Differentiating Skin-Limited and Multisystem Langerhans Cell Histiocytosis

      Objective

      To identify features associated with multisystem involvement and therapeutic failure in patients with skin Langerhans cell histiocytosis (LCH).

      Study design

      We reviewed medical records of 71 consecutive patients with LCH with skin involvement evaluated at Texas Children's Hospital and analyzed clinical features, laboratory results, and the presence of circulating cells with the BRAF-V600E mutation with respect to initial staging and clinical outcomes.

      Results

      Skin disease in patients older than 18 months of age at diagnosis was associated with the presence of multisystem disease (OR, 9.65; 95% CI, 1.17-79.4). Forty percent of patients referred for presumed skin-limited LCH had underlying multisystem involvement, one-half of these with risk-organ involvement. Patients with skin-limited LCH had a 3-year progression-free survival of 89% after initial therapy, and none developed multisystem disease. Patients with skin/multisystem involvement had a 3-year progression-free survival of 44% with vinblastine/prednisone therapy, and risk-organ involvement did not correlate with failure to achieve nonactive disease. Circulating cells with BRAF-V600E were detected at higher frequency in patients with multisystem involvement (8 of 11 skin/multisystem vs 1 of 13 skin-limited; P = .002).

      Conclusion

      Skin-limited LCH necessitates infrequent therapeutic intervention and has a lower risk of progression relative to skin plus multisystem LCH. The less-aggressive clinical course and lack of circulating cells with the BRAF-V600E mutation in skin-limited LCH suggest a different mechanism of disease origin compared with multisystem or risk-organ disease.
      AD (Active disease), LCH (Langerhans cell histiocytosis), NAD (Nonactive disease), OS (Overall survival), PFS (Progression-free survival)
      Langerhans cell histiocytosis (LCH) is an inflammatory myeloid neoplasia
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      • Lim K.P.
      • Peters T.
      • Price J.
      • Takizawa H.
      • Salmon H.
      • et al.
      BRAF-V600E expression in precursor versus differentiated dendritic cells defines clinically distinct LCH risk groups.
      characterized by the accumulation of clonal CD207+ myeloid dendritic cells amidst an inflammatory background of macrophages, T lymphocytes, and eosinophils.
      • Willman C.L.
      • Busque L.
      • Griffith B.B.
      • Favara B.E.
      • McClain K.L.
      • Duncan M.H.
      • et al.
      Langerhans' cell histiocytosis (histiocytosis X): a clonal proliferative disease.
      • Yu R.C.
      • Chu C.
      • Buluwela L.
      • Chu A.C.
      Clonal proliferation of Langerhans cells in Langerhans cell histiocytosis.
      • Berres M.L.
      • Allen C.E.
      • Merad M.
      Pathological consequence of misguided dendritic cell differentiation in histiocytic diseases.
      LCH presents most commonly in infants and children. The effects of LCH are highly variable, ranging from single-system disease in skin or bone to multisystem disease, potentially with risk-organ (ie, liver, spleen, and bone marrow) involvement that is predictive of increased mortality.
      • Gadner H.
      • Minkov M.
      • Grois N.
      • Potschger U.
      • Thiem E.
      • Arico M.
      • et al.
      Therapy prolongation improves outcome in multisystem Langerhans cell histiocytosis.
      Patients with LCH frequently present with cutaneous signs that sometimes resemble eczema or seborrheic dermatitis, with the scalp the most common site of involvement.
      • Munn S.
      • Chu A.C.
      Langerhans cell histiocytosis of the skin.
      LCH lesions involving the skin may represent skin-limited disease that can resolve spontaneously or with minimal chemotherapy. Alternatively, skin lesions may represent the most clinically evident manifestation of potentially life-threatening multisystem disease. Previous studies have reported that 53% of patients with multisystem LCH present with skin lesions
      • Titgemeyer C.
      • Grois N.
      • Minkov M.
      • Flucher-Wolfram B.
      • Gatterer-Menz I.
      • Gadner H.
      Pattern and course of single-system disease in Langerhans cell histiocytosis data from the DAL-HX 83- and 90-study.
      • Gadner H.
      • Heitger A.
      • Grois N.
      • Gatterer-Menz I.
      • Ladisch S.
      Treatment strategy for disseminated Langerhans cell histiocytosis. DAL HX-83 Study Group.
      ; however, the true incidence of skin-limited LCH may be underestimated, because patients with spontaneously resolving or mild disease may go undiagnosed or might not be referred to specialists.
