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Presence of low-grade IPMN at the pancreatic transection margin does not have prognostic significance after resection of IPMN-associated pancreatic adenocarcinoma

  • Carl-Stephan Leonhardt
    Affiliations
    Department of General, Visceral and Transplantation Surgery, Heidelberg University Hospital, Im Neuenheimer Feld 420, 69120, Heidelberg, Germany

    Department of General Surgery, Division of Visceral Surgery, Medical University of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria
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  • Ulf Hinz
    Affiliations
    Department of General, Visceral and Transplantation Surgery, Heidelberg University Hospital, Im Neuenheimer Feld 420, 69120, Heidelberg, Germany
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  • Jörg Kaiser
    Affiliations
    Department of General, Visceral and Transplantation Surgery, Heidelberg University Hospital, Im Neuenheimer Feld 420, 69120, Heidelberg, Germany
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  • Thomas Hank
    Affiliations
    Department of General, Visceral and Transplantation Surgery, Heidelberg University Hospital, Im Neuenheimer Feld 420, 69120, Heidelberg, Germany

    Department of General Surgery, Division of Visceral Surgery, Medical University of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria
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  • Christine Tjaden
    Affiliations
    Department of General, Visceral and Transplantation Surgery, Heidelberg University Hospital, Im Neuenheimer Feld 420, 69120, Heidelberg, Germany
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  • Frank Bergmann
    Affiliations
    Institute of Pathology, University Hospital Heidelberg, Im Neuenheimer Feld 224, 69120, Heidelberg, Germany
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  • Thilo Hackert
    Affiliations
    Department of General, Visceral and Transplantation Surgery, Heidelberg University Hospital, Im Neuenheimer Feld 420, 69120, Heidelberg, Germany
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  • Markus W. Büchler
    Affiliations
    Department of General, Visceral and Transplantation Surgery, Heidelberg University Hospital, Im Neuenheimer Feld 420, 69120, Heidelberg, Germany
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  • Author Footnotes
    1 Present Address: Department of General Surgery, Division of Visceral Surgery Medical University of Vienna, Währinger Gürtel 18–20, 1090 Vienna, Austria, P: +43 (0)1 40400–56470 E-Mail: [email protected]
    Oliver Strobel
    Correspondence
    Corresponding author. Department of General, Visceral and Transplantation Surgery, Im Neuenheimer Feld 420, 69120, Heidelberg, Germany.
    Footnotes
    1 Present Address: Department of General Surgery, Division of Visceral Surgery Medical University of Vienna, Währinger Gürtel 18–20, 1090 Vienna, Austria, P: +43 (0)1 40400–56470 E-Mail: [email protected]
    Affiliations
    Department of General, Visceral and Transplantation Surgery, Heidelberg University Hospital, Im Neuenheimer Feld 420, 69120, Heidelberg, Germany

    Department of General Surgery, Division of Visceral Surgery, Medical University of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria
    Search for articles by this author
  • Author Footnotes
    1 Present Address: Department of General Surgery, Division of Visceral Surgery Medical University of Vienna, Währinger Gürtel 18–20, 1090 Vienna, Austria, P: +43 (0)1 40400–56470 E-Mail: [email protected]
Open AccessPublished:August 09, 2022DOI:https://doi.org/10.1016/j.ejso.2022.08.003

      Abstract

      Introduction

      Resection margin status is a well-established prognosticator in pancreatic cancer. The prognostic impact of IPMN dysplasia at the pancreatic transection margin in IPMN-associated carcinoma (IPMN-Ca) remains unclear, hence institutional practices on additional resections vary.

      Methods

      Patients undergoing partial pancreatectomy or attempted partial pancreatectomy converted to total pancreatectomy for IPMN-Ca between 04/2002 and 12/2018 were identified. Final pathology of the definitive pancreatic transection margin was identified. The association between the presence of IPMN dysplasia at the margin and overall survival (OS) was assessed.

      Results

      Of 302 patients with IPMN-Ca, 181 (59.9%) patients received partial pancreatoduodenectomy, 61 (20.2%) distal pancreatectomy, and 60 (19.9%) were converted to total pancreatectomy. Median OS was 98.6 months in R0 (≥1 mm), 39.3 months in R1 (<1 mm), and 22.0 months in R1(direct) resected patients, respectively (p < 0.0001). No IPMN dysplasia at the definitive margin was present in 103 (34.1%), low-grade in 131 (43.4%), and high-grade/R1 in 8 (2.6%) patients. Low-grade dysplasia or total pancreatectomy were not associated with shorter OS compared to dysplasia-free margin across the entire cohort. Sensitivity analyses confirmed a lack of prognostic relevance of low-grade IPMN dysplasia at the pancreatic margin in R0 resected IPMN-Ca and in R0 resected UICC stage IA/IB IPMN-Ca.

      Conclusions

      Low-grade IPMN at the transection margin is not associated with shorter overall survival after partial pancreatectomy for IPMN-Ca. Additional resections for low-grade dysplasia, up to total pancreatectomy do not result in a survival benefit and should be omitted. Due to limited sample size, high-grade dysplasia could not be analyzed.

