Download Langerhans Cell Histiocytosis in Adults: An Interdisciplinary Challenge

MEDICINE
REVIEW ARTICLE
Langerhans Cell Histiocytosis
in Adults: An Interdisciplinary
Challenge
Joachim Fichter, Claus Doberauer, Heinrich Seegenschmiedt
SUMMARY
Introduction: Langerhans cell histiocytosis (LCH) is characterized by proliferation of histiocytes,
lymphocytes and eosinophils, of unknown etiology. Methods: Selective review of literature and
of treatment guidelines for adults. Results and discussion: Whereas generalized involvement of
liver, spleen, bone marrow and lungs is common in children, the predominant feature in adults is
isolated pulmonary involvement, which affects almost exclusively smokers. Bone and skin
manifestations are less common. Single organ disease is distinguished from disease with
multi-organ involvement. Because of the risk of a generalized disease, investigation should
focus on those organs most commonly affected, such as lungs, bones and skin. Where there is
lung involvement, spontaneous remission is common, hence glucocorticoid therapy should be
restricted to patients with symptomatic nodular disease. In unilocular osseous lesions, local
therapy/radio therapy is preferable. Systemic treatment is indicated where there are multiple
bony lesions. They can affect the lumbar spine and carry a risk of cord compression, involve the
cranial bone with intracranial progression, or occur in multisystemic disease. However, the
quality of the available evidence for treatment in adults is poor.
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Key words: Langerhans cell histiocytosis, diagnosis, differential diagnosis, local treatment,
systemic treatment
L
angerhans cell histiocytosis (LCH) is a rare disease that most often arises in children
aged 1 to 15 years. In this age group, it typically presents with disseminated
involvement of the internal organs and the central nervous system. When it arises in adults,
however, it usually affects the lungs exclusively, though many other organs can be involved,
singly or in combination (cf. case illustration). The treatment options are limited in adults, as
opposed to children, because no controlled therapeutic studies in adults have been performed
to date (box). This review article, based on existing guidelines and a selective review of the
literature, is therefore devoted to the topic of our current knowledge concerning the clinical
features, diagnostic evaluation, and interdisciplinary treatment of LCH in adults.
The term LCH encompasses a variety of clinical conditions characterized by a local or
generalized proliferation of histiocytes, whose ultimate cause currently remains unclear.
Histiocytes are differentiated cells of the monocyte-macrophage series. In adults, isolated
pulmonary LCH may involve either poly- or monoclonal histiocyte proliferation (1, 2, 3).
Other, historical designations for LCH include histiocytosis X, Abt-Letterer-Siwe disease,
Hand-Schüller-Christian disease, and eosinophilic granuloma. These terms are all obsolete
today, because the major considerations for the course of the disease is whether a single organ
system or multiple organ systems are affected, and whether (a) particular organ(s) is (are)
affected whose involvement puts the patient at special risk. The "risk organs" in children
with LCH are the liver, spleen, bone marrow, and lungs. Isolated pulmonary involvement
occurs only rarely in children but is the most common form of LCH in adults.