      • Lau L.
      • Krafchik B.
      • Trebo M.M.
      • Weitzman S.
      Cutaneous Langerhans cell histiocytosis in children under one year.
      The potential of skin-limited LCH to “metastasize” to other organs is not clear, with previous studies reporting widely varying rates of progression of isolated skin LCH to multisystem disease (0-60%).
      • Titgemeyer C.
      • Grois N.
      • Minkov M.
      • Flucher-Wolfram B.
      • Gatterer-Menz I.
      • Gadner H.
      Pattern and course of single-system disease in Langerhans cell histiocytosis data from the DAL-HX 83- and 90-study.
      • Lau L.
      • Krafchik B.
      • Trebo M.M.
      • Weitzman S.
      Cutaneous Langerhans cell histiocytosis in children under one year.
      • Battistella M.
      • Fraitag S.
      • Teillac D.H.
      • Brousse N.
      • de Prost Y.
      • Bodemer C.
      Neonatal and early infantile cutaneous langerhans cell histiocytosis: comparison of self-regressive and non-self-regressive forms.
      • Minkov M.
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      • Grois N.
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      • Kaatsch P.
      • et al.
      Langerhans cell histiocytosis in neonates.
      • Larralde M.
      • Rositto A.
      • Giardelli M.
      • Gatti C.F.
      • Santos-Munoz A.
      Congenital self-healing Langerhans cell histiocytosis: the need for a long-term follow-up.
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      • Gatti C.F.
      Santos Munoz A. Congenital self-healing histiocytosis (Hashimoto-Pritzker).
      • Willis B.
      • Ablin A.
      • Weinberg V.
      • Zoger S.
      • Wara W.M.
      • Matthay K.K.
      Disease course and late sequelae of Langerhans' cell histiocytosis: 25-year experience at the University of California, San Francisco.
      • Hashimoto K.
      • Bale G.F.
      • Hawkins H.K.
      • Langston C.
      • Pritzker M.S.
      Congenital self-healing reticulohistiocytosis (Hashimoto-Pritzker type).
      • Ng S.S.
      • Koh M.J.
      • Tay Y.K.
      Cutaneous Langerhans cell histiocytosis: study of Asian children shows good overall prognosis.
      Risk-organ involvement and inadequate response to initial therapy are the major clinical features currently associated with adverse outcomes in patients with skin LCH.
      • Gadner H.
      • Minkov M.
      • Grois N.
      • Potschger U.
      • Thiem E.
      • Arico M.
      • et al.
      Therapy prolongation improves outcome in multisystem Langerhans cell histiocytosis.
      • Gadner H.
      • Grois N.
      • Arico M.
      • Broadbent V.
      • Ceci A.
      • Jakobson A.
      • et al.
      A randomized trial of treatment for multisystem Langerhans' cell histiocytosis.
      • Gadner H.
      • Grois N.
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      • Arico M.
      • Braier J.
      • et al.
      Improved outcome in multisystem Langerhans cell histiocytosis is associated with therapy intensification.
      Other predictors of disease extent, risk of progression or recurrence, or survival remain to be elucidated. The somatic BRAF-V600E mutation has been identified in pathological dendritic cells of LCH lesions in approximately 60% of patients.
      • Badalian-Very G.
      • Vergilio J.A.
      • Degar B.A.
      • MacConaill L.E.
      • Brandner B.
      • Calicchio M.L.
      • et al.
      Recurrent BRAF mutations in Langerhans cell histiocytosis.
      Although BRAF status of the lesion does not predict risk-organ involvement, detection of BRAF-V600E in circulating blood cells has been associated with an increased risk of disease recurrence independent of risk-organ involvement.
      • Berres M.L.
      • Lim K.P.
      • Peters T.
      • Price J.
      • Takizawa H.
      • Salmon H.
      • et al.
      BRAF-V600E expression in precursor versus differentiated dendritic cells defines clinically distinct LCH risk groups.
      Among patients with BRAF-V600E mutation identified in lesional biopsy specimens, the presence of circulating cells with the BRAF-V600E mutation was highly sensitive and specific for multisystem high-risk LCH.
      • Berres M.L.
      • Lim K.P.
      • Peters T.
      • Price J.
      • Takizawa H.
      • Salmon H.
      • et al.
      BRAF-V600E expression in precursor versus differentiated dendritic cells defines clinically distinct LCH risk groups.
      In this study, we evaluated the significance of clinical variables, including age and presence of circulating cells with BRAF-V600E, with respect to the extent of disease at diagnosis and clinical outcomes in patients with LCH skin lesions.

