Review Article The development of the TNM classification of gastric cancer

bs_bs_banner Pathology International 2015; 65: 399 403 doi:10.1111/pin.12306 Review Article The development of the TNM classification of gastric cancer Christian Wittekind Institute of Pathology, University Hospital Leipzig, Leipzig, Germany The first tumor, node, metastasis (TNM) classification for stomach tumors was published in the second edition of the TNM classification of malignant tumors in 1974 and was followed by additional editions up to the seventh edition published in 2010. In the Buffalo Meeting 2008 a harmonization between the Eastern (Japanese) and Western stomach tumor classification was achieved with only minor remaing differences. The present TNM classification of stomach tumors has been criticized but it can be considered generally accepted worldwide. For generating data based on this new TNM classification it is important to correctly use TNM and ptnm. The decions on therapy and the estimation of prognosis are based on TNM. New molecular factor studies will be correlated and based on the results of the TNM classification. Key words: development, gastric cancer, TNM classification The TNM System was developed by Pierre Denoix between 1943 and 1952. 1 In 1958 the first recommendation for clinical stage classification (breast) was published for clinical use and evaluation. 2 1968 the so-called Livre de Poche was published. 3 From 1974 on further editions of TNM were published. 4 8 In the last decades the UICC s TNM Prognostic Factors Project has instituted a process for evaluating proposals to improve the TNM Classification. The UICC believes that it is important to reach agreement on the recording of accurate information on the anatomical extent of the disease for each site, because the precise clinical description of malignant neoplasms and histopathological classification may serve a number of related objectives, namely: 1 To aid the clinician in the planning of treatment, 2 To give some indication of prognosis, 3 To assist in the evaluation of the results of treatment, Correspondence: Christian Wittekind, MD, Institut für Pathologie, Universitätsklinikum Leipzig, Liebigstraße 26, D-04103 Leipzig, Germany. Email: christian.wittekind@medizin.uni-leipzig.de Received 16 March 2015. Accepted for publication 10 April 2015. 2015 Japanese Society of Pathology and Wiley Publishing Asia Pty Ltd 4 To facilitate the exchange of information between treatment centers, 5 To contribute to the continuing investigation of human cancer, 6 To support cancer control activities. Today, besides the clinical classification (ctnm or TNM) and the pathohistological classification (ptnm) which should be documented for each case separately and completely, further types of TNM can be used, especially in patients whose carcinomas can be treated neoadjuvantely: Clinical classification after neoadjuvant therapy (yctcncm) Clinical classification after neoadjuvant therapy (yptpn c or pm) The history of the TNM classification of stomach tumors is an excellent example for demonstrating the development of TNM, including difficulties. HISTORY OF TNM OF STOMACH TUMORS The first TNM classification for stomach tumors was published in the second edition of the TNM classification of malignant tumors (Table 1) in 1974. 4 It was followed by a third edition in 1978 and a fourth edition in 1987. 5,6 The TNM system for stomach cancer was stabilized and accepted in the Western world with the publication of the second revision of the fourth edition in 1992 (Table 2). 6 Up until this edition, Table 1 TNM classification of stomach tumors 2nd edition 1974 4 T1 T4 Tumor limited to the mucosa or mucosa and submucosa independent of tumor size Tumor shows invasion but not more than half of its region Tumor shows invasion, more than half of its region, < one region Tumor shows invasion, more than one region, adjacent structures There are additional clinical N classification and pathological N classification.

