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Page 1: Management of adult patients with Langerhans cell histiocytosis

REV I E W Open Access

Management of adult patients with Langerhanscellhistiocytosis:recommendations from anexpert panelon behalf of Euro-Histio-NetMichaelGirschikofsky1*,Maurizio Arico2,Diego Castillo3, Anthony Chu4, Claus Doberauer5, Joachim Fichter6,Julien Haroche7,Gregory A Kaltsas8, Polyzois Makras9, Angelo V Marzano10,Mathilde de Menthon11,Oliver Micke12,Emanuela Passoni10,Heinrich M Seegenschmiedt13, Abdellatif Tazi14and Kenneth L McClain15

AbstractLangerhans CellHistiocytosis (LCH) is an orphan disease of clonaldendritic cells which may affect any organ of thebody.Most of the knowledge about the diagnosis and therapy is based on pedriatic studies.Adult LCH patients areoften evaluated by physicians who focus on only the most obviously affected organ without sufficient evaluation ofother systems,resulting in patients being underdiagnosed and/or incompletely staged.Furthermore they may betreated with pediatric-based therapies which are less effective and sometimes more toxic for adults.The publishedliterature on adult LCH cases lacks a comprehensive discussion on the differences between pediatric and adultpatients and there are no recommendations for evaluation and comparative therapies.In order to fillthis void,anumber of experts in this field cooperated to develop the first recommendations for management of adult patientswith LCH.Key questions were selected according to the clinicalrelevance focusing on diagnostic work up,therapy,and follow up.Based on the available literature up to December 2012,recommendations were established,draftswere commented by the entire group,and redrafted by the executive editor.The quality of evidence of therecommendations is predominantly attributed to the levelof expert opinion.Finalagreement was by consensus.Keywords:Langerhans,Adult,Histiocytosis

Background, process of development andrestrictionsThere are no universally accepted internationalguide-lines available for the diagnosis and treatmentof adultLCH patients.The largest number ofpatients was pub-lished in a pooled retrospective analysis from several na-tional registries [1].

Based on the available literature up to December 2012and personal experience the following recommendationswere established by an internationalgroup ofacademicclinicians who are recognized experts in the field of his-tiocytic disorders.Grading ofrecommendationsbasedon levels ofevidence and agreement between experts islisted in Table 1.

Due to the diversity ofclinicalcourse ofLCH, evenrecommendations which are established as standard ofcare may need to be critically appraised in an individualcase and involvement of a LCH expert should be consid-ered.A map of experts,reference centers and additionalinformation aboutthe disease is available on the web-site ofEuro-Histio-Net(http://www.eurohistio.net)andthe Histiocytosis Association (https://www.histio.org/).

General considerationThe etiology ofLCH is unknown.LCH cells are clonal(exceptprimary pulmonary LCH)[2,3]and a cancer-associated mutation (BRAFV600E)wasfound in morethan half of investigated specimens,indicating that LCHmay be more a neoplastic (not a malignant!) disease thana reactive disorder,but the pathogenesis is stillunclear[4,5].Although apparent associations between LCH andmalignanttumorshavebeen recognized,thesecases

* Correspondence:[email protected] of Medicine I,Center of Hematology an Stem CellTransplantation,Hemostasis and MedicalOncology InternalMedicine I,Elisabethinen Hospital,Fadinger Str.1 4010,Linz,AustriaFulllist of author information is available at the end of the article

© 2013 Girschikofsky et al.;licensee BioMed CentralLtd.This is an Open Access article distributed under the terms of theCreative Commons Attribution License (http://creativecommons.org/licenses/by/2.0),which permits unrestricted use,distribution,and reproduction in any medium,provided the originalwork is properly cited.

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Page 2: Management of adult patients with Langerhans cell histiocytosis

represent a minority of allLCH patients and the patho-physiologic relationship remains undefined [6].

The disease may affect any organ or system,more fre-quently bones,skin,and pituitary gland.Lymph nodes,liver,spleen,gut,the centralnervous system,pituitary,and the hematopoieticsystem areless frequentlyaf-fected.Lungsmay be affected simultaneously orcon-secutivelywith otherorgans,but isolated pulmonaryLCH (PLCH) occurs frequently in adults and may proceedto multisystem involvement.PLCH requiresa differentmanagement in contrast to multi-organ involvement andis therefore discussed in a separate section.

Clinicalmanifestations of LCH vary depending on theorgan orsystem affected,from self-healing disease tochronic recurrences.A rapid progressive form,seen inchildren,is usually notobserved in adults.Langerhanscell sarcoma (malignant histiocytosis) can occur de novoor from an antecedentLCH [7]. This paperwill notcover other histiocyticdisorderssuch as Erdheim-Chester disease (ECD),Rosai-Dorfman disease (RDD) ormalignanthistiocytosis.In cases ofoccurrence ofLCHand ECD or RDD in the same patient,the managementis based on the predominant disease.

Treatmentoptions vary depending on disease extentand severity atonset.A uniform diagnostic work-up isnecessary (see Figure 1).One of the main problems ofLCH in adults is the variety ofpotentially involved or-gans resulting in severalphysicians being consulted.Fre-quently only the most obviously affected site is consideredand a complete examination isnot done thusmissingother sites of disease.

