Real World Outcomes in Adult Histiocytosis: 23-Year Canadian Single Center Analysis
Authors: Sharma Rintu , De La Torre Alfredo H. , Falcone Umberto , Atenafu Eshetu G. , Vohra Harjot , Delabie Jan , Crump Michael , Kukreti Vishal 
Published: December 2024

Background: Adult histiocytic disorders are rare. Existing knowledge has largely been extrapolated from the pediatric counterparts. Langerhans Cell Histiocytosis (LCH), Erdheim Chester Disease (ECD) and Rosai-Dorfman Disease (RDD) are three most encountered histiocytic disorders. This study aimed to address the paucity of data on the clinical findings and outcomes in adult histiocytic disorders.
Methods: Using REB approved Princess Margaret Cancer Center database, we did a retrospective analysis on adult patients (aged &gt;18 years) with histiocytic disorders presenting to our center from January 2000 to June 2023.
Results: We identified 96 patients with various primary adult histiocytic disorders. Median age was 45.5 (range 18-80) years; 54 (56%) were males. LCH constituted the majority at 62% (n=60), followed by RDD 20% (n=19), ECD 11% (n=11) and non-LCH histiocytosis 7% (n=6) patients.
Unisystem involvement occurred in 34 (57%) LCH patients; isolated bone in 18 (30%), primary pulmonary LCH in 9 patients (15%), isolated skin/subcutaneous in 3 (5%) and, lymph node in 1 patient. Multisystem LCH occurred in 26 (43%) patients; &gt;2 organ systems were involved in 11 (18%) patients. Sixteen patients (27%) patients had high-risk organ (HRO) involvement defined as involvement of spleen, liver, CNS, or bone marrow. Twelve (20%) patients had CNS involvement; diabetes insipidus in 11 (18%) patients. History of smoking was significantly elicited in patients with LCH compared to ECH or RDD. (67% vs 13% vs 16%; p&lt;0.0001). Although BRAF V600E positivity was low (28%; available in 36 patients) in our cohort, it was equally distributed amongst unisystem (33%) and multisystem (24%) disease. (p= 0.51).
Amongst ECD patients, common (often overlapping) presentations included retroperitoneal or mediastinal fibrosis in 6, exophthalmos secondary to periorbital infiltration in 4 and cerebellar symptoms (ataxia and dysarthria) in 3 patients. Surprisingly, bone involvement was only seen in 36% of the patients. BRAF V600E mutation was positive in 7 (70%) of the 10 patients with available results. Classic nodal involvement was seen in only 8 (42%) of RDD patients and extranodal involvement included subcutaneous masses (n=5), CNS involvement (n=4) and visceral involvement (n=4).
Preferred management strategies for unisystem LCH included surgical intervention (n=25), localised radiation (n=4) or “wait and watch” along with smoking cessation (n=14). Systemic cladribine was the given in 15 multisystem LCH patients- 9 received as first line and 6 in subsequent lines. Overall response rates (ORR) after first line of therapy were significantly better in patients with unisystem (76%) compared to multisystem (52%) disease (p=0.049). Twenty (33%) LCH patients required subsequent lines of therapies with four patients receiving targeted therapies (Cobimetinib-3; vemurafenib-1); all these patients attained at least a partial response. Various first line systemic therapies given in ECD were cladribine (n=1), interferon alfa (n=5), anakinra (n=3), vemurafenib (n=1) with ORR of 40%. Eight patients (72%) required subsequent therapies with cladribine in 4, vemurafenib in 2 and dabrafenib and trametinib combination in 2 patients. RDD was managed with systemic steroids in 8 (42%) patients while 4 patients underwent diagnostic surgical excision of the tumour.
Concurrent or subsequent hematological malignancies were seen in 3 (5%; included Acute Myeloid Leukemia (AML), Hairy Cell Leukemia (HCL) and JAK2 positive Myeloproliferative Neoplasm (MPN)) LCH patients, 3 ECD patients (CALR mutated MPN, JAK2 positive MPN, Chronic Lymphocytic Leukemia) and 2 RDD patients (AML and MPN).
At median follow up of 39.5 months (range 1- 266; IQR-15-96), median Overall Survival (OS) of our cohort was 206 months with 2-year and 5-year OS of 96% and 88% respectively. Although patients with ECD had inferior 5-year OS (79%) compared to patients with LCH (96%) or RDD (86%), it was not statistically significant. (p=0.179)
Conclusion: High suspicion is needed in the background of appropriated clinical context since clinical presentation varies widely in adult histiocytic disorders. High incidence of second hematological malignancies in our small cohort warrants more efforts to establish the association between the two entities. Prospective, multicenter studies with molecular discoveries are needed in adult counterpart of this orphan disease.