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Hilmi M, Delecourt F, Raffenne J, Bourega T, Dusetti N, Iovanna J, Blum Y, Richard M, Neuzillet C, Couvelard A, Tihy M, de Mestier L, Rebours V, Nicolle R, Cros J. Redefining phenotypic intratumor heterogeneity of pancreatic ductal adenocarcinoma: a bottom-up approach. J Pathol 2025; 265:448-461. [PMID: 39935174 PMCID: PMC11880971 DOI: 10.1002/path.6398] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2024] [Revised: 11/22/2024] [Accepted: 12/19/2024] [Indexed: 02/13/2025]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) tumor interpatient heterogeneity has been well described with two major prognostic subtypes (classical and basal-like). An important intrapatient heterogeneity has been reported but has not yet been studied extensively due to the lack of standardized, reproducible, and easily accessible high-throughput methods. We built an immunohistochemical (IHC) tool capable of differentiating RNA-defined classical and basal-like tumors by selecting relevant antibodies using a multistep process. The successive stages of (i) an in silico selection from a literature review and a bulk transcriptome analysis of 309 PDACs, (ii) a tumor-specific selection from 30 patient-derived xenografts and single-cell data, followed by (iii) the validation on tissue microarrays in 50 PDAC were conducted. We used our final IHC panel on two independent cohorts of resected PDAC (n = 95, whole-slide, n = 148, tissue microarrays) for external validation. After digitization and registration of pathology slides, we performed a tile-based analysis in tumor areas to identify relevant marker combinations. Sequential marker selection led to the following panel: GATA6, CLDN18, TFF1, MUC16, S100A2, KRT17, PanBasal. Four different phenotypes were identified: one classical, one intermediate (KRT17+), and two basal-like (MUC16+ versus S100A2+) with specific biological properties. The presence of a minor basal contingent drastically reduced overall survival [hazard ratio (HR) = 1.90, p = 0.03], even in classical predominant PDACs. Analysis of preneoplastic lesions suggested that pancreatic carcinogenesis might follow a progressive evolution from classical toward a basal through an early intermediate phenotype. In conclusion, our IHC panel redefined and easily assessed the high degree of intra- and intertumoral heterogeneity of PDAC. © 2025 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
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Affiliation(s)
- Marc Hilmi
- Molecular Oncology Team, UMR 144Institut CurieParisFrance
- Medical Oncology DepartmentInstitut CurieSaint‐CloudFrance
| | - Flore Delecourt
- Pathology Department, APHP Nord, FHU MOSAICBeaujon HospitalClichyFrance
| | | | - Taib Bourega
- Centre de Recherche sur l'Inflammation (CRI), INSERM, U1149, CNRS, ERL 8252Université Paris CitéParisFrance
| | - Nelson Dusetti
- Centre de Recherche en Cancérologie de Marseille (CRCM), INSERM U1068, CNRS UMR 7258, Parc Scientifique et Technologique de LuminyAix‐Marseille Université and Institut Paoli‐CalmettesMarseilleFrance
| | - Juan Iovanna
- Centre de Recherche en Cancérologie de Marseille (CRCM), INSERM U1068, CNRS UMR 7258, Parc Scientifique et Technologique de LuminyAix‐Marseille Université and Institut Paoli‐CalmettesMarseilleFrance
| | - Yuna Blum
- Univ Rennes, CNRS, INSERM, IGDR (Institut de Génétique et Développement de Rennes) – UMR 6290, ERL U1305RennesFrance
| | - Magali Richard
- Université Grenoble Alpes, CNRS, UMR 5525, VetAgro Sup, Grenoble INP, TIMCGrenobleFrance
| | - Cindy Neuzillet
- Molecular Oncology Team, UMR 144Institut CurieParisFrance
- Medical Oncology DepartmentInstitut CurieSaint‐CloudFrance
| | - Anne Couvelard
- Centre de Recherche sur l'Inflammation (CRI), INSERM, U1149, CNRS, ERL 8252Université Paris CitéParisFrance
- Pathology Department, APHP NordBichat HospitalParisFrance
| | - Matthieu Tihy
- Pathology Department, APHP NordBichat HospitalParisFrance
