|Ahead of print publication
Evaluation of the relationship between the eighth edition of TNM staging, the mMasoaka, and World Health Organization histopathological classification for thymoma
Fatma Sert1, Beril Balci1, Ayse Gul Ergonul2, Deniz Yalman1, Serdar Ozkok1
1 Department of Radiation Oncology, Thoracic Surgery, Ege University School of Medicine, Izmir, Turkey
2 Department of Thoracic Surgery, Ege University School of Medicine, Izmir, Turkey
|Date of Submission||22-Apr-2022|
|Date of Decision||17-Jun-2022|
|Date of Acceptance||22-Jun-2022|
|Date of Web Publication||13-Oct-2022|
Department of Radiation Oncology, Ege University School of Medicine, Kazım Dirik Mah, Üniversite Cad. No: 1, Izmir
Source of Support: None, Conflict of Interest: None
Aim of Study: The aim of this study was to describe the correlation between the eighth tumor, node, and metastasis (TNM), mMasaoka staging, and the World Health Organization (WHO) histopathologic classification and to identify prognostic values in predicting survival and recurrence of thymoma.
Materials and Methods: Medical files of 90 patients with thymoma diagnosed between 1992 and 2018 were evaluated for this trial.
Results: The distributions of patients were similar between mMasaoka and eighth TNM staging according to early (I, II) and advanced stages (IIIA, IIIB, IV). Interestingly, 55 of 63 stage I patients with TNM staging showed difference as 31 of them up-staged to stage IIA and 24 of them up-staged to stage IIB in mMasoaka staging. Both staging systems closely correlated with WHO classification (p < 0.001); stages I and II were associated with low-risk groups (type A, AB, B1), and stages III and IV were associated with high-risk groups (type B2, B3). WHO classification was not a prognostic factor for overall survival (OS) (P = 0.13) and progression-free survival (PFS) (p = 0.08), but it was a prognostic factor for 10-year cancer-specific survival (CSS) (p = 0.04). Myasthenia gravis was associated to early stages (stage I, II) (p = 0.007) and related with better prognosis.
Conclusions: Our study showed a correlation between both staging system and WHO classification. A certain difference was found between eighth TNM staging and the mMasoaka staging in terms of stage I disease. Both staging systems effectively prognosticated OS, CSS, and PFS. To clarify the prognostic relevance and clinical usefulness of the WHO classification may be beneficial in clinical practice for the treatment decision.
Keywords: Masaoka, modified Masaoka, radiotherapy, staging, thymoma
|How to cite this URL:|
Sert F, Balci B, Ergonul AG, Yalman D, Ozkok S. Evaluation of the relationship between the eighth edition of TNM staging, the mMasoaka, and World Health Organization histopathological classification for thymoma. J Can Res Ther [Epub ahead of print] [cited 2022 Dec 9]. Available from: https://www.cancerjournal.net/preprintarticle.asp?id=358583
| > Introduction|| |
Thymic epithelial tumors (TETs), which include thymoma and thymic carcinoma, could be accepted as a rare disease with an incidence of 3/1,000,000 per year. However, thymoma is the most common neoplasm of the anterior mediastinum, and ~50% of the cases are well encapsulated and therefore considered benign. TETs may have different symptoms in presentation, manifesting either concurrently with auto-immune diseases such as myasthenia gravis (MG) (nearly one-third of cases), with local symptoms (e.g., chest pain, neck mass, superior vena cava syndrome; one-third), or asymptomatically as mediastinal mass on chest radiography (approximately one-third of cases).
Cancer staging systems and histopathological examination are essential for assessing the cancer status and the decision of treatment strategies. The modified Masaoka staging system, which is based on the extent of tumor invasion, implantation, lymph node, and/or hematogenous metastases, has been used for many years. However, this classification system has a deficiency as to the surrounding tissues of the tumor, the involvement of the affected lymph node region, and distant spread and is not sufficiently detailed. An official stage classification system for TETs has recently been adopted by the American Joint Committee on Cancer (AJCC) and the Union for International Cancer Control (UICC). It presented the T, N, and M descriptors; lymph node map; and stage classifications for TETs created by the International Association for the Study of Lung Cancer (IASLC) and the International Thymic Malignancy Interest Group (ITMIG) and recently included in the eighth edition of the AJCC staging manual.
