Euro Histio Net Guidelines November 2011, Version 1.1on 1

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LANGERHANS CELL HISTIOCYTOSIS (LCH)

Recommendations for Diagnosis, Clinical Work-up and Treatment of adults

Euro Histio Net Work Group for LCH Guidelines - alphabetically: Maurizio Arico1, Anthony Chu

2, Claus

Doberauer3, Joachim Fichter

4, Michael Girschikofsky (Executive Editor)

5; Julien Haroche

6, Gregory A.

Kaltsas7, Polyzois Makras

8, Angelo V. Marzano

9, Kenneth L. McClain

10, Mathilde de Menthon

11, Oliver

Micke12

, Emanuela Passoni9, M. Heinrich Seegenschmiedt

13, Abdellatif Tazi

14, Diego C. Villegas

15.

1 Department of Pediatric Hematology Oncology, Azienda Ospedaliero Universitaria A. Meyer, Florence, Italy; 2 Imperial NHS Trust, London, UK; 3 Clinic for Internal Medicine, Evangelic Clinics, Gelsenkirchen, Germany; 4 Paracelsus Klinik, Osnabrück, Germany; 5 Internal Medicine I, Elisa-bethinen Hospital, Linz, Austria; 6 Service de Medicine Interne, Groupe Hospitalier Pitie-Salpetiere, Paris, France; 7 Department of Pathophysiol-ogy, University of Athens School of Medicine, Athens, Greece; 8 Endocrinology and Diabetes, 251 Hellenic Air Force & VA General Hospital, Athens, Greece; 9 UO Dermatologica, Fondazione IRCCS Ca´s Granda-Ospedale Maggiore Policlinico, Milano, Italy; 10 Texas Children´s Cancer Center/Hematology Service, Houston, TX, USA; 11 Dept. of Internal Medicine, Hospital Saint Louis, Paris, France; 12 Franziskus Hospital, De-partment of Radiotherapy and Radiation Oncology, Bielefeld, Germany; 13 Radiation Oncology Center, Hamburg, Germany; 14 Pulmonolgy Dept, Saint Louis Teaching Hospital, Paris, France; 15 Servicio de Neumologia, Hospital de la Santa Creu I Sant Pau,IIB, Barcelona, Spain.

BACKGROUND, PROCESS OF DEVELOPMENT

AND RESTRICTIONS:

There are no universally accepted international

guidelines available for the diagnosis and treat-

ment of adult patients in contrast to childhood

LCH. Clinical Study results as a backbone for

strong evidence-based recommendations are also

missing. In this field a literature search results

mainly in single case or small series reports and

the largest number of patients was published in a

pooled retrospective analysis from several na-

tional registries [1].

Based on the available literature up to June 2011,

but even more on their personal experience the

following recommendations were designed and

established by an international group of physi-

cians. These individuals are academic clinicians

who have worked in the field of histiocytic dis-

orders, are leaders of the national registries, ac-

tive members of different national societies and

of the international medical society of histiocyto-

sis (Histiocyte Society).

Drafts were commented by the entire group and

redrafted by the executive editor. Final agree-

ment was by consensus. The quality of evidence

of the following recommendations is predomi-

nantly attributed to the level of expert opinion.

This paper cannot replace the physician’s own

professional judgment based on the patient’s

special clinical circumstances. Due to the diversi-

ty of clinical course of LCH, even recommenda-

tions which are established as standard of care

may need to be critically appraised in an individ-

ual case. We suggest that you never hesitate to

contact LCH experts in case that the clinical

course raises questions or doubts. An appropriate

web-based platform will be available shortly for

medical colleagues as well as patients on the

home-page of the EHN (http://www.eurohistio.net/

index_eng.html).

GENERAL CONSIDERATIONS

The etiology of LCH is unknown. LCH cells are

clonal [2] and cancer-associated mutations were

found in more than a half of investigated speci-

mens, indicating that LCH may be a neoplastic

disease [3]. There seems to be an association

between LCH and malignant tumors as well. In

most cases, LCH occurs before or concurrently

with the associated neoplasma, histopathological-

Euro Histio Net Guidelines November 2011, Version 1.1on 1

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ly mainly lymphomas or solid tumors. An ap-

pearance of leukemia is found more frequently

after LCH and is presumably more often related

to therapy than a de-novo disease [4].

The disease may affect any organ or system of

our body, but those more frequently affected are

the bone, skin, and pituitary gland. Other organs

often involved are the lymph nodes, liver, spleen,

gut, the central nervous system excluding the

pituitary, extremely rare the hematopoietic sys-

tem. Although the lungs may be affected simul-

taneously with other organs an isolated pulmo-

nary LCH is observed more frequently and

represents a special form of adult LCH. There-

fore this manifestation is highlighted in an own

chapter.

Generally clinical manifestations of the disease

vary depending on the organ or system affected,

ranging from an isolated lesion as in the skin or

in the bone, to a more severe clinical manifes-

tations affecting the same tissue in multiple sites,

or several organs. The clinical course may vary

from self-limiting and self-healing disease to a

chronic recurrent one. But in contrast to LCH in

childhood a rapid progressive form is usually not

observed in adults and accordingly other malig-

nant histiocytic disorder should be considered

and excluded, respectively. Langerhans cell sar-

coma can occur as well de novo as from an ante-

cedent LCH [5]. In this chapter we do not dis-

cuss the even more rare histiocytic disorders such

as Erdheim Chester and malignant histiocytosis

or histiocytic sarcomas.

When a comparison is sought then the clinical

course of chronic recurrent LCH reminds one of

the rheumatic disorders rather than anything else.

Permanent consequences and late effects of the

disease and its therapy lead in some cases to

severe impairment of the quality of life. A symp-

tom related approach to avoid overtreatment that

could result in late sequelae is recommended.

Generally treatment options vary depending on

disease extent and severity at onset, and on the

response to front-line treatment. Thus, after diag-

nosis is confirmed, it is important to have the

diagnostic and the clinical work-up performed

according to uniform recommendations.

One of the main problems of LCH in adults is the

variety of potentially involved organs, which

results in a large number of different physicians

who may be consulted at the time of the first

contact. Thus, in many cases only the apparently

affected site is recognized and a complete exami-

nation in order to detect the whole extent of the

disease is unfortunately often not done.

Based on the mentioned considerations we report

the level of agreement between experts (see table

1).

