Nodular Development of Spontaneous Epithelial Thymoma in (ACI/NMs × BUF/Mna)F1 Rats

The BUF/Mna strain is a high thymoma line of rats, and virtually all rats develop overt thymomas by the age of 40 weeks. To reveal the early morphologic changes in this thymomagenesis, thymuses and thyraomas were studied in (ACI/NMs × BUF/Mna)Fl (ABF1) rats, which inherit a thymoma susceptibility gene ( Tsr-1 ) from the BUF/Mna strain. At 50 weeks of age, 18% of ABF1 rats had developed medium to large thymomas, 54% had just began to develop multiple, small round nodules in their involuted thymuses, and the remaining 29% had involuted thymus only. The nodules were, microscopically, composed of cortex-like tissues with a starry-sky pattern, showing a quite similar structure to that of the large macroscopic thymomas of predominantly lymphocytic type seen in 104-week-old ABF1 or BUF-Mna rats. Thus, the nodule was actually a small thymoma. In fact, their epithelial cells often had larger atypical nuclei than those in the adjacent involuted thymus cortex. At 104 weeks of age, the incidences of the medium to large thymomas and the small thymoma nodules in ABF1 rats were 64 and 19%, respectively. These results suggest that the thymoma of ABF1 rats occurs initially as multiple small nodules which develop further into medium to large overt thymomas as a result of growth and fusion.     

Chromosomal Mapping of Genetic Locus Associated with Thymus-size Enlargement in BUF/Mna Rats

The thymoma-prone rat of the BUF/Mna strain is a useful model for human thymoma. In this strain thymoma development is regulated by a single autosomal susceptible gene, Tsr-1. At pre-thymoma age, BUF/Mna rats have extremely large thyrauses, when compared to those of other strains of rats. Genetic studies in crosses between BUF/Mna rats with large thymuses and WKY/NCrj rats with small thymuses suggested the presence of a major autosomal gene, Ten-1 , which contributes to thymus enlargement in a backcross population. Linkage studies between Ten-1 and microsatellite markers in backcross rats of (WKY/NCrj×BUF/Mna)Fl×BUF/Mna have led to the localization of Ten-1 in chromosome 1. This result may provide an approach to clone Tsr-1 , which could be allelic to Ten-1.     

An intrinsic thymic epithelial abnormality is responsible for the spontaneous development of predominantly lymphocytic thymomas in BUF/Mna rats.

The nature of tumorigenesis of predominantly lymphocytic thymoma was examined using an animal model. Rats of the inbred BUF/Mna strain were found spontaneously to develop predominantly lymphocytic thymomas, histologically indistinguishable from their human counterparts, at an incidence of virtually 100%. Thymic rudiments of BUF/Mna rats grafted 17 months previously under the renal capsule of young athymic ACI/NMs-rnu/rnu rats also gave rise to similar lesions. The lymphocytes in the thymomas expressed T-cell antigens (rat Lyt-1 and Lyt-2.3), as in the normal case, and ACI rat specific antigen. When BUF/Mna rats of thymoma age were irradiated with a lethal dose of 12 Gy and then received a single injection of bone marrow cells (8 x 10(7)) from BALB/c-nu/nu mice, thymomas were re-formed three weeks later (in 2 of 5 rats) with the replacement lymphocytes expressing mouse Thy-1.2 antigen. These results indicate that an intrinsic thymic epithelial abnormality is responsible for the development of predominantly lymphocytic thymomas in BUF/Mna rats.     

An Intrinsic Thymic Epithelial Abnormality Is Responsible for the Spontaneous Development of Predominantly Lymphocytic Thymomas in BUF/Mna Rats

The nature of tumorigenesis of predominantly lymphocytic thymoma was examined using an animal model. Rats of the inbred BUF/Mna strain were found spontaneously to develop predominantly lymphocytic thymomas, histologically indistinguishable from their human counterparts, at an incidence of virtually 100%. Thymic rudiments of BUF/Mna rats grafted 17 months previously under the renal capsule of young athymic ACI/NMs- rnu/rnu rats also gave rise to similar lesions. The lymphocytes in the thymomas expressed T-cell antigens (rat Lyt-1 and Lyt-2.3), as in the normal case, and ACI rat specific antigen. When BUF/Mna rats of thymoma age were irradiated with a lethal dose of 12 Gy and then received a single injection of bone marrow cells (8 × 10⁷) from BALB/c- nu/nu mice, thymomas were re-formed three weeks later (in 2 of 5 rats) with the replacement lymphocytes expressing mouse Thy-1.2 antigen. These results indicate that an intrinsic thymic epithelial abnormality is responsible for the development of predominantly lymphocytic thymomas in BUF/Mna rats.     

