Histiocytosis encompasses a group of diverse disorders with a common primary event: the accumulation and infiltration 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. Although nearly a century has passed since histiocytic disorders were recognized, their pathophysiology remains an enigma, and treatment is nonspecific. These problems underscore the need for an improved understanding of the etiology and pathogenesis of histiocytosis.
Over the past 50 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. For example, the entity now referred to as Langerhans cell histiocytosis (LCH) was initially divided into eosinophilic granuloma, Hand-Schüller-Christian disease, and 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. Most recently, this designation was changed to Langerhans cell histiocytosis to reflect the recognition of the primary cell involved and the pathophysiology of the disease.[3, 4] Although several histiocytic disorders are briefly discussed in this article (see History), the primary focus is on Langerhans cell histiocytosis.
Improved understanding of the pathology of histiocytic disorders requires knowledge of the origins, biology, and physiology of the cells involved. Normal histiocytes originate from pluripotent stem cells, which can be found in bone marrow. Under the influence of various cytokines (eg, granulocyte-macrophage colony-stimulating factor [GM-CSF], tumor necrosis factor-alpha [TNF-alpha], interleukin [IL]-3, IL-4), these precursor cells can become committed and differentiate to become a specific group of specialized cells. Committed stem cells can mature to become antigen-processing cells, with some possessing phagocytic capabilities. These cells include tissue macrophages, monocytes, dendritic cells, interdigitating reticulum cells, and Langerhans cells. Pluripotent stem cells can also be committed to produce dendritic cells. Each category of histiocytosis can be traced to reactive or neoplastic proliferation and disorder of cells in one of these groups.
The importance of dendritic cells in presenting antigens to T and B lymphocytes is increasingly recognized. Dendritic cells appear to develop in several pathways. 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). These cells can capture antigen and migrate to lymphoid organs, where they present the antigens to naive T cells. Dendritic cells are also efficient stimulators of B-cell lymphocytes.
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 appropriate function. 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. 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 (ie, second signal) is between CD80(B7.1)/CD86(B7.2) on the dendritic cell, with CD28 on the T cells.[11, 12, 13] 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. In perforin-deficient mice, abnormally heightened cytokine production by T cells is due to overstimulation by APCs after a viral infection.
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.[11, 12]
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.[15, 16] Monocyte-conditioned media contain critical maturation factors to catalyze 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.[17, 18, 19, 20] 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[22, 23, 24] and can stimulate maturation of dendritic cells, whereas IL-10 opposes it.
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.
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. CD95 (Fas) is suggested to have a role in the death of the dendritic cell.[27, 28] Although dendritic cells express CD95, CD95 ligation does not induce apoptosis.
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. 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 has been reported and disputed. Mature dendritic cells are 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. Overexpression of C-FLIP inhibits signals of death receptor. 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. 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.
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.[34, 35] 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 this protein. The information gained from normal physiology of dendritic cells may potentially lead to treatment modalities for histiocytic disorders.
The incidence of Langerhans cell histiocytosis is 4-5.4 per million population. However, because many bone and skin lesions may not be diagnosed as Langerhans cell histiocytosis, this rate may be an underestimate. The estimated incidence of neonatal Langerhans cell histiocytosis, determined by using the population-based German Childhood Cancer Registry, is 1-2 per million neonates.
The overall male-to-female ratio is 1.5:1. The male-to-female ratio in individuals who have a single organ system involvement is 1.3:1, and the male-to-female ratio in individuals with multisystem disease 1.9:1.
The disease can occur in individuals of any age. Langerhans cell histiocytosis can be congenital[39, 40] or may occur in adults. The disease is seen in all age groups, ranging from neonates to adults.[42, 43, 44, 37] 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 (0.1-15.1 y) than those with multisystem involvement (0.09-14.8 y).
Langerhans cell histiocytosis (LCH) can be local and asymptomatic, as in isolated bone lesions, or can involve multiple organs and systems, with clinically significant symptoms and consequences. The clinical manifestations depend on the site of the lesions and on the organs and systems involved and their functions (see Physical).
