When Biopsy Helps or Harms in ACC

Initial Diagnostic Workflow

Adrenal biopsy in the setting of suspected adrenocortical carcinoma (ACC) is a limited, selective procedure within the initial diagnostic workflow for adrenal masses. In contemporary ACC evaluation, biochemical testing and adrenal-focused cross-sectional imaging usually precede any consideration of tissue sampling, because these modalities more directly establish hormonal activity, assess resectability, and frame the differential diagnosis between primary ACC, benign adrenal neoplasms, pheochromocytoma, and metastasis to the adrenal gland.¹²³⁴ The central clinical issue is often not whether a mass is malignant in the abstract, but whether it represents a potentially resectable primary adrenocortical cancer or a different process that would alter treatment strategy.

Biopsy has a constrained role because small-volume cytology or core samples do not reliably distinguish ACC from adrenal adenoma, and may also misclassify ACC as another malignant process.⁵⁶⁷ This limitation is clinically important: a negative or nonspecific biopsy does not safely exclude ACC, and misleading results may delay definitive management of a lesion that would otherwise proceed to surgery.⁸⁹ Reported procedural harms, including hemorrhage and needle-tract tumor seeding, appear uncommon but potentially consequential in a disease where complete oncologic resection is central to local control.¹⁰¹¹

The evidence base is largely retrospective and indirect. Much of current practice rests on reviews, small institutional series, pathology correlation studies, and case reports rather than prospective comparative trials.⁵⁷¹² As a result, conclusions are more consistent at the level of broad clinical principle than at the level of precise diagnostic accuracy or complication rates: biopsy may help when the main question is metastatic disease to the adrenal or another non-ACC diagnosis, but it is generally not used to confirm a resectable primary ACC.¹³¹³

Diagnostic context

Suspected ACC is typically evaluated through endocrine assessment and imaging before any invasive procedure is considered. Reviews and practice-oriented summaries describe a pathway centered on testing for cortisol excess and other steroid secretion, followed by CT-based lesion characterization and staging, with MRI used selectively for additional anatomic definition.¹²³⁴ This approach is more reliable than biopsy for establishing functional status, supporting adrenal cortical origin, and determining whether the lesion should proceed directly to surgical management.

An important prerequisite to any adrenal biopsy is exclusion of pheochromocytoma, because biopsy of an occult catecholamine-secreting tumor may cause serious complications.³¹² Retrospective data suggest this precaution is not universally observed in routine practice, which reinforces that adrenal biopsy should be interpreted as part of a specialized adrenal workup rather than as a generic image-guided sampling procedure.¹² Practically, biopsy is most defensible only after the lesion has been placed in a structured endocrine and radiographic differential diagnosis.

Situations in which biopsy may help

Against that background, the most accepted indication for biopsy is the distinction between adrenal metastasis and a primary adrenal tumor. This question becomes most relevant in patients with a known extra-adrenal malignancy, in patients with lesions that are unresectable at presentation, or when biochemical and imaging findings are not typical of ACC and a tissue diagnosis would redirect staging or systemic therapy.^1141513

Retrospective data and review-level guidance suggest that biopsy is most useful when the result is expected to change management and when surgery is not already the preferred next step.²⁴¹¹ What is relatively reliable is the management principle, not the exact performance characteristics: biopsy may support treatment selection in carefully chosen nonoperative or metastatic scenarios, but the result still requires integration with imaging, endocrine findings, and clinical history because tissue interpretation alone remains imperfect.⁷¹²

When histology is necessary, sampling a non-adrenal or technically safer metastatic site may be preferable to direct adrenal biopsy. Case-based experience in advanced disease supports obtaining tissue from more accessible lesions when possible, especially if the leading concern is metastatic carcinoma of unknown primary rather than localized ACC.¹⁶¹⁵ Indirect evidence from thoracic oncology similarly suggests that alternative approaches such as EUS-guided sampling of left adrenal lesions may be useful in selected staging settings, although this experience mainly concerns suspected metastases and does not validate routine biopsy for primary ACC.¹⁷

Why biopsy is often avoided in suspected primary ACC

The main reason biopsy is generally avoided in a potentially resectable adrenal mass suspicious for ACC is that it often does not answer the decision that matters most. Small-sample pathology may detect malignancy broadly while still failing to distinguish ACC from adenoma or incorrectly suggesting metastatic carcinoma.⁵⁶⁷ Across study types, the most consistent finding is negative: biopsy cannot reliably rule out ACC when the clinical and radiographic suspicion remains high.

