Update on Molecular Genetics of Gastrointestinal Stromal Tumors

Abstract

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. The majority are sporadic, solitary tumors that harbor mutually exclusive KIT or PDGFRA gain-of-function mutations. The type of mutation in addition to risk stratification corresponds to the biological behavior of GIST and response to treatment. Up to 85% of pediatric GISTs and 10-15% of adult GISTs are devoid of these (KIT/PDGFRA) mutations and are referred to as wild-type GISTs (wt-GIST). It has been shown that these wt-GISTs are a heterogeneous tumor group with regard to their clinical behavior and molecular profile. Recent advances in molecular pathology helped to further sub-classify the so-called "wt-GISTs". Based on their significant clinical and molecular heterogeneity, wt-GISTs are divided into a syndromic and a non-syndromic (sporadic) subgroup. Recently, the use of succinate dehydrogenase B (SDHB) by immunohistochemistry has been used to stratify GIST into an SDHB-retained and an SDHB-deficient group. In this review, we focus on GIST sub-classification based on clinicopathologic, and molecular findings and discuss the known and yet emerging prognostic and predictive genetic alterations. We also give insights into the limitations of targeted therapy and highlight the mechanisms of secondary resistance.

Keywords: GIST; KIT; NF1; PDGFRA; SDH-competent; SDH-deficient; SDHB; wild-type.

Figure 1

Morphology and immunohistochemical findings in GIST (Gastrointestinal Stroma Tumor). (A) Spindle cell GIST (inset: IHC DOG1+). (B) Epithelioid GIST (inset: IHC DOG1+). (C) Spindle cell GISTs with nuclear palisading, (D) GIST with storiform growth pattern, and (E) GIST with prominent paranuclear vacuolation. (F) Epithelioid GIST with a prominent plasmacytoid morphology. (G) Pleomorphic GIST (inset: IHC KIT+). (H) Dedifferentiated GIST (inset: IHC DOG1− and KIT−). IHC (immunohistochemistry); −(negative); +(positive).

Figure 2

Sub-classification of GISTs into a succinate dehydrogenase (SDH)-competent and an SDH-deficient group by using an SDHB IHC ^#. Legend: CSS: Carney–Stratakis Syndrome; CT: Carney triad; CT *: in some cases, mutations described [9]; wt: wild type. Grey rectangle: DNA- and RNA sequencing in a specialized center.

Figure 3

Graphical representation of KIT and PDGFRA transmembrane tyrosine kinase receptors with frequency and localization/distribution of primary mutations found in sporadic GIST (adapted from [53,54]).

Figure 4

Secondary KIT mutations and predictive response to most frequently used TKIs (IM:imatinib; SU: sunitinib; RE: regorafenib). Adapted from [80].

Figure 5

Diagnostic algorithm in wild-type gastrointestinal stromal tumors (wt-GISTs). Legend: Assoc.: associated; CSS: Carney–Stratakis Syndrome; CT: Carney triad; IHC: immunohistochemistry; PC: pulmonary chondroma; PGL: paraganglioma; SDHB: Succinate dehydrogenase B; wt: wild type; *: rarely reported.

Figure 6

Diagnostic and molecular testing algorithm for GIST. * Our GIST mutation-panel includes following genes: PDGFA, KRAS, NRAS, HRAS, BRAF, KIT (Exon 8,9,10,11,12,13,17,18), PDGFRB (Exon 12,13,14,17,18), TP53 (Exons 4–10), SDHA, SDHB, SDHC, SDHD, NF1, CDKN2A and RB1. ** If available, mutation-panel is performed. TKI: Tyrosin Kinase Inhibitor.

Figure 7

Immunohistochemical staining with pan-TRK antibody in GIST shows diffuse cytoplasmic and membranous expression. (Scale bar shows 0.1 mm).

Figure 8

Morphology and immunohistochemical findings in SDHB-deficient GIST. (A) The gastric tumor with multilobulated/plexiform growth pattern. (B) The tumor is composed of epithelioid cells with a syncytial appearance. (C,D) Immunohistochemically, the tumor shows positivity for KIT and DOG1 (C), while the expression of SDHB is lost (D); the cytoplasmic stain of the endothelial cells shows the positive internal control).