Table 1 Determination of the Level of Agreement

AGREEMENT CRITERIA

+ According evidence and/or general

agreement

Discussed evidence and/or discussed

recommendation, but no strong objec-

tions

– Conflicting evidence and/or diver-

gence of opinion

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TABLE OF CONTENTS

1. DIAGNOSIS

1.1. Biopsy and Histological Examination 1.2. Diagnostic Criteria

2. PRETREATMENT CLINICAL EVALUATION 2.1. Complete History 2.2. Complete Physical Examination 2.3. Laboratory and Radiographic Evalua-

tion 2.4. Specific Clinical Scenarios and Recom-

mended Additional Testing 2.4.1. Endocrinological dysfunction

2.4.1.1. Diabetes insipidus 2.4.1.2. Anterior Pituitary Hormonal

Deficiencies 2.4.1.3. Hypothalamic involvement 2.4.1.4. Metabolic abnormalities 2.4.1.5. Bone metabolism 2.4.1.6. Other endocrine tissue in-

volvement 2.4.1.7. Investigation of hormonal

deficiencies 2.4.2. Dermatological involvement 2.4.3. Gastrointestinal involvement

2.5. Definition of Organ Involvement 2.5.1. Possible involved Organs 2.5.2. Risk organs 2.5.3. Special Sites

3. STRATIFICATION

3.1. Clinical Classification 3.1.1. Single System LCH (SS-LCH) 3.1.2. Multisystem LCH (MS-LCH)

4. TREATMENT 4.1. Management Algorithms 4.2. Local Therapy or Careful Observation 4.3. Systemic Therapy

4.3.1. Front Line Treatment 4.3.2. Evaluation of Response 4.3.3. Maintenance Therapy 4.3.4. Salvage Therapy

4.4. Treatment in Case of Reactivation 4.4.1. In Single System Disease 4.4.2. After Systemic Therapy

4.5. Treatment and Hormon replacement of Endocrinopathies

4.6. Central nervous system involvement 4.6.1. Tumorous lesions 4.6.2. Neurodegenerative LCH

4.7. Radiotherapy

5. ISOLATED PULMONARY LCH

6. PREGNANCY

7. FOLLOW -UP 7.1. General considerations 7.2. Of Endocrinopathies

8. REFERENCE LIST

1. DIAGNOSIS

1.1. BIOPSY AND HISTOLOGICAL EXAMINATION

The diagnosis of LCH should be based on histo-

logical and immunophenotypic examination of a

biopsy of the lesional tissue. Biopsy should be

taken from the most accessible organ: skin if

involved; while in case of multiple skeletal in-

volvement, the bony lesion that is most easily

accessible should be chosen for biopsy. The

main diagnostic feature is the morphologic iden-

tification of the characteristic LCH cells, but

positive staining of the lesional cells with CD1a

and/or Langerin (CD207) is required for defi-

nitive diagnosis [6-8]. Electron microscopy is no

longer recommended since it has been shown that

the expression of Langerin fully correlates with

the presence on electron microscopy of Birbeck

granules, which were previously one of the crite-

ria required for definitive diagnosis. There are,

however, very few exceptions as the fact that in

organs such as liver Birbeck granules are not

present and CD1a may be negative.

When tissue sample is taken from a bone lesion,

curettage of the center of the lesion is usually

sufficient for pathologic diagnosis and also may

trigger the initiation of a healing process. Com-

plete excision of bone lesions is not indicated in

all cases since it may increase the size of the

bony defect and the time to healing; it might also

result in permanent skeletal defects.

In very few circumstances, when the only lesion

involves particular structures and the risk of bi-

opsy outweighs the need for a definitive diagno-

sis, the risk/ benefit of biopsy should be carefully

considered. This is the case in patients with ra-

ther extended isolated pulmonary LCH. Another

possible, but rare situation is that of pituitary

deficit (e.g. diabetes insipidus) in absence of a

larger tumor and/or a small and not easily access-

ible lesion on head or spinal MRI. Without prov-

en diagnosis both situations do not require initial

cytotoxic medication. Close monitoring and reas-

sessment of the need for biopsy is recommended

in patients with minor and acceptable symptoms.

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The probability of other diagnoses than LCH is

usually higher, thus in all other situations per-

forming a biopsy is generally recommended. For

example in case of lytic bone lesions or lympha-

denopathy other clinical conditions that might

lead to a similar radiological finding, such as

myeloma lesions, bone metastases, sarcoma or

lymphoma have to be considered with a higher

probability.

LCH in adults is rather a random than an ex-

pected diagnosis!

1.2. DIAGNOSTIC CRITERIA

The diagnosis is clinicopathologic and should

only be made in the correct clinical setting to

prevent misdiagnosis in the presence of normal

reactive Langerhans cells particularly in regional

lymph nodes.

The two levels of certainty of LCH diagnosis

which are generally agreed upon are shown in

table 2.

Table 2 Diagnostic Criteria of LCH

► DEFINITIVE

= Based on microscopic examination and at least one

of the following immunological staining:

♦ Langerin (CD 207) positivity

♦ CD1a positivity

♦ Presence of Birbeck granules on electronic mi-croscopy.

► PRESUMPTIVE (OR COMPATIBLE) = Based only on clinico-radiological evidence, without

biopsy, as in case of: e.g.: Pulmonary lesions on CT scan with typical

cysts and nodules in a smoker (however, biopsy should be considered in order to reach a more defin-itive diagnosis)

2. PRETREATMENT CLINICAL EVALUATION

2.1. COMPLETE HISTORY

At the beginning, patients with LCH are often

asymptomatic or show only mild symptoms,

which are depending on the clinical manifesta-

tions of the disease.

Most common symptoms are dyspnea on exer-

tion or at rest and productive or non-productive

cough, local bone pain, an abnormal growth of

soft tissue over the affected area of bone, exan-

thema of the skin, pruritus, increased thirst, and

swelling of lymph nodes. Additional signs are

fatigue, generalized weakness, weight loss, night

sweats, nausea, and fever.

Because of the potential for generalized in-

volvement, a thorough history should be per-

formed including the question after unexplained

symptoms in the past (especially after “idiopath-

ic” eczema, thyroid disease or diabetes insipidus,

lung cysts or fibrosis, or bony lesions), the smok-

ing behavior and not at least the family history (a

few familial cases are reported [9]).

2.2. COMPLETE PHYSICAL EXAMINATION

For staging and determination of organ dysfunc-

tion a comprehensive physical examination is

necessary. In particular, the skin and the visible

mucous membranes should be inspected. Sup-

plemental neurological and/or psychological

investigations are useful in patients presenting

with neuromyopathy or cognitive impairment.

2.3. LABORATORY AND RADIOGRAPHIC EVALUATION

The laboratory tests to be performed include a

complete blood count, blood chemistry, liver

enzymes, albumin, total protein, erythrocyte

sedimentation rate, C-reactive protein Coagula-

tion studies and urine test strip analysis. Serum

levels of cytokines have been evaluated by sever-

al groups around the world and in some cases,

seem to correlate with disease activity. But today,

there is no established specific biological marker

for disease activity.

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A skeletal survey, skull series (if available re-

placed by low dose whole bone CT) and chest x-

ray (AP and lateral) are the first radiographic

examinations to be done. CT of specific areas of

the skeleton are indicated when mastoid, orbital,

scapular, vertebral, or pelvic lesions are found by

plain x-rays. MRI allows to detection additional

extraosseous lesions. Skeletal scintigram (bone

scan) alone does not suffice for diagnostic pur-

poses. Any evidence of a pathological thoracic

finding should be followed up by high-resolution

chest CT. An ultrasonographic examination of

the abdomen should be done looking for evi-

dence of hepatic abnormalities. An ultrasound of

the neck with attention to the thyroid gland may

be indicated if there are thyroid nodules or evi-

dence of thyroid dysfunctions. For brain exami-

nation with a critical view to the hypothalamic-

pituitary area a MRI of head is useful. PET-(CT)

scan may identify lesions missed by other modal-

ities and is suitable to document response to ther-

apy [10]. The decision whether further investiga-

tions should be performed is based on the pa-

tient's symptoms and the findings of the basic

diagnostic tests (which should be performed

independently of the extension of the disease -

see Table 3).