| | - Louis de Mestier
- Centre de Recherche sur l'Inflammation (CRI), INSERM, U1149, CNRS, ERL 8252Université Paris CitéParisFrance
- Department of Pancreatology and Digestive Oncology, APHP Nord, FHU MOSAICBeaujon HospitalClichyFrance
| | - Vinciane Rebours
- Centre de Recherche sur l'Inflammation (CRI), INSERM, U1149, CNRS, ERL 8252Université Paris CitéParisFrance
- Department of Pancreatology and Digestive Oncology, APHP Nord, FHU MOSAICBeaujon HospitalClichyFrance
| | - Rémy Nicolle
- Centre de Recherche sur l'Inflammation (CRI), INSERM, U1149, CNRS, ERL 8252Université Paris CitéParisFrance
| | - Jérôme Cros
- Pathology Department, APHP Nord, FHU MOSAICBeaujon HospitalClichyFrance
- Centre de Recherche sur l'Inflammation (CRI), INSERM, U1149, CNRS, ERL 8252Université Paris CitéParisFrance
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Xu Z, Theisen BK, Chang Q, Schultz D, Ahsan BU. Survival outcomes of poorly differentiated colorectal carcinoma variants: Insights from a single teaching institute. Hum Pathol 2024; 154:105710. [PMID: 39716575 DOI: 10.1016/j.humpath.2024.105710] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/11/2024] [Revised: 11/16/2024] [Accepted: 12/18/2024] [Indexed: 12/25/2024]
Abstract
The morphologic diagnosis of colorectal carcinoma (CRC) is typically straight forward. However, there are certain subtypes of CRC that pose diagnostic challenges for daily practice due to sometimes overlapping morphologic and immunohistochemical features. These subtypes include poorly differentiated adenocarcinoma NOS, in the absence of conventional morphology (PDA-NOS), large cell neuroendocrine carcinoma (LCNEC), medullary carcinoma (MC), undifferentiated carcinoma (UC) and lymphoepithelioma-like carcinoma (LELC). This study aims to see if there is a survival difference between poorly differentiated variants of CRC, as well as other clinicopathological features that may affect prognosis. Additionally, we analyzed interobserver agreement among gastrointestinal pathologists (GP) at our institution in subclassifying poorly differentiated CRC. All consecutive patients with the diagnoses of PDA-NOS, MC, LCNEC, UC and LELC between July 2018 and July 2023 were included. Cox proportional regression test was used for multivariate analysis, while log-rank and Kaplan-Meier tests were used for univariate and survival analyses. Out of the same cohort of patients, 58 samples identified and reviewed by 3 GI-subspecialty-trained pathologists who were asked to assign the cases as PDA-NOS, LCNEC, MC, UC and LELC. Interobserver agreement was analyzed using Fleiss Kappa. Of the total 77 patients, 63 were PDA-NOS, 3 were LCNEC, 6 were MC, 4 were UC and 1 was LELC patients. Multivariate analysis using Cox proportional regression showed that tumor size (p = 0.001, HR = 1.22, 95% CI 1.08-1.38), patient age (p = 0.001, HR 1.73, 95% CI 1.24-2.40), and M stage (p = 0.02, HR 2.22, 95% CI 1.14-4.32) were significantly associated with worse OS. For the 58 cases analyzed, 3 GP agreed on 42 (72%) cases. The most common diagnosis was PDA-NOS and for 33 (57%) agreement was unanimous. There was moderate agreement (k 0.41-0.60) between all 3 GP. Our study evaluated the challenges associated with histological evaluation of colon cancers with poorly differentiated morphologies. Among the diagnoses considered in the study, MC and LCNEC had different prognostic implications compared to PDA-NOS and UC. Additionally, our GP showed moderate interobserver agreement, indicating that some level of variability in diagnosing poorly differentiated CRC subtypes may be inevitable.
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Affiliation(s)
| | - Brian K Theisen
- Henry Ford Health, Detroit, MI, USA; Michigan State University College of Human Medicine, East Lansing, MI, USA
| | | | | | - Beena U Ahsan
- Henry Ford Health, Detroit, MI, USA; Michigan State University College of Human Medicine, East Lansing, MI, USA.
