Novel insights into the polycythemia-paraganglioma-somatostatinoma syndrome

Abstract

Worldwide, the syndromes of paraganglioma (PGL), somatostatinoma (SOM) and early childhood polycythemia are described in only a few patients with somatic mutations in the hypoxia-inducible factor 2 alpha (HIF2A). This study provides detailed information about the clinical aspects and course of 7 patients with this syndrome and brings into perspective these experiences with the pertinent literature. Six females and one male presented at a median age of 28 years (range 11-46). Two were found to have HIF2A somatic mosaicism. No relatives were affected. All patients were diagnosed with polycythemia before age 8 and before PGL/SOM developed. PGLs were found at a median age of 17 years (range 8-38) and SOMs at 29 years (range 22-38). PGLs were multiple, recurrent and metastatic in 100, 100 and 29% of all cases, and SOMs in 40, 40 and 60%, respectively. All PGLs were primarily norepinephrine-producing. All patients had abnormal ophthalmologic findings and those with SOMs had gallbladder disease. Computed tomography (CT) and magnetic resonance imaging revealed cystic lesions at multiple sites and hemangiomas in 4 patients (57%), previously thought to be pathognomonic for von Hippel-Lindau disease. The most accurate radiopharmaceutical to detect PGL appeared to be [¹⁸F]-fluorodihydroxyphenylalanine ([¹⁸F]-FDOPA). Therefore, [¹⁸F]-FDOPA PET/CT, not [⁶⁸Ga]-(DOTA)-[Tyr3]-octreotate ([⁶⁸Ga]-DOTATATE) PET/CT is recommended for tumor localization and aftercare in this syndrome. The long-term prognosis of the syndrome is unknown. However, to date no deaths occurred after 6 years follow-up. Physicians should be aware of this unique syndrome and its diagnostic and therapeutic challenges.

Keywords: HIF2A mutation; paraganglioma; pheochromocytoma; polycythemia; somatostatinoma.

Figure 1

Ages at diagnosis of polycythemia, pheochromocytoma (PHEO)/paraganglioma (PGL) and somatostatinoma (SOM) for individual patients in chronological order. Ages at latest outpatient visit, gender, mutation status with (^‡) and without (^†) mosaicism of HIF2A, numbers (multiple = >3), sites (right, left) and recurrence (recur.) of lesions, presence of metastatic disease (_MET), and number of surgical interventions (1^st – 4^th Sx, etc.) and/or radiotherapy (Rx) are indicated.

Figure 2

Erythropoietin (EPO), hemoglobin (HGB), and hematocrit (HCT) levels over the course of several visits for patient No. 3, starting from first presentation at NIH, prior to and after surgeries (prior OP1, after OP1, and prior OP2), and during intermediate follow-up visits (FU) before the second surgery at the NIH. Respective upper and lower reference intervals are indicated for EPO, HGB, and HCT in gray, light gray, and dark gray, respectively. EPO levels did not normalize after surgeries, strongly refuting EPO production by tumor tissue.

Figure 3

Functional imaging with [⁶⁸Ga]-DOTATATE, [¹⁸F]-FDG, [¹⁸F]-FDOPA, and [¹⁸F]-FDA PET/CT in patient No. 2. Radiotracer uptake is similar in [¹⁸F]-FDA PET/CT and [¹⁸F]-FDOPA, showing 5 and 6 retroperitoneal lesions, respectively. On [⁶⁸Ga]-DOTATATE PET/CT only 3 retroperitoneal lesions could be identified. All of these radiopharmaceuticals showed an additional lesion at the jugular foramen (see black arrow), which was negative with [¹⁸F]-FDG. [¹⁸F]-FDG PET/CT showed only one of the retroperitoneal lesions. All retroperitoneal lesions are also indicated with black arrows.