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Introduction: Langerhans cell histiocytosis (LCH) is a rare MAPK-ERK pathway driven histiocytic neoplasm that occurs in pediatric as well as adult population. Despite improvement in clinical outcomes, there is some data to suggest an increased propensity to develop second primary malignancies (SPMs) in LCH patients. However, population-based studies analyzing the incidence and spectrum of SPMs in pediatric and adult LCH patients are lacking. In this study, we utilized the Surveillance, Epidemiology and End Results (SEER) database to examine the various SPMs occurring among pediatric and adult LCH cases. Methods: We used the November 2018 submission of the SEER 18 registry, which covers ~27.8% of the US population based on the 2010 census, as our database. We used the SEER*Stat version 8.3.6 statistical software to analyze data. We identified cases diagnosed with LCH as their first primary malignancy between 2000 and 2016 using International Classification of Diseases for Oncology edition 3 (ICD-O-3) codes, including LCH NOS (not otherwise specified) (9751/1), LCH (9751/3), LCH, unifocal (9752/1), LCH, multifocal (9753/3), LCH, disseminated, borderline (9754/1) and Disseminated LCH (9754/3). These cases were followed for 180+months, and the standardized incidence ratio (SIR) or relative risk and absolute excess risk (AER) were calculated. We examined the differences in occurrence of SPMs among the pediatric (Age <18 years) and adult population (Age ≥18 years). Additionally, we evaluated the concurrent and prior cancers in LCH patients as an exploratory objective. Results: The study included 1392 cases with LCH (Table 1), with median age at diagnosis 8 years (range newborn - 86 years). Out of these cases, 1205 (87%) were diagnosed as LCH and 186 (13%) as disseminated LCH. 936 cases (67%) were diagnosed at age <18 years (pediatric LCH), while 456 cases (33%) were diagnosed at age ≥18 years (adult LCH). The overall age-adjusted incidence rate for LCH was found to be 1 per 1,000,000. The incidence rate was 2.6 per 1,000,000 in pediatric LCH group and 0.4 per 1,000,000 in the adult LCH group. Out of the entire cohort, 20 (1.4%) cases developed a total of 21 SPMs [SIR 2.07; 95% Confidence Interval (CI): 1.28-3.16]. Median latency period to development of SPMs was 28 months. The pediatric LCH group had an overall higher risk of developing SPMs [SIR 6.42, 95%CI 2.08-14.97] than the general population, especially for hematologic malignancies [SIR 18.76, 95%CI 6.09-43.78], mainly, nodal Hodgkin lymphoma [SIR 60.93, 95%CI 7.38-220.12] and extranodal non-Hodgkin lymphoma [SIR 60.88, 95%CI 1.54-339.2]. No solid tumors were seen in this group. The adult LCH group did not have an overall increased risk of developing SPMs than the general population [SIR 1.71, 95%CI 0.98-2.77], except for Acute Lymphocytic Leukemia (ALL) [SIR 66.29, 95%CI 1.68-369.36] especially 60-119 months from diagnosis of LCH and miscellaneous cancers [SIR 11.43, 95%CI 2.36-33.39] especially 12-59 months after diagnosis of LCH. 62.5% of SPMs that developed in the adult LCH group were solid tumors, however, the overall risk for developing solid tumors was not higher than the general population [SIR 1.2, 95%CI 0.58-2.2], except for carcinoma in-situ of vulva [SIR 62.72, 95%CI 1.59-349.45] 2-11 months from diagnosis of LCH. Overall, tumors of the respiratory system (21%), female breast (13%) and prostate (9%) were the most common malignancies occurring prior to development of LCH whereas tumors of the respiratory system (28%), non-Hodgkin lymphoma (20%) and endocrine system (13%) occurred concurrent to LCH. Conclusion: To our knowledge, this is the first comprehensive population-based study assessing the incidence of SPMs in pediatric and adult LCH. Our study shows that the incidence of LCH is higher in the pediatric age group compared to adults. We found an increased risk for hematologic malignancies, specifically for Hodgkin and non-Hodgkin lymphoma in pediatric LCH compared to the general population. Among adult LCH, however, the risk was higher for development of ALL and carcinoma in-situ of vulva when compared to the general population. Our results may help guide survivorship and surveillance strategies among LCH patients. More studies are needed to understand the molecular underpinning leading to increased SPM formation in LCH patients. Disclosures No relevant conflicts of interest to declare.

