The impact of the length of proximal margin on the prognosis of adenocarcinoma of gastroesophageal junction and strategies : A real-world study

doi:10.21203/rs.3.rs-3578036/v1

Download PDF

Research Article

The impact of the length of proximal margin on the prognosis of adenocarcinoma of gastroesophageal junction and strategies : A real-world study

https://doi.org/10.21203/rs.3.rs-3578036/v1

This work is licensed under a CC BY 4.0 License

Journal Publication

published 01 Apr, 2024

Read the published version in Asian Journal of Surgery →

Version 1

posted

You are reading this latest preprint version

Background: The optimal proximal margin (PM) length for SiewertII/III adenocarcinoma of the esophagogastric junction (AEJ) remains unclear. This study aimed to determine the optimal PM length using an abdominal approach to guide surgical decision-making.

Methods: A prospective study analyzed 304 consecutive patients diagnosed with SiewertII/III AEJ between January 2019 and December 2021. Total gastrectomy was performed via the abdominal approach, and PM length was measured on fixed gross specimens. X-Tile software determined the optimal PM cut-point based on progression-free survival (PFS). Univariate analyses compared baseline characteristics across PM groups, while survival analyses utilized Kaplan-Meier estimation and Cox proportional hazards regression for assessing the impact of margin length on survival. Multivariable analyses were conducted to adjust for confounding variables.

Results: The study included 264 AEJ cases classified as Siewert II (71.97%) or III (28.03%). The median gross PM length was 1.0 cm (IQR: 0.5 cm-1.5 cm, range: 0 cm-6 cm). PM length ≥1.2 cm was associated with a lower risk of disease progression compared to PM length 0.4 cm on PFS (HR = 0.41, 95% CI 0.20-0.84, P = 0.015). Moreover, PM ≥1.2 cm improved prognosis in subgroups of T4 or N3, tumor size <4 cm, Siewert II, and Lauren classification.

Conclusions: For Siewert type II/III AEJ, a proximal margin length ≥1.2 cm (1.65 cm in situ) is associated with improved outcomes. These findings offer valuable insights into the association between PM length and outcomes in SiewertII/III AEJ, providing guidance for surgical approaches and aiding clinical decision-making to enhance patient outcomes.

Adenocarcinoma of the esophagogastric junction

proximity margin

surgical approaches

Neoadjuvant therapy

signet ring cells

The annual incidence of adenocarcinoma of the esophagogastric junction (AEJ) is increasing in both Western and Asian populations^[1]. AEJ affects both the esophagus and stomach, but there is no consensus on its origin and unique biological characteristics^[2]. Surgical resection remains the primary treatment approach for AEJ, and obtaining pathological negative margins is an important goal of surgical treatment, and numerous studies have demonstrated a clear association between positive pathological margins and poor prognosis^[3–5]. Based on existing studies, the 5-year survival rate for patients undergoing R0 resection, where negative margins are achieved, ranges between 53% and 60%. In contrast, patients undergoing R1 resection, where positive margins are present, have significantly lower survival rates, ranging from 13–26%^[6–9]. Research has provided evidence that prolonged esophagectomy is associated with higher survival rates in patients with adenocarcinoma of the esophagogastric junction (AEJ). Studies have reported an average survival time of approximately 37 months for patients undergoing prolonged esophagectomy. This finding contrasts with the average survival time of 22 months observed in patients who undergo standard gastrectomy^[10]. Indeed, the prognostic significance of esophageal proximal margin length (PM) has been a topic of great interest and importance among gastrointestinal surgeons. PM refers to the distance between cancerous tissue and the healthy tissue left behind during surgery. The determination of the optimal PM length has sparked debates regarding various treatment strategies for patients with AEJ. These discussions encompass areas such as perioperative treatment, surgical approach, extent of lymph node dissection, and the type of esophagectomy performed^[11].

Typically, surgeons assess surgical margins through visual examination and tactile sensation to determine the adequacy of resection. However, among the 13 previous studies focusing on PM length in AEJ, only 5 studies have specifically addressed the minimum length required for the PM. In the previous study, the PM length range from 5 to 12cm was found to be necessary to ensure complete tumor removal^{[10, 12–15]}. Based on the study findings, it is important to consider the recommendations provided by certain gastric cancer guidelines regarding the optimal PM length in gastrectomy. Specifically, the 5th edition of the Japanese Guidelines for gastric cancer treatment (JGCTGs) suggested that advanced AEJ patients should have a minimum PM of at least 3 cm for Borrmann types I/II and 5 cm for Borrmann types III/IV^[16]. These values have not been altered in the 6th edition of the guidelines. The Dutch guidelines recommend a minimum PM length of 6cm, while the German guidelines suggest 5cm for intestinal-type AEJ and 8cm for diffuse gastric cancer^[17]. However, these recommendations do not obtain sufficient scientific evidence. When longer esophageal specimens were removed to obtain longer PM lengths, the esophagus was transectional in the deeper and narrower spaces of the posterior mediastinum. So during the reconstruction process, lifting the jejunum or the remnant stomach and connecting it to the esophageal margin is also concealed regardless of the chosen reconstruction type used. When postoperative anastomosis fails, mediastinal infections sometimes occur and can be associated with fatal problems. Therefore, determining the minimum length of an oesophagectomy is particularly useful and important.

