pathogenesis of langerhans cell histiocytosis · 2018. 10. 7. · out the mysterious x, the name...

PM08CH01-Rollins ARI 13 December 2012 18:46

Pathogenesis of LangerhansCell HistiocytosisGayane Badalian-Very,1 Jo-Anne Vergilio,2

Mark Fleming,3 and Barrett J. Rollins11Department of Medical Oncology, Dana-Farber Cancer Institute, and Department ofMedicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts02215; email: [email protected], [email protected] of Pathology, University of Michigan Medical School, Ann Arbor,Michigan 48109; email: [email protected] of Pathology, Children’s Hospital Boston and Harvard Medical School,Boston, Massachusetts 02115; email: [email protected]

Annu. Rev. Pathol. Mech. Dis. 2013. 8:1–20

First published online as a Review in Advance onAugust 6, 2012

The Annual Review of Pathology: Mechanisms ofDisease is online at pathol.annualreviews.org

This article’s doi:10.1146/annurev-pathol-020712-163959

Copyright c© 2013 by Annual Reviews.All rights reserved

Keywords

dendritic cells, BRAF

Abstract

Langerhans cell histiocytosis (LCH) combines in one nosological cat-egory a group of diseases that have widely disparate clinical manifes-tations but are all characterized by accumulation of proliferating cellswith surface markers and ultrastructural features similar to cutaneousLangerhans cells (LCs). Despite this unified nosology, important ques-tions about LCH remain unanswered. First, despite having phenotypicfeatures of LCs, LCH cell gene-expression patterns differ from those inLCs. Although this observation suggests that LCH may arise from anearlier precursor, it is not necessarily inconsistent with the hypothesisthat LCs are the cell of origin for LCH. Second, LCH’s prominentinflammatory component and occasional benign clinical course sug-gest that LCH may not be a neoplasm. However, the demonstrationthat LCH cells are clonal, along with the recent discovery of activatingBRAF mutations in LCH cells, strongly suggests that LCH is a neoplas-tic disease. These new observations point the way to rationally targetedtherapies.

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HISTORICAL CONSIDERATIONS

To most physicians the rarer diseases of bone withtheir multiple polysyllabic and still more confusingeponymic terminologies constitute the most per-plexing field in medicine, a field so esoteric thatit is apt to be relegated far back into the realms ofthe subconscious.

T.B. Mallory, 1942 (1)

Recognizing the Disease

In 1893, Alfred Hand, Jr. (2), a resident physi-cian at Children’s Hospital in Philadelphia,described a child with exophthalmos, dia-betes insipidus, skull lesions, and a cutaneouseruption “something like scabies,” which he as-cribed to tuberculosis. It was not until 1915 thatArtur Schüller (3), working at the AllgemeinesKrankenhaus in Vienna, reported another childand an adolescent with skull lesions and exoph-thalmos. The child had diabetes insipidus andthe adolescent had adiposogenital dystrophy,which led Schüller to infer that both had adisease involving the hypophysis. However,the earliest suggestion that this collection ofsigns might be stereotypic was made by HenryA. Christian, the first physician-in-chief atPeter Bent Brigham Hospital in Boston.Christian conveniently rereported Schüller’scases in English and added a third case in apaper he prepared for a volume celebratingSir William Osler’s seventy-fifth birthday (4).Calling the presentations a “truly remarkableclinical picture,” Christian enshrined thetriad of exophthalmos, skull lesions, anddiabetes insipidus, which came to be knownas Christian or Schüller–Christian disease. Hememorably wrote that the skull defects “canbest be described by comparing them to theirregular holes in a bit of moth-eaten flannelor the appearance of a pasteboard box gnawedfull of holes by mice.” (Interestingly, bothSchüller and Christian suggested that the bonechanges in the skull were the consequence ofa pituitary disorder, rather than the other wayaround.) Meanwhile, although Hand’s 1893case had been little noted, Hand long remem-bered it and reported two additional cases

in 1921, citing similarities to Christian’s andSchüller’s cases (5). This later report led to theeponymous usage, especially in the Europeanliterature, of Hand–Schüller–Christian disease.Hand foreshadowed 90 years of controversy bysuggesting that this disease could be either aneoplastic or chronic infectious process.

Meanwhile, in 1924, Erich Letterer (6) inTübingen described an infant with a pur-puric rash, hepatosplenomegaly, and anemia, inwhom large, pale, reticuloendothelial cells in-vaded and defaced the structure of skin, liver,spleen, lymph nodes, and bone marrow. A fewsimilar cases then followed in the literature;they were collected and added to by Sture A.Siwe (7) of the University of Lund in 1933.Siwe proposed that these cases were part ofa defined clinicopathological entity of unclearetiology, but his concept did not gain tractionuntil 1936, when Arthur F. Abt and EdwardJ. Denenholz (8) at Michael Reese Hospital inChicago highlighted these cases, added anotherof their own, and proposed that the entity benamed Letterer–Siwe disease. (Abt’s contribu-tion is sometimes honored by referring to thedisease as Abt–Letterer–Siwe disease.) In addi-tion to the rash, hepatosplenomegaly, and ane-mia, Abt and Denenholz noted frequent bone“tumors” that were often visible only by X-ray, and they described involvement of thymus,lung, and intestinal lymphoid tissue in additionto the organs mentioned by Letterer and Siwe.Microscopic pathology consisted of a general-ized hyperplasia of macrophages in involved or-gans. Although Abt and Denenholz could notidentify an etiology, they insisted that Letterer–Siwe disease not be characterized as a reticu-loendothelial disease primarily because “a termwhich is as broad and inclusive as this is ofquestionable aid in understanding the processinvolved.”

A third entity began receiving attention in1940. Sadao Otani and John C. Ehrlich (9) atMt. Sinai and Louis Lichtenstein and HenryL. Jaffe (10) at the Hospital for Joint Diseases,both in New York City, semi-independentlyreported a series of cases characterized bysolitary bone lesions. (The latter physicians

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Histiocytes: tissue-localized cells derivedfrom the monocyticlineage (asdistinguished fromcirculating monocyticcells)

had consulted on at least one of the for-mer two’s cases.) Although the radiographicpicture suggested a neoplasm, both sets ofauthors observed excellent clinical responses tocurettage alone or curettage accompanied byradiotherapy. The lesions were characterizedby infiltration of pale histiocytic cells withinfolded nuclei. However, these cells wereinvariably accompanied by eosinophils andmultinucleated giant cells, which led Otani &Ehrlich (9) to name the lesion solitary granu-loma of bone. However, Lichtenstein & Jaffe(10) won the marketing battle by coining theterm eosinophilic granuloma, although theyconceded that the name they “proposed forthis lesion is not altogether above criticism.”

