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The 2015 World Health Organization Classification of Tumors of the Thymus: Continuity and Changes

      Abstract

      This overview of the 4th edition of the World Health Organization (WHO) Classification of thymic tumors has two aims. First, to comprehensively list the established and new tumor entities and variants that are described in the new WHO Classification of thymic epithelial tumors, germ cell tumors, lymphomas, dendritic cell and myeloid neoplasms, and soft-tissue tumors of the thymus and mediastinum; second, to highlight major differences in the new WHO Classification that result from the progress that has been made since the 3rd edition in 2004 at immunohistochemical, genetic and conceptual levels. Refined diagnostic criteria for type A, AB, B1–B3 thymomas and thymic squamous cell carcinoma are given, and it is hoped that these criteria will improve the reproducibility of the classification and its clinical relevance. The clinical perspective of the classification has been strengthened by involving experts from radiology, thoracic surgery, and oncology; by incorporating state-of-the-art positron emission tomography/computed tomography images; and by depicting prototypic cytological specimens. This makes the thymus section of the new WHO Classification of Tumours of the Lung, Pleura, Thymus and Heart a valuable tool for pathologists, cytologists, and clinicians alike. The impact of the new WHO Classification on therapeutic decisions is exemplified in this overview for thymic epithelial tumors and mediastinal lymphomas, and future perspectives and challenges are discussed.

      Key Words:

      The 4th edition of the World Health Organization (WHO) Classification of Tumours of the Lung, Pleura, Thymus and Heart is largely a revision of the 3rd edition that was published in 2004 under the editorship of Travis et al.
      • Travis WD
      • Brambilla E
      • Müller-Hermelink HK
      • et al.
      It was for the first time that the WHO Classification gathered all thoracic tumors in one book. In contrast, the previous 2nd edition of the WHO Classification of Tumours of the Thymus, edited by Dr. Juan Rosai, was published in 1999 and addressed only thymic tumors. In this edition, the concept of type A, AB, and B1–B3 nomenclature was introduced for thymomas.

      Rosai J, Sobin L. Histological Typing of Tumours of the Thymus, 1999.

      The 3rd and the new 4th editions
      • Travis WD
      • Brambilla E
      • Burke AP
      • et al.
      perpetuate this unique nomenclature for thymomas because it has achieved worldwide acceptance and has not been challenged seriously by new data.
      • Ströbel P
      • Hartmann E
      • Rosenwald A
      • et al.
      Corticomedullary differentiation and maturational arrest in thymomas.
      In the 3rd edition, the histopathology of thymic tumors was complemented with descriptions of their clinical symptoms, macroscopic, immunohistological and genetic features, and prognostic data.
      In the 4th edition of the WHO Classification of thoracic tumors edited by William D. Travis, Elizabeth Brambilla, Allen Burke, Alexander Marx, and Andrew G. Nicholson, this interdisciplinary perspective on thymic tumors is further strengthened by involving clinical experts from radiology, thoracic surgery, and oncology as co-authors and by the incorporation of state-of-the-art computed tomography and positron emission tomography/computed tomography images (Fig. 1) and cytology (Fig. 2). The foundations for this interdisciplinary approach and the broad consensus on conceptual changes and histological criteria for improved thymoma subtyping were greatly aided by two international interdisciplinary conferences organized by the International Thymic Malignancy Interest Group (ITMIG) in New York City and Mannheim, Germany and convened experts from North America, Asia, and Europe. Another focus of the 4th edition was the revision and refinement of histological and immunohistochemical diagnostic criteria for a more robust and reproducible subtyping of thymomas and for the distinction between thymomas and thymic carcinomas. The necessary preparatory work for this refinement of histological criteria was achieved at the ITMIG consensus meetings in New York and Mannheim
      • Marx A
      • Ströbel P
      • Badve SS
      • et al.
      ITMIG consensus statement on the use of the WHO histological classification of thymoma and thymic carcinoma: refined definitions, histological criteria, and reporting.
      and is reflected in the 4th edition not only in the “histopathology” but also “differential diagnosis” paragraphs. Furthermore, the epidemiological and prognostic data in the chapters on thymic epithelial tumors (TETs) were for the first time not only based on single-center experience or small meta-analysis, but on recent data derived from the worldwide, retrospective database of the ITMIG that has compiled more than 6000 cases of thymomas, thymic carcinomas, and thymic neuroendocrine neoplasms.
      • Weis CA
      • Yao X
      • Deng Y
      • et al.
      Contributors to the ITMIG Retrospective Database. The impact of thymoma histotype on prognosis in a worldwide database.
      • Ahmad U
      • Yao X
      • Detterbeck F
      • et al.
      Thymic carcinoma outcomes and prognosis: results of an international analysis.
      • Huang J
      • Ahmad U
      • Antonicelli A
      • International Thymic Malignancy Interest Group International Database Committee and Contributors
      • et al.
      Development of the International Thymic Malignancy Interest Group international database: an unprecedented resource for the study of a rare group of tumors.
      • Filosso PL
      • Yao X
      • Ahmad U
      • European Society of Thoracic Surgeons Thymic Group Steering Committee
      • et al.
      Outcome of primary neuroendocrine tumors of the thymus: a joint analysis of the International Thymic Malignancy Interest Group and the European Society of Thoracic Surgeons databases.
      Figure thumbnail gr1
      FIGURE 1Images of a fluorodeoxyglucose (FDG) positron emission tomography–computed tomography (PET-CT) of a 71-year-old woman with type B3 thymoma. A, Axial CT image at the level of the left main bronchus (B) demonstrates an anterior mediastinal mass (M) and low right paratracheal lymphadenopathy. Infiltration of superior recess of the pericardium is indicated by arrow. B. Axial fused image at the same level demonstrates that both the primary tumor and the metastasis are FDG avid.
      Figure thumbnail gr2
      FIGURE 2Cytology of World Health Organization (WHO) type B2 thymoma (fine needle aspirate). Large tumor cells with elongated or round nuclei and nucleoli intermingled with small lymphocytes.
      In the chapters on germ cell tumors (GCTs), lymphoid, hematopoietic and soft-tissue neoplasms, there are no changes of concept or diagnostic criteria in the 4th compared with the 3rd edition. Minor revisions concern new immunohistochemical and genetic data and the adaptation of nomenclature and definitions to the WHO Classifications of Tumours of the Haematopoietic and Lymphoid Tissue,
      • Swerdlow SH
      • Campo E
      • Harris NL
      • et al.
      Tumours of Soft Tissues and Bone
      • Fletcher CDM
      • Bridge JA
      • Hogendorn PCW
      • et al.
      and Tumours of the Urinary System and Male Genital Organs (H. Moch, et al., forthcoming).
      The following “overview” focuses on differences between the 3rd and 4th edition of the WHO Classification of tumors of the thymus rather than providing comprehensive description of the tumors.

      NOVELTIES IN THE NEW WHO CLASSIFICATION OF MEDIASTINAL TUMORS

      Thymomas

      Conceptual continuity

      The nomenclature of the major thymoma subtypes based on letters and numbers (type A, AB, B1–B3)

      Rosai J, Sobin L. Histological Typing of Tumours of the Thymus, 1999.

