RESUMEN
Uterine mesenchymal neoplasms are a challenging group of tumors that often show overlapping morphologic features and immunohistochemical profiles. The increasing use of molecular testing in these tumors has enabled a better appreciation of their pathobiology, resulting in a wave of emerging neoplasms and improved characterization of ones previously considered exceptionally rare. Identification of specific molecular alterations has permitted targeted therapy options in tumors that were typically unresponsive to conventional therapies, as well as recognition that a subset can have a hereditary basis. This review will discuss the more "common" of the uncommon uterine mesenchymal neoplasms, including inflammatory myofibroblastic tumor, perivascular epithelioid cell tumor, uterine tumor resembling ovarian sex cord tumor, and embryonal rhabdomyosarcoma. This will be followed by an overview of emerging entities, including NTRK-rearranged uterine sarcoma, SMARCA4-deficient uterine sarcoma, KAT6B/A::KANSL1 fusion uterine sarcoma, and MEIS1::NCOA2/1 fusion sarcoma.
RESUMEN
Uterine inflammatory myofibroblastic tumors (IMTs) are rare mesenchymal neoplasms of uncertain malignant potential. Aside from the recently described risk stratification score, which has not been validated by other studies, and rare reports of aberrant p16 expression in malignant tumors, there are no criteria to reliably predict behavior. Herein, we evaluated the clinicopathologic features and p16 expression patterns in 30 IMTs, with genomic profiling performed in a subset (13 malignant, 3 benign). Fifteen patients had malignant IMTs, defined by extrauterine disease at diagnosis (n=5) or recurrence (n=10; median: 24 mo). Patients ranged from 8 to 65 (median: 51) years and tumors from 6 to 22 (median: 12.5) cm. In primary tumors (n=13), infiltrative borders were noted in 10, moderate/severe cytologic atypia in 9, tumor cell necrosis in 7, and lymphovascular invasion in 6, while mitoses ranged from 0 to 21 (median: 7) per 10 high-power fields. In contrast, 15 patients with benign IMTs ranged from 28 to 65 (median: 44) years, with follow-up of 18 to 114 (median: 41) months. Tumors ranged from 1.9 to 8.5 (median: 5.5) cm, 2 demonstrated infiltrative borders, and 1 had moderate cytologic atypia. No other high-risk histologic features were observed. Application of the previously described clinicopathologic risk stratification score in all primary IMTs with complete data (n=18) classified 8 as high-risk (all malignant), 8 as intermediate-risk (3 malignant, 5 benign), and 2 as low-risk (benign). p16 was aberrant in all malignant IMTs, with <1% expression noted in 10, overexpression (>90%) in 4, and subclonal loss in 1; all benign tumors had patchy staining (20% to 80%; median 50%). Molecular analysis detected CDKN2A deletions in 8 of 9 tumors with <1% p16 expression, while the other harbored a TERT promoter mutation. TERT promoter mutations were also identified in 2 of 3 IMTs with p16 overexpression. Neither of these alterations was detected in the 3 sequenced benign IMTs. Thus, we recommend performing p16 on all uterine IMTs, which, combined with the risk stratification score, is a promising and cost-effective tool for predicting CDKN2A status and outcome in these patients. It may be particularly useful for tumors with incomplete information for risk stratification (ie, morcellated tumors) and for further stratifying intermediate-risk IMTs when sequencing is unavailable.
Asunto(s)
Biomarcadores de Tumor , Inhibidor p16 de la Quinasa Dependiente de Ciclina , Neoplasias Uterinas , Humanos , Femenino , Neoplasias Uterinas/genética , Neoplasias Uterinas/patología , Neoplasias Uterinas/química , Inhibidor p16 de la Quinasa Dependiente de Ciclina/análisis , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Persona de Mediana Edad , Adulto , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/análisis , Anciano , Adolescente , Adulto Joven , Niño , Eliminación de Gen , Neoplasias de Tejido Muscular/genética , Neoplasias de Tejido Muscular/patología , Neoplasias de Tejido Muscular/química , Inmunohistoquímica , Valor Predictivo de las Pruebas , Recurrencia Local de Neoplasia , Carga Tumoral , Factores de RiesgoRESUMEN
Endometrial stromal tumors represent the second most common category of uterine mesenchymal tumors. Several different histologic variants and underlying genetic alterations have been recognized, one such being a group associated with BCORL1 rearrangements. They are usually high-grade endometrial stromal sarcomas, often associated with prominent myxoid background and aggressive behavior. Here, we report an unusual endometrial stromal neoplasm with JAZF1-BCORL1 rearrangement and briefly review the literature. The neoplasm formed a well-circumscribed uterine mass in a 50-yr-old woman and had an unusual morphologic appearance that did not warrant a high-grade categorization. It was characterized by a predominant population of epithelioid cells with clear to focally eosinophilic cytoplasm growing in interanastomosing cords and trabeculae set in a hyalinized stroma as well as nested and fascicular growths imparting focal resemblance to a uterine tumor resembling ovarian sex-cord tumor, PEComa, and a smooth muscle neoplasm. A minor storiform growth of spindle cells reminiscent of the fibroblastic variant of low-grade endometrial stromal sarcoma was also noted but conventional areas of low-grade endometrial stromal neoplasm were not identified. This case expands the spectrum of morphologic features seen in endometrial stromal tumors, especially when associated with a BCORL1 fusion and highlights the utility of immunohistochemical and molecular techniques in the diagnosis of these tumors, not all of which are high grade.
