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Angiomyolipoma (AML) is a neoplasm within the perivascular epithelioid cell tumor family that occurs somewhat frequently in the kidney. Most are indolent and discovered incidentally, with rare tumors demonstrating malignant clinical behavior. A small subset of renal AMLs with epithelioid features are associated with aggressive behavior, and may demonstrate morphologic overlap with renal cell carcinomas (e.g., clear cell renal cell carcinoma (RCC), TFE3-rearranged RCC). Prior studies of spindle cell and epithelioid AMLs have identified rare examples with underlying TFE3 gene fusions. TFE3 protein expression (demonstrated by immunohistochemistry) with no evidence of concurrent TFE3 rearrangements has been reported previously in 4/24 AMLs (17%) (Argani et al. Am J Surg Pathol 34:1395-1406, 2010). Currently, the relationship between TFE3 protein expression, TFE3 fusions, and expression of TFE3-mediated genes remains incompletely understood in renal epithelioid AMLs. We sought to explore these relationships using TFE3 break-apart fluorescence in situ hybridization (FISH) and TRIM63 RNA in situ hybridization (ISH) on epithelioid AMLs with moderate to strong TFE3 expression by immunohistochemistry. RNA sequencing (fusion panel) was performed on two cases with negative FISH results to assess for FISH-cryptic gene fusions. The series comprised five epithelioid AMLs from four patients (three women, one man) aged 13 to 76 years. All were considered positive for TFE3 by immunohistochemistry (2 + /3 + expression). TRIM63 ISH was performed on four specimens from three patients, yielding positive results in 3/3 tumors (100%) that were successfully analyzed. TFE3 break-apart FISH was performed on all samples, demonstrating a TFE3 rearrangement in only 1/4 tumors (25%). RNA sequencing demonstrated the absence of productive TFE3 gene fusions in three tumors with negative break-apart TFE3 FISH results. This study demonstrates that renal epithelioid AMLs overexpress TFE3 and TFE3-mediated genes (TRIM63) even in the absence of TFE3 rearrangements. This finding could be explained by functional upregulation of TFE3 secondary to activation of the mammalian target of rapamycin complex 1 (mTORC1). Expression of TFE3 and TRIM63 in this tumor type represents a potential pitfall, given the morphologic and immunophenotypic overlap between epithelioid AML and TFE3-altered renal cell carcinoma.
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Notch signaling can have either an oncogenic or tumor suppressive function in cancer depending on the cancer type and cellular context. While Notch can be oncogenic in early prostate cancer, we identified significant downregulation of the Notch pathway during prostate cancer progression from adenocarcinoma to neuroendocrine prostate cancer where it functions as a tumor suppressor. Activation of Notch in neuroendocrine and Rb1/Trp53-deficient prostate cancer models led to phenotypic conversion towards a more indolent non-neuroendocrine state with glandular features and expression of luminal lineage markers. This was accompanied by up-regulation of MHC and type I interferon and immune cell infiltration. Overall, these data support Notch signaling as a suppressor of neuroendocrine differentiation in advanced prostate cancer and provides insights into how Notch signaling influences lineage plasticity and the tumor microenvironment.
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Ovarian-type epithelial tumors involving the testis and paratestis are rare, with clear cell carcinomas (CCC) one of the least frequent. We report our experience with 4 müllerian-type (MT) CCCs presenting as testicular/scrotal masses and arising in the paratestis (n=2) and seminal vesicle (n=2; well supported in 1 case and likely in the other). In addition, we document 3 cases of papillary CCC exclusively within the rete testis (RTCCC) and seminiferous tubules and differing from the MT tumors. The patients with MTCCC were 24 to 85 years old (median, 42 y), and 2 had metastases at presentation. The 2 originating in the paratestis were associated with other MT tumors, an endometrioid borderline tumor and a papillary serous borderline tumor. The other 2 MTCCCs likely involved the testis via extension from seminal vesicle primaries through the vasa deferentia. All MTCCCs showed typical features, including tubules, simple papillae with hyalinized cores, and solid nests of polygonal clear cells with occasional hobnail features. Both paratesticular primaries showed sarcomatoid foci with tumor-associated neutrophilic infiltrates. The 3 RTCCCs presented in 54-, 57-, and 60-year-old men as testicular masses; they showed intrarete arborizing papillary growth with nonhyalinized fibrous cores and piled-up, solid foci, lacked hobnail cells, and expressed carbonic anhydrase IX (2/2) and CD10 (2/2) but not CA125, unlike the MTCCCs. On follow-up, 2 patients with MTCCC died of metastatic tumor (4 and 13.5 mo), a third developed ileal and retroperitoneal metastases at 13 months; and the fourth died at 13.5 months of unspecified cause. Follow-up of 2 patients with RTCCCs showed 1 disease free at 8 months and another alive with unknown disease status at 13 years. We conclude that CCCs involving the testis may either be of MT with often aggressive courses or show some features of renal tumors, with confinement to the rete testis and indolent behavior.
