SDH-deficient Gastrointestinal Stromal Tumor: Understanding Your Pathology Report

by Jason Wasserman MD PhD FRCPC
April 6, 2026

SDH-deficient gastrointestinal stromal tumor (GIST) is a rare and distinct subtype of gastrointestinal stromal tumor 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 movement. What sets this tumor apart is that it is caused by a problem in a group of proteins called the succinate dehydrogenase (SDH) complex, which plays an important role in how cells produce energy. SDH-deficient GISTs behave differently from conventional GISTs in several important ways — including who they affect, how they spread, and how they respond to treatment.

This article explains the findings in your pathology report for SDH-deficient GIST, including how the diagnosis is made, what each finding means, and how the results guide your care.

Where does SDH-deficient GIST develop?

Nearly all SDH-deficient GISTs arise in the stomach, most commonly in the antrum (lower part of the stomach) or along the greater curvature. Unlike conventional GISTs, which typically form a single, well-defined mass, SDH-deficient GISTs are frequently multifocal — meaning two or more separate tumor nodules may be present at the same time in the same stomach. Your pathology report may describe the tumor as multifocal or multinodular, which is a recognized feature of this subtype rather than evidence of spread.

What are the symptoms?

Many patients with SDH-deficient GIST have no symptoms at all, and the tumor is found incidentally during endoscopy or imaging performed for another reason. When symptoms occur, they may include abdominal pain or discomfort, gastrointestinal bleeding (which may show up as black or tarry stools, or blood in vomit), anemia from chronic bleeding, or a feeling of fullness. These symptoms are similar to those of other stomach tumors.

Who gets SDH-deficient GIST?

SDH-deficient GISTs account for approximately 3% of all GISTs overall but represent about 5–7.5% of GISTs arising in the stomach. They are rare in the general population, but are the most common type of GIST diagnosed in children and adolescents — in fact, nearly all GISTs occurring before adulthood are SDH-deficient. In adults, the median age at diagnosis is around 22 years, far younger than the typical age for conventional GIST. SDH-deficient GIST also shows a strong female predominance, with women affected approximately three times more often than men.

What causes SDH-deficient GIST?

The underlying problem in all SDH-deficient GISTs is dysfunction of the succinate dehydrogenase (SDH) complex — a group of proteins that work together inside cell mitochondria (the cell’s energy-producing structures) to help convert nutrients into usable energy. When the SDH complex stops working properly, a substance called succinate accumulates inside the cell. This buildup disrupts normal gene regulation and, over time, can drive tumor development. The most visible consequence of SDH dysfunction is the loss of the SDHB protein, which pathologists can detect using a special stain.

There are two main ways SDH dysfunction can arise:

• SDHC promoter hypermethylation (epimutation) — In approximately half of cases, the SDHC gene is chemically silenced by a process called hypermethylation. This is an acquired change that occurs in the tumor cells and is not inherited — it is not passed on to family members. This molecular mechanism is characteristic of Carney triad, a non-inherited condition in which SDH-deficient GIST occurs alongside paraganglioma (a type of neuroendocrine tumor) and pulmonary chondroma (a benign lung tumor). Carney triad is rare and predominantly affects young women.
• Inherited (germline) SDH gene mutations — In the remaining cases, SDH-deficient GIST is caused by an inherited mutation in one of the SDH subunit genes — most commonly SDHA, followed by SDHB, SDHC, or SDHD. These mutations are present in every cell of the body from birth, can be inherited, and are associated with Carney-Stratakis syndrome. This inherited condition predisposes to both GIST and paraganglioma.

Because purely tumor-confined (non-inherited) SDH gene loss is extremely rare, a diagnosis of SDH-deficient GIST is considered strong evidence of an underlying SDH syndrome. Genetic counseling and germline testing are recommended for virtually all patients with SDH-deficient GIST, even in the absence of a known family history, because the findings have direct implications for the patient and their relatives.

How is the diagnosis made?

The diagnosis of SDH-deficient GIST is made after tumor tissue is examined under the microscope by a pathologist. The tissue is obtained by biopsy during an endoscopy or endoscopic ultrasound, or at the time of surgical removal. The diagnosis depends on recognizing the characteristic microscopic features and confirming the loss of SDH proteins using special laboratory staining.

Under the microscope, SDH-deficient GISTs have several features that help distinguish them from conventional GISTs:

• The tumor cells are most often epithelioid — round and plump, resembling epithelioid ce,s — rather than the long, thin, spindle-shaped cells more typical of conventional gastric GISTs.
• The tumor grows in a multinodular or plexiform pattern — forming multiple connected nodules that spread throughout the layers of the stomach wall — rather than as a single smooth mass.
• The tumor tissue contains a rich network of small blood vessels, giving it a highly vascular appearance under the microscope.
• Compared to other GISTs, the cells often look more uniform and may show low mitotic activity (few dividing cells), even in cases that later spread to other parts of the body. This is one of the key reasons why standard GIST risk scoring based on mitotic count does not apply to this subtype.

