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ORGAN SYSTEMS

Gastrointestinal stromal tumors (GISTs)

Introduction

  • M/C mesenchymal tumour of the gastrointestinal tract (80%)
  • M/C malignant subepithelial lesions (SELs) of the gastrointestinal tract

History:

What is now known as GIST, used to be called gastrointestinal (GI) smooth muscle tumour: leiomyoma if benign, leiomyosarcoma if malignant, and leiomyoblastoma if with epithelioid histology. Tumours previously classified as gastrointestinal autonomic nerve tumours have also turned out to be GISTs, as have many tumours historically classified as gastrointestinal schwannomas or other nerve sheath tumours.

Electron microscopic studies from the late 1960s and on demonstrated that most of the “GI smooth muscle tumours” differed from typical smooth muscle tumours by their lack of smooth muscle-specific ultrastructure. Immunohistochemically they lacked smooth muscle antigens, especially desmin. As they also lacked Schwann cell features, gastrointestinal stromal tumour was then proposed as a histogenetically non-committal term for these tumours. Kindblom and associates in 1998 found that these tumours actually originate from the interstitial cells of Cajal. Hirota and colleagues discovered that these tumours express CD117 antigen (C-Kit), a gain of function mutation responsible for activating the growth of these tumours. Although GISTs are considered rare tumours, most GISTs are discovered incidentally so the true prevalence is unknown. Traditional chemotherapy and radiation are not effective on GISTs, therefore surgical resection has always been the mainstay of treatment. With the discovery of mutations associated with these tumours, the treatment has changed dramatically. Imatinib mesylate, a selective tyrosine kinase receptor inhibitor (TKI), is used as an adjuvant or neoadjuvant therapy to improve the morbidity and mortality associated with GISTs. Due to growing resistance, sunitinib and regorafenib are effective second-line TKIs.


Pathophysiology

Originate from the interstitial cells of Cajal located within the muscle layer and are characterized by over-expression of the tyrosine kinase receptor KIT.

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Mutations:

  • Tyrosine kinase receptor KIT (75-80%)
  • Platelet-derived growth factor receptor-α (PDGFR-α) (8%)

Morphology:

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A gastric GIST with a nodulular surface and thin capusle. The cut surface reveals coarse granular and solid white tan suface with hemarrhage and cavities | Zhao, X., & Yue, C. (2012). Gastrointestinal stromal tumor. Journal of gastrointestinal oncology, 3(3), 189–208. https://doi.org/10.3978/j.issn.2078-6891.2012.031

Carney triad (CT):

Carney triad (CT), named for J Aidan Carney, is considered to be a specific type of multiple endocrine neoplasia (MEN). The three classically associated tumors are a subset of gastric epithelioid leiomyosarcoma (it is now known that this subset is actually gastrointestinal stromal tumor arising from the interstitial cells of Cajal), pulmonary chondroma, and extra-adrenal paraganglioma. The condition manifests more commonly in females. Multiple tumors in multiple organs in young patients, with occasional sibling involvement, suggested an inherited disorder, but the underlying genetic basis has not been identified.
  • Gastric gastrointestinal stromal tumor (GIST)
  • Pulmonary chondroma
  • Extra-adrenal paraganglioma

Clinical features

  • Asymptomatic (15-30%): Incidental finding
  • Gastrointestinal bleeding (M/C): Acute melena and hematemesis
    • Subsequent anemia, weakness
  • Tumour-induced mass effect: Abdominal pain, distension, and discomfort
  • Subclinical microscopic or mini (< 1 cm) GISTs (35%)

Diagnosis

Immunohistochemistry (IHC):

  • M/C IHC marker: KIT (CD117) (DIAGNOSTIC)
  • M/specific marker: Discovered on gastrointestinal stromal tumor 1 (DOG1)
  • CD34
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Flow chart of diagnosis of gastrointestinal mesenchymal tumors using immunohistochemical or genetic analysis. Solitary fibrous tumors should be ruled out. | GIST: Gastrointestinal stromal tumor. | Nishida T, Blay JY, Hirota S, Kitagawa Y, Kang YK. The standard diagnosis, treatment, and follow-up of gastrointestinal stromal tumors based on guidelines. Gastric Cancer. 2016;19:3–14.

