Mirella Marino

Thymoma and thymic carcinoma. Relation of thymoma epithelial cells to the cortical and medullary differentiation of thymus.

Based on the light microscopical features of normal thymic epithelial cells, human thymoma was divided in different types, namely cortical, medullary, and mixed ones, according to the epithelial cell (EC) type. Lymphoid cell populations with morphological features of either cortical or medullary thymocytes were found according to different types of EC in thymoma. The histological variation of the different types of thymoma are demonstrated. In a retrospective study of 58 thymomas and 13 thymic carcinomas, malignant invasive character as well as the occurrence of myasthenia gravis were both found to be related to the neoplastic proliferation of the cortical epithelial cells, whereas in the usual mixed type of thymoma and the medullary type no gross invasion or metastases were noticed. These results are discussed in view of recent concepts and immunological findings of thymus microarchitecture.

Epstein-Barr Virus–Associated B-Cell Lymphoproliferative Disorders in Angioimmunoblastic T-Cell Lymphoma and Peripheral T-Cell Lymphoma, Unspecified

Various patterns of Epstein-Barr virus (EBV)-associated B-cell lymphoproliferation occur in patients with immunodeficiency. We studied 17 cases of T-cell lymphoma displaying extensive EBV-driven B-cell lymphoproliferation or simultaneous/subsequent EBV-associated B-cell lymphoma. In 10 cases of angioimmunoblastic T-cell lymphoma, an uncommonly prominent population of EBV+ atypical, activated, focally confluent large transformed B cells was found in the background of T-cell lymphoma. In 4 cases, an EBV-associated B-cell neoplasm (3 diffuse large B-cell lymphomas, 1 plasmacytoma) occurred in patients with T-cell lymphoma. Three cases were composite lymphomas of a peripheral T-cell lymphoma, unspecified, combined with EBV-associated diffuse large B-cell lymphoma. The transformed B-cell population displayed EBV latency types 2 and 3. Monoclonal and oligoclonal B-cell populations were detected in 5 and 6 cases, respectively. Similar to other states of immunodeficiency, disease-related and therapy-induced immunosuppression in T-cell lymphoma may lead to a prominent EBV-associated B-cell lymphoproliferation and to EBV+ B-cell neoplasms.

The IASLC Lung Cancer Staging Project: Proposals for Coding T Categories for Subsolid Nodules and Assessment of Tumor Size in Part-Solid Tumors in the Forthcoming Eighth Edition of the TNM Classification of Lung Cancer

ABSTRACT This article proposes codes for the primary tumor categories of adenocarcinoma in situ (AIS) and minimally invasive adenocarcinoma (MIA) and a uniform way to measure tumor size in part‐solid tumors for the eighth edition of the tumor, node, and metastasis classification of lung cancer. In 2011, new entities of AIS, MIA, and lepidic predominant adenocarcinoma were defined, and they were later incorporated into the 2015 World Health Organization classification of lung cancer. To fit these entities into the T component of the staging system, the Tis category is proposed for AIS, with Tis (AIS) specified if it is to be distinguished from squamous cell carcinoma in situ (SCIS), which is to be designated Tis (SCIS). We also propose that MIA be classified as T1mi. Furthermore, the use of the invasive size for T descriptor size follows a recommendation made in three editions of the Union for International Cancer Control tumor, node, and metastasis supplement since 2003. For tumor size, the greatest dimension should be reported both clinically and pathologically. In nonmucinous lung adenocarcinomas, the computed tomography (CT) findings of ground glass versus solid opacities tend to correspond respectively to lepidic versus invasive patterns seen pathologically. However, this correlation is not absolute; so when CT features suggest nonmucinous AIS, MIA, and lepidic predominant adenocarcinoma, the suspected diagnosis and clinical staging should be regarded as a preliminary assessment that is subject to revision after pathologic evaluation of resected specimens. The ability to predict invasive versus noninvasive size on the basis of solid versus ground glass components is not applicable to mucinous AIS, MIA, or invasive mucinous adenocarcinomas because they generally show solid nodules or consolidation on CT.

