Gastrointestinal stromal tumor (GIST) is the most common sarcoma of the gastrointestinal tract with an annual incidence of ~6,000 cases in the United States ¹,and originates from the autonomous nervous system recapitulating interstitial cell of Cajal differentiation.^2,3

Key Words: Gastrointestinal tract; Cajal cells; paraganglioma; pulmonary chondroma; CD117; DOG-1; CD34; SDHA; SDHB; tyrosine kinase; KIT mutation; PDGFRA mutation; SDH deficiency; targeted therapy

GIST mostly affects middle-aged adults around 60 years of age with a wide age range.⁴ A subset of GISTs with SDH-deficiency predominantly occur in younger adults ⁵, in patients with non-hereditary Carney triad OMIM:604287 ⁶(together with paraganglioma and pulmonary chondroma) and autosomal-dominant Carney-Stratakis syndrome OMIM:606864 (together with paragangliomas) with germ-line SDH subunit mutations.⁶

GISTs mostly present in the stomach (60%) and small intestine (25%), and are less common in the colon, rectum, esophagus, mesentery, and omentum.¹GISTs present as sharply demarcated subserosal tumors. Nearly all SDH-deficient GISTs occur in the stomach ⁷.

GISTs display either spindled (70%), epithelioid (20%) or mixed (10%) cytomorphology ^4,8 (Figure 1A, B). SDH-deficient GISTs are characterized by epithelioid or mixed morphology, and unique multilobular or plexiform architecture.

GISTs are characterized by immunohistochemical expression of KIT in 95% of cases, DOG-1 in 98%, PDGFRA in 80%, CD34 in 70% to 80% of cases and retained expression of SDHB and SDHA (Figure 1C-F), except for succinate dehydrogenase (SDH)-deficient GIST (Figure 1E, F).^4,5,8 The latter are characterized by loss-of-function alterations of the SDH complex, comprised of SDHA, SDHB, SDHC, and SDHD. Inactivation of any of these components leads to loss of SDHB expression, making SDHB immunohistochemistry a useful diagnostic tool (Figure 1E). ⁷  SDHA-mutant GISTs show additional SDHA loss.⁷ (Figure 1F)

Figure 1. GIST histopathologic subtypes and diagnostic markers: Examples of GIST with spindle-cell (A) and epithelioid (B) morphology. Most GISTs show expression of KIT (C) and DOG-1 (D) as well as retained SDHB (E) and SDHA (F) expression. Loss of SDHB expression in tumor cells (E, inset) is characteristic of SDH-deficient GISTs. SDHA-mutant GISTs show additional SHDA loss (F, inset); retained SDHB and SDHA expression In scattered nonneoplastic cells (E inset, F inset) serves as positive control.

Approximately 30% of GISTs are malignant. Risk stratification systems are used to estimate risk of malignant behavior based on histopathologic criteria. The first classification system was introduced by Fletcher et al. in 2002 ⁹, based on tumor size and mitotic rate, and classifies GISTs into very low, low, intermediate, and high-risk categories. Miettinen et al. further modified this system in 2006 ¹⁰  to include anatomic site as additional parameter. The latter classification led to the Armed Forces Institute of Pathology criteria and the National Comprehensive Cancer Network (NCCN) criteria that assess risk of progression in primary GIST ¹¹  (Table 1).

Table 1

National Comprehensive Cancer Network (NCCN) criteria for risk assessment in GIST ¹¹ (after Schaefer et al).⁸

GISTs may recur locally and metastasize to the peritoneum and liver or distant sites at advanced stages. Before the advent of targeted therapies, the prognosis of patients with advanced GISTs was poor, given their lack of response to conventional chemotherapy or radiation. Surgery remains the standard of care for patients with localized GIST. Low-to-intermediate risk GISTs do not require adjuvant treatment, but high-risk GISTs are usually treated with the tyrosine kinase inhibitor (TKI) imatinib (Table 2). Imatinib has revolutionized GIST treatment and extended the median overall survival for patients with metastatic disease from 19 months to 5 years . ¹² While ~80% patients show dramatic initial response, secondary drug resistance eventually develops through selection of resistant subclones and localize to the KIT ATP-binding pocket (KIT exons 13 and 14) or activation loop (KIT exons 17 and 18). In such cases, patients may be eligible to receive sunitinib, regorafenib or ripretinib ^13-15  (Table 2). Avapritinib shows unique activity in advanced GISTs with imatinib-resistant PDGFRA exon 18 D842V mutation, the most frequent type of PDGFRA mutation ¹⁶ (Table 2).

Table 2

TKI sensitivity by GIST molecular subtype .^15-19

*Except for D861V

•    ~85% of GISTs have mutually exclusive KIT or PDGFRA oncogenic mutations⁸ (Figure 2).
•    KIT primary mutations target exon 11 or 9, whereas exon 13 or 17 are involved in only very few cases (Figure 3).
•    PDGFRA primary mutations involve exon 18 (mostly codon 842), and rarely exon 12 or 14.
•    The remaining 15% of GISTs have loss-of-function mutations or epigenetic silencing of NF1 or SDH-complex genes (Figure 2).⁸
•    Additional genomic aberrations required for malignant progression are 14q deletion – leading to inactivation of the tumor suppressor MAX ²⁰ – followed by deletions in 22q, 1p and 15q, together with cell cycle dysregulating events ^8,21-23 , and inactivation of dystrophin, encoded by DMD on Xp21.1.²⁴
•    SDH-deficient GISTs have occasional 1q deletion, presumably targeting SDHC.^6,25

Figure 2. Overview of GIST molecular subtypes (after Schaefer et al. ⁸). SDH: succinate-dehydrogenase.

Figure 3. Next-generation sequencing in a metastatic GIST identifies a primary KIT exon 11 in-frame deletion p.Q556_V559delinsH (A) and secondary KIT exon 17 p.Y823D missense mutation (B).