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Evaluating an Adrenal Mass When ACC Is Possible

Initial Diagnostic Workflow

Evaluating an adrenal mass when adrenocortical carcinoma (ACC) is possible refers to the initial diagnostic assessment used to distinguish a rare primary adrenal cortical malignancy from the much more common benign adrenal adenoma, hormonally active adrenal disorders, metastatic disease, and nonadrenal mimics.123 In the ACC care pathway, this evaluation precedes decisions about biopsy, operative strategy, staging, and surveillance. Because complete resection offers the main chance of cure for localized ACC, early recognition is important, but overtreatment of benign incidentalomas remains a competing risk.456

The standard diagnostic framework is integrated rather than test-specific. Contemporary reviews and guidelines generally recommend confirming that the lesion is truly adrenal, assessing hormone secretion, and estimating malignant potential with dedicated adrenal imaging, usually beginning with noncontrast CT.789 Findings such as larger size, high unenhanced attenuation, heterogeneity, interval growth, mixed steroid secretion, local invasion, or metastatic spread increase suspicion for ACC, but no single preoperative feature reliably establishes or excludes the diagnosis in all patients.101112

The evidence base is constrained by the rarity of ACC. Most recommendations derive from retrospective incidentaloma cohorts, referral-center surgical series, and expert guidelines rather than prospective comparative trials, while many uncommon presentations are documented only in case reports.131415 A consistent limitation is that imaging alone cannot definitively distinguish ACC from adenoma in indeterminate lesions, and tissue sampling is also imperfect because percutaneous biopsy often cannot reliably separate benign from malignant adrenocortical tumors and may introduce procedural risk.161718

Diagnostic context

Adrenal masses are frequently detected incidentally, whereas ACC is uncommon even in specialist incidentaloma cohorts.1920 For this reason, the diagnostic problem is usually framed around two linked questions: whether the lesion is hormonally active and whether it appears malignant.7821 This framework is well established and clinically reliable as an entry point, but it does not fully classify many indeterminate lesions.

In practice, interpretation depends on combining imaging, endocrine data, symptoms, age, prior malignancy, and lesion growth pattern.1412 The practical implication is that the same radiologic abnormality may prompt surveillance, immediate staging, or expedited surgery depending on overall context rather than morphology alone.

Initial clinical and biochemical evaluation

Routine hormonal assessment is recommended for nearly all newly identified adrenal masses, including lesions found incidentally and lesions without overt endocrine symptoms.222324 Basic testing typically includes evaluation for cortisol excess and biochemical exclusion of pheochromocytoma, with aldosterone-renin testing in patients with hypertension or hypokalemia.2824 When ACC is specifically suspected, additional assessment of androgens, dehydroepiandrosterone sulfate, or steroid precursors may strengthen suspicion because malignant cortical tumors may produce disorganized or mixed steroid patterns.252627

What is reliable is that hormonal testing helps identify clinically important secretory tumors and shapes procedural safety. What is less reliable is using a normal biochemical screen to exclude ACC, because some tumors are nonfunctioning or only partially autonomous.42829 Clinically, negative hormone studies reduce but do not eliminate concern when imaging remains suspicious.

Biochemical testing also helps with differential diagnosis. Hypercortisolism may arise from adrenal ACC, adrenal adenoma, pituitary disease, or ectopic ACTH secretion, and assay interference may occasionally produce misleading endocrine results.303132 Congenital adrenal hyperplasia is another important mimic, especially in patients with bilateral enlargement or androgen excess, although broad genetic screening is not supported for all incidentalomas.333435

One of the most consistent safety principles is that pheochromocytoma should be excluded before biopsy or other puncture-based procedures.363738 This remains true even when imaging appears favorable for adenoma, because imaging overlap is well recognized and rare ACCs may themselves show biochemical overlap with catecholamine-producing tumors.394041

Imaging approach and radiologic risk stratification

After biochemical triage, diagnostic emphasis shifts toward radiologic characterization and staging. Dedicated noncontrast adrenal CT is the usual first-line imaging test when ACC is in the differential diagnosis.529 CT is used to assess lesion size, attenuation, heterogeneity, calcification, necrosis, local invasion, venous extension, and metastatic disease, while MRI is mainly reserved for indeterminate lesions or better definition of vascular, hepatic, or retroperitoneal relationships.14243

Tumor size is among the most reproducible predictors of malignancy risk across retrospective cohorts. Larger lesions are more likely to be malignant, and many historic management thresholds have clustered around 4 to 6 cm.444546 However, size is not diagnostic by itself: small ACCs are reported, and many large adrenal masses prove to be diagnoses other than ACC.471448 The practical implication is that size is useful for risk stratification and surgical discussion, but not as a sole rule-in or rule-out criterion.

Imaging becomes more informative when size is interpreted together with attenuation and morphology. Higher unenhanced attenuation, heterogeneous internal architecture, low washout, interval growth, and evidence of invasion all increase concern for ACC, whereas clearly lipid-rich homogeneous lesions are more often benign.101112 Even so, the reliable conclusion is only probabilistic rather than definitive: no current imaging phenotype fully separates adenoma from ACC across all indeterminate lesions.2321 This is why multidisciplinary review is emphasized for masses that are neither clearly benign nor clearly unresectable.2015

Adjunctive modalities such as MRI, FDG-PET, contrast-enhanced ultrasound, and multimodal prediction models may add information in selected cases.495051 Their most established role is in staging or clarifying indeterminate masses rather than replacing the standard CT-plus-biochemical workflow.527

Differential diagnosis and common pitfalls

Once a lesion appears radiologically suspicious, the main challenge is often distinguishing ACC from clinically important mimics rather than simply separating benign from malignant disease. Relevant alternatives include adrenal metastasis, pheochromocytoma, lymphoma, hemorrhage, cystic lesions, myelolipoma-like tumors, renal masses, and anatomic variants such as adrenohepatic fusion.52535455

The most dependable generalization is that atypical imaging appearances are nonspecific. Case reports show that benign, metastatic, hematologic, and nonadrenal processes may closely resemble ACC, but they do not provide strong estimates of frequency.565758 The clinical implication is that unusual lesions should trigger broader endocrine evaluation, careful review of cancer history, and expert imaging reassessment rather than immediate diagnostic closure.

