Activation of matrix metalloproteinase-2 is correlated with invasiveness in thymic epithelial tumors

BACKGROUND AND OBJECTS: Matrix degradation, which is a critical event in the process of tumor invasion and metastasis, is considered to be caused by the action of proteolytic enzymes. METHODS: We examined the gelatinolytic activity of matrix metalloproteinase (MMP)-9, and the activity of active and inactive forms of MMP-2 in five thymi, five noninvasive thymomas, eight invasive thymomas, and five thymic carcinomas by quantitative gelatinolytic zymography. RESULTS: The gelatinolytic activity of active MMP-2 in five thymi was zero. The mean gelatinolytic activity of active MMP-2 was 0.020 +/- 0.015 in noninvasive thymoma, 0.084 +/- 0.098 in invasive thymoma and 0.246 +/- 0.194 in thymic carcinoma. The gelatinolytic activity of active MMP-2 correlated with the invasiveness of thymic epithelial tumors (Spearman rank correlation: r-value = 0.532). The gelatinolytic activity of active MMP-2 in three thymoma cases with microscopic capsular invasion was the same as that of noninvasive thymoma. When thymoma cases showing microscopic capsular invasion were classified into the "macroscopically noninvasive thymoma" group, the gelatinolytic activity of active MMP-2 correlated with the invasiveness of thymic epithelial tumors (Spearman rank correlation: r-value = 0.621). CONCLUSIONS: The gelatinolytic activity of active MMP-2 significantly correlated with the invasiveness in thymic epithelial tumors. J. Surg. Oncol. 2001;76:169-175.     

Relationship Between Computed Tomography Manifestations of Thymic Epithelial Tumors and the WHO Pathological Classification

Objective: To explore the relationship between computed tomography (CT) manifestations of thymoma andits WHO pathological classification. Methods: One hundred and five histopathologically confirmed cases werecollected for their pathological and CT characteristics and results were statistically compared between differentpathological types of thymoma. Results: Tumor size, shape, necrosis or cystic change, capsule integrity, invasionto the adjacent tissue, lymphadenopathy, and the presence of pleural effusion were significantly different betweendifferent pathological types of thymomas (P <0.05). Type B2, B3 tumors and thymic carcinomas were greater insize than other types. More than 50% of type B3 tumors and thymic carcinomas had a tumor size greater than10 cm. The shape of types A, AB, and B1 tumors were mostly round or oval, whereas 75% of type B3 tumorsand 85% of thymic carcinomas were irregular in shape. Necrosis or cystic change occurred in 67% of type B3thymomas and 57% of thymic carcinomas, respectively. The respective figures for capsule destruction were 83%and 100% . Increases in the degree of malignancy were associated with increases in the incidence of surroundingtissue invasion: 33%, 75%, and 81% in type B2, type B3, and thymic carcinomas, respectively. Pleural effusionoccurred in 48% of thymic carcinomas, while calcification was observed mostly in type B thymomas. Conclusions:Different pathological types of thymic epithelial tumors have different CT manifestations. Distinctive CT featuresof thymomas may reflect their pathological types.     

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.     

Thymoma. A comparative study of clinical stages, histologic features, and survival in 200 cases

Two hundred thymomas, surgically treated between 1955 and 1982 at the Marie Lannelongue Surgical Center, were subjected to statistical analysis, comparing clinical stages and histologic types and relating them to survival. Clinical stages were defined as follows. Stage I: no invasiveness, total excision; Stage II: localized invasiveness (no more than two mediastinal structures); Stage III: largely invasive, with or without distant tumorous grafts, lymph node deposits, or metastases. Four histologic types were retained: (1) spindle or oval cell type thymoma, (2) lymphocyte-rich thymoma, (3) differentiated epithelial thymoma, and (4) undifferentiated epithelial thymoma. Invasiveness remained a major prognostic factor, but the degree of invasion did not affect the survival rate or always justify radical surgery. Thus, the survival rate dropped from 85% at 5 years and 80% at 10 years in noninvasive tumors to 50% and 35%, respectively, in invasive tumors, but without significant difference between moderately invasive Stage II and largely invasive Stage III tumors. Histologic typing indicated a good correlation between the degree of differentiation of the tumors and prognosis. The survival rates were 80% at 5 years and 75% at 10 years for spindle cell type 1 and lymphocyte-rich type 2 thymomas, 75% at 5 years and 50% at 10 years for differentiated epithelial type 3, and nil at 5 years for undifferentiated type 4 thymomas. Although invasiveness often paralleled histologic typing, they appeared as two distinct parameters with separate prognostic significance, particularly in differentiated and undifferentiated epithelial tumors. One hundred five patients had myasthenia gravis and 14 had another autoimmune disease. The associated syndromes were no longer an adverse factor in the prognosis of thymoma.     

