Infant with a skin lesion and respiratory distress

Accepted 16 February 2018 DesCripTion A 2-month-old full-term male infant presented with worsening tachypnoea and a rapidly enlarging, smooth-topped, infiltrative, bronze-yellow nodule with overlying telangiectasias on the mid-sternum (figure 1A). CT imaging demonstrated multiple pulmonary nodules, and enhancing extradural masses compressing the L4–L5 vertebral neural foramina. Immunohistochemical staining of biopsies from skin and pulmonary lesions demonstrated a highly proliferative histiocytosis (figure 1B), which was positively immunoreactive for ALK (anaplastic lymphoma kinase) (figure 1C), CD33 and factor XIIIa, weakly positive for CD68, and negative for CD1a, Langerin, CD34, CD20, CD3, CD43, SOX10, S100, C-KIT, lysozyme and myeloperoxidase. These findings were consistent with a diagnosis of ALK+ histiocytosis with pathological features of juvenile xanthogranulomatosis (JXG). Whole body MRI and positron emission tomography (PET)/ CT imaging (figure 2) confirmed that the extensive pulmonary and compressing spinal cord lesions were fluorodeoxyglucose (FDG)-avid, and further revealed an additional, metabolically active right meningeal/parietal parenchymal brain tumour and extensive mediastinal/abdominal lymphadenopathy. Flourescence in situ hybridization (FISH) and DNA mutation sequencing of the histiocytomas revealed a translocated KIF5B-ALK fusion rearrangement. Together, these findings revealed that this was a rare case of systemic non-Langerhans ALK+ JXG with central nervous system (CNS) involvement (~1%–2% of cases), which has been reported to be associated with significant morbidity and mortality. Langerhans cell histiocytosis (LCH) and JXG are rare histiocytic disorders with clinically variable neoplastic behaviours and are characterised by a clonal proliferation of cells of the monocyte-dendritic lineage. The majority (~80%) of JXG cases present with solitary skin lesions, and can be managed with conservative observation or surgical resection, if cosmetically desired. 2 Chemotherapy (eg, corticosteroids and vinca alkaloids) or low-dose radiation therapy has also been employed with success. The ALK-KIF5B fusion is a known oncogenic activating mutation and is frequently identified in lung adenocarcinoma and anaplastic lymphomas. ALK-KIF5B fusions are rare in histiocytic disorders and have been reported in only a handful of cases. The presence of aberrant ALK+ genomic lesions may define a clinically distinct class of aggressive non-Langerhans histiocytic disorders. 4 The role and long-term efficacy of targeted ALK inhibitor (eg, crizotinib) therapies in the treatment of ALK+ histiocytic disorders currently remain unknown, but potentially beneficial. Given the known aggressive nature of ALK mutations in other neoplastic disorders and the presence of systemic and CNS disease in this patient, chemotherapy was initiated with the purine analogue cladribine (2-CDA; 2 -chlorodeoxyadenosine). This drug was chosen based on established efficacy in the treatment of adult and paediatric multifocal, systemic LCH and JXG with CNS involvement. 2 Follow-up PET imaging after six cycles of 2-CDA therapy demonstrated a near-complete resolution of all FDG-avid lesions. The patient was subsequently started on low-dose daily 6-mercaptupurine and weekly methotrexate maintenance Figure 1 (A) The presenting primary skin lesion with an erythematous base and raised yellow discoloured central region characteristic of juvenile xanthogranulomas. (B) H&E and (C) anaplastic lymphoma kinase antigen immunostaining of dermal lesion.