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Pathology reporting of pancreatic cancer following neoadjuvant therapy: Challenges and uncertainties

  • C. Verbeke
    Correspondence
    Corresponding author at: Division of Pathology, Department of Laboratory Medicine, Karolinska Institute, Hälsovägen, 141 86 Stockholm, Sweden. Tel.: +46 8585 81089; fax: +46 8585 81005.
    Affiliations
    Division of Pathology, Department of Laboratory Medicine, Karolinska Institute, Hälsovägen, 141 86 Stockholm, Sweden

    Department of Pathology & Cytology, Karolinska University Hospital, Hälsovägen, 141 86 Stockholm, Sweden
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  • Author Footnotes
    1 Tel.: +46 8585 89591.
    M. Löhr
    Footnotes
    1 Tel.: +46 8585 89591.
    Affiliations
    Gastrocentrum, Karolinska Institute, Hälsovägen, 141 86 Stockholm, Sweden
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  • Author Footnotes
    2 Tel.: +46 8585 84721.
    J. Severin Karlsson
    Footnotes
    2 Tel.: +46 8585 84721.
    Affiliations
    Department of Pathology & Cytology, Karolinska University Hospital, Hälsovägen, 141 86 Stockholm, Sweden
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  • Author Footnotes
    3 Tel.: +46 8585 80000.
    M. Del Chiaro
    Footnotes
    3 Tel.: +46 8585 80000.
    Affiliations
    Division of Surgery, Department of Clinical Science, Intervention and Technology (CLINTEC), Karolinska Institute, Hälsovägen, 141 86 Stockholm, Sweden
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  • Author Footnotes
    1 Tel.: +46 8585 89591.
    2 Tel.: +46 8585 84721.
    3 Tel.: +46 8585 80000.
Published:November 15, 2014DOI:https://doi.org/10.1016/j.ctrv.2014.11.002

      Highlights

      • Key outcome measures for neoadjuvant treatment (NAT) of pancreatic cancer (PC) are pathology-based.
      • Pathology examination of PC following NAT is difficult and lacks consensus.
      • Variation in sampling and regression grading affects the assessment of tumour response.
      • Margin assessment following NAT lacks an evidence-based definition.
      • Lack of uniformity in pathology assessment hampers the study of the efficacy of NAT of PC.

      Abstract

      An increasing number of studies investigate the use of neoadjuvant treatment for ductal adenocarcinoma of the pancreas. While a strong rationale supports this approach, study results are difficult to interpret and compare due to marked variance in multiple aspects of study design and performance. Divergence in pathology examination and reporting as a cause for heterogeneity and incomparability of study results has not been brought into this discussion yet, despite the fact that several key outcome measures for neoadjuvant treatment are pathology-based. This article discusses areas of controversy and difficulty regarding the evaluation of the extent of residual tumour tissue, grading of tumour regression and assessment of the margins, and explains the important clinical implications of the present uncertainty and divergence in pathology practice.

      Keywords

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      References

        • Siegel R.
        • Naishadham D.
        • Jemal A.
        Cancer statistics, 2013.
        CA Cancer J Clin. 2013; 63: 11-30
        • Yachida S.
        • Jones S.
        • Bozic I.
        • Antal T.
        • Leary R.
        • Fu B.
        • et al.
        Distant metastasis occurs late during the genetic evolution of pancreatic cancer.
        Nature. 2010; 467: 1114-1117
        • Alexakis N.
        • Halloran C.
        • Raraty M.
        • Ghaneh P.
        • Sutton R.
        • Neoptolemos J.P.
        Current standards of surgery for pancreatic cancer.
        Br J Surg. 2004; 91: 1410-1427
        • Hidalgo M.
        Pancreatic cancer.
        N Engl J Med. 2010; 362: 1605-1617
        • Crane C.H.
        • Varadhachary G.
        • Wolff R.A.
        • Pisters P.W.
        • Evans D.B.
        The argument for pre-operative chemoradiation for localized, radiographically resectable pancreatic cancer.
        Best Pract Res Clin Gastroenterol. 2006; 20: 365-382
        • Gillen S.
