RESUMEN
Mesonephric carcinoma of the cervix is a rare tumor derived from Wolffian remnants. Mesonephric-like carcinomas of the ovary and endometrium, while morphologically similar, do not have obvious Wolffian derivation. Here, we sought to characterize the repertoire of genetic alterations in primary mesonephric and mesonephric-like carcinomas, in the distinct histologic components of mixed cases, as well as in matched primary tumors and metastases. DNA from microdissected tumor and normal tissue from mesonephric carcinomas (cervix, n = 8) and mesonephric-like carcinomas (ovarian n = 15, endometrial n = 13) were subjected to sequencing targeting 468 cancer-related genes. The histologically distinct components of four cases with mixed histology and four primary tumors and their matched metastases were microdissected and analyzed separately. Mesonephric-like carcinomas were underpinned by somatic KRAS mutations (25/28, 89%) akin to mesonephric carcinomas (8/8, 100%), but also harbored genetic alterations more frequently reported in Müllerian tumors. Mesonephric-like carcinomas that lacked KRAS mutations harbored NRAS (n = 2, ovary) or BRAF (n = 1, endometrium) hotspot mutations. PIK3CA mutations were identified in both mesonephric-like (8/28, 28%) and mesonephric carcinomas (2/8, 25%). Only mesonephric-like tumors harbored CTNNB1 hotspot (4/28, 14%) and PTEN (3/13, 23%) mutations. Copy number analysis revealed frequent gains of chromosomes 1q and 10 in both mesonephric (87% 1q; 50% chromosome 10) and mesonephric-like tumors (89% 1q; 43% chromosome 10). Chromosome 12 gains were more frequent in ovarian mesonephric-like carcinomas, and losses of chromosome 9 were more frequent in mesonephric than in mesonephric-like carcinomas (both p = 0.01, Fisher's exact test). The histologically distinct components of four mixed cases were molecularly related and shared similar patterns of genetic alterations. The progression from primary to metastatic lesions involved the acquisition of additional mutations, and/or shifts from subclonal to clonal mutations. Our findings suggest that mesonephric-like carcinomas are derived from a Müllerian substrate with differentiation along Wolffian/mesonephric lines.
Asunto(s)
Neoplasias de los Genitales Femeninos/genética , Neoplasias de los Genitales Femeninos/patología , Mesonefroma/genética , Mesonefroma/patología , Adulto , Anciano , Femenino , Humanos , Persona de Mediana Edad , MutaciónRESUMEN
OBJECTIVE: To characterize and compare the molecular subtypes and profiles of prospectively-accrued newly-diagnosed early- and advanced-stage endometrial cancers (ECs). METHODS: EC patients consented to an IRB-approved protocol of massively parallel sequencing of 410-468 cancer-related genes; 175 ECs of 7 histologic types (n = 135 FIGO stages I/II, n = 40 FIGO stages III/IV) were included. Previously reported sequencing data from 99 additional advanced-stage ECs were retrieved for comparisons. RESULTS: Irrespective of histologic type, all 175 ECs could be stratified into the molecular subtypes, with 75 (43%) being of p53 wild-type, 49 (28%) MMR-deficient, 39 (22%) p53 abnormal and 12 (7%) of POLE molecular subtypes. Subtype distribution, mutational and copy number profiles varied according to histologic type. In endometrioid ECs, genetic alterations varied according to histologic grade. Potential therapeutic targets, including high tumor mutational burden, ERBB2 amplification and PIK3CA hotspot mutations, were found across histologic types in 63% (n = 110) of all ECs. Compared to their early-stage counterparts, advanced-stage endometrioid ECs had a significantly higher fraction of genome altered (median 0.1% vs 12%, p < 0.001) and ARID1B mutations (0% vs 11%, p = 0.01), and advanced-stage serous ECs harbored more frequent ERBB2 amplification (18% vs 8%, p > 0.05) and PIK3CA mutations (46% vs 27%, p > 0.05). Whole-genome doubling was found in advanced- but not early-stage carcinosarcomas and clear cell carcinomas. CONCLUSIONS: Our findings demonstrate the molecular heterogeneity within and across histologic types of EC and the increased genomic complexity of advanced-stage ECs. Molecular subtypes are present across EC histologic types and may help stratify EC patients for prognostic and therapeutic purposes.
