Analysis of medium-term prognostic factors for laparoscopic radical resection of serosal infiltrating (pT4a) gastric cancer: a retrospective cohort study

Abstract

Objective

To investigate the clinicopathological characteristics and factors influencing medium-term prognosis in patients with gastric cancer and serosal invasion (pT4a) following laparoscopic radical gastrectomy.

Methods

In this retrospective study, 461 patients with pT4a gastric cancer who underwent laparoscopic D2 radical gastrectomy at The First Affiliated Hospital of Shandong Second Medical University (October 2019-December 2024) were analyzed. Survival was assessed by the Kaplan–Meier method; prognostic factors were identified using univariate and multivariate Cox regression.

Results

Poorly differentiated/undifferentiated adenocarcinoma comprised 76.8% of cases, and 63.8% were of the diffuse Lauren type. Median tumor diameter was 5.5 cm (58.2% >5 cm). Lymphovascular and perineural invasion were present in 88.7% and 92.4% of patients, respectively; tumor deposits were found in 10.7%. Overall lymph node metastasis rate was 84.8% (pN3a: 25.2%, pN3b: 19.5%). With a median follow-up of 26.0 months, median overall survival (OS) was 49.0 months and median disease-free survival (DFS) was 37.0 months. Multivariate analysis identified independent adverse prognostic factors for OS: age (HR = 1.03, 95% CI 1.01–1.04, P = 0.001), elevated CA19−9 (HR = 1.58, 95% CI 1.15–2.17, P = 0.004), tumor deposits (HR = 1.40, 95% CI 1.01–1.94, P = 0.045), Lauren classification (HR = 1.32, 95% CI 1.04–1.68, P = 0.022), total gastrectomy (vs. partial/subtotal; HR = 1.81, 95% CI 1.35–2.43, P < 0.001), and advanced pN stage (HR = 1.54, 95% CI 1.26–1.88, P < 0.001). For DFS, independent predictors were age, elevated CA19−9, tumor deposits, total gastrectomy, and pN stage (all P < 0.05).

Conclusion

In this study cohort, patients with pT4a gastric cancer who underwent laparoscopic D2 radical resection achieved medium-term survival outcomes that are broadly comparable to those reported in historical open surgery cohorts. Age, elevated CA19−9, tumor deposits, Lauren classification(diffuse type), total gastrectomy, and advanced pN stage are independent adverse prognostic factors.

Supplementary Information

The online version contains supplementary material available at 10.1186/s12893-026-03897-x.

Background

Gastric cancer ranks among the most common malignant tumors [1, 2]. A significant proportion of patients are diagnosed at a locally advanced stage, among which a high percentage present with serosal invasion (pT4a) [3, 4]. Current studies on laparoscopic radical gastrectomy for gastric cancer predominantly include patients with mixed pT stages or focus primarily on technical feasibility and short-term outcomes. For patients with confirmed serosal invasion (pT4a), the efficacy of laparoscopic surgery remains controversial. Key concerns include whether pneumoperitoneum increases the risk of peritoneal dissemination, the adequacy of D2 lymphadenectomy in the context of extensive serosal exposure, and the lack of large-sample medium-term survival data for this high-risk subgroup. As a result, there remains a significant evidence gap regarding independent prognostic factors and medium-term oncologic outcomes following laparoscopic radical gastrectomy in pT4a gastric cancer.This study retrospectively analyzed the clinicopathological data of 486 patients with pT4a gastric cancer to investigate prognostic factors and to provide an evidence-based foundation for individualized clinical treatment.

Materials and method

Ethical approval was obtained from the Institutional Review Board of Weifang People’s Hospital for this study, which adhered to the principles of the Declaration of Helsinki. The board waived the need for informed consent due to the retrospective design of the research.

