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Year : 2019  |  Volume : 5  |  Issue : 1  |  Page : 24-28

Ampullary Neuroendocrine Tumor With Multiple Gastrointestinal Stromal Tumors in a Patient with Von Recklinghausen’s Disease Patient: A Case Report

1 Department of Pathology, All India Institute of Medical Sciences, Raipur, Chhattisgarh, India
2 Department of Gastrointestinal Surgery, All India Institute of Medical Sciences, Phulwari Shari, Patna, India
3 Department of Pathology, All Institute of Medical Sciences, Phulwari Shari, Patna, India

Date of Web Publication30-Apr-2019

Correspondence Address:
Dr. Rakesh Kumar Gupta
Department of Pathology, Academic Block, All India Institute of Medical Sciences, Raipur, Tatibandh - 492099
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/mamcjms.mamcjms_51_18

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Von Recklinghausen’s disease (VRD) is a hereditary disease that occurs because of mutation in NF1 gene located on chromosome 17. About 25% of VRD patients are reported to suffer from gastrointestinal lesions varying from hyperplasia of the gut neural tissue, endocrine tumors of the duodenum and the periampullary region, and gastrointestinal stromal tumors. Herein, we describe a case of ampullary neuroendocrine tumor with unique histology and immunohistochemistry in a 35-year-old male patient with VRD, detailed review of literature.

Keywords: Ampullary neuroendocrine tumor, gastrointestinal stromal tumor, NF1 gene, Von Recklinghausen’s disease

How to cite this article:
Gupta RK, Anand U, Parasar K, Kumari M, Bhadani PP. Ampullary Neuroendocrine Tumor With Multiple Gastrointestinal Stromal Tumors in a Patient with Von Recklinghausen’s Disease Patient: A Case Report. MAMC J Med Sci 2019;5:24-8

How to cite this URL:
Gupta RK, Anand U, Parasar K, Kumari M, Bhadani PP. Ampullary Neuroendocrine Tumor With Multiple Gastrointestinal Stromal Tumors in a Patient with Von Recklinghausen’s Disease Patient: A Case Report. MAMC J Med Sci [serial online] 2019 [cited 2020 Aug 3];5:24-8. Available from: http://www.mamcjms.in/text.asp?2019/5/1/24/257426

  Introduction Top

The Von Recklinghausen’s disease (VRD) is inherited as autosomal dominant, with a reported incidence of one in 3000 births. It is clinically characterized by presence of café-au-lait spots, cutaneous neurofibromas, and neoplasms of the central or peripheral nervous system.[1]

Gastrointestinal (GI) involvement is present in 10% to 25% of patients that typically vary from neural tissue hyperplasia to gastrointestinal stromal tumors (GISTs) and periampullary carcinoid tumors.[2]

Herein, we describe a case of VRD with ampullary neuroendocrine tumor (NET) displaying rare and unique glandular architecture, characteristic pan-cytokeratin expression, and multiple GIST nodules in the small intestinal wall with review of literature.

  Case Report Top

A 35-year-old male patient with features of VRD presented with the complaints of intermittent right upper quadrant abdominal pain, jaundice, and on and off fever since 1 month. On general examination, scleral icterus, mild right upper quadrant abdominal tenderness, and diffuse cutaneous neurofibromas were noted. Laboratory investigations showed hyperbilirubinemia, transaminitis, and very high leukocyte count. He was admitted and treated in the line of cholangitis with intravenous fluid and antibiotics. Percutaneous transhepatic biliary drainage initially external then internoexternal was performed because of persistent fever despite continuing antibiotics for 3 days.

Computed tomography (CT) of the abdomen and pelvis showed an ill-defined thickening in the ampullary region along with intra and extrahepatic biliary ductal dilatation. Side view endoscopy showed ampullary growth. A biopsy was performed and reported as adenocarcinoma. However, immunohistochemistry (IHC) characterization was not performed. Later, after control of transaminitis and leukocyte count, the patient underwent pancreaticoduodenectomy (Whipple’s procedure). Intraoperatively, a well-defined ampullary growth measuring about 2.5 cm with multiple intestinal wall nodules were noted [[Figure 1]A].
Figure 1: (A) Intraoperative image showing multiple gastrointestinal stromal tumors (GISTs) (arrow) in the intestinal wall. (B) Gross photograph showing a well-defined tumor in the ampulla (yellow arrow) and GIST nodule in the intestinal wall (black arrow).