      is maintained in the 4th edition (Table 1), as is the recommendation to use the modified Masaoka–Koga system for the staging of thymomas.
      • Detterbeck FC
      • Nicholson AG
      • Kondo K
      • Van Schil P
      • Moran C
      The Masaoka–Koga stage classification for thymic malignancies: classification and definition of terms.
      A new tumor, node, metastasis (TNM) staging system is currently being jointly developed by the International Association for the Study of Lung Cancer and ITMIG, but preliminary staging proposals
      • Kondo K
      • Van Schil P
      • Detterbeck FC
      • Staging and Prognostic Factors Committee
      • Members of the Advisory Boards
      • Participating Institutions of the Thymic Domain
      • et al.
      The IASLC/ITMIG Thymic Epithelial Tumors Staging Project: proposals for the N and M components for the forthcoming (8th) edition of the TNM classification of malignant tumors.
      • Nicholson AG
      • Detterbeck FC
      • Marino M
      • Staging and Prognostic Factors Committee
      • Members of the Advisory Boards
      • Participating Institutions of the Thymic Domain
      • et al.
      The IASLC/ITMIG Thymic Epithelial Tumors Staging Project: proposals for the T Component for the forthcoming (8th) edition of the TNM classification of malignant tumors.
      should not be used in clinical settings before the approval by the Union for International Cancer Control (UICC) and the American Joint Committee on Cancer (AJCC).
      • Detterbeck FC
      • Stratton K
      • Giroux D
      • Staging and Prognostic Factors Committee
      • Members of the Advisory Boards
      • Participating Institutions of the Thymic Domain
      • et al.
      The IASLC/ITMIG Thymic Epithelial Tumors Staging Project: proposal for an evidence-based stage classification system for the forthcoming (8th) edition of the TNM classification of malignant tumors.
      TABLE 1Epithelial Tumors
      Thymoma
       Type A thymoma, including atypical variant8581/3
      These new codes were approved by the IARC/WHO Committee for ICD-0.
       Type AB thymoma8582/3
      These new codes were approved by the IARC/WHO Committee for ICD-0.
       Type B1 thymoma8583/3
      These new codes were approved by the IARC/WHO Committee for ICD-0.
       Type B2 thymoma8584/3
      These new codes were approved by the IARC/WHO Committee for ICD-0.
       Type B3 thymoma8585/3
      These new codes were approved by the IARC/WHO Committee for ICD-0.
       Micronodular thymoma with lymphoid stroma8580/1
      These new codes were approved by the IARC/WHO Committee for ICD-0.
       Metaplastic thymoma Other rare thymomas8580/3
       Microscopic thymoma8580/0
       Sclerosing thymoma8580/3
       Lipofibroadenoma9010/0
      These new codes were approved by the IARC/WHO Committee for ICD-0.
      Thymic carcinoma
       Squamous cell carcinoma8070/3
       Basaloid carcinoma8123/3
       Mucoepidermoid carcinoma8430/3
       Lymphoepithelioma-like carcinoma8082/3
       Clear cell carcinoma8310/3
       Sarcomatoid carcinoma8033/3
       Adenocarcinomas
       Papillary adenocarcinoma8260/3
      Thymic carcinoma with adenoid cystic8200/3
      These new codes were approved by the IARC/WHO Committee for ICD-0.
       carcinoma-like features
       Mucinous adenocarcinoma8480/3
       Adenocarcinoma, NOS8140/3
       NUT carcinoma8023/3
      These new codes were approved by the IARC/WHO Committee for ICD-0.
       Undifferentiated carcinoma8020/3
       Other rare thymic carcinomas
       Adenosquamous carcinoma8560/3
       Hepatoid carcinoma8576/3
      Thymic carcinoma, NOS8586/3
       Thymic neuroendocrine tumors
       Carcinoid tumors
       Typical carcinoid8240/3
       Atypical carcinoid8249/3
       Large-cell neuroendocrine carcinoma8013/3
       Combined large-cell neuroendocrine carcinoma8013/3
       Small-cell carcinoma (SCC)8041/3
       Combined SCC8045/3
      Combined thymic carcinomas Germ cell tumors of the mediastinum
       Seminoma9061/3
       Embryonal carcinoma9070/3
       Yolk sac tumor9071/3
       Choriocarcinoma9100/3
       Teratoma
       Teratoma, mature9080/0
       Teratoma, immature9080/1
       Mixed germ cell tumors9085/3
       Germ cell tumors with somatic-type solid malignancy9084/3
       Germ cell tumors with associated hematological malignancy9086/3
      These new codes were approved by the IARC/WHO Committee for ICD-0.
      Lymphomas of the mediastinum
       Primary mediastinal large B-cell lymphoma9679/3
       Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma)9699/3
      Other mature B-cell lymphomas
      This can be any mature B-cell lymphoma and the respective ICD-O code from the WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues.10
      T lymphoblastic leukaemia / lymphoma9837/3
      Anaplastic large-cell lymphoma (ALCL) and other rare mature T- and NK-cell lymphomas
       ALCL, ALK-positive (ALK+)9714/3
       ALCL, ALK-negative (ALK-)9702/3
      Hodgkin lymphoma9650/3
      B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell and classical Hodgkin lymphoma9596/3
      Histiocytic and dendritic cell neoplasms of the mediastinum Langerhans cell lesions
       Thymic Langerhans cell histocytosis9751/1
       Langerhans cell sarcoma9756/3
       Histiocytic sarcoma9755/3
       Follicular dendritic cell sarcoma9758/3
       Interdigitating dendritic cell sarcoma9757/3
       Fibroblastic reticular cell tumor9759/3
       Indeterminate dendritic cell tumor9757/3
      Myeloid sarcoma and extramedullary acute myeloid leukaemia9930/3
      Soft-tissue tumors of the mediastinum
       Thymolipoma8850/0
       Lipoma8850/0
       Liposarcoma
       Well-differentiated8850/3
       Dedifferentiated8858/3
       Myxoid8852/3
       Pleomorphic8854/3
      Solitary fibrous tumor8815/1
       Malignant8815/3
      Synovial sarcoma
       Synovial sarcoma, NOS9040/3
       Synovial sarcoma, spindle cell9041/3
       Synovial sarcoma, epithelioid cell9042/3
       Synovial sarcoma, biphasic9043/3
      Vascular neoplasms
       Lymphangioma9170/0
       Hemangioma9120/0
       Epithelioid hemangioendothelioma9133/3
       Angiosarcoma9120/3
      Neurogenic tumors Tumors of peripheral nerves
       Ganglioneuroma9490/0
       Ganglioneuroblastoma9490/3
       Neuroblastoma9500/3
      Ectopic tumors of the thymus Ectopic thyroid tumors Ectopic parathyroid tumors Other rare ectopic tumors
      The morphology codes are from the International Classification of Diseases for Oncology (ICD-O). Behavior is coded /0 for benign tumors; /1 for unspecified, borderline, or uncertain behavior; /2 for carcinoma in situ and grade III intraepithelial neoplasia; and /3 for malignant tumors. The classification is modified from the previous WHO classification, 1 taking into account changes in our understanding of these lesions.
      WHO, World Health Organization; NUT, nuclear protein in testis.
      a These new codes were approved by the IARC/WHO Committee for ICD-0.
      b This can be any mature B-cell lymphoma and the respective ICD-O code from the WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues.10