Asunto(s)
Neoplasias Endometriales/genética , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma Endometrioide/genética , Carcinoma Endometrioide/patología , Neoplasias Endometriales/patología , Femenino , Amplificación de Genes , Duplicación de Gen , Genes erbB-2 , Genoma Humano , Inestabilidad Genómica , Humanos , Persona de Mediana Edad , Estadificación de Neoplasias , Receptor ErbB-2/genéticaRESUMEN
Primary extrarenal Wilms tumor of the gynecologic tract is extremely rare with scattered case reports occurring in the ovary, uterine corpus and cervix. Only 9 cases of primary ovarian Wilms tumor have been reported to date. Here, we provide an extensive literature review and describe 2 patients with ovarian Wilms tumor: a 36-yr-old female (patient 1) and a 16-yr-old female (patient 2), both presenting with abdominal pain and suspected ovarian torsion. They were each found to have unilateral ovarian masses measuring >15 cm in size which were removed by unilateral salpingo-oophorectomy. Microscopically, the tumors exhibited the typical triphasic histology of Wilms tumor. In addition, the tumor from patient 1 contained elements of mature cystic teratoma, while an extensive rhabdomyosarcomatous component was identified in patient 2. Both tumors were diffusely and strongly positive for WT1 with variable staining for other biomarkers. The cases were diagnostically challenging and referred to our center for an expert opinion. Teratoid Wilms tumor in patient 1 is the second reported case of ovarian Wilms tumor arising in association with teratoma. Recognition of primary ovarian Wilms tumor requires a high index of suspicion and exclusion of other entities based on tumor morphology and immunohistochemical studies.
Asunto(s)
Neoplasias Renales/patología , Neoplasias Ováricas/patología , Tumor de Wilms/patología , Adolescente , Adulto , Niño , Preescolar , Femenino , Humanos , Inmunohistoquímica , Lactante , Neoplasias Renales/diagnóstico , Persona de Mediana Edad , Neoplasias Ováricas/diagnóstico , Ovario/patología , Rabdomiosarcoma/diagnóstico , Rabdomiosarcoma/patología , Teratoma/diagnóstico , Teratoma/patología , Tumor de Wilms/diagnóstico , Adulto JovenRESUMEN
Mesonephric adenocarcinoma (MA) and mesonephric-like adenocarcinoma (MLA) are uncommon neoplasms of the gynecologic tract that have until recently been poorly understood. Although their morphologic, immunohistochemical, and molecular profiles have been recently defined, little is known about their clinical behavior. Small studies have demonstrated inconsistent findings and no large studies have examined the clinical behavior of these adenocarcinomas. In this multi-institutional study, representing the largest and most stringently defined cohort of cases to date, we examined the clinicopathologic features of 99 MAs and MLAs (30 MAs of the uterine cervix, 44 MLAs of the endometrium, and 25 MLAs of the ovary). Only tumors with characteristic mesonephric morphology and either immunohistochemical or molecular support were included. Our results demonstrate that the majority of mesonephric neoplasms presented at an advanced stage (II to IV) (15/25 [60%] MA of the cervix, 25/43 [58%] MLA of the endometrium, and 7/18 [39%] MLA of the ovary). The majority (46/89 [52%] overall, 12/24 [50%] MA of the cervix, 24/41 [59%] MLA of the endometrium, and 10/24 [42%] MLA of the ovary) developed recurrences, most commonly distant (9/12 [75%] MA of the cervix, 22/24 [92%] MLA of the endometrium, and 5/9 [56%] MLA of the ovary). The 5-year disease-specific survival was 74% (n=26) for MA of cervix, 72% (n=43) for MLA of endometrium, and 71% (n=23) for MLA of ovary. Our results confirm that mesonephric neoplasms are a clinically aggressive group of gynecologic carcinomas that typically present at an advanced stage, with a predilection for pulmonary recurrence.
