Pheochromocytoma: Understanding Your Pathology Report

Section Editor: Jason Wasserman MD PhD FRCPC
May 29, 2026

Pheochromocytoma is a neuroendocrine tumor that starts in the adrenal medulla, the inner part of the adrenal gland. There are two adrenal glands in the body, one on top of each kidney. The adrenal medulla normally produces hormones called catecholamines, including adrenaline (epinephrine) and noradrenaline (norepinephrine), which help control blood pressure, heart rate, and the body’s response to stress. Many pheochromocytomas continue to produce catecholamines, which is why they often cause episodes of high blood pressure, fast heartbeat, and other symptoms.

The current World Health Organization (WHO) classification of endocrine and neuroendocrine tumors, published in 2022, no longer divides pheochromocytomas into “benign” and “malignant” categories. Instead, all pheochromocytomas are considered to have some risk of spreading to other parts of the body. The challenge for the pathologist is to estimate that risk based on the appearance of the tumor under the microscope and on additional tests. About 5 to 15 percent of pheochromocytomas eventually spread, and recurrence can occur many years after the original surgery, so long-term follow-up is recommended for everyone with this diagnosis.

This article will help you understand the findings in your pathology report, what each term means, and why those findings matter for your care.

Where does pheochromocytoma start?

Pheochromocytoma starts in the adrenal medulla. Tumors that look similar but arise outside the adrenal gland are called paragangliomas. Pheochromocytomas and paragangliomas are closely related and are often grouped together in scoring systems, risk assessments, and research studies. They are sometimes referred to jointly as PPGLs (pheochromocytomas and paragangliomas). The two are distinguished only by location.

What causes pheochromocytoma?

Pheochromocytoma has the strongest inherited component of any common adult cancer. About 30 to 40 percent of patients with pheochromocytoma carry an inherited (germline) genetic change. Because the chance of an inherited cause is so high, current guidelines recommend that all patients with pheochromocytoma be offered genetic counseling and testing, even when there is no known family history.

The inherited syndromes most often linked to pheochromocytoma include:

Multiple endocrine neoplasia type 2 (MEN2A and MEN2B) — Caused by inherited changes in the RET gene. People with MEN2 often develop pheochromocytoma along with medullary thyroid carcinoma and (in MEN2A) parathyroid tumors.
Von Hippel-Lindau (VHL) syndrome — Caused by inherited changes in the VHL gene. People with VHL syndrome can develop pheochromocytoma along with hemangioblastomas of the brain and retina, kidney cancer, and tumors of the pancreas and inner ear.
Neurofibromatosis type 1 (NF1) — Caused by inherited changes in the NF1 gene. Pheochromocytoma occurs in a small percentage of people with NF1.
Hereditary paraganglioma-pheochromocytoma syndromes — Caused by inherited changes in one of the succinate dehydrogenase genes (SDHA, SDHB, SDHC, SDHD, and SDHAF2). These genes make parts of an enzyme complex called succinate dehydrogenase, which helps cells produce energy. Tumors linked to SDHB have the highest risk of spreading to other parts of the body.
Other rarer hereditary causes — Including changes in the TMEM127, MAX, and FH genes.

The remaining 60 to 70 percent of pheochromocytomas are described as sporadic, meaning they appear without a known trigger. Sporadic tumors can still have mutations in some of the same genes listed above, but the changes are found only in the tumor cells and not in the rest of the body, so they cannot be passed on to children.

What are the symptoms of pheochromocytoma?

Symptoms come from the excess catecholamines that the tumor releases into the bloodstream. The classic pattern is sudden episodes (called spells) of:

High blood pressure, which may come and go.
Pounding or racing heartbeat (palpitations).
Headache.
Sweating.
Trembling.
Anxiety or a feeling of panic.
Pale skin.
Chest pain or shortness of breath.

Spells can be triggered by stress, exercise, certain foods or medications, or surgery. Between spells, the symptoms may settle and blood pressure may return to normal. Some patients have continuously high blood pressure rather than episodes.