        • Schuster T.
        • Meyer zum Büschenfelde C.
        • Friess H.
        • Kleeff J.
        Preoperative/neoadjuvant therapy in pancreatic cancer: a systematic review and meta-analysis of response and resection percentages.
        PLoS Med. 2010; 7: e1000267
        • Belli C.
        • Cereda S.
        • Anand S.
        • Reni M.
        Neoadjuvant therapy in resectable pancreatic cancer: a critical review.
        Cancer Treat Rev. 2013; 39: 518-524
        • Morganti A.G.
        • Massaccesi M.
        • La Torre G.
        • Caravatta L.
        • Piscopo A.
        • Tambaro R.
        • et al.
        A systematic review of resectability and survival after concurrent chemoradiation in primarily unresectable pancreatic cancer.
        Ann Surg Oncol. 2010; 17: 194-205
        • Katz M.H.
        • Pisters P.W.
        • Lee J.E.
        • Fleming J.B.
        Borderline resectable pancreatic cancer: what have we learned and where do we go from here?.
        Ann Surg Oncol. 2011; 18: 608-610
        • 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
        • Katz M.H.
        • Marsh R.
        • Herman J.M.
        • Shi Q.
        • Collison E.
        • Venook A.P.
        • et al.
        Borderline resectable pancreatic cancer: need for standardization and methods for optimal clinical trial design.
        Ann Surg Oncol. 2013; 20: 2787-2795
        • Royal College of Pathologists
        Standards and datasets for reporting cancers. 3rd ed. Dataset for colorectal cancer histopathology reports. Royal College of Pathologists, London2014
        • Van de Velde C.J.
        • Boelens P.G.
        • Borras J.M.
        • Coebergh J.W.
        • Cervantes A.
        • Blomqvist L.
        • et al.
        EURECCA colorectal: multidisciplinary management: European consensus conference colon & rectum.
        Eur J Cancer. 2014; 50 (e1-1.e34): 1
        • Quirke P.
        • Palmer T.
        • Hutchins G.G.A.
        • West N.P.
        Histopathological work-up of resection specimens, local excisions and biopsies in colorectal cancer.
        Dig Dis. 2012; 30: 2-8
        • Thies S.
        • Langer R.
        Tumor regression grading of gastrointestinal carcinomas after neoadjuvant treatment.
        Front Oncol. 2013; 3: 262
        • 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
        • Kang C.M.
        • Chung Y.E.
        • Park J.Y.
        • Sung J.S.
        • Hwang H.K.
        • Choi H.J.
        • et al.
        Potential contribution of preoperative neoadjuvant concurrent chemoradiation therapy on margin-negative resection in borderline resectable pancreatic cancer.
        J Gastrointest Surg. 2012; 16: 509-517
        • 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
        • Katz M.H.
        • Fleming J.B.
        • Bhosale P.
        • Varadhachary G.
        • Lee J.E.
        • Wolff R.
        • et al.
        Response of borderline resectable pancreatic cancer to neoadjuvant therapy is not reflected by radiographic indicators.
        Cancer. 2012; 118: 5749-5756
        • Chatterjee D.
        • Katz M.H.
        • Rashid A.
        • Estrella J.S.
        • Wang H.
        • Varadhachary G.R.
        • et al.
        Pancreatic intraepithelial neoplasia and histological changes in non-neoplastic pancreas associated with neoadjuvant therapy in patients with pancreatic ductal adenocarcinoma.
        Histopathology. 2013; 63: 841-851
        • Ishikawa O.
        • Ohhigashi H.
        • Teshima T.
        • Chatani M.
        • Inoue T.
        • Tanaka S.
        • et al.
        Clinical and histopathological appraisal of preoperative irradiation for adenocarcinoma of the pancreatoduodenal region.
        J Surg Oncol. 1989; 40: 143-151
        • Chatterjee D.
        • Katz M.H.
        • Rashid A.
        • Varadhachary G.R.
        • Wolff R.A.
        • Wang H.
        • et al.
