A Case of Neurofibromatosis Type 1 With Early Gastric Cancer and Multiple Small Bowel Gastrointestinal Stromal Tumors

Abstract

Neurofibromatosis type 1 (NF1) is a multisystem genetic disorder that primarily affects the skin and nervous system, leading to characteristic skin changes and the development of benign or malignant tumors with a broad spectrum of severity and complications. Gastrointestinal stromal tumors (GISTs) are the most common non-neurological tumors occurring in patients with NF1. The clinical, genetic, and pathological features of these tumors differ significantly from those of sporadic GISTs. Very rarely, other gastrointestinal malignancies, such as small bowel adenocarcinomas, neuroendocrine tumors, and gastric adenocarcinomas, have occurred in patients with NF1. Here, we report a case of multiple duodenal GISTs and early gastric cancer in a patient with NF1.

INTRODUCTION

Neurofibromatosis type 1 (NF1), also known as von Recklinghausen’s disease, is a common genetic disorder characterized by changes in skin pigmentation and the growth of tumors along nerves in the skin, brain and other parts of the body. It is caused by mutations in the NF1 gene on chromosome 17, which codes for the protein neurofibromin—a tumor suppressor that regulates cell growth. When neurofibromin is deficient or absent, cells can grow uncontrollably, leading to tumor formation [1]. NF1 shows a variety of clinical manifestations in the bone, soft tissue, nervous system and skin; café-au-lait spots, which are freckles on the armpits and groin, and Lisch nodules, which are benign raised spots on the iris, are common. The hallmark of NF1 is the development of benign nerve sheath tumors called neurofibromas, which appear on or under the skin and sometimes inside the body [2]. NF1 is commonly associated with the development of benign or malignant tumors of the digestive system. Gastrointestinal stromal tumors (GISTs) develop in 5%–25% of NF1 patients, making them the most frequent non-neurological tumors in this population [1,3]. These tumors differ significantly from sporadic GISTs in their clinical, genetic, and pathological features. Other rare gastrointestinal malignancies, such as small bowel adenocarcinoma and gastric neuroendocrine tumor have also been reported in NF1 patients but are far less common [4]. The authors investigated synchronous occurrence of GISTs and early gastric cancer (EGC) in patients with neurofibromatosis. Here, we report a case of multiple duodenal GISTs and EGC in a patient with neurofibromatosis.

CASE REPORT

A 65-year-old woman presented to the hospital with EGC found during a gastroscopy done at the local health screening center. She was asymptomatic with no significant past medical history other than neurofibromatosis diagnosed at another hospital several decades ago. The past medical history of her parents and siblings was unknown, and there was no medical history of her children. On presentation, her blood pressure was 120/80 mm Hg, pulse rate was 76 bpm, respiratory rate was 20 breaths/min, temperature was 36.0°C, and she was alert. On physical examination, there was no abdominal tenderness nor mass and no palpable hepatomegaly. Neurofibromatosis nodules with café-au-lait spots of various sizes, light brown spots, and freckles were observed over the whole body, including the anterior chest, abdomen, and extremities (Fig. 1). Peripheral blood work showed white blood cells 5470/mm³, hemoglobin 12.0 g/dL, and platelets 193000/mm³, and serum biochemistry showed AST/ALT 32/45 IU/L, BUN 14.3 mg/dL, and creatinine 0.9 mg/dL.

Fig. 1.

Neurofibromatosis nodules with café-au-lait macules of various sizes, light brown patches and freckles were observed over the whole body.

Her endoscopy showed multiple elongated, flat, submucosal elevated lesions clustered in a club-like pattern at the lesser curvature side of gastric body, one of which was a 2.0×1.5 cm stage IIa EGC.

The lumen of the duodenal bulb and second segment was very wide and contained multiple flat submucosal elevated lesions with a gastric-like appearance. A 1.5 cm hard subepithelial tumor protruding from the lumen was found at the third part the duodenum (Fig. 2). Endoscopic ultrasound revealed an additional 2.0×2.0 cm subepithelial tumor at the anterior wall of the duodenal bulb that protruded outside of the lumen in addition to the one at the third part of the duodenum. On endoscopic ultrasound, both subepithelial tumors were originating from muscularis propria, which were highly vascular and heterogeneously hypoechoic. There was no evidence of internal calcification or necrosis (Fig. 3).

Fig. 2.

Endoscopic finding shows multiple, elongated, club-like lesion at the lesser curvature of the gastric body which was early gastric cancer and subepithelial tumors at duodenum.

Fig. 3.

Endoscopic ultrasound showing subepithelial tumors on the anterior wall of the duodenal bulb and in the 3rd portion of the duodenum.

Abdominal CT showed multiple hypervascular nodules at pancreaticoduodenal groove and subepithelial area of proximal jejunum and a 2 cm polypoid mass in duodenum, highly suggestive of neurogenic tumor or GIST (Fig. 4).

Fig. 4.

