Langerhans Cell Histiocytosis (Lch)

Euro Histio Net Guidelines November 2011, Version 1.1on 1

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 Chu2, Claus Doberauer3, Joachim Fichter4, Michael Girschikofsky (Executive Editor)5; Julien Haroche6, Gregory A. Kaltsas7, Polyzois Makras8, Angelo V. Marzano9, Kenneth L. McClain10, Mathilde de Menthon11, Oliver Micke12, Emanuela Passoni9, M. Heinrich Seegenschmiedt13, Abdellatif Tazi14, Diego C. Villegas15.

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 of the following recommendations is predomi- AND RESTRICTIONS: nantly attributed to the level of expert opinion.

There are no universally accepted international This paper cannot replace the physician’s own guidelines available for the diagnosis and treat- professional judgment based on the patient’s ment of adult patients in contrast to childhood special clinical circumstances. Due to the diversi- LCH. Clinical Study results as a backbone for ty of clinical course of LCH, even recommenda- strong evidence-based recommendations are also tions which are established as standard of care missing. In this field a literature search results may need to be critically appraised in an individ- mainly in single case or small series reports and ual case. We suggest that you never hesitate to the largest number of patients was published in a contact LCH experts in case that the clinical pooled retrospective analysis from several na- course raises questions or doubts. An appropriate tional registries [1]. web-based platform will be available shortly for medical colleagues as well as patients on the Based on the available literature up to June 2011, home-page of the EHN (http://www.eurohistio.net/ but even more on their personal experience the index_eng.html). following recommendations were designed and established by an international group of physicians. These individuals are academic clinicians GENERAL CONSIDERATIONS who have worked in the field of histiocytic disorders, are leaders of the national registries, ac- The etiology of LCH is unknown. LCH cells are tive members of different national societies and clonal [2] and cancer-associated mutations were of the international medical society of histiocyto- found in more than a half of investigated speci- sis (Histiocyte Society). mens, indicating that LCH may be a neoplastic disease [3]. There seems to be an association Drafts were commented by the entire group and between LCH and malignant tumors as well. In redrafted by the executive editor. Final agree- most cases, LCH occurs before or concurrently ment was by consensus. The quality of evidence with the associated neoplasma, histopathological- Page 1 of 18

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ly mainly lymphomas or solid tumors. An ap- One of the main problems of LCH in adults is the pearance of leukemia is found more frequently variety of potentially involved organs, which after LCH and is presumably more often related results in a large number of different physicians to therapy than a de-novo disease [4]. who may be consulted at the time of the first contact. Thus, in many cases only the apparently The disease may affect any organ or system of affected site is recognized and a complete exami- our body, but those more frequently affected are nation in order to detect the whole extent of the the bone, skin, and pituitary gland. Other organs disease is unfortunately often not done. often involved are the lymph nodes, liver, spleen, gut, the central nervous system excluding the Based on the mentioned considerations we report pituitary, extremely rare the hematopoietic sys- the level of agreement between experts (see table tem. Although the lungs may be affected simul- 1). taneously with other organs an isolated pulmonary LCH is observed more frequently and represents a special form of adult LCH. There- fore this manifestation is highlighted in an own Table 1 Determination of the Level of Agreement chapter. AGREEMENT CRITERIA Generally clinical manifestations of the disease + According evidence and/or general vary depending on the organ or system affected, agreement ranging from an isolated lesion as in the skin or in the bone, to a more severe clinical manifes-  Discussed evidence and/or discussed tations affecting the same tissue in multiple sites, recommendation, but no strong objec- or several organs. The clinical course may vary tions from self-limiting and self-healing disease to a chronic recurrent one. But in contrast to LCH in – Conflicting evidence and/or diver- gence of opinion childhood a rapid progressive form is usually not observed in adults and accordingly other malignant histiocytic disorder should be considered and excluded, respectively. Langerhans cell sarcoma can occur as well de novo as from an ante- cedent LCH [5]. In this chapter we do not discuss 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 symptom 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 diagnosis is confirmed, it is important to have the diagnostic and the clinical work-up performed according to uniform recommendations. Page 2 of 18

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TABLE OF CONTENTS 8. REFERENCE LIST

1. DIAGNOSIS 1. DIAGNOSIS 1.1. Biopsy and Histological Examination 1.1. BIOPSY AND HISTOLOGICAL EXAMINATION 1.2. Diagnostic Criteria The diagnosis of LCH should be based on histo- 2. PRETREATMENT CLINICAL EVALUATION logical and immunophenotypic examination of a 2.1. Complete History 2.2. Complete Physical Examination biopsy of the lesional tissue. Biopsy should be 2.3. Laboratory and Radiographic Evalua- taken from the most accessible organ: skin if tion involved; while in case of multiple skeletal in- 2.4. Specific Clinical Scenarios and Recom- mended Additional Testing volvement, the bony lesion that is most easily 2.4.1. Endocrinological dysfunction accessible should be chosen for biopsy. The 2.4.1.1. Diabetes insipidus main diagnostic feature is the morphologic iden- 2.4.1.2. Anterior Pituitary Hormonal tification of the characteristic LCH cells, but Deficiencies 2.4.1.3. Hypothalamic involvement positive staining of the lesional cells with CD1a 2.4.1.4. Metabolic abnormalities and/or Langerin (CD207) is required for defi- 2.4.1.5. Bone metabolism nitive diagnosis [6-8]. Electron microscopy is no 2.4.1.6. Other endocrine tissue in- longer recommended since it has been shown that volvement 2.4.1.7. Investigation of hormonal the expression of Langerin fully correlates with deficiencies the presence on electron microscopy of Birbeck 2.4.2. Dermatological involvement granules, which were previously one of the crite- 2.4.3. Gastrointestinal involvement ria required for definitive diagnosis. There are, 2.5. Definition of Organ Involvement 2.5.1. Possible involved Organs however, very few exceptions as the fact that in 2.5.2. Risk organs organs such as liver Birbeck granules are not 2.5.3. Special Sites present and CD1a may be negative.

