Expression of apoptosis-regulatory proteins in lesions of pulmonary Langerhans cell histiocytosis

AIMS: Pulmonary Langerhans cell histiocytosis (PLCH) is characterized by the presence of lesions containing numerous activated Langerhans cells (LCs). An uncontrolled immune response sustained by activated LCs seems to be involved in the pathogenesis of the disease. The aim of this study was to establish whether disruption of LC apoptosis related to the expression of the Bcl-2 family proteins is implicated in the maintenance of PLCH lesions. METHODS: Six patients with PLCH were evaluated by morphological and immunohistochemical techniques to explore the incidence of apoptosis in pathological LCs and to characterize the expression of Bcl-2-related proteins by these cells. RESULTS: Very few LCs present in PLCH lesions exhibited nuclear apoptotic changes or expressed cleaved caspase-3, whereas they all strongly expressed the anti-apoptotic molecule Bcl-x(L). Interestingly, pulmonary LCs present in intervening lung tissue not involved by the pathological process and known to be immature dendritic cells did not express Bcl-2 family proteins. CONCLUSIONS: These findings suggest that activated LCs present within PLCH lesions are poorly susceptible to apoptosis and, thus, are able to sustain the pathological process by causing continuous local stimulation of T cells. Functional studies are needed, however, to demonstrate that they are actually resistant to programmed cell death.     

Langerhans cell histiocytosis of the stomach with atypical morphological features

We report the unique case of a 52-year-old patient with atypical morphological features of gastric Langerhans cell histiocytosis. The man was admitted because of increasing upper abdominal pain and weight loss. The upper gastrointestinal endoscopy showed a submucous, hemispherical tumor of the stomach wall along the lesser curvature. The tumor was completely removed and the patient was discharged 11 days later. Two months later, he died at home. The cause of death is unknown, because the autopsy was denied by the relatives. Macroscopically, the stomach showed a 4.5 x 2.5 cm large, spherical tumor of the lesser curvature of the corpus, which infiltrated the perigastric omenta and lymph nodes, the distal pancreas and the glissonian liver capsule. The vast majority of neoplastic cells were intensely positive for S-100 and CD1a. Typical Birbeck granules could be identified in almost all cells. Cell nuclei analyzed by flow cytometry showed an aneuploid peak, a feature typically associated with malignant disease.     

累及甲状腺的Langerhans''组织细胞增生症

朗格汉斯细胞增生症是一种较少见的疾病,累及甲状腺者更为罕见。本文报道了2例甲状腺朗格汉斯细胞增生症患者,均经病理证实,主要临床表现为甲状腺肿大,1例表现为继发性甲状腺功能低减,两例患者均伴有肺部和垂体受累。累及甲状腺的朗格汉斯细胞增生症临床症状不典型,无特异的实验室检查指标,临床应注意与慢性淋巴细胞性甲状腺炎、甲状腺良性或恶性肿瘤等鉴别,甲状腺细针穿刺活检有助于诊断。目前有效的治疗包括化疗和局部放疗及手术,化疗是主要治疗手段,多数患者经化疗后可达到临床部分缓解。     

Ultrasonographic features of Langerhans cell histiocytosis of the thyroid

Langerhans cell histiocytosis (LCH) is a rare disease, especially when it involves the thyroid gland. Awareness of ultrasonic features will be helpful for a clinician who should consider this disease in the differential diagnosis from other more common thyroid disorders, especially prior to surgery. Here, we report two patients who have histologically confirmed LCH of the thyroid and summarize the reported cases with ultrasonographic scans from the last 10 years (n=10). Ultrasonograms showed isolated or multiple hypoechoic nodules in unilateral or bilateral thyroid gland. Internal acoustic features of most nodules was heterogeneous (n=5) or hypoechoic (n=2).     

Gene expression analysis of dendritic/Langerhans cells and Langerhans cell histiocytosis

Langerhans cell histiocytosis (LCH) is a neoplastic disorder that results in clonal proliferation of cells with a Langerhans cell (LC) phenotype. The pathogenesis of LCH is still poorly understood. In the present study, serial analysis of gene expression (SAGE) was applied to LCs generated from umbilical cord blood CD34+ progenitor cells to identify LC-specific genes and the expression of these genes in LCH was investigated. Besides the expression of several genes known to be highly expressed in LCs and LCH such as CD1a, LYZ, and CD207, high expression of genes not previously reported to be expressed in LCs, such as GSN, MMP12, CCL17, and CCL22, was also identified. Further analysis of these genes by quantitative RT-PCR revealed high expression of FSCN1 and GSN in all 12 LCH cases analysed; of CD207, MMP12, CCL22, and CD1a in the majority of these cases; and CCL17 in three of the 12 cases. Immunohistochemistry confirmed protein expression in the majority of cases. The expression of MMP12 was most abundant in multi-system LCH, which is the LCH type with the worst prognosis. This suggests that expression of MMP12 may play a role in the progression of LCH. These data reveal new insight into the pathology of LCH and provide new starting points for further investigation of this clonal proliferative disorder.     

