Management of Malignant Vulval Melanoma: A Retrospective Case Series and Review of the Literature.

OBJECTIVES: The aims of the study were to evaluate clinicopathologic features, management, and outcomes in vulval melanoma and to review the literature. MATERIALS AND METHODS: Data were collected retrospectively on patients with vulval melanoma from 2001 to 2017 in 5 gynecological oncology cancer centers (Bristol, Taunton, Truro, Plymouth, and Cheltenham). SPSS software was used for univariate and multivariate statistical analysis. Disease-specific median survival was calculated using Kaplan-Meier curves. RESULTS: Forty-four patients with vulval melanoma were included, with a median age of 71 years. Forty-three of 44 had wide local excision with full inguinal lymphadenectomy if abnormal lymph nodes. Seven patients had sentinel lymph nodes. However, 2 patients with negative sentinel lymph nodes had distant recurrences within 16 months.On univariate analysis, presence of ulceration (p = .012), perineural invasion (p = .03), and area of lesion (p = .016) were associated with risk of recurrence but only presence of microsatellites (p = .01) was associated with risk of death.There were 31 deaths (70%): 29 (94%) of 31 from melanoma and 28 (64%) of 44 recurrences: 17 local (10 groin, 7 vulval) and 9 distant. Overall median survival was 32.5 months (95% CI, 17.8-46.5 months) and median recurrence-free survival 12.6 months (95% CI, 7.7-17.4 months). CONCLUSIONS: This retrospective multicenter study highlights the high recurrence rate and poor prognosis of vulval melanoma. Lymph node surgery did not make any difference to recurrence-free survival or overall survival. The presence of microsatellites was associated with a statistically increased risk of death.

British Gynaecological Cancer Society Recommendations for Evidence Based, Population Data Derived Quality Performance Indicators for Ovarian Cancer.

Ovarian cancer survival in the UK lags behind comparable countries. Results from the ongoing National Ovarian Cancer Audit feasibility pilot (OCAFP) show that approximately 1 in 4 women with advanced ovarian cancer (Stage 2, 3, 4 and unstaged cancer) do not receive any anticancer treatment and only 51% in England receive international standard of care treatment, i.e., the combination of surgery and chemotherapy. The audit has also demonstrated wide variation in the percentage of women receiving anticancer treatment for advanced ovarian cancer, be it surgery or chemotherapy across the 19 geographical regions for organisation of cancer delivery (Cancer Alliances). Receipt of treatment also correlates with survival: 5 year Cancer survival varies from 28.6% to 49.6% across England. Here, we take a systems wide approach encompassing both diagnostic pathways and cancer treatment, derived from the whole cohort of women with ovarian cancer to set out recommendations and quality performance indicators (QPI). A multidisciplinary panel established by the British Gynaecological Cancer Society carefully identified QPI against criteria: metrics selected were those easily evaluable nationally using routinely available data and where there was a clear evidence base to support interventions. These QPI will be valuable to other taxpayer funded systems with national data collection mechanisms and are to our knowledge the only population level data derived standards in ovarian cancer. We also identify interventions for Best practice and Research recommendations.

ULBP2 and RAET1E NKG2D ligands are independent predictors of poor prognosis in ovarian cancer patients.

The human activating immune receptor, NKG2D, binds to a diverse array of cellular ligands of the MIC and unique long 16 (UL16)-binding protein (ULBP)/retinoic acid early transcript (RAET) family. NKG2D is thought to participate in anticancer immune responses. By using tissue microarrays representing over 300 patients with defined clinicopathological factors, we present the first comprehensive screen of the expression of all NKG2D ligands in primary ovarian cancers. NKG2D ligands were expressed by the majority of tumors; however, the level of expression varied considerably. By categorizing each tumor as having negative, low or high expression, it was shown that high expression of several NKG2D ligands is inversely correlated with disease survival. Patients whose tumors had high expression of RAET1E (p = 0.037), ULBP1 (p = 0.036) and ULBP3 (p = 0.004) surviving a median of 11, 14 and 11 months, respectively, compared with disease-specific survival of 29, 30 and 25 months in patients whose tumors showed no expression of these ligands. These results contrast with previous findings showing that high level NKG2D ligand expression is associated with good prognosis in colorectal cancer and suggest a fundamental difference in the involvement of NKG2D-mediated immunity in these two types of cancer. By using multivariate analysis, the factors retaining independent prognostic significance were International Federation of Gynecologists and Obstetricians stage (p < 0.001), presence of residual disease (p = 0.003), ULBP2 (p = 0.042) and RAET1E (p = 0.030).

Cytoplasmic p27 expression is an independent prognostic factor in ovarian cancer.

