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   Table of Contents      
REVIEW ARTICLE
Year : 2020  |  Volume : 6  |  Issue : 1  |  Page : 1-6

Current Management of Gastrointestinal Stromal Tumor


Department of Surgery, Maulana Azad Medical College and associated Lok Nayak Hospital, New Delhi, India

Date of Submission14-Oct-2019
Date of Decision10-Dec-2019
Date of Acceptance02-Feb-2020
Date of Web Publication30-Apr-2020

Correspondence Address:
Gautam Shubhankar
MBBS, MS General Surgery (Post Graduate resident), N/26, Professor colony, Kankarbagh, Patna 800020, Bihar
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/mamcjms.mamcjms_81_19

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  Abstract 


Gastrointestinal stromal tumors (GISTs) are the commonest mesenchymal tumors of the gastrointestinal tract. The tumors originate from the interstitial cells of Cajal in the gastrointestinal tract. The tumor may present with a variety of different signs and symptoms, depending on the site and pathology of the tumor. Once the diagnosis is established, an aggressive and meticulous approach is required by the treating surgeon to eradicate the disease using multimodal therapy. Treatment of GIST is primarily surgical, with an adjunctive chemotherapy in the form of tyrosinase kinase inhibitors. The stagewise surgical and medical management of GIST will be discussed in this report. A Pubmed search, with relevant terms, was performed for selecting articles, collection of data and analysis for the compilation of this report. In this article, we attempt to outline the current approaches to the successful management of GISTs. The content of this article is based on available literature in print and Internet and experience in the management and treatment of patients with GIST at our institution.

Keywords: Current management, gastrointestinal stromal tumor (GIST), imatinib


How to cite this article:
Shubhankar G, Singh R, Vats M, Reddy D A, Solanki NK. Current Management of Gastrointestinal Stromal Tumor. MAMC J Med Sci 2020;6:1-6

How to cite this URL:
Shubhankar G, Singh R, Vats M, Reddy D A, Solanki NK. Current Management of Gastrointestinal Stromal Tumor. MAMC J Med Sci [serial online] 2020 [cited 2020 Jul 14];6:1-6. Available from: http://www.mamcjms.in/text.asp?2020/6/1/1/283514



Key Messages (Provide appropriate messages of about 35-50 words to be printed in centre box):

Gastrointestinal stromal tumors are the most common mesenchymal tumors of the GI tract with a characteristic pathology and immunohistochemistry. The presence of c-KIT mutation enables targeted therapy using tyrosine kinase inhibitors (TKIs); which increases the long-term survival even in patients with metastatic disease. However, surgical resection remains the mainstay of therapy.


  Introduction Top


Gastrointestinal stromal tumors (GISTs) originate from a precursor cell that normally gives rise to the interstitial cells of Cajal (pacemaker cells) of the myenteric plexus in intestine. The median age of presentation is in the sixth decade. Both the genders are equally affected. In adults, the stomach (60%) and small intestine (30%) are the commonest primary sites, whereas the duodenum (5%) and colorectum (<5%) are rarely involved. Esophagus, appendix, mesentery, omentum, and retroperitoneum account for <1% of the cases.[1],[2],[3],[4],[5],[6],[7],[8] The tumor may present with pressure symptoms due to mass, dysphagia, upper GI bleeding, or metastases (mainly in liver), depending on the site of origin, or may just be incidentally detected.[9],[10]

A Pubmed search with the terms “Gastrointestinal Stromal Tumours” showed more than 10000 articles. The words “Current Management of Gastrointestinal Stromal Tumour” yielded 181 results. Further screening, by deciding the relevance of the article to our work, refined the list to 57 published articles; which were referred to while compiling our manuscript [Figure 1].
Figure 1 Flowchart of Methodology for Data Collection

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  Pathology Top


There are three types of histologic patterns: spindle cell type (70%), epithelioid cell type (20%), or mixed type. A few gastric GISTs show a specific feature of prominent paranuclear vacuoles, while many small bowel GISTs have hyaline eosinophilic material known as skeinoid fibers with extensive nuclear palisading.[11],[12],[13],[14],[15],[16],[17] Approximately 95% of GISTs express the c-KIT protooncogene. CD117 is the protein coded by this gene [Figure 1] and [Figure 2].[18]
Figure 2 The c-KIT receptor is a transmembrane protein (CD 117). The receptor is divided into an extra-cellular domain, a trans-membrane domain, and an intra-cellular tail. The intra-cellular part is further divided into a juxta-membrane domain and a tyrosine kinase domain. Different types of GISTs have different mutations expressing changes in different parts of the transmembrane receptor protein.