      Keywords

      1. Introduction

      Intraductal papillary mucinous neoplasm (IPMN) can presents with a wide spectrum of dysplasia, all of which are regarded as neoplastic [
      • Basturk O.
      • Hong S.M.
      • Wood L.D.
      • Adsay N.V.
      • Albores-Saavedra J.
      • Biankin A.V.
      • et al.
      A revised classification system and recommendations from the Baltimore consensus meeting for neoplastic precursor lesions in the pancreas.
      ]. Traditionally, the World Health Organization (WHO) classified noninvasive IPMN dysplasia into a three-tier system consisting of low-grade, intermediate-grade, as well as high-grade dysplasia [
      • Longnecker D.
      • Adler G.
      • Hruban R.
      • Kloppel G.
      World Health Organization classification of tumors. Pathology and genetics of tumors of the digestive system.
      ]. To account for the uncertain prognostic relevance of low-grade versus intermediate-grade IPMN dysplasia, in 2019 the WHO adapted its classification from a three-tier system to a two-tier grading system, omitting the category of intermediate-grade dysplasia and now only distinguishing between low and high-grade dysplasia, based on the highest grade of dysplasia detected [
      • Basturk O.
      • Hong S.M.
      • Wood L.D.
      • Adsay N.V.
      • Albores-Saavedra J.
      • Biankin A.V.
      • et al.
      A revised classification system and recommendations from the Baltimore consensus meeting for neoplastic precursor lesions in the pancreas.
      ,
      • Nagtegaal I.D.
      • Odze R.D.
      • Klimstra D.
      • Paradis V.
      • Rugge M.
      • Schirmacher P.
      • et al.
      The 2019 WHO classification of tumours of the digestive system.
      ].
      Presence of high-grade dysplasia in resected noninvasive IPMN is associated with a significantly lower 5-year survival compared to low- and intermediate-grade dysplasia [
      • Dhar V.K.
      • Merchant N.B.
      • Patel S.H.
      • Edwards M.J.
      • Wima K.
      • Imbus J.
      • et al.
      Does surgical margin impact recurrence in noninvasive intraductal papillary mucinous neoplasms?: a multi-institutional study.
      ]. The degree of dysplasia has been implicated as the most important risk factor for recurrence of noninvasive IPMN [
      • Kang M.J.
      • Jang J.Y.
      • Lee K.B.
      • Chang Y.R.
      • Kwon W.
      • Kim S.W.
      Long-term prospective cohort study of patients undergoing pancreatectomy for intraductal papillary mucinous neoplasm of the pancreas: implications for postoperative surveillance.
      ]. A large single-center study reported that progression of low or intermediate-grade dysplasia to invasive cancer in the pancreatic remnant occurred after a median of 69 months, while in patients with high-grade dysplasia progression only took a median of 47 months [
      • Rezaee N.
      • Barbon C.
      • Zaki A.
      • He J.
      • Salman B.
      • Hruban R.H.
      • et al.
      Intraductal papillary mucinous neoplasm (IPMN) with high-grade dysplasia is a risk factor for the subsequent development of pancreatic ductal adenocarcinoma.
      ].
      Resection margin status regarding the invasive component is a well-established prognosticator in classical PDAC as well as in IPMN-Ca [
      • Hank T.
      • Hinz U.
      • Tarantino I.
      • Kaiser J.
      • Niesen W.
      • Bergmann F.
      • et al.
      Validation of at least 1 mm as cut-off for resection margins for pancreatic adenocarcinoma of the body and tail.
      ,
      • Strobel O.
      • Hank T.
      • Hinz U.
      • Bergmann F.
      • Schneider L.
      • Springfeld C.
      • et al.
      Pancreatic cancer surgery: the new R-status counts.
      ,
      • Kaiser J.
      • Scheifele C.
      • Hinz U.
      • Leonhardt C.S.
      • Hank T.
      • Koenig A.K.
      • et al.
      IPMN-associated pancreatic cancer: survival, prognostic staging and impact of adjuvant chemotherapy.
      ]. During resections of noninvasive IPMN and IPMN-Ca, IPMN with varying grades of dysplasia is frequently encountered at the pancreatic transection margin [
      • Dhar V.K.
      • Merchant N.B.
      • Patel S.H.
      • Edwards M.J.
      • Wima K.
      • Imbus J.
      • et al.
      Does surgical margin impact recurrence in noninvasive intraductal papillary mucinous neoplasms?: a multi-institutional study.
      ,
      • Couvelard A.
      • Sauvanet A.
      • Kianmanesh R.
      • Hammel P.
      • Colnot N.
      • Levy P.
      • et al.
      Frozen sectioning of the pancreatic cut surface during resection of intraductal papillary mucinous neoplasms of the pancreas is useful and reliable: a prospective evaluation.
      ]. Several studies addressed the prognostic impact in noninvasive IPMN, yet controversy remains. A recent multicenter study comprising 330 patients with resected noninvasive IPMN failed to detect a significant association between margin positivity and recurrence at the resection margin itself [
      • Dhar V.K.
      • Merchant N.B.
      • Patel S.H.
      • Edwards M.J.
      • Wima K.
      • Imbus J.
      • et al.
      Does surgical margin impact recurrence in noninvasive intraductal papillary mucinous neoplasms?: a multi-institutional study.
      ]. Of note, definition of margin positivity consisted of low as well as high-grade dysplasia. In contrast, a large single center study reported a 25% recurrence rate independent of the exact location if IPMN was present at the margin versus 14% if no IPMN was present (p = 0.008). High-grade dysplasia at the margin had a significantly increased risk of recurrence compared to negative margins, while this was not observed in cases of low- and intermediate grade dysplasia [
      • Marchegiani G.
      • Mino-Kenudson M.
      • Ferrone C.R.
      • Morales-Oyarvide V.
      • Warshaw A.L.
      • Lillemoe K.D.
      • et al.
      Patterns of recurrence after resection of IPMN: who, when, and how?.
      ]. Further series provided evidence that high-grade dysplasia at the margin is associated with earlier recurrence and shortened overall survival [
      • Chari S.T.
      • Yadav D.
      • Smyrk T.C.
      • DiMagno E.P.
      • Miller L.J.
      • Raimondo M.
      • et al.
      Study of recurrence after surgical resection of intraductal papillary mucinous neoplasm of the pancreas.
      ,
      • Raut C.P.
      • Cleary K.R.
      • Staerkel G.A.
      • Abbruzzese J.L.
      • Wolff R.A.
      • Lee J.H.
      • et al.
      Intraductal papillary mucinous neoplasms of the pancreas: effect of invasion and pancreatic margin status on recurrence and survival.
      ,
      • Frankel T.L.
      • LaFemina J.
      • Bamboat Z.M.
      • D'Angelica M.I.
      • DeMatteo R.P.
      • Fong Y.
      • et al.
      Dysplasia at the surgical margin is associated with recurrence after resection of non-invasive intraductal papillary mucinous neoplasms.
      ].
      In resected IPMN-Ca, there is a lack of data regarding the prognostic impact of IPMN dysplasia at the pancreatic transection margin. Interestingly, a recent single-center study described that the degree of IPMN dysplasia at the pancreatic transection margin was independently associated with recurrence only in noninvasive IPMN, while in IPMN-Ca presence of high-grade dysplasia was associated with recurrence only on univariable analysis [
      • Marchegiani G.
      • Mino-Kenudson M.
      • Ferrone C.R.
      • Morales-Oyarvide V.
      • Warshaw A.L.
      • Lillemoe K.D.
      • et al.
      Patterns of recurrence after resection of IPMN: who, when, and how?.
      ]. A limited number of patients and a lack of consensus what constitutes a positive margin has contributed to these conflicting results in the literature [
      • Griffin J.F.
      • Poruk K.E.
      • Wolfgang C.L.
      Is it time to expand the role of total pancreatectomy for IPMN?.
      ]. While some consider the presence of low-grade dysplasia as a negative margin, others consider all grades of dysplasia including invasive carcinoma as a positive margin [
      • Frankel T.L.
      • LaFemina J.
      • Bamboat Z.M.
      • D'Angelica M.I.
      • DeMatteo R.P.
      • Fong Y.
      • et al.
      Dysplasia at the surgical margin is associated with recurrence after resection of non-invasive intraductal papillary mucinous neoplasms.
      ].
      The revised 2017 international consensus Fukuoka guideline recommends additional resection if high-grade dysplasia or invasive carcinoma is present at the pancreatic resection margin during resection of IPMN without explicitly referring to cases of IPMN-Ca. Resection should be extended until low-grade dysplasia or dysplasia-free margins are obtained. In cases of low-grade dysplasia, no further resection is advised [
      • Tanaka M.
      • Fernandez-Del Castillo C.
      • Kamisawa T.
      • Jang J.Y.
      • Levy P.
      • Ohtsuka T.
      • et al.
      Revisions of international consensus Fukuoka guidelines for the management of IPMN of the pancreas.
      ]. Similarly, the evidence-based European guidelines advocate no further resection in cases of low-grade IPMN at the margin (GRADE 2C recommendation), but point out as limitation that the data in the literature on this topic are variable [
      European Study Group on Cystic Tumours of the P
      European evidence-based guidelines on pancreatic cystic neoplasms.
      ]. Of note, additional resection up to total pancreatectomy is associated with increased morbidity and a reduced quality of life due to pancreatic endocrine and exocrine insufficiency with the necessity of life-long insulin and pancreatic enzyme substitutions [
      • Reddy S.
      • Wolfgang C.L.
      • Cameron J.L.
      • Eckhauser F.
      • Choti M.A.
      • Schulick R.D.
      • et al.
      Total pancreatectomy for pancreatic adenocarcinoma: evaluation of morbidity and long-term survival.
      ,
      • Barbier L.
      • Jamal W.
      • Dokmak S.
      • Aussilhou B.
      • Corcos O.
      • Ruszniewski P.
      • et al.
      Impact of total pancreatectomy: short- and long-term assessment.
      ]. Importantly, despite the obvious clinical relevance, these recommendations do not specifically address the scenario of IPMN dysplasia at the margin during resections for IPMN-Ca. In particular, no data exists on the prognostic relevance of IPMN dysplasia at the pancreatic transection margin in resected IPMN-Ca in the context of the R status of the invasive component.
      As no specific guidelines exist for this specific situation, institutional practices to address the presence of dysplasia at the pancreatic resection margin for IPMN-Ca resections vary. While in most institutions, high-grade dysplasia at the resection margin is addressed by an additional resection, institutional practices vary for the presence of low-grade dysplasia. The aim of this study was to investigate the association between IPMN dysplasia at the pancreatic transection margin in resected IPMN-Ca and overall survival in consideration of the R status of the invasive cancer.

