RESUMO
Undifferentiated round cell sarcomas (URCS) represent a diverse group of tumors, including conventional Ewing sarcoma, round cell sarcoma with EWSR1/FUS-non-ETS fusions, CIC-rearranged sarcoma, and sarcoma with BCOR alterations. Since 2018, 3 cases of URCS with a novel CRTC1::SS18 gene fusion have been reported in the literature. Herein, we report 3 additional cases of CRTC1::SS18 sarcoma, thereby doubling the number of described cases and expanding the clinicopathologic features of this rare translocation sarcoma. Together with the previously reported cases, we show that the male-to-female ratio is 1:2 with a median age of 34 years (range, 12-42 years). Tumors occurred primarily in intramuscular locations involving the lower extremity. Histologically, all tumors contained uniform round-to-epithelioid cells with a moderate amount of eosinophilic cytoplasm growing in sheets and nests with prominent desmoplastic stroma reminiscent of desmoplastic small round cell tumor. Immunohistochemical results were nonspecific, demonstrating variable expression of CD99 (patchy), ALK, GATA3, and cyclin D1. RNA sequencing revealed CRTC1::SS18 gene fusions in all cases, involving exons 1 to 2 of CRTC1 (the 5' partner gene) on chromosome 19 and either exon 2 or exon 4 of SS18 (the 3' partner gene) on chromosome 18. The clinical course was variable. Although 1 previously reported case demonstrated aggressive behavior with a fatal outcome, 2 others had a relatively indolent course with gradual growth for 6 to 7 years prior to resection. Two cases developed metastatic disease, including 1 case with bilateral lung metastasis and 1 with locoregional spread to a lymph node. By analyzing the clinicopathologic features, we aimed to improve recognition of this rare translocation sarcoma to better understand its biologic potential, optimize patient management, and expand the current classification of URCS.
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Mesenchymal tumors with GLI1 fusions or amplifications have recently emerged as a distinctive group of neoplasms. The terms GLI1-altered mesenchymal tumor or GLI1-altered soft tissue tumor serve as a nosological category, although the exact boundaries/criteria require further elucidation. We examined 16 tumors affecting predominantly adults (median age: 40 years), without sex predilection. Several patients had tumors of longstanding duration (>10 years). The most common primary site was soft tissue (n = 9); other sites included epidural tissue (n = 1), vertebra (n = 1), tongue (n = 1), hard palate (n = 1), and liver (n = 1). Histologically, the tumors demonstrated multinodular growth of cytologically uniform, ovoid-to-epithelioid, occasionally short spindled cells with delicate intratumoral vasculature and frequent myxoid stroma. Mitotic activity ranged from 0 to 8 mitoses/2 mm2 (mean 2). Lymphovascular invasion/protrusion of tumor cells into endothelial-lined vascular spaces was present or suspected in 6 cases. Necrosis, significant nuclear pleomorphism, or well-developed, fascicular spindle-cell growth were absent. Half demonstrated features of the newly proposed subset, "distinctive nested glomoid neoplasm." Tumors were consistently positive for CD56 (n = 5/5). A subset was stained with S100 protein (n = 7/13), SMA (n = 6/13), keratin (n = 2/9), EMA (n = 3/7), and CD99 (n = 2/6). Tumors harbored ACTB::GLI1 (n = 15) or PTCH1::GLI1 (n = 1) fusions. The assays used did not capture cases defined by GLI1 amplification. We also identified recurrent cytogenetic gains (1q, 5, 7, 8, 12, 12q13.2-ter, 21, and X). For patients with available clinical follow-up (n = 8), half were disease free. Half demonstrated distant metastases (lungs, bone, or soft tissue). Of cases without follow-up (n = 8), 2 were known recurrences, and 1 was presumed metastasis. Our results imply a more aggressive biological potential than currently reported. Given the possibility for metastasis and disease progression, even in cytologically bland, nested tumors, close clinical surveillance, akin to that for sarcoma management, may be indicated. The term GLI1-altered mesenchymal tumor with malignant potential is proposed.
