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Image of the Week
Edited and moderated by Stacey Mills, MD, Pathology Network's Image of the Week Blog is a forum for the discussion of interesting and often diagnostically challenging pathology images.
Wednesday, January 16, 2013
A 67-year-old man with a right-sided colon mass.
A 67-year-old man underwent a right colectomy for a cecal mass.  Microscopic sections from the resultant specimen are shown below. 

The tumor consists of sheets of neoplastic cells with greatly enlarged but relatively uniform nuclei with prominent nucleoli.  Mitotic rate is brisk with numerous mitotic figures easily identified, including a few overtly atypical forms.  No glandular or squamous differentiation is present.  There is a prominent lymphoid infiltrate associated with and infiltrating the tumor cells.
What is your diagnosis?
This is an example of medullary (undifferentiated, non-neuroendocrine) carcinoma of the colon.  The tumor cells were negative for both CK20 and CDX2 (not shown) indicating absence of the conventional colonic adenocarcinoma phenotype.  Immunohistochemical staining for mismatch repair protein MLH1 is shown below.


The tumor cell nuclei are completely negative with strong positivity in the associated lymphoid cells.
Immunhistochemical reactivity for mismatch repair protein PMS2 was similarly absent, while MSH2 and MSH6 were intact.  Thus, this tumor has features of a carcinoma with microsatellite instability (MSI).  About 2/3rds of MSI carcinomas are sporadic with the remainder associated with germline mutations (HNPCC).  Sporadic MSI cancers appear to be associated with hypermethylation of MLH1 as opposed to somatic gene mutation.  Sporadic cases are also frequently associated with BRAF (V600E) mutations, and appear to arise via the serrated polyp pathway, whereas germline mutation cases seem to arise via adenomatous changes.  MSI cases typically have wild-type p53, which is typically mutated in microsatellite stable carcinomas.
In addition to the medullary pattern seen in this case, MSI colonic carcinomas also tend to show mucinous, signet-ring, and other poorly differentiated phenotypes.  The most helpful features to suspect an MSI tumor are right-sided location, generally poor (or absent) differentiation, and the presence of tumor infiltating lymphocytes.  The latter was a prominent feature of the current case.  There may also be a Crohn's-like reaction in the deeper subserosal tissues.
MSI colonic carcinomas have been noted to typically present at low stage and to have a better survival, stage for stage than microsatellite stable (MSS) carcinomas when treated surgically.  MSI carcinomas do not respond well to 5-FU chemotherapy.  Because of differences in prognosis and therapeutic response knowledge of mismatch repair protein status is important in colorectal carcinomas.  Although, as noted above, there are features which should lead to a strong suspicion of an MSI carcinoma, there are enough outlier cases to support reflexive testing for mismatch repair proteins on all resected colonic carcinomas.
About the Author

Stacey E. Mills, MD
Stacey E. Mills, MD, a graduate of University of Virginia (UVA) and the UVA Medical Center, has authored nearly 230 articles, 20+ books, atlases and monographs—including the renowned Sternberg's Diagnostic Surgical Pathology. He has been a practicing Professor and Staff Pathologist at UVA for 30+ years and is Director of Surgical Pathology and Cytopathology. His clinical specialty is general surgical pathology with emphasis on neoplasms and neoplasm-like lesions. Dr. Mills is also Editor-in-Chief of The American Journal of Surgical Pathology.