In this real-world study, our primary objective was to investigate the impact of PM length on prognosis in transabdominal Siewert Ⅱ/Ⅲ AEJ patients. Meanwhile we aimed to determine the optimal PM length for transabdominal oesophageal resection and to determine the differences in baseline characteristics between different PM lengths. Additionally, we sought to assess the degree of PM influence on prognosis in different subgroups, providing valuable insights for selecting appropriate preoperative treatment strategies.

Patient selection

In this study, we conducted a prospective analysis of 304 AEJ patients who were treated at the gastrointestinal surgery department of the First Affiliated Hospital of Naval Military Medical University between 2019 and 2021. Among these patients, 6 were classified as Siewert type I. Additionally, 27 patients were lost to follow-up, and 7 patients had missing baseline data. After excluding these cases, a total of 264 patients were included in the study. Among them, 33 patients underwent neoadjuvant treatment(NACT). All the gross specimens in the included medical records were negative, but there were 27 cases positive margins in microscopic (R1), and no additional resection was received for patients with positive pathologic PM.(Figure1)

For all of the patients, the following demographic, clinical and pathological variables were recorded and inserted into the computer database: age, sex, type of gastrectomy, NACT, PM lengths (post-fixed specimens assessed by pathologists), AEJ location, tumor diameter (long diameter), T category, N category, Lauren classification, signet ring cell histology, presence of carcinoma nodules, presence of vascular, lymphatic and perineural invasion, human epidermal growth factor receptor 2 (HER 2) gene overexpression / amplification, tumor regression grade (TRG) (accepted only Patients in NACT), disease progression-free survival (PFS), and overall survival (OS).

Patients were followed up every 3 months after surgery.Median follow-up time is 24 months(range: 1–52 months).

The study has been registered by the Chinese Clinical Laboratory Center with registration number (ChiCTR2100050226) and approved by the Ethics Committee of Changhai Hospital with ethics approval number (CHEC2021-100).

Surgical procedures

Preoperative evaluation of Siewert Ⅱ/Ⅲ gastroesophageal junction tumors and feasible elective surgery for patients with open or laparoscopic radical total gastrectomy. Total gastrectomy and lymph node dissection were performed according to the guidelines of Chinese Primary gastric Cancer (CSCO), and the dissection range reached D2 or D2 +. The length of the esophagectomy was determined by the attending physician based on the findings of intraoperative palpation tumor and examination of the serosa surface, taking into account the results of preoperative endoscopic and imaging examinations.

Measurement of gross and pathological PM lengths

Each specimen was stirred in 10% formalin solution for 48 hours for pathological examination; the specimen was then naturally deployed and fixed on the fat plate with measured side-up to obtain the distance (PM) between the upper margin and the esophageal margin, based to 27% shrinkage after fixation^[10]. The distance between tumor upper margin and esophageal margin in body specimens PM1 = PM /(1–27%). Serial longitudinal sections of the tumors were performed and underwent subsequent pathological evaluation according to JCGC^[18]. Stratifying the specimens to determine the microscopic distance (PM2) between the positive tumor edge and the esophageal edge. The location of the proximal border of pathology and pathological PM length were determined by daily practice in pathology reports.

Statistical analysis

We calculated median and IQR (interquartile range) for continuous variables and frequencies and percentages for categorical variables to describe the demographic and clinical baseline characteristic.The optimal cut-point of PM was found by using X -Tile (Version 3.6.1) software based on the endpoint of PFS.We applied the Kruskal-Wallis H test and Cochran–Mantel–Haenszel test to conduct univariate analyses for the comparison of baseline characteristics across three PM groups.

The PFS and OS endpoints included the survival rate and survival curve estimated on the basis of the Kaplan-Meier estimator. Multivariable Cox proportional hazards models were used to obtain adjusted hazard ratios (HRs) and corresponding 95% confidence interval (CI) of different PM groups for PFS and OS outcomes, and the lowest PM were treated as the reference. In consideration of the hypothesis that the relationship between PM and PFS or OS outcomes was nonlinear, we further performed Cox proportional hazards models with restricted cubic splines (RCS) with 3 knots (25%, 50%, 75%) for PM adjusting for all covariates.to further explore the association between PM and PFS outcomes among different subgroup population, subgroup analyses were conducted based on JGCA RM Safe treatment distances Guidelines for treatment^[19]: T or N stage, tumor size, Siewert types, and Lauren patterm.

