Despite its incidence in Western countries had a steady decline over the last decade, gastric cancer (GC) still represents one of the major causes of cancer mortality worldwide (1). The prognosis of GC is mostly related to disease extension according to the seventh TNM classification (2). Currently, the clinical or pathological stage is the only validated tool available in the clinical practice to drive treatment decision-making. However, it must be pointed out that the individual risk of recurrence significantly varies within the same stage, and overall survival (OS) profoundly depends on additional prognostic factors (3,4).
The diffuse and intestinal types of GC describe two histological entities that are different with regard to epidemiology, pathogenesis, biological features and clinical behavior. Currently, there is no difference in the clinical management of these two main histotypes identified by both World Health Organization and Lauren’s classification systems (5,6). It is generally recognized that GC with a differentiated histology or intestinal-type shows a better prognosis than individual with a poorly differentiated histology or a diffuse-type (7). However, most available studies were limited by the small sample size and retrospective nature, with consequent methodological limitations and barriers in validating the histotype as an independent prognostic factor.
In this systematic review and meta-analysis, we aimed at clarifying the prognostic value of Lauren’s classification in patients with surgically resected GC.
The search was performed searching the electronic database PubMed, the Cochrane Library, SCOPUS, Web of Science, EMBASE and CINAHL up to December 2015. Searches included the terms (“gastric cancer” or “gastric carcinoma”) and (“Lauren” or intestinal or diffuse) and (multivariate or multivariable or cox regression) and (hazard ratio). Manual selection of relevant studies was carried out based also on the related articles function. The citation lists of all retrieved articles were analyzed to identify other potentially relevant reports.
Study selection and data extraction
The following criteria for eligibility among studies were set before collecting articles: (I) histology according to Lauren classification was evaluated in primary GC tissue (biopsies or surgical specimen of primary tumor); (II) survival information (median OS) at specific follow-up was reported in the article as HR according to multivariate analysis, after histology classification resulted significantly in univariate analysis; (III) articles were published in English language; (IV) when several articles were published by the same authors or group, the newest or most informative single article was selected. Exclusion criteria were the following: (I) no information on OS was provided; (II) letters to editor/commentary, reviews, and articles published in a book or papers; (III) clinical studies with chemotherapy or concurrent chemoradiotherapy treatment investigating response rates only.
Two authors (FaP and RB) did the search and identification independently, and selection of an article was reached by consensus with a third author (FiP). The following information was extracted from each report by the two authors independently: year of publication, country, patient size, type of study, histology (intestinal vs. diffuse disease rates), disease stage (locoregional tumors vs. stage IV), surgery (rate), type and rate of (neo)adjuvant therapy, survival data (HRs) and covariates indagates in multivariate analysis.
For analysis of survival results, HRs were pooled to provide an aggregate value. In this analysis, all HRs with 95% confidence intervals (CIs) adjusted for the maximum number of covariates (significantly associated with OS in univariate analysis) and available in the articles, were combined for obtaining a prognostic information of diffuse (vs. intestinal) histology, independent of other clinicopathological covariates. Subgroup analysis was performed according to race (Asiatic vs. non-Asiatic origin, localized vs. stage IV disease, and no systemic therapy vs. systemic therapy exposure). Data were entered into the Comprehensive Meta Analysis software v 3.3.070 (November 20th* 2014). The Cochran’s test was used to assess the heterogeneity of included studies. For heterogeneity tests, P<0.05 was considered to indicate significance. If the test of heterogeneity was significant (P<0.05 or I2 >50%), the random-effect model was used. Otherwise, the fixed-effect model was used. By convention, an observed HR of >1 implied the worst survival for the group with diffuse histology.
We finally investigated publication bias for OS meta-analysis with a visual inspection of funnel plots and with the Begg-Mazumdar Kendall’s tau and Egger’s bias test (8,9). Moreover, in the presence of publication bias for the primary analyses, we conducted a trim-and-fill-adjusted analysis (10) to remove the most extreme small studies from the positive side of the funnel plot, and recalculated the effect size at each iteration, until the funnel plot was symmetric about the (new) effect size.
A total of 1,228 potentially relevant citations were reviewed (Figure 1). Among them, 23 reported OS data as risk ratio or odds ratio or did not report 95% CI for inclusion in the final analysis. Ultimately, 73 studies (Table 1) that reported the prognostic value of histology classification for OS were analyzed. The total number of patients included was 61,468, ranging from 41 to 11,189 patients per study (median, 274). The major characteristics are shown in Table 1.