      Methods

      Medical records of 71 consecutive patients who presented with any LCH skin lesions, either as skin-limited disease or as multisystem disease, at the Texas Children's Cancer and Hematology Centers between March 2005 and October 2011 were reviewed. Patients who presented either with de novo disease or from referral after diagnosis were included in this study. The age, date of diagnosis, date of symptom onset, location of LCH involvement, type of therapy, response to therapy, and time to recurrence or disease progression were recorded. The review of patient records was performed according to protocols approved by the Institutional Review Board of Baylor College of Medicine.
      The incidence and location of progression and recurrence were recorded as counts and proportions using categorical variables, and age of symptom onset, age at diagnosis, and time to disease progression were recorded as means and ranges. Disease state and response criteria were defined according to the Histiocyte Society's evaluation and treatment guidelines for LCH.

      Minkov M, Grois N, McClain K, Nanduri V, Rodriguez-Galindo C, Simonitsch-Klupp I, et al. Histiocyte Society evaluation and treatment guidelines, April 2009. www.histiocytesociety.org/document.doc?id=290. Accessed June 1, 2013.

      Disease state was classified as nonactive disease (NAD) or active disease (AD). Response in patients with AD was noted as AD/better (improving disease), AD/intermediate (stable disease, or regression with new sites of disease), or AD/worse. Progression was defined as development of AD/worse. Progression-free survival (PFS) was calculated using the Kaplan-Meier method and compared using the Mantel-Cox log-rank test, with data censored at the time of last follow-up. Clinical variables between groups of patients were compared using the 2-tailed Mann-Whitney test for nonparametric data. Contingency analyses were performed with the Fisher exact test. ORs and 95% CIs were calculated to determine the association between clinical features of skin LCH and multisystem disease. The Mantel-Haenszel method was used to determine the hazard ratio of disease progression between skin-limited and skin plus multisystem disease. Data analyses were performed using Prism version 5.0 (GraphPad, La Jolla, California).
      A highly sensitive quantitative polymerase chain reaction strategy was used to detect cells with the BRAF-V600E allele in LCH biopsy specimens and peripheral blood mononuclear cells, as described previously.
      • Berres M.L.
      • Lim K.P.
      • Peters T.
      • Price J.
      • Takizawa H.
      • Salmon H.
      • et al.
      BRAF-V600E expression in precursor versus differentiated dendritic cells defines clinically distinct LCH risk groups.
      Experiments were performed and clinical data collected according to protocols approved by Baylor College of Medicine's Institutional Review Board.

      Results

      Seventy-one patients presented with LCH skin lesions between March 2005 and August 2012 (Table). Of these patients, 21 were determined to have skin-limited disease, and 43 patients had multisystem involvement. Seven patients with multisystem disease, referred late in the course of treatment, could not be categorized due to incomplete information at diagnosis, and these patients were not included in subsequent analyses.
      TablePatient characteristics
      CohortsNumber of patientsSex distributionAge at symptom onset, mo, median (range)Age at diagnosis, mo, median (range)
      Skin-only LCH2114 males, 7 females1.2 (birth-30.5)5.9 (birth-33.5)
      Multisystem LCH (extent known at presentation)4320 males, 23 females1.8 (0.1-206)11.6 (0.2-207)
      Multisystem LCH (extent not known at presentation)74 males, 3 femalesBirth (birth-2.8)4.7 (birth-27.1)
      Total7138 males, 33 females1.6 (birth-206)7.2 (birth-207)
      The majority of patients with skin-limited and skin plus multisystem disease were under 1 year of age at diagnosis (Table). Older age was correlated with the presence of multisystem disease (P = .01; Figure 1, A). Skin disease diagnosed in patients aged >18 months was associated with the presence of multisystem disease (OR, 9.65; 95% CI, 1.17-79.4); however, the appearance of LCH skin lesions at a younger age was not correlated with the absence of multisystem disease, and LCH rash developing in the first week of life was not significantly associated with the absence of multisystem disease (OR, 0.51; 95% CI, 0.17-1.5; Figure 1, B). An interval of >100 days between symptom onset and diagnosis was correlated with the presence of multisystem disease (OR, 3.82; 95% CI, 1.24-11.8).
      Figure thumbnail gr1
      Figure 1A, Patient age distribution at diagnosis. P < .05. B, Onset of symptoms at birth was not significantly associated with the absence of multisystem disease.
      Patients with LCH skin lesions were evaluated for multisystem disease by radiographic skeletal survey and skull series, complete blood counts, hepatic function studies, and chest radiography. Additional tests (ie, brain magnetic resonance imaging, chest or abdominal computed tomography) were obtained based on the findings of previous studies or clinical presentation.
      • Broadbent V.
      • Gadner H.
      • Komp D.M.
      • Ladisch S.
      Clinical Writing Group of the Histiocyte Society
      Histiocytosis syndromes in children, II: approach to the clinical and laboratory evaluation of children with Langerhans cell histiocytosis.
      Fourteen of 35 patients (40%) referred by primary care providers for presumed skin-limited LCH, ranging in age at symptom presentation from birth to age 30 months, were subsequently found to have multisystem involvement. The most common additional site of involvement was bone, in 10 of 14 patients (71%). Risk-organ disease (liver, spleen, or bone marrow) occurred in 7 of 14 patients (50%). Lung disease (no longer considered a risk-organ site)
      • Braier J.
      • Latella A.
      • Balancini B.
      • Castanos C.
      • Rosso D.
      • Chantada G.
      • et al.
      Outcome in children with pulmonary Langerhans cell histiocytosis.
      • Ronceray L.
      • Potschger U.
      • Janka G.
      • Gadner H.
      • Minkov M.
      Pulmonary involvement in pediatric-onset multisystem Langerhans cell histiocytosis: effect on course and outcome.
      was also present in 3 of 14 patients at the time of postdiagnostic evaluation.

