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.     

Steroid receptor expression in thymomas and thymic carcinomas

BACKGROUND:

Although protein expressions of glucocorticoid receptor (GR), estrogen receptors (ERα and ERβ), progesterone receptor A (PgR‐A), and androgen receptor (AR) were shown to play roles in the growth and differentiation of normal thymus and thymic tumors, to the authors' knowledge their association with patient characteristics and prognosis has yet to be determined.

METHODS:

A series of 140 thymic epithelial tumors (57 type A + AB thymomas, 40 type B1 + B2 thymomas, 6 type B3 thymomas, and 37 thymic carcinomas) were examined for GR, ERα, ERβ, PgR‐A, and AR expression using immunohistochemistry. In addition, the correlation between expression of these hormone receptors and clinicopathologic factors and overall survival (OS) was assessed.

RESULTS:

GR and ERβ demonstrated a high rate of expression in thymomas and thymic carcinomas (82.9% and 76.4%, respectively), whereas rates of ERα, PgR‐A, and AR expression were low (13.6%, 0.71%, and 23.6%, respectively). A significant correlation (P < .05) was found between ERα expression and tumor size and between ERβ expression and tumor stage. Multivariate analyses revealed that histologic subtype (P = .0039), tumor stage (P = .0012), and GR expression (P = .0025) were significantly correlated with the 10‐year OS rate.

CONCLUSIONS:

GR and ERβ demonstrated high rates of expression in thymomas and thymic carcinomas. Furthermore, multivariate analysis revealed that GR expression was associated with better prognosis in patients with surgically resected thymomas and thymic carcinomas. Cancer 2011;. © 2011 American Cancer Society.     

Diagnostic and clinical significance of KIT(CD117) expression in thymic epithelial tumors in China

Aims: To study KIT (CD117) expression in thymic epithelial tumors in China, and investigate diagnosticand clinical significance. Material and Methods: Thymic epithelial tumors (TETs) from 102 patients (3 type A,29 type AB, 5 type B1, 22 type B2, 29 typeB3 and 16 thymic carcinomas) were examined. Immunohistochemicalstaining with an antic-kit monoclonal antibody was performed on a tissue microarray. Relationships betweenKIT positive expression and the TET clinical characteristics (WHO histologic classification and Masaoka stagesystem) were analysed. Results: The KIT positive expression rate was significantly higher in thymic carcinoma(60%, 9/16) than in thymoma (8%, 7/86), a strong correlation being found with the WHO classification, but notthe Masaoka tumor stage. The overall survival for patients with KIT positive lesions was significantly worse.Conclusions: KIT is a good molecule marker to differentially diagnose thymic carcinoma from thymoma, whilealso serving as a predictor of prognosis for TETs. Further research into KIT mutations in Chinese TETs shouldbe conducted to assess the efficacy of targeted therapy.     

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.     

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.     

多层螺旋CT在低危和高危胸腺瘤及胸腺癌鉴别诊断中的价值

目的:探讨低危和高危组胸腺瘤及胸腺癌的增强CT特征。方法:回顾性分析61例胸腺瘤及胸腺癌患者,分为低危组胸腺瘤组（n=20）、高危组胸腺瘤组（n=18）和胸腺癌组（n=23）。所有患者均行CT增强检查,分析肿瘤最大径、最小径、形态、密度、边缘、是否存在坏死及钙化、是否存在淋巴结转移或远处转移、是否存在周围组织结构侵袭以及是否出现胸腔积液等。结果:胸腺癌组肿瘤包膜完整性、周围侵犯、是否合并胸腔积液、淋巴结转移,与低危组胸腺瘤组和高危组胸腺瘤组比较,均有显著差异（P＜0.05）;低危组胸腺瘤组与高危组胸腺瘤组比较,在肿瘤的形态、包膜完整性及周围侵犯方面差异均具有统计学意义;低危组胸腺瘤组增强CT值高于高危组胸腺瘤组、高危组胸腺瘤组增强CT值高于胸腺癌组（P＜0.05）。结论:增强CT对低危、高危胸腺瘤及胸腺癌具有良好的鉴别诊断价值。     

