In the 1960s, thymomas were classified into two categories: noninvasive and invasive. Bernatz et al.1 proposed a histologic classification and described four histologic subtypes: predominantly lymphocytic type, predominantly epithelial type, predominantly mixed type, and predominantly spindle cell type. Tumors belonging to the first three categories consisted of round epithelial cells and lymphocytes with differences in the ratio of the two components determining the category that the tumor belonged to. Bernatz et al. found that the predominantly epithelial subtype of thymoma was the most dominant among invasive thymomas.
To quantify the ratio of epithelial cells and lymphocytes, we2 calculated the numbers of these cells and determined the lymphocytes to epithelial cells ratio (L/E ratio). In our series of 22 cases, L/E ratios ranged from 0.27 to 4.10 with a mean value of 1.93 (Figure 1).
We also found a significant difference in the L/E ratios of invasive and noninvasive thymomas (Figure 2) with invasive thymomas having a lower ratio than noninvasive thymomas. This had also been recognized by Bernatz et al. In our series, we found three cases of recurrent thymoma with L/E ratios that were strikingly lower as compared with tumors at the time of diagnosis (Figure 3). Hence, it seemed that the L/E ratio changed based on the biologic behavior of the tumor: a decrease in the L/E ratio seemed to correlate with a change in the nature of the tumor from encapsulated thymoma to invasive thymoma. This finding led to propose a staging system for thymomas.
MASAOKA STAGING SYSTEM
To establish a new staging system for thymomas, we took into consideration a few basic characteristics of the disease:
1. Thymoma is a very slow growing tumor. In our experience, it could take as long as 30 years for a noninvasive thymoma to become invasive if it was not surgically resected.
2. Some noninvasive thymomas that had been resected completely recurred in the same region.
3. Some patients with completely resected invasive thymomas could survive.
4. Pleural dissemination is a frequent site of progression.
5. Some patients develop lymphogenous or hematogeneous metastases.
Two other staging systems were developed by Bergh et al.3 and Wilkins and Castleman4 (Table 1). The difference between the two systems was limited to one point: stage II Wilkins thymoma involved pleura and pericardial invasion.
In our opinion, there were some major inadequacies in the staging systems of Bergh et al. and Wilkins and Castleman: (1) the actual sites of intrathoracic metastasis were not clear, (2) the description of invasion was inadequate, (3) stage III includes too broad spectrum of disease, and (4) hematogenous and lymphogenous metastases were not well represented.
We proposed a surgical and pathologic staging system based on the extent of disease in 1981 (Table 2).5 We defined tumor extent as follows: (1) stage I: completely encapsulated, (2) stage II: invasion by the second layer surrounding the tumor (defined below), (3) stage III: direct invasion beyond the second layer, and (4) discontinuous progression.
The anatomic layers surrounding the tumor are depicted in Figure 4. Invasion into the pleural cavity is preceded by breaching of anatomic barriers in the following sequence: capsule, mediastinal pleura, visceral pleura, and finally lung. On the other hand, when the tumor invades the mediastinum, it invades through the capsule, mediastinal adipose tissue, pericardium or great vessels, and finally heart. Accordingly, the second layer surrounding the tumor is either the mediastinal pleura or mediastinal adipose tissue.
There are two points that need to be stressed. First, stage II disease involves invasion into the mediastinal pleura at perioperative inspection, even if histologic invasion could not be proved. We believe that this finding precedes histologic invasion.
Second, stage IV disease is divided into two categories IVa and IVb. Stage IVa consists of serosal dissemination, i.e., involvement of the pleura and pericardium. Stage IVb consists of metastasis via lymphogenous and hematogenous routes. Accordingly, stage IVb includes cases with lymph node metastasis at any station.
In 1981, we reviewed 93 thymoma cases at Osaka University.5 The stage of disease is shown in Table 3. All three cases of stage IVb disease had hematogenous metastasis involving the liver, lung, and rib. Survival curves associated with these four stages are shown in Figure 5.
CHANGE IN THE OPERATIVE PROCEDURE FOR THYMOMA
In 1970s, an important problem for thoracic surgeons was the operative route in thymectomy for myasthenia gravis. Whether transsternal or transcervical, the target of resection was the intracapsular thymus. I call it simple thymectomy.
However, we became aware that the results of transcervical thymectomies were inferior to those of transsternal thymectomies. We suspected that parts of the thymic tissues might be left in the transcervical thymectomies. So, we investigated the presence and distribution of thymic tissues in the anterior mediastinum systematically.6 As a result of this study, we found many foci of thymic tissues in the extrathymic anterior mediastinal adipose tissues in most cases.
I thought that to eliminate the thymic tissues, en bloc resection of the anterior mediastinal adipose tissues including the thymus gland is necessary. So, I advocated to apply this procedure in the treatment of myasthenia gravis, and named it “extended thymectomy”.7 It could improve the operative results for myasthenia gravis.
