In the absence of (early) invasive carcinoma, vulvar intraepithelial neoplasia associated with lichen sclerosus is mainly of undifferentiated type: new insights in histology and aetiology

BACKGROUND: Differentiated vulvar intraepithelial neoplasia (VIN) is presumed to be the precursor of invasive squamous cell carcinoma (SCC) of the vulva. It is commonly assumed that differentiated VIN is related to lichen sclerosus (LS). However, evidence for this is limited to a small number of studies describing epithelial alterations adjacent to vulvar SCC. AIM: To study the histology and human papillomavirus (HPV) status in patients with a history of both LS and VIN without coexistent SCC. METHODS: Original biopsy specimens and surgical specimens of patients retrieved from the pathology files were revised for the presence of LS, VIN and (early) invasive SCC, specifically focused on the two different types of VIN: differentiated and undifferentiated. Thereafter, VIN lesions were tested for the presence of HPV DNA. RESULTS: Twenty-seven patients fulfilled the criteria for LS and VIN without SCC. In all 27 patients, LS was found to be related to undifferentiated VIN. Grading yielded the following results: VIN 1 (n=10), VIN 2 (n=11) and VIN 3 (n=6). Additionally, VIN lesions from 26 patients could be tested for the presence of HPV DNA. HPV DNA, predominantly type 16, was present in 8 (31%) of them. Seven of these eight patients had VIN 2 or 3. During follow-up, three patients progressed to (early) invasive carcinoma. In two of these patients, differentiated VIN was observed overlying early invasive SCC. CONCLUSIONS: VIN related to LS without coexisting SCC is likely to be undifferentiated, in contrast to what was previously thought. HPV DNA was demonstrated in 31% of the lesions, and was strongly related to high-grade VIN.     

Review of precancerous vulvar lesions

Classification of squamous vulvar precancerous lesions is based on the concept of vulvar intraepithelial neoplasia (VIN) and incorporates a three grade evaluation of the intensity of dysplastic changes (VIN I, II and III). On the basis of histological features, VIN has been subdivided into the usual VIN (u-VIN) and differentiated VIN (d-VIN), which represent the two basic pathways of the pathogenesis of vulvar squamous cell carcinoma. Although u-VIN is etiologically associated with the human papillomavirus (HPV) infection and histologically corresponds to cervical intraepithelial neoplasia, d-VIN represents the HPV-negative sequence of vulvar carcinogenesis, which is linked to lichen sclerosus (LS) and lichen simplex chronicus (LSC). u-VIN preferentially occurs in relatively young women with a history of cervical, vaginal or vulvar premalignant lesions. On the other hand, d-VIN usually affects postmenopausal women without anamnestic data of other dysplastic lesions of the lower female genital tract. d-VIN is characterized by a higher tendency of stromal invasion than u-VIN and its malignant potential is analogous to carcinoma in situ (VIN III). The histological appearance of d-VIN is subtle with basal atypia and a well-preserved differentiation of the superficial parts of the squamous epithelium, therefore it is frequently misdiagnosed for u-VIN I, LS or LSC in vulvar biopsies. Primarily because of the low diagnostic reproducibility of the u-VIN I category and the doubts about its precancerous potential as well as due to the questionable differentiation between u-VIN II and III, a revised VIN classification was proposed in 2004. The grading of vulvar precancerous lesions was abandoned, the u-VIN I category was discontinued and u-VIN II and III were merged. In the revised terminology, the term u-VIN represents HPV-associated high grade precancerous vulvar lesions (formerly u-VIN II and III) and d-VIN encompasses HPV-negative high grade dysplasias. Keywords: vulvar intraepithelial neoplasia - VIN of the usual type - VIN of the differentiated type - lichen sclerosus - lichen simplex chronicus - HPV.     