MMP-9和TIMP-1与脑膜瘤的侵袭性

目的研究基质金属蛋白酶-9(metallopro-teinase,MMP-9)及其组织抑制因子-1(tissue inhibitorof MMP,TI MP-1)与脑膜瘤侵袭性的关系。方法采用SP法检测10例正常蛛网膜组织、28例非侵袭性脑膜瘤和32例侵袭性脑膜瘤组织中MMP-9及TI MP-1的表达水平。结果MMP-9在正常蛛网膜组织、非侵袭性脑膜瘤和侵袭性脑膜瘤组织中的阳性表达率分别为0(0/10)、32.1%(9/28)和84.4%(27/32)。MMP-9的表达强度在侵袭性脑膜瘤中(平均秩和24.80)高于非侵袭性脑膜瘤(平均秩和50.48),P=0.000;而在非侵袭性脑膜瘤和正常蛛网膜组织中差异无统计学意义,P=0.231。TI MP-1在正常蛛网膜组织、非侵袭性脑膜瘤和侵袭性脑膜瘤中的阳性表达率分别为100%(10/10)、89.3%(25/28)和12.5%(4/32)。TI MP-1的表达强度在正常蛛网膜组织中最高,非侵袭性脑膜瘤次之,侵袭性脑膜瘤最低,各组间的差异有统计学意义,P=0.000。结论MMP-9的高表达在脑膜瘤的侵袭过程中起重要作用;TI MP-1的低表达与脑膜瘤的发病及侵袭过程有关。     

Molecular Profiling of Thymoma and Thymic Carcinoma: Genetic Differences and Potential Novel Therapeutic Targets

Thymoma and thymic carcinoma are thymic epithelial tumors (TETs). We performed a molecular profiling to investigate the pathogenesis of TETs and identify novel targets for therapy. We analyzed 37 thymomas (18 type A, 19 type B3) and 35 thymic carcinomas. The sequencing of 50 genes detected nonsynonymous mutations in 16 carcinomas affecting ALK, ATM, CDKN2A, ERBB4, FGFR3, KIT, NRAS and TP53. Only two B3 thymomas had a mutation in noncoding regions of the SMARCB1 and STK11 gene respectively. Three type A thymomas harbored a nonsynonymous HRAS mutation. Fluorescence in situ hybridization detected in 38 % of carcinomas a CDKN2A, in 32 % a TP53 and in 8 % an ATM gene deletion, whereas only one B3 thymoma exhibited a CDKNA deletion, and none of the type A thymomas showed a gene loss. Sequencing of the total miRNA pool of 5 type A thymomas and 5 thymic carcinomas identified the C19MC miRNA cluster as highly expressed in type A thymomas, but completely silenced in thymic carcinomas. Furthermore, the miRNA cluster C14MC was downregulated in thymic carcinomas. Among non-clustered miRNAs, the upregulation of miR-21, miR-9-3 and miR-375 and the downregulation of miR-34b, miR-34c, miR-130a and miR-195 in thymic carcinomas were most significant. The expression of ALK, HER2, HER3, MET, phospho-mTOR, p16^INK4A, PDGFRA, PDGFRB, PD-L1, PTEN and ROS1 was investigated by immunohistochemistry. PDGFRA was increased in thymic carcinomas and PD-L1 in B3 thymomas and thymic carcinomas. In summary, our results reveal genetic differences between thymomas and thymic carcinomas and suggest potential novel targets for therapy.     

The distribution of epithelial membrane antigen in thymic epithelial neoplasms.

