Introduction

Histiocytosis is a rare group of diseases where certain immune cells, called histiocytes, build up too much in different parts of the body. These conditions range from mild, self-limiting lesions to aggressive, multi-organ diseases. Subtypes vary in their underlying biology, tissue involvement, diagnostic features, and treatment approaches.^1,2

This article compares Erdheim-Chester disease (ECD) with other major histiocytoses, including Langerhans cell histiocytosis (LCH), Rosai–Dorfman disease (RDD), and juvenile xanthogranuloma (JXG), focusing on differences in clinical presentation, histology, imaging, and management. 

Overview of histiocytoses

Histiocytoses are a group of rare disorders, characterised by the proliferation and accumulation of histiocytes within various tissues. Histiocytes are immune cells derived from the monocyte, macrophage or dendritic cell lineage. Macrophages are key immune cells responsible for engulfing pathogens (phagocytosis), presenting antigens to other immune cells, and releasing chemical signals to coordinate immune responses.

Dendritic cells also present antigens to other immune cells, especially T cells, helping the body launch a targeted defence. In histiocytic disorders, changes in certain cell signals can cause these cells to stay active for too long and build up in different organs, which can lead to damage.^1,2

Traditional classification of histiocytoses

Traditionally, histiocytoses have been divided into two major categories based on their cell features:¹

Langerhans cell histiocytosis 

In this type, there is an overgrowth of Langerhans-type dendritic cells. These cells have specific markers on their surface, CD1a, Langerin (CD207), and S100, and unique structures called Birbeck granules seen under an electron microscope.

Non-langerhans histiocytoses

This is a mixed group that includes ECD, JXG, and RDD. These cells usually lack CD1a and Langerin and have features more like macrophages or other types of dendritic cells.

Updated classification of histiocytosis

With modern discoveries in molecular biology and cell markers, the Histiocyte Society introduced a more up-to-date classification system in 2016. It divides histiocytic disorders into five main groups:³

• L group (Langerhans-related): This group includes LCH, ECD, and indeterminate cell histiocytosis, which often share dendritic cell lineage and mutations
• C group (cutaneous and mucocutaneous): Encompasses benign histiocytic disorders confined to the skin or mucous membranes, such as JXG
• R group (Rosai–Dorfman disease-related): Characterised by large, painless lymph node swelling and sometimes other organ involvement
• M group (malignant histiocytic disorders): Includes rare neoplastic histiocytoses such as histiocytic sarcoma and monocytic leukaemia
• H group (haemophagocytic lymphohistiocytosis and macrophage activation syndrome): Severe inflammatory conditions where immune cells become overactive, often due to genetic defects, infections, cancer, or autoimmune diseases

Erdheim-Chester disease 

ECD is a rare condition where histiocytes build up abnormally in different parts of the body. These histiocytes contain fatty deposits (making them look “foamy” under the microscope) and can damage tissues where they collect. The disease was first described in 1930 by Jakob Erdheim and William Chester. 

The disease is mainly caused by changes (mutations) in genes that control how cells grow and survive. These changes make histiocytes multiply too much and release inflammatory signals that damage surrounding tissues.⁴ 

Clinical features

ECD can affect many parts of the body, so symptoms vary widely:^4,5

• Bones: Pain in the legs is common due to thickening (sclerosis) of the long bones, like the femur and tibia
• Hormones: Diabetes insipidus, which causes extreme thirst and frequent urination, often appears first due to pituitary gland involvement
• Heart and blood vessels: The aorta may become wrapped in thick tissue (“coated aorta”), and the heart may develop fluid around it or masses inside it
• Kidneys and abdomen: Tissue may collect around the kidneys (“hairy kidney” sign), sometimes causing kidney failure
• Brain and nerves: Problems with balance, memory, or seizures can develop if the brain is affected
• Eyes and lungs: Bulging eyes, lung scarring, and breathing difficulties may also occur