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  Classification Top


On the basis of type of mutation, GISTs can be classified into the following types:
  1. GISTs with c-KIT/ platelet-derived growth factor receptor-alpha (PDGFRA) mutation: These are the commonest type. Activating mutations of the KIT gene occur most frequently in exon 11 (juxtamembrane domain), followed by KIT exon 9 (extracellular domain). The presence of a KIT exon 11 mutation shows a favourable response to Imatinib and has a superior progression-free survival (PFS) and overall survival as compared to those with exon 9 mutation or wild-type GIST. If an exon 9 KIT mutation is identified in a patient planned for neoadjuvant imatinib, a double dose (800 mg/day) should be considered.
  2. Wild-type GISTs: Nearly 10 to 15% of GISTs are negative for c-KIT and PDGFRA gene mutations and are referred to as the wild-type. They are less responsive to imatinib and have a poorer prognosis. Aberrant expression of IGF1R may be associated, which is correlated with higher mitotic index and larger, higher risk, metastatic and relapsed GISTs. Other mutations include SDH-deficient, NF1-related GISTs, and BRAFV600 mutation GISTs.
  3. Familial GISTs: These are characterized by inherited germline mutations in either c-KIT or PDGFRA. They have additional associated clinical findings such as cutaneous hyperpigmentation and gastrointestinal symptoms, including irritable bowel syndrome, dysphagia, and diverticular disease. The median age of onset is 47 years. They are typically multifocal, have a low mitotic rate, and are more common in the small bowel than other anatomic sites. Familial GISTs seem to have favourable histologic features and the diagnosis does not lead to shortened survival.[2],[3],[4],[5],[6],[7],[8]



  Presentation Top


  1. Incidental finding on imaging, endoscopy, or exploration: Lesions >2 cm should be resected. For lesions <2 cm, endoscopic ultrasound (EUS) should be performed and if it shows high-risk features, such as irregular border, cystic spaces, intra-lesion ulceration, echogenic foci, and heterogeneity, resection is indicated. In the absence of high-risk features, patients can be kept for endoscopic surveillance or computed tomography (CT) scans at 6 to 12 months intervals.
  2. Emergency occurrence of intra-abdominal haemorrhage, GI bleeding, perforation, or bowel obstruction: Such patients should undergo emergency intervention with resection of the mass if possible or a diversion procedure with control of haemorrhage. Upper GI bleed due to gastric GISTs may be amenable for endoscopic management.
  3. Palpable abdominal mass: Large solid abdominal mass/masses without other symptoms raise the suspicion of a GIST. A contrast-enhanced CT (CECT) scan is considered as the initial investigation of choice. Resection is the best option. In cases of borderline resectable masses, neoadjuvant imatinib therapy is initiated, with resection deferred till it becomes resectable.
  4. Metastatic: If the tumor is metastatic or unresectable, maintenance imatinib therapy is prescribed. In both unresectable and borderline resectable cases, a core needle biopsy is recommended before starting treatment. Surgery is reserved for complications such as bleeding or obstruction. [2],[3],[4],[5],[6],[7],[8]



  Investigations Top


  1. Endoscopic ultrasound: This is recommended in patients presenting with UGI bleeding or a mass projecting in the gastric lumen detected on imaging. On EUS, malignancy might be suspected in masses with a larger size (e.g., >4 cm), in case of irregular borders, anechoic spaces, and/or echogenic foci. EUS enables us to identify the layers of the gastrointestinal wall distinctly. Any reduction in the thickness of the tissue, distortion in any of the layers or irregular margins compared to the surrounding tissue will help to identify ulcers on EUS. The combined presence of two out of three EUS features has a positive predictive value of 100% for a malignant or borderline GIST. Such GISTs should be resected irrespective of the size. Combined use of cytological analysis and immunohistochemistry for the detection of KIT mutations (CD 117) by EUS-guided fine-needle aspiration (FNA) may enhance the sensitivity and specificity to 82 and 100% for diagnosis of GIST.[27]
  2. Fluorodeoxyglucose positron emission tomography (FDG PET): It is the modality of choice for evaluation of response to chemotherapy. PET can assess treatment response as early as 24 hours after initiation of therapy, although in practice it is usually performed after 2 to 3 months. It also helps in detecting metastasis that may otherwise be inapparent on CT scan, or in detecting an otherwise unknown primary site. In a meta-analysis, it was observed that the sensitivity and specificity of PET scan were 88% each in diagnosing GISTs.[25],[26],[28],[29]
  3. Core needle biopsy: This is not routinely performed. It is essential if neoadjuvant or palliative imatinib therapy is planned.[25],[26],[28]