When only a single organ system is affected, a distinction is drawn between unilocular
and multilocular disease, e.g., the involvement of a single versus multiple bones (monostotic
versus polyostotic involvement). When multiple organ systems are affected (= disseminated
involvement), a further important consideration is whether there is, or is not, a functional
Paracelsus Klinik, Osnabrück: Prof. Dr. med. Fichter; Evangelische Kliniken Gelsenkirchen: Prof. Dr. med. Doberauer; Alfried Krupp
Krankenhaus Essen: Prof. Dr. med. Seegenschmiedt
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CASE ILLUSTRATION
Unilocular
involvement of the
right iliac bone;
confirmation of
the diagnosis by
CT-guided biopsy
This 45-year-old woman underwent diagnostic evaluation for exercise-induced
dyspnea and was found to have radiological evidence of an interstitial lung
disease. An atypical pulmonary wedge resection was performed through
a minimally invasive right thoracotomy. The histological finding was Langerhans
cell histiocytosis of the lung. The patient presented again 4 months later with
polydipsia and was found to have central diabetes insipidus. Magnetic resonance
imaging revealed a circumscribed thickening of the pituitary stalk. The patient
was treated with desmopressin. A further 4 months later, weeping erosions
appeared in the skin folds under both breasts and on the mons pubis, and
histological examination revealed that these, too, were cutaneous manifestations
of Langerhans cell histiocytosis. Cytostatic chemotherapy with vinblastine,
6-mercaptopurine, etoposide, and prednisolone was given and resulted in
regression of the skin lesions and a stable pulmonary condition. 4 years later, the
patient, who had continued to smoke cigarettes, developed increasing dyspnea
on exertion and was found to have increased interstitial lung markings as well as
a new, painful, weeping skin eruption. Sciatica-like pains prompted a radiological
examination, which revealed a focus of osteolytic destruction in the right ilium
(illustrated). This lesion was treated with local radiotherapy. Treatment with
topical glucocorticoids, 8-methoxypsoralen, and UV-A light was unsuccessful.
The patient's further course was stable, and no further chemotherapy was given.
disturbance of one or more of these systems (4). The organs most commonly involved by
LCH in adults are the lungs, skeleton, and skin, but endocrine disturbances such as
diabetes insipidus are also fairly common.
Epidemiology
Although LCH is a rare disease, its incidence and prevalence are underestimated, because
it can occur in oligosymptomatic forms and it can also remit spontaneously (5). The disease
arises before age 10 in more than 50% of affected patients and before age 30 in 75%. A
clue to its true incidence is provided by a histopathological study of interstitial lung disease:
in 6 years, Colby et al. (6) found 15 cases of LCH and 274 of sarcoidosis. It can be inferred
from this that the incidence of LCH in adults is at least 10 to 15 per million persons per year.
Because the incidence of the disease is low, our current knowledge of its clinical course is
mostly based on retrospective data gathered over many years.
Women are more commonly affected than men (7). Vassallo (3) found that women also
made up a larger percentage of patients with isolated pulmonary LCH. Islinger et al. (8),
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however, found that patients with predominantly osseous LCH are more often male. The
reported mean age of onset of the disease ranges from 29 to 38 years (3, 8), with differences
resulting from the different age criteria for inclusion in different studies. LCH is a disease
that nearly exclusively affects persons of Caucasian ethnic origin (9).
Immunology and pathomorphology
Langerhans cells (LH cells) are a component of the dendritic cell network. They are
derived from bone marrow stem cells and present various antigens. Cytokines including
granulocyte-macrophage colony stimulating factor (GM-CSF) and tumor necrosis factor
(TNF) play a central role in the differentiation of LH cells into various subtypes.
A feature of LH that permits their unambiguous identification is the presence of Birbeck
granules, which are visible under the electron microscope as five-layered, rod-shaped
intracellular structures and probably serve to present antigens. The formation of Birbeck
granules is induced by langerin (DC207), a lectin that is specific to Langerhans cells (10).
LH cells can also be marked with anti-langerin antibodies. A further feature of LH cells
is the expression of CD1a antigen at the cell surface (figure 1). An accumulation of LH
cells in addition to lymphocytes and eosinophilic granulocytes is a central histopathological
feature of LCH.
Clinical features
In one study, the most common clinical manifestation of LCH was dyspnea on
exertion or at rest, affecting 66% of patients (11). The second most common manifestation
was productive or non-productive cough. Patients also reported fatigue, weight loss,
generalized weakness, pruritus, night sweats, memory disturbances, increased thirst,
nausea, and fever. 14.7% of patients with pulmonary LCH were asymptomatic (3).
It is known that patients with pulmonary LCH are often oligosymptomatic at first
(9, 12), though the disease can also begin acutely with fever, dyspnea, cough, and
weight loss (6, 9, 13).