A growing number of pheochromocytomas are discovered by chance on an imaging test performed for an unrelated reason (an incidental finding). These tumors may cause only mild symptoms or none at all even though hormone testing is often abnormal. Other pheochromocytomas are found during screening of people known to carry an inherited genetic change in one of the genes listed above.

Rarely, pheochromocytomas produce hormones other than catecholamines and can cause unusual syndromes, such as Cushing syndrome (from cortisol-related hormones) or severe diarrhea (from a hormone called vasoactive intestinal peptide).

How is the diagnosis made?

The diagnosis of pheochromocytoma is made by combining clinical history, blood and urine tests, imaging, and pathology. Blood or urine tests measure breakdown products of catecholamines called metanephrines. Metanephrines are produced within the tumor itself and are more reliable markers than catecholamines, which fluctuate from minute to minute. Common tests include plasma-free metanephrines and 24-hour fractionated urine metanephrines. An additional marker, 3-methoxytyramine, is measured in some cases.

Imaging tests, most often CT and MRI of the abdomen, are used to locate the tumor and to look for spread. MRI is often preferred in children to avoid radiation exposure. Specialized nuclear medicine scans, such as MIBG scintigraphy or gallium-68 DOTATATE PET, can detect multiple tumors at once, identify spread, or help plan treatment in selected cases.

Needle biopsy of an adrenal mass is generally avoided when pheochromocytoma is suspected. Sampling a pheochromocytoma can release a surge of catecholamines into the bloodstream, causing a dangerous spike in blood pressure. The diagnosis is therefore made after the tumor is surgically removed and examined under the microscope by a pathologist.

Under the microscope, pheochromocytoma usually shows a characteristic growth pattern called Zellballen, in which nests of tumor cells are surrounded by a delicate network of small blood vessels. The tumor cells have granular cytoplasm and nuclei with a fine “salt-and-pepper” appearance. The microscopic appearance alone does not reliably predict how the tumor will behave, so pathologists also apply structured scoring systems (PASS and GAPP, described in the next sections) and special tests, including immunohistochemistry.

Immunohistochemistry uses antibodies to detect specific proteins in tissue. Pheochromocytomas typically express neuroendocrine markers, including chromogranin A, synaptophysin, and INSM1, and they do not express cytokeratins, which helps distinguish them from adrenal cortical tumors. Special stains such as S100 or SOX10 may highlight the supporting sustentacular cells around the tumor nests. A stain called SDHB is particularly important and is discussed in the biomarker section below.

PASS score (Pheochromocytoma of the Adrenal Gland Scaled Score)

The PASS score is a system that pathologists use to estimate the risk that a pheochromocytoma will spread to other parts of the body. Because pheochromocytomas cannot be reliably classified as “benign” or “malignant” based on appearance alone, the PASS score helps identify tumors that may behave more aggressively.

The pathologist examines the tumor for the following microscopic features. Each feature contributes one or two points, and the points are added together to give a total score:

Invasion into surrounding fat — Tumor cells have grown beyond the adrenal gland into the nearby fat (2 points).
Vascular invasion — Tumor cells are seen inside blood vessels (1 point).
Capsular invasion — Tumor cells have grown into or through the fibrous capsule around the tumor (1 point).
Large nests or diffuse growth — Tumor cells grow in large sheets rather than the typical small rounded nests (2 points).
Necrosis — Areas of tumor cell death (2 points).
High cellularity — Tumor cells are densely packed together (2 points).
Cellular monotony — Tumor cells all look very similar to one another (2 points).
Spindle-shaped tumor cells — The cells are elongated rather than round (2 points).
Increased mitotic activity — More than 3 dividing cells in 10 high-power microscope fields (2 points).
Atypical mitotic figures — Dividing cells with an abnormal shape or pattern (2 points).
Marked nuclear variation — Tumor cell nuclei vary widely in size and shape (1 point).
Hyperchromatic nuclei — Tumor cell nuclei appear very dark because they contain extra genetic material (1 point).

