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CORRESPONDENCE
Year : 2014  |  Volume : 10  |  Issue : 2  |  Page : 443-445

An esophageal gastrointestinal stromal tumor in a patient with MEN1-related pancreatic gastrinoma: An unusual association and review of the literature


1 Gastroenterology and Endoscopy Unit, Department of Pathophysiology and Transplant, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Italy
2 Gastroenterology and Endoscopy Unit, Department of Pathophysiology and Transplant, Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico; Universitą degli Studi di Milano, Milan, Italy
3 Universitą degli Studi di Milano, Milan; Division of Pathology, Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico, Italy
4 Universitą degli Studi di Milano; Endocrinology and Diabetology Unit, IRCCS Policlinico S. Donato, Milan, Italy

Date of Web Publication14-Jul-2014

Correspondence Address:
Sara Massironi
Gastroenterology Unit II, Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico, Via F. Sforza 35, Milano
Italy
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1482.136685

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 > Abstract 

Both multiple endocrine neoplasia type 1 (MEN1)-related gastrinomas and gastrointestinal stromal tumors (GISTs) are rare neoplasms, and their association has been rarely reported. We describe an unusual association between a GIST and a MEN1-related gastrinoma. A 44-year-old man had undergone surgical removal of a pancreatic gastrinoma in 2004 and was then administered long-term somatostatin analogs, and diagnosed as having MEN1 syndrome. Following an uneventful follow-up, in April 2009, an upper gastrointestinal tract endoscopy showed esophageal narrowing, with evidence of a 2-cm solid mass on endoscopic ultrasonography. Histology revealed a tumor composed of elongated cells with plump cytoplasm arranged in a storiform pattern. The immunophenotype of the lesion was CD117 and Platelet Derived Growth Factor (PDGF) positive, whereas alpha-1 muscle actin and S-100 protein were negative. Due to morphological and immunohistochemical results, a final diagnosis of esophageal GIST was made. The association between GISTs and MEN1 could be casual, although a single case of the coexistence of a GIST and a MEN1-related gastrinoma has already been reported. A role of the MEN1 gene in the pathogenesis of GISTs could be hypothesized.

 > Abstract in Chinese 

一个食管胃肠间质瘤病人并发MEN1相关的胰腺胃泌素瘤:不寻常的联系及文献回顾
摘要
多发性内分泌瘤病1型(MEN1)相关的胃泌素瘤和胃肠道间质瘤(GIST)都是罕见的肿瘤,而它们两者相伴发生很少有报道。我们报道一例少见的GIST 和MEN1相关的胃泌素瘤。一个44岁的病人在2004年接受了胰腺胃泌素瘤的手术切除,然后给予长效生长抑素类似物,并被诊断为MEN1综合征。后来的随访无特别事件,到2009年4月,上消化道内镜检查发现食管狭窄,内镜超声检查证实为2厘米的固体团块。组织学显示为细长的胞质和饱满的细胞排列成席纹状图案的肿瘤。病变的免疫表型为CD117和血小板源性生长因子(PDGF)阳性,而α1肌动蛋白和S 100蛋白均为阴性。由于形态学和免疫组化结果,确诊为食管瘤。GIST和MEN1之间的关联可能是偶然的,尽管已有一个两病共存的报告。MEN1基因在胃肠道间质瘤的发病机制起作用可成为一种假设。
关键词:胃泌素瘤,胃肠道间质瘤,多发性内分泌肿瘤1型综合征,神经内分泌肿瘤,Zollinger-Ellison综合征


Keywords: Gastrinoma, gastrointestinal stromal tumors, multiple endocrine neoplasia type 1 syndrome, neuroendocrine tumor, zollinger ellison syndrome


How to cite this article:
Massironi S, Rossi RE, Ferrero S, Cavalcoli F, Spampatti MP, Conte D, Corbetta S, Peracchi M. An esophageal gastrointestinal stromal tumor in a patient with MEN1-related pancreatic gastrinoma: An unusual association and review of the literature. J Can Res Ther 2014;10:443-5

How to cite this URL:
Massironi S, Rossi RE, Ferrero S, Cavalcoli F, Spampatti MP, Conte D, Corbetta S, Peracchi M. An esophageal gastrointestinal stromal tumor in a patient with MEN1-related pancreatic gastrinoma: An unusual association and review of the literature. J Can Res Ther [serial online] 2014 [cited 2019 Dec 10];10:443-5. Available from: http://www.cancerjournal.net/text.asp?2014/10/2/443/136685