Thymic carcinomas arising within a thymoma have been reported, but the relationship between thymoma and thymic carcinoma is poorly understood. Epithelial membrane antigen (EMA) is known to be an effective marker for establishing the epithelial nature of neoplastic cells, and it is reported that staining of tumors is clearly related to the degree of tumor differentiation. Eighty-one thymomas (59 noninvasive, 22 invasive) and 14 thymic carcinomas were studied immunohistologically using antiepithelial membrane antigen (anti-EMA) monoclonal antibody. Thymic carcinomas tended to express much larger quantities of EMA than thymomas, and instances of EMA-positive thymoma were seen significantly more often in invasive thymomas than in noninvasive ones (P < 0.05). However, EMA positivity was also associated with gland-like structures, which were not necessarily associated with malignant disease. Nevertheless, in view of the concept that thymoma and thymic carcinoma show a similar cellular differentiation, EMA-positive epithelial cells in thymoma with no relation to gland-like configurations might represent a pool of cells having a latent potential for malignant disease and might be transformed into thymic carcinoma cells under certain conditions. Immunolabeling for EMA appears to be a useful tool for determining the degree of malignant disease among thymic epithelial neoplasms.     

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.     

Expression and mutation statuses of epidermal growth factor receptor in thymic epithelial tumors

BACKGROUND: Epidermal growth factor receptor (EGFR) gene mutations have been reported to correlate with the sensitivity to the tyrosine kinase inhibitor treatment for advanced lung cancers. Since several reports have shown that invasive thymoma overexpress the EGFR protein, we examined the EGFR expression and mutation statuses in thymoma and thymic carcinoma tissues. METHODS: EGFR mutation statuses from 99 thymic epithelial tumor samples were evaluated by a rapid and sensitive TaqMan assay using Applied Biosysytems 7500 real-time PCR system. Probes were designed according to the 13 different EGFR mutations reported previously in lung cancers. A total of 38 thymoma samples were directly sequenced for the EGFR gene. Protein expressions were evaluated for 56 thymic epithelial tumors by immunohistochemistry. RESULTS: EGFR gene mutations were not detected in any of the thymoma and thymic cancer samples using TaqMan PCR assay. Of the 38 samples 3 showed a heterozygous silent mutation without changes in the protein, a G to A transition at the nucleotide 2361 in exon 18. EGFR expression was significantly higher in invasive thymomas (stages III-IV, 15/19 were positive) than in early stage thymomas (stages I-II, 7/33 were positive) (P < 0.0001). All four carcinomas and all seven B3 thymomas showed EGFR positive staining. CONCLUSIONS: Although EGFR mutation at the tyrosine kinase domain is unlikely to be a therapeutic target for thymoma, the information about EGFR expression would contribute to the further identification of the therapeutic target for advanced thymomas.     

基质金属蛋白酶和组织金属蛋白酶抑制剂表达失衡与胃癌浸润转移的关系

背景和目的：基质金属蛋白酶－9（matrix metalloproteinase-9,MMP-9)及其相应的组织金属蛋白酶抑制剂－1（tissue inhibifor of metalloproteinase-1 TIMP-1)在肿瘤细胞浸润和转移过程中起重要的调节作用,本研究观察二者在胃癌中的共表达情况,探讨其表达失衡与胃癌浸润转移和预后的关系。方法：应用免疫组化方法检测256例胃癌细胞MMP－9、TIMP－1和细胞增殖核抗原Ki-67的表达,并行回顾性随访。结果：胃癌侵及肌层以上者的MMP－9表达（70．13％）明显高于胃癌仅限于粘膜及粘膜下层者（42．50％,P＜0．05）,MMP－9表达与肿瘤细胞增殖指数、淋巴结转移呈正相关,TNM分期高者MMP－9表达（75．00％）高于TNM分期低者（46．15％,P＜0．05）;TIMP－1的表达与胃癌浸润程度、淋巴结转移及TNM分期呈负相关（Pearson列联系数分别为0．1688,0．3556和0．3004,P＜0．05）。胃癌组织中MMP－9和TIMP－1表达失衡有4种类型,其中MMP－9表达超过TIMP－1者胃癌发生浆膜浸润、淋巴结转移的比例明显高于TIMP－1表达超过MMP－9者或二者表达平衡者（P＜0．05）,而术后胃癌患者的生存率情况则相反,MMP－9表达超过TIMP－1者术后生存率明显低于TIMP－1表达超过MMP－9者（P＜0．05）。结论：MMP－9阳性表达与胃癌浸润转移呈正相关,而TIMP－1阳性表达与胃癌浸润转移呈负相关,二者在胃癌浸润转移中的关系表现为MMP－9促进肿瘤转移为主,TIMP－1对胃癌有独立的抑制作用,MMP－9阳性表达而TIMP－1阴性表达者提示胃癌患者预后不良。     

