ABSTRACT
Uterine tumor resembling ovarian sex-cord tumor (UTROSCT) is a rare and distinctive neoplasm of unclear histogenesis, and uncertain malignant potential. These neoplasms morphologically resemble sex-cord stromal tumors of the ovary, and possess a polyphenotypic immunophenotype. Their molecular pathogenesis has yet to be elucidated; notably, however, tumors lack alterations found in other uterine tumors bearing sex-cord-like differentiation, such as endometrial stromal sarcoma. Following identification of an index patient with an ESR1-NCOA3 fusion gene by RNA-sequencing, we undertook a retrospective review for additional cases of UTROSCT. We identified a total of 4 patients, with an average age of 53 years (range, 38 to 68 y). RNA-sequencing was performed in all cases, revealing an ESR1-NCOA3 fusion in 2 cases and one case each with related ESR1-NCOA2 and GREB1-NCOA2 fusions. Each of the tumors showed histologic and an immunophenotype features within the previously reported spectrum of UTROSCT; interestingly, one case contained prominent spindle cell fascicles and another was largely comprised of sheets of small round cells. Our results demonstrate UTROSCT are defined by recurrent fusions involving NCOA2 or NCOA3, a finding that is directly amenable to diagnostic evaluation. This study confirms UTROSCT is molecularly distinct from endometrial stromal sarcoma, and raises intriguing new questions into the pathogenesis of these neoplasms and possible relationship with other NCOA fusion-positive uterine tumors.
Subject(s)
Endometrial Neoplasms/genetics , Endometrial Stromal Tumors/genetics , Nuclear Receptor Coactivator 2/genetics , Nuclear Receptor Coactivator 3/genetics , Adult , Aged , Endometrial Neoplasms/pathology , Endometrial Stromal Tumors/pathology , Female , Humans , Middle Aged , Recombinant Fusion Proteins , Retrospective StudiesABSTRACT
Endometrial stromal sarcoma encompasses a heterogeneous group of uterine mesenchymal neoplasms, which are currently divided into low-grade and high-grade subtypes. Low-grade endometrial stromal sarcoma is morphologically bland; molecularly, these tumors frequently contain JAZF1-SUZ12, JAZF1-PHF1, and EPC1-PHF1 fusions. In contrast, high-grade endometrial stromal sarcoma is characterized by morphologically undifferentiated neoplasms with high-grade nuclear features; these tumors likewise appear to be genetically diverse with YWHAE-NUTM2 and ZC3H7B-BCOR representing the most frequent gene fusions. Herein, we describe two novel EPC1 fusion genes in endometrial stromal sarcoma: EPC1-SUZ12 and EPC1-BCOR. Both tumors were characterized be an aggressive clinical course.
Subject(s)
Chromosomal Proteins, Non-Histone/genetics , Endometrial Neoplasms/genetics , Oncogene Proteins, Fusion/genetics , Repressor Proteins/genetics , Sarcoma, Endometrial Stromal/genetics , Chromosomal Proteins, Non-Histone/chemistry , Endometrial Neoplasms/pathology , Female , Humans , Middle Aged , Oncogene Proteins, Fusion/chemistry , Repressor Proteins/chemistry , Sarcoma, Endometrial Stromal/pathologyABSTRACT
AIM: Micropapillary/borderline (LMP) ovarian tumours are rarely included in clinical trials and are intrinsically resistant to radiation and chemotherapy. Platinum resistant epithelial ovarian cancer (EOC) has a poor prognosis. The histone deacetylase inhibitor belinostat demonstrated antitumour activity in pre-clinical ovarian cancer models. METHODS: A phase II study was performed to evaluate the activity of belinostat in two patient populations: women with metastatic or recurrent platinum resistant (progression within 6 months) EOC and LMP ovarian tumours, both groups had received no more than 3 prior lines of chemotherapy. Belinostat 1000 mg/m(2)/d was administered iv days 1-5 of a 21 d cycle. Peripheral blood mononuclear cells (PBMCs) and tumour biopsies, where possible, for correlative studies were obtained prior to and following treatment. RESULTS: Eighteen patients with EOC and 14 patients with LMP tumours were enrolled on study. Belinostat was well tolerated with no grade four toxicity (179 cycles). Grade 3 toxicity consisted of thrombosis (3 patients), hypersensitivity (1) and elevated ALP (1). One patient with LMP tumour had a partial response (unconfirmed) and 10 had stable disease (SD), 3 were non-evaluable. Median progression-free survival (PFS) was 13.4 months (95% confidence interval (CI), 5.6--not reached). Best response in patients with EOC was SD (nine patients) and median PFS was 2.3 months (95% CI, 1.2-5.7 months). An accumulation of acetylated histones H3 and H4 was noted in PBMCs and in tumour tissue. CONCLUSIONS: Belinostat is well tolerated in both patient groups and shows some activity in patients with micropapillary (LMP) disease.
Subject(s)
Antineoplastic Agents/administration & dosage , Carcinoma, Papillary/drug therapy , Histone Deacetylase Inhibitors/administration & dosage , Hydroxamic Acids/administration & dosage , Neoplasm Recurrence, Local/drug therapy , Ovarian Neoplasms/drug therapy , Acetylation/drug effects , Adult , Aged , Aged, 80 and over , Antineoplastic Agents/adverse effects , Drug Resistance, Neoplasm , Female , Histone Deacetylase Inhibitors/adverse effects , Histones/metabolism , Humans , Hydroxamic Acids/adverse effects , Infusions, Intravenous , Middle Aged , Sulfonamides , Treatment OutcomeABSTRACT
Sweat gland carcinoma of the vulva is rare and may be classified as being of eccrine, apocrine, or mixed origin. Most reported cases of vulvar sweat gland carcinomas associated with extramammary Paget disease describe a tumor of apocrine origin. We report a case of a vulvar sweat gland carcinoma of eccrine origin associated with Pagetoid extension. A review of the literature and the differential diagnosis are also presented. To our knowledge, this is the second case of vulvar sweat gland carcinoma of eccrine origin associated with extramammary Paget disease.
