Neurofibromatosis 1 (NF1) is a tumor suppressor gene and a member of the ras regulatory protein family. Inactivation of the NF1 gene occurs in about 1 of 3000 births, making it a relatively common condition. NF1 inactivation can be a familial condition involving an autosomal dominant inheritance pattern. However, about half of cases may occur randomly (sporadic, not familial). Characteristics shown by NF1 patients include pigmentation abnormalities such as café au lait spots (light brown birthmarks), a predisposition to various tumors, and multiple neurofibromas (benign nerve sheath tumors). About 10% of patients develop malignant peripheral nerve sheath tumors.

Persons affected by NF1 have a much greater probability of developing GIST than the general population. The prevalence of GIST is about 5-25% in the NF1 population, with the higher estimates including symptom-free tumors diagnosed only at autopsy (Ghrist, 1963; Fuller et al, 1991; Giuly et al, 2003; Zoller et al, 1997). GIST tumors in NF1 usually have not shown mutations in the c-kit gene or the PDGFR gene; that is, they have normal or "wild type" KIT and PDGRFA. One exception involving a patient with an exon 11 mutation in c-kit was described by Yantiss et al (2004). Cheng (2004) also reported one mutant case. Takazawa et al (2005) reported mutations in at least one tumor from 3 of 9 NF1 patients. Both KIT and PDGFRA mutations were identified. Different tumors from a single patient could show different mutations, and the same patient could have both GISTs with mutations and other tumors that were wild-type.

The GISTs in NF1 patients are usually multiple and usually found in the small intestine, though a few have been found in the stomach. Areas of hyperplasia of ICCs between GISTs in NF1 may be precursor lesions (Andersson et al, 2005). NF1 GISTs do generally stain positive for KIT, like most other GISTs. Compared to sporadic GISTs, NF1 GISTs are more likely to show S-100 reactivity (a marker of neural differentiation), entrapped myenteric nerves within the tumor, and skeinoid fibers within the tumor (Takazawa et al, 2005). Although they may fall into any GIST risk category, NF1 GISTs usually show low cell proliferation (growth) indicators such as mitotic count or Ki-67 index (Andersson et al, 2005). NF1 GISTs rarely metastasize (Levy et al, 2004). Andersson et al (2005) reported follow-up for 9 NF1 patients who had surgery for GIST; none of the patients died of GIST, and 6 of 9 were well up to 32 years later.

Because these GISTs generally do not exhibit c-kit or PDGFR mutations, they are apparently driven by some undiscovered alternative mechanism. When KIT or PDGFRA mutations are found, they are apparently a late event in the tumor's development, not a necessary event. The mutation(s) causing GIST in NF1 have not yet been identified. Andersson et al (2005) discuss the possibility that NF1 inactivation could lead to constitutive activation of ras and increased MAP kinase signaling.  Maertens et al (2006) found no KIT or PDGFRA mutations in tumors from three NF1 patients, and also showed that inactivation of neurofibromin was sufficient to hyper-activate the MAPK pathway, which is more important in NF1 GISTs than in sporadic GISTs. 

There is only one published paper about response of NF1 GISTs to tyrosine kinase inhibitor drugs such as imatinib (Gleevec);  Lee et al (2006) report a case of NF1 GIST that did respond to imatinib.  As discussed on our Gleevec page, some wild-type (unmutated) GISTs do respond to imatinib.

Tsukuda et al (2007) reported using laparoscopic surgery to remove intestinal GISTs in a NF-1 patient.