Clinicopathological characteristics and prognostic analysis of Lauren classification in gastric adenocarcinoma in China
- Miao-zhen Qiu†1,
- Mu-yan Cai†2,
- Dong-sheng Zhang1,
- Zhi-qiang Wang1,
- De-shen Wang1,
- Yu-hong Li1 and
- Rui-hua Xu1Email author
© Qiu et al.; licensee BioMed Central Ltd. 2013
Received: 6 September 2012
Accepted: 20 February 2013
Published: 6 March 2013
According to the Lauren classification, gastric adenocarcinomas are divided into diffuse and intestinal types. The causative attribution explaining the dismal prognosis of diffuse-type remains unknown.
We examined the archive of 1000 patients with gastric adenocarcinomas who received radical gastrectomy in our center and assessed the effect of the Lauren classification on survival in a multivariate approach. Moreover we compared the variation of clinical features between the diffuse-type and intestinal-type and explored the contributing factors for the prognostic difference.
There were 805 resectable patients for the final analysis. Diffuse-type comprised of 48.7% in the gastric carcinoma in our group and showed poorer prognosis than intestinal-type (P=0.013). Multivariate analysis revealed that independent prognostic factors for gastric carcinoma patients were T stage (P<0.001), N stage (P<0.001) tumor size (P<0.001) and Lauren classification (P=0.003). For the clinical features, diffuse-type was significantly associated with younger age (p<0.001), female preponderance (p <0.001), distal location (P<0.001), advanced pT (p < 0.001), advanced pN (p < 0.001) and advanced TNM stage (p = 0.027).
Diffuse type adenocarcinoma carries a worse prognosis that may be partially explained by the tendency of this subtype to present at more advanced T and N stage. However, Lauren classification has prognostic significance that is independent of T and N stage as well as other prognostic variables based on the multivariate cox analysis.
KeywordsGastric cancer Lauren classification Prognostic analysis
About one million people are diagnosed with gastric carcinoma each year all over the world, making it the fourth most common cancer and the second leading cause of cancer related death. The incidence rate of gastric carcinoma varies dramatically from one part of the world to another and it is particularly common in Eastern Asia, including China. The prognosis for gastric adenocarcinoma patients remains poor and our understanding of this cancer entity is still limited.
According to the Lauren classification, gastric adenocarcinomas can be divided into two major histological types, diffuse and intestinal type. The intestinal type is characterized by cohesive cells which form gland-like structures, while for the diffuse type, tumor cells lack cell-to-cell interactions and infiltrate the stroma as single cell or small subgroups, leading to a population of non-cohesive, scattered tumor cells. Although the Lauren classification system can date back to 1965, it is still widely accepted and employed by pathologists and physicians today and represents a simple but robust classification approach. The two Lauren types have several distinct clinical and molecular characteristics, including etiology, carcinogenesis, epidemiology and progression, message ribonucleic acid (mRNA) and / or protein expression profile, microsatellite instability, and mutation profiles. Thus, it is widely accepted that they represent distinct disease entities which may benefit from different therapeutic approaches. In the recent reported clinical trial—Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA), patients in the control group had a higher overall survival rates than expected and the authors considered that it might be due to the higher percentage of intestinal-type tumors in the control group compared with other phase III studies. It was reported that the expression of human epidermal growth factor receptor-2 (HER2) was more common in intestinal-type tumors and such patients have a better outcome than patients with diffuse-type tumors[7–10]. The importance of Lauren classification took our attention.
The aims of our present study are: (1) to analyze the prognostic value of Lauren classifications in resectable gastric cancer patients in China, (2) to compare the clinicopathological characteristics of diffuse-type and intestinal-type in gastric cancer and identify the clinicopathological factors which may explain the different prognosis of the these two types.
Materials and methods
All patients provided written informed consent for their information to be stored and used in the hospital database. Study approval was obtained from independent ethics committees at Cancer Center of Sun Yat-Sen University. The study was undertaken in accordance with the ethical standards of the World Medical Association Declaration of Helsinki.