      Conceptual changes

      One new feature of the 4th edition is that some histological criteria for the characterization of thymomas using hematoxylin and eosin (HE)-stained specimens are now considered “obligatory/indispensable,” and others as “optional” according to their importance for diagnosis (Table 2).
      • Marx A
      • Ströbel P
      • Badve SS
      • et al.
      ITMIG consensus statement on the use of the WHO histological classification of thymoma and thymic carcinoma: refined definitions, histological criteria, and reporting.
      It is hoped that these clarifications will reduce previous ambiguity and may help to overcome the unsatisfactory reproducibility of the WHO classification reported by some studies.
      • Roden AC
      • Yi ES
      • Jenkins SM
      • et al.
      Modified Masaoka stage and size are independent prognostic predictors in thymoma and modified Masaoka stage is superior to histopathologic classifications.
      • Suster S
      • Moran CA
      Histologic classification of thymoma: the World Health Organization and beyond.
      • Detterbeck FC
      Clinical value of the WHO classification system of thymoma.
      TABLE 2Refinement of Diagnostic Criteria of Thymomas in the 2015 WHO Classification of Thymic Tumors3 by Stressing Obligatory and Optional Features
      Thymoma SubtypeObligatory CriteriaOptional Criteria
      Type AOccurrence of bland, spindle-shaped epithelial cells (at least focally); paucity
      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”
      or absence of immature (TdT+) T cells throughout the tumor
      Polygonal epithelial cells; CD20+ epithelial cells
      Atypical type A variantCriteria of type A thymoma; in addition, comedo-type tumor necrosis; increased mitotic count (>4/2 mm2); nuclear crowdingPolygonal epithelial cells; CD20+ epithelial cells
      Type ABOccurrence of bland, spindle-shaped epithelial cells (at least focally); abundance
      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”
      of immature (TdT+) T cells focally or throughout tumor
      Polygonal epithelial cells; CD20+ epithelial cells
      Type B1Thymus-like architecture and cytology: abundance of immature T cells, areas of medullary differentiation (medullary islands); paucity of polygonal or dendritic epithelia cells without clustering (i.e., <3 contiguous epithelial cells)Hassall's corpuscles; perivascular spaces
      Type B2Increased numbers of single or clustered polygonal or dendritic epithelial cells intermingled with abundant immature T cellsMedullary islands; Hassall's corpuscles; perivascular spaces
      Type B3Sheets of polygonal slightly to moderately atypical epithelial cells; absent or rare intercellular bridges; paucity or absence of intermingled TdT+ T cellsHassall's corpuscles; perivascular spaces
      MNT
      Microscopic thymoma, sclerosing thymoma, lipofibroadenoma.
      Nodules of bland spindle or oval epithelial cells surrounded by an epithelial cell-free lymphoid stromaLymphoid follicles; monoclonal B cells and/or plasma cells (rare)
      Metaplastic thymomaBiphasic tumor composed of solid areas of epithelial cells in a background of bland-looking spindle cells; absence of immature T cellsPleomorphism of epithelial cells; actin, keratin, or EMA-positive spindle cells
      Rare others
      Microscopic thymoma, sclerosing thymoma, lipofibroadenoma.
      The atypical type A thymoma variant (in bold) is the only new addition to the “historic” list of thymoma subtypes.1
      WHO, World Health Organization; MNT, micronodular thymoma with lymphoid stroma.
      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.
      Another conceptual change concerns the reporting of more than 30% of thymomas that show more than one histological pattern (Moran et al.
      • Moran CA
      • Weissferdt A
      • Kalhor N
      • et al.
      Thymomas I: a clinicopathologic correlation of 250 cases with emphasis on the World Health Organization schema.
      find >50% on extensive sampling).
      • Ströbel P
      • Bauer A
      • Puppe B
      • et al.
      Tumor recurrence and survival in patients treated for thymomas and thymic squamous cell carcinomas: a retrospective analysis.
      Instead of using the term “combined TETs,”
      • Travis WD
      • Brambilla E
      • Müller-Hermelink HK
      • et al.
      the diagnosis should list all the histological thymoma types that are encountered, starting with the most prominent component; minor components should be reported subsequently and quantified in 10% increments.
      • Marx A
      • Ströbel P
      • Badve SS
      • et al.
      ITMIG consensus statement on the use of the WHO histological classification of thymoma and thymic carcinoma: refined definitions, histological criteria, and reporting.
      This rule is not applicable to type AB thymoma (a distinct thymoma entity) and tumors with a carcinoma component of whatever size (see “Combined thymic carcinomas” below).
      A third conceptual change is the introduction of immunohistochemical features as criteria for diagnosis of thymomas with ambiguous histology. Examples are the distinction of type A and AB thymomas by the paucity versus abundance of immature TdT+ T cells, or the different patterns of coarse versus delicate cytokeratin networks in type AB and B1 thymomas (see below). Routine immunohistochemical markers that are recommended in otherwise difficult-to-classify thymomas and thymic carcinomas are given in Table 3.
      • Travis WD
      • Brambilla E
      • Burke AP
      • et al.
      TABLE 3Markers Considered to Be Useful for the Routine Immunohistochemical Characterization of Otherwise Difficult-to-Classify Thymomas and Thymic Carcinomas3
      MarkerCellular and Subcellular Targets of Mediastinal Tumors
      CytokeratinsEpithelial cells of normal thymus, thymomas,
      Beware of rare cytokeratin-negative thymomas (that typically maintain expression of p63/p40).82
      thymic carcinomas, neuroendocrine tumors, many germ cell tumors, rare sarcomas, and dendritic cell tumors; metastases to the mediastinum
      Cytokeratin 19Epithelial cells of normal thymus, thymomas,
      Beware of rare cytokeratin-negative thymomas (that typically maintain expression of p63/p40).82
      and thymic carcinomas
      Cytokeratin 20Negative in normal thymus and thymomas. May be positive in rare thymic adenocarcinomas, teratomas, or metastases
      P63Nuclei of normal and neoplastic thymic epithelial cells, squamous epithelial cells (e.g., in teratoma, metastasis), primary mediastinal large B-cell lymphoma
      P40Nuclei of normal and neoplastic thymic epithelial cells, squamous epithelial cells (e.g., in teratoma, metastasis)
      TdTImmature T cells of normal thymus, >90% of thymomas, and neoplastic T cells of T lymphoblastic lymphoma
      CD5Immature and mature T cells of thymus and >90% of thymomas, neoplastic T cells of many T lymphoblastic lymphomas; epithelial cells in 70% of thymic carcinomas
      Beware of adenocarcinoma metastases to the mediastinum that can be CD5+ as well.
      CD20Normal and neoplastic B cells, epithelial cells in 50% of cases of type A and AB thymoma
      CD117Epithelial cells in 80% of thymic carcinomas, neoplastic cells in most seminomas
      a Beware of rare cytokeratin-negative thymomas (that typically maintain expression of p63/p40).82
      b Beware of adenocarcinoma metastases to the mediastinum that can be CD5+ as well.
      A final conceptual change concerns the appreciation that all major thymoma subtypes can behave in a clinically aggressive fashion
      • Moran CA
      • Weissferdt A
      • Kalhor N
      • et al.
      Thymomas I: a clinicopathologic correlation of 250 cases with emphasis on the World Health Organization schema.
      and therefore should no longer be called benign tumors, irrespective of tumor stage. Accordingly, their ICD-O codes now have a /3 suffix, labeling them as malignant (Table 1). Exceptions are micronodular and microscopic thymomas, for which fatal outcomes are not on record.

      Key new discoveries

      Improved genetic,
      • Wang Y
      • Thomas A
      • Lau C
      • et al.
      Mutations of epigenetic regulatory genes are common in thymic carcinomas.
      • Petrini I
      • Meltzer PS
      • Kim IK
      • et al.
      A specific missense mutation in GTF2I occurs at high frequency in thymic epithelial tumors.
      • Girard N
      • Shen R
      • Guo T
      • et al.
      Comprehensive genomic analysis reveals clinically relevant molecular distinctions between thymic carcinomas and thymomas.
      epigenetic,
      • Petrini I
      • Wang Y
      • Zucali PA
      • et al.
      Copy number aberrations of genes regulating normal thymus development in thymic epithelial tumors.
      • Chen C
      • Yin B
      • Wei Q
      • et al.
      Aberrant DNA methylation in thymic epithelial tumors.
      and transcriptomic
      • Girard N
      • Shen R
      • Guo T
      • et al.
      Comprehensive genomic analysis reveals clinically relevant molecular distinctions between thymic carcinomas and thymomas.
      • Huang B
      • Belharazem D
      • Li L
      • et al.
      Anti-apoptotic signature in thymic squamous cell carcinomas—functional relevance of anti-apoptotic BIRC3 expression in the thymic carcinoma cell line 1889c.
      analyses have augmented our knowledge about the distinct molecular basis of thymomas and thymic carcinomas. The latter show mutations of epigenetic regulatory genes,
      • Wang Y
      • Thomas A
      • Lau C
      • et al.
      Mutations of epigenetic regulatory genes are common in thymic carcinomas.
      methylation patterns,
      • Chen C
      • Yin B
      • Wei Q
      • et al.
      Aberrant DNA methylation in thymic epithelial tumors.
      and expression profiles of antiapoptotic genes
      • Huang B
      • Belharazem D
      • Li L
      • et al.
      Anti-apoptotic signature in thymic squamous cell carcinomas—functional relevance of anti-apoptotic BIRC3 expression in the thymic carcinoma cell line 1889c.
      that clearly distinguish them from thymomas. On the other hand, the identification of a highly recurrent point mutation in the GTF2I oncogene in all major thymoma subtypes and thymic carcinomas
      • Petrini I
      • Meltzer PS
      • Kim IK
      • et al.
      A specific missense mutation in GTF2I occurs at high frequency in thymic epithelial tumors.
      is a seminal finding that underlines the unique tumor biology of TETs and lends strong support to the WHO-based subtyping of thymic tumors.
      • Rajan A
      • Girard N
      • Marx A
      State of the art of genetic alterations in thymic epithelial tumors.
      Nevertheless, new predictive markers with therapeutic perspective are still awaited.
      • Lopez-Chavez A
      • Thomas A
      • Rajan A
      • et al.
      Molecular profiling and targeted therapy for advanced thoracic malignancies: a biomarker-derived, multiarm, multihistology phase II basket trial.
      • Marx A
      • Weis CA
      Sunitinib in thymic carcinoma: enigmas still unresolved.

      Individual changes concerning thymoma subtypes

      Atypical type A thymoma:

      A new addition in the 4th edition is the delineation of an “atypical type A thymoma variant” from conventional type A thymomas (Table 1). The new term reflects the experience that rare type A thymomas can show hypercellularity, increased mitotic activity, and necrosis (Fig. 3). Necrosis in particular appears to correlate with advanced stage, including metastasis.
      • Marx A
      • Ströbel P
      • Badve SS
      • et al.
      ITMIG consensus statement on the use of the WHO histological classification of thymoma and thymic carcinoma: refined definitions, histological criteria, and reporting.
      • Green AC
      • Marx A
      • Strobel P
      • et al.
      Type A and AB thymomas: histological features associated with increased stage.
      • Nonaka D
      • Henley JD
      • Chiriboga L
      • et al.
      Diagnostic utility of thymic epithelial markers CD205 (DEC205) and Foxn1 in thymic epithelial neoplasms.
      • Vladislav IT
      • Gokmen-Polar Y
      • Kesler KA
      • Loehrer Sr, PJ
      • Badve S
      The role of histology in predicting recurrence of type A thymomas: a clinicopathologic correlation of 23 cases.
      Rare type AB thymomas can show similar features.
      • Green AC
      • Marx A
      • Strobel P
      • et al.
      Type A and AB thymomas: histological features associated with increased stage.
      The clinical significance of this variant needs further studies.
      Figure thumbnail gr3
      FIGURE 3Conventional type A thymoma versus atypical type A thymoma variant. A, Conventional type A thymoma exhibiting areas composed of spindle cells (upper half) and polygonal cells (lower half) separated by a broad fibrous septum. B and C. Atypical type A thymoma variant showing various degrees of spontaneous necrosis in polygonal cell areas. This tumor invaded the lung and showed a missense mutation (chromosome 7 c.74146970T>A) in the GTF2I gene that is common in type A thymomas but rare in type B thymomas and thymic carcinomas.
      • Petrini I
      • Meltzer PS
      • Kim IK
      • et al.
      A specific missense mutation in GTF2I occurs at high frequency in thymic epithelial tumors.