A single dominant susceptible gene determines spontaneous development of thymoma in BUF/Mna rat

Rats of the BUF/Mna strain developed spontaneous epithelial thymomas morphologically indistinguishable from human homologues at virtually 100% incidence. Segregation of thymoma development among crosses between BUF/Mna and ACI/NMs, which has 0% thymoma incidence, indicated that thymoma susceptibility was determined principally by a single autosomal dominant gene Tbm-1 (thymoma in BUF/Mna rats). In these crosses, another autosomal dominant or semidominant gene(s) contributed by ACI/NMs parents moderately reduced the thymoma incidence.     

Possible single dosage effects of the nude gene: suppression of spontaneous development of thymoma and nephropathy in BUF/Mna-rnu/+ rats

Single dosage effects of the rat nude gene (rnu) on spontaneous development of epithelial thymoma, muscle atrophy and nephrotic syndrome were studied by comparing littermates of rnu /+ and +/+ rats on a high thymoma strain, BUF/Mna, background. Heterozygous rnu/+ rats had a significantly smaller thymus than the +/+ littermates at 6 weeks of age. The incidence of thymoma at 12 months of age was extremely low in the female rnu/+ rats (3%) as compared with that of the +/+ rats (94%). Development of the nephrotic syndrome but not of the muscle atrophy was also suppressed in the heterozygotes. The results suggest that a recessive mutant gene, rnu, in a single dosage, interfered with critical steps of the disease processes of the thymoma and nephrotic syndrome in BUF/Mna-background rats.     

Establishment of Transplantable Tumor Lines and in vitro Cell Lines of Malignant Thymoma Developed in a BUF/Mna Rat

A spontaneous malignant thymoma was found in an 18-month-old female BUF/Mna rat and serially transplanted subcutaneously in both syngeneic BUF/Mna rats (designated as MTH-R) and KSN nude mice (MTH-NM) for more than 5 years. Both tumors shared the histological appearance of sarcomatoid carcinoma as seen in the original tumor. However, MTH-NM grew faster than MTH-in the respective hosts. The MTH-NM grew in both KSN-nude mice and BUF/Mna- rnu/rnu rats but not in BUF/Mna rats the host of the original tumor. Three continuous tissue culture cell lines (MTHC-1, MTHC-2 and MTHC-3) were established from the MTH-NM tumors at the 2nd, 15th and 17th transplantation generations, respectively. The MTH-NM tumors and latter two tissue culture cell lines carried one or more mouse chromosomes, probably acquired by cell fusion with mouse cells during passages in vivo. The presence of the mouse chromosomes was confirmed by the presence of mouse DNA and of antibodies to the MTHC-2 and MTHC-3 cells in the sera of BUF/Mna rats transplanted with MTH-NM.     

Establishment of transplantable tumor lines and in vitro cell lines of malignant thymoma developed in a BUF/Mna rat.

A spontaneous malignant thymoma was found in an 18-month-old female BUF/Mna rat and serially transplanted subcutaneously in both syngeneic BUF/Mna rats (designated as MTH-R) and KSN nude mice (MTH-NM) for more than 5 years. Both tumors shared the histological appearance of sarcomatoid carcinoma as seen in the original tumor. However, MTH-NM grew faster than MTH-R in the respective hosts. The MTH-NM grew in both KSN-nude mice and BUF/Mna-rnu/rnu rats but not in BUF/Mna rats, the host of the original tumor. Three continuous tissue culture cell lines (MTHC-1, MTHC-2 and MTHC-3) were established from the MTH-NM tumors at the 2nd, 15th and 17th transplantation generations, respectively. The MTH-NM tumors and latter two tissue culture cell lines carried one or more mouse chromosomes, probably acquired by cell fusion with mouse cells during passages in vivo. The presence of the mouse chromosomes was confirmed by the presence of mouse DNA and of antibodies to the MTHC-2 and MTHC-3 cells in the sera of BUF/Mna rats transplanted with MTH-NM.     

