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.     

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.     

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.     

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.     

胸腺瘤的外科治疗和预后分析

目的探讨外科治疗在胸腺瘤治疗中的作用及预后的影响因素。 方法回顾性分析2004年1月—2017年1月就诊于甘肃省人民医院胸外科并接受手术治疗的55例胸腺瘤患者的临床资料。生存率的计算及单因素生存分析采用Kaplan-Meier法进行,组间差异使用Log-rank检验进行计算,所有经单因素生存分析有意义的参数均纳入多因素生存,采用Cox分析确定与预后相关的因素。 结果55例胸腺瘤患者中,成功随访53例,失访2例。53例患者均接受手术治疗,中位随访时间75.3个月,1、3、5、10年生存率分别为71.1%、56.7%、39.3%和23.3%。单因素分析结果显示：临床症状、肿瘤直径、肿瘤切除范围、Masaoka分期、WHO组织学分类及放化疗对胸腺瘤患者术后长期生存率均有显著影响(P<0.01);多因素Cox分析表明肿瘤切除方式(HR＝5.15,95% CI：1.573～16.883,P<0.05)、肿瘤直径(HR＝5.53,95% CI：1.879～11.797,P<0.05)、WHO分型(HR＝13.23,95% CI：3.015～29.230,P<0.05)、Masaoka分期(HR＝5.18,95%CI：1.597～13.737,P<0.05)以及放化疗(HR＝12.14,95% CI：2.979～49.503,P<0.05)是影响胸腺瘤术后生存率的独立因素。 结论肿瘤直径、肿瘤切除方式、WHO分型、Masaoka分期以及术后放化疗是影响胸腺瘤患者预后的独立因素。     

Pathology of thymic tumors

As the thymus is composed of heterogeneous admixture of lymphoid and epithelial elements, tumors originating in the thymus may be of varied histologic types. Thymomas are the most common thymic tumor in adults. Thymoma classification has historically been controversial, but a system put forth by the World Health Organization (WHO) in 2004 has been generally accepted as a reproducible and clinically relevant classification. In addition to histologic subtype, tumor stage and resection status are important factors in determining outcome in thymomas. Thymic lymphomas typically occur in younger patients than thymomas. The most common thymic lymphomas are precursor T-lymphoblastic lymphoma, Hodgkin lymphoma, and primary mediastinal large B-cell lymphoma. Thorough histologic sampling and, in some cases, the appropriate use of ancillary studies such as immunohistochemistry, flow cytometry, and molecular studies, are important in proper pathologic evaluation of thymic tumors.     

Clinical value of the WHO classification system of thymoma

Since the World Health Organization (WHO) histologic classification system for thymoma was introduced in 1999, several centers have published results using this system. This review of the published experience with the WHO system examines whether the classification is reproducible, whether the WHO system defines clinically distinct patient groups, assesses the independent prognostic value of the WHO type by multivariate analysis, and discusses the impact of the WHO system on clinical management decisions.     

恶性胸腺瘤的外科治疗进展

胸腺肿瘤在所有恶性疾病中占0．2～1．5％，是成人较常见的前纵隔肿瘤之一，大约占50％，其中恶性胸腺瘤约占纵隔肿瘤的8％～10％。目前主要通过WHO胸腺肿瘤组织学分型进行分类，临床上常用Masaoka分期。手术治疗是目前公认的治疗胸腺瘤，尤其是恶性胸腺瘤的主要方法之一。本文对国内外有关恶性胸腺瘤的治疗方法、手术方式及预后进行综述。     

Long-term survival and prognostic factors in thymic epithelial tumours.

