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Cancers
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Novel Approaches in Thymic Epithelial Tumors Diagnosis and Treatment
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Novel Approaches in Thymic Epithelial Tumors Diagnosis and Treatment

A special issue of Cancers (ISSN 2072-6694).

Deadline for manuscript submissions: closed (31 May 2022) | Viewed by 22753

Special Issue Editors

Dr. Mirella Marino

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Guest Editor
Regina Elena National Cancer Institute, 00144 Rome, Italy
Interests: Thymic epithelial tumors; thymoma; thymic carcinoma; diagnosis; biomarkers; MicroRNA; Lung carcinoma; Hematopathology
Prof. Nicolas Girard

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Guest Editor
Département d'Oncologie médicale - Pneumologie, Institut du Thorax Curie Montsouris, Institut Curie, 75248 Paris, France
Interests: thoracic oncology; thymomas and thymic carcinomas treatment; diagnosis

Special Issue Information

Dear Colleagues,

Epithelial thymic tumors (TET) represent a heterogeneous group of rare solid adult malignancies with unknown etiology, complex classification, and uncertain or overt malignant clinical behavior. Their classification has long been debated among pathologists due to uncertainty in the identification of neoplastic epithelial cells in the background of thymocytes, to the wide variety of rare tumors occurring in the anterior mediastinum, and to the contemporary occurrence of complex and heterogeneous autoimmune diseases. Moreover, the unique thymic immunological role and functions have been only recently discovered, and the thymus itself, in normal conditions, undergoes spontaneous atrophy from late childhood. The difficulties in TET treatment derive from their still largely unknown biology and pathogenetic mechanisms, from delayed or inadequate diagnoses, and from the rarity of expert centers and lack of standardized treatments. Significant progress in treatment of TET could be expected in the framework of expert multidisciplinary teams and of international networks, based on worldwide databases specifically dealing with these rare tumors

We hereby invite for this Special Issue of Cancers contributions describing novel molecular alterations underlying the pathobiology of TET possibly impacting epithelial cell growth and survival. In addition, manuscripts discussing developments in diagnostics or therapeutics for TET and related autoimmune diseases are also encouraged. We invite researchers to submit up-to-date original research articles, short communications, and comprehensive review articles on the topic highlighted in this Special Issue of Cancers.

Dr. Mirella Marino
Prof. Nicolas Girard
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • thymic epithelial tumors
  • thymoma
  • thymic carcinoma
  • diagnosis
  • pathology
  • imaging
  • surgery
  • chemotherapy
  • radiotherapy
  • network
  • biomarker
  • gene expression profiling
  • immunotherapy
  • autoimmune disease treatment

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Published Papers (6 papers)

