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Year : 2018  |  Volume : 61  |  Issue : 3  |  Page : 401-403
Duodenal neuroendocrine tumor, adenocarcinoma and gastrointestinal stromal tumor in association with neurofibromatosis type 1: An unique occurrence

Department of Pathology, Sagar Hospital, Bengaluru, Karnataka, India

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Date of Web Publication13-Jul-2018


Mixed endocrine–nonendocrine neoplasms are rare tumors and pose challenges in diagnosis and management. Neurofibromatosis-1 (NF-1) patients are known to develop malignancies. Although neuroendocrine tumors and gastro-intestinal stromal tumors are seen in NF-1, its association with adenocarcinoma is rare. The existence of these three entities with NF-1 is extremely rare. NF1 patients presenting with symptoms suggestive of malignancies should alert the physician for a detailed clinical work up. Diagnosis of these malignancies often requires a meticulous histopathological and immunohistochemical examination. We report the first case from Indian experience.

Keywords: Gastrointestinal stromal tumor, mixed endocrine–nonendocrine neoplasms, neurofibromatosis-1

How to cite this article:
Shamila M A, Reddy P S. Duodenal neuroendocrine tumor, adenocarcinoma and gastrointestinal stromal tumor in association with neurofibromatosis type 1: An unique occurrence. Indian J Pathol Microbiol 2018;61:401-3

How to cite this URL:
Shamila M A, Reddy P S. Duodenal neuroendocrine tumor, adenocarcinoma and gastrointestinal stromal tumor in association with neurofibromatosis type 1: An unique occurrence. Indian J Pathol Microbiol [serial online] 2018 [cited 2021 Jul 25];61:401-3. Available from: https://www.ijpmonline.org/text.asp?2018/61/3/401/236616

   Introduction Top

Mixed endocrine– nonendocrine neoplasms (MiNENs) are rare and perplexing with regard to the diagnosis and management. The diagnosis of endocrine and glandular component in these tumors is difficult on morphological basis alone and requires immunohistochemical assistance. Management of these complex tumors by surgical resection and chemotherapy poses challenges.[1]

Patients with neurofibromatosis (NF) are prone to develop tumors, both benign and malignant. The target is NF-1 gene, a large tumor-suppressor gene located on chromosome 17q11.2. It has one of the highest new mutation rates resulting in a multisystem disorder with varying combinations of benign and malignant tumors, developmental dysplasias, and functional deficits. Malignancies occur in 3%–15% of the patients and gastrointestinal (GI) manifestations occur in one-fourth of these cases.[2]

Many case reports have been published reporting the association of NF-1 with neuroendocrine tumors (NET) and gastro-intestinal stromal tumors (GIST), but its association with adenocarcinoma is very rare. Here, we report three discrete synchronous neoplasms in a patient with NF-1. This is the first case from Indian experience.

   Case Report Top

A 60-year-old hypertensive lady presented with itching all over the body and high-colored urine of 3 weeks' duration. There was a history of dyspepsia, vomiting, and loss of weight. She was known to have NF for 50 years. Physical examination revealed icterus and multiple neurofibromas all over the body. Abdominal examination revealed a palpable mass in the right hypochondrium. Ultrasonography abdomen and pelvis showed a grossly distended gallbladder and dilated common bile duct. Computed tomography (CT) scan was done elsewhere; hence, only reports without scan films were available. CT scan abdomen and pelvis demonstrated a heterogeneously enhancing irregular thickening in the periampullary region of 1.8 cm × 1.3 cm. Both the common bile duct and pancreatic duct were dilated each to about 16 mm. CEA and CA 19-9 were within normal limits.

Endoscopy showed an ampullary mass lesion with ulceration which was biopsied. Histopathology showed features of chronic duodenitis only and a repeat biopsy was suggested but was not done. Subsequently, the patient underwent exploratory laparotomy and Whipple's surgery in view of obstructive symptoms and CT findings. Intraoperatively, there were multiple nodules all over the small bowel and there was no evidence of peritoneal and hepatic metastasis. The resected specimen was submitted for histopathological examination.

Gross examination showed duodenojejunectomy specimen measuring 22 cm in length with head of pancreas measuring 4 cm × 5 cm and a common bile duct of 0.5 cm. Serosal surface and head of the pancreas were studded with multiple nodules ranging in diameter of 0.1 cm to 1 cm. Gallbladder measured 9 cm and the mucosal surface was unremarkable.

