Your pathology report for SDH-deficient gastrointestinal stromal tumor

by Jason Wasserman MD PhD FRCPC
January 13, 2026

SDH-deficient gastrointestinal stromal tumour is a rare type of gastrointestinal stromal tumour (GIST) that almost always develops in the stomach. Like other GISTs, it arises from specialized cells in the wall of the digestive tract that help regulate gut motility. What makes this tumour different is that it is caused by a problem in a group of proteins called succinate dehydrogenase (SDH), which are important for normal cell metabolism.

This article explains the pathology report for SDH-deficient GIST, including how it is diagnosed, what features pathologists look for, and how these findings relate to prognosis and treatment.

Where does SDH-deficient GIST develop?

Nearly all well-studied SDH-deficient GISTs arise in the stomach. These tumours often grow from the muscle layer of the stomach wall and can push toward either the mucosa (inner lining) or the serosa (outer surface).

Unlike most other GISTs, SDH-deficient GISTs are frequently multifocal, meaning that more than one tumour nodule may be present at the same time.

What are the symptoms of SDH-deficient GIST?

Many patients with SDH-deficient GIST have no symptoms, and the tumour is found incidentally during imaging or endoscopy for another reason.

When symptoms occur, they may include:

• Abdominal pain or discomfort.

• Gastrointestinal bleeding.

• Anemia (low red blood cell count).

• A feeling of fullness.

Although features such as young age, stomach location, multiple tumours, or lymph node involvement can suggest SDH-deficient GIST, patients usually present in the same way as other GIST types.

Who gets SDH-deficient GIST?

SDH-deficient gastrointestinal stromal tumours are uncommon overall, accounting for about 3% of all GISTs and approximately 5–7.5% of GISTs that arise in the stomach. They are, however, the most common type of GIST diagnosed in children and represent the majority of GISTs seen in adolescents and young adults. The median age at diagnosis is around 22 years, which is much younger than for other types of GIST. This tumour also shows a strong female predominance, with women affected about three times more often than men.

What causes SDH-deficient GIST?

Most SDH-deficient GISTs are linked to an underlying problem affecting the succinate dehydrogenase (SDH) complex, a group of proteins that help cells produce energy. In about half of cases, the SDH genes are turned off by a chemical change called hypermethylation of the SDHC gene. This mechanism is characteristic of Carney triad, a non-inherited condition that includes SDH-deficient GIST, paraganglioma, and pulmonary chondroma.

In the remaining cases, SDH-deficient GIST is caused by inherited (germline) mutations in one of the SDH genes, most commonly SDHA, and less often SDHB, SDHC, or SDHD. Because purely tumour-only (non-inherited) SDH gene loss is extremely rare, the diagnosis of SDH-deficient GIST almost always raises concern for an SDH-deficient tumour syndrome, even if there is no known family history.

How does SDH-deficient GIST develop?

The SDH complex is an enzyme system in mitochondria that helps cells produce energy. When any part of this complex does not work properly, a substance called succinate accumulates in the cell.

Excess succinate disrupts normal cellular regulation and induces long-term changes in how genes are turned on and off. Over time, these changes can drive tumour development.

A key consequence of SDH dysfunction is the loss of the SDHB protein, which pathologists can detect using special stains. This loss is a defining feature of SDH-deficient GIST.

How is the diagnosis made?

The diagnosis of SDH-deficient GIST is made by examining tumour tissue under the microscope and performing immunohistochemical staining, a technique that identifies specific proteins within tumour cells.

Microscopic (pathologic) features

When examined under the microscope, SDH-deficient gastrointestinal stromal tumours have several features that help pathologists distinguish them from other types of GIST.

These tumours are most often composed of epithelioid cells, which are rounder with more visible cytoplasm, rather than the long, spindle-shaped cells seen in many other GISTs. The tumour usually grows in a multinodular or plexiform pattern, meaning that it forms multiple connected nodules rather than a single smooth mass. This growth pattern is one reason why SDH-deficient GISTs are frequently multifocal.

The tumour tissue usually contains a rich network of small blood vessels, giving it a highly vascular appearance. The tumour cells may be arranged in vague nests or clusters, sometimes separated by delicate connective tissue. Compared with other GISTs, SDH-deficient tumours often appear more uniform. They may lack obvious aggressive features such as high mitotic activity, even when they later spread to other parts of the body.

