In patients with FAP, desmoid tumours are caused by a mutation of the
adenomatous polyposis coli (
APC) gene [
3]. By contrast, 75% of desmoid tumour patients without FAP harbour a somatic mutation in either the
APC or β
-catenin genes, resulting in β-catenin protein stabilisation [
3-
5]. Several NSAIDs have been shown to inhibit the activity of β-catenin-dependent reporter genes in malignant cell lines, and to induce β-catenin degradation [
6,
7]. Moreover, NSAIDs appear to inhibit the initial stages of the colorectal adenoma-carcinoma sequence, suggesting a link to the APC/β-catenin/TCF pathway (Wnt-signalling pathway), and the colonic polyps of patients treated with NSAIDs demonstrate reduced nuclear accumulation of β-catenin [
6]. Oncogenic activation of the Wnt-signalling pathway by mutations in
APC or β
-catenin, which results in the accumulation and nuclear translocation of β-catenin and in β-catenin/TCF4-regulated transcription of TCF target genes, is mandatory for the initial neoplastic transformation of intestinal epithelium [
8,
9]. The basic and clinical data imply that NSAIDs inhibit β-catenin activity or its stability. Theoretically, NSAIDs may, hence, have the potency to inhibit the development of some desmoid tumours
via interference of β-catenin function, although the biochemical basis for these effects has not been clarified.
The treatment of desmoid tumours remains enigmatic despite longstanding investigation. However, it appears that analysis of APC/β-catenin expression in desmoid tumours might determine the efficacy of NSAIDs, and contribute to tumour-growth inhibition and survival in desmoid patients with β-catenin protein stabilisation. Surgical treatment is difficult and requires a wide resection margin to prevent tumour recurrences. Desmoid tumours are locally invasive lesions that do not metastasizes; thus, a decrease in the growth rate could prevent the need for more radical treatments, which would be beneficial for elderly patients in poor general condition. At our institution, a chemotherapeutic regimen of doxorubicin plus dacarbazine is the preferred first-line treatment for FAP-associated unresectable intra-abdominal desmoids. However, its application is restricted to patients with symptoms of bowel obstruction. Other patients are treated initially with COX-2 inhibitors. In the present case, the tumour demonstrated PR following treatment with etodolac, even though the COX-2 selectivity of this NSAID is far weaker than that of meloxicam. The patient was offered no additional therapy, and remained asymptomatic even after two year of follow-up, without any evidence of deterioration. This suggests that the COX-2 selectivity of NSAIDs might not be critical for determining inhibitory effect against desmoid tumours.
Surgery is the treatment of choice for patients with desmoids loco-regionally confined to the body wall. However, surgical excision provides for only a narrow therapeutic window, when desmoid tumours are located in the abdominal cavity and recur even if they are not associated with FAP. Therefore, the efficient blockade of β-catenin by NSAIDs might be useful in achieving significant and durable cytoreduction, obviating the need for surgical intervention in patients with sporadic desmoid tumour as well as those with FAP-associated desmoids, especially when they show a high risk of operation (general condition, age, complication, quality of life, etc.) Continued efforts at improving the efficacy of such regimens with possible addition of novel molecule-targeting agents should be made in the future.
1,2,3 Hidenori Yanagi,1 Makoto Gega,1 Yoshinori Fujiwara,1 Tomoko Hashimoto-Tamaoki,2,3 Syozo Hirota,4 Tohru Tsujimura,5 and Naohiro Tomita1
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