Epithelial Thymoma Research Articles

Hematopoietic progenitor cells as possible origins of epithelial thymoma in a human T lymphocyte virus type I pX gene transgenic rat model

We earlier reported that Fischer 344/jcl strain (F344) rats carrying a unique pX gene of human T lymphocyte virus type I (HTLV-I) under control of a rat lymphocyte-specific protein tyrosine kinase (p56lck) type I promoter (lck-pX rats) spontaneously developed epithelial thymomas from the thymic medulla. To investigate the role of bone marrow cells carrying the HTLV-I pX gene in development of thymomas, the bone marrow of normal F344 rats after lethal irradiation was reconstituted by bone marrow mononuclear cells (BMMC) of lck-pX rats. Epithelial thymomas similar to the original thymoma of lck-pX rats frequently developed in the nontransgenic recipients within 5 months after the BMMC transplantation. The thymomas expressed the pX gene, thereby indicating the thymoma cells to be of donor BMMC origin. Since the thymoma also developed in nontransgenic recipients reconstituted by BMMC depleted of adherent cells, it is suggested that nonadherent BMMC of donor lck-pX rats may migrate to and lodge in the thymus of recipient nontransgenic rats then transform into thymoma cells with epithelial characteristics. The thymoma cells were shown to bind to Ulex europaeus Agglutinin-1 (UEA-1) lectin, which binds epithelial cells in the thymic medulla. It was also shown that the nonadherent BMMC fraction used for bone marrow reconstitution contained a number of UEA-1-positive cells. Taken together, UEA-1 positive BMMC may be progenitor cells of the epithelial thymoma. The epithelial thymoma in lck-pX rats sheds light on epithelial cell development in thymic medulla and for oncogenesis of epithelial thymoma in humans.

High Incidence of Thymic Epithelial Tumors in E2F2 Transgenic Mice

In virtually all human tumors, genetic and epigenetic alterations have been found which affect the INK4/-CYCLIN D/RB pathway, which regulates cell cycle entry and exit in normal cells. E2F transcription factors are important downstream components of this pathway, which act by controlling the expression of genes involved in DNA replication and cell cycle progression. To determine whether E2F2 deregulation promotes proliferation and tumorigenesis in vivo, we generated E2F2 transgenic mice, in which the Emu and murine pim1 promoter (pp) direct high expression of E2F2 in thymic epithelial cells. Emu-pp-E2F2 mice start to develop cytokeratin- and ER-TR4-positive cortical thymomas from the age of 20 weeks, and within 1 year, nearly all mice succumb to gross thymic epithelial tumors. General thymic morphology is largely maintained, but T cell development is perturbed in thymomas, with proportionately less CD4(+)CD8(+) double-positive thymocytes. In the first 3 months, E2F2 transgenic thymi exhibit only mild epithelial hyperplasia, and thereafter thymomas arise stochastically, probably following additional mutations. Interestingly, Emu-pp-E2F1 mice do not display cortical thymomas. These data argue that E2F2 promotes unscheduled cell division and oncogenic transformation of thymic epithelial cells.

Hematopoietic progenitor cells as possible origins of epithelial thymoma in a human T lymphocyte virus type I pX gene transgenic rat model

We earlier reported that Fischer 344/jcl strain (F344) rats carrying a unique pX gene of human T lymphocyte virus type I (HTLV-I) under control of a rat lymphocyte-specific protein tyrosine kinase (p56lck) type I promoter (lck-pX rats) spontaneously developed epithelial thymomas from the thymic medulla. To investigate the role of bone marrow cells carrying the HTLV-I pX gene in development of thymomas, the bone marrow of normal F344 rats after lethal irradiation was reconstituted by bone marrow mononuclear cells (BMMC) of lck-pX rats. Epithelial thymomas similar to the original thymoma of lck-pX rats frequently developed in the nontransgenic recipients within 5 months after the BMMC transplantation. The thymomas expressed the pX gene, thereby indicating the thymoma cells to be of donor BMMC origin. Since the thymoma also developed in nontransgenic recipients reconstituted by BMMC depleted of adherent cells, it is suggested that nonadherent BMMC of donor lck-pX rats may migrate to and lodge in the thymus of recipient nontransgenic rats then transform into thymoma cells with epithelial characteristics. The thymoma cells were shown to bind to Ulex europaeus Agglutinin-1 (UEA-1) lectin, which binds epithelial cells in the thymic medulla. It was also shown that the nonadherent BMMC fraction used for bone marrow reconstitution contained a number of UEA-1-positive cells. Taken together, UEA-1 positive BMMC may be progenitor cells of the epithelial thymoma. The epithelial thymoma in lck-pX rats sheds light on epithelial cell development in thymic medulla and for oncogenesis of epithelial thymoma in humans.

