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CURRENT HISTOLOGICAL CLASSIFICATION AND
STAGING OF PRIMARY THYMIC EPITHELIAL
NEOPLASMS
Prof. Dr. Thomas Tousseyn

Dept. Pathology, University Hospitals Leuven, Belgium

Translational Cell and Tissue Research Lab, KU Leuven, Belgium
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 Introduction
AIMS
• Histology of normal thymus
• Differential diagnosis of anterior mediastinal masses
• Histologic classification of primary thymic epithelial neoplasms
• Staging of primary thymic epithelial neoplasms
1. Histology of normal thymus
Thymus

• Anterior mediastinum
– At birth: 15g; 5x6x0,6 cm: purple
– At puberty: 35g
– At 25y: 25g
– At 75y: 6g: yellow
• Maturation and selection of
immature T-cell precursors
(prothymocytes) to mature, naïve T-
cells
S C
M

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CAPSULE

CORTEX
LYMPHOCYTES

EPITHELIAL
CELLS

MEDULLA
 CD2+ CD3+
CD4/CD8+/+
TdT+
CD1a+

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 http://audilab.bmed.mcgill.ca/HA/

CD2+ CD3+
CD4/CD8+/- or -/+
TdT-
CD1a-
 venule (V)

T: Hassal’s
corpuscle

11
BLOOD-THYMUS Epithelial reticular cells
BARRIER

Perivascular space

L: lymphocytes
enule

12
Child Age-related involution

80% lymphoid at 20y -> 5% at 40y

2. Differential diagnosis of anterior mediastinal
masses
 ANTERIOR MEDIASTINAL MASS
Lymphoid - haematopoietic Epithelial tumors
• T- acute lymphoblastic lymphoma • Thymoma - Thymic carcinoma
• Primary mediastinal large B-cell • Metastatic
lymphoma
• Hodgkin lymphoma Germ cell tumors
• Grey zone lymphoma • Seminoma
• Histiocytic-dendritic cell tumor • Embryonal carcinoma
• Myeloid sarcoma (chloroma) • Yolk sac tumour
Mesenchymal tumors • Choriocarcinoma
• Teratoma (im/mature)
• Lipoma/sarcoma
• Solitary fibrous tumor, …
3. Histologic classification of primary thymic epithelial
neoplasms
 TUMOURS OF THE THYMUS
• Epithelial cells: structure and shape
– thymoma – thymic carcinoma
• Lymphocytes: most of the rest
– Hodgkin – non-Hodgkin lymphoma
• Kulchitsky/neuroendocrine cells: sparse
– carcinoid tumors
 Thymoma: clinico-pathological considerations
• Rare tumour : 1,5 cases for every million people each year (US):
400 cases/year
• Most common tumour in the anterior mediastinum
• Slow-growing, tendency to recur locally, seldom metastasize
• 4/10 asymptomatic when tumor is found on RX/CT
• Symptoms
– Related to the mass: dyspnea, dysphagia, cough, chest pain, superior
vena cava syndrome
– Not directly related to the mass: paraneoplastic : myasthenia gravis
(30% vs 10%), red cell aplasia (5%), hypogammaglobulinaemia (5%)
• Majority of cases are cured. When fatal: cardiorespiratory
problems resulting from pericardial and pleural metastases.
 THYMOMA: DEFINITION
• Epithelial tumours that may or may not be extensively
infiltrated by lymphocytes : primary thymic epithelial neoplasm

• invasive versus noninvasive

– intact fibrous capsule, mobile and easily resected.
– invasion of the tumour capsule or surrounding organs, or by the
presence of a metastasis. About 30-40% of all thymomas are invasive.
• Differentiate from other anterior mediastinal tumours germ cell
tumours, lymphomas, carcinoids, and T-cell leukemias.
Histologic classification of primary thymic epithelial neoplasms
• Difficult
• ‘Traditional’ Bernatz et al. (1961 Mayo clinic)
– relative proportion of epithelial cells to lymphocytes + shape of the
tumor cells
– 4 basic types: lymphocyte-rich - epithelial-rich - mixed lymphoepithelial -
spindle cell thymoma
• Other:
– Japan: 1981 Masaoka
– France, Italy
– Germany: 1985 Müller-Hermelink
=> no universal acceptance !
 WORLD HEALTH ORGANIZATION (WHO)
• 1999: final proposal for the
histopathologic classification of thymic
epithelial neoplasms : ed. J. Rosai
• 2003: minor modifications, in the latest
WHO publication on the histologic
classification of tumours of the lung,
pleura, thymus, and heart; 2003 W.D.
Travis, E. Brambilla, H.K. Müller-
Hermelink, et al.
 WHO 1999
• Morphology of epithelial cell • Extent of lymphocytic infiltrate

