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Anogenital and oropharyngeal infections with human papilloma viruses (HPV) are common. Clinically manifest disease may significantly impact quality of life; the treatment of HPV-associated lesions is associated with a high rate of recurrence and invasive neoplasms, such as cervical, anal, vulvar, penile, and oropharyngeal cancers, which are characterized by significant morbidity and mortality. Vaccination against HPV is an effective and safe measure for the primary prevention of HPV-associated lesions, but immunization rates are still low in Germany. The present publication is an abridged version of the German evidence and consensus-based guideline "Vaccination recommendations for the prevention of HPV-associated lesions", which is available on the website of the German Association of the Scientific Medical Societies (AWMF). On the basis of a systematic review with meta-analyses, a representative panel developed and agreed upon recommendations for the vaccination of different populations against HPV. In addition, consensus-based recommendations were developed for specific issues relevant to everyday practice. Based on current evidence and a representative expert consensus, these recommendations are intended to provide guidance in a field in which there is often uncertainty and in which both patients and health care providers are sometimes confronted with controversial and emotionally charged points of view.

Purpose This is an official guideline, published and coordinated by the Gynecological Oncology Working Group (AGO) of the German Cancer Society (DKG) and the German Society for Gynecology and Obstetrics (DGGG). Vaginal cancers are rare tumors, which is why there is very little evidence on these tumors. Knowledge about the optimal clinical management is limited. This first German S2k guideline on vaginal cancer has aimed to compile the most current expert knowledge and offer new recommendations on the appropriate treatment as well as providing pointers about individually adapted therapies with lower morbidity rates than were previously generally available. The purpose of this guideline is also to set up a register to record data on treatment data and the course of disease as a means of obtaining evidence in future. Methods The present S2k guideline was developed by members of the Vulvar und Vaginal Tumors Commission of the AGO in an independently moderated, structured, formal consensus process and the contents were agreed with the mandate holders of the participating scientific societies and organizations. Recommendations To optimize the daily care of patients with vaginal cancer: 1. Monitor the spread pattern; 2. Follow the step-by-step diagnostic workup based on initial stage at detection; 3. As part of individualized clinical therapeutic management of vaginal cancer, follow the sentinel lymph node protocol described here, where possible; 4. Participate in the register study on vaginal cancer.

Objectives The accuracy of colposcopy as the gold standard to manage abnormal screening tests depends on qualification and well defined standards. A recent survey of the European Federation for Colposcopy (EFC) found strong heterogeneity in the practice of colposcopy across Europe. EFC defined four quality indicators (QIs) to enable quality assessment in colposcopy as one tool to harmonize colposcopy standards. We undertook a pilot project to estimate the utility of these QIs for an independent external quality assessment in daily routine colposcopy. Study design Participating colposcopy clinics used newly developed software for data collection. Data were automatically anonymized, encrypted and stored in a secure relational database located within the clinics’ network and allowed for an independent external benchmarking comparing the performance of participating clinics according to EFC QIs. Results 10,869 patients referred for routine colposcopy were included. On average none of the four EFC QIs was fulfilled. One target was almost met with 83.3% instead of 85% excisional treatments/conizations containing CIN2+ and for another QI the difference of 94.4% instead of 100% cases having a colposcopic examination prior to treatment for abnormal cervical cytology was mainly explained by wrong documentation. For a third QI, visibility of the squamocolumnar junction (SCJ) was only reported in 90.9% instead of 100% but reporting improved to 94.7% after a consensus meeting. The last QI, >80% clear margins in excised lesions/conizations were not considered as useful by some clinics and therefore not documented. Discussion and conclusions At least 3 out of 4 QIs seemed to be useful for quality assessment in colposcopy but will need rewording and readjustment. All tools for an independent electronic quality assessment with the use of EFC-QI are available and could be used to achieve a high quality standard in colposcopy across Europe.

