Incidentally Discovered Adrenal Masses*
RICHARD T. KLOOS, MILTON D. GROSS, ISAAC R. FRANCIS, MELVYN KOROBKIN, AND BRAHM SHAPIRO
Divisions of Endocrinology and Metabolism (R.T.K.), and Nuclear Medicine (R.T.K., M.D.G., B.S.) The Department of Internal Medicine, and The Department of Radiology (I.R.F., M.K.), The University of Michigan and Department of Veterans Affairs Medical Centers, Ann Arbor, Michigan 48109-0028
I. Introduction
II. Prevalence of Incidentally Discovered Adrenal Masses
III. Differential Diagnosis of Incidentally Discovered Ad- renal Masses
A. Hypersecretory vs. nonhypersecretory adrenal masses
1. Epidemiology of nonhypersecretory adrenal adenomas
2. Hypersecretory adrenal masses
B. Benign vs. malignant masses
1. Patients without known extraadrenal primary malignancy
2. Patients with known extraadrenal primary malig- nancy
3. Size criteria
4. Serial imaging protocols
5. CT imaging criteria
6. MRI imaging criteria
C. FNA biopsy of the adrenal gland
D. Adrenocortical scintigraphic characterization of in- cidentally discovered adrenal masses
1. Underlying principles
2. Scintigraphic imaging patterns in unilateral le- sions
3. Scintigraphic imaging patterns in bilateral lesions
4. Significance of concordant imaging patterns with contralateral suppression of radiotracer uptake
IV. Summary and Conclusions
I. Introduction
B EFORE 1974, the literature contained 178 clinical cases of nonhypersecretory adrenal cortical tumors (see Table 1 for nomenclature) (4). Since the early 1980s, incidentally dis- covered adrenal masses have become a common clinical problem as a result of the more widespread use of high resolution anatomical imaging procedures [computed to- mography (CT), magnetic resonance imaging (MRI), ultra- sound]. In patients without a known extraadrenal primary
malignancy, the vast majority of these lesions are benign and nonhypersecretory (Fig. 1) (5, 6). These same lesions are present in a significant fraction (in some series the majority) of incidentally discovered adrenal masses in patients with known extraadrenal primary malignancies. However, it is important to distinguish these benign nonhypersecretory le- sions from those in which intervention, or the lack thereof, may alter patient morbidity and mortality. These latter ad- renal lesions would include biochemically hypersecretory masses and both primary and metastatic malignancies. The current clinical approach to incidentally discovered adrenal masses must balance diagnostic costs, discomfort, risks, con- sequences of false-positive results, and low disease preva- lence against the value of making an expeditious diagnosis that may result in curative therapy in the minority of patients in whom intervention would be indicated. Widely practiced management algorithms are based heavily upon statistical models attempting to optimize these variables. Anatomical imaging (CT, MRI, and ultrasound) characteristics (7-9) and mass size (10-12) are frequently unable to reliably distin- guish between these various etiologies. Fine needle aspira- tion (FNA) cytology is an invasive procedure with well doc- umented risks of complications. FNA is most helpful in distinguishing adrenal from nonadrenal tissue (e.g. metas- tases), and is least helpful in distinguishing benign adrenal adenomas from primary adrenocortical carcinomas (4, 13- 19). Adrenocortical scintigraphy noninvasively provides functional and anatomical information and is most useful in combination with a preceding biochemical evaluation. The high sensitivity of adrenocortical scintigraphy begins to di- minish when mass size is less than 2 cm in diameter (20, 21). This article reviews the prevalence of incidentally discovered adrenal masses, their differential diagnosis along with their prevalences, and currently used strategies for evaluation of adrenal masses.
II. Prevalence of Incidentally Discovered Adrenal Masses
CT is reported to identify adrenal masses as small as 0.5 cm or smaller in diameter (22-24). Adrenal masses are found in approximately 0.35-4.36% of patients imaged with CT for reasons other than suspected adrenal pathology (Table 2). Such lesions are referred to as adrenal “incidentalomas.” However, based on the approximately 4-fold greater inci- dence of adrenal adenomas at autopsy (Table 3), it is clear
Address reprint requests to: Richard T. Kloos, M.D., University of Michigan Medical Center, University Hospital, 1500 East Medical Center Drive, B1G412 Box 0028, Ann Arbor, Michigan 48109-0028.
*Partial support for this manuscript was provided by the NIH Train- ing Program in Endocrinology and Metabolism Grant 5 T32 DK- 07245-17 and the Cancer Research Training in Nuclear Medicine Grant NCI 2 T32 CA-09015-19.
| "Euadrenal" | This term is used to describe a patient's hormonal status which is grossly normal in the clinical and biochemical sense of global adrenal secretion. As with the term "euthyroid" in regards to thyroid-secretory status, "euadrenal" does not address the issues of focal hypersecretion or hyposecretion, nor does it address glandular morphology. This term does not exclude possible subtle hypersecretion without overall obvious biochemical abnormality and implies the absence of a recognized pathological hypersecretory condition warranting immediate clinical intervention. |
| Hypersecretory vs. nonhypersecretory | The term "hypersecretory" is applied to adrenal mass lesions which produce sufficient hormonal secretions so as to be recognizably abnormal on standard, global biochemical screening procedures such as the 1·mg overnight dexamethasone suppression test for glucocorticoid autonomy, or plasma and/or urinary catecholamine evaluation for the diagnosis of pheochromocytoma. [Nevertheless, some published reports indicate that 80% or more of patients with adrenal incidentalomas that are "nonhypersecretory" by this definition may in fact demonstrate subtle evidence of excess hormone production when evaluated by more sensitive biochemical testing procedures (1-3).] |
| Function vs. nonfunction | We have chosen not to use the term "function" to describe hormonal biochemical status; rather we refer to "function" in the sense of the ability of a mass lesion to accumulate sufficient NP-59 or other adrenocortical radiotracers to permit scintigraphic visualization. As most nonhypersecretory adrenal adenomas accumulate sufficient NP- 59 to generate a concordanta scintigraphie pattern, we consider these masses to be "functioning." Destructive or space-occupying lesions that are not visualized by NP-59, and thus yield discordant" images are considered "nonfunctioning." |
ª See Table 8 for adrenal scintigraphy nomenclature.
120
100
Adrenal tumors, no.
Benign nonfunctional
80
Benign functional
Malignant
60
40
20
0
0
20 30 40 50 60 70 80
90
Age, yr
that routine screening CT, despite its high spatial resolution, does not, in fact, identify many adrenal masses harbored by the population at large, some of which exceed 0.5 cm in diameter. This prediction is consistent with oncological ana- tomicopathological data which have shown that only 20%- 41% of adrenal gland metastases are detected by CT (46). This may, in part, reflect the fact that relatively thick (e.g. 1.0 cm) scan slices are used for routine abdominal imaging. Thus, it is possible that a further increase in the prevalence of inci- dentally discovered adrenal masses may occur if the spatial resolving capacity of abdominal imaging technology progresses, if abdominal imaging is used more frequently, and if the thickness of routine abdominal imaging slices is decreased.
III. Differential Diagnosis of Incidentally Discovered Adrenal Masses
A. Hypersecretory vs. nonhypersecretory adrenal masses
The differential diagnosis of adrenal masses and their rel- ative prevalences as incidentalomas are shown in Tables 4 and 5. Values at the higher end of the range are most likely skewed by the small sample sizes of the studies from which they were derived.
1. Epidemiology of nonhypersecretory adrenal adenomas. The majority of incidentally discovered adrenal masses are nonhypersecretory benign adrenal adenomas, representing 36-94% (more likely 70-94%) of all adrenal masses in non-
| Study | Total patients | Scan increment | Scan thickness | Study qualifications | Frequency of adrenal masses |
|---|---|---|---|---|---|
| Glazer et al., 1982 (7) | 2200 | NSª | NS | Excluded those with abnormal biochemistry, clinical suspicion of adrenal disease, cysts, or myelolipomas. Included oncology patients | 0.60% |
| Prinz et al., 1982 (25) | 1423 | NS | NS | Included all adrenal tumor types Included oncology patients | 0.35% |
| Abecassis et al., 1985 (6) | 1459 | 1-2 cm | 1-1.5 cm | Excluded metastatic surveys in oncology patients Included oncology patients otherwise Included all adrenal tumor types | 1.30% |
| Belldegrun et al., 1986 (26) | 12000 | 1 cm | 1 cm | Included staging studies in oncology patients Included all adrenal tumor types | 0.70% |
| Kley et al., 1990 (24) | 2568 | NS | NS | Imaged for nonendocrinologic disorders | |
| Total adrenal tumors ≥ 0.2 cm | 10.86% | ||||
| Adrenal tumors 0.2-0.9 cm | 6.50% | ||||
| Adrenal tumors 1.0 cm or greater | 4.36% | ||||
| Adrenal tumors > 5 cm | 0.27% | ||||
| Herrera et al., 1991 (5) | 61054 | NS | NS | Included symptomatic and known hypersecretory tumors Included all adrenal tumor types Included oncology patients | 3.38%b |
| Excluded patients with previous or concurrent malignancy Excluded those with abnormal biochemistry Excluded those with clinical suspicion of adrenal disease Excluded tumors with local symptoms Excluded patients with strong suspicion of malignancy Included only tumors > 1 cm, well-circumscribed, and no adjacent local invasion | 0.42% |
ª NS, Not specified.
b Includes symptomatic and known hypersecreting tumors.
oncological and general patient populations (6, 25, 47, 48, 50, 58, 60). The reported prevalence of adrenal adenomas and nodules in autopsy and tissue pathology series varies widely and ranges as high as 68% (42, 68). This reflects the fact that a sharp distinction between accessory cortical nodules, focal hyperplasia, and true adenomas cannot always be made. The resultant inconsistency of tumor classification most signifi- cantly impacts on the reporting of small lesions that range from microscopic to approximately 2-8 mm in diameter (28, 69, 70). Thus, the reported varying frequencies reflect indi- vidual selection criteria and the detail of the examinations performed. In tumors greater than 2-8 mm in diameter, the variability of findings between series is less. Nonhyperse- cretory adrenocortical adenomas are found in autopsy and tissue pathology series in 1.05-32% of cases; however, most series are in the range of 1.38-8.9% (Table 3). These lesions occur equally in males and females and are uncommon in patients under the age of 30 yr, and their prevalence increases with age (Tables 3 and 6). Limited data have associated a higher prevalence of nonhypersecretory adrenocortical ad- enomas with blacks when compared with whites (33), dia- betes mellitus (2- to 5-fold increased prevalence of adrenal adenomas over nondiabetics) (27, 44), obesity (71), and fa- milial multiple endocrine neoplasia syndromes (71, 72). One study argued against a relationship to diabetes mellitus (38). The controversial relationship between adrenal adenomas and hypertension has been the most thoroughly investigated (Table 7). Frank glucocorticoid or mineralocorticoid hyper-
secretion from these adenomas or nodules as a cause of hypertension appears to be an infrequent occurrence, while subtle states of hypersecretion of unknown physiological significance appear more common (1, 2, 73). Alternatively, some have speculated that these adenomas or nodules are a secondary manifestation of hypertension-induced adrenal arteriosclerotic disease (74).
