Paediatric Update
The histiocytoses: The fall of the Tower of Babel

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Introduction

The history of our understanding and treatment of patients suffering from the group of diverse disorders, termed ‘the histiocytoses’, is characteristic of the self-correcting chain of events which often occurs in science and medicine. To this day these disorders remain enigmatic. In nearly all examples we do not understand their aetiology. There is a primitive view of their pathophysiology. Their classification continues to change and their treatment remains empirical at best1, 2, 3, 4, 5. Yet, progress has been made as evidenced both by the level of data-driven discussion and, most importantly, the fact that more patients now survive.

This update will examine: (1) some of the historical developments associated with our understanding of these disorders; (2) issues concerning their classification; (3) data upon which interpretations concerning aetiology and pathogenesis can be made; (4) the successes and failures of different treatment approaches; (5) late sequelae; and (6) future areas of challenge.

Section snippets

Historical nomenclature

When Metchnikov described the reaction of cells of the larval starfish to a rose thorn in the late 1800s, the first building blocks of a system which would eventually be referred to as the Tower of Babel were set[6]. Based on the observations and conceptual framework of Metchinkov's work on phagocytic cells, Aschoff introduced the term ‘reticuloendothelial system’ (RES)[7]. ‘Reticulo’ refers to the characteristic of cells comprising this compartment to form a ‘lattice or reticulum by

A common origin but separate lives

Much debate has occupied the search for the cell of origin of histiocytes from their initial description. Macrophages were first to arise locally from mesenchymal tissue components[8]. Blood monocytes were considered to be circulating progeny of similar tissue resident cells. Other groups believed monocytes to be derived from endothelial precursors[8]. For many years it was not clear that blood cells had a very high turnover in the adult; thus, there was no reason to assume that a common

Discriminating features and classification of the common histiocytic disorders

The critical importance of understanding the distinguishing characteristics of the different types of disorders involving the RES is exemplified by recent improvements in outcome through directed therapeutic approaches to specific subtypes of disease class. Historically this has not always been the case[31].

In 1893 Dr Alfred Hand from Philadelphia published a case report of a 3-year-old boy with failure to thrive, exopthalmos, hepatosplenomegaly, lymphadenopathy, a scabies-like rash, diabetes

LCH–epidemiology

Although epidemiological analyses cannot define a cause, such studies often provide clues to where one should look with cellular and molecular tools. In the case of LCH, several tantalising associations have been observed.

The annual incidence of LCH has been calculated to be between 3 and 7 cases per million people with males being more frequently affected than females49, 50, 51. Although a Danish population based study showed no significant associations of LCH with neonatal and perinatal

Separate treatment approaches for separate diseases

The initial historical lack of distinction of severe LCH and HLH also resulted in these different disorders being treated similarly. However, with the improved understanding of these two disorders in terms of their underlying biology and distinct clinical courses, therapeutic approaches have diverged.

Some thoughts for the present and future

While significant progress has been made in the treatment of histiocytic disorders over the past 100 years, advances have come about through relatively empirical approaches based on successes in what were considered different manifestations of the same disease. For example, when LCH was considered to be due to a type of infection, antimicrobial agents were used. When it was considered to be a disorder of immune dysregulation, then immunosuppressive or immunostimulatory approaches were used. And

Acknowledgements

I am indebted to Drs Lisa Filipovich, Tom Gross and Ted Zwerdling for their input and critique. Special thanks also go to Drs Maarten Egeler, B.E. Favara, M. van Meurs, J.D. Laman and E. Claassen for sharing unpublished results on cytokines, receptors, CD40 and CD40L expression in LCH. My sincerest thanks also go to Dr Jon Pritchard for his continued encouragement and to Paul, Elizabeth and Nikolas Kontoyannis for continuing to challenge all of us to work together to improve the lives of

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References (231)

  • S. Ladisch et al.

    Immunologic and clinical effects of repeated blood exchange in familial erythrophagocytic lymphohistiocytosis

    Blood

    (1982)
  • J-I. Henter et al.

    Familial hemophagocytic lymphohistiocytosis

    Hemat. Oncol. Clin. North Am.

    (1998)
  • G. Janka et al.

    Infection- and malignancy-associated hemophagocytic syndromes

    Hemat. Oncol. Clin. North Am.

    (1998)
  • S. Bhatia et al.

    Epidemiologic study of Langerhans cell histiocytosis in children

    J. Pediat.

    (1997)
  • A.M. Katz et al.

    Langerhans cell histiocytosis in monozygotic twins

    J. Am. Acad. Dermat.

    (1991)
  • E. Bayar et al.

    Monozygotic twins with congenital acute lymphoblastic leukemia (ALL) and t(4;11)(q21;q23)

    Cancer Genet. Cytogenet.

    (1996)
  • R.C. Yu et al.

    Clonal proliferation of Langerhans cells in Langerhans cell histiocytosis

    Lancet

    (1994)
  • H. Kurahashi et al.