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Neoplasias de Tecido Conjuntivo e de Tecidos Moles , Sarcoma , Neoplasias de Tecidos Moles , Adulto , Humanos , Proteína GLI1 em Dedos de Zinco/genética , Neoplasias de Tecidos Moles/genética , Neoplasias de Tecidos Moles/patologia , Proteínas S100 , Sarcoma/patologia , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/análiseRESUMO
AIMS: Liquid biopsy (LBx)-based next-generation sequencing (NGS) of circulating tumour DNA (ctDNA) can facilitate molecular profiling of haematopoietic neoplasms (HNs), particularly when tissue-based NGS is infeasible. METHODS AND RESULTS: We studied HN LBx samples tested with FoundationOne Liquid CDx, FoundationOne Liquid, or FoundationACT between July 2016 and March 2022. We identified 271 samples: 89 non-Hodgkin lymphoma (NHL), 43 plasma-cell neoplasm (PCN), 41 histiocytoses, 27 myelodysplastic syndrome (MDS), 25 diffuse large B-cell lymphoma (DLBCL), 22 myeloproliferative neoplasm (MPN), 14 Hodgkin lymphoma (HL), and 10 acute myeloid leukaemia (AML). Among 73.4% with detectable pathogenic alterations, median maximum somatic allele frequency (MSAF) was 16.6%, with AML (36.2%), MDS (19.7%), and MPN (44.5%) having higher MSAFs than DLBCL (3.9%), NHL (8.4%), HL (1.5%), PCN (2.8%), and histiocytoses (1.8%) (P = 0.001). LBx detected characteristic alterations across HNs, including in TP53, KRAS, MYD88, and BTK in NHLs; TP53, KRAS, NRAS, and BRAF in PCNs; IGH in DLBCL; TP53, ATM, and PDCD1LG2 in HL; BRAF and MAP2K1 in histiocytoses; TP53, SF3B1, DNMT3A, TET2, and ASXL1 in MDS; JAK2 in MPNs; and FLT3, IDH2, and NPM1 in AML. Among 24 samples, the positive percent agreement by LBx was 75.7% for variants present in paired buffy coat, marrow, or tissues. Also, 75.0% of pairs exhibited alterations only present on LBx. These were predominantly subclonal (clonal fraction of 3.8%), reflecting the analytical sensitivity of LBx. CONCLUSION: These data demonstrate that LBx can detect relevant genomic alterations across HNs, including at low clonal fractions, suggesting a potential clinical utility for identifying residual or emerging therapy-resistant clones that may be undetectable in site-specific tissue biopsies.
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Biomarcadores Tumorais , DNA Tumoral Circulante , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Biópsia Líquida , DNA Tumoral Circulante/genética , DNA Tumoral Circulante/sangue , DNA Tumoral Circulante/análise , Biomarcadores Tumorais/genética , Masculino , Pessoa de Meia-Idade , Feminino , Idoso , Adulto , Mutação , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/patologia , Neoplasias Hematológicas/diagnóstico , Nucleofosmina , Transtornos Mieloproliferativos/genética , Transtornos Mieloproliferativos/diagnóstico , Transtornos Mieloproliferativos/patologia , Transtornos Mieloproliferativos/sangueRESUMO
Clear cell mesothelioma is uncommon and shows predominance of clear cells with resemblance to clear cell carcinomas. Clinicopathologic and molecular descriptions of clear cell mesothelioma remained limited. In this study, we identified an index patient with clear cell mesothelioma, confirmed by immunohistochemical and ultrastructural studies. Targeted next-generation sequencing revealed the presence of an inactivating VHL mutation. We then systematically searched for VHL-mutant mesotheliomas in a comprehensive genomic profiling database of 1532 mesotheliomas. Collectively, we identified a cohort of four VHL-mutant clear cell mesotheliomas, including three peritoneal and one pleural tumors from three females and one male, with age range of 47-68 (median 63) years. Histologically, each tumor showed a microcystic to tubulopapillary architecture with prominent clear cells. By next-generation DNA sequencing, each of the four clear cell mesotheliomas harbored inactivating VHL mutations, while lacking other alterations typical of mesotheliomas such as BAP1, NF2, SETD2, CDKN2A, CDKN2B, TP53, and PTEN. By using low-pass whole genome sequencing on the index case and targeted next-generation sequencing on the remaining three cases, we identified extensive loss of heterozygosity throughout the genome but consistently sparing chromosomes 5, 7, and 20, characteristic of genomic near-haploidization. In summary, clear cell mesotheliomas were characterized by inactivating VHL mutations and genomic near-haploidization and appeared to represent a distinct clinicopathologic and molecular category of mesotheliomas. Our findings implicate VHL in the pathogenesis of a subset of mesotheliomas, particularly those with clear cell morphology.
