A 2-year-old previously healthy girl presented to the pediatric dermatology clinic with recalcitrant diaper dermatitis for 6 months despite treatment with topical antifungals and topical antibacterials. The girl had a history of fatigue and a 2-week history of bilateral ear discharge. Functional enquiry findings were otherwise unremarkable.
On physical examination, the child had erosive erythematous plaques over the inguinal areas bilaterally with involvement of the perivulvar skin (Figure 1). There were multiple papules covered by yellow-brown scales overlying the scalp (Figure 2). Otorrhea was noted bilaterally. The inguinal lymph nodes were enlarged bilaterally. There was no hepatosplenomegaly. The rest of the physical examination findings were unremarkable.
Laboratory investigations revealed a normal complete blood cell count, C-reactive protein level, serum electrolyte levels, creatinine level, liver enzyme levels, coagulation profiles, and urine specific gravity. Abdominal ultrasonography revealed no hepatosplenomegaly. A radiographic skeletal survey showed multiple “punched-out” lytic lesions in the skull (Figure 3) consistent with Langerhans cell histiocytosis (LCH).
Computed tomography (CT) scanning of the head revealed extensive erosions of the skull and auditory canal. Biopsy of a scalp lesion and a groin lesion showed infiltrates of eosinophils, T lymphocytes, macrophages, multinucleated giant cells, and Langerhans cells. Immunohistochemical staining of Langerhans cells was positive for CD1a and CD207 (Langerin), confirming the diagnosis of LCH.
LCH is a proliferative disease of Langerhans cells derived from myeloid progenitor cells from the bone marrow.1,2 The exact pathogenesis is not known. It is debatable whether LCH is reactive or neoplastic in nature.3 The estimated annual incidence of LCH is 2 to 9 cases per million children younger than 15 years of age.1 Although LCH can occur at any age, it is mainly a disease of childhood, with a peak incidence between 1 and 3 years of age.4
Generally, patients with LCH can be divided into two groups based on the extent of involvement at diagnosis—namely, single-system LCH and multisystem LCH.5-7 In single-system LCH, only one organ or system is involved such as bone, skin, lymph node (not the draining lymph node of another LCH location), central nervous system, or lungs.5-7 The involvement may be unifocal (single lesion on bone or lymph node) or multifocal (multiple lesions on bone or multiple lymph nodes).5-7 In multisystem LCH, two or more organs or systems are involved at diagnosis, with or without involvement of risk organs (spleen, liver, and/or hematopoietic system).5-7
LCH is a disease with many faces. Clinical manifestations vary depending on the sites and extent of involvement.8 Sites of involvement, in order of decreasing frequency, include the bone (79%), skin (36%), pituitary gland (25%), liver (16%), bone marrow (15%), spleen (14%), lymph nodes (13%), lungs (13%), and central nervous system (5%).5,9
Although bone lesions can be asymptomatic, pain and a soft raised mass in a localized area of the bone are common.3,5 Typical radiographic findings include a solitary “punched-out” lytic lesion of the skull, endosteal scalloping in long bones, and symmetric flattening of the anterior and middle vertebral column (vertebra plana).10,11
Common cutaneous manifestations include seborrheic dermatitis–like eruption, eczematous lesions, and erythematous/reddish-brown crusted/scaly papules/maculopapules/plaques/patches.3,11 Familiarity with the cutaneous manifestations of LCH is important, since the cutaneous manifestations are often the leading clue for disease diagnosis, as is illustrated in the case described above.
