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    Drugs & Diseases>Pediatrics: General Medicine

    Histiocytosis

    Updated: Jan 11, 2023
    • Author: Cameron K Tebbi, MD; Chief Editor: Vikramjit S Kanwar, MBBS, MBA, MRCP(UK), FRCPCH, FAAP  more...
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    Overview

    Practice Essentials

    Histiocytoses encompass a group of diverse proliferative disorders characterized by the accumulation and infiltration of variable numbers of monocytes, macrophages, and dendritic cells in the affected tissues. Such a description excludes diseases in which infiltration of these cells occurs in response to a primary pathology. The clinical presentations vary greatly, ranging from mild to life threatening. While cases of histiocytosis were first described by Dr. Thomas Smith, in 1865, [1]  only in recent years, with the application of molecular analyses, has the pathophysiology of these disorders begun to be elucidated.

    Over the last several decades, the nomenclature used to describe histiocytic disorders has substantially changed to reflect the wide range of clinical manifestations and the variable clinical severities of some disorders that have the same pathologic findings. [2]  For example, the entity now referred to as Langerhans cell histiocytosis (LCH) was initially divided into eosinophilic granuloma, Hand-Schüller-Christian disease, and Abt-Letterer-Siwe disease, depending on the sites and severity. Later, these were found to be manifestations of a single entity and were unified under the term histiocytosis X. [3, 4]  This designation was changed to Langerhans cell histiocytosis based on the suggestion by Nezelof that the Langerhans cell represented the primary cell involved in the pathophysiology of the disease. [5, 6] Although several histiocytic disorders are briefly discussed in this article (see History), the primary focus is on Langerhans cell histiocytosis. [7, 8]

    Signs and symptoms of histiocytosis

    The clinical manifestations of histiocytosis depend on the organs and systems involved, as well as their level of involvement. Langerhans cell histiocytosis (LCH) can be localized and manifest as pain or may even be asymptomatic, as is the case in isolated bone lesions. LCH can also involve multiple organs and systems, with clinically significant symptoms and consequences.

    Workup in histiocytosis

    Laboratory studies in LCH include the following:

    • Hemoglobin and/or hematocrit
    • Leukocyte count and differential cell count
    • Liver function tests
    • Coagulation studies
    • Urine osmolality test after overnight water fast

    Imaging studies in LCH include the following:

    • Chest, posteroanterior, and lateral radiography
    • Skeletal survey (radiography)

    Management of histiocytosis

    Decisions regarding treatment for histiocytosis depend on the type, site, and extent of the disease; the organs involved; biologic findings; the genetics of the disease; the degree of risk involved; and a host of other factors. Substantial variation of the disease and the fact that 10-20% of patients with LCH achieve spontaneous regression complicate comparisons of current nonspecific therapies. [9, 10, 11] Several agents, including drugs for cancer chemotherapy, have been effective in the treatment of LCH.

    Due to the wide spectrum of findings in LCH, significant stratification is required. For example, LCH with a single bone lesion can be successfully treated with curettage and, possibly, local corticosteroid injection. [12] In contrast, multiple bone lesions, alone or in association with a nonrisk site, may, although nonfatal, require 1 year of therapy with combination treatments such as prednisone plus vincristine.

    Patients with high-risk LCH must receive at least 1 year of combination therapy, such as a vincristine, prednisone, mercaptopurine combination. Agents such as vinblastine, prednisone, cytarabine, cladribine, and clofarabine can be subsequently used in refractory or recurrent cases, as needed. In patients with pituitary involvement and central nervous system (CNS) disease, treatment with clofarabine or cytarabine (with the latter in higher doses) should be considered.  

