Adrenocortical Carcinoma Arising From a Long-standing Adrenal Mass
KATTRON R. COFIELD III, MS; LARRY K. CANTLEY, MD; KIM R. GEISINGER, MD; RON J. ZAGORIA, MD; AND NANCY D. PERRIER, MD
Adrenocortical carcinoma is a rare tumor with a dismal prognosis. In stark contrast, benign incidental adrenal lesions are detected commonly on routine abdominal imaging. We report a case of a 74- year-old man with a history of germ cell testicular carcinoma who presented with a 4.8-cm left adrenal lesion. The lesion remained stable for 8 years, at which time the patient became symptomatic from an excess of cortisol hormone. Biopsy findings confirmed adrenocortical carcinoma. We describe the presentation, clinical findings, diagnostic work-up, and follow-up of this patient and review the literature.
Mayo Clin Proc. 2005;80(2):264-266
ACC = adrenocortical carcinoma; CT = computed tomography
A drenocortical carcinoma (ACC) is usually a fatal dis- ease. Most reports describe a rapidly progressive course of hormonal excess that coincides with an un- resectable mass. We describe an adrenal mass in a patient with a history of testicular carcinoma, which after 8 years proved to be an ACC. Early biopsy of all adrenal lesions in a patient with known prior malignancy is recommended. Functional assessment to rule out catecholamine excess al- ways should precede any intervention to prevent a rare but potentially fatal pheochromocytoma hypertensive crisis.
REPORT OF A CASE
A 74-year-old man presented with recent episodes of sys- tolic hypertension, hyperglycemia, and hypokalemia. The patient’s medical history was notable for a stage I mixed germ cell tumor treated with left orchiectomy 8 years previ- ously. The patient subsequently experienced excellent health with no limitations until 3 months before presenta- tion. At that time, a review of systems revealed a 20-kg weight loss in the past 3 months, a decline in physical function, progressive weakness, and an inability to ambu- late independently. Examination of the patient revealed a frail, elderly man with truncal obesity, thinning skin, and multiple areas of ecchymosis over the upper extremities.
From the Department of General Surgery (K.R.C., N.D.P.), Department of Endocrinology (L.K.C.), Department of Pathology (K.R.G.), and Department of Radiology (R.J.Z.), Wake Forest University of Health Sciences, Winston-Salem, NC. Dr Perrier is now with UTMD Anderson Cancer Center, Houston, Tex.
Individual reprints of this article are not available. Address correspondence to Nancy D. Perrier, MD, UTMD Anderson Cancer Center, Department of Surgical Oncology, Unit 444, PO Box 301402, Houston, TX 77230-1402 (e-mail: nperrier @mdanderson.org).
He also had prominent wasting over the extensor surface of the hands, proximal muscle weakness, and bilateral pitting edema of at least 3 cm extending proximally to the knees.
The patient was admitted to the pulmonary service for a presumed diagnosis of congestive heart failure. He under- went diuresis to alleviate peripheral edema, but his pulmo- nary status remained tenuous. Computed tomography (CT) of the chest revealed pulmonary edema and a left adrenal mass. Laboratory test results revealed hyperglycemia (se- rum glucose level, >1000 mg/dL) and hypokalemia (serum potassium level, 2.7 mEq/L). Both morning values of se- rum corticosterone and 24-hour urinary cortisol levels were extremely elevated at 11,216 ng/dL (AM reference range, 130-820 ng/dL) and 2061 µg/24 h (reference range, 3.5- 45.0 µg/24 h), respectively. The patient’s cortisol level remained elevated despite his undergoing overnight dexa- methasone suppression testing, suggestive of a primary adrenal etiology. His adrenocorticotropic hormone level was undetectable. Levels of 24-hour urinary vanillyl- mandelic acid, urinary metanephrine, urinary normeta- nephrine, urinary 17-ketosteroids, serum aldosterone, and serum renin were all normal. Levels of aldosterone precur- sors (11-deoxycorticosterone and 18-hydroxycorticoste- rone) were elevated. Alpha fetoprotein and ß-human chori- onic gonadotropin levels, which had been used to monitor the germ cell tumor, remained normal.
Computed tomography of the abdomen revealed a 4.8- cm irregularly shaped left adrenal mass of heterogeneous density with enhancement and attenuation characteristics suggestive of malignancy. Also, a 2-cm round, smooth right adrenal nodule exhibiting benign characteristics was noted (Figure 1). A comparison with previous CT scans obtained 8, 7, and 6 years earlier revealed that the left adrenal mass had been present for at least 8 years and had not changed (Figure 2). Although slightly different tech- niques had been used for the original scan, the lesion was 4.8 cm. Previous functional studies had not been obtained. Compared with scans from CT performed 4 weeks previ- ously at a hospital elsewhere, the most current CT scans showed new small pulmonary nodules bilaterally and a new small lesion in the caudate lobe of the liver.
Positron emission tomography revealed increased activ- ity in the left adrenal gland, throughout both lungs, and within both femurs, all suggestive of metastatic disease. Magnetic resonance imaging was not performed because the patient had a ventricular pacemaker.
The patient underwent fine-needle aspiration of the left adrenal gland. Microscopic specimens were highly cellular, with many individually scattered tumor cells and cohesive aggregates. The latter varied from small and flat to large and 3-dimensional. Many of the individual cells had nuclei stripped of most or all of their cytoplasm. In the air-dried specimens, abundant lipid droplets were present, typical of adrenocortical samples. Most of the nuclei were almost per- fectly round; they were also hyperchromatic with fine to coarsely granular chromatin and contained small nucleoli.
