Microscopic thymoma: histological evidence of multifocal cortical and medullary origin

Twenty cases of macroscopically non-neoplastic thymuses obtained from patients with myasthenia gravis have been studied histologically. Seven cases were characterized by lymphoid follicular hyperplasia and 13 by involutional changes of variable degree. In three cases (15%), one with lymphoid follicular hyperplasia and two with involutional changes, multiple microscopic epithelial lesions, 0.2-0.4 mm in diameter and consistent with foci of microscopic thymoma, were observed. Most of them were related to the thymic cortex and one, displaying a different histological pattern, was located in a medullary area. These observations provide morphological evidence of a possible multifocal origin of thymoma from distinct epithelial clones present in the different topographic areas of the human thymus.     

Expression of metallothionein in lung carcinoma: correlation with histological type and grade

AIMS: Over-expression of cellular metallothionein occurs frequently in human tumours but the underlying mechanism remains unknown. The aim of this study was to assess metallothionein expression in cases of lung carcinoma and to correlate it with histopathological parameters. METHODS AND RESULTS: Tumour tissue samples from 89 patients with lung carcinoma were immunostained by the streptavidin-biotin-peroxidase technique, using a monoclonal antibody against both metallothionein-1 and -2 isoforms. Positive matallothionein immunostaining was prominent in 44 out of 89 (49%) and negative in 45 out of 89 (51%) cases of lung carcinoma examined. Metallothionein positivity was prominent in 32 out of 43 (74%) cases of squamous cell lung carcinoma, and in 12 out of 35 (34%) cases of adenocarcinoma, while it was negative in all 11 cases of small-cell lung carcinoma examined, presenting a statistically significant difference between the different histological types. The intensity of metallothionein staining revealed a statistically significant difference between the squamous cell and adenocarcinoma cases examined. The pattern and extent of metallothionein staining in tumour cells and the expression of metallothionein in stromal cells were not correlated with histopathological parameters (type and grade) in metallothionein-positive cases of lung carcinoma examined. No association was found between metallothionein expression and lymph node status in the examined cases of lung carcinoma. CONCLUSIONS: Our findings indicate that expression of metallothionein was evident in squamous cell lung carcinoma and adenocarcinoma, but absent in small-cell lung carcinoma, supporting evidence for participation of this protein in the biological mechanisms underlying the carcinogenic evolution in the lung.     

Fine‐needle aspiration cytology of type A thymoma with adenoid cystic pattern: A case report with emphasis on peculiar hyaline globules in cytologic smear

Here we report a case of type A thymoma with adenoid cystic pattern, which extended to the lower anterior neck and clinically mimicked a nontoxic thyroid goiter. The cytologic smears of fine‐needle aspiration showed cohesive fragments of short spindle cells with finely granular chromatin and inconspicuous nucleoli. Scant interspersed lymphocytes were present. On air‐dried Liu stained preparation, there were many magenta‐colored hyaline globules wrapped by spindle tumor cells. The cytomorphologic findings correlated with the adenoid cystic pattern in histology. The cytologic differential diagnosis and the prognostic aspects of type A thymoma were briefly discussed. Diagn. Cytopathol. 2015;43:247–250. © 2014 Wiley Periodicals, Inc.     

Immunohistochemical metallothionein expression in colorectal adenocarcinoma: correlation with tumour stage and patient survival

Metallothioneins (MTs), a set of ubiquitous low-molecular-weight proteins essential for the protection of cells against heavy metal ion toxicity, were demonstrated immunohistochemically using a monoclonal antibody (E9) against a conserved epitope of I and II isoforms in a series of 109 colorectal adenocarcinomas. In a semiquantitative analysis strong MT expression in the majority of tumour cells was observed in 34 (31%) cases, 24 (22%) tumours showed a focal MT positivity, and 51 (47%) almost completely lacked MT expression. These differences in MT expression were statistically significantly (P<0.05) associated with the tumour stage (Dukes classification) and the lymph node involvement at the time of operation (pN stages). However, in contrast to previous findings obtained on a variety of tumours, MT positivity was associated with a favourable clinical outcome in colonic carcinoma, which may indicate their different biological behaviour. Survival curves of cases with MT-positive and MT-negative status differed from each other in a univariate analysis (Mantel-Haenszel: 8.9, P<0.05) but lost significance when a multivariate analysis was carried out by means of the Cox proportional regression model with Dukes' stages as a stratification factor. It is concluded that immunohistochemically demonstrated MT expression is significantly associated with tumour stages but does not represent an independent prognostic variable in colorectal cancer. However, it may provide important information about some of the biological mechanisms underlying progression in colorectal cancer.     

