Stage-Stratified Prognosis of Signet Ring Cell Histology in Patients Undergoing Curative Resection for Gastric Adenocarcinoma

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1 Ann Surg Oncol DOI /s ORIGINAL ARTICLE GASTROINTESTINAL ONCOLOGY Stage-Stratified Prognosis of Signet Ring Cell Histology in Patients Undergoing Curative Resection for Gastric Adenocarcinoma Zubin M. Bamboat, MD 1, Laura H. Tang, MD, PhD 2, Eduardo Vinuela, MD 1, Deborah Kuk, MS 3, Mithat Gonen, PhD 3, Manish A. Shah, MD 4, Murray F. Brennan, MD 1, Daniel G. Coit, MD 1, and Vivian E. Strong, MD 1 1 Gastric and Mixed Tumor Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY; 2 Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, NY; 3 Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY; 4 Gastrointestinal Oncology Service, Department of Medicine, Weill Cornell Medical College, New York, NY ABSTRACT Background. The prognosis of signet ring cell (SRC) gastric adenocarcinoma is regarded as poor, although studies addressing outcomes in relation to non-src tumors are conflicting. Our objective was to compare the survival of SRC tumors with stage-matched intestinal-type tumors in a cohort of Western patients. Methods. Review of a prospectively maintained database identified 569 patients undergoing curative resection (R0) from 1990 to Patients were divided into three histologic groups on the basis of the Lauren classification: SRC (n = 210), intestinal well- or moderately differentiated (WMD, n = 242) disease, and intestinal poorly differentiated (PD, n = 117) disease. Patient demographics, clinicopathologic features, and postoperative outcomes were determined. Stage-stratified disease-specific mortality was calculated and multivariate analysis performed. Results. When compared with WMD and PD tumors, SRC tumors were associated with younger age (63 years SRC vs. 71 years WMD and 72 years PD, p \ ) and with Zubin M. Bamboat and Laura H. Tang have contributed equally to this study. Electronic supplementary material The online version of this article (doi: /s ) contains supplementary material, which is available to authorized users. Ó Society of Surgical Oncology 2014 First Received: 14 August 2013 V. E. Strong, MD strongv@mskcc.org female sex (58 % SRC vs. 40 % WMD and 40 % PD, p = ). Median follow-up was 115 months. Patients with stage Ia SRC lesions had a better 5-year diseasespecific mortality compared with stage-matched intestinaltype tumors (0 % SRC vs. 8 % WMD and 24 % PD, p = 0.001). In contrast, SRC patients with stage III disease fared significantly worse (78 % SRC vs. 54 % WMD and 72 % PD, p = 0.001). On multivariate analysis, the risk of death from gastric cancer comparing all three groups was lowest for SRC in stage I and highest for SRC in stage III disease (stage III hazard ratio: SRC 1 vs. 7 WMD and 5 PD). Conclusions. When compared with intestinal-type tumors, SRC tumors at early stages are not necessarily associated with poor outcomes. Despite a decrease in the incidence of gastric cancer, there has been a steady increase in the diffuse signet ring cell (SRC) subtype in the United States. 1,2 Although SRC is typically associated with an ominous outcome, the prognostic significance of this histologic subtype needs clarification because the literature is conflicting. 2 SRC has been reported to have worse, similar, or better prognosis compared with other histologic subtypes in early and advanced stages of disease Most of the studies addressing this issue come from Asia, where the epidemiology and disease biology may differ from Western countries. Methodology and study design issues can also explain these apparent inconsistencies. Many comparisons are performed with poorly defined and heterogeneous non- SRC groups with tumor grades ranging from well differentiated to undifferentiated. Stage-stratified analyses are

