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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

2014; Elsevier BV; Volume: 9; Issue: 9 Linguagem: Inglês

10.1097/jto.0000000000000293

1556-1380

Faiz Y. Bhora, David J. Chen, Frank Detterbeck, Hisao Asamura, Conrad Falkson, Pier Luigi Filosso, Giuseppe Giaccone, James Huang, Young Tae Kim, Kazuya Kondo, Marco Lucchi, Mirella Marino, Edith M. Marom, Andrew G. Nicholson, Meinoshin Okumura, Enrico Ruffini, Paul Van Schil, Peter Goldstraw, Ramón Rami–Porta, David Ball, David G. Beer, Ricardo Guijarro, Vanessa Bolejack, Kari Chansky, John Crowley, Wilfried Eberhardt, John Edwards, Françoise Galateau-Sallé, Dorothy J. Giroux, Fergus Gleeson, Patti A. Groome, Catherine J. Kennedy, Young Tae Kim, Laura Kingsbury, Haruhiko Kondo, Mark Krasnik, Kaoru Kubota, Antoon Lerut, Gustavo Lyons, Jan P. van Meerbeeck, Alan Mitchell, Takashi Nakano, Anna K. Nowak, Michael Peake, Thomas W. Rice, Kenneth E. Rosenzweig, Valerie W. Rusch, Nagahiro Saijo, Jean Paul Sculier, Lynn Shemanski, Kelly Stratton, Kenji Suzuki, Yuji Tachimori, Charles F. Thomas, William D. Travis, Ming‐Sound Tsao, Andrew Turrisi, Johan Vansteenkiste, Hirokazu Watanabe, Yi‐Long Wu, Paul Baas, Jeremy J. Erasmus, Seiki Hasegawa, Kouki Inai, Kemp H. Kernstine, Hedy L. Kindler, Lee M. Krug, Kristiaan Nackaerts, Harvey I. Pass, David C. Rice, Eugene H. Blackstone,

Salivary Gland Tumors Diagnosis and Treatment

Although the presence of nodal disease is prognostic in thymic malignancy, the significance of the extent of nodal disease has yet to be defined. Lymph node dissection has not been routinely performed, and there is currently no node map defined for thymic malignancy. To establish a universal language for reporting as well as characterize the staging of this disease more accurately, an empiric node map is proposed here. This was developed using prior classification systems, series reporting specifics of nodal involvement, anatomical studies of lymphatic drainage, and preexisting node maps of the chest as defined by the International Association for the Study of Lung Cancer and the neck as defined by the American Academy of Otolaryngology—Head and Neck Surgery and the American Society for Head and Neck Surgery. The development of this node map was a joint effort by the International Thymic Malignancy Interest Group and the Thymic Domain of the IASLC Staging and Prognostic Factors Committee. It was reviewed and subsequently approved by the members of ITMIG. This map will be used as an adjunct to define node staging as part of a universal stage classification for thymic malignancy. As more data are gathered using definitions set forth by this node map, a revision may be undertaken in the future. Although the presence of nodal disease is prognostic in thymic malignancy, the significance of the extent of nodal disease has yet to be defined. Lymph node dissection has not been routinely performed, and there is currently no node map defined for thymic malignancy. To establish a universal language for reporting as well as characterize the staging of this disease more accurately, an empiric node map is proposed here. This was developed using prior classification systems, series reporting specifics of nodal involvement, anatomical studies of lymphatic drainage, and preexisting node maps of the chest as defined by the International Association for the Study of Lung Cancer and the neck as defined by the American Academy of Otolaryngology—Head and Neck Surgery and the American Society for Head and Neck Surgery. The development of this node map was a joint effort by the International Thymic Malignancy Interest Group and the Thymic Domain of the IASLC Staging and Prognostic Factors Committee. It was reviewed and subsequently approved by the members of ITMIG. This map will be used as an adjunct to define node staging as part of a universal stage classification for thymic malignancy. As more data are gathered using definitions set forth by this node map, a revision may be undertaken in the future. For many decades, little progress has been made in outcomes of patients with thymic malignancies. As an orphan disease, it has proven difficult to assemble a large series of patients to establish an evidence base. A further problem has been a lack of clear definitions of terms. This issue hampers communication between centers and the ability to compare and combine data. The International Thymic Malignancies Interest Group (ITMIG) was created to provide infrastructure to overcome these hurdles. ITMIG conducted several international workshops and developed standard definitions of terms and policies that were overwhelmingly endorsed by the ITMIG membership. ITMIG has also partnered with the International Association for the Study of Lung Cancer (IASLC) to develop proposals for a validated stage classification system. To date, 15 major stage classification systems have been proposed, with most being relatively empiric based on a small number of patients. ITMIG and IASLC