Friederike Gieseking

Vaccination trial with HPV16 L1E7 chimeric virus-like particles in women suffering from high grade cervical intraepithelial neoplasia (CIN 2/3).

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 μg or 250 μg) 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.

Estimation of the incidence of genital warts and the cost of illness in Germany: A cross-sectional study

BackgroundHuman 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.MethodsThis 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.ResultsFor 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.ConclusionThe 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.

Clinical management of primary vulvar cancer

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.

Prognostic Role of Lymph Node Metastases in Vulvar Cancer and Implications for Adjuvant Treatment

Objective Lymph 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. Methods One 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. Results Median 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). Conclusions The 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.

Treatment of extramammary Paget disease of the vulva with imiquimod: A retrospective, multicenter study by the German Colposcopy Network

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 gene copy number increase in vulvar carcinomas is linked with poor clinical outcome

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 (p<0.001), 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 (p<0.05). 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 (p<0.001) 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.

Carbonic anhydrase IX is strongly overexpressed in adenocarcinoma in situ of the cervix uteri.

Tomonori Kawasaki Gianni Bussolati Caterina Marchi o Isabella Castellano Lorenzo Daniele Luca Molinaro Michiko Hinata Kazushige Furuya Hiroshi Nakagomi Toshio Oyama Hiroko Tsunoda Tamotsu Sugai Ryohei Katoh Anna Sapino Department of Medical Sciences, University of Turin, Turin, Italy, Department of Pathology, University of Yamanashi, Yamanashi, Japan, Institute ‘Victor Babes’, Bucharest, Romania, Department of Surgery, Division of Pathology, Yamanashi Prefectural Central Hospital, Yamanashi, Department of Radiology, St Luke’s International Hospital, Tokyo, and Department of Molecular Diagnostic Pathology, Iwate Medical University School of Medicine, Morioka, Japan

Vulväre intraepitheliale Neoplasie (VIN)

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”).