RESUMEN
AIMS: Metaplastic thymoma is a rare thymic tumour characterized by Yes Associated Protein 1 (YAP1) and Mastermind Like Transcriptional Coactivator 2 (MAML2) gene fusions resulting from an intrachromosomal inversion of chromosome 11. Immunohistochemistry with an antibody directed against the C-terminus of YAP1 has shown loss of expression in YAP1-rearranged vascular neoplasms, poromas, and porocarcinomas. This study aimed to validate an anti-YAP1 C-terminal antibody as an ancillary immunohistochemical marker for the diagnosis of metaplastic thymoma. MATERIALS AND METHODS: Ten metaplastic thymomas were selected for the current study. Fluorescence in situ hybridization (FISH), next-generation sequencing (NGS), and reverse transcription-polymerase chain reaction (RT-PCR) analyses were performed to detect YAP1::MAML2 fusions. We then performed immunohistochemistry to detect YAP1 C-terminus expression in 10 metaplastic thymomas, 50 conventional thymomas (10 each of type A thymoma, type AB thymoma, type B1 thymoma, type B2 thymoma, and type B3 thymoma) and seven thymic carcinomas. RESULTS: All 10 cases showed narrow split signals with a distance of nearly two signal diameters and sometimes had false-negative results in YAP1 and MAML2 break-apart FISH (BA-FISH). Abnormal colocalized signals of the YAP1::MAML2 fusion were observed in all 10 cases using fusion FISH (F-FISH) assays. Eight of 10 cases with adequate nucleic acids were successfully sequenced and all showed YAP1::MAML2 fusions; in two cases the fusions were detected by both DNA and RNA sequencing and in six cases by RNA sequencing only. YAP1::MAML2 fusion transcripts were identified in four cases by RT-PCR. Metaplastic thymoma showed loss of YAP1 C-terminus expression in all 10 (100%) cases. All other thymic neoplasms showed retained YAP1 C-terminus expression. CONCLUSION: YAP1 C-terminus immunohistochemistry is a highly sensitive and specific ancillary marker that distinguishes metaplastic thymoma from its mimics. BA-FISH assays could not effectively detect YAP1::MAML2 fusions due to the proximity of the two genes. Loss of YAP1 C-terminus expression is a reliable surrogate for the detection of YAP1::MAML2 fusions in metaplastic thymoma.
Asunto(s)
Timoma , Neoplasias del Timo , Humanos , Timoma/diagnóstico , Timoma/genética , Timoma/metabolismo , Hibridación Fluorescente in Situ , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Neoplasias del Timo/diagnóstico , Neoplasias del Timo/genética , Neoplasias del Timo/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética , Reordenamiento Génico , Transactivadores/genéticaRESUMEN
The classification of the distinct group of mesenchymal neoplasms, first described as 'Xp11 translocation perivascular epithelioid cell tumor (PEComa)' and for which the term 'melanotic Xp11 neoplasm' or 'Xp11 neoplasm with melanocytic differentiation' has recently been proposed, remains challenging and controversial. We collected 27 melanotic Xp11 neoplasms, the largest series to date, for a comprehensive evaluation. Fourteen of the cases, together with eight alveolar soft part sarcomas (ASPS), nine conventional PEComas and a control group of seven normal tissues were submitted to RNA sequencing. Follow-up available in 22 patients showed 5-year overall survival and 5-year disease-free survival of 47.6 and 35.7%, respectively, which were similar to ASPS and significantly worse than conventional PEComa. Univariate analysis of location (occurring in the kidney versus not kidney), infiltrative growth pattern, nuclear pleomorphism, mitotic activity ≥2/50 high-power fields (HPF), necrosis and lymphovascular invasion were found to be associated with overall survival and/or disease-free survival. Multivariate analysis identified that location was the only factor found to independently correlate with disease-free survival. More importantly, RNA sequencing-based clustering analysis segregated melanotic Xp11 neoplasm and ASPS from other tumors, including conventional PEComa and Xp11 translocation renal cell carcinoma, and formed a compact cluster representative of the largely similar expression signature. Here we clearly define the true biologic nature of melanotic Xp11 neoplasms which are distinctive malignant mesenchymal tumors, rather than simply PEComa variants with occasionally unpredictable behavior. Meanwhile, melanotic Xp11 neoplasm and ASPS more likely represent phenotypic variants of the same entity, which is distinct from conventional PEComa and Xp11 translocation renal cell carcinoma. Based on these important findings, melanotic Xp11 neoplasm might be reclassified into a distinctive entity together with ASPS, independent from PEComa, in future revisions of the current WHO categories of tumors of soft tissue and bone for the improved reclassification. © 2020 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Asunto(s)
