Evidence Report/Technology Assessment No. 56
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Under its Evidence-based Practice Program, the Agency for Healthcare Research and Quality (AHRQ) is developing scientific information for other agencies and organizations on which to base clinical guidelines, performance measures, and other quality improvement tools. Contractor institutions review all relevant scientific literature on assigned clinical care topics and produce evidence reports and technology assessments, conduct research on methodologies and the effectiveness of their implementation, and participate in technical assistance activities.
Overview / Reporting the Evidence / Methodology / Findings / Future Research / Ordering Information
Authors: Lau J, Balk E, Rothberg M, Ioannidis JPA, DeVine D, Chew P, Kupelnick B, Miller K.
The evidence report on the topic of Management of the Clinically Inapparent Adrenal Mass was produced on request from the Office of Medical Application and Research (OMAR) at the National Institutes of Health for a State-of-the-Science Conference. This document summarizes key points from that report.
The widespread use of computed tomography (CT), diagnostic ultrasound imaging (US), and magnetic resonance imaging (MRI) has resulted in the incidental discovery of asymptomatic adrenal masses (also referred to as incidentaloma). While there is little debate about the management of large adrenal masses, there is disagreement over the proper management of adrenal masses smaller than 6 cm.
Adrenal incidentaloma is not a single pathological entity. Adenoma, adrenocortical carcinoma, pheochromocytoma, metastases, myelolipoma, and cysts may all present as incidentalomas. The likelihood of any specific pathology depends both on the circumstances of discovery and the definition of incidentaloma. Depending on the presence or absence of known cancer, patient age, indication for imaging, presenting signs and symptoms, and the performance characteristics of the initial test, different pathologies will be more or less likely. Mass size and appearance on imaging further modify this likelihood. Appropriate management depends on understanding the influence of these factors on disease prevalence.
Modalities for diagnosing adrenal masses include CT, MRI, transcutaneous needle biopsy (TNB), radioisotope imaging, and biochemical tests. Each of these has an associated degree of diagnostic accuracy as well as risk.
Management of adrenal incidentaloma is a complex decisionmaking process that involves considering a range of possible diagnoses and their natural history, diagnostic testing and interpretation, and weighing the risks and benefits of interventions in light of the patient's age and the tumor size.
While some authors have advocated surgical removal of all incidentally discovered adrenal masses, because complete and early removal of small, potentially cancerous lesions could be life saving, removal of all such lesions would result in unnecessary surgery for most patients. This is further complicated by recent studies reporting that some adenomas are subclinical biochemically active and lead to long-time morbidities.
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Reporting the Evidence
The following key questions and related subquestions were formulated by the State-of-the-Science conference planning committee, composed of staff from OMAR, National Institute of Child Health and Human Development, National Cancer Institute, national and international experts on this topic, and Evidence-based Practice Center (EPC) staff.
Question 1. What are the causes and prevalence of clinically inapparent adrenal masses that are identified by CT, MRI, or ultrasound and are confirmed by histology?
- What are the prevalence rates for the various causes of inapparent adrenal masses?
- Are there differences in the rates among the initial diagnostic tests used?
- What is the relationship of the age and sex of the patient to the likelihood of having a particular pathology?
- What is the relationship of the size of the mass with the likelihood of having a particular pathology?
Question 2. What is the diagnostic accuracy (sensitivity, specificity) of evaluation modalities (fine needle aspiration/biopsy, CT, MRI, US, biochemical tests) used to differentiate adrenal masses (adrenal carcinoma, pheochromocytoma, adenoma, adrenal hyperplasia, etc.)?
- What is the risk of metastatic spread of adrenal carcinoma by fine needle aspiration (FNA)?
Question 3. What are the surgical complication rates for various approaches used to excise adrenal masses—specifically: laparoscopic, transabdominal, and retroperitoneal approaches?
Question 4. What are the patient outcomes after surgical excision of adrenocortical carcinoma (morbidity and mortality)?
- Are there data on the influence of age and tumor size on the outcomes?
Question 5. What evidence is there to support the use of periodic biochemical and imaging studies to follow untreated adrenal masses?
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Definition Of Incidentaloma
Authors have used a wide range of definitions for incidentaloma. Rather than choosing a narrow definition that may exclude potentially relevant situations and many relevant studies, we accepted all studies that used their own definitions of incidentaloma.
