The RNA component of telomerase as a marker of biologic potential and clinical outcome in childhood neuroblastic tumors

BACKGROUND. Telomerase is a ribonucleoprotein enzyme associated with cellul ar immortality that may be useful in determining the biologic potential of a tumor. Neuroblastoma (NB), ganglioneuroblastoma (GNB), and ganglioneuroma (GN) are neuroblastic tumors (NTs) that exhibit a spectrum of histologic f eatures and are often associated with unpredictable behavior and clinical o utcome. METHODS. The authors investigated the expression of the RNA component of hu man telomerase (hTR) by in situ hybridization in 32 cases of NTs (including 24 NBs, 4 GNBs, and 4 GNs), using [S-35]-UTP labeled single stranded sense and antisense RNA probes. Eight NBs were early stage, 12 NBs were advanced stage, and 4 NBs were Stage NS, a widely metastatic variant associated wit h an excellent clinical prognosis. Four NBs had N-myc amplification. In add ition, the authors compared a proliferation marker, MIB-1, with hTR express ion in a subset of tumors. RESULTS, Thirty of 32 NTs expressed hTR, with expression varying from weak (1+) to intense (4+). Most advanced stage NBs (9 of 12) and only 2 of 8 ear ly stage NBs had moderate to intense (2 to 4+) expression of hTR. The remai ning early stage tumors (6 of 8) and 3 of 12 advanced stage NBs had absent or weak expression of hTR (0 to 1+). There was no disease progression in an y of the patients with absent or weak expression of hTR. In contrast, 8 tum ors (from 7 patients) with moderate to intense expression of hTR in the tum or sections had adverse clinical outcomes, including recurrence, persistent disease, or death, hTR expression in all the Stage IVS tumors was weak, de spite the fact that the patients had widely metastatic disease at presentat ion. The mean hTR score of 3.1 for NBs associated with an adverse outcome ( n = 8) was significantly different from the mean hTR score of 1.3 for NBs a ssociated with a favorable outcome (n = 16), P < 0.001. hTR expression in t he GNB/GNs was limited to the ganglion cells only; Schwann cells were negat ive for hTR expression. Stage IVS tumors, which are associated with an exce llent outcome, had high MIB-1 but weak hTR expression, indicating that the latter may be a better discriminator of true biologic potential and that hT R levels do not always correlate with cell proliferation. CONCLUSIONS. Increased hTR expression may reflect the potential for aggress ive behavior within the spectrum of NTs; conversely, down-regulation of hTR may be useful in identifying subsets with limited capacity for progression and a favorable prognosis. Cancer 1999;85:741-9. (C) 1999 American Cancer Society.