Br. J. Cancer SI -S3 '." Macmillan Press Ltd., 1994 Br. J. Cancer (1994), 70, (Suppl. XXIII) SI-S3 1994 Histiocytosis An Introduction Jon Pritchard FRCP' & Valerie Broadbent FRCP2 'Department of Haematology/Oncology, Hospitalfor Sick Children, Great Ormond Street, London, WCIN 3JH, England. 2Consultant Paediatric Oncologist, Paediatric Oncology Unit, Box No 181, Addenbrooke's Hospital, Hills Road, Cambridge, CB2 2QQ, England. Summary The Histiocytoses are a group of rare and puzzling multisystem disorders, currently regarded as non-malignant but often treated with 'cancer chemotherapy'. In this article, the origins of histiocytes and of the Histiocyte Society's classification of the Histiocytoses are described with suggested minor modifications to the classification. The current nomenclature for the 2 principal diseases, now named 'Langerhans cell histiocytosis' and 'Haemophagocytic Lymphohistiocytosis', is less confusing than the terms originally chosen. The article sets the scene for the succeeding papers, which focus on 'Langerhans cell histiocytosis'. Histiocytosis Histiocytes (Gk = iatos = tissue, ic(6TTapo = cell) are formed three disorders known as "eosinophilic granuloma", "Hand- in the bone marrow (Figure 1) from a pluripotential self- Schuller-Christian Disease" and "Letterer-Siwe Disease" renewing haemopoietic stem cell via a colony-forming cell were actually part of a spectrum of one disease process, for (the CFU-GM) capable of differentiation only into granu- which he coined the term "Histiocytosis X" (Lichtenstein, locytes and cells of the monocyte lineage. Histiocytes are of 1953). Nezelof et al., identified a Langerhans-like cell as two types (a) mononuclear phagocytes and (b) 'professional' diagnostic of the process (Nezelof et al., 1973) and the desig- antigen-presenting cells. Mononuclear phagocytes (often nation "Langerhans cell histiocytosis", proposed by the known as "ordinary" histiocytes because they are the more Minnesota Group, was adopted by the Histiocyte Society familiar) are 'antigen-processing' histicocytes and phagocyto- (Writing Group of the Histiocyte Society, 1987). The LCH sis is an essential part of their main function which is to label has "stuck" and hardly any publications now use the dispose of unwanted particulate matter. Some, for example older description. the blood monocyte, are migratory whilst others, for example In LCH, lesional "LCH cells" (a term suggested by Dr A the pulmonary alveolar macrophage, the hepatic Kupffer cell, C Chu) are prominent (see Favara, B.E. & Jaffe, R; this the sinusoidal histiocyte in the spleen and the brain microglia volume) but "ordinary" (phagocytic) histiocytes are often are essentially sessile ('fixed' histiocytes). Despite their histor- also present. By contrast, in haemophagocytic lymphohistio- ical classification as 'antigen-processing cells', some "ordinary cytosis (HLH), antigen-presenting cells are rare. The tissue histiocytes" eg. macrophages are capable of antigen presenta- tion. 'Professional' antigen-presenting histiocytes are generally non-phagocytic. Under the microscope they have a dendritic morphology, an evolutionary device by which they increase, Bone Marrow Origin many-fold, their surface area to maximise the chance of successful antigen presentation to specific subsets of T cells. of Histiocytes There are three types of antigen-presenting cells (a) the lym- phoid dendritic cell of the blood (b) Langerhans cells, nor- mally found only in the epidermis of the skin and, sparsely, in the main bronchi, oral mucosa, oesophagus and lower PPSC colon and (c) dendritic reticulum cells and irrter-digitating reticulum cells, found lining lymph node sinusoids. The exact relationship between these cells is uncertain but there is evidence that interdigitating reticulum cells are derived from Langerhans cells that have picked up antigen in the skin, then migrated to adjacent lymph nodes. Histiocytes and other immuno-regulatory and inflammatory cells are believed to communicate with each other via a variety of inter-cellular messenger molecules known as "cytokines" (eg. the Inter- leukins, GM-CSF and tumour necrosis factor alpha), which inulocytes engage and influence neighbouring cells and distant cells through specific surface receptors. The Histiocytoses, an intriguing but puzzling group of diseases, arise when one or more of these cell types accumulates and/or proliferates in a tissue and causes a pathological process. The 2 forms of histiocytosis most often "Professional" encountered in paediatric practice are termed (a) Langerhans antigen- IMononuclear phagocytes cell histiocytosis (LCH), and (b) Haemophagocytic Lympho- presenting cells I('ordinary' histiocytes) histiocytosis (HLH). Other, rarer disorders eg. Rosai- Langerhans