Unification

These three syndromes are notable for theirdistinct and well-defined clinical presentations.However, by the 1940s, astute clinical scientistswere beginning to sense common threads de-spite deeply ingrained assumptions that workedagainst unification. One of the most insidiousassumptions appeared in a highly influential1928 paper by Russell S. Rowland (11), who,solely on the basis of birefringent staining ofhistiocytes in some cases, inferred that Hand–Schüller–Christian disease was a cholesterol-storage disorder. For more than a decade,this disease’s pathogenesis was thought to beanalogous to what was then understood aboutGaucher or Niemann–Pick disease; the onlydifference was the type of lipid that the histio-cytes accumulated. This assumption created aproblem for scientists who thought they sawsimilarities between Hand–Schüller–Christianand Letterer–Siwe diseases but were dissuadedfrom pursuing a unifying nosology because ev-eryone knew that Letterer–Siwe disease was nota lipid-driven granulomatous disease. In fact,one of its names at the time was nonlipoid gran-ulomatosis. Abt & Denenholz even entertainedthe notion that Letterer–Siwe disease might besimilar to Hand–Schüller–Christian disease butdismissed the possibility because of the absenceof lipid-containing cells in the former (8).

Arvid Wallgren (12) of Göteborg shouldbe better recognized as a towering figure inthis field because he marshaled substantialevidence from published case reports thatHand–Schüller–Christian disease is not acholesterol-storage disorder. In particular, hecited several cases in which reticular cell prolif-eration was not associated with cholesterol, andhe suggested that the appearance of foam cellsis simply a late-stage phenomenon associatedwith tissue destruction. Furthermore, he citedcases in which the clinical boundaries betweenHand–Schüller–Christian and Letterer–Siwediseases seemed fluid: exophthalmos anddiabetes insipidus accompanied by progres-sive anemia in some cases, Letterer–Siwedisease accompanied by lipid-laden foamcells in others. Wallgren stated clearly thatcholesterol storage is not pathognomonic ofHand–Schüller–Christian disease and, moreimportantly, that the histologic picture ofHand–Schüller–Christian disease is generallysimilar to that of Letterer–Siwe disease.

Another impediment to unification was theassumption that the patterns of bone involve-ment are distinct among the three diseases:multiple calvarial lesions in Hand–Schüller–Christian disease, disseminated bone lesionsin Letterer–Siwe disease, and single bonelesions in eosinophilic granuloma. The firstperson to challenge this assumption explicitlywas Sidney Farber of Boston. At a meeting ofthe American Association of Pathologists andBacteriologists in 1941, he presented 10 casesof eosinophilic granuloma (as defined by thecriteria of Otani & Ehrlich or Lichtenstein& Jaffe) (13). In addition to noting that theradiographic appearance of these lesions wasidentical to that of Hand–Schüller–Christianbone lesions, he showed that the microscopicpathology was also identical not only to that ofHand–Schüller–Christian disease but also tothat of Letterer–Siwe disease. Farber suggestedthat all three diseases are “variations in degree,stage of involvement, and localization of thesame basic disease process.” [Perhaps not sur-prisingly, Lichtenstein & Jaffe were recordedin the meeting proceedings as objecting

www.annualreviews.org • Langerhans Cell Histiocytosis 3

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Histiocytosis:general term denotingan accumulation oftissue macrophages

LC: Langerhans cell

Birbeck granules:pentalaminarmembranousorganelles found in thecytoplasm of LCs andthe cells of LChistiocytosis

because they saw Farber present no criteriasolidly linking Hand–Schüller–Christian andLetterer–Siwe diseases (13).] The followingyear, Farber published his cases with a detaileddescription of lesion evolution that couldencompass the histopathological pictures of allthree diseases (14). As for the disease-specificpatterns of bone involvement, it is interestingto note in retrospect that both Schüller (3) andChristian (4) mentioned that the patients theydescribed also had radiolucent lesions in theirpelvises as well as their skulls. Appreciation forthe potentially systemic nature of eosinophilicgranuloma was solidified with the advent ofsafe open-lung biopsies, which demonstratedpulmonary lesions in some cases (15).

Over the next decade, researchers reached aconsensus around the idea that Hand–Schüller–Christian disease, Letterer–Siwe disease, andeosinophilic granuloma were manifestations ofthe same fundamental disease process (see, e.g.,Reference 1). But in 1953, Lichtenstein (16)scored another branding triumph by suggestingthat all three diseases be grouped under the sin-gle heading of histiocytosis X. He rejected thethen-popular alternative of reticuloendothelio-sis because the cells in these diseases wereclearly histiocytes (in the Aschoff sense) withphagocytic properties. Also, he liked the termhistiocytosis because it connotes “an inflamma-tory proliferative reaction [that] is the one fea-ture common to all of the various pathologic ex-pressions of the disease.” What kind of histio-cytosis is it? Lichtenstein rejected the term id-iopathic histiocytosis because it was too broad;after all, sarcoidosis is an idiopathic histiocyto-sis. Instead, he chose X because he thought itwould “emphasize the necessity for an inten-sive search for the etiologic agent.” Althoughit seems likely that the search for the etiologywould have progressed just as vigorously with-out the mysterious X, the name found its wayinto general usage and remained unchallengedfor nearly 35 years.

Solving for X

The next wave of advances in understandingthis disease came from progress in identifying

the lineage of the histiocyte. The phagocytic ca-pacity of the pathologic cell in histiocytosis X,whether for cholesterol or erythrocytes, sug-gested to most investigators that it was derivedfrom a histiocyte, that is, a tissue macrophage.This view began to change in 1961, whenan electron microscopic analysis of vitiliginousskin revealed the presence of pentalaminar,membranous granules in the high-level clearcells of the epidermis (17). These aureophiliccells had first been described by Langerhansas “nerves of human skin” (18) and have sincebeen named Langerhans cells (LCs). The gran-ules themselves were initially termed Langer-hans granules but are more commonly knownas Birbeck granules; they are named for the firstauthor of the paper that described them (17).

By 1967, a handful of electron microscopystudies had been performed on histiocytosisX samples. Strikingly, they demonstrated thepresence of Birbeck granules in most of thenonkeratinized cells in the epidermal samples(19, 20). Despite this significant clue, inves-tigators resisted the idea that histiocytosis Xcells were derived from LCs. In retrospect,this resistance is somewhat understandable be-cause, prior to the groundbreaking demonstra-tions that LCs are antigen presenting cells,their function was unknown (21, 22). Theyhad been variously suggested to be “exhausted”melanocytes, epidermal neural elements (onthe basis of their dendritic morphology), orSchwann cells (17). Furthermore, prior to 1976(23), the LC was thought not to be phagocytic,whereas the histiocytosis X cell was.

