July 2016 Case 2

A 15-year-old male with a left lower eyelid lesion

Colleen J. Beatty, MSIII, Christine James, D.O., and H. James Williams, M.D.

Overview

A 15-year-old male presented to his dermatologist with a solitary, yellow-red nodule located on his left lower eyelid.  The patient noticed the lesion several weeks prior to presenting in clinic.  The lesion was non-painful and had not grown in size since discovery.  The patient had no significant past medical history, and a review of systems was negative.  The remainder of his physical exam and skin examination was unremarkable.  A biopsy of the nodule was performed in clinic and the specimen was sent to pathology for review.

Gross Description

The patient underwent excision of the lower eyelid nodule.  H&E-stained sections of the tissue revealed a dermal mass, with no apparent connection to the epidermis.  The epidermis appeared intact, without ulcerations or evidence of inflammatory or infiltrative processes (Figure 1).   The dermal mass was well-circumscribed, but non-encapsulated.  Magnification of the dermal infiltrate revealed a cellular proliferation including Touton giant cells and lymphocytes (Figures 2 and 3).

Figure 1 (H&E, 2x). Mass is located within the dermis with no apparent connection to the overlying epidermis.
Figure 2 (H&E, 10x). The dermal infiltrate is composed of Touton giant cells and lymphocytes against a background of cells with low N/C ratio and abundant eosinophilic cytoplasm.
Figure 3 (H&E, 40x). Touton giant cells are characterized by an inner core of smooth central cytoplasm, a wreath of bland nuclei, and an outer ring of foamy cytoplasm.

Diagnosis

Which of the following is the correct diagnosis?

Answer

Please select an answer above.

Discussion

Juvenile xanthogranuloma (JXG) is a benign proliferative disorder of non-Langerhans cell histiocytes.  As its name implies, it most commonly presents in the pediatric population, and on histology, is composed of Touton giant cells and lipid-laden histiocytes.  Cutaneous lesions are the most typical manifestation of this disorder, and the dermis is the most common site of involvement.5

Etiology and epidemiology

Juvenile xanthogranuloma is believed to be a reactive response by histiocytes to a stimulus.  The stimulus remains to be elicited; both physical and infectious causes have been proposed.6,7

JXG most commonly appears in the pediatric population, with the majority of tumors appearing within the first year of life.7  However, cases have been reported in adults. The prevalence is slightly higher in males than females (1.15:1) in cases of solitary cutaneous lesions.  Cases of multiple cutaneous lesions strongly favor males (12:1).5 

Clinical Presentation

Clinically, JXG may present as solitary or multifocal cutaneous lesions.  They are well-demarcated, firm, papules or nodules with yellow-red coloring, ranging in size from 1 millimeter to 2 centimeters.  Generally, the lesions are asymptomatic.  The most common location is on the head and neck, however they have been reported in almost every anatomic region of the skin.  Rarely, JXG can present in subcutaneous or extracutaneous locations, or even as systemic disease.5 

Dermatoscopy may be used by the dermatologist to narrow the differential diagnosis, but most cases still require histologic interpretation.  On dermatoscopy, clinicians may appreciate the orange-yellow, “setting sun appearance” of the background, “clouds” of yellow deposits (likely representing collections of lipid-laden histiocytes), and whitish streaks of fibrosis.8 

Classification system

Juvenile xanthogranuloma belongs to the class of non-Langerhans cell histiocytoses.   Histiocytoses collectively describe a group of disorders characterized by an infiltration of histiocytes, which are antigen-presenting cells found within tissues. The classification schema of histiocytoses remains in flux, but immunohistochemical features are commonly used to divide the disorders into Langerhans cell histiocytoses and non-Langerhans cell histiocytoses.  Langerhans cell histiocytoses are characterized by nuclear groves, and positive staining for S100 and CD1a.  On electron microscopy, Birbeck granules can be seen.  In contrast, the disorders that fall under the umbrella classification of non-Langerhans cell histiocytoses fail to stain for CD1a and lack Birbeck granules.  Another classification schema uses the constituent mononuclear cell of these disorders as the identifying feature.  In juvenile xanthogranuloma the proliferating cell is a dendrocyte, while the antigen-presenting cell in other non-Langerhans cell histiocytoses is a macrophage.4 