have brought together the global community and amassed a database of more than 10,000 patients to inform the stage classification proposals. There is a need to develop a universally accepted definition of areas of nodal involvement from thymic malignancies. Unfortunately, the large database assembled for the stage classification project is retrospective, and details regarding which nodes were involved are vague. To gather data for a more accurate assessment, it is necessary to establish a consistent starting point, similar to the development of other standards that ITMIG has undertaken in this disease. Therefore, ITMIG established a workgroup to accomplish this and combined this effort with the Thymic Domain of the IASLC Staging and Prognostic Factors Committee (TD-SPFC). This article is the result of this effort. An initial core workgroup was assembled to review existing literature that was relevant to a node classification system for thymic malignancies (David Chen, Faiz Bhora, and Frank Detterbeck). This included in broad terms, previously proposed classification systems, series reporting specifics of nodal involvement, existing maps for other spatially related tumors (i.e., lung, laryngotracheal, and oropharyngeal cancers), and anatomical studies of the lymphatic drainage of the mediastinum. Based on this review, the core workgroup formulated preliminary recommendations, which were further discussed at a meeting of the large diverse international group of specialists at the 2013 ITMIG annual meeting (Bethesda, MD, September 2013). The ensuing proposals were further refined by the TD-SPFC, which functioned as an extended workgroup (Hisao Asamura, Conrad Falkson, Pier Luigi Filosso, Giuseppe Giaccone, James Huang, Jhingook Kim, Kazuya Kondo, Marco Lucchi, Mirella Marino, Edith Marom, Andrew Nicholson, Meinoshin Okumura, Enrico Ruffini, and Paul van Schil). Funding for the TD-SPFC was provided by IASLC. Comments were also sought from the entire ITMIG membership, which represents the vast majority of investigators active in this disease, in keeping with an ITMIG process for the development and acceptance of proposed standards. This process also included eventual formal approval by the members of ITMIG for adoption going forward as the standard to follow. Because no data was available to analyze relative to the node map beyond what the TD-SPFC performed for T, N and M components of the proposed thymic stage classification (reported elsewhere), Cancer Research And Biostatistics (CRAB) and the full IASLC SPFC committees and advisory boards encompassing all thoracic disease sites were only indirectly involved. Input was specifically sought out from the TNM committee of the Japan Lung Cancer Society (Jun Nakjima, Masaki Hara, Kazuya Kondo, Meinoshin Okumura, Yoshihiro Matsuno, Motoki Yano), because of the work that this group and others in Japan have done to investigate the impact of nodal involvement in thymic malignancies. After careful evaluation of all input, the final node classification system was defined as presented in this article. An official, universally accepted staging system has not been available for thymic epithelial tumors. Previously proposed thymic stage classification systems have been recently summarized.1Filosso PL Ruffini E Lausi PO Lucchi M Oliaro A Detterbeck F Historical perspectives: the evolution of the thymic epithelial tumors staging system.Lung Cancer. 2014; 83: 126-132Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar The most widely accepted system is the Masaoka classification, initially established in 1981 and modified in 1994 by Koga et al.2Koga 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: 359-367Crossref PubMed Scopus (366) Google Scholar The four-tiered Masaoka-Koga system stratifies stages I to IVA based on tumor stage/extent of invasion, whereas stage IVB is reserved for nodal and distant metastasis combined; this was endorsed by the International Thymic Malignancy Interest Group (ITMIG) in 2011.3Detterbeck FC Nicholson AG Kondo K Van Schil P Moran C The Masaoka-Koga stage classification for thymic malignancies: clarification and definition of terms.J Thorac Oncol. 2011; 6: S1710-S1716Abstract Full Text Full Text PDF PubMed Scopus (256) Google Scholar,4Huang J Detterbeck FC Wang Z Loehrer Sr, PJ Standard outcome measures for thymic malignancies.J Thorac Oncol. 2011; 6: S1691-S1697Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar The Masaoka-Koga system seems to be a good predictor of prognosis for thymoma, the most common thymic epithelial tumor; however, it may not be as accurate for staging thymic carcinoma and neuroendocrine tumors of the thymus.5Kondo K Monden Y Lymphogenous and hematogenous metastasis of thymic epithelial tumors.Ann Thorac Surg. 2003; 76: 1859-1865Abstract Full Text Full Text PDF PubMed Scopus (123) Google Scholar,6Kondo K Tumor-node metastasis staging system for thymic epithelial tumors.J Thor Onc. 2010; 5: S352-S356Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar Despite sharing anatomical origin, thymomas are clinicopathologically distinct from thymic carcinomas and neuroendocrine tumors of the thymus; nodal metastasis is rare in the former, more common in the latter. Four thymic classification systems have defined N subgroups, summarized in Table 1. The Yamakawa/Masaoka7Yamakawa Y Masaoka A Hashimoto T et al.A tentative tumor-node-metastasis classification of thymoma.Cancer. 