Invasive Vulvar Cancers Research Articles

Baseline Incidence of HPV-Associated Invasive and in Situ Cancers in Germany Prior to Potential Vaccination Effects

Vaccines against human papillomaviruses are covered by statutory health insurances in Germany since March 2007. A reduction of cervical and other HPV-associated cancers is expected. Incidence rates of HPV-associated cancers preceding the introduction of vaccines are unknown. These, however, are important for assessing the effects of HPV vaccines. The aim of the present study was to bridge this knowledge gap. Based on cancer registry data from seven federal states, average yearly incidence rates for cervical, anogenital, oropharyngeal cancers and cancers of the oral cavity were calculated for the period 2003 to 2007. Additionally, estimated numbers of cases give an overview on the total burden of disease caused by HPV-associated cancers in Germany. Incidence trends from 2003 to 2013 are also presented. In Germany, 11,686 cases of invasive HPV-associated cancers occurred yearly before the introduction of HPV vaccines. The most common sites are cervical cancers for women (4,387 cases) and oropharyngeal cancers for men (2,770 cases) with age-standardized incidence rates of 8.8 and 5.9 cases per 100,000 persons, respectively. The age-standardized incidence rate for in situ cervical cancers amounts to 23.5 cases per 100 000 women. Incidence trends show significant increases of invasive vulvar, penile and anorectal cancers. This work presents robust incidence data of HPV-associated cancers in Germany prior to the introduction of the HPV vaccine. Effects of HPV vaccines on the incidence of HPV-associated cancers can be estimated for Germany earliest in 2019.

Analysis of full coding sequence of the TP53 gene in invasive vulvar cancers: Implications for therapy

ObjectiveThis study evaluates the frequency and type of TP53 gene mutations and HPV status in 72 consecutively diagnosed primary invasive vulvar squamous cell carcinomas (SCC) during the past 5years. MethodsDNA of formalin-fixed and paraffin embedded tumour tissue was analysed for 32 HPV subtypes and the full coding sequence of the TP53 gene, and correlated with results of p53 immunohistochemistry. Results13/72 (18%) cancers were HPV-induced squamous cell carcinomas, of which 1/13 (8%) carcinoma harboured a somatic TP53 mutation. Among the 59/72 (82%) HPV-negative cancers, 59/72 (82%) SCC were HPV-negative with wild-type gene in 14/59 (24%) SCC and somatic TP53 mutations in 45/59 (76%) SCC. 28/45 (62%) SCC carried one (n=20) or two (n=8) missense mutations. 11/45 (24%) carcinomas showed a single disruptive mutation (3× frame shift, 7× stop codon, 1× deletion), 3/45 SCC a splice site mutation. 3/45 (7%) carcinomas had 2 or 3 different mutations. 18 different “hot spot” mutations were observed in 22/45 cancers (49%; 5× R273, 3× R282; 2× each Y220, R278, R248). Immunohistochemical p53 over expression was identified in most SCC with missense mutations, but not in SCC with disruptive TP53 mutations or TP53 wild-type. 14/45 (31%) patients with TP53 mutated SCC died of disease within 12months (range 2–24months) versus 0/13 patients with HPV-induced carcinomas and 0/14 patients with HPV-negative, TP53 wild-type carcinomas. Conclusion80% of primary invasive vulvar SCC were HPV-negative carcinomas with a high frequency of disruptive mutations and “hot spot” TP53 gene mutations, which have been linked to chemo- and radioresistance. The death rate of patients with p53 mutated vulvar cancers was 31%. Immunohistochemical p53 over expression could not reliably identify SCC with TP53 gene mutation. Pharmacological therapies targeting mutant p53 will be promising strategies for personalized therapy in patients with TP53 mutated vulvar cancers.