Asunto(s)
Neoplasias Endometriales , Tumores Estromáticos Endometriales , Sarcoma Estromático Endometrial , Neoplasias Uterinas , Femenino , Humanos , Tumores Estromáticos Endometriales/diagnóstico , Tumores Estromáticos Endometriales/genética , Neoplasias Endometriales/diagnóstico , Neoplasias Endometriales/genética , Neoplasias Endometriales/química , Sarcoma Estromático Endometrial/diagnóstico , Sarcoma Estromático Endometrial/genética , Neoplasias Uterinas/patología , Útero/patología , Proteínas de Unión al ADN/genética , Proteínas Co-Represoras/genética , Proteínas Represoras/genéticaRESUMEN
Immature neuroectodermal tissue can be found in the ovary as part of an immature teratoma or as part of a teratoma with malignant neuroectodermal transformation. Such lesions may closely resemble central nervous system tumors, but their biologic similarity is unclear. We describe an 18-yr-old female who presented with abdominal pain caused by an ovarian mass with widespread metastases. Histology showed a primitive, high-grade tumor arising in the background of a mature teratoma. The tumor was SOX10 positive, with focal expression of GFAP, S100, NSE, and synaptophysin. Molecular analysis demonstrated co-amplification of PDGFRA and KIT , alterations common in high-grade gliomas. By whole-genome methylation profiling, it clustered into the "diffuse pediatric-type high-grade glioma, RTK1 subtype, subclass c" group. Despite progressing through 2 lines of chemotherapy with widespread metastatic disease, she achieved an excellent response to chemotherapy directed toward aggressive germ cell tumors. This case emphasizes the importance of immunohistochemical, genomic, and epigenetic analyses to accurately classify these exceedingly rare tumors and determine the optimal therapy.
Asunto(s)
Glioma , Neoplasias de Células Germinales y Embrionarias , Neoplasias Ováricas , Teratoma , Humanos , Femenino , Niño , Neoplasias Ováricas/genética , Neoplasias Ováricas/patología , Teratoma/complicaciones , Teratoma/genética , Glioma/complicaciones , Glioma/genéticaRESUMEN
Ovarian steroid and Leydig cell tumors (SCT and LCT, respectively) are rare stromal tumors, with aggressive behavior described in approximately one third of SCTs. Previously reported features potentially predictive of malignancy include size ≥7 cm, gross hemorrhage, necrosis, grade 2 or 3 nuclear atypia, and mitoses ≥2/10 HPFs; however, no subsequent studies have corroborated these findings. Herein, we evaluated a series of 25 tumors (21 SCT, 4 LCT) to explore their clinicopathologic and molecular features. Patients ranged from 16 to 79 years (median: 53 y) and all tumors were FIGO stage I. Recurrences occurred in 3 patients, all of whom died from disease. At least 1 atypical feature was identified in 63% of SCT/LCT and included hemorrhage (n=9), grade 2 or 3 atypia (n=7), mitoses≥2/10 HPFs (n=7), size≥7.0 cm (n=6), and necrosis (n=2); only malignant SCTs demonstrated 4 or 5 atypical features. Next-generation sequencing revealed malignant SCTs were genomically unstable, with uncommon and nonrecurring gene-level alterations ( MDM2/CDK4 coamplification, ATRX rearrangement, BAP1 mutation). One SCT with limited follow-up harbored FH and TP53 mutations and occasional arm-level copy number alterations, while all other sequenced tumors (n=7) were genomically stable; 1 had a CTNNB1 mutation and another a CASP10 mutation. In summary, the presence of at least 1 atypical feature is common in SCT/LCT, but most patients demonstrate a benign clinical course. Genomic alterations are infrequent but occur in malignant SCTs as well as a subset of benign SCTs. Molecular analysis of additional malignant SCTs is necessary to identify recurring and/or potentially actionable targets.