Resistance began to fade when Tarnowski& Hashimoto (24) first provided ultrastructuralevidence for the phagocytic nature of patho-logic LCs. They based their inference on thefacts that Birbeck granules are present in der-mal macrophages in Letterer–Siwe disease andthat these cells are clearly phagocytic. Addi-tional support came from the realization thatBirbeck granules are not viral inclusion parti-cles, as had originally been suggested (20), butrather are derived from cellular membranousstructures that are internalized during endocy-tosis (24, 25).


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CD1a:a transmembraneprotein structurallyrelated to majorhistocompatibilitygroup proteins andinvolved in lipidantigen presentation;expressed by humanLCs

LCH: Langerhanscell histiocytosis

CD207 (also knownas langerin): a C-typelectin involved inantigen presentationand expressed by asubset of DCs,including LCs

These results led, in part, to Nezelof et al.’s(26) grand synthesis in 1973. Reviewing all ofthe available data, these authors restated theclinical and pathological characteristics thatwould qualify a disease to be named histiocyto-sis X, then turned their attention to the questionof the cell of origin. By this time, the phago-cytic nature of LCs had become accepted, andNezelof et al. stated that histiocytosis X is prob-ably a “tumoral process in which the Langer-hans cell would be the stem cell.” The diseaseitself was proposed to be the result of the prolif-eration and dissemination of these pathologicLCs, although its etiology was still obscure.

During the subsequent decade, new tech-nologies spawned observations that strength-ened the connection between LCs and the cellsof histiocytosis X. For example, the anti-T6monoclonal antibody (27), which recognizesCD1a, was shown to stain LCs specifically (28,29). The same antibody, as well as an anti-Ia an-tibody, stained Birbeck granule-positive histio-cytosis X cells (30–32), demonstrating a strongphenotypic linkage between LCs and histiocy-tosis X cells. Of course, CD1a positivity is nowconsidered a diagnostic marker for this disease.

Decades of unification and synthesis offormerly disparate diseases culminated inthe 1987 recommendation by the WritingGroup of the Histiocyte Society to renamethis disorder Langerhans cell histiocytosis(LCH) (33). The Writing Group intendedthis designation to embrace histiocytosis X aswell as all the other variant names, such as LCgranulomatosis. The Writing Group’s goalwas to provide a broadly inclusive name whileadhering to strict diagnostic criteria, and therapid acceptance of LCH by the clinical andresearch community suggests that it succeeded.Notably, the Writing Group also offered aconsensus on etiology: “There is no evidencethat the disease is a malignant neoplasticprocess . . . . Some evidence suggests that thedisorder is a manifestation of an immunologicalaberration” (33). (In contrast, the WritingGroup readily suggested that the immunolog-ical deficiencies observed in hemophagocyticlymphohistiocytosis are secondary to the

perforin mutations that cause the disease.) Thisviewpoint dominated the scientific approachto LCH for the next 10 years.

CONTROVERSIES

Recognition of the close similarities betweenLCH cells and normal LCs, and an understand-ing that the distinct clinical entities defined inthe first half of the twentieth century are mani-festations of the same disease, has helped or-ganize thinking about LCH. Nonetheless, atleast two questions that are central to an under-standing of LCH remain controversial. One iswhether the LC is truly the precursor of the ab-normal cell in LCH, and the other is whetherLCH is a neoplasm.

Origin of the Pathologic Cell inLangerhans Cell Histiocytosis

One of the most significant conceptual break-throughs in the understanding of this diseasewas the discovery of a link between the patho-logic cells of LCH and normal epidermal LCson the basis of shared surface markers and ultra-structural features. The simplest pathogeneticinference that was drawn from this connectionis that the normal epidermal LC is the precur-sor cell for LCH. Whether the disease arises inresponse to an external inflammatory stimulusor as the result of a cell-autonomous geneticevent (see the section titled Neoplasm VersusImmune Disorder, below), the cellular targetof these changes has been assumed to be theepidermal LC.

A 2010 study challenges this assumption(34). It compared global gene expression inCD207-positive cells from 12 LCH sampleswith CD207-positive LCs obtained from 13samples of normal skin. CD207, also knownas langerin, is a type II transmembrane pro-tein that is expressed in LCH and normal LCs.It is unsurprising, and superficially consistentwith their presumed common origin, that morethan 95% of the >47,000 surveyed messengerRNAs were expressed at similar levels in thetwo cell types. Nonetheless, informatic analysesgrouped the LCH samples into one cluster and


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DC: dendritic cell

Epithelial-mesenchymaltransition (EMT):a phenotypic alterationin which epithelialcells take on the motileand othercharacteristics ofmesenchymal cells;thought to be acomponent ofmetastatic competencyin cancer

the normal LC samples into another; the cor-relation coefficient between them was only 0.2.Although this observation can be interpreted indifferent ways, the authors of the 2010 studysuggested that it is consistent with a model inwhich the cell of origin for LCH is not a matureepidermal LC. Rather, because several genesencoding myeloid dendritic cell (DC) markers,including CD1d, CD33, and CD44, were over-expressed in CD207-positive cells from LCHpatients compared with normal LCs, the au-thors suggested that this finding is evidence fora myeloid DC precursor of the pathologic cellin LCH. They pointed out that other DCs canalso be CD207 positive (35, 36), and perhaps theprecursor cell for LCH is also a precursor forthis cell type. Perhaps the field has been misledby the CD207 positivity of LCs.

If LCH were to arise from a myeloid pre-cursor rather than a mature LC, at what stagein myeloid DC maturation might this occur?Because the pathologic cell in LCH shares fea-tures with LCs that are nearly specific for thislineage, an understanding of LC ontogeny mayhelp answer this question. Importantly, whenLCs are placed broadly within the DC family,LCs are more closely related to classical DCsthan to plasmacytoid DCs, given their sharedexpression of CD11d and major histocompati-bility (MHC) class II antigens. However, care-ful studies of LC precursors in mouse modelssuggest that they arise from a lineage that isdistinct from that of classical DCs. In partic-ular, investigators have identified murine LCprecursors that are CD207 and CD24 nega-tive (37, 38). These cells begin to populate theepidermis during development of the stratumcorneum and remain CD207 and MHC class IInegative until approximately a week after birth(39–41). Merad and colleagues (42–45) iden-tified the precursors of these CD207-negativecells as a population that derives from themonocyte lineage. Like other monocytoid cells,these CD207-negative cells are CD11b posi-tive, F4/80 positive, colony-stimulating factor1 receptor positive, and CX3CR1 positive, al-though, unlike most monocytes, they are Gr-1negative.

Some lines of evidence point to a yolksac origin for these early cells. For example,the CD207-negative LC precursors appear inlimb buds at approximately the same time thatyolk sac–derived macrophages begin to pop-ulate the skin. In addition, yolk sac–derivedprimitive macrophages have the same distinc-tive set of monocytoid surface markers as theearly LC precursors, including the absence ofGr-1. The Merad group (46) suggests that dur-ing embryogenesis yolk sac–derived primitivemacrophages migrate to the skin, where theydifferentiate into CD207-positive LCs. Thus,this lineage is distinct from that of classicalmyeloid DCs. If myeloid DC lineage specificitywere the reason that the handful of genes thatare expressed in myeloid DCs are also expressedin LCH cells, then the cellular target for theinitiating event in LCH would have to be aneven earlier precursor common to the LC andmyeloid DC lineages—a very early precursor,indeed.

