Pathology – Research and Practice 211 (2015) 2–11

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Staging of thymic epithelial neoplasms: Thymoma and thymic carcinoma Annikka Weissferdt ∗ , Cesar A. Moran Department of Pathology, MD Anderson Cancer Center, Houston, TX, USA

a r t i c l e

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Article history: Received 25 November 2013 Received in revised form 9 April 2014 Accepted 17 June 2014 Keywords: Thymoma Thymic carcinoma Thymic epithelial neoplasm Staging

a b s t r a c t Thymic epithelial neoplasms are uncommon tumors that have been the subject of interest in the last few decades with regard to their histogenesis, histopathologic classification, treatment and prognosis. These tumors are a group of heterogenous neoplasms that are often difficult to subtype and the value of such subclassification with regard to prognosis remains obscure. One factor, however, that appears strongly associated with clinical behavior is tumor staging. The focus of this review will be an overview of the different staging systems for thymic epithelial neoplasms that have been presented in the literature over the years. Particular emphasis is paid to the latest developments in this context. © 2014 Elsevier GmbH. All rights reserved.

Introduction

Staging systems

Staging is an important tool in the management of cancer patients. The stage of a tumor is defined by its site of origin, its biology and its extent at the time of diagnosis. The purpose of a good staging system is: to guide the clinician in the selection of appropriate therapy; to provide prognostic information; to evaluate treatment results; to exchange knowledge with other investigators and to continue cancer research. Certain characteristics are fundamental to good staging systems: they must be evidence based, reproducible, practical, and ideally also adaptive to latest research developments [1,2]. With the advancement of treatment protocols over the last few decades, thymic epithelial neoplasms have generated interest in terms of histologic classification, treatment and prognosis. Thymic epithelial neoplasms are notoriously difficult to classify histopathologically due to their morphologic heterogeneity. Over the years, several attempts at histopathologic subclassification have been made [3–8], the value of which in terms of relation to prognosis is still controversial. More so than histologic typing, staging has been associated with prognosis in thymic epithelial neoplasms and over the years several proposals for staging systems have been presented in the literature. Herein we provide an overview of the history of staging these tumors with special emphasis on recent advances in this field.

Bergh et al. [9] and Wilkins and Castleman [10]

∗ Corresponding author at: Department of Pathology, MD Anderson Cancer Center, Houston, TX 77030, USA. Tel.: +1 713 792 5665; fax: +1 713 745 0785. E-mail address: [email protected] (A. Weissferdt). http://dx.doi.org/10.1016/j.prp.2014.06.007 0344-0338/© 2014 Elsevier GmbH. All rights reserved.

In 1978, Bergh et al. [9] presented one of the first staging attempts for thymic epithelial neoplasms investigating 43 thymomas. They devised a system with 3 stage groups and based their classification on operative findings and histological examination (Table 1):

• stage I – intact capsule or growth within the capsule • stage II – pericapsular growth into the mediastinal fat tissue • stage III – invasive growth into the surrounding organs, intrathoracic metastases, or both

Clinical follow-up showed a low recurrence rate and no tumor deaths in stages I and II at 10 years. An aggressive surgical approach was considered the best treatment modality. One year later, Wilkins and Castleman [10] slightly modified the system proposed by Bergh et al. [9] by placing pleural or pericardial invasion into stage II (Table 1). In their series of 103 patients with thymoma, the 10-year survival rates were 67% for encapsulated tumors and 40% for invasive lesions. These systems were later criticized for several aspects: the actual site of intrathoracic metastasis, inadequate description of invasion, too broad classification of stage III and lack of representation of lymphogenous or hematogenous metastasis.

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Table 1 Comparison of conventional staging systems for thymoma. Conventional staging systems for thymoma Stage

Bergh et al. [9]

Wilkins and Castleman [10]

Masaoka et al. [11]

Curran et al. [25]

Gamondes et al. [26]

Koga et al. [12]

0 I

– Intact capsule or growth within the capsule

– Intact capsule or growth within the capsule

Pericapsular growth into mediastinal fat tissue

Pericapsular growth into mediastinal fat tissue or adjacent pleura or pericardium

– Macroscopic complete encapsulation; microscopic invasion into but not through the capsule Macrcoscopic invasion into surrounding fatty tissues or mediastinal pleura or microscopic invasion through the capsule