400 C. Wittekind the concept of regional lymph node classification by anatomical extent (distance to the primary tumor rule) was used. It seemed to be biologically helpful but it was poorly reproducible, particularly in Western countries where pathologists were performing the preparation of the regional lymph nodes. A change occurred in the publication of the fifth edition in 1997 with the introduction of the number of lymph node metastasis classification. 7 No changes were seen in the sixth edition 8 but important changes as to the definition of the T- and N categories were published in the seventh edition in 2010 9 based on data from Japan and Korea. 10 This fifth edition was attacked, mostly by Japanese surgeons because the distance to the primary tumor rule was skipped in the definition of regional lymph node metastasis, which was considered an important achievement of the Japanese Gastric Cancer Classification. However, with further publications of studies comparing the Japanese and the UICC TNM classification of stomach tumors it became evident that the UICC number of regional lymph nodes classification was more reproducible and thus better. 11,12 Because of these different ways to approach stomach cancer staging it was a long way to harmonization. Different time points are mentioned below: Japanese Classification of Gastric Carcinoma, 1st English Ed., 1995 Japanese Classification of Gastric Carcinoma, 2nd English Ed., 1998 UICC 4th ed., 2nd rev, 1992 UICC 5th ed. (number of lymph nodes!!) 1997 UICC 6th edition not (completely) harmonized 2002 Buffalo Meeting 2008: In preparation of the 7th ed. East and West stomach tumor classification (nearly) harmonized. NEW PRINCIPLES OF THE TNM CLASSIFICATION OF STOMACH TUMORS After a period of having introduced biological thoughts and concepts without too much data-based evidence the UICC Table 2 TNM classification of stomach tumors 4th edition, second revision 1992 6 T1 T4 N1 N2 Tumor invades lamina propria or submucosa Tumor invades muscularis propria or subserosa Tumor penetrates the serosa without invasion of adjacent structures Tumor invades adjacent structures Metastasis in perigastric lymph node(s) within 3 cm of the edge of the primary tumor Metastasis in perigastric lymph nodes(s) more than 3 cm from the edge of the primary tumor or in lymph nodes along the left gastric, common hepatic, splenic or coeliac arteries decided in the beginning of the 21st century to introduce evidence-based medicine in the change process of TNM. Based on the requests of many users it was further decided that the classification should be simple to use, thus supporting a reasonable reproducibility. In addition, the applicability should be considered from a practical clinical perspective, e.g., particularly T categories should be easy to determine by clinical imaging techniques as well as by pathological examination. SUMMARY OF CHANGES IN THE T AND N CATEGORIES OF THE SEVENTH EDITION OF TNM In developing the definitions of the seventh edition it was basically intented to adapt those to the T categories of other gastrointestinal tumor sites, e.g., oesophageal, small bowel and colorectal tumors. In testing large datasets from Japan and Korea it could be shown that these T categories showed significant prognostic differences. 10 The definition of the affected number of regional lymph nodes in the N category was changed, too (Table 3). The histological examination of a regional lymphadenectomy specimen will ordinarily include 16 or more lymph nodes to fulfill the minimal criteria to classify N3b/pN3b. STAGE GROUPING In the seventh edition several changes in the stage grouping of stomach tumors were introduced. 9 The stage groups IIA to IV were newly defined (Table 4). A major change in Table 3 TNM classification of stomach tumors, comparison of 6th and 7th edition 8,9 6th edition Definition 7th edition T1 Tumor invades lamina propria or submucosa T1a T1b Tumor invades muscularis propria or subserosa Tumor penetrates the serosa without T4a invasion of adjacent structures T4 Tumor invades adjacent structures T4b N1 Metastasis in 1 to 2 regional lymph nodes N1 Metastasis in 4 to 6 lymph nodes N2 N2 Metastasis in seven to 15 regional lymph N3a nodes N3 Metastasis in more than 15 regional lymph N3b nodes M0 No distant metastasis M0 M1 Distant metastasis M1 pm1 Distant metastasis microscopically confirmed pm1 Note: Distant metastasis includes peritoneal seeding, positive peritoneal cytology, and omental tumor not part of continuous extension.

