Langerhans' cell histiocytosis cells are activated langerhans' cells

Langerhans' cell histiocytosis (LCH) is characterized by the presence of large mononucleated cells, associated with inflammatory cells. The Langerhans' cell (LC) lineage of the mononucleated cells is suggested by the presence of Birbeck granules and the expression of CD1a. We investigated the presence of 14 markers expressed by normal LCs in vitro. Nine skin and one lymph node frozen biopsies of LCH children were analysed by in situ immunohistochemistry. The data were compared with six skin and five lymph node frozen biopsies. LCH cells of the ten samples were positivie for all 14 LC markers. We observed three different groups of markers, according to the respective staining of normal LCs and LCH cells. Group 1 included DR, DQ, CD1a, CD1c, and ICAM-3. Markers of group 1 were present on the majority of both normal LCs and LCH cells. Group 2 included CD1b, CD4, LFA-1, LFA-3, CD32, and CD68. Markers of group 2 were detected on the majority of LCH cells, but only on a fraction of normal LCs. Group 3 included CD11b, CD24, and B7/BB1. Markers of this group were detected on LCH cells, but not on normal LCs. This in situ immunohistochemical study confirms that LCH cells belong to the LC lineage. The different clinical LCH syndromes had the same immunohistochemical staining. The expression of some markers of groups 2 and 3 is known to be related to the activation of LCs in vitro. Our study suggests that LCH cells are activated LCs.     

Langerhans cell histiocytosis in Chinese adults: absence of BRAF mutations and increased FOXP3+ regulatory T cells

Langerhans cell histiocytosis (LCH) is a rare disorder characterized by the proliferation of abnormal Langerhans cells. Previous studies mainly focused on children with LCH. However, there is limited information on the clinical and pathological aspects of LCH in adults. Therefore, this study aimed to investigate the clinical and pathological aspects of LCH in Chinese adults. The results showed that the average age of 18 LCH patients was 35.22 ± 16.57 years old. The ratio of male to female was 3.5:1.14 patients (77.8%) had single-system involvement and 4 patients (22.2%) had multi-system diseases. The skin (38.9%) and lungs (44.4%) were the mainly affected organs. No BRAF mutations were detected in the lesions of 18 cases. The number of FOXP3⁺ Tregs was significantly increased in LCH. In conclusion, clinical features of LCH in adults are distinct from those in children. Adult LCH has a relatively good prognosis and presents as a benign disease. Immune regulation plays an important role in the pathogenesis of adult LCH.     

THE PRESENCE OF CYTOKINES IN LANGERHANS' CELL HISTIOCYTOSIS

Langerhans' cell histiocytosis (LCH) is characterized by an accumulation and/or proliferation of cells with a Langerhans' cell (LC) phenotype. The aetiology and pathogenesis of LCH are unknown; it is suggested that LCH is caused by an immunological dysregulation. Production of cytokines is a central feature of immunological regulation. LCH lesions and normal LCs were studied for the presence of cytokines known to influence the functioning of LCs: IL-1α, IL-1β, IL-4, GM-CSF, IFN-γ, TGF-α, TGF-β, bFGF, and TNF-α. Cytokines were abundantly present within LCH lesions; LCH cells stained for IL-1α, IL-1β, IL-4, GM-CSF, TGF-α, TGF-β, TNF-α, and IFN-γ. Macrophages, lymphocytes, eosinophil granulocytes, and, surprisingly, multinucleated giant cells were also sources of cytokines. These results suggest that cytokines play a prominent role in the pathogenesis of LCH and may explain phenomena that often occur in LCH, such as osteolysis and fibrosis and the recruitment of typical inflammatory infiltrates. The results also suggest that a ‘down-regulatory’ signal is lacking in LCH, resulting in an accumulation and/or proliferation of abnormal LCs.     