Aberrant methylation: common in thymic carcinomas, rare in thymomas

Thymic carcinoma, which is a rare epithelial neoplasm of the thymus gland, is different from thymoma in its clinical and pathological features. To clarify the mechanism underlying the aggressive behavior of thymic carcinoma, we examined the clinicopathologic features, aberrant methylation patterns of the tumor suppressor genes, and epidermal growth factor receptor (EGFRs) mutation in both thymic carcinomas and thymomas. Clinical data of 11 thymic cancers and 13 thymomas were reviewed. Resected samples of 5 thymic cancers and 6 thymomas selected from 24 cases were used for methylation and mutation studies. Positive tumor markers were more frequent in thymic cancers than in thymomas (p=0.0233), and the methylation index, which reflects the overall methylation pattern, was significantly higher in thymic carcinomas (p=0.0053). No tumors showed a mutation of EGFR, KRAS, and HER2. Thymic carcinoma is distinct from thymoma not only with respect to clinicopathological features, but also aberrant methylation patterns of the tumor suppressor genes.     

COX-2 upregulation in thymomas and thymic carcinomas

The treatment of advanced stage thymomas and thymic carcinomas is a multimodal therapy. New therapeutic targets are currently under investigation, including the epidermal growth factor receptor (EGFR) as well as KIT. A number of studies have shown protumorigenic potential of Cyclooxygenase-2 (COX-2) in a variety of human malignancies, but so far it is unknown whether COX-2 is expressed in primary malignancies of the thymus. Using tissue microarrays, the expression of COX-2, microsomal-PGES-1 and -PGES-2 (mPGES-1 and mPGES-2), as well as EGFR was evaluated in different subtypes of thymoma and thymic carcinomas. COX-2 was expressed in all subtypes as determined by immunohistochemistry. Some cases of type B2 and thymic carcinomas had COX-2 staining levels classified as mild to moderate. However, when measuring the optical color intensity, no significant differences could be detected. Concerning the expression levels, a weak correlation between the expression of COX-2, mPGES-1 and mPGES-2 as well as EGFR was found. Furthermore, additional cases of thymomas and thymic carcinomas were analyzed by COX-2 Western immunoblot analysis and were compared to normal thymi. The analysis showed that thymomas and thymic carcinomas had a significantly stronger COX-2 expression than that of the normal thymi (p < 0.04). In summary, COX-2 is expressed in all subtypes of thymomas and thymic carcinomas and thus represents, in addition to EGFR and KIT, a potential therapeutic target. Further studies are needed in order to determine whether a combined therapy using COX-2 inhibitors in addition to the evolving anti-EGFR antibody therapy may be considered as a treatment option.     

Clusters of chromosomal imbalances in thymic epithelial tumours are associated with the WHO classification and the staging system according to Masaoka

Using comparative genomic hybridisation, we investigated chromosomal imbalances in 28 cases of thymic epithelial neoplasms including type A, B2, B3, the A component of type AB and different subtypes of type C thymoma. To identify different patterns of chromosomal aberrations associated with the biological behaviour and the histological diversity of thymomas, a hierarchical cluster analysis of 65 cases was performed. The here-reported Comparative Genomic Hybridisation (CGH) data (28 cases) of partly uninvestigated tumour subtypes were pooled with previously published data of chromosomal imbalances of 37 thymomas (Zettl et al. [Am J Pathol 2000;157:257-66]). The analysis of 278 chromosomal subbands yielded 2 main clusters. The first main cluster was characterised by gains of the chromosomal arm 1q, consisted only of type C and B3 thymomas and was further subdivided into 2 subgroups. To the first subgroup only thymomas were attributed, which, in addition to gains of the chromosomal arm 1q, showed losses on 6q and 16q, whereas tumours belonging to the second subgroup exhibited no further recurrent chromosomal alterations. The second main cluster was formed by a heterogeneous group of thymoma types (types A, AB, B2, B3 and C), showing no specific pattern of chromosomal imbalances. In 19 thymomas, no chromosomal imbalances could be detected (3 type B2 and 5 type A thymomas of our study as well as 11 type A thymomas investigated by Zettl et al., Am J Pathol 2000;157:257-66). Chromosomal imbalances were more frequent in type C thymomas than in other subtypes. The distribution of tumour stages according to Masaoka (p = 0.003) and the World Health Organisation (WHO) classification (p < 0.0001) was significantly different in the clusters and subgroups obtained. The groups reflect the staging system and the WHO classification and show that type B3 and type C carcinomas have a strong relationship concerning their chromosomal imbalances. Furthermore, chromosomal imbalances detected in some type A thymomas might be responsible for the aggressive behaviour described in a few cases of this thymoma subtype.     

