The Current Staging Systems of Thymoma 2010 대한흉부외과학회 춘계학회 The Current Staging Systems of Thymoma 성균관대학교 흉부외과 최용수

Thymoma the most common neoplasm of the anterior mediastinum “rather enigmatic tumor” controversy on histologic classification & staging - low incidence - wide range of histological appearance - unique biologic behavior

Case : M/40, symptoms of myasthenia gravis Bx. (mediastinotomy) ; Thymoma, WHO type A Mass excision : Thymoma, WHO type B3

Definition & terms : confusion Thymoma Thymic epithelial tumor Thymic carcinoma Malignant thymoma Invasive thymoma Atypical thymoma

Thymoma : benign or malignant ? Thymic carcinoma : 흉선암, malignant Thymoma : 흉선종, benign? invasiveness of thymoma no clear histologic distinction Lymphoma, melanoma : malignant tumor

Histologic classification of thymic epithelial neoplasm (1) Bernatz (1961) Kirchner & Muller-Hermelink (1989) WHO (1999) Lymphocyte-predominant Mixed lymphoepithelial Epithelial- predominant Medullary Mixed Predominantly cortical Cortical A (medullary) AB (mixed) B1 (organoid, predominantly cortical) B2 (cortical) Epithelial-predominant with cytologic atypia Well-differentiated thymic carcinoma B3 (epithelial) High-grade carcinoma C*(thymic carcinoma) Now excluded in the new WHO classification (2004) and placed in a separate group of malignant epithelial tumors.

Histologic classification of thymic epithelial neoplasm (2) WHO (1999) Suster &Moran (1999) Suster & Moran(2006) A (medullary) AB (mixed) B1 (organoid, predominantly cortical) B2 (cortical) Thymoma Well-differentiated thymic ca. (thymoma, low-grade or grade I) B3 (epithelial) Atypical thymoma Moderately differentiated thymic ca. (thymoma, intermediate grade or grade II) C* (thymic carcinoma) Thymic carcinoma Poorly differentiated thymic ca. (thymoma, high grade or grade III) Now excluded in the new WHO classification (2004) and placed in a separate group of malignant epithelial tumors.

WHO classification & clinical staging Okumura (2001) Type Number of cases Stage I II III IVa IVb Invasive tumors (%) A 8 7 1 12.5 AB 44 27 15 38.6 B1 25 5 4 40.0 B2 36 11 10 12 2 69.4 B3 6 80.0 C 14 100.0 Unclassified 3 0.0 Totals 140 65 33 32 53.6

Staging of thymoma Staging of thymoma continues to be a controversial issue.

Thymoma has no official staging system!

Staging schemes of thymoma Stage Bergh(1978) Wilkins(1979) Masaoka(1981) I Intact capsule or growth within the capsule “ Macroscopically completely encapsulated and microscopically no capsular invasion II Pericapsular growth into the mediastinal fat tissue + or adjacent pleura or pericardium Macroscopic invasion into surrounding fatty tissue or mediastinal pleura II-1 (IIa) Microscopic invasion into capsule II-2 (IIb) III Invasive growth into the surrounding organs and/or intrathoracic metastases Macroscopic invasion into a neighboring organ (e.g., pericardium, great vessels, or lung) Pleural or pericardial dissemination IVa Hematogenous or lymphogenous metastases IVb

Overall survival rates of thymoma Authors Patients number Complete resection rate (%) 5-year, 10-year survival Stage I Stage II Stage III Stage IVa Kondo (2003) 924 92 100%, 100% 98%, 98% 89%, 78% 71%, 47% Nakahara(1988) 141 80 92%, 84% 88%, 77% 47%, 47% Pan(1994) 112 94%, 87% 85%, 69% 63%, 58% 41%, 22%

Survival curve of thymoma : Korea n=108 n=195 연세대. Chest (2005) 성균관대. Br J Ca (2007)

Criticisms on Masaoka staging Bedini (2005), Kondo(2005) not well suited for the staging of thymic carcinomas not provide an appreciable prognostic separation between stages I and II Definition of stage II is unclear. Tumors invading the mediastinal pleura are at higher risk of recurrence than the other stage II tumors. no description of residual tumor Stage III thymoma is highly heterogenous in terms of involved organs. The TNM system classification of thymic epithelial tumors has not been established.

Modification of Masaoka staging Koga et al. (1994) simplified into two groups non-invasive for stages I and II invasive for stages III and IV

Modification of Masaoka staging Stage Trastek(1989) Kornstein(1995) I Completely encapsulated No capsular invasion Intact capsule II Growth into capsule Invasion into surrounding fat; adjacent mediastinal pleura Growth within capsule (a) Microscopic invasion through capsule into adjacent mediastinal tissue (b) Gross and microscopic invasion through capsule into surrounding fat or adjacent pleura or pericardium III Invasion into neighboring structures (pericardium, lung, great vessels) Invasion into surrounding structures (great vessels, lung) IV (a) Pleural or pericardial metastasis (b) Lymphatic or hematogenous metastasis (a) Pleural or pericardial dissemination (b) Lymphogenous or hematogenous metastasis

Staging (French Classification) - Groupe d'Etudes des Tumeurs Thymique, GETT 1982 Stage I Encapsulated, noninvasive. Total excision. Localized invasion to mediastinal structures. Total excision. Stage II Invasive growth into the surrounding organs. Total excision. Stage III Invasive growth into the surrounding organs. Incomplete excision. Invasive growth into the surrounding organs. Biopsy of tumor. Stage IV Largely invading tumor cells with (supra)clavicular nodes or pleural or pulmonary grafts (metastases) . Hematogenous metastasis (1 or more).