Dysregulation of the cell cycle is an important prerequisite for cancer development. p27 has an established role in cell cycle control and hence may be disrupted during carcinogenesis. The influence of p27 expression, including its subcellular location, on tumor behavior in ovarian cancer has been controversial. The purpose of this study was to evaluate the expression of p27 in a large population of patients with ovarian cancer and correlate this to clinicopathologic variables including overall survival. Using a tissue microarray of 339 primary ovarian cancers, the expression of p27 was assessed immunohistochemically. Coupled to a comprehensive database of clinicopathologic variables, its effect on these factors and survival was studied. Cytoplasmic p27 showed a progressively negative impact on overall survival (P=0.004). Tumors displaying nuclear p27 also had poorer prognosis (P=0.014). Factors shown to predict prognosis independently of each other were age, stage, and the absence of macroscopic disease after surgery. Cytoplasmic p27 expression, but not nuclear, was independently predictive of prognosis on multivariate analysis (P=0.042). Both subcellular locations of p27 expression were more frequently observed in serous compared with mucinous subtypes. Cytoplasmic p27 independently predicts poorer prognosis in ovarian carcinoma. These results seem counterintuitive, when considering the antiproliferative role of p27, but may reflect a more complex function of p27 within cell cycle regulation. These data support a novel role for p27 within the cytoplasm, possibly through effects on apoptosis, cellular motility, and drug resistance.

British Gynaecological Cancer Society (BGCS) vulval cancer guidelines: Recommendations for practice.

The purpose of this guideline is to collate evidence and propose evidence-based guidelines for the diagnosis and management of adult patients with vulva carcinoma treated in the UK. Malignant melanoma may present via similar routes and will be discussed. The reader is referred to the Ano-uro-genital Mucosal Melanoma Full Guideline [1] for more detailed recommendations. The management of vulval sarcoma is outside of the scope of this guideline. For further information, including details of guideline development and GRADE of recommendations, please see BGCS website for details (https://www.bgcs.org.uk/professionals/guidelines-for-recent-publications/).

Vascular endothelial growth factor expression in ovarian cancer: a model for targeted use of novel therapies?

PURPOSE: Angiogenesis has a vital role in tumor growth and metastasis, and vascular endothelial growth factor (VEGF) represents a potent cytokine in this process. However, the influence of VEGF in ovarian cancer remains controversial. Interest has focused on the use of antiangiogenic drugs in ovarian cancer. This study aims to establish the pattern of expression and effect on prognosis of VEGF in a large population of ovarian cancer patients and to potentially identify a cohort in whom antiangiogenic therapy is appropriate. EXPERIMENTAL DESIGN: Using a tissue microarray of 339 primary ovarian cancers, the expression of VEGF was assessed immunohistochemically. Coupled to a comprehensive database of clinicopathologic variables, its effect on these factors and survival was studied. RESULTS: Tumors expressing high levels of VEGF had significantly poorer survival (P = 0.04). Factors shown to predict prognosis independently of each other were age, International Federation of Gynecologists and Obstetricians stage, and the absence of macroscopic disease after surgery. VEGF was independently predictive of prognosis on multivariate analysis (P = 0.02). There was no correlation between VEGF and any clinicopathologic variable. High expression of VEGF was seen in only 7% of the tumors, suggesting that the role of antiangiogenic drugs may be limited to a small subset of patients. CONCLUSION: High VEGF expression occurs in a small proportion of ovarian cancers, and this independently predicts poor prognosis. The small percentage of tumors with high levels of VEGF activity suggests that the role of bevacizumab may potentially be limited to a few patients; these patients could be targeted by molecular profiling.

Human leukocyte antigen class I antigen expression is an independent prognostic factor in ovarian cancer.

PURPOSE: Despite improvements in cancer treatment, the prognosis of ovarian cancer remains low and imperfectly predicted by traditional pathologic criteria. Biomarkers that predict prognosis independently of such criteria shed light on important molecular variations, aiding in the development and targeting of novel therapies. Previous work has shown human leukocyte antigen (HLA) class I antigen expression to be independently predictive of prognosis in colorectal and breast cancer. We investigated the prognostic potential of HLA class I antigen expression by studying a large series of ovarian cancers. EXPERIMENTAL DESIGN: A tissue microarray of 339 ovarian cancer cases linked to prospectively recorded clinicopathologic and follow-up data was constructed. This was stained following a standard immunohistochemical protocol for HLA class I heavy chain (HC-10) and beta(2)-microglobulin (beta(2)-m). HLA class I antigen expression was compared with clinicopathologic factors and overall disease-specific survival using the Pearson chi(2) test, Kaplan-Meier curves, and the log-rank test. Cox regression was used to test for the independence and magnitude of effects. RESULTS: There were no univariate correlations between HLA class I antigen expression and clinicopathologic factors. Deviation from an HC-10(+)/beta(2)-m(+) phenotype correlated with reduced survival in univariate analysis (log-rank, 5.69; P = 0.017); a retained HC-10(+)/beta(2)-m(+) phenotype predicted improved prognosis independently of age, stage, level of cytoreduction, and chemotherapy usage on multivariate analysis (hazard ratio, 0.587; 95% confidence interval, 0.442-0.781; P < 0.001). CONCLUSIONS: HLA class I antigen expression is an independent prognostic marker in ovarian cancer, its loss correlating with a poor prognostic outcome.

