Gastrointestinal Stromal Tumors of Neurofibromatosis Type I (von Recklinghausen's Disease)

Abstract

Gastrointestinal stromal tumor (GIST), as well as the hyperplastic lesions of intestinal neural tissue and its supporting structures, is a gastrointestinal complication of type 1 neurofibromatosis (NF1) (von Recklinghausen's disease). In the present study, we analyzed the histologic and immunohistochemical features, and the c-kit and PDGFRA gene mutations of 36 GISTs derived from 9 NF1 patients. Distinctively, multiple GISTs arose preferentially in the small intestine. The histologic features of NF1-associated GISTs are almost similar to those of non-NF1 GISTs, but characteristically most of the NF1-associated GISTs contained skeinoid fibers. Thirty-three GISTs (92%) showed immunoreactivity for KIT, and 23 tumors (64%) showed diffuse or mosaic-like immunoreactivity for S-100 protein. Hyperplasic lesions, which may be the hyperplasia of interstitial cells of Cajal, were observed around some GISTs. Exons 9, 11, 13, and 17 of the c-kit gene and exons 12 and 18 of the PDGFRA gene were amplified and directly sequenced. Point mutations of c-kit gene or PDGFRA gene were identified only in three (8%) and two (6%) tumors, respectively. NF1-associated GISTs, showing the dual differentiation of interstitial cells of Cajal and Schwann cells, develop in close association with the myenteric nerve structure of gastrointestinal tract of NF1 patients. The point mutations of c-kit and PDGFRA gene may play a limited role in the tumorigenesis of NF1-associated GISTs.

Review article: the biology, diagnosis and management of gastrointestinal stromal tumours

“…14 Rectal GIST, although rare, most commonly present with haematochezia. 15 GIST may occur as part of a syndrome, such as Carney's triad (gastric GIST, paraganglioma, pulmonary chondroma), 16 Neurofibromatosis type 1 (with predominately spindle cell type of GIST) 17,18 or Von Hippel Lindau disease.…”

KIT and PDGFRA mutations in gastrointestinal stromal tumors (GISTs)

“…However, one study identified two KIT (Pro627Leu and Ile653Thr) and two PDGFRA (Pro589Lys and Arg822Ser) missense mutations in two separate lesions from two patients. 120 These mutations might be random genetic events related to the tumor progression. In another study, an identical 1697TϾA mutation leading at the protein level to Val559Asp substitution has been identified in three tumors from one patient.…”

“…16,43,117 KIT and PDGFRA mutational status in NF1 and pediatric and Carney triad GISTs Several studies evaluated KIT and PDGFRA mutation status in GISTs from neurofibromatosis type 1 (NF1) patients. [118][119][120][121][122][123][124] In general, no mutations in GIST-specific KIT or PDGFRA mutational "hot spots" have been found in multiple tumors from NF1 patients. However, one study identified two KIT (Pro627Leu and Ile653Thr) and two PDGFRA (Pro589Lys and Arg822Ser) missense mutations in two separate lesions from two patients.…”

Multiple Gastrointestinal Stromal Tumors and Their Association with Other Rare Tumors: Case Report

“…In re cent ye ars, examp les of fa mi li al GIST ha ve be en re por ted in which germ li ne mu ta ti ons of KIT or PDGFRA re sult in mul tip le GISTs, skin di sor ders, and ot her ab nor ma li ti es. Alt ho ugh most of mul tip le GISTs pa ti ents in the li te ra tu re de ve lo ped in the set ting of NF1, 4,5,12 mul tip li city in spo ra dic GIST pa ti ents wit ho ut fa mily his tory or NF-1 has be en al so des cri bed. 4 In the pre sent study, we analy zed the his to lo gi cal and im mu nohis toc he mi cal fe a tu res from three NF1 and one spo ra dic pa ti ent.…”