Seminoma and dysgerminoma: evidence for alignment of clinical trials and de-escalation of systemic chemotherapy.

Malignant germ cell tumours are a group of rare cancers whose incidence peaks in late adolescence and early adulthood. Dysgerminomas of the ovary and seminomas of the testis are analogous diseases, but seminomas have a 10-fold higher incidence. The two tumours are morphologically identical and are only differentiated by surrounding organ-specific tissue or testicular germ cell neoplasia in situ. They share genetic features including KIT and RAS mutations, amplification of chromosome 12p, and expression of pluripotency markers (NANOG (Nanog homeobox), OCT3/4 (Octamer-binding transcription factor 3/4), and SAL4 (Spalt-like trascription factor 4)). Both histologies are exquisitely sensitive to platinum chemotherapy, and the combination of bleomycin, etoposide, and cisplatin (BEP) yields survival rates greater than 90%. However, BEP causes significant, lifelong toxicity (cardiovascular, renal, respiratory, and neurological) in these young patients with an expectation of cure. Here, we comprehensively review the biological features of dysgerminoma and seminoma to demonstrate that they are biologically analogous diseases. We present available clinical trial data supporting de-escalation of chemotherapy treatment. Finally, we propose that future trials should enrol men, women, and children to benefit all patients regardless of age or sex.

Surgical management and outcomes for stage 1 malignant ovarian germ cell tumours: A UK multicentre retrospective cohort study.

OBJECTIVE: To describe the current surgical management of stage 1 malignant ovarian germ cell tumours and correlated oncological outcomes. STUDY DESIGN: We undertook a retrospective study of all stage 1 primary ovarian germ cell tumours treated in four major UK gynaecology oncology centres over 12 years. We assessed route of surgery, fertility-sparing approaches, ovarian cystectomy alone, and surgical staging and correlated these with clinical outcomes. RESULTS: Eighty-six patients were followed-up for a median of 4.4 years (IQR 4.3). The median age was 26 (range 11-47). There were 24 (27.9%) dysgerminomas, 13 (15.1%) yolk sac tumours, 10 (11.3%) mixed germ cell tumours, and 39 (45.3%) immature teratomas. Overall survival was 96.6% (OS, 95% CI 91.9-100%), with event free survival of 81.8% (EFS, 95% CI 72.5-92.3) at 5 years. The majority had fertility-sparing surgery (93%, n = 80). In a subset of patients with immature teratoma, there was no significant difference in recurrence or survival if patients underwent unilateral cystectomy only or salpingo-oophorectomy. Laparotomy was the most common approach (n = 66, 76.7%), used more frequently for larger tumours > 10 cm. Surgical staging procedures were undertaken in 42 (48.6%) patients with no significant difference in rates of staging across histological subtypes. Peritoneal biopsies were taken in 11 (12.7%), omental assessment in 40 (46.5%) and lymphadenectomy in 10 (11.6%). There was no significant difference in EFS between patients who underwent staging procedures (83%, CI 71-98%) versus those that did not (84%, CI 72-98%). There was no significant difference in the rate of staging procedures in paediatric (42.1% 8/19) and adult (57.9% 34/67) populations. CONCLUSIONS: Across all histologies and ages, the absence of surgical staging did not impact upon disease free or overall survival in this cohort. This study also raises the possibility of a role for ovarian cystectomy in immature teratoma. These findings warrant investigation in larger prospective studies.

Performance of ultrasound as a second line test to serum CA125 in ovarian cancer screening.

