RESUMO
INTRODUCTION: There are scant data on renal cell carcinoma (RCC) from relatively younger patients in South America using contemporary classification. METHODS: Fifty-nine consecutively treated patients with RCC (≤40 years old) were assessed from the National Institute of Neoplastic Diseases in Peru from 2008 to 2020 (34 males; 25 females), age range of 13 to 40 years. RESULTS: Most common presenting symptoms were flank pain (n = 40), hematuria (n = 19), and weight loss (n = 12). Associated conditions included 4 patients with proven or presumed tuberous sclerosis and 1 patient with von Hippel Lindau syndrome, all with clear cell RCC. Tumor histopathology was clear cell RCC in 32 of 59 (54%), chromophobe RCC in 6 of 59 (10%), and 5 of 59 (8%) each of papillary RCC and MiT family translocation-associated RCC. Four of 59 (7%) were FH-deficient RCC and 2 of 59 (3%) remained unclassified. The remaining tumors were isolated examples of clear cell papillary renal cell tumor, eosinophilic solid and cystic RCC (ESC RCC), RCC with fibromyomatous stroma, sarcomatoid RCC, and sarcomatoid clear cell RCC. Of the 4 FH-deficient RCCs, none had the classic morphology. The 5 MiT family translocation RCCs had variable morphology. There were 41 tumors without recurrence or metastases, 3 tumors with local recurrence only, 8 tumors with metastases only, and 7 tumors with both local recurrence and metastases. CONCLUSIONS: The current study demonstrates the importance of special studies in accurately classifying RCC in younger individuals. The distribution of RCC subtypes in younger individuals is similar between 2 representative large institutions of the United States and Peru.
Assuntos
Carcinoma de Células Renais , Neoplasias Renais , Masculino , Feminino , Humanos , Adolescente , Adulto Jovem , Adulto , Carcinoma de Células Renais/patologia , Neoplasias Renais/patologia , Peru/epidemiologia , Translocação Genética , HematúriaRESUMO
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.
Assuntos
Biomarcadores Tumorais/deficiência , Carcinoma de Células Renais/patologia , Fumarato Hidratase/deficiência , Medula Renal/patologia , Neoplasias Renais/patologia , Túbulos Renais Coletores/patologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Austrália , Biomarcadores Tumorais/genética , Biópsia , Brasil , Canadá , Carcinoma de Células Renais/classificação , Carcinoma de Células Renais/enzimologia , Carcinoma de Células Renais/genética , Criança , Análise Mutacional de DNA , Diagnóstico Diferencial , Europa (Continente) , Feminino , Fumarato Hidratase/genética , Predisposição Genética para Doença , Humanos , Imuno-Histoquímica , Medula Renal/enzimologia , Neoplasias Renais/classificação , Neoplasias Renais/enzimologia , Neoplasias Renais/genética , Túbulos Renais Coletores/enzimologia , Masculino , Pessoa de Meia-Idade , Mutação , Gradação de Tumores , Fenótipo , Valor Preditivo dos Testes , Estudos Retrospectivos , Estados Unidos , Adulto JovemRESUMO
We report 2 primary renal sarcomas demonstrating BCOR-CCNB3 gene fusions that have recently been identified in undifferentiated round cell sarcomas of bone and soft tissue. These neoplasms occurred in male children aged 11 and 12 years, and both were cystic as a result of entrapment and dilatation of native renal tubules. Both cases were composed of variably cellular bland spindle cells with fine chromatin set in myxoid stroma and separated by a branching capillary vasculature. Both neoplasms demonstrated immunoreactivity for BCOR, cyclin D1, TLE1, and SATB2 in the spindle neoplastic cells and negativity in the prominent capillary vasculature. One case was extensively cystic and had hypocellular areas that simulated cystic nephroma; this neoplasm recurred 3 years later as a solid, highly cellular spindle cell sarcoma in the abdominal cavity. The morphology and immunoprofile of these renal neoplasms was compared with a control group of other sarcomas with BCOR genetic abnormalities, including clear cell sarcoma of the kidney (CCSK), infantile undifferentiated round cell sarcomas of soft tissue/primitive myxoid mesenchymal tumor of infancy, and bone/soft tissue sarcomas with BCOR-CCNB3 gene fusion; along with primary renal synovial sarcoma. Our findings show that the renal sarcomas with BCOR-CCNB3 gene fusion overlap with CCSK. These results are in keeping with a "BCOR-alteration family" of renal and extrarenal neoplasms which includes CCSK and undifferentiated round cell sarcomas of soft tissue/primitive myxoid mesenchymal tumor of infancy (which typically harbor BCOR internal tandem duplication), and BCOR-CCNB3 sarcomas, all of which are primarily driven by BCOR overexpression and have overlapping (but not identical) clinicopathologic features.
