Clinicopathological Characteristics and Risk Factors of Young-Onset Gastric Carcinoma: A Systematic Review and Meta-analysis

Abstract

INTRODUCTION:

The characteristics of gastric carcinoma in young individuals differ from that in older individuals. We conducted a systematic review and meta-analysis to explore the clinicopathological features and risk factors associated with young-onset (younger than 50 years) gastric carcinoma.

METHODS:

We searched for studies published between January 1, 1990, and September 1, 2023, on patients with young-onset gastric carcinoma in PubMed, EMBASE, Web of Science, and MEDLINE to explore clinicopathological characteristics among this specific patient group. Extracted information included the proportion of patients with symptoms or family history of gastric cancer, tumor location, and histological features such as Lauren or World Health Organization histological classification and degree of differentiation. Additional analyses were conducted on risk factors such as positive family history, Helicobacter pylori infection, or high-risk nutritional or behavioral factors. The estimates were derived using random or fixed-effect models and included subgroup analyses based on different sex and age groups. This study was registered in PROSPERO (CRD42023466131).

RESULTS:

We identified 5,696 records, 1,292 were included in the quality assessment stage. Finally, 84 studies from 18 countries or regions including 89,447 patients with young-onset gastric carcinoma were included. Young-onset gastric carcinoma has slight female predominance (53.7%, 95% confidence interval [CI]: 51.6–55.7%), with most having symptoms (87.0%, 95% CI: 82.4%–91.7%). Family history was reported in 12.1% (95% CI: 9.5%–14.7%). H. pylori infection was detected in 60.0% of cases (95% CI: 47.1%–72.8%). Most of these carcinomas were in the non-cardia region (89.6%, 95% CI: 82.4%–96.8%), exhibiting Lauren diffuse-type histology (71.1%, 95% CI: 66.8%–75.3%) and poor/undifferentiated features (81.9%, 95% CI%: 79.7–84.2%). A positive family history of gastric cancer was the most important risk factor associated with the development of gastric carcinoma in young individuals (pooled odds ratios 4.0, 95% CI: 2.8–5.2), followed by H. pylori infection (odds ratio 2.3; 95% CI: 1.4–3.2) and dietary and other lifestyle risk factors.

DISCUSSION:

Young-onset gastric carcinoma exhibits specific clinicopathological characteristics, with positive family history being the most important risk factor. Most of the patients were symptomatic at diagnosis. These findings could help to inform future strategies for the early detection of gastric carcinoma among young individuals.

INTRODUCTION

The global incidence of gastric cancer has been declining steadily over the past few decades, which is attributed to improvement in socioeconomic conditions, identification and eradication of Helicobacter pylori infection, and utilization of screening in some high-risk countries (1–3). Nevertheless, according to the Global Cancer Statistics 2020 report by the International Agency for Research on Cancer, gastric cancer continues to account for 5.6% of all new cancer cases (ranking fifth in incidence) and 7.7% of all cancer deaths (ranking fourth in mortality), highlighting its impact on cancer burden (4). In recent years, several studies have demonstrated a rise in gastric cancer among young adults, which raises interest in improving early detection among this group of younger individuals (5,6). However, a recent study showed that despite the increase in the total number of new cases of young gastric cancer, the age-standardized incidence has been decreasing (7).

Unlike colorectal cancer, there is no universally accepted definition for young-onset gastric cancer, as cutoff age ranges from 30 to 50 years have been used, varying across different studies (8–10). In certain studies, young-onset gastric cancer is defined as occurring before the age of 40, while in others, the definition generally encompasses all patients diagnosed before the age of 45 or 50 years (6,11–13).

Given various limitations including the appropriate cutoff age for young-onset gastric cancer, the prognosis for these patients remains controversial. As the most prevalent histological type of gastric cancer, the clinicopathological characteristics of gastric carcinoma have been observed to differ between younger and older patients, leading to the general belief that younger patients may experience a worse prognosis due to delayed diagnosis or more aggressive tumor behavior (14–16). The majority of current research on the clinicopathological characteristics of young-onset gastric carcinoma has been conducted in single-center studies. These studies are primarily in East Asian countries, such as Japan, South Korea, and China, with limited sample sizes (8,17,18). However, a comprehensive systematic summary of the clinicopathological features specific to patients with young gastric carcinoma at the global level is lacking.

Generally, the progression of gastric carcinoma, particularly intestinal-type adenocarcinoma, follows a well-defined and identifiable cascade of events that includes progression from inflammation to atrophy, intestinal metaplasia, dysplasia, and eventually carcinoma (3,19,20). This disease is closely associated with environmental factors, dietary habits, genetic mutations, and epigenetic changes. Efforts to enhance screening programs and facilitate early detection and treatment of gastric carcinoma are crucial, and prioritizing proactive measures to address preventable factors contributing to the development of this disease is imperative. Thus far, research on risk factors of young-onset gastric carcinoma remains limited, other than the World Health Organization's (WHO) comprehensive listing of factors such as H. pylori infection, salty fish, and alcohol use (21–23).

