Residency Program - Case of the Month
October 2011 - Presented by Elham Vali Khojeini, M.D.
Histologic sections of the tumor display vascular invasion and extracapsular extension (Figure1) into the peri-adrenal fat. There is an increased mitotic index (20/50 HPF) (Figure 2), and extensive necrosis (Figure 3). The is predominance of the diffuse architecture pattern (Figure 4), and only a minority (25%) of tumor cells are clear cells.
Immunohistochemistry was done on a biopsy at an outside hospital which showed the tumor was positive for Melan-A, vimentin, KC3 and synaptophysin, and was negative for S-100, EMA, and CD-117.
Adrenal cortical carcinoma (ACC) is a rare tumor (estimated lifetime incidence of two cases per million population) which usually affects older individuals (fifth to seventh decade of life), but also occurs in the pediatric age group. ACC has a heterogeneous presentation and a variable, but generally poor prognosis. Many are non-functional. ACCs are usually large tumors compared with adenomas, but very small adrenal cortical tumors (i.e., <40 g) can metastasize rarely, while very large tumors (1400 g or more) may fail to behave in a malignant fashion. The average weight in several studies varied from 705 g to 1210 g. ACC often presents as a bulky mass with coarse nodularity, along with areas of necrosis, hemorrhage, and occasionally cystic degeneration. Viable tumors may appear yellow, yellow-orange, or tan to brown.
Microscopically, architectural patterns of ACC can generally be classified as trabecular, alveolar (or nested), or diffuse (solid) and there may be admixture in any individual tumor. A characteristic pattern is trabecular with broad anastomosing cords or columns of cells with intervening delicate vascular spaces, some areas sectioned in a particular plane may show free floating balls of tumor cells. A more delicate trabecular pattern of blunt cords or a serpentine alignment of cells may also be apparent. A myxoid pattern has also been described. While most myxoid adrenal cortical tumors are carcinomas, some are classified as adenomas. Most cells appear lipid-depleted with compact, eosinophilic cytoplasm; occasional cases show condensation of cell cytoplasm and, in a small proportion of tumors, intracytoplasmic hyaline globules can be detected.
In a study of 30 adrenal cortical neoplasms in children, hyaline globules were detected in three tumors (one ACA (adenoma), two ACC). In a study by Michalkiewicz et al they confirmed that pediatric ACTs are more common in girls and are almost always associated with increased production of adrenal androgens. It also revealed that pediatric ACTs are heterogeneous and comprise at least two subtypes with different pathogenetic mechanisms. Regardless of the type, complete resection is mandatory for definitive disease control. Among patients who have had complete resection, tumor size is a strong prognostic indicator.
It should be noted that, in some cases, an adrenal cortical tumor can be very difficult to differentiate from a pheochromocytoma. This may be due to a combination of unexpected imaging characteristics on magnetic resonance imaging, a nested growth pattern, compact lipid depleted cytoplasm, the presence of intra cytoplasmic hyaline globules and positive immunostaining for neuroendocrine markers such as a neuron-specific enolase and synaptophysin. Rarely, adrenal cortical tumors have been reported to mimic pheochromocytomas clinically due to elevated catecholamine secretion.
Histologic criteria for malignant adrenal cortical tumors include: broad fibrous bands, diffuse growth pattern, vascular invasion, widespread tumor necrosis, >10 mitoses per 100 high power field, cellular pleomorphism and capsular invasion. Nuclear pleomorphism can be a remarkable feature in some ACC, but this finding alone is not a reliable predictor of clinical behavior. Mitotic figures may be conspicuous, including atypical forms. Mitotic counts have been used to distinguish low grade (≤20 mitoses per 50 high-power fields) from high grade (>20 mitoses per 50 high-power field), which have a shorter median survival. Tumor necrosis may be a prominent feature and can be massive and confluent, with isolation of viable cells in a perivascular distribution. There may be small foci of calcification either within broad fibrous bands or in zones of necrosis. Another feature associated with malignancy is vascular invasion, and this is often apparent as loose plugs of tumor cells within vascular channels. Marked local invasion beyond the confines of the adrenal bed and/or invasion of adjacent organs or tissues is a reliable indication of malignancy.
Adrenocortical tumors, both benign and malignant, are characteristically immunoreactive for Melanin-A as well as inhibin and calretinin. Synethesis of synaptophysin has been demonstrated in ACC by in-situ hybridization for mRNA. Immunostaining for chromogranin is negative in ACC but positive in pheochromocytomas which may provide assistance in distinguishing between these two neoplasms.
The monoclonal antibody D11 has been shown to have utility in distinguishing adrenocortical neoplasms from other tumors, but does not differentiate benign from malignant adrenal cortical tumors. Using immunohistochemistry for the nuclear proliferation-associated antigen (Ki67), a high tumor proliferating factor, as well as p53 positivity has been shown to be strongly correlated with malignant behavior.
Fine-needle aspiration can be helpful in diagnosis but careful correlation must be made with clinical and endocrinological data, as well as with tumor size and location. The probability of diagnosing an ACC as an incidental adrenal nodule detected on abdominal CT scan is very low.
The mortality in adults with ACC ranges from 70 to 92%, with most tumor-related deaths occurring within the first 12 months following diagnosis. Liver and lung are the most common sites of metastasis.
Prognostic parameters include tumor stage, mitotic rate, and invasion of adjacent organs. In childhood may be a tendency to diagnose adrenal cortical tumors as of indeterminate potential or as ACC. In these younger patients, two clinical groups have been identified based upon age: an infantile and an adolescent group, with survival in the latter being significantly poorer.
Christopher Fletcher, Diagnostic histopathology of tumors,2007
E. Michalkiewicz, Clinical and Outcome Characteristics of Children With Adrenocortical Tumors: A Report From the International Pediatric Adrenocortical Tumor Registry, J Clin Oncol 22:838-845, 2004
Seung Hoon Beom et al, Metastatic Adrenocortical Carcinoma Presenting Simultaneously with Cushing’s and Conn’s Syndromes: A Case Report, Jpn J Clin Oncol 2011