RESUMEN
Fumarate hydratase (FH)-deficient renal cell carcinomas are rare neoplasms characterized by wide morphologic heterogeneity and pathogenetic mutations in the FH gene. They often show aggressive behavior with rapid diffusion to distant organs, so novel therapeutic scenarios have been explored, including EGFR inhibitors and PD-L1 expression for targeted immunotherapy. Herein, we investigated a series of 11 primary FH-deficient renal cell carcinomas and 7 distant metastases to evaluate tumor heterogeneity even in metastatic sites and estimate the specific spread rates to various organs. Furthermore, the tumors were tested for immunohistochemical PD-L1 expression and EGFR mutations. Most metastatic cases involved the abdominal lymph nodes (4/7; 57%), followed by the peritoneum (3/7; 42%), the liver (2/7; 29%), and the lungs (1/7; 14%). Six metastatic localizations were histologically documented, revealing a morphologic heterogeneous architecture often differing from that of the corresponding primary renal tumor. Peritoneal involvement morphologically resembled a benign reactive mesothelial process or primary peritoneal mesothelioma, thus advocating to perform an accurate immunohistochemical panel, including PAX8 and FH, to reach a proper diagnosis. A pure low-grade succinate dehydrogenase-looking primary FH-deficient renal cell carcinoma was also recorded. As for therapy, significant PD-L1 labeling was found in 60% of primary renal tumors, whereas none of them carried pathogenetic EGFR mutations. Our data show that FH-deficient renal cell carcinoma may be morphologically heterogeneous in metastases as well, which involve the lymph nodes, the liver, and the peritoneum more frequently than other renal tumors. Due to the high frequency of this latter (42%), pathologists should always be concerned about ruling out mesothelial-derived mimickers, and the occurrence of rarer, primary, low-grade-looking types. Finally, contrary to EGFR mutations, PD-L1 expression could be a possible predictive biomarker for the therapy of these tumors.
RESUMEN
BACKGROUND: Warthin's tumour (WT) is a common benign lesion of the major salivary glands. The nature of WT remains controversial, with particular regard to the presence of clonal chromosomal abnormalities, including the t(11;19) translocation involving the CRTC1 and MAML2 genes, that have been identified in both WT and mucoepidermoid carcinoma. In this study, we focused our attention on metaplastic WT variants, and we conducted a fluorescent in situ hybridisation (FISH) analysis for the presence of MAML2 gene rearrangement. METHODS: Dual-colour FISH analysis was performed on paraffin-embedded sections of eight WTs showing metaplastic changes (five with squamous metaplasia, two with mucinous metaplasia and one with both) using a MAML2 break-apart probe. RESULTS: Presence of split signals indicative of gene rearrangement was identified in a subset of cells in areas of squamous metaplasia in two samples of WT. No rearrangement was observed in the oncocytic epithelium, in lymphocytes and in areas of mucinous metaplasia. CONCLUSIONS: The presence of a small subpopulation of cells carrying MAML2 rearrangement in areas of squamous metaplasia within WT could predispose these lesions to malignant transformation in mucoepidermoid carcinoma and could represent a molecular link between the two entities.