2 Z. M. Bamboat et al. lacking, and unadjusted overall survival is predominantly used as the primary outcome measure despite SRCs association with significantly younger age. Studies that performed an adequate multivariate analysis of survival also have conflicting results. 5,6,8 10 On the basis of the Lauren classification, intestinal-type tumors comprise the non-src/cohesive gastric adenocarcinoma group. In contrast to SRC lesions that are invariably poorly differentiated, intestinal-type tumors range from well to poorly differentiated. SRC and intestinal-type tumors are considered distinct biologic entities with different carcinogenic pathways. 15 The clinical impact of these differences, however, is often masked by the dominating role of the tumor, node, metastasis classification staging system. To define the prognostic significance of SRC, we compared disease-specific mortality in stage-matched SRC patients undergoing R0 resection with that of well- and poorly differentiated intestinal-type adenocarcinomas. PATIENTS AND METHODS A total of 1794 patients who underwent curative (R0) resection for gastric adenocarcinoma between 1990 and 2009 at Memorial Sloan-Kettering Cancer Center (MSKCC) were identified from a prospectively maintained database. Patients with M1 disease, Siewert types 1 and 2 gastroesophageal junction cancer, or hereditary diffuse gastric cancer were excluded. Clinical data obtained included demographic characteristics, clinicopathologic findings, and follow-up status. Access to patient information was approved by the MSKCC institutional review and privacy board. Patients were categorized as shown in Supplementary Fig. S1. First, patients were grouped according to the Lauren classification on the basis of histologic analysis of the resected specimen. Patients with mixed-type tumors or with \15 lymph nodes were excluded from the study. Of the patients with diffuse-type tumors, only those with a SRC component greater than 50 % were included according to the World Health Organization classification. 16 Patients with intestinal-type cancers were further categorized according to the degree of differentiation into well- or moderately differentiated (WMD) and poorly differentiated (PD) groups. Patients with intestinal type cancers with a signet ring component in the final pathology report were excluded. This selection process rendered three clearly defined histological groups to be compared: diffuse SRC, intestinal WMD, and intestinal PD. In order to avoid the confounding effects of downstaging, patients who received neoadjuvant therapy were excluded. The 7th edition of the American Joint Committee on Cancer (AJCC) staging manual was used. Association between histologic groups and clinical variables were analyzed by Fisher s exact test for categorical variables and the Kruskal Wallis test for continuous variables. Disease-specific mortality was defined as the time from surgery to death due to gastric cancer. Death due to other causes was treated as a competing event. The cumulative incidence function (CIF) was used to describe gastric cancer-specific mortality. Gray s test was performed to assess differences in disease-specific mortality between the histologic groups. A multivariate fine and gray regression model was built using prognostic factors previously identified during the development of a postoperative prognostic nomogram. 17 An interaction term between histologic group and tumor stage was included. Cumulative incidence curves of disease-specific mortality by stage and histology showed a possible interaction between these two variables. Pathologic T (pt) and N (pn) were significant in the univariate setting but were excluded in the multivariate analysis as a result of the significant interaction between histology and stage, which encompasses pt and pn. A p-value of \0.05 was considered statistically significant. Statistical analyses were performed using R (R Development Core Team, 2011), including the cmprsk packages. RESULTS Clinicopathologic Characteristics After the selection process, 569 patients were suitable for inclusion in this study. Of these, 210 patients (37 %) had SRC, 242 patients (42 %) had WMD, and 117 patients (21 %) had PD tumors. Clinicopathologic variables are outlined in Table 1. Patients with SRC tumors were younger (63 vs. 71 and 72 years in WMD and