Langerhans Cell Histiocytosis

  • Dana-Farber/Brigham and Women's Cancer Care

    Langerhans cell histiocytosis (LCH) is a group of rare disorders in which too many Langerhans cells (a type of white blood cell) grow in certain tissues and organs including the bones, skin, and lungs, and damage them. Learn about Langherhans cell histiocytosis and find information on how we support and care for people with LCH before, during, and after treatment.

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Langerhans Cell Histiocytosis (LCH)

Overview

Langerhans cell histiocytosis is a disease that can damage tissue or cause lesions to form in one or more places in the body.

Langerhans cell histiocytosis (LCH) is a rare disease that occurs when the body makes too many Langerhans cells. A Langerhans cell is a type of white blood cell that helps the body fight infection. Langerhans cells (also called histiocytes) are normally found in the skin, lymph nodes, spleen, bone marrow, and lungs. In LCH, extra Langerhans cells spread through the blood and build up in certain parts of the body, where they can damage tissue or form tumors.

Scientists do not agree on whether LCH is a type of cancer or is a condition caused by a change in theimmune system. LCH is often treated with anticancer drugs that may also be used to treat immune system conditions.

LCH may occur at any age, but is most common in young children. The treatment of LCH in children and adults is described in separate sections.

Having a parent who was exposed to certain chemicals and family history may increase the risk of developing LCH.

Anything that increases your risk of getting a disease is called a risk factor. Having a risk factor does not mean that you will get the disease; not having risk factors doesn't mean that you will not get the disease. People who think they may be at risk should discuss this with their doctor. Risk factors for LCH may include the following:

  • Having a parent who was exposed to certain chemicals such as benzene.
  • Having infections as a newborn.
  • Having a family history of thyroid disease.

The cause of LCH is unknown.

Symptoms

The signs and symptoms of LCH depend on where it occurs in the body.

These and other symptoms may be caused by LCH. Other conditions may cause the same symptoms. A doctor should be consulted if any of the following problems occur:

Skin
In infants, signs and symptoms of LCH may include:

  • Flaking of the scalp that may look like “cradle cap”.
  • Raised, brown or purple spots anywhere on the body.

In children and adults, signs and symptoms of LCH may include:

  • Flaking of the scalp that may look like dandruff.
  • Raised, red or brown, crusted rash in the groin area, abdomen, back or chest.
  • Bumps or ulcers behind the ears, on the scalp, or in the groin area.

Mouth
Signs and symptoms of LCH may include:

  • Swollen gums.
  • Sores on the roof of the mouth, inside the cheeks, or on the tongue or lips.

Bone
Signs and symptoms of LCH may include:

  • Swelling or a lump over a bone, such as the skull, hip, ribs, spine, or elbow.
  • Pain where there is swelling or a lump over a bone.

Lymph nodes and thymus
Signs and symptoms of LCH may include:

  • Swollen lymph nodes.
  • Trouble breathing.

Pituitary gland
Signs and symptoms of LCH may include:

  • Diabetes insipidus. This can cause a strong thirst and frequent urination.
  • Slow growth.
  • Late puberty.

Thyroid
Signs and symptoms of LCH may include:

  • Swollen thyroid gland.
  • Hypothyroidism. This can cause tiredness, lack of energy, being sensitive to cold, constipation, dry skin, thinning hair, memory problems, trouble concentrating, and depression. In infants, this can also cause a loss of appetite and choking on food. In children and teens, this can also cause behavior problems, weight gain, slowed growth, and late puberty.
  • Trouble breathing.

Central nervous system
Signs and symptoms of LCH may include:

  • Diabetes insipidus. This can cause a strong thirst and frequent urination.
  • Trouble breathing.
  • Loss of balance, uncoordinated body motions, and trouble walking.
  • Trouble speaking.
  • Changes in behavior.
  • Memory problems.

Liver and spleen
Signs and symptoms of LCH may include:

  • Swelling in the abdomen caused by a build up of extra fluid.
  • Yellowing of the skin and whites of the eyes.
  • Easy bruising or bleeding.

Lung
Signs and symptoms of LCH may include:

  • Spontaneous pneumothorax. This can cause chest pain or tightness, trouble breathing, feeling tired, and the skin to turn a bluish color.
  • Trouble breathing, especially in adults who smoke.

Bone marrow
Signs and symptoms of LCH may include:

  • Easy bruising or bleeding.
  • Fever.
  • Frequent infections.
Tests

Tests that examine the organs and body systems where LCH may occur are used to detect (find) and diagnose LCH.

The following tests and procedures may be used to detect (find) and diagnose LCH or conditions caused by LCH: 

  • Physical exam and history: An exam of the body to check general signs of health, including checking for signs of disease, such as lumps or anything else that seems unusual. A history of the patient's health habits and past illnesses and treatments will also be taken.

     
  • Neurological exam: A series of questions and tests to check the brain, spinal cord, and nervefunction. The exam checks a person's mental status, coordination, and ability to walk normally, and how well the muscles, senses, and reflexes work. This may also be called a neuro exam or a neurologic exam.

     
  • Complete blood count (CBC) with differential: A procedure in which a sample of blood is drawn and checked for the following:
    • The amount of hemoglobin (the protein that carries oxygen) in the red blood cells.
    • The portion of the blood sample made up of red blood cells.
    • The number and type of white blood cells.
    • The number of red blood cells and platelets.
     
  • Blood chemistry studies: A procedure in which a blood sample is checked to measure the amounts of certain substances released into the body by organs and tissues in the body. An unusual (higher or lower than normal) amount of a substance can be a sign of disease in the organ or tissue that makes it.
  • Liver function test: A blood test to measure the blood levels of certain substances released by theliver. A high or low level of these substances can be a sign of disease in the liver.
  • Urinalysis: A test to check the color of urine and its contents, such as sugar, protein, red blood cells, and white blood cells.
  • Water deprivation test: A test to check how much urine is made and whether it becomes concentrated when little or no water is given. This test is used to diagnose diabetes insipidus, which may be caused by LCH.
  • Bone marrow aspiration and biopsy: The removal of bone marrow, blood, and a small piece of bone by inserting a hollow needle into the hipbone or breastbone. A pathologist views the bone marrow, blood, and bone under a microscope to look for signs of LCH.
  • Bone scan: A procedure to check if there are rapidly dividing cells in the bone. A very small amount ofradioactive material is injected into a vein and travels through the bloodstream. The radioactive material collects in the bones and is detected by a scanner.
  • X-ray: An x-ray of the organs and bones inside the body. An x-ray is a type of energy beam that can go through the body and onto film, making a picture of areas inside the body.
  • CT scan (CAT scan): A procedure that makes a series of detailed pictures of areas inside the body, taken from different angles. The pictures are made by a computer linked to an x-ray machine. A dye may be injected into a vein or swallowed to help the organs or tissues show up more clearly. This procedure is also called computed tomography, computerized tomography, or computerized axial tomography.
  • MRI (magnetic resonance imaging): A procedure that uses a magnet, radio waves, and a computer to make a series of detailed pictures of areas inside the body. A substance called gadolinium may be injected into a vein. The gadolinium collects around the LCH cells so that they show up brighter in the picture. This procedure is also called nuclear magnetic resonance imaging (NMRI).
  • Somatostatin receptor scintigraphy: A type of radionuclide scan used to find certain tumors. A small amount of a radioactive drug similar to somatostatin is injected into a vein and travels through the bloodstream. The radioactive drug attaches to tumor cells that have receptors for somatostatin. Aradiation -measuring device detects the radioactive drug and makes pictures showing where the tumor cells are in the body. Also called octreotide scan and SRS.
  • PET scan (positron emission tomography scan): A procedure to find tumor cells in the body. A small amount of radioactive glucose (sugar) is injected into a vein. The PET scanner rotates around the body and makes a picture of where glucose is being used in the body. Tumor cells show up brighter in the picture because they are more active and take up more glucose than normal cells do.
  • Ultrasound exam: A procedure in which high-energy sound waves (ultrasound) are bounced off internal tissues or organs and make echoes. The echoes form a picture of body tissues called a sonogram. The picture can be printed to be looked at later.
  • Endoscopy: A procedure to look at organs and tissues inside the body to check for abnormal areas. An endoscope is inserted through an incision (cut) in the skin or opening in the body, such as the mouth. An endoscope is a thin, tube-like instrument with a light and a lens for viewing. It may also have a tool to remove tissue or lymph node samples, which are checked under a microscope for signs of disease.
  • Biopsy: The removal of cells or tissues so they can be viewed under a microscope by a pathologist to check for Birbeck granules. Birbeck granules are found in Langerhans cells. To diagnose LCH, a biopsy of bone lesions, skin, lymph nodes, or the liver may be done.
Certain factors affect prognosis (chance of recovery) and treatment options.

LCH in organs such as the skin, bones, lymph nodes, or pituitary gland usually gets better with treatment and is called "low- risk". LCH in the spleen, liver, bone marrow, or lung is harder to treat and is called "high-risk."

The prognosis (chance of recovery) and treatment options depend on the following:

  • Whether the disease is found in one or more places in the body.
  • Whether the disease is found in the liver, spleen, lung, bone marrow, or certain bones in the skull.
  • How quickly the disease responds to initial treatment.
  • Whether the disease has just been diagnosed or has come back (recurred).
  • In infants up to one year of age, LCH may disappear without treatment.

General Information About Langerhans Cell Histiocytosis (LCH)

The histiocytic diseases in children and adults include three major classes of disorders. Only Langerhans cell histiocytosis (LCH), a dendritic cell disorder, is discussed in detail in this summary. Erdheim-Chester disease (primarily found in adults) and juvenile xanthogranuloma (diagnosed in children and adults) are macrophage disorders. Other disorders of the macrophage/monocytoid lineages include Rosai-Dorfman disease and hemophagocytic lymphohistiocytosis. Malignant disorders include malignant histiocytosis of various histiocyte lineages (formerly called histiocytic sarcoma) and the monocytic or myelomonocytic leukemias.

LCH results from the clonal proliferation of immunophenotypically and functionally immature, morphologically rounded LCH cells along with eosinophils, macrophages, lymphocytes, and occasionally, multinucleated giant cells.[1] The term LCH cells is used because there are clear morphologic, phenotypic, and gene expression differences between Langerhans cells of the epidermis (LCs) and those in LCH lesions (LCH cells). Controversy exists regarding whether the clonal proliferation of LCH cells results from a malignant transformation or is the result of an immunologic stimulus.[2][3]

The recent discovery that approximately 60% of LCH biopsy specimens demonstrate the V600E mutation in the BRAF oncogene, regardless of stage or organ involvement, has led to the conclusion that LCH is a clonal neoplastic disorder. The same mutation has been found in other cancers, including malignant melanoma; however, V600E-mutated BRAF is also present in benign nevi, possibly indicating the need for additional mutations to render the cell malignant.[4] This finding has raised the possibility of future targeted therapy with inhibitors already in use in melanoma, and several trials of BRAF inhibitors are open in adults and children with BRAF V600E mutated tumors, including LCH. Regardless of the etiology of the clonal proliferation, the primary treatment is chemotherapy.

Langerhans cell histiocytosis is the terminology currently preferred over histiocytosis X, eosinophilic granuloma, Abt-Letterer-Siwe disease, Hand-Schuller-Christian disease, or diffuse reticuloendotheliosis. This is based on the observation that the pathologic histiocyte common to all of these diagnoses has the identical immunophenotypic characteristics including the presence of Birbeck granules identified by electron microscopy; in addition, the pathologic histiocyte or LCH cell has a gene expression profile more closely resembling a myeloid dendritic cell, raising the possibility that LCH cells arise from a circulating precursor cell rather than the skin LC.[5][6] (Refer to the Cytogenetic and Genomic Studies section of this summary for more information.)

LCH may involve a single organ (single-system LCH), which may be a single site (unifocal) or involve multiple sites (multifocal); or LCH may involve multiple organs (multisystem LCH), which may involve a limited number of organs or be disseminated.

References:

  1. Laman JD, Leenen PJ, Annels NE, et al.: Langerhans-cell histiocytosis 'insight into DC biology'. Trends Immunol 24 (4): 190-6, 2003.

  2. Willman CL, Busque L, Griffith BB, et al.: Langerhans'-cell histiocytosis (histiocytosis X)--a clonal proliferative disease. N Engl J Med 331 (3): 154-60, 1994.

  3. Yu RC, Chu C, Buluwela L, et al.: Clonal proliferation of Langerhans cells in Langerhans cell histiocytosis. Lancet 343 (8900): 767-8, 1994.

  4. Badalian-Very G, Vergilio JA, Fleming M, et al.: Pathogenesis of Langerhans cell histiocytosis. Annu Rev Pathol 8: 1-20, 2013.

  5. Allen CE, Li L, Peters TL, et al.: Cell-specific gene expression in Langerhans cell histiocytosis lesions reveals a distinct profile compared with epidermal Langerhans cells. J Immunol 184 (8): 4557-67, 2010.

  6. Ginhoux F, Merad M: Ontogeny and homeostasis of Langerhans cells. Immunol Cell Biol 88 (4): 387-92, 2010 May-Jun.

Childhood LCH

Children and adolescents with Langerhans cell histiocytosis (LCH) should be treated by a multidisciplinary team of health professionals who are experienced with this disease and its treatment. This multidisciplinary team approach incorporates the skills of the primary care physician, pediatric surgical subspecialists, radiation oncologists, pediatric medical oncologists/hematologists, rehabilitation specialists, pediatric nurse specialists, social workers, and others to ensure that children receive treatment, supportive care, and rehabilitation that will achieve optimal survival and quality of life.

Clinical trials organized by the Histiocyte Society have been accruing patients on childhood treatment studies since the 1980s. Information on centers enrolling patients on these trials can be found on the NCI Web site.

Children with high-risk or low-risk disease should be followed annually to document and attempt to correct adverse side effects of therapy or the disease. (Refer to the Late Disease and Treatment Effects of Childhood LCH section of this summary for more information about the incidence, type, and monitoring of late effects of childhood cancer and its therapy.)

Incidence

The annual incidence of LCH has been estimated to be two to ten cases per 1 million children aged 15 years or younger.[1][2] The male to female ratio (M/F) is close to one and the median age of presentation is 30 months.[3] A report from Stockholm County, Sweden, described an annual incidence of 8.9 cases of LCH per 1 million children with a total of 29 cases in 10 years.[4] Most of these cases were diagnosed between September and February (M/F = 1.2). A 4-year survey of 251 new LCH cases in France found an annual incidence of 4.6 cases per 1 million children younger than 15 years (M/F = 1.2).[5] A survey of LCH in northwest England (Manchester) revealed an overall incidence of 2.6 cases per 1 million child-years.[6]

Identical twins with LCH, and non-twin siblings or multiple cases in one family, have been reported.[7] Over 90% of adult pulmonary LCH occurs in young adults who smoke, often more than 20 cigarettes per day.[8][9]

Risk Factors

Although the following risk factors have been identified for LCH, strong and consistent associations have not been confirmed:

  • Solvent exposure in parents.[10]
  • Family history of cancer.[11]
  • Personal or family history of thyroid disease.[10][12]
  • Perinatal infections.[10][11]
  • Parental occupational exposure to metal, granite, or wood dust.[11]

Prognosis

Prognosis is closely linked to the extent of disease at presentation when high-risk organs (liver, spleen, and/or bone marrow) are involved and to the response to initial treatment. The high-risk designation comes from the high mortality rate (35%) in those who did not respond well to therapy in the first 6 weeks. For many years, lung was thought to be a high-risk organ but isolated lung involvement in pediatric LCH is no longer considered to pose a significant risk of death.[13] Because of treatment advances, the outcome for children with LCH involving high-risk organs has improved.[14][15] Data from HISTSOC-LCH-III showed an 84% overall survival (OS) rate for patients treated for 12 months with systemic chemotherapy.[16]

Patients with single-system disease and low-risk multisystem disease do not usually die from LCH, but recurrent disease may result in considerable morbidity and significant late effects.[17] The major treatment challenge is to reduce the 20% to 30% incidence of recurrent lesions and the significant incidence of permanent consequences in this group of patients. HISTSOC-LCH-III data showed that there was a significant difference in reactivation for risk organ subjects when comparing 6 months versus 12 months of treatment, with 12 months being better (54% vs. 37%).[16]

Prognostic factors in LCH have been identified and can be categorized as follows:

  • Age at diagnosis: Although age younger than 2 years was once thought to portend a worse prognosis, data from the LCH-II study showed that patients aged 2 years or younger without high-risk organ involvement had the same response to therapy as older patients.[15] By contrast, the OS was poorer in neonates with risk-organ involvement compared with infants and children with the same extent of disease when patients were treated for only 6 months.[15]
  • Response to treatment: Response to therapy at 6 to 12 weeks has been shown to be a more important prognostic factor than age.[18] The overall response to therapy is influenced by the duration and intensity of treatment.[14][15]
  • Organ involvement: Involvement of craniofacial bones including orbital, mastoid, and temporal bones is associated with an increased risk of diabetes insipidus and an increased frequency of anterior pituitary hormone deficiencies and neurologic problems. (Refer to the Endocrine system subsection in the Multisystem Disease Presentation section of this summary for more information on diabetes insipidus.)

References:

  1. Carstensen H, Ornvold K: The epidemiology of Langerhans cell histiocytosis in children in Denmark, 1975-89. [Abstract] Med Pediatr Oncol 21 (5): A-15, 387-8, 1993.

  2. Salotti JA, Nanduri V, Pearce MS, et al.: Incidence and clinical features of Langerhans cell histiocytosis in the UK and Ireland. Arch Dis Child 94 (5): 376-80, 2009.

  3. A multicentre retrospective survey of Langerhans' cell histiocytosis: 348 cases observed between 1983 and 1993. The French Langerhans' Cell Histiocytosis Study Group. Arch Dis Child 75 (1): 17-24, 1996.

  4. Stålemark H, Laurencikas E, Karis J, et al.: Incidence of Langerhans cell histiocytosis in children: a population-based study. Pediatr Blood Cancer 51 (1): 76-81, 2008.