Studies were identified primarily through a MEDLINE® search of the English language literature published between 1966 and October 2000. We also consulted technical experts and examined references of selected review articles to identify additional studies. Articles that met the inclusion criteria were incorporated into our evidence report. The staff at the National Library of Medicine conducted a search in October 2000 on the following databases: MEDLINE®, PreMEDLINE, BIOSIS®, and EMBASE®. The content of the original key questions was later expanded, and we conducted an updated search in March 2001 in the MEDLINE® database. Additional subject headings were included to address questions on diagnostic accuracy, surgical complication rates, morbidity and mortality outcomes for adrenal masses, and monitoring strategies for untreated adrenal masses.
The literature searches yielded a total of 5,386 independent citations. The abstracts were screened and reports published only as letters or abstracts in proceedings were rejected from further consideration. We retrieved 602 articles. Specific inclusion criteria and methods of synthesis were developed for each of the key questions. In general, we included all English language studies with at least 10 human subjects. There were no age limitations.
Summarizing the Literature
About 194 articles met our inclusion criteria for one of the key questions and were included in the evidence report. Forty-five studies provided data about the prevalence of incidentaloma or the distribution of adrenal pathologies. Thirty-one studies evaluated various diagnostic tests to differentiate adrenal masses. Over 80 studies provided outcome information on various adrenal surgical techniques. Thirty-two studies reported prognostic information on patients with adrenal carcinoma after surgical excision, and nine articles reported results of followup strategies.
From these articles, we abstracted detailed information into evidence tables and summary tables. We also assessed the methodological quality of studies that evaluated diagnostic performance and adrenal surgery. Using a three-category scale, we graded these articles based on study design, conduct, and reporting. We also assessed the applicability of studies to the population of interest as determined by study location, tumor size, and tumor type.
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Causes and Prevalence of Clinically Inapparent Adrenal Masses
Over 44 reports from various countries described the causes and prevalence of various pathologies found in incidentaloma. Because incidentaloma is not a disease entity, the prevalence of incidentaloma will vary with the circumstances. We found one study that used transabdominal ultrasound for general health examination reported 11 adrenal masses (verified clinically or with pathology) out of 41,357 subjects (prevalence 0.027 percent). The prevalence of incidentaloma has been reported to be 0.6 percent in a study of 2,200 patients undergoing upper abdominal CT.
Combining the studies that used the broadest definitions and that reported individual cases, the prevalence among incidentaloma was as follows: adenoma 41 percent, metastases 19 percent, adrenocortical carcinoma 10 percent, myelolipoma 9 percent, pheochromocytoma 8 percent, with other, mostly benign lesions comprising the remainder. This distribution is similar to that reported in a single large study. Sixty percent of the incidentalomas occurred between the ages of 41 and 60, and 90 percent between the ages of 31 and 70.
For tumors 4 cm or less, the data are limited. Sixty-five percent were adenomas and approximately 21 percent were metastases. For tumors above 6 cm, adrenal carcinomas comprised 25 percent and adenomas only 18 percent. The percentage of metastases was 18 percent. Approximately 64 percent of the adenomas and 70 percent of the adrenal carcinomas were found in females, whereas 60 percent of metastases were in males.
Diagnostic Performance of Tests to Assess Adrenal Incidentaloma
We identified 32 studies that met the search criteria for this report and reported diagnostic performance of tests to evaluate adrenal masses. Four studies included only subjects with adrenal incidentalomas. Overall, about one-third of the subjects were reported to have incidentalomas. Study quality was as follows: 1 good, 16 fair, and 15 poor.
Ten studies (n=467) evaluated CT. Four studies of unenhanced CT to diagnose adrenal cancer found high sensitivity and moderate to high specificity at density thresholds below 18 Hounsfield units. Three studies of enhanced CT found that high sensitivity could be achieved only with low specificity, and vice versa. Two studies of delayed enhanced CT found high sensitivity (83 to 100 percent) and high specificity (91 to 100 percent). One of three studies of combined unenhanced and enhanced CT found excellent test performance; the other two found poor test performance. Nine studies of size and other morphological features on various types of CT found overall poor test performance. Three studies concluded that on unenhanced CT, attenuation performs better than morphological parameters. Two other studies of enhanced CT concluded that attenuation and size perform similarly, and both were worse than delayed enhanced CT.