Typical manifestations of bone involvement are local bony pain, often when the bone is
under mechanical stress but sometimes also at night, and an abnormal growth of soft tissue,
often painless, over the affected area of bone. Lesions in the skull and ribs are usually
asymptomatic, while lesions in the long bones more commonly cause pain on mechanical
stress because of their predominantly weight-bearing function and the increased remodeling
that takes place within them. Abnormal warmth or redness over the affected bone is rare; in
such cases, LCH must be differentiated from other diseases producing these signs, such as
osteomyelitis or malignant tumors. Lesions of the spine rarely produce neurological deficits
as the presenting manifestation of the disease. Spontaneous fractures of the long bones or
ribs can also occur.
Diagnostic evaluation
Because of the potential for generalized involvement, a thorough history should be taken
and a comprehensive physical examination performed in any patient presenting with LCH.
In particular, the skin and the visible mucous membranes should be inspected. The laboratory
tests to be performed include a complete blood count, erythrocyte sedimentation rate,
C-reactive protein, creatinine, sodium, potassium, calcium, glutamate-oxaloacetate
transaminase (GOT), glutamate-pyruvate transaminase (GPT), gammaglutamyl transpeptidase
(GGT), alkaline phosphatase (AP), bilirubin, and urinalysis. An ultrasonographic examination
of the neck and thyroid as well as of the abdomen and pelvis should be performed, and plain
x-rays of the chest, skull, spine, pelvis, and long bones should be taken. Any evidence of a
pathological finding should be followed up by high-resolution chest CT or by MRI of the
head and spine.
Because bone involvement is often associated with osteolytic lesions, a skeletal scintigram
(bone scan) alone does not suffice for diagnostic purposes. It seems possible to demonstrate
active foci of disease with somatostatin receptor scintigraphy (14). The decision whether
further studies should be performed is based on the patient's symptoms and the findings of
the basic battery of diagnostic tests. The disease may be classified as active, inactive,
progressive, regressive, or stable. In the following sections, the special features of involvement
of individual organ systems will be described.
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BOX
Clinical aspects of Langerhans cell
histiocytosis in adults
> Isolated pulmonary involvement is the most common
manifestation
> Arises only in smokers or ex-smokers
> Other organs may be involved, most commonly bone,
skin, and the pituitary gland
> High rate of spontaneous remission
> There is no current treatment for this disease in adults
that is based on convincing evidence from a therapeutic
trial due to rarity of occurrence
> The treatment options include surgery, radiotherapy,
and systemic treatment
Pulmonology
Although pulmonary LCH is classified as an interstitial lung disease, it begins as a
disease of the bronchioles, with variable extension into the interstitial tissue. X-rays
usually reveal symmetrical involvement of both lungs. Typically, the costophrenic angle
is spared. There are usually nodular foci of disease with blurred margins. There are also
reticular changes with cavitation, sometimes appearing as sharply demarcated ring
structures in a diffuse pattern of distribution. The characteristic findings of pulmonary
LCH on high-resolution computerized tomography of the chest are irregularly bordered,
often confluent cystic changes (figure 2) (4). The differential diagnosis in women
includes lymphangioleiomyomatosis (LAM); in this condition, however, the cysts have
thinner walls and are more evenly distributed.
Pulmonary gas exchange is impaired, as can be demonstrated with high sensitivity by a
low level of CO transfer factor and of the Krogh factor. In terms of pulmonary mechanics,
there may be an obstructive pattern, sometimes with overinflation as well. In addition,
a restrictive component may appear. A bronchoalveolar lavage yielding more than 4%
CD1-positive cells supports the diagnosis of pulmonary LCH (4, 13, 15, 16). The diagnostic
yield of bronchoscopic biopsy for LCH is low, because the condition usually involves
small, disseminated foci of disease. The diagnostic method of choice is therefore videothoracoscopic lung biopsy.
