Correspondence *Department of Urology, New York Presbyterian Hospital, Weill Cornell Medical College, 525 East 68th Street, Starr 900, New York, NY 10021, USA

Email ril9010@nyp.org

The case

A 39-year-old, white, female nonsmoker with a history of diabetes mellitus and morbid obesity was found to have a left adrenal mass on abdominal CT during a preoperative evaluation for gastric bypass surgery. She denied any history of hypertension, headaches, palpitations, excessive perspiration, muscle weakness, bruising easily, fatigue, or hematuria. Physical examination was unremarkable; specifically, no masses, costovertebral angle tenderness, lymphadenopathy, peripheral edema, cushingoid features, striae, or petechiae were noted. The patient's complete blood count, urine analysis and levels of serum electrolytes, blood urea nitrogen, and creatinine were all within normal limits. In addition, 24 h levels of plasma and urinary free cortisol, 17-hydroxy corticosteroids, and catecholamines were unremarkable. The level of urinary 17-ketosteroids, however, was elevated at 31.4 mg/24 h (normal range 6–15 mg/24 h). CT revealed the presence of a 6 5 5 cm left adrenal mass. MRI was performed to characterize the lesion further, and confirmed the absence of fat within the solid lesion. T2-weighted MRI did not reveal any areas of signal enhancement.

On the basis of the size, appearance, and functional status of the mass, the decision was made to perform a left adrenalectomy. Given the patient's body habitus, an open flank approach was chosen. It became evident perioperatively that the mass was encapsulated within the left adrenal gland. The entire gland was carefully dissected from surrounding structures without complications. The patient's postoperative course was uneventful, and urinary 17-ketosteroid levels normalized. No signs of disease were evident on follow-up CT.

The tumor was a well-circumscribed tan mass, weighing 120 g and measuring 6 cm in length. The cut surface revealed pinkish-tan, soft, homogenous tissue with streaks of hemorrhage and focal areas of necrosis. It was surrounded by an intact fibrous capsule attached to normal adrenal tissue. Under the microscope, the tumor cells were revealed to be polygonal-shaped with abundant granular, intensely eosinophilic cytoplasm. There was a diffuse pattern of growth, with prominent nuclear pleomorphism and atypia and occasional nucleoli (Figure 1). No mitotic figures were identified, nor was evidence of capsular or vascular invasion seen. The tumor cells were immunoreactive for inhibin, HMB-45 and synaptophysin. No immunoreactivity was detected for chromogranin and the S-100 protein, and the proliferation marker Ki-67 showed nuclear immunoreactivity in less than 5% of cells.

Figure 1 Microscopy of the adrenal oncocytoma.

Microscopic inspection of the adrenocortical tumor showed eosinophilic 'oncocytic' cells arranged in diffuse sheets and nests. (A) Tumor cells have pleomorphic nuclei and occasional nucleoli (hematoxylin and eosin stain, 20). (B) When immunohistochemistry is performed, tumor cells are diffusely immunoreactive to inhibin (inhibin stain, 20).

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Discussion of diagnosis

Oncocytic neoplasms predominantly comprise large eosinophilic and epithelioid cells that contain cytoplasm packed with eosinophilic granulations.¹ These lesions can arise in various organs, including the kidney, salivary glands, thyroid, parathyroids, pituitary, lung, liver, breast, ovary, stomach, small intestine, paraganglia, thymus, and prostate. Oncocytic neoplasms arising in the adrenal cortex are relatively rare, with only 29 cases described to date, including the present case.^{2, 3, 4, 5} Overall, the mean age of these individuals at diagnosis was 47.6 years (range 27–72 years), the mean tumor size was 9.4 cm (range 3–17 cm), and the mean tumor mass was 569.4 g (range 30–1,800 g). Tumors occurred on the left side in 18 cases, on the right side in 9 cases, and in a heterotopic or adjacent location in 2 cases.^{6, 7} Adrenal oncocytoma has even been reported to occur during pregnancy.⁸

Most of the reported tumors were asymptomatic at the time of diagnosis, and were detected incidentally during a clinical work-up for another complaint, such as abdominal pain, obstructive voiding symptoms, hematuria, essential hypertension, and fatigue. Most of the tumors were nonfunctional as well, although a significantly elevated level of 17-ketosteroid (591 mg/24 h; normal level 4–15 mg/24 h) was found in one patient who experienced virilization; these levels returned to normal after surgical resection.⁹ In the present case, the adrenal mass was asymptomatic, despite elevated levels of 17-ketosteroid.

