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. 2024 Jul 26;19(7):e0307876. doi: 10.1371/journal.pone.0307876

Prognostic impact of the distance from the anterior surface to tumor cells in pancreatoduodenectomy with neoadjuvant chemoradiotherapy for pancreatic ductal adenocarcinoma

Miki Usui 1, Katsunori Uchida 1,2,*, Aoi Hayasaki 3, Masashi Kishiwada 3, Shugo Mizuno 3, Masatoshi Watanabe 1
Editor: Paolo Aurello4
PMCID: PMC11280245  PMID: 39058712

Abstract

Purpose

Several reports have shown the importance of margins in pancreatoduodenectomy (PD) specimens; however, whether anterior surfaces are included as margins varies among reports. In this study, we aimed to examine the impact of the anterior surface on disease-free survival (DFS) and overall survival (OS).

Method

In total, 98 patients who underwent PD after chemoradiotherapy for pancreatic ductal adenocarcinoma at Mie University Hospital between January 1, 2012, and December 31, 2019, were included. We investigated the prognostic impact of the distance from the anterior surface to tumor cells on DFS and OS using a log-rank test. Multivariate analysis was performed using Cox proportional hazards analysis.

Results

A significant difference in DFS and OS was observed up to a distance of 5 mm from the anterior surface of tumor cells. The multivariate analysis revealed that the distance from the anterior surface to tumor cells (≤5 mm) was an independent poor prognostic factor for DFS and OS.

Conclusion

In patients with PD treated with neoadjuvant therapy, the distance from the anterior surface to tumor cells is an important assessment and should be included in the pathology report.

Introduction

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease, and the 5-year survival rate for all stages combined is 12%, according to the American Cancer Society [1]. Currently, the usefulness of neoadjuvant therapy has been reported not only for borderline disease but also for resectable disease [2]. The National Comprehensive Cancer Network (NCCN) guidelines indicate that neoadjuvant therapy is the first-line treatment for resectable or borderline resectable pancreatic cancer. Consequently, an increasing number of cases of chemoradiotherapy followed by surgical treatment is predicted in the future.

Several reports have examined prognostic factors in PD specimens, and the distance between the tumor cells and the margin is an independent prognostic factor [3–16]. Among these reports, some included the anterior surface as a margin, whereas others did not, suggesting that it is debatable whether the anterior surface should be considered a margin. The College of American Pathologists (CAP) protocol specifies that the presence of tumor cells within 1 mm of the resection margin is considered a positive margin; however, this rule does not apply to the anterior and posterior surfaces because they are not resection margins. It also states that reporting tumor invasion on the anterior and non-uncinate posterior surfaces is recommended but not required [17]. One report showed that invasion of the anterior surface was a poor prognostic factor [3]. In contrast, another study reported that tumor cells less than 1 mm away from the anterior surface had no prognostic impact [4]. However, these reports were based on patients who did not receive neoadjuvant therapy, and the prognostic relationship between the margin and prognosis in patients receiving neoadjuvant therapy is unclear.

We investigated the prognostic impact of the anterior surface in PD specimens treated with neoadjuvant therapy.

Materials and methods

Patients

This study was approved by the Clinical Research Ethics Review Committee of Mie University Hospital, waiving the need for informed consent due to the unfeasibility of obtaining individual consent from many dead patients and the retrospective nature of the study (reference number: H2018-073). The patients were given the opportunity to opt out of the study at any time, with details available on the Mie University School of Medicine website, ensuring adherence to the ethical standards outlined in the Declaration of Helsinki. Patient clinical and pathological data were extracted from the hospital’s electronic medical records, anonymized, and stored in a database, maintaining strict confidentiality and being used solely for research purposes. The data cutoff was June 23, 2023. We extracted the clinical and pathological data of 134 patients who underwent pancreatectomy following chemoradiotherapy with gemcitabine and S-1 for pancreatic ductal adenocarcinoma at Mie University Hospital from January 1, 2012, to December 31, 2019 (Fig 1). Among these patients, one underwent total pancreatectomy, and 24 underwent distal pancreatectomy. We excluded five cases with no residual tumor, four cases where the tumor margin distance was indeterminable, and two cases of R2 resection.

Fig 1. Flow diagram of patient inclusion in the study.

Fig 1

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Pathological examination

The portal vein (PV)/superior mesenteric vein (SMV) margin, superior mesenteric artery (SMA) margin, and posterior surface of the PD specimens were inked according to the color code assigned by the surgeon. The anterior area without inking was designated as the anterior surface area. The specimens were fixed overnight in a 10% neutral-buffered formalin solution. Pathologists sliced the PD specimen into 5-mm-thick slices in the axial plane, sampled all pancreatic tissues, and evaluated the pathological findings [18–20].

