Gastric gastrointestinal stromal tumor in a patient with neurofibromatosis type I presenting with anemia: A case report

Abstract

BACKGROUND

Gastrointestinal stromal tumors (GISTs) are caused by mutations in the KIT and platelet derived growth factor receptor alpha genes in approximately 90% of cases. A minority of wild-type GISTs are associated with neurofibromatosis type 1 (NF1), an autosomal dominant genetic disease resulting from pathogenic mutations in the NF1 gene, which encodes the neurofibromin protein. NF1 patients often exhibit multi-system involvement, with café-au-lait macules and neurofibromas being characteristic symptoms. GISTs are a rare complication of NF1, with the tumors most frequently occurring in the small intestine (90% of cases), while occurrences in the stomach are rare.

CASE SUMMARY

A 51-year-old woman presented to the emergency department with complaints of dizziness, fatigue, chest tightness, and dark stools. Initial examination revealed a red blood cell count of 1.99 × 10¹²/L and a hemoglobin level of 43 g/L. She underwent blood transfusions and fluid replacement to stabilize her condition. Further investigations identified typical café-au-lait macules on her trunk, limbs, and face, along with neurofibromas. Endoscopy showed coffee-colored fluid in the gastric cavity, a large submucosal elevation with an exudative covering, and ulcer formation on the gastric fundus. Exploratory laparoscopy confirmed the tumor’s origin in the gastric fundus, and resection of the giant GIST was performed. Pathological analysis revealed a necrotic GIST measuring 18 cm × 14 cm, classified as high-risk, with approximately 5 mitotic figures per 10 high-power fields and no tumor at the margins. Immunohistochemistry results were CD117 (+), delay of germination 1 (+), CD34 (+), and succinate dehydrogenase complex iron sulfur subunit B intact expression. Genetic testing using next-generation sequencing confirmed an NF1 gene mutation. The patient underwent successful tumor resection and was discharged home with postoperative regorafenib therapy. A follow-up at one year showed no recurrence.

CONCLUSION

Given the diversity of clinical symptoms associated with NF1 and the complexity of NF1-related GISTs, surgical resection with complete tumor removal remains the preferred treatment option. However, the absence of a standardized treatment protocol for adjuvant therapy presents numerous challenges for clinicians.

Key Words: Neurofibromatosis type 1; Gastrointestinal stromal tumors; Regorafenib: Anemia; Case report

Core Tip: Gastrointestinal stromal tumor (GIST) is one of the rare complications of neurofibromatosis type 1 (NF1). In NF1-related GISTs, tumors are more common in the small intestine (90%) and are rarely found in the stomach. The condition of NF1-related GIST is complex, and there is no standard treatment plan for postoperative adjuvant therapy. Postoperative regorafenib treatment was administered in this patient, and no recurrence was noted at the one-year follow-up.

INTRODUCTION

Neurofibromatosis encompasses a group of tumor syndromes characterized by genetic heterogeneity, leading to tumors in the central and peripheral nervous systems and causing various types of systemic damage. This autosomal dominant genetic disease results from genetic defects. The global incidence is approximately 1 in 3000 to 1 in 4000 individuals. Neurofibromatosis type 1 (NF1) is the most prevalent type, accounting for approximately 96% of cases, whereas NF2 represents around 3%. Schwannomas are even rarer[1,2]. NF1 is caused by pathogenic mutations in the NF1 gene, which encodes neurofibromin. Characteristic symptoms of NF1 include café-au-lait macules (CALMs) and neurofibromas, while gastrointestinal stromal tumors (GISTs) are rare complications. Among NF1-related GISTs, 90% occur in the small intestine, with gastric occurrences being extremely rare. These tumors are complex, making complete surgical resection challenging. There is currently no standardized protocol for adjuvant therapy post-surgery, necessitating vigilant clinical attention.

CASE PRESENTATION

Chief complaints

The 51-year-old female patient had been suffering from anemia for the past two years and tested positive for fecal occult blood one year ago.

History of present illness

Over the last two years, the patient frequently experienced episodes of sudden dizziness and fatigue. Recently, she experienced symptoms including dizziness, weakness, chest tightness, and the passage of black stools.

History of past illness

The patient had multiple CALMs and skin nodules distributed across the head, face, trunk, and limbs, with both the quantity and size progressively escalating over the preceding 30 years. A biopsy conducted three decades ago on a nodular mass located on the upper limb yielded findings consistent with neurofibroma. Additionally, the patient reported experiencing symptoms of skin itching. Moreover, the patient exhibited normal intelligence, vision, and hearing, with no documented history of hypertension, diabetes, heart disease, or epilepsy.

Personal and family history

The patient is unmarried and has no children. Both her maternal grandmother and mother have a history of neurofibromatosis, while the rest of the family members do not have this condition (Figure 1).

Figure 1  Family history of the patient.