Adrenal hemorrhage is a particularly important pitfall because it may both mimic and conceal ACC.5960 In hemodynamically stable patients, repeat structured endocrine and cross-sectional evaluation may be more informative than relying on the initial emergency presentation.

Biopsy and tissue diagnosis

These diagnostic uncertainties lead directly to the question of tissue confirmation. Histopathology remains the definitive standard for diagnosing ACC, but routine preoperative adrenal biopsy is generally discouraged when primary ACC is suspected.616227 Across reviews and retrospective studies, biopsy has limited performance for distinguishing adrenal adenoma from well-differentiated ACC, may produce false-negative or nondiagnostic results, and carries risks including bleeding, tumor seeding, and catecholamine crisis if an occult pheochromocytoma is sampled.63641718

This is one of the more consistent conclusions in the literature. The main accepted indication for biopsy is a selective one, usually when metastasis, lymphoma, or another non-ACC process is more likely and histology would change management, after pheochromocytoma has been excluded and after multidisciplinary discussion.65666

Role in management and follow-up

The purpose of the initial evaluation is to direct the patient toward timely surgery, additional staging, surveillance, or an alternate diagnostic pathway.53 Compared with routine incidentaloma care, suspected ACC usually prompts broader endocrine assessment, expedited imaging review, and referral to centers with endocrine, radiologic, and surgical expertise.156

Observational cohorts and modeling studies support conservative management for small, nonfunctioning, clearly benign-appearing lesions, reflecting the low absolute prevalence of ACC among incidentalomas.6768 However, this reassurance is less secure for indeterminate masses, and occasional delayed diagnoses after apparent short-term stability have been reported.6970 The practical implication is that surveillance is most defensible for lesions with convincingly benign features, whereas indeterminate lesions should not be considered low risk solely because of modest size or limited interval stability.

Emerging directions

Recent studies suggest that urine steroid metabolomics, expanded steroid precursor panels, inflammatory blood markers, and machine-learning models may improve preoperative discrimination between ACC and other adrenal masses.71277251 At present, these approaches remain investigational or incompletely standardized. Their main significance is to highlight a persistent gap in current practice: a substantial subset of adrenal masses remains diagnostically indeterminate despite conventional imaging and biochemical testing.

