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Ann Thorac Surg 2000;69:1550-1555
© 2000 The Society of Thoracic Surgeons

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Original articles: General thoracic

Prognostic relevance of Masaoka and Müller-Hermelink classification in patients with thymic tumors

^a Department of Thoracic and Cardiovascular Surgery, University of Berne, Berne, Switzerland
^b Institute of Pathology, University of Berne, Berne, Switzerland
^c Division of Pulmonary Medicine, University of Berne, Berne, Switzerland
^d Institute of Oncology, University of Berne, Berne, Switzerland
^e Clinic of Radio-oncology, University of Berne, Berne, Switzerland

Address reprint requests to Dr Ris, Department of Surgery, University Hospital of Lausanne, Rue du Bugnon 46, CH 1011 Lausanne, Switzerland
e-mail: hris{at}chuv.hospvd.ch

	Abstract

Top Abstract Introduction Patients and methods Results Comment References

 
Background. To compare the prognostic relevance of Masaoka and Müller-Hermelink classifications.

Methods. We treated 71 patients with thymic tumors at our institution between 1980 and 1997. Complete follow-up was achieved in 69 patients (97%) with a mean follow up-time of 8.3 years (range, 9 months to 17 years).

Results. Masaoka stage I was found in 31 patients (44.9%), stage II in 17 (24.6%), stage III in 19 (27.6%), and stage IV in 2 (2.9%). The 10-year overall survival rate was 83.5% for stage I, 100% for stage IIa, 58% for stage IIb, 44% for stage III, and 0% for stage IV. The disease-free survival rates were 100%, 70%, 40%, 38%, and 0%, respectively. Histologic classification according to Müller-Hermelink found medullary tumors in 7 patients (10.1%), mixed in 18 (26.1%), organoid in 14 (20.3%), cortical in 11 (15.9%), well-differentiated thymic carcinoma in 14 (20.3%), and endocrine carcinoma in 5 (7.3%), with 10-year overall survival rates of 100%, 75%, 92%, 87.5%, 30%, and 0%, respectively, and 10-year disease-free survival rates of 100%, 100%, 77%, 75%, 37%, and 0%, respectively. Medullary, mixed, and well-differentiated organoid tumors were correlated with stage I and II, and well-differentiated thymic carcinoma and endocrine carcinoma with stage III and IV (p < 0.001). Multivariate analysis showed age, gender, myasthenia gravis, and postoperative adjuvant therapy not to be significant predictors of overall and disease-free survival after complete resection, whereas the Müller-Hermelink and Masaoka classifications were independent significant predictors for overall (p < 0.05) and disease-free survival (p < 0.004; p < 0.0001).

Conclusions. The consideration of staging and histology in thymic tumors has the potential to improve recurrence prediction and patient selection for combined treatment modalities.

	Introduction

Top Abstract Introduction Patients and methods Results Comment References

 
Thymic tumors are uncommon neoplasms, and their morphologic heterogeneity has caused much confusion regarding their classification. Several classifications have been proposed to correlate histology and clinical course. Previous studies have shown that the propensity of mediastinal invasion as reflected by the staging system of Masaoka and colleagues [1] negatively affects survival in those patients [2–9]. However, stage II tumors can recur after complete resection. In addition, the reported results regarding the benefit of adjuvant treatment after resection are controversial, indicating that the Masaoka classification might not be sufficient to classify the role of combined treatment modalities in patients with advanced disease [7, 10, 11]. Therefore, not only staging the tumor extent but also grading the tumor could be required to predict prognosis and recurrence pattern in thymic tumors, which might help to define more precisely the role of adjuvant and neoadjuvant treatments. Several histologic classifications have been assessed, but they did not help to predict the evolution of thymic tumors after resection [3]. Recently, Marino and Müller-Hermelink [12] proposed a new morphological classification of thymic tumors based on the resemblance of the neoplastic cells to subtypes of the normal thymic epithelial cells. Several studies have demonstrated the validity [6, 8, 13–15] and interobserver reproducibility [16] of this classification for general diagnostic use, as well as its prognostic relevance independent of tumor stage [13]. However, the interrelationship with the Masaoka staging system and its prognostic relevance regarding survival and recurrence has not been fully investigated. In this study, we did a multivariate analysis on patients operated on for epithelial thymic tumors in order to delineate the prognostic relevance of the two classifications for survival and recurrence.

	Patients and methods

Top Abstract Introduction Patients and methods Results Comment References

 
All patients treated for thymic tumors at the Department of Thoracic and Cardiovascular Surgery of the University of Berne between 1980 and 1997 were included in this retrospective study. All patients were followed up to determine recurrence and disease-related death. The histologic slides were reclassified according to the Müller-Hermelink system [12] by an independent pathologist (H.L.) who had no knowledge of the outcome of the patients.