Carcinoma de Células Renales/clasificación , Neoplasias Renales/clasificación , Neoplasias de Células Epitelioides Perivasculares/clasificación , Sarcoma de Parte Blanda Alveolar/clasificación , Translocación Genética , Adolescente , Adulto , Carcinoma de Células Renales/genética , Carcinoma de Células Renales/patología , Niño , Preescolar , Análisis por Conglomerados , Estudios de Cohortes , Femenino , Perfilación de la Expresión Génica , Humanos , Neoplasias Renales/genética , Neoplasias Renales/patología , Masculino , Persona de Mediana Edad , Neoplasias de Células Epitelioides Perivasculares/genética , Neoplasias de Células Epitelioides Perivasculares/patología , Sarcoma de Parte Blanda Alveolar/genética , Sarcoma de Parte Blanda Alveolar/patología , Análisis de Secuencia de ARN , Análisis de Supervivencia , Adulto JovenRESUMEN
This study aimed to investigate the association of SDH gene mutations and promoter methylation with succinate dehydrogenase-deficient gastrointestinal stromal tumors (SDH-deficient GISTs) and to further discuss the potential molecular mechanisms underlying SDHB expression loss in these tumors. First, a total of 26 patients with SDH-deficient GISTs were selected by identifying the loss of SDHB protein expression and wild-type for KIT and PDGFRa mutations. Then SDH gene mutations and promoter methylation were detected by DNA sequencing and methylation-specific polymerase chain reaction, respectively, and the clinical and pathological data of SDH-deficient GISTs patients were collected and analyzed accordingly. The results of genetic testing demonstrated that 38.46% (10/26) of these patients harbored mutations in SDHB, SDHC, and SDHD genes (3 cases with double mutations). Besides, aberrant promoter methylation of SDH genes was detected in 10 out of 26 cases (38.46%), including 8 cases in SDHA gene, 3 cases in SDHB gene, 1 case in both SDHA and SDHB genes. It is suggested that SDH gene mutations and promoter methylation may contribute to the loss of SDH protein expression in sporadic SDH-deficient GISTs. This study indicated that the genetic and epigenetic alterations of SDH genes may occur during tumor formation.
Asunto(s)
Epigénesis Genética/genética , Tumores del Estroma Gastrointestinal/patología , Succinato Deshidrogenasa/genética , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Tumores del Estroma Gastrointestinal/genética , Humanos , Masculino , Proteínas de la Membrana/metabolismo , Persona de Mediana Edad , Mutación/genética , Regiones Promotoras Genéticas , Proteínas Proto-Oncogénicas c-kit/genética , Succinato Deshidrogenasa/deficienciaRESUMEN
Both Xp11 translocation renal cell carcinomas and the corresponding mesenchymal neoplasms are characterized by a variety of gene fusions involving TFE3. It has been known that tumors with different gene fusions may have different clinicopathologic features; however, further in-depth investigations of subtyping Xp11 translocation-associated cancers are needed in order to explore more meaningful clinicopathologic correlations. A total of 22 unusual cases of Xp11 translocation-associated cancers were selected for the current study; 20 cases were further analyzed by RNA sequencing to explore their TFE3 gene fusion partners. RNA sequencing identified 17 of 20 cases (85%) with TFE3-associated gene fusions, including 4 ASPSCR1/ASPL-TFE3, 3 PRCC-TFE3, 3 SFPQ/PSF-TFE3, 1 NONO-TFE3, 4 MED15-TFE3, 1 MATR3-TFE3, and 1 FUBP1-TFE3. The results have been verified by fusion fluorescence in situ hybridization (FISH) assays or reverse transcriptase polymerase chain reaction (RT-PCR). The remaining 2 cases with specific pathologic features highly suggestive of MED15-TFE3 renal cell carcinoma were identified by fusion FISH assay. We provide the detailed morphologic and immunophenotypic description of the MED15-TFE3 renal cell carcinomas, which frequently demonstrate extensively cystic architecture, similar to multilocular cystic renal neoplasm of low malignant potential, and expressed cathepsin K and melanotic biomarker Melan A. This is the first time to correlate the MED15-TFE3 renal cell carcinoma with specific clinicopathologic features. We also report the first case of the corresponding mesenchymal neoplasm with MED15-TFE3 gene fusion. Additional novel TFE3 gene fusion partners, MATR3 and FUBP1, were identified. Cases with ASPSCR1-TFE3, SFPQ-TFE3, PRCC-TFE3, and NONO-TFE3 gene fusion showed a wide variability in morphologic features, including invasive tubulopapillary pattern simulating collecting duct carcinoma, extensive calcification and ossification, and overlapping and high columnar cells with nuclear grooves mimicking tall cell variant of papillary thyroid carcinoma. Furthermore, we respectively evaluated the ability of TFE3 immunohistochemistry, TFE3 FISH, RT-PCR, and RNA sequencing to subclassify Xp11 translocation-associated cancers. In summary, our study expands the list of TFE3 gene fusion partners and the clinicopathologic features of Xp11 translocation-associated cancers, and highlights the importance of subtyping Xp11 translocation-associated cancers combining morphology, immunohistochemistry, and multiple molecular techniques.
