Criteria for Risk Stratification of Vulvar and Vaginal Smooth Muscle Tumors: An Evaluation of 71 Cases Comparing Proposed Classification Systems.

Accurate risk stratification of smooth muscle tumors (SMTs) is essential for appropriate patient management. Yet, the rarity of SMTs of the vagina and vulva makes development of a prognostically meaningful classification system challenging. While 2 classification methods for vulvar SMTs and 1 for vaginal SMTs have been proposed, it is our experience that many pathologists tend to apply criteria for uterine SMTs when evaluating vulvovaginal tumors. We retrospectively reviewed a large cohort of vulvovaginal SMTs with clinical follow-up and evaluated which method most accurately classified tumors according to patient outcome. A total of 71 tumors, 53 vaginal (75%) and 18 vulvar (25%), from 71 patients were identified. All tumors were centrally examined for degree of cytologic atypia, morphology (spindled, epithelioid, myxoid), mitotic index per 10 high power fields, atypical mitotic figures, tumor cell necrosis, ischemic necrosis, tumor interface (circumscribed or infiltrative) and margin status. Clinical features were recorded for each patient. Follow-up was available for 63 patients (89%), and ranged from 1 to 234 months (median: 64 mo). While site-specific and uterine criteria showed equally excellent sensitivity in classifying smooth muscle neoplasms as leiomyosarcoma according to patient outcome, uterine criteria showed improved specificity relatively to site-specific methods in classifying tumors as nonsarcoma according to patient outcome. We recommend that uterine SMT criteria and nomenclature be adopted for evaluation and classification of vulvovaginal SMTs.

[Nomenclature of squamous cell precursor lesions of the lower female genital tract : Current aspects]. / Nomenklatur der plattenepithelialen Präkanzerosen des unteren weiblichen Genitales : Aktuelle Aspekte.

The majority of precancerous lesions of the lower female genital tract (intraepithelial neoplasia, IN) are caused by human papillomavirus (HPV) infections resulting in cellular atypia and in turn an altered tissue architecture. Depending on the pathogenesis, a distinction is made between vulvar intraepithelial neoplasia (VIN) classified as classical VIN associated with high-risk HPV infections (u-VIN) and differentiated VIN (d-VIN), which is associated with lichen sclerosus et atrophicus and p53 alterations. In the current World Health Organization (WHO) classification a novel grading system for squamous cell precancerous lesions of the lower female genital tract has been proposed, differentiating low grade squamous intraepithelial lesions (L-SIL) including condyloma and HPV-associated alterations plus VIN 1, vaginal intraepithelial neoplasia (VaIN 1) and cervical intraepithelial neoplasia (CIN 1) from high grade squamous intraepithelial lesions (H-SIL) with VIN 2 and 3, VaIN 2 and 3 as well as CIN 2 and 3. The use of p16 immunohistochemistry can assist the differentiation. The new binary classification, however, contradicts the German cytological nomenclature (Munich nomenclature III), which differentiated three grades of dysplasia in order to avoid overtreatment of patients with moderate IN. The individual nomenclatures are compared to each other. It is recommended to report the grade of precancerous lesions in addition to the SIL classification of the WHO.

[Modern biomarkers for precancerous lesions of the uterine cervix : Histological-cytological correlation and use]. / Moderne Biomarker bei Präkanzerosen der Cervix uteri : Histologische-zytologische Korrelation und Einsatz.

The correlation between the cytological findings from the PAP smear and the histological outcome in cases where the cytological findings must be histologically verified, is an integral component of the German screening program for cervical cancer. These data are collected nationwide as part of a benchmarking process by the individual Associations of Statutory Health Insurance Physicians (KV) in the federal states and reported to the National Association of Statutory Health Insurance Physicians (KBV) in Berlin. In most cases there is a good correlation between cytology and histology but in some cases either a different grade of severity of cervical intraepithelial neoplasia (CIN) is found or the histological findings are negative. The reasons for a lack of correlation can be insufficient sampling in the cytology or the biopsy or a misinterpretation of the individual findings. Although the findings from H&E sections are considered to be the gold standard in the histological evaluation, it has long been known that the interobserver agreement in these preparations is only moderate. A significant improvement becomes apparent, firstly by the classification of cervical cancer precursors into low-grade and high-grade groups and secondly by the targeted application of biomarkers, in particular p16 and Ki-67, according to the recommendations of the lower anogenital squamous terminology standardization (LAST) project. The biomarkers p16 and Ki-67 should be used in the differential diagnostics between reactive and reparative alterations and for further differentiation of a CIN grade 2 but not to confirm a CIN grade 3. It is still unclear whether p16 is suitable as a prognostic marker for low-grade lesions.