This is a comprehensive systematic review and meta-analysis of global studies pertaining to young-onset gastric carcinoma spanning from 1990 to 2023. We aimed to provide a comprehensive summary of the clinicopathological characteristics specific to this population and to identify risk factors associated with young-onset gastric carcinoma.

METHODS

Search strategy

This systematic review and meta-analysis followed the Meta-analyses Of Observational Studies in Epidemiology guidelines (24). We searched PubMed, EMBASE, Web of Science, and MEDLINE for all observational studies, including cohort studies or cross-sectional studies, published between January 1, 1990, and September 1, 2023, without language restriction. To obtain a more comprehensive outcome and minimize the impact resulting from the selected age threshold, we have chosen 50 years as the cutoff age for young-onset gastric carcinoma in this study to encompass a broader study population. The primary search terms included the following related to gastric carcinoma (e.g., “Gastric Neoplasm,” “Gastric Carcinoma,” “Stomach Carcinoma,” “Stomach Neoplasm”) and our targeted population (e.g., “young,” “young onset,” “early onset”). Detailed search strategies for each database are shown in Supplementary Digital Content (see Supplementary Table 1, http://links.lww.com/CTG/B123). Study types that were excluded from this review were meta-analyses, systematic reviews, conference papers, editorials, case reports, and animal experimental studies. The search was not restricted by language or region. This systematic review and meta-analysis were registered with PROSPERO (CRD42023466131). We used the EndNote X9 (Clarivate, Philadelphia, PA) for literature management.

The clinical characteristics investigated in this study included the following: patient's sex, symptoms at presentation (substratified into abdominal pain, anorexia/weight loss, dyspepsia/vomiting/nausea/early satiety, dysphagia, and gastrointestinal bleeding), tumor location (cardia vs non-cardia), functional regions (body, fundus, antrum, angular incisure, and multifocal (whole gastric)), and anatomical regions (proximal, middle, distal, or overlapping) (25). The pathological features included the Lauren histological classification, WHO histological classification, and degree of differentiation (26,27). The risk factors considered included positive family history of gastric cancer, H. pylori infection, high consumption of sodium-rich or other detrimental foods (refers to more frequent intake of beef and canned, smoked, and salted food and less frequent intakes of fresh fruit/vegetables as suggested by Chung et al (28)), alcohol intake, obesity, and smoking. Stratified analyses were conducted based on age (≤30 years vs 31–50 years), sex groups, Asian or non-Asian countries, and countries with national gastric cancer screening programs (Japan and South Korea) vs those without. Studies that reported survival outcomes (including 1-, 3-, and 5-year overall survival rates) for young-onset gastric carcinoma were also documented.

Exclusion criteria were set as (i) studies that set the cutoff age of young-onset gastric carcinoma over 50 years, (ii) included data from specific study populations (e.g., pregnant, hereditary carcinoma, or patients with other specific chronic diseases [such as comorbidity with inflammatory bowel diseases]), (iii) studies solely conducted in a single pathological type (e.g., exclusively focusing on signet ring cell carcinoma), and (iv) studies investigated among pathological types other than carcinoma (e.g., neuroendocrine tumor, lymphoma, sarcoma). Eligible studies presented the raw data as either a proportion (or odds ratio [OR] for risk factors) with confidence interval (CI) or SE or provided sufficient information to calculate the CI, such as total sample size. The Wilson score interval method, an extension of the normal approximation to account for the loss of coverage typical in Wald intervals, was used to calculate all CIs not described in the original articles (29).

Data extraction and quality assessment

The studies obtained from the databases were stored in the reference management software EndNote. The EndNote search function was used for extracting relevant studies before screening the citations against the inclusion and exclusion criteria by 2 independent authors (Y.H.L. and J.F.). In cases where duplicates or publications from the same study were identified, preference was given to selecting the more recent publication or the one with greater detail for inclusion in the review. A third investigator (W.K.L.) mediated any discrepancies in article inclusion or data extraction. Data extracted included the authors' names, publication year, sample collection period (year), lesion location, number of participants, average age (or age scale), study settings (hospital, regional/community, or national registry-based), clinicopathological information, and risk factors and their related ORs (with 95% CIs) (see Supplementary Tables 2 and 3, http://links.lww.com/CTG/B123). Studies were not included if full-text articles were unable to be obtained from all sources including direct contact with the authors. Studies published in languages other than English were translated with Google Translate. To verify the accuracy of the critical data for statistical analysis, we have listed the assistance of proficient users of these languages. Funnel plot and Egger's test were used to assess the presence of publication bias for the H. pylori infection rate and proportion of positive gastric cancer family history.

