Neurofibromatosis type-1 (NF-1), also known as von Recklinghausen disease, is a common autosomal dominant condition occurring in approximately 1/3000 births. NF-1 is known to be associated with gastrointestinal neoplasms in 2-25 per cent of patients. We report the first case of gastric outlet obstruction with perforation caused by neurofibroma in a patient with NF-1. The literature is reviewed, examining 61 previously reported cases of noncarcinoid gastrointestinal (GI) neoplasms in patients with NF-1 for symptoms, location, and types of neoplasms. Neoplasms were located most often in the small intestine (72%). Neurofibromas, found in 52 per cent of patients, were the most frequently diagnosed benign neoplasms followed by leiomyomas (13%), ganglioneurofibromas (9.8%), and gastrointestinal stomal tumor (GIST) (6.5%). Adenocarcinoma was present in 23 per cent of patients. Patients with NF-1 and GI symptoms are at risk for gastrointestinal neoplasms from which symptomatic patients are likely to experience significant morbidity.
NEUROFIBROMATOSIS TYPE-1 (NF-1), also known as von Recklinghausen neurofibromatosis, is a common autosomal dominant condition occurring in approximately 1/3000 births.1-3 NF-1 is known to be associated with gastrointestinal neoplasms in 2-25 per cent of patients.3-6
Case Report
A 21-year-old African-American man presented to the hospital emergency department with a chief complaint of gastrointestinal (GI) bleed. He arrived with periumbilical pain, intermittent nausea, vomiting, and anorexia gradually worsening over 3 to 4 days, now with transitory coffee-ground emesis. He reported no bowel movement for 3 days. He denied fever, hematochezia, or dysuria. His past medical history was significant for NF-1 complicated by a below- knee amputation during childhood, related to his NF-1, and two episodes of GI bleed: the first, 5 years prior to presentation, and the second episode, 8 weeks prior to presentation, was treated with H-2 blocker.
On physical exam, the patient was awake, alert, and oriented. His mucous membranes were dry. His abdomen was taut, distended, diffusely tender with guarding and rebound tenderness. Bowel sounds were hypoactive. The patient’s physical condition declined while under observation. His temperature increased from 38.1C to 38.9C, blood pressure of 100/88 mm Hg dropped to 100/80 mm Hg, and heart rate increased from 120-130 heats per minute with respirations of 18 per minute. Blood chemistry, amylase, and lipase remained within normal limits. Coagulation studies were abnormal with an elevated international normalized ratio (INR) at 1.4 (normal. 0.8-1.0). Stool was heme negative.
Free air, multiple air fluid levels, and small bowel distention were seen on X-ray obstruction series (Fig. 1). These findings led to the working diagnosis of perforated viscous. While undergoing fluid resuscitation, the patient was transported from the emergency department to the operating room with an acute abdomen.
At exploratory laparotomy, a perforated 3.5- to 4-cm ulcer located on the anterior surface of the mid portion of the stomach was seen. The stomach appeared thick-walled, however, no mass lesions were noted. The omentum was closely approximated to the inflammation and formed a phlegmon extending to the posterior aspect of the stomach and pancreatic bed involving the lesser sac. Multiple enlarged lymph nodes were present. The patient underwent a subtotal gastrectomy with a Billroth II gastrojejunostomy for a perforated gastric ulcer.
Gross examination of the antrectomy specimen revealed an 8.5 cm by 7 cm by 5 cm specimen with a 2-cm transmural perforating ulcer seen on the anterior wall of the stomach (Fig. 2). The gastric wall appeared thickened throughout with stenosis at the gastroduodenal junction. However, no discrete mucosal lesions were identified aside from the perforation.
On microscopic examination, diffuse neurofibromatosis was present, predominantly localized to the submucosa but involving all layers of the gastric wall. In addition, plexiform neurofibromas were seen associated with the areas of diffuse neurofibromatosis and extending into the subserosal fat. A decreased number of oxyntic cells were noted. Throughout the body end of the specimen, vascular changes of marked intimai hypertrophy, media hypertrophy, and occasional recunali/ed thrombi were noted in areas where neurofibroma had elicited collagenous reaction. No vasculitis was present.