Classification of diseases involving histiocytic and dendritic cells is difficult, and classification systems must include a broad range of diseases. Therefore, most systems have been incomplete and arbitrary. The location of lesions and the extent of the disease substantially affect the course of the disease and the patient's prognosis. Decisions regarding treatment are based on the extent of the disease.
Classification of the World Health Organization
Table 1 shows the classification of histiocytic and dendritic cell disorders the World Health Organization (WHO) proposed.
Table 1. Classification of Histiocytosis Syndromes in Children
The WHO classification of neoplastic disorders of histiocytes and dendritic cells is as follows:
Macrophage or histiocyte related
Histiocytic sarcoma, mainly localized
Generalized malignant histiocytosis (may be related to acute monocytic leukemia)
2A - Localized or generalized Langerhans cell histiocytosis
2B - Langerhans cell sarcoma
2C - Interdigitating dendritic cell sarcoma
2D - Follicular dendritic cell sarcoma or tumor
Classification of the Histiocyte Society
Table 2 shows the working classification of histiocytosis syndromes from the Histiocyte Society.
Table 2. Histiocyte Society Classification of Histiocytosis Syndromes
The following, adapted from the Writing Group of the Histiocyte Society, describes confidence levels for the diagnosis of class I Langerhans cell histiocytosis:
Designated diagnosis - Light morphologic features plus 2 or more supplemental positive stains for the following:
Definitive diagnosis - Light morphologic characteristics plus Birbeck granules in the lesional cell on electron microscopy and/or positive staining for CD1a antigen (T6) on the lesional cell
Previous and other classifications
Langerhans cell histiocytosis formerly was divided into 3 disease categories: eosinophilic granuloma, Hand-Schüller-Christian disease, and 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, 14]
Some classifications simply divide histiocytic disorders into class I Langerhans cell disease, class II nonLangerhans 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, can provide a means to compare patient data and prognoses. Various categories, such as restricted and extensive multiorgan involvement, have also been proposed. Data regarding treatment results are needed to validate any classification system.
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. At-risk organs and systems identified in those trials included the liver, lung, spleen, and hematopoietic system. This risk classification is used in the treatment protocol of the third international study for Langerhans cell histiocytosis (Langerhans cell histiocytosis III).
Patients are stratified into 3 groups: (1) at-risk patients, or those with multisystemic involvement including 1 or more at-risk organs; (2) low-risk patients, or those with multisystem involvement not including at-risk organs; and (3) other patients, or 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) that can lead to persistent soft-tissue swelling.
In the trial, at-risk patients are 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.
Although this article focuses mainly on Langerhans cell histiocytosis, other histiocytoses are as follows:
Multiple yellow-to-pink cutaneous nodules, which usually appear in the head and neck region, clinically characterize JXG. The nodules are often 0.5-1 cm in diameter, but a macronodular variant with lesions that measure several centimeters can also be seen. Lesions have been observed in the deep soft tissues or organs.[50, 51] The condition usually presents at birth but can be observed during infancy. Similar lesions may be seen in 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 lesion. 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.
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.
Also called Rosai-Dorfman disease, this is persistent, massive enlargement of the nodes with an inflammatory process. The disease is rarely familial.
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.
The male-to-female ratio is 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.[53, 55, 16]
Immunologic abnormalities can be observed. Leukocytosis; mild normochromic, normocytic, or microcytic anemia; increased Ig levels; abnormal rheumatoid factor; and positive results for lupus erythematosus are also reported.
The disease is benign and has a high rate of spontaneous remission, but persistent cases requiring therapy have occurred.[56, 53, 57] In exceptional cases with obstructive complications, surgery, radiation therapy, and chemotherapy have been used to treat the disease.
HLH reactive hemophagocytic syndrome
This is a reversible proliferation of histiocytes in response to viral, bacterial, fungal, and parasitic infections, as well as to various cancers. This syndrome is most prevalent in individuals of Asian descent. The disease may be a manifestation of impaired immune response to an infection or to secondary immunodeficiency, with many of the patients having defects in cellular cytotoxicity and immune deficiencies.
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 may be a 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.
HLH malignant T-cell lymphoma with erythrophagocytosis: Instances of a combination of T-cell lymphoma with benign infiltration of histiocyte-simulating histiocytosis are reported.[59, 60, 61] 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. Occurrence of Langerhans cell histiocytosis with various leukemias and solid tumors has been reported.
