cancers Systematic Review Clinical Features of Gastric Signet Ring Cell Cancer: Results from a Systematic Review and Meta-Analysis Mariagiulia Dal Cero 1,2 , Maria Bencivenga 1, *, Drolaiz H. W. Liu 3,4 , Michele Sacco 1 , Mariella Alloggio 1 , Kelly G. P. Kerckhoffs 3,5 , Federica Filippini 1 , Luca Saragoni 6 , Mar Iglesias 7 , Anna Tomezzoli 8 , Fátima Carneiro 9 , Heike I. Grabsch 3,10 , Giuseppe Verlato 11 , Lorena Torroni 11 , Guillaume Piessen 12 , Manuel Pera 2 and Giovanni de Manzoni 1 1 General and Upper GI Surgery Division, Department of Surgery, University of Verona, Borgo Trento Hospital, Piazzale Stefani 1, 37124 Verona, Italy; 1325220@uab.cat (M.D.C.) 2 Section of Gastrointestinal Surgery, Hospital Universitario del Mar, Hospital del Mar Medical Research Institute (IMIM), Department of Surgery, Universitat Autònoma de Barcelona, 08003 Barcelona, Spain 3 Department of Pathology, GROW School for Oncology and Reproduction, Maastricht University Medical Center, 6229 HX Maastricht, The Netherlands 4 Institute of Clinical Pathology and Molecular Pathology, Kepler University Hospital and Johannes Kepler University, 4021 Linz, Austria 5 Department of Pathology, VieCuri Medical Centre, 5912 BL Venlo, The Netherlands 6 Pathology Unit, Morgagni-Pierantoni Hospital, 47100 Forlì, Italy 7 Department of Pathology, Hospital Universitario del Mar, Hospital del Mar Medical Research Institute (IMIM), 08003 Barcelona, Spain 8 Department of Pathology, Verona University Hospital, 37134 Verona, Italy 9 Department of Pathology, Medical Faculty of the University of Porto/Centro Hospitalar Universitário São João and Ipatimup/i3S, 4200-319 Porto, Portugal 10 Division of Pathology and Data Analytics, Leeds Institute of Medical Research at St. James’s, University of Leeds, Leeds LS2 9JT, UK 11 Unit of Epidemiology and Medical Statistics, Department of Diagnostics and Public Health, University of Verona, 37126 Verona, Italy Citation: Dal Cero, M.; Bencivenga, 12 Department of Digestive and Oncological Surgery, Lille University Hospital, 59000 Lille, France M.; Liu, D.H.W.; Sacco, M.; Alloggio, * Correspondence: maria.bencivenga@univr.it; Tel.: +0039-04-5812-3063 M.; Kerckhoffs, K.G.P.; Filippini, F.; Saragoni, L.; Iglesias, M.; Tomezzoli, Simple Summary: The clinical behaviour of signet ring cell histology in gastric cancer has long A.; et al. Clinical Features of Gastric been a subject of controversy. Recent years have underscored the pressing issue of a lack of a Signet Ring Cell Cancer: Results from standardised definition for signet ring cell histology, leading to its often-ambiguous placement within a Systematic Review and Meta- broader categories associated with poor prognosis. Conversely, comparisons of signet ring cell Analysis. Cancers 2023, 15, 5191. gastric cancer have been made against a wide spectrum of non-signet ring cell cases, introducing https://doi.org/10.3390/ significant heterogeneity. The primary objective of this literature search and subsequent meta-analysis cancers15215191 was to gain a deeper understanding of signet ring cell gastric cancer. Our findings revealed that Academic Editors: Yasuhide Yamada the prognosis of signet ring cell gastric cancer is intricately tied to the disease stage, yet it is also and Naoki Takahashi contingent on the specific comparison group employed. The variability in signet ring cell cancer’s Received: 5 September 2023 clinical behaviour may stem from the absence of a standardised definition. Therefore, it is imperative Revised: 17 October 2023 to work towards a uniform classification system for gastric cancer to enhance clarity and coherence Accepted: 26 October 2023 in future research and clinical practice. Published: 28 October 2023 Abstract: Background: Conflicting results about the prognostic relevance of signet ring cell histol- ogy in gastric cancer have been reported. We aimed to perform a meta-analysis focusing on the clinicopathological features and prognosis of this subgroup of cancer compared with other histolo- Copyright: © 2023 by the authors. gies. Methods: A systematic literature search in the PubMed database was conducted, including Licensee MDPI, Basel, Switzerland. all publications up to 1 October 2021. A meta-analysis comparing the results of the studies was This article is an open access article distributed under the terms and performed. Results: A total of 2062 studies referring to gastric cancer with signet ring cell histology conditions of the Creative Commons were identified, of which 262 studies reported on its relationship with clinical information. Of these, Attribution (CC BY) license (https:// 74 were suitable to be included in the meta-analysis. A slightly lower risk of developing nodal creativecommons.org/licenses/by/ metastases in signet ring cell tumours compared to other histotypes was found (especially to undif- 4.0/). ferentiated/poorly differentiated/mucinous and mixed histotypes); the lower risk was more evident Cancers 2023, 15, 5191. https://doi.org/10.3390/cancers15215191 https://www.mdpi.com/journal/cancers Cancers 2023, 15, 5191 2 of 22 in early and slightly increased in advanced gastric cancer. Survival tended to be better in early stage signet ring cell cancer compared to other histotypes; no differences were shown in advanced stages, and survival was poorer in metastatic patients. In the subgroup analysis, survival in signet ring cell cancer was slightly worse compared to non-signet ring cell cancer and differentiated/well-to- moderately differentiated adenocarcinoma. Conclusions: Most of the conflicting results in signet ring cell gastric cancer literature could be derived from the lack of standardisation in their classification and the comparison with the different subtypes of gastric cancer. There is a critical need to strive for a standardised classification system for gastric cancer, fostering clarity and coherence in the forthcoming research and clinical applications. Keywords: gastric cancer; signet ring cells; survival; poorly cohesive; pathological classification 1. Introduction Gastric cancer (GC) is a complex and heterogeneous disease. Despite its declining incidence in developed countries, such as