The medical records of 1000 patients with pathologically-confirmed gastric adenocarcinoma between January 1996 and December 2006 were retrospectively analyzed. They all received D2 resection carried out by experienced surgeons in the Cancer Center of Sun Yat-Sen University following the Japanese Gastric Cancer Association (JGCA) guidelines. Both the proximal and distal margins are negative and at least 3 cm away from the tumor. Besides, the surgeon dissected the station D2 lymph nodes. There is no macroscopic or microscopic residual tumor. The total number of dissected lymph nodes of the 1000 gastric carcinoma patients was 16008, with an average of 18.8 ±5.3 (means±s.d.) dissected nodes per case (median 24.0, range 13–72). The number of excised lymph nodes was less than 15 in 24.2% of patients who received resection.
We excluded 82 patients (8.2%) because of missing baseline characteristics, 75 patients (7.5%) younger than 18 years old, 32 patients (3.2%) with incomplete follow-up and 6 patients (0.6%) with secondary malignancy. None of the patients received neoadjuvant treatment. The final study involved 805 patients.
Demographics and univariate survival analysis results of the 805 gastric carcinoma patients
5 year survival rate (%)
Age median 59
Location of tumor
Number of lymph nodes
Type of gastrectomy
The 7th T stage (AJCC)
The 7th N stage (AJCC)
The 7th TNM stage (AJCC)
During the study period we did not have a standardized protocol for postoperative chemotherapy and (or) radiotherapy. Adjuvant therapy was considered in patients with T3-T4 classification and/or positive lymph node involvement. In the present study, only 532 (66.1%) patients completed the adjuvant chemotherapy (2–6 cycles). Agents using for chemotherapy included oxaliplatin, 5-fluorouracil, capecitabine, S-1, irinotecan, docetaxol and taxol. The median number of cycles was 4. No patients received adjuvant radiotherapy. As of May 1st, 2012, 403 patients had died from the disease.
Tissue samples from resected tumors were classified and staged by an experienced pathologist according to the WHO classification and the TNM staging system following general pathological guidelines. Assignment of the histologic type was based on the Lauren criteria. The intestinal type was described as a tumor with glandular architecture, resembling colonic carcinoma; the diffuse type, as a tumor composed of solitary or small clusters of cells, and lacking glandular structures. The mixed type was described as the combination of these two features. Two pathologists reviewed the original diagnostic slides in order to grade, stage and classify the tumors as intestinal or diffuse type.
All statistical analyses were performed by Statistical Package of Social Sciences 13.0 software. P value < 0.05 was considered to be statistically significant. The Kaplan-Meier method was used to estimate overall survival. For patients who remained alive, data were censored at the date of the last contact. Kaplan-Meier analysis with log-rank testing was used for univariate analysis. The definition of the overall survival interval was the duration between the date of diagnosis and the date of last contact. Variables showing a trend for association with survival (P < 0.05) and variables that were known to have prognostic value were selected in the final multivariable Cox proportional hazards model, while variables that are highly associated with others were excluded from the final multivariable model. The chi-square test was used to compare the clinicopathologic data.
The median age of the 805 patients was 59 years (ranging from 20 to 84 years old). Among them 557 were male and 248 were female. The overall 5-year survival for the patient population was 48.2%, with a median survival of 53.4 months. The median follow-up for the entire cohort was 42.0 months (range 3.0–173.0 months). The characteristics of the 805 gastric adenocarcinoma patients and the effect of clinical features on survival are summarized in Table 1.
There were 396 (49.2%) patients with diffuse-type and 352 (43.7%) patients with intestinal-type carcinoma. The remaining 57 patients belonged to the mixed-type carcinoma. In the following analysis, we only included the 748 patients with the diffuse-type or intestinal-type carcinoma.