Concurrent epithelial thymoma and T-cell lymphoblastic lymphoma

The occurrence of an epithelial thymoma concomitant with a primary thymic T-cell lymphoblastic lymphoma is rare. This paper describes the case of a patient with a synchronous epithelial thymoma and thymic T-cell lymphoblastic lymphoma, characterized by a rapidly fatal clinical course. A review of the literature is reported.

A novel animal model of thymic tumour: development of epithelial thymoma in transgenic rats carrying human T lymphocyte virus type I pX gene.

The pX region encodes a major product of human T lymphocyte virus type I (HTLV-I) that has been implicated previously in tumour formation. To investigate the pathogenesis of pX gene in lymphoid tissues, we established a series of novel transgenic rats carrying the pX gene under the control of a rat lymphocyte-specific protein tyrosine kinase (p56lck) proximal promoter. The transgene was constructed with the -269 to +26 region of a rat p56lck proximal promoter and the pX cDNA, and was microinjected into fertilized ova of Fischer 344/jcl female rats. Six transgenic lines from 114 pups were established. Integration and expression of the transgene were detected by polymerase chain reaction (PCR) and Southern hybridization or by reverse transcriptase-PCR, northern hybridization, and immunostaining. Thymic tumours with lethal expansion occurred in 4 of 6 transgenic lines. The tumour consisted of spindle shaped cells. Immunohistochemical and ultra-structural analysis characterized the tumour cells to as epithelial cell type, and in the tumour arose in the medulla. Therefore, the tumour is classified into predominantly epithelial and spindle cell of medullary thymoma (type A of the new World Health Organization classification), as based on the human classification. Tumor occurrence increased in proportion to levels of the pX transcription in the thymus, for each line, and sex distinction was evident regarding rates related to tumour expansion. The transgenic rat model described here is suitable as a model for analysing tumorigenesis in epithelial thymoma occurring in humans.

Transsternal Thymectomy

Transsternal Thymectomy

Biopsy of Mediastinal Tumors: Needle Biopsy versus Mediastinoscopy

Biopsy of Mediastinal Tumors: Needle Biopsy versus Mediastinoscopy

Ki67 labelling index correlates with stage and histology but not significantly with prognosis in thymoma.

There have been several cell kinetic studies of thymoma, but the effectiveness of using Ki67 antibody as a tool to measure proliferative activity in this tumour was rarely evaluated. We carried out an immuno-histochemical study using this antibody to assess the clinicopathological correlation and the prognostic significance of this technique. Ninety-one cases of thymoma were collected. Double immunostaining with Ki67 and cytokeratin KL-1 antibodies was performed on paraffin sections. Ki67 labelling index (LI) was expressed as a percentage of Ki67 immunopositive nuclei by counting at least 1000 epithelial cells. The LIs were correlated with stages, histological subtypes based on both Lattes-Bernatz and Müller-Hermelink-Kirchner classifications, and length of survival. There were statistically significant differences of LIs between stage I and stage III and between stage I and stage IV tumours. Histologically, statistically significant differences were identified between predominantly epithelial thymoma and every other subtype of the Lattes-Bernatz classification and between well-differentiated thymic carcinoma and medullary or mixed thymomas of the Müller-Hermelink-Kirchner classification. Regarding the prognostic implication of Ki67 LI, although there appeared a trend that patients with tumours of higher LIs had slightly worse survival, the difference was not statistically significant in both univariate and multivariate survival analyses. We have demonstrated the proliferative potential in thymoma is associated with stage and histology. However, its clinical usefulness is limited on account of the overlap of LIs and lack of prognostic significance.

Intrathyroidal epithelial thymoma (ITET)/carcinoma showing thymus-like differentiation (CASTLE) exhibits CD5 immunoreactivity: new evidence for thymic differentiation.

