Stage 4S Neuroblastoma: Molecular, Histologic, and Immunohistochemical Characteristics and Presence of 2 Distinct Patterns of MYCN Protein Overexpression-A Report From the Children’s Oncology Group

Kawano A, Hazard FK, Chiu B, Naranjo A, LaBarre B, London WB, Hogarty MD, Cohn SL, Maris JM, Park JR, Gastier-Foster JM, Ikegaki N, Shimada H. Stage 4S Neuroblastoma: Molecular, Histologic, and Immunohistochemical Characteristics and Presence of 2 Distinct Patterns of MYCN Protein Overexpression-A Report From the Children’s Oncology Group. Am J Surg Pathol. 2021 Aug 1;45(8):1075-1081. doi: 10.1097/PAS.0000000000001647. PubMed PMID: 33739795; PubMed Central PMCID: PMC8217390.

Stage 4S neuroblastoma (4SNB) is associated with spontaneous tumor regression and an excellent prognosis. However, a small group of the patients have a poor prognosis. 185 4SNB cases filed at the Children’s Oncology Group Neuroblastoma Pathology Reference Laboratory were studied. MYCN oncogene status [Non-Amplified (NA) vs. Amplified (A)] determined by FISH, MYC-family (MYCN/MYC) protein expression [no-overexpression(−)/(+/−) vs. overexpression(+)] by immunohistochemistry and histopathology by International Neuroblastoma Pathology Classification [Favorable Histology (FH) vs. Unfavorable Histology (UH)] with particular attention to nucleolar hypertrophy [NH(−) vs. (+)] were assessed with patient survival. 147 (79.5%) tumors were MYCN-NA, FH, MYC-family protein(−)/(+/−), and NH(−) with a good prognosis [88.5+3.1% 5-year Event-free survival (EFS); 94.1+2.3% 5-year Overall survival (OS)]. Among MYCN-NA tumors, 11 demonstrated MYCN protein(+) with a moderate and uniform (M/U) staining pattern: they were FH(10/11), NH(−), one showed MYC protein(+) simultaneously, and all patients are alive. Also found were 5 MYC protein(+) and MYCN(−)/(+/−) tumors; they were FH without NH(4/5), and all patients are alive. Among MYCN-A tumors, 18 had MYCN protein(+) with a strong and heterogeneous (S/H) staining pattern, 9 had UH (44.4+23.4% EFS/OS) and 9 had FH (68.6+19.2% EFS/OS), and 15 showed NH(+). Two tumors had MYCN protein(−)/(+/−) despite MYCN-A; both were FH and NH(−), and one patient died. S/H staining pattern of MYCN protein overexpression by immunohistochemistry was associated with MYCN amplification, NH(+) and a poor prognosis. In contrast, the M/U staining pattern was associated with MYCN non-amplification and NH(−), and had no adverse prognostic effects for the 4SNB patients.