Two independent authors (Y.H.L. and J.F.) performed quality assessments as recommended by Loney et al (30). The intact quality assessment procedure has a maximum score of 8 points, encompassing 3 key aspects: valid study methods, result interpretation, and result applicability. Disagreement on quality assessment score was settled with discussion. Studies with a quality assessment score of 50% or above were included in the final meta-analysis. Detailed information about the quality assessment and study settings of the included research are presented in Supplementary Table 4, http://links.lww.com/CTG/B123.

Statistical analysis

The pooled proportions or the OR and corresponding 95% CI were calculated using either the inverse-variance fixed-effects model or the DerSimonian and Laird random-effects model, based on the estimation of heterogeneity variance (31,32). The selection of the random-effects model and fixed-effects model was determined by I² values, with a threshold of ≥50% for the random-effects model and fixed-effects model. The pooled OR was excluded if it was calculated based on fewer than 3 studies. Heterogeneity was assessed by using the I² index and Cochran Q test. A P value of less than 0.05 between subgroups implied that the element is a source of heterogeneity. High between-study heterogeneity (I² > 75%) was investigated using a leave-one-out method for sensitivity analysis and subgroup analysis (33,34). To evaluate the significance between the 2 groups, we assessed the coverage of pooled 95% CI (35). The temporal trend of the H. pylori infection rate was evaluated by the midpoint of the sample collection time and the infection rate of individual studies, using a generalized linear model. Statistical analyses were performed by using Stata (version 17.0; Stata Corp, College Station, TX) and R software (version 4.2.1, package: binom, ggplot2).

RESULTS

A total of 5,696 articles published between January 1, 1990, and September 1, 2023, were identified after the initial search. The first stage excluded 2,369 duplicate records by the literature manager; 2,035 duplicate records, unrelated articles, or animal experiments were further removed manually. A total of 1,292 full texts were reviewed for quality assessment, with 1,208 articles further excluded as per exclusion criteria defined above. Ultimately, 84 studies (with publication years ranging from 1992 to 2023) from 18 countries or regions were included for analysis, including 9 studies that reported risk factors of young-onset gastric carcinoma (Figure 1). Most of the included studies (54 studies, 64.3%) were conducted in Asia, particularly China (24 studies, 28.6%), South Korea (15 studies, 17.9%), and Japan (15 studies, 17.9%). The majority (60 studies, 71.4%) were hospital-based studies, followed by 15 (17.9%) national registry-based studies and 9 (10.7%) regional/community registry-based studies. The quality of the included studies was relatively high according to the quality assessment results (points scale: 4–7, average points: 6.6) (see Supplementary Table 4, http://links.lww.com/CTG/B123).

Figure 1.

Flowchart for study selection following the Meta-analyses Of Observational Studies in Epidemiology (MOOSE) guidelines.

Clinicopathological characteristics

Young-onset gastric carcinoma cases have a slight female predominance (53.7%, 95% CI: 51.6%–55.7%) than male (46.4%, 95% CI: 44.3%–48.4%). Most of the patients in the included studies were symptomatic (87.0%, 95% CI: 82.4%–91.7%), with symptoms including abdominal pain (61.9%, 95% CI: 54.2–69.7), anorexia/weight loss (29.9%, 95% CI: 17.5%–42.2%), dyspepsia-associated symptoms (vomiting, nausea, or early satiety) (24.6%, 95% CI: 16.7–32.5), dysphagia (18.5%, 95% CI: 10.4%–26.6%), and gastrointestinal bleeding (or with anemia) (14.1%, 95% CI: 8.9%–19.3%) (Table 1 and see Supplementary Figures 1–2, http://links.lww.com/CTG/B123).

Table 1.

Clinicopathological characteristics of young-onset gastric carcinoma (<50 years)