Orthopedics
X-rays reveal non-specific, solitary osteolytic lesions that range from well-demarcated
areas of osteolysis with a sclerotic edge to seemingly moth-eaten areas of bone destruction
with erosion of destruction of compact bone, depending on the stage and level of activity of
FIGURE 1:
Nodular activation
of Langerhans
cells in the lung;
immunochemical
reaction with
CD1a antibodies
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FIGURE 2:
High-resolution
computerized
tomography (CT) of
the chest revealing
extensive cystic
changes in both
lungs
FIGURE 3:
Langerhans cell
histiocytosis
involving the
gingiva of teeth
4–2 and 4–3.
Gingival retraction
and inflammation
in this case
simulate the
appearance of
parodontitis
marginalis.
the disease. Sharply demarcated, round osteolytic lesions ("punched-out lesions") of variable
diameter are often seen in the skull. Multiple foci may be confluent and produce the
appearance of bone sequestra in between. Lesions of the long bones usually affect the
diaphysis, less commonly the metaphysis or epiphysis. Complete replacement of the marrow
space by LCH creates the appearance of osteopenia of the spongiosa. In active lesions,
onion-skin-like periosteal reactions are often seen. Spinal lesions usually affect the
vertebral bodies but may extend to the laminae and spinous or transverse processes. Extensive
involvement may cause vertebral body collapse, with the classic radiological finding of
vertebra plana ("flat vertebra").
A biopsy of the focus is required for differential diagnosis. Other disease entities
affecting the long bones that must be ruled out include solitary bone cysts and malignant
processes and, in younger patients, Ewing's and osteosarcoma, chondrogenic tumors,
and inflammatory changes. MRI and CT rarely suffice for differential diagnosis but
yield important information about the extent of the lesions and the degree of soft tissue
involvement. The findings of scintigraphy depend on the level of activity of the lesion
and range from a lack of uptake in exclusively lytic, inactive lesions to markedly
increased uptake in active processes, mainly in their periphery.
Oral and maxillofacial surgery
The most common clinical manifestations of LCH in the jaws are pain and swelling of
uncertain origin (17). Gingival involvement may clinically simulate severe marginal
parodontitis (figure 3). The gingival edge is typically markedly erythematous and hyperplastic
and often ulcerated in the area of the gingival papillae. In advanced lesions, teeth may
loosen or fall out (18). If such teeth are pulled because of marked loosening and the cause
of the condition is not recognized, non-healing of the extraction wound is practically
pathognomonic for LCH.
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Dermatology
The clinical appearance of mucocutaneous LCH is highly variable. Acute LCH is characterized
by disseminated, often hemorrhagic and hemorrhagic/necrotizing papules and plaques.
In chronic LCH, the lesions may acquire a yellow or yellowish-brown color through
xanthomization. Sites of predilection for these painful, pruritic lesions are the hairy scalp,
the intertriginous areas, seborrheic areas of the skin, and the oral and, less commonly,
genital mucosa. The scaly, erosive lesions of the scalp resemble those of seborrheic eczema,
while the ulcerating plaques in the groin resemble intertrigo. Thus, in cases of intractable
scalp eczema or intertrigo, LCH should be excluded by tissue biopsy.
Treatment and prognosis
The treatment of LCH in adults depends on the classification and status of the disease in the
individual patient (tables 1 and 2). Factors that portend a poorer prognosis are advanced
age, extensive organ involvement, and dysfunction of the affected organs (3). Nezelof et al.
(19) reported a correlation between the number of organs affected and mortality. Because
the course of LCH is unpredictable – progression and spontaneous remission are both
possible – prognostication is difficult.