      Type A versus AB thymoma:

      The distinction between type A and AB thymoma has been notoriously difficult.
      • Roden AC
      • Yi ES
      • Jenkins SM
      • et al.
      Modified Masaoka stage and size are independent prognostic predictors in thymoma and modified Masaoka stage is superior to histopathologic classifications.
      • Suster S
      • Moran CA
      Histologic classification of thymoma: the World Health Organization and beyond.
      • Detterbeck FC
      Clinical value of the WHO classification system of thymoma.
      It is now stressed that both thymoma types share the occurrence of bland-looking spindle epithelial cells (that may optionally be accompanied by oval or polygonal tumor cells) and are distinguished from each other by a low and high content of immature T cells, respectively (Fig. 4A–C). Any lymphocyte-dense areas (with crowded TdT+ cells that are “impossible to count” in “type B-like” areas) or more than 10% tumor areas with a moderate infiltrate of immature T cells should prompt classification as type AB thymoma.
      • Marx A
      • Ströbel P
      • Badve SS
      • et al.
      ITMIG consensus statement on the use of the WHO histological classification of thymoma and thymic carcinoma: refined definitions, histological criteria, and reporting.
      The close relationship between type A and AB thymomas is strongly supported by largely overlapping genetic alterations.
      • Petrini I
      • Meltzer PS
      • Kim IK
      • et al.
      A specific missense mutation in GTF2I occurs at high frequency in thymic epithelial tumors.
      However, it will be interesting to study whether this genetic overlap applies to lymphocyte-poor and lymphocyte-rich areas in type AB thymoma alike.
      Figure thumbnail gr4
      FIGURE 4Immunohistochemistry: an important tool for the diagnosis of difficult-to-classify type A versus AB thymomas. A, Abundance of TdT+ immature T cells in type AB thymoma; any such crowding of TdT+ T cells excludes the diagnosis of type A thymoma. B, Moderate numbers of TdT+ immature T cells in a spindle cell thymoma imply a diagnosis of type AB thymoma when occurring in more than 10% of the tumor, if occurring in less than or equal to 10% of the tumor, a diagnosis of type A thymoma should be rendered. C, Near absence of TdT+ immature T cells in type A thymoma.

      Type B thymomas and distinction from thymic carcinoma:

      Type B1 and B2 thymomas are, by definition, both lymphocyte-rich tumors. To improve their distinction from one another, which can be difficult,
      • Suster S
      • Moran CA
      Histologic classification of thymoma: the World Health Organization and beyond.
      • Detterbeck FC
      Clinical value of the WHO classification system of thymoma.
      the thymus-like architecture and cytology of B1 thymomas are highlighted as obligatory criteria, including presence of medullary islands as a “must” and absence of epithelial cell clusters. By contrast, type B2 thymomas must show a higher than normal number of polygonal (nonspindle) neoplastic epithelial cells that usually occur in clusters (defined as three or more contiguous epithelial cells). Medullary islands optionally occur in type B2 thymomas, whereas Hassall's corpuscles occur as optional feature usually in type B1 and rarely in B2 thymomas (Table 2). Cytokeratin (and p40/p63) expression patterns may be helpful to distinguish type B1 from type B2 (and AB) thymoma (Fig. 5).
      Figure thumbnail gr5
      FIGURE 5Immunohistochemical staining of keratin across the spectrum of type A to B3 thymomas. Of note, among the lymphocyte-rich thymomas a dense epithelial cell networks is typical of type AB and type B2 thymoma, whereas a delicate network is an obligatory feature of type B1 thymoma.
      Type B3 thymoma is a lymphocyte-poor, epithelial-rich tumor but distinction from type B2 thymomas may be difficult.
      • Marx A
      • Ströbel P
      • Badve SS
      • et al.
      ITMIG consensus statement on the use of the WHO histological classification of thymoma and thymic carcinoma: refined definitions, histological criteria, and reporting.
      Because of the lack of distinguishing markers, the differential diagnosis rests on the visual impression that type B2 thymomas look blue on HE staining (because of the presence of many admixed lymphocytes), whereas type B3 thymomas look pink (because of sheets of confluent tumor cells).
      The distinction of type B3 thymoma from thymic squamous cell carcinoma (TSQCC) can be a challenge when rare tumors with a type B3 thymoma morphology show focal expression of “TSQCC-markers” (such as CD5 and CD117) and/or lack of “type B3 thymoma markers” (such as TdT+ T cells), or when tumors with a TSQCC morphology harbor (usually rare) TdT+ immature T cells.
      • Marx A
      • Ströbel P
      • Badve SS
      • et al.
      ITMIG consensus statement on the use of the WHO histological classification of thymoma and thymic carcinoma: refined definitions, histological criteria, and reporting.
      In the 4th edition, it is now stated that tumors that look like type B3 thymoma on HE staining should be diagnosed as type B3 thymoma, and tumors with TSQCC morphology should be labeled as TSQCC, irrespective of immunohistochemistry.

      Other thymomas:

      No major changes have been introduced. In metaplastic thymomas, exclusive staining of the polygonal but not the spindle cell component for p63 or p40 may be diagnostically helpful.

      Thymic Carcinomas Including Combined Thymic Carcinomas

      Conceptual continuity

      With few exceptions [e.g., nuclear protein in testis (NUT) carcinomas, adenocarcinomas], the nomenclature and diagnostic criteria of almost all thymic carcinoma subtypes remain unchanged. The Masaoka–Koga staging system may still be used for thymic carcinomas till publication of the new UICC/AJCC–approved TNM system (supposedly in 2016).

      Conceptual changes

      The thymic adenocarcinomas are gathered in one chapter and labeled according to their HE histology, abandoning the distinction between papillary and nonpapillary adenocarcinomas.
      Although the term “combined TETs” was abandoned in the 4th edition (see above), the term Combined thymic carcinomas was introduced for tumors that are either composed of different types of thymic carcinomas (extremely rare) or of a thymic carcinoma and any type of thymoma or carcinoid (rare). However, in analogy to the lung, heterogeneous TETs with a small-cell carcinoma (SCC) component or a large-cell neuroendocrine carcinoma (LCNEC) component are not counted among the combined thymic carcinomas but among the neuroendocrine carcinomas (see below). The reporting of a combined thymic carcinoma must start with the carcinoma component irrespective of its proportion, followed by the thymoma component.
      • Marx A
      • Ströbel P
      • Badve SS
      • et al.
      ITMIG consensus statement on the use of the WHO histological classification of thymoma and thymic carcinoma: refined definitions, histological criteria, and reporting.
      In case of two or more carcinoma components, the dominant component is reported first.

      Changes concerning individual thymic carcinoma subtypes

      Thymic squamous cell carcinomas:

      FoxN1 and CD205 are novel markers
      • Nonaka D
      • Henley JD
      • Chiriboga L
      • et al.
      Diagnostic utility of thymic epithelial markers CD205 (DEC205) and Foxn1 in thymic epithelial neoplasms.
      that complement CD5 and CD117 as markers that are expressed in most TSQCC but not in pulmonary squamous cell carcinomas. In 10% to 20% of mediastinal squamous cell carcinomas without expression of these markers, staging remains paramount to distinguish thymic from pulmonary primaries. Among the many new molecular findings in thymic carcinoma (reviewed by Rajan et al.
      • Rajan A
      • Girard N
      • Marx A
      State of the art of genetic alterations in thymic epithelial tumors.
      ) significant predictive markers remain to be identified.

      Basaloid carcinoma of the thymus:

      In the lung, carcinomas with basaloid features, including prominent palisading as hallmark, are termed “basaloid squamous cell carcinoma” and considered a high-grade variant of squamous cell carcinoma with distinct genetic features.
      • Brambilla C
      • Laffaire J
      • Lantuejoul S
      • et al.
      Lung squamous cell carcinomas with basaloid histology represent a specific molecular entity.
      In the thymus, cancers with basaloid features show a more varied histology (including a wide range of proliferative activities, common macropapillary growth pattern, and association with cysts) and a broader spectrum of clinical aggressiveness.
      • Brown JG
      • Familiari U
      • Papotti M
      • et al.
      Thymic basaloid carcinoma: a clinicopathologic study of 12 cases, with a general discussion of basaloid carcinoma and its relationship with adenoid cystic carcinoma.
      Genetic data are sparse and not overlapping with those of pulmonary basaloid squamous cell carcinoma.
      • Zhou R
      • Zettl A
      • Ströbel P
      • et al.
      Thymic epithelial tumors can develop along two different pathogenetic pathways.
      Therefore, the term “basaloid carcinoma of the thymus” is maintained in the 4th edition (Table 1).

