Malignant pheochromocytoma: Clinical, biological, histologic and therapeutic data in a series of 20 patients with distant metastases

Abstract

Twenty patients, 16 males and 4 females, aged 11-76 yr, were treated for a metastatic pheochromocytoma at our institution between 1985 and 1990. A neurofibromatosis was associated in 4. Thirteen patients had a unilateral adrenal tumor, 3 had an extraadrenal retroperitoneal tumor, 2 had a bilateral adrenal pheochromocytoma, one had a unilateral tumor with a contralateral medullary hyperplasia and one an adrenal and an extraadrenal pheochromocytoma. Metastases occurred in all patients, at presentation in 11, 10 to 30 months later in 7, and 9 and 28 yr later, respectively in two. Histology did not afford conclusive evidence for malignancy. Catecholamine hyperproduction was present in all, predominantly affecting norepinephrine. Neuron Specific Enolase level was elevated in 11, Neuro-Peptide Y level in 9 and procalcitonin level in 11/18. High dopamine, methoxytyramine and homovanillic acid excretion levels seemed to correlate with large tumors or terminal stage. MIBG uptake was found in 16 after a diagnostic dose and in 1 only after a therapeutic dose. Surgery was performed on primary tumor in 18 and on distant metastase in 10. Iodine-131 MIBG therapy was performed in 11, among whom 9 were evaluable. Cumulative activity ranged from 100 to 711 mCi, in 1 to 6 courses. Symptomatic improvement occurred in 5 patients, stabilization was observed in 3 and tumor partial response in two, which lasted for 28 and 9 months, respectively terminating in a rapidly progressing disease with bone marrow involvement. Moderate myelosuppression occurred in 4 patients. Chemotherapy gave no response in 7 evaluable patients. Fourteen patients died with a median survival of 16 months from diagnosis of metastases (range 3-60). Response to therapy was poor and warrants further cooperative trials.

Predictive Characteristics of Malignant Pheochromocytoma

“…Although none of our patients with malignant pheochromocytomas were alive after 10 years, others have reported somewhat better results [2]. The poor prognosis of patients with malignancy is thought to be attributable to dissemination to other organs, along with the heart failure associated with hypercatecholaminemia [6,[13][14][15][16][17][18]. Thus, long-term prognosis will not improve unless other features that can predict malignant behavior can be identified.…”

“…Previous studies have not been successful in identifying distinctive factors for malignant pheochromocytoma. Although some histopathological features have been suggested to be associated with an increased incidence of malignancy, including tumor necrosis, mitosis rate ＞3/30 HPF, capsular invasion, vascular invasion, large nests with central degeneration, a lack of hyaline globules, a high nuclear/cytoplasmic ratio, monotony of cytological pattern, and spindle cell patterns [6,17,19], none of these differences is sufficiently diagnostic. Moreover, molecular markers, including telomerase [20], inhibins, activins [21], endothelial Per-ARNT-Sim domain protein-1, vascular endothelial growth factor, endothelin receptor type B [22], and cyclooxygenase [21], have been found to be significant but unreliable and not readily applicable for distinguishing benign from malignant pheochromocytomas.…”

Results of Surgery for a Compound Adrenal Tomor Consisting of Pheochromocytoma and Ganglioneuroblastoma in an Adult. 5-year Follow-up.

“…Complete resection of the localized tumor was performed. The pheochromocytomacomponentwas considered benign because of the absence of metastases in aberrant chromaffin tissue (9). Therefore, the key to determining the prognosis was dependent on the malignant ganglioneuroblastoma component,which occupied most of the tumor (1, 5, 6).…”

“…In these two cases, the hormonelevels were not reported (Table 1). Dopamine abnormalities are muchmorecommon with an ordinary ganglioneuroblastoma than with an ordinary pheochromocytoma ( 1 7, 1 8), apart from a malignant pheochromocytoma (9,19,20). If such elevations are noted in patients suspected of having a benign pheochromocytoma, the possibility of a compoundtumor containing ganglioneuroblastoma should be considered.…”

Malignant Pheochromocytoma Lacking Clinical Features of Catecholamine Excess Until the Late Stage.

“…The reported incidence varies from less than 1% to 19% of all pheochromocytomas (1)(2)(3)(4)(5), and when the primary lesion is extraadrenal, this may rise to 24% (6) or 30% (7). Recurrence usually occurs several years after removal of the primary tumor (5,8,9), and bone is the most commonsite for metastases (8). The diagnosis of malignant pheochromocytoma is difficult, because it cannot be defined based on histologic criterion, and the clinical manifestations overlap those seen in benign pheochromocytomaexcept for the mass effect of tumors in the late stage. Wereport here a patient with malignant pheochromocytoma which recurred 12 years after successful removal of the primary tumor.…”