DiagnosisThe diagnosis of LCH should be based on histologic andimmunophenotypic examination of a lesional biopsy.Nor-malLangerhans cells stain positively with CD1a and/orLangerin [8-10].Misdiagnoses ofLCH have occurred,asthe presence of normalreactive LCs in skin and regionallymph nodes may be confusing.

The two levels of certainty of LCH diagnosis which aregenerally agreed upon are shown in Table 2 [11].

Pretreatment clinical evaluationComplete historyPatients with LCH are often asymptomatic or show onlymild symptoms.The most common symptoms are dys-pnea,cough,bone pain,an abnormalgrowth of soft tis-sue over the affected bone,rash,pruritus,increasedthirst,and lymphadenopathy.Additional signs are fatigue,generalized weakness,weightloss,nightsweats,nausea,and fever.

A thorough history should be performed including thequestioning aboutunexplained symptomsin the pastsuch as “idiopathic” eczema,thyroid disease or diabetesinsipidus,lung cysts or pneumothorax,or bony lesions,the smoking and family history with specialattention toautoimmune disease.A very smallnumberof familialcases are reported [12].

Table 1 Grade of recommendationLevel of evidence Level of agreement between expertsA meta-analyses,high quality

systematic reviews,orrandomized controlled trials

2 generalagreement betweenallexperts

B systematic reviews of casecontrolor cohort studies

1 discussed recommendation,but noformalobjections between experts

C non-analytic studies:for example,case reports,case series,smallretrospective studies

0 divergence of opinion

D expert opinion

Diagnosis LCH (Table 2)

Primarypulmonary

LCH

Single systemLCH

Multi systemLCH

Pretreatment clinical evaluation(Table 3 and 4; Table 7 in suspected pLCH)

Is therapy required ?

Follow up (Table 9)

Local therapy Table 5

No

Multifocalor special site

Table 8

Yes Single site

Figure 1 Management of Langerhans Cell Histiocytosisin adults.

Table 2 Diagnostic criteria of LCHDefinitive: Presumptive (or compatible):Based on clinic-pathologicalevidence with microscopicexamination and at least one of thefollowing immunologicalstaining:

Based only on clinico-radiologicalevidence,without biopsy,asin case of:

• Langerin (CD 207) positivity e.g.:Pulmonary lesions on CT scanwith typicalcysts and nodules in asmoker.(however,biopsy shouldbe considered in order to reach amore definitive diagnosis)

• CD1a positivity• Presence of Birbeck granuleson electronic microscopy

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Complete physical examinationA comprehensive physical examination is necessary.Theskin and visible mucous membranes should be inspected.Supplementalneurologicaland/or psychologicalinves-tigationsare usefulin patientspresenting with neuro-myopathy or cognitive impairment.

Laboratory and radiographic evaluationThe laboratory tests to be performed for allpatients in-dependently of affected organs include a complete bloodcount, blood chemistry,coagulationstudies,thyroidstimulating hormone (TSH),freeT4 and urine analysis -see Table 3 (Grade D2).

A skeletalsurvey,skullseries (or low dose whole boneCT [13]) and chestx-ray (AP and lateral)are the firstradiographic examinations to be done. CT of specific areasof the skeleton are indicated when mastoid, orbital, scapu-lar,vertebral,or pelvic lesions are found by plain x-rays.MRI may detect additional osseous or extraosseous lesions.A skeletal scintigram (bone scan) alone does not suffice.

Any evidence of a pathological thoracic finding shouldbe followed up by high-resolution chest CT.Ultrasono-graphic examination of the abdomen may revealhepaticabnormalities.An ultrasound of the neck with attentionto the thyroid gland may be indicated if there are thyroidnodules or evidence ofthyroid dysfunction.A MRI ofhead is needed for hypothalamic/pituitary or brain abnor-malities.PET-(CT) scan may identify lesions missed byother modalities and documents response to therapy [14].

Further investigations may be indicated based on thepatient's symptoms and the findings ofthe basic diag-nostic tests - see Table 3 and 4 (Grade D2).

Definition of organ involvementPossibly involved organsAfter the diagnosis of LCH has been made,involvementof other organs should be evaluated and defined accordingto the clinical, biological or radiological criteria.

Risk organs (bone marrow,liver,spleen, CNS)Involvement in the hematopoietic system (extremely rarein adults),spleen,liver or CNS indicates a less favorableprognosis,with possible mortality if the patient does notrespond to therapy.Although this has never been provenfor adults,retrospective analysesof nationalregistriesand the experts’experience support the existence of theabove mentioned “risk organs”.

Fever,night-sweatsand weightloss combined withpoor performance score mightpredictthe rarely ob-served aggressive course of LCH in adults comparable tothat of high grade non-Hodgkin lymphoma [15,16].

“Special Sites” and “CNS-Risk” bone involvementVertebrallesions with intraspinalor cranofacialbone le-sions with soft tissue extensions (orbit,mastoid,sphen-oid or temporalbones) may cause immediate risk to thepatientbecause ofthe criticalanatomicalsite and thehazards ofattempting localtherapy.Isolated disease inthese “SpecialSites” justifies systemic therapy for chil-dren because of spinal cord compression and the associ-ation of cranio-facial bone lesions with an increased riskof developing diabetes insipidus [17].It is unclear ifthisconnection might be extrapolated to adults,but most ex-perts treating LCH patient follow the same guidelines fortheir adult patients as with the pediatric cases (Grade D2).

