Histopathology (international neuroblastoma pathology classification) and MYCN status in patients with peripheral neuroblastic tumors - A report fromthe children's cancer group

BACKGROUND. The International Neuroblastoma Pathology Classification (Inter national Classification), which was established in 1999, is significant pro gnostically and is relevant biologically for the evaluation and analysis of patients with neuroblastic tumors (NTs). MYCN amplification is a known mol ecular marker for aggressive progression of NTs. These have been used toget her as important prognostic factors to define risk groups for patient strat ification and protocol assignment. METHODS. A total of 628 NTs (535 neuroblastomas [NBs]); 21 ganglioneuroblas toma, intermixed [GNBi]; 9 ganglioneuromas [GN]; and 63 ganglioneuroblastom a, 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 m olecularly for MYCN status (amplified vs. nonamplified). Four tumor subsets (FH-nonamplified, FH-amplified, UH-nonamplified, and UH-amplified) were de fined by histopathology and MYCN status, and their prognostic effects were analyzed. Detailed analysis between morphologic indicators (grade of neurob lastic differentiation and mitosis-karyorrhexis index [MKI]) and MYCN statu s 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 tumo rs (EFS, 40.9%); and 109 UH-amplified tumors (EFS, 15.0%). The prognostic e ffects on patients with tumors in the four subsets were independent from th e 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 pat ients with tumors in the NB category, patients with FH-nonamplified tumors (309 patients) had an excellent prognosis, and patients with UH-amplified t umors (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 patien ts with UH-amplified tumors (median age, 2.14 years) were diagnosed at a si gnificantly younger age compared with the patients with UH-nonamplified tum ors (median age, 3.55 years). Histologically, MYCN-amplified tumors lacked neuroblastic differentiation regardless of the age of patients. MYCN amplif ication also was linked generally to increased mitotic and karyorrhectic ac tivities. However, MKI classes in patients with MYCN-amplified tumors varie d significantly, depending on the age at diagnosis, and younger patients ha d 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 regardless of patient age and for increasing mitot ic and karyorrhectic activities in an age dependent manner. (C) 2001 Americ an Cancer Society.