The same cells that repair your body from stress can become the source of a rare cancer.
Perched atop our kidneys like tiny triangular caps, the adrenal glands wield power far beyond their modest size. These crucial endocrine organs produce hormones that regulate essential bodily functions—from managing our stress response through cortisol to controlling blood pressure via aldosterone and influencing sexual characteristics with androgens. When adrenal cancer strikes, it disrupts this delicate hormonal balance, often with devastating consequences.
Despite its rarity—affecting only 0.5-2 people per million annually—adrenal cancer presents substantial challenges for patients and clinicians alike 4 . The cancer's heterogeneity means that outcomes vary dramatically between individuals, with some experiencing aggressive disease progression while others live with indolent tumors for years. Recent research has unveiled fascinating new insights into how these cancers begin, not from specialized hormone-producing cells, but from their supporting cast—the very cells tasked with maintenance and repair 1 . This article explores the latest advances in understanding, diagnosing, and treating this complex disease.
0.5-2
per million people annually
For decades, scientists believed that the specialized cells producing adrenaline and noradrenaline in our adrenal glands were the primary suspects in cancer formation. But a groundbreaking 2025 study from Karolinska Institutet revealed a surprising twist: the true origin may lie in the gland's support cells known as sustentacular cells 1 .
These glial-like cells were found to act like stem cells after birth, regenerating hormone-producing tissue—a capacity previously thought to exist only during embryonic development. This regenerative ability, while essential for maintaining healthy tissue, creates a vulnerability where genetic mutations can redirect healing toward cancer formation 1 .
The researchers identified a critical interaction between two proteins—DLK1 and NOTCH—that acts as a cellular switch, determining whether sustentacular cells generate healthy tissue or contribute to tumor formation 1 . This discovery is particularly significant because DLK1 has previously been identified as a target for immunotherapy in neuroblastoma, suggesting potential parallel treatment strategies for adrenal cancers 1 .
"In tumors with germline VHL mutations, subsets of these support cells showed loss of chromosome 3p, the 'second hit' leading to VHL inactivation. This suggests they may be the origin of certain tumors," explains Dr. Michael Mints, co-corresponding author of the study 1 .
Sustentacular cells support and maintain healthy adrenal tissue
These cells demonstrate stem cell-like properties after birth
Mutations in genes like VHL disrupt normal cellular regulation
DLK1-NOTCH interaction malfunctions, leading to tumor formation
Diagnosing adrenal tumors presents unique challenges due to their biological diversity and rarity. The diagnostic journey typically begins when patients present with symptoms or when incidentalomas (unexpectedly discovered adrenal masses) are found during imaging for other conditions.
Adrenal cancer symptoms generally fall into two categories: those caused by tumor growth and those resulting from hormone imbalances 3 .
Modern adrenal tumor diagnosis employs sophisticated laboratory techniques and imaging studies:
now utilizes two parallel approaches:
have revolutionized our understanding of adrenal tumors. Next-generation sequencing (NGS) has revealed that up to 35-40% of pheochromocytoma patients carry genetic variants, far higher than the previously estimated 10-15% 2 . Newly identified genes including CSDE1, H3F3A, MET, MERTK, and IRP1 have expanded our knowledge of the genetic basis of these tumors 2 .
| Tumor Type | Key Genetic Alterations | Clinical Implications |
|---|---|---|
| Pheochromocytoma | CSDE1, H3F3A, MET, MERTK, IRP1 | Up to 40% have germline variants, requiring genetic counseling |
| Aldosterone-producing adenomas | KCNJ5, CACNA1D, ATP1A1, ATP2B3, CACNA1H | 90% of APAs have somatic variants; treatment targeting possible |
| Primary bilateral macronodular adrenal hyperplasia | ARMC5, KDM1A | Enables early detection in relatives; 100% of GIP-responsive cases have KDM1A variants |
| Adrenocortical carcinoma | TP53, BRD9, TERT, CTNNB1, CDK4, FLT4, MDM2 | 50% of advanced cases have potentially targetable alterations |
The treatment landscape for adrenal cancer has evolved significantly from a one-size-fits-all approach to personalized strategies based on tumor characteristics, staging, and genetic markers.
