Diagnosis, Therapy and Follow-up Care of Vulvar Cancer and its Precursors. Guideline of the DGGG and DKG (S2k-Level, AWMF Registry Number 015/059, November 2015.

Purpose: This is an official guideline, published and coordinated by the Arbeitsgemeinschaft Gynäkologische Onkologie (AGO, Study Group for Gynecologic Oncology) of the Deutsche Krebsgesellschaft (DKG, German Cancer Society) and the Deutsche Gesellschaft für Gynäkologie und Geburtshilfe (DGGG, German Society for Gynecology and Obstetrics). The number of cases with vulvar cancer is on the rise, but because of the former rarity of this condition and the resulting lack of literature with a high level of evidence, in many areas knowledge of the optimal clinical management still lags behind what would be required. This updated guideline aims to disseminate the most recent recommendations, which are much clearer and more individualized, and is intended to create a basis for the assessment and improvement of quality care in hospitals. Methods: This S2k guideline was drafted by members of the AGO Committee on Vulvar and Vaginal Tumors; it was developed and formally completed in accordance with the structured consensus process of the Association of Scientific Medical Societies in Germany (Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften, AWMF). Recommendations: 1. The incidence of disease must be taken into consideration. 2. The diagnostic pathway, which is determined by the initial findings, must be followed. 3. The clinical and therapeutic management of vulvar cancer must be done on an individual basis and depends on the stage of disease. 4. The indications for sentinel lymph node biopsy must be evaluated very carefully. 5. Follow-up and treatment for recurrence must be adapted to the individual case.

Tumor proliferation in squamous cell carcinoma of the vulva.

Tumor proliferation is of important prognostic significance for several neoplasms. The very few previous studies on this parameter in vulvar carcinoma have shown contradictory results. The aim of this study was to determine the prognostic significance of tumor proliferation in vulvar carcinoma. Paraffin-embedded tissue of 74 squamous cell carcinomas of the vulva was immunostained for MIB-1, detecting Ki-67, and analyzed for staining patterns and the percentage of positive cells. There were three general staining patterns: a diffuse distribution (diffuse type), a localized staining at the infiltrating tumor border (infiltrating type), and a localized staining in basal parts of infiltrating tumor cell aggregates (basal type). The percentage of positive cells was not correlated with morphologic or clinical parameters, nor was it correlated with disease-free and overall survival. MIB-1 staining types were correlated with tumor type and grading. Tumors of diffuse and infiltrating type seemed to have more frequent lymph node metastasis (p = 0.053) and shorter disease-free survival (p = 0.076). In these tumors, overall survival time was reduced significantly (p = 0.02). In multivariate analysis, MIB-1 staining types were the most important factor for overall survival with an odds ratio of 4.73. In conclusion, distribution and not the percentage of proliferating cells is of prognostic significance in squamous cell carcinoma of the vulva.

Regulation of apoptosis in squamous cell carcinoma of the vulva.

OBJECTIVE: To analyze the expression of Bcl-2, Bax and ICH-1-L in squamous cell cancer of the vulva. STUDY DESIGN: Slides of 72 vulvar squamous cell carcinomas were stained immunohistologically for Bcl-2, Bax and ICH-1-L. They were analyzed for the percentage of positive tumor cells, staining intensity and pattern, and amount of Bcl-2-positive lymphocytes around the tumor. Results were analyzed for correlations with clinical and histologic characteristics. Disease-free and overall survival were evaluated by Kaplan-Meier curves with the log-rank test. RESULTS: Strong expression of Bcl-2 was present in 15% of tumors. Carcinomas with high Bcl-2 expression more frequently had lymph node metastasis (P = .03), without significant differences in other clinical or histologic parameters, disease-free and overall survival. Strong Bax expression was observed in 57%, without prognostic significance. Carcinomas showed high ICH-1-L expression in 35%. These tumors seemed to have longer disease-free survival, while overall survival was significantly longer (P = .02). A strong Bcl-2-positive inflammatory infiltrate was highly predictive of lymph node metastasis (P = .02) and disease-free survival (P = .03). CONCLUSION: In squamous cell carcinoma of the vulva, inhibition of apoptosis is associated with a more-aggressive phenotype, and a Bcl-2-positive inflammatory infiltrate is predictive of prognosis. A study with more patients should confirm the importance of apoptosis in vulvar carcinoma.

