[GENOTYPE-PHENOTYPE CORRELATIONS BY SPECIFIC FOUNDER VARIANTS IN BRCA IN ISRAELI WOMEN].

INTRODUCTION: Hereditary breast and ovarian cancer (HBOC) is predominantly accounted for by pathogenic variants (PVs) in BRCA1/BRCA2 genes. Population screening for recurring PVs in Ashkenazi Jews (AJ) was incorporated into the Israeli health basket in 2020, increasing the identification of BRCA carriers. Information on cancer risks for each PV in Israel is limited. AIMS: To assess genotype phenotype correlations of recurring BRCA PVs in Israeli carriers. METHODS: A retrospective cohort of 3,478 BRCA carriers followed-up in 12 medical centers, comprising the HBOC Consortium, formed the basis of the study. Data were collected using the electronic database, and analyzed by Chi square, t-tests and Kaplan-Meier survival analysis. RESULTS: Overall, 2145 BRCA1, 1131 BRCA2, and 22 double heterozygote PV carriers were analyzed. BRCA1 carriers had more cases of cancer (53.1% vs. 44.8%, p<0.001), ovarian cancer (OC) (17.1% vs. 10.6%, p<0.001), younger age at breast cancer (BC) (45.4 ±11.6SD years vs. 49.1 ±11.1SD years, p<0.001) and OC diagnosis (52.8 ±10.1SD yrs. vs. 61±10.6SD yrs. p<0.001), and more family history of BC (64.5% vs. 59.0%, p<0.001) and OC (36.7% vs. 27.3%, p<0.001) compared with BRCA2 carriers. Carriers of BRCA15382insC had more BC and less OC than BRCA1185delAG: 46.4% vs. 38.6% and 12.9% vs. 17.6% (p<0.04), respectively. CONCLUSIONS: In our population, similar to others, BRCA1 carriers have higher cancer rates and earlier age at diagnosis compared with BRCA2 carriers. The two recurring BRCA1 PVs have different risks: 5382insC carriers had more BC; 185delAG carriers had more OC. Risk-reducing measures should be based on variant-specific cancer risk.

A Pilot Study of Guided Conservative Hysteroscopic Evacuation of Early Miscarriage.

STUDY OBJECTIVE: To evaluate initial feasibility and experience with guided hysteroscopic morcellation for uterine evacuation of early miscarriage. DESIGN: A prospective pilot study of 10 cases. SETTING: A tertiary university hospital in Israel. PATIENTS: Women with confirmed early miscarriage at a gestational age of below 10 weeks from the last menstrual period. INTERVENTIONS: From May 2020 to October 2020, the hysteroscopic TruClear tissue removal system (Medtronic, Minneapolis, MN) was used for evacuation of early miscarriage in 10 women. The procedures were recorded. MEASUREMENTS AND MAIN RESULTS: Data including the length of the procedure, visibility, complete evacuation, bleeding, complications, and follow-up ultrasonography (US) were recorded. The mean duration of the procedure was 24 minutes. Complete evacuation was recorded in all cases. No adverse events were recorded in any of the 10 procedures. Normal uterine cavity without evidence of retained products of conception was documented in follow-up evaluation by US in all cases. Four patients underwent a follow-up office hysteroscopy that demonstrated a normal cavity without evidence of adhesions. In 4 cases (40%), an additional suction curettage was performed immediately after the hysteroscopic procedure owing to obscured visibility or an abnormal US scan at the end of the procedure. However, retained products of conception were found in only 1 of these 4 suction specimens (25%). CONCLUSION: Hysteroscopic morcellation under vision seems to be a safe and feasible technique for management of early missed abortion. This method may have potential as an innovative treatment of miscarriage in selected cases. Further studies are needed to refine the indications and the surgical technique.

Integration of PET/CT into the preoperative evaluation of patients with early cervical cancer does not decrease the proportion of patients with positive lymph nodes found after surgery.

