Langerhans cell histiocytosis

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Langerhans cell histiocytosis

Thiviyani Maruthappu and Anthony C. Chu

Evidence Levels: A Double-blind study B Clinical trial ≥ 20 subjects C Clinical trial < 20 subjects D Series ≥ 5 subjects E Anecdotal case reports

Langerhans cell histiocytosis (LCH) is a reactive condition defined by the accumulation/proliferation of a clonal population of epidermal Langerhans cells. Patients can have either single or multiple organ involvement. Children tend to have more aggressive disease than adults.

LCH encompasses the diseases previously known as histiocytosis X, eosinophilic granuloma, Hand–Schuller–Christian disease, Letter Siwe disease, congenital self-healing reticulohistiocytosis (Hashimoto–Pritzker), Langerhans cell granulomatosis, and non-lipid reticuloendotheliosis.

Management strategy

Prior to institution of therapy a full investigation must be completed. A definitive diagnosis can be made histologically by identification of Langerhans cells that express CD1a by immunohistochemistry and the finding of Birbeck granules by electron microscopy.

Treatment depends on the organ(s) involved and the severity of the disease and thus should be tailored to the individual patient. Most published data is based on case reports and small case series in children and this evidence may not always be directly applicable to adults. Patients are staged as single system disease (with bone involvement this is further stratified into mono-ostotic and poly-ostotic bone disease), multisystem disease, and multisystem disease with evidence of organ dysfunction. Although some patients with LCH may undergo spontaneous remission, the disease is unpredictable and many patients progress from single system disease to multisystem disease. Organs most commonly involved include the bone, skin, lymph nodes, pituitary, liver, lungs, central nervous system, gastrointestinal tract, spleen, bone marrow, and endocrine system.

Single system bone or skin disease has a good prognosis and may not require treatment. Curettage or intralesional steroid injections can also be used in single system bone disease. Single system skin disease may respond to local measures with topical steroids, topical nitrogen mustard, topical tacrolimus or phototherapy. Single system lung disease may respond to prednisolone at 2 mg/kg/day. In single system disease that does not respond to these measures, single system lymph node disease and multisystem disease without organ dysfunction, systemic treatment with azathioprine (2 mg/kg/day) with or without low dose, weekly methotrexate (5–10 mg/week) may lead to resolution.

In recalcitrant disease or in multisystem disease with evidence of organ dysfunction, treatment will depend on the age of the patient. Organ dysfunction of key organs – liver, lungs, spleen and bone marrow – carries the worst prognosis. Trials have demonstrated that, in pediatric patients, prednisolone with vinblastin is the treatment of choice. This combination is less effective in adults, who are also more sensitive to their side effects. In adult patients, first-line treatment is etoposide. In pediatric studies the use of maintenance therapy has been shown to reduce the overall morbidity of the disease. Adults often have a more chronic and relapsing course to their disease and maintenance therapy with azathioprine for 1 year should be considered in all patients with multisystem disease. In both children and adults with multisystem disease with organ dysfunction, there remains a small group who do not respond to conventional therapy. In these patients, 2-chlorodeoxyadenosine has proved useful and, in severe disease, bone marrow transplantation has been successful. A number of drugs have been used in various stages of the disease but most are anecdotal case reports. Long-term morbidity can be correlated to organ involvement or occur as a direct consequence of treatment, and includes skeletal deformities, risk of secondary malignancies (particularly with the use of alkylating agents and radiotherapy), endocrine dysfunction, and infertility.

Specific investigations

Routine investigations

Biopsy of organ involved for staining for S100 and CD1a or electron microscopy for Birbeck granules. The presence of Birbeck granules may also be demonstrated by immunohistochemical staining of langerin (CD207)

Full blood count with differential

Coagulation tests (PT, APTT)

Whole body MRI is the most effective way to identify both skeletal and non-skeletal disease

Indicated investigations

Lung function tests in patients with lung disease

CT chest for all adult smokers or children with chest signs or symptoms

Bronchoalveolar lavage for CD1a+ cells or open lung biopsy if evidence of lung involvement

CT brain and pituitary fossa if signs of diabetes insipidus

Plasma and urine osmolality if signs of diabetes insipidus. A water deprivation test, if required

Full hormone screen if diabetes insipidus confirmed

MRI brain if lytic skull lesions, diabetes insipidus or symptoms suggestive of CNS involvement

Panorthogram if gum involvement

Bone marrow biopsy if hematological abnormalities

Abdominal ultrasound and liver biopsy if abnormal liver function

Multiple bowel biopsies if evidence of malabsorption or failure to thrive in an infant

Histiocytosis syndromes in children: approach to the clinical and laboratory evaluation of children with Langerhans cell histiocytosis.