Included Articles

  • PMID 1289268: A case of a large right upper-pole mass showed that standard imaging and angiography may not reliably distinguish adrenal from renal origin. Preserved bilateral uptake on I-131 cholesterol adrenocortical scintigraphy suggested an intact adrenal gland and helped identify the lesion as renal cell carcinoma rather than an adrenal tumor.52
  • PMID 2150809: In incidentally discovered asymptomatic adrenal masses, this review found that imaging and routine hormonal data often could not reliably distinguish adrenocortical carcinoma from benign cortical tumors, particularly in smaller lesions. The authors therefore recommended resection for masses larger than 3 cm and careful follow-up for smaller cortical tumors.16
  • PMID 164276: This series of ectopic ACTH-producing nonadrenal tumors shows that severe hyperadrenocorticism may occur without classical Cushingoid appearance and may even develop later during the disease course, supporting a broad differential when evaluating cortisol excess and helping distinguish ectopic ACTH syndromes from adrenal ACC.30
  • PMID 2996312: In a small CRF stimulation study of Cushing’s syndrome etiologies, both ACC cases had suppressed basal ACTH and little or no ACTH and cortisol response, except for a slight response in one patient after successful mitotane treatment. The authors suggest CRF testing can help distinguish pituitary Cushing’s disease from autonomous cortisol secretion.73
  • PMID 3426447: This retrospective surgical series argues that asymptomatic, nonfunctioning adrenal masses under 6 cm can usually be managed conservatively with interval CT follow-up, because no incidental ACC was found and all ACCs were at least 7 cm or were symptomatic or functional. The article also notes that endocrine evaluation and assessment for metastatic disease should precede decisions about surgery.74
  • PMID 7624763: In a retrospective series of adrenal masses, fine needle biopsy was presented as a diagnostic option mainly for nonfunctioning tumors in patients with a prior cancer history and for incidentalomas measuring 4-6 cm. The study also found that biopsy often could not exclude well-differentiated adrenocortical carcinoma when only adrenal tissue was sampled.63
  • PMID 7867431: In a small incidental adrenal mass series that included one adrenocortical carcinoma, the authors emphasize that evaluation should determine whether the lesion is truly adrenal, whether it is benign or malignant, and whether it is hormonally active. They recommend routine hormonal testing even without overt endocrine symptoms and selective surgery for functional or enlarging larger masses.75
  • PMID 8001691: In six adrenal incidentaloma cases with hypertension and/or diabetes, combined endocrine testing and imaging were used to distinguish adenoma, cyst, myelolipoma, and one functional adrenocortical carcinoma, informing surgical decisions. The report also supports observation rather than resection for stable nonfunctional adenomas 3 cm or smaller and for cysts or myelolipoma.76
  • PMID 8521790: This review of incidentally discovered adrenal masses emphasizes that evaluation should first distinguish benign nonhypersecretory lesions from hypersecretory or malignant tumors using biochemical assessment and imaging. It notes that fine-needle aspiration is invasive and least helpful for separating adrenal adenoma from primary adrenocortical carcinoma.77
  • PMID 8846310: In primary hyperaldosteronism with an adrenal mass, calcification alone does not distinguish aldosterone-producing ACC from adenoma. The report emphasizes integrating endocrine testing, localization studies, imaging, and pathology because no single preoperative feature is definitively diagnostic.78
  • PMID 9059555: In a series of adrenal incidentalomas, evaluation emphasized CT confirmation, endocrine testing for subtle hormonal excess, and selection for surgery based on malignancy risk or hormone production. Most ACCs were larger than 7 cm, but one carcinoma measured 3.2 cm, underscoring that size alone does not exclude malignancy.47
  • PMID 9267279: In a retrospective incidentaloma cohort, adrenocortical carcinoma risk correlated strongly with tumor diameter, and a 5 cm cutoff showed 93% sensitivity and 64% specificity for malignancy among cortical lesions. The study supports surgery for masses larger than 5 cm or for lesions of any size with suspicious imaging features.44
  • PMID 9860225: In adrenal incidentalomas, this surgical series found adrenocortical carcinoma to be uncommon while nonfunctional pheochromocytoma was a more important immediate diagnostic concern. The authors support restrictive surgery, recommend basic hormonal screening including catecholamine testing, and advise against routine fine-needle aspiration.79
  • PMID 10219021: In a retrospective incidentaloma series, ACC accounted for 2 of 33 cases, and the authors emphasize that evaluation should combine endocrine testing with CT or MRI assessment rather than rely on size alone, because small malignant lesions and large non-ACC masses both occurred. Fine-needle aspiration was frequently non-diagnostic.80
  • PMID 10634355: A case of cortisol-secreting ACC showed false-positive 123I-MIBG uptake despite normal catecholamines and no chromaffin cells on histology. The report argues MIBG should not be used routinely to distinguish pheochromocytoma from ACC and should be reserved for cases with clinical or biochemical suspicion of catecholamine excess.81
  • PMID 10724358: This case report highlights congenital adrenal hyperplasia due to 21-hydroxylase deficiency as an important alternative diagnosis in patients with incidentally detected bilateral adrenal masses. Markedly elevated 17-hydroxyprogesterone with dexamethasone suppression supported a nonmalignant endocrine cause and the authors caution that ruling this out may prevent unnecessary carcinoma-directed evaluation or surgery.33
  • PMID 10870039: In surgically selected adrenal incidentalomas, systematic endocrine evaluation identified secretion abnormalities in both adrenocortical carcinomas and in all tested pheochromocytomas, while older age, weight loss, bilateral disease, and lesion size over 60 mm were associated with malignancy. The study also supports careful follow-up rather than immediate surgery for hormonally normal lesions under 30 mm, given a low malignant yield.82
  • PMID 11572033: This review emphasizes that suspected ACC requires combined preoperative biochemical and radiographic assessment to identify functional tumors, exclude pheochromocytoma, and guide timely adrenalectomy. It argues that size alone is insufficient, because some ACCs are smaller than 5 to 6 cm and suspicious imaging features should prompt resection regardless of size.4
  • PMID 11583337: This review of adrenal incidentalomas emphasizes that suspected malignant or hormonally active adrenal masses require combined CT or MRI characterization plus hormonal testing, with surgery recommended for subclinical functional lesions, solitary adrenal metastases, and nonhypersecretory primary tumors measuring 4 cm or larger.83
  • PMID 12478091: This review recommends that all patients with adrenal masses, including incidentalomas, undergo hormonal assessment, with CT as the first imaging study. It also advises surgical removal of solid incidentalomas larger than 5 cm and emphasizes evaluating for pheochromocytoma and vena caval thrombus when clinically relevant.22
  • PMID 12530700: In patients with nonadrenal malignancies and small indeterminate adrenal masses, a short ACTH stimulation test with stimulated 17-hydroxyprogesterone may help distinguish primary adrenal lesions from adrenal metastases when CT or MRI is inconclusive. The test did not separate benign from malignant adrenocortical tumors.84
