RESUMO
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.
RESUMO
In summary, the study's investigation of KMT2C and TSC2 variants in ACD-RCC marks a significant advancement in comprehending this distinct kidney tumor. By illuminating the molecular landscape of ACD-RCC, the research sets the stage for future studies aimed at revealing the complex mechanisms driving tumor development and progression. This understanding could eventually lead to more effective management and treatment strategies for renal cancer patients.
RESUMO
AIMS: Renal cell carcinoma (RCC) with clear cells and psammoma-like calcifications would often raise suspicion for MITF family translocation RCC. However, we have rarely encountered tumours consistent with clear cell RCC that contain focal psammomatous calcifications. METHODS AND RESULTS: We identified clear cell RCCs with psammomatous calcifications from multiple institutions and performed immunohistochemistry and fluorescence and RNA in-situ hybridisation (FISH and RNA ISH). Twenty-one tumours were identified: 12 men, nine women, aged 45-83 years. Tumour size was 2.3-14.0 cm (median = 6.75 cm). Nucleolar grade was 3 (n = 14), 2 (n = 4) or 4 (n = 3). In addition to clear cell pattern, morphology included eosinophilic (n = 12), syncytial giant cell (n = 4), rhabdoid (n = 2), branched glandular (n = 1), early spindle cell (n = 1) and poorly differentiated components (n = 1). Labelling for CA9 was usually 80-100% of the tumour cells (n = 17 of 21), but was sometimes decreased in areas of eosinophilic cells (n = 4). All (19 of 19) were positive for CD10. Most (19 of 20) were positive for AMACR (variable staining = 20-100%). Staining was negative for keratin 7, although four showed rare positive cells (four of 20). Results were negative for cathepsin K (none of 19), melan A (none of 17), HMB45 (none of 17), TFE3 (none of 5), TRIM63 RNA ISH (none of 13), and TFE3 (none of 19) and TFEB rearrangements (none of 12). Seven of 19 (37%) showed chromosome 3p deletion. One (one of 19) showed trisomy 7 and 17 without papillary features. CONCLUSIONS: Psammomatous calcifications in RCC with a clear cell pattern suggests a diagnosis of MITF family translocation RCC; however, psammomatous calcifications can rarely be found in true clear cell RCC.
Assuntos
Calcinose , Carcinoma de Células Renais , Neoplasias Renais , Feminino , Humanos , Carcinoma de Células Renais/patologia , Neoplasias Renais/patologia , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/genética , Translocação Genética , Aberrações Cromossômicas , Biomarcadores Tumorais/genéticaRESUMO
A small subset of male germ cell tumors (GCT) demonstrates overgrowth of histologic components that resemble somatic malignancies (e.g., sarcoma, carcinoma). The presence of so-called "somatic-type" malignancies (SM) in GCT has been associated with chemotherapy-resistance and poor clinical outcomes in prior studies. However, the molecular characteristics of these tumors remain largely undescribed. In this study, we performed a multi-platform molecular analysis of GCTs with SM diagnosed in 36 male patients (primary site: testis, 29 and mediastinum, 7). The most common histologic types of SM were sarcoma and embryonic-type neuroectodermal tumor (ENT, formerly known as "PNET"), present in 61% and 31% of cases, respectively. KRAS and TP53 mutations were identified by DNA sequencing in 28% of cases each, with enrichment of TP53 mutations in mediastinal tumors (86%). Gains in the short arm of chromosome 12 were seen in 91% of cases, likely reflecting the presence of isochromosome 12p. Numerous copy number changes indicative of widespread aneuploidy were found in 94% of cases. Focal homozygous deletions and amplifications were also detected, including MDM2 amplifications in 16% of cases. Sequencing of paired samples in 8 patients revealed similar mutational and copy number profiles in the conventional GCT and SM components. Oncogenic gene fusions were not detected using RNA sequencing of SM components from 9 cases. DNA methylation analysis highlighted the distinct methylation profile of SM components that sets them apart from conventional GCT components. In conclusion, GCT with SM are characterized by widespread aneuploidy, a distinct epigenetic signature and the presence of mutations that are otherwise rare in testicular GCT without SM. The similarity of the mutational and DNA methylation profiles of different histologic types of SM suggests that the identification of SM components could be more important than their precise histologic subclassification, pending confirmation by further studies.