Squamous cell carcinoma of the vulva. Expression of tumor proteases cathepsin-D and pro-cathepsin-L.

OBJECTIVE: To analyze the expression of cathepsin (cath)-D and pro-cath-L in squamous cell carcinoma of the vulva and to determine whether those proteases have prognostic significance. STUDY DESIGN: Seventy-eight carcinomas were evaluated for tumor type, grade, inflammation and vascular space involvement. Formalin-fixed, paraffin-embedded tissue was stained for cath-D and pro-cath-L. Distribution, intensity and number of stained cells were examined and analyzed by the chi 2 test and receiver operator characteristic curves. RESULTS: Cath-D and pro-cath-L staining showed different distribution patterns. Cath-D expression at the tumor border was associated with development of recurrence (P = .018). Lymph node involvement was dependent on the staining patterns of cath-D and pro-cath-L. The number of pro-cath-L-positive cells correlated with the development of recurrence (P < .01). CONCLUSION: Protease expression of cath-D and pro-cath-L is localized in different tumor areas. The different staining patterns are associated with lymph node involvement and development of recurrence. The number of pro-cath-L-positive cells may be useful for predicting tumor recurrence.

Accuracy of preoperative histology and macroscopic assessment of cervical involvement in endometrial carcinoma.

OBJECTIVE: To compare the diagnostic accuracy between the preoperatively and macroscopically established determination of cervical involvement in endometrial carcinoma. STUDY DESIGN: During the period 1987 to 1991, 154 patients with endometrial cancer were evaluated in a retrospective blind manner with the objective of assessing the diagnostic accuracy of the preoperative (prehysterectomy curettage) and the macroscopic (sectioned surgical specimen) determination of th involvement of the cervix. The results were compared with histological findings of the hysterectomy specimen (gold standard). RESULTS: Preoperative pre-hysterectomy curettage established a sensitivity of 38% and a specificity of 91% whereas the macroscopic findings (gross appearance) confirmed a sensitivity of 50% and a specificity of 95%. A prevalence of 17% for cervical involvement was found. In patients with cervical involvement diagnosed on pre-hysterectomy curettage, a positive predictive value of 45% and negative predictive value of 88% were established. A positive predictive value of 68% and a negative predictive value of 90% resulted from the judgement of the cervical gross appearance. CONCLUSIONS: We conclude that the cervical involvement of endometrial carcinoma diagnosed on pre-hysterectomy tissue is less predictive than the judgement of the intraoperative gross appearance of the cervix.

Malignant melanoma of the vulva. Report of 89 patients.

BACKGROUND: Rates of melanoma have increased worldwide over the last few decades. Currently, this rate of increase is greater for melanoma than for any other cancer in the U.S. Approximately 3% of all melanomas diagnosed in women are located within the genital tract, predominantly affecting the vulva. Overall, melanomas of the vulva account for 2-10% of all malignancies of the female external genitalia. Due to the rarity of this disease, treatment recommendations do not exist. METHODS: This retrospective study was designed to evaluate the significance of clinical and pathologic features for survival among 89 patients examined for malignant melanoma at 5 hospitals in Germany from 1978 to 1991. A complete workup based on age, initial symptoms, tumor localization, presence of ulceration, postoperative stage, surgical procedure, and survival, was performed. RESULTS: The overall 5-year survival rate of 36.7% confirms the poor prognosis of this disease. Definitive treatment concepts require a standardized treatment of patients with malignant melanoma of the vulva; however, because of the rarity of vulvar melanomas, prospective studies are difficult to perform. CONCLUSIONS: Parameters such as age, Breslow's thickness of invasion, Clark's level of invasion, lymph node involvement, anatomic site, and postoperative stage are prognostic factors for survival. Surgery should be performed in accordance with the accepted standards for cutaneous melanoma.

Conservative treatment of endometrial cancer permitting subsequent triplet pregnancy.