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Neoplasias Pulmonares , Mesotelioma Maligno , Mesotelioma , Feminino , Masculino , Humanos , Pessoa de Meia-Idade , Idoso , Haploidia , Neoplasias Pulmonares/genética , Mesotelioma/genética , Mutação , Aberrações Cromossômicas , Genômica , Ubiquitina Tiolesterase/genética , Proteína Supressora de Tumor Von Hippel-Lindau/genéticaRESUMO
Gene fusions involving EWSR1 or FUS as the 5' partner have been reported in a diverse array of sarcomas. Here, we characterize the histopathology and genomics of six tumors harboring a gene fusion between EWSR1 or FUS and POU2AF3, an understudied, putative colorectal cancer predisposition gene. Striking morphologic features reminiscent of synovial sarcoma were observed including a biphasic appearance with variable fusiform to epithelioid cytomorphology and staghorn-type vasculature. RNA sequencing demonstrated variable breakpoints in EWSR1/FUS along with similar breakpoints in POU2AF3 that encompassed a 3' portion of this gene. For cases in which additional information was available, the behavior of these neoplasms was aggressive with local spread and/or distant metastases. Although further studies are needed to confirm the functional significance of our findings, POU2AF3 fusions to EWSR1 or FUS may define a novel type of POU2AF3-rearranged sarcomas with aggressive, malignant behavior.
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Sarcoma Sinovial , Sarcoma , Neoplasias de Tecidos Moles , Humanos , Proteína EWS de Ligação a RNA/genética , Sarcoma/genética , Neoplasias de Tecidos Moles/genética , Fusão Gênica , Hibridização in Situ Fluorescente , Biomarcadores Tumorais/genética , Proteínas de Fusão Oncogênica/genética , Proteínas de Neoplasias/genética , Proteína FUS de Ligação a RNA/genéticaRESUMO
Sinonasal myxoma (SNM) is a rare benign mesenchymal tumor that arises in the sinonasal cavity or maxilla and almost exclusively affects young children. Currently, it is considered a specific entity, but its molecular characteristics have not been reported. Lesions diagnosed as SNM and odontogenic myxoma/fibromyxoma were identified from the participating institutions, and the clinicopathologic features were recorded. Immunohistochemistry for ß-catenin was performed in all cases with available tissue. Next-generation sequencing was performed in all cases with SNM. Five patients with SNM were identified, including 3 boys and 2 girls with an age range of 20-36 months (mean: 26 months). The tumors were well defined, centered in the maxillary sinus, surrounded by a rim of woven bone, and composed of a moderately cellular proliferation of spindle cells oriented in intersecting fascicles in a variably myxocollagenous stroma that contained extravasated erythrocytes. Histologically, the tumors resembled myxoid desmoid fibromatosis. Three tested cases showed nuclear expression of ß-catenin. In 3 tumors, next-generation sequencing revealed intragenic deletions of APC exons 5-6, 9 and 15, or 16, respectively, with concurrent loss of the other wild-type copy of APC predicted to result in biallelic inactivation. The deletions were identical to those that occur in desmoid fibromatosis, and copy number analysis raised the possibility that they were germline. In addition, 1 case showed the possible deletion of APC exons 12-14, and another case exhibited a CTNNB1 p. S33C mutation. Ten patients with odontogenic myxoma/fibromyxoma were identified, including 4 women and 6 men (mean age: 42 years). Seven tumors involved the mandible and 3 the maxilla. Histologically, the tumors differed from SNM, and all cases lacked nuclear expression of ß-catenin. These findings suggest that SNM represents a myxoid variant of desmoid fibromatosis that often arises in the maxilla. The APC alterations might be germline, and therefore, genetic testing of the affected patients should be considered.