To validate the margins, the anterior surface and other margins (PV/SMV margin, SMA margin, and posterior surface) were validated as different factors. The distance from the anterior surface to the tumor cells and its impact on prognosis were examined at 0 mm, 0–X mm, and > X mm (X = 1, 2, 3, 4, 5, and 6). R1 was defined as the presence of tumor cells at a distance of 1 mm from any other margin except the anterior surface. Additionally, pancreatic transection, bile duct, and proximal/distal enteric margins were evaluated as independent factors.

Statistical analysis

The Kaplan–Meier method was used to analyze disease-free survival (DFS) and overall survival (OS), with the surgery date as the starting point. The log-rank test was used to compare survival time distributions between the groups. A multivariate analysis was performed using the Cox proportional hazards model to identify significant prognostic factors. Statistical significance was set at p < 0.05. All statistical analyses were performed using EZR (Saitama Medical Center, Jichi Medical University, Saitama, Japan), a graphical user interface for R (The R Foundation for Statistical Computing, Vienna, Austria) [21].

Results

Patient characteristics

Of the 98 patients, 57 were male and 41 were female. The mean age at diagnosis was 66.6 years and ranged from 41 to 86 years. Sixty-one (62.2%) patients died of pancreatic cancer, 18 (18.4%) died of other causes, and 19 (19.4%) survived. Seventy (71.4%) patients experienced recurrence. The median time to recurrence was 13.5 months, and the median survival time was 25.5 months. Eighty-seven (88.7%) patients underwent resection of the PV or SMV. The relationship between each clinicopathological factor and DFS/OS is presented in Table 1. In one patient, preoperative serum CA19-9 levels were not measured, and in two patients, histological evaluation of extra-pancreatic nerve plexus invasion was impossible.

Table 1. Pathological and clinical findings and outcomes.

variable Number of patients (%) Median DFS (months) Log-rank p-value (DFS) Median OS (months) Log-rank p-value (OS)
Overall 98 13.50 25.49
Age, years
 <65 35 (35.7%) 16.43 0.156 32.56 0.104
 ≧65 63 (64.3%) 12.16 22.90
Gender
 Male 57 (58.2%) 15.44 0.961 22.90 0.666
 Female 41 (41.8%) 12.32 26.28
Performance status
 0 68 (69.4%) 14.85 0.371 26.87 0.041
 1 23 (23.5%) 12.68 22.87
 2 6 (6.1%) 8.16 14.34
 3 1 (1.0%) 8.25 9.86
Preoperative CA19-9
 ≦37 66 (68.0%) 21.91 0.048 29.47 0.278
 >37 31 (32.0%) 15.87 32.53
Resectability after neoadjuvant therapy
 R 31 (31.6%) 29.80 0.057 43.04 0.034
 BR-PV 19 (19.4%) 10.05 20.99
 BR-A 18 (18.4%) 11.14 24.87
 UR-LA 30 (30.6%) 11.24 19.55
Adjuvant therapy
 No adjuvant 17 (17.3%) 7.72 0.092 7.79 0.017
 Adjuvant 81 (82.7%) 14.26 29.50
Tumor size
 ≦20 35 (35.7%) 27.66 0.007 36.44 0.055
 >20 63 (64.3%) 11.14 22.74
Tumor grade
 Well 31 (31.6%) 20.99 0.467 26.87 0.689
 Moderate 25 (25.5%) 9.86 21.39
 Poor 42 (42.9%) 13.04 29.50
Perineural invasion
 Negative 38 (38.9%) 29.21 0.003 38.41 0.013
 Positive 60 (61.2%) 11.99 22.74
Lymphovascular invasion
 Negative 76 (77.6%) 16.49 0.035 26.87 0.234
 Positive 22 (22.4%) 8.79 16.99
Extra-pancreatic nerve plexus invasion
 Negative 63 (64.3%) 16.56 0.021 35.32 0.011
 Positive 33 (35.7%) 11.83 22.77
Grading of histological response a
 1 28 (28.6%) 15.21 0.037 35.91 0.032
 2 65 (66.3%) 11.83 21.78
 3 5 (5.1%) 29.80 34.60
pT-stage b
 1 39 (39.8%) 27.86 0.0011 41.43 0.054
 2 51 (52.0%) 10.05 22.21
 3 7 (7.1%) 4.57 12.71
 4 1 (1.0%) 19.81 32.30
pN-stage b
 0 67 (68.4%) 15.44 0.603 26.87 0.717
 1 21 (21.4%) 12.94 25.82
 2 10 (10.2%) 4.22 12.63
Margin status
 R0 (>1 mm) 64 (65.3%) 15.93 0.105 26.58 0.371
 R1 (≦1 mm) 34 (34.7%) 12.07 22.90
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Abbreviation: DFS: disease-free survival; DSS: disease-specific survival; OS: overall survival; R: resectable;

BR-PV: borderline resectable-portal vein; BR-A: borderline resectable-artery; UR-LA: unresectable-locally advanced.

a College of American Pathologists system.

b Union for International Cancer Control (UICC) TNM Classification of Malignant Tumors (ed 8), 2018.