the USA, it remains the fourth leading cause of cancer-related mortality [1]. Signet ring cell carcinoma (SRCC) is a subtype of poorly cohe- sive gastric cancer, which can be challenging to diagnose with conventional methods [2], and accurate disease staging can be complicated. An explorative laparoscopy is required to detect peritoneal carcinomatosis, which is more common in poorly cohesive cancers and usually not detectable on a CT scan [3–5]. It has been suggested that the prognosis of patients with signet ring cell (SRC) gastric cancer depends on the disease stage as for other histological subtypes [6]. Whether the percentage of SRC within the tumour may predict survival and response to preoperative therapy is still a matter of debate [7,8]. SRCC was described as a histological subtype of gastric cancer in the 1st edition (1977) of the World Health Organization (WHO) classification [9] and was defined as a tumour predominantly or exclusively composed of signet ring cells [10]. Since the publication of the 4th edition of the WHO classification (2010), SRCC has been considered a subtype of poorly cohesive carcinoma [11]. In the recent 5th edition of the WHO classification, poorly cohesive (PC) gastric cancer was subdivided into the SRCC subtype (>90% SRC) and PC not otherwise specified (PC-NOS) [12]. The Japanese Gastric Cancer Association (JGCA) classification originally classified SRCC as undifferentiated adenocarcinoma. Since the 2nd edition (1993), poorly differentiated adenocarcinoma (PDA) has been subdivided into solid and non-solid subtypes [13]. The non-solid subtype PDA corresponds to the poorly cohesive subtype of the WHO classification and the diffuse type in the Laurèn classification [11]. In the Laurèn classification, SRCC and other poorly cohesive GCs are classified as “diffuse”-type GCs [14]. The Nakamura classification includes SRCC in the “undifferentiated” category [15]; see Figure 1. A significant difference between the classifications most commonly used in the West (WHO and Laurèn) and those used in the East (JGCA, Nakamura) is that, in the West, there is a concept of ‘poorly cohesive’ cancer. In the East, there is a concept of ‘poorly differentiated’ cancer [12]. Unfortunately, these two concepts do not fully overlap, causing difficulties in interpreting study results with subsequent knowledge gaps. Generally, GC should be composed predominantly or exclusively of SRC to be classi- fied as SRCC. According to several authors, SRCC is an adenocarcinoma in which more than 50% of the tumour consists of isolated or small groups of malignant cells containing intra-cytoplasmic mucins [11]. Despite this, a universal standardised definition of SRCC is yet to be found, and, frequently, it is not clear which criteria are used to classify SRCC. Many studies including clinical trials lump SRCC with other subtypes; therefore, this study aims to investigate the use of different definitions and histopathological classifi- cations of SRCC through a comprehensive literature review and meta-analysis. We will further analyse the relationship between pathological classifications with prognosis and treatment outcome. Cancers 2023, 15, 5191 3 of 22 Cancers 2023, 15, x FOR PEER REVIEW 3 of 22 Figure 1. Pathological classifications of gastric cancers. Figure 1. Pathological classifications of gastric cancers. A significant difference between the classifications most commonly used in the West 2. Materials and (WHO Methodsand Laurèn) and those used in the East (JGCA, Nakamura) is that, in the West, there 2.1. Search Strategy andis Study a concept of poorly cohesive’ cancer. In the East, there is a concept of poorly Selection differentiated’ cancer [12]. Unfortunately, these two concepts do not fully overlap, causing This literature review difficulties and meta-analysis in interpreting study results with were conducted subsequent knowledgefollowing gaps. the PRISMA Generally, guidelines [16]. The study was GCnot should be composed registered in predominantly PROSPERO.or exclusively of SRC to be clas- sified as SRCC. According to several authors, SRCC is an adenocarcinoma in which more A comprehensive literature search was performed using the PubMed database, in- than 50% of the tumour consists of isolated or small groups of malignant cells containing cluding articles published intra-cytoplasmic in English mucins [11].from 1947 Despite toa 1universal this, October 2021, using standardised synonyms definition of SRCC and is yet to be found, Medical Subject Headings (MeSH) and, terms frequently, for it‘gastric’ is not clear which and criteria are used ‘signet-ring celltocancer’ classify SRCC. (Table S1). Many studies including clinical trials lump SRCC with other subtypes; therefore, this Two authors (MDC and LT) independently conducted the search and study aims to investigate the use of different definitions and histopathological classifica- identification of manuscripts thattionscould be included in this study by screening publication of SRCC through a comprehensive literature review and meta-analysis. We will fur- titles and ab- stracts, while a third ther author analyse the (MB) checkedbetween relationship any disagreement and confirmed pathological classifications that theand with prognosis selected manuscripts met treatment outcome. the inclusion criteria. We included2.studies Materials that andreported Methods on clinical aspects of SRCC in gastric cancer patients. We excluded studies reporting 2.1. Search Strategy and (1)Study results from less than 10 SRCC cases; (2) case reports Selection referring to hereditary This diffuse literature gastric review andcancer (HDGC); meta-analysis were(3) cell culture-based conducted following the PRISMAstudies or guidelines [16]. animal studies reporting only Theon study was not registered oesophageal in PROSPERO. adenocarcinomas; and (4) studies where A comprehensive literature search was performed using the PubMed database, in- we were unable cluding to retrieve the full-text version of an article. We also excluded studies articles published in English from 1947 to 1 October 2021, using synonyms and focussing on histopathological Medical Subject Headingsaspects(MeSH) as