Tumor-cytotoxicity of nitric-oxide produced from alveolar macrophages directly stimulated with tumor-cells

Macrophages activated by lipopolysaccharide or interferon-gamma have been shown to be cytotoxic to tumor cells by releasing nitric oxide. Here, we report that unstimulated rat alveolar macrophages cultured with certain tumor cells produce nitric oxide and are cytotoxic to these tumor cells. Alveolar macrophages were taken from BUF/Mna rats, which were known to produce spontaneous thymoma, and cultured with syngeneic BUF/Mna-derived thymoma cells. They were killed by syngeneic or allogeneic alveolar macrophages and this killing was partially abolished by addition of N(G)-monomethyl-L-arginine. X-ray irradiated, mitomycin C-treated or membranous fragments of BUF/Mna-derived thymoma cells directly stimulated rat alveolar macrophages to produce nitric oxide.     

胸腺瘤组织中PTEN基因基质金属蛋白酶-2和基质金属蛋白酶-9的表达

目的 探讨PTEN基因、基质金属蛋白酶(MMP)-2和MMP-9在胸腺瘤中的表达及其与胸腺瘤临床病理特征的关系.方法 应用免疫组织化学SP方法,检测45例胸腺瘤和16例非瘤胸腺(对照组)组织中PTEN、MMP-2和MMP-9的表达.结果 PTEN、MMP-2和MMP-9在胸腺瘤组织中的阳性表达率分别为53.5%、48.9%和62.2%,在对照组中的阳性表达率分别为93.8%、6.3%和25.0%,差异均有统计学意义(P<0.05).PTEN和MMP-2的表达与胸腺瘤的恶性程度(世界卫生组织分型)有关(P<0.05),与胸腺瘤的侵袭性(Masaoka分期)有关(P<0.01).MMP-9的表达与胸腺瘤的恶性程度和侵袭性无关(P>0.05).结论 PTEN、MMP-2和MMP-9与胸腺瘤的发生、发展可能有关,且PTEN和MMP-2与胸腺瘤的恶性程度和侵袭性相关.     

Cytogenetic studies on rat thymic lymphomas induced by N-propyl-N-nitrosourea

N-Propyl-N-nitrosourea (PNU) was proved to be a strong leukemogen, which induces myelogenous leukemia or thymic lymphoma in rats. BUF/Mna rats and F344 rats were the strain most susceptible to thymic lymphomagenic activity of PNU. In addition, F1 rats between BUF/Mna and WKY rats were also susceptible to PNU-lymphomagenic activity. In the present experiment, karyotypes of 31 thymic lymphomas induced by PNU in BUF/Mna rats and in F1 rats between BUF/Mna and WKY rats were analysed for chromosomal abnormalities. Although no specific chromosomal abnormalities were observed throughout all lymphomas, del(11q) and dup(2q) were observed frequently in BUF/Mna rat lymphomas. Breakpoints and/or fusion-points were frequently observed in chromosome 11, followed by chromosomes 2, 5 and 6. Trisomy of chromosome 7, on which c-myc oncogene is mapped, was observed in seven cases, and monosomy of chromosomes 12, 18, 19, 20 and X was seen in seven or eight cases each, though these changes were generally observed in minor cell population in each case.     

