ALK‐rearranged renal cell carcinomas in children

Abstract

Knowledge of the clinicopathological and molecular spectrum of pediatric renal cell carcinomas (RCC) remains limited, and approximately 16%-24% of these neoplasms cannot be classified into specific subtypes. In this review of 168 pediatric RCC prospectively registered on Children's Oncology Group AREN03B2 protocol, six RCC (3.5%) that demonstrated a unique epithelioid morphology and a peculiar immunophenotypic profile that includes expression of ALK, TFE3, and retention of INI1 was identified. Further investigation revealed ALK rearrangements in all cases, manifested molecularly by fusion transcripts of either VCL-ALK (3 patients all with sickle cell trait which had been previously reported) or TPM3-ALK (3 patients, none with sickle cell trait). Based on the shared unique morphologic, immunophenotypic, and genetic features, it was proposed that these neoplasms belonged to a distinct subgroup of RCC frequently occurring in pediatric patients, which they have termed as ALK-rearranged RCC. Importantly, additional therapeutic options may be available for these patients.

New and emerging renal entities: a perspective post‐WHO 2016 classification

“…In a recent prospective study of RCCs in paediatric and young adult patients, 3.8% were found to be ALK ‐rearranged . To our knowledge, since the first report in 2011, a total of 22 cases of ALK rearrangement‐associated RCC have been reported . The majority of patients were male (male/female ratio of 1.4:1), and they demonstrated a wide age range.…”

“…On microscopy, the group of VCL – ALK ‐rearranged and TPM3 – ALK ‐rearranged RCCs showed marked similarities to adult renal medullary carcinoma (RMC), i.e. diffuse solid or focal reticular/tubular growth, with a background of prominent but delicate vascularisation . The neoplastic cells were discohesive, and showed epithelioid features ranging from polygonal, spindle, cuboidal to low columnar, and had abundant eosinophilic cytoplasm with frequent intracytoplasmic lumina (Figure A).…”

Expanding the spectrum of ALK‐rearranged renal cell carcinomas in children: Identification of a novel HOOK1‐ALK fusion transcript

“…Within the total of 13 reported cases, the fusion partners include TPM3 (4 cases, 3 pediatric and 1 adult), VCL (3 pediatric cases, all with sickle cell disease or trait), STRN (2 adult cases) and EML4 (1 adult case). Those involving STRN, the adult case involving TPM3 (Sugawara et al, 2012) and our case involving HOOK1 share a predominantly papillary architecture, mucin deposition and calcifications, which were absent in our original six cases (Cajaiba et al, 2016). These observations add to the notion that the morphological spectrum of ALK -rearranged RCC may indeed be wider than we originally thought.…”

“…We have recently characterized the morphologic, immunohistochemical and molecular features of a distinctive group of renal cell carcinomas (RCC) occurring in children and characterized by ALK gene rearrangements (Cajaiba et al, 2016). These tumors manifested either VCL-ALK (3 patients) or TPM3-ALK (3 patients) fusion transcripts.…”

“…RNA was extracted from archival formalin-fixed paraffin-embedded (FFPE) tissue as previously described, and in-depth molecular analysis using next generation sequencing (NGS) methodology was then performed in this case in an attempt to identify an ALK fusion transcript, using previously described methodology (Cajaiba et al, 2016). The results demonstrated the presence of a HOOK1-ALK fusion transcript spanning exon 20 of HOOK1 and exon 21 of ALK .…”