Asunto(s)
Carcinoma de Células Renales/genética , Cromosomas Humanos Par 11 , Cromosomas Humanos X , Neoplasias Renales/genética , Fusión de Oncogenes/genética , Proteínas de Fusión Oncogénica/genética , Translocación Genética , Adulto , Carcinoma de Células Renales/patología , Femenino , Humanos , Hibridación Fluorescente in Situ , Neoplasias Renales/patología , Masculino , Persona de Mediana Edad , Análisis de Secuencia de ARN , Adulto JovenRESUMEN
AIMS: MITF, TFE3, TFEB and TFEC belong to the same microphthalmia-associated transcription factor family (MiT). Two transcription factors in this family have been identified in two unusual types of renal cell carcinoma (RCC): Xp11 translocation RCC harbouring TFE3 gene fusions and t(6;11) RCC harbouring a MALAT1-TFEB gene fusion. The 2016 World Health Organisation classification of renal neoplasia grouped these two neoplasms together under the category of MiT family translocation RCC. RCCs associated with the other two MiT family members, MITF and TFEC, have rarely been reported. Herein, we identify a case of MITF translocation RCC with the novel PRCC-MITF gene fusion by RNA sequencing. METHODS AND RESULTS: Histological examination of the present tumour showed typical features of MiT family translocation RCCs, overlapping with Xp11 translocation RCC and t(6;11) RCC. However, this tumour showed negative results in TFE3 and TFEB immunochemistry and split fluorescence in-situ hybridisation (FISH) assays. The other MiT family members, MITF and TFEC, were tested further immunochemically and also showed negative results. RNA sequencing and reverse transcription-polymerase chain reaction confirmed the presence of a PRCC-MITF gene fusion: a fusion of PRCC exon 5 to MITF exon 4. We then developed FISH assays covering MITF break-apart probes and PRCC-MITF fusion probes to detect the MITF gene rearrangement. CONCLUSIONS: This study both proves the recurring existence of MITF translocation RCC and expands the genotype spectrum of MiT family translocation RCCs.
Asunto(s)
Carcinoma de Células Renales/genética , Proteínas de Ciclo Celular/genética , Neoplasias Renales/genética , Factor de Transcripción Asociado a Microftalmía/genética , Proteínas de Neoplasias/genética , Proteínas de Fusión Oncogénica/genética , Carcinoma de Células Renales/patología , Humanos , Hibridación Fluorescente in Situ , Neoplasias Renales/patología , Masculino , Persona de Mediana Edad , Análisis de Secuencia de ARNRESUMEN
Xp11 translocation renal cell carcinomas are characterized by several different translocations involving the TFE3 gene. Tumors with different specific gene fusions may have different clinicopathological manifestations. Fewer than 10 renal cell carcinoma cases with NONO-TFE3 have been described. Here we examined eight additional cases of this rare tumor using clinicopathological, immunohistochemical, and molecular analyses. The male-to-female ratio of our study cohort was 1:1, and the median age was 30 years. The most distinctive feature of the tumors was that they exhibited glandular/tubular or papillary architecture that was lined with small-to-medium cuboidal to high columnar cells with indistinct cell borders and an abundantly clear or flocculent eosinophilic cytoplasm. The nuclei were oriented toward the luminal surface and were round and uniform in shape, which resulted in the appearance of secretory endometrioid subnuclear vacuolization. The distinct glandular/tubular or papillary architecture was often accompanied by sheets of epithelial cells that presented a biphasic pattern. Immunohistochemically, all eight cases demonstrated moderate (2+) or strong (3+) positive staining for TFE3, CD10, RCC marker, and PAX-8. None of the tumors were immunoreactive for CK7, Cathepsin K, Melan-A, HMB45, Ksp-cadherin, Vimentin, CA9, 34ßE12 or CD117. NONO-TFE3 fusion transcripts were identified in six cases by RT-PCR. All eight cases showed equivocal split signals with a distance of nearly 2 signal diameters and sometimes had false-negative results. Furthermore, we developed a fluorescence in situ hybridization (FISH) assay to serve as an adjunct diagnostic tool for the detection of the NONO-TFE3 fusion gene and used this method to detect the fusion gene in all eight cases. Long-term follow-up (range, 10-102 months) was available for 7 patients. All 7 patients were alive with no evidence of recurrent disease or disease progression after their initial resection. This report adds to the known data regarding NONO-TFE3 renal cell carcinoma.
