EDITORIAL
Introduction to 2021 WHO Classification of
Thoracic Tumors
Ming-Sound Tsao, MD,a,* Andrew G. Nicholson, DM,b,c
Joseph J. Maleszewski, MD,d Alexander Marx, MD,e William D. Travis, MDf
Introduction
The WHO classification system of tumors is adopted
worldwide and is fundamental to how tumor or
tumor-like conditions are clinically managed or treated.
It is considered the international accepted standard for
the diagnosis of tumors for clinical care of patients and
education and research into the etiology, prevention, and
treatment of cancers. The International Agency for
Research on Cancer (IARC) has been responsible for the
publication of the WHO classification of tumors books,
often known as the Blue Book, since the third edition of
the WHO Classification of Tumors of the Lung, Pleura,
Thymus, and Heart was published in 2004,1 and the
fourth edition in 2015.2
The fifth edition of the WHO Classification book on
Thoracic Tumors was published in April 2021.3 In addi-
tion to a printed book, there is an online version that
includes not only text, tables, and figures, but also whole-
slide images (https://tumourclassification.iarc.who.int/
welcome/). The volume was produced in collaboration
with the International Association for the Study of Lung
Cancer, the International Thymic Malignancy Interest
Group, and the International Mesothelioma Panel. Com-
mon to all fifth edition books, the editorial board, with
Prof. Ian Cree from IARC as the board chair, included
organ-specific expert members and standing members.
The expert members for the Thoracic Tumor Blue Book
include 18 pathologists with known expertise and pub-
lication record in the pathology, imaging, and treatment
of tumors of the lung, pleura and pericardium, thymus
and mediastinum, heart and genetic tumor syndromes
involving the thorax.
The fifth edition Thoracic Tumor Blue Book was
formulated by an international, multidisciplinary group
of 217 expert authors and editors. Because the fourth
edition was published only 6 years ago, few new tumor
entities have been recognized and added to this fifth
edition. However, a large volume of new published data
and updates especially in the epidemiology, histopathol-
ogy, immunohistochemistry, and molecular pathology,
and diagnostics of thoracic tumors have been incorpo-
rated into this new edition.
This manuscript will briefly summarize some of the
key changes and features implemented in the fifth
edition of the WHO Classification of Thoracic Tumors.
Separate articles focusing on tumors of the lung, pleura,
and pericardium, heart, and mediastinum will be pub-
lished; these will resemble those published on the fourth
edition of the Thoracic WHO Blue Book.4–7 In addition, a
new article that addresses thoracic hematopoietic
tumors will be published.
Key New Features in the Fifth Edition
The fifth edition has been expanded to include 10
chapters (Table 1). Tumors of the lung, tumors of the
pleura and pericardium, tumors of the heart, tumors of
the thymus are assigned as separate chapters. In
contrast to the fourth edition, separate chapters have
been created for mesenchymal tumors involving
*Corresponding author.
a
Princess Margaret Cancer Centre, University Health Network and
Department of Laboratory Medicine and Pathobiology, University of
Toronto, Toronto, Ontario, Canada, bRoyal Brompton and Harefield NHS
Foundation Trust, London, United Kingdom, cNational Heart and Lung
Institute, Imperial College, London, United Kingdom, dDepartment of
Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota,
e
Institute of Pathology, University Medical Centre Mannheim and Med-
ical Faculty Mannheim, Heidelberg University, Mannheim, Germany,
and fMemorial Sloan Kettering Cancer Center, New York, New York.
Disclosure: Dr. Tsao reports receiving grants and personal fees from
AstraZeneca, Bayer; personal fees from Bristol-Myers Squibb, AbbVie,
Eli Lilly, and Amgen outside of the submitted work. Dr. Nicholson re-
ports receiving personal fees from Merck, Boehringer Ingelheim;
grants and personal fees from Pfizer; and personal fees from Novartis,
AstraZeneca, Bristol-Myers Squibb, Roche, AbbVie, Oncologica, Upto-
Date, European Society of Oncology, and Liberum outside of the sub-
mitted work. The remaining authors declare no conflict of interest.
