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Year : 2019  |  Volume : 15  |  Issue : 1  |  Page : 138-141

Discovered on gastrointestinal stromal tumor 1, a keystone in the diagnosis of extraintestinal gastrointestinal stromal tumors

Department of Pathology, Kasturba Medical College, Manipal University, Mangalore, Karnataka, India

Date of Web Publication13-Mar-2019

Correspondence Address:
Dr. Rohit Tapadia
Department of Pathology, Kasturba Medical College, Manipal University, Light House Hill Road, Mangalore - 575 001, Karnataka
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jcrt.JCRT_28_17

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 > Abstract 

Introduction: Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract (GIT) but have a low incidence. Arising from the interstitial cells of Cajal, GISTs occur at different sites in the GIT with stomach being the most common. They can rarely be seen at sites outside the GIT such as omentum, retroperitoneum and are called as extraintestinal GISTs (EGIST). They have a spindle or epithelioid cell morphology and show positivity by immunohistochemistry (IHC) for CD117. Our aim was to study the clinicopathological and immunohistochemical profile of our cases of EGISTs.
Materials and Methods: A cross-sectional study of EGISTs received from 2010 to 2015 was done. IHC with CD117 and discovered on GIST1 (DOG1) was performed and tumors were scored based on the percentage of cells that stained positive. Thirteen abdominal non-GIST spindle cell tumors were included in the study as controls.
Results: Seven cases of EGIST were included (four-omental, three-retroperitoneal). All cases stained positive for CD117 and DOG1. One case of epithelioid EGIST scored 4 + with DOG1 and 2 + with CD117. Another case with mixed morphology scored 2 + with DOG1 and 4 + with CD117. All controls were negative for both markers.
Conclusion: EGISTs are one of the rare differentials for spindle cell lesions outside the GIT. Although both markers stain positive, DOG1 showed higher score with epithelioid GISTs.

Keywords: CD117, discovered on gastrointestinal stromal tumor 1, extraintestinal gastrointestinal stromal tumor, immunohistochemistry

How to cite this article:
Sahu KK, Tapadia R, Kini JR, Pai RR, Kini H, Nirupama M, Pooja K S. Discovered on gastrointestinal stromal tumor 1, a keystone in the diagnosis of extraintestinal gastrointestinal stromal tumors. J Can Res Ther 2019;15:138-41

How to cite this URL:
Sahu KK, Tapadia R, Kini JR, Pai RR, Kini H, Nirupama M, Pooja K S. Discovered on gastrointestinal stromal tumor 1, a keystone in the diagnosis of extraintestinal gastrointestinal stromal tumors. J Can Res Ther [serial online] 2019 [cited 2020 Jul 12];15:138-41. Available from: http://www.cancerjournal.net/text.asp?2019/15/1/138/214737

 > Introduction Top

The gastrointestinal tract (GIT) is home to myriads of mesenchymal tumors with gastrointestinal stromal tumors (GISTs) being the most common.[1] According to a systematic review, the incidence of GIST is ascertained to be 10–15/million/years without significant geographical variation.[2] Most cases occur between the ages 60–65 years, rarely before 40 years and only <1% occur below 21 years. In the GIT, stomach is the most common site, followed by jejunum, ileum, duodenum, and colorectum in decreasing order of frequency.[3] Rarely, they are seen at extraintestinal sites such as omentum,[4] mesentery,[5] gall bladder,[6] pancreas,[7] retroperitoneum,[8] paravaginal tissue, periprostatic tissue,[9] and in the pleura.[10] Traditionally, GISTs are diagnosed based on their morphology (spindle cell, epithelioid, or mixed) and immunohistochemistry (IHC) with CD117, though it has low specificity. Over time, a more sensitive and specific marker, discovered on GIST1 (DOG1) was developed.

Although considered to be the most common mesenchymal tumors of the GIT, the overall incidence of GISTs is low and that of extraintestinal GISTs (EGIST) is even rarer.[11] We present a series of seven cases of EGISTs that were received in our department between January 2010 and December 2015.

