Limited Value of Adrenal Biopsy in the Evaluation of Adrenal Neoplasm
A Decade of Experience
Peter J. Mazzaglia, MD; Jack M. Monchik, MD
Objective: To determine the value of percutaneous ad- renal biopsy in the evaluation of adrenal neoplasm.
Design: Retrospective review.
Setting: Tertiary referral center.
Patients: All adult patients undergoing image-guided adrenal biopsy from 1997 to 2007.
Main Outcome Measure: Biopsy sensitivity for ma- lignancy.
Results: There were 163 biopsies performed on 154 pa- tients. Mean (SD) age was 66 (12.5) years. Eighty-eight biopsies (53.4%) were performed in patients with a prior diagnosis of cancer. Forty-five (26.4%) were performed when imaging study results suggested previously undi- agnosed cancer with a simultaneous adrenal metastasis. Thirty (20.2%) were performed for isolated adrenal in- cidentalomas. Rates of positive biopsy results in these 3 groups were 70.6%, 69.0%, and 16.7%, respectively. Pre- biopsy evaluation for pheochromocytoma was per-
formed in less than 5% of patients with established or suspected nonadrenal malignancies and 32% of patients with incidentalomas. In patients with isolated adrenal in- cidentaloma, a radiology report recommended biopsy 33% of the time for characteristics inconsistent with benign adenoma. Benign incidentalomas measured mean (SD) 4.2 (2.1) cm (range, 1.4-10.7 cm), and malignancies mea- sured mean (SD) 9.3 (3.3) cm (range, 5.3-14 cm) (P <. 05). All incidentalomas 5 cm or less (n=18) were benign. There were 4 false-negative biopsy results: 3 ad- renocortical carcinomas and 1 pheochromocytoma.
Conclusions: Biopsy is unhelpful in patients with iso- lated adrenal incidentaloma. Despite atypical radio- graphic findings, all nonfunctioning nodules 5 cm or less were benign. The negative predictive value is unaccept- ably low and cannot be relied on to rule out malig- nancy. The value of biopsy remains the diagnosis of meta- static carcinoma in patients with a nonadrenal primary malignancy, proven by the more than 70% positive rate in this group.
Arch Surg. 2009;144(5):465-470
Author Affiliations: Rhode Island Hospital, Warren Alpert School of Medicine, Brown University, Providence.
A DRENAL INCIDENTALOMAS are defined as adrenal neo- plasms 1 cm or more in diameter identified on a ra- diologic examination per- formed for indications other than adre- nal disease. The traditional definition of incidentaloma excludes patients under- going imaging procedures as part of stag- ing and workup for cancer, as well as those in whom the diagnosis of a symptomatic adrenal-dependent syndrome was missed because of insufficient suspicion or inves- tigation.1,2 The incidence of adrenal inci- dentaloma is rising because of the in- creased use of cross-sectional imaging, and studies show that an adrenal inciden- taloma will be identified in 1.3% to 3.4% of abdominal and chest computed tomo- graphic examinations (CTs) performed.3 A recent review of more than 2000 inci-
dentalomas identified nonfunctioning ad- enoma to be the most likely diagnosis at 82%, followed by subclinical Cushing’s syndrome (5.3%), pheochromocytoma (5.1%), adrenocortical carcinoma (4.7%), metastatic disease (2.5%), and aldoster- onoma (1.0%).4
Once discovered, incidentalomas should be assessed for biochemical func- tion and malignant potential, as it is gen- erally agreed that all functioning and po- tentially malignant lesions should be removed.2,5,6 The complexities of this in- vestigation for some lesions cannot be overstated, and they demand the exper- tise of multiple specialists, including sur- gery, endocrinology, and radiology. Un- fortunately, because of the growing volume of such patients, many incidentalomas are often managed without appropriate en- docrine evaluation. Some who have sub-
| Patient's Prebiopsy Malignancy Status | Site of Primary Malignancy | No. (%) of Biopsy Results Positive for Malignancy |
|---|---|---|
| Established nonadrenal cancer | Lung | 43 (90.7) |
| Renal cell | 15 (80.0) | |
| Other | 27 (33.3) | |
| Combined | 85 (70.6) | |
| Suspected nonadrenal cancer | Lung suspected | 39 (69.2) |
| Other | 3 (66.6) | |
| Combined | 42 (69.0) | |
| Incidentaloma | 30 (16.7) |
clinical Cushing’s syndrome or pheochromocytoma are being subjected to inappropriate and potentially danger- ous adrenal biopsy, when biochemical testing would have established the diagnosis.