Coated Langerhans cell granules in histiocytosis X cells

Histiocytosis X cells (HXC) and epidermal Langerhans cells (LC) are thought to be closely related because they share morphologic features and immunologic markers. One of these common markers, the LC granule, is an acknowledged morphologic criterion for the identification of these cell types, but its function and, thus, significance are as yet unknown. In this study, we report the presence of a fuzzy coat radiating from the cytoplasmic face of the LC granule membrane in HXC. This bristly coat is indistinguishable from that of coated vesicles and pits and, thus, represents a strong morphologic clue to the function of LC granules because coated structures have been shown to be involved in the selective transport of molecules in eukaryotic cells.     

Immunohistochemical study of the abnormal cells in Langerhans cell histiocytosis (Histiocytosis x)

Summary The immunophenotypic properties of the abnormal cells in routine specimens from 16 cases of Langerhans cell histiocytosis (LCH) were examined. In five cases, cryostat sections were also available. The abnormal cells expressed a similar phenotype and were positive for HLA-DR, S-100 protein, peanut agglutinin (PNA), CD1a, CD4 and several macrophage-associated markers, including CD11c, CDw32 and CD68 (the latter detectable in routine sections with antibody KP1). Staining with CD14, CD35 (C3b receptor), and CD11b (C3bi receptor) was negative with the exception of one of the cases in which a proportion of the cells showed faint positivity with CD11b. Staining for pan-T-cell (CD2, CD3, CD5) and panB-cell (CD 19, CD22) antigens was negative in all lesions. It is concluded that LCH expresses a characteristic phenotype with some heterogeneity with regard to macrophage markers and that immunohistochemical methods in cryostat sections and routine specimens form a useful supplement to other techniques for the diagnosis of this condition.     

38例儿童Langerhans细胞组织细胞增生症临床病理观察

目的探讨儿童Langerhans细胞组织细胞增生症(Langerhans cell histiocytosis,LCH)的临床特点、病理形态学及免疫表型特征,并分析其与预后的关系。方法分析38例儿童LCH的临床及病理资料,其中18例做了免疫组化染色。结果在38例儿童LCH中,单发为30例(占78·9%),多发为8例(占21·1%)。病变发生于骨组织34例(占89·5%)(其中1例伴有皮肤病变),发生于皮肤组织3例,发生于淋巴结1例。镜下病变主要由Langerhans细胞及嗜酸性粒细胞组成。免疫组化结果显示Langerhans细胞阳性表达CD1a为100%(13/13),S-100蛋白为88·2%(15/17),vimentin为90·0%(9/10),CD68为81·8%(9/11),Mac387为30·0%(3/10),lysozyme为40·0%(4/10),CK、EMA、CD45均阴性。结论儿童LCH最多发生于骨组织,在病理学上具有特殊的形态学表现以及免疫组化表型。疾病的预后与病理分型及临床分级有关。     

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.     

Nodal Langerhans cell histiocytosis with prominent eosinophilic emperipolesis

Multinucleated giant cells of osteoclastic type are known to occur in nodal and extranodal lesions of Langerhans cell histiocytosis (LCH). These giant cells are thought to be derived from phagocytic histiocytes, which correlate with the degree of necrosis in LCH lesions. Emperipolesis commonly seen in Rosai–Dorfman disease is a distinct phenomenon characterized by intact phagocytosed cells in an intracytoplasmic vacuole protected from proteolytic digestion. We present a case of emperipolesis of inflammatory cells especially of eosinophils by multinucleated giant cells of Langhans type in a lymph node involved by LCH—a finding that has not been described previously in the literature. Diagn. Cytopathol. 2015;43:1000–1002. © 2015 Wiley Periodicals, Inc.     

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.     

