Histiocytosis

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Background

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 past 60 years, 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]

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.[9] 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).[10]  Each category of histiocytosis can be traced to reactive or neoplastic proliferation in one of these cell lineages.[10]

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.[11] 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).[12] These cells can capture antigen and migrate to lymphoid organs, where they present the antigens to naive T cells.[13] Dendritic cells are also efficient stimulators of B-cell lymphocytes.[14]

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.[15] 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.[16, 17] 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.[18, 19, 20] 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.[17] In perforin-deficient mice, abnormally heightened cytokine production by T cells is due to overstimulation by APCs after a viral infection.[18]

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.[18, 21, 22, 23, 24]

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.[25] 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[26, 27] and can stimulate maturation of dendritic cells, whereas IL-10 opposes it.[28]

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.[12]

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.[29, 30] CD95 (Fas) is suggested to have a role in the death of the dendritic cell.[31, 32, 33] However, although dendritic cells express CD95, CD95 ligation does not induce apoptosis.[34]

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.[35] 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.[36, 37] Overexpression of C-FLIP inhibits signals of death receptor.[38] 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.[39] 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.[40, 41]

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.[42] 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.

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.[43] The estimated incidence of neonatal Langerhans cell histiocytosis,[44] 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.[45]

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

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.[46]

Age

LCH can occur in individuals of any age.[44, 47, 48, 49, 50, 51, 52, 53] 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.[44, 54]

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.[55] This mutation may be associated with a two-fold increase in the risk of treatment failure.

History

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.

Classification

Classification of diseases involving histiocytic and dendritic cells is difficult because it requires inclusion of a broad range of diverse diseases. Therefore, most classifications are incomplete. The location of lesions and the extent of the disease substantially affect the course of the disease and the patient's prognosis. Thus, decisions regarding treatment are usually based on the extent of the disease and evidence of critical organ (risk organ) dysfunction (ie, lung, liver, spleen, bone marrow).

Since the initial classification of histiocytosis disorders in 1987 by the Histiocyte Society, this organization has made a number of revisions this categorization. It should be noted that several other classifications by other groups or sources are also available, some of which are shown below. The Histiocyte Society's 2016 revision of the classification of histiocytosis and neoplasms of the macrophage and dendritic cell lineages is as follows.[56]  

L (Langerhans) group diseases

Members of the L group include the following:

Langerhans cell histiocytosis

Subtypes of Langerhans cell histiocytosis include the following:

ECD

Subtypes of ECD include the following:

C group (non–Langerhans cell histiocytosis of skin and mucosa) 

​Members of the C group include the following:

Cutaneous non–Langerhans cell histiocytosis 

Types of cutaneous non–Langerhans cell histiocytosis belong to the following families:   

Cutaneous non–Langerhans cell histiocytosis with a major systemic component 

The following types of cutaneous non–Langerhans cell histiocytosis with a major systemic component also belong to the xanthogranuloma and non-xanthogranuloma families:

​M Group (malignant histiocytosis)

The M group includes primary and secondary malignant histiocytosis.

Primary malignant histiocytosis

This is characterized by negative phenotypic analysis for keratins, epithelial membrane antigen (EMA), Melan-A, HMB45, follicular dendritic cell markers, and B- and T-lymphocyte markers, as well as positivity for at least two of the following markers: CD68, CD163, CD4, and lysozyme. Primary malignant histiocytosis is localized to the skin, lymph nodes, digestive system, central nervous system (CNS), or others or is disseminated.

Secondary malignant histiocytosis

This occurs following or in association with conditions such as the following:

R Group (Rosai-Dorfman disease and miscellaneous noncutaneous, non–Langerhans cell histiocytoses)

R group histiocytosis includes the following:

Familial Rosai-Dorfman disease

Familial Rosai-Dorfman disease includes the following:

Classical (nodal) Rosai-Dorfman disease 

Classical (nodal) Rosai-Dorfman disease includes the following:

Extranodal Rosai-Dorfman disease

Extranodal Rosai-Dorfman disease includes the following:

Neoplasia-associated Rosai-Dorfman disease

Neoplasia-associated Rosai-Dorfman disease includes the following:

Immune disease–associated Rosai-Dorfman disease

Immune disease–associated Rosai-Dorfman disease includes the following:

H Group (hemophagocytic lymphohistiocytosis)

The H group includes the following:

Primary HLH

This includes the following:

Secondary HLH - infection associated

Infection-associated secondary HLH includes the following:

Secondary HLH - malignancy associated

Malignancy-triggered HLH occurring at the onset of malignancy is associated with the following:

Other malignancy-associated forms of HLH include the following:

Secondary HLH associated with rheumatologic conditions

This includes HLH associated with the following:

Secondary HLH - other types

Classification of the World Health Organization

The classification of histiocytic disorders the World Health Organization (WHO) has proposed is as follows:[57]

The WHO classification of neoplastic disorders of histiocytes and dendritic cells is as follows:

2D - Follicular dendritic cell sarcoma or tumor 

Prior classification by the Histiocyte Society

The prior working classification of histiocytosis syndromes from the Histiocyte Society is as follows:

The following, adapted from the Writing Group of the Histiocyte Society, describes confidence levels for the diagnosis of class I Langerhans cell histiocytosis:[5]

Prior to this system,[56] the Histiocyte Society developed a classification based on risk groups that arose from the first and second international (Langerhans cell histiocytosis I and II, respectively) trials of chemotherapy.[58] At-risk organs and systems identified in those trials included the liver, lung, spleen, and hematopoietic system. This risk classification was used in the treatment protocol of the third international study for Langerhans cell histiocytosis (LCH III). Patients were stratified into 3 groups: (1) patients with multisystem disease associated with risk organ dysfunction (2) patients with multisystem involvement but without risk organ dysfunction, and (3) those with single-system multifocal bone disease or localized involvement of special sites (intraspinal extension or involvement of the paranasal, parameningeal, periorbital, or mastoid region). In the trial, at-risk patients were randomly assigned to 1 of 2 treatment arms. Low-risk patients receive standard therapy for 6-12 months, and those with multifocal bone or special-site involvement receive the standard therapy for 6 months.

Other classifications

Langerhans cell histiocytosis formerly was divided into 3 disease categories: eosinophilic granuloma, Hand-Schüller-Christian disease, and Letterer-Siwe (or Abt-Letterer-Siwe) disease, depending on the severity and extent of involvement. This classification and its related risk groups no longer are used. Systems based on these categories were meant to reflect the extent of involvement and its relationship to the patient's prognosis.[1, 59]

Some classifications, such as that of the 1987 Histiocyte Society classification schema, simply divide histiocytic disorders into class I Langerhans cell disease, class II non-Langerhans cell histiocytic disease without features of malignant disorders, and class III malignant histiocytic disorders.

A clinical-grouping system for Langerhans cell histiocytosis based on age, extent of the disease, and organ dysfunction, as once constructed,[60] can provide a means to compare patient data and prognoses. Various categories, such as limited and extensive multiorgan involvement, have also been proposed.

Other Histiocytoses

Dendritic-cell disorders

Juvenile xanthogranuloma 

Juvenile xanthogranuloma (JXG) is a self-limited dermatologic disease of infancy with rare systemic manifestation. The dermatologic findings often include multiple yellow-to-pink, firm, slightly raised cutaneous papulonodules, which usually appear in the head and neck region. The nodules often measure several millimeters in diameter, but a macronodular variant with lesions that measure several centimeters has also been described. Lesions can be observed in the deep soft tissues or organs.[61, 62, 63] The condition usually presents at birth but can be found during infancy. Similar lesions may also be seen in children and adults.

In histologic evaluation, the lesions are well circumscribed and consist of an accumulation of histiocytic cells with giant cells and spindle cells. Immunohistochemical studies usually reveal positivity for factor XIIIa, fascin CD68, and peanut agglutinin lectin. Results for S-100 protein is often, but not exclusively, negative.

The course of JXG is usually marked by spontaneous resolution of the lesions. Systemic forms of JXG that involve the CNS can be devastating. Although no treatment is usually necessary, chemotherapy may be required to manage systemic forms of the disease.

Histiocytic disorders

Sinus hyperplasia

This disorder is a generally benign condition observed in lymph nodes, draining extremities, mesenteric regions, sites of malignant disorders, or foreign bodies. Erythrophagocytosis may be present in the involved lymph nodes. Sinuses are dilated and contain histiocytes. This is not a true histiocytic disorder but rather a normal lymph node response to draining antigen.

Sinus histiocytosis with massive lymphadenopathy (SHML)

Also called Rosai-Dorfman disease,[64, 65, 56] this is a usually persistent, massive enlargement of the nodes by proliferation and accumulation of histiocytes that are characterized by emperipolesis.[66] The disease is rarely familial.[66, 67, 68, 69]  SHML can occur after bone marrow transplant for acute lymphoblastic leukemia, after or concurrent with diagnosis of lymphoma, human herpesvirus 6 (HHV6), and EBV infections.[67, 68, 69]

Although the disease is rarely familial,[66] a rare familial variation, termed Faisalabad histiocytosis, has been described in 2 families. These individuals have multiple congenital abnormalities including fractures, short stature, hearing impairment, joint contractures, and massive enlarged lymph nodes resembling Rosai-Dorfman disease. The disorder appears to be transmitted as an autosomal recessive syndrome.[70]

SHML cells are positive for CD68, CD163, α-antichymotrypsin, α-antitrypsin, Fascin and HAM-56. SHML cells express moderate IL6 cytokine.

The male-to-female ratio is about 4:3, with a higher prevalence in blacks than in whites. Systemic symptoms, such as fever, weight loss, malaise, joint pain, and night sweats, may be present. Cervical lymph nodes are most characteristically involved, but other areas, including extranodal regions, can be affected. These disorders can manifest with only rash or bone involvement.[64, 66, 71]

Immunologic abnormalities can be observed,[72] including leukocytosis; mild normochromic, normocytic, or microcytic anemia; increased Ig levels; and abnormal rheumatoid factor. Positive results for lupus erythematosus have also been reported.

The disease is pathologically benign and has a high rate of spontaneous remission, but persistent cases requiring therapy have occurred.[66, 72, 73] In exceptional cases with obstructive complications, surgery, radiation therapy, and chemotherapy have been used to treat the disease.[66]  Death from SHML is known to occur.[72]

Primary hemophagocytic lymphohistiocytosis (HLH)

Primary HLH (familial hemophagocytic lymphohistiocytosis [FHL], familial histiocytic reticulosis)[56] is a life-threatening disorder characterized by fever, enlargement of the liver (93%) and spleen (94%), rash (30%),[74] and cytopenia.[75]  Other symptoms may include enlarged lymph nodes and respiratory, cardiac, renal, and neurologic abnormalities. The neurologic symptoms can include irritability, fatigue, change in mental status, ataxia, loss of vision, abnormal muscle tone, stiff neck, seizure, cranial nerve palsies, hemiplegia, quadriplegia, and coma. The disease can manifest itself in utero, early in the neonatal period, during childhood, or, uncommonly, in adulthood. Typically, the symptoms manifest during the first months or years of life. .