cells Blood monocytes Dorfman Disease are hardly ever life-threatening or even Interdigitating reticulum cells Tissue macrophages disabling. Figures 2a and 2b show the evolution of the Dendritic reticulum cells current terminology. In 1959, Lichtenstein realised that the Lymphoid dendritic cell (blood) PPSC = pluripotential bone Correspondence: Jon Pritchard, FRCP, Department of Haematology/Oncology, Hospital for Sick Children, Great Ormond marrow stem cell Street, London WCIN 3JH, England. Figure 1 The bone marrow origin of histiocytes S2 J. PRITCHARD & V. BROADBENT Nomenclature of the 'Class I Histiocytoses Table 1 Histiocytosis syndromes -a current working classification* Class I Langerhans cell histiocytosis ('LCH') Eosinophilic Hand -Schuller-Christian Letterer-Siwe Class II Haemophagocytic lymphohistiocytosis ('HLH') granuloma disease disease - Genetic (Hand, 1893) 11893/1915/19201 11924/1933) - Sporadic Class III Malignant disorders of histiocytes - Acute monocytic leukaemia (FAB M5) - Malignant histiocytosis Class IV Other histiocytosis syndromes Histiocytosis X - Sinus histiocytosis with massive (Lichtenstein, 1959) lymphadenopathy - Xanthogranuloma - Reticulohistiocytoma * Adapted from the "Writing Group of the Histiocyte Society" classification, 1987 (see text) Langerhans Cell Histiocytosis IHistiocyte Society, 19871 infiltrate in both diseases is heterogeneous. Histiocytes are Figure 2a Past and present nomenclature of the 'Class I' admixed with many other types of haemopoietic cells especi- Histiocytoses. ally T- and B-lymphocytes but also neutrophils and, in LCH, eosinophils. This heterogeneity is regarded as reflecting "inter-cellular conversation" between the various cell types, Nomenclature of the major 'Class II' Histiocytoses via a cytokine- mediated "vocabulary". Normally, the various types of histiocytes, and the cells with which they interact, behave in an orderly manner, fulfilling their own function and own Familial erythrophagocytic Virus-associated haemophagocytic generally "minding their business". In the lymphohistiocytosis IFEL) syndrome (VAHS) Histiocytoses, their behaviour becomes disorderly and mis- (Farquhar & Claireaux, 1965) (Risdall et al, 1979) leading "messages" are conveyed to adjacent and distant cells. The "decoding" of this process, and an understanding of the trigger mechanism(s), is the key to understanding the pathogenesis of the Histiocytoses. This "decoding" function is the principle objective of the Nikolas Symposia. The term HLH embraces 2 similar disease processes (Figure 2b) characterised by intense haemophagocytosis most readily demonstrated in the bone marrow, liver, spleen, Haemophagocytic lymphohistiocytosis (HLH) lymph nodes and/or central nervous system (CNS). Although (Henter & Elinder, 1992) an autosomal recessive form of HLH is acknowledged, the Histiocyte Society wished to stress that (a) the sporadic form (infection-provoked in some cases) is at least as common as Figure 2b Past and present nomenclature of the 'Class II' the inherited form and that the two are clinic- Histiocytoses. (b) processes Estimate of relative frequency of the Histiocytoses ~~Class I\ / ~Langerhans Cell\ / ~~Histiocytosis -~t Class III - malignant histiocytosis (< 1%) Non-malignant> Histiocytosis of * This diagram excludes 'localised' phagocytic cells* cutaneous Class 11 Histiocytoses eg. xanthogranuloma because there are hardly ever any 'systemic' implica- tions. Figure 3 Estimate of the relative frequency of the Histiocytoses. The original Histiocyte Society classification is used in this diagram. The shaded area reflects uncertainty concerning the relative frequency of the 2 commonest disorders. HISTIOCYTOSIS - INTRODUCTION S3 ally, pathologically and biochemically indistinguishable. fication is suggested. The term 'Histocytic Lymphoma', with When a case has occurred in a particular family, or there is its intrinsic contradiction, is deleted and the localised forms consanguinity, the Society has suggested the use of the term of skin 'Histiocytosis', usually managed by dermatologists, "familal-HLH" (Henter et al., 1991). are moved from 'Class II' to a new class - 'Class IV'. It In 1987, the Histiocyte Society (an international body of should be noted that this suggestion has not yet been approv- clinicians, pathologists and laboratory scientists, founded in ed or ratified by the Histiocyte Society. 1987) proposed a sensible and workable classification of the Patients with histiocytosis, especially LCH (see Broadbent Histiocytoses which has now gained widespread acceptance et al., this volume), can present to a variety of organ (Writing Group of the Histiocyte Society, 1987). Class I and specialists, both in paediatrics and in adult medicine. Both Class II Histiocytoses were