Immunohistochemical expression of metallothionein in normal human colorectal mucosa, in adenomas and in adenocarcinomas and their associated metastases

The immunohistochemial distribution pattern of metallothionein, a low molecular weight protein with strong affinity for divalent heavy metal ions, has been investigated in normal and neoplastic conditions of the large bowel. Utilizing a monoclonal mouse antibody the following formalin-fixed paraffin-embedded surgical or biopsy samples were studied: tubulo-villous adenomas (8 cases); adenocarcinomas with various degree of differentiation (85), nine of which were mucinous-type; synchronous tubular or tubulo-villous adenomas separate from carcinomas (30); transitional mucosa (45); metastases in lymph nodes (43); and distant metastases (45). Twenty biopsies from the right and left colon of 10 patients affected by irritable bowel syndrome were also analyzed. Normal colonic mucosa as well as transitional mucosa showed metallothionein immunopositivity in enterocytes at the luminal surface and crypts. Evident nuclear and cytoplasmic staining was encountered in tubulo-villous adenomas; the same reactivity was noted in the basal glandular component of colorectal carcinomas-synchronous adenomas, while less intense staining was noted in the apical villous portions. A variable metallothionein immunostaining was observed in adenocarcinomas (62.3%), in lymph node (55.8%) and distant hepatic (17.2%) and omental (43.8%) metastases, although it was not always concordant with that reported in the corresponding primary tumour. Whether the metallothionein positivity observed in normal and neoplastic cells is the result of expression of a stable form of the protein or an accumulation in the nucleus and cytoplasm remains to be clarified.     

Micronodular thymoma: an epithelial tumour with abnormal chemokine expression setting the stage for lymphoma development

The aetiology of primary B-cell lymphomas of the thymus is enigmatic. Although thymic follicular lymphoid hyperplasia (TFH) is commonly associated with myasthenia gravis (MG), lymphoma is not a complication of this condition. The present paper reports a high frequency of monoclonal B-cell populations (6 of 18 cases; 33%) in micronodular thymoma (MNT), a peculiar thymic epithelial neoplasm with a B-cell-rich stroma, while B cells were consistently polyclonal in TFH (25 cases) and other types of thymomas (15 cases) (p < 0.001). An intratumoural lymphoma could be identified in three of the six monoclonal MNTs. Sequencing of the monoclonal IgH chain revealed partially overlapping VDJ gene usage in MNT and thymic mucosa-associated lymphoid tissue (MALT) lymphomas. The neoplastic epithelium of MNTs, but not of TFH and other types of thymoma, expressed high levels of dendritic cell, T-cell, and B-cell chemoattractants, such as CCL18, CCR6, and CCL20. It is concluded that abnormal chemokine expression in an epithelial tumour, MNT, can promote the recruitment of MALT, the emergence of monoclonal B cells, and, eventually, the subsequent development of mediastinal lymphomas. More generally, the concept that expression of a 'high-risk' spectrum of chemokines due to local or genetic factors may interfere with B-cell homeostasis and may contribute to MALT lymphoma development in chronic inflammatory states is proposed.     

Pigmented spindle cell carcinoid tumour of the thymus with ectopic adrenocorticotropic hormone secretion: report of a rare variant and differential diagnosis of mediastinal spindle cell neoplasms

AIMS: A variety of histological variants of thymic carcinoid tumour have been described. A rare case of pigmented spindle cell carcinoid tumour of the thymus is documented and compared with the reported cases of thymic pigmented carcinoid tumour in the literature, with a discussion of the differential diagnosis of spindle cell tumours of the mediastinum. METHODS AND RESULTS: A thymic tumour with ectopic adrenocorticotropic hormone (ACTH) secretion was resected from a 24-year-old man suffering from Cushing's syndrome. Histological, immunohistochemical, and ultrastructural studies revealed an ACTH-producing spindle cell carcinoid tumour harbouring pigmented melanocytes. Among four thymic pigmented carcinoid tumours reported before, only one was similar to the present case by being also an ACTH-secreting pigmented spindle cell thymic carcinoid tumour. The clinicopathological features of this tumour distinguish it from a spindle cell thymoma, spindle cell thymic carcinoma, and other mediastinal spindle cell tumours. CONCLUSIONS: This case illustrates an extremely rare variant of thymic carcinoid tumour exhibiting a spindle cell morphology and harbouring pigmented melanocytes. Awareness of this histological variant is important in the differential diagnosis of spindle cell tumours of the mediastinum.     

