Neurofibromatosis type 1 with multiple gastrointestinal stromal tumors: A case report

Abstract

BACKGROUND

Neurofibromatosis type 1 (NF1) is characterized by café-au-lait patches on the skin and the presence of neurofibromas. Gastrointestinal stromal tumor (GIST) is the most common non-neurological tumor in NF1 patients. In NF1-associated GIST, KIT and PDGFRA mutations are frequently absent and imatinib is ineffective. Surgical resection is first-line treatment.

CASE SUMMARY

A 56-year-old woman with NF1 was hospitalized because of an incidental pelvic mass. Physical examination was notable for multiple café-au-lait patches and numerous subcutaneous soft nodular masses of the skin of the head, face, trunk, and limbs. Her abdomen was soft and nontender. No masses were palpated. Digital rectal examination was unremarkable. Abdominal computed tomography was suspicious for GIST or solitary fibrous tumor. Laparoscopy was performed, which identified eight well-demarcated masses in the jejunum. All were resected and pathologically diagnosed as GISTs. The patient was discharged on day 7 after surgery without complications. No tumor recurrence was evident at the 6-mo follow-up.

CONCLUSION

Laparoscopy is effective for both diagnosis and treatment of NF1-associated GIST.

Key Words: Neurofibromatosis type 1; Gastrointestinal stromal tumors; KIT; PDGFRA; Laparoscopy; Case report

Core Tip: A thorough medical history and physical examination are imperative in patients with neurofibromatosis type 1 and gastrointestinal symptoms. Such symptoms may indicate the presence of one or more gastrointestinal stromal tumors. Abdominal computed tomography, capsule endoscopy, or small bowel endoscopy should be performed. Laparoscopy may also be performed for both diagnosis and treatment.

INTRODUCTION

Neurofibromatosis type 1 (NF1), also known as von Recklinghausen's disease, is an autosomal dominant disorder with an incidence of 1/3000 to 1/4000[1]. Clinical diagnosis of NF1 is based on the presence of at least two of the following criteria: (1) Six or more café-au-lait patches over 5 mm in diameter in prepubertal children and over 15 mm in diameter in postpubertal individuals and adults; (2) two or more neurofibromas or one plexiform neurofibroma; (3) freckles in the axilla or inguinal region; (4) optic glioma; (5) two or more Lisch nodes; (6) osseous lesion; and (7) first-degree relative with NF1[2]. Gastrointestinal stromal tumor (GIST) is a tumor of mesenchymal origin that usually arises in the stomach (60%–70%) or small intestine (20%–30%). Multiple GISTs are uncommon[3]. We report an NF1 patient with a pelvic mass who underwent laparoscopic examination of the abdomen and pelvis and was diagnosed with multiple GISTs.

CASE PRESENTATION

Chief complaints

A 56-year-old woman with NF1 was hospitalized because of an incidental pelvic mass.

History of present illness

Ultrasonography of the pelvis performed at another hospital showed a mixed echoic mass approximately 4.5 cm × 4.5 cm × 4.0 cm in size in the left lower abdomen. Boundaries were clear and shape was irregular. No internal fluid echoes were visualized. Color Doppler flow imaging showed abundant blood flow signals within the mass. Clinically, the patient denied any gastrointestinal symptoms.

History of past illness

The patient had multiple café-au-lait patches and cutaneous nodular masses on the head, face, trunk, and limbs which had been increasing in number and size for more than 30 years. She had no symptoms of itchy skin. Biopsy of a nodular upper limb mass 10 years previously was consistent with neurofibroma. She had undergone laparoscopic cholecystectomy for a gallbladder stone 10 years previously and partial ileal resection for a strangulated bowel obstruction associated with adhesions 8 years previously. She had no history of hypertension, diabetes mellitus, or heart disease.

Personal and family history

The patient had no history of smoking or drinking. One sister and one brother had NF1.

