Groin Surveillance by Serial Ultrasonography Rather Than Sentinel Node Biopsy or Inguinofemoral Lymphadenectomy for Patients with Vulvar Cancer: A Pilot Study.

A pilot study was conducted to determine whether 3-monthly groin ultrasonography could eliminate groin dissection after a negative bilateral groin ultrasound in three groups of patients: (i) Those with a unifocal stage 1B squamous cell carcinoma of up to 20 mm in diameter. (ii) Those with an ipsilateral squamous cell carcinoma of any size which extended to within 1 cm either side of the midline. These patients underwent ipsilateral inguinofemoral lymphadenectomy and ultrasonic surveillance of the contralateral groin. (iii) Patients with multifocal invasive lesions with the largest individual focus 20 mm or less in diameter. Three additional patients were added because they either refused groin dissection or were considered unfit for surgery. All ultrasonically positive nodes were confirmed histologically. Thirty-two patients were entered, and no patients were lost to follow-up. Forty-three groins were followed. With a median follow-up of 37 months, three positive nodes (9.4%) were detected. One patient died of her recurrence (3.1%), and 39 groins (90.7%) were preserved. The overall sensitivity of ultrasonic surveillance was 100% (95% CI: 44-100%), with a specificity of 97% (95% CI: 83-99%) and a negative predictive value of 100% (95% CI: 88-100%). This pilot justifies a larger study on serial ultrasonography in lieu of groin dissection in selected patients with vulvar cancer.

CCNE1 and survival of patients with tubo-ovarian high-grade serous carcinoma: An Ovarian Tumor Tissue Analysis consortium study.

BACKGROUND: Cyclin E1 (CCNE1) is a potential predictive marker and therapeutic target in tubo-ovarian high-grade serous carcinoma (HGSC). Smaller studies have revealed unfavorable associations for CCNE1 amplification and CCNE1 overexpression with survival, but to date no large-scale, histotype-specific validation has been performed. The hypothesis was that high-level amplification of CCNE1 and CCNE1 overexpression, as well as a combination of the two, are linked to shorter overall survival in HGSC. METHODS: Within the Ovarian Tumor Tissue Analysis consortium, amplification status and protein level in 3029 HGSC cases and mRNA expression in 2419 samples were investigated. RESULTS: High-level amplification (>8 copies by chromogenic in situ hybridization) was found in 8.6% of HGSC and overexpression (>60% with at least 5% demonstrating strong intensity by immunohistochemistry) was found in 22.4%. CCNE1 high-level amplification and overexpression both were linked to shorter overall survival in multivariate survival analysis adjusted for age and stage, with hazard stratification by study (hazard ratio [HR], 1.26; 95% CI, 1.08-1.47, p = .034, and HR, 1.18; 95% CI, 1.05-1.32, p = .015, respectively). This was also true for cases with combined high-level amplification/overexpression (HR, 1.26; 95% CI, 1.09-1.47, p = .033). CCNE1 mRNA expression was not associated with overall survival (HR, 1.00 per 1-SD increase; 95% CI, 0.94-1.06; p = .58). CCNE1 high-level amplification is mutually exclusive with the presence of germline BRCA1/2 pathogenic variants and shows an inverse association to RB1 loss. CONCLUSION: This study provides large-scale validation that CCNE1 high-level amplification is associated with shorter survival, supporting its utility as a prognostic biomarker in HGSC.

Gene-Expression Profiling of Mucinous Ovarian Tumors and Comparison with Upper and Lower Gastrointestinal Tumors Identifies Markers Associated with Adverse Outcomes.