The prevalence of HLH is estimated to be in 0.12-1 cases per 100,000 live births, with an equal male-to-female ratio. FHL is a heterogenous autosomal recessive disorder that is often seen in parental consanguinity. Five genetic subtypes (ie, FHL1, FHL2, FHL3, FHL 4, FHL 5), caused by genetic mutations, have been identified. The genetic cause of type 1 is still unknown. Types 2-5 are caused by mutation in PRF1. Molecular testing for FHL2 (PRF1), FHL3 (UNC13D), FHL4 (STX11), and FHL5 (STXBP2) is available.

FHL results from uncontrolled proliferation of overactivated T lymphocytes and macrophages, as well as overproduction of inflammatory cytokines and immune dysregulation. Laboratory evaluation may disclose increased liver enzymes and hemophagocytosis in the bone marrow. Elevated levels of triglycerides, ferritin, and CD25, along with evidence of hemophagocytosis and a decrease in or absence of NK cells, may be present.

The disease is rapidly progressive, and occurrence of infections during the course of FLH is common. Without appropriate treatment, the disorder can be fatal. The median survival in untreated children can be as short as a few months. Appropriate treatment, however, has brought significant improvements in survival.

Diagnosis of FHL is based on clinical findings and genetic testing. Because the disease may develop in utero, it can potentially be present at birth. Patients with nonsense mutation, including those with homozygosity for PRF, (p. Leu17 Argfs Ter 34) mutation and who are often of African descent, have tendency for onset of the disease at an earlier age. Also, in most cases, individuals with PRF1 mutations have an earlier onset of the disease than those with UNC13D mutation or patients for whom no mutations are identified.[76]

In general, those with missense mutations have later onset of their disease.[77] However, FHL is usually diagnosed in childhood and rarely in adults as an acute disease. The symptoms include prolonged fever, cytopenia, hemoglobin level less than 9 g/L (93%), platelets less than 100 X 109/L (98%), neutrophils less than 1 X 109/L (75%), increased serum ferritin levels (93%), hypofibrinogenemia (76%), and CSF pleocytosis (52%).[74]  Enlargement of liver, spleen and lymph nodes occur occasionally and are accompanied by a rash. Neurologic symptoms range from irritability, lethargy, hypotoma, hypertoma, ataxia, seizure disorder, increased intracranial pressure, hemi or quadriplegia, and cranial nerve involvement, including loss of vision. Liver dysfunction, including icterus and elevation of liver enzymes, is common;[78] hypertriglyceridemia and hypofibrinogenemia is seen as well.

HLH patients are prone to various infections. CSF may be positive for protein, increased mononuclear cells, or hemophagocytic cells. Bone marrow aspiration and biopsy typically reveals hemophagocytosis, which is the hallmark of this disease. This, however, may not be apparent early in the course. Genetic studies, as outlined above, are essential for definitive diagnosis. Cytolytic T lymphocyte (CTL)-mediated cytotoxicity can be impaired. Deficient natural killer cell (NK cell) activity is more often seen in individuals with PRF1 mutation than in those without. Immune dysregulation is one of the hallmarks of the disease, paralleling reduced or absent activity of the NK cells in most cases. CTL activity is also compromised.

Various mutations, deletions, or insertions that cause frameshift or missense mutation in perforin genes (PRF1 and PRF2),[79]  MUNC 13-4, and syntaxin 11 have been reported. These findings often appear during the first year of life and almost always appear before age 17 years. Primary HLH is linked to chromosomes 9 and 10. Genetic mutations in the perforin gene on chromosome 10 cause the disease in about 25-40% of genetically related patients. Perforin gene mutation is reported in approximately one third of HLH cases. Mutation in MUNC 13-4, a gene involved in cellular cytotoxicity that encodes for a protein that controls the fusion of the lytic granules to the plasma membranes, is associated with some FHL cases (FHL3). The mutations can be scattered over different exons but, in most cases, fall within the protein functional domain.[80] A male predominance has been reported.[81, 82] In approximately 50-75% of patients, the disease is hereditary, with an autosomal recessive trait pattern. Parental consanguinity is common.[83]

HLH is fatal if untreated. Allogeneic bone marrow transplantation is the treatment of choice. However, the HLH-94 international protocol including VP16, steroids, and cyclosporine has had excellent activity in achieving remission in most patients. When this protocol is combined with allogeneic bone marrow transplantation, more than 50% of patients can be cured.[84]

In patients with HLH, CNS disease is frequently seen. Almost 70% of patients have nonspecific abnormalities detectable with CT scan and MRI of the brain. The most common abnormalities include periventricular white matter involvement, with enlarged ventricular system, gray matter disorders, and brainstem and corpus callosum disease. Involvement of meninges is uncommon.[85]

Familial cases appear to be clustered in certain geographic areas of the world. PRF1 gene mutations are seen in whites, blacks, Japanese, Hispanics, and mixed races. Clusters of the disease have been reported in Asian, Turkish, Kurdish, Arabic, and Nordic populations. Associations with genes on other chromosomes have also been demonstrated. In a series of Japanese patients with HLH, 25% had mutations in the MUNC 13-4 gene (FHL2), a regulator of exocytosis in perforin-containing vesicles.[76] A small subgroup, dubbed FHL4, has been described in patients of Kurdish descent. A large consanguineous Kurdish kindred with 5 affected children had deletions in the syntaxin 11 gene on chromosome 6 (FLH4). Syntaxin 11 is a regulator of endocytosis.[86] This mutation is seen in approximately 21% of cases.[87] Further genetic mutations are under investigation.

Griscelli syndrome type II

This generally has the same symptoms as HLH because of associated immunodeficiency.

HLH reactive hemophagocytic syndrome

This is a reversible proliferation of histiocytes in response to viral, bacterial, fungal, and parasitic infections and autoimmune disorders, as well as secondary to various cancers.[56] This syndrome is most prevalent in individuals of Asian descent.[88] The disease may be a manifestation of impaired immune response to an infection or to secondary immunodeficiency, with many patients having defects in cellular cytotoxicity and immune deficiencies.[89]

Symptoms are often systemic and include fever and a viral-like illness. Patients frequently have a rash and an enlarged liver, spleen, and lymph nodes. Pancytopenia, increased liver enzyme levels, and an abnormal coagulation profile are common. Epstein-Barr virus is a common triggering organism.

Pathologically enlarged lymph nodes may have intact architecture with increased histiocytes in the sinusoids and paracortical areas. Histiocytes may exhibit platelet phagocytosis. Histiocytic hyperplasia may also be evident in the liver and spleen. The disease is usually self-limiting, but treatment with chemotherapy may be required when the disease is severe.

Instances of a combination of T-cell lymphoma with benign infiltration of histiocytes have been reported.[90, 91, 92] Upon histologic analysis, the process involves various types of malignant lymphomas, which are often of T-cell origin. Production of cytokines by lymphoma cells is suspected to cause phagocytosis. Upregulation of the TNF-alpha gene by Epstein-Barr virus and activation of macrophages by T cells infected with this virus, with interferon (INF) and other cytokine production, have been found.[93] Occurrence of LCH with various leukemias and solid tumors has also been reported.[94]

Lymphoma-associated hemophagocytic syndrome (LAHS) is a major subtype of the adult onset secondary HLH. This disorder often lacks mass formation and delayed enlargement of the lymph nodes. The ratio of serum soluble interleukin-2 receptor to ferritin has been shown to be useful as a marker in the diagnosis of LAHS.[95]

In some disorders, such as Kikuchi-Fujimoto disease (KFD) (histiocytic necrotizing lymphadenitis), which is a self-limiting disorder that affects cervical lymph nodes; hemophagocytic lymphohistiocytosis is seen.[96, 97]

Malignant T cells that express T-cell receptor gamma/delta have been found in adult and, rarely, pediatric patients with fever and hepatosplenomegaly. The red pulp of spleen and sinusoids of the liver contain large lymphoid cells with erythrophagocytosis.[98, 99, 100, 101]

Histiocytic necrotizing lymphadenitis

This is a disease of unknown etiology and is usually observed in adolescents and adults. A female predilection is reported. The disease occurs in the cervical region; however, other locations, multiple sites, and rare extranodal involvement are reported.

Constitutional symptoms, such as fever, weight loss, nausea, vomiting, myalgia, arthralgia, and upper respiratory infection, may be present.[102]

Upon histologic study, necrosis of the nodes is observed in the paracortical area and, to a lesser extent, in the cortical area, with fibrin deposits, karyorrhectic debris, and macrophage infiltration. Areas adjacent to the foci of necrosis exhibit a reactive immunoblastic proliferation.

Laboratory findings are not diagnostic. The hematologic changes are nonspecific. Antibodies to Yersinia enterocolitica have been reported. The disease spontaneously resolves and rarely recurs. Systemic lupus erythematosus has been reported.[102]

Almost 70% of all patients with HLH have CNS abnormalities that can be seen using CT scanning or MRI. These findings are often nonspecific.[85]

Using flow cytometry, CD107a expression can be diagnostic for MUNC 13-4 defect and can potentially discriminate between genetic subtypes of FHL.[103]

Dendritic lymphadenitis is a benign condition in which draining lymph nodes react to a skin lesion with paracortical expansion, dendritic cell infiltrates, and various degrees of follicular hyperplasia. Melanin pigment may be present.

Interdigitating dendritic cell sarcoma, indeterminate cell neoplasm, and fibroblastic reticular cell neoplasm are rare and nearly always affect adults.

Congenital solitary histiocytoma is a variant of self-healing solitary lesion of Hashimoto-Pritzker histiocytosis. This rare entity is seen in otherwise normal infants in the form of a solitary 5-mm to 15-mm nodule or papule at birth. Pathologically the skin lesion consists of predominantly histiocytes with admixture of lymphocyte and eosinophiles. Protein S100 and CD1a are positive and Birbeck granules may be present. Skin is the only site of involvement. Other organs and systems are not affected. The lesion is self-healing, apparently with no incidence of recurrence. However, regular follow-up physical examination is recommended.[104]

Physical

When the disease is focal, establishing the diagnosis of Langerhans cell histiocytosis depends on a high level of suspicion. When advanced multisystem involvement is observed, diagnosis is often easy. Adequate workup to determine the extent of the disease and possible complications is essential. Biopsy and pathologic evaluation are needed to establish the diagnosis.