Pericardial involvement by thymomas

Thymomas are usually found in the anterior mediastinum, the normal location of the thymus. Involvement of the pericardium by thymic tumors is seen in invasive or metastasized thymoma. Very rarely, thymomas arise primarily in the pericardium. These tumors are believed to derive from thymic tissue which was misplaced in the pericardium during embryologic development. In contrast to patients with orthotopic thymoma who commonly suffer from paraneoplastic diseases, especially myasthenia gravis, patients with intrapericardial thymoma manifestations mainly have symptoms of congestive heart failure which are caused by local complications of tumor growth. In this study, we present two cases of thymoma involving the pericardium. Both tumors were polygonal-oval cell thymomas. In one of the cases diagnosis of an entirely intrapericardial thymoma was established by autopsy. In the other case, explorative thoracotomy revealed massive pericardial and pleural tumor manifestations. The latter tumor showed a peculiar histological pattern with multiple glomeruloid bodies, a finding reported only once for thymomas.     

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.     

Thymomas

Forty-six thymomas, defined as neoplasms of thymic epithelium, were assessed in respect to histologic type, clinical manifestations and end results. Twenty-three were lymphoepithelial, 12 epithelial, and 11 spindled cell tumors. The sex distribution for all thymomas was approximately equal for males and females but the lymphoepithelial tumors were more common in females and the epithelial tumors more common in males. There was no distribution difference in sex for the spindled cell thymomas which occurred much later in life than the other types. Twenty-five percent of patients were asymptomatic, the tumors being discovered on roentgenograms done on a routine basis or for an unrelated purpose. The most common presenting symptoms were related to myasthenia gravis, and symptoms due to pressure on mediastinal structures were next in frequency. Other endocrine abnormalities were present in 20% of patients. Two male patients also had carcinomas of the thyroid gland. Twenty thymomas were infiltrative tumors having invaded the adjacent mediastinum. There were no examples of extrathoracic spread. Twelve of 16 patients with myasthenia gravis had lymphoepithelial thymomas and four epithelial thymomas. There were no cases of myasthenia gravis in patients with spindled cell thymomas. The crude five-year survival rate was 65%. Only 17% of patients died as a result of recurrent and infiltrative thymomas; the other 18% of patients died from a variety of causes not directly related to the thymomas. The epithelial type of thymoma tended to be more extensive and to pursue a more aggressive course but histologic classification was of little value in predicting final outcome. Poor prognosis is more closely associated with tumors having an infiltrative character. Classification is of importance, however, in alerting the clinician to certain associated diseases.     

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.     

18F‐fluorodeoxyglucose and 11C‐acetate positron emission tomography are useful modalities for diagnosing the histologic type of thymoma

BACKGROUND:

The objective of this study was to clarify the usefulness of positron emission tomography (PET) using¹⁸F‐fluorodeoxyglucose (FDG) and carbon 11‐labeled acetate (AC) for predicting the histologic types and tumor invasiveness of thymoma in a multicenter study.

METHODS:

Forty thymomas were examined using both FDG‐PET and AC‐PET before surgery. The histologic types were type A in 1 thymoma, type AB in 12 thymomas, type B1 in 11 thymomas, type B2 in 7 thymomas, type B3 in 6 thymomas, and type C in 3 thymomas. Tumor invasiveness was assessed by pathologic tumor stage and was identified as stage I in 17 tumors, stage II in 17 tumors, stage III in 4 tumors, and stage IV in 2 tumors. FDG and AC uptake was measured as the maximum standard uptake value (SUV).

RESULTS:

The FDG‐SUV in type C thymomas was significantly higher than that in the other types (A‐B3; P = .001 – P = .048). The AC‐SUV in type A/AB thymomas was significantly higher than that in the other tumor types (B1‐C; P < .001 – P = .002). All 3 type C tumors had an FDG‐SUV ≥6.3, and all 13 type A/AB tumors had an FDG‐SUV <6.3 and an AC‐SUV ≥5.7. All 17 thymomas that had an FDG‐SUV <6.3 and an AC‐SUV <5.7 were type B1, B2, or B3. Neither the FDG‐SUV nor the AC‐SUV differed significantly between the stages I/II tumors and stage III/IV tumors.

