AN UPDATE ON CLONALITY, CYTOKINES, AND VIRAL ETIOLOGY IN LANGERHANS CELL HISTIOCYTOSIS

doi:10.1016/S0889-8588(05)70519-0

Hematology/Oncology Clinics of North America

Volume 12, Issue 2, 1 April 1998, Pages 407-416

https://doi.org/10.1016/S0889-8588(05)70519-0 Get rights and content

Although the first clinical description of Langerhans cell histiocytosis (LCH) was published more than a century ago, the etiology and pathogenesis of this enigmatic disorder remain unknown. The clinical scope of the disease is wide, ranging from a potentially lethal leukemia-like process that primarily affects infants to a solitary lytic lesion of bone that is usually cured by simple curettage. Intermediate forms of the disease, characterized by lesions of bone, skin, and mucous membranes, may be associated with varying degrees of organ dysfunction, diabetes insipidus, and a chronic indolent course. The histopathologic features of each form of LCH are highly similar, but it is not yet known whether each manifestation of the disease has a common cause or each has a separate and distinct initial cause.

Immunologic, viral, and malignant neoplastic causes have all been considered for LCH. Several observations seemed incompatible with LCH being a cancer. Among these were (1) the high probability of survival in LCH, particularly in patients more than 2 years of age at diagnosis and without organ dysfunction15, 20, 27; (2) the occurrence of rare spontaneous remissions⁶; (3) the failure to detect aneuploidy in LCH lesions using flow cytometric techniques28, 33; and (4) the failure to obtain metaphases and detect karyotypic abnormalities in lesional cells. These factors contributed to the opinion that LCH was a reactive disorder of immune regulation and not a neoplastic process; however, as discussed in this article, no studies to date have implicated a primary immune abnormality in the etiology of the disease. Similarly, no viral genomes have been consistently detected in LCH tissues.

Using X chromosome–linked DNA probes that can detect clonal or polyclonal X chromosome inactivation patterns in female tissues, several investigators have now detected clonal CD1a+ histiocytes in all LCH lesions tested to date. In contrast, all investigators have determined that lesional T cells are polyclonal. Although the biologic significance of the detection of clonality in the histiocytic lineage is not yet fully understood, these data suggest that LCH may be a clonal neoplastic disorder with highly variable biologic behavior and clinical severity.

Section snippets

AN UPDATE ON STUDIES OF THE MOLECULAR ASSESSMENT OF CLONALITY

One of the most important features identifying a cell as being neoplastic is its clonal origin or derivation from a single cell. Although clonality can be readily assessed in lymphoid neoplasms by the detection of clonal rearrangements in immunoglobulin or T-cell receptor genes, there have been no suitable markers for the assessment of clonality in nonlymphoid lineages. The recent development, however, of molecular techniques that reveal random (polyclonal) versus nonrandom (monoclonal)

CYTOKINES AND THEIR IMPACT ON LANGERHANS CELLS (LC)

Although no clear cause of LCH has been defined, the consensus is that there is an underlying immune defect (or defects) in these patients. In the past few years, proteins that regulate the immune and hematopoietic systems (cytokines) have been identified and are now the targets of the search for clues as to the pathophysiology of LCH. The mechanism of LC dysregulation in LCH has remained enigmatic despite advances in understanding that LCH is a clonal disease and several cytokines are

IS THERE A VIRAL CAUSE OF LANGERHANS CELL HISTIOCYTOSIS?

The theoretic links of viruses and LCH are intriguing because of the pleiotropic effects of viruses on cytokine expression; however, there is no compelling epidemiologic evidence to suggest that an unknown viral illness might be responsible for LCH. There has been no clustering of cases by time or place coincident with viral infections and no consistent history of viral illnesses preceding the onset of LCH; however, several investigations have been published in attempts to define a viral cause

CONCLUSION

Recent scientific studies have provided new insights into the cause and pathogenesis of LCH. The role of viruses in initiating this disease remains under study, but no viral genomes have been consistently detected in LCH lesions. Immunologic studies indicate that although altered immune responses and immune dysfunction may play a role in the pathophysiology of the disease, there is no evidence to date that LCH arises from a primary defect in the immune system. Molecular studies of clonality on

