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The opinions and assertions contained herein are the private views of the authors, and are not to be construed as official, or as reflecting the view of the Department of the Air Force, Army, or Defense.
Neurofibromatosis, von Recklinghausen disease, gastrointestinal stromal tumor, carcinoid, neuroendocrine tumor
Introduction:
Neurofibromatosis-1 (NF1), also known as von Recklinghausen disease, is an autosomal dominant disorder with high penetrance, but variable expression resulting from mutations in the NF1 gene located on chromosome 17. Many types of abdominal tumors have been found in these patients. Here we report a case of a patient with NF1 and three separate types of abdominal tumors - a duodenal / periampullary psammomatous somatostatinoma, a gastrointestinal stromal tumor, and a neurofibroma.
History:
A 48-year-old man with a history of neurofibromatosis-1 presented with abdominal pain, nausea, vomiting, weight loss, and symptoms of gastroesophageal reflux.
Physical Exam:
On physical examination, he was noted to be cachectic, but was in no acute distress and his vital signs were within normal limits. No palpable abdominal masses were noted and he was not jaundiced.
Laboratory Studies:
The patient was reported to have had an increased gastrin level in the past (value not available).
Radiology Studies:
CT scan of the abdomen showed a partially obstructing 4.0 cm heterogeneously enhancing mass arising from the medial wall of the second portion of the duodenum that was causing dilatation of the stomach and first portion of the duodenum. The adjacent pancreas was normal. There was no evidence of biliary dilatation. A second 2.0 mass was present adjacent to the uncinate process of the pancreas. The scan also demonstrated ascites within the peritoneal cavity and scoliosis of the spine.
Endoscopy:
At endoscopy, severe gastroesophageal reflux with esophagitis was found. Approximately 1500 cc of fluid was suctioned from his stomach, and he was found to have a nearly obstructing duodenal stricture with a massively dilated duodenal bulb. Endoscopic ultrasound identified pancreatic head and peripancreatic masses without ductal dilatation or evidence of biliary obstruction.
Other studies:
Octreotide study reportedly showed uptake in the patient's right arm, consistent with a neurofibroma, but no increased uptake in his abdomen.
Procedure and findings:
At exploratory laparotomy, a large duodenal mass, as well as multiple peripancreatic, periaortic, and mesenteric lymph nodes / masses found. A Whipple resection was performed to remove the duodenal mass and multiple lymph nodes / masses in the mesentery were biopsied or removed.
Pathology:
The mass obstructing the duodenum was removed at operation separate from the Whipple resection, measured 2.5 x 1.5 x 1.3 cm, and had a bulging fleshy tan cut surface. By histology, this lesion and a separate lesion removed from the root of the superior mesenteric vein were gastrointestinal stromal tumors with spindled cells arranged in intersecting fascicles and whorls. Areas of nuclear palisading were present as well as occasional perinuclear halos. Because the lesion was greater than 2 cm, but less than 5 cm in maximal dimension and had fewer than 5 mitoses per 50 high powered (40X) fields, it was identified as having a low risk for progressive disease or uncertain malignant potential.
Gross examination of the Whipple resection specimen showed multiple periduodenal and peripancreatic mass lesions as well as submucosal lesions in the duodenum proximal to the ampulla of Vater causing polypoid mucosal lesions. On histology, the polypoid duodenal areas were morphologically consistent with a psammomatous somatostatinoma with nests and tubuloglandular structures comprised of cells with round central nuclei containing dispersed "salt and pepper" chromatin, abundant pink cytoplasm, and foci of psammoma bodies (concentric lamellated calcifications) in the gland-like spaces. Microscopic sections showed the tumor was centered in the region of the ampulla of Vater and infiltrated both the duodenum and head of the pancreas. Significant cellular atypia, numerous mitoses, and tumor necrosis were not present. Despite the absence of significant atypia, tumor was present in sections taken from the periduodenal and transverse mesocolon lymph nodes, indicative of metastasis.
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Figure 10 |
A small neurofibroma with delicate thin spindle cells admixed with fibrous tissue, neural elements, and a slightly myxoid stroma in continuity with a large peripheral nerve was present adjacent to the bile duct margin of the Whipple specimen.
Discussion:
Neurofibromatosis-1 (NF1), also known as von Recklinghausen disease, is an autosomal dominant disorder with high penetrance, but variable expression resulting from mutations in the NF1 gene located on chromosome 17. This gene plays a role in controlling cell proliferation via regulation of the activity of the p21 product of the ras oncogene.1 Patients with the disorder have hamartomatous lesions as well as varied benign and malignant tumors. The diagnosis of NF1 is based primarily on physical manifestations of the disease to include café-au-lait spots, Lisch nodules of the iris, neurofibromas (plexiform neurofibromas are a diagnostic finding alone), and freckling in the intertriginous areas.
