Staging and Classification of Thymoma
Establishing a staging system for thymic epithelial tumors (TETs) has been difficult due to the rarity of these tumors. [1] Staging has most commonly been performed using the Masaoka-Koga Staging System. [2] This system, based on a small single-center study, was first developed by Akira Masaoka in 1981 and was updated by Kenji Koga in 1994. Though several other staging systems were previously proposed, the Masaoka-Koga system has been widely used because it is a prognostic indicator for thymic malignancy and a predictor of tumor recurrence. [3]
The Masaoka-Koga Staging system is based on the local micro- and/or macroscopic invasion of the tumor and the presence of lymphogenous or hematogenous metastasis. See Table 1, below.
Table 1. Modified Masaoka Clinical Staging of Thymoma (Open Table in a new window)
Stage |
Definition |
I |
Macroscopically and microscopically completely encapsulated |
IIA |
Microscopic transcapsular invasion |
IIB |
Macroscopic invasion into surrounding fatty tissue or grossly adherent to but not through mediastinal pleura or pericardium |
III |
Macroscopic invasion into neighboring organs (ie, pericardium, great vessels, or lung) |
IVA |
Pleural or pericardial dissemination |
IVB |
Lymphogenous or hematogenous metastasis |
The World Health Organization (WHO) developed a histologic classification system in 1999, with revisions in 2004, and later 2015. [4] The WHO classification system has produced a standard agreement among pathologists at varying institutions. This system appears to be a prognostic indicator for tumor recurrence both independently and when combined with the Masaoka staging system. However, it may not be suitable as an independent prognostic indicator. [5, 6] The 2004 WHO histologic classification system is shown in Table 2, below.
Table 2. 2004 WHO Histologic Classification System (Open Table in a new window)
Type |
Histologic description |
A |
Tumor in which foci having features of type A thymoma are admixed with foci rich in lymphocytes |
B1 |
Tumor resembles normal functional thymus; combines large expanses having an appearance practically indistinguishable from that of normal thymic cortex with areas resembling thymic medulla |
B2 |
Tumor in which neoplastic epithelial component appears as scattered plump cells with vesicular nuclei and distinct nucleoli among a heavy population of lymphocytes; perivascular spaces are common and sometimes very prominent; a perivascular arrangement of tumor cells resulting in a palisading effect may be seen. |
B3 |
Thymoma predominantly composed of epithelial cells having a round or polygonal shape and exhibiting no or mild atypia; they are admixed with a mild component of lymphocytes, resulting in a sheetlike growth of the neoplastic epithelial cells |
C |
Thymic tumor exhibiting clear-cut cytologic atypia and a set of cytoarchitectural features no longer specific to the thymus, but rather analogous to those seen in carcinomas of the other organs; type C thymomas lack immature lymphocytes; whatever lymphocytes may be present are mature and usually admixed with plasma cells |
The 2015 refinement of the WHO histologic classfication system added obligatory and optional features for clarification of previously ambiguous histologic criteria, including improved staining methods and immunohistochemistry. Thymomas frequently exhibit multiple histologic patterns, and instead of classifying them as "combined" types, the 2015 classfication system lists the differing subtypes separately. The system also includes immunohistochemical features in the criteria, and includes a new atypical type A variant subtype of thymoma. [4]
While the clinical significance of the WHO classification system is debatable, the system is useful as a tool that provides standardization among pathologists. We recommend using the updated 2015 WHO classification system, shown in Table 3, below.
Table 3. 2015 Revised WHO Classification System (Open Table in a new window)
| Thymoma Subtype | Obligatory Criteria | Optional Criteria |
|---|---|---|
| Type A | Occurrence of bland, spindle-shaped epithelial cells (at least focally); paucitya or absence of immature (TdT+) cells throughout the tumor | Polygonal epithelial cells; CD20+ epithelial cells |
| Atypical type A variant | Criteria of type A thymoma; in addition, comedo-type tumor necrosis; increased mitotic count (>4/2 mm2); nuclear crowding | Polygonal epithelial cells; CD20+ epithelial cells |
| Type AB | Occurrence of bland, spindle-shaped epithelial cells (at least focally); abundancea of immature (TdT+) T cells focally or thoughout tumor | Polygonal epithelial cells; CD20+ epithelial cells |
