Assessment of incidental adrenal mass

If the adrenal lesion has >10 Hounsfield units attenuation, the diagnosis is uncertain (it may represent a lipid-poor adenoma, an adrenocortical carcinoma, adrenal metastasis, or phaeochromocytoma). In this case, a contrast-enhanced CT scan is performed to assess the washout of initial enhancement in the lesion: adrenal adenomas display ≥60% enhancement washout at 15 minutes (sensitivity 88% and specificity 96% for diagnosis of benign adrenal lesion).[37]Avram AM, Fig LM, Gross MD. Adrenal gland scintigraphy. Semin Nucl Med. 2006 Jul;36(3):212-27. http://www.ncbi.nlm.nih.gov/pubmed/16762612?tool=bestpractice.com

Used to differentiate adrenal adenomas from metastases, and it is the preferred anatomical imaging method in children and pregnant women.

Sensitivity of 78% and specificity of 87% for diagnosing adrenal adenoma.[37]Avram AM, Fig LM, Gross MD. Adrenal gland scintigraphy. Semin Nucl Med. 2006 Jul;36(3):212-27. http://www.ncbi.nlm.nih.gov/pubmed/16762612?tool=bestpractice.com

131-I NP-59 scintigraphy is used to distinguish adrenal adenomas from non-adenomatous lesions (primary adrenal cancer, adrenal metastases, cysts, haematoma/haemorrhage, lipoma, myelolipoma and pseudo-adrenal masses). For characterising an adrenal mass as an adenoma, NP-59 imaging had a positive predictive value of 89%; in contrast, the negative predictive value to rule out this type of tumour was 100%.[37]Avram AM, Fig LM, Gross MD. Adrenal gland scintigraphy. Semin Nucl Med. 2006 Jul;36(3):212-27. http://www.ncbi.nlm.nih.gov/pubmed/16762612?tool=bestpractice.com

Useful for metabolic characterisation of adrenal lesions (benign versus malignant). [Figure caption and citation for the preceding image starts]: 18-fluoro-2-deoxyglucose (FDG) PET-CT: adrenal adenoma. 46-year-old man with squamous cell carcinoma of the neck (TxN1 tumour) status post-external beam radiotherapy; restaging PET-CT demonstrates low-attenuation, non-FDG avid, 3.7 cm left adrenal nodule consistent with adrenal adenoma; FDG PET study excluded distant metastasis to the adrenal glandGross MD, Avram A, Fig LM, et al. Eur J Nucl Med Mol Imaging. 2007 Apr;34(4):547-57; used with permission [Citation ends].

One of the first-line tests to consider in any patient with suspected Cushing syndrome.[26]Fleseriu M, Auchus R, Bancos I, et al. Consensus on diagnosis and management of Cushing's disease: a guideline update. Lancet Diabetes Endocrinol. 2021 Dec;9(12):847-75. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8743006 http://www.ncbi.nlm.nih.gov/pubmed/34687601?tool=bestpractice.com ​ Value greater than the upper limit of normal is considered positive. Normal values vary greatly depending on the assay and clinical laboratory used. Followed with confirmatory testing: urinary free cortisol and overnight dexamethasone suppression.[12]Terzolo M, Pia A, Alì A, et al. Adrenal incidentaloma: a new cause of the metabolic syndrome? J Clin Endocrinol Metab. 2002 Mar;87(3):998-1003. https://academic.oup.com/jcem/article/87/3/998/2846606 http://www.ncbi.nlm.nih.gov/pubmed/11889151?tool=bestpractice.com

One of the first-line tests to consider in any patient with suspected Cushing syndrome.[26]Fleseriu M, Auchus R, Bancos I, et al. Consensus on diagnosis and management of Cushing's disease: a guideline update. Lancet Diabetes Endocrinol. 2021 Dec;9(12):847-75. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8743006 http://www.ncbi.nlm.nih.gov/pubmed/34687601?tool=bestpractice.com

Should be a first-line test in any patient with suspected Cushing syndrome, except those taking drugs affecting dexamethasone metabolism (phenytoin, carbamazepine, rifampicin [rifampin], and cimetidine).

Positive results should be confirmed with late-night salivary cortisol or 24-hour urinary free cortisol.

In patients with incidentally discovered adrenal nodules without clinical features of Cushing syndrome, the 1 mg dexamethasone suppression test should be the initial diagnostic test because urinary free cortisol and late-night salivary cortisol have a lower sensitivity in these patients.[41]Masserini B, Morelli V, Bergamaschi S, et al. The limited role of midnight salivary cortisol levels in the diagnosis of subclinical hypercortisolism in patients with adrenal incidentaloma. Eur J Endocrinol. 2009 Jan;160(1):87-92. http://www.ncbi.nlm.nih.gov/pubmed/18835977?tool=bestpractice.com [42]Pivonello R, De Martino MC, Colao A. How should patients with adrenal incidentalomas be followed up? Lancet Diabetes Endocrinol. 2014 May;2(5):352-4.

