How would you treat an early-stage dMMR rectal squamous cell carcinoma in an otherwise healthy elderly patient?

With no squamous cells in the actual rectum, I typically treat this as I would anal cancer—definitive chemoradiotherapy, ideally with capecitabine/5-FU-mitomycin (Day 1 only).

Squamous cell carcinoma of the rectum is a rare histologic subtype, accounting for approximately 0.3% of rectal cancers, with anatomic and histologic similarities to anal squamous cell carcinoma. (Copur et al., PMID 29447418) It has molecular profiling distinct from rectal adenocarcinoma with a high prevalence of human papillomavirus (HPV) positivity (100% in one series) and a genomic landscape closely resembling anal squamous cell carcinoma. Deficient mismatch repair (dMMR) status has been documented in isolated case reports, including HPV-negative anorectal squamous cell carcinomas, and may have clinical relevance in this histology. (Astaras et al., PMID 36357817; Jiang et al., PMID 30729336) Although dMMR is uncommon, it may predict resp...

I have only seen one MSI-H anal SCC; it was metastatic, and I treated it with chemo-immunotherapy. Hard to know the contribution of components. Your rectal SCC is likely anorectal (low rectal tumor) and should be treated like an early-stage anal cancer. I would recommend CRT. While it's attractive to incorporate immunotherapy or rely on definitive IO for treatment, the rarity of the entity and the lack of data to guide treatment give me pause. If there is an incomplete response (rare) or cancer relapses, I would challenge with chemo-IO (carboplatin/paclitaxel x4-6 + retifanlimab or pembrolizumab).