The Lower Anogenital Squamous Terminology Standardization Project for HPV-Associated Lesions: background and consensus recommendations from the College of American Pathologists and the American Society for Colposcopy and Cervical Pathology.

The terminology for human papillomavirus (HPV)-associated squamous lesions of the lower anogenital tract has a long history marked by disparate diagnostic terms derived from multiple specialties. It often does not reflect current knowledge of HPV biology and pathogenesis. A consensus process was convened to recommend terminology unified across lower anogenital sites. The goal was to create a histopathologic nomenclature system that reflects current knowledge of HPV biology, optimally uses available biomarkers, and facilitates clear communication across different medical specialties. The Lower Anogenital Squamous Terminology (LAST) Project was cosponsored by the College of American Pathologists and the American Society for Colposcopy and Cervical Pathology and included 5 working groups; 3 work groups performed comprehensive literature reviews and developed draft recommendations. Another work group provided the historical background and the fifth will continue to foster implementation of the LAST recommendations. After an open comment period, the draft recommendations were presented at a consensus conference attended by LAST work group members, advisors, and representatives from 35 stakeholder organizations including professional societies and government agencies. Recommendations were finalized and voted on at the consensus meeting. The final, approved recommendations standardize biologically relevant histopathologic terminology for HPV-associated squamous intraepithelial lesions and superficially invasive squamous carcinomas across all lower anogenital tract sites and detail the appropriate use of specific biomarkers to clarify histologic interpretations and enhance diagnostic accuracy. A plan for disseminating and monitoring recommendation implementation in the practicing community was also developed. The implemented recommendations will facilitate communication between pathologists and their clinical colleagues and improve accuracy of histologic diagnosis with the ultimate goal of providing optimal patient care.

[Revised FIGO staging systems for gynecologic malignancies--2009 update]. / Zmiany klasyfikacji zaawansowania nowotworów narzadu plciowego u kobiet--stan na 2009 rok.

Neoplasm staging system was created to facilitate making diagnoses and planning treatment for cancer patients. Since medical research and practice in the field of oncology have shown explosive growth, the staging of some of the gynecologic cancers did not give a good spread of prognostic groupings. In the light of these breakthroughs, the following changes to the staging of gynecological cancers were proposed and approved by the FIGO Committee. In vulvar cancer Stage IA remained unchanged but Stage I and II have been combined. The number and morphology of the involved nodes have been taken into account, and the bilaterality of positive nodes has been discounted. In cervical cancer Stage 0 has been deleted and substages in Stage IIA have been included. In endometrial cancer Stage IA and IB have been combined so that now Stage IA involves the endometrium and/or less than one-half myometrial invasion and IB is equal to or greater than the outer one-half of the myometrium. Stage II no longer has a subset A and B. Involvement in the endocervical glandular portion of the cervix is now considered Stage I. Pelvic and para-aortic node involvement have been separated. The committee has also established a sarcoma staging system based on the criteria used in other soft tissue sarcomas.

Tissue-based classification of HPV infections of the uterine cervix and vagina (mucosal HPV infections).

Terminology of HPV infections of the uterine cervix and vagina is somewhat confusing, with various terms having different meanings to different authors. This prompted us to revise the current terminology and propose a "tissue-based" classification of HPV infections of the cervix and vagina (mucosal HPV infections), which is based on histological appearance of the lesions and should be clear-cut in everyday practice of managing these patients. We hope the proposed nomenclature may overcome some of the confusion and controversy that exist in the current terminologies describing these lesions.

The role of interstitial brachytherapy in the treatment of vaginal and vulvar malignancies.