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Pathological Findings

Gross: The Whipple’s pancreatico-duodenectomy (WPD) specimen showed an ampullary growth limited to duodenum measuring 2.7 × 1.4 cm. In addition, multiple intestinal wall nodules, largest measuring 0.8 cm were noted [[Figure 1]B].

Microscopy: Sections examined from ampullary growth showed a tumor in the duodenal wall arranged in nests and sheet and displayed glandular/acinar pattern [[Figure 2]A]. High-power images delineated monomorphic cells with round to oval nuclei, salt and pepper-like chromatin, inconspicuous nucleoli, abundant amount of eosinophilic cytoplasm, and indistinct cell outlines [[Figure 2]B]. Psammomatous calcification was noted in the lumen [[Figure 2]C]. No significant mitotic activity, cellular atypia, or necrosis was seen. Total 15 isolated lymph nodes showed reactive changes, free of tumor. No pancreatic invasion was seen, hence a pathological stage pT2N0M0 was given. The IHC revealed diffuse and strong synaptophysin, CD56, and chromogranin-A positivity [[Figure 3]A–3C]. Additionally, pan-cytokeratin showed cup-shaped diffuse positivity [[Figure 3]D]. The Ki-67 index was about 1% to 2%. The section from the intestinal wall nodules showed a tumor comprising of bland-looking spindle cells arranged in interlacing fascicles with few intervening dilated capillary channels [[Figure 4]A]. On high power, cells showed elongated hyperchromatic nuclei with blunt ends and scant amount of cytoplasm [[Figure 4]B]. Occasional ganglion cells were also noted. No significant mitotic activity, cellular atypia, or necrosis was seen. IHC showed diffuse and strong CD117 and DOG-1 positivity [[Figure 4]C–4D], whereas it was negative for S-100 stain.
Figure 2: Histological images showing a tumor (A) distinctly involving and limited to the smooth muscle of ampulla (hematoxylin and eosin, HE, 40x). (B) The tumor comprises of back-to-back arranged glands and acini with few intervening muscle fibers (HE 100x). (C) The tumor shows monomorphic cells with salt and pepper chromatin, abundant amount of eosinophilic cytoplasm, occasional cytoplasmic globule, and psammomatous calcifications (arrows) (HE 400x).

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Figure 3: Immunohistochemistry (IHC) images showing (A) chromgranin-A (IHC 200x), (B) synaptophysin (IHC 200x), (C) CD56 (IHC 200x), and (D) Pan-cytokeratin positivity in the ampullary tumor.

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Figure 4: Hematoxylin and eosin (HE) and IHC images from the intestinal wall nodules showing (A) a tumor comprising of spindle cells arranged in interlacing fascicles (HE 100x), (B) focal neuronal differentiation, ganglion cells (HE 400x), (C) CD117 (IHC 200x), and (D) DOG-1 (IHC 200x) diffuse positivity. IHC, immunohistochemistry.

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Based on the above findings, a final pathological diagnosis of ampullary neuroendocrine tumor with multiple small bowel GISTs was made. Postoperative course was uneventful. No adjuvant chemotherapy was planned. At 2 months of follow-up, patient is symptom free.

  Discussion Top

VRD is a hereditary disease that occurs because of mutation in NF1 gene located on chromosome 17. The mutation in NF1 results in uncontrolled and nonregulated cell proliferation and development of neoplastic lesions at different stages in these patients. In addition to cutaneous neurofibromas, GIST, gastrointestinal (GI) neuroendocrine tumor, pheochromocytoma, and brain tumor are very frequently observed in VRD patients. The present case presented with multiple cutaneous neurofibromas, periampullary neuroendocrine tumor, and numerous GISTs. No adrenal lesions were noted in the abdominal computed tomography scan. No radiological work-up was performed to rule out brain tumors; however, no specific related symptoms were seen.

About 25% of VRD patients are reported to suffer from GI lesions that can be classified into three groups: (1) hyperplasia of the gut neural tissue and its supporting structures leading to abnormalities of GI motility, (2) endocrine tumors of the duodenum and the periampullary region, and (3) GIST with different degrees of neural and smooth muscle differentiation and biological behavior.[3] In the present case, GIST histologically showed neural differentiation in the form of ganglion cell.