Endocrinologic dysfunctionLCH exhibits a predilection for the hypothalamo-pituitary(HP) region leading to permanent posterior and/or anter-ior pituitary hormonal deficiencies in a subset of patients.

Diabetes Insipidus (DI)is the mostcommon disease-related consequence that can predate the diagnosis or de-velop anytime during the course of the disease [18,19].DIis found in up to 30% ofpatients [1],but may reach to40% in patients with multisystem disease or 94% in thepresence ofother pituitary deficiencies [18,20].Polyuriaand polydipsia,and/or structuralabnormalities of the HPregion dictate investigations to confirm DI.

Anterior pituitary dysfunction (APD) is found in up to20% of patients,almost always with DI [18,21].AlthoughAPD is not invariably associated with abnormalHP im-aging it is almost always encountered in patients with MSLCH who have DI and HP pathology on MR imaging [22].Growth hormone deficiency (GHD) is the most frequentdisease-related APD found in up to 50% of patients withDI [20]. In adults there are no specific GHD-related symp-toms thatcan suggestthe diagnosis [23].Gonadotropin

Table 3 Baseline laboratory and radiographic evaluationRecommendation GradeFullBlood Count (Hemoglobin,White blood celland differentialcount,Platelet count)

D2

Blood Chemistry (Totalprotein,Albumin,Bilirubin ,ALT (SGPT),AST (SGOT)

D2

Alkaline phosphatase (AP),gammaglutamyltranspeptidase (γGT)Creatinine,Electrolytes,CRP (C-reactive Protein)Erythrocyte Sedimentation Rate (ESR) D1Coagulation Studies (INR/PT,Fibrinogen) D2Thyroid Stimulating Hormone (TSH),freeT4 D2Morning Urine Osmolarity D1Urine Test Strip D2Ultrasound (liver,spleen,lymph-nodes,thyroid gland) D2Chest Radiograph (CXR) D2Low Dose Whole Body (Bone) CT (if not available:X-RaySkeletal/ScullSurvey)

D2

Optional:Baseline Head-MRI D2Optional:PET-CT instead of Ultrasound,CXR and Bone CT D2

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deficiency is the second mostcommon deficiency,pre-senting with menstrualdisturbances in women and de-creased libido in men [20].ACTH deficiency may bepartialor complete and presenteither with non-specificsymptomsor as acuteadrenalinsufficiencyfollowingstressfulevents.TSH deficiency isalmostalwaysasso-ciated with panhypopituitarism and maypresentwithsubtlesymptomsor obvioussignsof hypothyroidism.Moderately elevated prolactin levels attributed to pituitary

stalk infiltration can cause galactorrhoea in females andgonadotropin deficiency in allpatients.Established endo-crinedeficienciesalmostneverrecoverover time,al-though apparent HP abnormal imaging may often regresseither in response to treatment or as a result of the “nat-ural course” of the disease [22].

Hypothalamic involvement is less frequent than pituit-ary involvementand leadsto not only pituitarydys-function,but neuropsychiatric and behavioraldisorders,

Table 4 Specific clinical scenarios: recommended additional testingRecommendation GradeHistory of polyuria or polydipsia: D2• Urine and Plasma osmolality• Water deprivation test• MRIof the headSuspected Other Endocrine Abnormality: D2• Endocrine assessment (including dynamic tests of the anterior pituitary,MRIof the head)Bi- or Pancytopenia, Or Persistent Unexplained Single Cytopenia: D2• Any other cause of cytopenia has to be ruled out according to standard medicalpractice• Bone marrow aspirate and trephine biopsy to exclude causes other than LCH• In case of morphologicalsigns of hemophagocytosis additionaltests like serum-ferritin should be performed (criteria of HLH)Liver Or Spleen Abnormalities: D2• In case of any unclear sonographically pathology CT,PET-CT,MRIor Scans should be added (the choice is depending on thesonomorphology – discuss with your radiologist)• Visuable lesions of the liver should be biopsied if possible• Other causes of splenomegaly has to be ruled out before it may be assigned to LCH• ERCP (Endoscopic Retrograde Cholangiopancreatography) or MRCP (Magnetic Resonance Cholangiopancreatography) should be performedin case of elevated serum cholestasis markers or sonomorphologically dilatated bile ducts.Primary biliary cirrhosis and primary sclerosingcholangitis have to be ruled out.Unexplained Chronic Diarrhea, Weight loss, Evidence Of Malabsorption Or Hematochezia D2• GI-Exploration (Endoscopy with biopsies,capsule endoscopy)Enlarged Lymph Nodes (LN): D2• If found by screening ultrasound or physicalexamination the best suitable LN should be extirpated.A LN needle biopsy should be avoided.• CT scans or a PET-CT should be performed additionallyLung Involvement - In case of abnormal Chest X Ray or symptoms/signs suggestive for lung involvement or suspicion of apulmonary infection:

D2

• Lung high resolution computed tomography (HR-CT)• Lung function tests (Spirometry,Diffusing capacity,Oxygen desaturation during exercise (6MWT),blood gases)• Bronchoalveolar lavage (BAL):> 5% CD1a + cells in BAL fluid may be diagnostic of LCH• Lung biopsy (if BAL is not diagnostic),ideally Video-assisted thoracoscopic surgery (VATS)Osseous Disease: D2• CT +/- MRIshould be performed in case of craniofacialor vertebrallesions or signs of additionalsoft tissue involvement• Biopsies should be taken from the most suitable region in case of multifocalbone diseaseSkin, Oral And Genital Mucosa lesions: D2• Biopsies should be takenAural Discharge Or Suspected Hearing Impairment / Mastoid Involvement: D2• Formalhearing assessment• MRIof head

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disturbances ofthermo-regulation and sleeping pattern,and autonomic and metabolic abnormalities.The mostfrequent consequence is severe obesity due to increasedappetite. Hypothalamic-related adipsia may seriously com-plicate the management of DI.

Metabolic abnormalities:One study involving 14 adultpatients and 42 controls has shown that adults with LCHare athigh risk ofdeveloping abnormalities ofcarbohy-drate metabolism (diabetes mellitus,impaired glucose tol-erance) and lipid metabolism leading to increased insulinresistance even in the absence of obesity [24].

Bone metabolism:Adults with LCH may present witha lower than expected bone mineraldensity atany ageespecially during periods of active disease [25].

Investigation ofhormonaldeficiencies:Evaluation ofTSH, free T4 and morning urine osmolality isrecom-mended in all patients,further procedures (water depriva-tion test,plasma osmolality,serum cortisol,insulin likegrowth factor I,gonadal steroids and gonadotropin serumlevels) to detect partial DI or anterior pituitary deficienciesshould be performed when clinical symptoms are present(Grade D2).

Dermatological involvementCutaneous LCH can be the great pretender,mimicking anumber of common dermatoses,and may represent theearliest sign of the disease [26].The typicalscalp lesionsare small translucentpapules,1-2 mm in diameter,slightly raised and rose-yellow in colour.These lesionsfrequently show scaling or crusting,often leading to amisdiagnosis of seborrheic dermatitis.

Intertriginous involvement in the axillary,inguinal,vul-var,or anogenital regions with erythema and erosions arefrequently misdiagnosed as eczema,psoriasis,Candida in-fection,or intertrigo.Generalised skin eruptionscanmimic guttate psoriasis prurigo nodularis or lichen planus.

Gingivalinvolvementis frequently associated with al-veolar bone involvementand loosening ofteeth.Toothextraction should be avoided as with treatment they willembed into the recovering alveolar bone.Nail changesinclude paronychia,onycholysis,subunguealhyperkera-tosis and purpuric striae ofthe nailbed,suggesting awide panelof conditions.Dark-brown striae similar tothose drug-induced are also seen.

Cutaneous LCH has so many differentmanifestationsthat one needs a high level of suspicion and biopsy is es-sential. Although skin disease may be the primary presenta-tion, one must investigate for systemic disease (Grade D2).

Gastrointestinal involvementGastrointestinal(GI) tractinvolvementby LCH is rareand may appear as a solitary colorectalpolyp or multiplegranulomatouslesionsof the mucousmembraneinthe upper and lower GItract[27].Patients are often

asymptomatic.Multiple infiltrationsare associated withabdominal pain, diarrhea, and hypoalbuinemia.

Liver infiltration is characterized sometimes by infiltra-tion of CD1a+ cells in nodules or by lymphocytes alonealong theportaltractswhich maylead to sclerosingcholangitis.In case ofsplenomegaly other causes thanLCH primarily have to be ruled out.Pancreatic involve-ment (mainly tumorous) is extremely rare.

StratificationSingle System LCH (SS-LCH): One organ/system involved(uni- or multifocal):

➢ Bone: unifocal (single bone) or multifocal (> 1 bone)➢ Skin➢ Lymph node➢ Hypothalamic-pituitary / Central nervous system➢ Lungs (primary pulmonary LCH)➢ Other (e.g. thyroid, gut)

Multisystem LCH (MS-LCH):Two or more organs/sys-tems involved:

➢ With involvement of “Risk Organs” (Hematopoieticsystem, spleen, and/or liver, tumorous CNS)➢ Without involvement of “Risk Organs”

TreatmentManagement algorithms (see Figure 1)Treatmentrecommendations are based on site and ex-tension of the disease.

Careful observation,local or “mild systemic” therapy

Bone involvementIn case ofsingle system LCH withunifocal bone involvement of “non-CNS-Risk facial bones”localtherapy and carefulobservation isrecommended.The modality of treatment depends on location,size,andsymptoms ofthe disease.Biopsy or curettage is suitablefor histopathologicdiagnosisand initiatinga healingprocess. Complete excision of bone lesions is not indicatedas it may increase the size of the bony defect and the timeto healing or result in permanent skeletaldefects.Intra-lesionalinjection ofsteroid may hasten healing.Dosagesof 40 – 160 mg ofmethylprednisolone have been used[28] (Grade C2).Radiotherapy is indicated ifthere is animpending neurologicaldeficitand a high surgicalrisk,e.g.lesion in the odontoid peg or cranial base.For multi-focalbone LCH and forbone lesions in “specialsites”systemic therapy (see nextpage underfrontline treat-ment) should be given (Grade D2).