Clinicopathologic features and Lauren classification
Location of tumor
The 7th T stage (AJCC)
The 7th N stage (AJCC)
The 7th TNM stage (AJCC)
Well + Moderate
Poor + signet ring cell
Univariate and multivariable analyses of overall survival
Multivariate analysis of overall survival in gastric carcinoma
Type of gastrectomy
In 1965, Lauren proposed a division of gastric carcinoma into two structurally distinct types, the intestinal-type and the diffuse-type. The former was most frequently seen in men and older patients and the latter had a worse prognosis and was more frequent in women and younger patients. He proposed that these two types could account for approximately 85% of gastric carcinomas, and the remainder comprised mixed types and other less common histologies. Several studies have found that the Lauren classification is reproducible[12–16]. Our study confirmed the fact that patients with the diffuse-type of gastric carcinoma had poorer prognosis than patients with intestinal type (P = 0.013) in our Chinese patient population. Multivariate analysis revealed that independent prognostic factors for patients with resected gastric adenocarcinoma were TNM stage, tumor size and the Lauren classification. Our previous studies also showed that tumor size was an independent negative predictor of survival in lymph nodes negative gastric carcinoma patients. While the histology was eliminated. Several studies have indicated that patients with intestinal-type tumors had a better outcome than those with diffuse-type tumors[8–10]. The two Lauren types varied in several clinical and molecular characteristics. We tried to seek the difference between these two types in the clinical features which may be responsible for the survival variation.
In our study, diffuse-type gastric carcinoma was significantly associated with younger age (p <0.001), female preponderance (p <0.001), distal location (P<0.001), advanced pT (p < 0.001), advanced pN (p < 0.001) and advanced TNM stage (p = 0.027). Though the impact of age, gender and location as prognostic factors was still controversial, it is well accepted that advanced pN as well as advanced pT are poor prognostic factors for gastric carcinoma[17–20]. The higher percentage of patients with advanced pN and advanced pT subtypes in the diffuse-type gastric carcinoma as compared with the intestinal-type may contribute to the poor prognosis of patients with diffuse-type. Yamashita K et al. revealed that the more dismal prognosis of diffuse-type gastric carcinoma than intestinal-type could be explained by propensity of deeper invasion and emerging peritoneal cancer cell in the Japanese population. In our study, we demonstrated that high percentage of advanced pN was also responsible for the poor prognosis of diffuse-type in Chinese patients with resectable gastric carcinoma.
Ratio of the diffuse type to intestinal type of gastric carcinoma in different areas
Hawaii Japanese 16
In our study we found that the intestinal-type was more frequently in males and in elderly patients, while the diffuse-type occurred more frequently in women and young patients. This results confirms the observations of others[12–15]. The 3.6 ma1e:female ratio for the intestinal type and 0.86 ratio for diffuse tumors in our study is comparable to that noted in Fukuoka, Japan , where they were 2.60 and 0.5 respectively, and in Hawaii Japanese, where these ratio were 2.39 and 0.86 respectively.
In China, not all the patients would go to the same hospital during the course of treatment, maybe after recurrence they would transfer to the local hospital or quit treatment. We tried to get the data of recurrence but some of the patients forgot the date of recurrence. That is why we don’t analyze the recurrence free survival.
In our previous study, we showed that as the age increased there was a steady increasing in the proportion of male and steady decreasing of female. Similarly, we presently also found a steady increasing in the ratio between male and female as the age increased. This suggests a positive relationship between the age and the male: female ratio, however the exact nature of the correlation between gender, age and Lauren classifications warrants further study.
In our study, we found a decrease in the ratio between diffuse type to intestinal type over time from 1.57 (from January 1996 to December 2000) to 1.03 (from January 2001 to December 2006), P=0.041. However, Pekka A et al. found that in a Finland based population,the ratio of diffuse-type to intestinal-type increased over time suggesting differences in the epidemiologic shift of gastric carcinomas between Eastern and Western populations.
The limitation of current study is its retrospective methodology from a single-institution experience. The impact of various treatments related outcome could not be fully evaluated. Moreover, it is inaccurate to analyze the recurrence free interval. External validation by using other large database for evaluating the prognostic effect of Lauren classification would be of value to further explore the mechanism of different prognosis between diffuse-type and intestinal-type gastric carcinoma.
The authors are not aware of any previous studies which address the clinicopathological characteristics and prognostic impact of the Lauren classification in patients with resectable gastric cancer in China. In this retrospective study conducted with 805 patients with gastric adenocarcinoma we submit the following conclusions: 1) The combination of TNM staging with Lauren classification and tumor size are the most meaningful prognostic factors. 2) Advanced pN as well as advanced pT appear to account for the poor prognosis of diffuse-type in Chinese patients with resectable gastric carcinoma.
Miao-zhen Qiu and Mu-yan Cai are co-first authors.
