Langerhans Cell Histiocytosis Treatment & Management

  • Author: Christopher R Shea, MD; Chief Editor: Dirk M Elston, MD   more...
 
Updated: Oct 29, 2010
 

Medical Care

No consensus exists for the optimal therapy for Langerhans cell histiocytosis (LCH), particularly in the case of multisystem organ disease. However, the Histiocyte Society has conducted a number of prospective, randomized control trials to study the effect of various chemotherapeutic regimens in the treatment of LCH, which have resulted in recommendations by the Histiocyte Society.

Generally, the choice of therapeutic regimen is based on disease severity. The International LCH Study of the Histiocyte Society proposes the stratification of LCH cases by the number of systems involved. They further categorize those cases with single-system involvement by the number of sites within that system (eg, monostotic vs polyostotic bone disease, solitary vs multiple lymph node involvement). In addition, the presence or the absence of risk-organ dysfunction is used to stratify patients with multisystemic disease; the presence of risk-organ dysfunction portends a poorer prognosis.

Notably, most trials for the treatment of LCH have been performed in pediatric populations, and their results have typically been extrapolated to adults. This has resulted in a call for more prospective, randomized trials looking specifically at the treatment of LCH in adults and whether changes in chemotherapeutic regimens and their duration may be appropriate.[42]

Single-system disease

Solitary bone lesions are treated locally with curettage or excision. Painful bone lesions may require intralesional steroid injection (triamcinolone acetonide). Bisphosphonates such as zoledronic acid can also be used to reverse bone destruction and mitigate the pain of bony lesions.[43] Early treatment with vinblastine and prednisolone has been suggested for bony lesions at vital anatomic locations requiring prompt resolution.[17] Rarely, lesions that are unusually large and painful occur in inaccessible sites or involve vital structures require radiation therapy (3-6 Gy [300-600 rad]).

Polyostotic bone lesions are best treated with indomethacin or a short course of systemic steroids.[44] A case report on pharmacologic management of single-system bony disease using naproxen indicates that multiple COX antagonists may be used in treating this form of LCH.[45]

Localized skin disease is best treated with moderate-to-potent topical steroids (eg, mometasone furoate [Elocon] cream 0.1%, triamcinolone [Kenalog] cream 0.1%, fluocinolone [Synalar] ointment 0.025%) or superpotent topical steroids (eg, clobetasol propionate 0.05%). In cases of severe cutaneous involvement, topical nitrogen mustard (20% solution) may be used. Acitretin may also be an effective agent for patients with primarily cutaneous manifestations of LCH.[46]

Psoralen plus ultraviolet A (PUVA) is another effective modality for cutaneous-only LCH or for cutaneous involvement in multisystemic disease. PUVA consists of photosensitizing psoralens (8-methoxypsoralen or 5-methoxypsoralen) either applied topically or ingested systemically 2 hours prior to treatment with long-wave ultraviolet A (320-400 nm). The purpose of this treatment is to induce remission of skin diseases by inducing a repeated and controlled phototoxic reaction. The photoconjugation of psoralens with DNA produces an antiproliferative reaction in the skin, generates programmed cell death (apoptosis), and induces down-regulation of the cutaneous immune system.[47]

Ultraviolet B excimer laser has been found in at least one case report to offer effective adjuvant therapy in the management of cutaneous LCH, and it may be particularly useful for patients with comorbidities who cannot tolerate more aggressive treatment.[48]

For single lymph node infiltration, excision is the treatment of choice. Regional lymph node enlargement can be treated with a short course of systemic steroids. Treatment-resistant nodes with sinus tracts to the skin may require systemic chemotherapy.

Smoking cessation is an important intervention in cases of pulmonary LCH.[20]

Single-agent chemotherapy with cladribine (2-chlorodeoxyadenosine/2-CdA) may be a promising treatment for single-system pulmonary Langerhans cell histiocytosis.[49]

Multisystem disease

Systemic chemotherapy is indicated for multisystem disease and cases of single-system disease not responsive to other treatment. The combination of cytotoxic drugs and systemic steroids is generally effective. Low-to-moderate doses of methotrexate, prednisone, and vinblastine are used.