  5. Guyot-Goubin A, Donadieu J, Barkaoui M, et al.: Descriptive epidemiology of childhood Langerhans cell histiocytosis in France, 2000-2004. Pediatr Blood Cancer 51 (1): 71-5, 2008.

  6. Alston RD, Tatevossian RG, McNally RJ, et al.: Incidence and survival of childhood Langerhans cell histiocytosis in Northwest England from 1954 to 1998. Pediatr Blood Cancer 48 (5): 555-60, 2007.

  7. Aricò M, Nichols K, Whitlock JA, et al.: Familial clustering of Langerhans cell histiocytosis. Br J Haematol 107 (4): 883-8, 1999.

  8. Tazi A, Soler P, Hance AJ: Adult pulmonary Langerhans' cell histiocytosis. Thorax 55 (5): 405-16, 2000.

  9. Vassallo R, Ryu JH, Colby TV, et al.: Pulmonary Langerhans'-cell histiocytosis. N Engl J Med 342 (26): 1969-78, 2000.

  10. Bhatia S, Nesbit ME Jr, Egeler RM, et al.: Epidemiologic study of Langerhans cell histiocytosis in children. J Pediatr 130 (5): 774-84, 1997.

  11. Venkatramani R, Rosenberg S, Indramohan G, et al.: An exploratory epidemiological study of Langerhans cell histiocytosis. Pediatr Blood Cancer 59 (7): 1324-6, 2012.

  12. Nicholson HS, Egeler RM, Nesbit ME: The epidemiology of Langerhans cell histiocytosis. Hematol Oncol Clin North Am 12 (2): 379-84, 1998.

  13. Ronceray L, Pötschger U, Janka G, et al.: Pulmonary involvement in pediatric-onset multisystem Langerhans cell histiocytosis: effect on course and outcome. J Pediatr 161 (1): 129-33.e1-3, 2012.

  14. Gadner H, Grois N, Arico M, et al.: A randomized trial of treatment for multisystem Langerhans' cell histiocytosis. J Pediatr 138 (5): 728-34, 2001.

  15. Gadner H, Grois N, Pötschger U, et al.: Improved outcome in multisystem Langerhans cell histiocytosis is associated with therapy intensification. Blood 111 (5): 2556-62, 2008.

  16. Gadner H, Minkov M, Grois N, et al.: Therapy prolongation improves outcome in multisystem Langerhans cell histiocytosis. Blood 121 (25): 5006-14, 2013.

  17. Haupt R, Nanduri V, Calevo MG, et al.: Permanent consequences in Langerhans cell histiocytosis patients: a pilot study from the Histiocyte Society-Late Effects Study Group. Pediatr Blood Cancer 42 (5): 438-44, 2004.

  18. Minkov M, Prosch H, Steiner M, et al.: Langerhans cell histiocytosis in neonates. Pediatr Blood Cancer 45 (6): 802-7, 2005.

Histopathologic, Immunologic, and Cytogenetic Characteristics of LCH

Cell of Origin and Biologic Correlates

Modern classification of the histiocytic diseases subdivides them into dendritic cell–related, monocyte/macrophage-related, or true malignancies. Langerhans cell histiocytosis (LCH) is a dendritic cell disease.[1][2] The Langerhans cells (LCH cells) in LCH lesions are immature dendritic cells making up less than 10% of the cells present in LCH lesions.[3][4] Comprehensive gene expression array data analysis on LCH cells is consistent with the concept that the skin LC is not the cell of origin for LCH.[5] Rather it is likely to be a myeloid dendritic cell, which expresses the same antigens (CD1a and CD207) as the skin LC.[6] This concept was further supported by a study reporting that the transcription profile of LCH cells was distinct from myeloid and plasmacytoid dendritic cells, as well as epidermal LCs.[6][7]

LCH lesions also contain lymphocytes, macrophages, neutrophils, eosinophils, fibroblasts, and sometimes multinucleated giant cells. In the brain, the following three types of histopathologic findings have been described in LCH:

  • Mass lesions in meninges or choroid plexus with CD1a-positive LCH cells and predominantly CD8-positive lymphocytes.
  • Mass lesions in connective tissue spaces with CD1a-positive LCH cells and predominantly CD8-positive lymphocytes causing an inflammatory response and neuronal loss.
  • Predominantly CD8+ lymphocyte infiltration with neuronal degeneration, microglial activation, and gliosis.[8]

Immunologic Abnormalities

Normally, the LC is a primary presenter of antigen to naïve T-lymphocytes. However, in LCH, the pathologic dendritic cell does not efficiently stimulate primary T-lymphocyte responses.[9] Antibody staining for the dendritic cell markers, CD80, CD86, and class II antigens, has been used to show that in LCH, the abnormal cells are immature dendritic cells that present antigen poorly and are proliferating at a low rate.[3][9][10] Transforming growth factor-beta (TGF-beta) and interleukin (IL)-10 are possibly responsible for preventing LCH cell maturation in LCH.[3] The expansion of regulatory T cells in patients with LCH has been reported.[10] The population of CD4-positive CD25(high) FoxP3(high) cells was reported to comprise 20% of T cells and appeared to be in contact with LCH cells in the lesions. These T cells were present in higher numbers in the peripheral blood of patients with LCH than in controls and returned to a normal level when patients were in remission.[10]

Etiology

The etiology of LCH is unknown. Efforts to define a viral cause have not been successful.[11][12] One study has shown that 1% of patients have a positive family history for LCH.[13]

Cytogenetic and Genomic Studies

Studies showing clonality in LCH using polymorphisms of methylation-specific restriction enzyme sites on the X-chromosome regions coding for the human androgen receptor, DXS255, PGK, and HPRT were published in 1994.[14][15] Biopsies of lesions with single-system or multisystem disease were found to have a proliferation of LCH cells from a single clone. Pulmonary LCH in adults is usually nonclonal and it is possible that this group represents a reactive process to smoking.[16] Cytogenetic abnormalities in LCH have rarely been reported. One study described an abnormal clone t(7;12)(q11.2;p13) from a vertebral lesion of one patient.[17] This study also reported nonclonal karyotypic abnormalities in three patients. An increase in chromosomal breakage was also noted.

BRAF-RAS pathway
Figure courtesy of Rikhia Chakraborty, Ph.D. Permission to reuse the figure in any form must be obtained directly from Dr. Chakraborty.

An activating mutation of the BRAF oncogene (V600E) was detected in 35 of 61 (57%) LCH biopsy samples, with mutations being more common in patients younger than 10 years (76%) than in patients aged 10 years and older (44%).[18] A subsequent study with a larger sample size did not confirm this association.[19] The RAS signaling pathway ( Figure) transmits signals from a cell surface receptor (e.g., a growth factor) through the RAS pathway (via one of the RAF proteins [A, B, or C]) to phosphorylate MEK and then ERK, which leads to nuclear signals affecting cell cycle and transcription regulation. The V600E mutation of BRAF leads to continuous phosphorylation, and thus activation, of MEK and ERK without the need for an external signal.

The RAS pathway was activated in a few samples that were tested for MEK and ERK expression, whether or not the BRAF V600E mutation was present. The BRAF V600E mutation in LCH has been demonstrated in flow-sorted CD1a-positive LCH cells from fresh lesions in 11 of 16 samples.[20] Another BRAF mutation (BRAF 600DLAT) was identified that resulted in the insertion of four amino acids and that also appeared to activate MAPK pathway signaling.[20] No clinical characteristics associated with the BRAF mutation have been identified.[18][19][20]

A series of 135 biopsies from 100 patients were tested for the BRAF V600E mutation by a sensitive quantitative polymerase chain reaction technique and found the mutation in 65% of patients.[19] Circulating cells with the BRAF V600E mutation could be detected in all high-risk patients and in a subset of low-risk multisystem patients. Presence of the circulating cells with the mutation conferred a twofold increased risk of relapse. The myeloid dendritic cell origin of LCH was confirmed by finding CD34+ stem cells with the mutation in the bone marrow of high-risk patients. Those with low-risk disease had more mature myeloid dendritic cells with the mutation, but not the stem cells suggesting the stage of cell development is critical in defining the clinical characteristics of LCH, which can now be considered a myeloid neoplasia.

Activating BRAF mutations are also found in selected nonmalignant conditions (e.g., benign nevi) [21] and low-grade malignancies (e.g., pilocytic astrocytoma).[22][23] All of these conditions have a generally indolent course with spontaneous resolution sometimes occurring. This distinctive clinical course may be a manifestation of oncogene-induced senescence.[21][24]

Cytokine Analysis by Immunohistochemical Staining and Gene Expression Array Studies

Immunohistochemical staining of LCH lesions has shown apparent upregulation of the chemokines CCR6 and possibly CCR7.[25][26] In an analysis of gene expression in LCH by gene array techniques, 2,000 differentially expressed genes were identified. Of 65 genes previously reported to be associated with LCH, only 11 were found to be upregulated in the array results. The most highly upregulated gene in both CD207 and CD3-positive cells was osteopontin; other genes that activate and recruit T cells to sites of inflammation are also upregulated. The expression profile of the T cells was that of an activated regulatory T-cell phenotype with increased expression of FOXP3, CTLA4, and osteopontin. These findings support a previous report on the expansion of regulatory T cells in LCH.[10] There was pronounced expression of genes associated with early myeloid progenitors including CD33 and CD44, which is consistent with an earlier report of elevated myeloid dendritic cells in the blood of patients with LCH.[27] A model of "Misguided Myeloid Dendritic Cell Precursors" has been proposed, whereby myeloid dendritic cell precursors are recruited to sites of LCH by an unknown mechanism and the dendritic cells in turn recruit lymphocytes by excretion of osteopontin, neuropilin-1, and vannin-1.[5]

Several investigators have published studies evaluating the level of various cytokines or growth factors in the blood of patients with LCH that have included many of the genes found not to be upregulated by the gene expression results discussed above.[5] One explanation for elevated levels of these proteins is a systemic inflammatory response with the cytokines/growth factors being produced by cells outside the LCH lesions. A second possible explanation is that macrophages in the LCH lesions produce the cytokines measured in the blood or are concentrated in lesions.

IL-1 beta and prostaglandin GE2 levels were measured in the saliva of patients with oral LCH lesions or multisystem high-risk patients with and without oral lesions; levels of both were higher in patients with active disease and decreased after successful therapy.[28]

Human Leukocyte Antigen (HLA) Type and Association With LCH

Specific associations of LCH with distinct HLA types and extent of disease have been reported. In a study of 84 Nordic patients, those with only skin or bone involvement more frequently had HLA-DRB1*03 type than those with multisystem disease.[29] In 29 patients and 37 family members in the United States, the Cw7 and DR4 types were significantly more prevalent in Caucasians with single-bone lesions.[30]

References:

  1. Laman JD, Leenen PJ, Annels NE, et al.: Langerhans-cell histiocytosis 'insight into DC biology'. Trends Immunol 24 (4): 190-6, 2003.

  2. Jaffe R: The diagnostic histopathology of langerhans' cell histiocytosis. In: Weitzman S, Egeler R M, eds.: Histiocytic Disorders of Children and Adults. Cambridge, United Kingdom: Cambridge University Press, 2005, pp 14-39.

  3. Geissmann F, Lepelletier Y, Fraitag S, et al.: Differentiation of Langerhans cells in Langerhans cell histiocytosis. Blood 97 (5): 1241-8, 2001.

  4. Berres ML, Allen CE, Merad M: Pathological consequence of misguided dendritic cell differentiation in histiocytic diseases. Adv Immunol 120: 127-61, 2013.

  5. Allen CE, Li L, Peters TL, et al.: Cell-specific gene expression in Langerhans cell histiocytosis lesions reveals a distinct profile compared with epidermal Langerhans cells. J Immunol 184 (8): 4557-67, 2010.

  6. Ginhoux F, Merad M: Ontogeny and homeostasis of Langerhans cells. Immunol Cell Biol 88 (4): 387-92, 2010 May-Jun.

  7. Hutter C, Kauer M, Simonitsch-Klupp I, et al.: Notch is active in Langerhans cell histiocytosis and confers pathognomonic features on dendritic cells. Blood 120 (26): 5199-208, 2012.

  8. Grois N, Prayer D, Prosch H, et al.: Neuropathology of CNS disease in Langerhans cell histiocytosis. Brain 128 (Pt 4): 829-38, 2005.

  9. Yu RC, Morris JF, Pritchard J, et al.: Defective alloantigen-presenting capacity of 'Langerhans cell histiocytosis cells'. Arch Dis Child 67 (11): 1370-2, 1992.

  10. Senechal B, Elain G, Jeziorski E, et al.: Expansion of regulatory T cells in patients with Langerhans cell histiocytosis. PLoS Med 4 (8): e253, 2007.

  11. McClain K, Jin H, Gresik V, et al.: Langerhans cell histiocytosis: lack of a viral etiology. Am J Hematol 47 (1): 16-20, 1994.

  12. Jeziorski E, Senechal B, Molina TJ, et al.: Herpes-virus infection in patients with Langerhans cell histiocytosis: a case-controlled sero-epidemiological study, and in situ analysis. PLoS One 3 (9): e3262, 2008.

  13. Aricò M, Nichols K, Whitlock JA, et al.: Familial clustering of Langerhans cell histiocytosis. Br J Haematol 107 (4): 883-8, 1999.

  14. Willman CL, Busque L, Griffith BB, et al.: Langerhans'-cell histiocytosis (histiocytosis X)--a clonal proliferative disease. N Engl J Med 331 (3): 154-60, 1994.

  15. Yu RC, Chu C, Buluwela L, et al.: Clonal proliferation of Langerhans cells in Langerhans cell histiocytosis. Lancet 343 (8900): 767-8, 1994.

  16. Dacic S, Trusky C, Bakker A, et al.: Genotypic analysis of pulmonary Langerhans cell histiocytosis. Hum Pathol 34 (12): 1345-9, 2003.

  17. Betts DR, Leibundgut KE, Feldges A, et al.: Cytogenetic abnormalities in Langerhans cell histiocytosis. Br J Cancer 77 (4): 552-5, 1998.

  18. Badalian-Very G, Vergilio JA, Degar BA, et al.: Recurrent BRAF mutations in Langerhans cell histiocytosis. Blood 116 (11): 1919-23, 2010.

  19. Berres ML, Lim KP, Peters T, et al.: BRAF-V600E expression in precursor versus differentiated dendritic cells defines clinically distinct LCH risk groups. J Exp Med 211 (4): 669-83, 2014.

  20. Satoh T, Smith A, Sarde A, et al.: B-RAF mutant alleles associated with Langerhans cell histiocytosis, a granulomatous pediatric disease. PLoS One 7 (4): e33891, 2012.

  21. Michaloglou C, Vredeveld LC, Soengas MS, et al.: BRAFE600-associated senescence-like cell cycle arrest of human naevi. Nature 436 (7051): 720-4, 2005.

  22. Jones DT, Kocialkowski S, Liu L, et al.: Tandem duplication producing a novel oncogenic BRAF fusion gene defines the majority of pilocytic astrocytomas. Cancer Res 68 (21): 8673-7, 2008.

  23. Pfister S, Janzarik WG, Remke M, et al.: BRAF gene duplication constitutes a mechanism of MAPK pathway activation in low-grade astrocytomas. J Clin Invest 118 (5): 1739-49, 2008.

  24. Jacob K, Quang-Khuong DA, Jones DT, et al.: Genetic aberrations leading to MAPK pathway activation mediate oncogene-induced senescence in sporadic pilocytic astrocytomas. Clin Cancer Res 17 (14): 4650-60, 2011.

  25. Fleming MD, Pinkus JL, Fournier MV, et al.: Coincident expression of the chemokine receptors CCR6 and CCR7 by pathologic Langerhans cells in Langerhans cell histiocytosis. Blood 101 (7): 2473-5, 2003.

  26. Annels NE, Da Costa CE, Prins FA, et al.: Aberrant chemokine receptor expression and chemokine production by Langerhans cells underlies the pathogenesis of Langerhans cell histiocytosis. J Exp Med 197 (10): 1385-90, 2003.

  27. Rolland A, Guyon L, Gill M, et al.: Increased blood myeloid dendritic cells and dendritic cell-poietins in Langerhans cell histiocytosis. J Immunol 174 (5): 3067-71, 2005.

  28. Preliasco VF, Benchuya C, Pavan V, et al.: IL-1 beta and PGE2 levels are increased in the saliva of children with Langerhans cell histiocytosis. J Oral Pathol Med 37 (9): 522-7, 2008.

  29. Bernstrand C, Carstensen H, Jakobsen B, et al.: Immunogenetic heterogeneity in single-system and multisystem langerhans cell histiocytosis. Pediatr Res 54 (1): 30-6, 2003.

  30. McClain KL, Laud P, Wu WS, et al.: Langerhans cell histiocytosis patients have HLA Cw7 and DR4 types associated with specific clinical presentations and no increased frequency in polymorphisms of the tumor necrosis factor alpha promoter. Med Pediatr Oncol 41 (6): 502-7, 2003.

Presentation of LCH in Children

Langerhans cell histiocytosis (LCH) most commonly presents with a skin rash or a painful bone lesion. Systemic symptoms of fever, weight loss, diarrhea, edema, dyspnea, polydipsia, and polyuria, relate to specific organ involvement and single-system or multisystem disease presentation as noted below.

Specific organs are considered high-risk or low-risk when involved with disease presentation. Risk refers to the risk of mortality.

  • High-risk organs include liver, spleen, and bone marrow.
  • Low-risk organs include skin, bone, lung, lymph nodes, gastrointestinal tract, pituitary gland, and central nervous system (CNS).

Patients may present with a single organ (single-system LCH), which may involve a single site (unifocal) or multiple sites (multifocal). Bone is the most common single organ site. Less commonly, LCH may involve multiple organs (multisystem LCH), which may involve a limited number of organs or it may be disseminated. Treatment decisions for patients are based upon whether high-risk or low-risk organs are involved and whether LCH presents as single-system or multisystem disease. Patients can have LCH of the skin, bone, lymph nodes, and pituitary in any combination and still be considered at low-risk of death, although there may be relatively high-risk for long-term consequences of the disease.

