Case Report
DIAGNOSTIC CHALLENGES IN ADRENOCORTICAL CARCINOMA: RECOMMENDATIONS FOR SURVEILLANCE AFTER SURGICAL RESECTION OF SELECTED ADRENAL NODULES
Gilbert G. Fareau, MD, and Rena Vassilopoulou-Sellin, MD, FACE
ABSTRACT
Objective: To discuss challenges in the diagnosis of adrenocortical carcinoma and to suggest surveillance mea- sures after removal of selected adrenal nodules.
Methods: We present the case of a 65-year-old man with worsening hypertension and new-onset hypokalemia attributed to primary hyperaldosteronism due to a 3-cm right adrenal nodule.
Results: A laparoscopic right adrenalectomy was performed, and the histologic diagnosis was a benign adenoma. The patient’s hypertension and hypokalemia improved postoperatively but recurred 8 months later, and florid Cushing’s syndrome developed. Magnetic reso- nance imaging showed an 8-cm mass in the right adrenal bed and multiple hepatic metastatic lesions. Fine-needle biopsy confirmed the presence of adrenocortical carcinoma.
Conclusion: Despite a comprehensive biochemical, radiologic, and histologic assessment, the diagnosis of adrenocortical carcinoma can be missed. Particularly, we caution against undue reliance on the initial tumor size. We recommend that abdominal imaging be performed every 3 months for the first year and every 6 months for the second year after surgical removal of selected adrenal nodules. (Endocr Pract. 2007;13:636-641)
Abbreviations:
ACC = adrenocortical carcinoma; CT = computed tomography; HU = Hounsfield units; MRI = magnetic resonance imaging
Submitted for publication September 26, 2006
Accepted for publication January 8, 2007
From the Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas M. D. Anderson Cancer Center, Houston, Texas. Address correspondence and reprint requests to Dr. Rena Vassilopoulou- Sellin, Department of Endocrine Neoplasia and Hormonal Disorders, Unit 435, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030.
@ 2007 AACE.
INTRODUCTION
Identification of an adrenal tumor necessitates a thor- ough and thoughtful assessment to exclude the presence of adrenocortical carcinoma (ACC). We present the case of a patient who received treatment for a histologically diag- nosed benign adrenal nodule, which subsequently was identified as ACC. We review the various methods used to assess an adrenal nodule and provide recommendations for further surveillance after surgical resection of selected adrenal nodules in which some suspicion of malignant involvement remains.
CASE REPORT
A 65-year-old man with a history of stable hyperten- sion was noted to have worsening of his hypertension (sys- tolic blood pressure >200 mm Hg and diastolic pressure >90 mm Hg) despite adherence to his antihypertensive regimen. An initial laboratory evaluation was notable for a serum potassium level of 2 mEq/L. Potassium supplemen- tation was begun, and multiple changes were made to his antihypertensive medications; however, the hypertension persisted. Computed tomography (CT) of the abdomen identified a 3-cm, well-circumscribed right adrenal nodule with no other focal lesions (Fig. 1 A). The patient was diagnosed as having primary hyperaldosteronism on the basis of an elevated plasma aldosterone level and decreased plasma renin activity. Subsequent adrenal venous sampling localized the hormone excess to the side of the adrenal nodule. The right adrenal gland was removed laparoscopically, and the histologic diagnosis was a benign adenoma. The patient’s serum potassium level normalized postoperatively, and his blood pressure was controlled with his preoperative drug regimen.
Eight months later, the patient’s blood pressure increased again, and hypokalemia recurred. Magnetic res- onance imaging (MRI) of the abdomen disclosed an 8-cm irregularly shaped mass in the right adrenal bed and sever- al tumors in the liver believed to be metastatic lesions. A CT-guided fine-needle biopsy of the adrenal bed mass was positive for ACC. The patient was referred to our medical center for further management.