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Fibromatose Agressiva , Criança , Masculino , Humanos , Feminino , Pré-Escolar , Lactente , Adulto , Fibromatose Agressiva/genética , Fibromatose Agressiva/patologia , beta Catenina/genética , beta Catenina/análise , Mutação , Testes Genéticos , ÉxonsRESUMO
ABSTRACT: Some have proposed that melanomas in situ may be associated with fields of melanocytic dysplasia, particularly on sun-damaged skin, whereas others maintain that the atypical junctional melanocytic hyperplasia (MH) at the periphery of melanomas is simply background junctional MH of sun-damaged skin. The biological potential of atypical junctional MH at the periphery of melanomas is uncertain. We examined whether atypical junctional MH was intrinsic to the melanoma itself (ie, melanoma-associated field of melanocytic dysplasia) or was simply the predictable junctional MH associated with long-standing sun exposure. We retrospectively compared 106 cutaneous melanoma excisions without residual tumor with 105 nonmelanoma cutaneous tumor excisions (ie, basal cell or squamous cell carcinomas) without residual tumor. MH with atypia occurred significantly more frequently in melanoma than in nonmelanoma cutaneous tumor excisions (55.7% vs. 24.8%, P < 0.001). Solar elastosis occurred significantly less frequently in melanoma than in nonmelanoma cutaneous tumor excisions; 33.0% of melanoma excisions and 8.6% of nonmelanoma excision samples exhibited no solar elastosis, respectively (P < 0.001). After controlling for solar elastosis using multivariable linear regression, the association between MH with atypia and melanoma excisions remained significant (P < 0.001). Our results, therefore, demonstrate that melanomas were associated with atypical junctional MH that could not solely be accounted for by the extent of sun damage as measured by solar elastosis.
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Melanoma , Dermatopatias , Neoplasias Cutâneas , Humanos , Melanoma/patologia , Neoplasias Cutâneas/patologia , Hiperplasia , Neoplasia Residual/complicações , Estudos Retrospectivos , Luz Solar , Dermatopatias/patologia , Melanoma Maligno CutâneoRESUMO
ABSTRACT: Dysplastic nevi are an important subset of melanocytic nevi with atypical clinical, histopathologic, as well as genomic features compared with common acquired nevi. Dysplastic nevi are characterized histologically by both cytologic atypia and architectural disorder. The established criteria for cytologic atypia used to distinguish between low-grade and high-grade dysplastic nevi are often subjective, although there is a dearth of more objective, reproducible features of architectural disorder (eg, pagetoid scatter) that have been validated to differentiate between low-grade and high-grade dysplastic nevi. In this study, we sought to determine whether the presence and degree of follicular extension differ between low-grade and high-grade dysplastic nevi. We retrospectively examined the histopathologic features of 90 dysplastic nevi: 60 cases of low-grade dysplastic nevi (average age of 47.2 ± 18.1 years; 62.7% female) and 30 cases of high-grade dysplastic nevi (average age of 47.4 ± 19.8 years; 60.0% female). After examination, 50% of the cases of dysplastic nevi (n = 45) had hair follicles within the lesion, for which the presence and degree of follicular extension was then determined. Low-grade and high-grade dysplastic nevi do not differ significantly regarding the presence of follicular extension, average depth of follicular extension, and confluence of nevus cells along the follicular epithelium. Both low-grade and high-grade dysplastic nevi in our study demonstrated follicular extension that was superficial, that is, above the level of isthmus of hair follicles (insertion of sebaceous gland into hair follicle). Future studies are warranted to confirm these preliminary findings.
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Síndrome do Nevo Displásico , Nevo Pigmentado , Nevo , Neoplasias Cutâneas , Humanos , Feminino , Adulto , Pessoa de Meia-Idade , Idoso , Masculino , Síndrome do Nevo Displásico/patologia , Neoplasias Cutâneas/patologia , Estudos Retrospectivos , Nevo Pigmentado/patologia , HiperplasiaRESUMO
Androgen receptor (AR) inhibitor therapy is a developing treatment for AR-positive breast cancer (BC) with ongoing clinical trials. AR splice variant-7 (AR-V7) is a truncated variant of AR that leads to AR inhibitor therapy resistance in prostate cancer; recent studies have identified AR-V7 in BC and theorized that AR-V7 can have a similar impact. This study assessed the prevalence and clinicopathologic features associated with AR-V7 in a large BC cohort. BC samples were evaluated by MSK-Fusion targeted RNAseq for AR-V7 detection and MSK-IMPACT targeted DNAseq, including triple-negative tumors with no driver alteration and estrogen receptor-positive/ESR1 wildtype tumors progressing on therapy. Among 196 primary and metastatic/recurrent cases (196 RNAseq, 194DNAseq), 9.7% (19/196) were AR-V7 positive and 90.3% (177/196) AR-V7 negative. All AR-V7 positive BC were AR-positive by immunohistochemistry (19/19). The prevalence of AR-V7 by receptor subtype (N = 189) was: 18% (12/67) in ER-/PgR-/HER2-negative BC, 3.7% (4/109) in ER-positive/HER2-negative BC, and 15.4% (2/13) in HER2-positive BC; AR-V7 was detected in one ER-positive/HER2-unknown BC. Apocrine morphology was observed in 42.1% (8/19) of AR-V7 positive BC and 3.4% (6/177) AR-V7 negative BC (P < 0.00001). Notably, AR-V7 was detected in 2 primary BC and 7 metastatic/recurrent BC patients with no prior endocrine therapy. We conclude that positive AR IHC and apocrine morphology are pathologic features that may indicate testing for AR-V7 is warranted in both primary and metastatic BC in the appropriate clinical context. The study findings further encourage the assessment of AR-V7 as a predictive biomarker for AR antagonist benefit in ongoing clinical BC trials.