        Histologic grading of the extent of residual carcinoma following neoadjuvant chemoradiation in pancreatic ductal adenocarcinoma: a predictor for patient outcome.
        Cancer. 2012; 118: 3182-3190
        • Le Scodan R.
        • Mornex F.
        • Partensky C.
        • Mercier C.
        • Valette P.J.
        • Ychou M.
        • et al.
        Histopathological response to preoperative chemoradiation for resectable pancreatic adenocarcinoma: the French Phase II FFCD 9704-SFRO Trial.
        Am J Clin Oncol. 2008; 31: 545-552
        • Chun Y.S.
        • Cooper H.S.
        • Cohen S.J.
        • Konski A.
        • Burtness B.
        • Denlinger C.S.
        • et al.
        Significance of pathologic response to preoperative therapy in pancreatic cancer.
        Ann Surg Oncol. 2011; 18: 3601-3607
        • Heinrich S.
        • Schäfer M.
        • Weber A.
        • Hany T.F.
        • Bhure U.
        • Pestalozzi B.C.
        • et al.
        Neoadjuvant chemotherapy generates a significant tumor response in resectable pancreatic cancer without increasing morbidity: results of a prospective phase II trial.
        Ann Surg. 2008; 248: 1014-1022
        • Heinrich S.
        • Pestalozzi B.C.
        • Schäfer M.
        • Weber A.
        • Bauerfeind P.
        • Knuth A.
        • et al.
        Prospective phase II trial of neoadjuvant chemotherapy with gemcitabine and cisplatin for resectable adenocarcinoma of the pancreatic head.
        J Clin Oncol. 2008; 26: 2526-2531
        • Turrini O.
        • Viret F.
        • Moureau-Zabotto L.
        • Guiramand J.
        • Moutardier V.
        • Lelong B.
        • et al.
        Neoadjuvant chemoradiation and pancreaticoduodenectomy for initially locally advanced head pancreatic adenocarcinoma.
        Eur J Surg Oncol. 2009; 35: 1306-1311
        • Ishikawa O.
        • Ohhigashi H.
        • Sasaki Y.
        • Imaoka S.
        • Iwanaga T.
        • Teshima T.
        • et al.
        The histopathological effect of preoperative irradiation in adenocarcinoma of the periampullary region.
        Nihon Gan Chiryo Gakkai Shi. 1988; 23: 720-727
        • Evans D.B.
        • Rich T.A.
        • Byrd D.R.
        • Cleary K.R.
        • Connelly J.H.
        • Levin B.
        • et al.
        Preoperative chemoradiation and pancreaticoduodenectomy for adenocarcinoma of the pancreas.
        Arch Surg. 1992; 127: 1335-1339
        • White R.R.
        • Xie H.B.
        • Gottfried M.R.
        • Czito B.G.
        • Hurwitz H.I.
        • Morse M.A.
        • et al.
        Significance of histological response to preoperative chemoradiotherapy for pancreatic cancer.
        Ann Surg Oncol. 2005; 12: 214-221
      1. Washington K, Berlin J, Branton P, Burgart LJ, Carter DK, Compton CC et al. Protocol for the examination of specimens from patients with carcinoma of the exocrine pancreas. College of American Pathologists (2013 Oct 1). Available from: www.cap.org.

        • Verbeke C.S.
        • Knapp J.
        • Gladhaug I.P.
        Tumour growth is more dispersed in pancreatic head cancers than in rectal cancer: implications for resection margin assessment.
        Histopathology. 2011; 59: 1111-1121
        • Fareed K.R.
        • Ilyas M.
        • Kaye P.V.
        • Soomro I.N.
        • Lobo D.N.
        • Parsons S.L.
        • et al.
        Tumour regression grade (TRG) analyses in patients with resectable gastro-oesophageal adenocarcinomas treated with platinum-based neoadjuvant chemotherapy.
        Histopathology. 2009; 55: 399-406
        • Verbeke C.
        • Sheridan M.
        • Scarsbrook A.
        • Albazaz R.
        • Smith A.
        • Menon K.
        • et al.
        How accurate is size assessment of pancreatic head cancers by radiology and pathology?.