      2. Methods

      2.1 Study design and study population

      This study was approved by the ethics committee at Heidelberg University Hospital (Approval S-069/2016) and conducted according to the STROBE recommendations for observational studies [
      • von Elm E.
      • Altman D.G.
      • Egger M.
      • Pocock S.J.
      • Gotzsche P.C.
      • Vandenbroucke J.P.
      • et al.
      The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies.
      ]. All patients with pathologically confirmed IPMN-Ca who underwent partial pancreatectomy or attempted partial pancreatectomy converted to total pancreatectomy between 04/2002–12/2018 were identified from a prospectively maintained database at the Department of General Surgery, Heidelberg University Hospital.
      Exclusion criteria consisted of pancreatic tumors other than IPMN-Ca, M1 stage other than paraaortic lymph node metastasis, presence of other tumors on pancreatic transection margins, R2 resection and indeterminable margin status (Rx) resection. Since overall survival dependent on margin status was the primary outcome, patients who died within the same hospital stay and patients who were lost to follow-up were also excluded.
      Data on patient's demographics, type of resection, tumor localization, tumor size, grading, TNM classification, IUCC staging, and lymph node status were extracted from a prospectively maintained data base. Data on pancreatic resection margins were extracted from pathology reports available for all patients through the electronical hospital record system. Classification of IPMN into main-duct IPMN; branch-duct IPMN, and mixed-type IPMN based on preoperative cross-sectional imaging was retrieved from medical records.
      Survival data was collected through consultations in our pancreas outpatient clinic, by contacting general practitioners as well as from regional and national tumor registries. The last update of follow-up data was performed in 07/2020.

      2.2 Surgical and oncological management

      Primary resection was attempted if patients were deemed fit for surgery and tumors regarded as resectable or borderline resectable based on preoperative cross-sectional imaging. Resectability was defined according to the International Study Group of Pancreatic Surgery criteria [
      • Bockhorn M.
      • Uzunoglu F.G.
      • Adham M.
      • Imrie C.
      • Milicevic M.
      • Sandberg A.A.
      • et al.
      Borderline resectable pancreatic cancer: a consensus statement by the international study group of pancreatic surgery (ISGPS).
      ]. In cases of locally advanced unresectable tumors, neoadjuvant chemotherapy was performed. In the event of tumor contact with the celiac trunk or superior mesenteric artery, an artery-first approach was employed to assess resectability and to avoid R2 resections [
      • Weitz J.
      • Rahbari N.
      • Koch M.
      • Buchler M.W.
      The "artery first" approach for resection of pancreatic head cancer.
      ]. If infiltration of portal vein or superior mesenteric vein was suspected, venous resection was performed. Intraoperative frozen section examination of the pancreatic transection margin was routinely performed; while the gastric margin, bile duct margin, and duodenal transection margins were examined dependent on tumor location and according to the surgeon's discretion. Invasive cancer or high-grade dysplasia on intraoperative frozen section examination were routinely addressed by additional resections up to total pancreatectomy. In cases of low-grade IPMN dysplasia and a lack of clinical evidence, additional resection was carried out as part of an individualized therapy.

      2.3 Pathologic workup

      A standardized pathology protocol was used to evaluate resected specimens [
      • Esposito I.
      • Kleeff J.
      • Bergmann F.
      • Reiser C.
      • Herpel E.
      • Friess H.
      • et al.
      Most pancreatic cancer resections are R1 resections.
      ]. Pancreatic neck, bile duct, gastric and duodenum transection margins were reported separately, while the anterior, posterior, medial and uncinate margins were each analyzed separately but margin status was reported combined. Resection margin was reported according to the revised R status definition with R0 corresponding to a 1 mm tumor-free margin [
      • Strobel O.
      • Hank T.
      • Hinz U.
      • Bergmann F.
      • Schneider L.
      • Springfeld C.
      • et al.
      Pancreatic cancer surgery: the new R-status counts.
      ]. Additionally, R1(<1 mm) and R1 (direct) with tumor cell directly at the resection margin were reported separately.
      Tumors were classified according to the current TNM staging system [
      • Brierley J.
      • Gospodarowicz M.K.
      • Wittekind C.
      TNM classification of malignant tumours.
      ]. T stage was defined based on the maximum diameter of the invasive component. Grading of the carcinoma component followed WHO recommendations [
      • Nagtegaal I.D.
      • Odze R.D.
      • Klimstra D.
      • Paradis V.
      • Rugge M.
      • Schirmacher P.
      • et al.
      The 2019 WHO classification of tumours of the digestive system.
      ]. Prognostic staging was performed according the 8th edition of the AJCC/UICC cancer staging manual [
      • Amin M.B.
      American Joint committee on cancer., American cancer society. AJCC cancer staging manual.
      ].
      Epithelial dysplasia at the pancreatic transection margin was classified according to the contemporary WHO criteria at the time of surgery and pathological evaluation into dysplasia-free margin, low-grade IPMN dysplasia, intermediate-grade IPMN dysplasia, high-grade IPMN dysplasia, and invasive IPMN/R12. To reflect the revised 2019 WHO classification criteria, low-grade and intermediate-grade IPMN were subsequently combined as low-grade IPMN dysplasia [
      • Nagtegaal I.D.
      • Odze R.D.
      • Klimstra D.
      • Paradis V.
      • Rugge M.
      • Schirmacher P.
      • et al.
      The 2019 WHO classification of tumours of the digestive system.
      ]. Similarly, high-grade IPMN and R1 at the transection margin were grouped together due to a low number of patients. If different degrees of dysplasia existed, the highest degree was recorded. Definitive pancreatic transection margin was defined as the margin after any type of additional resection independent of its reason.

      2.4 Statistical analysis

      Quantitative parameters are expressed as median and interquartile range (IQR), unless otherwise indicated. Categorical parameters are depicted as absolute numbers and relative frequencies. Comparisons between the three R status groups and categorical histopathological parameters were performed using the chi square test, if appropriate, or the Fisher's exact test. Survival curves were created according to Kaplan-Meier method [
      • Kaplan E.L.
      • Meier P.
      Nonparametric estimation from incomplete observations.
      ]. Survival differences were assessed using the log-rank test. Overall survival was defined as the time from resection to either death from any cause or last follow-up. Patients alive at last follow-up were censored. Due to the exploratory nature of the analyses performed, all p-values were interpreted descriptively. Statistical significance was set at p < 0.05. SAS® release 9.4 (SAS Institute, Cary, North Carolina, USA) was used for statistical analysis.

      3. Results

      3.1 Clinicopathologic characteristics

      In total, 332 patients undergoing partial pancreatectomy or attempted partial pancreatectomy converted to total pancreatectomy for IPMN-Ca between 04/2002 and 12/2018 were identified (Fig. 1). Some 28 patients were excluded because of distant metastases other than paraaortic lymph nodes (n = 14), loss to follow-up (n = 12), presence of additional pancreatic neuroendocrine carcinoma (n = 1), and Rx resection (n = 1). In-hospital mortality was 0.6% (n = 2) and these two patients were also excluded.
      The final study cohort consisted of 302 patients with IPMN-Ca including 151 males (50.0%) and 151 females (50.0%) with a median age of 68.3 years (Table 1). Of 302 patients, 181 (59.9%) patients underwent a classical or pylorus-preserving partial pancreatoduodenectomy, while 61 (20.2%) patients underwent a distal pancreatectomy and in 60 (19.9%) patients an attempted partial pancreatectomy was converted to a total pancreatectomy. Median OS was 41.5 months with a 5-year survival rate of 42.2% and a median follow-up of 51.9 months (IQR: 28.2–102.8 months). In total, 237 (78.5%) patients had IPMN-Ca of the tubular subtype, whereas 65 (21.5%) patients had IPMN-Ca of the colloid subtype.
      Table 1Clinicopathologic characteristics of 302 patients with resected IPMN-associated carcinoma. Values in parentheses are percentages unless indicated otherwise.
      ParameterCategoryTotal (n = 302)
      GenderMale151 (50.0)
      Female151 (50.0)
      Median age (IQR) [years]68.3 (61.7–73.8)
      Age (years)<6061 (20.2)
      60-<70108 (35.8)
      ≥70133 (44.0)
      Median BMI (IQR) [kg/m2]24.6 (22.5–26.8)
      ASA classificationASA 19 (3.1)
      ASA 2158 (55.1)
      ASA 3119 (41.5)
      ASA 41 (0.3)
      Missing values15
      Median Ca 19–9 (IQR) [U/mL]82.9 (18.0–434.4)
      Ca 19–9 (U/mL)<37102 (34.9)
      37-<400114 (39.0)
      ≥40076 (26.0)
      Missing values10
      Median CEA (IQR) [g/L]1.8 (1.0–3.7)
      CEA (g/L)<2.5174 (60.4)
      ≥2.5114 (39.6)
      Missing values14
      Neoadjuvant chemotherapyyes9 (3.0)
      Type of surgeryPancreatoduodenectomy181 (59.9)
      Distal Pancreatectomy61 (20.2)
      Total Pancreatectomy60 (19.9)
      Vascular resectionyes57 (18.9)
      Tumor locationhead210 (69.5)
      body15 (5.0)
      tail39 (12.9)
      multifocal38 (12.6)
      Median invasive tumor diameter (IQR) [cm]3.0 (2.0–4.2)
      HistologyIPMN associated carcinoma tubulary type237 (78.5)
      colloid IPMN carcinoma65 (21.5)
      Tumor status (T 8th)T174 (25.9)
      T2136 (48.2)
      T371 (25.2)
      T42 (0.7)
      Missing values20
      Lymph nodes status (N 8th)N0113 (37.4)
      N194 (31.1)
      N295 (31.5)
      Distant metastasis-status (M)M0294 (97.4)
      M18 (2.6)
      Grading (G)G117 (5.8)
      G2199 (68.2)
      G376 (26.0)
      GX10
      Resection margin status (R)R0134 (44.4)
      R1(<1 mm)60 (19.9)
      R1(direct)108 (35.8)
      AJCC/UICC stage (8th)IA52 (17.2)
      IB36 (11.9)
      IIA25 (8.3)
      IIB92 (30.5)
      III89 (29.5)
      IV8 (2.6)
      Median postoperative hospital stay (IQR) [days]12 (10–17)
      Adjuvant therapy∗∗Yes163 (74.4)
      No56 (25.6)
      Missing data83
      AJCC/UICC: American Joint Committee on Cancer/Union for International Cancer Control; ASA: American Society of Anesthesiologists Classification; BMI: Body mass index; Ca 19–9: Carbohydrate-Antigen 19–9; CEA: Carcinoembryonic antigen.