Clinicopathological characteristics	No. of studies	No. of patients	Estimated proportion (95% CI)b	P heterogeneity/I2	P between groups
Positive family history of gastric cancer	27	3,562	12.1% (9.5–14.7)	<0.001/86.1%
At least in 1 first-degree relative	5	516	8.3% (5.0–11.6)	0.031/62.5%
Symptomatic	13	1,906	87.0% (82.4–91.7)	<0.001/94.8%
Sex ratio					<0.001
Male	62	7,499	46.4% (44.3–48.4)	<0.001/80.1%
Female	62	7,967	53.7% (51.6–55.7)	<0.001/80.2%
Symptoms				<0.001/98.1%	<0.001
Abdominal pain	20	1885	61.9% (54.2–69.7)	<0.001/92.9%
Anorexia/weight loss	12	1,176	29.9% (17.5–42.2)	<0.001/97.6%
Dyspepsia/vomiting/nausea/early satiety	16	1,517	24.6% (16.7–32.5)	<0.001/97.4
Dysphagia	9	897	18.5% (10.4–26.6)	<0.001/94.4%
GIB (melena/hematemesis/anemia)	11	1,105	14.1% (8.9–19.3)	<0.001/89.6%
Topography					<0.001
Cardia carcinoma	12	541	10.7% (4.6–16.9)	<0.001/97.6%
Non-cardia carcinoma	12	4,520	89.3% (83.2–95.5)	<0.001/97.6%
Anatomical location				<0.001
Proximal	33	5,174	17.2% (14.4–20.0)	<0.001/87.6%
Middle	33	5,056	30.3% (25.7–35.0)	<0.001/93.2%
Distal	33	5,014	46.0% (41.2–50.7)	<0.001/91.7%
Multifocal (whole gastric)	19	3,222	6.1% (4.4–7.8)	<0.001/75.7%
Overlapping/NOS	1	760	17.9% (19.3–20.8)	—
Functional region				<0.001
Fundus	6	510	6.8% (2.3–11.4)	0.004/71.3%
Body	14	5,296	40.6% (30.1–51.1)	<0.001/97.6%
Angular incisure	3	398	7.6% (4.5–10.6)	0.286/20.1%
Antrum	14	5,205	41.3% (33.5–49.2)	<0.001/95.7%
Multifocal	16	5,554	11.9% (7.6–16.3)	<0.001/96.3%
Lauren classification					<0.001
Diffuse type	38	4,564	71.1% (66.8–75.3)	<0.001/90.9%
Intestinal type	38	1,522	21.4% (17.3–25.5)	<0.001/93.0%
Mixed type	24	725	10.9% (8.1–13.7)	<0.001/89.5%
WHO classification					<0.001
Tubular/papillary adenocarcinoma	12	5,340	65.1% (57.0–73.3)	<0.001/96.5%
Signet-ring cell carcinoma	18	2,973	31.3% (23.7–38.9)	<0.001/97.6%
Mucinous cell carcinoma/others	13	6,721	3.9% (2.6–5.3)	<0.001/69.8%
Differentiation					<0.001
Poorly/undifferentiated	46	7,963	81.9% (79.7–84.2)	<0.001/87.9%
Well/moderately differentiated	46	1,516	15.6% (13.7–17.5)	<0.001/83.7%
Helicobacter pylori infection rate (%)		5,213	60.0% (47.1–72.8)	0.836/98.7%	<0.001
Histology	4	273	61.5% (27.5–95.4)	<0.001/98.1%
Mixed methodsa	5	376	63.2% (37.2–89.2)	<0.001/97.5%
RUT	3	263	69.3% (45.9–92.7)	<0.001/93.7%
Serology	3	3,404	60.7% (14.3–97.2)	<0.001/99.5%
Not mentioned	5	897	49.6% (26.5–72.7)	<0.001/98.4%

CI, confidence interval; GIB, gastrointestinal bleeding; NOS, not otherwise specified; RUT, rapid urease test; WHO, World Health Organization.

^aMixed methods represented more than 2 methods mentioned in the original studies.

^bThe random or fixed-effects model calculated pooled proportion (and 95% CI).

Non-cardia carcinoma (89.3%, 95% CI: 83.2%–95.5%) was significantly more common than cardia carcinoma (10.7%, 95% CI: 4.6%–16.9%; Table 1). Based on anatomical categorization, the proportion of gastric carcinoma in the distal region (41.4%, 95% CI: 33.3%–49.6%) and middle region (30.3%, 95% CI: 25.7%–35.0%) was higher than in proximal or multifocal lesions. In terms of functional categorization, tumors were more commonly located in the antrum (41.3%, 95% CI: 33.5%–49.2%) and corpus (40.6%, 95% CI: 30.1%–51.1%; Table 1 and see Supplementary Figure 3, http://links.lww.com/CTG/B123).

Most of the cases of young-onset gastric carcinoma were characterized as poorly differentiated or undifferentiated (81.9%, 95% CI: 79.7%–84.2%), with a small proportion of well or moderately differentiated lesions (15.6%, 95% CI: 13.7%–17.5%; Table 1 and see Supplementary Figure 4, http://links.lww.com/CTG/B123). For Lauren histological classification, diffuse-type carcinoma (71.1%, 95% CI: 66.8%–75.3%) was significantly more prevalent than intestinal type (21.4%, 95% CI: 17.3%–25.5%) and mixed type (10.9%, 95% CI: 8.1%–13.7%; see Supplementary Figures 4–2). Regarding the WHO classification, tubular or papillary adenocarcinoma accounted for the highest proportion of carcinomas (65.1%, 95% CI: 57.0%–73.3%), followed by signet-ring cell carcinoma (31.3%, 95% CI: 23.7%–38.9%) and mucinous cell adenocarcinoma (3.9%, 95% CI: 2.6%–5.3%, see Supplementary Figures 4–3, http://links.lww.com/CTG/B123).

