Clinical and functional significance of WHO classification on human thymic epithelial neoplasms: a study of 146 consecutive tumors

We examined the clinical and functional significance of histologic classification of thymic epithelial neoplasms proposed by the World Health Organization (WHO), based on an analysis of 146 consecutive tumors derived from 141 patients and 47 normal thymuses derived from children ranging in age from 1 to 9 years. Invasive tumors were seen in 12.5%, 38.6%, 40.0%, 69.4%, 80.0%, and 100% of type A, AB, B1, B2, B3, and C primary tumors, respectively. All of six recurrent or metastatic lesions were type B2 tumors. Myasthenia gravis was associated in 0%, 6.8%, 40.0%, 55.6%, 10.0%, and 0% in patients with type A, AB, B1, B2, B3, and C tumors, respectively. The average number (x10(6)) of tumor-associated CD4+CD8+ cells present in 1 g of tumor tissue was 1.5, 391.1, 1041.7, 333.9, 24.5, and 0.2 in type A, AB, B1, B2, B3, and C, respectively, and it was 1168.2 in the normal thymuses. Thus, type B1 tumor retained the function to induce CD4+CD8+ double-positive cells at a level comparable to that of the normal thymic cortical epithelial cells, followed by type AB and type B2 tumors. Type A and B3 tumors had this function at a barely detectable level, and type C tumor was nonfunctional. WHO histologic classification was shown to reflect the clinical features and the T-cell-inducing function of thymic epithelial tumors.     

Clinical usefulness of the WHO histological classification of thymoma.

PURPOSE: Rosai et al. published the World Health Organization (WHO) classification of thymic epithelial tumors in 1999, and its clinical usefulness seems to be established. It is our purpose to find the clinically relevant diagnostic points in the WHO Histological Classification of Thymoma. METHODS: Thymomas surgically removed from 100 consecutive patients at Juntendo University Hospital between October 1983 and February 2002 were classified according to the WHO histological classification. We assessed overall survival and recurrence-free rate calculated for each tumor type in the WHO classification compared with those of tumors classified by the Masaoka system. RESULTS: The thymic epithelial tumors in this series comprised 10 type A, 15 type AB, 18 type B1, 21 type B2, 33 type B3, and 3 type C tumors according to the WHO classification. Based on the Masaoka system, the disease was stage I in 53 patients, stage II in 30, stage III in 15, and stage IV in 2. The 15-year recurrence-free rate was 100% for type A, AB and B1, while the rates for types B2 and B3 were 66.7% and 54.5%, respectively. The 10-year recurrence-free rate was 66.7% for type C. The 15-year recurrence-free rate of the 64 patients with type A, AB, B1, and B2 thymomas was significantly higher from that of the 33 patients with type B3 thymoma (p=0.0026). CONCLUSION: When using the WHO classification, it is critical to distinguish type B3 thymoma from other tumor types.     

Surgery for thymomas and thymic carcinomas; treatment results in terms of WHO histologic typing,Masaoka staging system,and p53 expression

Forty thymomas and thymic carcinomas were classified in terms of WHO histologic typing, Masaoka staging system, and p53 expression. In WHO histologic typing, type A, AB, B1, B2, B3, and C were 1, 10, 16, 5, 4, and 4 cases, respectively. In Masaoka staging system, I, II, III, and IV were 15, 9, 10, and 6 cases, respectively. Thirteen thymomas exhibited positive p53 expression and 27 did not. Type A and AB thymomas had more favorite prognosis than type B3 and C thymomas, and prognosis of type B1 and B2 was middle. Staging by the Masaoka system also correlated with survival rates. Patients who had p53-negative thymomas survived longer than those who had p53-positive thymomas. A treatment strategy for thymomas and thymic carcinomas should be made on the basis of WHO histologic typing, Masaoka staging system, and p53 expression.     

Clinicopathological character and long-term results of thymic epithelial tumor categorized by WHO classification

We analyzed clinicopathological character and long term results of 50 thymic epithelial tumors with reference to WHO histologic classification. There were 1 type A tumor, 8 type AB tumors, 13 type B1 tumors, 16 type B2 tumors, 10 type B3 tumors, and 2 type C tumors. Clinical stages were progressive in order of classification type A, AB, B1, B2, B3, and C. Type B1 and B2 were highly associated with myasthenia gravis (MG). There were four multiple thimic tumor in patients of advance clinical stage with polygonal epithelial cell tumor. Long term results were poor in order of the classification of type A, AB, B1, B2, B3, and C. In our study, WHO classification finely reflected the clinical character and prognosis of thymic epithelial tumors.     