Other clinical manifestations or complications include, among others, central (neurogenic) diabetes insipidus manifesting as polyuria and polydipsia; growth failure; precocious or delayed puberty; hepatomegaly and/or splenomegaly; lymphadenopathy; anemia; leukopenia; and thrombocytopenia.3,5,11
A definitive diagnosis can be made by histologic/immunohistochemical examination of a biopsy of lesional tissue. Positive CD1a and CD207 (Langerin) immunohistochemical staining of lesional cells has replaced electron microscopy for the detection of Birbeck granules, which are cytoplasmic tennis-racquet–shaped organelles characteristic of LCH cells, because expression of Langerin has 100% concordance with the ultrastructural presence of Birbeck granules.6,7,11Treatment:
Our patient had multisystem LCH with involvement of the skin and bone. The current recommended first-line therapy for patients with multisystem LCH is 12 months of therapy with prednisone and vinblastine.5,8,12,13 The regimen consists of 6 weeks of initial therapy with prednisolone (40 mg/m2/day orally for 4 weeks, and then tapered over 2 weeks) and vinblastine (6 mg/m2 weekly intravenous bolus for 6 weeks).5 This is followed by a continuation therapy for a total treatment duration of 12 months.5,13 Continuation therapy consists of prednisolone (40 mg/m2/day) given orally for 5 days and vinblastine (6 mg/m2) as an intravenous bolus every 3 weeks.13 Mercaptopurine (50 mg/m2/day orally) is added for patients with risk organ involvement.5
Alexander K. C. Leung, MD Clinical Professor of Pediatrics, University of Calgary, and Pediatric Consultant, Alberta Children’s Hospital, Calgary, Alberta, Canada
Joseph M. Lam, MD Clinical Associate Professor, University of British Columbia, and Associate Member, Department of Dermatology and Skin Sciences, University of British Columbia, Vancouver, British Columbia, Canada
Kin Fon Leong, MD Consultant Pediatric Dermatologist, Pediatric Institute, Kuala Lumpur General Hospital, Kuala Lumpur, Malaysia
1. Papadopoulou M, Panagopoulou P, Papadopoulou A, et al. The multiple faces of Langerhans cell histiocytosis in childhood: a gentle reminder. Mol Clin Oncol. 2018;8(3):489-492.
2. Yurkovich M, Wong A, Lam JM. Solitary congenital self-healing Langerhans cell histiocytosis: a benign variant of Langerhans cell histiocytosis? Dermatol Online J. 2013;19(1):3.
3. Jezierska M, Stefanowicz J, Romanowicz G, Kosiak W, Lange M. Langerhans cell histiocytosis in children – a disease with many faces. Recent advances in pathogenesis, diagnostic examinations and treatment. Postepy Dermatol Alergol. 2018;35(1):6-17.
4. Bi L, Sun B, Lu Z, Shi Z, Wang D, Zhu Z. Langerhans cell histiocytosis with multisystem involvement in an infant: a case report. Exp Ther Med. 2015;9(6):2137-2140.
5. McClain KL. Clinical manifestations, pathologic features, and diagnosis of Langerhans cell histiocytosis. UpToDate. https://www.uptodate.com/contents/clinical-manifestations-pathologic-features-and-diagnosis-of-langerhans-cell-histiocytosis. Updated July 30, 2019. Accessed September 12, 2019.
6. Donadieu J, Chalard F, Jeziorski E. Medical management of langerhans cell histiocytosis from diagnosis to treatment. Expert Opin Pharmacother. 2012;13(9):1309-1322.
7. Haupt R, Minkov M, Astigarraga I, et al; Euro Histio Network. Langerhans cell histiocytosis (LCH): guidelines for diagnosis, clinical work-up, and treatment for patients till the age of 18 years. Pediatr Blood Cancer. 2013;60(2):175-184.
8. Thacker NH, Abla O. Pediatric Langerhans cell histiocytosis: state of the science and future directions. Clin Adv Hematol Oncol. 2019;17(2):122-131.
9. Papo M, Cohen-Aubart F, Trefond L, et al. Systemic histiocytosis (Langerhans cell histiocytosis, Erdheim–Chester disease, Destombes–Rosai–Dorfman disease): from oncogenic mutations to inflammatory disorders. Curr Oncol Rep. 2019;21(7):62.
10. DiCaprio MR, Roberts TT. Diagnosis and management of Langerhans cell histiocytosis. J Am Acad Orthop Surg. 2014;22(10):643-652.
11. Leung AKC, Lam JM, Leong KF. Childhood Langerhans cell histiocytosis: a disease with many faces [published online August 28, 2019]. World J Pediatr. doi:10.1007/s12519-019-00304-9.
12. Krooks J, Minkov M, Weatherall AG. Langerhans cell histiocytosis in children: history, classification, pathobiology, clinical manifestations, and prognosis. J Am Acad Dermatol. 2018;78(6):1035-1044.
13. Minkov M. An update on the treatment of pediatric-onset Langerhans cell histiocytosis through pharmacotherapy. Expert Opin Pharmacother. 2018;19(3):233-242.