Histopathology (International Neuroblastoma Pathology Classification) and MYCN status in patients with peripheral neuroblastic tumors

Abstract

BACKGROUND The International Neuroblastoma Pathology Classification (International Classification), which was established in 1999, is significant prognostically and is relevant biologically for the evaluation and analysis of patients with neuroblastic tumors (NTs). MYCN amplification is a known molecular marker for aggressive progression of NTs. These have been used together as important prognostic factors to define risk groups for patient stratification and protocol assignment. METHODS A total of 628 NTs (535 neuroblastomas [NBs]); 21 ganglioneuroblastoma, intermixed [GNBi]; 9 ganglioneuromas [GN]; and 63 ganglioneuroblastoma, nodular [GNBn]) from the Children's Cancer Group studies were evaluated histologically (favorable histology [FH] tumors vs. unfavorable histology [UH] tumors) according to the International Classification and were tested molecularly for MYCN status (amplified vs. nonamplified). Four tumor subsets (FH‐nonamplified, FH‐amplified, UH‐nonamplified, and UH‐amplified) were defined by histopathology and MYCN status, and their prognostic effects were analyzed. Detailed analysis between morphologic indicators (grade of neuroblastic differentiation and mitosis‐karyorrhexis index [MKI]) and MYCN status was done by using tumors in the NB category. RESULTS There were 339 FH‐nonamplified tumors (5‐year event free survival [EFS], 92.1%); 8 FH‐amplified tumors (EFS, 37.5%); 172 UH‐nonamplified tumors (EFS, 40.9%); and 109 UH‐amplified tumors (EFS, 15.0%). The prognostic effects on patients with tumors in the four subsets were independent from the factors of patient age and disease stage (P < 0.0001). MYCN amplification was seen almost exclusively in tumors of the NB category, and no patients with tumors in either the GNBi category or in the GN category and only two patients with tumors in the GNBn category had amplified MYCN. Among the patients with tumors in the NB category, patients with FH‐nonamplified tumors (309 patients) had an excellent prognosis, and patients with UH‐amplified tumors (107 patients) had the poorest clinical outcome in any age group. The prognosis for children with UH‐nonamplified tumors (111 patients) was poor when they were diagnosed at age > 1.5 years. It was also noted that patients with UH‐amplified tumors (median age, 2.14 years) were diagnosed at a significantly younger age compared with the patients with UH‐nonamplified tumors (median age, 3.55 years). Histologically, MYCN‐amplified tumors lacked neuroblastic differentiation regardless of the age of patients. MYCN amplification also was linked generally to increased mitotic and karyorrhectic activities. However, MKI classes in patients with MYCN‐amplified tumors varied significantly, depending on the age at diagnosis, and younger patients had higher MKI classes. CONCLUSIONS The combination of histopathologic evaluation and MYCN status distinguishes four clinical and biologic tumor subsets in patients with NTs. MYCN amplification seems to be the powerful driving force for preventing cellular differentiation regardles...

Low expression of human tubulin tyrosine ligase and suppressed tubulin tyrosination/detyrosination cycle are associated with impaired neuronal differentiation in neuroblastomas with poor prognosis

“…In contrast, tumors in the UH&A subset are known to be the most aggressive with the poorest clinical outcome. 27 Four m thick sections from the formalin-fixed and paraffin-embedded tissue samples were deparaffinized and microwaved for 3 ϫ 5 min in Na-citrate buffer (pH 6.0) for antigen retrieval. The slides were first immersed in 0.3% hydrogen peroxide in methanol for 20 min and then in 10% normal goat serum for 30 min.…”

Dickkopf‐3 expression is a marker for neuroblastic tumor maturation and is down‐regulated by MYCN

“…11 Ganglioneuromas and ganglioneuroblastomas rarely have amplification of MYCN. 12 MYCN is a member of the myc family of oncogenes, which code for transcription factors containing a basic-helix-loop-helix-leucine zipper domain. Myc family members activate transcription by dimerization with Max and binding to E-boxes (CAC(A/G)TG) within the proximal promoter of target genes.…”

Chromogenic in situ hybridization-detected hotspot MYCN amplification associates with Ki-67 expression and inversely with nestin expression in neuroblastomas

“…2 There is a correlation between MYCN amplification and specific histological appearance, as MYCN-amplified neuroblastomas lack neuroblastic differentiation. 3 In addition, MYCN-amplified neuroblastomas have significantly higher proliferation rates than nonamplified tumors. 4 MYCN amplification, with the overall prevalence of about 20-30% in neuroblastomas, is an independent molecular indicator almost invariably predicting an aggressive clinical behavior and poor prognosis, especially in localized disease.…”

“…6 Despite the laboriousness and relative error-proneness of MKI evaluation, it has remained the most used method in estimating proliferation status of neuroblastomas. As neuroblastomas display intratumoral heterogeneity of biological variables including proliferation activity 3 and MYCN copy number, 7 the estimation of prognostic parameters is complicated. Therefore, a welldefined selection of a single spot, which would represent the tumor in the analysis of the proliferation activity, MYCN copy number and other prognostic parameters, might unify results and facilitate evaluations.…”