The histopathology of Erdheim-Chester disease: a comprehensive review of a molecularly characterized cohort

Abstract

Erdheim-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 involve virtually any organ system; most commonly the bones, skin, retroperitoneum, heart, orbit, lung, and brain are affected. Although a histiocytic proliferation is the histological hallmark of the disease, a wide range of morphological appearances have been described as part of case studies or small series. A comprehensive review of histopathological features in clinically and molecularly defined Erdheim-Chester disease has yet to be characterized. To address this issue and help guide clinical practice, we comprehensively analyzed the pathological spectrum of Erdheim-Chester disease in a clinically and molecularly defined cohort. We reviewed 73 biopsies from 42 patients showing involvement by histiocytosis from a variety of organ systems, including bone (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 marrow biopsies were performed due to clinical indication and an accompanying myeloid neoplasm was detected in six of them. Thirty-eight cases were investigated for genetic abnormalities. Somatic mutations involving BRAF (25/38), MAP2K1 (6/38), ARAF (2/38), MAP2K2 (1/38), KRAS (1/38), and NRAS (1/38) genes were detected. One of the cases with a MAP2K1 mutation also harbored a PIK3CA mutation. We have observed marked heterogeneity in histology and immunophenotype, identified site-specific features, overlap with other histiocytic and myeloid disorders and potential diagnostic pitfalls. We hope that broadening the spectrum of recognized pathologic manifestations of Erdheim-Chester disease will help practicing clinicians and pathologists to diagnose Erdheim-Chester disease early in the disease course and manage these patients effectively.

Figure 1

Histopathologic features of intraosseous Erdheim-Chester disease. (a) A case, harboring BRAFV600E mutation, with mild fibrotic background reveals the classical morphology of Erdheim-Chester disease involvement. Lipid-laden histiocytes tended to form loose clusters with scant inflammatory cells. (b) In a case, a prominent fibrotic background obscured the morphology, and scant infiltrate including amorphous lipid-laden and granular histiocytes (inset) were seen instead of the classical morphology. MAP2K1 and PIK3CA mutations are co-detected in this specimen. (c) In a calvarium biopsy of an Erdheim-Chester disease patient, areas of dense lymphoplasmacytic infiltrate whose presence may prompt the diagnostic consideration of osteomyelitis or Rosai-Dorfman disease. Whole exome sequencing of tumor tissue demonstrates ARAFS214A mutation in the tumor. (d) Femur biopsy of an Erdheim-Chester disease patient shows prominent fibrosis and osteosclerosis. Despite the decalcification procedure, BRAFV600E mutation is detected in that specimen.

Figure 2

Histopathologic features of retroperitoneal (upper row) and orbital (lower row) lesions of Erdheim-Chester disease. Biopsy from retroperitoneal region, harboring NRASQ61R mutation, with typical foamy histiocytic infiltrate (a) reveals abundant plasma cell infiltration by CD138 immunostain (b). Biopsy from the orbital region, harboring the BRAFV600E mutation, without characteristic lesional histiocytes in areas containing a dense lymphoplasmacytic infiltrate (c). Representative biopsy from orbit shows nodular aggregates of foamy histiocytes (d).

Figure 3

Histopathologic features of central nervous system lesions in Erdheim-Chester disease. (a) Typical brain lesion showing subtle histiocytic infiltrate without aggregate formation. Lesional histiocytes had indistinct cellular borders and non-lipidized cytoplasm. (b) Histiocytic markers (CD68 or CD163) were required to highlight the infiltrate. (c) One patient’s biopsy showed astrogliosis with focally prominent Rosenthal fiber formation (arrows). (d) Classical foamy and xanthomatous appearance in fibrotic background and Touton-type giant cells were seen in only one patient. (e,f) Neurofilament (NF) and myelin basic protein (MBP) immunostain showed areas of myelin loss with relative axonal preservation in the same region. However, this was not the total and sharply circumscribed type of myelin loss that characterizes classic demyelinating disease.

Figure 4

Histopathologic features of lung involvement in Erdheim-Chester disease. (a,b) Lung lesions had a characteristic septal and subpleural pattern. Perivascular interstitium with involvement of the peribronchiolar areas were also seen. (c) The infiltrates were characterized by histiocytic infiltrates in the background of fibrosis. (d) FXIIIa immunostain showing strong cytoplasmic and nuclear expression in lesional histiocytes.

Figure 5

Histopathologic features of cutaneous involvement in Erdheim–Chester disease. (a) Representative cutaneous infiltrate in Erdheim–Chester disease demonstrated xanthogranulomatous quality and was dominated by large histiocytes with Touton-type giant cells. (b) BRAF VE1 immunostain disclosed cytoplasmic staining of both histiocytes and Touton cells (arrows), which confirmed that Touton cells are also part of the neoplastic process rather than reactive. (c) In some lesions, focal clusters of neutrophils were present. (d) Some lesions showed a subtle perivascular/interstitial histiocytic infiltration pattern. (e) One of the patients developed multiple dermatofibroma-like lesions during the disease course. Detection of a MAP2K1 mutation in such a skin lesion, which is morphologically unusual for an Erdheim–Chester disease involvement, confirmed the diagnosis. (f) Dense lymphoplasmacytic infiltrate constantly in perivascular location was seen in some biopsies.

Figure 6

Rare biopsy sites in Erdheim–Chester disease. Pulmonary valve (a) and atrial mass (b) biopsies showed exuberant histiocytic infiltrate. In atrial mass lesion (b), the cells are infiltrating between muscle fibers and replacing the myocardial connective tissue. (c) Biopsy from an epidural mass lesion showed amorphous histiocytic infiltrate within the fibrous tissue. (d) Langerhans cell histiocytosis (arrows) and Erdheim–Chester disease lesions were present but distinguishable in the same biopsy from a patient with mixed histiocytosis. (e) Tongue involvement of Erdheim–Chester disease harbored prominent neutrophils and was mimicking reactive granulation tissue. Infiltrating histiocytes were cytologically atypical (e, inset). (f) Teeth extraction material; histiocytes with xanthomatous quality spreading into extracellular basophilic matrix.

Figure 7

Arising testicular and bone marrow lesions in the course of Erdheim–Chester disease. (a) Testis biopsies showed replacement of the testis by Rosai-Dorfman disease with a well-defined border separating Rosai-Dorfman disease and adjacent testis. (b) Higher magnification revealed emperipolesis (arrow). (c) Significant S100 expression was seen in testis lesions. (d) Bone marrow biopsy from a patient with NRASQ61R-mutant Erdheim–Chester disease revealed accompanying chronic myelomonocytic leukemia. (e-g) Bone marrow biopsy from a patient with BRAFV600E mutant mixed histiocytosis (Erdheim–Chester disease/Langerhans cell histiocytosis) showed myelodysplastic syndrome. Immunohistochemical studies showed increased CD34-positive blasts (e). Aberrant CD34 expression was also noted in dysplastic megakaryocytes (e, arrows). BM aspirate smear of the same patient demonstrated dysplastic megakaryocytes with widely separated nuclei (f) and nuclear abnormalities in erythroid precursors (binucleation, nuclear budding) (arrow) (g).

Figure 8

Graphical summary of diverse kinase alterations in the Erdheim–Chester disease study cohort. Pie chart illustrating the activating kinase alterations uncovered in the Erdheim–Chester disease study cases by whole exome sequencing and targeted mutational profiling.