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.

Clinical Oncology

Department of Experimental Pathology and Tumor Biology Nagoya City University Nagoya Japan

Department of Pathology and Laboratory Medicine Milan Italy

Department of Pathology Central Clinical Hospital of the Ministry of Interior

Department of Pathology Nagoya City East Medical Center

Department of Pathology Pomeranian Medical University

Department of Pathology Prof Orłowski Memorial Independent Public Clinical Hospital and Center for Medical Postgraduate Education Warszawa

Department of Pathology West Pomeranian Specialist Hospital Gryfice

Department of Pathology Zhongshan Hospital Fudan University Shanghai People's Republic of China

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

Departments of Biology and Genetics

Departments of Molecular Diagnostics

Division of Medical Biology Institute of Biology

Education and Research Center for Advanced Medicine

Faculty of Health Sciences Jan Kochanowski University Kielce

Faculty of Medicine Lazarski University

Health Sciences and Physical Education University of Technology and Humanities Radom

Ignyta Inc San Diego CA

Independent Laboratory of Pathology Zdunomed Szczecin

Institute of Pathology University Hospital of Erlangen Erlangen Germany

Laboratory of Pathology National Cancer Institute Bethesda MD

Pathology and Neuropathology Medical University of Gdansk Gdansk

Pathomorphology

Sikl's Institute of Pathology Faculty of Medicine and Teaching Hospital in Plzen Charles University Plzen Czech Republic

Surgical Pathology Holycross Cancer Center

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