CONCLUSIONS:

Although neither the FDG‐SUV nor the AC‐SUV can predict the invasiveness of thymomas assessed by tumor stage, they are useful for predicting histologic types of thymoma. Thymomas with an FDG‐SUV <6.3 and an AC‐SUV ≥5.7 almost certainly are types A/AB, which is of considerable prognostic and management significance. Cancer 2009. © 2009 American Cancer Society.     

p16INK4, pRB,p53 and cyclin D1 expression and hypermethylation of CDKN2 gene in thymoma and thymic carcinoma

There have been few reports on genetic alterations in thymomas. To investigate the expression of p16^INK4A, RB, p53 and cyclin D1 in thymomas, we first examined 36 thymomas (non-invasive type, 16 cases; invasive type, 20 cases) and 3 thymic carcinomas, using immunohistochemistry. Abnormal expression of p16^INK4A, RB, p53 and cyclin D1 was observed in 18, 8, 10 and 7 cases, respectively. Only a subgroup of invasive thymomas and thymic carcinomas showed an inverse correlation between p16^INK4A and RB expression. Subsequently, we examined the 36 thymomas and 4 thymic carcinomas for mutations in p53 and CDKN2 genes, using PCR-SSCP and direct-sequencing analyses. No mutation of these genes was detected in the thymomas and thymic carcinomas examined. A polymorphism in the 3′ untranslated region of exon 3 of CDKN2 was detected in 5 cases of thymoma. We searched for hypermethylation in the promoter region of CDKN2, observing it in 4 thymomas and 1 thymic carcinoma. Our data suggest that, unlike other more common cancers, alteration of the p53 gene may not play a significant role in the tumorigenesis of thymoma. However, inactivation of p16^INK4A and RB may play a role in the progression of thymoma and thymic carcinoma. Int. J. Cancer 73:639–644, 1997. © 1997 Wiley-Liss, Inc.     

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.     

Analysis of the tumor microenvironment and mutation burden identifies prognostic features in thymic epithelial tumors

Thymic epithelial tumors (TETs) are one of the rarest adult malignancies in the anterior mediastinum. Thymic carcinomas (TCs) are less prevalent among TETs, but they are more clinically aggressive. Immunotherapy has emerged as a promising therapeutic approach for refractory TETs, even though chemotherapy remains the conventional treatment for the advanced disease. However, limited attention has been paid to the features of the tumor microenvironment (TME) which might provide clinically relevant information and guide treatment regimen design. Especially, to date, there have been only a few studies focusing on the differences between the TME and genomic features preserved by TETs and TCs. We analyzed the TME and genomic characteristics of TETs using RNA sequencing and whole-exome sequencing, finding that distinct characteristics of TME in different pathogenic subtypes of TETs. According to those findings, we found that thymic carcinomas had significantly lower expression of HMGB1, a pro-inflammatory cytokine-related gene, than thymomas, and low HMGB1 expression was linked to a poor prognosis. Additionally, higher mutation burdens were significantly associated with the later stage and more advanced pathological types. Thymoma patients with lower mutation burdens tended to relapse within 3 years. In summary, different characteristics of TME and genomic features between thymoma and thymic carcinoma were associated with clinical outcomes of TETs and presented promisingly predictive value for efficacy and toxicity of immunotherapy.     

Role of combined F-FDG-PET/CT for predicting the WHO malignancy grade of thymic epithelial tumors: A multicenter analysis

Introduction

To investigate the performance of combined ¹⁸F-FDG-PET/CT as a predictor of the WHO-classification based malignancy grade in thymic epithelial tumors.

Methods

From 05/06 to 02/12, the data of 47 patients with thymic epithelial tumors assessed by ¹⁸F-FDG-PET/CT before being surgically treated were collected in 3 centers and retrospectively reviewed for the purposes of this study. The SUVmax and the SUVmax/T index (the ratio tumor-SUVmax to tumor-size) have been matched with specific subgroups of the WHO-classification: low-risk thymomas (types A–AB–B1), high-risk thymomas (types B2–B3) and thymic carcinomas (type C).