    Monoclonal nature of transient abnormal myelopoiesis in Down's syndrome

    Blood

    (1991)
  • T. Golub et al.

    Fusion of PDGF receptor beta to a novel ets-like gene, tel, in chronic myelomonocytic leukemia with t(5;12) chromosomal translocation

    Cell

    (1994)
  • T. Golub

    TEL gene rearrangements in myeloid malignancy

    Hemat. Oncol. Clin. North Am.

    (1997)
  • D. Amor et al.

    High frequency of t(12;21) in childhood acute lymphoblastic leukemia detected by RT–PCR

    Pathology

    (1998)
  • M. Loh et al.

    Incidence of TEL/AML1 fusion in children with relapsed acute lymphoblastic leukemia

    Blood

    (1998)
  • C. Hage et al.

    Langerhans' cell histiocytosis (histiocytosis X): immunophenotype and growth fraction

    Hum. Pathol.

    (1993)
  • Y. Osugi et al.

    Cytokine production regulating Th1 and Th2 cytokines in hemophagocytic lymphohistiocytosis

    Blood

    (1997)
  • T. Chu et al.

    Histiocytosis syndromes in children

    Lancet

    (1987)
  • J.I. Henter et al.

    Diagnostic guidelines for hemophagocytic lymphohistiocytosis

    Semin. in Oncol.

    (1991)
  • J. Pritchard et al.

    Histiocytosis—an introduction

    Br. J. Cancer

    (1994)
  • P.H. Lieberman et al.

    Langerhans cell (eosinophilic) granulomatosis. A clinicopathologic study encompassing 50 years

    Am. J. Surg. Pathol.

    (1996)
  • B.E. Favara et al.

    Contemporary classification of histiocytic disorders. The WHO Committee On Histiocytic/Reticulum Cell Proliferations. Reclassification Working Group of the Histiocyte Society

    Med. Pediat. Oncol.

    (1997)
  • E.A. Gall

    The cytochemical identification and interrelation of mesenchymal cells of lymphoid tissue

    Ann. NY Acad. Sci.

    (1958)
  • L. Aschoff

    Das Reticulo-Endotheliale System

    Ergebn. Inn. Med. Kinderhulk

    (1924)
  • Craddock CG. Defenses of the body: the initiators of defense, the ready reserves, and the scavengers. In Wintrobe MM,...
  • R. Van Furth

    Origin and kinetics of monocytes and macrophages

    Semin. Hemat.

    (1970)
  • P. Langerhans

    Über die Nerven der menschlichen Haut

    Virchows Arch. Pathol. Anat.

    (1868)
  • P. Langerhans

    Berichtigungen

    Archiv. Mikroskopische. Anatomie.

    (1882)
  • I. Silberberg et al.

    The role of Langerhans cells in contact allergy. I. An ultrastructural study in actively induced contact dermatitis in guinea pigs

    Acta Dermato-Venereologica

    (1974)
  • R. Steinman et al.

    Immunogenicity: role of dendritic cells

    BioEssays

    (1989)
  • Tavassoli M. Bone marrow: the seedbed of blood. In Wintrobe MM, ed. Blood, Pure and Eloquent. New York, McGraw-Hill,...
  • F. Dieterlen-Lievre et al.

    Initiation of hemopoiesis in the mouse embryo

    Ann. NY Acad. Sci.

    (1994)
  • I.E. Godin et al.

    Para-aortic splanchnopleura from early mouse embryos contains B1 a cell progenitors

    Nature

    (1993)
  • Lajtha LG. The common ancestral cell. In Wintrobe MM, ed. Blood, Pure and Eloquent. New York, McGraw-Hill, 1980,...
  • R. Thomas et al.

    Dendritic cells: origin and differentiation

    Stem cells

    (1996)
  • Ishii E, Watanabe S. Biochemistry and biology of the Langerhans cell. In Osband ME, Pochedly C, eds. Hemat Oncol Clin...
  • J. Banchereau et al.

    Dendritic cells and the control of immunity

    Nature

    (1998)
  • Arceci R. Histiocytoses and disorders of the reticuloendothelial system. In Handin RI, Lux SE, Stossel TP, eds. Blood:...
  • B.E. Favara et al.

    The histopathology of Langerhans cell histiocytosis

    Br. J. Cancer

    (1994)
  • A.J. Hand

    Polyuria and tuberculosis

    Arch. Pediat.

    (1893)
  • A. Schüller

    Über eigenartige Schädeldefekte im Jugendalter

    Fortschrifte Roentgenstrahlen

    (1915)
  • H.A. Christian

    Defects in membranous bones, exophthalmos and diabetes insipidus; an unusual syndrome of dyspituitarism

    Med. Clin. North Am.

    (1919)
  • E. Letterer

    Aleukämische Retikulose (Ein Beitrag zu den proliferativen Erkankungen des Retikuloendothelialapparates

    Frankfurter Zeitschrift für Pathologie

    (1924)
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