The life expectancy of adult patients who have had pulmonary LCH for 15 years is
approximately 40% lower than that of the normal population (3). This is due, above all, to
the possibility that respiratory insufficiency may develop. The identified diagnostic predictors
TABLE 1
Interdisciplinary treatment and typical pattern of involvement of LCH
Medical specialty
Typical pattern of involvement
Pulmonology
Lungs and mediastinum
Hematology and radiation oncology
Bone marrow and multiple organs
Endocrinology
Pituitary gland: diabetes insipidus
Dermatology
Skin and subcutaneous tissue
Orthopedics
Bone and soft tissues
Oral and maxillofacial surgery
Gums, maxilla, and mandible
Otorhinolaryngology
Oral mucosa and lymph nodes
for a poor prognosis include bronchial obstruction, hyperinflation, and limited transfer
factor. In this study (3), additional extrapulmonary involvement was not prognostically
unfavorable. There are no evidence-based data supporting cortisone therapy for pulmonary
LCH. Any possible therapeutic benefit for symptomatic patients should, therefore, be
carefully weighed against the potential undesired effects of this form of treatment, because
spontaneous remissions do occur. Tazi (20) recommends steroid therapy for symptomatic
patients with the nodular form of pulmonary LCH.
Orthopedic surgical treatment is tailored to the site and extent of the lesion(s). Local
therapy is the treatment of choice for monostotic lesions. Painful foci without risk of
fracture can be treated with local instillation of corticosteroid; for radiotherapy the recurrence
rate is 3 to 10% (evidence level IIb) (21). If there is a risk of fracture, the focus should be
resected, usually in combination with a spongiosa reconstructive procedure (21). Local
recurrences then generally do not arise (evidence level IIb). Radiotherapy is indicated if there
is an impending neurological deficit and a high surgical risk, e.g., when the optic nerve is
involved. The dose should be between 16 and 30 Gy. Radiotherapy, alone or in combination
with other treatments, can achieve local control of uni- or multilocular bony manifestations
of LCH without involvement of other organs in up to 96% of cases (evidence level IIb) (12,
13, 19). Systemic therapy is preferred if multiple bones are affected, especially the spine or
skull, with impending spinal cord compression or intracranial tumor extension, or when
multiple organ systems are involved.
Immunosuppressive drugs are used to suppress active disease, prevent reactivation, and
protect against late organ damage. Only moderately toxic treatment regimens come into
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TABLE 2
Treatment options in adults
Treatment
Dosage
Duration
Evidence level
Tapered over
6 months
IIb
Isolated pulmonary involvement (symptomatic nodular form)
Prednisolone
1 mg/kg per day
max. 60 mg
Isolated (symptomatic) cutaneous involvement
Topical
Glucocorticoid ointment
Tacrolimus ointment
IIIa
Systemic
Methotrexate
Thalidomide
6 months
12 months
IIIa
Monostotic lesion
Without risk of fracture
Local corticosteroid
instillation
IIIa
With risk of fracture
Surgical resection and
spongiosa reconstruction
IIb
Impending neurological deficits or high surgical risk
Radiotherapy
16–30 Gy
IIb
Polyostotic involvement, including the spine, with impending spinal cord compression or including the skull,
with intracranial spread of tumor, or multisystem involvement
Initial treatment
Maintenance treatment
Prednisolone
1 mg/kg per day
max. 60 mg
Vinblastine IV
6 mg/m2 max. 10 mg,
days 1, 8, 15, 22, 29, 36
6-mercaptopurine
30 mg/m2 per day
max. 50 mg
Vinblastine IV
6 mg/m2 max. 10 mg,
day 1 every 3 weeks
Prednisolone
1 mg/kg per day
max. 60 mg
days 1–5 every 3 weeks
Patients with a poor prognosis
or who have experienced
a recurrence after a
short interval
2-chlorodeoxyadenosine
alone or in combination
with cytosine arabinoside
Supportive treatment in case
of multiple bone involvement
Biphosphonate
6 weeks
IIb
6 or 12 months
IIIa
Over 12 months
IV
consideration because of the variable course of disease and the potential for spontaneous
remission. Prospective, multicenter studies in children with multiple organ system
involvement have shown that risk-adapted combination chemotherapy over the course of a
year leads to a higher response rate and a lower chance of reactivation of disease than
monotherapy with vinblastine or etoposide for 6 months, but does not significantly prolong
survival (evidence level IIa) (21, 22, 23, 24). A positive response in the first 6 weeks is an
important prognostic factor (23). There is no difference in effectiveness between vinblastine
and etoposide (evidence level IIa). In children with multiple organ system involvement
including risk organs such as the liver, spleen, lungs, and/or bone marrow, the addition of
etoposide to vinblastine and prednisolone did not lead to any improvement in outcome
(evidence level IIa) (22). A number of smaller studies also suggest that the results found in
children with multiple organ system involvement are also applicable to adults.
