A 5-year-old boy presents with a 3-month history of polyuria, polydipsia, and bilateral proptosis. His parents report he was hit in the head during play 6 months ago but had no serious injury. Lateral skull radiograph shows multiple well-circumscribed lytic lesions with characteristic beveled edges (uneven destruction of inner and outer tables creating a 'hole-within-a-hole' appearance) in the calvarium, and a destructive lesion in the temporal bone. Urine specific gravity is 1.002 and fails to concentrate with water deprivation but normalizes with desmopressin. Biopsy of a skull lesion reveals sheets of cells with grooved nuclei, abundant eosinophils, and CD1a+ immunostaining. The pathologic process marked **A** in the diagram is a clonal neoplastic proliferation of which cell type?

Explanation

## Why myeloid-derived dendritic cells (Langerhans cells) expressing CD1a, CD207 (langerin), and S100 is right The clinical presentation of the classic Hand-Schüller-Christian triad (lytic skull lesions with beveled edges, diabetes insipidus from pituitary stalk infiltration, and exophthalmos from orbital involvement) combined with CD1a+ biopsy findings is pathognomonic for Langerhans cell histiocytosis (LCH). LCH is a clonal neoplastic proliferation of pathologic Langerhans cells, which are myeloid-derived dendritic cells that characteristically express CD1a, CD207 (langerin), and S100 protein. Electron microscopy would reveal the pathognomonic Birbeck granules ('tennis racket'-shaped cytoplasmic inclusions). This diagnosis is further supported by the beveled-edge lytic lesions in the calvarium, which are the hallmark radiographic finding of Hand-Schüller-Christian disease (Nelson Pediatrics 22e; Histiocyte Society Guidelines). ## Why each distractor is wrong - **Plasma cells expressing CD138 and producing monoclonal immunoglobulin**: This describes multiple myeloma (option B in the diagram), which presents with lytic lesions but typically in adults, lacks the beveled-edge pattern, does not cause diabetes insipidus or exophthalmos, and would show monoclonal spike on serum/urine electrophoresis with CD138+ plasma cells on biopsy, not CD1a+ histiocytes. - **Neural crest-derived sympathetic neuroblasts with MYCN amplification**: This describes metastatic neuroblastoma (option C in the diagram), which can cause lytic bone lesions but typically presents with abdominal mass, elevated catecholamine metabolites (VMA/HVA), and MYCN amplification; it does not produce the characteristic beveled-edge skull lesions, diabetes insipidus, or CD1a+ histology. - **Fibroblasts with constitutive TGF-β signaling and GNAS mutations**: This describes fibrous dysplasia (option D in the diagram), which causes sclerotic or mixed lytic-sclerotic lesions with a 'ground glass' appearance, not well-circumscribed lytic lesions with beveled edges; it does not cause diabetes insipidus, exophthalmos, or CD1a+ histology. **High-Yield:** Hand-Schüller-Christian disease = CD1a+ Langerhans cell histiocytosis with the classic triad of beveled-edge skull lesions, diabetes insipidus (permanent), and exophthalmos; ~50% harbor BRAF V600E mutations amenable to targeted therapy. [cite: Nelson Pediatrics 22e — LCH; Histiocyte Society Evaluation and Treatment Guidelines]