Langerhans Cell Histiocytosis Treatment (PDQ®): Treatment - Health Professional Information [NCI]

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Langerhans Cell Histiocytosis Treatment

Purpose of This PDQ Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of childhood and adult Langerhans cell histiocytosis. This summary is reviewed regularly and updated as necessary by the PDQ Pediatric Treatment Editorial Board.

Information about the following is included in this summary:

  • Incidence.
  • Cellular classification and biologic correlates.
  • Childhood Langerhans cell histiocytosis presenting symptoms.
  • Diagnostic evaluation.
  • Childhood Langerhans cell histiocytosis treatment information.
  • Late disease and treatment effects.
  • Adult Langerhans cell histiocytosis symptoms and treatment information.

This summary is intended as a resource to inform and assist clinicians and other health professionals who care for pediatric cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

Some of the reference citations in the summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Pediatric and Adult Treatment Editorial Boards use a formal evidence ranking system in developing their level-of-evidence designations. Based on the strength of the available evidence, treatment options are described as either "standard" or "under clinical evaluation." These classifications should not be used as a basis for reimbursement determinations.

This summary will soon be available in a patient version, which is written in less-technical language, and in Spanish.

General Information

The National Cancer Institute provides the PDQ pediatric cancer treatment information summaries as a public service to increase the availability of evidence-based cancer information to health professionals, patients, and the public.

Langerhans cell histiocytosis (LCH) results from the proliferation of immunophenotypically and functionally immature, morphologically rounded Langerhans cells along with eosinophils, macrophages, lymphocytes, and commonly, multinucleated giant cells. Controversy exists regarding whether the clonal proliferation is sufficient to consider this a neoplasm or whether the immunologic abnormalities observed in LCH are the cause of the clonal proliferation of lesional Langerhans cells.[1] In either case, the primary treatment is with chemotherapeutic agents. Some of the chemotherapy drugs used also have immunomodulatory activity.

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 because the pathologic Langerhans cell is the cell type common to all of these diagnoses and is a member of the dendritic cell family, a cell found intermittently in the dermal-epidermal junction of the skin.[2,3,4]

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. Nezelof C, Basset F, Rousseau MF: Histiocytosis X histogenetic arguments for a Langerhans cell origin. Biomedicine 18 (5): 365-71, 1973.
3. Coppes-Zantinga A, Egeler RM: The Langerhans cell histiocytosis X files revealed. Br J Haematol 116 (1): 3-9, 2002.
4. Arceci RJ, Longley BJ, Emanuel PD: Atypical cellular disorders. Hematology Am Soc Hematol Educ Program : 297-314, 2002.

Childhood Langerhans Cell Histiocytosis

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. (Refer to the PDQ Supportive and Palliative Care summaries for specific information about supportive care for children and adolescents with cancer.)

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.

Because of treatment advances, the outcome for children with LCH involving high-risk organs (spleen, liver, bone marrow, and lung) has improved.[1] The outcome for children with LCH involving low-risk organs (skin, bones, lymph nodes, and pituitary gland) has always been excellent, but the major challenge is to reduce the relatively high incidence (20%–30%) of recurrent lesions. 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 PDQ summary on Late Effects of Treatment for Childhood Cancer for more information about the incidence, type, and monitoring of late effects of childhood cancer and its therapy.)

Incidence

The incidence of LCH has been estimated to be two to ten cases per million children aged 15 years or younger.[2] The male/female (M/F) ratio is close to one and the median age of presentation is 30 months.[3] A report from Stockholm County, Sweden described an incidence of 8.9 cases of LCH per million children with a total of 29 cases in 10 years.[4] A majority 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 unusual incidence of 4.6 per million children younger than 15 years (M/F = 1.2).[5] Identical twins with LCH, as well as nontwin siblings or multiple cases in one family, have been reported.[6] A survey of LCH in northwest England (Manchester) revealed an overall incidence of 2.6 cases per million child years.[7]

Risk Factors

Solvent exposure in parents and perinatal infections have a weak association with LCH, but there is no increase in cases after viral epidemics.[8] An increased frequency of family members with thyroid disease has been reported.[9]

Prognosis

The nomenclature used for LCH indicates the disease extent (i.e., single organ, single site [single system], multisystem [multisite or multiple sites], or multiple organs [diffuse disease]). Prognosis and treatment are closely linked to the extent of disease at presentation and whether high-risk organs (liver, spleen, lung, bone marrow) are involved. If patients with involvement of high-risk organs do not respond adequately by the 12th week of therapy, their chance of survival is 25% to 40%.[1] 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.[1] Involvement of orbital, mastoid, and temporal bones is associated with an increased risk of diabetes insipidus in addition to increased frequency of anterior pituitary hormone deficiencies and neurologic problems. (See discussion below on CNS Risk areas.)

References:

1. 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.
2. 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.
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. Aricò M, Nichols K, Whitlock JA, et al.: Familial clustering of Langerhans cell histiocytosis. Br J Haematol 107 (4): 883-8, 1999.
7. 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.
8. Nicholson HS, Egeler RM, Nesbit ME: The epidemiology of Langerhans cell histiocytosis. Hematol Oncol Clin North Am 12 (2): 379-84, 1998.
9. Bhatia S, Nesbit ME Jr, Egeler RM, et al.: Epidemiologic study of Langerhans cell histiocytosis in children. J Pediatr 130 (5): 774-84, 1997.

Histopathologic, Immunologic, and Cytogenetic Characteristics of Langerhans Cell Histiocytosis

Cell of Origin and Biologic Correlates

The Langerhans cell (LC) originates from bone marrow stem cells as an immature dendritic cell (DC), which can then develop into the LC under the influence of several cytokines, including granulocyte-macrophage colony-stimulating factor (GM-CSF), tumor necrosis factor alpha (TNF alpha), and others.[1] These immature cells are found in the skin, lymph nodes, spleen, bone marrow, and lungs. LCs differ from other histiocytes in that they are CD1a-positive and CD207 (Langerin)-positive.[2] This cell characteristic along with the classic histology (see below) is used to identify LCs in lesions where they also maintain an immature dendritic cell phenotype (see below).[3] Suspected Langerhans cell histiocytosis (LCH) lesions also contain lymphocytes, macrophages, neutrophils, eosinophils, fibroblasts and sometimes multinucleated giant cells. It has been proposed that the LC is the cellular pathologic culprit for LCH lesions, however, definitive evidence of this has yet to be obtained.[2]

In the brain, three types of histopathologic findings have been described in LCH:

  • Granulomas in meninges or choroid plexus with CD1a+ LC and predominantly CD8+ lymphocytes.
  • Granulomas in connective tissue spaces with CD1a+ LC and predominantly CD8+ lymphocytes causing an inflammatory response and neuronal loss.
  • Predominantly CD8+ lymphocyte infiltration with tissue degeneration, microglial activation, and gliosis.[4]

Immunologic Abnormalities

Normally, the LC is a primary presenter of antigen to naïve T lymphocytes. However, in LCH, the LC does not efficiently stimulate primary T lymphocyte responses.[5] Antibody staining for the DC markers, CD80, CD86, and class II antigens, has been used to show that in LCH, the abnormal cells are immature DCs that present antigen poorly and are proliferating at a low rate.[3,6] Transforming growth factor-beta (TGF-beta) as well as interleukin (IL)-10 are possibly responsible for preventing LC maturation in LCH.[3] The expansion of regulatory T cells in LCH patients has been reported.[6] The population of CD4+ CD25 high FoxP3high cells was reported to comprise 20% of T cells and appeared to be in contact with LC in LCH lesions. These T cells were present in higher numbers in the peripheral blood of LCH patients than in controls and returned to a normal level when patients were in remission.

