Familial GIST was first reported by Nishida T in 199811. It is a very rare inherited disease and has been reported in 35 different families and 8 individuals with germline KIT mutations so far 12. Most affected families, including the members described in our study, have been shown to harbor a germline KIT mutation in exon 11 (encoding the juxtamembrane domain) 9, 13. While previous studies showed that some GIST families which had been confirmed with a germline PDGFRA mutation 1, 14. In the family described by Nishida et al. 15 that 1 of 2 consecutive Val residues (codons 559 and 560, GTT-GTT) of the KIT JM structural domain was missing, in which 2 family members showed skin pigmentation in the perineum. By histologic and immunohistochemical examinations, as well as molecular genetic analysis, we uncovered a single germline mutation in codon 560 (c.560T>G, p.V560G) at KIT exon 11 in a family with GISTs and hyperpigmentation.
The origin of mesenchymal tumors in the gastrointestinal tract has long been served a focus of debate. Previous studies 16 have demonstrated that abnormalities of ICC, the “pacemaker cells of the gut”, may cause various motility disorders of the gastrointestinal tract. Miettinen et al. 17 argued that GISTs were derived from transformed neoplastic precursors of the ICC. ICC hyperplasia and multiple cecal physicians were produced in mice transfected with the knock-in mutant KIT (V558del) 18. In this study, the diffuse ICC hyperplasia, presented in the muscularis propria in the non-tumorous wall of the small bowel, could be found in two patients. Immunohistochemical examination of tumors resected from patientsⅡ:1 andⅢ:1 showed that most tumor cells were positive for DOG-1 and CD117 (KIT protein). What’s more, ICC were confirmed to express not only CD117, but also DOG-1. Therefore, data from a transgenic mouse model19, together with histologic findings in previous researches20 and ours, indicated that activation of germline KIT results in hyperplasia of the ICC cells from which GISTs derive.
Clinically, symptoms such as multiple primary neoplasms (with several affected relatives), dysphagia and abnormal pigmentation 1, 13, 21 can be observed in familial GISTs. Median age at diagnosis of sporadic GISTs is around 60 years, while tumors of familial GISTs may present at earlier ages than that of sporadic GISTs 21. The kindred in our study demonstrated some of these traits. It is worth noting that patient Ⅲ:1 andⅡ:1(with the same mutation)who were diagnosed with multiple GISTs in their 20 s and 30 s were also noted to have cutaneous pigmentation which developed a few months after birth and increased in size and number with age. Ⅳ: 1, the daughter of patient Ⅲ:1 received genetic counseling and testing for early detection of GIST. Prior researches of familial GISTs have illustrated an association with cutaneous hyperpigmentation 22.This association results from the role of KIT in development of melanocytes, as well as ICCs from which GISTs derive 23. One of the dead family member (grandma of Ⅲ:1) in this study in earlier generation (Ⅰ:2) indicated that “multiple lesions in abdominal cavity” might be the cause of death. The diagnosis was not clear at that time, probably because GISTs had not yet been considered as a unique clinicopathological entity.
Although the effectiveness of imatinib, a tyrosine kinase inhibitor, in the treatment of familial GISTs had not been defined yet, many individuals with this disease accepted the therapy of imatinib, which might result in resolution of the hyperpigmentation and stable disease 3, 24. However, not all patients experience pigmentary changes and tumor regression in response to imatinib, nor did all patients experience the same degree of changes 22. Conca et al. 25 showed GIST in two family members with the L576P mutation (in exon 11) who had a poor response to imatinib since the tumors persisted microscopically. What’s more, Divya G et al. 9 reported two siblings of hereditary GISTs with the missense mutation p. (Val559Ala). Both patients were treated with imatinib, but only one patient’s condition changed to stable after such treatment; after a stable period of more than one year, progression of the disease could be observed in another. The different responses to imatinib may due to secondary drug resistance, the type of mutation and its location. Patients in our study were treated with adjuvant imatinib (400 mg/ day) after surgery (Ⅱ:1 after second surgery), within several months of imatinib treatment these hyperpigmentation diminished and the skin tone became lighter. Previous studies have demonstrated that KIT and its ligand stem cell factor (SCF) are considered to play significant roles in the development of 4 cell lineages: hematopoietic cells, melanocytes, germ cells, and mast cells 24, 26. As it is known to all, imatinib has been identified as the inhibition of KIT, which may leads to downstream inhibition of tyrosinase gene promoter and subsequent melanin synthesis inhibition. In vitro studies22, 27, researchers have reported that melanocytes with decreased proliferation in fibroblasts and low tyrosinase activity can be observed in imatinib-treated skin. This indicates that SCF-KIT interaction can regulate the development and survival of melanocytes in the context of GISTs 28.
Although GIST associated with germline KIT mutations is very rare, it should be taken into consideration when we encounter patients with multiple lesions, cutaneous hyperpigmentation, multiple lentigines, mastocytosis and other typical manifestation. We should emphasize the importance of inquiring about a detailed family history in individuals with abnormal pigmentation, especially any history of GI lesions. What’s more, the possibility of genetic testing and counseling to distinguish individuals with high risk from those with little/no risk is essential. Detecting for the KIT mutation should prior to the start of imatinib therapy, for it can help predicting tumor response. Imatinib as a therapeutic inhibition in these rare disease remains to be determined, mainly because data on therapeutic effects of imatinib in familial GISTs is limited. In addition, careful monitoring for the development of GIST (during and after treatment) is reasonable. The specific secondary mutations can direct the clinician to select other appropriate second-line treatment of patients with imatinib resistance.