In general, a PASS score of 3 or less suggests the tumor is likely to behave in a non-aggressive manner and may be cured by surgery alone. A PASS score of 4 or higher suggests a higher risk of aggressive behavior, including spread to other parts of the body.

The PASS score is not used alone. It is interpreted together with the GAPP score, tumor size, SDHB results, genetic testing findings, and imaging. This combined approach provides a more accurate risk assessment. The PASS score also has known limitations: different pathologists may score the same tumor slightly differently, and some inherited tumors (especially those related to MEN2) can have a high PASS score but still behave in a non-aggressive way.

GAPP score (Grading of Adrenal Pheochromocytoma and Paraganglioma)

The GAPP score is a newer system that some pathology teams use alongside or instead of PASS. It combines microscopic features with the type of hormone produced by the tumor and with the Ki-67 proliferation index (a measure of how many tumor cells are actively dividing).

The GAPP score is based on six features, with a maximum total of 10 points:

Growth pattern — Zellballen (typical nested) pattern = 0 points; large or irregular nests = 1 point; pseudorosettes (small ring-like structures of cells) = 1 point.
Cellularity — Low = 0 points; moderate = 1 point; high = 2 points.
Comedo-type necrosis — Areas of tumor cell death surrounded by living tumor cells. Absent = 0 points; present = 2 points.
Capsular or vascular invasion — Absent = 0 points; present = 1 point.
Ki-67 labeling index — Less than 1 percent = 0 points; 1 to 3 percent = 1 point; greater than 3 percent = 2 points.
Catecholamine type — Adrenergic (producing adrenaline) or non-functional = 0 points; noradrenergic (producing noradrenaline) = 1 point.

Based on the total score, the tumor is classified into one of three categories:

Well-differentiated (0 to 2 points) — Lowest risk of metastasis; reported 5-year survival close to 100 percent in the original study.
Moderately differentiated (3 to 6 points) — Intermediate risk; reported 5-year survival around 65 to 70 percent.
Poorly differentiated (7 to 10 points) — Highest risk; reported 5-year survival around 20 to 25 percent.

Like the PASS score, the GAPP score is not used alone. The treatment team considers it together with the other findings on the pathology report and with the results of genetic testing. Loss of SDHB staining (described in the biomarker section) is sometimes added to the GAPP score to create a modified GAPP score, which improves the accuracy of risk estimates in patients with hereditary tumors.

Capsular and vascular invasion

Capsular invasion means that tumor cells are growing into or through the fibrous capsule that surrounds the tumor. Vascular invasion means that tumor cells are seen inside a blood vessel. Both findings are part of the PASS and GAPP scoring systems and are recorded separately on the pathology report.

Vascular invasion is the more important of the two because blood vessels can carry tumor cells to distant organs such as the lungs, liver, or bones. The pathologist is careful to distinguish true vascular invasion (tumor cells fixed inside a vessel and attached to the wall or mixed with blood clot material) from an artifact, in which tumor cells appear to be inside a vessel only because they were displaced during tissue handling.

Surgical margins

A margin is the cut edge of the tissue removed at surgery. The pathologist examines the margins to see whether the tumor was completely removed. For pheochromocytoma, the standard surgical approach is to remove the involved adrenal gland together with its surrounding capsule and fat in one piece.

Negative margin — No tumor cells are seen at the cut edge. This suggests the tumor was completely removed.
Positive margin — Tumor cells reach the cut edge. A positive margin indicates that some tumor may have been left behind and is linked to a higher risk of local recurrence. Additional surgery may be considered when feasible.
Capsular rupture during surgery — If the surface of the tumor was disrupted during the operation, tumor cells may have spilled into the surgical bed, even when the formal margin is negative. This is associated with a higher risk of local recurrence.

Lymph nodes

Lymph nodes are small bean-shaped structures throughout the body that filter fluid and house immune cells. The lymph nodes that drain the adrenal gland are located around the major blood vessels behind the abdominal organs. Routine removal of all nearby lymph nodes is not standard for every patient with pheochromocytoma, but the surgeon may remove suspicious lymph nodes when the tumor is large or when imaging suggests involvement. The pathology report will state how many lymph nodes were examined and how many contained tumor cells. Lymph node involvement is uncommon at the time of diagnosis but is associated with a higher pathologic stage and a higher risk of further spread.