A
B
The patient presented to our clinic with home-record- ed systolic blood pressures of 160 to 170 mm Hg and dias- tolic pressures of 80 to 90 mm Hg. He was taking irbesartan, felodipine, terazosin, finasteride, potassium, and levobunolol eyedrops (for glaucoma). There was no family history of adrenal or other endocrine disorders. The patient appeared cushingoid, with mild facial plethora and a moon facies. His blood pressure was 177/83 mm Hg. Palpation of the abdomen revealed a firm, nontender, 3- cm hemispheric mass in the right lower abdominal quad- rant. Initial laboratory workup was notable for the following findings (reference ranges shown parenthetical- ly): plasma aldosterone, 309 ng/dL (3 to 16); evening serum cortisol, 37.2 ug/dL (4.3 to 22.4); adrenocorti- cotropic hormone, <5 pg/mL (9 to 52); serum potassium, 3.5 mEq/L (3.5 to 5.0); total testosterone, 128 ng/dL (241 to 827); serum thyroid-stimulating hormone, 0.75 uIU/mL (0.5 to 5.5); and free thyroxine, 1.0 ng/dL (0.9 to 1.8). CT of the abdomen revealed an 8-cm soft tissue mass in the right adrenal bed (Fig. 1 B) and multiple hepatic nodules (the largest measuring 5.8 cm). A subcutaneous implant in the right lower abdomen and extensive peritoneal metastatic lesions were noted and were new since perfor- mance of abdominal MRI 1 month earlier.
The patient was diagnosed as having metastatic ACC with hypersecretion of aldosterone and cortisol. Surgical debulking was considered for control of his hormone excess, but on a return visit 5 weeks later, he had diffuse peritoneal carcinomatosis and malignant ascites necessi- tating frequent paracentesis. Systemic chemotherapy was recommended, and he is undergoing treatment.
DISCUSSION
ACC is a rare endocrine malignant tumor with an incidence of 2 cases per million people per year (1). There
is a bimodal age distribution, with peaks before age 5 years and in the fourth to fifth decades of life (2). ACC is an aggressive and lethal neoplasm, and up to a third of the affected patients have distant metastatic lesions at presen- tation (3). Complete surgical resection offers the greatest potential for cure and is best accomplished at the earliest evidence of disease, when the cancer is most likely to be localized to the region of the adrenal bed (4). The 5-year overall survival rate ranges from 32% to 60% with com- plete resection; without treatment, this rate declines to 3% to 12% (3,5).
The discovery of an adrenal mass necessitates a thoughtful and comprehensive assessment to ensure that, if a malignant lesion is present, it is diagnosed and treated at the earliest opportunity. Evaluation of an adrenal tumor should include assessment of tumor function, tumor size, and radiologic characteristics, and if resection is per- formed, a detailed histologic inspection of the removed gland is important. Nevertheless, despite a thorough assessment, accurate diagnosis of an adrenal tumor can be difficult.
Tumor Function
The initial step in the assessment of an adrenal mass is the determination of hormonal secretion (6). Typical laboratory screening tests include measurements of 24- hour urinary fractionated metanephrines and cate- cholamines, serum electrolytes, and 24-hour urinary free cortisol as well as dexamethasone (1 mg) suppression test- ing. If the patient has hypertension, serum aldosterone and plasma renin activity should be measured. Serum dehy- droepiandrosterone sulfate and urinary 17-ketosteroids should be measured if there is clinical evidence of viril- ization or feminization.
Approximately half of the ACCs are functional, secreting multiple hormones (35%), cortisol (30%), andro-
gens (20%), estrogens (10%), or aldosterone (<2%) (1). Resection is indicated if the adrenal tumor is hormonally functional, but the appropriate surgical approach is deter- mined on the basis of the degree of suspicion for malig- nant involvement. A rapid onset or clinically severe form of hormone excess may increase the suspicion of cancer, but substantial overlap occurs between benign and malig- nant hormone-secreting adrenal tumors. In our patient’s case, the presence of primary hyperaldosteronism would have lowered the suspicion for ACC because aldosterone- producing malignant tumors are extremely rare. Therefore, hormonal function cannot definitively distin- guish benign from malignant disease.