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Research

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17 pages, 3010 KiB  
Article
ED-B-Containing Isoform of Fibronectin in Tumor Microenvironment of Thymomas: A Target for a Theragnostic Approach
by Iacopo Petrini, Martina Sollini, Francesco Bartoli, Serena Barachini, Marina Montali, Eleonora Pardini, Irene Sofia Burzi and Paola Anna Erba
Cancers 2022, 14(11), 2592; https://doi.org/10.3390/cancers14112592 - 24 May 2022
Cited by 9 | Viewed by 2550
Abstract
Aim: to exploit tissue-specific interactions among thymic epithelial tumor (TETs) cells and extra-domain B fibronectin (ED-B FN). Material and methods: The stromal pattern of ED-B FN expression was investigated through tumor specimen collection and molecular profiling in 11 patients with recurrent TETs enrolled [...] Read more.
Aim: to exploit tissue-specific interactions among thymic epithelial tumor (TETs) cells and extra-domain B fibronectin (ED-B FN). Material and methods: The stromal pattern of ED-B FN expression was investigated through tumor specimen collection and molecular profiling in 11 patients with recurrent TETs enrolled in prospective theragnostic phase I/II trials with Radretumab, an ED-B FN specific recombinant human antibody. Radretumab radioimmunotherapy (R-RIT) was offered to patients who exhibited the target expression. Experiments included immunochemical analysis (ICH), cell cultures, immunophenotypic analysis, Western blot, slot-blot assay, and quantitative RT-PCR of two primary thymoma cultures we obtained from patients’ samples and in the Ty82 cell line. Results: The in vivo scintigraphic demonstration of ED-B FN expression resulted in R-RIT eligibility in 8/11 patients, of which seven were treated. The best observed response was disease stabilization (n = 5/7) with a duration of 4.3 months (range 3–5 months). IHC data confirmed high ED-B FN expression in the peripherical microenvironment rather than in the center of the tumor, which was more abundant in B3 thymomas. Further, there was a predominant expression of ED-B FN by the stromal cells of the thymoma microenvironment rather than the epithelial cells. Conclusions: Our data support the hypothesis that thymomas induce stromal cells to shift FN production to the ED-B subtype, likely representing a favorable hallmark for tumor progression and metastasis. Collectively, results derived from clinical experience and molecular insights of the in vitro experiments suggested that R-RIT inefficacy is unlikely related to low target expression in TET, being the mechanism of R-RIT resistance eventually related to patients’ susceptibility (i.e., inherent characteristics), the pattern expression of the target (i.e., at periphery), the biological characteristics of the tumor (i.e., aggressive and resistant phenotypes), and/or to format of the target agent (i.e., 131I-L19-SIP). Full article
(This article belongs to the Special Issue Novel Approaches in Thymic Epithelial Tumors Diagnosis and Treatment)
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17 pages, 16791 KiB  
Article
CD117, BAP1, MTAP, and TdT Is a Useful Immunohistochemical Panel to Distinguish Thymoma from Thymic Carcinoma
by Mounika Angirekula, Sindy Y Chang, Sarah M. Jenkins, Patricia T. Greipp, William R. Sukov, Randolph S. Marks, Kenneth R. Olivier, Stephen D. Cassivi and Anja C Roden
Cancers 2022, 14(9), 2299; https://doi.org/10.3390/cancers14092299 - 5 May 2022
Cited by 9 | Viewed by 3068
Abstract
Background: The morphologic distinction between thymic carcinomas and thymomas, specifically types B3, A, and occasionally micronodular thymomas with lymphoid stroma (MNTLS) can be challenging, as has also been shown in interobserver reproducibility studies. Since thymic carcinomas have a worse prognosis than thymomas, the [...] Read more.