Malignancy and differentiation of neoplastic epithelial cells of thymoma

Fifteen fetal thymuses and 100 thymomas were examined concerning the degree of differentiation of thymic epithelial cells by light and electron microscopy. The following results were obtained. The embryologic process of the fetal thymus was categorized into four stages (8, 12, 15, and 17 weeks or more of gestation) based on the morphological features of epithelial cells and the maturity of thymic tissues. Thymomas were classified into the undifferentiated, and poorly, moderately, and well-differentiated types by their morphological features in comparison with the fetal thymuses. The incidences of the respective types in the 100 thymomas were 5, 16, 68, and 11 cases. The moderately differentiated type was divided into three subtypes; namely, polygonal cell (49 cases), clear cell (6), and spindle cell type (13). The degree of differentiation of the thymomatous epithelial cells showed strong correlations with both the invasiveness and the prognosis of the thymoma. The ratios of invasive thymomas were 36, 47, 25, and 100% for the well-differentiated, moderately-differentiated, poorly-differentiated, and undifferentiated types, respectively. The 10-year survival rates were 87.5, 62.5, 46.9 and 0% for the well-differentiated, moderately-differentiated, poorly-differentiated, and undifferentiated thymomas.     

An immunohistologic study of the epithelial components of 81 cases of thymoma.

Eighty-one cases of thymoma were studied immunohistologically with the use of three mouse monoclonal antibodies: one was specific for subcapsular-cortical, one for intra-cortical, and one for medullary epithelial cells. Twenty-eight (60.9%) of 46 polygonal cell thymomas were of the cortical type and 1 (2.2%) was of the medullary type. Ten (55.6%) of 18 spindle cell thymomas and 7 (41.2%) of 17 mixed cell thymomas were of the medullary type, and 1 (5.6%) of 18 spindle cell thymomas was of the cortical type. Fourteen (17.3%) of 81 thymomas were composed of epithelial cells that were triple positive immunologically; although these are unusual, they also may be present in the normal thymus. Based on these findings, triple-positive epithelium in the normal thymus consists of common stem cells that can differentiate into subcapsular-cortical, intra-cortical, and medullary epithelium; these cells may be the target cells for tumorigenesis. Epithelium in polygonal cell thymoma tends to differentiate into cortical epithelium, whereas epithelium in spindle and mixed cell thymomas differentiates into medullary epithelium.     

Heritable lympho-epithelial thymoma resulting from a transgene insertional mutation

Thymoma is the most common tumor of the anterior-superior mediastinum. We have identified a line of transgenic mice which spontaneously and heritably develop thymomas at a very high penetrance. The available data suggest that thymoma formation in these mice results as a consequence of transgene insertional mutagenesis. Immune histologic analyses indicate that the thymomas are of epithelial cell origin. Survival studies indicate that tumor progression is more aggressive in females as compared to males (73.9 vs 41.7% mortality at 20 weeks of age, respectively). Fluorescent in situ hybridizations have localized the transgene integration site to the F2-G region of mouse chromosome 2. Translocation encompassing the syntenic region in humans has been implicated in lympho-epithelial thymoma. These animals may constitute a useful resource for the identification of gene(s) which participate in thymoma progression, as well as a model system for screening anti-thymoma therapeutic agents.     

胸腺肿瘤诊断和治疗的有关问题 (附73例报告)

目的：探讨良性胸腺瘤复发原因及胸瘤新的分类方法、恶性胸肿瘤的影像学诊断特点、手术方式、合并重症肌无力患者的处理、胸腺肿瘤术后治疗等。方法：１９７５年１月－１９９５年１２月手术治疗的７３例胸腺肿瘤和囊肿。结果：总结了恶性胸腺瘤的ＣＴ特征,恶性胸腺肿瘤应争取全胸腺及用脂肪组织切除,重视合并重症肌无力的围手术期 和潜在恶笥胸腺瘤术后应放疗,复发病例再手术仍能获得较好疗效。结论：提出了一种胸腺瘤新的分类方     

Ultrastructure of spontaneous and urethan-induced thymomas in buffalo rats.