OBJECTIVE: The aim of this study is to analyze long-term survival and the prognostic significance of some factors after surgical resection of thymic epithelial tumours. METHODS: We performed a retrospective analysis of clinical and histopathological data on 132 patients operated on for thymic tumours, from 1970 and 2001. Histologic diagnosis based on the new WHO classification system was made by a single pathologist. A univariate and multivariate analysis of prognostic factors predicting survival was carried out. RESULTS: There were: 108 complete resections (81.8%), 12 partial resections (9.1%) and 12 biopsies (9.1%). Overall 5, 10 and 15-year survival rate was 72, 61 and 52.5%, respectively. The Masaoka staging system showed 44 stage I, 18 stage II, 52 stage III and 18 stage IV. Histologic results were: 14 subtype A, 31 AB, 20 B1, 28 B2, 29 B3 and 10 C; the respective proportions of invasive tumour (stage II-IV) was 28.6, 58.1, 50, 75, 86.2 and 100%. There were 16 tumour recurrences (14.8%) of 108 radically resected thymomas, 10 were treated with radical re-resection. In univariate analysis, four prognostic factors were statistically significant: radical resection, Masaoka clinical staging, WHO histologic subtype and resectable tumour recurrence. In multivariate analysis, the independent factors predicting long-term survival were WHO histology and Masaoka stage. CONCLUSIONS: The WHO histologic classification seems to be the most significant prognostic factor reflecting the invasiveness of the thymic tumour. Completeness of resection and Masaoka stage I and II assure a better survival. Unresectable recurrence of thymic tumour predicted a worse prognosis.     

Microscopic thymoma

Microscopic thymoma was first described in 1976 and remains in the latest WHO classification (2004). It defines an epithelial proliferation, with <1 mm in diameter, usually multifocal, that preferentially occurs in patients suffering from myasthenia gravis without a macroscopically evident tumour. A series of 87 thymectomies realised in myasthenic patients between 1992 and 2005 was reviewed. We describe three cases of microscopic thymoma: two male and one female with an average age of 41.6 years. All patients suffered from myasthenia gravis positive for acetylcholine receptor antibodies without any tumour detectable on chest tomodensitometric examination. Thymectomy was performed in all cases, enlarged to the mediastinal fat in one. Microscopic examination revealed three type-A microscopic thymoma, one multifocal, associated with lymphoid hyperplasia in two cases. After surgery, all patients had clinically improved. In summary, chest computed tomography is unable to detect microscopic thymoma. Histological examination of the entire specimen is indicated after thymectomy in myasthenic patients even if the thymus appears normal on radiographic examination. The role of microscopic thymoma as a predictor of clinical thymoma has not been proven.     

胸腺瘤的诊断、治疗和预后

目的：探讨影响胸腺瘤的诊断,治疗及预后的相关因素。方法：回顾性分析116例胸腺瘤的临床资料,运用寿命表法计算其生存率,以生存,复发或转移率为指标,进行研究。结果：胸部X线等影像学检查是本病诊断的主要手段,重症肌无力是最常见的伴随疾病,发生率为25．0％（29／116）。扩大胸腺及胸腺瘤切除可降低Ⅰ、Ⅱ期肿瘤的复发率（x^2=4.941,P=0.0219),放疗和化疗等综合治疗可以提高疗效。组织学分型（M－H）法与临床分期有明显的相关性,能更有效地反映胸腺瘤的侵袭性(=0.385,P=0.007),本组患者3,5,10年生存率分别为81．2％,67．9％和40．5％,肿瘤分期与生存率明显呈负相关（r=-0.897,P=0.000)。结论：肿瘤的组织类型,病理分期及综合治疗方法是影响患者预后的重要因素,伴随疾病对患者的预后无明显影响。     

Thymic carcinoma. A clinicopathologic study of 13 cases.