Abdominal masses in patients with NF1 have been categorized into based on the "cell of origin" of the tumor - neurogenic, neuroendocrine, non-neurogenic mesenchymal, embryonal, and adenocarcinomas. Some neoplasms, such as a plexiform neurofibroma, are pathognomonic of the disease. Other neoplasms, such as duodenal carcinoid tumors (which would include the psammomatous somatostatinoma) have been reported to occur more frequently in NF1 patients than the general population.2 Psammomatous somatostatinomas are found exclusively in the duodenal / periampullary region and have fairly unique histology of a neuroendocrine tumor with tubuloglandular architecture and psammoma bodies. However, if the psammoma bodies are infrequent, the tumor can be histologically confused with a well differentiated pancreaticobiliary adenocarcinoma, which would have a significant impact on patient prognosis. While immunoreactive for somatostatin, the tumors usually do not secrete hormones and are not associated with symptoms of increased somatostatin such as diabetes mellitus, steatorrhea, or cholelithiasis.3 These lesions have been described as occurring more frequently in African-American patients with NF1 than in other races.4 Up to a quarter of these tumors have been metastatic to lymph nodes at time of operation. However, death is not usually directly attributable to the tumor.5
Gastrointestinal stromal tumors (GIST's) also have been well described in patients with NF1 and are different from sporadic GIST's. Most sporadic GIST's have mutations of the KIT or PDGFRA genes which encode for tyrosine kinase receptors involved in cell signal transduction. Gastrointestinal stromal tumors occurring in patients with NF1 are frequently multiple and located in the small intestine, particularly the jejunum.6 In addition, despite being immunoreactive for CD117 (c-kit), and morphologically indistinguishable from sporadic GIST's, many GIST's in patients with NF1 have been found not to have KIT or PDGRFA mutations.6,7,8,9 Many NF1 patients also have foci of hyperplasia of interstitial cells of Cajal, the cell of origin of GIST's. GIST's in patients with NF1 usually have spindle cell morphology and have a relatively low risk for progressive disease based on size and mitotic activity of the lesions.
Neurofibromas are well described in patients with NF1 with the skin and gastrointestinal tract as the two most frequently described locations for tumors. Plexiform neurofibromas occur exclusively in patients with NF1, although this patient did not have a plexiform neurofibroma discovered at operation. Despite having multiple tumors, many patients with NF1 have nonspecific physical complaints and the tumors are not infrequently discovered incidentally during a workup or operation performed for other reasons. Some patients will present with intermittent gastrointestinal bleeding and pain secondary to erosions, intussusception, obstruction, or volvulus.
Patients with NF1 have a variety of intra-abdominal lesions to include neuroendocrine tumors, particularly in the duodenum / ampullary region, and gastrointestinal stromal tumors. Patients can present with symptoms related to obstruction or can be asymptomatic. The patient in this report had significant weight loss, as well as nausea and vomiting secondary to gastric outlet obstruction secondary to the mass effect from the duodenal psammomatous somatostatinoma. Preoperative evaluation for endocrine tumors was negative in this patient, although an octreotide study would only identify functioning or secreting tumors. A high index of suspicion for unusual intra-abdominal lesions is needed when evaluating patients with NF1 who have gastrointestinal complaints.
References
1. Martin GA, Viskochil D, Bollag G, McCabe PC, Crosier WJ, Haubruck H, et al. The GAP-related domain of the neurofibromatosis type 1 gene product interacts with ras p21. Cell 1990;63:843-849.
2. Dayal Y, Tallberg KA, Nunnemacher G et al. Duodenal carcinoids in patients with and without neurofibromatosis. Am J Surg Pathol 1986;10:348-357.
3. William GT. Endocrine tumours of the gastrointestinal tract-selected topics. Histopathology 2007;50:30-41.
4. Burke AP, Sobin LH, Federspiel BH, Shekitka KM, Helwig EB. Somatostatin producing carcinoids in patients with von Recklinghausen's neurofibromatosis: a predilection for Black patients? Cancer 1990;65:1591-1595.
5. Bettini R, Falconia M, Crippa S, Capelli P, Boninsegna L, Pederzoli P. Ampullary somatostatimomas and jejunal gastrointestinal stromal tumor in a patient with Von Recklingausen's disease. World J Gastroenterol 2007; 13(19):2761-2763.
6. Kang DY, Park CK, Choi JS, Jin SY, Kim HJ, Joo M, et al. Multiple gastrointestinal stromal tumors: Clinicopathologic and genetic analysis of 12 patients. Am J Surg Pathol 2007:31(2):224-232.
7. Stewart DR, Corless CL, Rubin BP, Heinrich MC, Messiaen LM, Kessler LJ, et al. Mitotic recombination as evidence of alternative pathogenesis of gastrointestinal stromal tumours in neurofibromatosis type 1. J Med Genet 2007:44(1):e61.
8. Maertens O, Prenen H, Debiec-Rychter M, Wozniak A, Sciot R, Pauwels P, et al. Molecular pathogensis of multiple gastrointestinal stromal tumors in NF1 patients. Hum Mol Genet 2006;15(6):1015-1023.
9. Miettinen M, Fetsch JF, Sobin LH, Lasota J. Gastrointestinal stromal tumors in patients with neurofibromatosis 1: a Clinicopathologic and molecular genetic study of 45 cases. Am J Surg Pathol 2006:30(1):90-96.
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