Assuntos
Neoplasias Embrionárias de Células Germinativas , Sarcoma , Neoplasias Testiculares , Humanos , Masculino , Neoplasias Embrionárias de Células Germinativas/genética , Neoplasias Testiculares/genética , Neoplasias Testiculares/patologia , AneuploidiaRESUMO
A subset of testicular sex cord-stromal tumors (SCST), which includes neoplasms with mixed histology, cannot be classified into a specific histologic subtype. This study evaluated the clinicopathologic, immunophenotypic and molecular features of 26 SCST not amenable to specific classification by expert uropathologists. Median age at diagnosis was 43 years and median tumor size was 2.4 cm. Follow-up information was available for 18 (69%) patients, with evidence of an aggressive clinical course in 6 patients (4 alive with disease, 2 dead of disease 3 months and 6 months after orchiectomy). Microscopically, SCST not amenable to specific classification demonstrated monophasic epithelioid (9/26, 35%), monophasic spindle cell (5/26, 19%), and biphasic or mixed histology (12/26, 46%). One or more aggressive histopathologic features were seen in 11 cases. DNA sequencing was successful in 22 tumors. Pathogenic CTNNB1 and APC alterations were seen in 7 (33%) and 2 (10%) cases, respectively, with additional variants (e.g., CDKN2A, RB1, TP53, BRCA2) being identified in individual cases. Combined evaluation of morphology, sequencing data and beta-catenin immunohistochemistry resulted in reclassification of 6 (23%) tumors as Sertoli cell tumor, not otherwise specified. This was supported by comparing the methylation profiles of a subset of these tumors and those of typical Sertoli cell tumors. Additionally, a subset of 5 neoplasms (19%) with spindle cell or biphasic histology and SMA expression was characterized by hyperdiploid genomes with recurrent chromosomal gains and absence of driver mutations, possibly representing a distinct tumor type. The SCST that remained not amenable to specific histologic classification (15/26, 58%) were enriched for aggressive histologic features and malignant clinical behavior. In conclusion, this study demonstrated that a subset of testicular SCST that were originally not amenable to specific classification could be reclassified by combined evaluation of morphology, immunohistochemistry and molecular data.
Assuntos
Tumores do Estroma Gonadal e dos Cordões Sexuais , Neoplasias Testiculares , Masculino , Humanos , Tumores do Estroma Gonadal e dos Cordões Sexuais/genética , Tumores do Estroma Gonadal e dos Cordões Sexuais/metabolismo , Tumores do Estroma Gonadal e dos Cordões Sexuais/patologia , Neoplasias Testiculares/patologia , Imuno-Histoquímica , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismoRESUMO
We evaluated the clinicopathologic and molecular characteristics of mostly incidentally detected, small, papillary renal neoplasms with reverse polarity (PRNRP). The cohort comprised 50 PRNRP from 46 patients, divided into 2 groups. The clinically undetected (<5 mm) neoplasms (n = 34; 68%) had a median size of 1.1 mm (range 0.2-4.3 mm; mean 1.4 mm), and the clinically detected (≥5 mm) neoplasms (n = 16; 32%) which had a median size of 13 mm (range 9-30 mm; mean 16 mm). Neoplasms were positive for GATA3 (n = 47; 100%) and L1CAM (n = 34/38; 89%) and were negative for vimentin (n = 0/44; 0%) and, to a lesser extent, AMACR [(n = 12/46; 26%; weak = 9, weak/moderate = 3)]. KRAS mutations were found in 44% (n = 15/34) of the clinically undetected PRNRP and 88% of the clinically detected PRNRP (n = 14/16). The two clinically detected PRNRP with wild-type KRAS gene were markedly cystic and contained microscopic intracystic tumors. In the clinically undetected PRNRP, the detected KRAS mutations rate was higher in those measuring ≥1 mm vs <1 mm [n = 14/19 (74%) vs n = 1/15 (7%)]. Overall, the KRAS mutations were present in exon 2-codon 12: c.35 G > T (n = 21), c.34 G > T (n = 3), c.35 G > A (n = 2), c.34 G > C (n = 2) resulting in p.Gly12Val, p. Gly12Asp, p.Gly12Cys and p.Gly12Arg, respectively. One PRNRP had a G12A/V/D complex mutation. Twenty-six PRNRP were concurrently present with other tumors of different histologic subtypes in the ipsilateral kidney; molecular testing of 8 of the latter showed wild-type KRAS gene despite the presence of KRAS mutations in 5 concurrent PRNRP. On follow up, no adverse pathologic events were seen (range 1-160 months; mean 44 months). In conclusion, the presence of KRAS mutations in small, clinically undetected PRNRP provides a unique finding to this entity and supports its being an early event in the development of these neoplasms.