Risk factors of young-onset gastric carcinoma

The pooled proportion of patients with a positive family history of gastric cancer was 12.1% (95% CI: 9.5%–14.7%) while the pooled rate of H. pylori infection was 60.0% (95% CI: 47.1%–72.8%; Table 2 and Figure 2a). The pooled H. pylori infection rate showed a decline over the past 3 decades (Figure 2b). The current H. pylori infection rate (66.3%, 95% CI: 48.9%–83.6%; tested by histology or rapid urease test) was higher compared with the infection rates obtained through other diagnostic methods (55.8%, 39.6%–72.0%). Further stratified analysis based on different diagnostic methods revealed that studies based on the rapid urease test reported the highest rate of H. pylori infection of 69.3% (95% CI: 45.9%–92.7%). The reported proportion of positive family history of gastric cancer (P_{Egger's test} <0.001) and H. pylori infection rate (P_{Egger's test} = 0.017) showed significant publication bias but remained stable after sensitivity analysis (see Supplementary Figure 7, http://links.lww.com/CTG/B123).

Table 2.

Estimated pooled odds ratio of risk factors of young-onset gastric carcinoma

Risk factors	No. of studies	Study population	Estimated odds ratio (95% CI)	P heterogeneity	I 2
Positive family history of gastric cancer	3	6,534	4.0 (2.8–5.2)	0.760	0%
Helicobacter pylori infection	7	6,718	2.3 (1.4–3.2)	0.001	72.8%
Salty food or other high-risk dieta	3	6,563	2.1 (1.3–2.8)	0.008	59.3%
Alcohol intake	4	6,559	2.0 (1.3–2.6)	0.047	62.2%
Smoking	5	7,295	1.5 (0.6–2.3)	<0.001	64.9%
Obesityb	4	1,309	1.7 (1.5–2.0)	0.322	14.0%

CI, confidence interval.

^aRefers to more frequent intake of beef and canned, smoked, and salted food and less frequent intake of fresh fruit/vegetables.

^bCutoff value: body mass index ≥35 kg/m² (2 studies); body mass index ≥30 kg/m² (2 studies).

Figure 2.

Pooled Helicobacter pylori infection rate of young-onset gastric carcinoma (a); temporal trend of H. pylori infection rate (b). The bubble area represents the number of subjects included in an individual report. The bubble's position was determined by the study year of the report (midpoint year of the study period) and the infection rate. The bubble's color was determined by the diagnostic methods. The fitted curve was drafted to show the time trend of infection rate (default method: generalized linear model [glm]). RUT, rapid urease test.

Nine studies reported on risk factors of young-onset gastric carcinoma. Among the 6 risk factors, positive family history of gastric cancer was found to have the highest OR associated with the development of gastric carcinoma in young individuals (pooled OR: 4.0; 95% CI: 2.8–5.2), followed by H. pylori infection (pooled OR: 2.3; 95% CI: 1.4–3.2; see Supplementary Figure 8, http://links.lww.com/CTG/B123). As for dietary or behavioral risk factors, intake of salty food or other high-risk diets was found to have a pooled OR of 2.1 (95% CI: 1.3–2.8), followed by alcohol consumption (pooled OR: 1.9, 95% CI: 1.3–2.6), smoking (pooled OR: 1.5, 95% CI: 0.6–2.3), and obesity (pooled OR: 1.7, 95% CI: 1.5–2.0). The pooled OR of positive H. pylori infection remained stable after sensitivity analysis, despite the presence of high heterogeneity (I² = 72.8%). Other risk factors demonstrated relatively low to middle-level heterogeneity (I² < 70%).

Age, sex, and regional-stratified analysis

Very early-onset carcinoma (age ≤30 years) constitutes 20.5% (95% CI: 17.6%–23.4%) of all young-onset carcinoma cases (see Supplementary Table 5 and Supplementary Figure 9, http://links.lww.com/CTG/B123). In this subgroup of very early-onset carcinoma, the proportion of undifferentiated tumors was higher (94.5%, 95% CI: 84.9–99.0%) than in the 31–50 years age group (83.7%, 95% CI: 74.2%–94.5%), based on 2 studies with relevant data. The Lauren type classification in different age groups was only reported in one study by Li et al (36), which revealed a significantly higher proportion of diffuse histological type and a lower proportion of mixed type among individuals aged 30 years and older (see Supplementary Figure 10, http://links.lww.com/CTG/B123).