Impact of the distance from the margin to the tumor cells

Log-rank tests showed a statistically significant difference between groups with a distance from the anterior surface to the tumor cells of X mm or less and greater than X mm for X = 1, 2, 3, 4, and 5. However, there was a significant difference in DFS (p = 0.027) but not in OS (p = 0.059) at X = 6 (Figs 2 and 3); when X ≤ 5 mm, significant differences in DFS and OS were shown between the groups. In contrast, margins other than the anterior surface (R1) were not prognostic for DFS or OS (p > 0.05) (Table 1). No tumor cells were within 1 mm of the pancreatic transection, bile duct, or proximal/distal enteric margins. Multivariate analysis also showed that tumor cells within X mm of the anterior surface were an independent poor prognostic factor for DFS and OS at X = 1, 2, 3, 4, and 5 (Table 2).

Fig 2. Kaplan–Meier curves for 98 patients stratified into two groups by the distance from the anterior surface to tumor cells for DFS.

Fig 2

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(A) 0 mm, (B) 1 mm, (c) 2 mm, (D) 3 mm, (E) 4 mm, (F) 5mm, (G) 6 mm.

Fig 3. Kaplan–Meier curves for 98 patients stratified into two groups by the distance from the anterior surface to tumor cells for OS.

Fig 3

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(A) 0 mm, (B) 1 mm, (c) 2 mm, (D) 3 mm, (E) 4 mm, (F) 5mm, (G) 6 mm.

Table 2. Multivariate analysis.

Variable DFS OS
HR 95% CI p-value HR 95% CI p-value
0 mm
Resectability after neoadjuvant therapy, BR-PV+BR-A+UR-LA 1.535 0.904–2.608 0.113 1.576 0.922–2.693 0.097
Tumor size >20 mm 1.305 0.747–2.280 0.349 1.116 0.628–1.983 0.709
Perineural invasion, positive 1.496 0.816–2.745 0.193 1.389 0.756–2.554 0.290
Lymphovascular invasion, positive 1.551 0.899–2.676 0.115 1.366 0.794–2.351 0.260
Extra-pancreatic nerve plexus invasion, positive 1.004 0.579–1.741 0.989 1.163 0.665–2.033 0.598
Grading of histological response, Score 3 1.626 0.917–2.885 0.096 1.848 1.039–3.286 0.037
Distance from the anterior surface to the tumor cells: 0 mm 8.761 1.884–40.740 0.006 31.70 5.886–170.800 p<0.001
1.0 mm
Resectability after neoadjuvant therapy, BR-PV+BR-A+UR-LA 1.419 0.825–2.439 0.206 1.481 0.856–2.561 0.160
Tumor size >20 mm 1.331 0.766–2.315 0.311 1.179 0.666–2.088 0.572
Perineural invasion, positive 1.495 0.810–2.758 0.199 1.342 0.728–2.472 0.346
Lymphovascular invasion, positive 1.720 0.985–3.002 0.056 1.289 0.750–2.216 0.358
Extra-pancreatic nerve plexus invasion, positive 0.844 0.475–1.502 0.565 0.941 0.520–1.702 0.841
Grading of histological response, Score 3 1.496 0.847–2.643 0.165 1.765 1.002–3.110 0.049
Distance from the anterior surface to the tumor cells: ≤1 mm 2.765 1.422–5.379 0.003 2.966 1.512–5.820 0.002
2.0 mm
Resectability after neoadjuvant therapy, BR-PV+BR-A+UR-LA 1.480 0.870–2.516 0.148 1.492 0.870–2.559 0.147
Tumor size, >20 mm 1.213 0.689–2.134 0.503 1.056 0.591–1.889 0.854
Perineural invasion, positive 1.516 0.823–2.791 0.182 1.438 0.783–2.639 0.241
Lymphovascular invasion, positive 1.758 1.015–3.047 0.044 1.410 0.822–2.421 0.212
Extra-pancreatic nerve plexus invasion, positive 0.751 0.415–1.359 0.344 0.828 0.448–1.530 0.547
Grading of histological response, Score 3 1.407 0.793–2.498 0.243 1.605 0.908–2.840 0.104
Distance from the anterior surface to the tumor cells: ≤2 mm 2.880 1.585–5.234 p<0.001 3.078 1.631–5.809 p<0.001
3.0 mm
Resectability after neoadjuvant therapy, BR-PV+BR-A+UR-LA 2.225 1.277–3.875 0.005 2.171 1.245–3.786 0.006
Tumor size, >20 mm 1.220 0.699–2.131 0.484 1.070 0.602–1.902 0.817
Perineural invasion, positive 1.236 0.670–2.283 0.498 1.132 0.617–2.079 0.689
Lymphovascular invasion, positive 1.654 0.963–2.839 0.068 1.367 0.799–2.338 0.253
Extra-pancreatic nerve plexus invasion, positive 0.794 0.446–1.412 0.432 0.948 0.533–1.686 0.855
Grading of histological response, Score 3 1.563 0.877–2.785 0.130 1.704 0.961–3.024 0.068
Distance from the anterior surface to the tumor cells: ≤3 mm 2.650 1.561–4.497 p<0.001 2.468 1.452–4.195 p<0.001
4.0 mm
Resectability after neoadjuvant therapy, BR-PV+BR-A+UR-LA 2.152 1.251–3.700 0.006 2.113 1.226–3.640 0.007
Tumor size, >20 mm 1.072 0.613–1.875 0.806 0.944 0.530–1.683 0.845
Perineural invasion, positive 1.579 0.871–2.861 0.132 1.349 0.750–2.428 0.318
Lymphovascular invasion, positive 1.845 1.063–3.202 0.029 1.493 0.867–2.572 0.148
Extra-pancreatic nerve plexus invasion, positive 0.804 0.459–1.406 0.443 0.981 0.561–1.713 0.945
Grading of histological response, Score 3 1.455 0.826–2.566 0.195 1.676 0.952–2.950 0.074
Distance from the anterior surface to the tumor cells, ≤4 mm 2.684 1.605–4.487 p<0.001 2.498 1.496–4.169 p<0.001
5.0 mm
Resectability after neoadjuvant therapy, BR-PV+BR-A+UR-LA 1.735 1.034–2.912 0.037 1.716 1.018–2.892 0.043
Tumor size, >20 mm 1.149 0.650–2.032 0.634 1.022 0.568–1.840 0.942
Perineural invasion, positive 1.448 0.795–2.637 0.226 1.291 0.710–2.348 0.403
Lymphovascular invasion, positive 1.806 1.031–3.163 0.039 1.493 0.860–2.593 0.155
Extra-pancreatic nerve plexus invasion, positive 0.991 0.577–1.701 0.973 1.167 0.675–2.021 0.580
Grading of histological response, Score 3 1.398 0.793–2.463 0.247 1.598 0.908–2.812 0.104
Distance from the anterior surface to the tumor cells ≤5 mm 1.964 1.211–3.187 0.006 1.789 1.105–2.895 0.018
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Abbreviation: HR: hazard ratio; CI: confidence intervals.

