Xanthogranulomais a benign, asymptomatic, and self-healing disorder of non-Langerhans cell histiocytosis, affecting mostly infants, children, and rarely adults. Diagnosis is easy in typical cases but become more complex in unusual forms.
We report a case of a 28-year-old male patient who presented with multiple diffuse brown-to-yellowish papulonodular eruptions over extremities, ears, face, trunk, and extensors of joints with almost bilaterally symmetrical distribution for a period of one month. Histopathological examination of the skin biopsy specimen revealed features of xanthogranuloma.
The patient was put on isotretinoin 20 mg once daily. Most of the lesions subsided or flattened within two months of isotretinoin therapy. This case is interesting because of the severity and atypical nature of the disease and also, the patient responded with isotretinoin therapy. But further study is required to observe the effectiveness of isotretinoin in xanthogranuloma.
Xanthogranulomas are benign, usually asymptomatic, self-healing, red, yellow, or brown papules, nodules composed of histiocytic cells that predominantly occur in infancy and childhood. Papules, nodules occur in skin, eyes, and viscera. Adamson first reported juvenile xanthogranuloma (JXG) in 1905. But during 1912, McDonough reviewed the condition and renamed it as nevoxanthoendothelioma.
In 1954, Helwig and Hackney re-termed it as JXG, reflecting its histopathological appearance. An adult form of xanthogranuloma was first described by Gartmann and Tritsch in 1963. It belongs to a heterogeneous group of non-Langerhans cell histiocytoses, which are characterized by benign dermal proliferations of histiocytic cells in the absence of any known stimuli.
Approximately 35% of cases of JXG occur at birth, with as many as 71% of cases occurring in first year. Usually, xanthogranuloma is termed as JXG though around 10% of cases manifest in adulthood. Up to 81% of cutaneous JXG cases manifest as a solitary lesion. This form is also more common in cases of adult onset. Extracutaneous JXG is rare (3.9%) and most commonly involves eye. Histopathological examination of JXG demonstrates a variety of findings.
A time-dependant progression exists in development of characteristic histological features which correlates with age of lesions. Early biopsy specimen reveals a dense monomorphous histiocytic infiltrate in dermis. Older lesions contain foam cells, Touton giant cells and foreign body giant cells. A mixed cellular infiltrate of neutrophils, lymphocytes, eosinophils and rarely mast cells may be noted.
Anticipatory care, with patient reassurance, is appropriate because of self-limiting benign nature of disease. Ocular and systemic lesions may respond to steroids or radiotherapy. But diffuse and multiple cutaneous lesions also need some treatment.
The etiology of JXG is unknown. JXG is believed to result from a disordered macrophage response to a nonspecific tissue injury, resulting in a granulomatous reaction. JXG is on a spectrum of histiocytic disorders that includes benign cephalic histiocytosis, generalized eruptive histiocytosis, adult xanthogranuloma, and progressive nodular histiocytosis. These diseases are less common than the related Langerhans cell histiocytoses.
A 28-year-old healthy male patient presented in our department with one-month history of diffuse numerous papulonodular eruptions at extremities, ears, face, and trunk. The majority of lesions were present over extensors of joints. The lesions developed suddenly at first over right leg with mild itching. No other constitutional symptom was present.
Cutaneous examination revealed yellow-brown, relatively well-demarcated papulonodular lesions with variable sizes (1–5 mm in diameter). Lesions were shiny, soft to elastic in consistency consistency present almost all over the body and majority being over upper and lower extremities, ears, and chin . The surface of some lesions were scaly. There was no vesiculation, erosion, or crusting. The mucous membranes, palms and soles were unaffected and ophthalmologic examination was normal. No other systemic involvement was noted. No other family members were affected.
Histopathologically, xanthogranuloma in adult is identical to that of JXG. Serum lipid profiles are normal in patients with both juvenile and adult form of xanthogranuloma. The number of lesions in adult xanthogranuloma is lesser than in juvenile form. Of 31 patients, 27 (87%) with adult onset xanthogranuloma in Japanese literature had a solitary lesion. Multiple adult xanthogranuloma is a rare entity and 16 cases were reported since 1963.
There seemed to be no definite sites of predilection for adult onset xanthogranuloma and lesions were usually asymptomatic. Spontaneous resolution does not occur in adult form, whereas juvenile form usually involutes spontaneously within a year.
Earlier published report of nine cases of adult xanthogranuloma did not notice any spontaneous resolution. Extracutaneous involvements of eye, lung, testis and pericardium have been reported in patients with JXG. In contrast, no concomitant extracutaneous lesions have been found in adult form, although solitary extracutaneousxanthogranuloma without cutaneous lesions have been reported.
