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 Table of Contents  
ORIGINAL ARTICLE
Year : 2016  |  Volume : 2  |  Issue : 2  |  Page : 84-91

Clinicopathologic and immunohistochemical study of gastrointestinal stromal tumor (ten cases) and extragastrointestinal stromal tumor (six cases) with review of literature


Department of Pathology, Smt. Kashibai Navale Medical College, Pune, Maharashtra, India

Date of Submission16-May-2016
Date of Acceptance10-Oct-2016
Date of Web Publication13-Jan-2017

Correspondence Address:
Vandana L Gaopande
Department of Pathology, Smt. Kashibai Navale Medical College, Off Katraj Bypass Highway Overbridge, Ambegaon, Narhe, Pune - 411 041, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2455-3069.198367

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  Abstract 

Aims: The diagnosis of gastrointestinal stromal tumor (GIST) and extragastrointestinal stromal tumor (EGIST) depends on both characteristic histopathology (HP) and immunohistochemistry. The aim of the present study is to study the clinicopathological and immunohistochemical features of these tumors.
Materials and Methods: This is a 6-year (2009–2015) retrospective study conducted in a tertiary care center. It includes all the cases of GIST and EGIST diagnosed in that period. Clinical records and HP slides of all cases were reviewed. Appropriate tissue blocks were selected for making a manual tissue microarray. Using the microarray, immunostaining for CD117, discovered on GIST-1 (DOG-1), S-100, desmin, smooth muscle actin, CD34, and vimentin was performed.
Results: GISTs (total 10 with 3 low-risk, 4 intermediate-risk, and 3 high-risk type) were abdominal masses located commonly in the small intestines of adult men (mean age 52 years). EGISTs (6 cases all high-risk type) were larger abdominal masses affecting younger patients (mean age 50 years) located in the mesentery and retroperitoneum. All GIST and EGIST showed Cd117 and vimentin positivity. DOG-1 clone 1.1 was positive in 6 of 7 GIST (85.7%) and 2 of 3 EGIST (66.6%). Immunoreactivity for DOG-1 clone K9 was observed in 2 of 7 GIST (28.5%) and in 1 of 3 EGIST (33.3%).
Conclusion: This study reaffirms the importance of CD117 in diagnosis of GIST and EGIST. Of the two clones of DOG-1 used, clone1.1 is a more sensitive marker.

Keywords: Extragastrointestinal stromal tumor, gastrointestinal stromal tumor, immunohistochemistry


How to cite this article:
Gaopande VL, Joshi AR, Bhayekar PD, Khandeparkar SG. Clinicopathologic and immunohistochemical study of gastrointestinal stromal tumor (ten cases) and extragastrointestinal stromal tumor (six cases) with review of literature. J Curr Res Sci Med 2016;2:84-91

How to cite this URL:
Gaopande VL, Joshi AR, Bhayekar PD, Khandeparkar SG. Clinicopathologic and immunohistochemical study of gastrointestinal stromal tumor (ten cases) and extragastrointestinal stromal tumor (six cases) with review of literature. J Curr Res Sci Med [serial online] 2016 [cited 2017 Jun 24];2:84-91. Available from: http://www.jcrsmed.org/text.asp?2016/2/2/84/198367


  Introduction Top


Gastrointestinal stromal tumors (GISTs), the most common mesenchymal tumors arising from the gastrointestinal tract (GIT), are those spindle cell or epithelioid tumors of GIT that are CD117 (c-kit)-positive.[1] The interstitial cells of Cajal (ICC-pacemakers of GIT) are the cell of origin.[2] ICC are found in the muscularis propria and around the myenteric plexus and are immunoreactive with CD117, CD34, and discovered on GIST-1 (DOG-1).[3],[4] Gain of function mutations in kit gene and platelet-derived growth factor receptor alpha (PDGFRA) gene mutations are both reported to contribute independently to the development of GIST.[2],[5],[6] CD117 is a reliable and sensitive diagnostic tool for GIST. With the tyrosine kinase inhibitor therapies against KIT and PDGFRA, inoperable or metastatic GISTs are now treatable. In the present study, the immunohistochemistry (IHC) markers used are CD117, DOG-1, S-100, desmin, smooth muscle actin (SMA), CD34, and vimentin. Extragastrointestinal stromal tumors (EGISTs) are tumors histopathologically and immunohistologically similar to GIST. They are located in the omentum, mesentery, or retroperitoneum and do not have any connection with the wall of GIT including its serosal surface.[7]