Table 3 Baseline Laboratory and radiographic evaluation

Agree- Ment

►FULL BLOOD COUNT ♦ Hemoglobin ♦ White blood cell and differential count ♦ Platelet count ►BLOOD CHEMISTRY ♦ Total protein, Albumin ♦ Bilirubin ♦ ALT (SGPT), AST (SGOT ♦ Alkaline phosphatase (AP) ), gammaglutamyl transpeptidase (γGT) ♦ Creatinine ♦ Electrolytes ♦ CRP (C-reactive Protein) ►ERYTHROCYTE SEDIMENTATION RATE (ESR) ►COAGULATION STUDIES ♦ INR/PT ♦ Fibrinogen ►THYROID STIMULATING HORMONE (TSH), FREE T4 ►URINE TEST STRIP

+ + +

+ + + +

+ +

o

+ +

+

+

►ULTRASOUND ♦ Size and structure of liver and spleen ♦ Lymph-nodes ♦ Thyroid gland ►CHEST RADIOGRAPH (CXR) ►LOW DOSE WHOLE BODY (BONE) CT (IF NOT AVAILABLE: X-RAY SKELETAL/SKULL SURVEY )

+ + +

+

+

►OPTIONAL: BASELINE HEAD- MRI + ►OPTIONAL: PET-CT INSTAED OF ULTRASOUND, CXR AND BONE CT

+

2.4. SPECIFIC CLINICAL SCENARIOS AND RECOM-

MENDED ADDITIONAL TESTING

2.4.1. Endocrinologic dysfunction

LCH exhibits a particular predilection for in-

volvement of the hypothalamo-pituitary (HP)

region leading to almost always permanent post-

erior and/or anterior pituitary hormonal deficien-

cies.

2.4.1.1. Diabetes Insipidus (DI)

DI is the most common disease-related conse-

quence that can predate the diagnosis or develop

anytime during the course of the disease [11, 12].

DI is found in up to 30% of patients [1], but may

reach to 40% in patients with multisystem dis-

ease or 94% in the presence of other pituitary

deficiencies, respectively [11, 13]. In the pres-

ence of polyuria and polydipsia, and/or structural

abnormalities of the HP region investigations to

confirm DI should be undertaken (see 2.4.1.7.)

and when present promptly treated with desmo-

pressin (see 4.5.).

2.4.1.2 Anterior Pituitary Hormonal Deficiencies

Anterior pituitary dysfunction is found in up to

20% of patients almost always associated with DI

[11, 14]. Similar to DI, LCH-induced anterior

pituitary deficiencies (APD) need appropriate

replacement therapy since they appear to be per-

manent. GH deficiency (GHD) is the most fre-

quent disease-related APD found in up to 50% of

patients with DI [13]. In adults there are no spe-

cific GHD-related symptoms that can suggest the

diagnosis, as growth arrest that develops in child-

ren, and may be missed if not specifically consi-

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dered. GHD might also develop following thera-

peutic pituitary irradiation even in doses ranging

from 15 to 30 Gy [15]. The effect of irradiation

may apply for all other APDs, as well.

Gonadotropin deficiency is the second most

common deficiency, presenting with menstrual

disturbances in women and decreased libido in

men [13]. ACTH deficiency is relatively rare

and, apart from a few exceptions, it develops in

the context of panhypopituitarism. ACTH defi-

ciency may be partial or complete and present

either with non-specific symptoms or as acute

adrenal insufficiency following stressful events.

TSH deficiency is almost always associated with

panhypopituitarism and may present with subtle

symptoms and signs of hypothyroidism. Mod-

erately elevated PRL levels attributed to pituitary

stalk infiltration can cause galactorrhoea in fe-

males and gonadotropin deficiency in all patients

with intact pituitary function.

2.4.1.3. Hypothalamic involvement

Hypothalamic involvement is less frequent than

pituitary involvement leading to pituitary dys-

function, neuropsychiatric and behavioral disord-

ers, disturbances of thermo-regulation and sleep-

ing pattern, and autonomic and metabolic abnor-

malities. The most frequent consequence is se-

vere obesity due to increased appetite, whereas

hypothalamic-related adipsia may seriously com-

plicate the management of DI.

2.4.1.4. Metabolic abnormalities

One study has shown that adults with LCH are at

high risk of developing abnormalities of carbo-

hydrate (diabetes mellitus, impaired glucose

tolerance) and lipid metabolism secondary to the

disease’s inflammatory process, hormonal defi-

ciencies and/or concomitant medication, leading

to increased insulin resistance even in the ab-

sence of obesity [16].

2.4.1.5. Bone metabolism

Adults with LCH may present with a lower than

expected bone mineral density at any age espe-

cially during periods of active disease. Either

osteoporosis or osteopenia might be frequent in

postmenopausal women and men over 50-years

old. [17].

2.4.1.6. Other endocrine tissue involvement

The thyroid gland may occasionally be involved

in the disease process while fine needle aspira-

tion or even histological specimens may be mis-

taken with thyroid carcinoma. Unlike the lower

genital tract, ovaries are quite rarely involved,

mostly in the context of disseminated disease.

Adrenal infiltration has been described in autop-

sy series although without any obvious clinical

findings. Pancreatic involvement is also extreme-

ly rare, although there are reports of glucose

metabolism abnormalities secondary to pancrea-

tic and/or hepatic infiltration and dysfunction.

2.4.1.7. Investigation of hormonal deficiencies

A plasma osmolality in the range of 280-

295mOsmol/Kg in combination with a urine to

plasma osmolality ratio > 2:1 exclude apparent

DI, whereas a water deprivation test is usually

required to reveal cases of partial DI. An early

morning serum cortisol level ≥ 500 nmol/l (18

μg/dl) virtually excludes ACTH deficiency, whe-

reas a cortisol level < 100 nmol/l (3.6 μg/dl) is

suggestive of ACTH deficiency. For intermediate

serum cortisol values an insulin tolerance test

(ITT), if not contra-indicated, can access the

adequacy of hypothalamic (HP)-adrenal axis as

well as GH reserve. Although an insulin-like

growth factor I (IGF-I) level below the age-

adjusted normal range may be suggestive of

growth hormone deficiency (GHD) is not as

reliable as the GH response to the ITT or other

dynamic tests. Low basal gonadal steroids along

with low gonadotropin levels in the presence of a

relevant clinical setting are suggestive of hypo-

gonadotropin hypogonadism. Occasionally in

young females with menstrual disturbances and

low oestradiol levels, failure of gonadotropin

levels to rise in response to clomiphene stimula-

tion is required to confirm the diagnosis. Finally,

lack of TSH elevation in the presence of a low

serum T4 level is indicative of TSH deficiency in

the absence of the non-thyroidal illness syndrome

(NTIS).