  Management OF GIST Top


Primary GISTs

Surgical resection remains the mainstay for localized, primary GIST (R0 resection). The margin should be 1 to 2 cm. In gastric GISTs, a wedge resection, partial or total gastrectomy, may be required depending on the site and size of the tumor. In small and large bowel GISTs, limited resection with 1 to 2 cm margin should be performed. If the tumor involves adjacent structures, a limited resection is performed with the aim of organ preservation. Duodenal GIST tumors >2 cm from the ampulla of Vater should undergo wedge resection; pancreaticoduodenectomy is indicated for tumors within 2 cm of the ampulla; and segmental resection may be possible for tumors in the third or fourth part of the duodenum. Neoadjuvant chemotherapy is indicated in cases of borderline resectable tumors. These include tumors encasing left gastric artery, gastroduodenal artery, celiac axis, superior mesenteric artery, superior mesenteric and portal veins, rectal GISTs, or deep-seated retroperitoneal extension. Reduction in tumor size would significantly decrease the morbidity of surgical resection in such cases. Imatinib (400 mg OD) for at least 6 months is currently the drug of choice. However, upfront surgery may be indicated for patients with a PDGFRA mutation or those with wild-type tumors, as imatinib is not effective in them.[25],[26],[28] Relapse following resection is approximately 54% in 5 years. Adjuvant imatinib is indicated in all high-risk [Table 1] patients at a dose of 400 mg daily for at least 3 years. This recommendation is based on a Scandinavian trial that showed significantly greater recurrence of free survival (71 vs. 52%) and overall survival (92 vs.85%).[21],[22],[23],[24],[25]
Table 1 Risk assessment for primary GISTs [26]

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Metastatic, unresectable or recurrent GIST

Contrast CT or FDG-PET is recommended within 3 months of initiating tyrosinase kinase inhibitor (TKI) therapy in patients with unresectable or metastatic disease for assessment of response. The Choi criteria are commonly used to assess response to therapy [Table 2].
Table 2 Response evaluation following chemotherapy (Choi criteria on CT scan)

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Although chemotherapy (imatinib, sunitinib, and regorafenib) remains the mainstay of salvage therapy, cytoreductive surgery may be indicated in the following situations:
  1. Stable or responsive GIST to TKI therapy when complete resection is possible.
  2. Isolated clones progressing on TKI therapy after initial response (indicative of secondary drug resistance), while other sites of disease remain stable (limited disease progression).
  3. Complications, such as hemorrhage, perforation, obstruction, or abscess formation.


The median time to development of secondary resistance to imatinib is approximately 2 years. Thus, resection should be performed within 2 years of starting chemotherapy, and ideally after 6 to 12 months of disease stability or response. Post resection, imatinib is to be continued lifelong.[27],[30] Studies have shown that imatinib has an overall response rate of 68.1% with a progression-free survival rate of 24 months. In patients with imatinib-resistant GISTs, sunitinib and regorafenib have an additional overall response rate of 7 and 4.5%, respectively, and an additional progression-free survival of 6 and 4 months, respectively.[2],[3],[4],[5],[6],[7],[8][12],[13],[14],[15],[16],[17],[31],[32],[33],[34],[35],[36],[37]

Follow-Up

Following an R0 resection, a contrast CT is recommended every 3 to 6 months for 3 to 5 years and then annually. For patients with more locally advanced or metastatic disease who are receiving imatinib, CT scan is recommended every 3 to 6 months lifelong.[26],[37],[38],[39],[40],[41]

Summary

Gastrointestinal stromal tumors are common tumors, with specific pathologic and immunohistochemical features. The presence of c-KIT mutation enables targeted therapy using tyrosine kinase inhibitors (TKIs), although surgical resection remains the mainstay of therapy. The introduction of targeted therapy enables long-term survival even in patients with metastatic disease.

Acknowledgement

The authors would like to thank Dr P.N. Agarwal, Ex- HOD and Director Professor, Department of Surgery, Lok Nayak Hospital for his guidance and support.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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