Dendritic cells in cutaneous lupus erythematosus: a clue to the pathogenesis of lesions

In view of the critical role of dendritic cells in immune mediated skin diseases, we have investigated the membrane antigen patterns and ultrastructure of cutaneous dendritic cells in eight patients with chronic discoid lupus erythematosus and five with subacute cutaneous lupus erythematosus. In the lesional epidermis, the expression of HLA-DR antigens by epidermal dendritic cells was reduced, as compared with perilesional, clinically normal skin. In addition, only few CD1a+ dendritic cells (Langerhans' cells), along with some CD11c+ and CD14+ cells (presumable precursors of Langerhans' cells), were found in atrophic areas of lesional epidermis. In contrast, the number of Langerhans' cells in non-atrophic areas of lesional epidermis was similar to that in perilesional skin. On electronmicroscopy, epidermal Langerhans' cells appeared depleted of organelles and dendrites and contained tubuloreticular inclusions. In the lesional dermis, both CD1a+ and CD36+ dendritic cells were found, associated with CD4+ and CD8+ T-cells, respectively. Moreover, CD11c+ and CD14+ cells were found around capillaries in the papillary dermis on electronmicroscopy. Indeterminate cells (dendritic cells with features of Langerhans' cell lineage, but apparently without Birbeck granules) and dendritic macrophages were found, associated with lymphocytes and mast cells. No cells with intermediate/transitional features between these two dendritic cell types were found. Conversely, peculiar dendritic cells—with short and blunt dendrites and cytoplasm containing many flat, rough cisternae, moderately well developed Golgi apparatus and no lysosomes—were found in the same location as the CD11c+ and CD14+ cells identified by light microscopy. These findings might be interpreted as follows: 1 the alterations in cytological differentiation and expression of functionally meaningful molecules by epidermal Langerhans' cells in cutaneous lupus erythematosus lesions suggest an impairment of their immunological efficiency; 2 in the lesional dermis of cutaneous lupus erythematosus, a CD4+ T-cell/CD1a+ dendritic cell-based, delayed-type immune response is possibly modulated by a suppressor T-cell circuit in which CD36+ dendritic cells may act as accessory cells; 3 CD11c+ and CD14+ cells with peculiar ultrastructure are possible precursors of both CD1a+ indeterminate cells and CD36+ dermal dendrocytes in the dermis.     

朗格汉斯组织细胞增生症的诊治进展

朗格汉斯组织细胞增生症（LCH）是一种少见的、病因尚不明确的单核-巨噬细胞异常增生性疾病,其临床表现具有多样性,累及多个系统,且发病机制复杂,目前主要认为是炎性髓样肿瘤,治疗上仍以联合化疗为主,随着靶向药物及骨髓移植应用逐渐增多,其并发症及不良反应需进一步解决。对于单系统受累LCH 患者预后较佳,临床报道治愈病例较多。而多系统受累LCH患者预后不佳,病死率高。本文就近年来有关LCH的发病机制、临床表现、诊断与治疗及预后进展进行综述。     

Gastrointestinal involvement in Langerhans cell histiocytosis (histiocytosis X): diagnosis by rectal biopsy

We report two patients with biopsy-proven involvement of the gastrointestinal tract by Langerhans cell histiocytosis (LCH). The two patients were infants with congenital cutaneous lesions and bloody diarrhea beginning at 1 or 2 wk of age. Rectal biopsy specimens showed a mucosal infiltrate of typical Langerhans cells that focally invaded and destroyed the crypt epithelium. Gastrointestinal involvement by LCH is unusual and only rarely has represented a prominent clinical manifestation. In most cases, such involvement has been an indicator of widespread multisystemic disease. Its distinctive morphologic and immunohistochemical features allow LCH to be distinguished from other histiocytic infiltrations found in mucosal biopsy specimens.     