2. Hypersecretory adrenal masses. Hypersecretory masses re- quire specific therapy (most often surgical extirpation). Ev- idence of excess secretion of cortisol, androgens, estrogens, mineralocorticoids, and catecholamines should be consid- ered in patient history and physical examination. Clues ob- tained from this evaluation should obviously be pursued. However, the need for initial adequate biochemical screening of all adrenal masses without an obvious radiological diag- nosis (simple cyst, myelolipoma), regardless of a nonsug- gestive history and physical examination, cannot be over- emphasized. Partially cystic lesions also warrant complete evaluation regarding their secretory status and as potential malignancies. It is well established that CT and MRI are unable to distinguish hypersecretory from nonhypersecre- tory lesions (23, 75-77). Clinically silent hypersecretory adrenal masses are well represented in the literature [pheo- chromocytomas (3, 5, 16, 22, 23, 25, 66, 78-82), aldosterono- mas (66, 83), cortisol-secreting tumors (2, 5, 66, 67, 82-92), while hormone-secreting adrenocortical carcinomas com-
| Study | Adenoma criteria | Study qualifications | Total patients | Adenoma frequency | % Adenoma in males | % Adenoma in females |
|---|---|---|---|---|---|---|
| Aubertin and Ambard, 1904 (34) | "Macroscopic" | Nephritis and other illnesses without HTNb | 19 | 5.30% | c | c |
| Oppenheimer and Fishberg, 1924 (35) | c | Successive autopsies | 50 | 2% | c | c |
| Rineheart et al., 1941 (36) | Approximately 1 cm | Adults, normal blood pressure | 100 | 3.00% | C | c |
| Dempsey, 1942 (37) | 0.6 cm and over | Adults, normal blood pressure | 50 | 8% | c | c |
| Castleman and Smithwick, 1943 | Visible at sympathectomy | Ages 18 to 56 yr, HTN (most 200+/100+ | 100 | 6% | c | c |
| (surgical series) (45) | mm Hg) | |||||
| Russi and Blumenthal, 1945 (44) | Average size 1 cm | All ages | 9000 | 1.45% | 1.20% | 2% |
| Age 30+ years | 7380 | 1.76% | c | c | ||
| Commons and Callaway, 1948 (38) | >0.3 cm | All ages | 7437 | 2.86% | 2.88% | 2.84% |
| Age 30+ years | 6151 | 3.45% | € | c | ||
| Schroeder, 1953 (39) | Adenoma or focal hyperplasia | ¢ | 4000 | 1.38% | c | c |
| Dawson, 1956 (40) | 0.2-1.6 cm | Adults, 0.3-0.4 cm adrenal gland sections | 45 | 8.90% | c | c |
| Holmes et al., 1956 (41) | c | Normal size heart, presumably normal BPª | 53 | 1.90% | c | c |
| Shamma et al., 1958 (42) | 1.5 cm and over | Age 16+ yr, normal BP | 220 | 1.80% | c | c |
| Spain and Weinsaft, 1964 (43) | 0.5+ cm, solitary and unilateral | Age 70+ yr | 200 | 15.50% | 2% | 29% |
| Devenyi, 1967 (29) | >0.3 cm | All ages | 5120 | 3.55% | 3.61% | 3.62% |
| Age 31+ yr | 3272 | 5.65% | 5.56% | 5.75% | ||
| Kokko et al., 1967 (32) | >0.5 cm | All ages | 2000 | 1.05% | c | c |
| Age 10+ yr | 1495 | 1.41% | c | c | ||
| Hedeland et al., 1968 (27) | 0.2 cm and over | . Age 20+ yr, 0.1 cm sections | 739 | 8.70% | 10.34% | 7.16% |
| Dobbie, 1969 (30) | Nodule > 1 cm | Age 24-78 years, 0.3-cm sections | 50 | 32% | c | c |
| Yamada and Fukunaga, 1969 (31) | >0.3 cm | Age 20+ yr, Japanese ancestry | 948 | 5.40% | C | ¢ |
| Granger and Genest, 1970 (28) | 0.8 cm and over | No pediatric or obstetric cases | 2425 | 2.52% | 2.58% | 2.43% |
| Russell et al., 1972 (33) | "Grossly visible" | All ages | 35000 | 1.97% | 1.92% | 2.05% |
| Abecassis et al., 1985 (6) | 1.0 cm and over | Age 18+ yr | 988 | 1.90% | c | c |
” BP, Blood pressure.
b HTN, Hypertension.
c Not specified.
| Mass etiology | Frequency among incidentalomas (5,6,22,25,26,47-60) |
|---|---|
| Adrenal cortex | |
| Adenoma | |
| Nononcology and nonselected series | 36-94% |
| Oncology patients | 7-68% |
| Pigmented nodules ["black adenomas"] | a |
| Nodular hyperplasia | 7-17% |
| Carcinoma | 0-25% |
| Adrenal medulla | |
| Carcinoma | a |
| Ganglioneuroma | 0-6% |
| Ganglioneuroblastoma | a |
| Pheochromocytoma | 0-11% |
| Neuroblastoma (rare outside of early childhood) | a |
| Other adrenal masses | |
| Angiomyolipoma | a |
| Abscess | a |
| Amyloidosis | a |
| Cysts (61) | 4-22% |
| Parasitic (echinococcal most common): 6% of cysts | 0-1% |
| Retention: 2% of cysts | <1% |
| Endothelial (lymphatic or angiomatous): 44% of cysts | 2-10% |
| Degenerative adenomas: 7% of cysts | 0-2% |
| Pseudocyst (most likely due to hemorrhage into normal tissue or adrenal neoplasm): 39% of cysts | 2-9% |
| Other (e.g. dermoid): 2% of cysts | <1% |
| Cytomegalovirus | α |
| Fibroma Granulomatosis (histoplasmosis, coccidiomycosis, blastomycosis, tuberculosis, sarcoidosis) | @ a |
| Hamartoma | a |
| Hematoma/hemorrhage | 0-4% |
| Hemangioma/lymphangiomas | α |
| Lipoma | 0-11% |
| Liposarcoma | a |
| Myelolipoma [0.2% autopsy incidence (6,62)] | 7-15% |
| Myoma | a |
| Neurofibroma | a |
| Teratoma | @ |
| Xanthomatosis | ₡ |
| Metastases | |
| Nononcology and nonselected series | 0-21% |
| Oncology patients | 32-73% |
| Breast carcinoma | a |
| Kidney | a |
| Leukemia | a |
| Lung cancer | a |
| Lymphoma | a |
| Melanoma | a |
| Ovarian | a |
| Others | a |
| Pseudoadrenal masses (more common on the left side) including lesions of the: | 0-10% |
| Diaphragmatic crura | @ |
| Dilated inferior vena cava | a |
| Gallbladder | a |
| Kidney | a |
| Liver | a |
| Lymph nodes (para-aortic, paracaval, retropancreatic, retrocrural) | a |
| Omentum | a |
| Pancreas | a |
| Primary retroperitoneal neoplasms, hematomas, and cysts | a |
| Small and large bowel | a |
| Spleen/accessory spleen | a |
| Stomach/gastric diverticulum | a |
| Other vessels [especially aneurysms, varices (63), tortuosities, renal veins] Technical artifacts (particularly in patients with prior abdominal surgery) | a a |
” Rare or not clearly defined in the literature. [Adapted with permission from J. L. Siekavizza et al .: Urology 18:625-632, 1981 (65); and M.
D. Gross et al .: J Clin Endocrinol Metab 77:885-888, 1993 (64). @ The Endocrine Society.]
| Hypersecretory state | Frequency among incidentalomasª | Screening test | Costª U.S. $ |
|---|---|---|---|
| Pheochromocytoma | 0-11% | Serum catecholamines | $130 |
| Or 24 h urinary catecholamines | $ 95 | ||
| Or 24 h urinary metanephrines | $ 73.50 | ||
| Cushing's or pre-Cushing's syndrome | 0-12% | 1 mg oral overnight dexamethasone suppression test for 0800 h serum cortisol® | $ 70 |
| Mineralocorticoid hypertension | 0-7% | Blood pressure | $ 0 |
| Serum potassium | $ 40ª | ||
| Additionally in hypertensive patients: upright plasma renin | $ 84 | ||
| activity and plasma aldosterone concentration paired | $150 | ||
| Masculinizing tumor | 0-11% | Serum dehydroepiandrosterone sulfate (Serum total and free testosterone and congenital adrenal hyperplasia evaluation in virilized females and boys with precocious sexual development) | $ 90 |
| Feminizing tumor | rare | (Serum estradiol in feminized men) | |
| Total cost | $273.50-$659 |
@ Data from Refs. 2, 3, 5, 22, 25, 29, 49-51, 56-59, 66 and 67.
Preferred over urinary free cortisol (see text).
” At the University of Michigan Medical Center (December 1994).
d Electrolytes (usually obtained previously for other reasons).
| Author(s) | |||||||
|---|---|---|---|---|---|---|---|
| Russi and Blumenthal, 1945 (44) | Commons and Callaway, 1948 (38)ª | Spain and Weinsaft, 1964 (43) | Kokko et al., 1967 (32) | Devenyi 1967 (29)6 | Russell et al., 1972 (33) | ||
| Total patients | 9,000 | 7,437 | 200 | 505 | 5,120 | 35,000 | 57,262 |
| Age (years) | Averaged | ||||||
| Premature | 0% | c | c | c | c | c | 0% |
| 0-9 | 0.15% | 0% | C | 0% | 0% | 0.15% | 0.06% |
| 10-19 | 0% | 0% | C | c | 0% | 0.36% | 0.09% |
| 20-29 | 0% | 0.51% | e | c | 0% | 0.39% | 0.14% |
| 30-39 | 0.27% | 1.97% | c | c | 1.37% | 1.62% | 1.31% |
| 40-49 | 1.60% | 2.38% | c | c | 3.89% | 2.95% | 2.71% |
| 50-59 | 1.98% | 2.78% | c | c | 5.24% | 4.18% | 3.55% |
| 60-69 | 2.22% | 4.93% | C | C | 6.01% | 4.57% | 4.43% |
| 70 and over | 1.76% | 4.03% | 15.50% | c | 8.22% | 5.21% | 6.94% |
Actual age group years: ” 0-10, 10-20, etc; b 0-10, 11-20, 21-30, etc.
