Specific Guidelines Including Multidisciplinary Approach Is Critical of Management of Langerhans Cell Histiocytosis in Adults
Authors: Rizzo Lorenzo , Santopietro Michelina , Sfaciotti Gianluca , Brunori Marco , Cardarelli Luisa , Palumbo Giovanna , De Benedittis Daniela , Di Palma Martina , Moleti Maria Luisa , Testi Anna Maria , Di Pippo Tiziana , Giona Fiorina 
Published: November 2019

The knowledge of Langerhans Cell Histiocytosis (LCH) is based on pediatric studies. Adults with LCH are usually treated with pediatric protocols. In 2001, guidelines for adults with LCH (GIMEMA LCH 2001) were proposed, in order to standardize the diagnostic and therapeutic approaches for this category of patients. The aims of this retrospective study are: a) to evaluate the role of a multidisciplinary assessment in adults with LCH, according to the GIMEMA LCH 2001 guidelines, and b) to analyze the results obtained with the GIMEMA LCH 2001 guidelines and those obtained with pediatric protocols.
Pts aged >18 years with a diagnosis of LCH (S-100+, CD1a+, CD207+) managed at our Institution since 1985 to 2018 were considered. As diagnostic and treatment approaches, two different strategies were used over time: the GIMEMA LCH 2001 guidelines and the pediatric protocols. The GIMEMA LCH 2001 guidelines included a multidisciplinary diagnostic work-up with complete odontostomatologic, pulmonary and endocrinologic assessments; treatment strategy consisted of: wait and see or local therapy in unifocal single system (SS), indomethacin in bone multifocal SS and vinblastine combined with low-dose prednisone (PDN) in multi-system (MS), PDN in pulmonary honey-combing disease (PHCD) and cladribine in central nervous system involvement. DAL-HX 83 and 90, LCH-I and LCH II were the pediatric protocols utilized over time. Response to treatment was defined as complete (CR) or intermediate (IR). Persistence of the symptoms and/or appearance of new lesions were defined no response (NR). Progression was considered the appearance of symptoms and/or new lesions after initial response.
One-hundred-thirty-one LCH pts (females 72, males 59) with a median age at diagnosis of 36 years (range 18 - 71) were considered. Median follow up was 43 months (range 12 - 330). One-hundred-seven patients were managed according to the GIMEMA LCH 2001 guidelines, 16 of them previously treated with a pediatric protocol. Pulmonary and/or oral involvements were identified in 31/107 (29%) and 12/107 (11%) patients, respectively, 5/16 (31%) and 3/16 (19%), respectively, of previously treated asymptomatic patients.
Ninety-one newly diagnosed patients (median age at diagnosis: 36 years) were treated according to the GIMEMA LCH 2001 guidelines and 40 (median age at diagnosis: 33 years) were managed with pediatric protocols. All patients treated with the GIMEMA LCH 2001 were evaluable for response. In particular, all patients with SS-LCH achieved a response (100%), that was complete in 20/26 (76.9%) unifocal-SS and in 10/14 (71.4%) multifocal-SS. All but one patient with MS-LCH reached a response that was complete in 22/45 (48.9%). Of 6 pts with PHCD, 5 had a IR and one a CR. No pt presented CNS involvement at initial diagnosis.
Thirty-nine of 40 pts managed with pediatric protocols were evaluable for response. All 13 pts with SS-LCH had a response that was complete in 6 (46.1%). Among 26 patients with MS-LCH, 3 of them with organ risk involvement achieved a response, that was complete in 1, while among 23 patients without organ risk, 12 (52.2%), 8 (34.8%) and 3 (13%) had a CR, IR and NR, respectively.
Overall, 12 patients were lost to follow-up. Disease progression was recorded in 47/95 pts (49.5%) after a median time of 19 months (range: 6-147 months). The progression-free survival at 43 months was significantly better for patients treated according to the GIMEMA LCH 2001 guidelines compared to those managed with pediatric protocols, 67% (IC95% 53.14 - 80.86%) vs 48% (IC95% 31.37 - 64.63%), respectively (p 0.005). Overall, 7 deaths were recorded, 5 in patients treated with the pediatric protocols. The overall survival at 43 months, was similar in patients managed with the GIMEMA LCH 2001 guidelines and in those treated with pediatric protocols (97.9%, CI 95%: 93.75% - 100% and 97.3%, (IC95% 91.96% - 100%). BRAF V600E mutation was found in 13/35 (37%) evaluable cases. No differences in response and outcome between BRAFV600E-mutated patients and those not-mutated were found.
Our experience in a large cohort of LCH adults shows that a multidisciplinary approach is useful in identifying organ involvement in adults, including those asymptomatic. This is critical for an adequate treatment. Moreover, guidelines specific for adults with LCH proved efficacy in improving the outcome in this category of patients.

Disclosures
No relevant conflicts of interest to declare.