Adrenocortical carcinoma: Report of two cases.

Adrenocortical carcinoma (ACC) is a rare neoplasm with a slight predilection for female patients. We report two cases of ACC. The first case was of a 7-year-old girl who presented with clitoromegaly. The second case was of a 22-Year-old female who presented with a lump in the abdomen and features of Cushing's syndrome with virilization.The clinical, biochemical, histological features along with differential diagnosis are discussed. These cases are presented because of their rarity, and also to highlight the importance of differentiating ACC from an adenoma particularly in pediatric patients.

INTRODUCTION

Adrenocortical carcinoma (ACC) is a rare neoplasm with an incidence of about one case per million population.[1] They have a bimodal peak; the first one is in the fourth and fifth decades of life and the second one in the first decade. About 60% are functional tumors that secrete hormones and present with clinical features like Cushing's syndrome due to cortisone, virilizing tumor due to androgens, or feminizing tumor due to estrogens.[2] ACC in children appears to behave differently than that in the adult patients. Virilization is more frequently seen and has a better prognosis after complete resection than in adults. The overall 5-year survival rate ranges from 16% to 38%.[3] Recurrence, even after seemingly complete resection, is common, occurring in 23% to 85% of patients.[3] Death usually occurs in the first 2 years.

CASE REPORTS

Case 1

A 7-year-old girl came with a complaint of clitoromegaly. MRI of the abdomen showed a right supra renal mass of mixed intensity measuring 6.5×5.3×3.5 cm causing minimal indentation over upper pole of the kidney. The clinical diagnosis was a benign cortical adenoma. The left adrenal gland was normal. Biochemically plasma cortisol and testosterone were elevated. Per operatively as there were adhesions to the kidney, the entire tumor was not removed.

We received a grayish brown mass weighing 45 g measuring 6×5×3 cm. Cut section was variegated and partly capsulated. Microscopy revealed a tumor composed of polygonal cells arranged in solid sheets along with thick trabeculae patterns and delicate sinusoids [Figure 1]. Nuclear-grade (Fuhrman) was 3 to 4. Tumor giant cells, confluent areas of necrosis and foci of vascular invasion were also seen. Mitotic figures were more than 20 per high power field (HPF). Patient died with a liver metastasis resulting in hypoproteinemia and cancer induced cachexia.

Figure 1

Tumor cells arranged in thick trabecular patterns (H and E, ×400)

Case 2

A 22-year-old mentally retarded female with short stature came with a complaint of abdominal pain and lump and three episodes of seizures 2 months ago. On examination, she had cushingoid features such as central obesity, hoarseness, hirsutism, and hypertension [Figure 2]. Biochemical parameters estradiol, T3, T4, TSH, FSH and 24 hr urinary metanephrine were within normal limits. Testosterone and serum cortisol were elevated.

Figure 2

Case 2 patient showing cushingoid features and hirsutism

On abdominal sonography a large exophytic mass of 9×8 cm from upper lobe of right kidney was identified, right adrenal could not be identified separately. A differential diagnosis of right ACC vs. renal cell carcinoma was made. Per operatively the tumor was adherent to the inferior surface of liver, kidney, and inferior venacava. We received a grayish brown mass weighing 356 g and measuring 12.5×6.5×5.5 cm that was partly circumscribed and friable.

Histologically, the tumor was composed of polygonal cells arranged in solid sheets and thick trabecular patterns with delicate sinusoids lined by flattened endothelial cells. Uninucleate, multinucleate tumor giant cells, atypical mitoses, necrosis, vascular and capsular invasion were seen [Figure 3]. Mitoses were >20 per HPF. Focal areas showed tumor cells with bizarre nuclei [Figure 4]. Patient died after surgery due to postoperative diffuse oozing of blood. Immunohistochemistry (IHC) study in both cases was positive for vimentin and inhibin and negative for cytokeratin and chromogranin [Figure 5]. Hence, the tumors were diagnosed as ACC high grade, stage 3, with Cushing's syndrome and virilization.

Figure 3

Tumor showing vascular invasion (H and E, ×400)

Figure 4

Tumor cells showing bizarre nuclei (H and E, ×400)

Figure 5

Tumor cells showing inhibin positivity and inset shows chromogranin negativity (×400)

DISCUSSION

ACC is a rare neoplasm with poor prognosis and with an incidence of one in one million population. There is a slight female predilection (58.6%).[1] They have a bimodal peak in the fourth and fifth decades and a second one in the first decade. In children, the incidence is 0.3/million under 15 years of age. In Southern Brazil, it is 10–15 times higher. ACC occurs with increased frequency in children with Beckwith–Wiedmann syndrome and Li-Fraumani syndrome. However, most of the tumors are sporadic.[45]

The ACC may be functional with a clinically pure endocrine syndrome like Cushing's or it may be a mixed syndrome as Cushing's with virilization. Virilization is frequent in children and indicates 70% chance of malignancy.[5] Virilization is due to dehydroepiandrosterone and dehydroepiandrosterone sulphate rather than testosterone. In this study both cases showed features of virilization and a rise in serum testosterone levels.[6]

The main differential diagnoses are adrenocortical adenoma, Pheochromocytoma, and renal cell carcinoma. The features that differentiate adenoma from carcinoma are weight of the tumor, if more than 95 g is usually malignant. But sometimes tumors less than 50 g can metastasize and tumors over 1000 g may clinically benign. We have followed the Weiss criteria [Table 1] for assessing the prognosis.[7]

Table 1

Results according to Weiss criteria

Tumor is low grade if the mitotic figures are <20 per HPF, high grade if the mitotic figures are >20 per HPF. If any three of nine criteria are present, the tumor is malignant. In this study, both cases showed more than three features, so they were diagnosed as malignant. IHC of the tumor showed negativity for cytokeratin supporting the diagnosis.

For staging of the tumor, we followed the TNM staging:

Stage 1: tumor 5cm or less with no spread to surrounding tissues or lymph nodes without distant metastasis.

Stage 2: tumor >5 cm with other stage 1 characteristics.

Stage 3: tumor invading nearby tissues and/or spread to nearby lymph nodes.

Stage 4: Distant metastasis.

In this study, both cases were in stage 3.

The second differential diagnosis was a Pheochromocytoma. Histologically, typical zellballen pattern, raised catecholamine levels in serum and positivity for immunohistochemical markers like chromogranin will favor a Pheochromocytoma. Whereas inhibin, Melan-A, and calretinin positivity favor ACC. Sometimes a Pheochromocytoma can cause Cushing's syndrome.

The third differential diagnosis was a renal cell carcinoma (RCC) which can infiltrate adrenal gland directly or metastasize to it. Presence of glands with red blood cells and abundant cytoplasmic glycogen and positivity for immunohistochemical markers such as cytokeratin and EMA will favor RCC. In this study we have excluded RCC, Pheochromocytoma, and an adrenal cortical adenoma by the morphology, IHC markers, and also correlating with clinical and biochemical features.

CONCLUSION

ACC is an extremely rare neoplasm and particularly if it occurs in children, it is essential to differentiate it from an adrenocortical adenoma by correlating with clinical, biochemical, imaging, and histological features, because their prognoses are different.