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Langerhans cell histiocytosis: Current insights in a molecular age with

emphasis on clinical oral and maxillofacial pathology practice

John Hicks, DDS, MS, PhD, MD,a and Catherine M. Flaitz, DDS, MS,b Houston, Tex

TEXAS CHILDRENS HOSPITAL, BAYLOR COLLEGE OF MEDICINE, AND THE UNIVERSITY OF TEXASHEALTH SCIENCE CENTER AT HOUSTON

Langerhans cell histiocytosis (LCH) commonly involves the oral and maxillofacial region, and comes to the attention

of dental practitioners when a patient presents with orofacial pain and a bony or soft tissue lesion. This is a relatively rare entity,

which has made it difficult to investigate the clinical, biologic, and molecular aspects of the disease. Treatment protocols are not

well defined, particularly in adults. During the past decade, the Histiocyte Society has formulated various LCH categories, based

on risk stratification, and treatment protocols for the pediatric population. Adult trials are currently available through the

Histiocyte Society. Although there has been considerable controversy, the neoplastic nature of LCH has been established by

demonstrating clonality. LCH symptoms and the development and persistence of LCH lesions have been ascribed to a

chemokine/cytokine storm due to autocrine and paracrine mechanisms. Discovery of biologic, cytogenetic, and molecular

abnormalities in LCH have already affected treatment by providing novel therapeutic targets. (Oral Surg Oral Med Oral Pathol

Oral Radiol Endod 2005;100:S42-66)

Langerhans cell histiocytosis is rare and unique

among human diseases. Our understanding of this

condition has significantly advanced and evolved over

the past century.1,2 Recognition of the disease entity

took a considerable period of time. Although not

recognized as a histiocytic disease, the first case was

described in 1865 in a 4-year-old child with impetigo

andlarge punched-out osteolytic lesions in his calvar-

ium.1,2 At that time, the bony lesions were considered to

be congenital in nature, and the child died 1 month later

of respiratory compromise. The clinical entity Hand-Schuller-Christian disease came about with independent

case reports of children with exophthalmos, polyuria,

great thirst (polydypsia), osteomalacia, and map-like

skull defects by Hand in 1892, Schuller in 1915, and

Christian in 1919.1,2 The disease was initially attributed

to tuberculosis. Letterer-Siwe Disease was initially

described in 1924 by Letterer and later in 1933 by Siwe

as an acute fulminant nonleukemic disorder of the

reticuloendothelial system in 2 young children.1,2 This

condition was characterized by marked splenomeg-

aly, hepatomegaly, lymphadenopathy, localized bone

tumors, hemorrhagic diathesis, anemia, and hyperplasia

of nonlipidized histiocytes. This disease was consid-

ered to be a rare unknown storage disorder. Eosinophilic

granuloma of bone was described first in 1930 by

Mignon as a granulomatous bone lesion in an adolescent

boy.1,2 It was Lichenstein and Jaffe in 1940 who coined

the term eosinophilic granuloma of bone, and these

lesions were thought to represent viral granulomasdespite their propensity to destroy bone.1,2

The suggestion that Hand-Schuller-Christian disease,

Letterer-Siwe disease, and eosinophilic granuloma of

bone were part of thesame disease process with variation

in severity, site of involvement, and stage was made

by Farber in 1941.1,2 Lichenstein and Jaffe embraced

this idea, and in 1953 included allthese entities under the

general category of Histiocytosis X.1-3 This term was

intended to reflect the inflammatory and proliferativenature of the disease. The unification of these three

separately described diseases under one category was

based on the nearly identical histopathologic featuresof the lesions, which were composed of eosinophils,

histiocytes, and lymphocytes. Histiocytosis X was sub-

divided into acute and subacute disseminated, chronic

disseminated, and localized forms. The original disease

designations, Hand-Schuller-Christian disease, Letterer-

Siwe disease, and eosinophilic granuloma, are still used

by some practitioners when referring to the clinical

features of Langerhans cell histiocytosis (LCH).

In the inaugural 1948 volume ofOral Surgery, Oral

Medicine, and Oral Pathology,which has since evolved

aProfessor of Pathology, Medical Director of Surgical and Ultra-

structural Pathology, Texas Childrens Hospital; Medical Director ofTexas Childrens Cancer Center, Cytogenetics and Molecular

Genetics, Baylor College of Medicine; and Adjunct Professor,

Department of Pediatric Dentistry, The University of Texas Health

Science Center at Houston, Dental Branch, Houston, Tex.bDean and Professor, Departments of Diagnostic Sciences and

Pediatric Dentistry, The University of Texas Health Science Center

at Houston, Dental Branch, Houston, Tex.

Received for publication Jun 14, 2005; returned for revision Jun 19,

2005; accepted for publication Jun 24, 2005.

1079-2104/$ - see front matter

2005 Mosby, Inc. All rights reserved.

doi:10.1016/j.tripleo.2005.06.016

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into the current journal, eosinophilic granuloma of the

jaw in a 31-year-old man with an anal fistula was

chronicled.3 From 1942 until 1945, the patient under-

went several oral surgical procedures with biopsies

that revealed features that would now be recognized as

LCH, but were referred to as an unusual inflammatory,

infectious, and peculiar granulomatous process. Similarfindings were noted in the anal ulcer. It was not until late

1945 that the quite probable diagnosis of eosinophilic

granuloma of bone was rendered. Radiation therapy was

initiated and the jaw lesions resolved with no evidence

of disease at a 1-year follow-up.

Although LCH is a rare orphan disease, consider-

able advances have been made since the first case report

of eosinophilic granuloma of the jaw occurred in the

1948 volume ofOral Surgery, Oral Medicine, and Oral

Pathology.3 Clinical classification, advances in clinical

and pathologic diagnostic methods, identification of the

responsible cell type, and characterization of cellular

components and molecular genetics in this disease

process have been further defined.

CELL OF ORIGIN: LANGERHANS CELLHISTIOCYTES

Almost 140 years ago, Langerhans cells in the skin

were discovered using gold labeling techniques and

described as being intraepidermal receptors for cutane-

ous nervous system signals.1,2 Little progress was made

in understanding the nature of Langerhans cells until the

early 1960s when electron microscopy became avail-

able. Definitive identification of Langerhans cells was

possible with characterization of a cell-specific organ-elle, the Langerhans body, and the histiocytic nature of

the cell became apparent.1,2 This unique ultrastructural

organelle is commonly known as the Birbeck granule.

With the development of immunocytochemical anti-

body techniques, in situ hybridization, and molecular

techniques, a great deal of knowledge regarding these

cells has been gained. Langerhans cells have proven to

be bone marrowederived antigen processing cells and

represent the most peripheral extension of the immune

system. These cells were considered to be histiocytes.

The pathologic proliferation of these cells is referred to

as LCH.Langerhans cells are derived from CD34-positive

(1) hematopoietic myeloid stem cells in the bone

marrow.4-15 Under the influence of various immune

modulators, the progenitor cells can be induced to

become typical macrophages (histiocytes, monocytes)

or transitional macrophages/dendritic cell precursors.

These precursor cells give rise to a variety of dendritic

cells when specific inducing cytokines, chemokines,

and growth factors are present. Langerhans cells, in-

determinant cells, interdigitating dendritic cells, dermal

dendrocytes, and follicular dendritic cells arise from

these transitional macrophage/dendritic precursors.

Mesenchymal progenitor cells may further influence

differentiation toward dermal dendrocytes and lymph

node follicular dendritic cells.

With the advent of immunocytochemical and flow

cytometric methods, it has been possible to defineseveral different disease entitiesbased on the cell types

and clinical features (Table I).4-15 The contemporary

classification of histiocytic disorders is based on the

cell of origin responsible for the disease, relatively well-

characterized clinical features, the biologic behavior

of the disease, and proven malignant potential. LCH

is classified under dendritic cellerelated disorders of

varied biologic behavior, and the responsible cell is con-

sidered to be an immature dendritic cellthe Langer-

hans cell histiocyte. It is interesting to note that had the

dendritic origin of the proliferating cells in LCH been

recognized during Lichenstein and Jaffes era, this

disease would probably be known currently as Langer-

hans cell dendritocytosis.

LANGERHANS CELLS AND LANGERHANS CELLHISTIOCYTES: A COMPARISON

Langerhans cells are freely mobile cells that originate

from bone marrow myeloid precursors, and migrate via

afferent lymphatic channels to populate the epidermis,

regional lymph nodes, thymic epithelium, and oral and

bronchial mucosa.1,2,4-15 Although these cells represent

less than 2% of the epidermal cell population, their

dendritic processes cover 25% of all epithelial cell

surfaces in the epidermis. Each Langerhans cell pos-sesses many dendritic processes that may overlap with

processes from other Langerhans cells. The Langerhans

cell is a mature dendritic cell that has important immu-

nologic functions. These cells are antigen-presenting

cells, and are capable of presenting alloantigens and

soluble foreign antigens to naive helper T-cell lympho-

cytes (CD4 positive). Langerhans cells are nonadherent

and do not proliferate in normal tissue culture condi-

tions. Even though these cells can endocytose soluble

antigens, they are considered to be nonphagocytic cells.