Asunto(s)
Adenolinfoma/genética , Proteínas de Unión al ADN/genética , Reordenamiento Génico/genética , Proteínas Nucleares/genética , Neoplasias de la Parótida/genética , Factores de Transcripción/genética , Adenolinfoma/patología , Adulto , Anciano , Carcinoma Mucoepidermoide/genética , Carcinoma Mucoepidermoide/patología , Sondas de ADN , Células Epiteliales/patología , Femenino , Fibrosis , Colorantes Fluorescentes , Histiocitos/patología , Humanos , Hibridación Fluorescente in Situ , Linfocitos/patología , Masculino , Metaplasia/genética , Persona de Mediana Edad , Necrosis , Células Oxífilas/patología , Neoplasias de la Parótida/patología , TransactivadoresRESUMEN
Pulmonary hamartoma (PH) may show various combinations of mesenchymal tissues with entrapment of respiratory epithelium. An uncommon variant of PH prevalently consisting of smooth muscle with mucinous proliferation has been reported in literature under several definitions as sporadic reports. We collected a series of 6 leiomyomatous PH associated with mucinous growth from consultation files (3 cases) and multicentric revision of archival files among 128 consecutive surgically resected PH. The lesions have a prevalence for male gender (5:1) and lower lobes (5:1), with a mean age at diagnosis of 61 years. All cases were incidentally disclosed in asymptomatic patients and had an indolent behavior. At histology, 2 cases consisted uniquely of smooth muscle and 4 also showed mature adipose tissue. The mucinous proliferation consisted of a monotonous growth of columnar cells lacking p63-positive basal cells and expressing pan-CKs, MUC5A, and CK7, but negative with TTF-1, napsin, MUC1, MUC2, MUC6, CK20, and CDX2. Smooth muscle was negative with hormonal receptors. Molecular analysis using a multiplex gene panel did not reveal gene mutations, while ALK, BRAF, and ROS1 were negative. In conclusion, we describe a small series of uncommon PH with prevalent leiomyomatous mesenchymal component associated with a mucinous growth (mucinous adenomyomatous hamartoma). Despite the lack of basal cells coating mucinous proliferation and irregular architecture, the favorable outcome and lack of molecular alterations most likely lay for a benign/low-grade tumor. Pathologists should be aware of this unusual occurrence to prevent a diagnosis of overt malignancy, particularly in frozen section, small biopsy, and cytology.
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Hamartoma/diagnóstico , Enfermedades Pulmonares/diagnóstico , Pulmón/patología , Mucosa Respiratoria/patología , Anciano , Enfermedades Asintomáticas , Biomarcadores/análisis , Diagnóstico Diferencial , Femenino , Hamartoma/patología , Humanos , Hallazgos Incidentales , Enfermedades Pulmonares/patología , Masculino , Persona de Mediana Edad , Factores de Riesgo , Factores SexualesRESUMEN
BACKGROUND: PARV4 is a new member of the Parvoviridae family not closely related to any of the known human parvoviruses. Viremia seems to be a hallmark of PARV4 infection and viral DNA persistence has been demonstrated in a few tissues. Till now, PARV4 has not been associated with any disease and its prevalence in human population has not been clearly established. This study was aimed to assess the tissue distribution and the ability to persist of PARV4 in comparison to parvovirus B19 (B19V). RESULTS: PARV4 and B19V DNA detection was carried out in various tissues of individuals without suspect of acute viral infection, by a real time PCR and a nested PCR, targeting the ORF2 and the ORF1 respectively. Low amount of PARV4 DNA was found frequently (>40%) in heart and liver of adults individuals, less frequently in lungs and kidneys (23,5 and 18% respectively) and was rare in bone marrow, skin and synovium samples (5,5%, 4% and 5%, respectively). By comparison, B19V DNA sequences were present in the same tissues with a higher frequency (significantly higher in myocardium, skin and bone marrow) except than in liver where the frequency was the same of PARV4 DNA and in plasma samples where B19V frequency was significantly lower than that of PARV4 CONCLUSIONS: The particular tropism of PARV4 for liver and heart, here emerged, suggests to focus further studies on these tissues as possible target for viral replication and on the possible role of PARV4 infection in liver and heart diseases. Neither bone marrow nor kidney seem to be a common target of viral replication.
