Abstract-Chromaffin granule transmitters such as chromogranin A and catecholamines have been used in the diagnosis of pheochromocytoma, but the diagnostic and prognostic value of chromogranin A have not been explored in malignant pheochromocytoma. We evaluated these transmitters in patients with pheochromocytoma (nϭ27), both benign (nϭ13) and malignant (nϭ14). Patients with benign pheochromocytoma were studied before and after surgical excision (nϭ6), whereas patients with malignant pheochromocytoma were evaluated before and after combination chemotherapy with regular cycles of cyclophosphamide/dacarbazine/vincristine (nonrandomized trial in nϭ9). During treatment, patient responses to chemotherapy were divided according to anatomic and clinical criteria: responders (nϭ5) versus nonresponders (nϭ4). Plasma chromogranin A rose progressively (PϽ0.0001) from control subjects (48.0Ϯ3.0 ng/mL) to benign pheochromocytoma (188Ϯ40.5 ng/mL) to malignant pheochromocytoma (2932Ϯ960 ng/mL). Parallel changes were seen for plasma norepinephrine (PϽ0.0001), though plasma epinephrine was actually lower in malignant than benign pheochromocytoma (Pϭ0.0182). In bivariate analyses, chromogranin A, norepinephrine, and epinephrine discriminated between pheochromocytoma and control subjects (all PϽ0.0001), whereas in a multivariate analyses, norepinephrine was the best discriminator (Pϭ0.011). Chromogranin A was significantly different in benign versus malignant pheochromocytoma on both bivariate (Pϭ0.0003) and multivariate (Pϭ0.011) analyses. After excision of benign pheochromocytoma, chromogranin A (Pϭ0.028), norepinephrine (Pϭ0.047), and epinephrine (Pϭ0.037) all fell to values near normal. During chemotherapy of malignant pheochromocytoma (nϭ9), plasma chromogranin A (Pϭ0.047) and norepinephrine (Pϭ0.02) fell but not epinephrine. In 5 responders to chemotherapy, there were significant declines in chromogranin A (Pϭ0.03) and norepinephrine (Pϭ0.03) but not epinephrine; in 4 nonresponders, none of the transmitters changed. Plasma chromogranin A varied longitudinally with tumor response and relapse. We conclude that plasma chromogranin A is an effective tool in the diagnosis of pheochromocytoma, and markedly elevated chromogranin A may point to malignant pheochromocytoma. During chemotherapy of malignant pheochromocytoma, chromogranin A can be used to gauge tumor response and relapse. (Hypertension. 2000;36:1045-1052.)Key Words: plasma Ⅲ chromogranins Ⅲ norepinephrine Ⅲ epinephrine M alignant pheochromocytoma presents several difficulties in management, both in diagnosis 1,2 and in effective treatment. [2][3][4] Even after excision, the diagnosis of malignant pheochromocytoma cannot be made reliably on histological grounds 2 ; thus, extensive evaluations of tumor location are required to ascertain the presence of local or distant invasion or metastases by either surgical exploration, imaging, or regional venous blood sampling. 2 Specific biochemical diagnosis of malignant pheochromocytoma has received only limited attention. 1 Once d...