Familial HLH (FHLH)
This is a rare disorder with multiorgan involvement that manifests as fever and enlargement of the liver (93%) and spleen (94%), rash (30%), and CNS disease (30%).
Laboratory findings include thrombocytopenia (98%), increased serum ferritin (93%), anemia (89%), hypofibrinogenemia (76%), neutropenia (75%), and CSF pleocytosis (52%).
Immune dysregulation is one of the hallmarks of the disease, characterized by reduced or absent activity of the natural killer cells (NK cells) in most cases.
Various mutations, deletions, or insertions that cause frameshift or missense mutation in perforin genes (PRF1 and PRF2), 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 MUNC13-4, 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 FHLH cases (FHL3). The mutations can be scattered over different exons but, in most cases, fall within the protein functional domain.
A male predominance has been reported.[67, 68]
In approximately 50-75% of patients, the disease is hereditary, with an autosomal recessive trait pattern. Parental consanguinity is common.
The disease is fatal if untreated.
Allogeneic bone marrow transplantation is the treatment of choice. However, the HLH-94 international protocol of VP16, steroids, and cyclosporine has 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.
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.
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. 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. This mutation is seen in approximately 21% of cases. Further genetic mutations are under investigation.
Griscelli syndrome type II generally has the same symptoms as HLH because of associated immunodeficiency.
Hepatosplenic T-cell lymphoma: Malignant T cells that express T-cell receptor gamma/delta have been found in adult and (rare) pediatric patients with fever and hepatosplenomegaly. The red pulp of spleen and sinusoids of the liver contain large lymphoid cells with erythrophagocytosis.[75, 76, 77, 78]
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.
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.
Almost 70% of all patients with HLH have CNS abnormalities that can be seen using CT scanning or MRI. These findings are often nonspecific.
Using flow cytometry, CD107a expression can be diagnostic for MUNC 13-4 defect and can potentially discriminate between genetic subtypes of FHLH.
Dendritic lymphadenitis: This 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.
Follicular lymphadenitis: Interdigitating dendritic cell sarcoma, indeterminate cell neoplasm, and fibroblastic reticular cell neoplasm are rare and nearly always affect adults.
Congenital solitary histiocytoma: This is a variant of self-healing solitary lesion of Hashimoto-Pritzker histiocytosis. This rare entity is seen in otherwise normal infants in 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. Other organs and systems are not affected. The lesion is self-healing, apparently with no incidence of recurrence. Regular follow-up physical examination has been recommended.
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.
Bone involvement is observed in 78% of patients with Langerhans cell histiocytosis and often includes the skull (49%), innominate bone (23%), femur (17%), orbit (11%), and/or ribs (8%). Lesions of other bones are less common. See the image below.
Clinically detectable skull lesions in a child with advanced Langerhans cell histiocytosis (LCH).
Upon clinical evaluation, the lesions can be singular or multiple. Asymptomatic or painful involvement of vertebrae can occur and can result in collapse.
Long-bone involvement can induce fractures. The lesions sometime cause a clinically significant periosteal reaction. Extension to the adjacent tissues can produce symptoms that may be unrelated to the bone involvement. Likewise, extraosteal involvement can occur in virtually any anatomic location, causing severe symptoms.
In patients with advanced Langerhans cell histiocytosis, lesions may be clinically detectable in the skull (see Imaging Studies and the image above).
Ocular and periorbital involvement have been reported. Manifestation of the disease often includes periorbital edema. Imaging studies may reveal destructive osteolytic lesions. The disease is usually unilateral, but bilateral involvement can occur. Biopsy is needed for confirmation. Treatment often includes partial resection and chemotherapy.
Purulent otitis media may occur and may be difficult to distinguish from infectious etiologies. Long-term sequelae, including deafness, are reported. Orbital involvement may cause proptosis. Involvement of the eyes in the form of uveitis and iris nodules are reported.
