RESUMEN
Renal medullary carcinomas (RMCs) and collecting duct carcinomas (CDCs) are rare subsets of lethal high-stage, high-grade distal nephron-related adenocarcinomas with a predilection for the renal medullary region. Recent findings have established an emerging group of fumarate hydratase (FH)-deficient tumors related to hereditary leiomyomatosis and renal cell carcinoma (HLRCC-RCCs) syndrome within this morphologic spectrum. Recently developed, reliable ancillary testing has enabled consistent separation between these tumor types. Here, we present the clinicopathologic features and differences in the morphologic patterns between RMC, CDC, and FH-deficient RCC in consequence of these recent developments. This study included a total of 100 cases classified using contemporary criteria and ancillary tests. Thirty-three RMCs (SMARCB1/INI1-deficient, hemoglobinopathy), 38 CDCs (SMARCB1/INI1-retained), and 29 RCCs defined by the FH-deficient phenotype (FH/2SC or FH/2SC with FH mutation, regardless of HLRCC syndromic stigmata/history) were selected. The spectrum of morphologic patterns was critically evaluated, and the differences between the morphologic patterns present in the 3 groups were analyzed statistically. Twenty-five percent of cases initially diagnosed as CDC were reclassified as FH-deficient RCC on the basis of our contemporary diagnostic approach. Among the different overlapping morphologic patterns, sieve-like/cribriform and reticular/yolk sac tumor-like patterns favored RMCs, whereas intracystic papillary and tubulocystic patterns favored FH-deficient RCC. The tubulopapillary pattern favored both CDCs and FH-deficient RCCs, and the multinodular infiltrating papillary pattern favored CDCs. Infiltrating glandular and solid sheets/cords/nested patterns were not statistically different among the 3 groups. Viral inclusion-like macronucleoli, considered as a hallmark of HLRCC-RCCs, were observed significantly more frequently in FH-deficient RCCs. Despite the overlapping morphology found among these clinically aggressive infiltrating high-grade adenocarcinomas of the kidney, reproducible differences in morphology emerged between these categories after rigorous characterization. Finally, we recommend that definitive diagnosis of CDC should only be made if RMC and FH-deficient RCC are excluded.
Asunto(s)
Biomarcadores de Tumor/deficiencia , Carcinoma de Células Renales/patología , Fumarato Hidratasa/deficiencia , Médula Renal/patología , Neoplasias Renales/patología , Túbulos Renales Colectores/patología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Australia , Biomarcadores de Tumor/genética , Biopsia , Brasil , Canadá , Carcinoma de Células Renales/clasificación , Carcinoma de Células Renales/enzimología , Carcinoma de Células Renales/genética , Niño , Análisis Mutacional de ADN , Diagnóstico Diferencial , Europa (Continente) , Femenino , Fumarato Hidratasa/genética , Predisposición Genética a la Enfermedad , Humanos , Inmunohistoquímica , Médula Renal/enzimología , Neoplasias Renales/clasificación , Neoplasias Renales/enzimología , Neoplasias Renales/genética , Túbulos Renales Colectores/enzimología , Masculino , Persona de Mediana Edad , Mutación , Clasificación del Tumor , Fenotipo , Valor Predictivo de las Pruebas , Estudios Retrospectivos , Estados Unidos , Adulto JovenRESUMEN
Between 10% and 15% of colorectal carcinomas demonstrate sporadic DNA mismatch-repair protein deficiency as a result of MLH1 promoter methylation and are thought to arise from sessile serrated adenomas, termed the serrated neoplasia pathway. Although the presence of the BRAF V600E mutation is indicative of a sporadic cancer, up to 30% to 50% of colorectal carcinomas with MLH1 promoter hypermethylation will lack a BRAF mutation. We report the clinicopathologic and molecular features of MLH1-deficient colorectal carcinoma with wild-type BRAF and MLH1 promoter hypermethylation (referred to as MLH1-hypermethylated BRAF wild-type colorectal carcinoma, n=36) in comparison with MLH1-deficient BRAF-mutated colorectal carcinoma (n=113) and Lynch syndrome-associated colorectal carcinoma (n=36). KRAS mutations were identified in 31% of MLH1-hypermethylated BRAF wild-type colorectal carcinomas compared with 0% of MLH1-deficient BRAF-mutated colorectal carcinomas and 37% of Lynch syndrome-associated colorectal carcinomas. When a precursor polyp was identified, MLH1-hypermethylated BRAF wild-type colorectal carcinomas arose from precursor polyps resembling conventional tubular/tubulovillous adenomas in contrast to MLH1-deficient BRAF-mutated colorectal carcinomas, which arose from precursor sessile serrated adenomas (P<0.001). Both MLH1-hypermethylated BRAF wild-type colorectal carcinoma and MLH1-deficient BRAF-mutated colorectal carcinoma had a predilection for the right colon compared with Lynch syndrome-associated colorectal carcinoma (86% vs. 92% vs. 49%, P<0.001). There was no significant difference in mucinous differentiation, tumor-infiltrating lymphocytes, Crohn-like reaction, and medullary differentiation between the 3 tumor groups. Using Kaplan-Meier survival functions, there was no significant difference in disease-specific survival between the 3 patient groups (P>0.05). In conclusion, our results indicate that MLH1-hypermethylated BRAF wild-type colorectal carcinomas can harbor KRAS mutations and arise from precursor polyps resembling conventional tubular/tubulovillous adenomas.
