Histiocytosis: Definition, Pathophysiology, Symptoms, Causes, Diagnosis, Treatment and Investigation

The clinical presentations vary widely, from mild to life-threatening.

Histiocytosis, also known as Langerhans cell histiocytosis (LCH) and formally called histiocytosis X, represents a group of rare disorders that involve specific cells that generally play an important role as part of the immune system.

Histiocytosis encompasses a group of various disorders characterized by the accumulation and infiltration of varying numbers of monocytes, macrophages, and dendritic cells into affected tissues.

Such description excludes diseases in which the infiltration of these cells occurs in response to a primary pathology.

Although almost a century has passed since histiocytic disorders were recognized, their pathophysiology has begun to be elucidated with the application of molecular analysis.

In the past 50 years, the terminology used to describe histiocytic disorders has changed substantially to reflect the wide range of clinical manifestations and the varying clinical severity of some diseases with the same pathologic findings.

For example, the Langerhans cell histiocytosis entity was initially divided into eosinophilic granuloma, Hand-Schüller-Christian disease, and Abt-Letterer-Siwe disease, depending on the sites and severity.


Later, they were found to be manifestations of a single entity and were unified under the term histiocytosis X.

More recently, this designation was changed to Langerhans cell histiocytosis based on Nezelof’s suggestion that the Langerhans cell represented the primary cell involved in the pathophysiology of the disease.


A better understanding of the pathology of histiocytic disorders requires knowledge of the origins, biology, and physiology of the cells involved.

Normal histiocytes originate from pluripotent stem cells found in the bone marrow. Under the influence of various cytokines, such as:

Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF). Tumor necrosis factor-alpha (TNF-alpha). Interleukin [IL] -3, IL-4.

These precursor cells can become compromised and differentiated to become a specific group of specialized cells.

Compromised stem cells can mature into antigen-processing cells, and some possess phagocytic capabilities.

These cells include tissue macrophages, monocytes, dendritic cells, interdigitating reticular cells, and Langerhans cells.

Pluripotent stem cells can also commit to producing dendritic cells. Each category of histiocytosis can be traced to reactive or neoplastic proliferation in one of these cell lines.

The importance of dendritic cells in presenting antigens to T and B lymphocytes is increasingly recognized. Dendritic cells appear to develop in several ways.

Immature dendritic cells respond to granulocyte-macrophage colony-stimulating factor (not macrophage colony-stimulating factor [M-CSF]). They are committed to generating dendritic cells, “professional” antigen-presenting cells (APCs). Its acronym in English).

These cells can capture the antigen and migrate to the lymphoid organs, where they present the antigens to naïve T cells. Dendritic cells are also efficient stimulators of B cell lymphocytes.

Effective induction of antigen-specific T cell responses requires interaction between dendritic cells and T lymphocytes to prime the latter cells for expansion and subsequent immune responses.

The antigen-presenting cell surface contains two peptide-binding proteins: that is, major histocompatibility complex (MHC) classes I and II.

What can stimulate: cytotoxic T cells (TC), T regulatory cells (Treg), and T helper cells (TH).

Although circulating T-cell lymphocytes can recognize antigens independently, their number is small.

Dendritic cells display many histocompatibility complex peptide complexes on their surface. They can increase the expression of costimulatory receptors and migrate to lymph nodes, spleen, and other lymphoid tissues, where they activate specific T cells.

The first signal may involve the interaction between a major histocompatibility complex peptide complex I and major histocompatibility complex II in an antigen-presenting cell with the T-cell receptor (RCT) on effector lymphocytes.

T cell receptors can recognize antigen fragments bound to the major histocompatibility complex on the surface of an antigen-presenting cell.

The costimulatory interaction (i.e., the second signal) is between CD80 (B7.1) / CD86 (B7.2) in the dendritic cell and CD28 in the T cells.

A combination of the two signals activates the T cell, resulting in upregulation of CD40L expression, which, in turn, can interact with the CD40 receptor expressed on dendritic cells.