There is neither standard nor strongly advised staging system for TETs. Despite their common use, both the Masaoka and TNM staging systems have some uncertainties in terms of predicting outcome and guiding treatment decisions. Our aim was to describe the correlation between the TNM, the mMasaoka staging, and the World Health Organization (WHO) classification and to identify, through regression models, how these variables relate to each other and whether they have a prognostic value in predicting survival and recurrence of disease.
| > Patients and Methods|| |
We retrospectively reviewed our institutional database maintained and updated by xxx University Medical Faculty Department of Radiation Oncology to identify TET patients treated with Radiotherapy (RT)+/−Chemotherapy (CT) between January 1992 and December 2018. For eligibility, patients had to meet the following requirements as well: an age more than 18 years, histological proof of malignancy, no previous CT or RT history, adequate bone marrow, hepatic and renal functions, and a body mass index (BMI) >20 kg/m2. Patients with metastatic diseases were not included.
TETs were categorized by the WHO classification based on histological findings. The WHO classification categorizes thymoma into five types: types A, AB, B1, B2, and B3. According to the WHO classification, the thymic carcinoma sub-type is classified as type C. The disease staging was determined using both the mMasoaka and TNM staging systems. Histological classification was made based on WHO histopathological examination.
All cases were staged by thoracic computed tomography (tCT) and/or magnetic resonance imaging (MRI) and/or positron-emission computed tomography (PET/CT) after 2006.
Ethics and permissions
The study was conducted by following the Helsinki Declaration and Rules of Good Clinical Practice, and the study design was approved by the Institutional Ethical Committee review board of xxx University Medical Faculty before any data collection. All patients provided written informed consent before the initiation of treatment either themselves or through legally authorized representatives for the collection and analysis of blood samples, pathologic specimens, and publication of their outcomes.
Complete resection, particularly total thymectomy, was performed in all patients. In cases of gross involvement of surrounding organs including the mediastinal pleura, lung, pericardium, and superior vena cava, extended resections were applied. Complete resection with negative surgical margins was described as R0, incomplete resection with microscopic residues was described as R1, and sub-total resection with gross residues was described as R2.
There is controversy about whether post-operative RT should be used for completely resected invasive thymomas. Post-operative RT was considered depending on the pathological report according to the extent of disease such as extracapsular extension and surgical margin. In our department, we routinely discuss TETs in our multi-disciplinary tumor boards with our thoracic surgeons and pathologists for post-operative treatment decisions. For completely resected thymoma cases, we have post-operative RT indication for capsular invasion, and additionally, we add post-operative RT for all locally advanced cases. For adjuvant treatment, the total RT doses were 50–54 Gy with 1.8–2 Gy daily fractions for R0 resection, 54–60 Gy for R1 resection, and 60–66 Gy for R2 resection. Definitive RT was given for patients with the unresectable disease at a dose of a 64 Gy.
Patients were followed with the clinical and radiological examination at 3-month intervals for the first 2 years, at 6-month intervals up to 5 years, and annually thereafter.
IBM SPSS Statistics 24 was used for statistical evaluation. Survival rates were calculated from the diagnosis until the time of death or the last day of follow-up using the Kaplan–Meier method. Pearson's Chi-square test was used to evaluate the association between categoric variables, Fisher's exact test was used when the number of patients is a small number, and t-test was used for numeric variables. The time to local or distant recurrence was calculated from the time of diagnosis until the date of imaging that revealed a sign of any recurrence. Patients still living on the last date of follow-up were censored from the analysis. A P value of <0.05 was considered statistically significant.
| > Results|| |
Ninety patients were included in this retrospective cohort analysis. The median age was 51 years (range 23–84), and the median tumor size was 6 cm (range 1.3–13 cm). Patient, tumor, and treatment characteristics are indicated in [Table 1]. The Masaoka and TNM stages were divided into two groups: early stages including stages I and II patients and advanced stages including stages IIIA, IIIB, and IV patients. Additionally, WHO histopathological classifications were divided into two sub-groups: low-risk (type AB–B1) and high-risk (type B2–B3) groups to compare the correlations of the used staging system.