This limitation has direct implications because localized ACC is usually managed surgically rather than through a biopsy-confirmed neoadjuvant pathway.²⁴ Compared with standard endocrine and imaging workflows, biopsy adds less dependable diagnostic certainty for primary adrenocortical malignancy and may introduce delay, false reassurance, or confusion without improving the core surgical decision.⁹¹³ In practice, a large or radiographically aggressive adrenal mass that appears operable is generally worked up for resection rather than sampled percutaneously.

Diagnostic pitfalls and interpretive limits

A recurrent problem is discordance between biopsy findings and the overall clinical picture. Tumor heterogeneity, limited sampling, and well-differentiated areas may yield false-negative, nondiagnostic, or nonspecific results, and available series suggest that a negative biopsy has poor value for excluding ACC.⁸⁷ The practical implication is that biopsy results should not supersede concerning growth, hormonal abnormalities, or imaging features suggestive of adrenocortical malignancy.

Biopsy may also mislead when adrenal tumors mimic lesions of adjacent organs. Unusual presentations, including adreno-hepatic fusion or adrenal tumors abutting the liver, show that ACC may appear radiologically or histologically similar to hepatocellular or other non-adrenal malignancies if adrenal origin is not specifically considered.¹⁸¹⁹ These reports are narrow and not broadly generalizable, but they illustrate a durable principle: anatomic context, endocrine data, and targeted immunohistochemistry may be more informative than repeated small-volume sampling in anatomically ambiguous cases.

Indirect evidence from nonhuman cytology studies suggests that limited-sample aspiration may sometimes separate broad adrenal lineages, such as cortical versus medullary tumors, but this does not address the central human ACC problem of reliably distinguishing adenoma from carcinoma on biopsy.²⁰ The implication for ACC care is therefore modest and conceptual rather than practice-changing.

Risks and procedural harms

Reported harms of adrenal biopsy in suspected ACC include hemorrhage and needle-tract tumor seeding.¹⁰¹¹ The true incidence is uncertain because the literature is dominated by retrospective cohorts and case reports, so rare but serious complications may be either undercounted or preferentially published.¹² What is more reliable than any single rate estimate is the risk-benefit asymmetry: even infrequent procedural harms may carry substantial weight when the expected diagnostic gain is limited and curative-intent surgery remains feasible.

This distinguishes ACC from many other solid tumors in which pretreatment tissue confirmation is routine. In ACC, local control depends heavily on complete resection, and any procedure that may contribute to rupture or tract dissemination has outsized implications relative to its usual diagnostic yield.¹⁰²²¹ Clinically, this leads to a higher threshold for biopsy than in standard oncologic workflows.

Role in management and research

Overall, the literature supports a selective, management-changing use of biopsy rather than routine biopsy when ACC is in the differential diagnosis.¹³⁴ Biopsy may be reasonable when metastatic disease is more likely than primary ACC, when the lesion is unresectable, or when histology from the adrenal or another accessible site would materially alter systemic therapy, staging, or palliative planning.¹⁵¹¹ By contrast, available reviews and retrospective evidence generally argue against biopsy as a confirmation step for a radiographically suspicious, potentially resectable primary adrenal mass.²¹³

For research, the field remains limited by small cohorts, selection bias, and publication bias toward unusual complications or diagnostically discordant cases.⁷¹² Current evidence therefore supports broad workflow principles more strongly than precise estimates of diagnostic accuracy, comparative safety, or outcome benefit.