Address for correspondence: Ming-Sound Tsao, MD, Department of Pa-
thology, University Health Network, 200 Elizabeth Street, 11th Floor,
Toronto, Ontario M5G 2C4, Canada. E-mail: ming.tsao@uhn.ca
ª 2021 International Association for the Study of Lung Cancer.
Published by Elsevier Inc. All rights reserved.
ISSN: 1556-0864
https://doi.org/10.1016/j.jtho.2021.09.017
Journal of Thoracic Oncology Vol. 17 No. 1: e1-e4
e2 Tsao et al
Table 1. Main Chapters in the Fifth Edition (2021) WHO
Classification of Thoracic Tumors
1. Tumors of the lung
2. Tumors of the pleura and pericardium
3. Tumors of the heart
4. Mesenchymal tumors of the thorax
5. Tumors of the thymus
6. Germ cell tumors of the mediastinum
7. Hematolymphoid tumors of the mediastinum
8. Ectopic tumors of the thyroid and parathyroid origin
9. Metastases
10. Genetic tumor syndromes involving the thorax
multiple organ systems in the thorax, germ cell tumors
of the mediastinum, hematolymphoid tumors of the
mediastinum, and ectopic tumors of the thyroid and
parathyroid origin. However, mesenchymal tumors that
are specific to the lung are included in the chapter on
tumors of the lung. Metastatic tumors were moved to a
separate chapter that addresses this topic for each site.
In addition, a new chapter on genetic syndromes
involving the thorax has been created.
New features in the fifth edition are sections on
“Diagnostic molecular pathology” and “Essential and
desirable diagnostic criteria.” These highlight key clin-
ical, pathologic, immunohistochemical, and molecular
diagnostic features of an individual entity.
Key Updates on Tumors of the Lung
For most tumors, the diagnostic criteria remain
essentially unchanged since 2015, but there is consider-
ably more detail to reflect recent scientific advances. As
approximately two-thirds of lung tumors are diagnosed at
an advanced stage and, thus, the diagnoses are made on
small biopsy samples, the chapter entirely dedicated to
the classification of small diagnostic samples is retained.
Furthermore, given advances in molecular pathology,
there is an even greater emphasis on genetic testing, not
just in relation to common lung cancers but also new
molecular characteristics in rarer tumors. Other key up-
dates include the following: (1) recommendation on the
application of percentage of histologic patterns to a formal
grading system in invasive nonmucinous adenocarci-
nomas, (2) recognition of spread through airspaces as a
prognostically significant histologic feature, (3) simplifi-
cation of classification of squamous cell carcinomas and
recognition of lymphoepithelial carcinoma as a squamous
cell carcinoma, (4) recognition of bronchiolar adenoma/
ciliated muconodular papillary tumor as a new entity
within the adenoma subgroup (5) recognition of thoracic
SMARCA4-deficient undifferentiated tumor, (6) recogni-
tion of hyalinizing clear cell carcinoma and myoepithe-
lioma and myoepithelial carcinoma as new types of
Journal of Thoracic Oncology Vol. 17 No. 1
salivary gland-type tumors, and (7) new data to reflect
evolving concepts in lung neuroendocrine neoplasm.
Key Updates on the Tumors of the Pleura
and Pericardium
The most significant addition to the fifth edition is
“mesothelioma in situ,” which has recently been recog-
nized as a preinvasive lesion of diffuse mesothelioma.8,9
The need for a multidisciplinary approach including
clinical, histopathologic, and molecular features as
essential diagnostic criteria for mesothelioma in situ is
emphasized. For diffuse pleural and pericardial meso-
thelioma, the term malignant has been omitted, but the
three subtypes (epithelioid, biphasic, and sarcomatoid)
are maintained. More importantly, there is a more
organized stratification of histologic features into archi-
tectural patterns and cytologic and stromal features,
including “transitional” and “lymphohistiocytic,” with
prognostic implications documented.10 A further
advance is the recommendation of a grading system for
epithelioid mesothelioma, which should, henceforth, be a
part of diagnostic reports. Finally, there was consensus
that the word “tumor” should substitute “mesothelioma”
in a well-differentiated papillary mesothelial tumor as
the previous terminology was inconsistent with the
benign clinical course of the lesion after resection.