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AIMS: Urothelial carcinoma (UC) demonstrates significant molecular and histologic heterogeneity. The WHO 2022 classification has hinted at adding molecular signatures to the morphologic diagnosis. As morphology and associated molecular repertoire may potentially translate to choices of and response to therapy and relapse rate, broader acceptability of recognizing these key features among uropathologists is needed. This prompted an international survey to ascertain the practice patterns in classical/subtype UC among uropathologists across the globe. METHODS AND RESULTS: A survey instrument was shared among 98 uropathologists using SurveyMonkey software. Anonymized respondent data were analysed. The response rate was 85%. A majority were in concordance with the profiles of luminal (93%) and basal (82%) types. Opinion on the FGFR3 testing platform was variable. While 95% concurred that TERT promoter mutation is the key driver in UC, 72% had the opinion that APOBEC mutagenesis is the main signature in muscle invasive bladder cancer (MIBC). Uropathologists have divergent opinions on MIBC and ERCC2 mutations. Among the participants, 94% would quantify aggressive micropapillary and sarcomatoid histology, while 88% would reevaluate another transurethral resection of the bladder tumour specimen in nonmuscle invasive tumour with micropapillary, small cell, or sarcomatoid histology. A leading number agreed to specific molecular signatures of micropapillary (93%), plasmacytoid (97%), and small cell (86%) subtypes. Ninety-six percent of participants agreed that a small-cell component portends a more aggressive course and should be treated with neoadjuvant chemotherapy and 63% would perform HER2/neu testing only on oncologist's request in advanced tumours. Ninety percent agreed that microsatellite instability testing, although not a standard protocol, should be considered in young patients with upper tract UC. Eighty-six percent agreed that UC with high tumour mutational burden would be a better candidate for immunotherapy. CONCLUSION: In the era of precision medicine, enhanced understanding of molecular heterogeneity of UC will contribute to better therapeutic options, novel biomarker discovery, innovative management protocols, and outcomes. Our survey provides a broad perspective of pathologists' perceptions and experience regarding incorporation of histomolecular approaches to "personalize" therapy. Due to variable clinical adoption, there is a need for additional data using uniform study criteria. This will drive generation of best practice guidelines in this area for widespread and consistent clinical utility.
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Spermatocytic tumors are rare testicular tumors occurring predominantly in older men. Most show a classical tripartite morphology (different from seminoma) and are benign. However, well-documented cases of malignant spermatocytic tumors exist. Our previous work showed that a subset of spermatocytic tumors exhibiting TP53 mutations, DNA methylation profiles closer to seminomas, and/or gains in chromosome 12p exhibited aggressive characteristics, including sarcomatoid transformation and metastatic dissemination. The microRNA-371-373 cluster is a promising biomarker which is upregulated in non-teratoma germ cell tumors with malignant behavior. In this work we analyze microRNAs-371-373 b y quantitative real-time polymerase chain reaction in 18 spermatocytic tumors representative of the whole clinical spectrum, including 6 with aggressive features (sarcomatoid transformation, metastases, or gains in chromosome 12p). The levels of microRNAs-371-373 were significantly higher in non-teratoma germ cell tumors compared to spermatocytic tumors, overall (p < 0.0001). Importantly, levels of microRNA-371-373 were higher in spermatocytic tumors with aggressive features compared to non-aggressive neoplasms. The highest levels were observed in one tumor showing isochromosome 12p. These results further support our previous findings that a subset of spermatocytic tumors are intermediate between so-called type II and type III germ cell tumors and that embryonic microRNAs play a role in aggressive behavior in spermatocytic tumors. Accordingly, this subset of tumors may behave aggressively and require close follow up. In the future, this opens an opportunity for microRNA testing in serum of spermatocytic tumor patients for risk stratification purposes.