All analyses were performed using R software (version 4.1.2).All reported p values were two-sided, and a p value < 0.05 was regarded as statistically significant.This study is an exploratory real-world study, therefor, the problem of multiple comparisons was not considered.

Basic clinical features

Patient clinicopathological and procedure-related characteristics are summarized in Table 1. Among these patients, 225 (85.23%) were male and 39 (14.77%) were female. Patient age, with a median of 70 years (IQR: 63-75). Among these, type Siewert II is 190 (71.97%) and III is 74 (28.03%). All patients underwent total gastrectomy, and the median length of the gross proximal margin of the postoperative case was 1.0cm (IQR: 0.5cm-1.5cm, range: 0cm-6cm). Margin 27 (10.23%) were positive and 237 (89.77%) were negative. Lauren 130 intestinal type (49.24%) and 134 diffuse / mixed type (50.76%). There were 34(12.88%) carcinoma nodules, 97 (36.74%) vascular infifiltration and 151 (57.2%) nerve invasion. Tumor size was grouped according to the measured length, ranging from 0 to 10 cm. 33 patients underwent neoadjuvant chemotherapy（NACT）, compared with only 5 patients in TRG0-1(Table 1). 6 patients with peritoneal metastasis（M1） were treated surgically after transformation therapy.

Figure1 Patient cohorts were stratified according to the length of PM

TABLE 1 Patient and tumor characteristics

Variable	Value (N=264)
Sex
Male	225(85.23)
Female	39(14.77)
Age	70.00(63.00,75.00)
Age-group
≤70	145(54.92)
>70	119(45.08)
Differentiation
High and moderate differentiation	118(44.70)
Poorly differentiation	146(55.30)
Positive rate of margin
Negative	237(89.77)
Positive	27(10.23)
Cancerous node
Negative	230(87.12)
Positive	34(12.88)
Nerve invasion
Negative	113(42.80)
Positive	151(57.20)
Vascular infiltration
Negative	167(63.26)
Positive	97(36.74)
Lauren pattern
Intestinal	130(49.24)
Diffuse/mixed	134(50.76)
Siewert type
II	190(71.97)
III	74(28.03)
T category
T1	38(14.39)
T2-T3	188(71.21)
T4	38(14.39)
N category
N0	118(44.70)
N1-2	96(36.36)
N3	50(18.94)
M category
M0	258(97.73)
M1	6(2.27)
Tumor grade
I-II	164(62.12)
III-IV	100(37.88)
Tumor size
0-2cm	34(12.88)
2-4cm	100(37.88)
4-5cm	69(26.14)
＞5cm	61(23.11)
Signet-ring cell histological appearance	24(9.09)
FISH: HER2	45(17.05)
NACT	33(12.50)
TRG （only for NACT ）
0-1	5（15.15）
2-3	28（84.85）

HER2 human epidermal growth factor receptor 2, NACT neoadjuvant chemotherapy, TRG tumor regression grade

Effect of PM on PFS and OS

According to the results of X-Title (Version 3.6.1) software (Figure S1), we divided PM into three groups: ≤0.4cm, 0.5-1.1cm, ≥1.2cm, and analyzed related factors, and found that differentiation, whether with cancer nodules, nerve invasion, Lauren classification, tumor size, T stage, N stage, and whether signet ring cell carcinoma had significant correlation on PM length (P <0.05). Less differentiated tumors were more likely to obtain a shorter PM. Similarly, patients with cancerous nodules or nerve invasion had shorter PM, diffuse / mixed, T and N stages also affected the acquisition of PM length, and a larger proportion of signet ring cell carcinoma was distributed in the ≤0.4cm group(P <0.05). However, gender, age, Siewert classification, vascular invasion, tumor size, and neoadjuvant chemotherapy (NCAT) did not show statistical differences in PM (Table 2).