Discussion

Several studies have examined the relationship between the distance from the margin to tumor cells and the prognosis of PD specimens. However, there are limited data on the prognostic impact of the distance between the anterior surface and tumor cells and the validation of PD specimens treated with neoadjuvant therapy. We showed that tumor cells within 5 mm of the anterior surface were associated with a poorer OS prognosis than those in the >5 mm group. In contrast, tumor cells within 1 mm of the margin, excluding the anterior surface (R1), did not affect DFS or OS.

Several reports have examined the distance between the margin and tumor cells and the prognosis in PD specimens without neoadjuvant therapy [3–16]. Some of these reports have not validated the anterior surfaces, likely because they were not resection margins [5, 6]. In addition, some reports did not describe the margins subjected to validation in detail [7, 8]. In these reports, depending on the study, the range of distances from the margin to the tumor cells that affected DFS and OS was from 0 to 2 mm. This may be caused by the differences between studies in the targeted margins, the distance defined as “a positive margin,” whether or not inking was used, the extent of sampling, and so on. Few studies have examined individual margins. Regarding the distance between the anterior surface and tumor cells, one report showed that invasion of the anterior surface is a poor prognostic factor for 3-year survival [3], whereas another report showed that the presence of tumor cells within 1 mm of the anterior surface is associated with poor DFS [9]. However, some reports have shown that tumor cells within 0–2 mm of the anterior surface did not affect OS [4, 10]. All these reports were based on patients who did not receive neoadjuvant therapy. In our study, the distance from the anterior surface to the tumor cells for better DFS and OS was longer than that in previous reports. This discrepancy may be due to neither of these reports providing a detailed description of their tissue sampling methods and potentially sampling less tissue compared to our method, which sampled all pancreatic tissue. In pancreatectomy specimens post-preoperative adjuvant therapy, validated studies with extensively sampled specimens showed a pathological complete response rate of 2.5% [22], whereas validated studies with fewer sampled specimens tended to report higher rates [23, 24]. This suggests that a greater number of samples increases the detection rate of tumor cells, which may also impact the assessment of the distance from margins to the tumor cells. Few studies have investigated the relationship between the margins and prognosis of PD specimens after neoadjuvant therapy. Although one report indicated that the presence of tumor cells within 1 mm of the margin was associated with poor DFS and OS, no details were provided regarding which margins were validated [7]. Another report showed that the presence of a tumor within 1 mm of any of the margins was associated with poor DFS and OS, targeting the superior mesenteric/medial, pancreatic neck, bile duct, proximal gastric or duodenal, and distal jejunal margins, anterior surface, and posterior surface, but this was not verified for each margin [11]. A report analyzing the prognostic significance of tumor cell distance from margins in total and distal pancreatectomy following neoadjuvant therapy revealed that in total pancreatectomy, the proximity of tumor cells to the SMA margin impacts OS, whereas the distance from other margins does not influence survival. In contrast, for distal pancreatectomy, the proximity of tumor cells to both the anterior and posterior surfaces does not affect survival [25]. Extensive tissue sampling was conducted for pathological examinations in this study. Patients undergoing either total or distal pancreatectomy generally present with fewer symptoms of biliary stenosis and typically have more advanced tumors at diagnosis compared to those undergoing pancreatoduodenectomy; therefore, our findings are not directly comparable. Moreover, in PDAC, the closeness of tumor cells to the anterior surface is not the sole determinant of OS. Furthermore, distinguishing between non-neoplastic ductal cells and intraepithelial and invasive carcinoma in pancreatectomy specimens after preoperative adjuvant therapy can be challenging. Accurate pathological assessment is essential, as diagnostic discrepancies among pathologists may influence study outcomes [26].