Immunohistochemistry

Immunohistochemistry is a laboratory technique that uses special stains to detect specific proteins within tumour cells. This testing plays a central role in diagnosing SDH-deficient GIST.

All SDH-deficient GISTs show loss of SDHB staining by immunohistochemistry, regardless of which SDH gene is affected. This loss appears as an absence of the normal granular staining pattern that reflects mitochondrial localization of the protein. Surrounding non-tumour cells, such as endothelial cells or inflammatory cells, should show strong granular staining and act as internal controls. In some cases, tumour cells may show a weak, diffuse background stain rather than true granular staining, and careful comparison with internal controls is required to avoid misinterpretation.

In addition to SDHB loss, these tumours show strong, diffuse expression of KIT and DOG1, confirming that the tumours belong to the GIST family. This is an essential feature because SDH-deficient GISTs lack KIT or PDGFRA mutations yet still strongly express these proteins. This finding helps distinguish them from other gastric tumours and from some PDGFRA-mutant GISTs, which may show weak or absent KIT expression.

In tumours associated with SDHA mutations, immunohistochemistry also shows loss of SDHA protein expression. In contrast, tumours related to SDHB, SDHC, or SDHD mutations, or with SDHC epimutation, retain SDHA expression.

Molecular testing

Molecular testing examines the DNA and regulatory changes within tumour cells and is important for understanding the cause of SDH-deficient GIST. However, it is not required to establish the diagnosis once SDHB loss has been demonstrated.

Unlike most other GISTs, SDH-deficient GISTs do not have mutations in the KIT or PDGFRA genes. Instead, they are associated with dysfunction of one of the SDH genes (SDHA, SDHB, SDHC, or SDHD) or with epigenetic silencing of SDHC. About half of the cases are caused by SDHC promoter hypermethylation, the molecular hallmark of Carney triad. This non-inherited condition includes SDH-deficient GIST, paraganglioma, and pulmonary chondroma.

The remaining cases are associated with inherited (germline) mutations, most commonly in SDHA, and less frequently in SDHB, SDHC, or SDHD. Because isolated, tumour-only loss of SDH function is sporadic, the diagnosis of SDH-deficient GIST is considered strong evidence of an underlying SDH-deficient tumour syndrome. For this reason, referral for genetic counselling and testing is recommended for all patients, even in the absence of a known family history.

Molecular testing can also help clarify the significance of uncertain genetic findings. For example, SDHA variants are relatively common in the general population and often have low clinical penetrance. In these cases, correlation with immunohistochemistry (showing true SDH deficiency in the tumour) is essential before drawing conclusions about inherited risk.

How is SDH-deficient GIST staged?

SDH-deficient GISTs are staged using the same TNM system as other GISTs. However, it is important to know that tumour size and mitotic rate do not reliably predict outcome in this subtype.

What is the prognosis for a person with SDH-deficient GIST?

The behaviour of SDH-deficient GIST is very different from that of other GISTs. Unlike conventional GISTs, the risk of spread cannot be reliably predicted by tumour size or the number of mitotic figures (dividing tumour cells). Small tumours with very low mitotic activity can still spread to lymph nodes or distant sites, and lymph node involvement is relatively common.

When metastases occur, they often grow slowly and may remain stable for many years. As a result, despite reported metastatic rates of up to 50% within two years and more than 70% within five years, long-term outcomes can still be favourable.

Standard GIST treatments, such as imatinib, are generally ineffective in SDH-deficient GIST. Some patients may benefit from newer targeted therapies or, in selected cases, chemotherapy drugs such as temozolomide. Because these tumours are often syndromic, multifocal, and long-lasting, lifelong surveillance for recurrence and for other SDH-deficient tumours is recommended.

Questions to ask your doctor

• Is my tumour confirmed to be SDH-deficient based on pathology testing?
• Should I be referred for genetic counselling or testing?
• Does this diagnosis affect my family members?
• What type of follow-up or surveillance will I need long-term?
• Which treatments are most appropriate for this specific type of GIST?