– (a) Encapsulated, non-invasive, total excision; (b) localized invasion to mediastinal structures, total excision (a) Invasive growth into the surrounding organs, total excision

– Grossly and microscopically completely encapsulated

II

– Macroscopically completely encapsulated and microscopically no capsular invasion 1. Macroscopic invasion into surrounding fatty tissue or mediastinal pleura; 2. microscopic invasion into capsule

III

Invasive growth into the surrounding organs, intrathoracic metastases, or both –

Invasive growth into the surrounding organs, intrathoracic metastases, or both –

Macroscopic invasion into neighboring organs, i.e. pericardium, great vessels, or lung

Macroscopic invasion into neighboring structure, i.e. pericardium, great vessels, or lung

(a) Pleural or pericardial dissemination; (b) lymphogenous or hematogenous metastasis

Pleural or pericardial dissemination or metastases

(a) Invasive growth into the surrounding organs, incomplete excision; (b) invasive growth into the surrounding organs, biopsy of the tumor (a) Largely invading tumor cells with clavicular lymph nodes or pleural or pulmonary grafts; (b) hematogenous metastasis (1 or more)

IV

Masaoka et al. [11] In 1981, a Japanese group led by Masaoka [11] introduced a new staging system with focus on the extent of the disease. They separated 96 cases of thymoma into 4 different stages according to macroscopic and microscopic examination (Table 1): • stage I – macroscopically completely encapsulated and microscopically no capsular invasion • stage II – 1. macroscopic invasion into surrounding fatty tissue or mediastinal pleura or 2. microscopic invasion into capsule • stage III – macroscopic invasion into neighboring organs, i.e. pericardium, great vessels, or lung • stage IV – (a) pleural or pericardial dissemination or (b) lymphogenous or hematogenous metastasis Using this system, the authors were able to demonstrate a stepwise decline of survival in association with the advance of clinical stage thereby establishing its use in the prognosis of these tumors. Complete surgical resection was deemed best treatment to ensure long term survival. Although this and the subsequent Koga-modified Masaoka staging systems [12] remain the most commonly applied systems for the purpose of staging thymic epithelial neoplasms, critical examination of these proposals has raised several issues. Many of these surround discrepancies between perioperative (clinical) and pathological examination. For instance, on review of the definitions of the stages, stage II-1 is defined as macroscopic invasion into surrounding fatty tissue or mediastinal pleura at perioperative inspection, even if subsequent histologic invasion is disproved. From a pathologist’s point of view this may be difficult to comprehend [13]. Similarly, stage II-2, defined as microscopic invasion into but not through the capsule, is not a feature of invasive tumors in the pathological sense [13–15]. Another rather ambiguous issue regarding

1. Microscopic transcapsular invasion; 2. macroscopic invasion into thymic or surrounding fatty tissue, or grossly adherent to but not breaking through mediastinal pleura or pericardium Macroscopic invasion of neighboring organ (i.e. pericardium, great vessel, or lung) (a) Pleural or pericardial dissemination or (b) lymphatic or hematogenous metastasis

stage definitions pertains to stages III and IVa. While stage III is defined as “macroscopic invasion into neighboring organs, i.e. pericardium, great vessels, or lung”, stage IVa is defined as “pleural or pericardial dissemination”. From a histological point of view this can cause confusion as the line between these two definitions is rather vague and tumors that infiltrate the pleura or pericardium can be placed in either one of those categories by the pathologist. From a prognostic point of view, concern has been raised that the system provides appreciable prognostic separation only between stages I and III and stages I and IV, respectively, but not between stages I and II or stages III and IV, respectively [16–20] and that tumors invading the mediastinal pleura have a higher risk of recurrence than other stage II tumors [15,21]. Lastly, several investigators noted that the staging proposed by Masaoka et al. [11] is unsuitable for the staging of thymic carcinomas [22–24]. Curran et al. [25] Curran et al. [25] presented a study of 103 thymoma cases evaluating the role of mediastinal irradiation in the treatment of these tumors. For this purpose, they used an adapted staging system based on those proposed by Bergh et al. [9] and Masaoka et al. [11] (Table 1): • stage I – macroscopic complete encapsulation; microscopic invasion into but not through the capsule • stage II – macroscopic invasion into surrounding fatty tissues or mediastinal pleura or microscopic invasion through the capsule • stage III – macroscopic invasion into neighboring structures, i.e. pericardium, great vessels, or lung • stage IV – pleural or pericardial dissemination or metastases Using this approach, the group observed 5-year survival and relapse free survival rates of 67 and 100% for stage I, 86 and 58% for