 > Materials and Methods Top

A cross-sectional study was performed which included cases of EGIST which presented to our department between January 2010 and December 2015. We included those cases which were morphologically diagnosed as GIST, confirmed with CD117 IHC and were located outside the GIT with no primary tumors in the GIT and no connection to the GIT.

The clinical data and slides of the cases were reviewed to confirm the diagnosis. Representative blocks of the tumors were selected, and IHC was performed with DOG1 mouse monoclonal antibody obtained from Gene Pulse Scientific, following the standard operating protocol.

The morphology of the tumor was categorized as spindle cell type or epithelioid type or mixed type. The tumors were graded based on the number of mitotic figures with Grade 1 (G1) being assigned to ≤5 mitoses/50 high-power fields (HPFs) and Grade 2 (G2) for >5 mitoses/50 HPF.[12] The presence and absence of necrosis were recorded. The risk of progression of the tumors was assigned according to the criteria from the College of American Pathologists protocol for GIST version[12] The IHC staining was scored based on the number of tumor cells that stained positive for the individual IHC markers with a score of 0 for negative, 1+ for <5% positive cells, 2+ for 5%–25% positive cells, 3+ for 25%–50% positive cells, and 4+ for >50% positive cells.[13] The intensity of staining was graded as mild, moderate, and severe.

Nine intraabdominal nonuterine leiomyomas, three leiomyosarcomas, and one fibrosarcoma were stained with CD117 and DOG1 to test the specificity of these IHC markers.

 > Results Top

A total of 51 cases of GIST were evaluated during the study period, only seven of which were EGISTs. The age of the patients ranged from 24 to 63 years with mean age being 48 years. The male to female ratio was 4:3. The most common presenting feature was mass per abdomen (n = 5), followed by abdominal pain. Vomiting and difficulty in swallowing were other symptoms. Four of the seven cases were anemic.

Based on location, four cases were omental, and three were retroperitoneal GISTs. In all the cases, there was absence of any association to the GIT radiologically or peroperatively. The size of the tumors ranged from 31 cm in largest dimension (omental GIST) to 8 cm in smallest. In one case, multiple tumors were noted in the omentum.

Morphologically, four cases were of spindle cell type, one case was epithelioid, and two cases were of mixed type. All the cases had <5 mitoses/50 HPF (G1). Necrosis was seen in five cases. The majority of the cases were of intermediate risk [Figure 1].
Figure 1: (a) Spindle cell gastrointestinal stromal tumor (H and E, ×20). (b) Spindle cell and epithelioid component of a mixed morphology gastrointestinal stromal tumor (H and E, ×10). (c) Epithelioid gastrointestinal stromal tumor showing hyalinization (H and E, ×20). (d) Spindle cell gastrointestinal stromal tumor with necrosis (H and E, ×10)

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On IHC, cytoplasmic staining was considered positive for CD117, and either cytoplasmic or membranous or both were considered positive for DOG1 [Figure 2]. The results of IHC analysis are detailed in [Table 1]. All the 13 non-GIST abdominal tumors (nine leiomyomas, three leiomyosarcomas, and one fibrosarcoma) were negative for both CD117 and DOG1 immunostaining.
Figure 2: (a) CD117 (immunohistochemistry stain, ×10). (b) discovered on gastrointestinal stromal tumor 1 (IHC stain, ×10)

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Table 1: Clinicopathological and immunohistochemical results

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 > Discussion Top

GISTs were initially grouped along with smooth muscle tumors of the GIT and were classified as leiomyomas if benign, leiomyosarcomas if malignant and leiomyoblastomas if they had epithelioid features.[14] Over time, it was discovered that GISTs were a unique group of tumors which originated from the interstitial cells of Cajal[15] and differed from other soft-tissue tumors of GIT. Morphologically, they are composed of spindle cells or epithelioid cells or a mixture of both.[16]

GISTs show mutations in the KIT gene (exon 11, exon 9, exon 13, and exon 17) in 80% of the cases. Platelet-derived growth factor receptor alpha (PDGFRA) mutations are seen in the 8% to 10% of the cases (PDGFRA exon 18, PDGFRA exon 12, and PDGFRA exon 14). Receptor tyrosine kinase (RTK) mutations can be seen in 10% of the cases which are classified as wild type (WT). These include succinate dehydrogenase B (SDH B) deficient, RTK WT GIST, and RTK WT/SDH positive GIST.[17]

Although rare, GISTs do occur outside the GIT and are grouped together as EGISTs. While determining the origin of EGISTs, the theories considered were that the interstitial cells of Cajal are located at sites outside the GIT, or the mesenchymal cells recapitulate the morphology of these cells.[18] Expression of CD117 is taken as a reliable marker for the diagnosis of both intestinal and EGISTs.