Single-System Disease Presentation

In single-system LCH, as the name implies, the disease presents with involvement of a single site or organ, including skin and nails, oral cavity, bone, lymph nodes and thymus, pituitary gland, and thyroid.

Skin and nails

  • Infants: Seborrheic involvement of the scalp may be mistaken for prolonged cradle cap in infants. Infants with LCH may also present with a generalized skin rash, which may mimic many other skin disorders. Skin LCH in infants may be limited to skin (skin-only disease) or may be part of multisystem LCH. In a report of 61 neonatal cases from 1,069 patients in the Histiocyte Society database, nearly 60% had multisystem disease and 72% had risk-organ involvement.[1]

    Skin-only LCH, which had historically been known as Hashimoto-Pritzer, may be self-limited as the lesions may disappear with no therapy during the first year of life. Therapy is used only for very extensive rashes, pain, ulceration, or bleeding. Importantly, these patients must be watched closely as skin-only LCH may also progress within weeks or months to high-risk multisystem disease, which may be life-threatening.[2][3][4]

    A review of patients presenting in the first 3 months of life with skin-only LCH compared the clinical and histopathologic findings in 21 children whose skin LCH regressed with ten children who did not regress. Patients with regressing disease had distal lesions that appeared in the first 3 months of life and were necrotic papules or hypopigmented macules. Patients with nonregressing disease who required systemic therapy were more often intertriginous. Immunohistochemical studies showed no difference in interleukin (IL)-10, Ki-67, E-cadherin expression, or T-reg number between the two clinical groups.

  • Children and adults: Children and adults may develop a red papular rash in the groin, abdomen, back, or chest that resembles a diffuse candidal rash. Seborrheic involvement of the scalp may be mistaken for a severe case of dandruff in older individuals. Ulcerative lesions behind the ears, involving the scalp, under the breasts, or genitalia or perianal region are often misdiagnosed as bacterial or fungal infections. Vesicular lesions may be seen and need to be differentiated from herpetic lesions.

    Fingernail involvement is an unusual finding that may present as a single site or with other sites of LCH involvement. There are longitudinal, discolored grooves and loss of nail tissue. This condition often responds to the usual LCH therapies.[5]

Oral cavity

In the mouth, presenting symptoms include gingival hypertrophy and ulcers of the soft or hard palate, buccal mucosa, or on the tongue and lips. Hypermobile teeth (floating teeth) and tooth loss usually indicate involvement of underlying bone.[6][7] Lesions of the oral cavity may precede evidence of LCH elsewhere.

Bone

LCH can occur in any bone of the body, although the hands and feet are often spared. Sites of LCH in children include the following:

  • Lytic lesion of the skull: The most frequent site of LCH in children is a lytic lesion of the skull vault,[8] which may be asymptomatic or painful. It is often surrounded by a soft tissue mass that may extend internally to impinge on the dura.
  • Femur, ribs, humerus, and vertebra: Other frequently involved skeletal sites are femur, ribs, humerus, and vertebra. Spine lesions may involve any vertebra, although involvement of the cervical vertebrae is most common and spine lesions are frequently associated with other bone lesions. Spine lesions may result in collapse of the vertebral body (vertebra plana). Vertebral lesions with soft tissue extension often present with pain and may present with significant neurologic deficits,[9] an indication for an urgent magnetic resonance imaging (MRI) scan.
  • CNS-risk bones: Proptosis from an LCH mass in the orbit mimics rhabdomyosarcomas, neuroblastoma, and benign fatty tumors of the eye.[10]

    Lesions of the facial bones or anterior or middle cranial fossae (e.g., temporal, orbit, sphenoid, ethmoid, zygomatic) with intracranial tumor extension comprise a CNS-risk group. These patients have a threefold increased risk of developing diabetes insipidus and other CNS disease. Because of the increased risk of diabetes insipidus, treatment is recommended for these patients.

Lymph nodes and thymus

The cervical nodes are most frequently involved and may be soft- or hard-matted groups with accompanying lymphedema. An enlarged thymus or mediastinal node involvement can mimic an infectious process and may cause asthma-like symptoms. Accordingly, biopsy with culture is indicated for these presentations. Mediastinal involvement is rare (<5%) and usually presents with respiratory distress, superior vena cava syndrome, or cough and tachypnea. The 5-year survival is 87%, with deaths mostly attributable to hematologic involvement.[11]

Pituitary gland

The posterior part of the pituitary gland and pituitary stalk can be affected in patients with LCH, causing central diabetes insipidus. (Refer to the Endocrine subsection in the Multisystem Disease Presentation section of this summary for more information.) Anterior pituitary involvement often results in growth failure and delayed or precocious puberty. Rarely, hypothalamic involvement may cause morbid obesity.

Thyroid

Thyroid involvement has been reported in LCH. Symptoms include massive thyroid enlargement, hypothyroidism, and respiratory symptoms.[12]

Multisystem Disease Presentation

In multisystem LCH, the disease presents in multiple organs or body systems including bone, abdominal/gastrointestinal system (liver and spleen), lung, bone marrow, endocrine system, eye, CNS, skin, and lymph nodes.

Bone and other organ systems

Patients with LCH may present with multiple bone lesions as a single site (single-system multifocal bone) or bone lesions with other organ systems involved (multisystem including bone). A review of patients with single-system multifocal bone presentation and patients with multisystem including bone presentation who were treated on the Japanese LCH study (JLSG-02) found that patients in the multisystem including bone group were more likely to have lesions in the temporal bone, mastoid/petrous bone, orbit, and zygomatic bone (CNS risk).[13] Patients with multisystem including bone presentation had a higher incidence of diabetes insipidus, correlating with the higher frequency of lesions in the noted facial bones. There was no difference in the outcome of treatment, which was more intense in the JLSG-02 study than in the LCH-II study.

Abdominal/gastrointestinal system

In LCH, the liver and spleen are considered high-risk organs, and involvement of these organs affects prognosis. Involvement in this context means the liver and spleen are enlarged from direct infiltration of LCH cells or as a secondary phenomenon of excess cytokines, which cause macrophage activation or infiltration of lymphocytes around bile ducts. LCH cells have a portal (bile duct) tropism that may lead to biliary damage and ductal sclerosis. A percutaneous (peripheral) liver biopsy may not be diagnostic of the infiltrate that tends to be more central in the liver, but will show the upstream obstructive effects of distal biliary occlusion. Hepatic enlargement can be accompanied by dysfunction, leading to hypoalbuminemia with ascites, hyperbilirubinemia, and clotting factor deficiencies. Sonography, computed tomography (CT), or MRI of the liver will show hypoechoic or low-signal intensity along the portal veins or biliary tracts when the liver is involved with LCH.[14]

Liver (sclerosing cholangitis)

One of the most serious complications of hepatic LCH is cholestasis and sclerosing cholangitis.[15] This usually occurs months after initial presentation, but on occasion may be present at diagnosis. The median age of children with this form of hepatic LCH is 23 months.

Patients with hepatic LCH present with hepatomegaly or hepatosplenomegaly, and elevated alkaline phosphatase, liver transaminases, and gamma glutamyl transpeptidase levels. While ultrasound and/or MRI-cholangiogram can be helpful in the diagnosis of this complication, liver biopsy is currently the only definitive way to determine whether active LCH or hepatic fibrosis is present. Biopsy results often show lymphocytes and biliary obstructive effects without LCH cells. Peribiliary LCH cells and, rarely, nodular masses of LCH, may also be present. It is thought that cytokines, such as transforming growth factor-beta (TGF)-beta, elaborated by lymphocytes during the active phase of the disease, leads to fibrosis and sclerosis around the bile ducts.[16]

Seventy-five percent of children with sclerosing cholangitis will not respond to chemotherapy because the LCH is no longer active, but the fibrosis and sclerosis remain. Liver transplantation is the only alternate treatment when hepatic function worsens. In one series of 28 children undergoing liver transplantation, 78% survived and 29% had recurrence of LCH, but only two cases of recurrent LCH occurred in the transplanted liver, although other cases have been reported since the initial data was published.[17] If at all possible, active LCH should be under control before transplant. The patients who undergo liver transplant for LCH may have a higher incidence of posttransplant lymphoproliferative disease.[18]

Spleen

Massive splenomegaly may lead to cytopenias because of hypersplenism and may cause respiratory compromise. Splenectomy typically provides only transient relief of cytopenias, as increased liver size and reticuloendothelial activation result in peripheral blood cell sequestration and destruction. Although rare, LCH infiltration of the pancreas and kidneys has been reported.[19] Splenectomy is performed only as a life-saving measure.

Other gastrointestinal manifestations

Patients with diarrhea, hematochezia, perianal fistulas, or malabsorption have been reported.[20][21] Diagnosing gastrointestinal involvement with LCH is difficult because of patchy involvement. Careful endoscopic examination including multiple biopsies is usually needed.

Lung

In LCH, the lung is less frequently involved in children than in adults, because smoking in adults is a key etiologic factor.[22] The cystic/nodular pattern of disease reflects the cytokine-induced destruction of lung tissue. Classically, the disease is symmetrical and predominates in the upper and middle lung fields, sparing the costophrenic angle and giving a very characteristic picture on high-resolution CT scan.[23] Confluence of cysts may lead to bullous formation and spontaneous pneumothorax can be the first sign of LCH in the lung, although patients may present with tachypnea or dyspnea. Ultimately, widespread fibrosis and destruction of lung tissue may lead to severe pulmonary insufficiency. Declining diffusion capacity may also herald the onset of pulmonary hypertension.[24] Widespread fibrosis and declining diffusion capacity are much less common in children. In young children with diffuse disease, therapy can halt progress of the tissue destruction and normal repair mechanisms may restore some function, although scarring or even residual nonactive cysts may continue to be visible on radiologic studies.

Pulmonary involvement is present in approximately 25% of children with multisystem low-risk and high-risk LCH.[25] However, a multivariate analysis of pulmonary disease in multisystem LCH did not show pulmonary disease to be an independent prognostic factor, with a 5-year overall survival rate of 94% versus 96% for those with or without pulmonary involvement.[26]

Bone marrow

Most patients with bone marrow involvement are young children who have diffuse disease in the liver, spleen, lymph nodes, and skin who present with significant thrombocytopenia and anemia with or without neutropenia.[27] Others have only mild cytopenias and are found to have bone marrow involvement with LCH by sensitive immunohistochemical or flow cytometric analysis of the bone marrow.[28] A high content of bone marrow macrophages can obscure LCH cells.[29] Patients with LCH who are considered at very high risk sometimes present with hemophagocytosis involving the bone marrow.[30] The cytokine milieu driving LCH is probably responsible for the epiphenomenon of macrophage activation, which in the most severe cases, present with typical manifestations of hemophagocytic lymphohistiocytosis including cytopenias and hyperferritinemia.

Endocrine system

Diabetes insipidus, caused by LCH-induced damage to the antidiuretic hormone-secreting cells of the posterior pituitary, is the most frequent endocrine manifestation in LCH.[31] MRI scans usually show nodularity and/or thickening of the pituitary stalk and loss of the pituitary bright spot on T2-weighted images. Pituitary biopsies are rarely done and usually only when the stalk is greater than 6.5 mm or there is a hypothalamic mass.[32] Pituitary disease is often associated with other sites of involvement; in order to avoid biopsy of the pituitary, these sites can be biopsied to establish the diagnosis.

Approximately 4% of LCH patients present with an apparently idiopathic presentation of diabetes insipidus before other lesions of LCH are identified. A review of pediatric patients presenting with idiopathic central diabetes insipidus showed that 19% eventually developed manifestations of LCH.[33] Approximately 50% of patients who present with isolated diabetes insipidus as the initial manifestation of LCH either have anterior pituitary deficits at the time of diagnosis or develop them within 10 years of diabetes insipidus onset.[34][35] These included secondary amenorrhea, panhypopituitarism, growth hormone deficiency, hypoadrenalism, and abnormalities of gonadotropins.

Patients with diabetes insipidus due to LCH have a 50% to 80% chance of developing other lesions diagnostic of LCH within 1 year of diabetes insipidus onset, including bone, lung, and skin.[32][34] A study of 589 patients with LCH revealed the 10-year risk of pituitary involvement was 24%.[31] No decrease in incidence of diabetes insipidus was seen in chemotherapy-treated patients, but this may reflect the length of the therapy and/or the number of drugs used.[32] Using longer therapy and more drugs, the German-Austrian-Dutch (Deutsche Arbeits-gemeinschaft für Leukaemieforschung und-therapie im Kindesalter [DAL]) Group found the cumulative incidence to be 12%.[36][37] Diabetes insipidus followed initial LCH diagnosis at a mean of 1 year and growth hormone deficiency occurred 5 years later. The incidence of diabetes insipidus was lower in patients treated with more intensive chemotherapy regimens on the LCH-III and JLSG-96 and JLSG-02 studies in Japan (8.9% for multisystem patients) than on the LCH-I and LCH-II studies (14.2%).[37][38][39][40] Fifty-six percent of diabetes insipidus patients will develop anterior pituitary hormone deficiencies (growth, thyroid, or gonadal-stimulating hormones) within 10 years of the onset of diabetes insipidus. Diabetes insipidus occurs in 11% of patients treated with multiagent chemotherapy and in up to 50% of patients treated less aggressively.[35][41]

Patients with multisystem disease and craniofacial involvement at the time of diagnosis, particularly of the orbit, mastoid, and temporal bones, carried a significantly increased risk of developing diabetes insipidus during their course (relative risk, 4.6), with 75% of patients with diabetes insipidus having these CNS-risk bone lesions.[36] The risk increased when the disease remained active for a longer period of time or reactivated. The risk of diabetes insipidus development in this population was 20% at 15 years after diagnosis.

Ocular

Although rare, there have been several cases of ocular involvement by LCH, sometimes leading to blindness. Patients may have other organ systems involved, and the ocular LCH may not respond well to conventional chemotherapy.[10]

Central nervous system

CNS disease manifestations

Patients with LCH may develop mass lesions in the hypothalamic-pituitary region, the choroid plexus, the grey matter, or the white matter.[42] These lesions contain CD1a-positive LCH cells and CD8-positive lymphocytes, and are, therefore, active LCH lesions.[43]

Patients with large pituitary tumors (>6.5 mm) have a higher risk of anterior pituitary dysfunction and neurodegenerative CNS LCH.[44] A retrospective study of 22 patients found that all had radiologic signs of neurodegenerative CNS LCH detected at a median time of 3 years and 4 months after LCH diagnosis and that it worsened in 19 patients. Five had neurologic dysfunction. Eighteen of 22 patients had anterior pituitary dysfunction and 20 had diabetes insipidus. Growth hormone deficiency occurred in 21 patients; luteinizing hormone/follicle-stimulating hormone deficiency occurred in ten patients; and thyroid hormone deficiency occurred in ten patients.

LCH CNS neurodegenerative syndrome

A chronic neurodegenerative syndrome that is manifested by dysarthria, ataxia, dysmetria, and sometimes behavior changes develops in 1% to 4% of patients with LCH. These patients may develop severe neuropsychologic dysfunction with tremor, gait disturbances, ataxia, dysarthria, headaches, visual disturbances, cognitive and behavioral problems, and psychosis. MRI scan results from these patients show hyperintensity of the dentate nucleus and white matter of the cerebellum on T2-weighted images or hyperintense lesions of the basal ganglia on T1-weighted images and/or atrophy of the cerebellum.[45] The radiologic findings may precede the onset of symptoms by many years or be found coincidently. A study of 83 patients with LCH who had at least two MRI studies of the brain for evaluation of craniofacial lesions, diabetes insipidus, and/or other endocrine deficiencies of neuropsychological symptoms has been published.[46] Forty-seven of 83 patients (57%) had radiological neurodegenerative changes at a median time of 34 months from diagnosis. Of the 47 patients, 12 (25%) developed clinical neurological deficits that presented 3 to 15 years after the LCH diagnosis. Fourteen of the 47 patients had subtle deficits in short-term auditory memory.

A study of CNS-related permanent consequences (neuropsychologic deficits) in 14 of 25 patients with LCH who were monitored for a median of 10 years has been published.[47] Seven of these patients had diabetes insipidus and five patients had radiographic evidence of LCH CNS neurodegenerative changes.[47] Patients with craniofacial lesions had lower performance and verbal intelligence quotient scores than those with other LCH lesions.

Histological evaluation of these neurodegenerative lesions shows a prominent T-cell infiltration, usually in the absence of the CD1a-positive dendritic cells along with microglial activation and gliosis. The neurodegenerative form of the disease has been compared to a paraneoplastic inflammatory response.[43]

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  36. Grois N, Pötschger U, Prosch H, et al.: Risk factors for diabetes insipidus in langerhans cell histiocytosis. Pediatr Blood Cancer 46 (2): 228-33, 2006.

  37. Shioda Y, Adachi S, Imashuku S, et al.: Analysis of 43 cases of Langerhans cell histiocytosis (LCH)-induced central diabetes insipidus registered in the JLSG-96 and JLSG-02 studies in Japan. Int J Hematol 94 (6): 545-51, 2011.

  38. Gadner H, Grois N, Arico M, et al.: A randomized trial of treatment for multisystem Langerhans' cell histiocytosis. J Pediatr 138 (5): 728-34, 2001.

  39. Gadner H, Grois N, Pötschger U, et al.: Improved outcome in multisystem Langerhans cell histiocytosis is associated with therapy intensification. Blood 111 (5): 2556-62, 2008.

  40. Gadner H, Minkov M, Grois N, et al.: Therapy prolongation improves outcome in multisystem Langerhans cell histiocytosis. Blood 121 (25): 5006-14, 2013.

  41. Gadner H, Heitger A, Grois N, et al.: Treatment strategy for disseminated Langerhans cell histiocytosis. DAL HX-83 Study Group. Med Pediatr Oncol 23 (2): 72-80, 1994.