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2.4.2. Dermatological involvement

Skin involvement in the adult patient is a com-

mon presentation of LCH and can be protean.

Cutaneous LCH can be the great pretender, mi-

micking a number of common dermatoses, and may represent the earliest sign of the disease

[18]. As in childhood disease, a common manife-

station is with scalp involvement. The typical

lesions are small translucent papules, 1-2 mm in

diameter, slightly raised and rose-yellow in co-

lour; these lesions frequently show scaling or

crusting, often leading to a misdiagnosis of se-

borrheic dermatitis. However, unlike seborrheic

dermatitis, scalp LCH generally shows petechial

haemorrhages which should help to differentiate

it. Scaling and crusted lesions of the scalp simu-

late also tinea favosa. Pustules, which are com-

monly seen on the scalp, may be misdiagnosed as

decalvant folliculitis or erosive pustular dermato-

sis of the scalp.

In adults, intertriginous involvement is often see,

the mainly affected skin folds being axillary,

inguinal and anogenital. This presents with ery-

thema and erosions, which are frequently mis-

diagnosed as eczema or psoriasis, but the lesions

may be interpreted as a Candida infection or

simply intertrigo; in these locations, Haley-Haley

disease should also be considered. Pustular le-

sions involving the major cutaneous folds lead to

the suspicion of hidradenitis or a new clinical

entity within the spectrum of neutrophilic derma-

toses, the so-called amicrobial pustulosis of the

folds. A common presentation in men is with

severe pruritus ani and ulceration around the

anus; vulval irritation and ulceration is also not

uncommon. Ulcerative lesions and ulcerated

nodules located to the anogenital area may mimic

several conditions, both inflammatory, notably

pyoderma gangrenosum and Crohn’s disease, and

neoplastic, particularly extramammary Paget’s

disease and Bowen’s disease, as well as infec-

tious and sexually transmitted diseases such as

orificial tuberculosis and chancroid, respectively.

Generalised skin eruptions can look like guttate

psoriasis with erythematous scaly patches cover-

ing the body, or prurigo nodularis with small

hard papules and nodules, particularly on the

trunk. Multiple erythematous papules involving

mainly the trunk and extending to the extremities

may also resemble lichen planus, especially the

follicularis variant, or a lichenoid dermatitis of

different causes; if vesicles are associated, the

lesions can mimic varicella. When the cutaneous

picture is polymorphic with papules, vesicles and

necrotic-ulcerative lesions, acute pytiriasis liche-

noides of Mucha-Habermann can be misdiag-

nosed. In addition to the more widespread dis-

ease, isolated erythematous papules may be the

only manifestation with some patients only pre-

senting with a single lesion and the diagnosis is

only made when the lesion is removed for cos-

metic reasons or due to concern about the possi-

bility of a skin tumour. In fact, a single papule or

nodule can suggest several neoplastic conditions,

most notably cutaneous lymphomas, epithelial or

adnexal tumours, sarcomas and metastases.

Overlying involved lymph nodes or bone, LCH

can present as ulceration or persistant sinus ana-

logous to tuberculous scrofuloderma. Gum in-

volvement is a common presentation in the adult

patient, almost always associated with alveolar

bone involvement and loosening of the teeth. It is

very important not to allow the dentist to extract

the teeth as with treatment they will embed into

the recovering alveolar bone. Nodular-ulcerative

lesions involving the gums resemble the so-

called strawberry gingivitis of Wegener’s granu-

lomatosis, which is an unique form of gingival

hyperplasia also mimicking that seen as possible

side effect of oral cyclosporine. Nail changes,

include paronychia, onycholysis, subungueal

hyperkeratosis and purpuric striae of the nail bed,

suggesting a wide panel of conditions that affect

the nails. Dark-brown striae similar to those

drug-induced are also seen.

In conclusion, due to its polymorphism to make

the diagnosis of cutaneous LCH you need a high

level of suspicion and biopsy is essential. Al-

though skin disease may be the primary presenta-

tion you must investigate the patient for other

system disease.

2.4.3 Gastrointestinal involvement

Gastrointestinal (GI) tract involvement by LCH

is a rare condition. In adults, it may appear as an

incidental solitary colorectal polyp or as multiple

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granulomatous lesions of the mucous membrane

in the upper and lower GI tract [19]. Patients are

often asymptomatic. Multiple infiltrations are

associated with systemic disease. In asymptomat-

ic patients, endoscopy is not obligatory on stag-

ing.

Table 4 Specific Clinical Scenarios: Recommended Additional testing

Agree- ment

►History of Polyuria or Polydipsia ♦ Urine and plasma osmolality +

♦ Water deprivation test +

♦ MRI of the head ► Suspected Other Endocrine Abnormality ♦ Endocrine assessment (including dynamic tests of the anterior pituitary, MRI of the head, see 2.4.1.7)

+

+

►Bicytopenia, Pancytopenia, or Persistent Unex-plained Single Cytopenia

♦ Any other cause of cytopenia has to be ruled out according to standard medical practice.

+

♦ Bone marrow aspirate and trephine biopsy to exclude causes other than LCH.

+

♦ In case of morphological signs of hemopha-gocytosis additional tests like serum-ferritin should be performed (criteria of HLH)

+

►Liver or Spleen Abnormalities ♦ In case of any unclear sonographically

pathology CT, PET-CT, MRI or Scans should be added (the choice is depending on the sono-morphology – discuss with your radiologist)

+

♦ Visuable lesions of the liver should be biopsied if possible

+

♦ Other causes of splenomegalie has to be ruled out before it may be assigned to LCH

+

♦ ERCP (Endoscopic Retrograde Cholangio-pancreatography) should be performed in case of elevated serum cholestasis markers or sonomor-phologically dilatated bile ducts.

Primary biliary cirrhosis and primary sclerosing cholangitis have to be ruled out.

+

►Enlarged Lymph Nodes (LN) ♦ If found by screening ultrasound or physical

examination the best suitable LN should be ex-stirpated. A LN needle biospsy should be avoided.

+

♦ CT scans or a PET-CT should be performed additionally

+

►Lung Involvement

In case of abnormal Chest X Ray or symp-toms/signs suggestive for lung involvement or suspicion of a pulmonary infection:

♦ Lung high resolution computed tomography (HR-CT)

+

♦ Lung function test + ♦ Bronchoalveolar lavage (BAL): > 5% CD1a +

cells in BAL fluid may be diagnostic of LCH in a non-smoker

+

♦ Lung biopsy (if BAL is not diagnostic) or Video-assisted thoracoscopic surgery

(VATS)

+

►Osseous Disease ♦ MRI should be performed in case of cra-

niofacial or vertebral lesions or signs of additional soft tissue involvement

♦ Biopsie should be taken from the most suitable region in case of multifocal bone disease

+ +

► Skin, Oral and Genital Mucosa lesions ♦ Biopsie should be taken

+

► Aural Discharge or Suspected Hearing Impairment

/ Mastoid Involvement ♦ Formal hearing assessment ♦ MRI of head ► Visual Abnormalities ♦ Ophthalmological assessment ♦ MRI of head ► Neurological or cognitive Abnormalities ♦ Neurological/Neuropsychometric assessment ♦ MRI of head

+ + + + + +

►Unexplained Chronic Diarrhea, Weight loss, Evi-

dence of Malabsorption or Hematochezia ♦ GI-Exploration (Endoscopy with biopsies,

capsule endoscopy)

+

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2.5. DEFINITION OF ORGAN INVOLVEMENT

2.5.1. Possibly Involved Organs

After the diagnosis of LCH has been made, in-

volvement of other organs should be evaluated

and defined according to the clinical, biological

or radiological criteria.