  Materials and Methods Top


Inclusion criteria

All tumors diagnosed as GIST/EGIST were included.

Data collection

Review of records (clinical and pathology) and histopathology (HP) slides was done. Risk stratification of GIST was done using criteria of the National Institute of Health (NIH), GIST workshop, as well as the recent criteria which take into account tumor location in addition to size and mitosis.[8],[9] Risk stratification of EGIST was done using NIH criteria.

Tissue microarray

The materials used for preparing the manual microarray block [Figure 1] were skin punch biopsy needle (3-mm diameter), donor blocks, steel wire with one round end (stylet), embedding mold fitted with double-sided adhesive tape at the bottom. The places for attaching cores on the tape were marked, and a grid was prepared showing the place of every core. The marked areas on slides were superimposed on corresponding donor blocks and they were cored with the punch biopsy needle. Stylet was used to gently loosen the core. Core was attached to exposed surface of tape, cutting surface facing downward. After all cores were in place, melted paraffin was gently poured from the sides. Mold was cooled initially at room temperature and later in refrigerator. Adhesive tape was peeled off to expose the cutting surface of the microarray block.[10] Sections of 3 micron thickness were cut and picked up on poly-L-lysin-coated slides.
Figure 1: (a) A steel mold with adhesive tape at the bottom and attached donor block cores, (b) a tissue microarray block, (c) a stained microarray slide

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Immunohistochemistry

Antigen retrieval was done in citrate buffer using a pressure cooker. The primary antibodies used were CD117 (Novocastra clone T595), S-100 (Novocastra clone 5E2), desmin (Dako clone D33), SMA (Dako clone 1A4), CD34 (Novacastra clone QBEnd/10), and vimentin (Dako clone V9). For detection, the chromogen used was diaminobenzidine. Appropriate controls were used for all the antibodies. The CD117 stain may be cytoplasmic, membrane-associated, or sometimes as perinuclear dots. The CD34 stain may be cytoplasmic or membranous. S-100 stains the cytoplasm and nuclei. Desmin, SMA, and vimentin are all cytoplasmic stains. In 10 cases, DOG-1 stain was done using DOG-1 (Novocastra clone K9) and DOG-1 (PathnSitu clone 1.1). For DOG-1 clone 1.1, the detection system of PathnSitu was used. DOG-1 stain is cytoplasmic and membranous. Reporting of IHC was done by two pathologists and staining of more than 10% tumor cells was reported as positive for all the antibodies.


  Results Top


[Table 1] shows the details of every GIST case and [Table 2] of every EGIST cases. A comparison of GIST and EGIST is given in [Table 3].
Table 1: Clinicopathological and immunohistochemical features of gastrointestinal stromal tumors (ten cases)

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Table 2: Clinicopathological and immunohistochemical features of extragastrointestinal stromal tumors (six cases)

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Table 3: Comparison of gastrointestinal stromal tumors and extragastrointestinal stromal tumors

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Clinical presentation

Abdominal mass was detected in all patients. The mean age of presentation was 52 years (34–80 years) for GIST and 50.1 years (38–70 years) for EGIST. GIST category showed male preponderance (M:F-4:1). EGIST did not show any sex predilection (M:F was 1:1).

Gross pathology

Maximum GISTs (7) were located in small intestine while most EGISTs were mesenteric. Average size of EGIST (15.5 cm) was more than double of GIST (7.55 cm).