Key Updates on the Tumors of the Heart
Several nomenclatures and classification changes
were made to the chapter on tumors of the heart to better
reflect our contemporary understanding of lesion patho-
biology and provide consistency among lesions. Molecular
data were expanded for both cardiac myxoma and papil-
lary fibroelastoma, the latter of which is now formally
recognized as neoplastic on the basis of the identification
of oncogenic driver mutations in these tumors.
The term histiocytoid cardiomyopathy was updated
to conduction system hamartoma in recognition of its
similarity pathologically and genetically with other
hamartomas lesions. The list of hamartomatous lesions
was also expanded to include distinctive entities.
The list of specific malignancies was condensed to
reflect frequently encountered malignancies, with some
tumors (e.g., myxofibroasarcoma, synovial sarcoma) be-
ing relocated to the chapter on mesenchymal tumors of
the thorax given their similar presentation and
implication.
Key Updates on the Tumors of the
Mediastinum
The classification of thymic tumors has largely been
maintained. Recent advances mainly concern thymic
epithelial tumors—that is, thymomas, thymic carcinomas
January 2022
(TCs), and neuroendocrine neoplasms. These comprise
rare new entities (e.g., hyalinizing clear cell carcinomas),
new molecular features of well-known entities (e.g.,
MAML2 translocations in metaplastic thymomas), the
refinement of diagnostic criteria (e.g., for adenocarci-
nomas by obligatory immunohistochemical features),
and the streamlining of nomenclature, as exemplified by
the term lymphoepithelial carcinoma for analogous tu-
mors in the thymus and lung, replacing the historic
“thymic lymphoepithelioma-like carcinoma.” Some new
observations may even have the potential to change
current therapies, including microsatellite instability in
TCs11 and the delineation of molecular subgroups among
neuroendocrine neoplasms12 that are, however, still
classified through classical morphologic criteria as
typical and atypical carcinoids, large cell neuroendocrine
carcinoma, and small cell carcinoma.
On germ cell tumors of the mediastinum, the devel-
opment of mediastinal teratomas along different path-
ways seems a major advance.13
Key Updates on Thoracic
Hematolymphoid Tumors of Mediastinum
In continuity with the fourth edition, the chapter on
hematolymphoid tumors of the mediastinum covers
lymphomas, dendritic cell tumors, and myeloid sarcoma.
If arising in mediastinal lymph nodes, virtually all lym-
phomas, dendritic cell tumors, and myeloid neoplasia
may be encountered. Their diagnostic criteria remain
unchanged.
Table 2. Hereditary Genetic Disorders Associated With Familial Predisposition to Particular Thoracic Neoplasm
Hereditary Genetic Disorder
Li-Fraumeni syndrome
BAP1 tumor predisposition syndrome
Carney complex
DICER1 syndrome
Tuberous sclerosis
Gorlin syndrome
Gardner syndrome
Neurofibromatosis type 1
Neurofibromatosis type 2
Germline SMARCB1 or LZTR1 mutations
Multiple endocrine neoplasia type 2
Von Hippel–Lindau syndrome
Hereditary paraganglioma-phaeochromocytoma
syndrome
Carney–Stratakis syndrome
Peutz–Jeghers syndrome
Germline EGFR p.T790M
ERBB2 germline mutations
Reprinted from WHO Classification of Tumours, Thoracic Tumours, fifth edition. Lazar AJ, Cooper WA, Genetic tumor syndromes involving the thorax: intro-
duction; IARC, 2021:473.
IARC, International Agency for Research on Cancer.