PURPOSE: The aim of this study was to evaluate whether preoperative positron emission tomography/computed tomography (PET/CT) in patients with early-stage cervical carcinoma reduced the proportion of patients with metastatic lymph nodes identified after surgery. PATIENTS AND METHODS: This is a multicenter case-control study of 599 patients with early cervical cancer who underwent radical hysterectomy and pelvic lymphadenectomy at 1 of 10 gynecological oncology units in Israel. The patients were divided into 2 groups according to whether or not they underwent a preoperative PET/CT. The primary outcome was the proportion of patients with nodal involvement. The 2 groups were compared with regard to the clinical and histological variables. RESULTS: Of the 599 patients who underwent surgery, 180 (36%) had preoperative PET/CT study. There were no significant differences between the PET/CT and control groups with regard to clinical and histological risk factors. The proportion of patients with involved nodes was similar in the control and PET/CT groups (20.8% vs 19%; P = 0.73) as well as the proportion of patients receiving adjuvant radiotherapy/chemoradiation (58.3% vs 55.1%; P = 0.55). CONCLUSIONS: Preoperative PET/CT in patients with early cervical cancer does not reduce proportion of patients with metastatic nodal involvement and the employment of multimodality treatment. Prospective clinical trials comparing management based on PET/CT findings are warranted.

Chorangiocarcinoma: a case report and review of the literature.

Chorangiocarcinoma is the name designated to a chorangioma with trophoblastic proliferation manifesting increased proliferative activity. Only 3 such cases have been published so far. Other studies challenged this entity by demonstrating that proliferation of the trophoblast around chorangioma is a common phenomenon. We present a case of a unique vascular lesion in a term placenta with a malignant trophoblastic component. Microscopic examination of a well-demarcated placental mass revealed a chorangioma with multiple nodules composed of pleomorphic cells displaying focal multinucleation, large areas of necrosis, and high mitotic activity. Immunohistochemical stains of these cells were strongly positive for pancytokeratin and the beta subunit of human chorionic gonadotropin and focally positive for HSD3B1. There was no invasion of the basement membrane, and no free-floating tumor cells in the intervillous space. No evidence of metastasis was found on follow-up of the mother and newborn. It is concluded that the tumor presented herein, displaying a histologically unequivocal malignant trophoblastic component in a benign chorangioma, is a true chorangiocarcinoma, and should be included within the category of gestational neoplasia as a tumor closely related to choriocarcinoma.

Recurrence of endometrial carcinoma presenting as vulvar lesions.

Vulvar metastasis is an unusual presentation of recurrent endometrial cancer and should be part of the differential diagnosis of vulvar lesion.

Primary amelanotic melanoma of the vagina.

BACKGROUND: Primary malignant melanoma of the vagina is extremely rare, accounting for 0.3-0.8% of all malignant melanomas. True amelanotic vaginal melanoma showing no melanin on histological examination is exceedingly rare, accounting for only 2% of all vaginal melanomas. CASE REPORT: We describe a 31-year-old female patient who presented with locally advanced amelanotic melanoma of the vagina, with no evidence of metastatic spread on the computerized tomography (CT) scan, but who was subsequently diagnosed as suffering from metastatic disease by positron emission tomography (PET)-CT performed a few weeks following posterior pelvic exenteration. CONCLUSION: Specific immunohistochemical staining with melanoma markers should be performed to confirm or exclude a diagnosis of amelanotic melanoma in all patients presenting with a vaginal mass composed of undifferentiated epithelioid malignant cells. Fluorodeoxyglucose (FDG)-PET-CT should be performed as part of the preoperative evaluation, to identify the presence or absence of metastatic disease in all patients with vaginal melanoma.

[Treatment of post hysterectomy vaginal vault prolapse: was a solution found?].

Vaginal vault prolapse is a well known entity occurring mostly after hysterectomy. It has recently attained a higher focus in medical practice and literature due to the changes in lifestyle and life expectation amongst Western women. Segev et al in their present review describe the various surgical and conservative approaches toward dealing with the problem. Whilst one can appreciate the vast spectrum of treatments available, there is concurrent understanding that there is no optimal option that suits all patients. This phenomenon is due, in part, to the differences amongst patients but may also point to a lack of definite anatomic and pathophysiologic understanding as to the cause of the prolapse. Therefore, future advances in this field depend not solely on refined surgical technique but also on basic research towards the causes of this condition. With improved understanding, one may expect new surgical and medical modalities that will allow better results and improved quality of life for women suffering from this disabling condition.