Physical examination

The patient exhibited soft cutaneous nodular masses of 0.2 to 3 cm in diameter on the head, face, trunk, and limbs as well as multiple café-au-lait patches (Figure 1). Examinations of the eyes, lungs, and heart were normal. Hearing testing was normal. Freckles were seen in the axilla and inguinal region. No lymphadenopathy was detected in the neck, axilla, or inguinal region. The abdomen was soft and without tenderness or palpable masses. Bowel sounds were normal. Digital rectal exam was unremarkable.

Figure 1 Café-au-lait patches and cutaneous nodular masses. A: Multiple cutaneous nodular masses on the head and face; B: Multiple café-au-lait patches and cutaneous nodular masses on the back.

Laboratory examinations

White blood cell count was 7.2 × 10⁹/L. Red blood cell count was 4.45 × 10¹²/L. Hemoglobin concentration was 136 g/L. Platelet count was 260.0 × 10⁹/L. C-reactive protein concentration was 3.65 mg/L. Fecal occult blood testing was negative. Concentrations of carcinoembryonic antigen, cancer antigen 125, and carbohydrate antigen 19-9 were all within normal range.

Imaging examinations

Contrast-enhanced computed tomography (CT) of the abdomen showed an irregular cystic mass with an oblique diameter of approximately 44 mm in the left pelvis. Its solid component exhibited contrast enhancement (Figure 2) and had no clear border with the adjacent intestinal wall. GIST of the small intestine or solitary fibrous tumor was suspected.

Figure 2 Abdominal computed tomography. A: A cystic solid mass with an oblique diameter of approximately 44 mm is seen in the left pelvis; B: The solid component exhibits arterial enhancement.

FINAL DIAGNOSIS

NF1 with GISTs.

TREATMENT

After multidisciplinary team consultation, laparoscopy was performed. Eight well-demarcated encapsulated masses were found in the jejunum between 20 and 120 cm from the Trietz ligament. The remainder of the small intestine was free of masses. The largest mass was approximately 4.5 cm in diameter and located 20 cm from the Trietz ligament. The others were 0.3 to 0.8 cm in diameter. The small intestine was approximately 200 cm in length and the original small intestine anastomosis from her previous surgery was open. Because resecting 100 cm of the intestine could cause short bowel syndrome, we elected to perform resection of the jejunal masses. A 6 cm median upper abdominal incision was made to raise the small intestine into the abdominal cavity. Partial jejunostomy was performed 20 cm from the Trietz ligament and the masses were resected (Figure 3). Histopathology of the 4.5 cm jejunal mass was consistent with GIST with hemorrhagic infarction. Mitosis count was < 5 in 50 high-power fields. Based on the modified National Institutes of Health criteria, the tumor was classified as low risk. The other masses were also diagnosed as GISTs. None exhibited invasive growth. CD34, CD117, and DOG-1 staining was positive (Figure 4). S-100 staining was negative. Ki-67 index was less than 5%. Genetic testing demonstrated wild type KIT and PDGFRA genes. The final diagnosis was multiple NF1-associated GISTs.

Figure 3 Intraoperative view. A: Multiple masses in the jejunal wall demonstrated clear borders; B: A 4.5 cm diameter tumor in the jejunum 20 cm from the Trietz ligament; C: Large tumor with a grayish white, nodular, cystic surface; D: Small tumor with an oval shape and solid nodules.

Figure 4 Postoperative pathology and immunohistochemical results. A: Diffuse spindle cells with rod-shaped nuclei (hematoxylin–eosin, × 200); B: Diffusely strong expression of CD117 (× 200); C: Diffusely strong expression of DOG-1 (× 200).

OUTCOME AND FOLLOW-UP

The patient was discharged on day 7 after surgery. No complications occurred. No sign of tumor recurrence or metastasis was present at the 6-mo follow-up. Annual follow-up by contrast-enhanced abdominal CT or magnetic resonance imaging is planned. Any small recurrent tumors in the small intestine will be removed enteroscopically.