Broadbent V, Gadner H, Komp DM, Ladisch S. Med Pediatr Oncol 1989; 17: 492–5.

Multiple organ systems may be affected in patients with LCH. Therefore, the following studies are recommended for all patients at diagnosis: a complete blood count with white blood cell differential, liver function tests, coagulation times (PT and PTT), chest radiograph, and radiographic skeletal survey (more sensitive than a radionuclide bone scan for detecting bone lesions). A measurement of urine osmolality after overnight water deprivation should also be obtained. Further evaluations should be tailored to patients based on specific presenting signs and symptoms.

First-line therapies

Skin disease
Topical nitrogen mustard	C
Phototherapy (PUVA, narrowband UVB)	E
Topical tacrolimus	E
Multisystem disease
Vinblastine	B
Etoposide (VP16)	B

Topical nitrogen mustard: an effective treatment for cutaneous Langerhans cell histiocytosis.

Sheehan MP, Atherton DJ, Broadbent V, Pritchard J. J Pediatr 1991; 119: 317–21.

Sixteen children with multisystem LCH with severe skin involvement were treated with topical nitrogen mustard with rapid clinical improvement. One child developed a contact allergy after use.

Long term follow up of topical mustine treatment for cutaneous Langerhans cell histiocytosis.

Hoeger PH, Nanduri VR, Harper JI, Atherton DA, Pritchard J. Arch Dis Child 2000; 82: 483–7.

Topical nitrogen mustard (0.02% mechlorethamine hydrochloride mustard) was found to be safe in cutaneous disease. Follow-up in this study was an average of 8.3 years.

Topical nitrogen mustard ointment with occlusion for Langerhans’ cell histiocytosis of the scalp.

Treat JR, Suchin KR, James WD. J Dermatolog Treat 2003; 14: 46–7.

Topical nitrogen mustard ointment 0.01% under occlusion cleared a patient with scalp LCH in 3 weeks without irritation.

Topical nitrogen mustard in patients with Langerhans cell histiocytosis.

Lindahl LM, Fenger-Gron M, Iversen L. Br J Dermatol 2012; 166: 642–5.

Ten children and four adults with skin involvement with LCH treated with nitrogen mustard and studied retrospectively. In five patients the skin improved but in four patients systemic disease progressed; six patients developed contact dermatitis.

Topical nitrogen mustard is the best studied and most effective topical therapy. Contact allergy and risk of cutaneous carcinogenicity limit its use. It is not recommended for disease involving large areas of skin.

Satisfactory remission achieved by PUVA therapy in Langerhans cell histiocytosis in an elderly patient.

Sakai H, Ibe M, Takaahashi H, Matsuo S, Okamoto K, Makino I, et al. J Dermatol 1996; 23: 42–6.

Case report of a 74-year-old man with cutaneous LCH and diabetes insipidus. Five weeks of PUVA therapy led to complete clearance of skin lesions. The endocrinopathy persisted.

Cutaneous Langerhans cell histiocytosis in an elderly man successfully treated with narrowband ultraviolet B.

Imafuku S, Shibata S, Tashiro A, Furue M. Br J Dermatol 2007; 157: 1277–9.

Doses of 0.4 J/cm² to 1.0 J/cm² were given incrementally (total irradiation of 9.3 J/cm²). Eleven sessions led to almost complete resolution in a Japanese man which persisted at least 12 months after therapy discontinued.

Etoposide in recurrent childhood Langerhans cell histiocytosis: an Italian cooperative study.

Ceci A, De Terlizzi M, Colella R, Balducci D, Toma MG, Zurlo MG, et al. Cancer 1988; 62: 2528–31.

Twelve of 18 patients with recurrent LCH had a complete response and three a partial response after treatment with etoposide (200 mg/m²/day given 3 days every 3 weeks).

