Histiocytosis Clinical Presentation

  • Author: Cameron K Tebbi, MD; Chief Editor: Max J Coppes, MD, PhD, MBA   more...
 
Updated: Apr 3, 2012
 

History

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.[46] The clinical manifestations depend on the site of the lesions and on the organs and systems involved and their functions (see Physical).

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Classification

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.[47]

Table 1. Classification of Histiocytosis Syndromes in Children (Open Table in a new window)

Class Syndromes
I
  • Langerhans cell histiocytosis
II
  • Histiocytosis of mononuclear phagocytes other than Langerhans cells
  • Familial and reactive hemophagocytic lymphohistiocytosis (HLH)
  • Sinus histiocytosis with massive lymphadenopathy (SHML), Rosai-Dorfman disease
  • Juvenile xanthogranuloma (JXG)
  • Reticulohistiocytoma
III
  • Malignant histiocytic disorders
  • Acute monocytic leukemia (FAB M5)
  • Malignant histiocytosis
  • True histiocytic lymphoma

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)
  • Dendritic-cell related
    • 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 (Open Table in a new window)

Class Syndromes
Dendritic-cell related
  • Langerhans cell histiocytosis
  • Xanthogranuloma
Macrophage related
  • HLH, genetic or sporadic
  • SHML
Malignant disorders
  • Monocyte related, monocytic leukemia
  • Dendritic-cell related
  • Localized or macrophage related
  • Disseminated (malignant histiocytosis)

The following, adapted from the Writing Group of the Histiocyte Society, describes confidence levels for the diagnosis of class I Langerhans cell histiocytosis:[3]

  • Presumptive diagnosis - Light morphologic characteristics
  • Designated diagnosis - Light morphologic features plus 2 or more supplemental positive stains for the following:
    • Adenosinetriphosphatase
    • S-100 protein
    • Alpha-D-mannosidase
    • Peanut lectin
  • 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,[48] 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.[49] 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.

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Other Histiocytoses

Although this article focuses mainly on Langerhans cell histiocytosis, other histiocytoses are as follows:

  • Dendritic-cell disorders
    • 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.
  • 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.
    • SHML
      • Also called Rosai-Dorfman disease,[52] this is persistent, massive enlargement of the nodes with an inflammatory process. The disease is rarely familial.[53]
      • 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.[54]
      • 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.[56] 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.[53]
    • 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.[58] 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.[62] Occurrence of Langerhans cell histiocytosis with various leukemias and solid tumors has been reported.[63]
    • 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%).[64]
      • Laboratory findings include thrombocytopenia (98%), increased serum ferritin (93%), anemia (89%), hypofibrinogenemia (76%), neutropenia (75%), and CSF pleocytosis (52%).[64]
      • 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),[65] 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.[66]
      • 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.[69]
      • 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.[70]
      • 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.[71]
      • 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.[72] 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.[73] This mutation is seen in approximately 21% of cases.[74] 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.[79]
      • 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.[79]
      • Almost 70% of all patients with HLH have CNS abnormalities that can be seen using CT scanning or MRI. These findings are often nonspecific.[71]
      • Using flow cytometry, CD107a expression can be diagnostic for MUNC 13-4 defect and can potentially discriminate between genetic subtypes of FHLH.[80]
    • 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.[81]
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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.

  • 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 witClinically 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.[82]
    • 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.[40]
  • 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.[83]
  • 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.[90] 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 appearanceErosion 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 aCutaneous Langerhans cell histiocytosis (LCH) in a child. Skin infiltrates are seen on the face, and the chest has maculoerythematous, petechial, and xanthomatous appearance.
  • 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 erythSevere 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.[100] 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.[30]
  • Infiltration of various areas of the brain gives rise to corresponding signs and symptoms, including cerebellar dysfunction and loss of coordination.[103] 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.
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Causes

The causes of most histiocytoses are not known. Factors implicated in the etiology and pathophysiology of these disorders include infections, especially viral infections;[105] 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.[37]

  • One report from Sweden suggests an increased rate of diagnosed histiocytosis in children conceived using in vitro fertilization.[123] 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.[124] Using this standard, Langerhans cell histiocytosis is considered to be a neoplastic disease rather than a reactive disorder, as was previously proposed.[125]
  • The role of genetics is not well defined. The occurrence of several cases in one family is rare but has been reported.[126] 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.[127] 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.[35]
  • 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.[128]
  • Spontaneous cytotoxicity of circulating lymphocytes is observed in patients with Langerhans cell histiocytosis. Antibody formation to autologous erythrocyte has also been reported.[129] 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.[58]
  • 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]
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Contributor Information and Disclosures
Author

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

Cameron K Tebbi, MD is a member of the following medical societies: American Association for Cancer Research, American Society of Pediatric Hematology/Oncology, Children's Oncology Group, Histiocyte Society, and International Society of Paediatric Oncology

Disclosure: Nothing to disclose.