Immunohistological evidences of cortical and medullary differentiation in thymoma

The phenotypical characteristics of human epithelial and lymphoid cells have been studied with immunohistochemical methods on frozen sections of 12 thymomas. On the basis of the cytohistological characteristics of thymoma epithelial cells (EC) the thymomas were divided in cortical, medullary and mixed types, according to recently developed light microscopical criteria. When tested with a series of monoclonal antibodies, thymoma EC were all stained by the antibody Ki-M3 (as in the thymus), but reacted with anti-HLA-DR, anti-HLA-A,B,C and with a new monoclonal antibody to cortical EC,21A6, to a lesser extent and with weaker, variable intensity in comparison with the normal thymus. Cortical type thymomas were most reactive and the medullary type almost negative. Thymomas, like normal thymus showed different immunoreactivity patterns with antibodies to prekeratins of different specificities. Cortical type thymomas and areas in mixed thymoma showed an EC staining with the antibody to non-squamous type keratin (35βH11) whereas medullary type thymomas and areas showed staining with antibodies to squamous-type keratin (34βE12-IV/82) in addition. Lymphoidcellswithcortical(OKT6+,Leu 1 weakly+,Leu2a+,Leu3a+) or mature medullary (OKT6-, Leu 1 strongly+, Leu 2a or Leu 3a+) phenotype were found to colonize tumours with diferent EC types. These immunohistochemical findings largely confirm our earlier cytological distinction of thymoma EC. In addition important differences have been observed in neoplastic cortical EC concerning the HLA-DR and 21A6 immunoreactivity that may be intimately related to the neoplastic process and paraneoplastic immune phenomena.

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

A universal and consistent stage classification system, which describes the anatomic extent of a cancer, provides a foundation for communication and collaboration. Thymic epithelial malignancies have seen little progress, in part because of the lack of an official system. The International Association for the Study of Lung Cancer and the International Thymic Malignancies Interest Group assembled a large retrospective database, a multispecialty international committee and carried out extensive analysis to develop proposals for the 8th edition of the stage classification manuals. This tumor, node, metastasis (TNM)-based system is applicable to all types of thymic epithelial malignancies. This article summarizes the proposed definitions of the T, N, and M components and describes how these are combined into stage groups. This represents a major step forward for thymic malignancies.

ITMIG Consensus Statement on the Use of the WHO Histological Classification of Thymoma and Thymic Carcinoma: Refined Definitions, Histological Criteria, and Reporting

Introduction: The 2004 version of the World Health Organization classification subdivides thymic epithelial tumors into A, AB, B1, B2, and B3 (and rare other) thymomas and thymic carcinomas (TC). Due to a morphological continuum between some thymoma subtypes and some morphological overlap between thymomas and TC, a variable proportion of cases may pose problems in classification, contributing to the poor interobserver reproducibility in some studies. Methods: To overcome this problem, hematoxylin-eosin–stained and immunohistochemically processed sections of prototypic, “borderland,” and “combined” thymomas and TC (n = 72) were studied by 18 pathologists at an international consensus slide workshop supported by the International Thymic Malignancy Interest Group. Results: Consensus was achieved on refined criteria for decision making at the A/AB borderland, the distinction between B1, B2, and B3 thymomas and the separation of B3 thymomas from TCs. “Atypical type A thymoma” is tentatively proposed as a new type A thymoma variant. New reporting strategies for tumors with more than one histological pattern are proposed. Conclusion: These guidelines can set the stage for reproducibility studies and the design of a clinically meaningful grading system for thymic epithelial tumors.

Expression of autoimmune regulator gene (AIRE) and T regulatory cells in human thymomas

