasia (VIN), and carcinoma were microdissected in duplicate, and each extracted DNA was analyzed in duplicate for LOH at 10 chromosomal loci by PCR and polyacrylamide gel electrophoresis. Patterns of LOH were compared within different sites of tumors and between the tumor and the noninvasive epithelia. Of three tumors with multiple invasive foci analyzed, divergent patterns of LOH were identified in two, correlating in one with differences in tumor grade. In one HPV-16-positive case, multiple sites of VIN displayed heterogeneity for LOH consistent with divergent clonal or subclonal populations, some of which were not shared by the tumor. In one HPV-negative case, LOH was found in foci of hyperplasia and differentiated VIN (atypical hyperplasia), the latter sharing LOH with the invasive carcinoma at some but not all chromosomal loci. This study suggests that a genetic relationship exists between VIN and carcinoma, irrespective of HPV involvement. It also suggests that in HPV-negative tumors, allelic loss may predate the onset of invasive carcinoma and, in some cases, cellular atypia (VIN). However, the divergent patterns of LOH observed imply that many genetic alterations in the adjacent vulvar epithelium are not directly related to the invasive carcinoma.     

Role of CD4+ and CD8+ T cells in regulating the chronic development of liver injury induced by delayed-type hypersensitivity to picryl chloride

Lectins were used to investigate the cell surface oligosaccharide expression in normal vulvar epithelium from premenopausal and postmenopausal volunteer women. In addition, histologically normal epithelium adjacent to high-grade vulvar intraepithelial neoplasia (VIN III) and adjacent to vulvar tumors was examined with lectins for evidence of a possible "field change" surrounding these vulvar lesions. Seventeen vulvar biopsies were obtained prospectively from volunteer women, and 20 and 40 cases, respectively, of VIN III and vulvar squamous cell carcinoma were randomly chosen from pathology archives. Thirteen of the 20 VIN cases and all 40 vulvar carcinomas contained at least 2 cm of histologically normal-appearing epithelium adjacent to the vulvar lesion suitable for analysis. No alterations to lectin binding in normal vulvar epithelium with respect to patient age, menopausal status, phase of menstrual cycle, estrogen therapy, or history of cervical intraepithelial neoplasia were shown. ABO blood group antigen status affected epithelial binding for lectins HPA and UEAI (p < 0.005 and p < 0.001, respectively). In addition, lectins SNA, MPA, and LCA identified markers of cellular differentiation and maturation. T-antigen expression (as shown by the lectin PNA) was almost universally present in histologically normal epithelium adjacent to VIN and vulvar tumors, contrasting with the lack of PNA binding in normal vulvar epithelium from volunteer women (p < 0.001 and p < 0.001), a finding suggestive of a local "field change" surrounding preinvasive and invasive vulvar lesions.     

Vulvar vestibulitis is rarely associated with human papillomavirus infection types 6, 11, 16, or 18

Vulvar vestibular biopsy specimens from 31 women with clinical and pathologic findings of vulvar vestibulitis were studied using polymerase chain reaction (PCR) for the identification of human papilloma virus (HPV). The PCR technique specifically probed for HPV types 6, 11, 16, and 18. Of the 31 subjects, three were found to have HPV within the biopsy specimens; two had HPV type 11 and one had HPV 16. Five of the 31 cases had histopathologic features of koilocytosis consistent with HPV effect; three of these five were found to have HPV. The findings support the hypothesis that HPV types 6, 11, 16, and 18 are rarely associated with vulvar vestibulitis. The frequencies identified were similar to those seen with control patients. True koilocytosis is the most useful pathologic feature distinguishing HPV-related cases; it is rarely identified in typical vulvar vestibulitis. Nonspecific changes in the vestibular epithelium associated with glycogen effect should not be interpreted as koilocytosis.     

The surgical therapy of prostatic tumors]

A random sample of 26,000 Swedish women who were asked about their smoking habits in the early 1960s have now been followed for 26 years with respect to cancer incidence. Most findings regarding tobacco smoking and cancer from studies of men were confirmed also among the women. Elevated relative risk for current smokers compared with women who never smoked regularly were seen for cancers of the lung, upper aerodigestive sites, pancreas, bladder, cervix and all cancers combined, as well as a notably high relative risk for cancers of organs of the urinary tract other than kidney and bladder. Relative risk increased with dose, measured as grams of tobacco smoked per day, for cancers of the upper aerodigestive sites, lung, cervix, bladder, organs of the urinary tract other than kidney and bladder and all cancers combined. For cancers of the lung, bladder and cervix, there was an inverse relationship with age when starting to smoke tobacco. The reported inverse relationship between smoking and endometrial cancer could not be corroborated, nor was there any significant relationship between smoking and colorectal or breast cancer.     

