Discussion
Appendix carcinoma is rare, and accounts for 0.4% of all gastrointestinal malignancies(15). Furthermore, UC-associated appendix carcinoma is extremely rare, and only a limited number of cases have been reported (11, 16, 17, 19). The homology of pathogenesis between UC-associated appendix carcinoma and UC-associated CRC remains poorly understood.
Chronic mucosal inflammation is considered to be a main driver of UC-associated CRC (6, 7), and established risk factors include prolonged disease duration, extensive colonic involvement, family history of CRC, and coexistence of primary sclerosing cholangitis (2, 4, 6, 7). The severity of histologic inflammation is an independent risk factor (7). However, the relationship between long-term mucosal inflammation and appendix carcinoma remains unclear, because previously published cases have shown that appendix carcinoma developed not only in patients with pancolitis but also in those with left-sided colitis.
Sporadic CRC develops through the adenoma-carcinoma sequence (4), but UC-associated CRC is characterized by the inflammation-dysplasia-carcinoma sequence (5). A typical feature of UC is a continuous mucosal inflammatory lesion extending proximally from the rectum without any skip lesion. However, previous studies have reported that isolated peri-appendiceal inflammation is frequently observed as a “skip lesion” in more than half of patients with left-sided colitis or distal type colitis (9, 12). In this case, a colonoscopy performed one year earlier had revealed an isolated inflammation (mucosal redness and granularity) surrounding the appendix orifice. These findings indicate the presence of sustained inflammation in the appendix of patients with left-sided colitis as well as those with pancolitis, raising the possibility that like UC-associated CRC, continuous inflammation may be associated with the development of appendix carcinoma.
On the other hand, there are contrasting reports on the contribution of the inflammation-dysplasia sequence to UC-associated appendix adenocarcinoma. The presence of dysplasia is an important finding for the diagnosis of UC-associated CRC. However, dysplasia of the colonic mucosa was not identified in some previously published cases of UC-associated appendix carcinoma nor in the current case (11, 16, 19). Furthermore, pathological examination in this case showed the presence of an adenoma component. These suggest that some UC-associated appendix carcinomas might develop via the non-inflammatory carcinogenesis pathway.
Advances in the genetic approaches to cancer have led to the characterization of the genomic landscape of various types of tumors. Robles et al. revealed that the KRAS mutation was detected at a significantly lower rate in UC-associated CRC than in sporadic CRC (14). Matsumoto et al . recently reported that UC-associated CRC developed through the inflammatory carcinogenesis pathway is characterized by the TP53 mutation but those through the noninflammatory pathway are characterized by the KRAS mutation (10). We detected the KRAS G13D mutation. This finding also lends support to the theory of a contribution by the non-inflammatory carcinogenesis pathway in this case.
A preoperative diagnosis of appendix carcinoma has been reported to be extremely difficult, since there are no pathognomonic signs or symptoms (1). In this case, a colonoscopy performed one year earlier revealed no evidence of appendix carcinoma. Since more than 70% of patients with appendix carcinoma present with clinical symptoms of acute appendicitis (1), we should pay attention to such symptoms in the follow-up of UC patients presenting a skip lesion at the appendix orifice.
Finally, this case suggests an association between UC-associated appendix carcinoma and the non-inflammatory carcinogenesis pathway. Genetic approaches will be helpful in defining the pathological mechanisms underlying this malignant disorder.