Study population and design

Patients and Methods We conducted a single-center retrospective study at The First Affiliated Hospital of Shandong Second Medical University (Weifang People’s Hospital). We consecutively enrolled patients with locally advanced gastric cancer who had undergone radical gastrectomy from December 2019 to December 2024. Expert Surgical Team: All procedures were conducted by a fixed, specialized laparoscopic team. The lead surgeons each had experience of > 50 prior laparoscopic D2 gastrectomies. Standardized Protocol: D2 lymphadenectomy was performed according to established Japanese Gastric Cancer Treatment Guidelines and the Chinese Guideline for Laparoscopic Gastric Cancer Surgery. Inclusion Criteria: Patients were included if they (1) were aged 18–80 years; (2) underwent laparoscopic D2 radical gastrectomy; (3) had pathologically confirmed gastric adenocarcinoma; (4) were staged pT4aN0−3bM0 (AJCC 8th edition); and (5) had complete clinical and pathological records. Exclusion Criteria: Patients were excluded for (1) emergency surgery; (2) non-R0 resection; (3) concomitant or prior malignancy; (4) neoadjuvant therapy; or (5) pre-/intraoperative detection of distant metastasis.

Data collection

Baseline parameters collected included: age, sex, body mass index (BMI), hypertension, coronary heart disease, diabetes, smoking history, carcinoembryonic antigen (CEA; elevated if ≥ 5 ng/mL), carbohydrate antigen 19−9 (CA19−9; elevated if ≥ 37 U/mL), carbohydrate antigen 72−4 (CA72−4; elevated if ≥ 6.9 U/mL), alpha-fetoprotein (AFP), preoperative albumin, preoperative hemoglobin, tumor differentiation (well/moderately/poorly), tumor diameter (cm), perineural invasion, lymphovascular invasion, total number of lymph nodes dissected, tumor deposits, Lauren classification (intestinal/mixed/diffuse), extent of gastrectomy (total vs. partial/subtotal), pT stage, and pN stage.

Pathological diagnostic criteria for tumor deposits

Tumor deposits (TDs) were diagnosed according to the criteria defined in the 8th edition of the American Joint Committee on Cancer (AJCC) gastric cancer staging system. A tumor deposit was defined as a discrete tumor nodule within the lymphatic drainage area of the primary tumor, separate from a lymph node and lacking histological evidence of residual lymph node, vascular wall, or neural structure.All pathological slides were independently reviewed by two senior gastrointestinal pathologists until a consensus was reached.

Statistical analysis

All statistical analyses were performed using R software (version 4.4.2). Survival rates were estimated using the Kaplan-Meier method, and prognostic factors were assessed by univariate and multivariate analyses with the Cox proportional hazards regression model. A two-sided P-value < 0.05 was considered statistically significant.

Follow-up

Follow-up protocol

Surveillance involved clinic visits and telephone calls scheduled every 3–6 months for the initial 2 years, and every 6–12 months afterwards, concluding on December 31, 2025. Assessments included physical exam, tumor markers (CEA, CA19−9, CA72−4), gastroscopy, and contrast-enhanced CT of the chest/abdomen.

Endpoint definitions

Overall Survival (OS): Time from surgery to death (any cause). Patients alive at last contact were censored.Disease-Free Survival (DFS): Time from surgery to first recurrence (local/regional or distant), metastasis, or death.

The analysis used December 31, 2025 as the final follow-up date.

Clinicopathological characteristics

The main clinicopathological characteristics of the 461 pT4a gastric cancer patients are summarized in Table 1.

Table 1.