Tyrosine phosphatase SHP-1 is expressed higher in multisystem than in single-system Langerhans cell histiocytosis by immunohistochemistry

Langerhans cell histiocytosis (LCH) is a proliferative disorder of Langerhans cell (LC)-like CD1a-positive cell (LCH cell) with unknown causes. LCH consists of two subtypes: single-system LCH (LCH-SS) with favorable prognosis and multisystem LCH (LCH-MS) with poor prognosis. LCH has been indicated as a neoplastic disorder from monoclonal characteristics of LCH cells. This study aimed to investigate an expression of tyrosine phosphatase SHP-1 in LCH, since its expression levels were variously reported in many tumors, overexpression in ovarian cancers (a candidate oncoprotein), and downregulation by methylation in gastric cancers, prostate cancers, malignant lymphomas, and leukemias (a putative tumor suppressor). By immunohistochemistry (IHC), the SHP-1 expression in LCs and LCH cells was compared in LCH (two subtypes: LCH-SS = 21, LCH-MS = 12), dermatopathic lymphadenopathy (DLA) (n = 9) and normal epidermal LCs (n = 3) near LCH lesion. IHC results were analyzed semiquantitatively using a Photoshop software. The mean intensity score (IS) of DLA, LCH-SS, LCH-MS, and LCs were 47, 100, 139, and 167 (in arbitrary unit), respectively. The IS had significant differences among LCH-SS, LCH-MS, and DLA (p < 0.01). SHP-1 is expressed significantly higher in LCH-MS than in LCH-SS. SHP-1 can be a progression marker of LCH. SHP-1 is also useful for differential diagnosis between LCH in lymph nodes and DLA.     

Isolated Langerhans cell histiocytosis of the sublingual gland in an adult

Langerhans cell histiocytosis (LCH) is a rare disorder characterized by the proliferation of pathologic Langerhans cells. Its clinical presentation is highly variable, that range from single-system, limited disease to severe, multi-organ disease with high mortality. LCH usually affects children and young adults. The most frequent sites for LCH are the bone, skin, lung, pituitary gland, and lymph nodes. Salivary gland involvement by LCH is extremely rare, and only a few cases of LHC involving the parotid glands have been reported in the English literature. To our knowledge, the involvement of the sublingual gland as a part of single or multisystem LCH has not been previously described. Herein we reported the first case of primary LCH of the sublingual gland. A 40-year-old woman presented with a 2-month history of a painless mass on the right sublingual area. Excision of the lesion including the right sublingual gland was performed. Histopathological diagnosis of LCH was rendered. The patient remains free of symptoms 17 months after surgery.     

Up-regulation of human epidermal Langerhans' cell B7-1 and B7-2 co-stimulatory molecules in vivo by solar-simulating irradiation

Ultraviolet (UV) radiation impairs cutaneous immune functions and induces antigen-specific tolerance both locally at the irradiated skin site, as well as at distant skin sites and systemically. It has been postulated that in the local model, altered Langerhans' cells (LC) provide tolerogenic signals, and studies in vitro have indicated that UV radiation may down-regulate the expression of co-stimulatory molecules on the surface of these cells. To examine the effect of UV radiation on LC co-stimulatory molecules in vivo, we irradiated human volunteers with erythematogenic doses of solar-simulating UV radiation (SSR), and analyzed the expression of cell surface markers in dermatome skin samples obtained 1–72 h post-irradiation. For flow cytometric analysis, epidermal cell (EC) suspensions were prepared and double labeled with monoclonal antibodies against CD1a or HLA-DR, and B7-1 (CD80), B7-2 (CD86), ICAM-1 (CD54), ICAM-3 (CD50), LFA-3 (CD58), E-cadherin, or integrin-β₄ (CD104). In unirradiated control skin samples, keratinocytes (KC) expressed high levels of E-cadherin. LC expressed high levels of both E-cadherin and ICAM-3, and low levels of B7-2, LFA-3, ICAM-1, and integrin-β₄. Following SSR, a triphasic reaction pattern was seen: an immediate, down-regulatory phase prevailing 2–6 h post-irradiation, when the number of DR⁺ and CD1a⁺ cells were temporarily reduced; a delayed, up-regulatory phase in which the number of LC was increased and the expression intensities of CD1a, HLA-DR, B7-1, and B7-2 were strongly up-regulated, maximally evident 12–24 h after irradiation, but no more seen at 48 h; and a late phase at 72 h, in which an influx of monocytes and a concomitant rise in DR⁺ cells was recorded. We conclude that to understand real-life cutaneous UV immunology, studies in vitro need to be complemented with studies in vivo. In the case of LC, the effects of erythematogenic UV radiation in vivo on human LC B7 co-stimulatory molecules include an up-regulatory stage.     