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Table 2 TNM staging systems for thymic epithelial neoplasms. TNM staging systems for thymic epithelial neoplasms and thymic carcinoma TNM stage

Yamakawa et al. [27]

Bedini et al.a [28]

Tsuchiya et al.b [23]

T1

Macroscopically completely encapsulated and microscopically no capsular invasion Macroscopically adhesion or invasion into surrounding fatty tissue or mediastinal pleura or microscopic invasion into capsule

No capsular invasion

Completely encapsulated tumor

Microscopic invasion into the capsule, or extracapsular involvement limited to the surrounding fatty tissue or normal thymus

T3

Invasion into neighboring organs such as pericardium, great vessels, and lung

Direct invasion into the mediastinal pleura and/or anterior pericardium

T4

Pleural or pericardial dissemination

N1

N3

Metastasis to anterior mediastinal lymph nodes Metastasis to intrathoracic lymph nodes except anterior mediastinal lymph nodes Metastasis to extrathoracic lymph nodes

M0 M1

No hematogenous metastasis Hematogenous metastasis

Direct invasion into neighboring organs, such as sternum, great vessels, and lungs; implants on the mediastinal pleura or pericardium, only if anterior to phrenic nerves Metastasis to anterior mediastinal lymph nodes Metastasis to intrathoracic lymph nodes other than anterior mediastinal Metastasis to prescalene or supraclavicular nodes No hematogenous metastasis (a) Implants to the pericardium or mediastinal pleura beyond the sites defined in the T4 category; (b) hematogenous metastasis to other sites, or involvement of lymph nodal stations other than those described in the N categories

Tumor breaking through capsule, invading thymus or fatty tissue (may be adherent to mediastinal pleura but not invading neighboring organs) Tumor breaking through the mediastinal pleura or pericardium, or invading neighboring organs such as great vessels or lung Tumor with pleural or pericardial implantation

Stage I II

T1 N0 M0 T2 N0 M0

III

T3 N0 M0

IV

(a) T4 N0 M0 (b) any T N1M0, any T N2 M0, any T N3 M0 or any T any N M1

T2

N2

Locally restricted disease: T1–T2 N0 M0 Locally advanced disease: T3–T4 N0 M0 or any T N1-2 M0 Systemic disease: any T N3 M0 or any T any N M1 –

Metastasis in anterior mediastinal lymph nodes Metastasis in intrathoracic lymph nodes excluding anterior mediastinal lymph nodes Metastasis in extrathoracic lymph nodes No distant organ metastasis With distant organ metastasis

T1, T2 N0 M0 T1, T2 N1 M0 T3 N0, N1 M0 (a) T4 N0, N1 M0 (b) Any T N2, N3 M0 (c) Any T any N M1

a Classification of residual disease: R0 – no residual tumor; R1 – microscopic residual tumor; R2 – (a) local macroscopic residual tumor after reductive resection (>80% of the tumor) or (b) other features of residual tumor. b System by Tsuchiya et al. applies to thymic carcinoma only.

stage II, and 69 and 53% for stage III, respectively. Among the most significant findings of this study was a lower recurrence rate for stage I compared with other stages and the need for postoperative radiotherapy following total resection of stage II and III tumors. Gamondès et al. [26] In 1991, Gamondès et al. [26] reported a series of 65 patients with thymoma and stratified their cases into a 4-tier system based on surgical/anatomical criteria as proposed by the French Group d’Etudes des Tumeurs Thymiques (GETT) (1982) (Table 1): • stage I – (a) encapsulated, non-invasive, total excision or (b) localized invasion to mediastinal structures, total excision • stage II – (a) invasive growth into the surrounding organs, total excision • stage III – (a) invasive growth into the surrounding organs, incomplete excision or (b) invasive growth into the surrounding organs, biopsy of the tumor • stage IV – (a) largely invading tumor cells with clavicular lymph nodes or pleural or pulmonary grafts or (b) hematogenous metastasis (1 or more) As mentioned above, this staging system incorporates surgical and anatomical criteria for tumor classification and is modeled after two major influential factors on outcome, macroscopic aspect of the tumor and the type of intervention. Although the authors

acknowledged that little distinction can be made between stages III and IV tumors using this system, they argued that both stages are associated with reserved prognosis and that the most important observation was that stage I tumors have by far the best prognosis (5 and 10 year survival of 96 and 88%, respectively for stage I, 84 and 56% for stage III, and 73 and 18% for stage IV).