Loss of IFN gamma receptor is an independent prognostic factor in ovarian cancer.

PURPOSE: There is evidence that IFN gamma plays an important role in ovarian cancer development. IFN gamma produces numerous antitumor effects and it may be evasion of these effects which allows tumor progression. We postulate that genetic instability in tumor cells may lead to modulation of expression of the IFN gamma receptor, thus leading to altered tumor biology and patient prognosis. This hypothesis would support the theory of immunoediting in ovarian cancer. EXPERIMENTAL DESIGN: Using tissue microarray technology of 339 primary ovarian cancers, the expression of IFN gamma receptor was assessed immunohistochemically. Coupled to a comprehensive database of clinicopathologic variables, its effect on these factors was studied. RESULTS: Tumors expressing high levels of IFN gamma receptor had significantly improved survival (P=0.017) compared with tumors expressing low levels of the receptor; this was also seen with complete receptor loss (P=0.014). Factors shown to predict prognosis independently of each other were the following: age, International Federation of Gynecologists and Obstetricians stage, and the absence of macroscopic disease after surgery. The level of IFN gamma receptor expression and complete receptor loss were independently predictive of prognosis on multivariate analysis. There was no correlation between receptor status and any of the standard clinicopathologic variables. CONCLUSIONS: Loss of IFN gamma receptor independently predicts poor prognosis in ovarian cancer. Loss of receptor expression may be responsible for the limited success in the therapeutic use of IFN gamma in ovarian cancer trials and highlights a subgroup of high expressing IFN gamma receptor tumors which are more likely to be susceptible to such treatments.

The ubiquitin-binding protein p62 is expressed in breast cancers showing features of aggressive disease.

p62 is a multi-functional protein, which induces nuclear factor-kappaB (NFkappaB) activation through multiple upstream signalling pathways, including those triggered by the epidermal growth factor (EGF) family of receptors. We hypothesised that p62 overexpression increased EGF family receptor expression and worse outcome in breast cancer would be associated. We stained a tissue microarray representing 523 breast cancers using a commercial guinea pig anti-human p62 sera and standard immunohistochemical methods to address this. Out of n = 106 tumours, 20.3% stained positively. p62 expression correlated with grade (P = 0.010) and distant metastasis (P = 0.04) and EGF receptor (EGFR) (P = 0.012), HER2 (P = 0.016), HER3 (P = 0.007) and HER4 (0.002) expressions. Though expression correlated with reduced 5-year survival (58.5 vs 73.6%), there was no association with overall disease specific survival. p62 expression may represent a marker of activation of the NFkappaB pathway.

BGCS uterine cancer guidelines: Recommendations for practice.

The British Gynaecological Cancer Society has issued the first Endometrial (Uterine) Cancer guidelines as recommendation for practice for the UK.

The p53 positive Bcl-2 negative phenotype is an independent marker of prognosis in breast cancer.

The purpose of this work was to determine if the immunohistochemical p53 (+) Bcl-2 (-) phenotype predicts survival in breast cancer patients. Tissue from 819 cases of resected primary breast cancer, presented between 1986 and 1998, were assembled in tissue microarray format. Clinicopathological data and prospective disease specific survival data were collected prospectively and immunohistochemical analyses of p53 and Bcl-2 expression were performed using antibodies DO-7 (p53) and 124 (Bcl-2) employing a standard IHC protocol. The expression data were correlated with clinicopathological variables and outcomes in both univariate (chi(2)) and multivariate (Cox's regression) analyses. Abnormal p53 expression and positive Bcl-2 expression were detected in 29% (193/673) and 46% (307/673) of tumours, respectively. On univariate analysis Bcl-2 expression was correlated with the clinicopathological features of less aggressive disease and loss of Bcl-2 expression correlated with a reduction in survival (log rank = 11.91; p < 0.001). p53 expression correlated with the clinicopathological features of aggressive cancers and a reduction in survival (log rank = 17.81; p < 0.001). Nineteen percent (127/673) of tumours displayed a p53 (+) Bcl-2 (-) phenotype. Kaplan-Meier analysis revealed a significant reduction in survival in these cases (log rank 34.01; p < 0.001). Multivariate analysis showed that while neither p53 expression nor Bcl-2 expression alone had independent prognostic significance, the p53 (+) Bcl-2 (-) phenotype remained independently associated with a worse prognosis (HR 1.79 95%CI 1.10-2.89 p = 0.018).