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Biomarcadores Tumorais , MicroRNAs , Neoplasias Embrionárias de Células Germinativas , Neoplasias Testiculares , Humanos , Masculino , MicroRNAs/genética , Neoplasias Testiculares/genética , Neoplasias Testiculares/patologia , Neoplasias Embrionárias de Células Germinativas/genética , Neoplasias Embrionárias de Células Germinativas/patologia , Adulto , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/análise , Pessoa de Meia-Idade , Idoso , Reação em Cadeia da Polimerase em Tempo Real , Regulação Neoplásica da Expressão Gênica , Adulto JovemRESUMO
Postchemotherapy postpubertal-type yolk sac tumors (YST) with glandular and solid phenotypes are aggressive and commonly resistant to systemic chemotherapy. These neoplasms show morphologic features that significantly overlap with those of somatic carcinomas with "enteroblastic" or "fetal" phenotype (the preferred terminology depends on the site of origin). They often present as late or very late recurrences, and their diagnosis is challenging because they frequently affect patients in an age group at risk for carcinomas of somatic origin. Recently, we incidentally identified examples of postchemotherapy glandular and solid YST with "enteroblastic" phenotypes and nuclear expression of beta-catenin, prompting us to further evaluate the prevalence of this phenomenon. We found nuclear expression of beta-catenin in 10 (29%) of 34 such tumors. A subset of cases with nuclear beta-catenin expression was further analyzed with a DNA sequencing panel (n = 6) and fluorescence in situ hybridization for isochromosome 12p [i(12p); n = 5]. Sequencing identified exon 3 CTNNB1 variants in 3 (50%) of 6 analyzed cases, and fluorescence in situ hybridization was positive for i(12p) in 5 of 5 cases. In conclusion, a significant subset of postchemotherapy YST with glandular or solid architecture and "enteroblastic" phenotype demonstrates beta-catenin alterations, suggesting that activation of Wnt signaling may play a role in the progression of these neoplasms. Moreover, nuclear beta-catenin expression in these tumors represents a potential diagnostic pitfall given that carcinomas of true somatic origin with overlapping morphology may also be positive for this marker.
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Tumor do Seio Endodérmico , beta Catenina , Humanos , beta Catenina/genética , beta Catenina/metabolismo , Tumor do Seio Endodérmico/patologia , Tumor do Seio Endodérmico/tratamento farmacológico , Tumor do Seio Endodérmico/genética , Tumor do Seio Endodérmico/metabolismo , Feminino , Masculino , Hibridização in Situ Fluorescente , Criança , Pré-Escolar , Adolescente , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/análise , Adulto , Adulto Jovem , Lactente , FenótipoRESUMO
Introduction: Self-medication is a prevalent behavior with significant health implications. Understanding its psychosocial determinants can inform preventative strategies and interventions. Methods: We evaluated the psychometric properties of the Self-Medication Behavior Inventory (SMBI-9) in a binational study with 779 Colombian and Mexican participants. Concurrent validity was assessed through correlations with related inventories, and confirmatory factor analysis tested the proposed four-factor model. Results: The SMBI-9 demonstrated high model fit (CFI = 0.995, TLI = 0.991) and invariance across countries. The factors-Social Influence, Attitude toward Medicine, Avoidance, and Prevention-varied significantly with knowledge of medicine, schooling, health insurance status and gender, underscoring the role of social and personal beliefs in self-medication practices. Discussion: SMBI-9 emerged as a reliable tool for capturing the multifaceted nature of self-medication behaviors. Findings highlight the influence of social norms and personal attitudes, suggesting targeted approaches for behavioral interventions.