Enhanced expression of tissue inhibitor of metalloproteinase-2 (TIMP-2) in the stroma of breast carcinomas correlates with tumor recurrence

The 72-kDa (MMP-2, gelatinase A) and the 92-kDa (MMP-9, gelatinase B) matrix metalloproteinases have been associated with tumor cell invasion and metastasis. Immunohistological staining of MMP-2 and MMP-9, basal lamina collagen IV and TIMP-2 were performed on frozen sections of 83 invasive breast carcinomas. MMP-2 and MMP-9 were associated with neoplastic cell plasma membrane in 72% of cases and exhibited inter-tumoral variability of staining intensity. MMP-2 and MMP-9 staining was not correlated with presence of metastases at time of diagnosis or with disease outcome. TIMP-2 was detected in the peri-tumoral stroma and was present in 87% of cases. Residual benign breast tissue was negative for TIMP-2 staining. Neoplasms with diffuse TIMP-2 staining (24%) recurred significantly more frequently (75% recurred) than cases with focal (42% recurred) or absent (27% recurred) TIMP-2. Presence of collagen IV was negatively correlated with gelatinase staining. We conclude that up-regulation of MMP-2 and MMP-9 expression in breast tumor cells is reciprocally correlated to collagen IV staining. Clinical outcome, however, is more closely related to the presence of TIMP-2 than the corresponding MMPs. Enhanced TIMP-2 expression, therefore, may denote a stromal response to tumor invasion, indicative of aggressive behavior in a subset of breast carcinomas. © 1994 Wiley-Liss, Inc.     

NPTX1在胸腺瘤患者中的表达及诊断价值

背景与目的胸腺瘤是原发于前纵隔最常见的恶性肿瘤,但对于胸腺瘤的诊断没有特异性的实验室指标。本研究旨在通过mRNA微阵列分析技术筛选出对胸腺瘤诊断有提示作用的肿瘤标志物,并加以证实。方法前期对31份胸腺瘤和瘤旁胸腺组织进行mRNA微阵列分析,发现胸腺瘤中神经细胞正五聚体1(neuronal pentraxin 1,NPTX1)基因转录水平上调超过4倍。为进一步验证上述结果,采用实时荧光定量聚合酶链反应(polymerasechain reaction,PCR)法、免疫组化法和酶联免疫吸附测定法(enzyme-linkedimmunosorbentassay,ELISA)对60例胸腺瘤患者和30例胸腺囊肿患者NPTX1基因的转录和表达水平进行检测,并应用受试者工作特征曲线(receiver operating characteristic curve, ROC)分析其在胸腺瘤中的诊断价值。结果胸腺瘤组织中NPTX1 mRNA转录水平明显高于对照组胸腺组织[(2.88±1.02) vs (1.35±0.47), P<0.001];胸腺瘤组织中NPTX1蛋白的表达水平明显高于对照组胸腺组织(2 vs 1, P<0.001);术前胸腺瘤患者血清中NPTX1蛋白含量明显高于对照组胸腺囊肿患者[(1,018.29±209.38) pg/mL vs(759.95±66.02)pg/mL,P<0.001];血清中NPTX1蛋白含量以842.22pg/mL为诊断节点,诊断胸腺瘤的敏感性为85.00%,特异性为93.33%,ROC曲线下面积为0.902。结论 NPTX1在胸腺瘤患者中高表达,且对胸腺瘤有诊断价值。     

Expression of p53, bcl-2, E-cadherin, matrix metalloproteinase-9, and tissue inhibitor of metalloproteinases-1 in paired primary tumors and brain metastasis.

