Intestinal tumors in neurofibromatosis 1 with special reference to fatal gastrointestinal stromal tumors (GIST)

Abstract

Background Type 1 neurofibromatosis (NF1) is a genetic tumor predisposing Rasopathy. NF1 patients have an increased risk for developing benign and malignant tumors, but the occurrence of intestinal tumors has not been investigated at the population level. Methods In this retrospective register‐based total population study, diagnoses of gastrointestinal tract tumors were retrieved from the Finnish Care Register for Health Care for 1,410 NF1 patients and 14,030 reference persons. We also reviewed the death certificates of 232 NF1 patients who died during years 1987–2013, and specifically searched for diagnosis of gastrointestinal stromal tumor (GIST). Results The register analysis revealed an increased overall hazard ratio (HR) of 2.6 (95% CI 1.9–3.6) for intestinal tumors in NF1 compared to general population. The highest HR of 15.6 (95% CI 6.9–35.1) was observed in the small intestine. The focused analysis of NF1 death certificates and GISTs demonstrated that the GIST was the primary cause of death in seven patients. Conclusion This study emphasizes the need for careful evaluation of NF1 patients with gastrointestinal complaints. The challenge in diagnosis is that the tumors preferably occur at the small intestine, which is difficult target for diagnostic procedures. We also show that the NF1 GISTs may lead to fatal outcome despite of benign histopathological findings at the time of the diagnosis.

Small bowel gastrointestinal stromal tumor presenting with gastrointestinal bleeding in patient with type 1 Neurofibromatosis: Management and laparoscopic treatment. Case report and review of the literature

“…Type 1 Neurofibromatosis (NF1, von Recklinghausen disease) is an autosomal and dominant disorder caused by the inactivation of the NF1 gene on chromosome 17, which is a tumour suppressor gene in some cell types, encoding the neurofibromin protein, a member of the RAS family [ [21] , [22] , [23] , [24] , [25] ]. This condition is characterised by cutaneous neurofibromas, café au lait macules, axillary and inguinal freckling, and Lish nodules.…”

“…NF1 is associated with several tumours, including those of the GI tract, and GISTs are indicated as the most commonly GI NF1 associated tumours [ 25 , 26 ]. The incidence of GIST in the NF1 population is estimated to be markedly higher compared to that of the general population [ [22] , [23] , [24] ], although the frequency of NF1 GIST varies greatly in the literature, ranging from 5% to 29% [ 24 , 27 , 28 ]. Levy et al [ 29 ] showed, significantly, in four out of five (80%) patients with multiple lesions, only one tumour was identified on preoperative CT scan, a finding reflected in our case.…”

“…Levy et al [ 29 ] showed, significantly, in four out of five (80%) patients with multiple lesions, only one tumour was identified on preoperative CT scan, a finding reflected in our case. Many studies reported several differences between GISTs associated with NF1 syndrome and sporadic GISTs, in fact the literature would seem to demonstrate a distinct and peculiar phenotype of NF1 GIST: the predominant localisation is the small intestine rather than the stomach [ 4 , 23 , [22] , [23] , [24] , [25] , 29 , 30 ], with multiple localisations, occurring in younger patients. The estimated risk for malignancy is low [ 23 ], suggesting a good long-term prognosis [ 31 ], although one report concluded that NF1 GISTs are not always indolent and they can lead to death [ 23 ].…”

“…On the other hand, the majority of NF1 GISTs showed the absence of Kit and/or PDGRFA mutations [ 25 , 28 ], for this reason, this type of GIST does not respond well to imatinib treatment [ [23] , [24] , [25] , 28 ] which is considered ineffective and not recommended [ 23 , 50 ].…”

Circulating free DNA in the plasma of individuals with neurofibromatosis type 1

“…Unlike the general population, the incidence of MPNSTs starts to increase already at teenage in NF1, and the standardized incidence ratio of MPNST in NF1 may be as high as 2,056 (95% CI 1,561–2,658) (Uusitalo et al, 2016; Peltonen et al, 2019). In addition to tumors of the nervous system and brain, other cancers associated with NF1 include, for example, those of the breast and gastrointestinal tract (Sharif et al, 2007; Uusitalo et al, 2016; Seminog and Goldacre, 2013; Ylä‐Outinen et al, 2019; Kenborg et al, 2020).…”