Assuntos
Neoplasias Colorretais , Neoplasias Renais , Neoplasias Colorretais/patologia , Genes ras , Humanos , Rim/patologia , Neoplasias Renais/genética , Mutação , Proteínas Proto-Oncogênicas p21(ras)/genéticaRESUMO
It is estimated that 5-8% of renal tumours are hereditary in nature, with many inherited as autosomal-dominant. These tumours carry a unique spectrum of pathological and molecular alterations, the knowledge of which has expanded in recent years. Due to this knowledge, many advances in the treatment of these tumours have been achieved. In this review, we summarize the current understanding of the genetic renal neoplasia syndromes, clinical and pathological presentations, molecular pathogenesis, advances in therapeutic implications and targeted therapy.
Assuntos
Carcinoma de Células Renais , Neoplasias Renais , Síndromes Neoplásicas Hereditárias , Doença de von Hippel-Lindau , Carcinoma de Células Renais/genética , Predisposição Genética para Doença , Humanos , Neoplasias Renais/genética , Neoplasias Renais/terapia , Biologia Molecular , Síndromes Neoplásicas Hereditárias/genética , Doença de von Hippel-Lindau/complicações , Doença de von Hippel-Lindau/genética , Doença de von Hippel-Lindau/terapiaRESUMO
Adenocarcinomas of the rete testis (ACRT) are rare and aggressive testicular neoplasms that present predominantly in older men and have a tendency for early systemic spread. Their morphology spans a wide spectrum, including tumors with glandular, solid, papillary, micropapillary, glomeruloid, cribriform, and sarcomatoid growth patterns, or a combination thereof. The genomic alterations associated with these tumors have not been studied previously. We assessed eight ACRT published in prior clinicopathologic series using a solid tumor DNA sequencing panel. Pathogenic variants were identified in 6/8 cases. More specifically, four cases demonstrated inactivation of genes involved in cell cycle regulation, including CDKN2A, BAP1, TP53, and RB1. CDKN2A was the only recurrently affected gene, with pathogenic variants detected in 3/8 cases. One of these three cases had molecular evidence of concurrent homozygous (i.e. biallelic) NF2 inactivation by a frameshift variant and loss of the wildtype copy of the gene. One case had an internal tandem duplication in AKT, which has been previously described in juvenile granulosa cell tumor and sclerosing pneumocytoma and results in downstream activation of PI3K signaling. The remaining case with positive molecular findings harbored two concurrent truncating SETD2 variants. Multiple arm-level and chromosome-level copy number events were present in 3/8 cases, all of which harbored variants in genes involved in cell cycle regulation. In summary, ACRT are rare tumors with frequent inactivation of genes that play a major role cell cycle regulation, and a subset harbors variants that are potentially amenable to targeted therapy.
