GI Pathology · Soft Tissue Tumours

A high-yield review of GIST pathology, focusing on KIT-negative variants, DOG1 sensitivity, PDGFRA mutations and SDH-deficient diagnostic algorithms for exams.

The diagnosis of gastrointestinal stromal tumour (GIST) has evolved from a purely morphological assessment to a molecular-driven classification. While GIST is the most common mesenchymal tumour of the GI tract, approximately 5–10% of cases are KIT (CD117) negative, requiring advanced IHC markers for identification.

1. What defines the paradigm shift in GIST diagnosis?

Fig 1The “classic” spindle cell morphology associated with the majority of KIT-positive GISTs — fascicles of spindle cells on H&E.

Most GISTs arise from the interstitial cells of Cajal (ICC). When CD117 is negative, pathologists must evaluate DOG1 and SDHB to identify KIT-negative molecular subsets.

2. How does the IHC traffic light system work?

The IHC traffic light system is a diagnostic triage tool used to categorise GIST based on the expression of CD117 and DOG1.

Fig 2A visual guide for triaging GIST cases into KIT-positive, PDGFRA-likely and SDH-deficient categories.

Light	CD117 / DOG1	Interpretation	Next step
Green	KIT+ / DOG1+	Classic GIST	KIT mutation analysis
Yellow	KIT− / DOG1+	Suggests PDGFRA	PDGFRA sequencing (exon 18 D842V)
Red	KIT− / DOG1−	Possible SDH-deficient or non-GIST	SDHB IHC to rule out syndromic associations

3. What are the features of KIT-mutant GIST?

KIT-mutant GIST is the prototype of this tumour class, accounting for roughly 80% of all cases.

Fig 3Histological and IHC profile of the most common GIST subtype.

4. Why is PDGFRA GIST considered the epithelioid outlier?

PDGFRA-mutant GISTs frequently present with an epithelioid morphology and are predominantly located in the stomach.

Fig 4Morphology of the KIT-negative gastric GIST subtype.

5. How to identify paediatric and syndromic SDH-mutant GIST?

SDH-deficient GISTs represent a distinct clinical entity often seen in younger patients and are characterised by a loss of SDHB expression on IHC.

Fig 5IHC showing the absence of SDHB protein expression in tumour cells.

6. Comparative master table: GIST variants

Feature	KIT-mutant	PDGFRA-mutant	SDH-deficient
Frequency	~80%	~10%	~5%
IHC profile	KIT+, DOG1+	KIT−, DOG1+	KIT (var), SDHB lost
Morphology	Spindle (classic)	Epithelioid	Epithelioid
Primary site	Any GI site	Stomach	Stomach
Treatment	Imatinib	Avapritinib (D842V)	Temozolomide / trials

7. What is the diagnostic algorithm for mesenchymal GI masses?

A systematic approach is required to differentiate GIST from other mesenchymal mimics like leiomyomas or schwannomas.

Fig 6Algorithmic approach starting with KIT/DOG1 and progressing to SDHB.

8. Conclusion: the clinical necessity of DOG1

DOG1 (Discovered on GIST-1) has become an essential marker because it remains positive in the majority of KIT-negative PDGFRA cases.

Fig 7DOG1 vs KIT sensitivity — simultaneous testing and interpretation of PDGFRA and SDHB results.

Dual testing (KIT + DOG1) is the clinical gold standard to prevent misdiagnosis of imatinib-resistant PDGFRA variants.

Test yourself

GIST pathology board review: top high-yield MCQs on KIT, PDGFRA and IHC. Choose an answer for each question and submit to see the explanation.

Watch the video review, then see the related post.

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