BACKGROUND: Irradiation has established itself as a treatment for vulvar and vaginal malignancies. Due to the sensitive nature of the vulvar and vaginal tissues, interstitial brachytherapy (iBT) provides an effective, gentle and individualized therapy. PATIENTS AND METHODS: Patients with vulvar (nine of 22) and vaginal (13 of 22) malignancies were treated using interstitial pulsed-dose-rate brachytherapy (PDR-iBT). Twelve out of 22 patients were additionally treated using external-beam therapy to the pelvis and regional lymph nodes. The median total dose of PDR-iBT administered to patients with vulvar carcinoma was 55.0 Gy. The median total PDR dose administered to patients with vaginal malignancies amounted to 20.25 Gy. RESULTS: The median follow-up time for patients with vulvar cancer was 19 months and for patients with vaginal malignancies 27 months. Acute mucositis or skin reactions during iBT were observed in 15 of 22 patients. Two of 22 patients showed delayed side effects. After 6 months, 77.8% of the patients with vulvar cancer (seven out of nine) and 100% of the patients with vaginal malignancies (13 out of 13) achieved complete local remission. One patient out of nine with vulvar carcinoma developed local recurrence, four out of nine regional recurrence, and two out of nine developed regional recurrence and had local tumor following therapy. In patients with malignancies of the vagina, no cases of local recurrence were observed, but distant metastases were found in five out of 13 patients. At the time of analysis, eleven out of 22 patients with vulvar or vaginal carcinoma were still alive. CONCLUSION: IBT achieved good local control without serious delayed side effects in both localizations. However, survival is limited by regional or distant metastases.

Primary neuroendocrine carcinoma of the vagina with Merkel cell carcinoma phenotype.

We describe a case of primary neuroendocrine carcinoma arising from the anterior vaginal wall of a 67-year-old woman. Primary neuroendocrine carcinoma of the vagina is a rare entity with only 25 previously reported cases in the literature. In previous reports, these tumors have not been distinguished from primary neuroendocrine carcinoma of the skin (Merkel cell carcinoma). The tumor was composed of cells that showed neuroendocrine-type nuclear features with hyperchromasia, nuclear molding, occasional small nucleoli, and a chromatin pattern that was finely granular. The tumor cells were positive for cytokeratin 20 (CK20), neuron specific enolase, pancytokeratin, epithelial membrane antigen, and chromogranin A expression. Ki-67, a marker of proliferation, was also positive in>90% of cells. The tumor cells showed intense expression of Bcl-2 oncoprotein and mild to moderate expression of c-KIT. Synaptophysin, neurofilament, CD45, CD56, CD10, S-100, HMB-45, cytokeratin 7, and thyroid transcription factor 1 were negative. This pattern of staining is consistent with a Merkel cell carcinoma. This is the first report of a primary neuroendocrine carcinoma of the vagina with a Merkel cell phenotype. Previous studies have not distinguished primary neuroendocrine carcinoma of the vagina from Merkel cell carcinoma of the skin. Positive expression of CK20 in primary small cell carcinoma of the vagina might represent a Merkel cell carcinoma subtype of this tumor.

Vaginal melanoma: a clinicopathologic and immunohistochemical study of 26 cases.

Malignant melanomas of the vagina are rare tumors. In this study we present the clinicopathologic features and immunohistochemical analysis of 26 such cases seen in our institution over a period of 30 years. The patients' age ranged from 38 to 90 years (mean 60 years); three patients were premenopausal. Ethnicity was known in 24 patients: 20 white, 2 hispanic, 1 black, and 1 Asian. The most common presenting symptom was vaginal bleeding, followed by vaginal mass. Grossly, the tumor was polypoid-nodular in the majority of cases. The neoplastic cells were epithelioid in 15 cases and spindled in three cases; eight cases had both cell types. Vascular-lymphatic invasion was seen in six cases and perineural invasion was seen in four cases. S-100 was strongly and diffusely positive in 25 of 26 cases (96%). HMB-45 was strongly positive in 16 (62%), 3 (11%) were focally positive, 1 case showed a rare positive cell, and 6 (23%) were negative. With MART-1, 20 cases (77%) were strongly positive, 1 (4%) showed a rare weakly positive cell, and 5 (19%) were negative. Twenty-one cases (81%) expressed tyrosinase and 20 (77%) expressed microphthalmia transcription factor. Twenty cases were Chung's level IV, 3 were level III, and 2 were level II. The patients were treated as follows: anterior exenteration with or without lymph node dissection and with or without radiotherapy (RT) or chemotherapy (CT) (7 cases), wide local excision with or without lymph node dissection and RT/CT (10 cases), hysterectomy with vaginectomy with or without RT/CT (3 cases), vaginectomy with RT (1 case), RT (1 case), and RT and CT (1 case). One patient had palliative RT for the brain metastasis only. Follow-up was available in 23 patients ranging from 3 to 276 months (median 18 months). Local recurrence after primary treatment was seen in six patients and distant metastases in 11 patients. Fifteen patients died of the disease (3-83 months), 4 have no evidence of disease (5-24 months), and 4 are alive with disease (6-276 months). This study confirms the poor prognosis of patients with vaginal melanoma. S-100 remains the most sensitive marker for these tumors. HMB-45 is negative in 23% cases of vaginal melanoma. Tyrosinase and MART-1 are useful markers when S-100 is negative or only focally positive.