Eight studies (n=302) evaluated unenhanced MRI in diagnosing adrenal cancer. They found sensitivity of 50 to 100 percent and specificity of 24 to 100 percent. Four studies found the best test performance using adrenal mass to spleen signal intensity ratio. Sensitivity was 95 to 100 percent and specificity was 78 to 100 percent.
One study (n=33), which combined unenhanced CT and MRI to diagnose adrenal cancer, reported sensitivity of 100 percent and specificity of 94 percent. Six studies (n=387) using different parameters to categorize scintigraphy to diagnose adrenal cancer, reported sensitivity of 71 to 100 percent and specificity of 50 to 100 percent. One study (n=54) of ultrasound to diagnose adrenal cancer found sensitivity of 67 percent and specificity of 52 percent. One study (n=20) of positron emission tomography to diagnose adrenal cancer found sensitivity and specificity of 100 percent.
Nine studies (n=515) of FNA to diagnose adrenal cancer found sensitivity of 81 to 100 percent and specificity of 83 to 100 percent. Inconclusive biopsies occurred in 6 to 50 percent of samples.
Three studies evaluated biochemical tests to diagnose adrenal cancer in patients with adrenal incidentaloma. One study (n=84) found that elevated or normal morning dihydro-epiandrostenedione sulfate level had a sensitivity of 100 percent and specificity of 38 percent.
Risk of Complications Due to Fine Needle Aspiration
Twelve studies reported on 888 biopsies of adrenal masses in 866 patients. Only two studies explicitly reported data on the risk of metastatic spread due to biopsy. One patient (0.3 percent of subjects with long-term followup) with bronchogenic carcinoma had needle tract metastasis after adrenal biopsy. Thirty-six complications (4 percent) were reported, including 26 that were potentially serious. Because of the wide variety of biopsy techniques, unclear or incomplete reporting, and the small study sizes, no reliable estimates can be made about the relative safety of the different biopsy techniques.
Complication Rates of Surgical Approaches to Excise Adrenal Masses
We evaluated 9 case series of open adrenalectomy, 4 studies comparing open adrenalectomy techniques, 20 series of transperitoneal laparoscopic adrenalectomy, 10 series of retroperitoneal laparoscopic adrenalectomy, 28 studies comparing laparoscopic adrenalectomy to open surgery, and 9 studies comparing transperitoneal with retroperitoneal laparoscopy. Overall study quality was poor.
The open series included 525 patients. Major complications occurred in 2 to 24 percent of patients and minor complications in 0 to 14 percent. Mortality occurred in 0 to 3 percent of patients. The most common complications included pleural tear, wound infection, bleeding, splenectomy, and urinary tract infection. Four studies comparing the open transabdominal and posterior approaches in 566 patients found similar complication rates with both approaches, but average length of stay was shorter with the posterior approach.
The transperitoneal laparoscopic series included 1,189 patients. Major complications occurred in 0 to 25 percent of patients and minor complications occurred in 0 to 72 percent. Two deaths were reported. The most common complications were bleeding, wound infection, and deep vein thrombosis. The retroperitoneal laparoscopic series included 537 patients. Major complications occurred in 0 to 10 percent of patients and minor complications occurred in 0 to 63 percent. One patient died. The most common complications included retroperitoneal hematoma, subcutaneous emphysema, and pancreatic or splenic injury. Complications were less common in larger studies.
Studies comparing open and laparoscopic surgery included 1,388 patients. Most studies did not apply statistical methods to analyze complication rates. Five studies found laparoscopy to have fewer complications, while one found no difference. Studies comparing different laparoscopic approaches did not find any statistical differences in complications, operating time, or blood loss.
Patient Outcomes After Surgical Excision of Adrenocortical Carcinoma
Thirty-two studies with a total of 1,684 patients were examined to gather information about patient outcomes after surgical excision of adrenocortical carcinoma. Most of these data came from retrospective studies. There were wide variations in the quality and quantity of reported information about the tumor size, patient characteristics, surgical approaches, and outcomes. Nine studies reported patients who had surgery in the 1940s and 1950s. One study went back to 1929. Fifteen of the 32 studies reported perioperative mortality data. Twenty perioperative deaths were reported out of a total of 625 patients, a rate of 4.6 percent.
There were diverse methods of reporting the long-term survival. Seventeen studies reported 5-year survival data that ranged from 19 to 62 percent with a median of 34 percent (weighted average = 34.6 percent). There does not appear to be any important difference in the overall survival rates between the earlier and the more recent series. Most of the studies included patients over a wide range of years, making it difficult to discern any trend over time. Age and tumor size did not appear to influence prognosis after surgery.