HPV-assoziierte Ver?nderungen an Vulva und Vagina

Non-neoplastic HPV-induced alterations of the vulva and vagina are frequent. The traditional three-tier grading system of vulvar intraepithelial neoplasia (VIN) will be replaced by the definition of usual and simplex type of VIN. The usual type is characterized by a strong association to high-risk HPV infections, the occurrence at younger age and multifocality, mostly associated with non-keratinizing squamous cell carcinoma. The differentiated (or simplex) type is rare and shows an association to older age and p53 alterations and is typically diagnosed co-incidentally with keratinizing squamous cell carcinoma. Vaginal intraepithelial neoplasia (VAIN) is still graded into VAIN 1-3 where VAIN?1 and 2 are mostly associated with low-risk HPV infections and a high spontaneous regression rate whereas VAIN 3 represents a high-risk HPV-associated lesion with capable progression into (micro-)invasive carcinoma. The differential diagnosis between a non-neoplastic condylomatous lesion and VIN common type and VAIN may be aided by p16 immunohistochemistry. The HPV-associated invasive vulvo-vaginal cancers are verrucous carcinoma (low-risk HPV) and the high-risk HPV-induced (non-keratinizing) squamous cell carcinoma (NOS), the condylomatous (warty) carcinoma and the very rare vaginal squamo-transitional carcinoma.     

Immunohistochemical localization of telomerase hTERT protein and analysis of clonality in multifocal vulvar intraepithelial neoplasia

Vulvar intraepithelial neoplasias (VINs) are potentially premalignant lesions of the squamous mucosa. The immunohistochemical distribution of the catalytic protein subunit of telomerase (hTERT) and the patterns of X chromosome inactivation were investigated as markers of neoplasia in samples from a patient with multifocal and diffuse VIN. hTERT nuclear staining in VIN correlated with squamous maturation and the degree of nuclear atypia. Normal mucosa revealed faint nuclear staining of parabasal cells and lower intermediate layer squamous cells. Monoclonal composition was demonstrated in 0 of 3 samples of VIN1, 2 of 3 samples of VIN2, and 13 of 13 samples of VIN3. The patterns of X chromosome inactivation indicated intramucosal extension and multifocal origin of individual lesions. Five samples of histologically normal vulvar squamous epithelium revealed a random pattern of X chromosome inactivation, consistent with polyclonal composition. All 19 samples from 9 lesions contained human papillomavirus (HPV)-16 sequences. Neither mutations in the p53 tumor suppressor gene or K-ras oncogenes nor loss of heterozygosity at 7 chromosomal loci were detected in any of the 19 samples of VIN. These results demonstrate that HPV-associated VIN may result from multifocal and diffuse 2-dimensional intraepithelial expansion of an immortalized monoclonal cell population.     

Aberrant promoter methylation of SH3GL2 gene in vulvar squamous cell carcinoma correlates with clinicopathological characteristics and HPV infection status

Objective: This study attempted to examine the methylation status of SH3GL2 gene in different types of human vulvar lesions and its correlation with clinicopathological parameters. Methods: Immunohistochemical analysis was used to identify the expression status of SH3GL2 in vulvar squamous cell carcinoma (VSCC), vulvar intraepithelial neoplasia (VIN) and benign vulvar squamous epithelium tissues. Bisulfite genomic sequencing method was used to detect methylation status of the SH3GL2 gene. Clinicopathological correlation of the alterations was analysed by the chi-square tests. Results: Immunohistochemical analysis showed expression of SH3GL2 in VSCC was significantly downregulated than that in VIN and normal vulvar tissues. In accordance with higher frequency of methylation status in SH3GL2, statistical analysis showed methylation status of SH3GL2 was closely related to tumor TNM stage (P=0.003), but not related to age, tumor volume, tumor differentiation, lymph node metastasis and VIN grade. High-methylation status of SH3GL2 showed significant association with HPV infection status. Conclusions: Our results indicated that the methylation status of SH3GL2 gene was associated with the TNM staging and HPV infection status of VSCC, suggesting that it might play a synergistic role in the development of VSCC.     

Pathologisch-anatomische Aufarbeitung und Befundung von Präparaten bei Präkanzerosen und Karzinomen der Vulva

On the basis of varying morphology and pathogenesis, two types of vulvar intraepithelial neoplasias (VIN) have been defined: the common type (~98%), classic VIN, is characterised by strong association to high-risk HPV infection (up to 90%), occurrence at younger age (median age 30--40 years) and multifocality. The differentiated (or simplex) type is rare (1%--2%) and is associated with older age (median age 65 years) and p53 alterations. It is usually diagnosed in combination with vulvar (keratinizing) squamous cell carcinoma. The classification currently preferred by the WHO in which VIN are classified into VIN 1--3 is to be replaced due to new data and according to a proposal by the International Society for the Study of Vulvovaginal Diseases (ISSVD) which eliminates VIN 1 and combines VIN 2 and 3 to VIN of common or, depending on histopathology, differentiated type. Prognostically relevant factors in vulvar cancer include stage of disease, inguinal lymph node involvement, size of metastatic deposits and presence of extracapsular extension, depth of invasion and distance of the tumor from resection margins. Tumor grade and the presence of lymphovascular space involvement are controversially discussed.     