With the uptake of antigen, Langerhans cells migrate

to afferent lymphatic channels and make their way toparacortical zones in regional lymph nodes. Once there,

the endocytosed antigens are presented to naive helper

T cells. Keratinocytes produce certain cytokines that

can inhibit normal Langerhans cell function. Ultraviolet

light reduces their antigen-presenting function and may

be a primary factor in skin cancer development. Langer-

hans cells may be induced to express CD4 on their

surfaces. This allows for infection by human immuno-

deficiency virus (HIV), andLangerhans cells are consid-

ered a reservoir for this virus. Strong chemoattractants

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that induce migration of Langerhans cells include

interleukin (IL)-1-beta, IL-8, and granulocyte macro-

phage-colony stimulating factor (GM-CSF). Langer-

hans cells also produce IL-1-beta and tumor necrosis

factor (TNF)-alpha. Langerhans cells have not proven to

be clonal. These cells are primary antigen processing

cells, and represent the most peripheral extension of the

immune system.

In contrast to normal Langerhans cells, Langerhans

cell histiocytes are immature dendritic cells that areresponsible for a rare, unique disease process

Langerhans cell histiocytosis.1,2,4-15 These histiocytes

are a constituent of lesions occurring in bone, skin,

lymph nodes, spleen, liver, thymus, bone marrow, the

central nervous system, and the gastrointestinal tract.

Despite the activated state of Langerhans cell histio-

cytes, their ability to present antigens is either absent

or rarely observed. These cells do not have the ability

to migrate from the lesional tissue, and along with

inflammatory cells recruit other cells to thelesion. These

unique histiocytes lack dendritic cell processes and

have a round to ovoid, epithelioid morphology. Typical

cytokines produced by Langerhans cell histiocytes

include IL-1-beta, IL-3, IL-4, IL-8, TNF-alpha, and

GM-CSF. These cytokines provide an autocrine, as well

as a paracrine, function in lesion establishment and

persistence. These cells have proven to be clonal.Langerhans cell histiocytes are immature dendritic cells

that lack the ability to be functional antigen-presenting

cells.

The common origin of Langerhanscells andLangerhans

cell histiocytes1,2,4-15 is based on the discovery of Birbeck

granules with transmission electron microscopy. Only

these 2 cell types possess such pentalaminar structures.

Extensive immunocytochemical and flow cytometric

analyses have also provided additional support for the

shared origin of these 2 cell types. Both express S100

protein, HLA-DR, CD1a, and CD207 (langerin), while

being negative for macrophage markers (CD68, lyso-

zyme, CD14, CD163).

LANGERHANS CELL HISTIOCYTOSIS:GENERAL OVERVIEWClassification schemes

Several clinical classifications of LCH are used

by many practitioners (Table II and Table III).4-24

Eosinophilic granuloma represents the most common

form of this disease and is typically a localized, unifocal

osteolytic lesion. Older children and adults are com-

monly affected, but most patients are younger than 20

years of age. Multifocal lesions are less common and

skin lesions are quite rare. Letterer-Siwe disease affectsinfants, with mucocutaneous lesions being common.

Seborrheic dermatitiselike lesions, ulcers, and purpuric

nodules of the skin and subcutis occur at multiple sites.

The lung, liver, and spleen may be involved also. Hand-

Schuller-Christian disease is characterized by a classic

triad with osteolytic lesions, exophthalmos, and diabe-

tes insipidus. Those affected tend be young children.

A unique form of LCH is congenital and typically

undergoes involution over time. Congenital self-healing

LCH presents in the neonate or young infant as viola-

ceous red-brown firm nodules (Table II).18,21,25 Such a

pattern of clinical presentations may raise concernregarding the possibility of congenital leukemia and

neuroblastoma or an infectious process. The presenta-

tion at birth or shortly after is beneficial in identifying

this rare entity and avoiding unnecessary medical man-

agement. Certain ultrastructural features are specific to

the congenital self-healing form of LCH. Young adult

smokers have a unique form of LCH with pulmonary

involvement only (Table II andTable III).4,17,22-24 No

other lesional sites are found in these individuals. The

major sequelae of pulmonary LCH are progressive

Table I. Contemporary classification of histiocyticdisorders*

Disorders of varied biological behavior

Dendritic cellrelated disorders

Langerhans cell histiocytosis

Secondary dendritic processes (association with Hodgkin

lymphoma, acute lymphoblastic leukemia, acute

myelogenous leukemia)Juvenile xanthogranuloma and related disorders

Solitary histiocytomas of various dendritic cell phenotypes

Macrophage-related disorders

Hemophagocytic syndromes

Primary hemophagocytic lymphohistiocytosis

(familial, sporadic, and viral infection associated)

Secondary hemophagocytic lymphohistiocytosis

Infection associated

Malignancy associated

Other

Rosai-Dorfman disease

(sinus histiocytosis with massive lymphadenopathy)

Solitary histiocytoma with macrophage phenotype

Malignant disordersMonocyte-related disorders

Leukemias

Acute monocytic leukemia (FAB M5A and M5B)

Acute myelomonocytic leukemia (FAB M4)

Chronic myelomonocytic leukemia

Extramedullary monocytic tumor of sarcoma

(monocyte-derived granulocytic sarcoma)

Dendritic cellrelated histiocytic sarcoma

Follicular dendritic cell sarcoma

Interdigitating dendritic cell sarcoma

Dendritic cell sarcomas (based on phenotype)

Macrophage-related histiocytic sarcoma

*Modified from reference4: Working Group of The Histiocyte Society

and World Health Organization Committee on Histiocytic/ReticulumCell Proliferations.

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interstitial fibrosis and respiratory compromise. There is

an association with malignant tumor development. This

disease is extremely rare in children.

The most current method for the categorization of

LCH is based on risk stratification of affected individ-

uals into recommended treatment protocols formulatedby the Histiocyte Society.4,17 The Histiocyte Society has

placed LCH into several disease groups (Table II).

Unifocal disease involves a single disease system with a

single site of involvement. There is a good prognosis in

this group, typically composed of older children and

adults. Multifocal single system disease is present when

several lesions are identified in a single organ system.

Bone is most commonly involved, and this representsmultifocal eosinophilic granuloma. The prognosis is

intermediate in this group that typically involves young

children. The worst prognosis is found in the multifocal

multisystem disease group. Multiple lesions are found inmore than one organ group. Commonly affected organ

systems include bone, skin, liver, spleen, and lymph

nodes. Children younger than 2 years of age represent

the majority of patients in this group. The Histiocyte

Society also recognizes congenital self-healing and

pulmonary-only LCH groups. The final disease group is

secondary LCH that is associated with a variety of

tumors. The malignancies most frequently associated

with LCH are leukemias and lymphomas, and less

commonly sarcomas and carcinomas.4,17,26

Table II. Langerhans cell histiocytosis: clinical typesand categorization schemes*

Clinical types of Langerhans cell histiocytosis

Eosinophilic granuloma

Most common form of Langerhans cell histiocytosis

Localized form, most benign

Older children and adults

[75% of affected individuals younger than 20 years of ageUnifocal lesions 3 times more common

(skull[ femur[pelvis[vertebra[jaws)

Multifocal lesions less common (50% skull, 16% jaws)

Rare skin lesions

Letterer-Siwe disease

Usually 1st year of life

Mucocutaneous lesions including gingiva and oral mucosa

Seborrheic dermatitis-like skin lesions

Purpuric red-brown nodules

Ulcerated painful nodules involving perineal, inguinal,

retroauricular, and external auditory canal regions

Lung, liver, and spleen involvement

Hand-Schuller-Christian disease

Usually 2- to 6-year-old children

Classic triad: osteolytic lesions, exophthalmos, and

diabetes insipidus

Skin and oral lesions

Congenital self-healing Langerhans cell histiocytosis

(reticulohistiocytosis, Hashimoto-Pritzker disease)

Pulmonary Langerhans cell histiocytosis

Categorization by Histiocyte Society for treatment

protocols (current)

Unifocal disease

Single system disease with single site of involvement

Most commonly bone

Older children and adults

Good prognosis

Multifocal single system disease

Multiple sites of involvement in single organ system

Most commonly bone

Young children

Intermediate prognosis

Multifocal multisystem disease

Multiple involved sites in more than one organ system

Most commonly bone, skin, liver, spleen, and lymph nodes

Children younger than 2 years of age and infants

Poor prognosis


Multiple skin lesions at birth or shortly after mimicking

congenital neuroblastoma or leukemia (blueberry

muffin baby)

Neonates and infants

Self-healing involutionPulmonary Langerhans cell histiocytosis

Young adult smokers (smokers malady)

Indolent progression to pulmonary fibrosis

Strong association with malignancies

Extremely rare in children

Secondary Langerhans cell histiocytosis associated

with neoplasms

Acute lymphoblastic and myelogenous leukemias

Chronic myelogenous leukemia

Myelodysplastic disorder association

Non-Hodgkin and Hodgkin lymphoma

Retinoblastoma

Table II. Continued

Osteosarcoma

Thyroid carcinoma

Lung cancer (adenocarcinoma, small cell carcinoma)

Prostate cancer

Breast cancer

Parathyroid adenoma

Pancreatic cystadenoma

Categorization by extent of disease

Restricted Langerhans cell histiocytosis

1. Skin rash with no other sites of involvement

(biopsy proven)

2. Monostotic bone lesions with or without diabetes

insipidus, regional lymph node involvement, or skin rash

3. Polyostotic bone lesions, consisting of several different

bones or \2 bone lesions in a single bone, with or without

diabetes insipidus, regional lymph node involvement, or skin

rash

Extensive Langerhans Cell Histiocytosis

1. Visceral organ involvement with or without bone

involvement, diabetes insipidus, regional lymph node

involvement or skin rash, and without signs of organdysfunction

2. Visceral organ involvement with or without bone

involvement, diabetes insipidus, regional lymph node

involvement or skin rash, and with signs of organ

involvement of lung, liver or hematopoietic system

*Compiled from references4 to 24.