The average age of patients included in our study was 48 years with the youngest being 24 years. Of the 48 EGISTs studied by Reith et al., it was seen that the cases ranged from 31 to 82 years, and the youngest case was 31 years.[18] Todoroki et al. noted 31 years as the lowest age in their study of EGISTs. However, the lowest age in our case series was significantly lower.[19] Studies by Liegl-Atzwanger et al. have revealed that 70% of GISTs are symptomatic while 20% are asymptomatic and 10% are detected on autopsy.[3] The most common symptom in our case series was mass per abdomen followed by abdominal pain. Similar results were obtained in the EGISTs studied by Reith et al.[18] Anemia was seen in four of our cases, a finding which was not described in other studies. The diagnostic workup revealed that the tumors had no primaries in the GIT or associated connections to the wall of the intestine and were thus true EGISTs.

While the literature mentions the average dimension of omental EGISTs is 15.35 cm, Murayama et al. reported a lesion of 19 cm size.[4] The average size of 48 EGISTs studied by Reith et al. was 12 cm while the largest dimension was that of a retroperitoneal GIST (32 cm).[18] In our cases, two omental EGISTs measured 31 cm in largest dimension. The morphology of the tumors in our study varied, with spindle cell type being the most common (n = 4) followed by mixed pattern (n = 2). Only one case had an epithelioid cell morphology. Todoroki et al. reviewed the available literature on GISTs and stated that spindle cell is the most common morphology of GISTs (85%). However, among their cases of omental EGISTs, it was found that only half of the cases were of spindle cell type while the remaining cases were of either epithelioid or mixed type.[19] Necrosis was seen in five of our cases, and all the tumors were of Grade 1 (≤5 mitoses/50 HPF).

One case in our study had multiple omental nodules. GISTs are usually solitary, and the presence of multiple GISTs is usually considered to be metastasis from a primary tumor. However, in the study by Gasparotto et al., it was seen that six of the ten cases of multifocal GISTs had different mutations in tumors at various locations in the same patient and were thus independent primaries. In our case, the GIT did not show any evidence of a primary GIST. Thus, the case was considered as primary EGIST of the omentum.[20]

The differential diagnosis for EGISTs includes spindle cell tumors such as leiomyomas, leiomyosarcomas, and fibrosarcomas among others. In many cases, it is difficult to discriminate between them solely based on morphology; hence, IHC becomes important. Positivity for CD117 has been considered as diagnostic criteria for GISTs. It is however known that a few other spindle cell tumors may be positive for CD117, but they will be negative for DOG1. Thus, we included 13 spindle cell lesions which occur in the abdomen as controls. All thirteen controls stained negative for both markers. All 62 leiomyomas studied by Miettinen et al. were negative for CD117 while 4 of 50 leiomyosarcomas were positive.[21]

To diagnose a tumor as GIST and initiate RTK inhibitor therapy, positivity with CD117 was considered to be a requirement.[22] In a study by Liegl et al., it was seen that 5% of the GISTs were negative for CD117 immunostaining. It was also noted that the CD117 negative cases benefited from therapy.[23] Since CD117 is known to be positive in a variety of tumors,[24] the search for a better maker which was more sensitive and specific than CD117 and could diagnose the CD117 negative GISTs as well, led to the discovery of DOG1 also called as Anoctamin1. This marker was determined to be more sensitive and more specific than CD117.[25]