TABLE 2 Analysis of factors associated with different lengths of PM

	PM
Variable	≤0.4cm (N =59)	0.5-1.1cm (N =104)	≥1.2cm (N =101)	P value
Sex				0.9472
Male	50(84.75)	88(84.62)	87(86.14)
Female	9(15.25)	16(15.38)	14(13.86)
Age	70.00 (62.00,77.00)	70.00 (63.50,75.00)	70.00 (64.00,73.00)	0.5774
Age-group				0.7218
≤70	30(50.85)	57(54.81)	58(57.43)
>70	29(49.15)	47(45.19)	43(42.57)
Differentiation				0.0425
High and moderate differentiation	18(30.51)	52(50.00)	48(47.52)
Poorly differentiation	41(69.49)	52(50.00)	53(52.48)
Positive rate of margin				<0.0001
Negative	32(54.24)	104(100.00)	101(100.00)
Positive	27(45.76)	0(0.00)	0(0.00)
Cancerous node				0.0042
Negative	45(76.27)	98(94.23)	87(86.14)
Positive	14(23.73)	6(5.77)	14(13.86)
Nerve invasion				0.0161
Negative	16(27.12)	52(50.00)	45(44.55)
Positive	43(72.88)	52(50.00)	56(55.45)
Vascular infifiltration				0.1293
Negative	31(52.54)	71(68.27)	65(64.36)
Positive	28(47.46)	33(31.73)	36(35.64)
Lauren pattern				0.0479
Intestinal	21(35.59)	53(50.96)	56(55.45)
Diffuse/mixed	38(64.40)	51(49.04)	45(44.55)
Siewert type				0.7346
II	44(74.58)	76(73.08)	70(69.31)
III	15(25.42)	28(26.92)	31(30.69)
T category				0.0233
T1	2(3.39)	16(15.38)	20(19.80)
T2-T3	46(77.97)	78(75.00)	64(63.37)
T4	11(18.64)	10(9.62)	17(16.83)
N category				0.0109
N0	21(35.59)	55(52.88)	42(41.58)
N1-2	19(32.20)	32(30.77)	45(44.55)
N3	19(32.20)	17(16.35)	14(13.86)
M category				0.2904
M0	56(94.92)	103(99.04)	99(98.02)
M1	3(5.08)	1(0.96)	2(1.98)
Tumor grade				0.3088
I-II	32(54.24)	69(66.35)	63(62.38)
III-IV	27(45.76)	35(33.65)	38(37.62)
Tumor size				0.0246
<4cm	21(35.59)	55(52.88)	58(57.43)
≥4cm	38(64.41)	49(47.12)	43(42.57)
Signet-ring cell histological appearance				0.0382
deny	49(83.05)	95(91.35)	96(95.05)
yes	10(16.95)	9(8.65)	5(4.95)
FISH: HER2				0.5538
negative	48(81.36)	84(80.77)	87(86.14)
positive	11(18.64)	20(19.23)	14(13.86)
NACT				0.3125
deny	50(84.75)	95(91.35)	86(85.15)
yes	9(15.25)	9(8.65)	15(14.85)

We observed a significant impact of PM length on patient outcomes. As the PM length increased, we noted clear differences in patient progression-free survival (PFS) (P < 0.05). Patients with a PM length greater than 1.2 cm have a lower risk of disease progression than those with a PM length less than or equal to 0.4 cm (HR =0.41, 95% CI 0.20-0.84, P=0.015), the effect on OS was not seen (PM≥1.2cm vs PM≤0.4cm: HR =0.83, 95% CI 0.32-2.16, P=0.709, Figure2 and Table 3). According to the restrictive cubic spline (RCS), the risk of PFS events gradually decreased with the increase of margin distance. With 0.4cm as a control, the L curve is presented. As can be seen from the figure, the risk of basic PFS events does not change significantly after the margin distance exceeds 1.2cm (Figure2 B1). For OS, the confidence interval (gray interval of the curve) is wide, although the estimate shows a U-shaped trend, but not statistically significant (Figure2 B2).

Figure 2 A1 shows that PFS occurred significantly sooner in patients measuring ≤0.4 cm than in those measuring ≥1.2 cm. A2 shows that no significant differences in OS events were observed between the three groups. B1 and B2 are nonlinear fit maps of the upper edge distance of PFS and OS, respectively, the horizontal axis, the vertical axis is the corrected HR value, the horizontal dashed line is the reference line of HR=1, and the two dashed lines in the longitudinal direction are 0.4cm and 1.2cm, respectively, with the distance equal to 0.4cm as the reference.

Table 3 Survival analysis of the distance from the tumor to the lower cut end

	Univariate analysis		Model I		Model II
	HR (95％ CI)	P	HR (95％ CI)	P	HR (95％ CI)	P
PFS
≤0.4cm	Ref	-	Ref	-	Ref	-
0.5-1.1cm	0.64(0.37-1.09)	0.098	0.65(0.38-1.11)	0.112	0.66(0.33-1.30)	0.226
≥1.2cm	0.47(0.26-0.83)	0.010	0.47(0.26-0.83)	0.010	0.41(0.20-0.84)	0.015
OS
≤0.4cm	Ref	-	Ref	-	Ref	-
0.5-1.1cm	0.65(0.32-1.30)	0.223	0.66(0.33-1.33)	0.247	0.82(0.31-2.12)	0.675
≥1.2cm	0.72(0.36-1.44)	0.347	0.71(0.36-1.43)	0.339	0.83(0.32-2.16)	0.709

Model I: The multi variable Cox proportional hazard regression model adjusted for age and sex.