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Nozzoli F, Catalano M, Messerini L, Cianchi F, Nassini R, De Logu F, Iannone LF, Ugolini F, Simi S, Massi D, Geppetti P, Roviello G. Perineural invasion score system and clinical outcomes in resected pancreatic cancer patients. Pancreatology 2024; 24:553-561. [PMID: 38514359 DOI: 10.1016/j.pan.2024.03.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2024] [Revised: 02/21/2024] [Accepted: 03/06/2024] [Indexed: 03/23/2024]
Abstract
BACKGROUND/OBJECTIVES Perineural invasion (PNI), classified according to its presence or absence in tumor specimens, is recognized as a poor prognostic factor in pancreatic ductal adenocarcinoma (PDAC) patients. Herein, we identified five histological features of PNI and investigated their impact on survival outcomes of PDAC resected patients. METHODS Five histopathological features of PNI (diameter, number, site, sheath involvement, and mitotic figures within perineural invasion) were combined in an additional final score (ranging from 0 to 8), and clinical data of PDAC patients were retrospectively analyzed. PNI + patients were stratified in two categories according to the median score value (<6 and ≥ 6, respectively). Impact of PNI on disease-free survival (DFS) and overall survival (OS) were analyzed. RESULTS Forty-five patients were enrolled, of whom 34 with PNI (PNI+) and 11 without PNI (PNI-). The DFS was 11 months vs. not reached (NR) (p = 0.258), while the OS was 19 months vs. NR (p = 0.040) in PNI+ and PNI- patients, respectively. A ≥6 PNI was identified as an independent predictor of worse OS vs. <6 PNI + patients (29 vs. 11 months, p < 0.001) and <6 PNI+ and PNI- patients (43 vs. 11 months, p < 0.001). PNI ≥6 was an independent negative prognostic factor of DFS vs. <6 PNI+ and PNI- patients (13 vs. 6 months, p = 0.022). CONCLUSIONS We report a PNI scoring system that stratifies surgically-treated PDAC patients in a graded manner that correlates with patient prognosis better than the current dichotomous (presence/absence) definition. However, further and larger studies are needed to support this PNI scoring system.
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Affiliation(s)
- Filippo Nozzoli
- Section of Anatomic Pathology, Department of Health Sciences, University of Florence, Florence, Italy.
| | - Martina Catalano
- Section of Clinical Pharmacology & Oncology, Department of Health Sciences, University of Florence, Florence, Italy
| | - Luca Messerini
- Section of Anatomic Pathology, Department of Health Sciences, University of Florence, Florence, Italy
| | - Fabio Cianchi
- Section of Surgery, Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Romina Nassini
- Section of Clinical Pharmacology & Oncology, Department of Health Sciences, University of Florence, Florence, Italy
| | - Francesco De Logu
- Section of Clinical Pharmacology & Oncology, Department of Health Sciences, University of Florence, Florence, Italy
| | - Luigi Francesco Iannone
- Section of Clinical Pharmacology & Oncology, Department of Health Sciences, University of Florence, Florence, Italy
| | - Filippo Ugolini
- Section of Anatomic Pathology, Department of Health Sciences, University of Florence, Florence, Italy
| | - Sara Simi
- Section of Anatomic Pathology, Department of Health Sciences, University of Florence, Florence, Italy
| | - Daniela Massi
- Section of Anatomic Pathology, Department of Health Sciences, University of Florence, Florence, Italy
| | - Pierangelo Geppetti
- Section of Clinical Pharmacology & Oncology, Department of Health Sciences, University of Florence, Florence, Italy
| | - Giandomenico Roviello
- Section of Clinical Pharmacology & Oncology, Department of Health Sciences, University of Florence, Florence, Italy
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Mallik MK, Qadan LR, Mohanty AK, Alali A, Kapila K. Grading pancreatic adenocarcinomas on fine needle aspiration cytology. The outstanding issues. Cytopathology 2024; 35:256-265. [PMID: 38050715 DOI: 10.1111/cyt.13343] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2023] [Revised: 10/08/2023] [Accepted: 11/10/2023] [Indexed: 12/06/2023]
Abstract