In VRD, the periampullary endocrine tumors usually show a glandular/trabecular architecture, containing psammomatous calcification in the lumen. This glandular pattern with psammoma bodies is peculiar for somatostatin-positive tumors. However, these tumors are usually nonfunctional and symptoms are related to local mass effects such as obstructive jaundice, hemorrhage, intestinal obstruction, and cholangitis.[4] The present case also showed glandular pattern with focal psammomatous calcification; however, somatostatin positivity was not demonstrated because of limitations of resources. The patient showed features of cholangitis but symptoms of somatostatinoma such as diabetes mellitus, steatorrhea, and cholelithiasis were not present. These periampullary NETs are usually positive for common neuroendocrine markers such as synaptophysin and chromogranin-A as well as other markers like PGP9.5, CD56, and neuron-specific enolase. However, cytokeratin expression is very unusual and described only in one case reported by Suzuki et al.[5] in the setting of VRD with associated GIST. The glandular pattern with cytokeratin immunoreactivity may mislead to make an incorrect diagnosis of adenocarcinoma with neuroendocrine differentiation or mixed adeno-neuroendocrine tumor.

The incidence of GIST in VRD patients varies from 4% to 25% whereas the rate of neurofibromatosis (NF) in patients with GIST is 6%.[6],[7] It has been suggested that the pathogenesis of GIST in NF-1 may be different from that of non-NF1 patients. The c-kit and platelet-derived growth factor receptor alpha mutation, which are generally seen in non-NF-1 GISTs, are mostly absent in NF-1 patients and somatic inactivation of the wild-type NF-1 gene is noted in them.[8],[9] However, no significant histological differences were reported between GISTs associated with VRD and those occurring in non-NF-1 patients. In our case, focal neuronal differentiation was also noted in the form of scattered ganglion cells.

To conclude, VRD is a predisposing condition for the development of periampullary NET with multifocal GISTs. A careful evaluation and interpretation of IHC, particularly, cytokeratin and other epithelial markers, is crucial for lending correct diagnosis.

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Conflicts on interest

There are no conflicts of interest.

  References Top

Barker D, Wright E, Nguyen K, Cannon L, Fain P, Goldgar D et al. Gene for von Recklinghausen neurofibromatosis is in the pericentromeric region of chromosome 17. Science 1987;236:1100-2.  Back to cited text no. 1
Relles D, Baek J, Witkiewicz A, Yeo CJ. Periampullary and duodenal neoplasms in neurofibromatosis type 1: two cases and an updated 20- year review of the literature yielding 76 cases. J Gastrointest Surg 2010;14:1052-61.  Back to cited text no. 2
Behranwala KA, Spalding D, Wotherspoon A, Fisher C, Thompson JN. Small bowel gastrointestinal stromal tumors and ampullary cancer in type 1 neurofibromatosis. World J Surg Oncol 2004;2:1.  Back to cited text no. 3
Bettini R, Falconi M, Crippa S, Capelli P, Boninsegna L, Pederzoli P. Ampullary somatostatinomas and jejunal gastrointestinal stromal tumor in a patient with Von Recklinghausen’s disease. World J Gastroenterol 2007;13:2761-3.  Back to cited text no. 4
Suzuki S, Sato K, Katada E, Kuno Y, Mizoguchi N, Tokuda H et al. Periampullary somatostatinoma and multiple gastrointestinal stromal tumors associated with von Recklinghausen’s disease. J Gastroenterol 2004;39:1011-2.  Back to cited text no. 5
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;30:90-6.  Back to cited text no. 6
Andersson J, Sihto H, Meis-Kindblom JM, Joensuu H, Nupponen N, Kindblom LG. NF1-associated gastrointestinal stromal tumors have unique clinical, phenotypic, and genotypic characteristics. Am J Surg Pathol 2005;29:1170-6.  Back to cited text no. 7
Kinoshita K, Hirota S, Isozaki K, Ohashi A, Nishida T, Kitamura Y et al. Absence of c-kit gene mutations in gastrointestinal stromal tumors from neurofibromatosis type 1 patients. J Pathol 2004;202:80-5.  Back to cited text no. 8
Maertens O, Prenen H, Debiec-Rychter M, Wozniak A, Sciot R, Pauwels P et al. Molecular pathogenesis of multiple gastrointestinal stromal tumors in NF1 patients. Hum Mol Genet 2006;15:1015-23.  Back to cited text no. 9


  [Figure 1], [Figure 2], [Figure 3], [Figure 4]


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