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.     

Thymoma: a clinicopathologic study based on the new World Health Organization classification

OBJECTIVE: This study explored the relationship between the histologic subtype of thymoma according to the new World Health Organization histologic classification and the clinical findings, as well as the prognostic significance of the classification. METHODS: A total of 130 patients with thymoma, who underwent resection at the National Cancer Center Hospital, Tokyo, from 1962 to 2000, were studied retrospectively. The histologic subtype of thymoma was determined according to the new World Health Organization histologic classification. The stage was also determined according to a modified Masaoka's classification as stage I, II, III, IVa, or IVb. To determine the factors that may affect the prognosis of thymoma, a multivariate analysis with Cox's proportional hazards regression model was performed. RESULTS: The distribution of histologic subtype was type A (n = 18), type AB (n = 56), type B1 (n = 15), type B2 (n = 29), and type B3 (n = 12). A close correlation was seen between the histologic subtype and stage (P =.000). The overall survivals at 5 and 10 years were 92% and 91%, respectively. The 5- and 10-year survivals according to stage were 100% and 100% (stage I, n = 40; stage II, n = 54), 81% and 76% (stage III, n = 25), and 47% and 47% (stage IV, n = 11), respectively. The difference in survival between stage III and stage IV was significant (P =.000). Patients with type A or AB thymoma demonstrated a 100% survival at both 5 and 10 years. Recurrences were seen in 12 patients with complete resection. According to a multivariate analysis, tumor size (P =.001), completeness of resection (P =.002), histologic subtype (P =.011), and stage (P =.00) were significant prognostic factors. CONCLUSION: The World Health Organization histologic classification significantly correlated with the clinical stage. Tumor size, completeness of resection, histologic subtype, and stage predicted the prognosis of thymoma.     

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.     

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.     

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.     

Management of myasthenic patients with thymoma

Myasthenia gravis (MG) associated with thymomas differs from nonthymomatous MG, and thymomas associated with MG are also different from non-MG thymomas. According to the World Health Organization classification, the incidence of MG in thymomas was the highest in the subtypes B2, B1, and AB. Transsternal approach is still regarded as the gold standard for surgical treatment of thymomas. Less-invasive techniques of thymectomy are promising, but it is too early to estimate their real oncological value. In the series including more than 100 patients, the prognosis for survival is better in patients with thymomas associated with MG than in those with non-MG thymomas, and the prognosis for patients with MG associated with thymoma is worse than that for patients with nonthymomatous MG.     

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.     

Diagnostic reproducibility of thymic epithelial tumors using the World Health Organization classification: note for thoracic clinicians

Objective

Histopathological diagnosis of thymic epithelial tumors according to the current World Health Organization classification is not adequately reproducible; however, most thoracic clinicians are unaware of this. We illustrate this problem in practical settings to raise clinician awareness.

Methods

An expert pathologist specialized in thymic pathology and a trained general pathologist independently diagnosed 158 resected thymic epithelial tumors. Assuming that the expert’s diagnoses were more accurate, the two pathologists’ diagnoses were judged to be concordant when tumor subtypes (thymoma) or categories (thymic carcinoma and neuroendocrine tumor) were in agreement.

Results

The concordance rates for different thymoma subtypes were 75 % (3/4), 30 % (11/37), 100 % (17/17), 80 % (39/49), and 53 % (9/17) for types A, AB, B1, B2, and B3, respectively. Discordant cases of type AB thymoma were mainly diagnosed as type B1 or B2 by the general pathologist. Discordant cases of type B2 thymoma were diagnosed as type AB, B1, or B3, and discordant cases of type B3 thymoma were diagnosed as type A, B2, or carcinoma. Discordant cases of thymic carcinoma were diagnosed as type A or B3 thymoma.

Conclusion

Investigation of the concordant and discordant cases suggested that reasonable discrepancies can occur because of the noncommittal categorical boundaries inherent in this classification. Thoracic clinicians should consider this potential problem in daily practice.     

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 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.     

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.     

Prognosis of thymic epithelial tumors according to the new World Health Organization histologic classification

Background

The aim of this study was to document the prognosis of thymic epithelial tumors (TETs) according to new the World Health Organization (WHO) classification.

Methods

We retrospectively reviewed 150 patients with TETs that were confirmed pathologically during 11 years (from 1992 to 2002) in Severance Hospital, Seoul, Korea.