Isolated lymph nodes involvement Isolated lymph nodesinvolvementis rare butspontaneousregressionshave

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been observed. Thus extensive surgery (e.g. neck-dissection)and systemic therapy should be omitted [29] (Grade C2).

Skin Involvement Surgical excision should be limited tosolitary lesions,but mutilating surgeries such as hemi-vulvectomy should not be performed (Grade D2).If thepatient is being treated for multisystem disease the skinwill respond to treatment.In single system skin diseaseor in the rare instance where the skin fails to respond fullyto systemic treatment for multisystem disease there are anumber of treatments directed specifically to the skin.

Topical nitrogen mustard: 20% nitrogen mustard appliedto the skin is an effective treatment in children [30]. Thereis no published data on treatment in adults and there areproblems with availability in most countries (Grade C1).

Phototherapy:Psoralen plus ultraviolet A (PUVA) [31]and narrow band ultraviolet (UV) B [32] are effective intreating cutaneous LCH in individualcase reports.It isdifficultto treat patients with intertriginous or scalp in-volvement and would be contraindicated in penile disease(Grade C1).

Thalidomide: is a TNF-α antagonist and has been shownto be effective in treating cutaneous LCH [33] but givespoor responses in high risk multisystem disease [34]. Doseof 100mg/day in adults is generally used but toxicity withperipheral neuropathy must be monitored (Grade C2).

Azathioprine:There are no published reports of the useof azathioprine (orits metabolite 6-mercaptopurine)inadults with cutaneous LCH but it is a useful drug in singlesystem skin as wellas multisystem disease [35].Patientsneed to be tested for thiopurine methyl transferase,and ifnormalshould be treated at a dose of2mg/kg/day.Thedrug takes about 6 weeks to become effective (Grade D1).

Methotrexate:There are published reports on the useof low dose methotrexate as eithersingle agenttreat-ment or in combination with azathioprine or prednisol-one.Methotrexate was used successfully at the dosagesof 20mg once weekly [36] (Grade C1).

Involvement of the oral mucous membranes These le-sions should be treated with “mild systemic” therapy asdescribed above and extraction of teeth should be avoidedas much as possible.In refractory cases more intensivesystemictreatmentis required(see next paragraph)(Grade D2).

Systemic therapy

Front line treatmentSystemic therapy should be con-sidered 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 standard first line therapy like in pediatricLCH. Vinblastine/prednisolone is mentioned in variouschemotherapeutic manuals,but has never been proveneffective for adults in a prospective study. An internationaltrialfailed because of low recruitment rate.Due to lowerrisk of neurotoxicity and frequently observed unacceptablesteroid induced side effects some experts prefer mono-therapy with cladribine,cytarabine or etoposide [35].In aretrospective study evaluating 58 adult patients with bonelesions the authors observed a clearsuperiority ofcyt-arabine especially to vinblastine/prednisolone but even to2-CDA in terms ofresponse and toxicity [37].Intensivecombination chemotherapies (e.g.MACOP-B) are effect-ive [38] but should be used only in rare cases of an aggres-sive LCH form [15] (Grade C1).

Until recently,most experts started with 2-CDA in caseof risk organ or tumorouscerebralinvolvement,butcytarabine may be a reasonable alternative (Grade C2).

Some investigatorshave used bisphosphonatesformultifocal bone disease,but patients have to be advised tothe risk of osteonecrosis of the jaw and its prevention [39].COX-Inhibitors might be more than analgetic drugs andregression of LCH was observed [40] (Grade C2).

Grade ofrecommended systemic firstline therapy islisted in Table 5.

Evaluation ofresponse Evaluation is done after 2 to 3cycles of chemotherapy.If there is disease progression orreactivation,complete evaluation as recommended in theprevious section has to be performed (Grade D2).

Maintenance therapy Etoposide or 2-CDA are usuallyadministered up to 6 months.Cytarabine can be given atlow dose monthly up to a year in most patients (6-12 cy-cles) (Grade D2).Table 5 First line systemic therapyRecommendation GradeMild Symptoms, No Risk Organ Involved:• Methotrexate 20 mg per week p.o/i.v. C1• Azathioprine 2 mg/kg/d p.o D1• Thalidomide 100mg/d p.o in skin or soft tissue multifocalsingle system LCH

C2

Additionally In Multifocal Bone LCH• zoledronic acid 4 mg i.v. C2q 1 (- 6) month (depending on extent and response) C1Symptomatic, MS-LCH, No Risk Organs involved• Cytarabine 100 mg/m2 d1-5 q4w i.v. C1• Etoposide 100 mg/m2 d1-5 q4w i.v. D1• Vinblastin/Prednisolone (like in pediatric studies) C1MS-LCH, Risc Organs Involved• 2-CDA 6 mg/m2 d1-5 q4w s.c./i.v. C2

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SalvagetherapyRefractory diseaseshould betreatedwith drugs not used for the first course.In case of furtherprogression,especiallyin CNS involvementcytarabinemay be added to 2-CDA (both drugs cross the blood brainbarrier) [41].Some cases with response to tyrosine kinaseinhibitors (imatinib)have been reported [42,43].In therare case ofa mostaggressive course ofdisease hema-topoietic stem cell transplant has been performed success-fully aswell [44,45].Clofarabine hasbeen effective forrefractory childhood LCH [46] (Grade C2).