Tumor Size
Typically, adrenal tumor size is regarded as the single best predictor of the presence of malignant potential (1), but determining the appropriate threshold for concern has been a challenge. Many ACCs are more than 10 cm in greatest diameter when discovered, and very few are less than 4 cm (6). A diameter exceeding 5 cm was previously shown to have a sensitivity of 93% and a specificity of 64% for distinguishing benign lesions from ACC (7). In a study by Herrera et al (8), use of a cutoff value of 4 cm as the criterion for resection of an adrenal nodule resulted in a benign to malignant tumor ratio of 8:1, avoiding unnec- essary surgical intervention in up to 88% of patients. In a study by Mantero et al (9), 12% of patients (47 of 380) with surgically removed adrenal nodules had ACCs of 2 to 25 cm; applying a 4-cm cutoff level for resection would have had a sensitivity of 93% for identifying a malignant lesion. Sturgeon et al (10) reported that the likelihood of ACC doubles for adrenal tumors exceeding 4 cm in diam- eter and increases by more than ninefold for tumors of 8- cm diameter or larger.
Although adrenal tumor size may help guide manage- ment, it has limitations as the sole criterion for predicting malignant potential. In a review of 117 patients with inci- dentally discovered adrenal tumors, 38 ACCs were identi- fied, and 5 of them (13%) were 4 cm or smaller (11). Conversely, 10 benign tumors were 5 cm or larger (13%), and 6 of those tumors were larger than 8 cm. Thus, both small ACCs and large benign tumors are not uncommon. Use of any recommended threshold of size would have failed to predict malignant involvement in our patient’s case.
Radiologic Assessment
Advances in imaging during the past 20 years have provided valuable methods for identifying and assessing adrenal masses. The expanded use of CT and MRI has resulted in increased identification of adrenal masses (adrenal nodules are seen in up to 4% of abdominal CT studies) (1). Defining specific radiologic criteria to improve the prediction of malignant disease has been the subject of intense study. The diagnosis of a malignant lesion is obvious when there is evidence of direct invasion
or metastatic disease, but when these features are absent, assessment is limited to the characteristics of the nodule. Worrisome tumor features on CT and MRI include het- erogeneity, irregular shape, irregular margins, hemor- rhage, and large size (12).
CT attenuation values have been studied as predictors of malignant adrenal tumors. Attenuation values of 18 Hounsfield units (HU) or lower on non-contrast-enhanced CT were shown by Korobkin et al (13) to have a sensitiv- ity of 85% and a specificity of 100% in identifying adre- nal adenomas. More recently, non-contrast-enhanced CT attenuation value thresholds of 10 HU and 20 HU were reported to have specificities of 100% and 96.9% and sen- sitivities of 40.5% and 58.2%, respectively, in distinguish- ing adrenal adenomas from nonadenomas (14).
The rate of loss of contrast enhancement on delayed CT may provide additional information on tumor biologic features, inasmuch as washout of contrast material tends to occur faster in adenomas because of their greater vascu- larity. Hamrahian et al (14) reported that a washout of less than 60% on CT scans obtained 15 minutes after adminis- tration of the contrast agent was associated with a speci- ficity of 95% for identifying nonadenomas. Szolar et al (15) reported that 50% or greater washout at 10 minutes on delayed contrast-enhanced CT had 100% sensitivity and specificity for diagnosing adrenal adenoma. A study by Korobkin et al (16) found that a cutoff value of 37 HU at 15 minutes on delayed contrast-enhanced CT had a sensi- tivity and specificity of 96% for identifying benign adre- nal lesions. Most radiologic studies have been designed to distinguish adrenal adenomas from all nonadenomas, with few data specifically comparing adrenal adenomas with ACCs.
On the initial abdominal CT assessment, our patient’s adrenal tumor was small, homogeneous, and well circum- scribed. The tumor enhanced with administration of con- trast medium, but calculation of washout was not performed. The overall appearance was suggestive of an adrenal adenoma. Because up to 30% of adrenal adenomas are “lipid-poor” and do not have low attenuation values (17), there is substantial overlap in signal intensity between ACCs and benign adenomas on contrast- enhanced CT.