We report on a 28-year-old woman who received conservative treatment of endometrial carcinoma by curettage and progestins. After regression of endometrial lesions the patient's infertility was treated by gamete intrafallopian transfer (GIFT). Intact triplet pregnancy was diagnosed 3 weeks later. The patient was delivered of three infants by caesarean section following premature rupture of membranes at 30 weeks of gestation. Subsequent standard treatment of endometrial cancer by abdominal hysterectomy and bilateral salpingo-oophorectomy after 4 weeks revealed no clinical or histological evidence of persistent carcinoma. One year after surgery the patient remained without evidence of disease. We believe that individualized cancer therapy may be safely performed in carefully selected cases.

[Endometrial carcinoma and vaginal ultrasound: studies of the diagnostic validity]. / Endometriumkarzinom und Vaginalsonographie: Untersuchungen zur diagnostischen Validität.

BACKGROUND: Up to now, there has been no effective diagnostic procedure for early diagnosis of endometrial cancer. During recent years, however, study results on transvaginal sonography (TVS) of the endometrium have been published recommending TVS as a screening method for early diagnosis of endometrial cancer in postmenopausal women. OBJECTIVE: The purpose of this study was to determine the sensitivity and specificity of TVS in measuring endometrial thickness and the resulting performance under screening conditions. PATIENTS AND METHODS: Patients with postmenopausal bleeding were included in a prospective blind diagnostic study. Endometrial thickness was measured with TVS before D&C. The histological findings of D&C were used as a control. Sensitivity and specificity were calculated after combining the separately and blindly determined findings. RESULTS: The study comprised 195 patients. Endometrial cancer was diagnosed in 29 of these patients, a prevalence of 15%. The median endometrial thickness was 5.5 mm (0-10 mm) in women with endometrial cancer and 4 mm (0-15 mm) in women without cancer (p > 0.05 Mann-Whitney U-test). For a cut-off > or = 4 mm, the sensitivity is 62% and the specificity is 50%. The sensitivities and specificities for all cut-offs are displayed in a receiver operating characteristic (ROC) curve. The relationship between the positive predictive values and the different prevalences is demonstrated in another curve. Using the results of this and other comparable studies, only very low positive predictive values can be calculated (0.03-1.9%) with prevalences expected under screening conditions (0.02-0.12%). CONCLUSION: Transvaginal sonography is not a useful method in early diagnosis of endometrial cancer.

Reliability of tumor typing of endometrial carcinoma in prehysterectomy curettage.

The aim of this study was to determine the sensitivity and the specificity of tumor typing in the prehysterectomy curettage in order to assess the diagnostic accuracy in patients with endometrial cancer. Tumor typing was performed on complete prehysterectomy curettages of 154 patients with endometrial cancer treated during 1987-1991. The results were compared with the histologic findings of the hysterectomy specimen as the gold standard. Patients with no carcinoma demonstrable postoperatively in the removed uterus were excluded from the study. Tumor typing on prehysterectomy curettage revealed only a moderate sensitivity of 46-64%. In contrast, the specificity was > 90% for all histologic subtypes with the exception of the endometrioid tumor type (68%). The histologic subtypes (papillary, adenocarcinoma with squamous differentiation, mucinous, serous papillary, clear cell) achieved similar high predictive values despite a much lower prevalence due to the high values of specificity. Tumor typing of endometrial carcinoma based upon the findings of the prehysterectomy curettage reveals different reliabilities depending on the tumor type.

Prognostic factors that predict pelvic lymph node metastasis from endometrial carcinoma.

BACKGROUND: Recent reports indicate that certain pre- and intraoperatively determined risk factors are predictive of pelvic lymph node metastases from endometrial cancer, allowing selective pelvic lymph node dissection. The objective of this study was to evaluate the accuracy of pre-, pre-/intra- and postoperatively determined tumor characteristics. METHODS: The study is based on 100 patients treated from 1987-1991 with total abdominal hysterectomy and bilateral salpingo-oophorectomy. In all patients thorough pelvic lymphadenectomies were performed (no sampling). These patients were evaluated according to different macroscopic and histologic tumor characteristics retrospectively in a blind fashion (the lymph node status was later determined separately). Multivariate analysis was applied and the results were compared using receiver operator characteristic curves. In 15 of 100 patients, pelvic lymph node metastases could be histologically demonstrated. RESULTS: Multivariate analysis of 22 tumor characteristics identified the following as being independent in relation to pelvic lymph node metastases: preoperatively determined characteristics: serous papillary tumor type, invasion of myometrium, and histologic grade (Christopherson); pre-/intraoperatively: serous papillary type, histologic grade (Christopherson), and cervical involvement; and postoperatively: lymphangiosis carcinomatosa and hemangiosis carcinomatosa. Receiver operator characteristic curves show that for pelvic node metastases the postoperatively determined histologic findings are more predictive than all other factors that can be evaluated pre- and/or intraoperatively. CONCLUSION: Pre- and intraoperative tumor characteristics can determine the individual risk for pelvic lymph node involvement, but additional studies addressing the therapeutic value of pelvic lymphadenectomy would be necessary to define a probability threshold for lymphadenectomy in a decision analysis.