Yamakawa et al. [27] In the same year, Yamakawa et al. [27] introduced the first Tumor-Node-Metastasis (TNM) system for thymic epithelial neoplasms after changes in surgical technique (“extended thymectomy” versus “simple thymectomy”) led to the identification of lymph node metastasis in the anterior mediastinal adipose tissue. In this system, the T stage was modeled after the Masaoka system and additional N and M categories were added (Table 2): • T1 – macroscopically completely encapsulated and microscopically no capsular invasion; T2 – macroscopically adhesion or invasion into surrounding fatty tissue or mediastinal pleura or microscopic invasion into capsule; T3 – invasion into neighboring organs such as pericardium, great vessels, and lung; T4 – pleural or pericardial dissemination • N0 – no lymph node metastasis; N1 – metastasis to anterior mediastinal lymph nodes; N2 – metastasis to intrathoracic lymph

A. Weissferdt, C.A. Moran / Pathology – Research and Practice 211 (2015) 2–11 Table 3 Staging system for thymoma by Moran et al. [13].

Table 4 Staging system for thymic carcinoma by Weissferdt and Moran [30].

Stage

Moran et al. [13]

TNM

Weissferdt and Moran [30]

0

Encapsulated thymoma (all encapsulated thymomas without microscopic or macroscopic evidence of tumor breaching the fibroconnective tissue capsule) Invasive tumor into perithymic adipose tissue (invasive thymomas, histologically proven, in which invasion through the capsule and into perithymic adipose tissue is present) (a) Invasive thymoma into innominate vein, mediastinal pleura (tumor invading submesothelial fibrous layer) or lung (tumor invading alveolated lung parenchyma); (b) into pericardium (tumor invading submesothelial fibrous layer); (c) into great vessels (aorta, superior vena cava) or heart (a) Intrathoracic structures (so called drop metastases: discontinuous tumor spread intrathoracic structures, in particular diaphragm) or lymph nodes; (b) extrathoracic spread (tumor extends beyond diaphragm or thoracic inlet)

T1 T2

Tumor limited to the thymic gland Tumor invading any of these structures – visceral pleura, lung, pericardium, great vessels, chest wall or diaphragm Direct extrathoracic tumor extension – beyond the thoracic inlet (consisting of the manubrium, the first thoracic vertebra, and the first ribs and their cartilages) or below the diaphragm – No lymph node metastasis Lymph node metastasis to intrathoracic lymph nodes – – No distant metastasis Distant metastasis (indirect tumor spread including metastasis to extrathoracic lymph nodes)

I

II

III

nodes except anterior mediastinal lymph nodes; N3 – metastasis to extrathoracic lymph nodes • M0 – no hematogenous metastasis; M1 – hematogenous metastasis • Stage grouping: stage I – T1 N0 M0; stage II – T2 N0 M0; stage III – T3 N0 M0; stage IV – (a) T4 N0 M0 or (b) any T N1M0, any T N2 M0, any T N3 M0 or any T any N M1 Such stratification according to metastatic factors was thought to be useful for choosing interdisciplinary therapies. Accordingly, this system was applied to 207 thymomas, 13 thymic carcinomas and 6 thymic carcinoid tumors with the observation that this system had little advantage over conventional staging for thymomas, but was considered useful for thymic carcinomas and thymic carcinoid tumors, i.e. lesions that may present with metastatic disease in locally less advanced cases. Although subsequent validation studies confirmed the Yamakawa system to be an excellent predictor for the prognosis of thymic epithelial neoplasms (including thymic carcinoma) and that N and M factors influence survival more than the T stage, more recent studies have demonstrated lack of statistical significance between the stages when applied to cases of thymic carcinoma [23,24]. Either way, it has to be noted that this system has not been adopted to a significant degree for the purpose of staging thymic epithelial neoplasms. Koga et al. [12] Recognizing the controversy caused by some of the definitions used in the Masaoka system [11], Koga et al. in 1994 [12] modified and adjusted this system based on the most contentious issue: the fact that microscopic invasion into the capsule was classified as stage II-2, contrary to common pathological understanding. In their system, tumors invading into but not through the capsule are classified as stage I and a tumor infiltrating through the capsule and into normal thymic or fatty tissue as stage II-2 (Table 1): • stage I – grossly and microscopically completely encapsulated • stage II – 1. microscopic transcapsular invasion or 2. macroscopic invasion into thymic or surrounding fatty tissue, or grossly adherent to but not breaking through mediastinal pleura or pericardium • stage III – macroscopic invasion of neighboring organ (i.e. pericardium, great vessel, or lung) • stage IV – (a) pleural or pericardial dissemination or (b) lymphatic or hematogenous metastasis In a similar manner to Masaoka’s original proposal, application of this modified 4-category system on their 73 cases of