An alternative explanation for the expressionof some myeloid DC precursor genes in LCHis that epidermal LCs are, in fact, the precur-sors of LCH cells but that they undergo re-activation of these early myeloid marker genesas a consequence of transformation-induced re-programming of the LC transcriptional profile.This process used to be interpreted as dedif-ferentiation, but we now know that a similartranscriptional reprogramming forms the basisof epithelial-mesenchymal transition (EMT),which may be necessary for neoplastic cellsto invade and spread (47). Despite the nameEMT, the phenotypic changes associated withthis transition are not restricted to epithelialcancers, and some of the alterations that are themost characteristic of EMT are also observedin LCH. In particular, the loss of E-cadherin isboth a hallmark of EMT and a well-describedchange in LCH cells compared with restingLCs (48). Another marker of EMT is upreg-ulation of osteopontin, which has also been de-scribed in LCH (34). Furthermore, the conceptof EMT may be particularly relevant to LCHbecause of the evidence that tumor-associatedinflammatory cells may be important inducers


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and reinforcers of EMT (49, 50). Thus, the al-terations in gene expression that may suggest adifferent cell of origin for LCH may be simplythe consequence of an EMT-like change. Res-olution of this question will require continuedcareful analyses of LC precursors in tractablesettings, such as mouse models, coupled withongoing references to human physiology anddisease.

The idea that the epidermal LC is the cellof origin for LCH has also been questioned be-cause LCs are a stable, localized cell populationand are therefore unlikely to be responsible fordisseminated forms of LCH (34). Again, thereare different ways to interpret these facts, but anunderstanding of LC homeostasis can informthe discussion. As noted above, LCs are phe-notypically related to classical DCs, and bothclassical DCs and LCs are derived from circu-lating hematopoietic precursor cells. The bonemarrow source of classical DCs is convincinglydemonstrated by the wholesale replacement ofhost DCs, including those residing in mucosalsites, by donor cells after hematopoietic stemcell transplantation (51–54). Similarly, donorbone marrow cells can replace a significant pro-portion of host LCs when transplanted intolethally irradiated recipients (55, 56), althoughthere is a caveat: The replacement of host LCsis not complete. Approximately 20% of LCs re-tain host markers, which may be a consequence,in part, of the relative radioresistance of LCscompared with that of classical DCs. The lin-eage of the bone marrow–derived replacementcell is monocytoid, according to the finding thatblood monocytes can replenish cutaneous LCsfollowing UV irradiation (43); this process re-quires expression of both the chemokine recep-tor CCR2, for cells to enter the dermis, andCCR6, for the cells to reach their final destina-tion in the epidermis.

However, these observations may have lit-tle relevance to patterns of steady-state LChomeostasis. For example, conditioning regi-mens for hematopoietic stem cell transplanta-tion induce systemic hyperinflammatory states,which lead to LC activation and emigrationfrom the epidermis. In contrast, in mouse

models under steady-state, noninflammatoryconditions, LC populations are extraordinarilystable; their half-lives in the epidermis are 53 to78 days (57, 58), and the proliferating fractionis only 1% to 2% (59). In these settings, slowrenewal of skin LCs is accomplished by localproliferation; bone marrow–derived precursorsare not required. This renewal has been demon-strated directly through the use of parabiosismodels in mice (45). Similarly, noninflamma-tory depletion of epidermal LCs achieved withtransgenically targeted expression of diphtheriatoxin suggests that proliferation of local precur-sors slowly leads to their replacement (60). Evenin mild inflammatory states such as atopic der-matitis, in which the dermal-epidermal junc-tion remains intact, replacement of LCs appearsto occur primarily through local proliferation(39).

Thus, experimental and clinical evidenceshows that epidermal LCs are a stable cellpopulation that renews itself primarily throughregulated proliferation of local precursor cells.However, this physiology does not necessarilypreclude LCs’ dissemination to other organsin the setting of LCH. An epidermal LC,activated either by an inflammatory stimulusor by an oncogenic event, may be capableof leaving the epidermis and migrating todistant organs. Even under normal conditions,activation of LCs induces their departure fromthe epidermis and migration to regional lymphnodes in a manner that may be dictated bypatterns of chemokine receptor expression.Pathological activation in LCH may takeadvantage of elements of this preexistingprogram to produce characteristic patternsof organ involvement. Transformation mayalso be accompanied by EMT, as describedabove. The analogy to metastatic canceris apparent. Thus, it is not necessary to posita bone marrow–derived precursor to explainmultiorgan involvement in LCH.

Neoplasm Versus Immune Disorder

Uncertainty about so fundamental a questionas whether or not LCH is a neoplasm is


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understandable. Unification of the various clin-ical presentations of LCH creates a single noso-logical category, but it simultaneously embracesa broad spectrum of clinical presentations: dis-eases with generally good outcomes, such aseosinophilic granuloma, along with diseasesthat behave as aggressive malignancies, such assome cases of infantile Letterer–Siwe disease.Furthermore, there are well-documented re-ports of spontaneous remissions even in multi-system LCH in infants (61). This propensity forfavorable outcomes is of more than academicinterest because, during the ascendancy of cyto-toxic chemotherapy for cancer in the 1970s and1980s, similar treatments were used for LCH.Even though those treatments were clinicallyeffective in multisystem disease, recognition ofthe potential for spontaneous remissions andthe possibility that LCH is not neoplastic ap-propriately tempered the tendency to adminis-ter overly aggressive treatments.

The granulomatous nature of LCH lesionsand the generally benign morphology of patho-logic LCs have suggested possible infectious,environmental, or autoimmune pathogeneses.Nonneoplastic etiologies do not preclude ag-gressive and occasionally fatal outcomes. Forexample, secondary hemophagocytic lympho-histiocytosis, which can also be fatal, arises afterviral infection (62). However, despite decades ofsearching, no convincing evidence has emergedfor an infectious cause of LCH. Herpesvirusessuch as Epstein–Barr virus, cytomegalovirus,and human herpesvirus 6 have been detectedin clinical samples (cited in Reference 63), butthey are unlikely to be pathogenetic because nodifferences in the overall prevalence or titers ofantibodies against these viruses have been de-tected in comparisons between LCH patientsand case-matched controls (63). This findingis consistent with earlier reports that were un-able to document an association between her-pesviruses and LCH (64).