2.5.2. Risk Organs

Based on previous experience of pediatric stu-

dies, disease involvement in the hematopoietic

system, spleen, liver or CNS is a marker of a less

favorable prognosis, even of mortality if the pa-

tient does not respond to standard therapy. Al-

though this has never been proved for adults,

retrospective analyses of national registries and

the experts experience support the existence of

the above mentioned “risk organs” even in this

age cohort.

Beside the type of the involved organ clinical

pictures like B-symptoms (fever, night-sweats

and weight loss) combined with significantly

reduced general condition might predict the rare-

ly observed aggressive course of LCH in adults

comparable to that of high grade Non Hodgkin

lymphoma [20, 21].

2.5.3. “Special Sites”

In certain situations, such as vertebral lesions

with intraspinal or cranofacial bone with intra-

cranial soft tissue extension, lesions are located

in functionally critical anatomical sites. These

lesions may cause immediate risk to the patient

because of the critical anatomical site and the

hazards of attempting local therapy. Isolated

disease in these “Special Sites” may justify sys-

temic therapy, especially in childhood. Alterna-

tively irradiation might be considered in adults.

These lesions need to be distinguished from other

bone lesions.

In children other “Special Sites” are craniofacial

bone lesions that are associated to diabetes insi-

pidus, which can either develop on a long term or

can be present first. It is unclear if that might be

extrapolated to adults.

3. STRATIFICATION

3.1. CLINICAL CLASSIFICATION

3.1.1. Single System LCH (SS-LCH)

One organ/system involved (uni- or multifocal):

Bone: unifocal (single bone) or multi-

focal (> 1 bone)

Skin

Lymph node

Hypothalamic-pituitary / Central nerv-

ous system

Lungs (primary pulmonary LCH)

Other (e.g. thyroid, gut)

3.1.2. Multisystem LCH (MS-LCH)

Two or more organs/systems involved:

With involvement of “Risk Organs”

(Hematopoietic system, spleen, and/or

liver, tumorous CNS)

Without involvement of “Risk Organs”

4. TREATMENT

4.1. MANAGEMENT ALGORITHMS

Treatment recommendations are based on site

and extension of the disease

Figure 1: Management of Langerhans Cell Histi-

ocytosis in adults

Diagnosis LCH (Table 2)

Primary

pulmonary

LCH

Single system

LCH

Multi system

LCH

Pretreatment clinical evaluation(Table 3 and 4)

Is therapy required ?

Follow up (Table 7)

Local therapy Table 5

No

Multifocal

or special site

Figure 2

Yes Single site

Euro Histio Net Guidelines November 2011, Version 1.1on 1

Page 10 of 18

Figure 2: Management of pulmonary LCH in

adults

(will be added finally)

4.2. LOCAL THERAPY OR CAREFUL OBSERVATION

In case of single system LCH with unifocal bone

involvement of non-“CNS-Risk facial bones)

local therapy or careful observation is recom-

mended. The modality of treatment depends on

location, size, and symptomatic of the disease.

Observation can be sufficient in non-risk lesions.

Biopsy or curettage is suitable for histopatholog-

ic diagnosis and initiating a healing process. To

accelerate this process, intralesional injection of

steroid is suggested. Dosages of 40 – 160 mg of

methylprednisolone have been used [22]. Com-

plete excision is only necessary in risk of frac-

ture, usually in combination with a reconstructive

procedure. Radiotherapy is indicated if there is

an impending neurological deficit and a high

surgical risk, e.g. lesion in the odontoid peg or

cranial base (see 4.7). For multifocal bone LCH

and for bone lesions in “special sites” systemic

therapy should be given (see 2.5.3).

Isolated involvement of lymph nodes is rare but

spontaneous regressions were observed repeated-

ly. So, watchful waiting may be adequate in cas-

es of adult lymph node LCH (e.g. isolated cer-

vical lymph nodes [23]).

Skin Involvement: Treatment of skin disease will

depend on a number of factors:

i) Single system disease versus multisys-

tem disease;

ii) Site of involvement – mucosal versus

glabrous skin;

iii) Extent of the disease;

iv) Response to previous treatment.

In general, if the patient is being treated for mul-

tisystem disease, the skin disease will respond to

treatment as the skin is probably the most res-

ponsive organ. In single system skin disease or

in the rare instance where the skin fails to re-

spond fully to systemic treatment for multisys-

tem disease, there are a number of treatments

that have been used that can be directed specifi-

cally to the skin:

Topical nitrogen mustard:

20% nitrogen mustard applied to the skin has

been shown to be an effective treatment in child-

ren [24]. There is no published data on treatment

in adults and there are problems with availability

in most countries.

Phototherapy: Psoralen plus ultraviolet A (PU-

VA) [25] and narrow band ultraviolet (UV) B

[26] have been shown to be effective in treating

cutaneous LCH in individual case reports. The

Langerhans cell is very sensitive to ultraviolet

light, so response to UV treatment is not surpris-

ing. It is difficult to treat patients with intertri-

ginous or scalp involvement and would be con-

traindicated in penile disease. Certainly failures

on both PUVA and narrow band (TLO1) light

treatment have been observed.

Thalidomide: is a TNF-α antagonist and has been

shown to be effective in treating cutaneous LCH

[27] but gives poor responses in high risk multi-

system disease [28]. Dose of 100mg/day in adults

is generally used but toxicity with peripheral

neuropathy is not uncommon.

Azathioprine: There are no published reports of

the use of azathioprine (or its metabolite 6-

mercaptopurine) in adults with cutaneous LCH

but it is a very useful drug in single system skin

as well as multisystem disease. Patients need to

be tested for thiopurine methyl transferase, and if

normal should be treated at a dose of

2mg/kg/day. The drug takes about 6 weeks to

become effective.

Methotrexate: There is only few published data

on the use of low dose methotrexate as either

single agent treatment or in combination with

azathioprine or prednisolone. Methotrexate was

used successfully at the dosages of 20mg once

weekly [29] .

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4.3. SYSTEMIC THERAPY

4.3.1. Front Line Treatment

Systemic therapy should be considered in case of

the following disease category:

MS-LCH with/without involvement of “risk

organs”

SS-LCH with multifocal lesions

SS-LCH with “special site” lesions

There is no consensus for one special schedule of

first line therapy. Vinblastin/Prednisolon is men-

tioned in various chemotherapeutical manuals as

standard therapy, but has never been proved

prospectively for adults. An attempt of an inter-

national trial failed due to the aggravation of the

regulations for academically trials resulting in a

low recruitment rate and premature closing. Nev-

ertheless this schedule is effective as published in

numerous case reports, but the risk of neuropathy,

especially in patients with co-morbidities like

diabetes mellitus has to be taken into account.