Several reports have been published on the prognostic impact of tumor cell distance from the margins in PD specimens. However, no definite conclusion has been reached because of the varying verification methods used in individual reports. The prognostic impact of the distance from an individual margin to tumor cells depends on the margin to which the tumor cells are in proximity [3, 11, 13]; further studies using appropriate inking and sampling specimens are required.

Limitations

Our study has some limitations. First, this was a retrospective study and did not correct for patient characteristics. Second, this study was performed at a single center, and the influence of random errors caused by a relatively small number of cases could not be ruled out. Therefore, a multicenter study with a larger number of patients is required.

Conclusion

This study is the first to focus on the anterior surface as the distance from the tumor margin in PD specimens treated with neoadjuvant therapy. We showed that tumor cells within 5 mm of the anterior surface were a poor prognostic factor for recurrence and survival. Therefore, the pathological report should describe the distance from the anterior surface to the tumor cells.

Supporting information

S1 Table. Patient data used for this study.

(XLSX)

pone.0307876.s001.xlsx (21.5KB, xlsx)

Acknowledgments

The authors thank the members of the Departments of Oncological Pathology and Hepato-Biliary-Pancreatic and Transplant Surgery at Mie University for their valuable discussions and support.

Data Availability

All relevant data are within the manuscript and its Supporting information files.

Funding Statement

The author(s) received no specific funding for this work.