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T3

T4 N0 N1 N2 N3 M0 M1 Stage I II III

T1 N0 M0 T2 N0 M0 T3 N0 M0 or any T N1 M0 or any T any N M1

thymoma revealed that no significant survival differences were present between stages I and II or between stages III and IV. The authors concluded that the staging system is not very useful for thymoma which could easily be divided into non-invasive and invasive forms but was deemed more useful for thymic carcinoma. In addition, the authors advocated that the system would be helpful for institution of postoperative radiotherapy in cases of stage II thymoma. Although the modification by Koga et al. [12] added a better definition of microscopic transcapsular invasion and also addressed the issue of “adherence” versus “invasion” for stage II, several questions remain unanswered: 1. How to categorize tumors that lack a distinct or complete capsule? 2. How to define macroscopic invasion that is not present microscopically? 3. Is there a difference between macroscopic invasion and adherence to the mediastinal pleura or pericardium (stage II-2 versus stage III)? 4. The extent of pericardial involvement in stages II-2 and III is ambiguously worded. 5. Definition of pericardial invasion again remains vague and is not addressed from a histological aspect meaning that tumors showing pericardial involvement may be categorized as stage III or IVa from a pathological point of view. 6. How to distinguish separate foci of tumor from hematogenous metastasis? 7. As in the original Masaoka system [11], difference of survival remains statistically insignificant between stages I and II and III and IV, respectively. 8. The applicability of this system to thymic carcinoma remains uncertain.

Tsuchiya et al. [23] The recognition that thymomas and thymic carcinomas display different biologic behavior led Tsuchiya et al. [23] to introduce the first staging system exclusively for thymic carcinomas. Based on the higher incidence of metastasis among these tumors, the authors adapted the TNM system proposed by Yamakawa et al. [27] according to the biologic characteristics of thymic carcinoma (Table 2): • T1 – completely encapsulated tumor; T2 – tumor breaking through capsule, invading thymus or fatty tissue (may be

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Fig. 1. (a) Illustrative presentation of stage 0 thymoma: encapsulated thymoma [Reprinted with permission from the authors. Moran et al. [13]]. (b). Thymoma separated from the surrounding tissue by a thick fibrous capsule (H&E).

adherent to mediastinal pleura but not invading neighboring organs); T3 – tumor breaking through the mediastinal pleura or pericardium, or invading neighboring organs, such as great vessels and lung; T4 – tumor with pleural or pericardial implantation • N0 – no lymph node metastasis; N1 – metastasis in anterior mediastinal lymph nodes; N2 – metastasis in intrathoracic lymph nodes excluding anterior mediastinal lymph nodes; N3 – metastasis in extrathoracic lymph nodes • M0 – no distant organ metastasis; M1 – with distant organ metastasis • Stage grouping: stage I – T1 or T2 N0 M0; stage II – T1 or T2 N1 M0; stage III – T3 N0 or N1 M0; stage IV – (a) T4 N0 or N1 M0 or (b) any T N2 or N3 M0 or (c) any T any N M1 The authors evaluated the utility of this system on their experience with 16 thymic carcinomas. Unfortunately, a statistically significant difference between the different stages was not achieved, a fact attributed to the small number of cases. A few other concerns have been raised with regard to the practicability of this system. Similar to several of the other systems, the stage division between stages T3 and T4 is ill defined and may cause confusion. Another contentious issue involves the lymph node categories. The presence of 4 different N categories seems rather elaborate for a type of tumor, the resection of which is not performed in any standardized manner and where formal lymph node dissection takes place only in a minority of cases [24]. In addition, the 16 cases of thymic carcinoma were only represented by 3 different tumor

