Lymph nodes metastases in thymic malignancies: we need prospective studies

Thymic epithelial tumors (TET) are rare malignancies of the anterior mediastinum with a wide spectrum of biologic behavior. It is generally accepted that thymomas become more invasive as their World Health Organization (WHO) histologic classification advances to B2 and B3. Thymic carcinomas and neuroendocrine tumors of the thymus (NETT) are more difficult to treat as these are often invasive and give rise to metastases earlier than thymomas. It is important for the practitioner to understand that thymomas, thymic carcinomas, and NETT are not a spectrum of worsening malignancy, but rather three different pathologies, with different behavior and different response to surgery, chemotherapy, and radiation therapy. The WHO recognized this and now separately classified thymoma, thymic carcinoma, and thymic neuroendocrine tumors as distinct diseases (1).

Until recently, the Masaoka-Koga classification was the most widely staging system used for TET (2). This staging system allowed for proper survival stratification of patients with TET but had one significant drawback as it was not based on a Tumor/Node/Metastases (TNM) but rather on the invasiveness of the primary tumor and the presence of local or distant metastases. Importantly, the Masaoka-Koga system did not require knowledge of nodal status for the final staging and generically classified all nodal metastases as stage IVB. This has likely discouraged surgeons from performing lymph node dissection in patients with TET. Over this background, it is easy to understand that nodal metastases in TET is a topic with much discussion but without high-quality data. The recently proposed TNM classification of TET by the International Association for the Study of Lung Cancer (IASLC) and the International Thymic Malignancies Interest Group (ITMIG) (3) includes a proposal for a nodal mapping for TET (4) and will likely increase awareness among surgeons to the importance of at least nodal sampling in this patient population.

Available literature is sparse on nodal metastases from TET. Kondo was one of the first to investigate this topic (5,6). Using a questionnaire sent to 185 institutions in Japan Kondo compiled a database of 1,320 patients (1,093 thymomas, 186 thymic carcinomas, 41 thymic carcinoids). The incidence of nodal metastases was 1.8% in thymomas, 26.8% in thymic carcinomas, and 27.5% in thymic carcinoids. Our own work with the Surveillance, Epidemiology, and End Results (SEER) registry revealed an incidence of nodal metastases in thymomas of 13.4% (7), 33.5% in thymic carcinomas, and 62.3% in thymic neuroendocrine tumors (8). These numbers must be interpreted with caution as part of the inclusion criteria for the study was the presence of at least one lymph node examined and the majority of resected patients were not included in the analysis. Why would some patients have nodal sampling while the majority does not? It is likely that in patients who had nodes sampled, surgeons must have identified a reason to sample nodes, possibly increase in size of a lymph node. It is likely that the true incidence of nodal metastases is lower than the reported by Weksler et al. Both Kondo’s and Weksler’s studies should be viewed with relative suspicion, as both are based on retrospective database without confirmation of pathology, besides other well-known deficiencies of large retrospective databases.

A somewhat higher quality data was offered by Park and colleagues (9) which looked retrospectively at 37 patients with thymic carcinoma, 8 had no node dissection (Nx), 13 had limited node dissection and were N0, 10 had extensive node dissection and were N0, and 6 had nodal metastasis (N1). Twenty-nine patients had node dissection and the average nodal yield was 9.4. Six patients had nodal metastases to 19 nodes. The authors confirmed that nodal metastases were more common in patients who had invasion of adjacent organs, and interestingly, the majority of metastases were to the right paratracheal area, independent of the location of the tumor. The incidence of nodal metastases in this cohort of patients was 16.2% (6/37), but if only those patients who had nodal sampling are included, the incidence raises to 20.7% (6/29), a number not far from Kondo’s study, but still significantly lower than Weksler’s studies.

Recently, Gu and colleagues from the Chinese Alliance for Research in Thymoma (10) presented their work on the incidence of nodal metastases in patients with TET. Utilizing a large database maintained by the Chinese Alliance for Research in Thymoma, the authors identified 1,617 eligible cases, the majority (1,310, 81.0%) being thymomas. There were 265 (16.4%) patients with thymic carcinoma, and 42 (2.6%) with thymic neuroendocrine tumors. The overall incidence of nodal metastases was 2.2% and more specifically 0.5% in thymomas, 7.9% in thymic carcinomas, and 16.7% in thymic neuroendocrine tumors. Multivariable analysis showed that tumors other than thymomas, and T stage above T1 were risk for nodal metastases. Although survival was significantly lower in patients with nodal metastases, multivariable analysis revealed that only complete resection and histological grade were factors significantly affecting survival, while nodal status did not make the final multivariable model.