  • PMID 12943041: This case report frames ACC as a possible diagnosis among adrenal incidentalomas and emphasizes structured initial evaluation using lesion size, imaging appearance, and biochemical testing for hormone excess, including exclusion of pheochromocytoma before intervention or adrenal fine-needle aspiration.85
  • PMID 16118181: This letter highlights an important adrenal mass differential pitfall relevant when ACC is suspected: pheochromocytoma can occasionally show low unenhanced CT attenuation below 10 HU and greater than 60% delayed washout, imaging features that may otherwise suggest adenoma and should not exclude pheochromocytoma in clinically suspicious cases.39
  • PMID 16491828: In a retrospective Korean adrenal incidentaloma series, ACC accounted for 6% of histologically confirmed lesions and tumor size was the main discriminator of malignancy, with a 4.75 cm ROC-derived cutoff. The study recommends endocrine testing for all incidentalomas and adrenalectomy for lesions 5 cm or larger or with adrenocortical hyperfunction.86
  • PMID 16500246: In suspected adrenocortical carcinoma, tumor size meaningfully shifts preoperative malignancy risk for localized adrenal cortical tumors. Compared with a 5% pretest probability, size thresholds of 4 cm, 6 cm, and 8 cm corresponded to approximate posttest malignancy probabilities of 10%, 19%, and 47%, informing surgical planning when invasion or metastases are absent.45
  • PMID 16882496: This review outlines the initial evaluation of suspected ACC as a combined endocrine and imaging workup for any adrenal mass. It emphasizes hormonal testing including catecholamine exclusion, CT as first-line characterization, MRI for local invasion such as IVC involvement, and size or suspicious imaging features that support prompt resection-oriented management.1
  • PMID 17009139: In patients with known or suspected extra-adrenal malignancy, an adrenal mass should not be presumed metastatic without endocrine evaluation. The report emphasizes excluding pheochromocytoma before surgery or adrenal biopsy, because even asymptomatic patients can develop life-threatening intraoperative hypertensive crises.36
  • PMID 17679462: In a prospective series of nonfunctioning adrenal incidentalomas at least 3 cm, MRI outperformed CT for identifying malignancy, and combining MRI with image-guided fine-needle aspiration cytology achieved 100% sensitivity and accuracy in this surgical cohort. The study also found size criteria alone were not reliable for distinguishing benign from malignant adrenal masses.42
  • PMID 18030443: This review outlines the preoperative workup for suspected adrenocortical carcinoma: mandatory hormonal evaluation including exclusion of pheochromocytoma, CT or MRI-based staging, and selective avoidance of biopsy because it often cannot distinguish benign from malignant adrenal tumors and may risk tumor seeding.61
  • PMID 18032908: In a surgical series of adrenal incidentalomas, the authors recommend endocrine testing regardless of lesion size and advise resection for hormonally active masses. For hormonally inactive lesions, they propose surgery once tumor diameter reaches 3 cm, noting that some ACCs in their cohort measured only 3.4 to 5.0 cm.87
  • PMID 18174744: This review frames adrenocortical carcinoma within the work-up of adrenal incidentalomas, emphasizing that every incidentally detected adrenal mass requires assessment for hormone hypersecretion and growth potential. It highlights tumor size as a malignancy clue, with lesions over 6 cm carrying high risk and prompting concern for ACC.88
  • PMID 18490838: This review emphasizes the preoperative challenge of distinguishing ACC from other malignant adrenal tumors, especially primary adrenal lymphoma, and argues that every adrenal mass should undergo endocrine assessment and malignancy evaluation. It also states that fine-needle aspiration should be avoided when ACC is suspected, because early accurate diagnosis is critical to selecting appropriate treatment.89
  • PMID 18552288: This guideline notes that in patients with confirmed primary aldosteronism, adrenal CT is recommended as the initial subtype study and specifically to exclude large adrenal masses that may represent adrenocortical carcinoma. It situates ACC in the differential diagnosis of adrenal lesions discovered during endocrine workup.90
  • PMID 19451490: In a tertiary-center retrospective series, percutaneous adrenal biopsy had limited value for isolated adrenal incidentalomas, with false-negative results including adrenocortical carcinoma and pheochromocytoma. The study supports prioritizing biochemical evaluation and imaging-based risk assessment over biopsy when ACC is a consideration.64
  • PMID 19959148: In a multicenter incidentaloma series, evaluation was directed at excluding hormonally active or malignant adrenal lesions while most masses were ultimately benign. The report outlines real-world use of endocrine testing and CT-based characterization, and notes ongoing controversy about optimal diagnostic and follow-up protocols for nonoperated lesions.13
  • PMID 20625655: This case highlights that congenital adrenal hyperplasia due to 21-hydroxylase deficiency can mimic androgen-secreting ACC in a patient with a large adrenal mass and hyperandrogenism. The authors recommend ruling out CAH in incidentally detected adrenal masses to avoid unnecessary surgery when benign myelolipoma is the true diagnosis.34
  • PMID 21210792: In the evaluation of an adrenal incidentaloma, ACC is an uncommon but high-mortality diagnosis that should be actively considered alongside pheochromocytoma, aldosteronism, metastasis, and benign adenoma. The review emphasizes assessment for malignancy and hormone excess, with lesion size and radiologic characteristics as the main predictors of malignant potential.19
  • PMID 21632813: This review frames adrenal incidentaloma assessment around two key questions relevant to possible ACC: whether the lesion is malignant and whether it is hormonally active. It recommends CT-based characterization, routine hormonal testing including pheochromocytoma exclusion, and surgical consideration for lesions with suspicious imaging features or size greater than 4 cm without benign characteristics.7
  • PMID 21667434: In a prospective referral-center cohort of 116 adrenal masses, contrast-enhanced ultrasound showed excellent sensitivity but only moderate specificity for detecting adrenal malignancy, supporting its use as an adjunct rather than a standalone test. The study situates CEUS within multimodal work-up alongside CT or MRI and hormonal evaluation, with biopsy or adrenalectomy reserved for suspicious lesions.49
  • PMID 21831516: This review outlines the initial ACC workup as coordinated endocrine testing and staging imaging before intervention. It emphasizes excluding pheochromocytoma prior to invasive procedures, avoiding routine biopsy for isolated adrenal masses, and reserving biopsy for selected metastatic or alternate-primary scenarios after endocrine evaluation.37
  • PMID 22473597: This review outlines the preoperative workup when ACC is suspected: mandatory endocrine assessment with cortisol testing and DHEAS, cross-sectional imaging to assess malignancy risk and resectability, selective adjunctive PET-based imaging, and caution that adrenal biopsy has limited sensitivity for primary ACC and requires pheochromocytoma exclusion first.25