Impact of BRCA mutations on outcomes among patients with serous endometrial cancer.

OBJECTIVE: To compare the outcome of patients with uterine papillary serous cancer (UPSC) carrying a BRCA mutation with that of patients with UPSC who are BRCA wild-type. METHODS: The present retrospective, multicenter cohort study included women with UPSC who were diagnosed between January 1, 1993, and December 31, 2014, and were tested for the BRCA mutation at three Israeli medical centers. Data were collected from the medical records, and patient and tumor characteristics and disease outcomes were compared between BRCA mutation carriers and noncarriers. The primary outcome was overall survival. RESULTS: In total, 14 BRCA mutation carriers and 50 noncarriers were included. Both groups had similar treatment modalities (P=0.530). A non-significant trend toward BRCA mutation carriers being diagnosed more frequently at an advanced stage compared with noncarriers was observed (P=0.090). Median overall survival (25 vs 37 months; P=0.442), progression-free survival (37 vs 29 months; P=0.536), and disease-specific survival (60 vs 39 months; P=0.316) were similar between the carrier and noncarrier groups. CONCLUSIONS: Although not significant, BRCA mutation carriers tended to have more advanced disease at diagnosis. However, the survival was similar irrespective of the BRCA status in this small group. Further research is needed to confirm these findings in a larger cohort.

Perinatal outcome of teenage pregnancies in a selected group of patients.

STUDY OBJECTIVE: To explore the effect of young age on the outcome of teenage pregnancies by studying teenage deliveries in our unique population. DESIGN, SETTING, AND PARTICIPANTS: Retrospective chart review of teenage gravidas (age 19 and younger), who had delivered in our hospital. OUTCOME MEASURES: Mode of delivery, gestational age at delivery, newborn's weight and Apgar scores and maternal and neonatal complications. RESULTS: We recruited 565 teenage delivery cases from the hospital's computerized database. Mean maternal age was 18 (14-19). Most (96%) were married. Fifty-one percent were Jewish and 44% were Muslim. Most of the girls were nulligravidas. Mean gestational age at delivery was 39 weeks (33-44 weeks). A normal vaginal delivery ensued in 72.7%, while 9% had a cesarean section and 17.4% instrumental deliveries (compared to 85.75%, 10% and 4.25% in our adult population, respectively) and 1% underwent vaginal breech delivery. Mean birth weight was 3108 g (1450-4980 g). Apgar score of 9 at 5 minutes was recorded in 97.8% of the newborns. Prenatal care included a mean of 6 prenatal visits with a range of 1-18. The main complication was anemia; 41% had hemoglobin levels of less than 11 g/dL. The rate of other complications was low. CONCLUSIONS: In our homogenous group of teenagers, there was a similar complication rate as in the adult population. The only significant complication was anemia (less than 11 g/dL). There was a higher rate of instrumental deliveries and the cesarean delivery rate was slightly lower than in our adult population. Teenage pregnancy should not be considered as a high-risk situation as long as it is planned and followed with the normal routines of prenatal care.

Evaluation of Clinical and Pathologic Risk Factors May Reduce the Rate of Multimodality Treatment of Early Cervical Cancer.

OBJECTIVE: To assess the rate of postoperative adjuvant treatment in patients who underwent radical hysterectomy for early cervical cancer and to suggest criteria for the triage of patients who have a high probability of multimodality treatment. METHODS: This was a multicenter retrospective study of 514 patients with FIGO stages IA2-IIA cervical cancer who underwent radical hysterectomy between 1999 and 2010. The patients were divided into 2 groups according to whether or not postoperative radiation was administered. The 2 groups were compared with regard to clinical and histopathologic variables divided into major and minor criteria (intermediate risk factors) based on lymph nodes status, parametrial involvement, tumor size, deep stromal invasion, and lymph-vascular space invasion. RESULTS: We identified 294 (57.2%) patients who received adjuvant postoperative radiotherapy (RT) or chemoradiation. Fifty-three percent of these patients who were treated by adjuvant radiation had only intermediate risk factors. Combining the various combinations of 2 out of 3 of the following criteria, we found that 89% of patients with tumors ≥2 cm and lymph-vascular space invasion received RT, 76% of patients with tumors ≥2 cm and depth of invasion >10 mm received RT, and 87% of patients with tumors depth of invasion >10 mm and lymph-vascular space invasion received RT. CONCLUSIONS: This study suggests that in patients with early cervical cancer, clinicopathologic evaluation of tumor size and lymph-vascular space invasion should be undertaken before performing radical hysterectomy. This approach can serve to tailor treatment, reducing the rate of employing both radical hysterectomy and chemoradiation.