IHC revealed that all seven cases were positive for CD117 with six cases scoring 4+. The remaining case had a CD117 score of 2+ but a DOG1 score of 4+. The EGIST with the low CD117 score had an epithelioid morphology. It has been seen the GISTs with PDGFRA mutations usually present with an epithelioid or a mixed morphology.[17] The low score of CD117 with a high DOG1 score could be because CD117 is negative or minimally positive in 5% of the cases of GIST as compared to the marker DOG1 which has a higher sensitivity then CD117 for such cases.[26] Todoroki et al. also noticed that EGISTs with an epithelioid morphology had a weaker staining with CD117.[19] All seven cases were positive for DOG1 IHC with six cases scoring 4+. One case Scored 2+ with DOG1 and 4+ with CD117. This could be attributed to the focal nature of DOG1 staining.[13]

On analyzing the intensity of staining, it was seen that CD117 stained with a high intensity in six cases and low in one case. DOG1 stained high in four cases, moderate in one case, and low in two cases. Similar findings were seen in the study by Hwang et al. where they noticed that the intensity of staining of DOG1 on the resected specimens was lower than CD117.[27]

 > Conclusion Top

EGISTs are rare, nonetheless they have to be included in the differential diagnosis for abdominal masses as these patients will benefit from RTK inhibitor therapy. DOG1 is expressed in the EGISTs just as well as it is in intestinal GISTs and it may be more adept at diagnosing GISTs with an epithelioid morphology. However, we were limited by the small number of cases. Due to the rarity of the EGISTs, sufficient data are not available on the risk of progression or the malignant nature of large lesions. Hence, documentation of these cases is important for further study.

Financial support and sponsorship

Grant provided by Indian Council of Medical Research (ICMR), India.

Conflicts of interest

There are no conflicts of interest.