Biomarker and molecular testing

Biomarker testing is an important part of the pheochromocytoma workup. The tests below help confirm the diagnosis, identify inherited causes, and estimate the risk of recurrence.

SDHB immunohistochemistry

Succinate dehydrogenase (SDH) is an enzyme complex inside cells that helps produce energy. It has four parts: SDHA, SDHB, SDHC, and SDHD. The pathologist uses immunohistochemistry to look for the SDHB protein in tumor cells. The result is described in one of two ways:

Retained (preserved) SDHB expression — Tumor cells show granular brown staining, similar to surrounding non-tumor cells. This pattern makes a hereditary SDH-related tumor less likely.
Loss of SDHB expression — Tumor cells do not stain for SDHB, while normal cells in the background still do. This pattern strongly suggests an SDH-deficient tumor.

Loss of SDHB staining is important because it:

Raises concern for an inherited change in one of the SDH genes (most often SDHB, but also SDHA, SDHC, SDHD, or SDHAF2), even when there is no family history.
Is associated with a higher lifetime risk of metastasis, especially in tumors linked to SDHB.
Triggers a recommendation for genetic counseling, germline (blood) testing, and long-term follow-up for the patient and (if applicable) for family members.

Ki-67 proliferation index

Ki-67 is a protein found only in cells that are actively dividing. The pathologist quantifies the percentage of tumor cells staining positive for Ki-67 in the most active area (the hot spot). The result is reported as a percentage. Most pheochromocytomas have a Ki-67 index below 3 percent. A higher Ki-67 index is a component of the GAPP score and is associated with a higher risk of recurrence and spread.

Genetic testing

Genetic testing is recommended for all patients with pheochromocytoma. Testing is usually arranged through a genetic counselor and involves a blood test that assesses the genes most commonly associated with pheochromocytoma (RET, VHL, NF1, SDHA, SDHB, SDHC, SDHD, SDHAF2, TMEM127, MAX, FH, and others). Results may show an inherited change, a tumor-only change, or no detectable change. An inherited change confirms a hereditary syndrome and prompts:

Screening of other family members who may carry the same change.
Long-term surveillance for other tumors associated with the syndrome.
More intensive follow-up of the patient for new pheochromocytomas, paragangliomas, or distant spread.

For more information on biomarker testing in cancer, please visit our Biomarkers section.

Pathologic stage (pTNM)

Pheochromocytomas are staged using the American Joint Committee on Cancer (AJCC) Cancer Staging Manual, currently in its 8th edition. The system has three parts: tumor (pT), nodal (pN), and metastasis (pM). The M category (whether the cancer has spread to distant organs) is determined by imaging rather than by pathology.

Tumor stage (pT)

pT1 — Pheochromocytoma less than 5 centimeters in greatest dimension, with no spread outside the adrenal gland.
pT2 — Pheochromocytoma 5 centimeters or larger, with no spread outside the adrenal gland.
pT3 — Tumor of any size with invasion into surrounding tissues or organs (for example, the kidney, liver, pancreas, or spleen, or the fat around the adrenal gland).

Nodal stage (pN)

pN0 — No tumor cells in any regional lymph nodes examined.
pN1 — Tumor cells are present in one or more regional lymph nodes (around the aorta and behind the abdominal organs).

Stage grouping

Stage I — pT1, pN0, M0. Tumor less than 5 cm, confined to the adrenal gland, no nodal or distant spread.
Stage II — pT2, pN0, M0. Tumor 5 cm or larger, confined to the adrenal gland, no nodal or distant spread.
Stage III — Tumor of any size with either local extension (pT3) OR regional lymph node involvement (pN1), without distant spread.
Stage IV — Distant spread (M1), regardless of the pT or pN category.

Can pheochromocytoma spread?