3. STRATIFICATION When tissue sample is taken from a bone lesion, 3.1. Clinical Classification 3.1.1. Single System LCH (SS-LCH) curettage of the center of the lesion is usually 3.1.2. Multisystem LCH (MS-LCH) sufficient for pathologic diagnosis and also may trigger the initiation of a healing process. Com- 4. TREATMENT plete excision of bone lesions is not indicated in 4.1. Management Algorithms 4.2. Local Therapy or Careful Observation all cases since it may increase the size of the 4.3. Systemic Therapy bony defect and the time to healing; it might also 4.3.1. Front Line Treatment result in permanent skeletal defects. 4.3.2. Evaluation of Response 4.3.3. Maintenance Therapy In very few circumstances, when the only lesion 4.3.4. Salvage Therapy 4.4. Treatment in Case of Reactivation involves particular structures and the risk of bi- 4.4.1. In Single System Disease opsy outweighs the need for a definitive diagno- 4.4.2. After Systemic Therapy sis, the risk/ benefit of biopsy should be carefully 4.5. Treatment and Hormon replacement of considered. This is the case in patients with ra- Endocrinopathies 4.6. Central nervous system involvement ther extended isolated pulmonary LCH. Another 4.6.1. Tumorous lesions possible, but rare situation is that of pituitary 4.6.2. Neurodegenerative LCH deficit (e.g. diabetes insipidus) in absence of a 4.7. Radiotherapy larger tumor and/or a small and not easily access- 5. ISOLATED PULMONARY LCH ible lesion on head or spinal MRI. Without proven diagnosis both situations do not require initial 6. PREGNANCY cytotoxic medication. Close monitoring and reas-

sessment of the need for biopsy is recommended 7. FOLLOW -UP 7.1. General considerations in patients with minor and acceptable symptoms. 7.2. Of Endocrinopathies

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The probability of other diagnoses than LCH is 2. PRETREATMENT CLINICAL EVALUATION usually higher, thus in all other situations per- forming a biopsy is generally recommended. For 2.1. COMPLETE HISTORY example in case of lytic bone lesions or lympha- At the beginning, patients with LCH are often denopathy other clinical conditions that might asymptomatic or show only mild symptoms, lead to a similar radiological finding, such as which are depending on the clinical manifesta- myeloma lesions, bone metastases, sarcoma or tions of the disease. lymphoma have to be considered with a higher probability. Most common symptoms are dyspnea on exer- tion or at rest and productive or non-productive LCH in adults is rather a random than an ex- cough, local bone pain, an abnormal growth of pected diagnosis! soft tissue over the affected area of bone, exan- thema of the skin, pruritus, increased thirst, and

swelling of lymph nodes. Additional signs are

1.2. DIAGNOSTIC CRITERIA fatigue, generalized weakness, weight loss, night sweats, nausea, and fever. The diagnosis is clinicopathologic and should only be made in the correct clinical setting to Because of the potential for generalized in- prevent misdiagnosis in the presence of normal volvement, a thorough history should be per- reactive Langerhans cells particularly in regional formed including the question after unexplained lymph nodes. symptoms in the past (especially after “idiopath- The two levels of certainty of LCH diagnosis ic” eczema, thyroid disease or diabetes insipidus, which are generally agreed upon are shown in lung cysts or fibrosis, or bony lesions), the smok- table 2. ing behavior and not at least the family history (a few familial cases are reported [9]).

2.2. COMPLETE PHYSICAL EXAMINATION

Table 2 Diagnostic Criteria of LCH For staging and determination of organ dysfunction a comprehensive physical examination is ► DEFINITIVE necessary. In particular, the skin and the visible = Based on microscopic examination and at least one mucous membranes should be inspected. Sup- of the following immunological staining: plemental neurological and/or psychological investigations are useful in patients presenting ♦ Langerin (CD 207) positivity with neuromyopathy or cognitive impairment.

♦ CD1a positivity 2.3. LABORATORY AND RADIOGRAPHIC EVALUATION

♦ Presence of Birbeck granules on electronic mi- The laboratory tests to be performed include a

croscopy. complete blood count, blood chemistry, liver

enzymes, albumin, total protein, erythrocyte ► PRESUMPTIVE (OR COMPATIBLE) = Based only on clinico-radiological evidence, without sedimentation rate, C-reactive protein Coagula- biopsy, as in case of: tion studies and urine test strip analysis. Serum levels of cytokines have been evaluated by sever- e.g.: Pulmonary lesions on CT scan with typical al groups around the world and in some cases, cysts and nodules in a smoker (however, biopsy seem to correlate with disease activity. But today, should be considered in order to reach a more definitive diagnosis) there is no established specific biological marker for disease activity.

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A skeletal survey, skull series (if available replaced by low dose whole bone CT) and chest x- ►ULTRASOUND ♦ Size and structure of liver and spleen + ray (AP and lateral) are the first radiographic ♦ Lymph-nodes + examinations to be done. CT of specific areas of ♦ Thyroid gland + the skeleton are indicated when mastoid, orbital, ►CHEST RADIOGRAPH (CXR) + scapular, vertebral, or pelvic lesions are found by plain x-rays. MRI allows to detection additional ►LOW DOSE WHOLE BODY (BONE) CT + extraosseous lesions. Skeletal scintigram (bone (IF NOT AVAILABLE: X-RAY SKELETAL/SKULL SURVEY ) scan) alone does not suffice for diagnostic pur- ►OPTIONAL: BASELINE HEAD- MRI + poses. Any evidence of a pathological thoracic ►OPTIONAL: PET-CT INSTAED OF ULTRASOUND, CXR + AND BONE CT finding should be followed up by high-resolution chest CT. An ultrasonographic examination of the abdomen should be done looking for evidence of hepatic abnormalities. An ultrasound of 2.4. SPECIFIC CLINICAL SCENARIOS AND RECOM- the neck with attention to the thyroid gland may MENDED ADDITIONAL TESTING be indicated if there are thyroid nodules or evi- 2.4.1. Endocrinologic dysfunction dence of thyroid dysfunctions. For brain examination with a critical view to the hypothalamic- LCH exhibits a particular predilection for in- pituitary area a MRI of head is useful. PET-(CT) volvement of the hypothalamo-pituitary (HP) scan may identify lesions missed by other modal- region leading to almost always permanent post- ities and is suitable to document response to ther- erior and/or anterior pituitary hormonal deficien- apy [10]. The decision whether further investiga- cies. tions should be performed is based on the pa- 2.4.1.1. Diabetes Insipidus (DI) tient's symptoms and the findings of the basic diagnostic tests (which should be performed DI is the most common disease-related conse- independently of the extension of the disease - quence that can predate the diagnosis or develop see Table 3). 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 disease or 94% in the presence of other pituitary Table 3 Baseline Laboratory and Agree- radiographic evaluation Ment deficiencies, respectively [11, 13]. In the pres-