TNM gastric cancer 401 Table 4 Stage grouping of stomach tumors, 7th edition 9 Stage 0 Tis N0 M0 Stage IA T1 N0 M0 Stage IB N0 M0 T1 N1 M0 Stage IIA N0 M0 N1 M0 T1 N2 M0 Stage IIB T4a N0 M0 N1 M0 N2 M0 T1 N3 M0 Stage IIIA T4a N1 M0 N2 M0 N3 M0 Stage IIIB T4b N0, N1 M0 T4a N2 M0 N3 M0 Stage IIIC T4a N3 M0 T4b N2, N3 M0 Stage IV Any T Any N M1 comparison to former TNM editions was that stage IV contained only cases with distant metastasis. CRITICISM OF THE SEVENTH EDITION STOMACH TUMORS Generally, it was stated in several publications that the seventh edition was superior to the sixth edition. 13 16 Ahn et al. 13 concluded that the seventh edition provided a more detailed classification of prognosis than the sixth edition, especially between and tumors and N1 and N2 tumors although further studies were found to be needed for the N3a and N3b classification. Therefore, the seventh edition classification seemed to be acceptable and superior to the fifth and sixth edition. 13 It was suggested that N classification needs redefinition of cut-off points and N1 and N2 tumors. However, redifinitions have been asked for since the number of regional lymph nodes classification was introduced in 1997. 7 Others confirmed the prognostic validity of the seventh edition but complained about the complexity. 14 Stage grouping was critized as being partly heterogeneous and too complicated for use. It demonstrated relatively increased homogeneity in each TNM stage, although the seventh TNM T-, N-, and M classifications were more detailed. Stage IV only with distant metastasis was critized and it was discussed that patients with N3b/pN3b also had a very poor prognosis. WHEN IS A GASTRIC TUMOR CLASSIFIED AS A GASTRIC TUMOR? An issue of major concern was the following rule: A tumor the epicenter of which is within 5 cm of the esophagogastric Table 5 Comparison of TNM classification of esophagus and stomach Stage grouping Esophagus TN Stage grouping Stomach Stage IA T1N0 Stage IA Stage IB N0 Stage IB Stage IIA N0 Stage IIA Stage IIIA T4aN0 Stage IIIA Stage IIB T1N1 Stage IB Stage IIB N1 Stage IIA Stage IIIA N1 Stage IIB Stage IIIC T4aN1 Stage IIIA junction and also extends into the esophagus is classified and staged using the oesophageal scheme. Tumors with an epicenter in the stomach greater than 5 cm from the oesophagogastric junction or those within 5 cm of the oesophagogastric junction without extension in the esophagus are classified and staged using the gastric carcinoma scheme. This change was based on data Rice et al. 17 20 Thus, biologically a tumor of the stomach with regard to anatomical extent is classified as a tumor of the esophagus. Differences occur in stage grouping when regional lymph node metastases are diagnosed (Table 5). A carcinoma with T1N1 is grouped in Stage IIB of oesophageal tumors and in Stage IB in stomach tumors. There has been an ongoing debate if the proposals to classify the so-called Siewert II and III carcinomas 21,22 are prognostically justified. Gertler et al. 23 in their paper on 2920 patients came to the conclusion that the new seventh edition improved the predictive ability for cancers of the esophagus. They recommended to condense stage groups to a clinically relevant number and emphasized the separation of squamous cell carcinomas and adenocarcinomas into two separate entities. Hasegawa et al. 24 tried to answer to the question if tumors of the esophagogastric junction (Siewert II and III) should be classified according to the esophagus or stomach tumor classification of the seventh TNM edition. They concluded that the TNM of stomach tumors is better for classifying patients with adenocarcinoma of the esophagogastric junction than TNM of esophageal tumors in regard to the distribution of the patients, the correlation between Hazard ratio and stage, the separation of the survival between stages II and III, and the homogeneity of the survival in stage III. Kim et al 25 concluded from their results that neither the esophageal nor the gastric staging system (7th edition) could provide appropriate anatomic definition of tumor depth for cancer of esophagogastric junction. They therefore recommended to modify the current staging systems to better fit the needs of junction cancers. Preliminary data of Rice and his group (not yet published) collected form 27 000 patients have been announced to show that the rules of the seventh edition for classifying Siewert type II/III tumors in the same way as esophageal tumors are justified.

402 C. Wittekind TNM CLASSIFICATION OF NEOADJUVANTLY TREATED TUMORS USE OF THE PREFIX Y After multimodal therapy the pathological assessment may be affected by possible tumor regression or other treatment effects. A clinical TNM classification performed after neoadjuvant therapy should be identified by the prefix y, e.g., yctcncm. Since the use of the prefix y in most cases includes a resection of the primary tumor it will be followed by a yptpn classification supplemented by a cm0 or pm1 if distant metastatic tumor has been confirmed microscopically. The yptnm classification deals with the extent of cancer after neoadjuvant therapy. Therefore, the ytnm/yptnm should consider only viable tumor cells and not signs of regressed tumor tissue such as necrotic cell debris, scars, fibrotic areas, fibrotic nodules, granulation tissue, mucin lakes, etc. In analyzing the results it should be always differentiated between patients treated with primary surgery (ctnm, ptnm) and those treated by