Tumor grade and mitotic count

In conventional GISTs, the mitotic count (the number of tumor cells actively dividing under the microscope) is one of the most important factors for predicting behavior and guiding treatment. In SDH-deficient GIST, this relationship does not hold. Tumors with low mitotic counts can still spread to lymph nodes or distant organs, while tumors with apparently high counts may follow an indolent course. For this reason, while your pathology report will still include the mitotic count, this number cannot be used to predict your individual prognosis in the same way it is used for conventional GIST.

Tumor size

Similarly, tumor size — which is a major predictor of behavior in conventional GISTs — is a less reliable indicator of prognosis in SDH-deficient GIST. Small tumors can spread to lymph nodes or the liver, and large tumors may remain stable for many years. Tumor size is still reported and contributes to pathologic staging (see below), but it should not be interpreted through the lens of standard GIST risk categories.

Tumor rupture

Tumor rupture means the tumor broke open before or during surgery, releasing tumor cells into the abdominal cavity. If tumor rupture is noted in your pathology report, this is an important finding associated with a higher risk of peritoneal spread (spread throughout the lining of the abdomen). Your report will state whether a rupture occurred.

Surgical margins

A margin is the edge of the tissue removed during surgery. The pathologist examines the cut surfaces to determine whether tumor cells are present at the edge of the specimen.

• Negative margin — No tumor cells at the cut edge. This suggests the visible tumor was completely removed.
• Positive margin — Tumor cells are present at the cut edge, raising concern that some tumor remains. This increases the risk of local recurrence.

Because SDH-deficient GISTs are frequently multifocal, a negative margin does not guarantee that no other tumor nodules remain in the stomach: surgical planning and follow-up for this subtype account for the disease’s multifocal nature.

Lymph nodes

In conventional KIT- or PDGFRA-mutant GISTs, spread to lymph nodes is extremely rare. SDH-deficient GISTs are a significant exception. Lymph node involvement is relatively common in SDH-deficient GIST. It does not necessarily indicate a rapidly progressive or fatal disease — some patients with lymph node metastases follow a slow, indolent course over many years. Finding cancer in lymph nodes changes the pathologic nodal stage (pN1) and is an important part of overall staging and treatment planning. Still, its long-term significance depends on the broader clinical picture.

Your report will state the total number of lymph nodes examined and whether any contain tumor cells.

Immunohistochemistry

Immunohistochemistry is a laboratory technique that uses special stains to detect specific proteins within tumor cells. It plays a central role in diagnosing SDH-deficient GIST and distinguishing it from other stomach tumors.

• SDHB — Loss of SDHB protein expression is the defining immunohistochemical finding in all SDH-deficient GISTs, regardless of which SDH gene is affected. It appears as an absence of the normal granular brown staining in tumor cells, while surrounding non-tumor cells (which serve as internal controls) retain their staining. Your report will state that SDHB expression is “lost” or “absent” in the tumor cells.
• SDHA — When an SDHA gene mutation causes the tumor, the SDHA protein is also lost—loss of both SDHB and SDHA points toward an SDHA germline mutation. If only SDHB is lost but SDHA is retained, the cause is more likely an SDHB, SDHC, or SDHD mutation, or SDHC promoter methylation (Carney triad).
• CD117 (KIT) and DOG1 — SDH-deficient GISTs retain strong, diffuse expression of CD117 and DOG1 — the same markers that confirm a tumor belongs to the GIST family — despite having no KIT or PDGFRA mutations. This combination of positive CD117/DOG1 together with absent SDHB is highly characteristic of SDH-deficient GIST.
• CD34 — Usually positive, supporting the GIST diagnosis.

Biomarker and molecular testing

Molecular testing examines the DNA of tumor cells and, in some cases, normal tissue (blood or saliva), to identify the specific genetic or epigenetic change underlying SDH deficiency. While the diagnosis of SDH-deficient GIST can be established by immunohistochemistry alone (SDHB loss), molecular testing provides additional information that is critical for genetic counseling and treatment planning.

Tumor molecular testing

Testing of tumor tissue typically uses next-generation sequencing (NGS) or targeted gene sequencing to identify mutations in the SDH subunit genes (SDHA, SDHB, SDHC, SDHD) and to confirm the absence of KIT and PDGFRA mutations. Finding an SDH gene mutation in the tumor is important, but it does not by itself reveal whether the mutation is inherited or arose only in the tumor cells. For this distinction, germline testing is required.

Testing may also identify SDHC promoter hypermethylation — the molecular hallmark of Carney triad — which, when present, indicates the mutation is non-inherited.

Germline (inherited) testing

Because the vast majority of SDH-deficient GISTs are associated with either an inherited SDH gene mutation or a non-inherited condition (Carney triad), germline genetic testing is recommended for all patients. This is usually done on a blood or saliva sample, rather than on the tumor itself. Results fall into one of three categories:

• Inherited (germline) SDH mutation found — The patient has Carney-Stratakis syndrome. First-degree family members (parents, siblings, children) are at risk of carrying the same mutation and should be offered genetic testing. These individuals have an increased lifetime risk of SDH-deficient GIST and paraganglioma.
• No germline mutation found — The SDH deficiency is likely due to SDHC promoter hypermethylation (Carney triad). This is not inherited and does not significantly increase risk for family members, though the patient remains at risk for other components of Carney triad (paraganglioma, pulmonary chondroma).
• Variant of uncertain significance (VUS) — A gene change is found whose clinical significance is not yet fully known. Correlation with immunohistochemistry results and close follow-up is needed.