Microscopy

Spindle cell morphology was most common [Figure 2]a. Two high-risk EGISTs and one intermediate-risk GIST showed epithelioid areas [Figure 2]b. There were three high-risk, four intermediate-risk and three low-risk GISTs. GISTs of stomach were low risk. All EGISTs were high risk and were otherwise similar to GIST morphologically.
Figure 2: (a) Large mesenteric extragastrointestinal stromal tumor with a bulging predominantly gray-white cut surface, (b) small bowel gastrointestinal stromal tumor showing luminal narrowing, mucosal ulceration, and hemorrhage and necrosis on cut surface

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Immunohistochemistry

All cases were Cd117 and vimentin positive. Among ten GISTs, SMA (four cases) and S-100 (three cases) were most frequently expressed. Among 6 EGISTs, SMA (four cases) and CD34 (two cases) were most frequently expressed. DOG-1 clone 1.1 is more sensitive for diagnosis of GIST.


  Discussion Top


Hirota identified GIST as a distinct soft-tissue tumor, with kit immunostaining as its major diagnostic tool.[2] Three years later, GIST became the first solid tumor to be given targeted chemotherapy.[11] In 2003, PDGFRA gene mutations were found in GISTs without kit gene mutation.[5],[6]

GIST are mesenchymal tumors including spindle cells, epithelioid cells, or occasionally pleomorphic mesenchymal cells and express c-kit (CD117) protein.[1] Both histology and immunochemistry for c-kit are important for diagnosis. Tumors other than GIST may show c-kit positivity. A few GISTs which may lack c-kit expression are immunoreactive for DOG-1, protein kinase C theta, or PDGFRA.[12] GISTs show a wide range of biologic behavior.

An autopsy study revealed small (<10 mm) GISTs in 22.5% of individuals older than 50 years.[13] The incidence of GIST varies between 6.5 cases/million/year in Norway to 14.5 cases/million/year in Sweden.[14],[15]

Common sites for GIST are stomach (60%) and small intestine (30%). Colorectum, esophagus, and appendix are rarely affected.[16] In the present study, the most common location for GIST was small intestine. GISTs are well-circumscribed lesions arising in the submucosal layer of GIT and may be covered by intact mucosal layer on the luminal side. Their clinical presentation depends on location and size. Often, nonspecific symptoms such as nausea, vomiting, dyspepsia, abdominal pain, distension, or change in bowel habits are seen at presentation. Patients with advanced disease may present with symptoms of mass lesion or bleeding. Obstruction and rupture are rare. Investigations such as ultrasound, computerized tomography, and magnetic resonance imaging help in localization of the tumor to submucosa of GIT. The results of endoscopic forceps biopsy are often negative, especially with small, early GISTs. Endoscopic ultrasound-guided fine-needle aspiration is recognized as the only accurate diagnostic modality for the diagnosis of GISTs.[17] Definitive diagnosis is usually made postoperatively after histopathological and IHC studies. EGIST are large (often >10 cm) abdominal masses arising from the mesentery or in retroperitoneum. They are usually diagnosed as soft-tissue tumors on imaging studies and HP of surgical specimen gives the definitive diagnosis.

In the present study, the average size of EGIST was more than double the average size of GIST. The cut surface ranged from homogeneously gray-white to variegate with areas of necrosis, hemorrhage, and cystic change [Figure 2]. EGISTs arise commonly from omentum, peritoneum, and mesentery. They are either gastrointestinal GISTs that have separated from their origin or they arise primarily from the peritoneum.[18] We found three mesenteric, two retroperitoneal, and one multicentric EGISTs. They presented at a younger age (mean age 50 years). Our findings are similar to previous reports.[7] Multicentric GISTs are thought to be metastatic growths from a single primary. Different clonal origin of multicentric sporadic GISTs has been recently reported in a few cases.[19] Multicentric GISTs are also found in the tumor syndromes. There are three tumor syndromes associated with GIST: neurofibromatosis 1 (NF1), familial GIST, and Carney triad. NF1-GISTs appeared early are often intestinal and multiple. They are usually low-risk GISTs without kit and PDGFRA mutations.[20] Familial GIST commonly shows germline mutations of exon 11 KIT.[21] The Carney triad includes gastric GIST with paraganglioma and pulmonary chondroma. Carney triad GISTs are distinctive since they show female predilection, young patient age, epithelioid cell predominance, multifocality, frequent lymph node metastasis, serial tumor occurrence, and unpredictable behavior.[22] None of the tumor syndromes were found in the multicentric GIST in the present study.