Efficacy differences in chemotherapeutic agents

Multiple large clinical trials have examined differences in efficacy between chemotherapeutic agents.

One cooperative clinical trial in Europe used vinblastine, etoposide, and prednisolone for 6 weeks, followed by mercaptopurine, vinblastine, and prednisolone for 1 year. If soft tissue was involved, treatment was supplemented with etoposide, and, if the patient has organ dysfunction, methotrexate was added. Initial complete resolution occurred in 86% of patients, with a mortality rate of 9% and a disease-free survival rate of 77% at a median follow-up time of 6 years.[50]

The LCH-I trial sponsored by the Histiocyte Society used etoposide or vinblastine for 24 weeks. These agents produced equivalent responses at week 6 and had similar effects on survival and disease recurrence. Lack of response at 6 weeks was associated with an increased likelihood of treatment failure and a worse prognosis. The survival rate was slightly better in the aforementioned European trial than in LCH-I, but the difference was not statistically significant. A greater probability of developing diabetes insipidus occurred in the LCH-I trial.[51]

The LCH-II randomized clinical trial compared the effectiveness of 24 weeks of combined therapy with vinblastine, oral prednisone, and mercaptopurine, versus the same combination with the addition of etoposide. The overall survival in patients treated with etoposide was marginally improved compared with treatment without it; this effect was more pronounced in those patients with risk-organ involvement. However, although the addition of etoposide produced slightly more favorable therapeutic responses, it did not decrease the likelihood of disease recurrence.[52] Ultimately, the Histiocyte Society concluded that early therapy intensification (when compared with the LCH-I trial) had a positive effect on survival.[52] However, the addition of etoposide appeared to be of minimal therapeutic benefit and it use was not included in the recommendations of the Histiocyte Society released in April 2009.

The LCH-III study is an ongoing, prospective, randomized clinical trial evaluating the efficacy of adding methotrexate to vinblastine and prednisone in the treatment of LCH in multisystem risk patients. It also includes evaluation of the optimal duration of treatment (6 mo vs 12 mo) using prednisone and vinblastine for multisystem low-risk patients. Finally, it includes a pilot study for patients with single-system multifocal bone disease and localized special sites, including the CNS. Preliminary results of LCH-III have resulted in the following recommendations from the Histiocyte Society, released in February 2008:

  • Risk patients should be treated with oral prednisone daily and intravenous vinblastine weekly for 6 weeks. Patients who continue to have active disease should repeat this regimen for another 6 weeks. Patients who have no active disease after 6-week induction therapy should begin continuation treatment with oral 6-mercaptopurine daily, supplemented with pulses of oral prednisone and intravenous vinblastine, for 12 months of total treatment. The addition of methotrexate to LCH treatment is not recommended in current practice.
  • Low-risk patients should be treated with oral prednisone and intravenous vinblastine for 12 months total.
  • Patients with multifocal bone disease or CNS risk should be treated with oral prednisone daily and intravenous vinblastine weekly for 6 weeks. Patients should then be supplemented with pulses of oral prednisone and intravenous vinblastine for 6 months of total treatment.

The LCH-A-I clinical trial is another open study aimed to define and implement a uniform initial evaluation and stratification of adults with single-system disease, CNS lesions, isolated pulmonary disease, and multisystem LCH.

Treatment of refractory disease

LCH-S-98 is a prospective, phase II Histiocyte Society study evaluating 2-chlorodeoxyadenosine (2-CdA) as salvage monotherapy for patients with risk-organ involvement refractory to initial therapy with 3 agents (excluding 2-CdA) or patients with recurrent, low-risk LCH (ie, patients with non–risk-organ involvement, including multifocal bone disease).[53] The study concluded that 2-CdA is active as salvage therapy for LCH, but that it is more effective in low-risk patients or patients with multifocal bone disease. Those patients with risk-organ involvement who responded to 2-CdA therapy had a good prognosis, while those who were refractory typically had grim outcomes. Notably, patients older than 2 years and those with a longer time between diagnosis and 2-CdA therapy had better responses, presumably because their disease was less aggressive.[53]

The combination of 2-CdA and cytosine arabinoside (Ara-C) has also shown promise as an effective combination therapy for refractory multisystem LCH, but it is associated with considerable bone marrow toxicity.[54, 55] The LCH-S-2005 study of the Histiocyte Society is currently evaluating these initial results more thoroughly.

