Your pathology report for pheochromocytoma

by Ashley Flaman MD and Bibianna Purgina MD FRCPC
January 18, 2026

Pheochromocytoma is a neuroendocrine tumour that starts in the adrenal medulla, the inner part of the adrenal gland. The adrenal glands sit on top of the kidneys and make hormones that help control blood pressure, heart rate, and the body’s response to stress. Many pheochromocytomas produce hormones called catecholamines (such as adrenaline and noradrenaline), which is why they can cause episodes of high blood pressure and other symptoms.

This article explains the pathology report for pheochromocytoma, including how it is diagnosed, what features pathologists look for, and how these findings relate to prognosis and long-term follow-up.

Where does pheochromocytoma start?

Pheochromocytoma starts in the adrenal gland, specifically in the adrenal medulla. Tumours that look similar but arise outside the adrenal gland are called paragangliomas and are covered in a separate article.

What are the symptoms of pheochromocytoma?

Some pheochromocytomas cause symptoms because they release excess catecholamines. Symptoms can include high blood pressure (which may come and go), headaches, palpitations, sweating, tremor, and anxiety or panic-like episodes. Some people experience these symptoms as short “spells” that come and go.

Many pheochromocytomas are now found incidentally on imaging studies done for other reasons, or during screening for inherited genetic conditions. In these cases, symptoms may be mild or absent even though hormone testing is often abnormal.

Rarely, pheochromocytomas produce other hormones and can cause unusual syndromes such as Cushing syndrome or severe diarrhea.

What causes pheochromocytoma?

Pheochromocytoma is strongly associated with a type of genetic change called a mutation. A mutation is an alteration in DNA, the instruction manual inside cells. These mutations affect how cells grow, divide, or respond to signals.

Up to 40% of pheochromocytomas are linked to inherited (germline) mutations. Examples include RET, VHL, NF1, SDHA, SDHB, SDHC, SDHD, and other genes because of this high rate of inherited disease, genetic counselling and testing are often recommended, even when there is no known family history.

How is this diagnosis made?

Pheochromocytoma is diagnosed by combining clinical history, hormone (biochemical) testing, imaging, and pathology. Pathology includes examining the tumour under a microscope and performing specialised tests, such as immunohistochemistry. In selected cases, molecular or genetic testing helps guide long-term follow-up and family screening.

Biochemical (hormone) testing

Most patients are tested using blood or urine measurements of catecholamine breakdown products called metanephrines. These tests are often preferred over direct catecholamine measurement because metanephrines are produced within the tumour itself and tend to be more reliable markers.

Testing commonly includes plasma-free metanephrines or 24-hour fractionated urine metanephrines. In some cases, an additional marker, 3-methoxytyramine, is measured.

Imaging

Imaging studies such as CT and MRI help locate the tumour and assess its size. MRI is often preferred in children to avoid radiation exposure. Some pheochromocytomas appear very bright on specific MRI sequences.

Special functional imaging studies may be used to detect multiple tumours, assess tumour spread, or guide therapy in selected cases.

Microscopic features

Under the microscope, pheochromocytoma most often shows a characteristic growth pattern called Zellballen, which means nests of tumour cells surrounded by a delicate network of small blood vessels.

The tumour cells typically have granular cytoplasm and nuclei with a fine “salt-and-pepper” appearance. Some tumours show variation in cell size or shape, and occasional unusual features, such as clear cell or oncocytic change, may be seen. Importantly, the microscopic appearance alone does not reliably predict whether the tumour will spread.

Because some adrenal tumours can look similar, the pathologist may also examine the surrounding adrenal tissue for additional small nodules that can suggest an inherited condition.

Immunohistochemistry

Immunohistochemistry is a laboratory test that uses special stains to detect proteins inside cells. It helps confirm the diagnosis and can provide clues about inherited tumour syndromes.

Pheochromocytomas typically express neuroendocrine markers such as chromogranin, synaptophysin, and INSM1, and they are usually negative for cytokeratins, which helps distinguish them from adrenal cortical tumours. S100 or SOX10 may highlight sustentacular cells (supporting cells) around tumour nests.

Immunohistochemistry for SDHB

In pheochromocytoma, IHC for SDHB is particularly important because it helps identify tumours associated with succinate dehydrogenase (SDH) gene abnormalities, which are linked to inherited tumour syndromes and a higher risk of aggressive behaviour.