Pathways of vulvar intraepithelial neoplasia and squamous cell carcinoma

Vulvar squamous cell carcinoma (VSCC) accounts for >90% of the malignant tumours of the vulva. Most VSCCs originate in intraepithelial lesions, named vulvar intraepithelial neoplasia (VIN), that precede the development of VSCC by a variable period of time. Strong evidence has accumulated showing that there are two different aetiopathogenic pathways for the development of VSCC and VIN, one associated with infection by human papillomavirus (HPV), and a second independent of HPV infection. These two different types of VSCC have different epidemiological, pathological and clinical characteristics, and should therefore be considered as two separate entities. Histologically, HPV‐associated VSCCs are of the basaloid or warty type, and arise from VIN of the usual type. Inactivation of p53 and the retinoblastoma tumour suppressor gene product by the viral gene products E6 and E7 is involved in the process of malignant transformation. HPV‐independent VSCCs are histologically keratinizing, are associated with differentiated VIN and lichen sclerosus, and frequently show mutations of p53. p16^INK4a and p53 immunostaining can be useful for classifying VSCC into HPV‐associated or HPV‐independent. Although large, multicentre studies are needed to definitively assess the involvement of HPV in the prognosis of VSCC, most studies have not found clear differences in survival between HPV‐associated and HPV‐independent tumours.     

Chromosome 17 aneusomy detected by fluorescence in situ hybridization in vulvar squamous cell carcinomas and synchronous vulvar skin

Vulvar squamous cell carcinoma (SCC) affects a spectrum of women with granulomatous vulvar diseases, human papillomavirus (HPV) infections, and chronic inflammatory vulvar dermatoses. To determine whether there is evidence of chromosomal instability occurring in synchronous skin surrounding vulvar SCCs, we investigated abnormalities in chromosome 17 copy number. Samples of SCC, vulvar intraepithelial neoplasia (VIN), and surrounding vulvar skin were obtained from all vulvar excisions performed for squamous neoplasia at Albany Medical College from 1996 to 1997. Histological categorization, fluorescent in situ hybridization (FISH) for the alpha satellite region of chromosome 17, DNA content by image analysis, and Ki-67 labeling were evaluated. Controls of normal vulvar skin not associated with cancer were used for comparison. One hundred ten specimens were obtained from 33 patients with either SCC or VIN 3 and consisted of 49 neoplastic, 52 nonneoplastic, and 9 histologically normal vulvar skin samples. The majority of SCCs (88%) and a minority (18%) of VIN 3 excisions were associated with lichen sclerosus. Normal vulvar skin controls did not exhibit chromosome 17 polysomy (cells with more than four FISH signals), whereas 56% of normal vulvar skin associated with cancer did. Moreover, the frequency of polysomy significantly increased as the histological classification progressed from normal to inflammatory to neoplastic lesions. The largest mean value and variance for chromosome 17 copy number was identified in SCCs (2.4 +/- 1.0) with intermediate values identified, in decreasing order, for SCC in situ (2.1 +/- 1.0), VIN 2 (2.1 +/- 0.8), lichen sclerosus (2.0 +/- 0.5), lichen simplex chronicus (1.9 +/- 0.4), and normal skin associated with SCC (1.8 +/- 0.4) compared with control vulvar skin (1.5 +/- 0. 05). Concordance of chromosome 17 aneusomy between cancers and synchronous skin lesions was found in 48% of patients. Loss of chromosome 17 was identified 5% of all samples and was significantly associated with women with SCC in situ (HPV-related). Both DNA content and Ki-67 labeling positively and significantly correlated with mean chromosome 17 copy number (r = 0.1, P: = 0.007). A high degree of genetic instability (aneuploidy) occurs in the skin surrounding vulvar carcinomas. As these events could be detected in histologically normal skin and inflammatory lesions (lichen sclerosus), chromosomal abnormalities may be a driving force in the early stages of carcinogenesis. Differences in chromosomal patterns (loss or gain) support the concept of at least two pathways in vulvar carcinogenesis.     