Some investigators have strongly advocated a role for adrenal biopsy in the workup of adrenal incidentaloma to distinguish malignant from benign cortical lesions.7 However, the ability of adrenal biopsy to differentiate be- nign cortical neoplasms from adrenocortical carcinoma remains limited at best, and in general, its accuracy can- not be relied on to safely recommend observation over surgery.6,8,9 In patients with a known extra-adrenal ma- lignancy who have undergone disease-appropriate treat- ment, a new adrenal lesion should not be considered an incidentaloma, but instead should raise the specter of metastatic disease. Studies show that 40% to 75% of ad- renal neoplasms in this patient population represent meta- static disease.1,10,11 Because of this high prevalence, both the accuracy and effectiveness of adrenal biopsy to firmly establish the diagnosis of metastatic cancer has been well established in these patients.11-13
This study reviews all adrenal biopsies performed at a single institution over 10 years to determine patient se- lection criteria, evaluation for hormonal function, and value of biopsy in patients with incidentaloma vs those with a known or suspected extra-adrenal malignancy.
METHODS
After obtaining appropriate institutional review board ap- proval, the pathology database at Rhode Island Hospital was queried for the word “adrenal,” using a natural language search, for the period from October 1997 to October 2007. The re- sults were reviewed to select only patients who had under- gone percutaneous image-guided adrenal biopsy. These biop- sies included either fine-needle aspiration for cytology or core needle biopsy for histopathology; however, they are both re- ferred to as “biopsy” for the purposes of this study. These pa- tients’ computerized records and hospital medical records were retrospectively reviewed. Patients were placed into 1 of 3 pre- biopsy categories: (1) patients with an established nonadrenal malignancy, (2) patients without a cancer diagnosis but imaging suggestive of a nonadrenal primary malignancy with a simul- taneous adrenal metastasis, and (3) patients with adrenal le-
sions discovered on imaging performed for unrelated reasons (adrenal incidentaloma). The maximum diameter of the adre- nal lesion was obtained from the radiology report. The pathol- ogy results from the percutaneous image-guided biopsy were categorized as (1) positive for metastatic disease, (2) benign (cortical neoplasm without malignant features), (3) adreno- cortical cancer, (4) other (ie, lymphoma, sarcoma, ganglioneu- roma), or (5) nondiagnostic. The accuracy of each biopsy was established for the 3 categories of patients based on long-term clinical follow-up documented in hospital and clinic comput- erized records and/or surgical pathology in the patients who underwent adrenalectomy. Records for patients who were not operated on were examined from the time of biopsy through 2006 for all documentation regarding the status of their adre- nal tumors. Statistical analysis was performed using x2 and t tests.
RESULTS
A total of 163 biopsies were performed in 154 patients. There were 95 men and 59 women. Mean (SD) age was 66 (12.5), and age did not differ among the 3 categories of patients. The mean (SD) tumor size was 3.9 (2.2) cm. In group 1, 84 patients had a prior diagnosis of nonad- renal cancer. The most common malignancies in this group were lung (44), renal cell (12), and colorectal (4). In group 2, 42 patients had imaging results that sug- gested the diagnosis of a nonadrenal malignancy with a synchronous adrenal metastasis. In group 3, 28 patients had an adrenal incidentaloma. The percentage of total patients in each group was 54%, 26%, and 20%, respec- tively. The average ages were similar across groups. Men accounted for 67% and 64% of patients in groups 1 and 2 and 43% in group 3. The mean (SD) size of all biop- sied lesions was 3.9 (2.2) cm, but it differed signifi- cantly among the 3 groups. Lesions in group 1, pre- sumed adrenal metastases, measured mean (SD) 3.3 (1.6) cm. Suspected adrenal metastases (group 2) measured mean (SD) 4.4 (2.4) cm and incidentalomas measured mean (SD) 4.6 (2.5) cm. The total number of adrenal bi- opsies performed per year ranged from 10 to 21. The num- ber of incidentalomas biopsied ranged from 1 to 4 per year until 2006 but jumped to 8 in 2007.