Objective To compare the distribution of International Federation for Cervical Pathology and Colposcopy (IFCPC) transformation zone (TZ) types among women in different age groups referred to 8 colposcopy clinics. Materials and methods Between February 2012 and February 2013, we prospectively collected individual patient data from 8 clinics within the German Colposcopy Network (G-CONE). Data were analyzed using ODSdysplasie, software designed to allow continuous quality assessment in colposcopy clinics. The distribution of IFCPC-classified TZ was compared between different centers for the following age groups: younger than 30 years, between 30 and 50 years, and older than 50 years. Results Of 3,761 patients included in the analysis, 2,153 (57%) were classified as having type 2 TZ, 906 (24%) as type 1 TZ, and 702 (19%) as type 3 TZ. Type 3 TZ was the most commonly reported type in women older than 50 years (70%). We found that the relative distribution of type 3 TZ between age groups was similar in the participating colposcopy clinics. However, there was evidence of heterogeneous distribution of types 1 and 2 TZ between age groups in different clinics, ranging from 7.8% to 66.4% for type 1 TZ in women younger than 30 years and 28.9% to 78.1% for type 2 TZ in women 30 to 50 years old. Conclusions Although IFCPC type 3 TZ seems to be a reproducible finding, the distribution of types 1 and 2 TZ showed significant heterogeneity. A more precise anatomic distinction between types 1 and 2 TZ in the IFCPC terminology could improve reporting of colposcopy findings.

Sexual activity (SA) and sexual function (SF) are central outcome measures in women affected by preinvasive (vulvar intraepithelial neoplasia, VIN) and invasive (vulvar cancer, VC) vulvar lesions. Data on sexuality after treatment are scarce. Validated questionnaires including the female sexual function index (FSFI-d) were provided to 166 women with a history of VIN and VC who attended the colposcopy units of the University Medical Center Hamburg-Eppendorf and Asklepios Medical Clinic Altona for follow-up between March 2011 and June 2012. Additional patients (n = 14) assessed the questionnaires online through the website of the German Vulvar Cancer Support Group (VulvaKarzinom SHG e.V.) during the same time period. Twenty-four patients with VIN and 34 with VC were evaluable. Median age was 51.5 years, with 34 (58.6 %) of the patients being postmenopausal. Median time since completion of treatment was 17 months. All women had undergone vulvar surgery (laser/cold knife/combination). Overall, 14 (24.1 %) women reported no SA during the last 4 weeks. SF was clearly impaired compared with previously described normal cohorts. SA and SF of active patients did not differ significantly between those with VIN and VC. Analyses contrasting surgical treatment methods yielded no significant associations; likewise, time since diagnosis did not affect SA and SF significantly. Increasing age was negatively associated with most dimensions of the FSFI-d [desire (p = 0.011), arousal (p = 0.004), lubrication (p = 0.003), orgasm (p = 0.013), satisfaction (p = 0.345), pain (p

Vulvare intraepitheliale Neoplasien (VIN) sind uberwiegend plattenepithelial und HPV-assoziiert. Zwei Unterformen werden unterschieden: die HPV-assoziierte uVIN und die seltenere HPV-unabhangige dVIN. Neben der HPV-Infektion gelten Immunsuppression und Nikotinabusus sowie ein Lichen sclerosus als Risikofaktoren. Damit bieten sich die HPV-Impfung und das Nichtrauchen zur primaren Pravention an. Therapieresistente Symptome vermeldet die Halfte der Patientinnen. Die Diagnose kann histologisch zumeist an Stanzbiopsaten gestellt werden. Die Behandlung hat die Entfernung der Lasion im Gesunden zum Ziel. Als wesentliche Verfahren gelten die Exzision und die Laserdestruktion. Bei uVIN konnen Immunmodulatoren lokal in speziellen Fallen eingesetzt werden (“off-label use”). Die Rezidivraten liegen bei 25 %, davon sind etwa 3 % invasiv. VIN-Patientinnen sollen nach der Behandlung regelmasig in einer qualifizierten Nachsorge verbleiben, im besten Fall lebenslang. Als Sonderform einer intradermalen potenziellen Praneoplasie gilt der Morbus Paget der Vulva. Die Therapie bestand uber lange Zeit in der chirurgischen Entfernung der Haut. In neuerer Zeit werden die Lasionen – insbesondere bei wiederholten Rezidiven nach operativer Therapie – erfolgreich lokal mit immunmodulatorischen Substanzen behandelt (“off-label use”).

Purpose: This is an official guideline, published and coordinated by the Arbeitsgemeinschaft Gynakologische Onkologie (AGO, Study Group for Gynecologic Oncology) of the Deutsche Krebsgesellschaft (DKG, German Cancer Society) and the Deutsche Gesellschaft fur Gynakologie 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.