In n=7 publications a retrospective analysis of prospective trials was presented, all other publications reported a retrospective analysis of surgically treated series of patients with GC. The majority (n=45) were Asiatic countries publications; the remaining n=28 publication were of Western origin (including n=3 multinational, n=5 US, n=1 Brazilian, n=16 European, n=1 Giordany, n=1 Tunisian and n=1 Turkish series). Surgery of the primary tumor was performed in all patients in n=68 studies. Chemotherapy, plus or minus radiotherapy was offered to many patients except in n=20 publication where no patients received systemic therapy (in n=18 studies this data was not reported). When reported, intestinal histology ranged from 8.5% to 83% of patients, diffuse subtype from 9.8% to 73.5% (only in n=6 studies rates of different histologies were not reported).
Meta-analysis of adjusted hazard ratios (HRs) for OS (all studies)
The effect of histology classification on OS was evaluated in all studies with a total of 61,468 patients analyzed. Overall, the HRs of each study (adjusted for the maximum number of the covariates available and with significant association in univariate analysis) were pooled using a random-effect model, and the final value (HR 1.23; 95% CI, 1.17–1.29; P<0.0001; I2 38%, P for heterogeneity 0.001; Figure 2), indicates that diffuse histology was an indicator of worst prognosis.
Subgroup analysis according to race, stage and systemic therapy
In studies selected for the country (Asiatic vs. non-Asiatic countries, only n=2 studies not included for mixed origins) the increased risk of death associated with diffuse histology was similar (HR 1.22; 95% CI, 1.15–1.29; P<0.0001 vs. HR 1.28; 95% CI, 1.19–1.38; P<0.0001 according to random effect model).
The combined HR according to the stage of disease (stage I–III in all tumors vs. stage IV disease only) was statistically significant. In fact, a poorer prognosis was observed for both stage I–III and more advanced stages GCs (n=25 vs. n=7 studies) with diffuse histology (HR 1.21; 95% CI, 1.12–1.3; P<0.0001 vs. HR 1.25; 95% CI, 1.04–1.5; P=0.014 according to random effect model).
In patients exposed to systemic therapy (either for early or advanced disease), the results were similar, with diffuse histology associated with adverse prognosis (HR 1.27; 95% CI, 1.17–1.37; P<0.0001). Similar results were observed in studies that not included patients treated with systemic therapy (HR 1.15; 95% CI, 1.07–1.24; P<0.0001 according to random effect model).
Both Begg’s and Egger’s test were significant for publication bias (Figure 3). Given the publication bias observed, we calculated the Trim-and-Fill-adjusted analysis. With this analysis, 16 missing studies based on a random effects model (according to trim and fill method), put to the left side of the mean effect, are calculated for a final HR 1.18 (95% CI, 1.12–1.24). Finally, the overall result remains unchanged after the one-study-removed procedure, so no dominant study was included.
According to Lauren’s classification, GC is categorized as intestinal- and diffuse types (5). Although the Lauren classification system was developed in 1965, it is still widely accepted and employed by pathologists and oncologist, and represents a simple, reproducible and robust classification approach. Intestinal-type GC is more prevalent in men and older people and is associated with chronic inflammation: as a consequence of Helicobacter Pylori-related atrophic gastritis in the antrum, and as a result of reflux in the gastroesophageal junction. Diffuse-type GC is more prevalent in younger people and women, with the absence of a pathogenetic role of inflammation and strong relationship with cell adhesion dysfunction—even as part of hereditary syndromes in germline CDH1 mutated patients. Clinically, the two histotypes of GC have a different pattern of metastatic spread, with more frequent peritoneal involvement in diffuse cancers (84). Currently, the management of patients with GC is mostly dependent on prognostic assessment based on clinical and pathological stage, while histology still needs to be validated as a prognostic or even predictive factor in patients with GC. As a consequence, treatment algorithms and clinical trials have not been tailored on histotype yet.