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Portador Sano/epidemiología , ADN Viral/aislamiento & purificación , Infecciones por Parvoviridae/epidemiología , Parvoviridae/clasificación , Parvoviridae/aislamiento & purificación , Adulto , Anciano , Anciano de 80 o más Años , Médula Ósea/virología , Portador Sano/virología , ADN Viral/genética , Corazón/virología , Humanos , Riñón/virología , Hígado/virología , Pulmón/virología , Persona de Mediana Edad , Sistemas de Lectura Abierta , Parvoviridae/genética , Infecciones por Parvoviridae/virología , Plasma/virología , Reacción en Cadena de la Polimerasa , Piel/virología , Membrana Sinovial/virología , Tropismo ViralRESUMEN
BACKGROUND: Although imaging techniques have demonstrated the existence of microvascular abnormalities in hypertrophic cardiomyopathy (HCM), a detailed histopathological assessment is lacking as well as a comparison between different phases of the disease. We aimed to compare microvasculopathy and myocardial fibrosis in hypertrophic obstructive cardiomyopathy (HOCM) versus end-stage (ES) HCM. METHODS: 27 myectomy specimens of HOCM patients and 30 ES-HCM explanted hearts were analyzed. Myocardial fibrosis was quantitatively determined with dedicated software and qualitatively classified as scar-like or interstitial. Intramural coronary arteries were evaluated separately according to lumen diameter: 100-500⯵ versus <100⯵. Microvasculopathy assessment included the description of medial and intimal abnormalities and stenosis grading. The two subgroups were compared considering only the anterobasal septum of ES explanted hearts. RESULTS: Median value of fibrosis in the anterobasal septum of explanted hearts was 34.6% as opposed to 10.3% of myectomy specimens (pâ¯<â¯0.001). Scar-like fibrosis was widely found in ES hearts while interstitial fibrosis was distinctive of HOCM (pâ¯<â¯0.001). All slides showed 100-500⯵ microvasculopathy without any differences between subgroups in terms of lumen narrowing, extent of the disease and type of parietal involvement. Among ES hearts these lesions were associated with scar-like fibrosis (pâ¯=â¯0.034). <100-µ microvasculopathy was also frequent with no differences between subgroups. CONCLUSIONS: Microvasculopathy is an intrinsic feature of HCM with similar characteristics across the natural phases of the disease. Conversely, myocardial fibrosis changes over time with ES hearts showing a three-fold greater amount, mainly scar-like. ES showed a closer association between microvasculopathy and replacement fibrosis.
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Cardiomiopatía Hipertrófica/patología , Vasos Coronarios/patología , Fibrosis Endomiocárdica/patología , Microvasos/patología , Remodelación Vascular/fisiología , Adulto , Cardiomiopatía Hipertrófica/diagnóstico por imagen , Vasos Coronarios/diagnóstico por imagen , Fibrosis Endomiocárdica/diagnóstico por imagen , Femenino , Humanos , Masculino , Microvasos/diagnóstico por imagen , Persona de Mediana EdadRESUMEN
BACKGROUND: Current therapies are ineffective in preventing the development of cardiac phenotype in young carriers of mutations associated with hypertrophic cardiomyopathy (HCM). Ranolazine, a late Na+ current blocker, reduced the electromechanical dysfunction of human HCM myocardium in vitro. METHODS AND RESULTS: To test whether long-term treatment prevents cardiomyopathy in vivo, transgenic mice harboring the R92Q troponin-T mutation and wild-type littermates received an oral lifelong treatment with ranolazine and were compared with age-matched vehicle-treated animals. In 12-months-old male R92Q mice, ranolazine at therapeutic plasma concentrations prevented the development of HCM-related cardiac phenotype, including thickening of the interventricular septum, left ventricular volume reduction, left ventricular hypercontractility, diastolic dysfunction, left-atrial enlargement and left ventricular fibrosis, as evaluated in vivo using echocardiography and magnetic resonance. Left ventricular cardiomyocytes from vehicle-treated R92Q mice showed marked excitation-contraction coupling abnormalities, including increased diastolic [Ca2+] and Ca2+ waves, whereas cells from treated mutants were undistinguishable from those from wild-type mice. Intact trabeculae from vehicle-treated mutants displayed inotropic insufficiency, increased diastolic tension, and premature contractions; ranolazine treatment counteracted the development of myocardial mechanical abnormalities. In mutant myocytes, ranolazine inhibited the enhanced late Na+ current and reduced intracellular [Na+] and diastolic [Ca2+], ultimately preventing the pathological increase of calmodulin kinase activity in treated mice. CONCLUSIONS: Owing to the sustained reduction of intracellular Ca2+ and calmodulin kinase activity, ranolazine prevented the development of morphological and functional cardiac phenotype in mice carrying a clinically relevant HCM-related mutation. Pharmacological inhibitors of late Na+ current are promising candidates for an early preventive therapy in young phenotype-negative subjects carrying high-risk HCM-related mutations.
