Union for International Cancer Control (UICC) released the 8th edition of TNM Classification of Malignant Tumours (1) and it became effective since the beginning of 2017. On the other hand, Japan Esophageal Society (JES) released the 11th edition of Japanese Classification of Esophageal Cancer (2,3) in October, 2015. The former is almost identical to AJCC classification (4) and used as international common scale for the staging of esophageal cancer. The latter is widely accepted particularly in Asian countries (5,6) where squamous cell cancer is the major pathology and also in Europe (7) mainly because of its meticulous anatomical classification of lymph node stations. In this review, we would like to clarify the difference of basic concepts of the two classifications and discuss their advantage and disadvantage.
Both UICC and JES Classifications consist of three main categories, i.e., T, N, and M.
The definition and expression of T-category are almost identical except for two points. One is the fact that “T4” can be applied in JES classification not only to main tumor but also to metastatic lymph nodes with extranodal tumor involvement. Another difference is the much more detailed sub-classification of T1 tumors in JES system. T1a and T1b in UICC classification are both subclassified into three levels, i.e., T1a to T1a-EP, T1a-LPM, and T1a-MM, and T1b to T1b-SM1, T1b-SM2, and T1b-SM3. This meticulous subclassification in JES system is based on the large data of superficial cancer treatments in Japan (8,9), T1a-EP and T1a-LPM are usually handled in one group and regarded as good candidates of local treatment such as endoscopic submucosal dissection (ESD) because almost no lymph node metastases have been experienced in these patients (10). T1b-SM2 and T1b-SM3 are associated with 40% or more frequent nodal involvement, and radical surgery similar to T2 or more advanced tumors is recommended.
N-category shows the largest difference between the two systems. UICC defines the N-category according to only the number of the metastatic regional lymph nodes. In JES system, regional nodes are subgrouped into group 1 to 4 in 5 different patterns according to the main tumor location. The highest number of the lymph node group containing metastasis is defined as N-category of the patient. Although many Japanese surgeons admit that number of metastatic nodes is the strongest prognostic factor (11,12), it is also true that the Japanese N-category and number of metastatic nodes have close relation (13). Because clinical diagnosis of lymph node metastasis still remains far from ideal (14-16), UICC cN-category which is defined by counting number of metastatic nodes in imaging examinations seems unreliable. The concept of regional nodes in JES system is applied to group 1, 2, and 3 nodes and metastasis in group 4 nodes is almost regarded as distant metastasis, but it is still expressed as N4 instead of M1 and only Stage IVa is applied as long as neither hematogenous metastasis nor serosal dissemination is diagnosed. The regional nodes in JES system vary according to main tumor location, but they always contain supraclavicular nodes and cervical paraesophageal nodes when the main tumor locates in the thoracic esophagus. In the abdomen, nodes around the celiac axis (No. 9 in JES system) are not regional nodes for upper thoracic esophageal cancer, but not only No. 9 nodes but also nodes along the common hepatic artery (No. 8) and nodes along the proximal half of splenic artery (No. 11p) are all included in regional nodes when the tumor locates in the lower thoracic esophagus. Compared to this, the definition of regional nodes in UICC system is static and uniform. The cervical paraesophageal nodes and celiac axis nodes are clearly included in the 8th edition, but supraclavicular nodes are definitely excluded even when the tumor locates in the upper thoracic esophagus.
M-category is almost similar in the two systems except the difference of the definition of regional nodes and the handling of extra-regional node metastasis in JES system (described in the previous paragraph).
Both systems have different complicated staging matrix defined by the combination of T, N, and M categories. It is very natural that one patient is often classified in different stage groups in the two systems, because the stage matrix was determined so that it would stratify the prognoses clearly at every point of time and precisely in order of stages (17-19) but using completely different databases. The databases for two classifications should be largely different in distribution of tumor location, extent of lymph node dissection in surgery, treatment patterns other than surgery and pathology. One system includes the information of tumor location as an important key and another does not. Japanese surgeons feel that for at least squamous cell cancer, which occurs at any level of the esophagus and generally has tendency of higher location, JES system can express more precise state of tumor spread.
Clinical stage and pathological stage
UICC defines two different staging systems for clinical stage and pathological stage. The clinical stage classifications for squamous cell carcinoma and adenocarcinoma are a little bit different, though the pathological stage matrix is identical. This very complicated definition might be the result of the intention to make the prognoses of patients with the same stage expression in different staging systems similar. However, as a consequence, some patients with accurate clinical staging can be up-staged after operation in spite that the preoperative clinical staging was very accurate. For example, a patient with squamous cell carcinoma diagnosed as cT1N1M0 is classified as cTNM Stage I, but after operation, if the diagnosis was accurate, then the one will be classified as pT1N1M0, pTNM Stage IIB. If the pathology is adenocarcinoma, the similar tumor will be classified as cTNM Stage IIA and will be up-staged as pTNM Stage IIB. This seems very strange.
