Xanthogranuloma

Juvenile xanthogranuloma (JXG) is a rare type of histiocytic disorder that mostly occurs in children (average age 2 years), but can rarely occur in adults as well, in which case it is called adult xanthogranuloma (AXG).

Juvenile xanthogranuloma (JXG) is a rare type of histiocytic disorder that mostly occurs in children (average age 2 years), but can rarely occur in adults as well, in which case it is called adult xanthogranuloma (AXG). The cause of JXG is unknown at this time, although it can sometimes be seen in association with conditions named as neurofibromatosis type 1 and juvenile myelomonocytic leukemia. Rarely, JXG can be driven by genetic changes (mutations) in the MAPK pathway, including the BRAF and ALK genes. These mutations occur in the tumor cells, and not in the DNA that is transmitted to children.

This disease may have been first reported by Rudolf Virchow in 1871 and again in 1905 by H.G. Adamson. In 1954, it was named juvenile xanthogranuloma to reflect the appearance of the cells under a microscope. JXG/AXG involves the over-production of a kind of histiocyte called a dendritic cell (not a macrophage). These cells then accumulate and lead to various symptoms, depending on location. The cause of this disease is not known, and the total number of patients is not known, but may be higher than reported on since this disease is sometimes misdiagnosed or may spontaneously improve.

It occurs most often in the skin of the head, neck, and trunk but can also occur in the arms, legs, feet, and buttocks. JXG/AXG can affect the eye, most commonly in young children with multiple skin lesions. Less commonly JXG/AXG may involve locations such as the lung, liver, adrenal gland, appendix, bones, bone marrow, pituitary gland, central nervous system, kidney, heart, small and large intestines, and spleen. Skin lesions cam be self-limited and rarely require treatment in most patients. Those with large abdominal masses, liver, bone marrow, or central nervous system involvement may do well with treatment such as chemotherapy similar to that used for Langerhans cell histiocytosis. In about 10% of patients, JXG occurs at birth, and is seen to affect more males than females.

Because JXG is so rare, no large studies have been performed, and there is no established, proven treatment for the more complicated cases. However, the Histiocytosis Association continues to work closely with an international group of physicians, known as the Histiocyte Society, who are dedicated to studying all of the histiocytic disorders. Through their combined efforts, awareness about JXG has increased, and progress has been made in the understanding of this disease.

Symptoms

Most commonly (90% of the time), it presents as a single skin lesion which varies in size, but children less than 6 months of age are more likely to have multiple lesions. It occurs at birth (congenital) in about 10% of patients, and more males are affected than females. Adult XG is less well understood at this time, and appears to sometimes share features with Erdheim-Chester disease, a related histiocytic disorder.

JXG can affect the skin only, the eye, and/or other locations in the body such as the lung, liver, adrenal gland, appendix, bones, bone marrow, pituitary gland, central nervous system, kidney, heart, small and large intestines, and spleen. The skin is the most common location of involvement and often does not require treatment. In one study of 129 patients (Kiel Pediatric Tumor Registry), 71% of the cases were diagnosed within the first year of life, and 81% were single skin lesions. There is an overall rate of 7% to 10% of patients (including adults) with multi-system JXG. Children younger than 6 months are more likely to have multiple lesions.

Skin lesions usually do not have symptoms such as pain or itching. They present as reddened, yellowish or brownish, slightly raised, and rubbery bumps on the skin. They may also appear in the fat layer beneath the skin.

Eye lesions may or may not occur in the presence of skin involvement. Eye involvement with JXG needs to be treated to prevent visual problems. JXG/AXG involving the eye, which is the second most common location, usually affects the iris, which is the colored, ring-shaped part of the eye. Lesions can, however, occur in other parts of the eye including the eyelid or inside of the eye, usually on one side only. Approximately one- half of patients with eye involvement also have skin lesions. Eye lesions are less likely to improve without treatment than skin involvement and can progress without treatment. Because many patients with JXG/AXG of the eye are without symptoms, the diagnosis may be delayed and/or difficult. Eye lesions may be discovered by accident, often noted by watchful parents or the primary care physician.

