Clinical Features and Outcomes of Unifocal Adult Langerhans Cell Histiocytosis

Purpose: Langerhans cell histiocytosis (LCH) is a rare histiocytic disorder that presents with a wide spectrum of clinical diseases, ranging from single-organ lesions to systemic disease. Although previously thought of as an immune disorder, LCH was reclassified as an inflammatory myeloid neoplasm in the 2016 Histocyte Society classification after discovery of BRAF V600E or MAP2K1 gain-of-function mutations and evidence of clonality in most LCH patients. In this revised classification, LCH was divided into single-system LCH, pulmonary LCH, or multisystem LCH. However, there is a lack of data on clinical features and outcomes in the subgroup of "unifocal" non-pulmonary LCH in adults. In this study, we sought to address the gaps in knowledge for unifocal adult LCH utilizing our institution's experience over 20 years.

Methods: We retrospectively reviewed the medical records of 189 adult patients (defined as >18 years old at diagnosis) with histopathologically confirmed LCH who were seen at our tertiary referral center between 1997 and 2018. Of these, 44 met criteria for unifocal LCH at diagnosis after careful exclusion of other sites of disease involvement.

Results: We included 44 adult patients with unifocal LCH at diagnosis, with median age 42 years (range 19 to 88) and 55% males. 84% were Caucasians and 50% were smokers. Most commonly involved disease sites included bone (43%), skin (25%), pituitary (14%), and gastrointestinal (11%), with common presenting symptoms of head pain/swelling (25%), skin rash (20%), abdominal pain/diarrhea (11%), and diabetes insipidus (9%). Resection/excision was the most common first line therapy in 24 patients (63%); none had local recurrence and 3 patients developed recurrence at a new site. Radiation was the second most common therapy in 6 patients, with an overall response rate of 83%; none had local recurrence and 1 patient had recurrence at a new site. Other less common first-line treatments included resection followed by radiation (2), topical immunosuppression (2), dexamethasone (1), cladribine (1), smoking cessation (1), and observation (1) (Table 1). Cladribine used as first-line therapy for pituitary LCH resulted in progressive disease, but cladribine used as second-line therapy in 2 cases (including one who had progressed to multisystem disease) resulted in partial remission with no further recurrence in both cases. Patients were followed for a median of 3.8 years (range 0.1 to 18.8), with 5 patients lost to follow-up. By time of last follow-up, 11 (28%) had developed recurrence: 1 had local recurrence, 5 developed disease at a new site within the same system (skin or bone), and 5 developed multisystem disease (Figure 1). Median time to recurrence was 2 years (range 0.2 to 6.6). 2 out of 5 patients tested for BRAF had a V600E mutation, both of whom had isolated unifocal bone disease and remained in complete remission following resection at time of last follow-up. Median overall survival (OS) from time of diagnosis was not reached and overall 5-year OS was 94%. 3 patients died, only 1 of progressive LCH.

Conclusion: In our study, most patients with unifocal adult LCH achieved a complete remission with surgical resection or local radiation. None of the patients treated with resection or radiation developed local recurrence, but around 1 in 5 developed distant recurrence within 5 years. However, the overall prognosis was very good, and none of the patients in the cohort progressed to "high-risk" organ (liver, spleen, or bone marrow) involvement or pulmonary involvement. Further studies are warranted to assess the role of MAPK-ERK mutations in the prognosis of unifocal LCH.

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