Resident Program - Case of the Month

Discussion

Neoplasms in the adrenal medulla can be derived from chromatin cells and/or sympathetic ganglia. Tumor arising from chromaffin cells is known as pheochromocytomas, while others arising from sympathetic ganglia are classified based on their extent of maturation. These neuroblast-derived neoplasms include neuroblastomas (poorly differentiated), ganglioneuroblastomas (intermediate levels of differentiation) and ganglioneuromas (well-differentiated). Composite tumors comprised of a pheochromocytoma and a neuroblast-derived neoplasm are exceedingly rare. The estimate of incidence rate is less than 3% of all pheochromocytomas. Over 70% of these composite tumors are comprised of pheochromocytomas and ganglioneuroma components.

Composite pheochromocytoma and ganglioneuroma (PHEO-GN) is a well-defined neoplasm of the adrenal medulla, consisting of both endocrine and neural components. It is a very rare adrenal tumor. To date, less than 50 cases have been reported in the English literature.  The patients ranged from 5 to 82 years old, with the majority in the age range of 40 to 60 years, and these tumors occurred with approximately equal frequency in male and female. Most cases of composite PHEO-GNs were functional, with increased level of catecholamines. It is difficult to diagnose a composite tumor based on clinical or imaging data. Only the histopathological findings can give the definitive diagnosis of a composite tumor.

Immunohistochemically, the individual components of these tumors resemble their normal counterparts or pure tumors of the same type. Synaptophysin and chromogranin is strongly and diffusely positive in pheochromocytoma, while weak or focal in ganglioneuroma or neuroblasts. Staining for S-100 protein identifies spindle-shaped Schwannian cells and sustentacular cells while neurofilament only stains the neural part of the composite tumor, i.e. the spindled Schwannian cells and ganglion cells. Inhibin stains adrenal cortical cells and can distinguish adrenocortical tumors from adrenal medulla tumors.

The composite adrenal PHEO-GNs may be associated with sporadic tumors or as part of familial tumors such as neurofibromatosis type 1 (NF1), von Hippel-Lindau disease, multiple endocrine neoplasia type 2A (Men2A) syndromes. In our case, the PHEO-GN was associated with a sporadic tumor, duodenal adenocarcinoma. The underlying genetic/molecular mechanism for this composite adrenal tumor remains unknown. So far, no genetic abnormalities were found to distinguish composite tumors from pure pheochromocytomas.

The definitive treatment for composite adrenal PHEO-GN is complete surgical resection. Prognosis of completely resected composite adrenal PHEO-GNs is excellent without further therapies. The recurrence rate for the composite PHEO-GN is extremely low. However, distant metastasis has been reported. Therefore, composite adrenal PHEO-GNs should be surgically excised completely and should be followed for a long period after operation.

References

Comstock, J.M., et al., Composite pheochromocytoma: a clinicopathologic and molecular comparison with ordinary pheochromocytoma and neuroblastoma. American Journal of Clinical Pathology, 2009. 132(1): p. 69–73.

Khan, A.N., S.S. Solomon, and R.D. Childress, Composite pheochromocytoma-ganglioneuroma: a rare experiment of nature. Endocrine Practice: Official Journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists, 2010. 16(2): p. 291–299.

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Lam, K.Y. and C.Y. Lo, Composite pheochromocytoma-ganglioneuroma of the adrenal gland: an uncommon entity with distinctive clinicopathologic features. Endocrine Pathology, 1999. 10(4): p. 343–352.

Hu, J., et al., Retroperitoneal composite pheochromocytoma-ganglioneuroma: a case report and review of literature. Diagnostic Pathology, 2013. 8: p. 63.

Gupta S, Zhang J, Erickson LA., Composite Pheochromocytoma/Paraganglioma-Ganglioneuroma: A Clinicopathologic Study of Eight Cases with Analysis of Succinate Dehydrogenase. Endocrine Pathology, 2017 Sep;28(3): p. 269-275.

Mahajan H, Lee D, Sharma R, Chin P, Watt WH, McBride G, Bilous M: Composite phaeochromocytoma-ganglioneuroma, an uncommon entity: report of two cases. Pathology 2010, 42:295–298.