In perforin-deficient mice, abnormally potentiated cytokine production by T cells is due to the overstimulation of antigen-presenting cells after viral infection.

This cell-to-cell interaction between dendritic and T cells generates an antigen-specific T cell response.

The practical function of antigen presentation by dendritic cells is presumed to reflect that these cells, besides the major histocompatibility complex molecules, express a high density of other costimulatory factors.

Dendritic cells can produce several cytokines, including IL-12, which is critical for the development of naïve CD4 + T cell TH 1 cell.

Ligation of CD40 in dendritic cells triggers the production of large amounts of IL-12, which enhances the stimulatory capacity of T cells.

This observation suggests that feedback to dendritic cells results in critical signals for the induction of immune responses.

The nature of the latter interaction and the requirement for optimal dendritic cell activation is not fully understood.

Cultured dendritic cells from human blood monocytes exposed to granulocyte-macrophage colony-stimulating factor and IL-4 followed by maturation in a monocyte-conditioned medium have increased antigen-presenting activity.

Monocyte conditioned media contain critical maturation factors that contribute to this process.

Dendritic cells are present in tissues in a resting state and cannot stimulate T cells. Their function is to capture and phagocytize antigens, which, in turn, induce their maturation and mobilization.

Immature dendritic cells reside in the blood, lungs, spleen, heart, kidneys, and tonsils, among other issues. Its function is to capture the antigen and migrate it to the draining lymphoid organs to prime the CD4 + and CD8 + T cells.

In their function, these cells mature and increase their ability to express costimulatory receptors and decrease their ability to process antigens.

These cells can phagocytose, forming pinocytic vesicles to sample and concentrate their surrounding medium, called macropinocytosis.

Immature dendritic cells express receptors that mediate endocytosis, including type C lectin receptors, such as the macrophage mannose receptor and the DEC205, Fc-gamma, and FC-epsilon receptors.

Microbial components, IL-1, granulocyte, macrophage colony-stimulating factor, and tumor necrosis factor-alpha, play an essential role in cellular response and stimulate dendritic cell maturation, while IL-10 is opposed.

Mature dendritic cells possess numerous exemplary processes (leaflets, dendrites) and are highly mobile.

These cells, rich in the significant classes of histocompatibility complexes I and II, have abundant molecules for T cell binding and costimulation, involving CD40, CD54, CD58, CD80 / B7-1, and CD86 / B7-1.

Mature dendritic cells express high levels of IL-12. High levels of CD83 (a member of the immunoglobulin [Ig] superfamily) and p55 or fascin (an actin-binding protein) are present in these cells, unlike the low levels that are present in immature cells.

IL-1 improves dendritic cell function. This effect appears to be indirect due to the activation of factors associated with the tumor necrosis factor receptor (TRAF).

Mature dendritic cells also express high levels of the NF-kappaB family of transcriptional control proteins.

These proteins regulate the expression of several genes that encode inflammatory and immune proteins.

Signaling via the tumor necrosis factor receptor family (eg, tumor necrosis factor-R, CD40, tumor necrosis factor activation-induced cytokine [TRANCE], NF-kappaB receptor activator [RANK] ) activates NF-kappaB.

The immune response of dendritic cells to a given antigen involves the triggering of signal transduction pathways involving the tumor necrosis factor R family and factors associated with the tumor necrosis factor receptor.

Information on the fate of dendritic cells after these events is scarce. Dendritic cells disappear from lymph nodes 1-2 days after antigen presentation, possibly due to apoptosis.

The CD95 (Fas) protein is suggested to have a role in dendritic cell death. However, although dendritic cells express CD95, CD95 ligation does not induce apoptosis.

Experiments indicate that immature dendritic cells are partially susceptible to receptor-mediated apoptosis of death. The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) can bind to 5 different receptors.

The functional domains of cytoplasmic death characterize TRAIL-R1 receptors, TRAIL-R2 receptors, and CD95 receptors. In contrast, TRAIL-R3 is a truncated membrane-anchored receptor, and TRAIL-R4 does not have a functional death domain.