References

  • 1.American Cancer Society; 2023 [Cited January 14, 2024]. In: Cancer Statistics Center [Internet]. cancerstatisticscenter.cancer.org.
  • 2.Motoi F, Kosuge T, Ueno H, Yamaue H, Satoi S, Sho M, et al. Randomized phase II/III trial of neoadjuvant chemotherapy with gemcitabine and S-1 versus upfront surgery for resectable pancreatic cancer (Prep-02/JSAP05). Jpn J Clin Oncol. 2019;49: 190–194. doi: 10.1093/jjco/hyy190 [DOI] [PubMed] [Google Scholar]
  • 3.Nagakawa T, Sanada H, Inagaki M, Sugama J, Ueno K, Konishi I, et al. Long-term survivors after resection of carcinoma of the head of the pancreas: significance of histologically curative resection. J Hepatobiliary Pancreat Surg. 2004;11: 402–408. doi: 10.1007/s00534-004-0917-4 [DOI] [PubMed] [Google Scholar]
  • 4.Campbell F, Smith RA, Whelan P, Sutton R, Raraty M, Neoptolemos JP, et al. Classification of R1 resections for pancreatic cancer: the prognostic relevance of tumour involvement within 1 mm of a resection margin. Histopathology. 2009;55: 277–283. doi: 10.1111/j.1365-2559.2009.03376.x [DOI] [PubMed] [Google Scholar]
  • 5.Obonyo D, Uslar VN, Münding J, Weyhe D, Tannapfel A. The impact of resection margin distance on survival and recurrence in pancreatic ductal adenocarcinoma in a retrospective cohort analysis. PLoS One. 2023;18: e0281921. doi: 10.1371/journal.pone.0281921 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6.Chang DK, Johns AL, Merrett ND, Gill AJ, Colvin EK, Scarlett CJ, et al. Margin clearance and outcome in resected pancreatic cancer. J Clin Oncol. 2009;27: 2855–2862. doi: 10.1200/JCO.2008.20.5104 [DOI] [PubMed] [Google Scholar]
  • 7.Chopra A, Zenati M, Hogg ME, Zeh HJ III, Bartlett DL, Bahary N, et al. Impact of neoadjuvant therapy on survival following margin-positive resection for pancreatic cancer. Ann Surg Oncol. 2021;28: 7759–7769. doi: 10.1245/s10434-021-10175-y [DOI] [PubMed] [Google Scholar]
  • 8.Ocuin LM, Miller-Ocuin JL, Zenati MS, Vargo JA, Singhi AD, Burton SA, et al. A margin distance analysis of the impact of adjuvant chemoradiation on survival after pancreatoduodenectomy for pancreatic adenocarcinoma. J Gastrointest Oncol. 2017;8: 696–704. doi: 10.21037/jgo.2017.04.02 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9.Sohn HJ, Kim H, Kim SJ, Lee KB, Han Y, Lee JM, et al. Oncologic outcomes according to the location and status of resection margin in pancreas head cancer: role of radiation therapy in R1 resection. Ann Surg Treat Res. 2022;102: 10. doi: 10.4174/astr.2022.102.1.10 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10.Osipov A, Nissen N, Rutgers J, Dhall D, Naziri J, Chopra S, et al. Redefining the positive margin in pancreatic cancer: Impact on patterns of failure, long-term survival and adjuvant therapy. Ann Surg Oncol. 2017;24: 3674–3682. doi: 10.1245/s10434-017-6076-z [DOI] [PubMed] [Google Scholar]
  • 11.Takahashi C, Shridhar R, Huston J, Meredith K. Adjuvant therapy for margin positive pancreatic cancer: A propensity score matched analysis. Pancreatology. 2022;22: 396–400. doi: 10.1016/j.pan.2022.03.008 [DOI] [PubMed] [Google Scholar]
  • 12.Kaltenmeier C, Nassour I, Hoehn RS, Khan S, Althans A, Geller DA, et al. Impact of resection margin status in patients with pancreatic cancer: A national cohort study. J Gastrointest Surg. 2021;25: 2307–2316. doi: 10.1007/s11605-020-04870-6 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13.Jamieson NB, Chan NIJ, Foulis AK, Dickson EJ, McKay CJ, Carter CR. The prognostic influence of resection margin clearance following pancreaticoduodenectomy for pancreatic ductal adenocarcinoma. J Gastrointest Surg. 2013;17: 511–521. doi: 10.1007/s11605-012-2131-z [DOI] [PubMed] [Google Scholar]
  • 14.Janot MS, Kersting S, Belyaev O, Matuschek A, Chromik AM, Suelberg D, et al. Can the new RCP R0/R1 classification predict the clinical outcome in ductal adenocarcinoma of the pancreatic head? Langenbecks Arch Surg. 2012;397: 917–925. doi: 10.1007/s00423-012-0953-5 [DOI] [PubMed] [Google Scholar]
  • 15.Jamiyan T, Shiraki T, Kurata Y, Ichinose M, Kubota K, Imai Y. Clinical impacts of resection margin status and clinicopathologic parameters on pancreatic ductal adenocarcinoma. World J Surg Oncol. 2020;18. doi: 10.1186/s12957-020-01900-0 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16.Maeda S, Moore AM, Yohanathan L, Hata T, Truty MJ, Smoot RL, et al. Impact of resection margin status on survival in pancreatic cancer patients after neoadjuvant treatment and pancreatoduodenectomy. Surgery. 2020;167: 803–811. doi: 10.1016/j.surg.2019.12.008 [DOI] [PubMed] [Google Scholar]
  • 17.The College of American Pathologists. Cancer protocol templates. 2023 [Cited January 14, 2024]. In: Protocols and templates [Internet]. https://www.cap.org/protocols-and-guidelines/cancer-reporting-tools/cancer-protocol-templates.
  • 18.Verbeke CS. Resection margins and R1 rates in pancreatic cancer–are we there yet? Histopathology. 2008;52: 787–796. doi: 10.1111/j.1365-2559.2007.02935.x [DOI] [PubMed] [Google Scholar]
  • 19.Verbeke CS, Leitch D, Menon KV, McMahon MJ, Guillou PJ, Anthoney A. Redefining the R1 resection in pancreatic cancer. Br J Surg. 2006;93: 1232–1237. doi: 10.1002/bjs.5397 [DOI] [PubMed] [Google Scholar]
  • 20.Adsay NV, Basturk O, Saka B, Bagci P, Ozdemir D, Balci S, et al. Whipple made simple for surgical pathologists: Orientation, dissection, and sampling of pancreaticoduodenectomy specimens for a more practical and accurate evaluation of pancreatic, distal common bile duct, and ampullary tumors. Am J Surg Pathol. 2014;38: 480–493. doi: 10.1097/PAS.0000000000000165 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21.Kanda Y. Investigation of the freely available easy-to-use software ‘EZR’ for medical statistics. Bone Marrow Transplant. 2013;48: 452–458. doi: 10.1038/bmt.2012.244 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 22.Zhao Q, Rashid A, Gong Y, Katz MH, Lee JE, Wolf R, et al. Pathologic complete response to neoadjuvant therapy in patients with pancreatic ductal adenocarcinoma is associated with a better prognosis. Ann Diagn Pathol. 2012;16: 29–37. doi: 10.1016/j.anndiagpath.2011.08.005 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23.Strobel O, Berens V, Hinz U, Hartwig W, Hackert T, Bergmann F, et al. Resection after neoadjuvant therapy for locally advanced, “unresectable” pancreatic cancer. Surgery. 2012;152: S33–S42. doi: 10.1016/j.surg.2012.05.029 [DOI] [PubMed] [Google Scholar]
  • 24.Denost Q, Laurent C, Adam J- P, Capdepont M, Vendrely V, Collet D, et al. Pancreaticoduodenectomy following chemoradiotherapy for locally advanced adenocarcinoma of the pancreatic head. HPB (Oxford). 2013;15: 716–723. doi: 10.1111/hpb.12039 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 25.Aaquist T, Fristrup CW, Hasselby JP, Hamilton-Dutoit S, Eld M, Pfeiffer P, et al. Prognostic value of margin clearance in total and distal pancreatectomy specimens with pancreatic ductal adenocarcinoma in a Danish population-based nationwide study. Pathol Res Pract. 2024;254: 155077. doi: 10.1016/j.prp.2023.155077 [DOI] [PubMed] [Google Scholar]
  • 26.Janssen BV, van Roessel S, van Dieren S, de Boer O, Adsay V, Basturk O, et al. Histopathological tumour response scoring in resected pancreatic cancer following neoadjuvant therapy: international interobserver study (ISGPP-1). Br J Surg. 2022;110: 67–75. doi: 10.1093/bjs/znac350 [DOI] [PMC free article] [PubMed] [Google Scholar]

