The diagnosis of ECD in our patient, initially established on clinical and radiological grounds, was confirmed by appropriate morphologic evaluation. ECD is a rare, non-inherited disease of uncertain pathogenesis first described in 1930 by Chester as a distinct form of “lipogranulomatosis with bony alterations.”[19
] It is now known to be a primary disorder of monocytes–macrophages that exhibit distinct cytokine activation.[20
] Some cases may even represent clonal histiocytic proliferations.[22
] While most patients with ECD present with osteosclerotic lesions of the long bones,[24
] extraskeletal involvement occurs in many reported cases.[7
] Our patient manifested with bilateral exophthalmos, central nervous system and cardiac disease, as well as retroperitoneal fibrosis with histiocytic infiltration. ECD may present initially with retroperitoneal fibrosis,[26
] and in this anatomic location could mimic other non-neoplastic (e.g. fibromatosis) and neoplastic (e.g. sarcoma) entities. In the retroperitoneum, the mass-like or perirenal rind-like histiocytic proliferation of ECD may be also be misdiagnosed as xanthogranulomatous pyelonephritis.[27
] Treatment of patients with ECD is reserved for those individuals who are symptomatic, have organ dysfunction or central nervous system involvement. While there is no cure, current treatment options include interferon alpha, systemic chemotherapy, corticosteroids and/or radiation therapy.
The diagnosis of ECD typically requires a biopsy of involved tissues, since this disease must be distinguished from the more common LCH, with which it shares similar clinical features. The histopathology of ECD is well characterized and usually shows infiltrates of monomorphic foamy (xanthomatous) macrophages, scattered multinucleate (Touton) giant cells and interspersed chronic inflammatory cells (predominantly lymphocytes) surrounded by fibrosis. While eosinophils may rarely be seen in ECD, they tend to be fewer in number than the eosinophilia observed in specimens procured from patients with LCH. ECD must be distinguished from other histiocytic conditions (e.g. LCH, hemophagocytic lymphohistiocytosis), dendritic cell disorders, granular cell tumor, metastatic solid and hematopoietic neoplasms (e.g. renal cell carcinoma, oncocytic neoplasms) and reactive conditions (e.g. granulomas, malakoplakia). It is important not to dismiss such a case of ECD as merely benign fibrous tissue with associated hisitocytes. Thus, clinical and radiological correlation along with appropriate immunostaining in clinically suspicious cases can be very helpful given the bland, benign-appearing nature of these lesions. A comparison of the pathology between ECD and LCH is shown in . The foamy macrophages of ECD demonstrate non-Langerhans features including lack of nuclear grooves, absence of Birbeck granules and immunoreactivity for CD68 (PGM1), lysozyme, α-1-antitrypsin, CD163, Factor XIIIa, CD14 and fascin, with concomitant negative staining for CD1a and Langerin. There are some reported cases of ECD in which histiocytes demonstrated S100 positivity.[11
] Cytologic atypia (e.g. prominent nucleoli and spindle cell sarcoma-like areas), as may be identified in histiocytic sarcoma and dendritic cell sarcoma, is not a feature of ECD. No consistent cytogenetic or molecular genetic abnormalities have been identified with ECD.
Comparison of the pathology in Erdheim–Chester disease and Langerhans cell histiocytosis (LCH)
The cytopathology of ECD is not yet characterized. To the best of our knowledge, we are aware of only one other case report describing the cytologic features of ECD in the literature.[18
] In this other case report, the diagnosis of ECD was made on an intraoperative squash preparation from a brain lesion of a 26-year-old young man. The squash preparations showed a mixed cellular proliferation of lymphohistiocytic elements along with large, multinucleated cells with vesicular nuclei, prominent nucleoli and abundant cytoplasm. In our case, the specimen was of low cellularity due to the associated fibrosis; however, there were foamy histiocytes including binucleate and multinucleated cells. Obtaining a concomitant core biopsy in such cases is therefore recommended. Unlike LCH, these macrophages neither exhibited nuclear grooves, pseudoinclusions or dendrite-like cytoplasmic processes, nor were associated with eosinophils. The cytologic findings of deep-seated juvenile xanthogranulomas may show similar features.[30
Albeit that ECD is a rare condition, patients presenting with the clinical features of this histiocytosis will likely require a pathologic evaluation during their work-up in order to determine the correct diagnosis. This case not only highlights the cytologic features of ECD that may be encountered, but also alerts cytologists to consider this non-Langerhans histiocytic disorder in cases showing xanthogranulomatous infiltration.