1991; 68: 1984-1987Crossref PubMed Scopus (160) Google Scholar and National Cancer Center Hospital of Japan8Tsuchiya R Koga K Matsuno Y Mukai K Shimosato Y Thymic carcinoma: proposal for pathological TNM and staging.Pathol Int. 1994; 44: 505-512Crossref PubMed Scopus (77) Google Scholar systems are the same with respect to definition of the N subgroups (they differ in the T definitions and the stage groupings). The World Health Organization Consensus Committee9Travis WD Brambilla E Muller-Hermelink HK Harris CCKleihues P Sobin LH Pathology and genetics of tumors of the lung, pleura, thymus and heart. WHO Classification of Tumors. 2nd Ed. IARC Press, Lyon2004: 5-15Google Scholar and the Istituto Nazionale Tumori10Bedini AV Andreani SM Tavecchio L et al.Proposal of a novel system for the staging of thymic epithelial tumors.Ann Thorac Surg. 2005; 80: 1994-2000Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar systems are also almost identical to one another. Overall, the primary difference in these systems is that the more recent ones specify specific neck nodes as N3 instead of simply grouping all extrathoracic nodes together. Specific definitions of anatomic boundaries of the nodal regions were not provided in these manuscripts.TABLE 1Thymic Malignancy Classification SystemsYamakawaNCCHJWHOINTN0No lymph node metastasisNo lymph node metastasisNo lymph node metastasisNo lymph node metastasisN1Metastasis to anterior mediastinal lymph nodesMetastasis to anterior mediastinal lymph nodesMetastasis to anterior mediastinal lymph nodesMetastasis to anterior mediastinal lymph nodesN2Metastasis to intrathoracic lymph nodes except anterior mediastinal lymph nodesMetastasis to intrathoracic lymph nodes excluding anterior mediastinal lymph nodesMetastasis to other intrathoracic lymph nodes excluding anterior mediastinal lymph nodesMetastasis to intrathoracic lymph nodes other than anterior mediastinal lymph nodesN3Metastasis to extrathoracic lymph nodesMetastasis to extrathoracic lymph nodesMetastasis to scalene and/or supraclavicular lymph nodesMetastasis to prescalene or supraclavicular lymph nodesNCCHJ, National Cancer Center Hospital of Japan; WHO, World Health Organization; INT, Istituto Nazionale Tumori. Open table in a new tab NCCHJ, National Cancer Center Hospital of Japan; WHO, World Health Organization; INT, Istituto Nazionale Tumori. A review of 1320 thymic epithelial tumors by Kondo6Kondo K Tumor-node metastasis staging system for thymic epithelial tumors.J Thor Onc. 2010; 5: S352-S356Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar revealed a 3.2% incidence of lymphogenous and/or distant metastasis (stage IVB) in patients with thymoma, and a 33% incidence of such metastases in thymic carcinoma patients. He also calculated significant 5-year survival differences between stages IVA and IVB (p = 0.019 for overall, p = 0.023 tumor-specific 5-year survival). This indicates that the presence of nodal or distant metastasis influences prognosis, warranting further investigation. Anterior mediastinal lymph nodes seem to be the primary drainage basin for thymic epithelial tumors. This has been determined based on frequency and pattern of metastasis in addition to anatomical location (however, thymic carcinomas may exhibit skip metastases). If there is nodal involvement, these are located in the anterior mediastinum in approximately 90% in thymomas, 70% in thymic carcinomas, and 90% in neuroendocrine tumors of the thymus.5Kondo K Monden Y Lymphogenous and hematogenous metastasis of thymic epithelial tumors.Ann Thorac Surg. 2003; 76: 1859-1865Abstract Full Text Full Text PDF PubMed Scopus (123) Google Scholar Kondo et al also subclassified stage IVB into IVBi (TanyN1M0), IVBii (TanyN2-3M0), and IVBiii (TanyNanyM1), but found no differences in 5-year survival (p = 0.24 between IVA and IVBi, p = 0.25 between IVBi and IVBii, and p = 0.52 between IVBii and IVBiii).6Kondo K Tumor-node metastasis staging system for thymic epithelial tumors.J Thor Onc. 2010; 5: S352-S356Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar The small size of these subgroups (IVBi n = 25, IVBii n= 25, and IVBiii n = 26) undermines the ability to assess statistical significance; however, there was a trend toward improved survival for the N1 group compared with the N2/N3 group. In addition, there may have been unresectable stage IVB cases that were not included in the database provided by the member surgeons of the Japanese Association for Chest Surgery. Although the mere presence of nodal disease has prognostic influence, the prognostic effect of characteristics of metastasis such as location, number of nodes, number of stations, presence of angiolymphatic invasion, perineural involvement, and extracapsular involvement remains to be determined. . An extensive literature search reveals that there is no established lymph node nomenclature delineating the anterior mediastinal nodes other than the N staging systems presented in Table 1.7Yamakawa Y Masaoka A Hashimoto T et al.A tentative tumor-node-metastasis classification of thymoma.Cancer. 