Cases of intrathyroidal epithelial thymoma (ITET)/carcinoma showing thymus-like differentiation (CASTLE) were examined for CD5 immunoreactivity, a feature of true thymic carcinoma, but not other thymic epithelial neoplasms or carcinomas of other sites. ITET/CASTLE, a rare, low-grade malignant neoplasm arising within the thyroid gland which resembles lymphoepithelioma-like and squamous cell carcinoma of the thymus, is postulated to arise from remnants of branchial pouch capable of thymic differentiation, but thymic differentiation in this neoplasm remains unproven. The largest published series of cases of ITET/CASTLE was examined for CD5 immunoreactivity using an anti-CD5 antibody reactive in fixed, paraffin-embedded tissue with microwave antigen retrieval. Neoplastic cells in all five cases of ITET/CASTLE studied were immunoreactive for CD5, including foci of tumour metastatic to lymph node and lung. In contrast, none of five cases of thyroid carcinoma with squamous differentiation was immunoreactive for CD5. A minority of cases of typical thyroid carcinomas showed some weak immunoreactivity for CD5. Other carcinomas of the head and neck were nonimmunoreactive for CD5. CD5 immunoreactivity in ITET/CASTLE is new evidence in support of thymic differentiation in this neoplasm.

Lymphoepithelioma-like carcinoma of the thyroid gland: Lack of evidence of association with Epstein-Barr virus

Lymphoepithelioma-like carcinomas (LELC) occurring in sites derived from the primitive pharynx and foregut have been reported to show a strong association with Epstein-Barr virus (EBV), especially in the Oriental population. Primary lymphoepithelioma-like carcinoma of the thyroid is an extremely rare neoplasm which has been known under many different names, such as intrathyroidal epithelial thymoma, primary thyroid thymoma, carcinoma of the thyroid showing thymoma-like features, and carcinoma showing thymus-like differentiation (CASTLE). We report one such case in a Chinese woman, whose tumor was negative for EBV by in situ hybridization technique. This finding suggests that LELC of the thyroid may be biologically different from other LELCs, and that detection of EBV may aid in diagnosis when the LELC presents initially in lymph nodes or other metastatic sites.

Solid tumour and glomerulopathy

We retrospectively examined the prevalence of solid tumours in patients with glomerulonephritis (GN) followed in our regional renal unit between 1977 and 1994. We identified 17 cases of what was thought to be solid-tumour-related glomerulonephritis. Tumours and GN were diagnosed together in six cases, and within a year of each other in another four. In addition, there were seven other cases with a weaker temporal relationship (median duration between GN and cancer diagnosis, two and a half years) but which nonetheless could be tumour-related. In total, there were seven membranous GN, four mesangial proliferative GN, five crescentic GN and one case of focal segmental GN. Bronchogenic (6) and gastrointestinal carcinoma (CA) (5) were the commonest tumours encountered. Other tumours included breast CA (1), renal cell CA (1), prostatic CA (1), an epithelial thymoma and a leiomyosarcoma of the lung. All MGN and mesangial proliferative GN cases developed nephrotic range proteinuria, whereas all patients with rapidly progressive crescentic GN presented with acute renal failure. Four cases had received immunosuppressive therapy prior to tumour diagnosis. We discuss the validity of each case as tumour-related glomerulonephritis.

Thymomas express epitopes shared by the ryanodine receptor

Myasthenia gravis (MG) patients with thymoma have antibodies against ryanodine receptor (RyR) of skeletal and heart muscle. In this study, thymomas were examined for reactivity with a panel of polyclonal rabbit antibodies against various short peptides of RyR. An antibody against peptide C2 in the transmembrane region of RyR stained thymoma epithelial cells in crγδsections of 17/23 thymomas, and detected a 40-kDa peptide in Western blotting of a thymoma membrane fraction. The other RyR antibodies did not react with thymoma tissue. The anti-C2 RyR antibody did not react with normal thymus, tonsil or carcinoma of colon. The results strongly indicate that epithelial thymoma cells express an epitope shared by the transmembrane region of skeletal and cardiac muscle RyR.

Linkage of the athymic nude locus with the myeloperoxidase locus in the rat.