A substantial literature has described im-mune dysregulation and abnormal cytokine ex-pression in LCH patients and has been citedas support for the idea that the nature ofLCH is predominantly immune or inflamma-

tory. Although an initial crude examination ofimmune status in LCH patients revealed nogross abnormalities (65), later studies indicateda deficiency of circulating suppressor T lym-phocytes (66). Considering the role that LCsplay in shaping T cell responses, this observa-tion raises the possibility that pathologic LCsmay drive immune dysfunction. High levelsof circulating cytokines such as granulocytemacrophage colony–stimulating factor (GM-CSF), macrophage colony–stimulating factor(M-CSF), and FLT3 ligand have been detectedin LCH patients, although their cellular sourcesand their pathogenetic relevance have not al-ways been well documented (67–71).

In this regard, a current controversy con-cerns the cytokine interleukin (IL)-17A. Onegroup has reported high plasma levels of IL-17A in LCH and its expression by pathologicLCs (72). This observation is provocative be-cause, in the same study, the authors demon-strated that IL-17A stimulates DC fusion invitro, which may explain the frequent appear-ance of multinucleated giant cells in LCH le-sions. However, a second group was unable todetect IL-17A messenger RNA or protein in acollection of LCH samples; these authors sug-gest that the original finding may have been theunfortunate consequence of a nonspecific anti-body (73). Nonetheless, demonstrating the DCfusion activity of IL-17A in vitro did not de-pend on an IL-17A antibody and has not yetbeen challenged, so IL-17A secreted by someother cell type may still play a role in LCHpathobiology (74).

Altered Transcriptional Programs inLangerhans Cell Histiocytosis

Several cell-surface markers that are char-acteristic of activated LCs, including CD2,CD11b, CD24, CD44, CD54, CD58, CD80,and CD86, have been identified on LCH cells(69, 75, 76). Also, similar to activated LCs,LCH cells express the γ chain of the GM-CSF receptor (77), which may provide a mech-anism whereby elevated circulating GM-CSF(70) stimulates their proliferation. Patterns of


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adhesion molecule expression are also consis-tent with an activated phenotype, namely thepresence of β1 and β2 integrins, which restingLCs do not express (69, 75, 78), and the absenceof E-cadherin, which is downregulated follow-ing LC activation (48, 79).

However, LCH cells also have some featuresof resting LCs. In particular, Birbeck granules,which are a sine qua non of pathologic LCs,are present in resting LCs and absent from ac-tivated cells (80). Furthermore, despite the ex-pression of some of the activation surface mark-ers described in the previous paragraph, LCHcells are poor stimulators of naı̈ve T lympho-cytes, which is a characteristic of resting LCs(81, 82). Similarly, although LCH cells showpatterns of adhesion molecule expression thatare characteristic of activated LCs, they alsoexpress VLA-5 and L-selectin, which are ex-pressed by resting cells (83).

Analysis of chemokine receptor expressionis also consistent with a mixed resting/activatedphenotype in pathologic LCs. Resting LCs ex-press CCR6, which is thought to anchor thesecells in the epidermis through chemoattractionto CCL20, a CCR6 ligand that is secreted byepidermal keratinocytes. Following activation,LCs downregulate CCR6 and replace it withCCR7, which directs LCs to regional lymphnodes, the source of CCR7 ligands CCL19and CCL21 (84–86). Some investigators havereported coincident expression of CCR6 andCCR7 by pathologic LCs in all the cases theyexamined (87). Another group has identifiedonly CCR6 expression (88). Although the ba-sis for this discrepancy has not been identi-fied, both groups agree that LCH cells expressCCR6, which is characteristic of resting LCs.

Taken together, these phenotyping stud-ies paint a picture of disordered maturationin pathologic LCs. The mixture of markersthat are characteristic of both resting and ac-tivated cells may be consistent with (a) matu-ration arrest after stimulation of resting cells;(b) partial reversion to a resting phenotype byan activated cell; or (c) the transcriptional pro-gram associated with EMT, as described above.The findings could also be consistent with a

cell-autonomous abnormality that disrupts theLC activation program, an influence of the mi-lieu (such as abnormal cytokine expression) thatresults in the same phenotype, or both as hy-pothesized in the EMT model (49). Notably,however, this phenotype is preserved after cellsare explanted in vitro and requires further ma-nipulation to alter it. For example, as men-tioned above, pathologic LCs are not potentstimulators of resting T cells despite their ex-pression of CD80 and CD86 (81, 82). CD40ligand treatment in vitro can make pathologicLCs potent antigen presenting cells (89). Theseobservations argue that the defect in patho-logic LCs is stable and, to some extent, cellautonomous.

LANGERHANS CELLHISTIOCYTOSIS AS ANEOPLASTIC DISEASE

Determining whether LCH is a neoplastic dis-ease has therapeutic implications. If LCH werea reactive inflammatory disease, then prolifer-ating LCH cells would be intrinsically normaland definitive treatment could focus on remov-ing the inciting inflammatory stimulus. In con-trast, documentation of recurrent genomic ab-normalities in LCH cells may suggest that LCHis susceptible to molecularly targeted antineo-plastic therapies, which would place the diseasewithin the contemporary paradigm that has rev-olutionized cancer treatment. Resolution of thisdistinction will dictate the direction of develop-mental therapeutics in LCH.

Molecular Evidence for Neoplasia

Careful molecular analyses performed overseveral years have been consistent with bothof the models described above, but the findingthat pathologic LCs in nonpulmonary LCHare clonal has lent the strongest support forthe idea that LCH is a neoplastic disease(90, 91). However, although clonality maybe a necessary attribute of neoplasia, it is notsufficient. For example, some clinically aggres-sive immune disorders may be characterized


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CGH: comparativegenomic hybridization

FFPE: formalin-fixed,paraffin-embedded

by oligoclonal expansion of nonneoplastic Tlymphocytes (92). To establish a neoplasticpathogenesis for LCH, investigators mustidentify recurrent genomic abnormalities.

The search for molecular genetic alterationsin LCH has been severely impeded by the rar-ity of the disease. Abnormalities identified in asmall collection of samples have often not beenconfirmed in later studies of a larger number ofsamples. For example, cytogenetic alterationswere reported in an examination of five LCHcases (93), but none recurred within the sam-ple set and none were observed in a later studyof 31 samples (94). In fact, the later study doc-umented diploid genomes in all cases, which,if anything, casts additional doubt on the neo-plastic origin of LCH. Copy number analy-sis has been attempted using array comparativegenomic hybridization (array CGH) and poly-merase chain reaction (PCR). One study thatexamined seven LCH bone samples with arrayCGH reported numerous copy number alter-ations throughout the genome and recurrentloss of heterozygosity at several loci (95). Simi-larly, a PCR-based study of 24 samples found ahigher degree of fractional allelic loss in samplesfrom multisystem and high-risk patients com-pared with those from single-system and low-risk patients (96). Again, however, a larger studyusing PCR and high-density single-nucleotidepolymorphism arrays detected no significantcopy number alterations (94).