Diabetes insipidus and delayed puberty are observed in as many as 50% of patients (usual range is 15-25%).[84, 85, 86, 87, 88] Hypothalamic disease may also result in growth-hormone deficiency and short stature.[87, 89]
Maxillary, mandibular, and gingival disease may cause loss of teeth, hemorrhagic gum, and mucosal ulceration and bleeding. Erosion of the gingiva (see the image below) may give the appearance of premature eruption of the teeth in young children.[91, 90]
Erosion of the gingiva that creates the appearance of premature eruption of the teeth in a young child.
Cutaneous Langerhans cell histiocytosis is observed in as many as 50% of patients with Langerhans cell histiocytosis.[92, 93, 94, 95] Rash is a common presentation, and skin lesions may be the only evidence of the disease or may be part of systemic involvement (see the image below). Skin infiltrates have a predilection for the midline of the trunk and the peripheral and flexural areas of skin. Skin infiltrates can be maculoerythematous, petechial xanthomatous, nodular papular, or nodular in appearance. Bronzing of the skin can occur.
Cutaneous Langerhans cell histiocytosis (LCH) in a child. Skin infiltrates are seen on the face, and the chest has maculoerythematous, petechial, and ....
Scalp disease frequently presents as scaly, erythematous patches, which may become petechial and eroded with serous crust (see the image below). The lesions often are not pruritic, but tenderness and alopecia can occur. In infants, a nodular form of the disease marked by eruption of lesions that mimic varicella has been reported.[96, 97, 98] This variety of the disease may spontaneously remit; this feature led to the name self-healing Langerhans cell histiocytosis.
Severe scalp disease in a patient with scaly erythematous patches. Patches of alopecia are present. The lesions were not pruritic.
Pulmonary involvement is observed in 20-40% of patients and may result in respiratory symptoms, such as cough, tachypnea, dyspnea, and pneumothorax. A male predominance is observed. Pulmonary function test results may be abnormal.[99, 31] Diffuse cystic changes, nodular infiltrate, pleural effusion, and pneumothorax are known to occur. Imaging studies may reveal cysts and micronodular infiltrates. Pulmonary function tests may reveal restrictive lung disease with decreased pulmonary volume.[99, 31]
GI bleeding may be the presenting sign of patients with GI involvement. Appropriate imaging studies, endoscopy, and biopsy may be helpful to confirm the diagnosis. Liver involvement is characterized by elevated transaminase levels and, less commonly, increased bilirubin levels. Marrow involvement or enlargement of the spleen may cause hematologic changes.
Lymph node enlargement is observed in approximately 30% of patients. In rare cases, the nodes are symptomatic. If the volume is massive, it may obstruct or damage the surrounding organs and tissues.[101, 102] Suppuration and chronic drainage may occur. Lymph node enlargement surrounding the respiratory tract may result in pulmonary-related symptoms, such as cough, dyspnea, or cyanosis. Involvement of the thymus is relatively uncommon but does occur.
Infiltration of various areas of the brain gives rise to corresponding signs and symptoms, including cerebellar dysfunction and loss of coordination. Disruption of hypothalamic and pituitary function is most common. This includes symptoms secondary to diabetes insipidus and, to a lesser extent, growth-hormone deficiency and hypopituitarism.[103, 89, 104] Other symptoms, such as seizures and those related to increased intracranial pressure, depend on the site and volume of the space-occupying lesion. Anemia, leukopenia, thrombocytopenia, and their related symptoms are uncommon.
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,[106, 107] including dysfunction of lymphocytes and cytokines;[108, 109, 110] neoplastic mechanisms; genetic factors;[111, 5, 112, 113, 114, 115, 116, 117] cellular adhesion molecules;[118, 119, 120] and their combinations. Although human herpes virus 6 has been found in lesions of Langerhans cell histiocytosis, its etiologic significance has been questioned.[118, 121, 122] Extensive searches for evidence of viral infection have been unrevealing.
One report from Sweden suggests an increased rate of diagnosed histiocytosis in children conceived using in vitro fertilization. In FLH, distinct genetic mutations have been clearly demonstrated (see Other histiocytoses).
Cytokines play an important role in the physiology and biology of dendritic cells and macrophages. LCH lesions contain various cytokines.[108, 109, 110] 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.[109, 110]
Expression of abnormal leukocyte cellular adhesion molecules in Langerhans cell histiocytosis has been reported.[119, 120] These molecules mediate cell-to-cell and cell-to-matrix adhesion.
