The Cytology of Langerhans Cell Histiocytosis (Histiocytosis X)

The cytomorphology of 13 cases of Langerhans cell histiocytosis is described. The most striking features were the presence of intranuclear clefts, pale nuclei and inconspicuous nucleoli, together with ample pale cytoplasm, only slight cellular pleomorphism, and an admixture of varying numbers of eosinophils, macrophages and degenerated cells. In 13 of 16 cases investigated ultrastructurally, characteristic Birbeck granules were detected. Out of six cases tested, four exhibited positivity for S-100, and of three cases tested, all were positive for CD1a (leu 6) and HLA-DR. In one case malignant transformation occurred, terminating in monocytic leukaemia.     

High serum osteopontin levels in pediatric patients with high risk Langerhans cell histiocytosis

Osteopontin (OPN) acts as an osteoclast activator, a proinflammatory cytokine, and a chemokine attracting histiocytes/monocytes and is abundantly expressed in Langerhans cell histiocytosis (LCH). We investigated whether serum OPN levels are related to disease types in LCH. Fifty-eight newly diagnosed LCH patients were studied; eight with risk organ (liver, spleen and/or hematopoietic) involvements positive multisystem (MS+) disease, 27 with risk organ involvement negative multisystem (MS−) disease and 23 with single system (SS) disease. Pediatric patients with non-inflammatory disease (n = 27) were used as controls. All of patients with MS+ disease were younger than 3 years. Serum OPN levels and 44 kinds of humoral factors were measured by ELISA and Bio-Plex suspension array system, respectively. In the patients younger than 3 years, the median serum OPN level (interquartile range) was 240.3 ng/ml (137.6–456.0) in MS+ (n = 8); 92.7 ng/ml (62.0–213.8) in MS− (n = 14) and 72.5 ng/ml (55.6–94.0) in SS (n = 9) and 74.4 ng/ml (42.2–100.0) in control (n = 12). The OPN values were significantly higher in the MS+ group than the MS−, SS and control groups (p = 0.044, p = 0.001 and p = 0.002, respectively), but not different between the MS−, SS and control groups. In the patients older than 3 years, the median level of serum OPN (IQR) was 56.2 ng/ml (22.9–77.5) in MS− (n = 13), 58.9 ng/ml (31.0–78.7) in SS (n = 14) and 41.9 (28.9–54.1) in control (n = 15). These values did not differ significantly between each group. The serum OPN levels were positively correlated with the serum IL-6, CCL2, IL-18, IL-8 and IL-2 receptor concentration. OPN may be involved in risk organ dissemination and poor prognosis of LCH through the function as inflammatory cytokine/chemokine.     

儿童朗格汉斯细胞组织细胞增生症临床研究

目的:探讨观察儿童朗格汉斯细胞组织增生症临床治疗方案和效果。方法:选取我院2007年4月-2014年11月收治的儿童朗格汉斯细胞组织细胞增生症65例,按随机数字表法分为观察组(32例)和对照组(33例)。对照组给予朗格汉斯细胞组织细胞增生症-Ⅲ(LCH-Ⅲ)治疗方案,观察组给予难治性2008方案。观察两组患者临床疗效、复发率、并发症、生存率。结果:观察组完全缓解率显著高于对照组(P0.05),而两组患者的复发率和总有效率之间的差异无统计学意义(P0.05);两组治疗后9个月、12个月、24个月生存率差异无统计学意义(P0.05);观察组不良反应发生率为9.38%,对照组为24.24%,观察组稍低于对照组,但两组差异无统计学意义(P0.05)。结论:采用难治性2008方案治疗儿童朗格汉斯细胞组织细胞增生症较LCH-Ⅲ方案疗效更佳,且远期生存率明显改善,还可减少不良反应,值得在临床治疗中推广应用。     

Langerhans cell sarcoma: Response to radiotherapy

We present the case of a patient with progressive Langerhans cell sarcoma whose cutaneous lesions and nodal masses were treated with palliative radiotherapy. Response to relatively low doses of radiotherapy was both good and sustained. We recommend a dose of 15–30 Gy depending on treatment intention and volume of the lesions.     

A macrophage-monocyte cell line from a dog with malignant histiocytosis

Summary The DH82 cell line was established from the neoplastic progenitor cells of canine MH and was characterized as histiocytic in origin based on light microcopic and ultrastructural morphology, positive staining reactions for alpha naphthyl acetate esterase and acid phosphatase, presence of Fc receptors, phagocytosis of latex beads, and plastic adherence in culture.     

