Intracranial low-grade tumors with ALK rearrangement: diverse tumor types with shared molecular alterations

Although anaplastic lymphoma kinase (ALK) gene fusions are increasingly recognized in newly classified pediatric high-grade gliomas, intracranial low-grade tumors harboring ALK rearrangements remain under characterized in the literature. Herein, we present five cases of low-grade intracranial tumors with ALK rearrangements that were diagnosed at a single institution over a continuous 24-month period. Comprehensive clinicopathological evaluation integrating morphological analysis, immunohistochemical profiling, and molecular characterization of fusion partners was performed. Microscopic examination was performed to assess histologic features. A panel of antibodies were used to evaluate protein expression including ALK, desmin, GFAP, Olig2, S100, NeuN, EMA, and CD34. DNA and RNA sequencing was performed, and potential fusion transcripts were analyzed using seed count and structural chromosomal aberrations. All five tumors harbored structural aberrations involving the ALK locus 2p23, and no additional pathogenic mutations, amplifications, deletions, or fusions were identified in all the cases. Among them, two tumors were inflammatory myofibroblastic tumors (IMT) with SQSTM1::ALK, and NPM1::ALK fusion, respectively. One was a tanycytic supratentorial ependymoma (ST-EPN) with HNRNPA1::ALK fusion, and another was ganglioglioma (GG) with PPP1CB::ALK fusion. Interestingly, one case presented as a low-grade myxoid mesenchymal neoplasm with ATIC::ALK rearrangement that did not fit any existing tumor category. All patients underwent complete tumor resection, and were alive with no signs of recurrence during a follow-up period ranging from 1 to 18 months. In summary, ALK fusions may be shared features of a group of low-grade intracranial tumors including IMT, tanycytic ST-EPN, GG, and ALK-rearranged low-grade myxoid mesenchyma neoplasm. Future studies using larger cohorts are warranted to further characterize their clinical and pathological features.