Etiology

The etiology of LCH is unknown. Efforts to define a viral cause have not been successful.[7,8]

Chromosomal Studies

Studies showing clonality in LCH have been published since 1997 using polymorphisms of methylation-specific restriction enzyme sites on the X-chromosome regions coding for the human androgen receptor, DXS255, PGK, and HPRT.[9,10] Biopsies of lesions with single system or multisystem disease were found to have a proliferation of LCs from a single clone. Pulmonary LCH in adults is usually nonclonal.[11] Cytogenetic abnormalities in LCH have rarely been reported. One study described an abnormal clone (t7;12)(q11.2;p13) from a vertebral lesion of one patient.[12] This study also reported nonclonal karyotypic abnormalities in three patients. An increase in chromosomal breakage was also noted.

Three studies have used comparative genomic hybridization (CGH) to analyze bone and pulmonary LCH.[13,14,15] Analysis of seven bone lesions by CGH and loss of heterozygosity (LOH) has provided further evidence to suggest that chromosomal aberrations may be an intrinsic problem in LCH.[13] One study evaluated 14 cases of pulmonary LCH for LOH [14] and found LOH of 1p, 1q, 3p, 5p, 17p, and 22q. Allelic loss of one or more tumor suppressor genes was identified in 19 of 24 specimens. Researchers at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins demonstrated that significantly shortened telomeres in the LCH lesional LCs compared with LCs in inflammatory disorders such as dermatopathic lymphadenitis.[16] An Italian group demonstrated that high-risk LCH patients had DNA polymorphisms of two cytokine genes (IL-4 and interferon gamma), which were associated with high-expresser phenotypes.[17]

Cytokine Analysis by Immunohistochemical Staining

Several cytokines have apparent higher expression levels in LCH lesions than in normal tissue. Among the cytokines expressed at high levels are GM-CSF, interferon gamma, IL-1, sIL-2r, IL-10, and the TNF receptor family member, RANK.[6,18] Lesional T cells stain with antibodies to TNF alpha, various interleukins, CD40L, and sCD154.[18,19] Prominent expression of angiotensin-converting enzyme, TGF-beta, and IL-11 in LCH biopsies have been reported.[20] Increased expression of the chemokine receptor, CCR6, has been observed in LCH lesions and may contribute to the accumulation of LCs in skin. Increased CCR7 expression may cause the LC to home to lymphoid tissue.[21] These data are somewhat anomalous because it is expected that CCR6 would be down-regulated in the activated LCs in these lesions. However, prominent staining of CCR6 and its ligand CCL20/M1P-3alpha has been found in other studies.[22] Further evidence for the altered biology of LCs in LCH is the increased expression of the antiapoptotic protein, Bcl-2, as well as several other genes (e.g., Ki-67, TGFB1, TGBF2, MDM2, p53, p21, p16, and RB).[23]

Gene Expression by Microarray Analysis

Two papers have been published on analysis of gene expression in LCH by gene array techniques.[24,25] In the first report, a laser-capture microdissection was used to purify LCs from frozen biopsy specimens or normal LCs from the skin.[24] The level of cytokine and growth factor gene expression in the control LCs versus those from patient biopsies showed a striking similarity in expression of RNA of the TNF family of genes and several interleukins. Only macrophage colony-stimulating factor (M-CSF), TGF-beta receptor and IL-1 alpha transcripts were expressed at higher levels in the LCs from LCH patients. In the second report, a very different approach was used, generating LCs from CD34 stem cells in vitro followed by a serial analysis of gene expression library to identify highly expressed genes in these LCs.[25] Several of the highly expressed genes were then chosen to test for RNA levels from whole LCH biopsy specimens. High expression of FSCN1, GSN MMP12, CCL22, CD1a, and CD207 was commonly observed.

Cytokine Levels and Association with Diagnosis, Prognosis, or Response to Therapy

Several groups have measured cytokines or other markers of immune activation in the plasma or serum of patients with LCH to determine whether these levels could be of diagnostic or prognostic importance or whether the levels could be helpful for evaluating response to therapy. One group reported consistently higher levels of IL-2 receptor in LCH biopsy specimens,[26] however, they found no increased expression of IL-1 beta, TNF-alpha, and IL-2, which were all within normal limits. Another group used a similar assay technique and identified increased levels of the IL-1 receptor agonist and TNF-alpha in plasma from LCH patients.[27] Vascular endothelial growth factor has also been identified by immunohistochemistry in five of five patients with multisystem LCH and two of five patients with single system LCH.[28] A third group found markedly elevated levels of FLT3-ligand and M-CSF in the serum of LCH patients with good correlation to the extent of disease as well as response to treatment and increased circulating immature myeloid dendritic cells.[29] It should be noted that this latter finding was not confirmed by a later study; however, there was a trend toward higher myeloid DC levels in patients.[6] Elevated levels of another regulator of the immune system and bone metabolism, osteoprotegerin (OPG), are present in the plasma of patients with active LCH.[30,31] OPG levels reported in this study were highest in patients with multisystem disease and decreased with response to therapy, similar to the findings with FLT-3 ligand and M-CSF.

Human Leukocyte Antigen Type and Association with Langerhans Cell Histiocytosis

Specific associations of LCH with distinct human lymphocyte antigen (HLA) types and extent of disease have been published. 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.[32] 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.[33]