Medullary thymoma (Fig 1A) is characterized by spindle-shaped epithelial cells and low to moderate counts of lymphocytes. They are encapsulated by a thick layer of fibrous tissue, whereas in contrast to other types of thymoma, intratumoral fibrous septa are unusual findings. Nuclear atypia is absent, and mitotic activity is very low. Individual spindle cells are capable of basement membrane formation. Individual deposits are highlighted in reticulin and periodic acid-Schiff stains, and in immunohistochemical preparations for collagen IV and laminin.

View larger version (183K): [in this window] [in a new window]   Fig 1. Histologic features of thymic tumors according to the Marino and Müller-Hermelink classification. (A) medullary tumor, (B) mixed tumors, (C) organoid tumor, (D) cortical tumor, (E) well-differentiated thymic carcinoma, and (F) endocrine carcinoma (hematoxylin and eosin, original magnification x400).

Organoid thymoma (predominantly cortical) (Fig 1C) has recapitulation of both cortical and medullary areas of the normal thymus including Hassall’s corpuscles, hence the alternative term organoid thymoma. Organoid thymomas often lack a complete fibrous capsule and may invade adjacent organs by their plump, pushing periphery. Organoid thymomas have the highest lymphocyte content. The few epithelial cells are small but elongated and correspond to those normally found in the corticomedullary junction.

Cortical thymomas (Fig 1D) are lobulated tumors with interlobular fibrous septa but often incomplete capsules and invasion of neighboring structures. The lymphocyte count is less than in organoid thymoma. Squamous differentiation is encountered occasionally at the periphery of the tumor. The predominant immunophenotype of intratumoral lymphocytes indicates an immature CD1⁺ T cell, as usually found in the normal thymic cortex.

Well-differentiated thymic carcinomas (WDTC) (Fig 1E) are lymphocyte-poor tumors growing in solid epithelial strands and infiltrating extrathymic organs. Palisading phenomena around perivascular spaces is a distinct morphologic feature of WDTC. In contrast to cortical thymoma, epithelial tumor cells are smaller and nucleoli are inconspicuous. Cytologic atypia and mitotic figures are regularly present. In approximately half of these tumors, a component of cortical or organoid thymoma can be found.

Endocrine carcinomas (Fig 1F) are neoplasms of the diffuse endocrine system and differ from thymomas. Its primary site in the thymus is rare. The endocrine carcinoma is surrounded by an incomplete capsule and often exhibits local invasiveness, metastases in draining lymph nodes, and, less frequently, distant sites. Typical histoarchitectural patterns include trabecular, acinar, glandular, and tubular formations. The defining cytologic features are the granular cytoplasm and finely granular so-called salt and pepper chromatin. Carcinoid tumors express neuroendocrine antigens, most regularly synaptophysin, chromogranin, neuron specific enolase, and CD56.

Pathologic staging was done according to Masaoka and colleagues [1]. Stage I included encapsulated thymoma without microscopic evidence of capsule invasion; stage II, macroscopic (II a) or microscopic (II b) invasion into surrounding fatty tissue or mediastinal pleura; stage III, macroscopic invasion into a neighboring organ such as pericardium, great vessels, or lung; and stage IV, pleural or pericardial dissemination (IVa) and lymphogenous or hematogenous metastasis (IVb).

Surgical procedures included complete en bloc resection of the tumor and the thymus and adjacent involved structures (pleura, phrenic nerve, pericardium, lung, anonymous vein, vena cava) through a full median sternotomy or a clam-shell approach. Postoperative external beam radiation therapy was offered to all patients with stage II to IVa disease. All patients were followed up annually until December 1997 or until death, with clinical examinations and anteroposterior and lateral chest x-rays.

Statistical analysis of the data was done at the Institute of Mathematical Statistics of the University of Berne. The ² and Kruskal-Wallis tests were used where appropriate. Kaplan-Meier survival curves were generated, and comparison of survival and disease-free survival in patients with complete resection was done using the log rank test. Multivariate analysis was performed by use of the Cox proportional hazards model. A two-tailed hypothesis was used for analysis, and significance was accepted at p less than 0.05.

	Results

Top Abstract Introduction Patients and methods Results Comment References

 
We treated 71 patients with thymic tumors between 1980 and 1997. Complete follow-up until December 1997 or until death was obtained in 69 patients (97%), with a mean follow-up time of 8.3 years (range, 9 months to 17 years). The mean age of the patients at operation was 62 years, ranging from 30 to 88 years. There were 31 men and 38 women.

At admission, 32 (47%) of the patients had no symptoms, 17 (24%) had myasthenia gravis, and 20 (29%) had intermittent pain or coughing. Preoperative chest x-rays found a mediastinal tumor in 13 patients (19%), pleural effusion in 5 (7%), pleural metastases in 2 (3%), and no radiologic findings in 49 (71%). The histologic diagnoses were obtained by use of computed tomography–guided tru-cut biopsy or anterior mediastinotomy in 66 patients (95%).

