Histiocytosis Clinical Presentation

Updated: Nov 08, 2018
  • Author: Cameron K Tebbi, MD; Chief Editor: Vikramjit S Kanwar, MBBS, MBA, MRCP(UK), FAAP  more...
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Presentation

History

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

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Classification

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

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

L (Langerhans) group diseases

Members of the L group include the following:

  • Langerhans cell histiocytosis
  • Indeterminate cell histiocytosis (ICH) - Including polyostotic sclerosing histiocytosis (Erdheim-Chester disease [ECD]) and mixed Langerhans cell histiocytosis/ECD

Langerhans cell histiocytosis

Subtypes of Langerhans cell histiocytosis include the following:

  • Single system
  • Lung
  • Multiple system - No risk organs involved
  • Multiple system - Risk organs involved
  • Associated or not associated with another myeloproliferative or myelodysplastic disorder

ECD

Subtypes of ECD include the following:

  • Classical type
  • Without bone involvement
  • Associated with another myeloproliferative/myelodysplastic disorder
  • Extracutaneous or disseminated juvenile xanthogranuloma with mutation in mitogen-activated protein kinase (MAPK) pathway or anaplastic lymphoma kinase (ALK) translocation

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

​Members of the C group include the following:

  • Cutaneous non–Langerhans cell histiocytosis 
  • Cutaneous non–Langerhans cell histiocytosis with a major systemic component 

Cutaneous non–Langerhans cell histiocytosis 

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

  • Xanthogranuloma family - Juvenile xanthogranuloma, adult xanthogranuloma, solitary reticulohistiocytoma, benign cephalic histiocytosis, progressive nodular histiocytosis
  • Non-xanthogranuloma family - Cutaneous Rosai-Dorfman disease, necrobiotic xanthogranuloma, cutaneous histiocytoses not otherwise specified

Cutaneous non–Langerhans cell histiocytosis with a major systemic component 

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

  • Xanthogranuloma family - Xanthoma disseminatum
  • Non-xanthogranuloma family - Multicentric reticulohistiocytosis                 ​

​M Group (malignant histiocytosis)

The M group includes primary and secondary malignant histiocytosis.

Primary malignant histiocytosis

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

Secondary malignant histiocytosis

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

  • Follicular lymphoma
  • Lymphocytic leukemia/lymphoma
  • Hairy cell leukemia
  • Acute lymphoblastic leukemia
  • Histiocytosis (Langerhans cell histiocytosis, Rosai-Dorfman disease, others)
  • Other hematologic neoplasias

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

R group histiocytosis includes the following:

  • Familial Rosai-Dorfman disease
  • Classical (nodal) Rosai-Dorfman disease
  • Extranodal Rosai-Dorfman disease
  • Neoplasia-associated Rosai-Dorfman disease
  • Immune disease–associated Rosai-Dorfman disease
  • Other non-C, non-L, non-M, non-H histiocytoses

Familial Rosai-Dorfman disease

Familial Rosai-Dorfman disease includes the following:

  • Faisalabad (or H) syndrome (OMIM #602782)
  • Fas protein deficiency or autoimmune lymphoproliferative syndrome (ALPS)–related Rosai-Dorfman disease (OMIM #601859)
  • Familial Rosai-Dorfman disease not otherwise specified  

Classical (nodal) Rosai-Dorfman disease 

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

  • Without immunoglobulin G4 (IgG4) syndrome
  • IgG4 associated

Extranodal Rosai-Dorfman disease

Extranodal Rosai-Dorfman disease includes the following:

  • Bone Rosai-Dorfman disease
  • CNS with and without IgG4 syndrome association
  • Single-organ Rosai-Dorfman disease (other than lymph node, skin, and CNS) without IgG4 syndrome
  • Single-organ Rosai-Dorfman disease (other than lymph node, skin, and CNS) with IgG4 association
  • Disseminated Rosai-Dorfman disease

Neoplasia-associated Rosai-Dorfman disease

Neoplasia-associated Rosai-Dorfman disease includes the following:

  • Rosai-Dorfman disease postleukemia
  • Rosai-Dorfman disease postlymphoma
  • Rosai-Dorfman disease associated with malignant histiocytosis
  • Rosai-Dorfman disease associated with Langerhans cell histiocytosis or ECD

Immune disease–associated Rosai-Dorfman disease

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

  • Systemic lupus erythematosus related
  • Idiopathic juvenile arthritis related
  • Autoimmune hemolytic anemia associated
  • Human immunodeficiency virus associated

H Group (hemophagocytic lymphohistiocytosis)

The H group includes the following:

  • Primary hemophagocytic lymphohistiocytosis (HLH) - Mendelian-inherited condition
  • Secondary HLH - HLH that is apparently non-Mendelian

Primary HLH

This includes the following:

  • HLH associated with lymphocyte cytotoxic defects - Familial hemophagocytic lymphohistiocytosis type 2 (FHL2 [ PRF1]), FHL3 ( UNC13D), FHL4 ( STX11), FHL5 ( STXBP2), X-linked lymphoproliferative disease type 1 (XLP1 [ SH2D1A]),  Griscelli syndrome type 2 ( RAB27A),  Chediak-Higashi syndrome ( LYST)​
  • HLH associated with abnormalities of inflammasome activation - XLP2 ( BIRC4), NLRC4
  • HLH associated with defined Mendelian disorders affecting inflammation - Lysinuric protein intolerance ( SLC7A7), HMOX1, other defined Mendelian disorders affecting inflammation
  • Familial (apparently Mendelian) hemophagocytic lymphohistiocytosis of unknown origin

Secondary HLH - infection associated

Infection-associated secondary HLH includes the following:

  • Viral - Epstein-Barr virus, cytomegalovirus, herpes, human immunodeficiency virus, influenza
  • Bacterial
  • Fungal
  • Parasitic agents

Secondary HLH - malignancy associated

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

  • Hematologic malignancies - T-cell lymphoblastic leukemia/lymphoma, T-cell non-lymphoblastic lymphomas, B-cell leukemias, B-cell lymphomas (non-Hodgkin), Hodgkin lymphomas, NK-cell lymphomas/leukemias, myeloid neoplasia, other hematologic malignancies
  • Solid tumors 
  • Unclassified malignancies

Other malignancy-associated forms of HLH include the following:

  • HLH occurring during chemotherapy - Unassociated with the initial malignancy diagnosis
  • HLH associated with a malignancy but not further defined

Secondary HLH associated with rheumatologic conditions

This includes HLH associated with the following:

  • Systemic onset juvenile idiopathic arthritis
  • Adult-onset Still disease
  • Systemic lupus erythematosus
  • Vasculitis
  • Additional defined or undefined autoimmune conditions

Secondary HLH - other types

  • Transplant-related HLH
  • HLH associated with iatrogenic immune activation 
  • HLH associated with iatrogenic immune suppression
  • HLH associated with other apparently non-Mendelian conditions
  • HLH of unknown/uncertain origin

Classification of the World Health Organization

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

  • Class I - Langerhans cell histiocytosis

  • Class 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

  • Class 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 

Prior classification by the Histiocyte Society

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

  • Dendritic-cell related

    • Langerhans cell histiocytosis

    • Xanthogranuloma

    • Erdheim-Chester disease

  • 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: [5]

  • 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

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

Other classifications

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

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

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

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Other Histiocytoses

Dendritic-cell disorders

Juvenile xanthogranuloma 

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

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

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

Histiocytic disorders

Sinus hyperplasia

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

Sinus histiocytosis with massive lymphadenopathy (SHML)

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

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

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

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

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

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

Primary hemophagocytic lymphohistiocytosis (HLH)

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

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

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

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

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

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

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

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

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

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

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

Griscelli syndrome type II

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

HLH reactive hemophagocytic syndrome

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

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

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

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

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

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

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

Histiocytic necrotizing lymphadenitis

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

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

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

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

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

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

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

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

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

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

     

    See the list below:

    • 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. [105]

    • 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. [106] 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. [107]

  • 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. [108]

  • Diabetes insipidus and delayed puberty are observed in as many as 50% of patients (usual range is 15-25%). [109, 110, 111, 112, 113] Hypothalamic disease may also result in growth-hormone deficiency and short stature. [112, 114]

  • Maxillary, mandibular, and gingival disease may cause loss of teeth, hemorrhagic gum, and mucosal ulceration and bleeding. [115] Erosion of the gingiva (see the image below) may give the appearance of premature eruption of the teeth in young children. [115, 116]

    Erosion of the gingiva that creates the appearance 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. [117, 118, 119, 120] 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). [121] 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.