Results

There were 22 men and 25 women (age range: 31–84 yrs). Mean tumor size was 44.7 ± 19.0 mm. The WHO-classification was: type-A #2, type-AB #11, type-B1 #9, type-B2 #9, type-B3 #9 and type-C #7. The SUVmax and the SUVmax/T were found to be predictive factors useful to distinguish thymomas from thymic carcinomas (SUVmax: area under ROC-curve: 0.955, p = 0.0045; SUVmax/T-size: area under ROC-curve: 0.927, p = 0.0022). Moreover, both parameters were found to be correlated with the WHO malignancy grade (low-risk thymomas; high-risk thymomas; thymic carcinoma), Spearman correlation coefficients being 0.56 (p < 0.0001) and 0.76 (p < 0.0001), respectively for the SUVmax and for the SUVmax/T index. In addition, the SUVmax is also significantly correlated with Masaoka stage (Spearman correlation coefficient: 0.30, p = 0.0436)

Conclusions

A significant relationship was observed between ¹⁸F-FDG-PET/CT findings and histologic WHO-classification for this cohort of thymic epithelial tumors. Thus, on the basis of these evidences, we infer that ¹⁸F-FDG-PET/CT may be useful to predict histology and the WHO classes of risk.     

Increased expression of matrix metalloproteinase-2 and tissue inhibitor of metalloproteinase-2 is correlated with poor prognostic variables in patients with thymic epithelial tumors

BACKGROUND: A distinction between noninvasive, invasive, and metastatic thymoma on the basis of the cytologic features is difficult. The current study investigated whether the expression of MMP and TIMP was correlated with tumor invasiveness and prognosis in patients with thymoma. METHODS: Tumor tissue samples were obtained from 42 patients with thymic epithelial tumors between 1974 and 2001 at Tokushima University Hospital. Three-micrometer-thick, formalin-fixed, paraffin-embedded tissue sections were immunostained using specific antibodies against MMP-2, MMP-9, TIMP-1, and TIMP-2. RESULTS: MMP-2 expression was detected in 30 tumors (71%), and TIMP-2 expression was detected in 31 tumors (74%). MMP-9 expression was detected in 22 of 36 tumors (61%), and TIMP-1 expression was detected in only 7 tumors (19%). MMP-2 and TIMP-2 expression levels were very low (10% and 0%, respectively) in noninvasive tumors but were very high (91% and 97%, respectively) in invasive tumors. In thymic epithelial tumors, the more progressive the clinical stage of tumor, the higher the strongly positive rate of MMP-2 and TIMP-2 expression. There was no correlation between positivity for MMP-9 and stage. Twenty-five percent of Type AB thymomas and 50% of Type B1 thymomas expressed MMP-2 and TIMP-2. Most of Type A, Type B2, Type B3, and Type C thymomas expressed MMP-2 and TIMP-2. There were significant differences in disease-free survival at 5 years between patients without and with MMP-2 expression (91% vs. 55%, respectively) and patients without and with TIMP-2 expression (100% vs. 53%, respectively). CONCLUSIONS: MMP-2 and TIMP-2 are key enzymes for invasiveness of thymic epithelial tumors. The expression of these proteins can predict a poor outcome in patients with thymoma.     

High frequency of p53 protein expression in thymic carcinoma but not in thymoma.

Thymic epithelial tumours are broadly classified into thymomas and thymic carcinomas. Although both tumours occasionally show invasive growth, they exhibit different clinical and biological findings. The oncogene and anti-oncogene in thymic epithelial tumours have not been evaluated fully. We investigated the expression of p53 protein by immunohistochemical analysis using the anti-p53 polyclonal antibody (CM-1) in 17 thymomas and 19 thymic carcinomas. We also examined p53 gene (exon 5-8) mutation in 18 thymic carcinomas by using polymerase chain reaction-single-strand conformation polymorphism methods and direct sequencing. Of the thymoma cases, only one invasive thymoma showed focal nuclear staining. Fourteen of the 19 thymic carcinomas (74%) showed nuclear staining. Point mutations of the p53 gene were recognized in only 2 of the 18 thymic carcinomas (11%). One was the mutation C to T transition in the first letter of codon 222 in exon 6, which results in the amino acid substitution from proline to serine. Another was a silent mutation. p53 protein accumulation is highly frequent in thymic carcinomas but not in thymomas, and gene mutation is uncommon in thymic carcinomas.