Etiology of xanthogranuloma is unknown. The tumor represents accumulations of differentiated histiocytes. These cells express phenotype of dermal dendrocytes, although a recent study has suggested that cell of its origin could be plasmacytoid monocytes. The appearance of giant cell and foamy lipid-laden histiocyte occur late and they are almost certainly secondary events, possibly in response to cytokine production by the lesion histiocyte.
JXG has been noted in association with different diseases like neurofibromatosis, Niemann-Pick disease, urticariapigmentosa, juvenile chronic myelogenous leukemia. However no association was found with the adult form. Ocular and systemic lesions may respond to steroids or radiotherapy, and severe systemic JXG have required single and mutagenic chemotherapeutic regimens.
Commonly, no treatment is necessary for cutaneous xanthogranuloma, but severe cutaneous involvement of adult form like our case may require some treatment to hasten disease improvement.
The growth of a number of tumor cell lines seems to be inhibited by retinoids, but response may be variable. It affects transformed cell surfaces and leads to anchorage-independent growth, cell adhesiveness and density-dependant growth. For these reasons, we started isotretinoin and noticed significant clinical improvement within two months. As spontaneous resolution does not occur in adult xanthogranuloma, we think that this type of early resolution may be due to isotretinoin. But further large study is required to see the effectiveness of isotretinoin in xanthogranuloma.
The frequency is unknown, but it may be higher than reported, since lesions occur early in life, may be misdiagnosed, and spontaneously regress. In those affected, 92% of ocular involvement occurs before age 2 years.
Cutaneous lesions generally are self-limited and rarely require treatment. The risk of morbidity is high with ocular involvement and can include hyphema, glaucoma, corneal blood staining, cataract, vascular occlusion, and retinal detachment, all of which can lead to amblyopia in childhood. Rarely, death has been reported among children with visceral JXG.
No reported predilection of race exists in JXG, although few African American patients have been described.
Cutaneous JXG is reported 1.5 times more in male children, but no sex predilection exists in adults. Both sexes are equally at risk for ocular involvement.
JXG may be present at birth (in about 10%) but most often arises in infancy. Children younger than 6 months are more likely to have multiple lesions. Zimmerman reported 64% of cutaneous lesions to be present by age 7 months and 85% before 1 year. Adult onset is reported infrequently.
What is juvenile xanthogranuloma?
Juvenile xanthogranuloma is a type of non-Langerhan’s cell histiocytosis. It presents as skin lesions predominantly in infants and young children, more often males, and is present at birth in 20% of cases. However, 10% of cases are adults. It is more common in Caucasians than in those of oriental origin. The cause is unknown.
At first the lesions are smooth and pink bumps, but later develop a yellowish appearance and may become scaly. Most are under 0.5 cm in diameter (papules), but giant nodules may be as large as 2 cm. They may arise on any site of the body, but more frequently appear on the trunk and upper extremities. Occasionally they also appear in the eye or internal organs.
Juvenile xanthogranuloma is difficult to distinguish from several other conditions.
- Benign cephalic histiocytosis
- Generalised eruptive histiocytosis
They are increasingly thought of as the same condition.
The differential diagnosis includes other histiocytoses such as benign cephalic histiocytosis, generalized eruptive histiocytosis, papular xanthoma, xanthoma disseminatum, Langerhans cell histiocytosis (LCH), and other miscellaneous disorders such as pyogenic granuloma, Spitz nevus, mastocytosis, and molloscumcontagiousum.
Benign cephalic histiocytosis affects infants and toddlers up to age three, tends to present with multiple flatter lesions that are confined to the head and neck, and spares the mucous membranes. Touton giant cells are absent in benign cephalic histiocytosis.
Generalized eruptive histiocytosis is more common in adults, presents with hundreds of red-brown papules, and can be differentiated histopathologically by the absence of cellular lipidization and giant cells.
Xanthoma disseminatum is characterized by the triad of mucous membrane involvement, generalized symmetric eruption of cutaneous xanthomas, and associatied diabetes insipidus.
Nodular lesions of LCH may mimic JXG clinically and must be distinguished by histology and immunohistochemistry. Of particular note is the presence of Birbeck granules, and S-100 and CD1a positivity in LCH. Some authors believe that these histiocytic disorders fall within a spectrum, as opposed to rather that representing and do not representindividual diseases, as there are reports of various histiocytoses co-existing in the same patient.
Dermatoscopy may aid in establishing the diagnosis. A characteristic finding is an orange-yellow color with a surrounding rim of erythema. This has been likened to a setting sun. White streaks may also be present representing fibrosis.
Who is at Risk for Developing this Disease?
NXG is an uncommon disease with approximately 100 cases reported in the literature since 1980, when it was first described.
A review of 48 cases found the age range to be 17 to 85 years with a mean age of onset in the sixth decade. Men and women are affected equally. The periorbital area is the most frequently involved site.