Men had worse outcomes: in the three studies that reported individual patient data, out of 18 men, only 3 survived more than 24 months, and none survived to 5 years. However, men tended to have nonfunctional tumors, which are typically asymptomatic until a late stage.
Use of Periodic Biochemical and Imaging Studies to Follow Untreated Adrenal Masses
There were four prospective studies of incidentaloma with established followup protocols for untreated patients. Two studies were clearly prospective, one was ambiguous, and one study identified patients retrospectively from medical records but prospectively followed the patients who gave consent. Two studies did not report exclusion criteria. The other two excluded patients with hormonally active and/or malignant tumors, and one excluded cysts as well. Overall, of 121 patients followed, 78 had no changes, 20 had increases in tumor size, and 11 had either decreases in tumor size or disappearance of the tumor. There were two cancer deaths unrelated to adrenal pathology. Adenoma was confirmed at autopsy.
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Need to Understand Issues Related to Diagnosis of Incidentaloma
Adrenal incidentaloma is neither a single pathological entity nor a disease. A strict definition of incidentaloma would aid in the interpretation of results from clinical studies; however, it will not be sufficient to address the diverse manifestations of this condition that are also clinically relevant. Future studies of incidentaloma need to broadly cover all possible scenarios but individual studies should apply rigorous inclusion criteria for each of these scenarios or provide careful analyses of well defined subgroups.
Many studies assumed that the major reason for the further evaluation of adrenal incidentalomas is for the purpose of detecting adrenal carcinoma. Given the rarity of this tumor and the lack of effective therapy in the later stages, the overall benefit of detection is small. On the other hand, subclinical, biochemically active adrenal adenomas are common and need to be better understood regarding their prevalence and long-term clinical outcomes. Given their prevalence and the significance of hypertension and diabetes, these tumors may become the reason for aggressive intervention in adrenal incidentaloma.
Diagnostic Tests to Evaluate Adrenal Mass
With few exceptions, the overall methodological quality of the studies we examined was poor. Higher quality studies are needed to properly assess the clinical usefulness of various diagnostic tests for adrenal incidentalomas. In contrast to published studies, future studies should make a rigorous attempt to clearly define and report eligibility criteria, sample characteristics, test methodology, and the definitions of positive and negative tests. Reference standards should be clearly delineated, completely independent of the tests being investigated, and as much as possible, include well defined outcomes, such as surgical or autopsy diagnoses.
Assessment of Surgical Techniques for Adrenalectomy
Future research should concentrate on defining the best procedure for each indication, as well as identifying other factors that may contribute to operating complications, such as the number of operations performed by the surgeon. In order to compare across series, it would be useful for authors to agree on standard definitions of such seemingly simple outcomes as operating time or post-operative length of stay. It would also be particularly useful to standardize the measurement and reporting of complications.
Followup of Untreated Adrenal Masses
There is very sparse data to guide the management of untreated, incidentally discovered adrenal masses. Most of the available studies are either too small to provide meaningful results or suffer from methodological problems. Future studies should include prospective application of pre-specified protocols to clearly defined populations. Given the rarity of adrenocortical carcinoma, assessing the usefulness of followup protocols will require a large number of subjects. If recent studies are confirmed, followup strategies that include biochemical evaluations for subclinical biochemically active adrenal masses will be useful.
Need for International Registry of Adrenal Incidentaloma
Well-designed clinical trials will provide the most reliable evidence regarding the management of these patients, but these trials will take many years and may not always be feasible. An alternative approach would be to create an international registry of patients with well-documented adrenal incidentaloma. This registry should be established using standardized definitions and inclusion criteria. Investigators could then analyze individual patient data to understand the influence of specific factors such as tumor size, age, and inclusion criteria on the development of subsequent adrenal pathologies.
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The full evidence report from which this summary was taken was prepared for AHRQ by the New England Medical Center Evidence-based Practice Center, Boston, MA, under contract No. 290-97-0019. Printed copies may be obtained free of charge from the AHRQ Publications Clearinghouse by calling 800-358-9295. Requesters should ask for Evidence Report/Technology Assessment No. 56, Management of Clinically Inapparent Adrenal Mass.
The Evidence Report is also online on the National Library of Medicine Bookshelf.
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Current as of February 2002
AHRQ Publication No. 02-E013