Physical examination

The patient was alert but exhibited poor mental status and a pale appearance, without cyanosis or jaundice of the skin or mucous membrane. Scattered, coffee-colored spots of varying sizes were observed, which were not raised above the skin surface, with lentil-sized raised points that matched the skin color and had a soft texture present on the face, trunk, and limbs (Figure 2A-C). The abdomen was distended, with a large palpable mass approximately 18 cm × 14 cm in the left upper abdomen. There was slight tenderness in the left abdomen, but no rebound tenderness, visible dilated veins on the abdominal wall, or intestinal peristalsis waves. The liver and spleen were not palpable, and Murphy’s sign was negative.

Figure 2 Clinical presentation of the patient. A: Multiple café-au-lait patches and cutaneous nodular masses on the abdomen; B: Multiple café-au-lait patches and cutaneous nodular masses on the back; C: Multiple café-au-lait patches and cutaneous nodular masses on the arm; D: Gastric stromal tumor with bleeding ulcer in gastroscopy.

Laboratory examinations

An urgent complete blood count revealed the following results: Red blood cell count 1.99 × 10¹²/L and hemoglobin 43 g/L. A blood transfusion was administered as symptomatic treatment to stabilize the patient’s condition.

Imaging examinations

Gastroscopy revealed a substantial volume of coffee-colored liquid in the gastric cavity. After rinsing, a large submucosal elevation was observed at the stomach fundus, covered with dirt-like deposits and exhibiting ulcer formation (Figure 2D). Chest and abdominal computed tomography (CT) scans (both plain and enhanced) revealed a large dense soft tissue lesion in the splenic gastric recess, measuring approximately 18 cm × 14 cm. The lesion had indistinct boundaries with the gastric wall, compressing the adjacent stomach and spleen, and communicated locally with the gastric cavity, exhibiting ulcer changes in the gastric recess occupying lesion. The enhanced scan shows heterogeneous enhancement, suggesting an interstitial tumor (Figure 3A). Additionally, multiple soft tissue nodules were present in the abdominal wall (Figure 3B and C).

Figure 3 Imaging manifestations of the patient. A: Huge stromal tumor in the abdominal cavity, squeezing abdominal organs; B: Cutaneous nodular masse on the abdomen; C: Subcutaneous nodule masse on the back; D: 12 months after surgery, no relapse in the tangential line and abdominal cavity.

FINAL DIAGNOSIS

On reviewing the patient’s medical history, she had a past diagnosis of neurofibromatosis and multiple CALMs on her body. The patient was admitted for weakness and dizziness due to anemia. During hospitalization, she underwent surgery for GIST. Postoperatively, pathology indicated a GIST (spindle cell type), and genetic testing confirmed the diagnosis of NF1.

TREATMENT

After multidisciplinary consultation, the patient underwent laparoscopic exploratory surgery, which confirmed that the tumor originated from the stomach fundus, leading to resection of a large GIST. Pathological results showed a GIST with necrosis, measuring 18 cm × 14 cm × 11 cm, categorized as high risk, with approximately 5 mitoses per 10 high-power fields. No tumor was found at the surgical margins. Immunohistochemistry results revealed positivity for CD117, delay of germination 1, CD34, succinate dehydrogenase complex iron sulfur subunit B, Ki-67 (5%), and phosphorylated histone H3 (< 1%) (Figure 4). Subsequently, next-generation sequencing genetic testing detected an NM_001042492.3 NF1: c.479+5G>A: p.? variant, not found in the 1000G, ExAC, gnomAD, and iJGVD databases, but documented as pathogenic in the ClinVar database (ID = 565507, with a rating of two stars) (Figure 5). Blood RNA analysis indicated that this variant caused a frameshift in exon 4, resulting in a premature stop codon (p.Gln97Valfs*13), supporting its pathogenic nature.

Figure 4 Postoperative immunohistochemical results. A: Diffusely strong expression of CD117 (× 100); B: Diffusely strong expression of delay of germination 1 (× 100); C: Diffusely strong expression of CD34 (× 100); D: Diffusely strong expression of succinate dehydrogenase complex iron sulfur subunit B (× 100); E: Diffusely strong expression of Ki67 (× 100); F: Diffusely strong expression of phosphorylated histone H3 (× 100).

Figure 5  Mutation site on chromosome.

OUTCOME AND FOLLOW-UP

The patient was discharged on the 7^th day after surgery without any complications. Following a definitive diagnosis, the patient received oral regorafenib as adjuvant therapy, which was discontinued after six months. Twelve months later, follow-up examinations showed no signs of tumor recurrence or metastasis (Figure 3D). The patient is scheduled to undergo annual follow-up evaluations with abdominal CT, magnetic resonance imaging, and gastrointestinal endoscopy.