       Skin-Limited LCH

      Skin-limited LCH in this cohort often resolved spontaneously, did not progress to involve other organs, and in most cases responded to primary therapy. Of the 20 patients with skin-limited LCH with follow-up data, 17 initially underwent a period of observation, and 3 were treated at the time of diagnosis. Twelve patients (60%) had spontaneous resolution without any intervention or subsequent recurrence. Six patients (30%), 5 of whom were observed initially, experienced disease progression or recurrence. This series included no patients with skin-limited LCH defined by comprehensive staging at diagnosis with evidence of subsequent progression to other organ systems.
      Only 2 patients with skin-limited LCH experienced disease progression after the initial therapy. Of the 8 patients who were eventually treated, 5 achieved NAD after initial therapy, 2 developed AD/worse, and 1 patient was lost to follow-up before the response to therapy could be assessed. Both patients with AD/worse posttreatment received oral methotrexate as initial therapy. Of the 20 patients with skin-limited LCH, 18 (90%) had NAD at the time of last follow-up. Three-year overall survival (OS) of all patients with skin-limited LCH was 100%. Progression was noted in 6 patients (3-year PFS, 70%). If only progression after initiation of therapy was considered, however, the 3-year PFS was 89% (Figure 2, A).
      Figure thumbnail gr2
      Figure 2A, OS and PFS of patients with skin-limited LCH. B, Progression in skin-limited LCH vs skin plus multisystem disease. C and D, Progression for risk-organ involvement in C, the entire series and in D, patients receiving uniform initial therapy. E, Progression necessitating second therapy in skin plus multisystem disease vs skin-limited disease. F, BRAF-V600E mutation was detected in circulating peripheral blood cells in 8 of 11 patients with active skin plus multisystem LCH, but in only 1 of 13 patients with active skin-limited LCH, and in only a low percentage of cells (P = .0009).

       Multisystem LCH Including Skin Lesions

      Patients with skin plus multisystem LCH were treated with systemic chemotherapy. Thirty-nine patients had an evaluable response to therapy, 3 were lost to follow-up, and 1 with risk-organ involvement died before initiation of therapy. The 3-year OS of patients with skin plus multisystem disease who received treatment was 100%; however, patients with skin plus multisystem disease were significantly more likely to progress than those with skin-limited disease (3-year progression, 77% vs 30%; P = .005; Figure 2, B). Forty-four percent of patients with skin plus multisystem disease had risk-organ involvement at diagnosis. There was no significant difference in progression between skin plus multisystem patients with risk-organ involvement (n = 17) and those without risk-organ involvement (n = 22) (3-year progression, 80% vs 68%; P = .26; Figure 2, C). The median time to progression was 11 months in risk-organ disease and 16.3 months without risk-organ disease.
      To evaluate the effect of standard vinblastine/prednisone-based therapy in the management of skin plus multisystem LCH, as well as to minimize referral bias, we separately evaluated the 17 patients treated with this regimen as primary therapy within our institution and identified no significant difference in progression between patients with and those without risk-organ disease (Figure 2, D). More than one-half (56%) of these patients with skin plus multisystem disease experienced disease progression during or after initial therapy, compared with only 11% of patients with skin-limited disease (hazard ratio, 4.00; 95% CI, 1.22-13.18; P = .02; Figure 2, E). Of the 6 patients with risk-organ involvement who experienced disease progression, 5 had persistence or progression of disease in risk organs, and none achieved NAD before disease progression. Of the 3 patients without risk-organ involvement that recurred, all 3 achieved NAD before recurrence, and only 1 had disease recurrence in an organ besides the skin.
      Patients with skin plus multisystem disease usually responded to salvage therapy but often required multiple different regimens for a durable complete response. Of the 39 patients with an evaluable response to therapy, 29 (74%) had NAD at the time of last follow-up after a median of 3 distinct therapy regimens. Among patients with AD at last evaluation, 5 patients were AD/better and 5 were AD/worse after a median of 2.5 regimens. Risk-organ involvement did not predict eventual failure to develop NAD (P = 1.00). No deaths occurred after initiation of treatment in this series.

       Circulating Cells with the BRAF-V600E Mutation in Patients with Skin LCH

      Pretherapy peripheral blood samples were analyzed for circulating cells with the BRAF-V600E mutation. Of the 13 patients with active skin-limited disease, only 1 (8%) had detectable circulating cells with the BRAF-V600E mutation. These results were compared with previously analyzed peripheral blood samples from 11 patients with skin plus multisystem LCH.
      • Berres M.L.
      • Lim K.P.
      • Peters T.
      • Price J.
      • Takizawa H.
      • Salmon H.
      • et al.
      BRAF-V600E expression in precursor versus differentiated dendritic cells defines clinically distinct LCH risk groups.
      BRAF-V600E was identified in the circulating cells of 8 of these 11 patients (72%), all of whom had BRAF-V600E identified in the diagnostic biopsy analysis. Six of the 8 patients with circulating BRAF-V600E cells had risk-organ involvement. Circulating cells with BRAF-V600E were detected in patients with skin/multisystem involvement not only at a higher frequency, but also in a higher percentage of cells (0.05%-0.98% vs 0.02% in the 1 skin-limited patient with detectable mutation; P < .001; Figure 2, F). In the patient with skin-limited LCH and circulating BRAF-V600 E cells at diagnosis, BRAF-V600E cells were not detected after effective treatment with oral methotrexate. Although diagnostic skin biopsy tissue was not available for evaluating the frequency of BRAF-V600E in skin-limited patients, we hypothesize that it occurs with similar frequency as that of LCH in general (50%-65%), given that all studies reported to date have found a common frequency across clinical risk groups.
      • Berres M.L.
      • Lim K.P.
      • Peters T.
      • Price J.
      • Takizawa H.
      • Salmon H.
      • et al.
      BRAF-V600E expression in precursor versus differentiated dendritic cells defines clinically distinct LCH risk groups.
      • Badalian-Very G.
      • Vergilio J.A.
      • Degar B.A.
      • MacConaill L.E.
      • Brandner B.
      • Calicchio M.L.
      • et al.
      Recurrent BRAF mutations in Langerhans cell histiocytosis.
      • Haroche J.
      • Charlotte F.
      • Arnaud L.
      • von Deimling A.
      • Helias-Rodzewicz Z.
      • Hervier B.
      • et al.
      High prevalence of BRAF V600E mutations in Erdheim-Chester disease but not in other non-Langerhans cell histiocytoses.
      • Satoh T.
      • Smith A.
      • Sarde A.
      • Lu H.C.
      • Mian S.
      • Trouillet C.
      • et al.
      B-RAF mutant alleles associated with Langerhans cell histiocytosis, a granulomatous pediatric disease.
      Thus, we hypothesize that these results reflect a lack of circulating LCH lesion precursors in patients with skin-limited disease.