Thymic carcinoma (TCA) is a thymic epithelial neoplasm with obvious cytologic atypia. We studied 13 cases of TCA by light microscopy, immunohistochemistry, and electron microscopy and correlated the findings with clinical features. The patients' mean age was 54.2 years (range 30-74); the male/female ratio was 7/6. Twelve of the 13 patients presented with signs and symptoms caused by compression of mediastinal organs; the other patient was asymptomatic. Paraneoplastic syndromes were never seen. At thoracotomy, 11 tumors invaded or adhered to surrounding structures; the other two were encapsulated. The histologic types include squamous carcinoma including the lymphoepithelioma-like subtype (seven cases), small cell carcinoma (four cases), clear cell carcinoma (one case), and adenosquamous carcinoma (one case). Positive immunoperoxidase studies were as follows: keratin (13 cases), epithelial membrane antigen (EMA) (13 cases), leukocyte common antigen (none), carcinoembryonic antigen (CEA) (five cases), B72.3 (seven cases), Leu 7 (two cases), human placental alkaline phosphatase (none), vimentin (none), and chromogranin (one case). This profile is similar to those of normal thymus and thymoma except for the absence of CEA, B72.3, EMA in normal thymus, and the absence of CEA and B72.3 in thymoma. Electron-microscopic studies performed on eight cases showed glandular and squamous differentiation in one adenosquamous carcinoma, squamous differentiation in five squamous carcinomas, and neuroendocrine differentiation in one small-cell carcinoma. Nine patients died (three due to postoperative complications and six due to recurrences or metastasis at 3-36 months). Four patients (all with squamous carcinoma) were alive without disease at 2-60 months. The clinical and pathologic features were comparable with those of approximately 62 other cases of TCA previously reported. There are a number of well-defined histologic types of TCA that allow the pathologist to make a differential diagnosis of TCA from tumors extending or metastatic to thymus or other primary mediastinal tumors. Although neither asymptomatic presentation nor encapsulation improves the poor prognosis of TCA, the squamous carcinoma subtype is associated with a better outcome than the other subtypes. Based on the electronmicroscopic and immunohistochemical findings, the presence of normal thymic tissue at the periphery of several tumors, and the observation that several TCA arose from preexisting thymomas or thymic cysts, we conclude that TCA is derived from thymic epithelium.     

Adjuvant radiotherapy after complete resection of thymoma.

Seventy patients were studied after undergoing complete resection of thymoma to determine the effect of postoperative adjuvant mediastinal radiotherapy on prognosis, with regard to clinical stage, histological type, and pleural factor. Pleural factor was defined as follows: p0, no adhesion to the mediastinal pleura; p1, fibrous adhesion to the mediastinal pleura without microscopic invasion; and p2, microscopic invasion of the mediastinal pleura. Recurrence of thymoma after complete resection was observed in 13 patients, 12 (92%) with pleural dissemination, 6 (46%) with local recurrence, and 2 (15%) with distant metastasis (types of recurrence are overlapping). In stage I and stage II p0 patients, no recurrence was observed, regardless of mediastinal radiotherapy. Whereas mediastinal irradiation completely prevented recurrence in stage II p1 patients, 4 (36.4%) nonirradiated stage II p1 patients experienced recurrence. In stage II p2 patients, 75% had pleural dissemination even after radiotherapy. A high incidence of recurrence was also observed in stage III, nonirradiated (25%) and irradiated (30%) patients. The results suggest that mediastinal irradiation for stage I and II p0 patients is not always necessary, and that therapy for stage II p1 is essential and also expected to decrease the recurrence rate. On the other hand, in stage II p2 and stage III thymomas, mediastinal irradiation is not sufficient to prevent pleural recurrence even after complete resection. Our classification based on pleural factor is useful for better selection of appropriate postoperative treatment for thymoma patients.     

Morphologic and clinical correlations in medullar thymoma

The medullar thymoma is a rare and distinctive epithelial thymoma, a thymic tumor characterized histologically by a mixture of spindle epithelial cells and lymphoid cells. We are presenting this tumor to a 68 years old man, admitted at CCI, for a mediastinal tumor, treated by tumorectomy, for revealing the cytological, histological and immunohistochemical characteristic features. The surgical biopsy was prepared by using usual histological techniques and haematoxilin eosin and Van Gieson stainings. We are discussing the relation between the thymoma clinicopathological and prognostic features, resulting a clear correlation between histological type and clinical study. We also pointed the Muller-Hermelink thymoma histological subtypes and their correspondence with OMS histological types, reflecting realistically the thymoma clinical behavior.     

