PHOX2B Immunolabeling

Abstract

Peripheral neuroblastic tumors are the most commonly occurring extracranial tumors in children. Although a reliable diagnosis is achievable in the majority of cases, diagnosis of a minority of peripheral neuroblastic tumor cases (especially undifferentiated neuroblastoma) poses a challenge compared with that of other pediatric small round blue-cell tumors. A panel of immunohistochemical markers and fusion transcripts is available for the diagnosis of such tumors, but the markers for neuroblastoma lack specificity and sensitivity. As the transcription factor PHOX2B is highly specific for the peripheral autonomic nervous system from which peripheral neuroblastic tumors are derived, we have assessed PHOX2B immunolabeling as a diagnostic tool in pediatric small round blue-cell tumors. We observed PHOX2B expression in all peripheral neuroblastic tumors, paragangliomas, and pheochromocytomas tested but in no other pediatric tumors among the 388 cases studied by expression microarray and the 109 cases studied by immunohistochemical analysis. We then assessed the results of PHOX2B immunohistochemistry in 12 cases of undifferentiated pediatric neoplasms: PHOX2B was expressed in 6/6 undifferentiated neuroblastomas and in no other small round blue-cell tumors. Finally, we showed that PHOX2B immunohistochemical analysis improves the diagnosis of undifferentiated neuroblastoma with high specificity and sensitivity.

Wild-type ALK and activating ALK-R1275Q and ALK-F1174L mutations upregulate Myc and initiate tumor formation in murine neural crest progenitor cells

“…All mice implanted with MONC-1-ALK-F1174L cells developed highly malignant undifferentiated tumors, as they strongly expressed the mesechymal/stem marker CD44 and the neural stem/progenitor cell marker nestin, but did not stain for the neuronal marker Ncam1, the adrenergic differentiation marker tyrosine hydroxylase (Th), and the sympathoadrenal marker Phox2b, recently demonstrated as a highly specific marker of undifferentiated NB [30] (Figure 1C). In contrast, MONC-1 cells gave rise to various tumor types, as 3/7 mice developed osteosarcoma with chondrosarcoma components (Figure 1D), 1/7 mouse developed a highly malignant Phox2b − /nestin + undifferentiated tumor (Figure 1E), and 3/7 mice developed Phox2b + /Th − /nestin − undifferentiated NB (Figure 1F).…”

Clinical Characteristics and Outcome of Patients with Neuroblastoma Presenting Genomic Amplification of Loci Other than MYCN

“…In addition to atypical clinical features, the overall genomic pattern of these NBs revealed atypical segmental patterns. Although histological analysis confirmed the diagnosis of NB, novel histology characterisation using PHOX2B immuno-staining might be useful in this context of atypical NB to help in the diagnosis of undifferentiated types [31]. Indeed PHOX2B immunolabelling has been shown to improve the diagnosis of undifferentiated NB among childhood small round blue-cell tumours with high specificity and sensitivity.…”

TRIM proteins in neuroblastoma

“…Moreover, PHOX2B, whose coding gene is located on chromosome 4p13, is originally found in a NB cell line. It is expressed specifically in the nervous system and has a vital effect on the formation and differentiation of sympathetic neurons and chromaffin cells [34]. In addition, it has been reported that PHOX2B germline mutations, which account for 6% hereditary NBs, are involved in the initiation of NB tumorigenesis [35].…”