| Type B1 | Thymuslike architecture and cytology: abundance of immature T cells, areas of medullary differentiation (medullary islands); paucity of polygonal or dendritic epithelial cells without clustering (ie, < 3 contiguous epithelial cells) | Hassall's corpuscles; perivascular spaces |
| Type B2 | Increased numbers of single or clustered polygonal or dendritic epithelial cells intermingled with abundant immature T cells | Medullary islands; Hassall corpuscles; perivascular spaces |
| Type B3 | Sheets of polygonal slightly to moderately atypical epithelial cells; absent or rare intercellular bridges; paucity or absence of intermingled (TdT+) T cells | Hassall corpuscles; perivascular spaces |
| MNTb | Nodules of bland spindle or oval epithelial cells surrounded by an epithelial cell-free lymphoid stroma | Lymphoid follicles; monoclonal B cells and/or plasma cells (rare) |
| Metaplastic thymoma | Biphasic tumor composed of solid areas of epithelial cells in a background of bland-looking spindle cells; absence of immature T cells | Pleomorphism of epithelial cells; actin, keratin, or EMA-positive spindle cells |
| Rare othersb | ||
a Paucity versus abundance: any area of crowded immature T cells or moderate numbers of immature T cells in more than 10% of the investigated tumor are indicative of "abundance." b Microscopic thymoma, sclerosing thymoma, lipofibroadenoma. WHO = World Health Organization; MNT = micronodular thymoma with lymphoid stroma; EMA = epithelial membrane antigen |
More recently, a traditional tumor, nodes, metastasis (TNM) system has been developed for the staging of thymoma and thymic cancer. A TET TNM staging system and node map proposed by the International Thymic Malignancies Interest Group (ITMIG) and the Thymic Domain of the Staging and Prognostic Factors Committee (TD-SPFC) of the International Association for the Study of Lung Cancer (IASLC) have been included in the 8th edition of the American Joint Committee on Cancer's AJCC Cancer Staging Manual. [7, 2, 8, 9, 10]
This system has similarities to the Masaoka-Koga Staging system, especially the T component, and also includes parts of the WHO histologic classification system. The TNM system contains differences from the Masaoka-Koga system, including the distinction of whether the tumor is encapsulated or not, as encapsulation does not appear to be clinically relevant. The capsule is believed to be a process induced by the tumor rather than a normal anatomic structure. [2] The TNM system is outlined in Tables 4 and 5, below.
Table 4. TNM Staging of Thymoma (Open Table in a new window)
Primary tumor (T) |
|
| TX | Primary tumor cannot be assessed |
| T0 | No evidence of primary tumor |
| T1 | Tumor encapsulated or extending into the mediastinal fat; may involve the mediastinal pleura T1a - Tumor with no mediastinal pleura involvement T1b - Tumor with direct invasion of mediastinal pleura |
| T2 | Tumor with direct invasion of the pericardium (partial or full thickness) |
| T3 | Tumor with direct invasion into any of the following: lung, brachiocephalic vein, superior vena cava, phrenic nerve, chest wall, or extrapericardial pulmonary artery or veins |
| T4 | Tumor with invasion into any of the following: aorta (ascending, arch, or descending) arch vessels, intrapericardial pulmonary artery, myocardium, trachea, esophagus |
Regional lymph nodes (N) |
|
| NX | Regional lymph nodes cannot be assessed |
| N0 | No nodal involvement |
| N1 | Anterior (perithymic) nodes |
| N2 | Deep intrathoracic or cervical lymph nodes |
Distant metastasis (M) |
|
| M0 | No pleural, pericardial, or distant metastases |
| M1a | Separate pleural or pericardial nodule(s) |
| M1b | Pulmonary intraparenchymal nodule or distant organ metastasis |
Table 5. Stage Grouping (Open Table in a new window)
| Stage | T | N | M |
|---|---|---|---|
| I | T1a,b | N0 | M0 |
| II | T2 | N0 | MO |
| IIIA | T3 | N0 | M0 |
| IIIB | T4 | N0 | M0 |
| IVA | Any T |
N1 |
M0 |
Any T |
N0,N1 | M1a | |
| IVB | Any T |
N2 |
M0,M1a |
Any T |
Any N |
M1b |
For the 9th edition of the AJCC staging system, the TD-SPFC of the IASL has recommended the following changes for the T component [11] :
-
T1: Divide by tumor size—T1a ≤5 cm and T1b > 5 cm—irrespective of mediastinal pleura invasion
-
T2: Include direct invasion of the pericardium, lung, or phrenic nerve
-
T3: Denote as direct invasion of the brachiocephalic vein, superior vena cava, chest wall, or extrapericardial pulmonary arteries and veins
-
T4: No changes
A review by the TD-SPFC of the IASL validated the differences in the N and M categories in the 8th edition and recommended maintaining those categories with no changes for the upcoming 9th edition. [12]
There is hope that the TNM system will provide a unified clinical and pathologic staging system that maintains the prognostic significance of the Masaoka-Koga staging system. More studies will be needed to establish this conclusion definitively.