type B1 type B2 type B3

spindle/oval plump/epithelioid
(type A) admixture (type B) • Cytologic evidence for
(AB) malignancy type C = carcinoma
 UPDATE WHO 2004
• Morphology of epithelial cell • Extent of lymphocytic infiltrate

type B1 type B2 type B3

spindle/oval round/epithelioid
(type A) admixture (type B) • Cytologic evidence for
(AB) malignancy type C => thymic
• Rare types: metaplastic, micronodular, sclerosing, carcinoma
microscopic, and anaplastic thymoma
 UPDATE WHO 2004
• retained the original basic schema : types A, B, and AB, but
• eliminated the type C -> separate category of thymic carcinoma
• unclassifiable rare cases - > separate types: metaplastic,
micronodular, sclerosing, microscopic, and anaplastic thymoma

• Subtle shifts in the defining criteria -> uncertainty + confusion +

difficulties for the reproducibility !
 PROBLEMS & INCONSISTENCIES
• lack of adequate inter- + intraobserver reproducibility
• lack of clinical predictive value for the various categories
– (no) linear progression in terms of malignancy for types A, AB, B1, B2, B3?
• observation of tumor progression in thymoma
– tumor recurrences have shown transformation of a low-grade histologic type to that
of a higher-grade histology
– demonstration of transitions between well-, moderately, and poorly differentiated
areas within the same neoplasm
• histologic subclassification of thymoma, particularly for the most
common variants, is of limited clinical value
• regardless of morphologic features, clinical staging is thé most
significant parameter for predicting biologic behavior
 EFFORTS TO SIMPLIFY WHO CLASSIFICATION
• Rieker et al. 2002 : identified 3 subgroups with distinct survival
– merging types A, AB, B1, B2 into a single group, type B3 as a separate group,
and type C as a third group
• Marchevsky et al. 2008: 3 categories (excluding thymic
carcinoma), of which only 2 prognostically relevant
• Suster and Moran classification 2006: 3 categories: thymoma –
atypical thymoma – thymic carcinoma
– Premise: primary thymic epithelial neoplasms form part of a continuous
spectrum of lesions that range from well-differentiated to moderately
differentiated to poorly differentiated tumors
 Atypical Thymoma/
Moderately
Thymoma/ Well diffd thymic epithelial neoplasm differentiated TEN

“predominantly epithelial thymomas”

Kalhor N, Moran CA. Thymoma: current concepts. Oncology (Williston Park). 2012 Oct;26(10):975-81
 Poorly differentiated thymic epithelial neoplasm = Thymic carcinoma
Squamous cell carcinoma Basaloid carcinoma Anaplastic carcinoma

Mucoepidermoid carcinoma Clear cell carcinoma Sarcomatoid carcinoma Rhabdoid carcinoma

Moran CA, Suster S. Thymic carcinoma: current concepts and histologic features. Hematol Oncol Clin North Am. 2008 Jun;22(3):393-407
 COMPARISON OF CLASSIFICATIONS

Traditional WHO 2004 Suster and Moran

Spindle cell A Thymoma Well differentiated

— AB Thymoma
Continuous
Lymphocyte-rich B1 Thymoma spectrum
Mixed lymphoepithelial B2 Thymoma of lesions

Epithelial-rich B3 Atypical thymoma

— Thymic carcinoma Thymic carcinoma Poorly differentiated

Am J Clin Pathol 2006;125:542-554

How to determine the degree of differentiation of thymic epithelial
neoplasm?