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. Weitzman S, Egeler R M, eds.: Histiocytic Disorders of Children and Adults. Cambridge, United Kingdom: Cambridge University Press, 2005.
3. Geissmann F, Lepelletier Y, Fraitag S, et al.: Differentiation of Langerhans cells in Langerhans cell histiocytosis. Blood 97 (5): 1241-8, 2001.
4. Grois N, Prayer D, Prosch H, et al.: Neuropathology of CNS disease in Langerhans cell histiocytosis. Brain 128 (Pt 4): 829-38, 2005.
5. 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.
6. 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.
7. McClain K, Jin H, Gresik V, et al.: Langerhans cell histiocytosis: lack of a viral etiology. Am J Hematol 47 (1): 16-20, 1994.
8. Glotzbecker MP, Dormans JP, Pawel BR, et al.: Langerhans cell histiocytosis and human herpes virus 6 (HHV-6), an analysis by real-time polymerase chain reaction. J Orthop Res 24 (3): 313-20, 2006.
9. 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.
10. Yu RC, Chu C, Buluwela L, et al.: Clonal proliferation of Langerhans cells in Langerhans cell histiocytosis. Lancet 343 (8900): 767-8, 1994.
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. Betts DR, Leibundgut KE, Feldges A, et al.: Cytogenetic abnormalities in Langerhans cell histiocytosis. Br J Cancer 77 (4): 552-5, 1998.
13. Murakami I, Gogusev J, Fournet JC, et al.: Detection of molecular cytogenetic aberrations in langerhans cell histiocytosis of bone. Hum Pathol 33 (5): 555-60, 2002.
14. Dacic S, Trusky C, Bakker A, et al.: Genotypic analysis of pulmonary Langerhans cell histiocytosis. Hum Pathol 34 (12): 1345-9, 2003.
15. Chikwava KR, Hunt JL, Mantha GS, et al.: Analysis of loss of heterozygosity in single-system and multisystem Langerhans' cell histiocytosis. Pediatr Dev Pathol 10 (1): 18-24, 2007 Jan-Feb.
16. Bechan GI, Meeker AK, De Marzo AM, et al.: Telomere length shortening in Langerhans cell histiocytosis. Br J Haematol 140 (4): 420-8, 2008.
17. De Filippi P, Badulli C, Cuccia M, et al.: Specific polymorphisms of cytokine genes are associated with different risks to develop single-system or multi-system childhood Langerhans cell histiocytosis. Br J Haematol 132 (6): 784-7, 2006.
18. Egeler RM, Favara BE, van Meurs M, et al.: Differential In situ cytokine profiles of Langerhans-like cells and T cells in Langerhans cell histiocytosis: abundant expression of cytokines relevant to disease and treatment. Blood 94 (12): 4195-201, 1999.
19. Egeler RM, Favara BE, Laman JD, et al.: Abundant expression of CD40 and CD40-ligand (CD154) in paediatric Langerhans cell histiocytosis lesions. Eur J Cancer 36 (16): 2105-10, 2000.
20. Brown RE: Angiotensin-converting enzyme, transforming growth factor beta(1), and interleukin 11 in the osteolytic lesions of Langerhans cell histiocytosis. Arch Pathol Lab Med 124 (9): 1287-90, 2000.
21. 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.
22. 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.
23. Schouten B, Egeler RM, Leenen PJ, et al.: Expression of cell cycle-related gene products in Langerhans cell histiocytosis. J Pediatr Hematol Oncol 24 (9): 727-32, 2002.
24. McClain KL, Cai YH, Hicks J, et al.: Expression profiling using human tissues in combination with RNA amplification and microarray analysis: assessment of Langerhans cell histiocytosis. Amino Acids 28 (3): 279-90, 2005.
25. Rust R, Kluiver J, Visser L, et al.: Gene expression analysis of dendritic/Langerhans cells and Langerhans cell histiocytosis. J Pathol 209 (4): 474-83, 2006.
26. Schultz C, Klouche M, Friedrichsdorf S, et al.: Langerhans cell histiocytosis in children: does soluble interleukin-2-receptor correlate with both disease extent and activity? Med Pediatr Oncol 31 (2): 61-5, 1998.
27. Rosso DA, Ripoli MF, Roy A, et al.: Serum levels of interleukin-1 receptor antagonist and tumor necrosis factor-alpha are elevated in children with Langerhans cell histiocytosis. J Pediatr Hematol Oncol 25 (6): 480-3, 2003.
28. Pavlakovic H, Von Schütz V, Rössler J, et al.: Quantification of angiogenesis stimulators in children with solid malignancies. Int J Cancer 92 (5): 756-60, 2001.
29. 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.
30. Ishii R, Morimoto A, Ikushima S, et al.: High serum values of soluble CD154, IL-2 receptor, RANKL and osteoprotegerin in Langerhans cell histiocytosis. Pediatr Blood Cancer 47 (2): 194-9, 2006.
31. Rosso DA, Karis J, Braier JL, et al.: Elevated serum levels of the decoy receptor osteoprotegerin in children with langerhans cell histiocytosis. Pediatr Res 59 (2): 281-6, 2006.
32. 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.
33. 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 Langerhans Cell Histiocytosis in Children

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

In LCH, specific organs are considered high-risk or low-risk organs when involved with disease presentation. High-risk organs include liver, spleen, lung, and bone marrow. Low-risk organs include skin, bone, lymph nodes, and the pituitary gland. Additionally, patients may present with disease in one site or organ (single site or single system) or in multiple sites or organs (multisystem or multisite). Treatment decisions for patients are based upon whether high-risk or low-risk organs are involved and whether LCH presents as a single site or multisystem disease. Patients can have LCH of the skin, bone, lymph nodes, and pituitary in any combination and still be considered low-risk.

Single-Site Disease Presentation

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

Skin

  • Infants: Seborrheic involvement of the scalp may be mistaken for prolonged cradle cap in infants. Infants may also present with brown to purplish papules over any part of their body (Hashimoto-Pritzker disease).[1] Similar to that of stage IVS neuroblastoma, this manifestation may be self-limited as the lesions often disappear with no therapy during the first year of life. However, these patients must be watched very closely for systemic disease which may present after the initial skin lesions.[2,3] 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.[4] The overall survival was poorer in neonates with risk organ involvement compared with infants and children with the same extent of disease. Response to therapy at 12 weeks was more important than age.
  • 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, genitalia, or perianal region are often misdiagnosed as bacterial or fungal infections.

Oral mucosa

In the mouth, presenting symptoms include gingival hypertrophy, and ulcers of the soft or hard palate, buccal mucosa, or on the tongue and lips. Lesions of the oral mucosa may precede evidence of LCH elsewhere.[5]

Bone

The most frequent site of LCH in children is a lytic lesion of the skull,[6] which may be asymptomatic or painful. LCH can occur in any bone of the body. The most frequently involved skeletal sites are skull, femur, ribs, vertebra, and humerus. Spine lesions are most often located in the cervical vertebrae and are frequently associated with other bone lesions. Proptosis from an LCH mass in the orbit mimics rhabdomyosarcomas, neuroblastoma, and benign fatty tumors of the eye. Some skull lesions are not only lytic but may have an accompanying soft tissue mass that impinges on the dura. Lesions of the facial bones or anterior or middle cranial fossae (e.g., temporal, sphenoid, ethmoid, zygomatic) with intracranial tumor extension comprise part of a CNS-risk group. These patients have a threefold increased risk for developing diabetes insipidus (DI) and an increased risk of other central nervous system (CNS) disease (see below).

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 lymphoma or an infectious process and may cause asthma-like symptoms. Accordingly, biopsy with culture and histologic examination is mandatory for these presentations.

Pituitary gland

The posterior part of the pituitary gland can be affected in patients with LCH causing central DI (see Endocrine and Central Nervous System sections below). Anterior pituitary involvement often results in growth and sexual maturation failure.

Thyroid

Thyroid involvement has been reported in LCH. Symptoms include massive thyroid enlargement, hypothyroidism, and respiratory symptoms.[7]

Multisystem Disease Presentation

In multisystem LCH, the disease presents in multiple organs or body systems including liver and spleen, lung, bone marrow, endocrine system, gastrointestinal system, and CNS.