Causes

The causes of most histiocytoses are not known. Factors implicated in the etiology and pathophysiology of these disorders include infections, especially viral infections; cellular and immune dysfunction, including dysfunction of lymphocytes and cytokines; neoplastic mechanisms; genetic factors; and cellular adhesion molecules.[10, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146]

Hemophagocytic lymphohistiocytosis (HLH)

HLH is characterized by the uncontrolled proliferation of activated lymphocytes and histiocytes secreting a large amount of inflammatory cytokines. HLH can be inherited or acquired; however, all forms of the disease have impaired function of natural killer cells and cytotoxic T cells in common. The genetic form of HCH occurs in families (FHL) and in various inherited immune disorders, including Chédiak-Higashi syndrome 1 (CHS1), Griscelli syndrome 2 (GS2) (mutation in RAB27A), and X-linked lymphoproliferative syndrome (XLP). XLP is caused by a mutation in the SH2D1A gene and is inherited as an X-linked genetic disorder.[56] In most cases of acquired HLH, the immune system is normal and the disease is triggered by an infection, underlying malignancy, immune deficiency disorder, or Kawasaki disease.

As noted above, FHL is a rare, genetically heterogeneous immune disorder with incidence of 0.12-1 cases per 100,000. It is inherited as an autosomal recessive disorder; thus, each sibling has a 25% chance of the disease, 50% are carriers, and 25% remain unaffected. Five genetic loci (ie, FHL1, FHL2, FHL3, FHL4, FHL5) are associated with familial HLH.

Table 1. Genetics in FHL[147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 56, 172, 173]



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FHL results in disturbance of regulatory pathways that mediate immune defense and natural termination of immune/inflammatory response. The expressions of genes associated with natural killer cells (NK-cell) functions, innate and adaptive immune responses, proapoptic proteins, and B-cell and T-cell differentiation have been shown to be down-regulated in this disorder.[167]

Some studies suggest the use of perforin expression by peripheral lymphocytes, assessment of the behavior of the 2B4 lymphocyte receptor and NK-cell activity as the bases to identify different subgroups of HLH.[160]

Mutations of MRNA splicing commonly are the underlying molecular defect in patients with FLH3. The Munc 13-4 protein primes the secondary mutation in this gene and can result in defective cellular cytotoxicity. In a study of 31 families with FHL, at least one mutation responsible for splicing error was identified. The deep intronic mutations detected affected regulatory sequences resulting in aberrant splicing. Therefore, the UNC13D mutations appear to lead to splicing errors, which results in common symptomatologies seen in FLH3.[174]

A genomic region (ie, 9gr21) has been linked to FHL1; however, the gene responsible for the specific product or action remains unknown.[155]

In FHL2, gene encoding perforin, which is located on chromosome 10 (ie, 10gr21-21) has been identified. Perforin along with granzyme B are intracellular contents of lysosomal granules in cytotoxic T and NK cells, which are essential for appropriate function of microtubule organizing complex (MTOC). More than 50 mutations of perforin have been described with predominance of blacks, some degree of prevalence in Turkey, and to a lesser extent in Japan. In 62.5% of Japanese patients, the perforin mutation is the 1090-1091delCT and in the remaining 37.5%, 207delC.[151]  In Turkish patients, the perforin mutation often is Trp 374X and results in an early onset of the disease.[166]  In Italian cases, A91V sequence variant is seen with onset of the disease later in life. IN FHL3, the UNC13D gene is located on chromosome 17 (17gr25), which encodes for the production of Munc 13-4 protein is involved. At least 18 separate mutations have been identified. Despite the genetic findings, the course of the disease is identical to those of FHL2. Munc 13-4 protein, a member of the UNC13 family of intracellular protein, is essential for vesicle priming. In patients with FHL3, Munc 13-4 mutation results in defects in the priming of the lytic granules containing perforin and granzymes A and B.

In FHL4, the syntaxin 11 (STX11) gene is located on chromosome 6 (6gr24), which encodes the production of syntaxin 11. A syntaxin mutation finding is not consistent in all affected patients. Although it accounts for 14% of non-FHL1 cases, it is more frequently found in Turkish patients (21%) and is not present in the Japanese cases.[175, 176]

In FHL5, the STXBP2 gene is located on chromosome 19 (19p), which encodes for the protection of Munc 18-2 (ie, syntaxin binding protein 2), and STXBP2 is involved. This protein regulates intracellular trafficking and control of SNARE complex assembly and disassembly, thus exocytosis machinery.[177, 178]

Most reported cases, as expected, are consanguineous families and are due to homozygous missense mutations. The mutation has been reported in Turkish, Saudi Arabian, and central European countries.

HLH can occur in the absence of a genetic mutation or factors and conditions associated with genetic predisposition/alteration or consanguinity. Although the data is sparse, secondary HLH likely has by far greater incidences than FLH.[179]

The most common causes of secondary HLH are as follows:[180, 181, 182, 183, 184, 185, 186]

Polyostotic sclerosing histiocytosis (Erdheim-Chester disease or syndrome)

Polyostotic sclerosing histiocytosis, often referred to as Erdheim-Chester disease or syndrome (ECD), is characterized by excessive proliferation of histiocytes and infiltration of lipid-laden tissue macrophages, multinucleated giant cells, lymphocytes, and histiocytes into the bone marrow. It predominantly affects middle-aged adults. Generalized and symmetrical metaphyseal sclerosis of long bones are characteristic of this disease. In approximately 50% of patients, however, extraskeletal involvement is seen; this includes involvement of the skin, brain (including the pituitary gland), retro-orbital tissues, lungs, heart, pericardium, and kidneys.

Common symptoms include bone pain, mostly in the lower extremities; this pain is often mild and involves the knees and ankles. Other symptoms may include hyperpituitarism, diabetes insipidus, neurologic manifestations such as ataxia, exophthalmus, pericarditis, dyspnea, liver and renal failure, and retroperitoneal fibrosis.  

The etiology of polyostotic sclerosing histiocytosis is not clear. Mutation of NRAS[187] and BRAF-V600E[188] has been reported.[188]

Langerhans Cell histiocytosis (LCH)

As with other histiocytoses, the etiology of LCH is not known. Extensive searches for evidence of viral infection have been unrevealing.[189]  In one study, it was hypothesized that LCH occurs as a result of Merkel cell polyomavirus infection triggering an IL-1 activation loop.

Tyrosine phosphatase SHP-1, which binds IL-1 receptor-associated kinase 1, was found to have a significantly greater level of expression in cases of LCH with multiple organ involvement than in LCH cases impacting a single organ system. In the former group, the level of IL-17A receptor was also reported to be higher.[190]  A report from Sweden suggests that there is an increased rate of diagnosed histiocytosis in children conceived using in vitro fertilization.[191] In FLH, distinct genetic mutations have been clearly demonstrated.

Cytokines play an important role in the physiology and biology of dendritic cells and macrophages. LCH lesions contain various cytokines.[192, 143, 144] Large amounts of cytokines are produced by CD1a+ LCH and by CD3+ T cells, including IL-2, IL-4, IL-5, and TNF-alpha, which are exclusively generated by T cells. IL-1a is derived from Langerhans cells. T cells and macrophages can produce GM-CSF and INF-alpha, whereas LCHs and macrophages produce IL-10, and T cells and macrophages produce IL-3. Macrophages produce IL-7. Eosinophils are partly responsible for the production of IL-5, INF-gamma, GM-CSF, IL-10, IL-3, and IL-4.[143, 144]

Expression of abnormal leukocyte cellular adhesion molecules in LCH has been reported.[193, 145] These molecules mediate cell-to-cell and cell-to-matrix adhesion.

Using the X-linked human androgen receptor polymerase chain reaction (PCR)-based assay to assess clonality, researchers demonstrated that all forms of LCH are clonal; therefore, LCH is a clonal neoplastic disorder. Origination from a single cell is postulated to indicate neoplasia, although it does not mean that the process is histologically malignant.[194] Using this standard, LCH is considered to be a neoplastic disease rather than a reactive disorder.[195]  However, identification of a putative myeloid progenitor, along with the discovery that most patients with severe LCH have a BRAF-V600E gain-of-function mutation, may indicate that LCH is a reactive disorder with underlying neoplastic potential, possibly a myeloid neoplasm.[10, 40, 196, 197, 198, 199]

The role of genetics in LCH is not well defined. Although HHV6 has been found in LCH lesions, its etiologic significance has been questioned.[200, 201] ​BRAF-V600E mutations are seen in over 50% of LCH lesions. The B-Raf protein is a central kinase of the MAPK pathway and regulates major cellular functions. BRAF-V600E mutation results in constitutive activation of the downstream MAPK/ERK kinase (MEK) pathway and extracellular signal-regulated kinase (ERK) proteins.

The prevalence of MAP2K1 mutations in BRAF-V600E mutation–negative LCH is high.[202] MAP2K1, encoding the protein MEK1, is seen in 33-50% of LCH lesions, ie, those in which BRAF is not mutated. Some studies suggest that the existence of mutually exclusive recurrent somatic mutations in MAP2K1 and BRAF indicates that ERK activation plays a central part in the pathogenesis of LCH.[196]

Identification of BRAF mutation in LCH and recognition of the importance of microenvironment in progression of this disorder provides opportunities for targeted therapy, such as treatment with vemurafenib (which is commercially available). 

The occurrence of several cases of LCH in one family is rare but has been reported.[203, 204] LCH has been reported in several monozygotic and dizygotic twins.[137, 139, 139, 140, 141, 142, 205] Some consanguinity and involvement in close relatives (cousins) has been reported.[206] Nevertheless, the relative rarity of the familial occurrence does not indicate a notable hereditary influence. Conversely, FHL, which is transmitted as autosomal recessive trait abnormalities of genes localized to bands 9q21.2-22 and 10q21-22 (perforin), is reported in some families.[143, 144] As expected, numerous familial cases of erythrophagocytic lymphohistiocytosis have been reported.[98]

The fusion of nucleophosmin (NPM) and anaplastic lymphoma kinase (ALK) genes that results in NPM-ALK fusion protein, which can be immunohistochemically demonstrated, is reported in malignant histiocytosis. A study reported three cases of histiocytosis in early infancy with enlarged liver and spleen, anemia, and thrombocytopenia. In one case, analysis had revealed TPM-3-ALK fusion.[205]

Spontaneous cytotoxicity of circulating lymphocytes is observed in patients with LCH. Antibody formation to autologous erythrocyte has also been reported.[207] Given these findings, treatment with crude calf-thymus extract, although not substantially successful, was clinically devised and used.[207, 208]

A prominent feature of patients with HLH is deficiency in NK-cell function against MHC-negative K652 target cells. Patients with FHL usually exhibit this defect at diagnosis. Patients with infection-associated hemophagocytic syndrome may have normal function, they may never have completely negative function, or they may develop negative NK-cell activity during the course of the disease.[179]

The etiologic role of impaired effector function of perforin with subsequent inability to release perforin-containing granules is demonstrated in HLH. It is similar to the mononuclear cell infiltration associated with Chediak-Higashi Syndrome and Griscelli Syndrome.[209, 210, 211]

Association of LCH with leukemias and lymphomas has been described.[212]  A study by Yokokawa et al examining the development of LCH during maintenance chemotherapy for T-cell acute lymphoblastic leukemia suggested that cells associated with both diseases arise from a common precursor cell featuring a T-cell receptor rearrangement and a single NOTCH1 mutation.[213]

Laboratory Studies

Laboratory investigations and diagnostic tests should partly be tailored to the extent of disease suspected on the basis of the patient's history and physical findings. For genetic studies of FHL, please see the Etiology section.