Diagnosis

Radiological imaging is essential for diagnosis and typically shows characteristic patterns:^4,5,6

• Skeletal scintigraphy or PET-CT: Symmetrical uptake in the long bones, especially the femur and tibia
• CT or MRI: Evidence of retroperitoneal fibrosis, the classic “coated aorta” sign, and central nervous system (CNS) lesions
• Cardiac MRI: Useful for detecting myocardial or pericardial infiltration

A tissue biopsy can confirm the diagnosis, revealing foamy, lipid-laden macrophages with varying degrees of fibrosis and chronic inflammation. These cells often surround or infiltrate organs, causing structural damage. Immunohistochemistry typically shows that the cells are CD1a-negative.

Treatment options

Management of ECD depends on disease severity and mutation status:⁶

• Targeted therapy: BRAF inhibitors (e.g., vemurafenib, dabrafenib) and MEK inhibitors (e.g., cobimetinib) are used in mutation-positive disease
• Interferon-alpha: Historically, the first-line treatment, particularly effective in stabilising the disease
• Corticosteroids: Used for symptom control or in acute presentations
• Immunosuppressive or cytotoxic agents: Less commonly used; roles are limited in the era of targeted therapy
• Multidisciplinary care: Given the potential for multi-organ involvement, patients often require input from cardiology, endocrinology, nephrology, neurology, and oncology

Langerhans cell histiocytosis 

LCH is the most common type of histiocytic disorder. It occurs when dendritic cells start multiplying in an uncontrolled way. These abnormal cells share features with Langerhans cells found in the skin and carry specific markers, CD1a, CD207, and S100 (see above). Most cases of LCH are driven by gene mutations and have been classified as an inflammatory myeloid neoplasia (a type of immune-related tumour).⁷

Clinical features

LCH exhibits highly variable clinical behaviour, ranging from isolated skin or bone lesions to widespread multisystem disease. Common presentations include:⁸

• Bone lesions
• Skin involvement
• Pulmonary LCH
• Liver, spleen and haematopoietic system involvement

Diagnosis 

Diagnosis requires a biopsy of the affected tissue. Lab tests show the abnormal cells are CD1a-, Langerin (CD207)-, and S100-positive, confirming LCH. Birbeck granules, if seen on electron microscopy, provide additional confirmation. Further tests, such as PET-CT, MRI, or endocrine evaluation, help determine the extent of the disease.^7,8

Treatment and prognosis

Management depends on the extent and severity of disease:^7,8,9

• Single-system disease (e.g., isolated bone or skin lesions): May resolve spontaneously or require limited surgery, corticosteroids, or local radiotherapy
• Multisystem disease: Treated with systemic chemotherapy (e.g., vinblastine and steroids)
• Pulmonary LCH: Smoking cessation is crucial; systemic treatment is reserved for progressive cases

Prognosis varies:

• Localised disease has a favourable outcome
• Multi-organ disease, involving risk organs, carries a higher risk of complications or mortality

Rosai-Dorfman disease 

RDD, also known as sinus histiocytosis with massive lymphadenopathy, is a rare disorder where histiocytes build up in the lymph nodes and sometimes in other organs. It was first described in 1969 by Rosai and Dorfman.¹⁰ RDD is generally a benign but long-lasting inflammatory condition. 

Most cases occur for unknown reasons, although some have been linked to immune system problems, infections such as Epstein–Barr virus, or autoimmune diseases. More recently, changes in genes that control cell growth have been found in some patients, suggesting that RDD may be a type of low-grade tumour in certain cases.¹¹

Clinical features

The classic presentation includes:^10,12

• Painless, bilateral cervical lymphadenopathy (often massive)
• Fever, night sweats, and weight loss
• Elevated inflammatory markers (such as erythrocyte sedimentation rate & C-reactive protein)

Extranodal involvement

In up to 40% of cases, RDD involves extranodal sites, including:^10,12

• Skin
• Upper respiratory tract (e.g., nasal cavity, sinuses)
• Orbit and eyelids
• Bone
• CNS (rare but can mimic tumours)

Diagnosis

Under the microscope, RDD shows:¹⁰

• Large histiocytes with pale cytoplasm
• Emperipolesis, a key feature, is where these histiocytes “swallow” intact immune cells like lymphocytes but do not destroy them
• A background of plasma cells and lymphocytes

The immunophenotype typically shows S100-positive and CD68-positive cells, but CD1a-negative cells.

