eMedicine Specialties > Oncology > Carcinomas of Endocrine Organs

Adrenal Carcinoma: Differential Diagnoses & Workup

Author: Bagi RP Jana, MD, Assistant Professor, University of Central Florida College of Medicine; Attending Physician, Department of Medicine, Florida Hospital Cancer Institute, Orlando
Coauthor(s): Kush Sachdeva, MD, Southern Oncology and Hematology Associates, South Jersey Healthcare, Fox Chase Cancer Center Partner
Contributor Information and Disclosures

Updated: Dec 4, 2009

Differential Diagnoses

Adrenal Adenoma
Neuroblastoma
Pancreatic Cancer
Renal Cell Carcinoma

Other Problems to Be Considered

In children, consider the following:
Neuroblastoma (particularly neonates)
Nephroblastoma
Congenital adrenal hyperplasia
Metastatic adrenal deposits
Ganglioneuroma/ganglioneuroblastoma

In adults, consider the following:
Pheochromocytoma
Massive macronodular adrenal hyperplasia
Functional ovarian tumors (although easily distinguishable with good imaging modalities such as abdominal CT or MRI scans)
Adrenal myelolipoma
Adrenal angiomyolipomas
Metastatic deposits
Adrenal hamartoma
Adrenal teratoma
Plexiform neurofibromas
Adrenal amyloidosis
Various adrenal granulomas (eg, tuberculosis, blastomycosis, histoplasmosis)
Various soft-tissue sarcomas

Workup

Laboratory Studies

  • Include screening tests that can exclude excess hormone production when evaluating all primary adrenal masses.
  • The best screening tests for Cushing syndrome are the standard 1-mg dexamethasone suppression test and the 24-hour urinary cortisol excretion test. The recent recognition of the relatively high prevalence of subclinical Cushing syndrome in adrenal incidentalomas (some reports suggest a prevalence as high as 5-8%) that may otherwise appear hormonally silent informs the policy of some experts to perform more in-depth testing of the HPA axis in patients with identified adrenal masses. Such testing would include the screening tests mentioned as well as diurnal rhythm evaluation with 8 am and midnight serum or salivary cortisol estimations, corticotropin-releasing hormone (CRH) stimulation test, serum adrenocorticotropic hormone (ACTH) estimations (generally found to be low), and serum dehydroepiandrosterone (DHEAS) levels (also generally found to be suppressed). Alternatively, 24-hour urinary cortisol and its metabolites can be measured.
  • Screen for hyperaldosteronism by using simultaneous aldosterone and renin levels to compute aldosterone-to-renin ratios.
  • Screen for virilization syndromes using serum adrenal androgens (androstenedione, dehydroepiandrosterone, dehydroepiandrosterone sulfate), serum testosterone, and 24-hour urinary 17 ketosteroids.
  • Plasma estradiol and/or estrone tests can help screen for feminization syndromes.
  • The evaluation of adrenal masses also must include screening for possible pheochromocytoma, including, at a minimum, a 24-hour urinary estimation of catecholamines (epinephrine, norepinephrine, dopamine) and metabolites (particularly metanephrines and normetanephrines). In addition, plasma metanephrines and catecholamines can be assayed.