When considering the patient's sex, both sexes exhibited similar functional and anatomical tumor distribution. Female patients were, however, found to have a higher proportion of poor/undifferentiated tumor histology compared with male patients (91.2%, 95% CI: 87.1%–95.3% vs 72.8%, 95% CI: 63.8%–81.8%). Although both sexes shared a comparable distribution of WHO histological classification subtypes, female patients demonstrated a higher proportion of diffuse-type tumors than male patients (82.2%, 95% CI: 74.7%–89.6% vs 72.2%, 95% CI: 61.9%–82.0%, respectively; Table 3 and see Supplementary Figures 11–12, http://links.lww.com/CTG/B123). Female patients also had a higher prevalence of positive family history of gastric cancer compared with male patients (15.6%, 95% CI: 1.8%–29.4% vs 12.6%, 95% CI: 2.7%–22.5%). The infection rate of H. pylori was also higher in female patients compared with male patients (85.7%, 95% CI: 73.8%–97.6% vs 73.3%, 95% CI: 56.3%–90.4%), although this was only reported in a single study by Ławniczak et al (37). Limited studies investigated the sex-stratified OR of various risk factors, and male patients had higher exposure to risk factors including alcohol, smoking, and H. pylori infection than female patients (see Supplementary Figure 13, http://links.lww.com/CTG/B123).

Table 3.

Sex-stratified analysis on clinicopathological characteristic of young-onset gastric carcinoma

Clinicopathological characteristics	Sex	No. of studies	Study population	Estimated pooled proportion (95% CI)	P heterogeneity	I 2
Anatomical regions
Antrum	Male	2	437	62.3% (57.8–66.8)	0.728	0.00%
	Female	2	391	57.3% (52.5–62.2)	0.553	0.00%
Corpus	Male	2	437	21.7% (8.2–35.2)	0.002	89.30%
	Female	2	391	20.7% (0.8–42.1)	<0.001	96.00%
Multifocal	Male	2	437	8.1% (0.8–16.9)	0.019	81.90%
	Female	2	391	17.0% (0.3–39.0)	<0.001	94.30%
Functional regions
Proximal	Male	4	205	8.8% (4.8–12.8)	0.712	0.00%
	Female	4	170	7.6% (3.5–11.8)	0.392	0.00%
Middle	Male	4	205	38.6% (27.7–49.5)	0.052	61.20%
	Female	4	198	37.8% (22.0–53.5)	<0.001	83.60%
Distal	Male	4	205	47.2% (32.0–62.4)	0.002	79.90%
	Female	4	198	48.1% (29.6–66.7)	<0.001	87.90%
Multifocal	Male	4	205	3.0% (0.4–5.7)	0.636	0.00%
	Female	4	198	6.2% (2.6–9.8)	0.923	0.00%
Differentiation
Well/moderate differentiated	Male	6	639	27.2% (18.2–36.2)	<0.001	81.10%
	Female	6	626	8.8% (4.7–12.9)	0.019	62.90%
Poor/undifferentiated	Male	6	639	72.8% (63.8–81.8)	<0.001	81.10%
	Female	6	626	91.2% (87.1–95.3)	0.019	62.90%
Lauren classification
Diffuse	Male	3	205	72.2% (61.9–82.5)	0.197	38.50%
	Female	3	176	82.2% (74.7–89.6)	0.181	41.50%
Intestinal	Male	3	205	18.3% (11.6–24.9)	0.483	0.00%
	Female	3	176	10.3% (0.7–20.0)	0.008	79.30%
Mixed	Male	3	205	9.5% (3.1–16.0)	0.273	23.00%
	Female	3	176	6.6% (0.6–13.8)	0.03	71.50%
WHO classification
Tubular/papillary adenocarcinoma	Male	3	432	78.0% (74.1–81.8)	0.525	0.00%
	Female	3	450	77.0% (70.2–83.9)	0.094	57.70%
Signet-ring cell carcinoma	Male	3	432	18.6% (15.0–22.3)	0.662	0.00%
	Female	3	388	16.0% (1.9–30.1)	0.001	91.60%
Mucinous/others	Male	3	432	3.4% (1.6–5.2)	0.698	0.00%
	Female	3	450	10.6% (0.7–20.6)	<0.001	88.70%
Positive family history of gastric cancer	Male	3	401	12.6% (2.7–22.5)	0.077	61.00%
	Female	3	379	15.6% (1.8–29.4)	0.005	81.00%
Helicobacter pylori infection rate (%)	Male	1	33	73.3% (56.3–90.4)	NAa	0.00%
	Female	1	23	85.7% (73.8–97.6)	NAa	0.00%

CI, confidence interval; WHO, World Health Organization.