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Neoplasias Ovarianas , Proteína FUS de Ligação a RNA , Tumores do Estroma Gonadal e dos Cordões Sexuais , Neoplasias Testiculares , Humanos , Feminino , Tumores do Estroma Gonadal e dos Cordões Sexuais/genética , Tumores do Estroma Gonadal e dos Cordões Sexuais/patologia , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Masculino , Neoplasias Testiculares/genética , Neoplasias Testiculares/patologia , Neoplasias Testiculares/cirurgia , Proteína FUS de Ligação a RNA/genética , Biomarcadores Tumorais/genética , Proteínas de Fusão Oncogênica/genéticaRESUMO
Vasculogenic mesenchymal lesions (VMLs) of germ cell tumor origin are thought to originate in postpubertal-type yolk sac tumor components and include a spectrum of lesions from teratoma with vasculogenic stroma (TVS), to low and high-grade vasculogenic mesenchymal tumors (VMTs). VMLs exhibit rudimentary to well-developed neoplastic vessels within primitive mesenchyme, being considered a neoplastic reiteration of embryonic vasculogenesis in the splanchnic mesoderm of the yolk sac. They occur in patients with primary mediastinal germ cell tumors after chemotherapy, and a subset progresses to "somatic-type" sarcomas [including angiosarcoma (AS)], with high-grade VMTs likely portending a higher risk. Recently, we encountered a low-grade VMT that progressed to metastatic AS during follow-up. In this case, both the low-grade VMT and the subsequent AS demonstrated p53 overexpression, suggesting that p53 alterations may precede histopathologic transformation. To test this hypothesis, we evaluated neoplasms representing the entire spectrum of VMLs using p53 immunohistochemistry (IHC; clone DO-7, Dako). Overexpression was defined as nuclear positivity in > 80% of neoplastic cells. Because the distinction between high-grade VMT and AS can be subjective in some cases, they were grouped together in a single category. Thirty-nine VMLs were assessed: 16 high-grade VMT/AS, 19 low-grade VMT, and 4 TVS. Patient age ranged from 19 to 46 years (mean, 30 years; male = 97%). Four high-grade VMT/AS and one low-grade VMT showed p53 overexpression (5/39 VMLs, 13%; 4/16 high-grade VMT/AS, 25%). These tumors included 1 unequivocal AS and 1 high-grade VMT/AS with progression to rhabdomyosarcoma. The only low-grade VMT with p53 overexpression demonstrated progression to AS. Another high-grade VMT that progressed to sarcoma demonstrated p53 overexpression in the sarcoma component, but it was excluded because the VMT was not represented in the material available at the time of the study. Lesions with intratumoral grade heterogeneity (classified based the highest grade), demonstrated more pronounced p53 overexpression in the high-grade components. P53 overexpression is associated with disease progression in a subset of VMTs and may precede morphologic transformation to sarcoma. Routine evaluation of VMTs with p53 IHC seems justified, with overexpressors likely requiring an close clinical surveillance.
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Biomarcadores Tumorais , Progressão da Doença , Neoplasias Embrionárias de Células Germinativas , Proteína Supressora de Tumor p53 , Adulto , Feminino , Humanos , Masculino , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/metabolismo , Imuno-Histoquímica , Neoplasias Embrionárias de Células Germinativas/patologia , Neoplasias Embrionárias de Células Germinativas/metabolismo , Neovascularização Patológica/patologia , Proteína Supressora de Tumor p53/análise , Proteína Supressora de Tumor p53/metabolismo , Adulto Jovem , Pessoa de Meia-IdadeAssuntos
Reparo de Erro de Pareamento de DNA , Prostatectomia , Neoplasias da Próstata , Humanos , Masculino , Neoplasias da Próstata/patologia , Neoplasias da Próstata/cirurgia , Reparo de Erro de Pareamento de DNA/genética , Idoso , Biópsia , Pessoa de Meia-Idade , Próstata/patologia , Próstata/cirurgia , Estudos ProspectivosRESUMO
We report a 40-year-old male presenting with right testicular pain. Following right orchiectomy demonstrating pT1bS0N0M0 teratoma with extensive necrosis, the patient opted for surveillance. With new retroperitoneal lymphadenopathy, the patient underwent a robotic-assisted laparoscopic retroperitoneal lymph node. After final pathology demonstrated extensive necrosis, the initial orchiectomy specimen was re-reviewed which revealed 60/40 ratio of non-seminomatous teratoma to nephroblastoma. Adult presentation of testicular nephroblastoma is exceedingly rare and such reports contribute to the understanding of adult teratoid Wilms tumor pathogenesis. This case emphasizes the need for comprehensive diagnostic approaches and further research into the pathophysiology of extrarenal teratoid Wilms tumors.