The relation between the eighth edition of TNM staging and Masaoka staging
The proposed Masaoka and TNM stages of the patients are shown in [Table 1]. A similar patient distribution was found in the comparison between the Masaoka staging and the eighth edition of TNM staging when we compared them according to early versus advanced stages. In other words, the same number and group of patients were distributed to the same risk groups in both staging systems. According to the TNM staging, 63 patients were in stage I, but 31 of them staged as stage IIA and 24 of them staged as stage IIB with the Masaoka staging system [Table 2].
|Table 2: Distribution of the patients according to both the Masaoka staging system and the eighth edition of the TNM staging system (Blue: Early stages; Red: Advanced stages)|
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The relation between the eighth edition of TNM staging and WHO histopathological classification
The distributions of the patients according to both the TNM staging system and WHO histopathological classification are shown in [Table 1]. It was seen that the advanced stage was related to the high-risk histopathological group (p < 0.001). A significant association was shown between both TNM staging groups and WHO classification. Similarly, according to the Masaoka staging system, advanced stage was related to the high-risk histopathological group (p < 0.001). A significant association was detected between the Masaoka staging groups and WHO classification [Figure 1].
|Figure 1: Distribution of the Masaoka staging groups according to the WHO histopathologic classification|
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The median follow-up time was 87.5 months (range 3–269 months). Recurrence occurred in 14 patients (15.6%), seven of whom were both local and distant. Local recurrence alone was detected in three patients. At the time of this analysis, 66 (73.3%) patients were alive, four of whom were followed up with the disease. Fifteen (16.7%) patients died of non-cancer-related reasons, and nine (10%) patients died of cancer. The 10-year overall survival (OS) and progression-free survival (PFS) rates were 76.6% and 83.6%, respectively. The cancer-specific survival (CSS) was 88.9% for 10 years.
Regarding the survival rates of early and advanced stages of diseases, both 10-year OS and PFS were statistically worse in advanced stages (p < 0.001). According to low-risk and high-risk WHO histopathological grouping, a significant relation was detected for 10-year CSS (p = 0.04). However, the 10-year OS and PFS rates were not related to WHO histopathological grouping (p = 0.13, P = 0.08; respectively) [Table 3].
|Table 3: Survival analysis according to the early/advanced stages and WHO histopatological low/high-risk grouping|
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In univariate analysis, having MG (p < 0.001), achieving R0 resection (p < 0.001), the absence of capsular invasion (p = 0.015), <6 cm tumor size (p = 0.001), and the absence of pleural invasion (p < 0.001) were favorable factors for OS. All the above-mentioned factors except the capsular invasion also favorably affected both PFS and CSS rates [Table 4]. In multi-variate analysis, achieving R0 resection was the only factor affecting OS, CSS, and PFS rates. Also, pleural invasion was related to both CSS and PFS rates in the multi-variate analysis.
| > Discussion|| |
In 2014, a new staging for thymoma was proposed, which was subsequently published in 2016 in the eighth edition of the TNM classification of malignant tumors.,, However, the Masaoka staging system was proposed nearly 40 years ago. Although the TNM system has already been published, the Masaoka staging system has continued to be used commonly. There is no consensus regarding the preferred staging system. The primary goal of this study was to evaluate the correlation between the new TNM staging system, already used Masaoka staging system, and WHO histopathological classification. Another objective of this study was to analyze how these two elements relate one another in terms of the oncological long-term outcome and RT indications. Additionally, we wanted to obtain a clear explanation about the prognostic role of used staging systems because of the conflicting results of some published trials.,,
There have not been many studies in the literature analyzing the relation between the Masaoka and TNM staging systems. Tamburini N et al. detected a correlation between both staging systems, and only Masaoka stage II cases were redistributed in TNM stage I, stage II, and stage IIIA. In our analysis, when two staging systems were separated as early and advanced stages, the distributions of patients did not show any difference in both staging groups. However, 55 of 63 stage I patients with TNM staging showed difference according to the Masaoka staging system evaluation. Thirty-one of them up-staged to stage IIA, and 24 of them up-staged to stage IIB in the Masaoka staging system. Considering the above-mentioned data, we observed that nearly 70% stage I disease according to the TNM staging system was treated with adjuvant RT. It could be argued that favorable local control rates were obtained because of treated stage I patients. We should wait for new randomized trial results arranged using the new staging system for treatment decisions.