Complete resection was obtained in 61 patients (88%) and incomplete resection in 8 (12%). Patients with incomplete resection included 4 with WDTC, 2 with cortical tumors, and 2 with endocrine carcinomas. The 30-day mortality rate of the entire series was 0%. Postoperative adjuvant radiation therapy was done in 32 patients (46%).

The distribution of the tumors according to the Müller-Hermelink and Masaoka classification is shown in Table 1. There was a significant correlation between medullary, mixed, and organoid tumors and stage I and II disease, and between cortical tumors, WDTC, and endocrine carcinoma and stage III and IV disease, (p < 0.001).

View larger version (20K): [in this window] [in a new window]   Fig 2. Kaplan-Meier–generated overall survival curves of patients after complete resection of thymic tumors according to the (A) Masaoka staging and (B) Marino and Müller-Hermelink classification.

View larger version (21K): [in this window] [in a new window]   Fig 3. Kaplan-Meier–generated disease-free survival curves of patients after complete resection of thymic tumors according to the (A) Masaoka staging and (B) Marino and Müller-Hermelink classification.

	Comment

Top Abstract Introduction Patients and methods Results Comment References

 
The tumor characteristics of our patients and the distribution according to the Masaoka and Müller-Hermelink classifications are comparable with those of other series [2, 7, 13]. There was a significant correlation between histology and stage; medullary, mixed, and organoid tumors were related to stage I and II disease, and WDTC and endocrine carcinoma to stage III and IVa disease, respectively. This correlation was also found in other series [9, 15].

Complete surgical resection of the entire thymus with en bloc resection of all involved adjacent structures remains the mainstay of treatment of patients with thymic tumors and was achieved in 88% of our patients. This was somewhat higher than reported in the literature and might indicate a lower percentage of bulky stage III disease in conjunction with the lower frequency of symptoms in our patients. Incomplete resection was correlated with WDTC, cortical tumors, and endocrine carcinomas but not with medullary, organoid, and mixed tumors.

Complete clinical and radiologic follow up was obtained in 97% of our patients, with a mean follow-up time of 8.3 years. Multivariate analysis after complete resection found that age, gender, and myasthenia gravis were not significant prognostic indicators of overall and disease-free survival. These findings are in concordance with most other reports, although some series have reported an adverse influence of younger age on survival [5]. Postoperative adjuvant therapy was not correlated with better overall and disease-free survival in our series, however, cautious interpretation is indicated because adjuvant therapy was applied only in thymic tumors invading the mediastinum and hence can not be considered an independent variable. The merit of adjuvant irradiation in thymic tumors is controversial but irradiation is used in most institutions for stage II and III disease [7, 9–11, 17].

In contrast, the Masaoka and Müller-Hermelink classifications were both strong and independent prognostic determinors of overall and disease-free survival in our series. These conclusions were found in other series assessing the Masaoka and Müller-Hermelink classifications in this respect [6, 8, 13, 14], which justifies using both classifications for establishing prognosis and treatment guidelines.

Ten patients (16.4%) had recurrent disease after complete resection, all of them with local (mediastinum, pleura, or lung) and only three with local and distant manifestations, indicating that thymic tumors manifest as a disease with propensity for local spread. Moreover, 30% of our patients with recurrence presented initially with encapsulated stage II disease, which is amenable to resection via a minimally invasive approach [18, 19]. We speculate that the local recurrence rate in our series might have been higher if less radical surgery had been used. No patient with initial stage I disease had recurrence irrespective of histology. This finding is in accordance with most other studies that do not consider these patients for adjuvant therapy. In addition, no patient with medullary and mixed thymic tumor had a recurrence during follow-up irrespective of the stage of disease, although 29% of the medullary tumors were stage III and 29% of the mixed tumors stage II or III at operation. The same results were obtained by others [13], suggesting that adjuvant therapy might not be indicated in medullary and mixed tumors after complete resection. In contrast, 50% of stage II and III organoid tumors and 29% of stage II and III cortical tumors had local recurrence after complete resection. Because no distant manifestations were observed in these patients, re-resection might be a valid option in recurrent organoid and cortical tumors [17]. Twenty-seven percent of patients with stage II and III WDTC and 40% of patients with endocrine carcinoma had a recurrence during follow up, despite complete resection, and most of them had both local and distant manifestation. Combined treatment regimens seem, therefore, to be an attractive therapy in these situations.

Given the high recurrence rate in stage II and III cortical and organoid tumors, WDTC, and endocrine carcinoma, multimodality treatment regimens should be considered in these situations. Because adjuvant protocols have not convincingly demonstrated an improved outcome, neoadjuvant radiochemotherapy might be considered [20].

In conclusion, we found, in accordance to those of others, that the Masaoka and Marino and Müller-Hermelink classifications were significant and independent prognostic indicators of overall and disease-free survival in patients with epithelial thymic tumors. The consideration of both classifications has the potential to improve prediction of recurrence and patient selection for combined treatment modalities.

	References

Top Abstract Introduction Patients and methods Results Comment References

 

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