Utilization of a TFE3 Break-Apart FISH Assay in a Renal Tumor Consultation Service
Whitney M Green, George J Netto, Constance Griffin, Laura Morsberger, Peter B Illei, Xue Zhou, Pedram Argani. The Johns Hopkins Hospital, Baltimore, MD
Background: Xp11 translocation Renal Cell Carcinomas (RCC) are characterized by chromosome translocations involving the Xp11.2 breakpoint, resulting in gene fusions involving the TFE3 transcription factor. In archival material, the diagnosis can often be confirmed by TFE3 immunohistochemistry (IHC), but variable fixation (especially prevalent in consultation material) can lead to equivocal results. A TFE3 break-apart FISH assay has been developed to detect TFE3 gene rearrangements; however, the utility of this assay in a renal tumor consultation practice has not been examined.
Design: We reviewed our renal tumor consultation cases which were sent to rule in or rule out Xp11 translocation RCC. TFE3 FISH results were evaluated in the context of other clinical, morphologic, and IHC features of the cases, including TFE3 IHC.
Results: 62 cases were submitted to rule in or rule out Xp11 translocation RCC. 22 were positive for TFE3 rearrangements by FISH, including 21 Xp11 translocation RCC and 1 melanotic Xp11 translocation renal cancer. Patients ranged from 6 to 67 years of age (mean=28.9; median=27). Novel or distinctive morphologic features of these cases included extensive cystic change simulating multilocular cystic RCC (2 cases), sarcomatoid transformation (2 cases), trabecular architecture mimicking a carcinoid tumor (1 case), and focal desmin and diffuse racemase immunoreactivity (1 case each). 16 of the 21 FISH-positive cases were unequivocally (3+) positive for TFE3 by IHC, but 4 were equivocal and 1 was negative. Of the 40 other cases, which were negative by both FISH and IHC, 10 could be classified as clear cell RCC, 3 as clear cell papillary RCC, 3 as papillary RCC, 2 as RCC in the setting of tuberous sclerosis, and 1 as chromophobe RCC, while 21 remained unclassified. Of these 21 cases, 6 were morphologically indistinguishable from Xp11 translocation RCC. All 6 of the latter cases were TFEB negative by IHC, and 4 of 6 were diffusely immunoreactive for Cathepsin K (an otherwise specific marker of translocation RCC).
Conclusions: Utilizing a TFE3 break-apart FISH assay, we identify 21 novel genetically confirmed Xp11 translocation RCC. These results expand the morphologic and immunohistochemical spectrum of these neoplasms. TFE3 FISH resolves cases with equivocal TFE3 IHC results. While many cases in the differential diagnosis of Xp11 translocation RCC can be confidently reclassified into other existing RCC categories, a subset of cases overlaps greatly with Xp11 translocation RCC, and may represent a novel translocation RCC subtype in which not TFE3 but a related gene is implicated.
Category: Genitourinary (including renal tumors)
Monday, March 19, 2012 9:30 AM
Poster Session I Stowell-Orbison/Surgical Pathology/Autopsy Awards Poster Session # 120, Monday Morning