The objectives of this study were to: (a) characterize the immunohistochemical expression of p53, bcl-2, E-cadherin (EC), matrix metalloproteinase-9 (MMP-9), and tissue inhibitor of metalloproteinases-1 (TIMP-1) in brain metastases; (b) compare immunohistochemical (IHC) expression of brain metastases with their primary tumors; and (c) assess the prognostic value of expression of these markers. Tumors from 35 patients with brain metastasis were studied for IHC expression of p53, bcl-2, EC, MMP-9, and TIMP-1. In 17 cases, primary tumors were also available for study. In brain metastases, p53 was positive in 91% of cases and intermediate in 9%, MMP-9 was positive in all cases, TIMP-1 was intermediate in 6% and negative in 94% of cases, EC expression was positive in 86% of cases and intermediate in 14%, and bcl-2 was variable. All primary tumors were positive for p53 and MMP-9, 3% were intermediate for TIMP-1 and 97% were negative, 65% were positive for EC and 35% were intermediate, whereas bcl-2 expression was variable. Neither p53, bcl-2, TIMP-1, or EC staining correlated with overall survival or survival with brain metastases. No assessment of survival differences could be made for MMP-9 because of its overexpression in all tissues. This study found that MMP-9 and p53 were markedly overexpressed in primary tumors and matched brain metastasis, TIMP-1 expression was negative in the majority of specimens, whereas EC expression was maintained in both primary tumors and brain metastases and bcl-2 expression was variable. This study suggests that the functional balance of MMP-9 and TIMP-1 is shifted toward extracellular matrix degradation in brain metastases and that deregulation of cell cycle control by p53 also exists in brain metastases. The high expression of EC may indicate the importance of adherence at late stages of metastasis but requires further study.     

p53蛋白与PCNA在胸腺上皮性肿瘤中的表达及其意义

目的　探讨p5 3蛋白和增殖细胞核抗原 (PCNA )在胸腺上皮性肿瘤中表达的意义及相互关系。方法　采用S P免疫组化法 ,检测良性胸腺瘤 18例 ,恶性胸腺瘤 16例 ,胸腺癌 16例的 p5 3蛋白与PCNA的表达。 结果　p5 3蛋白和PCNA的Ⅲ～Ⅳ级指数在 3组胸腺上皮性肿瘤中阳性表达率分别为 3 3 .3 % ( 6/18) ,62 .5 % ( 10 /16) ,81.3 % ( 13 /16)和 3 8.9% ( 7/18) ,68.8% ( 11/16) ,81.3 % ( 13 /16) ,(P <0 .0 5 ) ;其阳性表达率与临床分期、淋巴结转移密切相关 (P <0 .0 5 )。结论　p5 3蛋白和PCNA阳性表达率可提示肿瘤恶性程度及其侵袭力和转移能力。     

Gli-2 在胸腺肿瘤组织中的表达及其与Ki-67的关系

目的：探讨Gli- 2 蛋白和核增殖标志物Ki-67与胸腺肿瘤的临床病理特征及预后的关系。方法：采用免疫组织化学方法,检测64例胸腺肿瘤（9 例A 型、6 例AB型、11例B 1 型、22例B 2 型及16例C 型）组织中Gli- 2 及Ki-67蛋白的表达情况。结果：1）Gli- 2 在胸腺瘤A 、AB、B 1、B 2、C 型的阳性率分别为1/ 9（11.11%）、2/ 6（33.33%）、2/ 11（18.18%）、5/ 22（22.73%）、13/ 16（81.25%）,表达差异有统计学意义（P < 0.05）;Gli- 2 阳性率在Masaoka分期Ⅰ、Ⅱ、Ⅲ、Ⅳ期中分别为2/ 10（20%）、12/ 41（29.27%）、4/ 6（66.67%）、5/7（71.43%）,表达差异有统计学意义（P < 0.05）;2）患者肿瘤组织中Gli- 2 的高表达与性别、年龄、出血坏死及合并重症肌无力（myasthenia gravis,MG ）无相关性,但与肿瘤是否侵及胸膜密切相关;3）Ki-67在侵袭性胸腺瘤与非侵袭性胸腺瘤中的阳性标记指数
（LI ）分别为7.14± 6.99、15.24± 9.13,差异具有明显统计学意义（P < 0.05）,Ki-67在胸腺瘤中的表达与Gli- 2 的表达呈正相关（r s =0.529,P < 0.05）;4）Gli- 2 阳性组患者5 年无进展生存率（PFS）56.5%（13/ 23）较阴性组的5 年无进展生存率92.7%（38/ 41）低,Ki-67阳性组的胸腺肿瘤患者5 年无进展生存率61.5%（16/ 26）也较阴性组的5 年无进展生存率92.1%（35/ 38）低,且差异具有统计学意义（P < 0.05）。 Cox 比例风险回归模型分析结果显示,Gli- 2 阳性、Ki-67阳性、有胸膜侵袭是影响胸腺肿瘤患者预后的独立危险因素。结论：Gli- 2 与Ki-67在胸腺肿瘤组织中的表达呈正相关,检测二者的表达对判断胸腺肿瘤患者的临床特征及预后有一定提
示作用。     