Fig. 2. (a) Illustrative presentation of stage I thymoma: invasive thymoma into perithymic adipose tissue. [Reprinted with permission from the authors. Moran et al. [13]]. (b) Thymoma showing invasion into perithymic adipose tissue (H&E).

types (squamous cell carcinoma, undifferentiated carcinoma and basaloid carcinoma). Thymic carcinoma, however, encompasses a wide range of tumor subtypes and application of a staging system to only 3 of those may limit the validity of this study. Bedini et al. [28] More recently, a new TNM staging system was presented to replace Masaoka’s system [11] as the standard [28]. A total of 123 cases of thymic epithelial tumors were evaluated using the so called Istituto Nazionale Tumori (INT) system including 106 cases of thymoma and 17 thymic carcinomas. This system uses 11 definitions and stratifies cases into 3 stage groups depending on the extent of the disease (locally restricted versus locally advanced versus systemic disease) (Table 2): • T1 – no capsular invasion; T2 – microscopic invasion into the capsule, or extracapsular involvement limited to the surrounding fatty tissue or normal thymus; T3 – direct invasion into the mediastinal pleura and/or anterior pericardium; T4 – direct invasion into neighboring organs, such as sternum, great vessels, and

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Fig. 3. (a) Illustrative presentation of stage IIa thymoma: continuous invasion into mediastinal pleura, lung, and/or innominate vein [Reprinted with permission from the authors. Moran et al. [13]]. (b) Stage IIa thymoma with invasion into the pulmonary parenchyma (H&E). (c) Illustrative presentation of stage IIb thymoma: continuous invasion into pericardium [Reprinted with permission from the authors. Moran et al. [13]]. (d) Illustrative presentation of stage IIc thymoma: continuous invasion into great vessels or heart [Reprinted with permission from the authors. Moran et al. [13]]. (e) Thymoma demonstrating invasion of great vessel wall (asterisk) (H&E).

lungs; implants to the mediastinal pleura or pericardium, only if anterior to phrenic nerves • N0 – no lymph node metastasis; N1 – metastasis to anterior mediastinal lymph nodes; N2 – metastasis to intrathoracic lymph

nodes other than anterior mediastinal; N3 – metastasis to prescalene or supraclavicular nodes • M0 – no hematogenous metastasis; M1 – (a) implants to the pericardium or mediastinal pleura beyond the sites defined in the

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Fig. 4. (a) Illustrative presentation of stage IIIa thymoma: discontinuous invasion of tumor into diaphragm or lymph nodes [Reprinted with permission from the authors. Moran et al. [13]]. (b) Drop metastasis to diaphragm (H&E).

T4 category or (b) hematogenous metastasis to other sites, or involvement of lymph nodal stations other than those described in the N categories • Stage grouping: stage I – locally restricted disease: T1–T2 N0 M0; stage II – locally advanced disease: T3–T4 N0 M0 or any T N1-2 M0; stage III – systemic disease: any T N3 M0 or any T any N M1 The suggestion that debulking procedures may be potentially curative prompted the authors to include the presence or absence of residual tumor with classification according to surgical results: • R0 – no residual tumor • R1 – microscopic residual tumor • R2 – (a) local macroscopic residual tumor after reductive resection (>80% of the tumor) or (b) other features of residual tumor The authors concluded that in contrast to Masaoka’s schema [11], the INT system appears suited to stage all subtypes of the WHO nomenclature and has high prognostic distinctiveness. In addition, they proposed that the different stages present distinct treatment options: surgery alone for limited disease, multimodality treatment for locally advanced disease and primary chemotherapy plus radiotherapy as palliative or adjuvant treatment in cases of systemic disease. This system, however, was deemed too complicated to be practical enough [29] and has not been adopted to a great extent.

Fig. 5. (a) Illustrative presentation of stage I thymic carcinoma: tumor limited to thymic gland [Reprinted with permission from the authors. Weissferdt and Moran [30]]. (b) Tumor limited to the thymic fatty tissue (H&E).

