Vulvar intraepithelial neoplasia (VIN 2/3): comparing clinical outcomes and evaluating risk factors for recurrence.

OBJECTIVE: To evaluate demographic and clinical characteristics associated with the development of vulvar intraepithelial neoplasia (VIN 2/3), and factors associated with recurrence. METHODS: A retrospective chart review of 303 patients with VIN 2/3 evaluated at a single institution between 1993 and 2011 was performed. Medical records were reviewed for demographic information, risk factors, treatment type, pathologic diagnosis, and recurrence/outcome information. RESULTS: Median age at diagnosis was 47 years (range 14-87). 40% of patients reported current tobacco use and 26% reported previous use. Primary treatment included excision (n=176, 59%), laser ablation (n=40, 13%), imiquimod (n=22, 7.4%), excision with laser (n=24, 8.1%), excision with imiquimod (n=10, 3.4%), and laser with imiquimod (n=3, 1.0%). 92 patients (62.6%) were noted to have positive margins, which was associated with larger tumor size (p=0.004). 87 patients (28.7%) developed recurrent disease, which was associated with smoking (p<0.001), larger lesion size (p=0.016), and positive margins (p=0.005). On univariate analysis, higher rates of recurrence were associated with laser ablation (45.0%) compared with excision (26%) or imiquimod (13.6%) (p=0.018). However, on multivariate analysis of recurrence-free survival (RFS) these therapies were equivalent when used individually, but the use of excision plus laser had an adverse impact on RFS (p<0.001). 7 patients (2.3%) recurred with invasive disease a median of 109 months (range 12-327) from initial VIN 2/3 diagnosis. CONCLUSIONS: This large cohort of women with VIN 2/3 further delineates the demographic and clinical factors associated with VIN 2/3. High rates of recurrence were noted and found to be associated with smoking, larger lesion size, and positive margins. While higher rates of recurrence were found among those treated with laser ablation, it was not inferior with respect to RFS when used alone, but the use of laser with excision was associated with decreased RFS. Our findings provide hypothesis-generating material for further research in the management of VIN2/3.

Heterogeneous etiology of squamous carcinoma of the vulva.

OBJECTIVE: To correlate various previously identified risk factors, different histologic types, and the presence of human papillomaviruses (HPV) in squamous vulvar carcinomas and intraepithelial precursor lesions. METHODS: Cases of squamous vulvar carcinomas and intraepithelial precursor lesions from a case-control study were analyzed by histologic type, the presence of HPV, and HPV type. These findings were correlated with demographic and interview data. RESULTS: Significant differences (P < .001) in the prevalence of HPV DNA were noted between the following: 1) patients with high-grade vulvar intraepithelial neoplasia (VIN) (48 of 54 [88.9%]), 2) different types of squamous carcinomas, designated basaloid and warty carcinomas (18 of 21 [85.7%]), and 3) keratinizing squamous carcinoma (three of 48 [6.3%]). When the risk factor profiles for basaloid or warty carcinoma and keratinizing squamous carcinoma were compared, it was found that basaloid and warty carcinoma was significantly associated with the classical cervical cancer risk factors (lifetime number of sexual partners, age at first intercourse, abnormal Papanicolaou smears, venereal warts, low socioeconomic status, and cigarette smoking) whereas keratinizing squamous carcinoma was less strongly linked to these factors and in some cases not at all. The risk profile for VIN was similar to that of basaloid and warty carcinoma (with respect to sexual and reproductive history and smoking), although effects were weaker for some factors. CONCLUSION: The results of this study further support the view that vulvar carcinoma has two different etiologies, one related to HPV infection and one that is not.

Relationship of factor XIIIa-positive dermal dendrocytes to Kaposi's sarcoma.