Migration and differentiation of Langerhans cell precursors

Epidermal Langerhans cells (LC) are the first sentinels of the skin immune system. To study immigration of human LC precursor cells into the skin, we established a two-compartmental skin model consisting of a dermal matrix and an epidermal sheet of keratinocytes. We tested the individual components of the skin model for their influence on phenotype and function of LC precursors. A time window at day 5/6 of differentiation was determined, during which in vitro generated LC precursors expressed adhesion molecules and chemokine receptors required for transmigration across endothelial cell layers and the dermis towards the epidermis. They expressed L-selectin, integrins, platelet endothelial cell adhesion molecule-1, E-cadherin and CC-chemokine receptor 6 and were thus fitted out for transendothelial migration and immigration into the dermis. In a transwell system, these LC precursors migrated towards the chemokine MIP3alpha, demonstrating functional integrity of chemokine receptor 6. For the in vitro reconstituted skin, keratinocytes were grown on a de-epidermized dermis for one to three weeks and formed an epidermal sheet. We allowed LC precursor cells to migrate into this two-compartmental model from the dermal side and examined the presence of CD1alpha--positive cells. LC precursors migrated through the dermal matrix towards the layer of keratinocytes representing the epidermis and could be identified by immunohistology. Experiments designed to investigate the influence of signals provided by both the skin components and by the LC precursors on LC immigration into the skin are in progress.     

无创性皮肤屏障功能检测在朗格汉斯细胞组织细胞增生症中的应用

摘要 目的：探讨无创性皮肤屏障功能检测在朗格汉斯细胞组织细胞增生症(Langerhans cell histiocytosis,LCH)中的应用价值。方法：研究时间为2017年1月到2020年12月,选择在本院诊治的朗格汉斯细胞组织细胞增多症患者72例作为LCH组,同期选择健康体检者72例作为对照组。采用无创性皮肤屏障功能检测皮肤水分、经皮水分丢失(Transdermal water loss,TEWL)、油脂水平,同时检测所有入选者的免疫功能、皮肤菌群并进行相关性分析。结果：LCH组的皮肤水分低于对照组(P<0.05),TEWL、油脂水平高于对照组(P<0.05)。LCH组的乳酸杆菌(La)阳性率低于对照组(P<0.05),表皮葡萄球菌(Se)、痤疮丙酸杆菌(Pa)、金黄色葡萄球菌(Sa)阳性率高于对照组(P<0.05)。LCH组的CD163、ki-67表达阳性率分别为77.8 %、52.8 %,高于对照组的19.4 %和6.9 %(P<0.05)。在LCH组中,Pearson相关性分析显示皮肤水分与乳酸杆菌呈现正相关性(P<0.05),TEWL、油脂与表皮葡萄球菌、痤疮丙酸杆菌、金黄色葡萄球菌、CD163、ki-67呈现正相关性(P<0.05)。结论：无创性皮肤屏障功能检测在朗格汉斯细胞组织细胞增生症中的应用可反映患者的皮肤水分与油脂状况,也可间接反映患者的皮肤微生态与免疫功能状况。     

Acute-phase ITIH4 levels distinguish multi-system from single-system Langerhans cell histiocytosis via plasma peptidomics

Background

Langerhans cell histiocytosis (LCH) is a proliferative disorder in which abnormal Langerhans cell (LC)-like cells (LCH cells) intermingle with inflammatory cells. Whether LCH is reactive or neoplastic remains a controversial matter. We recently described Merkel cell polyomavirus (MCPyV) as a possible causative agent of LCH and proposed interleukin-1 loop model: LCH is a reactive disorder with an underlying oncogenic potential and we now propose to test this theory by looking for acute markers of inflammation. We detected MCPyV-DNA in the peripheral blood cells of patients with high-risk organ-type (LCH-risk organ (RO) (+)) but not those with non–high-risk organ-type LCH (LCH-RO (−)); this difference was significant. LCH-RO (−) is further classified by its involvement of either a single organ system (SS-LCH) or multiple organ systems (MS-LCH). In patients with LCH-RO (−), MCPyV-DNA sequences were present in LCH tissues, and significant differences were observed between LCH tissues and control tissues associated with conditions such as dermatopathic lymphadenopathy and reactive lymphoid hyperplasia. Although MCPyV causes subclinical infection in nearly all people and 22 % of healthy adults will harbor MCPyV in their buffy coats, circulating monocytes could serve as MCPyV reservoirs and cause disseminated skin lesions.

Methods

Plasma sample from 12 patients with LCH-RO (−) (5 MS-LCH and 7 SS-LCH) and 5 non-LCH patients were analyzed by peptidomics. Mass spectrometry (MS) spectra were acquired and peptides exhibiting quantitative differences between MS-LCH and SS-LCH patients were targeted.