European guidelines suggest using the term mild autonomous cortisol excess in patients without signs and symptoms of overt Cushing syndrome where the results are >50 nmol/L (>1.8 micrograms/dL) (without any further stratification based on the degree of cortisol non-suppressibility).[9]Fassnacht M, Tsagarakis S, Terzolo M, et al. European Society of Endocrinology clinical practice guidelines on the management of adrenal incidentalomas, in collaboration with the European Network for the Study of Adrenal Tumors. Eur J Endocrinol. 2023 Jul 20;189(1):G1-42. https://academic.oup.com/ejendo/article/189/1/G1/7198474 http://www.ncbi.nlm.nih.gov/pubmed/37318239?tool=bestpractice.com ​ These patients may require further evaluation for signs of Cushing syndrome that may have been missed initially, and to demonstrate suppressed or low-normal morning plasma adrenocorticotrophic hormone (ACTH) (which confirms ACTH independency).[9]Fassnacht M, Tsagarakis S, Terzolo M, et al. European Society of Endocrinology clinical practice guidelines on the management of adrenal incidentalomas, in collaboration with the European Network for the Study of Adrenal Tumors. Eur J Endocrinol. 2023 Jul 20;189(1):G1-42. https://academic.oup.com/ejendo/article/189/1/G1/7198474 http://www.ncbi.nlm.nih.gov/pubmed/37318239?tool=bestpractice.com

Cushing syndrome commonly leads to diabetes and glucose intolerance.

Normal ranges vary by assay method.

Positive results should be confirmed with late-night salivary cortisol or 1 mg overnight dexamethasone suppression testing.

Exercise caution in interpretation of values as assays differ between different laboratories. Should be obtained only after biochemical diagnosis of hypercortisolism (Cushing syndrome) has been established.

Used to determine the source of ectopic ACTH syndrome.[Figure caption and citation for the preceding image starts]: Incidentally discovered, 1.8 cm diameter, right adrenal mass in a 37-year-old man. Abdominal CT (A) depicts the mass as lipid-poor with atypical contrast enhancement; NP-59 scintigraphy done without dexamethasone suppression; (B) demonstrates a concordant pattern of imaging with right > left adrenal accumulation of iodocholesterol on the fifth and sixth days post-injection, compatible with a benign aetiologyDeGroot LJ, Jameson JL, eds. Endocrinology, 5th ed. Philadelphia, PA: Elsevier; 2006; used with permission [Citation ends].

May be helpful in selected cases of ectopic ACTH syndrome to localise tumour.

Sensitivity 97%; specificity 85%.[43]Sawka AM, Jaeschke R, Singh RJ, et al. A comparison of biochemical tests for pheochromocytoma: measurement of fractionated plasma metanephrines compared with the combination of 24-hour urinary metanephrines and catecholamines. J Clin Endocrinol Metab. 2003 Feb;88(2):553-8. https://academic.oup.com/jcem/article/88/2/553/2845079 http://www.ncbi.nlm.nih.gov/pubmed/12574179?tool=bestpractice.com

Sensitivity 90%; specificity 98%.[43]Sawka AM, Jaeschke R, Singh RJ, et al. A comparison of biochemical tests for pheochromocytoma: measurement of fractionated plasma metanephrines compared with the combination of 24-hour urinary metanephrines and catecholamines. J Clin Endocrinol Metab. 2003 Feb;88(2):553-8. https://academic.oup.com/jcem/article/88/2/553/2845079 http://www.ncbi.nlm.nih.gov/pubmed/12574179?tool=bestpractice.com

MIBG scintigraphy is very useful for detection of extra-adrenal phaeochromocytomas and metastases of malignant phaeochromocytoma. Sensitivity 87% to 94%; specificity 92% to 99%.​[33]Jacobson AF, Deng H, Lombard J, et al. 123I-meta-iodobenzylguanidine scintigraphy for the detection of neuroblastoma and pheochromocytoma: results of a meta-analysis. J Clin Endocrinol Metab. 2010 Jun;95(6):2596-606. https://academic.oup.com/jcem/article/95/6/2596/2598082 http://www.ncbi.nlm.nih.gov/pubmed/20392867?tool=bestpractice.com [39]Wong KK, Arabi M, Bou-Assaly W, et al. Evaluation of incidentally discovered adrenal masses with PET and PET/CT. Eur J Radiol. 2012 Mar;81(3):441-50. http://www.ncbi.nlm.nih.gov/pubmed/21295930?tool=bestpractice.com