CXCR4 expression enhances diffuse large B cell lymphoma dissemination and decreases patient survival

The chemokine receptor CXCR4 has been implicated in the migration and trafficking of malignant B cells in several haematological malignancies. Over‐expression of CXCR4 has been identified in haematological tumours, but data concerning the role of this receptor in diffuse large B cell lymphoma (DLBCL) are lacking. CXCR4 is a marker of poor prognosis in various neoplasms, correlating with metastatic disease and decreased survival of patients. We studied CXCR4 involvement in cell migration in vitro and dissemination in vivo. We also evaluated the prognostic significance of CXCR4 in 94 biopsies of DLBCL patients. We observed that the level of expression of CXCR4 in DLBCL cell lines correlated positively with in vitro migration. Expression of the receptor was also associated with increased engraftment and dissemination, and decreased survival time in NOD/SCID mice. Furthermore, administration of a specific CXCR4 antagonist, AMD3100, decreased dissemination of DLBCL cells in a xenograft mouse model. In addition, we found that CXCR4 expression is an independent prognostic factor for shorter overall survival and progression‐free survival in DLBCL patients. These results show that CXCR4 mediates dissemination of DLBCL cells and define for the first time its value as an independent prognostic marker in DLBCL patients. Copyright © 2014 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd     

Langerhans' cell histiocytosis associated with Hodgkin's disease: a case report.

A patient who developed pulmonary Langerhans'' cell histiocytosis after chemotherapy for nodular sclerosing Hodgkin''s disease is presented. Twenty-one cases of Langerhans'' cell histiocytosis associated with Hodgkin''s disease have been reported in the literature. Such an association seems to be more than fortuitous. The possibilities of a common etiological agent inducing both Hodgkin''s disease and Langerhans'' cell histiocytosis and of a reactive proliferation of Langerhans'' cells after radiotherapy or chemotherapy for Hodgkin''s disease are discussed.     

Identification of the V600D mutation in Exon 15 of the BRAF oncogene in congenital,benign langerhans cell histiocytosis

Langerhans cell histiocytosis (LCH) is a well‐known but rare disease that may occur at any age with markedly variable clinical features: self‐regressive, localized, multiorgan, aggressive, or fatal outcome. Congenital LCH is rare and often clinically benign. While LCH is characterized by a clonal proliferation of Langerhans cells, its etiology is unknown. Although BRAF V600E mutations were recently identified as a recurrent genetic alteration in LCH cases, the clinical significance of this mutation within the heterogeneous spectrum of LCH is also currently unknown. We studied a cutaneous, benign form of congenital LCH that occurred in a newborn male, without recurrence for 8 years. Histopathologically, the skin lesion excised after birth showed the typical cytologic and immunophenotypic features of LCH. Sequencing analysis of Exon 15 of the BRAF gene revealed the V600D mutation, with an allelic abundance of 25–30%, corresponding to the LCH cells being hemizygous for the mutant allele. BRAF V600E‐specific polymerase chain reaction was negative. Our report is the first to identify the rare, variant BRAF V600D mutation in LCH, and provides support for constitutively activated BRAF oncogene‐induced cell senescence as a mechanism of regression in congenital, benign LCH. Further, our clinicopathologic findings provide proof for the first time that the V600D mutation can also occur in the absence of ultraviolet light, and can occur in a clinically benign proliferation, similar to the V600E mutation. Additional clinicopathologic studies in larger numbers of LCH patients may be valuable to ascertain the pathophysiologic role of BRAF mutations in LCH. © 2012 Wiley Periodicals, Inc.     

