Neval Ozkaya

A somatic mutation in erythro-myeloid progenitors causes neurodegenerative disease

The pathophysiology of neurodegenerative diseases is poorly understood and there are few therapeutic options. Neurodegenerative diseases are characterized by progressive neuronal dysfunction and loss, and chronic glial activation. Whether microglial activation, which is generally viewed as a secondary process, is harmful or protective in neurodegeneration remains unclear. Late-onset neurodegenerative disease observed in patients with histiocytoses, which are clonal myeloid diseases associated with somatic mutations in the RAS–MEK–ERK pathway such as BRAF(V600E), suggests a possible role of somatic mutations in myeloid cells in neurodegeneration. Yet the expression of BRAF(V600E) in the haematopoietic stem cell lineage causes leukaemic and tumoural diseases but not neurodegenerative disease. Microglia belong to a lineage of adult tissue-resident myeloid cells that develop during organogenesis from yolk-sac erythro-myeloid progenitors (EMPs) distinct from haematopoietic stem cells. We therefore hypothesized that a somatic BRAF(V600E) mutation in the EMP lineage may cause neurodegeneration. Here we show that mosaic expression of BRAF(V600E) in mouse EMPs results in clonal expansion of tissue-resident macrophages and a severe late-onset neurodegenerative disorder. This is associated with accumulation of ERK-activated amoeboid microglia in mice, and is also observed in human patients with histiocytoses. In the mouse model, neurobehavioural signs, astrogliosis, deposition of amyloid precursor protein, synaptic loss and neuronal death were driven by ERK-activated microglia and were preventable by BRAF inhibition. These results identify the fetal precursors of tissue-resident macrophages as a potential cell-of-origin for histiocytoses and demonstrate that a somatic mutation in the EMP lineage in mice can drive late-onset neurodegeneration. Moreover, these data identify activation of the MAP kinase pathway in microglia as a cause of neurodegeneration and this offers opportunities for therapeutic intervention aimed at the prevention of neuronal death in neurodegenerative diseases.

Functional evidence for derivation of systemic histiocytic neoplasms from hematopoietic stem/progenitor cells

Langerhans cell histiocytosis (LCH) and the non-LCH neoplasm Erdheim-Chester disease (ECD) are heterogeneous neoplastic disorders marked by infiltration of pathologic macrophage-, dendritic cell-, or monocyte-derived cells in tissues driven by recurrent mutations activating MAPK signaling. Although recent data indicate that at least a proportion of LCH and ECD patients have detectable activating kinase mutations in circulating hematopoietic cells and bone marrow-based hematopoietic progenitors, functional evidence of the cell of origin of histiocytosis from actual patient materials has long been elusive. Here, we provide evidence for mutations in MAPK signaling intermediates in CD34+ cells from patients with ECD and LCH/ECD, including detection of shared origin of LCH and acute myelomonocytic leukemia driven by TET2-mutant CD34+ cell progenitors in one patient. We also demonstrate functional self-renewal capacity for CD34+ cells to drive the development of histiocytosis in xenotransplantation assays in vivo. These data indicate that the cell of origin of at least a proportion of patients with systemic histiocytoses resides in hematopoietic progenitor cells prior to committed monocyte/macrophage or dendritic cell differentiation and provide the first example of a patient-derived xenotransplantation model for a human histiocytic neoplasm.

Anakinra as efficacious therapy for two cases of intracranial Erdheim-Chester disease.

To the editor: Erdheim-Chester disease (ECD) is a myeloid neoplasm characterized by recurrent mutations in mitogen-activated protein kinase pathway genes, including BRAF , ARAF , N/KRAS , MAP2K1 , and PIK3CA mutations and fusions in ALK and NTRK1 .[1][1][⇓][2][⇓][3]-[4][4] Lesional ECD cells

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

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.

High prevalence of myeloid neoplasms in adults with non-Langerhans cell histiocytosis

Erdheim-Chester disease (ECD) is a rare non-Langerhans cell histiocytosis that most commonly affects adults and is driven by a high frequency of mutations in BRAF, MAP2K1, and kinases promoting MAPK signaling. Because of the relative rarity of ECD, key clinical features of the disease may not be well defined. Across a multi-institutional cohort of 189 patients with ECD and ECD overlapping with Langerhans cell histiocytosis (so-called mixed histiocytosis [MH]), we identified an unexpected and heretofore undescribed frequent occurrence of myeloid neoplasms among patients with ECD and MH. Some 10.1% (19/189) of patients with ECD have an overlapping myeloid neoplasm, most commonly occurring as a myeloproliferative neoplasm (MPN), myelodysplastic syndrome (MDS), or mixed MDS/MPN overlap syndrome (including chronic myelomonocytic leukemia). Consistent with this, molecular analysis frequently detected hallmark driver mutations of myeloid neoplasms (such as JAK2V617F and CALR mutations) coexisting with those characteristic of histiocytosis (such as BRAFV600E and MAP2K1 mutations). Histiocytosis patients diagnosed with a concomitant myeloid malignancy were significantly older at diagnosis and more commonly presented with MH than those without a myeloid malignancy. In some cases, the presence of distinct kinase mutations in the histiocytosis and myeloid neoplasm resulted in discordant and adverse responses to kinase-directed targeted therapies. These data highlight the clinical importance of evaluating adults with histiocytosis for a concomitant myeloid neoplasm.