The histogenesis of Kaposi's sarcoma (KS) has been the subject of controversy, much of which has centered around whether the spindle cells of KS are derived from vascular endothelium or from lymphatics. Recently, some investigators have speculated that the spindle cells of KS are derived from dermal dendrocytes, a population of mononuclear dendritic cells normally present in the papillary and upper reticular dermis. These cells have been shown to proliferate in response to a variety of stimuli and have been reported to express the plasma proenzyme factor XIIIa. We examined immunohistochemically sections fixed in formaldehyde solution and embedded in paraffin from 20 tumor-stage, 15 patch-stage, and 15 plaque-stage lesions of KS with antibodies directed against factor XIIIa, factor VIII-related antigen, Ulex europaeus lectin, and LN3 (anti-HLA-DR) to investigate the relationship of dermal dendrocytes to KS in general and to try to clarify the histogenesis of this tumor. Our results revealed that the dermis of patch- and plaque-stage KS lesions contains an increased number of factor XIIIa-positive dermal dendrocytes compared with normal dermis and that some of these cells are spindle shaped. Many of the spindle cells in patch- and plaque-stage lesions of KS, however, are negative for factor XIIIa. The cells lining the slitlike spaces and some spindle-shaped cells in close proximity to the vascular spaces stain for factor VIII-related antigen and for Ulex europaeus lectin. LN3 labeled many cells resembling macrophages within the lesions and in papillary dermis. Less than 25% of the dendritic cells within the lesions and in the adjacent dermis expressed both factor XIIIa and LN3. Tumor-stage lesions showed focal but unequivocal staining of the spindle cells for factor VIII-related antigen and Ulex europaeus lectin. Tumor spindle cells were negative for factor XIIIa. Factor XIIIa-positive dendrocytes were plentiful in the uninvolved dermis and were aggregated around the periphery of the tumor nodules. The expression of factor VIII-related antigen and Ulex europaeus lectin by the spindle cells of nodular KS, and their lack of expression of factor XIIIa, suggests that the spindle-shaped tumor cells in all stages of KS are derived from endothelial cells and not from dermal dendrocytes. Dermal dendrocytes appear to undergo hyperplasia in response to KS of all stages. In patch- and early plaque-stage KS lesions, dermal dendrocytes are near factor VIII-related antigen-positive spindle cells and tumor vessels. The mechanism reactive dermal dendrocyte hyperplasia in KS remains obscure.

Ovarian tumors of low malignant potential.

Ovarian tumors of low malignant potential (LMP) differ from epithelial ovarian carcinoma in etiology, molecular biology, and prognosis. LMP tumors are not precursor lesions to ovarian carcinoma. Treatment is primarily surgical. Women found to have an ovarian tumor of LMP should undergo removal of the involved adnexa; surgical staging; and cytoreductive surgery. Women in the reproductive years should be given the option of conservative surgery, preserving the contralateral adnexa and uterus. There is no proven benefit to adjuvant chemotherapy or radiotherapy after primary surgery. In most cases, the diagnosis of an ovarian tumor of LMP conveys good prognosis, with excellent long-term survival.

Management of epithelial ovarian tumors of low malignant potential.

The distinct pathologic and biologic nature of ovarian tumors of low malignant potential (LMP) has been officially recognized by FIGO and the World Health Organization. LMP tumors may comprise 10% of ovarian neoplasms; they occur at a mean age of 40 years. Pregnancy, breast-feeding, and the use of oral contraceptives are protective against the development of tumors of LMP. A history of infertility and use of infertility drugs appear to increase the risk of these tumors. No association with hereditary ovarian cancer syndromes has been reported. The survival associated with these tumors is 99% at mean follow-up of 7 years for patients with stage I disease, and 92% for those with stage II and II disease. Retrospectively, more patients appear to have died from complications associated with adjuvant therapy than from progressive disease. The recommended treatment is surgical, consisting of total abdominal hysterectomy, bilateral salpingo-oophorectomy, pelvic and para-aortic lymph node biopsies, peritoneal washings, and tumor debulking. In young patients with early-stage disease, conservative surgery, preserving the uterus and contralateral ovary, is acceptable. A role has not yet been established for adjuvant therapy, whether radiotherapy or chemotherapy. Laboratory investigations have not demonstrated that these tumors represent an intermediate step between benign ovarian tumors and carcinoma nor have they identified that small subset of tumors with aggressive clinical behavior. We should perhaps consider tumors of LMP in the same light as "benign" proliferative gynecologic conditions, such as endometriosis and leiomyomata.

The behavior of serous tumors of low malignant potential: are they ever malignant?

