The vescicular monoamine transporters (VMAT1 and 2) transport monoamines from the cytosol into the secretory vescicles of monoaminergic neurons and neuroendocrine cells. Although the analogues of dopamine (DOPA) and nor-epinephrine (MIBG) used for PET and SPECT imaging of paragangliomas (PGL), respectively, seem to have different uptake mechanisms correlated to VMAT, expression of the latter has so far been investigated only in limited series. In this study we evaluated the expression of VMAT1 and 2 in a series of PGL patients.
62 patients (40/22 F/M; mean age 46.8 years, range 14–74) included 27 parasympathetic PGLs (neck and chest), 8 sympathetic abdominal extra-adrenal PGLs and 27 pheochromocytomas (PHEOs). All patients underwent complete diagnostic work-up (urinary metanephrines, CT or MRI, and analysis of susceptibility genes), while MIBG SPECT/CT or 18F-DOPA PET/CT were performed in subsets of patients. 26 out of the 56 patients subjected to genetic analysis had a gene mutation: 4 SDHB, 3 SDHC, 13 SDHD, 3 VHL e 3 RET. Immunohistochemical analysis using anti-VMAT1 and 2 antibodies was scored from 0 to 6 according to increasing fraction of VMAT1/2-positive cells. All patients underwent to surgical removal of the tumor with subsequent diagnostic confirmation by histological examination.
19/20 patients were positive at MIBG SPECT/CT, and 14/14 at 18F-DOPA PET/TC. 60/62 patients were positive for VMAT1 staining, with a significantly higher density in the parasympathetic and sympathetic PGLs than in PHEOs (5.2±0.2 vs 3.9±0.4, mean±SE, P=0.007) and this difference persisted comparing only parasympathetic PGLs than PHEOs (5.2±0.2 vs 3.9±0.4, mean±SE, P<0.05). Tumors of patients with a gene mutation had a lower expression of VMAT1. This difference was detected in both the total group (parasympathetic, sympathetic PGLs and PHEOs, P<0.05) and in the subgroup of PHEOs (P=0.007), while in the remaining subgroups is maintained a difference between mutated and wild-type although this did not reach statistical significance.
MIBG uptake was independent from the presence and score of VMAT1 expression. Instead, VMAT2 was expressed systematically with a high score (5.7±0.2) and irrespective of sympathetic or parasympathetic origin, except for lack of expression in 2 PHEOs. No differences were found in the distribution of VMAT2 between the group of patients mutated and the wild-type. On the other hand, 18F-DOPA uptake was associated with the presence and extent of expression of both VMAT1 and VMAT2.
These results indicate (unlike the VMAT2 that are overexpressed in all cases) a different VMAT1 expression between the parasympathetic PGLs and PHEOs (greater in PGLs). VMAT1 are less expressed in mutated patients than in non-mutated and suggest that the presence and density of VMAT expression are not crucial for MIBG uptake.