Prognostic value of HPV-PCR, p16 and p53 immunohistochemical status on local recurrence rate and survival in patients with vulvar squamous cell carcinoma.

The primary aim of this study was to assess the association between human papilloma virus (HPV) and p53 expression and local recurrence (LR), disease specific survival (DSS), and overall survival (OS) in patients with vulvar squamous cell carcinoma (VSCC). Secondary, the accuracy of p16 immunohistochemistry for HPV status was assessed. The tumor tissue of 255 patients, surgically treated for primary unifocal VSCC between 2000 and 2010, was analyzed. HPV-PCR and P16 and p53 immunohistochemical stainings were performed. All histologic slides were independently reviewed by two expert gyneco-pathologists. Time to first LR, DSS, and OS for the variables p16, p53, and HPV-PCR were compared using univariable and multivariable Cox-regression analyses. In 211/255 (83.5%) patients, HPV-PCR was negative. The local recurrence rate was significantly lower in patients positive with HPV-PCR (10-year LR rate 24.6%) versus negative tumors (47.5%), p = 0.004. After multivariable analyses, this difference remained significant (HR 0.23 (95% CI 0.08-0.62) p = 0.004). There was no difference in LR rate correlated to the p53 expression. DSS and OS did not significantly differ after multivariable analyses for all different subgroups. Sensitivity and specificity of p16 staining for presence of HPV detected by HPV-PCR were 86.4% and 93.8%, respectively. In conclusion, patients with HPV-negative VSCCs have significantly more LR compared to patients with HPV-positive VSCCs, and p16 immunohistochemistry is a reliable surrogate marker for HPV status. No relevant subgroup for LR or survival based on HPV/p53 status could be identified. We advise to perform an HPV-PCR or p16 IHC staining in all patients with VSCC.

Vulvar cancer: Two pathways with different localization and prognosis.

BACKGROUND: Two etiologic pathways for vulvar squamous cell carcinoma (SCC) are described: in a background of lichen sclerosus and/or differentiated vulvar intraepithelial neoplasia and related to high-risk human papillomavirus (HPV) infection with high grade squamous intraepithelial lesion (HSIL) as precursor. The aim was to compare the predilection site and survival of HPV-related to non HPV-related vulvar SCCs. METHODS: Data of patients treated for primary vulvar SCC at the Radboudumc between March 1988 and January 2015 were analyzed. All histological specimens were tested for HPV with the SPF10/DEIA/LiPA25 system assay and p16INK4a staining was performed using CINtec® histology kit. Vulvar SCCs were considered HPV-related in case of either >25% p16INK4a expression and HPV positivity or >25% p16INK4a expression and HSIL next to the tumor without HPV positivity. Tumor localization, disease specific survival (DSS), disease free survival (DFS) and overall survival (OS) of patients with HPV-related and non HPV-related vulvar SCC were compared. RESULTS: In total 318 patients were included: 55 (17%) had HPV-related (Group 1) and 263 (83%) had non HPV-related vulvar SCC (Group 2). Tumors in Group 1 were significantly more often located at the perineum compared to Group 2, 30% and 14%, respectively (p=0.001). The DSS, DFS and OS were significantly better in HPV-related than in non HPV-related vulvar SCC patients. CONCLUSION: HPV-related vulvar SCCs are more frequently located at the perineum and have a favorable prognosis compared to non HPV-related vulvar SCCs. Both localization and HPV-relation could explain this favorable prognosis. HPV-related vulvar SCC seems to be a separate entity.

Volume-controlled versus short drainage after inguinofemoral lymphadenectomy in vulvar cancer patients: A Dutch nationwide prospective study.

