Additive Prognostic Impact of Gastrointestinal Involvement in Severe Multisystem Langerhans Cell Histiocytosis.

OBJECTIVE: To evaluate the prognostic impact of gastrointestinal involvement on the survival of children with Langerhans cell histiocytosis (GI-LCH) registered with the international clinical trials of the Histiocyte Society. STUDY DESIGN: This was a retrospective analysis of 2414 pediatric patients registered onto the consecutive trials DAL-HX 83, DAL-HX 90, LCH-I, LCH-II, and LCH-III. RESULTS: Among the 1289 patients with single-system LCH, there was no single case confined to the GI tract; 114 of 1125 (10%) patients with multisystem LCH (MS-LCH) had GI-LCH at initial presentation. GI-LCH was significantly more common in children aged <2 years at diagnosis (13% vs 6% in those aged >2 years; P < .001) and in those with risk organ involvement (15% vs 6% in those without risk organ involvement; P < .001). The 5-year overall survival (OS) in patients without risk organ involvement was excellent irrespective of GI disease (98% vs 97% in patients with GI-LCH; P = .789). In patients with risk organ involvement, the 5-year OS was 51% in 70 patients with GI-LCH vs 72% in 394 patients without GI-LCH (P < .001). CONCLUSIONS: GI-LCH has an additive unfavorable prognostic impact in children with MS-LCH and risk organ involvement. The emerding need for more intensive or alternative treatments mandates prospective evaluation.

Langerhans Cell Histiocytosis of the Orbit: Spectrum of Clinical and Imaging Findings.

OBJECTIVE: To evaluate the clinical and imaging characteristics of orbital lesions of pediatric Langerhans cell histiocytosis (LCH). STUDY DESIGN: A retrospective analysis of clinical data and central review of magnetic resonance imaging scans in patients with LCH, enrolled into one of the consecutive international trials LCH I-III, or submitted for a second opinion between 1994 and 2015. RESULTS: Data from 31 children (34 involved orbits) were analyzed. Orbital LCH was the only disease manifestation in 15, part of a multifocal skeletal in 5, or a multisystem LCH in 11 patients. Orbital LCH was part of the initial disease presentation in 23 or developed at relapse in 8 cases. Orbital involvement was unilateral in 28 and bilateral in 3 patients (34 affected orbits). Proptosis was present in 9 patients. Frontal and zygomatic bone were most commonly affected. All orbital lesions were extraconal. Associated extraorbital imaging findings were dural tail sign in 19, neurodegeneration in 8, and hypothalamic-pituitary mass in 3 patients. Sixteen patients (52%) had at least 1 documented disease relapse. Permanent consequences were prominent proptosis in 1, diabetes insipidus in 8, growth hormone deficiency in 2, radiologic neurodegeneration in 8, and clinical neurodegeneration in 3 patients. CONCLUSIONS: Predominantly unilateral orbital LCH can be the only disease manifestation or part of a disseminated disease. Orbital lesions in LCH are exclusively extraconal, typically located at the roof and the lateral wall of the orbit. The optimal treatment approach of unifocal LCH of the orbit remains controversial and warrants a prospective evaluation.

Pulmonary involvement in pediatric-onset multisystem Langerhans cell histiocytosis: effect on course and outcome.

OBJECTIVES: To assess the effect of pulmonary involvement on the course and outcome of multisystem Langerhans cell histiocytosis (MS-LCH) in children. STUDY DESIGN: We conducted a retrospective analysis of 420 consecutive patients with MS-LCH. In this analysis, the term "risk organs" is defined as involvement of the liver, spleen, and/or hematopoietic system. The effect of pulmonary involvement on survival was assessed with multivariate Cox regression with adjustment for risk organs involvement and age. RESULTS: Pulmonary involvement in MS-LCH was present at diagnosis in 102 patients (24%). Of the 318 patients without pulmonary involvement at diagnosis, it developed in 28 within a median of 10 months (range, 1 month-5.5 years). The 5-year overall survival rate in patients without risk organ involvement at diagnosis was 96% in patients without pulmonary involvement and 94% in those with pulmonary involvement. In patients with risk organ involvement at diagnosis, the 5-year overall survival rate was 73% in patients without pulmonary involvement and 65% in patients with pulmonary involvement. In multivariate analysis, pulmonary involvement at diagnosis had no significant impact on survival rats (P = .109, hazard ratio = 1.5). CONCLUSIONS: In multivariate analysis, pulmonary involvement was not an independent prognostic variable and should therefore be excluded from the definition of risk organ involvement in MS-LCH.

Reactivations in multisystem Langerhans cell histiocytosis: data of the international LCH registry.

OBJECTIVE: To assess multisystem Langerhans cell histiocytosis reactivation and its impact on morbidity and mortality. STUDY DESIGN: Retrospective analysis of 335 patients with MS-LCH and documented complete disease resolution (NAD1). RESULTS: The probability of a reactivation within 5 years of NAD1 was 46%. The first reactivation occurred within 2 years after NAD1 in most of the patients. Of 134 events, 35% were confined to skeleton, 24% were single-system nonbony lesions, 24% were multisystem reactivations without risk-organ involvement, and 10% with risk-organ involvement. In 7%, the location was unspecified. Only 3 deaths (2.2%) were documented within the context of a first reactivation. Second disease resolution (NAD2) was achieved in 85% of the cases. The probability of a second reactivation within 5 years of NAD2 was 44%. The risk for permanent consequences in patients with reactivations was higher, compared with patients without reactivation (RHR 2.2, P = .046). CONCLUSIONS: Reactivation is a frequent and early event in MS-LCH, but involvement of risk organs at reactivation is rare and mortality is minimal. However, reactivations increase the risk for permanent consequences by about 2-fold. Prospective trials targeting reduction of acute morbidity and permanent disabilities through nontoxic treatment of the reactivations are warranted.