Dendritic cells express CD95, TRAIL-R2, and TRAIL-R3 at relative levels. Similar to the role of CD95L, that of TRAIL-mediated apoptosis of mature dendritic cells has been controversial.

Data on TRAIL-mediated apoptosis in these cells have also been published, although these data remain controversial. Mature dendritic cells are often resistant to TRAIL- and CD95L-mediated apoptosis.

C-FLIP, the caspase-8 inhibitory protein capable of inhibiting apoptosis mediated by the death receptor, is highly expressed in mature dendritic cells, while only low levels are found in immature cells.

C-FLIP overexpression inhibits death receptor signals. The expression of C-FLIP in dendritic cells is up-regulated during maturation.

Note that the involvement of CD95 in immature dendritic cells by CD95L induces the phenotypic and functional maturation of these cells.

Furthermore, a CD95-activated dendritic cell up-regulates the expression of class II major histocompatibility complex and costimulatory receptors, which is essential for the function of these cells.

Furthermore, such an interaction positively regulates the expression of dendritic cell lysosome-associated membrane protein (DC-LAMP) and causes the secretion of pro-inflammatory cytokines, including IL-1 beta and TNF-alpha.

Some articles suggest the classification of high-risk Langerhans cell histiocytosis (HCL) as a myeloid neoplasm and the hypothesis that high-risk disease arises from the somatic mutation of a hematopoietic progenitor.

Some authors propose that low-risk disease arises from somatic mutation of tissue-restricted dendritic precursor cells.

These hypotheses are based on the finding of the BRAF-V600E mutation in the circulating CD11C (+) and CD14 (+) fractions and in the CD34 (+) hemopoietic progenitor cells of the bone marrow.

On the other hand, the mutation was limited to lesional CD207 (+) dendritic cells in low-risk Langerhans cell histiocytosis patients.

Langerhans cell histiocytosis is currently believed to arise from the proliferation of Langerhans and dendric cells, which are generally restricted to the skin and lymphatics.

The function of normal Langerhans cells is skin immunosupervision. These cells can migrate to regional lymph nodes and potentially present antigen to paracortical T cells and cause their transformation into interdigitating dendritic cells.

Some cancer cells disrupt dendritic cell function, block the development of tumor-specific immune responses, and allow tumors to avoid recognition.

To counteract this effect, dendritic cells can produce the anti-apoptotic protein Bcl-xL.

Stimulation of dendritic cells by CD154, IL-12, or IL-15 increases the expression of Bcl-xL. The information gained from normal dendritic cell physiology can potentially lead to treatment modalities for histiocytic disorders.

Symptoms of histiocytosis

Although the cause of Langerhans cell histiocytosis is unknown, Langerhans cell histiocytosis can often behave like cancer and is therefore treated by cancer specialists.

A histiocyte is a normal immune cell found in many parts of the body, especially the bone marrow, bloodstream, skin, liver, lungs, lymph glands, and spleen.

In histiocytosis, histiocytes move to tissues where they are generally not found and cause damage to those tissues. Some forms are genetic.

The first sign of histiocytosis is usually a rash on the scalp. There may be a pain in a bone, discharge from the ear, loss of appetite, and fever. Sometimes the stomach is bloated and painful.

Occasionally, an area of ​​the brain known as the pituitary gland is affected, and this can cause the child to pass large amounts of urine and become very thirsty.

Other possible signs and symptoms include: weight loss, jaundice, vomiting, lameness, short stature, delayed puberty, mental decline, headache, dizziness, seizures, bumps in the eyes, and generalized rash.

Skin – Red, scaly bumps in skin folds are standard. Babies with Langerhans cell histiocytosis may have red, scaly scalps, often mistaken for dandruff, a common skin condition.

Liver: Usually, only severe cases of Langerhans cell histiocytosis affect the liver. Your skin may appear jaundiced or yellow, and your blood may take longer to clot.