Model II: The multi variable Cox proportional hazard regression model adjusted for all of the covariates listed in table 1.

Prognostic effect of PM in the different subgroups

In a subgroup analysis of PFS endpoints, we found the four subgroups showed statistical significance that T4 or N3 group, tumor size <4cm, Siewert Ⅱ, and Lauren classification (Figure3). In the T4 or N3 group, when the PM length was 0.5cm or greater, there was a trend of improved prognosis (P <0.05), while in the T2-3N0-2 group, increasing PM length did not show a trend of improved prognosis. When the tumor size was ＜4cm, PM≥1.2cm significantly improved prognosis(P <0.05), while the effect of PM on prognosis ≥4cm of tumor size was not significant. In Siewert Ⅱ, we found that PM≥1.2cm showed an effect on improved prognosis(P <0.05), whereas in Siewert Ⅲ, the relationship between PM and prognosis was not significantly related. Meanwhile, PM≥1.2cm also had a positive effect on prognosis improvement in AEJ. Although there was no statistical difference (Figure4) in diffuse / mixed type, a trend of decreased disease risk with PM can be seen in Figure 3 and Figure4.

Figure 3 The RCS plot of the Figure 3-subgroup analysis

Figure 4 The degree of PM effect on prognosis in different subgroups

Table 4 Changes in R0 resection rates after neoadjuvant therapy
Study	N （AEG）	R0 resection rates
Study	N （AEG）	Surgery alone	NACT	NACRT	P value
FNCLCC^[79]	168	73%	84%		0.04
MRC trial^[80]	206	76.4%	75%		/
European Organisation^[81]	144	66.7%	81.9%		0.036
Bosset study^[82]	297			81%	/
Lee study^{[82, 83]}	101	95%		100%	/
Cross trial^[32]	275	69%		92%	＜0.001
Burmeister's study^[84]	75		80.5%	84.6%	0.61
Nusrath's study^[85]	70		86%	88%	1
Germany trial^[86]	126		69.5%	71.5%	/

The discussion surrounding resection margins in adenocarcinoma of the gastroesophageal junction has long been a challenging and crucial issue for gastrointestinal surgeons. In this prospective real-world study, we aimed to analyze the PM in patients who underwent surgery for gastroesophageal junction adenocarcinoma between 2019 and 2021. Our findings suggest that obtaining a smaller PM value may be more likely in patients with later clinical stages. This observation is not limited to T and N stages but also includes factors such as tumor size, presence of cancer nodules, and nerve invasion. The same conclusion also appeared in different histological types, the diffuse/mixed histological type was more likely to have shorter PM lengths. Advanced and diffuse/mixed tumors are less likely to achieve a longer PM,possibly related to the extent of esophageal invasion and the limitations of the transabdominal approach. Interestingly, we also observed greater errors in gross measured distance and microscopic measured distance in 24 cases of signet ring cell carcinoma, which may be attributed to the characteristics of signet ring cell carcinoma, as it tends to exhibit delayed submucosal invasion growth^{[20, 21]}. Therefore, further studies with a larger sample size are needed to explore this relationship in more detail. Interestingly, we did not observe an increase in PM length with neoadjuvant therapy, which is consistent with the findings reported by Bissolati et al^[5].

Regarding the prognostic impact of PM, it is important to acknowledge that our study had a relatively short follow-up period with a median duration of 24 months. However, even after excluding other influencing factors, we still observed a significant effect of PM on PFS. Particularly, when the PM length reached 1.2cm, the incidence of PFS was significantly lower compared to cases with a PM length of 0.4cm. These findings align with previous studies on the subject^{[6–8, 22–25]}. It is worth noting that the measurement of PM was performed after formalin fixation, and it is known that the fresh in situ esophagus tends to contract by approximately 27% during this process. Next, we measured the PM distance in the body specimen, accounting for the 27% contraction after formalin fixation. We defined the PM in this stage as PM1, calculated as PM1 = PM × (1–27%). Notably, our findings revealed that when the intraoperative PM1 distance was equal to or greater than 1.65cm, it had a significant positive impact on the prognosis of patients, leading to improved outcomes. In comparison to the study conducted by Mine in 2013^[26], which recommended a PM of 2cm or PM1 ≥ 2.8cm in transabdominal surgery, our findings indicate a shorter PM1 distance requirement. The difference in recommended distances may be attributed to variations in enrolled cases or to improved postoperative outcomes as chemotherapy program and medication progress.