Abdominal/gastrointestinal system

In LCH, the liver and spleen are considered high-risk organs, and involvement of these organs effects prognosis, so enlargement of either liver or spleen is a worrisome finding. Hepatic enlargement can be accompanied by dysfunction, leading to hypoalbuminemia with ascites, hyperbilirubinemia, and clotting factor deficiencies. Sonography, computed tomography (CT), or magnetic resonance imaging (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.[8] One of the most serious complications of hepatic LCH is cholestasis and sclerosing cholangitis.[9] The median age of children with hepatic LCH is 23 months, and they present with hepatomegaly or hepatosplenomegaly, elevated alkaline phophatase, liver transaminases, and gamma glutamyl transpeptidase. Biopsies show no Langerhans cells (LCs) so it is thought that cytokines elaborated by lymphocytes may damage the bile ducts. Seventy-five percent of children with sclerosing cholangitis will not respond to chemotherapy; liver transplantation is the only alternate treatment when hepatic function worsens. Massive splenomegaly may lead to cytopenias because of hypersplenism and respiratory compromise. Performing a splenectomy for these problems is not customary, although one may be forced to do this when salvage chemotherapy is not working fast enough. Unfortunately, splenectomy typically provides only transient relief of cytopenias, as increased liver size and reticuloendothelial activation results in peripheral blood cell sequestration and destruction. Although rare, LCH infiltration of the pancreas and kidneys has been reported.[10]

A few patients with diarrhea, hematochezia, perianal fistulas, diarrhea or malabsorption have been reported.[11,12] 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 also considered a high-risk organ, but is less frequently involved in children than in adults, in whom smoking is a key etiologic factor.[13] The cystic/nodular pattern of disease leads to the destruction of lung tissue. A 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 leads to severe pulmonary insufficiency. A study reporting outcomes for children with only low-risk organ disease (skin, bone, lymph nodes, or pituitary gland) or pulmonary plus low-risk organs revealed that patients with pulmonary involvement had a 5-year survival of 83% as opposed to 94% for those with only low-risk organ involvement.[14] Declining diffusion capacity may also herald the onset of pulmonary hypertension.[15] In young children with diffuse disease, therapy can halt progress of the tissue destruction and normal repair mechanisms may restore some function.

Bone marrow

Most patients with bone marrow involvement are young children who have diffuse disease in the liver, spleen, lymph nodes, skin and significant thrombocytopenia or neutropenia.[16] 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.[17] Patients with LCH who are considered at very high risk sometimes present with hemophagocytosis involving the bone marrow.[18] The cytokine milieu driving LCH is probably responsible for the epiphenomenon of macrophage activation. These patients may be confusing as to which histiocytic syndrome is primary: hemophagocytic lymphohistiocytosis or LCH. Evidence of bone involvement or the characteristic LCH skin rash can simplify the diagnostic dilemma, but careful clinical evaluation is needed in these cases.

Endocrine system

Diabetes insipidus is the most frequent endocrine manifestation in LCH. Some patients may present with an apparent idiopathic presentation of DI before other lesions are identified. A review of such patients found that 51% will have other lesions diagnostic of LCH within a year of identifying DI.[19] A study of 589 LCH patients in France revealed the 10-year risk of pituitary involvement was 24%.[20] These investigators did not see a decreased incidence of DI in chemotherapy-treated patients (see Central Nervous System section below). The German-Austrian-Dutch (Deutsche Arbeits-gemeinschaft für Leukaemieforschung und-therapie im Kindesalter, DAL) Group found the cumulative incidence to be 12%.[21] DI followed initial LCH diagnosis by a mean of 1 year and growth hormone deficiency 5 years later.

Patients with multisystem disease and craniofacial involvement at the time of diagnosis, particularly of the ear, eye, and oral region, carried a significantly increased risk of developing DI during their course (relative risk, 4.6).[22] This risk increased when the disease remained active for a longer period of time or reactivated. The risk for development of DI in this population was 20% at 15 years after diagnosis.

Central nervous system

Diabetes insipidus

DI (considered both an endocrine and a central nervous system manifestation of LCH) can present as an acute or chronic condition.

Acute manifestations of diabetes insipidus

DI caused by damage to the posterior pituitary region by LCH is the most frequent initial sign (and acute manifestation) in the CNS.[21] DI is the presenting symptom in approximately 4% of patients subsequently found to have LCH. DI occurred in 12% of all LCH patients in the DAL studies.[21] Six percent of patients presented with this manifestation at the time of diagnosis. Pituitary biopsies are rarely done and most often only when the stalk is greater than 6.5 mm or there is a hypothalamic mass. Most often the diagnosis is established by biopsying the skin, bone, or lymph node of a patient who also has the pituitary abnormalities noted above.

Chronic manifestations of diabetes insipidus

Ten percent to 24% of all LCH patients will develop DI sometime during the course of their treatment and usually within 4 years from diagnosis of another lesion.[20] The frequency of DI appears to be increased in patients with bone lesions in the orbit, mastoid, and temporal bone since 75% of patients with DI have these CNS-risk lesions.[21] However, another study did not find this association despite showing that the risk of ear, nose, and throat involvement was higher in patients with endocrinopathies.[20] Additional data showed that 56% of DI patients will develop anterior pituitary hormone deficiencies (growth, thyroid, or gonadal-stimulating hormones) within 10 years of the onset of DI. DI occurs in 11% of patients treated with multiagent chemotherapy and in up to 50% of patients treated less aggressively.[23,24]

Other chronic central nervous system disease manifestations

LCH patients may develop mass lesions of the choroid plexus, grey matter, or white matter.[25] These lesions contain CD1a+ LCs and CD8+ lymphocytes.[26]

Langerhans cell histiocytosis central nervous system neurodegenerative syndrome

Another chronic CNS problem that occurs in 1% to 4% of LCH patients is a neurodegenerative syndrome that is manifested by dysarthria, ataxia, dysmetria, and sometimes behavior changes. MRI 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.[27] The radiologic findings may preceed the onset of symptoms by many years or be found coincidently. A study of 83 LCH patients who had at least two MRI imaging studies of the brain for evaluation of craniofacial lesions, DI, and/or other endocrine deficiencies of neuropsychological symptoms has been published.[28] 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%) had clinical neurological deficits that presented 3 to 15 years after the LCH diagnosis.

A study of CNS-related permanent consequences (neuropsychologic deficits) in 14 of 25 LCH patients followed for a median of 10 years has been published.[29] Seven of these patients had DI and five patients had radiographic evidence of LCH CNS neurodegenerative changes.[29] Patients with craniofacial lesions had lower performance and verbal intelligence quotient scores than those with other LCH lesions. Another study reported significant deficits in two LCH patients with abnormalities of the cerebellum and pituitary as shown by MRI scans.[30]

Histological evaluation of these neurodegenerative lesions has been shown to contain a prominent T-cell infiltration in the absence of the CD1a+ dendritic cells along with microglial activation and gliosis. Rarely, CD1a+ LCs are observed. The neurodegenerative form of the disease has been compared to a paraneoplastic inflammatory response.[26]

References:

1. Munn S, Chu AC: Langerhans cell histiocytosis of the skin. Hematol Oncol Clin North Am 12 (2): 269-86, 1998.
2. Stein SL, Paller AS, Haut PR, et al.: Langerhans cell histiocytosis presenting in the neonatal period: a retrospective case series. Arch Pediatr Adolesc Med 155 (7): 778-83, 2001.
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. Minkov M, Prosch H, Steiner M, et al.: Langerhans cell histiocytosis in neonates. Pediatr Blood Cancer 45 (6): 802-7, 2005.
5. Mortellaro C, Pucci A, Palmeri A, et al.: Oral manifestations of langerhans cell histiocytosis in a pediatric population: a clinical and histological study of 8 patients. J Craniofac Surg 17 (3): 552-6, 2006.
6. Slater JM, Swarm OJ: Eosinophilic granuloma of bone. Med Pediatr Oncol 8 (2): 151-64, 1980.
7. Burnett A, Carney D, Mukhopadhyay S, et al.: Thyroid involvement with Langerhans cell histiocytosis in a 3-year-old male. Pediatr Blood Cancer 50 (3): 726-7, 2008.
8. Wong A, Ortiz-Neira CL, Reslan WA, et al.: Liver involvement in Langerhans cell histiocytosis. Pediatr Radiol 36 (10): 1105-7, 2006.
9. 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.
10. Goyal R, Das A, Nijhawan R, et al.: Langerhans cell histiocytosis infiltration into pancreas and kidney. Pediatr Blood Cancer 49 (5): 748-50, 2007.
11. Hait E, Liang M, Degar B, et al.: Gastrointestinal tract involvement in Langerhans cell histiocytosis: case report and literature review. Pediatrics 118 (5): e1593-9, 2006.
12. Geissmann F, Thomas C, Emile JF, et al.: Digestive tract involvement in Langerhans cell histiocytosis. The French Langerhans Cell Histiocytosis Study Group. J Pediatr 129 (6): 836-45, 1996.
13. Vassallo R, Ryu JH, Colby TV, et al.: Pulmonary Langerhans'-cell histiocytosis. N Engl J Med 342 (26): 1969-78, 2000.
14. Braier J, Latella A, Balancini B, et al.: Outcome in children with pulmonary Langerhans cell Histiocytosis. Pediatr Blood Cancer 43 (7): 765-9, 2004.
15. Bernstrand C, Cederlund K, Henter JI: Pulmonary function testing and pulmonary Langerhans cell histiocytosis. Pediatr Blood Cancer 49 (3): 323-8, 2007.
16. McClain K, Ramsay NK, Robison L, et al.: Bone marrow involvement in histiocytosis X. Med Pediatr Oncol 11 (3): 167-71, 1983.
17. Minkov M, Pötschger U, Grois N, et al.: Bone marrow assessment in Langerhans cell histiocytosis. Pediatr Blood Cancer 49 (5): 694-8, 2007.
18. Favara BE, Jaffe R, Egeler RM: Macrophage activation and hemophagocytic syndrome in langerhans cell histiocytosis: report of 30 cases. Pediatr Dev Pathol 5 (2): 130-40, 2002 Mar-Apr.
19. Prosch H, Grois N, Prayer D, et al.: Central diabetes insipidus as presenting symptom of Langerhans cell histiocytosis. Pediatr Blood Cancer 43 (5): 594-9, 2004.
20. Donadieu J, Rolon MA, Thomas C, et al.: Endocrine involvement in pediatric-onset Langerhans' cell histiocytosis: a population-based study. J Pediatr 144 (3): 344-50, 2004.
21. 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.
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. 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.
24. 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.
25. 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.
26. Grois N, Prayer D, Prosch H, et al.: Neuropathology of CNS disease in Langerhans cell histiocytosis. Brain 128 (Pt 4): 829-38, 2005.
27. 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.
28. Wnorowski M, Prosch H, Prayer D, et al.: Pattern and course of neurodegeneration in Langerhans cell histiocytosis. J Pediatr 153 (1): 127-32, 2008.
29. 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.
30. Whitsett SF, Kneppers K, Coppes MJ, et al.: Neuropsychologic deficits in children with Langerhans cell histiocytosis. Med Pediatr Oncol 33 (5): 486-92, 1999.

Diagnostic Evaluation of Childhood Langerhans Cell Histiocytosis

The complete evaluation of any patient, whether presenting with single system or multisystem disease, should 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, alkaline phosphatase, prothrombin time/partial thromboplastin time in patients with hepatomegaly, jaundice, elevations of liver enzymes or low albumin), and serum electrolytes.
  • URINE TESTS: Urine tests include urinalysis and a water-deprivation test if diabetes insipidus (DI) is suspected.
  • BONE MARROW ASPIRATE AND BIOPSY: The bone marrow aspirate and biopsy should be stained with anti-CD1a and/or anti-CD207 (langerin) for patients with thrombocytopenia or anemia not explained by other causes.
  • NEUROLOGIC EXAM
  • RADIOLOGIC AND IMAGING TESTS: Radiologic tests include skeletal survey, skull series, positron emission tomography (PET) or bone scans, chest x-ray, and computed tomographic (CT) scan of the head (if orbital or mastoid involvement is suspected). Imaging tests may include magnetic resonance imaging (MRI) scan with gadolinium contrast of the brain for patients with DI or suspected neurologic involvement.[1]

    A CT scan of the lungs is indicated for patients with abnormal chest xrays or pulmonary symptoms. High-resolution CT scans may show evidence of pulmonary Langerhans cell histiocytosis (LCH) when the chest x-ray is normal, thus in infants and toddlers with normal chest x-rays, a CT scan may be considered.[2] LCH causes fatty changes in the liver or hypodense areas along the portal tract, which can be identified by CT scans.[3] Newer diagnostic imaging modalities, such as somatostatin analogue scintigraphy or F18-FDG PET scans, which augment these standard methods may prove useful.[4,5,6] PET scans may be helpful in following the response to therapy since the intensity of the PET image diminishes with healing of a bone or other lesion.[7,8]

    Fludeoxyglucose F 18 (18F-FDG) PET scan abnormalities have been reported in the brains of seven LCH patients with neurologic and radiographic signs of neurodegenerative disease.[9] The investigators acquired the images beginning 30 minutes after isotope injection instead of the customary 1 hour for body imaging. Areas of hypometabolism in the caudate nuclei, vermis of cerebellum, and hypermetabolism in the amygdala were found by group analysis. 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.[9]

    MRI findings of central nervous system LCH include enhancement of the pons, basal ganglia, and white matter of the cerebellum, as well as mass lesions or meningeal enhancement. In a report of 163 patients,[7] meningeal lesions were found in 29% and choroid plexus involvement in 6%. Paranasal sinus or mastoid lesions were found in more than 50% 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 lesions biopsied for diagnosis of LCH. The Langerhans cells (LCs) should stain with antibodies to CD1a or anti-langerin (CD207) to confirm the diagnosis of LCH. CD1a is more specific for LCH than antilangerin, since normal dendritic LCs in lymph nodes and liver may stain for CD207, but not CD1a.[10] Since other types of histiocytes and macrophages may stain with S-100, this, and morphology of hematoxylin and eosin stained sections, are not considered sufficient to establish the diagnosis of LCH.[10] A liver biopsy is indicated when a child with LCH presents with hypoalbuminemia not caused by gastrointestinal LCH or other etiology. These patients may not have elevated levels of bilirubin or liver enzymes. An open lung biopsy is the preferred method of obtaining tissue for diagnosis of pulmonary LCH as bronchoalveolar lavages may be nondiagnostic.