ence of polyuria and polydipsia, and/or structural ►FULL BLOOD COUNT abnormalities of the HP region investigations to ♦ Hemoglobin + ♦ White blood cell and differential count + confirm DI should be undertaken (see 2.4.1.7.) ♦ Platelet count + and when present promptly treated with desmopressin (see 4.5.). ►BLOOD CHEMISTRY ♦ Total protein, Albumin + ♦ Bilirubin + 2.4.1.2 Anterior Pituitary Hormonal Deficiencies ♦ ALT (SGPT), AST (SGOT + ♦ Alkaline phosphatase (AP) ), + Anterior pituitary dysfunction is found in up to gammaglutamyl transpeptidase (γGT) 20% of patients almost always associated with DI ♦ Creatinine + ♦ Electrolytes + [11, 14]. Similar to DI, LCH-induced anterior ♦ CRP (C-reactive Protein) pituitary deficiencies (APD) need appropriate replacement therapy since they appear to be per- ►ERYTHROCYTE SEDIMENTATION RATE (ESR) o manent. GH deficiency (GHD) is the most fre- ►COAGULATION STUDIES quent disease-related APD found in up to 50% of ♦ INR/PT + patients with DI [13]. In adults there are no spe- ♦ Fibrinogen + cific GHD-related symptoms that can suggest the ►THYROID STIMULATING HORMONE (TSH), FREE T4 + diagnosis, as growth arrest that develops in children, and may be missed if not specifically consi- ►URINE TEST STRIP + Page 5 of 18

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dered. GHD might also develop following thera- postmenopausal women and men over 50-years peutic pituitary irradiation even in doses ranging old. [17]. from 15 to 30 Gy [15]. The effect of irradiation may apply for all other APDs, as well. 2.4.1.6. Other endocrine tissue involvement

Gonadotropin deficiency is the second most The thyroid gland may occasionally be involved common deficiency, presenting with menstrual in the disease process while fine needle aspira- disturbances in women and decreased libido in tion or even histological specimens may be mis- men [13]. ACTH deficiency is relatively rare taken with thyroid carcinoma. Unlike the lower and, apart from a few exceptions, it develops in genital tract, ovaries are quite rarely involved, the context of panhypopituitarism. ACTH defi- mostly in the context of disseminated disease. ciency may be partial or complete and present Adrenal infiltration has been described in autop- either with non-specific symptoms or as acute sy series although without any obvious clinical adrenal insufficiency following stressful events. findings. Pancreatic involvement is also extreme- TSH deficiency is almost always associated with ly rare, although there are reports of glucose panhypopituitarism and may present with subtle metabolism abnormalities secondary to pancrea- symptoms and signs of hypothyroidism. Mod- tic and/or hepatic infiltration and dysfunction. erately elevated PRL levels attributed to pituitary 2.4.1.7. Investigation of hormonal deficiencies stalk infiltration can cause galactorrhoea in females and gonadotropin deficiency in all patients A plasma osmolality in the range of 280- with intact pituitary function. 295mOsmol/Kg in combination with a urine to plasma osmolality ratio > 2:1 exclude apparent 2.4.1.3. Hypothalamic involvement DI, whereas a water deprivation test is usually Hypothalamic involvement is less frequent than required to reveal cases of partial DI. An early pituitary involvement leading to pituitary dys- morning serum cortisol level ≥ 500 nmol/l (18 function, neuropsychiatric and behavioral disord- μg/dl) virtually excludes ACTH deficiency, whe- ers, disturbances of thermo-regulation and sleep- reas a cortisol level < 100 nmol/l (3.6 μg/dl) is ing pattern, and autonomic and metabolic abnor- suggestive of ACTH deficiency. For intermediate malities. The most frequent consequence is se- serum cortisol values an insulin tolerance test vere obesity due to increased appetite, whereas (ITT), if not contra-indicated, can access the hypothalamic-related adipsia may seriously com- adequacy of hypothalamic (HP)-adrenal axis as plicate the management of DI. well as GH reserve. Although an insulin-like growth factor I (IGF-I) level below the age- 2.4.1.4. Metabolic abnormalities adjusted normal range may be suggestive of growth hormone deficiency (GHD) is not as One study has shown that adults with LCH are at reliable as the GH response to the ITT or other high risk of developing abnormalities of carbo- dynamic tests. Low basal gonadal steroids along hydrate (diabetes mellitus, impaired glucose with low gonadotropin levels in the presence of a tolerance) and lipid metabolism secondary to the relevant clinical setting are suggestive of hypo- disease’s inflammatory process, hormonal defi- gonadotropin hypogonadism. Occasionally in ciencies and/or concomitant medication, leading young females with menstrual disturbances and to increased insulin resistance even in the ab- low oestradiol levels, failure of gonadotropin sence of obesity [16]. levels to rise in response to clomiphene stimula- tion is required to confirm the diagnosis. Finally, 2.4.1.5. Bone metabolism lack of TSH elevation in the presence of a low Adults with LCH may present with a lower than serum T4 level is indicative of TSH deficiency in expected bone mineral density at any age espe- the absence of the non-thyroidal illness syndrome cially during periods of active disease. Either (NTIS). osteoporosis or osteopenia might be frequent in