A prospective, seroepidemiological study of the role of human papillomavirus in esophageal cancer in Norway

Infection with the human papillomavirus (HPV), notably HPV type 16, has been associated with esophageal cancer in seroepidemiological studies. To evaluate the consistency of the association, we performed a nested case-control study of HPV seropositivity and risk of esophageal cancer within a prospectively followed cohort of 300,000 Norwegian men and women who had donated blood samples to a serum bank. The data file of the serum bank was linked with the nationwide Cancer Registry of Norway to identify esophageal cancers diagnosed after donation of the serum sample. Fifty-seven cases and 171 matched controls were analyzed for antibodies to specific microorganisms, and odds ratios for developing esophageal cancer were calculated. There was an increased risk of developing esophageal cancer among HPV 16-seropositive subjects (odds ratio = 6.6; 95% confidence interval, 1.1-71) but not among Chlamydia trachomatis-seropositive subjects. Adjustment for the presence of serum cotinine, a marker of smoking habits, did not affect the estimates substantially. The seroepidemiological association between HPV 16 and esophageal cancer seems to be consistent in different countries.     

Risk factors for HPV detection in archival Pap smears. A population-based study from Greenland and Denmark

The most important risk factor for cervical cancer is genital infection with certain types of human papillomavirus (HPV). The presence of HPV was studied in archival smears from a random sample of women living in Greenland (GW) and Denmark (DW) having, respectively, a high risk and an intermediate risk for cervical cancer. Risk factors were also examined of the original 126 Danish and 129 Greenlandic archived smears collected during October and November 1988. 125 were located from each country including all abnormal smears. HPV DNA was isolated from the smears and detected by means of a consensus polymerase chain reaction (PCR) detecting a broad spectrum of genital HPV types. HPV was detected in all the abnormal smears and in 22 and 33% respectively of the cytological normal smears from DW and GW. Risk of HPV was significantly higher in smears from women who started sexual life relatively recently (respectively, < or = 4 and < or = 6 years ago in DW and GW) compared with > or = 10 years ago (adjusted prevalence-OR: 9.3; 95% CI: 2.2-39.2 in DW and 5.9; 95% CI: 1.4-25.3 in GW). Among other important risk factors were age in both areas, lifetime number of sex partners and current smoking in DW and ever and gonorrhoea in GW. This study confirms the usefulness of the method as all abnormal smears were positive and, furthermore, the predictors for HPV presence in the normal smears corroborate with those found in recent studies of HPV in fresh cervical swabs. Thus, this method can be useful for large-scale epidemiological studies of HPV DNA in already sampled material.     

Clinicopathological features of human papilloma virus associated squamous cell carcinomas of the vulva

OBJECTIVE: To investigate the relationship between human papilloma virus (HPV) status and clinicopathological features of vulva carcinoma and its clinical significance. METHODS: Histological sections of 37 cases of vulval carcinoma were subclassified. Standard PCR (HPV types 6/11, 16, 18) were applied to formalin fixed, paraffin wax sections. RESULTS: There were 24 cases of keratinizing squamous cell carcinoma (KSC), 7 cases of basaloid carcinoma (BC) and 6 cases of warty carcinoma (WC). HPVs, Mainly HPV 16, were detected in 10 of the 37 cases, and all of them were women with BC and WC types. Although BC and WC constituted 35% of the total number of cases, the HPV detective rate was significantly higher than that of KSC (83.3% vs 0.0%), and the tumors were frequently accompanied by valvar intra-epithelial neoplasm (VIN). Clinically, women with BC and WC were younger than women with KSC (mean age at diagnosis for WC, BC and KSC were 36.7, 58.9, 63.3 years respectively). Besides, the incidence of lymph node metastasis in BC and WC were lower than that in KSC (7.6% vs 25.0%). BC and WC were more likely to have another invasive or noninvasive squamous neoplasm of the cervix and vagina (3/13 vs 0/24), and recurrence rate was higher (12.5% vs 7.7%). However, their survival rates following surgical treatment of recurrences were also higher. Squamous cell carcinoma of the vulva are etiologically diverse tumors which have different clinical and pathological profiles. CONCLUSION: It is suggested that an etiological classification of squamous carcinoma of the vulva may at least be grouped at present into a small but substantial proportion (BC and WC) related to HPV and the majority portion (KSC) of unknown etiology.     

Perinatal transmission and maternal risks of human papillomavirus infection

We conducted a prospective study to investigate whether human papillomavirus (HPV) could be vertically transmitted to neonates. Pregnant women (N = 203) were tested for HPV DNA infection during the third trimester and again during labor prior to delivery. Their newborns (N = 203) were tested 1 to 3 days after delivery. Among the mothers, 12.3% (N = 25/203) typed HPV positive at either or both maternal specimen collection periods, whereas only 1.0% of the neonates (N = 2/203) typed positive. This low transmission rate may be due in part to the fact that 65% of mothers who were HPV positive during the third trimester tested HPV negative by labor/delivery. The higher frequency of risks associated with maternal HPV infection were similar to those found in studies of cervical dysplasia and cancer: younger age at first intercourse and first pregnancy, number of sexual partners, and longer duration in use of oral contraceptives. In addition, those who were past smokers and had a shorter recency and latency period in smoking were more likely to be detected with HPV.     