Langerhans cell histiocytoma

Table 2 shows minimal frequencies of follow-up. Testing more frequent than that shown might be necessary.

Table 2. Laboratory and Imaging Studies in Patients With LCH



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Table 3 lists the indications for various laboratory evaluations, with the minimal frequencies of follow-up. Testing more frequent than that shown might be necessary.

Table 3. Indication for Laboratory Evaluations Based on Findings in LCH



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Although high serum levels of interleukin-17 (ILITA), which is a T-cell–specific cytokine involved in chronic inflammation processes, have been found in LCH with correlation to the activity of the disease. However, this is not expressed by CD207 t-cells in LCH lesions.[224, 225]

Polyostotic sclerosing histiocytosis

The diagnosis of polyostotic sclerosing histiocytosis depends on the area of involvement. Due to the rarity of this disease, the diagnosis can be difficult and even with appropriate biopsy, may require exclusion of other disorders. Unlike Langerhans cell histiocytosis lesions, those of polyostotic sclerosing histiocytosis do not stain positive for S100 proteins or group 1 CD1a glycoproteins and do not reveal Birbeck granules under electron microscopic examination. Infiltration of tissues with lipid-laden macrophages, multinucleated giant cells, lymphocytes, and histiocytes is seen, with the histiocytes staining positive with CD68, CD163, and factor XIIIa and negative with CD1a.

The X-chromosome inactivation pattern of the human androgen receptor gene (HUMARA) assay can assess clonality and has been used in a variety of tumors, including those of Langerhans cell histiocytosis and polyostotic sclerosing histiocytosis. This assay, however, is effective only if monoclonal cells make up more than 20% of the total tumor cell population. (In a study of five cases of polyostotic sclerosing histiocytosis, histiocytes were monoclonal in three cases, polyclonal in one, and homozygous in one.) Investigation of CNS involvement and genetic mutations, including in NRAS and BRAF-V600E, should be performed.[187, 188, 226, 227, 45, 228] Consensus guidelines for the diagnosis and clinical management of this disease are available.[226]

Evaluation of the extent of the disease must be performed, having significant value. This includes imaging studies such as computed tomography (CT) scanning of the chest and abdomen, bone scanning, skeletal survey, magnetic resonance imaging (MRI) of the head, and positron emission tomography (PET) scanning, as well as biopsy and special staining with CD68, CD1a, and S100; chromosome studies (BRAF gene mutation, RAS/MAPK pathway); evaluation to rule out diabetes insipidus; bone marrow aspiration and biopsy; echocardiography; and liver and renal evaluations.

Imaging Studies

See the tables above for appropriate imaging studies when LCH is suspected.

Radiographic imaging of lytic lesions of the skull reveals a punched-out pattern without evidence of periosteal reaction or marginal sclerosis, shown below.



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Radiograph of lytic lesions of the skull reveals a punched-out pattern without evidence of periosteal reaction or marginal sclerosis.

Radionuclide bone scanning with technetium-99m polyphosphate may reveal a localized increased uptake. This study is complementary to plain radiography.

MRI sometimes helps in identifying lesions that cannot be detected with other modalities. For example, in one study, 28% of children with Langerhans cell histiocytosis had MRI findings suggestive of neurodegenerative disease.[85]

Neurologic findings may not always be correlated with the MRI results and may lag behind findings on MRI.[85, 106, 229]

CT and MRI can show the detailed anatomic pattern of involvement and can help in staging the disease.[230]

Positron emission tomography (PET) with 18F-fluoro-deoxyglucose (FDG) may be an effective tool for evaluating LCH and may provide additional information regarding the activity of the lesions.[201] In a retroactive study of F-18 FDG PET/MRI scan in 16 children with LCH, PET scanning produced less false-positive results in the follow-up of patients undergoing chemotherapy compared with MRI. However, the MRI had a higher sensitivity for primary staging.[231]

In neurodegenerative LCH, F-18 FDGPET may be a useful tool for an early diagnosis before neuroradiologic abnormalities appear.[232]

With pulmonary involvement, CT scanning is the best modality to reveal cysts and micronodular infiltrates.

Other Tests

When pulmonary involvement occurs, pulmonary function may be abnormal.[123, 124] Diffuse cystic changes, nodular infiltrate, pleural effusion, and pneumothorax are known to occur. Pulmonary function tests may reveal restrictive lung disease with decreased pulmonary volume and are critical components of follow-up in patients with pulmonary involvement.[123, 124]

Procedures

Biopsy is needed to establish the diagnosis of Langerhans cell histiocytosis.

Histologic Findings

Regardless of the clinical severity, the histopathology of Langerhans cell histiocytosis is generally uniform. To some extent, the location and age of the lesion may influence the histopathology of the disease.[233, 234] Early in the course of the disease, lesions tend to be cellular and contain aggregates of pathologic Langerhans cells (PLCs), intermediate cells, interdigitating cells, macrophages, T cells, and giant histiocytes. Mitotic figures number 0-23 per 10 high-power fields.[235]

Multinucleated giant cells are common, and some may exhibit phagocytosis. Lesions may also include eosinophils, necrotic cells, and Langerhans cell histiocytosis cells. With time, the cellularity and number of Langerhans cell histiocytosis cells are reduced, and macrophages and fibrosis become eminent. The infiltrates tend to destroy epithelial cells. Table 5 shows the phenotypes and cell-marker characteristics of Langerhans cell histiocytosis.

LCH is characterized by accumulation and proliferation of histiocytic cells displaying the phenotype of the pathological Langerhans cell, positive for CD207(+) (also known as langerin) and CD1a.[236]  CD207 is a transmembrane receptor that binds endogenous ligands, including components of the extracellular matrix and pathogens that express surface mannose-containing glycoconjugates. Intracellular adhesion molecules CD54 and CD58 are upregulated in LCH cells, with a consequent abnormal chemokine-mediated trafficking to aberrant anatomic sites and with Langerhans cells accumulating in affected tissues.[10]  Shortened length of telomere has been described in all stages of LCH.

Table 4. Cell Markers and Phenotypes of Histiocytic and Related Disorders



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Table 5 shows specialized stains for diagnosing these disorders, and Table 7 shows labeling pattern of histiocytes and dendritic cells.

Table 5. Stains for Diagnosing Histiocytosis



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Table 6. Labeling Pattern of Histiocytes and Dendritic Cells



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Langerhans cells express CD1a antigen, HLA-DR, and a subunit S-100 protein. See the image below.



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Photomicrograph shows sample of Langerhans cell histiocytosis (LCH) that immunocytochemically stains positive for S-100 protein.

Upon morphologic evaluation, cells are 12 µm in diameter with moderately abundant cytoplasm and a medium-sized folded, indented, or lobulated nucleus that has vesicular chromatin with 1-3 nucleoli and an elongated central groove producing a coffee-bean appearance.[237, 238, 239]

The histopathology of the Langerhans cell histiocytosis does not appear to be prognostic of the outcome of the disease.[235] The aggregation of Langerhans cells is observed in various disorders, such as lymphomas (eg, Hodgkin disease), lung cancer, and thyroid cancer. However, these disorders are secondary and resolve with control of the primary disorder.[6, 240]

In LCH, the cytoplasm and, rarely, the nucleus contain the characteristic structures termed Birbeck granules.

These trilaminar organelles are 190-360 nm long and approximately 33 nm wide, with a central striated line. These are derived from cytoplasmic membrane and are involved in receptor (T6)-mediated and non–receptor-mediated endocytosis. An electron microscopic finding of racquet-shaped granules in the cells can be helpful in confirming the pathologic diagnosis.

Relatively nonspecific findings include cytoplasmic, trilaminar, membranous loops and laminated substructures of lysosomes.[241] Langerin is a type II transmembrane C-type lectin associated with formation of Birbeck granules. This can be used as a selective marker for Langerhans cells and cells involved in Langerhans cell histiocytosis. Langerin expression is present in most cases of Langerhans cell histiocytosis.[242] Immunohistochemical determination of Langerin and CD1a may be used to separate Langerhans cell histiocytosis from other histiocyte proliferations. (However, a study by Lommatzsch et al suggested that in pulmonary LCH, CD80 is a more sensitive and specific marker of the disease than CD1a, with the expression of CD80 being low on myeloid dendritic cells in the bronchoalveolar lavage fluid of these patients.[243] )

Birbeck granules are the products of internalization of complexes originating from cell-membrane antigens and corresponding antibodies. CD1a antigen can be detected in paraffin-embedded tissues to provide for reliable diagnostic testing.[244, 245] ATPase peanut lectin and alpha-D-mannoside can be positive in the dendritic reticulum. An electron microscopic finding of racquet-shaped granules in the cells can be helpful to confirm the pathologic diagnosis.[189, 241, 246] Enzyme histochemistry and immunocytochemistry can also aid in the diagnosis of histiocytosis.[47]

The organs and tissues most commonly involved are the bones, skin, lymph nodes,[128] bone marrow, lungs,[124] brain,[247] hypothalamic-pituitary axis, spleen, liver, GI tract, and orbits.[107] Multisystemic involvement is common.[248] Bones can be involved in isolation or as a part of multisystemic disease. The skull or large bones are often involved. Bone lesions may contain an accumulation of eosinophils, multinucleated giant histiocytes, necrosis, and hemorrhage. The term eosinophilic granuloma was previously used to describe single bone lesions of Langerhans cell histiocytosis.

Cutaneous involvement can also be singular or can be a part of generalized involvement.[117, 119, 120, 249] A spontaneously regressing nodular form of cutaneous Langerhans cell histiocytosis is reported in infants; it involves deep dermis with a nodular aggregate of histiocyte and is called congenital self-healing reticulohistiocytosis.[9, 118, 122, 250] In general, skin lesions have a pattern of diffuse or multifocal nodular aggregation of PLCs deep in the papillary dermis; destruction of epidermal-dermal interface; and infiltration of histiocytes, T-cell lymphocytes, and eosinophils. The lymph nodes and thymus can be involved as a primary site or as a part of multiorgan and systemic involvement. The most common sites are the cervical, inguinal, axillary mediastinal, and retroperitoneal areas.[126, 251]

Five histologic motifs have been recognized. These include sinusoidal, limited sinusoidal, epithelioid granulomatous, partial effacement, and total effacement. However, the prognostic significance of these appearances is not proven. The cellular composition includes Langerhans cells, macrophages, multinucleated giant histiocytes, T lymphocytes, and eosinophils.[237, 238] Histologic involvement may have different appearances in lesions from separate sites. In some instances, lymph nodes are massive and cause airway obstructions.