Latest developments Taking into consideration that the mode of spread for thymoma and thymic carcinoma is often divergent, and that some of the landmarks used for staging of these tumors are somewhat different, more modern and pathological user friendly schemata for staging thymoma and thymic carcinoma have been presented [13,30] (Tables 3 and 4). It is important to highlight that both of those schemata are based on complete surgical resections. It is obvious that patients in whom complete surgical resection is not feasible often present in advanced stages of the disease and will likely benefit from additional medical therapy. The main goal of these schemata is for any pathologist to be able to follow these outlines; however, one additional goal especially for thymomas is the potential use of such schema for the separation of patients who may benefit from additional therapy. Therefore, the clearly defined role for the pathologist is to comment on the specific anatomical areas that are involved by the tumor and thus separating tumors that are limited to the mediastinal compartment from those that are invading adjacent anatomical structures. This schema has the potential to avoid additional treatment in patients who may benefit from complete surgical resection alone. Also important to note is that by providing specific information about the anatomical structures involved a more targeted treatment approach may take place.

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Fig. 6. (a) Illustrative presentation of stage II thymic carcinoma: tumor invading visceral pleura, lung, pericardium, great vessels, chest wall or diaphragm [Reprinted with permission from the authors. Weissferdt and Moran [30]]. (b) Tumor invading visceral pleura (H&E). (c) Tumor invading the pericardium (H&E). (d) Tumor involving the skeletal muscle of the chest wall (H&E).

Thymoma staging [13] • stage 0 – encapsulated thymoma (all encapsulated thymomas without microscopic or macroscopic evidence of tumor breaching the fibroconnective tissue capsule) (Fig. 1a and b) • stage I – invasive tumor into perithymic adipose tissue (invasive thymomas, histologically proven, in which invasion through the capsule and into perithymic adipose tissue is present) (Fig. 2a and b) • stage II (direct invasion) – (a) invasive thymoma into innominate vein, mediastinal pleura (tumor invading submesothelial fibrous layer) or lung (tumor invading alveolated lung parenchyma) (Fig. 3a and b) or (b) into pericardium (tumor invading submesothelial fibrous layer) (Fig. 3c) or (c) into great vessels (aorta, superior vena cava) or heart (Fig. 3d and e) • stage III (metastatic disease) – (a) to intrathoracic structures (so called drop metastases: discontinuous tumor spread to intrathoracic structures, in particular diaphragm) or lymph nodes (Fig. 4a and b) or (b) extrathoracic spread (tumor extends beyond diaphragm or thoracic inlet) This system offers several advantages over previous ones. Firstly, this is the largest and most representative series addressing the issue of thymoma staging. Secondly, contrary to its predecessors, this system provides a clear definition of encapsulated

versus invasive thymomas as well as providing clarification of the terms “pleural” and “pericardial involvement”, respectively. In addition, the issue of the so called “drop metastasis” is addressed and defined as discontinuous tumor extension to the diaphragm or other intrathoracic structures (stage IIIa) as opposed to direct tumor invasion of intrathoracic structures (stage II) or metastatic lymphogenous or hematogenous extrathoracic spread (stage IIIb). Furthermore, the concept of stage 0 is introduced to emphasize the similarity of these tumors with in situ malignancies of other organ sites, in which complete resection of the lesion will likely result in a complete cure. The results of the statistical analysis derived from these data also demonstrated no significant difference in survival by comparing stages 0 and I but improved overall survival and rates of recurrence for patients with stages 0 and I tumors as opposed to patients with stage II and III lesions, indicating that the former group of patients may benefit from complete surgical resection alone whereas the latter group likely requires additional therapies. Another interesting finding was, that, contrary to the belief of some investigators, histological subclassification did not correlate with tumor stage. Thymic carcinoma staging [30] • T1 – tumor limited to the thymic gland (Fig. 5a and b); T2 – tumor invading any of these structures – visceral pleura, lung, pericardium, great vessels, chest wall or diaphragm (Fig. 6a–d);

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This new schema for the staging of thymic carcinomas appears to be an improved and more practical system than those currently in use; more importantly, this system demonstrated better correlation with clinical outcome by providing statistically significant differences for all tumor stages. Comment

Fig. 7. Illustrative presentation of stage III thymic carcinoma: direct extrathoracic tumor extension (beyond thoracic inlet or diaphragm) Reprinted with permission from the authors. Weissferdt and Moran [30].