1991; 68: 1984-1987Crossref PubMed Scopus (160) Google Scholar, 8Tsuchiya R Koga K Matsuno Y Mukai K Shimosato Y Thymic carcinoma: proposal for pathological TNM and staging.Pathol Int. 1994; 44: 505-512Crossref PubMed Scopus (77) Google Scholar, 9Travis WD Brambilla E Muller-Hermelink HK Harris CCKleihues P Sobin LH Pathology and genetics of tumors of the lung, pleura, thymus and heart. WHO Classification of Tumors. 2nd Ed. IARC Press, Lyon2004: 5-15Google Scholar, 10Bedini AV Andreani SM Tavecchio L et al.Proposal of a novel system for the staging of thymic epithelial tumors.Ann Thorac Surg. 2005; 80: 1994-2000Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar There were, however, several sources that were helpful in identifying mediastinal nodes and drainage patterns: 1.Caplan11Caplan I Anatomical review of the lymph nodes of the human mediastinum.Surg Radiol Anat. 1990; 12: 9-18Crossref PubMed Scopus (30) Google Scholar: Classification of the human mediastinum based upon a longitudinal series of 984 autopsies over 17 years. Injection of hydrogen peroxide was used to delineate lymphatic drainage in cadaveric subjects. Of particular note, the anterior mediastinum was determined to contain five major node groups on the right and six major node groups on the left: right and left superior internal thoracic, right and left brachiocephalic, right superior phrenic (superior precaval), left superior phrenic (preaortic), right inferior phrenic (inferior precaval), left inferior phrenic (prepericardial), azygos arch, aortic arch/pulmonary artery, and left superior vagal/preaortic subclavian-carotid chain.2.Murakami et al12Murakami G Sato T Takiguchi T Topographical anatomy of the bronchomediastinal lymph vessels: their relationships and formation of the collecting trunks.Arch Histol Cytol. 1990; 53: 219-235Crossref Scopus (26) Google Scholar: Classification of bronchomediastinal collecting vessels based on cadaveric dissection of eight subjects. The authors observed consistent lymphatic trunks, or large collecting vessels, on the right in an anterior and posterior pathway, and variable trunks on the left in a superior and inferior pathway with three consistent contributory node groups. In particular, the divisions on the right included the right brachiocephalic and anterior/posterior mediastinal trunks, whereas the divisions on the left included the uppermost paratracheal nodes, anterior mediastinal nodes (surrounding the phrenic nerve anterior and inferior to the aortic arch), and the left tracheobronchial nodes. They also observed a prominent communicating vessel between the right and left systems situated anterior to the trachea and above the aortic arch; it was often associated with the brachiocephalic angle nodes. Altogether, the results suggested prominence of the following nodal groups: brachiocephalic angle, right/left venous angles (jugulo-subclavian junction), phrenic, paratracheal, and tracheobronchial.3.Gregoire et al13Gregoire V Scalliet P Ang K Clinical Target Volumes in Conformal and Intensity Modulated Radiation Therapy: a Clinical Guide to Cancer Treatment. Springer, BerlinNovember 2003: 14-18Google Scholar: Description of anatomic and functional mediastinal drainage pathways as it relates to clinical target volumes for radiation therapy in cancer treatment. The thorax is divided into four major compartments: parasternal, brachiocephalic, intertracheobronchial, and posterior mediastinal. The parasternal area is defined craniocaudally by the sternoclavicular joints and the xiphoid, and in an anterior/posterior plane by the deep surface of the sternum to the transversus thoracis, respectively. The brachiocephalic area includes the anterior mediastinal fat and the area anterior to the great vessels; craniocaudally, its boundaries are the clavicle and T6, and its lateral boundaries are the right and left mediastinal pleura. In addition, the entire thorax was functionally classified into an anterior, central, and posterior stream. The anterior stream includes the parasternal and brachiocephalic compartments and unites with the central (primarily tracheobronchial) stream in the superior mediastinum to form the common bronchomediastinal trunks. In the IASLC lung cancer node map proposal,14Rusch VW Asamura H Watanabe H Giroux DJ Rami-Porta R Goldstraw P Members of IASLC Staging Committee. The IASLC lung cancer staging project: a proposal for a new international lymph node map in the forthcoming seventh edition of the TNM classification for lung cancer.J Thorac Oncol. 