ourterms group for published gastric’ and these studies signet-ring separately cell cancer ’ (Table [17]. We finally refined S1). Two the authorsselection, (MDC anddetecting LT) independently papers that contained conducted the search anduseful data of identification for the manuscripts that could be included in this study by screening publication titles and ab- meta-analysis, such as the lymph node metastasis and lymphovascular invasion and stracts, while a third author (MB) checked any disagreement and confirmed that the se- survival hazard ratio lected(HR) or relative manuscripts met therisk (RR)criteria. inclusion in SRCC compared to other common gastric cancer histotypes. All Wethe definitions included ofreported studies that SRC were accepted; on clinical aspects ofnevertheless, SRCC in gastric to reduce cancer pa- the tients. We excluded variability, we eventually excluded studies formerreporting studies (1) results (before from less than 2010, when 10 the SRCC cases; (2) of category case poorly reports referring to hereditary diffuse gastric cancer (HDGC); (3) cell culture-based cohesive gastric cancer was introduced [11]) and studies that utilised non-comparable groupings (for instance, papers comparing pure SRCC to SRCC with 50–100% or 10–90% SRC; papers where SRCCs were grouped together with PDA; papers where SRCCs were compared to uncommon gastric cancer as adenosquamous or hepatoid; papers focussing on node-negative or synchronous multifocal gastric cancer). The following study characteristics were recorded: name of the first author, year of publication, country and continent of patient cohort origin, stage of gastric disease cancer, the total number of patients included in the study, number of SRCC and non-signet ring cell carcinoma (NSRCC) patients, histopathological classification used, % of patients with lymph node metastasis, presence of lymphovascular invasion, and relationship between histological phenotype and survival. The observational studies were evaluated to assess the risk of bias using the Newcastle–Ottawa scale (NOS) [18], a scale designed to assess the quality of nonrandomised studies in interpreting meta-analytic results. Cancers 2023, 15, 5191 4 of 22 2.2. Analysis of Histopathologic Classification Systems and Definitions of SRCC For each of the studies included, we first analysed which histopathological classifi- cation was used and whether a specific definition of SRC was provided. We reported the histopathologic classification systems and definitions of SRCC used in the different studies according to the reference systems reported above [12–14]. 2.3. Statistical Analysis—Meta-Analysis A meta-analysis was conducted in the selected studies, comparing the results of the various studies and focusing on lymph node and lymphovascular invasion and survival, which are important features in the prognosis of gastric cancer. The RR was calculated for categorical variables (lymph node and lymphovascular invasion), and the HR for time- dependent variables (survival). To evaluate the variability among studies, we computed a heterogeneity test and the I2 statistic, indicating the proportion of total variation among the effect estimates of different studies attributed to heterogeneity rather than sampling error. When the heterogeneity test was not significant (p > 0.050), I2 was less than 30% [19,20], and significant heterogeneity was ruled out. In this case, a fixed-effects model was adopted to evaluate the results pooled using the method of Mantel and Haenszel. Otherwise, a random effects model was used, and the pooling of results was performed using the DerSimonian and Laird method [21]. Egger’s test and the funnel plot addressed the small study effect. The level of statistical significance was set at 5%, and confidence intervals (CI) were calculated at 95%. The results were displayed graphically using forest plots. The STATA software, version 17 (StataCorp, College Station, TX, USA), was used for the analysis. 3. Results The literature search in PubMed (Figure 2) resulted in 2062 articles published between 1947 and 1 October 2021. We excluded 1799 articles: 693 case reports, 493 focused on pathological aspects, 403 were not relevant, 85 cell culture-based studies or animal studies, Cancers 2023, 15, x FOR PEER REVIEW 75 on HDGC, and 33 with less than ten or no SRCC cases, 14 7 of did 22 not have full-text availability, and 4 focused on oesophageal carcinoma. In total, 262 articles were included. Figure 2. Flow Figure 2. chart Flowofchart the literature of thesearch and selection literature searchofand studies. selection of studies. In the set of 74 selected articles, we searched for the definition of SRCC and the patho- logical classification used, and we found that both varied between studies (Figure 3). The WHO classification [12] was most frequently used (27 studies—37%), 7 studies (10%) used the Japanese classification [13], and 1 study (1%) used Laurèn’s classification [14]. A total of 24 studies (32%) used more than one classification (WHO, Japanese, Laurèn, Naka- Cancers 2023, 15, 5191 5 of 22 By searching for papers that contained useful data for the meta-analysis and excluding studies from before 2010, we finally included 74 papers. We first evaluated these studies according to the Newcastle–Ottawa scale: 19 scored six points (26%), 25 scored seven points (34%), 23 scored eight points (31%), and 7 scored nine points (9%) (Table S2). Since we consider the quality threshold of six points, all 74 studies were included in the meta-analysis (Figure 2). The general characteristics of the included studies are presented in Table 1 and, more specifically, in Table S3. Table 1. Information of the included studies sorted by continent and stage. Patients’ Author Year Continent Stage n. SRCC n. NSRCC % SRCC Source Single 1 Efared B [22] 2020 Africa AGC 56 127 31% institution Single 2 Lee JH [23] 2010 Asia EGC 448 914 33% institution Single 3 Nam MJ [24] 2010 Asia EGC 720 1804 29% institution Single 4 Kim HM [25] 2011 Asia EGC 419 288 59% institution Single 5 Tong JH [26] 2011 Asia EGC 102 320 24% institution Single 6 Huh CW [27] 2013 Asia EGC 696 1512 32% institution