SDHB is one part of the SDH enzyme complex, which usually helps cells produce energy. When any part of this complex is dysfunctional, the SDHB protein becomes unstable and is lost from tumour cells. As a result, loss of SDHB staining on immunohistochemistry is a reliable sign that the tumour is SDH-deficient, even if the specific genetic mutation is not yet known.

Pathology reports typically describe SDHB results in one of the following ways:

• Retained (positive) SDHB expression – Tumour cells show normal granular staining, similar to surrounding non-tumour cells. This makes an SDH-related tumour syndrome less likely.

• Loss of SDHB expression – Tumour cells do not stain for SDHB, while normal cells in the background do. This finding suggests an SDH-deficient pheochromocytoma.

Loss of SDHB expression is important because it:

• Raises concern for an inherited SDH gene mutation, even in patients without a family history.

• It is associated with a higher lifetime risk of metastasis, particularly in tumours linked to SDHB mutations.

• Often leads to a recommendation for genetic counselling and germline testing, as well as long-term follow-up for the patient and, if applicable, family members.

Molecular testing

Molecular testing is not required to confirm pheochromocytoma, but genetic testing is commonly recommended because of the strong association with inherited conditions. Results may show an inherited mutation, a tumour-only mutation, or no detectable mutation. These results help guide long-term surveillance and family testing.

PASS score (Pheochromocytoma of the Adrenal Gland Scaled Score)

The PASS score is a system that pathologists may use to estimate how a pheochromocytoma is likely to behave over time. Because pheochromocytomas cannot be reliably classified as “benign” or “malignant” based on appearance alone, the PASS score helps identify tumours that may carry a higher risk of spread.

The score is calculated by examining the tumour under the microscope and assigning points for specific features associated with more aggressive behaviour. These points are added together to give a total PASS score.

In general:

• A PASS score of 3 or less suggests the tumour is likely to behave in a non-aggressive manner and may be cured with surgery alone.

• A PASS score of 4 or higher suggests a higher risk of aggressive behaviour, including spread to other parts of the body.

To determine the PASS score, pathologists look for the following microscopic features:

• Invasion into fat around the adrenal gland – Tumour cells have spread beyond the adrenal gland into nearby fat tissue.

• Increased mitotic activity – More than 3 dividing tumour cells seen in 10 high-power microscope fields.

• Atypical mitotic figures – Abnormal patterns of cell division.

• Necrosis – Areas where tumour cells have died.

• Spindle-shaped tumour cells – Cells are elongated rather than round.

• Cellular monotony – Tumour cells all look very similar to one another.

• Large nests or diffuse growth – Tumour cells grow in large sheets rather than small, rounded groups (zellballen).

• High cellularity – Tumour cells are densely packed together.

• Marked nuclear pleomorphism – Tumour cell nuclei vary significantly in size and shape.

• Capsular invasion – Tumour cells extend through the outer covering of the adrenal gland.

• Vascular invasion – Tumour cells are found inside blood vessels.

• Hyperchromatic nuclei – Tumour cell nuclei appear very dark due to increased genetic material.

Each feature contributes 1 or 2 points, depending on its significance.

It is important to note that the PASS score is not used alone. Doctors interpret it together with:

• Tumour size and spread.

• SDHB immunohistochemistry results.

• Genetic findings.

• Imaging and clinical features.

This combined approach provides a more accurate risk assessment and helps guide follow-up and management.

Can pheochromocytoma spread?

Yes. Spread (metastasis) occurs when tumour cells are found in locations where adrenal medulla tissue does not normally occur, such as lymph nodes, bone, or other organs. Because no single pathology feature reliably predicts spread, all pheochromocytomas are considered to have malignant potential, and long-term follow-up is recommended.

What is the prognosis for a person with pheochromocytoma?

Most patients do well after complete surgical removal of the tumour. However, a small percentage develop metastatic disease, and spread can occur many years after the original diagnosis. Risk depends on multiple factors, including tumour size, invasion, genetic background, and specific molecular findings. Tumours associated with SDHB mutations have the highest metastatic risk.

What happens after the diagnosis?

After diagnosis, most patients are treated with surgery. Blood pressure and hormone levels are monitored closely before and after treatment. Genetic counselling and testing are often recommended. Long-term follow-up typically includes repeat hormone testing and imaging, especially for patients with inherited mutations or higher-risk disease.

Questions to ask your doctor

• Does my tumour produce excess catecholamines?
• Was SDHB testing performed, and what did it show?
• Should I have genetic testing, and should my family members be tested as well?
• What follow-up testing and imaging will I need over time?