Asunto(s)
Adenocarcinoma/genética , Adenoma/genética , Neoplasias Colorrectales/genética , Metilación de ADN , Homólogo 1 de la Proteína MutL/deficiencia , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Proto-Oncogénicas p21(ras)/genética , Adenocarcinoma/mortalidad , Adenocarcinoma/patología , Adenoma/mortalidad , Adenoma/patología , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/deficiencia , Biomarcadores de Tumor/genética , Estudios de Casos y Controles , Neoplasias Colorrectales/mortalidad , Neoplasias Colorrectales/patología , Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Bases de Datos Factuales , Femenino , Estudios de Seguimiento , Humanos , Inmunohistoquímica , Estimación de Kaplan-Meier , Masculino , Inestabilidad de Microsatélites , Persona de Mediana Edad , Homólogo 1 de la Proteína MutL/genética , Mutación , Regiones Promotoras GenéticasRESUMEN
Current guidelines on germline mutation testing for patients suspected of having Lynch syndrome are not entirely clear in patients with tumors demonstrating isolated loss of PMS2 immunohistochemical expression. We analyzed the clinical and pathologic features of patients with tumors demonstrating isolated loss of PMS2 expression in an attempt to (1) determine the frequency of germline MLH1 and PMS2 mutations and (2) correlate mismatch-repair protein immunohistochemistry and tumor histology with germline mutation results. A total of 3213 consecutive colorectal carcinomas and 215 consecutive endometrial carcinomas were prospectively analyzed for DNA mismatch-repair protein expression by immunohistochemistry. In total, 32 tumors from 31 patients demonstrated isolated loss of PMS2 immunohistochemical expression, including 16 colorectal carcinomas and 16 endometrial carcinomas. Microsatellite instability (MSI) polymerase chain reaction was performed in 29 tumors from 28 patients with the following results: 28 tumors demonstrated high-level MSI, and 1 tumor demonstrated low-level MSI. Twenty of 31 (65%) patients in the study group had tumors demonstrating histopathology associated with high-level MSI. Seventeen patients underwent germline mutation analysis with the following results: 24% with MLH1 mutations, 35% with PMS2 mutations, 12% with PMS2 variants of undetermined significance, and 29% with no mutations in either MLH1 or PMS2. Three of the 4 patients with MLH1 germline mutations had a mutation that results in decreased stability and quantity of the MLH1 protein that compromises the MLH1-PMS2 protein complex, helping to explain the presence of immunogenic but functionally inactive MLH1 protein within the tumor. The high frequency of MLH1 germline mutations identified in our study has important implications for testing strategies in patients suspected of having Lynch syndrome and indicates that patients with tumors demonstrating isolated loss of PMS2 expression without a germline PMS2 mutation must have MLH1 mutation analysis performed.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/genética , Adenosina Trifosfatasas/deficiencia , Biomarcadores de Tumor/deficiencia , Biomarcadores de Tumor/genética , Carcinoma/química , Carcinoma/genética , Neoplasias Colorrectales Hereditarias sin Poliposis/química , Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Enzimas Reparadoras del ADN/deficiencia , Proteínas de Unión al ADN/deficiencia , Neoplasias Endometriales/química , Neoplasias Endometriales/genética , Mutación de Línea Germinal , Inmunohistoquímica , Proteínas Nucleares/genética , Proteínas Adaptadoras Transductoras de Señales/análisis , Adulto , Anciano , Biopsia , Carcinoma/patología , Neoplasias Colorrectales Hereditarias sin Poliposis/patología , Reparación de la Incompatibilidad de ADN , Análisis Mutacional de ADN , Neoplasias Endometriales/patología , Femenino , Predisposición Genética a la Enfermedad , Humanos , Masculino , Inestabilidad de Microsatélites , Persona de Mediana Edad , Endonucleasa PMS2 de Reparación del Emparejamiento Incorrecto , Homólogo 1 de la Proteína MutL , Proteínas Nucleares/análisis , Fenotipo , Reacción en Cadena de la Polimerasa , Valor Predictivo de las Pruebas , Estudios ProspectivosRESUMEN