PURPOSE: Advanced-stage mucinous ovarian carcinoma (MOC) has poor chemotherapy response and prognosis and lacks biomarkers to aid stage I adjuvant treatment. Differentiating primary MOC from gastrointestinal (GI) metastases to the ovary is also challenging due to phenotypic similarities. Clinicopathologic and gene-expression data were analyzed to identify prognostic and diagnostic features. EXPERIMENTAL DESIGN: Discovery analyses selected 19 genes with prognostic/diagnostic potential. Validation was performed through the Ovarian Tumor Tissue Analysis consortium and GI cancer biobanks comprising 604 patients with MOC (n = 333), mucinous borderline ovarian tumors (MBOT, n = 151), and upper GI (n = 65) and lower GI tumors (n = 55). RESULTS: Infiltrative pattern of invasion was associated with decreased overall survival (OS) within 2 years from diagnosis, compared with expansile pattern in stage I MOC [hazard ratio (HR), 2.77; 95% confidence interval (CI), 1.04-7.41, P = 0.042]. Increased expression of THBS2 and TAGLN was associated with shorter OS in MOC patients (HR, 1.25; 95% CI, 1.04-1.51, P = 0.016) and (HR, 1.21; 95% CI, 1.01-1.45, P = 0.043), respectively. ERBB2 (HER2) amplification or high mRNA expression was evident in 64 of 243 (26%) of MOCs, but only 8 of 243 (3%) were also infiltrative (4/39, 10%) or stage III/IV (4/31, 13%). CONCLUSIONS: An infiltrative growth pattern infers poor prognosis within 2 years from diagnosis and may help select stage I patients for adjuvant therapy. High expression of THBS2 and TAGLN in MOC confers an adverse prognosis and is upregulated in the infiltrative subtype, which warrants further investigation. Anti-HER2 therapy should be investigated in a subset of patients. MOC samples clustered with upper GI, yet markers to differentiate these entities remain elusive, suggesting similar underlying biology and shared treatment strategies.

Medial Inguino-Femoral Lymphadenectomy for Vulvar Cancer: An Approach to Decrease Lymphedema without Compromising Survival.

BACKGROUND: Lower limb lymphedema is a long-term complication of inguino-femoral lymphadenectomy and is related to the number of lymph nodes removed. Our hypothesis was that lymph nodes lateral to the femoral artery could be left in situ if the medial nodes were negative, thereby decreasing this risk. METHODS: We included patients with vulvar cancer of any histological type, even if the cancer extended medially to involve the urethra, anus, or vagina. We excluded patients whose tumor extended (i) laterally onto the thigh, (ii) posteriorly onto the buttocks, or (iii) anteriorly onto the mons pubis. After resection, the inguinal nodes were divided into a medial and a lateral group, based on the lateral border of the femoral artery. RESULTS: Between December 2010 and July 2018, 76 patients underwent some form of groin node dissection, and data were obtained from 112 groins. Approximately one-third of nodes were located lateral to the femoral artery. Positive groin nodes were found in 29 patients (38.2%). All patients with positive nodes had positive nodes medial to the femoral artery. Five patients (6.6%) had positive lateral inguinal nodes. The probability of having a positive lateral node given a negative medial node was estimated to be 0.00002. CONCLUSION: Provided the medial nodes are negative, medial inguino-femoral lymphadenectomy may suffice and should reduce lower limb lymphedema without compromising survival.

Radiotherapy is not indicated in patients with vulvar squamous cell carcinoma and only one occult intracapsular groin node metastasis.

OBJECTIVE: Most guidelines advise no adjuvant radiotherapy in vulvar squamous cell carcinoma and a single occult intracapsular lymph node metastasis. However, several recent studies have questioned the validity of this recommendation. The aim of this study was to analyze the groin recurrence rate in patients with a single intracapsular positive lymph node treated without adjuvant radiotherapy. METHODS: Patients with a single clinically occult intracapsular lymph node metastasis, treated without adjuvant radiotherapy, formed the basis for this study. Groin recurrences, and the risk of death, were analyzed in relation to the size of the metastasis in the lymph node and the lymph node ratio. Data were analyzed using SPSS, version 26.0 for Windows. RESULTS: After a median follow-up of 64 months, one of 96 patients (1%) was diagnosed with an isolated groin recurrence and another two (2.1%) were diagnosed with a combination of a local and a groin recurrence. The only isolated groin recurrence occurred in a contralateral lymph node negative groin. Size of the metastasis and lymph node ratio had no impact on the groin recurrence risk, nor on survival. The 5-year actuarial disease-specific and overall survivals were 79% and 62.5% respectively. The 5-year actuarial groin recurrence-free survival was 97%. CONCLUSION: Because of the low risk of groin recurrence and the excellent groin recurrence-free survival, we recommend that adjuvant radiotherapy to the groin in patients with vulvar squamous cell carcinoma and a single occult intracapsular lymph node metastasis can be safely omitted to prevent unnecessary toxicity and morbidity.