Prediction of thymoma histology and stage by radiographic criteria

Thymic epithelial tumors, such as thymomas and thymic carcinomas, are the most common primary neoplasms of the mediastinum. In 1999, the World Health Organization (WHO) proposed a consensus classification of thymic epithelial tumors based on the morphology of the epithelial cells and the ratio of lymphocytes to epithelial cells, which was revised in 2004. The latest classification system stratifies thymic epithelial tumors into six categories: types A, AB, B1, B2, B3, and thymic carcinoma. This article describes the prediction of thymoma histology and stage on the basis of radiographic criteria by reviewing the following: the WHO histologic classification of thymic epithelial tumors, the clinical staging of thymomas based on prognosis, and the radiographic appearance of thymomas according to the WHO histologic classification.     

Oncological significance of WHO histological thymoma classification

OBJECTIVES: The clinical significance of thymoma histology remains controversial because of the numerous histological classifications of thymic epithelial tumors. Universal classification of such tumors was achieved by the World Health Organization (WHO) in 1999. We studied the prognostic significance of this classification. METHODS: We studied clinical features and postoperative survival in cases of thymoma, but not thymic carcinoma, based on WHO histological classification in 286 patients undergoing surgery between 1958 and 2001. RESULTS: Tumors were 19 type A, 79 type AB, 59 type B1, 102 type B2, and 27 type B3. The proportion of invasive tumors increased by type--from A to AB, B1, B2, and B3. The great vessels were involved more frequently in type B2 and B3 tumors than in type A, AB, and B1 tumors. The 20-year survival was 100% in type A, 87% in type AB, 91% in type B1, 65% in type B2, and 38% in type B3 tumors. Multivariate analysis showed Masaoka staging and WHO histological classification to be significant independent prognostic factors, while age, gender, myasthenia gravis association, resection completeness and great vessel involvement were not. In stage III patients, 13 of 45 patients with type B2 and B3 tumor died of their tumors, while no tumor deaths occurred in 11 patients with type A, AB, and B1 tumors. CONCLUSION: WHO histological classification realistically reflects the oncological behavior of thymoma.     

Clinical and pathological aspects of thymic epithelial tumors

A histological classification of thymic epithelial tumors was presented by the World Health Organization (WHO) in 1999 and again in 2004 following slight modifications, in which thymic epithelial tumors were categorized as thymomas and thymic carcinomas. Whereas thymoma is defined as an organotypic (thymuslike) tumor, thymic carcinoma is a malignant epithelial neoplasm with a morphology similar to that of malignant neoplasms arising from other organs. Herein, the recent progress in research of thymic epithelial tumors is reviewed with reference to the WHO histological classification system, with the focus on thymomas. Thymomas are classified into five types—A, AB, B1, B2, B3—according to the shape and atypia of their epithelial cells as well as the abundance of lymphocytes. The invasiveness, prognosis, and genetic imbalance of thymomas have been shown to be related to this classification system. Myasthenia gravis is frequently associated with types B1 and B2. The WHO histological classification of thymomas is not only useful for treatment but reflects their biological characteristics, including genetic alterations. Advances are expected in future studies of thymomas from the standpoint of their clinical, pathological, and biological aspects. This review was submitted at the invitation of the editorial committee.     

Clinical and functional aspects of the World Health Organization histologic classification of thymic epithelial tumors

The World Health Organization (WHO) histologic classification was presented by the international committee to provide a universal system for clinicians and researchers in 1999 and was further modified in 2004. This classification is mainly based on Müller-Hermelink et al.'s system and six distinct types were defined. Thymomas were classified into type A, AB, B1, B2, and B3 tumors, according to the shape and atypia of epithelial cells and also the abundance of lymphocytes. Another type of tumor is thymic carcinomas, which have apparent atypia of neoplastic cells. Neuroendocrine tumor (carcinoid) of the thymus was categorized as thymic carcinoma because of the resemblance of genetic aberrations. Several studies have shown that the WHO histologic type is correlated with the proportion of invasive tumors and is an independent prognostic factor along with Masaoka stage. Furthermore, association with myasthenia gravis, ability to induce CD4+CD8+T cells and express HLA-DR molecules, and chromosomal imbalances such as loss of heterogeneity were found to be correlated with the WHO histologic type. Thus, the WHO histologic classification system reflects the oncologic, immunologic, and genetic characteristics of thymic epithelial tumors. The clinical application of this classification system is expected.     