High expression of markers of apoptosis in Langerhans cell histiocytosis

AIMS: Langerhans cell histiocytosis is a rare disease with clonal proliferation of dendritic histiocytes, occurring most frequently in infancy and early childhood. In the localized form (single system), the disease is self-limiting, but in the cases of multisystem disease a third of the patients develop organ dysfunction. In these cases the prognosis is poor. Our objective has been to study the immunohistochemical expression of Fas and Fas-ligand (Fas-L) in order to determine whether the level of expression of these proteins could predict the outcome of the disease. We also wanted to determine the number of apoptotic cells to compare with the expression of Fas and Fas-L. METHODS AND RESULTS: We analysed the expression of Fas and Fas-L in 76 infiltrates from 49 paediatric patients with Langerhans cell histiocytosis. We also compared the results with the expression of the tumour suppressor protein p53 and the number of cells in apoptosis detected with TUNEL. Langerhans cell histiocytosis cells showed strong expression of p53 and in some cases co-expression of Fas and Fas-L. The expression of Fas-L was significantly higher in infiltrates from patients with single-system disease. The actual number of pathological Langerhans cells in apoptosis as estimated by TUNEL was low. CONCLUSIONS: The low number of TUNEL-reactive cells can be explained by the rapid turnover of apoptotic cells in the tissue, not leaving the apoptotic cells long enough in the tissue to be detected. The co-expression of Fas and Fas-L in some Langerhans cells can lead to an autocrine apoptotic shortcut, mediating the death of the double-positive cells. Our findings suggest that apoptosis mediated through the Fas/Fas-L pathway may contribute to the spontaneous regression of lesions in single-system disease. A delicate balance between autocrine death and survival of Langerhans cells may have been disturbed in patients with multisystem lesions.     

Langerhans cell histiocytosis of the skull on cytologic squash preparations

We present a case in which a primary cytodiagnosis of Langerhans cell histiocytosis (LCH) of the skull was made using squash preparations. The patient, a 25-year-old male, presented with raised intracranial pressure and decreased visual acuity. Magnetic resonance imaging revealed a large skull lesion with osteolytic features in the left frontal bone. The patient underwent surgical resection by the extended basal frontal epidural approach. The squash preparation smears were cellular and demonstrated a mixed population of small, mature lymphocytes, eosinophils, and a high histiocytes content. The histiocytes occurred as isolated or loosely cohesive and clustered. They possessed abundant cytoplasm with rounded cell shape and had characteristic nuclear features, composed of fine chromatin and delicate nuclear membranes. The cytologic features of these histiocytes were consistent with Langerhans cells (LCs). A final impression of LCH of the skull was rendered. Subsequent histopathology confirmed the diagnosis. LCs reacted with both S-100 protein and CD1a immunohistochemically. The demonstration of Birbeck granules on electron microscopic study was also noted. Whenever squash preparation yields a mixed population of mature lymphocytes, eosinophils, and histiocytes, the cytologists should be aware of and consider LCH as a diagnostic possibility.     

Fine-needle aspiration cytology in a case of isolated involvement of thyroid with Langerhans cell histiocytosis

We present an unusual case of isolated thyroid involvement with Langerhans cell histiocytosis (LCH), diagnosed presumptively by fine-needle aspiration (FNA) cytology and subsequently confirmed by immunohistochemistry in a 13-yr-old boy. The cytologic findings include high cellularity in a hemorrhagic background, the presence of characteristic mononucleated and multinucleated Langerhans cells with prominent nuclear grooves, and abundant foamy cytoplasm in a background of mixed eosinophilic and lymphocytic infiltrate, along with the presence of few focal aggregates of benign thyroid follicular cells. Further diagnostic confirmation was obtained by positive S-100 protein immunohistochemistry of the Langerhans histiocytes on paraffin-embedded sections of open thyroid biopsy of the prominently enlarged left lobe. We present the complete clinicopathologic features of this case, along with ultrasound, computerized axial tomographic, and technetium-99 scan findings. We also discuss possible differential diagnostic consideration in light of a review of the literature and the role of FNA cytologic diagnosis in such a rare yet cytomorphologically characteristic case. Diagn. Cytopathol. 1998;19:33–37. © 1998 Wiley-Liss, Inc.     

Presence of circulating abnormal CD34+ progenitors in adult Langerhans cell histiocytosis.

Langerhans cell histiocytosis (LCH) is related to the proliferation of cells, which are similar to Langerhans cells (LC) but possess many abnormal characteristics. Lesions are widespread and this fact suggests that LCH cells or their precursors are present in the blood of patients. In five adult patients, we have isolated and cultured CD34+ blood progenitors of dendritic cells. We studied their phenotype by flow cytometry and their functional properties in mixed culture with heterologous lymphocytes and with autologous lymphocytes in the presence of tri-nitro-phenyl antigen (TNP). The amount of CD34+ precursors was dramatically higher than controls but a high mortality occurred during the in vitro differentiation. The phenotype of surviving cells was similar to LC phenotype (CD1a+, CD83+, Lag+) but some of them expressed CD2. These cells were able to induce T cell proliferation in mixed culture. They could not initiate primary response to TNP, except in a patient treated with thalidomide. In our hands, these CD34+ cells may be precursors of LCH cells.     

