The histopathology of Erdheim–Chesterdisease: a comprehensive review of amolecularly characterized cohortNeval Ozkaya1, Marc K Rosenblum1, Benjamin H Durham2, Janine D Pichardo1,Omar Abdel-Wahab2, Meera R Hameed1, Klaus J Busam1, William D Travis1,Eli L Diamond3,4and Ahmet Dogan1,41Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA;2Human OncologyPathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA and3Department ofNeurology, Memorial Sloan Kettering Cancer Center, New York, NY, USAErdheim–Chester disease is a rare, non-Langerhans cell histiocytosis histologically characterized by multi-systemic proliferation of mature histiocytes in a background of inflammatory stroma. The disease can involvevirtually any organ system; most commonly the bones, skin, retroperitoneum, heart, orbit, lung, and brain areaffected. Although a histiocytic proliferation is the histological hallmark of the disease, a wide range ofmorphological appearances have been described as part of case studies or small series. A comprehensivereview of histopathological features in clinically and molecularly defined Erdheim–Chester disease has yet to becharacterized. To address this issue and help guide clinical practice, we comprehensively analyzed thepathological spectrum of Erdheim–Chester disease in a clinically and molecularly defined cohort. We reviewed73 biopsies from 42 patients showing involvement by histiocytosis from a variety of organ systems, includingbone (16), retroperitoneum (11), skin (19), orbit (6), brain (5), lung (6), cardiac structures (2), epidural soft tissue(3), oral cavity (2), subcutaneous soft tissue (2), and testis (2). In eight patients, one or more bone marrowbiopsies were performed due to clinical indication and an accompanying myeloid neoplasm was detected in sixof them. Thirty-eight cases were investigated for genetic abnormalities. Somatic mutations involvingBRAF(25/38),MAP2K1(6/38),ARAF(2/38),MAP2K2(1/38),KRAS(1/38), andNRAS(1/38) genes were detected. One ofthe cases with aMAP2K1mutation also harbored aPIK3CAmutation. We have observed marked heterogeneity inhistology and immunophenotype, identified site-specific features, overlap with other histiocytic and myeloiddisorders and potential diagnostic pitfalls. We hope that broadening the spectrum of recognized pathologicmanifestationsofErdheim–Chesterdisease willhelppracticingcliniciansandpathologiststodiagnoseErdheim–Chester disease early in the disease course and manage these patients effectively.Modern Pathology(2018)31,581–597; doi:10.1038/modpathol.2017.160; published online 1 December 2017Erdheim–Chester disease is a rare, non-Langerhanscellhistiocytosishistologicallycharacterizedbymulti-systemic proliferation of maturehistiocytesinabackgroundofinflammatorystroma.Theinfiltrate can occur in virtually any organ systemalthough most commonly involves the bones, skin,retroperitoneum, heart, orbits, lung, and brain.