      Mucoepidermoid carcinoma:

      Translocation of the MAML2 gene is characteristic of almost all low-grade mucoepidermoid carcinomas (MECs) and many high-grade MECs of salivary glands,
      • Tonon G
      • Modi S
      • Wu L
      • et al.
      t(11; 19)(q21; p13) translocation in mucoepidermoid carcinoma creates a novel fusion product that disrupts a Notch signaling pathway.
      bronchi, and lung.
      • Achcar Rde O
      • Nikiforova MN
      • Dacic S
      • et al.
      Mammalian mastermind like 2 11q21 gene rearrangement in bronchopulmonary mucoepidermoid carcinoma.
      This translocation has recently been observed in thymic MECs as well,
      • Roden AC
      • Erickson-Johnson MR
      • Yi ES
      • et al.
      Analysis of MAML2 rearrangement in mucoepidermoid carcinoma of the thymus.
      allowing their distinction from adenosquamous carcinomas and adenocarcinomas.

      Sarcomatoid carcinoma:

      The microscopic description of sarcomatoid carcinoma has been refined and now distinguishes (1) spindle cell carcinoma (malignant transformation of type A thymoma); (2) sarcomatoid transformation of preexisting thymic carcinoma; and (3) true carcinosarcoma with heterologous component(s).

      Adenocarcinomas:

      Papillary adenocarcinomas of the thymus usually co-occur with type A and AB thymomas and are now defined as low-grade carcinomas, while high-grade adenocarcinomas with (usually focal) papillary growth are counted among the “adenocarcinomas, not otherwise specified.”
      Thymic carcinomas that were called “adenoid cystic carcinomas (ACC)” in the 3rd edition are now labeled as “thymic carcinomas with ACC-like features” in the 4th edition because they lack the immunohistochemical features of true ACC in other organs.
      • Di Tommaso L
      • Kuhn E
      • Kurrer M
      • et al.
      Thymic tumor with adenoid cystic carcinoma like features: a clinicopathologic study of 4 cases.
      Enteric differentiation (as shown by immunohistochemistry) occurs in a subset of mucinous carcinomas and adenocarcinomas, NOS, and is currently of unknown clinical significance. Such cases require clinical staging to exclude metastasis from a colorectal primary.
      • Moser B
      • Schiefer AI
      • Janik S
      • et al.
      Adenocarcinoma of the thymus, enteric type: report of 2 cases, and proposal for a novel subtype of thymic carcinoma.

      NUT carcinoma:

      These highly aggressive cancers that were first observed as midline thoracic tumors in children and young adults and harbored a unique t(15; 19)-translocation with generation of a BRD4–NUT fusion oncogene were called “carcinoma with t(15; 19) translocation” in the 3rd edition. These tumors are now known to occur at all ages, outside the thorax (and rarely outside the midline) in approximately 40% and to show variant NUT translocations in approximately 30% of cases.
      • French CA
      • Rahman S
      • Walsh EM
      • et al.
      NSD3-NUT fusion oncoprotein in NUT midline carcinoma: implications for a novel oncogenic mechanism.
      • Bauer DE
      • Mitchell CM
      • Strait KM
      • et al.
      Clinicopathologic features and long-term outcomes of NUT midline carcinoma.
      Therefore, these tumors are now labeled NUT carcinomas irrespective of anatomical location. Analysis for NUT overexpression by immunohistochemistry is now possible and highly sensitive and should be considered in any undifferentiated cancer, particularly if there is focal squamous differentiation.

      Undifferentiated carcinoma:

      This tumor shows epithelial differentiation but is otherwise a diagnosis of exclusion. Poorly differentiated squamous cell carcinoma, lymphoepithelioma-like carcinoma, sarcomatoid carcinoma, NUT carcinoma, SCC and LCNEC, and adenocarcinoma of the thymus, GCT, extension from the lung and metastasis must be excluded. By definition, immunohistochemical markers (e.g., CK5/6, p63, CD5) of any of the aforementioned tumors are absent, but CD117 and PAX8 may be expressed.

      Clinical relevance of refined thymoma and thymic carcinoma diagnosis

      The first step when assessing a mediastinal mass is to establish a differential diagnosis between TETs, lymphomas, and other neoplasms, including metastasis. This relies on clinical presentation, including neurological examination, tumor marker profiles, and imaging features.
      • den Bakker MA
      • Roden AC
      • Marx A
      • Marino M
      Histologic classification of thymoma: a practical guide for routine cases.
      In thymic epithelial lesions, next steps are the differentiation of thymic malignancy from hyperplasia or noninvoluted thymus and the assessment of upfront resectability of the tumor, as complete resection is the most significant prognostic variable. In a postoperative setting, precise histopathological subtyping is of major importance for treatment decisions. In this setting, postoperative radiotherapy may be considered after complete resection of stage II thymomas with more aggressive histology, including B2 and B3 subtypes. Chemoradiotherapy is a major component of the therapeutic strategy of thymic carcinomas, as perioperative or exclusive treatment modality.
      • Girard N
      Thymic epithelial tumours: from basic principles to individualised treatment strategies.
      In advanced stage refractory disease, KIT mutations have exclusively been reported to occur in thymic carcinomas, but their potential role as biomarkers needs further studies; meanwhile, targeting angiogenesis using multikinase inhibitors is of higher relevance in carcinomas irrespective of their KIT mutational status.
      • Thomas A
      • Rajan A
      • Berman A
      • et al.
      Sunitinib in patients with chemotherapy-refractory thymoma and thymic carcinoma: an open-label phase 2 trial.
      By contrast, the histone deacetylase inhibitor, belinostat,
      • Thomas A
      • Rajan A
      • Szabo E
      • et al.
      A phase I/II trial of belinostat in combination with cisplatin, doxorubicin, and cyclophosphamide in thymic epithelial tumors: a clinical and translational study.
      the insulin-like growth factor 1 receptor-targeting antibody, cixutumumab,
      • Rajan A
      • Carter CA
      • Berman A
      • et al.
      Cixutumumab for patients with recurrent or refractory advanced thymic epithelial tumours: a multicentre, open-label, phase 2 trial.
      and somatostatin analogues
      • Loehrer Sr., PJ
      • Wang W
      • Johnson DH
      • Aisner SC
      • Ettinger DS
      • Eastern Cooperative Oncology Group Phase II Trial
      Octreotide alone or with prednisone in patients with advanced thymoma and thymic carcinoma: an Eastern Cooperative Oncology Group Phase II Trial.
      are more effective in thymomas. The importance of diagnosing NUT carcinoma results from the ineffectiveness of conventional chemotherapeutic regimens and availability of promising new targeted agents.
      • French C
      NUT midline carcinoma.

      Thymic Neuroendocrine Tumors

      Conceptual continuity

      These chapters cover neuroendocrine epithelial tumors (NETs), but not paraganglioma and neurogenic tumors. In the 4th edition, the nomenclature and criteria (Table 4) of thymic typical and atypical carcinoids, LCNEC, and SCC remain the same as in the 3rd edition.
      • Travis WD
      • Brambilla E
      • Müller-Hermelink HK
      • et al.
      The definition of “neuroendocrine differentiation” in the carcinoids and LCNECs, i.e., strong and diffuse expression of usually more than one of the four neuroendocrine markers (chromogranin A, synaptophysin, CD56, and neuron-specific enolase) in more than 50% of tumor cells, has been maintained. As before, SCC remains a histological diagnosis; expression of neuroendocrine markers is often present but not required.
      TABLE 4Thymic Neuroendocrine Tumors Covered by the 4th Edition of the WHO Classification of Tumours of the Lung, Pleura, Thymus and Heart3
      Distinguishing Histological Criteria
      Typical carcinoid<2 mitoses/2 mm2; no necrosis
      Atypical carcinoid<2 mitoses/2 mm2; with necrosis; or 2–10 mitoses/2 mm2; + or – necrosis
      LCNEC>10 mitoses/2 mm2; no small-cell features
      Combined LCNECLCNEC combined with any thymoma(s) or thymic carcinoma(s)
      SCCTypical SCC histology
      Combined SCCSCC combined with any thymoma(s) or thymic carcinoma(s)

      Conceptual changes

      The descriptive terms “well-differentiated neuroendocrine carcinoma” (referring to carcinoids) and “poorly differentiated neuroendocrine carcinoma” (referring to LCNEC and SCC) of the 3rd edition were abandoned, because LCNECs and even SCC may be highly differentiated in terms of neuroendocrine features. Following the strategy in the lung, the 4th edition instead separates typical and atypical carcinoids as low-grade and intermediate-grade neuroendocrine tumors, respectively, from high-grade neuroendocrine carcinomas that comprise LCNEC and SCC.