The World Health Organization histologic classification system reflects the oncologic behavior of thymoma: a clinical study of 273 patients

BACKGROUND: Although the histologic classification of thymic epithelial tumors has been confusing and controversial, an agreement on the universal classification system for thymic epithelial tumors was achieved by the World Health Organization (WHO) in 1999. The authors previously reported that the WHO histologic classification system reflects invasiveness and immunologic function of thymic epithelial tumors. In this subsequent study, they examined the prognostic significance of this classification system. METHODS: Clinical features as well as postoperative survival of patients with thymoma, but not thymic carcinoma, were examined with reference to WHO histologic classification based on an experience with 273 patients over a 44-year period. RESULTS: There were 18 type A tumors, 77 type AB tumors, 55 type B1 tumors, 97 type B2 tumors, and 26 type B3 tumors. In patients with type A, AB, B1, B2, and B3 tumors, the respective proportions of invasive tumor were 11.1%, 41.6%, 47.3%, 69.1%, and 84.6%; the respective proportions of tumors with involvement of the great vessels were 0%, 3.9%, 7.3%, 17.5%, and 19.2%; and the respective 20-year survival rates were 100%, 87%, 91%, 59%, and 36%. According to the Masaoka staging system, the 20-year survival rates were 89%, 91%, 49%, 0%, and 0% in patients with Stage I, II, III, IVa, and IVb disease, respectively. By multivariate analysis, the Masaoka staging system and the WHO histologic classification system were significant independent prognostic factors, whereas age, gender, association with myasthenia gravis, completeness of resection, or involvement of the great vessels were not significant independent prognostic factors. CONCLUSIONS: This study showed that histologic appearance reflects the oncologic behavior of thymoma when the WHO classification system is adopted. The WHO classification system may be helpful in clinical practice for the assessment and treatment of patients with thymoma.     

Expression of type IV collagen, metalloproteinase-2, metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 in laryngeal squamous cell carcinomas

Objective: To investigate the significance of type IV collagen, metalloproteinase-2 (MMP-2), metalloproteinase-9 (MMP-9) and tissue inhibitor of metalloproteinase-1 (TIMP-1) expression in laryngeal squamous cell carcinomas (LSCCs). Methods: Expression was quantified in 44 LSCC and 22 adjacent non-cancer normal tissues using a streptavidin-peroxidase conjugated immunohistochemistry and associations between the levels of the four proteins and clinicopathological characteristics in LSCC were analyzed. Results: Significantly different expression of all four proteins was observed in LSCC and adjacent non-cancer normal tissues (P<0.05). Expression of type IV collagen correlated with primary cancer status (P = 0.04), clinical stage (P = 0.04) and histological grade (P = 0.01). Expression of MMP-9 correlated with the location of the tumor (P = 0.04), cervical node metastasis (P = 0.02) and prognosis (P = 0.02). The (MMP-2+MMP-9)/TIMP-1 score was associated with the prognosis of LSCC (P < 0.01). Conclusions: This study suggests that expression of type IV collagen and its regulators is strongly associated with the development of LSCC. Type IV collagen and MMP-9 may be more valuable than MMP-2 and TIMP-1 for the evaluation of clinical characteristics. Regulation of type IV collagen may contribute to the balance of MMPs and TIMPs in LSCC.