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Neoplasias da Mama , Receptores Androgênicos , Neoplasias da Mama/genética , Feminino , Humanos , Recidiva Local de Neoplasia , Isoformas de Proteínas/uso terapêutico , Receptores Androgênicos/genéticaRESUMO
Pancreatic neoplasms are heterogenous and have traditionally been classified by assessing their lines of cellular differentiation using histopathologic methods, particularly morphologic and immunohistochemical evaluation. These methods frequently identify overlapping differentiation along ductal, acinar, and neuroendocrine lines, raising diagnostic challenges as well as questions regarding the relationship of these neoplasms. Neoplasms with acinar differentiation, in particular, frequently show more than one line of differentiation based on immunolabeling. Genome methylation signatures, in contrast, are better conserved within cellular lineages, and are increasingly used to support the classification of neoplasms. We characterized the epigenetic relationships between pancreatoblastomas, acinar cell carcinomas (including mixed variants), pancreatic neuroendocrine tumors, solid pseudopapillary neoplasms, and pancreatic ductal adenocarcinomas using a genome-wide array platform. Using unsupervised learning approaches, pancreatic neuroendocrine tumors, solid pseudopapillary neoplasms, ductal adenocarcinomas, and normal pancreatic tissue samples all localized to distinct clusters based on their methylation profiles, whereas all neoplasms with acinar differentiation occupied a broad overlapping region located between the predominantly acinar normal pancreatic tissue and ductal adenocarcinoma clusters. Our data provide evidence to suggest that acinar cell carcinomas and pancreatoblastomas are similar at the epigenetic level. These findings are consistent with genomic and clinical observations that mixed acinar neoplasms are closely related to pure acinar cell carcinomas rather than to neuroendocrine tumors or ductal adenocarcinomas.
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Carcinoma de Células Acinares , Neoplasias Pancreáticas , Carcinoma de Células Acinares/genética , Carcinoma de Células Acinares/patologia , Epigênese Genética , Humanos , Pâncreas/metabolismo , Neoplasias Pancreáticas/patologiaRESUMO
Activation of the tyrosine kinase receptor IGF1R is targetable with existing tyrosine kinase inhibitors (TKIs) and monoclonal antibodies, but mutations in IGF1R have not been systematically characterized. Pan-cancer analysis of 326,911 tumors identified two distinct, activating non-frameshift insertion hotspots in IGF1R, which were significantly enriched in adenoid cystic carcinomas (ACCs). IGF1R alterations from 326,911 subjects were analyzed by variant effect prediction class, position within the gene, and cancer type. 6502 (2.0%) samples harbored one or more alterations in IGF1R. Two regions were enriched for non-frameshift insertions: codons 663-666 at the hinge region of the fibronectin type 3 domain and codons 1034-1049 in the tyrosine kinase domain. Hotspot insertions were highly enriched in ACCs (27.3-fold higher than in the remainder of the pan-cancer dataset; P = 2.3 × 10-17). Among salivary gland tumors, IGF1R hotspot insertions were entirely specific to ACCs. IGF1R alterations were most often mutually exclusive with other ACC drivers (9/15, 60%). Tumors with non-frameshift hotspot IGF1R insertions represent a novel, potentially targetable subtype of ACC. Additional studies are needed to determine whether these patients respond to existing IGF1R inhibitors.