      Key new findings

      A major advance has been the elucidation of genetic alterations at the comparative genomic hybridization level by an international consortium.
      • Ströbel P
      • Zettl A
      • Shilo K
      • et al.
      Tumor genetics and survival of thymic neuroendocrine neoplasms: a multi-institutional clinicopathologic study.
      The progressive increase and overlap of genetic gains and losses from typical carcinoids through atypical carcinoids to LCNECs and SCCs lend support to the WHO classification. Genetic alterations in thymic and pulmonary carcinoids are significantly different from each other, whereas the genetics of high-grade neuroendocrine tumors from thymus and lung are indistinguishable.
      • Ströbel P
      • Zettl A
      • Shilo K
      • et al.
      Tumor genetics and survival of thymic neuroendocrine neoplasms: a multi-institutional clinicopathologic study.
      It is the currently favored concept that different molecular pathways lead to thymic carcinoids and thymic high-grade neuroendocrine carcinomas.
      • Ströbel P
      • Zettl A
      • Shilo K
      • et al.
      Tumor genetics and survival of thymic neuroendocrine neoplasms: a multi-institutional clinicopathologic study.
      The recent description of shared genetic alterations in thymic carcinoids and associated synchronous or metachronous high-grade neuroendocrine carcinomas challenge this view
      • Pelosi G
      • Bimbatti M
      • Fabbri A
      • et al.
      Thymic neuroendocrine neoplasms (T-NENs) with CTNNB1 (beta-catenin) gene mutation show components of well-differentiated tumor and poorly-differentiated carcinoma, challenging the concept of secondary high-grade neuroendocrine carcinoma.
      and suggest that transformation of carcinoids might be an alternative pathway leading to high-grade neuroendocrine carcinomas.
      • Pelosi G
      • Bimbatti M
      • Fabbri A
      • et al.
      Thymic neuroendocrine neoplasms (T-NENs) with CTNNB1 (beta-catenin) gene mutation show components of well-differentiated tumor and poorly-differentiated carcinoma, challenging the concept of secondary high-grade neuroendocrine carcinoma.
      • Moran CA
      • Suster S
      Thymic neuroendocrine carcinomas with combined features ranging from well-differentiated (carcinoid) to small cell carcinoma. A clinicopathologic and immunohistochemical study of 11 cases.
      There are currently no immunohistological markers that can unequivocally distinguish between thymic and pulmonary primaries, although a TTF1–/PAX8 (polyclonal)+ profile appears to be more common in thymic carcinoids.
      • Weissferdt A
      • Tang X
      • Wistuba II,
      • Moran CA
      Comparative immunohistochemical analysis of pulmonary and thymic neuroendocrine carcinomas using PAX8 and TTF-1.
      Clinical and radiological correlation remains the mainstay for the distinction between thymic and pulmonary neuroendocrine tumors.

      Individual changes in subtypes of thymic NETs

      Except for new genetic data, there are no further changes in individual thymic NETs.

      GCTs of the Mediastinum, Including

      GCTs with Somatic-Type Malignancy

      Conceptual continuity

      The nomenclature and histological criteria defining the main mediastinal GCT categories are maintained in the 4th edition of the WHO Classification with one minor exception: GCT with somatic-type malignancy that is a clonally related sarcoma, carcinoma, or both is now called “GCT with somatic-type solid malignancy” to stress the distinction from GCT with associated clonally related hematological malignancies. GCTs with the latter variant of somatic-type malignancy are unique to the mediastinum and called “GCTs with associated hematological malignancy” (Table 5).
      TABLE 5Germ Cell Tumors Covered by the 4th Edition of the WHO Classification of Tumours of the Lung, Pleura, Thymus and Heart3 and Useful Immunohistological Markers That Were not Mentioned in the 3rd Edition
      OCT4SALL4Glypican 3SOX2SOX17
      Seminoma+++
      Embryonal carcinoma+++
      Yolk sac tumor++
      Choriocarcinoma++
      Mononuclear trophoblast.
      +
      Syncytiotrophoblast.
      Mature teratoma−/++/-
      Immature teratoma−/++/-
      Mixed GCTs
      GCTs with associated somatic-type solid malignancy
      GCTs with associated hematological malignancy
      In bold is the new addendum “solid” to the name of GCTs that are composed of a GCT component and associated sarcoma and/or carcinoma.
      GCT, germ cell tumors; WHO, World Health Organization.
      a Mononuclear trophoblast.
      b Syncytiotrophoblast.

      Conceptual changes

      There have been no conceptual changes.

      Individual changes of GCT subtypes

      The classic immunohistological markers (keratins, placental alkaline phosphatase, CD117; CD30; alpha-fetoprotein; β-subunit of human chorionic gonadotropin) are usually sufficient to recognize even complex GCTs. Several new markers, such as OCT4, glypican 3, and SOX2 (Table 5), may help to more precisely delineate the individual components.
      • de Jong J
      • Stoop H
      • Gillis AJ
      • et al.
      Differential expression of SOX17 and SOX2 in germ cells and stem cells has biological and clinical implications.
      • Looijenga LH
      • Stoop H
      • de Leeuw HP
      • et al.
      POU5F1 (OCT3/4) identifies cells with pluripotent potential in human germ cell tumors.
      • Zynger DL
      • Everton MJ
      • Dimov ND
      • Chou PM
      • Yang XJ
      Expression of glypican 3 in ovarian and extragonadal germ cell tumors.

      Lymphomas of the Mediastinum

      Conceptual continuity, no conceptual changes

      The “new” classification of mediastinal lymphomas was streamlined according to the 4th edition of the WHO Classification of Tumours of the Haematopoietic and Lymphoid Tissues.
      • Swerdlow SH
      • Campo E
      • Harris NL
      • et al.
      There have been no conceptual changes (Table 1).

      Individual changes of lymphoma subtypes

      Primary mediastinal large B-cell lymphomas:

      The typical immunophenotype of primary mediastinal large B-cell lymphomas (PMBL) as reported in the 3rd edition
      • Travis WD
      • Brambilla E
      • Müller-Hermelink HK
      • et al.
      (CD20+ CD79a+ PAX5+ CD30+/– CD15– CD10– IRF4/MUM1+/– HLADR–) has been complemented, among others, by CD23 (positive in 70%) and p63 (positive in >90%), whereas p40 is absent.
      • Zamo A
      • Malpeli G
      • Scarpa A
      • Doglioni C
      • Chilosi M
      • Menestrina F
      Expression of TP73L is a helpful diagnostic marker of primary mediastinal large B-cell lymphomas.
      As a caveat, p63 is also expressed in normal and neoplastic thymic epithelial cells,
      • Dotto J
      • Pelosi G
      • Rosai J
      Expression of p63 in thymomas and normal thymus.
      although it is typically accompanied by p40 expression.
      • Chilosi M
      • Zamò A
      • Brighenti A
      • et al.
      Constitutive expression of DeltaN-p63alpha isoform in human thymus and thymic epithelial tumours.
      Despite a characteristic immunohistochemical profile, and a gene expression profile that extensively overlaps with that of Hodgkin lymphoma (HL) but not other B-cell lymphomas,
      • Rosenwald A
      • Wright G
      • Leroy K
      • et al.
      Molecular diagnosis of primary mediastinal B cell lymphoma identifies a clinically favorable subgroup of diffuse large B cell lymphoma related to Hodgkin lymphoma.
      the diagnosis of PMBL in daily practice still requires clinical data (particularly absence of extensive extrathoracic lymph node infiltration) to exclude systemic diffuse large B-cell lymphoma with mediastinal involvement.
      Among the novel genetic alterations reported since 2004, the following are of special interest from a biological and potentially immunotherapeutic perspective: translocations of the HLA class II transactivator CIITA at 16p13.13 associated with downregulation of human leukocyte antigen class II molecules and the almost specific amplification and/or translocation of the 9p24.1 region including the loci coding for the immune checkpoint molecules PD-L1 and programmed death-ligand-2 (PD-L2),
      • Twa DD
      • Chan FC
      • Ben-Neriah S
      • et al.
      Genomic rearrangements involving programmed death ligands are recurrent in primary mediastinal large B-cell lymphoma.
      • Steidl C
      • Shah SP
      • Woolcock BW
      • et al.
      MHC class II transactivator CIITA is a recurrent gene fusion partner in lymphoid cancers.
      which are overexpressed and helpful immunohistochemical markers in PMBL.
      • Shi M
      • Roemer MG
      • Chapuy B
      • et al.
      Expression of programmed cell death 1 ligand 2 (PD-L2) is a distinguishing feature of primary mediastinal (thymic) large B-cell lymphoma and associated with PDCD1LG2 copy gain.

      MALT lymphoma:

      New genetic findings include a high frequency of trisomy 3, low incidence of trisomy 18, and no translocations involving MALT1 and IGH.
      • Kominato S
      • Nakayama T
      • Sato F
      • et al.
      Characterization of chromosomal aberrations in thymic MALT lymphoma.
      • Go H
      • Cho HJ
      • Paik JH
      • et al.
      Thymic extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue: a clinicopathological and genetic analysis of six cases.