Monoclonal gamma-T-cell receptor rearrangement in vulvar lichen sclerosus and squamous cell carcinomas

Risk factors for vulvar squamous cell carcinoma (SCC) are human papilloma virus (HPV) infections and lichen sclerosus (LS). The significance of monoclonal gamma-T-cell receptor (gamma-TCR) rearrangement in the lymphoid infiltrate of LS and the consequence for vulvar carcinogenesis is unknown. One hundred sixty-one biopsies of vulvar LS and SCC, with and without LS, were examined for monoclonal gamma-TCR rearrangement and HPV16 expression, and for the expression of B- and T-cell markers and fascin. Monoclonal gamma-TCR rearrangement was identified in 8 of 17 patients with LS and 11 of 21 patients with SCC arising in LS with only occasional HPV16 DNA detection. None of the 19 SCC without LS showed monoclonal gamma-TCR rearrangement, but 14 of 19 patients had strong HPV16 detection. The lichenoid infiltrate of LS with germline configuration consisted predominantly of T cells (CD8 > CD4), along with numerous B cells. However, in biopsies with monoclonally rearranged gamma-TCR, CD4-positive T cells dominated along with B cells and fascin-positive cells in the lichenoid infiltrate and in deeply located lymphocyte aggregates (LAs). These LAs additionally contained fascin-positive dendritic cells with only individual CD8, CD57, and granzyme-positive cells. LAs in biopsies with germline configuration demonstrated numerous T cells (CD8 >CD4), but only single peripheral B cells, CD57, and fascin-positive lymphocytes. Our data suggest that monoclonal gamma-TCR rearrangement is characteristic for and limited to LS and SCC arising in LS, raising the question for a LS-associated antigen. We interpret B cells, CD4-positive T cells, and fascin-expressing dendritic cells within LS as a cellular immune response to antigen or proliferating T-cell clones. The resulting local immune dysregulation in LS may provide a permissive environment for the development of a SCC.     

人乳头状瘤病毒不同型别与宫颈病变的相关性研究

目的探讨人乳头状瘤病毒（ＨＰＶ）不同型别与宫颈病变性质的关系。方法应用ＰＣＲ技术和原位杂交方法对６１例宫颈上皮内瘤（ＣｅｒｖｉｃａｌｉｎｔｒａｅｐｉｔｈｅｌｉａｌＮｅｏｐｌａｓｉａＣＩＮ）和１２例宫颈鳞癌（ＳＣＣ）进行ＨＰＶ６Ｂ／１１、１６、１８ＤＮＡ检测。结果ＰＣＲ检测结果显示ＨＰＶ６、１１主要分布于低度鳞状上皮内病变（６１９％）和一部分ＣＩＮⅡ中（２０％），而在ＣＩＮⅢ和ＳＣＣ中检测不到；ＨＰＶ１６、１８的检出率随ＣＩＮ级别增高而增加，在ＳＣＣ中高达８３３％。原位杂交结果显示在低度鳞状上皮内病变中，地高辛（Ｄｉｇ）标记的ＨＰＶ６Ｂ／１１、１６、１８ＤＮＡ杂交物质在核中均呈细颗粒状，为“游离型”。上述杂交阳性信号形态亦出现于ＣＩＮⅡ的所有ＨＰＶ６Ｂ／１１及部分ＨＰＶ１６、１８型感染中，而ＣＩＮⅢ和宫颈鳞癌及部分ＣＩＮⅡ中，其杂交阳性信号均为非颗粒状的“整合型”。结论低度鳞状上皮内病变是以ＨＰＶ６、１１低危型为主的多型别病毒的繁殖性感染，ＣＩＮⅢ和宫颈鳞癌为ＨＰＶ１６、１８高危型病毒的整合型感染，而在ＣＩＮⅡ中存在着ＨＰＶ６，１１和ＨＰＶ１６，１８的繁殖性感染及ＨＰＶ１６，１８的整合型感染     

