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PubMed This is a summary of 16 peer-reviewed journal articles Updated
Endocrinology

Staging and Risk: Predicting Your Tumor's Behavior

At a Glance

For adrenal cancer, ENSAT stage shows how far the tumor has spread, while Ki-67, surgical margins, cortisol production, and selected genetic findings help estimate recurrence risk. These factors guide follow-up and treatment discussions but cannot predict one person’s outcome.

Staging and risk stratification are the tools your doctors use to determine how aggressive your cancer is and how likely it is to return after treatment. It is important to remember that these statistics describe groups of people and cannot predict your exact individual outcome.

Staging Adrenocortical Carcinoma (ACC)

The most common way to stage ACC is the ENSAT system (European Network for the Study of Adrenal Tumors). This system groups patients into four stages based on where the cancer is located [1][2]:

  • Stage I: The tumor is 5 centimeters (about 2 inches) or smaller and is contained entirely within the adrenal gland [1].
  • Stage II: The tumor is larger than 5 centimeters but is still contained within the adrenal gland [1].
  • Stage III: The cancer has begun to spread to nearby tissues, such as the fat around the kidney, or into nearby lymph nodes or major blood vessels [1][2].
  • Stage IV: The cancer has spread (metastasized) to distant parts of the body, such as the lungs, liver, or bones [2].

While staging describes where the cancer is, risk stratification looks at the biology of the tumor to predict how it might behave in the future.

The Ki-67 Index: Your Tumor’s “Speedometer”

In localized ACC (Stages I–III), the Ki-67 index is considered a vital predictor of whether the cancer will return [3][4]. This percentage tells your doctors how many cells are actively dividing.

  • Low Risk (Ki-67 < 10%): These tumors generally grow more slowly and have a better long-term outlook [3].
  • Intermediate Risk (Ki-67 10–19%): These tumors have a moderate growth rate [3].
  • High Risk (Ki-67 ≥ 20%): These tumors are dividing rapidly and require intensive monitoring [3][5].

Resection Margins: Was it All Removed?

After surgery, a pathologist examines the edges of the removed tissue to see if any cancer cells were left behind. This is called the resection margin [6].

  • R0 (Complete Resection): No cancer cells are visible at the margins under a microscope. This offers the best chance of a cure [6][7].
  • R1 (Microscopic Residual): The surgeon removed everything they could see, but the pathologist found cancer cells at the very edge of the tissue under a microscope [6][7].
  • R2 (Macroscopic Residual): Some tumor tissue was intentionally or unintentionally left behind [6].

Having an R1 or R2 margin significantly increases the risk that the cancer will come back. This finding often prompts your multidisciplinary team to discuss additional treatments like mitotane, radiation, or closer surveillance [8][4]. Adjuvant treatment is a highly individualized decision, not an automatic rule.

Hormones and Molecular Profiles in ACC

Two other factors can help fine-tune your risk assessment:

  • Hormone Production: Tumors that secrete excess cortisol are associated with higher-risk disease and a greater chance of complications [9][10].
  • Molecular Profiling: Scientists can look at the “genetic signature” of a tumor, including its DNA methylation [11][12]. Certain methylation patterns (like the “CIMP-high” profile) are linked to a higher risk of the cancer spreading [13]. While promising, this is primarily a research classification and does not currently dictate routine treatment decisions for most patients.

Staging and Risk in PPGL

Risk assessment for Pheochromocytoma and Paraganglioma (PPGL) is different. While the AJCC has staging systems for some specific PPGL sites, there is no single universally adopted system comparable to ENSAT.

Instead, clinicians combine multiple factors to assess risk. All PPGLs have the potential to spread (metastasize), but not all of them will. Metastatic PPGL is generally defined by spread to tissues where chromaffin cells do not normally exist (like bones or the liver) [14]. Risk is assessed by looking at the size of the tumor, its location (tumors outside the adrenal gland are often higher risk), its biochemical phenotype, and whether you carry a specific genetic mutation, such as SDHB [15][16].

Common questions in this guide

How is adrenocortical carcinoma staged?
ACC is commonly staged with the ENSAT system, which uses tumor size and spread. Stage I tumors are 5 cm or smaller and confined to the adrenal gland, while Stage II tumors are larger than 5 cm but still confined there. Stage III involves nearby tissues, lymph nodes, or major blood vessels, while Stage IV has spread to distant organs such as the lungs, liver, or bones.
What does my Ki-67 result mean?
Ki-67 estimates the percentage of tumor cells actively dividing in localized ACC. A result below 10% is generally lower risk, 10–19% is intermediate risk, and 20% or higher is higher risk; high values often lead to more intensive monitoring. Ki-67 describes patterns seen in groups of patients and cannot determine one person’s exact outcome.
What do R0, R1, and R2 mean after adrenal cancer surgery?
R0 means no cancer cells are seen at the edge of the removed tissue under a microscope. R1 means cancer cells remain at the edge microscopically, and R2 means visible tumor tissue remains. R1 or R2 findings increase recurrence risk and may lead the care team to discuss mitotane, radiation, or closer surveillance.
Can cortisol production change adrenal cancer risk?
Yes. ACCs that produce excess cortisol are associated with higher-risk disease and a greater chance of complications. Your care team may use hormone test results when planning treatment and monitoring.
How do doctors assess risk in pheochromocytoma and paraganglioma?
PPGL does not have one universally used staging system equivalent to ENSAT. Doctors combine tumor size, location, biochemical phenotype, and genetic findings such as an SDHB mutation. All PPGLs can metastasize, but not all will; spread to areas such as bone or liver is generally considered metastatic because those tissues do not normally contain chromaffin cells.
Can my stage or risk score predict exactly what will happen?
No. Stage and risk factors estimate how a cancer may behave by comparing your findings with patterns seen in groups of patients. They help guide treatment and follow-up discussions, but they cannot predict an individual outcome with certainty.

Questions to Ask Your Doctor

Curated prompts to bring to your next appointment.

  1. 1.What is my ENSAT stage, and does it involve any nearby organs or lymph nodes?
  2. 2.What was my Ki-67 index? Based on that number, do you consider me at low, intermediate, or high risk for recurrence?
  3. 3.Was my surgery an R0 resection? If not, how does the presence of microscopic residual cells change my follow-up plan?
  4. 4.Does my tumor's hormone production, especially cortisol, impact how we should monitor for recurrence?
  5. 5.If I have a PPGL, what specific risk factors (like size, location, or genetics) are we using to determine my follow-up plan?

Questions For You

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References

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This page is for informational purposes only and does not constitute medical advice. Your oncology team should interpret your adrenal cancer results and recommend follow-up for your specific situation.

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