Verley and Hollmann classification (1985) Stage Characteristics I Encapsulated, noninvasive tumor; total excision Ia without adhesion to the environment Ib with fibrous adhesion to mediastinal structures II Localized invasiveness, e.g., pericapsular growth into the mediastinal fat tissue or adjacent pleura or pericardium IIa complete excision IIb incomplete excision, with local remnants of tumor III Largely invading tumor IIIa invasive growth into the surrounding organs and/or intrathoracic tumorous grafts (pleura, pericardium) IIIb lymphogenous or hematogenous metastasis

Prognostic categories for thymoma proposed by Suster and Moran (2003) Favorable Group I Encapsulated or minimally invasive thymoma Completely excised Equivalent to WHO histologic types A, AB, B1, B2 Group II Equivalent to WHO histologic type B3 Group III Widely invasive thymoma or thymoma with implants All histologic types Unfavorable Group IV Incompletely excised Group V Widely invasive thymoma with or without intrathoracic metastases Unresectable/biopsy only Group VI Widely invasive thymoma with distant metastases

New staging systems for testing Asamura (2004) Stage Description I Tumors without any invasion into other structures/structures/structures/organs regardless of capsular involvement II Scheme 1: tumors smaller than 10 cm in diameter and involving only one neighboring structure/organ Scheme 2: tumors of all combinations of diameter and number of involved strctures/organs other than those in stage III III Scheme 1: tumors of all combinations of diameter and number of involved structures/organs other than those in stage II Scheme 2: tumors 10 cm or more in diameter and involving two or more neighboring structures/organs IV Tumors with pleural or pericardial dissemination (IVa) or lymphatic/vascular metastasis (IVb) Masaoka staging Scheme 1 Scheme 2

Tumor size : thymoma prognosis Bloomberg(1995) : 11cm Wright(2005) : 8cm Nakagawa(2003) : 10cm

Survival of patients with stage III disease Results Of Surgical Treatment Of Thymomas With Special Reference To The Involved Organs Okumura (1999) Survival of patients with stage III disease

Stage III Thymic Epithelial Neoplasms are Not Homogeneous with Regard to Clinical, Pathological, and Prognostic Features 성균관대. J Thorac Oncol (2009)

LN metatasis : 2.4% hematogenous metastasis : 5.3%

Proposed TNM schemes for thymoma and thymic carcinoma Yamakawa, Masaoka (1991) T T1 Macroscopically completely encapsulated and without microscopic capsular invasion T2 Macroscopic adhesion or invasion into surrounding fatty tissue or pleura or microscopic invasion of the capsule T3 Invasion into neighboring organs such as great vessels, pericardium, lung T4 Pleural or pericardial dissemination N N0 No lymph node metastasis N1 Metastasis to anterior mediastinal lymph nodes N2 Metastasis to intrathoracic lymph nodes (other than anterior mediastinal nodes) N3 Metastasis to extrathoracic lymph nodes M M0 No distant metastases M1 Hematogenous metastases Stage T N M I T1 N0 M0 II T2 III T3 IVA T4 IVB Any N1-3 M1

Pattern of LN metastasis Kondo (2003) Thymoma Thymic carcinoma

The INT (Istituto Nazionale Tumori) TNM-Based Staging System 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 lungs; implants to the mediastinal pleura or pericardium, only if anterior to phrenic nerve N0 No lymph node metastasis N1 Metastasis to anterior mediastinal lymph nodes N2 Metastasis to intrathoracic lymph nodes other than anterior mediastinal nodes N3 Metastasis to prescalene or supraclavicular nodes M0 No hematogenous metastasis M1a Implants to the pericardium or mediastinal pleura beyond the sites defined in the T4 category M1b Hematogenous metastasis to other sites, or involvement of lymph nodal stations other than those described in the N categories Stage grouping Classification of residual disease i Locally restricted disease T1-2 N0 M0 ii Locally advanced disease T3-4 anyT N1-2 iii Systemic disease N3 anyN M1 R0 No residual tumor R1 Microscopic residual tumor R2a Local macroscopic residual tumor after reductive resection (> 80% of the tumor) R2b Other features of residual tumor

Progression-free survival Masaoka staging INT(Istituto Nazionale Tumori) staging

Thymoma vs. Thymic ca. thymoma normal thymus thymic carcinoma

Thymic carcinomas Low-grade malignancy High-grade Well-differentiated squamous cell carcinoma Basaloid carcinoma Mucoepidermoid carcinoma Large-cell carcinoma with Castleman's disease High-grade Lymphoepithelioma-like carcinoma Poorly differentiated squamous cell Adenosquamous carcinoma Clear cell carcinoma Papillary adenocarcinoma Mucinous adenocarcinoma Sarcomatoid carcinoma Poorly differentiated carcinoma Hepatoid thymic carcinoma Anaplastic/undifferentiated carcinoma

1. stage III thymoma 2. thymic carcinoma

Key points of thymic tumor staging Frank C. Detterbeck, Alden M. Parsons Pearson’s thoracic and esophageal surgery, 3rd Edition. chapter 131. Thymic tumors: A review of current diagnosis, classification and treatment By multivariate analysis, the most important prognostic factors in patients with thymomas are stage and completeness of resection. All stages and all histologic subtypes of thymoma have the potential to spread to distant sites.

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