Included Articles

• PMID 3119168: This review outlines a practical diagnostic approach when ACC is suspected: confirm hormone excess with biochemical testing, localize and stage with CT as the primary imaging modality, use MRI as complementary, and reserve percutaneous adrenal biopsy for cases where metastatic disease is strongly suspected and surgery is not planned.¹

• PMID 11490263: This case report describes rupture of a large adrenocortical carcinoma shortly after CT-guided fine needle aspiration, with massive retroperitoneal hemorrhage and later psoas-track metastatic seeding. It highlights biopsy-related bleeding and tumor spread as potential harms when evaluating a suspected adrenal malignancy.¹⁰

• PMID 12612887: In an ex vivo multicenter study of adrenal core biopsy, malignant adrenal lesions were detected with high sensitivity and specificity, but ACC was correctly identified in only about three quarters of cases and was sometimes misclassified as metastasis. The authors conclude biopsy may help classify adrenal tumors if tissue is adequate, while emphasizing that clinical benefit versus procedural risk remains uncertain.⁵

• PMID 12788327: A case report highlights that percutaneous adrenal biopsy can yield a false-negative result in a well-differentiated, nonfunctioning 4 cm adrenocortical carcinoma initially read as adenoma. When imaging findings are suspicious and discordant with biopsy pathology, surgical intervention is recommended.⁸

• PMID 16888426: In surgically treated adrenal incidentalomas, the authors emphasize that lesion size alone should not determine management, note that fine-needle biopsy does not distinguish adenoma from adrenocortical carcinoma, and recommend individualized evaluation incorporating age, growth, hormonal testing, and suspicion of malignancy.⁶

• PMID 19500769: This review outlines a suspected ACC workup centered on comprehensive endocrine testing and cross-sectional staging before surgery, while emphasizing that fine-needle biopsy is rarely justified because modern imaging and hormonal assessment usually suffice and biopsy carries needle-track metastasis risk.²

• PMID 20389162: In a small series of indeterminate adrenal lesions, percutaneous adrenal biopsy had limited performance for malignancy, with ACC missed or misclassified in several cases and a low negative predictive value. The study supports reserving biopsy as a last diagnostic step, excluding pheochromocytoma beforehand, and not using a negative biopsy to rule out ACC.⁷

• PMID 24866075: This review emphasizes that suspected ACC requires mandatory preoperative endocrine assessment to define hormonal activity, support adrenocortical origin, and prevent postoperative adrenal insufficiency. It also highlights exclusion of pheochromocytoma before any invasive procedure and notes limited, controversial value of fine-needle biopsy because of poor discrimination and potential seeding risk.³

• PMID 27248805: In a retrospective cohort of adrenal biopsies performed largely for suspected metastases rather than ACC, percutaneous biopsy had moderate diagnostic performance for malignancy and occasional misclassification of ACC. The study also highlights that pheochromocytoma biochemical testing was often omitted before biopsy, reinforcing the need for careful prebiopsy endocrine evaluation and selective use of biopsy.¹²

• PMID 29103668: This case report describes metastatic adrenocortical carcinoma diagnosed by flexible bronchoscopy after a nondiagnostic liver fine-needle aspiration. It highlights diagnostic workflow issues in advanced ACC, including endocrine evaluation and exclusion of pheochromocytoma before biopsy of an adrenal-region mass.¹⁶

• PMID 30844886: This review outlines the initial evaluation of adrenal tumors when ACC is in the differential, recommending unenhanced CT attenuation and a 1 mg overnight dexamethasone suppression test for patients without prior cancer, with targeted additional hormone testing when indicated. It also notes that adrenal biopsy should generally be avoided when ACC is suspected because of limited diagnostic accuracy and risk of tumor dissemination.⁴

• PMID 30945697: This case report emphasizes that suspected ACC should generally not undergo adrenal biopsy, because biopsy may be misleading and can risk tumor seeding when ACC is present. In a rapidly enlarging heterogeneous adrenal mass, whole-tumor excision with definitive histopathologic assessment was more informative than prior needle biopsy.²¹

