Retrospective application of the pathologic tumor-node-metastasis classification system for pheochromocytoma and abdominal paraganglioma in a well characterized cohort with long-term follow-up.

BACKGROUND: A pathologic tumor-node-metastasis staging algorithm for pheochromocytoma and sympathetic paraganglioma was introduced recently in the 8th Edition of the cancer staging manual of the American Joint Committee on Cancer. There is no information, however, as to how this staging correlates to well-established clinical cohorts of pheochromocytoma and sympathetic paraganglioma with extensive follow-up. METHODS: We applied the pathologic tumor-node-metastasis staging retrospectively to a cohort of 118 patients with pheochromocytoma and sympathetic paraganglioma, in which the majority has been characterized for susceptibility gene mutations and global mRNA expressional patterns as well as histologic risk criteria using the pheochromocytoma of the adrenal gland scaled score (PASS). RESULTS: The overall tumor stage correlated with the presence of metastases, disease-related death, and PASS scores as well as established mutational and expressional clusters. CONCLUSION: Stage III to IV pheochromocytomas and sympathetic paragangliomas are associated with increased mortality, increased PASS scores, and mutational and expressional aberrancies in the pseudo-hypoxia pathway cluster. These findings validate the stratification proposed by the American Joint Committee on Cancer staging manual by linking malignancy-associated pheno- and genotypes to more advanced stages. Moreover, because few pheochromocytomas and sympathetic paragangliomas are metastatic at the time of the original presentation, the staging relies heavily on identifying histologic signs of extra-adrenal invasion.