Background: The morphologic distinction between thymic carcinomas and thymomas, specifically types B3, A, and occasionally micronodular thymomas with lymphoid stroma (MNTLS) can be challenging, as has also been shown in interobserver reproducibility studies. Since thymic carcinomas have a worse prognosis than thymomas, the diagnosis is important for patient management and treatment. This study aimed to identify a panel of immunohistochemical (IHC) markers that aid in the distinction between thymomas and thymic carcinomas in routine practice. Materials and Method: Thymic carcinomas, type A and B3 thymomas, and MNTLS were identified in an institutional database of thymic epithelial tumors (TET) (1963–2021). IHC was performed using antibodies against TdT, Glut-1, CD5, CD117, BAP1, and mTAP. Percent tumor cell staining was recorded (Glut-1, CD5, CD117); loss of expression (BAP1, mTAP) was considered if essentially all tumor cells were negative; TdT was recorded as thymocytes present or absent (including rare thymocytes). Results: 81 specimens included 44 thymomas (25 type A, 11 type B3, 8 MNTLS) and 37 thymic carcinomas (including 24 squamous cell carcinomas). Using BAP1, mTAP, CD117 (cut-off, 10%), and TdT, 88.9% of thymic carcinomas (95.7% of squamous cell carcinomas) and 77.8% of thymomas could be predicted. Glut-1 expression was not found to be useful in that distinction. All tumors that expressed CD5 in ≥50% of tumor cells also expressed CD117 in ≥10% of tumor cells. In four carcinomas with homozygous deletion of CDKN2A, mTAP expression was lost in two squamous cell carcinomas and in a subset of tumor cells of an adenocarcinoma and was preserved in a lymphoepithelial carcinoma. Conclusion: A panel of immunostains including BAP1, mTAP, CD117 (using a cut-off of 10% tumor cell expression), and TdT can be useful in the distinction between thymomas and thymic carcinomas, with only a minority of cases being inconclusive. Full article
(This article belongs to the Special Issue Novel Approaches in Thymic Epithelial Tumors Diagnosis and Treatment)
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13 pages, 2166 KiB  
Article
Thymic Hyperplasia with Lymphoepithelial Sialadenitis (LESA)-Like Features: Strong Association with Lymphomas and Non-Myasthenic Autoimmune Diseases
by Stefan Porubsky, Zoran V. Popovic, Sunil Badve, Yara Banz, Sabina Berezowska, Dietmar Borchert, Monika Brüggemann, Timo Gaiser, Thomas Graeter, Peter Hollaus, Katrin S. Huettl, Michaela Kotrova, Andreas Kreft, Christian Kugler, Fabian Lötscher, Burkhard Möller, German Ott, Gerhard Preissler, Eric Roessner, Andreas Rosenwald, Philipp Ströbel and Alexander Marxadd Show full author list remove Hide full author list
Cancers 2021, 13(2), 315; https://doi.org/10.3390/cancers13020315 - 16 Jan 2021
Cited by 15 | Viewed by 4304
Abstract
Thymic hyperplasia (TH) with lymphoepithelial sialadenitis (LESA)-like features (LESA-like TH) has been described as a tumor-like, benign proliferation of thymic epithelial cells and lymphoid follicles. We aimed to determine the frequency of lymphoma and autoimmunity in LESA-like TH and performed retrospective analysis of [...] Read more.
Thymic hyperplasia (TH) with lymphoepithelial sialadenitis (LESA)-like features (LESA-like TH) has been described as a tumor-like, benign proliferation of thymic epithelial cells and lymphoid follicles. We aimed to determine the frequency of lymphoma and autoimmunity in LESA-like TH and performed retrospective analysis of cases with LESA-like TH and/or thymic MALT-lymphoma. Among 36 patients (21 males) with LESA-like TH (age 52 years, 32–80; lesion diameter 7.0 cm, 1–14.5; median, range), five (14%) showed associated lymphomas, including four (11%) thymic MALT lymphomas and one (3%) diffuse large B-cell lymphoma. One additional case showed a clonal B-cell-receptor rearrangement without evidence of lymphoma. Twelve (33%) patients (7 women) suffered from partially overlapping autoimmune diseases: systemic lupus erythematosus (n = 4, 11%), rheumatoid arthritis (n = 3, 8%), myasthenia gravis (n = 2, 6%), asthma (n = 2, 6%), scleroderma, Sjögren syndrome, pure red cell aplasia, Grave’s disease and anti-IgLON5 syndrome (each n = 1, 3%). Among 11 primary thymic MALT lymphomas, remnants of LESA-like TH were found in two cases (18%). In summary, LESA-like TH shows a striking association with autoimmunity and predisposes to lymphomas. Thus, a hematologic and rheumatologic workup should become standard in patients diagnosed with LESA-like TH. Radiologists and clinicians should be aware of LESA-like TH as a differential diagnosis for mediastinal mass lesions in patients with autoimmune diseases. Full article
(This article belongs to the Special Issue Novel Approaches in Thymic Epithelial Tumors Diagnosis and Treatment)
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Review