” Not specified or not studied.
d Studies weighted equally as variations are likely due to selection criteria and examination detail rather than prevalence variations.
prise 24-96% (most 50-70%) of all adrenocortical carcinomas (16, 93, 94)].
a. Pheochromocytoma. Given that the prevalence of pheo- chromocytoma in a nonreferred hypertensive patient pop- ulation with the symptom triad of episodic headache, pal- pitations, and diaphoresis is 5.9% (95), the presence of an incidentally discovered adrenal mass appears to offer a com- parable yield (Table 5). Several series have reported that 19-76% of pheochromocytomas are not diagnosed until after death (78, 80, 96). However, given our inability to noninva- sively determine the malignant potential of pheochromocy- tomas, and which pheochromocytomas will present with crisis (due to spontaneous hemorrhage/necrosis, or emer- gent anesthesia induction), we are reluctant to “expectantly” follow such individuals once identified. Sixty-five percent of pheochromocytomas are reported to have an overlap with adrenal metastases in relative signal intensity on T2- weighted, spin-echo MRI (97), and percutaneous needle bi- opsy of an unsuspected pheochromocytoma may precipitate a hypertensive crisis, severe retroperitoneal bleeding, and even death (98, 99). Several series have reported that up to
80% of patients with unsuspected pheochromocytoma who underwent surgery or anesthesia have died (80, 81, 96, 100). For these reasons, we strongly advocate that a screening biochemical investigation be done in all patients to exclude the possibility of pheochromocytoma. Plasma or urinary cat- echolamines, urinary total metanephrines, and urinary va- nillymandelic acid all have their advocates but are of ap- proximately equal utility; however, some data suggest that the latter may be the least sensitive (100-104). An under- standing of factors that may result in false-negative and false-positive tests results is required for proper test selec- tion, performance, and interpretation (101). Pharmacological stimulation or suppression tests may occasionally be helpful (101, 104). We advocate [131I]metaiodobenzylguanidine (MIBG) scintigraphy for further evaluation of patients with abnormal biochemical screening for pheochromocytoma. [123I or 131]]MIBG and [111 In]pentetreotide (Octreoscan) have nearly equal sensitivity for detection of pheochromocytomas (88%). However, MIBG has the added advantages of greater sensitivity for neuroblastoma (92% vs. 77%) and ganglion- euroma (100%), lack of confounding renal accumulation of
| Study | Total patients | Study qualifications | Frequency | Association claimed | |
|---|---|---|---|---|---|
| Aubertin and Ambard, 1904 (34) | 8 | % | of hypertensive interstitial nephritis patients with adenoma | 37.50% | Association |
| 7 19 | % of nonhypertensive nephritic patients with adenoma % of nonhypertensive nephritic and other illness patients with adenoma | 0% | Suggested | ||
| 5.30% | |||||
| Oppenheimer and Fishberg, 1924 (35) | 30 | % | of hypertensive patients with adenoma | 16.67% | Yes |
| 50 | % | of nonhypertensive autopsy patients with adenoma | 2% | ||
| Rinehart et al., 1941 (36) | 26 | % | of essential hypertension patients (BP, heart wt 410-1000 g) with adenoma | 19.20% | Yes |
| 100 | % | of nonhypertensive autopsy patients (heart wt <350 g) with adenoma | 3.00% | ||
| Dempsey, 1942 (37) | 50 | % | of nonhypertensive patients with adenoma (BP 140-/90- mm Hg, heart weight < 400 g in men. < 300 g in women. | 8% | No |
| 21 | Intermediate group | 9.50% | |||
| 19 | % | of essential hypertension patients with adenoma (BP 160+/90+ mm Hg or 150+/100+ mm Hg, and heart wt 450+ g in men, 350+ g in women) | 15.80% | ||
| Bruger et al., 1944 (68) | HTN defined as 2 or more of the following: (1) systolic BP 140+ mm Hg (2) diastolic BP 90+ mm Hg (3) LVH > 12 mm (4) increased heart wt for age (5) arteriolar sclerosis | No | |||
| 70 | % | of normotensive patients with hyperplastic or adenomatous changes (no size criteria) | 47% | ||
| 65 | % | of hypertensive patients with hyperplastic or adenomatous changes (no size criteria) | 46% | ||
| Russi and Blumenthal, 1945 (44) | 14849 | % | of control population with diastolic BP > 95 mm Hg | 22.36% | Yes |
| 100 | % | of adenoma patients with diastolic BP > 95 mm Hg | 42% | ||
| 9000 | % | of control population with heart wt > 350 g | 13.93% | Yes | |
| 122 | % | of adenoma patients with heart wt > 350 g | 72.90% | ||
| Commons and Callaway, 1948 (38) | 100 | % | of consecutive adenoma autopsies with hypertensive cardiovascular disease (youngest age 42 yr) | 25% | No |
| 1353 | % | of unselected conselective autopsies with | 14.60% | ||
| hypertensive cardiovascular disease (all ages) | |||||
| 100 | % | of consecutive adenoma autopsies with heart wt > 350 g (youngest age 42 yr) | 51% | No | |
| 200 | % | of conselective autopsies with heart wt > 350 g (age > 14 yr) | 62% | ||
| Schroeder, 1953 (39) | 39 | % | of adenoma, focal or diffuse hyperplasia male patients at autopsy with heart wt 350+ g | 84.62% | Yes |
| 32 | % | of adenoma, focal or diffuse hyperplasia female patients at autopsy with heart wt 300+ g | 84.38% | ||
| 71 | % | of adenoma, focal or diffuse hyperplasia patients at autopsy with heart wt 50 g above expected for body wt [heart wt (g) = body wt (kg) x 0.43 (males) or 0.4 (females)] | 95.77% | ||
| 71 | % | of adenoma, focal or diffuse hyperplasia patients at autopsy with certain or probably hypertension (cardiac enlargement and hypertension or nephrosclerosis) | 81.69% | ||
| Dawson, 1956 (40) | 45 | % | of normotensive patients with adenoma at autopsy or adrenalectomy. (BP 110-130/65-80 mm Hg, heart wt < 330 g in men or <300 g in women, no LVH, normal renal histology) | 8.90% | Yes |
| 45 | % | of essential hypertension patients with adenoma (autopsy and adrenalectomy) BP > 150/95 mm Hg heart wt > 400 g in men or >350 g in women due to LVH | 15.60% | ||
| 22 | % | of renal HTN patients with adenoma (autopsy cases with history, renal function tests, and histology) | 4.50% | ||
| Holmes et al., 1956 (41) | 49 | Enlarged heart presumably due to hypertension (250+ g/sm2 body surface) | 6.10% | Yes | |
| 53 | Normal heart wt (175- g/sm2 body surface) | 1.90% | |||
| Study | Total patients | Study qualifications | Frequency | Association claimed | |
|---|---|---|---|---|---|
| Shamma et al., 1958 (42) | 220 | % of HTN patients with adenomas at autopsy (BP 150+/100+ mm Hg or heart wt 500+ g for men, 450+ g for women) | 20.45% | Yes | |
| 78 | % of HTN patients and unilateral or bilateral adrenalectomy with adenomas | 16.67% | |||
| 220 | % of normotensive patients with adenomas at autopsy (BP 140-/90- mm Hg, and heart wt 400- g for men, 350- g for women) | 1.80% | |||
| Spain and Weinsaft, 1964 (43) | HTN defined as "evidence (history, clinical, and autopsy) of existing or previous hypertension" | ||||
| 31 | % of adenoma patients with HTN | NS | No | ||
| 169 | % of nonadenoma patients with HTN | NS | |||
| Devenyi, 1967 (29) | 755 22 | % of autopsy patients age 31-50 yr with essential HTN | 2.60% | NS | |
| % of adenoma patients age 31-50 yr with essential HTN | 9.09% | ||||
| Kokko et al., 1967 (32) | 17 | % of adenoma patients with HTN (BP > 150/100 mm | 58.60% | No | |
| Hg) | |||||
| 110 | % of nonadenoma patients with HTN (BP > 150/100 mm Hg) | 64.40% | |||
| 11 | % of adenoma patients with normal BP | 37.90% | |||
| 57 | % of nonadenoma patients with normal BP | 33.30% | |||
| 1 | % of adenoma patients with borderline HTN | 3.50% | |||
| 4 | % of nonadenoma patients with borderline HTN | 2.30% | |||
| Hedeland et al., 1968 (27) | 620 | % of nonhypertensive patients with an adenoma | 7.90% | No | |
| 119 | % of hypertensive patients (diastolic > 100 mm Hg and EKG or x-ray consistent with LVH or LVH at autopsy) with an adenoma | 12.40% | |||
| Dobbie 1969 (30) | 50 | % | of cortical nodularity patients at autopsy with heart weight above expected for age and sex | 80% | NS |
| 25 | % of nonhypertensive patients with cortical nodule > 1 cm | 40% | NS | ||
| 25 | % of HTN patients with cortical nodule > 1 cm (150+/ 100+ mm Hg, or heart wt 500+ g) | 24% | |||
| 40 | % of normal adrenal architecture patients with HTN (150+/100+ mm Hg) | 12.50% | NS | ||
| 57 | % of mild adrenal nodularity patients with HTN (150+/ 100+ mm Hg) | 29.82% | |||
| 16 | % of distinct adrenal nodularity patients with HTN (150+/100+ mm Hg) | 37.50% | |||
| Yamada and Fukunaga, 1969 (31) | 313 | % of HTN patients [BP > 150/100 mm Hg, or heart wt 400+ g in males, 350+ g in females with borderline BP (140/90 mm Hg)] with adenomas | 15.30% | Yes | |
| 635 | % of nonhypertensive patients with adenomas | 0.50% | |||
| Granger and Genest, 1970 (28) | HTN defined as: BP > 140/90 mm Hg, or BP 160+/<90 and heart wt > 350 g for men and >300 g for women, or if no clinical data available and heart wt > 400 g for men and >350 g for women | Yes | |||
| 1074 | % of HTN patients with adenoma 0.8 cm and over | 4.19% | |||
| 1351 | % of normotensive patients with adenoma | 1.18% | |||
| 1074 | % of HTN patients with nodules (<0.8 cm) | 1.30% | |||
| 1351 | % of normotensive patients with nodules | 0.07% | |||
| 1074 | % of HTN patients with hyperplasia (microscopic | 1.49% | |||
| observation) | |||||
| 1351 | % of normotensive patients with hyperplasia | 0.30% | |||
| Russell et al., 1972 (33) | 608 | % of adenoma patients with essential +/- accelerated HTN (BP 150+/95+ mm Hg) | 34.21% | Yes | |
| 608 | % of non-adenoma patients with essential +/- accelerated HTN (BP 150+/95+ mm Hg) | 25% | |||
NS, Not specified; EKG, electrocardiogram; LVH, left ventricular hypertrophy; BP, blood pressure; HTN, hypertension.