Microscopically, GISTs show predominantly spindle cell morphology. Epithelioid morphology is seen in few GISTs and rarely pleomorphic pattern may be observed. Epithelioid morphology in intestinal GISTs is essentially limited to malignant tumors. In the present study, all cases showed spindle cell pattern and an additional epithelioid component was found in three cases (two high-risk EGIST, one intermediate-risk GIST) [Figure 3]. Schwannomatosis pattern was observed in seven cases. An Indian study reported 40% spindle cell morphology, 33% epithelioid morphology, and 27% mixed morphology.[23] Liu et al. reported spindle cell morphology in 38%, epithelioid cell morphology in 38%, and mixed in 24%.[24] GISTs that have been treated with tyrosine kinase inhibitors show dramatically decreased cellularity and stromal changes such as hyalinization and myxoid features.[25] EGISTs show a morphology similar to GIST. Most important histologic criteria for malignant EGIST are cellularity (as defined by areas with frequent overlapping nuclei), mitotic activity in excess of 2/50 hpf, and any amount of coagulative necrosis.[7]
Figure 3: (a) Spindle cell gastrointestinal stromal tumor, (b) epithelioid gastrointestinal stromal tumor (a and b: H and E, ×400)

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[Table 4] presents the IHCresults of various studies on GIST and EGIST. In the present study, percentage of GIST showing CD34 positivity was low compared to other studies. However, we found that EGIST are more frequently CD34-positive. CD117 positivity in GISTs is strong and global. Membrane staining is often present. Many GISTs show paranuclear dot positivity (Golgi zone pattern).[31] The characteristic diagnostic pattern is combined membrane and cytoplasmic positivity.[32] All three patterns of staining were observed in the present study. It has been reported that type of distribution of c-kit significantly affects overall survival and biological behavior in GIST (P = 0.06) and univariate analysis correlated significantly with time to progression/relapse in localized disease.[33] Inconsistent immunoreactivity was reported for formalin-fixed and paraffin-embedded GIST tissues when monoclonal CD117 was used, and therefore, polyclonal CD117 antibodies are considered best for immunostaining of GISTs.[31] In the present study, monoclonal CD117 was used. IHC spectrum of GISTs at different sites has been studied and maximum CD34 positivity was found in GISTs of rectum and esophagus (96%–100%), SMA expression was most frequent in small bowel GISTs (47%), while S-100 expression was seen most frequently in small intestinal GISTs (15%).[34] In the present study, esophageal or rectal GISTs were not found and that may be a contributory factor for the low CD34 positivity. Belev et al. found that in patients with localized disease, SMA expression has an impact on relapse (P = 0.034).[33] In the present study, the SMA positivity was high (GIST-40% and EGIST-83%) and most of the SMA-positive tumors were high-risk tumors. Positivity for desmin is rare in GISTs of all sites.[34] The present study reports similar finding. DOG-1 is expressed almost ubiquitously in GISTs irrespective of the type of activating mutations, is rarely expressed in other soft tissue tumors, and is positive in CD117-negative GISTs with PDGFRA mutations.[35] This protein has 8 transmembrane function domains and is supposed to be a calcium-regulated chloride ion channel protein. It is not known why DOG-1 is so widely expressed in GISTs. It may be that the protein has a role in receptor kinase type III signal transduction pathways. In a recent study, the overall sensitivity of DOG-1 and KIT in GISTs was nearly identical: 94.4% and 94.7% but in the intestinal GISTs, KIT was slightly more sensitive than DOG-1.[4] Our results indicate that of the two clones of DOG-1 studied, clone 1.1 gave better sensitivity. [Table 5] shows the findings of DOG-1 immunostaining (clones 1.1 and K9) as reported in literature. It is our recommendation that for diagnosis of GIST it is preferable to use a polyclonal DOG-1. The clinicopathological differential diagnosis of GIST includes intramural or retroperitoneal leiomyomas, leiomyosarcomas, glomus tumors, gastrointestinal schwannomas, inflammatory fibroid polyp, inflammatory myofibroblastic tumor, desmoid tumor, dedifferentiated liposarcoma, undifferentiated sarcoma, metastatic melanoma, rarely malignant epithelial tumors, and lymphohematopoietic tumors. Tumors that show CD117 positivity are mastocytoma, seminoma, pulmonary small cell carcinoma, and granulocytic sarcoma.[36] Fibromatosis involving the GIT may be misdiagnosed as GIST because they are CD117-positive but the staining is localized to the cytoplasm and is coarsely granular.[32] These tumors are distinct clinicopathologically from GIST. Abdominal or gastrointestinal tumors that are variably CD117-positive are metastatic melanoma, clear cell sarcoma, primitive neuroectodermal tumor family of tumors, childhood neuroblastoma, and angiosarcoma.[31] They all have different morphology and IHC profiles. DOG-1-positive non-GIST mesenchymal tumors include uterine type retroperitoneal leiomyoma, peritoneal leiomyomatosis, synovial sarcoma, angiosarcoma, leiomyosarcoma, fibrosarcoma, and Ewing's sarcoma.[4],[35],[36] Leiomyomas colonized by DOG-1-positive Cajal cells should not be confused with GISTs.[4]
Table 4: Immunohistochemistry results of various studies on gastrointestinal stromal tumors and extragastrointestinal stromal tumors