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LCH has also been categorized according to extent of

disease (Table II).2,20 Restricted and extensive cate-

gories have been defined. The restricted LCH category is

composed of skin rash only, monostotic bone lesion, and

polyostotic bone lesion subcategories, as detailed in

Table II. The extensive LCH category is based on vis-ceral organ involvement with or without organ dysfunc-

tion. As expected, outcome is worse in those with

extensive disease versus those with restricted diseases.

Treatment decisions may be based on this categorization

system with some protocols.

EpidemiologyLCH is a rare disease that affects 5 children per

million population and about 1 to 2 adults per million

population.1,2,4-6,9,15-17,22-25 It is predominantly a child-

hood disease with more than 50% of affected individuals

being younger than 15 years. The peak incidence is

between 1 and 4 years of age. This disease (Table III)

affects a young agepopulation (mean age27 years), with

a young adult smoker population affected by pulmonary-

only disease (mean age 41 years) and primarily neonates

Table III. Langerhans cell histiocytosis: clinical fea-tures*

Distribution by category, %

Unifocal disease 36

Multifocal single system disease 33

Multifocal multisystem disease 31

Age (mean)

Langerhans cell histiocytosis (all) 27 yUnifocal single system disease 18 y

Multifocal single system disease 26 y

Multifocal multisystem disease 25 y

PulmonaryLangerhanscellhistiocytosis 41 y

Congenital self-healing Langerhans

cell histiocytosis

5.2 d

Langerhans cell histiocytosis (all)

Age range Neonate to 83 y

\20 years of age 42%

Gender, M:F

Langerhans cell histiocytosis (all) 1.0:1.1

Pulmonary Langerhanscell histiocytosis 1.0:2.2

Congenital self-healing Langerhans

cell histiocytosis

1.0:1.0

Presenting clinical features, %

Local bone pain 41

Dyspnea 14

Malaise 9

Abnormal chest x-ray 9

Painful scalp mass 7

Pneumothorax 6

Diabetes insipidus 5

Scalp rash 3

Skin rash on trunk 3

Head and neck lymphadenopathy 2

Otitis media 2

Mucous membrane ulcer 2

Orbital proptosis 2

Chronic cough 1Scrotal mass \1

Pathologic fracture \1

Loose teeth \1

Cor pulmonale \1

Bony involvement sites, %

Head and neck

Skull 27-43

Mandible 7-9

Maxilla 1

Cervical vertebra 2

Extremities

Lower extremity, proximal 14-15

Upper extremity, proximal 6-7

Lower extremity, distal 2-3

Upper extremity, distal 1-2Ribs 10-14

Pelvis 9-12

Thoracic, lumbar, and sacral

vertebrae

5-10

Scapula 5

Clavicle 3

Treatment and outcome

Unifocal bone disease Local Excision with or

without radiation

11% Relapse

97% Disease-freesurvival

Table III. Continued

Multifocal bone disease only Local excision with or

without radiation

and/or chemotherapy

76% Relapse


6% Alive with disease

3% Died of diseaseMultifocal multisystem disease Combination surgery, che-

motherapy, and radiation

95% Relapse


11% Alive with disease

15% Died of disease

Pulmonary disease only Prednisone and/or

chemotherapy and/or

surgery


4% Alive with

progressive disease

11% Died of disease

Morbidity: lifelong sequelae

Diabetes iInsipidus

Growth hormone deficiency

Orthopedic problems

Pulmonary fibrosis

Biliary cirrhosis

Cerebellar ataxia

Cognitive dysfunction

Mortality with or without risk

organ involvement (lung, liver,

bone marrow, spleen), %

Without risk organ involvement 10

With risk organ involvement 30-50

*Compiled from references7, 16, and 17.

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with congenital self-healing disease (mean age 5.2

days). Unifocal single system, multifocal single system,

and multifocal multisystem disease tend to be nearly

equally represented (Table III). The gender ratio is equal

in all LCH categories, with the exception of pulmonary-

only disease, where women are affected more than twice

as often.The most commonpresenting symptom is local bone

pain (41%,Table III).7,16,17 Various symptoms based on

organ system involvement have been noted (Table III).

Of interest for the head and neck region are painful scalp

mass (6%), scalp rash (3%), cervical lymphadenopathy

(2%), otitis media (2%), mucous membrane ulcer (2%),

orbital proptosis (2%), and, rarely, loose teeth (\1%).

Despite the low proportion of symptoms in the head and

neck region, bony involvement by LCH is quite com-

mon (Table III). The skull and mandible are frequently

affected, as well.

Treatment of LCH has been quite variable during

the past 50 years, and there has been a lack of coordi-

nated treatment protocols, particularly for adults (Table

III).2,7,16 With unifocal bone disease, local excision withor without radiation therapy has led to more than 95%

disease-free survival. However, relapse occurs in about

10% of cases. Multifocal bone disease may have similar

surgical treatment with or without the addition of

chemotherapy. Relapses are quite frequent with multi-

focal bone disease (76%). However, disease-free sur-

vival can be achieved in most of the affected patients

(91%). A small proportion of individuals die of their

disease (3%). Treatment of multifocal multisystem

disease employs the combination of surgery, chemo-therapy, and radiation therapy. The vast majority of

individuals have relapses (95%). One sixth will die of

disease. Disease-free survival is achieved by about 75%

of affected individuals. With pulmonary disease only,

treatment is quite variable ranging from prednisone

therapy to chemotherapy to surgery for lesions com-

promising the respiratory tract. A certain percentage of

individuals die of disease (11%). Disease-free survival

is noted in 85%. This form of LCH may have ongoing

progressive interstitial fibrosis in many affected pa-

tients, even when tobacco use is discontinued.

LCH produces lifelong effects, the nature of whicharedependent on the organ system(s) involved (Table

III).7,16,17 In particular when there is hypothalamic/pituitary gland involvement, the affected individual

may experience diabetes insipidus and growth hormone

deficiency. Central nervous system lesions may lead to

cerebellar ataxias with gait and mobility abnormalities

and cognitive dysfunction. With extensive or multifocal

bony lesions, skeletal growth and orthopedic abnor-

malities may be seen. The liver is particularly suscep-

tible to biliary cirrhosis due to bile duct damage and

sclerosis caused by the infiltration of Langerhans cell

histiocytes.

Certain organ systeminvolvement increases the risk

for mortality (Table III).7,16,17 High-risk organs include

the lung, liver, bone marrow, and spleen. Death occurs in

30% to 50% of those with high-risk organ involvement,

comparedwith only 10% without lesions in these organs.Certain factors are predictive of progressive

disease in LCH (Table IV).7,16,17 Several factors have

an extremely high relative risk for progressive disease,

such as osseous and mucocutaneous disease, osseous

and extraosseous disease, and treatment relapse with

multifocal multisystem disease. The presence of these

factors necessitates aggressive therapy. In the pediatric

age group, risk stratification for more intensive treat-

ment is based on sites of involvement.17 Low-risk sites

are defined as skin, bone, lymph nodes, and pituitary

glands. High-risk sites include lung, liver, bone marrow,

and spleen. Special sites that demand more aggressivetherapy are the mastoid bone, orbit, temporal bone, and

central nervous system.

Children and adults show different patterns of

involvement by LCH (Table V).16,17,22-24 Bone disease

is extremely frequent in children and less frequent in

adults. The jaws are involved in 30% of adults, but in

less than 10% of children. Skull lesions are about twice

as common in children. Skin disease is seen with equal

frequency. Pulmonary disease either in multifocal or

isolated LCH is very frequent in adults and infrequent

Table IV. Predictive factors in progression of Lang-erhans cell histiocytosis and low-risk and high-riskcategories for pediatric Langerhans cell histiocytosis*

Predictive factors in progression Relative risk

Osseous and mucocutaneous disease 40.7

Osseous and extraosseous disease 37.3

Treatment relapse with multifocal

multisystem disease

37.2

Osseous disease involving 3 or more bones 6.1

Mucous membrane disease 5.1

Hepatosplenomegaly in patient younger

than 3 years old

4.5

Pituitary-hypothalamic axis involvement

and multisystem disease

2.2

Younger than 5 years of age at presentation 2.1

3 or more organ systems involved by disease 1.8

Pediatric categorization for therapy

Low-risk sites: skin, bone, lymph nodes,

and pituitary

High-risk sites: lung, liver, bone marrow,

and spleen

Special site lesions: skull (mastoid, orbit,

temporal bone; associated with diabetes

insipidus and parenchymal brain lesions

with neurodegenerative process)

*Compiled from references16, 17.

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to rare in children. Genital lesions are frequent in adults

and rare in children. Diabetes insipidus is found fre-

quently in both children and adults.

ORAL AND MAXILLOFACIAL LANGERHANSCELL HISTIOCYTOSIS

LCH involves the head and neck region quite

commonly, and, in particular, the bones of the skull

and jaws (Table IV, Table V, Figs 1-4).27-35 With oral and

maxillofacial LCH (Table V, Fig 1-4), more than 90% of

affected individuals are younger than 40 years of age,

with a mean age of about 19 years. Unifocal single

system disease represents about 50% of maxillofacial

LCH, with multifocal single system disease and mul-

tifocal multisystem disease equally distributed in the

remaining 50% of cases. The jaws are involved twice

as frequently as the oral soft tissues. The mandible is

3 times more frequently affected than the maxilla. Theposterior regions of the jaws are more frequently in-

volved than the anterior regions. Oral soft tissue lesions

are most commonly found with the gingiva and hard

palate. The floor of the mouth, maxillary sinus, and

buccal mucosaeach account forless than 10% of lesions.