Treatment options in case of reactivationReactivations of LCH in adults occur in about 25-38% ofthe patients (European nationalregistry data and [37]).Patients may have further reactivations especially thosewith multisystem disease.

Reactivation of single system diseaseThe choice oftreatmentoptions is based on the sameprinciples as for initial disease.

The options for reactivations ofSS-LCH (skin,bone,other) include

I. Wait and watch approachII. Local therapy including irradiation (as above)III.Bisphosphonates for bony disease (as above)IV.Chemotherapy (as above)

In case of a multisystem reactivation of a SS-LCH, treat-mentshould follow the options for MS-LCH includingsystemic therapy (Grade D2).

The efficacy of 2-CDA for single and multisystem reac-tivated LCH has been proved in a phase II trial [47].

Reactivation after systemic therapy

I. If the reactivation is more than one year aftercompletion of treatment,re-induction with the priorchemotherapy may be effective.If however,thedisease is not responsive we suggest discussion withthe reference centre for your country.

II. If reactivation occurs while on treatment,potentially2nd line strategies as described above,but should begenerally discussed with your reference centre(Grade D2).

RadiotherapyIn contrast to pediatric recommendations,radiotherapy isan effective treatment option with acceptable side-effectsfor adult patients with LCH in selected situations [48-52].

Most literature data concerning radiotherapy in adultLCH dealwith uni- or multifocalosseous single-systemdisease.The localcontrolratesranged from 75-100%,complete remission from 79-100%,respectively [53].

The dose recommendation for radiotherapy is still con-troversialand an exactdose-effectrelationship hasnotbeen established.There is a wide dose range ofappliedtotaldoses from 1,4 Gy up to 45 Gy.In general,a doserange from 10 to 20 Gy is recommended in adults [50,54])(Grade C2).

Recommended indications for the use ofradiotherapyin adults with LCH are listened in Table 6.

Treatment and hormone replacement of endocrinopathiesDI should be treated with desmopressin.The timing anddosage must be individualized.In proven LCH new on-setDI is a sign ofactive disease and initiation ofsys-temic treatmentis recommended to try to preventthedevelopmentof further hormonaldeficiencies althoughexisting ones usually do notresolve [55].Adequate re-placementof hormonaldeficiencies should be initiatedas soon the diagnosis is made (Grade D2).

Central nervous system involvementTumorous lesionsThese lesionsare most frequentlyobservedin thehypothalamic-pituitaryregion.The tumor size rangesfrom discrete thickening of the pituitary stalk to larger tu-mors.Parenchymal,meningealor choroid plexus lesionsoccur less frequently [56].

In addition to hormone replacement isolated cerebraltumors should be treated with irradiation or chemother-apy and pituitary/hypothalamic lesions with chemother-apy.Multifocalbrain lesions or single brain lesions withmultisystem disease need to be treated with chemother-apy.The most suitable drugs are Cladribine or Cytarabineas described above (Grade C2).

Neurodegerative LCHNon-tumorous MRIfindings ofthe cerebellum,and/orbrain stem are histopathologically different than the typ-ical LCH mass lesions.The neurodegenerative lesionslack CD1a+ histiocytes and have infiltrating CD8+ lym-phocytes [55].Some of these patients show no symptoms,othershave clinicalsignsranging from subtile tremor,

Table 6 Possible indications for the use of radiotherapyin adultsRecommendation GradeIsolated “Unresectable” lesion: C2if a resection would significantly compromise anatomicfunction,e.g.odontoid peg,CNSRecurrent or progressive lesion: C2In multifocalor multisystem disease only in case of minorresponse to standard systemic therapyAdjuvant treatment following marginal or incompleteresection: especially in single system bone disease with softtissue involvement

C2

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dysarthria,dysphagia,and motor spasticity to pronouncedataxia,behavioraldisturbancesand severepsychiatricdisease.

Retinoic acid and intravenous immunoglobulin may sta-bilize such patients [57,58].Improvement with infliximabhas been observed in one case [59].Cytarabine with orwithout Vincristine provided improvement in 5/8 patientsof which 4/8 remained stable over more than 7 years offollow-up and one relapsed butis improved after treat-ment with intravenousMethotrexate.Patientswhoresponded to Cytarabine/Vincristine had symptomsforlessthan 18 monthsbefore starting treatment[60,61].Thus early onsetof Cytarabine is recommended as firstline therapy,but for any case ofneurodegenerative LCHwe suggest discussion with the reference centre for yourcountry (Grade C1).

Primary pulmonary LCHEpidemiologyThe incidence ofpulmonary LCH (PLCH) is unknown.Reports provided by histopathologicalstudies and inter-stitial lung diseases registries revealed about 5% of PLCHin this population [62].Data from a Japanese surveyshow an estimated prevalence of 0.07-0.27/100000 popu-lation in females and males,respectively [63].The preva-lence may be underestimated.

