Thymic carcinomas vs. lung carcinomas—pathologist’s perspective: extended abstract

A pathologist analyzing the sample obtained from mediastinal tumor often faces the problem of differentiation between thymic carcinoma (TC) and metastatic lung carcinoma (LC).

LCs are the third most common types of cancer (SEER database: 43.2/100,000 people) and the most common cause of death due to cancer. TCs are very rare (0.2/100,000 people), they are often not included into statistical databases, and the available data about their biology is still scant (1).

Both lungs and thymus develop from the endoderm but from its different segments. Lungs arise directly from the anterior foregut endoderm and the thymus develops more cranially from the endoderm of the third pharyngeal pouch. Both organs develop different, highly specialized epithelial cells. In the thymus multiple types of medullary and cortical epithelial cells necessary for proper thymocyte differentiation are found. Epithelial component of the lungs is constituted by a variety of bronchial cells and pneumocytes involved in gas exchange between the external environment and the cardiovascular system (2-4). All pulmonary and thymic epithelial cells can transform into carcinomas.

Despite different histology and embryological development, a microscopic morphology of TCs and LCs is often similar or even identical, e.g., morphology of squamous cell carcinomas (SqCC), majority of adenocarcinomas (ADC) and many other histological subtypes included into the current (2021) WHO histological classification (5). Thus morphology usually does not allow to establish the point of origin of a neoplasm.

Immunohistochemical reactions, used in routine histopathological diagnostics, may help to differentiate between TCs and LCs, however, they are not in a 100% specific or sensitive. The specificity depends on the tumor (poorly differentiated tumors may lose “typical” markers or may gain unusual immunophenotype) or on the clone of antibody used for the test, e.g., for the lung cancers [ADC or neuroendocrine tumors (NETs)] the clone 8G7G3/1 of TTF-1 is the most specific. The sensitivity may be affected by the tumor itself, the condition of neoplastic cells (e.g., necrotizing cells of SqCC quickly lose the expression of p40) and type of fixative used (nuclear reactions are weaker after fixation in alcohol—own observations).

SqCC is the most frequent subtype of TCs. Its etiology in the thymus is unknown and it is not associated with smoking, opposite to lung SqCC. The most useful and relatively the most specific immunohistochemical markers for thymic SqCC are CD5, co-expression of CD5 and CD117 and FOXN1. Other often used markers like CD117 alone, CD205 and PAX8 may be helpful but they can be also positive in some percentage of lung SqCC (6-11).

ADC is currently the most common subtype of LCs. The most important markers pathologists use to differentiate between thymic and lung ADC and to confirm pulmonary origin are TTF-1 and Napsin A. The CD5 and CD117 are not useful since in many thymic ADCs they are negative and, on the other hand, in some lung ADCs these reactions reveal positive results (6,7,10,11).

In many mediastinal masses, especially in some rare histological subtypes of carcinomas microscopic analysis does not allow to establish unequivocally the organ of origin, i.e., thymus vs. lung. Clear cell carcinoma often associated with distinct hyalinization of the stroma reveals in both organs squamous cell differentiation and, in many cases, the fusion of EWSR1-ATF1 gene. Of note, in the thymus the tumor behaves aggressively with local recurrences and metastases while the pulmonary variant is regarded as low-grade tumor and no recurrences has been reported (12,13). Lymphoepithelial carcinoma of both, thymus and lung, may be associated with EBV infection and both thymic and lung mucoepidermoid carcinoma may reveal CRTC1-MAML2 gene fusion (14,15). In such cases and in all cases of carcinomas with negative immunohistochemical results the final decision, whether the tumor originates from the lung or from the thymus, requires radiological and clinical correlation.

Thymic and lung NETs, which in WHO classification are separated from the carcinomas and represent the distinct histological subgroups, pose the similar diagnostic problem for pathologists. Histological criteria for thymic and lung subtypes of NETs (typical and atypical carcinoids, large cell neuroendocrine carcinomas and small cell carcinomas) are the same (5). TTF-1 may be positive in both thymic and lung NETs and only PAX8 may help - if positive, it enforces the diagnosis of thymic NET. The differences in genetic alterations between thymic and lung NETs have been found, however, such tests are not widely available for pathologists, and they are not recommended by WHO classification for routine diagnostics (16-18).

