GISTs are mesenchymal tumors of the digestive tract and are thought to arise from ICCs [4]. Gain-of-function mutations of the KIT or PDGFRA gene in the ICCs cause ligand-independent activation of the corresponding receptor for tyrosine kinase and subsequently activate common downstream signaling pathways. KIT mutations in sporadic GISTs, which account for 80–90% of all GISTs, have been reported in exon 9, 11, 13, and 17 of the gene. The mutation in exon 11 accounts for more than 50%, the mutation in exon 9 is found in 10–20%, and mutations in exons 13 and 17 are rarely found [5, 6]. ICCs are innervated cells associated with Auerbach’s plexus that regulate gastrointestinal (GI) motility and coordinate peristalsis throughout the GI tract. Because ICCs are present throughout in the gastrointestinal wall, GISTs can occur anywhere, especially in the stomach (50%) and small bowel (25%) [4, 7].

After the first report by Nishida et al. [8], over 40 families who have multiple family members developing GIST have been identified. Familial GIST is an inherited neoplastic disease with multiple GISTs throughout the GI tract caused by germline mutations in KIT gene or PDGFRA gene [9, 10]. In familial GISTs, 55% of families had mutations in exon 11 of the KIT gene and 20% of families had mutations in exon 13 of the KIT gene [8, 9]. The median age of patients with familial GISTs is lower than that of patients with sporadic GISTs. Hyperplasia of ICC is observed histologically, resulting in acquisition of other gene mutations, development of monoclonal GIST, and occurrence of malignant transformation of tumors. Multiple GISTs have been observed in the small intestine and stomach, but rarely in the colon [8, 9]. Clinically, it is important not to misdiagnose multiple GISTs as peritoneal metastasis.

These mutations cause not only multiple GISTs but also diffuse ICC hyperplasia in GI tract, skin pigmentation, vitiligo, mastocytomas, and dysphagia due to ICC function disorder in the esophagogastric junction. In the report by Hirota et al., the hyperplasia of ICCs in the myenteric plexus region of the esophagus was observed pathologically and endoscopic ultrasound of the esophagocardiac junction showed a thickened hyperechoic layer between the circular and longitudinal muscle layers without mechanical obstruction of the esophagus [8,9,10].

Abnormalities of ICCs have been implicated in various motility disorders of the GI tract [11, 12]. The disordered motility associated with ICC hyperplasia might lead to decreased peristalsis, cause achalasia-like disorder [11], and predispose patients to diverticula formation. This patient and his father had a germline mutation in exon 17 of the KIT gene and had also multiple GISTs and esophageal motility disorder. Furthermore, Shintaku et al. reported the relationship between GISTs and diverticular structure [13]. The study stated that GISTs might locally alter gut motility and induce disturbed peristalsis. In the present case, numerous familial GISTs in stomach also can alter gut motility and result in food residue accumulation in esophagus, with extension of the lumen of the esophagus forming the large esophageal diverticulum.

Considering about the operative procedure in this case, there are some other procedures, such as resection of the diverticulum preserving the esophagus. However, the location of the diverticulum was near from the esophageal gastric junction and it is difficult to resect only the diverticulum. In addition, because this patient has the esophageal motility disorder genetically, it may cause esophageal reflux symptom in the future and we decided to this operative method. Furthermore, we examined the patient’s abdominal cavity laparoscopically and confirmed multiple small tumors throughout the stomach. However, because the patient was predicted to have numerous GISTs throughout the GI tract and he wished to avoid total gastrectomy, we decided to perform proximal gastrectomy and to perform reconstruction via the subcutaneous route for future possibility of re-gastrectomy. Laparoscopic–thoracoscopic esophageal resection for the treatment of large epiphrenic esophageal diverticulum has been previously reported [14]; however, this is the first report of laparoscopic–thoracoscopic surgery for not only a large esophageal diverticulum but also for familial GISTs.