– presence or absence of the

characteristic organotypical
features of differentiation of the
normal thymus
– degree of cytologic atypia of the
neoplastic thymic epithelial cells
• How to determine the degree of differentiation of thymic
epithelial neoplasm?
– Well differentiated (ie, thymoma): display most or all the organotypical features
of thymic differentiation and absence of cytologic atypia
– Moderately differentiated (ie, atypical thymoma); tumors that retain only some
of the organotypical features of differentiation of the thymus but which already
display mild to moderate cytologic atypia
– Poorly differentiated (ie, thymic carcinoma); total absence of the organotypical
features of the thymus and showing overt cytologic evidence of malignancy.
• Simple, easily reproducible
– requires only familiarity with the organotypical features of differentiation for
the different stages of maturation of the normal thymus, with attention to the
degree of cytologic atypia displayed by the neoplastic epithelial cells
 Conclusion
• progress has been made in the understanding of the biology and
morphology of thymoma, but controversial issues still remain
• part of the solution may lie in simplifying the classification
• term thymic carcinoma
– historically reserved for tumors with more aggressive behavior than
thymoma and has become deeply ingrained in the literature
– seems to imply that thymoma refer to a benign condition. In reality, all
thymic epithelial neoplasms harbor a definite malignant potential and
should therefore be approached as malignant neoplasms from inception,
capable of following an aggressive behavior if left untreated.
• Need for a unified terminology!
 PROPOSED ALTERNATIVE TERMINOLOGY FOR
THYMIC EPITHELIAL NEOPLASMS

By degrees of
By tumor grade By cytologic atypia
differentiation
Well-differentiated TEN
Low-grade thymoma Thymoma grade I
(thymoma)
Moderately differentiated Intermediate-grade
Thymoma grade II
TEN (atypical thymoma) thymoma
Poorly differentiated TEN High-grade thymoma Thymoma grade III (thymic
(thymic carcinoma) (thymic carcinoma) carcinoma)

cfr. lymphoma, melanoma:

varying degrees of malignant potential
Need for re-education!
4. Staging of primary thymic epithelial neoplasms
MASAOKA STAGING SYSTEM, 1981
The Masaoka-Koga Stage Classification
PROGNOSTIC RELEVANCE OF MASAOKA
‘UNOFFICIAL’ UICC TNM STAGING
COMPARISON (KOGA et al)
 3-TIERED SUSTER & MORAN CLASSIFICATION
RELEVANT FOR PROGNOSTICATION

• Separates low-grade from

intermediate- and high-grade

Am J Clin Pathol 2006;125:542

tumors.
• After a tumor has been
assigned to the well-
differentiated category of
thymic epithelial neoplasms,
reliable prognostication can
be determined by clinical
staging of the lesion.
 Conclusion
• All thymomas have the potential to become invasive tumors
• Although much emphasis in recent years has been placed on
the histological classification of thymoma, the bulk of the
evidence continues to point to clinical staging as the most
important parameter for prognostication
 References
• (2003) WHO publication on the histologic classification of tumors of the lung, pleura, thymus, and heart;
2003 W.D. Travis, E. Brambilla, H.K. Müller-Hermelink, et al. Chapter 3
• Rieker R J, Hoegel J, Morresi‐Hauf A. et al Histologic classification of thymic epithelial tumors:
comparison of established classification schemes. Int J Cancer 2002;98(6):900–6
• Marchevsky AM, Gupta R, McKenna RJ, Wick M, Moran C, Zakowski MF, Suster S. Evidence-based
pathology and the pathologic evaluation of thymomas: the World Health Organization classification can
be simplified into only 3 categories other than thymic carcinoma. Cancer. 2008 Jun 15;112(12):2780-8
• Suster S, Moran C A. Problem areas and inconsistencies in the WHO classification of thymoma. Semin
Diagn Pathol 2005;22(3):188–97
• Suster S, Moran C A. Thymoma, atypical thymoma and thymic carcinoma. A novel conceptual approach to
the classification of neoplasms of thymic epithelium. Am J Clin Pathol 1999;111(6):826–33
• Suster S, Moran CA. Thymoma classification: current status and future trends. Am J Clin Pathol. 2006
Apr;125(4):542-54
• Moran CA, Weissferdt A, Kalhor N, Solis LM, Behrens C, Wistuba II, Suster S. Thymomas I: a
clinicopathologic correlation of 250 cases with emphasis on the World Health Organization schema. Am J
Clin Pathol. 2012 Mar;137(3):444-50.
• Kalhor N, Moran CA. Thymoma: current concepts. Oncology (Williston Park). 2012 Oct;26(10):975-81
• Moran CA, Suster S. Thymic carcinoma: current concepts and histologic features. Hematol Oncol Clin
North Am. 2008 Jun;22(3):393-407
• https://www.itmig.org/