Despite similar microscopic morphology, the biology of TCs and LCs differs importantly. This corresponds with availability of predictive biomarkers for these diseases. Currently in all advanced lung ADC it is mandatory to assess the EGFR, ALK, ROS1 genes and it is recommended to test additionally BRAF, MET, RET, NTRK-family, HER2, KRAS genes. The mutations or rearrangements found in these genes may qualify the patient to relevant targeted therapies. Pathologists should also assess in all advanced lung non-small cell carcinomas the immunohistochemical expression of PD-L1. High expression (>50% positive neoplastic cells) is associated with higher probability of positive response to the treatment with some of the immune check-point inhibitors (11). There are not such recommendations for TCs since no clinically relevant biomarkers for these tumors have been established yet. The potential biomarkers (e.g., mutations in KIT, PDGFRA, CDKN2A, FGFR3 genes or expression of mesothelin) are analyzed in many studies but their utility is still under evaluation. PD-L1 expression in many TCs is high, however, the efficiency and safety of the treatment with immune check-point inhibitors still require further analysis in clinical trials. The list of predictive biomarkers for LCs is growing but for TCs it is still under evaluation (19-22).

In conclusion, despite different biology, the morphology of TCs and LCs is often very similar so immunohistochemical differential diagnostics is required. However, it may not be sufficient to establish the point of origin of the tumor. The final diagnosis must be correlated with clinical data and radiological findings.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Mediastinum for “The Series Dedicated to the 11th International Thymic Malignancy Interest Group Annual Meeting (Virtual ITMIG 2021)”. The article has undergone external peer review.

Conflicts of Interest: The author has completed the ICMJE uniform disclosure form (available at https://med.amegroups.com/article/view/10.21037/med-21-52/coif). “The Series Dedicated to the 11th International Thymic Malignancy Interest Group Annual Meeting (Virtual ITMIG 2021)” was commissioned by the editorial office without any funding or sponsorship. MS served as the unpaid Guest Editor of the series and serves as an unpaid editorial board member of Mediastinum from June 2021 to May 2023. MS is a current Secretary of ITMIG, Chair of Thymic and Mediastinal Working Group in European Society of Pathology, and Member of Main Revisory Board in the Polish Society of Pathology. Disclosures outside this manuscript include paid lectures for MSD Polska, Roche Polska, AstraZeneca Pharma Poland, Boehringer Ingelheim, and Pfizer Polska. The author has no other conflicts of interest to declare.