Single 7 Kim BS [28] 2014 Asia EGC 345 1705 17% institution Single 8 Guo CG [29] 2015 Asia EGC 198 869 19% institution Single 9 Jin EH [30] 2015 Asia EGC 227 877 21% institution Single 10 Lee SH [31] 2015 Asia EGC 114 582 16% institution Single 11 Wang Z [32] 2015 Asia EGC 115 219 34% institution Single 12 Hwang CS [33] 2016 Asia EGC 233 317 42% institution Single 13 Imamura T [34] 2016 Asia EGC 190 556 25% institution Single 14 Kim YH [35] 2016 Asia EGC 927 368 72% institution Single 15 Yoon HJ [36] 2016 Asia EGC 930 2489 27% institution Single 16 Bang CS [37] 2017 Asia EGC 89 186 32% institution Single 17 Kang Sun H [38] 2017 Asia EGC 91 731 11% institution Single 18 Lee IS [39] 2017 Asia EGC 652 1185 35% institution Single 19 Horiuchi Y [40] 2018 Asia EGC 129 139 48% institution Cancers 2023, 15, 5191 6 of 22 Table 1. Cont. Patients’ Author Year Continent Stage n. SRCC n. NSRCC % SRCC Source Single 20 Kwak DS [41] 2018 Asia EGC 331 206 62% institution Single 21 Nakamura R [42] 2019 Asia EGC 209 117 64% institution Single 22 Ryu DG [43] 2019 Asia EGC 233 143 62% institution Single 23 Zhu ZL [44] 2020 Asia EGC 287 230 56% institution Single 24 Zou Y [45] 2020 Asia EGC 146 177 45% institution Single 25 Zu H [46] 2014 Asia AGC 44 697 6% institution Single 26 Alshehri A [47] 2020 Asia AGC 219 1786 11% institution Single 27 Cho JH [48] 2015 Asia MGC 111 125 47% institution Single 28 Men HT [49] 2016 Asia MGC 40 17 70% institution Single 29 Choi JH [50] 2020 Asia MGC 171 516 25% institution Single 30 Zhang M [51] 2010 Asia All Stages 218 1221 15% institution Single 31 Chiu CT [52] 2011 Asia All Stages 505 1934 21% institution Single 32 Jiang CG [53] 2011 Asia All Stages 211 2104 9% institution Single 33 Lee HH [54] 2012 Asia All Stages 320 1056 23% institution Single 34 Bu Z [55] 2013 Asia All Stages 107 74 59% institution Single 35 Jiang H [56] 2013 Asia All Stages 288 80 78% institution Single 36 Kwon KJ [57] 2014 Asia All Stages 108 661 14% institution 37 Shim JH [58] 2014 Asia Multicentric All Stages 377 2266 14% Single 38 Liu X [59] 2015 Asia All Stages 138 1326 9% institution Single 39 Hsu JT [60] 2016 Asia All Stages 545 925 37% institution Single 40 Kong P [61] 2016 Asia All Stages 90 390 19% institution Single 41 Lu M [62] 2016 Asia All Stages 354 1845 16% institution Single 42 Tang X [63] 2016 Asia All Stages 260 244 52% institution Single 43 Wang Z [64] 2016 Asia All Stages 620 3310 16% institution Cancers 2023, 15, 5191 7 of 22 Table 1. Cont. Patients’ Author Year Continent Stage n. SRCC n. NSRCC % SRCC Source Single 44 Chon HJ [65] 2017 Asia All Stages 1646 6021 21% institution Single 45 Chen J [66] 2018 Asia All Stages 62 179 26% institution Single 46 Lee D [67] 2018 Asia All Stages 176 588 23% institution Single 47 Kao YC [68] 2019 Asia All Stages 755 2216 25% institution Single 48 Ahn H [69] 2020 Asia All Stages 200 260 43% institution Single 49 Huang KH [70] 2020 Asia All Stages 181 260 41% institution Single 50 Wang JB [71] 2020 Asia All Stages 449 2893 13% institution Single 51 Dong X [72] 2021 Asia All Stages 254 3885 6% institution Single 52 Jin X [73] 2021 Asia All Stages 121 2045 6% institution Single 53 Zhao B [74] 2021 Asia All Stages 235 1656 12% institution Asia– Single 54 Bozkaya Y [75] 2016 All Stages 142 51 74% Europe institution 55 Gronnier C [76] 2013 Europe Multicentric EGC 104 317 25% 56 Lemoine N [77] 2016 Europe Multicentric MGC 57 146 28% Swedish 57 Riihimäki M [78] 2016 Europe MGC 82 736 10% registry Single 58 Piessen G [79] 2012 Europe All Stages 96 158 38% institution Single 59 Heger U [8] 2014 Europe All Stages 235 488 33% institution 60 Schmidt T [80] 2014 Europe Multicentric All Stages 221 516 30% 61 Voron T [81] 2016 Europe FREGAT All Stages 899 900 50% 62 Khan N [82] 2020 Europe Multicentric All stages 198 2302 8% North 63 Shridhar R [83] 2013 SEER MGC 372 4200 8% America North 64 Taghavi S [84] 2012 SEER All Stages 2666 7580 26% America North Single 65 Bamboat ZM [6] 2014 All Stages 210 359 37% America institution North 66 Postlewait LM [85] 2015 Multicentric All Stages 312 456 41% America Charalampakis N North Single 67 2016 All Stages 62 45 58% [86] America institution North 68 Liu K [87] 2017 SEER All Stages 4418 14877 23% America North Single 69 Luu C [88] 2017 All Stages 57 153 27% America institution Cancers 2023, 15, 5191 8 of 22 Table 1. Cont. Patients’ Author Year Continent Stage n. SRCC n. NSRCC % SRCC Source North 70 Benesch MGK [89] 2020 SEER All Stages 17942 65218 22% America Figure 2. Flow chart of the literature search and selection of stu North 71 Tang CT [90] 2020 SEER All Stages 5265 752 88% America North Wei Q [91] 72 In the set of 74SEER 2020 America selected All Stages articles, 1751 7493 we searched 19% for the d North 73 logical Zhao X [92] 2021classification America SEER used, and we3006found 3673 All Stages that both 45% varied de Aguiar VGWHO classification [12] was most frequently used 33% (27 stu South Single 74 [93] 2019 All Stages 72 144 America institution theAbbreviations: Japanese EGC: earlyclassification gastric cancer; AGC: advanced[13], and gastric cancer; 1metastatic MGC: study gastric(1%) used La cancer; FREGAT: French EsoGastric Tumours registry; SEER: Surveillance, Epidemiology, and End Results Program registry. of 24Instudies (32%) used more than one classification ( the set of 74 selected articles, we searched for the definition of SRCC and the mura), and pathological 15 studies classification used, and(20%) we found thatdid bothnot specify varied between studiesthe(Figure classificat 3). The WHO classification [12] was most frequently used (27 studies—37%), 7 studies (10%) used used the termclassification the Japanese “poorly [13],cohesive and 1 study (1%) carcinoma” as proposed used Laurèn’s classification [14]. A total of 24 studies (32%) used more than one classification (WHO, Japanese, Laurèn, WHO classification Nakamura), and 15 studies (20%) [11,12]. did not specify the classification used. Only 1 (1%) study [38] used the term “poorly cohesive carcinoma” as proposed in the 4th and 5th edition of the WHO classification [11,12]. Figure 3. Use of pathological classification in gastric cancer. In the whole cohort of studies, 1 study (1%) cited the 1st edition of the WHO clas- Figure 3. 