  • PMID 23363322: This case report describes diagnosis of adrenocortical carcinoma by endosonography-guided fine-needle aspiration of an inferior vena cava tumor thrombus arising from a right adrenal mass with caval invasion. It highlights a rare tissue-acquisition approach when direct right adrenal visualization is difficult on EUS.91
  • PMID 24279337: In a multicenter surgical series of adrenal incidentalomas, guideline-concordant preoperative biochemical and imaging workup identified most ACCs and pheochromocytomas, while understudied patients had more unnecessary adrenalectomies and a higher conversion-to-open rate. Increasing incidentaloma size, especially above 6 cm, was associated with ACC risk, but occasional small or benign-appearing ACCs occurred.14
  • PMID 24485291: These guideline recommendations emphasize a structured preoperative workup for suspected ACC: abdominal CT as the first-line study, endocrinology-led hormonal assessment before management, FDG-PET for suspected ACC and metastatic staging, and avoidance of percutaneous biopsy except when adrenal metastasis is suspected after excluding pheochromocytoma.5
  • PMID 24621966: This review outlines a general adrenal-mass workup in which suspected adrenal disease is approached with hormone testing for hyperfunction followed by imaging to characterize morphology and adjacent structures. For incidentalomas, the key initial tasks are to exclude hormonal activity and malignancy, with CT often first-line and MRI, washout CT, SPECT, or PET/CT used when findings are indeterminate.92
  • PMID 24836548: In suspected ACC presenting as a single large adrenal mass, transcutaneous adrenal biopsy is usually unnecessary because diagnostic sensitivity is limited and complications, including bleeding and rare needle-track seeding, can occur. Biopsy should generally be reserved for select situations such as suspected metastasis from another known primary after biochemical exclusion of pheochromocytoma.62
  • PMID 25077599: A cortisol-secreting adrenal adenoma with multiple FDG-avid pulmonary nodules mimicked metastatic ACC, but lung biopsy showed Kaposi sarcoma and adrenal pathology was benign. The case underscores careful endocrine workup of adrenal incidentalomas and caution that hypercortisolism-related opportunistic disease can confound presumed metastatic ACC.93
  • PMID 26392447: This case report highlights that adrenal extramedullary haematopoiesis can mimic ACC on CT, including a large heterogeneous adrenal mass with necrosis and calcification. In patients with relevant haematologic disorders, hormonal evaluation should precede image-guided biopsy, which may confirm a benign mimic and avoid unnecessary adrenalectomy.53
  • PMID 26612225: This review emphasizes that suspected ACC should be evaluated in clinical context before tissue sampling, with biochemical exclusion of pheochromocytoma and assessment of hormone excess. It notes that fine-needle aspiration is generally inadequate to distinguish adenoma from ACC and is mainly useful when adrenal metastasis from another primary is suspected.65
  • PMID 26919651: In adults with adrenal incidentalomas, routine CYP21A2 genetic testing for congenital adrenal hyperplasia is not supported by current evidence, and 17-hydroxyprogesterone screening appears nonspecific in this setting. The review also notes that unrecognized CAH before adrenalectomy could predispose to perioperative adrenal crisis.35
  • PMID 26934393: In patients with primary aldosteronism, the guideline recommends adrenal CT as the initial subtype study specifically to exclude large adrenal masses that may represent adrenocortical carcinoma and to assist procedural planning. This supports considering ACC in the diagnostic workflow of aldosterone-producing adrenal lesions.94
  • PMID 27036860: In primary aldosteronism, adrenal CT or MRI is recommended for all patients and may exceptionally reveal adrenocortical carcinoma. When imaging suggests suspected ACC, adrenal vein sampling is considered noncontributory because surgery is indicated for oncologic resection regardless of lateralization testing.95
  • PMID 27082051: Guideline recommendations for adult adrenal incidentaloma emphasize an ACC-aware initial workup using unenhanced adrenal CT first, followed by washout CT or MRI when attenuation exceeds 10 HU, alongside routine hormonal testing to exclude pheochromocytoma and hypercortisolism. Adrenal biopsy has very limited indications and is contraindicated when ACC is suspected.23
  • PMID 27213037: This review outlines the initial evaluation of a suspected ACC as history and physical examination plus biochemical testing for hormone excess, followed by cross-sectional imaging to define tumor size, vascular invasion, distant disease, and technical resectability, with early emphasis on whether curative surgery is indicated and feasible.43
  • PMID 27257146: This systematic review indicates adrenal biopsy has limited performance for diagnosing adrenocortical carcinoma and is most useful when confirming adrenal metastasis in patients with a known extra-adrenal malignancy. Biopsy should be reserved for situations where results would change management and only after biochemical exclusion of pheochromocytoma.17
  • PMID 27277982: This case series on adrenal masses supports a selective role for percutaneous ultrasound-guided biopsy or aspiration, particularly when metastatic adrenal disease is suspected and tissue diagnosis may prevent unnecessary surgery. It also emphasizes endocrinologic screening to exclude pheochromocytoma before puncture and advises avoiding biopsy when radical surgery is planned because of seeding risk.66
  • PMID 27278528: In a retrospective incidentaloma cohort, ACC was uncommon but clinically relevant, with malignant risk rising sharply above 4 cm and only one malignant tumor at 4 cm or smaller. The study also highlights the need for routine biochemical evaluation, especially because many pheochromocytomas were missed preoperatively before adrenalectomy.96
  • PMID 27390021: This guideline outlines the initial evaluation of adrenal incidentalomas when ACC is a concern: use noncontrast CT first to assess benign versus malignant features, perform hormonal testing including dexamethasone suppression and pheochromocytoma exclusion, and generally avoid adrenal biopsy unless specific criteria are met.2
  • PMID 27432826: This case highlights that ACC may present as a large nonfunctioning adrenal mass with metastatic disease, and emphasizes excluding pheochromocytoma before intervention. It also notes that preoperative transcutaneous biopsy is often unnecessary, has limited diagnostic sensitivity, and carries complications.97
  • PMID 28118677: In adrenal incidentalomas, preoperative suspicion for ACC was associated with larger tumor size, CT heterogeneity, relative contrast washout below 40%, elevated urinary free cortisol, elevated DHEAS, and younger age. A size-and-density algorithm showed moderate discrimination but missed at least one smaller ACC, supporting broader integrated assessment.10
  • PMID 28181818: This guideline-based review addresses how incidental adrenal masses should be triaged when malignancy, including ACC, is a concern. It emphasizes non-contrast CT as the primary first test, multidisciplinary decision-making for indeterminate lesions, and recommends against adrenal biopsy in most cases, particularly when ACC is suspected.20
  • PMID 28356253: This case highlights a diagnostic pitfall in Cushing syndrome where ACC can be mistaken for pituitary Cushing disease when ACTH is in the grey zone and a small pituitary microadenoma is present. It supports repeated ACTH sampling, adrenal imaging, and bilateral inferior petrosal sinus sampling for pituitary lesions smaller than 6 mm before pituitary surgery.31