Assuntos
Biomarcadores Tumorais/genética , Ciclina B/genética , Fusão Gênica , Neoplasias Renais/genética , Proteínas Proto-Oncogênicas/genética , Proteínas Repressoras/genética , Sarcoma de Células Claras/genética , Sarcoma/genética , Biomarcadores Tumorais/análise , Biópsia , Criança , Ciclina B/análise , Diagnóstico Diferencial , Predisposição Genética para Doença , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Neoplasias Renais/química , Neoplasias Renais/patologia , Neoplasias Renais/cirurgia , Masculino , Fenótipo , Valor Preditivo dos Testes , Proteínas Proto-Oncogênicas/análise , Proteínas Repressoras/análise , Sarcoma/química , Sarcoma/patologia , Sarcoma/cirurgia , Sarcoma de Células Claras/química , Sarcoma de Células Claras/patologiaRESUMO
Most institutions reflexively test all breast core needle biopsy specimens showing ductal carcinoma in situ (DCIS) for estrogen receptor (ER) and progesterone receptor (PR). However, 5 factors suggest that this reflex testing unnecessarily increases costs. First, ER/PR results do not currently impact the next step in standard therapy; namely, surgical excision. Second, a subset of surgical excisions performed for DCIS diagnosed on core needle biopsy will harbor infiltrating mammary carcinoma, which will then need to be retested for ER/PR. Third, because ER and PR labeling is often heterogeneous in DCIS, negative results for ER/PR on small core needle biopsy specimens should logically be repeated on surgical excision specimens with larger amounts of DCIS to be sure that the result is truly negative. Fourth, many patients with pure ER/PR-positive DCIS after surgical excision will decline hormone therapy, so any ER/PR testing of their DCIS is unnecessary. Fifth, PR status in DCIS has no proven independent value. We now examine the unnecessary added costs associated with reflex ER/PR testing of DCIS on core needle biopsy specimens due to these factors. We reviewed 58 core needle biopsies showing pure DCIS that also had a resulting surgical excision specimen at our institution over a period of 2 years. No patient received neoadjuvant hormone therapy. On surgical excision, 5 (8.6%) had only benign findings, 44 (75.9%) had pure DCIS, and 9 (15.5%) had DCIS with invasive mammary carcinoma. The 9 cases with invasive mammary carcinoma in the surgical excision specimen (16%) and the 4 pure DCIS in surgical excision specimens that were ER/PR negative on core needle biopsy would need repeat ER/PR testing. The total unnecessary increased cost of core needle biopsy specimen testing of these 13 cases was $8148.92 ($140/patient for the 58 patients in the study). We found that ER/PR testing results impacted patient management in only 16/49 pure DCIS cases after surgical excision (33%), indicating that ER/PR testing costing $20,685.72 ($357/patient in the study) had been performed unnecessarily. PR testing could have been omitted in the 16 cases in which ER/PR results were used, which would have saved $5014.72, or $86.46 per patient. Extrapolating the increased cost of $583 per DCIS diagnosis on core needle biopsy to 60,000 new cases of DCIS in the United States each year, reflex core needle biopsy ER/PR testing unnecessarily increases costs by approximately $35 million. We recommend that ER/PR not be reflexively ordered on core needle biopsy specimens or surgical excision specimens containing DCIS, but instead that ER alone be performed on surgical excision specimens only when hormone therapy is a serious consideration after medical oncology consultation.