On the other hand, at that time, another problem concerning thymomectomy was pointed out. It was the occurrence of myasthenia gravis after thymomectomy for nonmyasthenic patients.8 In this era, resection of only the thymoma was the standard operation for thymoma. I call it simple thymomectomy. I thought, to prevent the occurrence of postthymomectomy myasthenia gravis, surgeons should perform the extended thymectomy, instead of simple thymomectomy for the thymoma patients, too.5
The aim of this procedure was prevention of the postthymomectomy myasthenia gravis, and its conduct in all thymoma patients was supported by finding of lack of immunologic deficiency in the myasthenic patients, who had undergone these operations.
Table 4 shows transition of operative procedures in Nagoya City University occurring every 5 years. In early 1980s, simple thymomectomy was dominant, but later the extended thymectomies were performed in most patients. After the extended thymectomy became a routine operation for thymoma, we encountered lymphnode metastases, which were found in the anterior mediastinal adipose tissues resected by this operation. This let us propose our tumor, node, metastasis (TNM) classification system.
TNM CLASSIFICATION SYSTEM
In 1991, we proposed a TNM classification system for thymoma (Table 5).9 T factors mimicked the staging criteria. N1 corresponds to anterior mediastinal, N2 other mediastinal, and N3 extrathoracic lymphnode metastasis. M1 means hematogenous metastasis in any organ.
However, the staging system was not revised. All N-positive and M-positive cases were included in stage IVb.
EVALUATION OF THE MASAOKA STAGING SYSTEM AS A PROGNOSTIC FACTOR
Many authors investigated the relationship between the Masaoka stage and survival. Major articles on these investigations since 1990 are listed in Table 6.10–26 Almost all authors except Wilkins et al.13 recognized a significant correlation between staging and survival.
REINVESTIGATION OF THE MASAOKA STAGING SYSTEM
In 1980, I was transferred to Nagoya City University from Osaka University. In 2010, we performed a follow-up study of thymomas in Nagoya City University and reinvestigated the relationship between stages and survival after an interval of 30 years from the Osaka series.27
The series consists of 211 thymomas treated in Nagoya City University Hospital from 1971 to 2008. Of these, 201 patients underwent operations: exploratory thoracotomy in 7, subtotal resection of tumor in 30, simple thymomectomy in 33, and extended thymectomy in 131 patients. Stage distribution is as follows: stage I 76 (36.0%), stage II 61 (28.9%), stage III 31 (14.7%), stage IVa 33 (15.6%), and stage IVb 10 (4.7%). Two survival parameters were adopted: overall survival and progression-free survival.
The overall survivals of each stage are shown in Figure 6 and Table 7. The curves are arranged stepwise according to the stages. Survival of IVb seems somewhat superior to that of IVa. Significant differences are found in I versus III, I versus IVa, I versus IVb, II versus III, II versus IVa, II versus IVb.
The progression-free survivals are shown in Figure 7 and Table 8. The survival curves of I and II become much closer and have high percentage of survival (stage I: 100%, stage II: 94.1%). The survival curves of stage IVa and IVb are nearly superimposed. Overall survival curves seem to fall into three groups; stage I and II, stage III, and stage IVa and IVb.
The reason why the progression-free survival rates of stage I and II lie higher than the overall survival curves is that most of the deaths in stage I and II are due to the associated disease or complication of therapies, but not the tumor. Indeed, only one patient with stage II died due to tumor recurrence. In contrast, the progression-free survival rates of stage IVb were lower than the overall survival rates. This finding was due to the presence of persistent tumor in surviving patients with stage IVb.
Univariate analysis proved that the relationship between overall survival and stage is significant (p < 0.0001). However, we could not show a relation between progression-free survival and stage, because the progression-free survival in stage I remained 100% up to 20-year follow-up.
COMPARISON OF THE RESULTS OF THE OSAKA SERIES AND THE NAGOYA SERIES
I compared the results of the Osaka series (n = 93) and the Nagoya series (n = 211). Both were investigated with 30 years follow-up. Differences are as follows; (1) the overall survivals in stage I and II of the Nagoya series are superior to those of Osaka series (10-year survival rates of stage I: 87.1% versus 66.7%, those of stage II: 80.6% versus 60.0%), (2) the overall survivals in stage IV of Nagoya series are superior to that of Osaka series (10-year survival rates of stage IV: IVa 20.0%, IVb 51.9% versus IV 0%).
These differences might be caused by the change in the operative procedures. In the Osaka series, a majority of patients underwent simple thymomectomies, whereas a majority of patients in the Nagoya series underwent extended thymectomies. The extended thymectomies could reduce tumor recurrence, particularly in stage I and II, and increase incidence of N+ cases classified in stage IVb.
Indeed, in the Osaka series, recurrences occurred in two of 37 of stage I and three of 13 of stage II. On the other hand, in the Nagoya series, recurrence occurred only in one of 61 of stage II, who had undergone simple thymomectomy.
Furthermore, in the Nagoya series, nine N+ cases were detected, whereas no N+ cases were observed in the Osaka series. There were five cases of T3N1M0. Although the mean follow-up period was only 4.3 years, two T3N1M0 cases had recurrences. Prognosis of N+ thymoma is a significant problem.