Pathological prognostic group
UICC has another complicated classification of pathological prognostic grouping. Here, a factor other than TNM appears. It is histopathological grading, and is the concept first introduced in the 7th edition of TNM classification. The complicated modification of the pathological stage to pathological prognostic group is defined only in rather early stages or groups (Stage/Group IB to IIB). It is not defined either dominant histopathological grade or the highest grade should be adopted. Although I admit that histopathological grading surely has close relation to the probability of lymph node involvement in T1a-MM and T1b tumors, more detailed discussion is necessary on this issue (20-22). Though this grouping would have been defined so that the prognoses can be properly stratified, it should be database-restricted, and i.e., therapeutic measure-restricted. Perhaps because of the complexity, pathological prognostic group does not affect NCCN guidelines directly.
JES system includes the information of tumor location at the first step of staging through the definition of N-grouping which is tumor location dependent. In UICC system, it is mentioned only in very small part of the definition of pathological prognostic group for squamous cell cancer. It seems to me that UICC does not suppose that adenocarcinoma can occur in upper thoracic esophagus and it suppose that upper and middle thoracic esophageal squamous cell cancer inevitably has worse prognosis. Distribution of lymph node metastasis and its impact on prognosis has been clearly shown to be related to tumor location by many investigators (13,23). Therefore, we have been claiming that N category should be defined in relation to main tumor location, or at least, the definition of regional lymph nodes should be. The ultimate difference of the two systems lies on this point. The typical conflict is the attitude toward the supraclavicular nodes.
Significance of supraclavicular node metastasis
As has been discussed, the implication of the metastasis in supraclavicular nodes in UICC and JES system is largely different. Many Japanese surgeons have tried to claim that the supraclavicular nodes should be regarded as regional nodes at least for upper and middle thoracic esophageal cancer (13,24,25). This argument has been supported by some Asian and western surgeons (26,27). In the latest JES classification, supraclavicular nodes are classified as group 3 nodes for lower thoracic esophageal cancer. Because group 3 nodes mean most distant regional nodes, many proposals of their selective dissection have been reported (28-30). On the other hand, supraclavicular nodes are classified as group 2 for upper and middle thoracic esophageal cancer (2) and the value of their dissection has been widely accepted.
Why the two systems differ so much?
As has been discussed, JES system seems more practical and widely adaptable to esophageal cancers in any location. It can be more detailed guide to determine actual treatment strategy. UICC system is based on too simplified definition of regional lymph nodes and too complicated staging matrix. We can imagine several reasons for the difference occurred between the two systems.
One is the difference of major pathology. Squamous cell carcinoma is the majority in Asian countries. It occurs widely at any location of the esophagus. On the other hand, adenocarcinoma, which usually arises in the Barrett mucosa, tends to be located in the lower esophagus. Therefore, it might be a rare occasion for western doctors to face the need for consideration of cervical lymph node metastases. However, we think that the staging system of esophageal cancer should include all the possible location of tumors irrespective of pathology.
Another reason is the difference of basic concept of cancer treatment. Although the concept of radical surgery had been emphasized in western countries (31), it has shifted to multimodality treatment, and the role of radical surgery became smaller. All the malignancies are regarded as potentially systemic diseases, and marginal spread of cancer such as supraclavicular lymph node metastasis from thoracic esophageal cancer seems to change its position from regional disease to an expression of systemic disease. The importance of multimodal treatment is recognized in Japan also. Japanese current nation-wide RCT of JCOG1109 is a three-armed comparative study of neoadjuvant treatments (32). However, the radical surgery represented by 3-field lymph node dissection still maintains the popularity, and included in the requirement of surgery in such studies. This “dependence” on radical surgery in Japan has been supported by our excellent short term results (33) and good long term survival (34,35). Because of the relatively larger role of surgery, the importance of detailed definition of each lymph node station and the evaluation of “efficacy index” of each station has been emphasized (13,36).
The other reason is the difference of handling of surgical specimen. In Japan, lymph nodes are meticulously detached from the operative specimen by surgeons and sorted out according to JES classification of lymph node stations. Pathologists, even when the total number of such lymph nodes exceeds 100, examine all the nodes histopathologically and send back surgeons a full report sorted out along JES classification. We believe that this collaboration is of great importance. Surgical anatomy is too complicated for pathologists to carry out this “another operation” on the specimen accurately. Based on the large database prepared this way, JES system has been created and revised to the current style. This complexity and requirement of elaboration is a large obstacle for new entrants. Compared to this, UICC classification is much easier to adopt except for complicated prognostic grouping.