      Discussion

      LCH occurs in 2-10 per million children and 1-2 per million adults per year, with extreme clinical heterogeneity.
      • Salotti J.A.
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      Incidence and clinical features of Langerhans cell histiocytosis in the UK and Ireland.
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      Multisystem Langerhans cell histiocytosis in children: current treatment and future directions.
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      • McClain K.L.
      Langerhans cell histiocytosis: a review of past, current and future therapies.
      Involvement of risk organs (liver, spleen, and bone marrow) and failure to respond to the first 12 weeks of therapy predict increased mortality risk.
      • Gadner H.
      • Minkov M.
      • Grois N.
      • Potschger U.
      • Thiem E.
      • Arico M.
      • et al.
      Therapy prolongation improves outcome in multisystem Langerhans cell histiocytosis.
      • Gadner H.
      • Heitger A.
      • Grois N.
      • Gatterer-Menz I.
      • Ladisch S.
      Treatment strategy for disseminated Langerhans cell histiocytosis. DAL HX-83 Study Group.
      Accurate staging is essential to determine optimal therapy, because observation or curettage may be appropriate for single-system disease, whereas systemic chemotherapy is required for multisystem LCH. Survival of patients with LCH is >90% in non–risk-organ disease, and the recent LCH-III trial has shown decreased disease reactivation rates in both risk-organ and non–risk-organ disease with prolongation of therapy from 6 months to 1 year.
      • Gadner H.
      • Minkov M.
      • Grois N.
      • Potschger U.
      • Thiem E.
      • Arico M.
      • et al.
      Therapy prolongation improves outcome in multisystem Langerhans cell histiocytosis.
      • Morimoto A.
      • Ikushima S.
      • Kinugawa N.
      • Ishii E.
      • Kohdera U.
      • Sako M.
      • et al.
      Improved outcome in the treatment of pediatric multifocal Langerhans cell histiocytosis: results from the Japan Langerhans Cell Histiocytosis Study Group-96 protocol study.
      • Ceci A.
      • de Terlizzi M.
      • Colella R.
      • Loiacono G.
      • Balducci D.
      • Surico G.
      • et al.
      Langerhans cell histiocytosis in childhood: results from the Italian Cooperative AIEOP-CNR-H.X '83 study.
      However, all patients with LCH, especially those with prolonged uncontrolled disease, may develop long-term morbidity, including chronic pain, problems with growth, endocrinopathies, and neurocognitive deficits.
      • Haupt R.
      • Nanduri V.
      • Calevo M.G.
      • Bernstrand C.
      • Braier J.L.
      • Broadbent V.
      • et al.
      Permanent consequences in Langerhans cell histiocytosis patients: a pilot study from the Histiocyte Society Late Effects Study Group.
      Therefore, timely recognition, staging, and therapy of LCH are essential for optimal outcomes.
      Skin lesions are a classical feature of LCH. Because the appearance of LCH skin lesions is variable and easily confused with more common childhood rashes, such as eczema or seborrheic dermatitis (Figure 3), consideration of LCH and diagnostic biopsy are often delayed. In this series, the median time from onset of symptoms to diagnostic biopsy exceeded 3 months. Although some patients have self-resolving skin lesions,
      • Titgemeyer C.
      • Grois N.
      • Minkov M.
      • Flucher-Wolfram B.
      • Gatterer-Menz I.
      • Gadner H.
      Pattern and course of single-system disease in Langerhans cell histiocytosis data from the DAL-HX 83- and 90-study.
      • Lau L.
      • Krafchik B.
      • Trebo M.M.
      • Weitzman S.
      Cutaneous Langerhans cell histiocytosis in children under one year.
      our experience has been that many patients diagnosed with LCH by skin biopsy analysis are frequently assumed to have skin-limited disease without further evaluation.
      Figure thumbnail gr3
      Figure 3Skin LCH has a variable appearance, including A, eczematous dermatitis; B, hypopigmented, eroded papules; C, hypopigmented macules; or D and E, crusted papulonodules. Presentation does not reflect presence or absence of multisystem disease; despite similar appearance, the patient in D, had a single lesion, but the patient in E, had risk-organ involvement.
      To identify clinical characteristics of skin LCH that might distinguish children with skin-limited disease from those with multisystem disease, we reviewed 71 patients treated at Texas Children's Hospital over a 5-year period. In this series, age >18 months at the time of diagnosis of LCH was strongly associated with the risk of multisystem disease. Similar to the DAL-HX 83/90 studies, in which the majority of patients with skin-only disease were also observed without therapy,
      • Titgemeyer C.
      • Grois N.
      • Minkov M.
      • Flucher-Wolfram B.
      • Gatterer-Menz I.
      • Gadner H.
      Pattern and course of single-system disease in Langerhans cell histiocytosis data from the DAL-HX 83- and 90-study.