For more information about biomarker testing in gastrointestinal tumors, visit our Biomarkers and Molecular Testing section.

Pathologic stage (pTNM)

SDH-deficient GISTs are staged using the same TNM staging system used for conventional GISTs, based on the American Joint Committee on Cancer (AJCC) guidelines. Tumor stage (pT) is based on tumor size, and nodal stage (pN) reflects whether lymph nodes are involved. However, it is essential to understand that this staging system was not designed for SDH-deficient GISTs and does not reliably predict outcome in this subtype. The risk assessment score used for conventional GISTs also does not apply here, because tumor size and mitotic count do not predict behavior in the same way.

Tumor stage (pT)

• pT1 — Tumor is 2 cm or smaller.
• pT2 — Tumor is more than 2 cm but no more than 5 cm.
• pT3 — Tumor is more than 5 cm but no more than 10 cm.
• pT4 — Tumor is more than 10 cm.

Nodal stage (pN)

• pN0 — No tumor cells found in any lymph nodes examined.
• pN1 — Tumor cells found in one or more lymph nodes.
• pNX — No lymph nodes were available for examination.

What is the prognosis for SDH-deficient GIST?

The prognosis for SDH-deficient GIST differs from, and is often more favorable than, what the pathology findings might suggest by conventional standards. Because mitotic count and tumor size are poor predictors of behavior in this subtype, patients and their doctors should avoid applying the risk categories used for conventional GIST to interpret SDH-deficient GIST results.

The most important characteristics of SDH-deficient GIST prognosis are:

• High metastatic potential but often slow progression — Metastatic rates have been reported at up to 50% within two years and over 70% within five years of diagnosis. However, these metastases — most often to the liver and lymph nodes — frequently grow very slowly. Many patients live for a decade or more with stable or slowly progressing disease, even without active treatment.
• Lymph node spread does not equal a poor short-term outlook — Unlike most cancers, finding tumor cells in lymph nodes in SDH-deficient GIST does not necessarily predict rapid decline. Some patients with lymph node involvement remain well for many years.
• Resistance to standard GIST targeted therapy — SDH-deficient GISTs lack the KIT or PDGFRA mutations that targeted drugs like imatinib are designed to block. As a result, these tumors do not respond to the drugs that are highly effective in conventional GIST. When systemic therapy is needed, treatment is individualized and often involves participation in clinical trials.
• Risk of other SDH-related tumors — Patients — especially those with germline SDH mutations — are at risk for developing other SDH-associated tumors over their lifetime, including paraganglioma and pheochromocytoma. Lifelong surveillance for these tumors is an important part of follow-up care.

What happens after diagnosis?

For localized SDH-deficient GIST, the primary treatment is surgical removal of the tumor. Because these tumors do not respond to imatinib, neoadjuvant targeted therapy (drug treatment to shrink the tumor before surgery) is generally not used. When the tumor is multifocal or when complete removal is not feasible, decisions about surgery are made on a case-by-case basis, weighing the extent of disease against surgical risk.

For metastatic disease — most commonly spread to the liver or lymph nodes — the slow growth pattern of SDH-deficient GIST often means that active systemic therapy can be deferred and surveillance continued until progression warrants intervention. When treatment is needed, options may include sunitinib, regorafenib, or other agents explored in clinical trials, though responses are often modest. Clinical trial participation is strongly encouraged for patients with advanced SDH-deficient GIST.

Long-term follow-up is essential for all patients, given the high rate of late recurrence and the risk of other SDH-related tumors. Surveillance typically includes periodic imaging (CT or MRI) and screening for paraganglioma. The specific schedule will be tailored to the individual patient, the SDH gene involved, and the results of germline testing.

Questions to ask your doctor

Your pathology report contains important information that will guide your care. The following questions may help you prepare for your next appointment.

• Is my tumor confirmed to be SDH-deficient based on immunohistochemistry (loss of SDHB staining)?
• Was SDHA also lost on immunohistochemistry, and what does that mean for my genetic testing?
• Was molecular testing of the tumor performed, and were any SDH gene mutations or SDHC methylation identified?
• Should I have germline genetic testing on a blood sample, and will I be referred to a genetics specialist?
• Does this diagnosis affect my family members, and should they be tested?
• Was the tumor completely removed with negative margins?
• Was the tumor multifocal — were there multiple nodules?
• Were any lymph nodes involved, and what does that mean for my prognosis?
• Does the standard GIST risk scoring (based on size and mitotic count) apply to my tumor?
• Am I a candidate for any targeted therapy, or is my tumor resistant to imatinib?
• Are there clinical trials available for SDH-deficient GIST that I should consider?
• What long-term surveillance will I need for this tumor and for other SDH-related tumors, such as paraganglioma?
• How often should I have follow-up imaging, and what type of scans will be used?