Results

One new candidate biomarker, m/z 3145 was selected and identified after obtaining a MS/MS fragmentation pattern using liquid chromatography-MS/MS. This peak was identified as a proteolytic fragment derived from inter-alpha-trypsin inhibitor heavy chain 4 (ITIH4, [PDB: {"type":"entrez-protein","attrs":{"text":"Q14624","term_id":"229463048","term_text":"Q14624"}}Q14624]).

Conclusions

Peptidomics of LCH have revealed that the level of acute-phase ITIH4 distinguishes MS-LCH-RO (−) from SS-LCH-RO (−). Acute-phase proteins serve non-specific, physiological immune functions within the innate immune system. LCH may be a reactive disorder with both underlying neoplastic potential of antigen presenting cells harboring BRAF mutations and hyper-immunity of other inflammatory cells against MCPyV infection. Among LCH-RO (−), MCPyV-DNA sequences were present in both MS-LCH tissues and SS-LCH tissues without significant differences. ITIH4 may show that LCH activity or LCH subtypes correlates with the systemic or localized reactions of MCPyV infection.     

1,25 二羟基维生素D3 对兔角膜碱烧伤朗格罕氏细胞影响

目的:研究1,25二羟基维生素D3(骨化三醇)对兔角膜碱烧伤后角膜朗格罕氏细胞分布的影响,并初步探讨其作用机制。方法:在兔角膜制作碱烧伤模型,然后实验组局部和全身给予1,25二羟基维生素D3,分别在第3,7,21天时对正常组,实验组和对照组家兔行角膜共聚焦显微镜,HE染色观察角膜病理改变。结果:正常组角膜中央在三个时间点均未检测出朗格罕氏细胞。实验组和对照组碱烧伤后3、7天角膜中央出现朗格罕氏细胞,对照组密度高于实验组(p<0.05);碱烧伤后21天两组朗格罕氏细胞密度相近(p>0.05)。实验组炎性反应程度在第7,21天时轻于对照组。结论:1,25二羟基维生素D3能够在兔角膜碱烧伤早期抑制朗格罕氏细胞的向心性迁移,并且能在一定程度上抑制炎性反应。     

Langerhans's cell histiocytosis in old subjects: two rare case reports and review of the literature

doi: 10.1111/j.1741‐2358.2012.00629.x Langerhans’s cell histiocytosis in old subjects: two rare case reports and review of the literature Background: Langerhans cell histiocytosis (LCH) is a proliferative disease of histiocyte‐like cells that generally affects children; LCH onset is rare in adults; immunohistochemistry is essential to obtain the correct diagnosis, and treatment protocols are controversial. Objective: To describe two new cases of adult onset oral LCH. Case reports: Case 1: a 71‐year‐old woman, complaining of diffuse oral pain, presented with erythematous mucosal lesions; the panoramic radiograph and CT scan showed multiple mandible radiolucent areas. Immunohistochemical assay for S‐100, CD1a and langerin test was essential in reaching the correct diagnosis. Case 2: a 77‐year‐old female patient presented with a non‐painful, non‐bleeding, slightly elevated erythematous palatal lesion of 6 months duration, together with a genital vulvar lesion of uncertain nature. The pathology confirmed the diagnosis of LCH. Many therapies (etoposid, radiotherapy) could induce only a clinical partial remission; Cladribine induced a complete recovery. Conclusion: The first case was difficult to diagnose: the clinical presentation and course of the disease (LCH) in the elderly are multiple and unpredictable. An immunohistochemistry study is often essential to obtain the correct diagnosis. The second case required several therapeutic interventions: even though some cases regress spontaneously, others require systemic chemotherapy.     

Cytology of primary cutaneous Langerhans cell histiocytosis with a malignant phenotype. A case report

BACKGROUND: Langerhans cell histiocytosis (LCH) is a proliferative disorder of Langerhans cells, but the nature of LCH, whether reactive, benign, or malignant and neoplastic, is controversial. We encountered a case of LCH showing a malignant phenotype initially localized in the skin of an elderly woman. Since there is no other report on the cytologic appearance of primary cutaneous LCH or on LCH with a malignant phenotype, we compared the cytologic features of this case with those of benign cases at other sites reported in the literature. CASE: A 74-year-old woman presented with a gradually enlarging and partially ulcerated skin lesion expanding both sides of her right hand. On histologic and ultrastructural analyses of surgically resected tissue, we diagnosed the lesion as Langerhans cell histiocytosis originating in the skin. Although the patient had no recurrence or metastases for six months after surgical resection of the primary skin lesion and radiation therapy, the tumor extended multisystemically, and the patient died of multiple organ failure 14 months after the initial diagnosis. CONCLUSION: Imprint and scrape cytology of multiple skin lesions six months after surgery was useful in immediately diagnosing the recurrent LCH. The tumor cells had indented, twisted or grooved nuclei, and some had intranuclear inclusions. Immunocytochemically the cells were positive for CD1a and S-100 protein. Numerous eosinophils were seen in the background.     