Therefore some experts prefer monotherapy with

Cytarabine or Etoposide alternatively.

Patients with mild symptoms and lacking risk

organ involvement may be treated with a more

immunosuppressive than cytotoxic attempt

represented in drugs like Methotrexate, 6-Mer-

captopurine or Azathioprine. In multifocal bone

disease bisphosphonates [30] are used front-up,

but patients have to be advised to the risk of os-

teonecrosis of the jaw and its prevention (dental

hygiene). Against pain of bony lesions COX-

Inhibitors might be more than an analgetic drugs

and regression of LCH was observed [31] .

Most experts prefer to start initially with 2-CDA

in case of risk organ or tumorous cerebral in-

volvement.

4.3.2. Evaluation of Response

Using Vinblastin/Prednisolon therapy response

assessment is generally performed at week 6 (re-

garding to the pedriatic studies). In other scedules

the evaluation has to be done after 2 to 3 cycles of

chemotherapy as usually in malignant disorders.

LCH may be quite unpredictable and recurrences

or reactivations of the disease may occur. In the

case of clinical suspicion for disease progression

or reactivation, complete evaluation as recom-

mended in the previous section 2 has to be per-

formed in order to make decisions on further

treatment strategy.

4.3.3. Maintenance Therapy

Having started with Vinblastin/Prednisolon main-

tenance therapy comparable to that in pediatric

protocols is used for 6 to 12 months (3-weekly

with addition of continuously oral 6-MP). Other

chemotherapeutical drugs (ARA-C, VP-16 or 2-

CDA) are usually administered, depending on

response up to 6 cycles.

4.3.4. Salvage Therapy

Refractory disease should be treated with 2-CDA.

In case of further progression, especially in CNS

involvement Cytarabine may be added [32]. In the

rare case of a most aggressive course of disease

hematopoietic stem cell transplant has been per-

formed successfully as well [33, 34].

4.4. TREATMENT OPTIONS IN CASE OF REACTIVATION

Reactivations of LCH in adults occur in about 1/4

of the patients (registry data). Patients may have

further reactivations in course, which seems to be

more often in multisystem disease.

4.4.1. Reactivation of Single System Disease

The choice of treatment options is based on the

same principles as for initial disease.

The options for reactivations of SS-LCH (skin,

bone, other) include

I. Wait and watch approach

II. Local therapy including irradiation (as

above)

III. bisphosphonates for bony disease (as

above)

IV. Chemotherapy (as above)

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In case of a multisystemic reactivation of a SS-

LCH, treatment should follow the options for MS-

LCH including systemic therapy (see 4.3. and

4.4.2.).

4.4.2. Reactivation after Systemic Therapy

I. If the reactivation is more than one year after

completion of treatment, re-induction with the

prior used chemotherapy may be effective and

there is no need to switch to alternative thera-

py. If however, the disease is not responsive

we suggest discussion with the reference cen-

tre for your country.

II. If reactivation occurs while on treatment,

potentially 2nd line strategies are described in

4.3.4, but should be generally discussed with

your reference centre, taking into account dis-

ease severity and the respective risk for unfa-

vorable outcome.

Table 5 First line systemic therapy Agree- Ment

►MILD SYMPTOMS, NO RISK ORGANS INVOLVED ♦ Methotrexate 20 mg per week p.o/i.v. ♦ Azathioprine 2 mg/kg/d p.o ♦ Thalidomide 100mg/d p.o in skin or soft tissue multifocal single system LCH

+ + +

►ADDITIONALLY IN MULTIFOCAL BONE LCH ♦ zoledronic acid 4 mg i.v. monthly

+

►SYMPTOMATIC, MS-LCH, NO RISK ORGANS INVOLVED ♦ Vinblastin/Prednisolon (like in pediatric studies) ♦ Cytarabine 100 mg/m² d1-5 q4w ♦ Etoposide 100 mg/m² d1-5 q4w ►MS-LCH, RISK ORGANS INVOLVED ♦ 2-CDA 6 mg/m² d1-5 q4w

o + +

+

4.5. TREATMENT AND HORMON REPLACEMENT OF

ENDOCRINOPATHIES

DI should be treated with desmopressin while the

timing and dosage must be individualized. In

proven LCH new onset DI is a sign of active dis-

ease and the LCH-CNS study group recommends

the initiation of systemic therapy (chemotherapy),

irrespective of the findings of HP region imaging,

to prevent further damage and hormonal deficien-

cies [35]. Radiotherapy, at doses up to 30Gy, has

been also used in cases with hormonal deficiencies

and radiological evidence of HP involvement.

Despite apparent radiological improvement, the

absence of significant clinical responses in combi-

nation with potential adverse late effects of the

treatment no longer suggest radiotherapy as the

treatment of choice[35]. Cytarabine may be a

reasonable therapy for patients with recurrent

LCH of the pituitary-hypothalamic region as this

drug has good penetration in the CSF.

Adequate replacement of hormonal deficiencies

should be initiated as soon the diagnosis is made.

There are currently no data regarding the adminis-

tration of GH in GHD adults, although it is ex-

pected to be beneficial in some somatometric and

metabolic parameters and improve quality of life.

In cases of gonadotropin deficiency fertility may

be achieved with exogenous gonadotropin admin-

istration. Adequate sex steroid replacement thera-

py is required in all patients not desiring fertility.

ACTH deficiency should be promptly replaced

with daily divided doses of hydrocortisone, and

levothyroxine replacement therapy should be ti-

trated to achieve mid-normal serum free T4 levels.

Dopamine agonists can be used for normalization

of PRL levels in case of hyperprolactinaemia-

induced gonadotropin deficiency.

4.6. CENTRAL NERVOUS SYSTEM INVOLVEMENT

4.6.1. Tumorous lesions

These lesions are most frequently observed in the

hypothalamic-pituitary region resulting in hor-

mone deficiencies, mainly diabetes insipidus cen-

tralis (DI) (see 4.5.). The tumor size ranges from

discrete thickening of the pituitary stalk to larger

tumors, latter have to be biopsied in case of idi-

opathic DI (no other apparent LCH involvement).

Parenchymal, meningeal or plexus choroideal

lesions occur less frequently[35].

In addition to hormone replacement therapy iso-

lated tumors should be treated if any locally with

surgery, irradiation or radiosurgery. In case of

multi system disease chemotherapy (most suitable

2-CDA +/- Cytarabine) has to be applied as de-

scribed in 4.3.1.