Tables
Stage |
Definition |
I |
Macroscopically and microscopically completely encapsulated |
IIA |
Microscopic transcapsular invasion |
IIB |
Macroscopic invasion into surrounding fatty tissue or grossly adherent to but not through mediastinal pleura or pericardium |
III |
Macroscopic invasion into neighboring organs (ie, pericardium, great vessels, or lung) |
IVA |
Pleural or pericardial dissemination |
IVB |
Lymphogenous or hematogenous metastasis |
Type |
Histologic description |
A |
Tumor in which foci having features of type A thymoma are admixed with foci rich in lymphocytes |
B1 |
Tumor resembles normal functional thymus; combines large expanses having an appearance practically indistinguishable from that of normal thymic cortex with areas resembling thymic medulla |
B2 |
Tumor in which neoplastic epithelial component appears as scattered plump cells with vesicular nuclei and distinct nucleoli among a heavy population of lymphocytes; perivascular spaces are common and sometimes very prominent; a perivascular arrangement of tumor cells resulting in a palisading effect may be seen. |
B3 |
Thymoma predominantly composed of epithelial cells having a round or polygonal shape and exhibiting no or mild atypia; they are admixed with a mild component of lymphocytes, resulting in a sheetlike growth of the neoplastic epithelial cells |
C |
Thymic tumor exhibiting clear-cut cytologic atypia and a set of cytoarchitectural features no longer specific to the thymus, but rather analogous to those seen in carcinomas of the other organs; type C thymomas lack immature lymphocytes; whatever lymphocytes may be present are mature and usually admixed with plasma cells |
| Thymoma Subtype | Obligatory Criteria | Optional Criteria |
|---|---|---|
| Type A | Occurrence of bland, spindle-shaped epithelial cells (at least focally); paucitya or absence of immature (TdT+) cells throughout the tumor | Polygonal epithelial cells; CD20+ epithelial cells |
| Atypical type A variant | Criteria of type A thymoma; in addition, comedo-type tumor necrosis; increased mitotic count (>4/2 mm2); nuclear crowding | Polygonal epithelial cells; CD20+ epithelial cells |
| Type AB | Occurrence of bland, spindle-shaped epithelial cells (at least focally); abundancea of immature (TdT+) T cells focally or thoughout tumor | Polygonal epithelial cells; CD20+ epithelial cells |
| Type B1 | Thymuslike architecture and cytology: abundance of immature T cells, areas of medullary differentiation (medullary islands); paucity of polygonal or dendritic epithelial cells without clustering (ie, < 3 contiguous epithelial cells) | Hassall's corpuscles; perivascular spaces |
| Type B2 | Increased numbers of single or clustered polygonal or dendritic epithelial cells intermingled with abundant immature T cells | Medullary islands; Hassall corpuscles; perivascular spaces |
| Type B3 | Sheets of polygonal slightly to moderately atypical epithelial cells; absent or rare intercellular bridges; paucity or absence of intermingled (TdT+) T cells | Hassall corpuscles; perivascular spaces |
| MNTb | Nodules of bland spindle or oval epithelial cells surrounded by an epithelial cell-free lymphoid stroma | Lymphoid follicles; monoclonal B cells and/or plasma cells (rare) |
| Metaplastic thymoma | Biphasic tumor composed of solid areas of epithelial cells in a background of bland-looking spindle cells; absence of immature T cells | Pleomorphism of epithelial cells; actin, keratin, or EMA-positive spindle cells |
| Rare othersb | ||
a Paucity versus abundance: any area of crowded immature T cells or moderate numbers of immature T cells in more than 10% of the investigated tumor are indicative of "abundance." b Microscopic thymoma, sclerosing thymoma, lipofibroadenoma. WHO = World Health Organization; MNT = micronodular thymoma with lymphoid stroma; EMA = epithelial membrane antigen |
Primary tumor (T) |
|
| TX | Primary tumor cannot be assessed |
| T0 | No evidence of primary tumor |
| T1 | Tumor encapsulated or extending into the mediastinal fat; may involve the mediastinal pleura T1a - Tumor with no mediastinal pleura involvement T1b - Tumor with direct invasion of mediastinal pleura |
| T2 | Tumor with direct invasion of the pericardium (partial or full thickness) |
| T3 | Tumor with direct invasion into any of the following: lung, brachiocephalic vein, superior vena cava, phrenic nerve, chest wall, or extrapericardial pulmonary artery or veins |
| T4 | Tumor with invasion into any of the following: aorta (ascending, arch, or descending) arch vessels, intrapericardial pulmonary artery, myocardium, trachea, esophagus |
Regional lymph nodes (N) |
|
| NX | Regional lymph nodes cannot be assessed |
| N0 | No nodal involvement |
| N1 | Anterior (perithymic) nodes |
| N2 | Deep intrathoracic or cervical lymph nodes |
Distant metastasis (M) |
|
| M0 | No pleural, pericardial, or distant metastases |
| M1a | Separate pleural or pericardial nodule(s) |
| M1b | Pulmonary intraparenchymal nodule or distant organ metastasis |
| Stage | T | N | M |
|---|---|---|---|
| I | T1a,b | N0 | M0 |
| II | T2 | N0 | MO |
| IIIA | T3 | N0 | M0 |
| IIIB | T4 | N0 | M0 |
| IVA | Any T |
N1 |
M0 |
Any T |
N0,N1 | M1a | |
| IVB | Any T |
N2 |
M0,M1a |
Any T |
Any N |
M1b |