Although the literature describing the clinicopathologic features of serous borderline or low malignant potential (LMP) tumors of the ovary is extensive, the behavior of these neoplasms is not well understood. While some studies indicate a 30 to 40% mortality for advanced stage tumors, it is not clear whether this poor outcome is related to "benign" complications of the disease, such as bowel obstruction from adhesions, or to development of carcinomatosis from malignant transformation. In an effort to determine more clearly the cause of death of patients with serous LMP tumors and to assess the malignant potential of these tumors, defined by progression to invasive serous carcinoma, we reviewed 22 series, totalling 953 patients. Analysis of these studies reveals that for patients with stage I tumors, survival is 99%. For advanced stage disease, survival is 92%. Advanced-stage tumors associated with so-called invasive implants were excluded from this analysis because they were considered invasive serous carcinomas at the time of diagnosis rather than noninvasive LMP tumors. Various causes of death in patients with advanced-stage tumors include complications of the disease, complications of therapy, and, rarely, malignant transformation. Our review of 953 cases disclosed only seven (0.7%) tumors that appeared to have undergone malignant transformation, resulting in death from intraabdominal carcinomatosis. Because the rate of malignant transformation is exceedingly low and because classifying these tumors as malignant often leads to unnecessary treatment, we believe that the term low malignant potential or borderline tumor is not justified.(ABSTRACT TRUNCATED AT 250 WORDS)

Human papillomavirus and the pathogenesis of vulvar carcinoma.

The pathogenesis of vulvar and cervical cancer are thought to be similar and to be related to a sexually transmitted agent, which, in recent years, has been demonstrated to be human papillomavirus. These two neoplasms differ dramatically in age distribution and relationship to precursor lesions, making a common etiology unlikely. The apparent discrepancies can be explained by a hypothesis that implicates human papillomavirus as an etiologic factor for the majority of cervical carcinomas but for only a small proportion of vulvar carcinomas. Most vulvar carcinomas occur in older women and are not related to human papillomavirus, whereas a subset of vulvar carcinomas occur in young women and are related to this virus. Characterization of two distinct types of vulvar carcinoma may clarify associated risk factors and may have important implications in the clinical management of this disease.

The distribution of factor XIIIa-positive cells in the human fetus and placenta.

Immunohistochemical staining for factor XIIIa, a transglutaminase, revealed a variety of positively stained cells in human fetal tissues. Factor XIIIa-positive cells were most numerous in the dermis and connective tissues. Numerous large, stellate cells in placental villi, decidua, and chorionic membranes also expressed factor XIIIa at 7-9 weeks gestational age, before the onset of fetal hematopoiesis. There was heterogeneity in the staining for factor XIIIa in the early and late fetal tissues, in both rounded and in dendritic cells. In preparations of consecutive sections and in double-labelling experiments, some cells expressed both factor XIIIa and certain monocyte markers and were identified in close association with blood vessels and lymphoid organs in the late fetus and in the placental villi at the end of gestation. Other rounded and dendritic cells expressed factor XIIIa but not monocyte markers, and were found in adult and fetal connective tissues at all gestational ages. These results suggest that there are two factor XIIIa-positive cell populations. One population is present at all developmental stages, does not express monocyte markers, and probably differentiates in situ from primitive mesenchyme. The other population appears mainly after the onset of fetal hematopoiesis, coexpresses some monocyte markers, is HLA-DR positive and may be capable of antigen presentation.

Synchronous mature teratomas of the ovary and liver: a case presenting 11 years following chemotherapy for immature teratoma.

Immature teratoma is a rare ovarian germ cell tumor with an aggressive clinical behavior. Treatment involves surgical resection, usually followed by chemotherapy. Since the introduction of postoperative chemotherapy several cases of "transformation" of this malignant tumor into mature teratoma (retroconversion) have been described. Usually retroconversion presents during the first year of diagnosis. We report a case of synchronous mature teratomas of the ovary and liver presenting 11 years following chemotherapy for stage III immature ovarian teratoma. The CT scan appearance, incidence, and biological significance of this phenomena are discussed.

Cervical neoplasia and repeated positivity of human papillomavirus infection in human immunodeficiency virus-seropositive and -seronegative women.