Trends in incidence and survival of women with invasive vulvar cancer in the United States and Canada: A population-based study

AimThe aim of this study is to estimate trends in incidence and relative survival in women diagnosed with invasive squamous cell vulvar cancer in the United States (U.S.) and Canada over the periods of 1973–2010 for U.S. and 1992–2008 for Canada. MethodsWe identified patients with primary invasive squamous cell vulvar cancers in the Surveillance, Epidemiology, and End Results cancer registry database and the Canadian Cancer Registry dataset. Women younger than 40years were excluded because of the small number of patients in this age group. A flexible parametric model was used to estimate two- and five-year relative survival ratios and excess mortality rate. ResultsIn total 15,041 patients diagnosed with invasive squamous cell vulvar cancer were included in this analysis. The incidence rate of vulvar cancer increased in both U.S. and Canada. Two- and five-year relative survival ratios decreased over time for both countries, particularly for patients 80years and over. ConclusionsThe incidence rate of invasive vulvar cancer continued to increase in U.S. and Canada while its two- and five-year relative survival ratios gradually decreased for all age groups over the last few decades. Also, excess mortality rate reaches to its peak after about 6months from diagnosis and then starts to decline. This is the first report that examine relative survival ratio for vulvar cancer in Canada and U.S. and serves as a basis for future similar studies.

Association of CXC Chemokine Receptor Type 4 Expression and Clinicopathologic Features in Human Vulvar Cancer

Although CXC chemokine receptor type 4 (CXCR4) is known to be expressed in various solid tumors and plays an integral role in cancer invasion and metastasis, expression of CXCR4 in human vulvar cancer has not yet been investigated. We examined distribution and expression of this chemokine receptor in specimens of invasive and noninvasive human vulvar neoplasms to elucidate its clinical significance. Study patients were 38 consecutive patients (31 with primary vulvar cancers and 7 with intraepithelial neoplasms) treated at one of our hospitals. Sections of all specimens were evaluated for CXCR4 expression by means of immunohistochemistry. Relations between CXCR4 expression and clinicopathologic features including prognosis were investigated. None of the 7 vulvar intraepithelial lesions expressed CXCR4. Of the 31 invasive vulvar tumor samples examined, 19 (61%) stained positively for CXCR4; 15 (68%) of 22 squamous cell carcinomas and 2 (29%) of 7 Paget tumors were CXCR4 positive. The difference in expression between invasive cancers and intraepithelial neoplasms was significant (P = 0.003). FIGO (International Federation of Gynecology and Obstetrics) stage III-IV cancers, in comparison to FIGO stage I-II cancers, were more likely to be positive for CXCR4 (82% vs 50%, P = 0.08). In terms of disease-free survival, prognosis of cancers that expressed CXCR4 was poorer than that of CXCR4-negative cancers (P = 0.013), but in terms of disease-specific survival, prognosis did not differ significantly between CXCR4-positive and -negative cancers (P = 0.111). More than half of invasive squamous cell vulvar cancers can be expected to express CXCR4, and CXCR4 expression correlates with poor disease prognosis.

Prevalence of Human Papillomavirus Types in Invasive Vulvar Cancers and Vulvar Intraepithelial Neoplasia 3 in the United States Before Vaccine Introduction

