Histiocytosis Clinical Presentation

Updated: Feb 14, 2017
  • Author: Cameron K Tebbi, MD; Chief Editor: Vikramjit S Kanwar, MBBS, MBA, MRCP(UK), FAAP  more...
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Presentation

History

LCH can be localized and manifest as pain or may even be asymptomatic, as in isolated bone lesions. LCH can also involve multiple organs and systems, with clinically significant symptoms and consequences. [54] The clinical manifestations depend on the organs and systems involved as well as their level of involvement (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. 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).

Classification of the World Health Organization

The classification of histiocytic disorders the World Health Organization (WHO) has proposed is as follows: [55]

  • 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

Classification of the Histiocyte Society

The 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

Previous and 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, 56]

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, [57] can provide a means to compare patient data and prognoses. Various categories, such as limited and extensive multiorgan involvement, have also been proposed.

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 is used in the treatment protocol of the third international study for Langerhans cell histiocytosis (LCH III).

Patients are 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.

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Other Histiocytoses

Although this article focuses mainly on Langerhans cell histiocytosis, other histiocytoses include those listed below.

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. [59, 60, 61] 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. 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, [62, 63] this is a usually persistent, massive enlargement of the nodes by proliferation and accumulation of histiocytes that are characterized by emperipolesis. [64] The disease is rarely familial. [64, 65, 66, 67]

SHML is seen after bone marrow transplant for acute lymphoblastic leukemia, after or concurrent with diagnosis of lymphoma, herpes virus 6 (HHV6), and EBV infections. [65, 66, 67]

Although the disease is rarely familial, [64] 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. [68]

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. [62, 64, 69]

Immunologic abnormalities can be observed, [70] including leukocytosis; mild normochromic, normocytic, or microcytic anemia; increased Ig levels; abnormal rheumatoid factor; and positive results for lupus erythematosus are also reported.

Death from SHML is known to occur. [70]

The disease is pathologically benign and has a high rate of spontaneous remission, but persistent cases requiring therapy have occurred. [64, 70, 71] In exceptional cases with obstructive complications, surgery, radiation therapy, and chemotherapy have been used to treat the disease. [64]

Primary hemophagic lymphohistiocytosis (HLH)

Also known as familial erythrophagocytic lymphohistiocytosis (FHLH), this is a life-threatening disorder characterized by fever, enlargement of the liver (93%), spleen (94%), rash (30%), [72] and cytopenia. [73] The prevalence of FHLH is estimated to be in 0.12-1 in 100,000 live births, with equal male-to-female ratio. The disease is as a result of uncontrolled proliferation of activated lymphocytes and macrophages, as well as production of inflammatory cytokines.

This is a heterogenous autosomal recessive disorder, which is often seen in parental consanguinity. Five genetic subtypes (ie, FHL1, FHL2, FHL3, FHL 4, FHL 5) have been identified; molecular testing for FHL2 (PRF1), FHL3 (UNC13D), FHL4 (STX II), and FHL5 (STXBP2) are available.

The disease can manifest itself in utero, early in the neonatal period, during childhood, or, uncommonly, in adults. Manifestation of the disease includes neurological abnormalities, including irritability, stiffness of the neck, hypotoma or hypertoma, cranial nerve palsies, hemiaplasia, quadriplegia, loss of vision, ataxia, convulsions, and coma. Less common findings include rash and enlarged lymph nodes. Laboratory evaluation may disclose increased liver enzymes and finding hemophagocytosis in the bone marrow.

The disease is rapidly progressive and infections are common. Without appropriate treatment, the disease can be fatal. The median survival rate in untreated children is younger than 2 months.

Diagnosis of FHLH is based on the 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, generally, individuals with PRF1 mutations have an earlier onset of the disease than those with UNC13D mutation or patients for whom no mutations are identified. [74]

In general, those with missense mutations have later onset of their disease. [75] However, FHLH 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%). [72]

Enlargement of liver, spleen and lymph nodes occur occasionally and are accompanied by a rash. Neurological 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; [76] hypertriglyceridemia and hypofibrinogenemia is seen as well.

These 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 cells (NK cell) activity is more often seen in individuals with PRF1 mutation than those without.

Immune dysregulation is one of the hallmarks of the disease, characterized by 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), [77] 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. [78] A male predominance has been reported. [79, 80] In approximately 50-75% of patients, the disease is hereditary, with an autosomal recessive trait pattern. Parental consanguinity is common. [81] The disease 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 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. [82]

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. [83]

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. [74] 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. [84] This mutation is seen in approximately 21% of cases. [85] Further genetic mutations are under investigation.

Griscelli syndrome type II 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 to various cancers. This syndrome is most prevalent in individuals of Asian descent. [86] 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. [87]

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. [88, 89, 90] 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. [91] Occurrence of LCH with various leukemias and solid tumors has also been reported. [92]

Lymphoma-associated hemophagocytic syndrome (LAHS) is a major subtype of the adult onset secondary HLH. This disorder has 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 diagnosis of LAHS. [93]

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. [94, 95]

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. [96, 97, 98, 99]

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. [100]

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. [100]

Almost 70% of all patients with HLH have CNS abnormalities that can be seen using CT scanning or MRI. These findings are often nonspecific. [83]

Using flow cytometry, CD107a expression can be diagnostic for MUNC 13-4 defect and can potentially discriminate between genetic subtypes of FHLH. [101]

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. Regular follow-up physical examination has been recommended. [102]