        Pancreatology. 2010; 10: 300
        • Chetty R.
        • Gill P.
        • Govender D.
        • Bateman A.
        • Chang H.J.
        • Driman D.
        • et al.
        A multi-centre pathologist survey on pathological processing and regression grading of colorectal cancer resection specimens treated by neoadjuvant chemoradiation.
        Virchows Arch. 2012; 460: 151-155
        • Lindebjerg J.
        • Hansborg N.
        • Ploen J.
        • Rafaelsen S.
        • Jorgensen J.C.
        • Jakobsen A.
        Factors influencing reproducibility of tumour regression grading after high-dose chemoradiation of locally advanced rectal cancer.
        Histopathology. 2011; 59: 18-21
        • Bateman A.C.
        • Jaynes E.
        • Bateman A.R.
        Rectal cancer staging post neoadjuvant therapy – how should the changes be assessed?.
        Histopathology. 2009; 54: 713-721
        • Verbeke C.S.
        Resection margins in pancreatic cancer.
        Surg Clin North Am. 2013; 93: 647-662
        • Adam I.J.
        • Mohamdee M.O.
        • Martin I.G.
        • Scott N.
        • Finan P.J.
        • Johnston D.
        • et al.
        Role of circumferential margin involvement in the local recurrence of rectal cancer.
        Lancet. 1994; 344: 707-711
        • Wibe A.
        • Rendedal P.R.
        • Svensson E.
        • Norstein J.
        • Eide T.J.
        • Myrvold H.E.
        • et al.
        Prognostic significance of the circumferential resection margin following total mesorectal excision for rectal cancer.
        Br J Surg. 2002; 89: 327-334
        • Campbell F.
        • Smith R.A.
        • Whelan P.
        • Sutton R.
        • Raraty M.
        • Neoptolemos J.P.
        • 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
        • Chang D.K.
        • Johns A.L.
        • Merrett N.D.
        • Gill A.J.
        • Colvin E.K.
        • Scarlett C.J.
        • et al.
        Margin clearance and outcome in resected pancreatic cancer.
        J Clin Oncol. 2009; 27: 2855-2862
        • Delpero J.R.
        • Bachellier P.
        • Regenet N.
        • Le Treut Y.P.
        • Paye F.
        • Carrere N.
        • et al.
        Pancreaticoduodenectomy for pancreatic ductal adenocarcinoma: a French multicentre prospective evaluation of resection margins in 150 evaluable specimens.
        HPB (Oxford). 2014; 16: 20-33
        • Katz M.H.
        • Wang H.
        • Balachandran A.
        • Bhosale P.
        • Crane C.H.
        • Wang X.
        • et al.
        Effect of neoadjuvant chemoradiation and surgical technique on recurrence of localized pancreatic cancer.
        J Gastrointest Surg. 2012; 16: 68-78
        • Evans D.B.
        • Varadhachary G.R.
        • Crane C.H.
        • Sun C.C.
        • Lee J.E.
        • Pisters P.W.
        • et al.
        Preoperative gemcitabine-based chemoradiation for patients with resectable adenocarcinoma of the pancreatic head.
        J Clin Oncol. 2008; 26: 3496-3502
        • Turrini O.
        • Ychou M.
        • Moureau-Zabotto L.
        • Rouanet P.
        • Giovannini M.
        • Moutardier V.
        • et al.
        Neoadjuvant docetaxel-based chemoradiation for resectable adenocarcinoma of the pancreas: new neoadjuvant regimen was safe and provided an interesting pathologic response.
        Eur J Surg Oncol. 2010; 36: 987-992
        • Wilkowski R.
        • Thoma M.
        • Schauer R.
        • Wagner A.
        • Heinemann V.
        Effect of chemoradiotherapy with gemcitabine and cisplatin on locoregional control in patients with primary inoperable pancreatic cancer.
        World J Surg. 2004; 28: 1011-1018
        • Zhao Q.
        • Rashid A.
        • Gong Y.
        • Katz M.H.
        • Lee J.E.
        • 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
        • Calvo F.A.
        • Matute R.
        • García-Sabrido J.L.
        • Gómez-Espí M.