The probability that an adrenal biopsy specimen would be positive for malignancy was 70.6% in group 1, 69.0% in group 2, and 16.7% in group 3 (Table 1). In group 1, patients with a primary lung cancer had the highest likelihood (90.7%) of a positive biopsy result, followed by patients with renal cell cancer (80.0%). The remain- ing patients in this group had a 33.3% likelihood of iden- tifying adrenal metastases at the time of biopsy. In group 2, where 69% of biopsy specimens showed metastatic dis- ease, 39 of 42 patients had imaging results suggestive of lung cancer with a synchronous adrenal metastasis.
Table 2 details the size, indication for biopsy, bi- opsy result, biochemical screen, and surgical pathology result for the 30 biopsies performed on incidentalomas. In group 3 incidentalomas, 3 biopsy specimens (10%) were interpreted by cytopathology to be adrenocortical cancer. Additional malignancies were identified by bi- opsy in 2 patients, 1 lymphoma and 1 sarcoma. Two of the biopsy specimens revealed pheochromocytoma, 1 in a patient whose prior biochemical testing predicted this
| Reason for Imaging | Tumor Size, cm | Biopsy Indicationª | Pheo Screen | Biopsy Result | Surgical Pathology |
|---|---|---|---|---|---|
| R/O malignancy | Not done | Cortical adenoma | |||
| Anemia | 1.4 | R/O malignancy | Not done | Negative for malignancy | |
| 2.0 | Atypical for adenoma | Not done | Cortical adenoma | ||
| Trauma | 2.3 | Atypical for adenoma | Negative results prebiopsy | Benign spindle cell | |
| F/U adrenal lesion | 2.3 | Enlarging lesion | Negative results prebiopsy | Cortical adenoma | |
| 2.5 | R/O malignancy | Not done | Ganglioneuroma | ||
| 3.0 | Atypical for adenoma | Negative results prebiopsy | Cortical adenoma | ||
| 3.0 | R/O malignancy | Not done | Cortical tissue | ||
| Weight loss | 3.0 | Atypical for adenoma | Not done | Cortical tissue | |
| 3.5 | Atypical for adenoma | Not done | Cortical adenoma | ||
| Renal condition | 3.5 | R/O malignancy | Not done | Cortical tissue | Macronodular hyperplasia |
| Pleural effusion b | 3.5 | R/O malignancy | Negative results postbiopsy | Negative for malignancy | ACC |
| Nephrolithiasis | 3.6 | Atypical for adenoma | Negative results prebiopsy | Cortical adenoma | |
| Hospitalization | 4.0 | Atypical for adenoma | Not done | Cortical adenoma | |
| Abdominal pain | 4.0 | Atypical for adenoma | Negative results prebiopsy | Necrotic tissue | |
| Repeat biopsyc | 4.0 | R/O malignancy | Positive results postbiopsy | Pheo | Pheo |
| Abdominal pain | 4.2 | R/O malignancy | Positive results prebiopsy | Cortical adenoma | Adenoma |
| Panniculitis | 4.5 | R/O malignancy | Not done | Cortical adenoma | |
| Abdominal pain | 4.5 | R/O malignancy | Positive results prebiopsy | Pheo | Pheo |
| Abdominal pain | 5.0 | R/O malignancy | Not done | Adrenal cortex | |
| Abdominal pain℃ | 5.0 | R/O malignancy | Not done | Cortical adenoma | Pheo |
| 5.3 | R/O malignancy | Not done | Myxoid sarcoma | Sarcoma | |
| Second biopsyb | 7.0 | R/O malignancy | Negative results postbiopsy | ACC | ACC |
| 7.0 | R/O malignancy | Not done | Myelolipoma | ||
| F/U 3.7-cm lesion | 7.0 | Atypical + increased size | Not done | Organized fibrin | ACC clinically nonoperative |
| 10.0 | R/O malignancy | Not done | Cortical neoplasm | ACC clinically | |
| 10.0 | R/O malignancy | Negative results prebiopsy | Lymphoma | nonoperative | |
| Typhoid fever | 10.7 | R/O malignancy | Not done | Nerve sheath tumor | |
| Renal hypertension | 14.0 | R/O malignancy | Negative results prebiopsy | ACC | Hospice |
| R/O malignancy | Not done | ACC | Nonoperative |
Abbreviations: ACC, adrenocortical carcinoma; F/U, follow-up; pheo, pheochromocytoma; R/O, rule out.