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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. [103]
    • 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. [104] 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. [105]
  • 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. [106]
  • Diabetes insipidus and delayed puberty are observed in as many as 50% of patients (usual range is 15-25%). [107, 108, 109, 110, 111] Hypothalamic disease may also result in growth-hormone deficiency and short stature. [110, 112]
  • Maxillary, mandibular, and gingival disease may cause loss of teeth, hemorrhagic gum, and mucosal ulceration and bleeding. [113] Erosion of the gingiva (see the image below) may give the appearance of premature eruption of the teeth in young children. [113, 114]
    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. [115, 116, 117, 118] 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.
  • 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. [116, 117, 119] 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. [120, 121] Diffuse cystic changes, nodular infiltrate, pleural effusion, and pneumothorax are known to occur. [122] Imaging studies may reveal cysts and micronodular infiltrates. Pulmonary function tests may reveal restrictive lung disease with decreased pulmonary volume. [120, 121]
  • 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. [123, 124] 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. [125]
  • Infiltration of various areas of the brain gives rise to corresponding signs and symptoms, including cerebellar dysfunction and loss of coordination. [126] 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. [112, 126, 127] 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. [128]
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Causes

The etiology of histiocytosis disorders depends on the type of disease involved. [129] Because of the significant variation, the etiologies of HLH, ECD, and LCH are described separately.

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. Genetic form of HCH occurs in families (FHLH) 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). In most cases with acquired HLH, the immune system is normal and the disease is triggered by an infection, underlying malignancy, immune deficient disorder, or Kawasaki disease.

FHLH 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 FHLH [130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 54, 155, 156] (Open Table in a new window)

Genetic defect/syndrome Genetic Defect Protein Frequency % FHL cases (location) Mutation Type Function
FHLH1 Unknown (9 gr 21.3-22) Rare



Pakistan



FHLH2 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
FHLH3 UNC13D



(17 gr 25)



MUNC 13-4 20-30%



Worldwide, Turks, Kurds, US, Europe



>18 deep intronic mutations and large inversion Vesicle forming
FHLH4 STX 11



(6 gr 24)



Syntaxin-11 10-20%



Worldwide, Central Europe, Turkey, Saudi Arabia



Variable Vesicle transport and fusion
FHLH5 STXBP2



(19p)



MUNC 18-2 5-20%



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



Multiple motatronin 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 Rab 27A 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

 

FHLH 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. [150]

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. [143]

Mutations of MRNA splicing commonly are the underlying molecular defect in patients with FLH3. The MUNC13-4 protein primes the secondary mutation in this gene and can result in defective cellular cytotoxicity. In a study of 31 families with FHLH, 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. [157]

A genomic region (ie, 9gr21) has been linked to FHLH1; however, the gene responsible for the specific product or action remains unknown. [138]

In FHLH2, 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. [134]

In Turkish patients, the perforin mutation often is Trp 374X and results in an early onset of the disease. [149]

In Italian cases, A91V sequence variant is seen with onset of the disease later in life. IN FHLH3, the UNC13D gene is located on chromosome 17 (17gr25), which encodes for the production of MUNC13-4 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 FHLH2. MUNC13-4 protein, a member of the UNC13 family of intracellular protein, is essential for vesicle priming. In patients with FHLH3, MUNC13-4 mutation results in defects in the priming of the lytic granules containing perforin and granzymes A and B.

In FHLH4, 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-FHLH1 cases, it is more frequently found in Turkish patients (21%) and is not present in the Japanese cases. [158, 159]

In FHLH5, the STXBP2 gene is located on chromosome 19 (19p), which encodes for the protection of MUNC18-2 (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. [160, 161]

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. [162]

The most common causes of secondary HLH are as follows: [163, 164, 165, 166, 167, 168, 169]

  • 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

Erdheim-Chester disease (polyostotic sclerosing histiocytosis) is characterized by proliferation of histiocytes, infiltration of lipid-laden tissue macrophages and multinucleated giant cells. It predominantly affects middle-aged adults. The disease often involves long bones; however, in half of the cases, extraskeletal involvement is reported. The etiology of this disorder is not known.

In summary, the causes of most histiocytoses are not known. Factors implicated in the etiology and pathophysiology of these disorders include infections, especially viral infections; [170] cellular and immune dysfunction, [171, 172] including dysfunction of lymphocytes and cytokines; [173, 174, 175] neoplastic mechanisms; genetic factors; [176, 177, 178, 179, 180, 181, 182, 183] cellular adhesion molecules; [184, 185, 186] and their combinations.

Although HHV6 has been found in lesions of LCH, its etiologic significance has been questioned. [184, 187, 188] Extensive searches for evidence of viral infection have been unrevealing. [129]

One report from Sweden suggests an increased rate of diagnosed histiocytosis in children conceived using in vitro fertilization. [189] 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. [173, 174, 175] 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. [174, 175]

Expression of abnormal leukocyte cellular adhesion molecules in LCH has been reported. [185, 186] 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. [190] Using this standard, LCH is considered to be a neoplastic disease rather than a reactive disorder, as was previously proposed. [191]

The role of genetics is not well defined. The occurrence of several cases in one family is rare but has been reported. [192, 193] LCH has been reported in several monozygotic and dizygotic twins. [178, 180, 180, 181, 182, 183, 194] Some consanguinity and involvement in close relatives (cousins) has been reported. [195] 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. [174, 175] As expected, numerous familial cases of erythrophagocytic lymphohistiocytosis have been reported. [96]

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. [194]

Spontaneous cytotoxicity of circulating lymphocytes is observed in patients with LCH. Antibody formation to autologous erythrocyte has also been reported. [196] Given these findings, treatment with crude calf-thymus extract, although not substantially successful, was clinically devised and used. [196, 197]

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. [162]

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. [198, 199, 200]

Association of LCH with leukemias and lymphomas has been described. [201]  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. [202]

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