DISCUSSION

The gene responsible for NF1 is located at chromosome 17q11.2. Mutations can result in inability to produce the corresponding neurofibromin protein. Deletion leads to abnormal activation of the RAS/RAF/MAP signaling pathway, which results in loss of neurofibromin’s tumor suppressor function and increases susceptibility to development of tumors such as neurofibroma, optic glioma, malignant peripheral nerve sheath tumor, neuroblastoma, pheochromocytoma, and breast cancer[1]. GIST is rare and develops in approximately 7% of all NF1 patients[4]. It originates from mesenchymal tissue of the gastrointestinal tract, usually in the stomach and small intestine, and pathology mainly shows spindle cells and epithelioid cells. KIT mutations are detected in approximately 90% of GISTs, while PDGFRA mutations are found in approximately 5%[5]. Mutations of these two genes are the main cause of GIST, although BRAF mutations are present in some cases. GISTs are multiple in less than 5% of cases. Multiple GISTs are frequently associated with NF1 and familial GIST. GIST is the most common non-neurological tumor in NF1 patients. Incidence of GIST is 45 times higher in NF1 patients than in the general population. Unlike sporadic GIST, NF1-associated GIST develops at a younger age and is more common in women[6]; moreover, most tumors are multiple and located in the small intestine (90%)[7]. Pathologically, NF1-associated GIST consists predominantly of spindle cells and behaves as a low-grade malignancy with slow progression. KIT and PDGFRA mutations are frequently not present, suggesting a different pathogenesis from the sporadic form. Prognosis is better for NF1-associated GIST than the sporadic form (Table 1). GIST may present with abdominal pain, nausea and vomiting, gastrointestinal bleeding, anemia, abdominal mass, intestinal obstruction. However, it may be asymptomatic and found incidentally. Since NF1-associated GIST is usually located in the small intestine, gastroscopy is often negative. Therefore, middle-aged and elderly NF1 patients with gastrointestinal symptoms should undergo abdominal CT or magnetic resonance imaging[8]. Abdominal CT can reveal tumor size, location, border, and relationship with surrounding tissues, as well as metastases. Capsule endoscopy and small bowel endoscopy are also commonly used for diagnosis, which is confirmed via pathologic examination and immunohistochemical and genetic testing of a tumor specimen. CD117 and CD34 are positive in most cases of NF1-associated GIST, which facilitates diagnosis[9]. Tumor location, size, and mitotic activity are GIST prognostic factors. Ki-67 index is associated with recurrence and survival[10]. Imatinib is ineffective in most NF1-associated GISTs because of their lack of KIT and PDGFRA mutations[11]. Surgical resection of tumor or bowel segment is the first choice of treatment, depending on tumor size. Usually a resection margin of 1 cm is sufficient[12]. Complete removal without lymph node dissection is recommended[13]. Even after radical surgical treatment, approximately 50% of patients experience relapse[14]. The recurrence rate in patients with NF1 is similar to that in patients with sporadic GIST. Laparoscopic surgery is as effective as open surgery and associated with a similar rate of recurrence; however, procedure-related pain is less, recovery is faster, and length of hospital stay is shorter.

Table 1 Comparison of neurofibromatosis 1-associated and sporadic gastrointestinal intestinal stromal tumor.

	NF1 with GIST	Sporadic GIST
Age of onset	Young	Older
Most common sites	Small intestine (90%)	Stomach (60%-70%)
Number of tumors	Often multiple	Often solitary
Nuclear fission rate	Low	High
KIT and PDGFRA gene mutation	Rare	Common
Imatinib treatment	Ineffective	Effective
Disease progression	Slow	Quick
Postoperative recurrence rate	Low	High
Prognosis	Good	Common

NF1: Neurofibromatosis 1; GIST: Gastrointestinal stromal tumor.

CONCLUSION

GIST should be suspected in NF1 patients with gastrointestinal symptoms. NF1 should be considered in patients with multiple GISTs located outside the stomach. A thorough medical history and physical examination are imperative, and abdominal CT, capsule endoscopy, or small bowel endoscopy should be performed. Laparoscopy may also be performed for both diagnosis and treatment.