A core needle biopsy was performed (Figure 3). The cores contained neoplastic cells arranged in nests and cords in a trabecular pattern. The cells had scant to moderate amounts of lipid-poor eosinophilic cytoplasm. Nuclear di- ameters varied remarkably, but most nuclei were round. The nuclear chromatin was hyperchromatic, and small nucleoli were apparent. Numerous nitrate figures, some of which were atypical, were seen (about 7 per 50 high-power fields). Necrosis was not seen. On immunohistochemical analysis, the tumor cells were positive for inhibin and vimentin and negative for cytokeratins, calretinin, and thy- roid transcription factor 1. Results from staining to rule out a germ cell tumor were negative.1
Adrenocortical carcinoma with probable distant me- tastases (stage IV disease) was diagnosed on the basis of rapid onset of clinical symptoms, excess secretion of mul- tiple hormones, tumor characteristics on CT, and patho- logic review. Confirmation of metastatic disease was not possible because the pulmonary and hepatic lesions were located in areas not accessible by CT-guided biopsy.
Because of the patient’s fragile state, he and his family declined surgical intervention and oral mitotane therapy. Supportive measures were taken: potassium was replaced, blood glucose levels were controlled, and elevated serum cortisol levels were managed pharmacologically with high- dose ketoconazole (600 mg 3 times daily). The patient also underwent CT-guided radiofrequency ablation to treat the left adrenal mass. The procedure was performed pallia- tively to lessen the tumor burden and the enormous amount of cortisol excess. During the procedure, the patient experi- enced a hypertensive episode, with systolic blood pressure at 220 mm Hg, which was pharmacologically managed. His immediate postprocedural course was uneventful. The patient was discharged home and was given ketoconazole and narcotics. He died at home 1 month after diagnosis. His family declined an autopsy.
DISCUSSION
Adrenocortical carcinomas are rare, highly aggressive tu- mors that are among the most lethal of all neoplasms.2 The overall disease-free actuarial 5-year survival rate ranges
from 32% to 48% in patients who undergo complete resec- tion3,4 but is only 3% to 12% in patients who receive no treatment; the mean survival time without complete resec- tion was 3 months.5 Adrenocortical carcinoma may be clinically silent and may be discovered either incidentally during imaging for reasons other than adrenal disease or during cancer surveillance. Also, ACCs may be discovered during evaluation of clinical signs and symptoms sugges- tive of hormonal disturbance or as a result of the tumor’s mass effect or local invasion. Functional ACCs most com- monly produce cortisol, causing Cushing syndrome in at least 30% of patients.4
In our patient, an adrenocortical tumor had been present for at least 8 years. However, he experienced the clinical sequelae of hormonal excess only in the last 3 months before presentation. Rapid onset of symptoms is characteristic of functional ACC.5 Furthermore, our patient’s tumor met more than 6 of the Weiss histologic criteria6 used to distinguish ACCs from benign masses. The criteria are high nuclear
grade, mitotic rate greater than 5 per 50 high-power fields, atypical mitotic figures, eosinophilic tumor cell cytoplasm, diffuse architecture in 33% or more of the tumor, necrosis, invasion of venous structures, invasion of sinusoids, and capsular invasion.6 Because of our patient’s poor pulmonary status, his presumed metastatic disease, and the availability of pharmacological therapy to lessen the hormonal excess, he and his family refused surgical intervention.
The management of adrenal masses between 3 and 6 cm that are nonfunctional and have stable, benign imaging characteristics is controversial. Factors such as patient age and health and tumor characteristics including growth rate must be considered when deciding between adrenalectomy and close follow-up.5,7,8 However, in the context of a previ- ously known malignancy, a biopsy of adrenal masses larger than 1 cm should be performed to rule out metastasis from another site.9 Biopsy always should be preceded by func- tional assessment to rule out catecholamine excess. Failure to do so could result in a potentially fatal pheochromocy- toma hypertensive crisis. In our patient, the decision to monitor the lesion was presumably based on its size (<5 cm) and unchanging nature on serial CT examinations during the first 2 years. Despite our patient’s history of
malignancy, biopsy of the lesion was likely not performed because of the low prevalence of germ cell tumors metasta- sizing to the adrenal glands. The primary care physician presumably believed the lesion was an incidentally identi- fied benign adrenal adenoma. We assume that the stable size provided false assurance that the lesion was a benign incidental finding. Functional studies were not performed, and further follow-up was not recorded. Biopsy of isolated adrenal masses usually is reserved for patients with a his- tory of melanoma, lymphoma, or carcinoma of the lung, breast, stomach, kidney, or colon, or for patients with symptoms, physical examination findings, or biochemical or radiographic evidence of an underlying malignancy (such as change in size or size >5 cm).
Our case is unusual because the tumor did not seem to change or enlarge during an 8-year period of observation before the patient’s clinical presentation. The case is also unusual because the symptoms (weight loss, weakness, hyperglycemia, and hypokalemia) representative of func- tional ACC did not begin until 3 months before his death. From his history and available laboratory and pathologic findings, we postulate that the tumor underwent malignant transformation from a benign, nonfunctional adrenal mass to a highly aggressive, metastatic, functional ACC, which led to the patient’s rapid decline and death. Such malignant transformation has not been reported in adrenocortical tu- mors but appears to have occurred in this patient.
A biopsy should be performed of all adrenal lesions larger than 1 cm in patients with a history of malignancy after ruling out production of catecholamine excess. Any func- tional tumor should be removed surgically. Functional stud- ies and radiographic imaging should be repeated at a desig- nated 6-month or 1-year interval for nonfunctional tumors. Symptoms of multihormone production, rapid onset of symptoms, and weight loss strongly suggest carcinoma.
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