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L’histiocytose langerhansienne pulmonaire est une pneumopathie infiltrante diffuse kystique rare, de cause inconnue, qui touche électivement les jeunes patients fumeurs des deux sexes. Les travaux multicentriques menés par le centre de référence ont permis de mieux connaître l’histoire naturelle à court et moyen termes de la maladie et de préciser les modalités de suivi des patients. Une altération importante de la fonction respiratoire peut survenir précocement après le diagnostic chez une proportion significative de patients. Le risque d’une telle évolution diminue après le sevrage tabagique. La cladribine, cystostatique analogue des purines, peut entraîner une amélioration franche de la fonction respiratoire des patients ayant une forme clinique progressive de la maladie, mais ce traitement demeure du domaine de la recherche clinique. Les traitements spécifiques de l’hypertension pulmonaire (anti-récepteurs de l’endothéline, inhibiteurs des phosphodiestérases) peuvent être utilisés avec prudence chez les patients ayant une hypertension pulmonaire sévère, dans des centres spécialisés. La mise en évidence de la présence de la mutation V600E de l’oncogène BRAF dans près de 50 % des lésions d’histiocytose langerhansienne, y compris pulmonaires, constitue une avancée importante dans la compréhension de la pathogénie de cette maladie et ouvre la voie à des approches thérapeutiques plus ciblées.
Pulmonary Langerhans cell histiocytosis is a rare diffuse cystic interstitial pneumonia of unknown etiology that occurs selectively in young smokers of both genders. The multicenter studies conducted by the reference center have better defined the short and medium terms natural history of the disease and the clinical management of patients. A substantial proportion of patients experience a dramatic decline in their lung function soon after diagnosis. Importantly, smoking cessation is associated with a decreased risk of subsequent deterioration. Cladribine, a purine analogue, chemotherapy may dramatically improve lung function in patients with progressive pulmonary Langerhans cell histiocytosis, but this treatment should be used only in the setting of clinical research. Specific pulmonary hypertension therapies (anti-endothelin receptors, inhibitors of phosphodiesterases) may be used with caution in specialized centres for patients with severe pulmonary hypertension, and seem to be well tolerated. The recent identification of the V600E mutation of the BRAF oncogene in approximately half of the Langerhans cell histiocytosis lesions, including pulmonary granulomas, represents an important step forward in the understanding of the pathogenesis of Langerhans cell histiocytosis. Potentially it opens the way to targeted therapies.
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2009, Neurochirurgie
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View all citing articles on Scopus

: Address reprint requests to Cheryl L. Willman, MD, University of New Mexico, Center for Molecular and Cellular Diagnostics, UNM School of Medicine and UNM Health Science Center, Albuquerque, NM 87131–5636

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AN UPDATE ON CLONALITY, CYTOKINES, AND VIRAL ETIOLOGY IN LANGERHANS CELL HISTIOCYTOSIS

Section snippets

AN UPDATE ON STUDIES OF THE MOLECULAR ASSESSMENT OF CLONALITY

CYTOKINES AND THEIR IMPACT ON LANGERHANS CELLS (LC)

IS THERE A VIRAL CAUSE OF LANGERHANS CELL HISTIOCYTOSIS?

CONCLUSION

Hum Immunol

Lancet

Blood

Genomics

J Invest Dermatol

J Pediatr

J Invest Dermatol

Blood

Hematol Oncol Clin North Am

Lancet

A highly informative X-chromosome probe, M27 can be used for the determination of tumour clonality

Br J Haematol

Methylation of Hpall and Hhal sites near the polymorphic CAG repeat in the human androgen-receptor gene correlates with X chromosome inactivation

Am J Hum Genet

Histiocytosis X purified (T6+) cells from bone granuloma produce interleukin 1 and protaglandin E2 in culture

J Clin Invest

Experimental investigations in human eosinophilic granuloma. Note II. Morphologic and immunofluorescent study of cells infected in vitro with the agents isolated from three clinical cases

Rev Roum D'Inframicrobiol

GM-CSF and TNFa co-operate in the generation of dendritic Langerhans cells

Nature

Regulation of tumor necrosis factor alpha transcription in macrophages: Involvement of four kB-like motifs and of constitutive and inducible forms of NF-kB

Mol Cell Biol

Spontaneous healing of Langerhans cell histiocytosis (histiocytosis X)

Eur J Pediatr

Clonality in myeloproliferative disorders: Analysis by means of the polymerase chain reaction

Proc Natl Acad Sci USA

Identification of a novel cyclosporin-sensitive element in the human tumor necrosis factor a gene promoter

J Exp Med

Langerhans' cell histiocytosis: Expression of leukocyte cellular adhesion molecules suggests abnormal homing and differentiation

Am J Pathol

Results of treatment of 127 patients with systemic histiocytosis (Letterer-Siwe syndrome, Schuller-Christian syndrome, and multifocal eosinophilic granuloma)

Medicine

Variable X chromosome DNA methylation patterns detected with the probe M27 in a series of lymphoid and myeloid malignancies

Br J Haematol