INTRODUCTION: As limited data among German women exist about HPV, Chlamydia trachomatis (CT) and Neisseria gonorrhoeae, we report the prevalence of these genital infections and general baseline demographics of the young German women enrolled in the phase III trials of the quadrivalent HPV vaccine. MATERIALS AND METHODS: German females (n = 437; 9-23 years) were recruited among 3 international phase 3 studies of an HPV-6/11/16/18 vaccine. We present baseline characteristics, prevalence of HPV-6/11/16/18 and, for women aged 16-23, abnormal cervical cytology and sexually transmitted diseases. RESULTS: Chlamydia trachomatis and Neisseria gonorrhoeae prevalence was 5 and 0.3%, respectively. Approximately 17% of participants had HPV-6, 11, 16, or 18 DNA or antibodies. All subjects

Conization for suspected high grade cervical intraepithelial neoplasia (CIN) is often performed based on abnormal cytology only. Loop electrosurgical excision procedure (LEEP) is a very common technique in this context. The present study analyses the accuracy of preoperative assessment of CIN with cytology plus colposcopic biopsy and assesses the efficacy of LEEP for the treatment of CIN. Two-hundred and sixty-six consecutive patients treated with LEEP for suspected CIN at our center were retrospectively analyzed. Cytology, HPV-DNA testing, colposcopically directed cervical biopsy and/or endocervical curettage were performed to assess cervical lesions before and 3–6 months after surgery. Median age of the patients was 34 years. Median follow-up was 50 months. Preoperative HPV testing was positive for high risk types in 77.9 %. All patients underwent LEEP without further ablative procedures. Complete excision of the lesion could be achieved in 84.3 %; in 13.5 % margins were not securely cleared and in 2.2 % the lesion was not excised entirely. Overall complication rate was 5.4 % (mainly postoperative bleeding and pain). Overall concordance of colposcopic biopsy and cone histology was 85.8 %. The concordance rate was higher for CIN 2/3 (95.1 %) compared with CIN 1 (63.2 %). Nine patients (3.4 %) had persistent disease after 3 months, 4 (1.5 %) developed disease recurrence and underwent re-conization. HPV testing at 3–6 months after surgery was negative in 78.5 %; 2 of the patients developing disease recurrence had a persistent HPV infection after surgery. Assessment of cervical lesions with colposcopic biopsy is an accurate method (concordance with cone histology 85.8 %). Surgical treatment of high grade CIN with LEEP is a safe procedure with low recurrence rates, resulting in a clearance of cervical HPV infection in the majority of cases.

ObjectiveLymph node metastases are the most important prognostic factor for recurrence and survival in vulvar cancer. However, information regarding the impact of the number of positive nodes in vulvar cancer is inconsistent, and so are recommendations when to apply adjuvant radiotherapy.MethodsOne hundred fifty-seven consecutive patients with primary squamous cell cancer of the vulva treated at our center were analyzed. All patients underwent primary surgery by triple incision resulting in complete tumor resection.ResultsMedian age was 61 years; 49 patients (31%) had lymph node metastases; 21 patients had 1, 13 had 2, and 15 had more than 2 positive lymph nodes. Thirty-two percent of the patients received adjuvant radiotherapy. The risk of lymph node metastases increased with age, greater tumor size, deeper invasion, and higher tumor grade. Median follow-up was 36 months; 23 patients (14.6%) developed disease recurrence (61% vulva, 35% groins, and 4% both). Compared with node-negative patients, survival in all node-positive patients was significantly impaired (P < 0.001; disease-free patients after 2 years: 88% in node-negative patients; 60%, 43%, and 29% in patients with 1, 2, and >2 affected nodes, respectively), whereas no significant difference between the node-positive subgroups could be demonstrated regarding disease-free survival. In multivariate analysis, lymph node status remained the most important prognostic factor regarding disease-free survival, but the effect of positive nodes differed significantly dependent on adjuvant treatment (P = 0.001). In patients without adjuvant radiotherapy to the groins/pelvis, the number of metastatic nodes was highly relevant for prognosis (hazard ratio, 1.752; P < 0.001), whereas this effect disappeared in patients who were treated with adjuvant radiotherapy (hazard ratio, 0.972; P = 0.828).ConclusionsThe negative impact of lymph node metastases is already evident in patients with only 1 affected lymph node. In patients receiving adjuvant radiotherapy, the negative effect of additional lymph node metastases is reduced; adjuvant treatment might therefore be beneficial in patients with only 1 positive node.