Normal thymuses from Buffalo and Long-Evans rats of various ages, and spontaneous and urethan-induced thymomas in Buffalo rats, were examined by electron microscopy. Histological variabilities among thymomas of the lymphoid, mixed, and epithelial cell types were a reflection of the number of lymphoid cells within the network composed of neoplastic epithelial reticular cells. In the cytoplasm of these cells, development of tonofilaments and membrane-bound bodies and inverse development of the rough-surfaced endoplasmic reticulum were recognized in the sequential process from the lymphoid cell type to the epithelial cell type. An important role of the development of the rough-surfaced endoplasmic reticulum for thymic function was suggested. Phagocytic activity of the neoplastic epithelial reticular cells was revealed, and some of the membrane-bound bodies in these cells, especially those with moniliform structures, were regarded as remnants of damaged lymphocytes. Evidence for neoplastic epithelial reticular cell-lymphoid cell transformation could not be established from study of the thymoma tissue. No virus-like structures were observed in these thymomas.     

Incidence, morphology, and ultrastructure of spontaneous thymoma--the most common neoplasm in W/Nhg rats

Spontaneous thymoma was observed with an incidence of 97 and 36% in female and male rats, respectively, from an inbred Wistar/Neuherberg strain (W/Nhg). The thymomas often caused dyspnea and were occasionally the direct cause of death. The neoplasms resembled human thymomas and showed a variable cell composition, ranging from mainly lymphocytic to mainly epithelial. The detailed ultrastructural findings are described and compared with those in other rat thymomas and in human thymomas. A characteristic feature of all dividing lymphocytes was the presence of often multilayered, confronting cisternae. As in more than 50% of human thymomas, W/Nhg rat thymomas were not associated with myopathies or any other possibly autoimmune diseases. They may thus offer a useful model for the study of thymoma without associated parathymic syndromes.     

New WHO histologic classification predicts prognosis of thymic epithelial tumors: a clinicopathologic study of 200 thymoma cases from China

BACKGROUND: In 1999, a World Health Organization (WHO) committee published histologic criteria for distinct thymoma entities (labeled as Type A, AB, B1, B2, B3 thymomas) and for the heterogeneous group of thymic carcinomas, collectively called Type C thymomas. Whether WHO-defined histologic thymoma subtypes are of independent prognostic relevance has yet to be proved. METHODS: Two hundred thymomas from the Shanghai Chest Hospital with a mean follow-up time of 15 years (range, 1-246 months) were studied for the relevance of WHO histologic subtype and other factors (stage, therapy, and myasthenia gravis [MG]) for survival. RESULTS: In order of frequency, 68 patients (34.0%) had Type AB, 39 (19.5%) had Type B2, 36 (18.0%) had Type C, 27 (13.5%) had Type B3, 17 (8.5%) had Type B1, and 8 (4.0%) had Type A thymoma. Five cases (2.5%) were rare thymomas not mentioned in the WHO classification. Survival data showed significant differences among the histologic subtypes (log rank test: P < 0.001). Among patients with Type A and AB thymomas, none died of tumor; of the Type B1 thymoma patients, only one (5.9%) died at 22 months. Type B2, B3, and C thymomas had a significantly worse prognosis with 5-year survival rates of 75.0%, 70.0%, and 48.0%, respectively. Ninety-six patients (48.0%) were in Masaoka Stage I, 26 (13.0%) were in Stage II, 65 (32.5%) were in Stage III, and 13 (6.5%) were in Stage IV. Stage was highly significant in predicting survival (log rank, test P < 0.001). The association between histologic subtype and invasive behavior (stage) was statistically significant (P < 0.001). However, histology was an independent predictive factor of survival in Stage I and II thymomas: Type B2, B3, and C thymomas had a worse prognosis than Type A, AB, and B1 thymomas (log rank test: P < 0.003). Thirty patients (15.0%) presented with MG. MG was significantly more frequent in Type B2 and B3 than in Type A, AB, and B1 thymomas (P < 0.01). On multivariate analysis, MG had no adverse effect on survival (P = 0.17). Radiation or chemotherapy improved patients' survival at 5 and 10 years in Type B2, B3, and C thymomas (log rank test: P < 0.003). CONCLUSIONS: Tumor stage is the most important determinant of survival in thymoma patients, but the WHO histologic subtype is an independent prognostic factor in Stage I and II thymomas, among which WHO Type A, AB, and B1 thymomas form a low-risk group. Patients with high-risk thymomas might profit from novel adjuvant radiochemotherapy regimens.