Differentiating benign from malignant

Theo Falke and Robin Smithuis

Radiology Department of the Groene hart hospital in Gouda and the Rijnland hospital in Leiderdorp, the Netherlands


Update: 19-5-06
Adrenal masses are seen in 1% of CT-examinations.
Most of these masses are benign.
Even in patients with a known malignancy these masses are usually non-functioning adenomas.
The issue is how to differentiate these benign adenomas from malignant adrenal masses.

Adrenal masses: benign versus malignant

  • adenoma
Right adrenal gland with a lipid-rich adenoma

The most common tumor in the adrenal gland is the adenoma.
Adenomas are reported to occur in from 1.4% to 8.7% of postmortem examinations.
Adenomas large enough to be recognized at abdominal CT examination are found in 1% of patients.

  • CT-measurement
ROI at least 1/2 size of mass. Do not include adjacent periadrenal fat.


Adrenal adenomas have two properties that differentiate them from non-adenomas. (1)
1. 70% of adenomas contain high intracellular fat (lipid-rich adenomas) and will be of low attenuation on unenhanced CT.
2. Adenomas rapidly wash out contrast.

Unenhanced CT. Using a safe threshold value of 10HU on a native CT scan results in a sensitivity of 70% and a high specificity of 98% for the diagnosis of an adenoma.
A density equal to or below 10 HU is considered diagnostic of adenoma.
30% of adrenal adenomas do not contain enough intracellular lipid to have a density of less than 10 HU and cannot be differentiated from malignant masses on an unenhanced CT.
These adenomas are called lipid-poor (3).

  • the washout formula
Absolute enhancement wash out > 60% = adenomaRelative enhancement wash out > 40% = adenoma

Enhanced and Delayed scan.
Although on the initial enhanced CT (at 60 sec) most adenomas show mild enhancement, while malignant tumors and pheochromocytomas show strong enhancement, there is too much overlap in attenuation values to allow differentiation between malignant and benign.
A number of these adenomas however can be differentiated from malignant masses on the basis of their fast wash-out of contrast.
The wash-out can be calculated by comparing the attenuation value at 60 sec with the attenuation value on a delayed scan at 15 minutes.

The most commonly used formula is the 'enhancement wash out' formula presented on the left (sometimes called absolute wash out).
Attenuation values are measured on unenhanced, initial enhanced (at 60 sec) and delayed CT (at 15 min) .

Click here to go to the Adrenal Characterization Calculator.

A calculator for the enhancement washout formula aswell as another formula for the 'relative wash out' (only based on the enhanced and delayed scan) is given in reference 1.
You only need to fill in the attenuation values and an answer is given whether the mass is probably an adenoma or not. (1)

  • Algorithm
Algorithm for differentiating adenomas from non-adenomas.

CT-Algorithm benign versus malignant

Mostly an adrenal mass will be found on an enhanced CT that is performed in patients with abdominal complaints or patients that are referred for lungcarcinoma staging.
As differentiation between benign and malignant is usually not possible on the initial enhanced CT (at 60sec), ordering the patient back for a dedicated adrenal-CT is the best strategy ( although some prefer MRI).
If on the unenhanced-CT the density is equal to or below 10 HU the lesion is considered to be an adenoma and no further workup is neccessary
If the density is more than 10 HU the wash out should be calculated.
If the washout is not compatible with an adenoma, a biopsy can be performed if a definitive diagnosis is crucial to the patients management.

  • adenoma lungca
Adenoma in patient with lungcarcinoma. LEFT: initial enhanced CT (22HU). RIGHT: unenhanced CT (-19HU).

On the left an adrenal mass identified during staging for lungcarcinoma.
On an enhanced CT at 60 sec the attenuation value was 22HU.
The next day patient was ordered back for dedicated adrenal CT.
On the unenhanced CT the attenuation value was -19HU indicating the presence of a lipid-rich adenoma.
No further work up was needed.

  • CT wash out
Dedicated adrenal protocol in a patient with an adrenal mass

On the left a dedicated adrenal protocol in a patient with an adrenal mass.
On the unenhanced CT there is a small homogeneous mass that is well defined. The density is 9 HU, which is characteristic of a lipid-rich adenoma.
Although the protocol should have stopped at that moment, i.v. contrast was given to determine the washout.
The enhancement washout = (43 - 22) : (43 - 9) = 62% indicating a fast washout characteristic of an adenoma.
The lower the density on the unenhanced CT and the faster the washout the more confident you can be in making the diagnosis of an adenoma..