Using the X-linked human androgen receptor (humara) polymerase chain reaction (PCR)-based assay to assess clonality, researchers demonstrated that all forms of Langerhans cell histiocytosis are clonal; therefore, Langerhans cell histiocytosis 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. Using this standard, Langerhans cell histiocytosis is considered to be a neoplastic disease rather than a reactive disorder, as was previously proposed.
The role of genetics is not well defined. The occurrence of several cases in one family is rare but has been reported. Langerhans cell histiocytosis has been reported in several monozygotic and dizygotic twins.[115, 5, 116, 114, 117, 127, 113] Some consanguinity and involvement in close relatives (cousins) has been reported. Nevertheless, the relative rarity of the familial occurrence does not indicate a notable hereditary influence. Conversely, FHLH, 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.[109, 110] As expected, numerous familial cases of erythrophagocytic lymphohistiocytosis have been reported.
The fusion of nucleaphosmin (NPM) and anaplastic lymphoma kinase (ALK) genes that results in NPM-ALK fusion protein, which can be immunohistochemically demonstrated, is reported in malignant histiocytosis. Recently, 3 cases of histiocytosis in early infancy with enlarged liver and spleen, anemia, and thrombocytopenia are reported. In one case, analysis had revealed TPM-3-ALK fusion.
Spontaneous cytotoxicity of circulating lymphocytes is observed in patients with Langerhans cell histiocytosis. Antibody formation to autologous erythrocyte has also been reported. Given these findings, treatment with crude calf-thymus extract, although not substantially successful, was clinically devised and used.[129, 130]
A prominent feature of patients with HLH is deficiency in NK-cell function against MHC-negative K652 target cells. Patients with FHLH 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.
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.[131, 132, 133]
See Table 3-4 for appropriate imaging studies when Langerhans cell histiocytosis 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.
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.
Neurologic findings may not always be correlated with the MRI results and may lag behind findings on MRI.
CT and MRI can show the detailed anatomic pattern of involvement and can help in staging the disease.
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. However, this ability has not been definitively studied.
With pulmonary involvement, CT scanning is the best modality to reveal cysts and micronodular infiltrates.
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. 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.
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.
Table 5. Cell Markers and Phenotypes of Histiocytic and Related Disorders
Table 6 shows specialized stains for diagnosing these disorders, and Table 7 shows labeling pattern of histiocytes and dendritic cells.
Table 6. Stains for Diagnosing Histiocytosis
Table 7. Labeling Pattern of Histiocytes and Dendritic Cells
Langerhans cells express CD1a antigen, HLA-DR, and a subunit S-100 protein. See the image below.
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.[148, 149, 150]
The histopathology of the Langerhans cell histiocytosis does not appear to be prognostic of the outcome of the disease. 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.[4, 151]
In Langerhans cell histiocytosis, the cytoplasm and, rarely, the nucleus contain the characteristic structures termed Birbeck granules, shown below.
Transmission electron micrograph shows a diagnostic rod-shaped Langerhans Birbeck granule.
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. 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. Immunohistochemical determination of Langerin and CD1a may be used to separate Langerhans cell histiocytosis from other histiocyte proliferations.
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.[154, 155] 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. Enzyme histochemistry and immunocytochemistry can also aid in the diagnosis of histiocytosis.
The organs and tissues most commonly involved are the bones, skin, lymph nodes, bone marrow, lungs, hypothalamic-pituitary axis, spleen, liver, GI tract, and orbits. Multisystemic involvement is common. 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.[92, 93, 94, 95] 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.[96, 97, 98] 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.[101, 157]
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.[148, 149] 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. 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.[99, 31] Small cysts can coalesce and rupture into the pleural cavity, leading to pneumothorax.
CNS involvement, including pituitary involvement, is often part of systemic disease.[158, 159, 160] The CNS is rarely a primary site of Langerhans cell histiocytosis involvement.[161, 162, 163, 164, 165, 166, 167, 168] The most common site of CNS involvement in persons with Langerhans cell histiocytosis is the hypothalamic-pituitary axis, which results in diabetes insipidus in 10-50% of patients. Histiocytosis can be associated with cerebellar white matter abnormalities. Pathologic changes in the cerebellum, basal ganglia, and pons have been reported.