Ethical Statement: The author is accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Surveillance, Epidemiology, and End Results (SEER) Program (www.seer.cancer.gov). SEER*Stat Database: Incidence - SEER 9 Regs Research Data, Nov 2020 Sub (1975-2018), National Cancer Institute, DCCPS, Surveillance Research Program, Surveillance Systems Branch, released April 2021, based on the November 2020 submission.
2. Grevellec A, Tucker AS. The pharyngeal pouches and clefts: Development, evolution, structure and derivatives. Semin Cell Dev Biol 2010;21:325-32. [Crossref] [PubMed]
3. Herriges M, Morrisey EE. Lung development: orchestrating the generation and regeneration of a complex organ. Development 2014;141:502-13. [Crossref] [PubMed]
4. Figueiredo M, Zilhão R, Neves H. Thymus Inception: Molecular Network in the Early Stages of Thymus Organogenesis. Int J Mol Sci 2020;21:5765. [Crossref] [PubMed]
5. WHO Classification of Tumours Editorial Board. Thoracic tumours. Lyon (France): International Agency for Research on Cancer 2021. (WHO classification of tumours series, 5th ed.; vol. 5). Available online: https://publications.iarc.fr/595
6. Jha V, Sharma P, Mandal AK. Utility of Cluster of Differentiation 5 and Cluster of Differentiation 117 Immunoprofile in Distinguishing Thymic Carcinoma from Pulmonary Squamous Cell Carcinoma: A Study on 1800 Nonsmall Cell Lung Cancer Cases. Indian J Med Paediatr Oncol 2017;38:430-3. [Crossref] [PubMed]
7. Kriegsmann M, Muley T, Harms A, et al. Differential diagnostic value of CD5 and CD117 expression in thoracic tumors: a large scale study of 1465 non-small cell lung cancer cases. Diagn Pathol 2015;10:210. [Crossref] [PubMed]
8. Nakagawa K, Matsuno Y, Kunitoh H, et al. Immunohistochemical KIT (CD117) expression in thymic epithelial tumors. Chest 2005;128:140-4. [Crossref] [PubMed]
9. Nonaka D, Henley JD, Chiriboga L, et al. Diagnostic utility of thymic epithelial markers CD205 (DEC205) and Foxn1 in thymic epithelial neoplasms. Am J Surg Pathol 2007;31:1038-44. [Crossref] [PubMed]
10. Asirvatham JR, Esposito MJ, Bhuiya TA. Role of PAX-8, CD5, and CD117 in distinguishing thymic carcinoma from poorly differentiated lung carcinoma. Appl Immunohistochem Mol Morphol 2014;22:372-6. [Crossref] [PubMed]
11. Planchard D, Popat S, Kerr K, et al. Metastatic non-small cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2018;29:iv192-237. [Crossref]
12. Porubsky S, Rudolph B, Rückert JC, et al. EWSR1 translocation in primary hyalinising clear cell carcinoma of the thymus. Histopathology 2019;75:431-6. [Crossref] [PubMed]
13. Shahi M, Dolan M, Murugan P. Hyalinizing Clear Cell Carcinoma of the Bronchus. Head Neck Pathol 2017;11:575-9. [Crossref] [PubMed]
14. Zhang G, Yu Z, Shen G, et al. Association between Epstein-Barr virus and Thymic epithelial tumors: a systematic review. Infect Agent Cancer 2019;14:32. [Crossref] [PubMed]
15. Roden AC, Erickson-Johnson MR, Yi ES, et al. Analysis of MAML2 rearrangement in mucoepidermoid carcinoma of the thymus. Hum Pathol 2013;44:2799-805. [Crossref] [PubMed]
16. Baudin E, Caplin M, Garcia-Carbonero R, et al. Lung and thymic carcinoids: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2021;32:439-51. Erratum in: Ann Oncol 2021;32:1453-55. [Crossref] [PubMed]
17. Travis WD, Rush W, Flieder DB, et al. Survival analysis of 200 pulmonary neuroendocrine tumors with clarification of criteria for atypical carcinoid and its separation from typical carcinoid. Am J Surg Pathol 1998;22:934-44. [Crossref] [PubMed]
18. Bi Y, Deng Y, Li S, et al. Immunophenotypic and prognostic analysis of PAX8 and TTF-1 expressions in neuroendocrine carcinomas of thymic origin: A comparative study with their pulmonary counterparts. J Surg Oncol 2016;114:697-702. [Crossref] [PubMed]
19. Sakane T, Murase T, Okuda K, et al. A mutation analysis of the EGFR pathway genes, RAS, EGFR, PIK3CA, AKT1 and BRAF, and TP53 gene in thymic carcinoma and thymoma type A/B3. Histopathology 2019;75:755-66. [Crossref] [PubMed]
20. Sakane T, Sakamoto Y, Masaki A, et al. Mutation Profile of Thymic Carcinoma and Thymic Neuroendocrine Tumor by Targeted Next-generation Sequencing. Clin Lung Cancer 2021;22:92-99.e4. [Crossref] [PubMed]
21. Sakane T, Murase T, Okuda K, et al. A comparative study of PD-L1 immunohistochemical assays with four reliable antibodies in thymic carcinoma. Oncotarget 2018;9:6993-7009. [Crossref] [PubMed]
22. Cho J, Kim HS, Ku BM, et al. Pembrolizumab for Patients With Refractory or Relapsed Thymic Epithelial Tumor: An Open-Label Phase II Trial. J Clin Oncol 2019;37:2162-70. [Crossref] [PubMed]