Langerhans cell histiocytosis in childhood: results from the Italian Cooperative AIEOP-CNR-H.X. ‘83 study.

Ceci A, de Terlizzi M, Colella R, Loiacono G, Balducci D, Surico G, et al. Med Pediatr Oncol 1993; 21: 259–64.

Ninety patients were divided into those with and without organ dysfunction. Monotherapy with either vinblastine or etoposide was an effective treatment in patients without organ dysfunction.

A randomised trial of treatment for multisystem Langerhans’ cell histiocytosis.

Gadner H, Grois N, Arico M, Broadbent V, Ceci A, Jakobson A, et al. J Pediatr 2001; 138: 728–34.

This controlled trial of 24 weeks of vinblastin (6 mg/m², IV weekly) or etoposide (150 mg/m²/day for 3 days every 3 weeks) and an initial dose of methylprednisolone (30 mg/kg/day for 3 days), recruited 143 untreated children with multisystem LCH. The two treatments were found to be equally effective with response rates of 58% for vinblastin and 69% for etoposide. Vinblastin is considered safer for use in children

Etoposide has been consistently shown to be effective in multifocal LCH. However, the small risk of secondary leukemia following treatment in children with etoposide limits its use to the most high-risk pediatric patients.

Second-line therapies

Prednisolone	B
6-Mercaptopurine	B
Thalidomide	C
Methotrexate	C
Cytosine arabinoside (Ara-C)	C
2-Chlorodeoxyadenosine (2-CdA)	C

Improved outcome in multisystem Langerhans cell histiocytosis is associated with therapy intensification.

Gadner H, Grois N, Pötschger U, Minkov M, Aricò M, Braier J, et al. Histiocyte Society. Blood 2008; 111: 2556–62.

This randomized controlled trial had 193 patients with multisystem disease. Arm A consisted of 4 weeks prednisone 40 mg/m² once daily tapering over 2 weeks, vinblastine 6 mg/m² IV weekly for 6 weeks followed by 18 weeks of 6-mercaptopurine 50 mg/m² daily with vinblastine (6 mg/m²) and prednisolone (40 mg/m² for 5 days) pulses every 3 weeks; etoposide 150 mg/m² weekly for the first 6 weeks followed by pulsed therapy every 3 weeks were added in arm B. Both regimens had similar response rates (63% vs 71%), 5-year survival probability (74% vs 79%), relapse rate (46% vs 46%). The more intense chemotherapy regimen with etoposide was better in patients with liver, lung, spleen, and hematopoietic system involvement.

Treatment strategy for disseminated Langerhans cell histiocytosis.

Gadner H, Heitger A, Grois N, Gatterer-Menz I, Ladisch S. Med Pediatr Oncol 1994; 23: 72–80.

A study on 106 patients divided into three groups: group A (multifocal bone disease); group B (soft-tissue disease without organ dysfunction); group C (patients with organ dysfunction). All patients received 6 weeks of etoposide, vinblastine, and prednisone, followed by continuation therapy with 1 year of 6-mercaptopurine, vinblastine, and prednisone. Patients in group B also received etoposide during continuation therapy and group C received both etoposide and methotrexate. A complete response was seen in 89% of group A, 91% of group B, and 67% of group C patients.

This study treated patients with 1 year of ‘maintenance’ chemotherapy, which has not been shown to be superior to the use of intermittent treatment for disease exacerbations.

A case of adult Langerhans cell histiocytosis showing successfully regenerated osseous tissue of the skull after chemotherapy.

Suzuki T, Izutsu K, Kako S, Ohta S, Hangaishi A, Kanda Y, et al. Int J Hematol 2008; 87: 284–8.

A case report of an adult with large osteolytic lesions in the skull that successfully responded to 6 weeks of prednisolone and vinblastine, followed by the addition of 6-mercaptopurine for a further 12 months. After treatment X-ray examination confirmed bone regeneration.

Successful treatment of cutaneous Langerhans cell histiocytosis with thalidomide.

Sander CS, Kaatz M, Elsner P. Dermatology 2004; 208: 149–52.

Thalidomide 200 mg OD was given to a 38-year-old male with recurrent mucocutaneous LCH. He had significant improvement within 4 weeks and complete healing after 3 months. Treatment was continued at 100 mg OD without relapse.