The authors A. Schneider and P. Hillemanns welcome the revision of the previous Munich II cytology nomenclature and its international harmonization. However, they criticize statements by the authors of Munich III about the contribution Munich III can make towards improving communications between doctors, avoiding unnecessary follow-up examinations and therapies, and reducing subsequent costs. The authors also denounce a lack of evidence and criticize basing recommendations on individual cytological diagnostic groups; they recommend that the Munich III Nomenclature be simplified in analogy to the Bethesda System (TBS). They ignored the importance of the revised cytological nomenclature of Munich III for colposcopic diagnosis and for interventional colposcopy of precancerous squamous and glandular cells of the cervix and vagina. The Board of the Study Group for Cervical Pathology and Colposcopy (AG-CPC) is of the opinion that the Munich III Nomenclature represents a considerable improvement compared to Munich II and TBS classifications of cytological abnormalities. Munich II was not used systematically in Germany. In some laboratories, the unofficial category IIw (IIk) was the most common finding, but this category did not appear in other laboratories. Its morphological characteristics had never been defined. For this reason it could never be included in official statistics. Because the forte of colposcopy is not screening but the diagnosis of abnormal cytological findings, colposcopic diagnoses did not refer to clearly defined cytological call changes. In the past, this has led some authors to water down their assessments and their scientific analyses of data. In some publications, category IIw was assigned to screening for cervical cancer and to colposcopy investigations of unremarkable cytological findings, but sometimes also to the TBS category ASCUS. The previous IIID category (Munich II) included both low-grade and medium dysplasias and corresponded to CIN 1 and CIN 2. Morphological investigations and scientific data have shown that colposcopy which identifies “minor changes” (colposcopic terminology of the 2011 IFCPC Nomenclature, Rio 2011) cannot differentiate low-grade dysplasias (CIN 1) and HPV positivity from physiological findings (including metaplasias) (limited discriminatory power, low AUC value in ROC analysis). Medium-grade dysplasias (category IIID2 in Munich III) are more likely to present as “major changes” in colposcopy (colposcopic terminology of the 2011 IFCPC Nomenclature, Rio 2011), which will require closer monitoring than category IIID1 (Munich III) or colposcopic “minor changes”. With its HSIL category, TBS does not differentiate ctyologically between medium-grade and high-grade dysplasias which correspond to CIN 2 and CIN 3, respectively. Category IV a (Munich III) which consists mainly of “major changes” visible on colposcopy (high selectivity, high AUC value in ROC analysis) offers a better differentiation between the different biological behaviors of high-grade CINs than TBS does. Remission can occur with CIN 2 (category IIID2 in Munich III), which means that, depending on the colposcopic findings (localization, size and extent of the lesion, minor or major changes), surgery may not be mandatory. The authors of the Comments ignored the importance of glandular cell changes which were newly included in Munich III; in particular, they did not mention ACIS or adenocarcinomas which have an incidence of around 18 %. The simplification the authors demand would hamper the urgently needed colposcopic assessment and classification of glandular lesions. The current colposcopic terminology is only valid for CINs and squamous cell carcinomas. Munich III has remedied this deficiency of Munich II, which omitted glandular cell changes and in the past could result in colposcopy findings being classed as less serious. The new cytological nomenclature of Munich III will thus contribute to developing colposcopic criteria for a colposcopic nomenclature for ACIS and adenocarcinomas using newly included and clearly defined cellular criteria for glandular lesions. Even though the cytological nomenclature in Munich III does not correspond to that of TBS in certain significant areas, it can be rendered into TBS terminology, making it possible to carry out high-level colposcopy research and clinical studies in Germany with results that can be published in international journals. The revision and simplification of Munich III demanded by the authors would undo the efforts that have been made to make colposcopy in Germany internationally reputable again. We find the criticism directed by the authors against recommendations based on cytological findings incomprehensible with regard to the use of colposcopy for diagnosis. Colposcopy is the only method which can be used to localize precancerous lesions or early stage (vaginal/cervical) cancers and describe their extent and size. This means that colposcopy is indicated for all abnormal cytological findings. In summary, the cytological nomenclature of Munich III, which will come into general use from July 2014, offers considerable benefits for the routine use of colposcopy in practice. Clearly defined, suspicious cell changes can be assigned without difficulty to one of the categories described in the colposcopic terminology of the 2011 IFCPC Nomenclature (Rio 2011). The inclusion of glandular changes in Munich III, identified by the suffix (g), means that the colposcopic characteristics of glandular precancerous lesions (ACIS) and cervical adenocarcinomas can be reappraised for the first time to create a consistent colposcopic nomenclature for non-squamous cell carcinomas. Munich III with its categories IIID1 and IIID2 and subsequent colposcopic assessment based on the criteria of IFCPC Colposcopy Nomenclature (Rio 2011) gives a much better picture of the biological behavior of the various CIN categories than TBS does with LSIL and HSIL. The Board of the AG-CPC recommends that gynecologists use both the revised cytological classification (Munich III) and the international colposcopic terminology of the 2011 IFCPC Nomenclature (Rio 2011). For the Authors: Prof. Dr. med. W. Kuhn Gynecologist and obstetricianPathologistMember of the Board and Deputy Chairman of the AG-CPC and Dr. Friederike Gieseking GynecologistMember of the Board of the AG-CPC