radiotracer, and evaluation of MIBG avidity for potential therapy should the neural crest tumor prove malignant (105). MIBG is specifically taken up by cells of neural crest origin by an active uptake-1 mechanism at the cell membrane and
concentrated intracellularly. Drugs known to interfere with MIBG uptake and/or retention include several antihyper- tensive/cardiovascular agents (e.g. labetalol, reserpine, cal- cium-channel blockers), tricyclic antidepressants, sympatho-
mimetics (including those found in nonprescription decongestants and “diet-aids”), and cocaine, which must be discontinued for an appropriate interval before radiotracer administration. A suitable iodide-containing compound [e.g. saturated potassium iodide solution (SSKI) or strong iodine solution (Lugol’s solution)] is begun before administration of the radiotracer to block thyroid accumulation of free 1311 (half-life 8 days) or 123] (half-life 13.3 h) while laxatives are used to decrease background gastrointestinal activity. [123I]MIBG is an investigational drug, which offers signifi- cantly better radiation dosimetry with superior image qual- ity and identification of more metastatic foci than [13] ]]MIBG. Single photon emission computed tomography (SPECT) im- aging may be performed when indicated. However, the cost and limited availability of sufficiently pure 123I have limited its more widespread use. [123I or 131]]MIBG is administered as a slow intravenous injection. Imaging is generally per- formed after 24 and 48 h with additional imaging after 72 h for [131I]MIBG (105-108). Some data suggest that [123I or 131I]MIBG and [111In]pentetreotide may serve complemen- tary roles (105). The utility of scintigraphy in patients with normal biochemistry and discordant adrenocortical scintig- raphy is uncharacterized.
b. Cortisol-secreting masses. A significant body of data in- dicates that a spectrum of cortisol excess exists and that clinically obvious manifestations may occur relatively late along this spectrum, while loss of diurnal variation and loss of cortisol suppressibility often occur before baseline steroid hormone excretion exceeds established normal limits (3, 73, 82, 87, 89, 90, 109). Because patients with incidentally dis- covered adrenal masses are evaluated due to the presence of a mass, and (by definition) not for clinical symptoms of Cushing’s syndrome, it would not be surprising to find a higher proportion of patients with subtle states of cortisol excess in this group. Thus, we and others have suggested that the cortisol secretory status of patients with incidentalomas be initially investigated with an overnight 1.0 mg dexameth- asone suppression test (3, 73, 90, 109). Given the prevalence of Cushing’s and pre-Cushing’s syndrome (biochemical ev- idence of Cushing’s syndrome without physical stigmata) among patients with incidentalomas (Table 5), and the rel- atively low cost of serum cortisol determination, we disagree with Ross and Aron’s recommendation of abandoning this screening test in the evaluation of incidentalomas (59). One may also consider determination of cortisol secretory rhythm with paired 0800 h and 1600 h cortisol levels (87, 90) or a single 2400 h cortisol value (110). However, studies to sup- port surgical intervention in the presence of an abnormal serum cortisol rhythm with a normal overnight dexameth- asone suppression test, 24 h urinary free cortisol (UFC) ex- cretion, and absence of physical stigmata of Cushing’s syn- drome are not available (3, 73).
As adrenocortical cancers are known to have inefficient steroid hormone biosynthetic mechanisms (111, 112), some of these patients may have elevated urinary excretion rates of 17-hydroxycorticosteroids, 17-ketosteroids, or 17-ketogenic steroids despite a normal 24 h UFC excretion rate (87, 113, 114). Thus, many authors suggest measuring all of these parameters (16, 52, 86). We currently do not advocate this more costly and cumbersome practice for incidentally dis-
covered adrenal masses in patients with unremarkable his- tories and physical examinations, as we anticipate functional NP-59 scintigraphy to demonstrate an imaging pattern sus- picious for a space-occupying or destructive lesion in these unusual cases. This point is discussed further below under adrenocortical scintigraphy.
c. Mineralocorticoid-secreting masses. Blood pressure and se- rum potassium should be measured in all patients to exclude mineralocorticoid excess. Sodium restriction leads to potas- sium retention and minimizes hypokalemia. Thus, moder- ately low sodium diets (<100 mEq/day) may partially ac- count for the approximately 20% of patients with primary aldosteronism without spontaneous hypokalemia (115, 116). The addition of 10-12 g sodium chloride to the patient’s daily dietary sodium intake for 3-7 days may decrease this false- negative rate to approximately 10% [i.e. “easily provoked hypokalemia” (117)]. In patients without hypertension, we do not pursue the diagnosis of mineralocorticoid excess if a random serum potassium is normal (>3.5 mmol/liter). Spontaneous or easily provoked hypokalemia (≤3.5 mmol/ liter), or diuretic-induced hypokalemia (≤3.0 mmol/liter) should prompt further evaluation for primary mineralocor- ticoid excess (59, 117, 118). In patients with hypertension, we also obtain a paired upright (>2 h since supine) plasma aldosterone concentration (PAC) along with PRA. Clearly, these determinations are most accurate when interfering medications have been discontinued for an appropriate in- terval. It is usually suggested that spironolactone and estro- gens be withheld for 6 weeks, diuretics for 4 weeks, and antihypertensive sympathetic inhibitors for 1-2 weeks before biochemical evaluation (117, 118). Prazosin (Minipress), gua- nadrel (Hylorel), and guanethidine (Ismelin) may be used at moderate dosages if some type of antihypertensive pharma- cological therapy is required during the course of evaluation (118). However, we and others have found that adequate exclusion of primary aldosteronism may occur in the ma- jority of patients even in the face of continued antihyper- tensive medications (119). The presence of an elevated PAC along with suppressed PRA suggests the diagnosis of pri- mary aldosteronism regardless of the patient’s medications. Patients taking ß-blockers and antisympathetic agents may have falsely reduced PRA values; however, these agents do not cause elevation of PAC. Patients with elevated PAC and nonsuppressed PRA should undergo further evaluation after discontinuation of all potentially interfering medications. The presence of a normal PAC strongly argues against pri- mary aldosteronism; however, calcium channel blockers may rarely increase PRA and reduce PAC to normal in pa- tients with primary aldosteronism (120-123). The presence of suppressed PRA and PAC with hypokalemia suggests the presence of non-aldosterone-mediated mineralocorticoid hypertension.
d. Sex hormone-secreting masses. Dehydroepiandrosterone sulfate (DHEAS) as a marker of adrenal androgen excess (and also as a marker of adrenal carcinomas) should be measured in all incidentalomas. Reduced DHEAS values may suggest suppression of ACTH and hence normal adre- nal tissue androgen secretion due to autonomous cortisol hypersecretion from the mass (3), and thus DHEAS should not be measured concomitantly with the overnight dexa-
methasone suppression test. Given the rarity of benign ad- renocortical adenomas secreting masculinizing or feminiz- ing hormones, we do not routinely obtain testosterone or estradiol levels as screening tests in asymptomatic patients.
We also do not advocate screening for congenital adrenal hyperplasia in asymptomatic individuals as some propose (124, 125), as NP-59 scintigraphy in uncomplicated cases will suggest a benign process (concordant pattern, see Table 8). Congenital adrenal hyperplasia should, of course, be con- sidered in the differential diagnosis of androgen and min- eralocorticoid excesses.
e. Recommended adequate initial hormonal evaluation. Table 5 suggests a minimal, yet adequate, initial screening evalua- tion for patients with incidentally discovered adrenal masses. Abnormalities detected during this procedure should be further investigated.
B. Benign vs. malignant masses
Once an adrenal mass has been deemed hormonally non- hypersecretory, the possibility of primary or metastatic ma- lignancy must be excluded. Early studies of incidentalomas based predominantly on x-ray and intravenous pyelography were biased toward quite large masses where, not unexpect- edly, high rates of malignancy were found. As a result, sur- gical exploration was favored (57, 126). These data are less relevant to current clinical practice with high resolution CT and MRI detecting a greater total number of masses with a much smaller average size. A summary of the rates of ma- lignancy are shown in Fig. 1 and Table 4.
1. Patients without known extraadrenal primary malignancy. In the clinical setting of patients having no known extraadrenal primary malignancy, the overall rate for discovering a met- astatic or primary adrenal malignancy is low. However, a few studies with limited numbers of patients have reported such lesions and perhaps may have exaggerated their true incidence (Table 4).
2. Patients with known extraadrenal primary malignancy. In the setting of known or suspected extraadrenal primary malig- nancy, a situation in which CT or MRI is widely performed for tumor diagnosis and staging, the incidence of malignancy in incidentally discovered adrenal masses is increased (Table 4). The distinction between a metastasis and other causes of
adrenal masses may be critical in those patients with no other evidence of metastatic disease, as they may benefit from curative surgery of their primary malignancy if the adrenal lesion is not a metastasis. The presence of an adrenal mass in a patient with a known extraadrenal primary malignancy with obvious evidence of other metastatic disease (e.g. to liver, bone, or lymph nodes) does not pose a major manage- ment problem as tumor staging is not altered. From 8-38% of patients with known extraadrenal malignancies have ad- renal metastases at autopsy (65, 127-132); most commonly the primary malignancies are of breast (133), lung, kidney, melanoma, and lymphoma (65, 128). [A 1983 study by Pagani (134) disturbingly reported that 17% of patients with small cell lung cancer and morphologically normal adrenal glands by CT had adrenal metastases demonstrated by percutane- ous FNA.] Pagani and Bernardino (135) reported a 6% rate of adrenal masses on CT among 621 oncology patients. Nielsen et al. (136) reported that 21.4% of patients with non- small cell bronchogenic carcinoma had adrenal masses on CT. Oliver et al. (53) reported adrenal masses on CT in 10% of patients with non-small cell bronchogenic carcinoma with- out other evidence of metastatic malignancy. Malignancy rates of adrenal mass lesions in the setting of a known ex- traadrenal primary malignancy have ranged from 32-73%, while benign masses have been reported in 27-68% of such cases (14, 22, 26, 49, 51, 53-55, 137-139). Further, in this setting, malignancy rates in adrenal masses ≤ 3 cm have ranged from 0-50%, while in adrenal masses larger than 3 cm malignancy rates have ranged from 43-100% (8, 12, 14, 26, 49, 53, 54, 139).