Assuntos
Biomarcadores Tumorais/análise , Neoplasias da Mama/economia , Carcinoma Intraductal não Infiltrante/economia , Receptores de Estrogênio/análise , Receptores de Progesterona/análise , Adulto , Idoso , Biópsia com Agulha de Grande Calibre , Neoplasias da Mama/diagnóstico , Carcinoma Ductal de Mama/diagnóstico , Carcinoma Ductal de Mama/economia , Carcinoma Intraductal não Infiltrante/diagnóstico , Análise Custo-Benefício , Feminino , Humanos , Pessoa de Meia-Idade , Estados UnidosRESUMO
ER/PR/Her2 are often reflexively assessed in all core needle biopsies (CNBXs) containing invasive mammary carcinoma (IMC) so that neoadjuvant therapy can be considered. ER/PR/Her2 can be heterogenous, and there is growing consensus that negative results for any of these markers in small CNBXs should be repeated in larger excision specimens (EXS). The frequency and added cost of repeat testing of EXS containing untreated IMC with negative ER/PR/Her2 CNBX results has not previously been studied. We reviewed 198 CNBXs containing IMC, which had reflex ER/PR/Her2 testing and for which there was an EXS for review. We determined the number of cases in which ER/PR/Her2 immunohistochemistry and Her2 fluorescence in situ hybridization were negative on CNBX. Twenty-seven (13.6%) patients received neoadjuvant chemotherapy, and 8 (4%) patients did not have IMC on follow-up EXS, so for them testing the CNBX was necessary. Of the remaining 163 IMCs, 17% were ER negative, and 26% were PR negative, whereas 85% were Her2 negative or equivocal. At our institution, ER/PR were repeated on slightly more than one half of ER/PR-negative tumors, whereas Her2 was repeated on less than one third of Her2-negative/equivocal tumors. Had all negative tests been repeated, the increased cost of testing both the CNBX and EXS would be $100,821. Extrapolating to 230,000 new cases of IMC in the United States each year, the increased cost of repeat testing of all negative ER/PR/Her2 CNBX results would be >$117 million dollars. Limiting reflex testing to ER would decrease the cost of repeat testing to $10 million dollars. We suggest that ER/PR/Her2 should not be reflexively performed on all CNBX specimens containing IMC but instead be routinely performed on EXS and only selectively on CNBX specimens if neoadjuvant chemotherapy is a serious consideration for that individual patient.
Assuntos
Neoplasias da Mama/química , Neoplasias da Mama/economia , Carcinoma Ductal de Mama/química , Carcinoma Ductal de Mama/economia , Custos de Cuidados de Saúde , Receptor ErbB-2/análise , Receptores de Estrogênio/análise , Receptores de Progesterona/análise , Idoso , Biópsia com Agulha de Grande Calibre/economia , Neoplasias da Mama/patologia , Carcinoma Ductal de Mama/patologia , Feminino , Humanos , Pessoa de Meia-IdadeRESUMO
Targeted therapy in advanced clear cell renal cell carcinomas (RCC) is now an established modality. The latter is in stark contrast to non-clear cell subtypes. We explored the translational support for the use of antagonists of the mammalian target of rapamycin (mTOR) and the vascular endothelial growth factor pathways in chromophobe RCC. The immunoexpression of PTEN, phos-AKT, phosphorylated S6 (phos-S6), 4EBP1, p27, c-MYC, and HIF-1α was evaluated in 33 patients with chromophobe RCC who were treated by partial/radical nephrectomy without adjuvant therapy. PTEN was lower in tumor than in normal kidney (P<.001), and loss of PTEN expression was found in 67% of the tumors. In tumor tissues, phos-S6 and 4EBP1 were higher than in normal kidney (P≤.005). Conversely, scores of p27 were lower in tumor than in normal kidney (P<.001). Finally, scores of phos-AKT, c-MYC, and HIF-1α were not significantly different in tumor and in normal kidney. Overall mortality and cancer-specific mortality were 9% and 0%, respectively. Multifocal tumors had higher levels of PTEN, phos-AKT, and HIF-1α (P≤.01). None of the clinicopathologic variables (age, ethnicity, gender, pT stage, tumor size, multifocality, and positive surgical margins) was associated with outcome. Similarly, none of the tested biomarkers predicted overall mortality, either in unadjusted or adjusted Cox regression models. In summary, our study provides new evidence of dysregulation of the mTOR pathway in chromophobe RCC. Immunohistochemistry for mTOR pathway and hypoxia-induced pathway members lacked prognostic significance in our cohort.