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.     

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.     

Is postoperative radiotherapy for thymoma effective?

OBJECTIVE: The authors determined the effect of postoperative mediastinal irradiation in preventing local and pleural recurrence of thymoma. SUMMARY BACKGROUND DATA: The role of mediastinal irradiation after incomplete resection or biopsy of an invasive thymoma is well established. However, routine use of adjuvant mediastinal irradiation for patients with thymoma after complete resection remains controversial. METHODS: During the 19-year period from 1973 to 1992, operations were performed on 89 patients with thymoma. Of these 89 patients, 80 patients who underwent gross complete tumor resection including adjacent tissues that appeared to be invaded by tumor were selected for this study. The effects of postoperative mediastinal irradiation on the recurrence rate of thymoma were analyzed according to histologic type, clinical stage, and whether adhesions to or invasion of the pleura or pericardium were present. RESULTS: Recurrence of thymoma was observed in 13 of 80 (16.3%) patients. No recurrence was observed in 23 patients with noninvasive thymoma. In patients with invasive thymoma whose tumor was macroscopically adherent to the pleura but not microscopically invasive (p1), recurrence was observed in 4 of 11 patients (36.4%) when mediastinal irradiation was not performed, but in none of 10 patients who received mediastinal irradiation. However, in patients with microscopic pleural invasion (p2), a high recurrence rate was observed with mediastinal irradiation (40%, 6/15 patients) or without mediastinal irradiation (30%, 3/10 patients). Postoperative mediastinal irradiation for patients with microscopical invasion to pericardium (c2) did not decrease the recurrence rate. Analysis of the mode of recurrence showed that mediastinal irradiation may have been effective in preventing local recurrence, but it did not control the pleural dissemination that was observed in 12 of 13 recurrent cases. CONCLUSIONS: Mediastinal irradiation is not necessary for patients with noninvasive thymoma. In patients with invasive thymoma, postoperative mediastinal irradiation is effective in preventing recurrence in patients with p1 thymoma, but not in patients with p2 or c2 tumors. Further adjuvant therapy should be performed to supplement mediastinal irradiation in patients with p2 or c2 thymoma, even after complete resection.     

Huge thymoma: role of preoperative WHO histological classification

A 57-year-old woman was admitted to our hospital with complaints of recent onset of dyspnea on exertion. A chest computed tomography revealed a large mediastinal mass which extrinsically compressed the heart and mediastinal structures, occupying one half of the hemithorax. A needle biopsy was performed to find a thymoma with type AB according to the WHO classification. Based on the radiological and histological finding a surgery for the tumor was achieved by exploratory VATS thoracotomy followed by thymectomy through a median sternotomy with tumor extirpation of 910 g in weight. A definite diagnosis of thymoma (Masaoka I) without capsular invasion was obtained from the pathologic findings, including positive immunohistochemical staining for CD1a and cytokeratin.     

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.     

胸腺瘤患者预后因素分析

目的 探讨影响胸腺瘤患者术后远期生存率的相关因素。方法 回顾性分析我科1973—2000年间手术治疗的69例胸腺瘤，应用Kaplan—Meier法和Cox比例风险模型对可能影响胸腺瘤术后远期生存率的因素进行单因素和多因素分析。结果 全组患者5年、10年、15年生存率分别为83．3％、67．4％、41．9％。单因素分析显示年龄、Masaoka分期、WHO组织学分类、肿瘤切除范围、Rosai／Levine分类对胸腺瘤患者术后长期生存率有显著影响(P＜0．01)，但经多因素分析表明仅Masaoka分期(P＜0．01)、肿瘤切除范围(P＜0．05)、年龄(P＜0．05)是独立的预后因素。结论 对胸腺瘤应积极进行手术治疗，即使姑息性切除亦有助于提高远期生存。