A retrospective study evaluating the efficacy of 2-CdA (+/- arabinoside) in treating refractory LCH in 17 Japanese patients similarly concluded that 2-CdA is effective for the treatment of refractory disease.[56] Notably, patients whose disease reactivated following the conclusion of their initial therapy had improved outcomes compared with those patients who had primary refractory disease or those who experienced reactivation during their initial chemotherapy. This same study also suggested that 2-CdA may be effective in the treatment of LCH with CNS involvement.[56]

In LCH patients with a very poor prognosis (rapid disease progression, refractory to conventional treatment, or with disseminated risk-organ involvement), bone marrow transplantation (BMT) or reduced-intensity condition stem cell transplantation has shown promise as effective salvage therapy.[57, 58, 59] However, cautious optimism is warranted regarding this treatment because optimal conditioning regimens and the timing of such transplantations have not been rigorously evaluated.[60]

Resistant LCH may also be treated with a combination of cyclosporin A, antithymocyte globulin, and prednisolone if patients do not have a matched donor for BMT.

Thalidomide has also been proposed as an agent for treating refractory/relapsing multisystem disease, but its efficacy appears to be limited to low-risk patients with only skin or bone involvement. Its use also is associated with significant toxicities, including pancytopenia and pulmonary failure.[61]

Other treatment options

A paucity of clinical trials for the treatment of LCH in adults has lead to the report by Derenzini and colleagues of a monocentric, retrospective study on the use of intense MACOP-B therapy (a common therapeutic regimen in aggressive non-Hodgkin lymphoma) without continued maintenance therapy, in the treatment of adults with LCH.[36]

In this study, 7 patients were treated with MACOP-B (methotrexate, doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomycin) weekly for 12 weeks. A retrospective analysis of these patients showed a complete response (defined as no evidence of active disease, plus a regression of signs and symptoms at physical examination and on imaging) in all 7 patients, although 3 patients subsequently had reactivation of their disease. Taken together, the authors conclude that more intense initial therapy may induce a better disease response in adults than alternative regimens that induce partial response to induction chemotherapy followed by a maintenance regimen.[36] However, these results require more formal evaluation.

Other potential treatments include monoclonal antibody targeting with indium–labeled anti-CD1a, cytokine inhibitors, alemtuzumab, low-dose oral cyclophosphamide, and all-trans retinoic acid.[62, 63, 64] Imatinib has been proposed as a potential therapy for LCH, owing to its ability to inhibit signaling through the platelet-derived growth factor (PDGF), macrophage-colony stimulating factor (MCSF), and c-kit receptors, which are present on the surface of histiocytes. However, clinical application of this therapy has shown mixed efficacy.[65, 66]

Diabetes insipidus is treated symptomatically with desmopressin acetate (DDAVP).

Next

Consultations

Consultation with the following specialists may be warranted in patients with Langerhans cell histiocytosis (LCH):

  • Referral to an orthopedic surgeon has important diagnostic and management implications when bone lesions are present.
  • An otolaryngologist may aid in the treatment of otitis media caused by destruction of the temporal and mastoid bones.
  • Consultation with an ophthalmologist is suggested for a vision check and an assessment of the need for decompression in patients with proptosis.
  • Consultation with a dentist is indicated if loose teeth result from infiltration of the mandibles.
  • Referral to an endocrinologist may help in the design of treatment of the endocrine abnormalities.
  • Long-term hearing loss can cause significant morbidity, owing to ear involvement by LCH, as well as to the use of other medications (ie, aminoglycosides) as adjuncts to chemotherapy. It has been proposed that all LCH patients with ear involvement have regular audiometry and CT/MRI of the petrous temporal bones, as well as long-term follow up with an audiologist to monitor for hearing loss.[37]
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Contributor Information and Disclosures
Author