Grossly, these tumors tend to be rounded, well-circumscribed, and brownish-tan in color when cut. A defining feature of oncocytic neoplasms seen under the microscope is the proliferation of mitochondria with abnormal morphology, almost to the exclusion of other organelles.¹⁰ Neoplastic cells retain characteristics consistent with their adrenal origin: abundant swollen and disrupted mitochondrial cristae; a prominent smooth endoplasmic reticulum; and stacked cisternae of rough endoplasmic reticulum. A strongly eosinophilic and granular cytoplasm, secondary to the presence of abundant mitochondria, can be seen on electron microscopy, and the cells can be arranged in alveolar, tubular, or solid patterns.¹ The classic central radiating scar described in renal oncocytoma can be absent in the adrenal variant, and sparse lipid droplets are sometimes evident.

Adrenal oncocytomas have an unknown pathogenesis. Some have speculated that it arises from heterotopic adrenocortical tissue. Alternatively, it could merely represent an oncocytic change in a discrete neoplasm.⁷ The abnormal proliferation of mitochondria could be the result of a compensatory mechanism secondary to deficient organelle activity in oncocytic cells.

Treatment and management

Distinguishing between malignant and benign tumors represents the main challenge in the management of adrenocortical tumors. Although most reported cases of adrenal oncocytoma have been benign, four malignant tumors have been described by Hoang et al. One demonstrated invasion into the inferior vena cava with atrial thrombus, another showed pulmonary and bony metastases, and the remaining two were classified as malignant using histologic criteria.¹¹ El-Naggar et al. reported another case, demonstrating local invasion into the inferior vena cava with metastasis to the liver.¹² Unfortunately, radiographic imaging alone is usually insufficient to predict malignant behavior. Although several alternative systems have been devised, no single histologic feature can determine whether adrenocortical neoplasms are malignant or benign. For example, adrenal oncocytoma can show considerable cytologic atypia, whereas adrenocortical carcinoma can demonstrate a low mitotic index, thus making diagnosis difficult when it is based on simple morphology alone. Proper diagnosis, therefore, must rely on a combination of biochemical, histopathologic, and clinical features. The Weiss classification system uses nine histologic criteria, as described in Box 1.¹³ The presence of three or more of these criteria is indicative of a malignant tumor, although the tumor is always malignant if the following triad of characteristics is present: venous invasion; atypical mitotic figures; and a mitotic rate higher than 5 mitotic figures per 50 microscopic high power fields. An increase in the proliferative activity of tumor cells, as measured by nuclear overexpression of Ki-67 protein, has recently been found to correlate with adverse patient outcomes.14 Although focal areas of necrosis were present in the case described here, there was no evidence of mitosis, capsular, venous, or sinusoidal invasion. Furthermore, Ki-67 protein was expressed in less than 5% of tumor cells.

The common use of ultrasound and CT imaging has led to increased detection of asymptomatic adrenal masses. Indeed, adrenal incidentalomas will be identified in 1–2% of all patients.¹⁵ The differential diagnosis of these lesions must include both benign and malignant entities, including adrenal cyst, myelolipoma, cortical adenoma, cortical carcinoma, pheochromocytoma, or metastasis to the adrenal. Careful biochemical analyses should be undertaken to rule out the presence of functioning cortical adenomas, carcinomas, or pheochromocytomas, all of which require surgical resection. Clinical management of incidental, nonfunctioning adrenal masses, however, is less well established; lesions thought to be benign can, in fact, demonstrate malignant behavior. Mass size has been considered the most important predictor of malignancy risk. Belldegrun et al. established that adrenal lesions greater than 6 cm in size have a high probability of being malignant. Most investigators agree that such lesions should be resected, whereas lesions smaller than 6 cm should be closely followed up.¹⁶ Recently, some surgeons have advocated that the size criterion for surgical removal of a lesion be reduced to 4 cm or 5 cm, as long as imaging characteristics such as calcification, hemorrhage, or necrosis are absent, and as long as the morbidity and mortality associated with surgery are considered.^{17, 18} Others urge against using this approach, however, as radiographic imaging tends to systematically underestimate the size of an adrenal lesion, compared with pathologic analysis.¹⁹ In the case described here, the adrenal lesion was 6 cm and mildly functional, thus fulfilling the criteria for removal.

Conclusion

Compared with other lesions, adrenocortical tumors with extensive oncocytic change, also known as adrenal oncocytomas, are rare, with only 29 cases described to date. Although uncommon, these lesions should be considered in the differential diagnosis of an incidentally detected solid adrenal mass and managed accordingly. It remains challenging, however, to distinguish between benign and malignant adrenal oncocytomas. A combination of biochemical, histopathologic, radiologic, and clinical features can be used to guide appropriate management, but surgical resection remains the mainstay of treatment for lesions deemed to be malignant.

In the case described here, the adrenal lesion measured 6 cm in size, which fulfilled the size criterion for surgical removal. In addition, the lesion displayed mild functionality, with an elevated 24 h urinary 17-ketosteroid level, and thus fulfilled further criteria for removal. Focal areas of necrosis were seen on histopathologic analysis, although none of the other Weiss criteria were met; this reinforces the expectation of benign behavior for this lesion.

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