^aNA: data not available.

The clinicopathological characteristics were found to be similar in countries with or without national screening programs, regarding the predominance of sex or the proportion of histological types. Asian countries (64.8%, 95% CI: 41.0%–86.5%) and countries with national screening programs for gastric cancer (61.1%, 95% CI: 34.8%–87.4%) were shown to have a higher H. pylori infection rate but without significance. In addition, Asian studies reported slightly higher but similar pooled OR of H. pylori infection than non-Asian studies (3.5, 95% CI: 1.9–6.3 vs 3.3, 95% CI: 2.0–5.2) (see Supplementary Figure 14, http://links.lww.com/CTG/B123).

In total, 12 studies reported the survival outcomes of patients with young-onset gastric carcinoma. The pooled 1-, 3-, and 5-year overall survival was 76.7% (95% CI: 64.3%–92.1%), 49.5% (95% CI: 34.0%–61.9%), and 42.6% (95% CI: 32.2%–53.1%), respectively (see Supplementary Figure 14, http://links.lww.com/CTG/B123). The survival outcome for young-onset gastric carcinoma of different sexes was reported in only 2 studies. Park et al observed that male patients exhibited a higher 5-year survival rate compared with female patients (73.9% vs 64.0%, P = 0.004) (36). Similarly, Lu et al reported a significantly shorter median survival time for female patients when compared with male patients (19 months vs 35 months, P = 0.022) (18).

DISCUSSION

This is the first systematic review and meta-analysis to explore the clinicopathological characteristics and risk factors of young-onset gastric carcinoma globally over the past 3 decades. We found that young-onset gastric carcinoma had a slight female predominance, and most of the tumors were localized to the middle and distal gastric and were characterized as diffuse or poorly differentiated adenocarcinomas. Positive family history and H. pylori infection were the 2 most important risk factors, and most of the young-onset cases presented with symptoms rather being detected by screening examinations, with abdominal pain being the most common.

Our findings that gastric carcinoma in younger individuals has distinct characteristics align with what has been described in prior studies (38–40). We observed that young-onset cases typically present as poorly differentiated and diffuse-type carcinomas. This specific pathological pattern incurs diffuse and infiltrated growth, which contributes to higher rates of lymphovascular invasion and worse prognosis (41–43). Therefore, early diagnosis at an early disease stage, followed by prompt surgical resection, could lead to a better prognosis (44).

While gastric carcinoma is usually a male-predominant disease, we found a higher proportion of female patients among this younger carcinoma population, which aligns with prior reports (45,46). The slight female predominance of young-onset gastric carcinoma has been previously hypothesized to be driven by hormonal factors, including the harmful role of estrogen or the higher expression of estrogen receptor-positive cells (47,48). Notably, our study shows that young female patients also have additional risk factors that may play a key role in pathogenesis, including higher rates of family history of gastric cancer and higher rates of H. pylori infection than their male counterparts. Our stratified analysis also showed that female patients were more likely to have undifferentiated or poorly differentiated carcinomas, which could be associated with worse outcomes. The impact of female sex on the prognosis or other pathological characteristics of young-onset gastric carcinoma requires further study to better understand these factors.

In our study, we found that over 60% of the patients with young-onset gastric carcinoma were H. pylori infected, with an OR of 2.3. Gastric carcinogenesis is closely associated with H. pylori infection, which leads to gastric carcinoma through various mechanisms including chronic inflammation, protein modulation, epigenetic changes, and genetic mutation (49,50). According to previous reports from Japan and South Korea, the prevalence of H. pylori in gastric carcinoma was usually found to exceed 90%, which was much higher than our findings. This may be potentially due to predominantly elderly patients and also taking into account history of infections (51). Although most studies have demonstrated a reduced risk of gastric carcinoma following successful eradication of H. pylori, the benefits of eradication in this group of patients remain uncertain and the relatively high OR of H. pylori infection among patients with young gastric carcinoma still reiterates the importance of timely intervention for those infected.

We found that 12.1% of young-onset cases had a family history of gastric cancer, which is similar to previous reports of approximately 10% (52). Given that positive family history was the most important risk factor of young-onset gastric carcinoma, it would be important to consider whether screening individuals with family history would facilitate early detection of these carcinomas, particularly in those infected with H. pylori. On the other hand, the role of other risk factors, such as dietary or behavioral factors such as smoking and alcohol use, were controversial in prior studies (53–55). In this study, we observed a roughly 2-fold higher risk of young-onset gastric carcinoma in those with excessive intake of salty food and heavy smoking and alcohol consumption. These factors were especially prominent among male patients. Therefore, this systematic review and meta-analysis help to shed additional light on the contribution of these lifestyle factors to young-onset gastric carcinoma.

