On the staging of thymic epithelial neoplasms

The recent article by White et al. in the European Journal of Cardiothoracic Surgery on the efficacy of chest computed tomography prediction of the pathological TNM stage of thymic epithelial tumors (1) underscores an issue that has impacted the field of thymoma studies, namely what is the proper way for staging such tumors. The study by White et al. (1) shows that preoperative chest CT is able to accurately predict p-TNM stage in only two thirds of surgically resected thymic epithelial tumors. Thus, one third of patients will have false positives or false negatives that may adversely affect the management options for those patients, including decisions of whether to offer preoperative radiation that may lead to incomplete surgical resections or overtreatment of the lesions with added morbidity.

The study compares the effect of CT staging with pathologic staging using both the recently introduced TNM staging scheme of the Union for International Cancer Control (UICC)/American Joint Committee on Cancer (AJCC) (2) and the more traditional modified Masaoka staging by Koga et al. (3). Unfortunately, neither of these two staging systems completely addresses the issues in the staging of thymoma. The TNM staging recently introduced in the 8^th edition of the AJCC lends itself well for assessing some of the more aggressive variants of thymic epithelial neoplasms, such as thymic carcinoma and neuroendocrine carcinomas of the thymus, which often present in more advanced stages and with metastatic spread, but for the majority of the more conventional thymic epithelial neoplasms (i.e., thymomas), the N and M categories will be of little value given that regional lymph node and distant metastases are rather rare in such tumors (4).

The original Masaoka (5) scheme and its modified Koga staging system (3), which has stood the test of time and has been favored as the standard method for staging of thymoma for nearly 40 years, has also suffered from several limitations. Various studies have called attention to the fact that the distinction between infiltration into the capsule and invasion through the capsule do not result in significantly different outcomes (6). The study by Koga and colleagues (3) introduced changes to the original Masaoka staging that simplified the system and divided these tumors into two broad categories: invasive (for modified stages III and IV) and non-invasive (for modified stages I and II). The problem with the modified Masaoka staging is that it continues to rely on gross evaluation at the time of surgery for stages IIb and III (“Macroscopic invasion into thymic or surrounding fat…” for IIb and “Macroscopic invasion of neighboring organs…” for stage III).

Experience has repeatedly shown us that gross evaluation by the surgeon of invasion at the time of surgery can sometimes be inaccurate and misleading. Both thymomas and benign processes affecting the thymus can often lead to firm adhesions of the tumor to the pleura, pericardium and other structures, which can be grossly mistaken for invasion but that upon histopathologic examination are demonstrated to represent fibrous adhesions secondary to inflammation (7). Moreover, the current staging criteria take out of the hands of the pathologist the capability for rendering a reliable and definitive pathologic staging of the lesion, as communication between the surgeon and the pathologist is not always optimal. The ideal way to establish invasion in such instances is for the surgeon to biopsy the grossly suspicious area and submit it separately with a specific site designation and with the specific query of “rule out invasion”. Unfortunately, this is not a common practice as evidenced by the numerous surgical pathology reports from a wide number of sources reviewed in our consultative practice.

What has emerged over time as a much more reliable feature for assessing prognosis in these tumors is the completeness of resection. Previous studies addressing this parameter have demonstrated that incomplete resection in thymoma, even for the low-grade organotypic tumors, is associated with increased incidence of recurrence and a more protracted clinical course (8,9). More recently, the same has been shown for thymic carcinoma, in which tumors that were completely resected with clear margins observed a much better prognosis than tumors with positive margins independent of the histology (10). Proper assessment of the status of the margins in thymoma thus represents a critical component in the evaluation of these tumors.

Unfortunately, there is no standard protocol or grossing guidelines that have yet been universally adopted for the handling of these specimens in pathology laboratories. Since a large proportion of these tumors are operated on in small, private community hospitals in the United States, the majority of cases submitted in consultation to experts in academic medical centers do not have adequate orientation or properly designated margins. Most pathologist have taken the approach of inking the entire outer surface of the specimen sent to pathology and of designating it as the “margins”. Technically speaking, however, a true margin is only represented by tissues that have been transected by the surgeon and separated from adjoining structures. Since thymomas are located in the anterior mediastinum, a virtual cavity, the areas of the tumor that were not adhered or attached to other structures do not represent true margins but simply constitute the “outer surface” of the specimen. It would thus be misleading to indicate that the margins are positive if the tumor reaches up to the inked outer surface of what is not really a margin.

A few years ago, several members of ITMIG (International Thymic Malignancies Interest Group) published a consensus guideline for the grossing of thymomas (11). The guidelines were developed by a panel of surgical pathologists with special interest/expertise in mediastinal pathology in collaboration with thoracic surgeons. The guidelines called for separate and specific inking or marking of the more relevant areas of the surgical specimen so the pathologist could provide a more accurate rendering of the true margins. Adoption of such guidelines could go a long way in helping improve the accuracy of staging in these tumors and may improve our ability to establish prognosis for these patients.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the Editorial Office, Mediastinum. The article did not undergo external peer review.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/med.2019.04.02). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are 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.

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References

1. White DB, Hora MJ, Jenkins SM, et al. Efficacy of chest computed tomography prediction of the pathological TNM stage of thymic epithelial tumours. Eur J Cardiothorac Surg 2019; [Epub ahead of print]. [Crossref] [PubMed]
2. Amin MB, Edge S, Greene F, et al. editors. AJCC Cancer Staging Manual, 8th Ed., American Joint Committee on Cancer, American Cancer Society, Chicago, IL: Springer, 2017.
3. Koga K, Matsuno Y, Noguchi M, et al. A review of 79 thymomas: modification of staging system and reappraisal of conventional division into invasive and non-invasive thymoma. Pathol Int 1994;44:359-67. [Crossref] [PubMed]
4. Suster S, Moran CA. Mediastinum. In: Modern Surgical Pathology, 2nd. Ed, Weidner N, Cote R, Suster S, et al. editors. Philadelphia: Saunders (Elsevier), 2009:454-516.
5. Masaoka A, Hashimoto T, Shibata K, et al. Thymomas associated with pure red cell aplasia. Histologic and follow-up studies. Cancer 1989;64:1872-8. [Crossref] [PubMed]
6. Curran WJ Jr, Kornstein MJ, Brooks JJ, et al. Invasive thymoma: the role of mediastinal irradiation following complete or incomplete surgical resection. J Clin Oncol 1988;6:1722-7. [Crossref] [PubMed]
7. Suster S, Rosai J. Multilocular thymic cyst: an acquired reactive process. Study of 18 cases. Am J Surg Pathol 1991;15:388-98. [Crossref] [PubMed]
8. Regnard JF, Magdeleinat P, Dromer C, et al. Prognostic factors and long-term results after thymoma resection: a series of 307 patients. J Thorac Cardiovasc Surg 1996;112:376-84. [Crossref] [PubMed]
9. Gamondès JP, Balawi A, Greenland T, et al. Seventeen years of surgical treatment of thymoma: factors influencing survival. Eur J Cardiothorac Surg 1991;5:124-31. [Crossref] [PubMed]
10. Suster D, Pihan G, Mackinnon AC, et al. Poorly Differentiated Nonkeratinizing Squamous Cell Carcinoma of the Thymus: Clinicopathologic and Molecular Genetic Study of 25 Cases. Am J Surg Pathol 2018;42:1224-36. [Crossref] [PubMed]
11. Detterbeck FC, Moran C, Huang J, et al. Which way is up? Policies and procedures for surgeons and pathologists regarding resection specimens of thymic malignancy. J Thorac Oncol 2011;6:S1730-8. [Crossref] [PubMed]