TFE3-Translokationen im Nierenzellkarzinom: Korrelation von Morphologie, Immunhistochemie und Molekularpathologie sowie klinischer Verlauf
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Philipps-Universität Marburg
Abstract
Renal cell carcinoma is the third most common urological cancer in Germany, accounts for more than 95 % of all renal malignancies in adults and is a distinctly heterogeneous group of malignant kidney tumours known for their great variation in clinical presentation and histological appearance. The current edition of the WHO Classification of Malignant Tumours (2016) distinguishes several subtypes of renal cell carcinomas; among them are Xp11 translocation renal cell carcinomas which belong to the MiT family translocation renal cell carcinoma. Xp11 translocation renal cell carcinomas are characterized by translocations involving the TFE3 gene located on chromosome Xp11.2. A particular focus of the present work was the evaluation of the correlation between the histomorphologic apperance and the molecular detection of TFE3 translocations in renal cell carcinomas.
To investigate the occurrence of TFE3 translocations in different histological subtypes of renal cell carcinomas, 14 morphologically suspicious cases resembling Xp11 translocation renal cell carcinomas as well as 32 clear cell renal cell carcinomas and 11 papillary renal cell carcinomas were selected from a large collective of more than 600 cases which were diagnosed during the period from 2002 to 2011 in the Institute for Pathology of the Klinikum Fulda. The 57 choosen cases were screened for TFE3 translocations using a TFE3 break-apart fluorescence in situ hybridization. Then, a selection of these tumours was immunohistochemically characterized and their clinical course was evaluated.
The analysis of the 57 renal cell carcinomas showed that TFE3 translocations using fluorescence in situ hybridization could be detected in all examined renal cell carcinomas regardless of the histological subtype and even in healthy, tumour-free kidneys. For the first time, a distinct inter- and intratumoural heterogeneity of the absolute number of TFE3 translocations in renal cell carcinomas could be shown. The average absolute number of TFE3 translocations as the sole criterion was neither useful in assigning the renal cell carcinomas to the histological subtypes nor suitable to reliably identify Xp11 translocation renal cell carcinomas.
Using additional TFE3 immunohistochemistry, one case of Xp11 translocation renal cell carcinoma could be identified. This renal cell carcinoma with heteromorphic clear cell histomorphology was the only case showing a diffuse and strong TFE3 immunoreactivity. The diagnosis was confirmed by the results of the further immunohistochemical stainings with conventional markers. The identified Xp11 translocation renal cell carcinoma was diagnosed in a 51-year-old female patient at an early tumour stage without evidence of lymphogenic or haematogenic metastasis.
The immunohistochemical studies of the remaining cases showed that due to morphological diversity, it was not possible to assign a renal cell carcinoma to one of the examined subtypes solely based on the histomorphological appearance. In addition to light microscopy, immunohistochemical analyses for subtyping renal cell carcinomas were required in order to take the morphological heterogeneity into account. Nevertheless, even after immunohistochemical analysis some cases had to be diagnosed as unclassified renal cell carcinomas according to the current edition of the WHO Classification since a characteristic marker profile was missing.
To sum it up, for the reliable diagnosis of Xp11 translocation renal cell carcinomas, further cytogenetic and/or molecular pathological studies are necessary in addition to TFE3 immunohistochemistry and TFE3 fluorescence in situ hybridization. Besides, standardised evaluation and interpretation criteria for both TFE3 fluorescence in situ hybridization and TFE3 immunohistochemistry are required. Moreover, larger case studies simultaneously implementing immunohistochemistry, fluorescence in situ hybridization as well as cytogenetic and/or molecular pathological studies are required to determine the therapeutic and prognostic relevance of TFE3 translocations in renal cell carcinomas.
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