References:

1. 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.
2. 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.
3. 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.
4. 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.
5. 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.
6. 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.
7. 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.
8. 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.
9. 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.
10. 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 Langerhans Cell Histiocytosis

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 2 years thereafter for 10 years to detect evidence of CNS disease. The Histiocyte Society CNS LCH Committee does not recommend any treatment for radiologic CNS LCH of the neurodegenerative type. However, being aware of its presence is important and careful neurologic examinations and appropriate imaging with MRIs are done at regular intervals. Brain stem auditory evoked responses should also be done at regular intervals to define the onset of clinical CNS LCH. When clinical signs are present, intervention may be indicated.

Vertebral lesions can be effectively followed by MRI scans and pelvic lesions by computed tomography (CT) scans or MRI scans.

For children with LCH in the lung, pulmonary function testing and chest CT scans are sensitive methods for detecting disease progression.[1]

References:

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

Treatment of Childhood Langerhans Cell Histiocytosis

Treatment of Langerhans cell histiocytosis (LCH) may include surgery, oral, topical and intravenous medications and chemotherapy, or radiation therapy depending on the site and extent of disease. The recommended duration of therapy is 6 months for patients who require chemotherapy for bone, skin, or lymph node LCH and 12 months if the liver, spleen, bone marrow, or lungs are involved. It is preferable that LCH patients be enrolled in a clinical trial whenever possible so that advances in therapy can be achieved more quickly and to ensure optimal care.

Standard Treatment Options by Organ, Site or System Involvement

The standard treatment of 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 which lack the evidence-based strength of the trials.

Skin involvement only

  • Observation.
  • Topical steroids.[1] (Although topical steroid creams are rarely effective.)
  • Oral methotrexate (20 mg/m2) weekly for 6 months.[2]
  • Oral thalidomide 50 mg to 200 mg nightly.[3]
  • Topical application of nitrogen mustard is effective for cutaneous LCH that is resistant to oral therapies, but not for disease involving large areas of skin.[4]
  • Psoralen and long-wave ultraviolet radiation.[5]

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

  • Curettage only or curettage plus injection of methylprednisolone.[6]

Skull lesions in the mastoid, temporal, or orbital bones

The purpose of treating these patients is to decrease the chances of developing diabetes insipidus (DI).[7]

  • Six months of vinblastine and prednisone: 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. Afterwards prednisone is given for 5 days at 40 mg/m2 every 3 weeks with the vinblastine injections.[7]
  • Ear, nose, and throat surgeons have reported a series of patients with orbital or mastoid lesions who received only surgical curettage.[8] None of these patients developed DI. However, when comparing the incidence rates of DI in patients who received little or no chemotherapy (20%–50% incidence of DI) versus DI incidence rates reported by the German-Austrian-Dutch (DAL) Group HX-83 trial (10% incidence of DI in patients treated for LCH), it appears that the weight of evidence from the DAL HX-83 trial supports treatment to prevent DI in patients with the mastoid, temporal, or orbital bones.[9,10]

Multiple bone lesions; or combinations of skin, lymph node, or pituitary gland with or without bone lesions

  • Vinblastine and prednisone: Six months of treatment with weekly vinblastine (6 mg/m2) for 7 weeks then every 3 weeks for good response. 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. An 18% reactivation rate with a multidrug regimen for 6 months versus an historical reactivation rate of 50% to 80% with surgery alone, or with a single-drug treatment regimen has been reported.[11]

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

  • The standard therapy length used for LCH in the spleen, liver, bone marrow, or lung (high-risk organs) is based upon LCH-I, LCH-II, and the DAL-HX 83 studies and varies from 6 months (LCH-I and LCH-II) to 1 year (DAL-HX-83).[7,10] The LCH-II study was a randomized trial to compare treatment of patients with velban/prednisone/mercaptopurine or velban/etoposide/prednisone/mercaptopurine.[12][Level of evidence: 1iiA] There outcomes of response at 6 weeks, 5 year probability of survival, relapses, and permanent consequences had no statistical difference between the two treatments. Hence, etoposide has not been used in subsequent Histiocyte Society trials. There was reduced mortality of patients with risk organ involvement in the etoposide arm. Although controversial, a comparison of patients in the LCH-I to LCH-II trials suggested that increased treatment intensity promoted additional early responses and reduced mortality.

Vertebral or femoral bone lesions at risk for collapse

  • Radiation therapy is indicated for patients with bone lesions of the vertebrae or femoral neck, which are at risk of collapse.[13,14] Certain skull lesions, not in the central nervous system (CNS)-risk region, could be considered for radiation therapy. When instability of the cervical vertebrae and neurologic symptoms are present, bracing or spinal fusion may be needed.[15]

Central nervous system

  • Treatment of mass lesions with cladribine (2-CdA) has been effective in 13 reported cases.[16,17,18][Level of evidence: 3iiiDiii] Mass lesions included enlargement of the hypothalamic-pituitary axis, parenchymal mass lesions, and leptomeningeal involvement. Doses of 2-CdA ranged from 5 to 13 mg/m2 given at varying frequencies.[18][Level of evidence: 3iiiDiii]
  • For treatment of symptoms of LCH CNS neurodegenerative syndrome, dexamethasone, 2-CdA, retinoic acid and intravenous immunoglobulin (IVIgG) have been used.[18][Level of evidence: 3iiiDiii][19,20,21] Retinoic acid was given at a dose of 45 mg/m2 daily for 6 weeks, then 2 weeks a month for 1 year.[19] Intravenous immunoglobulin (400 mg/m2) was given monthly and chemotherapy consisting of oral prednisolone with or without oral or intravenous methotrexate and oral 6-mercaptopurine were given for at least one year.[20] Magnetic resonance imaging findings were stable but clinical efficacy was difficult to judge as patients were reported to have no progression in their neurologic symptoms.

Multisystem disease

  • The Japan Langerhans Cell Histiocytosis 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 (induction regimen of cytosine arabinoside, vincristine, and prednisolone followed by 6 months of maintenance therapy). If patients had a poor response to this initial regimen, they were switched to a salvage regimen of intensive combination doxorubicin, cyclophosphamide, vincristine, and prednisolone.[22]
  • Results from the LCH-II trial for multisystem LCH showed a 5-year survival rate of 74% for patients treated with vinblastine/prednisone/mercaptopurine, versus a 79% 5-year survival rate for those patients who had etoposide added to the vinblastine/prednisone/mercaptopurine regimen. There is no statistical difference for the 5-year survival rates between the two arms of this trial.[12] No salvage regimen was recommended as part of the LCH-II trial.
  • The percentage of reactivations was nearly the same in the Japanese trial [22][Level of evidence: 1iiA] and the LCH-II trial [12] (45% vs. 46%, respectively). Both studies concluded that intensified treatment increased rapid response, particularly in young children and infants younger than 2 years, and reduced mortality.

Treatment Options for Childhood Langerhans Cell Histiocytosis No Longer Considered Effective

Treatments for LCH in any location which have been used in the past but are no longer recommended include cyclosporine [23] and interferon-alpha.[24] 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 chemotherapy can heal bone or skin lesions.