Until recently, the only reliably recurrentmolecular abnormality in LCH was overexpres-sion of p53 (97), which is most commonly de-tected by immunohistochemistry. The molec-ular basis for its overexpression is not known.No mutations in TP53 or MDM2 were foundin the 10 cases in which overexpression wasoriginally described, nor were they found in alater survey of a larger number of cases (94),although that survey did confirm p53 overex-pression in most cases. To date, only one TP53mutation has been reported in LCH (98). Insome settings, overexpression of p53 may re-flect the persistence of an abnormal non- or hy-pofunctioning allele; in such cases, p53 may bea primary contributor to a hyperproliferative,

transformed phenotype through its inability toinduce apoptosis. However, p53 overexpressionmay, instead, be a normal secondary responseto a proliferative stimulus. Furthermore, p53overexpression by itself cannot be cited as evi-dence of the neoplastic nature of LCH becausethere are examples of benign proliferative dis-orders that are characterized by high levels ofp53 expression (99–102).

Some of the most important mechanis-tic insights into cancer pathobiology havecome from global, nonbiased assessments ofsmall genomic abnormalities, such as pointmutations and short insertions or deletions.Until recently, the relevant technologieshave been insufficiently robust to providereliable measurements through the use ofDNA extracted from archived formalin-fixed,paraffin-embedded (FFPE) samples. Thisproblem has placed LCH investigators at adisadvantage because the rarity of the diseaseis surpassed only by the rarity of fresh frozensamples that are sufficiently large for such anal-yses. Fortunately, an appreciation of the wealthof genomic information in archived clinicalpathology specimens has driven an explosion intechnological advances that permit reliable ge-nomic analyses of these specimens. The studyof LCH has benefited from this technologicalevolution.

Next-generation DNA sequencing plat-forms, especially those that perform targeted orwhole-exome sequencing, will almost certainlybe used to analyze DNA extracted from FFPEsamples in the very near future. Meanwhile,however, an example of a relatively nonbiasedtechnology that has already demonstrated itsutility in the analysis of archived specimens isthe mass spectrometry genotyping platform de-veloped by the Sequenom Corporation (103).By use of genomic DNA as a template, shortamplicons are generated by PCR around thepolymorphic loci of interest, and the distinctproducts of polymorphic templates are iden-tified by their characteristic molecular masseswith MALDI-TOF (matrix-assisted laser des-orption/ionization time-of-flight) mass spec-trometry. Because this technology can separate


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OncoMap: a massspectrometry–basedallelotyping systemfocused on cancer-related variants

and identify amplicons with very small differ-ences in mass, the process can be multiplexedto permit the analysis of several loci in a sin-gle run. A version of this platform customizedfor oncology, OncoMap, can test a sample forthe presence of more than 1,000 distinct allelesfrom 140 cancer-related genes in a single run(104).

The inherent difficulty of analyzing DNAfrom FFPE samples is that the DNA is frag-mented. Although this drawback can make di-rect sequencing approaches difficult, it presentsa less daunting challenge to the mass spectro-metric approach because the amplicons it gen-erates, generally 200–400 base pairs in length,are smaller than the median size of the DNAfragments from FFPE material (105). In a directcomparison between OncoMap’s performanceon fresh frozen samples and on FFPE samplesof pediatric low-grade astrocytomas, the sensi-tivities and specificities of the test were nearlyidentical in both tissue types (106).

BRAF Mutations

Recently, a version of OncoMap that tests 983alleles from 115 cancer-related genes was usedto analyze 61 archived LCH cases (98). Themost striking finding was the presence of theoncogenic BRAF V600E mutation in 57% ofthe cases. The mutation was validated usingpyrosequencing as an orthogonal technologyin these samples and in a fresh frozen sam-ple. The presence of mutated BRAF was notassociated with disease stage, but it did cor-relate negatively with age. Other point muta-tions detected in this analysis included TP53R175H, a known cancer-related mutation inp53; KRAS G13D, a transforming allele of K-Ras; and MET E168D, a possible transform-ing allele of c-Met, although that allele maybe a nonpathogenic polymorphism. None ofthe other mutations assayed by this version ofOncoMap were detected, but recall that On-coMap is not truly unbiased and other muta-tions not included in this testing panel may bepresent in LCH.

This study also employed several controlsto demonstrate the specificity of BRAF V600Efor LCH. For example, the mutation was notdetected in dermatopathic lymphadenopathy, adisease characterized by proliferation of normalLCs, which suggests that BRAF V600E is spe-cific for pathologic LCs and is not present innormal proliferating LCs. The mutation alsowas not detected in non-LC histiocytoses suchas juvenile xanthogranulomatosis and Rosai–Dorfman disease (sinus histiocytosis with mas-sive lymphadenopathy).

If BRAF V600E were pathogenetic in LCH,then this allele should be present specifically inthe pathologic LCs, as opposed to other celltypes in the samples. Identification of the cellthat harbors this mutation in mixed cellularitysamples such as LCH is challenging because ofthe absence of a validated antibody that specifi-cally recognizes the mutant BRAF protein. In-stead, the authors of this study inferred the spe-cific presence of BRAF V600E in pathologicLCs by the severalfold-higher abundance of themutant allele in CD1a-positive versus CD1a-negative cells harvested by laser-capture mi-crodissection, as analyzed by pyrosequencing.Similarly, the relative abundance of the mutantallele compared with that of the wild-type allele,quantified either by OncoMap mass spectrom-etry or by pyrosequencing, was proportional tothe number of pathologic LCs in all of the sam-ples that contained the mutant allele. Interest-ingly, the proportion of mutated alleles was ap-proximately half the proportion of pathologicLCs. This finding may suggest that the mutantallele is present as a single copy, which wouldbe consistent with the pathogenic behavior of adominant oncogene.

B-Raf is an important component of thesignaling cascade that ordinarily begins when agrowth factor or other ligand engages its recep-tor tyrosine kinase. The signal is passed via se-quential phosphorylation steps to Ras, then Raf,then MEK and ERK kinases, which ultimatelyleads to modulation of gene expression (107).Investigators obtained evidence for the activa-tion of this pathway in LCH by demonstratingthat MEK and ERK are phosphorylated in


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pathologic LCs. The fact that phospho-MEKand phospho-ERK were observed by im-munofluorescence only in LCs and not in othercell types in LCH provides further evidence forthe cell type specificity of mutant BRAF V600E.