Asunto(s)
Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice/genética , Carcinoma de Células Renales/genética , Reordenamiento Génico , Neoplasias Renales/genética , Proteínas Asociadas a Matriz Nuclear/genética , Factores de Transcripción de Octámeros/genética , Fusión de Oncogenes , Proteínas de Unión al ARN/genética , Adulto , Carcinoma de Células Renales/patología , Proteínas de Unión al ADN , Femenino , Humanos , Neoplasias Renales/patología , Masculino , Persona de Mediana Edad , Pronóstico , Adulto JovenRESUMEN
AIMS: The aim of this study was to evaluate the mutation status of epidermal growth factor receptor (EGFR) in gastrointestinal stromal tumours (GISTs) and its association with various clinicopathological variables, as well as to discuss further the effects of EGFR mutations on tumour formation and progression. METHODS AND RESULTS: A well-characterized cohort of 323 GISTs, obtained between 2010 and 2015 from the surgical pathology files of at the Department of Pathology of the Nanjing Jinling Hospital, was screened for mutations in exons 19 and 21 of the EGFR gene. Patient clinical data and clinicopathological features were collected if available in the medical records. Among the 323 primary GISTs, we identified three cases (0.93%) of EGFR mutations; these mutations never occurred together with KIT, PDGFRα, KRAS or BRAF mutations. In two cases, tumour cells exhibited spindle cell morphology and, in one case, epithelioid cell morphology. Additionally, the morphology and immunophenotype of these three cases did not show significant differences compared to common GISTs. The clinical results in summary were that two cases of EGFR-mutated GISTs occurred in females and in the stomach. The mean age of EGFR-mutated cases was 54.33 years, and the follow-up data indicated that these tumours were low risk and exhibited low recurrence. CONCLUSIONS: We first established that GISTs carrying EGFR mutation are relatively benign tumours. Although EGFR mutations were rarely present in GIST, EGFR seems to play a significant role in the development and progression of GIST.
Asunto(s)
Receptores ErbB/genética , Tumores del Estroma Gastrointestinal/genética , Adulto , Estudios de Cohortes , Femenino , Tumores del Estroma Gastrointestinal/patología , Humanos , Inmunoquímica , Masculino , Persona de Mediana Edad , MutaciónRESUMEN
AIMS: The aim of this study was to investigate potential molecular mechanisms associated with loss of BRM expression in poorly differentiated clear cell renal cell carcinoma (ccRCC). METHODS AND RESULTS: Nineteen previously selected BRM-negative RCC tissues were examined by DNA sequencing, fluorescence in-situ hybridization (FISH) and methylation-specific polymerase chain reaction (PCR) of the BRM gene. BRM mutation was identified in 78.9% (15 of 19) cases, chromosome 9 monosomy or BRM deletion in 43.8% (seven of 16) and BRM promoter region cytosine-phosphate-guanine (CpG) methylation in 42.8% (six of 14). These results indicated that 89.5% (17 of 19) of the cases harboured at least one type of BRM genetic alteration, with two or more types of alteration in 47.4% (nine of 19). Such alterations were found rarely in adjacent non-neoplastic tissues and low-grade areas of composite tumours. CONCLUSIONS: BRM gene mutation, chromosome 9 monosomy or BRM deletion and CpG methylation contribute collectively to the loss of BRM expression in ccRCC. This work focusing on composite tumours indicated that BRM abnormality occurred during tumour progression.
Asunto(s)
Carcinoma de Células Renales/genética , Neoplasias Renales/genética , Factores de Transcripción/genética , Metilación de ADN/genética , Análisis Mutacional de ADN , Eliminación de Gen , Humanos , Inmunohistoquímica , Hibridación Fluorescente in Situ , Mutación , Reacción en Cadena de la Polimerasa , Regiones Promotoras Genéticas/genéticaRESUMEN
To investigate that whether myoepithelial tumors of salivary glands (MTs) with EWSR1 rearrangement display distinctive morphological characteristics and whether EWSR1 detection aids to distinguish malignant myoepithelial tumors (MMTs) from benign myoepithelial tumors (BMTs) of salivary glands. We examined 37 cases of MTs, including 24 BMTs, 13 MMTs, by histological, immunohistochemical, and molecular analysis. All of 37 cases were immunoreactive for CKpan, and at least one myoepithelial marker. 26 of 37 cases of MTs were available to be analyzed for EWSR1 rearrangement, with the result that EWSR1 gene break was detected in 4 cases of 15 BMTs, and 4 cases of 11 MMTs. In addition, the 8 EWSR1-rearranged cases displayed not exactly similar morphological features, covering 4 clear-cell cases, 1 plasmacytoid-cell case, 1 spindle-cell case, 1 epithelioid-cell case, and 1 chordoid-cell case. Our study proposed that EWSR1 rearrangement was present in a subset of MTs, with variable morphological features. Moreover, the presence of EWSR1 rearrangement could not be a forceful evidence to distinguish MMTs from BBTs.