OBJECTIVE: To assess the performance of ultrasonography in a multimodal ovarian cancer screening strategy. DESIGN: Prospective ovarian cancer screening trial between December 1986 and June 1993. SETTING: General practice, occupational health departments and an ovarian cancer screening clinic at a London teaching hospital. POPULATION: Postmenopausal women, ≥ 45 years with a raised CA125. METHODS: Volunteers with a CA125 ≥ 30 U/mL underwent a pelvic ultrasound. Scans were classified as normal, abnormal (ovarian volume ≥ 8.8 mL) or equivocal (normal volume with abnormal morphology). Abnormal ovarian morphology was subclassified as simple cyst (single, thin walled cyst with no septa or papillary projections) or complex (all other abnormalities). Volunteers with abnormal scans were referred for a gynaecological opinion. Follow up was via the cancer registry and postal questionnaires. MAIN OUTCOME MEASURES: Sensitivity, specificity and positive predictive value of different ultrasound criteria for detection of index cancer (e.g. primary invasive epithelial carcinoma of the ovary and fallopian tube). RESULTS: Seven hundred and forty-one women underwent 1219 scans and 20 index cancers occurred during a median follow up of 6.8 years. The sensitivity for detection of ovarian cancer of different ultrasound criteria was 100% for abnormal morphology, 89.5% for abnormal volume and 84% for complex morphology. The highest specificity (97%) and positive predictive value (37.2%) was achieved using complex morphology. CONCLUSION: A variety of ultrasound criteria can achieve high sensitivity, specificity and positive predictive value for index cancers in postmenopausal women with an elevated CA125. Use of ovarian morphology to interpret ultrasound may increase sensitivity and use of complex ovarian morphology may increase the positive predictive value.

Significance of PTEN alterations in endometrial carcinoma: a population-based study of mutations, promoter methylation and PTEN protein expression.

Mutations in the PTEN gene are frequent in endometrial carcinoma. PTEN methylation is an alternative mechanism of gene inactivation. To elucidate different mechanisms of PTEN gene inactivation, we have studied a population-based series of endometrial carcinomas for PTEN mutations in relation to clinicopathologic characteristics, promoter methylation and protein expression. PTEN mutations were found in 54%, mainly in exons 5 and 8; with at least two different mutations in 21%. Presence of PTEN mutation was significantly correlated with young age, low FIGO-stage, endometrioid subtype, low grade, microsatellite instability and favourable prognosis. Previous studies of these tumours have observed PTEN methylation in 18% and low protein expression in 20%. Low expression of PTEN-antibody 6H2.1 was correlated with the presence of mutations in exon 8 among patients with 'two hits'; i.e. > or =2 mutations, or mutation(s) plus methylation (p=0.001). Number of PTEN hits was significantly associated with microsatellite instability, low hMLH1 expression and hMLH1 methylation. Thus, PTEN mutations are frequent in sporadic endometrial carcinoma and define a prognostically favourable subgroup, whereas the relationship with PTEN protein expression is complex. A pathway in endometrial carcinogenesis involving PTEN mutation and microsatellite instability is confirmed, and this study also indicates the importance of PTEN and hMLH1 methylation in this pathway.

MSI-low, a real phenomenon which varies in frequency among cancer types.

This study assessed whether low-level microsatellite instability (MSI-L) is a phenomenon specific to colorectal cancers or is also present in other tumour types. Breast (grade III ductal and lobular), endometrial and ovarian carcinomas, as well as colorectal cancers, were analysed for MSI-L using eight microsatellite markers. The markers were selected from a panel that had previously been shown to be sensitive for the detection of MSI-L in colorectal cancers. It was found that MSI-L was present in 30 of 87 (35%) colorectal cancers, 2 of 59 (3%) grade III breast carcinomas, 1 of 35 (3%) lobular breast cancers, 16 of 50 (32%) endometrial cancers, and 9 of 34 (26%) ovarian cancers. These results suggest that MSI-L is a very rare occurrence in breast carcinomas, but does occur as a real phenomenon in colorectal, endometrial, and ovarian carcinomas, which are all part of the hereditary non-polyposis colon cancer (HNPCC) syndrome. PCR artefact was also found to masquerade as MSI-L; criteria for the assessment of MSI-L are suggested to eliminate this problem.