PD, respectively, p \ ) and more frequently were women (58 vs. 40 and 40 % in WMD and PD, respectively, p = ). A higher proportion of SRC tumors were located in the proximal/body region of the stomach, which was similar to the intestinal types. Although an unusual finding, total gastric involvement was usually associated with the SRC type. The median lymph node yield was highest in SRC lesions (29 vs. 26 and 25 for WMD and PD tumors, respectively, p = 0.04). SRC and WMD tumors were smaller than PD tumors (4 vs. 5 cm for PD, p = 0.002). In addition, WMD tumors more frequently present as early stage (40 % T1, 58 % N0, and 44 % stage I) compared with the other subtypes (SRC: 24 % T1, 39 % N0, and 26 % stage I; PD: 14 % T1, 34 % N0, and 20 % stage I). Serosal involvement (pt4) was found more often in the SRC group (46 vs. 18 and 30 % for WMD and PD, respectively, p \ ). When lymph nodes were involved, the number of positive nodes was significantly higher in the SRC group (7 vs. 4 nodes for

3 Signet Ring Cell Prognosis in Gastric Cancer TABLE 1 Clinicopathologic data SRC signet ring cell, WMD well or moderately differentiated, PD poorly differentiated a Only among patients with positive nodes b Includes chemotherapy, radiotherapy, or chemoradiotherapy p-value from Fisher s exact test for categorical variables or Kruskal Wallis test for continuous variables Characteristic SRC Intestinal WMD Intestinal PD p value N \ Age (years) 63 (25 96) 71 (41 89) 72 (36 93) Gender Female 121 (58 %) 97 (40 %) 47 (40 %) Male 89 (42 %) 145 (60 %) 70 (60 %) Location Antrum/pylorus 84 (40 %) 95 (39 %) 32 (27 %) Proximal/body 112 (53 %) 145 (60 %) 83 (71 %) Entire stomach 14 (7 %) 2 (1 %) 2 (2 %) No. of collected nodes, median (range) 29 (15 69) 26 (15 84) 25 (15 65) 0.04 Tumor size, cm, median (range) 4 (0.1 21) 4 (0.1 19) 5 (0.5 12) pt T1 50 (24 %) 97 (40 %) 16 (14 %) \ T2 18 (9 %) 28 (12 %) 23 (20 %) T3 46 (22 %) 73 (30 %) 43 (37 %) T4 96 (46 %) 44 (18 %) 35 (30 %) pn N0 82 (39 %) 140 (58 %) 40 (34 %) \ N1 26 (12 %) 42 (17 %) 23 (20 %) N2 33 (16 %) 31 (13 %) 26 (22 %) N3 69 (33 %) 29 (12 %) 28 (24 %) No. of positive nodes, median (range) a 7 (1 63) 4 (1 30) 4 (1 60) \ Stage I 55 (26 %) 106 (44 %) 23 (20 %) \ II 52 (25 %) 68 (28 %) 39 (33 %) III 103 (49 %) 68 (28 %) 55 (47 %) Adjuvant therapy b Stage I 1/55 (2 %) 0/106 (0 %) 0/23 (0 %) 0.31 Stage II 6/52 (12 %) 7/68 (10 %) 6/39 (15 %) 0.73 Stage III 32/103 (31 %) 8/68 (12 %) 11/55 (20 %) 0.01 WMD and PD, p \ ). Patients with stage III SRC tumors were more likely to receive postoperative therapy in the form of chemotherapy and/or radiotherapy compared with WMD and PD groups (31 vs. 12 vs. 20 %, p = 0.01). Survival Analysis The median length of follow-up was 61 months. At last contact, 427 (75 %) patients had died, with 279 (49 %) dying from gastric cancer and 148 (26 %) dying from other causes. Figure 1a shows the overall cumulative incidence of gastric cancer specific death. Five- and 10-year cumulative mortality for all stages was significantly better in the WMD group at 24 and 29 %, respectively, versus 49 and 57 % for SRC and 43 and 51 % for PD (p \ ). The interaction between tumor histology and tumor stage is evident from the stage-stratified cumulative incidence curves of gastric cancer-specific mortality. For patients with stage Ia tumors, the 5- and 10-year gastric cancer-specific mortality was lowest for SRC (0 and 4 %), followed by WMD (8 and 11 %) and then PD (24 and [36 %, p = 0.001), which was significantly higher (Fig. 1b). Only one patient in the SRC group died of gastric cancer during follow-up compared with 5 patients in the PD group (p = by pairwise comparison). There were no significant differences in disease-specific mortality among groups for stage Ib and II disease (Fig. 1c, d). Substage analysis for patients with stage II disease revealed similar rates of stage IIa and IIb disease among histologic subtypes (Fig. 1; Table 1). In contrast, despite having the highest rates of postoperative therapy (Table 1), patients with stage III SRC tumors had the highest 5- and 10-year cumulative mortality (78 and 84 %), which was significantly worse than the other two groups (WMD: 53 and 56 %; PD: 71 and 74 %, p \ ) (Fig. 2a). There was, however, a significantly greater proportion of stage IIIc