[Figure caption and citation for the preceding image starts]: Meta-iodobenzylguanidine (MIBG) scan demonstrating intensely focal tracer activity in the left adrenal gland consistent with phaeochromocytoma in a 56-year-old woman with HTN, elevated plasma noradrenaline (norepinephrine) levels, and a 3 cm left adrenal mass seen on cross-sectional anatomical imagingAvram A, Fig LM, Gross MD. Semin Nucl Med. 2006 Jul;36(3):212-27; used with permission [Citation ends].[Figure caption and citation for the preceding image starts]: Malignant, metastatic phaeochromocytoma demonstrated by 123-I-meta-iodobenzylguanidine (MIBG) and CT in a 31-year-old woman after bilateral adrenalectomy and persistent HTN complicated by renal insufficiency and recent development of superior vena cava (SVC) obstruction; (A) anterior chest and abdomen scan. L = normal liver uptake while arrows depict multiple, abnormal foci of 123-1-MIBG in metastatic phaeochromocytoma deposits in the mediastinum and para-aortic regions; (B) chest CT identifies the superior mediastinal mass responsible for SVC obstruction (white arrow)Rubello D, Bui C, Casara D, et al. Eur J Endocrinol. 2002 Jul;147(1):13-28; used with permission [Citation ends].

Phaeochromocytomas are metabolically active tumours and focally concentrate FDG in approximately 75% cases, FDG uptake being more common in malignant phaeochromocytoma than in benign phaeochromocytoma.

Some phaeochromocytomas that poorly concentrated MIBG were well visualised with FDG, and all phaeochromocytomas that failed to accumulate FDG were detected with MIBG.[44]Shulkin BL, Thompson NW, Shapiro B, et al. Pheochromocytomas: imaging with 2-[fluorine-18]fluoro-2-deoxy-D-glucose PET. Radiology. 1999 Jul;212(1):35-41. http://www.ncbi.nlm.nih.gov/pubmed/10405717?tool=bestpractice.com

Sensitivity 100%; specificity 100%.[45]Hoegerle S, Nitzsche E, Altehoefer C, et al. Pheochromocytomas: detection with 18F DOPA whole body PET - initial results. Radiology. 2002 Feb;222(2):507-12. http://www.ncbi.nlm.nih.gov/pubmed/11818620?tool=bestpractice.com

Hypokalaemia in a hypertensive patient suggests hyperaldosteronism, but normokalaemia does not exclude it.

This is not a reliable screening test as many patients with aldosterone-producing adenomas may have normal serum potassium levels.

Blood sample for aldosterone to plasma renin activity ratio measurement is obtained in the morning after 30 minutes in the seated position: ratio >23.6; sensitivity 97%, specificity 94%.[46]Gopan T, Remer E, Hamrahian AH. Evaluating and managing adrenal incidentalomas. Cleve Clin J Med. 2006 Jun;73(6):561-8. http://www.ncbi.nlm.nih.gov/pubmed/16784156?tool=bestpractice.com [47]Tiu SC, Choi CH, Shek CC, et al. The use of aldosterone-renin ratio as a diagnostic test for primary hyperaldosteronism and its test characteristics under different conditions of blood sampling. J Clin Endocrinol Metab. 2005 Jan;90(1):72-8. https://academic.oup.com/jcem/article/90/1/72/2835601 http://www.ncbi.nlm.nih.gov/pubmed/15483077?tool=bestpractice.com

Plasma aldosterone levels should be measured in the early morning (8 am) after at least 4 hours of recumbency.[46]Gopan T, Remer E, Hamrahian AH. Evaluating and managing adrenal incidentalomas. Cleve Clin J Med. 2006 Jun;73(6):561-8. http://www.ncbi.nlm.nih.gov/pubmed/16784156?tool=bestpractice.com

The patient should be maintained on a high-sodium diet.

Confirmatory test. Sensitivity 100%; specificity 76.5%.[47]Tiu SC, Choi CH, Shek CC, et al. The use of aldosterone-renin ratio as a diagnostic test for primary hyperaldosteronism and its test characteristics under different conditions of blood sampling. J Clin Endocrinol Metab. 2005 Jan;90(1):72-8. https://academic.oup.com/jcem/article/90/1/72/2835601 http://www.ncbi.nlm.nih.gov/pubmed/15483077?tool=bestpractice.com Saline loading is obtained by administration of 2 to 4 L of isotonic NaCl solution over 2 to 4 hours.