  • PMID 28687023: In a surgical incidentaloma series, about 10% of resected lesions were adrenocortical carcinomas, with malignancy risk increasing strongly with tumor size. The center used standardized endocrine testing and CT-based imaging for all patients, reserving surgery for secreting lesions, atypical imaging features, or tumors larger than 4 cm when malignancy could not be excluded.98
  • PMID 28699986: In primary aldosteronism workup, adrenal CT is recommended as the initial subtype study specifically to exclude adrenocortical carcinoma, particularly when an adrenal mass is larger than 4 cm and aldosterone-producing carcinoma becomes a rare consideration. The review also notes MRI offers no advantage over CT for this purpose.99
  • PMID 29129360: In patients with 1 to 4 cm, nonfunctional, benign-appearing adrenal incidentalomas showing less than 10 HU on noncontrast CT after initial hormonal exclusion of pheochromocytoma, hypercortisolism, and hyperaldosteronism, a decision model found one-time follow-up with repeat noncontrast CT and biochemical evaluation to be cost-effective, whereas more intensive surveillance added cost without benefit.67
  • PMID 29141379: In a large retrospective adrenal incidentaloma cohort, increasing tumor size was associated with higher malignancy risk, including ACC, and a 4 cm cutoff provided the best discrimination for malignant tumors with high sensitivity and very high negative predictive value. The authors suggest observation rather than routine surgery for lesions 4 cm or smaller when hormonal evaluation shows no excess.46
  • PMID 29202492: In primary aldosteronism, CT is recommended as the initial adrenal imaging test not for reliable subtype assignment but to exclude the occasional aldosterone-producing adrenocortical carcinoma and to assist planning for adrenal venous sampling. The review emphasizes that CT alone has limited accuracy for functional lateralization.100
  • PMID 29241951: This editorial discusses adrenal incidentaloma evaluation when malignancy including ACC is a concern, emphasizing noncontrast CT as first-line imaging and multidisciplinary review for indeterminate lesions. It also notes urgent evaluation in patients younger than 40 years or during pregnancy because of higher malignancy likelihood.101
  • PMID 30780866: This review outlines an incidental adrenal mass workup relevant when ACC is possible: assess malignancy risk by tumor size and CT or MRI phenotype, perform endocrine testing including pheochromocytoma exclusion, and avoid routine fine-needle biopsy except when suspected metastasis would change management.102
  • PMID 30909165: This case report on complex adrenal incidentalomas underscores that suspicious adrenal masses require systematic hormonal assessment and malignancy evaluation, with pheochromocytoma exclusion before intervention. It also highlights that percutaneous adrenal biopsy can be misleading and should be reserved for select situations rather than used to reassure against malignancy.103
  • PMID 31544898: In adrenal masses with indeterminate CT attenuation, this multicenter study frames pheochromocytoma as an important alternative diagnosis to ACC and notes that imaging suspicion should prompt immediate biochemical evaluation, with repeat testing considered if initial results are negative despite high radiologic concern.104
  • PMID 31610872: This guideline summary frames suspected ACC evaluation around sequential hormonal testing, morphologic and functional imaging, and histologic confirmation, noting that preoperative suspicion is driven by radiologic malignancy features, local invasion, distant metastases, and secretion pattern. It also places adrenal incidentaloma workup in a stepwise pathway with endocrine assessment before malignancy stratification.50
  • PMID 32088909: This case report describes a 31 HU adrenal incidentaloma with initially negative hormonal testing and 4 years of size stability that later presented as stage IV ACC. It highlights that stability over limited follow-up may not fully exclude malignancy in an indeterminate adrenal lesion.69
  • PMID 32189021: This review outlines the initial evaluation of adrenal incidentalomas when ACC is a consideration: biochemical testing for cortisol excess and pheochromocytoma in all patients, selective androgen and steroid assessment when imaging suggests ACC, and avoidance of fine-needle aspiration for suspected primary ACC.28
  • PMID 32266384: In adrenal incidentaloma evaluation, ACC is uncommon but must be excluded through a personalized initial assessment centered on unenhanced CT of both adrenal glands and endocrine testing. Pheochromocytoma and autonomous cortisol secretion should be excluded in every case, with aldosteronism assessed when hypertension or hypokalemia is present.8
  • PMID 32541223: In a contemporary adrenal incidentaloma cohort, ACC was uncommon overall but risk rose with larger size, higher noncontrast attenuation, male sex, and growth above 0.6 cm per year. The findings support evaluating suspected ACC using combined hormonal testing and imaging features rather than size alone.11
  • PMID 32856984: This review of adrenal incidentaloma guidelines highlights broad agreement that newly discovered adrenal masses should undergo unenhanced CT and initial hormonal screening, with additional sex hormone and steroid precursor testing when ACC is suspected. It also emphasizes that biopsy has limited value and should not be part of routine initial workup.26
  • PMID 33065058: In newly diagnosed adrenal masses, the authors support using maximum tumor diameter of 4 cm and unenhanced CT attenuation above 20 HU, rather than 10 HU, as practical thresholds for considering ACC in the differential diagnosis. They also note that adding urine steroid metabolomics can further improve diagnostic accuracy, though implementation issues remain.71
  • PMID 33102022: This case report adds a cautionary diagnostic point for large adrenal masses in the ACC differential: although lesions over 6 cm strongly suggest ACC, rare non-ACC malignancies such as primary adrenal small cell carcinoma can mimic it. The report supports avoiding routine adrenal biopsy, while considering biopsy when disease appears unresectable and tissue diagnosis would alter systemic therapy.105
  • PMID 33349429: This guideline review outlines the initial malignancy assessment of an adrenal incidentaloma when ACC is a consideration: complete history and physical examination, biochemical and hormonal testing for subclinical secretion, then morphological and functional imaging, with histologic confirmation required for definitive ACC diagnosis.106
  • PMID 33354270: This case report highlights that a fat-containing adrenal ganglioneuroma can mimic myelolipoma and remain indistinguishable from adrenocortical carcinoma on imaging. In an indeterminate adrenal mass larger than 4 cm without clearly benign diagnostic features, the excerpt notes guideline support for surgical resection without biopsy because of possible primary ACC.107
  • PMID 33675218: This case highlights that a malignant adrenal lesion discovered during follow-up of an extra-adrenal cancer can still represent primary ACC rather than metastasis. It notes guideline-based adrenal hormonal assessment and that biopsy is generally recommended for adrenal masses in patients with other cancers except when ACC is suspected, supporting individualized multidisciplinary decision-making.108
  • PMID 33868171: This study on primary adrenal lymphoma highlights an ACC-relevant diagnostic pitfall: PAL can mimic silent ACC or pheochromocytoma, including occasional catecholamine elevation, yet surgery offers little benefit. In selected nonfunctional adrenal masses, the authors support considering adrenal biopsy once pheochromocytoma is excluded.56