The study aimed to determine the baseline prevalence of human papillomavirus (HPV) types in invasive vulvar cancer (IVC) and vulvar intraepithelial neoplasia 3 (VIN 3) cases using data from 7 US cancer registries. Registries identified eligible cases diagnosed in 1994 to 2005 and requested pathology laboratories to prepare 1 representative block for HPV testing on those selected. Hematoxylin-eosin-stained sections preceding and following those used for extraction were reviewed to confirm representation. Human papillomavirus was detected using L1 consensus polymerase chain reaction (PCR) with PGMY9/11 primers and type-specific hybridization, with retesting of samples with negative and inadequate results with SPF10 primers. For IVC, the confirmatory hematoxylin-eosin slides were re-evaluated to determine histological type. Descriptive analyses were performed to examine distributions of HPV by histology and other factors. Human papillomavirus was detected in 121/176 (68.8%) cases of IVC and 66/68 (97.1%) cases of VIN 3 (p < .0001). Patients with IVC and VIN 3 differed by median age (70 vs 55 y, p = .003). Human papillomavirus 16 was present in 48.6% of IVC cases and 80.9% of VIN 3 cases; other high-risk HPV was present in 19.2% of IVC cases and 13.2% of VIN 3 cases. Prevalence of HPV differed by squamous cell carcinoma histological subtype (p < .0001) as follows: keratinizing, 49.1% (n = 55); nonkeratinizing, 85.7% (n = 14), basaloid, 92.3% (n = 14), warty 78.2% (n = 55), and mixed warty/basaloid, 100% (n = 7). Nearly all cases of VIN 3 and two thirds of IVC cases were positive for high-risk HPV. Prevalence of HPV ranged from 49.1% to 100% across squamous cell carcinoma histological subtypes. Given the high prevalence of HPV in IVC and VIN 3 cases, prophylactic vaccines have the potential to decrease the incidence of vulvar neoplasia.

Hospitalization in Spain associated with malignant neoplasias of the vulva and vagina (1997-2008)

An important percentage of vulvar and vaginal cancers may be attributed to infections by the human papillomavirus. Although the incidence of invasive vulvar and vaginal cancers is low, it has remained stable over the past years. Hospital discharges related to malignant neoplasias and in situ carcinomas of the vulva and vagina from 1997 to 2008 were selected from the Minimum Data Set of the Ministry of Health in Spain. 17,883 hospital admissions related to vulvar and vaginal malignant neoplasias and 2,185 admissions related to in situ carcinomas of the vulva and vagina were gathered, with a hospitalization rate of 7,054 and 0.862 discharges per 100,000 women/year, respectively. The mean age of patients was 57 (SD:18) years, and the mean length of hospital stay was 8 (SD:10) days. There was a statistically significant increase in the hospitalization rate for malignant neoplasias and in situ carcinomas with increasing patient age. This increase was significant for all locations. Overall, there was a case fatality rate of 9.34% for vulvar and vaginal malignant neoplasias and 0.46% for in situ carcinomas of an external genital organ. Mortality and case fatality rates increased significantly throughout the length of the study. 92% of all deaths occurred in those older than 55 years of age. Mortality and case fatality rates also increased significantly with age. The hospitalization rate follows a north-south pattern. These data of the pre-anti-HPV vaccine era may be useful to develop cost-effectiveness models and strategies and evaluate the impact of HPV vaccination in Spain.

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Incidence of in situ and invasive vulvar cancer in the US, 1998-2003.

The human papillomavirus (HPV) vaccine has been shown to prevent precancerous lesions of the vulva with the potential to prevent a percentage of vulvar cancers. To provide a baseline picture before HPV vaccine implementation, the authors described vulvar cancer epidemiology by age, race, ethnicity, and histology in the US. The authors examined incidence data from 39 population-based cancer registries that met high-quality data standards from 1998 to 2003, covering approximately 83% of the US population. They limited their analysis to in situ and invasive vulvar squamous cell carcinomas (SCCs). In situ vulvar cancers did not include vulvar intraepithelial neoplasia type 3 (VIN 3). SCC accounted for 77% of in situ cases and 75% of invasive vulvar cancers, an annual burden of 1498 in situ and 2266 invasive SCC vulvar cancers. Greater than 75% of the in situ and invasive SCCs had no specific histology identified. White women had the highest rates of vulvar cancer; the incidence rates of invasive vulvar SCC among black women and Hispanic women were approximately one-third lower than for their counterparts (white women and non-Hispanic women, respectively). For women aged <50 years, the age-specific rates of invasive SCC were approximately the same among whites and blacks. Increases in rates after age 50 years, however, were noted to be more rapid among white than among black women. Distinct age-specific incidence rate patterns of invasive vulvar SCC by race and ethnicity and the higher incidence rates observed among white women compared with women of other races and ethnicities were opposite to patterns noted for cervical cancer. Underestimations of the burden of in situ vulvar cancers were a result of the inability to examine VIN 3 in the authors' data. Encouragement of cancer registries to report and submit VIN 3 data and more research on data quality will allow a thorough assessment of the impact of HPV vaccine by providing a basis for examining the true burden and quality of these precancerous vulvar tumors. Increased documentation of histologic subtypes in pathology reports and in cancer registry data can help differentiate the burden ofHPV-associated types from non-HPV-associated types of vulvar cancers.

