Description of a Novel ERBB4 -rearranged Uterine Sarcoma.

High-grade endometrial stromal sarcoma (HGESS) is an uncommon tumor accounting for <1% of all uterine malignancies. Currently this designation is largely reserved for neoplasms harboring YWHAE-NUTM2A/B and ZC3H7B-BCOR translocations. Here, we report a novel CIQTNF1-ERBB4 translocation in a uterine neoplasm arising in a 49-yr-old woman with morphology suggestive of HGESS. Histologic examination of the 5 cm polypoid uterine corpus mass showed a neoplasm composed of a monotonous population of cells with moderately atypical ovoid to spindle shaped nuclei with easily identifiable mitotic activity and prominent vasculature with focal intravascular extension. Immunohistochemistry showed variable positivity with desmin, estrogen receptor, progesterone receptor, AE1/3 and cyclin D1, and molecular testing showed a translocation between CIQTNF1 on chromosome 17 and ERBB4 on chromosome 2. This represents the first report of this translocation in a uterine neoplasm and adds to the growing list of translocations identified in uterine sarcomas. Although the morphology is suggestive of HGESS, this neoplasm is currently best termed an ERBB4 -rearranged uterine sarcoma until additional cases are reported to more fully characterize these neoplasms.

Metastatic Malignant Struma Ovarii and Graves' Disease: A Rare Occurrence.

OBJECTIVE: Malignant struma ovarii (SO) is a rare condition. Although there have been a few reported cases of malignant SO with coexisting Graves' disease (GD), the exact incidence of metastasis in these cases is not known. We report a rare case of metastatic malignant SO coexisting with GD. METHODS: Clinical examination, pelvic ultrasound, and histopathology of the resected tumor were performed, followed by iodine-131 (I-131) and whole body scan. Antithyroglobulin titers were postoperatively followed. RESULTS: A 43-year-old woman with a history of left ovarian cystic teratoma with SO resected 8 years ago and recently diagnosed GD presented with lower abdominal fullness. Pelvis ultrasound showed a 13.8-cm left adnexal mass, and she underwent left salpingo- oophorectomy. Histology confirmed an intraovarian thyroid tissue housing a highly differentiated follicular thyroid carcinoma, with metastatic peritoneal deposits. She underwent completion surgery and total thyroidectomy. Histology showed no evidence of intrathyroidal malignancy. I-131 therapy was administered, and posttherapeutic I-131 whole body scan revealed a remnant disease. She was started on suppressive levothyroxine therapy and remained clinically well at her 1-year follow-up with downtrending antithyroglobulin titers. CONCLUSION: The coexistence of malignant SO and GD is very rare, and even rarer is the coexistence of metastasis malignant SO and GD. To the best of our knowledge, this is the first reported case of metastatic malignant SO in the setting of GD.

Vulvar basal cell carcinoma: clinical features and treatment outcomes from a tertiary care centre.

We retrospectively reviewed the clinical features, management and outcomes of patients diagnosed with basal cell carcinoma (BCC) of the vulva at the Gynaecological Cancer Centre, KK Women's and Children's Hospital, Singapore, between 1 January 2000 and 28 February 2014. Patients with vulvar BCC were identified from the cancer registry, and their medical records reviewed and analysed. A total of 11 patients with vulvar BCC were identified. Mean age at diagnosis was 63 (range 30-85) years. Ethnically, ten patients were Chinese and one was Malay. Average time from onset of symptoms to diagnosis was 13.8 (range 2-60) months. The most common presenting symptoms were lump and pruritus. All patients were managed surgically. Recurrence was noted in only one patient. Vulvar BCC, although rare, has an excellent prognosis when managed appropriately. Histological diagnosis of all persistent papules, plaques and pigmented lesions is important for early diagnosis.

ZC3H7B-BCOR-Rearranged Endometrial Stromal Sarcomas: A Distinct Subset Merits its Own Classification?

A 41-yr-old lady with abnormal uterine bleeding underwent total abdominal hysterectomy. Histologic assessment revealed an endometrial stromal sarcoma (ESS) with minimal cytologic atypia and low mitotic count (up to 7/10 high-power fields) with only focal myxoid areas, morphologically corresponding to a low-grade ESS. Immunohistochemical stains showed cyclin D1 and CD10 positivity, and negative staining for CD117 and progesterone receptor. This tumor was clinically aggressive and recurred 6 mo later. The patient died 19 mo following initial diagnosis. Molecular analysis revealed a ZC3H7B (exon 10)-BCOR (exon 7) gene fusion. Subsequent BCOR immunohistochemistry was weakly positive. ESS with ZC3H7B-BCOR gene fusion is classified as a low-grade ESS in some classification schemes, and is also characterized as being typically myxoid. This report supports emerging evidence that ESS with ZC3H7B-BCOR gene fusion may have an aggressive clinical course in spite of its low-grade histology. This report further expands the morphologic spectrum of ZC3H7B-BCOR fusion ESS to include nonmyxoid histology. Finally, this report underlines the value of molecular analysis in the proper classification of this aggressive tumor with deceptive low-grade histology.

Mutation spectrum of POLE and POLD1 mutations in South East Asian women presenting with grade 3 endometrioid endometrial carcinomas.