In 2004, the Histiocyte Society launched the international LCH-A1 study to document
the course of the illness and determine suitable treatment strategies for adults with Langerhans
cell histiocytosis. This study includes patients with multilocular bone involvement, with
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bone involvement conferring a risk of spinal cord compression or intracranial tumor
extension, or multiple organ system involvement. The treatment consists of systemic initial
therapy with vinblastine and prednisolone for 6 weeks followed by maintenance therapy
with 6-mercaptopurine, vinblastine and prednisolone for 6 or 12 months.
Patients with a poor prognosis or early recurrences may benefit from other cytostatic
drugs such as 2-chlorodeoxyadenosine (25) alone or in combination with cytosine arabinoside
(evidence level IIb) (e1). Immunosuppressive medications such as ciclosporine (e2) or
immunomodulatory substances such as thalidomide (e3) were moderately effective in
patients who had no involvement of "risk organs" (evidence level IIb). Painful multiple
bone involvement can also be effectively treated with supportive therapy with a biphosphonate
(evidence level IIb) (15).
Autologous and allogeneic stem cell transplantation offer a chance for cure but are
fraught with high morbidity and mortality. These are therefore used at present only in cases
where their use is justified by otherwise intractable progression of disease (e4). Advanced
organ failure can only be treated with liver or lung transplantation (e5, 6). The disease may,
however, reappear in the transplanted organ (e7, 8).
Summary and prospects
Because of the rarity of LCH, particularly in adults, there is as yet no systematic,
interdisciplinary approach to its diagnostic assessment, treatment, and long-term follow-up.
The care of adult patients with LCH should involve multiple medical specialties from the
start. Interdisciplinary guidelines are needed for the standardization of the diagnostic
assessment and treatment of LCH in adults and for the establishment of a centralized patient
data registry (11). An international therapeutic trial on adults has just begun, and all
physicians are invited to enroll patients in it (www.ehx-ev.de, www.histio.org) so that the
treatment of LCH in adults can be optimized.
Acknowledgements
The authors would like to thank Prof. Dr. med. Ulrich Costabel, Ruhrlandklinik, Essen; Prof. Dr. med. Arnold Ganser, Medizinische
Hochschule, Hannover; Prof. Dr. med. Gerhard Kolde, Berlin; Prof. Dr. med. C. Niekhart, Universitätsklinik Aachen; Dr. med. Thomas
Olschewski, Alfried Krupp Krankenhaus, Essen; and Prof. Dr. med. Thomas Wilhelm, Städtisches Klinikum, Nürnberg.
Conflict of Interest Statement
The authors state that they have no conflict of interest as defined by the guidelines of the International Committee of Medical
Journal Editors.
Manuscript received on 9 March 2006; final version accepted on 19 April 2007.
Translated from the original German by Ethan Taub, M.D.
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GUIDELINES
Leitlinien zur Diagnostik und Therapie in der Pädiatrischen Onkologie und Hämatologie Langerhans-Zell-Histiozytose
(LCH) in: Deutsche Gesellschaft für Kinderheilkunde und Jugendmedizin. Leitlinien. München: Elsevier 2007.
Deutsche Gesellschaft für Orthopädie und Traumatologie und Berufsverband der Ärzte für Orthopädie (Hrsg). Leitlinien
der Orthopädie. Köln: Deutscher Ärzte-Verlag 1999; 49ff.
Corresponding author
Prof. Dr. med. Joachim Fichter
Paracelsus Klinik
Am Natruper Holz 69
49076 Osnabrück, Germany
[email protected]
Dtsch Arztebl 2007; 104(34–35): A 2347–53 ⏐ www.aerzteblatt.de
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