A Summary of the Inaugural WHO Classification of Pediatric Tumors: Transitioning from the Optical into the Molecular Era

Abstract

Pediatric tumors are uncommon, yet are the leading cause of cancer-related death in childhood. Tumor types, molecular characteristics, and pathogenesis are unique, often originating from a single genetic driver event. The specific diagnostic challenges of childhood tumors led to the development of the first World Health Organization (WHO) Classification of Pediatric Tumors. The classification is rooted in a multilayered approach, incorporating morphology, IHC, and molecular characteristics. The volume is organized according to organ sites and provides a single, state-of-the-art compendium of pediatric tumor types. A special emphasis was placed on "blastomas," which variably recapitulate the morphologic maturation of organs from which they originate. SIGNIFICANCE: In this review, we briefly summarize the main features and updates of each chapter of the inaugural WHO Classification of Pediatric Tumors, including its rapid transition from a mostly microscopic into a molecularly driven classification systematically taking recent discoveries in pediatric tumor genomics into account.

Figure 1.

A, Intertumoral heterogeneity of soft-tissue and bone tumors as assessed by DNA methylation array. Unsupervised, nonlinear t-distributed stochastic neighbor embedding projection of methylation array profiles of 610 soft-tissue and bone tumor samples. Samples have been selected from a large database of sarcoma datasets to serve as reference profiles for training a supervised classification model based on strict criteria. B–G, Undifferentiated small round cell sarcomas of bone and soft tissue. B, Ewing sarcoma with EWSR::FLI 1 fusions. C, Soft-tissue sarcoma with BCOR alteration (BCOR::MAML3 fusion). D, CIC::DUX4 sarcoma. CD99 membranous staining varies from strong and diffuse in ES (E) and BCOR::MAML (F) to focal in CIC::DUX4 (G).

Figure 2.

A–D, Fetal adrenal gland at 21–22 weeks of gestation. A, Migrating neural crest cells penetrate through the mesodermally derived fetal adrenal cortex homing into the future adrenal medulla (H&E; original magnification 200×). B, SOX10 IHC stain highlights the nuclei of migrating neural crest cells at the periphery of the migratory clusters, representing future Schwann cell precursors (SOX10 IHC; original magnification 200×). C, Migrating neural crest cells forming a Homer Wright rosette, indistinguishable from a similar structure in a poorly differentiated neuroblastoma (see E and F). The Homer Wright rossete is shown in the center, surrounded by fetal adrenal cortex (H&E; original magnification 200×). Inset shows the nonneoplastic Homer Wright rossete at a higher magnification (400×). Note the fine cytoplasmic prolongations of the future adrenal medullary cells in the center of the rosette. D, PHOX2B IHC stain showing strong nuclear reactivity in the migrating neural crest cells of the future fetal adrenal medulla (PHOX2B IHC; original magnification 200×). E and F, Poorly differentiated neuroblastoma from a 1-year-old patient. E, Several Homer Wright rosettes are seen with their characteristic central area of neuropil (H&E; original magnification 200×). F, PHOX2B IHC stain highlighting the nuclei of the neoplastic neural crest cells (neuroblasts) in multiple Homer Wright rosettes (PHOX2B IHC; original magnification 200×).

Figure 3.

Molecular groups of pediatric CNS tumors (at the level of superfamilies). Unsupervised, nonlinear t-distributed stochastic neighbor embedding (t-SNE) projection of methylation array profiles from 4,427 tumors. Samples were selected from a large database of >90,000 CNS tumor datasets to serve as reference profiles for training a supervised classification model based on strict criteria: all these samples showed a high calibrated classification score (>0.9) when applying the brain tumor classifier available at https://www.molecularneuropathology.org.

Figure 4.

Overview on CPSs. For the purpose of this review, syndromes were grouped into eight categories: (1) Li-Fraumeni syndrome; (2) syndromes predisposing to Wilms tumor; (3) syndromes predisposing to endocrine tumors; (4) syndromes predisposing to hematopoietic malignancies; (5) constitutional mismatch repair deficiency; (6) other syndromes predisposing to gastrointestinal tumors; (7) syndromes predisposing to neural tumors; and (8) other cancer-prone syndromes. Cancer predisposition syndromes listed in the WHO Classification of Pediatric Tumors and displayed in Suppementary Table S5 are marked with an asterisk.