[Diagnostic results and their clinical interpretation--or: what you never wanted to know about diagnosis]. / Diagnostische Ergebnisse und ihre klinische Interpretation--oder: Was Sie schon immer über Diagnostik nicht wissen wollten.

Diagnostic test results become only relevant if clinically interpreted. A key issue in clinical interpretation is the predictive value which, however, in daily practice and even in medical literature, is frequently misunderstood, as if the predictive value would be about the same as sensitivity. Sensitivity and specificity of a test only together with the prevalence of the target disease allow estimation of the predictive values. This correlation will be exemplified with the diagnosis of chorioamnionitis measuring C-reactive protein: The predictive value is not constant, but depends on prevalence. Prevalence, however, changes with clinical situation, therefore similar test results must be clinically interpreted very differently. Finally, considering these correlations, decision analysis using the "threshold model" shows how to develop a rational, quantitative approach to the selection and interpretation of diagnostic tests. Although more and more studies on decision analysis in diagnostics are published, up to now, there is little response in day-to-day practice. This situation should be changed for the sake of our patients.

[What benefit and harm can be expected from screening and routine examinations and from their omission?]. / Welcher Nutzen und welcher Schaden kann von Screening- und Routineuntersuchungen erwartet werden und von deren Unterlassung?

Benefit and harm of screening and routine tests or their omission are dealt with in four parts. In the first part methods are described to evaluate the diagnostic value of medical testing. The concepts of diagnostic sensitivity, diagnostic specificity, and pre- and posttest probability of a diagnosis are defined. It is then shown how these concepts intercorrelate and how their numerical values can be calculated ("Bayes" theorem"). In consideration of the above mentioned intercorrelations, the second and third parts deal with the diagnostic value of preoperative routine tests from an anaesthesiological viewpoint, and the diagnostic value of other screening and follow-up tests is discussed from a gynaecological point of view. Pre-operative laboratory tests are necessary, and necessary only then, if careful evaluation of patient history and physical examination reveal pathological findings or risk factors. The benefits from regular lab-screening tests and follow-up tests, as recommended to the gynaecologists, are low. This is due to the large share of "healthy" women among the gynaecological patients, as well as the fact that treatment of early detected recurrences shows no demonstrable advantage over treatment of later detected recurrences. In the fourth part, we show that no adverse forensic consequences are to be expected if diagnostic tests are omitted because of demonstrably low diagnostic value. In case of legal procedures against the physician, a medical expert will have to evaluate the diagnostic value of the omitted test objectively from an "ex-ante" point of view, using the methods defined in the first part.(ABSTRACT TRUNCATED AT 250 WORDS)

[Serous papillary adenocarcinoma of the endometrium]. / Das serös papilläre Adenokarzinom des Endometriums.

7 cases of serous-papillary adenocarcinoma of the endometrium (UPSC) were found in a retrospective study of 80 patients which were treated at the Department of Gynaecology of the University of Munich from August 1987 to December 1989 because of endometrial adenocarcinoma. Characteristic histologic findings and prognostic factors of the UPSC were examined by means of large scale sections of the completely worked-up uteri and compared with the usual adenocarcinoma of the endometrioid type (UEC). Despite only minimal myometrial infiltration in some cases, lymphangiosis carcinomatosa was almost always present (6/7) and more than 50% of patients showed evidence of blood vessel involvement. In all patients with pelvic lymph node dissection metastases were found. According to our results in line with the literature, UPSC is a highly malignant and morphologically distinct variant of endometrial adenocarcinoma without promising treatment to date.