      3.2 Resection margin and overall survival

      Of 302 patients, R0 resections were achieved in 134 (44.4%) patients, whereas 60 (19.9%) patients had an R1(<1 mm) resection and 108 (35.8%) patients an R1 (direct) resection. R0 resections were associated with a significantly longer median OS of 98.6 months and a 5-year survival of 58.5% compared to R1(<1 mm) resections (median OS 39.2 months; 5-year survival 39.6%) and R1 (direct) resections (median OS 22.0 months; 5-year survival 23.1%), respectively (Fig. 2a, p < 0.0001). The distribution of prognostic factors in the subgroups of different resection margin status is depicted in Table 2. Histological subtype of IPMN-Ca as well as AJCC/UICC stage differed significantly between R0, R1(<1 mm), and R1 (direct) groups (p < 0.0001).
      Fig. 2
      Fig. 2Kaplan-Meier curves for overall survival according to R status (a) and according to pancreatic transection margin (b) in 302 IPMN-Ca patients.
      Table 2Pathological parameters according R-classification in the study cohort. Values in parentheses are percentages unless indicated otherwise.
      ParameterR0R1(<1 mm)R1 (direct)P Value
      n13460108
      AJCC/UICC (8th)<0.0001
      IA48 (35.8)3 (5.0)1(0.9)
      IB19 (14.2)6 (10.0)11 (10.2)
      IIA18 (13.4)2 (3.3)5 (4.6)
      IIB31 (23.1)30 (50.0)31 (28.7)
      III15 (11.2)19 (31.7)55 (50.9)
      IV3 (2.2)0 (0.0)5 (4.6)
      Histology<0.0001
      Tubular IPMN-Ca86 (64.2)57 (95.0)94 (87.0)
      Colloid IPMN-Ca48 (35.8)3 (5.0)14 (13.0)
      Pancreatectomy after frozen section (TP)28 (20.9)16 (26.7)16 (14.8)0.1678
      Pancreas resection margin without TP10644920.0589
      Tumor-free51 (48.1)18 (40.9)34 (37.0)
      Low-grade54 (50.9)26 (59.1)51 (55.4)
      High grade/R11 (0.9)0 (0.0)7 (7.6)
      Further resection without TP14 (13.2)3 (6.8)12 (13.0)0.5685
      AJCC/UICC: American Joint Committee on Cancer/Union for International Cancer Control; IPMN-Ca: IPMN- associated pancreatic adenocarcinoma.

      3.3 Prognostic relevance of IPMN dysplasia at the pancreatic transection margin

      Of 242 patients with partial pancreatectomy, 103 (42.6%) patients had no evidence of dysplasia at the definitive pancreatic transection margin, 131 (43.4%) had low-grade IPMN, and 8 (2.6%) had high-grade IPMN or R1 status (Table 2). Kaplan-Meier survival analysis did not reveal a significant difference in OS between the subgroups (log-rank p = 0.48) (Fig. 2b). Of note, due to the surgical strategy employed, cases of high-grade IPMN (n = 4) and R1 (n = 4) at the resection margin were rare. Hence, survival data for this group has to be interpreted with caution.
      Conversion of partial pancreatectomy to total pancreatectomy based on intraoperative findings was performed in 60 patients, primarily due to R1 status (n = 20, 36.4%) or presence of IPMN with high-grade dysplasia (n = 17, 30.9%) at the pancreatic transection margin. In 23 (38.3%) patients, conversion to total pancreatectomy was performed for low-grade and intermediate-grade IPMN.
      As there was no prognostic relevance of IPMN dysplasia at the pancreatic transection margin in the univariable analysis of the entire study cohort, multivariable survival analyses were not performed. However, several subgroup analyses were performed to investigate if IPMN dysplasia at the pancreatic transection margin may be relevant in specific subgroups with favorable prognosis.

      3.3.1 Subgroup analysis of IPMN dysplasia and survival according to R status

      First, survival analyses for the subgroups of R0, R1(<1 mm) and R1 (direct) resection margin status of the IPMN-Ca were performed. Of note, frequency of additional parenchymal resection as well as total pancreatectomy did not differ significantly between the 3 subgroups (Table 2).
      Of the 134 patients with R0 resections, 51 had no dysplasia at the definitive pancreatic transection margin, 55 had low-grade IPMN dysplasia, and 28 were converted to a total pancreatectomy. Only one patient had high-grade dysplasia and was analyzed together with the low-grade group for the purpose of this analysis due to low patient number. In patients with R0 resection of IPMN-Ca, no significant difference in OS was observed between the subgroup with or without low-grade IPMN or with total pancreatectomy (Fig. 3a, p = 0.75).
      Fig. 3
      Fig. 3Kaplan-Meier curves for overall survival according to pancreatic transection margin in 134 R0 (a), 60 R1 (<1 mm) (b) and 108 R1 (direct) (c) resected IPMN-Ca patients and in 67 R0 resected AJCC/UICC stage IA/IB IPMN-Ca patients (d).
      Of 60 patients with R1(<1 mm) resections, dysplasia-free margin was present in 18 patients, 26 patients had low-grade dysplasia, and 16 underwent conversion to total pancreatectomy. No patient had high-grade dysplasia at the definitive margin in the R1(<1 mm) group. In patients with R1 (<1 mm) resected IPMN-CA low-grade dysplasia and total pancreatectomy were associated with a significantly worse survival compared to no evidence of dysplasia at the transection margin (Fig. 3b, p = 0.03). Further analysis revealed that this survival difference is explained by a worse survival of patients who underwent total pancreatectomy as no difference in survival was detected between patients without dysplasia at the margin (n = 18) versus low-grade dysplasia (n = 26) (p = 0.15). In contrast, total pancreatectomy showed a significantly worse survival than patients who underwent partial pancreatectomy in the R1(<1 mm) group (p = 0.02).
      Of 108 patients with R1 (direct) resections, no significant difference in OS stratified according to the definitive pancreatic transection margin was observed (Fig. 3c, p = 0.39).