        • Martínez N.E.
        • Lozano M.A.
        • et al.
        Neoadjuvant chemoradiation with tegafur in cancer of the pancreas: initial analysis of clinical tolerance and outcome.
        Am J Clin Oncol. 2004; 27: 343-349
        • Desai S.P.
        • Ben-Josef E.
        • Normolle D.P.
        • Francis I.R.
        • Greenson J.K.
        • Simeone D.M.
        • et al.
        Phase I study of oxaliplatin, full-dose gemcitabine, and concurrent radiation therapy in pancreatic cancer.
        J Clin Oncol. 2007; 25: 4587-4592
        • Kopelson G.
        Curative surgery for adenocarcinoma of the pancreas/ampulla of Vater: the role of adjuvant pre or postoperative radiation therapy.
        Int J Radiat Oncol Biol Phys. 1983; 9: 911-915
        • Estrella J.S.
        • Rashid A.
        • Fleming J.B.
        • Katz M.H.
        • Lee J.E.
        • Wolf R.A.
        • et al.
        Post-therapy pathologic stage and survival in patients with pancreatic ductal adenocarcinoma treated with neoadjuvant chemoradiation.
        Cancer. 2012; 118: 268-277
        • Chatterjee D.
        • Rashid A.
        • Wang H.
        • Katz M.H.
        • Wolff R.A.
        • Varadhachary G.R.
        • et al.
        Tumor invasion of muscular vessels predicts poor prognosis in patients with pancreatic ductal adenocarcinoma who have received neoadjuvant therapy and pancreaticoduodenectomy.
        Am J Surg Pathol. 2012; 36: 552-559
        • Varadhachary G.R.
        • Wolff R.A.
        • Crane C.H.
        • Sun C.C.
        • Lee J.E.
        • Pisters P.W.
        • et al.
        Preoperative gemcitabine and cisplatin followed by gemcitabine-based chemoradiation for resectable adenocarcinoma of the pancreatic head.
        J Clin Oncol. 2008; 26: 3487-3495
        • Chun Y.S.
        • Milestone B.N.
        • Watson J.C.
        • Cohen S.J.
        • Burtness B.
        • Engstrom P.F.
        • et al.
        Defining venous involvement in borderline resectable pancreatic cancer.
        Ann Surg Oncol. 2010; 17: 2832-2838
        • Katz M.H.
        • Pisters P.W.
        • Evans D.B.
        • Sun C.C.
        • Lee J.E.
        • Fleming J.B.
        • et al.
        Borderline resectable pancreatic cancer: the importance of this emerging stage of disease.
        J Am Coll Surg. 2008; 206: 833-846
        • Murata Y.
        • Mizuno S.
        • Kishiwada M.
        • Hamada T.
        • Usui M.
        • Sakurai H.
        • et al.
        Impact of histological response after neoadjuvant chemoradiotherapy on recurrence-free survival in UICC-T3 pancreatic adenocarcinoma but not in UICC-T4.
        Pancreas. 2012; 41: 130-136
        • Therasse P.
        • Arbuck S.G.
        • Eisenhauer E.A.
        • Wanders J.
        • Kaplan R.S.
        • Rubinstein L.
        • et al.
        New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada.
        J Natl Cancer Inst. 2000; 92: 205-216
        • Stokes J.B.
        • Nolan N.J.
        • Stelow E.B.
        • Walters D.M.
        • Weiss G.R.
        • de Lange E.E.
        • et al.
        Preoperative capecitabine and concurrent radiation for borderline resectable pancreatic cancer.
        Ann Surg Oncol. 2011; 18: 619-627
        • Dudeja V.
        • Greeno E.W.
        • Walker S.P.
        • Jensen E.H.
        Neoadjuvant chemoradiotherapy for locally advanced pancreas cancer rarely leads to radiological evidence of tumour regression.
        HPB (Oxford). 2013; 15: 661-667
        • Arvold N.D.
        • Ryan D.P.
        • Niemierko A.
        • Blaszkowsky L.S.
        • Kwak E.L.
        • Wo J.Y.
        • et al.