  42. Grois NG, Favara BE, Mostbeck GH, et al.: Central nervous system disease in Langerhans cell histiocytosis. Hematol Oncol Clin North Am 12 (2): 287-305, 1998.

  43. Grois N, Prayer D, Prosch H, et al.: Neuropathology of CNS disease in Langerhans cell histiocytosis. Brain 128 (Pt 4): 829-38, 2005.

  44. Fahrner B, Prosch H, Minkov M, et al.: Long-term outcome of hypothalamic pituitary tumors in Langerhans cell histiocytosis. Pediatr Blood Cancer 58 (4): 606-10, 2012.

  45. Prayer D, Grois N, Prosch H, et al.: MR imaging presentation of intracranial disease associated with Langerhans cell histiocytosis. AJNR Am J Neuroradiol 25 (5): 880-91, 2004.

  46. Wnorowski M, Prosch H, Prayer D, et al.: Pattern and course of neurodegeneration in Langerhans cell histiocytosis. J Pediatr 153 (1): 127-32, 2008.

  47. Mittheisz E, Seidl R, Prayer D, et al.: Central nervous system-related permanent consequences in patients with Langerhans cell histiocytosis. Pediatr Blood Cancer 48 (1): 50-6, 2007.

Diagnostic Evaluation of Childhood LCH

The complete evaluation of any patient, whether presenting with single-system or multisystem disease, should include the following:[1]

  • History and physical exam: A complete history and physical exam with special attention to the skin, lymph nodes, ears, oral pharynx, gingiva, tongue, teeth, bones, lungs, thyroid, liver and spleen size, bone abnormalities, growth velocity, and history of excessive thirst and urination.

Other tests and procedures include the following:

  • Blood tests: Blood tests include complete blood count with leukocyte differential and platelet count, liver function tests (e.g., bilirubin, albumin, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, and prothrombin time/partial thromboplastin time in patients with hepatomegaly, jaundice, elevations of liver enzymes, or low albumin), and serum electrolytes.
  • BRAF V600E: Although BRAF mutation assessment is not a required part of the workup for Langerhans cell histiocytosis (LCH), the BRAF mutation can be detected by either immunohistochemistry or molecular diagnostic methods.
  • Urine tests: Urine tests include urinalysis and a water-deprivation test if diabetes insipidus is suspected. Water deprivation tests in very young children, especially infants, is performed under medical monitoring.
  • Bone marrow aspirate and biopsy: The bone marrow aspirate and biopsy is indicated for patients with multisystem disease who have unexplained anemia or thrombocytopenia. The biopsy should be stained with anti-CD1a and/or anti-CD207 (langerin) and anti-CD163 immunostains to facilitate the detection of LCH cells.
  • Radiologic and imaging tests: Radiologic tests for the first level of screening include skeletal survey, skull series, bone scans, and chest X-ray. Newer diagnostic imaging modalities, such as somatostatin analog scintigraphy or fludeoxyglucose F 18 (18F-FDG) positron emission tomography (PET) scans, augment, but do not replace the standard tests.[2][3][4][5][6]
    • Computed tomography (CT) scan: CT scan of the head may be indicated if orbital, mastoid, or other maxillofacial involvement is suspected. Imaging tests may include magnetic resonance imaging (MRI) scan with gadolinium contrast of the brain for patients with diabetes insipidus or suspected brain or vertebral involvement.[7]

      CT scan of the lungs may be indicated for patients with abnormal chest X-rays or pulmonary symptoms. High-resolution CT scans may show evidence of pulmonary LCH when the chest X-ray is normal, thus in infants and toddlers with normal chest X-rays, a CT scan may be considered.[8]

      LCH causes fatty changes in the liver or hypodense areas along the portal tract, which can be identified by CT scans.[9]

    • 18F-FDG PET scan: 18F-FDG PET scan abnormalities have been reported in the brains of seven patients with LCH, with neurologic and radiographic signs of neurodegenerative disease.[6] There was good correlation with MRI findings in the cerebellar white matter, but less so in the caudate nuclei and frontal cortex. It was suggested that PET scans of patients at high risk for developing neurodegenerative LCH could show abnormalities earlier than MRI.[6] PET scans often demonstrate lesions not found by other modalities and show a decrease of activity after 6 weeks of therapy, thus providing a better assessment of response to therapy than bone scans or plain X-rays.[5]
    • MRI: MRI findings of patients with diabetes insipidus include thickening and nodularity of the pituitary stalk with loss of the posterior pituitary bright spot reflecting absence of anti-diuretic hormone. Later in the course, the stalk generally atrophies but this should not be used as evidence of response to therapy.

      All patients with vertebral body involvement need careful assessment of associated soft tissue, which may impinge on the spinal cord.

      MRI findings of central nervous system LCH include T2 fluid attenuated inversion recovery (FLAIR) enhancement in the pons, basal ganglia, white matter of the cerebellum, and mass lesions or meningeal enhancement. In a report of 163 patients,[10] meningeal lesions were found in 29% and choroid plexus involvement in 6%. Paranasal sinus or mastoid lesions were found in 55% of patients versus 20% of controls, and accentuated Virchow-Robin spaces in 70% of patients versus 27% of controls.

  • Biopsy: Lytic bone lesions, skin, and lymph nodes are the most frequent sites biopsied for diagnosis of LCH. A liver biopsy is indicated when a child with LCH presents with hypoalbuminemia not caused by gastrointestinal LCH or other etiology. These patients usually have elevated levels of bilirubin or liver enzymes. An open lung biopsy may be necessary for obtaining tissue for diagnosis of pulmonary LCH when bronchoalveolar lavage is nondiagnostic.

    A pathologic diagnosis is always required to make a definitive diagnosis. However, this may sometimes be difficult or contraindicated, such as in isolated pituitary stalk disease when the risk outweighs the benefit of a firm diagnosis. LCH cells are large cells with abundant pink cytoplasm and a bean-shaped nucleus on hematoxylin and eosin. LCH cells should stain positively with antibodies to CD1a and/or anti-langerin (CD207) to confirm the diagnosis of LCH.[11]

References:

  1. Haupt R, Minkov M, Astigarraga I, et al.: Langerhans cell histiocytosis (LCH): guidelines for diagnosis, clinical work-up, and treatment for patients till the age of 18 years. Pediatr Blood Cancer 60 (2): 175-84, 2013.

  2. Calming U, Jacobsson H, Henter JI: Detection of Langerhans cell histiocytosis lesions with somatostatin analogue scintigraphy--a preliminary report. Med Pediatr Oncol 35 (5): 462-7, 2000.

  3. Calming U, Bemstrand C, Mosskin M, et al.: Brain 18-FDG PET scan in central nervous system langerhans cell histiocytosis. J Pediatr 141 (3): 435-40, 2002.

  4. Binkovitz LA, Olshefski RS, Adler BH: Coincidence FDG-PET in the evaluation of Langerhans' cell histiocytosis: preliminary findings. Pediatr Radiol 33 (9): 598-602, 2003.

  5. Phillips M, Allen C, Gerson P, et al.: Comparison of FDG-PET scans to conventional radiography and bone scans in management of Langerhans cell histiocytosis. Pediatr Blood Cancer 52 (1): 97-101, 2009.

  6. Ribeiro MJ, Idbaih A, Thomas C, et al.: 18F-FDG PET in neurodegenerative Langerhans cell histiocytosis : results and potential interest for an early diagnosis of the disease. J Neurol 255 (4): 575-80, 2008.

  7. Grois N, Prayer D, Prosch H, et al.: Course and clinical impact of magnetic resonance imaging findings in diabetes insipidus associated with Langerhans cell histiocytosis. Pediatr Blood Cancer 43 (1): 59-65, 2004.

  8. Ha SY, Helms P, Fletcher M, et al.: Lung involvement in Langerhans' cell histiocytosis: prevalence, clinical features, and outcome. Pediatrics 89 (3): 466-9, 1992.

  9. Prasad SR, Wang H, Rosas H, et al.: Fat-containing lesions of the liver: radiologic-pathologic correlation. Radiographics 25 (2): 321-31, 2005 Mar-Apr.

  10. Prayer D, Grois N, Prosch H, et al.: MR imaging presentation of intracranial disease associated with Langerhans cell histiocytosis. AJNR Am J Neuroradiol 25 (5): 880-91, 2004.

  11. Chikwava K, Jaffe R: Langerin (CD207) staining in normal pediatric tissues, reactive lymph nodes, and childhood histiocytic disorders. Pediatr Dev Pathol 7 (6): 607-14, 2004 Nov-Dec.

Follow-up Considerations in Childhood LCH

Patients with diabetes insipidus and/or skull lesions in the orbit, mastoid, or temporal bones appear to be at higher risk for Langerhans cell histiocytosis (LCH) central nervous system (CNS) involvement and LCH CNS neurodegenerative syndrome. These patients should have magnetic resonance imaging (MRI) scans with gadolinium contrast at the time of LCH diagnosis and every 1 to 2 years thereafter for 10 years to detect evidence of CNS disease.[1] The Histiocyte Society CNS LCH Committee does not recommend any treatment for radiologic CNS LCH of the neurodegenerative type if there is no associated clinical neurodegeneration. However, careful neurologic examinations and appropriate imaging with MRI is suggested at regular intervals. Brain stem auditory evoked responses should also be done at regular intervals to define the onset of clinical CNS LCH as early as possible, as this may affect response to therapy.[2] When clinical signs are present, intervention may be indicated. Available studies of different forms of therapy for CNS neurodegeneration suggest that the neurodegenerative changes may be stabilized or improved, but only if therapy is started early.[2] (Refer to the LCH CNS neurodegenerative syndrome section of this summary for more information.) Careful follow-up of patients at risk is critical.

For children with LCH in the lung, pulmonary function testing and chest computed tomography scans are sensitive methods for detecting disease progression.[3]

In summary, many patients with multisystem disease will experience long-term sequelae due to their underlying disease and/or treatment. Endocrine and CNS sequelae are the most common. These long-term sequelae significantly affect health quality of life in many of these patients.[4][Level of evidence: 3iiiC] Specific long-term follow-up guidelines after treatment of childhood cancer or in those who have received chemotherapy have been published by the Children's Oncology Group and are available on their Web site.

References:

  1. Wnorowski M, Prosch H, Prayer D, et al.: Pattern and course of neurodegeneration in Langerhans cell histiocytosis. J Pediatr 153 (1): 127-32, 2008.

  2. Allen CE, Flores R, Rauch R, et al.: Neurodegenerative central nervous system Langerhans cell histiocytosis and coincident hydrocephalus treated with vincristine/cytosine arabinoside. Pediatr Blood Cancer 54 (3): 416-23, 2010.

  3. Bernstrand C, Cederlund K, Henter JI: Pulmonary function testing and pulmonary Langerhans cell histiocytosis. Pediatr Blood Cancer 49 (3): 323-8, 2007.

  4. Nanduri VR, Pritchard J, Levitt G, et al.: Long term morbidity and health related quality of life after multi-system Langerhans cell histiocytosis. Eur J Cancer 42 (15): 2563-9, 2006.

Treatment of Childhood LCH

Depending on the site and extent of disease, treatment of Langerhans cell histiocytosis (LCH) may include surgery, radiation therapy, or oral, topical, and intravenous medication. The recommended duration of therapy is 12 months for patients who require chemotherapy for single-system bone, skin, or lymph node involvement. For patients with both high-risk and low-risk multisystem disease, the reactivation rate following 6 months of therapy was as high as 50% on the LCH-I and LCH-II trials.[1]. Based upon data from the German-Austrian-Dutch (Deutsche Arbeits-gemeinschaft für Leukaemieforschung und-therapie im Kindesalter [DAL]) Group trials, which treated patients for 1 year and had fewer relapses (29%),[1] the LCH-III trial was designed to give 12 months of chemotherapy for all high-risk multisystem patients and to randomly assign low-risk multisystem patients to either 6 months or 12 months of therapy. In patients with low-risk or high-risk disease who received 12 months of therapy, the reactivation rate was significantly reduced to approximately 30%.[2] The LCH-IV trial will assess whether extending the duration of therapy further will reduce the incidence of reactivations and late effects. Although the LCH-IV study is open in several European centers, it is not open in the United States.

It is preferable that patients with LCH be enrolled in a clinical trial whenever possible so that advances in therapy can be achieved more quickly, utilizing evidence-based recommendations and to ensure optimal care. Information about clinical trials for LCH in children is available from the Histiocyte Society Web site.

Standard Treatment Options by Organ, Site or System Involvement for Pediatric Patients

The standard treatment for LCH is best chosen based on data from international trials with large numbers of patients. However, some patients may have LCH involving only the skin, mouth, pituitary gland, or other sites not studied in these international trials. In such cases therapy recommendations are based upon case series that lack the evidence-based strength of the trials.

Treatment of low-risk disease (single-system or multisystem)

Isolated skin involvement

  • Observation. Observation is recommended for all pediatric patients with skin-only LCH. Therapy is suggested only for symptomatic disease such as extensive rashes, pain, ulceration, or bleeding.
  • Topical steroids. Medium to high potency steroids are effective but the effect is usually not long lasting.[3]
  • Oral methotrexate (20 mg/m2) weekly for 6 months.[4]
  • Oral thalidomide 50 mg to 200 mg nightly.[5] Oral thalidomide may be effective for both pediatric and adult patients.
  • Topical application of nitrogen mustard can be effective for cutaneous LCH that is resistant to oral therapies, but not for disease involving large areas of skin.[6][7]
  • Psoralen and long-wave ultraviolet A radiation (PUVA) and UVB can be effective in skin LCH but its use is limited by the potential for late skin cancers, especially in patients with light skin tones.[8][9]

Skeletal involvement

Single skull lesions of the frontal, parietal, or occipital regions, or single lesions of any other bone

  • Curettage only is the recommended therapy, when possible for isolated bone lesions; curettage plus injection of methylprednisolone may be used. Low-dose radiation therapy is effective but its use is limited in pediatric patients to lesions that threaten organ function.[10][11]; [12][Level of evidence: 3iiiA] LCH bone lesions may not need complete excision, as this only increases healing time and the risk of long-term complications.

Skull lesions in the mastoid, temporal, or orbital bones

The purpose of treating patients with isolated skull lesions in the mastoid, temporal, or orbital bones is to decrease the chance of developing diabetes insipidus and other long-term problems.[13] Comparison of diabetes insipidus incidence with no systemic therapy (40%) versus 6 months of vinblastine/prednisone (20%) strongly supports treatment of the central nervous system (CNS)–risk bones even when it occurs in a single site.[14] However, the efficacy of therapy and the optimal length of therapy have yet to be proven in a prospective trial.

  • Twelve months of vinblastine and prednisone as per the LCH-III study results: Weekly vinblastine (6 mg/m2) for 7 weeks then every 3 weeks for good response. Daily prednisone (40 mg/m2) for 4 weeks then tapered over 2 weeks. Afterward prednisone is given for 5 days at 40 mg/m2 every 3 weeks with the vinblastine injections.[2][13]
  • There is some controversy about whether systemic therapy is required for the first presentation with unifocal bone LCH even in the CNS risk bones. Ear, nose, and throat surgeons have reported a series of patients with orbital or mastoid lesions who received only surgical curettage.[15] None of these patients developed diabetes insipidus. However, when comparing the incidence rates of diabetes insipidus in patients who received little or no chemotherapy (20%–50% incidence of diabetes insipidus) versus diabetes insipidus incidence rates reported by the German-Austrian-Dutch (DAL) Group HX-83 trial (10% incidence of diabetes insipidus in patients treated for LCH), it appears that the weight of evidence from the DAL HX-83 trial supports chemotherapy treatment to prevent diabetes insipidus in patients with LCH of the mastoid, temporal, or orbital bones.[16][17] It should be noted, however, that the DAL HX studies used more drugs and treated patients for a duration of 12 months.

Vertebral or femoral bone lesions at risk for collapse

  • A single vertebral body lesion without soft tissue extension to the extradural space may be observed only.
  • Low-dose radiation therapy may be used to try to promote resolution in an isolated vertebral body lesion or a large femoral neck lesion at risk for fracture, where chemotherapy is not usually indicated (single bone lesion). Despite the low dose required (700–1,000 cGy), radiation therapy should be used with caution in the area of the thyroid gland, brain, or any growth plates.[18]
  • Patients with soft tissue extension from vertebral lesions are often treated successfully with chemotherapy,[19][Level of evidence: 3iiDiii] but prolonged therapy does not appear to be needed beyond the period required to reduce the mass and any risk to the spinal cord. The risk of reactivation of a single bone lesion was only 9% in one large retrospective series.[20]
  • When instability of the cervical vertebrae and/or neurologic symptoms are present, bracing, or rarely, spinal fusion may be needed.[21] Patients with soft tissue extension from the vertebral lesions are often treated successfully with chemotherapy.[19][Level of evidence: 3iiDiii]

Multiple bone lesions (single-system multifocal bone)

  • The most commonly used systemic chemotherapy regimen is the combination of vinblastine and prednisone. Based on the results of the HISTSOC-LCH-III trial, 12 months of treatment with weekly vinblastine (6 mg/m2) for 7 weeks then every 3 weeks is used for good responders.[2] Prednisone (40 mg/m2) is given daily for 4 weeks then tapered over 2 weeks. Afterwards prednisone is given for 5 days at 40 mg/m2 every 3 weeks with the vinblastine injections. A short (<6 months) treatment course with only a single agent (e.g., prednisone) is not sufficient, and the number of relapses is higher. A reactivation rate of 18% was reported with a multidrug treatment regimen that was used for 6 months versus a historical reactivation rate of 50% to 80% with surgery alone or with a single-drug treatment regimen.[22]

Multiple bone lesions in combination with skin, lymph node, or diabetes insipidus (low-risk multisystem LCH)

  • Vinblastine and prednisone in combination. Based on the results of the randomized HISTSOC-LCH-III trial, the same chemotherapy regimen of vinblastine and prednisone as described above is used for 12 months. Patients without risk-organ involvement who were randomly assigned to 12 months of vinblastine/prednisone had a lower 5-year reactivation rate (37%) than did patients who received only 6 months of treatment (54%; P = .03) and patients treated with historical 6-month schedules (52% [LCH-I] and 48% [LCH-II]; P < .001). Most disease reactivations were in bone, skin, or other nonrisk locations.[2]
  • Other chemotherapy regimens have also been effective, including the following:
    • Vincristine, cytosine arabinoside, and prednisone in combination.[23] This combination has been proven to be an effective frontline or salvage therapy. However, prednisone is given for a much shorter duration than was originally published; currently, prednisone is given for 4 to 6 weeks during the induction phase and then for 5 days every 3 weeks with a single dose of vincristine and 5 days of cytosine arabinoside during maintenance.
    • Cladribine. Cladribine given at 5 mg/m2/day for 5 days every 3 weeks for two to six cycles can be an effective salvage therapy for recurrent bone or low-risk multisystem disease. More than six cycles is not recommended because of the risk of cumulative cytopenias.
    • Pamidronate can also be effective for treating LCH bone lesions.[24] A nationwide survey from Japan described 16 children treated with bisphosphonates for bone LCH. All had bone disease; none had risk-organ disease. Most patients received six cycles of pamidronate at 1 mg/kg/course given at 4-week intervals. In 12 of 16 patients, all active lesions including skin (n = 3) and soft tissues (n = 3) resolved. Eight remained disease free at a median of 3.3 years.[25] Other bisphosphonates, such as zoledronate and oral alendronate, have been used to successfully treat bone LCH.