The strength of this study is the first and most up-to-date study that investigated the clinicopathological characteristics and risk factors of young-onset gastric carcinoma. Unlike previous single-center or regional studies (11,56,57), we have conducted a comprehensive aggregated analysis based on 74 studies from across the globe over the past 3 decades. The large number of studies allowed us to conduct several subanalyses, including stratifications based on the sex and age of patients. Furthermore, we have derived more comprehensive insights into areas that were overlooked in prior studies, such as the presence of alarming symptoms, lesion location, and pathological features based on different criteria. In addition, our study has provided a comprehensive summary of the risk factors associated with gastric carcinoma within this specific age group, thereby offering evidence for future carcinoma prevention efforts.

Nonetheless, our results should also be interpreted in the context of several limitations. First, we mainly used proportion data extracted from the original studies. Despite providing a relative ratio of clinicopathological characteristics, the use of patients' characteristic averages or proportions may result in common ecological bias and underestimate their influence. Second, we excluded selected patient groups such as those limited to metastatic cancer or patients with other specific chronic diseases, which may alter the results. While we felt it was important to exclude these groups to limit bias, the risk of early-onset gastric carcinoma in these groups warrants future research. Third, some specific pathological types of gastric carcinoma were not reported in the study due to their limited documentation among young individuals. The contribution of these pathological tumor cell types to gastric carcinoma should be acknowledged. For example, neuroendocrine tumors have been recently recognized as significant factors in the pathogenesis of gastric cancer (58). Moreover, neuroendocrine cells and stem cells have been implicated as the primary sources of diffuse and intestinal-type gastric carcinoma, respectively, which are the 2 most prevalent Lauren type in young patients, thereby elucidating the role of gastrin in cancer development (59). Further studies are necessary to address this in the future. Fourth, while we set the cutoff age of 50 years as our definition of young-onset carcinoma, the age definition is not yet standardized. It is possible that setting the threshold younger could result in different findings. Fifth, only a limited number of studies provided data on the risk factors of gastric carcinoma. Sixth, it is worth noting that a significant proportion (64.3%) of the studies included in this analysis were conducted in Asian countries. While this may be partly due to the high incidence of gastric cancer in these regions, it should be acknowledged that the generalizability of our findings to other populations may be limited. Finally, the limited data on specific characteristics of young-onset carcinomas, such as age and sex stratifications, survival outcomes, and risk factors, as well as the inclusion of multiple retrospective studies with varying patient populations, contribute to significant heterogeneity. Therefore, caution should be exercised when interpreting the pooled findings from subgroup analysis due to the small number of studies with substantial heterogeneity.

In this comprehensive review of the clinicopathological characteristics of young-onset gastric carcinoma, we found that young-onset carcinoma is characterized by a slight female predominance and is frequently symptomatic at presentation. Histologically, these carcinomas are primarily characterized by Lauren diffuse type and poor differentiation. Overall, 12.1% patients had family history of gastric cancer and, approximately 60% of them were infected with H. pylori. Our findings provide valuable insights for informing future strategies on the early detection and prevention of gastric carcinoma in younger individuals.

CONFLICTS OF INTEREST

Guarantor of the article: Wai K. Leung, MD, FACG.

Specific author contributions: Y.L. was involved with study design, data analysis, data collection, and interpretation of data; drafting of the manuscript; and approval of the final version of the manuscript. A.I.H., M.L., and F.J. were involved with statistical analysis; critical revision of the manuscript for important intellectual content; and approval of the final version of the manuscript. A.G.Z. and W.K.L. were involved with the study concept and design; supervision; drafting of manuscript; critical revision of the manuscript for important intellectual content; study supervision; and approval of the final version of the manuscript.

Financial support: None to report.

Potential competing interests: A.I.H., M.L., and A.G.Z. were supported in part through the NIH/NCI Cancer Center Support Grant [P30 CA008748]. M.L. was also supported by a grant from the NIDDK of the National Institutes of Health [K08 DK125876] and a grant from the National Cancer Institute of the National Institutes of Health [U01 CA265729].

Data availability: Data generated or analyzed in this article are included in the supplementary material.

Study Highlights.

WHAT IS KNOWN

• ✓ Gastric carcinoma in young individuals may have a distinct clinicopathological feature

WHAT IS NEW HERE

• ✓ In this updated meta-analysis and systematic review, young-onset gastric carcinoma shows a slight female predominance and most patients are symptomatic at diagnosis

• ✓ The majority of young-onset carcinoma exhibit poor differentiation and Lauren's diffuse-type histology

• ✓ A positive family history is the major risk factor, follows by Helicobacter pylori infection and high-risk dietary behaviours

Supplementary Material

ct9-15-e1b-s001.docx ^{(8MB, docx)}