However, most authorities have reported that there was a correlation between the Masaoka staging system and the WHO histopathological classification;,,, regarding the literature for the relationship between the TNM staging system and the WHO histopathological classification, there have been very few publications. Tamburini N et al. showed that there was a significant correlation between the TNM staging system and the WHO histopathological classification. Our data showed that there was a significant correlation between the TNM staging system and the WHO histopathologic classification (p < 0.001); stages I and II were associated with low-risk groups (types A, AB, and B1), and stages III and IV were associated with high-risk groups (type B2 and B3). Also, the percentage of stages III and IV is much higher in B2, especially in B3, than in A, AB, and B1. Similarly, the Masaoka early stage patients (Stage I-II) were associated with the low-risk group (type A, AB, B1) (p < 0.001), and advanced stage patients (Stage III-IV) were associated with the high-risk group (type B2, B3) (p < 0.001). In our data, we determined similar results with the above-mentioned literature.
Tamburini N et al. reported that MG was a positive predictive factor for OS (p = 0.07); MG was more frequent in stages I and II thymomas (17 cases) and rare in stages III and IV (only 3 cases). Similar to the results of Tamburini N et al., Ruffini et al. reported that MG was positively correlated with WHO histopathological classification and the Masaoka staging system. They concluded that MG was a significant prognostic indicator of OS. Distinct from the above-mentioned trials, Okumura M et al. showed that MG was not a prognostic factor for thymomas. However, the association between MG and the TNM staging system was not widely evaluated in the current literature. In our analysis, according to the staging systems, MG and both staging systems were inter-related. MG was associated with early stages (stage I, II) (p = 0.007). In contrast, there was not any significant relationship between MG and WHO histopathological sub-types (p = 0.37). As regards 10-year OS, CSS, and PFS rates, patients with MG were higher than patients without MG. It was determined that MG was related to better prognosis. This association was also reported by other authors,, and in our opinion, this could be explained by the stricter and prompt radiological examination performed on every myasthenic patient to exclude thymic disease.
During follow-up, mortality is mostly related to non-cancer reasons, especially for the patients with thymoma. In our study, 15 patients (16.7%) died of non-cancer-related reasons. Because of this, we analyzed the rates of CSS. The Masaoka staging system remains a valuable prognostic factor in survival analysis., We found that both staging systems were important prognostic factors for OS, CSS, and PFS. Considering an early stage (stage I, II) and advanced stage (stages III, IV), there were significant differences in survival curves (p < 0.001) [Figure 2]a, [Figure 2]b, [Figure 2]c. Besides, differences in survival rates between the patients with and without great vessel invasion in stage III were significant (5y-OS and CSS rates; Stage IIIA 85.7%, 100%; Stage IIIB 28.6%, 40%, respectively). Although most publications have reported a trend toward survival decrement proceeding from A to B3 WHO histopathological classification, there has not been any clear evidence of the impact of histologic sub-groups on oncologic outcomes yet clinical usefulness of the WHO histological classification of thymoma.,,,, In our data, the association between WHO histopathological sub-types and OS outcomes was not found to statistically significant (p = 0.13). However, the 10-year CSS rates were 96.8% for low-risk (type AB, B1) and 83% for high-risk (type B2, B3) histopathologic groups (p = 0.04). Histopathologic classification was not a prognostic factor for PFS (p = 0.08). R0 resection rates were higher in early stages (stage I, II) (p < 0.001) and the low-risk histopathological group (p = 0.08). The similar survival results for R0 and R1 resections could be explained by the fact that patients with a R1 resection received adjuvant radiation therapy.
|Figure 2: Comparison of the treatment outcomes in terms of early and advanced stages of thymomas. (a) Overall Survival Comparison (b) Progression free Survival Comparison (c) Cancer Spesific Survival Comparison|
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| > Conclusions|| |
Our study confirms that there is a correlation between the two WHO risk groups (low vs high risk) and the two eighth TNM groups (early vs advanced stages). MG is more frequently observed in early stage tumors. The ability to achieve a complete resection, the rate of recurrence, and survival are significantly correlated with the stage. It also warrants how both WHO histopathological classification and stage correlate with PFS. We saw a certain difference between eighth TNM staging and the Masaoka staging in terms of stage I disease. According to the Masaoka staging system, more than half of the stage I diseases are upstaged to stage II disease with Masaoka. This could be an important issue to be investigated in terms of the indications for adjuvant RT. We should create an evidence-based therapeutic decision tool by the light of the current literature with the help of future molecular and/or genetic trials.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| > References|| |
de Jong WK, Blaauwgeers JL, Schaapveld M, Timens W, Klinkenberg TJ, Groen HJ. Thymic epithelial tumours: A population-based study of the incidence, diagnostic procedures and therapy. Eur J Cancer 2008;44:123-30.