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The current WHO classification of testicular germ cell tumors is based on the pathogenesis of the tumors driven by different genomic events. The germ cell neoplasia in situ is the precursor lesion for all malignant germ cell tumors. The current understanding of pathogenesis is that the developmental and environmental factors with the erasure of parental genomic imprinting lead to the development of abnormal gonocytes that settle in the "spermatogonial Niche" in seminiferous tubules. The abnormal primordial germ cells in the seminiferous tubules give rise to pre-GCNIS cells under the influence of TPSY and OCT4 genes. The whole genome duplication events give rise to germ cell neoplasia in situ, which further acquires alterations in 12p along with NRAS and KRAS mutations to produce seminoma. A subset of seminomas acquires KIT mutation and does not differentiate further. The remaining KIT-stable seminomas differentiate to nonseminomatous GCTs after obtaining recurrent chromosomal losses, epigenetic modification, and posttranscriptional regulation by multiple genes. Nonseminomatous germ cell tumors also develop directly from differentiated germ cell neoplasia in situ. TP53 pathway with downstream drivers may give rise to somatic-type malignancies of GCT. The GCTs are remarkably sensitive to cisplatin-based combination chemotherapy; however, resistance to cisplatin develops in up to 8% of tumors and appears to be driven by TP53/MDM2 gene mutations. Serum and Plasma miRNAs show promise in diagnosing, managing, and following up on these tumors. The mechanisms underlying the development of most tumors have been elucidated; however, additional studies are required to pinpoint the events directing specific characteristics. Advances in identifying specific molecular markers have been seen recently and may be adopted as gold standards in the future.
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Neoplasias Embrionárias de Células Germinativas , Seminoma , Neoplasias Testiculares , Masculino , Humanos , Seminoma/metabolismo , Cisplatino , Neoplasias Testiculares/patologia , Neoplasias Embrionárias de Células Germinativas/genéticaRESUMO
BACKGROUND: Carcinomas of the seminal vesicle are exceedingly rare, with a limited number of cases described in the literature. Reported cases span a relatively wide morphological spectrum, and their genomic features remain unexplored. DESIGN: In this study, we interrogated five primary epithelial neoplasms of the seminal vesicle using a targeted DNA sequencing platform (OncoPanel, 447 genes). RESULTS: The tumours included one adenocarcinoma with intestinal phenotype presenting after external beam radiation (for prostatic adenocarcinoma), one carcinoma with Müllerian-type clear cell phenotype, two mucinous tumours resembling low-grade mucinous neoplasms of the appendix (LAMN) and one mucinous cystadenoma. The post-radiation mucinous adenocarcinoma had genomic findings consistent with bi-allelic inactivation of TP53, as well as multiple copy-number changes with regional and chromosomal arm-level copy-number losses. The Müllerian-type clear cell carcinoma exhibited a complex copy-number profile with numerous regional and arm-level copy-number changes, as well as focal amplification events, including copy-number gain of 8q and amplification of a region within 20q13. Both low-grade mucinous tumours resembling LAMN harboured hot-spot gain-of-function KRAS variants (p.G12V and p.G13D) as the only genomic alteration. No genomic alterations were detected inthe lesion diagnosed as mucinous cystadenoma. CONCLUSION: Our results suggest that primary low-grade mucinous neoplasms of the seminal vesicle may represent a distinct entity equivalent to appendiceal counterparts, driven by gain-of-function variants of RAS GTPases. The remaining tumours showed genomic features that closely resembled those of neoplasms with comparable phenotypes and/or biological characteristics arising in other sites, suggesting that they could be managed similarly, with special considerations related to their anatomical location.
