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Case Reports
. 2015 Jul 2;126(1):26-35.
doi: 10.1182/blood-2014-12-569301. Epub 2015 Mar 31.

How I Treat Langerhans Cell Histiocytosis

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Free PMC article
Case Reports

How I Treat Langerhans Cell Histiocytosis

Carl E Allen et al. Blood. .
Free PMC article

Abstract

"Langerhans cell histiocytosis" (LCH) describes a spectrum of clinical presentations ranging from a single bone lesion or trivial skin rash to an explosive disseminated disease. Regardless of clinical severity, LCH lesions share the common histology of CD1a(+)/CD207(+) dendritic cells with characteristic morphology among an inflammatory infiltrate. Despite historical uncertainty defining LCH as inflammatory vs neoplastic and incomplete understanding of mechanisms of pathogenesis, clinical outcomes have improved markedly over the past decades through cooperative randomized clinical trials based on empiric therapeutic strategies. Significant advances include recognition of high- and low-risk clinical groups defined by hematopoietic and/or hepatic involvement, and of the importance of optimal intensity and of duration of chemotherapy. Nevertheless, mortality of high-risk patients, disease recurrence, lack of robustly tested salvage strategies, and significant disease morbidity of both high- and low-risk patients remain challenges. Recent discovery of recurrent somatic mutations in mitogen-activated protein kinase pathway genes at critical stages of myeloid hematopoietic differentiation in LCH patients supports redefinition of the disease as a myeloproliferative disorder and provides opportunities to develop novel approaches to diagnosis and therapy.

Figures

Figure 1
Figure 1
Histology of LCH lesions. This figure depicts a typical LCH lesion with characteristic histology. Pathologic “histiocytes” with reniform nuclei and eosinophilic cytoplasm are scattered among an infiltrate of lymphocytes, eosinophils, and macrophages. The LCH cells react to immunostains for CD207, CD1a, and S100, but not for fascin or factor XIIIa. This biopsy could be from any child or adult with low- or high-risk LCH. H&E, hematoxylin and eosin. Images courtesy of John Hicks, Baylor College of Medicine.
Figure 2
Figure 2
Recurrent activating MAPK mutations in LCH. Known recurrent mutations in LCH are depicted. The majority of patients have mutually exclusive activating mutations in BRAF (BRAF-V600E) or MAP2K1. Individual cases of mutations in ARAF and ERBB3 have also been reported (*). In 15% to 40% of LCH lesions, no MAPK somatic mutations are identified. However, early series suggest ERK is activated in all cases of LCH. The dashed black line represents mechanisms of ERK activation outside of the MAPK pathway that remain to be defined. “Rx” represents steps in ERK activation that may be therapeutic targets. The red dashed line represents potential to target mechanisms outside of the MAPK pathway (eg, phosphatidylinositol 3-kinase/AKT) that may inhibit ERK activation by alternative pathways. The lightning bolt represents mechanisms downstream of ERK activation, that remain to be defined, that lead to LCH pathogenesis.
Figure 3
Figure 3
Misguided myeloid DC model of LCH pathogenesis. According to this model, the stage of differentiation in which pathologic ERK activation arises determines the clinical manifestations of LCH. In this model, activating mutations in hematopoietic stem cells or undifferentiated myeloid DC precursors result in multifocal high-risk disease, whereas mutations in tissue-restricted precursors results in multifocal low-risk disease, and mutations in more differentiated tissue-restricted precursor cells result in a single lesion. The CD207+ cells in LCH lesions represent differentiated myeloid cells with indistinguishable phenotype regardless of cell of origin that presumably recruit and activate other inflammatory cells.
Figure 4
Figure 4
PET/CT scans are effective to stage disease and to evaluate response to therapy in LCH. Examples of 18-fluoro-deoxyglucose–PET scans with CT identifying response to therapy. (A) A patient with multifocal bone disease with interval improvement of pelvic lesion and decreased PET avidity. (B) A patient with multifocal lymph node disease (cervical, axillary, inguinal) who initially failed to respond to cytarabine therapy, then had significant response to 2 cycles of clofarabine.
Figure 5
Figure 5
LCH bone lesions may remodel if margins remain intact. These cases highlight the potential for even very large bone lesions to remodel following disease resolution. (A) Skull CT scans before and after chemotherapy in a patient with multifocal bone LCH. Remodeling following systemic chemotherapy nearly normalizes bone structure in a patient with significant skull lesions. This patient did not have any curettage or excisional surgery in the skull. (B) Brain MRI in a patient with multifocal bone LCH before and after complete excision with placement of mesh grafts. Complete excision of LCH lesion with margins into healthy bone inhibits potential for remodeling. Following resections and successful chemotherapy, skull defects persist.
Figure 6
Figure 6
Neuroimaging of LCH lesions. These examples demonstrate typical manifestations of LCH CNS and spinal cord lesions. (A) Brain MRI demonstrates T2-hyperintensity in cerebellum classic for LCH neurodegenerative syndrome. In this case, the patient had radiologic and clinical response to treatment with cytarabine. (B) Spinal MRI demonstrates significant spinal cord lesions. This is a somewhat atypical case of a 13-year-old girl who had marginal response to cytarabine, then clofarabine. BRAF-V600E was detected in cells from the CSF, and the patient ultimately had radiologic and clinical response to vemurafenib. (C) Brain MRI demonstrates a pituitary mass classic for LCH, though differential diagnosis also includes germinoma, lymphoma, and pituitary hypophysitis. In this case, the lesion was biopsy proven to be LCH, and the patient responded to cytarabine therapy.
Figure 7
Figure 7
Pulmonary LCH. This high-resolution CT scan demonstrates pulmonary lesions and associated cysts in a 3-year-old girl with high-risk LCH. LCH lesions were cleared from lung parenchyma following cladribine therapy, though some cystic disease was irreversible.

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