OBJECTIVE: Somatic POLE mutations have been found in a subset of endometrioid ECs particularly in FIGO grade 3 tumors while POLD1 mutations are reportedly rare in ECs. While it has been suggested that POLE mutation confers good prognosis, the data remains conflicting. Our study aims to determine the mutation spectrum of somatic and germline POLE and POLD1 gene mutations in South East Asian (SEA) women with FIGO grade 3 endometrioid ECs. METHODS: Forty-seven patients diagnosed with FIGO grade 3 endometrioid EC, diagnosed between 2009 and 2013 were included. Next generation sequencing (NGS) using formalin fixed embedded (FFPE) tissue was utilized to sequence tumor and matched normal tissue. Tumors were also assessed for other clinicopathologic and microsatellite status phenotype. Survival curves for pathogenic somatic POLE mutated and wild-type tumors were estimated by Kaplan-Meier method. RESULTS: Pathogenic POLE (somatic or germline) and POLD1 (germline) mutations were detected in 29.7% (14/47) and 4.3% (2/47) patients, respectively. Three pathogenic germline mutations; one POLE and two POLD1 mutations were novel. Pathogenic germline and somatic POLE and POLD1 mutations were associated with 100% recurrence free survival. In contrast, among the wild-type POLE and POLD1 patients, 25% (8/32) had recurrence with 15.6% (5/32) subsequently dying of the disease. Somatic POLE-mutated tumors were more commonly associated with microsatellite stable (MSS) ECs (83% vs 49%; p=0.04) and peritumoral lymphocytic infiltration (75% vs 42%; p=0.05). All tumors with tumoral infiltrating lymphocytes exhibited peritumoral lymphocytic infiltrate but not vice versa. CONCLUSION: Mutations in POLE and POLD1 in SEA women with grade 3 endometrioid ECs are associated with improved recurrence free survival. Notably, germline mutations in either POLE/POLD1 were seen in 8.5% of patients who will require appropriate genetic counseling regarding risk of developing colorectal carcinoma and on the need for additional surveillance for colonic changes. MSS and peritumoral lymphocytic infiltration may be useful histological features for distinguishing POLE mutated grade 3 endometrioid ECs.

Endometrioid adenocarcinoma of the ovary mimicking serous borderline tumor: report of a series of cases.

Ovarian endometrioid adenocarcinomas may have an extremely variable morphologic appearance and mimic a number of other epithelial malignancies as well as nonepithelial tumors. We report the clinicopathologic features of a small series of ovarian endometrioid adenocarcinomas (n=5), 4 of which were received in consultation, which were originally diagnosed as or were suspected to represent serous borderline tumor, with or without a component of low-grade serous adenocarcinoma. The patients were aged between 47 and 74 yr (mean, 60 yr), and all tumors were unilateral and Stage 1C. Serous borderline tumor was suspected on the basis of the predominant architectural pattern with prominent papillary formations consisting of rather bland epithelial cells covering stromal cores which projected into cystic spaces. In all cases, there were areas of typical endometrioid adenocarcinoma, although these foci were minor. Features useful in confirming an endometrioid neoplasm, not all of which were present in every case, were a monomorphous cell population, areas of cytoplasmic clearing, areas of more pronounced nuclear atypia, and mitotic activity than is typical of low-grade serous neoplasms, squamous elements, endometriosis and absent or only focal WT1 immunohistochemical staining. The close mimicry of a serous borderline tumor by an endometrioid adenocarcinoma is a diagnostic pitfall which has not been reported in the literature and represents yet another example of the propensity for ovarian endometrioid adenocarcinomas to mimic other neoplasms. Pathologists should consider an endometrioid adenocarcinoma when faced with a presumed serous borderline tumor with any of the features listed above. Extensive sampling may be of value in revealing more typical areas of endometrioid neoplasia and negative staining with WT1 of use in excluding a serous neoplasm.

Borderline ovarian mucinous neoplasm recurring as small cell carcinoma of hypercalcemic type: evidence for an epithelial histogenesis and relationship with ovarian mucinous tumors for this enigmatic neoplasm.

Ovarian small cell carcinoma of hypercalcemic type (OSCCHT) is an uncommon neoplasm of uncertain histogenesis. As far as we are aware, this neoplasm has never been reported in association with another primary ovarian tumor. We report a case in a 33-year-old patient in whom an extraovarian pericolonic neoplasm with the morphological features and immunohistochemical profile of OSCCHT developed 5 years after removal of an ovarian mucinous borderline tumor of the intestinal type. Together with the observation that mucinous epithelium is seen in some OSCCHTs, this case raises the possibility that this enigmatic neoplasm is of epithelial origin and is related to primary ovarian mucinous neoplasms. The pericolonic tumor exhibited an unusual immunophenotype with positive staining with CD99 and FLI-1, suggesting the possibility of a neoplasm in the Ewing family of tumors. This was excluded by molecular studies that showed no evidence of EWS/FLI-1 or EWS/ERG translocation.

Cervical adenocarcinoma resembling breast lobular carcinoma: a hitherto Undescribed Variant of Primary Cervical Adenocarcinoma.

Most cervical adenocarcinomas are of the so-called usual or endocervical type, and consist entirely or predominantly of glandular formations. We describe 3 cases of an unusual morphologic variant of cervical adenocarcinoma largely composed of bland epithelial cells, with occasional intracytoplasmic lumina, arranged in a variety of architectural patterns, including diffuse, small glandular, insular, trabecular, and Indian file arrangements. The overall appearances closely resembled a breast lobular carcinoma. In all cases, there was a minor superficial component of well-differentiated adenocarcinoma, suggesting that the component that resembled breast lobular carcinoma, arose from the differentiated neoplasm. All cases were diffusely p16-positive, and 2 that underwent human papillomavirus testing contained high-risk oncogenic human papillomavirus, type 16 and 18 in 1 case each. In all cases, there was loss of e-cadherin membranous immunoreactivity in the areas resembling breast lobular carcinoma, a similar pattern of staining to that seen in the latter neoplasm and possibly accounting for the morphologic features. In 2 cases, there was extracervical spread, including distant lymph node metastasis in 1. In reporting these cases, we highlight an unusual morphologic variant of cervical adenocarcinoma closely resembling breast lobular carcinoma and which may have an aggressive behavior.