Refractory Stage M Ganglioneuroblastoma With Bone Metastases and a Favorable, Chronic Course of Disease: Description of a Patient Cohort

Abstract

Refractory stage M neuroblastoma (NB) is associated with a poor prognosis and a progressive course of disease. Here, we describe a unique group of patients with a discrepant clinical course. Seven histologically confirmed ganglioneuroblastoma (GNB) (n=6) and differentiating NB (n=1) patients were identified who were diagnosed with stage M disease based on iodine-123-metaiodobenzylguanidine avid bone metastases. Six patients started on high-risk treatment, without tumor response (stable disease). Treatment was discontinued before the start of consolidation treatment because of refractory response in all patients. Unexpectedly, after cessation of treatment no progression of disease occurred. In 2 patients, the primary tumors expanded (>25%) very slowly during 1.5 and 3 years, and remained stable thereafter. Metabolically, a slow decrease of urinary homovanillic acid and vanillylmandelic acid levels and iodine-123-metaiodobenzylguanidine avidity was observed. All patients are alive with presence of metastatic disease after a median follow-up of 17 years (range: 6.7 to 27 y). Interestingly, at diagnosis, 6 patients were asymptomatic, 6 patients had GNB morphology, and 5 patients had meningeal metastases. These are all features seen in only a small minority of stage M patients. This GNB entity illustrates the clinical heterogeneity of neuroblastic tumors and can be used to further study the developmental origin of different NB subtypes.

FIGURE 1

Imaging and pathologic follow-up of patient 1. A, ¹²³I-MIBG scans of patient 1 made 0, 1, 4, and 6 years after diagnosis. Pathologic uptake is marked by arrows. B, Chest radiograph made 17 years after diagnosis showing the large thoracic primary tumor, marked by 4 asterisks. C–E, Hematoxylin-Eosin staining of (C) the primary tumor at diagnosis showing large ganglion cells (arrows) with mature stroma, classified ads ganglioneuroblastoma nodular subtype (without a nodule in this sample). D, Bone marrow at diagnosis show infiltration of neuroblasts (within dashed line) in a background of fibrotic bone marrow and (E) bone marrow at latest follow-up, 2 years after diagnosis, showing large ganglion cells (arrows) with mature Schwannian stroma. ¹²³I-MIBG indicates iodine-123-metaiodobenzylguanidine.

FIGURE 2

Imaging follow-up of patient 2. A, ¹²³I-MIBG scans of patient 2, performed 4, 5, 6.5, and 13 years after diagnosis. Pathologic uptake is marked by arrows. At the last ¹²³I-MIBG scan there was still pathologic uptake at the left temporal bone, right parietal bone, and both femora. Suspected uptake was seen at the right mandibular angle and at a rib. B and C, T1 (2B) and T2 (2C) weighted MRI with gadolinium contrast showing a large metastasis in the left temporal bone, 11.5 years after diagnosis. ¹²³I-MIBG indicates iodine-123-metaiodobenzylguanidine; MRI, magnetic resonance imaging.

FIGURE 3

Meningeal metastases of patient 6. Sagittal T1 weighted MRI of patient 6 at diagnosis, showing meningeal and bone metastases. MRI indicates magnetic resonance imaging.

FIGURE 4

Fold change of homovanillic acid and vanillylmandelic acid over time. Homovanillic acid (A) and vanillylmandelic acid (B) per patient as fold change of age-related upper limit. On the x-axis, time from diagnosis is given.

FIGURE 5

Metastatic neuroblastoma stages related to the embryonic development of neural crest (NC) cells. The upper bar indicates the relative role of craniocaudal orientation, epithelial to mesenchymal transition (EMT), migration and differentiation of the NC cells during embryonic development. In the center, the development of the cranial (orange) and trunk (light blue) NC cells is presented as a time line. In dark blue, the sympathoadrenal (SA) progenitor as a precursor cells is depicted. In green, the Schwann cell precursor (SCP). In the boxes below the graph, the origin of the different tumor entities are postulated. BM indicates bone marrow; GNB, ganglioneuroblastoma.