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Neoplasias Císticas, Mucinosas e Serosas , Neoplasias Epiteliais e Glandulares , Glândulas Seminais , Humanos , Masculino , Adulto , Idoso , Adulto Jovem , Pessoa de Meia-Idade , Proteínas Proto-Oncogênicas p21(ras)/genética , Glândulas Seminais/patologia , Neoplasias Epiteliais e Glandulares/genética , Neoplasias Epiteliais e Glandulares/patologia , Adenocarcinoma/genética , Adenocarcinoma/patologia , Cistadenoma Mucinoso/genética , Cistadenoma Mucinoso/patologia , Neoplasias Císticas, Mucinosas e Serosas/genética , Neoplasias Císticas, Mucinosas e Serosas/patologiaRESUMO
Biphasic papillary renal cell carcinoma (synonymous with biphasic squamoid alveolar renal cell carcinoma) is considered within the spectrum of papillary renal cell carcinoma (PRCC). With < 70 reported cases of biphasic PRCC, there is limited data on the pathologic spectrum and clinical course. Seventeen biphasic PRCC cases and 10 papillary adenomas with similar biphasic morphology were assessed. The mean age of the biphasic PRCC patients was 62 years (male to female ratio of 1.8:1), from 10 partial nephrectomies, 6 radical nephrectomies, and 1 biopsy. The mean tumor size was 3.6 cm (range 1.6-8 cm), with 24% showing multifocality. Fifteen out of 17 cases were limited to the kidney (one of which was staged as pT2a but had lung metastases at diagnosis) and 2/17 cases were staged as T3a. All tumors showed typical biphasic morphology with an extent of squamoid foci widely variable from 10 to 95%. Emperipolesis was identified in 88% of cases. All biphasic PRCC tested exhibited positivity for PAX8 (16/16), keratin 7 (17/17), EMA (15/15), AMACR (17/17), and vimentin (12/12) in both large and small cells; cyclin D1 was only expressed in the large cells (16/16). The 10 papillary adenomas showed a similar immunoprofile to biphasic PRCC. NGS testing performed on 13 biphasic PRCC revealed 4 (31%) harboring MET SNVs. In 1/5 (20%) papillary adenomas, a pathogenic MET SNV was identified. Biphasic PRCC is rare with a generally similar immunoprofile to "type 1" PRCC but with notable strong positivity for cyclin D1 in the large cell component. Although most of the biphasic PRCC cases were of small size, low stage, and with an indolent behavior, one patient had metastatic disease and one patient died of the disease.
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Adenoma , Carcinoma de Células Renais , Neoplasias Renais , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Carcinoma de Células Renais/patologia , Neoplasias Renais/patologia , Ciclina D1 , Biomarcadores Tumorais , Imuno-HistoquímicaRESUMO
Prepubertal-type teratomas are uncommon, especially in postpubertal male patients. We document a case of a 28-year-old man with a lifelong history of bilateral testicular masses who presented with scrotal fistulas and no clinical evidence of extratesticular disease. Bilateral radical orchiectomies demonstrated large bilateral solid and cystic masses that contained grossly visible hairs. Microscopically, both tumors consisted of pure teratomas comprising a mixture of mature tissues derived from the three embryonic layers. Germ cell neoplasia in situ was not identified, and fluorescence in situ hybridization studies demonstrated the absence of i(12p), supporting a diagnosis of prepubertal-type teratoma. The absence of metastases in this patient with longstanding tumors highlights the benign nature of prepubertal-type teratomas affecting postpubertal patients. Furthermore, this case illustrates that at least a subset of prepubertal-type teratomas seen in adult men represent a late diagnosis of a largely pediatric entity. Additionally, we performed a comprehensive review of the literature on this topic.
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Teratoma , Neoplasias Testiculares , Humanos , Masculino , Teratoma/patologia , Teratoma/diagnóstico , Adulto , Neoplasias Testiculares/patologia , Neoplasias Testiculares/diagnóstico , Orquiectomia , Hibridização in Situ FluorescenteRESUMO
The differential diagnosis for oncocytic renal tumors spans the spectrum from benign entities to more aggressive renal cell carcinomas (RCC). Recent work has characterized a provisional renal oncocytic neoplasm, namely the low-grade oncocytic tumor (LOT), which demonstrates overlapping morphologic features with oncocytoma and chromophobe RCC, but also has a unique immunoprofile (ie, diffusely positive for KRT7, negative for KIT) and a high rate (80% to 100%) of mTOR pathway gene alterations. Given the diagnostic overlap among oncocytic tumors, we looked for concordance between mTOR pathway mutations and LOT. Thirty low-grade renal oncocytic neoplasms underwent histologic review and immunohistochemistry for KRT7 and KIT. Tumors were classified as "determinate" (eg, LOT) for tumors with solid, nested or vaguely tubular growth and diffuse KRT7 staining and negative KIT, or "indeterminate" if the morphology and/or immunostains did not fully support a definitive LOT diagnosis. Next-generation sequencing was performed without any knowledge of the diagnoses, and identified mTOR pathway mutations in 80% (12/15) of the determinate tumors, compared with 7% (1/15) in the indeterminate group. One determinate tumor was reclassified as papillary RCC (MTOR mutation negative) and 6 indeterminate tumors were confirmed to be oncocytoma (N = 4), clear cell RCC or papillary RCC with reverse polarity, respectively. Overall, integration of morphology, immunohistochemistry, and molecular data enabled a final definitive diagnosis for 70% of tumors (21 of the total 30), with a high concordance (93%) for LOT specifically in the determinate group; the remaining 9 tumors (30%) were classified as renal oncocytic neoplasm, not otherwise specified.
