Pathologic responses to neoadjuvant therapy in thymic epithelial tumors: extended abstract

The goal of neoadjuvant therapy in thymic epithelial tumors (TETs) is to decrease tumor stage and therefore to increase resectability of the tumor (1). In TET complete resection and stage are the most important prognostic parameter (2-4). Neoadjuvant therapy should also prevent systemic disease progression (1). While pathologic response to neoadjuvant therapy is reported in resection specimens of TET as percentage of viable tumor, it is not clear whether percentage of viable tumor in post-neoadjuvant therapy specimens is of prognostic value. Large studies are lacking, mainly because of the paucity of these tumors.

In TET complete pathologic response has been reported in 0% to 31% of thymomas and 0% to 14% of thymic carcinomas (1,5-8). Near complete response rate was defined as less than 10% of viable tumor and was reported in 20% to 40% of TET following chemotherapy or chemoradiation (7,9,10). There is a suggestion that the pathologic response is larger in thymic carcinoma than thymoma (5), however, that finding has not been validated.

Pathologic response to neoadjuvant treatment has been used as a surrogate endpoint for overall survival in clinical trials in other tumors such as melanoma, breast carcinoma, colorectal carcinoma, and non-small cell lung carcinoma (NSCLC). Major pathologic response, as defined as less or equal to 10% of viable tumor has been utilized as surrogate of long-term survival after neoadjuvant chemotherapy and immunotherapy in clinical trials in NSCLC. In addition, there are recommendations for standardized practices for the pathologic assessment of response to neoadjuvant therapies in other organs such as breast and lung (11-13). For instance, recommendations for a standardized approach to evaluation of the pathologic response to treatment in NSCLC in the setting of clinical trials includes mapping of the tumor on the gross specimen. Percentage of viable tumor, percentage of necrosis, and percentage of stroma (encompassing fibrosis and inflammation) should sum up to 100% of the tumor bed. Staging of the tumor should be performed according to the size of viable tumor calculated as percentage of viable tumor multiplied by the size of the tumor bed (11,14).

In TET the International Collaboration on Cancer Reporting (ICCR) recommends to report the percentage of viable tumor in relation to the tumor bed including metastases and implants, to sample at least one block/cm of maximum tumor diameter or, in case of complete pathologic response, the entire tumor if feasible (15,16). National accreditation institutions such as the College of American Pathologists also recommend to report the percentage of viable tumor. Only a few studies evaluated the pathologic response to neoadjuvant therapy in TET. In a study of 28 thymomas stages I through III that were treated with neoadjuvant chemotherapy followed by resection the authors found necrosis in 75% of tumors, histiocytic proliferation (75%), hemorrhage (54%), calcifications (29%), cholesterol granulomas (25%), and cystic changes (21%) in the treated tumors (17). However, none of these findings are specific to post-neoadjuvant TETs as they can also be seen in TETs without neoadjuvant therapy. In this study, tumor viability ranged between 100% for type A thymomas, 10% to 100% for B1 and B2 thymomas, and 80% to 100% for B3 thymomas. Another study including 28 unresectable thymomas and 21 thymic carcinomas that were resected after chemotherapy, radiation, or chemoradiation revealed that thymic carcinomas had a significantly higher response to treatment with lower percentage of viable tumor and more necrosis than thymomas (5). That study used a 5-tiered tumor response grading with grade 1 representing complete pathologic response and grade 5 showing no obvious pathologic tumor response. In that study, 14% of thymic carcinomas had a complete pathologic response and 19% a tumor response grade 2 while none of the thymomas had a complete pathologic response and only a single type B3 thymoma had a tumor response grade of 2. However, there was no significant difference in the post-neoadjuvant therapy resection rate between thymomas and thymic carcinomas.

There are many opportunities for future studies. For instance, what is the effect of neoadjuvant therapy on thymoma vs. carcinoma? What should encompass standardized reporting of pathologic treatment response in TET beyond percentage of viable tumor? Should post-neoadjuvant therapy staging be based on percentage of viable tumor or size of tumor bed? To obtain sufficient power, these and other questions need to be investigated in multi-institutional and global studies.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the Guest Editors (Malgorzata Szolkowska, Chul Kim, Mohammad Ashraghi, and Claudio Silva) for “The Series Dedicated to the 13th International Thymic Malignancy Interest Group Annual Meeting (ITMIG 2023)” published in Mediastinum. The article has undergone external peer review.

Peer Review File: Available at https://med.amegroups.com/article/view/10.21037/med-23-62/prf

Conflicts of Interest: The author has completed the ICMJE uniform disclosure form (available at https://med.amegroups.com/article/view/10.21037/med-23-62/coif). “The Series Dedicated to the 13th International Thymic Malignancy Interest Group Annual Meeting (ITMIG 2023)” was commissioned by the editorial office without any funding or sponsorship. A.C.R. reports having served on the advisory board of Sanofi and as a consultant to Bristol Myers Squibb. She also reports royalties for educational material of Up-to-Date, honorarium for educational lecture from Princeton Integrated Pathology Symposium and Pathology Learning Center, and travel support from Korean Association for Lung Cancer. None of the disclosures are related to this extended abstract. She is the President of the International Thymic Malignancy Interest Group. She serves as an unpaid Associate Editor of Mediastinum from July 2023 to June 2025. 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/.

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