When detected early, complete surgical removal of the tumor offers the best chance for cure 5 . The complexity of surgery depends on tumor size, location, and involvement of surrounding structures. For localized adrenocortical carcinoma, complete resection is the primary goal, while for pheochromocytomas, careful preoperative management is crucial to prevent dangerous blood pressure fluctuations during surgery 2 .
For advanced or metastatic disease, several treatment options exist:
Two novel approaches presented at the 2025 ESMO Sarcoma & Rare Cancers Congress show promise for predicting outcomes:
In metastatic pheochromocytomas and paragangliomas, ctDNA has proven to be a significant prognostic marker. Patients with detectable ctDNA tumor fraction had a 24-month overall survival rate of just 24%, compared to 85% for those without detectable ctDNA 4 .
For adrenocortical carcinoma, the BUCEN system incorporates four easily measurable parameters:
This scoring system effectively stratifies patients by predicted outcomes and treatment responses, with scores of 3 or more associated with significantly shorter survival 4 .
| Parameter | Scoring Criteria | Points |
|---|---|---|
| Tumor Burden | Based on tumor size, local recurrence, and metastases | 0, 1, or 2 |
| Cortisol Excess | Present or absent | 1 if present |
| ECOG Performance Status | 0, 1, or 2-3 | 0, 1, or 2 respectively |
| Neutrophil-to-Lymphocyte Ratio | <5 or ≥5 | 1 if ≥5 |
The groundbreaking discovery that sustentacular cells can initiate adrenal cancer emerged from meticulous research combining multiple advanced techniques. Let's examine the key experiment that revealed this unexpected connection.
The research team employed complementary methods to unravel the complex cellular relationships:
The experiments yielded several crucial findings:
| Research Tool | Function/Application | Research Context |
|---|---|---|
| Single-cell RNA sequencing | Profiles gene expression in individual cells | Identified cellular subtypes and lineages in healthy and tumor tissue |
| Genetic tracing models | Tracks cell lineages and fate over time | Demonstrated postnatal chromaffin cell regeneration from sustentacular cells |
| Immunostaining (SF-1, Ki-67) | Identifies cell types and proliferation markers | Differentiated adrenal cortical cells and measured proliferation rates |
| Plasma ctDNA analysis | Detects tumor DNA fragments in blood | Used as prognostic marker in metastatic pheochromocytoma/paraganglioma |
| LC-MS/MS | Precise hormone measurement | Enabled comprehensive steroid profiling for diagnosis |
The evolving understanding of adrenal cancer biology is paving the way for more targeted and effective treatments. Several promising directions are emerging:
The discovery of the DLK1-NOTCH interaction as a key switch suggests new therapeutic possibilities 1 .
Since DLK1 has been identified as an immunotherapeutic target in neuroblastoma, similar strategies might prove effective for adrenal cancers 1 .
Combining imaging, biochemical profiling, genetic analysis, and liquid biopsies for comprehensive patient-specific profiles.
The landscape of adrenal cancer research and treatment is transforming at an unprecedented pace. What was once a poorly understood rarity is now revealing its secrets, from the surprising origins of tumors in support cells to the genetic switches that determine healing or harm. These discoveries are not just academic exercises—they're paving the way for real clinical advances that offer hope to patients facing this challenging diagnosis.
As research continues to unravel the complexities of adrenal cancer, the medical community moves closer to a future where each patient's treatment is as unique as their tumor, where detection happens earlier, and where therapies are more effective and less toxic. The journey from scientific insight to clinical impact continues, powered by collaborations across institutions and countries that pool knowledge about these rare diseases. For patients and families affected by adrenal cancer, these advances promise a future with more options and better outcomes.