1,25二羟基维生素D_3对兔角膜碱烧伤朗格罕氏细胞影响

目的：研究1,25二羟基维生素D3（骨化三醇）对兔角膜碱烧伤后角膜朗格罕氏细胞分布的影响,并初步探讨其作用机制。方法：在兔角膜制作碱烧伤模型,然后实验组局部和全身给予1,25二羟基维生素D3,分别在第3,7,21天时对正常组,实验组和对照组家兔行角膜共聚焦显微镜,HE染色观察角膜病理改变。结果：正常组角膜中央在三个时间点均未检测出朗格罕氏细胞。实验组和对照组碱烧伤后3、7天角膜中央出现朗格罕氏细胞,对照组密度高于实验组（p〈0.05）;碱烧伤后21天两组朗格罕氏细胞密度相近（p〉0.05）。实验组炎性反应程度在第7,21天时轻于对照组。结论：1,25二羟基维生素D3能够在兔角膜碱烧伤早期抑制朗格罕氏细胞的向心性迁移,并且能在一定程度上抑制炎性反应。     

Langerhans cells in cutaneous tumours: immunohistochemistry study using a computer image analysis system

Immunohistochemistry, based on antibody anti-S100 protein, was used to evaluate the Langerhans cells (LC) in benign and malign skin neoplasias. These cells were quantitatively estimated using a computer image analysis (OPTIMAS software system, Version 6.1) in skin biopsies diagnosed as basal cell carcinoma (BCC), epidermoid carcinoma (EpC), trichoepithelioma (TE), keratoacanthoma (KA), seborreic keratosis (SK) and actinic keratosis (AK). The antibody anti-S100 protein recognized them. No significant variations were observed in the number of LC among malignant tumour (BCC = 23.25 ± 5.81 and EpC = 20.88 ± 4.24). Benign lesions (AK = 33.04 ± 7.11; TE = 55.74 ± 9.35; SK = 42.38 ± 9.92, and KA = 47.62 ± 10.4) presented a higher number of LC when they were compared among them and to malignant and normal tissues. No significant differences were observed in LC area and volume between benign and malign neoplasias. These results indicate possibly differences in the immunogenicity between benign and malign epidermic tumours. In conclusion, the experimental computer assessment method was reliable and consistent to morphometric analysis of tumoural tissues.     

Nonenzymic in vitro isolation of perinatal islets of Langerhans

Summary We have developed a method to circumvent the use of exogenous proteolytic enzymes in the isolation of islets of Langerhans from the perinatal rodent pancreas. Advantage is taken of the propensity of fibroblastlike cells to attach and migrate on polystyrene at low-serum concentrations (5%). In contrast, at this serum level, rat islet epithelial cells tend not to adhere to the substrate. At 3 d of culture, islets are visible at the edges of the explants. With further fibroblast outgrowth the majority of islets are freefloating by 7 d. Simple agitation of the medium and centrifugation yields approximately 50 μg of islet tissue per perinatal pancreas. Further purification of the islets can be obtained by subculture. Rat islets can be maintained in this manner for several months in Medium F12 supplemented with 25% horse serum in an atmosphere of 5% CO₂ and air at 37° C. Hormone content of the islet tissue remains constant during prolonged subculture and such islets continue to exhibit appropriate insulin and glucagon responses to glucose and theophylline. The morphological integrity of the endocrine cells within the cultured islets was confirmed by immunocytochemistry and ultrastructural study. Nonendocrine cells are not identifiable within the long-term cultured islets. This research was supported in part by Grants AM 19899 and HD 00412 from the National Institutes of Health, Bethesda, MD, and grants from the American Diabetes Association, Minnesota Affiliate. Portions of this work were presented at the Thirty-third Annual Meeting of the Tissue Culture Association, held in San Diego, California, June 6–10, 1982.     

Langerhans cells in the lymph node: mirror section and immunoelectron microscopic studies

Cells immunostained with antibodies against both OKT-6 and S-100 protein were observed only in superficial and hilar lymph nodes draining tissues with predominantly squamous epithelia. In contrast, in mesenteric lymph nodes and the spleen, only S-100 protein-positive, but OKT-6-negative cells were found. We suspect that the S-100 and OKT-6-positive cells might be Langerhans cells (LC) and the S-100-positive, OKT-6-negative cells, interdigitating reticulum cells (IDC). We further postulate that the LC in superficial and hilar lymph nodes might migrate from squamous epithelia, with which contact is required for the formation of Birbeck granules.