Final Diagnosis -- Erdheim-Chester Disease

FINAL DIAGNOSIS

Erdheim-Chester Disease

DISCUSSION

Erdheim-Chester disease (ECD) is an uncommon systemic histiocytic disorder with a predilection for adult males (3:1), 30-65 years of age. The disease may affect any organ; however, skeletal lesions are present in the vast majority (>95%) of patients. Cardiovascular involvement, retroperitoneal fibrosis, xanthelasma of the eyelids and periorbital edema are less frequent manifestations. The central nervous system (CNS) is affected in 56% of cases (2). Lesions typically arise in the pituitary stalk, orbit, dura and posterior fossa. Accordingly, patients commonly present with diabetes insipidus, visual disturbances, cerebellar and pyramidal syndromes. Orbital, CNS and cardiovascular involvement seems to portend a worse prognosis (3). Interestingly, CNS disease also correlates with a higher rate of kidney involvement. Histiocytoses are traditionally classified into Langerhans cell, non-Langerhans cell and malignant histiocytosis. In Langerhans cell histiocytosis (LCH), the histiocytes, 'Langerhans cells, harbor clefted, lobulated nuclei and immunolabel with CD1a or CD207 (Langerin), S100 and CD68. The microscopic features of ECD are non-specific, comprising foamy macrophages, and scattered giant cells. Occasionally, as in this case, emperipolesis with S100-positivity, characteristic findings in Rosai-Dorfman disease (RDD), are seen. In general, ECD should be negative for CD207 and RDD negative for the BRAF^V600E mutation. In the current case, the clinical phenotype with skeletal involvement and the BRAF-mutation strongly favors ECD. Of note, 20% of patients with ECD also harbor Langerhans cell populations, sometimes within the same biopsy. In addition, both diseases share clonal mutations in the MAPK pathway (3). In the histiocytosis classification recently proposed by Emile (3), LCH and ECD are grouped in the same category, with overlapping features observed in the mixed LCH/ECD subtype. Contemporary therapeutic strategies for ECD vary according to the location of lesions and the degree of involvement. In the past, corticosteroids and cytotoxic drugs were the mainstay of therapy. Currently, first line therapy is interferon-alpha. Agents targeting TNF-alpha (Infliximab), tyrosine kinase - inhibitor (Imatinib) and recombinant interleukin-1 receptor (Anakinra) have been successfully used in selected cases (1). More recently, patients with BRAF^V600E mutations, present in approximately 50%, have shown dramatic responses to therapy with the BRAF inhibitor vemurafenib 4). However, long-term survival data is still lacking.

REFERENCES

1. Campochiaro C, Tomelleri A, Cavalli G, Berti A, Dagna L. (2015). Erdheim-Chester disease. Eur J Intern Med, 26(4), 223-229. doi:10.1016/j.ejim.2015.03.004
2. Cives, M, Simone, V, Rizzo, F M, Dicuonzo, F, Cristallo Lacalamita M, Ingravallo G, Silvestris F, Dammacco, F. (2015). Erdheim-Chester disease: a systematic review. Crit Rev Oncol Hematol, 95(1), 1-11. doi:10.1016/j.critrevonc.2015.02.004
3. Emile JF, Abla O, Fraitag S, Horne A, Haroche J, Donadieu J, Requena-Caballero L, Jordan MB, Abdel-Wahab O, Allen CE, Charlotte F, Diamond EL, Egeler RM, Fischer A, Herrera JG, Henter JI, Janku F, Merad M, Picarsic J, Rodriguez-Galindo C, Rollins BJ, Tazi A, Vassallo R, Weiss LM; Histiocyte Society. Histiocyte, S. (2016). Revised classification of histiocytoses and neoplasms of the macrophage-dendritic cell lineages. Blood, 127(22), 2672-2681. doi:10.1182/blood-2016-01-690636
4. Haroche J, Cohen-Aubart F, Emile JF, Arnaud L, Maksud P, Charlotte F, Cluzel P, Drier A, Hervier B, Benameur N, Besnard S, DonadieuJ, Amoura Z (2013). Dramatic efficacy of vemurafenib in both multisystemic and refractory Erdheim-Chester disease and Langerhans cell histiocytosis harboring the BRAF V600E mutation. Blood, 121(9), 1495-1500. doi:10.1182/blood-2012-07-446286

Contributed by Daniel Kirschenbaum,MD, Christoph Woernle, MD, Eugenia Haralambieva MD, Ewerton Marques Maggio MD, René Bernays, MD, Ulrike Camenisch, PhD, Elisabeth J. Rushing, MD