Massive edema of the ovary: a case report and review of the pertinent literature.

BACKGROUND: Massive edema of the ovary is a rare entity affecting mainly young women. It is often misdiagnosed for a malignancy, posing the young patient at risk for over-treatment with resultant loss of hormonal function and fertility. CASE: A 13-year-old premenarchal girl presented with a large solid pelvic mass after recurrent episodes of self-limited abdominal pain. With a working diagnosis of malignant ovarian tumor, an exploratory laparotomy was done in which a twisted ovarian mass was found and excised completely. Pathological examination of the mass revealed massive edema of the ovary with hemorrhagic necrosis. CONCLUSION: After extensive review of the literature, it seems most cases were over-treated, as was ours. This entity should be suspected in women at the fertile age range with solid enlargement of the ovary and definite treatment should be undertaken only after confirmed pathological diagnosis. Conservative treatment is feasible and should be the rule in these cases, where fertility preservation is mandatory.

Symptomatic diaphragmatic endometriosis ten years after total abdominal hysterectomy.

BACKGROUND: Endometriosis is a disease that affects women, mostly in the age range of 25-35 years, and in most cases pelvic organs are involved. Involvement of the diaphragm after hysterectomy is extremely uncommon. CASE: A 50-year-old woman presented to our department with right upper-quadrant abdominal pain. Ten years before her admission, she underwent total hysterectomy and right salpingo-oophorectomy for a large leiomyomatous uterus. On evaluation, a right diaphragmatic lesion was identified by computed tomography. An explorative laparotomy was then performed, which revealed a 4-cm diaphragmatic cyst compressing the liver surface and containing thick chocolate-colored material. The lesion was totally excised. Pathological examination confirmed the diagnosis of endometriotic cyst. CONCLUSION: The diagnosis of endometriosis involving the diaphragm with no evidence of disease in the pelvis 10 years after hysterectomy, although a rare situation, should be considered in the differential diagnosis of a symptomatic diaphragmatic lesion in a woman with a single functioning ovary.

BRCA germline mutations in Jewish women with uterine serous papillary carcinoma.

OBJECTIVE: Our recent study determined the possible effects and incidence of BRCA1 and BRCA2 germline mutations in uterine serous papillary carcinoma (USPC). The purpose of this study was to determine the incidence of these mutations in an enlarged series of USPC. METHODS: We screened DNA from 27 women with USPC for BRCA1 and BRCA2 germline mutations common in the Jewish population (BRCA1-185delAG and 5382 insC,BRCA2-6174delT). In women with germline mutations, tumor DNA was screened for loss of heterozygosity (LOH) at the appropriate loci. RESULTS: Women (20) were of Jewish Ashkenazi origin and seven were non-Ashkenazi. Four of 20 (20%) Ashkenazi women were carriers of germline mutations: three 185delAG mutation and one 5382insC mutation. All carriers had strong family histories of breast-ovarian carcinoma. Seven out of 20 (35%) women had been diagnosed for breast carcinoma before diagnosis of USPC. Family histories of 12 women (60%) showed at least one first-degree relative with breast, ovarian, or colon carcinoma. Loss of heterozygosity analysis found a loss of the wild-type BRCA1 allele in three of the four primary uterine tumors that were examined. CONCLUSIONS: Our findings further support our previous published data suggesting a high incidence of BRCA carriers among USPC Ashkenazi Jewish patients. The loss of heterozygosity in the tumor tissue of carriers coupled with the high frequency of patient and family history of breast and ovarian malignancies suggest that USPC might be part of the manifestation of familial breast-ovarian cancer in Ashkenazi Jewish patients.