  • PMID 34148966: This case report describes preoperative diagnosis of a left adrenal ACC using endoscopic ultrasound-guided fine-needle aspiration after biochemical and scintigraphic exclusion of pheochromocytoma. It suggests EUS-FNA can help clarify indeterminate adrenal masses and support surgical planning, while emphasizing that whole-lesion pathology remains necessary for definitive diagnosis.109
  • PMID 34230070: This review outlines a stepwise evaluation of adrenal masses relevant to suspected ACC: initial CT or MRI characterization combined with biochemical screening, followed by selective functional imaging when lesions are hormonally active or remain indeterminate. It also notes that biopsy should generally be reserved for unresolved cases after excluding pheochromocytoma.110
  • PMID 34290815: This case report describes an adrenal incidentaloma that later enlarged substantially and showed mildly increased catecholamines and metanephrines, creating a biochemical impression of pheochromocytoma before surgical pathology confirmed ACC. The report emphasizes excluding pheochromocytoma biochemically before invasive procedures and maintaining follow-up of adrenal incidentalomas because biochemical findings may be misleading.111
  • PMID 34813452: A case of ACC presenting with dyspnea and bilateral leg edema shows that point-of-care ultrasound may unexpectedly detect a large heterogeneous or cystic right upper quadrant mass, prompting confirmatory CT and expedited diagnosis. The report also notes standard ACC workup with steroid hormone testing and cross-sectional imaging.112
  • PMID 34840751: This case highlights that a giant suprarenal mass suspected to be ACC should undergo urgent cross-sectional imaging and endocrine evaluation, with explicit exclusion of pheochromocytoma before intervention when feasible. The report also states adrenal biopsy is generally not recommended because of risks including tumor spill, bleeding, and adrenal crisis.113
  • PMID 35501776: In a retrospective multicenter series of nonfunctional adrenal incidentalomas resected without prior malignancy, all ACC cases were at least 6 cm and tumor size predicted malignancy. The findings challenge the routine 4 cm surgery threshold and support integrating size with imaging characteristics and endocrine workup when selecting patients for adrenalectomy.48
  • PMID 35662767: In adrenal incidentaloma evaluation, suspected ACC cases were assessed with biochemical testing including DHEAS alongside CT imaging, while the study emphasizes that imaging alone can misclassify adrenal masses and that careful preoperative hormonal workup is necessary before intervention.114
  • PMID 35784570: In children and adolescents with adrenal masses that may mimic neuroblastoma, adrenocortical tumors can be missed without targeted endocrine testing and expert pathology review. The report emphasizes avoiding biopsy when ACT is possible and prioritizing comprehensive biochemical assessment plus complete resection by experienced surgeons.115
  • PMID 36400477: These French guidelines outline the first-line evaluation of an adrenal incidentaloma when ACC is possible: complete history and examination, biochemical and hormonal assessment, and adrenal imaging, with diagnosis of ACC often suspected preoperatively but confirmed histologically. They also emphasize expert multidisciplinary review in an adrenal cancer referral network.15
  • PMID 36617747: This case report describes adrenal hemorrhage with acute flank pain as the first manifestation of ACC despite nondiagnostic hormonal testing and imaging. It argues that hemodynamically stable patients with adrenal bleeding of unclear cause should undergo early elective surgery after pheochromocytoma-style preoperative preparation, while unstable patients require urgent surgery.59
  • PMID 36654569: In a retrospective adrenal incidentaloma series, adrenocortical carcinoma accounted for 5.8% of cases. The excerpt emphasizes a standard initial workup of adrenal incidentalomas with CT or MRI plus hormonal testing, including metanephrines for all patients, dexamethasone suppression testing for cortisol excess, and aldosterone-renin assessment when hypertension or hypokalemia is present.24
  • PMID 36787883: In a large adrenal lesion cohort, hormone excess and malignancy required systematic evaluation with biochemical testing and non-contrast CT, using MRI selectively for indeterminate lesions. Surgical selection reflected malignancy suspicion: among lesions operated for size at least 6 cm, 12.1% were primary ACC, and among 4-6 cm lesions with suspicious imaging, 4.8% were primary ACC.116
  • PMID 36943310: This review notes that rare benign adrenal lesions can mimic adrenocortical carcinoma on imaging, especially when cystic or indeterminate. It supports thorough hormonal evaluation of non-typical adrenal cystic lesions and highlights imaging features such as solid components, heterogeneity, or thick enhancing rims that should raise concern for alternative etiologies including ACC.54
  • PMID 37052304: Adrenohepatic fusion is a not uncommon right-sided adrenal-liver fusion that can make benign adrenal adenomas appear radiologically similar to hepatocellular carcinoma or ACC with liver invasion. The review emphasizes awareness of this differential diagnosis and notes that adrenal biopsy is not first-line, partly because it is often non-diagnostic for adenoma versus ACC and may be hazardous if pheochromocytoma is present.55
  • PMID 37061367: These French multidisciplinary ACC guidelines outline the initial workup of suspected ACC: rapid pretherapeutic assessment within one month, systematic hormonal testing including exclusion of pheochromocytoma, cross-sectional staging with CT and FDG PET before surgery, and restricted use of percutaneous biopsy only in selected nonsecretory or diagnostically uncertain cases discussed in expert multidisciplinary review.6
  • PMID 37318239: These adrenal incidentaloma guidelines outline when an adrenal mass should raise concern for ACC and how initial workup should proceed. They recommend dedicated noncontrast CT, multidisciplinary review for non-benign or hormonally active lesions, staging before surgery for high-risk masses, avoidance of adrenal biopsy in most cases, and steroid precursor profiling when ACC is suspected.21
  • PMID 37697772: This case report on adrenal schwannoma emphasizes that large or young-age adrenal incidentalomas can mimic ACC and should undergo structured radiologic and hormonal evaluation before intervention. It notes pheochromocytoma exclusion, assessment for cortisol and sex hormone excess when clinically indicated, and the diagnostic role of excision with histopathology for rare non-ACC lesions.117
  • PMID 37877600: In patients without a known or suspected extra-adrenal primary malignancy, image-guided adrenal mass biopsy had limited utility for incidental adrenal masses because overall diagnostic yield and accuracy for malignancy were modest. Biopsy results labeled as adrenocortical tumors did not reliably distinguish benign from malignant lesions, arguing against routine reliance on biopsy in this setting.18
  • PMID 38281194: This review outlines a preoperative ACC workup centered on native adrenal CT and comprehensive endocrine testing for all suspected cases, while emphasizing that biopsy is generally not recommended except selected cases of possible adrenal metastasis from an extra-adrenal primary. It also notes emerging noninvasive biomarkers, especially steroid metabolomics and miRNA assays, as likely future diagnostic adjuncts.27