Asunto(s)
Neoplasias Ováricas , Tumores de los Cordones Sexuales y Estroma de las Gónadas , Femenino , Humanos , Recurrencia Local de Neoplasia , Neoplasias Ováricas/genética , Neoplasias Ováricas/patología , Necrosis , HemorragiaRESUMEN
The anti-programmed cell death (PD-1) checkpoint inhibitor pembrolizumab is approved for the treatment of cervical carcinoma with a programmed cell death-ligand 1 (PD-L1) Combined Positive Score (CPS) of ≥1. We assessed interobserver agreement in cervical carcinoma PD-L1 CPS to identify whether it may affect patient selection for immunotherapeutic candidacy. Twenty-nine cervical carcinomas were stained for PD-L1 (Dako 22C3), and slides were interpreted by 5 subspecialty-trained gynecologic pathologists with experience reading PD-L1 immunohistochemistry. Expression was scored using CPS and read out as positive (≥1) or negative (<1); in positive cases, a final score was assigned (1 to 100). There was consensus agreement across all 5 pathologists for 90% (26/29) (Fleiss Kappa value for interobserver agreement: 0.799). The 3 cases with disagreement were composed of 2 squamous cell carcinomas and 1 small cell carcinoma. Of the 26 with unanimous agreement, 88% (23/26) were positive and 12% (3/26) were negative. All (16/16) pure squamous cell carcinomas with full consensus were interpreted as positive, whereas tumors with glandular components were commonly consensus negative (33%, 3/9); this difference was significant ( P =0.037). Disagreements were attributable to low CPS versus negative reads (2 cases) and difficulty discerning glandular involvement from pushing invasion (1 case). In summary, experienced gynecologic pathologists showed substantial interobserver agreement in the interpretation of PD-L1 CPS at the Food and Drug Administration-approved treatment threshold, with the majority of tumors being classified as positive. Pure squamous histology was strongly associated with a consensus-positive read, whereas a subset of tumors with glandular differentiation was negative by all readers. Disagreements occurred in tumors with low versus negative CPS values and in the setting of limited invasion.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Carcinoma de Células Escamosas , Neoplasias Pulmonares , Humanos , Femenino , Antígeno B7-H1/metabolismo , Patólogos , Variaciones Dependientes del Observador , Carcinoma de Pulmón de Células no Pequeñas/patología , Biomarcadores de Tumor/metabolismo , Neoplasias Pulmonares/patologíaRESUMEN
Subclonal loss of mismatch repair (MMR) proteins has been described in a small subset of endometrial carcinomas (ECs), but the genomic basis for this phenomenon has received limited attention. Herein, we retrospectively evaluated all ECs with MMR immunohistochemistry (n=285) for subclonal loss, and in those (n=6), performed a detailed clinicopathologic and genomic comparison of the MMR-deficient and MMR-proficient components. Three tumors were FIGO stage IA, and one each stage IB, II, and IIIC2. Patterns of subclonal loss were as follows: (1) 3 FIGO grade 1 endometrioid carcinomas with subclonal MLH1/PMS2, MLH1 promoter hypermethylation, and no MMR gene mutations; (2) POLE -mutated FIGO grade 3 endometrioid carcinoma with subclonal PMS2, and PMS2 and MSH6 mutations limited to the MMR-deficient component; (3) dedifferentiated carcinoma with subclonal MSH2/MSH6, as well as complete loss of MLH1/PMS2, MLH1 promoter hypermethylation, and PMS2 and MSH6 mutations in both components; (4) dedifferentiated carcinoma with subclonal MSH6, and somatic and germline MSH6 mutations in both components, but with a higher allele frequency in MMR-deficient foci. Recurrences occurred in 2 patients, one consisted of the MMR-proficient component from a FIGO 1 endometrioid carcinoma, while the other was from the MSH6 -mutated dedifferentiated endometrioid carcinoma. At the last follow-up (median: 44 mo), 4 patients were alive and disease-free and 2 were alive with disease. In summary, subclonal MMR loss reflects subclonal and often complex genomic and epigenetic alterations, which may have therapeutic implications and therefore must be reported when present. In addition, subclonal loss can occur in both POLE -mutated and Lynch syndrome-associated ECs.