    Next: Pathophysiology

    Pathophysiology

    Improved understanding of the pathology of histiocytic disorders requires knowledge of the origins, biology, and physiology of the cells involved. Macrophages and monocytes are members of the mononuclear phagocyte system. Histiocytes are tissue-resident macrophages. Normal histiocytes originate from pluripotent stem cells, which can be found in bone marrow. [13] Under the influence of various cytokines (eg, stem cell factor [SCF], granulocyte colony-stimulating factor [G-CSF], granulocyte-macrophage colony-stimulating factor [GM-CSF], tumor necrosis factor-alpha [TNF-alpha], interleukin [IL]-3, IL-4, and others), histiocytes can become committed, differentiating into specific groups of specialized cells. Committed histiocytes can mature into one of two lineages: (1) antigen-processing cells, ie, macrophages and monocytes, or (2) antigen-presenting cells, ie, dendritic cells, interdigitating reticulum cells, and Langerhans cells (with Langerhans cells being dendritic cells located in the epidermis). [14]  Each category of histiocytosis can be traced to reactive or neoplastic proliferation in one of these cell lineages. [14]

    The importance of dendritic cells in the capture, uptake, processing, and, ultimately, presentation of antigens to T and B lymphocytes has been increasingly recognized. Dendritic cells appear to develop in several pathways. [15] Immature dendritic cells respond to GM-CSF (not to macrophage colony-stimulating factor [M-CSF]) and become committed to generating dendritic cells, which are “professional” antigen-presenting cells (APCs). [16] These cells can capture antigen and migrate to lymphoid organs, where they present the antigens to naive T cells. [17] Dendritic cells are also efficient stimulators of B-cell lymphocytes. [18]

    Effective induction of antigen-specific T-cell responses requires interaction between the dendritic cells and T lymphocytes to prime the latter cells for expansion and subsequent immune responses. [19] The surface of the APC contains 2 peptide-binding proteins (ie, major histocompatability complex [MHC] classes I and II), which can stimulate cytotoxic T (TC) cells, regulatory T (Treg) cells, and helper T (TH) cells. [20, 21] Although circulating T-cell lymphocytes can independently recognize antigens, their number is small. Dendritic cells display a large amount of MHC-peptide complexes at their surface and can increase the expression of costimulatory receptors and migrate to the lymph nodes, spleen, and other lymphoid tissues, where they activate specific T cells.

    The first signal may involve interaction between an MHC I–bound and/or MHC II–bound peptide on an APC with the T-cell receptor (TCRs) on the effector lymphocytes. TCRs can recognize fragments of antigen attached to MHC on the surface of an APC. Costimulatory interaction (i.e., second signal) is between CD80(B7.1)/CD86(B7.2) on the dendritic cell, and CD28 on the T cells. [22, 23, 24] A combination of the 2 signals activates the T cell, resulting in upregulation of the expression of CD40L, which, in turn, can interact with the dendritic cell–expressed CD40 receptor. [21] In perforin-deficient mice, abnormally heightened cytokine production by T cells is due to overstimulation by APCs after a viral infection. [22]

    This cell-to-cell interaction between dendritic cells and T cells generates an antigen-specific T-cell response. The effective function of antigen presentation by dendritic cells is presumed to reflect that these cells, in addition to MHC molecules, express a high density of other costimulatory factors. Dendritic cells can produce several cytokines, including IL-12, which is critical for the development of TH 1 cells from naive CD4+ T cells. [22, 25, 26, 27, 28]

    Ligation of CD40 on dendritic cells triggers the production of large amounts of IL-12, which enhances T-cell stimulatory capacity. This observation suggests that feedback to dendritic cells results in signals that are critical for induction of immune responses. The nature of the latter interaction and requirement for optimal dendritic cell activation is not fully understood. Dendritic cells in culture derived from human blood monocytes exposed to GM-CSF and IL-4 followed by maturation in a monocyte-conditioned medium have heightened antigen-presenting activity. Monocyte-conditioned media contain critical maturation factors that contribute to this process.

    Dendritic cells are present in tissues in a resting state and cannot stimulate T cells. Their role is to capture and phagocytize antigens, which, in turn, induce their maturation and mobilization. [29] Immature dendritic cells reside in blood, lungs, spleen, heart, kidneys, and tonsils, among other tissues. Their function is to capture antigen and migrate to the draining lymphoid organs to prime CD4+ and CD8+ T cells. In the process of their function, these cells mature and increase their capacity to express costimulatory receptors and decrease their capacity to process antigen. These cells can phagocytize, forming pinocytic vesicles for sampling and concentrating their surrounding medium, which is called macropinocytosis.