Langerhans cell histiocytosis with vulvar involvement and responding to thalidomide therapy – case report.

Fernandes LB, Guerra JG, Costa MB, Paiva IG, Duran FP, Jaco DN. An Bras Dermatol 2011; 86: S78–81.

A 57-year-old woman with extensive skin involvement including the scalp, face, trunk, axillae, and vulva. Systemic steroids and thalidomide at 100 mg/day led to complete resolution after 4 months. Disease relapsed on stopping treatment but was brought under control with thalidomide at 50 mg/day as maintenance therapy.

A phase II trial using thalidomide for Langerhans cell histiocytosis.

McClain KL, Kozinetz CA. Pediatr Blood Cancer 2007; 48: 44–9.

Sixteen patients with LCH who had relapsed once or twice despite treatment were included in the trial. Six patients were considered high risk. The rest consisted of patients with skin and/or bone and/or brain involvement. Adults were commenced at 100 mg (children 50 mg) daily, which was increased by 50 mg per month until efficacy or toxicity was achieved. No high-risk patient responded to treatment. Four low-risk patients had complete responses, three had partial responses, and two did not respond.

Oral methotrexate and alternate-day prednisone for low-risk Langerhans cell histiocytosis.

Womer RB, Anunciato KR, Chehrenama M. Med Pediatr Oncol 1995; 25: 70–3.

Thirteen low-risk children were treated successfully with prednisone 40 mg/m²/day on alternate days and weekly methotrexate 20 mg/m² for a minimum of 3 months. Toxicity was minimal, and recurrences were treated with the same regimen.

Cytosine-arabinoside, vincristine, and prednisolone in the treatment of children with disseminated Langerhans cell histiocytosis with organ dysfunction: experience at a single institution.

Egeler RM, de Kraker J, Voûte PA. Med Pediatr Oncol 1993; 21: 265–70.

Eighteen patients with multiorgan involvement (eight with organ dysfunction and 10 without organ dysfunction) received chemotherapy containing cytosine-arabinoside, vincristine, and prednisolone. Sixty-three percent of patients with organ dysfunction and 80% without the organ dysfunction had sustained remission.

This regimen is well tolerated and avoids the risk of secondary malignancies associated with etoposide. Results compare satisfactorily with other chemotherapeutic regimens.

Successful treatment of Langerhans cell histiocytosis with 2-chlorodeoxyadenosine.

Goh NS, McDonald CE, MacGregor DP, Pretto JJ, Brodie GN. Respirology 2003; 8: 91–4.

A young man with LCH involving lungs and bone who had previously failed to respond to two chemotherapy regimens. Complete symptomatic remission was achieved following five cycles of 2-CdA (0.1 mg/kg/day for 7 days per cycle) with no evidence of recurrence at 5 years.

Efficacy of continuous infusion 2-CDA (cladribine) in pediatric patients with Langerhans cell histiocytosis.

Stine KC, Saylors RL, Saccente S, McClaine KL, Becton DL. Pediatr Blood Cancer 2004; 43: 81–4.

Ten children with reactivated LCH or high-risk disease were treated with 2-CdA (initially 5 mg/m²/day for 3 days increasing to 6.5 mg/m²/day for 3 days). All ten had clinical responses. Seven patients remained disease free for a median of 50 months. Three patients needed further drug therapy but were clinically in remission.

Cladribine (2-chlorodeoxyadenosine) in frontline chemotherapy for adult Langerhans cell histiocytosis: a single centre study of seven cases.

Adam Z, Szturz P, Vanicek J, Moulis M, Pour L, Krejci M, et al. Acta Oncol 2012; [Epub ahead of print].

Retrospective study of six males with multisystem disease and one male with multifocal bone disease treated with cladribine at 5 mg/m² subcutaneously in five cases or intravenously in two. Treatment was enhanced with cyclophosphamide and corticosteroids in two patients. Durable complete remissions were achieved in six patients with a median follow-up of 37 months. One patient had an early relapse.

This confirms the efficacy of 2-CdA in LCH, particularly in patients that have failed on other forms of treatment.

