Molecular Diagnostics and the Histiocytoses

The histiocytoses are a group of rare proliferative disorders derived from dendritic cells and macrophages. The prognosis is variable, ranging from benign lesions though chronic debilitating illness to rare true malignant disorders. Diagnosis is by clinical features, histology including morphology and immunohistochemistry, and recently in haemophagocytic lymphohistiocytosis, using molecular diagnostic techniques. The aetiology of Langerhans cell histiocytosis is still unclear. Recent molecular studies suggest that lesions do not arise from epidermal Langerhans cells, but from accumulation of bone-marrow derived immature myeloid dendritic cells that recruit activated lymphocytes. Macrophage activation syndromes appear to result from lymphocyte/NK cell-driven uncontrolled macrophage activation which leads to proliferation of histiocytes and T cells, and disseminated overactivity of macrophages with cytokine overproduction. Haemophagocytoc lymphohistiocytosis (HLH) refers to a group of recessively inherited disorders that have the clinical and pathological features of an acute and usually fatal form of uncontrolled macrophage activation syndrome. Primary” HLH has been used to describe young children with HLH with proven gene mutations or family history. Evidence of bi-allelic mutations in PRF1 (encodes perforin), UNC13D (encodes MUNC13-4), or syntaxin 11 are diagnostic of HLH SH2D1A, the gene encoding SLAM (signaling lymphocyte activation molecule)-associated protein, SAP, is mutated in X-linked lymphoproliferative disease (XLP) and is associated with HLH in boys with XLP with EBV infections. In patients with Griscelli syndrome type 2, mutations in RAB27A, and in patients with Chediak-Higashi syndrome type 1, LYST mutations are associated with HLH. In many patients with inherited HLH, the responsible gene or genes remain to be defined.