Assuntos
Adenocarcinoma , Rede do Testículo , Neoplasias Testiculares , Adenocarcinoma/genética , Adenocarcinoma/patologia , Idoso , Ciclo Celular , Humanos , Masculino , Rede do Testículo/patologia , Neoplasias Testiculares/genética , Neoplasias Testiculares/patologiaRESUMO
AIMS: Large cell calcifying Sertoli cell tumour (LCCSCT) is a rare testicular sex cord-stromal tumour that primarily affects young patients and is associated with Carney complex. We sought to characterise the clinicopathological features of a series of LCCSCT and evaluate the diagnostic utility of PRKAR1A immunohistochemistry (IHC). METHODS AND RESULTS: The LCCSCT cohort (n = 15) had a median age of 16 years (range = 2-30 years). Four patients were known to have Carney complex. PRKAR1A IHC was performed in each case. For comparison, PRKAR1A IHC was also assessed in other sex cord-stromal tumours, including Sertoli cell tumour, not otherwise specified (SCT, NOS; n = 10), intratubular large cell hyalinising Sertoli cell tumour (n = 1) and Leydig cell tumour (n = 23). Loss of cytoplasmic PRKAR1A expression was observed in all but one LCCSCT (14 of 15; 93%). PRKAR1A expression was retained in all SCTs, NOS (10 of 10; 100%), the majority of Leydig cell tumours (22 of 23; 96%) and an intratubular large cell hyalinising Sertoli cell tumour (1 of 1; 100%). One Leydig cell tumour showed equivocal staining (multifocal weak expression). CONCLUSIONS: Overall, PRKAR1A loss is both sensitive (93%) and highly specific (97%) for the diagnosis of LCCSCT. PRKAR1A loss may aid its diagnosis, particularly in sporadic cases and those that are the first presentation of Carney complex.
Assuntos
Calcinose/complicações , Subunidade RIalfa da Proteína Quinase Dependente de AMP Cíclico/análise , Tumor de Células de Sertoli/química , Tumor de Células de Sertoli/complicações , Tumor de Células de Sertoli/patologia , Neoplasias Testiculares/química , Neoplasias Testiculares/complicações , Neoplasias Testiculares/patologia , Adolescente , Adulto , Criança , Pré-Escolar , Humanos , Imuno-Histoquímica , Masculino , Adulto JovemRESUMO
Renal oncocytoma is the most common benign epithelial renal neoplasm. Several adverse features that would typically increase the stage of renal cell carcinomas are not uncommon in renal oncocytoma, including perinephric, sinus fat, or renal vein invasion. Herein, we report the largest single institutional series of renal oncocytoma with adverse pathologic features. The cohort comprised 50 patients, 38 were men (76%) and 12 were women (24%), with a mean age of 68 years (range, 50-87 years). All cases were diagnosed on nephrectomy specimens. No laterality predilection was noted. The tumors ranged in size from 1.5-15.7 cm (mean, 5.3 cm). Adverse pathologic features included perinephric fat invasion (n = 25; 50%), renal sinus fat invasion (n = 9; 18%), and renal vein invasion (n = 5; 10%). More than one adverse feature was seen in 11 tumors (22%). All tumors showed diffuse reactions to KIT (n = 40; 100%) and cyclin D1 (n = 27; 100%). Keratin 7 highlighted rare (<5%) scattered cells, as well as entrapped renal tubules (n = 21; 100%). Reaction to DOG1 was patchy in three tumors (n = 27; 11%) while reactions to vimentin (n = 31) and Hale colloidal iron special stain (n = 30) were negative. On follow-up, no tumor recurrence or metastasis was observed over a follow-up range of 1-144 months (mean, 54 months; median, 60 months). Our data suggest that adverse pathologic features in renal oncocytoma do not alter their benign course.