In this meta-analysis, we explored whether histology, according to Lauren classification, retains an independent prognostic significance in GC. To our knowledge, this is the first meta-analysis to address this issue. The final pooled analysis showed that diffuse histology, as literature data previously suggested, is confirmed as an independent prognostic factor in multivariate analysis in more than 60,000 patients with resected, localized or advanced GC. In the global population, the risk of death was increased by 23%, and this increased risk was not altered by race, stage (locally advanced vs. metastatic) and exposure to chemotherapy. As for now, this represents the most updated systematic on this topic. Liu et al. (7), previously, conducted a meta-analysis examining the survival outcomes among patients with diffuse vs. intestinal histology. They found a better 5-year OS for patients treated with surgery compared with radiotherapy. A major limitation of their study was that they used adjusted and unadjusted odds ratios that do not take into account adjustment for common clinicopathological variables as our paper did.
In patients with GC, the clinical experience suggests a significant variability of outcomes and responsiveness to treatments. The heterogeneity of GC is related to several factors such as epidemiology, pathogenesis, and disease biology. Prognostic and predictive factors beyond disease stage (3,4) are clearly needed, and histotype could be proposed as a surrogate marker of disease biology. A 3-group classification was previously proposed according to histology and tumor site, namely “proximal non-diffuse”, “diffuse”, and “distal non-diffuse” types (85,86). It was shown that the subtypes have distinct gene expression profiles. Moreover, the TCGA study showed the presence of four genomic subtypes [namely, EBV-positive, microsatellite instable, Genome Stable and Chromosomal Instability (87)]. It must be pointed out that microsatellite instable GC is mainly represented by non-diffuse distal cancers while genome stable by intestinal-type ones and chromosomal instability by diffuse-type ones. Thus, there seems to be a good correlation between histology and biology within the TGCA dataset.
The clinical relevance of these data will hopefully allow the distinction in managing each subtype separately. While increasing our knowledge of biological heterogeneity of GC, the goal is to use the distinct biologic subtypes as prognostic and predictive biomarkers to improve patients’ management and outcome. However, limited work has been done to create a consensus about the several published subtypes, and their clinical applicability is still difficult due to limited widespread of technologies and costs. Some tools are nowadays implemented for estimating patients’ outcome, such as nomograms. One example in GC is the nomogram developed by Kattan et al. (88), where the predictions were based on the following established prognostic factors: patient’s age and gender, tumor size, depth of tumor invasion, percentage of positive and negative nodes and, notably, tumor primary location and histology. Based on these data and our results, histology may be already used as a simple, costless and easy stratification factor in clinical trials for patients with homogeneous disease stage. It may be also used with predictive purposes when assessing the efficacy of newer drugs. Notably, it was already shown that HER-2 amplification is mostly found in intestinal-type and proximal cancers (89), while FGFR2 amplification is typical of diffuse tumors (90), and even anti-angiogenic drugs may be more effective in intestinal-type GC (91).
A limitation of this review, as with any review or meta-analysis, is publication bias. Publication bias occurs when negative results (negative histology results in our case), which are often not published, are excluded. Analyses of efficacy by histologic subtype may not be reported for several reasons: the histology data were not collected; analyses were not performed because the study was inadequately powered or because historical evidence suggested such analyses were not important; analyses were performed but results were negative (and/or inconsistent across other endpoints) and therefore not reported; or results of analyses were positive but not reported because it was unclear how to interpret the findings. However, heterogeneity was moderate (I2 =38%), and it has been taken in account through a random effect model analysis. Also, even if publication bias was somewhat significant with Begg’s and Egger’s tests, the leave-one-out procedure, excluded any “dominant” study. Furthermore, sensitivity analysis adjusting for race, use of systemic therapy or stage did not modify the overall result substantially. Finally, the trim-and-fill procedure found that putting 16 asymmetric studies on the left of the mean effect of the funnel plot; the final results remained substantially unaltered. A second limitation is the use of the Lauren instead World Health Organization classification, that split adenocarcinomas in papillary, tubular mucinous, poorly cohesive and mixed forms. Only two papers included into classification of diffuse types poorly cohesive or signet ring cases, and aim of paper was the validation of prognostic significance of Lauren’s subtypes, that is still controversial.
On the contrary, major strengths of this paper are the comprehensive search strategy, careful selection of studies, the attempt of subgroup analyses, and the use of survival outcome that consider HRs adjusted for common confounders.
Many biomarkers are being evaluated to establish prognostic or predictive factors in GC, and several have been identified for their potential key role, but their clinical use remains controversial. In this scenario, the prognostic role of histology seems to confirm a valid prognostic indicator and will play a significant role in future clinical trials.
Conflicts of Interest: The authors have no conflicts of interest to declare.
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