Asunto(s)
Mioepitelioma/genética , Proteína EWS de Unión a ARN/metabolismo , Neoplasias de las Glándulas Salivales/genética , Glándulas Salivales/patología , Biomarcadores de Tumor/análisis , Células Epitelioides/patología , Femenino , Reordenamiento Génico/genética , Humanos , Hibridación Fluorescente in Situ/métodos , Masculino , Proteína EWS de Unión a ARN/genética , Neoplasias de las Glándulas Salivales/metabolismo , Neoplasias de las Glándulas Salivales/patología , Neoplasias de los Tejidos Blandos/genéticaRESUMEN
Recently, an increasing number of TFE3 rearrangement-associated tumours have been reported, such as TFE3 rearrangement-associated perivascular epithelioid cell tumours (PEComas), melanotic Xp11 translocation renal cancers and melanotic Xp11 neoplasms. We have suggested that these tumours belong to a single clinicopathological spectrum. 'Xp11 neoplasm with melanocytic differentiation' or 'melanotic Xp11 neoplasm' have been proposed to designate this unique neoplasm. Herein, we describe the first case of an Xp11 neoplasm with melanocytic differentiation to be described in the prostate, bearing the novel NONO-TFE3 gene fusion. This study both adds to the spectrum regarding melanotic Xp11 neoplasms and expands its gene fusion spectrum. Moreover, we discuss the relationship of these rare tumours to neoplasms such as conventional PEComas, alveolar soft part sarcomas, malignant melanomas, clear cell sarcomas and Xp11 translocation renal cancers.
Asunto(s)
Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice/genética , Proteínas Asociadas a Matriz Nuclear/genética , Factores de Transcripción de Octámeros/genética , Neoplasias de la Próstata/genética , Proteínas de Unión al ARN/genética , Adulto , Biomarcadores de Tumor/análisis , Cromosomas Humanos X/genética , Proteínas de Unión al ADN , Humanos , Inmunohistoquímica , Hibridación Fluorescente in Situ , Masculino , Melanocitos/patología , Fusión de Oncogenes/genética , Neoplasias de la Próstata/patología , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
OBJECTIVE: To study the pathological morphology, immunohistochemical characteristics, and molecular changes of type â ¡ testicular germ cell tumors (TGCT) and investigate the possible value of immunohistochemistry and fluorescence in situ hybridization (FISH) in the diagnosis of TGCT. METHODS: We collected for this study 97 cases of TGCT, including 75 cases of seminoma, 17 cases of embryonal carcinoma, 11 cases of yolk sac tumor, 16 cases of mature teratoma, 3 cases of immature teratoma, and 1 case of epidermoid cyst, in which normal testicular tissue was found in 20 and non-TGCT in 6. We detected the expressions of different antibodies in various subtypes of TGCT by immunohistochemistry and determined the rate of chromosome 12p abnormality using FISH. RESULTS: The immunophenotypes varied with different subtypes of TGCT. SALL4 and PLAP exhibited high sensitivity in all histological subtypes. CD117 and OCT4 showed strongly positive expressions in invasive seminoma and germ cell neoplasia in situ (GCNIS) but not in normal seminiferous tubules. GPC3 was significantly expressed in the yolk sac tumor, superior to GATA3 and AFP in both range and intensity. CKpan, OCT4, and CD30 were extensively expressed in embryonal carcinoma, while HCG expressed in choriocarcinoma. The positivity rate of isochromosome 12p and 12p amplification in TGCT was 96.7% (29/30). CONCLUSIONS: The majority of TGCT can be diagnosed by histological observation, but immunohistochemical staining is crucial for more accurate subtypes and valuable for selection of individualized treatment options and evaluation of prognosis. Chromosome 12p abnormality is a specific molecular alteration in type â ¡ TGCT, which is useful for ruling out other lesions.
Asunto(s)
Aberraciones Cromosómicas , Cromosomas Humanos Par 12 , Inmunohistoquímica , Hibridación Fluorescente in Situ , Neoplasias de Células Germinales y Embrionarias/diagnóstico , Neoplasias Testiculares/diagnóstico , Biomarcadores de Tumor/metabolismo , Carcinoma Embrionario/diagnóstico , Carcinoma Embrionario/genética , Carcinoma Embrionario/metabolismo , Carcinoma Embrionario/patología , Tumor del Seno Endodérmico/diagnóstico , Tumor del Seno Endodérmico/genética , Tumor del Seno Endodérmico/metabolismo , Tumor del Seno Endodérmico/patología , Marcadores Genéticos , Humanos , Masculino , Neoplasias de Células Germinales y Embrionarias/genética , Neoplasias de Células Germinales y Embrionarias/metabolismo , Neoplasias de Células Germinales y Embrionarias/patología , Pronóstico , Túbulos Seminíferos/metabolismo , Seminoma/diagnóstico , Seminoma/genética , Seminoma/metabolismo , Seminoma/patología , Teratoma/diagnóstico , Teratoma/genética , Teratoma/metabolismo , Teratoma/patología , Neoplasias Testiculares/genética , Neoplasias Testiculares/metabolismo , Neoplasias Testiculares/patologíaRESUMEN
Renal cell carcinoma (RCC) compromises multiple types and has been emerging dramatically over the recent several decades. Advances and consensus have been achieved targeting common RCCs, such as clear cell carcinoma, papillary RCC and chromophobe RCC. Nevertheless, little is known on the characteristics of several newly-identified RCCs, including clear cell (tubulo) papillary RCC, Xp11 translocation RCC, t(6;11) RCC, succinate dehydrogenase (SDH)-deficient RCC, acquired cystic disease-associated RCC, hereditary leiomyomatosis RCC syndrome-associated RCC, ALK translocation RCC, thyroid-like follicular RCC, tubulocystic RCC and hybrid oncocytic/chromophobe tumors (HOCT). In current review, we will collect available literature of these newly-described RCCs, analyze their clinical pathologic characteristics, discuss their morphologic and immunohistologic features, and finally summarize their molecular and genetic evidences. We expect this review would be beneficial for the understanding of RCCs, and eventually promote clinical management strategies.
