Histiocytosis Treatment & Management

Updated: Nov 08, 2018
  • Author: Cameron K Tebbi, MD; Chief Editor: Vikramjit S Kanwar, MBBS, MBA, MRCP(UK), FAAP  more...
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Treatment

Medical Care

Langerhans cell histiocytosis

Optimal treatment of Langerhans cell histiocytosis (LCH) has not been established. In ideal cases, the differences between normal cells and pathologic Langerhans cells (PLCs) should be used to guide treatment of the disease. However, lack of sufficient information has hampered specific therapy. Some suggest that treatment of LCH should be conservative and limited to individuals with constitutional symptoms, such as pain, fever, failure to thrive, and vital organ disorder, as well as those at risk for CNS involvement. [273]

Decisions regarding treatment for histiocytosis depend on the type, site, and extent of the disease; the organs involved; biologic findings; the genetics of the disease; the degree of risk involved; and a host of other factors. Substantial variation of the disease and the fact that 10-20% of patients with LCH achieve spontaneous regression complicate comparisons of current nonspecific therapies. [274, 275, 276] Several agents, including drugs for cancer chemotherapy, have been effective in the treatment of LCH.

Due to the wide spectrum of findings in LCH, significant stratification is required. For example, LCH with a single bone lesion can be successfully treated with curettage and, possibly, local corticosteroid injection. [277] In contrast, multiple bone lesions, alone or in association with a nonrisk site, may, although nonfatal, require 1 year of therapy with combination treatments such as prednisone plus vincristine.

Thoroughly investigated limited skin lesions in infants can potentially be self resolving, while in other age groups, as shown in one study, 40% of patients with LCH that was presumed to be limited to the skin had multisystem involvement. [121] Thus, careful and judicious evaluation, such as with imaging studies/PET scans, appropriate biopsies, including of bone marrow, and investigation of BRAF-V600E expression, markers, and biochemical profile, among other tests, should be performed as necessary. If the disease is indeed local and limited to the skin, it can be treated with resection, steroids, nitrogen mustard, imiquimod, and other therapies, with careful, continuous follow-up. If needed, systemic therapy can be judiciously used.

While it is often relatively obvious which patients should be considered high risk, such identification can at times be difficult, since risk-organ involvement can be subtle and histologic analysis is not always accurate. Special attention in LCH must be given to the possibility of CNS involvement. Patients with bone lesions in the sphenoid, clivus, mastoid, orbit, and temporal bone have an increased incidence of CNS disease. In symptomatic CNS disease, the most frequent sign is the presence of diabetes insipidus due to pituitary involvement. CNS cytology is often negative; evaluation of the peripheral blood and CNS fluid for BRAF-V600E to support the diagnosis is warranted.

Patients with high-risk disease must receive at least 1 year of combination therapy, such as a vincristine, prednisone, mercaptopurine combination. Agents such as vinblastine, prednisone, cytarabine, cladribine, and clofarabine can be subsequently used in refractory or recurrent cases, as needed. In patients with pituitary involvement and CNS disease, treatment with clofarabine or cytarabine (with the latter in higher doses) should be considered.   

A study of by Rigaud et al of 1478 patients with Langerhans cell histiocytosis found that following a change in therapeutic strategy—an increase in the treatment period from 6 to 12 months, the use of repeated induction therapy in patients who responded poorly to initial induction with vinblastine and steroids, and the treatment of refractory disease in a risk organ with cladribine and cytarabine—the 5-year survival rate improved from 92% to 99%. In the specific group of patients with refractory disease in a risk organ, the 5-year survival rate increased from 60% to 92%. [278]

A study by Duan et al indicated that in adult patients with either multisystem or multifocal single-system Langerhans cell histiocytosis, treatment with either vindesine and prednisone or cyclophosphamide, etoposide, vindesine, and prednisone was similarly effective. The study, which involved 45 patients, also found high disease recurrence and the need for second-line therapy associated with the two regimens. [279]

Experience shows that  the drug combinations commonly used in children, as outlined above, is far more toxic and much less effective in adult population. In this population, cytarabine is effective and much better tolerated.