Clinicopathological characteristics of the 461 pT4a gastric cancer patients

Characteristic	Value
Total number of patients	461
Tumor differentiation: poorly / undifferentiated	76.8%
Lauren classification: diffuse type	63.8%
Median maximum tumor diameter (cm)	5.5
Tumor diameter > 5 cm	58.2%
Lymphovascular invasion	88.7%
Perineural invasion	92.4%
Tumor deposits	10.7%
Lymph node metastasis (overall)	84.8%
pN stage distribution
pN0	15.2%
pN1	16.3%
pN2	23.8%
pN3a	25.2%
pN3b	19.5%

Analysis of prognostic factors for overall survival

Univariate Cox regression analysis revealed that age, elevated CA19−9, poor tumor differentiation, presence of tumor deposits, Lauren classification (diffuse vs. intestinal), total gastrectomy (vs. partial/subtotal), and higher pN stage were significantly associated with worse OS (all P < 0.05). Multivariate analysis identified age (HR = 1.03, 95%CI:1.01–1.04, P = 0.001), elevated CA19−9 (HR = 1.58, 95%CI:1.15–2.17, P = 0.004), tumor deposits (HR = 1.40, 95%CI:1.01–1.94, P = 0.045), Lauren classification (HR = 1.32, 95%CI:1.04–1.68, P = 0.022), type of gastrectomy (total vs. partial/subtotal, HR = 1.81, 95%CI:1.35–2.43, P < 0.001), and pN stage (HR = 1.54, 95%CI:1.26–1.88, P < 0.001) as independent adverse prognostic factors for OS. (Table 2).

Table 2.

Prognostic Factors for Overall Survival (OS): Univariate and Multivariate Analyses in 461 T4a Gastric Cancer Patients

Clinicopathological Characteristics	Univariate Analysis			Multivariate Analysis
Variable	HR	CI	P	HR	CI	P
sex	0.96	(0.69–1.35)	0.833
age	1.03	(1.01–1.04)	0.002	1.03	(1.01–1.04)	0.001
BMI	0.97	(0.93–1.01)	0.168
hypertension	1.10	(0.81–1.50)	0.537
CHD	0.89	(0.47–1.69)	0.723
DM	0.88	(0.57–1.36)	0.560
Smoking	1.03	(0.77–1.39)	0.830
CEA	1.36	(0.96–1.93)	0.082
CA199	1.61	(1.18–2.20)	0.003	1.58	(1.15–2.17)	0.004
CA724	1.28	(0.93–1.77)	0.127
AFP	0.78	(0.42–1.44)	0.424
Alb	0.99	(0.96–1.03)	0.660
HB	1.00	(1.00−1.01)	0.860
Tumor differentiation	1.65	(1.12–2.44)	0.011	1.06	(0.62–1.79)	0.836
Tumor diameter	1.06	(0.70–1.61)	0.767
Perineural invasion	2.06	(0.96–4.38)	0.062
Lymphovascular invasion	1.54	(0.68–3.48)	0.299
Total number of lymph nodes dissected	1.00	(0.99−1.00)	0.788
Tumor deposits	1.92	(1.40–2.63)	< 0.001	1.40	(1.01–1.94)	0.045
Lauren classification	1.39	(1.16–1.66)	< 0.001	1.32	(1.04–1.68)	0.022
pNstage*	1.69	(1.40–2.05)	< 0.001	1.54	(1.26–1.88)	< 0.001
Type of Gastrectomy (Total vs. Partial/Subtotal)	1.85	(1.39–2.48)	< 0.001	1.81	(1.35–2.43)	< 0.001

*pN stage was entered as an ordinal variable, and the HR reflects the change in hazard for each one-category increase in pN stage (from pN0 to pN1, pN1 to pN2, etc.)

Analysis of prognostic factors for disease-free survival

Univariate analysis showed that age, elevated CEA, elevated CA19−9, poor tumor differentiation, presence of tumor deposits, perineural invasion, Lauren classification, and higher pN stage were significantly associated with worse DFS (all P < 0.05).For DFS, independent predictors included age (HR = 1.02, 95%CI:1.00−1.03, P = 0.014), elevated CA19−9 (HR = 1.63, 95%CI:1.21–2.20, P = 0.001), tumor deposits (HR = 1.46, 95%CI:1.07–1.98, P = 0.017), type of gastrectomy (HR = 1.91, 95%CI:1.45–2.51, P < 0.001), and pN stage (HR = 1.48, 95%CI:1.23–1.78, P < 0.001). (Table 3)

Table 3.