RESUMEN
AIMS: Malignant rhabdoid tumours (MRTs) are highly aggressive malignancies of early infancy characterized by inactivation of SMARCB1, a core member of the SWI/SNF chromatin-remodelling complex. The aim of this study was to explore the status of multiple key subunits of the SWI/SNF complex in MRTs. METHODS AND RESULTS: We screened the key subunits of the SWI/SNF complex, including SMARCB1, SMARCA2, PBRM1, SMARCA4, and ARID1A, in four MRTs by immunohistochemistry, sequencing, and fluorescence in-situ hybridization (FISH). Complete loss of SMARCB1, SMARCA2 and PBRM1 expression and corresponding mutations in the same genes were observed in all cases. The mutations included seven missense, three same-sense, four frameshift and two truncating mutations. FISH revealed heterozygous deletion of SMARCB1 in one case, and monoploidy of chromosome 22, which harbours SMARCB1, in another case. Furthermore, trisomy of chromosome 9, which harbours SMARCA2, was observed in two cases. Abnormality of PBRM1 was not found in any case. CONCLUSIONS: We report, for the first time, co-inactivation and frequent mutations of SMARCB1, SMARCA2 and PBRM1 in MRTs. Multiple subunit abnormalities of the SWI/SNF complex potentially act together to contribute to the tumorigenesis of MRTs, which provides unique insights into this disease.
Asunto(s)
Proteínas Cromosómicas no Histona/genética , Proteínas de Unión al ADN/genética , Silenciador del Gen , Mutación/genética , Proteínas Nucleares/genética , Tumor Rabdoide/genética , Factores de Transcripción/genética , Preescolar , Proteínas Cromosómicas no Histona/metabolismo , Análisis Mutacional de ADN , Proteínas de Unión al ADN/metabolismo , Femenino , Humanos , Inmunohistoquímica , Hibridación Fluorescente in Situ , Masculino , Datos de Secuencia Molecular , Proteínas Nucleares/metabolismo , Proteína SMARCB1 , Análisis de Secuencia de ADN , Factores de Transcripción/metabolismoRESUMEN
AIMS: The aim of this study was to examine the status of Brahma (BRM), a key SWI/SNF complex subunit, in clear cell renal cell carcinomas (RCCs), and to analyse the histopathology, immunophenotype, molecular features and prognosis of the BRM-negative cases. METHODS AND RESULTS: We identified 19 cases of grade 4 tumours lacking BRM expression among 625 clear cell RCCs. All 19 cases exhibited features of poor differentiation: 13 showed pure poorly differentiated morphology, while six were composite tumours with an admixed typical low-grade component. Besides negative BRM expression, the immunophenotype of these cases was similar to clear cell RCC. VHL gene mutations were identified in nine of the 19 patients (47%). Chromosome 3p deletion was detected in 11 of 13 poorly differentiated RCCs and both areas of five of five composite tumours. All poorly differentiated tumour areas showed polysomy of chromosome 3. No losses or gains of chromosome 3 were observed in low-grade tumour areas of five of five composite RCCs. CONCLUSIONS: We have shown that loss of BRM expression is a common feature among poorly differentiated tumours in clear cell RCCs. We hypothesize that loss of BRM expression is involved in tumor de-differentiation in clear cell RCCs and may play an important role during tumour progression.
Asunto(s)
Carcinoma de Células Renales/metabolismo , Neoplasias Renales/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Adulto , Anciano , Carcinoma de Células Renales/genética , Carcinoma de Células Renales/patología , Femenino , Humanos , Neoplasias Renales/genética , Neoplasias Renales/patología , Masculino , Persona de Mediana Edad , Mutación , PronósticoRESUMEN
ABSTRACT: Renal hemangioblastoma (HB) is a rare subset of HBs arising outside of the central nervous system (CNS), with its molecular drivers remaining entirely unknown. There were no significant alterations detected in previous studies, including von Hippel-Lindau gene alterations, which are commonly associated with CNS-HB. This study aimed to determine the real molecular identity of renal HB and better understand its relationship with CNS-HB. A cohort of 10 renal HBs was submitted for next-generation sequencing technology. As a control, 5 classic CNS-HBs were similarly analyzed. Based on the molecular results, glycoprotein nonmetastatic B (GPNMB) immunohistochemistry was further performed in the cases of renal HB and CNS-HB. Mutational analysis demonstrated that all 10 renal HBs harbored somatic mutations in tuberous sclerosis complex 1 ( TSC1 , 5 cases), TSC2 (3 cases), and mammalian target of rapamycin (2 cases), with the majority classified as pathogenic or likely pathogenic. The CNS-HB cohort uniformly demonstrated somatic mutations in the von Hippel-Lindau gene. GPNMB was strong and diffuse in all 10 renal HBs and completely negative in CNS-HBs, reinforcing the molecular findings. Our study reveals a specific molecular hallmark in renal HB, characterized by recurrent TSC/mammalian target of rapamycin mutations, which defines it as a unique entity distinct from CNS-HB. This molecular finding potentially expands the therapeutic options for patients with renal HB. GPNMB can be considered for inclusion in immunohistochemical panels to improve renal HB identification.