surgery following neoadjuvant treatment (yctnm, yptnm). In addition to the use of the prefix y regression scores are used to describe the extent of carcinoma regression in the primary tumor or in the regional lymph node metastasis. These regression scores should be used in addition to the yptnm classification. Consequently, a tumor treated neoadjuvantly with a complete regression of the primary tumor and eventually lymph node metastasis should be classified as ypt0pn0m0 (if there are clinically no distant metastasis). FUTURE FIELDS WITH POTENTIAL FOR CHANGES OF TNM CLASSIFICATION OF STOMACH TUMORS It is not to be expected that the general rules of the TNM System will be changed in the next, eighth, edition. As to the T classification of stomach tumors it has been discussed if a ramification of the category would be helpful: a Inner layer of muscularis propria b Outer layer of muscularis propria Others have discussed if it woul be appropriate to consider lymphatic and venous invasion in the T classification? Both of these issues are not yet decided, mainly, because there are no sufficient and reproducible data to decide on. In the N classification the threshold of the number of regional lymph nodes relevant for the definition of the N categories are constantly under discussion. The role of isolated tumor cells in regional lymph nodes of the stomach is also discussed. Presently, the isolated tumor cells are classified pn0(i+). It has been questioned if pn1(i+) would be mode appropriate. Other parameters which are not considered in the N/pN classification are the extracasular extension (ECE) of regional lymph node metastasis in the adjacent soft tissue of a lymph node and the lymph node ratio. 26 30 The definitions of lymph node metastasis sites show differences between the Japanese classification and the AJCC/ UICC TNM classification in that lymph node metastasis of the hepatoduodenal ligament are considered regional in the UICC TNM classification and in the Japanese classification. 31 Metastasis in paraaortic lymph nodes are classified as regional in the Japanese classification and as distant metastasis in the UICC TNM classification. The differences in definitions of lymph node metastasis are shown in the TNM Supplement. 32 It has to be decided if a ramification of the M category in stomach tumors would be helpful for treatment planning and estimating prognosis. A more precise definition of stage groups has been requested taking into account that patients with N3/pN3 lymph node metastasis have a very poor prognosis. It would be justified to group those in a new stage group IVA and have patients with distant metastasis in a separate stage group IVB. Finally, a complete harmonization between the TNM classification of stomach tumors proposed by AJCC, UICC, and Japanese Gastric Cancer Association (JGCA) would be of great importance. A complete regression without viable tumor cells is observable in 10 15% of the primary gastric carcinomas. These cases are classified as ypt0pn0m0. It is not yet clear in which stage group such cases should be assigned. The tumor regression seen in lymph node metastasis which is much rarer than tumor regression in the primary stomach tumor also has to be addressed and grouped adequately. An issue which is not addressed in the AJCC cancer staging manual 33 and the UICC TNM booklet is the standard of pathohistological specimen preparation (e.g., blocks of the primary tumor), number of examined and involved lymph nodes (lymph node ratio), necessity of immunohistochemistry of lymph nodes to detect isolated tumor cells (ITC), etc. FUTURE AND OPEN QUESTION In the development of the TNM classification of stomach tumors there have been great achievements and considerable progress. Nevertheless, there are quite a lot of open questions remaining. Are there differences in tumor biology between carcinomas arinsing in Eastern and Western countries? Should they be considered in the TNM classification and how? In which way should standards of surgical techniques in different institutions be considered? How can molecular findings in stomach tumors, e.g., HER2 immunoreactivity be considered in TNM or should these findings only be seen as an additional (hopefully) prognostic factor?

TNM gastric cancer 403 In the next decade it will be important to collect data worldwide to find answers to the many open questions in the TNM classification of stomach tumors. None declared. DISCLOSURE STATEMENT REFERENCES 1 Denoix PF. Nomenclature des cancer. Bull Inst Nat Hyg (Paris) 1944: 69 73. 1945: 82-84 1950:81-84, 1952 743-748. 2 International Union Against Cancer (UICC) Committee on Clinical Stage Classification and Applied Statistics. Clinical Stage Classification and Presentation of Results, Malignant Tumors of the Breast and Larynx. Paris: UICC, 1958. 3 International Union Against Cancer (UICC). TNM Classification of Malignant Tumors. Geneva: UICC, 1968. 4 International Union Against Cancer (UICC). TNM Classification of Malignant Tumors, 2nd edn. Geneva: UICC, 1974. 