  • PMID 38287660: This case report highlights that primary adrenal diffuse large B-cell lymphoma can mimic a large nonfunctional adrenal mass suspicious for ACC on CT and MRI, creating a diagnostic dilemma because biopsy is often avoided when ACC is suspected despite lymphoma requiring tissue diagnosis and systemic immunochemotherapy.57
  • PMID 38341198: This case highlights that in suspected hormone-secreting ACC, markedly elevated ACTH can be spurious when immunoassay results conflict with the clinical picture of an adrenal cortisol- and androgen-producing mass. Repeating ACTH measurement with an alternative assay and coordinating with the laboratory may prevent unnecessary pituitary or ectopic ACTH investigations.32
  • PMID 38757020: In a single-center adrenalectomy series, adrenocortical carcinoma was uncommon and could be preoperatively classified as a non-functioning adrenal tumor or as recurrence after prior adrenal resection. The report emphasizes maintaining suspicion for malignancy when evaluating apparently non-functioning lesions or recurrent adrenal masses.29
  • PMID 39164941: In a retrospective adrenal incidentaloma cohort, both ACC cases were larger than 6 cm and all ACCs were at least 4 cm. The study concludes that incidental adrenal lesions, especially those 4 cm or larger, warrant thorough biochemical evaluation for hormonal excess and assessment for malignancy, often followed by surgery.118
  • PMID 39421117: In a multidisciplinary adrenal lesion cohort that included four ACC cases, the report reiterates that pheochromocytoma should be excluded before adrenal intervention, especially for incidental nodules with attenuation above 10 HU, because biopsy of an unsuspected pheochromocytoma can be catastrophic. It notes all ACC cases had normal plasma and urinary catecholamine measurements.38
  • PMID 39425921: In a large tertiary-centre cohort of adrenal masses, standardized initial assessment combined unenhanced adrenal CT, endocrine biochemical testing, and multidisciplinary review. Predictors of malignancy included indeterminate or heterogeneous imaging, androgen excess, lesion size of at least 4 cm, detection during cancer surveillance, and male sex.12
  • PMID 39569244: This case highlights a diagnostic pathway for suspected advanced ACC presenting with bone metastases and later hypercortisolism with refractory hypokalemia. The excerpt emphasizes adrenal-focused CT, hormonal evaluation including pheochromocytoma exclusion, additional metastatic imaging, and that adrenal biopsy is usually avoided but may be considered in metastatic disease when surgery is not feasible.119
  • PMID 39581666: This guideline update frames ACC within the assessment of adrenal incidentalomas, recommending history, examination, first-line hormonal testing, and morphological or functional imaging to evaluate malignancy. It emphasizes that ACC is usually suspected preoperatively but confirmed histologically, with expert multidisciplinary discussion for suspected malignant cases.3
  • PMID 39620178: This case highlights that ACC can rarely show biochemical overlap with pheochromocytoma, including markedly elevated normetanephrine, so comprehensive endocrine evaluation and pheochromocytoma exclusion are important before invasive procedures. It also notes adrenal biopsy is generally avoided in suspected ACC, but may be justified in inoperable metastatic disease when histologic confirmation is needed for treatment planning.40
  • PMID 39840167: This case-based review emphasizes that adrenal incidentalomas require structured biochemical testing and risk-stratified imaging follow-up to assess secretory function and malignant potential. It also notes that indeterminate lesions with attenuation above 10 HU warrant further characterization, while adrenal biopsy is generally discouraged because it does not reliably distinguish benign from malignant disease.70
  • PMID 40007812: This case-based review highlights that ACC can rarely mimic pheochromocytoma, including isolated elevation of dopamine metabolite 3-methoxytyramine, so both entities should remain in the differential for adrenal masses with non-adenoma imaging features. It emphasizes comprehensive hormonal and imaging evaluation and notes that adrenal biopsy is usually inappropriate because of dissemination risk and potential catecholamine crisis.41
  • PMID 40304946: This review outlines how ACC should be approached when detected as part of an adrenal incidentaloma evaluation: prioritize biochemical testing and non-contrast CT characterization, reserve MRI or PET/CT for indeterminate or suspicious lesions, and avoid routine adrenal biopsy because of limited sensitivity for adrenocortical cancer and risks including tumor seeding.9
  • PMID 40383456: A simulation study of adults with incidental 1 to 4 cm adrenal nodules and no known malignancy found that limited follow-up with noncontrast CT at diagnosis was the only strategy meeting a standard cost-effectiveness threshold for detecting ACC, whereas washout CT-based strategies were not cost effective.68
  • PMID 40469217: This case report highlights that mixed cystic or pseudocystic adrenal lesions can closely mimic ACC on CT and MRI, including apparent venous invasion and mild autonomous cortisol secretion. It recommends evaluating such lesions like solid adrenal tumors with further imaging and biochemical hormonal assessment, with resection when malignancy or hormonal activity is suspected.58
  • PMID 41209753: In adrenal hemorrhage, ACC is an important underlying malignant cause and may be the first or only manifestation of disease. The review recommends structured CT/MRI and endocrine evaluation for all cases, with management guided by hemodynamic stability, capsule integrity, and suspicion of malignancy.60
  • PMID 41368262: In a retrospective cohort, preoperative neutrophil-to-lymphocyte ratio greater than 3 and platelet-to-lymphocyte ratio greater than 140 were associated with ACC versus other adrenal tumors, but these markers lost discriminatory value in patients with Cushing syndrome. The study supports using these inexpensive blood-based markers only as adjuncts within cortisol-aware preoperative evaluation.72
  • PMID 41598318: In adrenal incidentalomas with non-benign CT features, this pilot machine-learning study supports pre-surgical differentiation of pheochromocytoma from ACC and non-functioning adenoma using combined clinical, laboratory, and imaging variables. The work reinforces that lesion size contributes to distinguishing PCC from ACC in diagnostically challenging adrenal masses.51
  • PMID 14655606: A case report described an incidental adrenal cortical adenoma discovered with ipsilateral renal cell carcinoma; despite largely normal baseline hormonal testing, additional endocrine and scintigraphic findings suggested partial cortical autonomy. Although not focused on ACC, it highlights a diagnostic pitfall relevant to evaluating adrenal masses in patients who also have another malignancy, because a concurrent adrenal lesion is not necessarily metastatic or fully nonfunctioning.120
  • PMID 22583144: An editorial on functional adrenal neoplasms emphasizes that bilateral functioning adrenal disease has no uniform surgical standard, and that adrenal-sparing approaches are context-dependent tradeoffs rather than general rules. For the ACC note, this mainly adds nuance to management framing by distinguishing bilateral benign or hereditary endocrine scenarios from suspected malignant adrenal masses.121

References

Footnotes

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