OBJECTIVE The three-tier grading scheme described in "The Papanicolaou Society of Cytopathology (PSC) System for reporting Pancreaticobiliary Cytopathology" (TPSCRPBC) which remained unchanged following the WHO Reporting System for Pancreaticobiliary Cytopathology (WRPBC) was evaluated on pancreatic adenocarcinomas (PACs) reported on endoscopic ultrasound-guided fine needle aspiration cytology (EUS-FNAC). METHODS The Papanicolaou and May Grunwald Giemsa-stained smears from 116 cases of PACs were graded using the three-tier grading scheme laid down by TPSCRPBC/WRPBC. Cases exhibiting multiple grades were assigned primary, secondary and tertiary grades. Each case was assigned a grade score, either by adding the primary and secondary grades, by adding the primary and tertiary grades when the tertiary grade was 3 or by doubling the grade when only one grade existed. Necrosis was estimated semi-quantitatively. The inter-observer reproducibility in grading was evaluated using Kappa and Kendall's tau-c. Correlations between the various grades, the stage of the tumour and the amount of necrosis were assessed using Spearman rho and Kendall's tau-b. RESULTS 31.89% of cases showed one grade, and 68.11% showed at least two grades. 16.38% showed three grades. The two commonest grade scores were 3 and 5. The inter-observer reproducibility for grading and grade scoring was satisfactory. A positive correlation was noted between the grades and the amount of necrosis. No significant correlation was found between the grades, grade scores and the stage of the tumours. CONCLUSIONS The TPSCRPBC/WRPBC grading scheme can be suitably applied to PACs with good inter-observer reproducibility. Cases often show multiple grades in the same tumour.
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Affiliation(s)
- Mrinmay Kumar Mallik
- Cytopathology Unit, Department of Laboratory Medicine, Mubarak Al Kabeer Hospital, Safat, Kuwait
| | - Laila Rafiq Qadan
- Department of Medicine, Faculty of Medicine, Kuwait University, Safat, Kuwait
| | - Asit Kumar Mohanty
- Department of Medical Oncology, Kuwait Cancer Control Center, Shuwaikh, Kuwait
| | - Ali Alali
- Department of Gastroenterology and Hepatology, Mubarak Al Kabeer Hospital, Safat, Kuwait
| | - Kusum Kapila
- Department of Pathology, Faculty of Medicine, Kuwait University, Safat, Kuwait
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Verbeke C, Webster F, Brosens L, Campbell F, Del Chiaro M, Esposito I, Feakins RM, Fukushima N, Gill AJ, Kakar S, Kench JG, Krasinskas AM, van Laethem JL, Schaeffer DF, Washington K. Dataset for the reporting of carcinoma of the exocrine pancreas: recommendations from the International Collaboration on Cancer Reporting (ICCR). Histopathology 2021; 79:902-912. [PMID: 34379823 DOI: 10.1111/his.14540] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2021] [Revised: 08/04/2021] [Accepted: 08/08/2021] [Indexed: 11/29/2022]
Abstract
BACKGROUND AND OBJECTIVES Current guidelines for the pathology reporting on pancreatic cancer differ in certain aspects, resulting in divergent reporting practice and a lack of comparability of data. Here we report on a new international dataset for the pathology reporting of resection specimens with cancer of the exocrine pancreas (ductal adenocarcinoma and acinar cell carcinoma). The dataset was produced under the auspices of the International Collaboration on Cancer Reporting (ICCR), a global alliance of major (inter-)national pathology and cancer organisations. METHODS AND RESULTS According to the ICCR's rigorous process for dataset development, an international expert panel consisting of pancreatic pathologists, a pancreatic surgeon and an oncologist produced a set of core and non-core data items based on a critical review and discussion of current evidence. Commentary was provided for each data item to explain the rationale for selecting it as a core or non-core element, its clinical relevance, and to highlight potential areas of disagreement or lack of evidence, in which case a consensus position was formulated. Following international public consultation, the document was finalised and ratified, and the dataset, which includes a synoptic reporting guide, was published on the ICCR website. CONCLUSIONS This first international dataset for cancer of the exocrine pancreas is intended to promote high quality, standardised pathology reporting. Its widespread adoption will improve consistency of reporting, facilitate multidisciplinary communication and enhance comparability of data, all of which will help to improve the management of pancreatic cancer patients.