3. Size criteria. Attempts to separate benign from malignant lesions on the basis of anatomical imaging studies initially focused on size (greatest diameter), and subsequently on other characteristics. Management strategies based on adre- nal mass size (3, 5, 7, 14, 16, 23, 26, 47, 49, 52, 59, 140-146) are neither sensitive nor specific (Fig. 2) (10-12). Reports from the earlier literature indicated a high frequency of malig- nancy among all nonhypersecretory adrenal masses (65, 147, 148) and a large size of adrenocortical carcinomas (19). These data reflect the fact that predominantly only large adrenal masses were identified, and that the diagnosis of nonhyper- secretory adrenocortical carcinoma was made late in the course of the disease. Hussain et al. (8) applied logistic re- gression analysis to estimate the probability of a malignant
| Image pattern | Description of pattern | Lesion responsible |
|---|---|---|
| Concordant pattern | Increased radiotracer uptake by the adrenal mass disclosed by previous anatomical imaging study | Benign adrenal adenoma or nodular hyperplasia |
| Discordant pattern | Absent, decreased, or distorted adrenal radiotracer uptake by the adrenal mass disclosed by previous anatomical imaging study | Destructive or space occupying lesion (e.g. primary or metastatic malignancy, adrenomedullary tumor, hemorrhage, cyst, granulomatous disease) Lesion frequently not of adrenal origin. See Table 4 for differential diagnosis of pseudoadrenal masses |
| Nonlateralizing pattern | Normal symetrical adrenal radiotracer uptake despite "adrenal" mass lesion >2 cm in greatest diameter disclosed by previous anatomical imaging study | |
| Nonlateralizing pattern | Normal symetrical adrenal radiotracer uptake despite "adrenal" mass lesion ≤2 cm in greatest diameter disclosed by previous anatomical imaging study | Pseudoadrenal mass possible, but due to the low spatial resolution and other limitations of adrenocortical scintigraphy, some benign adenomas and some destructive or space- occupying lesions may give rise to this pattern |
METASTASES
PRIMARY MALIGNANCIES
PHEOCHROMOCYTOMAS
ADENOMAS
0
1
2
3
4
5
6
7
8
9
10
11
12
13
14
DIAMETER (cm)
mass as a function of tumor size. The probability range in- cluded: 0.16 for a 2-cm mass, 0.48 for a 5-cm mass, 0.62 for a 6-cm mass, and 0.82 for an 8-cm mass. However, these regression model data were created from a patient popula- tion consisting of roughly equal numbers of metastatic le- sions, primary adrenal carcinomas, adenomas, and pheo- chromocytomas. The applicability of this formula to patient populations in which a majority will have benign lesions is questionable. Herrera et al. (5) reported a ratio of 8:1 benign to malignant masses at a cut off of greater than 4 cm in diameter. In more recent reviews of nonhypersecretory uni- lateral masses confined to the adrenal gland and 5 cm in diameter or larger, benign lesions were reported in 13 of 17 (76%) cases by Khafagi et al. (149), and 9 of 9 (100%) cases by Siren et al. (58). Conversely, malignant tumors less than 2.5 cm are well described (8, 10, 20, 21, 143, 150, 151). These data are in agreement with other authors who report that size criteria are of little value toward differentiating benign ad- renal masses from adrenal gland metastases from extraad- renal malignancies (6, 50).
Primary adrenocortical carcinoma is rare (1 per 450,000 to 1 per 1.6 million annual incidence) (152-154). Hormonally nonhypersecretory carcinomas tend to present in males and in older patients (4, 100, 155-157), with a larger size and at a more advanced clinical stage (158). Copeland (16) esti- mated the prevalence of adrenal masses equal to or greater than 6 cm due to benign adrenocortical adenomas as 1 per 4,000, and that of biochemically silent adrenocortical carci- nomas as 1 per 250,000. Thus, at a threshold diameter of 6 cm, more than 60 adrenalectomies would be needed to remove one adrenocortical carcinoma (16). Of 630 incidentalomas in
the literature, 26 were found to be adrenocortical carcinomas (85% of these were >6 cm) (58). However, long term survival from adrenocortical carcinoma is highest when the primary tumor removed is less than 5 cm in diameter (19, 159, 160). Fishman et al. (158) reported a series of adrenocortical car- cinomas (both hypersecretory and nonhypersecretory) in which 24% were 6 cm or less, and 16% were 5 cm or less. Thus, as is intuitively obvious, at some point in their devel- opment primary adrenocortical carcinomas must be small (<5 cm), and it is at this stage that surgical intervention would be most beneficial. However, among small adrenal lesions, primary adrenocortical carcinomas represent only a small minority. Consequently, it does not seem either clin- ically or financially prudent to remove all small adrenal lesions (Table 9). Postoperative complication rates of 20%- 30% for resection of adrenal masses between 1968-1986 have been reported (52, 161). Current operative complication rates are likely to be lower and may be in the 5% range for open posterior adrenalectomies (162). Recently, extraperitoneal and laparoscopic surgical techniques used separately and together have drawn praise as being simple, quickly per- formed, and effective with relatively low (but still present) perioperative morbidity and more rapid postoperative re- covery (163-173).
4. Serial imaging protocols. Serial imaging protocols (5, 7, 12, 16, 47, 50, 52, 140, 144, 145, 174) subject a large number of patients with benign nonhypersecretory adrenal cortical ad- enomas to significant cumulative radiation exposure and financial expense. At our institution the cost of a noncontrast CT scan and interpretation is $827.00 in US dollars, and most
| Test | Cost (U.S.$)ª |
|---|---|
| Computed tomography (including technical and professional fees) | |
| CT scan without iv contrast | $827 |
| CT scan with iv contrast | $1,048 |
| CT scan with and without iv contrast | $1,345 |
| CT guided fine-needle aspiration | |
| Professional fee for fine-needle aspiration | $142 |
| CT scan without iv contrast | $827 |
| Pathology professional and technical fees for cytopathology | $169 |
| Scintigraphy (including technical and professional fees) | Total $1,138 |
| NP-59 scintigraphy | $746 |
| Magnetic resonance imaging (including technical and professional fees) | |
| MRI without iv contrast | $1,369 |
| MRI with iv contrast | $1,563 |
| Unilateral adrenalectomy | |
| Surgical professional fee for uncomplicated unilateral adrenalectomy and postoperative care | $2,683 |
| Anesthesiology professional fee based on a 2.5-h procedure | $535 |
| Operating room fee based on a 2.5-h procedure | $1,786 |
| Recovery room charge based on a 2-h stay | $427 |
| Miscellaneous charges for medications, equipment, laboratory services, etc. for a 5-day | $3,600 |
| hospitalization | |
| Hospital room charge based on a 5-day hospital stay | $2,475 |
| Pathology professional and technical fees for histopathology | $398 |
| Total $11,904 |
ª At the University of Michigan Medical Center (December 1994)
serial imaging protocols require an additional two to five CT scans before the possibility of malignancy is excluded (6, 50, 52, 60). However, Singer et al. (141) reported a metastatic adrenal mass that was stable in size and CT appearance over an 18-month interval. Those patients with malignancies di- agnosed only after demonstrable growth on serial anatom- ical imaging studies may suffer from a delay in diagnosis and definitive therapy. Furthermore, there is the increased op- portunity for metastasis and the very real possibility that the patient may be lost to follow-up (26).
5. CT imaging criteria. An attempt to categorize adrenal masses on the basis of initial imaging characteristics arose as a result of the diagnostic deficiencies of initial size and sub- sequent growth criteria (Table 10). In most instances of CT imaging, 10 mm thick contiguous sections are used for the evaluation of the adrenal glands, and intravenous contrast enhancement is not needed. Three or 5 mm thick contiguous sections are used when greater imaging detail is needed. Intravenous contrast enhancement is not essential in most instances; however, it may be useful in demonstrating the heterogeneous enhancement of malignant adrenal neo- plasms and for exclusion of tumor extension into the inferior vena cava. Oral contrast is recommended for opacification of the gastrointestinal tract to avoid the appearance of pseudo- tumors (Table 4). Imaging may be technically difficult due to lack of body fat only in the thinnest and youngest patients. The image produced by CT reflects electron density of the medium investigated. However, most CT imaging charac- teristics are generally not helpful in distinguishing benign from malignant lesions (10, 50, 51). Hussain et al. (8) reported that mass consistency did not add to the predictive capacity when size and contrast enhancement were known. Logistic regression analysis for enhancing lesions in the range of 2-8 cm in diameter demonstrated that the probability of malig- nancy increased from 0.43 to 0.86 as mass diameter increased.
However, this regression model may be subject to the same faults as mentioned above and to our knowledge has not been tested prospectively. Further, a subsequent publication by this group reverted to surgical decision making based on size criteria alone (resecting lesions >3.5 cm) (26). CT con- trast enhancement characteristics have received little further attention (10). Unenhanced CT attenuation measurements appear to distinguish benign from metastatic lesions better than size criteria (150) yet remain only partially helpful as a significant overlap exists between benign and metastatic le- sions. An unenhanced CT attenuation coefficient of 0 Hounsfield units (HU) or less has been reported as 100% specific for a benign adenoma vs. a metastatic lesion (Fig. 3) (10, 141, 150), but given the high percentage of benign ad- renal adenomas with attenuation values greater than 0 HU, low sensitivities of only 33% (141) and 47% (150) have been reported. Similarly, a threshold of 10 HU results in a sensi- tivity of 58% and specificity of 92% (141). Two recent studies have reported somewhat discrepant results with thresholds of 16.5-18 HU yielding sensitivities of 88%-100% and spec- ificities of 95%-100% (143, 192).