Imaging Studies

  • CT scans and MRI
    • Adrenal CT scans and MRI are the imaging studies of choice. The typical case is characterized by a large unilateral adrenal mass with irregular edges. The presence of contiguous adenopathy serves as corroborating evidence. While the issue of exactly what cutoff dimension size of adrenal masses should elicit a decision for surgical removal irrespective of hormonal functionality, clearly larger tumors have a greater chance of being carcinomatous. The National Italian Study Group review of adrenal incidentalomas demonstrated that 90% of AC cases had diameters of 4 cm or larger on radiologic imaging. This study, based on a cohort of 887 patients, showed that using the 4 cm cutoff resulted in a 90% sensitivity but a poor specificity.1
    • Targeted CT scans of the adrenal using 3- to 5-mm sections offer the best resolution and are particularly useful in detecting tumors that are 1 cm or smaller.
    • Intravenous contrast generally is not necessary for localization of adrenal masses but is useful for demonstrating vascularity and clarifying sites of metastases. Some reports have also shown that adrenal adenomas compared with ACs have a much earlier washout of contrast enhancement and that this may be of diagnostic utility. The contrast washout at 5 minutes postinjection is approximately 50% versus 8% in adenomas versus nonadenomas, and at 15 minutes, the contrast washout is approximately 70% versus 20%.
    • Accumulating evidence suggests that low attenuation values on unenhanced CT scans can distinguish benign adrenal adenomas from AC or metastatic adrenal deposits that have attenuation values generally greater than 20 Hounsfield units (HU). Authorities suggest that adenomas have HU values of 10 or less. However, many caveats significantly limit the clinical utility of this. Authorities also suggest using norms for HU values in intravenous contrast studies to assist in distinguishing adrenal adenomas from AC. The sensitivity and specificity for the 10 and 20 HU cutoffs in distinguishing adenomas from nonadenomas, including AC and pheochromocytoma, were 40.5% and 100% for adenomas and 58.2% and 96.9% for nonadenomas. These numbers suggest that, while limited as a screening instrument, the HU score has considerable utility in making definitive diagnoses when the scores are either less than 10 HU or greater than 20 HU.
    • The MRI, in particular, shows significant utility in distinguishing adrenocortical carcinoma from nonfunctional adenomas and pheochromocytomas. The malignant lesions tend to be intermediate-to-high density on T2 imaging, while the nonfunctional adenomas are low intensity, and pheochromocytomas have a very high signal intensity. On gadolinium–diethylenetriamine pentaacetic acid (DTPA) contrast-enhanced MRIs, adenomas generally demonstrate mild enhancement with rapid contrast washout, while ACs show rapid and intense enhancement with sluggish washout. The relatively higher fat content of adrenal adenomas compared with ACs has also been used in the new chemical shift imaging (CSI) MRI protocols to further enhance the distinguishing capacity of these studies.
  • Ultrasonography
    • This test has less sensitivity in detecting adrenal tumors and is highly user-dependent in its interpretation and quality of results.
    • It has particular utility, however, in the follow-up of previously detected incidentalomas.
  • Iodocholesterol scans rarely are indicated in suspected cases of AC, and the findings generally are negative in this setting, unlike in steroid-secreting adrenal adenomas.
  • Arteriography and venography currently have very little, if any, place in the diagnostic evaluation of adrenal masses suspected to be AC.
  • The following are the major imaging features that serve as red flags for a possible AC on adrenal imaging:
    • Irregular shape
    • Large size (larger than 4 cm in diameter)
    • Intralesional calcification
    • Tumor heterogeneity on both plain and contrast enhancement, which may indicate intralesional hemorrhage, necrosis, or both (Inhomogeneous density estimates by CT in various parts of the tumor on both plain and contrast-enhanced images may also indicate intralesional hemorrhage.)
    • Unilateral location
    • High CT attenuation values (especially with >20 HU)
    • Evidence of tumor invasion of local structures or extension into major vessels

Other Tests

  • Because the histologic analysis of these masses may be unreliable, fine and/or core tissue needle aspiration biopsies (percutaneous route) generally are not recommended except for possible metastatic deposits.
  • Fine-needle aspiration and core tissue biopsy
    • The fine-needle and/or percutaneous core biopsies may be CT-guided or ultrasound-guided. Presently, the only setting where this is justified is in the evaluation of patients with a known malignancy, in order to exclude adrenal metastases.
    • Fine-needle aspiration or core tissue biopsy has no role in the diagnostic workup of adrenal incidentalomas because of both the minimal likelihood of a definitive diagnosis and the potential for tumor seeding into the retroperitoneum.
    • Never perform fine-needle aspirations on any adrenal mass without first definitively excluding a pheochromocytoma; otherwise, the procedure may precipitate a potentially fatal crisis.

Histologic Findings

A specific histologic diagnosis may be difficult in a case that is lacking clinical evidence of metastasis. Some of the macroscopic features that suggest malignancy include a weight of more than 500 g, the presence of areas of calcification or necrosis, and a grossly lobulated appearance.

In the Weiss system, which is considered the standard for determining malignancy in adrenocortical tumors, tumors are scored from 0 to 9, with a higher score correlating with increased malignancy.2 As an adjunct to the Weiss score, Soon et al studied the use of microarray gene expression profiling to discriminate between adrenocortical adenomas and carcinomas; they found that the combination of IGF2 and Ki-67 overexpression identified adrenocortical carcinomas with 96% sensitivity and 100% specificity.3

Cortical tumors

These typically have a yellowish-brown appearance on the cut surface. Pathologic features suggestive of malignancy are the large size of the primary tumor (tumor weights >100 g suggest malignancy); high mitotic rate; atypical mitoses; high nuclear grade; large areas of necrosis; low percentage of clear cells; diffuse cellular architecture; and evidence of capsular, lymphatic, or vascular invasion.

Tumors may have broad fibrous bands separating them into nodules, and they often have a variegate appearance, a zona glomerulosalike appearance, or a fasciculata and reticularis appearance. Still, other areas may show near-total dedifferentiation.

Most of the cells are lipid-poor compared to typical adrenocortical cells, and they have an eosinophilic cytoplasm. Pleomorphic bizarre-looking cells and multinucleate giant cells also may be evident. Predicting the hormonal products of a particular tumor based on histologic appearance is impossible.