Asunto(s)
Carcinoma Endometrioide , Neoplasias Endometriales , Femenino , Humanos , Carcinoma Endometrioide/genética , Carcinoma Endometrioide/patología , Endonucleasa PMS2 de Reparación del Emparejamiento Incorrecto/genética , Endonucleasa PMS2 de Reparación del Emparejamiento Incorrecto/metabolismo , Reparación de la Incompatibilidad de ADN/genética , Estudios Retrospectivos , Homólogo 1 de la Proteína MutL/genética , Homólogo 1 de la Proteína MutL/metabolismo , Neoplasias Endometriales/genética , Neoplasias Endometriales/patología , GenómicaRESUMEN
Most low-grade, early-stage endometrial endometrioid carcinomas (EEC) have an excellent prognosis; however, recurrences occur in a small subset with several studies reporting an increase in CTNNB1 exon 3 mutations in this population. Herein we evaluated 10 recurrent low-grade (FIGO 1 or 2), early-stage (FIGO IA) EECs matched to 10 nonrecurrent EECs to further characterize their clinicopathologic features and molecular phenotype. Cases were matched to controls based on size, grade, and depth of invasion. All tumors were evaluated for specific clinicopathologic parameters followed by next-generation sequencing using a 1213 gene panel. Recurrent EECs demonstrated no significant clinicopathologic differences when compared with nonrecurrent EECs, in terms of age, body mass index, pattern of invasion, presence of endometrial atypical hyperplasia/endometrioid intraepithelial neoplasia, associated metaplastic changes, peritumoral lymphocytes, mitoses, and tumor-infiltrating lymphocytes. Both cohorts also showed a similar number of pathogenic mutations, including CTNNB1 exon 3 mutations, as well as tumor mutational burden and microsatellite profiles. Although in this particular study, the lack of correlation between CTNNB1 exon 3 mutation and recurrence might be secondary to a small sample size, it also suggests the presence of other contributing factors. Thus, it helps set the foundation for larger series incorporating whole genome, transcriptome, proteome, and epigenome analyses to answer this clinically important question.
Asunto(s)
Carcinoma Endometrioide , Hiperplasia Endometrial , Neoplasias Endometriales , Femenino , Humanos , Carcinoma Endometrioide/genética , Carcinoma Endometrioide/patología , Estudios de Casos y Controles , Estadificación de Neoplasias , Neoplasias Endometriales/genética , Neoplasias Endometriales/patología , Hiperplasia Endometrial/patologíaRESUMEN
Signet-ring stromal tumor (SRST) is a rare ovarian stromal neoplasm characterized by a population of bland signet-ring cells, devoid of mucin or lipid, in a generally cellular fibromatous stroma. Previous reports have described heterogenous immunohistochemical and molecular genetic findings, including occasional nuclear ß-catenin expression and/or CTNNB1 mutations. We report 10 ovarian stromal neoplasms originally diagnosed as SRST. All but 1 tumor underwent detailed immunohistochemical analysis (including ß-catenin) and 5 of 10 had CTNNB1 mutation analysis performed. All tumors contained a population of morphologically bland signet-ring cells that ranged from 15% to 95% of the neoplasm, characterized by a single large empty intracytoplasmic vacuole, mostly with nuclear indentation. Six of the 10 tumors contained cellular fibroma-like areas, comprising from 10% to 85% of the neoplasm. Three of the 10 tumors were reclassified as microcystic stromal tumor with signet-ring cells on the basis of the microcyst formation and hyalinized stroma, beta-catenin and cyclin D1 nuclear expression and/or CTNNB1 mutation, CD10 staining and largely absent expression of inhibin and calretinin. In the remaining 7 tumors, the diagnosis of SRST remained, constituting the largest series of SRST reported in the literature to date. The results of our study suggest that a subset of tumors diagnosed as ovarian SRST, especially those which show ß-catenin nuclear positivity and/or CTNNB1 mutation, likely represent microcystic stromal tumor with variant morphology. We also suggest that at least a subset of SRSTs without evidence of Wnt/ß-catenin pathway abnormalities may be related to ovarian fibromas. We discuss the differential diagnosis of ovarian neoplasms containing signet-ring cells.
