Histiocytic disorders are a group of rare disorders characterised by the abnormal accumulation of histiocytes, a type of immune cell often found in tissues that regulates immune functions. There are three primary types of histiocytes, including monocytes (plays a role in inflammatory and anti-inflammatory responses during an immune response), macrophages (responsible for ingesting and eliminating foreign substances during an immune reaction), and dendritic cells (initiate and regulate the adaptive immune response).  

Histiocytic disorders are broadly classified into five different groups: L group, C group, M group, R group, and H group. The L group, or Langerhans group, are classified as diseases involving Langerhans cells (an immune cell responsible for initiating an immune response when coming into contact with a foreign material), such as Langerhans cell histiocytosis (LCH). The C group, also known as cutaneous and mucocutaneous non-Langerhans cell histiocytosis, are classified as non-Langerhans cell histiocytic disorders that are localised to the skin or mucosal surfaces, such as the mouth, nose, and gastrointestinal system. The M group, also known as malignant histiocytic disorders, are classified by the presence of malignant (or cancerous) cells within the tumour(s). The R group, also known as Rosai-Dorfman disease and miscellaneous non-cutaneous non-Langerhans cell histiocytosis or sinus histiocytosis, are classified as non-Langerhans histiocytic disorders that often involve lymph nodes. The H group, also known as hemophagocytic lymphocytosis and macrophage activation syndrome, is composed entirely of hemophagocytic lymphohistiocytosis, a rare and aggressive disease caused by the overactivation of the immune system.

This page will focus specifically on C group histiocytic disorders, which includes various skin conditions such as xanthogranuloma (juvenile and adult), reticulohistiocytosis (solitary and multicentric), and cephalic histiocytosis.

C group histiocytic disorders are slightly more common in males, with the average age of diagnosis varying between subtypes. However, anyone can develop this disease. 

Types of C Group Histiocytic Disorders

There are two primary types of C group histiocytic disorders, which are categorised by the number of bodily systems affected.

Cutaneous non-Langerhans Cell Histiocytosis

Cutaneous non-Langerhans cell histiocytosis is generally divided into xanthogranuloma (nodules of the skin that are characterised by a large type of macrophage, known as xanthoma cells), and non-xanthogranuloma families.

Xanthogranuloma Family

Xanthogranulomas are nodules of the skin caused by the accumulation of large macrophage cells, also known as xanthoma cells. These conditions are generally considered benign, and can have an excellent prognosis. Types of conditions in the xanthogranuloma family include:

• Juvenile xanthogranuloma (most common; often affects children under one year old).
• Adult xanthogranuloma (affects people between the ages of 20-30; often persistent).
• Solitary reticulohistiocytoma. 
• Benign cephalic histiocytosis.
• Generalised eruptive histiocytosis.
• Progressive nodular histiocytosis (a very rare condition categorised by hundreds of papules and nodules; may not have as good of a prognosis as other types of xanthogranuloma family conditions).

Non-Xanthogranuloma Family

The non-xanthogranuloma family consists of all other cutaneous non-LCH that does not meet the criteria for the xanthogranuloma family. These conditions are generally considered benign, and can have a good prognosis. Types of conditions in the non-xanthogranuloma family include:

• Cutaneous Rosai-Dorfman disease.
• Necrobiotic xanthogranuloma.
• Cutaneous histiocytosis not otherwise specified (NOS).

Cutaneous non-Langerhans Cell Histiocytosis with a Major Systematic Component

Cutaneous non-Langerhans cell histiocytosis with a major systematic component is also classified into xanthogranuloma and non-xanthogranuloma families.

Xanthogranuloma Family – Xanthoma Disseminatum

The xanthogranuloma family of this subtype consists only of xanthoma disseminatum (XD), a rare cancer-like condition characterized by hundreds of small yellowish-brown or reddish-brown nodules on the face and trunk of the body. It most commonly develops before the age of 25, however has been reported in patients up t0 80 years old. XD is often aggressive, but can have a good prognosis when caught early.

Non-Xanthogranuloma Family – Multicentric Reticulohistiocytosis

The non-xanthogranuloma family of this subtype consists only of multicentric reticulohistiocytosis (also known as lipoid dermatoarthritis), a rare systemic condition associated with multiple reticulohistiocytotic lesions and rapidly destructive arthritis. Unlike most other histiocytic disorders, this subtype is more common in females, and tends to present around the age of 50. Multicentric reticulohistiocytosis is often aggressive, but can have a good prognosis.

Treatment 

Each patient with a C group histiocytic disorder will present with a unique disease behaviour, with varying locations, and symptoms. As such, there is no one treatment method that will work for everyone, and there is no standard staging system for this disease.  Instead of staging and grading, your doctor will recommend a treatment plan based on the following factors:   

• Tumour location.
• Whether or not the tumour(s) have spread.
• Your age.
• General health.
• Treatment preferences.

Your doctor may recommend genetic testing, which analyses your tumour DNA and can help determine which treatment has the greatest chance of success. Your doctor will discuss the most appropriate course of treatment for you.

Treatment options for an C group histiocytic disorder may include:

• Watch and wait.
• Surgery to remove lesion(s). 
• Steroids.
• Radiation therapy (extreme cases).
• Chemotherapy (extreme cases).
• Clinical trials.
• Palliative care.

For more information on the treatment options, please refer to the Rare Cancers Australia treatment options page. 

Risk factors 

Because of how rare C group histiocytic disorders are, there has been limited research done into the risk factors of this disease.

Early symptoms 

Symptoms of C group histiocytic disorders often vary by subtype. 