Tumor cell contamination of stem cell collections harvested from breast cancer patients is a common phenomenon described by several investigators but with findings that vary among reports. Although so-called co-mobilization of these cells has been hypothesized, the origin of tumor cell contamination in stem cells is still unknown. A total of 47 G-CSF mobilized stem cell grafts from patients with nodal-positive (n = 30), chemosensitive metastatic (n = 11), and 5 women with inflammatory breast cancer were evaluated for cancer cells by immunocytochemistry. Additionally, 40 bone marrow aspirations and 23 peripheral blood samples collected prior to apheresis and after one to two cycles of conventional chemotherapy were available for examination. Tumor cell contamination of leukapheresis correlated best with preharvest blood state. This was valid when the nominal (positive/negative) presence of tumor cells in blood was compared to the nominal presence of tumor cells in apheresis samples and when the it was correlated to the tumor cell load of apheresis samples (TCL = tumor cells per 10(6) nucleated cells investigated). The correlation between blood and stem cells was better (nominal and quantitative) than that between marrow and stem cells, despite the larger sample size of marrow aspirations. The presence or absence of cancer cells in apheresis samples could not be safely predicted by the presence or absence of tumor cells in marrow or blood alone. Diagnostic specificity seems to improve from a combination of results from marrow and blood analysis. No correlation was found in quantitative analysis of tumor cell contamination between marrow and blood. In conclusion, the results suggest that blood and bone marrow represent different compartments for epithelial cancer cells and that contaminating tumor cells in stem cell harvests may be derived from the blood and/or marrow compartment. The tumor cell contamination of a stem cell harvest cannot be safely predicted by a preceding blood or marrow analysis.

Disseminated tumor cells are detected frequently in bone marrow, peripheral blood, and cytokine-mobilized peripheral blood cell products of women undergoing high-dose therapy for breast cancer. Several attempts were made to purge autografts from contaminating cancer cells; however, the biological and clinical impact of these contaminations has not been clarified so far. Expression of distinct phenotypes is a surrogate marker for metastatic behavior of cancer cells. The expression of the urokinase-like plasminogen activator receptor seems to be a factor of high importance. It is not expressed by normal mammary tissue. Disseminated cancer cells from marrow, blood, and stem cell products have been investigated by double-stain technique for urokinase-like plasminogen activator receptor (uPA-R) expressing cytokeratin-positive cells. uPA-R(+)/CK(+) cells could be found in all qualities of samples; however, significantly less in G-CSF-mobilized peripheral blood stem cells compared to samples of other provenance (p = 0.02). It can be concluded that epithelial cells of malignant phenotype occur in blood, marrow, and autografts of breast cancer patients. Populations of disseminated tumor cells are phenotypically heterogeneous. Reduced uPA-R expression on cancer cells from leukapheresis samples might suggest a less aggressive nature of these cells compared to disseminated cells found in bone marrow. Furthermore, the data suggest that the phenotype of tumor cell contamination in leukapheresis products differs significantly from those of disseminated cancer cells in bone marrow or blood.