        Long-term outcomes of neoadjuvant chemotherapy before chemoradiation for locally advanced pancreatic cancer.
        Cancer. 2012; 118: 3026-3035
        • Duldulao M.P.
        • Lee W.
        • Streja L.
        • Chu P.
        • Li W.
        • Chen Z.
        • et al.
        Distribution of residual cancer cells in the bowel wall after neoadjuvant chemoradiation in patients with rectal cancer.
        Dis Colon Rectum. 2013; 56: 142-149
        • Blaauwgeers J.L.
        • Kappers I.
        • Klomp H.M.
        • Belderbos J.S.
        • Dijksman L.M.
        • Smit E.F.
        • et al.
        Complete pathological response is predictive for clinical outcome after tri-modality therapy for carcinomas of the superior pulmonary sulcus.
        Virchows Arch. 2013; 462: 547-556
        • Nakamura T.
        • Kuwai T.
        • Kitadai Y.
        • Sasaki T.
        • Fan D.
        • Coombes K.R.
        • et al.
        Zonal heterogeneity for gene expression in human pancreatic carcinoma.
        Cancer Res. 2007; 67: 7597-7604
        • Niedergethmann M.
        • Alves F.
        • Neff J.K.
        • Heidrich B.
        • Aramin N.
        • Li L.
        • et al.
        Gene expression profiling of liver metastases and tumour invasion in pancreatic cancer using an orthotopic SCID mouse model.
        Br J Cancer. 2007; 97: 1432-1440
        • Kim H.J.
        • Czischke K.
        • Brennan M.F.
        • Conlon K.C.
        Does neoadjuvant chemoradiation downstage locally advanced pancreatic cancer?.
        J Gastrointest Surg. 2002; 6: 763-769
        • Verbeke C.S.
        • Gladhaug I.P.
        Resection margin involvement and tumour origin in pancreatic head cancer.
        Br J Surg. 2012; 99: 1036-1049
        • Wanebo H.J.
        • Glicksman A.S.
        • Vezeridis M.P.
        • Clark J.
        • Tibbetts L.
        • Koness R.J.
        • et al.
        Preoperative chemotherapy, radiotherapy, and surgical resection of locally advanced pancreatic cancer.
        Arch Surg. 2000; 135: 81-87
        • Brunner T.B.
        • Grabenbauer G.G.
        • Kastl S.
        • Herrmann O.
        • Baum U.
        • Fietkau R.
        • et al.
        Preoperative chemoradiation in locally advanced pancreatic carcinoma: a phase II study.
        Onkologie. 2000; 23: 436-442
        • Snady H.
        • Bruckner H.
        • Cooperman A.
        • Paradiso J.
        • Kiefer L.
        Survival advantage of combined chemoradiotherapy compared with resection as the initial treatment of patients with regional pancreatic carcinoma. An outcomes trial.
        Cancer. 2000; 89: 314-327
        • Adhoute X.
        • Smith D.
        • Vendrely V.
        • Rault A.
        • Sa Cunha A.
        • Legoux J.L.
        • et al.
        Subsequent resection of locally advanced pancreatic carcinoma after chemoradiotherapy.
        Gastroenterol Clin Biol. 2006; 30: 224-230
        • Massucco P.
        • Capussotti L.
        • Magnino A.
        • Sperti E.
        • Gatti M.
        • Muratore A.
        • et al.
        Pancreatic resections after chemoradiotherapy for locally advanced ductal adenocarcinoma: analysis of perioperative outcome and survival.
        Ann Surg Oncol. 2006; 13: 1201-1208
        • Pomianowska E.
        • Clausen O.P.F.
        • Gladhaug I.P.
        Reclassification of tumour origin in resected periampullary adenocarcinomas reveals underestimation of distal bile duct cancer.
        Eur J Surg Oncol. 2012; 38: 1043-1050
        • Spitz F.R.
        • Abbruzzese Jl
        • Lee J.E.
        • Pisters P.W.T.
        • Lowy A.M.
        • et al.
        Preoperative and postoperative chemoradiation strategies in patients treated with pancreaticoduodenectomy for adenocarcinoma of the pancreas.