The most common oral cavity signs and symptoms at

presentation are intraoral mass, pain, gingivitis, loose

teeth, oral mucosal ulcer, impaired healing, and halito-

sis. Extraoral signs and symptoms are quite common,

and include soft tissue and bone lesions outside the oral

cavity. Diabetes insipidus, lymphadenopathy, anemia,

skin lesions, exophthalmos, and hepatomegaly are lesscommon. The skull and lower extremities are the most

common extraoral sites of bony involvement.

Jaw lesions tend to have a unilocular radiolucent

appearance (Table VI, Fig 3), with well-demarcated

borders in two thirds of the cases and poorly defined

borders in the remainder.27-35 Tooth displacement is

associated with about half of the bony lesions. Root

resorption is seen less frequently.

Surgical management alone is used in 50% of cases

with an additional 23% of the lesions being treated with

both surgery and radiation therapy.27-35 Radiation alone

is used in one fifth of affected individuals. Chemo-

therapy and intralesional steroid injection are infre-

quently employed.

Recurrence of LCH is variable, but similaramong the

various disease categories (Table VI). 27-35 A single

recurrence is noted in 15% and a second recurrence inless than 5% of patients. Treatment modalities vary in

the proportion of cases with recurrences. Chemotherapy

has had no reported recurrences, however this form of

therapy has not been used frequently enough to assess its

effect accurately. Surgery alone has a 12% recurrence

rate, compared with 25% for radiation therapy alone and

19% for combined surgery and radiation therapy.

Survival in oral and maxillofacial LCH is quite

favorable with only 7% of patients dead from disease

(Table VI).27-35 Following treatment, there was no

evidence of disease in slightly over half of the patients;

while 17% were alive with disease.

PATHOLOGIC FEATURES OF LANGERHANSCELL HISTIOCYTOSISLight microscopic features

The histopathologic features of LCH are well char-

acterized and recognized readily by oral and maxillo-

facial pathologists (Fig 5).1,2,4-7,9-12,21,36-38 The typical

lesion is composed of an admixture of Langerhans cell

histiocytes, intermediate cells and interdigitating cells

of a dendritic cell lineage, T-cell lymphocytes, eosin-

ophils, and macrophages. The hallmark cell is the

Langerhans cell histiocyte. This cell has abundant

eosinophilic to amphophilic cytoplasm and a nucleusthat appears reniform, deeply indented, or grooved. The

number of eosinophils is quite variable from being

abundant with eosinophilic abscesses to sparse or even

absent. Occasional giant cells representing fusion of

either macrophages or Langerhans cell histiocytes may

be seen. The presence of this granulomatous inflamma-

tion with occasional giant cells raises the concern for an

infectious process, such as tuberculosis in the past, and

viral infection with an agent that is capable of inducing

syncytial (giant) cells. Necrosis within this granulom-

atous lesion is not unusual, and again reinforced the

suggestion in the past that these lesions represented aninfectious process. The lesions vary from an indistinct

focus with blending into the adjacent normal tissue to

nodular in appearance, depending on tissue types in-

volved. Although present, mitotic activity tends to be

low to moderate without atypical mitotic figures. The

lesions may take on a more atypical appearance and

appear as epithelioid granulomas (Fig 5, D) that lack

the typical features of LCH. The lesions may resemble

other histiocytic lesions, such as early juvenile xantho-

granuloma that lack characteristic Touton giant cells.

Table V. Comparison of childhood and adult Langer-hans cell histiocytosis

Children Adults

Bone disease Extremely frequent Frequent

Jaws 8% 30%

Skull 40% 21%

Skin disease Frequent Frequent

Dental disease Infrequent Frequent

Pulmonary disease Infrequent Very frequent

Pulmonary disease alone Rare Very frequent

Genital involvement Rare Frequent

Diabetes insipidus Frequent Frequent

Compiled from references 22-24.

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Definitive diagnosis with these atypical lesions requires

immunocytochemistry and occasionally electron mi-

croscopy.

Immunocytochemical featuresLCH can be distinguished from other dendritic cell

disorders on the basis of cytoplasmic and cell surface

markers that it expresses (Table VII, Fig 6).5,11,12,21,36-38

In the past, S100 protein, Lag antigen, and peanut

agglutinin were used. With the development of more

specific and sensitive antibodies to cell surface mark-

ers associated with Langerhans cell histiocytes, these

markers are rarely used for diagnostic purposes. CD1a

(OKT6) is a well-recognized marker that immunoreacts

with Langerhans cells in the epidermis. This antibody

also identifies Langerhans cell histiocytes, cortical

thymocytes, and interdigitating dendritic cells within

the dermis andlymph nodes. Langerhans cell histiocytes

Fig 1. Clinical appearance of oral and maxillofacial Langerhans cell histiocytosis (LCH).A, Seborrheic-like dermatitis appearance

of LCH in postauricular region.B, Diffuse gingival enlargement secondary to LCH. C, Infiltration of maxillary frenum by LCH.

D, Maxillary alveolar and palatal LCH mass. E, Palatal diffusely ulcerated LCH. (Fig 1, A and B courtesy of Dr Moise Levy,

Houston Tex; Fig 1C courtesy of Dr Megan Dishop, Houston Tex; Fig 1, E reprinted with permission from Eisen D, Lynch D,

editors. The mouth: diagnosis and treatment. St. Louis, Mo: Elsevier Publishers; 1998.)

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demonstrate a membranous to cytoplasmic pattern

with the CD1a antibody (Fig 6, A). According to the

Histiocyte Society, a definitive diagnosis of LCH maybe rendered with the appropriate histopathology and

when immunoreaction with CD1a is present. This

antibody may be used with formalin-fixed paraffin-

embedded tissues, and eliminates the need for frozen

tissue for immunocytochemistry.

More recently, a highly specific and sensitive anti-

body against Langerhans cells and Langerhans cell

histiocytes has become commercially available (Fig 6,

B).21,39-43 CD207 (langerin) is a monoclonal antibody

against a type II transmembrane protein expressed with

Langerhans cells and Langerhans cell histiocytes.

CD207 reacts with a 40-kD langerin protein purportedly

specific to these cells. Langerin is located on the cellsurface of Langerhans cells and Langerhans cell histi-

ocytes and induces membrane superimposition and

zippering that leads to Birbeck granule formation

(LC granules, Birbeck-Broadbent granules). These

pentalaminar structures with a bulbous end (tennis

racket and handle) represent a means to capture antigen

for antigen processing. These structures are rapidly

internalized into the cells. The CD207 (langerin) anti-

body requires antigen unmasking with formalin-fixed,

paraffin-embedded tissues.

Fig 2. Diagnostic imaging of skull and rib in LCH. A, Well-circumscribed parietal bone LCH lesion. B, Destruction of

right zygomatic process of maxilla secondary to LCH with significant soft tissue component. C, Bilateral mastoid involvement by

LCH with soft tissue mass anteriorly displacing ears bilaterally. D, Left rib with loss of cortical bone and soft tissue mass bulging

into parietal pleura.

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Fig 3. Clinical and radiographic appearance of oral and maxillofacial LCH.A and B, Young child with gingival soft tissue LCH

mass (A) with mild lingual displacement of the primary molars and a diffuse radiolucent lesion ( B) with loss of bone surrounding

the primary first molar and mesial root of primary second molar. C-E,A 34-year-old woman with erythematous lingual mucosa

adjacent to a second molar (C) with root canal therapy 6 years previously. Periapical radiograph (D) with diffuse bone loss

secondary to biopsy-proven LCH. E, Same patient with progressive mandibular and maxillary LCH involvement with tooth loss

over a 3-year period. F and G, Elderly man with diffusely erythematous mandibular gingiva and mucosa with tissue loss due to

LCH (F). Periapical radiograph (G) reveals diffuse bone loss secondary to LCH. (Fig 3, A and B reprinted with permission from

Neville B, Damm D, Allen C, Bouquot J, editors. Oral and maxillofacial pathology. 2nd ed. St. Louis, Mo: WB Saunders Co; 2002.

Fig 3, C, D, and Ecourtesy of Dr Brad Neville and Dr John Hann, Charleston SC. Fig 3, Fand G courtesy of Dr Alan Gould,

Crestwood, Ky.)

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Fig 3. Continued.

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Fig 4. Congenital self-healing LCH.A, Periorbital nodular lesions in a neonate. B, Characteristic histopathologic appearance of

LCH with admixture of Langerhans cell histiocytes with deeply indented, grooved, and reniform nuclei and abundant eosinophilic

to amphophilic cytoplasm, eosinophils and lymphocytes (hematoxylin and eosin, original magnification 3400). C, Concentric

laminated bodies in Langerhans cell histiocytes pathognomonic for congenital self-healing LCH (transmission electron

microscopy, original magnification 310 000). (Fig 4, A courtesy of Dr Denise Walker Metry, Houston Tex.)

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Differentiation of LCH from other dendritic cell dis-

orders is important. The immunophenotypes of dendritic

cell disorders are presented in Table VII.5,11,12,21,36-43

Dendritic cell disorders may contain a certain percent-

age of normal Langerhans cells that are trafficking

back to regional lymph nodes to perform their antigen-

presenting cell functions. In such cases, where there may

be a certain population of Langerhans cells or macro-

phages that have morphology similar to Langerhans cell

histiocytes, further characterization with immunocyto-

chemistry would be necessary. Xanthogranulomatous

processes are defined by immunoreaction with dendritic

cell markers (Factor XIIIa, fascin) and macrophage

markers (CD68 [PGM1], CD163). It is important to

recognize that juvenilexanthogranuloma may be seen

in children with LCH.44-46 Juvenile xanthogranuloma

may appear before, concurrent with, or following the

diagnosis of LCH. Children with juvenile xanthogran-

ulomas should be evaluated for and have appropriate

follow-up to assess concurrent or development of LCH.