Peripheral blood stem cells were mobilised with G-CSF from steady-state haemopoiesis after previous anthracyclin-containing standard dose chemotherapy in patients with high-risk breast cancer. 48 samples were obtained from patients with stage II-III breast cancer andor = 10 lymph nodes, 15 samples from patients with chemotherapy sensitive metastatic disease, and 13 samples from women with inflammatory breast cancer. 44 samples were first or single leukaphereses and 32 samples were second or third harvests. Aliquots were searched for contaminating tumour cells by immunocytochemistry (IC) and cytokeratin-19 reverse transcriptase polymerase chain reaction rtPCR). The median count of MNCs examined by IC was 2 x 10(6); cDNA prepared from 2 x 10(7) cells was subjected to PCR. Fifty-nine samples were examined by immunocytochemistry, 36 samples by rtPCR, and 19 samples by both techniques. Samples investigated by IC and rtPCR were judged as positive if there was at least one positive test. On the whole, 42/79 (55.3%) of the samples were positive with an insignificant trend to a higher positivity rate in second or subsequent leukaphereses (52.3% vs 59.3%). The median tumour cell load per 10(6) MNCs was low with 0.5 (0-7) cells in all, and a total of 2.2 (0.5-7) cells in positive specimen. Differences in the cancer cell load of first and subsequent leukaphereses and between subgroups of patients were not found. PCR and IC gave consistent results in 63.2%. This phenomenon can be explained by the greater sensitivity of the molecular method and by a Poisson distribution of coharvested tumour cells in samples. Tumour cell contamination in G-CSF mobilised stem cells from patients with breast cancer from steady state haemopoiesis after preceding anthacyclin-containing chemotherapy is frequent, but the tumour cell load is low. To allow a comparison of different studies dealing with cancer cell contamination in stem cells, standardisation of assays is necessary.

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Background Extramammary Paget disease (EMPD) is a very rare genital neoplasia associated with a high frequency of local recurrences. Surgical excision is the standard treatment, but results in mutilating procedures in patients with advanced or recurrent disease. Case reports have shown clinical responses to imiquimod in patients with EMPD, but this therapy has not been evaluated systematically. Objective The aim of this study was to evaluate imiquimod as local treatment of first-time and recurrent EMPD. Methods All cases of biopsy-proven EMPD of the vulva treated within the German Colposcopy Network or other institutions specializing in vulvar diseases in Germany were included in this retrospective analysis. Results A total of 21 women with EMPD treated with imiquimod were identified: 11 (52.4%) achieved complete response, 6 (28.6%) achieved partial response, and there were no cases of progressive disease. The dose and duration of imiquimod differed between patients. The mean duration of treatment exceeded 16 weeks in women achieving complete response. Limitations EMPD is rare and this retrospective study is limited by the small number of patients identified. Conclusion When associated cancers and invasive growth are excluded, imiquimod appears to be a useful treatment option for recurrent EMPD and may avoid extensive mutilating surgical treatment.

EGFR copy number increases have been frequently reported in cancer including vulvar carcinomas. Co-amplification of cancer genes plays an important role in the development of many tumour types. To better understand the effect of EGFR aberrations on vulvar cancer phenotype and patient prognosis, the authors analysed EGFR copy number changes using fluorescence in situ hybridisation and EGFR expression by immunohistochemistry in a tissue microarray containing 183 squamous cell carcinomas of vulva. Furthermore, the authors analysed the co-amplification frequency of EGFR with HER2, CCND1, MYC and PIK3CA, respectively. EGFR copy number increase was found in 39.3% of the tumours. Seventeen per cent of vulvar carcinomas showed EGFR high polysomy including 9% with amplification of the EGFR gene. Copy number gain of the EGFR locus was associated with non-basaloid phenotype (p=0.03), high-tumour stage (p0.001), human papillomaviruse negativity of tumours (p=0.04) and the number of lymph node metastases (p=0.02). EGFR protein expression was statistically correlated to EGFR copy number increase (p0.05). The observed co-amplification rate of EGFR with all four additionally examined oncogenes was much higher than statistically expected. There was a highly significant association between EGFR copy number increase and CCND1 amplifications (p0.001) as well as the total number of gene amplifications (p=0.04). EGFR copy number gains were significantly related to unfavourable patient outcome in univariate analysis and multivariate Cox regression analysis. In conclusion, EGFR copy number increases are detectable in a substantial proportion of vulvar carcinomas with relationships to advanced tumour stages and the development of lymph node metastases. EGFR copy number aberrations are connected to other gene amplifications and probably define an human papillomaviruses-independent pathway in the development of vulvar carcinomas. These data support the potential utility of EGFR inhibitors as a therapeutic alternative in a subset of vulvar carcinomas.