Asunto(s)
Neoplasias Ováricas , Tumores de los Cordones Sexuales y Estroma de las Gónadas , Femenino , Humanos , beta Catenina/análisis , Diagnóstico Diferencial , Análisis Mutacional de ADN , Biomarcadores de Tumor/análisis , Tumores de los Cordones Sexuales y Estroma de las Gónadas/patología , Neoplasias Ováricas/diagnóstico , Neoplasias Ováricas/genética , Neoplasias Ováricas/patologíaRESUMEN
Embryonal rhabdomyosarcoma of the uterine cervix (cERMS) is rare and frequently associated with DICER1 mutations. We report 94 tumors that arose in patients aged 7 to 59 (median=23) years and presented with vaginal bleeding (52), protruding vaginal mass (17), cervical polyp (8), or expelled tumor fragments per vagina (5). Nine had DICER1 syndrome, 8 of whom had other syndromic manifestations including ovarian Sertoli-Leydig cell tumor (7), multinodular goiter (3), pleuropulmonary blastoma (2), pineoblastoma (1), and osteosarcoma (1). Syndromic patients were younger than nonsyndromic patients (16 vs. 24 y). Tumor size ranged from 2 to 24 (median=4.5) cm. Ninety-two tumors were polypoid, most being grape-like (77 of 92). They were characterized by aggregates of primitive cells, almost always exhibiting a cambium layer, within a variably myxoedematous stroma and were hypocellular (63), moderately cellular (22), or hypercellular (9). Entrapped glands, typically scant, were present in 84 tumors. Primitive hyperchromatic ovoid to spindled cells with minimal cytoplasm predominated but differentiated rhabdomyoblasts with abundant eosinophilic cytoplasm (having cross-striations in 30) were seen in 83 tumors; they were often sparse but predominated in three. Nine tumors showed areas of intersecting fascicles and 4 zones with densely cellular (solid) growth. Cartilage was present in 38. Anaplasia was seen in 15 tumors, as was necrosis. Mitotic activity ranged from 1 to 58/10 high-power fields (median=8). The varied microscopic features resulted in a spectrum of differential diagnostic considerations, mainly typical and cellular forms of fibroepithelial polyps, Mullerian adenosarcoma, and other sarcomas. Follow-up was available for 79 patients ranging from 6 to 492 (median=90) months. Treatment information was available in 62 and included polypectomy in 6 patients (2 also received chemotherapy), limited resection in 26 (14 also received chemotherapy), hysterectomy in 29 (15 with adjuvant chemotherapy), and biopsies only in 1 (with chemotherapy). Staging was possible in 56 tumors; according to the "uterine sarcoma" system (tumor size and extent) they were: stage I (10/56; could not be further subclassified as size not available), IA (22/56), IB (18/56), IIA (2/56), IIB 3/56), IIIC (1/56). According to the "adenosarcoma" system (depth of invasion and extent) they were: stage IA (26/56), IB (14/56), IC (10/56), IIA (2/56), IIB (3/56), IIIC (1/56). Eight patients had local recurrence following incomplete excision (10%). Eleven of 79 patients had extrauterine recurrences (14%) and 9 died of disease (11%). Older age was associated with extrauterine recurrence (median 44 vs. 22; P =0.002) and decreased disease-specific survival (median 44 vs. 22; P =0.02). For patients with tumors initially confined to the cervix, the adenosarcoma staging system was superior to the uterine sarcoma staging system for predicting survival ( P =0.02). Three patients with DICER1 syndrome who underwent fertility-preserving surgery developed a second primary cERMS 7, 7, and 12 years after their primary tumor. All 9 patients with DICER1 syndrome had tumors confined to the cervix and none died of disease. This study highlights the intriguing clinical aspects of cERMS including its long-known tendency to occur in the young but also more recently appreciated association with DICER1 syndrome. Establishing the diagnosis may still be difficult because of the hazard of sampling a neoplasm which in areas may appear remarkably bland and also because of its potential confusion with other neoplasms. This study indicates that this tumor has a good prognosis at this site and in selected cases a conservative surgical approach is a realistic consideration.
Asunto(s)
Adenosarcoma , Síndromes Neoplásicos Hereditarios , Rabdomiosarcoma Embrionario , Neoplasias del Cuello Uterino , Neoplasias Uterinas , Cuello del Útero/patología , ARN Helicasas DEAD-box , Diagnóstico Diferencial , Femenino , Humanos , Pronóstico , Rabdomiosarcoma Embrionario/genética , Rabdomiosarcoma Embrionario/patología , Rabdomiosarcoma Embrionario/terapia , Ribonucleasa III , Neoplasias del Cuello Uterino/patología , Neoplasias Uterinas/genética , Neoplasias Uterinas/patologíaRESUMEN
This review focuses on recent advances in epithelioid and myxoid uterine mesenchymal neoplasms, a category of tumors whereby diagnostic criteria have been rapidly evolving due to advances in molecular testing. Pertinent clinicopathological and molecular features are highlighted for perivascular epithelioid cell tumors, uterine tumors resembling ovarian sex cord tumors, BCOR/BCORL1-altered high-grade endometrial stromal sarcomas, and inflammatory myofibroblastic tumors. Novel developments in epithelioid and myxoid leiomyosarcomas are briefly discussed, and differential diagnoses with key diagnostic criteria are provided for morphologic mimickers.