In rats of the BUF/Mna strain epithelial thymoma development is regulated by a single autosomal susceptible gene, Tsr-1. In pre-thymoma stage, BUF/Mna rats have extremely large thymuses, when compared with those of other strains of rats. The large thymus size of this strain is contributed by a thymus-enlargement gene, Ten-1. On the other hand, reduced thymus size and suppression of thymoma development were found in heterozygous BUF/Mna-rnu/+ rats. Linkage studies between RNU and microsatellite and restriction fragment length polymorphism markers in ([BUF/Mna-rnu/rnu x WKY/NCrj] F1 x WKY/NCrj)- and (WKY/NCrj x [BUF/Mna-rnu/rnu x WKY/NCrj] F1)- backcross rats have led to the localization of RNU on chromosome 10. The rat homolog of mouse Mpo (myeloperoxidase) was also assigned to the chromosome 10. The gene order on the chromosome was MYHSE (myosin heavy chain of embryonic skeletal muscle)--(1.0 centimorgan [cM])--SHBG (sex hormone-binding globulin)--(4.0 cM)--RNU (Rowett rat nude)--(10.0 cM)--MPO--(13.0 cM)--AEP (anion exchange protein). Conserved linkage of homologous loci mapped to rat chromosome 10 and mouse chromosome 11 supports the hypothesis that the RNU and MPO loci are rat homologs of the mouse nu and Mpo loci.

Cystic Squamous Cell Carcinoma of the Thyroid A Possible New Subgroup of Intrathyroidal Epithelial Thymoma.

In the thyroid gland, both squamous cell carcinoma and intrathyroidal epithelial thymoma are rare tumors with squamous features, but their prognoses differ; the former is usually fatal, and the latter is favorable. We describe a 38-yr-old female patient with a cystic tumor diagnosed cytologically as squamous cell carcinoma, who was treated with subtotal thyroidectomy. The tumor was located intrathyroidally in the middle third of the left lobe, and no invasion to the surrounding tissues was found. Histologic examination disclosed a cyst lined by epithelial cells with squamous cell differentiation. The tumor cells had ill-defined cell borders and large nuclei with prominent nucleoli. Invasion of the tumor capsule, a few mitoses, and infiltration of lymphocytes in the tumor periphery were noted, but neither necrosis nor metastasis to lymph nodes was observed. The patient has been free from recurrence for 3 yr after thyroid lobectomy. We propose that this type of cystic intrathyroidal squamous cell carcinoma may represent a cystic variant of intrathyroidal epithelial thymoma.

THE RET PROTOONCOGENE IS EXPRESSED IN PREDOMINANTLY EPITHELIAL HUMAN THYMOMAS

Thymomas are thymic tumors composed of epithelial cells with various number of lymphocytes. On the basis of lymphocytes number, they can be histologically classified into predominantly lymphocytic, predominantly epithelial and mixed lympho-epithelial. These tumors are rare and their prognosis is not well known yet. In this study we demonstrate by in situ hybridization the presence of RET transcripts in the medullary part of normal murine thymus and in epithelial thymomas. Conversely RET expression was not detected in the cortical part of the thymus and in thymomas with the predominance of the lymphocytic component, suggesting that its expression could be a specific marker of the predominantly epithelial histotype.

Well-differentiated thymic carcinoma: a clinico-pathological study.

Well-differentiated thymic carcinoma (WDTC) is a recently described epithelial tumour of the thymus previously classified as cortical or predominantly epithelial thymoma. The authors have reviewed a series of 15 cases of WDTC with the aim of further defining the clinicopathological features of this neoplasm. Histologically, the number of lymphocytes was always low; perivascular spaces and epithelial palisading around blood vessels and/or along fibrous septa were prominent features; 6 cases (40%) were associated with areas of typical cortical thymoma. All cases showed slight to moderate cytological atypia and nuclear grooving was frequently detected. Mitotic activity was variable but usually low. Clinically, all but 3 cases (80%) were invasive at surgery; myasthenia gravis was present in 9 cases (60%); 5 patients (33.3%) died due to disease and 2 additional patients (13.3%) had tumor recurrence. Our study indicates that WDTC has fairly distinctive clinicopathological features and that it is histologically and histogenetically related to cortical thymoma. The definition "well-differentiated carcinoma" is justified because of low-grade cytological atypia and retention of some organotypical histological features, in a tumour otherwise often displaying aggressive and sometimes clear-cut malignant clinical behaviour.