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2.4.2. Dermatological involvement mainly the trunk and extending to the extremities may also resemble lichen planus, especially the Skin involvement in the adult patient is a com- follicularis variant, or a lichenoid dermatitis of mon presentation of LCH and can be protean. different causes; if vesicles are associated, the Cutaneous LCH can be the great pretender, mi- lesions can mimic varicella. When the cutaneous micking a number of common dermatoses, and picture is polymorphic with papules, vesicles and may represent the earliest sign of the disease necrotic-ulcerative lesions, acute pytiriasis liche- [18]. As in childhood disease, a common manife- noides of Mucha-Habermann can be misdiag- station is with scalp involvement. The typical nosed. In addition to the more widespread dis- lesions are small translucent papules, 1-2 mm in ease, isolated erythematous papules may be the diameter, slightly raised and rose-yellow in co- only manifestation with some patients only pre- lour; these lesions frequently show scaling or senting with a single lesion and the diagnosis is crusting, often leading to a misdiagnosis of se- only made when the lesion is removed for cos- borrheic dermatitis. However, unlike seborrheic metic reasons or due to concern about the possi- dermatitis, scalp LCH generally shows petechial bility of a skin tumour. In fact, a single papule or haemorrhages which should help to differentiate nodule can suggest several neoplastic conditions, it. Scaling and crusted lesions of the scalp simu- most notably cutaneous lymphomas, epithelial or late also tinea favosa. Pustules, which are com- adnexal tumours, sarcomas and metastases. monly seen on the scalp, may be misdiagnosed as decalvant folliculitis or erosive pustular dermato- Overlying involved lymph nodes or bone, LCH sis of the scalp. can present as ulceration or persistant sinus ana- logous to tuberculous scrofuloderma. Gum in- In adults, intertriginous involvement is often see, volvement is a common presentation in the adult the mainly affected skin folds being axillary, patient, almost always associated with alveolar inguinal and anogenital. This presents with ery- bone involvement and loosening of the teeth. It is thema and erosions, which are frequently mis- very important not to allow the dentist to extract diagnosed as eczema or psoriasis, but the lesions the teeth as with treatment they will embed into may be interpreted as a Candida infection or the recovering alveolar bone. Nodular-ulcerative simply intertrigo; in these locations, Haley-Haley lesions involving the gums resemble the so- disease should also be considered. Pustular le- called strawberry gingivitis of Wegener’s granu- sions involving the major cutaneous folds lead to lomatosis, which is an unique form of gingival the suspicion of hidradenitis or a new clinical hyperplasia also mimicking that seen as possible entity within the spectrum of neutrophilic derma- side effect of oral cyclosporine. Nail changes, toses, the so-called amicrobial pustulosis of the include paronychia, onycholysis, subungueal folds. A common presentation in men is with hyperkeratosis and purpuric striae of the nail bed, severe pruritus ani and ulceration around the suggesting a wide panel of conditions that affect anus; vulval irritation and ulceration is also not the nails. Dark-brown striae similar to those uncommon. Ulcerative lesions and ulcerated drug-induced are also seen. nodules located to the anogenital area may mimic several conditions, both inflammatory, notably In conclusion, due to its polymorphism to make pyoderma gangrenosum and Crohn’s disease, and the diagnosis of cutaneous LCH you need a high neoplastic, particularly extramammary Paget’s level of suspicion and biopsy is essential. Al- disease and Bowen’s disease, as well as infec- though skin disease may be the primary presenta- tious and sexually transmitted diseases such as tion you must investigate the patient for other orificial tuberculosis and chancroid, respectively. system disease.

Generalised skin eruptions can look like guttate 2.4.3 Gastrointestinal involvement psoriasis with erythematous scaly patches cover- ing the body, or prurigo nodularis with small Gastrointestinal (GI) tract involvement by LCH hard papules and nodules, particularly on the is a rare condition. In adults, it may appear as an trunk. Multiple erythematous papules involving incidental solitary colorectal polyp or as multiple Page 7 of 18

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granulomatous lesions of the mucous membrane ♦ Lung high resolution computed tomography + in the upper and lower GI tract [19]. Patients are (HR-CT) ♦ Lung function test + often asymptomatic. Multiple infiltrations are ♦ Bronchoalveolar lavage (BAL): > 5% CD1a + + associated with systemic disease. In asymptomat- cells in BAL fluid may be diagnostic of LCH in a ic patients, endoscopy is not obligatory on stag- non-smoker ♦ Lung biopsy (if BAL is not diagnostic) or + ing. Video-assisted thoracoscopic surgery (VATS)

Table 4 Specific Clinical Scenarios: Agree- Recommended Additional testing ment ►Osseous Disease ♦ MRI should be performed in case of cra- ►History of Polyuria or Polydipsia + niofacial or vertebral lesions or signs of additional ♦ Urine and plasma osmolality + soft tissue involvement

♦ Water deprivation test + ♦ Biopsie should be taken from the most + ♦ MRI of the head + suitable region in case of multifocal bone disease

► Suspected Other Endocrine Abnormality ♦ Endocrine assessment (including dynamic + ► Skin, Oral and Genital Mucosa lesions tests of the anterior pituitary, MRI of ♦ Biopsie should be taken + the head, see 2.4.1.7)

► Aural Discharge or Suspected Hearing Impairment

►Bicytopenia, Pancytopenia, or Persistent Unex- / Mastoid Involvement + plained Single Cytopenia ♦ Formal hearing assessment ♦ Any other cause of cytopenia has to be ruled + ♦ MRI of head + out according to standard medical practice. ♦ Bone marrow aspirate and trephine biopsy + ► Visual Abnormalities to exclude causes other than LCH. ♦ Ophthalmological assessment + ♦ In case of morphological signs of hemopha- + ♦ MRI of head +

gocytosis additional tests like serum-ferritin ► Neurological or cognitive Abnormalities should be performed (criteria of HLH) + ♦ Neurological/Neuropsychometric assessment

♦ MRI of head + ►Liver or Spleen Abnormalities

♦ In case of any unclear sonographically +

pathology CT, PET-CT, MRI or Scans should be ►Unexplained Chronic Diarrhea, Weight loss, Evi- added (the choice is depending on the sono- dence of Malabsorption or Hematochezia morphology – discuss with your radiologist) ♦ GI-Exploration (Endoscopy with biopsies, ♦ Visuable lesions of the liver should be + + capsule endoscopy) 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 symptoms/signs suggestive for lung involvement or suspicion of a pulmonary infection:

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2.5. DEFINITION OF ORGAN INVOLVEMENT 3. STRATIFICATION

2.5.1. Possibly Involved Organs 3.1. CLINICAL CLASSIFICATION After the diagnosis of LCH has been made, in- 3.1.1. Single System LCH (SS-LCH) volvement of other organs should be evaluated and defined according to the clinical, biological One organ/system involved (uni- or multifocal): or radiological criteria.  Bone: unifocal (single bone) or multi- 2.5.2. Risk Organs focal (> 1 bone)  Skin Based on previous experience of pediatric stu-  Lymph node dies, disease involvement in the hematopoietic  Hypothalamic-pituitary / Central nerv- system, spleen, liver or CNS is a marker of a less ous system favorable prognosis, even of mortality if the pa-  Lungs (primary pulmonary LCH)  Other (e.g. thyroid, gut) tient does not respond to standard therapy. Al- though this has never been proved for adults, retrospective analyses of national registries and 3.1.2. Multisystem LCH (MS-LCH) the experts experience support the existence of Two or more organs/systems involved: the above mentioned “risk organs” even in this age cohort.  With involvement of “Risk Organs” (Hematopoietic system, spleen, and/or Beside the type of the involved organ clinical liver, tumorous CNS) pictures like B-symptoms (fever, night-sweats  Without involvement of “Risk Organs” and weight loss) combined with significantly reduced general condition might predict the rarely observed aggressive course of LCH in adults 4. TREATMENT comparable to that of high grade Non Hodgkin 4.1. MANAGEMENT ALGORITHMS lymphoma [20, 21]. Treatment recommendations are based on site and extension of the disease 2.5.3. “Special Sites” Figure 1: Management of Langerhans Cell Histi- In certain situations, such as vertebral lesions ocytosis in adults with intraspinal or cranofacial bone with intra- cranial soft tissue extension, lesions are located Diagnosis LCH (Table 2) in functionally critical anatomical sites. These lesions may cause immediate risk to the patient because of the critical anatomical site and the Pretreatment clinical evaluation (Table 3 and 4) hazards of attempting local therapy. Isolated disease in these “Special Sites” may justify sys- Primary temic therapy, especially in childhood. Alterna- Single system Multi system pulmonary LCH LCH tively irradiation might be considered in adults. LCH These lesions need to be distinguished from other Multifocal Is therapy required ? bone lesions. or special site In children other “Special Sites” are craniofacial Yes No Single site bone lesions that are associated to diabetes insi- Figure 2 Local therapy Table 5 pidus, which can either develop on a long term or can be present first. It is unclear if that might be extrapolated to adults. Follow up (Table 7)

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tem disease, there are a number of treatments that have been used that can be directed specifi- Figure 2: Management of pulmonary LCH in cally to the skin: adults (will be added finally) Topical nitrogen mustard:

20% nitrogen mustard applied to the skin has been shown to be an effective treatment in child- 4.2. LOCAL THERAPY OR CAREFUL OBSERVATION ren [24]. There is no published data on treatment In case of single system LCH with unifocal bone in adults and there are problems with availability involvement of non-“CNS-Risk facial bones) in most countries. local therapy or careful observation is recom- Phototherapy: Psoralen plus ultraviolet A (PU- mended. The modality of treatment depends on VA) [25] and narrow band ultraviolet (UV) B location, size, and symptomatic of the disease. [26] have been shown to be effective in treating Observation can be sufficient in non-risk lesions. cutaneous LCH in individual case reports. The Biopsy or curettage is suitable for histopatholog- Langerhans cell is very sensitive to ultraviolet ic diagnosis and initiating a healing process. To light, so response to UV treatment is not surpris- accelerate this process, intralesional injection of ing. It is difficult to treat patients with intertri- steroid is suggested. Dosages of 40 – 160 mg of ginous or scalp involvement and would be con- methylprednisolone have been used [22]. Com- traindicated in penile disease. Certainly failures plete excision is only necessary in risk of frac- on both PUVA and narrow band (TLO1) light ture, usually in combination with a reconstructive treatment have been observed. procedure. Radiotherapy is indicated if there is an impending neurological deficit and a high Thalidomide: is a TNF-α antagonist and has been surgical risk, e.g. lesion in the odontoid peg or shown to be effective in treating cutaneous LCH cranial base (see 4.7). For multifocal bone LCH [27] but gives poor responses in high risk multi- and for bone lesions in “special sites” systemic system disease [28]. Dose of 100mg/day in adults therapy should be given (see 2.5.3). is generally used but toxicity with peripheral neuropathy is not uncommon. Isolated involvement of lymph nodes is rare but spontaneous regressions were observed repeated- Azathioprine: There are no published reports of ly. So, watchful waiting may be adequate in cas- the use of azathioprine (or its metabolite 6- es of adult lymph node LCH (e.g. isolated cer- mercaptopurine) in adults with cutaneous LCH vical lymph nodes [23]). but it is a very useful drug in single system skin as well as multisystem disease. Patients need to Skin Involvement: Treatment of skin disease will be tested for thiopurine methyl transferase, and if depend on a number of factors: normal should be treated at a dose of i) Single system disease versus multisys- 2mg/kg/day. The drug takes about 6 weeks to tem disease; become effective. ii) Site of involvement – mucosal versus Methotrexate: There is only few published data glabrous skin; on the use of low dose methotrexate as either iii) Extent of the disease; single agent treatment or in combination with iv) Response to previous treatment. azathioprine or prednisolone. Methotrexate was In general, if the patient is being treated for mul- used successfully at the dosages of 20mg once tisystem disease, the skin disease will respond to weekly [29] . treatment as the skin is probably the most responsive organ. In single system skin disease or in the rare instance where the skin fails to respond fully to systemic treatment for multisys-

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4.3. SYSTEMIC THERAPY

4.3.1. Front Line Treatment LCH may be quite unpredictable and recurrences or reactivations of the disease may occur. In the Systemic therapy should be considered in case of case of clinical suspicion for disease progression the following disease category: or reactivation, complete evaluation as recom-  MS-LCH with/without involvement of “risk mended in the previous section 2 has to be per- organs” formed in order to make decisions on further  SS-LCH with multifocal lesions treatment strategy.  SS-LCH with “special site” lesions 4.3.3. Maintenance Therapy