Asunto(s)
Cardiomiopatía Hipertrófica/prevención & control , Miocitos Cardíacos/efectos de los fármacos , Ranolazina/farmacología , Bloqueadores de los Canales de Sodio/farmacología , Sodio/metabolismo , Animales , Western Blotting , Proteínas Quinasas Dependientes de Calcio-Calmodulina/metabolismo , Cardiomiopatía Hipertrófica/genética , Cardiomiopatía Hipertrófica/metabolismo , Cardiomiopatía Hipertrófica/fisiopatología , Modelos Animales de Enfermedad , Ecocardiografía Doppler , Acoplamiento Excitación-Contracción/efectos de los fármacos , Predisposición Genética a la Enfermedad , Frecuencia Cardíaca , Hipertrofia Ventricular Izquierda/genética , Hipertrofia Ventricular Izquierda/metabolismo , Hipertrofia Ventricular Izquierda/prevención & control , Imagen por Resonancia Magnética , Masculino , Potenciales de la Membrana , Ratones Endogámicos C57BL , Ratones Transgénicos , Microscopía Confocal , Mutación , Contracción Miocárdica/efectos de los fármacos , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , Fenotipo , Factores de Tiempo , Troponina T/genética , Disfunción Ventricular Izquierda/genética , Disfunción Ventricular Izquierda/metabolismo , Disfunción Ventricular Izquierda/prevención & control , Función Ventricular Izquierda/efectos de los fármacosRESUMEN
BACKGROUND: Ameloblastoma is a benign odontogenic tumour that may exhibit aggressive biological behaviour with local recurrence and metastasis following initial surgical resection. Surgery is the most acceptable modality of treatment, even if a biological approach is currently on study. We report a case of maxillary ameloblastoma with development of neck and brain metastases after repeated local recurrences. Molecular analysis was performed with the aim to better characterize this neoplasm and its peculiar behaviour. METHODS: We investigated the status of tumour protein p53 (TP53), epidermal growth factor receptor (EGFR), B-Raf proto-oncogene (BRAF) and human epidermal growth factor receptor 2 (HER2) genes with immunohistochemical, fluorescent in situ hybridization and/or direct sequencing in order to clarify their possible role in the development of this neoplasm and the possibility of a targeted treatment. RESULTS: The histological appearance of the tumour was the same in the primary lesion, in the recurrence and in the metastases. EGFR positivity was present in the recurrence and the brain metastasis, while HER2 was negative in all samples tested. Fluorescent in situ hybridization analysis for EGFR showed disomy of neoplastic cells. Direct DNA sequencing of TP53 gene exons 5 - 9 was carried out in tumour samples from the infratemporal recurrence and brain metastasis, with no mutational alteration detected. Similarly, sequencing analysis of BRAF exon 15 (V600) and EGFR gene showed wild type results in all samples tested. CONCLUSIONS: Further studies are needed to identify molecular pathways that may provide an opportunity of alternative treatments and/or new potential predictive markers of local and distant spread of this rare tumour.
RESUMEN
Epithelioid angiosarcoma of the thyroid is a rare mesenchymal neoplasm, mainly described in the Alpine area. This lesion was initially considered an anaplastic carcinoma, but immunohistochemical and ultrastructural features have proven the endothelial differentiation of tumor cells. In fact, the peculiarity of this tumor concerns the expression of low-molecular weight cytokeratins by neoplastic cells of endothelial origin. We describe a case of epithelioid angiosarcoma of the thyroid occurred in a 73-year-old woman from an Italian non-Alpine area, and a review of non-Alpine primary thyroid epitheliod angiosarcoma is presented.
