Rosai-Dorfman-Destombes disease (RDD) is a rare non-Langerhans cell histiocytosis characterized by accumulation of activated histiocytes within affected tissues. RDD, which now belongs to the R group of the 2016 revised histiocytosis classification, is a widely heterogeneous entity with a range of clinical phenotypes occurring in isolation or in association with autoimmune or malignant diseases. Recent studies have found ,, , and mutations in lesional tissues, raising the possibility of a clonal origin in some forms of RDD. More than 1000 reports have been published in the English literature; however, there is a lack of consensus regarding approach for the clinical management of RDD. Although in most cases RDD can be observed or treated with local therapies, some patients with refractory or multifocal disease experience morbidity and mortality. Here we provide the first consensus multidisciplinary recommendations for the diagnosis and management of RDD. These recommendations were discussed at the 32nd Histiocyte Society Meeting by an international group of academic clinicians and pathologists with expertise in RDD. We include guidelines for clinical, laboratory, pathologic, and radiographic evaluation of patients with RDD together with treatment recommendations based on clinical experience and review of the literature.

Key Points Reactivations of multisystem Langerhans cell histiocytosis (MS-LCH) are reduced by prolonging initial chemotherapy. The previously high mortality of high-risk (risk-organ–positive) MS-LCH in children has been markedly reduced.

Multisystem Langerhans cell histiocytosis (MS-LCH) is associated with high mortality when patients have risk organ involvement (RO ؉)or are younger than 2 years. In an international randomized trial, LCH-II, we intensified their treatment: arm A consisted of 6 weeks of daily prednisone and weekly vinblastine followed by 18 weeks of daily 6-mercaptopurine with vinblastine/prednisone pulses; etoposide was added in arm B. Considering all 193 randomized risk patients, there were similar outcomes: rapid (6 weeks) response (arm A vs arm B: 63%/ 71%), 5-year survival probability (74%/79%), disease reactivation frequency (46%/46%), and permanent consequences (43%/37%). However, (1) patients younger than 2 years without RO involvement (RO ؊ ) had 100% survival and uniformly high (> 80%) rapid response, (2) RO ؉ patients not responding within 6 weeks had highest mortality, and (3) importantly, the more intensive arm B reduced mortality in RO ؉ patients (relative hazard rate, accounting for differences in risk organ involvement, of 0.54; 95% CI ‫؍‬ 0.29-1.00 IntroductionLangerhans cell histiocytosis (LCH) is a reactive clonal proliferation of dendritic cells 1-3 that comprises a wide range of clinical presentations, from localized disease (single-system disease) with excellent outcome to disseminated disease involving 2 and more organs or systems (multisystem disease, MS-LCH). [4][5][6] Treatment has varied from conservative to intensive combination chemotherapy. 7-10 When the systems involved are "risk organs" and/or the patient is younger than 2 years at diagnosis, MS-LCH has been considered particularly devastating, and as carrying a potentially fatal prognosis. 11,12 In 1991, the Histiocyte Society initiated LCH-I, a randomized international clinical trial for MS-LCH, comparing the efficacy of 6-month single-agent therapy with either vinblastine or etoposide (VP-16). 13 The drugs did not differ in disease response, reactivation, permanent consequences, survival, or toxicity. However, the results were inferior in some respects to previous reports based on more aggressive therapy. 8,13 That suggested that therapy for MS-LCH patients should be intensified. We therefore designed the next randomized controlled trial, LCH-II, to evaluate combining vinblastine and VP-16, in an intensified 6-month regimen. Methods Patient entry and randomizationEligible patients (confirmed histopathology, multisystem [MS] disease, age younger than 18 years, and no prior specific therapy) were entered, with informed consent obtained in accordance with the Declaration of Helsinki, from 98 pediatric institutions through 7 study subcenters and stratified into 2 groups, risk and low risk. 14,15 The study and study protocol have been approved by the Institutional Review Board of each institution participating in the trial. The risk patients, the subject of this report, either had involvement of risk organs (RO ϩ ; ie, liver, lung, and hematopoietic system or spleen) or had disease onset at younger than 2 years of age. 11,12 Low-risk MS-LCH patients...

Patients with multisystem disease and craniofacial involvement at diagnosis, in particular of the "ear," "eye," and the oral region carry a significantly increased risk to develop DI during their course. This risk is augmented when the disease remains active for a longer period or reactivates.

BackgroundPermanent consequences (PC) are often described among subjects with Langerhans cell histiocytosis (LCH) but data on the real incidence are scarce. Within the Histiocyte Society (HS), and in order to design a definitive late effects study, a retrospective survey was organized to describe the prevalence of PC among long‐term survivors of LCH.MethodsNine institutions contributed with their LCH patients having a minimum follow‐up of 3 years. Information was collected on their disease‐history, and on type and date of onset of any PC. Because of the retrospective type of this study, it was accepted that each institution might have used different criteria to assess PC.ResultsOne hundred eighty‐two subjects were registered and in 95 (52%) at least 1 PC was reported. For some specific PC (e.g., anterior pituitary dysfunction) information was too scarce to provide reliable data. PC were more frequent among subjects with multisystem (MS) disease (71%), compared to those with single system (SS) disease (24%); P < 0.0001. The most frequently reported PC were diabetes insipidus (DI) (24%) orthopedic abnormalities (20%), hearing loss (13%), and neurological consequences (11.0%). Analysis of cumulative risk showed that some types of PC may become manifest more than 10 years from diagnosis.ConclusionsThis survey on selected cases of LCH survivors has confirmed that late sequels are frequent, and that they are even more common among those with MS LCH. Our findings highlight the need for long‐term and patient‐oriented follow‐up in children with LCH. © 2004 Wiley‐Liss, Inc.