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Page 13 of 18

4.6.2. Neurodegerative LCH

Non-tumorous MRI findings (might be helpful to

have a baseline MRI to compare) of the cerebel-

lum, and/or brain stem are histopathologically

different to typical LCH granulomas (lack of

CD1a and predominantly CD8+ lymphocytes,

which may be interpreted as a further inflammato-

ry step of disease)[36]. Some of these patients

show no symptoms, others have clinical signs

ranging from subtile tremor, dysarthria, dysphagia,

and motor spasticity to pronounced ataxia, beha-

vioral disturbances and severe psychiatric disease.

Unfortunately none of the previous treatment

attempts (retinoic acid, intravenous immunglobu-

lin, chemotherapy) could sufficiently influence the

course of disease so far. Cytarabine with and

without vincristine was shown to be effective for

reversing the neurologic and radiographic signs of

ND-CNS LCH in 5/8 patients [37]. Thus for any

case of neurodegenerative LCH we suggest dis-

cussion with the reference centre for your country.

4.7. RADIOTHERAPY

In contrast to treatment of childhood LCH, Radio-

therapy is still a feasible and effective treatment

option for adult patients with LCH. It has a long

tradition and the first successful radiation of LCH

was described in 1930 by Sosman [38]. Since

then, the effectivity of radiotherapy in LCH has

been shown in a large number of publications (in

extracts [39-44]), but all studies reported in litera-

ture have a retrospective nature and in general the

number of patients is not large.

Radiotherapy indications should respect the age of

patients, the possibility of radiogenic malignan-

cies, and the semi-benign character of disease.

This kind of treatment should be considered as a

palliative measure only when it is clearly war-

ranted by the presence of disease progression or

when location and extent of disease threat the

function of critical organs [42].

In general, two radiotherapy indications must be

distinguished: The treatment of painful or unstable

uni- or multifocal bone lesions and the treatment

of extra-osseous soft tissue or organ involvement

[42].

Table 6 Possible Indications for the Use of Radiotherapy in Adults

Agree- ment

► “UNRESECTABLE” LESIONS (IF A RESECTION WOULD SIGNIFICANTLY COMPROMISE ANATOMIC FUNCTION, E.G. ODONTOID PEG, CNS )

+

► RECURRENT OR PROGRESSIVE LESIONS (IN MULTIFOCAL OR MULTISYTEM DISEASE ONLY IN CASE OF MINOR RES- PONSIVESS TO STANDARD SYSTEMIC THERAPY) ► ADJUVANT TREATMENT FOLLOWING MARGINAL OR INCOMPLETE RESECTION (ESPECIALLY IN SINGLE SYS- TEM BONE DISEASE WITH SOFT TISSUE INVOLVEMENT)

+

+

Most literature data concerning radiotherapy in

adult LCH deal with in uni- or multifocal osseous

single-system disease. Summarizing the results in

these bone lesions, the local control rates ranged

from 75-100%, complete remission from 79-

100%, respectively. There is not much data in the

literature on radiotherapy in non-osseous single-

system disease, mostly presented as single case

reports. Nevertheless, in most cases a complete

remission is reported. Bony lesions are the predo-

minantly irradiated manifestations also in multi-

system disease. Local control rates ranged from

75% to 100%, complete remission rates were up to

85%. Thus in case of minor responsiveness to

standard systemic therapy Radiotherapy may be

considered as an additive treatment in multifocal

or multisystem disease.

Osseous and visceral lesions should be treated

with megavolte equipment (Linear accelerator),

whereas superficial x-rays or fast electrons are

used for cutaneous or subcutaneous lesions. In

external beam radiotherapy, individually opti-

mized radiation set-up and shielding using a mod-

ern three-dimensional conformal radiotherapy

technique should be used to minimize the volume

of not affected tissue neighboring the disease le-

sion. An adequate margin of 1-2 cm of normal

tissue around the treated lesion should be in-

cluded, but in bony lesions the whole bone must

not to be included [45].

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The dose recommendation for radiotherapy is still

controversial, because the optimal dose is not well

defined, and an exact dose-effect relationship has

not been established. There is a wide dose range of

applied total doses from 1,4 Gy up to 45 Gy. In

general, a dose range from 10 to 20 Gy is recom-

mended in adults but a dose range from 12-14 Gy

should sufficient for local control. Such total doses

should be delivered in fractions of 1-2 Gy per day

to avoid a possibly limited capacity for tissue

repair mechanisms in larger single doses [42, 46]).

Acute side effects of radiotherapy depend on the

localization of the irradiated body site. As the

applied total dose rarely exceeds 20 Gy, both

acute and subacute side effects are rare. Most

literature data do not provide any information

about acute side effects of radiotherapy. Late side

effects of radiotherapy are also rare due to the low

applied dose range. The only risk, which should be

mentioned, is the extremely low one of radiation-

induced carcinogenesis. Greenberger et al. (1979)

reported a rate of 3.9% for induction of malignant

tumors, but this data should be interpreted with

care, because many children were treated in this

collective. Even though the doses applied for local

control in adult LCH are low, several publications

in the literature describe the induction of leukae-

mias, osteosarcomas, teratoma, malignant menin-

gioma, thyroid and liver tumors (Heyd et al.

2000), but you should take in mind that most stu-

dies also treated children, who bear a much larger

risk of cancer induction, and there is a well-known

tendency of patients with LCH to develop malig-

nancies independently of therapies.

Finally, the radiation treatment technique has

substantially improved during the last decade

becoming a precise and normal tissue sparing

instrument. Nevertheless, the indication for radio-

therapy for a palliative treatment in LCH has to be

accurately set up with and the potential benefits of

radiation treatment must be carefully weighed

against its possible.

The exact target cells or structures affected by

radiotherapy in LCH remain unclear. Low doses

of radiotherapy not reaching a normal cell-killing

level have been shown to heal the disease, result-

ing in theories, that either radiotherapy suppresses

an inflammatory process and so reduces the de

novo- fraction of Langerhans cells, or that Lan-

gerhans cells themselves are a very sensitive

population to irradiation [43].

5. PRIMARY PULMONARY LCH (BY TAZI AND

FICHTER ) EXPECTED AT THE END OF 2011 6. PREGNANCY There are only a few reports about pregnancy and

LCH with worsening to no change of clinical

symptoms, but even improvement was observed.

In case of deterioration this was mainly related to

diabetes insipidus. But it is unclear, if worsening

or onset of DI during pregnancy is really caused

by LCH. This may also be observed in women

without suffering from a histiocytic disorder and

is caused by an accelerated degradation of vaso-

pressin through placental enzyme vasopressinase

[47].

Generally it is unpredictable if and in which way

pregnancy may influence the course of LCH. Oth-

erwise women may be pacified that vice versa no

adverse impacts of LCH on pregnancy or birth,

with exception of need for cesarean section in case

of involvement of the vulva have been reported

[48, 49].

7. FOLLOW UP 7.1. FOLLOW-UP

LCH may reactivate in course and induce organ

dysfunction. Moreover, LCH is associated with

malignant tumors. Therefore, follow-up investiga-

tions of disease and monitoring of functional im-

pairments are necessary.