Potential role of human papillomavirus in the development of subsequent primary in situ and invasive cancers among cervical cancer survivors

The recent licensure of human papillomavirus (HPV) vaccines will likely decrease the development of primary in situ and invasive cervical cancers and possibly other HPV-associated cancers such as vaginal, vulvar, and anal cancers. Because the HPV vaccine has the ability to impact the development of >1 HPV-associated cancer in the same individual, the risk of developing subsequent primary cancers among cervical cancer survivors was examined. Using the 1992 through 2004 data from the Surveillance, Epidemiology, and End Results (SEER) program, 23,509 cervical cancer survivors were followed (mean of 4.8 person-years) for the development of subsequent primary cancers. The observed number (O) of subsequent cancers of all sites were compared with those expected (E) based on age-/race-/year-/site-specific rates in the SEER population. Standardized incidence ratios (SIRs = O/E) were considered statistically significant if they differed from 1, with an alpha level of 0.05. Among cervical cancer index cases, there was a significant elevated risk for subsequent in situ cancers of the vagina and vulva (SIRs of 53.8 and 6.6, respectively); and invasive vaginal, vulvar, and rectal cancers (SIRs of 29.9, 5.7, and 2.2, respectively). Significantly elevated risks were observed across race and ethnic populations for subsequent vaginal in situ (SIR for whites of 49.4; blacks, 52.8; Asian/Pacific Islander [API], 91.4; and Hispanics, 55.7) and invasive cancers (SIR for whites of 25.7; blacks, 34.5; API, 48.5; and Hispanics, 25.2). The results of the current study demonstrate a substantially increased risk of the development of subsequent primary in situ and invasive cancers among cervical cancer survivors and have implications for the development of prevention and early detection strategies as the role of HPV infection becomes evident.

Lateral Microscopic Extension of Squamous Cell Carcinoma of the Vulva

Purpose.The aim of this study was to measure the radial occult microscopic spread of tumor in patients with invasive squamous cell carcinoma of the vulva.Materials and Methods.In the operating room the gross tumor border was marked. The pathologist took a radial section in each quadrant and measured the distance of occult lateral spread of the tumor.Results.From 7/01/93 to 6/30/96, 24 tumors from 21 patients were studied. The mean maximum tumor diameter was 3.2 cm (0.5–7.0) and the mean depth of invasion was 9.1 mm (1.1–28.0). The gross and microscopic extent correlated in 20 tumors. Maximum lateral microscopic extent of the other 4 tumors was 3.5, 5 (to the margin), 10, and 16 mm. These 4 tumors were ulcerative and infiltrative and arose from or involved mucosa.Conclusion.The gross and microscopic periphery of most invasive squamous vulvar cancers are approximately the same. Ulcerative tumors with an infiltrative pattern of invasion which involve mucosal epithelium may be more likely to extend beyond what is grossly apparent. Measurement of the tumor-free margin should be included in future studies.

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

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. 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). 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. 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.