Expression of the autoimmune regulator gene (AIRE) and the presence of CD25+/forkhead box p3 (FoxP3)+ T regulatory (Treg) cells were investigated in histologically normal adult thymi and in thymomas using immunohistochemistry and quantitative real‐time polymerase chain reaction (PCR). In the normal thymus staining for AIRE was detected in the nucleus of some epithelial‐like cells located in the medulla; in thymomas AIRE‐positive cells were extremely rare and could be detected only in the areas of medullary differentiation of two B1 type, organoid thymomas. RNA was extracted from 36 cases of thymoma and 21 non‐neoplastic thymi obtained from 11 myasthenic (MG+) and 10 non‐myasthenic (MG–) patients. It was found that AIRE is 8·5‐fold more expressed in non‐neoplastic thymi than in thymomas (P = 0·01), and that the amount of AIRE transcripts present in the thymoma tissue are not influenced by the association with MG, nor by the histological type. A possible involvement of AIRE in the development of MG was suggested by the observation that medullary thymic epithelial cells isolated from AIRE‐deficient mice contain low levels of RNA transcripts for CHRNA 1, a gene coding for acetylcholine receptor. Expression of human CHRNA 1 RNA was investigated in 34 human thymomas obtained from 20 MG– patients and 14 MG+ patients. No significant difference was found in the two groups (thymoma MG+, CHRNA1 = 0·013 ± 0·03; thymoma MG‐, CHRNA1 = 0·01 ± 0·03). In normal and hyperplastic thymi CD25+/Foxp3+ cells were located mainly in the medulla, and their number was not influenced by the presence of MG. Foxp3+ and CD25+ cells were significantly less numerous in thymomas. A quantitative estimate of Treg cells revealed that the levels of Foxp3 RNA detected in non‐neoplastic thymi were significantly higher (P = 0·02) than those observed in 31 cases of thymomas. Our findings indicate that the tissue microenvironment of thymomas is defective in the expression of relevant functions that exert a crucial role in the negative selection of autoreactive lymphocytes.

Cetuximab is an active treatment of metastatic and chemorefractory thymoma

Advanced chemorefractory thymic epithelial tumors still represent a challenge in clinical oncology. A rationale-based therapeutic approach targeting a key pathway should represent the ideal solution in a neoplasm that can over-express Epidermal Growth Factor Receptor (EGFR) in the epithelial component. On the basis of these considerations, two patients with metastatic heavily pretreated disease were evaluated for EGFR expression in the primitive tumor, being considered this data as a basis for an anti EGFR treatment with the monoclonal antibody cetuximab which targets EGFR. A strong EGFR expression was revealed by immunohistochemistry in the two cases considered, thus the patients received cetuximab and reported a partial response as assessed by Computed Tomography (CT), Positron Emission Tomography (PET) and fused PET-CT after three months of therapy. Therefore, both patients are still on therapy. This preliminary experience suggests that cetuximab may be a useful therapeutic choice in advanced pre-treated thymic tumors.

Human thymoma: immunologic characteristics of the lymphocytic component.

Several immunologic parameters were investigated in the lymphocytic component of ten thymomas, characterized by a variable degree of lymphocytic infiltration. The majority of thymoma lymphocytes are T‐cell in nature, as are lymphocytes from the normal thymus. Lymphocytes from six thymomas with moderate or predominant lymphocytic infiltrates were capable of forming stable E‐rosettes, (mean percentage ± SD: 78.0 ± 5.2); binding peanut agglutinin (67.3 ± 8.6); and exhibiting receptors for the Fc‐portion of IgM (21.8 ± 6.0) at percentages that were close to those found in the normal thymus. On the other hand, lower numbers of stable E‐rosetting cells (26.8 ± 8.7), PNA‐positive cells (27.5 ± 12.4), and remarkably higher percentages of cells with receptors for IgM (54.0 ± 4.2) were demonstrated by the lymphocytic population of four thymomas with scant lymphocyte components. In addition, lymphocytes from tumors with scant lymphocyte components show a higher proliferative response to phytomitogen (PHA), therefore exhibiting immunologic features comparable to those of the more mature pool of normal medullary thymocytes. The observed immunologic similarities between the populations of lymphocytes from thymomas and from the normal thymus gland suggest an exclusively epithelial origin of the thymoma.

The IASLC/ITMIG Thymic Malignancies Staging Project Development of a Stage Classification for Thymic Malignancies

The lack of an official-stage classification system for thymic malignancies is an issue that hampers progress in this rare disease. A collaborative effort by the International Association for the Study of Lung Cancer and the International Thymic Malignancies Interest Group is underway to develop proposals for such a system. A database of more than 10,000 cases worldwide has been assembled to provide a solid basis for analysis. This report outlines the structure of the effort and the process that has been designed.