Lynch syndrome associated endometrial carcinomas in Western Australia: an analysis of universal screening by mismatch repair protein immunohistochemistry.

BACKGROUND: In 2016 universal screening with mismatch repair protein immunohistochemistry in all newly diagnosed endometrial carcinomas was introduced in Western Australia. OBJECTIVE: To compare the prevalence of Lynch syndrome associated endometrial carcinomas between 2016 and 2019 with a historical control (2015). Additionally, to compare the number of cases appropriately referred for genetic assessment. METHODS: A cross-sectional study of cases presented at the Western Australia gynecologic oncology tumor board was carried out. The primary outcome was the prevalence of Lynch syndrome associated endometrial carcinomas. A secondary outcome was the number of cases appropriately referred for genetic assessment. The following variables were extracted: date of birth; age at diagnosis; vital status; tumor mismatch repair protein expression status (retained or lost) and if lost, the specific mismatch repair protein deficiency; patients who were referred to a genetic clinic; and family history, if recorded. Data were collected from the clinical databases of the Familial Cancer Program at Genetic Services of Western Australia and WOMEN Center, to determine whether patients were appropriately referred for genetic evaluation and to ascertain the results of genetic testing. RESULTS: Between 2016 and 2019, there were 1040 new endometrial carcinomas. Tumors of 883 (85%) patients underwent mismatch repair protein immunohistochemistry compared with 117 of 199 patients (59%) in 2015 (χ2 73.14, p<0.001). Of 883 tumors tested, 242 (27%) showed loss of mismatch repair protein expression. In 2015, 30 (26%) tumors of 117 tested showed loss of mismatch repair protein expression. During the 4 years of universal screening, 13 (1.5%) of 883 patients screened were diagnosed with Lynch syndrome compared with 2 (1.7%) of 117 in 2015 (Fisher's exact test 0.04, p=0.69). In 2015, 11 (37%) of 30 patients with loss of mismatch repair protein expression were not referred for genetic assessment compared with 36 (17%) of 209 patients in the universal screening group (χ2 6.28, p=0.02). No cases of Lynch syndrome were diagnosed in patients aged over 70 years. CONCLUSIONS: Universal immunohistochemical screening did not increase the proportion of Lynch syndrome associated endometrial carcinomas identified, although the study was underpowered to detect small differences. There was an improvement in appropriate referrals for genetic assessment.

Predictors of endometrial carcinoma in patients with atypical endometrial hyperplasia at a tertiary gynaecological cancer centre in Western Australia.

AIM: Our objective was to assess clinical and pathological factors associated with a final diagnosis of endometrial carcinoma in patients with atypical endometrial hyperplasia with a particular emphasis on the grading of atypia. MATERIALS AND METHODS: A retrospective review over five years on patients (N = 97) who underwent hysterectomy for a diagnosis of atypical endometrial hyperplasia at a statewide public tertiary gynaecologic oncology centre. Clinical and pathological characteristics were obtained. RESULTS: The rate of concurrent endometrial carcinoma was 34% (n = 33) with most being stage 1A endometrioid. A significant group difference was reported for age at diagnosis (t = -2.20 P = 0.031 d = 0.43) with carcinoma patients on average older (Mage  = 60.2 (8.9) years) than patients without carcinoma (Mage  = 55.5 (12.3) years). No significant group differences were found for body mass index, endometrial thickness or time between diagnosis and treatment. Significantly higher rates of carcinoma were reported in patients with moderate atypical hyperplasia (27.6%) and severe atypical hyperplasia (66.7%), compared to mild atypical hyperplasia (7.1%). Only severe atypical hyperplasia (odds ratio (OR) = 21.5, 95% CI 2.8-163.1, P = 0.003) and postmenopausal status (OR = 13.2, 95% CI 1.3-139.0, P = 0.032) significantly increased the risk of carcinoma in a multivariate model. CONCLUSION: Severe atypical hyperplasia and postmenopausal status were significant predictors of concurrent endometrial carcinoma in patients with atypical endometrial hyperplasia. The grading of atypical hyperplasia may be utilised by gynaecologic oncologists in the triage and referral process of managing these patients; however, the grading system requires external validation in larger prospective studies.