Assuntos
Adenoma Oxífilo/patologia , Neoplasias Renais/patologia , Rim/patologia , Adenoma Oxífilo/metabolismo , Idoso , Idoso de 80 Anos ou mais , Ciclina D1/metabolismo , Feminino , Humanos , Queratina-7/metabolismo , Rim/metabolismo , Neoplasias Renais/metabolismo , Masculino , Pessoa de Meia-IdadeRESUMO
Thyroid-like follicular renal cell carcinoma is an uncommon kidney tumor with no distinct molecular alteration described to date. This cohort of eight women with mean and median ages of 45 and 46 years, respectively (range 19-65 years), had unencapsulated, well-circumscribed tumors composed of tightly packed anastomosing follicle-like cysts filled with eosinophilic colloid-like material and lined by cuboidal cells with high nuclear to cytoplasmic ratios, oval to elongated nuclei with perpendicular arrangement toward the lumens, and prominent nuclear overlapping. The stroma between these was minimal with the exception of two tumors. Calcifications and necrosis were absent. Immunohistochemically, the tumors were positive for KRT19 (7/7), PAX8 (5/5), cyclin D1 (6/6), KRT7 (5/7), and AMACR (1/5; focal, weak), and were negative for WT1, TTF1 (transcription termination factor-1), and thyroglobulin. In three of three tumors tested molecularly, EWSR1-PATZ1 fusion was identified by RNA sequencing and confirmed by RT-PCR and Sanger sequencing. Over a follow-up period of 1-7 years, no evidence of recurrence or metastasis has been detected. The EWSR1-PATZ1 fusion has been recognized as a recurrent alteration in a subset of round to spindle cell sarcomas with EWSR1-non-ETS fusions (EWSR1-PATZ1 sarcoma) and in several central nervous system tumors. The finding of an EWSR1-PATZ1 fusion in all three of the thyroid-like follicular renal cell carcinomas for which sufficient tissue was available for genomic profiling provides the first distinct molecular abnormality in thyroid-like follicular renal cell carcinomas, supporting its designation as a distinct diagnostic entity.
Assuntos
Carcinoma de Células Renais/genética , Neoplasias Renais/genética , Fatores de Transcrição Kruppel-Like/genética , Fusão Oncogênica , Proteína EWS de Ligação a RNA/genética , Proteínas Repressoras/genética , Adulto , Idoso , Carcinoma de Células Renais/patologia , Feminino , Humanos , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
Testicular tumors are incredibly diverse and one of the most challenging areas in surgical pathology. Because of the rarity and overlapping features with numerous entities occurring in the testis and paratestis, these tumors pose a diagnostic challenge even to the most experienced general pathologists. In 2016, the latest "World Health Organization (WHO) classification of testicular tumors" was released, which incorporated several updates to the previous 2004 classification system. These updates involved several entities, including germ cell tumors, sex cord-stromal tumors, tumors containing both germ cells and sex-cord stromal cells, a miscellaneous group of testicular tumors and paratesticular tumors. In addition, significant changes were also introduced in the 2018 AJCC TNM staging (8th edition) regarding testicular tumors. The germ cell tumors are divided into 2 major groups; tumors derived from germ cell neoplasia in situ (GCNIS) and those unrelated to GCNIS. The GCNIS associated tumors include seminomatous and nonseminomatous germ cell tumors, which constitute a heterogeneous group of tumors. Non-GCNIS-associated tumors include prepubertal-type teratoma, prepubertal yolk sac tumor, mixed prepubertal-type teratoma and yolk sac tumor and spermatocytic seminoma. In the sex cord-stromal category, the tumors are classified based on their cells of origin. Most are Leydig cell tumors and Sertoli cell tumors; however, several mixed and diverse entities based on cell types are included in this group. Gonadoblastoma is the only tumor in the mixed germ cell and sex cord-stromal tumor category. Because of recent advances in molecular techniques, abundant new genetic information has emerged which helped classify the tumors based on the molecular alterations and provided insights into the tumor pathogenesis. This review focused on the updates related to testicular germ cell tumors and sex cord-stromal tumors and described the morphologic, immunohistochemical and molecular characteristics with an aim to provide a practical diagnostic approach and an update on relevant recent molecular advances.