As one of Japanese surgeons, I believe that JES system is superior to UICC system in describing the spread of a given esophageal cancer, and in discussing its treatment strategy. However, the strict and detailed definition of lymph node stations could be regarded as an obstacle to those who are not familiar with it. Some simplification can be done for at least clinical (non-surgical) staging. However, we strongly feel the need to maintain dynamic definition of regional lymph nodes linked to tumor location. To include supraclavicular nodes in regional lymph nodes of (upper and middle) thoracic esophageal cancer is one of the major points we would like to claim. If UICC system can accept this concept, I think the two systems can be unified, and we can obtain more practical and useful staging system as an international common language.
We would like to express our thanks to Dr. Po-Kuei Hsu, the Guest Editor, for giving us the opportunity to deliberate and argue on this very important topic.
Conflicts of Interest: The authors have no conflicts of interest to declare.
- Brierley JD, Gospodarowicz MK, Wittekind C, editors. TNM classification of malignant tumours. 8th edition. Oxford: Wiley Blackwell, 2017.
- Japan Esophageal Society. Japanese Classification of Esophageal Cancer, 11th Edition: part I. Esophagus 2017;14:1-36.
- Japan Esophageal Society. Japanese Classification of Esophageal Cancer, 11th Edition: part II and III. Esophagus 2017;14:37-65.
- Amin MB, Edge SB, Greene FL, et al. AJCC Cancer Staging Manual. 8th edition. New York: Springer, 2017.
- Huang W, Huang Y, Sun J, et al. Atlas of the thoracic lymph nodal delineation and recommendations for lymph nodal CTV of esophageal squamous cell cancer in radiation therapy from China. Radiother Oncol 2015;116:100-6. [Crossref] [PubMed]
- Wang F, Zheng Y, Wang Z, et al. Nodal Skip Metastasis in Esophageal Squamous Cell Carcinoma Patients Undergoing Three-Field Lymphadenectomy. Ann Thorac Surg 2017;104:1187-93. [Crossref] [PubMed]
- Hagens ERC, van Berge Henegouwen MI, Cuesta MA, et al. The extent of lymphadenectomy in esophageal resection for cancer should be standardized. J Thorac Dis 2017;9:S713-23. [Crossref] [PubMed]
- Kodama M, Kakegawa T. Treatment of superficial cancer of the esophagus: a summary of responses to a questionnaire on superficial cancer of the esophagus in Japan. Surgery 1998;123:432-9. [Crossref] [PubMed]
- Udagawa H, Ueno M, Tsutsumi K, et al. Surgical treatment of superficial esophageal cancer, its result and perspective. Esophagus 2007;4:155-8. [Crossref]
- Davydov M, Delektorskaya VV, Kuvshinov YP, et al. Superficial and early cancers of the esophagus. Ann N Y Acad Sci 2014;1325:159-69. [Crossref] [PubMed]
- Takeno S, Yamashita SI, Yamamoto S, et al. Number of metastasis-positive lymph node stations is a simple and reliable prognostic factor following surgery in patients with esophageal cancer. Exp Ther Med 2012;4:1087-91. [Crossref] [PubMed]
- Akutsu Y, Matsubara H. The significance of lymph node status as a prognostic factor for esophageal cancer. Surg Today 2011;41:1190-5. [Crossref] [PubMed]
- Udagawa H, Ueno M, Shinohara H, et al. The importance of grouping of lymph node stations and rationale of three-field lymphoadenectomy for thoracic esophageal cancer. J Surg Oncol 2012;106:742-7. [Crossref] [PubMed]
- Kato H, Miyazaki T, Nakajima M, et al. The incremental effect of positron emission tomography on diagnostic accuracy in the initial staging of esophageal carcinoma. Cancer 2005;103:148-56. [Crossref] [PubMed]
- Yokota T, Igaki H, Kato K, et al. Accuracy of preoperative diagnosis of lymph node metastasis for thoracic esophageal cancer patients from JCOG9907 trial. Int J Clin Oncol 2016;21:283-8. [Crossref] [PubMed]
- Choi J, Kim SG, Kim JS, et al. Comparison of endoscopic ultrasonography (EUS), positron emission tomography (PET), and computed tomography (CT) in the preoperative locoregional staging of resectable esophageal cancer. Surg Endosc 2010;24:1380-6. [Crossref] [PubMed]
- Rice TW, Ishwaran H, Hofstetter WL, et al. Recommendations for pathologic staging (pTNM) of cancer of the esophagus and esophagogastric junction for the 8th edition AJCC/UICC staging manuals. Dis Esophagus 2016;29:897-905.
- Rice TW, Ishwaran H, Blackstone EH, et al. Recommendations for clinical staging (cTNM) of cancer of the esophagus and esophagogastric junction for the 8th edition AJCC/UICC staging manuals. Dis Esophagus 2016;29:913-9.