 > Introduction Top


Gastrointestinal stromal tumors (GISTs), the most common mesenchymal tumors of the gastrointestinal (GI) tract, are characterized by CD117-positive mesenchymal spindle, epithelioid, or pleomorphic cells. [1] GISTs are thought to originate from the interstitial cells of Cajal, although GIST cells show signs of neuronal or smooth muscle differentiation, and more recently, a possible neuroendocrine phenotype has been hypothesized. [2]

An association between GIST and neurofibromatosis 1 (NF1) is already known, [3] and GISTs are also associated with other genetic syndromes, [4] such as paraganglioma syndromes type 1, type 3, and type 4, Carney-Stratakis syndrome, and the Carney triad. The concomitant occurrence of a GIST and a neuroendocrine tumor (NET) in the setting of NF1 has been reported in approximately 13 cases, [5] with seven additional NF1-independent cases. [6],[7] Moreover, an association between multiple endocrine neoplasia type 1 (MEN1) and stromal tumors has been reported: Four reports described an association between MEN1 and leiomyomas, [8] whereas only one report described an association between a GIST and a gastrinoma in a MEN1 patient. [7]


 > Case report Top


A 44-year-old man had a long-term history of epigastric pain, watery diarrhea and recurrence of Helicobacter pylori-negative peptic ulcers after the withdrawal of proton pump inhibitors (PPIs). He was diagnosed as having Zollinger-Ellison syndrome based on a marked increase in plasma gastrin and chromogranin A (CgA) levels, with the evidence of a 1-cm cephalo-pancreatic hypoechoic mass on endoscopic ultrasound (EUS) [Figure 1] and the presence of either a primary lesion or several hepatic areas that were hypercaptant on 111 In-pentetreotide somatostatin receptor scintigraphy, which was also confirmed by computed tomography (CT) scan.
Figure 1: Endoscopic ultrasound appearance of the primary gastrinoma: A small hypoechoic lesion (diameter 1.1 cm), which was histologically consistent with gastrinoma, was detected in the head of the pancreas

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The patient underwent surgical removal of the cephalo-pancreatic gastrinoma and liver metastases and received a medical regimen of somatostatin analogs (SSAs) and high-dose PPIs. Histology revealed a well-differentiated endocrine tumor, which was strongly positive for CgA, synaptophysin, and gastrin, infiltrating the surgical margins. The Ki-67 proliferation index was 1% [Figure 2]. The genetic analysis revealed MEN1 syndrome. Following a five-year uneventful follow-up, the patient reported heartburn and diarrhea. He had normal gastrin and CgA levels and a negative response to the secretin stimulation test. An upper GI tract endoscopy showed a thickening of the distal esophagus wall. EUS showed a hypoechoic 2-cm solid focal lesion [Figure 3]. Histological examination revealed a mesenchymal lesion composed of cells with plump cytoplasm arranged in a storiform pattern. The immunophenotype of the lesion was CD117 and platelet derived growth factor (PDGF) positive, whereas alpha-1 muscle actin and S-100 protein were negative. Due to morphological and immunohistochemical results, a final diagnosis of esophageal GIST was made.
Figure 2: Histological features of primary gastrinoma: EE= hematoxylin-eosin; immunohistochemical staining was performed for chromogranin A (CgA), gastrin (G), and Ki-67 (MIB1)

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Figure 3: Endoscopic ultrasound appearance of an esophageal GIST: A hypoechoic 2-cm solid focal lesion in the distal esophagus with regular margins that seemed to be included in the muscular layer

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The surgical approach was refused by the patient, who is currently in good clinical condition and on a medical regimen of long-acting SSAs and PPIs.


 > Discussion Top


Both GISTs and gastroenteropancreatic (GEP)-NETs (GEP-NETs) are rare neoplasms, and their association has mainly been described in the setting of NF1. [3],[5] Conversely, an association between stromal tumors and MEN1 syndrome has seldom been reported. [8] A single case with a concomitant GIST and a gastrinoma has been reported, [7] and thus, the present report represents the second case. The coexistence of a GIST and GEP-NET has been described in 20 cases: 13 in the setting of NF1, and the remaining 7 occurring independently of NF1. [5],[6],[7]

MEN1 is an inherited autosomal dominant disorder, and the MEN1 gene has been mapped on chromosome 11q13; high rates of loss of heterozygosity (LOH) in the 11q13 region have been reported in MEN1 classical neuroendocrine tumors, suggesting that the MEN1 gene acts as a recessive tumor suppressor gene and is responsible for the occurrence of multiple neoplasms. [9]