Immunohistochemical localization of metallothionein and p53 protein in pancreatic serous cystadenomas

Introduction  The objective of this study was to determine the expression levels of metallothionein (MT) and p53 protein, recognized neoplastic transformation markers, in pancreatic serous cystadenomas (SCA) and adenomocarcinomas. Materials and Methods  Neoplastic pancreatic tissue was taken from 20 patients with diagnosed benign (SCA: 5 cases) or malignant tumors (adenomocarcinomas: 15 cases) and control pancreatic tissue from healthy persons who had died in car accidents. Sections were stained with hematoxylin-eosin. Immunohistochemical localization of MT and p53 protein was carried out by LSAB2-HRP using specific antibodies against MT and p53. Results  Metallothionein expression was observed only in the epithelial cells of the neoplastic tissue of SCAs. MT expression in the cystadenomas was weaker than in the healthy pancreatic tissue. No tissue was found with p53 protein expression. In the adenomocarcinomas, positive staining for MT was observed in 67% and p53 was positive in the carcinoma cells. Conclusion  The weak MT expression and lack of p53 protein expression in pancreatic SCAs confirms the lack of local invasive potential of the neoplastic lesion. Increased expressions of MT and p53 were observed in the less differentiated tumors. Thus the expression of MT may be a potential prognostic marker for tumors.     

Ectopic hamartomatous thymoma: a case report with immunohistochemical and ultrastructural studies

A case of ectopic hamartomatous thymoma (EHT) arising in the supraclavicular region of a 52-year-old male is presented. The well-defined tumor measuring 1.7x1.5x0.7 cm consisted of three components: spindle cell (70%), epithelial (25%), and adipose (5%). The spindle cell component was characterized by sheet-like, haphazard and short fascicular arrangements of bland spindle cells. Neither mitotic figures nor cellular pleomorphism were found. Admixed with, and adjacent to, the spindle cell areas was an obviously epithelial component of variable appearance, ranging from glandular spaces lined by mainly cuboidal clear cells, irregularly anastomosing cords, and strands of epithelial cells to irregular solid nests of squamous epithelium with dark and clear cytoplasm. Myoepithelial cells were also observed. Immunohistochemically, the spindle cells were strongly and diffusely positive for cytokeratins and some of them were positive for BRST2, alpha-smooth muscle actin, and CD10. The tumor was negative for S-100 protein, glial fibrillary acidic protein, and CD34. Ultrastructurally, tonofilaments and desmosomes were observed in the spindle cells. The findings indicate an epithelial origin. The patient was well without recurrence or metastasis 8 months after excision. Pathologists and clinicians should be aware of the existence of ectopic hamartomatous thymoma in the supraclavicular or suprasternal region and should differentiate it from a high-grade sarcoma, such as biphasic synovial sarcoma or glandular malignant peripheral nerve sheath tumor.     

LncRNA XLOC_003810 promotes T cell activation and inhibits PD-1/PD-L1 expression in patients with myasthenia gravis-related thymoma

This study aimed to investigate the effect of long non-coding RNA XLOC_003810 on the activation of CD4⁺ T cells and expression of PD-1/PD-L1 in patients with myasthenia gravis-related thymoma (MG-T). Thymus specimens and thymic mononuclear cells were obtained from MG and MG-T patients or cardiac surgery patients undergoing thoracotomy who were selected as negative controls (NC). XLOC_003810 expression was examined using quantitative real-time PCR (qRT-PCR). Frequency of CD4⁺ T cells and proportion of CD4⁺PD-1⁺ T cells and CD14⁺PD-L1⁺ monocytes were quantified by flow cytometry. The release of inflammatory cytokines was measured by qRT-PCR and enzyme-linked immunosorbent assay. Compared with the NC group, expression of XLOC_003810, frequency of CD4⁺ T cells and the production of inflammatory cytokines were increased in patients with MG and MG-T. XLOC_003810 overexpression significantly increased the frequency of CD4⁺ T cells, facilitated the production of inflammatory cytokines and decreased the proportion of CD4⁺PD-1⁺ T cells and CD14⁺PD-L1⁺ monocytes in the thymic mononuclear cells. In contrast, XLOC_003810 knockdown exerted the opposite effect. Together, XLOC_003810 promotes T cell activation and inhibits PD-1/PD-L1 pathway in patients with MG-T.     

Impaired expression of MHC class II molecules in response to interferon-gamma (IFN-γ) on human thymoma neoplastic epithelial cells

A human thymoma is a neoplasm derived from the thymic epithelial cell, and is well known for its association with autoimmune diseases, especially myasthenia gravis. The neoplastic epithelial cells of thymoma clearly retain thymic epithelial functions, but the development of T cells in thymoma is somewhat impaired. In this study, we quantified by flow cytometry the in vitro expression of MHC molecules on neoplastic epithelial cells precultured with IFN-γ. While MHC class I expression was comparable with that on normal thymic epithelial cells, the level of MHC class II molecules on neoplastic epithelial cells was lower than in controls, and also varied greatly from case to case. Additionally, there was a significant positive correlation between the expression level of MHC class II and the proportion of mature CD3⁺ cells in the CD4⁺CD8^? subset. Thus, accumulation of CD3^?CD4⁺CD8^? cells in thymoma may result from impaired expression of the MHC class II molecules, suggesting that the function of the neoplastic epithelial cells might determine the maturation and the positively selected repertoire of T cells in thymomas.     