WHO Classification of Thoracic Tumors e3
Changes in the new edition include the following: (1)
the restriction to entities with “mediastinal peculiarities”
or relevant mediastinal prevalence; (2) the simplification
of the nomenclature “B-cell lymphoma, unclassifiable,
with features intermediate between DLBCL and classical
Hodgkin lymphoma” to “mediastinal gray zone lym-
phoma”; and (3) staging according to the Lugano clas-
sification that has been adopted from the eighth edition
of the TNM classification system. For entities beyond
nodular sclerosis classical Hodgkin lymphoma, primary
mediastinal large B-cell lymphoma, mediastinal gray
zone lymphoma, T-lymphoblastic lymphoma/leukemia,
mucosa-associated lymphoid tissue (MALT) lymphoma,
and follicular dendritic cell sarcoma, readers are
referred to the fourth edition of the WHO Classification of
Tumours of the Haematopoietic and Lymphoid Tissues.14
Genetic Tumor Syndromes Involving the
Thorax
A new chapter on genetic tumor syndromes was
added that addresses the uncommon germline mutations
among patients with lung cancer and references the
many hereditary genetic disorders that have been asso-
ciated with various thoracic neoplasms (Table 2). The
chapter includes a more detailed discussion on three
hereditary tumor syndromes. The Li-Fraumeni syn-
drome is caused by germline mutation involving the
TP53 tumor suppressor gene, with associated thoracic
malignancies including lung carcinoma, mediastinal/cardiac
sarcomas, and TC. BAP1 tumor predisposition syndrome
Associated Thoracic Neoplasms
Lung carcinoma, mediastinal/cardiac sarcomas, thymic carcinoma
Mesothelioma
Atrial myxoma
Pleuropulmonary blastoma
Lymphangioleiomyomatosis, perivascular epithelioid cell tumors (PEComas),
cardiac rhabdomyomas
Cardiac fibromas
Desmoid fibromatosis
Malignant peripheral nerve sheath tumor, paragangliomas
Schwannoma
Schwannomatosis
Paraganglioma
Paraganglioma
Paraganglioma
Paraganglioma
Lung carcinoma
Lung carcinoma
Lung carcinoma
e4 Tsao et al
results from germline mutation involving the BAP1 gene,
which predisposes the affected individual to pleural or
peritoneal mesothelioma. The Carney complex includes
atrial myxomas, endocrinopathy, and pigmented skin
lesions, and is associated with germline mutation
involving the PRKAR1A gene, which encodes for a regu-
latory subunit of the protein kinase A.
Hereditary lung adenocarcinomas have been re-
ported among family members of patients with germline
EGFR T790M mutation and YAP1 R331W risk allele
mutation.15 Interestingly, patients with lung adenocar-
cinoma and family history of lung cancer were reported
at higher risk of harboring EGFR mutation in their lung
cancers, albeit the mutation types are randomly
distributed,16,17 suggesting that additional studies are
warranted into genetic risk alleles involved in lung
carcinogenesis.
Conclusion
In conclusion, the fifth edition Blue Book should
serve as an important reference in the daily practice of
pathologists, and others involved in the education,
research, and care of patients with thoracic tumors. The
editors gratefully acknowledge the wonderful scientific
contributions and collegiality of each of the contributing
authors and the International Association for the Study
of Lung Cancer, International Thymic Malignancy Inter-
est Group, International Mesothelioma Panel, and IARC
in making publication of this book possible.
CRediT Authorship Contribution
Statement
Ming-Sound Tsao, Andrew G. Nicholson, Joseph J.
Maleszewski, Alexander Marx, William D. Travis:
Conceptualization, Data acquisition and analysis, Fund-
ing and supervision, Manuscript writing and editing,
Final manuscript approval.
Acknowledgments
The authors thank Prof. Ian Cree (editorial board chair),
all members of the editorial board for the Thoracic Tu-
mor Book, and the International Agency for Research on
Cancer staffs involved in the WHO Classification of Tu-
mours, fifth edition series, for their contribution to the
completion of the fifth edition book.
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