Introduction
Gastrointestinal stromal tumor (GIST) is an uncommon disease, accounting for 0.1–3.0 % of all gastrointestinal neoplasias [
1,
2]. GISTs preferentially develop in the stomach and the small bowel, although the tumors can arise anywhere in the digestive tract from the esophagus to the rectum. GISTs originating from the large bowel are rare, accounting for only 5 % of all GISTs [
3]. Colonic GIST is even rarer because many of the large bowel GISTs arise in the rectum. Owing to the lack of data on this rare malignancy, the clinical and pathological features of colonic GIST are still unclear.
Imatinib mesylate, a tyrosine kinase inhibitor, shows high clinical efficacy in advanced GIST [
4,
5] and is now the standard treatment for unresectable and metastatic GISTs [
6]. However, data on the efficacy of imatinib in colonic GIST are scarce only one report written in Japanese is available [
7]. The response to imatinib is known to depend on the mutation sites of the c-
kit gene or the platelet-derived growth factor receptor-alpha gene [
8]. However, because data on the mutation rate of the c-
kit gene and the genotypic profile in colonic GIST are also limited, it remains unknown whether or not colonic GIST is as sensitive as stomach and small bowel GISTs to imatinib.
We experienced a patient with advanced GIST of the transverse colon. The patient underwent palliative resection of the primary tumor and postoperative imatinib therapy. Here, we present the clinical course and our analysis of data on c-kit gene mutation in the surgically excised tumor.
Discussion
Clinicopathological data on colonic GIST patients are scarce [
9]. Only three case series studies concerning colonic GIST are available so far [
10‐
12]. We summarize the results of these three case series studies of colonic GIST in Table
1.
Table 1
Published case series studies of colonic GIST
The first one is the study by Miettinen et al. [
10]. They analyzed the clinicopathological features of 37 cases of colonic GISTs by reviewing the pathology files of the Armed Forces Institute of Pathology and Helsinki University. The study by Miettinen et al. included a much larger number of patients than the two other studies and thus can be regarded as the basis for consideration of the clinicopathological features of colonic GISTs. In their series, the most common location of colonic GIST was the sigmoid colon, followed by the transverse colon, the cecum, the descending colon, and the ascending colon. The sigmoid colon was also the most common site in a study by Chen et al. [
12]. However, in a study by Hassan et al [
11], three of four cases were found in the right-sided colon. Shonaka et al. [
13], by analyzing case reports of Japanese patients with colonic GISTs, found that six of 14 cases of colonic GIST developed in the sigmoid colon. Based on these case series studies, we can understand that the sigmoid colon is the most common site of colonic GISTs.
Concerning pathological features, the positive rates of KIT expression in colonic GISTs ranged from 50−100 % by immunohistochemical analysis. The tendency in immunohistochemical features was not specified by the previous studies. Meanwhile, as regards the malignant potential of tumors, all the three studies showed high rates of high-risk GIST, ranging from 43−75 %. A high malignant potential may be one of the pathological features of colonic GISTs. As a reflection of the high malignant potential, the prognoses for colonic GIST patients seemed to be poor overall. In Miettinen et al.’s study of the 28 patients who were followed up, 16 (57 %) died of the disease and the median survival time (MST) was 17 months. In the study by Hassan et al., three of four patients died of GIST within 20 months and MST was 12 months. Meanwhile, no patient died of the disease in the study by Chen et al. at the time of reporting, although the median follow-up time was as short as 27 months. More studies with long follow-up periods are needed to conclude that colonic GIST is a GIST subset that is characterized by poor prognosis.
The present case was positive for lymph node involvement. Lymph node metastasis of GIST is rare. Dematteo et al. [
14] found lymph node metastasis in six (3 %) of 200 cases of GISTs of the digestive tract, and Miettinen et al. [
10] reported no lymph node metastasis in 37 cases of colonic GISTs. In the present case, as the colonic tumor was associated with peritoneal metastasis, lymph node metastasis might be a reflection of the high grade malignancy of this tumor.
Molecularly targeted therapy with imatinib mesylate is the standard treatment for unresectable and metastatic GISTs. Furthermore, imatinib therapy is now recommended as postoperative adjuvant therapy for patients with high-risk GISTs [
15], as ample clinical evidence has been accumulated [
16,
17]. Thus, it is clinically important to reveal whether or not imatinib is as clinically effective in colonic GIST patients as in patients with stomach and small bowel GISTs. Recently, a case series study addressed the efficacy of imatinib against large bowel GISTs by analyzing exclusively patients with rectal GISTs and not including patients with colonic GISTs [
18]. In that study, of the 16 patients who underwent preoperative imatinib therapy, 12 (75 %) showed partial response and the remaining four, stable disease.
We searched published cases of colonic GIST patients who underwent imatinib therapy using PubMed and Japana Centra Revuo Medicina databases. The keywords were ‘colon’, ‘GIST’, and ‘imatinib’. Hits were carefully examined and only a single case report written in Japanese was found to fit the prerequisites [
7]. In that case report, a 46-year-old male patient with KIT-positive GIST of the ascending colon underwent postoperative imatinib therapy because the circumferential tumor margins were histologically positive. Despite ongoing imatinib therapy, disseminated peritoneal metastases appeared 9 months after the surgery and the patient died of the disease 1 month later. In that case, the patient had no target lesion and disease relapse occurred as early as 9 months after the surgery, making it difficult to evaluate the effect of imatinib. In our case, the hepatic metastases showed a significant response although it was evaluated as stable disease on the basis of RECIST criteria. Thus, the present case report is the first to indicate that imatinib was effective for colonic GIST.
Gene analysis is important not only for the precise diagnosis of GISTs but also for deciding the best treatment strategy for GIST patients, because the effect of imatinib is closely related to the mutation type of the c-
kit gene in the tumor. An exploratory study of patients enrolled in a phase II study (B2222) [
8] revealed that the response rates were 83.5 % in exon 11 mutations, 47.8 % in exon 9 mutations, and 0 % in the wild type. These findings should underscore the importance of adjuvant therapy in colonic GIST patients because there are no reliable data on the clinical efficacy of imatinib in these patients. Unfortunately, genotype data are also scarce in colonic GIST. Miettinen et al.’s study [
10] was the only study that conducted c-
kit gene analysis. They reported c-
kit mutations in five (36 %) of 14 colonic GISTs. The genotypes were a point mutation at codon 560 in two cases and a point mutation at codon 559, an in-frame deletion at codons 556–557, and an in-frame deletion at codons 557–558 in one case each. In the present case, an in-frame deletion mutation at codons 557–558 in exon 11 was found. These exon-11 mutations in colonic GISTs are similar to those in stomach and small bowel GISTs [
19], suggesting that fundamentally similar molecular alterations occur in colonic GIST.
In summary, we presented a case of a patient with a transverse colon GIST. Mutation analysis showed an in-frame deletion in exon 11 of the c-kit gene and confirmed the diagnosis of colonic GIST. The patient underwent imatinib therapy after palliative resection, and the treatment yielded a significant response. This is the first report demonstrating that imatinib was effective for the metastasis of colonic GIST. There are a limited number of colonic GIST patients in a single institution. To acquire fundamental clinical knowledge of colonic GIST, the accumulation of case reports is essential.