2009; 4: 568-577Abstract Full Text Full Text PDF PubMed Scopus (854) Google Scholar the workgroup notably identified that lymph node drainage in the superior mediastinum converges over the right paratracheal area and extends across the midline toward the left. Appropriately, the demarcation between right and left in terms of levels 2 and 4 needed not lie over the midline trachea, but instead to the left lateral border of the trachea. A recent retrospective review by Park et al15Park IK Kim YT Jeon JH et al.Importance of lymph node dissection in thymic carcinoma.Ann Thorac Surg. 2013; 96: 1025-1032Abstract Full Text Full Text PDF PubMed Scopus (29) Google Scholar corroborates this—metastasis was mainly found in the right paratracheal nodes, and they recommended dissection of 10 or more lymph nodes in the anterior mediastinum and the right paratracheal area in thymic carcinoma. The American Academy of Otolaryngology—Head and Neck Surgery/American Society for Head and Neck Surgery (AAO-HNS/ASHNS) node map16Robbins KT Clayman G Levine PA American Head and Neck Society; American Academy of Otolaryngology–Head and Neck Surgery et al.Neck dissection classification update: revisions proposed by the American Head and Neck Society and the American Academy of Otolaryngology-Head and Neck Surgery.Arch Otolaryngol Head Neck Surg. 2002; 128: 751-758Crossref PubMed Scopus (714) Google Scholar (established in 1991, updated in 2002) provides a correlate for neck lymph nodes as it relates to superior mediastinal tumors. The anterior lower neck is of particular interest as selective neck dissection of this region is indicated for thyroid cancer and cervical esophageal/tracheal cancer. These lymph nodes consist of paratracheal, precricoid (Delphian), and perithyroidal/recurrent laryngeal nodes. The node map that was developed is a functional demarcation of mediastinal regions that incorporates retrospective data, preexisting node classifications in the IASLC map and the AAO-HNS/ASHNS map, and prominent nodes defined by prior studies.11Caplan I Anatomical review of the lymph nodes of the human mediastinum.Surg Radiol Anat. 1990; 12: 9-18Crossref PubMed Scopus (30) Google Scholar, 12Murakami G Sato T Takiguchi T Topographical anatomy of the bronchomediastinal lymph vessels: their relationships and formation of the collecting trunks.Arch Histol Cytol. 1990; 53: 219-235Crossref Scopus (26) Google Scholar, 13Gregoire V Scalliet P Ang K Clinical Target Volumes in Conformal and Intensity Modulated Radiation Therapy: a Clinical Guide to Cancer Treatment. Springer, BerlinNovember 2003: 14-18Google Scholar Retrospective data and current N staging systems7Yamakawa Y Masaoka A Hashimoto T et al.A tentative tumor-node-metastasis classification of thymoma.Cancer. 1991; 68: 1984-1987Crossref PubMed Scopus (160) Google Scholar, 8Tsuchiya R Koga K Matsuno Y Mukai K Shimosato Y Thymic carcinoma: proposal for pathological TNM and staging.Pathol Int. 1994; 44: 505-512Crossref PubMed Scopus (77) Google Scholar, 9Travis WD Brambilla E Muller-Hermelink HK Harris CCKleihues P Sobin LH Pathology and genetics of tumors of the lung, pleura, thymus and heart. WHO Classification of Tumors. 2nd Ed. IARC Press, Lyon2004: 5-15Google Scholar, 10Bedini AV Andreani SM Tavecchio L et al.Proposal of a novel system for the staging of thymic epithelial tumors.Ann Thorac Surg. 2005; 80: 1994-2000Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar describe anterior mediastinal nodes as the primary drainage pathway and intrathoracic nodes excluding the anterior mediastinum as the secondary drainage pathway. Two major regions are defined by the map: anterior and deep. The most logical method of describing regions is based on the boundaries that define the peripheral extent of dissection in all axes; this reflects the method used for thymic dissection in which the specimen is removed en bloc. It is sometimes challenging to orient visceral anatomical landmarks relative to the thymus during dissection in vivo, and it is even more difficult to do so once the specimen has been explanted from the patient. Given that prognostic importance to particular regions has not been demonstrated, it seems more practical not to complicate the system by subdividing nodes beyond what is encompassed by an extensive en bloc resection as described. There may be more evidence to perform dedicated lymph node dissections15Park IK Kim YT Jeon JH et al.Importance of lymph node dissection in thymic carcinoma.Ann Thorac Surg. 2013; 96: 1025-1032Abstract Full Text Full Text PDF PubMed Scopus (29) Google Scholar in thymic carcinoma, but such nodes can be defined within these proposed regions. Similarly, the issue of laterality in node metastasis is not well defined. As aforementioned, there is data that suggest prominence of right paratracheal nodes in node-positive cases. Aside from that, however, there is no evidence to support the significance of laterality in other node stations. Prominent nodes defined uniformly by Caplan,11Caplan I Anatomical review of the lymph nodes of the human mediastinum.Surg Radiol Anat. 1990; 12: 9-18Crossref PubMed Scopus (30) Google Scholar Murakami et al,12Murakami G Sato T Takiguchi T Topographical anatomy of the bronchomediastinal lymph vessels: their relationships and formation of the collecting trunks.Arch Histol Cytol. 