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. 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.[143, 166] MRI abnormalities in cerebellar white matter, brain stem, basal ganglia and cerebral white matter are found.
Involvement of the anterior pituitary is relatively uncommon. However, it can result in growth-hormone deficiency or, in rare cases, panhypopituitarism. Cerebellar dysfunction with incoordination and white matter changes has been reported. Langerhans cell histiocytosis may affect the spleen and liver. Primary involvement of the liver is uncommon.[170, 7] Involvement of the liver is often part of multiorgan disease. Even when PLCs are not present, sclerosing cholangitis can be observed. 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. Lesions in the stomach, small bowel, colon, and rectum have been reported.[172, 17, 171, 109, 110] 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.[173, 174]
Langerhans cell histiocytosis rarely involves the intraocular structures. Isolated eye disease has been reported. 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.[175, 176, 177]
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.
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, a lack of sufficient information has hampered specific therapy.
Substantial variation of the disease and the fact that 10-20% of patients achieve spontaneous regression complicate comparisons of current nonspecific therapies.[179, 180, 181] Several agents, including drugs for cancer chemotherapy, have been effective in the treatment.
Some suggest that treatment of Langerhans cell histiocytosis should be conservative and limited to individuals with constitutional symptoms, such as pain, fever, failure to thrive, and vital organ disorder. Treatment of these disorders must often be tailored to the patient’s prognostic factors, such as the patient’s age, extent of the disease, sites of involvement, and complications. For example, the general agreement is that simple biopsy and curettage are adequate treatment for a solitary bone lesion.[183, 184]
See the Medication section for a discussion of agents used in the treatment of Langerhans cell histiocytosis.
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.
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.[185, 186, 187] This agent, initially used systemically, appears to provide rapid response within 10 days 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. In one study, skin lesions promptly healed in 14 of 22 children, and 2 had partial responses. 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. 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, antithymocyte globulin, biologic-response modifiers such as interleukin (IL)-2 and interferons (INFs), cellular treatment, and exchange transfusion.[190, 191] Most reports of treatment modalities lack controls, with most authors citing the rarity of the disease as justification for the lack.[57, 192]
Purine analogs with activity for treatment of Langerhans cell histiocytosis (LCH) include 2-chlorodeoxyadenosine (2CdA; cladribine [Leustatin]) and 2-deoxycoformycin (2CDF; pentostatin [Nipent]);[193, 194, 12, 195, 196, 24, 197] 2CdA has been found to be particularly toxic to monocytes. Justification for the use of 2CdA is that some histiocytes are derived from monocytes. 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.
As a single agent, cyclosporine has been used in pretreated patients with advanced Langerhans cell histiocytosis. Cyclosporine, a cyclic endecapeptide 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.
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.
INF-alpha had some effect in anecdotal cases of Langerhans cell histiocytosis.[200, 189]
Treatment of multifocal relapsing and resistant bone lesions in Langerhans cell histiocytosis 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 very small group of patients.
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. 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. 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. 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). 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. Using the Histiocyte Society’s Langerhans cell histiocytosis I protocol, investigators prospectively and randomly assigned patients with multisystemic Langerhans cell histiocytosis who met criteria based on standard diagnostic evaluation. 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 of the Histiocyte Society study is designed to determine if methotrexate administered during the initial 2 courses of treatment affects outcomes. In addition, investigators will determine whether maintenance therapy reduces the risk of recurrent disease and improves overall outcomes.
Radiation therapy is effective in Langerhans cell histiocytosis. 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.
Treatment for recurrent or refractory disease
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. 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.
Several studies, including an international phase II trial, demonstrated notable activity of 2CdA. This agent was originally used to treat patients with refractory hairy-cell leukemia and chronic lymphocytic leukemia. Response rates were more than 50%. 2CdA is both lympholytic and monolytic, making it 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.[205, 206]
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. In some studies, only patients with low-risk disease were likely to respond to thalidomide, whereas high-risk patients with organ involvement were not.[208, 121] . Further recognition of NF-kappaB pathway may improve the success of targeted therapy for Langerhans cell histiocytosis.[134, 135]
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.