Assuntos
Tumor do Seio Endodérmico/patologia , Neoplasias Embrionárias de Células Germinativas/patologia , Seminoma/patologia , Teratoma/patologia , Neoplasias Testiculares/patologia , Tumor do Seio Endodérmico/genética , Tumor do Seio Endodérmico/metabolismo , Humanos , Masculino , Estadiamento de Neoplasias , Neoplasias Embrionárias de Células Germinativas/genética , Neoplasias Embrionárias de Células Germinativas/metabolismo , Seminoma/genética , Seminoma/metabolismo , Teratoma/genética , Teratoma/metabolismo , Neoplasias Testiculares/genética , Neoplasias Testiculares/metabolismoRESUMO
We recently proposed that an epithelial renal tumor "papillary renal neoplasm with reverse polarity" represents a distinct entity. It constituted 4% of previously diagnosed papillary renal cell carcinoma at the participating institutions. Histologically, it is characterized by papillary or tubulopapillary architecture covered by a single layer of eosinophilic cells with finely granular cytoplasm and apically located nuclei. It is characteristically positive for GATA3 and L1CAM and lack vimentin and, to a lesser extent, α-methylacyl-CoA-racemase (AMACR/p504s) immunostaining. To investigate the molecular pathogenesis of these tumors, we performed targeted next-generation sequencing on ten previously reported papillary renal neoplasms with reverse polarity, followed by a targeted polymerase chain reaction analysis for KRAS mutations in a control series of 30 type 1 and 2 papillary renal cell carcinomas. KRAS missense mutations were identified in eight of ten papillary renal neoplasms with reverse polarity. These mutations were clustered in exon 2-codon 12: c.35 G > T (n = 6) or c.34 G > C (n = 2) resulting in p.Gly12Val and p.Gly12Arg alterations, respectively. One of the wild-type tumors had BRAF c.1798_1799delGTinsAG (p.Val600Arg) mutation. No KRAS mutations were identified in any of the 30 control tumors. In summary, this study supports our proposal that papillary renal neoplasm with reverse polarity is an entity distinct from papillary renal cell carcinoma and the only renal cell neoplasm to consistently harbor KRAS mutations.
Assuntos
Carcinoma de Células Renais/genética , Neoplasias Renais/genética , Mutação , Proteínas Proto-Oncogênicas p21(ras)/genética , Idoso , Carcinoma de Células Renais/patologia , Polaridade Celular/fisiologia , Feminino , Humanos , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-IdadeRESUMO
Testicular biopsy may be a component of the work-up of male infertility. However, no reliable diagnostic tools are available for objective quantitative assessment of spermatogenic cells. It is well known that MAGE-A4 is selectively expressed in spermatogonia and our group has previously demonstrated that DOG1 differentially stains germ cells. Therefore, we performed DOG1 and a double stain cocktail (DOG1 and 57b murine monoclonal anti-MAGE-A4) immunohistochemical stains on 40 testicular infertility biopsies (10 each with active spermatogenesis, Sertoli cell-only, hypospermatogenesis, and maturation arrest), 25 benign seminiferous tubules from radical orchiectomies, and 5 spermatocytic tumors (ST). In biopsies/resections with active spermatogenesis, DOG1 stained spermatocytes and spermatids and was absent in spermatogonia, while MAGE-A4 stained spermatogonia and primary spermatocytes (weak). In hypospermatogenesis, DOG1 highlighted decreased spermatocytes/spermatids and MAGE-A4 highlighted decreased spermatogonia. DOG1 staining confirmed decreased to absent spermatocytes in maturation arrest and MAGE-A4 staining established the presence of preserved spermatogonia in all cases. All STs were negative for DOG1 and positive for MAGE-A4, while all Sertoli cell-only cases were negative for DOG1 and the double stain cocktail. In conclusion, we confirmed that DOG1 is expressed in spermatocytes and spermatids and MAGE-A4 highlights primarily spermatogonia. Usage of these stains facilitates confirmation of maturation arrest, assessment of the percentage of testis involvement in hypospermatogenesis and identification of mixed patterns. Finally, this study supports that the differentiation of STs is more closely related to spermatogonia than the more mature spermatocytes.
