Revised classification of histiocytoses and neoplasms of the macrophage-dendritic cell lineages

Abstract

The histiocytoses are rare disorders characterized by the accumulation of macrophage, dendritic cell, or monocyte-derived cells in various tissues and organs of children and adults. More than 100 different subtypes have been described, with a wide range of clinical manifestations, presentations, and histologies. Since the first classification in 1987, a number of new findings regarding the cellular origins, molecular pathology, and clinical features of histiocytic disorders have been identified. We propose herein a revision of the classification of histiocytoses based on histology, phenotype, molecular alterations, and clinical and imaging characteristics. This revised classification system consists of 5 groups of diseases: (1) Langerhans-related, (2) cutaneous and mucocutaneous, and (3) malignant histiocytoses as well as (4) Rosai-Dorfman disease and (5) hemophagocytic lymphohistiocytosis and macrophage activation syndrome. Herein, we provide guidelines and recommendations for diagnoses of these disorders.

Figure 1

Histology and somatic mutations of histiocytoses of group L, C, R, M, and H. (A) L group: Histology of LCH (skin [i-ii] and bone [iii]) and of ECD (perirenal [iv-v]). Pie chart of relative frequencies of activating kinase mutations in LCH (vi) and ECD (vii). (B) C group: Histology of JXG (i-ii). (C) R group: Histology of RDD (meningeal with high IgG4⁺ plasma cell infiltration [i-ii]). (D) M group: Histology of MH (i-ii). (E) H group: Histology of inherited HLH (liver [i-ii]). Staining with CD1a (Lii in red), IgG4 (Rii in brown), CD163 (Hii in brown), or hematoxylin and eosin (all others). NOS, not otherwise specified.

Figure 2

Examples of clinical involvement by histiocytoses. (A) Examples of cutaneous manifestations in (i) a child with multisystemic LCH, (ii) adult with intertrigo-like lesions, (ii) xanthelasma of ECD (ii), and (iii) skin manifestations of RDD. (B) Radiographic imaging and CT scans of (i) lytic skull bone lesions and (ii) pulmonary nodules and cysts in LCH, (iii) CT scan revealing typical “hairy kidney” lesions and (iv) micronodular ground-glass opacities and thickening of interlobular pulmonary septa in ECD. (C) ¹⁸F-labeled fluorodeoxyglucose (PET) imaging revealing (i) bilateral and symmetric signal in femurs, tibiae, and humeri in ECD, (ii) cutaneous multiple lesions in RDD, and (iii) signal over wrist, knees, and ankles of a patient with XD.