This study summarizes the clinicopathological characteristics of ganglioneuroma and ganglioneuroblastoma cases by using the stringent criteria of the INPC. FH tumors, which include GN-M, GNB-I, and GNB-N-FS, usually presented as localized disease (stage 1, 2, or 3), and were often amenable to complete resection by either single or multiple surgical procedures. None of the patients with FH tumors died of tumor. In contrast, the prognosis of patients with UH tumor; i.e., GNB-N-US, was generally poor, and more than half of them had distant metastasis (stage 4) at the time of diagnosis.
In order to assure the diagnosis of FH tumors with excellent prognosis, there was a close communication and discussion between the central review pathologist and oncology team (institutional pathologist, oncologist, surgeons, and radiologist) at the participating institutions during the course of those CCG and COG Neuroblastoma studies. The discussion included reassessment/re-evaluation of primary tumor status and metastatic disease, if any, and planning of additional surgery, if necessary. As you see in , we clearly defined tumor resectability, and surgical margins were always examined carefully to rule out any possibility of aggressive NB growth. It was always ideal for pathologist to have a completely resected sample for the final diagnosis, so as not to miss any unfavorable nodules or different clones. However, in real life, we sometimes encountered the situation/clinical decision where we had to evaluate a biopsy or incompletely resected material. For those Inco-R cases, FH diagnosis of GN-M, GNB-I, or GNB-N-FS was accompanied by the remark of “the diagnosis is made based on review of a limited material”, and followed by a team effort to search for any hidden aggressive NB growth and to rule-in or -out a possibility of GNB-N-US.
As for the patients with GNB-N-US, this study revealed that their prognosis significantly depended on clinical stage, but not on the resectability of their primary tumor. It was of interest to note that almost half of the patients (74/159, 47%) included in this group had complete resection of their primary tumor with already established distant metastasis at the time of diagnosis. In rare cases (6 cases in our series), unfavorable NB nodule was detected only in the metastatic site even after complete pathology evaluation of their primary tumors. Aggressive primary tumor resection did not seem to be beneficial to GNB-N-US patients, regardless of whether metastasis was present or not.
The next consideration is the relationship between molecular/genetic markers (MYCN
status, DNA index) and histologic features of ganglioneuroma and ganglioneuroblastoma. MYCN
amplification, detected in about 15 to 20% of all pNTs, is a well-established indicator for a poor prognosis of the patients and almost exclusively found in the UH group (25
). As expected, there were only 4 FH tumors (4/210, 1.9%) that had amplified MYCN
in our series of GN-M (2 cases) and GNB-I (2 cases), and all 4 patients were alive and well at the time of last follow-up. It is suggested that amplified MYCN
may not have an adverse prognostic effect in these rare FH cases. No tumor in GNB-N-FH and only 6 tumors (3%) in GNB-N-UH had amplified MYCN
: Since these tumors are composed of different tumor histologies suggesting multiple distinct clones (24
), analysis of actual incidence and prognostic impact of MYCN
status cannot yield a conclusive statement in this study.
DNA index is another known prognostic factor useful for prognostic prediction of peripheral neuroblastic tumors especially in infants with pNTs. DNA index can distinguish biologically favorable tumors composed of hyperdiploid neuroblasts for a good prognosis from biologically unfavorable tumor composed of diploid neuroblasts for a poor prognosis(25
). In our series, the majority of GN-M and GNB-I tumors, even though they were biologically favorable with an excellent prognosis, had a diploid pattern determined by flow cytometry. This could be attributable to the fact that those tumors were mainly or predominantly composed of Schwannian stromal cells, and neuroblastic cells were not the main source of cells to be tested. Though there have been controversial reports on cellular origin of Schwannian stromal cells (28
), Ambros et al. report that Schwannian cells in GN-M and GNB-I are not neoplastic and do not share the same cellular origin of neural crest with neuroblastic cells, but they are normal diploid cells recruited by biologically favorable hyperdiploid neuroblastic cells. Recent study by Du et al. also suggested a possibility of bone marrow stroma cell origin of Schwannian stroma in neuroblastoma (30