During treatment, reevaluations are useful at each

parenteral application of cytostatic chemotherapy

or every 6 to 12 weeks in case of peroral cytostatic

or immunosuppressive treatment. The reevaluation

has regard to the known disease manifestations

and to new complaints of the patients. Follow-up

intervals depend on the primary extent and activity

Euro Histio Net Guidelines November 2011, Version 1.1on 1

Page 15 of 18

of disease with controls within 3 to 12 months (see

table 5). In case of affirmed reactivation, clinical

evaluation should include all investigations listed

above (chapter 2).

7.2. FOLLOW-UP, MONITORING OF ENDOCRINOLOGI-

CAL CONSEQUENCES

In case of established DI and/or APDs endocrino-

logical follow-up is warranted, at least on a yearly

basis, in order to insure adequate replacement

therapy and identify other evolving deficiencies.

In the absence of any endocrine deficiencies the

presence of relevant symptoms or signs (see

2.4.1.1.-6.) should lead to endocrinological eval-

uation especially in patients with multisystem

active disease. In particular, patients with long

acting and/or reactivating disease are adviced to

have a 6- or 12-month plasma and urine osmolali-

ty, morning serum cortisol and free T4 levels mea-

surement to exclude the more compelling diag-

noses. Finally, among patients with multisystem

disease a basal HP region MRI might prove very

helpful regarding future LCH-induced structural

changes.

Table 7 Recommendations for follow-up

TEST FREQUENCY Agree ment

► ALL PATIENTS WITH SINGLE SYSTEM DISEASE AND WITH

NO DISEASE ACTIVITY

♦ History (especially of thirst, polyuria, cough, dyspnea, bone pain, skin changes, neurological symptoms)

- Every clinic visit +

♦ Clinical assessment, blood count and blood chemi-stry (as described in baseline diagnostics), ultrasound, Chest XR

- End of therapy - every 6 month for

the next 2 years - then once a year for

at least 3 years

+

+

+

► ALL PATIENTS AFTER MULTI SYSTEM THERAPY AND

WITH NO DISEASE ACTIVITY

♦ History, especially of thirst, polyuria, cough, dyspnea, bone pain, skin changes, neurological symptoms.

- Every clinic visit +

♦ Clinical assessment, blood count and blood chemi-stry (as described in baseline diagnostics), ultrasound, Chest XR

- End of therapy - every 3 month for

the next 2 years - every 6 month for

the next 3 years - then once a year for

at least 5 years

+

+

+

+

♦ TSH, free T4 Once a year until end

of routinely follow up

+

► PATIENTS WITH ACTIVE DISEASE

♦ diagnostic procedures are depending on the site of organ involvement

Frequency is de-pending on rates and velocity of re-currences

+

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5. REFERENCE LIST:

1. Arico, M., et al., Langerhans cell histiocytosis in adults. Report from the International Registry of the Histiocyte Society. Eur J Cancer, 2003. 39(16): p. 2341-8.

2. Willman, C.L., et al., Langerhans'-cell histiocytosis (histiocytosis X)--a clonal proliferative dis-ease. N Engl J Med, 1994. 331(3): p. 154-60.

3. Badalian-Very, G., et al., Recurrent BRAF mutations in Langerhans cell histiocytosis. Blood, 2010. 116(11): p. 1919-23.

4. Egeler, R.M., et al., Association of Langerhans cell histiocytosis with malignant neoplasms. Cancer, 1993. 71(3): p. 865-73.

5. Lee, J.S., et al., Langerhans cell sarcoma arising from Langerhans cell histiocytosis: a case report. J Korean Med Sci, 2006. 21(3): p. 577-80.

6. Lau, S.K., P.G. Chu, and L.M. Weiss, Immunohistochemical expression of Langerin in Langer-hans cell histiocytosis and non-Langerhans cell histiocytic disorders. Am J Surg Pathol, 2008. 32(4): p. 615-9.

7. Swerdlow, S.H., C. International Agency for Research on, and O. World Health, WHO classifi-cation of tumours of haematopoietic and lymphoid tissues. 2008: International Agency for Research on Cancer.

8. Valladeau, J., et al., Langerin, a novel C-type lectin specific to Langerhans cells, is an endocytic receptor that induces the formation of Birbeck granules. Immunity, 2000. 12(1): p. 71-81.

9. Arico, M., et al., Familial clustering of Langerhans cell histiocytosis. Br J Haematol, 1999. 107(4): p. 883-8.

10. Phillips, M., et al., Comparison of FDG-PET scans to conventional radiography and bone scans in management of Langerhans cell histiocytosis. Pediatr Blood Cancer, 2009. 52(1): p. 97-101.

11. Kaltsas, G.A., et al., Hypothalamo-pituitary abnormalities in adult patients with langerhans cell histiocytosis: clinical, endocrinological, and radiological features and response to treat-ment. J Clin Endocrinol Metab, 2000. 85(4): p. 1370-6.

12. Prosch, H., et al., Central diabetes insipidus as presenting symptom of Langerhans cell histi-ocytosis. Pediatr Blood Cancer, 2004. 43(5): p. 594-9.

13. Makras, P., et al., Endocrine manifestations in Langerhans cell histiocytosis. Trends Endocri-nol Metab, 2007. 18(6): p. 252-7.

14. Amato, M.C., et al., Endocrine disorders in pediatric - onset Langerhans Cell Histiocytosis. Horm Metab Res, 2006. 38(11): p. 746-51.

15. Donadieu, J., et al., Incidence of growth hormone deficiency in pediatric-onset Langerhans cell histiocytosis: efficacy and safety of growth hormone treatment. J Clin Endocrinol Metab, 2004. 89(2): p. 604-9.

16. Alexandraki, K.I., et al., Cardiovascular risk factors in adult patients with multisystem Langer-hans-cell histiocytosis: evidence of glucose metabolism abnormalities. QJM, 2008. 101(1): p. 31-40.

17. Makras, P., et al., Reduced bone mineral density in adult patients with Langerhans cell histi-ocytosis. Pediatr Blood Cancer, 2011.

18. Caputo, R., A Text Atlas of Histiocytic Syndromes. 1998: Informa HealthCare. 19. Singhi, A.D. and E.A. Montgomery, Gastrointestinal tract langerhans cell histiocytosis: A clini-

copathologic study of 12 patients. Am J Surg Pathol, 2011. 35(2): p. 305-10. 20. Szturz, P., et al., [Lymphoma-like course in aggressive adult multisystem Langerhans cell his-

tiocytosis and the benefit of PET/CT imaging in evaluation of diffuse metabolic activity of lung parenchyma]. Vnitr Lek, 2010. 56(11): p. 1177-93.

21. Teng, C.L., et al., Rapidly fatal Langerhans' cell histiocytosis in an adult. J Formos Med Assoc, 2005. 104(12): p. 955-9.

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22. Yasko, A.W., et al., Percutaneous techniques for the diagnosis and treatment of localized Lan-gerhans-cell histiocytosis (eosinophilic granuloma of bone). J Bone Joint Surg Am, 1998. 80(2): p. 219-28.

23. Lo, W.C., et al., Isolated adult Langerhans' cell histiocytosis in cervical lymph nodes: should it be treated? J Laryngol Otol, 2009. 123(9): p. 1055-7.

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