Suppuration resembling infection has been reported.[127] The bone marrow may be normal or heavily involved. Bone marrow lesions may be focal with pathologic infiltration of Langerhans cells or may contain neutrophils, eosinophils, lymphocytes, multinucleated cells, fibrosis, and (in rare cases) eosinophilic accumulation. Pulmonary involvement is more common in adults than in children (especially adults with a history of smoking), but it occurs in 20-40% of all patients.[123, 124] Small cysts can coalesce and rupture into the pleural cavity, leading to pneumothorax.[125]

CNS involvement, including pituitary involvement, is often part of systemic disease.[252, 253, 254] The CNS is rarely a primary site of Langerhans cell histiocytosis involvement.[247, 255, 256, 257, 258, 259, 260, 261] The most common site of CNS involvement in patients with Langerhans cell histiocytosis is the hypothalamic-pituitary axis, which results in diabetes insipidus in 10-50% of patients.[262] Histiocytosis can be associated with cerebellar white matter abnormalities.[260] Pathologic changes in the cerebellum, basal ganglia, and pons have been reported.[222]

Local involvement of the temporal lobe has also been observed and represents a neurodegenerative disorder that is thought to be similar to a paraneoplastic syndrome.[260] The neurodegenerative changes may occur well before, during, or long after diagnosis of histiocytosis. Manifestation may include cerebellar and pyramidal dysfunction, hormonal abnormalities, ataxia, spasticity, and cognitive problems.[260, 223] MRI abnormalities in cerebellar white matter, brain stem, basal ganglia and cerebral white matter are found.[182, 260]

Involvement of the anterior pituitary is relatively uncommon. However, it can result in growth-hormone deficiency or, in rare cases, panhypopituitarism.[114] Cerebellar dysfunction with in coordination and white matter changes has been reported.[92] Langerhans cell histiocytosis may affect the spleen and liver. Primary involvement of the liver is uncommon.[263] Involvement of the liver is often part of multiorgan disease. Even when PLCs are not present, sclerosing cholangitis can be observed.[263] Liver infiltration may result in tissue damage and increased enzyme levels, jaundice, coagulation disorders, and hypoalbuminemia.

Involvement of the GI tract is probably more common than is clinically recognized.[264] Lesions in the stomach, small bowel, colon, and rectum have been reported.[264, 265, 266, 267] The usual pathology of GI involvement with Langerhans cell histiocytosis includes infiltration of lamina propria and submucosa with glandular, mucosal, and, possibly, villus atrophy. Diarrhea and GI bleeding can be the presenting features of the disease. Involvement of the pancreas is rare.[268]

Langerhans cell histiocytosis rarely involves the intraocular structures. Isolated eye disease has been reported.[218] Lytic lesions of the orbit and resulting soft-tissue extension may cause proptosis. Ptosis and optic atrophy rarely occur. Patients with ear involvement often present with chronic otorrhea, lesions of the external auditory meatus, middle-ear involvement, and mastoid involvement. Although rare, involvement of the genital tract has been reported.[269, 270, 271]

In patients with Langerhans cell histiocytosis and hematopoietic involvement, Langerhans cell infiltration is often not evident; however, other abnormalities are common. These include abnormal M:E ratio; hyperplasia and dysplasia of megakaryocytes, including mononucleated and bilobed micromegakaryocytes and paratrabecular and grouped megakaryocytes; existence of neutrophil remnants in megakaryocytes (emperipolesis); increased numbers of macrophages; hemophagocytosis; and myelofibrosis.[272]

Medical Care

Langerhans cell histiocytosis

Optimal treatment of Langerhans cell histiocytosis (LCH) has not been established. In ideal cases, the differences between normal cells and pathologic Langerhans cells (PLCs) should be used to guide treatment of the disease. However, lack of sufficient information has hampered specific therapy. Some suggest that treatment of LCH should be conservative and limited to individuals with constitutional symptoms, such as pain, fever, failure to thrive, and vital organ disorder, as well as those at risk for CNS involvement.[273]

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.[274, 275, 276] 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.[277] 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.

Thoroughly investigated limited skin lesions in infants can potentially be self resolving, while in other age groups, as shown in one study, 40% of patients with LCH that was presumed to be limited to the skin had multisystem involvement.[121] Thus, careful and judicious evaluation, such as with imaging studies/PET scans, appropriate biopsies, including of bone marrow, and investigation of BRAF-V600E expression, markers, and biochemical profile, among other tests, should be performed as necessary. If the disease is indeed local and limited to the skin, it can be treated with resection, steroids, nitrogen mustard, imiquimod, and other therapies, with careful, continuous follow-up. If needed, systemic therapy can be judiciously used.

While it is often relatively obvious which patients should be considered high risk, such identification can at times be difficult, since risk-organ involvement can be subtle and histologic analysis is not always accurate. Special attention in LCH must be given to the possibility of CNS involvement. Patients with bone lesions in the sphenoid, clivus, mastoid, orbit, and temporal bone have an increased incidence of CNS disease. In symptomatic CNS disease, the most frequent sign is the presence of diabetes insipidus due to pituitary involvement. CNS cytology is often negative; evaluation of the peripheral blood and CNS fluid for BRAF-V600E to support the diagnosis is warranted.

Patients with high-risk disease 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 CNS disease, treatment with clofarabine or cytarabine (with the latter in higher doses) should be considered.   

A study of by Rigaud et al of 1478 patients with Langerhans cell histiocytosis found that following a change in therapeutic strategy—an increase in the treatment period from 6 to 12 months, the use of repeated induction therapy in patients who responded poorly to initial induction with vinblastine and steroids, and the treatment of refractory disease in a risk organ with cladribine and cytarabine—the 5-year survival rate improved from 92% to 99%. In the specific group of patients with refractory disease in a risk organ, the 5-year survival rate increased from 60% to 92%.[278]

A study by Duan et al indicated that in adult patients with either multisystem or multifocal single-system Langerhans cell histiocytosis, treatment with either vindesine and prednisone or cyclophosphamide, etoposide, vindesine, and prednisone was similarly effective. The study, which involved 45 patients, also found high disease recurrence and the need for second-line therapy associated with the two regimens.[279]

Experience shows that  the drug combinations commonly used in children, as outlined above, is far more toxic and much less effective in adult population. In this population, cytarabine is effective and much better tolerated.

Radiation therapy is effective in LCH.[280] Doses ranging from 750-1500 cGy are usually administered, resulting in good local control of single lesions or metastasis, which can occur in critical areas or cause permanent damage. Fractionated doses of radiotherapy have also been used.[281]

Summary of suggested therapeutic approach

While there are no standards for the treatment of LCH, the following are suggested therapies, though not recommendations, based on published literature, with these treatments to be used alone on in combination, as needed.

Treatment for a single bone lesion may includes one or more of the following:

Treatment for multiple bone lesions+/- nonrisk site include the therapies listed above along with administration of vincristine plus prednisone (1 year).

Treatment for limited-skin-lesion LCH includes the following:

Treatment for LCH with single lymph node involvement includes excisional biopsy.

Treatment for primary pulmonary LCH includes the following:

Treatment for high-risk multisystem LCH includes the following:

Treatment for CNS-risk lesions, including, but not limited to, bone lesions of the mastoid, sphenoid, orbit, clivus, or temporal bone, includes the following:

Salvage therapy, depending on the prior treatments used, can be carried out via a number of options, including higher doses of some agents. Treatments include the following:

Polyostotic sclerosing histiocytosis

Treatment for polyostotic sclerosing histiocytosis includes the following:

Consultations

Multidisciplinary care is essential for all patients. Consultation with an oral surgeon, otolaryngologist, and endocrinologist, among others, may be required. Careful systematic short- and long-term follow-up is extremely important.

Long-Term Monitoring

Patients with Langerhans cell histiocytosis (LCH) must be followed for the disease and its possible complications and morbidities on a long-term basis. Even patients with low-risk disease can suffer long-term complications such as pain; growth delay; neurodegenerative disorders; pituitary dysfunction, including diabetes insipidus; hearing loss; and sclerosing cholangitis. In addition, the long-term side effects of treatment require careful follow-up. 

Damage due to LCH can be substantial. Polyendocrinopathies due to pituitary damage and neurodegenerative disorders of uncertain etiology are major concerns. The latter can occur several years after resolution of the disease. Progressive cerebellar atrophy has been reported. Symptoms such as ataxia, dysmetria, dysarthria, tremor, speech problems, visual disorders, kinetic malfunctions, and behavioral dysfunction require careful and complete neurologic evaluation and follow-up. This includes routine use of neurologic scales such as the ataxia rating scale, ophthalmologic exams, neuroendocrine tests, biochemical profiles, MRI, and appropriate referrals. 

Medication Summary

The aim of therapy in histiocytosis is to relieve clinical symptoms and prevent complications of the disease. For single-system disease (eg, of the skin or bone), no therapy or only local therapy may be necessary, although further treatment may be needed in certain circumstances.[42, 58, 282, 283, 277]

Localized skin lesions, especially in infants, can spontaneously regress. If treatment is required, topical corticosteroids may be tried. Use of extemporaneously prepared topical 0.02% nitrogen mustard has also been advocated, but concerns of its mutagenic activity, especially in children, should be considered.[283, 70, 284] This agent, initially used systemically, appears to provide rapid response within 10 days[285] with minimal adverse effects, such as contact allergy. Scarring at the site of the lesion is thought to be due to the disease and not therapy.[284] In one study, skin lesions promptly healed in 14 of 22 children, and two had partial responses.[285] Low-dose radiation therapy to the local lesions is often effective but is rarely needed. For unresponsive skin lesions, low-dose mild systemic therapy can be used.