Glycation accelerates the oxidation of low density lipoprotein by copper ions

The American Cancer Society recommends periodic mammography, clinical breast examination and breast self-examination beginning at age 40 years for asymptomatic women at average risk of breast cancer. Although there is substantial evidence from meta-analyses and non-randomized studies to support these recommendations, individual randomized clinical trials of breast cancer screening have not demonstrated mortality reduction in women aged 40-49 years. The opportunity to study this issue further in the United States has been diminished by the high prevalence of screening already being conducted in that population of younger women. The International Union Against Cancer, the American Cancer Society and the National Cancer Institute of the United States have convened a series of workshops and planning meetings to consider the available data and outline plans for future research. Plans are being developed to conduct a randomized trial of mammography in women younger than 50 years in multiple European sites. Successful completion of this trial may provide critical data on efficacy of breast cancer screening in younger women.     

Angiogenesis in vulvar intraepithelial neoplasia

Vulvar intraepithelial neoplasia (VIN) has been reported to be a precursor of invasive vulvar cancer. Switching to the angiogenic phenotype is considered a key step in tumor growth. Microvessel density (MVD) and vascular endothelial growth factor (VEGF), a highly angiogenic peptide, are important parameters of tumor angiogenesis. Forty-three histologic slides with 38 VIN I-III lesions were immunohistochemically stained for factor VIII-related antigen (F8-RA) and 44 slides with 37 VIN I-III for VEGF, since F8-RA reliably highlights tumor microvessels. Determination of MVD and VEGF expression was done by counting microvessels and VEGF-positive cells at a magnification of 200x and 400x. The highest concentration of F8-RA-stained MVD and VEGF expression was found at a small subepithelial area at the border of the VIN lesion to the stroma underneath but concentrations were low in all specimens of normal epithelium. High VEGF expression was significantly correlated to high MVD. For both MVD and VEGF expression the differences between VIN I and VIN III and between VIN II and VIN III were statistically significant (P < 0.0001). VIN III lesions are the clinical relevant precursors of invasive cancer of the vulva, as outlined by intense expression of VEGF protein and a highly dense network of microvessels underlying the dysplastic epithelium.     

Surgery for gynecologic cancer

Surgery is an integral part of staging procedures for ovarian, endometrial, and vulvar cancers, with a move toward surgicopathologic rather than clinical staging in cervical cancer. Morbidity can be reduced without compromising patient cure by individualizing surgery for patients with early vulvar cancer, and reproductive potential can be maintained in some women with early ovarian cancer. The place of prophylactic oophorectomy and primary and secondary surgery in ovarian cancer remain controversial and await prospective study. Recent developments in laparoscopic techniques have been applied to a number of problems in gynecologic cancer surgery, and the feasibility of laparoscopic lymphadenectomy and radical pelvic surgery has been demonstrated. Care must be taken, however, to ensure that the tenets of surgical oncology are not sacrificed in order to offer minimal-access surgery to women with gynecologic cancer.     

A model for the effect of cigarette smoking on lung cancer incidence in Connecticut

Population based data on smoking history derived from NCHS surveys were used to develop a model for lung cancer incidence in Connecticut. Trends in smoking prevalence suggest that, while the prevalence in men increased earlier than women, more male smokers have quit than their female counterparts. These trends in smoking prevalence suggest striking gender differences in a period effect for the smoking prevalence. Estimates of the proportion of current smokers, ex-smokers, and the mean duration of smoking were used in a model for the lung cancer incidence rates. The form for the relationship between smoking history and the incidence rate for these subgroups was based on information from cohort studies. The models represented a mixture of the smoking subgroups where the effect of smoking was considered to be either a multiplicative effect on the underlying age distribution, or a separate effect in which the level of exposure was the sole contribution to risk among smokers. The multiplicative model explained more than 80 per cent of the deviance for the period and cohort effects, while the non-multiplicative model could only account for trends in females. Hence, these results suggest that a sizeable portion of the period and cohort contributions to the lung cancer incidence trends in Connecticut can be attributed to the multiplicative model that utilizes this smoking information, although the lack of more detailed information is a limiting factor in developing the model.     

The effects of tamoxifen treatment on the endometrium

OBJECTIVE: To investigate the association between tamoxifen and endometrial cancer. BACKGROUND: Tamoxifen is a nonsteroidal antiestrogenic drug that has been used successfully for 15 years in the treatment of all stages of breast carcinoma. In light of the positive results, several studies are now being conducted to test prolonged tamoxifen treatment as a prophylaxis against breast cancer in high-risk women. Although tamoxifen was thought to have only a few side effects, reports indicate that it is associated with an increased incidence of proliferative and neoplastic changes in the endometrium. As the current trend is to administer tamoxifen for prolonged periods and for more indications, the detrimental effects on the endometrium have vast implications. METHODS: Review of the current literature. RESULTS: Tamoxifen treatment is associated with an increased incidence of proliferative and neoplastic changes in the endometrium, with a 1.3 to 7.5 relative risk of developing endometrial carcinoma. CONCLUSIONS: The results of tamoxifen treatment in breast carcinoma override the risk of developing endometrial carcinoma. Any vaginal bleeding in women treated with tamoxifen should be investigated carefully and promptly. In the future it may be necessary to advise these women to undergo routine uterine cavity examination.