Asunto(s)
Hemangioblastoma , Neoplasias Renales , Mutación , Serina-Treonina Quinasas TOR , Proteína 2 del Complejo de la Esclerosis Tuberosa , Humanos , Hemangioblastoma/genética , Hemangioblastoma/patología , Hemangioblastoma/química , Neoplasias Renales/genética , Neoplasias Renales/patología , Neoplasias Renales/química , Femenino , Masculino , Proteína 2 del Complejo de la Esclerosis Tuberosa/genética , Adulto , Persona de Mediana Edad , Serina-Treonina Quinasas TOR/genética , Serina-Treonina Quinasas TOR/metabolismo , Análisis Mutacional de ADN , Esclerosis Tuberosa/genética , Esclerosis Tuberosa/patología , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/análisis , Neoplasias del Sistema Nervioso Central/genética , Neoplasias del Sistema Nervioso Central/patología , Neoplasias del Sistema Nervioso Central/química , Inmunohistoquímica , Proteína 1 del Complejo de la Esclerosis Tuberosa/genética , Anciano , Predisposición Genética a la Enfermedad , Adolescente , Fenotipo , Adulto Joven , Niño , Secuenciación de Nucleótidos de Alto RendimientoRESUMEN
AIMS: Recent studies have demonstrated that cathepsin K seems to be a powerful marker in identifying renal perivascular epithelioid cell neoplasms (PEComas). However, the expression in extrarenal PEComas has not been well characterized due to their rare incidence. Our aim was to investigate the expression of cathepsin K in a wide spectrum of extrarenal PEComas and evaluate its potential diagnostic usefulness in comparison with other commonly used markers. METHODS AND RESULTS: Twenty-three cases of PEComa (liver, n = 9; lung, n = 1; broad ligament of uterus, n = 1; vertex subcutaneous soft tissue, n = 1; abdominal wall, n = 1; and kidney, n = 10) were selected for study. All displayed a high percentage of cells with moderately to strongly positive reactions for cathepsin K (mean 91%; range 80-100%). HMB45, Melan-A and smooth muscle actin (SMA) were expressed in 78, 87 and 87% of cases, respectively, with various percentages of positive cells (mean, 34, 40 and 38%; range 0-80, 0-90 and 0-90%). Transcription factor E3 (TFE3) was expressed strongly in only three cases; none exhibited evidence of TFE3 gene fusion or amplification. CONCLUSIONS: Cathepsin K appears to be more powerful than other commonly used markers in diagnosing a wide spectrum of PEComas and distinguishing them from the majority of human cancers.
Asunto(s)
Catepsina K/metabolismo , Neoplasias Renales/enzimología , Neoplasias Hepáticas/enzimología , Neoplasias de Células Epitelioides Perivasculares/enzimología , Neoplasias Uterinas/enzimología , Adulto , Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice/metabolismo , Biomarcadores de Tumor/metabolismo , Ligamento Ancho/patología , Recuento de Células , Femenino , Humanos , Neoplasias Renales/patología , Neoplasias Hepáticas/patología , Masculino , Persona de Mediana Edad , Neoplasias de Células Epitelioides Perivasculares/patología , Neoplasias Uterinas/patología , Adulto JovenRESUMEN
OBJECTIVE: To study the clinicopathologic features, immunophenotype and genetic changes of perivascular epithelioid cell neoplasms (PEComa). METHODS: A total of 25 cases of PEComa located in various anatomic sites were selected for immunohistochemical staining (SP or EnVision method). TFE3 fluorescence in-situ hybridization was also performed to determine the TFE3 gene status. RESULTS: The age of patient ranged from 21 to 61 years (mean = 43 years). The male-to-female ratio was 1: 1.3. Histologically, 22 cases represented conventional angiomyolipomas, composed of a mixture of adipose tissue, spindle element, epithelioid smooth muscle cells and abnormal thick-walled blood vessels in various proportions. Three cases involving lung, soft tissue and broad ligament had subtle but distinctive morphologic features. Nested or sheet-like architecture with epithelioid or spindle cells was observed. Immunohistochemical study showed that HMB 45, melan A, smooth muscle actin and cathepsin K were expressed in 80% (20/25), 88% (22/25), 88% (22/25) and 100% (25/25) of PEComa, respectively. Within positive cases, the average proportion of positive tumor cells was 36%, 41%, 35% and 90% respectively for HMB 45, melan A, smooth muscle actin and cathepsin K. TFE3 was negative in all of the 22 renal and hepatic PEComa studied, while it was positive in the 3 cases of extra-hepatorenal PEComa. None of the 25 cases exhibited evidence of TFE3 gene fusion or amplification. CONCLUSIONS: Extra-hepatorenal PEComa have distinctive morphologic features and are associated with TFE3 overexpression. Cathepsin K immunostaining demonstrates high sensitivity and specificity in PEComa, better than other commonly employed immunomarkers. This marker is thus useful in diagnosis of PEComa and distinction with other neoplasms.