Results of surgical treatment for thymic epithelial tumors with special reference to the WHO classification

We examined the clinical significance of World Health Organization (WHO) classification based on a surgical experience with 71 patients. There were 6, 21, 6, 10, 14, and 14 patients with type A, AB, B1, B2, B3 and C tumors. In these patients, average stage by Masaoka's classification was significantly associated with the WHO classification. Invasive tumors of stage III and IV were seen more frequently in patients with type B2, B3 and C tumors than in those with type A, AB and B1. The incidence of tumors invading the lung, the pericardia or the pleura was higher in type B2, B3 and C than in type A, AB or B1. Furthermore, tumor recurrences and tumor-related deaths were seen only in patients with type B2, B3 or C. This study suggested that type B2, B3 and C tumors had more malignant nature in terms of invasiveness, recurrence and prognosis following operation, and that WHO classification may be a useful guideline for planning treatment of thymic epithelial tumors.     

Expression of proteasome subunit β5t in thymic epithelial tumors

Recently, a proteasome β subunit expressed exclusively in thymic cortical epithelial cells was discovered in mice and humans. This subunit, designated β5t, is a component of the thymoproteasome, a specialized type of proteasome implicated in thymic positive selection. To investigate whether β5t could serve as a marker for the differential diagnosis of thymic epithelial tumors, we performed immunohistochemical analysis using anti-β5t antibody in 54 cases of thymic epithelial tumors comprising 41 cases of thymomas and 13 cases of thymic carcinomas. β5t was detected in the neoplastic epithelial cells of thymomas. Among the subtypes of thymoma, expression of β5t was observed in most cases of type B thymoma (20 of 21) but not in type A thymomas (0 of 3). In type AB thymomas, β5t expression was variable (6 of 17). Type B3 thymomas (4 cases) were positive for β5t but negative for CD5, c-kit, and glucose transporter 1 (GLUT-1), which are known as diagnostic markers for thymic carcinomas. In contrast, thymic carcinomas were negative for β5t (0 of 13) but expressed at least one and usually all of CD5, c-kit, and GLUT-1. Thus, β5t and CD5/c-kit/GLUT-1 were differentially expressed in type B3 thymoma and thymic carcinoma. We tested β5t expression in 39 cases of tumors arising from other organs, which showed the specific expression of β5t in thymic epithelial tumors. This study demonstrates that β5t is expressed in most type B and in some type AB thymomas and is a marker useful in differentiating type B3 thymomas from thymic carcinomas when used in combination with other diagnostic markers.     

Prognosis and therapeutic response according to the world health organization histological classification in advanced thymoma

Purpose

The clinical efficacy of the World Health Organization (WHO) classification of thymoma has been reported to be a prognostic factor for patients with thymomas. This study focuses on the relationship between the therapeutic response and the WHO histological classification in patients with advanced thymoma.

Methods

A retrospective review was performed on 22 patients with Masaoka stage III and IV thymoma treated from 1975 to 2007. There were 1, 1, 7, 3, and 10 patients with WHO histological subtypes A, AB, B1, B2, and B3, respectively.

Results

Surgery was performed on 10 patients. There were 2 complete resections, 2 incomplete resections, and 6 exploratory thoracotomies. Of 18 patients with unresectable tumors, 8, 5, and 5 were treated with radiotherapy, chemotherapy, and chemoradiotherapy as the initial therapy, respectively. The response rate in 9 patients with type A-B2 was significantly better than that in 9 patients with type B3 regardless of treatment modality (100% vs 11.1%, P = 0.0001). Only the WHO classification was significantly associated with survival, with type B3 having a worse prognosis than A-B2 (P = 0.01).

Conclusions

Type B3 thymoma showed a lower response rate to treatments and thus shorter survival. The WHO classification is a good predictive factor for therapeutic response in advanced thymoma.     

WHO histologic classification is a prognostic indicator in thymoma

BACKGROUND: The histologic classification of thymoma has remained a subject of controversy for many years. In 1999, the World Health Organization Consensus Committee published a histologic typing system for tumors of the thymus. METHODS: We reclassified a series of 100 thymomas resected at Tokushima University Hospital and four affiliated hospitals in Japan between 1973 and 2001 according to the World Health Organization histologic classification and reported its clinicopathologic relationship and prognostic relevance. RESULTS: There were 8 type A, 17 type AB, 27 type B1, 8 type B2, 12 type B3, and 28 type C thymomas. The frequency of invasion to neighboring organs increased according to tumor subtype in the order A (0%), AB (6%), B1 (19%), B2 (25%), B3 (42%), and C (89%). There was no recurrence in patients with type A, AB, or B2 thymoma. The recurrence rates of patients with B1, B3, or C thymoma were 15%, 36%, and 47%, respectively. The disease-free survival rates were 100% for types A and AB, 83% for types B1 and B2, 36% for type B3, and 28% for type C thymoma at 10 years. There were significant differences in disease-free survival between types A and AB and types B1 and B2 (p = 0.0436), and between type B3 and type C (p = 0.042). By multivariate analysis, only Masaoka clinical stage (p = 0.002) showed significant independent effects on disease-free survival. The 10-year survival rates of types A and AB, types B1 and B2, type B3, and type C thymoma were 100%, 94%, 92%, and 58%, respectively. CONCLUSIONS: The current study confirmed the World Health Organization histologic classification as a good prognostic factor.     