Background: Langerhans cell histiocytosis (LCH) is the most common histiocytic disorder that is now recognized as a neoplasm by the World Health Organization. It is generally classified based on the site and extent of disease involvement (single system or multisystem). Pulmonary LCH (pLCH), an uncommon interstitial lung disease associated with smoking, often presents as isolated pulmonary disease. It is unclear whether patients with clinically isolated pLCH have extra-pulmonary lesions at diagnosis or during the course of their disease. The role of [18F] fluorodeoxyglucose positron emission tomography-computed tomography (FDG-PET-CT) in the staging of pLCH remains unclear. Our study aims to better characterize the utility of radiographic staging studies at time of diagnosis and prevalence of extrapulmonary disease at follow up in pLCH. Methods: We conducted a retrospective study of patients presenting with clinical findings consistent with isolated pLCH seen at the Mayo Clinic from January 2000 to January 2020. All patients had a diagnosis of pLCH determined by chest imaging studies [computed tomography (CT) or high-resolution CT (HRCT)] or by histopathologic findings from surgical or transbronchial lung biopsy. Histopathologic findings for the diagnosis of pLCH required the presence of Langerhans cells (S100+/CD1a+/Langerin+). Patients were excluded if they had clinically apparent extra-pulmonary organ involvement at the time of diagnosis. BRAF V600E mutation was determined by immunohistochemistry (IHC) or cell-free DNA (cfDNA). Staging was defined as FDG-PET-CT or whole body CT imaging obtained within 3 months of diagnosis of pLCH. Extra-pulmonary LCH involvement was determined by imaging characteristics or by histopathologic findings. Descriptive statistics and overall survival (OS) were analyzed with JMP software, version 14 (SAS Institute Inc., Cary, NC). Results: A total of 112 patients with clinically isolated pLCH were identified. The median age at diagnosis was 45 years (range 21-73), and 48 (43%) were male. The majority (n=110, 99%) were former or current smokers with a median pack year of 25 (range 1-57). Three (3%) patients were noted to have occupational industrial exposure. Nine patients had a history of another cancer prior to their diagnosis and staging of pLCH [lung (n=4), breast (n=2), neuroendocrine (n=2), thyroid (n=1)]. Presenting symptoms included dyspnea on exertion 49 (44%), cough 18 (16%), chest pain 14 (13%), and 29 (28%) were incidentally discovered on imaging studies. On HRCT, the following characteristics were observed: 42 (38%) cystic, 32 (29%) cystic and nodular, 37 (33%) nodular, 1 (<1%) ground glass opacities. Seventy (63%) patients had lung biopsy confirmation, of which 11 (16%) patients underwent BRAF V600Emutation testing (7 by IHC, 4 by cfDNA). Six (55%) of these 11 patients were positive for BRAF V600E mutation. 34 (30%) patients underwent radiographic staging studies within 3 months of diagnosis of pLCH (25 FDG-PET-CT and 9 whole-body CT), and none of these imaging studies showed evidence of extra-pulmonary disease. Of the patients who had at least one year of follow-up (n=52), one (2%) developed extra-pulmonary disease. This patient did not undergo initial staging studies, developed headaches and was found to have a large calvarial lytic lesion within 2 months of pLCH diagnosis (BRAF V600E+). Among those who did not undergo staging at diagnosis (n=78), long term (>5 years) follow up data were available for 23 (29%), and none developed extra-pulmonary disease as determined by clinical notes or imaging studies. No patient had evidence of new extra-pulmonary involvement or second malignancy at the time of last known follow-up. After a median follow-up duration of 2.4 years (95% CI: 1.5-3.6, range: 0.1-17) ten (9%) patients died, of which 5 died of pLCH related complications. The median OS for entire cohort was 15 years (95% CI 9.1-not reached, Figure 1). Conclusion: Our study shows that adult patients with clinically isolated pLCH rarely present with extra-pulmonary manifestations at diagnosis or at follow up. These findings suggest a limited role of routine radiographic staging studies in pLCH unless clinically indicated. Studies on longer follow up of this cohort would provide further insights into the natural history of pLCH and are underway. Disclosures Bennani: Purdue Pharma: Other: Advisory Board; Verastem: Other: Advisory Board; Kite/Gilead: Research Funding; Affimed: Research Funding. Shah:Dren Bio: Consultancy.

Rosai-Dorfman disease (RDD) is a rare histiocytosis with heterogenous clinical features. In this study, we characterized the histologic and phenotypic features in 33 RDD patients to better define the pathologic diagnosis. Cases included 24 patients with extracutaneous disease (“R” group), and 9 patients with lesions limited to the skin or subcutaneous tissue (“C” group). We identified OCT2 as a novel marker for the monocyte-macrophage phenotype of RDD, expressed in 97% of RDD cases. In contrast, OCT2 expression was seen in 0% of Erdheim-Chester disease cases and 6.7% of Langerhans cell histiocytosis cases. Other markers useful in the diagnosis of RDD included S100 (100%), CD163 (88%), and cyclin D1 (97%). In a subset of cases, RDD showed moderate to strong expression of factor 13a (30%), p16 (64%), and phosphorylated extracellular signal-regulated kinase (45%); RDD was uniformly negative for ZBTB46, CD1a, and langerin. Within the “R group” of RDD, increased expression of factor 13a or phosphorylated extracellular signal-regulated kinase showed a statistically significant association with multifocal disease ( P <0.05). Identification of the unique monocyte-macrophage phenotype of RDD with OCT2 expression furthers our understanding of this complex disease and allows for more uniform classification.