      patients with single-system skin disease at diagnosis did not typically progress to involvement of other organs besides skin. OS in this series (98%, with the sole death occurring before initiation of therapy) was similar to that in previously published reports; however, despite the high OS and ability to treat recurrent or refractory disease with alternate chemotherapy agents, the majority of patients with skin plus multisystem LCH treated with the standard of care (ie, vinblastine/prednisone) did not have an initial durable response to therapy (PFS, 44%), and disease persisted or progressed in risk organs in those patients with risk-organ involvement at diagnosis. Circulating cells with the BRAF-V600E mutation were frequently observed in patients with active multisystem LCH, but only in a single patient with skin-limited LCH.
      Given the high frequency of multisystem involvement in patients with skin LCH, early biopsy of suspicious lesions and comprehensive organ evaluation has long been indicated for all patients diagnosed with skin LCH.
      • Lau L.
      • Krafchik B.
      • Trebo M.M.
      • Weitzman S.
      Cutaneous Langerhans cell histiocytosis in children under one year.
      • Broadbent V.
      • Gadner H.
      • Komp D.M.
      • Ladisch S.
      Clinical Writing Group of the Histiocyte Society
      Histiocytosis syndromes in children, II: approach to the clinical and laboratory evaluation of children with Langerhans cell histiocytosis.
      Our present findings illustrate the high frequency of multisystem disease found at the time of referral and the continuing delays between symptom onset and diagnosis. In this study, 40% of patients referred for apparently skin-limited LCH were found to have multisystem disease on complete evaluation, and 50% of these patients had risk-organ involvement. The incidence of skin plus multisystem LCH relative to skin-limited LCH (2:1 in this series) is consistent with a previously published single-institution study,
      • Lau L.
      • Krafchik B.
      • Trebo M.M.
      • Weitzman S.
      Cutaneous Langerhans cell histiocytosis in children under one year.
      albeit with lower death rates in this series, likely owing to improved salvage therapies in the last 2 decades.
      • Egeler R.M.
      • de Kraker J.
      • Voute P.A.
      Cytosine-arabinoside, vincristine, and prednisolone in the treatment of children with disseminated Langerhans cell histiocytosis with organ dysfunction: experience at a single institution.
      • Weitzman S.
      • Braier J.
      • Donadieu J.
      • Egeler R.M.
      • Grois N.
      • Ladisch S.
      • et al.
      2'-Chlorodeoxyadenosine (2-CdA) as salvage therapy for Langerhans cell histiocytosis (LCH): results of the LCH-S-98 protocol of the Histiocyte Society.
      • Bernard F.
      • Thomas C.
      • Bertrand Y.
      • Munzer M.
      • Landman Parker J.
      • Ouache M.
      • et al.
      Multi-centre pilot study of 2-chlorodeoxyadenosine and cytosine arabinoside combined chemotherapy in refractory Langerhans cell histiocytosis with haematological dysfunction.
      For reasons that remain unclear, the time from symptom onset to diagnosis was correlated with the presence of multisystem involvement. It is possible that patients with skin-limited disease have more clinically impressive lesions. Our data do not suggest that time to diagnosis results in progression from skin-limited disease to multisystem disease, although we were unable to evaluate the possibility of progression from skin-limited to multisystem disease in infants aged <3 months owing to low numbers of patients referred in this age group. Thus, these data highlight the continued delays in identifying children with LCH, despite decades of evidence and recommendations supporting early biopsy of progressive or treatment-refractory eczema or seborrheic dermatitis.
      • Lau L.
      • Krafchik B.
      • Trebo M.M.
      • Weitzman S.
      Cutaneous Langerhans cell histiocytosis in children under one year.
      • Broadbent V.
      • Gadner H.
      • Komp D.M.
      • Ladisch S.
      Clinical Writing Group of the Histiocyte Society
      Histiocytosis syndromes in children, II: approach to the clinical and laboratory evaluation of children with Langerhans cell histiocytosis.
      It is our view, consistent with others,
      • Lau L.
      • Krafchik B.
      • Trebo M.M.
      • Weitzman S.
      Cutaneous Langerhans cell histiocytosis in children under one year.
      that terms such as “Hashimoto-Pritzker disease” and “self-healing LCH” are diagnoses that can be made with certainty only in retrospect, and thus should not be used to describe patients with active disease. We urge providers to consider LCH in the differential diagnosis of such skin lesions to minimize the morbidity of untreated lesions and the potential for unrecognized high-risk disease.
      Patients in the present series with skin-limited LCH had a lower frequency of recurrence/relapse compared with those in previous studies,
      • Lau L.
      • Krafchik B.
      • Trebo M.M.
      • Weitzman S.