NXG typically follows a chronic and progressive but indolent course with a generally good prognosis. Prognosis is highly dependent on the extent of extracutaneous involvement and the presence of visceral malignancies. One study followed patients with NXG and multiple myeloma where there was 100% patient survival at 10 years and 90% at 15 years.
JXG is generally a disease of infancy and early childhood, with 40%-70% presenting in the first year of life. Between 5% and 17% are congenital. Approximately 1%-2% of children are affected, with a slight male predominance. Xanthogranulomas have been described in adults in whom the typical presentation is that of a large solitary nodule.
What is the Cause of the Disease?
The etiology is unknown. Some have postulated that JXG represents a reactive histiocytic process to an as yet unidentified stimulus.
Systemic Implications and Complications
JXGs may affect multiple organ systems. Extracutaneous disease has been reported in 4%-5% of patients with cutaneous lesions. Common sites of extracutaneous disease include the eyes, subcutaneous tissue, central nervous system, liver, spleen, lung, oropharynx, and muscle. Bone marrow, heart, kidney, gastrointestinal tract, bone, pancreas, adrenal gland, gonadal, and laryngeal involvement have also been described.
Fatalities are very rare, with only six cases reported, and most of these were in neonates with congenital disease. In general, routine screening for systemic involvement is not indicated unless symptoms or suggestive findings are present.
Ocular involvement is the most common extracutaneous manifestation, and this occurs in approximately 0.3%-0.4% of patients with cutaneous JXG. The iris is most frequently affected. Anterior chamber hemorrhage (hyphema) can cause glaucoma and subsequent blindness. Other sites include the cornea, sclera, conjunctiva, ciliary body, limbus, and optic nerve. Signs and symptoms of ocular involvement may include hyphema, eye redness, and photophobia.
Ocular involvement has been described only in children with multiple JXGs and more commonly occurs in children less than two years old.
There exists an association of JXG with neurofibromatosis 1 (NF-1). Importantly, the presence of JXGs in the setting of NF confers a higher risk (20-30 times) for developing juvenile myelomonocyticleukemia (JMML). Patients with NF and JXG should therefore be monitored closely for the development of JMML with serial complete hematologic evaluations, and referral to a hematologist.
Other hematologic malignancies have been reported in association with JXGs, including acute lymphoblastic leukemia, monocyticleukemia, hemophagocyticlymphohistiocytosis, and histiomonocyticreticulosis.
In adults, there have been six reported cases of xanthogranulomas linked to hematologic malignancies, including essential thrombocytosis, chronic lymphocytic leukemia, large B cell lymphoma, and monoclonal gammopathy. Some authors have advocated for hematologic evaluation in all adults who present with xanthogranulomas.
Treatment is not necessary for isolated cutaneous disease, as JXGs spontaneously involute and are usually asymptomatic.
Intraocular involvement often requires treatment with injectable or topical corticosteroids to prevent anterior chamber hemorrhage and glaucoma. Only when organ function is compromised in the context of systemic involvement is treatment indicated. Systemic therapy is similar to that for LCH and may include steroids, vinca alkaloid chemotherapeutics, and radiotherapy.
The diagnosis of JXG can be made clinically in the vast majority of patients, and a biopsy is generally not indicated. Histology can be a useful adjunct to rule out occasional clinical mimickers such as Spitz nevi or solitary mastocytoma. A biopsy may also be indicated to rule out more serious disease processes such as LCH if multiple lesions are present.
Optimal Therapeutic Approach for this Disease
As noted above, treatment is not indicated for asymptomatic cutaneous JXGs. If ulcerated, wound care with topical antibiotics or emollients is often adequate. Depending on location, size, and symptoms, excision may be indicated for ulcerated JXGs refractive to topical wound care, or very large JXGs in functionally critical sites such as the eyelid. Recurrences have been reported after excision.
Routine screening for extracutaneous disease is not indicated unless findings suggestive of systemic disease are present. A complete history, review of systems, and physical examination should be performed in all patients with JXG. A thorough history and physical exam is all that is required in cases of single JXG.
Given the risk of JMML in patients with NF and JXG, evaluate closely for stigmata of neurofibromatosis. Refer children less than two years old with multiple (two or more) JXGs located anywhere on the body to an ophthalmologist to evaluate for ocular involvement. For children who have a normal screening ophthalmologic exam, serial exams every six months until the child reaches age two are generally recommended.
Unusual Clinical Scenarios to Consider in Patient Management
Less common morphologic variants of JXG include subcutaneous, plaque-like, giant, clustered, keratotic, pedunculated, and disseminated. Subcutaneous JXG is the most common extracutaneous site and presents as an asymptomatic soft subcutaneous mass that is not attached to the overlying skin. Giant JXGs may be as large as 10cm and are typically congenital.
Disseminated juvenile xanthogranulomatosis is a term used to describe neonates with multiple JXGs and systemic involvement.
As previously stated, various hematologic malignancies have been reported in association with JXGs in both children and adults.
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