Rosai-Dorfman disease is characterized by reactivity

with S100 protein and macrophage markers, as well as

Table VI. Oral and maxillofacial Langerhans cellhistiocytosis: clinical features*

Mean age, y (range) 18.9 (Neonate-53)

Age, y

\10 29%

10-19 22%

20-39 44%

40-53 5%Gender ratio, M:F 3.9:1.0

Unifocal disease, % 49

Multifocal single system disease, % 25

Multifocal multisystem disease, % 25

Sites involved, %

Jaws 67

Mandible 76

Posterior 68

Anterior 32

Maxilla 24

Posterior 63

Anterior 37

Oral soft tissues 33

Gingiva 76

Hard palate 10

Floor of mouth 6

Maxillary sinus 5

Buccal mucosa 4

Symptoms at presentation, %

Mass/Lesion 59

Pain 46

Gingivitis 43

Loose teeth 41

Oral ulcer 19

Impaired healing 13

Halitosis 12

Masticatory problems 9

Vincents infection 7

Gingival bleeding 6Paresthesia 4

Extraoral symptoms at presentation, % 70

Extraoral lesions 50

Soft tissue lesion only 7

Bone and soft tissue 43


Lymphadenopathy 16

Anemia 15

Skin lesions 12

Exophthalmos 10

Hepatosplenomegaly 9

Otitis media 8

Fever 7

Leukocytosis 2

Mental disability 2Extraoral sites of involvement, %

Skull 37

Lower extremity 28

Upper extremity 13

Ribs 13

Lung 12

Skin 10

Liver 10

Spine 7

Orbit 7

Cervical lymph nodes 6

Table VI. Continued

Submandibular gland 2

Parotid gland 2

Radiographic appearance, %

Unilocular radiolucent lesions 100

Well-demarcated borders 63

Borders poorly corticated 24

Poorly defined borders 12Displaced teeth 51

Root resorption 17

Periosteal reaction 8

Treatment, %

Surgery alone 50

Radiation therapy alone 20

Surgery and radiation therapy 23

Chemotherapy 7

Intralesional steroids 1

Recurrence, %

Unifocal disease, 16

Multifocal single system disease 22

Multifocal multisystem disease 15

Single recurrence 15

Two recurrences 4

Surgery alone 12

Radiation therapy 25

Surgery and radiation therapy 19

Chemotherapy 0

Outcome, %

No evidence of disease 53

Alive with disease 17

Alive, status not known 7

Died of disease 7

Died of other causes 11

Died of unknown cause 3

*Compiled from references27-35.

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emperipolesis (leukocytes passing through the cyto-

plasm of macrophages).5-11,12,21,36-43 Indeterminantdendritic cell histiocytomas immunoreact with CD1a,

S100 protein, and fascin.5-11,12,21,36-43 Interdigitating

dendritic cell histiocytoma have a similarimmunophe-

notype, but also display CD83 expression.5-11,12,21,36-43

Follicular dendritic cell histiocytoma becomes an issue

if a lymph node or the spleen contains a histiocytic

lesion.5-11,12,21,36-43

The expression of CD21 and CD35would help to differentiate this tumor from other

histiocytic lesions.

Ultrastructural featuresThe gold standard for definitive diagnosis of LCH

is examination of tissue using transmission electron

microscopy (Table VIII, Fig 7).1,2,4-6,9,11,12,21,38 The

identification of Birbeck granules in the cytoplasm or

within the cell border of lesional cells provides the final

evidence necessary in difficult to characterize tumors, or

when there are aberrant immunocytochemical results.

All forms of LCH possess Birbeck granules. The typicalgranule is composed of a rod-shaped or tennis rackete

shaped structure with a length varying from 200 to

400 nm and a width of 33 nm. The rod (handle) region

has a zipper-like morphology and has been described as

pentalaminar owing to a central striated membrane anda

double electron dense outer sheath. The granules are

more easily identified in early lesions, rather than inlong-standing lesions. Birbeck granules tend to be rare

when LCH involves the liver, spleen, and gastrointesti-

nal tract. Other ultrastructural structures present within

the cytoplasm of Langerhans cell histiocytes are curvi-

linear and multivesicular bodies, tubuloreticular inclu-

sions, and cylindrical confronting cisterna.

Congenital self-healing LCHCongenital self-healing LCH deserves special atten-

tion because this disease spontaneously resolves over

Fig 5. Histopathologic features of LCH. A, Abundant eosinophils with frequent histiocytes and less apparent lymphocytes

(hematoxylin and esocin, original magnification 3100). B and C, Langerhans cell histiocytes with abundant eosinophilic to

amphophilic cytoplasm and deeply indented, reniform, and grooved nuclei (hematoxylin and eosin, original magnification 3400).

D,Atypical LCH lesion composed of epithelioid Langerhans cell histiocytes with abundant eosinophilic cytoplasm and lacking

typical reniform nuclei (hematoxylin and eosin, original magnification 3200). These histiocytic cells immunoreacted with CD1aand CD207, as well as demonstrated Birbeck granules (not shown).

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several months and may be confused with multifocal

single system or multifocalmultisystem disease that

requires treatment.4,17,21,25 Congenital self-healing

LCH has an identical histopathology and immunophe-

notype like all other forms of LCH, but has unique

ultrastructural features (Fig 4, Table VIII). Transmissionelectron microscopy will reveal laminated dense bodies

with a concentric myelin-like morphology and non-

laminated dense bodies. Birbeck granules are found, but

tend to be detected in less than one third of the

Langerhans cell histiocytes. The presence of laminated

dense bodies provides definitive proof for the diagnosis

of congenital-self healing LCH. This form of LCH

occurs predominantly in children younger than 1 year of

age. It is recommended that any child younger than 2

years with evidence of LCH should have transmission

electron microscopy performed on the biopsy or resec-

tion tissue to confirm or refute the diagnosis of typical

LCH or congenital self-healing LCH.

Tissue availability for electron microscopicevaluation

Ideally, tissue should be set aside in 2% to 3% bu f-

fered glutaraldehyde for possible ultrastructural study.21

In most oral and maxillofacial pathology services,

electron microscopy is not a high priority. Ultrastruc-

tural examination can be performed on residual tissue

fixed in buffered 10% formalin without deleterious

results. Alternatively, a portion of lesional tissue may be

removed from a tissue block and undergo paraffin

recovery, and then transmission electron microscopic

examination. Ultrastructure may be compromised to a

certain extent, however the tumor-defining structures

(Birbeck granules, laminated dense bodies) are usually

of adequate quality to provide for a definitive diagnosis.Stringent control of processing temperature of the tissue

and low-melting point paraffin for embedding the tissue

allows for better preservation of ultrastructural features.

RECOMMENDED EVALUATION FOLLOWINGDIAGNOSIS OF LANGERHANS CELLHISTIOCYTOSIS

Once a biopsy-proven diagnosis is obtained, the

patient should undergo referral to a specialist who is

well versed in LCH (pediatric or adult hematologist/

oncologist). For appropriate classification, the following

are recommended4,6,9,17:

d Thorough clinical examinationd Complete blood cell count with hematocrit, hemo-

globin, and platelet countd Liver function tests (serum transaminases, alkaline

phosphatase, bilirubin, albumin, total protein)d Coagulation studies (prothrombin and partial throm-

boplastin time, fibrinogen)d Urine osmolarityd Arginine vasopressin study for diabetes insipidusd Chest radiographd Skeletal radiograph surveyd

CT or ultrasound of chest and/or abdomen if organsystem involvement suspectedd MRI of the brain if central nervous system involve-

ment suspectedd Respiratory function tests if respiratory involvement

suspectedd Diagnostic endoscopy if gastrointestinal symptoms

suspected

BIOLOGIC, CYTOGENETIC, ANDMOLECULAR ASPECTSLCH: The Chemokine/Cytokine Storm

As noted previously, Langerhans cell histiocytes areconsidered to be immature dendritic cells that fail to

undergodifferentiationto mature dendritic cells.4,15,47-49

Similar to immature dendritic cells, Langerhans cell

histiocytes express receptors for inflammatory chemo-

kines (CCR1, CCR2, CCR5, CCR6, CXCR1), which

allow for the recruitment of additional immature den-

dritic cells (Table IX).50-54 Langerhans cell histiocytes

fail to mature and do not down-regulate the above-

mentioned chemokines associated with immature den-

dritic cells. In addition, these histiocytes fail to display

Table VII. Immunocytochemical features of dendriticcell disorders*


Markers important for diagnosis:

CD1a, CD207 (Langerin), S100, Lag antigen

Additional markers:

HLA-DR, E-cadherin, peanut agglutinin, CD4, CD31, CD40,

CD49d, CD52, CD54, CD80, CD86, CD116 (GM-CSFR),CD209 (DC-SIGN), CCR6, PLAP, NSE, vimentin, IL2-R

(CD25), IFN-gamma, TNF-alpha, acid phosphatase, CD68

(weak), LCA (CD45 weak), lysozyme weak)

Xanthogranuloma family (juvenile xanthogranuloma,

Erdheim-Chester disease, xanthoma disseminatum,

dermal dendrocytomas)

Factor XIIIa, Fascin, CD68 (PGM1), CD163, CD14,

Ki-M1P, CD45

Rosai-Dorfman disease (sinus histiocytosis with massive

lymphadenopathy, sinus dendritic cell)

CD68, S100, fascin, CD163, cathepsin E, alpha-1-antitrypsin,

Si-M9, CD31

Dendritic cell histiocytoma, indeterminant cell type

CD1a, S100, fascin, CD45

Dendritic cell histiocytoma, interdigitating dendritic cell type

CD1a, S100, Fascin, CD83, CD45

Dendritic cell histiocytoma, follicular dendritic cell type

CD21, CD35, Ki-M4, Fascin, S100 variable (6)

*Compiled from references5, 11, 12, 21, 36-43.

