Histiocytes

The histiocytoses are rare tumors characterized by the primary accumulation and tissue infiltration of histiocytes and dendritic cells. Identification of the activating BRAFV600E mutation in Erdheim-Chester disease (ECD) and Langerhans cell histiocytosis (LCH) cases provided the basis for the treatment with BRAF and/or MEK inhibitors, but additional treatment options are needed. Twenty-four cases of neoplastic histiocytic diseases [11 extrapulmonary LCH, 4 ECD, 4 extranodal Rosai-Dorfman disease (RDD), 3 follicular dendritic cell sarcoma (FDCS), 1 histiocytic sarcoma (HS) and 1 blastic plasmacytoid dendritic cell neoplasm (BPDCN)] were analyzed using immunohistochemical and mutational analysis in search of biomarkers for targeted therapy. BRAF V600E mutations were detected in 4/11 LCH and 4/4 ECD cases. A pathogenic PTEN gene mutation and loss of PTEN protein expression were identified in the case of HS. Increased expression of PD-L1 (≥2+/≥5%) was seen in 3/4 ECD, 7/8 LCH, 3/3 FDCS and 1/1 HS, with overall 81% concordance between 2 antibodies used in the study (SP142 vs. MAB1561 clone). These results show for the first time significant expression of the PD-L1 immune checkpoint protein in these disorders, which may provide rationale for addition of immune check-point inhibitors in treatment of disseminated and/or refractory histiocytoses.

For a growing number of tumors the BRAF V600E mutation carries therapeutic relevance. In histiocytic proliferations the distribution of BRAF mutations and their relevance has not been clarified. Here we present a retrospective genotyping study and a prospective observational study of a patient treated with a BRAF inhibitor. Genotyping of 69 histiocytic lesions revealed that 23/48 Langerhans cell lesions were BRAF-V600E-mutant whereas all non-Langerhans cell lesions (including dendritic cell sarcoma, juvenile xanthogranuloma, Rosai-Dorfman disease, and granular cell tumor) were wild-type. A metareview of 29 publications showed an overall mutation frequency of 48.5% and with N=653 samples this frequency is well defined. The BRAF mutation status cannot be predicted based on clinical parameters and outcome analysis showed no difference. Genotyping identified a 45 year-old woman with an aggressive and treatment-refractory, ultrastructurally confirmed systemic BRAF-mutant LCH. Prior treatments included glucocorticoid/vinblastine and cladribine-monotherapy. Treatment with vemurafenib over 3 months resulted in a dramatic metabolic response by FDG-PET and stable radiographic disease; the patient experienced progression after 6 months. In conclusion, BRAF mutations in histiocytic proliferations are restricted to lesions of the Langerhans-cell type. While for most LCH-patients efficient therapies are available, patients with BRAF mutations may benefit from the BRAF inhibitor vemurafenib.

A panel of monoclonal antileucocyte antibodies was used in a study of Hodgkin's disease (HD) to explore the phenotypic characteristics of Sternberg-Reed and related cells (collectively termed HD cells). Cryostat preparations of 31 lymph nodes and 2 spleens were obtained from 30 patients with active HD. The histological diagnoses were: lymphocyte predominance (LP), 4 patients; nodular sclerosis (NS), 22; mixed cellularity (MC), 2; lymphocyte depletion (LD), 2. The monoclonal antibodies used were: OKT3, T11, Leu-1 (pan T cell specific); Leu-3A (T "helper" specific); Leu-2A, OKT8 (T "suppressor" specific); immunoglobulin (Ig) antibodies: anti kappa and lambda light chains, anti mu and delta heavy chains; B1 (anti B lymphocyte); CA2-11 (anti HLA-DR); OKM1, Mo-2 (anti myeloid/monocyte); OKT9 (anti transferrin receptor); Leu-7 (anti "NK" cell) and J5 (anti common ALL antigen). Reactions with peanut lectin (PNL) were also studied. The reactions were developed using a modified "ABC" immunoperoxidase technique. Specific attention was paid to the cell surface phenotype and anatomical localisation of HD cells in relation to surrounding T and B lymphocytes. HD cells formed distinct "rosettes" with T cells of "helper" phenotype although in 3 cases (1: LP, 2: NS) Leu-7 positive cells formed a prominent component of these interactions. In partially involved lymph node and spleen, HD cells were prominently distributed in a perifollicular distribution. In addition follicular mantle zones were frequently infiltrated by HD cells, the degree of ensuing destruction being related to the extent of lymph node effacement by HD. In 2 cases (1: NS, 1: LD) HD cells expressed clear, positive reactions with B1 although in neither of these cases nor in any other instance, was surface Ig expressed on the HD cell surface. The great majority of HD cells reacted positively with both OKT9 and, as previously reported, with anti HLA-DR antibody. In addition, HD cells demonstrated intense surface and cytoplasmic staining with PNL. HD cells were negative with all other antibodies. On the basis of these findings, no lineage specificity can confidently be attributed to the HD cell. However, the pattern of immunohistological reactions suggest that it is related to a cell of B follicular origins.

Reactive and clonal proliferations of histiocytes (macrophages/dendritic cells) represent a broad spectrum of disorders, which can affect virtually any organ of the body. The clinical spectrum ranges from benign, localized and self-limiting manifestations to severe multi-system disease. Hemophagocytic lymphohistiocytosis (HLH) is a frequently life-threatening, systemic hyperinflammatory process triggered by massive cytokine release by activated, reactive macrophages. Familial and secondary forms of HLH are discerned. Histiocytoses are clonal inflammatory myeloid disorders characterized by proliferations of mature histiocytes/macrophages and dendritic cells with recurrent kinase-activating mutations which result in constitutive activation of the ERK signaling pathway. Although traditionally subclassified according to the phenotype of the lesional cells, the clonal cells can show significant plasticity, and the occurrence of mixed histiocytoses is increasingly recognized. This is in part due to their derivation from a myeloid progenitor cell and explains the frequent association with clonal hematopoiesis or overt myeloid neoplasms in adults. At the joint Workshop of the Chinese Society of Hematopathology, the European Association for Haematopathology and the Society for Hematopathology on histiocytic/dendritic cell proliferations, neoplasms, and their mimics in Hefei, China, April 2024, in sessions 1 and 2 a total of 8 cases of HLH, 9 cases of reactive histiocytic proliferations and 40 cases of histiocytoses were submitted and reviewed by the panel. The latter included cases of LCH, indeterminate cell histiocytosis, Erdheim Chester disease, juvenile xanthogranuloma, Rosai Dorfman disease, multicentric reticulohistiocytosis, ALK-positive histiocytosis, and mixed histiocytoses. The present report summarizes important findings and open questions arising from discussing the workshop cases.