Case Study: Divergent MMR Status in Synchronous Colorectal Adenocarcinomas

Overview

This case report describes a rare instance of synchronous colorectal adenocarcinomas with discordant mismatch repair (MMR) status arising from distinct tumorigenic pathways: Lynch-like syndrome and the serrated pathway. Lesion-specific molecular profiling combined with regional lymph node MMR phenotyping guided individualized treatment, resulting in no recurrence at 24 months.

Background

Colorectal cancer (CRC) is a leading cause of cancer mortality, with mismatch repair (MMR) status serving as a key biomarker for prognosis and therapy. Deficient MMR (dMMR) tumors respond well to immunotherapy, whereas proficient MMR (pMMR) tumors rely mainly on chemoradiotherapy. Synchronous colorectal cancers (SCRCs) with discordant MMR status occur in a minority of cases and pose diagnostic and therapeutic challenges, especially when arising from distinct molecular pathways such as Lynch-like syndrome and the serrated pathway.

Data Highlights

Key Findings

• Two synchronous primary colorectal adenocarcinomas exhibited discordant MMR status: dMMR in ascending colon tumor and pMMR in rectal tumor.
• The ascending colon tumor was associated with Lynch-like syndrome, confirmed by absence of germline MMR mutations, negative BRAF V600E mutation, and negative MLH1 promoter methylation.
• The rectal tumor was adjacent to a sessile serrated lesion, consistent with serrated pathway tumorigenesis and showed proficient MMR.
• Regional metastatic lymph nodes exhibited pMMR phenotype matching the rectal tumor, indicating higher metastatic potential of the pMMR lesion.
• Lesion-specific molecular profiling combined with lymph node MMR phenotyping informed risk-adapted, individualized adjuvant chemoradiotherapy (CAPEOX regimen).
• No tumor recurrence or metastasis was observed during 24 months of follow-up, with satisfactory patient quality of life.

Clinical Implications

This case highlights the importance of comprehensive lesion-specific molecular characterization in synchronous colorectal cancers with discordant MMR status to avoid misclassification and inappropriate treatment. Regional lymph node MMR phenotyping can identify the lesion with higher metastatic potential, guiding tailored adjuvant therapy. Such individualized approaches may improve outcomes in molecularly heterogeneous colorectal cancer cases.

Conclusion

Synchronous colorectal adenocarcinomas with divergent MMR status require detailed molecular and pathological evaluation for precise diagnosis and management. Integrating lesion-specific profiling with lymph node phenotyping supports personalized treatment strategies and may optimize patient prognosis.

References

1. Case Study Source 2024 -- Concurrent Colorectal Adenocarcinomas Exhibiting Divergent Mismatch Repair Status