  • 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. [118, 119, 122] This variety of the disease may spontaneously remit; this feature led to the name self-healing Langerhans cell histiocytosis.

  • 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. [123, 124] Diffuse cystic changes, nodular infiltrate, pleural effusion, and pneumothorax are known to occur. [125] Imaging studies may reveal cysts and micronodular infiltrates. Pulmonary function tests may reveal restrictive lung disease with decreased pulmonary volume. [123, 124]

  • 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. [126, 127] 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. [128]

  • Infiltration of various areas of the brain gives rise to corresponding signs and symptoms, including cerebellar dysfunction and loss of coordination. [129] 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. [114, 129, 130] 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.

  • CNS disease with CSF involvement especially in craniopharyngeal cases is known to occur. [131]

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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; cellular and immune dysfunction, including dysfunction of lymphocytes and cytokines; neoplastic mechanisms; genetic factors; and cellular adhesion molecules. [10, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146]

Hemophagocytic lymphohistiocytosis (HLH)

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

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

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

Genetic defect/syndrome

Genetic Defect

Protein

Frequency % FHL cases (location)

Mutation Type

Function

FHL1

Unknown (9 gr 21.3-22)

Rare

Pakistan

FHL2

PRF

(10 gr 21-22)

Perforin

20-40%

Often in blacks, Turks, Japanese

>50 deletions, non-sense and missense mutations; heterozygosity for C272T, A91V substitution

Pore-forming protein

FHL3

UNC13D

(17 gr 25)

Munc 13-4

20-30%

Worldwide, Turks, Kurds, US, Europe

>18 deep intronic mutations and large inversion

Vesicle forming

FHL4

STX11

(6 gr 24)

Syntaxin-11

10-20%

Worldwide, Central Europe, Turkey, Saudi Arabia

Variable

Vesicle transport and fusion

FHL5

STXBP2

(19p)

Munc 18-2

5-20%

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

Multiple mutations in the syntaxin binding protein Munc 18-2. Impaired binding to syntaxin-11

Vesicle transport and fusion SNARE complex assembly and disassembly

Immune deficiency and albinism

Chédiak-Higashi syndrome

LYST

LYST

Rare

Worldwide

Size function of lytic granules

Griscelli syndrome type II

RAB27A

Rab 27A

Rare

Northern Europe

Vesicle docking, granule movement

Hermansky-Pudlak syndrome Type II

AP3B1

Rare

Worldwide

Vesicle biogenesis, protein sorting

Primary Immune Deficiencies

X-linked lymphoproliferative disease Type I

SH2D1A

SAP

Worldwide

Signal transduction, activation of lymphocytes

X-linked lymphoproliferative disease Type II

BIRC4

XIAP

Worldwide

Inhibition of apoptosis

ITK deficiency

ITK

ITK

Worldwide

T-cell kinase

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

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

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

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

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

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

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

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

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

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

  • Infections (viral, bacterial, parasitic and fungal)

    • Epstein-Barr virus

    • Cytomegalovirus

    • Human herpes virus 8 (HHV8)

    • HIV

    • Mycoplasma mycobacteria

    • Leishmania

    • Plasmodium candida

    • Cryptococcus

    • Kala Azar

  • Immunosuppression - After organ transplantation

    • Cancer

    • T-cell lymphoma

    • Leukemias

  • Metabolic disorders

    • Lysinuric protein intolerance

    • Multiple sulfatase deficiency

    • Wolman disease

  • Autoimmune disorders - Systemic lupus erythematosus

  • Macrophage activation syndrome - Still disease

Polyostotic sclerosing histiocytosis (Erdheim-Chester disease or syndrome)

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

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

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

Langerhans Cell histiocytosis (LCH)

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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