Hepatosplenic T-cell lymphoma (HSTCL) is a rare subtype of T-cell lymphoma associated with an aggressive clinical course and a worse prognosis. HSTCL develops in the setting of chronic immune suppression or immune dysregulation in up to 20% of cases and is most often characterized by spleen, liver, and bone marrow involvement. Diagnosis and management of HSTCL pose significant challenges given the rarity of the disease along with the absence of lymphadenopathy and poor outcome with conventional chemotherapy regimens. These Guidelines Insights focus on the diagnosis and treatment of HSTCL as outlined in the NCCN Guidelines for T-Cell Lymphomas.

Abstract Langerhans cell histiocytosis (LCH) is a rare histiocytic neoplasm. To date, there is a lack of U.S. Food and Drug Administration–approved treatments in adult LCH to establish optimal first-line therapy. We conducted a retrospective, single-center case series evaluating the use of BRAF inhibitors in adult patients with BRAFV600E- LCH proven by biopsy. Our case series is the first to report the use of BRAF inhibitors as first-line therapy in adults with LCH. We also report the efficacy with single-agent dabrafenib in adult LCH. All but one of our patients had favorable response to targeted therapy.

Mycosis fungoides (MF) is the most common subtype of cutaneous T-cell lymphoma (CTCL), and Sézary syndrome (SS) is a rare erythrodermic and leukemic subtype of CTCL characterized by significant blood involvement. Although early-stage disease can be effectively treated predominantly with skin-directed therapies, systemic therapy is often necessary for the treatment of advanced-stage disease. Systemic therapy options have evolved in recent years with the approval of novel agents such as romidepsin, brentuximab vedotin, and mogamulizumab. These NCCN Guidelines Insights discuss the diagnosis and management of MF and SS (with a focus on systemic therapy).

Abstract Erdheim-Chester disease (ECD) is a rare histiocytosis that was recently recognized as a neoplastic disorder owing to the discovery of recurrent activating MAPK (RAS-RAF-MEK-ERK) pathway mutations. Typical findings of ECD include central diabetes insipidus, restrictive pericarditis, perinephric fibrosis, and sclerotic bone lesions. The histopathologic diagnosis of ECD is often challenging due to nonspecific inflammatory and fibrotic findings on histopathologic review of tissue specimens. Additionally, the association of ECD with unusual tissue tropism and an insidious onset often results in diagnostic errors and delays. Most patients with ECD require treatment, except for a minority of patients with minimally symptomatic single-organ disease. The first ECD consensus guidelines were published in 2014 on behalf of the physicians and researchers within the Erdheim-Chester Disease Global Alliance. With the recent molecular discoveries and the approval of the first targeted therapy (vemurafenib) for BRAF-V600–mutant ECD, there is a need for updated clinical practice guidelines to optimize the diagnosis and treatment of this disease. This document presents consensus recommendations that resulted from the International Medical Symposia on ECD in 2017 and 2019. Herein, we include the guidelines for the clinical, laboratory, histologic, and radiographic evaluation of ECD patients along with treatment recommendations based on our clinical experience and review of literature in the molecular era.

e19523 Background: Previous studies have shown a disparity in outcomes of MM between clinical trials and real-world practice. This could be partly due to clinical trial exclusion of patients who need urgent treatment due to high burden of disease or significant illness. In this study, we aim to analyze the impact of time to initiation of systemic therapy for MM on overall survival (OS). Methods: We included MM patients reported to National Cancer Data Base (2004-2014). We excluded 2,860 patients with suspected smoldering MM due to initial treatment beyond 120 days. Relative risk of delayed time to systemic therapy was assessed by logistic regression model. Kaplan-Meier method and Cox multivariate analysis were used to evaluate the association between time to therapy and OS. Results: A total of 53, 519 MM patients were included. Median time to systemic therapy in our cohort was 18 days (range 0-120). Of the entire cohort, 24% patients received systemic therapy for MM < 7 days from diagnosis, and 32% received it after 30 days. Factors associated with time to systemic therapy > 30 days were Black race (OR 1.12, CI 1.07-1.16), female sex (OR 1.10, CI 1.06-1.14), lower Charlson comorbidity score (OR 1.36, CI 1.28-1.45), and academic facility (OR 1.18, CI 1.13-1.24). The median OS for patients who initiated therapy > 30 days after diagnosis was longer than those who received it within 7 days (37 vs. 29 month, p < 0.001). Similarly, on multivariate analysis, patients who received treatment > 30 days after diagnosis were found to have a lower mortality as compared to those who initiated treatment < 7 days (HR 0.81, CI 0.79-0.83; Table). Conclusions: In our study, time to initiation of systemic therapy was an independent prognostic factor in MM. This could be related to the high-risk nature of disease of patients treated within a short duration of diagnosis. These findings have implications for future clinical trial design, which should allow for a pragmatic approach toward enrollment of these high-risk patients to improve external validity. [Table: see text]