Arch Pathol Lab Med—Vol 129, February 2005 Erdheim-Chester Disease With Hemophagocytosis—Rao et al e39 Fulminant Multisystem Non–Langerhans Cell Histiocytic Proliferation With Hemophagocytosis A Variant Form of Erdheim-Chester Disease R. Nagarjun Rao, MD; Chung-che Chang, MD, PhD; Nevin Uysal, MD; Kenneth Presberg, MD; Vinod B. Shidham, MD; Joseph F.Tomashefski, Jr, MD ● Hemophagocytosis (HP), a feature seen in malignant his- tiocytosis and infection- and lymphoma-associated disor- ders, has not been previously emphasized in Erdheim-Ches- ter disease (ECD). Generally, ECD is recognized as a rare, systemic, non–Langerhans cell histiocytosis with a variable clinical course. Herein, we describe a unique case of mul- tisystem non–Langerhans cell histiocytic proliferation with a fulminant clinical course (death occurred within 3 months of presentation) that showed prominent HP and extensive involvement of multiple organs, including the lungs, resulting in respiratory failure. Hemophagocytosis led to severe anemia that required transfusion and throm- bocytopenia. Antemortem lung and bone marrow biopsy specimens revealed involvement by a histiocytic infiltrate with features highly suggestive of ECD and HP. Further- more, the autopsy documented the presence of HP and the histiocytic infiltrate in multiple other organs. This case is best categorized as a variant form of ECD. Recognizing this variant has the following important implications: (1) HP may be a marker for fulminant clinical course in ECD, (2) the presence of HP does not exclude a diagnosis of ECD, and (3) ECD should be considered in the differential di- agnosis of HP. (Arch Pathol Lab Med. 2005;129:e39–e43) E rdheim-Chester disease (ECD) is a rare, systemic, non– Langerhans cell histiocytosis. 1 It usually affects adults older than 40 years, characteristically causing symmetrical sclerosis of the metaphyseal ends of long bones. Involve- ment of other organs, including the lung, is recognized. Accepted of publication September 23, 2004. From the Department of Pathology, Medical College of Wisconsin,Mil- waukee (Drs Rao, Presberg, and Shidham); Department of Pathology,The Methodist Hospital, Baylor College of Medicine, Houston, Tex (Dr Chang); Department of Pulmonary Medicine, American Hospital, Istan- bul, Turkey (Dr Uysal); and Department of Pathology, MetroHealth Med- ical Center and Case Western Reserve University, School of Medicine, Cleveland, Ohio (Dr Tomashefski). Dr Rao is currently with the Depart- ment of Pathology, Apollo Gleneagles Hospital, Calcutta, India. Presented in part at the American College of Chest Physicians Annual Meeting, San Diego, Calif, November 2002. The authors have no relevant financial interest in the products or companies described in this article. Corresponding author: Joseph Tomashefski, Jr, MD, Department of Pathology, MetroHealth Medical Center, 2500 Metrohealth Dr, Cleve- land, OH 44109 (e-mail: jtomashefski@metrohealth.org). The incidence of pulmonary involvement in ECD is vari- able, ranging from less than 20% in some pathologic de- scriptions 2,3 to up to 35% in clinical and radiologic stud- ies. 4 The lesional cells in ECD are recognized as non–Lan- gerhans cell histiocytes, which belong to the dendritic cell family. 2 The etiology of ECD is not well understood, al- though recent studies 5,6 have suggested that it may be a clonal disorder. In contrast to certain other systemic histiocytic prolif- erations (eg, Rosai-Dorfman disease [RDD], systemic hemophagocytic syndromes), emperipolesis or hemophag- ocytosis (HP) has not been emphasized in ECD. The ab- sence of emperipolesis has been specifically noted in 2 recent histopathologic studies of pulmonary ECD. 2,3 In this report, we describe a case of fulminant, multi- system, non–Langerhans cell histiocytic proliferation that shows histomorphologic features consistent with ECD. However, in the presence of HP and in the absence of symmetrical osteosclerosis of long bones, this case is best categorized as a variant form of ECD. The clinical features and morphologic findings of antemortem biopsy speci- mens and at autopsy are reported, and the relevance and implications of HP are emphasized. REPORT OF A CASE A 68-year-old white man presented with a 3-day history of dry cough and pleuritic chest pain. Radiologic studies (Figure 1, A) showed increased interstitial septal markings, bilateral ground glass infiltrates, and a small right pleural effusion. An open lung biopsy specimen yielded a diagnosis of xanthomatous pleuritis with involvement of interlobular septa consistent with ECD (Fig- ure 2, A). A subsequent iliac crest bone marrow biopsy for eval- uation of anemia (hemoglobin, 10.3 g/dL) and leukocytosis (platelets, 18.4  10 3 /L) revealed infiltration of bone marrow, with similar xanthomatous histiocytic cells showing HP (Figure 2, C and D). Retrospective examination of the lung biopsy spec- imens also revealed HP (Figure 2, B). Blood cultures remained sterile, and the results of virologic studies performed on lung tissue and pleural fluid for cytomegalovirus, herpes simplex vi- rus types 1 and 2, respiratory syncytial viruses A and B, influ- enza virus A and B, and parainfluenza viruses 1, 2, and 3 were negative. The results of a subsequent skeletal survey were neg- ative for symmetrical osteosclerosis of the long bones. Subse- quently, the hemoglobin level reached 8.3 g/dL, requiring a packed red blood cell transfusion, and the platelet count went from 310  10 3 /L to 102  10 3 /L. He did not respond to