Non-invasive method to assess for the source of aldosterone excess.[37]Avram AM, Fig LM, Gross MD. Adrenal gland scintigraphy. Semin Nucl Med. 2006 Jul;36(3):212-27. http://www.ncbi.nlm.nih.gov/pubmed/16762612?tool=bestpractice.com [Figure caption and citation for the preceding image starts]: Left adrenal aldosteronoma depicted with dexamethasone suppression NP-59 imaging: 57-year-old woman with biochemical evidence of hyperaldosteronism and a left adrenal mass. Abdominal CT (A) demonstrates a 2 cm left adrenal mass (black arrow), anterior and posterior abdominal NP-59 scans (B and C) on the third day post-injection; anterior and posterior abdominal NP-59 scans (D and E) on the fifth day post-injection; abnormal left adrenal uptake (black arrows) occurs early, before day 5 post-injection (B and C); normal uptake in liver (L), bowel (B), and gallbladder (GB)Rubello D, Bui C, Casara D, et al., Eur J Endocrinol. 2002 Jul;147(1):13-28; used with permission [Citation ends].

Adrenal cysts do not enhance on contrast-enhanced CT scan.[14]Kawashima A, Sandler CM, Fishman EK, et al. Spectrum of CT findings in nonmalignant disease of the adrenal gland. Radiographics. 1998 Mar-Apr;18(2):393-412. http://www.ncbi.nlm.nih.gov/pubmed/9536486?tool=bestpractice.com

In the healing stage of the disease the adrenal glands become calcified and atrophic.

Characterisation of primary adrenal lesion and evaluation for loco-regional and distant metastases; sensitivity 100% and specificity 94%.[48]Yun M, Kim W, Alnafisi N, et al. 18F-FDG PET in characterizing adrenal lesions detected on CT or MRI. J Nucl Med. 2001 Dec;42(12):1795-9. http://jnm.snmjournals.org/cgi/content/full/42/12/1795 http://www.ncbi.nlm.nih.gov/pubmed/11752075?tool=bestpractice.com [Figure caption and citation for the preceding image starts]: 18-fluoro-2-deoxyglucose (FDG) PET-CT: adrenocortical carcinoma. 51-year-old woman with Cushing's syndrome and large, multilobulated and intensely 18-F-FDG avid left adrenal mass and metastatic aortocaval and left para-aortic lymph nodesGross MD, Avram A, Fig LM, et al. Q J Nucl Med Mol Imaging. 2007 Sep;51(3):272-83; used with permission [Citation ends].

Sensitivity 74% to 100%; specificity 66% to 100% for detection of malignancy when adrenal lesion FDG uptake ≥ liver.[39]Wong KK, Arabi M, Bou-Assaly W, et al. Evaluation of incidentally discovered adrenal masses with PET and PET/CT. Eur J Radiol. 2012 Mar;81(3):441-50. http://www.ncbi.nlm.nih.gov/pubmed/21295930?tool=bestpractice.com [Figure caption and citation for the preceding image starts]: Left adrenal metastasis (arrow) depicted by 18-fluoro-2-deoxyglucose (FDG) PET-CT (A-C) in a patient with a non-small cell lung cancer (arrow); corresponding chest (D) and abdominal (E) CT scans identify the lung primary and the adrenal metastasis (arrow)Avram A, Fig LM, Gross MD. Semin Nucl Med. 2006 Jul;36(3):212-27; used with permission [Citation ends].

However, 16% of benign adrenal lesions have FDG uptake > background uptake.

Cannot differentiate between primary versus metastatic adrenal gland neoplasm.

For diagnostic evaluation of patients with history of cancer (particularly lung, breast, and kidney) and no other metastases.

Phaeochromocytoma should always be excluded before the procedure in order to avoid a hypertensive crisis.

There is a 2.8% complication rate including abdominal pain, adrenal haematoma, haematuria, pancreatitis, pneumothorax, formation of an adrenal abscess.[5]Young WF Jr. Clinical practice. The incidentally discovered adrenal mass. N Engl J Med. 2007;356:601-10. http://www.ncbi.nlm.nih.gov/pubmed/17287480?tool=bestpractice.com

There is a small risk of needle tract metastasis (0.3% of subjects with long-term follow-up).[2]Agency for Healthcare Research and Quality. Management of clinically inapparent adrenal mass. Feb 2002 [internet publication]. http://archive.ahrq.gov/clinic/tp/adrentp.htm

A benign cytologic diagnosis on FNA does not exclude malignancy because of high false-negative rate of this procedure.[1]Grumbach MM, Biller BM, Braunstein GD, et al. Management of the clinically inapparent adrenal mass ("incidentaloma"). Ann Intern Med. 2003 Mar 4;138(5):424-9. https://www.acpjournals.org/doi/full/10.7326/0003-4819-138-5-200303040-00013?rfr_dat=cr_pub++0pubmed&url_ver=Z39.88-2003&rfr_id=ori%3Arid%3Acrossref.org http://www.ncbi.nlm.nih.gov/pubmed/12614096?tool=bestpractice.com Generally FNA biopsy is not performed for suspected adrenocortical carcinoma due to concerns regarding seeding of malignancy along the needle tract. If there is a high suspicion surgical resection is indicated. FNA biopsy is not usually performed for suspected granulomatous disease, although this is a known cause of false-positive results on FDG PET.