      3.3.2 IPMN dysplasia in early-stage pancreatic cancer

      Considering its preneoplastic nature, it is conceivable that IPMN dysplasia at the pancreatic transection margin may most likely have an effect in patients with early-stage pancreatic cancer who have a long survival expectation. In total, 67 patients had a stage IA/IB tumor according to the UICC 8th edition and a R0 resection. In these patients, median overall survival was not yet reached with a median follow-up of 86.2 months (IQR 41.6–114.5 months) and the actuarial 5-year survival rate was 76.3%. Among these patients, 27 patients had no evidence of dysplasia at the definitive transection margin, 27 had low-grade IPMN, and 13 underwent total pancreatectomy. Kaplan-Meier survival analysis did not reveal a survival difference associated with IPMN-dysplasia at the pancreatic transection margin in patients with early-stage, R0-resected IPMN-Ca (Fig. 3d, p = 0.86).

      4. Discussion

      This study investigates the association between IPMN dysplasia at the pancreatic transection margin and overall survival in patients undergoing partial pancreatectomy or attempted partial pancreatectomy for IPMN-Ca. We provide evidence that the presence of low-grade IPMN dysplasia at the transection margin does not have prognostic relevance compared to a dysplasia-free transection margin after resection of IPMN-Ca. Moreover, total pancreatectomy in these patients does not confer a survival benefit. The lack of prognostic relevance of low-grade IPMN dysplasia at the pancreatic transection margin was confirmed in sensitivity analysis for early-stage (UICC I) and R0-resected IPMN-Ca. Based on these results, the presence of low-grade IPMN dysplasia at the pancreatic transection margin during resection for an IPMN-Ca does not warrant an additional resection.
      Prior to this study, there was a lack of evidence concerning the association between the prognostic effects of IPMN dysplasia at transection margin and survival in IPMN-Ca. However, data from noninvasive IPMN offers critical insights. Several series could show that although recurrence was associated with the degree of dysplasia at the transection margin, it rarely occurred at the margin itself [
      • Dhar V.K.
      • Merchant N.B.
      • Patel S.H.
      • Edwards M.J.
      • Wima K.
      • Imbus J.
      • et al.
      Does surgical margin impact recurrence in noninvasive intraductal papillary mucinous neoplasms?: a multi-institutional study.
      ,
      • Kang M.J.
      • Jang J.Y.
      • Lee K.B.
      • Chang Y.R.
      • Kwon W.
      • Kim S.W.
      Long-term prospective cohort study of patients undergoing pancreatectomy for intraductal papillary mucinous neoplasm of the pancreas: implications for postoperative surveillance.
      ,
      • Frankel T.L.
      • LaFemina J.
      • Bamboat Z.M.
      • D'Angelica M.I.
      • DeMatteo R.P.
      • Fong Y.
      • et al.
      Dysplasia at the surgical margin is associated with recurrence after resection of non-invasive intraductal papillary mucinous neoplasms.
      ,
      • Sohn T.A.
      • Yeo C.J.
      • Cameron J.L.
      • Hruban R.H.
      • Fukushima N.
      • Campbell K.A.
      • et al.
      Intraductal papillary mucinous neoplasms of the pancreas: an updated experience.
      ,
      • Schnelldorfer T.
      • Sarr M.G.
      • Nagorney D.M.
      • Zhang L.
      • Smyrk T.C.
      • Qin R.
      • et al.
      Experience with 208 resections for intraductal papillary mucinous neoplasm of the pancreas.
      ]. A large multi-center study comprising 330 patients with noninvasive IPMN and a median follow-up of 36 months did not detect an association between IPMN dysplasia at the margin and recurrence or development of invasive IPMN. Interestingly, noninvasive disease recurred after a median of 31 months and invasive disease after a median of 21 months, but 18% recurred after more than 5 years [
      • Dhar V.K.
      • Merchant N.B.
      • Patel S.H.
      • Edwards M.J.
      • Wima K.
      • Imbus J.
      • et al.
      Does surgical margin impact recurrence in noninvasive intraductal papillary mucinous neoplasms?: a multi-institutional study.
      ]. Further support for a process of field cancerization in IPMN is provided by the finding that concomitant IPMN in patients treated with partial pancreatectomy for classical PDAC was identified as an independent predictive factor for the development of recurrence in the remnant pancreas [
      • Matsuda R.
      • Miyasaka Y.
      • Ohishi Y.
      • Yamamoto T.
      • Saeki K.
      • Mochidome N.
      • et al.
      Concomitant intraductal papillary mucinous neoplasm in pancreatic ductal adenocarcinoma is an independent predictive factor for the occurrence of new cancer in the remnant pancreas.
      ].
      Evolutionary timeline analysis based on genomic data indicates that the progression of a cell with high-grade IPMN dysplasia to invasive carcinoma takes at least 3 years [
      • Noe M.
      • Niknafs N.
      • Fischer C.G.
      • Hackeng W.M.
      • Beleva Guthrie V.
      • Hosoda W.
      • et al.
      Genomic characterization of malignant progression in neoplastic pancreatic cysts.
      ]. To account for a time-dependent effect in carcinogenesis, subgroup analysis for R0 resected patients with AJCC/UICC 8th stage IA/IB IPMN-Ca was performed. Again, no association between IPMN dysplasia at the transection margin and survival could be observed, independent of R status at the other margins.
      Although no association between OS and degree of dysplasia at the pancreatic transection margin was detected across the entire study cohort, R0 resections were associated with a significantly improved OS compared to R1 (direct) resections. This emphasizes the importance of achieving a R0 resection in IPMN-Ca. The revised R status definition was applied in this study with R0 corresponding to ≥1 mm clear margin as previous studies in pancreatic cancer were able to show that it identifies a group of patients with favorable prognosis [
      • Hank T.
      • Hinz U.
      • Tarantino I.
      • Kaiser J.
      • Niesen W.
      • Bergmann F.
      • et al.
      Validation of at least 1 mm as cut-off for resection margins for pancreatic adenocarcinoma of the body and tail.
      ,
      • Strobel O.
      • Hank T.
      • Hinz U.
      • Bergmann F.
      • Schneider L.
      • Springfeld C.
      • et al.
      Pancreatic cancer surgery: the new R-status counts.
      ]. In our cohort, R1(<1 mm) resected patients had a significantly better prognosis and a median OS of 39.2 months versus 22.0 months for R1 (direct) resected patients, providing evidence that the revised R status carries prognostic significance in IPMN-Ca.
      Interestingly, subgroup analysis according to R status revealed significantly worse survival in R1(<1 mm) resected patients with presence of low-grade IPMN as well as total pancreatectomy compared to a dysplasia-free transection margin (p = 0.03). However, patient numbers in the R1(<1 mm) subgroup (n = 60) were smaller than in the R1 (direct) (n = 108) and R0 (≥1 mm) (n = 134) groups. Additionally, no difference in survival was detected when separately analyzing patients with low-grade dysplasia at the margin versus no evidence of dysplasia. Worse survival was due to the 16 patients who underwent total pancreatectomy. Considering the relatively low patient number and the fact that worse survival was primarily related to worse outcome in the total pancreatectomy group, this result should be interpreted with caution.
      In 2015, the Baltimore consensus conference proposed a simplified two-tier classification system of IPMN dysplasia combining low-grade dysplasia and intermediate-grade dysplasia to low-grade dysplasia [
      • Basturk O.
      • Hong S.M.
      • Wood L.D.
      • Adsay N.V.
      • Albores-Saavedra J.
      • Biankin A.V.
      • et al.
      A revised classification system and recommendations from the Baltimore consensus meeting for neoplastic precursor lesions in the pancreas.
      ,
      • Adsay V.
      • Mino-Kenudson M.
      • Furukawa T.
      • Basturk O.
      • Zamboni G.
      • Marchegiani G.
      • et al.
      Pathologic evaluation and reporting of intraductal papillary mucinous neoplasms of the pancreas and other tumoral intraepithelial neoplasms of pancreatobiliary tract: recommendations of verona consensus meeting.
      ]. In 2019 the WHO adopted this classification [
      • Nagtegaal I.D.
      • Odze R.D.
      • Klimstra D.
      • Paradis V.
      • Rugge M.
      • Schirmacher P.
      • et al.
      The 2019 WHO classification of tumours of the digestive system.
      ]. A lack of prognostic relevance associated with the presence of low-grade IPMN at the pancreatic transection margin during resection of IPMN-Ca support this revised classification system.
      The results of this study are in agreement with studies investigating the association between pancreatic intraepithelial neoplasia (PanIN) at the pancreatic transection margin and overall survival in patients resected for classical PDAC. Similar as our findings suggest, no association between survival and grade of low-grade dysplasia could be observed [
      • Adsay V.
      • Mino-Kenudson M.
      • Furukawa T.
      • Basturk O.
      • Zamboni G.
      • Marchegiani G.
      • et al.
      Pathologic evaluation and reporting of intraductal papillary mucinous neoplasms of the pancreas and other tumoral intraepithelial neoplasms of pancreatobiliary tract: recommendations of verona consensus meeting.
      ,
      • Matthaei H.
      • Hong S.M.
      • Mayo S.C.
      • dal Molin M.
      • Olino K.
      • Venkat R.
      • et al.
      Presence of pancreatic intraepithelial neoplasia in the pancreatic transection margin does not influence outcome in patients with R0 resected pancreatic cancer.