Chemotherapy for multisystemic disease with local or constitutional symptoms is used.[283] Single agents or adjuvant use of several chemotherapeutic agents and/or biologic-response modifiers may be effective. Published therapies include corticosteroids, vinca alkaloids, antimetabolites-nucleoside analogs, immune modulators such as cyclosporine,[286] antithymocyte globulin,[286] biologic-response modifiers such as interleukin (IL)-2 and interferon alpha (INF-alpha),[287] cellular treatment, and exchange transfusion.[288] Most reports of treatment modalities lack controls, with most authors citing the rarity of the disease as justification for this deficiency.[289, 73]

Phase I and II investigational therapies have included the use of single agents such as dabrafenib, GSK2110183, cladribine,[290] imatinib mesylate,[291] vemurafenib,[188] clofarabine,[292] and alemtuzumab[293] or combinations of agents such as alemtuzumab plus cyclophosphamide and busulfan plus fludarabine plus melphalan. Longer duration of therapy appear to improve the outcome in multisystem LCH.[294]

Purine analogs with activity for treatment of Langerhans cell histiocytosis (LCH) include 2-chlorodeoxyadenosine (2CdA; cladribine [Leustatin]) and 2-deoxycoformycin (2CDF; pentostatin;[295, 296, 297, 298, 299, 300, 301] 2CdA has been found to be particularly toxic to monocytes.[296, 297] Justification for the use of 2CdA is that some histiocytes are derived from monocytes.[204] In a review of 15 patients with multiorgan involvement receiving 2CdA and 2 receiving 2CDF, 6 had complete responses, 3 had partial responses, 5 had no response, and 1 died early. Fourteen had previously received significant treatments.[295]

As a single agent, cyclosporine has been used in pretreated patients with advanced Langerhans cell histiocytosis. Cyclosporine, a cyclic undecapeptide immunosuppressant of fungal origin, inhibits immune responses. The proposed mechanism of action is blockage of the transmission and synthesis of lymphokines, such as IL-2 and INF (ie, INF-alpha inhibition of the accessory cell function of Langerhans cells and reduced capacity of dendritic cells to enhance mitogenic stimulation of lymphocytes). Cyclosporine is postulated to disrupt abnormal cytokine-dependent activation of lymphocytes and histiocytes in the liver, spleen, lymph nodes, and bone marrow. The activation of lymphocytes is presumed to be secondary to uncontrolled proliferation of Langerhans cells. Furthermore, cyclosporine can inhibit cytokine-mediated cellular activation that potentially contributes to phagocytosis and disease progression.[286]

Cytosine arabinoside (cytarabine, ARA-C, Cytosar U), an antimetabolic chemotherapy agent, has been used for treatment of children and adults with Langerhans cell histiocytosis. The mechanism of action of this agent, has been used for treatment of children and adults with LCH. The mechanism of action of this agent is conversion to cytosine arabinoside triphosphate (Ara-CTP) by deoxycytidine kinase and other nucleotide kinases which results in cellular arrest in the S phase of inhibits RNA and DNA polymerases and nucleotide reductase enzymes necessary for DNA synthesis.

Cytosine arabinoside is converted to its inactive form, uracil arabinoside, by pyrimidine nucleoside deaminase. Because of its capability to cross the blood brain barrier, has efficacy in cases with CNS involvement. Cytosine arabinoside converts to uracil arabinoside (ARA-U) by pyrimidine nucleoside deaminase and is excreted mostly (80%) in the urine. This agent has been successfully used in single form or in combination in treatment of children and adults with LCH, including CNS involvement.[302, 303, 304, 305]

Clofarabine

This agent is a purine nucleoside metabolic inhibitor. Clofarabine is metabolized intracellularly to the 5’-monophosphate metabolism by deoxycytidine kinase and monokinase and diphosphokinase to the active 5’-triphosphate metabolite. This agent inhibits DNA synthesis by several mechanisms. This includes decreasing cellular deoxynucleotide substrate and deoxycytidine. Clofarabine inhibits DNA synthesis by reducing cellular deoxynucleotide phosphate pool via inhibition of ribonucleotide reductase and termination of DNA chain elongation.

Furthermore, it inhibits DNA repair through incorporation into the DNA chain by competitive inhibition of DNA polymerases. Clofarabine 5’-triphosphate disrupts repair by incorporation into the DNA chain during the repair process. It also disrupts integrity of mitochondrial membrane resulting in release of the proapoptotic mitochondrial proteins, cytochrome C, and apoptosis-inducing factor. This results in programmed cell death. After intravenous administration, clofarabine becomes bound to plasma proteins (47%) mainly albumin. The half-life of this agent, in pediatric patients, is 5.2 hours. Approximately, 49-60% of clofarabine is excreted in the urine unchanged.

Clofarabine, as a single agent and in combination, appears to be active in treatment of LCH, including advanced forms, not responding to the conventional therapies.[306]

In one study of 6 pediatric patients with multisystem LCH, this agent had shown promising results with significant side effects. In another report of 18 refractory patients who had previously received a median of three chemotherapeutic agents for Langerhans cell histiocytosis, juvenile xanthogranuloma and Rosai-Dorfman disease, 17 responses were noted after two to four cycles of therapy with clofarabine. These patients were treated with two to eight cycles of 25 mg/m2 for 5 days of clofarabine. Complete responses were seen in 61% and partial response in 22% with the remaining patients being on therapy at the time of the report. Neutropenia, vomiting, and infections were the major short term toxicities.

Partial and complete responses have been recorded in a small number of patients. Patients with partial response had achieved a complete response with prednisone and vinblastine chemotherapy. Cyclosporine A has also been used in familial erythrophagocytic lymphohistiocytosis (FEL). In one report of 2 children whose disease was resistant to steroids and etoposide, durable remission was obtained with this agent.[307]

INF-alpha had some effect in anecdotal cases of Langerhans cell histiocytosis.[287, 308]

Treatment of multifocal relapsing and resistant bone lesions in LCH is challenging. Langerhans cells are capable of releasing cytokines, which are potent activators of osteoclasts and can result in the lytic lesions seen in the disease. Pamidronate, a bisphosphonate agent, has been reported to induce response or result in disease stability in a small group of patients.[309]

Most chemotherapy agents for the treatment of Langerhans cell histiocytosis are used in combination. The length of therapy is arbitrarily chosen. In some studies, patients were stratified by risk factor.[310] Use of a combination of cytarabine arabinoside (Ara-C), vincristine, and prednisolone to treat disseminated Langerhans cell histiocytosis with organ dysfunction has been reported.

In a study of 18 pediatric patients with Langerhans cell histiocytosis and multiorgan involvement, 8 had additional organ dysfunction; 8 of 10 patients with organ involvement achieved complete remission.[311] Five of 8 patients with additional dysfunction achieved complete remission. Four (22%) of 18 patients developed diabetes insipidus. Two with organ dysfunction died at the time of the report. The regimen was described as being mildly toxic and relatively well tolerated. In this regimen, cytarabine (100 mg/m2/d for 4 consecutive days), vincristine (1.5 mg/m2 on day 1), and prednisone (40 mg/m2/d for 4 wk followed by 20 mg/m2 for 20 d) were administered. The combination of vincristine and cytarabine was repeated every other week for 4 weeks. Thereafter, the interval was extended by 1 week until this combination was administered every 6 weeks, until complete remission was achieved (4-16 wk).

In a multicenter study in 1983-1988, Italian investigators assigned 70 patients with biopsy-proven Langerhans cell histiocytosis into good-prognosis or poor-prognosis groups, depending on their organ dysfunction.[312] Sixteen patients with limited disease were treated with surgery alone, 5 received immunotherapy with thymus extract then chemotherapy, and 49 patients received chemotherapy with vinblastine (5.5 mg/m2/wk for 3 mo).

Poor responders in this group were then treated with doxorubicin (20 mg/m2 intravenously for 2 d every 3 wk for 3 mo). Patients who did not improve with this regimen were administered etoposide (200 mg/m2 intravenously) for 3 consecutive days every 3 weeks for at least 3 months or until their disease progressed.

The poor-prognosis group (11 patients) received doxorubicin (20 mg/m2 on days 1 and 2), prednisone (40 mg/m2 by mouth on days 1-29), vincristine (1.5 mg/m2 intravenously once a week for 4 wk starting on day 8), and cyclophosphamide (400mg/m2 on days 15 and 29 for 9 courses).

Only 1 of 10 patients with good prognosis had a favorable response during therapy with thymus extract. Of 54 patients receiving chemotherapy (49 as first-line treatment), 34 achieved complete remission with vinblastine, and 8 had a recurrence after 4-22 months. Of 15 patients achieving remission with etoposide, 1 had a relapse 10 months after therapy. In 11 patients with poor prognoses, 7 had progressive disease, and 6 died within 9 months of diagnosis. Organ dysfunction appeared to significantly affect survival, with only 46% of patients surviving for 12 months. The main complication was diabetes insipidus, which occurred in 20% of patients. The overall incidence of disease-related disabilities was 48%.

In the Austrian and German DAL-HX 83/90 study, patients were stratified into 3 groups: those with multifocal bone disease (group A), those with soft-tissue involvement but without organ dysfunction (group B), and those with organ dysfunction (group C).[310] Induction therapy consisted of etoposide (60 mg/m2/d for 5 d on days 1-5, followed by weekly dosing of 150 mg/m2), prednisone (40 mg/m2 on days 1-28), and vinblastine (6 mg/m2 starting at week 3 of therapy). Maintenance therapy was risk related and consisted of vinblastine, 6-mercaptopurine, and prednisone in all patients, with etoposide added in group B and methotrexate and etoposide added in group C. Mortality rates for groups A, B, and C were 8%, 9%, and 38%, respectively.

An organized international approach to LCH has been successful.[41, 283, 313] Using the Histiocyte Society’s Langerhans cell histiocytosis I protocol,[314, 282] investigators prospectively and randomly assigned patients with multisystemic Langerhans cell histiocytosis who met criteria based on standard diagnostic evaluation.[58] Patients received vinblastine (6 mg/m2 intravenously weekly for 24 wk) or etoposide (150 mg/m2 intravenously on 3 consecutive days every 3 wk for 24 wk). All patients received methylprednisolone (30 mg/kg intravenously for 3 consecutive days [maximum daily dose of 1 g]). Of the 447 patients who were registered from various countries, 192 had multisystemic disease, and 136 were randomly assigned (72 to the vinblastine arm and 64 to the etoposide arm).

Patients were evaluated at predetermined intervals. Responses at 6 weeks appeared to differentiate responders from nonresponders, who had poor outcomes. Neither the patients’ ages nor the number, type, or dysfunction of the organs differentiated the groups. At 6 weeks, 51 (50%) of 103 patients achieved a complete response or substantial disease regression, whereas 32 (31%) had stable disease or partial or mixed responses. Disease progression was reported in 19 patients. At 26 months, the mortality rate was 18%. Among the patients who died, 4 had an initial response, 5 had intermediate responses, and 9 had initial nonresponses.

The protocol allowed nonresponders to switch to another treatment arm. Only 34% of patients who had switched had favorable results. Disease recurrence was observed in 11 patients who received vinblastine and in 8 who received etoposide. The 2 arms were statistically similar in terms of initial responses, recurrences, and mortality rates. The overall probability of diabetes insipidus was 42%.