Lymph nodes: These glands, behind the ears, in the neck, and elsewhere, can become swollen. You may also have trouble breathing or have a cough.

In children, histiocytosis usually affects the bones and can consist of single or multiple sites. The skull is frequently involved.

The tumors produce a “punctured” appearance on X-rays of the bones. Sometimes children experience spontaneous fractures as a result of these bone injuries.

Children over five generally have the single-system disease, with only bone involvement. Young children, especially babies, are more likely to have multisystem illnesses.

Most cases of histiocytosis affect children between the ages of one and 15 years, although people of all ages can develop Langerhans cell histiocytosis.

The incidence peaks among children between the ages of 5 and 10. Histiocytosis affects about one to two in 200,000 people each year. The exact cause of histiocytosis is unknown.

However, recent studies indicate that it is caused by the development and expansion of an abnormal Langerhans cell which subsequently leads to the accumulation of other cells of the immune system, resulting in collections or tumors in various body areas.

Causes of histiocytosis

We do not know all the reasons why some people have Langerhans cell histiocytosis. About half of people with the disorder have a faulty gene that causes Langerhans immune cells to grow.

That genetic mutation occurs after birth, so you generally won’t get Langerhans cell histiocytosis from your parents. Researchers suspect that other things may also play a role:

  • Smoking, parents exposed to environmental toxins, such as benzene or wood dust, infections as a newborn, and a family history of thyroid disease.

Diagnostic tests for histiocytosis

Langerhans cell histiocytosis is often classified as a single system, when the disease affects only one part of the body, or multisystem when it affects more than one part of the body.

Diagnostic tests for children may include:

In a biopsy, a small sample of skin and bone is taken and examined under a microscope for abnormal cells (Biopsy of the skin and bone marrow to check for Langerhans cells).

X-rays of all the bones in the body to determine how many bones are affected; routine scans of the bones, skull, and lungs; and blood tests (complete blood count) and testing for a gene mutation in BRAF V600E.

These tests will help the doctor determine if the disease is single or multisystem.

An X-ray of the entire skeletal system can determine how extensive the disease is and whether or not systemic involvement is indicated.

Diagnostic tests for adults may also include:

  • Bronchoscopy with biopsy.
  • Chest x-ray
  • Pulmonary function tests.

Langerhans cell histiocytosis is sometimes related to cancer. CT scans and biopsy should be done to rule out possible cancer.

Treatment of histiocytosis

Depending on the extent of the disease, Langerhans cell histiocytosis is often treated with chemotherapy and steroids to suppress immune system function and histiocyte production.

The duration of treatment will vary from child to child. Many patients are eligible for international and local institutional trials.

Radiation therapy, targeted X-ray treatment, or limited surgery can also treat bone lesions in some situations.

Most patients who develop histiocytosis have complete recoveries. Sometimes the disease can recur, so that the patient will have regularly scheduled follow-up visits at the outpatient clinic as a precaution.

Histiocytosis investigation

New ideas are being tested to determine the causes of Langerhans cell histiocytosis and why some patients respond better to treatment.

New types of therapies are being developed, including new types of drugs and approaches that target antibodies or small molecules at the abnormal Langerhans cell without affecting normal tissues.


The incidence of Langerhans cell histiocytosis is 4-10 per million population. However, because many bones and skin lesions may not be diagnosed as Langerhans cell histiocytosis, this rate may underestimate.

The estimated incidence of neonatal Langerhans cell histiocytosis, determined by the population-based German Childhood Cancer Registry, is 1 to 2 per million newborns.

Morbidity and mortality


The total male-to-female ratio is 1.5: 1. The male-female ratio in individuals with single-organ system involvement is 1.3: 1, and the male-female ratio in individuals with the multisystem disease is 1.9: 1.


Langerhans cell histiocytosis can occur in individuals of any age. The incidence peaks in children 1 to 3 years of age. In one study, the age at diagnosis was 0.09-15.1 years.

Patients with single system involvement were more significant than those with multisystem involvement. Fetal and neonatal cases, although rare, can occur.