Symptoms of Juvenile and Adult Xanthogranulomas

Symptoms of juvenile and adult xanthogranulomas may include:

• A solitary skin lesion on the head and neck.
• Papules, plaques and/or nodules on the skin, often 1-10 mm in diameter. 
• Ulcerations of large nodules.
• Red, yellow, or brown papules, plaques and/or nodules.
• A red eye (if tumour develops in the eye, most common site is the iris). 
• Changes in vision (if tumour develops in the eye).

Symptoms of Solitary Reticulohistiocytoma

Symptoms of a solitary reticulohistiocytoma may include:

• Yellow to reddish-brown nodule/lesion.
• Smooth nodule/lesion.
• Firm nodule/lesion. 
• Nodule/lesion on the abdomen or limbs.
• Nodule/lesion less than 1cm in diameter.

Symptoms of Benign Cephalic Histiocytosis

Symptoms of benign cephalic histiocytosis may include:

• Yellow to red-brown lesions.
• Papules that are 2-4mm in diameter.
• Raised papules.
• Lesions on the head and neck, most commonly in the cheeks, eyelids, forehead and/or ears. 
• Multiple lesions.

Symptoms of Generalised Eruptive Histiocytosis

Symptoms of generalised eruptive histiocytosis may include:

• Red-brown papules/lesions.
• Lesions on the trunk and/or limbs.
• General feeling of discomfort.
• Spontaneous lesion eruption (lesion may ‘pop’ randomly and ooze liquid, such as pus or blood, similarly to the popping of a pimple).

Symptoms of Progressive Nodular Histiocytosis

Symptoms of progressive nodular histiocytosis may include:

• Yellow, orange, red or brown papules/nodules in the skin.
• Nodules/papules up to 5cm in diameter.
• Deep nodules/papules.
• Development of papules/nodules over time, potentially leading to hundreds of nodules being found. 

Symptoms of Cutaneous Rosai-Dorfman Disease

Symptoms of cutaneous Rosai-Dorfman disease may include:

• Yellow or purple lesions on the skin.
• Reddish rash-like inflammation on the skin.
• Lesions on the head and neck, most commonly on the face.

Symptoms of Necrobiotic Xanthogranuloma

Symptoms of necrobiotic xanthogranuloma may include:

• Multiple yellowish papules/nodules.
• Thickened or raised lesions around the eyes.
• Changes in vision, potentially including:
  • Double vision.
  • Blurred vision.
• Burning or itching of the eyes.
• Bulging of the eyes.
• Drooping of the eyelid.
• Restricted eye movement.
• Firm papules/nodules.

Symptoms of Cutaneous Histiocytosis NOS

Symptoms of cutaneous histiocytosis NOS may include papules, nodules or plaques of varying sizes, locations and colour.

Symptoms of Xanthoma Disseminatum

Symptoms of xanthoma disseminatum may include:

• Multiple lesions, papules and/or nodules, often oval shaped.
• Yellowish-brown or reddish-brown lesions, papules or nodules.
• Lesions, papules or nodules on the sides of the face, airways, eyes and/or abdomen.
• Warty plaques in the mouth (also known as verruciform xanthomas). 
• Diabetes insipidus, resulting in:
  • Frequent thirst.
  • Frequent urination.
• Difficulties with swallowing.
• Difficulties with breathing.
• Hoarseness of voice.

Symptoms of Multicentric Reticulohistiocytosis

Symptoms of multicentric reticulohistiocytosis may include:

• Pink or reddish-brown papules and/or nodules.
• Papules/nodules that range from1-2mm to several centimetres in diameter.
• Papules/nodules on the face, ears, lips, tongue, gums, nostrils, throat, eyelids, hands and/or forearms.
• Tiny lumps around the nails.
• Itchy nodules/papules. 
• Arthritis of the fingers, hands, knees and/or shoulders.

Not everyone with the symptoms above will have cancer, but see your general practitioner (GP) if you are concerned. 

Diagnosis/diagnosing 

If your doctor suspects you have a C group histiocytic disorder, they will order a range of diagnostic tests to confirm the diagnosis, and refer you to a specialist for treatment.

Physical examination

Your doctor will collect your overall medical history, as well as your current symptoms. Following this, they may examine your body to check for any abnormalities. More specifically, they will examine the suspicious lesion, papule and/or nodule. 

Imaging & blood tests

The doctor will take images of your body using magnetic resonance imaging (MRI), a computed tomography scan (CT scan), positron emission tomography scan (PET scan) and/or ultrasound, depending on where it is suspected the cancer is. The doctor may also look at other parts of the body and looks for signs of metastasis. Additionally, a blood test may be taken to assess your overall health and help guide treatment decisions.

Biopsy

Once the location(s) of the cancer has been identified, the doctor will perform a biopsy to remove a section of tissue using a needle. The tissue sample will then be analysed for cancer cells.  

Prognosis (Certain factors affect the prognosis and treatment options) 

While it is not possible to predict the exact course of the disease, your doctor may be able to give you a general idea based on the rate and depth of tumour growth, susceptibility to treatment, age, overall fitness, and medical history. Generally, early-stage C group histiocytic disorders have a better prognosis and survival rates. However, if the tumour has become malignant and spread, the prognosis may not be as good and there may be a higher risk of recurrence. It is very important to discuss your individual circumstances with your doctor to better understand your prognosis. 

References

• DermNet
• NCBI
• Radiopaedia

^{Some references are to overseas websites. There may be references to drugs and clinical trials that are not available here in Australia.}