      T lymphoblastic leukemia/lymphoma:

      The new edition highlights a subset of TdT-negative cases.
      • Zhou Y
      • Fan X
      • Routbort M
      • et al.
      Absence of terminal deoxynucleotidyl transferase expression identifies a subset of high-risk adult T-lymphoblastic leukemia/lymphoma.
      The latter might be related to early thymic progenitor T-ALLs that coexpress early myeloid markers and stem cell markers (CD34 and CD117). These are considered high-risk subgroups.
      • Bonn BR
      • Rohde M
      • Zimmermann M
      • et al.
      Incidence and prognostic relevance of genetic variations in T-cell lymphoblastic lymphoma in childhood and adolescence.
      • Coustan-Smith E
      • Mullighan CG
      • Onciu M
      • et al.
      Early T-cell precursor leukaemia: a subtype of very high-risk acute lymphoblastic leukaemia.
      Among many novel genetic alterations detected, mutations of NOTCH1/FXBW are associated with a favorable outcome,
      • Callens C
      • Baleydier F
      • Lengline E
      • et al.
      Clinical impact of NOTCH1 and/or FBXW7 mutations, FLASH deletion, and TCR status in pediatric T-cell lymphoblastic lymphoma.
      whereas loss of heterozygosity at 6q has a negative impact on prognosis.
      • Burkhardt B
      • Bruch J
      • Zimmermann M
      • et al.
      Loss of heterozygosity on chromosome 6q14-q24 is associated with poor outcome in children and adolescents with T-cell lymphoblastic lymphoma.

      Anaplastic large-cell lymphoma:

      In contrast to the 3rd edition, the 4th edition (like the WHO book on hematological malignancies
      • Swerdlow SH
      • Campo E
      • Harris NL
      • et al.
      ) emphasizes the difference between anaplastic lymphoma kinase (ALK)(+) and ALK(–) anaplastic large-cell lymphoma (ALCL). Both arise only exceptionally in the mediastinum. By immunohistochemistry, ALCL must be distinguished from other CD30-positive lymphomas and epithelial membrane antigen-positive solid tumors, including carcinomas, and from melanomas. However, the diagnosis of ALK(-) ALCL versus CD30-positive peripheral T cell lymphoma, NOS, still rests on the identification of “hallmark cells” in a background of large-cell lymphoma, but the distinction may sometimes be arbitrary.

      Hodgkin lymphoma:

      The diagnostic criteria of HL [virtually all mediastinal cases are nodular sclerosis classical HL (cHL)] have remained unchanged. A number of inactivating mutations, amplifications, and translocations have been described that affect nuclear factor kappa-light-chain-enhancer of activated B cells, Janus kinase and signal transucer and activator of transcription, DNA damage, and apoptosis pathways as well as epigenetic homeostasis (reviewed by Kuppers
      • Küppers R
      New insights in the biology of Hodgkin lymphoma.
      ). Recognition that genetic and transcriptomic variation of the tumor cells and tumor-associated T cells and macrophages have prognostic relevance is also new.
      • Greaves P
      • Clear A
      • Owen A
      • et al.
      Defining characteristics of classical Hodgkin lymphoma microenvironment T-helper cells.
      • Steidl C
      • Diepstra A
      • Lee T
      • et al.
      Gene expression profiling of microdissected Hodgkin Reed-Sternberg cells correlates with treatment outcome in classical Hodgkin lymphoma.
      • Steidl C
      • Lee T
      • Shah SP
      • et al.
      Tumor-associated macrophages and survival in classic Hodgkin's lymphoma.
      Nonetheless, stage remains the single most important prognostic factor in mediastinal HL.

      B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and classical HL:

      In the 3rd edition, this aggressive lymphoma was included in the “grey zone between HL and non-Hodgkin lymphoma.” A current synonym is “mediastinal grey zone lymphoma (MGZL).” Refined diagnostic criteria include a sheet-like growth pattern of large, pleomorphic tumor cells including Hodgkin cells, a less prominent inflammatory background than cHL, usually preserved B-cell program (expression of CD20, PAX5, OCT2, BOB.1; clonal immunoglobulin gene rearrangement), expression of CD30 (consistently) and CD15 (variably), and lack of CD10 and ALK1 expressions. There are distinctive genetic and epigenetic features of MGZL in addition to features that overlap with cHL and PMBL (Fig. 6).
      • Eberle FC
      • Rodriguez-Canales J
      • Wei L
      • et al.
      Methylation profiling of mediastinal gray zone lymphoma reveals a distinctive signature with elements shared by classical Hodgkin's lymphoma and primary mediastinal large B-cell lymphoma.
      • Eberle FC
      • Salaverria I
      • Steidl C
      • et al.
      Gray zone lymphoma: chromosomal aberrations with immunophenotypic and clinical correlations.
      • Vanhentenrijk V
      • Vanden Bempt I
      • Dierickx D
      • Verhoef G
      • Wlodarska I
      • De Wolf-Peeters C
      Relationship between classic Hodgkin lymphoma and overlapping large cell lymphoma investigated by comparative expressed sequence hybridization expression profiling.
      Figure thumbnail gr6
      FIGURE 6Distinct epigenetic profile of mediastinal grey zone lymphoma (MGZL) as assessed by principal component analysis. The methylation data for 1421 CpG targets from various lymphomas and reactive tonsillar B cells (RTB) were subjected to principal component analysis and projected onto the first three principal components. MGZL has a distinct epigenetic profile intermediate between classical Hodgkin lymphoma, nodular sclerosis subtype (CHLNS), and primary mediastinal large B-cell lymphoma (PMBL), but different from that of diffuse large B-cell lymphoma (DLBCL) and RTB. Adapted from Eberle et al.
      • Eberle FC
      • Rodriguez-Canales J
      • Wei L
      • et al.
      Methylation profiling of mediastinal gray zone lymphoma reveals a distinctive signature with elements shared by classical Hodgkin's lymphoma and primary mediastinal large B-cell lymphoma.
      with permission.

      Clinical relevance of refined mediastinal lymphoma diagnosis

      Accurate diagnosis is essential for the differential treatment of mediastinal cHL, PMBL, and MGZL. Patients with cHL currently receive polychemotherapy that seems to require inclusion of bleomycin and dacarbazin (e.g., ABVD) followed by involved field irradiation for optimal outcome.
      • Behringer K
      • Goergen H
      • Hitz F
      • German Hodgkin Study Group
      • Swiss Group for Clinical Cancer Research
      • Arbeitsgemeinschaft Medikamentöse Tumortherapie
      • et al.
      Omission of dacarbazine or bleomycin, or both, from the ABVD regimen in treatment of early-stage favourable Hodgkin's lymphoma (GHSG HD13): an open-label, randomised, non-inferiority trial.
      PMBL, despite its close molecular relationship to cHL, has been treated very differently, e.g., with CHOP and rituximab (R-CHOP) followed by radiotherapy. However, a recent study shows that radiation may be dispensable in PMBL when R-CHOP is replaced by the dose-adjusted etoposide, prednisone, vincristine, cyclophasphamide, doxorubicin plus rituximab regimen (DA-EPOCH-R).
      • Dunleavy K
      • Pittaluga S
      • Maeda LS
      • et al.
      Dose-adjusted EPOCH-rituximab therapy in primary mediastinal B-cell lymphoma.
      This might be advantageous usually in the young female patients with PMBL because mediastinal radiotherapy has potentially serious late effects, such as cardiovascular disease, lung cancer, and breast cancer.
      • LeMieux MH
      • Solanki AA
      • Mahmood U
      • Chmura SJ
      • Koshy M
      Risk of second malignancies in patients with early-stage classical Hodgkin's lymphoma treated in a modern era.
      For patients with MGZL, DA-EPOCH-R treatment alone may not be sufficient because they more often required additional radiation to achieve long-term complete remission than patients with PMBL.
      • Dunleavy K
      • Pittaluga S
      • Maeda LS
      • et al.
      Dose-adjusted EPOCH-rituximab therapy in primary mediastinal B-cell lymphoma.

      Histiocytic and Dendritic Cell Neoplasms of the Mediastinum

      Conceptual continuity

      The classification of mediastinal histiocytic and dendritic cell tumors was streamlined according to the 4th edition of the WHO Classification of Tumours of the Haematopoietic and Lymphoid Tissues.
      • Swerdlow SH
      • Campo E
      • Harris NL
      • et al.

      Conceptual changes

      The only changes are (i) the deletion of the terms “follicular dendritic cell (FDC) tumor” and “interdigitating dendritic cell (IDC) tumor” (i.e., tumors of unknown malignant potential, ICD-O codes: 9758/1 and 9757/1, respectively) because all FDC and IDC neoplasias are now considered malignant; (ii) the addition of the previously neglected “fibroblastic reticular cell tumors,” “indeterminate dendritic cell tumors,” and rare dendritic cell tumors with mixed phenotypes (hybrid dendritic cell tumors).

