Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the GI tract. GISTs most commonly develop in the stomach (50–60%) and small intestine (30–35%), although they may also arise in the large intestine (5–10%), esophagus (<1%) and, rarely, in locations outside the GI tract (mesentery, omentum and retroperitoneum, <5%) (1,2). GISTs originating from the vermiform appendix are rare, constituting only 0.1% of all GISTs, and they are sized <3 cm in 82.4% of the reported cases. Several previous studies have reported the usefulness of neoadjuvant therapy with imatinib mesylate, a selective tyrosine kinase inhibitor, in locally advanced or metastatic/recurrent GISTs (3). We herein report a case of a giant GIST of the appendix with a single peritoneal metastasis in a 67-year-old man, who subsequently underwent neoadjuvant imatinib therapy, which resulted in effective tumor shrinkage, allowing minimally invasive laparoscopic surgery.

A 67-year-old man with a 6-month history of lower abdominal pain due to a large abdominal mass lesion was referred to the Department of Surgical Oncology (University of Tokyo Hospital, Tokyo, Japan) in February, 2014. The patient's medical history included chronic rhinosinusitis 30 years prior and endoscopic colonic polypectomy 1 year prior. A physical examination revealed that the patient was afebrile, with normal vital signs. Mild tenderness was detected in the lower abdomen, with a palpable mass sized >20 cm. Laboratory tests revealed mildly decreased hemoglobin and albumin levels (11.0 and 3.4 g/dl, respectively), mildly elevated C-reactive protein level (1.39 mg/dl), normal white blood cell count (4,700/µl) and normal carcinoembryonic antigen level (2.1 ng/ml; normal level, <5 ng/ml). An abdominal computed tomography (CT) scan revealed a large mass (220×180×100 mm) with heterogeneous enhancement in the right lower abdominal quadrant. Due to its size, the tumor origin was unclear. A CT scan also revealed another mass (70×65×50 mm) located cranially to the main tumor (Fig. 1A and B). Esophagogastroduodenoscopy, colonoscopy and capsule endoscopy revealed no evidence of other neoplastic lesions. CT-guided fine-needle biopsy showed bundles of spindle cells stained positive for c-KIT (Fig. 2), with 5 mitotic cells per 50 high-power fields, and a Ki-67 (MIB-1) labeling index of >10%. There was no desmin or protein S100 immunoreactivity. On the basis of these findings, the tumors were diagnosed as GISTs, possibly arising from the ileum, cecum or appendix, with a peritoneal metastasis. The case was determined to be high-risk according to criteria proposed by Miettinen et al (1) and Joensuu et al (4).

Due to the size of the tumor and the presence of peritoneal metastasis, neoadjuvant therapy with imatinib 400 mg/day was initiated; no imatinib-related adverse events were detected during treatment. Follow-up imaging studies revealed a gradual decrease in tumor size. After 26 months of imatinib treatment, a final evaluation revealed 63×55-mm and 22×20-mm masses, without a significant change in size over the prior 3 months (Fig. 1C and D). Subsequently, laparoscopic exploration revealed that the main tumor originated from the tip of the vermiform appendix (Fig. 3) and that the peritoneal metastasis was located in the ascending mesocolon. Consequently, appendectomy and grossly complete resection of the peritoneal metastatic tumor were laparoscopically performed, without tumor rupture. The gross specimen of the main tumor was a whitish-gray hemorrhagic mass, sized 80×60×55 mm, growing outward from the tip of the appendix (50 mm in length, 10 mm in diameter). The peritoneal metastatic tumor (22×18×14 mm) had the same gross appearance. Microscopic examination revealed no lymphovascular invasion and a mitotic count of 2/50 high-power fields in the main tumor. The postoperative course was uneventful and the patient was discharged without complications. The patient commenced imatinib treatment 1 month after surgery and he remained alive and disease-free at the last follow-up, 6 months after the surgery. The date of the last follow-up was 8th March, 2017.

Written informed consent was obtained from the patient for the publication of the case details and associated images.

GISTs of the vermiform appendix constitute only 0.1% of all GISTs (1), with only 16 cases reported in the English literature to date (5–16). The characteristics of these 17 GIST cases (including the present case) are listed in Table I. The median patient age was 67 years (range, 7–88 years) and the male:female ratio was 2.4:1. The tumor originated from the proximal end of the appendix in 5 cases, from the middle in 5, from the tip in 5, and information on the origin was unavailable in 2 cases. Seven patients presented with appendicitis-like symptoms without histological evidence of acute appendicitis, suggesting that the symptoms were caused by the tumor. Two patients presented with peritonitis, which was caused by acute appendicitis in one case, and by formation of a peri-appendiceal abscess in the other case. The remaining 6 tumors were incidentally discovered during surgery for other diseases or during autopsy. The median size was 12.5 mm (range, 0.5–220 mm). To the best of our knowledge, the present case represents the largest appendiceal GIST reported to date. The tumor was so large that the patient experienced pain in the entire lower abdomen, and the origin of the tumor could not be determined by preoperative investigation. Furthermore, our case was classified as high-risk according to the criteria of Joensuu et al (4), whereas 14 of the 17 reported appendiceal GISTs (82.4%) were classified as very low- or low-risk.

Complete surgical resection is the only curative treatment for GIST. However, the introduction of imatinib therapy, which is established as an adjuvant therapy following surgery in high-risk cases, as well as first-line therapy in metastatic cases, has markedly improved the cure rate and the prognosis (17). In addition, several studies have demonstrated that neoadjuvant therapy with imatinib for locally advanced or metastatic/recurrent GISTs may offer advantages, such as cytoreduction, in order to facilitate R0 resection, the potential for organ preservation, a less invasive surgical approach and a lower risk of intraoperative tumor rupture (3,18,19). As the present case included a giant tumor with peritoneal metastasis, tumor rupture or macroscopic residual tumor (R2 resection) was a possible risk. Thus, neoadjuvant imatinib was administered to decrease the tumor size in order to achieve complete resection (R0/R1) (20). After 26 months of imatinib treatment, the patient underwent laparoscopic appendectomy and gross complete resection of the peritoneal metastatic tumor, without tumor rupture. The optimal duration of neoadjuvant therapy for GIST remains controversial. Theoretically, neoadjuvant therapy may be continued until the tumor size decreases or its metabolic activity reaches a plateau phase, but the development of resistance due to secondary KIT mutations during this stage remains a risk (21). The duration of neoadjuvant imatinib therapy in a metastatic setting should be case-based, depending on the response to treatment. The main aim of neoadjuvant treatment is to convert unresectable/borderline-resectable disease to resectable disease.

In conclusion, appendiceal GISTs sized >10 cm are extremely rare. We herein reported a case of an unusually large appendiceal GIST (22 cm) with a solitary peritoneal metastasis, which was successfully treated with neoadjuvant imatinib therapy and laparoscopic surgery. Therefore, in appropriately selected patients, neoadjuvant imatinib for borderline resectable or oligometastatic GISTs may be a reasonable choice.