PURPOSE: A growing body of evidence suggests that low testosterone can be an independent predictor of adverse clinicopathological features and worse prognosis in prostate cancer (PCa) patients. However, this association is still incompletely understood and the results are divisive. The aim of this study was to analyze testosterone as a predictor of aggressive disease in subjects with clinically localized PCa. MATERIALS AND METHODS: A cohort was conducted including the patients submitted to radical prostatectomy in our institution during a period of four years. The patients had clinically localized disease and their total testosterone (TT) was routinely measured preoperatively in the morning before surgery. They were stratified in groups with low (< 300 ng/dL) and normal TT (≥ 300 ng/dL). Tumor aggressiveness was inferred based on preoperative PSA levels, pathological Gleason score (lower, equal or greater than 7), TNM stage and surgical margins status. RESULTS: After analyzing 164 patients we found a significant association between mean preoperative TT and extraprostatic disease (379 for pT3 vs. 421 ng/for pT2 - p < 0.001, AUC > 0.99). Conversely, men with high Gleason score had similar mean TT compared to those with lower scores. Preoperative low TT (defined as TT < 300 ng/dL) could not be statistically correlated with either preoperative PSA levels, pathological Gleason score, extraprostatic extension, positive surgical margins or seminal vesicles involvement. CONCLUSIONS: This study indicates that testosterone may be a useful predictive tool once pathological extraprostatic extension was somewhat signaled by lower TT levels preoperatively. However, it does not consolidate a clear association between aggressive tumor biology and hypogonadism.
Asunto(s)
Biomarcadores de Tumor/sangre , Neoplasias de la Próstata/sangre , Neoplasias de la Próstata/patología , Testosterona/sangre , Adulto , Anciano , Biomarcadores de Tumor/deficiencia , Humanos , Masculino , Persona de Mediana Edad , Clasificación del Tumor , Valor Predictivo de las Pruebas , Pronóstico , Estudios Prospectivos , Antígeno Prostático Específico/sangre , Prostatectomía , Neoplasias de la Próstata/cirugía , Estadísticas no Paramétricas , Testosterona/deficienciaRESUMEN
Purpose A growing body of evidence suggests that low testosterone can be an independent predictor of adverse clinicopathological features and worse prognosis in prostate cancer (PCa) patients. However, this association is still incompletely understood and the results are divisive. The aim of this study was to analyze testosterone as a predictor of aggressive disease in subjects with clinically localized PCa. Materials and Methods A cohort was conducted including the patients submitted to radical prostatectomy in our institution during a period of four years. The patients had clinically localized disease and their total testosterone (TT) was routinely measured preoperatively in the morning before surgery. They were stratified in groups with low (< 300 ng/dL) and normal TT (≥ 300 ng/dL). Tumor aggressiveness was inferred based on preoperative PSA levels, pathological Gleason score (lower, equal or greater than 7), TNM stage and surgical margins status. Results After analyzing 164 patients we found a significant association between mean preoperative TT and extraprostatic disease (379 for pT3 vs. 421 ng/for pT2 - p < 0.001, AUC > 0.99). Conversely, men with high Gleason score had similar mean TT compared to those with lower scores. Preoperative low TT (defined as TT < 300 ng/dL) could not be statistically correlated with either preoperative PSA levels, pathological Gleason score, extraprostatic extension, positive surgical margins or seminal vesicles involvement. Conclusions This study indicates that testosterone may be a useful predictive tool once pathological extraprostatic extension was somewhat signaled by lower TT levels preoperatively. However, it does not consolidate a clear association between aggressive tumor biology and hypogonadism. .