Assuntos
Biomarcadores Tumorais/metabolismo , Carcinoma de Células Renais/metabolismo , Neoplasias Renais/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Renais/mortalidade , Carcinoma de Células Renais/patologia , Terapia Combinada , Feminino , Humanos , Rim/anatomia & histologia , Rim/metabolismo , Neoplasias Renais/mortalidade , Neoplasias Renais/patologia , Masculino , Maryland/epidemiologia , Pessoa de Meia-Idade , Nefrectomia , Prognóstico , Fatores de Risco , Taxa de SobrevidaRESUMO
BACKGROUND: Gallbladder cancer (GBC) is an uncommon neoplasm in the United States, but one with high mortality rates. This malignancy remains largely understudied at the molecular level such that few targeted therapies or predictive biomarkers exist. EXPERIMENTAL DESIGN: We built the first series of serial analysis of gene expression (SAGE) libraries from GBC and nonneoplastic gallbladder mucosa, composed of 21-bp long-SAGE tags. SAGE libraries were generated from three stage-matched GBC patients (representing Hispanic/Latino, Native American, and Caucasian ethnicities, respectively) and one histologically alithiasic gallbladder. Real-time quantitative PCR was done on microdissected epithelium from five matched GBC and corresponding nonneoplastic gallbladder mucosa. Immunohistochemical analysis was done on a panel of 182 archival GBC in high-throughput tissue microarray format. RESULTS: SAGE tags corresponding to connective tissue growth factor (CTGF) transcripts were identified as differentially overexpressed in all pairwise comparisons of GBC (P < 0.001). Real-time quantitative PCR confirmed significant overexpression of CTGF transcripts in microdissected primary GBC (P < 0.05), but not in metastatic GBC, compared with nonneoplastic gallbladder epithelium. By immunohistochemistry, 66 of 182 (36%) GBC had high CTGF antigen labeling, which was significantly associated with better survival on univariate analysis (P = 0.0069, log-rank test). CONCLUSIONS: An unbiased analysis of the GBC transcriptome by SAGE has identified CTGF expression as a predictive biomarker of favorable prognosis in this malignancy. The SAGE libraries from GBC and nonneoplastic gallbladder mucosa are publicly available at the Cancer Genome Anatomy Project web site and should facilitate much needed research into this lethal neoplasm.
Assuntos
Neoplasias da Vesícula Biliar/genética , Proteínas Imediatamente Precoces/genética , Peptídeos e Proteínas de Sinalização Intercelular/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/metabolismo , Biologia Computacional , Fator de Crescimento do Tecido Conjuntivo , Etnicidade/genética , Feminino , Vesícula Biliar/metabolismo , Neoplasias da Vesícula Biliar/metabolismo , Neoplasias da Vesícula Biliar/mortalidade , Neoplasias da Vesícula Biliar/patologia , Expressão Gênica , Perfilação da Expressão Gênica , Humanos , Proteínas Imediatamente Precoces/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Prognóstico , Análise de Regressão , Análise Serial de TecidosRESUMO
Reported is the case of a 17-year-old girl with a multicystic tumor in the middle of the right kidney. Partial nephrectomy revealed an epithelial neoplasm with multilocular cystic renal cell carcinoma pattern. The cells exhibited strong nuclear reactivity for TFE3 protein and supported the diagnosis of Xp11 translocation carcinoma of the kidney. A similar case has not been found in the literature. The example emphasizes the high index of suspicion needed for an accurate diagnosis of renal carcinomas.
Assuntos
Carcinoma de Células Renais/genética , Cromossomos Humanos Par 1 , Cromossomos Humanos X , Neoplasias Renais/genética , Translocação Genética , Adolescente , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/metabolismo , Carcinoma de Células Renais/metabolismo , Carcinoma de Células Renais/patologia , Núcleo Celular/metabolismo , Núcleo Celular/patologia , Feminino , Humanos , Neoplasias Renais/metabolismo , Neoplasias Renais/patologia , NefrectomiaRESUMO
BACKGROUND: Aberrant methylation of tumor-suppressor genes is associated with a loss of gene function that can afford selective growth advantages to sporadic neoplastic cells arising during gallbladder inflammation. METHODS: Fifty-four gallbladder neoplasms were selected from tumor banks in the United States and Chile. Each of the neoplasms was subjected to methylation-specific polymerase chain reaction to detect promoter methylation associated with six candidate tumor-suppressor genes (p16, APC, methylguanine methyltransferase, hMLH1, retinoic acid receptor beta-2, and p73) implicated in multiple human cancer types. RESULTS: Aberrant methylation of any of the six candidate tumor-suppressor genes was detected in 72% of the gallbladder neoplasms, 28% of the cases of chronic cholecystitis, and in only 1 of the 15 normal gallbladder controls. The four most commonly methylated genes in the gallbladder cancers were p16 (56%), p73 (28%), APC (27%), and hMLH1 (14%). Significant differences in gene methylation were discovered between US gallbladder cancers and those from Chile, where gallbladder cancer is one of the leading causes of cancer-related deaths. APC methylation was present in 42% of the US cases but in only 14% of the Chilean tumors (P =.028). p73 methylation was common among the Chilean cancers (40%) compared with those from the United States (13%; P =.034). CONCLUSIONS: The acquisition of hypermethylation at multiple tumor-suppressor gene-promoter sites may contribute to tumor formation and progression within the chronically inflamed gallbladder. The apparent differences in methylation patterns among the Chilean and US gallbladder cases may indicate a unique biology associated with this cancer in different parts of the world.