According to our current findings, the total distance required for PM appears to vary depending on the stage of the tumor. However, when analyzing subgroups in this study, we did not observe similar results as in previous studies. Our study included 38 patients with T1 tumors and 176 patients with T2-3N0-2M0 tumors, but we only observed 43 events during the follow-up period, and no significant relationship was found between PM and the outcome. To further investigate this matter, we plan to continue expanding the sample size and collecting additional follow-up data in order to obtain more conclusive results. However, our findings in the later staged T4 or N3 group (71 cases) contradict the belief proposed by Barbour et al. that the prognosis of advanced AEJ, such as N3, is primarily influenced by the stage of the disease, potentially masking the effect of PM^[27]. In our study, even with a shorter follow-up time, we observed a trend indicating that increasing PM length was associated with a significantly improved prognosis in this subgroup. These contrasting results highlight the need for further investigation and analysis to gain a better understanding of the relationship between PM and prognosis in advanced AEJ cases. In previous related studies^{[5, 13–15, 26]}that provided limited analysis on the prognostic effect of PM on late-staged AEJ, and no guidance was given. This study proposed for the first time that PM also has a significant impact on the prognosis of late staged AEJ.

In previous studies, it has been observed that patients with AEJ and larger tumor sizes are more likely to have positive margins, and larger tumors are generally associated with poorer prognosis^{[28, 29]}. In our study, we also found that tumor size was a significant factor influencing PM. Specifically, when the tumor size was less than 4cm, a PM of 1.2cm showed a significant improvement in prognosis. However, for tumors measuring 4cm or larger, the effect of PM on prognosis was not as pronounced. This discrepancy might be attributed to the prognostic impact of tumor size itself, which may overshadow the influence of PM on prognosis, or a longer PM may be required to counter the masking of this effect on prognosis.

At the same time, our study found that the most controversial SiewertⅡ, a PM length ≥ 1.2cm showed an improvement in prognosis, whereas no significant effect of PM on prognosis was observed in the SiewertⅢ. This finding contrasts with the results of Feng's study^[28], where they reported that esophageal invasion in SiewertⅡmeasuring 3cm or less and the length of the proximal margin did not impact patient outcomes following transabdominal gastrectomy. One possible explanation for this discrepancy is that SiewertⅡ tumors are more prone to invade above the dentate line, and whether invasion beyond the dentate line plays a crucial role in the prognostic impact of PM. However, further studies are needed to confirm this hypothesis.

Furthermore, our study revealed that PM had a more significant prognostic effect in different histological types, particularly in the intestinal type, where a PM length of above 1.2cm showed a stronger impact. In contrast, the diffuse/mixed type did not demonstrate a significant association between PM and prognosis. This discrepancy could be attributed to the fact that the resection margin achieved through abdominal surgery may not have reached an adequate length to exert a prognostic influence in these cases.

So far, the previous studies are still mainly retrospective studies based on the low level of evidence^[30]. Although this study has certain strengths, including a prospective design, a high number of included cases, and a comprehensive cohort, there are several limitations that need to be acknowledged. Firstly, the follow-up period was relatively short, resulting in a low incidence of events, particularly for early and progressive overall survival (OS) outcomes. Secondly, in order to obtain more comprehensive subgroup results, it is necessary to expand the sample size and increase the number of follow-up events, which will be pursued in future studies. Thirdly, as this was a real-world study, the PM length was not deliberately standardized or controlled. Therefore, the restriction on PM length due to transabdominal surgery might have affected the ability to evaluate the prognostic impact of longer PM lengths. Lastly, when comparing our results with previous studies, the improvement in prognosis achieved by increasing PM length has varied from 3cm in Barbour's study to 2cm in Mine's study, and finally to 1.2cm in our study. This discrepancy may be attributed to the optimization of therapeutic drugs and regimens, such as chemotherapy and targeted therapy, which may have diminished the prognostic effect of PM. These limitations should be considered in future research to further refine surgical strategies.

We have provided evidence that resection margins ≥ 1.2cm in the external proximal esophagus (1.65cm in situ) are associated with improved outcomes for Siewert II and type III adenocarcinoma of the gastroesophageal junction (AEJ). This effect is particularly pronounced in cases of T4 or N3 stage, tumor size less than 4cm, Siewert II classification, and Lauren intestinal type. However, it is important to note that the choice of surgical approach for Siewert II and III tumors should be individualized. Further subgroup analyses are needed, which will require expanding the sample size and increasing the follow-up duration to achieve these goals and provide more robust findings.

Compliance with Ethical Standards:

Funding: This study was funded by First Affiliated Hospital of Naval Military Medical University(grant number：2020YXK052)

Conflict of Interest: Author TaoPang declares that he has no conflict of interest. Author Yinyi Qin declares that he has no conflict of interest. Author KaiYin declares that he has no conflict of interest. Other authors declare that they has no conflict of interest.