FIG. 1. Chest X-ray: Lateral view demonstrating free air seen just below the diaphragm.
FIG. 2. Gross pathology demonstrating gastric perforation surrounded by erosive gastritis.
The area of perforation showed granulation tissue with a prominent reactive fibroproliferation. Within the segment of duodenum, multiple intramuscular neurofibromas extended into the submucosa and were associated with Brunner’s gland hyperplasia. The neurofibroma was diffuse and diminished the lumen of the duodenum (Fig. 3). A ganglioneuromatous proliferation was seen to replace the lamina propria focally. No neoplasm, necrosis, significant mitotic activity, or changes suggestive of malignant transformation were seen. There was no evidence of Helicohacter pylori, and the pacemaker cells of Cajal were normal in number.
The patient’s postoperative course was complicated by bowel obstruction caused by extensive adhesions. Pathologic examination of additionally resected small bowel showed Auerbach plexus hyperplasia in addition to the adhesions. No neurofibromas were seen.
Discussion
This case represents the first reported case of NF-1 and gastric outlet obstruction caused by neurofibromas resulting in perforation. Peptic ulcer, neoplasia, benign tumors, inflammation, and rare miscellaneous causes are known causes of gastric outlet obstruction. Malignancy must be excluded in all cases, as it can be present in 50 per cent of cases.
FIG. 3. Low power demonstrating the first portion of the duodenum with muscular hypertrophy and diffuse submucosal neurofibromas narrowing the lumen, causing gastric outlet obstruction.
An English literature search of gastrointestinal neoplasms and NF- 1 from 1975 to 2002 resulted in 61 previously reported cases associated with neoplasms of the GI tract.4, 6-63 Cases were excluded for carcinoid, pheochromocytoma, or other concurrent illnesses such as polyposis syndromes or birth defects.
No gastric perforations have been reported, however, three reported cases of intestinal perforation associated with NF-1 have been published.56, 59, 60 This makes perforation either a rare complication of a rare condition (GI-NF-1) or underreported. All reported perforations involved benign neoplasms located in the jejunum (Table 1). The site is likely reflective of the increased incidence of neoplasia at this location.
Due to its rarity, a high degree of suspicion for gastrointestinal tumor in patients with NF-1 is needed for timely diagnosis. Delay in diagnosis of gastrointestinal neurofibromatosis is common. The average interval from onset of GI symptoms to diagnosis with GI neoplasm was 2.8 years in patients reviewed in this study. Diagnosis may be difficult due to nonspecific symptoms, as well the predominantly small bowel location. Neurofibromas in particular may be diffuse and submucosal, making radiographic visualization difficult.
The development of neoplasms should be considered to be part of the disease process in patients with neurofibromatosis type-1.64 The gene for neurofibromatosis type-1 has been localized to chromosome 17 and encodes an RNA product called neurofibromin. Neurofibromin acts as a neoplasm suppressor,65 and patients with NF-1 have decreased levels of neurofibromin. This may explain the increased incidence of malignant neoplasms of all types in patients with neurofibromatosis compared to the general population.64
Among all 61 patients with neurofibromatosis and gastrointestinal neoplasm of any type, our patient was younger than the average age of 46 for diagnosis with GI neoplasm. Sixty-nine per cent of patients were over age 40 at time of diagnosis. More males, 59 per cent (n = 36), than females, 41 per cent (n = 25), were represented.
Symptoms of GI bleed (bright red blood per rectum), heme + stool, or hemetemesis were exhibited by 46 per cent (n = 28) of all patients. GI obstructive symptoms (obstruction, abdominal distention, and constipation with vomiting) were present in 16 per cent (n = 10) of patients. Hepatobiliary symptoms of jaundice or biliary obstruction were reported in 16 per cent (n = 10). Hepatobiliary symptoms were not found under age 20 and were associated with stomach or duodenal neoplasm in 8 of 10 cases and adenocarcinoma of the duodenum in 6 of 10 cases. Fifteen patients had only nonspecific gastrointestinal symptoms.