Treatment Options Under Clinical Evaluation for Childhood Langerhans Cell Histiocytosis

LCH-III trial

Treatment regimens for LCH patients with multisystem high-risk or low-risk organ disease, multiple bone, or CNS-risk lesions were studied by the Histiocyte Society on HISTSOC-LCH-III. Important treatment tenets of this trial are the following:

  • High-risk organ involvement: Patients with high-risk organ disease were randomly assigned to receive either vinblastine/prednisone/6-mercaptopurine alone, or in combination with methotrexate intravenously during induction therapy and orally during the maintenance phase.
  • Low-risk organ involvement: Those patients with a single bone lesion and skin, lymph node, or pituitary gland involvement were randomized to 6 or 12 months of treatment with vinblastine and prednisone.
  • CNS-risk site involvement: Special sites were designated CNS-risk because of the recognition that patients with multifocal bone disease and those patients with disease at the base of the skull are at high risk for CNS involvement. CNS-risk patients were treated with systemic therapy, not just local therapy or single-drug administration. These special anatomic sites and multifocal bone disease were treated with vinblastine and prednisone for 6 months.

Current Clinical Trials

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry 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. 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.
2. 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.
3. McClain KL, Kozinetz CA: A phase II trial using thalidomide for Langerhans cell histiocytosis. Pediatr Blood Cancer 48 (1): 44-9, 2007.
4. 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.
5. Kwon OS, Cho KH, Song KY: Primary cutaneous Langerhans cell histiocytosis treated with photochemotherapy. J Dermatol 24 (1): 54-6, 1997.
6. Nauert C, Zornoza J, Ayala A, et al.: Eosinophilic granuloma of bone: diagnosis and management. Skeletal Radiol 10 (4): 227-35, 1983.
7. 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.
8. 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.
9. 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.
10. 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.
11. 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.
12. 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.
13. Nesbit ME, Kieffer S, D'Angio GJ: Reconstitution of vertebral height in histiocytosis X: a long-term follow-up. J Bone Joint Surg Am 51 (7): 1360-8, 1969.
14. Womer RB, Raney RB Jr, D'Angio GJ: Healing rates of treated and untreated bone lesions in histiocytosis X. Pediatrics 76 (2): 286-8, 1985.
15. 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.
16. 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.
17. 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.
18. 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.
19. 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.
20. 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.
21. 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.
22. 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.
23. Minkov M, Grois N, Broadbent V, et al.: Cyclosporine A therapy for multisystem langerhans cell histiocytosis. Med Pediatr Oncol 33 (5): 482-5, 1999.
24. 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.

Treatment of Recurrent, Refractory, or Progressive Childhood Langerhans Cell Histiocytosis

Recurrent Low-Risk Organ Involvement

The optimal therapy for patients with relapsed or recurrent disease has not been determined. Several regimens exist. Patients with recurrent bone disease who reoccur 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 methotrexate weekly and mercaptopurine nightly.[1] An alternative treatment regimen employs vincristine and cytosine arabinoside.[2]

A phase II trial of thalidomide for Langerhans cell histiocytosis (LCH) patients (10 low-risk patients; 6 high-risk patients) who failed primary and at least one secondary regimen demonstrated complete (4 of 10) and partial (3 of 10) responses for the low-risk patients. However, dose-limiting toxicities may limit the overall usefulness of thalidomide.[3]

Refractory High-Risk Organ Involvement

The current Histiocyte Society clinical trial for patients with refractory high-risk organ (liver, spleen or bone marrow) involvement is an intensive acute myeloid leukemia-like protocol. Prompt change of therapy to 2-CdA and/or cytosine arabinoside may provide an improvement in overall survival.[4] This is a very intense regimen and requires that physicians are able to treat infectious and metabolic complications. Responses may be delayed. Hematopoietic stem cell transplantation (HSCT) has been done for patients with multisystem high-risk organ involvement that is refractory to chemotherapy.[5,6,7] HSCT has resulted in a relatively high toxic death rate. The use of reduced-intensity conditioning, especially for patients that have received intensive chemotherapy just prior to HSCT, may reduce toxic deaths and improve outcome.[8]

Progressive Multisystem Langerhans Cell Histiocytosis

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 German-Austrian-Dutch Group studies have shown that these children have only a 10% chance of surviving.[9] Results of 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.[10][Level of evidence: 1iiA] Those treated with vinblastine/prednisone/etoposide with a good response at 6 weeks had a 52% chance of survival. A report about the use of 2-CdA and 2'-deoxycoformycin as salvage therapies for LCH has been published.[11] In this trial, these drugs were more often effective for patients with bone, skin, or lymph node involvement. Only one-third of patients with LCH of the liver, bone marrow, spleen, or lung responded. Another study demonstrated that patients with multiple reactivations or high-risk disease could be effectively treated with continuous infusion 2-CdA for 3 days.[12] Seven of 10 patients on this trial required no more therapy.

References:

1. 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.
2. 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.
3. McClain KL, Kozinetz CA: A phase II trial using thalidomide for Langerhans cell histiocytosis. Pediatr Blood Cancer 48 (1): 44-9, 2007.
4. 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.
5. 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.
6. 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.
7. Caselli D, Aricò M; EBMT Paediatric Working Party.: The role of BMT in childhood histiocytoses. Bone Marrow Transplant 41 (Suppl 2): S8-S13, 2008.
8. 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.
9. 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.
10. 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.
11. 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.
12. 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.

Late Disease and Treatment Effects of Childhood Langerhans Cell Histiocytosis

The reported overall incidence 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.

Children with low-risk organ involvement (skin, bones, lymph nodes or pituitary gland) have an approximately 20% chance of developing long-term sequelae.[2] Those with diabetes insipidus (DI) 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 DI, 43% developed growth hormone (GH) deficiency. [3,4,5] The 5-year and 10-year risks of GH deficiency among children with LCH and DI were 35% and 54%, respectively. There was no increased reactivation of LCH in patients who received GH compared with those who did not.[3]

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.[2,3,4,5]

Hearing loss has been found in 13% of children treated for LCH.[5]

Neurologic symptoms secondary to vertebral compression of cervical lesions have been reported in 3 of 26 LCH patients with spinal lesions.[5] 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 magnetic resonance imaging abnormalities may develop in some long-term survivors with CNS-risk skull lesions.[6] Some patients have markedly abnormal cerebellar function and behavior abnormalities, while others have subtle deficits in short-term memory and brain stem-evoked potentials.[7]

Orthopedic problems from lesions of the spine, femur, tibia, or humerus may be seen in 20% of patients. These problems include vetebral 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 followed with pulmonary function testing, including the diffusing capacity of carbon monoxide and ratio of residual volume to total lung capacity.[8]

Liver disease may lead to sclerosing cholangitis, which rarely responds to any treatment other than liver transplant.[9]

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

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.[10,11] 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, for which the two disorders had shared markers of clonality, have been reported.[12,13] One study reported two cases in which clonality with the same T-cell receptor gamma genotype was found.[12] 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.[13]

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.

Follow Up for Childhood Langerhans Cell Histiocytosis Survivors

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 Curesearch Website.