4 Z. M. Bamboat et al. FIG. 1 Overall cumulative incidence curves of gastric cancer specific death for a stage I III, b stage Ia, c stage Ib, and d stage II disease a Probability of death due to disease Stage I III SRC (n = 210) WMD (n = 242) PD (n = 117) P-value < b Probability of death due to disease Stage Ia SRC (n = 36) WMD (n = 84) PD (n = 12) P-value < c Stage Ib SRC (n = 19) WMD (n = 22) PD (n = 11) P-value = 0.18 d Stage II SRC (n = 52) WMD (n = 68) PD (n = 39) P-value = patients in the SRC group than in the WMD and PD cohorts (p = , Fig. 2; Table 1). Disease-specific mortality by substage showed that patients with stage IIIc SRC tumors tended to do worse compared with the other two histologic subtypes (Fig. 2b d). In an attempt to understand why SRC tumors fare relatively well early in the course of disease, we evaluated rates of lymph node metastases in each histologic subtype after controlling for depth of invasion. There were no significant differences in nodal metastases among subtypes at any given T stage (not shown). Univariate and Multivariate Analysis Consistent with previous work from our institution, factors associated with disease-specific mortality on univariate analysis included tumor location and size, depth of invasion, and extent of nodal involvement (Table 2). 17 Tumor location, pathologic stage, and histologic subtype were independent predictors of disease-specific mortality on multivariate analysis. Patients with proximal/body lesions or tumors involving the entire stomach fared poorly compared with those with tumors in the antrum/pylorus (Table 2). Of the 18 patients with entire stomach involvement, 78 % died of disease, whereas only 30 % (64 of 211) with antrum/ pylorus tumors died of disease. After adjusting for all prognostic factors, stage-stratified hazard ratios and confidence intervals for each histologic group were calculated. Compared with the SRC group [hazard ratio (HR) of 1], the HRs of gastric cancer specific death for stage I WMD and PD tumors were 9 (p = 5) and 4.40 (p = 0.02, Table 3). For stage II disease, HRs relative to SRC were similar between subtypes (3 for WMD, p = 0.19 and 8 for PD, p = 0.09). In contrast to stage I disease, the risk of death from gastric cancer in stage III disease, was highest for SRC tumors (HR 7 for WMD, p \ 0.001, and HR 5 for PD, p = 7). DISCUSSION Increasing evidence suggests that gastric cancer is a heterogeneous disease whose behavior is dependent on tumor location and histopathology. SRC gastric cancers are commonly thought to portend a poor prognosis. This notion

5 Signet Ring Cell Prognosis in Gastric Cancer FIG. 2 Stage-stratified cumulative incidence curves of gastric cancer specific mortality for a stage III, b stage IIIa, c stage IIIb, and d stage IIIc disease a Probability of death due to disease Stage III P-value = b Probability of death due to disease Stage IIIa P-value = 0 SRC (n = 103) WMD (n = 68) PD (n = 59) SRC (n = 18) WMD (n = 27) PD (n = 17) c Stage IIIb P-value = 0.06 d Stage IIIc P-value = 0.12 SRC (n = 32) WMD (n = 25) PD (n = 16) SRC (n = 53) WMD (n = 16) PD (n = 22) comes from the lack of stage-stratified analyses and figures similar to our cumulative mortality curves for all patients (Fig. 1). The SRC survival curve is virtually superimposed with the PD one, which are both worse than the WMD group. Therefore, it may be tempting to merge SRC and PD tumors together as a single unfavorable prognostic group. In this study, we showed that after stratifying for tumor stage and adjusting for several known prognostic factors, SRC behaves differently from the PD intestinal subtype. Moreover, the mere presence of SRC histology should not be uniformly considered a poor prognostic feature; its effect on long-term outcome has to be considered within the context of extent of disease. Our data highlight the importance of studying stage-specific outcomes in SRC compared with