Decision Letter 0

Paolo Aurello

16 Jun 2024

PONE-D-24-08272Prognostic impact of the distance from the anterior surface to tumor cells in pancreatoduodenectomy with neoadjuvant chemoradiotherapy for pancreatic ductal adenocarcinomaPLOS ONE

Dear Dr. UCHIDA,

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Reviewer #1: Pancreatic ductal adenocarcinoma has a 5-year survival rate of 12% for all stages of disease, it is therefore important to assess the efficacy of neoadjuvant therapy for such tumors, very carefully. Whilst the distance between tumor cells and pancreatoduodenectomy (PD) resection margin is an accepted prognostic factor, the significance of distance from the anterior or posterior surface is currently debated. This study aims to assess the prognostic impact of the distance from the anterior surface in PD specimens that underwent neoadjuvant therapy, and to provide insights for future reporting guidelines to include the distance of tumor cells from the anterior surface.

The researchers gathered data from 134 individuals who had undergone pancreatectomy surgery following chemoradiotherapy at Mie University Hospital between 2012 and 2019. Of those, 98 eligible patients, were included in the analysis.

The authors performed multi variate analysis and and rank-sum tests that produced a significant p-value that may indicate an association with poor OS and DFS, when tumor cells are found within 5mm of the anterior surface, they also acknowledged the limitations of the study, being a retrospective study that was performed in a single center.

while the study informs the need for further investigation, however, it does not seem sufficient to inform standards for reporting guidelines.

The authors do not provide a clear explanation of the biological reasoning behind their conclusions, and the challenges of assessing post-NAT specimens, however, they do mention that "In our study, the distance from the anterior surface to the tumor cells for better DFS and OS was longer than that in previous reports. This could have been caused by neoadjuvant therapy; however, this could not be clarified" [1]

The authors should cite and consider recent publications on the prognostic value of margin clearance [2]

References

Verbeke, C., Löhr, M., Karlsson, J. S., & Del Chiaro, M. (2015). Pathology reporting of pancreatic cancer following neoadjuvant therapy: challenges and uncertainties. Cancer treatment reviews, 41(1), 17-26.

Aaquist, T., Fristrup, C. W., Hasselby, J. P., Hamilton-Dutoit, S., Eld, M., Pfeiffer, P., ... & Detlefsen, S. (2024). Prognostic value of margin clearance in total and distal pancreatectomy specimens with pancreatic ductal adenocarcinoma in a Danish population-based nationwide study. Pathology-Research and Practice, 254, 155077.

Reviewer #2: A patient data is missing is very important for the practice of general surgery. The manuscript is well written. The data used are secondary and the institutional ethical approval is appropriate. Exclusion criteria are well stated. There is a patient data missing in the CA-19-9 result. Please cross-check.

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Reviewer #1: No

Reviewer #2: Yes: PROF. LUKMAN OLAJIDE ABDUR-RAHMAN

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Attachment

Submitted filename: PONE-D-24-08272_reviewed copy.pdf

pone.0307876.s002.pdf (1.9MB, pdf)
PLoS One. 2024 Jul 26;19(7):e0307876. doi: 10.1371/journal.pone.0307876.r002

Author response to Decision Letter 0

12 Jul 2024

July 7th 2024

Paolo Aurello

Academic Editor

PLOS ONE

Response to Reviewer #1:

Thank you very much for reviewing our manuscript and offering valuable suggestions.

We have addressed your comments with point-by-point responses and revised the manuscript accordingly.