a Italics indicate biopsy recommended in radiology report.
b Second biopsy performed in patient with incidentaloma that doubled in size. First biopsy specimen was benign; second biopsy specimen was ACC.
c Second biopsy performed after 8-year interval. First biopsy specimen was benign; second biopsy specimen was pheo.
diagnosis. The other patient was not screened for cat- echolamine excess. Three benign nonadrenal tumors were biopsied: a ganglioneuroma, a benign spindle cell tu- mor, and a nerve sheath tumor. There was also 1 myelo- lipoma. Sixty-three percent (19 of 30) of the biopsy speci- mens in group 3 were interpreted as either benign cortical tissue (17) or a nondiagnostic specimen (2). Three of these 19 biopsy specimens were false negatives, 1 confirmed at the time of operation and 2 based on clinical progres- sion of disease. Six of the total 28 patients with inciden- taloma in group 3 underwent adrenalectomy, and their final surgical pathology results did confirm the prior bi- opsy diagnoses: 2 pheochromocytomas, 1 adrenocorti- cal carcinoma, 1 cortical adenoma, 1 macronodular hy- perplasia, and 1 sarcoma.
In all 3 groups, adrenal tumor size was a significant predictor of malignancy. In group 1, mean (SD) size was 2.4 (1.2) cm for benign lesions and 3.6 (1.6) cm for ma- lignant lesions (P =. 02). In group 2, benign lesions were mean (SD) 2.6 (0.6) cm and malignant were 5.2 (2.5) cm (P =. 003), and in group 3, benign lesions measured mean (SD) 4.2 (2.1) cm and malignant lesions were 9.3 (3.3) cm (P <. 001).
In the 30 biopsies performed for incidentaloma (group 3), there were 13 lesions less than 4 cm, 9 lesions 4 to 6 cm, and 8 lesions more than 6 cm. All lesions less than 5 cm in diameter (18 of 30) had a nonmalignant pathol- ogy report (Figure). However, one of these patient’s le- sions was discovered on follow-up CT to have doubled in size from 3.5 cm to 7 cm. A second biopsy was per-
16-
14
ACC
12
Nerve sheath tumor
Centimeters
10
ACC clinically
Lymphoma
8
ACC clinically, myelolipoma
ACC
6
Sarcoma not involving adrenal
4
2
0
Nonmalignant
Malignant
Biopsy Result
formed and the specimen was positive for adrenocorti- cal cancer. All of the other 17 incidentalomas 5 cm or less proved to be benign, including the 2 pheochromo- cytomas. In this series, the sensitivity of needle biopsy for detecting adrenocortical cancer was 50%, as only 3 of 6 biopsies performed on patients who ultimately were shown to have adrenocortical carcinoma were inter- preted as such.
Thirty-three percent of the patients with inciden- taloma (10 of 30) had a biopsy recommended within the text of the radiology report, and none of those 10 pa- tients had a malignant tumor. Nine were for lesions 4.0 cm or less in diameter. Indications included “atypical ad- enoma,” “enlarging lesion,” and “rule out malignancy.” Of 9 patients whose radiology reports contained refer- ences to “lesion characteristics atypical for a benign adenoma,” only 1 turned out to have adrenocortical cancer.