  • CT inhomogeneous lesion
Adenoma on the right is homogeneously of low density. Metastasis on the left is inhomogeneous and centrally of low attenuation due to necrosis.

The discriminating parameters on CT based on attenuation values only apply to homogenous lesions.
Metastases may have a relative low HU due to central necrosis.

  • opposed phase
Bilateral adrenal masses with signal drop on opposed phase MRI diagnostic of lipid containing adenomas.


Although chemical shift MRI is commonly performed, it is believed by some not to provide additional information beyond that which is already available on unenhanced CT (4).
The characterization of a lesion as an adenoma relies on the ratio of a decreased relative signal intensity from in phase to opposed phase images and the ratio of adrenal mass and various organs on T2-weighted and chemical shift images.
There are no reported studies yet that compare unenhanced CT, delayed enhanced CT, and chemical shift for the discrimination between adenomas and nonadenomas.

  • morphologic criteria with density measurements
In patients with a known extra-adrenal malignancy a total score > 7 points was highly accurate for the diagnosis metastasis.

Morphologic features

Adenomas are generally small, homogeneous and well-defined lesions with clear margins. Although the presence of these features are non-specific the absence strongly suggests a nonadenoma.
In a retrospective study Gufler et al (5) combined morphologic criteria with the density measurements on unenhanced CT and found a high accuracy in differentiating adrenal adenomas from metastases in patients with a known malignancy. They proposed a scoring system based on density (10% of HU), contour (plus 2 if blurred), homogeneity (plus 1 if inhomogeneous) and size (in cm).
By setting a threshold at 7 points all but one lesion in 56 patients were classified correctly.

  • Fine-needle aspiration
Fine-needle aspiration in an adrenal mass shows a cell with droplets of fat typical for a adrenocortical cell. As this sample was taken from an adrenal mass this finding was characteristic of an adenoma.

Percutaneous biopsy

With the new imaging algorithms there is a decreasing need to perform percutaneous Fine needle aspiration (FNA) for definitive characterization. Because a benign cytological diagnosis does not exclude malignancy, FNA cannot be recommended as a standard procedure in the diagnostic work-up.

Major complications (2.8-3.6%) include pneumothorax that requires treatment, hemorrhage, abscess, pancreatitis, and seeding along the track.
Prior to FNA a clinical and laboratory assessment should be done to exclude the possibility of a pheochromocytoma as FNA may precipitate a hypertensive crisis.

  • Biopsy
CT guided FNA of the left adrenal gland via a posterior approach. The black dot at the end of the needle (green arrow) indicates that the tip of the needle is seen in this image.

Adrenal biopsies can be performed via a posterior approach with the patient in the prone position. The risk of a pneumothorax can be reduced by caudal angulation of the gantry.
The lateral decubitus approach is also safe and well tolerated. The patient is placed 'downside' for whichever adrenal gland that is being biopsied. This position elevates the diaphragm on the lesion side and decreases the volume of the lung, thereby reducing the risk of the needle traversing the lung en route to the adrenal gland.

  • Transhepatic biopsy
Non-specific adrenal mass in a patient with lung cancer, who was a possible candidate for curative surgery. Transhepatic CT-guided FNA proved the presence of metastatic disease.

The reported accuracy of FNA is 90-96%. Findings from FNA are most likely to be conclusive if the mass is a metastatic tumor.
FNA should only be performed when the diagnosis is crucial to patient management (figure).

Specific Adrenal tumors

  • Adrenal carcinoma

Primary Adrenocortical carcinoma

Adrenocortical carcinomas are rare and often diagnosed at an advanced stage. They tend to be large at diagnosis. Patients present with abdominal pain, palpable mass or Cushing's syndrome (50%). The combination of Cushing's syndrome and virilization is frequently found. CT demonstrates a large inhomogeneous mass with heterogeneous enhancement. An adrenal carcinoma is not likely to be less than 5 cm in diameter. Central necrosis is common. Calcification is seen in 20-30% of cases.

  • Carcinoma 1
Large inhomogeneous mass with central calcification typical of an adrenal carcinoma.

Most tumours spread by both the haematogenous (lung, liver and bone) and the lymphogenous route. Metastases to the contralateral adrenal, or simultaneous bilateral involvement may occasionally be found.

  • Carcinoma 2
LEFT: Same case as above. Tumor thrombus extents into right atrium and causes tricuspid valve insufficiency. RIGHT: Tumor emboli in the lung following surgery..