Having started with Vinblastin/Prednisolon main- There is no consensus for one special schedule of tenance therapy comparable to that in pediatric first line therapy. Vinblastin/Prednisolon is men- protocols is used for 6 to 12 months (3-weekly tioned in various chemotherapeutical manuals as with addition of continuously oral 6-MP). Other standard therapy, but has never been proved chemotherapeutical drugs (ARA-C, VP-16 or 2- prospectively for adults. An attempt of an inter- CDA) are usually administered, depending on national trial failed due to the aggravation of the response up to 6 cycles. regulations for academically trials resulting in a low recruitment rate and premature closing. Nev- 4.3.4. Salvage Therapy ertheless this schedule is effective as published in Refractory disease should be treated with 2-CDA. numerous case reports, but the risk of neuropathy, In case of further progression, especially in CNS especially in patients with co-morbidities like involvement Cytarabine may be added [32]. In the diabetes mellitus has to be taken into account. rare case of a most aggressive course of disease Therefore some experts prefer monotherapy with hematopoietic stem cell transplant has been per- Cytarabine or Etoposide alternatively. formed successfully as well [33, 34]. Patients with mild symptoms and lacking risk organ involvement may be treated with a more immunosuppressive than cytotoxic attempt 4.4. TREATMENT OPTIONS IN CASE OF REACTIVATION represented in drugs like Methotrexate, 6-Mer- Reactivations of LCH in adults occur in about 1/4 captopurine or Azathioprine. In multifocal bone of the patients (registry data). Patients may have disease bisphosphonates [30] are used front-up, further reactivations in course, which seems to be but patients have to be advised to the risk of os- more often in multisystem disease. teonecrosis of the jaw and its prevention (dental hygiene). Against pain of bony lesions COX- 4.4.1. Reactivation of Single System Disease Inhibitors might be more than an analgetic drugs and regression of LCH was observed [31] . The choice of treatment options is based on the same principles as for initial disease. Most experts prefer to start initially with 2-CDA The options for reactivations of SS-LCH (skin, in case of risk organ or tumorous cerebral in- bone, other) include volvement. I. Wait and watch approach 4.3.2. Evaluation of Response II. Local therapy including irradiation (as Using Vinblastin/Prednisolon therapy response above) assessment is generally performed at week 6 (re- III. bisphosphonates for bony disease (as garding to the pedriatic studies). In other scedules above) the evaluation has to be done after 2 to 3 cycles of IV. Chemotherapy (as above) chemotherapy as usually in malignant disorders.

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In case of a multisystemic reactivation of a SS- cies [35]. Radiotherapy, at doses up to 30Gy, has LCH, treatment should follow the options for MS- been also used in cases with hormonal deficiencies LCH including systemic therapy (see 4.3. and and radiological evidence of HP involvement. 4.4.2.). Despite apparent radiological improvement, the absence of significant clinical responses in combi-

nation with potential adverse late effects of the 4.4.2. Reactivation after Systemic Therapy treatment no longer suggest radiotherapy as the I. If the reactivation is more than one year after treatment of choice[35]. Cytarabine may be a completion of treatment, re-induction with the reasonable therapy for patients with recurrent prior used chemotherapy may be effective and LCH of the pituitary-hypothalamic region as this there is no need to switch to alternative thera- drug has good penetration in the CSF. py. If however, the disease is not responsive Adequate replacement of hormonal deficiencies we suggest discussion with the reference cen- should be initiated as soon the diagnosis is made. tre for your country. There are currently no data regarding the adminis- II. If reactivation occurs while on treatment, tration of GH in GHD adults, although it is ex- potentially 2nd line strategies are described in pected to be beneficial in some somatometric and 4.3.4, but should be generally discussed with metabolic parameters and improve quality of life. your reference centre, taking into account dis- In cases of gonadotropin deficiency fertility may ease severity and the respective risk for unfa- be achieved with exogenous gonadotropin admin- vorable outcome. istration. Adequate sex steroid replacement therapy is required in all patients not desiring fertility.

ACTH deficiency should be promptly replaced Agree- with daily divided doses of hydrocortisone, and Table 5 First line systemic therapy Ment

levothyroxine replacement therapy should be ti- ►MILD SYMPTOMS, NO RISK ORGANS INVOLVED trated to achieve mid-normal serum free T4 levels. ♦ Methotrexate 20 mg per week p.o/i.v. + ♦ Azathioprine 2 mg/kg/d p.o + Dopamine agonists can be used for normalization ♦ Thalidomide 100mg/d p.o in skin or soft tissue + of PRL levels in case of hyperprolactinaemia- multifocal single system LCH induced gonadotropin deficiency.

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

4.6. CENTRAL NERVOUS SYSTEM INVOLVEMENT ►SYMPTOMATIC, MS-LCH, NO RISK ORGANS INVOLVED ♦ Vinblastin/Prednisolon (like in pediatric studies) o 4.6.1. Tumorous lesions ♦ Cytarabine 100 mg/m² d1-5 q4w + ♦ Etoposide 100 mg/m² d1-5 q4w + These lesions are most frequently observed in the hypothalamic-pituitary region resulting in hor- ►MS-LCH, RISK ORGANS INVOLVED ♦ 2-CDA 6 mg/m² d1-5 q4w + 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). 4.5. TREATMENT AND HORMON REPLACEMENT OF Parenchymal, meningeal or plexus choroideal ENDOCRINOPATHIES lesions occur less frequently[35]. DI should be treated with desmopressin while the In addition to hormone replacement therapy iso- timing and dosage must be individualized. In lated tumors should be treated if any locally with proven LCH new onset DI is a sign of active dis- surgery, irradiation or radiosurgery. In case of ease and the LCH-CNS study group recommends multi system disease chemotherapy (most suitable the initiation of systemic therapy (chemotherapy), 2-CDA +/- Cytarabine) has to be applied as de- irrespective of the findings of HP region imaging, scribed in 4.3.1. to prevent further damage and hormonal deficien- Page 12 of 18

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4.6.2. Neurodegerative LCH of extra-osseous soft tissue or organ involvement [42]. 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 Table 6 Possible Indications for the Use of Agree- Radiotherapy in Adults ment CD1a and predominantly CD8+ lymphocytes, which may be interpreted as a further inflammato- ► “UNRESECTABLE” LESIONS (IF A RESECTION WOULD + ry step of disease)[36]. Some of these patients SIGNIFICANTLY COMPROMISE ANATOMIC FUNCTION, E.G. ODONTOID PEG, CNS ) show no symptoms, others have clinical signs ranging from subtile tremor, dysarthria, dysphagia, ► RECURRENT OR PROGRESSIVE LESIONS (IN MULTIFOCAL + and motor spasticity to pronounced ataxia, beha- OR MULTISYTEM DISEASE ONLY IN CASE OF MINOR RES- PONSIVESS TO STANDARD SYSTEMIC THERAPY) vioral disturbances and severe psychiatric disease. ► ADJUVANT TREATMENT FOLLOWING MARGINAL OR + Unfortunately none of the previous treatment INCOMPLETE RESECTION (ESPECIALLY IN SINGLE SYS- attempts (retinoic acid, intravenous immunglobu- TEM BONE DISEASE WITH SOFT TISSUE INVOLVEMENT) lin, chemotherapy) could sufficiently influence the course of disease so far. Cytarabine with and without vincristine was shown to be effective for Most literature data concerning radiotherapy in reversing the neurologic and radiographic signs of adult LCH deal with in uni- or multifocal osseous ND-CNS LCH in 5/8 patients [37]. Thus for any single-system disease. Summarizing the results in case of neurodegenerative LCH we suggest dis- these bone lesions, the local control rates ranged cussion with the reference centre for your country. from 75-100%, complete remission from 79- 100%, respectively. There is not much data in the literature on radiotherapy in non-osseous single-