Granular cell lesions in the distal female reproductive tract of aged Sprague-Dawley rats.

During the review of a rat carcinogenicity study, a spectrum of granular cell lesions was recognized in the distal female reproductive tract. To verify the diagnoses, cell populations of nine granular cell alterations of the cervix or vagina were characterized immunohistochemically and four were evaluated ultrastructurally. Immunoreactivity was demonstrated in 8/9 cases with S100 protein, 6/9 cases with neuron-specific enolase, and 7/9 cases with Leu-7. Granular cells were negative for smooth muscle-specific actin and calretinin. The immunohistochemical profile of these lesions was similar to that previously reported in other species, including humans. Ultrastructurally, as expected many lysosomal bodies were present in the cytoplasm of granular cells in all specimens evaluated. Based on the detailed evaluation of a series of lesions, we adopted the following diagnostic criteria and nomenclature for the granular cell changes of the female reproductive tract of rats. Granular cell aggregates were non-space-occupying lesions composed of clusters of typical granular cells. Benign granular cell tumors were space occupying lesions that typically contained prominent interstitial collagen and were either discrete masses or were difficult to discern from the surrounding tissues. Some benign tumors also contained foci of spindle cells with decreased granularity. Malignant tumors exhibited pleomorphism and an increased nucleus: cytoplasm ratio morphologically but had the same biologic behavior as the benign tumors. We applied these diagnostic criteria during the review of controls from 9 carcinogenicity studies. Up to 23% of control females in those carcinogenicity studies had granular cell lesions that could be classified into one of the three categories. Granular cell lesions appear to be common in the cervix/vagina of the Sprague-Dawley rat, and tumors may develop from granular cell aggregates.

Non-Hodgkin's lymphoma involving the vagina: a clinicopathologic analysis of 14 patients.

Non-Hodgkin's lymphomas (NHL) uncommonly involve the vagina. In this study, 14 NHL involving the vagina are reported. Eight cases were stage IE or IIE and are presumed to be primary. The mean age of these eight patients at presentation was 42 years (range, 26-66 yrs), and four of eight patients complained primarily of vaginal bleeding. Histologically, all eight neoplasms were diffuse large B-cell lymphoma (DLBCL). Clinical follow up ranged from 1.8 to 18 years. Six of eight patients were alive without evidence of disease at the last follow up (range, 2.8-21 yrs), one patient died of unrelated causes at 9 years, and one patient died from NHL at 1.8 years. In six patients vaginal involvement was part of systemic disease at diagnosis, either stage IIIE or IV. The mean patient age at the time vaginal involvement was detected was 65 years (range, 49-82 yrs). Four of six patients had vaginal bleeding. Five neoplasms were DLBCL and one tumor was B-cell small lymphocytic lymphoma/chronic lymphocytic leukemia. Clinical follow up for these patients ranged from 2 weeks to 13 years. Two patients were free of disease after treatment at 4.5 and 13 years, two patients were alive with progressive NHL, one patient died of NHL, and one patient was recently diagnosed. The authors conclude that low-stage (presumably primary) vaginal NHL are DLBCL, tend to occur in younger women, and cause vaginal bleeding. High-stage NHL involving the vagina are usually DLBCL, tend to affect older women, and are relatively more heterogeneous clinically and histologically, but also usually cause vaginal bleeding.

Atypical squamous cells of undetermined significance: correlative histologic and follow-up studies from an academic medical center.