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Affiliation(s)
- Caroline Verbeke
- Department of Pathology, University of Oslo, Oslo University Hospital, Oslo, Norway
| | - Fleur Webster
- International Collaboration on Cancer Reporting, Sydney, Australia
| | - Lodewijk Brosens
- Department of Pathology, University Medical Centre Utrecht, Utrecht University, Utrecht, The Netherlands and Department of Pathology, Radboud University Medical Centre, Nijmegen, The Netherlands
| | - Fiona Campbell
- Department of Pathology, Royal Liverpool University Hospital, Liverpool, United Kingdom
| | - Marco Del Chiaro
- Department of Surgery, University of Colorado Denver - Anschutz Medical Campus, Aurora, 80045, Colorado, United States
| | - Irene Esposito
- Institute of Pathology, University Hospital Düsseldorf, Medical Faculty of Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - Roger M Feakins
- Department of Histopathology, Royal Free Hospital, London, United Kingdom
| | | | - Anthony J Gill
- Sydney Medical School, The University of Sydney, Sydney, Australia.,Cancer Diagnosis and Pathology Group, Kolling Institute of Medical Research, St Leonards, Australia.,NSW Health Pathology, Department of Anatomical Pathology, Royal North Shore Hospital, St Leonards, Australia
| | - Sanjay Kakar
- Department of Pathology, University of California, M590 San Francisco, United States
| | - James G Kench
- Sydney Medical School, The University of Sydney, Sydney, Australia.,Department of Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, New South Wales Health Pathology, Camperdown, Australia
| | - Alyssa M Krasinskas
- Department of Pathology and Laboratory Medicine, Emory University Hospital, Atlanta, United States
| | - Jean-Luc van Laethem
- Department of Gastroenterology and Medical Oncology, Hôpital Erasme and Laboratory of Experimental Gastroenterology, Université Libre de Bruxelles, Brussels, Belgium
| | - David F Schaeffer
- Division of Anatomic Pathology, Vancouver General Hospital, Vancouver, British Columbia, Canada.,Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada
| | - Kay Washington
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Centre, Nashville, Tennessee, United States
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Campbell F, Verbeke CS. Ductal Adenocarcinoma. PATHOLOGY OF THE PANCREAS 2021:145-201. [DOI: 10.1007/978-3-030-49848-1_9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Taggart MW, Foo WC, Lee SM. Tumors of the Gastrointestinal System Including the Pancreas. ONCOLOGICAL SURGICAL PATHOLOGY 2020:691-870. [DOI: 10.1007/978-3-319-96681-6_12] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
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Poizat F, Monges G, Raoul JL, Giovannini M, Delpero JR. Cancer du pancréas exocrine : compte rendu anatomopathologique type en 2015. ONCOLOGIE 2015. [DOI: 10.1007/s10269-015-2559-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
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Abstract
Despite decades of scientific and clinical research, pancreatic ductal adenocarcinoma (PDAC) remains a lethal malignancy. The clinical and pathologic features of PDAC, specifically the known environmental and genetic risk factors, are reviewed here with special emphasis on the hereditary pancreatic cancer (HPC) syndromes. For these latter conditions, strategies are described for their identification, for primary and secondary prevention in unaffected carriers, and for disease management in affected carriers. Nascent steps have been made toward personalized medicine based on the rational use of screening, tumor subtyping, and targeted therapies; these have been guided by growing knowledge of HPC syndromes in PDAC.