1990; 53: 219-235Crossref Scopus (26) Google Scholar and Gregoire et al13Gregoire V Scalliet P Ang K Clinical Target Volumes in Conformal and Intensity Modulated Radiation Therapy: a Clinical Guide to Cancer Treatment. Springer, BerlinNovember 2003: 14-18Google Scholar are included and distributed to the appropriate regions in this map ([1] low cervical/sternal notch, [2] venous angle: left and right, [3] brachiocephalic angle, [4] tracheobronchial: left and right, [5] paraaortic, [6] subaortic, [7] superior phrenic: left and right (preaortic/precaval), and [8] inferior phrenic: left and right). The anterior region (N1) (Table 2, FIGURE 1, FIGURE 2, FIGURE 3, FIGURE 4, FIGURE 5, FIGURE 6) encompasses the space surrounding the thymus that is anterior to the pericardium and great vessels, extending from the hyoid bone superiorly to the diaphragm inferiorly and between the mediastinal pleura. The anterior region extends from the back of the sternum anteriorly; the posterior border is the pericardium in the middle and the level of the phrenic nerves in the lateral aspects of the mediastinum. These boundaries reflect the conventional dissection performed in extended thymectomy (dissection of contiguous left and right mediastinal pleura, mediastinal, and pericardiophrenic fatty tissues and dissection of paraaortic [IASLC level 6] nodes in addition to complete removal of thymus).17Toker A Sonett J Zielinski M Rea F Tomulescu V Detterbeck FC Standard terms, definitions, and policies for minimally invasive resection of thymoma.J Thorac Oncol. 2011; 6: S1739-S1742Abstract Full Text Full Text PDF PubMed Scopus (119) Google Scholar The computed tomography images in the figures demonstrate the posterior floor of the anterior region in several representative sections. In those anatomical sections not represented by these figures, radiologists should follow the guideline of demarcating the regions by the peripheral extent of conventional surgical dissection as previously mentioned.TABLE 2Anterior Region (N1) (Anterior Mediastinal and Anterior Cervical Nodes)Region BoundariesNode Groups14,16Node Group BoundariesSup: Hyoid BoneLow Ant Cervical: Pretracheal, Paratracheal, Peri-thyroid, Sup: inferior border of cricoidLat: common carotid arteriesLat (Neck): Medial Border of Carotid SheathsPrecricoid/Delphian (AAO-HNS / ASHNS Level 6 / IASLC Level 1)Inf: superior border of manubriumLat (Chest): Mediastinal PleuraPeri-ThymicProximity to thymusAnt: SternumPrevascular (IASLC Level 3a) Sup: apex of chestAnt: posterior sternumPost (Medially): Great Vessels, Pericardium Post: anterior SVCInf: carinaPost (Laterally): Phrenic NerveParaaortic, Ascending Aorta, Superior Phrenics Sup: line tangential to sup border of aortic archInf: inf border of aortic archInf: Xiphoid, diaphragm(IASLC Level 6)Supradiaphragmatic / Inferior Phrenics / Pericardial (along inferior poles of thymus) Sup: inf border of aortic arch Ant: post sternumPost: phrenic nerve (laterally) or pericardium (medially)Inf: diaphragmRegion and node group boundaries adapted directly from definitions established by AAO-HNS, ASHNS, and IASLC.AAO-HNS, American Academy of Otolaryngology—Head and Neck Surgery; ASHNS, American Society for Head and Neck Surgery; IASLC, International Association for the Study of Lung Cancer; sup, superior; ant, anterior; inf, inferior; lat, lateral; post, posterior; SVC, superior vena cava. Open table in a new tab FIGURE 2Thoracic inlet, axial section. Anterior region (blue) and deep region (purple). CCA, common carotid artery; IJV, internal jugular vein; Tr, trachea; Clav, clavicle; E, esophagus.View Large Image Figure ViewerDownload (PPT)FIGURE 3Paraaortic level, axial section. Anterior region (blue) and deep region (purple). SVC, superior vena cava; E, esophagus; Tr, trachea.View Large Image Figure ViewerDownload (PPT)FIGURE 4Aortopulmonary window level, axial section. Anterior region (blue) and deep region (purple). Note: deep region includes aortopulmonary window nodes. AA, ascending aorta; DA, descending aorta; LPA, left pulmonary artery; SVC, superior vena cava; Az, azygos vein; RB, right main bronchus; LB, left main bronchus.View Large Image Figure ViewerDownload (PPT)FIGURE 5Carina level, axial section. Anterior region (blue) and deep region (purple). Note: deep region includes aortopulmonary window nodes. AA, ascending aorta; DA, descending aorta; PT, pulmonary trunk; LPA, left pulmonary artery; RPA, right pulmonary artery; SVC, superior vena cava; LSPV, left superior pulmonary vein; BR, bronchus; E, esophagus.View Large Image Figure ViewerDownload (PPT)FIGURE 6Diaphragm level, axial section. Anterior region (blue) and deep region (purple). RV, right ventricle; LV, left