Assuntos
Anoctamina-1/metabolismo , Biomarcadores Tumorais/metabolismo , Infertilidade Masculina/veterinária , Proteínas de Neoplasias/metabolismo , Biópsia , Humanos , Imuno-Histoquímica , Infertilidade Masculina/diagnóstico , Infertilidade Masculina/metabolismo , Infertilidade Masculina/patologia , Masculino , Túbulos Seminíferos/metabolismo , Túbulos Seminíferos/patologia , Células de Sertoli/metabolismo , Células de Sertoli/patologia , Espermatogênese , Espermatogônias/metabolismo , Espermatogônias/patologia , Coloração e Rotulagem , Testículo/metabolismo , Testículo/patologiaRESUMO
Mechanistic target of rapamycin kinase (mTOR) is a member of the phosphatidylinositol-3-hydroxide kinase (PI3 K)-related protein kinase family that functions as a central regulator of cell growth, metabolism, proliferation, and survival. The role of the TSC-mTOR signaling pathway in kidney tumors has been implicated in some hamartoma syndromes; however, with the advent and wide utilization of molecular studies, a growing number of kidney tumors have been linked to somatic or germline mutations involving genes that encode for this pathway, including eosinophilic solid and cystic renal cell carcinoma, low-grade oncocytic tumor, eosinophilic vacuolated tumor, renal cell carcinoma with fibromyomatous stroma and angiomyolipoma, among others. Herein, we review the contemporary developments of mTOR pathway-related renal neoplasia, focusing on the clinicopathologic features of the tumor entities.
Assuntos
Carcinoma de Células Renais , Neoplasias Renais , Transdução de Sinais , Serina-Treonina Quinases TOR , Humanos , Neoplasias Renais/patologia , Neoplasias Renais/genética , Serina-Treonina Quinases TOR/metabolismo , Carcinoma de Células Renais/patologia , Carcinoma de Células Renais/genéticaRESUMO
Adamantinoma-like Ewing sarcoma (ALES) is a newly described rare entity, which shows EWSR1::FLI1 rearrangement characteristic of Ewing sarcoma. This can be diagnostically challenging as it manifests histologically with epithelial differentiation and has diffuse keratin expression as well as p40 and p60 positivity. We hereby report a case of ALES in a 33-year-old woman with a past medical history of breast carcinoma who presented with a right-sided parotid mass. CT scan of the neck showed a heterogenous mass within the superficial lobe, measuring 17â mm in diameter for which the patient underwent superficial parotidectomy. Histopathology of the mass revealed a malignant neoplasm formed of solid nests, cords and sheets of cells with minimal cytoplasm and monomorphic nuclei with granular chromatin and indistinct nucleoli. Brisk mitotic activity and tumor necrosis were also present. The tumor showed strong and diffuse reactivity for pankeratin (clone AE1/AE3) and keratin 20, both in a dot-like pattern, raising the suspicion of metastatic Merkel cell carcinoma; however, molecular studies showed EWSR1::FLI1 rearrangement, supporting the diagnosis of ALES. In summary, it is prudent to have knowledge about this entity to avoid its misdiagnosis as other malignancies of the head and neck region which exhibit a different clinical course, prognosis and hence treatment modalities.
Assuntos
Adamantinoma , Carcinoma de Célula de Merkel , Sarcoma de Ewing , Neoplasias Cutâneas , Feminino , Humanos , Adulto , Sarcoma de Ewing/diagnóstico , Sarcoma de Ewing/genética , Sarcoma de Ewing/patologia , Adamantinoma/diagnóstico , Adamantinoma/genética , Adamantinoma/cirurgia , Glândula Parótida/patologia , Carcinoma de Célula de Merkel/patologia , Neoplasias Cutâneas/patologiaRESUMO
Renal cell carcinoma with fibromyomatous stroma, recognized as a provisional entity in the current 2022 World Health Organization classification of renal neoplasms, is rare. Recent evidence suggests recurrent alterations in the mTOR pathway, supporting its recognition as a distinct entity. Herein, we report 2 renal cell carcinomas with fibromyomatous stroma with MTOR mutations occurring in 62- and 72-year-old women and review the literature to support its recognition as a distinct entity, focusing on the characteristic morphology, immunohistochemical staining patterns as well as genetic alterations.
