Clinical history: 48 year old male with a mass arising in the right colon.
What is the most probable diagnosis?
Mucinous Carcinoma of the Colon, MLH1 deficient
Mucinous carcinoma of the colon is defined as a colon cancer having >50% extracellular mucinous component. The immunohistochemistry for MLH1 is negative in the tumour cells, but shows positive staining (nuclear) in the adjacent lymphocytes and normal colon (not seen in this image) as an internal control.
Having a tumour on the right side, with mucinous features should prompt thought of a deficiency in the mismatch repair (MMR) pathway. Other pathological features include: high histological grade, tumour infiltrating lymphocytes and Crohn’s like lymphoid reaction.
Germline mutations in any of the MMR genes (MLH1, MSH2, MSH6 and PMS2) are responsible for Lynch Syndrome or hereditary non-polyposis colorectal cancer (HNPCC), which causes increased risk of colon carcinoma, as well as increased carcinoma in the endometrium, ovary, stomach, small intestine, and hepatobiliary tract among others. These tumours tend to present at a younger age than expected.
Testing for MMR deficiency via immunohistochemistry is practical and helpful in both identifying possible syndromic families, as well as guiding treatment, as higher stage tumours that are MMR-deficient do not respond as well to certain chemotherapy regimes (e.g. 5-FU in Stage II).
In an older patient with these histological features, they are commonly MLH1 deficient, not by a mutation, but by epigenetic hypermethylation of the MLH1 promoter and subsequent gene expression silencing. Commonly these MLH1 hypermethylated tumours have an accompanying mutation in BRAF (V600E) which is mutually exclusive with germline mutations. Detection of this alteration via immunohistochemistry specific for the V600E BRAF mutation may be performed to elucidate sporadic colon carcinomas from the syndromic forms.
The Amsterdam Criteria are useful criteria for determining if a family may be affected:
Amsterdam Criteria (Must exclude FAP first):
At least 3 relatives with histologically confirmed colorectal cancer, 1 of whom is a first degree relative of the other 2