Asunto(s)
Neoplasias Endometriales , Leiomiosarcoma , Sarcoma Estromático Endometrial , Tumores de los Cordones Sexuales y Estroma de las Gónadas , Neoplasias Uterinas , Biomarcadores de Tumor/genética , Neoplasias Endometriales/patología , Femenino , Humanos , Leiomiosarcoma/diagnóstico , Leiomiosarcoma/genética , Leiomiosarcoma/patología , Sarcoma Estromático Endometrial/diagnóstico , Sarcoma Estromático Endometrial/genética , Sarcoma Estromático Endometrial/patología , Tumores de los Cordones Sexuales y Estroma de las Gónadas/diagnóstico , Tumores de los Cordones Sexuales y Estroma de las Gónadas/genética , Tumores de los Cordones Sexuales y Estroma de las Gónadas/patología , Neoplasias Uterinas/diagnóstico , Neoplasias Uterinas/genética , Neoplasias Uterinas/patologíaRESUMEN
Cervical clear cell carcinoma (CCC) is a rare human papillomavirus-independent adenocarcinoma. While recent studies have focused on gastric-type endocervical adenocarcinoma (GTA), little is known about CCC. A total of 58 (CCCs) were collected from 14 international institutions and retrospectively analyzed using univariable and multivariable methods and compared with 36 gastric-type adenocarcinomas and 173 human papillomavirus-associated (HPVA) endocervical adenocarcinoma (ECA) regarding overall survival (OS) and recurrence-free survival (RFS). Most cases were FIGO stage I (72.4%), with Silva C pattern of invasion (77.6%), and the majority were treated with radical surgery (84.5%) and adjuvant therapy (55.2%). Lymphovascular invasion was present in 31%, while lymph node metastasis was seen in 24.1%; 10.3% were associated with abdominopelvic metastases at the time of diagnosis; 32.8% had recurrences, and 19% died of disease. We did not find statistically significant differences in OS and RFS between CCC and GTA at 5 and 10 years (P=0.313 and 0.508, respectively), but there were significant differences in both OS and RFS between CCC and HPVA ECA (P=0.003 and 0.032, respectively). Also, OS and RFS in stage I clear cell and GTA were similar (P=0.632 and 0.692, respectively). Multivariate analysis showed that OS is influenced by the presence of recurrence (P=0.009), while RFS is influenced by the FIGO stage (P=0.025). Cervical CCC has poorer outcomes than HPVA ECA and similar outcomes to human papillomavirus-independent GTA. Oncologic treatment significantly influences RFS in univariate analysis but is not an independent prognostic factor in multivariate analysis suggesting that alternative therapies should be investigated.
Asunto(s)
Adenocarcinoma de Células Claras , Alphapapillomavirus , Carcinoma , Infecciones por Papillomavirus , Neoplasias del Cuello Uterino , Adenocarcinoma de Células Claras/patología , Adenocarcinoma de Células Claras/terapia , Carcinoma/patología , Cuello del Útero/patología , Femenino , Humanos , Estadificación de Neoplasias , Papillomaviridae , Pronóstico , Estudios Retrospectivos , Neoplasias del Cuello Uterino/patologíaRESUMEN
We report 27 solitary fibrous tumors of the female genital tract emphasizing nonvulvar locations, variant histology, and prognostic factors. The patients ranged from 25 to 78 years (most were over 40), and tumors occurred in the vulva (7), vagina (2), cervix (2), corpus (6), fallopian tube/paratubal soft tissue (5), and ovary (5). They ranged from 1.5 to 39 (mean=10.5) cm and were typically solid, but 4 were predominantly cystic. All had a haphazard arrangement of spindled to ovoid cells, with most demonstrating alternating cellular and hypocellular areas and prominent vessels, but 13 lacked hypocellular areas, and 7 had focal diffuse growth with inconspicuous vasculature. Other patterns included corded (8), fascicular (5), trabecular (1), and nested (1). Microcysts (6), myxoid background (8), hyalinization (8), lipomatous differentiation (2), and multinucleated cells (6) were also present, and 10 tumors had necrosis. Vasculature included thin-walled branching "staghorn" (27), thick-walled (7), and hyalinized vessels (5) or dilated anastomosing vascular channels (3). Nuclear atypia ranged from mild (19), moderate (7), to severe (1), and mitoses from 0 to 24/10 HPF (mean=4). STAT6 was positive in all 25 tumors tested. One tumor showed dedifferentiation; the remainder were classified as benign (19) or malignant (7) based on mitotic rate (univariate stratification model) and as low risk (14), intermediate risk (8), or high risk (4) based on the Demicco multivariate risk stratification score. Follow-up (median=23 mo) was available for 16 patients. Six tumors recurred (2 intermediate risk, 3 high risk, and the dedifferentiated tumor), 5 in the abdomen; the dedifferentiated tumor metastasized to the lung. Multivariate risk stratification was superior to univariate classification, as 5 "benign" tumors were reclassified as intermediate risk using the multivariate model; of these, 2 recurred, and 1 patient died of disease. Upper female genital tract tumors occurred in older patients, were larger, and more frequently classified as high risk compared with those of the lower tract. A trend toward increased cellularity was also seen in the upper tract tumors. Only size (P=0.04), necrosis (P=0.04), and Demicco score (P=0.01) independently correlated with recurrence. Female genital tract solitary fibrous tumors demonstrate a wide range of variant morphologies and occur in diverse sites in addition to the vulva. Tumors were often misdiagnosed as other neoplasms; thus, awareness of solitary fibrous tumors occurring at these sites is crucial in prompting staining for STAT6 to establish this diagnosis. The Demicco risk stratification system effectively predicts behavior.