Asunto(s)
Angiomiolipoma/metabolismo , Catepsina K/metabolismo , Neoplasias Renales/metabolismo , Neoplasias Hepáticas/metabolismo , Neoplasias de Células Epitelioides Perivasculares/metabolismo , Actinas/metabolismo , Adulto , Angiomiolipoma/patología , Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice/genética , Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice/metabolismo , Femenino , Humanos , Inmunohistoquímica , Neoplasias Renales/patología , Neoplasias Hepáticas/patología , Antígeno MART-1/metabolismo , Masculino , Antígenos Específicos del Melanoma/metabolismo , Persona de Mediana Edad , Neoplasias de Células Epitelioides Perivasculares/patología , Adulto Joven , Antígeno gp100 del MelanomaRESUMEN
Thyroid-like low-grade nasopharyngeal papillary adenocarcinoma (TLLGNPPA) is a rare nasopharyngeal carcinoma. To date, less than 60 cases of TLLGNPPA have been reported, and its clinical features and pathogenesis remain unclear. In this paper, four cases of TLLGNPPA were reported to clarify the clinicopathological and molecular features of this disease. Histopathological examination revealed that all tumors had papillary glandular arrangement, with a fibrovascular axis in the tumor stroma and focal nuclear groove. All tumors expressed pan-CK, CK7, and CK19, while TG and Pax-8 were negative, and the Ki-67 index was approximately 1-3%. The expression of TTF-1 was diffusely positive in two cases and focally positive in two cases. EBER was not expressed in four cases. Molecular testing was possible in three cases. No common driver event was noted, but unique, mutually exclusive molecular variants were found in each of the three tumors (FGFR4, PDK1, AXIN2, FOXL2, and PIK3C3), one also with copy number variants in MCL1 and STMN1. All four patients underwent surgical resection of the tumor and had no metastasis or recurrence from 7 to 60 months post-resection. Given the assertion that these tumors do not recur or metastasize in addition to their heterogeneous gene mutation spectrum, we propose that TLLGNPPA is a neoplasm with low malignant potential and should no longer to be referred to as an adenocarcinoma.
Asunto(s)
Adenocarcinoma Papilar , Neoplasias Nasofaríngeas , Humanos , Glándula Tiroides/cirugía , Glándula Tiroides/patología , Adenocarcinoma Papilar/genética , Adenocarcinoma Papilar/cirugía , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/patología , Inmunohistoquímica , Carcinoma NasofaríngeoRESUMEN
Low-grade oncocytic tumor (LOT) has recently been described as a distinct renal tumor. LOT shows consistent morphologic features and a CK7-positive/CD117-negative immunophenotype. To examine the clinicopathological, immunohistochemical, and molecular features of LOT, we searched our institutional archives and identified seven cases of LOT. All patients were female, with a mean age of 66 years (range 44-79 years). The average tumor size was 3.2 cm (range 1.6-5.5 cm). Macroscopically, the tumors showed tan-brown and solid cut surfaces. Microscopically, the tumors showed compact nested to solid growth pattern, three cases with areas of edematous stroma containing loosely connected small clusters, cords or dispersed single tumor cells. The tumor cells had uniformly round to oval nuclei with eosinophilic cytoplasm, and showed perinuclear halos. Two cases focally had nuclear irregularities and binucleated cells were occasionally seen in three cases. Immunohistochemically, diffuse positivity for CK7 and lack of CD117 expression were present in all cases. All of the tumors were negative for CD10, CK20, vimentin, CA9, TFE3, TFEB, HMB45, and Melan-A. All tumors were positive for MTOR and negative for Cathepsin-K. FH and SDHB were retained. Next generation sequencing identified genetic variations in the MTOR pathway related genes: TSC1 (4/7), TSC2 (5/7), and MTOR (1/7). All patients were alive and without disease progression, after a mean follow-up of 43 months (range 6-89 months). LOT is an uncommon eosinophilic renal neoplasm with unique morphological and characteristic immunophenotypic features, and may represent an emerging separate renal entity characterized by mutations in the TSC/MTOR pathway.