      ]. Moreover, Matthaei and co-workers did not detect any significant differences in survival between high-grade PanIN and low-grade PanIN [
      • Matthaei H.
      • Hong S.M.
      • Mayo S.C.
      • dal Molin M.
      • Olino K.
      • Venkat R.
      • et al.
      Presence of pancreatic intraepithelial neoplasia in the pancreatic transection margin does not influence outcome in patients with R0 resected pancreatic cancer.
      ].
      Omitting additional resection for low-grade IPMN at the margin did not carry prognostic relevance in our cohort, yet we were unable to investigate the effects on local recurrence. Notably, approximately 15–30% of patients with IPMN-Ca experience with local recurrence at the pancreatic remnant-either by itself or in combination with distant recurrence [
      • Kang M.J.
      • Jang J.Y.
      • Lee K.B.
      • Chang Y.R.
      • Kwon W.
      • Kim S.W.
      Long-term prospective cohort study of patients undergoing pancreatectomy for intraductal papillary mucinous neoplasm of the pancreas: implications for postoperative surveillance.
      ,
      • Partelli S.
      • Fernandez-Del Castillo C.
      • Bassi C.
      • Mantovani W.
      • Thayer S.P.
      • Crippa S.
      • et al.
      Invasive intraductal papillary mucinous carcinomas of the pancreas: predictors of survival and the role of lymph node ratio.
      ,
      • Kang M.J.
      • Lee K.B.
      • Jang J.Y.
      • Kwon W.
      • Park J.W.
      • Chang Y.R.
      • et al.
      Disease spectrum of intraductal papillary mucinous neoplasm with an associated invasive carcinoma invasive IPMN versus pancreatic ductal adenocarcinoma-associated IPMN.
      ]. Winter et al. reported that after resection of IPMN-Ca with an invasive component of <20 mm, 17 patients (24.3%) experienced recurrence within the follow-up time of which two-third had distant recurrence (either by itself or in combination with local recurrence) and one-third isolated local recurrence [
      • Winter J.M.
      • Jiang W.
      • Basturk O.
      • Mino-Kenudson M.
      • Fong Z.V.
      • Tan W.P.
      • et al.
      Recurrence and survival after resection of small intraductal papillary mucinous neoplasm-associated carcinomas (</=20-mm invasive component): a multi-institutional analysis.
      ].
      Subclinical foci of different degrees of dysplasia can coexist in the remnant pancreas independent of margin status, consistent with a theory of field cancerization and the reported multifocal nature of IPMN [
      • Izawa T.
      • Obara T.
      • Tanno S.
      • Mizukami Y.
      • Yanagawa N.
      • Kohgo Y.
      Clonality and field cancerization in intraductal papillary-mucinous tumors of the pancreas.
      ]. Almost 20% of co-occurring IPMN and PDAC appear to be genetically unrelated despite close physical proximity, hinting to a multifocal carcinogenic process [
      • Felsenstein M.
      • Noe M.
      • Masica D.L.
      • Hosoda W.
      • Chianchiano P.
      • Fischer C.G.
      • et al.
      IPMNs with co-occurring invasive cancers: neighbours but not always relatives.
      ].
      Of note, local recurrence might be amenable to re-resection. In classical PDAC re-resection for isolated local recurrence has been associated with encouraging survival [
      • Strobel O.
      • Hartwig W.
      • Hackert T.
      • Hinz U.
      • Berens V.
      • Grenacher L.
      • et al.
      Re-resection for isolated local recurrence of pancreatic cancer is feasible, safe, and associated with encouraging survival.
      ]. Similarly, a large study from the Japan Pancreas Society analyzed 247 resected IPMN-Ca patients, out of which 107 (43.4%) developed recurrence within the follow-up period. Median OS was significantly better in patients who underwent re-resection for local recurrence versus patients who did not (p = 0.04) [
      • Hirono S.
      • Shimizu Y.
      • Ohtsuka T.
      • Kin T.
      • Hara K.
      • Kanno A.
      • et al.
      Recurrence patterns after surgical resection of intraductal papillary mucinous neoplasm (IPMN) of the pancreas; a multicenter, retrospective study of 1074 IPMN patients by the Japan Pancreas Society.
      ]. Interestingly, higher UICC stage was associated with increased tendency of extra-pancreatic recurrence (p < 0.001). Another series by the same authors could show that while invasive IPMN, mixed-type IPMN, and high CA19-9 values were independent risk factors for extrapancreatic recurrence, a positive transection margin including LGD, HGD and invasive IPMN were independently predictive of recurrence in the pancreas remnant. Importantly, median OS differed significantly for recurrence in the pancreas versus extrapancreatic recurrence (21.8 vs. 110.6 months), supporting the hypothesis that the relevance of recurrence differs between invasive and noninvasive IPMN and in the former, prognosis is primarily determined by systemic recurrence [
      • Kaiser J.
      • Scheifele C.
      • Hinz U.
      • Leonhardt C.S.
      • Hank T.
      • Koenig A.K.
      • et al.
      IPMN-associated pancreatic cancer: survival, prognostic staging and impact of adjuvant chemotherapy.
      ,
      • Hirono S.
      • Kawai M.
      • Okada K.
      • Miyazawa M.
      • Shimizu A.
      • Kitahata Y.
      • et al.
      Long-term surveillance is necessary after operative resection for intraductal papillary mucinous neoplasm of the pancreas.
      ].
      This study has several key strengths: (1) It is the first study to systematically assess the prognostic relevance of IPMN dysplasia at the pancreatic resection margin in resected IPMN-Ca. (2) It describes for the first time the clinical significance of the revised R classification specifically in IPMN-Ca. (3) A large patient cohort enabled us to include patients who were converted to total pancreatectomy in the Kaplan-Meier survival analysis and therefore allowed a direct evaluation of its prognostic impact. (3) Subgroup analysis of early-stage IPMN-Ca patients accounted for a potential time-dependent effect of malignant transformation in IPMN dysplasia and therefore strengthens validity of results. (4) As a single-center study indications for resections and techniques of pathological evaluation of specimen were uniformly applied to all patients, thus circumventing variability associated with different surgical approaches and pathology protocols.
      There are several limitations. On one hand, the retrospective nature is associated with an inherent selection bias. On the other hand, due to the surgical strategy there was a low number of high-grade dysplasia/R1 at the final transection margin. While this is to be expected as high-grade dysplasia/R1 results in further resection in most institutions including our own, it prevented us from investigating the association between high-grade dysplasia at the margin and OS in IPMN-Ca patients. Of note, in our cohort patients with high-grade dysplasia/R1 status at the transection margin tended to have longer survival compared to low-grade IPMN. However, this effect is most likely associated with a total sample size of only 8 patients.
      Moreover, contemporary German guidelines do not recommend regular cross-sectional imaging after resection of pancreatic cancer [
      • Seufferlein T.
      • Porzner M.
      • Becker T.
      • Budach V.
      • Ceyhan G.
      • Esposito I.
      • et al.
      [S3-guideline exocrine pancreatic cancer].
      ]. Therefore, we were not able to assess patterns of recurrence and recurrence-free survival in this study. Similarly, although the median follow-up of 51.9 months is rather long it potentially could have been too short to detect a prognostic effect in low-grade IPMN as transformation from IPMN dysplasia to invasive carcinoma takes several years [
      • He J.
      • Cameron J.L.
      • Ahuja N.
      • Makary M.A.
      • Hirose K.
      • Choti M.A.
      • et al.
      Is it necessary to follow patients after resection of a benign pancreatic intraductal papillary mucinous neoplasm?.
      ]. Although desirable given different risks of malignant transformation, we were not able to separately assess the prognostic effects of epithelial subtype of IPMN [
      • Couvelard A.
      • Sauvanet A.
      • Kianmanesh R.
      • Hammel P.
      • Colnot N.
      • Levy P.
      • et al.
      Frozen sectioning of the pancreatic cut surface during resection of intraductal papillary mucinous neoplasms of the pancreas is useful and reliable: a prospective evaluation.
      ].
      In summary, low-grade (formerly low and intermediate-grade) IPMN dysplasia at the pancreatic transection margin in patients resected for IPMN-Ca does not have prognostic relevance. Based on these data, it can be recommended to abstain from additional resection and total pancreatectomy to address low-grade IPMN at the pancreatic transection margin during resection for IPMN-Ca, including resection for early stage UICC IA/IB tumors. Based on the available data from the literature, the presence of invasive IPMN at the pancreatic transection margin, constituting an R1 situation, should result in additional resection [
      • Kaiser J.
      • Scheifele C.
      • Hinz U.
      • Leonhardt C.S.
      • Hank T.
      • Koenig A.K.
      • et al.
      IPMN-associated pancreatic cancer: survival, prognostic staging and impact of adjuvant chemotherapy.
      ]. The data available in the literature and from our study do not allow a data-driven recommendation on how high-grade dysplasia at the pancreatic margin should be addressed. Rigorous pathological assessment including intraoperative frozen section analysis of the transection margin to obtain information on the presence of invasive cancer and IPMN with its grade of dysplasia remain essential to guide surgical decision-making during resection of IPMN-Ca. The results have a direct clinical relevance and considerably add to the growing body of literature on surgical management of IPMN-Ca.