Endoscopic ultrasonography (EUS):

  • Nonspecific smooth bulge covered with normal mucosa
  • GISTs are usually hard and the cushion sign is negative
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Endoscopic images of subepithelial lesions that can be diagnosed only with endoscopic ultrasound findings and their specific endoscopic ultrasonography images. A: Endoscopic image of a gastric lipoma (arrow); B: Endoscopic ultrasound (EUS) image of A (high-echo mass); C: Endoscopic image of a gastric cyst; D: EUS image of C (anechoic mass); E: Endoscopic image of extra-gastric compression due to splenic artery aneurysm; F: EUS image of E [normal gastric wall is compressed by a splenic artery aneurysm(SAA) (arrow). SA: splenic artery]; G: Endoscopic image of gastric varices (arrow); H: EUS image of G [varices are present in the submucosa from the outside of the wall (V) (arrow)]. | Akahoshi K, Inoue K, Oya M, Tamura S, Takaki M, Tatsushima S, Shiratsuchi Y, Kubokawa M, Gibo J, Yodoe K. Endoscopic ultrasonography-guided fine needle aspiration for gastrointestinal lesion. Endoscopia Digestiva. 2016;28:1581–1590.

EUS-guided fine needle aspiration (EUS-FNA):

  • Typical finding of KIT- or CD34-positive spindle-shaped cells or epithelial cells
  • Main morphologic types:
    • Spindle-shaped cell type (70%)
    • Epithelial cell type (20%)
    • Mixed type (10%)
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Endoscopic ultrasound images and corresponding endoscopic ultrasonography-guided fine needle aspiration specimens of hypoechoic solid tumors. A: Endoscopic ultrasound (EUS) image of a gastric gastrointestinal stromal tumor; B: EUS-guided fine needle aspiration (EUS-FNA) specimen tissue image of A (KIT-positive spindle-shaped tumor cells are observed); C: EUS image of gastric leiomyoma; D: EUS-FNA specimen tissue image of C [α-SMA-positive spindle-shaped tumor cells are observed; diagnosis of leiomyoma was made by immunohistochemical analysis, which revealed α-SMA (+), KIT (-), CD34 (-), and S-100 (-)]; E: EUS image of gastric malignant lymphoma; F: EUS-FNA specimen image of E (diagnosis of diffuse large B-cell lymphoma was made by CD20-positive lymphoid tumor cells); G: EUS image of rectal neuroendocrine tumor (NET); H: EUS-FNA specimen image of G (diagnosis of NET was made by typical findings of irregular nest of synaptophysin-positive epithelial-like cells). | Akahoshi K, Inoue K, Oya M, Tamura S, Takaki M, Tatsushima S, Shiratsuchi Y, Kubokawa M, Gibo J, Yodoe K. Endoscopic ultrasonography-guided fine needle aspiration for gastrointestinal lesion. Endoscopia Digestiva. 2016;28:1581–1590.

PET with fluorodeoxyglucose (FDG-PET):

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Gastrointestinal stromal tumors on positron emission tomography with fluorodeoxyglucose. A: Giant gastric GIST on a patient with neurofibromatosis type 1; B: Gastric GIST with an unique liver metastasis. GIST: Gastrointestinal stromal tumor. | Sanchez-Hidalgo, J. M., Duran-Martinez, M., Molero-Payan, R., Rufian-Peña, S., Arjona-Sanchez, A., Casado-Adam, A., Cosano-Alvarez, A., & Briceño-Delgado, J. (2018). Gastrointestinal stromal tumors: A multidisciplinary challenge. World journal of gastroenterology, 24(18), 1925–1941. https://doi.org/10.3748/wjg.v24.i18.1925

Differential diagnosis:

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Differential diagnosis of subepithelial lesions by endoscopic ultrasound. | GIST: Gastrointestinal stromal tumor. | Akahoshi K, Oya M, Motomura Y, Kubokawa M, Itaba S, Osoegawa T, Nakama N, Komori K, Gibo J, Yamada M, et al. Diagnosis of gastric submucosal tumor and submucosal tumor like lesion by endoscopic ultrasonography-guided fine needle aspiration. Endoscopia Digestiva. 2011;23:1530–1536.

Management

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Proposed algorithm for management of subepithelial lesions. | GIST: Gastrointestinal stromal tumor; GI: Gastrointestinal; SEL: Subepithelial lesion; EUS: Endoscopic ultrasound; EUS-FNA: Endoscopic ultrasound-guided fine needle aspiration. | Akahoshi K, Oya M. Gastrointestinal stromal tumor of the stomach: How to manage? World J Gastrointest Endosc. 2010;2:271–277

Surgical resection

For resectable GISTs without metastasis
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Laparoscopic resection of a small gastric gastrointestinal stromal tumor. A: Laparoscopic view of a small gastric gastrointestinal stromal tumor (arrow) during resection; B: Postoperative endoscopy shows mild postoperative deformity (arrow). | Akahoshi K, Oya M, Koga T. Diagnosis and treatment of gastrointestinal stromal tumor (GIST) Endoscopia Digestiva. 2012;24:626–632.

Tyrosine kinase inhibitors:

For unresectable, metastatic, or recurrent GISTs
  • Imatinib or sunitinib/regorafenib

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