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chemokines (CXCR4, CCR7) that are constitutively

expressed by mature dendritic cells. High levels of

other inflammatory chemokines (CCL20/MIP-3alpha,

CCL2/MCP-1, CCL3/MIP-1alpha, CCL4/MCP-4alpha,

CCL5/RANTES, CXCL8/IL-8, CXCL10/IL-10) are re-

leased by Langerhans cell histiocytes, and these chemo-

kines are also associated with immature dendritic cells.

These chemokines are important in the recruitment of

circulating immature dendritic cells, as well other im-

mune cell types (T lymphocytes, macropaghes, eosino-

phils). Langerhans cell histiocytes have high levels of

CD14, CD86, and intracellular MHC class II, and lack

CD83, CD86, and DC-LAMP, which are characteristicfor immature dendritic cells.4-15,17 It is quite obvious why

Langerhans cell histiocytes are considered to be in an

arrested state of activation and differentiation. This would

also explain thelack of thin, fingerlikedendritic processes

seen in normal Langerhans cells (mature dendritic cells),

and the characteristic ovoid to round morphology of

Langerhans cell histiocytes (immature dendritic cells).

The lack of maturation also prevents Langerhans cell

histiocytes from leaving the lesion site.

Up-regulation of many cytokines have been demon-

strated with LCH (Table IX).17,52-60 Histopathologic

examination of lesions notes a mixture of Langerhanscell histiocytes, lymphocytes (predominantly helper

[CD4] T lymphocytes), eosinophils, and macrophages.

Each of these cell types produces cytokines in the

lesions, which result in autocrine and paracrine stimu-

lation of the lesional cells. The major players are con-

sidered to be the Langerhans cell histiocytes and T-cell

lymphocytes (predominantly helper CD4 lymphocytes).

Major factors that participate are the cytokines IL-1,

IL-3, IL-4, IL-5, IL-8, IL-10, GM-CSF, TNF-alpha,

transforming growth factor (TGF)-beta, and leukemia

inhibitory factor (LIF) (Table IX). Many of the cyto-

kines favor recruitment of Langerhans cell progenitors

and rescue from apoptosis. Langerhans cell histiocytes,

macrophages, and T cells produce IL-10, GM-CSF, and

interferon (INF)-alpha. IL-1 is derived from Langerhans

cell histiocytes. T-cell lymphocytes synthesize IL-2,

IL4, IL-5 and TNF-alpha. Eosinophils produce IL-5,

INF-alpha, GM-CSF, IL-7, and IL-10.

These cytokines are important because they create

a cytokine storm in which autocrine and paracrine

stimulation is established among the cells, and in

particular, the Langerhans cell histiocytes and helper

T lymphocytes (CD4).17,52-60 For example, Langerhanscell histiocytes are stimulated by IL-1 and IL-2 pro-

duced by T lymphocytes. Both of these cell types also

upregulate INF-alpha, which stimulates IL-1 produc-

tion. Recruitment of Langerhans cell progenitors

occurs, in part, under the influence of GM-CSF that

is produced by both Langerhans cell histiocytes and

CD4 T lymphocytes. Interestingly, serum GM-CSF and

IL-2 levels are dramatically increased in patients

with multifocal multisystem disease. GM-CSF, IL-3,

TNF-alpha and other cytokines act as chemoattractants

for CD341 Langerhans cell precursors, eosinophils,

neutrophils, and macrophages. TNF-alpha inhibitsspon-taneous apoptosis of Langerhans cell histiocytes, there-

by promoting their survival. This anti-apoptotic effect is

further enhanced by IL-1-alpha, GM-CSF, and IL-3.

Only recently has it been possible to evaluate

expression profiles for LCH using laser capture micro-

dissection, RNA amplification, and gene microarray

techniques.60 Certain differences in cytokine expression

have been found. With LCH involving the liver and

spleen, the cytokines IL-13, nuclear factor kappa

B (NFkB), TNF receptor, p55, receptor-activator of

Fig 6. Immunocytochemical identification of LCH. A, Langerhans cell histiocytes reacting in a cytoplasmic pattern with

CD1a (immunocytochemistry anti-CD1a antibody, original magnification 3400). B, Langerhans cell histiocytes reacting in a

cytoplasmic pattern with CD207/langerin (immunocytochemistry anti-CD207 antibody, original magnification 3400).

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NF-kappa B ligand (RANKL), CD40-L and TGF-beta

receptor are significantly upregulated, compared with

normal Langerhans cells. Bone-only disease has a

different expression profile than multisystem disease.

The upregulated cytokines and genes in bone-only

disease, compared with multisystem disease, are CD40/

CD40L, GM-CSF, GM-CSF receptor, IL-1-3 receptor-1,

IL-2, IL-5 receptor, TNF-alpha, TGF-beta, TNF re-

ceptor associated factor 1 (TRAF1), and TRAF6. The

discovery of differences in cytokine and gene profile

expression for specific forms of LCH provides potential

avenues to explore in understanding pathogenesis andnew targets for therapy.

The symptoms associated with LCH, such as fever

and failure to thrive, have been associated with the

chemokine/cytokine storm effect.17,50-57,60 In addi-

tion, several of these factors promote osteoclastic

activity and osteolysis, promote fibrosis (liver andlung fibrosis, hypothalamic/pituitary axis sclerosis

leading to diabetes insipidus), hematologic dysfunction,

angiogenesis, and overgrowth of granulation tissue.

In addition to the chemokines and cytokines involved

in lesion formation with LCH, many different growth

factors, regulators of the cell cycle, adhesion molecules

andimmunologicmarkers have been implicated (Table

IX).17,52,53,56,58-69 It is obvious that the process of lesion

formation in LCH is quite complex, and involves

numerous mediators that cross-talk among the vari-ous cell types.

Lack of viral etiologyAt one point, the issue of whether LCH had a viral

etiology was raised. Convincing evidence from several

investigations using in situ hybridization and poly-

merase chain reaction techniques, as well as viralcul-

tures, has not surfaced to support a viral etiology.69-71

Adenovirus, cytomegalovirus, Epstein-Barr virus, her-

pes simplex virus, human herpesvirus type 6, HIV,

human T-cell leukemia virus types I and II, and

parvovirus have been shown not to be present in LCH.Some investigators have noted immunohistochemicalstaining for human herpesvirus 6 in lesions, but there

were no serologic data that showed a recent infection

had occurred. It was concluded that reactivation of a

latent viral infection could be the explanation, which is

common among herpesvirus family members.

Neoplastic process, cytogenetics, and moleculargenetics in LCH

During the past decade, there has been controversy

regarding whether LCH is a neoplastic or reactive

process (Table X).17,47,48,72-74 Clonal expansion of

Langerhans cell histiocytes has been shown repeatedly

in eosinophilic granuloma, Letterer-Siwe disease, and

Hand-Schuller-Christian disease. Clonality in these

disease processes has been proven by both human

androgen receptor (HUMARA) DNA assay and T-cell

receptor analysis.17,72-74 Of interest is the fact that the

pulmonary only form of LCH that occurs in young adult

smokers has not proven in multiple investigations to be

clonal. This would fit the clinical scenario, because it is

possible for these lesions to regress with smoking

cessation. Although not studied, lack of clonality in

congenital self-healing LCH would be expected.

Further evidence for a neoplastic process is familialclustering of LCH with multiple affected rela-

tives.17,74,75 Familial clustering of LCH accounts for

only about 1% of the cases. An association between

Table VIII. Langerhans cell histiocytosis: diagnosticcriteria

Presumptive diagnosis

Granulomatous inflammation and hallmark Langerhans cell

histiocytes identified on routinely stained tissue sections

(characteristic histopathology)

Definitive diagnosis

Characteristic histopathology and Birbeck granules on electronmicroscopy and/or CD1a immunoreactivity (CD207

Langerin substitute for CD1a)

Immunocytochemistry important for diagnosis

Positive for: CD1a, CD207 (langerin), S100 protein,

peanut agglutinin (PNA)

Negative for: Factor XIIIa, fascin

Ultrastructural features important for diagnosis


LC granules (Birbeck granules, pentalaminar structures)y

Multivesicular bodies

Curvilinear membranous formations (worm structures)

Tubuloreticular structures

Cylindrical confronting cisternae (comma-shaped structures)


(Reticulohistiocytosis; Hashimoto-Pritzker disease)

Laminated dense bodies (concentric, myelin-like bodies)y

Nonlaminated dense bodiesy

LC granules (Birbeck granules, pentalaminar structures,

\30% of Langerhans cell histiocytes)y

Compiled from references 1-6, 9-12, 17, 21, 25, 38.yTumor-defining structures.

Fig 7. Ultrastructure of LCH.A, Large histiocytic cells with abundant cytoplasm and deeply indented and irregular nuclei with

dispersed chromatin (transmission electron microscopy, original magnification 31500).B and C, Birbeck granules (LC granules)

characterized as tennis rackets with handles (arrow). More often, Birbeck granules are found as pentalaminar rod (handle only of

tennis racket) structures only, with some having rudimentary bulbous ends (transmission electron microscopy, original

magnification 328 000). (Fig 7, B and Ccourtesy of Dr Gary Mierau, Denver, Colo.)