• PMID 32138416: This review presents an older diagnostic approach to adrenal masses in which fine-needle aspiration biopsy helps distinguish adrenal metastases from primary adrenal lesions. It also recommends hormonal evaluation for incidental masses and surgical exploration for endocrine-active tumors, lesions larger than 5 cm, or masses with atypical cytology.¹⁴

• PMID 33948420: This case report highlights that adrenal incidentalomas suspicious for ACC should be evaluated with endocrine testing and cross-sectional imaging rather than fine-needle aspiration, which was repeatedly non-diagnostic and misleading. Large size and malignant CT features supported proceeding toward adrenalectomy instead of biopsy.⁹

• PMID 34011784: Two case reports describe unresectable unilateral adrenal masses initially suspected to be nonfunctioning ACC that were ultimately identified as carcinoma of unknown primary with isolated adrenal metastasis by CT-guided core needle biopsy. The report suggests considering biopsy when lesions are unresectable, hormonal excess is absent, and tumor markers raise suspicion for metastasis.¹⁵

• PMID 37023688: This case report highlights that ACC can mimic hepatocellular carcinoma on CT, MRI, and even biopsy when a lesion is located in the dorsal posterior hepatic segment. It recommends scrutinizing continuity with the right adrenal gland and using additional immunohistochemistry when the diagnosis is uncertain.¹⁸

• PMID 37425246: This case series emphasizes that large adrenal masses, particularly those exceeding 10 cm, should prompt strong consideration of adrenocortical carcinoma and systematic preoperative evaluation with hormonal testing and cross-sectional imaging. It also notes that percutaneous biopsy has limited value for distinguishing adenoma from ACC and is mainly reserved for unresolved cases or staging in patients with another known malignancy.¹³

• PMID 37435185: This case report documents abdominal wall recurrence consistent with needle tract seeding after transcutaneous biopsy of a primary ACC, underscoring why adrenal biopsy is generally avoided when ACC is suspected. The excerpt emphasizes that CT, MRI, FDG-PET, endocrine testing, and pheochromocytoma exclusion usually guide evaluation, reserving biopsy for suspected extra-adrenal metastasis to the adrenal or selected inoperable cases where pathology would change management.¹¹

• PMID 39822371: Adreno-hepatic fusion can cause adrenal cortical tumors near liver segments 6 or 7 to appear intrahepatic or falsely invasive on CT, MRI, biopsy, and PET, leading to both under- and over-diagnosis. The report highlights the need to suspect adrenal origin early, use endocrine evaluation, and recognize that biopsy may mislead when AHF is not considered.¹⁹

• PMID 21277038: A retrospective multicenter lung cancer series found that transgastric EUS-FNA of suspicious left adrenal lesions could provide tissue confirmation of metastasis with good sensitivity and no reported complications. For ACC, the relevance is indirect: it supports biopsy mainly when metastatic disease is the leading question, not for routine confirmation of a suspected primary adrenal cortical cancer.¹⁷

• PMID 40152647: A 2025 veterinary retrospective study found that adrenal FNA cytology in dogs could often distinguish adrenocortical tumors from pheochromocytomas with moderate accuracy and mostly self-limited complications, but the evidence is indirect for human ACC and does not address the central human problem of separating ACC from adenoma on biopsy.²⁰

References

Footnotes

1. Adrenocortical carcinoma.. CA Cancer J Clin. 1987. PMID: 3119168. Local full text: 3119168.md ↩ ↩² ↩³ ↩⁴ ↩⁵ ↩⁶

2. Clinical management of adrenocortical carcinoma.. Best Pract Res Clin Endocrinol Metab. 2009. PMID: 19500769. Local full text: 19500769.md ↩ ↩² ↩³ ↩⁴ ↩⁵ ↩⁶ ↩⁷

3. Adrenocortical carcinoma: what the surgeon needs to know. Case report and literature review.. Int J Surg. 2014. PMID: 24866075. Local full text: 24866075.md ↩ ↩² ↩³ ↩⁴ ↩⁵ ↩⁶