Unexpectedly, however, phospho-MEK andphospho-ERK were observed in the LCs of allLCH samples, regardless of their BRAF geno-type (98). This signaling pathway can also beactivated by duplication of a wild-type BRAFlocus, which has been observed in a significantnumber of pediatric low-grade astrocytomas(108, 109). However, BRAF duplication was notobserved by fluorescence in situ hybridizationanalysis in 43 LCH cases (98). Thus, the molec-ular basis for RAS-RAF-MEK pathway activa-tion is unknown in the ∼40% of LCH cases thatdo not harbor an activating BRAF mutation.One possibility is overexpression of a receptortyrosine kinase in LCH cells. Amplification of agene that might be responsible for such overex-pression cannot be detected by OncoMap butcould be revealed by next-generation sequenc-ing approaches. Another possible explanationfor pathway activation is high ambient levels of agrowth factor or cytokine whose cognate recep-tor is expressed by pathologic LCs. Several can-didates, including GM-CSF and M-CSF, arecited above (70, 71, 77).

Is Langerhans Cell Histiocytosisa Neoplasm?

The demonstration of BRAF V600E in morethan half of the archived LCH samples exam-ined to date provides the recurrent genomic ab-normality that is required, in addition to clon-ality, to assign LCH a neoplastic origin. Thisreview is very careful to use the word neoplas-tic rather than malignant. The most clinicallybenign forms of LCH may be mechanisticallyanalogous to nevi, which also contain BRAFV600E and are, of course, neoplastic. In fact,the benign nature of most nevi is now thoughtto be an in vivo example of oncogene-inducedsenescence in which the presence of an activat-ing oncogenic mutation, such as BRAF V600Ein melanocytes, can direct several rounds of cell

division that are superseded by a senescence re-sponse within the same cell, presumably as anorganism-level protection against malignancy(110). Perhaps, in some LCH cases, the appear-ance of BRAF V600E in LCs also leads to prolif-eration and the appearance of clinical LCH, butas in nevi, senescence supervenes, which causesthe spontaneous remissions that have been welldocumented in the literature.

More aggressive LCH cases may also be ex-plained by analogy to other diseases such asmelanoma. Although some melanocytes thatcarry BRAF V600E produce nevi, others be-come true melanomas. Careful molecular anal-yses have demonstrated that melanoma cellscontain additional genomic abnormalities, suchas loss of PTEN or CDKN2, that are presumedto be required for the progression to malig-nancy (111). Although the OncoMap analysisthat identified BRAF V600E did not find inac-tivating mutations of these genes and detecteda p53 mutation in only one case, this technol-ogy is limited by its inability to detect novelmutations or deletions. Thus, next-generationsequencing approaches that can reveal novelmutations as well as copy number alterations(and, in the case of whole-genome sequencing,translocations) may identify additional abnor-malities that could cause the development ofaggressive forms of LCH. These abnormalitiescould bypass the senescence response in BRAFV600E–positive cases or could engage novel,non-BRAF pathways in BRAF V600E–negativecases.

The discovery of BRAF mutations in LCHhas refocused attention on some areas of con-troversy. The first controversy is a debate aboutthe source of pathologic LCs in LCH lesions.If LCH is a neoplasm, then the presumptionis that lesions expand by local proliferationof neoplastic LCs. In contrast, if LCH is anoligoclonal reactive inflammatory disease, thenLCs might be recruited to lesions from cir-culating or bone marrow pools. Although thisdistinction is hardly absolute (inflammatorycells can proliferate locally), the controversywas stoked by a 1998 paper with the provoca-tive title “Langerhans Cells in Langerhans Cell


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Granulomatosis Are Not Actively ProliferatingCells” (112). This study examined 25 casesfrom various anatomic sites for markers of cellproliferation. The mitotic index for LCs was0.1% versus 0.3% for a small collection of non-small-cell lung cancer (NSCLC) cases; Ki67staining was present in only 5% of LCs versus18–33% of NSCLC cells; and assessment ofDNA content by Feulgen staining showedonly 5% to 6% of LCs with an S-G2-M DNAcontent versus 26% of NSCLC cells. Althoughthe authors observed comparable proportionsof PCNA-positive cells in LCH and NSCLCsamples, they suggested that the inconsistentlyhigh degree of staining in LCH was a conse-quence of PCNA’s ability to be expressed innondividing cells. Their overall conclusion wasthat local proliferation does not contribute tothe mass of pathologic LCs observed in LCHlesions.

Although these investigators clearlyoverstated their case, inasmuch as they diddocument some degree of local proliferation,the growth fraction within LCH lesions wasquite low in this study. However, other dataindicate that pathologic LCs actively prolifer-ate. One study demonstrated Ki67 staining in3% to 24% of pathologic LCs in 26 cases andfound that Ki67 positivity correlated closelywith PCNA positivity (113). Another study ex-amined 61 sections from 43 patients and foundmitotic cells in 56% of the sections, all of whichwere CD1a positive (114). All but one case hadKi67-positive pathologic LCs; 34 of the 43 caseshad greater than 10% Ki67-positive LCs, and11 of the 43 cases had greater than 50% Ki67-positive cells. The discrepancy in Ki67 stainingbetween these two reports and the first reportcould be due to differences in sample selection,sample preparation, antibody source, or stain-ing protocols. However, the weight of evidencefrom the latter two studies, among others (115),suggests that significant local proliferation ofpathologic LCs occurs in LCH. Of course, thisfinding does not preclude a contribution fromcirculating cells, which may have arisen fromproliferating pools at other sites such as bonemarrow.

The second controversy concerns pul-monary LCH, which has long been thoughtto be distinct from the nonpulmonary forms.Because it arises in adult smokers and thepathologic LCs are nonclonal, pulmonaryLCH has been classified as a reactive inflam-matory disease. Therefore, the finding that40% of pulmonary cases examined in the orig-inal OncoMap study contained BRAF V600Ewas surprising (98). Two possible explanationsfor this finding have been suggested. First, thenonclonality of pulmonary LCH may be anoverstatement. A careful analysis of clonality inpulmonary LCH demonstrated that 29% of thecases contained a clonal population of patho-logic LCs (116). This proportion is not very dif-ferent from the proportion of pulmonary caseswith BRAF V600E; perhaps a subtype of pul-monary LCH has the same molecular attributesof clonality and oncogenic BRAF mutationas nonpulmonary LCH. Second, pulmonaryLCH may arise in smokers who are renderedsusceptible to the disease by their inability torepair the T1799A transversion that underliesthe activating BRAF mutation. Their suscepti-bility may result in a “field defect” throughoutthe lung that could produce multiple indepen-dent clones of transformed LCs. The resultmay be numerous clonal sites of LCH that, inthe aggregate, appear to be polyclonal. A sim-ilar mechanism may give rise to some nevi thatcontain BRAF V600E but are also polyclonal(117).