Mikhail M, Mekhail Y, Mekhail T. Thymic neoplasms: A clinical update. Curr Oncol Rep 2012;14:350-8.
Thomas CR, Wright CD, Loehrer PJ Sr. Thymoma: State of the art. J Clin Oncol 1999;17:2280–9.
Masaoka A, Monden Y, Nakahara K, Tanioka T. Follow-up study of thymomas with special reference to their clinical stages. Cancer 1981;48:2485-92.
Bhora FY, Chen DJ, Detterbeck FC, Asamura H, Falkson C, Filosso PL, et al
. The ITMIG/IASLC thymic epithelial tumors staging project: A proposed lymph node map for thymic epithelial tumors in the forthcoming 8th
edition of the TNM classification of malignant tumors. J Thorac Oncol 2014;9 (9 Suppl 2):S88-96.
Detterbeck FC, Stratton K, Giroux D, Asamura H, Crowley J, Falkson C, et al
. The IASLC/ITMIG Thymic Epithelial Tumors Staging Project: proposal for an evidence-based stage classification system for the forthcoming (8th
) edition of the TNM classification of malignant tumors. J Thorac Oncol 2014;9 (9 Suppl 2):S65-72.
Rami-Porta R, editors. Staging Manual in Thoracic Oncology. 2nd
ed. North Fort Meyers (FL): Editorial Rx Press; 2016. p. 237–58.
Kondo K, Yoshizawa K, Tsuyuguchi M, Kimura S, Sumitomo M, Morita J, et al
. WHO histologic classification is a prognostic indicator in thymoma. Ann Thorac Surg 2004;77:1183-8.
Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: Development and validation. J Chronic Dis 1987;40:373-83.
Ruffini E, Filosso PL, Mossetti C, Bruna MC, Novero D, Lista P, et al
. Thymoma: Inter-relationships among World Health Organization histology, Masaoka staging and myasthenia gravis and their independent prognostic significance: A single-centre experience. Eur J Cardiothorac Surg 2011;40:146-53.
Tamburini N, Maniscalco P, Migliorelli A, Nigim F, Quarantotto F, Maietti E, et al
. Thymic epithelial tumors: Prognostic significance and relationship between histology and the new TNM staging system. Thorac Cardiovasc Surg 2020;68:433-9.
Chen G, Marx A, Chen WH, Yong J, Puppe B, Stroebel P, et al
. New WHO histologic classification predicts prognosis of thymic epithelial tumors: A clinicopathologic study of 200 thymoma cases from China. Cancer 2002;95:420-9.
Quintanilla-Martinez L, Wilkins EW Jr, Choi N, Efird J, Hug E, Harris NL. Thymoma histologic subclassification is an independent prognostic factor. Cancer 1994;74:606–17.
Kim HK, Choi YS, Kim J, Shim YM, Han J, Kim K. Type B thymoma: Is prognosis predicted only by World Health Organization classification? J Thorac Cardiovasc Surg 2010;139:1431-5.
Kim DJ, Yang WI, Choi SS, Kim KD, Chung KY. Prognostic and clinical relevance of the World Health Organization schema for the classification of thymic epithelial tumors: A clinicopathologic study of 108 patients and literature review. Chest 2005;127:755-61.
Okumura M, Ohta M, Tateyama H, Nakagawa K, Matsumura A, Maeda H, et al
. The World Health Organization histologic classification system reflects the oncologic behavior of thymoma: A clinical study of 273 patients. Cancer 2002;94:624-32.
Huang J, Detterbeck FC, Wang Z, Loehrer PJ Sr. Standard outcome measures for thymic malignancies. J Thorac Oncol 2010;5:2017-23.
Anya ML, Kaitlin W, Sara H. Clinical characteristics and outcomes for patients with thymic carcinoma: Evaluation of Masaoka staging. J Thorac Oncol 2014;9:1810-5.
Margaritora S, Cesario A, Cusumano G, Meacci E, D'Angelillo R, Bonassi S, et al
. Thirty-five-year follow-up analysis of clinical and pathologic outcomes of thymoma surgery. Ann Thorac Surg 2010;89:245-52; discussion 252.
Sonobe S, Miyamoto H, Izumi H, Nobukawa B, Futagawa T, Yamazaki A, et al
. Clinical usefulness of the WHO histological classification of thymoma. Ann Thorac Cardiovasc Surg 2005;11:367-73.
[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4]