16Use sification, (22%)of thepathological 2nd, 3 (4%) the 3rd,classification in gastric 16 (22%) the 4th, 2 (3%) the 5th. In cancer. parallel, Cancers 2023, 15, 5191 9 of 22 1 study (1%) cited the 1st edition of the Japanese classification, 6 (8%) the 2nd, 10 (11%) the 3rd, and 1 (1%) the 4th. Furthermore, 23 studies (31%) did not specify the classification edition used. Indeed, seven studies (9%) used information from the SEER database and, therefore, with a probable lack of specific clinical data, citied different editions of the WHO classification. Five studies (7%) only mentioned the type of classification in the introduction of the manuscript without specifying its use in the study. 3.1. Lymph Node Metastasis Among all of the studies reporting data about lymph node metastasis (LNM) in all stages of gastric cancer, 15 papers compared SRCC to NSRCC, 11 compared SRCC to differ- entiated carcinoma/well-to-moderately differentiated adenocarcinoma/adenocarcinoma not otherwise specified (DC/WMDA/ADK), 16 to undifferentiated carcinoma/poorly differentiated adenocarcinoma (UDC/PDA)/mucinous, and 2 to mixed adenocarcinoma. Among the studies reporting data about lymph node metastasis in early gastric cancer (EGC), 7 papers compared SRCC to NSRCC, 14 to DC/WMDA/ADK, 21 to UDC/PDA/ mucinous, and 5 to a mix of cancers. Among the studies reporting data about lymph node metastasis in advanced gastric cancer (AGC), 5 papers compared SRCC to NSRCC, 6 to DC/WMDA/ADK, and 6 to UDC/PDA/mucinous. Figure 4A shows the RR of lymph node metastasis considering all stages of gastric cancer. The forest plot comparing SRCC to other histologies showed a slightly lower risk of developing nodal metastases (RR = 0.93, 95% CI 0.87–0.98) with high variability across studies (I2 = 94.8%). When the histotype of controls stratified the analysis, a clear pattern emerged. Indeed, the risk of nodal metastases in SRCC was similar compared to NSRCC, lower compared to the UDC/PDA/mucinous and mixed group, or higher compared to the DC/WMDA/ADK group. Also, the variability across studies slightly decreased. Stratification of the studies according to the tumour stage showed that, in early gastric cancer, the RR of lymph node metastasis was clearly lower in SRCC compared to other histologies (RR = 0.68, 95% CI 0.58–0.79, see Figure 4B). The variability across studies, although still significant, markedly decreased (I2 was 77.5%). The pattern of the risks of nodal metastases in SRCC compared to other histotypes was overlapping in the early and all stages of SRCC with a shift to the left (with an overall lower risk of lymph node metastasis in SRCC). Conversely, in advanced gastric cancer, the risk of nodal metastases in SRCC slightly increased (RR = 1.05, 95% CI 1.00–1.10, see Figure 4C). Again, variability across studies decreased (I2 was 61.9%). 3.2. Lymphovascular Invasion A similar pattern was found for lymphovascular invasion (LVI) (see Figure S1). 3.3. Survival Figure 5A shows the comparison of multivariable HR/RR of survival of SRCC with other histotypes divided with regard to NSRCC (11 studies), DC/WMDA/ADK (4 studies), and UDC/PDA/mucinous (4 studies). The prognosis of SRC tumours was significantly worse than the other tumours (RR of mortality in SRCC versus controls = 1.16, 95% CI 1.07–1.24). SRCC survival was similar compared to UDC/PDA/mucinous, and slightly worse than NSRCC and DC/WMDA/ADK. The variability across studies was high (I2 = 84.6%). However, a qualitative interaction was observed between SRCC and tumour stage. Figure 5B shows survival for the early (9 studies, Guo CG has two HR because of the comparison of SRCC with the DC/WMDA/ADK group and the UDC/PDA/mucinous group), advanced (8 studies), and metastatic stages (6 studies). Compared to other histo- types, SRCC tumours had better survival in the early stages (RR = 0.67, 95% CI 0.38–0.97), a similar survival in the advanced stages (RR = 1.15, 95% CI 0.94–1.36), and worse survival in metastatic cancers (RR = 1.29, 95% CI 1.09–1.49). 2023, 15, Cancers 2023, 15, 5191 x FOR PEER REVIEW 9 of 10 of 22 Figure 4. Cont. Cancers 2023,15, Cancers2023, 15,5191 x FOR PEER REVIEW 11 10 of of2222 Figure 4. Cont. Cancers 2023, 15, 5191 x FOR PEER REVIEW 1112of of 22 Figure Figure 4.4. Forest Forest plot plotshowing showingmeta-analysis meta-analysis results results forfor lymph lymph node node metastasis metastasis between between SRCCSRCC and and other other histologies histologies (NSRCC, (NSRCC, UDC/PDA/mucinous, UDC/PDA/mucinous, DC/WMDA/ADK, DC/WMDA/ADK, mixed).mixed). Plot (A):Plot (A): with patients patients with all stages all stages cancer. of gastric of gastricPlotcancer. Plot (B): (B): patients withpatients with early early gastric cancer.gastric cancer. Plot (C): Plot (C): patients withpatients advanced with ad- gastric vanced gastric cancer. The blue square represents the size proportional to the weight of the study, cancer. The blue square represents the size proportional to the weight of the study, and the horizontal lines and the horizontal lines indicate the 95% CI of each study. The black vertical line represents the no- indicate the 95% CI of each study. The black vertical line represents the no-effect values, while the red effect values, while the red dashed vertical line represents the overall effect size. The red diamond dashed vertical expresses line represents the the group-specific overall effect size,effect and size. The red the green diamondrepresents diamond expresses the thegroup-specific global effect effectsize. size, and the green diamond represents the global effect size. References: References: Ahn H (2020) [69]; Alshehri A (2020) [47]; Bamboat ZM (2014) [6]; Bu Z (2013) Ahn H (2020) [69]; Alshehri [55]; Chen A (2020) [66]; J (2018) [47]; Bamboat Chiu CTZM (2014) (2011) [6];Chon [52]; Bu Z (2013) HJ (2017)[55];[65]; ChenDongJ (2018) [66]; Chiu X (2021) CTEfared [72]; (2011) B[52]; Chon (2020) HJ [22]; Gronnier (2017) [65];CDong (2013)X[76]; (2021)Guo CG [72]; (2015) Efared [29]; Heger B (2020) U (2014) C [22]; Gronnier [8]; Hsu [76]; (2013) JT (2016) Guo CG [60];(2015) Huh [29]; CW (2013) Heger [27]; Hwang U (2014) CS (2016) [8]; Hsu [33];[60]; JT (2016) Imamura Huh CW T (2016) (2013)[34]; [27];Jiang Hwang CG CS (2011) [53]; (2016) Jiang [33]; H (2013) Imamura [56]; Jin T (2016) X [34]; (2021)CG Jiang [73]; Jin EH (2011) (2015) [53]; Jiang[30]; Kang[56]; H (2013) Sun Jin H (2017) X (2021) [38]; Kao [73]; JinYCEH(2019) (2015)[68]; [30];Khan KangNSun (2020) [82]; Kim H (2017) [38]; BS Kao(2014) [28]; Kim YC (2019) YH (2016) [68]; Khan [35];[82]; N (2020) KimKimHMBS (2011) (2014)[25]; Kwak [28]; KimDS YH(2018) (2016)[41]; [35];Kwon Kim HM KJ (2014) (2011) [57]; [25]; Lee D (2018) [67]; Lee HH (2012) [54]; Lee IS (2017) [39]; Lee JH (2010) [23]; Lee SH (2015) [31]; Liu Kwak DS (2018) [41]; Kwon KJ (2014) [57]; Lee D (2018) [67]; Lee HH (2012) [54]; Lee IS (2017) [39]; Lee K (2017) [87]; Liu X (2015) [59]; Luu C (2017) [88]; Nakamura R (2019) [42]; Nam MJ (2010) [24]; JH (2010) [23]; Lee SH (2015) [31]; Liu K (2017) [87]; Liu X (2015) [59]; Luu C (2017) [88]; Nakamura R Piessen G (2012) [79]; Postlewait LM (2015) [85]; Ryu DG (2019) [43]; Shim JH (2014) [58]; Taghavi S (2019) (2012)[42]; [84];Nam TangMJ CT(2010) (2020)[24]; Piessen [90]; TangGX(2012) (2016)[79]; [63];Postlewait Tong JH LM (2015) (2011) [85]; [26]; Ryu T Voron DG (2019)[81]; (2016) [43];Wang Shim JH (2014) [58]; Taghavi S (2012) [84]; Tang CT (2020) [90]; Tang X (2016) [63]; Tong Z (2015) [32]; Wang JB (2020) [71]; Wei Q (2020) [91]; Yoon HJ (2016) [36]; Zhang M (2010) [51]; Zhao JH (2011) [26]; Voron T B (2016) (2021) [81]; [78]; Wang Zhao Z X (2015) (2021) [32]; [92]; Wang Zhu ZL JB (2020) [71]; [44]; Wei ZouQ Y (2020) (2020)[91]; [45];Yoon Zu HHJ (2016) (2014) [36]; Zhang M [46]. (2010) [51]; Zhao B (2021) [78]; Zhao X (2021) [92]; Zhu ZL (2020) [44]; Zou Y (2020) [45]; Zu H (2014) [46]. 3.2. Lymphovascular Invasion Publication Bias: The publication bias was evaluated with the funnel plot and Egger’s A similar pattern was found for lymphovascular invasion (LVI) (see Figure S1). test. No publication bias was found on early stage gastric cancer (p = 0.294) or on all-stage 1.07–1.24). SRCC survival was similar compared to UDC/PDA/mucinous, and slightly worse than NSRCC and DC/WMDA/ADK. The variability across studies was high (I2 = 84.6%). However, a qualitative interaction was observed between SRCC and tumour stage Figure 5B shows survival for the early (9 studies, Guo CG has two HR because of the Cancers 2023, 15, 5191 comparison of SRCC with the DC/WMDA/ADK group and the UDC/PDA/mucinous 13 of 22 group), advanced (8 studies), and metastatic stages (6 studies). Compared to other histo- types, SRCC tumours had better survival in the early stages (RR = 0.67, 95% CI 0.38–0.97) agastric similar survival cancer in thein (p = 0.861) advanced stages the survival (RR = 1.15, outcomes. The 95% CIplot funnel 0.94–1.36), and worse and Eggers’ test aresurviva in metastatic shown cancers (RR =Materials in the Supplementary 1.29, 95%section CI 1.09–1.49). (Figure S4). Figure 5. Cont. Cancers 2023,15, Cancers2023, 15,5191 x FOR PEER REVIEW 14 of 13 of 22 22 Figure5.5. Forest Figure Forest plot plot showing showing meta-analysis meta-analysis results results forfor survival survival (comparison (comparison ofofmultivariable multivariable HR/RR). Plot HR/RR). Plot (A): (A): comparison comparisonbetween betweenSRCCSRCCandandother otherhistologies histologies(NSRCC, (NSRCC,UDC/PDA/mucinous, UDC/PDA/mucinous, DC/WMDA/ADK) in DC/WMDA/ADK) in patients patients with all stages with all stages of of gastric gastric cancer. cancer. (B): (B): comparison comparisonbetween betweenSRCC SRCCand and other histologies in patients with early, advanced, and metastatic gastric cancer. The blue square other histologies in patients with early, advanced, and metastatic gastric cancer. The blue square represents the size proportional to the weight of the study, and the horizontal lines indicate the 95% represents the size proportional to the weight of the study, and the horizontal lines indicate the CI of each study. The black vertical line represents the no-effect values, while the red dashed vertical 95% line CI of each study. represents The black the overall effect vertical size. Theline redrepresents the no-effect diamond expresses the values, while the group-specific redsize, effect dashedand vertical the green diamond represents the global effect size. References: Ahn H (2020) [69]; Alshehri A effect line represents the overall effect size. The red diamond expresses the group-specific (2020) size, [47];and the green Benesch MGKdiamond represents (2020) [89]; the global Charalampakis N effect (2016)size. [86];References: Cho JH (2015) Ahn[48]; H (2020) Chon [69]; Alshehri HJ (2017) [65]; Ade(2020) Aguiar VGBenesch [47]; (2019) [93]; MGKDong X (2021) (2020) [72]; Gronnier N [89]; Charalampakis C (2016) (2013) [86]; [76]; Cho Guo JHCG(2015) (2015)[48]; [29];Chon Heger HJU (2014)[65]; (2017) [8]; Hsu JT (2016) de Aguiar VG [60]; (2019)Imamura [93]; DongT (2016) [34]; X (2021) Jiang [72]; CG (2011) Gronnier [53]; [76]; C (2013) Kao YCGuo(2019) [68]; Khan CG (2015) [29]; N (2020) [82]; Lemoine N (2016) [77]; Liu X (2015) [59]; Lu M (2016) [62]; Luu C (2017) [88]; Men HT (2016) [49]; Piessen G (2012) [79]; Postlewait LM (2015) [85]; Riihimäki M (2016) [78]; Schmidt T (2014) Cancers 2023, 15, 5191 15 of 22 Heger U (2014) [8]; Hsu JT (2016) [60]; Imamura T (2016) [34]; Jiang CG (2011) [53]; Kao YC (2019) [68]; Khan N (2020) [82]; Lemoine N (2016) [77]; Liu X (2015) [59]; Lu M (2016) [62]; Luu C (2017) [88]; Men HT (2016) [49]; Piessen G (2012) [79]; Postlewait LM (2015) [85]; Riihimäki M (2016) [78]; Schmidt T (2014) [80]; Shim JH (2014) [58]; Shridhar R (2013) [83]; Taghavi S (2012) [84]; Tang CT (2020) [90]; Voron T (2016) [81]; Wang Z (2015) [32]; Zhao X (2021) [92]; Zu H (2014) [46]. 