The study of Gu et al. adds important information to the current body of literature, mainly the very low incidence of nodal metastases in patient with thymoma. However, the study is fraught with the usual problems of a large retrospective database. The main piece of data that is missing is the number of lymph nodes harvested in patients with and without nodal metastases. It is well known from other thoracic malignancies that the incidence of nodal metastases increases with increasing number of harvested nodes. Is it possible that there were patients (in particular with thymic carcinoma and thymic neuroendocrine tumors) that had occult microscopic metastases to lymph nodes that were not detected during surgery as nodal sampling was not done? What is the prognostic implication of micrometastases? Finally, as in previous database studies, it is likely that pathology was not reviewed for all patients and there is data to suggest a significant disagreement among pathologists when it comes to the differentiation of B2 thymomas from B3, and B3 from thymic carcinoma (11,12).

The only way to know for sure the true incidence of nodal metastases in TET is with a prospective study in which all patients undergo a preset minimal nodal sampling, regardless of suspicious nodes on preoperative imaging, while standardizing the pathologic diagnosis and having pathology reviewed by at least two pathologists. Due to the rarity of the disease, this can and should be done within the aegis of a large multinational organization such as the ITMIG, which will allow collection of data prospectively and hopefully accrue patients at an expeditious pace. Until then, retrospective database studies will be unlikely to provide better data than what is already available in the literature.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned and reviewed by Section Editor Dr. Zhuoqi Jia (Thoracic Department, the First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China).

Conflicts of Interest: The author has completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/med.2017.10.08). The author is a proctor for Intuitive Surgery. 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. Travis WD, Brambilla E, Burke AP, et al. WHO Classification of Tumours of the Lung, Pleura, Thymus and Heart. 4th edition. WHO Classification of Tumours, 2015.
2. 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]
3. Detterbeck FC, Stratton K, Giroux D, et al. 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. J Thorac Oncol 2014;S65-72. [Crossref] [PubMed]
4. Bhora FY, Chen DJ, Detterbeck FC, et al. The ITMIG/IASLC Thymic Epithelial Tumors Staging Project: A Proposed Lymph Node Map for Thymic Epithelial TUmors in the Forthcoming 8th Edition of the TNM Classification of Malignant Tumors. J Thorac Oncol 2014;9:S88-96.
5. Kondo K, Monden Y. Therapy for thymic epithelial tumors: a clinical study of 1,320 patients from Japan. Ann Thorac Surg 2003;76:878-84; discussion 884-5. [Crossref] [PubMed]
6. Kondo K, Monden Y. Lymphogenous and hematogenous metastasis of thymic epithelial tumors. Ann Thorac Surg 2003;76:1859-64. [Crossref] [PubMed]
7. Weksler B, Pennathur A, Sullivan JL, et al. Resection of thymoma should include nodal sampling. J Thorac Cardiovasc Surg 2015;149:737-42. [Crossref] [PubMed]
8. Weksler B, Holden A, Sullivan JL. Impact of Positive Nodal Metastases in Patients with Thymic Carcinoma and Thymic Neuroendocrine Tumors. J Thorac Oncol 2015;10:1642-7. [Crossref] [PubMed]
9. Park IK, Kim YT, Jeon JH, et al. Importance of lymph node dissection in thymic carcinoma. Ann Thorac Surg 2013;96:1025-32; discussion 1032. [Crossref] [PubMed]
10. Gu Z, Wei Y, Fu J, et al. Lymph node metastases in thymic malignancies: a Chinese Alliance for Research in Thymomas retrospective database analysis. Interact Cardiovasc Thorac Surg 2017;25:455-61. [PubMed]
11. Roden AC, Yi ES, Cassivi SD, et al. Clinicopathological features of thymic carcinomas and the impact of histopathological agreement on prognostical studies. Eur J Cardiothorac Surg 2013;43:1131-9. [Crossref] [PubMed]
12. Verghese ET, den Bakker MA, Campbell A, et al. Interobserver variation in the classification of thymic tumours--a multicentre study using the WHO classification system. Histopathology 2008;53:218-23. [Crossref] [PubMed]