The randomized Langerhans cell histiocytosis II study of the Histiocyte Society was performed to compare the effects of oral prednisone with vinblastine (with or without etoposide) in patients with multisystemic disease. Patients were divided into low- or high-risk groups. All patients received prednisone (40 mg/m2/d for 28 d with weekly reduction afterward) and vinblastine (6 mg/m2 intravenously weekly for 6 wk). The low-risk group received continuation therapy with vinblastine (6 mg/m2 during weeks 9, 12, 15, 18, 21, and 24), as well as 5-day pulses of prednisone during the same weeks. Patients in the low-risk group were excluded from randomization.

Patients in the high-risk group were randomly assigned to treatment A or B. Treatment consisted of an initial 6 weeks of therapy with prednisolone and weekly vinblastine and continuation therapy, pulses of vinblastine and/or oral prednisone as in the low-risk group, and daily doses of 6-mercaptopurine (50 mg/m2 during weeks 6-24). Treatment B was the same as treatment A, with the addition of etoposide (150 mg/m2 administered on day 1 of weeks 9, 12, 15, 18, 21, and 24). Results of this protocol have not yet been published.

The Langerhans cell histiocytosis III study of the Histiocyte Society indicated that in children with multi-system Langerhans cell histiocytosis, the use of intense, prolonged initial treatment can produce an overall 5-year survival rate of 84%. High-risk patients in the study underwent 12 months of treatment, receiving one or two 6-week courses of chemotherapy and a subsequent course of milder continuation therapy, with the first 12 weeks of treatment appearing to be critical to patient outcomes.[315]

The severity of the recurrent disease often dictates the type of therapy that is most likely to be helpful. For example, recurrence of an isolated bone lesion can often be treated with nonsteroidal anti-inflammatory drugs (NSAIDs) or intralesional steroid injections. When bone lesions are multiple and cause clinically significant morbidity, systemic therapy can be helpful. In such circumstances, patients often respond to the same drugs that they previously received, such as vinblastine and/or corticosteroids.

A retrospective study by Sedky et al indicated that in children with Langerhans cell histiocytosis, those who suffer multiple reactivations of the disease respond well to repeated use of first-line treatment, with or without methotrexate. The study, which had a median follow-up period of 42 months, involved 80 pediatric patients with the condition who were treated according to the Langerhans cell histiocytosis III protocol; 25 patients experienced reactivation, including 5 who suffered multiple reactivations.[316]

Extensive recurrence of skin disease, including refractory perianal or vulvar involvement, often requires systemic chemotherapy.

When patients do not have an early (ie, by 6 wk of therapy) response to vinblastine, corticosteroids, methotrexate, 6-mercaptopurine, or even etoposide, alternate therapies should be administered. Although several immunomodulatory agents, such as cyclosporine, have been used in patients with refractory disease, the results have been inconsistent. Cytotoxic chemotherapy often needs to be administered as well. Vemurafenib has been reported to be a highly effective agent for the treatment of adults with multisystemic and refractory LCH and polyostotic sclerosing histiocytosis (Erdheim-Chester disease).

Several studies, including an international phase II trial, demonstrated notable activity associated with 2CdA. This agent was originally used to treat patients with refractory hairy-cell leukemia and chronic lymphocytic leukemia. Response rates were more than 50%. Because 2CdA has antiproliferative effects on lympholytic and histiocytic cells, it is a potentially ideal drug to use in Langerhans cell histiocytosis, which is characterized by reactive lymphocytic and dendritic and macrophage components. Response rates to 2CdA have been particularly good in patients with extensive skin and bone disease, and in some patients with pulmonary involvement. Overall response rates have been about 30-40% in children. In a study with a small number of adults, the response rate was less than 70%. In 2 reports, a combination of 2CdA and Ara-C seemed to have major effects in a small group of children with refractory disease, but clinically significant grade 4 toxicities and a sepsis-related death were reported.[302, 317]

For some patients whose disease does not respond to 2CdA alone, the combination of 2CdA and high-dose cytarabine has been effective. A similar regimen has also been effective in patients with relapses of acute myelogenous leukemia. Until additional information is obtained with this drug combination, the true response rate and the duration of response are difficult to determine.

Other approaches to the treatment of patients with refractory Langerhans cell histiocytosis that are being tested or developed and include agents such as thalidomide, which is used to inhibit tumor necrosis factor (TNF)-alpha and INF-gamma production.[318] (INF-gamma is a cytokine produced by a subgroup of lymphocytes to regulate immune responses.) In some studies, only patients with low-risk disease were likely to respond to thalidomide, whereas high-risk patients with organ involvement were not.[319, 320] Emapalumab, a monoclonal antibody that also inhibits INF-gamma, is under investigation for the treatment of hemophagocytic lymphohistiocytosis (HLH).

Further recognition of NF-kappaB pathway may improve the success of targeted therapy for Langerhans cell histiocytosis.[321]

Targeting humanized antibodies against lineage-specific antigens, such as CD1a antigens on Langerhans cell histiocytosis cells, is another treatment being developed. The application of inhibitors of activated cytokine receptors and their downstream signal-transduction pathways is also an important area of future therapeutic trials. Although hematopoietic stem-cell transplantation has been successful in some patients with refractory Langerhans cell histiocytosis, identifying patients who might benefit from such high-risk therapy is difficult, and this treatment is associated with significant acute and chronic complications.

In some studies, children with multisystem LCH and risk organ involvement who had not responded to conventional therapies underwent a reduced intensity conditioning regimen (RIC) followed by allogenic stem cell transplantation, which was associated with lower transplant-related morbidity and mortality as well as an improved outcome.[12]

Specific therapies, including monoclonal antibodies against the CD1a or CD52 epitopes found on Langerhans cells, are emerging.[305]

Local therapy with various agents has been reported. Intralesional infiltration with corticosteroids for treatment of localized LCH has been advocated.[322]

Myeloablative therapy followed by bone-marrow or stem-cell transplantation in disease refractory to the conventional therapy has been reported.[323] However, reporting of positive results are likely to bias such reports.

Intravenous immunoglobulin has been used to treat neurodegenerative LCH. However, to the authors’ knowledge, no formal study has been done to conclusively affirm the benefit of such a treatment. For FHL treatment, a combination of antithymocyte globulin, steroids and cyclosporin has been used.[324]

The need to develop effective treatments and, ultimately, strategies to prevention progressive fibrosis of the lung, sclerosing cholangitis, and fibrosis of the liver, and the neurodegenerative pattern of CNS involvement is immense. Additional clinical trials are needed to determine whether agents such as 2CdA or specific inhibitors of fibrosis can improve the outcomes of patients with these complications.

Further Outpatient Care

Long-term follow-up care by a multidisciplinary team with knowledge of Langerhans cell histiocytosis (LCH) is critical for all patients, not just those with extensive multisystem disease or those treated with systemic chemotherapy.[325]

Inpatient & Outpatient Medications

See the Medication section.

Complications

Patients with Langerhans cell histiocytosis, especially those with multisystemic disease or multifocal skeletal involvement with a relapsing course, have a significant risk of developing adverse late sequelae from their disease or therapy.

Neurocognitive and psychological problems are more frequently recognized likely because of intensified patient follow-up.

Proliferation of Kupffer cells may accompany the initial hepatic involvement with Langerhans cell histiocytosis and subsequently develop into sclerosing cholangitis. This, in turn, may lead to fibrosis and liver failure. Lung and liver transplantation have been successful in patients who develop organ failure due to progressive fibrosis.

Secondary malignancies are reported in patients with Langerhans cell histiocytosis. Malignancies include secondary leukemias (usually acute myelogenous leukemias) caused by exposures to alkylating agents and, in recent reports, to etoposide. Other cancers include thyroid carcinoma, lymphomas, and CNS tumors.

Prognosis

The location of the lesions and the extent of the disease substantially affect the course of the disease and the patient’s prognosis.

Involvement of risk organs (hemopoietic system, liver, spleen, and lungs) at diagnosis and failure of response to the initial therapy are poor prognostic signs. Reactivation of risk organs is relatively rare. In one study, this reactivation occurred in 2% of patients.[329] Involvement of the risk organs at reactivation had relatively low impact on survival. The degree of organ involvement is correlated with the patient’s prognosis.

Although Langerhans cell histiocytosis involvement of the spine causes lesions and, sometimes, asymmetric collapse, it is not usually associated with long-term sequelae and deformity. Therefore, aggressive surgical management of this involvement is generally not indicated.

Rapidity of the response to chemotherapy may also have prognostic value.

A study by Zeng et al suggested that in LCH, the presence of BRAF-V600E mutation is related to poor disease-free survival, with the mutation leading to interference with host-tumor immune surveillance.[330]

Patient Education

Known genetic factors, when applicable, must be explained to the patients and their families.

What is Langerhans cell histiocytosis (LCH)?What is the pathology of histiocytosis disorders?What is the pathology of Langerhans cell histiocytosis (LCH)?What is the global prevalence of Langerhans cell histiocytosis (LCH)?What is the prognosis of polyostotic sclerosing histiocytosis?What are the sexual predilections of histiocytosis?Which age groups have the highest prevalence of Langerhans cell histiocytosis (LCH)?How is risk determined for Langerhans cell histiocytosis (LCH)?Which clinical history findings are characteristic of Langerhans cell histiocytosis (LCH)?How are histiocytosis disorders classified?Which histiocytosis disorders are classified as C group (non–Langerhans cell histiocytosis of skin and mucosa)?What are the subtypes of cutaneous non–Langerhans cell histiocytosis with a major systemic component?Which histiocytosis disorders are classified as L (Langerhans) group diseases?What are the subtypes of Langerhans cell histiocytosis (LCH)?What are the subtypes of polyostotic sclerosing histiocytosis (Erdheim-Chester disease [ECD])?What are the subtypes of cutaneous non–Langerhans cell histiocytosis?Which histiocytosis disorders are classified as M Group (malignant histiocytosis)?Which histiocytosis disorders are classified as R Group (Rosai-Dorfman disease)?Which histiocytosis disorders are classified as H Group (hemophagocytic lymphohistiocytosis)?What is the WHO classification of histiocytic disorders?What is the Histiocyte Society classification of histiocytosis syndromes?Which histiocytosis classifications are no longer used?What is juvenile xanthogranuloma (JXG)?What is sinus hyperplasia?What is primary hemophagocytic lymphohistiocytosis (HLH)?What is Griscelli syndrome type II?What is HLH reactive hemophagocytic syndrome?What is histiocytic necrotizing lymphadenitis?Which physical findings are characteristic of Langerhans cell histiocytosis (LCH)?What causes histiocytosis?What causes hemophagocytic lymphohistiocytosis (HLH)?What causes polyostotic sclerosing histiocytosis (Erdheim-Chester disease)?What causes Langerhans cell histiocytosis (LCH)?Which conditions are included in the differential diagnoses of Langerhans cell histiocytosis (LCH)?Which conditions are included in the differential diagnoses of Langerhans cell histiocytosis (LCH) with bone involvement?Which conditions are included in the differential diagnoses of Langerhans cell histiocytosis (LCH) with skin lesions?Which lymphatic disorders are included in the differential diagnoses of Langerhans cell histiocytosis (LCH)?Which conditions are included in the differential diagnoses of Langerhans cell histiocytosis (LCH) with otorrhea?Which conditions are included in the differential diagnoses of multisystemic Langerhans cell histiocytosis (LCH)?Which conditions are included in the differential diagnoses of Langerhans cell histiocytosis (LCH) with hypothalamic and pituitary lesions?Which infectious conditions are included in the differential diagnoses of histiocytosis?What are the differential diagnoses for Histiocytosis?What is the role of lab tests in the workup of histiocytosis?Which lab tests and imaging studies are performed in the long-term monitoring of Langerhans cell histiocytosis (LCH)?How is polyostotic sclerosing histiocytosis diagnosed?What is the role of imaging studies in the workup of Langerhans cell histiocytosis (LCH)?What is the role of pulmonary function tests in the workup of Langerhans cell histiocytosis (LCH)?What is the role of biopsy in the workup of Langerhans cell histiocytosis (LCH)?Which histologic findings are characteristics of Langerhans cell histiocytosis (LCH)?How is Langerhans cell histiocytosis (LCH) treated?How is polyostotic sclerosing histiocytosis treated?Which specialist consultations are beneficial to patients with Langerhans cell histiocytosis (LCH)?Why is long-term monitoring required in patients with Langerhans cell histiocytosis (LCH)?What is the role of medications in the treatment of Langerhans cell histiocytosis (LCH)?Which medications are used as monotherapy in the treatment of Langerhans cell histiocytosis (LCH)?What is the role of chemotherapy in the treatment of Langerhans cell histiocytosis (LCH)?How is recurrent or refractory Langerhans cell histiocytosis (LCH) treated?Which patients should receive long-term monitoring of Langerhans cell histiocytosis (LCH)?What are the possible complications of Langerhans cell histiocytosis (LCH)?What is the prognosis of Langerhans cell histiocytosis (LCH)?What is included in patient education about histiocytosis?