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mannose-binding lectin alleles and susceptibility to

LCH in family members has been suggested as one

possible mechanism. In addition, LCH has occurred in

identical twins, with similar clinical features, dissem-

inated disease, and same sites of involvement.74,75 There

is an 86% concordance rate for identical twins, but no

evidence for concordance with fraternal twins.

Certain HLA haplotypes in different ethnic groups

increase the susceptibility for development of LCH.76

The exact reason for this is not known currently, but is

under investigation. Constitutional or acquired chromo-

somal instability may be another factor in LCH

development.74,75 This is illustrated by a child with an

unknown DNA breakage syndrome who developed

LCH, in addition to ataxia, ocular telangiectasia, and

chromosomal instability.77 Finally, there is a known

increased incidence of other malignancies in children

with LCH (acute and chronic leukemias, lymphomas,

solid tumors;Table II).4,17,26,69,74,78

Comparative genomic hybridization (CGH), loss of

heterozygosity (LOH), and conventional cytogenetics

have demonstrated several genomic abnormalities intissue from LCH (Table X).73,79-81 In particular, certain

chromosomal sites that have losses or gains in DNA

sequences and/or loss of heterozygosity in LCH are loci

where tumor suppressor genes are housed. One such

site in LCH is the short arm (p) of chromosome 1,

particularly 1p36. There are several tumor suppressor

genes at the 1p36 locus (IDE, CDC2L1, PAN, PAX7,

E2F2,TNFR-2,TCEB). Deletions and loss of heterozy-

gosity of the 1p arm have also been associated with

neuroblastoma, B cell chronic lymphocytic leukemia,

and Wilms tumor. Loss of chromosome 7 has been

noted on CGH and LOH studies with LCH. The tumorsuppressor gene plasminogen activator inhibitor is

located on this chromosome. Chromosome 7 loss and

abnormalities are linked to Fanconis anemia, myelo-

dysplastic disorders, and acute myeloid leukemia. 49,78

With LCH, chromosome 9 is affected by loss of DNA

sequences and loss of heterozygosity at 9p21.73,79-81

At chromosome 9p21 are several regulators of the

cell cycle (cyclin-dependent kinases, cyclin-dependent

kinase inhibitors, CDKN2A, p14, p15, p16).

Chromosome 9q is where the tuberous sclerosis tumor

Table IX. Cell proliferation factors in Langerhans cellhistiocytosis

Chemokines

CCR1

CCR2

CCR5

CCR6

CCL2/MCP-1CCL3/MIP-1alpha

CCL4/MCP-4alpha

CCL5/RANTES

CCL17/TARC

CCL20/MIP-3 alpha

CXCL8/IL-8

CXCL10/IL-10

CXCL11/I-TAC

CXCR1

CXCR3

Cytokines

Interleukins (IL) 1, 2, 3, 4, 6, 8, 9, 10, 11, 12, 13, 17, 22

Interferon-gamma (IFN)

Tumor necrosis factor (TNF)-alpha

TNF-receptor (p75)

TNF receptor associated factor (TRAF1, TRAF6)

Granulocyte macrophage-colony stimulating factor (GM-CSF)

GM-CSF receptor (GM-CSFR)

Macrophage-colony stimulating factor (M-CSF)

Stem cell factor (CD341)

Leukemia inhibitory factor (LIF)

CD40 ligand and receptor

Transforming growth factor (TGF)-alpha and beta

TGF-beta receptor

RANKL (receptor-activator of NF-kappa B ligand)

NF-kappa B (nuclear factor kappa B)

FMS-like tyrosine kinase ligase (FLT3-L; colony stimulating

factor 1 receptor, formerly McDonough feline sarcoma viral

oncogene homolog)Angiotensin-converting enzyme (ACE)

Prostaglandin E2

Exotaxin 1, 2, 3

Leptin

Growth Factors

Fibroblastic growth factor 6, 14 (FGF)

Vascular endothelial growth factor (VEGF)

Platelet-derived growth factor-receptor beta (PDGF-R beta)

PDGF-alpha

Bone morphogenic protein 8 (BMP)

Thrombopoietin

Allograft inflammatory factor 1

Cell cyclerelated gene products

MDM2

p53

p55

p21

p16

Rb

Bcl2

Cell adhesion

CD2

CD44

CD54

CD58

CD11c

Table IX. Continued

Immunologic markers

CD1a (OKT6)

CD207 (langerin)

CD4

CD45

MHC II

Compiled from references4-15, 17, 47-69.

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suppressor gene is found. Loss of heterozygosity with

the short arm (p) of chromosome 17 has been identified

in LCH.73,79-81 The tumor suppressor genep53 is located

at 17p13. Loss of heterozygosity has been demonstrated

on the long arm (q) of chromosome 22 in LCH. 73,79-81

The tumor suppressor gene NF2 is located on chromo-

some 22q. In addition, gains at chromosome 4q and 12phave been observed in osteosarcomas (4q), gliomas

(12p), and B-cell chronic lymphocytic leukemias

(12p).73,79-81 LCH has been shown to have DNA

sequence gains along the long arm (q) of chromosome

4 and with chromosome 12.

The finding of cytogenetic abnormalities in chromo-

some 7 (Table X) has further strengthened the link

that LCH is a myeloid stem cell disorder.49,73,78-81

Chromosomal abnormalities associated with chromo-

some 7 include Fanconis anemia, myelodysplastic

disorders, and acute myeloid leukemia. Recently, there

have been several children with concurrent LCH and

myelodysplasia. Interestingly, myelofibrosis may be

seen in LCH and has been ascribed to bone marrow

involvement. Perhaps greater attention will be directedtoward chromosome 7 in LCH on the basis of these

findings.

Cytogenetic studies (Table X) have shown that

tumor suppressor genes (p53), oncogenes (c-myc,

h-ras), adhesion molecules (E-cadherin), cell surface

immunologic markers, growth factors, and apoptotic

defects participate in LCH to some degree.69,72-75,80,81

These factors represent potential targets for therapy.

CURRENT TREATMENT PROTOCOLS ANDINNOVATIVE THERAPEUTIC AGENTS

Over the past decade, the Histiocyte Society initiated

a series of treatment protocols for LCH aimed at the

pediatric population, andmore recently has opened an

adult protocol (Table XI).15,17,82-86 The first pediatric

protocol (LCH-I) began in 1991 and was targeted

toward multisystem disease. The study analyzed the

effect of vinblastine and etoposide in combination with

intravenous steroids. The overall response was similar

with either treatment (58% vs 65% for vinblastine vs

etoposide). Survival was also not statistically different

between the groups (76% for vinblastine, 83% foretoposide). Of interest was the determination that chil-

dren who failed to respond to therapy within a 6-week

period were at increased risk for treatment failure and

required a different therapy. Mortality in these poor

responders was 66%. LCH-II compared treatment with

vinblastine, oral prednisone, and mercaptopurine with

or without etoposide. The addition of etoposide did not

provide any difference in survival, relapse, or toxicity.

Because of the risk for a second malignancy (myeloid

leukemia) with etoposide, this drug is no longer used

in LCH protocols. The prior finding of decreased sur-

vival in children who did not respond to therapy after

6 weeks was again noted (good responders 88% sur-

vival, poor responders 17% survival). The current

protocol (LCH-III) compares different therapies for

multisystem disease with high-risk sites, multisystem

disease with low-risk sites, multifocal single system

disease, and localized special site disease. This study

is currently accruing patients and results are not yetavailable.

The Histiocyte Society has recently launched a

protocol for adults with LCH (Table X).17,82-86 The

treatment groups are single system disease, central

nervous system disease, isolated pulmonary disease,

and multisystem disease. Accrual is ongoing and results

are not available at the present time.

The therapies available for those children and adults

not enrolled into the Histiocyte Society protocols are

determined by the patients oncologist on a case-by-case

Table X. Langerhans cell histiocytosis: cytogeneticsand molecular genetics*

Evidence for neoplastic process

Clonal expansion of Langerhans cell histiocytosis

Human androgen receptor (HUMARA) DNA assay

T-cell receptor analysis

Familial occurrence with multiple affected relatives and

identical twinsMannose-binding lectin allele

Immune system gene dysregulation

Increased incidence of other malignancies

HLA haplotypes (chromosome 6)

DR4, Cw7, B7, B8 (Caucasians, United States)

B7, DR2 (England)

B61, Cw7 (Japanese)

Comparative genomic hybridization (CGH)

Loss of DNA sequences on chromosomes

1p (1p36, 1p21-36), 2, 5, 6, 7, 9, 11p, 16, 17, 22q

Gain of DNA sequences on chromosomes

2q, 4q, 12

Loss of heterozygosity (LOH) with chromosomes

1p, 1p36, 1p22, 1p13, 1q31, 1q, 3p, 4q35, 5q, 7, 7p21, 7p15, 9, 9p,

9p21, 17p, 22, 22q, 22q11

Other cytogenetic abnormalities reported

t(7;12)(q11.2;p13)

Myelodysplastic disorder association (chromosome 7)

Paracentric inversion 13q

Susceptibility to chromatid and chromosomal breakage

Constitutional chromosomal instability

Chromosomal pulverization with herpesvirus and respiratory

syncytial virus

p53 overexpression

c-myc overexpression

H-ras overexpression

E-cadherin underexpression

Aneuploidy (DNA index[1.5)

Apoptosis defects

*Compiled from references17, 21, 69,72-75, 80, 81.