5 International Union Against Cancer (UICC). In: Harmer MH, ed. TNM Classification of Malignant Tumors, 3rd edn. Geneva: UICC, 1978; Enlarged and revised 1982. 6 International Union Against Cancer (UICC). In: Hermanek P, Sobin LH, eds. TNM Classification of Malignant Tumors, 4th edn. Berlin, Heidelberg, New York: Springer, 1987; Revised 1992. 7 Sobin LH, Wittekind C. UICC TNM Classification of Malignant Tumors, 5th edn. Berlin Heidelberg New York: Springer, 1997. 8 Sobin LH, Wittekind C. UICC TNM Classification of Malignant Tumors, 6th edn. New York: John Wiley & Sons, 2002. 9 Sobin LH, Gospodarowicz MK, Wittekind C. UICC TNM Classification of Malignant Tumors, 7th edn. Oxford: Wiley-Blackwell, 2010. 10 Sano T. Evaluation of gastric carcinoma treatment guidelines of the Japanese gastric cancer association. Gan to Kagaku Ryoho 2010; 37: 582 6. 11 Hermanek P. The second English edition of the Japanese classification of gastric carcinoma. A Western commentary. Gastric Cancer 1999; 2: 79 82. 12 Yoon SS. Staging gastric cancer patients after complete surgical resection: Which system should we use? Ann Surg Oncol 2012; 19: 2423 5. 13 Ahn HS, Lee HJ, Han S et al. Evaluation of the seventh American Joint committee on cancer/international Union against cancer classification of gastric adenocarcinoma in comparison with the sixth classification. Cancer 2010; 116: 5592 8. 14 Reim D, Loos M, Vogl F et al. Prognostic implications of the seventh edition of the international union against cancer classification for patients with gastric cancer: The Western experience of patients treated in a single-center European institution. J Clin Oncol 2013; 31: 263 71. 15 Graziosi L, Marino E, Cavazzoni EM, Donini A. Prognostic value of the seventh AJCC/UICC TNM classification of non-cardia gastric cancer. World J Surg Oncol 2013; 11: 103 10. 16 Marelli D, Morgagni P, de Manzoni G et al. Prognostic value of the 7th AJCC/UICC TNM classification of non-cardia gastric cancer. Ann Surg 2012; 255: 486 91. 17 Rice TW, Blackstone EH, Rybicki LA et al. Refining esophageal cancer staging. J Thorac Cardiovasc Surg 2003; 125: 1103 013. 18 Rice TW, Rusch VW, Apperon-Hansen C et al. Worldwide esophageal cancer collaboration. Dis Eosphagus 2009; 22: 1 8. 19 Rice TW, Blackstone E, Rusch VW. 7th edition of the AJCC cancer staging system: Esophagus and esophagogastric junction. Ann Surg Oncol 2010; 17: 1721 4. 20 Rice TW, Rusch VW, Ishwaran H, Blackstone EH, for the Worldwide Esophageal Cancer Collaboration. Cancer of the esophagus and esophagogastric junction: Data-driven staging for the seventh edition of the American Joint Committee on Cancer/ International Union Against Cancer Cancer Staging Manuals. Cancer 2010; 116: 3763 73. 21 Siewert JR, Stein HJ. Classification of adenocarcinoma of the oesophagogastric junction. Br J Surg 1998; 85: 1457 9. 22 Siewert JR. Adenocarcinoma of the esophagogastric junction. Gastric Cancer 1999; 2: 87 8. 23 Gertler R, Stein HJ, Langer R et al. Long-term outcome of 2920 patients with canncers of the esophagus and esophagogastric junction. Evaluation of the New Union International contre le cancer/american Joint Committee Cancer staging system. Ann Surg 2011; 253: 689 98. 24 Hasegawa S, Yoshikawa T, Aoyama T et al. Esophagus or stomach? The seventh TNM classification for Siewert Type II/III junctional adenocarcinoma. Ann Surg Oncol 2013; 20: 773 9. 25 Kim HI, Cheong JH, Song KJ et al. Staging of adenocarcinoma of the esopha gogastric junction: Comparison of AJCC 6th and 7th gastric and 7th esophageal staging system. Ann Surg Oncol 2013; 20: 2713 20. 26 Chen S, Zhao BW, Li YF et al. The prognostic value of harvested lymph nodes and the metastatic lymph node ratio for gastric cancer patients: Results of a study of 1,101 patients. PLOS ONE 2012; 7: e49424. 27 Alatengbaolide M, Lin D, Li Y et al. Lymph node ratio is an independent prognostic factor in gastric cancer after curative resection (r0) regardless of the examined numer of lymph nodes. Am J Clin Oncol 2013; 36: 325 30. 28 Zhou Y, Zhang J, Cao S, Li Y. The evaluation of metastatic lymph node ratio staging system in gastric cancer. Gastric Cancer 2013; 16: 309 17. 29 Aurello P, Catracchia V, Petrucciani N et al. What is the role of nodal ratio as a prognostic factor for gastric cancer nowadays? Comparison with new TNM staging system and analysis according to the number of resected nodes. Am Surg 2013; 79: 483 91. 30 Lee SY, Hwang I, Park YS et al. Metastatic lymph node ratio in advanced gastric carcinoma: A better prognostic factor than number of metastatic lymph nodes? Int J Oncol 2010; 36: 1461 7. 31 Japanese Gastric Cancer Association (JGCA) Japanese classification of gastric carcinoma. 2nd English Edition. Gastric Cancer 1998; 1: 10 24. 32 Wittekind C, Compton CC, Brierley J, Sonbin LH. TNM Supplement. A Commentary on Uniform Use, 4th edn. Oxford: Wiley- Blackwell, 2012. 33 AJCC. In: Edge SB, Byrd DR, Compton CC et al. Cancer Staging Manual, 7th edn. New York: Springer, 2009.