THE ADRENOCORTICAL CARCINOMA
May 22nd, 2008 by admin
We present a case of aldosterone-secreting adrenocortical carcinoma with concomitant myelolipoma. To the best of our knowledge, this is the first such reported case. The patient was a 43-year-old man with severe hypertension. Clinical workup revealed an increased serum aldosterone level, hypokalemia, and metabolic alkalosis, and a left adrenal mass was found on computed tomography. The patient underwent a unilateral adrenalectomy, which led to improvement in blood pressure, the serum potassium level, and aldosterone concentration. The tumor weighed 70 g and measured 5.0 cm. On microscopic examination, we found necrosis, focal cytologic atypia, diffuse eosinophilic cells comprising more than 75% of the tumor, 5 to 7 mitotic figures per 50 high-power fields, rare atypical mitosis, and venous invasion. At the periphery of the tumor but within the capsule, microscopic areas of myelolipoma were seen. Ki-67 staining was positive in 20% of the tumor cells. Although rare, aldosterone-secreting carcinoma associated with myelolipoma should be included in the differential diagnosis of adrenal gland masses.
Adrenocortical carcinoma is rare, with an annual incidence of about 1 case per million population,1 but it has a mortality rate of more than 50%.2 Aldosterone-secreting adrenocortical carcinomas are even rarer, accounting for only 2% to 7% of adrenocortical carcinomas in the largest series reported in the literature.3
Myelolipoma is a benign tumor that has been reported in association with adrenal hyperplasia, adrenocortical adenomas, ganglioneuroma,4,5 pheochromocytoma,5 and corticomedullary mixed tumor.6 Only 4 cases of adrenocortical carcinoma with concomitant myelolipoma have been reported in the medical literature. To the best of our knowledge, myelolipoma associated with adrenocortical carcinoma and hyperaldosteronism has not been reported previously. Thus, we describe the first case of aldosterone-secreting adrenocortical carcinoma with a myelolipomatous component.
A 43-year-old obese man (body weight, 107.8 kg; height, 1.73 m) with a family history of hypertension presented at our emergency room with vertigo in December 2003. Severe hypertension (206/110 mm Hg) was subsequently diagnosed with laboratory study results consistent with hyperaldosteronism (serum aldosterone, 26.6 ng/dL; normal, 1–21 ng/dL), hypokalemia (potassium, 3.1 mEq/L; normal, 3.6–4.8 mEq/L), and metabolic alkalosis (bicarbonate, 38 mEq/L; normal, 22–29 mEq/L). The levels of other cortical hormones and their metabolites were within normal limits. The results of pheochromocytoma workup were negative.
Abdominal magnetic resonance imaging revealed a 4.3-cm nodular mass in the left adrenal gland. Computed tomography of the abdomen revealed a 4.5 × 4.2-cm nodular mass of mixed heterogeneity . The patient underwent an uneventful unilateral adrenalectomy in February 2004 with substantial improvements in blood pressure (143/91 mm Hg) and serum potassium and aldosterone concentrations. He was discharged several days later with triamterene, potassium chloride, and clonidine. No recurrence or metastasis was noted at the most recent follow-up visit in late May 2004. He had negative computed tomography findings and blood pressure of 143/84 mm Hg.
The left adrenal gland weighed 70 g and measured 5.0 × 4.4 × 4.0 cm. The adrenal gland was almost totally replaced by a well-encapsulated bosselated tumor. A small portion of compressed nonneoplastic adrenal gland was seen on the surface. The cut surface of the tumor was multinodular, yellow, and soft with extensive areas of hemorrhage and necrosis .
On microscopic examination, the tumor was entirely encapsulated by a fibrous capsule of variable thickness. The cells were arranged in a sheetlike or trabecular pattern separated by relatively thick fibrous bands. The tumor was composed of mostly (>75%) round eosinophilic (compact) cells, with scattered foci of clear cells. There were extensive areas of hemorrhage, focal areas of necrosis, and areas of marked cytologic atypia with giant cells that had large, irregular, hyperchromatic nuclei. Five to 7 mitotic figures were seen in 50 high-power fields, with rare atypical mitosis. Focal vascular invasion was identified, but capsular invasion was not seen. At the periphery of the tumor but within the tumor capsule were few microscopic foci of myelolipoma composed of mature adipose tissue and normal-appearing trilineage hematopoietic cells. The transition between the tumor cells and the adipocytes was abrupt. The adjacent nonneoplastic adrenal gland was unremarkable.
Immunohistochemical staining for cytokeratin, epithelial membrane antigen, carcinoembryonic antigen, vimentin, S100 protein, melanin A, chromogranin, synaptophysin, inhibin, and Ki-67 was performed on paraffin-embedded tissue. The tumor cells were strongly positive for vimentin and focally positive for synaptophysin and showed a moderately proliferative rate with Ki-67 (staining in 20% of tumor cells). The tumor cells were negative for the remaining markers. The adipocytes were positive for S100 protein. The normal adjacent cortical cells were positive for inhibin and melanin A. Cells in the normal medulla stained positive for chromogranin, synaptophysin, and S100 protein.