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Affiliation(s)
- Ashton A Connor
- Division of General Surgery, Department of Surgery, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Steven Gallinger
- Division of General Surgery, Department of Surgery, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
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Patsouras D, Papaxoinis K, Kostakis A, Safioleas MC, Lazaris AC, Nicolopoulou-Stamati P. Fibroblast activation protein and its prognostic significance in correlation with vascular endothelial growth factor in pancreatic adenocarcinoma. Mol Med Rep 2015; 11:4585-90. [PMID: 25625587 DOI: 10.3892/mmr.2015.3259] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2014] [Accepted: 11/20/2014] [Indexed: 11/05/2022] Open
Abstract
Fibroblast activation protein (FAP), a selective protein for tumor stromal fibroblasts, is expressed in >90% of human epithelial carcinomas. A characteristic feature of pancreatic cancer is an extensive fibrotic or desmoplastic reaction surrounding the primary tumor. The present study aimed to evaluate the expression levels of FAP and vascular endothelial growth factor (VEGF) and determine their correlation in pancreatic adenocarcinoma. Confocal laser scanning microscopy and conventional immunohistochemical analysis were used to quantify FAP and VEGF expression levels in formalin‑fixed and paraffin‑embedded tissue biopsies from 46 patients (male, 26; female, 20; mean age, 66 years; age range, 53‑80 years) with pancreatic adenocarcinoma stage IIA or IIB. The expression levels of FAP in the neoplastic and adjacent normal tissue were significantly higher in stage IIB patients, compared with stage IIA patients. FAP expression was correlated with positive lymph nodes, resulting in poor prognosis for stage IIB patients. The partial correlation coefficient between FAP and VEGF expression levels was 0.39 (P=0.007), and the two factors had an effect on patient survival. Multivariate analysis demonstrated the prognostic superiority of FAP over VEGF, which is considered to be the most consistently reproducible molecular marker with prognostic value in resected pancreatic adenocarcinoma. Due to the limited beneficial effect of current systemic therapies for pancreatic adenocarcinoma, targeting FAP may be a potential therapeutic strategy and requires further investigation.
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Affiliation(s)
- Dimitrios Patsouras
- Department of GI Surgery, St. Thomas' Hospital, London SE1 7EH, United Kingdom
| | - Kostis Papaxoinis
- Gastroenterology Unit, 1st Department of Internal Medicine‑Propaedeutic, 'Laiko' General Hospital, Athens University Medical School, Athens GR‑11527, Greece
| | - Alkiviadis Kostakis
- Center of Experimental Surgery, Biomedical Research Foundation, Academy of Athens, Athens GR‑11527, Greece
| | - Michael C Safioleas
- Fourth Propedeutic Department of Surgery, Athens University Medical School, Attikon Hospital of Athens, Athens GR-12462, Greece
| | - Andreas C Lazaris
- 1st Department of Pathology, Athens University Medical School, Athens GR‑11527, Greece
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Gill AJ, Johns AL, Eckstein R, Samra JS, Kaufman A, Chang DK, Merrett ND, Cosman PH, Smith RC, Biankin AV, Kench JG. Synoptic reporting improves histopathological assessment of pancreatic resection specimens. Pathology 2009; 41:161-7. [PMID: 19320058 DOI: 10.1080/00313020802337329] [Citation(s) in RCA: 83] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
AIM We examined whether introduction of a standardised pancreatic cancer minimum data set improved the reporting of key pathological features across multiple institutions. METHODS From seven different pathology departments that are members of the New South Wales Pancreatic Cancer Network, 109 free text reports and 68 synoptic reports were compared. RESULTS AJCC stage could not be inferred from 44% of free text reports, whereas stage was reported in all 68 synoptic reports. In the free text reports 28 different names were used to designate margins. All margins were reported in only 12 (11%) of the free text reports compared with 64 (94%) of the synoptic reports (p = 0.0011). The presence or absence of lymphovascular or perineural invasion was reported in 72 (66%) and 92 (84%) of free text reports, respectively. In contrast, lymphovascular space and perineural invasion were reported in all synoptic reports (p = 0.0011 and p = 0.0058). CONCLUSION We conclude that synoptic reporting of pancreatic resections without any other intervention increases the information contained within histopathology reports. Therefore, the introduction of minimal data set synoptic reports is a simple and feasible mechanism to immediately improve reporting for pancreatectomy specimens.
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Affiliation(s)
- Anthony J Gill
- Department of Anatomical Pathology, Royal North Shore Hospital, Pacific Highway, St Leonards, NSW, Australia.