Neonatal Fc receptor induces intravenous immunoglobulin growth suppression in Langerhans cell histiocytosis

The neonatal Fc receptor (FcRn) plays a role in trafficking IgG and albumin and is thought to mediate intravenous immunoglobulin (IVIG) therapy for certain diseases. IVIG can be used for the treatment of human Langerhans cell histiocytosis (LCH); however, the mechanism remains unclear. The expression and function of FcRn protein have not been studied in LCH, though the expression of FcRn messenger RNA (mRNA) have been reported. In this report, we confirmed the expression of FcRn in 26 of 30 pathological cases (86.7%) diagnosed immunohistochemically as LCH. The expression was independent of age, gender, location, multi- or single-system, and the status of BRAFV600E immunostaining. We also confirmed the expression of FcRn mRNA and protein in the human LCH-like cell line, ELD-1. FcRn suppressed albumin consumption and growth of IVIG preparation-treated ELD-1 cells, but not of IVIG preparation-untreated or FcRn-knockdown ELD-1 cells. In addition, FITC-conjugated albumin was taken into Rab11-positive recycle vesicles in mock ELD-1 cells but not in FcRn-knockdown ELD-1 cells. IVIG preparation prolonged this status in mock ELD-1 cells. Therefore, ELD-1 recycled albumin via FcRn and albumin was not used for metabolism. Our results increase our understanding of the molecular mechanism of IVIG treatment of LCH.     

Langerhans cell histiocytosis: an unusual case illustrating the value of immunohistochemistry in diagnosis

The morphological features of Langerhans cell histiocytosis (histiocytosis X) are characteristic but the diagnosis can on occasion be difficult. A case is presented that illustrates the diagnostic value of immunohistochemistry in the differential diagnosis of this condition. The cells of Langerhans cell histiocytosis were found to express CD1, CD4, CD11b and CD11c. They also reacted with EBM11, UCHM1, KB61 and HLA-DR. Occasional cells showed nuclear staining with Ki67, but no other lymphoid antigens were detected. Immunoreactivity of the cells of Langerhans cell histiocytosis with antibodies that recognize antigens present on macrophages provides further evidence for immunological similarities between these cell types.     

Expression of CD56 antigen in Langerhans cell histiocytosis associated with T-lymphoblastic lymphoma in a same lymph node

Association of T-lymphoblastic lymphoma (LBL) and Langerhans cell histiocytosis (LCH) in the same lymph node is very rare. Herein, we report such two cases with expression of CD56 in Langerhans cells. Immunohistochemically, lymphoblasts were positive for anti-polyclonal CD3 antibody, CD34, CD7, CD99, and terminal deoxynucleotidyl transferase. LCH cells were positive for anti-S100 protein, CD1a, CD4, CD56, and CD68. Although those two populations were separated topographically, many histiocytes intermingled with lymphoblasts in the paracortex and a few lymphoblasts were scattered within the intrasinusoidal sheets of histiocytes. Neither admixed eosinophils nor multinucleated giant cells were observed. The pathogenetic mechanism of CD56 expression in LCH associated with LBL is discussed.     

Human cytomegalovirus infection in foci of Langerhans cell histiocytosis

 Langerhans cell histiocytosis (LCH) has been thought to be a disorder of immune regulation, and increasingly, evidence showing that the tissue damage in LCH involves lymphokines and pro-inflammatory cytokines is reported. We detected human cytomegalovirus (HCMV)-DNA in LCH cells in the foci of LCH lesions by immunohistochemistry, in situ hybridization and PCR. HCMV was detected in the nuclei and/or cytoplasm of LCH cells in 9 of 27 LCH cases by immunostaining. HCMV was probably an early antigen. In situ hybridization revealed signals for HCMV-DNA only in the nuclei of LCH cells in 10 of the 27 LCH cases. PCR analysis was performed in 20 of the LCH cases, and HCMV-DNA was detected in 7 of these. All 7 positive cases were also positive for HCMV by ISH and IHC. These findings suggested that early phase infection or reactivation of HCMV occurred in the LCH lesions. HCMV infection may be accompanied by impaired cytokine production. Our study also suggested a relationship between HCMV infection and expression of TNFα. In tissues affected by LCH, dermatopathic lymphadenopathy or malignant fibrous histiocytoma and in normal tissues no signals for Epstein-Barr virus-RNA were detected. These findings suggest that in some cases LCH is associated with HCMV infection. Received: 24 November 1998 / Accepted: 24 April 1998