Messenger ribonucleic acid
Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer
Human epidermal growth factor receptor-2
Japanese gastric cancer association
American joint committee on Cancer
World health organization
We gratefully thank Professor Liu Qing in the epidemiology department for his suggestion in the statistical analysis. Besides, we thank Sharlene Gill in the department of Medical Oncology, BC Cancer Agency, Vancouver, Canada to help us correct the grammatical and stylistic errors throughout the manuscript.
- Kamangar F, Dores GM, Anderson WF: Patterns of cancer incidence, mortality, and prevalence across five continents: defining priorities to reduce cancer disparities in different geographic regions of the world. J Clin Oncol. 2006, 24: 2137-50. 10.1200/JCO.2005.05.2308.View ArticlePubMed
- Moore MA, Eser S, Igisinov N, Igisinov S, Mohagheghi MA, Mousavi-Jarrahi A, Ozentürk G, Soipova M, Tuncer M, Sobue T: Cancer epidemiology and control in North-Western and Central Asia - past, present and future. Asian Pac J Cancer Prev. 2010, 11: 17-32.PubMed
- Lauren P: The two histologic main types of gastric carcinoma: diffuse and so-called intestinal type carcinoma. An attempt at a histo-clinical classification. Acta Parhol Microbid Scan. 1965, 64: 31-49.
- Vauhkonen M, Vauhkonen H, Sipponen P: Pathology and molecular biology of gastric cancer. Best Pract Res Clin Gastroenterol. 2006, 20: 651-674. 10.1016/j.bpg.2006.03.016.View ArticlePubMed
- Bang YJ, Van Cutsem E, Feyereislova A, Chung HC, Shen L, Sawaki A, Lordick F, Ohtsu A, Omuro Y, Satoh T, Aprile G, Kulikov E, Hill J, Lehle M, Rüschoff J, Kang YK, ToGA Trial Investigators: Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2 positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomized controlled trial. Lancet. 2010, 376: 687-697. 10.1016/S0140-6736(10)61121-X.View ArticlePubMed
- Van Cutsem E, Moiseyenko VM, Tjulandin S, Majlis A, Constenla M, Boni C, Rodrigues A, Fodor M, Chao Y, Voznyi E, Risse ML, Ajani JA, V325 Study Group: Phase III study of docetaxel and cisplatin plus fluorouracil compared with cisplatin and fluorouracil as first-line therapy for advanced gastric cancer: a report of the V325 Study Group. J Clin Oncol. 2006, 24: 4991-4997. 10.1200/JCO.2006.06.8429.View ArticlePubMed
- Tanner M, Hollmén M, Junttila TT, Kapanen AI, Tommola S, Soini Y, Helin H, Salo J, Joensuu H, Sihvo E, Elenius K, Isola J: Amplification of HER-2 in gastric carcinoma: association with Topoisomerase II alpha gene amplification, intestinal type, poor prognosis and sensitivity to trastuzumab. Ann Oncol. 2005, 16: 273-278. 10.1093/annonc/mdi064.View ArticlePubMed
- Yamashita K, Sakuramoto S, Katada N, Futawatari N, Moriya H, Hirai K, Kikuchi S, Watanabe M: Diffuse type advanced gastric cancer showing dismal prognosis is characterized by deeper invasion and emerging peritoneal cancer cell: the latest comparative study to intestinal advanced gastric cancer. Hepatogastroenterology. 2009, 56: 276-281.PubMed
- Miyahara R, Niwa Y, Matsuura T, Maeda O, Ando T, Ohmiya N, Itoh A, Hirooka Y, Goto H: Prevalence and prognosis of gastric cancer detected by screening in a large Japanese population: data from a single institute over 30 years. J Gastroenterol Hepatol. 2007, 22: 1435-1442. 10.1111/j.1440-1746.2007.04991.x.View ArticlePubMed
- Zheng H, Takahashi H, Murai Y, Cui Z, Nomoto K, Miwa S, Tsuneyama K, Takano Y: Pathobiological characteristics of intestinal and diffuse-type gastric carcinoma in Japan: an immunostaining study on the tissue microarray. J Clin Pathol. 2007, 60: 273-277.PubMed CentralView ArticlePubMed