- Tachimori Y, Ozawa S, Numasaki H, et al. Comprehensive Registry of Esophageal Cancer in Japan, 2010. Esophagus 2017;14:189-214. [Crossref] [PubMed]
- Ancona E, Rampado S, Cassaro M, et al. Prediction of lymph node status in superficial esophageal carcinoma. Ann Surg Oncol 2008;15:3278-88. [Crossref] [PubMed]
- Mitobe J, Ikegami M, Urashima M, et al. Clinicopathological investigation of lymph node metastasis predictors in superficial esophageal squamous cell carcinoma with a focus on evaluation of lympho-vascular invasion. Scand J Gastroenterol 2013;48:1173-82. [Crossref] [PubMed]
- Ito E, Ozawa S, Kijima H, et al. New invasive patterns as a prognostic factor for superficial esophageal cancer. J Gastroenterol 2012;47:1279-89. [Crossref] [PubMed]
- Tachimori Y. Pattern of lymph node metastases of squamous cell esophageal cancer based on the anatomical lymphatic drainage system: efficacy of lymph node dissection according to tumor location. J Thorac Dis 2017;9:S724-30. [Crossref] [PubMed]
- Tachimori Y, Ozawa S, Numasaki H, et al. Supraclavicular node metastasis from thoracic esophageal carcinoma: A surgical series from a Japanese multi-institutional nationwide registry of esophageal cancer. J Thorac Cardiovasc Surg 2014;148:1224-9. [Crossref] [PubMed]
- Yamasaki M, Miyata H, Miyazaki Y, et al. Evaluation of the nodal status in the 7th edition of the UICC-TNM classification for esophageal squamous cell carcinoma: proposed modifications for improved survival stratification: impact of lymph node metastases on overall survival after esophagectomy. Ann Surg Oncol 2014;21:2850-6.
- Altorki NK, Skinner DB. Occult cervical nodal metastasis in esophageal cancer: preliminary results of three-field lymphadenectomy. J Thorac Cardiovasc Surg 1997;113:540-4. [Crossref] [PubMed]
- Tong DK, Kwong DL, Law S, et al. Cervical nodal metastasis from intrathoracic esophageal squamous cell carcinoma is not necessarily an incurable disease. J Gastrointest Surg 2008;12:1638-45; discussion 1645. [Crossref] [PubMed]
- Miyata H, Yano M, Doki Y, et al. A prospective trial for avoiding cervical lymph node dissection for thoracic esophageal cancers, based on intra-operative genetic diagnosis of micrometastasis in recurrent laryngeal nerve chain nodes. J Surg Oncol 2006;93:477-84. [Crossref] [PubMed]
- Shimada Y, Sato F, Maeda M, et al. Validity of intraoperative pathological diagnosis of paratracheal lymph node as a strategy for selection of patients for cervical lymph node dissection during esophagectomy. Dis Esophagus 2003;16:246-51. [Crossref] [PubMed]
- Nagatani S, Shimada Y, Kondo M, et al. A strategy for determining which thoracic esophageal cancer patients should undergo cervical lymph node dissection. Ann Thorac Surg 2005;80:1881-6. [Crossref] [PubMed]
- Halsted WS. I. The Results of Operations for the Cure of Cancer of the Breast Performed at the Johns Hopkins Hospital from June, 1889, to January, 1894. Ann Surg 1894;20:497-555. [Crossref] [PubMed]
- Nakamura K, Kato K, Igaki H, et al. Three-arm phase III trial comparing cisplatin plus 5-FU (CF) versus docetaxel, cisplatin plus 5-FU (DCF) versus radiotherapy with CF (CF-RT) as preoperative therapy for locally advanced esophageal cancer (JCOG1109, NExT study). Jpn J Clin Oncol 2013;43:752-5. [Crossref] [PubMed]
- Takeuchi H, Miyata H, Gotoh M, et al. A risk model for esophagectomy using data of 5354 patients included in a Japanese nationwide web-based database. Ann Surg 2014;260:259-66. [Crossref] [PubMed]
- Udagawa H, Akiyama H. Surgical treatment of esophageal cancer: Tokyo experience of the three-field technique. Dis Esophagus 2001;14:110-4. [Crossref] [PubMed]
- Fujita H. History of lymphadenectomy for esophageal cancer and the future prospects for esophageal cancer surgery. Surg Today 2015;45:140-9. [Crossref] [PubMed]
- Tachimori Y, Ozawa S, Numasaki H, et al. Efficacy of lymph node dissection by node zones according to tumor location for esophageal squamous cell carcinoma. Esophagus 2016;13:1-7. [Crossref] [PubMed]