Reduced expression of the cadherin–catenin complex in oesophageal adenocarcinoma correlates with poor prognosis

The E-cadherin–catenin complex is important for cell–cell adhesion of epithelial cells. Impairment of one or more components of this complex is associated with poor differentiation and increased invasiveness of carcinomas. Oesophageal adenocarcinomas causes early metastases, progress rapidly, and consequently have a poor prognosis. By means of immunohistochemistry, the expression of E-cadherin and alpha- and beta-catenin was studied in 65 oesophageal adenocarcinomas and 15 lymph node metastases. Expression of these proteins was evaluated with respect to clinico-pathological parameters and patient survival. Expression of the proteins was strongly correlated. In carcinomas, reduced expression of E-cadherin, alpha-catenin, and beta-catenin was found in 74, 60, and 72 per cent, respectively. Expression of E-cadherin and alpha-catenin correlated significantly with stage and grade of the carcinomas, whereas expression of beta-catenin correlated only with grade. Reduced expression of all three proteins correlated with shorter patient survival. In contrast to grade, E-cadherin and beta-catenin were significant prognosticators for survival, independent of disease stage. We conclude that in oesophageal adenocarcinomas, decreased expression of E-cadherin, alpha-catenin and beta-catenin are related events. Furthermore, expression of at least E-cadherin and beta-catenin is significantly correlated with poor prognosis. © 1997 John Wiley & Sons, Ltd.     

The influence of clinical features mimicking primary immunodeficiency diseases (mPID) on children with Langerhans cell histiocytosis (LCH) — Four with mPID among 39 LCH children from one referral center during 18-year period

BackgroundRecurrent or refractory infections can be a warning sign of primary immunodeficiency diseases (PID). Such mimicking PID (mPID) can occur in patients with Langerhans cell histiocytosis (LCH). Because some cases with refractory molluscum contagiosum-like lesions and persistent otorrhea are finally diagnosed with LCH, we wondered whether such mPID can occur in LCH children and affect on their prognosis.MethodsWe retrospectively reviewed all children with LCH at our institute from 2001 to 2018. A complete medical review of sex, age, symptoms, treatment course, and outcome comparison was performed.ResultsOf 39 enrolled LCH patients, three had persistent otorrhea and one had refractory molluscum contagiosum-like lesions despite aggressive antibiotic therapy. These four cases with mPID had significantly higher rates of multi-system involvement, recurrence and 5-month more lag time, but no risk organ (liver, spleen and bone marrow) involvement compared to those without mPID, although bone and skin were the most involved in both groups. Overall, the lag-time in multi-system was longer than that in single-system involvement (median 2.5 vs. 1.0 months; p = 0.003). The diagnosis-age of risk organ involvement was younger than those without (median 8 vs. 43 months; p = 0.004). There were no significant differences in diagnosis-age, single/multi-system and risk organ involvement between remission and recurrence groups. All were alive excluding four who were lost to follow-up.ConclusionsThe LCH children with mPID had greater lag time, multi-system involvement, recurrence and more refractory treatment including transplantation despite the ratio of bone and skin lesions equal to those without mPID.     

Langerhans cell histiocytosis

Langerhans cell histiocytosis (LCH) is a rare clonal disorder that consists of single or multiple mass lesions composed of cells with an abnormal Langerhans cell phenotype. Its etiology remains unknown, despite extensive searches for evidence of consistent cytogenetic abnormalities, gene rearrangements, or viral genomes. Similarly, the pathogenesis of the disease is enigmatic, although the altered expression of cytokines and cellular adhesion molecules, important for migration and homing of the activated normal Langerhans cell, may play an important role. The biologic behavior of LCH ranges from spontaneous remission to lethal dissemination, and such behavior cannot be predicted on the basis of histologic features. The presence and degree of organ dysfunction, together with the patient's age at diagnosis, remain the most reliable indicators of prognosis. Treatment of severe, refractory disease continues to be controversial and, in many cases, ineffectual. The revised classification scheme for LCH and related disorders recognizes the uncertain biological potential of LCH and its relation to other processes of dendritic and macrophage origin.     