DISCUSSION

NF1 is an autosomal dominant genetic disorder caused by pathogenic variants in the NF1 gene, which encodes the neurofibromin protein, located on chromosome 17q11.2. The term “neurofibromas” was first introduced by von Recklinghausen in 1882, leading to the alternative name for the disease, von Recklinghausen’s disease. CALMs and neurofibromas are hallmark symptoms of NF1, while GISTs represent a rare complication. Individuals with NF1 typically exhibit CALMs on their skin, appearing as brownish circular, oval, or irregular patches with clear boundaries, ranging in diameter from a few millimeters to several centimeters. The color intensifies during childhood and gradually lightens in adulthood. CALMs can appear on any skin surface except the palms and soles, and are commonly found on the trunk, buttocks, and lower limbs, with less frequent facial involvement. In NF1 patients, CALMs are generally concentrated on the trunk and vary in size from a few millimeters to several centimeters (Figure 2A and B). The more typical the appearance of CALMs, the higher the likelihood of an NF1 diagnosis, with no correlation between their quantity and the severity of NF1[3,4].

Patients with NF1 often exhibit benign tumors originating from peripheral nerve sheaths. These tumors appear as multiple rubbery, flesh-colored, soft nodules, or subcutaneous lumps. They are slightly prominent, dome-shaped, easily compressible, and have palpable borders, ranging from 1 to 2 cm in diameter, and are randomly distributed throughout the body. Neurofibromas are more common on the torso and limbs (Figure 2A-C). On examination, subcutaneous lumps with a rubbery texture, well-defined borders, consistent elasticity, and tenderness upon compression can be felt. Deeper subcutaneous lesions are more challenging to palpate and require imaging for identification. CT scans revealed multiple soft tissue nodules on the abdominal wall, some on the skin surface and others beneath the skin (Figure 3B and C). Nodules in this area can be mistaken for abdominal metastases, necessitating careful differentiation. Additionally, the patient experienced skin itching, possibly related to significant infiltration of mast cells[3].

GISTs are caused by mutations in KIT and platelet derived growth factor receptor alpha (PDGFRA) in approximately 90% of cases, with a small number of wild-type GISTs being associated with NF1. NF1-related GISTs are linked to inactivation of the NF1 allele gene, with KIT and PDGFRA mutations typically absent[5]. The incidence of GISTs in NF1 patients is 7%, which is 45 times higher than that in the general population[6]. In NF1-related GISTs, tumors are more commonly found in the small intestine (90%) and are rarely located in the stomach[7]. In this patient, there was a large intra-abdominal tumor located between the stomach and spleen with unclear boundaries, causing compression of the stomach and spleen. The tumor communicated locally with the stomach cavity, showing ulcerative changes and heterogeneous enhancement on imaging (Figure 3A). During surgery, the tumor was observed to originate from the stomach wall, with anemia accompanying the ulceration caused by the GIST (Figure 6). Pathological examination post-surgery revealed positivity for CD117, delay of germination 1, and CD34 (Figure 4A-C), aiding in diagnosis of the disease[8]. The location, size, and mitotic activity of the tumor are prognostic factors for GISTs. The Ki-67 index is associated with recurrence and survival[9]. NF1-related GISTs have a better prognosis compared to sporadic ones[7]. Genetic testing in this patient revealed a mutation at intron 4 c.479+5G>A NM_001042492.3, leading to exon 4 skipping and the introduction of a stop codon (p.Gln97Valfs*13), resulting in NF1 protein inactivation (Figure 5). NF1 protein stabilizes the guanosine-triphosphate hydrolase activity of the RAS protein, leading to activation of the downstream RAS/RAF/MEK pathway and tumor formation[10,11]. The mutation rate of the NF1 gene is high, and there is no mutation hotspot[12]. Mutations can be located in the entire coding and non-coding regions, including different types of variations[13]. Even small changes in gene copy number can involve deletions, duplications, frameshifts, splicing, nonsense, missense, chromosomal microdeletions, and other variations in different exons[14,15]. Compared with the genotype-phenotype relationships reported previously, the phenotype of NF1 patients with chromosomal microdeletions is more severe than other mutation types. However, only a few genotype-phenotype correlations have been established, and further relevant studies are needed[16].

Figure 6 Intraoperative view. A: The stromal tumor is from the stomach; B: Size of stromal tumor.

Due to the absence of KIT and PDGFRA mutations in NF1-related GIST, imatinib is ineffective for these patients[17]. The European Society for Medical Oncology guidelines advise against the use of imatinib for treating NF1-GIST[18]. Currently, no standard treatment strategy exists for this disease, and only case reports have noted the effectiveness of regorafenib in NF1-associated GIST[19]. The molecular mechanism of regorafenib’s antitumor effect on NF1-GIST remains unclear, but it may be linked to its role as a multi-kinase inhibitor that can inhibit RAF-1, BRAF, and members of the vascular endothelial growth factor receptor family. The patient received oral regorafenib for six months post-discharge, and no recurrence was observed after one year of follow-up. However, its long-term efficacy requires further study. Given the central role of the RAS signaling pathway in NF1, small molecule inhibitors have become a focus of clinical research[16]. Selumetinib, a small molecule MEK1/2 inhibitor, has shown promising results in treating NF1-related neurofibromas, and its efficacy in NF1-associated GIST warrants further validation[20].

CONCLUSION

Due to the diversity of NF1 clinical symptoms and the complexity of its association with GISTs, clinicians continue to face significant challenges.