Asunto(s)
Adenocarcinoma/secundario , Neoplasias Endometriales/patología , Neoplasias Ováricas/patología , Neoplasias del Cuello Uterino/patología , Conductos Mesonéfricos/patología , Adenocarcinoma/química , Adenocarcinoma/genética , Adenocarcinoma/terapia , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/análisis , Biomarcadores de Tumor/genética , Bases de Datos Factuales , Neoplasias Endometriales/química , Neoplasias Endometriales/genética , Neoplasias Endometriales/terapia , Femenino , Humanos , Neoplasias Pulmonares/secundario , Persona de Mediana Edad , Recurrencia Local de Neoplasia , Estadificación de Neoplasias , América del Norte , Irlanda del Norte , Neoplasias Ováricas/química , Neoplasias Ováricas/genética , Neoplasias Ováricas/terapia , Supervivencia sin Progresión , Sistema de Registros , Factores de Tiempo , Neoplasias del Cuello Uterino/química , Neoplasias del Cuello Uterino/genética , Neoplasias del Cuello Uterino/terapia , Conductos Mesonéfricos/químicaRESUMEN
BACKGROUND: The optimal method for closing gastrotomies after transgastric instrumentation has yet to be determined. OBJECTIVE: To compare gastrotomy closure with endoscopically delivered bioabsorbable plugs with no closure. DESIGN: Prospective, controlled study. SETTING: Animal laboratory. SUBJECTS: Twenty-three dogs undergoing endoscopic transgastric peritoneoscopy between July and August 2007. INTERVENTIONS: Endoscopic anterior wall gastrotomies were performed with balloon dilation to allow passage of the endoscope into the peritoneal cavity. The plug group (n = 12) underwent endoscopic placement of a 4 x 6-cm bioabsorbable mesh plug in the perforation, whereas the no-treatment group (n = 11) did not. Animals underwent necropsy 2 weeks after the procedure. MAIN OUTCOME MEASUREMENTS: Complications related to gastrotomy closure, gastric burst pressures, relationship of burst perforation to gastrotomy, and the degree of adhesions and inflammation at the gastrotomy site. RESULTS: After the gastrotomy, all dogs survived without any complications. At necropsy, burst pressures were 77 +/- 11 mm Hg and 76 +/- 15 mm Hg (P = .9) in the plug group and no-treatment group, respectively. Perforations occurred at the site of the gastrotomy in 2 of 12 animals in the plug group and in none of the 11 dogs in the no-treatment group (P = .5). Finally, there were minimal adhesions in all dogs (11/11) in the no-treatment group and minimal adhesions in 3 and moderate adhesions or inflammatory masses in 9 of the 12 animals in the plug group (P = .004). LIMITATIONS: Small number of subjects, animal model, no randomization. Gastrotomy trauma during short peritoneoscopy may not be applicable to longer procedures. CONCLUSIONS: After endoscopic gastrotomy, animals that were left untreated did not show any clinical ill effects and demonstrated adequate healing, with fewer adhesions and less inflammation compared with those treated with a bioabsorbable plug.
Asunto(s)
Gastrostomía , Laparoscopía/métodos , Estómago/cirugía , Implantes Absorbibles , Animales , Cateterismo , Perros , Gastrostomía/efectos adversos , Masculino , Implantación de PrótesisRESUMEN
Adenosarcoma can mimic high-grade endometrial stromal sarcoma with ZC3H7B-BCOR fusion that may show entrapped glands and often exhibits diffuse BCOR expression. We encountered diffuse BCOR expression in rare adenosarcomas and sought to define its frequency among a larger cohort of these tumors. BCOR immunohistochemistry was performed on archival formalin-fixed paraffin-embedded tumor tissue in 13 of 14 adenosarcomas with and without stromal overgrowth arising in the uterus or ovary. The staining intensity and percentage of positive tumor nuclei in the mesenchymal component were evaluated. Eleven cases with sufficient tumoral tissue were subjected to fluorescence in situ hybridization for the detection of BCOR, BCORL1, NUTM1, ZC3H7B, and JAZF1 rearrangement. Three cases were subjected to targeted RNA sequencing. BCOR was expressed in 9 of 13 (70%) tumors, including 6 with and 3 without stromal overgrowth. Moderate to strong staining in >70% of cells was seen throughout in 1 low-grade and 6 high-grade tumors, 5 of which had stromal overgrowth. No staining was seen in 3 low-grade and 1 high-grade tumors with stromal overgrowth. One tumor demonstrating extensive sex cord-like differentiation and diffuse BCOR expression harbored JAZF1 and BCORL1 rearrangements. No BCOR or BCORL1 rearrangement was identified in the remaining tumors. BCOR expression is seen in most adenosarcomas with and without stromal overgrowth. BCORL1 rearrangement is seen in rare tumors with diffuse BCOR expression. Assessment of BCOR or BCORL1 rearrangement status is required in adenosarcomas demonstrating BCOR expression.