6. MRI imaging criteria. In the MRI assessment of adrenal masses, there are several pulse sequences that are used to provide not only anatomical detail, but also to enable tissue characterization. MRI has the advantages of scanning di- rectly in any plane and does not involve exposure to ionizing radiation. The image produced by MRI reflects the proton density and the chemical milieu of the medium being im- aged. However, the use of MRI to distinguish benign from malignant adrenal masses using adrenal-to-liver or adrenal- to-fat signal intensity ratios on both T1- and T2-weighted spin-echo images has shown a 20%-31% overlap (9, 75, 179, 193, 194). The use of adrenal-to-fat signal intensity ratios on T2-weighted images, T2 relaxation times, and adrenal-to- liver T2 ratios using a 1.5T MRI unit has been reported to
TABLE 10. Imaging characteristics of various adrenal neoplasms on CT, MRI, and ultrasound
Adrenocortical adenoma
Small (<3 cm) and rounded (8, 50)
Smooth, well defined margin (8, 50)
Homogenous (CT, MRI, and ultrasound) (8, 175, 176)
No perceptible wall
Substantially lower than water density on CT (<0-15 HU) (141,143,150,177) [some have soft tissue attenuation values, 10-30% are isodense to liver on CT (178)]
No (175) to mild (50, 178) homogeneous CT enhancement after iv contrast
Isointense to liver (or slightly hypointense) and normal adrenal gland on T1 and T2 weighted MRI (179) [some slightly hyperintense to liver on T2 (178, 180)]
Chemical shift image on MRI depicts high lipid content (78%-92% with opposed-phase images (slightly better sensitivity) or fat- suppressed images, 96% using both techniques) (180)
Hyperintense rim sign on fat-saturated spin-echo MRI (181)
Mild enhancement and quick washout of gadopentetate dimeglumine with dynamic gradient-recalled-echo MRI 77.3% unilateral and solitary, 2.7% unilateral and multiple, 14.6% bilateral and solitary, 5.4% bilateral and multiple (29) No size increase during follow-up (>1 yr)(50)
Hemorrhage, necrosis, and calcification are uncommon but do occur (8)
Vascular by arteriography: reticular network in arterial phase, localized blush in capillary phase (182)
Adrenocortical carcinoma
Equal incidence (155, 157) or possibly more common on left side (158) (60-70% left, 30-40% right) (4, 94, 183), 4%-10% bilateral (4, 184)
Equal or small female predisposition 1:1-1.5:1 (155, 157, 158, 183)
Frequently greater than 6 cm in diameter (8, 157, 177, 185)
Round, or lobulated mass
Irregular margin (8)
Thin, enhancing, capsule-like rim (18%) (158)
Soft tissue density on CT
Inhomogeneous, small tumors may be more homogeneous (CT, MRI, and ultrasound) (8, 176)
May contain cystic areas
Irregular enhancement of solid components on CT with intravenous contrast (8, 185)
Intermediate increased intensity on T2-weighted MRI as compared to liver, slightly higher than fat (179)
Isointense to liver on T1 (179)
Inversion-recovery images less intense than liver, slightly more than muscle (179)
Strong enhancement and slow washout of gadopentetate dimeglumine with dynamic gradient-recalled-echo MRI
Usually unilateral
Local invasion may be present (21%) (158)
Lymph node and other metastasis (lung and liver) may be present (50%) (158)
Frequent hemorrhage, central necrosis (68%) (158, 185)
Calcification in 24-30% (158, 185)
Hypervascular on angiography, often with neovascular changes, capillary blush, or venous pooling (182)
Cysts
Variable size
Right and left glands equally affected, may be bilateral [15% (176)]
3:1 female predilection
Oval or round, sharply marginated
Noncontrast enhancing
Homogeneous water density
No chemical shift image on MRI (180)
Hypointense relative to liver on T1-weighted MRI
High signal intensity on T2-weighted MRI
Walls vary from imperceptible to thick Pseudocysts may have internal septa, more commonly calcify
Soft tissue mass-like component requires further evaluation
May contain wall calcifications on sonography [15-20% (176)] or plain films
Echo-free with back wall enhancement on sonography (176)
May cause stretching and displacement of regional vessels on arteriography (182)
Granulomatous diseases
Usually bilateral, but often asymmetrical involvement
Mild to marked enlargement with active infection: often maintain a normal configuration
Inhomogeneous attenuations with single or multiple central low attenuation zones representing caseous necrosis
Calcifications common: often irregular or amorphous (182), often not visible on plain radiographs
May contain soft-tissue masses and cystic changes
With treatment, may stay the same, revert to normal, or atrophy (over months to years)
Hemorrhage
More common in neonates or patients on anticoagulants, trauma, severe stress
More common on right side, bilateral 10% (up to 20% in trauma)
Increased density (high CT attenuation: 50-80 HU) with acute hemorrhage on unenhanced CT
Streaky infiltration/stranding of periadrenal fat on CT common with blunt trauma Inhomogeneous
Isointense to liver on T1-weighted MRI, increased intensity on T2 images No chemical shift image on MRI (180)
TABLE 10. Continued
Sonography acutely hyperechoic with bright central echo becoming cystic on follow-up, less echogenic with time, disappearance or calcification in 4-9 months (186)
May be indistinguishable from other masses as density of hematoma decreases
May persist as an adrenal pseudocyst
Clustered calcifications suggest past hemorrhage (182)
Lymphoma
More common with non-Hodgkin lymphoma 4%
Usually diffuse rather than nodular
Seldom an isolated site of disease; usually other abdominal involvement (i.e. retroperitoneal lymph nodes) Bilateral in 50%
Well defined, relatively echopenic, and homogeneous on sonogram
Enlarged with either rounded or symmetrical, solid, homogeneous mass on CT Necrosis is uncommon
Rare calcification if ever
Contrast enhancement on CT
Metastases
Variable size (8)
Soft tissue density on CT
Inhomogeneous (175) (may be homogeneous, especially if <3 cm)
Irregular or poorly defined margins
May demonstrate calcification: pattern is variable, typically amorphous (182)
Isointense or slightly hypointense to liver on T1 (179, 187)
Intermediate increased intensity on T2-weighted MRI compared to liver (179) (~75% of cases)
May be indistinguishable from pheochromocytoma
MRI inversion-recovery sequences less intense than liver (179)
Thick, irregular enhancing rim after iv contrast on CT (58-80%) (8, 175)
No chemical shift image on MRI (180)
Strong enhancement and slow washout of gadopentetate dimeglumine with dynamic gradient-recalled-echo MRI Unilateral, or bilateral
May have areas of necrosis or hemorrhage
May be cystic
Invasion of adjacent structures
May have widespread metastatic disease, but solitary adrenal metastases occur Myelolipoma
Variable size
Occasionally bilateral
Fat density (markedly negative HU attenuation values on CT) with septations or fibrous bands of tissue
May be homogeneous or heterogeneous on sonography (188)
Highly echogenic on sonography (85%), hypoechoic (15%) (188)
Sonographic propagation speed artifact possible in tumors of 4 cm or larger
Uncommonly contain intratumoral hemorrhage or infarction
Contrast-enhanced CT may show positive attenuation values in predominantly myeloid tumors Avascular or hypovascular on arteriography (182)
High signal intensity on both T1 and T2 images (179)
May show calcification
Loses signal on MRI chemical shift imaging due to high lipid content
Ganglioneuroblastoma-neuroblastoma
Usually pediatric age group
May show calcification: typically fine, punctate, or psammomatous (182) May be cystic
Pheochromocytoma [0.09% (81)-0.13% (80) incidence at autopsy]
Approximately equal female to male ratio [0.8:1 (189), 1.3:1 (80)]
Right side more often than left side (190)
High signal intensity of T2-weighted MRI (may be higher than metastasis) (50)
Large variation in size, consistency (homogeneous vs. inhomogeneous), and margin (8, 175, 176) Soft tissue density on CT
Small pheochromocytomas and rims of large ones with signal intensities much higher than liver and similar to fat on T2-weighted MRI images, similar to liver on T1 (179)
Inversion recovery images on MRI less intense than liver, but more intense than muscle (179)
Significant enhancement after intravenous contrast on CT (23%) (8)
Calcification is uncommon
Bilateral in 10% of adults, 20% of children, 40-70% of familial forms (174, 191)
19% multiple, 11% malignant, 6% associated with multiple endocrine neoplasia (80)
10% 0 -< 2 cm, 47% 2 -< 5 cm, 33% 5 -< 10 cm, 9% ≥10 cm (189)
Malignancy suggested by retroperitoneal adenopathy, invasion of adjacent structures, or hepatic involvement
Hypervascular on angiography; a hypovascular center may be present; partial to complete hypovascularity has been reported (182)
[Adapted with permission from T. H. Falke: Curr Opin Radiol 3:681-686, 1991 (177); and M. D. Gross et al .: J Clin Endocrinol Metab 77:885-888, 1993 (64). @ The Endocrine Society.]
A
-4.9 HU
reveal similar utility as CT attenuation values (195). A sub- sequent study comparing size, CT attenuation values, MRI signal intensity ratios on T1- and T2-weighted sequences, cal- culated T2 relaxation times, and T2 relaxation time ratios re- ported that attenuation values on non-contrast-enhanced CT was the best discriminator (143). One study attempting to dif- ferentiate benign from metastatic adrenal masses in oncology patients reported sensitivities of 0.71, 0.96, and 1.0; specificities of 0.75, 0.88, 0.91; and overall accuracies of 0.56, 0.71, and 0.88 for CT, plain MRI, and simultaneous precontrast MRI and dy- namic contrast-enhanced MRI, respectively (196). Gadolinium- enhanced dynamic imaging using breath-held techniques have been applied to the differentiation of benign adenomas and malignant neoplasms. In some studies, adenomas demon- strated rapid contrast enhancement with rapid washout. In contrast, malignant neoplasms demonstrated a steeper rate of enhancement and tended to have a slower washout. Using these techniques, accuracies in the range of 90% have been reported; however, recent studies have been unable to repro- duce these high accuracy rates (Refs. 197 and 198 and M. Korobkin, T. J. Lombardi, A. M. Aisen, I. R. Francis, L. E. Quint, N. R. Dunnick, F. Londy, B. Shapiro, M. D. Gross, and N. W. Thompson, manuscript submitted).