Aims Vulvar cancer is a rare disease with increasing incidence over the last decades. Treatment includes surgical, radio- and chemotherapeutical options; however, due to the low incidence of the disease and the lack of randomised trials many questions regarding indication of different treatment approaches remain unanswered. This article discusses the current literature to elaborate recommendations for the management of primary vulvar cancer in clinical routine. Methods We reviewed the available literature on treatment of invasive vulvar cancer with emphasis on therapeutic strategies such as surgery and radio/chemotherapy. Results Surgery of the primary tumour and the groins remain the cornerstone of treatment in vulvar cancer with a strong trend towards a less radical approach in early stage disease. Complete vulvectomy was replaced by radical local excision with plastic reconstruction and the sentinel node technique was implemented to avoid the morbidity of complete groin dissection in node negative patients. In patients with advanced primary disease, treatment decisions are still a challenge. Criteria for the indication and performance of chemo/radiotherapy of the vulva/groins/pelvis are still not fully established and vary between different countries and institutions due to the low level of evidence. Often an individualised therapeutic approach aside from guidelines is necessary to treat these patients adequately. Conclusions To enable reasonable treatment decisions and avoid unnecessary morbidity, treatment in specialised centres should be intended at any time. Clinical studies performed by several study groups on an international level are urgently needed to further improve therapy.

A tumor-free resection margin of at least 8 mm is considered state of the art in vulvar cancer. This standard is based on small and heterogeneous patient cohorts, and its implementation can result in mutilation. One hundred two consecutive patients with primary squamous cell vulvar cancer were analyzed. All patients received resection of the primary tumor and the inguinofemoral lymph nodes via three separate incisions, resulting in complete tumor resection. Median follow-up was 31 months. Minimal margin distances were pathologically determined in all dimensions after fixation. Median age of the patients was 62 years; 38.2% had International Federation of Gynecology and Obstetrics (FIGO) stage I, 17.6% stage II, 24.4% stage III, and 8.8% stage IV disease. The median minimal resection margin was 5 mm (range 0.5–25 mm). Sixteen patients (15.6%) developed disease recurrence, of whom 10 (62.5%) at the vulva. Margin distance had no significant impact on disease-free survival when analyzed continuously (p = 0.388). When cases were divided into three subgroups of

Vulvar cancer is a rare disease and knowledge on prognostic factors is therefore limited and inconsistent. The aim of this study was to determine prognostic variables for recurrence and survival and to identify patterns of recurrence in patients with vulvar cancer.All patients (n = 103) with primary vulvar cancer treated at the University Medical Center Hamburg-Eppendorf between 1996 and 2003 were retrospectively analysed regarding the prognostic relevance of different clinicopathological variables. Recurrences were evaluated with regard to their characteristics and localisation.Age, lymph node metastasis, tumor size, depth of invasion and involvement of resection margins predicted poor disease-free and overall survival in univariate analysis. In multivariate analysis, lymph node status was the most important independent prognostic factor (p = 0.002). No correlation was observed between lymph node metastasis and localization of recurrent disease. Regardless of initial nodal involvement, recurrences occurred primarily in the vulvar region.Inguinofemoral lymph node status at initial diagnosis is of critical prognostic importance for patients with vulvar cancer. Further tumour biological characteristics need to be identified to stratify patients with nodal involvement for adjuvant radiotherapy of the vulva to prevent local recurrences.

Persistent infection with human papillomaviruses (HPV) is a prerequisite for the development of cervical cancer. Vaccination with virus-like particles (VLP) has demonstrated efficacy in prophylaxis but lacks therapeutic potential. HPV16 L1E7 chimeric virus-like particles (CVLP) consist of a carboxy-terminally truncated HPV16L1 protein fused to the amino-terminal part of the HPV16 E7 protein and self-assemble by recombinant expression of the fusion protein. The CVLP are able to induce L1- and E7-specific cytotoxic T lymphocytes. We have performed a first clinical trial to gain information about the safety and to generate preliminary data on the therapeutic potential of the CVLP in humans. A randomized, double blind, placebo-controlled clinical trial has been conducted in 39 HPV16 mono-infected high grade cervical intraepithelial neoplasia (CIN) patients (CIN 2/3). Two doses (75 mug or 250 mug) of CVLP were applied. The duration of the study was 24 weeks with 2 optional visits after another 12 and 24 weeks. The vaccine showed a very good safety profile with only minor adverse events attributable to the immunization. Antibodies with high titers against HPV16 L1 and low titers against HPV16 E7 as well as cellular immune responses against both proteins were induced. Responses were equivalent for both vaccine concentrations. A trend for histological improvement to CIN 1 or normal was seen in 39% of the patients receiving the vaccine and only 25% of the placebo recipients. Fifty-six percent of the responders were also HPV16 DNA-negative by the end of the study. Therefore, we demonstrated evidence for safety and a nonsignificant trend for the clinical efficacy of the HPV16 L1E7 CVLP vaccine.