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basis.17,82-85 Therapies vary considerably from surgical

curettage to excision with or without the addition of

radiation or chemotherapy. The Histiocyte Society is

contemplating recommending multiagent chemother-

apy for bone-only disease (unifocal or multifocal). Thisis based on clinical data indicating that single agent

chemotherapy, radiation therapy, or observation only is

associated with a high recurrence rate (50% to 80%)

compared with multiagent chemotherapy (18%, Table

X). In fact, some knowledgeable clinicians recommend

chemotherapy with extensive jawinvolvement to avoid

heroic surgery and loss of teeth.17 They contend that a

6-month course of vinblastine and prednisone has a high

likelihood to cure the disease, allow bone redeposition,

and avoid tooth loss.

Certain late effects among pediatric survivors of

LCH are more common that others (Table X).15,17,82-86

Late effects are about 3 times as common with multi-

system disease than with single system disease. Diabetes

insipidusand orthopedic problems occurin about 20%to

25% of children. Tooth loss is noted in less than 10%.

INNOVATIVE THERAPEUTIC AGENTSWith the identification of cytokines, chemokines,

growth factors, and various other proliferation factors in

LCH, avenues for employing new therapeutic agents

become available.17,82,83,87-94 One such agent is 2-CDA

Table XI. Treatment protocols and late effects inLangerhans cell histiocytosis*

Treatment protocols by The Histiocyte Society

LCH-I pediatric clinical trial: multisystem disease

Vinblastine and intravenous steroid or

Etoposide (possible risk of second malignancy)

and intravenous steroid

Prognostic factors in pediatric LCH-II clinical trialTherapeutic response at 6 weeks in high-risk patients

Good response: 94% survival

Poor response: 34% survival

LCH-II pediatric clinical trial: multisystem disease

for high-risk sites

Vinblastine, oral prednisone, mercaptopurine or

Vinblastine,oral prednisone,mercaptopurine, etoposide

Prognostic factors in pediatric LCH-II clinical trial

Therapeutic response at 6 weeks in high-risk patients

Good response: 88% survival

Poor response: 17% survival

Age: No effect on survival

LCH-III pediatric randomized clinical trial

Multisystem disease with high-risk sites

(lung, liver, bone marrow, spleen)

A: Vinblastine and prednisone for 12 months

B: Vinblastine, prednisone, and methotrexate

(1st 6 weeks),

Followed by maintenance vinblastine and

methotrexate, daily oral mercaptopurine and

oral methotrexate weekly for 12 months

Multisystem disease with low-risk sites

(skin, bone, lymph nodes, pituitary)

Vinblastine and prednisone (6 or 12 months)

Single system multifocal disease

Localized special sites (mastoid, orbit, temporal bones)

LCH-A-I adult clinical trial

Single system disease

CNS disease: vinblastine and prednisone

Isolated pulmonary disease: vinblastine and prednisone

Multisystem disease: vinblastine and prednisone

Current treatment reported for those not on The Histiocyte

Association LCH protocols

Unifocal osseous lesion

Surgical curettage or excision

Radiation therapy

Single agent chemotherapy

Combination of above

Multisystem, refractory, relapsing or progressive disease

Chemotherapy with or without radiation therapy

Comparison of bone disease recurrence

Multiagent chemotherapyBone-only disease: 18% recurrence

(unifocal or multifocal)

Single-agent chemotherapy, radiotherapy

or observation only

Bone-only disease: 50%-80% recurrence

Late effects among long-term pediatric survivors, %

At least 1 permanent consequence

All groups 52

Multisystem disease 71

Single system disease 24


Table XI. Continued

Orthopedic abnormalities 20

Hearing loss 13

Neurologic consequences 11

Growth retardation 9

Ophthalmic problems 8

Tooth loss 7

Pulmonary problems 4Skin problems 2

Innovative therapeutic agents

2-CDA (2-chloro-29-deoxyadenosine, cladribine)

Deoxycoformycin

Thalidomide

Alemtuzumab (anti-CD52 antibody)

Retinoic acid

Interleukin-2

Interferon-alpha

Cyclosporin A

Tacrolimus (FK506)

Monoclonal antibody against CD1a and CD207

(langerin)

Intralesional injection of steroids or chemotherapeutic

agent

Phototherapy (ultraviolet light treatment for skin disease)

Bone marrow transplantation (allogeneic or autologous

stem cell)

LCH, Langerhans cell histiocytosis; CNS, central nervous system.

*Compiled from references15, 17, 82-95.

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(2-chloro-29-deoxyadenosine; cladribine).87 This agent

has previously shown good results with lymphoblastic

leukemia, hairy-cell leukemia, chronic lymphocytic leu-

kemia, and Waldenstroms macroglobulinemia. Initial

studies in children with refractory or progressive multi-

focal bone disease or multiorgan disease involvement

have shown promise. All patients had a clinical responsewith 70% requiring no additional therapy after a median

of 50 months follow-up. The other 30% required addi-

tional therapy to become disease-free. Because 2-CDA

is a potent immunosuppressive agent, toxicity was

limited to manageable myelosuppression. Deoxycofor-

mycin is a therapeutic agent related to 2-CDA, which

has been used to a limited extent in other neoplastic

processes, and may be worth further investigation in

LCH.

Thalidomide has been used as a therapeutic agent

with cutaneous LCH with considerable success.88,89 In

13 adult patients, good responses were noted with

resolution of ulcers located on the skin and inguinal,

genital, and perianal areas, with replacement by scar

tissue. The lesions regressed within 1 to 3 months, butrecurred if oral thalidomide treatment was discontinued.

None of the patients reported peripheral neuropathy.

The teratogenic side effect of this drug is well known,

and birth control is mandated in females of child-

bearing age. Thalidomide is an inhibitor of TNF-alpha

and IL-6. Both of these cellular factors participate in

LCH disease. Of interest, another TNF-alpha inhibitor,

etanercept, has shown similar effects in a single case

study.

A monoclonal antibody against CD52 (alemtuzumab)has recently been developed, and is effective indeplet-

ing lymphocytes and dendritic cells in vivo.90 Quite

exciting is the finding that CD52 is expressed on

Langerhans cell histiocytes, but not on normal

Langerhans cells within the epidermis. This finding is

encouraging and provides potential targeted therapy for

patients with refractory high-risk disease resistant to

current therapy. Alemtuzumab has been well tolerated

in clinical trials with refractory chronic lymphocytic

leukemia patients.

Retinoic acid has the ability to induce differentiation

in several different cell types, including leukemic cells,neuroblastoma cells, and Langerhans cell histiocytes

in vitro.91,92 In patients with LCH, retinoic acid hasinduced remission in some cases and stabilized disease

progression in others. Additional coordinated studies

are necessary to determine the therapeutic potential of

this agent in LCH.

Several other therapeutic agents may induce immune

modulation (IL-2, IFN-alpha) or suppress the immune

system (cyclosporine A, tacrolimus).73,79-81-83,93,94

Monoclonal antibodies directed against CD1a or per-

haps even CD207 (langerin) may be employed as

treatment in the near future. Individual case reports have

shown regression of LCH lesions with intralesional

steroid and chemotherapeutic agent administration.17,95

The role of bone marrow transplantation and stem cell

reconstitution are still under investigation as treatment

adjuncts for refractory high-risk patients.

17,82,83

SUMMARYWhen the sentinel case report of eosinophilic gran-

uloma of the jaw with anal involvement was published

almost 6 decades ago, this entity had only recently been

included in the new category of Histiocytosis X.3 The

cell of origin was not known, however the transitive

phases between eosinophilic granuloma of the bone and

Letterer-Siwe disease was noted by the author due to

the histologic picture of both lesions showing eosin-

ophilic infiltration in the tissue3 (p. 256). As noted in the

current review, Langerhans cell histiocytes have been

determined to be the prime component of this disease. It

is also obvious that this cell is an immature dendritic cell

and not a histiocyte at all.

No doubt the extended period from presentation to

diagnosis with Schroffs case3 was related to the rarity

of such a lesion and lack of familiarity with this entity

by pathologists some 60 years ago. Only about 65 cases

were described in the worlds literature at that time.3

Although a rare orphan disease, LCH is readily

identified now by general and oral and maxillofacial

pathologists, as well as by residents in-training. The

clinical and radiographic features in the affected

gentleman are identical to those seen in patients withLCH today. While more sophisticated diagnostic imag-

ing techniques are available, current dental practitioners

use the same radiographic methods used more than 60

years ago to evaluate patients for jaw lesions. Many

sophisticated diagnostic tools are available to modern

day practitioners, such as computed tomography (CT),

magnetic resonance imaging (MRI), nuclear bone scans,

and positron emission tomography (PET). These may be

used to define the jaw lesions or for detection of other

organ and bone involvement.

Confirmation of the diagnosis of LCH has changed

considerably since the early 1940s. Electron micros-copy became available as a diagnostic tool in the early

1950s and was widely adopted in the late 1960s. A

lesion-defining ultrastructural feature for Langerhans

cell histiocytes was discovered in the early 1960sthe

Birbeck granule. The identification of this structure in

both normal Langerhans cells in the epidermis and in

histiocytes within lesional tissue provided the evi-

dence for the cell of origin for LCH. At the time of

Schroffs case report in 1948,3 immunocytochemical

techniques with tissue sections were not yet available.

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By the late 1970s, several immunocytochemical anti-

bodies had been developed for diagnostic purposes, but

required that lesional tissue be frozen at 708C.

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LCH Sunil Sir