Coauthor(s)

Robert J Arceci, MD, PhD  King Fahd Professor of Pediatric Oncology, Professor of Pediatrics, Oncology and the Cellular and Molecular Medicine Graduate Program, Kimmel Comprehensive Cancer Center at Johns Hopkins University School of Medicine

Robert J Arceci, MD, PhD is a member of the following medical societies: American Association for Cancer Research, American Association for the Advancement of Science, American Pediatric Society, American Society of Hematology, and American Society of Pediatric Hematology/Oncology

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

Specialty Editor Board

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.

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

Gary D Crouch, MD is a member of the following medical societies: American Academy of Pediatrics and American Society of Hematology

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

Helen SI Chan, MBBS, FRCP(C), FAAP is a member of the following medical societies: American Academy of Pediatrics, American Association for Cancer Research, American Society of Hematology, and Royal College of Physicians and Surgeons of Canada

Disclosure: Nothing to disclose.

Chief Editor

Max J Coppes, MD, PhD, MBA  Senior Vice President, Center for Cancer and Blood Disorders, Children's National Medical Center; Professor of Medicine, Oncology, and Pediatrics, Georgetown University School of Medicine; Clinical Professor of Pediatrics, George Washington University School of Medicine and Health Sciences

Max J Coppes, MD, PhD, MBA is a member of the following medical societies: American Association for Cancer Research, American Society of Pediatric Hematology/Oncology, and Society for Pediatric Research

Disclosure: Nothing to disclose.

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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.
Table 1. Classification of Histiocytosis Syndromes in Children
Class Syndromes
I
  • Langerhans cell histiocytosis
II
  • Histiocytosis of mononuclear phagocytes other than Langerhans cells
  • Familial and reactive hemophagocytic lymphohistiocytosis (HLH)
  • Sinus histiocytosis with massive lymphadenopathy (SHML), Rosai-Dorfman disease
  • Juvenile xanthogranuloma (JXG)
  • Reticulohistiocytoma
III
  • Malignant histiocytic disorders
  • Acute monocytic leukemia (FAB M5)
  • Malignant histiocytosis
  • True histiocytic lymphoma
Table 2. Histiocyte Society Classification of Histiocytosis Syndromes
Class Syndromes
Dendritic-cell related
  • Langerhans cell histiocytosis
  • Xanthogranuloma
Macrophage related
  • HLH, genetic or sporadic
  • SHML
Malignant disorders
  • Monocyte related, monocytic leukemia
  • Dendritic-cell related
  • Localized or macrophage related
  • Disseminated (malignant histiocytosis)
Table 3. Laboratory and Imaging Studies in Patients With Langerhans Cell Histiocytosis (LCH)*
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.
Table 4. Indication for Laboratory Evaluations Based on Findings in Langerhans cell histiocytosis
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
Endocrine investigationGrowth failure, diabetes insipidus, hypothalamic syndromes, galactorrhea, precocious or delayed puberty; hypothalamic and/or pituitary abnormality on CT or MRI None
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.



Table 5. Cell Markers and Phenotypes of Histiocytic and Related Disorders
Cell MarkerLCHSHMLFollicular Dendritic TumorHistiocytic SarcomaAcute Monocytic LeukemiaAnaplastic Large-Cell Lymphoma
CD1a+-----
CD4++-+++
CD21-+/-+---
CD25-+-++++
CD30-----++
CD35-++---
CD45-+-+/-++/-
CD68-+-+++/-
ALK-1-----+
S-100++-+/1--
Lysozyme-+-++-
Table 6. Stains for Diagnosing Histiocytosis
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.Table 7. Labeling Pattern of Histiocytes and Dendritic Cells
Table 7. Labeling Pattern of Histiocytes and Dendritic Cells
MarkerHistiocytesLangerhans CellsInterdigitating CellsFollicular 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.
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