T3 – direct extrathoracic tumor extension – beyond the thoracic inlet (consisting of the manubrium, the first thoracic vertebra, and the first ribs and their cartilages) or below the diaphragm (Fig. 7) • N0 – no lymph node metastasis; N1 – lymph node metastasis to intrathoracic lymph nodes • M0 – no distant metastasis; M1 – distant metastasis (indirect tumor spread including metastasis to extrathoracic lymph nodes) • Stage grouping: stage I – T1 N0 M0; stage II – T2 N0 M0; stage III – T3 N0 M0 or any T N1 M0 or any T any N M1 Although Tsuchiya et al. [23] in 1994 presented a system solely for the staging of thymic carcinomas, this system was not adopted widely and the Masaoka system [11] is still the most commonly employed not only for thymomas but also thymic carcinomas. However, both of these systems are not well suited for the staging of thymic carcinomas providing only limited prognostic value for this tumor type. Contrary to most other TNM systems for malignant tumors, the new schema uses only 3 instead of 4 stage categories for the staging of thymic carcinomas. This is based on the observation that statistically significant survival differences could only be demonstrated when combining 2 of the 4 stage categories of the Masaoka [11] and Tsuchiya systems [23] and reducing them into just 3 [30]. Another important point of the proposed new system pertains to the classification of lymph node involvement. It has recently been demonstrated that lymph node metastasis is not an uncommon finding in thymic carcinomas [24], however, lymph node dissection during thymectomy is neither performed routinely nor in any standardized manner. This has led to the suggestion of simplifying lymph node categories. As opposed to Tsuchiya et al. [23] who used 4 different lymph node stages requiring knowledge of the exact origin of the sampled nodes, a more basic approach is suggested, placing patients into N0 (lymph node negative) or N1 (lymph node positive) strata only. It is believed that until more standardized lymph node dissection becomes surgical standard, this system offers a more practical approach to lymph node staging [30]. Contrary to Tsuchiya et al. [23] and drawing from recent experience that lymph node involvement is a poor prognostic factor for thymic carcinomas [24], N1 disease was placed into stage category III regardless of concurrent T or M factors.

Over the last few decades, thymic epithelial neoplasms have generated intense interest and controversy regarding histopathologic classification, treatment and clinical behavior. While morphology and its relationship with clinical behavior have been at the center of attention for some investigators, others have emphasized the importance of staging for patient outcome. Although a number of staging systems for these tumors have been proposed over the years, the most popular one remains the one by Masaoka et al. [11] published in 1981. Over the years, however, it has been shown that there are significant drawbacks to the proposed systems including the one by Masaoka et al. [11], largely concerning lack of clear definitions, suboptimal correlation with clinical outcome, and insufficient applicability to thymic carcinomas. Recently, there have been attempts to clarify and redefine some of those issues in order to achieve more consistency in the use of the Masaoka–Koga classification [31]. For instance, tumors that lack a complete capsule should be staged as stage I unless clear involvement of any structures is present that would justify inclusion into a higher stage. In a similar manner tumors with pleural or pericardial involvement are regarded as stage III in cases of direct tumor extension whereas discontinuous tumor spread is considered stage IVa disease and for stage IVb, hematogenous or lymphogenous metastasis is interpreted to reflect distant metastasis, i.e. extrathoracic disease or nodules in the pulmonary parenchyma. In our most recent staging proposals [13,30], we have attempted to address the most important issues by providing systems that use clear stage definitions, demonstrate statistically significant correlation with prognosis and which are practical and reproducible enough for use not only for pathologists but also for other specialists involved in the care of these patients. Moreover, two separate staging systems for thymoma and thymic carcinoma have been introduced taking into account the different tumor characteristics displayed by these lesions. It is expected that the applicability of these latest proposals will lead to better stratification of patients who may need adjuvant treatment and that such proposals will improve the overall understanding of thymic epithelial neoplasms. Recommendation For practical purposes, if a core biopsy of an anterior mediastinal mass reveals the presence of a thymic epithelial neoplasm, we would recommend to use the term “thymic epithelial neoplasm” in the diagnosis text, followed by “favor thymoma or thymic carcinoma” depending on the more specific morphologic features. This approach will not only take into account tumors of mixed histology (i.e. combined thymoma and thymic carcinoma) but also ensure that at the time of resection, lymph node sampling is performed which will provide more accurate staging and prognostic evaluation. References [1] M. Gospodarowicz, L. Benedet, R.V. Hutter, I. Fleming, D.E. Henson, L.H. Sobin, History and international developments in cancer staging, Cancer Prev. Control. 2 (1998) 262–268. [2] F. Odicino, S. Pecorelli, L. Zigliani, W.T. Creasman, History of the FIGO cancer staging system, Int. J. Gynaecol. Obstet. 101 (2008) 205–210.

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