Distinction between adrenocortical and adrenomedullary tumors

These have distinctive histologic appearances and immunohistochemical staining patterns. While adrenomedullary tumors stain positive for neuroendocrine markers (eg, synaptophysin, neuron-specific enolase, chromogranin A), adrenocortical cells stain positive for D11, with very little overlap. ACs are virtually always unilateral. One report suggests that 2-10% of cases may be bilateral at initial diagnosis, but this finding has not been replicated. Ectopic adrenocortical tumors are exceedingly rare.

Staging

Staging for adrenal carcinoma, according to the International Union Against Cancer4 :

  • Tumor criteria
    • T1 - Tumor diameter £ 5 cm with no local invasion
    • T2 - Tumor diameter > 5 cm with no local invasion
    • T3 - Tumor of any size with local extension but not involving adjacent organs
    • T4 - Tumor of any size with local invasion of adjacent organs
  • Lymph node criteria
    • N0 - No regional lymph node involvement
    • N1 - Positive regional nodes
  • Metastasis criteria
    • M0 - No distant metastasis
    • M1 - Distant metastasis
  • Stages
    • Stage 1 - T1, N0, M0
    • Stage 2 - T2, N0, M0
    • Stage 3 - T1 or T2, N1, M
      • T3, N0, M0
    • Stage 4 -T3, N1, M0
      • T4, any N, M0
      • Any T, any N, M1
Fassnacht et al argue that the International Union Against Cancer has limited prognostic value. After reviewing 492 patients in the German adrenocortical carcinoma registry who were diagnosed between 1986 and 2007, these researchers proposed that the prognostic value would be improved if stage 3 disease were defined by the presence of positive lymph nodes, infiltration of surrounding tissue, or venous tumor thrombus, and if stage 4 were restricted to patients with distant metastasis.5

More on Adrenal Carcinoma

Overview: Adrenal Carcinoma
Differential Diagnoses & Workup: Adrenal Carcinoma
Treatment & Medication: Adrenal Carcinoma
Follow-up: Adrenal Carcinoma
References
Further Reading
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Further Reading

Related eMedicine topics
Adrenal Carcinoma (Pediatrics)

Adrenal Carcinoma (Radiology)

Adrenal Metastases (Radiology)

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Keywords

adrenal carcinoma, AC, adrenocortical carcinoma, adrenal cancer, adrenocortical cancer, primary adrenocortical malignancies, malignant adrenocortical neoplasms, malignant adrenal tumors, malignant adrenocortical tumors, adrenocortical masses, adrenal incidentalomas

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Contributor Information and Disclosures

Author

Bagi RP Jana, MD, Assistant Professor, University of Central Florida College of Medicine; Attending Physician, Department of Medicine, Florida Hospital Cancer Institute, Orlando
Bagi RP Jana, MD is a member of the following medical societies: American Medical Association and American Society of Clinical Oncology
Disclosure: Nothing to disclose.

Coauthor(s)

Kush Sachdeva, MD, Southern Oncology and Hematology Associates, South Jersey Healthcare, Fox Chase Cancer Center Partner
Disclosure: Nothing to disclose.

Medical Editor

Michael Perry, MD, MS, MACP, Nellie B Smith Chair of Oncology Emeritus, Professor, Department of Internal Medicine, Division of Hematology and Oncology, University of Missouri/Ellis Fischel Cancer Center
Michael Perry, MD, MS, MACP is a member of the following medical societies: Alpha Omega Alpha, American Association for Cancer Research, American College of Physicians, American College of Physicians-American Society of Internal Medicine, American Medical Association, American Society of Clinical Oncology, American Society of Hematology, International Association for the Study of Lung Cancer, and Missouri State Medical Association
Disclosure: Bionumerik Consulting fee Consulting; Proactya Consulting fee Consulting; GSK Consulting fee Consulting; NovoNordisk Consulting fee Consulting; Amgen Honoraria Speaking and teaching; GSK Consulting fee Speaking and teaching

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Managing Editor

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Benjamin Movsas, MD is a member of the following medical societies: American College of Radiology, American Radium Society, and American Society for Therapeutic Radiology and Oncology
Disclosure: Nothing to disclose.

CME Editor

Rajalaxmi McKenna, MD, FACP, Southwest Medical Consultants, SC, Department of Medicine, Good Samaritan Hospital, Advocate Health Systems
Rajalaxmi McKenna, MD, FACP is a member of the following medical societies: American Society of Clinical Oncology, American Society of Hematology, and International Society on Thrombosis and Haemostasis
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Chief Editor

Jules E Harris, MD, Clinical Professor of Medicine, Division of Hematology/Medical Oncology, Department of Internal Medicine, University of Arizona College of Medicine at Tucson; Consulting Staff, Arizona Cancer Center
Jules E Harris, MD is a member of the following medical societies: American Association for Cancer Research, American Association for the Advancement of Science, American Association of Immunologists, American Society of Hematology, and Central Society for Clinical Research
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