One potentially promising imaging technique is the use of chemical shift MRI, which relies on the difference in reso- nance frequency between protons in water and triglyceride molecules to distinguish benign adrenal lesions with rela- tively high lipid content (adenomas, myelolipomas) from adrenal lesions with characteristically low lipid content (me- tastases, hemorrhages, cysts, and pheochromocytomas). Mitchell et al. (180) reported that benign adrenal masses (≥1 cm) demonstrated the typical signal intensity loss on chem- ical shift imaging using opposed-phase images with 95% sensitivity, while 78% showed such loss using fat-suppressed images (Fig. 4). Ninety-six percent of benign lesions in this
A
B
series exhibited this signal intensity loss relative to muscle and liver by at least one of these two methods. These changes were not seen in a cyst, hemorrhages, or metastases (Fig. 5) (180). Thus, the finding of signal intensity loss was 100% specific for adrenal adenomas in this study. The clinical utility of chemical shift MRI to distinguish benign lesions from primary adrenal carcinoma has not been thoroughly characterized (199). While the latter may contain lipid, it is usually less than that in cortical adenomas (199, 200). Further, some metastases, such as those from renal cell carcinomas and some sarcomas (201), as well as primary adrenal lesions, such as pheochromocytomas, have been reported to contain lipid on pathological evaluation. Reinig et al. (202) reported significant quantitative signal loss on chemical shift imaging by pheochromocytomas. Thus, it remains hypothetically possible that neoplasms other than benign adenomas may contain sufficient lipid to “lose” signal on chemical shift imaging and resemble an adenoma. Conversely, there are some lipid-depleted adenomas that can mimic malignant neoplasms. Subsequent studies of chemical shift imaging to characterize incidentally discovered adrenal lesions have
M
A
M
B
been conducted, including the use of somewhat different imaging parameters. One study did not demonstrate the same clinical utility as that initially described above by Mitchell et al. (202). However, other studies and promising ongoing investigations indicate that additional studies con- taining larger numbers of both adrenal adenomas and non- adenomatous masses are necessary before more definite con- clusions regarding the ultimate clinical utility of this technique can be drawn (Refs. 198, 203, and 204 and M. Korobkin, T. J. Lombardi, A. M. Aisen, I. R. Francis, L. E. Quint, N. R. Dunnick, F. Londy, B. Shapiro, M. D. Gross, and N. W. Thompson, manuscript submitted).
C. FNA biopsy of the adrenal gland
Strategies that readily employ FNA biopsy of adrenal masses (7, 49, 178) subject large numbers of patients with
benign nonhypersecretory adrenal cortical adenomas to an invasive procedure that carries a low incidence of well doc- umented serious risks, including pneumothorax, hemotho- rax, fever, bacteremia, hemorrhage, renal and hepatic hematomas, hypotension, abdominal discomfort, nausea, hematuria, and pancreatitis, and a very low but identifiable risk of mortality (11, 13, 14, 55, 64, 137, 205, 206). The most common complication is pneumothorax. Silverman et al. (55) reported a 3% pleural complication rate with two of three patients requiring chest tube placement. Significant pain (enough to prematurely terminate the procedure or require narcotic analgesia) has been reported in 5.6-8.6% of biopsies (139, 206). Hemorrhage has been reported in 5.6% (no trans- fusion required) (139) to 12.7% (hematocrit drop of ≥3%) of patients (206). Bleeding has been reported more commonly in patients whose biopsy was positive for cancer (206). Over- all complication rates range from 8-12.7% when mild and self-limited events are included (55, 134, 139, 206). As with many endocrine tissues, histological distinction between be- nign and well differentiated primary malignancy of the ad- renal gland is often difficult (cytology sensitivity 54-86%) (4, 13-19). Percutaneous aspiration biopsy is best able to dis- tinguish adrenal from nonadrenal tissues and thus may be most useful in patients with known extraadrenal malignan- cies who are at risk for adrenal metastases. Multiple biopsies of a single mass may be necessary for adequate sampling (49, 139). Silverman et al. (55) reported an 86% diagnostic result on initial biopsy. Bernardino et al. (137) reported a correct diagnosis in 83% of their patients on initial biopsy. Four of their nine failures had repeat procedures, which yielded an overall diagnostic accuracy of 90.6% when both biopsies were included. The overall accuracies of FNA cytology range from 80-100% (13, 14, 55, 134, 137, 138, 206, 207). With ex- perienced cytopathologists, the positive predictive value for metastatic disease approaches 100% (14, 106, 137, 205, 206). Silverman et al. (55) reported a sensitivity of 93% and 100% negative predictive value (probability of no disease given a negative result) in masses 3 cm or larger. An overall negative predictive value of 91% was reported, as 7% of their patients with benign FNA results were shown surgically to have malignant disease (all had lesions <3 cm). Rates for nondi- agnostic FNA have ranged from 8-12% (139, 208).
CT is the imaging tool used to guide the biopsy in most instances, although for larger masses ultrasound guidance can be used. For the right sided mass, a posterior approach with the patient in the prone or right decubitus position or a transhepatic approach is used, with care being taken to avoid transgressing the pleura if at all possible. Left sided masses can be more difficult to biopsy as the posterior ap- proach may be the only safe one that is available, although at times an anterior or lateral approach can be used. There is a risk of pancreatitis when using the direct anterior approach to the left sided adrenal mass (209).
D. Adrenocortical scintigraphic characterization of incidentally discovered adrenal masses
1. Underlying principles. Adrenocortical scintigraphy pro- vides both anatomical localization and in vivo functional characterization of the adrenal glands due to the uptake and
accumulation of the radiotracer [e.g. [1311]-60-iodomethyl- norcholesterol (NP-59)] by functioning adrenal cortical tis- sues (106, 205). NP-59 is bound to low-density lipoproteins, which transport it to specific low-density lipoprotein recep- tors located on the adrenal cortical cell membrane (107). After receptor-mediated uptake by adrenal cortex cells, NP-59 is esterified and stored in the intracellular lipid droplets but is not further metabolized (107). Other adrenocortical radio- pharmaceuticals such as [13]]]-19-iodocholesterol and [75Se]- selenomethylnorcholesterol (Scintadren) have similar mech- anisms and utilities as NP-59.
The usual dose of NP-59 is 1 mCi (37 MBq) administered by slow intravenous injection (210). The procedure is best initiated Wednesday through Friday to avoid imaging over the weekend. SSKI (38 mg iodine/drop) 1 drop by mouth three times per day, potassium iodide solution (Pima syrup), Lugol’s solution (6.3 mg iodine/drop), or other suitable iodine-containing preparation (e.g. iodinated glycerol) is be- gun 24-48 h before NP-59 injection and is continued for 2 weeks to block the thyroidal uptake of free 131I derived from in vivo deiodination. If needed, iodide administration may be initiated as late as 30 min before radiotracer administration. Noncompliance may result in scintigraphic visualization of the thyroid gland; however, resultant hypothyroidism is un- likely given the limited dosimetry and has yet to be reported. Administration of a mild laxative is used to decrease bowel NP-59 background radioactivity due to the enterohepatic circulation of this radiopharmaceutical (bisacodyl 10 mg by mouth twice daily, beginning 2 days before planned imag- ing). Adrenal cortical images (at least 50,000 counts per im- age) are obtained by a y-camera interfaced with a dedicated, digital computer on day 5 after NP-59 administration. Ad- ditional images may be obtained on days 6 and 7 post NP-59 injection if needed. The posterior view affords the best vi- sualization of the adrenal glands. A lateral view is usually obtained to assist in adrenocortical localization. Occasion- ally, differentiation of radiotracer accumulation in the right adrenal gland from hepatic activity may be difficult. In this setting, the value of SPECT has yet to be fully characterized (20). However, superior SPECT image quality would be ex- pected with [75Se]selenomethylnorcholesterol over NP-59. High resolution pinhole images give the best resolution but require very long imaging times (up to 60 min per gland) and are seldom used. NP-59 and/or [75Se]selenomethylnorcho- lesterol is widely available commercially throughout the world as a routine imaging agent (especially in most Euro- pean countries). In the United States, NP-59 is available as an investigational new drug and can be obtained on a regular basis from the University of Michigan Nuclear Pharmacy after filing an abbreviated Physician Sponsored Investiga- tional New Drug Application with the U.S. Food and Drug Administration. Some have criticized NP-59 scintigraphy for the 5- to 7-day delay from injection to imaging. However, this turn-around time is comparable to that from FNA scheduling to final cytology results and is considerably shorter (by many months) than that required for serial imaging studies. The adequate interpretation of the adrenocortical scintiscan de- mands an understanding of the preceding endocrinological investigation, thus requiring moderate patient and physician effort, physician-to-physician communication, and schedul-
ing coordination. The scintigraphic study itself requires an initial abbreviated visit for radiotracer injection, and one to two subsequent 1- to 1.5-h return visits for imaging, which may modestly disrupt the patient’s routine daily schedule. The net yield, however, is a proper, cost-effective evaluation with an interpretable result.