well-defined intestinaltype tumors. With the latest AJCC staging system (7th edition), we have showed that SRC lesions exhibit favorable prognosis when diagnosed in early stage disease and fare worse in later stages. Using surveillance, epidemiology, and end results cancer registry data, a recent report by Taghavi et al. 18 found that SRC portends a similar prognosis at all stages compared with a heterogeneous group of non-src gastric adenocarcinomas. The authors acknowledged that receipt of perioperative chemotherapy was missing from the data set. In addition, rates of R0 versus R1 resection and extent of lymphadenectomy (D1 vs. D2) were not captured. The only other American study to look at the prognostic significance of SRC found no difference in stage-stratified mortality between SRC and non-src groups. 19 It is important to note that the authors did not use AJCC criteria, instead grouping patients into three broad categories: localized (N0), regional (T4 or N1), and distant (M1) disease. Another Western study that studied the prognostic significance of SRC found that compared with non-src tumors, SRC is an independent predictor of poor prognosis after R0 resection. 6 Because of insufficient numbers (n = 59 and 100 for SRC and non-src groups, respectively), the authors acknowledged that a stage-stratified analysis was not possible, and patients were instead grouped into early-stage (stages Ia IIIa) and late-stage (IIIb IV) groups. The SRC group fared worse in both early-stage and

6 Z. M. Bamboat et al. TABLE 2 Univariate and multivariate analysis Variable Univariate Multivariate HR 95 % Lower 95 % Upper p value HR 95 % Lower 95 % Upper p value Histology/stage interaction SRC/stage I NA NA SRC/stage II SRC/stage III \ \0.001 Intestinal WMD/stage I Intestinal WMD/stage II Intestinal WMD/stage III \ \0.001 Intestinal PD/stage I Intestinal PD/stage II Intestinal PD/stage III \ \0.001 Age Gender (M vs. F) Location Proximal/body versus antrum/pylorus \ Entire stomach versus antrum/pylorus \ Tumor size (cm) \ pt T2 versus T T3 versus T \0.001 T4 versus T \0.001 pn N1 versus N \0.001 N2 versus N \0.001 N3 versus N \0.001 No. of positive nodes \ Adjuvant chemotherapy (Y vs. N) \ SRC signet ring cell, NA not applicable, WMD well or moderately differentiated, PD poorly differentiated TABLE 3 Gastric cancer specific death rates based on disease stage and histology Characteristic Univariate Multivariate HR Lower Upper p value HR Lower Upper p value Stage I SRC NA NA Intestinal WMD Intestinal PD Stage II SRC NA NA Intestinal WMD Intestinal PD Stage III SRC NA NA Intestinal WMD \ \0.001 Intestinal PD SRC signet ring cell, NA not applicable, WMD well or moderately differentiated, PD poorly differentiated

7 Signet Ring Cell Prognosis in Gastric Cancer late-stage groups. Our results illustrate how stage-specific outcomes in SRC can be masked using stage grouping methodology, especially when the numbers of patients with early disease is small. Emerging data support the observation that gastric cancer represents multiple separate diseases with the same generic pathology but distinct pathogenesis. 20 SRC tumors are considered biologically distinct from intestinal-type tumors, which themselves differ according to tumor location and degree of differentiation. 21 Merging non-src tumors into a single group for outcome comparison after curative surgery is an oversimplification of this heterogeneous disease. To divide the non-src group into clinically relevant subsets, we compared SRC with intestinal tumors defined by their degree of differentiation (WMD and PD). The importance of this distinction is highlighted by the fact that WMD tumors were associated with better prognosis compared with PD tumors, regardless of stage. Moreover, despite all the SRC tumors in our data set being classified as poorly differentiated, their behavior differed compared with poorly differentiated tumors of the intestinal type. With the incidence of SRC rising in the United States, our findings have important prognostic implications that may shape treatment and follow-up strategies after curative surgery in a stage and subtype-dependent manner. 