        J Clin Oncol. 1997; 15: 928-937
        • Albores Saavedra J.
        • Simpson K.
        • Dancer Y.J.
        • Hruban R.
        Intestinal type adenocarcinoma: a previously unrecognized histologic variant of ductal carcinoma of the pancreas.
        Ann Diagn Pathol. 2007; 11: 3-9
        • Westgaard A.
        • Tafjord S.
        • Farstad I.N.
        • Cvancarova M.
        • Eide T.J.
        • Mathisen O.
        • et al.
        Pancreatobiliary versus intestinal histologic type of differentiation is an independent prognostic factor in resected periampullary adenocarcinoma.
        BMC Cancer. 2008; 8: 170
        • Westgaard A.
        • Pomianowska E.
        • Clausen O.P.
        • Gladhaug I.P.
        Intestinal-type and pancreatobiliary-type adenocarcinomas: how does ampullary carcinoma differ from other periampullary malignancies?.
        Ann Surg Oncol. 2013; 20: 430-439
        • Bronsert P.
        • Kohler I.
        • Werner M.
        • Makowiec F.
        • Kuesters S.
        • Hoeppner J.
        • et al.
        Intestinal-type of differentiation predicts favourable overall survival: confirmatory clinicopathological analysis of 198 periampullary adenocarcinomas of pancreatic, biliary, ampullary and duodenal origin.
        BMC Cancer. 2013; 13: 428
        • De Jong M.C.
        • Tsai S.
        • Cameron J.L.
        • Wolfgang C.L.
        • Hirose K.
        • van Vledder M.G.
        • et al.
        Safety and efficacy of curative intent surgery for peri-ampullary liver metastasis.
        J Surg Oncol. 2010; 102: 256-263
        • Michalski C.W.
        • Erkan M.
        • Hüser N.
        • Müller M.W.
        • Hartel M.
        • Friess H.
        • et al.
        Resection of primary pancreatic cancer and liver metastasis: a systematic review.
        Dig Surg. 2008; 25: 473-480
        • Hruban R.H.
        • Boffetta P.
        • Hiraoka N.
        • Iacobuzio-Donahue C.
        • Kato Y.
        • Kern S.E.
        • et al.
        Ductal adenocarcinoma of the pancreas.
        in: Bosman F.T. Carneiro F. Hruban R.H. Theise N.D. WHO classification of tumors of the digestive system. IARC, Lyon2010: 280-295
        • Becker K.
        • Mueller J.D.
        • Schulmacher C.
        • Ott K.
        • Fink U.
        • Busch R.
        • et al.
        Histomorphology and grading of regression in gastric carcinoma treated with neoadjuvant chemotherapy.
        Cancer. 2003; 98: 1521-1530
        • Aktepe F.
        • Kapucuoglu N.
        • Pak I.
        The effects of chemotherapy on breast cancer tissue in locally advanced breast cancer.
        Histopathology. 1996; 29: 63-67
        • Artinyan A.
        • Anaya D.A.
        • McKenzie S.
        • Ellenhorn J.D.
        • Kim J.
        Neoadjuvant therapy is associated with improved survival in resectable pancreatic adenocarcinoma.
        Cancer. 2011; 117: 2044-2049
        • Barbier L.
        • Turrini O.
        • Grégoire E.
        • Viret F.
        • Le Treut Y.P.
        • Delpero J.R.
        Pancreatic head resectable adenocarcinoma: preoperative chemoradiation improves local control but does not affect survival.
        HPB (Oxford). 2011; 13: 64-69
        • Bollschweiler E.
        • Hölscher A.H.
        • Metzger R.
        • Besch S.
        • Mönig S.P.
        • Baldus S.E.
        • et al.
        Prognostic significance of a new grading system of lymph node morphology after neoadjuvant radiochemotherapy for esophageal cancer.
        Ann Thorac Surg. 2011; 92: 2020-2027
        • Caricato M.
        • Ausania F.
        • De Dominicis E.
        • Vincenzi B.
        • Rabitti C.
        • Tonini G.
        • et al.