女性下生殖道癌临床病理特征与人乳头状瘤病毒型别间的相关性研究

目的：探讨女性下生殖道癌的临床病理与人乳头状瘤病毒（HPV）型别之间的关系。方法：回顾性研究100例下生殖道癌（宫颈癌63例,外阴癌37例）的临床病理特征,并应用PCR技术检测每份标本的HPV状态。结果：在模板内参照阳性的87份中,宫颈癌54份,外阴癌33份,HPV阳性率在宫颈癌中为88．3％,以HPV16型（55．6％）和HPV18型（24．4％）为主,在33例外阴鳞癌中,HPV阳性仅见于基底细胞癌和混疣样癌,阳性率均为83．3％,以HPV16型为主（70．0％）;6例基底细胞样癌中有3例合并宫颈鳞状上皮肿瘤,其中2例宫颈与外阴的肿瘤均为HPV16型阳性;21例角化鳞癌则未检测出HPV－DNA,但有发病年龄高（平均63．3岁）。形态学上角化明显和预后较差等特征。结论：HPV16型和18型在宫颈癌中性阳率较高,而在外阴癌中HPV阳性的意义则因组织学类型而不相同。     

HPV DNA in intraepithelial neoplasia and carcinoma of the vulva and penis.

Surgical specimens of 15 patients with early and 12 patients with advanced squamous cell carcinoma of the vulva and the penis were examined for the presence of human papillomavirus (HPV) type 6, 11, 16, and 18 DNA by Southern blotting (SB) and polymerase chain reaction (PCR) analysis. By SB, HPV type 16 DNA was detected in all early carcinomas and 2 of 12 cases of advanced squamous cell carcinoma (ISCC) of the vulva and penis. PCR revealed HPV DNA in four additional cases of vulvar and penile ISCC negative by SB. Three cases contained HPV16 and one HPV18. Two cases of vulvar and penile Buschke-L?wenstein (BL) tumor with malignancy and one case of vulvar verrucous carcinoma were also examined by both techniques. While BL tumors were associated with DNA of HPV6 or 11, no HPV association was found for verrucous carcinoma. Our results confirm that the detection rate of HPV DNA in early vulvar and penile carcinomas is much higher than in invasive carcinomas. In addition, we have shown that in the lower genital tract, 50% of cases of ISCC are HPV16 correlated. The absence of HPV DNA (types 6, 11, 16, and 18) in the remaining 50% of cases of ISCC thus suggests that vulvar and penile ISCC may have more than one pathogenetic pathway.     

Premalignant and malignant squamous lesions of the vulva

Vulvar premalignant squamous lesions include low- and high-grade intraepithelial neoplasias. High-grade lesions include usual (classic) and differentiated (simplex) vulvar intraepithelial neoplasia (VIN). Usual VIN (uVIN), the most common, is related to human papilloma virus (HPV), occurs in younger patients, and is frequently multifocal. Differentiated VIN (dVIN), less common, is related to lichen sclerosus and other chronic vulvar dermatoses, occurs in older women, and is usually unifocal. Terminology schemes for premalignant lesions are reviewed. Invasive squamous cell carcinoma also occurs in two distinct clinicopathologic settings. Most conventional keratinizing squamous cell carcinomas arise from a background of dVIN and comprise the majority of invasive squamous tumours. Warty and basaloid invasive squamous cell carcinomas likely develop from uVIN and comprise a minority of invasive tumours. Clinical features, microscopic findings, differential diagnoses, immunoprofiles, prognosis and treatment of premalignant and malignant lesions are addressed.     

Premalignant and malignant squamous lesions of the vulva

Vulvar premalignant squamous lesions include low- and high-grade intraepithelial neoplasias. High-grade lesions include classic (usual) and differentiated (simplex) vulvar intraepithelial neoplasia (VIN). Classic VIN (cVIN), the most common, is related to human papilloma virus (HPV), occurs in younger patients, and is frequently multifocal. Differentiated VIN (dVIN), less common, is related to lichen sclerosus and other chronic vulvar dermatoses, occurs in older women, and is usually unifocal. Terminology schemes for premalignant lesions are reviewed. Invasive squamous cell carcinoma also occurs in two distinct clinicopathologic settings. Most conventional keratinizing squamous cell carcinomas arise from a background of dVIN and comprise the majority of invasive squamous tumours. Warty and basaloid invasive squamous cell carcinomas likely develop from cVIN and comprise a minority of invasive tumours. Clinical features, microscopic findings, differential diagnoses, immunoprofile, prognosis and treatment of premalignant and malignant lesions are addressed.     