4.7. RADIOTHERAPY system disease, mostly presented as single case reports. Nevertheless, in most cases a complete In contrast to treatment of childhood LCH, Radio- remission is reported. Bony lesions are the predo- therapy is still a feasible and effective treatment minantly irradiated manifestations also in multi- option for adult patients with LCH. It has a long system disease. Local control rates ranged from tradition and the first successful radiation of LCH 75% to 100%, complete remission rates were up to was described in 1930 by Sosman [38]. Since 85%. Thus in case of minor responsiveness to then, the effectivity of radiotherapy in LCH has standard systemic therapy Radiotherapy may be been shown in a large number of publications (in considered as an additive treatment in multifocal extracts [39-44]), but all studies reported in litera- or multisystem disease. ture have a retrospective nature and in general the number of patients is not large. Osseous and visceral lesions should be treated with megavolte equipment (Linear accelerator), Radiotherapy indications should respect the age of whereas superficial x-rays or fast electrons are patients, the possibility of radiogenic malignan- used for cutaneous or subcutaneous lesions. In cies, and the semi-benign character of disease. external beam radiotherapy, individually opti- This kind of treatment should be considered as a mized radiation set-up and shielding using a mod- palliative measure only when it is clearly war- ern three-dimensional conformal radiotherapy ranted by the presence of disease progression or technique should be used to minimize the volume when location and extent of disease threat the of not affected tissue neighboring the disease le- function of critical organs [42]. sion. An adequate margin of 1-2 cm of normal tissue around the treated lesion should be in- In general, two radiotherapy indications must be cluded, but in bony lesions the whole bone must distinguished: The treatment of painful or unstable not to be included [45]. uni- or multifocal bone lesions and the treatment

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The dose recommendation for radiotherapy is still novo- fraction of Langerhans cells, or that Lan- controversial, because the optimal dose is not well gerhans cells themselves are a very sensitive defined, and an exact dose-effect relationship has population to irradiation [43]. 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- 5. PRIMARY PULMONARY LCH (BY TAZI AND mended in adults but a dose range from 12-14 Gy FICHTER ) EXPECTED AT THE END OF 2011 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]). 6. PREGNANCY

Acute side effects of radiotherapy depend on the There are only a few reports about pregnancy and localization of the irradiated body site. As the LCH with worsening to no change of clinical applied total dose rarely exceeds 20 Gy, both symptoms, but even improvement was observed. acute and subacute side effects are rare. Most In case of deterioration this was mainly related to literature data do not provide any information diabetes insipidus. But it is unclear, if worsening about acute side effects of radiotherapy. Late side or onset of DI during pregnancy is really caused effects of radiotherapy are also rare due to the low by LCH. This may also be observed in women applied dose range. The only risk, which should be without suffering from a histiocytic disorder and mentioned, is the extremely low one of radiation- is caused by an accelerated degradation of vaso- induced carcinogenesis. Greenberger et al. (1979) pressin through placental enzyme vasopressinase reported a rate of 3.9% for induction of malignant [47]. tumors, but this data should be interpreted with care, because many children were treated in this Generally it is unpredictable if and in which way collective. Even though the doses applied for local pregnancy may influence the course of LCH. Oth- control in adult LCH are low, several publications erwise women may be pacified that vice versa no in the literature describe the induction of leukae- adverse impacts of LCH on pregnancy or birth, mias, osteosarcomas, teratoma, malignant menin- with exception of need for cesarean section in case gioma, thyroid and liver tumors (Heyd et al. of involvement of the vulva have been reported 2000), but you should take in mind that most stu- [48, 49]. 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- 7. FOLLOW UP nancies independently of therapies. 7.1. FOLLOW-UP Finally, the radiation treatment technique has substantially improved during the last decade LCH may reactivate in course and induce organ becoming a precise and normal tissue sparing dysfunction. Moreover, LCH is associated with instrument. Nevertheless, the indication for radio- malignant tumors. Therefore, follow-up investiga- therapy for a palliative treatment in LCH has to be tions of disease and monitoring of functional im- accurately set up with and the potential benefits of pairments are necessary. radiation treatment must be carefully weighed against its possible. During treatment, reevaluations are useful at each parenteral application of cytostatic chemotherapy The exact target cells or structures affected by or every 6 to 12 weeks in case of peroral cytostatic radiotherapy in LCH remain unclear. Low doses or immunosuppressive treatment. The reevaluation of radiotherapy not reaching a normal cell-killing has regard to the known disease manifestations level have been shown to heal the disease, result- and to new complaints of the patients. Follow-up ing in theories, that either radiotherapy suppresses intervals depend on the primary extent and activity an inflammatory process and so reduces the de Page 14 of 18

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of disease with controls within 3 to 12 months (see Table 7 Recommendations for follow-up table 5). In case of affirmed reactivation, clinical evaluation should include all investigations listed Agree TEST FREQUENCY ment above (chapter 2). ► ALL PATIENTS WITH SINGLE SYSTEM DISEASE AND WITH NO DISEASE ACTIVITY 7.2. FOLLOW-UP, MONITORING OF ENDOCRINOLOGI- CAL CONSEQUENCES ♦ History (especially of - Every clinic visit + thirst, polyuria, cough, dyspnea, In case of established DI and/or APDs endocrino- bone pain, skin changes, logical follow-up is warranted, at least on a yearly neurological symptoms) basis, in order to insure adequate replacement ♦ Clinical assessment, - End of therapy + therapy and identify other evolving deficiencies. blood count and blood chemi- - every 6 month for + stry (as described in baseline the next 2 years In the absence of any endocrine deficiencies the diagnostics), ultrasound, - then once a year for + presence of relevant symptoms or signs (see Chest XR at least 3 years 2.4.1.1.-6.) should lead to endocrinological eval- ► ALL PATIENTS AFTER MULTI SYSTEM THERAPY AND uation especially in patients with multisystem WITH NO DISEASE ACTIVITY active disease. In particular, patients with long ♦ History, especially of - Every clinic visit + acting and/or reactivating disease are adviced to thirst, polyuria, cough, dyspnea, have a 6- or 12-month plasma and urine osmolali- bone pain, skin changes, ty, morning serum cortisol and free T4 levels mea- neurological symptoms. surement to exclude the more compelling diag- - End of therapy + noses. Finally, among patients with multisystem ♦ Clinical assessment, - every 3 month for + blood count and blood chemi- the next 2 years disease a basal HP region MRI might prove very stry (as described in baseline - every 6 month for + helpful regarding future LCH-induced structural diagnostics), ultrasound, Chest the next 3 years changes. XR - then once a year for + at least 5 years Once a year until end + ♦ TSH, free T4 of routinely follow up