4. Discussion SRC gastric carcinoma is a subtype of gastric cancer with peculiar and controversial characteristics. At first, SRCC was described as a tumour with a poor prognosis; however, the growing available literature recently affirmed that when SRCC is found at early stages, limited to the gastric mucosa or submucosa, it has a better prognosis than all the other GC subtypes. Still, when it progresses through the gastric wall, it becomes highly aggressive, carrying high rates of nodal metastases and peritoneal carcinomatosis [3–6]. Nevertheless, the wide heterogeneity of definitions and classifications of SRCC contributes to the great confusion about its behaviour. Moreover, the authors’ grouping of patients affected with SRCC with PDA or with other diffuse/poorly cohesive carcinomas decreases the homo- geneity in the literature even more. Therefore, a pivotal step to more robust evidence is standardising the terminology used to define this cancer subtype. Our study clarifies that the pathological classification used in the papers on gastric cancer and the definition of SRCC adopted in different studies are highly variable. We should pay attention to what is meant by SRCC in the different studies, and it is also important to what SRCC is compared with, that is, what is meant by NSRCC (some studies compare SRCC with well-differentiated tumours, while others with poorly differentiated tumours, which are still not as a type of SRCC). Therefore, the results of the studies found in this extensive literature review about SRCC have a great variability for this reason. Moreover, a particularly poor prognosis could be added if SRCC patients are grouped as diffused (Lauren classification) or undifferentiated (Nakamura and Japanese classifications). In fact, this would mean grouping SRCC with the poorly cohesive type 2 class (considering the Japanese classification) or to the poorly cohesive NOS class (considering the WHO classification). Only a few studies analysed the group poorly cohesive type 2 (Japanese classification)/poorly cohesive NOS (WHO classification) classes separately; therefore, this subtype is likely sometimes analysed with SRCC, and some others with NSRCC, which adds variability (see Figure 1). As such, there is a need to universalise the histopathological definitions used worldwide to allow for a more homogeneous comparison between the subgroups of gastric cancer. This study’s main result is that the prognosis of SRCC tumours largely depends on the stage of cancer, as confirmed by the other three meta-analyses that started investigating this topic. In fact, two of these three meta-analyses showed superimposable results, agreeing that lymph node metastasis was lower in ECG in SRCC compared to NSRCC, without differences in AGC [94,95]. Regarding survival, SRCC was associated with poorer overall survival when analysing all stages of gastric cancer [96], although this was not always statistically significant [94,95]. In EGC, the subgroup analysis showed better survival in two meta-analyses [95,96] and comparable survival outcomes in the other one [94]. Regarding AGC, one of the studies showed worse survival in SRCC when excluding patients with metastases. However, this sub-analysis evaluated only three studies, and the analysis, including metastatic patients, did not show statistical differences [96]. Another study demonstrated a worse prognosis in the advanced stage but did not separate patients with stage IV cancer [95]. The last meta-analysis also showed worse survival in the advanced tumour stage. No significant difference in survival outcomes was demonstrated in patients with metastases [94]. In our study, regarding lymph node invasion and considering all stages of gastric cancer, we found a slightly lower risk to develop nodal metastases in SRCC. The subgroup analysis comparing SRCC with different histotypes added the evidence that the risk of nodal metastases in SRCC tumours was lower, similar, or higher when compared to Cancers 2023, 15, 5191 16 of 22 UDC/PDA/mucinous, mixed, NSRCC, and to DC/WMDA/ADK respectively. In EGC, as demonstrated by the other two meta-analysis [94,95], SRCC was associated with a lower incidence of LNM. In the subgroup analysis, we noticed that the incidence of LNM was lower, especially when SRCC was compared to UDC/PDA/mucinous and mixed, rather than being similar when SRCC was compared to NSRCC and to DC/WMDA/ADK. The analysis of lymphovascular invasion highlighted a similar trend. Regarding survival, all stages of SRCC had worse prognostic outcomes than other histotypes. The separate analysis regarding the stage of cancer confirmed the evidence shown by the previous meta-analysis with a better prognosis in early SRCC than in other histotypes, a similar prognosis in advanced cancer (3 of the 8 studies included patients with stage IV cancer in the advanced group), and worse in patients with metastases. When sorting the studies by histologies, the worse prognostic outcome of SRCC was confirmed, especially when comparing SRCC to NSRCC and to DC/WMDA/ADK, while no difference was seen in the comparison to UDC/PDA/mucinous. Our analysis highlights the importance of identifying the comparison histologic group, which might provide significant variability in relation to the results. In addition, it confirms the different prognoses of SRCC based on stage—evidence that is becoming more and more clear. Indeed, these tumours tend to be more aggressive compared to other subtypes as they become more advanced, and this behaviour could be explained by the impact of peritoneal carcinomatosis. Patients with SRCC, in fact, are at an especially high risk for an occult misdiagnosed peritoneal disease, as it was shown by several studies [3–5]. A recent study found that peritoneal lavage during exploratory laparoscopy was positive in about 32.1% of the patients with SRCC cM0 [4]. Also, patients with gastric SRCC that are submitted to curative resection are at a risk of developing peritoneal metastasis [97–100]; recurrence was reported to occur in 51% of patients after a 54-month follow up, with 19% peritoneal recurrence [101]. Moreover, in SRCC with peritoneal metastasis, the prognosis appears to remain poor, irrespective of whichever treatment is used. Chemotherapy is less effective than other histologies and has a shorter survival rate [77]. Cytoreductive surgery, intraoperative hyperthermic intraperitoneal chemotherapy (CRS+HIPEC), and low-dose pressurised intraperitoneal aerosol chemotherapy (PIPAC) are techniques which are still under