      Individual changes of histiocytic and dendritic cell tumors:

      A new finding is the detection of BRAF mutations in approximately 50% of all cases of Langerhans cell histiocytosis, including mediastinal cases.
      • Haroche J
      • Cohen-Aubart F
      • Emile JF
      • et al.
      Dramatic efficacy of vemurafenib in both multisystemic and refractory Erdheim–Chester disease and Langerhans cell histiocytosis harboring the BRAF V600E mutation.
      In terms of differential diagnosis, the new WHO classification of tumors of the thymus clarifies some important diagnostic challenges that need careful immunohistochemical analysis:
      • 1.
        S100-positive Langerhans cell lesions, indeterminate dendritic cell tumors, and IDC sarcomas must be distinguished from the much more common metastatic melanoma, nerve sheath tumors, and myoepithelial lesions. CD1a+ Langerin+ Langerhans cell neoplasms need to be distinguished from CD1a+ Langerin– indeterminate dendritic cell tumors.
      • 2.
        The EMA-positive and/or D2-40-positive subset of FDC sarcomas must not be confused with cytokeratin-deficient thymomas,
        • Adam P
        • Hakroush S
        • Hofmann I
        • Reidenbach S
        • Marx A
        • Ströbel P
        Thymoma with loss of keratin expression (and giant cells): a potential diagnostic pitfall.
        meningioma, and mesothelioma.
      • 3.
        The cytokeratin-positive, actin-positive, or desminpositive subsets of fibroblastic reticular cell tumors need to be distinguished from spindle cell epithelial tumors (e.g., atypical type A thymomas and sarcomatoid carcinomas), smooth muscle and myofibroblastic tumors, and angiomatoid fibrous histiocytoma.

      Myeloid Sarcoma and Extramedullary Leukemia

      There have been no conceptual or individual changes.

      Soft-Tissue Tumors of the Mediastinum

      Conceptual continuity, no conceptual changes

      The classification of mediastinal soft-tissue tumors was streamlined according to the 4th edition of the WHO Classification of Tumours of Soft Tissue and Bone.
      • Fletcher CDM
      • Bridge JA
      • Hogendorn PCW
      • et al.
      There have been no conceptual changes since the 3rd edition of the WHO book (Table 1).

      Individual changes in subtypes of soft-tissue tumors

      Diagnostic criteria of all entities are maintained. New, diagnostically useful genetic alterations when compared with the 3rd edition are STAT6 translocation in solitary fibrous tumors
      • Robinson DR
      • Wu YM
      • Kalyana-Sundaram S
      • et al.
      Identification of recurrent NAB2-STAT6 gene fusions in solitary fibrous tumor by integrative sequencing.
      and MYC gene amplification in radiation-induced (angio-) sarcomas.
      • Käcker C
      • Marx A
      • Mössinger K
      • et al.
      High frequency of MYC gene amplification is a common feature of radiation-induced sarcomas. Further results from EORTC STBSG TL 01/01.
      • Manner J
      • Radlwimmer B
      • Hohenberger P
      • et al.
      MYC high level gene amplification is a distinctive feature of angiosarcomas after irradiation or chronic lymphedema.
      In contrast to the WHO Classification of Tumours of Soft Tissue and Bone,
      • Fletcher CDM
      • Bridge JA
      • Hogendorn PCW
      • et al.
      the 3rd and 4th editions of the WHO Classification of Tumours of the Lung, Pleura, Thymus and Heart cover neurogenic tumors that are among the most common tumors in the posterior mediastinum. The exceedingly rare neuroblastomas and ganglioneuroblastomas of the thymic region are unusual because they occur in elderly patients.
      • Ueda Y
      • Omasa M
      • Taki T
      • et al.
      Thymic neuroblastoma within a thymic cyst in an adult.
      • Pellegrino M
      • Gianotti L
      • Cassibba S
      • Brizio R
      • Terzi A
      • Borretta G
      Neuroblastoma in the elderly and SIADH: case report and review of the literature.
      It is unknown, whether they are genetically distinct from their childhood counterparts.

      Ectopic Tumors of the Thymus and Metastasis to the Thymus

      There have been no conceptual or individual changes.

      PERSPECTIVES AND CHALLENGES

      The molecular revolution has just begun to approach TETs,
      • Petrini I
      • Meltzer PS
      • Kim IK
      • et al.
      A specific missense mutation in GTF2I occurs at high frequency in thymic epithelial tumors.
      • Petrini I
      • Wang Y
      • Zucali PA
      • et al.
      Copy number aberrations of genes regulating normal thymus development in thymic epithelial tumors.
      but the understanding of their biology is far away from the level reached in many hematological and solid tumors. However, The Cancer Genome Atlas has recently included TETs for analysis of genetic, transcriptomic, and epigenetic changes in relation to clinicopathologic and follow-up data. Exploiting the databases compiled by the ITMIG
      • Weis CA
      • Yao X
      • Deng Y
      • et al.
      Contributors to the ITMIG Retrospective Database. The impact of thymoma histotype on prognosis in a worldwide database.
      • Ahmad U
      • Yao X
      • Detterbeck F
      • et al.
      Thymic carcinoma outcomes and prognosis: results of an international analysis.
      • Huang J
      • Ahmad U
      • Antonicelli A
      • International Thymic Malignancy Interest Group International Database Committee and Contributors
      • et al.
      Development of the International Thymic Malignancy Interest Group international database: an unprecedented resource for the study of a rare group of tumors.
      • Filosso PL
      • Yao X
      • Ahmad U
      • European Society of Thoracic Surgeons Thymic Group Steering Committee
      • et al.
      Outcome of primary neuroendocrine tumors of the thymus: a joint analysis of the International Thymic Malignancy Interest Group and the European Society of Thoracic Surgeons databases.
      might further promote our understanding of TETs and open perspectives for targeted therapies. In addition to this bench-to-bedside perspective, new clues to the molecular and cellular pathogenesis of thymic tumors can also be expected through clinical trials
      • Petrini I
      • Meltzer PS
      • Kim IK
      • et al.
      A specific missense mutation in GTF2I occurs at high frequency in thymic epithelial tumors.
      that segregate patients into responders and nonresponders and thus open new avenues for bedside-to-bench studies of unknown underlying molecular mechanisms.
      • Marx A
      • Weis CA
      Sunitinib in thymic carcinoma: enigmas still unresolved.
      An intriguing new molecular finding that may give a first hint to the etiology of TETs is the recent description of human polyomavirus 7 in the epithelial cells of the majority of TETs and of some hyperplastic thymuses of adults but not of fetal thymic tissue.
      • Rennspiess D
      • Pujari S
      • Keijzers M
      • et al.
      Detection of human polyomavirus 7 in human thymic epithelial tumors.
      If confirmed, this might have an impact on the classification of TETs and their clinical management.
      Finally, a new staging system for thymomas and thymic carcinomas is on the horizon
      • Detterbeck FC
      • Stratton K
      • Giroux D
      • Staging and Prognostic Factors Committee
      • Members of the Advisory Boards
      • Participating Institutions of the Thymic Domain
      • et al.
      The IASLC/ITMIG Thymic Epithelial Tumors Staging Project: proposal for an evidence-based stage classification system for the forthcoming (8th) edition of the TNM classification of malignant tumors.
      but awaits approval by UICC and AJCC.
      Taken together, the 4th edition of the WHO Classification of thymic tumors has added important new data to the previous edition but can be expected to require amendments or additions because of significant new discoveries before long.
      What are the challenges that need to be tackled in the years ahead to translate a foreseeable better understanding of thymoma and thymic carcinoma biology into improved management of patients? A so far unresolved key problem that has strongly inhibited functional in vitro and preclinical in vivo studies is the paucity of permanent bona fide thymoma and thymic carcinoma cell lines
      • Huang B
      • Belharazem D
      • Li L
      • et al.
      Anti-apoptotic signature in thymic squamous cell carcinomas—functional relevance of anti-apoptotic BIRC3 expression in the thymic carcinoma cell line 1889c.
      • Ehemann V
      • Kern MA
      • Breinig M
      • et al.
      Establishment, characterization and drug sensitivity testing in primary cultures of human thymoma and thymic carcinoma.
      • Gökmen-Polar Y
      • Sanders KL
      • Goswami CP
      • et al.
      Establishment and characterization of a novel cell line derived from human thymoma AB tumor.
      and the virtual absence of relevant spontaneous and xenograft-based animal models.
      • Marx A
      • Porubsky S
      • Belharazem D
      • et al.
      Thymoma related myasthenia gravis in humans and potential animal models.
      Except for the rarity of thymomas and thymic carcinomas, the lack of cell lines and functional xenografts is likely because of the essential need of neoplastic thymic epithelial cells for crosstalk with stromal cells and particularly developing T cells in the case of thymomas to prevent senescence in vitro.
      • Huang B
      • Belharazem D
      • Li L
      • et al.
      Anti-apoptotic signature in thymic squamous cell carcinomas—functional relevance of anti-apoptotic BIRC3 expression in the thymic carcinoma cell line 1889c.
      Therefore, systems biology approaches will likely be necessary to decipher the complex ligand-based and paracrine networks that help to sustain the survival of neoplastic epithelial cells in vivo and might be essential in vitro as well. This knowledge might be a prerequisite to establish relevant models for preclinical functional studies and, ultimately, high-throughput state-of-the-art drug testing.

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