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Adenoma Oxífilo , Carcinoma de Células Renais , Neoplasias Renais , Humanos , Carcinoma de Células Renais/diagnóstico , Carcinoma de Células Renais/genética , Adenoma Oxífilo/diagnóstico , Adenoma Oxífilo/genética , Neoplasias Renais/diagnóstico , Neoplasias Renais/genética , Mutação , Diagnóstico Diferencial , Serina-Treonina Quinases TOR/genética , Biomarcadores Tumorais/genéticaRESUMO
A small subset of testicular sex cord-stromal tumors, designated as Sertoli-stromal cell tumors (SSCTs), comprises a mixture of Sertoli, spindle, and/or Leydig cells. The clinicopathologic features of these tumors have not been studied in any detail, and their molecular features are unknown. We, therefore, assessed the morphologic and genomic features of 14 SSCTs, including 1 tumor with features similar to the ovarian Sertoli-Leydig cell tumor (SLCT) with retiform tubules. The median age of the patients was 24 years (range, 10-55 years), and the median tumor size was 2.3 cm (range, 0.7-4.7 cm). All tumors showed Sertoli-like sex cord cells arranged in variably developed tubular structures, typically also forming nests and cords. These imperceptibly blended with a neoplastic spindle cell stroma or, in the SLCT, vacuolated to eosinophilic Leydig cells. Genomic analysis demonstrated the presence of a hotspot loss-of-function DICER1 mutation in the SLCT (patient 1) and hotspot gain-of-function CTNNB1 mutations in the tumors of patients 2 and 3, with both CTNNB1 variants being interpreted as possible subclonal events. The mutations were the only relevant findings in the tumors of patients 1 and 2, whereas the tumor of patient 3 harbored concurrent chromosomal arm-level and chromosome-level copy number gains. Among the remaining 11 tumors, all of those that had interpretable copy number data (9 tumors) harbored multiple recurrent chromosomal arm-level and chromosome-level copy number gains suggestive of a shift in ploidy without concurrent pathogenic mutations. The results of the present study suggest that CTNNB1 mutations (likely subclonal) are only rarely present in SSCTs; instead, most of them harbor genomic alterations similar to those seen in testicular sex cord-stromal tumors with pure or predominant spindle cell components. A notable exception was a testicular SLCT with morphologic features identical to the ovarian counterpart, which harbored a DICER1 mutation.
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Neoplasias Ovarianas , Tumor de Células de Sertoli-Leydig , Tumores do Estroma Gonadal e dos Cordões Sexuais , Neoplasias Testiculares , Masculino , Feminino , Humanos , Criança , Adolescente , Adulto Jovem , Adulto , Pessoa de Meia-Idade , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Tumor de Células de Sertoli-Leydig/genética , Tumor de Células de Sertoli-Leydig/patologia , Neoplasias Testiculares/patologia , Tumores do Estroma Gonadal e dos Cordões Sexuais/genética , Tumores do Estroma Gonadal e dos Cordões Sexuais/química , Tumores do Estroma Gonadal e dos Cordões Sexuais/patologia , Aberrações Cromossômicas , Ribonuclease III/genética , RNA Helicases DEAD-box/genéticaRESUMO
Testicular sex cord-stromal tumors (TSCSTs) are relatively rare, representing ~5% of testicular neoplasms overall. Historically, TSCSTs have been classified into 3 major entities: Leydig cell tumor, Sertoli cell tumor, and granulosa cell tumor. In recent years, immunophenotypic and molecular analyses have led to a more detailed understanding of the biological and genomic features of these neoplasms, resulting in the description of new entities, some of which have been included in the latest WHO classification. This review summarizes novel histopathologic, clinical, and molecular findings that may lead to a reappraisal of established concepts and help improve the diagnosis and clinical management of TSCSTs in the coming years.