      Cutaneous Langerhans cell histiocytosis in children under one year.
      and most skin-limited patients had self-resolving disease. No standard of care exists for the initial therapy of skin-limited LCH. Reported therapies include topical steroids, nitrogen mustard, or imiquimod; surgical resection of isolated lesions; phototherapy or photochemotherapy; and systemic interferon-α2b, methotrexate, 6-mercaptopurine, vincristine, vinblastine, steroids, thalidomide, cladribine, and/or cytarabine.
      • Park L.
      • Schiltz C.
      • Korman N.
      Langerhans cell histiocytosis.
      • Neumann C.
      • Kolde G.
      • Bonsmann G.
      Histiocytosis X in an elderly patient: ultrastructure and immunocytochemistry after PUVA photochemotherapy.
      • Sakai H.
      • Ibe M.
      • Takahashi H.
      • Matsuo S.
      • Okamoto K.
      • Makino I.
      • et al.
      Satisfactory remission achieved by PUVA therapy in Langerhans cell hisiocytosis in an elderly patient.
      • Kwon O.S.
      • Cho K.H.
      • Song K.Y.
      Primary cutaneous Langerhans cell histiocytosis treated with photochemotherapy.
      • Hoeger P.H.
      • Nanduri V.R.
      • Harper J.I.
      • Atherton D.A.
      • Pritchard J.
      Long-term follow-up of topical mustine treatment for cutaneous langerhans cell histiocytosis.
      • Lindahl L.M.
      • Fenger-Gron M.
      • Iversen L.
      Topical nitrogen mustard therapy in patients with Langerhans cell histiocytosis.
      • Failla V.
      • Wauters O.
      • Caucanas M.
      • Nikkels-Tassoudji N.
      • Nikkels A.F.
      Photodynamic therapy for multi-resistant cutaneous Langerhans cell histiocytosis.
      • Steen A.E.
      • Steen K.H.
      • Bauer R.
      • Bieber T.
      Successful treatment of cutaneous Langerhans cell histiocytosis with low-dose methotrexate.
      • McClain K.L.
      Drug therapy for the treatment of Langerhans cell histiocytosis.
      • Do J.E.
      • Lee J.Y.
      • Kim Y.C.
      Successful treatment of cutaneous Langerhans' cell histiocytosis with targeted narrowband ultraviolet B phototherapy in an infant.
      • Chang S.E.
      • Koh G.J.
      • Choi J.H.
      • Lee K.H.
      • Sung K.J.
      • Moon K.C.
      • et al.
      Widespread skin-limited adult Langerhans cell histiocytosis: long-term follow-up with good response to interferon alpha.
      • McClain K.L.
      • Kozinetz C.A.
      A phase II trial using thalidomide for Langerhans cell histiocytosis.
      No regimen has been evaluated in a randomized-controlled trial, however, and most of the limited studies of these agents did not provide significant long-term follow-up data. Numerous different strategies were used to treat skin-limited LCH in this cohort, with variable efficacy; given the small numbers of patients, we cannot make a recommendation regarding an effective first-line treatment approach for patients with skin-limited disease requiring therapy. Because skin-limited disease in infants carries a high rate of spontaneous regression, we recommend surveillance for patients with skin-limited disease except in cases of skin rashes that cause identifiable morbidity or discomfort.
      No patient with skin-limited disease in our cohort developed disease in another organ site. Other series have reported rates of progression to other organ sites as high as 60%,
      • Titgemeyer C.
      • Grois N.
      • Minkov M.
      • Flucher-Wolfram B.
      • Gatterer-Menz I.
      • Gadner H.
      Pattern and course of single-system disease in Langerhans cell histiocytosis data from the DAL-HX 83- and 90-study.
      • Lau L.
      • Krafchik B.
      • Trebo M.M.
      • Weitzman S.
      Cutaneous Langerhans cell histiocytosis in children under one year.
      • Battistella M.
      • Fraitag S.
      • Teillac D.H.
      • Brousse N.
      • de Prost Y.
      • Bodemer C.
      Neonatal and early infantile cutaneous langerhans cell histiocytosis: comparison of self-regressive and non-self-regressive forms.
      • Minkov M.
      • Prosch H.
      • Steiner M.
      • Grois N.
      • Potschger U.
      • Kaatsch P.
      • et al.
      Langerhans cell histiocytosis in neonates.
      • Larralde M.
      • Rositto A.
      • Giardelli M.
      • Gatti C.F.
      • Santos-Munoz A.
      Congenital self-healing Langerhans cell histiocytosis: the need for a long-term follow-up.
      • Larralde M.
      • Rositto A.
      • Giardelli M.
      • Gatti C.F.
      Santos Munoz A. Congenital self-healing histiocytosis (Hashimoto-Pritzker).
      • Willis B.
      • Ablin A.
      • Weinberg V.
      • Zoger S.
      • Wara W.M.
      • Matthay K.K.
      Disease course and late sequelae of Langerhans' cell histiocytosis: 25-year experience at the University of California, San Francisco.
      • Hashimoto K.
      • Bale G.F.
      • Hawkins H.K.
      • Langston C.
      • Pritzker M.S.
      Congenital self-healing reticulohistiocytosis (Hashimoto-Pritzker type).