Asunto(s)
Neoplasias de los Genitales Femeninos/patología , Tumores Fibrosos Solitarios/patología , Adulto , Anciano , Diagnóstico Diferencial , Femenino , Estudios de Seguimiento , Neoplasias de los Genitales Femeninos/diagnóstico , Humanos , Persona de Mediana Edad , Pronóstico , Medición de Riesgo , Tumores Fibrosos Solitarios/diagnósticoRESUMEN
Uterine PEComas often present a diagnostic challenge as they share morphological and immunohistochemical features with smooth muscle tumors. Herein we evaluated a series of 19 uterine PEComas to compare the degree of melanocytic marker expression with their molecular profile. Patients ranged from 32-77 (median 48) years, with six tumors classified as malignant based on the modified gynecologic-specific prognostic algorithm. All patients with malignant PEComas were alive with disease or dead of disease at last follow-up, while all those of uncertain malignant potential were alive and well (median follow-up, 47 months).Seventeen of 19 (89%) PEComas harbored either a TSC1 or TSC2 alteration. One of the two remaining tumors showed a TFE3 rearrangement, but the other lacked alterations in all genes evaluated. All showed at least focal (usually strong) positivity for HMB-45, with 15/19 (79%) having >50% expression, while the tumor lacking TSC or TFE3 alterations was strongly positive in 10% of cells. Melan-A and MiTF were each positive in 15/19 (79%) tumors, but staining extent and intensity were much more variable than HMB-45. Five of six (83%) malignant PEComas also harbored alterations in TP53, ATRX, or RB1, findings not identified in any tumors of uncertain malignant potential. One malignant PEComa was microsatellite-unstable/mismatch repair protein-deficient.In summary, TSC alterations/TFE3 fusions and diffuse (>50%) HMB-45 expression are characteristic of uterine PEComas. In morphologically ambiguous mesenchymal neoplasms with myomelanocytic differentiation, especially those with metastatic or recurrent disease, next-generation sequencing is recommended to evaluate for TSC alterations; as such, patients can be eligible for targeted therapy.
Asunto(s)
Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice , Neoplasias de Células Epitelioides Perivasculares , Tumor de Músculo Liso , Proteína 1 del Complejo de la Esclerosis Tuberosa , Proteína 2 del Complejo de la Esclerosis Tuberosa , Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice/genética , Biomarcadores de Tumor/genética , Femenino , Humanos , Neoplasias de Células Epitelioides Perivasculares/genética , Neoplasias de Células Epitelioides Perivasculares/patología , Proteína 1 del Complejo de la Esclerosis Tuberosa/genética , Proteína 2 del Complejo de la Esclerosis Tuberosa/genéticaRESUMEN
Experimental data about gene functions curated from the primary literature have enormous value for research scientists in understanding biology. Using the Gene Ontology (GO), manual curation by experts has provided an important resource for studying gene function, especially within model organisms. Unprecedented expansion of the scientific literature and validation of the predicted proteins have increased both data value and the challenges of keeping pace. Capturing literature-based functional annotations is limited by the ability of biocurators to handle the massive and rapidly growing scientific literature. Within the community-oriented wiki framework for GO annotation called the Gene Ontology Normal Usage Tracking System (GONUTS), we describe an approach to expand biocuration through crowdsourcing with undergraduates. This multiplies the number of high-quality annotations in international databases, enriches our coverage of the literature on normal gene function, and pushes the field in new directions. From an intercollegiate competition judged by experienced biocurators, Community Assessment of Community Annotation with Ontologies (CACAO), we have contributed nearly 5,000 literature-based annotations. Many of those annotations are to organisms not currently well-represented within GO. Over a 10-year history, our community contributors have spurred changes to the ontology not traditionally covered by professional biocurators. The CACAO principle of relying on community members to participate in and shape the future of biocuration in GO is a powerful and scalable model used to promote the scientific enterprise. It also provides undergraduate students with a unique and enriching introduction to critical reading of primary literature and acquisition of marketable skills.