Cut section of the duodenum showed a nodule of 2 cm × 1.5 cm occupying the ampullary region. Cut section through the tumor showed a dilated duct. There was another nodule of 1 cm diameter located 1.5 cm away from the ampullary tumor toward the jejunal side [Figure 1]b. All other serosal nodules were well delineated, and some were pushing toward the mucosal surface [Figure 1]a. Surrounding mucosa was unremarkable. Cut section of the pancreas was unremarkable. Tiny lymph nodes were salvaged in the peripancreatic area. Lymph nodes along the hepatic artery were received separately.
Figure 1: (a) Duodenojejunectomy specimen showing multiple nodules (gastro-intestinal stromal tumors). (b) Duodenojejunectomy specimen. (A) a nodule of 2 cm × 1.5 cm in the ampullary region (adenocarcinoma), (B) Nodule of 1 cm in diameter located 1.5 cm away from A (neuroendocrine tumor), (c) Another nodule of 1 cm in diameter (gastro-intestinal stromal tumors)

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Microscopy sections from ampullary growth showed a moderately differentiated adenocarcinoma involving muscularis propria (T2N0M0) [Figure 2]a. Three nodes close to the tumor were uninvolved. No vascular or perineural invasion was noted. Nodules taken from the serosal surface of the duodenum and jejunal mass showed a spindle cell tumor suggestive of GIST pushing toward the mucosa but limited to the serosal surface (T1N0M0) [Figure 2]c. Mitosis was <5/50 HPF (G1). The section from the nodule close to the ampullary growth showed cells in cords and sheets having thin fibromuscular tissue separating them. Cells were round with stippled chromatin [Figure 3]a. The features were suggestive of a NET (T1N0M0) [Figure 3]c. The tumor was seen to involve the lamina propria and submucosa. Mitosis was <2/10 HPF (G1). The pancreas was uninvolved and showed features of chronic pancreatitis with acinar atrophy and hyperplastic islets of Langerhans. All lymphnodes and cut margins were free of tumor.
Figure 2: (a) Adenocarcinoma moderately differentiated (H and E, ×100). (b) Adenocarcinoma component positive for CK7. (c) Spindle cell tumor with no mitosis or pleomorphism suggestive of gastro-intestinal stromal tumors (H and E, ×400). (d) Spindle cell tumor positive for CD117

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Figure 3: (a) Tumor showing cells in cords and sheets. Nuclei showing stippled chromatin suggestive of neuroendocrine tumor (H and E, ×400). (b) Neuroendocrine tumor positive for chromogranin A. (c) Tumor cells positive for CD56. (d) Neuroendocrine tumor positive for synaptophysin

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On immunohistochemistry, adenocarcinoma component was positive for CK7 [Figure 2]b and negative for synaptophysin and chromogranin. Spindle cell tumor was positive for CD117 and DOG1 [Figure 2]d and smooth muscle actin (SMA) negative. The NET was positive for CD56, synaptophysin, and chromogranin [Figure 3]b-d] and negative for CK7 and CK20. Somatostatin was not done. Ki-67 was low in neuroendocrine areas and spindle cell areas.

The patient was referred to an oncology center and no further treatment details are known.

   Discussion Top

GI manifestations in NF occur in three forms, (1) hyperplasia of submucosal or myenteric nerve plexus, (2) GIST, and (3) periampullary carcinoids sometimes associated with pheochromocytomas.[2] Cancer risk is 2.7 times high in NF as compared to the general population and has a cumulative risk of 20% by 50 years.[3]

The most common GI tumor in NF-1 is GIST. The incidence of GIST in patients with NF varies from 4% to 25%. GISTs in NF tend to occur in younger patients. They are usually multiple, occur in the duodenum, and are usually low grade with low mitotic rates.[4] However, a study by Uusitalo et al. shows that NF-1-related cancers display an increased mortality rate. Apart from GIST, these malignancies also include breast cancer, pheochromocytoma, malignant fibrous histiocytoma, and thyroid cancer.[3] The average age of presentation of non-NF GIST is 61.4. They are single and occur in the stomach. NF GISTs exhibit succinate dehydrogenase B expression and lack GIST specific Kit and PDGFRA mutation. Hence, NF GISTs do not respond well to imatinib therapy.[5],[6]

Digestive NETs are reported in 1% of NF type 1 patients, with ampulla being the customary site. Somatostatinomas are the most common GI-NET in NF-1. NF somatostatinomas account for 48% of all duodenal somatostatinomas. They present with pancreatitis and biliary dilatation with metastasis to lymph nodes and liver. Gastrinomas, insulinomas, and nonfunctioning pancreatic tumors are other NETs associated with NF-1.[6],[7] Gregersen et al. have reported a goblet cell carcinoid in a patient with NF-1.[8]