    Immature dendritic cells express receptors that mediate endocytosis, including C-type lectin receptors, such as the macrophage mannose receptor and DEC205, FC-gamma, and FC-epsilon receptors. Microbial components, as well as IL-1, GM-CSF, and TNF-alpha, have an important role in cellular response [30, 31] and can stimulate maturation of dendritic cells, whereas IL-10 opposes it. [32]

    Mature dendritic cells possess numerous fine processes (veils, dendrites) and have considerable mobility. These cells, rich in MHC classes I and II, have abundant molecules for T-cell binding and co-stimulation, which involves CD40, CD54, CD58, CD80/B7-1, and CD86/B7-1. Mature dendritic cells express high levels of IL-12. High levels of CD83 (a member of the immunoglobulin [Ig] superfamily), and p55 or fascin (an actin-bundling protein) are present in these cells, as opposed to the low levels that are present in the immature cells. [16]

    IL-1 enhances dendritic cell function. This effect appears to be indirect and due to activation of TNF receptor–associated factors (TRAFs). Mature dendritic cells also express high levels of the NF-kappaB family of transcriptional control proteins. These proteins regulate the expression of several genes encoding inflammatory and immune proteins. Signaling by means of the TNF-receptor family (eg, TNF-R, CD40, TNF-related activation-induced cytokine [TRANCE], receptor activator of NF-kappaB [RANK]) activates NF-kappaB. Immunologic response of dendritic cells to a given antigen partly involves the triggering of signal-transduction pathways involving the TNF-R family and TRAFs.

    Information regarding the fate of dendritic cells after these events is sparse. Dendritic cells disappear from the lymph nodes 1-2 days after antigen presentation, possibly because of apoptosis. [33, 34] CD95 (Fas) is suggested to have a role in the death of the dendritic cell. [35, 36, 37] However, although dendritic cells express CD95, CD95 ligation does not induce apoptosis. [38]

    Experiments indicate that immature dendritic cells are partially susceptible to death receptor–mediated apoptosis. TNF-related apoptosis-inducing ligand (TRAIL) may bind to 5 separate receptors. [39] Functional cytoplasmic death domains characterize TRAIL-R1 receptors, TRAIL-R2 receptors, and CD95 receptors. In contrast, TRAIL-R3 is a membrane-anchored truncated receptor, and TRAIL-R4 does not have a functional death domain. Dendritic cells express CD95, TRAIL-R2, and TRAIL-R3 in comparative levels. Similar to the role of CD95L, that of TRAIL-mediated apoptosis of mature dendritic cells has been controversial. Data regarding in vitro TRAIL-mediated apoptosis in these cells have also been reported, although such data remain controversial. Mature dendritic cells are usually resistant to TRAIL- and CD95L-mediated apoptosis.

    C-FLIP, which is the caspase-8 inhibitory protein capable of inhibiting death receptor–mediated apoptosis, is highly expressed in mature dendritic cells, whereas only low levels are found in immature cells. [40, 41] Overexpression of C-FLIP inhibits signals of death receptor. [42] C-FLIP expression on dendritic cells is upregulated during maturation. Note that engagement of CD95 on immature dendritic cells by CD95L induces phenotypic and functional maturation of these cells.

    In addition, a CD95-activated dendritic cell upregulates the expression of MHC class II and costimulatory receptors, which is essential for the function of these cells. [43] Furthermore, such engagement upregulates the expression of dendritic-cell lysosome-associated membrane protein (DC-LAMP) and causes the secretion of proinflammatory cytokines, including IL-1 beta and TNF-alpha.