► PATIENTS WITH ACTIVE DISEASE

♦ diagnostic procedures are Frequency is de- + depending on the site of organ pending on rates involvement and velocity of recurrences

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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 disease. 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 classification 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 treatment. J Clin Endocrinol Metab, 2000. 85(4): p. 1370-6. 12. Prosch, H., et al., Central diabetes insipidus as presenting symptom of Langerhans cell histiocytosis. 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 histiocytosis. 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 clinicopathologic 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 histiocytosis 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. 24. Hoeger, P.H., et al., Long term follow up of topical mustine treatment for cutaneous langerhans cell histiocytosis. Arch Dis Child, 2000. 82(6): p. 483-7. 25. Sakai, H., et al., Satisfactory remission achieved by PUVA therapy in Langerhans cell hisiocyto- sis in an elderly patient. J Dermatol, 1996. 23(1): p. 42-6. 26. Imafuku, S., et al., Cutaneous Langerhans cell histiocytosis in an elderly man successfully treated with narrowband ultraviolet B. Br J Dermatol, 2007. 157(6): p. 1277-9. 27. Sander, C.S., M. Kaatz, and P. Elsner, Successful treatment of cutaneous langerhans cell histiocytosis with thalidomide. Dermatology, 2004. 208(2): p. 149-52. 28. McClain, K.L. and C.A. Kozinetz, A phase II trial using thalidomide for Langerhans cell histiocytosis. Pediatr Blood Cancer, 2007. 48(1): p. 44-9. 29. Steen, A.E., et al., Successful treatment of cutaneous Langerhans cell histiocytosis with low- dose methotrexate. Br J Dermatol, 2001. 145(1): p. 137-40. 30. Montella, L., et al., Zoledronic acid in treatment of bone lesions by Langerhans cell histiocytosis. J Bone Miner Metab, 2009. 27(1): p. 110-3. 31. Reichle, A., et al., Anti-inflammatory and angiostatic therapy in chemorefractory multisystem Langerhans' cell histiocytosis of adults. Br J Haematol, 2005. 128(5): p. 730-2. 32. McClain, K.L., Drug therapy for the treatment of Langerhans cell histiocytosis. Expert Opin Pharmacother, 2005. 6(14): p. 2435-41. 33. Ingram, W., et al., Reduced-intensity conditioned allogeneic haematopoietic transplantation in an adult with Langerhans' cell histiocytosis and thrombocytopenia with absent radii. Bone Marrow Transplant, 2006. 37(7): p. 713-5. 34. Xicoy, B., et al., [Sustained remission in an adult patient with Langerhans cell histiocytosis following T-cell depleted allogenic cell transplantation]. Med Clin (Barc), 2006. 127(18): p. 716. 35. Grois, N., et al., Central nervous system disease in Langerhans cell histiocytosis. J Pediatr, 2010. 156(6): p. 873-81, 881 e1. 36. Grois, N., et al., Neuropathology of CNS disease in Langerhans cell histiocytosis. Brain, 2005. 128(Pt 4): p. 829-38. 37. Allen, C.E., et al., Neurodegenerative central nervous system Langerhans cell histiocytosis and coincident hydrocephalus treated with vincristine/cytosine arabinoside. Pediatr Blood Cancer, 2010. 54(3): p. 416-23. 38. Sosman, M.C., Xanthomatosis (Schüller's Disease; Christian's Syndrome). A Report of 3 Cases Treated With Roentgen Rays. Am. J. Roentgenol. , 1930. 23: p. 581. 39. Atalar, B., et al., Adult langerhans cell histiocytosis of bones : a rare cancer network study. Acta Orthop Belg, 2010. 76(5): p. 663-8. 40. Gaundong Mbethe, G.L., et al., [Multifocal Langerhans cell histiocytosis of bone: indications for radiotherapy]. Cancer Radiother, 2010. 14(8): p. 759-62. 41. Heyd, R., et al., [Radiotherapy in Langerhans-cell histiocytosis. 2 case reports and review of the literature]. Rontgenpraxis, 2000. 53(2): p. 51-61. 42. Brady, L.W., et al., eds. Radiotherapy for Non-Malignant Disorders. Chapter: Langerhans Cell Histiocytosis ed. T. Olschewski, M.H. Seegenschmiedt, and O. Micke. 2008, Springer Verlag. 397-423. 43. Greenberger, J.S., et al., Radiation therapy in patients with histiocytosis: management of diabetes insipidus and bone lesions. Int J Radiat Oncol Biol Phys, 1979. 5(10): p. 1749-55. 44. Pereslegin, I.A., V.F. Ustinova, and E.L. Podlyashuk, Radiotherapy for eosinophilic granuloma of bone. Int J Radiat Oncol Biol Phys, 1981. 7(3): p. 317-21.

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45. Micke, O. and M.H. Seegenschmiedt, Consensus guidelines for radiation therapy of benign diseases: a multicenter approach in Germany. Int J Radiat Oncol Biol Phys, 2002. 52(2): p. 496-513. 46. Cassady, J.R., Current role of radiation therapy in the management of histiocytosis-X. Hematol Oncol Clin North Am, 1987. 1(1): p. 123-9. 47. Ananthakrishnan, S., Diabetes insipidus in pregnancy: etiology, evaluation, and management. Endocr Pract, 2009. 15(4): p. 377-82. 48. DiMaggio, L.A., H.A. Lippes, and R.V. Lee, Histiocytosis X and pregnancy. Obstet Gynecol, 1995. 85(5 Pt 2): p. 806-9. 49. Sharma, R., R. Maplethorpe, and G. Wilson, Effect of pregnancy on lung function in adult pulmonary Langerhans cell histiocytosis. J Matern Fetal Neonatal Med, 2006. 19(1): p. 67-8.

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