TABLE 1. Reported Cases in Patients With Neurofibromatosis, Noncarcinoid Neoplasm, and Perforation Since 1975
The most frequent location of GI neoplasms was the small intestine where 72 per cent (n = 44) of patients had neoplasms (Table 2). Most of these were found in the jejunum, 39.3 percent (n = 24). Forty-one percent (n = 25) of 61 patients had neoplasms in multiple locations.
The large percentage of small intestine tumors found in this population is in contr\ast to the general population in which small bowel neoplasms are rare, occurring at this location in only 5 per cent of cases.66 Comparison between these two populations also reveals that for patients with neurofibromatosis, neoplasms occur at a younger age (46 years compared to 59 years) and are most frequently neurofibromas, whereas leiomyomas are the most frequent benign small bowel neoplasm in the general population. In a patient with neurofibromatosis and GI symptoms, a high degree of suspicion for small bowel neoplasms should be maintained, although the reason for increased incidence of neoplasms at this location remains elusive.
Most patients with GI neoplasms and neurofibromatosis have benign neoplasms (Table 3). Benign neurofibromas are the most frequently occurring GI neoplasm for patients with NF-1. Auerbach plexus hyperplasia, as was noted in our patient, may be their site of origin. Benign neurofibromas undergo malignant transformation in 5- 15 per cent of patients over age 40.5 Neurofibromas were present in 52 per cent (n = 32) of all patients. Of this group, 21 patients had neurofibromatosis with GI neurofibromas and no additional neoplasm type identified.
Neurofibroma occurred most frequently as a well-defined nodule and was seen in 71 per cent (n = 15) of the 21 patients with neurofibromas, no other associated neoplasm, and was associated with symptoms of GI bleed or anemia in 52 per cent (n = 11) of patients.
TABLE 2. Location of Gastrointestinal Neoplasms in 61 Reviewed Cases with Neurofibromatosis
TABLE 3. Gastrointestinal Neoplasms in 61 Reviewed Cases with Neurofibromatosis
Although our patient’s neoplasm was benign, malignant neoplasms occurred in 30 per cent (n = 18) of all patients with GI neoplasms and neurofibromatosis. Adenocarcinoma was found most frequently, occurring in 23 per cent of reported cases.
There was a greater than expected incidence of gastrointestinal stomal tumor (GIST) in the reviewed population (6.5%). This is consistent with at least one other study of malignant and benign neoplasms, not limited to GI, in patients with neurofibromatosis where 7 per cent of patients with were found to have GIST.64 GIST has previously been reported in association with neurofibromatosis.54, 67 Recent developments enable neoplasm identification with KIT (CD 117) and treatment of metastatic disease with STI571 (Gleevec), a tyrosine kinase inhibitor. Past diagnosis with light microscope only may have been inadequate to identify correctly these neoplasms, making it possible that some of the neoplasms previously reported as neural or smooth muscle neoplasms were actually GIST.
Treatment of symptomatic GI tumors in patients with NF-1 remains surgical. Due to the high incidence of malignancy and the possibility of malignant degeneration in the more frequently occurring benign neoplasms, all neoplasms should be resected with the use of frozen sections to assure adequate margins. Follow-up in asymptomatic patients consists of annual CBC and hemoccult.36
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JENNIFER R. BAKKER, M.D.,* MARIAN M. HABER, M.D.,[dagger] FERNANDO U. GARCIA, M.D.[double dagger]
From the * Department of Surgery, Graduate Hospital, Philadelphia, Pennsylvania; [dagger] Department of Pathology, Drexel University, College of Medicine, Philadelphia, Pennsylvania; [double dagger] Department of Pathology, Drexel University, College of Medicine, Philadelphia, Pennsylvania
Address correspondence and reprint requests to Jennifer R. Bakker, M.D., Graduate Hospital, Pepper Pavillion, Department of Surgery, 18th and Pine, Philadelphia, PA 19146.
Copyright The Southeastern Surgical Congress Feb 2005
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