        Tumor regression in mesorectal lymphnodes after neoadjuvant chemoradiation for rectal cancer.
        Eur J Surg Oncol. 2007; 33: 724-728
        • Newman L.A.
        • Pernick N.L.
        • Adsay V.
        • Carolin K.A.
        • Philip P.A.
        • Sipierski S.
        • et al.
        Histopathologic evidence of tumor regression in the axillary lymph nodes of patients treated with preoperative chemotherapy correlates with breast cancer outcome.
        Ann Surg Oncol. 2003; 10: 734-739
        • Mirbagheri N.
        • Kumar B.
        • Deb S.
        • Poh B.R.
        • Dark J.G.
        • Leow C.C.
        • et al.
        Lymph node status as a prognostic indicator after preoperative neoadjuvant chemoradiotherapy of rectal cancer.
        Colorectal Dis. 2014; ([Epub ahead of print])https://doi.org/10.1111/codi.1268
        • Chatterjee D.
        • Katz M.H.
        • Rashid A.
        • Wang H.
        • Iuga A.C.
        • Varadhachary G.R.
        • et al.
        Perineural and intraneural invasion in posttherapy pancreaticoduodenectomy specimens predicts poor prognosis in patients with pancreatic ductal adenocarcinoma.
        Am J Surg Pathol. 2012; 36: 409-417
        • Yoshioka T.
        • Hosoda M.
        • Yamamoto M.
        • Taguchi K.
        • Hatanaka K.C.
        • Takakuwa E.
        • et al.
        Prognostic significance of pathologic complete response and Ki67 expression after neoadjuvant chemotherapy in breast cancer.
        Breast Cancer. 2013; ([Published Online First])https://doi.org/10.1007/s12282-013-0474-2
        • Von Minckwitz G.
        • Schmitt W.D.
        • Loibl S.
        • Müller B.M.
        • Blohmer J.U.
        • Sinn B.V.
        • et al.
        Ki67 measured after neoadjuvant chemotherapy for primary breast cancer.
        Clin Cancer Res. 2013; 19: 4521-4531
        • Crane C.H.
        Is personalization of care coming to pancreatic oncology?.
        Ann Surg Oncol. 2013; 20: 355-356
        • Wei C.H.
        • Gorgan T.R.
        • Elashoff D.A.
        • Hines O.J.
        • Farrell J.J.
        • Donahue T.R.
        A meta-analysis of gemcitabine biomarkers in patients with pancreaticobiliary cancers.
        Pancreas. 2013; 42: 1303-1310
        • Saif M.W.
        • Lee Y.
        • Kim R.
        Harnessing gemcitabine metabolism: a step towards personalized medicine for pancreatic cancer.
        Ther Adv Med Oncol. 2012; 4: 341-346
        • Bhutani M.S.
        The year of improved tissue acquisition, randomized trials, and endoscopic ultrasound-guided therapy.
        Endoscopy. 2011; 43: 993-999
      2. Standards and datasets for reporting cancer. Dataset for the histopathological reporting of carcinomas of the pancreas, ampulla of Vater and common bile duct. 2nd ed. London: The Royal College of Pathologists; 2010.

      3. Björnstedt M, Franzén L, Glaumann H, Nordlinder H, Palmqvist R, Rissler P et al. Gastrointestinal pathology – pancreas and peri-ampullary region. Recommendations from the KVAST Study Group of the Swedish Society for Pathology (2012). Available from: <http://svfp.se/files/docs/kvast/leverpatologi/Pankreas%20dok%202012.doc> [accessed 21.08.14].

        • Royal College of Pathologists of Australasia
        Cancer of the exocrine pancreas, ampulla of Vater and distal common bile duct, structured reporting protocol.
        1st ed. Springer, NY2014 (Available from: http://www.rcpa.edu.au/Library/Practising-Pathology/Structured-Pathology-Reporting-of-Cancer/Cancer-Protocols (accessed 2014 Aug 21))
        • Campbell F.
        • Verbeke C.S.
        Pathology of the pancreas – a practical approach.
        Springer Verlag, London2013 ([p. 27–43, 146–151])