Case report 657

Malignant epithelial thymomas are slowly growing anterior mediastinal tumors. Local invasion and intrathoracic spread are not uncommon. Evidence of extrathoracic metastases are found in up to 15% of patients, most commonly in the liver, kidney, and bone. Almost all reports of thymoma metastases to bone have described purely lytic lesions. Once extrathoracic metastatic deposits are discovered, the mean extent of survival is 18 months. A case of a malignant epithelial thymoma in a young woman with diffuse sclerotic metastases to bone is reported. This case is remarkable not only for the presence and extent of the osteoblastic metastases but also for the fact that this woman lived for 6 years following the discovery of the extrathoracic bone involvement.

Immunohistochemical Demonstration of H Antigen, Peanut Agglutinin Receptor, and Saphora japonica Receptor Expression in Infant Thymuses and Thymic Neoplasias

Ten infant thymuses and 13 primary thymic tumors obtained from archived paraffin-embedded tissue were examined for the presence of tissue blood group O antigen (H), peanut agglutinin receptor antigen (PNA-r), Saphora japonica agglutinin receptor antigen (SJA-r), carcinoembryonic antigen (CEA), cytokeratin (CK), and epithelial membrane antigen (EMA). In the thymuses studied, Hassall's corpuscles contained abundant immunoreactive CK, PNA-r, and H antigens, whereas CEA, SJA-r, and EMA were present focally in Hassall's corpuscles. Immunoreactive CK, PNA-r, and CEA were demonstrated focally in the subcapsular region, cortical nurse cells, and subcapsular-perivascular monocytic cells, respectively. PNA-r was present in all 12 epithelial type tumors, including all eight thymomas. CEA was present in nine tumors, including six thymomas. Six thymomas contained H antigen and SJA-r; five continued CK and EMA. SJA-r and EMA were also present in one carcinoid tumor of thymic origin. In epithelial thymomas, the antigens stained nests of epithelial cells resembling the pattern of staining in Hassall's corpuscles. Membrane staining of spindle cells of both spindle cell and epithelial thymomas was less intense than staining of epithelial type cells.

Immunohistochemical studies on a human thymic epithelial cell subset defined by the anti-cytokeratin 18 monoclonal antibody

Two monoclonal antibodies respectively recognizing cytokeratins (CK) 18 and 19 were applied to the human thymic epithelium (in vivo and in vitro) in normal and pathological conditions, including 12 thymomas. We observed that in both normal and hyperplastic thymuses (from patients with myasthenia gravis) virtually the entire epithelial network was CK19-positive as were the majority of cells growing in culture. In four thymomas, however, the expression of cytokeratin 19 was not detected by immunofluorescence. On the other hand, CK18 was expressed by a discrete subset of medullary thymic epithelial cells in normal and in hyperplastic thymuses. Among the thymomas a large majority was either negative or contained few isolated CK18-positive cells scattered within the tumour. Conversely, in the two undifferentiated epithelial thymomas, virtually all the tumoral network was strongly labeled with the anti-CK18 monoclonal antibody. The present investigation thus not only defines the human thymic epithelial cell subset on the basis of differential cytokeratin expression but also indicates that anti-CK antibodies with single cytokeratin specificities can be regarded as useful tools to study the heterogeneity of thymomas.

Epithelial thymus tumors--therapy and prognosis.

One hundred and two patients with epithelial thymoma (ET) and carcinoma have undergone surgical treatment since 1957. In this series thymomas were classified according to Masaoka's clinical staging criteria (encapsulated, invasive) and according to Müller-Hermelink's histological criteria of the resected specimens (medullary and cortical differentiation) and compared to clinical symptoms and survival rates (mean follow-up time 66.4 months). We found that it is not always possible to differentiate intraoperatively fibrous adhesions from infiltrations of the thymic capsule or to recognise thymus carcinoma as such macroscopically if they have not already infiltrated the organ's capsule. All ETs with cortical differentiation after thymectomy showed a malignant course; in contrary ETs with medullary differentiation we found without relapses of metastases. ETs with both histological types (hybrid typs) and cortical dominance took in only two out of 57 cases a malignant course though five of them showed an invasion into the capsule according to clinical staging criteria stage II. Therefore classifying ETs only into two categories, encapsulated and invasive, according to surgical and gross findings, seems to be not always possible and insufficient for the clinical assessment of the malignity and prognosis.