4. Screening in adrenal tumors.. Curr Opin Oncol. 2019. PMID: 30844886. Local full text: 30844886.md ↩ ↩² ↩³ ↩⁴ ↩⁵ ↩⁶

5. High diagnostic accuracy of adrenal core biopsy: results of the German and Austrian adrenal network multicenter trial in 220 consecutive patients.. Hum Pathol. 2003. PMID: 12612887. Local full text: 12612887.md ↩ ↩² ↩³ ↩⁴

6. Indications and results of surgery for incidentally found adrenal tumors.. Urol Int. 2006. PMID: 16888426. Local full text: 16888426.md ↩ ↩² ↩³

7. Percutaneous adrenal biopsy for indeterminate adrenal lesion: complications and diagnostic accuracy.. Urol Int. 2010. PMID: 20389162. Local full text: 20389162.md ↩ ↩² ↩³ ↩⁴ ↩⁵ ↩⁶ ↩⁷

8. False-negative results in percutaneous adrenal biopsies in oncology patients.. Clin Radiol. 2003. PMID: 12788327. Local full text: 12788327.md ↩ ↩² ↩³

9. Adrenocortical Carcinoma: A Case of Missed Diagnosis.. Cureus. 2021. PMID: 33948420. Local full text: 33948420.md ↩ ↩² ↩³

10. Rupture of adrenal carcinoma after biopsy.. J Urol. 2001. PMID: 11490263. Local full text: 11490263.md ↩ ↩² ↩³ ↩⁴

11. Adrenocortical cancer recurrence following initial transcutaneous biopsy: a rare demonstration of needle tract seeding.. Endocr Oncol. 2021. PMID: 37435185. Local full text: 37435185.md ↩ ↩² ↩³ ↩⁴ ↩⁵

12. Procedural and clinical outcomes of percutaneous adrenal biopsy in a high-risk population for adrenal malignancy.. Clin Endocrinol (Oxf). 2016. PMID: 27248805. Local full text: 27248805.md ↩ ↩² ↩³ ↩⁴ ↩⁵ ↩⁶ ↩⁷

13. The Spectrum of Large Adrenal Masses: A Case Series.. HCA Healthc J Med. 2020. PMID: 37425246. Local full text: 37425246.md ↩ ↩² ↩³ ↩⁴ ↩⁵

14. Fine needle aspiration biopsy of the adrenal gland: Cytological features and clinical applications.. Endocr Pathol. 1992. PMID: 32138416. Local full text: 32138416.md ↩ ↩²

15. Carcinoma of unknown primary origin with isolated adrenal metastasis: a report of two cases.. Endocr J. 2021. PMID: 34011784. Local full text: 34011784.md ↩ ↩² ↩³ ↩⁴

16. Diagnosis of Adrenocortical Carcinoma by Flexible Bronchoscopy.. Arch Bronconeumol (Engl Ed). 2018. PMID: 29103668. Local full text: 29103668.md ↩ ↩²

17. EUS-FNA for the detection of left adrenal metastasis in patients with lung cancer.. Lung Cancer. 2011. PMID: 21277038. Local full text: 21277038.md ↩ ↩²

18. Adrenocortical carcinoma mimicking hepatocellular carcinoma: A case report.. Int J Surg Case Rep. 2023. PMID: 37023688. Local full text: 37023688.md ↩ ↩²

19. Diagnostic challenges associated with adrenocortical neoplasms arising from adreno-hepatic fusion: a case report of two patients and a literature review.. Gland Surg. 2024. PMID: 39822371. Local full text: 39822371.md ↩ ↩²

20. Cytologic Evaluation as a Diagnostic Tool to Differentiate Adrenocortical Tumors and Pheochromocytomas.. J Vet Intern Med. 2025. PMID: 40152647. Local full text: 40152647.md ↩ ↩²

21. Adrenocortical carcinoma associated with giant bilateral myelolipomas in classic congenital adrenal hyperplasia.. Pol Arch Intern Med. 2019. PMID: 30945697. Local full text: 30945697.md ↩ ↩²