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Table 5: DOG-1 clone 1.1 and K9 comparative results

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Every GIST is now considered to be potentially malignant. The currently used risk stratification scheme uses the tumor size and the mitotic rate per 50 hpf to divide these tumors into four risk groups. In addition to these well-established prognostic determinants, tumor location is also an important determinant of prognosis. Gastric GISTs have a better prognosis compared to intestinal GISTs of similar size and mitotic activity.[38] The seventh edition of the International Union against Cancer (UICC) published in 2010 included for the first time a classification and staging system for GIST. It has four T-categories, separated on the basis of tumor size. The T-category is combined with mitotic rate and tumor site to define a clinical UICC stage.[39] There is a general agreement in literature that EGISTs are more aggressive than GIST. For EGIST, careful gross and microscopic assessment for the presence or absence of normal tissue on the peritoneal aspect of tumors and for any evidence of serosal tears or old sealed focal rupture has been advised because peritoneal involvement is a significant predictor of peritoneal disease recurrence.[32] Epithelioid morphology of GISTs is associated with a poor prognosis. Those GISTs showing any cytogenetic abnormality also have a worse prognosis compared to those with normal karyotype. PDGFRA mutations (almost always in gastric primaries) appear to be a very favorable prognostic factor for recurrence. It has been reported that aggressiveness of GIST correlated with increased number of tumors, higher clinical stage, epithelioid histology, higher cellularity, severe cellular atypia, the presence of necrosis, and mucosal invasion.[27] Small sample size and lack of molecular studies and follow-up are the drawbacks of this study.


  Conclusion Top


This study reaffirms the importance of CD117 in diagnosis of GIST. The DOG-1.1 antibody appears to be more sensitive for identification of GIST. Studies with larger sample size are needed for a definitive conclusion.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
  References Top

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    Figures

  [Figure 1], [Figure 2], [Figure 3]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]



 

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