What further work‑up is recommended for a patient with dMMR/MSI‑high colon adenocarcinoma and an isolated para‑aortic lymph node metastasis before initiating pembrolizumab?

Further Work-Up for dMMR/MSI-High Colon Adenocarcinoma with Isolated Para-Aortic Lymph Node Metastasis

Before initiating pembrolizumab, confirm the dMMR/MSI-H status with proper tissue handling and complete the mandatory molecular testing panel including KRAS, NRAS, BRAF, and HER2 status, followed by comprehensive staging with contrast-enhanced CT of chest/abdomen/pelvis and baseline CEA levels. 1

Essential Molecular Testing Confirmation

• Verify dMMR/MSI-H status using either immunohistochemistry for MMR proteins (MLH1, MSH2, MSH6, PMS2) or PCR-based microsatellite analysis, ensuring tissue was fixed in 10% neutral buffered formalin for 6-48 hours with tumor cell content >20% after macro-dissection 1

• Complete RAS mutation testing (KRAS and NRAS exons 2,3, and 4) even though pembrolizumab is the intended first-line therapy, as this information guides subsequent treatment decisions if immunotherapy fails 1

• Assess BRAF V600E mutation status simultaneously with RAS testing for prognostic assessment and to identify eligibility for targeted therapy combinations in later lines 1

• Test for HER2 amplification by IHC or FISH if RAS wild-type, as this identifies patients eligible for HER2-directed therapy in second-line and beyond 1

• Screen for NTRK fusions when feasible using IHC followed by next-generation sequencing confirmation, as these are rare (<0.5%) but actionable with larotrectinib or entrectinib after progression on at least two lines 1

• Test for DPD deficiency before any potential fluoropyrimidine-based chemotherapy, even though pembrolizumab monotherapy is planned, as this prevents severe toxicity if chemotherapy becomes necessary 1

Comprehensive Staging Evaluation

• Obtain contrast-enhanced CT of thorax, abdomen, and pelvis to fully characterize the extent of disease beyond the isolated para-aortic lymph node, as this is the standard staging modality 1

• Consider FDG PET scan specifically in this case with isolated para-aortic lymph node metastasis to definitively exclude additional occult metastatic sites that could alter treatment planning 1

• Measure baseline CEA and optionally CA 19-9 levels for prognostic assessment and to establish a baseline for monitoring treatment response 1

• Perform complete blood count and comprehensive metabolic panel including liver and renal function tests before initiating immunotherapy 1

Genetic Counseling Assessment

• Refer for genetic counseling and germline testing for Lynch syndrome, as dMMR/MSI-H status in colorectal cancer warrants evaluation for hereditary cancer predisposition 1

• Document family history of colorectal, endometrial, and other Lynch syndrome-associated cancers to assess pre-test probability 1

Pre-Treatment Baseline Assessments

• Document ECOG performance status as this is a critical prognostic factor and helps predict tolerance of immunotherapy 1

• Screen for autoimmune conditions and chronic infections (HIV, hepatitis B/C) as these may influence immunotherapy safety and efficacy 2, 3, 4

• Establish baseline thyroid function, cortisol, and glucose levels to facilitate early detection of immune-related endocrinopathies during pembrolizumab treatment 2, 3, 4

Critical Pitfalls to Avoid

• Do not delay molecular testing until after first-line progression, as comprehensive upfront testing enables optimal treatment sequencing and avoids time pressure when patients are clinically deteriorating 2

• Do not assume the para-aortic lymph node is the only site of metastasis without thorough imaging, as occult disease may be present and alter the treatment approach 1

• Ensure testing is performed in CLIA-certified laboratories that participate in external quality assessment schemes for molecular pathology to guarantee result accuracy 1

• Do not proceed with pembrolizumab if MSI-H/dMMR status cannot be definitively confirmed, as efficacy in MSS/pMMR disease is essentially zero (0% objective response rate) 2

Evidence Supporting This Approach

The ESMO 2023 guidelines provide Level I, Grade A recommendations for testing MMR status, KRAS, NRAS, and BRAF mutations at the time of metastatic colorectal cancer diagnosis 1. The KEYNOTE-177 study, with >5 years follow-up, demonstrated median overall survival of 77.5 months with first-line pembrolizumab versus 36.7 months with chemotherapy in MSI-H/dMMR metastatic colorectal cancer, establishing pembrolizumab as standard of care 5. Case reports specifically document successful treatment of colon cancer with isolated para-aortic lymph node metastasis using pembrolizumab, achieving complete clinical response 6, 7.