OBJECTIVE: Inguinofemoral lymphadenectomy for patients with vulvar squamous cell carcinoma is associated with a high incidence of postoperative wound complications, which may be influenced by inguinal drain management. The aim of this nationwide prospective study (MAMBO: Morbidity And Measurement of the BOdy) was to assess the feasibility and the incidence of complications after volume-controlled versus short drainage. METHODS: The MAMBO study consisted of two observational studies in all eight oncology centers in the Netherlands, conducted between 2012 and 2016. In the first study, the drain was removed when the production was <30ml/24h, except in the first 48h, and after a maximum of 28days (MAMBO-IA). In the second study, the drain was removed five days postoperatively regardless of production (MAMBO-IB). We assessed the complications within eight weeks after surgery using logistic regression to compare the incidence of one or more complications between the two drainage protocols, adjusting for possible confounders. RESULTS: We included 77 patients (139 groins) for volume-controlled drainage and 64 patients (112 groins) for short drainage. Volume-controlled drainage was associated with significant less lymphocele formation. Moreover, we found no difference in wound infection or primary wound breakdown. The estimated incidence of one or more complications was 46% per groin after volume-controlled drainage versus 75% after short drainage, (RD 29% (95% CI 8, 49) p=0.006). CONCLUSIONS: This prospective study shows that volume-controlled drainage is associated with significantly less complications compared to short drainage. We therefore recommend volume-controlled drainage after inguinofemoral lymphadenectomy in patients with vulvar squamous cell carcinoma.

Reactivation of Latent HPV Infections After Renal Transplantation.

Female renal transplant recipients (RTRs) have an increased risk for developing human papillomavirus (HPV)-related (pre)malignant lesions of the genital tract. This study aims to assess the genital prevalence of HPV before and after renal transplantation (RT). In female patients who were counseled for RT at the Radboud University Medical Center Nijmegen, the Netherlands, gynecological examination was performed at first visit, and 1 and 2 years later. HPV self-sampling and questionnaires on sexual behavior were performed every 3 months. In 65 patients who underwent RT, the high-risk human papillomavirus (hrHPV) prevalence as assessed with the highly sensitive SPF10 -LiPA25 test increased significantly from 19% before to 31% after RT (p = 0.045). Based upon the clinically validated Cobas 4800 HPV test, the hrHPV prevalence increased from 10% before to 14% after RT (p = 0.31). During follow-up, no changes in sexual behavior were reported. Thirty-three patients who did not undergo RT showed a hrHPV prevalence of 21% at study entry and of 27% after 12 months with the sensitive test, and a stable prevalence of 16% with the clinically validated test. The results of this study indicate that activation of latent HPV infections may contribute to the increased risk of HPV-related (pre)malignant lesions in female RTRs.

Clitoral involvement of squamous cell carcinoma of the vulva: localization with the worst prognosis.

OBJECTIVE: The overall 5-year survival of patients with vulvar squamous cell carcinoma (SCC) is 70%. The clinical impression is that localization of SCC on the clitoris may lead to worse prognosis. The aim of this study is to assess the disease specific survival (DSS) in patients with clitoral SCC compared to patients with SCC without clitoral involvement. METHODS: All consecutive patients with primary vulvar SCC treated with surgery at the Department of Gynaecologic Oncology at the Radboud university medical centre (Radboudumc) between March 1988 and January 2012, were analysed. The clinical and histopathological characteristics and DSS rates of patients with (N = 72) and without clitoral SCC (N = 275) were compared. Furthermore, patients with clitoral involvement were compared to patients with perineal SCCs (N = 52) and other central SCCs without clitoral and/or perineal involvement (N = 117). RESULTS: Patients with clitoral SCC more often had larger and deeper invaded tumours, lymphovascular space involvement (LVSI), positive surgical margins and a higher percentage of positive lymph nodes. Kaplan-Meier survival analyses showed worse DSS in patients with a clitoral SCC compared to patients without clitoral involvement. Multivariable analysis showed that not clitoral involvement, but invasion depth, differentiation grade and lymph node status are independent prognostic factors. CONCLUSIONS: Patients with clitoral SCC have worse survival compared to patients without clitoral involvement. This is probably caused by unfavourable histopathological characteristics of the tumour rather than the localization itself. Prospective studies are needed to further assess the influence of localization of the vulvar SCC on prognosis.

Cervicovaginal HPV infection in female renal transplant recipients: an observational, self-sampling based, cohort study.