Christopher R Shea, MD  Professor and Chief, Section of Dermatology, Department of Medicine, University of Chicago

Christopher R Shea, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American Society of Dermatopathology, Arthur Purdy Stout Society, Association of Professors of Dermatology, Chicago Dermatological Society, Dermatology Foundation, Illinois Dermatological Society, International Society of Dermatopathology, and Society for Investigative Dermatology

Disclosure: Nothing to disclose.

Coauthor(s)

Markus D Boos, MD, PhD  Resident, University of Chicago Comer Children's Hospital

Markus D Boos, MD, PhD is a member of the following medical societies: Alpha Omega Alpha

Disclosure: Nothing to disclose.

Specialty Editor Board

Bernice R Krafchik, MBChB, FRCPC  Professor Emeritus, Department of Pediatrics, Section of Dermatology, University of Toronto

Bernice R Krafchik, MBChB, FRCPC is a member of the following medical societies: American Academy of Dermatology, American Dermatological Association, Canadian Medical Association, College of Physicians and Surgeons of Ontario, Royal College of Physicians and Surgeons of Canada, and Society for Pediatric Dermatology

Disclosure: Nothing to disclose.

Richard P Vinson, MD  Assistant Clinical Professor, Department of Dermatology, Texas Tech University School of Medicine; Consulting Staff, Mountain View Dermatology, PA

Richard P Vinson, MD is a member of the following medical societies: American Academy of Dermatology, Association of Military Dermatologists, Texas Dermatological Society, and Texas Medical Association

Disclosure: Nothing to disclose.

Jeffrey Meffert, MD  Assistant Clinical Professor of Dermatology, University of Texas Health Science Center-San Antonio

Jeffrey Meffert, MD is a member of the following medical societies: American Academy of Dermatology, American Medical Association, Association of Military Dermatologists, and Texas Dermatological Society

Disclosure: Nothing to disclose.

Joel M Gelfand, MD, MSCE  Medical Director, Clinical Studies Unit, Assistant Professor, Department of Dermatology, Associate Scholar, Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania

Joel M Gelfand, MD, MSCE is a member of the following medical societies: Society for Investigative Dermatology

Disclosure: AMGEN Consulting fee Consulting; AMGEN Grant/research funds Investigator; Genentech Grant/research funds investigator; Centocor Consulting fee Consulting; Abbott Grant/research funds investigator; Abbott Consulting fee Consulting; Novartis investigator; Pfizer Grant/research funds investigator; Celgene Consulting fee DMC Chair; NIAMS and NHLBI Grant/research funds investigator

Chief Editor

Dirk M Elston, MD  Director, Department of Dermatology, Geisinger Medical Center

Dirk M Elston, MD is a member of the following medical societies: American Academy of Dermatology

Disclosure: Nothing to disclose.

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Letterer-Siwe disease. Bilateral inguinal erosive plaques and erythematous papules on the abdomen. Courtesy of Dr Neil S. Prose.
Abdominal area of an infant with multiple erythematous papules covered by scale and/or crust.
Typical purpuric lesions in Langerhans cell histiocytosis (must be distinguished from seborrheic dermatitis).
On a plain skull radiograph, lesions are typically lytic, with sharp borders and a punched out appearance.
High-power views. Marked epidermotropism is noted (left). The lesional cells are large, with abundant pink cytoplasm and reniform nuclei. An admixture of inflammatory cells, including occasional eosinophils, is present (right).
High-power views. Diffuse immunoreactivity for S-100 protein (right). Langerhans cells and lymphocytes (left, hematoxylin and eosin).
Widespread positivity for CD1a. Note the presence of epidermotropism (right). Langerhans cells and lymphocytes are present in the epidermis and the papillary dermis (left, hematoxylin and eosin).
Electron microscopy. Tennis racquet form of Birbeck granules with a small terminal expansion.
 
 
 
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