Systemic JXG, where lesions are present in more than one organ or body system, has been reported only in single- or small-case studies and usually requires treatment.

It is generally recommended that young children with multiple skin lesions be seen by an ophthalmologist every 3 months until 3 years of age.

Other symptoms related to JXG depend on the location of the disease. For example, if the bone marrow is involved, patients may have abnormalities in blood counts. Liver involvement can cause abnormalities in blood liver tests, as well as an elevated inflammation level (sedimentation rate) in the blood. Pituitary gland involvement can lead to diabetes insipidus.

It is important to remember that the diagnosis of JXG cannot be made on symptoms alone as it may present very similarly to LCH. It is therefore necessary to consult a knowledgeable physician to receive a thorough work-up and accurate diagnosis.

Diagnosis and Treatment

Diagnosis and Workup

The diagnosis of JXG relies on reviewing the biopsy of a tissue lesion under the microscope. Occasionally, the dermatologist may make a presumptive diagnosis based on the appearance of the skin lesions. When a biopsy is performed, a small piece of the tissue is obtained so that it can be viewed under a microscope by a pathologist. If the cells in the tissue have certain characteristics, the diagnosis of JXG can be made. JXG cells are negative for the presence of proteins called CD1a and CD207, while LCH cells are positive for those markers. Instead JXG cells are positive for proteins called CD68 and factor XIIIa. The pathologist may sometimes do additional tests on the tissues including mutational testing to help with arriving at a diagnosis. It is difficult to distinguish between JXG and Erdheim-Chester disease under the microscope. In patients with skin-limited lesions and no systemic symptoms or signs, evaluations should include a complete blood count, liver function tests, and ophthalmologic (eye) examinations.

An ultrasound may be performed to see if the JXG is in the abdominal organs such as liver or spleen. In addition, depending on the symptoms other tests such as CT scans, MRI scans, or bone X-rays may be done. Rarely, the physician might order a PET scan to look for various sites of involvement.

Treatment

Treatment varies according to the extent and severity of disease involvement. Most children with skin-limited lesions do not require treatment and can be observed with serial examinations. Surgical removal may be undertaken for several reasons: to obtain a biopsy for diagnosis, when there is an organ-function problem because of disease, for cosmetic reasons or to remove scar tissue. For the small percentage of individuals who have symptomatic or rapidly growing disease, treatment with chemotherapy or low-dose radiation has been reported, although there is no standard treatment that is agreed upon. With eye involvement, steroids may be applied to the surface of a lesion, injected within the lesion, or taken in pill form. Rarely low dose radiation treatment may be given to the eye to prevent visual loss. XG in adults (AXG) tends to be more complicated and is not known to improve spontaneously without treatment. This may involve surgical removal alone or additional therapy depending on the clinical situation. Most common treatment regimens for JXG or AXG are derived from LCH, such as cladribine, cytarabine, or vinblastine + prednisone. If there is a presence of a mutation (BRAF, ALK, etc.), specific pills targeting those genes can be utilized.

FAQ

What Do I Do Now?

A new diagnosis of a histiocytic disorder can bring feelings of being overwhelmed, bewildered, scared, angry, sad, disappointed, helpless, and sometimes even feelings of guilt.  It is a time filled with unknowns, change, and new people and situations.  Most parents feel ill-equipped to understand what is happening to their child and how to navigate through the illness to recovery.  There are, however, strategies and resources that can help you, your child, and other family members get through the uncertain times that lie ahead. One step at a time, you can gather information, create a support system, learn how to cope with stress, and become a strong advocate for your Histio Warrior as part of the medical team. The following tips and suggestions are provided to help guide you through this journey toward your Histio Warrior's good health.

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