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

Area of Science:

• Oncology
• Pathology
• Molecular Biology

Background:

• Colorectal carcinoma (CRC) typically presents with homogeneous morphology.
• Uncommon morphologic patterns in CRC may harbor distinct molecular drivers.
• Multivergent morphology, defined by two discrete nonconventional patterns, is a rare presentation.

Purpose of the Study:

• To investigate the clinicopathologic features of multivergent CRC.
• To determine if targetable molecular alterations can be identified by analyzing distinct morphologic areas within multivergent CRC.
• To assess the potential for personalized therapy based on molecular profiling of diverse CRC morphologies.

Main Methods:

• Evaluation of 213 consecutive CRC resections to identify cases with multivergent morphology.
• Next-generation sequencing (NGS) performed on two distinct morphologic areas from identified multivergent CRC cases.
• Comparison of clinicopathologic characteristics between multivergent and conventional CRC cases.

Main Results:

• Multivergent CRC cases were larger, with higher T and N stages, and more frequent distant metastasis compared to conventional CRC.
• A significant proportion of multivergent CRCs were mismatch repair (MMR)-deficient or showed atypical MMR patterns.
• Targetable molecular alterations, including those for FDA-approved therapies and clinical trials, were frequently identified in both morphologic areas, sometimes exclusively in one area.

Conclusions:

• Multivergent CRC is a rare subtype associated with aggressive clinicopathologic features.
• Targetable molecular alterations are common in multivergent CRC, offering potential therapeutic opportunities.
• NGS analysis of multiple distinct morphologic areas in multivergent CRC is crucial for identifying actionable molecular targets and expanding treatment options.