ALK-Rearranged Renal Cell Carcinoma

Due to its heterogeneous morphology and its rarity, anaplastic lymphoma kinase gene-rearranged renal cell carcinoma (ALK RCC) is a diagnostically challenging entity, often leading to labelling these tumors as RCC, not otherwise classified. This may have clinical and managerial implications, given that patients with ALK oncogene rearrangement may benefit from ALK-inhibitors. Therefore, we attempted to elucidate the clinicopathologic and immunophenotypical characteristics of ALK RCC in a large international cohort. Sixteen multi-institutional tumors were included in the study. Clinical, macroscopic, microscopic, immunohistochemical (IHC), molecular (DNA and RNA sequencing, FISH) and follow-up data were evaluated. There were 9 male and 7 female patients with tumor size ranging from 2 to 12.2 cm (mean=7.1 cm). All tumors had solid, tan-white with focal cystic changes and gelatinous appearance. Cystic changes and necrosis were seen in 7 and 6 tumors, respectively. Microscopically, a heterogeneous growth pattern was observed including solid (12), tubular (7), papillary (5), tubulocystic (2), pleomorphic epithelioid cells (6), sarcomatoid (2), rhabdoid (4), and intranuclear pseudoinclusions. All tumors were ALK-positive, coexpressing PAX8, KRT7, SDH, FH, and variably CD10, Vimentin, and AMACR. Molecular analysis through next-generation sequencing (NGS) was performed on 14/16 tumors. EML4::ALK (n=5) was the most common gene fusion observed; others included TPM1::ALK(n=4), TPM3::ALK(n=2), SLIT1::ALK(n=2)and VCL::ALK(n=1). Despite focal TFE3 immunoreactivity in 4/13 cases, the absence of TFE3 gene rearrangement by molecular analysis excludes TFE3- rearranged RCC as a differential diagnosis. Our study further expands the clinicopathologic, morphologic, and molecular genetic spectrum of ALK-RCC. ALK-RCC can be morphologically heterogeneous and mimic other well-established entities posing a misdiagnosis if appropriate IHC and/or molecular studies are not performed. Accurate diagnosis is of clinical significance as patients with this neoplasm may potentially benefit from ALK-inhibitors, particularly in a metastatic setting. As TFE3 immunoreactivity is not uncommon in ALK-RCC, documentation of ALK gene rearrangement is critical, either by surrogate IHC staining or cytogenetic/molecular analysis is essential.