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Hemangiosarcoma/patología , Sarcoma/patología , Neoplasias de la Tiroides/patología , Anciano , Femenino , Hemangiosarcoma/metabolismo , Humanos , Inmunohistoquímica , Italia , Sarcoma/metabolismo , Neoplasias de la Tiroides/metabolismoRESUMEN
PLAG1 (pleomorphic adenoma gene 1) is a proto-oncogene whose overexpression is a crucial oncogenic event in salivary gland pleomorphic adenomas (PA), and in carcinoma ex-PA. The aim of the present study is to evaluate the sensitivity and the specificity of PLAG1 as a marker in the differential diagnosis of salivary gland benign and malignant tumors. We examined 101 cases, including 36 PAs, 8 myoepitheliomas, 3 basal cell adenomas, and 1 canalicular adenoma among benign tumors; 16 mucoepidermoid carcinomas, 10 adenoid cystic carcinomas, 8 acinic cell carcinomas, 8 polymorphous low-grade adenocarcinomas, 7 salivary duct carcinoma, and 4 epithelial-myoepithelial carcinoma among malignant tumors. PLAG1 was diffusely positive in 94.4% of PAs and in all myoepitheliomas, although with a lower staining intensity. Among malignant tumors, 2 (25%) polymorphous low-grade adenocarcinomas and 1 salivary duct carcinoma ex-PA were positive. In conclusion, PLAG1 is a marker with good specificity for PA and could be a useful diagnostic adjunct in the diagnosis of salivary gland tumors. In particular, this marker is negative in the most common salivary carcinomas, including adenoid cystic carcinoma, mucoepidermoid carcinoma, and acinic cell carcinoma. However, some mimickers of PA, like polymorphous low-grade adenocarcinoma, may show occasional positivity for PLAG1, thus limiting its diagnostic use. In addition, carcinoma ex-PA shows consistent positivity, and therefore should be considered as a diagnostic possibility in case of a malignant tumor with PLAG1 expression.
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Adenoma Pleomórfico/diagnóstico , Biomarcadores de Tumor/metabolismo , Carcinoma/diagnóstico , Proteínas de Unión al ADN/metabolismo , Neoplasias de las Glándulas Salivales/diagnóstico , Diagnóstico Diferencial , Estudios de Factibilidad , Humanos , Inmunohistoquímica , Proto-Oncogenes Mas , Sensibilidad y EspecificidadRESUMEN
AIMS AND BACKGROUND: A number of immunohistochemical markers have been suggested as useful in the positive diagnosis of epithelioid mesothelioma. The most widely used mesothelioma markers are thrombomodulin, calretinin, cytokeratin 5/6, D2-40 and WT-1. Numerous investigations have demonstrated their variable sensitivity and specificity in differentiating epithelioid mesothelioma from lung adenocarcinoma. However, data on the expression of these markers in other types of lung carcinomas are very limited. We evaluated the expression of these markers in a series of 172 primary carcinomas of the lung and in 75 epithelioid pleural mesotheliomas. RESULTS: Thrombomodulin expression was found in squamous cell carcinomas (71%), small cell lung carcinomas (11%), adenocarcinomas (4%), large cell carcinomas (50%), large cell neuroendocrine carcinomas (25%) and in sarcomatoid carcinomas (10%). Calretinin expression was common in small cell lung carcinomas (44%) and large cell neuroendocrine carcinomas (25%), less common in squamous cell carcinomas (20%), rare and focal in adenocarcinomas (4%) and sarcomatoid carcinomas (10%). Cytokeratin 5/6 was expressed in most of the squamous cell carcinomas (94.5%). Immunoreactivity was also found in large cell carcinomas (50%), sarcomatoid carcinomas (30%) and rarely in adenocarcinomas (4%). D2-40 was consistently expressed in squamous cell carcinomas (42%). Focal immunoreactivity was found in adenocarcinomas (3%). WT-1 was focally present in one (2%) squamous cell carcinoma. CONCLUSIONS: These results indicate that some of the most commonly used mesothelioma markers may react with different types of primary lung carcinomas. These data should be taken into consideration especially when dealing with small biopsy fragments and poorly differentiated tumors.