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Colaboración de las Masas/métodos , Ontología de Genes , Anotación de Secuencia Molecular/métodos , Biología Computacional , Bases de Datos Genéticas , Humanos , Proteínas/genética , Proteínas/fisiologíaRESUMEN
â¢Metastatic SCC arising from the ovary is rare, and the optimal treatment is unknown.â¢Pembrolizumab successfully treated a patient with metastatic SCC.â¢Patients on pembrolizumab should be monitored for immune-related adverse events.
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Inflammatory myofibroblastic tumor (IMT) of the uterus is an uncommon mesenchymal neoplasm that frequently harbors ALK rearrangements. In this report, we describe the first uterine IMT with a FN1-ROS1 fusion, which occurred in a 43-year-old woman who presented with menorrhagia. Morphologically, the well-circumscribed 3 cm tumor was comprised of compact and myxoid foci of relatively bland spindle cells admixed with scattered chronic inflammatory cells limited to the myxoid areas. ROS1 showed moderate cytoplasmic granular staining in < 30% of cells in the myxoid foci, while ALK was negative. RNA sequencing detected a FN1-ROS1 rearrangement that fused FN1 exon 37 to ROS1 exon 34. Although non-ALK-rearranged uterine IMTs are exceedingly rare, this example highlights the importance of performing ROS1 immunohistochemistry and/or molecular analysis in ALK-negative uterine neoplasms morphologically compatible with IMT.
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Quinasa de Linfoma Anaplásico/genética , Fibronectinas/genética , Neoplasias de Tejido Muscular/genética , Proteínas Tirosina Quinasas/genética , Proteínas Proto-Oncogénicas/genética , Neoplasias Uterinas/genética , Adulto , Femenino , Humanos , Inflamación/diagnóstico , Inflamación/genética , Inflamación/patología , Neoplasias de Tejido Muscular/diagnóstico , Neoplasias de Tejido Muscular/patología , Proteínas de Fusión Oncogénica/genética , RNA-Seq , Neoplasias Uterinas/diagnóstico , Neoplasias Uterinas/patologíaRESUMEN
Corded and hyalinized and spindled carcinomas are rare variants of endometrioid carcinoma (EC) characterized by cords of low-grade epithelial cells (±spindle cells) within a hyalinized stroma or spindled epithelial cells, respectively, that merge with conventional low-grade EC. Due to their "biphasic" morphology, these tumors are often misdiagnosed as carcinosarcoma. The clinicopathologic features including mismatch repair protein (PMS2 and MSH6) and p53 immunohistochemical expression and POLE mutational status of 9 corded and hyalinized and spindled endometrial ECs were evaluated and classified into The Cancer Genome Atlas (TCGA) based molecular subgroups. Beta-catenin immunohistochemistry was performed as a surrogate for CTNNB1 mutational status. The mean age at diagnosis was 49 years (range: 34 to 68 y) with staging information available for 6 patients: stage IA (n=1), stage IB (n=1), stage II (n=2), stage IIIA (n=1), stage IIIC1 (n=1). A prominent corded and hyalinized component was present in 7 ECs comprising 15% to 80% of the tumor with a minor (5% to 15%) spindled morphology in 5. Two additional tumors were composed of a low-grade spindled component comprising 25% to 30% of the neoplasm. Tumors were grade 1 (n=3), grade 2 (n=5), and grade 2 to 3 (n=1) and squamous differentiation was identified in 8/9. All tumors had preserved expression of mismatch repair proteins with 8 showing a p53 wild-type phenotype including the grade 2 to 3 EC; 1 grade 2, stage IB tumor exhibited a mutant pattern of expression. All (n=7) but 1 tumor demonstrated nuclear beta-catenin expression in the glandular, squamous, and corded or spindled components. POLE exonuclease domain mutations were absent in all tumors. Based on our findings, corded and hyalinized EC and EC with spindle cells are usually low grade, low stage, and present at a younger age and exhibit squamous differentiation at an increased frequency compared to typical EC. Unlike carcinosarcomas, which frequently harbor TP53 mutations, these tumors usually exhibit wild-type p53 and nuclear beta-catenin expression, indicative of underlying CTNNB1 mutations. According to the TCGA subgroups of endometrial carcinoma, the majority of corded and hyalinized and spindled EC appear to fall into the copy number low ("no specific molecular profile") subgroup.