MRI has been variably successful in clarifying the diagnosis of adrenal tumors. Bilbey et al (18) reported that the use of chemical-shift MRI with in-phase T1-weighted spin-echo and opposed-phase gradient-echo sequences was associated with sensitivities and specificities of 90% to 100% in distinguishing benign adrenal adenomas from nonadenomas. A similar study by Outwater et al (19), however, found that T1-weighted chemical-shift MRI had a sensitivity of only 89% and a specificity of 87% in dis- tinguishing benign from malignant adrenal masses. The combination of T2-weighted and chemical-shift imaging, dynamic gadolinium enhancement, and size was reported by Slapa et al (20) to have a sensitivity and specificity of 100% for the diagnosis of benign adrenal lesions, and
Hönigschnabl et al (21) reported a sensitivity of 96.2% and a specificity of 89.8% for diagnosing adenomas with use of T1- and T2-weighted images, gadolinium enhance- ment, and, in most patients, chemical-shift imaging. To date, no published studies have established a clear benefit from the use of MRI over CT in the diagnosis of ACC. Because of the more limited availability and higher cost of MRI, CT remains the more common imaging modality for assessing adrenal nodules.
Pathologic Assessment
When there is suspicion of ACC, the use of fine-nee- dle aspiration to obtain tissue samples is discouraged. It has a low sensitivity for ACC (22) and cannot exclude the presence of a malignant lesion because of a high false-neg- ative rate (23). A greater concern is the risk of tumor spillage from capsular disruption and seeding along the needle tract (22). Laparoscopic resection of the tumor may also lead to tumor spillage or inadequate resection mar- gins; thus, the optimal procedure is an open adrenalecto- my (1,22,23) for both histologic diagnosis and treatment.
Large tumors on gross inspection (>100 g) are more likely to be ACCs, and smaller tumors (<50 g) are more likely to be adenomas (24). The presence of necrosis and hemorrhage should increase the suspicion of a malignant tumor, although these findings are also occasionally reported in large benign adrenal tumors (25). Of the scor-
ing systems devised to assist in the histologic diagnosis of ACC (26-28), the most widely applied is that of Weiss. Weiss observed that the presence of 3 or more of the fol- lowing criteria-nuclear grade III or IV, mitotic rate >5 per 50 high-power fields, atypical mitoses, 25% or fewer clear cells, diffuse architecture, necrosis, or invasion of venous structures, sinusoidal structures, or the tumor cap- sule-was consistent with a malignant tumor (28) and that more than 20 mitotic figures per 50 high-power fields dis- tinguished high-grade from low-grade primary ACCs on the basis of predicted median survival time (29). In a study by Aubert et al (30) of 24 adrenal adenomas and 25 ACCs, 24 adenomas met 2 or fewer Weiss criteria, whereas all 25 ACCs met 4 or more of these criteria. In that study, a Weiss score fulfilling 3 or more criteria had a specificity of 96% and a sensitivity of 100% for diagnosing ACC (30).
Determinations of nuclear grade, architecture, and cytoplasm characteristics are subjective assessments, and interpretation may be affected by the pathologist’s experi- ence and personal bias. Difficulty may also arise in distin- guishing a well-differentiated ACC from an adrenal adenoma. As an example, the predominant histologic appearance of normal adrenal architecture (Fig. 2 A) in our patient’s 3-cm tumor was consistent with a benign adeno- ma, but a detailed inspection identified foci of necrosis and vascular invasion (Fig. 2 B and C).
B
A
C
Surveillance
Our patient’s case demonstrates that even a seeming- ly benign adrenal nodule must be carefully scrutinized before definitive management is planned. Recurrence of ACC at the site of a removed adrenal nodule has been pre- viously reported (31-33); however, to our knowledge, no clearly stated recommendations for postoperative surveil- lance exist. As an extension of our experience with this patient’s case, and in consideration of other published experiences, we believe that surveillance for tumor recur- rence should be performed after surgical removal in select- ed cases in which concern about potential malignant involvement persists despite a benign histologic diagnosis. This concern about a malignant lesion might arise from an unusually rapid and severe initial presentation of hormone production, one or more worrisome characteristics on radi- ologic imaging, or narrowly missing the number of Weiss (or similar) criteria for malignant tumor on histologic assessment. We recommend that, in these selected cases, abdominal CT studies should be performed every 3 months for the first year and every 6 months for the sec- ond year after surgical resection of an adrenal nodule. Further annual follow-up may be continued at the clini- cian’s discretion.
ACKNOWLEDGMENT
We thank Drs. Pheroze Tamboli and Kristina Burt of the Department of Pathology and Dr. Barry Samuels of the Department of Radiology at The University of Texas M. D. Anderson Cancer Center.
DISCLOSURE
The authors have no conflicts of interest to disclose.
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