GI adenocarcinomas have been reported in the oesophagus, stomach, duodenum, small bowel, colon, gallbladder, biliary tract, and pancreas in NF-1. Twenty-three percent of the patients with NF-1 develop adenocarcinoma.[5] Jones and Marshall and Kistler et al. have described the association of NF and small bowel adenocarcinoma.[9],[10] Costi et al. and Behranwala et al. have reported the association of GIST with periampullary carcinoma in NF-1.[2],[11] MiNENs are generally highly aggressive neoplasms and managed as nonendocrine cancers. Prognosis is poor and is determined by the degree of differentiation of the nonendocrine component.[6]

About 5% of NF patients with abdominal malignancies are symptomatic. Intra-abdominal manifestations occur later than cutaneous manifestations. Many of them present in midlife or later. Surgical intervention is required in 2.5% of the cases.[9]

No formal guidelines exist for screening of GI cancer for patients with NF-1. Since upper GI tumors are common in patients with NF-1, upper GI endoscopic investigations to screen the patients at regular intervals are worthwhile. The age to start screening should be established through more clinical studies as data are limited.[10]

   Conclusion Top

Although NF patients are reported to have malignancies, it is very rare to see the synchronous presentation of three discrete tumors. A thorough literature search has revealed only one case with mixed periampullary carcinoma, GIST, and somatostatinoma which was reported by Tewari et al. in UK.[6] Our case appears to be the first reported from India.

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Conflicts of interest

There are no conflicts of interest.

   References Top

Deschamps L, Dokmak S, Guedj N, Ruszniewski P, Sauvanet A, Couvelard A, et al. Mixed endocrine somatostatinoma of the ampulla of vater associated with a neurofibromatosis type 1: A case report and review of the literature. JOP 2010;11:64-8.  Back to cited text no. 1
Costi R, Caruana P, Sarli L, Violi V, Roncoroni L, Bordi C, et al. Ampullary adenocarcinoma in neurofibromatosis type 1. Case report and literature review. Mod Pathol 2001;14:1169-74.  Back to cited text no. 2
Uusitalo E, Rantanen M, Kallionpää RA, Pöyhönen M, Leppävirta J, Ylä-Outinen H, et al. Distinctive cancer associations in patients with neurofibromatosis type 1. J Clin Oncol 2016;34:1978-86.  Back to cited text no. 3
Rastogi R. Intra-abdominal manifestations of von Recklinghausen's neurofibromatosis. Saudi J Gastroenterol 2008;14:80-2.  Back to cited text no. 4
[PUBMED]  [Full text]  
Salvi PF, Lorenzon L, Caterino S, Antolino L, Antonelli MS, Balducci G, et al. Gastrointestinal stromal tumors associated with neurofibromatosis 1: A single centre experience and systematic review of the literature including 252 cases. Int J Surg Oncol 2013;2013:398570.  Back to cited text no. 5
Tewari N, Rollins K, Gandhi N, Kaye P, Lobo DN. Mixed periampullary adenocarcinoma and somatostatinoma with small bowel gastrointestinal stromal tumour in neurofibromatosis type 1. JOP 2014;15:600-3.  Back to cited text no. 6
Lodish MB, Stratakis CA. Endocrine tumours in neurofibromatosis type 1, tuberous sclerosis and related syndromes. Best Pract Res Clin Endocrinol Metab 2010;24:439-49.  Back to cited text no. 7
Gregersen T, Holt N, Gronbaek H, Vogel I, Jørgensen LJ, Krogh K, et al. Goblet cell carcinoid in a patient with neurofibromatosis type 1: A rare combination. Case Rep Gastrointest Med 2012;2012:185730.  Back to cited text no. 8
Jones TJ, Marshall TL. Neurofibromatosis and small bowel adenocarcinoma: An unrecognised association. Gut 1987;28:1173-6.  Back to cited text no. 9
Kistler CA, Johnson JM, Winter JM, Baliff JP, Siddiqui AA, Sama AR, et al. A case of periampullary adenocarcinoma in neurofibromatosis type 1. J Gastrointest Oncol 2014;5:E96-9.  Back to cited text no. 10
Behranwala KA, Spalding D, Wotherspoon A, Fisher C, Thompson JN. Small bowel gastrointestinal stromal tumours and ampullary cancer in type 1 neurofibromatosis. World J Surg Oncol 2004;2:1.  Back to cited text no. 11

Correspondence Address:
P Somasekhara Reddy
Department of Laboratory Medicine, Sagar Hospital, Tilak Nagar, Jayanagar Extension, Bengaluru - 560 041, Karnataka
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/IJPM.IJPM_534_17

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