Third-line therapies

Radiotherapy	B
Cyclosporine	B
Bone marrow transplantation	C
Trimethoprim/sulfamethoxazole	C
Interferon-α	D
2-Deoxycoformycin	E
Interleukin-2	E
Isotretinoin	E
Acitretin	E
Lenalidomide	E
Photodynamic therapy	E
Clofarabine	E
Mistletoe	E

Results of treatment of 127 patients with systemic histiocytosis (Letterer-Siwe syndrome, Schüller-Christian syndrome, and multifocal eosinophilic granuloma).

Greenberger JS, Crocker AC, Vawter G, Jaffe N, Cassady JR Medicine 1981; 60: 311–38.

Many patients discussed in this retrospective study achieved remission from local radiation therapy for bone and soft tissue lesions.

Chemotherapy is now generally preferred due to the slight risk of secondary malignancy but also the fact that LCH is often a generalized disease and local treatment is thus limited.

Cyclosporin A therapy for multisystem Langerhans cell histiocytosis.

Minkov M, Grois N, Broadbent V, Ceci A, Jakobson A, Ladisch S. Med Pediatr Oncol 1999; 33: 482–5.

Twenty-six patients with refractory LCH were treated with cyclosporine alone or in combination with prednisolone, vinblastine or etoposide and/or antithymocyte globulin. The median dose was 6 mg/kg/day (range 2–12 mg/kg/day) for a median duration of 4.5 months. One patient had a complete response and three had a partial response.

Cyclosporine has been effective in only a small number of patients with LCH and remissions tend to be short.

Hematopoietic stem cell transplantation in patients with severe Langerhans cell histiocytosis and hematological dysfunction: experience of the French Langerhans Cell Study Group.

Akkari V, Donadieu J, Piguet C, Bordigoni P, Michel G, Blanche S, et al. Bone Marrow Transpl 2003; 31: 1097–103.

Eight patients with LCH and hematological dysfunction received a hematopoietic stem cell transplant (three autologous and five allogeneic). All had responded poorly to initial chemotherapy. Autologous transplant failed in all patients. Three patients had a complete response and two died from toxicity after the allogeneic transplant. Ultimately only two patients had no recurrences after 21 months and 7 years of follow-up.

Improved outcome of treatment resistant high risk Langerhans cell histiocytosis after allogenic stem cell transplantation with reduced-intensity conditioning.

Steiner M, Matthes Martin S, Attarbaschi A, Minkov M, Grois N, Unqer E, et al. Bone Marrow Transpl 2005; 36: 215–25.

Stem cell transplant for refractory LCH can be highly toxic but can achieve sustained disease control. Several other case reports have documented long-term remissions following bone marrow transplantation. This approach is generally reserved for patients with fulminant disease not responding to chemotherapy.

Effect of trimethoprim-sulphamethoxazole in Langerhans cell histiocytosis: preliminary observations.

Tzortzatou-Stathopoulou F, Xaidara A, Mikraki V, Moschovi M, Arvantis D, Ageloyianni P, et al. Med Pediatr Oncol 1995; 25: 74–8.

Twenty-three children with both single and multisystem disease were treated for a 4-week to 3-month duration. Patients with single system disease responded well, while those with multisystem disease had a more limited response.

Widespread skin-limited Langerhans cell histiocytosis: complete remission with interferon alpha.

Kwong YL, Chan ACL, Chan TK. J Am Acad Dermatol 1997; 36: 628–9.

Subcutaneous interferon-α at 6 MU daily for 9 months followed by 3 MU for 9 months lead to resolution of a patient with extensive single system cutaneous disease.

Intralesional interferon-α has been used for localized cutaneous disease also.

Successful treatment of two children with Langerhans’ cell histiocytosis with 2′-deoxycoformycin.

McCowage GB, Frush DP, Kurtzberg J. J Pediatr Hematol Oncol 1996; 18: 154–8.

Two patients (aged 3 and 5) who were refractory to multiple chemotherapeutic agents were treated with 2′-deoxycoformycin 4 mg/m² intravenously weekly for 8 weeks, then every 2 weeks for at least 16 months. Both patients achieved a sustained remission with continued treatment. Toxicity was limited to asymptomatic grade III-IV lymphopenia and abnormalities of lymphocyte mitogen responses.

Interleukin-2 therapy of Langerhans cell histiocytosis.