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Carcinoma Adenoide Cístico , Neoplasias das Glândulas Salivares , Humanos , Carcinoma Adenoide Cístico/genética , Carcinoma Adenoide Cístico/patologia , Fibronectinas , Neoplasias das Glândulas Salivares/genética , Neoplasias das Glândulas Salivares/patologia , Inibidores de Proteínas Quinases , Anticorpos Monoclonais , Receptor IGF Tipo 1/genéticaRESUMO
Correct use of statistical methods is important to ensure the reliability and value of the published experimental pathology literature. Considering increasing interest in the quality of statistical reporting in pathology, the statistical methods used in 10 recent issues of the American Journal of Pathology were reviewed. The statistical tests performed in the articles were summarized, with attention to their implications for contemporary pathology research and practice. Among the 195 articles identified, 93% reported using one or more statistical tests. Retrospective statistical review of the articles revealed several key findings. First, tests for normality were infrequently reported, and parametric hypothesis tests were overutilized. Second, studies reporting multisample hypothesis tests (eg, analysis of variance) infrequently performed post hoc tests to explore differences between study groups. Third, correlation, regression, and survival analysis techniques were underutilized. On the basis of these findings, a primer on relevant statistical concepts and tests is presented, including issues related to optimal study design, descriptive and comparative statistics, and regression, correlation, survival, and genetic data analysis.
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Patologia/estatística & dados numéricos , Estatística como Assunto , Humanos , Publicações Periódicas como Assunto , Reprodutibilidade dos Testes , Projetos de Pesquisa , Estudos RetrospectivosRESUMO
OBJECTIVES: Endometrial serous carcinoma (EMSC) is an aggressive variant of uterine cancer with limited therapeutic options. We sought to define distinct clinicopathologic and genomic EMSC subgroups. METHODS: We retrospectively analyzed 2159 EMSC and 2346 endometrioid-type endometrial carcinomas (EEC) tissue specimens that had undergone comprehensive genomic profiling (CGP) via the FoundationOne CDx assay during routine clinical care. High tumor mutational burden (TMB) was defined as ≥10mut/Mb using the FDA-approved CDx cutoff for pembrolizumab. Microsatellite instability (MSI) was determined on 95 loci. Evidence of homologous recombination deficiency (HRD) was determined via genomic loss of heterozygosity (gLOH), a validated HRD detection method for predicting PARP inhibitor effectiveness in ovarian carcinoma. High gLOH was defined as ≥16%. RESULTS: A genomic analysis of 2159 EMSCs revealed a predominance of TP53 mutations, microsatellite stability, low tumor mutational burden (TMB), and recurrent alterations of PIK3CA, PPP2R1A, ERBB2, CCNE1, FBXW7 and MYC. Evidence of HRD via high gLOH was identified in 22% of EMSCs. BRCA1 and BRCA2 alterations, as well as unique SET (solid, pseudo-endometrioid, and transitional cell-like) variant morphology, were enriched in HRD-EMSC. There was an increased frequency of CCNE1 amplification, a lower prevalence of PIK3CA and PPP2R1A alterations, and no differences in HRD, MSI or TMB biomarker frequencies in patients of predicted African ancestry. EMSC exhibited distinct gene mutation frequencies and MSI, TMB and gLOH biomarker signatures compared to a cohort 2346 EEC. CONCLUSIONS: Molecularly defined subgroups provide a framework to test the susceptibility of EMSC to targeted therapies in specific genetic settings (e.g. HRD, PIK3CA, PPP2R1A, ERBB2, MYC, CCNE1).
