Synchronous separate primary colon adenocarcinomas, one negative (distal tumor) for codon 12 or 13 KRAS mutation, and one positive (proximal tumor) for codon 12 KRAS mutation.
The vast majority of colorectal cancers express surface EGFR protein, but only a minority responds to anti-EGFR antibody therapy. In patients with metastatic colorectal cancer, the presence of a KRAS gene mutation predicts tumor resistance to anti-EGFR monoclonal antibody therapy. Current guidelines exclude KRAS mutation-positive metastatic colorectal cancer patients from receiving mAb's , panitumumab and erbitux. Conversely, wild-type KRAS is required, but not by itself, for assurance of tumor response to anti-EGFR mAb therapy. Mechanistically, colorectal carcinomas that are initiated or maintained by KRAS mutations appear to be EGFR-independent.
Although a very high concordance for KRAS mutation status exists between the primary and metastatic tumors, the incidence of discordant KRAS mutation status in synchronous tumors (found in ~ 5% of primary CRC) can be as high as 40%, indicating the need to thoroughly evaluate the resected colon for evidence of tumor; and, if KRAS mutation analysis is considered, test all lesions identified.
A 77-year-old male with endoscopic biopsy-proven colon cancer underwent segmental resection of the sigmoid colon.
The specimen revealed two distinct mucosal masses, one a raised, ulcerated 3 cm mass most closely approaching within 2.5 cm of the proximal resection margin, grossly approximating the deep serosal surface; the other a 1.7 cm superficial fungating mass most closely approaching within 1 cm of the distal margin and grossly penetrating only 0.4 cm deep
Both tumors demonstrate identical, moderately differentiated histologic features that are typical of primary colorectal adenocarcinoma, including gland formation and focal tumor necrosis.
Presence of two primary synchronous tumors, discordant for a KRAS codon 12 mutation identified.
|a .Block A5. Proximal.. KRAS mutation. (Gly12Asp)||b. Block A2. distal. No mutation detected|
KRAS mutation analysis was performed using the TrimGen Mutector TM II KRAS Mutation Differentiation Kit (TrimGen Inc. Sparks MD).
The incidence of KRAS mutations in CRC is approximatley 35-45%. The presence of a KRAS mutation is highly predictive of patients non-responsiveness to the EGFR inhibitors cetuximab and panitumumab. KRAS mutation testing should be considered in all CRC patients prior to the initiation of treatment.