2 Our study is limited by the fact that mostly Western patients were included. Because the epidemiology of gastric cancer in the west may differ from Asia, the applicability of our results to patients treated in the east is uncertain. In addition, because we focused on patients with either diffuse or intestinal tumors, the clinical implications of patients with Lauren mixed histology on pathological assessment remain unclear. We believe that grouping the mixed-type cases into a single cohort for survival analysis would be an unfair representation of the biology of this heterogenous group of tumors. An analysis of the mixed group subtype revealed patients with a large range of intestinal/src ratios. Those with a predominantly SRC component (e.g., 90 % SRC, 10 % intestinal), tended to have survival rates similar to the pure SRC-type patients in our cohort. Similarly, patients with mixed-type histology but with mainly an intestinal-type pattern tended to have disease that behaved more like that of the pure intestinal group. An in-depth analysis of this mixed cohort of patients is beyond our scope here; however, it is worthy of a separate study once more patients have been acquired and once followup is longer. To avoid the confounding effects of downstaging from preoperative chemotherapy and potential differences in chemosensitivity of each histologic subtype, we excluded patients who received preoperative chemotherapy. 21,22 Therefore, our results should not be extrapolated to patients with locoregionally advanced disease who were treated with neoadjuvant therapy. Interestingly, despite receiving higher rates of adjuvant therapy for stage III disease, the SRC group tended to have higher rates of mortality, suggesting that sensitivity to adjuvant therapy may be subtype specific. Although our data are at risk of unique outcome as a result of singleinstitution bias, there is supporting literature on the favorable prognosis of early-stage SRC as well as poor outcomes in SRC for advanced disease. 4,6,9,11,12 Interestingly, despite similar rates of lymph node dissection, lymph node yield and the median number of positive nodes were highest in patients with SRC tumors (Table 1). Although it is possible that stage migration may account for some of the differences in outcomes observed in the SRC group, decreasing the threshold for N2 and N3 categories in the 7th edition of the AJCC staging system reduces the effect of this shift considerably 23. Moreover, in the setting of collecting over 15 nodes, the impact of a difference in retrieved lymph nodes on disease-specific survival is still unknown and awaits prospective confirmation. Although data exist to support the prognostic value of lymph node ratio (metastatic nodes/total lymph nodes), optimal cutoff values for ratios are poorly defined, and their prognostic value over the latest AJCC nodal staging system is unproven. With a relatively large and histologically homogeneous data set, we have uncovered an interesting association worthy of further investigation. In contrast to the majority of studies that indicate that SRC is universally associated with poor survival, our results reveal that SRC histology is a prognostic marker dependent on stage. We hypothesize that driver mutations controlling the metastatic potential of SRC may occur late in the course of disease, rendering SRC tumors relatively indolent in the early stages. Further studies examining the genetic and tumor microenvironment changes at various stages of disease may clarify the transition of SRC from a relatively favorable prognostic feature in early disease to one with aggressive features in more advanced disease. DISCLOSURE REFERENCES None. 1. Antonioli DA, Goldman H. Changes in the location and type of gastric adenocarcinoma. Cancer. 1982;50: Henson DE, Dittus C, Younes M, Nguyen H, Albores-Saavedra J. Differential trends in the intestinal and diffuse types of gastric carcinoma in the United States, : increase in the signet ring cell type. 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