The Prognostic Role of the Surgical Margins in Squamous Vulvar Cancer: A Retrospective Australian Study.

For the last 30 years at the Royal Hospital for Women, unifocal vulvar squamous cancers have been treated by radical local excision, aiming to achieve a histopathological margin of ≥8 mm, equating to a surgical margin of 1 cm. The need for a margin of this width has recently been challenged. We aimed to determine the long-term outcome following this conservative approach, and the relationship between vulvar recurrences and surgical margins. Data were obtained retrospectively on 345 patients treated primarily with surgery for squamous vulvar cancer between 1987 and 2017. Median follow-up was 93 months. Five-year disease-specific survival was 86%. Of 78 vulvar recurrences, 33 (42.3%) were at the primary site and 45 (57.7%) at a remote site. In multivariable analysis, a margin < 5 mm showed a higher risk of all vulvar (Hazard ratio (HR), 2.29; CI, 1.12-4.70), and primary site recurrences (subdistribution hazard ratio (SHR), 15.20; CI, 5.21-44.26), while those with a margin of 5 to <8 mm had a higher risk of a primary site recurrence (SHR, 8.92; CI, 3.26-24.43), and a lower risk of remote site recurrence. Excision margins < 8 mm treated by re-excision or radiation therapy had a significantly decreased risk of recurrence. Guidelines should continue to recommend a surgical margin of 1 cm.

The Clinical Relevance of p16 and p53 Status in Patients with Squamous Cell Carcinoma of the Vulva.

OBJECTIVE: To investigate the prognostic significance of HPV status in vulvar squamous cell carcinomas (VSCC) and to determine whether preoperative determination of p16 or p53 status would have clinical relevance. METHODS: Patients treated for VSCC at a tertiary hospital in Sydney, Australia, from 2002 to 2014, were retrospectively evaluated (n = 119). Histological specimens were stained for p53 and p16 expression, and HPV status was determined by PCR detection of HPV DNA. RESULTS: HPV DNA was detected in 19%, p16 expression in 53%, and p53 expression in 37% of patients. Kaplan-Meier survival estimates indicated that p16/HPV-positive patients had superior five-year disease-free survival (76% versus 42%, resp., p = 0.004) and disease-specific survival (DSS) (89% versus 75% resp., p = 0.05) than p53-positive patients. In univariate analysis, nodal metastases (p < 0.001), tumor size >4 cm (p = 0.03), and perineural invasion (p = 0.05) were associated with an increased risk of disease progression and p16 expression with a decreased risk (p = 0.03). In multivariable analysis, only nodal metastases remained independent for risk of disease progression (p = 0.01). For DSS, lymph node metastases (p < 0.001) and tumor size (p = 0.008) remained independently prognostic. CONCLUSION: The p16/HPV and p53 status of VSCC allows separation of patients into two distinct clinicopathological groups, although 10% of patients fall into a third group which is HPV, p16, and p53 negative. p16 status was not independently prognostic in multivariable analysis. Treatment decisions should continue to be based on clinical indicators rather than p16 or p53 status.

Vulvar cancer in high-income countries: Increasing burden of disease.