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19 pages, 942 KiB  
Review
Immunotherapy for Management of Thymic Epithelial Tumors: A Double-Edged Sword
by Madison Ballman, Chen Zhao, Meredith J. McAdams and Arun Rajan
Cancers 2022, 14(9), 2060; https://doi.org/10.3390/cancers14092060 - 20 Apr 2022
Cited by 13 | Viewed by 3500
Abstract
Thymic epithelial tumors (TETs) are rare thoracic cancers that are broadly classified as thymomas and thymic carcinomas. Surgery is the cornerstone of management for early-stage disease. There are a limited number of effective treatment options for patients with advanced or recurrent disease. The [...] Read more.
Thymic epithelial tumors (TETs) are rare thoracic cancers that are broadly classified as thymomas and thymic carcinomas. Surgery is the cornerstone of management for early-stage disease. There are a limited number of effective treatment options for patients with advanced or recurrent disease. The occurrence of paraneoplastic autoimmune disorders in patients with TETs, especially thymomas, creates significant challenges for the development of immunotherapy, including immune checkpoint inhibitors, as a feasible treatment option. In addition, patients with TETs are at increased risk for the development of immune-mediated toxicity with a predilection for musculoskeletal and neuromuscular adverse events upon treatment with immunotherapy. The identification of biomarkers of response and toxicity is expected to play a key role in harnessing the benefits of immunotherapy for patients with TETs. In this paper we review the biology of TETs and the potential effects on the tolerability of immunotherapy. The results of clinical trials of immune checkpoint inhibitors for the treatment of advanced TETs are described to understand the potential risks and benefits of immunotherapy. We also provide an overview of future avenues for treatment with novel immunotherapeutic modalities and opportunities to develop biomarkers to improve the safety and tolerability of immunomodulatory treatments in patients with TETs. Full article
(This article belongs to the Special Issue Novel Approaches in Thymic Epithelial Tumors Diagnosis and Treatment)
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17 pages, 78646 KiB  
Review
Diagnostic Challenges in the Cytology of Thymic Epithelial Neoplasms
by Jonathan Willner, Fang Zhou and Andre L. Moreira
Cancers 2022, 14(8), 2013; https://doi.org/10.3390/cancers14082013 - 15 Apr 2022
Cited by 9 | Viewed by 4516
Abstract
Thymic epithelial neoplasms are rare tumors that constitute the majority of anterior mediastinal masses. They are classified as thymomas, thymic carcinomas, and thymic neuroendocrine neoplasms. Biopsy diagnosis is not common, and most tumors are surgically resected. Biopsy, including cytology, is indicated when a [...] Read more.
Thymic epithelial neoplasms are rare tumors that constitute the majority of anterior mediastinal masses. They are classified as thymomas, thymic carcinomas, and thymic neuroendocrine neoplasms. Biopsy diagnosis is not common, and most tumors are surgically resected. Biopsy, including cytology, is indicated when a non-surgical entity is suspected or in cases of locally advanced disease. Smears of thymomas consist of round or spindle epithelial cells admixed with varying amounts of lymphocytes depending on the type of thymoma. Smears of thymic carcinoma and thymic neuroendocrine neoplasms are often indistinguishable from corresponding tumor types from other organs. Accurate cytological diagnosis can be difficult due to the histological diversity of thymomas, as well as the morphological features that certain thymic tumors share with similar tumors from other organs. However, fine needle aspiration (FNA) of anterior mediastinal masses can provide clinically actionable information and can be used to determine whether lesions require surgical, systemic, or local noninvasive treatments. Ancillary studies, namely, immunocytochemical stains, flow cytometry, and radiology, are important tools in the evaluation of thymic aspirates. This review discusses the utility and limitations of thymic FNAs and illustrates the diagnostic features and pitfalls of these specimens. Full article
(This article belongs to the Special Issue Novel Approaches in Thymic Epithelial Tumors Diagnosis and Treatment)
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14 pages, 542 KiB  
Review
The Never-Ending History of Octreotide in Thymic Tumors: A Vintage or A Contemporary Drug?
by Liliana Montella, Margaret Ottaviano, Rocco Morra, Erica Pietroluongo, Pietro De Placido, Marianna Tortora, Chiara Sorrentino, Gaetano Facchini, Sabino De Placido, Mario Giuliano and Giovannella Palmieri
Cancers 2022, 14(3), 774; https://doi.org/10.3390/cancers14030774 - 2 Feb 2022
Cited by 3 | Viewed by 3405
Abstract
Thymic epithelial tumors are rare tumors usually presenting as a mass located in the anterior mediastinum and/or with symptoms deriving from associated paraneoplastic syndromes. Unresectable platinum-refractory tumors are often treated with alternative regimens, including chemotherapeutic agents as well as chemo-free regimens. The most [...] Read more.
Thymic epithelial tumors are rare tumors usually presenting as a mass located in the anterior mediastinum and/or with symptoms deriving from associated paraneoplastic syndromes. Unresectable platinum-refractory tumors are often treated with alternative regimens, including chemotherapeutic agents as well as chemo-free regimens. The most popular unconventional therapy is represented by the somatostatin analog octreotide, which can be used alone or with prednisone. The in vivo expression of somatostatin receptors documented by imaging with indium-labeled octreotide or gallium-68 Dotapeptides, the successful use of octreotide and prednisone in a chemo-refractory patient, and, thereafter, the experiences from a case series have enforced the idea that this treatment merits consideration—as proved by its inclusion in the National Comprehensive Cancer Network guidelines. In the present review, we analyze the preclinical basis for the therapeutic use of somatostatin and prednisone in refractory thymic tumors and discuss the available studies looking at future perspectives. Full article
(This article belongs to the Special Issue Novel Approaches in Thymic Epithelial Tumors Diagnosis and Treatment)
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