Increased risk for cervical intraepithelial neoplasia (CIN) in human immunodeficiency virus (HIV)-infected women may be explained by repeated positivity of human papillomavirus (HPV) infection facilitated by HIV infection and related immunosuppression. As part of a longitudinal study with semiannual examinations, 268 women in Baltimore, Maryland (of whom 184 were HIV+), provided 1,426 cervicovaginal lavage specimens tested for HPV DNA by a polymerase chain reaction-based assay between 1992 and 1998. HPV positivity and time to HPV clearance according to HIV serostatus and CD4+ cell count were compared using models for correlated binary data and survival analysis. Of the 187 participants who had at least one positive measurement, the probability of subsequent HPV positivity among HIV- women and HIV+ women with CD4+ > or =200 and <200 cells/microl was 47.5%, 78.7%, and 92.9% (p < 0.001). Within-women HPV results were correlated (i.e., clustered) in each group (p < 0.01). Compared with HIV-participants, the relative incidence of HPV clearance was 0.29 and 0.10 among HIV+ women with CD4+ > or =200 and <200 cells/microl (p < 0.001). At the end of follow-up, 11 women had biopsy-confirmed CIN. The association of HIV and CIN (p = 0.014) was fully explained by repeated HPV positivity induced by HIV infection (p = 0.648). Reversal of immunosuppression following potent antiretroviral therapy must be expected to have a dramatic impact on HIV-related CIN.

Reproducibility of the histopathological classification of vulvar squamous carcinoma and intraepithelial neoplasia.

Invasive vulvar carcinoma has been shown to be etiologically heterogeneous on the basis of pathological, virological, and epidemiological criteria. Human papillomavirus-related invasive vulvar carcinoma has basaloid or warty morphology and has adjacent basaloid or warty intraepithelial neoplasia. Invasive carcinoma unrelated to human papillomavirus is a keratinizing squamous carcinoma that may have adjacent squamous hyperplasia. We provided to 3 pathologists for their review and pathological diagnoses stained tissue sections from 95 patients with vulvar carcinoma. The reproducibility for grading individual categories of intraepithelial lesions was only fair (kappa values of 0.31-0.43). The reproducibility was better (moderate to good; kappa values of 0.58-0.59) for grading individual categories of invasive carcinomas. The agreements improved when the basaloid and warty categories were combined. Good agreement was achieved (kappa values of 0.55-0.79) in distinguishing human papillomavirus-related lesions from those unrelated to human papillomavirus; all three reviewers agreed on this classification for 67% of the cases. The intrareviewer agreement was of the same order as interreviewer agreement. Difficulties in differentiating between some lesions (e.g., a warty carcinoma with little atypia from a well- to moderately differentiated keratinizing squamous carcinoma) and concurrent occurrence of human papillomavirus-related lesions and those lesions unrelated to human papillomavirus in a patient may account for some of the discrepancies in the histopathological diagnoses of vulvar carcinoma.

Human papillomavirus-specific serologic response in vulvar neoplasia.

Epidemiological and virological evidence suggests that invasive squamous cell carcinoma (SCC) of the vulva is etiologically heterogeneous and that basaloid or warty SCC (BWSCC) and vulvar intraepithelial neoplasia (VIN) are linked to human papillomavirus (HPV) infections while keratinizing SCC (KSCC) is a non-HPV-associated malignancy. In the present study, HPV-specific antibodies in sera of patients with BWSCC, VIN, and KSCC and of controls were examined by ELISA for antibodies reactive to HPV-16 virus-like particles (VLP) and in radioimmunoprecipitation assays for antibodies to HPV-16 E6 and E7 proteins expressed by in vitro transcription and translation. The prevalences of antibodies to HPV-16 VLPs were significantly higher in HPV-associated VIN (59.1%) and BWSCC (50.0%) than in KSCC (22.2%) and controls (18.2%). Antibodies to E6 and E7 proteins were more prevalent in BWSCC than in any other groups. Prevalence of serum antibodies to any one of the antigen preparations was significantly higher in BWSCC (64.3%) and VIN (59.1%) than in KSCC (27.8%) and controls (22.2%). Also, sera with high antibody titers were found more frequently in BWSCC and VIN cases than in controls. These data provide immunological evidence in support of the observation that VIN and BWSCC, but not KSCC, are associated with HPV infections.