 > References Top

Alkhatib L, Albtoush O, Bataineh N, Gharaibeh K, Matalka I, Tokuda Y. Extragastrointestinal stromal tumor (EGIST) in the abdominal wall: Case report and literature review. Int J Surg Case Rep 2011;2:253-5.  Back to cited text no. 1
Søreide K, Sandvik OM, Søreide JA, Giljaca V, Jureckova A, Bulusu VR. Global epidemiology of gastrointestinal stromal tumours (GIST): A systematic review of population-based cohort studies. Cancer Epidemiol 2016;40:39-46.  Back to cited text no. 2
Liegl-Atzwanger B, Fletcher JA, Fletcher CD. Gastrointestinal stromal tumors. Virchows Arch 2010;456:111-27.  Back to cited text no. 3
Murayama Y, Yamamoto M, Iwasaki R, Miyazaki T, Saji Y, Doi Y, et al. Greater omentum gastrointestinal stromal tumor with PDGFRA-mutation and hemoperitoneum. World J Gastrointest Oncol 2012;4:119-24.  Back to cited text no. 4
Kirby R, Rajasagaram N, Ghusn M. Primary mesenteric gastrointestinal stromal tumour. J Surg Case Rep 2014;2014. pii: Rju050.  Back to cited text no. 5
Peerlinck ID, Irvin TT, Sarsfield PT, Harington JM. GIST (gastro-intestinal stromal tumour) of the gallbladder: A case report. Acta Chir Belg 2004;104:107-9.  Back to cited text no. 6
Trabelsi A, Yacoub-Abid LB, Mtimet A, Abdelkrim SB, Hammedi F, Ali AB, et al. Gastrointestinal stromal tumor of the pancreas: A case report and review of the literature. N Am J Med Sci 2009;1:324-6.  Back to cited text no. 7
Abuduwayite R, Muhemaiti A, Biekemituofu H. Malignant retroperitoneal extra-gastrointestinal stromal tumor: A case report. Br J Med Med Res 2012;2:142-9.  Back to cited text no. 8
Lam MM, Corless CL, Goldblum JR, Heinrich MC, Downs-Kelly E, Rubin BP. Extragastrointestinal stromal tumors presenting as vulvovaginal/rectovaginal septal masses: A diagnostic pitfall. Int J Gynecol Pathol 2006;25:288-92.  Back to cited text no. 9
Long KB, Butrynski JE, Blank SD, Ebrahim KS, Dressel DM, Heinrich MC, et al. Primary extragastrointestinal stromal tumor of the pleura: Report of a unique case with genetic confirmation. Am J Surg Pathol 2010;34:907-12.  Back to cited text no. 10
Casella C, Villanacci V, D'Adda F, Codazzi M, Salerni B. Primary extra-gastrointestinal stromal tumor of retroperitoneum. Clin Med Insights Oncol 2012;6:189-97.  Back to cited text no. 11
Rubin BP, Blanke CD, Demetri GD, Dematteo RP, Fletcher CD, Goldblum JR, et al. Protocol for the examination of specimens from patients with gastrointestinal stromal tumor. Arch Pathol Lab Med 2010;134:165-70.  Back to cited text no. 12
Abdel-Hadi M, Bessa SS, Hamam SM. Evaluation of the novel monoclonal antibody against DOG1 as a diagnostic marker for gastrointestinal stromal tumors. J Egypt Natl Canc Inst 2009;21:237-47.  Back to cited text no. 13
Miettinen M, Lasota J. Gastrointestinal stromal tumors. Gastroenterol Clin North Am 2013;42:399-415.  Back to cited text no. 14
Wang L, Vargas H, French SW. Cellular origin of gastrointestinal stromal tumors: A study of 27 cases. Arch Pathol Lab Med 2000;124:1471-5.  Back to cited text no. 15
Appelman HD. Morphology of gastrointestinal stromal tumors: Historical perspectives. J Surg Oncol 2011;104:874-81.  Back to cited text no. 16
Barnett CM, Corless CL, Heinrich MC. Gastrointestinal stromal tumors: Molecular markers and genetic subtypes. Hematol Oncol Clin North Am 2013;27:871-88.  Back to cited text no. 17
Reith JD, Goldblum JR, Lyles RH, Weiss SW. Extragastrointestinal (soft tissue) stromal tumors: An analysis of 48 cases with emphasis on histologic predictors of outcome. Mod Pathol 2000;13:577-85.  Back to cited text no. 18
Todoroki T, Sano T, Sakurai S, Segawa A, Saitoh T, Fujikawa K, et al. Primary omental gastrointestinal stromal tumor (GIST). World J Surg Oncol 2007;5:66.  Back to cited text no. 19
Gasparotto D, Rossi S, Bearzi I, Doglioni C, Marzotto A, Hornick JL, et al. Multiple primary sporadic gastrointestinal stromal tumors in the adult: An underestimated entity. Hum Cancer Biol 2008;14:5715-21.  Back to cited text no. 20
Miettinen M, Sobin LH, Sarlomo-Rikala M. Immunohistochemical spectrum of GISTs at different sites and their differential diagnosis with a reference to CD117 (KIT). Mod Pathol 2000;13:1134-42.  Back to cited text no. 21
Medeiros F, Corless CL, Duensing A, Hornick JL, Oliveira AM, Heinrich MC, et al. KIT-negative gastrointestinal stromal tumors: Proof of concept and therapeutic implications. Am J Surg Pathol 2004;28:889-94.  Back to cited text no. 22
Liegl B, Hornick JL, Corless CL, Fletcher CD. Monoclonal antibody DOG1.1 shows higher sensitivity than KIT in the diagnosis of gastrointestinal stromal tumors, including unusual subtypes. Am J Surg Pathol 2009;33:437-46.  Back to cited text no. 23
Cöl C, Yilmaz F. A case report of an extraintestinal GIST presenting as a giant abdominopelvic tumor. Gastrointest Cancer Res 2013;6:120-2.  Back to cited text no. 24
West RB, Corless CL, Chen X, Rubin BP, Subramanian S, Montgomery K, et al. The novel marker, DOG1, is expressed ubiquitously in gastrointestinal stromal tumors irrespective of KIT or PDGFRA mutation status. Am J Pathol 2004;165:107-13.  Back to cited text no. 25
Zhao X, Yue C. Gastrointestinal stromal tumor. J Gastrointest Oncol 2012;3:189-208.  Back to cited text no. 26
Hwang DG, Qian X, Hornick JL. DOG1 antibody is a highly sensitive and specific marker for gastrointestinal stromal tumors in cytology cell blocks. Am J Clin Pathol 2011;135:448-53.  Back to cited text no. 27


  [Figure 1], [Figure 2]

  [Table 1]


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