Treatment of high-risk multisystem disease

Spleen, liver, and bone marrow (may or may not include skin, bone, lymph node, lung, or pituitary gland)

  • The standard therapy length recommended for LCH involving the spleen, liver, or bone marrow (high-risk organs) is now 12 months based upon the DAL-HX-83 and HISTSOC-LCH-III studies.[13][17] In the Histiocyte Society LCH-II and LCH-III studies, the standard arm consisted of vinblastine and prednisone as described above under multifocal bone, but 6-mercaptopurine was added to the continuation phase of the protocol.
  • The LCH-II study was a randomized trial to compare treatment of patients with vinblastine, prednisone, and mercaptopurine or vinblastine, prednisone, mercaptopurine, and etoposide.[26][Level of evidence: 1iiA]

    There was no statistical significance in outcomes (response at 6 weeks, 5-year probability of survival, relapses, and permanent consequences) between the two treatment groups. Hence, etoposide has not been used in subsequent Histiocyte Society trials. Late review of the results, however, reported reduced mortality of patients with risk-organ involvement in the etoposide arm. Although controversial, a comparison of patients in the LCH-I trial with patients in the LCH-II trial suggested that increased treatment intensity promoted additional early responses and reduced mortality.

    It is important to note that those studies included lungs as risk organs. However, subsequent analyses have shown that lung involvement lacks prognostic significance.[27]

  • The LCH-III study randomly assigned risk organ–affected patients to either vinblastine/prednisone/6-mercaptopurine or vinblastine/prednisone/6-mercaptopurine plus methotrexate (intravenous during the induction phase and oral in the continuation phase).[2] The response rates at 6 and 12 weeks and overall survival were not improved; however, there were significantly increased grade 3 and grade 4 toxicities in patients who received methotrexate.

    An important finding of the LCH-III study was that the mortality of patients with high-risk LCH on both arms of the study was significantly reduced compared with the earlier LCH-II study, even though the standard arm utilizes the same drugs. Possible explanations for reduced mortality include the following:

    • A second 6-week induction phase of weekly vinblastine with prednisone given for 3 days per week. This reinduction phase was given to all patients who did not achieve a status of no active disease by the end of the 6-week induction phase, before going onto the every-3-weeks maintenance courses. The rate of no active disease increased after the second induction phase and this course may have played a significant role in the reduced mortality rate.
    • Better supportive care.
    • Earlier change to an effective salvage strategy for nonresponsive lesions.

    It should be noted that although survival was improved in the LCH-III study, only 60% of patients had no active disease in risk organs after a year of therapy and 25% to 29% of patients relapsed.

  • The Japan LCH Study Group (JLSG) reported 5-year response and overall survival rates of 78% and 95%, respectively, for patients with multisystem disease treated on the JLSG-96 trial (6-week induction regimen of cytosine arabinoside, vincristine, and prednisolone followed by 6 months of maintenance therapy with cytarabine, vincristine, prednisolone, and low-dose intravenous methotrexate). If patients had a poor response to the initial regimen, they were switched to a salvage regimen of intensive combination doxorubicin, cyclophosphamide, methotrexate, vincristine, and prednisolone.[28]

    Similar to the LCH-III study, the important finding of this study was the decreased mortality compared with previous JLSG studies and to the LCH-II study. This was attributed to the early change to a more effective salvage therapy for patients with nonresponsive disease, as well as better supportive care.[28]

  • Some patients develop a “macrophage activation” of their marrow. This may be confusing to clinicians who may think the patient has hemophagocytic lymphohistiocytosis and LCH. The best therapy for this life-threatening manifestation is not clear, because it tends not to respond well to standard hemophagocytic lymphohistiocytosis therapy. Clofarabine, anti-CD52 antibody alemtuzumab, or reduced-intensity allogeneic stem cell transplant could be considered.[29]

Treatment of CNS disease

CNS lesions

There are three types of LCH CNS lesions:

  • Mass lesions or tumors in the cerebrum, cerebellum, or choroid plexus.
  • Mass lesions of the hypothalamic-pituitary axis that are always associated with diabetes insipidus and are often associated with other endocrinopathies.
  • Neurodegenerative syndrome. T2 fluid attenuated inversion recovery (FLAIR) hyperintense signals are present, most often in the cerebellar white matter, pons, basal ganglia, and sometimes, in the cerebrum.

Drugs that cross the blood-brain barrier, such as cladribine, or other nucleoside analogs, such as cytarabine, are used for active CNS LCH lesions.

  • Treatment of mass lesions with cladribine has been effective in 13 reported cases.[30][31]; [32][Level of evidence: 3iiiDiii] Mass lesions included enlargement of the hypothalamic-pituitary axis, parenchymal mass lesions, and leptomeningeal involvement. Doses of cladribine ranged from 5 mg/m2 to 13 mg/m2, given at varying frequencies.[32][Level of evidence: 3iiiDiii]
  • Patients with LCH and mass lesions in the hypothalamic-pituitary region, the choroid plexus, the grey matter, or the white matter, may also respond to standard LCH chemotherapy.[33][34] Treatment with vinblastine with or without corticosteroids for patients with CNS mass lesions (20 patients; mainly pituitary) demonstrated an objective response in 15 patients, with 5 of 20 patients demonstrating a complete response and 10 of 20 patients demonstrating a partial response.

CNS neurodegenerative syndrome

Drugs used in active LCH, such as dexamethasone and cladribine, along with other agents, such as retinoic acid, intravenous immunoglobulin (IVIg), infliximab, and cytarabine with or without vincristine have been used in small numbers of patients with mixed results. Many of these agents may result in the complete or partial resolution of radiographic findings, but definitive clinical response rates have not been rigorously defined.[35][36][37][38][39]; [32][Level of evidence: 3iiiDiii]

  • Retinoic acid was given at a dose of 45 mg/m2 daily for 6 weeks, then 2 weeks per month for 1 year.[35] Patients were reported to have stable clinical status.
  • IVIg (400 mg/m2) was given monthly with chemotherapy consisting of oral prednisolone with or without oral or intravenous methotrexate and oral 6-mercaptopurine for at least 1 year.[36] Magnetic resonance imaging (MRI) findings were stable but clinical efficacy was difficult to judge because patients were reported to have no progression in their neurologic symptoms.
  • A study using cytarabine with or without vincristine for up to 24 months reported improvement in the clinical and MRI findings in some patients and stabilization of disease in the others.[38][Level of evidence: 3iiiC] Seven of eight patients have been followed for more than 8 years after stopping therapy and have had stable neurologic and radiographic findings.
  • In the Japan LCH Study Group-96 Protocol, cytarabine failed to prevent the onset of neurodegenerative syndrome. Patients received cytarabine 100 mg/m2 daily on days 1 to 5 during induction and 150 mg/m2 on day 1 of each maintenance cycle (every 2 weeks for 6 months). Three of 91 patients developed neurodegenerative disease, which is similar to the rate experienced on the Histiocyte Society studies.[28]

Perhaps the most important aspect of therapy for neurodegenerative disease is the early recognition of clinical neurodegeneration and institution of therapy. Studies combining MRI findings together with cerebrospinal fluid markers of demyelination, to identify patients who require therapy, even before onset of clinical symptoms, are currently underway in several countries.

Treatment Options for Childhood LCH No Longer Considered Effective

Treatments that have been used in the past but are no longer recommended for pediatric patients with LCH in any location include cyclosporine [40] and interferon-alpha.[41] Extensive surgery is also not indicated. Curettage of a circumscribed skull lesion may be sufficient if the lesion in not in the temporal, mastoid, or orbital areas (CNS risk). Patients with disease in these particular sites are recommended to receive 6 months of systemic therapy with vinblastine and prednisone. For lesions of the mandible, extensive surgery may destroy any possibility of secondary tooth development. Surgical resection of groin or genital lesions is contraindicated as these lesions can be healed by chemotherapy.

Radiation therapy use in LCH has been significantly reduced in pediatric patients, and even low-dose radiation therapy should be limited to single-bone vertebral body lesions or other single-bone lesions compressing the spinal cord or optic nerve that do not respond to chemotherapy.[42]

Assessment of Response to Treatment

Response assessment remains one of the most difficult areas in LCH therapy unless there is a specific area that can be followed clinically or with sonography, computed tomography (CT), or MRI scans of areas such as the skin, hepato/splenomegaly, and other mass lesions. Clinical judgment including evaluation of pain and other symptoms remains important.

Bone lesions may take many months to heal and are difficult to evaluate on plain radiographs, although sclerosis around the periphery of a bone lesion suggests healing. CT or MRI scans are useful in assessing response of a soft tissue mass associated with a bone lesion, but is not particularly helpful in lytic bone lesions. Technetium bone scans remain positive in healing bone. Positron emission tomography (PET) scans may be helpful in following the response to therapy since intensity of the PET image diminishes with response of lesions and healing of bone.[43]

For children or adults with lung LCH, pulmonary function testing and high resolution CT scans are sensitive methods for detecting disease progression.[44] Residual interstitial changes reflecting residual fibrosis or residual inactive cysts must be distinguished from active disease and somatostatin analogue scintigraphy may be useful in this regard.[45]

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with childhood Langerhans cell histiocytosis. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References:

  1. Braier JL, Rosso D, Latella A, et al.: Importance of multi-lineage hematologic involvement and hypoalbuminemia at diagnosis in patients with "risk-organ" multi-system Langerhans cell histiocytosis. J Pediatr Hematol Oncol 32 (4): e122-5, 2010.

  2. Gadner H, Minkov M, Grois N, et al.: Therapy prolongation improves outcome in multisystem Langerhans cell histiocytosis. Blood 121 (25): 5006-14, 2013.

  3. Lau L, Krafchik B, Trebo MM, et al.: Cutaneous Langerhans cell histiocytosis in children under one year. Pediatr Blood Cancer 46 (1): 66-71, 2006.

  4. Steen AE, Steen KH, Bauer R, et al.: Successful treatment of cutaneous Langerhans cell histiocytosis with low-dose methotrexate. Br J Dermatol 145 (1): 137-40, 2001.

  5. McClain KL, Kozinetz CA: A phase II trial using thalidomide for Langerhans cell histiocytosis. Pediatr Blood Cancer 48 (1): 44-9, 2007.

  6. Hoeger PH, Nanduri VR, Harper JI, et al.: Long term follow up of topical mustine treatment for cutaneous langerhans cell histiocytosis. Arch Dis Child 82 (6): 483-7, 2000.

  7. Lindahl LM, Fenger-Grøn M, Iversen L: Topical nitrogen mustard therapy in patients with Langerhans cell histiocytosis. Br J Dermatol 166 (3): 642-5, 2012.

  8. Kwon OS, Cho KH, Song KY: Primary cutaneous Langerhans cell histiocytosis treated with photochemotherapy. J Dermatol 24 (1): 54-6, 1997.

  9. Vogel CA, Aughenbaugh W, Sharata H: Excimer laser as adjuvant therapy for adult cutaneous Langerhans cell histiocytosis. Arch Dermatol 144 (10): 1287-90, 2008.

  10. Nauert C, Zornoza J, Ayala A, et al.: Eosinophilic granuloma of bone: diagnosis and management. Skeletal Radiol 10 (4): 227-35, 1983.

  11. Gramatovici R, D'Angio GJ: Radiation therapy in soft-tissue lesions in histiocytosis X (Langerhans' cell histiocytosis). Med Pediatr Oncol 16 (4): 259-62, 1988.

  12. Baptista AM, Camargo AF, de Camargo OP, et al.: Does adjunctive chemotherapy reduce remission rates compared to cortisone alone in unifocal or multifocal histiocytosis of bone? Clin Orthop Relat Res 470 (3): 663-9, 2012.

  13. Gadner H, Grois N, Arico M, et al.: A randomized trial of treatment for multisystem Langerhans' cell histiocytosis. J Pediatr 138 (5): 728-34, 2001.

  14. Grois N, Pötschger U, Prosch H, et al.: Risk factors for diabetes insipidus in langerhans cell histiocytosis. Pediatr Blood Cancer 46 (2): 228-33, 2006.

  15. Woo KI, Harris GJ: Eosinophilic granuloma of the orbit: understanding the paradox of aggressive destruction responsive to minimal intervention. Ophthal Plast Reconstr Surg 19 (6): 429-39, 2003.

  16. Dunger DB, Broadbent V, Yeoman E, et al.: The frequency and natural history of diabetes insipidus in children with Langerhans-cell histiocytosis. N Engl J Med 321 (17): 1157-62, 1989.

  17. Gadner H, Heitger A, Grois N, et al.: Treatment strategy for disseminated Langerhans cell histiocytosis. DAL HX-83 Study Group. Med Pediatr Oncol 23 (2): 72-80, 1994.

  18. Kotecha R, Venkatramani R, Jubran RF, et al.: Clinical Outcomes of Radiation Therapy in the Management of Langerhans Cell Histiocytosis. Am J Clin Oncol : , 2013.

  19. Peng XS, Pan T, Chen LY, et al.: Langerhans' cell histiocytosis of the spine in children with soft tissue extension and chemotherapy. Int Orthop 33 (3): 731-6, 2009.

  20. Lau LM, Stuurman K, Weitzman S: Skeletal Langerhans cell histiocytosis in children: permanent consequences and health-related quality of life in long-term survivors. Pediatr Blood Cancer 50 (3): 607-12, 2008.

  21. Mammano S, Candiotto S, Balsano M: Cast and brace treatment of eosinophilic granuloma of the spine: long-term follow-up. J Pediatr Orthop 17 (6): 821-7, 1997 Nov-Dec.

  22. Titgemeyer C, Grois N, Minkov M, et al.: Pattern and course of single-system disease in Langerhans cell histiocytosis data from the DAL-HX 83- and 90-study. Med Pediatr Oncol 37 (2): 108-14, 2001.

  23. Egeler RM, de Kraker J, Voûte PA: Cytosine-arabinoside, vincristine, and prednisolone in the treatment of children with disseminated Langerhans cell histiocytosis with organ dysfunction: experience at a single institution. Med Pediatr Oncol 21 (4): 265-70, 1993.

  24. Farran RP, Zaretski E, Egeler RM: Treatment of Langerhans cell histiocytosis with pamidronate. J Pediatr Hematol Oncol 23 (1): 54-6, 2001.

  25. Morimoto A, Shioda Y, Imamura T, et al.: Nationwide survey of bisphosphonate therapy for children with reactivated Langerhans cell histiocytosis in Japan. Pediatr Blood Cancer 56 (1): 110-5, 2011.

  26. Gadner H, Grois N, Pötschger U, et al.: Improved outcome in multisystem Langerhans cell histiocytosis is associated with therapy intensification. Blood 111 (5): 2556-62, 2008.

  27. Ronceray L, Pötschger U, Janka G, et al.: Pulmonary involvement in pediatric-onset multisystem Langerhans cell histiocytosis: effect on course and outcome. J Pediatr 161 (1): 129-33.e1-3, 2012.

  28. Morimoto A, Ikushima S, Kinugawa N, et al.: Improved outcome in the treatment of pediatric multifocal Langerhans cell histiocytosis: Results from the Japan Langerhans Cell Histiocytosis Study Group-96 protocol study. Cancer 107 (3): 613-9, 2006.

  29. Jordan MB, McClain KL, Yan X, et al.: Anti-CD52 antibody, alemtuzumab, binds to Langerhans cells in Langerhans cell histiocytosis. Pediatr Blood Cancer 44 (3): 251-4, 2005.

  30. Büchler T, Cervinek L, Belohlavek O, et al.: Langerhans cell histiocytosis with central nervous system involvement: follow-up by FDG-PET during treatment with cladribine. Pediatr Blood Cancer 44 (3): 286-8, 2005.

  31. Watts J, Files B: Langerhans cell histiocytosis: central nervous system involvement treated successfully with 2-chlorodeoxyadenosine. Pediatr Hematol Oncol 18 (3): 199-204, 2001 Apr-May.

  32. Dhall G, Finlay JL, Dunkel IJ, et al.: Analysis of outcome for patients with mass lesions of the central nervous system due to Langerhans cell histiocytosis treated with 2-chlorodeoxyadenosine. Pediatr Blood Cancer 50 (1): 72-9, 2008.

  33. Grois N, Fahrner B, Arceci RJ, et al.: Central nervous system disease in Langerhans cell histiocytosis. J Pediatr 156 (6): 873-81, 881.e1, 2010.