    Some articles suggest classification of high-risk Langerhans cell histiocytosis (LCH) as a myeloid neoplasia and hypothesize that the high-risk disease arises from somatic mutation of a hematopoietic progenitor. Some authors propose that low-risk disease arises from somatic mutation of tissue-restricted precursor dendritic cells. These hypotheses are based on the finding of BRAF-V600E mutation in circulating CD11C(+) and CD14(+) fractions and in bone marrow CD34(+) hemopoietic progenitor cells. On the other hand, the mutation was restricted to lesional CD207(+) dendritic cells in patients with low-risk Langerhans cell histiocytosis. [44, 45]

    Histiocytic diseases include disorders of dendritic cells, ie, Langerhans cell histiocytosis (LCH); abnormal multiplication of macrophages, as in polyostotic sclerosing histiocytosis (also known as Erdheim-Chester disease or syndrome [ECD]) and xanthogranuloma; and macrophage/monocytoid lineage conditions, including Rosai-Dorfman disease and hemophagocytic lymphohistiocytosis. Malignant histiocytosis and monocytic or myelomonocytic leukemias, while related, traditionally are separated as malignant disorders. Approximately 60% of biopsy specimens in Langerhans cell histiocytosis reveal V600E mutation in the BRAF oncogene, demonstrating that the disease is a clonal disorder. There is controversy as to whether this is a result of malignant transformation or immunologic stimulus. It should be noted that the same mutation is seen in benign lesions such as nevi. 

    The function of normal Langerhans cells is cutaneous immunosurveillance. These cells can migrate to the regional lymph nodes and potentially present antigen to paracortical T cells and cause their transformation to interdigitating dendritic cells. Some cancer cells disrupt dendritic-cell function, blocking the development of tumor-specific immune responses and allowing tumors to evade recognition. [46] To counteract this effect, dendritic cells may produce the antiapoptotic protein Bcl-xL. Stimulation of dendritic cells by CD154, IL-12, or IL-15 increases expression of Bcl-xL. The information gained from normal physiology of dendritic cells may potentially lead to treatment modalities for histiocytic disorders.

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    Next: Pathophysiology

    Epidemiology

    Frequency

    International

    The overall incidence of Langerhans cell histiocytosis is estimated to be 4-10 per million population. However, because many bone and skin lesions may not be diagnosed as Langerhans cell histiocytosis, this rate may be an underestimate. [47] The estimated incidence of neonatal Langerhans cell histiocytosis, [48] determined by using the population-based German Childhood Cancer Registry, is 1-2 per million neonates.

    Mortality/Morbidity

    Polyostotic sclerosing histiocytosis

    Negative prognostic factors in polyostotic sclerosing histiocytosis include central nervous system (CNS) involvement, cardiovascular disease, and the use of interferon alpha. [49]

    The 1- and 5-year survival rates in this disease are 96% and 68%, respectively. Causes of death include the following:

    • CNS involvement
    • Cerebral hypertension
    • Myocardial infarction
    • Gastrointestinal bleed
    • Pulmonary infections
    • Metabolic abnormalities

    Sex

    The overall male-to-female ratio is 1.5:1. The male-to-female ratio in individuals who have single organ system involvement is 1.3:1, and the male-to-female ratio in individuals with multisystem disease 1.9:1. [50]

    Age

    LCH can occur in individuals of any age. [48, 51, 52, 53, 54, 55, 56, 57] The incidence peaks in children aged 1-3 years. In one study, the age at diagnosis was 0.09-15.1 years. Patients with single system involvement were older than those with multisystem involvement. The mean age for development of polycystic sclerosing histiocytosis is between 55 and 60 years, but rare cases in the pediatric age group have been reported. Fetal and neonatal cases, although also rare, can occur. [48, 58]

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    Next: Pathophysiology

    Prognosis

    Risk stratification for Langerhans cell histiocytosis (LCH) requires evaluation of the site and extent of disease involvement and response to therapy. Involvement of the risk organs, including bone marrow, spleen, liver, and possibly lungs, substantially increases the risk of mortality. Pediatric patients with high-risk LCH have a nearly 90% chance of survival, but the prognosis worsens if there is progression of the disease during the first 12 weeks of therapy. Some studies implicate somatic mutation of BRAF-V600E in high-risk features, disease progression, permanent injury, and poor short-term chemotherapy response. [59] This mutation may be associated with a two-fold increase in the risk of treatment failure.

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