ventricle; IVC, inferior vena cava; DA, descending aorta; E, esophagus.View Large Image Figure ViewerDownload (PPT) Region and node group boundaries adapted directly from definitions established by AAO-HNS, ASHNS, and IASLC. AAO-HNS, American Academy of Otolaryngology—Head and Neck Surgery; ASHNS, American Society for Head and Neck Surgery; IASLC, International Association for the Study of Lung Cancer; sup, superior; ant, anterior; inf, inferior; lat, lateral; post, posterior; SVC, superior vena cava. This region includes anterior mediastinal nodes (perithymic, prevascular, paraaortic, and supradiaphragmatic nodes) and anterior cervical nodes (as conventionally defined by level 6 of the AAO-HNS/ASHNS classification). The term perithymic nodes is meant for lymph nodes immediately adjacent to the thymus that are not captured in one of the other categories (which were developed with lung cancer in mind). In the area of the great vessels, the posterior boundary of this region includes paraaortic nodes (IASLC level 6) but not aortopulmonary window nodes (IASLC level 5). Therefore, the posterior border of the anterior region is defined as the anterior border of the aortopulmonary window (Figures 4 and 5). The internal mammary nodes are excluded from this region (and allocated instead to the deep region) because they are rarely dissected in practice and there is no evidence to support the significance of disease in this area in thymic malignancy. The deep region (N2) (Table 3, FIGURE 1, FIGURE 2, FIGURE 3, FIGURE 4, FIGURE 5, FIGURE 6) describes the space distant to the anterior region within the mediastinum. It is situated posterior to the anterior mediastinum, anterior to the esophagus, and among the pulmonary hila; it extends into the neck on either side of the anterior cervical nodes.TABLE 3Deep Region (N2) (Middle Mediastinal and Deep Cervical Nodes)Region BoundariesNode Groups14,16Node Group BoundariesSup: Level of lower border of cricoid cartilageLower Jugular (AAO-HNS / ASHNS Level 4) Sup: Level of lower border of cricoid cartilageAnteromedial: lat border of sternohyoidPosterolateral: lat border of sternocleidomastoid Inf: clavicleAnteromedial (Neck): Lateral Border of Sternohyoid, Medial Border of Carotid SheathSupraclavicular/Venous Angle: Confluence of Internal Jugular & Subclavian Vein (AAO-HNS / ASHNS Level 5b) Sup: Level of lower border of cricoid cartilageAnteromedial: post border of sternocleidomastoidPosterolateral (Neck): Anterior Border of TrapeziusPosterolateral: ant border of trapezius Inf: clavicleInternal Mammary nodesProximity to internal mammary arteriesAnt (Chest): Aortic Arch, Aortopulmonary Window – Ant Border of SVCUpper Paratracheal (IASLC Level 2) Sup: sup border of manubrium, apices of lungsInf: intersection of lower border of innominate vein with trachea; sup border of aortic archPost (Chest): EsophagusLower Paratracheal (IASLC Level 4) Sup: intersection of lower border of innominate vein with trachea; sup border of aortic archInf: lower border of azygos vein, sup border of left main pulmonary arteryLat (Chest): Pulmonary HilaInf: DiaphragmSubaortic / Aortopulmonary Window (IASLC Level 5) Sup: inf border of aortic archInf: sup border of left main pulmonary arterySubcarinal (IASLC Level 7) Sup: carinaInf: upper border of lower lobe bronchus on the left; lower border of the bronchus intermedius on the rightHilar (IASLC Level 10) Sup: lower rim of azygos vein on right, upper rim of pulmonary artery on leftInf: interlobar region bilaterallyRegion and node group boundaries adapted directly from definitions established by AAO-HNS, ASHNS, and IASLC.AAO-HNS, American Academy of Otolaryngology—Head and Neck Surgery; ASHNS, American Society for Head and Neck Surgery; IASLC, International Association for the Study of Lung Cancer; sup, superior; ant, anterior; inf, inferior; lat, lateral; post, posterior; SVC, superior vena cava. Open table in a new tab Region and node group boundaries adapted directly from definitions established by AAO-HNS, ASHNS, and IASLC. AAO-HNS, American Academy of Otolaryngology—Head and Neck Surgery; ASHNS, American Society for Head and Neck Surgery; IASLC, International Association for the Study of Lung Cancer; sup, superior; ant, anterior; inf, inferior; lat, lateral; post, posterior; SVC, superior vena cava. This region includes tracheobronchial and aortopulmonary window nodes (as defined by the IASLC node map), internal mammary nodes, deep cervical nodes, and supraclavicular nodes (as defined by the AAO-HNS map). The aortopulmonary window nodes are included in the deep region. These nodes are posterior to the phrenic nerve and not always included in the field of dissection; also, there is no data to support specific prognostic significance of nodal disease in this area. Also, although internal mammary nodes are anatomically separate from the rest of the deep region, they are rarely positive for nodal disease and thus, they can be regarded as pathologically "distant." All nodes not defined by the