Yes. Although the appearance of the tumor under the microscope cannot reliably tell which tumors will spread, all pheochromocytomas are considered to have some risk of metastasis. This shift in thinking is reflected in the 2022 WHO classification, which moved away from the older labels “benign pheochromocytoma” and “malignant pheochromocytoma.”

Spread (metastasis) is diagnosed when tumor cells are found in places where adrenal medulla tissue does not normally occur, such as lymph nodes outside the abdomen, bones, liver, lungs, or other organs. Reported metastasis rates vary across studies but are generally in the range of 5 to 15 percent. Spread can occur many years (sometimes decades) after the original surgery, which is why long-term follow-up is essential.

What is the prognosis?

Most patients do well after complete surgical removal of the tumor. Overall 5-year survival is approximately 90 percent for tumors that have not spread and approximately 40 to 50 percent for tumors with distant metastasis at the time of diagnosis, although individual outcomes vary widely.

Pathologic and genetic features associated with a higher risk of recurrence or spread include:

Loss of SDHB staining or an inherited SDHB mutation — The strongest single predictor of metastatic disease in pheochromocytoma.
Large tumor size (greater than 5 centimeters) — Linked to higher recurrence and spread rates.
Higher PASS score (4 or greater) — Associated with more aggressive behavior, with the limitations described above.
Higher GAPP score (moderately or poorly differentiated category) — Linked to higher risk of metastasis and lower survival.
High Ki-67 proliferation index — Linked to a higher risk of recurrence.
Invasion into surrounding fat, blood vessels, or adjacent organs — Markers of more aggressive local behavior.
Lymph node involvement or distant metastasis at diagnosis — Indicates more advanced disease and lower survival.
Positive surgical margin or capsular rupture during surgery — Linked to higher risk of local recurrence.

What happens after this diagnosis?

The pathology findings guide the next steps in care rather than dictating a single treatment. After complete staging and recovery from surgery, the treatment team typically considers:

Blood pressure and hormone monitoring — Catecholamines and metanephrines are checked after surgery to confirm that the tumor has been removed and that hormone levels have normalized. These tests are then repeated at regular intervals as part of long-term follow-up.
Imaging surveillance — Repeat CT, MRI, or specialized nuclear medicine scans are used to look for new tumors or evidence of recurrence. The interval depends on tumor size, scoring system results, SDHB status, and genetic findings.
Genetic counseling and testing — Recommended for all patients with pheochromocytoma. The results guide screening for other family members and long-term surveillance for other tumors associated with the inherited syndrome.
Treatment of recurrence or metastatic disease — When the tumor returns or has spread, options can include further surgery (when the disease can be safely removed), targeted radionuclide therapy (such as 131I-MIBG or lutetium-177 DOTATATE), external beam radiation for symptom control, and systemic chemotherapy. Choice of treatment depends on the location of the disease, the patient’s symptoms, and the genetic findings.
Alpha-blockade before any surgery — If new tumors arise or surgery becomes necessary for another reason, patients with active catecholamine production are usually treated with medications called alpha-blockers (and sometimes beta-blockers) for several days before the operation to prevent dangerous swings in blood pressure.
Multidisciplinary care — Endocrine surgery, endocrinology, medical oncology, nuclear medicine, and genetics work together to plan follow-up. Care is often coordinated through a specialized center with experience in pheochromocytoma and paraganglioma.

Questions to ask your doctor

What was the size of my tumor, and was it confined to the adrenal gland?
What was my PASS score, and what does it mean?
Was a GAPP score reported, and what category did my tumor fall into?
What did the SDHB immunohistochemistry test show?
Was capsular or vascular invasion identified?
Was the tumor completely removed, and were the margins clear?
How many lymph nodes were examined, and were any involved by tumor?
What is my pathologic stage (pT, pN, and pM)?
What was the Ki-67 proliferation index?
Should I have genetic testing, and which genes should be tested?
If I have an inherited cause, what other tumors am I at risk for, and how will I be screened?
Should my family members be offered genetic counseling and testing?
How often will I need follow-up blood tests and imaging, and for how long?
Would referral to a specialized center experienced in pheochromocytoma and paraganglioma help guide my care?