Prebiopsy evaluation for pheochromocytoma was per- formed in less than 5% of patients with established or suspected nonadrenal primary malignancies and in 32.1% of patients with incidentaloma. Therefore, 19 of the 28 patients with adrenal incidentalomas had an unclear bio- chemical status at the time of biopsy. Of the 9 patients who were screened for pheochromocytoma prebiopsy, 2 actually had positive biochemical testing results. At sur- gery, 1 was confirmed to have a pheochromocytoma and the other had a cortical adenoma. Fortunately, neither these nor any others were reported to have hypertensive crises. Overall, there were few reported complications of adrenal biopsy, the most significant being an adrenal hem- orrhage causing pain that resolved without interven- tion. There were no reports of hemodynamic instability.
COMMENT
In this 10-year review of all image-guided percutaneous adrenal biopsies at a large tertiary care medical center, it is clear that adrenal lesions developing in patients like the 84 patients in group 1 with a known extra-adrenal malignancy have a high likelihood (70%) of harboring
metastatic cancer. A second group of patients, with a simi- lar 69% yield for metastatic cancer, were those 42 pa- tients in group 2, who were not previously known to have cancer but had imaging study results that suggested a non- adrenal primary cancer with a simultaneous adrenal me- tastasis. In group 1, making the diagnosis of metastatic cancer in the adrenal lesion was important both prog- nostically and in directing further therapy. In group 2 patients, percutaneous adrenal biopsy offered a rela- tively low-risk means of establishing a cancer diagnosis and avoided the potential hazards of biopsying a pri- mary lung lesion.
These results compare favorably with previously pub- lished studies. In 1994, Welch et al11 published the Mayo Clinic experience with 277 adrenal biopsies, all but 5 of which were performed in patients with extra-adrenal can- cer and presumed metastatic disease. More than half had a primary pulmonary malignancy, and the probability of identifying metastatic disease was 53.1%. Sensitivity and specificity were 81% and 99%, respectively. In 2002, Ha- risinghani et al13 reviewed 225 patients with extra- adrenal cancer who subsequently had image-guided bi- opsy of indeterminate adrenal lesions. Only 41 (18%) had biopsy specimens that were negative for metastatic dis- ease, and long-term follow-up confirmed the high speci- ficity of a benign biopsy. Data compiled by the National Institutes of Health revealed that 75% of adrenal lesions found in patients with a known extra-adrenal malig- nancy are metastases.1 Certainly this high pretest prob- ability improves the biopsy accuracy in this population. Recent advances in the use of chemical shift magnetic resonance imaging to differentiate adrenal adenomas from metastases may help decrease the need for adrenal bi- opsy to establish the diagnosis of metastatic cancer in such patients.14
In sharp contrast to the nearly 70% biopsy specimen positivity rate in groups 1 and 2 in this review, the like- lihood of identifying a primary adrenal malignancy in group 3 was only 30% (3 of 30). Two of these 3 patients were deemed inoperable, and the third underwent open adrenalectomy. Management was not impacted by the bi- opsy results, as the third patient met standard criteria for adrenalectomy for a lesion that had doubled in size from 3.5 to 7 cm over several weeks.5 In fact, a CT performed 8 months previously had shown a “normal” adrenal gland, and the adrenalectomy should have been scheduled on identification of the new 3.5-cm adrenal mass. Instead, the 3.5-cm mass was inappropriately biopsied and was interpreted to be benign. When a follow-up CT showed the mass to have doubled in size, a second unnecessary biopsy was performed, again increasing the risk for seed- ing the biopsy tract with malignant cells.15
Numerous reviews have substantiated the fact that needle biopsy specimens are inadequate for distinguish- ing benign from malignant adrenocortical tissue; there- fore, percutaneous biopsy of adrenal incidentaloma should not be performed.6,8,9,16 However, in this study alone, 30 biopsies were performed on adrenal incidentalomas, at least 11 of which were recommended within the text of the radiology report. Not only does the pathology litera- ture not support this practice, but there is also an abun- dance of evidence in the radiology literature to discour-
age this type of recommendation. While certain CT characteristics such as heterogeneity and Hounsfield unit density greater than 18 are more commonly seen with adrenocortical cancer, their positive predictive value re- mains less than 50% for adrenal incidentalomas.7 Two recent studies by Song et al17,18 demonstrated a 0% rate of malignancy in 973 cancer-free patients who pre- sented with adrenal incidentaloma, including all those with a Hounsfield unit density greater than 10.