      5. Conclusion

      Low-grade IPMN dysplasia is frequently encountered at the pancreatic transection margin during resection of IPMN-Ca, yet no evidence exists regarding intraoperative management. This study provides evidence that low-grade IPMN at the transection margin is not associated with shorter overall survival after partial pancreatectomy for IPMN-Ca. Additional resections up to total pancreatectomy for low-grade dysplasia do not seem to result in a survival benefit and should therefore be omitted.

      Source of funding

      None;

      Declaration of competing interest

      None.

      CRediT authorship contribution statement

      Carl-Stephan Leonhardt: Conceptualization, Methodology, Data curation, Writing – original draft, Writing – review & editing, Investigation. Ulf Hinz: Methodology, Formal analysis, Visualization, Writing – review & editing. Jörg Kaiser: Data curation, Writing – review & editing, Investigation. Thomas Hank: Data curation, Writing – review & editing, Investigation. Christine Tjaden: Data curation, Writing – review & editing. Frank Bergmann: Data curation, Resources, Writing – review & editing. Thilo Hackert: Conceptualization, Writing – review & editing. Markus W. Büchler: Conceptualization, Supervision, Funding acquisition, Project administration, Writing – review & editing. Oliver Strobel: Conceptualization, Supervision, Funding acquisition, Project administration, Writing – review & editing.

      Declaration of competing interest

      No competing interests to declare.

      Acknowledgements

      None.