GISTs can be sporadic or associated with familial NF1 syndrome at a rate of 4-25%. [6] Approximately, 85% of GISTs harbor activating mutations in KIT or the homologous receptor tyrosine-kinase PDGFRA gene. [1] GISTs have been demonstrated to express synaptic-like microvesicle (SLMV) proteins, ghrelin, and peptide hormone receptors, which are commonly expressed in NETs, suggesting that these stromal tumors might undergo neuroendocrine differentiation, showing a similar phenotype as NETs, with a possible analogous target of genetic mutations. [2]

Data are lacking about the pathogenetic mechanism(s) underlying the dual development of GISTs and NETs. Considering the available data on the association between GISTs and NF1, [5] a potential role for the NF1 gene in vascular smooth muscle proliferation has been suggested through the regulation of Ras signaling. [10] However, both GISTs and NETs can occur independently of NF1. [6],[7] It is possible to hypothesize a role for menin, which is ubiquitously expressed, in the tumorigenesis of GISTs through several genetic mechanisms, including the methylation of promoters and/or regulatory intronic sequences. [7] However, according to published data, no evidence for the loss of the wild-type MEN1 allele has been reported in GISTs; [7] thus, the occurrence of GISTs could be independent of the MEN1 gene and merely casual. Finally, the observation of c-KIT expression, which is typical of GISTs and other epithelial and neuroendocrine tumors, could increase our knowledge of the carcinogenesis of these neoplasms and open the field to potential new multitargeted molecules.


 > Acknowledgements Top


The authors acknowledge Alessandro Gronchi, MD (Sarcoma Unit, Department of Surgery, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy), and Silvia Carrara, MD (Vita-Salute San Raffaele University, San Raffaele Scientific Institute, Milan, Italy) for their help in the patient clinical management.

 
 > References Top

1.Liegl-Atzwanger B, Fletcher JA, Fletcher CD. Gastrointestinal stromal tumors. Virchows Arch 2010;456:111-27.  Back to cited text no. 1
    
2.Bümming P, Nilsson O, Ahlman H, Welbencer A, Andersson MK, Sjölund K, et al. Gastrointestinal stromal tumors regularly express synaptic vesicle proteins: Evidence of a neuroendocrine phenotype. Endocr Relat Cancer 2007;14:853-63.  Back to cited text no. 2
    
3.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. 3
    
4.Almeida MQ, Stratakis CA. Solid tumors associated with multiple endocrine neoplasias. Cancer Genet Cytogenet 2010;203:30-6.  Back to cited text no. 4
    
5.Barahona-Garrido J, Aguirre-Gutiérrez R, Gutiérrez-Manjarrez JI, Tellez-Avila FI, López-Arce G, Fomperoza-Torres A, et al. Association of GIST and somatostatinoma in a patient with type-1 neurofibromatosis: Is there a common pathway? Am J Gastroenterol 2009;104:797-9.  Back to cited text no. 5
    
6.Alabraba E, Bramhall S, O′Sullivan B, Mahon B, Taniere P. Pancreatic insulinoma co-existing with gastric GIST in the absence of neurofibromatosis-1. World J Surg Oncol 2009;7:18.  Back to cited text no. 6
    
7.Papillon E, Rolachon A, Calender A, Chabre O, Barnoud R, Fournet J. A malignant gastrointestinal stromal tumour in a patient with multiple endocrine neoplasia type 1. Eur J Gastroenterol Hepatol 2001;13:207-11.  Back to cited text no. 7
    
8.Dong Q, Debelenko LV, Chandrasekharappa SC, Emmert-Buck MR, Zhuang Z, Guru SC, et al. Loss of heterozygosity at 11q13: Analysis of pituitary tumors, lung carcinoids, lipomas, and other uncommon tumors in subjects with familial multiple endocrine neoplasia type 1. J Clin Endocrinol Metab 1997;82:1416-20.  Back to cited text no. 8
    
9.Brandi ML, Gagel RF, Angeli A, Bilezikian JP, Beck-Peccoz P, Bordi C, et al. Guidelines for diagnosis and therapy of MEN type 1 and type 2. J Clin Endocrinol Metab 2001;86:5658-71.  Back to cited text no. 9
    
10.Xu J, Ismat FA, Wang T, Yang J, Epstein JA. NF1 regulates a Ras-dependent vascular smooth muscle proliferative injury response. Circulation 2007;116:2148-56.  Back to cited text no. 10
    


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  [Figure 1], [Figure 2], [Figure 3]



 

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