Familial gastrointestinal stromal tumors, lentigines, and café-au-lait macules associated with germline c-kit mutation treated with imatinib

Int J Dermatol. 2017 Feb;56(2):195-201. doi: 10.1111/ijd.13516.

Abstract

Background: Familial lentiginosis syndromes are characterized by a wide array of manifestations resulting from activation of molecular pathways which control growth, proliferation, and differentiation of a broad range of tissues. Familial gastrointestinal stromal tumors (GISTs) are often accompanied by additional features like hyperpigmentation, mastocytosis, and dysphagia. They have been described with mutations in c-kit (most commonly), platelet-derived growth factor receptor A, neurofibromatosis-1, and succinate dehydrogenase genes.

Materials and methods: We report on molecular characterization and tumor histopathology of two siblings in whom lentigines and café-au-lait macules were present along with multifocal GIST. Immuhistochemical analysis of CD34 and CD117 was performed on GIST biopsy samples from both siblings, while c-kit mutational analysis was done by PCR and direct sequencing on DNA from peripheral blood leukocytes of all family members and from paraffin-embedded gastric biopsy specimens of affected siblings.

Results: Histopathology revealed positive expression of CD117 and CD34. Mutational analysis showed the germline c.1676T>C mutation in c-kit exon 11, (p.(Val559Ala)), in the peripheral blood of both siblings and a second exon 11 mutation, c.1669T>A (p.(Trp557Arg)) in the tumor biopsy of one of them. Initiation of imatinib treatment resulted in striking resolution of their hyperpigmentation and a stable gastrointestinal disease in one of them.

Conclusions: A c-kit mutational test in familial GISTs is indicated before initiation of imatinib therapy, as it can help predict tumor response to treatment.

Publication types

  • Case Reports

MeSH terms

  • Adult
  • Antineoplastic Agents / therapeutic use
  • Cafe-au-Lait Spots / complications
  • Cafe-au-Lait Spots / drug therapy
  • Cafe-au-Lait Spots / genetics*
  • Female
  • Gastrointestinal Neoplasms / complications
  • Gastrointestinal Neoplasms / drug therapy
  • Gastrointestinal Neoplasms / genetics*
  • Gastrointestinal Stromal Tumors / complications
  • Gastrointestinal Stromal Tumors / drug therapy
  • Gastrointestinal Stromal Tumors / genetics*
  • Germ-Line Mutation
  • Humans
  • Imatinib Mesylate / therapeutic use
  • Lentigo / complications
  • Lentigo / drug therapy
  • Lentigo / genetics*
  • Male
  • Pedigree
  • Proto-Oncogene Proteins c-kit / genetics*

Substances

  • Antineoplastic Agents
  • Imatinib Mesylate
  • Proto-Oncogene Proteins c-kit