anterior and deep regions are considered to be extrathoracic metastases (M1). These may include nodal disease in the axillary, retroperitoneal, or inguinal lymph node regions. Lymph node involvement carries prognostic significance. However, definition of the importance of the location or extent of nodal involvement is not possible at this time. There is insufficient data; moreover, there are numerous proposed TNM staging systems that describe N1, N2, and N3 in generic terms that are open to interpretation. The development of worldwide standards through the efforts of ITMIG, the collection of prospective data in the ITMIG database, and the anticipated implementation of an official uniform stage classification system provides an opportunity to gather the data needed to assess the impact of details of node involvement. A prerequisite is the availability of a method to classify nodes in a consistent manner. We can only advance our knowledge as much as our existing framework allows. The division of the mediastinum into an anterior and deep region is an empiric method of organizing these named nodes into a logical construct given our current data. It satisfies the need for a simple system to facilitate widespread adoption, and it builds on node classifications that are familiar to the community (namely, the IASLC and AAO-HNS/ASHNS node classifications) and anatomical patterns of mediastinal drainage. Consideration was given to defining the map based on discrete node stations, but a region-based system seems to be more appropriate to reflect the method of en bloc dissection in current practice and make this map globally applicable. By defining node areas both anatomically and on CT images, we may improve both clinical and pathological staging. Involved nodes should be classified as in either the "anterior region" or "deep region" according to the boundaries described; if possible, the specific location of the node should be recorded as well. Any invasion of nodes via direct extension should be considered nodal disease; this is similarly practiced with regard to N staging in lung cancer.18Goldstraw P IASLC Staging Manual in Thoracic Oncology. Editorial Rx Press, Orange Park, FL2009Google Scholar The ITMIG standard policies for surgeons encourage removal of anterior mediastinal nodes at the time of resection for tumors that seem localized to the thymus.19Detterbeck 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: S1730Google Scholar The classification outlined here fits this policy, because the generally accepted definition of an extended thymectomy includes nodes of the anterior region. Pathologists should examine all submitted lymph nodes and record whether they are positive or negative for tumor. In addition, the total number of nodes sampled from each region should be recorded and included in the prospective database. For thymomas with adjacent organ involvement (Masaoka stage III or IVA undergoing curative-intent resection), it is recommended that anterior mediastinal lymph nodes be routinely removed and submitted, and a systematic sampling of intrathoracic sites is encouraged (i.e., nodes corresponding to the deep region). For thymic carcinoma, a routine systematic removal and submission of nodes in both the anterior and deep regions are recommended. We accept that development of this mediastinal node map is essentially empiric. However, the process of establishing this lymph node map was similar to that utilized for the IASLC lung cancer lymph node map.14Rusch VW Asamura H Watanabe H Giroux DJ Rami-Porta R Goldstraw P Members of IASLC Staging Committee. The IASLC lung cancer staging project: a proposal for a new international lymph node map in the forthcoming seventh edition of the TNM classification for lung cancer.J Thorac Oncol. 2009; 4: 568-577Abstract Full Text Full Text PDF PubMed Scopus (854) Google Scholar They reconciled discrepancies in the definitions among various node classifications and established a universal map for application in future investigations. Cadaveric studies (as described above) delineating anatomical and functional lymph node drainage pathways via injection were referenced. Endorsement was achieved using a multidisciplinary workgroup within an international committee. It should be pointed out that in most tumor types, an initial node classification was developed empirically, and data accumulated later regarding the prognostic impact. Much work remains to be done to clarify and improve thymic epithelial tumor staging. A universally adopted nodal map is needed to collect data in a consistent manner. Through the process of building on existing maps, knowledge of mediastinal drainage, broad input from all major groups and organizations active in this area, and involvement of ITMIG and the IASLC Staging and Prognostics Factors Committee, consensus has been developed for a simple two-region node map. This will set the stage to gather more consistent information and potentially contribute to future stage classification systems.