More than half of adrenocortical carcinomas secrete hormones, most commonly cortisol, followed by androgens, estrogen, and aldosterone.7 Pure aldosterone-secreting adrenocortical carcinomas are extremely rare, with fewer than 30 well-documented cases reported in the medical literature.3 To our knowledge, this is the first reported case of a pure aldosterone-secreting adrenocortical carcinoma associated with myelolipoma.
Only 4 cases of adrenocortical carcinoma with a concomitant myelolipomatous component could be found in the medical literature.5,8,9 Two cases8 were reported with 49 other adrenal cortical carcinomas without specific description of the cases. The third case9 was found during the autopsy of a 57-year-old woman with multiple endocrine neoplasia syndrome type 1, which included hyperparathyroidism due to parathyroid hyperplasia, Zollinger-Ellison syndrome secondary to multiple islet cell adenomas, a 2.0-cm pituitary adenoma associated with a meningioma, a 23-g left adrenal adenoma, and a 325-g right adrenocarcinoma associated with myelolipoma. The fourth case5 was a 24-year-old man with Cushing syndrome; the size and weight of the lesion were not available. The myelolipoma component in these last 2 cases was similar to that in ours in that it was a lesion at the periphery of the adrenocortical carcinoma. In our case, the transition between the carcinoma and the myelolipoma was abrupt, and in some areas, the tumor nests within the myelolipoma simulated extracapsular extension.
Myelolipoma is a benign tumor that usually does not secrete hormones; however, its associations with
The main conditions to be considered in the differential diagnosis of myelolipoma are lipomatous metaplasia (presence of adipose tissue only), which has been found in the adrenal glands and is associated with pseudocysts; hyperplasia; primary pigmented nodular adrenocortical disease; adenomas; and carcinomas.12 In our case, the adipose tissue was associated with myeloid elements, which are features of myelolipoma.
Differentiating between adrenal adenoma and carcinoma in a small lesion can be challenging. Definitive diagnosis of malignancy in adrenocortical lesions is based on the presence of distant metastasis or local invasion. No single pathologic criterion of malignancy is reliable. Therefore, 3 multiparameter systems have been devised to help in delineating adrenocortical malignancies.13 Of the 3, the Weiss system,2,14 which evaluates 9 histologic criteria commonly associated with metastasis or recurrence, is the most widely used because of its simplicity and reliability. The 9 criteria used are high nuclear grade (based on the Fuhrman nuclear grade on the highest-grade areas of the neoplasm), mitotic rate of more than 5 mitoses per 50 high-power fields, presence of atypical mitotic figures, more than 75% of tumor cells with eosinophilic cytoplasm, more than 33% of tumor cells forming sheets, confluent nests of tumor cell necrosis, venous invasion, sinusoidal invasion, and capsular invasion (invasion of nests or cords of tumor cells extending into or through the capsule with corresponding stromal reaction). Originally, the presence of 4 or more of these histologic findings was defined as indicative of malignancy2; later, the threshold was modified to 3 or more.14 In this same study, Weiss et al14 found that the mitotic rate was a strong predictor of behavior and divided adrenocortical carcinomas into low-grade and high-grade lesions on the basis of mitotic count. Any carcinoma with more than 20 mitoses per 50 high-power fields is considered high grade. In their report, patients with high-grade tumors had a median survival of 14 months, versus 58 months for those with low-grade tumors. The tumor in our case met 6 of the 9 Weiss criteria for malignancy: diffuse growth, more than 75% eosinophilic cells, more than 5 mitoses per 50 high-power fields, rare atypical mitotic figures, necrosis, and venous invasion. On the basis of the mitotic rate, this tumor was classified as a low-grade adrenocortical carcinoma.
Another feature that favored malignant diagnosis in our case was the proliferative rate as determined by Ki-67 immunostaining. Ki-67 is a monoclonal antibody that recognizes 2 nuclear proteins in proliferating cells during all non-G0 phases of the cell cycle, and it has emerged as a promising, reliable indicator of cell proliferation.15 Although the exact Ki-67 threshold for malignancy in various studies has ranged from 4% to 10%,15 the cells in our case had 20% nuclear activity, a feature that supported the diagnosis of carcinoma.
In summary, we present the first case of aldosterone-secreting adrenocortical carcinoma with concomitant myelolipoma. The pathogenesis of the myelolipoma and its effect on the adrenocortical carcinoma are unknown. Aldosterone-secreting adrenocortical carcinoma associated with myelolipoma should be considered in the differential diagnosis of any adrenal mass.
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