Hirose M, Saito S, Yoshimoto T, Kuroda Y. Acta Pediatr 1995; 84: 1204–6.

A 20-month-old girl with disseminated LCH who had failed chemotherapy achieved a transient remission with intravenous IL-2.

Langerhans cell histiocytosis: complete remission after oral isotretinoin therapy.

Tsambaos D, Georgiou S, Kapranos N, Monastirli A, Stratigos A, Berger H. Acta Derm Venereol 1995; 75: 62–4.

A patient with single system cutaneous disease achieved a complete response to oral isotretinoin at 1.5 mg/kg/day for 9 months with no relapse at 5 years.

Langerhans cell histiocytosis in an adult: good response of cutaneous lesions to acitretin.

Cardoso JC, Cravo M, Cardosos R, Brites MM, Reis JP, Tellechea O, et al. Clin Exp Dermatol 2010; 35: 627–30.

Erosive LCH in the groin was treated with acitretin 25 mg/day and topical steroids. After 1 year the patient was free of skin lesions and treatment was stopped. No follow-up was documented.

Lenalidomide induced therapeutic response in a patient with aggressive multi-system Langerhans cell histiocytosis resistant to 2-chlorodeoxyadenosine and early relapse after high dose BEAM chemotherapy with autologous peripheral stem cell transplant.

Adam Z, Rehak Z, Koukalova R, Szturz P, Krejci M, Pour L, et al. Vnitr Lek 2012; 58: 62–71.

An adult patients with multisystem LCH had relapsed after treatment with a combination of etoposide and cyclophosphamide, then cladrabine, and then BEAM chemotherapy (carmustine, etoposide, cytarabine, melphalan) with autologous stem cell transplant. Treatment was started with lenalidomide 25 mg/day for 21 days in 28-day cycles. After four cycles, 50% reduction in size of lymph nodes was noted on imaging. With further cycles, etoposide 100 mg on days 22, 23, and 24 was added. After five cycles, complete remission was achieved and the patient underwent allogeneic bone marrow transplant 4 months later.

Photodynamic therapy for multi-resistant cutaneous Langerhans cell histiocytosis.

Failla V, Wauters O, Caucanas M, Nikkels-Tassoudji N, Nikkels AF. Rare Tumours 2010; 2: e34.

An 18-month-old boy with severe skin involvement failed to respond to topical steroids and topical nitrogen mustard. Systemic corticosteroids and vinblastin improved the trunk but not the scalp. Methlyaminolevulinate-based photodynamic therapy resulted in significant regression of the scalp lesions. Follow-up for 6 months showed no recurrence.

Clofarabine in refractory Langerhans cell histiocytosis.

Rodriguez-Galindo C, Jeng M, Khuu P, McCarville MB, Jeha S. Pediatr Blood Cancer 2008; [Epub ahead of print].

Two children with LCH refractory to treatment (including 2-CdA) were treated with five or six cycles of clofarabine (optimized to 25 mg/m²/day for 5 days) which induced remission in both patients.

Response to subcutaneous therapy with mistletoe in recurrent multisystem Langerhans cell histiocytosis.

Seifert G, Laengler A, Tautz C, Seeger K, Henze G. Pediatr Blood Cancer 2007; 48: 591–2.

A patient with multisystem disease, recurrent relapses and persistent cutaneous lesions, despite chemotherapy, was treated with an aqueous extract of mistletoe (Helixor®) subcutaneously three times a week, alternating doses weekly between 1 mg, 2.5 mg, and 5 mg. Cutaneous lesions cleared after 4 weeks of treatment and the patient remained in remission after 5 years on continuous treatment.

Future therapeutic approaches

Recurrent BRAF mutations in Langerhans cell histiocytosis.

Badalian-Very G, Vergilio JA, Degar BA, MacConaill LE, Brandner B, Calicchio ML, et al. Blood 2010; 116: 1919–23.

Oncogenic BRAF V600E mutations have been identified in 35 of 61 (57%) paraffin embedded biopsies from LCH granuloma specimens. It typically occurred in younger patients but was not associated with disease site or stage. This raises the possibility of the use of BRAF inhibitors such as vemurafenib in the management of LCH in individuals who show BRAF mutations.

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