PROPOSALS OF REVISION OF THE MASAOKA STAGING SYSTEM
Although the Masaoka staging system was in general recognized as a valuable prognostic indicator, some proposals for its revision have been suggested.
Combination of Stage I and II
Gupta et al.28 reviewed 21 papers published in the 21st century and performed a metaanalysis of the results of stage I and II cases. Because they did not find significant differences between them, they proposed to combine stage I and II, and collapse the staging system into three stages.
I had read these 21 articles in detail and found two issues that are important and need to be mentioned. The first is divergence of the definition of stage II among reports. Some include the cases with histologic invasion to mediastinal pleura into stage II, whereas others include them into stage III. Such confusion might originate from the insufficient description of stage II that I wrote myself. The paragraph in the definition of stage II 1 (Table 2) should be read as follows: with or without histologic invasion.
The second issue to be mentioned is the lack of description of operative procedures in many of these 21 reports. As mentioned earlier, the operative procedure might affect the results. Whether extended thymectomy or simple thymomectomy was used is an important issue. However, many authors did not describe it in their reports. The results of stage I and II should be reinvestigated after addressing these two issues.
Furthermore, there is a trend to use thoracoscopic surgery for stage I and II thymoma, which does not allow to perform an extended thymectomy. The prevalence of thoracoscopic surgery could affect the survival of stage I and II thymomas.
However, some reports recognized a significant difference between the results of stage I and II, as described by Haniuda et al.,29 Mineo et al.,24 Maggi et al.,30 and Lardinois et al.14
I did not observe significant differences between stage I and II in overall survival. However, progression-free survival of stage I remained at 100% for a long time in our series. In such circumstance, the presence of a tumor death case in stage II might be meaningful, even if the number of cases is very small.
Based on the above mentioned reasons, I think, it is better to keep the separation of stage I and II at the moment.
Separation of Subgroups in Stage III
Okumura et al.31 suggested to divide stage III into two subclasses, i.e., IIIa: without great vessel invasion and IIIb: with great vessel invasion, based on his own data.
However, we did not find significant differences in survival between the group with great vessel invasion and that without great vessel invasion in our Nagoya series.
There are scarce reports concerning this subdivision.
Introduction of Other Factors Into the Staging System
Asamura et al.32 proposed to add tumor size, based on his own data, considering that large tumors (>10 cm in diameter) have a worse prognosis. However, tumor extent, as proposed in the Masaoka staging system seems to be more relevant than dimension. Furthermore, the fact that some types of thymomas can be dramatically reduced in size rapidly after administration of steroids argues against this proposal for change.33
There have been proposals to include completeness of operation in the staging system.11,34 Needless to say, complete resection is the best prognostic factor. However, I think, that a staging system should offer a guideline to select the therapeutic modality. Completeness of resection could be designated by a separate parameter. I propose the following criteria for results of surgery:
R0a = complete resection by extended thymectomy,
R0b = complete resection by simple thymomectomy,
R1 = microscopically incomplete resection,
R2 = macroscopically incomplete resection.
The subdivision of R0 cases should be useful to analyze the results.
TNM CLASSIFICATION AND STAGE
In 2004, the World Health Organization (WHO) proposed a system of TNM classification and staging (Table 9).35 This system is similar except for two points: (1) histologic invasion into mediastinal pleura is categorized into T3, (2) T1N1M0, T2N1M0, and T3N1M0 belong to stage III.
In 2005, Bedini et al.26 proposed a new system named Istituto Nazionale Tumori TNM-based staging system (Table 10). I think, the system by Bedini et al. is too complicated and limitation of the involved area by dissemination might cause confusion in this staging system.
A major difference between the WHO system and mine focuses on the allocation of N1. In the WHO staging system, N1 is included in stage III, whereas it is included in stage IVb in my classification. My system respects the concept of invasion by contiguity (stage III) versus discontinuous progression (stage IV). On the contrary, the WHO staging system respects localization of the involved area, giving priority to the results of operation.
Staging systems of cancers of other organs use progression of metastasis to lymphnode stations as an important part of stage definition. However, lymphnode metastasis is a rare situation in thymoma, and its progression stages are poorly defined. Kondo and Monden36 collected follow-up data of 1064 thymomas in Japan and there were only 19 (1.8%) cases of N+ thymomas. This is a low incidence compared with the cancers of other organs. Also in our series, the incidence of N+ tumor was low: nine of 211 (4.3%). The behavior of lymphogenous metastasis of thymoma warrants further investigation. Until more information is obtained, it might be better to include the N+ thymomas in IVb stage.
The Masaoka staging system still remains a valuable and reproducible prognostic factor of thymoma. However, some proposals of revision of the staging system have been offered, to identify significant differences in survival between each identified stage. In my opinion, the staging system should obey the following principles:
1. It should be logically justified.
2. It should be simple to use.
3. Frequent revisions should be avoided.
Since modalities of diagnosis and treatment are progressing day by day, a staging system should be as comprehensive as yet as simple as possible.
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