This study determined the frequency and the clinicopathologic and genetic features of colorectal carcinomas driven by oncogenic fusions of the anaplastic lymphoma kinase gene (ALK). Of the 8150 screened tumors, 12 (0.15%) were immunohistochemically ALK-positive with D5F3 antibody. These cancers harbored CAD-ALK (n=1), DIAPH2-ALK (n=2), EML4-ALK (n=2), LOC101929227-ALK (n=1), SLMAP-ALK (n=1), SPTBN1-ALK (n=4), and STRN-ALK (n=1) fusions, as detected by an RNA-based next-generation sequencing assay. ALK fusion carcinomas were diagnosed mostly in older patients with a 9:3 female predominance (median age: 72 y). All tumors, except a rectal one, occurred in the right colon. Most tumors were stage T3 (n=7) or T4 (n=3). Local lymph node and distant metastases were seen at presentation in 9 and 2 patients. These tumors showed moderate (n=6) or poor (n=3) glandular differentiation, solid medullary growth pattern (n=2), and pure mucinous morphology (n=1). DNA mismatch repair-deficient phenotype was identified in 10 cases. Tumor-infiltrating lymphocytes were prominent in 9 carcinomas. In 4 carcinomas, tumor cells showed strong, focal (n=3), or diffuse programmed death-ligand 1 immunoreactivity. CDX2 expression and loss of CK20 and MUC2 expression were frequent. CK7 was expressed in 5 tumors. Four patients died of disease within 3 years, and 7 were alive with follow-up ranging from 1 to 8 years. No mutations in BRAF, RAS, and in genes encoding components of PI3K-AKT/MTOR pathway were identified. However, 1 tumor had a loss-of-function PTEN mutation. Aberration of p53 signaling, TP53 mutations, and/or nuclear accumulation of p53 protein was seen in 9 cases. ALK fusion colorectal carcinomas are a distinct and rare subtype of colorectal cancers displaying some features of mismatch repair-deficient tumors.

*Laboratory of Pathology National Cancer Institute Bethesda MD Departments of †Molecular Diagnostics Clinical Oncology ††††Surgical Pathology Holycross Cancer Center §Division of Medical Biology Institute of Biology ***Faculty of Health Sciences Jan Kochanowski University Kielce Departments of ‡Biology and Genetics ††Pathomorphology ****Pathology and Neuropathology Medical University of Gdansk Gdansk §§Department of Pathology Pomeranian Medical University ¶¶¶¶Independent Laboratory of Pathology Zdunomed Szczecin ∥∥Health Sciences and Physical Education University of Technology and Humanities Radom ¶¶Department of Pathology West Pomeranian Specialist Hospital Gryfice †††Department of Pathology Central Clinical Hospital of the Ministry of Interior ‡‡‡Faculty of Medicine Lazarski University §§§§Department of Pathology Prof Orłowski Memorial Independent Public Clinical Hospital and Center for Medical Postgraduate Education Warszawa §§§Department of Pathomorphology and Oncological Cytology Medical University of Wroclaw Wrocław ‡‡‡‡Department of Pathomorphology Jagiellonian University ∥∥∥∥Department of Tumor Pathology Maria Sklodowska Curie National Research Institute of Oncology Kraków Poland ∥Ignyta Inc San Diego CA ¶Department of Pathology Zhongshan Hospital Fudan University Shanghai People's Republic of China **Sikl's Institute of Pathology Faculty of Medicine and Teaching Hospital in Plzen Charles University Plzen Czech Republic Institute of Pathology University Hospital of Erlangen Erlangen Germany ‡‡Department of Pathology and Laboratory Medicine Milan Italy ∥∥∥Department of Pathology Nagoya City East Medical Center ¶¶¶Education and Research Center for Advanced Medicine Department of Experimental Pathology and Tumor Biology Nagoya City University Nagoya Japan

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