The aim of this study was to assess trends in the age-specific incidence of vulvar cancer in 13 high-income countries satisfying a priori conditions regarding the availability of cancer registry data over a 20-year period; these were Canada, the United States, nine European countries, Australia and Japan. Five-yearly incidence and population at risk were obtained from the International Agency for Research on Cancer's Cancer Incidence in Five Continents for the years 1988-1992 (Volume 7) to 2003-2007 (Volume 10). The 5-yearly average percent change (AvPC) over the period and standardised rate ratios (SRRs) for 2003-2007 versus 1988-1992 were used to assess changes in the age-standardised incidence rates of vulvar cancer for all ages, and for <60 years and 60+ years. During the study period, the 5-yearly AvPC across the 13 countries increased by 4.6% (p = 0.005) in women of all ages, and 11.6% (p = 0.02) in those <60 years. No change was observed in women aged 60+ years (5-yearly AvPC = 0.1%, p = 0.94). The SRR for 2003-2007 versus 1988-1992 was significantly elevated in women <60 years of age (SRR = 1.38, 95% CI: 1.30-1.46), but not in women of 60+ years (SRR = 1.01, 95% CI: 0.97-1.05). The increase in incidence in women <60 years of age drove a significant increase in the overall SRR in women of all ages (SRR = 1.14, 95% CI: 1.11-1.18). Some differences in the specific findings at the individual country level were observed. The findings are consistent with changing sexual behaviours and increasing levels of exposure to human papillomavirus (HPV) in cohorts born around/after about 1950, but younger cohorts offered HPV vaccination are likely to receive some protection against developing vulvar cancer in the future.

Changing Trends in Vulvar Cancer Incidence and Mortality Rates in Australia Since 1982.

BACKGROUND: The objective of this study was to assess trends in vulvar cancer incidence and mortality in Australia. METHODS: Case numbers for invasive carcinoma of the vulva (1982-2009) and vulvar cancer deaths (1982-2011) were obtained from the National Cancer Statistics database. Standardized rate ratios (SRRs) were used to assess changes in age-standardized incidence and mortality rates, for all ages and for younger than 60 years and 60+ years. RESULTS: Age-standardized incidence rates in women across all ages did not significantly change from 1982-1984 to 2007-2009 (from 2.1 to 2.5 per 100,000 women; SRR from the later to the earlier period, 1.13 [95% CI, 1.00-1.27]). However, there was a significant 84% increase in incidence in women younger than 60 years (SRR, 1.84 [95% CI, 1.49-2.26]), with no change for women 60+ years (SRR, 0.90 [95% CI, 0.79-1.04]). Age-standardized mortality in women across all ages significantly decreased by 22% from 1982-1986 to 2007-2011 (from 0.7 to 0.5 per 100,000 women; SRR, 0.78 [95% CI, 0.66-0.93]). However, this was driven by declines in older women, with stable rates in women younger than 60 years (SRR, 1.05 [95% CI, 0.62-1.79]); rates in 60+ years decreased by 24% (SRR, 0.76 [95% CI, 0.63-0.91]). CONCLUSION: Since the early 1980s, vulvar cancer incidence has increased by more than 80% in women younger than 60 years in Australia, but there has been no increased incidence in older women. These findings are consistent with the possibility of increased exposure to the human papillomavirus in cohorts born after 1950. By contrast, age-standardized vulvar cancer mortality rates have been stable in younger women, but have declined in older women.

Staging for vulvar cancer.

Vulvar cancer has been staged by the International Federation of Gynaecology and Obstetrics (FIGO) since 1969, and the original staging system was based on clinical findings only. This system provided a very good spread of prognostic groupings. Because vulvar cancer is virtually always treated surgically, the status of the lymph nodes is the most important prognostic factor and this can only be determined with certainty by histological examination of resected lymph nodes, FIGO introduced a surgical staging system in 1988. This was modified in 1994 to include a category of microinvasive vulvar cancer (stage IA), because such patients have virtually no risk of lymph node metastases. This system did not give a reasonably even spread of prognostic groupings. In addition, patients with stage III disease were shown to be a heterogeneous group prognostically, and the number of positive nodes and the morphology of those nodes were not taken into account. A new surgical staging system for vulvar cancer was introduced by FIGO in 2009. Initial retrospective analyses have suggested that this new staging system has overcome the major deficiencies in the 1994 system.

Sexuality and body image following treatment for early-stage vulvar cancer: a qualitative study.