Small vulvar squamous cell carcinomas and adjacent tissues. A morphologic study

Vulvar squamous cell carcinomas are of different subtypes and degrees of differentiation, and may be associated with adjacent lichen sclerosus and/or varying degrees of dysplasia. The aim of this investigation was to study small carcinomas with a diameter of less than 2 cm in order to find a possible relation between subtypes of carcinomas and adjacent epithelial changes. Fourteen cases of small vulvar squamous cell carcinomas were totally embedded in paraffin. Serial sectioning made a detailed mapping of all different lesions possible, and a two- and three-dimensional imaging was obtained in each case. Seven patients with keratinizing squamous cell carcinomas (median age 65) had adjacent lichen sclerosus. All carcinomas were completely surrounded by areas of VIN1. VIN2 and VIN3 were not found. Seven patients without lichen sclerosus (median age 58) showed squamous cell carcinomas of the keratinizing type (n=2) or the basaloid type (n=5). Five of these cases were incompletely surrounded by varying degrees of dysplasia, mainly VIN2 and VIN3. Two different pathogenetic pathways for the development of vulvar squamous cell carcinoma are likely.     

Collagenase-3 (MMP-13) is expressed by tumor cells in invasive vulvar squamous cell carcinomas

Collagenase-3 (MMP-13) is a human matrix metalloproteinase specifically expressed by invading tumor cells in squamous cell carcinomas (SCCs) of the head and neck. Here, we have further elucidated the role of MMP-13 in tumor invasion by examining its expression in invasive malignant tumors of the female genital tract. Using in situ hybridization, expression of MMP-13 mRNA was detected in 9 of 12 vulvar SCCs, primarily in tumor cells, but not in intact vulvar epithelium, in cervical SCCs (n = 12), or in endometrial (n = 11) or ovarian adenocarcinomas (n = 8). MMP-13 expression was especially abundant in vulvar carcinomas showing metastasis to lymph nodes and was associated with expression of membrane type 1 MMP by tumor cells and gelatinase-A (MMP-2) by stromal cells, as detected by immunohistochemistry. MMP-13 mRNAs were detected in 9 of 11 cell lines established from vulvar carcinomas and in 4 of 6 cell lines from cervical carcinomas, whereas endometrial (n = 10) and ovarian (n = 9) carcinoma cell lines were negative for MMP-13 mRNA. No correlation was detected between MMP-13 expression and p53 gene mutations in vulvar SCC cell lines. However, MMP-13 expression was detected in 5 of 6 vulvar and cervical SCC cell lines harboring HPV 16 or 68 DNA. These results show that MMP-13 is specifically expressed by malignantly transformed squamous epithelial cells, including vulvar SCC cells, and appears to serve as a marker for their invasive capacity.     

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.     

High-risk human papillomavirus infection of the genital tract of women with a previous history or current high-grade vulvar intraepithelial neoplasia

Human papillomavirus (HPV) infection is associated with high-grade vulvar intraepithelial neoplasia (VIN-3). The prevalence of anogenital HPV infection in women with previously treated VIN-3 has not been documented yet. This cross-sectional study compared high-risk HPV DNA detection rates in women with past (n = 30) and current (n = 22) VIN-3 to those without current or past VIN (n = 86). HPV DNA was detected in vulvar and cervical samples with Hybrid Capture 2 (HC-2). Smoking was associated in multivariate analysis with current VIN-3 (odds ratio (OR) 8.3, 95% confidence interval (CI) 2.0-8.2) and any VIN-3 history (OR 6.5, 95% CI 2.5-16.5). High-risk HPV DNA was found on the vulva of 64%, 33%, and 20% of women with current VIN-3, past VIN-3, and without previous or current VIN, respectively. After controlling for age and smoking, high-risk HPV vulvar infection was associated with cervical high-risk HPV infection (OR 8.6, 95% CI 2.8-26.5; P = 0.001). After controlling for age, HPV infection was more often multifocal in women with current VIN-3 compared to women with previous but no current VIN-3 lesion (OR 17.6, 95% CI 1.4-227.2). Multifocal vulvar HPV infection was detected in women with previous or active VIN-3. Longitudinal studies are required to determine if the multifocality of HPV infection on the vulva could explain the high recurrence rate of VIN-3.