- Japanese Gastric Cancer Association: Japanese classification of gastric carcinoma-2nd English edition. Gastric Cancer. 1998, 1: 10-24.View ArticlePubMed
- Correa P, Cuello C, Duque E: Carcinoma and intestinal metaplasia of the stomach in Colombian migrants. J Natl Cancer Inst. 1970, 44: 297-306.PubMed
- Muñoz N, Correa P, Cuello C, Duque E: Histologic types of gastric carcinoma in high- and low-risk areas. Int J Cancer. 1968, 3: 809-818. 10.1002/ijc.2910030614.View ArticlePubMed
- Stalsberg H: Histological typing of gastric carcinoma. A comparison of surgical and autopsy materials, and of primary tumours and metastases. Acta Pathol Microbiol Scand A. 1972, 80: 509-514.PubMed
- Kim KH, Chi CH, Lee SK, Lee D, Kubo T: Histologic types of gastric carcinoma among Koreans. Cancer. 1972, 29: 1261-1263. 10.1002/1097-0142(197205)29:5<1261::AID-CNCR2820290519>3.0.CO;2-M.View ArticlePubMed
- Stemmermann GN, Brown C: A survival study of intestinal and diffuse types of gastric carcinoma. A survival study of intestinal and diffuse types of gastric carcinoma. Cancer. 1974, 33: 1190-1195. 10.1002/1097-0142(197404)33:4<1190::AID-CNCR2820330444>3.0.CO;2-L.View ArticlePubMed
- Qiu MZ, Wang ZQ, Luo HY, Zhang DS, Zhou ZW, Li YH, Jiang WQ, Xu RH: Prognostic analysis in node-negative gastric cancer patients in China. Tumour Biol. 2011, 32: 489-492. 10.1007/s13277-010-0142-5.View ArticlePubMed
- Förster S, Gretschel S, Jöns T, Yashiro M, Kemmner W: THBS4, a novel stromal molecule of diffuse-type gastric adenocarcinomas, identified by transcriptome-wide expression profiling. Mod Pathol. 2011, 24: 1390-1403. 10.1038/modpathol.2011.99.View ArticlePubMed
- Qiu MZ, Wang ZQ, Zhang DS, Liu Q, Luo HY, Zhou ZW, Li YH, Jiang WQ, Xu RH: Comparison of 6th and 7th AJCC TNM staging classification for carcinoma of the stomach in China. Ann Surg Oncol. 2011, 18: 1869-1876. 10.1245/s10434-010-1542-x.View ArticlePubMed
- Qiu MZ, Han B, Luo HY, Zhou ZW, Wang ZQ, Wang FH, Li YH, Xu RH: Expressions of hypoxia-inducible factor-1α and hexokinase-II in gastric adenocarcinoma: the impact on prognosis and correlation to clinicopathologic features. Tumour Biol. 2011, 32: 159-166. 10.1007/s13277-010-0109-6.View ArticlePubMed
- Teh M, Lee Y-S: Intestinal and diffuse carcinoma of the stomach cancer among the ethnic and dialectic groups in Singapore. Cancer. 1987, 60: 921-925. 10.1002/1097-0142(19870815)60:4<921::AID-CNCR2820600435>3.0.CO;2-Z.View ArticlePubMed
- Ribeiro MM, Sarmento JA, Sobrinho Simões MA, Bastos J: Prognostic significance of Lauren and Ming classifications and other pathologic parameters in gastric carcinoma. Cancer. 1981, 47: 780-784. 10.1002/1097-0142(19810215)47:4<780::AID-CNCR2820470424>3.0.CO;2-G.View ArticlePubMed
- Yamamoto T, Kato H: Two major histological types of gastric carcinoma among the fixed population of Hiroshima and Nagasaki. Gann. 1971, 62: 381-387.PubMed
- Qiu MZ, Wang ZQ, Zhang DS, Luo HY, Zhou ZW, Wang FH, Li YH, Jiang WQ, Xu RH: Clinicopathological characteristics and prognostic analysis of gastric cancer in the young adult in China. Tumour Biol. 2011, 32: 509-514. 10.1007/s13277-010-0145-2.View ArticlePubMed
- Amorosi A, Palli D: Epidemiology of intestinal and diffuse types of gastric carcinoma: a time-trend study in Finland with comparison between studies from high- and low-risk areas. Cancer. 1994, 73: 1533-View ArticlePubMed
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.