  34. Ng Wing Tin S, Martin-Duverneuil N, Idbaih A, et al.: Efficacy of vinblastine in central nervous system Langerhans cell histiocytosis: a nationwide retrospective study. Orphanet J Rare Dis 6 (1): 83, 2011.

  35. Idbaih A, Donadieu J, Barthez MA, et al.: Retinoic acid therapy in "degenerative-like" neuro-langerhans cell histiocytosis: a prospective pilot study. Pediatr Blood Cancer 43 (1): 55-8, 2004.

  36. Imashuku S, Ishida S, Koike K, et al.: Cerebellar ataxia in pediatric patients with Langerhans cell histiocytosis. J Pediatr Hematol Oncol 26 (11): 735-9, 2004.

  37. Imashuku S, Okazaki NA, Nakayama M, et al.: Treatment of neurodegenerative CNS disease in Langerhans cell histiocytosis with a combination of intravenous immunoglobulin and chemotherapy. Pediatr Blood Cancer 50 (2): 308-11, 2008.

  38. Allen CE, Flores R, Rauch R, et al.: Neurodegenerative central nervous system Langerhans cell histiocytosis and coincident hydrocephalus treated with vincristine/cytosine arabinoside. Pediatr Blood Cancer 54 (3): 416-23, 2010.

  39. Chohan G, Barnett Y, Gibson J, et al.: Langerhans cell histiocytosis with refractory central nervous system involvement responsive to infliximab. J Neurol Neurosurg Psychiatry 83 (5): 573-5, 2012.

  40. Minkov M, Grois N, Broadbent V, et al.: Cyclosporine A therapy for multisystem langerhans cell histiocytosis. Med Pediatr Oncol 33 (5): 482-5, 1999.

  41. Lukina EA, Kuznetsov VP, Beliaev DL, et al.: [The treatment of histiocytosis X (Langerhans-cell histiocytosis) with alpha-interferon preparations] Ter Arkh 65 (11): 67-70, 1993.

  42. Gadner H, Ladisch S: The treatment of Langerhans cell histiocytosis. In: Weitzman S, Egeler R M, eds.: Histiocytic Disorders of Children and Adults. Cambridge, United Kingdom: Cambridge University Press, 2005, pp 229-53.

  43. Phillips M, Allen C, Gerson P, et al.: Comparison of FDG-PET scans to conventional radiography and bone scans in management of Langerhans cell histiocytosis. Pediatr Blood Cancer 52 (1): 97-101, 2009.

  44. Ha SY, Helms P, Fletcher M, et al.: Lung involvement in Langerhans' cell histiocytosis: prevalence, clinical features, and outcome. Pediatrics 89 (3): 466-9, 1992.

  45. Tazi A, Hiltermann J, Vassallo R: Adult lung histiocytosis. In: Weitzman S, Egeler R M, eds.: Histiocytic Disorders of Children and Adults. Cambridge, United Kingdom: Cambridge University Press, 2005, pp 187-207.

Treatment of Recurrent, Refractory, or Progressive Childhood LCH

Recurrent Low-Risk Organ Involvement

Reactivation of single-system and multisystem LCH

Reactivation of Langerhans cell histiocytosis (LCH) after complete response has been reported; usually occurring within the first 9 to 12 months after stopping treatment.[1] The percentage of patients with reactivations was 9% to 17.4% for single-site disease; 37% for single-system, multifocal disease; 46% for multisystem (nonrisk organ) disease; and 54% for patients with risk-organ involvement. Forty-three percent of reactivations were in bone, 11% in ears, 9% in skin, and 7% developed diabetes insipidus; a lower percentage of patients had lymph node, bone marrow, or risk-organ relapses.[1] The median time to reactivation was 12 to 15 months in nonrisk patients and 9 months in risk patients. One-third of patients had more than one reactivation varying from 9 to 14 months after the initial reactivation. Patients with reactivations were more likely to have long-term sequelae in the bones, diabetes insipidus, or other endocrine, ear, or lung problems.[1]

A comprehensive review of the German-Austrian-Dutch (Deutsche Arbeits-gemeinschaft für Leukaemieforschung und-therapie im Kindesalter [DAL]) and Histiocyte Society clinical trials revealed a reactivation rate of 46% at 5 years for patients with multisystem LCH, with most reactivations occurring within 2 years of first remission. A second reactivation occurred in 44%, again within 2 years of the second remission. Involvement of the risk organs in these reactivations occurred only in those who were initially in the high-risk group (meaning they had liver, spleen, or bone marrow involvement at the time of original diagnosis).[2][Level of evidence: 3iiiDiii] Most reactivations, even in patients with high-risk disease who initially responded to therapy, were in bone, skin, or other nonrisk locations.

The percentage of reactivations in multisystem disease was identical in the Japanese trial, [3][Level of evidence: 1iiA] and the LCH-II trial [4] (45% and 46%, respectively). There was not a statistically significant difference in reactivations between the high-risk and low-risk groups. Both the DAL-HX and Japanese studies concluded that intensified treatment increased rapid response, particularly in young children and infants younger than 2 years, and together with rapid switch to salvage therapy for nonresponders, reduced mortality for patients with high-risk multisystem LCH.

Treatment of low-risk organ involvement

The optimal therapy for patients with relapsed or recurrent LCH has not been determined. Several regimens exist, including the following:

  • Patients with recurrent bone disease who recur months after stopping vinblastine and prednisone can benefit from treatment with a reinduction of vinblastine weekly and daily prednisone for 6 weeks. If there is no active disease or very little evidence of active disease, treatment can be changed to every 3 weeks, with the addition of oral mercaptopurine nightly.[5]
  • An alternative treatment regimen employs vincristine, prednisone, and cytosine arabinoside.[6] The prednisone dose is reduced from the dose used in the original publication.
  • Bisphosphonate therapy is also effective for treating recurrent LCH bone lesions.[7] In a survey from Japan, bisphosphonate therapy successfully treated the bone lesions in 12 of 16 patients. Skin and soft tissue LCH lesions also resolved in the responding patients. None of the patients had risk-organ disease. Most patients received six cycles of pamidronate at 1 mg/kg/course, given at 4-week intervals. Eight of the 12 patients remained disease free at a median of 3.3 years.[8] Other bisphosphonates, such as zoledronate and oral alendronate, have also been successful in treating bone LCH.[9][10]
  • Cladribine at 5 mg/m2/day for 5 days per course has also been shown to be effective therapy for recurrent low-risk LCH (multifocal bone and low-risk multisystem LCH) with very little toxicity.[11] Cladribine therapy should, if possible, be limited to a maximum of six cycles to avoid cumulative and potentially long-lasting cytopenias.
  • A phase II trial of thalidomide for patients with LCH (ten low-risk patients; six high-risk patients) who failed primary and at least one secondary regimen demonstrated complete (four of ten) and partial (three of ten) responses for the low-risk patients. Complete remission was defined as healing of bone lesions on plain radiographs (n = 3) or complete resolution of skin rash (n = 4, including 3 with bone lesions that had complete resolution). Partial response was defined as healing of bone lesion, but then worsening of a skin rash that was partially resolved. However, dose-limiting toxicities, such as neuropathy and neutropenia, may limit the overall usefulness of thalidomide.[12] This agent is not used in pediatric patients to a significant degree.
  • Clofarabine is a proven effective therapy for patients with multiple relapses of low-risk or high-risk organs.[13]

Refractory High-Risk Organ Involvement

A new treatment plan is indicated when a patient with multisystem involvement shows progressive disease after 6 weeks of standard treatment, or has not had a partial response by 12 weeks. Data from the DAL Group studies have shown that these children have only a 10% chance of surviving.[14] Results from the LCH-II trial revealed that patients treated with vinblastine/prednisone who did not respond well by 6 weeks had a 27% chance of survival, compared with 52% for good responders.[4][Level of evidence: 1iiA] All studies suggest that patients with poorly responsive disease need to be changed early to salvage strategies at 6 weeks for progressive disease and no later than 12 weeks for those without at least a good response.

Cladribine and 2’-deoxycoformycin have been tested as salvage therapies for LCH.[11][15]; [16][Level of evidence: 3iiiDiv] A case series reported that patients with multiple reactivations or high-risk disease could be effectively treated with continuous-infusion cladribine for 3 days. Seven of ten patients on this trial required no more therapy.[17][Level of evidence: 3iiiDii]

Patients with refractory high-risk organ (liver, spleen, or bone marrow) involvement and resistant multisystem low-risk organ involvement have been treated with an intensive acute myeloid leukemia–like protocol. Prompt change of therapy to cladribine and cytosine arabinoside appeared to provide an improvement in overall survival (OS).[18]; [19][Level of evidence: 3iiiDii]; [20][Level of evidence: 3iiiDiv] This is a very intense regimen and requires that physicians are able to treat infectious and metabolic complications. Responses may be delayed.

Six patients with multiorgan LCH resistant to other agents, including cladribine, were reported to respond to treatment with clofarabine.[21]; [22][Level of evidence: 3iiiDii] An additional 11 patients with recurrent multisystem high-risk and low-risk disease had a 90% OS.[13] If confirmed in prospective trials, the reduced toxicity of this regimen, compared with the cladribine/cytarabine combination, could be advantageous despite the cost of the drug.

Hematopoietic stem cell transplantation (HSCT) has been used in patients with multisystem high-risk organ involvement that is refractory to chemotherapy.[7][23][24][25] The use of reduced-intensity conditioning, especially for patients that have received intensive chemotherapy just before HSCT, may reduce toxic deaths and improve outcome.[26]

Treatment Options Under Clinical Evaluation

New targeted therapies under investigation include the following:

  • RAS pathway inhibitors: The discovery that most patients with LCH have BRAF V600E or other mutations that result in activation of the RAS pathway, suggests that new therapies that target molecules within this pathway will become an important part of LCH therapy in the near future. NCT01677741 is currently open in the United States and Canada for adults with LCH and children with recurrent LCH. Although three adults with LCH and Erdheim-Chester disease had favorable responses to vemurafinib,[27] the 30% incidence of squamous cell carcinoma in melanoma patients receiving this drug needs to be taken into account with moderate- to long-term use in children.
  • Tyrosine kinase inhibitors: Several reports suggested that LCH, including central nervous system LCH, could be successfully treated with the tyrosine kinase inhibitor imatinib,[28] while other reports failed to show an effect.[29][30]

References:

  1. Pollono D, Rey G, Latella A, et al.: Reactivation and risk of sequelae in Langerhans cell histiocytosis. Pediatr Blood Cancer 48 (7): 696-9, 2007.

  2. Minkov M, Steiner M, Pötschger U, et al.: Reactivations in multisystem Langerhans cell histiocytosis: data of the international LCH registry. J Pediatr 153 (5): 700-5, 705.e1-2, 2008.

  3. Morimoto A, Ikushima S, Kinugawa N, et al.: Improved outcome in the treatment of pediatric multifocal Langerhans cell histiocytosis: Results from the Japan Langerhans Cell Histiocytosis Study Group-96 protocol study. Cancer 107 (3): 613-9, 2006.

  4. Gadner H, Grois N, Pötschger U, et al.: Improved outcome in multisystem Langerhans cell histiocytosis is associated with therapy intensification. Blood 111 (5): 2556-62, 2008.

  5. Titgemeyer C, Grois N, Minkov M, et al.: Pattern and course of single-system disease in Langerhans cell histiocytosis data from the DAL-HX 83- and 90-study. Med Pediatr Oncol 37 (2): 108-14, 2001.

  6. Egeler RM, de Kraker J, Voûte PA: Cytosine-arabinoside, vincristine, and prednisolone in the treatment of children with disseminated Langerhans cell histiocytosis with organ dysfunction: experience at a single institution. Med Pediatr Oncol 21 (4): 265-70, 1993.

  7. Kudo K, Ohga S, Morimoto A, et al.: Improved outcome of refractory Langerhans cell histiocytosis in children with hematopoietic stem cell transplantation in Japan. Bone Marrow Transplant 45 (5): 901-6, 2010.

  8. Farran RP, Zaretski E, Egeler RM: Treatment of Langerhans cell histiocytosis with pamidronate. J Pediatr Hematol Oncol 23 (1): 54-6, 2001.

  9. Morimoto A, Shioda Y, Imamura T, et al.: Nationwide survey of bisphosphonate therapy for children with reactivated Langerhans cell histiocytosis in Japan. Pediatr Blood Cancer 56 (1): 110-5, 2011.

  10. Sivendran S, Harvey H, Lipton A, et al.: Treatment of Langerhans cell histiocytosis bone lesions with zoledronic acid: a case series. Int J Hematol 93 (6): 782-6, 2011.

  11. Weitzman S, Braier J, Donadieu J, et al.: 2'-Chlorodeoxyadenosine (2-CdA) as salvage therapy for Langerhans cell histiocytosis (LCH). results of the LCH-S-98 protocol of the Histiocyte Society. Pediatr Blood Cancer 53 (7): 1271-6, 2009.

  12. McClain KL, Kozinetz CA: A phase II trial using thalidomide for Langerhans cell histiocytosis. Pediatr Blood Cancer 48 (1): 44-9, 2007.

  13. Simko SJ, Tran HD, Jones J, et al.: Clofarabine salvage therapy in refractory multifocal histiocytic disorders, including Langerhans cell histiocytosis, juvenile xanthogranuloma and Rosai-Dorfman disease. Pediatr Blood Cancer 61 (3): 479-87, 2014.

  14. Gadner H, Grois N, Arico M, et al.: A randomized trial of treatment for multisystem Langerhans' cell histiocytosis. J Pediatr 138 (5): 728-34, 2001.

  15. Weitzman S, Wayne AS, Arceci R, et al.: Nucleoside analogues in the therapy of Langerhans cell histiocytosis: a survey of members of the histiocyte society and review of the literature. Med Pediatr Oncol 33 (5): 476-81, 1999.

  16. Mottl H, Starý J, Chánová M, et al.: Treatment of recurrent Langerhans cell histiocytosis in children with 2-chlorodeoxyadenosine. Leuk Lymphoma 47 (9): 1881-4, 2006.

  17. Stine KC, Saylors RL, Saccente S, et al.: Efficacy of continuous infusion 2-CDA (cladribine) in pediatric patients with Langerhans cell histiocytosis. Pediatr Blood Cancer 43 (1): 81-4, 2004.

  18. Bernard F, Thomas C, Bertrand Y, et al.: Multi-centre pilot study of 2-chlorodeoxyadenosine and cytosine arabinoside combined chemotherapy in refractory Langerhans cell histiocytosis with haematological dysfunction. Eur J Cancer 41 (17): 2682-9, 2005.

  19. Apollonsky N, Lipton JM: Treatment of refractory Langerhans cell histiocytosis (LCH) with a combination of 2-chlorodeoxyadenosine and cytosine arabinoside. J Pediatr Hematol Oncol 31 (1): 53-6, 2009.

  20. Imamura T, Sato T, Shiota Y, et al.: Outcome of pediatric patients with Langerhans cell histiocytosis treated with 2 chlorodeoxyadenosine: a nationwide survey in Japan. Int J Hematol 91 (4): 646-51, 2010.

  21. Rodriguez-Galindo C, Jeng M, Khuu P, et al.: Clofarabine in refractory Langerhans cell histiocytosis. Pediatr Blood Cancer 51 (5): 703-6, 2008.

  22. Abraham A, Alsultan A, Jeng M, et al.: Clofarabine salvage therapy for refractory high-risk langerhans cell histiocytosis. Pediatr Blood Cancer 60 (6): E19-22, 2013.

  23. Akkari V, Donadieu J, Piguet C, et al.: Hematopoietic stem cell transplantation in patients with severe Langerhans cell histiocytosis and hematological dysfunction: experience of the French Langerhans Cell Study Group. Bone Marrow Transplant 31 (12): 1097-103, 2003.

  24. Nagarajan R, Neglia J, Ramsay N, et al.: Successful treatment of refractory Langerhans cell histiocytosis with unrelated cord blood transplantation. J Pediatr Hematol Oncol 23 (9): 629-32, 2001.

  25. Caselli D, Aricò M; EBMT Paediatric Working Party: The role of BMT in childhood histiocytoses. Bone Marrow Transplant 41 (Suppl 2): S8-S13, 2008.

  26. Steiner M, Matthes-Martin S, Attarbaschi A, et al.: Improved outcome of treatment-resistant high-risk Langerhans cell histiocytosis after allogeneic stem cell transplantation with reduced-intensity conditioning. Bone Marrow Transplant 36 (3): 215-25, 2005.

  27. Haroche J, Cohen-Aubart F, Emile JF, et al.: Dramatic efficacy of vemurafenib in both multisystemic and refractory Erdheim-Chester disease and Langerhans cell histiocytosis harboring the BRAF V600E mutation. Blood 121 (9): 1495-500, 2013.

  28. Janku F, Amin HM, Yang D, et al.: Response of histiocytoses to imatinib mesylate: fire to ashes. J Clin Oncol 28 (31): e633-6, 2010.

  29. Wagner C, Mohme H, Krömer-Olbrisch T, et al.: Langerhans cell histiocytosis: treatment failure with imatinib. Arch Dermatol 145 (8): 949-50, 2009.

  30. Baumann M, Cerny T, Sommacal A, et al.: Langerhans cell histiocytosis with central nervous system involvement--complete response to 2-chlorodeoxyadenosine after failure of tyrosine kinase inhibitor therapies with sorafenib and imatinib. Hematol Oncol 30 (2): 101-4, 2012.

Late Disease and Treatment Effects of Childhood LCH

The reported overall frequency of long-term consequences of Langerhans cell histiocytosis (LCH) has ranged from 20% to 70%. The reason for this wide variation is due to case definition, sample size, therapy used, method of data collection, and follow-up duration. Of note, in one study of the quality of life of long-term survivors of skeletal LCH, the quality-of-life scores were not significantly different from healthy control children and adults.[1] In addition, the quality-of-life scores were very similar between those with and without permanent sequelae. In another study of 40 patients who were carefully screened for late effects, adverse quality-of-life scores were found in more than 50% of patients.[2] Seventy-five percent of patients had detectable long-term sequelae—hypothalamic/pituitary dysfunction (50%), cognitive dysfunction (20%), and cerebellar involvement (17.5%) being the most common.