Histopathologic Diagnosis

Histologically, the lesion involves the dermis, with rare extension into the underlying subcutaneous tissue.  The epidermis and adnexal structures remain largely unaffected.  The lesion is well-circumscribed, but non-encapsulated, with a dense cellular infiltrate composed of histiocytes, giant cells, Touton cells, lymphocytes, eosinophils, and neutrophils.  Touton giant cells give the classic appearance to the infiltrate, with their inner smooth central cytoplasm, surrounded by a wreath of nuclei and an outer ring of foamy cytoplasm.  The histologic appearance of the infiltrate evolves as the lesion ages, with older lesions exhibiting more fibrosis.  Of note, juvenile xanthogranuloma lacks nuclear atypia, mitoses, and pleomorphism, helping to exclude malignancy from the differential diagnosis.8

If the diagnosis cannot be ascertained by basic H&E staining, IHC staining may be employed to distinguish between histiocytoses.  JXG stains positively for Factor XIIIa and CD68, and negatively for CD1a and S100.  Other non-Langerhans cell histiocytoses that are believed to derive from macrophages instead of dendrocytes do not stain for Factor XIIIa (a marker of dermal dendrocytes) and stain positively for S100, distinguishing them from the family of JXG.  Langerhans cell histiocytoses can be distinguished via IHC and electron microscopy.  Their staining characteristics include positivity for S100 and CD1a.  On EM, the classic Birbeck granules are seen, which is a key difference between Langerhans cell histiocytosis and non-Langerhans cell histiocytosis.4

Associated Conditions

Juvenile xanthogranuloma has been associated with neurofibromatosis type 1 (NF1), and is reported in approximately 5 to 10% of NF1 patients.  Upon detection of a juvenile xanthogranuloma, skin checks for café au lait spots are recommended.6  A triple association between JXG, NF1, and juvenile chronic myelomonocytic leukemia has also been described in the literature, however the underlying mechanism has yet to be elucidated.4,6

Treatment & Prognosis

The prognosis for cutaneous juvenile xanthogranuloma is good, as the disease is self-limiting.  Most cases will resolve spontaneously within several years.   A hyperpigmented or atrophic scar may remain after resolution.  If removed by excisional biopsy for cosmetic or diagnostic purposes, the majority of lesions will not recur.4,6

A variety of treatment modalities have been employed for extracutaneous disease, depending on the clinical scenario and anatomic location.  For cases of ocular juvenile xanthogranuloma, high-dose corticosteroids and radiation have been utilized, reserving surgery for therapy-resistant cases.6  For the rare cases of extensive systemic disease that are symptomatic, chemotherapy with vinca alkaloids has shown promise.  This regimen was adapted from systemic Langerhans cell histiocytosis treatment.4,7

References

  1. Ghosh C, Ghosh T. Eyelid lesions.  UpToDate.  Last updated 9/24/2015.
  2. Rohrich RJ, Janis JE, Pownell PH. Xanthelasma palpebrarum:  A review and current management principles.  Plastic Reconstructive Surgery.  2002.  110(5):  1310-4.
  3. Rosai J. Lymph nodes.  In Rosai and Ackerman’s Surgical Pathology.  (pp 1801-1805). 2011. Philadelphia:  Mosby Elsevier.
  4. Weitzman S, Jaffe R. Review:  Uncommon histiocytic disorders:  The non-Langerhans cell histiocytoses.  Pediatric Blood Cancer. 2005. 45:  256-264.
  5. Dehner LP. Juvenile xanthogranulomas in the first two decades of life:  A clinicopathologic study of 174 Cases with cutaneous and extracutaneous manifestations.  American Journal of Surgical Pathology.  2003.  27(5):  579-593.
  6. Hernandez-Martin A, Baselga E, Drolet BA, Esterly NB. Juvenile xanthogranuloma.  Journal of the American Academy of Dermatology.  1997.  36. 3(1):  355-367.
  7. Stover DG, Alapati S, Regueira O, Turner C, Whitlock JA. Treatment of juvenile xanthogranuloma.  Pediatric Blood Cancer.  2008.  51(1):  130-3. 
  8. Song M, Kim SH, Jung DS, Ko HC, Kwon KS, and Kim MB. Structural correlations between dermoscopic & histopathological features of juvenile xanthogranuloma.  Journal of the European Academy of Dermatology and Venereology.  2011. 25:  259-263.