      but the extent to which these patients underwent evaluation at diagnosis to ensure the absence of multisystem disease is unclear. We have occasionally observed severe disease progression in patients with skin LCH who were evaluated outside of this cohort, including 1 patient who died from widespread risk-organ disease after several years of severe skin and mucosal disease.
      • Simko S.J.
      • Tran H.D.
      • Jones J.
      • Bilgi M.
      • Beaupin L.K.
      • Coulter D.
      • et al.
      Clofarabine salvage therapy in refractory multifocal histiocytic disorders, including Langerhans cell histiocytosis, juvenile xanthogranuloma and Rosai-Dorfman disease.
      Although observation is a reasonable initial approach for skin-limited LCH after a comprehensive diagnostic evaluation, physicians should remain vigilant in follow-up of these patients, given that the true risk of progression remains undefined.
      The relative absence of circulating cells with the BRAF-V600E mutation in patients with skin-limited LCH is consistent with previous findings indicating that circulating cells with the BRAF-V600E mutation are generally found in patients with active multisystem risk-organ disease.
      • Berres M.L.
      • Lim K.P.
      • Peters T.
      • Price J.
      • Takizawa H.
      • Salmon H.
      • et al.
      BRAF-V600E expression in precursor versus differentiated dendritic cells defines clinically distinct LCH risk groups.
      This study was unable to define whether the BRAF-V600E mutation was absent in the circulation owing to its inherent absence in skin lesions or the restricted migratory potential of precursor LCH cells in skin-limited disease. We hypothesize that the latter is the case, considering that the mutation is present in equal frequency across clinical risk groups
      • Berres M.L.
      • Lim K.P.
      • Peters T.
      • Price J.
      • Takizawa H.
      • Salmon H.
      • et al.
      BRAF-V600E expression in precursor versus differentiated dendritic cells defines clinically distinct LCH risk groups.
      • Badalian-Very G.
      • Vergilio J.A.
      • Degar B.A.
      • MacConaill L.E.
      • Brandner B.
      • Calicchio M.L.
      • et al.
      Recurrent BRAF mutations in Langerhans cell histiocytosis.
      ; however, further evaluation of patients with skin lesions for the mutation is warranted. Although patients with multisystem disease without risk-organ involvement do not usually have circulating BRAF-V600E cells, 4 of the 5 patients previously described had skin involvement, and this group has a statistically higher relapse rate compared with other patients lacking risk-organ disease.
      • Berres M.L.
      • Lim K.P.
      • Peters T.
      • Price J.
      • Takizawa H.
      • Salmon H.
      • et al.
      BRAF-V600E expression in precursor versus differentiated dendritic cells defines clinically distinct LCH risk groups.
      We hypothesize that circulating LCH precursor cells in multisystem disease reflect a broader potential for migration of pathological dendritic cells than in tissue-restricted low-risk LCH, in which circulating precursor cells are not identified. Previous results demonstrate that the state of differentiation of the cell that acquires the BRAF-V600E mutation defines disease severity and tissue distribution of pathological dendritic cells in LCH.
      • Berres M.L.
      • Lim K.P.
      • Peters T.
      • Price J.
      • Takizawa H.
      • Salmon H.
      • et al.
      BRAF-V600E expression in precursor versus differentiated dendritic cells defines clinically distinct LCH risk groups.
      We speculate that the relative absence of circulating cells with the BRAF-V600E mutation in patients with spontaneously resolving skin-limited LCH could be consistent with a transient skin-restricted precursor cell population specific to early hematopoiesis, analogous to the transient myeloproliferative disorder of Down syndrome, which arises from abnormal hematopoietic cells from the fetal liver.
      • Roy A.
      • Cowan G.
      • Mead A.J.
      • Filippi S.
      • Bohn G.
      • Chaidos A.
      • et al.
      Perturbation of fetal liver hematopoietic stem and progenitor cell development by trisomy 21.
      The ability of circulating BRAF-V600E cells to predict skin-limited LCH vs multisystem LCH will require validation in future prospective clinical trials.
      LCH skin lesions are easily confused with other common pediatric dermatoses. Suspicion of LCH, biopsy, and comprehensive staging evaluation are essential first steps toward providing optimal clinical care for these patients, which may range from observation in mild skin-limited disease to cytotoxic chemotherapy in skin with associated multisystem disease. Prospective multicenter trials are needed to determine whether skin involvement is an independent predictor of poor therapeutic response in multisystem or risk-organ LCH, whether alternatives to vinblastine/prednisone are superior in patients with multisystem LCH involving the skin, and whether the presence of circulating cells with the BRAF-V600E mutation risk-stratifies patients or serves as a marker of disease activity.
      The authors thank Munu Bilgi for data collection.

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