Identification and Targeting of Kinase Alterations in Histiocytic Neoplasms

Histiocytic disorders represent clonal disorders of cells believed to be derived from the monocyte, macrophage, and/or dendritic cell lineage presenting with a range of manifestations. Although their nature as clonal versus inflammatory nonclonal conditions have long been debated, recent studies identified numerous somatic mutations that activate mitogen-activated protein kinase signaling in clinically and histologically diverse forms of histiocytosis. Clinical trials and case series have revealed that targeting aberrant kinase signaling using BRAF and/or MEK inhibitors may be effective. These findings suggest that a personalized approach in which patient-specific alterations are identified and targeted may be a critically important therapeutic approach.

Acute leukemia with a pure erythroid phenotype: underrecognized morphologic and cytogenetic signatures universally associated with primary refractory disease and a dismal clinical outcome

Pure erythroid leukaemia (PEL) is an extremely rare and aggressive subtype of acute myeloid leukaemia defined by the World Health Organization (WHO) as a neoplastic proliferation of immature cells committed exclusively to the erythroid lineage, comprising >80% of bone marrow cells and not meeting the criteria of other well‐defined myeloid neoplasms. The aim of this study was to describe the clinicopathological features of acute leukaemias with a pure erythroid phenotype (ALPEP) irrespective of their WHO classification and to determine if ALPEP represents a distinct clinicopathological entity.

Novel insights into the early histopathogenesis of immunodeficiency-associated Burkitt lymphoma: a case report of Burkitt microlymphoma arising within HIV lymphadenitis.

To report a case detailing the early histopathogenesis of Burkitt lymphoma (BL), Epstein‐Barr virus (EBV) positive, in the clinical setting of HIV infection.

Seroma-associated anaplastic large-cell lymphoma arising on the background of subcutaneous calcinosis: beyond breast implants.

Sir: Breast implant/seroma-associated anaplastic lymphoma kinase (ALK)-negative anaplastic large-cell lymphoma (ALCL) is a rare type of non-Hodgkin lymphoma presenting adjacent to breast implants. The disease is characterized by unique histological features, including fluid (seroma) accumulation around the implant capsule, and an infiltrate of anaplastic CD30-positive T cells suspended in the seroma without parenchymal invasion, and an indolent clinical course. Here, we report a unique case of ALK-negative ALCL that shows morphological, immunophenotypic and proteomic characteristics of breast implant/ seroma-associated ALCL. However, in this instance, there is no history of an implant, but instead the lymphoma appears to have arisen secondary to dystrophic calcifications caused by long-standing dermatomyositis. No body cavity effusions or other extranodal sites of disease were detected in staging studies. Like seroma-associated ALCL adjacent to breast implants, this case was also of a limited stage and followed an indolent clinical course. A 61-year-old woman who had a long-standing history of dermatomyositis complicated by subcutaneous dystrophic calcifications presented with a new mass over her posterior low thoracic and upper lumbar spine that gradually increased in size (Figure S1). An excisional biopsy of the enlarged mass was performed in December 2008. Formalin-fixed and paraffin-embedded tissue was subjected to haematoxylin and eosin staining and immunohistochemical (IHC) staining. All IHC staining was performed with routine methods for clinical diagnosis. Histopathologically, the biopsy represented subcutaneous tissue that was notable for extensive fibrinoid material, and an infiltrate of atypical lymphoid cells embedded in the fibrinoid matrix (Figure 1). The neoplastic cells were large and characterized by pleomorphic nuclei, abundant pale cytoplasm, with Golgi enhancement, and prominent nucleoli (Figure 1C,D). IHC staining showed that atypical lymphoid cells were diffusely and strongly positive for CD30 (Figure 2A), CD43 (Figure 2B), granzyme B (Figure 2C), and MUM1/IRF4, but negative for other T-cell [b-F1, CD2, CD3 (Figure 2D), and CD5] and B-cell lineage markers (CD20 and CD79a), as well as ALK (Figure 2E) and TIA-1. These morphological appearances and immunophenotype

Single-agent dabrafenib for BRAFV600E-mutated histiocytosis

Langerhans cell histiocytosis (LCH) and Erdheim-Chester disease (ECD) are clonal disorders of the monocyte/macrophage and dendritic cell lineages characterized by infiltration of histiocytes, acute and chronic inflammation, and fibrosis that can involve multiple organ systems and cause a wide range