Consent for publication:Not applicable

Ethical Statement:This study was conducted in accordance with the ethical principles outlined in the Declaration of Helsinki. The research protocol was reviewed and approved by the ethics committee of ChangHai Hospital prior to data collection. Informed consent was obtained from all participants included in the study. Confidentiality and data protection measures were strictly adhered to during the study to ensure the privacy and anonymity of the participants. The study was carried out with the utmost consideration for the welfare and rights of the participants involved.

Informed consent: Informed consent was obtained from all individual participants included in the study.

Availability of Data and Materials：All data were obtained from the Department of Gastrointestinal Surgery, First Hospital, Military Medical University, and are available for sharing upon publication. Authors are contacted at [email protected] for original data.

Author Contributions Statement

The research presented in this work reflects a collaborative effort where each author contributed their unique expertise and skills to different aspects of the project. The following author contributions statement outlines the specific roles and contributions of each author:

Tao Pang: [Provide a description of the contributions of the first author. This include conceptualization, methodology, data collection, analysis, interpretation, and writing.]

Mingming Nie: [Detail the contributions of the second author. This could involve tasks such as literature review, data analysis, experimental design, and manuscript editing.]

Lei Fan: [Explain the role of the third author, including areas like software development, data curation,and figure preparation.]

Jiayang Wang: [Specify the contributions of the fourth author. This could involve contributions to experimental execution, data validation, visualization creation, and critical review.]

Zhaorui Liu: [Elaborate on the contributions of the fifth author. This could involve contributions to theoretical frameworks, follow-up Patients, and manuscript revisions.]

Yinyi Qin: [Discuss the role of the sixth author. This may encompass aspects such as project supervision, statistical analysis, and final approval of the manuscript.]

Kai Yin：[Discuss the role of the seventh author. This may encompass aspects such as project supervision,experimental design, and final approval of the manuscript.]

Each author has reviewed and approved the final version of the manuscript and agrees to be accountable for the accuracy and integrity of the work presented. The order of authorship is reflective of the degree of contribution, with the first author making a substantial contribution to the initial conception and execution of the project, and subsequent authors building upon that foundation with their unique contributions.

Conflict of interest declarations: No

Funding: No

Correspondence: [email protected]

Ethical Considerations: The study has been registered by the Chinese Clinical Laboratory Center with registration number (ChiCTR2100050226) and approved by the Ethics Committee of Changhai Hospital with ethics approval number (CHEC2021-100).

In summary, this "Author Contributions Statement" underscores the valuable and distinct roles played by each author in the realization of this research project, ultimately contributing to the overall quality and depth of the presented work.