The diagnosis of ASCUS (atypical squamous cells of undetermined significance) was introduced in the 1988 Bethesda System for reporting cervical/vaginal cytologic findings. Outcome and appropriate management of patients with this diagnosis is not presently established. Criteria defining ASCUS are nuclear enlargement (2.5-3.0 times normal intermediate cell nucleus), mild nuclear hyperchromasia, smooth nuclear outlines with mild variation in nuclear size and shape, or else two, but not all three, cytologic criteria for human papilloma virus (HPV) cytopathic effect. All 668 cases reported as ASCUS from February 1992-December 1993 from our cytology laboratory were reviewed. These ASCUS cases represented 4.5% of all gynecologic cases diagnosed in that same time period. Of these, 284 (41%) had a subsequent colposcopic biopsy and/or endocervical curettage. The biopsied cases included 101 (36%) with condylomata, 38 (13%) with cervical intraepithelial neoplasia (CIN) I, 17 (6%) with CIN II, and 9 (3%) with CIN III. No cases of carcinoma were detected. Of patients with a cytologic diagnosis of ASCUS and subsequent cervical biopsy, 49% had low-grade cervical intraepithelial neoplasia (LGSIL), either condyloma or CIN I. Nine percent had high-grade cervical intraepithelial neoplasia, either CIN II or CIN III. These findings indicate that ASCUS defines cytologically a group of patients who may have either a concurrent or subsequent development of a squamous intraepithelial lesion (SIL). This forms a high-risk group. The management of cases with a cytologic diagnosis of ASCUS should be at least as aggressive as that of LGSIL.

Candida-related changes and ASCUS: a potential trap!

Detection of potential pitfalls for the ASCUS interpretation is essential for appropriate patient management. Between 1991-1994, 50 cervicovaginal specimens with Candida spp. were submitted for pathologists' review because of a possible ASCUS diagnosis. None had been preceded by abnormal smears, and all were followed by one or more benign smears and/or biopsy. Candida-associated changes included nuclear enlargement with focal hyperchromasia and cytoplasmic changes of orangeophilia, vacuoles, and perinuclear rings. Initially, 16 cases had been interpreted as ASCUS and 34 as benign. Upon review, utilizing strict Bethesda System criteria for ASCUS and awareness of Candida-associated changes, 10 of the 16 ASCUS cases were reclassified as benign. Knowledge of Candida-associated changes which may mimic ASCUS can prevent overuse of the ASCUS term, providing optimal, cost-effective management.

Influence of in utero diethylstilbestrol exposure on the prognosis and biologic behavior of vaginal clear-cell adenocarcinoma.

Most young women with clear-cell adenocarcinoma (CCA) of the vagina have a history of prenatal exposure to diethylstilbestrol (DES). Some, however, develop vaginal CCA without a prior history of DES exposure. We hypothesized that the natural history of DES-exposed vaginal CCA and DES-unexposed vaginal CCA may differ. Cases were identified from the Registry for Research on Hormonal Transplacental Carcinogenesis which maintains information on cases of CCA of the lower genital tract occurring in women born after 1940. Four hundred and thirty-one cases satisfied FIGO criteria for primary vaginal carcinoma of which 318 had prenatal, hospital, obstetrician, or pharmacy records available for review. Of these, 80% (255/318) had written documentation of prenatal exposure to DES (DES+) and 20% (63/318) had no evidence of DES exposure (DES-) in their medical records. DES exposure was undetermined in 113 cases due to lack of appropriate medical records. Among cases with documentation, DES exposure was not associated with mean age at diagnosis, (DES+, 20.3 years, DES-, 21.1 years), stage (stage I: DES+, 59%, DES-, 54%; stage II: DES+, 32%, DES-, 33%; stage III: DES+, 7%, DES-, 11%; stage IV: DES+, 2%, DES-, 2%, mean tumor diameter or surface area, grade, histology, cell type, or initial therapy. Among cases which underwent pelvic and paraaortic lymph node sampling (DES+, 63%; DES-, 56%; P = NS) the prevalence of pelvic node involvement was similar (DES+, 18.6%; DES-, 17.1%). However, only 1.2% (2/161) of DES+ cases had positive paraaortic lymph nodes compared to 8.6% (3/35) of DES- cases (P = 0.041). Survival differed significantly between the two groups. Probability of survival at 5 and 10 years for DES+ cases was 84 and 78%, respectively, compared to 69 and 60%, respectively, for DES- cases (5 years, P = 0.007, and 10 years, P = 0.008). Presently, 21% (53/255) of DES+ cases are known to have died, compared to 37% (23/63) of DES- cases (P = 0.008). Sites of disease recurrence also differed. DES- cases were more likely than DES+ cases to present with or to later develop distant tumor to the lungs (24% vs 9%; P = 0.002) or metastases to supraclavicular lymph nodes (8% vs 1.6%; P = 0.017). Among the 113 cases with an uncertain history of DES exposure, survival was intermediate between the well-documented cases (79% at 5 years and 65% at 10 years with 35/113 or 31% known dead), as was frequency of metastases to the lungs (13%) or supraclavicular lymph nodes (5.3%).(ABSTRACT TRUNCATED AT 400 WORDS)