Author

Cameron K Tebbi, MD, Director, Children's Cancer Research Group Laboratories; Pediatric Hematologist/Oncologist, Tampa General Hospital and St Joseph's Children’s Hospital

Disclosure: Nothing to disclose.

Specialty Editors

Mary L Windle, PharmD, Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Gary D Crouch, MD, Associate Professor, Program Director of Pediatric Hematology-Oncology Fellowship, Department of Pediatrics, Uniformed Services University of the Health Sciences

Disclosure: Nothing to disclose.

Chief Editor

Vikramjit S Kanwar, MBBS, MBA, MRCP(UK), FAAP, Adjunct Professor of Pediatrics, Albany Medical College

Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: CSL Behring.

Acknowledgements

Gary R Jones, MD Associate Medical Director, Clinical Development, Berlex Laboratories

Gary R Jones, MD is a member of the following medical societies: American Academy of Pediatrics, American Society of Pediatric Hematology/Oncology, and Western Society for Pediatric Research

Disclosure: Nothing to disclose.

Thomas W Loew, MD Clinical Professor of Pediatrics, Division Director of Pediatric Hematology/Oncology, University of Missouri Children's Hospital

Thomas W Loew, MD is a member of the following medical societies: American Academy of Pediatrics, American Academy of Pediatrics, American College of Physician Executives, American Medical Association, American Society of Clinical Oncology, American Society of Hematology, American Society of Pediatric Hematology/Oncology, and Children's Oncology Group

Disclosure: Genzyme Grant/research funds Independent contractor; Genzyme Honoraria Speaking and teaching; Amicus Grant/research funds Independent contractor; Purdue Pharmaceuticals Grant/research funds Independent contractor

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Clinically detectable skull lesions in a child with advanced Langerhans cell histiocytosis (LCH).

Erosion of the gingiva that creates the appearance of premature eruption of the teeth in a young child.

Radiograph of lytic lesions of the skull reveals a punched-out pattern without evidence of periosteal reaction or marginal sclerosis.

Photomicrograph shows sample of Langerhans cell histiocytosis (LCH) that immunocytochemically stains positive for S-100 protein.

Erosion of the gingiva that creates the appearance of premature eruption of the teeth in a young child.

Clinically detectable skull lesions in a child with advanced Langerhans cell histiocytosis (LCH).

Cutaneous Langerhans cell histiocytosis (LCH) in a child. Skin infiltrates are seen on the face, and the chest has maculoerythematous, petechial, and xanthomatous appearance.

Severe scalp disease in a patient with scaly erythematous patches. Patches of alopecia are present. The lesions were not pruritic.

Photomicrograph shows sample of Langerhans cell histiocytosis (LCH) that immunocytochemically stains positive for S-100 protein.

Photomicrograph of Langerhans cell histiocytosis (LCH) stained with hematoxylin and eosin. The characteristic Langerhans cells have reniform or convoluted nuclei and abundant cytoplasm.

Transmission electron micrograph shows a diagnostic rod-shaped Langerhans Birbeck granule.

Transmission electron photomicrograph shows Langerhans cells characterized by convoluted nuclear contours and abundant cytoplasm.

Radiograph of lytic lesions of the skull reveals a punched-out pattern without evidence of periosteal reaction or marginal sclerosis.

Three-dimensional reconstructive view of skull lesions in a child with Langerhans cell histiocytosis.

Genetic defect/syndrome Genetic Defect Protein Frequency % FHL cases (location) Mutation Type Function
FHL1Unknown (9 gr 21.3-22)…Rare



Pakistan



……
FHL2 PRF



(10 gr 21-22)



Perforin20-40%



Often in blacks, Turks, Japanese



>50 deletions, non-sense and missense mutations; heterozygosity for C272T, A91V substitutionPore-forming protein
FHL3 UNC13D



(17 gr 25)



Munc 13-420-30%



Worldwide, Turks, Kurds, US, Europe



>18 deep intronic mutations and large inversionVesicle forming
FHL4 STX11



(6 gr 24)



Syntaxin-1110-20%



Worldwide, Central Europe, Turkey, Saudi Arabia



VariableVesicle transport and fusion
FHL5 STXBP2



(19p)



Munc 18-25-20%



Worldwide, Italy, UK, Kuwait, Pakistan, North America



Multiple mutations in the syntaxin binding protein Munc 18-2. Impaired binding to syntaxin-11Vesicle transport and fusion SNARE complex assembly and disassembly
Immune deficiency and albinism
Chédiak-Higashi syndrome LYST LYSTRare



Worldwide



…Size function of lytic granules
Griscelli syndrome type II RAB27A Rab 27ARare



Northern Europe



…Vesicle docking, granule movement
Hermansky-Pudlak syndrome Type II AP3B1 …Rare



Worldwide



…Vesicle biogenesis, protein sorting
Primary Immune Deficiencies
X-linked lymphoproliferative disease Type I SH2D1A SAPWorldwide…Signal transduction, activation of lymphocytes
X-linked lymphoproliferative disease Type II BIRC4 XIAPWorldwide…Inhibition of apoptosis
ITK deficiency ITK ITKWorldwide…T-cell kinase
Type of Study Study Involvement With Monostotic Lesion
LaboratoryHemoglobin and/or hematocritMonthlyEvery 6 moNone
Leukocyte count and differential cell countMonthlyEvery 6 moNone
Liver function tests*MonthlyEvery 6 moNone
Coagulation studiesMonthlyEvery 6 moNone
Urine osmolality test after overnight water fastEvery 6 moEvery 6 moNone
RadiographyChest, posteroanterior and lateralMonthlyEvery 6 moNone
Skeletal surveyEvery 6 moNoneOnce at 6 mo
* Measurements of alanine transaminase (ALT), aspartate transaminase (AST), and alkaline phosphatase.
Evaluation Indication Follow-Up Interval
Bone-marrow aspiration biopsyAnemia, leukopenia, or thrombocytopenia6 mo
Pulmonary function testsAbnormal chest radiographic findings, tachypnea, intercostal retractions6 mo
Lung biopsy after bronchoalveolar lavage, if available*Abnormal findings on pretreatment chest radiography to rule out infectionNone
Small-bowel series and biopsyUnexplained chronic diarrhea, failure to thrive, malabsorptionNone
Hepatic ERCP, angiography, or biopsyHigh liver enzyme levels and hypoproteinemia not caused by protein-losing enteropathy to rule out active LCH vs liver cirrhosisWhen all evidence of disease resolves but hepatic dysfunction persists
IV gadolinium-enhanced MRI of brain and hypothalamic-pituitaryVisual, neurologic, hormonal abnormalities6 mo
Panoramic radiography of the teeth, mandible, and maxilla; consultation with an oral surgeonOral involvement6 mo
PET scanSurveillance6 mo
Endocrine investigationGrowth failure, diabetes insipidus, hypothalamic syndromes, galactorrhea, precocious or delayed puberty; hypothalamic and/or pituitary abnormality on CT or MRINone
Consultation with an audiologist and an otolaryngologistAural discharge, impaired hearing6 mo
Note.—ERCP = endoscopic retrograde cholangiopancreatography; IV = intravenous.



* Diagnostic findings on bronchoalveolar lavage obviate lung biopsy.



Cell Marker LCH SHML Follicular Dendritic Tumor Histiocytic Sarcoma Acute Monocytic Leukemia Anaplastic Large-Cell Lymphoma
CD1a+-----
CD4++-+++
CD21-+/-+---
CD25-+-++++
CD30-----++
CD35-++---
CD45-+-+/-++/-
CD68-+-+++/-
ALK-1-----+
S-100++-+/1--
Lysozyme-+-++-
Type of Test Stain Mononuclear Phagocytic System Langerhans Cells Interdigitating Dendritic Cells Dendritic Reticulum Cells
Frozen-section enzyme histochemistryNonspecific esterase----
Acid phosphatase+---
ATPase-++-
Lambda-mannosidase-+--
5' nucleotidase---+
ImmunohistochemistryCD14 (Leu M3/MY4)++++
CD11 C (Leu M5)++++
CD68 (EBM 11)+---
CD1a-++-
Paraffin-section immunohistochemistryHLA-DR++++
CD68+---
Mac 387+---
Lysozyme+---
Alpha-antitrypsin+---
S-100-++-
Peanut agglutininDiffuseHalo and dotHalo and dot-
Note.—ATPase = adenosine triphosphatase; HLA = human leukocyte antigen.
Marker Histiocytes Langerhans Cells Interdigitating Cells Follicular Dendritic Cells
CD1a0S00
S-100 protein0SSW
HLA-DRSSSW
CD45SWW0
Alpha-naphthyl acetate esteraseSWWW
ATPaseWSSS
Fascin00SS
R4/23000S
Note.—0 = no staining; S = strong and constant; W = weak or inconstant.