Immunosuppressive treatment of organ transplant recipients is associated with an increase in the occurrence of human papillomavirus (HPV) related anogenital (pre)malignancies. This cohort study investigated the genotype-specific prevalence of HPV infections in a large cohort of female renal transplant recipients (RTRs). Participants self-collected a cervicovaginal sample for detection and genotyping of HPV. Besides, they completed a questionnaire regarding sociodemographic variables, medical data and sexual behavior. Anogenital screening was offered to all HPV-positive participants. A total number of 218 female RTRs was included. The prevalence of mucosal HPV infections was 27.1% and 17.4% for high risk HPV in particular. The studied cohort showed a broad range of HPV genotypes and multiple HPV genotypes were found in 27.1% of HPV-positive patients. Seven participants were identified with occult premalignant anogenital lesions. In conclusion, this study shows a high point-prevalence of HPV in female RTRs (age-matched West-European general population: 9-10%) with a shift in the distribution of genotypes as compared with the general population. Moreover, a substantial number of patients with occult premalignancies was identified. The introduction of self-sampling for HPV positivity can help in early detection of (pre)malignant anogenital lesions in this vulnerable population.

HPV-related (pre)malignancies of the female anogenital tract in renal transplant recipients.

Renal transplantations (RTs) are performed routinely in many countries. After RT, the administration of lifelong immunosuppressive therapy is required. As a consequence, renal transplant recipients (RTRs) have a high risk to develop virus-associated (pre)malignancies, such as Human papillomavirus (HPV) related anogenital (pre)malignancies. It is known that the majority of the RTRs are infected with HPV and that these women have a 14-fold increased risk of cervical cancer, up to 50-fold of vulvar cancer and up to 100-fold of anal cancer. Often, treatment of these lesions requires concessions and may be suboptimal as radiation therapy and extensive surgery may damage the renal transplant. Therefore, prognosis may be compromised due to inadequately treated malignancies. Especially for these immunocompromised patients prevention is of utmost importance. Yearly cervical cancer screening for RTRs is advised, but appears to be executed poorly. For the future, optimizing screening and prevention of anogenital (pre)malignancies is an important issue for women after RT. This review gives a broad overview of all aspects regarding HPV-related (pre)malignancies of the female anogenital tract in RTRs.

Risk factors for short- and long-term complications after groin surgery in vulvar cancer.

BACKGROUND: The cornerstone of treatment in early-stage squamous cell carcinoma (SCC) of the vulva is surgery, predominantly consisting of wide local excision with elective uni- or bi-lateral inguinofemoral lymphadenectomy. This strategy is associated with a good prognosis, but also with impressive treatment-related morbidity. The aim of this study was to determine risk factors for the short-term (wound breakdown, infection and lymphocele) and long-term (lymphoedema and cellulitis/erysipelas) complications after groin surgery as part of the treatment of vulvar SCC. METHODS: Between January 1988 and June 2009, 164 consecutive patients underwent an inguinofemoral lymphadenectomy as part of their surgical treatment for vulvar SCC at the Department of Gynaecologic Oncology at the Radboud University Nijmegen Medical Centre. The clinical and histopathological data were retrospectively analysed. RESULTS: Multivariate analysis showed that older age, diabetes, 'en bloc' surgery and higher drain production on the last day of drain in situ gave a higher risk of developing short-term complications. Younger age and lymphocele gave higher risk of developing long-term complications. Higher number of lymph nodes dissected seems to protect against developing any long-term complications. CONCLUSION: Our analysis shows that patient characteristics, extension of surgery and postoperative management influence short- and/or long-term complications after inguinofemoral lymphadenectomy in vulvar SCC patients. Further research of postoperative management is necessary to analyse possibilities to decrease the complication rate of inguinofemoral lymphadenectomy; although the sentinel lymph node procedure appears to be a promising technique, in 50% of the patients an inguinofemoral lymphadenectomy is still indicated.

Diagnosis and treatment of postsurgical synovial fistula of the knee.

With the exception of post-arthroscopy synovial fistulae formation, which generally heal without additional treatment, postsurgical synovial fistulae are relatively uncommon. We describe the development of synovial fistulae after three different surgical procedures: a biopsy, a high tibial osteotomy, and an anterior cruciate ligament reconstruction. With treatment tailored to the individual patient, the synovial fistulae can be cured by closing the opening between the knee joint and the fistula.