Thymic carcinoma: is it a separate entity? From molecular to clinical evidence

The second edition of the World Health Organization (WHO) classification of thymic tumors (2004) has resumed the previous separation of thymic carcinomas (TCs) from?thymomas. This "reseparation" was mainly based on new genetic data. Consequently, it is no longer recommended to label TCs as type C thymomas. TCs are very heterogeneous and comprise squamous, basaloid cell, mucoepidermoid, neuroendocrine, and many other subtypes. They resemble morphologic mimics in other organs and are labeled accordingly. However, only thymic squamous cell carcinomas (TSCCs) and lymphoepithelioma-like carcinomas are relatively common. For TSCCs, quite specific immunohistochemical markers (eg, CD5, CD70, CD117, CD205, FOXN1) and chromosomal gains and losses have been defined that help to distinguish TSCCs not only from malignant thymomas but also from pulmonary squamous cell carcinomas. Recognition of these differences is clinically important, because the prognosis of TSCC is better compared with the other TC subtypes and also compared with lung tumors. Considering the need to treat advanced TC more effectively, disparate findings in predictive molecular markers (eg, KIT mutations in TSCC, but not in thymomas) suggest that targeted treatments will have to be different in thymomas and TC. Preliminary data from single case collections and small treatment trials support this prediction.     

Prognostic significance of CD44v5 expression in human thymic epithelial neoplasms

BACKGROUND: Cell surface glycoproteins of the CD44 family play roles in cell-cell and cell-matrix interactions. Their aberrant expression has been implicated in tumor invasion and metastasis of a variety of neoplasms, but not, to date, of thymic epithelial tumors. METHODS: To investigate the expression of CD44 molecules, immunohistochemical staining using monoclonal antibodies against human CD44 standard form (CD44 s) and two common splicing variant (CD44v) isoforms, CD44v5 and CD44v6, was performed on 64 resected thymomas and 20 normal thymuses. These tumors were categorized histologically according to the World Health Organization (WHO) histologic classification, and the pathologic staging was classified according to the definitions of Masaoka. RESULTS: The positive expression rates in these patients were as follows: CD44 s (normal thymuses, 10%; thymomas, 22%), CD44v5 (normal thymuses, 0%; thymomas, 67%), and CD44v6 (normal thymuses, 0%; thymomas, 26%). CD44 s and CD44v5 immunoreactivity showed a positive correlation with tumor stages (p = 0.034 and 0.027, respectively). The CD44v5 expression of neoplastic cells in tumor capsules has significant correlation with tumor stages (II, 5%; III, 70%; IVA, 100%; p < 0.001). On the basis of univariate survival analysis, the Masaoka staging system, WHO histologic classification, and CD44v5 expression showed a statistically significant positive relation to survival (p < 0.001, 0.002, 0.011, respectively). Using Cox's regression model, increasing CD44v5 expression, the Masaoka staging, and the WHO classification system were found to be significant independent prognostic factors. CONCLUSIONS: CD44v5 expression is independently positively correlated with the aggressiveness of thymic epithelial tumors. The expression of CD44v5 may be a potential trigger of tumor invasion in thymomas.     

Type AB thymoma with brain metastasis: Report of a case

Type AB thymomas are considered to be nonaggressive tumors, and the great majority are classified as Masaoka stage I or II. This report presents a case with Masaoka stage I and type AB thymoma, which metastasized to the brain 2 years 5 months after removal of the primary tumor. The original mediastinal lesion was adhesive but not invasive to the lung. The patient is now alive with multiple tiny pulmonary metastases 3 years after complete resection of the brain metastasis. Some reports of recurrent thymomas have suggested that the presence of peritumoral adherence to the adjacent structures might be a risk factor for recurrence in patients with such noninvasive thymomas. During the development of fibrosis which thus causes adhesion, the tumor may have an increased chance to metastasize because of the increased vessels and lymphatics.     