PLCH affectsmainly young,predominantly smoking(> 90%) adults with a peak at 20-40 years ofage and aslightpredominance ofwomen.It is unknown ifthereare any racial differences in this disease [62].

Clinical featuresPatients with PLCH often present with a non-productivecough or dyspnoea,chestpain,associated non-specificsymptomslike fatigue,weightloss,night sweatsandfevermay be observed [62,64].About20% ofpatientswith PLCH are initially asymptomatic and an equalper-centage ofpatients presentwith acute symptomsof apneumothorax.

It is important to exclude the existence of multi systemLCH. Thus,a thorough history,comprehensive physicalexamination,and baseline radiographic,blood and urinetests should be performed in any patient presenting withPLCH to avoid undertreatment. (see Table 3 and 4).

DiagnosisX-Ray ofthe chestshows a reticulo-micronodular pat-tern.In more advanced cases cysts may be visible withinthe infiltrates symmetrically in both lungs,but predom-inating in the middle and upper lung fields and sparingthe costophrenic angles [62].

High resolution CT (HRCT)is the mostimportantvisualizing toolfor PLCH [62].The typicalHRCT pat-tern is of smallnodules,cavitated nodules(both may

resolve),and thick- and finally thin-walled cysts.As thediseaseevolves,cysticlesionsbecomea predominantfinding.

Pulmonary lung function tests mostfrequently showreduced diffusing capacity ofthe lung for carbon mon-oxide (DLCO),70–90% ofthe patients.Lung volumesare impaired in a majority ofpatientswith decreasedvital capacity and air trapping (elevated residual volume).Total lung capacity is within normal values in most cases.An obstructive pattern is observed in a sizeable proportionof patients,particularly in advanced disease.Rarely a re-strictive componentmay appear[65].A predominantlynodular pattern suggestive of active inflammatory diseasecan have only moderate functional consequences [65].

Bronchoalveolar lavage (BAL) often shows high alveo-lar macrophage counts,reflective ofsmoking.Infectionshould be systematically ruled out.BAL yielding morethan 5% CD1-positive cells has previously reported tosupportthe diagnosisof pulmonary LCH [66].Whilethis has a high specificity,BAL results lack sensitivity.

Bronchialbiopsies are nothelpfulin the diagnosis ofPLCH but are usefulin ruling out other diagnoses in pa-tients with atypical manifestations. The diagnostic methodof choice is therefore videothoracoscopic lung biopsy afterHRCT evaluation (see Table 7).In asympto-matic patientswith a typicalHRCT pattern and a macrophage alveolitisby BAL,for whom no systemic therapy is required,a pre-sumptive diagnosis may be acceptable with a close follow-up.In patients with extensive cystic lesions,the risk ofinvasive procedures has to be balanced with the need fora definitive diagnosis (Grade D2).

Treatment and prognosisThe naturalhistory ofadults with PLCH is widely vari-able and mostly unpredictable in the individualpatient.About 40-50% of patients with PLCH experience a favor-able outcome and partialor complete clearance oftheradiological abnormalities occurs with or without therapy.

Serial lung function tests are essential for following pa-tients with PLCH.In a recent retrospective multicenterstudy,lung function (mainly DLCO and FEV1) deterio-rated in approximately 60% of the patients [65].An iso-lated decline ofDLCO in symptomatic patients shouldprompta search for pulmonary hypertension by echo-cardiography and in case of increased systolic pulmonaryTable 7 Diagnostic recommendations in pLCHRecommendation GradeConfirm definitive diagnosis• in allpatients before start of systemic therapy D2• prefer lung biopsy D2• HRCT is required in allpatients D2Exclude Existence Of Multi System LCH D2

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arterialpressureshould beconfirmed byright heartcatheterization [67].

Based on the epidemiologic data smoking cessation isessential.Patients with a stable disease despite ongoingsmoking should be told aboutall other known medicalreasons for ceasing smoking and enrollment in a supportgroup may be valuable [62,64].

There are no study-based data supporting cortisonetherapy forpulmonary LCH.Any possible therapeuticbenefitfor symptomatic patientsshould,therefore,becarefully weighed against the potentialundesired effectsof this form oftreatment,because spontaneous remis-sions do occur.If smoking cessation failed and treatmentis required systemic steroid therapy (usually 1mg/kg/day

for one month, followed by tapering dosages over months)may be given in patients with the nodular form ofpul-monary LCH [62,64].

Lower respiratory tract infection is a common cause ofdeterioration of PLCH and should lead to prompt treat-ment.Annualvaccination againstinfluenza aswell asanti-pneumococcalis recommended forpatientswithimpaired lung function.

ProgressivePLCH despite steroidtherapymay betreated with 2-CDA [68,69].A randomized controlledtrial evaluating the effectiveness and tolerance of 2-CDAin this subgroup of patients is ongoing.

Pneumothorax requires drainage and pleurodesis shouldbe considered in case of recurrence [70].Lung transplant-ation (LT) may represent a therapeutic option in case ofadvanced PLCH (severe respiratory failure or major pul-monary hypertension). Recurrence of LCH after transplata-tion occurs in 20% without impact on the survival rate [71].