Langerhans Cell Histiocytosis of the Vulva: An Ultrastructural Study

Langerhans cells histiocytosis (LCH) is a proliferative disorder of Langerhans cells. The lesions are normally characterized by infiltration of eosinophils, neutrophils, lymphocytes, plasma cells, and Langerhans cells. The specific cells of LCH contain Birbeck granules, express the phenotype of Langerhans cells but with markers fixed at an early stage of activation, and are functionally defective in antigen-presenting ability. The disease most often affects children; when it occurs in older patients, anal and groin involvement is quite common and vulvar lesions can be found in older females. The authors report a case of a 64-year-old woman with LCH of the vulva and diabetes insipidus. An immunohistochemical and ultrastructural study of the vulvar lesions showed an infiltrate in which antigenically and morphologically mature Langerhans cells, monocytoid cells, and cells with an intermediate phenotype between monocytes and Langerhans cells were concurrently observed. Although the clinical and histological aspects of LCH are well established, the pathogenetic mechanism of lesions is not yet known. The finding of an infiltrate composed by Langerhans cells and many putative precursors of these cells suggests the hypothesis of an in situ differentiation of Langerhans cells from immature monocytoid precursors.     

CD101 expression by Langerhans cell histiocytosis cells

AIMS: Our objective was to study the expression of a recently identified cell surface molecule, CD101 and in Langerhans cell histiocytosis (LCH) patients as CD101 has been shown to be present on dendritic cells. We wanted to determine if CD101 expression could be helpful for the diagnosis of LCH in conjunction with other markers (CD1a, S100 protein), and could be predictive of the evolution and dissemination of the disease. METHODS AND RESULTS: The expression of CD101 was studied by immunohistochemical technique in 11 cases of Langerhans cell histiocytosis on frozen sections. The expression of CD101 was positive in nine cases, high in six cases and low in three cases. There was no expression in the other two cases. No correlation with the evolution, the localization or the dissemination of the disease could be evidenced. CONCLUSIONS: CD101 is a new phenotypic marker that might be useful in combination with other markers for the diagnosis of LCH. However, as the anti-CD101 antibody works only in frozen sections, its value is limited compared to anti-CD1a antibody.     

Role of multidisciplinary approach in a case of Langerhans cell histiocytosis with initial periodontal manifestations

Introduction: Langerhans cell histiocytosis (LCH) is a rare inflammatory myeloid neoplasia of unknown etiology occurring in both children and adults. This condition is characterized by an abnormal proliferation of Langerhans cells that may virtually affect all sites in the human body. Oral manifestations of LCH could be the first clinical sign of disease and its periodontal localization could be easily mistaken for other more common entities, such as chronic periodontitis, aggressive periodontitis, and necrotizing ulcerative periodontitis. Case presentation: A 32-years old female visited a private dental practice with a chief complaint of sensitivity in the mandibular left first molar. Clinical and radiographic examination revealed deep periodontal pocket, recession, furcation involvement, mobility, severe alveolar bone destruction and a diagnosis of aggressive periodontitis was rendered. Multiple tooth extractions were carried out due to progressive periodontal destruction with impaired healing and development of ulcerative lesions. Multidisciplinary investigation demonstrated that the periodontal involvement was a manifestation of an underlying systemic disease. A biopsy of a bone lesion was therefore performed, revealing the presence of multifocal single system LCH. Conclusion: The identification of periodontal LCH is not trivial given that it may clinically resemble other periodontal disease entities. The dentist can be the first health care personnel to unravel the presence of an underlying systemic LCH.     

Langerhans-Zell-Histiozytose der Leber

We report on the difficult differential diagnosis of liver involvement in disseminated Langerhans' cell histiocytosis (LCH). Three years after treatment of LCH involving the skull and pelvic bones, an 18-year-old girl presented with abdominal pain and cholestatic liver disease. At this time, liver biopsy showed portal infiltrates which were diagnosed as chronic non-suppurative destructive cholangitis. Two years later, she was icteric under progredient hepatic failure. A second liver biopsy revealed biliary fibrosis and granulomatous inflammation with destruction of the portal bile ducts. The morphological changes in both liver biopsies could be identified as LCH by immunohistochemical detection of CD1a and S-100-positive Langerhans' cells. Morphological changes and clinical findings in LCH of the liver may resemble primary sclerosing cholangitis or chronic non-suppurative destructive cholangitis. Therefore, LCH is an important differential diagnosis of chronic destructive cholangitis with cholestatic liver disease, especially in children and young adults. The diagnosis can be verified by S-100 and CD1a immunohistochemistry.