Comments 1 and 2: The authors do not provide a clear explanation of the biological reasoning behind their conclusions, and the challenges of assessing post-NAT specimens, however, they do mention that "In our study, the distance from the anterior surface to the tumor cells for better DFS and OS was longer than that in previous reports. This could have been caused by neoadjuvant therapy; however, this could not be clarified" [1]

The authors should cite and consider recent publications on the prognostic value of margin clearance [2]

Response: We appreciate the helpful suggestion. Following the reviewer's comment, we have compared our conclusions with those of recent reports on the prognostic value of margin clearance. Many of these reports did not clearly describe the procedure for sampling, and, likely, the search was not adequate. We have added the following to the Discussion (p.13, lines 144-151 and p13, lines 157-p14, lines 170):

Regarding the longer distance from the anterior surface to tumor cells required to improve DFS and OS than previously reported, we have highlighted the method of tissue sampling (p.13, lines 144-151) and discrepancies in diagnosis between pathologists (p13, lines 157-p14, lines 170).

“This discrepancy may be due to neither of these reports providing a detailed description of their tissue sampling methods and potentially sampling less tissue compared to our method, which sampled all pancreatic tissue. In pancreatectomy specimens post-preoperative adjuvant therapy, validated studies with extensively sampled specimens showed a pathological complete response rate of 2.5% [22], whereas validated studies with fewer sampled specimens tended to report higher rates [23–24]. This suggests that a greater number of samples increases the detection rate of tumor cells, which may also impact the assessment of the distance from margins to the tumor cells.”

“A report analyzing the prognostic significance of tumor cell distance from margins in total and distal pancreatectomy following neoadjuvant therapy revealed that in total pancreatectomy, the proximity of tumor cells to the SMA margin impacts OS, whereas the distance from other margins does not influence survival. In contrast, for distal pancreatectomy, the proximity of tumor cells to both the anterior and posterior surfaces does not affect survival [25]. Extensive tissue sampling was conducted for pathological examinations in this study. Patients undergoing either total or distal pancreatectomy generally present with fewer symptoms of biliary stenosis and typically have more advanced tumors at diagnosis compared to those undergoing pancreatoduodenectomy; therefore, our findings are not directly comparable. Moreover, in PDAC, the closeness of tumor cells to the anterior surface is not the sole determinant of OS. Furthermore, distinguishing between non-neoplastic ductal cells and intraepithelial and invasive carcinoma in pancreatectomy specimens after preoperative adjuvant therapy can be challenging. Accurate pathological assessment is essential, as diagnostic discrepancies among pathologists may influence study outcomes [26].”

Response to Reviewer #2:

Thank you very much for reviewing our manuscript and offering valuable suggestions.

We have addressed your comments with point-by-point responses and revised the manuscript accordingly.

Comment: A patient data is missing is very important for the practice of general surgery. The manuscript is well written. The data used are secondary and the institutional ethical approval is appropriate. Exclusion criteria are well stated. There is a patient data missing in the CA-19-9 result. Please cross-check.

Response: We appreciate the helpful suggestion. Following the reviewer's comment, we can confirm that preoperative serum CA19-9 levels had not been measured in one patient; we have changed the following text in the Result (p.5, lines 103-105)

Histological evaluation of extra-pancreatic nerve plexus invasion was impossible in two patients.

In one patient, preoperative serum CA19-9 levels were not measured, and in two patients, histological evaluation of extra-pancreatic nerve plexus invasion was impossible.

Thank you again for your comments on our manuscript. I trust that the revised manuscript now meets the standards for publication in PLOS ONE.

Sincerely,

Katsunori Uchida

Department of Pathology, Kansai Medical University, Osaka, Japan

2-3-1 Shinmachi, Hirakata, Osaka, 573-1191, Japan

Phone number: +81-72-804-0101

Fax number: +81-72-804-2960

Email address: uchidkat@hirakata.kmu.ac.jp

Attachment

Submitted filename: Response to Reviewes.docx

pone.0307876.s003.docx (23.3KB, docx)

Decision Letter 1

Paolo Aurello

15 Jul 2024

Prognostic impact of the distance from the anterior surface to tumor cells in pancreatoduodenectomy with neoadjuvant chemoradiotherapy for pancreatic ductal adenocarcinoma

PONE-D-24-08272R1

Dear Dr. KATSUNORI UCHIDA

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Academic Editor

PLOS ONE

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Reviewers' comments:

Acceptance letter

Paolo Aurello

17 Jul 2024

PONE-D-24-08272R1

PLOS ONE

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Associated Data

    This section collects any data citations, data availability statements, or supplementary materials included in this article.

    Supplementary Materials

    S1 Table. Patient data used for this study.

    (XLSX)

    pone.0307876.s001.xlsx (21.5KB, xlsx)
    Attachment

    Submitted filename: PONE-D-24-08272_reviewed copy.pdf

    pone.0307876.s002.pdf (1.9MB, pdf)
    Attachment

    Submitted filename: Response to Reviewes.docx

    pone.0307876.s003.docx (23.3KB, docx)

    Data Availability Statement

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