Children with low-risk organ involvement (skin, bones, lymph nodes, or pituitary gland) have an approximately 20% chance of developing long-term sequelae.[3] Patients with diabetes insipidus are at risk for panhypopituitarism and should be monitored carefully for adequacy of growth and development. In a retrospective review of 141 patients with LCH and diabetes insipidus, 43% developed growth hormone (GH) deficiency. [4][5][6] The 5-year and 10-year risks of GH deficiency among children with LCH and diabetes insipidus were 35% and 54%, respectively. There was no increased reactivation of LCH in patients who received GH compared with those who did not.[4]

Growth and development problems are more frequent because of the young age at presentation and the more toxic effects of long-term prednisone therapy in the very young child. Patients with multisystem involvement have a 71% incidence of long-term problems.[3][4][5][6]

Hearing loss has been found in 38% of children who were treated for LCH.[6] Seventy percent of patients with LCH in this study had ear involvement which included aural discharge, mastoid swelling, and hearing loss. Of those with computed tomography or magnetic resonance imaging (MRI) abnormalities in the mastoid, 59% had hearing loss.[7][Level of evidence: 3iiiC]

Neurologic symptoms secondary to vertebral compression of cervical lesions have been reported in 3 of 26 patients with LCH and spinal lesions.[6] Central nervous system (CNS) LCH occurs most often in children with LCH of the pituitary or CNS-risk skull bones (mastoid, orbit, or temporal bone). Significant cognitive defects and MRI abnormalities may develop in some long-term survivors with CNS-risk skull lesions.[8] Some patients have markedly abnormal cerebellar function and behavior abnormalities, while others have subtle deficits in short-term memory and brain stem–evoked potentials.[9]

Orthopedic problems from lesions of the spine, femur, tibia, or humerus may be seen in 20% of patients. These problems include vertebral collapse or instability of the spine that may lead to scoliosis and facial or limb asymmetry.

Diffuse pulmonary disease may result in poor lung function with higher risk for infections and decreased exercise tolerance. These patients should be monitored with pulmonary function testing, including the diffusing capacity of carbon monoxide and ratio of residual volume to total lung capacity.[10]

Liver disease may lead to sclerosing cholangitis, which rarely responds to any treatment other than liver transplantation.[11]

Dental problems characterized by loss of teeth have been significant for some patients, usually related to overly aggressive dental surgery.[12]

Bone marrow failure secondary to LCH or from therapy is rare and is associated with a higher risk of malignancy. Patients with LCH have a higher-than-normal risk of developing secondary cancers.[13][14] Leukemia (usually acute myeloid) occurs after treatment, as does lymphoblastic lymphoma. Concurrent LCH/malignancy has been reported in a few patients, and some patients have had their malignancy first, followed by development of LCH. Three patients with T-cell acute lymphoblastic leukemia (T-ALL) and aggressive LCH were reported and, as with all histiocytic disorders associated with or following lymphoblastic malignancies, the same genetic changes were found in both diseases, suggesting a shared clonal origin.[15][16][17] One study reported two cases in which clonality with the same T-cell receptor gamma genotype was found.[16] The authors of this study emphasized the plasticity of lymphocytes developing into Langerhans cells. In the second study, one patient with LCH after T-ALL who had the same T-cell receptor gene rearrangements and activating mutations of the NOTCH1 gene was described.[17]

An association between solid tumors and LCH has also been reported. Solid tumors associated with LCH include retinoblastoma, brain tumors, hepatocellular carcinoma, and Ewing sarcoma.

References:

  1. Lau LM, Stuurman K, Weitzman S: Skeletal Langerhans cell histiocytosis in children: permanent consequences and health-related quality of life in long-term survivors. Pediatr Blood Cancer 50 (3): 607-12, 2008.

  2. Nanduri VR, Pritchard J, Levitt G, et al.: Long term morbidity and health related quality of life after multi-system Langerhans cell histiocytosis. Eur J Cancer 42 (15): 2563-9, 2006.

  3. Haupt R, Nanduri V, Calevo MG, et al.: Permanent consequences in Langerhans cell histiocytosis patients: a pilot study from the Histiocyte Society-Late Effects Study Group. Pediatr Blood Cancer 42 (5): 438-44, 2004.

  4. Donadieu J, Rolon MA, Pion I, et al.: Incidence of growth hormone deficiency in pediatric-onset Langerhans cell histiocytosis: efficacy and safety of growth hormone treatment. J Clin Endocrinol Metab 89 (2): 604-9, 2004.

  5. Komp DM: Long-term sequelae of histiocytosis X. Am J Pediatr Hematol Oncol 3 (2): 163-8, 1981.

  6. Willis B, Ablin A, Weinberg V, et al.: Disease course and late sequelae of Langerhans' cell histiocytosis: 25-year experience at the University of California, San Francisco. J Clin Oncol 14 (7): 2073-82, 1996.

  7. Nanduri V, Tatevossian R, Sirimanna T: High incidence of hearing loss in long-term survivors of multisystem Langerhans cell histiocytosis. Pediatr Blood Cancer 54 (3): 449-53, 2010.

  8. Nanduri VR, Lillywhite L, Chapman C, et al.: Cognitive outcome of long-term survivors of multisystem langerhans cell histiocytosis: a single-institution, cross-sectional study. J Clin Oncol 21 (15): 2961-7, 2003.

  9. Mittheisz E, Seidl R, Prayer D, et al.: Central nervous system-related permanent consequences in patients with Langerhans cell histiocytosis. Pediatr Blood Cancer 48 (1): 50-6, 2007.

  10. Bernstrand C, Cederlund K, Henter JI: Pulmonary function testing and pulmonary Langerhans cell histiocytosis. Pediatr Blood Cancer 49 (3): 323-8, 2007.

  11. Braier J, Ciocca M, Latella A, et al.: Cholestasis, sclerosing cholangitis, and liver transplantation in Langerhans cell Histiocytosis. Med Pediatr Oncol 38 (3): 178-82, 2002.

  12. Guimarães LF, Dias PF, Janini ME, et al.: Langerhans cell histiocytosis: impact on the permanent dentition after an 8-year follow-up. J Dent Child (Chic) 75 (1): 64-8, 2008 Jan-Apr.

  13. Egeler RM, Neglia JP, Puccetti DM, et al.: Association of Langerhans cell histiocytosis with malignant neoplasms. Cancer 71 (3): 865-73, 1993.

  14. Egeler RM, Neglia JP, Aricò M, et al.: The relation of Langerhans cell histiocytosis to acute leukemia, lymphomas, and other solid tumors. The LCH-Malignancy Study Group of the Histiocyte Society. Hematol Oncol Clin North Am 12 (2): 369-78, 1998.

  15. Castro EC, Blazquez C, Boyd J, et al.: Clinicopathologic features of histiocytic lesions following ALL, with a review of the literature. Pediatr Dev Pathol 13 (3): 225-37, 2010 May-Jun.

  16. Feldman AL, Berthold F, Arceci RJ, et al.: Clonal relationship between precursor T-lymphoblastic leukaemia/lymphoma and Langerhans-cell histiocytosis. Lancet Oncol 6 (6): 435-7, 2005.

  17. Rodig SJ, Payne EG, Degar BA, et al.: Aggressive Langerhans cell histiocytosis following T-ALL: clonally related neoplasms with persistent expression of constitutively active NOTCH1. Am J Hematol 83 (2): 116-21, 2008.

Adult LCH

General Information

The natural history of disease in adult Langerhans cell histiocytosis (LCH), with the exception of pulmonary LCH, is unknown. It is unclear whether there are significant differences from childhood LCH, although it appears that multisystem-risk LCH is less aggressive than childhood high-risk disease. The risk of reactivations is unknown.

A consensus group reported on the evaluation and treatment of adult patients with LCH.[1] However, discussion continues, particularly regarding optimal first-line therapy.

Incidence

It is estimated that one to two adult cases of LCH occur per 1 million population.[2] The true incidence of this disease is not known, however, because published studies are mostly nonpopulation based and the disorder is likely to be underdiagnosed. A survey from Germany reported that 66% of the patients with LCH were women, with an average age of 43.5 years for all patients.[3]

Presentation of adult LCH by organ, site, or system

Adult patients with LCH may have symptoms and signs for many months before a definitive diagnosis and treatment. LCH in adults is often similar to that in children, and appears to involve the same organs, although the proportions may be different. There is a predominance of lung disease in adults, usually occurring as single-system disease and closely associated with smoking and with some unique biologic characteristics. Most adult lung LCH cases are polyclonal and possibly reactive, while the minority of lung LCH cases are monoclonal. A German registry with 121 registrants showed that 62% had single-organ involvement and 38% had multisystem involvement, while 34% of the total had lung involvement. The median age at diagnosis was 44 years ± 12.8 years. The most common organ involved was lung followed by bone and skin. All organ systems found in childhood LCH were seen, including endocrine and central nervous system, liver, spleen, bone marrow, and gastrointestinal tract. The major difference is the much higher incidence of isolated pulmonary LCH in adults, particularly in young adults who smoke. Other differences appear to be the more frequent involvement of genital and oral mucosa. There may possibly be a difference in the distribution of bone lesions, but both groups suffer reactivations of bone lesions and progression to diabetes insipidus, although the exact incidence is unknown in adults.[4]

Presenting symptoms from published studies are (in order of decreasing frequency) dyspnea or tachypnea, polydipsia and polyuria, bone pain, lymphadenopathy, weight loss, fever, gingival hypertrophy, ataxia, and memory problems. The signs of LCH are skin rash, scalp nodules, soft tissue swelling near bone lesions, lymphadenopathy, gingival hypertrophy, and hepatosplenomegaly. Patients who present with isolated diabetes insipidus should be carefully observed for onset of other symptoms or signs characteristic of LCH. At least 80% of patients with diabetes insipidus had involvement of other organ systems, including bone (68%), skin (57%), lung (39%), and lymph nodes (18%).[5]

Skin and oral cavity

Thirty-seven percent of adults with LCH have skin involvement which usually occurs as part of multisystem disease. Skin-only LCH occurs but it is less common in adults than in children. The prognosis of adults with skin-only LCH is excellent, with 100% probability of 5-year survival. The cutaneous involvement is clinically similar to that seen in children and may take many forms.[6] Infra-mammary and vulvar involvement may be seen in adult women with skin LCH.

Many patients have a papular rash with brown, red, or crusted areas ranging from the size of a pinhead to a dime. In the scalp, the rash is similar to that of seborrhea. Skin in the inguinal region, genitalia, or around the anus may have open ulcers that do not heal after antibacterial or antifungal therapy. The lesions are usually asymptomatic but may be pruritic or painful. In the mouth, swollen gums or ulcers along the cheeks, roof of the mouth, or tongue may be signs of LCH.

Diagnosis of LCH is usually made by skin biopsy performed for persistent skin lesions.[6]

Bones

The relative frequency of bone involvement in adults differs from that in children: mandible (30% vs. 7%) and skull (21% vs. 40%).[2][3][4][5] The frequency of vertebrae (13%), pelvis (13%), extremities (17%), and rib (6%) lesions in adults are similar to those found in children.[2]

Lung

Pulmonary LCH in adults is usually single-system disease, but in a minority of patients other organs may be involved, including bone (18%), skin (13%), and diabetes insipidus (5%).[7]

Pulmonary LCH is more prevalent in smokers than in nonsmokers and the male to female ratio may be near unity depending on the incidence of smoking in the population studied.[7][8] Patients with pulmonary LCH usually present with a dry cough, dyspnea, or chest pain, although nearly 20% of adults with lung involvement have no symptoms.[9][10] Chest pain may indicate a spontaneous pneumothorax (10%–20% of adult pulmonary LCH cases). The LCH cells in adult lung lesions were shown to be mature dendritic cells expressing high levels of the accessory molecules CD80 and CD86, unlike Langerhans cells (LCs) found in other lung disorders.[10] In addition, pulmonary LCH in adults appears to be primarily a reactive process, rather than a clonal proliferation as seen in childhood LCH.[11]

The course of pulmonary LCH in adults is variable and unpredictable.[7] Fifty-nine percent of patients do well with either spontaneous remission with cessation of smoking, or with some form of therapy. Adults with pulmonary LCH who have minimal symptoms have a good prognosis, although some have steady deterioration over many years.[12] Age older than 26 years and lower forced expiratory volume/forced vital capacity (FEV1/FVC) ratio and higher residual volume/total lung capacity (RV/TLC) ratio are adverse prognostic variables.[13] About 10% to 20% have early severe progression to respiratory failure, severe pulmonary hypertension, and cor pulmonale. Adults who have progression with diffuse bullae formation, multiple pneumothoraces, and fibrosis have a poor prognosis.[14][15] The remainder have a variable course, with stable disease in some patients and relapses and progression of respiratory dysfunction in others, some after many years.[16] One study reported that smoking cessation did not increase the longevity of adults with pulmonary LCH, apparently because the tempo of disease is so variable.[13] Patients receiving lung transplantation for treatment of pulmonary LCH have a 77% survival rate at 1 year and 54% survival rate at 10 years, with a 20% chance of LCH recurrence.[17]

The most frequent pulmonary function abnormality finding in patients with pulmonary LCH is a reduced carbon monoxide diffusing capacity in 70% to 90% of cases.[13][18] A high-resolution computed tomography (CT) scan, which reveals a reticulonodular pattern classically with cysts and nodules, usually in the upper lobes and sparing the costophrenic angle, is characteristic of LCH. Despite the typical CT findings, most pulmonologists agree that a lung biopsy is needed to confirm the diagnosis.[19] The presence of cystic abnormalities on high-resolution CT scans appears to be a poor predictor of which patients will have progressive disease.[20] A study correlating lung CT findings and lung biopsy results in 27 patients with pulmonary LCH has shed some light on pulmonary LCH.[21] Thin-walled and bizarre cysts had active LCs and eosinophils. Fifty-two percent of patients improved, most with smoking cessation, and some with steroid treatment within 14 months of diagnosis. Four patients (15%) were stable, and nine patients (33%) progressed over 22 months.

Liver

Liver involvement in adults has been reported in 27% of a series of adult patients with LCH and multiorgan disease.[22] Hepatomegaly (48%) and liver enzyme abnormalities (61%) were present. CT and ultrasound imaging abnormalities are often found. The early histopathologic stage of liver LCH includes infiltration of CD1a+ cells and periductal fibrosis with inflammatory infiltrates with or without steatosis. The late stage is biliary tree sclerosis and treatment with ursodeoxycholic acid is suggested.

Multisystem disease

In a large series of patients from the Mayo Clinic, 31% had multisystem LCH compared with 69% registered on the Histiocyte Society adult registry; this likely reflects referral bias.[6][23] In the adult multisystem patients, the organs involved included the following:

  • Skin (50%).
  • Mucocutaneous (40%).
  • Diabetes insipidus (29.6%).
  • Hepatosplenomegaly (16%).
  • Hypothyroidism (6.6%).
  • Lymphadenopathy (6%).

References:

  1. Girschikofsky M, Arico M, Castillo D, et al.: Management of adult patients with Langerhans cell histiocytosis: recommendations from an expert panel on behalf of Euro-Histio-Net. Orphanet J Rare Dis 8: 72, 2013.

  2. Baumgartner I, von Hochstetter A, Baumert B, et al.: Langerhans'-cell histiocytosis in adults. Med Pediatr Oncol 28 (1): 9-14, 1997.

  3. Götz G, Fichter J: Langerhans'-cell histiocytosis in 58 adults. Eur J Med Res 9 (11): 510-4, 2004.

  4. Slater JM, Swarm OJ: Eosinophilic granuloma of bone. Med Pediatr Oncol 8 (2): 151-64, 1980.

  5. Kaltsas GA, Powles TB, Evanson J, et al.: Hypothalamo-pituitary abnormalities in adult patients with langerhans cell histiocytosis: clinical, endocrinological, and radiological features and response to treatment. J Clin Endocrinol Metab 85 (4): 1370-6, 2000.

  6. Aricò M, Girschikofsky M, Généreau T, et al.: Langerhans cell histiocytosis in adults. Report from the International Registry of the Histiocyte Society. Eur J Cancer 39 (16): 2341-8, 2003.

  7. Vassallo R, Ryu JH, Schroeder DR, et al.: Clinical outcomes of pulmonary Langerhans'-cell histiocytosis in adults. N Engl J Med 346 (7): 484-90, 2002.

  8. Schönfeld N, Frank W, Wenig S, et al.: Clinical and radiologic features, lung function and therapeutic results in pulmonary histiocytosis X. Respiration 60 (1): 38-44, 1993.

  9. Travis WD, Borok Z, Roum JH, et al.: Pulmonary Langerhans cell granulomatosis (histiocytosis X). A clinicopathologic study of 48 cases. Am J Surg Pathol 17 (10): 971-86, 1993.

  10. Tazi A, Moreau J, Bergeron A, et al.: Evidence that Langerhans cells in adult pulmonary Langerhans cell histiocytosis are mature dendritic cells: importance of the cytokine microenvironment. J Immunol 163 (6): 3511-5, 1999.

  11. Yousem SA, Colby TV, Chen YY, et al.: Pulmonary Langerhans' cell histiocytosis: molecular analysis of clonality. Am J Surg Pathol 25 (5): 630-6, 2001.

  12. Vassallo R, Ryu JH, Colby TV, et al.: Pulmonary Langerhans'-cell histiocytosis. N Engl J Med 342 (26): 1969-78, 2000.

  13. Delobbe A, Durieu J, Duhamel A, et al.: Determinants of survival in pulmonary Langerhans' cell granulomatosis (histiocytosis X). Groupe d'Etude en Pathologie Interstitielle de la Société de Pathologie Thoracique du Nord. Eur Respir J 9 (10): 2002-6, 1996.