Abdominal CT shows a 2 cm polypoid mass in the duodenum and subepithelial area of the proximal jejunum.

Small bowel enteroscopy was performed to the distal jejunum, but no additional subepithelial tumor protruding into the lumen was detected. The EGC lesion was completely resected by endoscopic submucosal dissection. Pathologic examination diagnosed well differentiated adenocarcinoma confined to the lamina propria with villous adenoma. The patient tested positive for Helicobacter pylori infection and was further treated with eradication therapy. Two duodenal submucosal tumors were confirmed as GISTs by endoscopic ultrasound fine needle biopsy and then duodenal wedge resection was performed. Immunochemistry of both tumors showed positive for CD117 and CD34; thus, diagnosed as very-low-risk GISTs (mitotic count 0/HPF, size 1.7×1.0 cm, mitotic count 0/HPF, size 1.0×1.0 cm each) (Fig. 5). CT scan performed after resection surgery showed multiple hypervascular nodules in pancreaticoduodenal groove with no change for more than one year. Endoscopy showed no recurrence and the patient was followed up without imatinib. She is being followed up without recurrence on endoscopy and CT for more than a year.

Fig. 5.

Pathological analysis revealed a GIST measuring 1.7 cm×1 cm, classified as very low risk, with 0 mitotic count per 10 high-power fields and no tumor at the margins. Immunohistochemistry (×200) results were CD117 (+), CD34 (+). GIST, gastrointestinal stromal tumor.

DISCUSSION

NF1 is a rare genetic disorder caused by mutations in the NF1 gene [4,5]. It is characterized by changes in skin coloring and the development of benign cutaneous and subcutaneous tumors called neurofibromas [4,5]. However, some patients with NF1 develop cancerous tumors, including malignant peripheral nerve sheath tumors, optic pathway gliomas, and other soft tissue sarcomas [1,4-6].

NF1 has well-documented association with GIST, particularly in the small intestine. NF1 patients have 34–45 times higher risk of acquiring GIST compared to the general population, resulting in 5%–25% of NF1 patients developing GISTs [7,8]. NF1-associated GISTs have unique clinical features that differ from that of sporadic GISTs; they are often presented in multiple tumors (synchronous or metachronous), are typically smaller in size with low mitotic activity, presented at younger age (often <50 years), and show female predominance. NF1-associated GISTs are most commonly found at the small intestine (about 90% of cases), especially at the jejunum and ileum, and rarely at the stomach [4,9,10]. They are often asymptomatic and discovered incidentally. Unlike sporadic GISTs, NF1-associated GISTs rarely harbor KIT or PDGFRA mutations. Instead, they arise from biallelic inactivation of the NF1 gene, leading to hyperactivation of the RAS/MAPK pathway [8,11]. Due to the lack of KIT/PDGFRA mutations, response to imatinib is poor; alternative therapies such as regorafenib may be considered [9]. They usually have better prognosis and slower progression compared to sporadic GISTs. Surgical resection is the mainstay.

Meanwhile NF1 is not strongly linked to an increased incidence of gastric cancer. Two case reports describe rare co-occurrences of NF1 and gastric adenocarcinoma [12,13]. Unlike NF1-associated GIST which lack KIT/PDGFRA mutations, gastric cancer pathogenesis typically involves distinct pathways (e.g., HER2, TP53, or CDH1 mutations). However, NF1 may act as a tumor suppressor by regulating the RAS/MAPK pathway. Loss of NF1 function may drive tumor aggressiveness in gastric cancer through RAS hyperactivation. In addition, reduced NF1 expression in gastric tumors predicts aggressive behavior and poor survival [11,14]. However, that evidence relies on small cohorts [11,14]. This contrasts with NF1’s established role in GIST pathogenesis, highlighting distinct molecular pathways. In this case, the patient was Helicobacter pylori positive, had atrophic gastric mucosa, and had intestinal metaplasia and villous adenoma with high-grade dysplasia surrounding the gastric cancer. Helicobacter pylori infection is likely the major contributing cause of this patient’s gastric cancer development. NF1 may play a role in the development or progression of gastric cancer, but the evidence is lacking.

The small bowel endoscopy performed on this patient did not reveal any additional submucosal tumors. However, CT showed multiple small hypervascular nodules on the small intestine outside the intestinal wall. Considering that submucosal tumors tend to be multiple; it may be necessary to combine CT with capsule endoscopy or small bowel endoscopy for follow-up. The multiple hypervascular nodules on CT were not treated with imatinib and were followed up for one year and have not progressed further, showing a very good outcome as previously reported.

Understanding the cancer risk of patients with NF1 is crucial for early detection, monitoring, and management. We report a case of multiple GISTs of the small intestine that were discovered during the workup of an asymptomatic EGC in a patient with neurofibromatosis. A multifaceted approach to the small bowel using ultrasound, CT, and small bowel enteroscopy in patients with NF1 appears to be effective.