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A rare case of Haemophagocytic Lymphohistiocytosis preceding a diagnosis of Langerhans cell histiocytosis

To the Editor: Here, we discuss a case of Langerhan’s cell histiocytosis (LCH) being diagnosed 9 months after treatment completion for haemophagocytic lymphohistiocytosis (HLH). Although published reports exist for LCH and HLH occurring in the same patient, the diagnostic sequence in this case (HLHpreceding LCH) is rare.1,2 In a study investigating32patients with both LCH and HLH, there were only two patients (6.3%) in which HLH preceded LCH.1 The underlying pathophysiology that links LCH andHLH is notwell understoodbut there is evidence that an etiological relationship does exist.2 LCH is a neoplastic inflammatory disorder typified by abnormal accumulation of histiocytes in various organ systems.1,3,4 Biopsy of involved tissue confirms diagnosis via morphological assessment and immunohistochemical analysis (CD1a and CD207 positivity).5 Cases are stratified into single or multi-system disease (≥2 organ systems), and whether there is risk organ involvement (liver, spleen, and haematopoietic system).1,2 HLH is characterised by immune system disturbance resulting in uncontrolled accumulation of macrophages, lymphocytes and hyperinflammation.6 The diagnostic criterion is based on clinical, laboratory and histopathological findings.5–7 Currently, the favoured terminology is to label patients that meet sufficient criteria to have “HLH syndrome.” Only a subset of these patients will have “HLH disease” where distinctive immune dysregulation is the core problem and they are likely to benefit from immune suppression treatment. The other patients that have disorders leading to HLH syndrome that would not benefit from immune suppression are labelled as having “HLH disease mimics.”8 Without timely and adequate treatment, HLH can be fatal.9 In this case, a 19-month-old female child presented to our hospital and met the following diagnostic criteria for HLH syndrome6: fever, splenomegaly, cytopenia affecting two cell lineages (haemoglobin 75 g/L and platelets 4 × 109/L), hyperferritinaemia (4316 μg/L), hypofibrinogenaemia (0.4 g/L), strongly positive soluble CD25/IL2R alpha (>2200pg/ml) andabonemarrowaspiratewhich showednumerous macrophages and frequent haemophagocytosis (see supplemental table S1 and supplemental figure S1). Her Epstein–Barr virus (EBV) titre was very high (44,000 IU/ml) and deemed to be the underlying cause of her HLH. Genetic testing revealed no known underlying causative variants. She commenced treatment as per the HLH2004 protocol, consisting of 8 weeks of a weaning course of dexamethasone, and biweekly, then weekly etoposide.9 After initially falling, the EBV titre climbed to 73,100 IU/ml by week 6. A dose of rituximab was subsequently given with good effect. After 8 weeks, treatment response assessment revealed the following normal results: full blood count, fibrinogen, EBV titre, ferritin, bone marrow assessment and spleen size on ultrasound. A complete response was noted and treatment was discontinued (see supplemental figure S2 for treatment timeline). The patient remained in remission from HLH for 9 months, with ongoing normal HLH screening investigations. She then developed left orbital proptosis. AnMagnetic Resonance Imaging (MRI) showed a significant bony infiltrative process involving the skull base, left orbit, and mastoid. A skeletal survey revealed a lytic lesion in the right proximal femur. Femoral lesion biopsy confirmed the diagnosis of LCH with a BRAF V600E mutation. The LCH was classified as "Single System, Multifocal Bone." Treatment was commenced following Stratum 1 of the LCH-IV protocol. The periodic treatment response assessments showed a strong response to therapy and the patient has remained in remission. Both HLH and LCH lie within a spectrum of disorders whose pathophysiology is characterised by immune dysregulation. HLH can arise from a variety of acquired causes such as rheumatological processes (e.g., systemic juvenile idiopathic arthritis), malignancies (leukaemias, lymphomas), and infectious triggers (e.g., EBV).5 Infection can also act as a triggering event for the other acquired causes of HLH.8 LCH has been reported to occur in association with some haematologic conditions (e.g., Rosai–Dorfman disease, Hodgkin disease, acute leukaemia); however, there are no studies that suggest an infectious or environmental stimulus for LCH.4,5,10 HLH cases have been more commonly described occurring after LCH. The pathophysiology of this is not well understood. Proposed mechanisms include systemic hypercytokinaemia and immune dysregulation inducing HLH.2,11 It is estimated that the cumulative incidence of HLH occurring in patients with LCH is as much as 9.3%.1,12 It can be challenging to distinguish betweenmulti-systemLCH (MS-LCH) and HLH due to an overlap of both clinical and laboratory findings.1,2 Interestingly, some studies have identified risk factors in LCH patients that predispose to HLH:MS-LCHwith risk organ positive disease; aged less than 2 years; female and patients without bone involvement.1,11 The main point of this case was that LCH occurred after successful treatment for HLH. Based on the cause, HLH can be classified as “HLH disease,” “HLH syndrome,” or “HLH disease mimics.” Also, with LCH, it is important to be aware of the potential for developing HLH particularly if risk factors (as described previously) are present.