Radiation therapy is effective in LCH. [280] Doses ranging from 750-1500 cGy are usually administered, resulting in good local control of single lesions or metastasis, which can occur in critical areas or cause permanent damage. Fractionated doses of radiotherapy have also been used. [281]

Summary of suggested therapeutic approach

While there are no standards for the treatment of LCH, the following are suggested therapies, though not recommendations, based on published literature, with these treatments to be used alone on in combination, as needed.

Treatment for a single bone lesion may includes one or more of the following:

  • Limited curettage or resection
  • Local corticosteroid injection
  • Radiation therapy
  • Systemic treatment

Treatment for multiple bone lesions+/- nonrisk site include the therapies listed above along with administration of vincristine plus prednisone (1 year).

Treatment for limited-skin-lesion LCH includes the following:

  • Local therapies - Surgical resection, topical steroids, nitrogen mustard, imiquimod, phototherapy
  • Systemic treatments - Steroids, methotrexate, 6-mercaptopurine, thalidomide, cladribine, cytarabine, vincristine, vinblastine

Treatment for LCH with single lymph node involvement includes excisional biopsy.

Treatment for primary pulmonary LCH includes the following:

  • ​Systemic therapy
  • Cladribine
  • Lung transplant

Treatment for high-risk multisystem LCH includes the following:

  • Vincristine + prednisone + 6-mercaptopurine (1 year)
  • Cytarabine

Treatment for CNS-risk lesions, including, but not limited to, bone lesions of the mastoid, sphenoid, orbit, clivus, or temporal bone, includes the following:

  • Surgery (if possible)
  • Radiation therapy
  • Systemic therapy - Clofarabine, cytarabine, cladribine, vincristine + prednisone

Salvage therapy, depending on the prior treatments used, can be carried out via a number of options, including higher doses of some agents. Treatments include the following:

  • Cytarabine
  • Cladribine
  • Clofarabine
  • Vemurafenib/targeted therapies 
  • Radiation therapy
  • Stem cell transplantation
  • Experimental treatment protocols, including phase-1 agents and targeted therapies

Polyostotic sclerosing histiocytosis

Treatment for polyostotic sclerosing histiocytosis includes the following:

  • Steroid therapy
  • Interferon alpha (regular or PEGylated)
  • Interleuken-1 receptor antagonists
  • Chemotherapy - Vinblastine, vincristine, cyclophosphamide, tyrosine kinase inhibitors, doxorubicin, cladribine, methotrexate, imatinib, tamoxifen, azathioprine, mycophenolate mofetil
  • Radiation therapy
  • Bisphosphonates
  • Vemurafenib [188]
  • Surgery
  • Transplantation with autologous hemopoietic stem cells
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Consultations

Multidisciplinary care is essential for all patients. Consultation with an oral surgeon, otolaryngologist, and endocrinologist, among others, may be required. Careful systematic short- and long-term follow-up is extremely important.

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Long-Term Monitoring

Patients with Langerhans cell histiocytosis (LCH) must be followed for the disease and its possible complications and morbidities on a long-term basis. Even patients with low-risk disease can suffer long-term complications such as pain; growth delay; neurodegenerative disorders; pituitary dysfunction, including diabetes insipidus; hearing loss; and sclerosing cholangitis. In addition, the long-term side effects of treatment require careful follow-up. 

Damage due to LCH can be substantial. Polyendocrinopathies due to pituitary damage and neurodegenerative disorders of uncertain etiology are major concerns. The latter can occur several years after resolution of the disease. Progressive cerebellar atrophy has been reported. Symptoms such as ataxia, dysmetria, dysarthria, tremor, speech problems, visual disorders, kinetic malfunctions, and behavioral dysfunction require careful and complete neurologic evaluation and follow-up. This includes routine use of neurologic scales such as the ataxia rating scale, ophthalmologic exams, neuroendocrine tests, biochemical profiles, MRI, and appropriate referrals. 

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