Specific therapies, including monoclonal antibodies against the CD1a or CD52 epitopes found on Langerhans cells, are emerging.[146, 209]
Local therapy with various agents has been reported. Intralesional infiltration of corticosteroids for treatment of localized Langerhans cell histiocytosis has been advocated.
Myeloablative therapy followed by bone-marrow or stem-cell transplantation in disease refractory to the conventional therapy has been reported. However, reporting of positive results are likely to bias such reports.
Intravenous immunoglobulin has been used to treat neurodegenerative Langerhans cell histiocytosis. However, to the authors’ knowledge, no formal study has been done to conclusively affirm the benefit of such a treatment.
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.
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.
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.
Some estimate that more than one half of patients have at least 1 clinically significant late effect. Therefore, long-term follow-up is of utmost importance.
In a study of a subset of 40 patients followed up for a median of 16 years, 51% had pronounced late sequelae. Those with multisystemic involvement had the greatest risk of late effects. They had 19% rate of CNS sequelae.
Some of the most important late effects involve the CNS and include diabetes insipidus and other deficiencies of hypothalamic-pituitary axis. These effects lead to stunted growth and failure to achieve sexual maturity.
Other late effects include orthopedic problems (particularly of the vertebral column), dental issues surrounding the loss of teeth and jawbone mass, hearing loss due to mastoid and inner-ear involvement (for which patients require cochlear implantation), and scarring of involved areas of skin.
In patients who develop pulmonary or hepatic fibrosis, progression of disease may result in a need for organ transplantation.
Patients with Langerhans cell histiocytosis may have a lifelong susceptibility to pulmonary disease associated with cigarette smoking.
Pulmonary involvement of the young child may be extensive and characterized by micronodular involvement and cystic formation. However, adequate treatment can resolve the disease and normalize lung findings and function.
Neurocognitive and psychological problems are more frequently recognized likely because of intensified patient follow-up.
Patients with neurodegenerative CNS involvement often present with ataxia and decreased coordination.
Pathologic examination of biopsy material usually reveals gliosis, some neuronal cell death, and, sometimes, areas of active Langerhans cell histiocytosis. Although the condition of neurodegenerative involvement of the CNS can remain stable for years, clinical progression may occur in the absence of MRI findings. No definitive treatment has been developed for this manifestation of Langerhans cell histiocytosis. Radiation therapy does not appear to provide any benefits.
Neuropsychological sequelae of Langerhans cell histiocytosis can be substantial. In one study of 10 children with Langerhans cell histiocytosis (aged 5-17 y), 3 scored one standard deviation or more below the reference range on perceptual tasks, and 4 of 10 children had deficiency in performance on perceptual tasks. Decreases in attention, speed of performance, verbal working memory, and visual recall were noted.
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.
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. 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.
Cameron K Tebbi, MD, Professor of Pediatrics, Chief, Division of Pediatric Hematology-Oncology, University of South Florida College of Medicine; Director, Children's Medical Services, Pediatric Hematology/Oncology, Tampa Division, State of Florida Department of Health
Disclosure: Nothing to disclose.
Robert J Arceci, MD, PhD, Director, Children's Center for Cancer and Blood Disorders, Department of Hematology/Oncology, Co-Director of the Ron Matricaria Institute of Molecular Medicine, Phoenix Children's Hospital; Editor-in-Chief, Pediatric Blood and Cancer; Professor, Department of Child Health, University of Arizona College of Medicine
Disclosure: Nothing to disclose.
Gary R Jones, MD, Associate Medical Director, Clinical Development, Berlex Laboratories
Disclosure: Nothing to disclose.
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.
Helen SI Chan, MBBS, FRCP(C), FAAP, Associate Senior Scientist, Research Institute; Professor, Division of Hematology/Oncology, Department of Pediatrics, The Hospital for Sick Children, University of Toronto Faculty of Medicine, Canada
Disclosure: Nothing to disclose.
Max J Coppes, MD, PhD, MBA, President, BC Cancer Agency, Vancouver
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
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