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.