Cumulative Risk of Second Primary Cancers in Women with Index Primary Cancers of Uterine Cervix and Incidence of Lower Anogenital Tract Cancers, Michigan, 1985–1992

A retrospective cohort study of women with cancers of the lower anogenital tract was derived from the Michigan Tumor Registry records for the years 1985–1992. Incidence rates of invasive cervical, vulvar, vaginal, and anal cancers were analyzed with respect to age, race, year of diagnosis, stage at diagnosis, and histopathology. The incidence of metachronous primary cancers following initial primaries of the cervix was also investigated. Anogenital cancers constituted about 4% of all cancers in Michigan women between 1985 and 1992. Age-adjusted incidence rates per 100,000 women per year for each site were found to be as follows: 10.1 (cervix), 1.9 (vulva), 1.0 (vagina), and 0.6 (anus). The incidence rates of women in the United States for cancers in the anogenital region were higher in blacks than in whites, with the exception of vulvar cancer. U.S. blacks were more likely to develop squamous cell carcinomas, but less likely to develop adenocarcinomas of the cervix and vagina when compared to whites. Over the 5- to 8-year follow-up period, 6.5% of the women with index cases of cervical cancer developed second primary cancers. This represented a 40% increase in the risk of incident primary cancers compared to the risk in the general population of Michigan women. The significant occurrence of second primaries of the vagina following index primaries of the cervix suggests a shared etiology, such as infection with human papillomavirus. The incidences of cancers related to smoking, including cancers of the urinary bladder, lung/bronchus, and lower anogenital tract were also increased.

Chromosome 11 abnormalities in Bowen disease of the vulva

Chromosomal cytogenetic abnormalities are common in tumor cells and are often the basis for more detailed chromosomal mapping of tumor suppressor and oncogenes. Chromosome 11 abnormalities are frequently recognized in various neoplasms. We report a case of Bowen disease (squamous cell carcinoma in situ) of the vulva with an isolated 11p cytogenetic abnormality. A chromosome 11 paint confirmed two copies of chromosome 11 in all analyzed metaphases. An 11p subtelomeric probe confirmed an abnormality of 11p15→pter indicative of a deletion. Previous studies of invasive vulvar cancers also frequently show 11p cytogenetic abnormalities, but never as an isolated finding. The patient suffered from other diseases that may also be related to this locus. Breakage and p53 studies were normal. It is possible that an 11p abnormality in Bowen's disease is a precursor in the evolution of invasive vulva cancer.

Vulvar squamous cell carcinoma and papilloma viruses: Two separate entities?

Vulvar squamous precancers (vulvar intraepithelial neoplasia) are associated with sexual factors, cigarette smoking, and human papillomaviruses. However, epidemiologic studies of invasive carcinoma of the vulva have produced conflicting evidence for these associations, in part because of a strong association with vulvar inflammatory disease (dystrophies) in older women. We analyzed a series of 42 vulvar invasive carcinomas for papillomavirus nucleic acids by deoxyribonucleic acid-deoxyribonucleic acid in situ hybridization and correlated their presence with age, smoking history, and morphologic type. The carcinomas were divided into well-differentiated, moderately and poorly differentiated, and intraepithelial-like growth patterns, the latter composed of nests of invasive neoplastic epithelium with preserved cell polarity, similar to intraepithelial disease. Of the lesions studied, 28% were human papillomavirus deoxyribonucleic acid-positive. Intraepithelial-like neoplasms segregated in women with a younger mean age (64 versus 73 years) than that of women with conventional squamous cell carcinoma and they more frequently had a history of cigarette smoking (88% versus 28%). Moreover, intraepithelial-like lesions contained human papillomavirus nucleic acids more frequently (67% versus 13%) when analyzed by in situ hybridization. These observations confirm the diverse nature of vulvar squamous cell carcinoma and may explain in part why conflicting results are obtained from studies investigating the role of sexual and viral factors in the genesis of vulvar cancer. They suggest that many invasive vulvar cancers may not be linked to papillomaviruses.

3H-labeled subgenomic mRNA probes can demonstrate subtle differences in human papilloma virus expression in preinvasive and invasive vulvar cancers

3H-labeled subgenomic mRNA probes can demonstrate subtle differences in human papilloma virus expression in preinvasive and invasive vulvar cancers