Prognosis of surgically treated thymic epithelial tumors

This study was performed to clarify the prognosis of patients with surgically treated thymic epithelial tumors. The records of 131 patients who underwent surgical treatment during 1985-2005 were retrospectively reviewed. Pathologic review was done according to the WHO classification of tumors of the thymus. Patients characteristics were: 76 male and 55 fimale; average age 53 (range 20-80) years; tumor stage was stage I in 42, stage II in 43, stage III in 23, stage IVa in 15, stage IVb in 1, and thymic carcinoma (squamous cell carcinoma) in 7 based on Masaoka's staging. There were 7 cases of type A, 23 of type AB, 30 of type B1, 27 of type B2, 29 of type B3, and 15 of type C. Surgical procedures performed were 5 partial resections, 5 tumoretomies, 5 thymectomies, 65 extended thymectomies, 4 tumorectomies plus adjunctive resections of surrounding tissue, and 51 extended thymectomies plus tumorectomies plus adjunctive resections of surrounding tissue including the pleura, pericardium, lung, and great vessels. Five-, 10-, and 15-year survival rates by Masaoka stage were 100%, 100%, and 100% in stage I; 100%, 100%, and 87.5% in stage II; 100%, 87.5%, and 87.5% in stage III; 71.1%, 53.3%, and 53.3% in stage IVa; and 42.9%, 42.9%, and 0% in thymic carcinoma. The prognosis of patients with stage IVa and thymic carcinoma was thus significantly poorer compared with that in the other groups. According to the WHO classification, the 5-year survival rate of type A was 100%, and the 5-, 10-, and 15-year survival rates were 100%, 100%, and 100% in type AB; 100%, 100%, and 75.0% in type B1; 92.6%, 86.4%, and 86.4% in type B2; 95.5%, 95.5%, and 81.8% in type B3; and 57.1%, 42.9%, and 0% in type C. The survival rate of patients with type C was the poorest and there was a significant difference between type C and all other groups. The prognosis of patients with thymic epithelial tumors after resection is thought to be determined by histologic classification and clinical invasiveness. In particular, patients with type B3 and type C thymomas should be considered for multidisciplinary treatment.     

Increased thymocyte CD4+CD8+ cells and T-cell receptor beta gene rearrangements in thymoma

Epithelial cells in thymoma and thymic carcinoma may influence T-cell development in the tumor. In this study, we investigated the cell surface phenotype and T-cell receptor (TCR) gene rearrangement of thymocytes in thymic tumors. TCR rearrangement was observed in all cases of thymoma (A, AB, B1–2). A faint band in each digestion suggested the deletion between D1 to C1 or D1 to J2, and an additional rearrangement band with BamHI suggested the rearrangement between D1 to J1. High percentages of CD1+ cells and CD4+CD8+ (DP) cells were detected in all cases of thymoma (A, AB, B1–2). There are two kinds of cell surface phenotypes increased in populations of thymoma; one is increased DP cells and the other is a relatively low percentage of DP cells accompanied by a relatively high percentage of CD3+CD69+ cells. These findings suggest that thymocytes in thymoma are derived from immature T-cell expansion.     

Thymomas: clinical-pathological correlations

AIM: Since World Health Organization (WHO) histologic typing of tumors of the thymus publication in 1999 only a few studies correlated this classification with the clinical features of the patients. We present the results of a retrospective analysis on patients, operated on for a thymoma, whose specimens were available, to compare the WHO thymoma histologic classification to the clinical behavior of the tumors. METHODS: The specimens of 69 patients, who underwent surgical treatment between 1983 and 1998, were analyzed, comparing the clinical features of the patients and the hystological typing of the neoplasm, according to the WHO classification. A survival analysis of clinical and pathological prognostic factors was carried out. RESULTS: The incidence of thymus-related syndrome was related to the histological subtype and increases progressively from A to B3, while in C subtype the incidence was nihl. With a mean follow-up of 108 months (range 54-239 months), we experienced 6 intrathoracic recurrencies, 3 of those were intrapleuric and 3 mediastinal. At the last follow-up, 52 patients were alive; 1 with disease. Five deaths were related to the tumor (2 mediastinal and 3 intrapleuric relapses). Actuarial five-year and ten-year survival was 95% and 88.9%. Because of the absence of deaths related to thymomas in most samples it was not possible to perform a comparison among different histological types and different clinical stages. CONCLUSIONS: The WHO histologic classification seems to correlate with the incidence of thymus related syndromes and the clinical stage of Masaoka. Despite the higher incidence of recurrences in type B3 and C thymoma the WHO classification did not prove to be a prognostic factor.