Women with breast cancer in a distinct stage of disease can benefit from high-dose therapy (HDT) with autologous stem cell support; however, a significant number of these patients relapse despite this intensive treatment. This study investigates the persistence of malignancy on the single-cell level. A total of 194 data sets consisting of bone marrow and blood samples obtained prior to and after HDT and of aliquots of apheresis products were searched with immunocytochemistry and reverse transcriptase polymerase chain reaction (RT-PCR) for disseminated cancer cells. Presence of cancer cells in the marrow is frequent prior to and after HDT, but HDT reduces the amount of malignant cells in marrow significantly. In contrast, there was no effect on the number of circulating cancer cells. Reinfusion of contaminated apheresis products was surprisingly associated with a low number of malignant cells in bone marrow after HDT and vice versa. The impact of disseminated tumor cells in bone marrow, apheresis, and peripheral blood on disease-free survival after HDT could be investigated in a total of 165 samples. Surprisingly, neither the presence of tumor cells in marrow or blood nor in apheresis was associated with a bad prognosis in Kaplan-Meyer survival analysis. These results suggest that apheresis products and bone marrow should be regarded as different biological compartments for epithelial cancer cells. It can be concluded that complete elimination of disseminated cancer cells by HDT is not always possible. The theory of reinduction of metastatic breast cancer by accidentally reinfused contaminants is not supported by this study so far. However, further research is necessary to identify distinct cell populations with the potentially capacity to metastasize.

e15514 Background: Lymph-node metastases to the groin are the most important prognostic factor in vulvar cancer. Prognosis in node-negative vulvar cancer is generally favorable, however, in a small...

5110 Background: A tumor-free resection margin of at least 8 mm is currently considered state of the art in vulvar cancer. However, this standard is based on small and heterogeneous patient cohorts...

Background Human papillomavirus (HPV) is a necessary cause of cervical cancer. HPV is also responsible for benign condylomata acuminata, also known as genital warts. We assessed the incidence of genital warts in Germany and collected information on their management to estimate the annual cost of disease. Methods This was a multi-centre observational (cross-sectional) study of genital warts in Germany. Data were collected from gynecologists, dermatologists, and urologists seeing patients with genital warts between February and April 2005. The number of patients with new and recurrent genital warts was used to estimate the incidence in Germany. We assessed resource use for patients with genital warts seen during a two-month period as well as retrospective resource use twelve months prior to the inclusion visit through a chart review. The mean costs of treatment of patients with genital warts from third-party payer and societal perspectives were estimated, and the total annual cost of genital warts was then calculated. Results For the incidence calculation 217 specialists provided information on 848 patients and 214 specialists provided resource use data for 617 patients to assess resource consumption. The incidence of new and recurrent cases of genital warts was 113.7 and 34.7 per 100 000, respectively, for women aged 14–65 years consulting gynecologists. The highest incidence was observed in women aged 14–25 years (171.0 per 100 000) for new cases and in women aged 26–45 years (53.1 per 100 000) for recurrent cases. The sample size for males was too small to allow a meaningful estimate of the incidence. The mean direct cost per patient with new genital warts was estimated at 378 euros (95% CI: 310.8–444.9); for recurrent genital warts at 603 euros (95% CI: 436.5–814.5), and for resistant genital warts at 1,142 euros (95% CI: 639.6–1752.3). The overall cost to third-party payers was estimated at 49.0 million euros, and the total societal cost at 54.1 million euros, corresponding to an average cost per patient of 550 euros and 607 euros, respectively. Conclusion The societal burden and costs of managing and treating genital warts in Germany are considerable. A vaccination programme using the quadrivalent human papillomavirus vaccine could provide a substantial health benefit and reduce the costs associated with genital warts in Germany.