Gastroenterology

Gastroenterology

Volume 122, Issue 5, May 2002, Pages 1493-1499
Gastroenterology

Case Report
Familial gastrointestinal stromal tumors associated with dysphagia and novel type germline mutation of KIT gene,☆☆

https://doi.org/10.1053/gast.2002.33024Get rights and content

Abstract

A family with multiple gastrointestinal stromal tumors (GISTs), a new type of germline mutation of KIT gene, and dysphagia is reported. The mutation was observed at Asp-820 in tyrosine kinase (TK) II domain. Mutations in TK II domain have been found in mast cell and germ cell tumors but not in GISTs, and the present family members are the first reported cases of GISTs with TK II domain mutations, including sporadic GISTs. Because interleukin 3–dependent Ba/F3 murine lymphoid cells transfected with the mutant KIT complementary DNA grew autonomously without any growth factors and formed tumors in nude mice, the mutation was considered to be gain-of-function type. Family members with the germline KIT mutation reported dysphagia, but those without the mutation did not. The mechanism of dysphagia was examined with gastrointestinal fiberscopy, endoscopic ultrasonography, and esophageal manometry. No mechanical obstruction was found, and the esophagus was not remarkably dilated. In the family members with dysphagia, endoscopic ultrasonography at the esophagocardiac junction showed a thickened hyperechoic layer between the circular and longitudinal muscle layers, suggesting hyperplasia of interstitial cells of Cajal at the myenteric plexus layer. Manometry showed low resting lower esophageal sphincter pressure and abnormal simultaneous contractions of the esophagus without normal peristalsis. These findings indicate that the dysphagia of the present family is different from typical achalasia. This is the first report of familial dysphagia caused by germline gain-of-function mutation of the KIT gene at the TK II domain.

GASTROENTEROLOGY 2002;122:1493-1499

Section snippets

Case report

A 71-year-old Japanese man (case 4 in Figure 1) underwent an operation for a large abdominal tumor.

. Pedigree of the family. Filled symbols showed the family members with both KIT mutation and GISTs. Case 2 died from a large abdominal tumor without operation. Squares and circles show male and female cases, respectively. Slashes indicate dead cases at the time of investigation.

Histologic diagnosis at that time was leiomyoma. He underwent another operation 1 year later for 2 submucosal tumors of

Materials and methods

The tumor tissues and the adjacent normal tissues were obtained during surgical procedures and were fixed in 10% formalin and embedded in paraffin. The sections (3 μm thick) were cut and used for H&E staining and for immunohistochemistry. Immunohistochemistry was performed as described previously.32 A rabbit polyclonal antibody against the human KIT was purchased from IBL Company (Fujioka, Gunma, Japan). A rabbit polyclonal antibody against human S-100 protein and mouse monoclonal antibodies

Immunohistochemistry

We examined whether the tumors resected from the proband (case 4) and his sister (case 7) were GISTs. Immunohistochemistry showed that the tumor cells were positive for both KIT and CD34 (Figure 2A and B) and negative for desmin, α–smooth muscle actin, and S-100 protein, indicating that the tumors were GISTs.

. (A and B) Immunohistochemical characteristics of the tumor and (C and D) hyperplastic spindle-shaped cells in the myenteric plexus layer of the small intestine of case 4. A and C were

Discussion

A family with multiple GISTs, new-type germline mutation of KIT gene, and dysphagia was described. To our knowledge, this is the sixth reported case of familial GISTs. In all families, germline mutation of KIT gene has been found. In 4 of 6 families, the mutation was observed in the juxtamembrane domain (Table 1).27, 28, 30, 31In a family in France, the mutation was detected in the TK I domain (Table 1).29 In the present family, the KIT mutation was identified in the TK II domain; Asp-820

References (38)

  • Q Tian et al.

    Activating c-kit gene mutations in human germ cell tumors

    Am J Pathol

    (1999)
  • K Isozaki et al.

    Germline-activating mutation in the kinase domain of KIT gene in familial gastrointestinal stromal tumors

    Am J Pathol

    (2000)
  • H Maeyama et al.

    Familial gastrointestinal stromal tumor with hyperpigmentation: association with a germline mutation of the c-kit gene

    Gastroenterology

    (2001)
  • JB Marshall et al.

    Achalasia due to diffuse esophageal leiomyomatosis and inherited as an autosomal dominant disorder. Report of a family study

    Gastroenterology

    (1990)
  • JM Monihan et al.

    CD34 immunoexpression in stromal tumours of the gastrointestinal tract and in mesenteric fibromatoses

    Histopathology

    (1994)
  • M Miettinen et al.

    Gastrointestinal stromal tumors-value of CD34 antigen in their identification and separation from true leiomyomas and schwannomas

    Am J Surg Pathol

    (1995)
  • S Hirota et al.

    Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors

    Science

    (1998)
  • L-G Kindblom et al.

    Gastrointestinal pacemaker cell tumor (GIPACT): gastrointestinal stromal tumors show phenotypic characteristics of the interstitial cells of Cajal

    Am J Pathol

    (1998)
  • M Sarlomo-Rikala et al.

    CD117: a sensitive marker for gastrointestinal stromal tumors that is more specific than CD34

    Mod Pathol

    (1998)
  • Cited by (0)

    Address requests for reprints to: Toshirou Nishida, M.D., Department of Surgery, Osaka University Medical School, Yamadaoka 2-2, Suita, Osaka 565-0871, Japan. e-mail: [email protected]; fax: (81) 6-879-3159.

    ☆☆

    Supported by grants from the Ministry of Education, Science, Culture and Sports of Japan and from the Sumitomo Foundation.

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