Asunto(s)
Adenosarcoma/diagnóstico , Biomarcadores de Tumor/análisis , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Represoras/metabolismo , Neoplasias Uterinas/diagnóstico , Adenosarcoma/metabolismo , Adenosarcoma/patología , Adulto , Anciano , Diagnóstico Diferencial , Neoplasias Endometriales/diagnóstico , Neoplasias Endometriales/metabolismo , Femenino , Humanos , Persona de Mediana Edad , Sarcoma Estromático Endometrial/diagnóstico , Sarcoma Estromático Endometrial/metabolismo , Neoplasias Uterinas/metabolismo , Neoplasias Uterinas/patología , Adulto JovenRESUMEN
Mesonephric carcinoma is a rare gynecologic neoplasm commonly mistaken for clear cell carcinoma, because of their overlapping morphologic features. Both tumors are negative for estrogen receptor and p16, magnifying this diagnostic dilemma. Recently, hepatocyte nuclear factor-1 beta (HNF-1ß), a marker for clear cell carcinoma, has also been shown to be positive in mesonephric carcinomas. Other more recent markers for clear cell carcinoma, however, such as Napsin-A and alpha-methylacyl-CoA racemase (AMACR), have not yet been studied in mesonephric carcinomas. Here we examine HNF-1ß, AMACR, and Napsin-A immunohistochemistry in 18 mesonephric and 55 endometrial/cervical clear cell carcinomas. HNF-1ß was considered positive if nuclear staining was present in ≥70% of cells and at least moderate intensity; for Napsin-A and AMACR, any cytoplasmic staining was considered positive (≥1%). H-scores were determined by multiplying the intensity score by proportion score. HNF-1ß was positive in a substantial portion of mesonephric carcinomas (9/18, 50%; H-score 98) and clear cell carcinomas (34/55, 62%; H-score 163) and did not distinguish between the 2 entities (specificity, 50%; P-value of H-score=0.08). Napsin-A and AMACR expression was significantly higher in clear cell [43/55 (78%) and 41/55 (75%), respectively] than mesonephric carcinomas [4/18 (22%) and 4/18 (22%) respectively], and helpful in this differential (specificity: 78% and 78%; P<0.05 for both). When Napsin-A and AMACR staining were seen in mesonephric carcinomas, staining was focal (≤5%), whereas staining in clear cell carcinomas was patchy/diffuse. In summary, Napsin-A and AMACR are helpful in distinguishing mesonephric carcinomas from clear cell carcinomas of the female genital tract, but HNF-1ß is not.
Asunto(s)
Adenocarcinoma de Células Claras/diagnóstico , Ácido Aspártico Endopeptidasas/metabolismo , Neoplasias Endometriales/diagnóstico , Factor Nuclear 1-beta del Hepatocito/metabolismo , Racemasas y Epimerasas/metabolismo , Neoplasias del Cuello Uterino/diagnóstico , Adenocarcinoma de Células Claras/metabolismo , Adenocarcinoma de Células Claras/patología , Adulto , Anciano , Estudios de Cohortes , Neoplasias Endometriales/metabolismo , Neoplasias Endometriales/patología , Femenino , Humanos , Inmunohistoquímica , Persona de Mediana Edad , Estadificación de Neoplasias , Análisis de Matrices Tisulares , Neoplasias del Cuello Uterino/metabolismo , Neoplasias del Cuello Uterino/patologíaRESUMEN
BACKGROUND: Mesonephric adenocarcinomas are rare neoplasms which most commonly arise in the lateral cervix and vagina. Tumors with similar morphologic, immunophenotypic, and molecular characteristics recently have been described in the uterine corpus and ovary. Herein, the authors sought to characterize the cytomorphologic features of adenocarcinomas exhibiting mesonephric-like differentiation arising in the upper gynecologic tract. METHODS: Institutional databases were queried retrospectively for tumors of the upper gynecologic tract described as a "tumor of Wolffian origin" or "with mesonephric features" between 2007 and 2017. All available cytologic material was reviewed. Cytomorphologic characteristics were evaluated by 3 pathologists. RESULTS: The current study cohort consisted of 8 cases taken from 7 patients. Primary sites included the ovary (3 cases); endometrium (4 cases); and pelvis, not otherwise specified (1 case). All cases demonstrated tight 3-dimensional clusters of overlapping cells. Additional architectural features included tubular (5 of 8 cases; 63%) and papillary (3 of 8 cases; 38%) formations. Cells were small with scant (7 of 8 cases; 88%) to moderate (1 of 8 cases; 12%) cytoplasm. Three of the 8 cases (38%) demonstrated extracellular hyaline globules. Nuclei were uniform in size (6 of 8 cases; 75%) or showed mild anisonucleosis (2 of 8 cases; 25%). Nuclear grooves and indentations were observed in all cases. Mitoses (5 of 8 cases; 63%) and apoptotic bodies (4 of 8 cases; 50%), when present, were rare. No necrosis was noted. CONCLUSIONS: Adenocarcinomas exhibiting mesonephric-like differentiation show a monotonous population of small cells with scant to moderate cytoplasm and abundant nuclear grooves arranged in tight, overlapping, 3-dimensional clusters. Occasionally, papillary or tubular architecture, as well as extracellular hyaline globules, may be seen. These features should prompt further testing (eg, immunohistochemistry) to confirm the diagnosis and to exclude potential mimics.