  14. Chaulagain CP: Pulmonary langerhans' cell histiocytosis. Am J Med 122 (11): e5-6, 2009.

  15. Lin MW, Chang YL, Lee YC, et al.: Pulmonary Langerhans cell histiocytosis. Lung 187 (4): 261-2, 2009.

  16. Tazi A, Hiltermann J, Vassallo R: Adult lung histiocytosis. In: Weitzman S, Egeler R M, eds.: Histiocytic Disorders of Children and Adults. Cambridge, United Kingdom: Cambridge University Press, 2005, pp 187-207.

  17. Dauriat G, Mal H, Thabut G, et al.: Lung transplantation for pulmonary langerhans' cell histiocytosis: a multicenter analysis. Transplantation 81 (5): 746-50, 2006.

  18. Crausman RS, Jennings CA, Tuder RM, et al.: Pulmonary histiocytosis X: pulmonary function and exercise pathophysiology. Am J Respir Crit Care Med 153 (1): 426-35, 1996.

  19. Diette GB, Scatarige JC, Haponik EF, et al.: Do high-resolution CT findings of usual interstitial pneumonitis obviate lung biopsy? Views of pulmonologists. Respiration 72 (2): 134-41, 2005 Mar-Apr.

  20. Soler P, Bergeron A, Kambouchner M, et al.: Is high-resolution computed tomography a reliable tool to predict the histopathological activity of pulmonary Langerhans cell histiocytosis? Am J Respir Crit Care Med 162 (1): 264-70, 2000.

  21. Kim HJ, Lee KS, Johkoh T, et al.: Pulmonary Langerhans cell histiocytosis in adults: high-resolution CT-pathology comparisons and evolutional changes at CT. Eur Radiol 21 (7): 1406-15, 2011.

  22. Abdallah M, Généreau T, Donadieu J, et al.: Langerhans' cell histiocytosis of the liver in adults. Clin Res Hepatol Gastroenterol 35 (6-7): 475-81, 2011.

  23. Howarth DM, Gilchrist GS, Mullan BP, et al.: Langerhans cell histiocytosis: diagnosis, natural history, management, and outcome. Cancer 85 (10): 2278-90, 1999.

Treatment of Adult LCH

Standard Treatment Options

The lack of clinical trials limits the ability to make evidence-based recommendations for adult patients with Langerhans cell histiocytosis (LCH).

Most investigators have previously recommended treatment according to the guidelines given above for standard treatment of children with Langerhans cell histiocytosis. It is unclear, however, whether adult LCH responds as well as the childhood form of the disease. In addition, the drugs used in the treatment of children are not as well-tolerated when used in adults. Excessive neurologic toxicity from vinblastine, for example, prompted closure of the LCH-A1 trial.

A consensus opinion reported on the evaluation and treatment of adult patients with LCH.[1] Discussion continues, however, particularly with regard to optimal first-line therapy with some experienced clinicians preferring to start with vinblastine and prednisone and others with alternative therapy, such as single-agent cytosine arabinoside or cladribine.

Treatment of pulmonary LCH

It is difficult to judge the effectiveness of various treatments for pulmonary LCH because patients can recover spontaneously or have stable disease without treatment. Smoking cessation is mandatory because the apparent causal effect of smoking in pulmonary LCH.[2] It is not known if steroid therapy is efficacious in the treatment of adult pulmonary LCH because reported case series did not control for smoking cessation. Most adult patients with LCH have gradual disease progression with continued smoking. The disease may regress or progress with the cessation of smoking.[3] Some patients have been reported to respond to cladribine therapy.

Lung transplantation may be necessary for adults with extensive pulmonary destruction from LCH.[4] This multicenter study reported 54% survival at 10 years posttransplant, with 20% of patients having recurrent LCH that did not impact survival; longer follow-up of these patients is needed. Another study confirmed an approximate 50% survival at 10 years and improved hemodynamic changes associated with pulmonary arterial hypertension, but did not alter pulmonary function testing or incidence of pulmonary edema.[5] The best strategy for follow-up of pulmonary LCH includes physical examination, chest radiographs, lung function tests, and high-resolution computed tomography (CT) scans.[6]

Treatment of bone LCH

As in children, adults with single-bone lesions should undergo curettage of the lesion followed by observation, with or without intralesional corticosteroids. Extensive or radical surgery leading to loss of function and disfigurement is contraindicated at any site, including the teeth or jaw bones. Systemic chemotherapy will cause bone lesions to regress and the involved teeth and jaw bones cannot reform. For those failing chemotherapy, low-dose radiation therapy may be indicated and should be tried before any radical surgery that leads to extensive loss of function and disfigurement. Radiation therapy is also indicated for impending neurological deficits from vertebral body lesions or visual problems from orbital lesions. A German cooperative radiation therapy group reported on a series of 98 adult patients with LCH, most of whom (60 of 98) had only bone lesions, and 24 had multisystem disease including bone, treated with radiation therapy.[7][Level of evidence: 3iiiDiv] Of 89 evaluable patients, 77% achieved a complete remission, 9% developed an infield recurrence, and 15.7% (14 of 89) experienced a progression outside the radiation field(s).

A variety of chemotherapy regimens, including cladribine, have been published in the treatment of a relatively limited number of patients. (Refer to the Chemotherapy section of this summary for more information.)

Anecdotal reports have described the successful use of the bisphosphonate pamidronate in controlling severe bone pain in patients with multiple osteolytic lesions.[8][9][10] Successful use of oral bisphosphonates have also been described and may be a useful and relatively less toxic way of treating adult bone LCH.[11] Because of the increased toxicity of chemotherapy in adults, bisphosphonate therapy could be used before chemotherapy in multifocal bone disease. Response of other organs, such as skin and soft tissue, to bisphosphonate therapy has been reported.[12]

Another approach using anti-inflammatory agents (pioglitazone and rofecoxib) coupled with trofosfamide in a specific timed sequence was successful in two patients who had disease resistant to standard chemotherapy treatment.[13]

Treatment of single-system skin disease

  • Localized lesions can be treated by surgical excision, but as with bone, mutilating surgery, including hemivulvectomy, should be avoided unless the disease is refractory to available therapy.
  • Topical therapies are described in greater detail in the childhood isolated skin involvement section of this summary and include topical or intralesional corticosteroid, topical tacrolimus, imiquimod, psoralen and long-wave ultraviolet A radiation (PUVA), and UVB.[14] Therapies such as PUVA/UVB may be more useful in adults when consideration of long-term toxicity may be less.[15][16][17]
  • Systemic therapy for severe skin LCH includes oral methotrexate, oral thalidomide, oral interferon-alpha, or combinations of interferon and thalidomide.[18][19] Recurrences after stopping treatment may occur but may respond to re-treatment.
  • Oral isotretinoin has achieved remission in some refractory cases of skin LCH in adults.[20]

Chemotherapy for the treatment of single-system and multisystem disease

Chemotherapy is generally used for skin LCH associated with multisystem disease in adults.

  • A single-center, retrospective review of 58 adult patients with LCH reported on the efficacy and toxicities of treatment with vinblastine/prednisone, cladribine, and cytarabine. Patients treated with vinblastine/prednisone had the worst outcome, with 84% not responding within 6 weeks or relapsing within a year. The no-response/relapse rate was 59% for cladribine and 21% for cytarabine. Grade 3 or 4 neurologic toxic effects occurred in 75% of patients treated with vinblastine. Grade 3 or 4 neutropenia occurred in 37% of patients treated with cladribine and in 20% of patients receiving cytarabine.[21]
  • Etoposide has been used with some success in single-system and multisystem LCH. Use of prolonged oral etoposide in adults with skin LCH has been reported with minimal toxicity, while 3-day courses of intravenous etoposide (100 mg/m2/day) achieved complete remission in a small number of patients with resistant single-system and multisystem disease.[22] Another study at the same center found that azathioprine was the most successful drug for localized disease in adults, with the addition of etoposide for refractory and multisystem disease.[23]
  • For patients who do not respond to front-line therapy with etoposide, cladribine is effective for adults with skin, bone, lymph node, and probably pulmonary and central nervous system (CNS) disease.[24][25] The first study that used cladribine to treat refractory and recurrent skin LCH disease reported on three patients (aged 33, 51, and 57 years) who received two to four courses of cladribine at 0.7 mg/kg intravenously over 2 hours/day for 5 days.[24] In a series of five adults (one untreated and four with refractory LCH treated with cladribine at the same dose noted above), three patients achieved a complete remission and two patients achieved a partial remission.[25]
  • An adult lymphoma treatment regimen, methotrexate, doxorubicin, cyclophosphamide, vincristine, prednisone and bleomycin (MACOP-B), was used in three patients with multisystem LCH and four with single-system multifocal bone LCH from 1995 to 2007.[26] Total duration of therapy was 12 weeks; response was seen in all patients, two with partial response and five with complete response. Three recurrences were seen after stopping therapy.[26] Despite the small number of patients and the retrospective nature of the study, MACOP-B may be useful as salvage therapy in adult patients with LCH and deserves further study.[27]
  • Anecdotal reports have described the successful use of the bisphosphonate pamidronate in controlling severe bone pain in patients with multiple osteolytic lesions.[8][9][10]
  • A case report suggests some benefit to treating neurodegenerative CNS LCH disease with infliximab, a tumor necrosis factor-alpha inhibitor.[28]
  • A report of stereotactic radiosurgery for the treatment of pituitary LCH in adults showed efficacy in reducing the masses.[29] However, radiation therapy is not considered the standard of care for children with pituitary involvement. Systemic chemotherapy with cytarabine and cladribine have been the preferred treatments.[30][31]

Targeted therapies for the treatment of single-system and multisystem disease

New targeted therapies under investigation include the following:

  • Tyrosine kinase inhibitors: Imatinib mesylate has been effective in the treatment of four adult patients with LCH who had skin, lung, bone, and/or CNS involvement.[32][33] Another adult patient with LCH did not respond to imatinib mesylate.[34]
  • RAS pathway inhibitors: The finding that most patients with LCH demonstrate BRAF and other RAS pathway mutations has led to a successful trial of vemurafenib, a BRAF V600E inhibitor, in adult patients with Erdheim-Chester disease and LCH.[35] A number of clinical trials of BRAF and other RAS pathway inhibitors in adults and children with LCH are ongoing. NCT01677741 is one such trial.

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with adult Langerhans cell histiocytosis. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References:

  1. Girschikofsky M, Arico M, Castillo D, et al.: Management of adult patients with Langerhans cell histiocytosis: recommendations from an expert panel on behalf of Euro-Histio-Net. Orphanet J Rare Dis 8: 72, 2013.

  2. Tazi A: Adult pulmonary Langerhans' cell histiocytosis. Eur Respir J 27 (6): 1272-85, 2006.

  3. Mogulkoc N, Veral A, Bishop PW, et al.: Pulmonary Langerhans' cell histiocytosis: radiologic resolution following smoking cessation. Chest 115 (5): 1452-5, 1999.

  4. Dauriat G, Mal H, Thabut G, et al.: Lung transplantation for pulmonary langerhans' cell histiocytosis: a multicenter analysis. Transplantation 81 (5): 746-50, 2006.

  5. Le Pavec J, Lorillon G, Jaïs X, et al.: Pulmonary Langerhans cell histiocytosis-associated pulmonary hypertension: clinical characteristics and impact of pulmonary arterial hypertension therapies. Chest 142 (5): 1150-1157, 2012.

  6. Abbritti M, Mazzei MA, Bargagli E, et al.: Utility of spiral CAT scan in the follow-up of patients with pulmonary Langerhans cell histiocytosis. Eur J Radiol 81 (8): 1907-12, 2012.

  7. Olschewski T, Seegenschmiedt MH: Radiotherapy of Langerhans' Cell Histiocytosis : Results and Implications of a National Patterns-of-Care Study. Strahlenther Onkol 182 (11): 629-34, 2006.

  8. Arzoo K, Sadeghi S, Pullarkat V: Pamidronate for bone pain from osteolytic lesions in Langerhans'-cell histiocytosis. N Engl J Med 345 (3): 225, 2001.

  9. Farran RP, Zaretski E, Egeler RM: Treatment of Langerhans cell histiocytosis with pamidronate. J Pediatr Hematol Oncol 23 (1): 54-6, 2001.

  10. Brown RE: Bisphosphonates as antialveolar macrophage therapy in pulmonary langerhans cell histiocytosis? Med Pediatr Oncol 36 (6): 641-3, 2001.

  11. Kamizono J, Okada Y, Shirahata A, et al.: Bisphosphonate induces remission of refractory osteolysis in langerhans cell histiocytosis. J Bone Miner Res 17 (11): 1926-8, 2002.

  12. Morimoto A, Shioda Y, Imamura T, et al.: Nationwide survey of bisphosphonate therapy for children with reactivated Langerhans cell histiocytosis in Japan. Pediatr Blood Cancer 56 (1): 110-5, 2011.

  13. Reichle A, Vogt T, Kunz-Schughart L, et al.: Anti-inflammatory and angiostatic therapy in chemorefractory multisystem Langerhans' cell histiocytosis of adults. Br J Haematol 128 (5): 730-2, 2005.

  14. Vogel CA, Aughenbaugh W, Sharata H: Excimer laser as adjuvant therapy for adult cutaneous Langerhans cell histiocytosis. Arch Dermatol 144 (10): 1287-90, 2008.

  15. Rieker J, Hengge U, Ruzicka T, et al.: [Multifocal facial eosinophilic granuloma: successful treatment with topical tacrolimus]. Hautarzt 57 (4): 324-6, 2006.

  16. O'Kane D, Jenkinson H, Carson J: Langerhans cell histiocytosis associated with breast carcinoma successfully treated with topical imiquimod. Clin Exp Dermatol 34 (8): e829-32, 2009.

  17. Taverna JA, Stefanato CM, Wax FD, et al.: Adult cutaneous Langerhans cell histiocytosis responsive to topical imiquimod. J Am Acad Dermatol 54 (5): 911-3, 2006.

  18. McClain KL, Kozinetz CA: A phase II trial using thalidomide for Langerhans cell histiocytosis. Pediatr Blood Cancer 48 (1): 44-9, 2007.

  19. Steen AE, Steen KH, Bauer R, et al.: Successful treatment of cutaneous Langerhans cell histiocytosis with low-dose methotrexate. Br J Dermatol 145 (1): 137-40, 2001.

  20. Tsambaos D, Georgiou S, Kapranos N, et al.: Langerhans' cell histiocytosis: complete remission after oral isotretinoin therapy. Acta Derm Venereol 75 (1): 62-4, 1995.

  21. Cantu MA, Lupo PJ, Bilgi M, et al.: Optimal therapy for adults with Langerhans cell histiocytosis bone lesions. PLoS One 7 (8): e43257, 2012.

  22. Tsele E, Thomas DM, Chu AC: Treatment of adult Langerhans cell histiocytosis with etoposide. J Am Acad Dermatol 27 (1): 61-4, 1992.

  23. Munn SE, Olliver L, Broadbent V, et al.: Use of indomethacin in Langerhans cell histiocytosis. Med Pediatr Oncol 32 (4): 247-9, 1999.

  24. Saven A, Foon KA, Piro LD: 2-Chlorodeoxyadenosine-induced complete remissions in Langerhans-cell histiocytosis. Ann Intern Med 121 (6): 430-2, 1994.

  25. Pardanani A, Phyliky RL, Li CY, et al.: 2-Chlorodeoxyadenosine therapy for disseminated Langerhans cell histiocytosis. Mayo Clin Proc 78 (3): 301-6, 2003.

  26. Derenzini E, Fina MP, Stefoni V, et al.: MACOP-B regimen in the treatment of adult Langerhans cell histiocytosis: experience on seven patients. Ann Oncol 21 (6): 1173-8, 2010.

  27. Gadner H: Treatment of adult-onset Langerhans cell histiocytosis--is it different from the pediatric approach? Ann Oncol 21 (6): 1141-2, 2010.

  28. Chohan G, Barnett Y, Gibson J, et al.: Langerhans cell histiocytosis with refractory central nervous system involvement responsive to infliximab. J Neurol Neurosurg Psychiatry 83 (5): 573-5, 2012.

  29. Hong WC, Murovic JA, Gibbs I, et al.: Pituitary stalk Langerhans cell histiocytosis treated with CyberKnife radiosurgery. Clin Neurol Neurosurg 115 (5): 573-7, 2013.

  30. Dhall G, Finlay JL, Dunkel IJ, et al.: Analysis of outcome for patients with mass lesions of the central nervous system due to Langerhans cell histiocytosis treated with 2-chlorodeoxyadenosine. Pediatr Blood Cancer 50 (1): 72-9, 2008.

  31. Egeler RM, de Kraker J, Voûte PA: Cytosine-arabinoside, vincristine, and prednisolone in the treatment of children with disseminated Langerhans cell histiocytosis with organ dysfunction: experience at a single institution. Med Pediatr Oncol 21 (4): 265-70, 1993.

  32. Montella L, Insabato L, Palmieri G: Imatinib mesylate for cerebral Langerhans'-cell histiocytosis. N Engl J Med 351 (10): 1034-5, 2004.

  33. Janku F, Amin HM, Yang D, et al.: Response of histiocytoses to imatinib mesylate: fire to ashes. J Clin Oncol 28 (31): e633-6, 2010.

  34. Wagner C, Mohme H, Krömer-Olbrisch T, et al.: Langerhans cell histiocytosis: treatment failure with imatinib. Arch Dermatol 145 (8): 949-50, 2009.

  35. Haroche J, Cohen-Aubart F, Emile JF, et al.: Dramatic efficacy of vemurafenib in both multisystemic and refractory Erdheim-Chester disease and Langerhans cell histiocytosis harboring the BRAF V600E mutation. Blood 121 (9): 1495-500, 2013.

Changes to the Summary (06/04/2014)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

This summary was comprehensively reviewed and extensively revised.

This summary is written and maintained by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ NCI's Comprehensive Cancer Database pages.


This information is provided by the National Cancer Institute.

This information was last updated on June 4, 2014.

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