Results

TETs were classified as type A, AB, B1, B2, B3, or C, tumors and these represented 7 (4.7%), 26 (17.3%), 13 (8.7%), 45 (30.0%), 26 (17.3%), and 33 (22.0%) cases, and the 5-year survival rates were 100%, 93%, 89%, 82%, 71%, and 23%, respectively. Their Masaoka stages were I, II, III, IVa, and IVb, with 53 (35.3%), 39 (26.0%), 20 (13.3%), 22 (14.7%), and 16 (10.7%) cases. Tumor invasiveness, recurrence, completeness of resection, and tumor-related death were more frequent in types AB, B2, B3, and C than in types A and B1. Multivariate analysis showed that Masaoka stage (p < 0.001) and the WHO classification (p = 0.019) were significant independent prognostic factors.

Conclusions

The WHO classification is associated with tumor invasiveness, recurrence, completeness of resection, and tumor-related death, and has good correlation with Masaoka stage. The WHO histologic subtypes are an independently significant prognostic factor with respect to survival in our multivariate analysis. Types AB, B2, B3, and C showed invasive behaviors and R1 or R2 resections were frequently performed. Postoperative adjuvant radiotherapy was effective, but long-term follow-up is recommended because of decreased survival after 5 years following operation. The WHO classification may be helpful in clinical practice for the assessment and treatment of TET patients.     

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.     

Is there a spectrum of cytologic atypia in type a thymomas analogous to that seen in type B thymomas? A pilot study of 13 cases

Thirteen cases of type A thymoma are reported showing the characteristic architectural attributes of this tumor type (World Health Organization), such as lobulation, perivascular spaces, gland-like formations, and cystic changes, but also displaying atypical features, as defined by increased mitotic activity, mild to moderate nuclear atypia, and/or scattered small foci of necrosis. The tumors were similar to type B3 thymomas in many respects, except for the fact that the tumor cells were spindled instead of round/polygonal. The existence of these cases suggests the desirability of an expansion of the type A thymoma category, analogous to that currently used for type B tumors. The various nomenclature options that could be used to name these tumors have been discussed.     

Spindle cell and mixed spindle/lymphocytic thymomas: an integrated clinicopathologic and immunohistochemical study of 81 cases

Forty-three cases of spindle cell thymoma (medullary, WHO type A) and 38 cases of mixed spindle/lymphocytic thymoma (WHO type AB) were studied for their clinicopathologic and immunohistochemical characteristics. Three histologic patterns of spindle cell thymoma were observed: short-spindled (57%), long-spindled (31%), and micronodular (12%). The short-spindled variant was composed of oval to short spindle cells commonly arranged in a hemangiopericytic or microcystic pattern. The long-spindled variant chiefly consisted of fibroblast-like epithelial cells mimicking fibrohistiocytic neoplasms. The micronodular variant was characterized by small nests of short spindle cells dispersed among a lymphoid stroma with frequent germinal centers. All kinds of spindle cell could be admixed with lymphocyte-rich "cortex"-like areas to constitute mixed spindle/lymphocytic thymomas. Immunohistochemically, the epithelial cells in up to 70% of the short-spindled and long-spindled variants of spindle cell thymoma and 90% of mixed spindle/lymphocytic thymomas were positive for CD20, whereas the epithelial cells in all micronodular spindle cell thymomas were negative. All of the spindle cell thymomas and most of the mixed spindle/lymphocytic thymomas in this study were found in stages I and II. Follow up of the patients did not disclose relapse or mortality directly resulting from the tumors. However, the prognosis of stage I and II spindle cell and mixed spindle/lymphocytic thymomas did not significantly differ from those of stage I and II thymomas of other types by a stage-matched survival analysis. Our data showed that spindle cell and mixed spindle/lymphocytic thymomas are distinctive in histologic pattern and immunohistochemical profile. When interpreted within the context of staging, spindle cell and mixed spindle/lymphocytic thymomas presenting in stages I and II most likely behave in an indolent fashion.     

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.     

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.     

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.     

Therapy for thymic epithelial tumors

Thymoma is the most common tumor of the anterior mediastinum. This tumor is associated with unique paraneoplastic syndromes. The rarity of this tumor has somewhat obscured the optimal treatment for this disease. The World Health Organization classification system, which published in 1999, appears to be an advance in our understanding of thymoma. The Masaoka classification is now the most widely accepted and is an excellent predictor of the prognosis of thymoma. Now the International Thymic Malignancy Interest Group is currently engaged in the development of a validated formal TNM classification system for thymic malignancies. The optimal treatment of thymoma is performed according to its clinical stage. Surgery remains the mainstay of treatment for thymic epithelial tumors. Minimally invasive surgery including thoracoscopic surgery and robotic surgery for stage I and II thymomas is increasing now. The value of postoperative radiotherapy in completely resected stage II or III tumors is questionable. As thymomas have a moderate response rate to chemotherapy or radiotherapy, multimodality therapy involving surgery, chemotherapy and radiotherapy appears to increase the rate of complete resection and survival in the advanced (stage III and IV) thymomas.