Prognostic Factors for Disease-Free Survival (DFS): Univariate and Multivariate Analyses

Clinicopathological Characteristics	Univariate Analysis			Multivariate Analysis
Variable	HR	CI	P	HR	CI	P
sex	0.93	(0.68–1.28)	0.670
age	1.02	(1.00−1.03)	0.024	1.02	(1.00−1.03)	0.014
BMI	0.97	(0.93–1.01)	0.141
hypertension	1.00	(0.75–1.34)	0.989
CHD	0.84	(0.46–1.54)	0.569
DM	0.83	(0.55–1.26)	0.379
Smoking	1.08	(0.82–1.43)	0.575
CEA	1.40	(1.01–1.94)	0.043	1.31	(0.94–1.83)	0.117
CA199	1.73	(1.29–2.30)	< 0.001	1.63	(1.21–2.20)	0.001
CA724	1.22	(0.90–1.65)	0.210
AFP	0.80	(0.45–1.40)	0.425
Alb	0.99	(0.96–1.02)	0.521
HB	1.00	(0.99–1.01)	0.992
Tumor differentiation	1.66	(1.16–2.38)	0.006	1.36	(0.82–2.23)	0.231
Tumor diameter	1.14	(0.77–1.70)	0.517
Perineural invasion	2.10	(1.04–4.27)	0.040	1.59	(0.78–3.23)	0.204
Lymphovascular invasion	1.33	(0.66–2.71)	0.425
Total number of lymph nodes dissected	1.00	(0.99−1.00)	0.644
Tumor deposits	1.97	(1.47–2.65)	< 0.001	1.46	(1.07–1.98)	0.017
Lauren classification	1.29	(1.10–1.52)	0.002	1.17	(0.94–1.45)	0.160
pNstage	1.66	(1.39–1.98)	< 0.001	1.48	(1.23–1.78)	< 0.001
Type of Gastrectomy (Total vs. Partial/Subtotal)	1.91	(1.45–2.51)	< 0.001	1.91	(1.45–2.51)	< 0.001

Postoperative follow-up and survival analysis

At the final follow-up (December 31, 2025), the median follow-up for the entire cohort was 26.0 months (95% CI: 24.0–28.0). The median overall survival (OS) was 49.0 months (95% CI: 44.0–54.0), with 1-, 3-, and 5-year OS rates of 89.2%, 64.5%, and 48.6%, respectively. The median disease-free survival (DFS) was 37.0 months (95% CI: 33.0–41.0), and the corresponding 1-, 3-, and 5-year DFS rates were 81.5%, 55.2%, and 41.4%.

Discussion

This study demonstrates that, when performed by an experienced surgical team, laparoscopic radical resection can achieve medium-term survival outcomes broadly comparable to those reported in historical open surgery cohorts for selected patients with pT4a gastric cancer. Compared with previous studies, our work features a relatively large sample size and focuses exclusively on pure pT4a cases, thereby addressing a gap in the literature, which has often included mixed-stage cohorts or been limited by smaller sample sizes [5–7].

CA19−9 emerged as one of the most robust hematological prognostic markers in our analysis (OS: HR = 1.58; DFS: HR = 1.63). Biologically, elevated CA19−9 may reflect a higher tumor burden and aberrant glycosylation patterns associated with aggressive tumor behavior. However, CA19−9 is known to yield false-negative or false-positive results in Lewis antigen-negative individuals and may also be elevated in benign conditions such as cholestasis or pancreatitis [8, 9]. Therefore, CA19−9 should be interpreted as an auxiliary tool rather than a standalone decision-making instrument and should be integrated with imaging and other biomarkers for comprehensive risk assessment.