      References

        • Basturk O.
        • Hong S.M.
        • Wood L.D.
        • Adsay N.V.
        • Albores-Saavedra J.
        • Biankin A.V.
        • et al.
        A revised classification system and recommendations from the Baltimore consensus meeting for neoplastic precursor lesions in the pancreas.
        Am J Surg Pathol. 2015; 39: 1730-1741
        • Longnecker D.
        • Adler G.
        • Hruban R.
        • Kloppel G.
        World Health Organization classification of tumors. Pathology and genetics of tumors of the digestive system.
        IARC, Lyon, France2000
        • Nagtegaal I.D.
        • Odze R.D.
        • Klimstra D.
        • Paradis V.
        • Rugge M.
        • Schirmacher P.
        • et al.
        The 2019 WHO classification of tumours of the digestive system.
        Histopathology. 2020; 76: 182-188
        • Dhar V.K.
        • Merchant N.B.
        • Patel S.H.
        • Edwards M.J.
        • Wima K.
        • Imbus J.
        • et al.
        Does surgical margin impact recurrence in noninvasive intraductal papillary mucinous neoplasms?: a multi-institutional study.
        Ann Surg. 2018; 268: 469-478
        • Kang M.J.
        • Jang J.Y.
        • Lee K.B.
        • Chang Y.R.
        • Kwon W.
        • Kim S.W.
        Long-term prospective cohort study of patients undergoing pancreatectomy for intraductal papillary mucinous neoplasm of the pancreas: implications for postoperative surveillance.
        Ann Surg. 2014; 260: 356-363
        • Rezaee N.
        • Barbon C.
        • Zaki A.
        • He J.
        • Salman B.
        • Hruban R.H.
        • et al.
        Intraductal papillary mucinous neoplasm (IPMN) with high-grade dysplasia is a risk factor for the subsequent development of pancreatic ductal adenocarcinoma.
        HPB. 2016; 18: 236-246
        • Hank T.
        • Hinz U.
        • Tarantino I.
        • Kaiser J.
        • Niesen W.
        • Bergmann F.
        • et al.
        Validation of at least 1 mm as cut-off for resection margins for pancreatic adenocarcinoma of the body and tail.
        Br J Surg. 2018; 105: 1171-1181
        • Strobel O.
        • Hank T.
        • Hinz U.
        • Bergmann F.
        • Schneider L.
        • Springfeld C.
        • et al.
        Pancreatic cancer surgery: the new R-status counts.
        Ann Surg. 2017; 265: 565-573
        • Kaiser J.
        • Scheifele C.
        • Hinz U.
        • Leonhardt C.S.
        • Hank T.
        • Koenig A.K.
        • et al.
        IPMN-associated pancreatic cancer: survival, prognostic staging and impact of adjuvant chemotherapy.
        Eur J Surg Oncol. 2021; 48: 1309-1320
        • Couvelard A.
        • Sauvanet A.
        • Kianmanesh R.
        • Hammel P.
        • Colnot N.
        • Levy P.
        • et al.
        Frozen sectioning of the pancreatic cut surface during resection of intraductal papillary mucinous neoplasms of the pancreas is useful and reliable: a prospective evaluation.
        Ann Surg. 2005; 242 (discussion 778-780): 774-778
        • Marchegiani G.
        • Mino-Kenudson M.
        • Ferrone C.R.
        • Morales-Oyarvide V.
        • Warshaw A.L.
        • Lillemoe K.D.
        • et al.
        Patterns of recurrence after resection of IPMN: who, when, and how?.
        Ann Surg. 2015; 262: 1108-1114
        • Chari S.T.
        • Yadav D.
        • Smyrk T.C.
        • DiMagno E.P.
        • Miller L.J.
        • Raimondo M.
        • et al.
        Study of recurrence after surgical resection of intraductal papillary mucinous neoplasm of the pancreas.
        Gastroenterology. 2002; 123: 1500-1507
        • Raut C.P.
        • Cleary K.R.
        • Staerkel G.A.
        • Abbruzzese J.L.
        • Wolff R.A.
        • Lee J.H.
        • et al.
        Intraductal papillary mucinous neoplasms of the pancreas: effect of invasion and pancreatic margin status on recurrence and survival.
        Ann Surg Oncol. 2006; 13: 582-594
        • Frankel T.L.
        • LaFemina J.
        • Bamboat Z.M.
        • D'Angelica M.I.
        • DeMatteo R.P.
        • Fong Y.
        • et al.
        Dysplasia at the surgical margin is associated with recurrence after resection of non-invasive intraductal papillary mucinous neoplasms.
        HPB. 2013; 15: 814-821
        • Griffin J.F.
        • Poruk K.E.
        • Wolfgang C.L.
        Is it time to expand the role of total pancreatectomy for IPMN?.
        Dig Surg. 2016; 33: 335-342
        • Tanaka M.
        • Fernandez-Del Castillo C.
        • Kamisawa T.
        • Jang J.Y.
        • Levy P.
        • Ohtsuka T.
        • et al.
        Revisions of international consensus Fukuoka guidelines for the management of IPMN of the pancreas.
        Pancreatology. 2017; 17: 738-753
        • European Study Group on Cystic Tumours of the P
        European evidence-based guidelines on pancreatic cystic neoplasms.
        Gut. 2018; 67: 789-804
        • Reddy S.
        • Wolfgang C.L.
        • Cameron J.L.
        • Eckhauser F.
        • Choti M.A.
        • Schulick R.D.
        • et al.
        Total pancreatectomy for pancreatic adenocarcinoma: evaluation of morbidity and long-term survival.
        Ann Surg. 2009; 250: 282-287
        • Barbier L.
        • Jamal W.
        • Dokmak S.
        • Aussilhou B.
        • Corcos O.
        • Ruszniewski P.
        • et al.
        Impact of total pancreatectomy: short- and long-term assessment.
        HPB. 2013; 15: 882-892
        • von Elm E.
        • Altman D.G.
        • Egger M.
        • Pocock S.J.
        • Gotzsche P.C.
        • Vandenbroucke J.P.
        • et al.
        The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies.
        Lancet. 2007; 370: 1453-1457
        • Bockhorn M.
        • Uzunoglu F.G.
        • Adham M.
        • Imrie C.
        • Milicevic M.
        • Sandberg A.A.
        • et al.
        Borderline resectable pancreatic cancer: a consensus statement by the international study group of pancreatic surgery (ISGPS).
        Surgery. 2014; 155: 977-988
        • Weitz J.
        • Rahbari N.
        • Koch M.
        • Buchler M.W.
        The "artery first" approach for resection of pancreatic head cancer.
        J Am Coll Surg. 2010; 210: e1-e4
        • Esposito I.
        • Kleeff J.
        • Bergmann F.
        • Reiser C.
        • Herpel E.
        • Friess H.
        • et al.
        Most pancreatic cancer resections are R1 resections.
        Ann Surg Oncol. 2008; 15: 1651-1660
        • Brierley J.
        • Gospodarowicz M.K.
        • Wittekind C.
        TNM classification of malignant tumours.
        eighth ed. John Wiley & Sons, Inc., Chichester, West Sussex, UK ; Hoboken, NJ2017
        • Amin M.B.
        American Joint committee on cancer., American cancer society. AJCC cancer staging manual.
        in: Amin Mahul B. Edge Stephen B. Gress Donna M. Meyer Laura R. American Joint committee on cancer. Springer, Chicago IL2017: 1024
        • Kaplan E.L.
        • Meier P.
        Nonparametric estimation from incomplete observations.
        J Am Stat Assoc. 1958; 53: 457-481
        • Sohn T.A.
        • Yeo C.J.
        • Cameron J.L.
        • Hruban R.H.
        • Fukushima N.
        • Campbell K.A.
        • et al.
        Intraductal papillary mucinous neoplasms of the pancreas: an updated experience.
        Ann Surg. 2004; 239 (; discussion 797-789): 788-797
        • Schnelldorfer T.
        • Sarr M.G.
        • Nagorney D.M.
        • Zhang L.
        • Smyrk T.C.
        • Qin R.
        • et al.
        Experience with 208 resections for intraductal papillary mucinous neoplasm of the pancreas.
        Arch Surg. 2008; 143 (; discussion 646): 639-646
        • Matsuda R.
        • Miyasaka Y.
        • Ohishi Y.
        • Yamamoto T.
        • Saeki K.
        • Mochidome N.
        • et al.
        Concomitant intraductal papillary mucinous neoplasm in pancreatic ductal adenocarcinoma is an independent predictive factor for the occurrence of new cancer in the remnant pancreas.
        Ann Surg. 2020; 271: 941-948
        • Noe M.
        • Niknafs N.
        • Fischer C.G.
        • Hackeng W.M.
        • Beleva Guthrie V.
        • Hosoda W.
        • et al.
        Genomic characterization of malignant progression in neoplastic pancreatic cysts.
        Nat Commun. 2020; 11: 4085
        • Adsay V.
        • Mino-Kenudson M.
        • Furukawa T.
        • Basturk O.
        • Zamboni G.
        • Marchegiani G.
        • et al.
        Pathologic evaluation and reporting of intraductal papillary mucinous neoplasms of the pancreas and other tumoral intraepithelial neoplasms of pancreatobiliary tract: recommendations of verona consensus meeting.
        Ann Surg. 2016; 263: 162-177
        • Matthaei H.
        • Hong S.M.
        • Mayo S.C.
        • dal Molin M.
        • Olino K.
        • Venkat R.
        • et al.
        Presence of pancreatic intraepithelial neoplasia in the pancreatic transection margin does not influence outcome in patients with R0 resected pancreatic cancer.
        Ann Surg Oncol. 2011; 18: 3493-3499
        • Partelli S.
        • Fernandez-Del Castillo C.
        • Bassi C.
        • Mantovani W.
        • Thayer S.P.
        • Crippa S.
        • et al.
        Invasive intraductal papillary mucinous carcinomas of the pancreas: predictors of survival and the role of lymph node ratio.
        Ann Surg. 2010; 251: 477-482
        • Kang M.J.
        • Lee K.B.
        • Jang J.Y.
        • Kwon W.
        • Park J.W.
        • Chang Y.R.
        • et al.
        Disease spectrum of intraductal papillary mucinous neoplasm with an associated invasive carcinoma invasive IPMN versus pancreatic ductal adenocarcinoma-associated IPMN.
        Pancreas. 2013; 42: 1267-1274
        • Winter J.M.
        • Jiang W.
        • Basturk O.
        • Mino-Kenudson M.
        • Fong Z.V.
        • Tan W.P.
        • et al.
        Recurrence and survival after resection of small intraductal papillary mucinous neoplasm-associated carcinomas (</=20-mm invasive component): a multi-institutional analysis.
        Ann Surg. 2016; 263: 793-801
        • Izawa T.
        • Obara T.
        • Tanno S.
        • Mizukami Y.
        • Yanagawa N.
        • Kohgo Y.
        Clonality and field cancerization in intraductal papillary-mucinous tumors of the pancreas.
        Cancer. 2001; 92: 1807-1817
        • Felsenstein M.
        • Noe M.
        • Masica D.L.
        • Hosoda W.
        • Chianchiano P.
        • Fischer C.G.
        • et al.
        IPMNs with co-occurring invasive cancers: neighbours but not always relatives.
        Gut. 2018; 67: 1652-1662
        • Strobel O.
        • Hartwig W.
        • Hackert T.
        • Hinz U.
        • Berens V.
        • Grenacher L.
        • et al.
        Re-resection for isolated local recurrence of pancreatic cancer is feasible, safe, and associated with encouraging survival.
        Ann Surg Oncol. 2013; 20: 964-972
        • Hirono S.
        • Shimizu Y.
        • Ohtsuka T.
        • Kin T.
        • Hara K.
        • Kanno A.
        • et al.
        Recurrence patterns after surgical resection of intraductal papillary mucinous neoplasm (IPMN) of the pancreas; a multicenter, retrospective study of 1074 IPMN patients by the Japan Pancreas Society.
        J Gastroenterol. 2020; 55: 86-99
        • Hirono S.
        • Kawai M.
        • Okada K.
        • Miyazawa M.
        • Shimizu A.
        • Kitahata Y.
        • et al.
        Long-term surveillance is necessary after operative resection for intraductal papillary mucinous neoplasm of the pancreas.
        Surgery. 2016; 160: 306-317
        • Seufferlein T.
        • Porzner M.
        • Becker T.
        • Budach V.
        • Ceyhan G.
        • Esposito I.
        • et al.
        [S3-guideline exocrine pancreatic cancer].
        Z Gastroenterol. 2013; 51: 1395-1440
        • He J.
        • Cameron J.L.
        • Ahuja N.
        • Makary M.A.
        • Hirose K.
        • Choti M.A.
        • et al.
        Is it necessary to follow patients after resection of a benign pancreatic intraductal papillary mucinous neoplasm?.
        J Am Coll Surg. 2013; 216 (discussion 665-657): 657-665