AIM: To describe women's experiences of sexuality and body image following treatment for early-stage vulvar cancer. BACKGROUND: There is limited information available on sexual function following treatment for early-stage vulvar cancer. A review of the literature has shown a lack of qualitative investigation into this topic. This study was undertaken to address this deficiency and to add to the existing body of knowledge describing the psychosexual outcomes for these women. DESIGN: Qualitative interview study. METHODS: A qualitative approach based on interpretive phenomenology was used to interview a purposive sample of 10 women (mean age 58 years) who had previously been treated for an early-stage vulvar cancer. Interviews were conducted from June-October 2009. Data were generated from verbatim transcription of the semi-structured in-depth interviews. Thematic analysis of these data revealed themes that were common to the women's experiences of sexuality and body image. FINDINGS: Four themes were identified that described the structure of the experience. Only two of these themes, sexuality and body image, will be discussed in this paper. CONCLUSIONS: Findings from this study indicated that the majority of women experienced little to no long-term disruption to sexuality and body image following conservative treatment for early-stage vulvar cancer. Intimacy and relationship status were more closely linked to women's sexual satisfaction than physical arousal. Factors contributing to women experiencing negative emotions were radical vulvar excision, multiple vulvar procedures and/or the development of lymphoedema.

Primary surgical management with tailored adjuvant radiation for stage IB2 cervical cancer.

OBJECTIVE: To examine the outcome for patients with stage IB2 cervical cancer treated primarily with radical hysterectomy, and to determine the need for adjuvant therapy, the sites of recurrence, and the morbidity of the treatment. METHODS: We reviewed our experience with 93 patients with stage IB2 cervical cancer treated with primary surgery at the Royal Hospital for Women in Sydney from 1988 to 2008. All patients underwent radical hysterectomy and pelvic lymphadenectomy. If bulky positive nodes were encountered, they were resected without complete lymphadenectomy. Postoperative radiation was tailored to the histologic findings. RESULTS: The mean age of the patients was 46 years, and 70% had squamous cell carcinomas. Tumor invaded into the outer third of the cervical stroma in 73 cases (78.5%), occult parametrial extension occurred in 15 cases (16.1%), and vascular space invasion occurred in 65 cases (69.9%). Positive pelvic nodes were present in 42 patients (45.2%) and bulky positive para-aortic nodes were present in 5 patients (5.4%). Some type of postoperative adjuvant (chemoradiation) radiation was given to 74 patients (79.6%). With a median follow-up of 96 months, the overall 5-year survival was 80.7%, being 85% for patients with negative nodes and 75% for those with positive nodes (hazard ratio 2.63, 95% confidence interval 1--5.6; P=.045). The major long-term surgical morbidity was lymphedema, which occurred in eight patients (8.6%). Serious long-term radiation morbidity (Radiation Therapy Oncology Group grade 3) occurred in three patients (3.2%). CONCLUSIONS: Primary radical hysterectomy with tailored postoperative adjuvant radiation for patients with stage IB2 cervical cancer provides good survival with acceptably low morbidity. LEVEL OF EVIDENCE: III.

Psychometric validation of the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Endometrial Cancer Module (EORTC QLQ-EN24).

AIM: A validation study was conducted to evaluate the psychometric properties of the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Endometrial Cancer Module (EORTC QLQ-EN24). This module was designed to assess disease and treatment specific aspects of the quality of life (QoL) of patients with endometrial cancer. METHODS: Two hundred and sixty-eight women with endometrial cancer were recruited in different phases of treatment: after pelvic surgery (Group 1); during adjuvant chemotherapy and/or radiotherapy (Group 2); after completion of treatment (Group 3). Patients completed the EORTC QLQ-C30, the endometrial cancer module and a short debriefing questionnaire. RESULTS: Multi-trait scaling analyses confirmed the hypothesised scale structure of the QLQ-EN24. Internal consistency reliability was good with Cronbach's alpha coefficients ranging from 0.74 to 0.86 (lymphoedema 0.80, urological symptoms 0.75, gastrointestinal symptoms 0.74, body image problems 0.86 and sexual/vaginal problems 0.86). Convergent and discriminant validity did not show any scaling errors for the subscales. The QLQ-EN24 module discriminated well between clinically different groups of patients. All items exhibited a high completion rate with less than 2% missing values except for the sexuality items (19%). CONCLUSION: The validation study supports the reliability, the convergent and divergent validity of the EORTC QLQ-EN24. This newly developed QLQ-EN24 module is a useful instrument for the assessment of the QoL in patients treated for endometrial cancer in clinical trials.