As in renal cell carcinoma tumour tends to spread early by direct invasion of surrounding structures. Extension of the tumour into the renal vein or inferior vena cava is not unusual. MR can be helpful in defining the cephalic extent of the tumour . This is important to the surgeon to gain vascular control.

  • Carcinoma 3
Venous extention of the tumor into the inferior vena cava.

On the left a patient with a small right adrenal carcinoma on CT with high SI on T2-weighted MRI, indistinguishable from lipid-poor adenoma except for invasion into the inferior vena cava.

  • Metastases
LEFT: Diffuse enlargement and irregular enhancement of the adrenal glands due to metastatic disease.RIGHT: Pathologic specimen. Notice extension of tumor into the peripelvine fat.


Adrenal metastases are found in 27% of postmortem studies in patients with malignant neoplasms. Lung and breastcarcinoma and melanoma are the most common primary tumors.
A diagnosis of adrenal metastasis is important in examining patients with cancer because the metastasis indicates inoperable stage IV disease (except in ipsilateral renal cancer).

  • Metastases 2
T1-weighted MRI demonstrates left adrenal metastasis in a patient with previous resection of the right liver lobe for metastasis.

Adrenal metastases have no specific imaging features. Statistically most non-adenomas are metastases.
On the left a patient with partial liver resection for metastasis of a colon carcinoma. Left adrenal metastasis in follow up with no specific imaging findings. The lesion is indistinguishable from a true lipid poor adenoma or non-adenoma such as a neuroendocrine tumour, primary adrenocortical carcinoma, sarcoma or lymphoma and infection.


As mentioned above adenomas can be divided into lipid-rich adenomas ( 10HU on unenhanced CT). Lipid-poor adenomas do contain intracellular lipid but not enough to be of an attenuation value The NIH state-of-the-science conference has proposed a minimal standard evaluation for adenomas to rule out endocrine function (4).

  • Myelolipoma
LEFT: adrenal mass containing islands of fat specific for the diagnosis myelolipoma.RIGHT: different case with high SI on T1WI indicating fat in myelolipoma.


Myelolipomas are benign tumors composed of bone marrow elements. Usually they are easy to recognize on CT or MR because they contain areas of fat. Calcifications are seen in 20% of cases.

  • Myelolipoma 2
Myelolipoma mainly composed of fat.

On the left another adrenal mass mainly composed of fat. Diagnosis myelolipoma.

  • Pheochromocytoma
Phaeochromocytoma (adrenal paraganglioma) on CT and MRI. There is strong enhancement on enhanced CT and very high signal intensity on T2-weighten MRI.


Pheochromocytomas are paragangliomas arising from the adrenal medulla. They are hormonally active in 90% of cases. Morphologic findings on CT and MRI include large variation in size, homogeneity, and margination of the tumours and significant enhancement in most cases. On MRI tumours have a low SI on T1-weighted images and a very high SI on T2-weighted images.

  • Extra-adrenal paraganglioma
Extra-adrenal paraganglioma on the left side of the aorta in Zuckerkandle's organ. Notice the very high signal on the T2-weighted MRI.

Pheochromocytomas are sometimes called the 10% tumor because they are associated with a 10% risk of malignancy, 10% of the tumors are bilateral, 10% are hormonally inactive and 10% are extra-adrenal (figure).
Usually, tumors are larger than 3 cm when seen. They are highly vascular, and larger tumors are prone to hemorrhage and necrosis, even when they are benign.

  • adrenal-hemorrhage
LEFT: chronic adrenal hemorrhage demonstrates a mass-like aspect of the left adrenal gland that is hyperintense in T1 and T2 MRI with an hypo-intense halo representing hemosiderin.RIGHT: Neonatal hemorrhage demonstrates a mass-like aspect of the right adrenal gland that is hyperintense in T1 and T2 with an hypointense ring which represents hemosiderin.


Extensive adrenal hemorrhage may occur at any age and under various circumstances such as severe stress as in surgery, sepsis, burns, hypotension, trauma, hemorrhagic diathesis and underlying conditions such as adenoma, cyst and tumour.

  • Cyst
Patient with a left adrenal cyst on T2-weighted TSE (left) and fat-suppressed T1W-image after i.v. injection of Gadolineum (right).


Cysts may be of any size and in most instances are unilateral. Large cysts may be complicated by hemorrhage and consequent onset of acute symptoms. Pathological substrates include epithelial , endothelial, parasitic, and pseudocysts. Most importantly lesions show a thin wall and no enhancement after intravenous contast material.