Discussion

A patient with multiple synchronous or metachronous tumours may have independent primaries or metastatic disease. These individual tumours with identical histological and IHC pattern are found to show different molecular aberrations.9 In the colon and rectum, incidence of multiple primary cancers is about 2%–5%10 and the discordance of MSI status has been identified in individual tumours.11 Accordingly, these tumours may possess different genetic profiles including a different KRAS mutation status.

The risk for ulcerative colitis associated colorectal cancer is increased at least 2-fold compared with the normal population. Colorectal cancer is observed in 5.5%–13.5% of all patients with ulcerative colitis.12 These cancers typically can occur in the colon, are often multifocal12 and have the same incidence of KRAS mutation in comparison with sporadic colorectal cancer.13 In this study, both tumours A and B from this patient had a similar MSI profile (MSI-L). Together with the similarity of histological appearance and immunohistochemical pattern, these findings initially suggest that tumours A and B might have evolved from an identical tumour clone. Moreover, the tumour grade, stage and location also suggest that tumour B in ascending colon with relatively lower grade and stage is likely a metastasis from the more advanced tumour A in sigmoid, possibly through the lymphovascular spread.

A seminal study by Al-Mulla et al14 has previously reported KRAS mutational heterogeneity in primary and secondary colorectal carcinomas. Although the same KRAS mutations are found in the majority of patients with primary carcinomas and their metastases, many patients have a KRAS mutation in their primary carcinoma but none in liver metastases or patients have mutations in liver or lymph node metastases but none in the primary carcinoma,14 indicating that KRAS mutations are not always essential for the metastatic potential or might occur at the later stages of tumour progression. Importantly, Al-Mulla et al also reported a patient who has multiple adenomas with different KRAS mutations but only one of these mutations is found in corresponding liver metastasis, suggesting that these adenomas are independent neoplasms.14 In this context, the present case report is consistent with and in agreement with these findings. In fact, molecular analysis reveals that tumour A and metastatic regional lymph nodes contained a mutated KRAS gene whereas tumour B had a wild-type KRAS gene. This result, together with the findings of clear margins and no lymph-vascular invasion in tumour B, diminishes the possibility that tumour B is a metastasis from tumour A. Based on the patient's possible history of ulcerative colitis, these findings support the notion that these two tumours most likely originated from distinct clones and that both tumours possibly developed synchronously, with tumour A displaying a more advanced stage.

It is possible that the tumour B may evolve later to have the same KRAS mutation found in tumour A at a later stage of tumour progression. The present analysis, however, has no direct evidence to support this possibility.

This patient likely needs adjuvant therapy besides surgery due to the high tumour stage (pT3N2b). If only tumour A had been sampled for molecular testing, a KRAS positive result would exclude this patient from anti-EGFR therapy. As a result, tumour B would lose the benefit of anti-EGFR therapy. Likewise, if only tumour B had been tested and showed that it has KRAS wild-type, the patient would have been treated with an anti-EGFR regimen. Tumour A, carrying a KRAS mutation, would have failed to respond this treatment.4 ,15 Unsuccessful outcome can be anticipated in either two scenarios. Instead, a combination of traditional chemotherapy and anti-EGFR therapy is likely the best treatment option with the best consequent prognosis for this patient.3