investigation but can be used; however, they should be restricted to highly selective patients [49,102,103]. This study, while providing valuable insights, still contains some limitations. Firstly, the quality of the meta-analysis heavily relies on the quality of the included studies. If the individual studies exhibit biases or methodological flaws, these can propagate into the meta- analysis, compromising the overall reliability of the findings. Moreover, the heterogeneity among the selected studies, such as variations in patient populations, diagnostic criteria (use of EUS/PET/diagnostic laparoscopy), and treatment modalities (such as multimodal treatment), can pose a challenge in drawing cohesive conclusions. Additionally, this meta- analysis might lack the ability to capture the recent advancements in diagnostic techniques or treatments due to the inclusion of studies conducted over extended periods of time. To encourage clinicians to offer a correct diagnosis, a recent expert consensus proposed a new classification system in which only PC carcinomas with more than 90% of SRC should be classified as SRCC. PC non-signet ring cell carcinomas should be further subdivided into PC carcinomas with a SRC component (10–90% SRC) and PC carcinomas not other- wise specified (< 10% SRC) [104]. This classification seems to have practical prognostic relevance [105,106]; in fact, confusing poorly cohesive tumours with different percentages of SRC could cause conflicting findings in the literature concerning the prognosis and the response to chemo-radiotherapy. Of note, this classification of PC carcinomas based on the amount of SRC has also been cited by the very last edition of the World Health Organization (WHO) classification that divides PC gastric cancer into SRCC (>90%) and PC non-otherwise specified (PC-NOS) [12]. The incidence of this subtype of tumour is increasing with a rise of young patients affected and a poor prognosis due to its rapid progression, high rate of peritoneal disease, and high recurrence, even after a curative Cancers 2023, 15, 5191 17 of 22 resection and early diagnosis. A correct definition and clear histological comparison of the disease are of primary concern, as the results of the diagnosis can completely change based on this information. Consequently, this would help in clarifying the prognosis and developing a correctly tailored treatment for each patient. 5. Conclusions In conclusion, most of the conflicting results found by analysing the available literature on SRCC could come from the lack of standardisation of its pathological definition and classification that is being used. Therefore, we suggest the use of a clear classification of SRCC, in addition to considering the percentage of SRC when investigating this type of tumour [104]. From the results of this meta-analysis, we concluded that SRCC has a lower ten- dency to lymph node invasion in the early stage of cancer, especially in comparison with UDC/PDA/mucinous and mixed tumours. This difference decreases with tumour progres- sion, as advanced SRCC tends to have similar lymph node metastasis as the other histotypes. Survival tends to be greater in early SRCC than in EGC of the other histotypes. At the same time, it is worse when all stages are compared together, likely reflecting the dramatic impact of peritoneal involvement in advanced SRCC compared to the other histologies. Over the years, there has been a trend towards a uniformity of data, probably thanks to a more precise and homogeneous pathological diagnosis. Hopefully, this harmonisation process will continue with the final aim of achieving a clearer prognosis and ameliorating the treatment of patients with SRCC. Supplementary Materials: The following supporting information can be downloaded at: https:// www.mdpi.com/article/10.3390/cancers15215191/s1, Table S1: Search terms used in PubMed; Table S2: Quality assessment of cohort studies according to the Newcastle-Ottawa Scale (NOS); Table S3: General information of the selected studies; Figure S1: Forest plot showing meta-analysis results for Lymphovas- cular Invasion between SRCC and other histologies (NSRCC, UDC/PDA/mucinous, DC/WMDA/ADK, mixed). (A): in All Stages Gastric Cancer patients. (B): in Early Gastric Cancer patients. (C): in Advanced Gastric Cancer patients; Figure S2: Forest plot showing meta-analysis results for survival (compari- son of multivariable HR/RR), subgroup analysis by stage and histology (between SRCC and NSRCC, UDC/PDA/mucinous, DC/WMDA/ADK). (A): in Early Gastric Cancer patients. (B): in Advanced Gastric Cancer patients; Figure S3: Forest plot showing meta-analysis results for survival (comparison of univariable HR/RR); Figure S4: Funnel plot and Egger’s Test. Author Contributions: All the author gave substantial contributions to the conception or design of the work, or the acquisition, analysis, or interpretation of data for the work. In particular: Study concepts: G.d.M., M.B., H.I.G., F.C.; Study design: M.B., H.I.G.; Data acquisition: M.S., M.A., F.F.; Data analysis and interpretation: G.V., M.B., M.D.C.; Statistical analysis: G.V., L.T.; Manuscript preparation: M.D.C., M.I.; Manuscript editing: D.H.W.L., K.G.P.K., L.S., A.T., G.P., M.P.; Manuscript review: M.B., H.I.G., F.C., G.d.M. All authors have read and agreed to the published version of the manuscript. Funding: This work would not have been possible without the financial support of the “Fondazione Gianesini” and the “Ricerchiamo ONLUS”. H.I.G. is supported in part by the National Institute for Health and Care Research (NIHR) Leeds Biomedical Research Centre. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care. Institutional Review Board Statement: This article does not contain any studies with human or animal subjects performed by any of the authors. Data Availability Statement: The original contributions presented in this study are included in the article/online resources. Acknowledgments: This study is part of a doctoral programme of the Department of Surgery at Universitat Autònoma de Barcelona. Conflicts of Interest: The authors declare no conflict of interest. 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