Primary mixed large cell neuroendocrine and high grade serous carcinoma of the endometrium.

Endometrial large-cell neuroendocrine carcinoma admixed with a high-grade serous (HGS) adenocarcinoma is extremely rare with only one reported case in the literature. We present the second reported case in a 47-year-old woman who presented with abdominal pain, distension and loss of weight. On examination she had a fixed pelvic mass and vascular left vaginal mass. Imaging confirmed a 13 cm solid cystic rectouterine pelvic mass, omental disease and retroperitoneal lymphadenopathy. She underwent a modified posterior exenteration, partial posterior vaginectomy, omentectomy and Hartmanns procedure with suboptimal debulking. Histopathology revealed a stage 4B mixed carcinoma with large cell neuroendocrine (70%) and HGS carcinoma (30%). Eight cycles of adjuvant cisplatin and paclitaxel were given with a complete radiological and biochemical response after 7 months. Unfortunately, she developed widespread recurrence at 9 month and was offered second line chemotherapy.

Invasive cervical adenocarcinoma arising from extension of recurrent vulval Paget's disease.

An 83-year-old woman with a long-standing history of both invasive and vulval extramammary Paget's disease (EMPD) was referred to a tertiary gynaecological oncology service for suspicion of contiguous extension to the vagina and cervix. Vaginal biopsies confirmed EMPD; however, a loop excision of the cervix demonstrated invasive adenocarcinoma arising from Paget's disease. The patient subsequently underwent laparoscopic radical hysterectomy, bilateral salpingo-oophorectomy and radical upper vaginectomy, confirming FIGO stage 1B1 cervical adenocarcinoma. She was recommended but declined to have adjuvant pelvic external beam radiotherapy. To our knowledge this is the second case of invasive cervical adenocarcinoma arising from vulval Paget's disease in the literature.

Challenging Salpingectomy as a Risk-Reducing Measure for Ovarian Cancer: Histopathological Analysis of the Tubo-Ovarian Interface in Women Undergoing Risk-Reducing Salpingo-oophorectomy.

OBJECTIVE: Opportunistic bilateral salpingectomy is now promoted for women at the time of hysterectomy for a benign disease, consequent to the fimbrial end of the fallopian tube emerging as the primary site for carcinogenesis in high-grade serous carcinomas. In high-risk women with an identified germ line mutation, bilateral salpingo-oophorectomy offers the greatest risk reduction for ovarian cancer. Currently, no prospective evidence exists with respect to the effectiveness of opportunistic salpingectomy alone in preventing ovarian cancer. Although it is thought that there is no direct connection between the ovary and its adjacent fallopian tube, we often find remnants of the fimbria adherent to the ovary at the time of surgery. If this tubo-ovarian interface is not separate, then practices such as salpingectomy and radical fimbriectomy may be incomplete, and the effectiveness of this technique as a prophylactic strategy may need reconsideration. We aimed to establish whether there might exist a direct attachment of the fimbria to the ovary by examining this interface in surgically removed specimens. METHODS: The tubes and ovaries of 20 women undergoing risk-reducing salpingo-oophorectomy were examined using the Sectioning and Extensively Examining the Fimbriated End of the Tubes protocol and p53 immunohistochemistry for lesions suspicious of serous intraepithelial tubal carcinoma. RESULTS: Three specimens showed fimbria adherent to the ovary at the histopathological analysis. One p53 signature was identified, but there were no occult cancers or serous intraepithelial tubal carcinomas. CONCLUSIONS: Although only a small study, the findings show that microscopic fimbriae are adherent to the ovary. This relationship challenges the recommendation for bilateral salpingectomy alone for risk-reducing surgery because the primary site of carcinogenesis may be left on the ovary to later develop into a high-grade serous carcinoma. A larger study is needed to assess our findings related to the tubo-ovarian interface and its implications for long-term ovarian cancer development. Until then, caution on using this technique alone in the high-risk patient should be adopted.