2. Scintigraphic imaging patterns in unilateral lesions. The pat- terns of imaging in adrenal scintigraphy with radiocholes- terol analogs have been compared with the patterns of per- technetate thyroid scanning for the characterization of lesions as nonfunctioning (“cold,” and possibly malignant) vs. functioning (“warm,” and probably benign) (21, 106, 211). Nonfunctioning primary and secondary malignancies, as well as other space-occupying or destructive lesions (e.g. cysts and hemorrhages), of the adrenal gland demonstrate an imaging pattern of decreased, distorted, or absent radiocho- lesterol uptake by the affected adrenal gland (11, 13, 54, 212). This imaging pattern is described as “discordant” (Fig. 6 and Table 8) (11). Hormonally hypersecretory (Cushing’s syn- drome, mineralocorticoid excess, hyperandrogen states) and nonhypersecretory adrenal adenomas, as well as a very small minority of hypersecretory adrenocortical carcinomas (149, 213-215), demonstrate NP-59 accumulation and thus scinti- graphic visualization on the side of the known adrenal mass. This imaging pattern is described as “concordant” (Fig. 7 and Table 8) (11). Whether or not adrenocortical carcinomas vi- sualize on scintigraphy is a function of radiotracer uptake per gram of tumor and may correlate with the degree of tumor differentiation (216). The vast majority of hypersecretory ad- renocortical carcinomas are relatively inefficient tumors with respect to both hormone synthesis and radiocholesterol up- take (as are thyroid cancers which image as “cold” lesions on pertechnetate scanning). Thus, in the setting of Cushing’s syndrome due to an adrenocortical carcinoma, there is typ- ically a scintigraphic pattern of bilateral nonvisualization due to poor tracer uptake by the carcinoma and suppressed function of the remaining normal adrenocortical tissues due to suppressed pituitary ACTH secretion (210, 215-217). We have seen only five patients in the past 25 yr with adrenal cancer which scintigraphically demonstrated NP-59 uptake into the adrenal mass or into the metastases after removal of the primary tumor (218, 219). All these patients presented with obvious Cushing’s syndrome or mineralocorticoid ex-
LAS
G
G
cess and abnormal biochemistry; none were incidentally dis- covered. Pasieka et al. (218) reported a total of 18 cases of adrenocortical carcinoma imaged with NP-59 scintigraphy. Only two of these cases were not associated with adreno- cortical hormone hypersecretion. However, both patients were being concomitantly treated with mitotane and cortisol, which may perhaps explain the absence of hormonal secre- tory excess. Reschini and Peracchi (214) have also reported that, very rarely, a well differentiated cortisol-hypersecreting adrenocortical carcinoma may demonstrate uptake of [75Se]- selenomethylcholesterol. Thus, while we emphasize that a biochemical evaluation for hormonal hypersecretion should precede studies to differentiate benign from malignant le- sions, we further believe that the combination of an inciden- tally discovered, NP-59 avid, adrenal carcinoma with normal screening biochemistry would be extremely unlikely. To date, in the setting of a normal biochemical evaluation (and in the absence of interfering medications, e.g. mitotane), NP-59 avidity has been a 100% accurate predictor of benig- nity, while discordant imaging has been a 100% accurate predictor of the absence of a simple nonhypersecretory ad- renal adenoma, and thus has suggested the possibility of malignancy (11, 54, 212). Similar accuracy has been reported for adrenal scintigraphy with [75Se]selenomethylcholesterol (20). Bilaterally symmetrical NP-59 uptake [normal, or non- lateralizing scan pattern (Table 8)] is seen in periadrenal and pseudoadrenal masses of all sizes. Unfortunately, for true adrenal masses ≤ 2 cm, the rate of nonlateralizing scans increases in patients harboring both benign and malignant lesions, including nonhypersecretory adenomas. This latter fact is reflected in the decreased sensitivity and predictive value of a negative test for distinguishing potentially ma- lignant lesions as reported in the evaluation of 229 patients with nonhypersecretory incidentally discovered adrenal masses by Gross et al. (21). In this study a sensitivity of 71%, specificity of 100%, accuracy of 93%, predictive value of a negative test 91% (concordant and nonlateralizing scans), and predictive value of a positive test 100% (discordant scan) was seen with NP-59 scintigraphy. Final diagnosis was es- tablished by adrenalectomy or FNA in 43%, and the remain- der serially followed with clinical, biochemical, and CT ex- aminations (range 6-36 months). Of NP-59 avid lesions,
adrenal adenomas were confirmed by FNA in 11%, adre- nalectomy in 15%, and serial CT examinations in 74% of cases. The nonadenomatous nature of discordant adrenal masses was universally confirmed in all cases by FNA or adrenalectomy.
In the past, no specific follow-up for patients with non- hypersecretory adrenal adenomas has been suggested. How- ever, in a small number of documented instances, progres- sion to frank Cushing’s syndrome has been reported and for this reason patients should, at a minimum, be followed with a complete history and physical examination on an annual basis. Overnight dexamethasone suppression testing in these patients on an infrequent basis may also be reasonable. There are currently no data to support the clinical use of serial NP-59 scintigraphy in the follow-up of this condition.
3. Scintigraphic imaging patterns in bilateral lesions. Incidentally discovered bilateral adrenal masses represent 11-16% of ad- renal masses, but have been infrequently discussed in the literature, with the usual assumptions being that they rep- resent metastases or that the larger of the two masses is malignant (12, 145, 186, 220, 221). Haab et al. (222) reported six patients with bilateral adrenal masses and normal bio- chemical evaluations. Pathological diagnosis after laparot- omy was bilateral metastasis in two and benign bilateral adenoma in four. In this setting, Gross et al. (151) considered NP-59 uptake that equaled or exceeded that of the contralat- eral adrenal gland and/or liver (as a normal reference tissue for radiocholesterol uptake) compatible with a benign pro- cess, while markedly decreased or absent NP-59 uptake com- pared with the contralateral adrenal gland and/or liver was considered abnormal and compatible with a destructive or space-occupying lesion (suggestive of potential malignancy). Adrenal metastases were reported in 45% of their cases, despite the fact that 59% had preexisting malignancies. Fur- ther, 7% of cases had both a nonhypersecretory adrenal ad- enoma and a contralateral metastasis in which the metastasis was the smaller of the two lesions (151). These findings sug- gest that NP-59 scintigraphy may identify those patients with bilateral benign adrenal masses, as well as those masses with the least NP-59 uptake toward which further evaluation with FNA should be directed. The importance of the initial clinical and biochemical evaluations in this setting remains critical, given not only the increased potential for the presence of congenital adrenal hyperplasia, but also the uncommon oc- currence of primary adrenal insufficiency due to bilateral destruction by solid tumor metastases (223-226), hemato- logical malignancy (227-233), hemorrhage (220, 234-236), or infectious (cytomegalovirus, mycobacterium, cryptococco- sis) (223, 237) or granulomatous diseases (223, 238-245).
4. Significance of concordant imaging patterns with contralateral suppression of radiotracer uptake. NP-59 adrenal imaging pat- terns can be considered analogous to standard scintigraphic imaging of functioning nodules in the thyroid (211). Unilat- eral benign nonhypersecretory adrenal nodules produce a range of imaging patterns spanning a spectrum from a func- tional “concordant” (NP-59 avid) nodule with clear visual- ization of the contralateral normal gland to a functional “con- cordant” nodule without visualization of the contralateral
radiographically normal gland (11, 21, 211, 212, 246-249). While some authors have stated that the cause of this latter finding is unclear (250), an obvious postulate is that the NP-59 uptake by normal adrenal cortical tissue is reduced due to suppression (albeit incomplete or partial) of ACTH by the functioning nodule, suggesting a degree of autonomy and relative hypersecretion by the adrenal mass despite overall “normal” biochemistry based upon simple screening tests [such as the 24-h UFC and 1 mg overnight dexameth- asone suppression test, which are probably best suited to detecting more advanced states of cortisol excess and au- tonomy]. Up to 21% of euthyroid “warm” or “hot” auton- omously functioning thyroid nodules may progress to thy- rotoxicosis or borderline thyrotoxicosis (251-253). The natural history of “warm” or “hot” concordant adrenal nod- ules with respect to hormonal secretion is not known but is currently under investigation (73). At present, there is no evidence to suggest that this subset of patients would benefit from adrenalectomy unless clear biochemical evidence of Cushing’s syndrome becomes manifest (with or without frank clinical features). An optimal follow-up schedule for these patients is not known. A prudent approach may be to follow such patients with 6 month follow-up history and physical examinations along with 1 mg overnight dexameth- asone suppression test screening for the first year, then de- creasing this evaluation to an annual frequency for several years, and eventually decreasing the frequency of the bio- chemical evaluation to every 2-5 yr.
The appropriate management of preclinical Cushing’s syndrome is controversial (3, 67). However, given the major adverse effects of excess glucocorticoids on bone density, hypertension, obesity, depression, lipid metabolism, glucose tolerance, and other physiological parameters, it is not un- reasonable to extirpate masses producing nonsuppressible cortisol levels with absent diurnal rhythm. For these reasons, we feel that adrenalectomy by an experienced surgeon is the best approach to manage these hypersecretory, but “clini- cally asymptomatic” masses. Patients with demonstrated contralateral adrenocortical suppression by adrenal scintig- raphy, for whom surgery is elected, must receive periopera- tive glucocorticoid therapy in a manner similar to that used in the setting of frank Cushing’s syndrome to avoid a post- operative Addisonian crisis (3, 85). We feel that identification of these latter patients is another benefit of adrenocortical scintigraphy and may explain previously reported instances of adrenal insufficiency after removal of apparently nonhy- persecretory adrenal adenomas (90). Our experience is that these patients frequently require several months for recovery of the hypothalamic-pituitary-adrenal axis.
IV. Summary and Conclusions
Independently, endocrinology, radiology, and nuclear medicine can not optimally differentiate the etiology of the incidental adrenal mass. Rather, the insight necessary for this task must be contributed by all three disciplines. In- cidentally discovered adrenal masses are being detected at an increasing rate. This trend is expected to continue based on the incidence of adrenal masses in autopsy series and
the increasing use of high resolution abdominal imaging techniques. CT and MRI are able to definitely characterize only a minority of these lesions (simple cyst, myelolipoma, obvious local malignant invasion). Biochemical screening for hormone excess is essential regardless of a nonsug- gestive complete history and physical examination. An argument may be made for not further pursuing nonhy- persecreting lesions with the typical features of a benign adenoma on CT scan and an attenuation value of 0 HU or less. Adrenocortical scintigraphy is recommended in all patients with normal biochemical screening tests, espe- cially those with CT attenuation values greater than 0 HU. In this setting, we believe that the functional and anatom- ical information provided by NP-59 and [75Se]selenom- ethylnorcholesterol scintigraphy allows one to noninva- sively, accurately, and less expensively (Table 9) categorize adrenal masses as benign nonhypersecretory adenomas (the vast majority) vs. a possibly malignant lesion (the minority). In the presence of normal biochem- istry, a concordant NP-59 imaging pattern is diagnostic of a nonhypersecretory benign adrenal adenoma and re- quires no immediate therapeutic intervention. Conversely, patients with discordant patterns of NP-59 scintigraphy have lesions that carry a significant risk for malignancy, and the pursuit of a tissue diagnosis is indicated, usually by means of FNA. Normal adrenocortical tissue on cyto- logical studies in this setting may represent inadvertent sampling of adjacent normal adrenocortical tissues or the presence of a well differentiated adrenocortical carcinoma. In patients with lesions larger than 2 cm in whom NP-59 scintigraphy is nonlateralizing, the possibility of a peria- drenal or pseudoadrenal mass is likely and should prompt review, or perhaps even repeat, of high resolution adrenal imaging (occasionally angiography may be helpful). In lesions shown to be 2 cm or less in size with a nonlater- alizing NP-59 scan, there is a possibility of a periadrenal or pseudoadrenal mass; however, once this is excluded it must be recognized that benign and malignant lesions, because of the limitations of scintigraphy, cannot always be clearly distinguished by this method when masses are small. In this setting, and when NP-59 or other suitable adrenocortical radiopharmaceuticals are not available, we currently advise FNA if an immediate diagnosis is needed (i.e. staging of a known extraadrenal primary malignancy without other evidence of metastatic disease, suspected granulomatous disease, etc.). In patients felt to be at low risk for harboring a malignancy (no known primary ma- lignancy, no constitutional symptoms) in whom an im- mediate diagnosis is not required, or if there are contra- indications to biopsy, chemical shift MRI (most likely in combination with at least one additional, subsequent fol- low-up CT or MRI to exclude an interval change) or stan- dard serial CT imaging (e.g. at 3, 9, and 18 months) may be employed.
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