Grades ofrecommendations for therapy in pLCH arelisted in Table 8.

PregnancyThere are only a few reports about pregnancy and LCHwith worsening to no change ofclinicalsymptoms,but

Table 8 Therapeutic recommendations in pLCHRecommendation GradeFirst step is smoking cessation in allpatients C2Watchfulwaiting in a- or minor symptomatic patients C2Systemic steroid therapy in symptomatic patients C2Chemotherapy (e.g.2-CDA) in progressive disease C2Consider lung transplantation in case of severe respiratoryfailure or major pulmonary hypertension

C2

Table 9 Recommendations for follow-upTest Frequency GradeSS-LCH And No Disease ActivityHistory (especially of thirst,polyuria,cough,dyspnea,bone pain,skin changes,neurologicalsymptoms)

• Every clinic visit D2

Clinicalassessment,blood count and blood chemistry (as described in baselinediagnostics),ultrasound

• End of therapy D2• every 6 month (for the next 2 years)• then once a year (for at least 3 years)

Chest XR • annually (for at least 3 years) D2After MS-LCH And With No Disease ActivityHistory (especially of thirst,polyuria,cough,dyspnea,bone pain,skin changes,neurologicalsymptoms)

• Every clinic visit D2

Clinicalassessment,blood count and blood chemistry (as described in baselinediagnostics),ultrasound

• End of therapy D2• 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)

Chest XR • annually (for at least 3 years) D2TSH,freeT4 • Once a year (untilend of routinely follow up) D2Patients With Active DiseaseDiagnostic procedures are depending on the site of organ involvementFrequency is depending on rates

and velocity of recurrencesD2

Patients With pLCHHistory (in case of non-pulmonary symptoms:look for MS LCH,see Table 4) • Every clinic visit D2Diagnostic procedures are depending on symptoms und course of PLCH(baseline:Chest X-ray,lung function (+DCLO)

• End of therapy D2• every 6 month (for the next 2 years)• then once a year (for at least 5 years)

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Page 10: Management of adult patients with Langerhans cell histiocytosis

even improvement was observed. Deterioration was main-ly related to diabetes insipidus.It is unclear ifworseningor onset of DI during pregnancy is really caused by LCH.This may also be observed in women not suffering froma histiocytic disorderand is caused by an accelerateddegradation ofvasopressin through placentalenzymevasopressinase [72].

It is unpredictable if and in which way pregnancy mayinfluence the course ofLCH. The scantliterature sug-gests there is no adverse impactof LCH on pregnancyor birth,with exception ofneed for cesarean section inselected cases [73,74] (Grade C2).

Follow upLCH may reactivate and lead to chronic local symptomsor induce organ dysfunction.Rarely LCH is associatedwith malignanttumors.Therefore,follow-up investiga-tionsof disease and monitoring offunctionalimpair-ments are necessary.

Restaging every 2-3 months is standard.Follow-up in-tervals depend on the primary extent and activity of dis-ease within 3 to 12 months(see Table 9).In case ofaffirmed reactivation,clinicalevaluation should includeall investigations listed above (Grade D2).Competing interestThe authors declare that they have no competing interests.

Authors’contributionsBased on the available literature up to December 2012,recommendationswere established,drafts were commented by the entire group,and redraftedby the executive editor.Allauthors read and approved the finalmanuscript.

Author details1Department of Medicine I,Center of Hematology an Stem CellTransplantation,Hemostasis and MedicalOncology InternalMedicine I,Elisabethinen Hospital,Fadinger Str.1 4010,Linz,Austria.2Department ofPediatric Hematology Oncology,Azienda Ospedaliero Universitaria A.Meyer,Florence,Italy.3Departament of Respiratory Medicine,Hospitalde la SantaCreu iSant Pau,Barcelona,Spain.4ImperialNHS Trust,London,UK.5Clinic forInternalMedicine,Protestant Clinics,Gelsenkirchen,Germany.6ParacelsusKlinik,Osnabrück,Germany.7Service de Medicine Interne,Groupe HospitalierPitie-Salpetiere,Paris,France.8Department of Pathophysiology,University ofAthens Schoolof Medicine,Athens,Greece.9Department of Endocrinologyand Diabetes,251 Hellenic Air Force & VA GeneralHospital,Athens,Greece.10U.O.Dermatologia,Fondazione IRCCS Ca´ Granda-Ospedale MaggiorePoliclinico,Milano,Italy.11Department of InternalMedicine,HospitalSaintLouis,Paris,France.12Department of Radiotherapy and Radiation Oncology,Franziskus Hospital,Bielefeld,Germany.13Radiation Oncology Center,Hamburg,Germany.14Pulmonolgy Department,Saint Louis TeachingHospital,Paris,France.15Texas Children’s Cancer Center/Hematology Service,Houston,TX,USA.

Received:10 February 2013 Accepted:2 May 2013Published:14 May 2013

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doi:10.1186/1750-1172-8-72Cite this article as:Girschikofsky et al.:Management of adult patientswith Langerhans cellhistiocytosis:recommendations from an expertpanelon behalf of Euro-Histio-Net.Orphanet Journalof Rare Diseases 20138:72.

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