RESUMO
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.
Assuntos
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
Acquired cystic disease associated renal cell carcinomas (ACD-RCC) are rare and their molecular and histopathological characteristics are still being explored. We therefore investigated the clinicopathologic and molecular characteristics of 31 tumors. The patients were predominantly male (n = 30), with tumors mainly left-sided (n = 17), unifocal (n = 19), and unilateral (n = 29) and a mean tumor size of 25 mm (range, 3-65 mm). Microscopically, several histologic patterns were present, including pure classic sieve-like (n = 4), and varied proportions of mixed classic sieve-like with papillary (n = 23), tubulocystic (n = 9), compact tubular (n = 4) and solid (n = 1) patterns. Calcium-oxalate crystals were seen in all tumors. Molecular analysis of 9 tumors using next generation sequencing showed alterations in SMARCB1 in 3 tumors (1 with frameshift deletion and 2 with copy number loss in chromosome 22 involving SMARCB1 region), however, INI1 stain was retained in all. Nonrecurrent genetic alterations in SETD2, NF1, NOTCH4, BRCA2 and CANT1 genes were also seen. Additionally, MTOR p.Pro351Ser was identified in one tumor. Copy number analysis showed gains in chromosome 16 (n = 5), 17 (n = 2) and 8 (n = 2) as well as loss in chromosome 22 (n = 2). In summary, ACD-RCC is a recognized subtype of kidney tumors, with several histological architectural patterns. Our molecular data identifies genetic alterations in chromatin modifying genes (SMARCB1 and SETD2), which may suggest a role of such genes in ACD-RCC development.
Assuntos
Carcinoma de Células Renais , Neoplasias Renais , Humanos , Masculino , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/patologia , Neoplasias Renais/genética , Neoplasias Renais/patologia , Feminino , Pessoa de Meia-Idade , Idoso , Adulto , Doenças Renais Císticas/genética , Doenças Renais Císticas/patologia , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/análise , Idoso de 80 Anos ou mais , Predisposição Genética para Doença , Sequenciamento de Nucleotídeos em Larga EscalaRESUMO
Large cell calcifying Sertoli cell tumors (LCCSCTs) are rare testicular tumors, representing <1 % of all testicular neoplasms. Almost 40 % of patients with LCCSCTs will present in the context of the inherited tumor predisposition syndrome, the Carney complex. While most LCCSCTs are benign, 10-20 % have malignant behavior. The aim of our study was to analyze LCCSCTs for novel molecular alterations in addition to PRKAR1A mutations and to identify potential drivers for malignant progression. Eight LCCSCTs diagnosed at two institutions were included. Two patients had the Carney complex confirmed on subsequent genetic testing, and two tumors had several adverse pathological findings. One patient presented with metastatic disease at the time of initial diagnosis. Targeted next-generation sequencing detected PRKAR1A alterations in all cases, with heterozygous PRKAR1A mutations in 5 tumors, germline Carney-complex-associated PRKAR1A mutation in 2 patients, and PRKAR1A fusion in 1 tumor. Additionally, sequencing the metastatic case identified CDKN1B and TERT promoter gene mutations. All tumors showed a low tumoral mutational burden and unremarkable copy number alterations except for frequent LOH of 17q24 encompassing the PRKAR1A locus. RNA expression analysis showed increased expression of several markers including novel PRUNE2, and usual markers like inhibin and calretinin. Our study showed that while LCCSCTs have been reported in the setting of cancer predisposition syndromes, the majority of these tumors occur sporadically. PRKAR1A alterations were present in all cases and appear to be the major driver in LCCSCTs. It remains to be determined whether malignant progression may be caused by additional driver mutations.