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Carcinoma Endometrioide , Cistadenocarcinoma Seroso , Neoplasias do Endométrio , Biomarcadores Tumorais/genética , Carcinoma Endometrioide/genética , Classe I de Fosfatidilinositol 3-Quinases/genética , Cistadenocarcinoma Seroso/tratamento farmacológico , Cistadenocarcinoma Seroso/genética , Neoplasias do Endométrio/diagnóstico , Neoplasias do Endométrio/tratamento farmacológico , Neoplasias do Endométrio/genética , Feminino , Humanos , Instabilidade de Microssatélites , Mutação , Estudos RetrospectivosRESUMO
BACKGROUND: Among patients with breast carcinoma who have metastatic disease, 15%-30% will eventually develop brain metastases. We examined the genomic landscape of a large cohort of patients with breast carcinoma brain metastases (BCBMs) and compared it with a cohort of patients with primary breast carcinomas (BCs). MATERIAL AND METHODS: We retrospectively analyzed 733 BCBMs tested with comprehensive genomic profiling (CGP) and compared them with 10,772 primary breast carcinomas (not-paired) specimens. For a subset of 16 triple-negative breast carcinoma (TNBC)-brain metastasis samples, programmed death-ligand 1 (PD-L1) immunohistochemistry (IHC) was performed concurrently. RESULTS: A total of 733 consecutive BCBMs were analyzed. Compared with primary BCs, BCBMs were enriched for genomic alterations in TP53 (72.0%, 528/733), ERBB2 (25.6%, 188/733), RAD21 (14.1%, 103/733), NF1 (9.0%, 66/733), BRCA1 (7.8%, 57/733), and ESR1 (6.3%,46/733) (p < .05 for all comparisons). Immune checkpoint inhibitor biomarkers such as high tumor mutational burden (TMB-high; 16.2%, 119/733); high microsatellite instability (1.9%, 14/733); CD274 amplification (3.6%, 27/733); and apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like mutational signature (5.9%, 43/733) were significantly higher in the BCBM cohort compared with the primary BC cohort (p < .05 for all comparisons). When using both CGP and PD-L1 IHC, 37.5% (6/16) of patients with TNBC brain metastasis were eligible for atezolizumab based on PD-L1 IHC, and 18.8% (3/16) were eligible for pembrolizumab based on TMB-high status. CONCLUSION: We found a high prevalence of clinically relevant genomic alterations in patients with BCBM, suggesting that tissue acquisition (surgery) and/or cerebrospinal fluid for CGP in addition to CGP of the primary tumor may be clinically warranted. IMPLICATIONS FOR PRACTICE: This study found a high prevalence of clinically relevant genomic alterations in patients with breast carcinoma brain metastasis (BCBM), suggesting that tissue acquisition (surgery) and/or cerebrospinal fluid for comprehensive genomic profiling (CGP) in addition to CGP of the primary tumor may be clinically warranted. In addition, this study identified higher positive rates for FDA-approved immunotherapy biomarkers detected by CGP in patients with BCBM, opening a possibility of new on-label treatments. Last, this study noted limited correlation between tumor mutational burden and PD-L1 immunohistochemistry (IHC), which shows the importance of testing patients with triple-negative BCBM for immune checkpoint inhibitor eligibility with both PD-L1 IHC and CGP.
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Neoplasias Encefálicas , Neoplasias de Mama Triplo Negativas , Biomarcadores Tumorais/genética , Neoplasias Encefálicas/genética , Genômica , Humanos , Estudos RetrospectivosRESUMO
BCORL1 is a transcriptional corepressor homologous to BCOR. We describe 12 BCORL1-altered uterine sarcomas with striking resemblance to BCOR-altered endometrial stromal sarcoma (BCOR-ESS), including 5 with BCORL1 rearrangements (JAZF1-BCORL1, EP300-BCORL1, or internal BCORL1 rearrangement), 5 with inactivating BCORL1 mutations (T513fs*22, P600fs*1, R945*, R1196*, or R1265fs*4) and 2 with homozygous BCORL1 deletion. The median patient age was 57.5 years (range 33-79). An association with aggressive clinical behavior was identified. Diagnoses assigned prior to genomic testing varied: 7 tumors were previously diagnosed as ESS, 2 as high-grade uterine sarcomas, 2 as myxoid uterine leiomyosarcomas, and 1 as a uterine spindle cell neoplasm consistent with leiomyosarcoma. Tumors harbored frequent gelatinous, mucomyxoid-like appearance by gross examination and unique histology with morphological overlap with BCOR-ESS. Key microscopic features included (1) a spindle cell appearance, most often with at least focal myxoid stroma, (2) variable amounts of hypocellular fibromyxoid spindle areas with lower grade atypia and/or (3) variable amounts of epithelioid areas with higher grade atypia. Specifically, spindle and epithelioid components were present in 100 and 75% of sarcomas, respectively; myxoid stroma was identified in 83%, collagen plaques or fibrosis in 50%, and high-grade nuclear atypia was present in 42%. Like BCOR-ESS, 50% of BCORL1-altered sarcomas exhibited CDK4 amplification or CDKN2A loss. In contrast, 33% harbored NF1 alterations, while 25% had other alterations in the NF2-mTOR pathway, expanding potential therapeutic targets. In conclusion, inactivating BCORL1 genomic alterations may define a distinct subset of high-grade endometrial stromal sarcomas with biological overlap with BCOR-ESS, both of which may mimic myxoid leiomyosarcomas.