cyclinD1、p16、Rb在胸腺瘤中表达及预后意义

目的：探讨ｃｙｃｌｉｎ Ｄ１、ｐ１６、Ｒｂ蛋白在胸腺瘤中表达及预后意义。方法；应用免疫组化Ｓ－Ｐ法，对５４例胸腺瘤标本进行检测。结果：ｃｙｃｌｉｎＤ１、ｐ１６，Ｒｂ蛋白在髓质型，混合型胸腺瘤中阳性表达率分别为２３．１％（３／１３）、６９．２％（９／１３），５３．９％（７／１３），器官样，普通皮质型胸腺瘤中阳性表达率分别为５０．０％（８／１６）、７５．０％（１２／１６）、７５．０％（１２／１６），高     

Over‐expression of metallothionein predicts chemoresistance in breast cancer

Metallothionein (MT) plays a role in fundamental cellular processes such as proliferation, apoptosis and differentiation. We examined MT expression in women with invasive breast ductal carcinoma who underwent mastectomy/lumpectomy without neo‐adjuvant treatment. We showed that MT was over‐expressed in 87.9% of breast cancer tissues examined, with the mean percentage of positive cells at 30%. There were two patterns of MT expression: predominantly cytoplasmic in 75.9% and nuclear in 24.1% of MT‐positive cases. Higher MT scores were associated with poorer histological grade (p = 0.009) but were independent of age, tumour size and oestrogen receptor status. For patients who were treated with adjuvant chemotherapy (cyclophosphamide/methotrexate/5 fluorouracil‐ or doxorubicin‐based regimes), those with high MT expression had a significantly lower recurrence‐free survival (p = 0.048), suggesting a role of MT in predicting disease recurrence. Down‐regulation of MT in MCF‐7 cells by silencing the MT‐2A gene (the most abundantly expressed of the 10 known functional MT isoforms) increased chemosensitivity of the cells to doxorubicin. To examine the mechanisms underlying these clinical data, we used siRNAs to decrease MT‐2A mRNA expression and protein expression. In MT down‐regulated cells challenged with the IC₅₀ concentration of doxorubicin, we observed a significant reduction in cell viability. Cell cycle analysis also revealed a corresponding increase in apoptosis in the MT down‐regulated cells following doxorubicin exposure, showing that down‐regulation of MT increased susceptibility to doxorubicin cytotoxicity. The data suggest that MT could be a potential marker of chemoresistance and a molecular therapeutic target. Copyright © 2009 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

Immunohistochemical expression of metallothionein in benign premalignant and malignant epithelium of the larynx: correlation with p53 and proliferative cell nuclear antigen

In this study we evaluated the immunohistochemical expression of metallothionein (MT) in 44 squamous cell carcinomas, 14 cases of in situ carcinoma, 47 with epithelial dysplasia, 11 papillomas and 21 cases of keratosis. The MT expression was studied in correlation with p53 protein expression and the proliferative cell nuclear antigen (PCNA). The monoclonal antibodies E9 (anti-MT), DO-7 (which reacts with a denaturation-resistant epitope in wild-type and mutant p53) and PC10 (anti-PCNA) on formalin-fixed, paraffin-embedded tissue were used employing the immunoperoxidase (ABC) method. The immunohistochemical localization of MT has shown its rather ubiquitous presence in the cytoplasm and nucleus of both benign and malignant epithelial cells. In most cases the adjacent "normal" epithelium showed low positivity in the basal portion. The mean value of metallothionein expression was 35.73 in squamous cell carcinomas, 32.21 in in situ carcinomas, 11.86 in dysplastic epithelium, 5.10 in papillomas and 3.5 in keratosis. In carcinomas, low MT expression (< 10% of neoplastic cells) was observed in 20.5% of the cases, moderate (10%-50% of neoplastic cells) in 54.5% and extensive expression (> 50% of neoplastic cells) in 25% of the cases. We did not find any statistically significant difference of MT expression between in situ and infiltrating carcinomas, while we did observe a significant difference between carcinomas and the other groups. There was a statistically significant difference in the PCNA values in both benign and malignant lesions, while no statistically significant difference was observed in p53 protein expression in the above groups. A positive correlation between MT expression and the PCNA value (p < 0.0001) in the benign and malignant groups was detected. The PCNA value was also correlated with the p53 protein expression (p = 0.001). No correlation was found between MT and p53 protein expression. In conclusion, these results suggest that the MT expression may play a role in the development of malignant disease of the larynx, from the early phase of laryngeal carcinogenesis, independently from the p53 expression. It is also possible to contribute to tumour cell growth, as determined by the PCNA score.