Initial studies of adrenal lesions showed a strong posi- tive correlation between lesion size and probability of ma- lignancy.19 Herrera et al20 demonstrated a benign to ma- lignant ratio of 8:1 for 4-cm lesions, the size cutoff currently in use by many endocrine surgeons for adre- nal resection.6,21 At 4 cm, sensitivity is 93%; specificity, 42%; and positive predictive value, 16% for adrenocor- tical carcinoma.22 In the 2002 National Institutes of Health consensus statement on adrenal incidentaloma, the like- lihood of adrenocortical carcinoma is most strongly linked to lesion size and accounts for 2% of tumors 4 cm or less, 6% of tumors 4.1 to 6 cm, and 25% of tumors more than 6 cm.1
Our study findings for patients with incidentaloma demonstrate that tumor size remains the strongest pre- dictor of malignancy.16 No lesion less than 5 cm had bi- opsy results positive for adrenocortical carcinoma; how- ever, there was a false-negative biopsy result of a 3.5-cm lesion as described earlier. Benign lesions in group 3 pa- tients averaged 4.2 cm, in stark contrast to the 9.3-cm average diameter of malignancies.
Three other patients were placed at potential risk for hemodynamic instability when undergoing biopsy, the 2 who eventually had pheochromocytoma resected and a third with prebiopsy laboratory values consistent with pheochromocytoma. All patients considered for adrenal biopsy should undergo an evaluation for excess catechol- amine production to prevent adverse outcomes.23-25 Any indication that the tumor is hypersecretory, be it corti- sol, catecholamine, aldosterone, or sex steroids, be- comes an automatic indication for surgery and elimi- nates any indication for biopsy.6 Screening for functionality was performed in only a third of patients with incidentaloma and in a small minority of patients in groups 1 and 2. As this and other series demonstrate, the frequency of pheochromocytoma among patients pre- senting with incidentaloma ranges from 5% to 10%.4,26 These not inconsequential numbers mandate biochemi- cal screening, which can be accomplished expeditiously by testing serum metanephrine levels. If elevated, the pa- tient should undergo formal evaluation by an endocri- nologist or endocrine surgeon prior to any further man- agement decisions. Similarly, 5% or more will test positive for cortisol hypersecretion, and evaluation for such with an overnight dexamethasone suppression test is neces- sary. Very few patients in this study were screened for Cushing’s syndrome. Unfortunately, it is clear that these deficiencies in the evaluation of adrenal incidentalomas are not institution specific. A recent review of patients from a major center for endocrine surgery referral illus- trates a similar pattern of inappropriate biopsy and in- adequate hormonal evaluation.27
CONCLUSIONS
Despite the inability of needle biopsy to accurately dif- ferentiate benign from malignant adrenal neoplasms, physicians continue to recommend this procedure in some patients with adrenal incidentaloma. This series confirms that lesions less than 4 cm have a very low risk for being carcinoma, even when atypical radiographic findings are present. Therefore, the vast majority of these should be assessed for hormonal production, and if nonfunctioning, they should be observed with annual imaging and assessment for hormone production. If ra- diographic characteristics are especially concerning, more frequent imaging is reasonable; however, resec- tion may be warranted. Currently, biopsy should only be considered for making the diagnosis of metastatic disease in patients with known or suspected nonadrenal cancer.
Accepted for Publication: January 2, 2009.
Correspondence: Peter J. Mazzaglia, MD, Warren Alp- ert School of Medicine at Brown University, 154 Water- man St, Providence, RI 02906 (pmazzaglia@lifespan .org).
Author Contributions: Study concept and design: Mazza- glia and Monchik. Acquisition of data: Mazzaglia. Analy- sis and interpretation of data: Mazzaglia. Drafting of the manuscript: Mazzaglia. Critical revision of the manuscript for important intellectual content: Mazzaglia and Mon- chik. Statistical analysis: Mazzaglia. Study supervision: Monchik.
Financial Disclosure: None reported.
Previous Presentations: This paper was presented at the 89th Annual Meeting of the New England Surgical So- ciety; September 26, 2008; Boston, Massachusetts; and is published after peer review and revision.
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