Pheochromocytoma: Time to Stamp Out “Malignancy”?

Abstract

Pheochromocytomas and extra-adrenal paragangliomas are slowly growing but potentially lethal tumors that can metastasize widely or extensively invade local structures. Patients with unresectable tumors have a poor prognosis, with death often occurring as a result of uncontrolled catecholamine secretion. Advances in genetics and gene expression profiling have led to new understanding of the pathobiology of pheochromocytoma and extra-adrenal paraganglioma. Up to 30% of these tumors are now known to have a genetic basis. In addition, tumor location, function, and risk of metastasis vary with the underlying genetic defect. Upward of 50% of tumors caused by SDHB mutations may ultimately metastasize, while those caused by mutated RET seldom do so. The “10 per cent rule” for pheochromocytoma/paraganglioma—10% familial, 10% malignant, 10% extra-adrenal—is no longer tenable [1]. Despite these advances, relatively little progress has been made in the diagnosis and treatment of biologically aggressive tumors. Parameters for predicting risk of metastasis before it occurs have been difficult to develop because the tumors metastasize infrequently and sometimes only after a long latency. Scoring systems have been proposed but have not been prospectively validated. Further, any particular finding might carry different weight in different patient cohorts. For example, local invasion might pose little metastatic risk in a tumor caused by mutated RET but be ominous in a tumor caused by mutated SDHB. It is increasingly clear that an additional impediment to progress is the definition of “malignancy”. According to the 2004 World Health Organization definition [2], “Malignant pheochromocytomas are currently defined by the presence of metastases”, not local invasion. In part, the rationale for this definition is that even extensive local invasion is a poor predictor of metastasis, and some tumors that metastasize show no apparent local invasion, suggesting that the two types of aggressive behavior have different biological bases. The definition based on metastasis can be seen as an attempt to provide a sharp focus for purposes of research and treatment. However, that definition has not been universally accepted. According to the 2007 Armed Forces Institute of Pathology Fascicle Tumors of the Adrenal glands and Extraadrenal Paraganglia [3], “...The diagnosis is based on evidence of extensive local invasion or, more reliably, documentation of metastases” (italics added). Two excellent, widely utilized, authoritative sources provide different definitions of the same term! The ambiguous definition of malignancy is not a new concern. Overall estimated rates of malignancy for adrenal pheochromocytomas range from approximately 2% to more than 13% [3], with differences based in part on the definition. One report of a large series implies that the rate may be even higher due to the presence of “microscopic malignant features”, defined as microscopic capsular or vascular invasion, even though none of the adrenal tumors with those features went on to metastasize [4]. In some papers, it is difficult to ascertain the numbers of tumors that were metastatic, locally invasive, or both. Additional confusion is caused by papers that pool data from intraand extra-adrenal tumors because extra-adrenal location is an independent risk factor for tumor aggressiveness [3] and is also the typical location of tumors caused by mutations of SDHB [1]. Endocr Pathol (2008) 19:207–208 DOI 10.1007/s12022-008-9047-x