Tumor deposits (TDs) were detected in 10.7% of our cohort and independently predicted worse OS and DFS (OS: HR = 1.40; DFS: HR = 1.46). TDs are thought to represent discontinuous tumor spread, venous invasion with extravascular deposition, or lymph nodes that have been completely replaced by tumor. Unlike conventional lymph node metastases, TDs often lack a surrounding capsule and may expose tumor cells more directly to the peritoneal environment, potentially accounting for their strong negative prognostic impact [10, 11]. Whether TDs should be incorporated into the N category or remain a separate prognostic factor is still debated, but our findings support their independent clinical relevance.

Lauren classification (diffuse vs. intestinal) was an independent prognostic factor for OS (HR = 1.32), consistent with the known aggressive biology of diffuse-type gastric cancer, including a higher propensity for peritoneal dissemination, lymph node metastasis, and chemoresistance [12]. Notably, Lauren classification did not reach statistical significance for DFS in multivariate analysis. One possible explanation is that its effect on recurrence risk is partly mediated through other variables such as pN stage and TDs, or it may be attributable to sample size and follow-up duration.

Although poorly differentiated/undifferentiated histology (76.8%), lymphovascular invasion (88.7%), and perineural invasion (92.4%) were highly prevalent in our cohort and associated with worse survival on univariate analysis, they did not retain independent prognostic significance in the multivariate analysis. This likely reflects collinearity with other strong prognostic factors, particularly pN stage and Lauren classification.

Total gastrectomy was associated with worse survival compared with partial/subtotal gastrectomy (OS: HR = 1.81; DFS: HR = 1.91). This difference likely reflects not merely the extent of resection but also confounding factors such as tumor location (upper stomach), higher nodal burden, and deterioration of postoperative nutritional status. Therefore, for pT4a patients requiring total gastrectomy, enhanced perioperative nutritional support and vigilant adjuvant therapy are especially important.

pN stage, analyzed as an ordinal variable, confirmed nodal metastatic burden as a core determinant of prognosis. In our cohort, the overall lymph node metastasis rate was 84.8%, with pN3a and pN3b accounting for 25.2% and 19.5% of cases, respectively. This high rate of advanced nodal disease in pT4a cases underscores the critical importance of postoperative adjuvant chemotherapy and close surveillance, as well as the need for more effective systemic therapies in this high-risk subgroup.

In light of the ongoing controversy surrounding laparoscopic surgery for pT4a tumors, all procedures in this study were performed by a single, experienced surgical team. Consistent with several previous reports, our findings indicate that laparoscopic D2 radical gastrectomy is both feasible and safe for pT4a gastric cancer when patient selection is appropriate [13].

Limitations and future directions

This study has several limitations. First, as a retrospective, single-center analysis, it is susceptible to selection bias. Second, detailed data on postoperative adjuvant chemotherapy (regimens, cycles, completion rates) were missing due to incomplete early records, which may have influenced the results. Third, the median follow-up of 26.0 months is insufficient for robust estimation of 5-year survival rates. Future multicenter prospective studies with standardized adjuvant therapy protocols and molecular profiling are needed. In addition, comparative studies evaluating robotic versus conventional laparoscopic surgery in pT4a gastric cancer are warranted but remain beyond the scope of the current work [14].

Authors’ contributions

Guangxu Zhu, Jianjun Qu, Chunxiao Liu, Yuzhi Chen, and Shengjie Zhou conjectured the study and reviewed the paper; Guangxu Zhu analyzed the data and wrote the draft; Yongning Liu selected the patients and collected the data.

Funding

There was no formal funding for this project.

Data availability

The datasets utilized and/or analyzed during the current study are available from the corresponding author upon reasonable request.

Declarations

Ethics approval and consent to participate

This study was conducted in accordance with the ethical principles outlined in the Declaration of Helsinki and approved by the Institutional Review Board of Weifang People’s Hospital. Due to its retrospective nature, the requirement for informed consent was waived by the Institutional Review Board of the Weifang People’s Hospital.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.