Next-Generation Sequencing of Multivergent Morphologies in Colorectal Carcinomas Identifies Unique Targetable Alterations

Typically, colorectal carcinoma (CRC) is morphologically relatively homogeneous. Uncommon morphologic patterns may be enriched for rare molecular drivers. This study examined the clinicopathologic characteristics of CRC with multivergent morphology (defined as 2 discrete nonconventional morphologic cytoarchitectural patterns) and whether potentially targetable molecular alterations could be identified by interrogating 2 distinct morphologic areas. Evaluation of representative sections from 213 consecutive CRC resections identified 11 with multivergent morphology. Next-generation sequencing (NGS) was performed on 2 morphologically discrete areas from multivergent cases. Compared with the remaining 202 CRCs, multivergent CRCs were larger (mean: 6.4 vs. 4.4 cm; P=0.038), had a higher T stage (100% vs. 78.2% ≥T3; P=5.0×10-4), a higher N stage (90.9% vs. 42.1% ≥N1, P=7.0×10-4), and more frequently had distant metastasis (36.4% vs. 10.9%; P=0.041). Multivergent CRCs were more likely to be mismatch repair (MMR)-deficient (45.5% vs. 15.8%; P=0.034) and to have an atypical MMR pattern (27.3% vs. 0.5%; P=1.7×10-7). Both areas of multivergent CRC often harbored molecular alterations associated with eligibility for Food and Drug Administration (FDA)-approved therapies (63.6%; 7/11) and clinical trials (72.7%; 8/11). Not uncommonly, a molecular alteration associated with eligibility for FDA-approved therapy (45.5%; 5/11) and clinical trials (72.7%; 8/11) was isolated to only one of the sequenced areas. Multivergent CRC is rare but associated with targetable molecular alterations. NGS of multiple areas with different morphologies may help identify potential therapeutic targets. While most cases have recognizable driver alterations, the less common, targetable alterations identified in these cases could open additional trial options for salvage therapy.