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Adenocarcinoma/metabolismo , Biomarcadores de Tumor/metabolismo , Carcinoma de Células Escamosas/metabolismo , Neoplasias Pulmonares/metabolismo , Mesotelioma/metabolismo , Neoplasias Glandulares y Epiteliales/metabolismo , Neoplasias Pleurales/metabolismo , Adenocarcinoma/diagnóstico , Anticuerpos Monoclonales de Origen Murino/química , Calbindina 2/metabolismo , Carcinoma de Células Escamosas/diagnóstico , Diagnóstico Diferencial , Humanos , Inmunohistoquímica , Queratina-5/metabolismo , Queratina-6/metabolismo , Neoplasias Pulmonares/diagnóstico , Glicoproteínas de Membrana/inmunología , Glicoproteínas de Membrana/metabolismo , Mesotelioma/diagnóstico , Neoplasias Glandulares y Epiteliales/diagnóstico , Neoplasias Pleurales/diagnóstico , Trombomodulina/metabolismo , Proteínas WT1/metabolismoRESUMEN
We tested a selected series of patients with single urothelial high-grade pT1 stage (pT1 HG) or urothelial carcinoma in situ (CIS) with a set of immunohistochemical markers to elaborate a risk score for progression. We retrospectively reviewed all first diagnoses of single, <3 cm, urothelial papillary carcinoma pT1 HG or isolated CIS between 2006 and 2009. Galectin-3, CD44, E-cadherin, CD138, p16, survivin, HYAL-1, and topoisomerase-II α were used. A grading score 0 or 1 for each immunohistochemical staining was assigned to obtain a total score for assessing the progression. The median "progression score" was selected as cutoff value for statistical analysis. Overall, 23 patients (19 pT1 HG and 4 CIS) were included in the study. After a median follow-up of 21 months (range, 12 to 34 mo), 9 patients (39.1%) showed disease recurrence whereas 4 patients (17.4%) showed tumor progression. Topoisomerase-II α, p16, survivin, galectin-3, and CD138 were significantly associated with progression. Progression score ranged from 0 (best prognosis) to 7 (worst prognosis). Using a score ≥5 as a threshold, specificity was 78.9%, sensitivity 100%, positive predictive value 50%, and negative predictive value 100%. ROC area (a 95% confidence interval, 0.807-1.000; P<0.001). This immunohistochemistry-based progression score using a threshold ≥5, might help the clinician to focus on patients with HG pT1 or extended CIS at high risk for disease progression. These patients might benefit from a more intensive follow-up program or early cystectomy.
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Biomarcadores de Tumor/genética , Carcinoma in Situ/diagnóstico , Carcinoma Papilar/diagnóstico , Proteínas de Neoplasias/genética , Neoplasias de la Vejiga Urinaria/diagnóstico , Vejiga Urinaria/patología , Anciano , Anciano de 80 o más Años , Carcinoma in Situ/genética , Carcinoma in Situ/patología , Carcinoma Papilar/genética , Carcinoma Papilar/patología , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Clasificación del Tumor , Estadificación de Neoplasias , Valor Predictivo de las Pruebas , Curva ROC , Vejiga Urinaria/metabolismo , Neoplasias de la Vejiga Urinaria/genética , Neoplasias de la Vejiga Urinaria/patologíaRESUMEN
Hepatoid adenocarcinoma is a rare neoplasm, which has a striking morphologic similarity to hepatocarcinoma. It has been described in different organs, the most common are stomach, lung, and pancreas. In some cases, it is characterized by high serum levels of α-fetoprotein. This tumor has a pattern similar to the hepatocarcinoma. The typical features are a combination of histopathologic aspects of solid nests and trabecular structures of polygonal atypical cells with eosinophil and granular cytoplasm and immunohistochemical expression of α-fetoprotein and of carcinoembryonic antigen in half of cases. Here, we report the case of an old female patient affected by hepatoid adenocarcinoma of the ureter with ovarian, small intestine, and hepatic involvement. We discuss the clinical aspects, the morphologic features, and the immunoistochemical staining useful for differential diagnosis.
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Adenocarcinoma/patología , Carcinoma Hepatocelular/patología , Intestino Delgado/patología , Neoplasias Hepáticas/secundario , Neoplasias Ováricas/secundario , Uréter/patología , Anciano de 80 o más Años , Femenino , Factor de Transcripción GATA3/metabolismo , Humanos , Inmunohistoquímica , Antígeno Lewis X/metabolismo , Neoplasias Hepáticas/patología , Proteínas de la Membrana/metabolismo , Neoplasias Ováricas/patologíaRESUMEN
Clear cell transitional carcinoma of the bladder is a subtype of transitional carcinoma that morphologically resembles a clear cell renal cell carcinoma. Although kidney tumors do not frequently metastasize to the bladder, the recurrence after a clear cell renal cell carcinoma has been reported even several years after nephrectomy. We report the case of a male patient to whom radical nephrectomy for a clear cell renal cell carcinoma has been done, with a bladder tumor featuring polygonal cells with abundant clear cytoplasm deeply infiltrating the vesical wall. We discuss the morphologic features, the immunohistochemical staining with a new marker and the UroVysion FISH analysis to achieve a definitive diagnosis.