Cutaneous Presentation of Langerhans Cell Histiocytosis in a Neonate

Authors:
Richard H. Flowers, BA
University of Mississippi School of Medicine, Jackson

Jennifer Kaley, MD, and Barbara B. Wilson, MD
University of Virginia Health System, Charlottesville

A 20-day-old girl presented with a rash that had been noted within 24 hours of her birth. The rash had started as “red bumps” on her arms and legs and had spread centripetally. She was otherwise in good health. 

Physical examination revealed a healthy-appearing neonate in no apparent distress. Numerous edematous and erythematous papules, vesicles, and pustules measuring from 1 to 3 mm were distributed diffusely over her body. No ocular or oral involvement was noted.

Results of a complete blood cell count (CBC) and a comprehensive metabolic panel (CMP) were unremarkable. Results of a Tzanck preparation of a ruptured vesicle were negative. Gram staining of a pustule showed sheets of neutrophils and numerous atypical-appearing mononuclear cells.

A 3-mm punch biopsy was performed. Microscopic examination showed numerous large, atypical, mononucleated cells with notched and kidney-shaped nuclei. The enlarged mononucleated cells within the dermis stained strongly with immunohistochemical staining for CD1a antigen. These cells were also positive for langerin, a protein specific to Langerhans cells.

A skeletal radiographic survey showed a lytic lesion in the right scapula, and a bone marrow biopsy revealed numerous histiocytic cells, suggesting proliferative infiltrate. Further imaging results were concerning for splenic and hepatic involvement. The child received a diagnosis of multisystem Langerhans cell histiocytosis (LCH). Induction therapy with vinblastine and pulse-dosed prednisone was initiated.

After a relapse several months later, the girl was treated with cytarabine and cladribine. She completed another round of vinblastine with prednisone and, finally, 1 year of 6-mercaptopurine and methotrexate. Now at 4 years of age, she has been disease-free for more than 2 years.

Langerhans cell histiocytosis is the preferred name for a disease that previously had been called histiocytosis X. Its variants include Hand-Schüller-Christian disease, Letterer-Siwe disease, and eosinophilic granulomatosis.¹ LCH is a disease of proliferation of histiocytic cells. While they appear morphologically similar to antigen-presenting Langerhans cells of the epidermis, recent studies on gene expression in these cells indicate that they in fact are derived from immature CD34⁺ myeloid precursor cells.²

LCH is broadly categorized as one of 2 types: single-system, which most commonly has bone-only or skin-only involvement and accounts for approximately 55% of cases, and multisystem, which accounts for approximately 45% of cases.³ Single-system disease is further classified as unifocal or multifocal, and multisystem disease is classified based on the presence or absence of organ failure and of “risk organ” involvement (ie, liver, spleen, lungs, and hematopoietic system). Children younger than 4 years of age are more likely than adults to present with multisystem disease.⁴

Clinical presentation of LCH often is dermatologic, with reddish brown papules, recalcitrant eczematous rash (particularly in the scalp and genital regions), or oral lesions. Workup to determine the extent of involvement includes physical examination, CBC and CMP, skeletal radiographic survey, and chest radiographs.

Differential diagnosis of a papulovesicular and pustular rash in a newborn includes congenital herpes simplex, miliaria, transient neonatal pustular melanosis, cutaneous candidiasis, staphylococcal infection, and erythema toxicum neonatorum. Biopsy can differentiate many of these conditions. Diagnosis of LCH relies on positive stains to CD1a, S-100 and langerin (CD207). Electron microscopy reveals pathognomonic Birbeck granules but rarely is performed due to its expense.

For multisystem disease, initial induction therapy generally involves vinblastine and prednisone for 6 weeks. If the response is positive, patients receive at least 12 months of continuation therapy with these chemotherapeutic agents, plus or minus mercaptopurine. Second-line chemotherapies are used in the absence of response.⁵

The course of LCH varies greatly depending on the manifestation and initial response to induction chemotherapy. The mortality rate for unifocal bone lesions is as low as 0.9% and for cutaneous-only involvement is as low as 2%.⁴ In one study, 7 of 12 neonates less than 1 year old with skin-only LCH experienced spontaneous and permanent regression of LCH.⁶ However, for multisystem involvement and a poor initial response to chemotherapy, mortality rates range from 30% to 83%, and relapse rates are approximately 95%.⁴

References

1. Coppes-Zantinga A, Egeler RM. The Langerhans cell histiocytosis X files revealed. Br J Haematol. 2002;116(1):3-9.

2. Allen CE, Li L, Peters TL, et al. Cell-specific gene expression in Langerhans cell histiocytosis lesions reveals a distinct profile compared with epidermal Langerhans cells. J Immunol. 2010;184(8):4557-4567.

3. Grois N, Pötschger U, Prosch H, et al; DALHX- and LCH I and II Study Committees. Risk factors for diabetes insipidus in Langerhans cell histiocytosis. Pediatr Blood Cancer. 2006;46(2):228-233.

4. Satter EK, High WA. Langerhans cell histiocytosis: a review of the current recommendations of the Histiocyte Society. Pediatr Dermatol. 2008;25(3):291-295.

5. Gadner H, Heitger A, Grois N, Gatterer-Menz I, Ladisch S; DAL HX-83 Study Group. Treatment strategy for disseminated Langerhans cell histiocytosis. Med Pediatr Oncol. 1994;23(2):72-80.

6. Lau L, Krafchik B, Trebo MM, Weitzman S. Cutaneous Langerhans cell histiocytosis in children under one year. Pediatr Blood Cancer. 2006;46(1):66-71.