Med Pediatr Oncol 2001;37:545

PERSPECTIVELangerhans Cell Histiocytosis: An Identity Crisis

The provocative report by Surico et al. [1], thecommentary by Egeler and Willman [2], and mostrecently Dr. Zelger's Position Paper in this issue [3]show continuing interest and inquiry into the pathogen-esis of Langerhans cell histiocytosis; neoplasia vs.atypical immunoreaction being the keywords.

The broad clinical spectrum of disease [4], therelationship to other disorders [5] and the failure to ®nda consistent underlying infectious or genetic basis [6]suggest that what we recognize as Langerhans cell his-tiocytosis may, in fact, be the re¯ection of a ®nal commonpathway for several different primary events. Theseevents share the capacity to cause immune dysregula-tion(s) that initiate(s) the pathologic cascades leading toLCH, a phenotype rather than a speci®c disease process.

Ronald Jaffe, Maarten Egeler, and I have recentlycompleted a descriptive study of 30 cases of LCH withvarying degrees of macrophage activation including 12that had stigmata of the hemophagocytic syndrome. This,yet another, disorder associated with LCH further invitesthe notion of a ®nal common pathway.

The hemophagocytic syndrome serves as a paradigm[7]. In a contemporary classi®cation of histiocyticdisorders a dichotomy of histiocytes forms the basis ofnosology [8]. The term `̀ histiocyte'' embraces dendriticimmune cells with principally antigen presenting func-tions and macrophages that excel at antigen processing.Lymphocytes are, not unexpectedly, key players in thevarious dendritic cell disorders and in macrophage-related disorders [7,9,10]. The concept of a ®nal commonpathway is epitomized in the macrophage-related dis-orders. Clearly most cases of hemophagocytic syndromeare secondary to infections, associated malignancyor primary immune defect. Certain familial disorders,initially classi®ed as primary hemophagocytic syndromeor familial hemophagocytic lympho-histiocytosis, haverecently been shown to be manifestations of geneticallydetermined perforin gene defects [11] or germlineSH2D1A mutations related to the X-linked lymphopro-liferative disorder [12]. The incidence of cases of primaryhemophagocytic syndrome is thus diminishing as basicdefects are identi®ed and primary cases are reclassi®ed assecondary hemophagocytic syndromes.

Perhaps the same scenario will evolve in LCH. As thesearch for the cause continues we should not lose sight ofthe different links that have been identi®ed, including thatproposed by Surico et al. They may be important piecesto this complex biological puzzle.

Blaise E. Favara, MD

Special Volunteer FacultyRocky Mountain Laboratories

Laboratory for Persistent Viral Diseases NationalInstitutes of Health

Department of PathologyUniversity of Utah

Salt Lake City, Utah

REFERENCES

1. Surico G, Muggeo P, Rigillo N, Gadner H. ConcurrentLangerhans cell histiocytosis and myelodysplasia in children.Med Pediatr Oncol 2000;35:421±425.

2. Egeler RM, Willman CL. Commentary: Is Langerhans cellhistiocytosis a myeloid dendritic stem cell disorder related tomyelodysplastic disorders? Med Pediatr Oncol 2000;35:426±427.

3. Zelger B. Langerhans cell histiocytosis: a reactive or neoplasticdisorder? Letter Med Ped Oncol 2001;37:543±544

4. Arico M, Egeler M. Clinical aspects of Langerhans cell histiocy-tosis. Hematol/Oncol Clinics of No. America 1998;12:247±258.

5. Egeler RM, Negglia JP, Arico M, et al. The relationship ofLangerhans cell histiocytosis to acute leukemia, lymphomas,and other solid tumors. Hematol/Oncol Clinics of No. America.1998;12:369±378.

6. Willman C, McClain KL. An update on clonality, cytokines, andviral etiology of Langerhans cell histiocytosis. Hematol/OncolClinics of No. America 1998;12:407±416.

7. Goldberg J, Nezelof C. Lymphohistiocytosis: A multi-factorialsyndrome of macrophagic activation. Clinico-pathological studyof 38 cases. Haematol Oncol 1989;4:275±289.

8. Favara BE, Feller AC, Paulli M, et al. Contemporary classi®cationof histiocytic disorders of childhood. Med Pediat Oncol 1997;29:157±166.

9. Egeler RM, Favara BE, van Meurs M, et al. Differential in situcytokine pro®les of Langerhans-like cells and T cells inLangerhans cell histiocytosis: abundant expression of cytokinesrelevant to disease and treatment. Blood 1999;94:4195±4201.

10. Schmitz L, Favara BE. Nosology and pathology of Langerhanscell histiocytosis. Hematol/Oncol Clinics of No. America 1998;12:221±246.

11. Stepp SE, Dufourcq-Lagelouse R, LeDeist F, et al. Perforin genedefects in familial hemophagocytic lymphohistiocytosis. Science1999;286:5446±5452.

12. Arico M, Imashuku S, Clementi R, et al. Hemophagocyticlymphohistiocytosis due to germline mutations in SH2D1A, theX-linked lymphoproliferative disease gene. Blood 2001;97:1131±1133.

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*Correspondence to: Blaise E. Favara, 1114 W. Main Street, Hamilton,MT 59840. E-mail: Blaise@svpeds.net

Received 24 May 2001; Accepted 8 June 2001

ß 2001 Wiley-Liss, Inc.