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Biomarcadores Tumorais/genética , Neoplasias do Endométrio/genética , Proteínas Repressoras/genética , Sarcoma do Estroma Endometrial/genética , Adulto , Idoso , Bases de Dados Factuais , Neoplasias do Endométrio/patologia , Feminino , Amplificação de Genes , Rearranjo Gênico , Predisposição Genética para Doença , Humanos , Pessoa de Meia-Idade , Técnicas de Diagnóstico Molecular , Mutação , Gradação de Tumores , Fenótipo , Valor Preditivo dos Testes , Estudos Retrospectivos , Sarcoma do Estroma Endometrial/patologiaRESUMO
AIMS: To characterise and compare the poorly understood clinicopathological and molecular characteristics of prostatic adenocarcinoma (PCa) in very young patients. METHODS AND RESULTS: We compared the clinicopathological and molecular characteristics of PCa diagnosed in 90 patients aged ≤45 years with those of PCa diagnosed in 200 patients of typical screening age (i.e. 60-65 years). Patients diagnosed at a younger age had a higher frequency of a family history of PCa and lower prostate-specific antigen (PSA) levels than those diagnosed at regular screening age. There were no statistically significant differences in clinical stage or pathological characteristics of the core biopsy specimens between the groups. Young patients had a higher frequency of Grade Group 1 disease at radical prostatectomy. A subset of 13 aggressive PCa cases from young patients underwent successful DNA-based next-generation sequencing. In all, 46.2% (6/13) had TMPRSS2 rearrangements and 23.1% (3/13) had relevant pathogenic variants in DNA damage repair genes, including a mismatch repair-deficient case with biallelic inactivation of MLH1. No statistically significant differences were observed in PCa-specific recurrence/progression between the younger and older patients, including after adjustment for clinical stage, PSA level, and Grade Group. CONCLUSIONS: In this study, the clinicopathological and molecular features of PCa diagnosed in young patients were comparable to those of PCa diagnosed in patients of screening age. Early-onset PCa cases were not enriched in any of the known molecular PCa subtypes in this small series.
Assuntos
Adenocarcinoma/diagnóstico , Próstata/patologia , Neoplasias da Próstata/diagnóstico , Adenocarcinoma/sangue , Adenocarcinoma/patologia , Adulto , Biópsia com Agulha de Grande Calibre , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Antígeno Prostático Específico/sangue , Neoplasias da Próstata/sangue , Neoplasias da Próstata/patologia , Estudos RetrospectivosRESUMO
PURPOSE: Modification of the trigger used to induce final oocyte maturation in in vitro fertilization (IVF) is a major strategy used to reduce the risk of ovarian hyperstimulation syndrome (OHSS). A novel trigger composed of 1500 IU of human chorionic gonadotropin (hCG) plus 450 IU of follicle-stimulating hormone (FSH) has been developed to reduce OHSS risk. This study compares outcomes of the novel trigger to conventional triggers used in high-risk OHSS patients undergoing IVF. METHODS: In this retrospective cohort study, IVF cycles at high risk for OHSS based on a serum estradiol > 5000 pg/ml on trigger day conducted between January 2008 and February 2016 were evaluated. Oocyte maturation was induced with the novel trigger (1500 IU hCG plus 450 IU FSH) or a conventional trigger [3300 IU hCG, gonadotropin-releasing hormone agonist (GnRHa) alone, or GnRHa plus 1500 IU hCG]. IVF cycle outcomes were compared. Trigger strategies were examined for associations with OHSS development using logistic regression. RESULTS: Among 298 eligible IVF cycles identified, there were no differences in oocyte maturation, fertilization, embryo quality, or pregnancy outcomes among all triggers. After adjusting for serum estradiol level and number of follicles, the novel trigger was associated with lower odds of OHSS symptom development compared to the 3300 IU hCG and GnRHa plus hCG 1500 IU triggers (p = 0.007 and 0.04, respectively). CONCLUSIONS: This study suggests that 1500 IU hCG plus 450 IU FSH may be associated with decreased OHSS symptoms compared to conventional triggers, while producing similar IVF and pregnancy outcomes. More important, this novel trigger may provide a superior alternative in down-regulated cycles and in patients with hypothalamic dysfunction where GnRHa triggers cannot be utilized.