Ahn HS, Lee HJ, Yoo MW, et al. Changes in clinicopathological features and survival after gastrectomy for gastric cancer over a 20-year period. Br J Surg. 2011;98(2):255–60.
Kauppila JH, Lagergren J. The surgical management of esophago-gastric junctional cancer. Surg Oncol. 2016;25(4):394–400.
Bozzetti F, Bonfanti G, Bufalino R, et al. Adequacy of margins of resection in gastrectomy for cancer. Ann Surg. 1982;196(6):685–90.
Esposito I, Kleeff J, Bergmann F, et al. Most pancreatic cancer resections are R1 resections. Ann Surg Oncol. 2008;15(6):1651–60.
Bissolati M, Desio M, Rosa F, et al. Risk factor analysis for involvement of resection margins in gastric and esophagogastric junction cancer: an Italian multicenter study. Gastric Cancer. 2017;20(1):70–82.
Sun Z, Li DM, Wang ZN, et al. Prognostic significance of microscopic positive margins for gastric cancer patients with potentially curative resection. Ann Surg Oncol. 2009;16(11):3028–37.
Nagata T, Ichikawa D, Komatsu S, et al. Prognostic impact of microscopic positive margin in gastric cancer patients. J Surg Oncol. 2011;104(6):592–7.
Wang SY, Yeh CN, Lee HL, et al. Clinical impact of positive surgical margin status on gastric cancer patients undergoing gastrectomy. Ann Surg Oncol. 2009;16(10):2738–43.
Woo JW, Ryu KW, Park JY, et al. Prognostic impact of microscopic tumor involved resection margin in advanced gastric cancer patients after gastric resection. World J Surg. 2014;38(2):439–46.
Barbour AP, Rizk NP, Gonen M, et al. Adenocarcinoma of the gastroesophageal junction: influence of esophageal resection margin and operative approach on outcome. Ann Surg. 2007;246(1):1–8.
Ronellenfitsch U, Schwarzbach M, Hofheinz R, et al. Predictors of overall and recurrence-free survival after neoadjuvant chemotherapy for gastroesophageal adenocarcinoma: Pooled analysis of individual patient data (IPD) from randomized controlled trials (RCTs). Eur J Surg Oncol. 2017;43(8):1550–8.
Mariette C, Castel B, Balon JM, Van Seuningen I, Triboulet JP. Extent of oesophageal resection for adenocarcinoma of the oesophagogastric junction. Eur J Surg Oncol. 2003;29(7):588–93.
Papachristou DN, Agnanti N, D'Agostino H, Fortner JG. Histologically positive esophageal margin in the surgical treatment of gastric cancer. Am J Surg. 1980;139(5):711–3.
Tsujitani S, Okuyama T, Orita H, et al. Margins of resection of the esophagus for gastric cancer with esophageal invasion. Hepatogastroenterology. 1995;42(6):873–7.
Ito H, Clancy TE, Osteen RT, et al. Adenocarcinoma of the gastric cardia: what is the optimal surgical approach. J Am Coll Surg. 2004;199(6):880–6.
Japanese gastric cancer treatment guidelines 2018 (5th edition). Gastric Cancer. 2021. 24(1): 1–21.
Moehler M, Al-Batran SE, Andus T, et al. [German S3-guideline Diagnosis and treatment of esophagogastric cancer]. Z Gastroenterol. 2011;49(4):461–531.
Japanese classification of gastric carcinoma. 3rd English edition. Gastric Cancer. 2011;14(2):101–12.
Japanese gastric cancer treatment. guidelines 2010 (ver. 3). Gastric Cancer. 2011;14(2):113–23.
Enlow JM, Denlinger CE, Stroud MR, Ralston JS, Reed CE. Adenocarcinoma of the esophagus with signet ring cell features portends a poor prognosis. Ann Thorac Surg. 2013;96(6):1927–32.
van Hootegem S, Smithers BM, Gotley DC, et al. The Impact of Signet Ring Cell Differentiation on Outcome in Patients with Esophageal and Gastroesophageal Junction Adenocarcinoma. Ann Surg Oncol. 2019;26(8):2375–84.
DiMusto PD, Orringer MB. Transhiatal esophagectomy for distal and cardia cancers: implications of a positive gastric margin. Ann Thorac Surg. 2007. 83(6): 1993-8; discussion 1998-9.
Javidfar J, Speicher PJ, Hartwig MG, D'Amico TA, Berry MF. Impact of Positive Margins on Survival in Patients Undergoing Esophagogastrectomy for Esophageal Cancer. Ann Thorac Surg. 2016;101(3):1060–7.
Bickenbach KA, Gonen M, Strong V, Brennan MF, Coit DG. Association of positive transection margins with gastric cancer survival and local recurrence. Ann Surg Oncol. 2013;20(8):2663–8.
Cho BC, Jeung HC, Choi HJ, et al. Prognostic impact of resection margin involvement after extended (D2/D3) gastrectomy for advanced gastric cancer: a 15-year experience at a single institute. J Surg Oncol. 2007;95(6):461–8.
Mine S, Sano T, Hiki N, et al. Proximal margin length with transhiatal gastrectomy for Siewert type II and III adenocarcinomas of the oesophagogastric junction. Br J Surg. 2013;100(8):1050–4.
Siu KF, Cheung HC, Wong J. Shrinkage of the esophagus after resection for carcinoma. Ann Surg. 1986;203(2):173–6.
Feng F, Tian Y, Xu G, et al. The length of proximal margin does not influence the prognosis of Siewert type II/III adenocarcinoma of esophagogastric junction after transhiatal curative gastrectomy. Springerplus. 2016;5:588.
Squires MH 3rd, Kooby DA, Pawlik TM, et al. Utility of the proximal margin frozen section for resection of gastric adenocarcinoma: a 7-Institution Study of the US Gastric Cancer Collaborative. Ann Surg Oncol. 2014;21(13):4202–10.
Niclauss N, Jung MK, Chevallay M, Mönig SP. Minimal length of proximal resection margin in adenocarcinoma of the esophagogastric junction: a systematic review of the literature. Updates Surg. 2019;71(3):401–9.

No competing interests reported.

FigureS1.tif

Download PDF

Journal Publication

published 01 Apr, 2024

Read the published version in Asian Journal of Surgery →

Version 1

posted

You are reading this latest preprint version

The impact of the length of proximal margin on the prognosis of adenocarcinoma of gastroesophageal junction and strategies : A real-world study

Status:

Journal Publication

Version 1

Abstract

Figures

Introduction

Patients and methods

Patient selection

Surgical procedures

Measurement of gross and pathological PM lengths

Statistical analysis

Result

Discussion

Conclusion

Declarations

References

Additional Declarations

Supplementary Files

Status:

Journal Publication

Version 1