Colorectal Adenocarcinomas Harboring ALK Fusion Genes: A Clinicopathologic and Molecular Genetic Study of 12 Cases and Review of the Literature

Abstract

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.

Figure 1.

Example of diffuse ALK immunoreactivity in colorectal carcinomas. Strong membrane staining for ALK in Case 1 with a SPTBN1-ALK fusion (A); strong cytoplasmic ALK staining in Case 6 with a DIAPH2-ALK fusion (B); moderate cytoplasmic ALK staining in Case 8 with an EML4-ALK fusion (C); weak cytoplasmic ALK staining in Case 9 with a LOC101929227-ALK fusion (D).

Figure 2.

Example of focal (A) and luminal (B) ALK immunoreactivity in ALK fusion negative colon carcinomas.

Figure 3.

A dual-color FISH analysis performed on interphase nuclei using a break-apart ALK gene probe in CRC (Case 9) harboring a LOC101929227-ALK fusion. A split of orange and green signal indicates an ALK rearrangement.

Figure 4.

Histologic features of colorectal carcinomas with diffuse ALK immunoreactivity. Case 1, moderately differentiated CRC harboring SPTBN1-ALK fusion (A); Case 2, poorly differentiated CRC harboring SPTBN1-ALK fusion (B); Case 12, medullary CRC harboring EML4-ALK fusion (C); Case 8, mucinous tumor harboring EML4-ALK fusion (D)