CONCLUSIONS

The discovery of frequently recurring onco-genic BRAF mutations in LCH, along withrare KRAS and TP53 mutations, supports theclassification of this disease as a neoplasm.Although this concept is useful in many ways,it leaves several questions unanswered. Forexample, is the expression of BRAF V600E inLCs necessary or sufficient for the developmentof LCH? In all cancers in which BRAF V600Ehas been detected, additional genomic abnor-malities are present. For example, expressionof BRAF V600E by itself in melanocytes


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generally produces benign nevi through aprocess of oncogene-induced senescence (110).Several additional mutations or deletions arerequired for the development of melanoma.Similarly, expression of BRAF V600E by itselfmay produce only self-limited forms of LCH;additional abnormalities may be required, inaddition to BRAF V600E, for the developmentof more aggressive LCH. Distinct suites ofgenetic changes may even be associated withthe different clinical subtypes of LCH. Al-though this model fits well within the currentlyunderstood models of cancer progression,another unresolved question is whether thecellular target for these genetic changes is themature LC itself or a precursor cell.

Some of these questions will be addressedthrough the application of more powerful andtruly unbiased genomic technologies to clinicalsamples of LCH. As more tissues from thevarious clinical types of LCH are more fullyanalyzed, various characteristic abnormalitiesmay emerge. Determining whether any ofthese changes is truly pathogenic will ulti-mately require the demonstration of a clinicalresponse to therapies targeted against them.In the interim, evidence for the causal natureof a genetic change in LCH could be obtainedthrough testing in mouse models. Unfortu-nately, no faithful murine models of LCHcurrently exist. Investigators have attemptedto create models by using molecular tools thatmay not be relevant to LCH (for example, onegroup employed SV40 large T antigen to targetthe retinoblastoma pathway, which seems notto be affected in LCH) in cells that may also notbe relevant (such as all CD11c-positive cells)(118). However, we can envision mouse modelsin which disease-associated genetic abnormal-ities such as BRAF V600E can be targeted tomature LCs or, to answer questions about cellu-lar provenance, to various candidate precursorcells.

Fortunately, the clinical development ofBRAF inhibitors has advanced so rapidly that itmay be possible to document mutant BRAF’simportance in LCH directly in a clinicaltrial. Despite the presence of other genomic

abnormalities, in addition to BRAF V600E,in metastatic melanoma, targeted inhibition ofthis mutant protein alone produces profoundclinical responses and prolonged survival (119).Furthermore, the presence of BRAF V600Ein patients’ tumors is a powerful predictor ofresponse. This clinical precedent may be suf-ficient justification for a direct test of BRAFV600E inhibition in LCH. The current gener-ation of inhibitors has a very favorable toxicityprofile but can induce squamous cell carcino-mas of the skin, probably through a mechanism-based effect (120, 121). This problem is con-sidered to be easily manageable in adults whohave life-threatening metastatic melanoma, butclinical trials in children with LCH shouldbe carefully planned in order to optimizethe risk-to-benefit ratio of BRAF V600Einhibition.

In focusing on LCH as a neoplasm, weshould not lose sight of its prominent inflamma-tory component. This feature was a major con-tributor to the century-long controversy aboutthe fundamental nature of LCH. The granulo-mas, the immune dysfunction, and the cytokine“storm” contribute to LCH’s clinical presenta-tion and point to additional targets for ther-apeutic intervention. Nonetheless, the driverof this disease appears to be the pathologicLC, which we now know is itself likely to bedriven by oncogenic mutations. This situationmay be similar to that of Hodgkin lymphoma,which is characterized by intense inflamma-tory or fibroblastic reactions accompanyingrare neoplastic and causal Reed–Sternbergcells.

Our understanding of LCH has been greatlyenhanced by the application of advanced ge-nomic technologies to the analysis of primaryhuman material. The demonstrations of clon-ality and BRAF mutations should be only thebeginning. The next phase of LCH researchwill include an even broader application of next-generation technologies, which will reveal ad-ditional abnormalities. Eventually, we shouldbe able to understand, at the molecular level,the basis for the multiple and distinct clinicalentities that are classified as LCH.


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SUMMARY POINTS

1. Evidence continues to support the rationale for unifying the disparate clinical entitiesHand–Schüller–Christian disease, Letterer–Siwe disease, eosinophilic granuloma, andhistiocytosis X under the single designation of LCH.

2. There is insufficient evidence to conclude that LCH cells either are or are not derivedfrom LCs, as opposed to a common precursor.

3. On the basis of LCH cell clonality and the presence of activating somatic BRAF mutationsin most patient samples, LCH is best understood as a neoplastic disease.

DISCLOSURE STATEMENT

The authors are not aware of any affiliations, memberships, funding, or financial holdings thatmight be perceived as affecting the objectivity of this review.

ACKNOWLEDGMENTS

The work of some of the authors has been supported by the Histiocytosis Association.

LITERATURE CITED

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Fortschr. Geb. Röntgenstr. 23:12–184. Christian HA. 1919. Defects in membranous bones, exophthalmos, and diabetes insipidus: an

unusual syndrome of dyspituitarism. In Contributions to Medical and Biological Research, Dedicatedto Sir William Osler, ed. CL Dana, pp. 390–401. New York: P.B. Hoeber

5. Hand A. 1921. Defects of membranous bones, exophthalmos and polyuria in childhood: Is it dyspitu-itarism? Am. J. Med. Sci. 162:509–15

6. Letterer E. 1924. Aleukämische Retikulose. (Ein Beitrag zu den proliferativen Erkrankungendes Retikuloendothelialen Apparates.) Frankf. Z. Pathol. 30:377–94

7. Siwe SA. 1933. Die Retikuloendotheliose, ein neues Krankheitsbild unter den Hepatosplenome-galien. Z. Kinderheilkd. 55:212–47

8. Abt AF, Denenholz EJ. 1936. Letterer–Siwe’s disease: splenohepatomegaly associated withwidespread hyperplasia of nonlipoid-storing macrophages; discussion of the so-called reticulo-endothelioses. Am. J. Dis. Child. 51:499–522

9. Otani S, Ehrlich JC. 1940. Solitary granuloma of bone: simulating primary neoplasm. Am. J.Pathol. 16:479–90

2–4, 6–10. Originaldescriptions of theclinical syndromes thatare now unified underthe term LCH.

10. Lichtenstein L, Jaffe HL. 1940. Eosinophilic granuloma of bone: with report of a case. Am. J.Pathol. 16:595–604

11. Rowland RS. 1928. Xanthomatosis and the reticulo-endothelial system: correlation of an unidentifiedgroup of cases described as defects in membranous bones, exophthalmos and diabetes insipidus (Chris-tian’s syndrome). Arch. Intern. Med. 42:611–74

12. Wallgren A. 1940. Systemic reticuloendothelial granuloma: nonlipoid reticuloendotheliosis andSchüller–Christian disease. Am. J. Dis. Child. 60:471–500

13. Farber S. 1941. The nature of “solitary or eosinophilic granuloma” of bone. Am. J. Pathol. 17:625–2914. Green W, Farber S. 1942. “Eosinophilic or solitary granuloma” of bone. J. Bone Jt. Surg. 24:499–

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