Treatment and prognosis

Treatment options include:^10,11,12

• Corticosteroids: Often used as first-line therapy
• Surgical excision: For accessible nodal or extranodal masses
• Radiotherapy or chemotherapy: In refractory or severe cases

Prognosis:

• Generally favourable in nodal RDD
• Variable in extranodal or multifocal disease, especially with CNS involvement
• Long-term follow-up may be needed to monitor relapses or complications

Juvenile xanthogranuloma

JXG is the most common type of non-Langerhans cell histiocytosis affecting the skin in children. It typically appears within the first year of life, most often in infants and toddlers, though older children and adults can be affected in rare cases. JXG is considered benign and self-limiting, and it is often identified incidentally or during dermatological evaluation. Most cases are restricted to the skin, and systemic (body-wide) involvement is rare.¹³

Clinical features

JXG usually presents as one or more small, yellowish or reddish bumps (papules) or dome-shaped nodules on the skin. They tend to occur on the head, neck, or upper body and are typically painless. Some lesions may break open (ulcerate) or bleed, but most cause no symptoms and disappear on their own over months to years.^13,14

In a small number of cases, especially in children under 2 years, JXG can affect internal organs such as the:¹³ 

• Eyes (ocular JXG): May cause complications like glaucoma or bleeding inside the eye (hyphaema) that threaten vision
• Lungs
• Liver
• Spleen
• Brain

Diagnosis

Under the microscope, JXG lesions show:¹⁵

• Lipid-laden macrophages (foam cells or xanthoma cells)
• Touton giant cells, which have a ring of nuclei surrounded by foamy cytoplasm
• A mix of immune cells, including lymphocytes and eosinophils

Immunophenotyping shows the cells are CD68-positive, CD1a-negative and S100-negative.

Treatment and prognosis

Most JXG lesions do not need treatment and go away naturally. Management depends on the presentation:¹⁵

• Surgical removal or laser therapy: Used if the lesions are disfiguring or the diagnosis is unclear
• Eye involvement: Needs urgent eye specialist care; treatment may include steroids or surgery
• Systemic disease: Extremely rare; may require corticosteroids, chemotherapy, or immunosuppressive drugs

Prognosis:^13,14,15

• Excellent in the vast majority of cutaneous cases
• Guarded in rare systemic cases, especially if the CNS or ocular structures are affected
• Lifelong follow-up is not typically required unless systemic involvement is documented 

Summary

Histiocytoses are rare conditions in which certain immune cells, known as histiocytes, build up abnormally in the body. These conditions can range from harmless skin spots to serious diseases affecting multiple organs. One key type is Erdheim-Chester disease, a rare disorder characterised by foamy immune cells that can affect the bones, brain, heart, and kidneys. It is often linked to gene mutations, and treatment commonly involves targeted therapies such as BRAF or MEK inhibitors. This contrasts with Langerhans cell histiocytosis, another major form, where abnormal immune cells may appear in the skin or bones and sometimes spread to multiple organs. Management for Langerhans cell histiocytosis can include surgery, steroids, or chemotherapy, depending on disease severity.

Moving from these more aggressive conditions, Rosai–Dorfman disease tends to present with swollen lymph nodes and immune cells that “engulf” other cells. Although usually mild, severe cases can still require steroids or surgical intervention. In comparison, juvenile xanthogranuloma is the least concerning type, being a relatively common and harmless skin condition in young children that usually resolves on its own, only rarely affecting the eyes or internal organs.