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. 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.
3. 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.
4. Komp DM: Long-term sequelae of histiocytosis X. Am J Pediatr Hematol Oncol 3 (2): 163-8, 1981.
5. 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.
6. 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.
7. 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.
8. Bernstrand C, Cederlund K, Henter JI: Pulmonary function testing and pulmonary Langerhans cell histiocytosis. Pediatr Blood Cancer 49 (3): 323-8, 2007.
9. 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.
10. Egeler RM, Neglia JP, Puccetti DM, et al.: Association of Langerhans cell histiocytosis with malignant neoplasms. Cancer 71 (3): 865-73, 1993.
11. 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.
12. 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.
13. 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 Langerhans Cell Histiocytosis

General Information

Incidence

It is estimated that one to two adult cases of Langerhans cell histiocytosis (LCH) occur per million population.[1] The true incidence of this disease is impossible to know because large published studies usually are from referral centers and the disorder often is under-diagnosed. A survey from Germany reported that 66% of the LCH patients were women with an average age of 43.5 years for all patients.[2]

Presentation of Adult Langerhans Cell Histiocytosis by Organ, Site or System

Adult LCH patients may have symptoms and signs for many months before a definitive diagnosis and treatment. LCH in adults is often similar to that in children, except that adult pulmonary LCH is closely associated with smoking. Adult pulmonary LCH has some unique biologic charcteristics.

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. Among 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 (DI) should be carefully observed for onset of other symptoms or signs characteristic of LCH. At least 80% of patients with DI had involvement of other organ systems: bone (68%), skin (57%), lung (39%), and lymph nodes (18%).[3]

Skin and oral mucosa

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. In the mouth, swollen gums or ulcers along the cheeks, roof of the mouth or tongue may be signs of LCH.

Bones

The relative frequency of bone involvement in adults differs from that in children: mandible (30% vs. 7%) and skull (21% vs. 40%).[1,2,3,4] The frequency in adults of vertebrae (13%), pelvis (13%), extremities (17%), and rib (6%) lesions are similar to those found in children.[1]

Lung

Pulmonary LCH is slightly more prevalent in smokers than in nonsmokers and the male/female ratio may be near unity depending on the incidence of smoking in the population studied.[5,6] Patients with pulmonary LCH usually present with cough, dyspnea, or chest pain, although nearly 20% of adults with lung involvement have no symptoms.[7,8] The presence of chest pain may indicate the presence of a spontaneous pneumothorax. The Langerhans cells (LCs) in adult lung lesions were shown to be mature dendritic cells expressing high levels of the accessory molecules CD80 and CD86, unlike LCs found in other lung disorders.[8] In addition, pulmonary LCH in adults appears to be primarily a reactive process, rather than a clonal proliferation as seen in childhood LCH.[9]

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.[10,11] A high-resolution computed tomography (CT) scan, which reveals cysts and nodules, usually in the upper lobes, are characteristic of LCH (see the Pulmonary Langerhans cell histiocytosis section on Computed tomography). Despite the typical CT findings, most pulmonologists agree that a lung biopsy is needed to confirm the diagnosis.[12] The presence of cystic abnormalities on high-resolution CT scans appears to be a poor predictor of which patients will have progressive disease.[13]

Multisystem disease

Adults with LCH can have multisystem disease including bone (18%), skin (13%), and DI (5%) in those with pulmonary disease.

References:

1. Baumgartner I, von Hochstetter A, Baumert B, et al.: Langerhans'-cell histiocytosis in adults. Med Pediatr Oncol 28 (1): 9-14, 1997.
2. Götz G, Fichter J: Langerhans'-cell histiocytosis in 58 adults. Eur J Med Res 9 (11): 510-4, 2004.
3. 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.
4. Slater JM, Swarm OJ: Eosinophilic granuloma of bone. Med Pediatr Oncol 8 (2): 151-64, 1980.
5. 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.
6. 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.
7. 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.
8. 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.
9. 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.
10. 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.
11. 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.
12. 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.
13. 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.

Treatment of Adult Langerhans Cell Histiocytosis

Standard Treatment Options

Most investigators would recommend treatment according to the guidelines given above for standard treatment of children with Langerhans cell histiocytosis (LCH). Extensive or mutilating surgery to remove teeth or jaw bones is not indicated. Systemic chemotherapy will cause bone lesions to regress and the involved teeth and jaw bones can reform. Thalidomide and oral methotrexate have been effective in adults with skin disease.[1,2]

Results from LCH studies in children show that the rate of recurrent disease is appreciably reduced when adult patients receive 6 months of treatment with vinblastine and prednisone as opposed to single-agent treatment or attempts to irradiate multiple bone lesions.[3]

Anecdotal reports have described the successful use of the bisphosphonate pamidronate in controlling severe bone pain in patients with multiple osteolytic lesions.[4,5,6]

Another approach using anti-inflammatory agents (pioglitazone and rofecoxib) coupled with trofosfamide in a specific timed sequence was successful in two patients with disease resistant to standard chemotherapy treatment.[7]

Treatment Options Under Clinical Evaluation

There have been no published clinical trial results for adult LCH patients.

  • The LCH-A1 trial for adult patients using vinblastine and prednisone with mercaptopurine is open for accrual. It should be noted that early toxicity data has shown that neuropathy secondary to vinblastine is frequent, so the protocol is in the process of being amended. For patients who do not respond to this front-line therapy, cladribine is effective for adults with skin, bone, lymph node, and probably pulmonary and central nervous system disease.[8,9,10]
    • Special considerations on the LCH-A1 trial for adult LCH patients with lung disease and who smoke cigarettes: Steroid efficacy for treating adult LCH is controversial because past case series reports on LCH patients with pulmonary disease 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.[11] In the LCH-A1 trial, patients are first offered a smoking cessation program and observation. If the smoking cessation program does not work, steroid treatment is started. Treatment of progressive disease after 6 months of steroids is up to the investigator's choice, but usually includes vinblastine and mercaptopurine or 2-chlorodeoxyadenosine.
  • Lung transplant may be necessary for adults with extensive pulmonary destruction from LCH.[12] A multicenter study documented a 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.

For more information about LCH trials for adults, see the Histiocyte Society Website

References:

1. McClain KL, Kozinetz CA: A phase II trial using thalidomide for Langerhans cell histiocytosis. Pediatr Blood Cancer 48 (1): 44-9, 2007.
2. 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.
3. 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.
4. 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.
5. Farran RP, Zaretski E, Egeler RM: Treatment of Langerhans cell histiocytosis with pamidronate. J Pediatr Hematol Oncol 23 (1): 54-6, 2001.
6. Brown RE: Bisphosphonates as antialveolar macrophage therapy in pulmonary langerhans cell histiocytosis? Med Pediatr Oncol 36 (6): 641-3, 2001.
7. 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.
8. Saven A, Foon KA, Piro LD: 2-Chlorodeoxyadenosine-induced complete remissions in Langerhans-cell histiocytosis. Ann Intern Med 121 (6): 430-2, 1994.
9. 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.
10. Pardanani A, Phyliky RL, Li CY, et al.: 2-Chlorodeoxyadenosine therapy for disseminated Langerhans cell histiocytosis. Mayo Clin Proc 78 (3): 301-6, 2003.
11. Mogulkoc N, Veral A, Bishop PW, et al.: Pulmonary Langerhans' cell histiocytosis: radiologic resolution following smoking cessation. Chest 115 (5): 1452-5, 1999.
12. Dauriat G, Mal H, Thabut G, et al.: Lung transplantation for pulmonary langerhans' cell histiocytosis: a multicenter analysis. Transplantation 81 (5): 746-50, 2006.

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