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12
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Adsay NV, Basturk O, Bonnett M, Kilinc N, Andea AA, Feng J, Che M, Aulicino MR, Levi E, Cheng JD. A proposal for a new and more practical grading scheme for pancreatic ductal adenocarcinoma. Am J Surg Pathol 2005; 29:724-33. [PMID: 15897739 DOI: 10.1097/01.pas.0000163360.40357.f1] [Citation(s) in RCA: 62] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
There is no uniformly applied grading system for pancreatic ductal adenocarcinoma (DA). The scheme advocated by the WHO is essentially that of Kloppel et al, and is based on the "highest grade" focus. Although it is precise with good prognostic value, it is unfortunately not widely applied, largely because of the lack of recognition and partly because of its complex nature (interpretation of multiple parameters). Furthermore, it is fundamentally different from the one used in Japan, which evaluates the overall pattern. To establish a more widely applicable, practical, and clinically relevant grading system, a scheme similar to Gleason's scoring system was developed and tested on 112 cases of resected pancreatic DA and was compared with the WHO system. In the grading system devised, patterns (P) of infiltration were classified as follows: P1, well-defined glands with easily discernible contours; P2, fused or poorly formed glands with ill-defined contours; P3, nonglandular patterns. A score was then obtained by the summation of the predominant and the secondary patterns. Scores < or =3 (at least some well-formed glands and no nonglandular pattern) was graded as G1, 4 as G2, and > or =5 (at least some nonglandular patterns and no well-formed glandular pattern) as G3. Seventy-three percent of the cases displayed mixed patterns, with disparate patterns (P1 with P3) in 13%, confirming the high degree of heterogeneity of DA. There was a significant correlation between grade and survival, better than the correlation between survival and either the major or minor patterns evaluated separately. The median survival for G1, G2, and G3 were 22, 14, and 8 months; 1-year survival 68%, 44%, and 33%; 2-year was 67%, 11%, and 0%; and 3-year was 23%, 4%, and 0%, respectively (P = 0.0019). In a multivariate analysis, correlating survival with grade, tumor size, and lymph node status, the grade was the strongest independent predictor of survival. Odds ratio of dying of disease were 3.56 (P < 0.0001) in G3 versus G1, 1.79 (P = 0.058) in G2 versus G1, and 1.98 (P = 0.03) in G3 versus G2. Compared with this, the same odds ratio were 1.17 (P = 0.01) in tumors >2 cm versus < or =2 cm and 1.78 (P = 0.01) in cases with positive versus negative lymph nodes. The WHO grading scheme was not found to have as good a correlation with survival in this study, with WHO grade 2 showing a better survival than 1. The reproducibility of both the proposed grading system and that of WHO were found to be moderately good (with kappa values of 0.43 and 0.44, respectively), when 32 slides of DA were graded by four independent observers. The grading scheme for pancreatobiliary adenocarcinoma proposed here is highly applicable because it is practical and readily adoptable. It reflects biologic characteristics of ductal carcinoma (prominent tubule formation and tumor heterogeneity). Most importantly, it is clinically relevant with good prognostic value. Lastly, it is also applicable for use in research, by utilizing "patterns," even in small specimens like microarrays or biopsies.
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Affiliation(s)
- N Volkan Adsay
- Department of Pathology, Karmanos Cancer Institute and Harper University Hospital, Wayne State University, 3990 John R. Street, Detroit, MI 48201, USA.
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13
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Li YJ, Wei ZM, Meng YX, Ji XR. β-catenin up-regulates the expression of cyclinD1, c-myc and MMP-7 in human pancreatic cancer: Relationships with carcinogenesis and metastasis. World J Gastroenterol 2005; 11:2117-23. [PMID: 15810077 PMCID: PMC4305780 DOI: 10.3748/wjg.v11.i14.2117] [Citation(s) in RCA: 133] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate whether abnormal expression of β-catenin in conjunction with overexpression of cyclinD1, c-myc and matrix metalloproteinase-7 (MMP-7) correlated with the carcinogenesis, metastasis and prognosis of pancreatic cancer, and to analyze the relationship of β-catenin expression with cyclinD1, c-myc and MMP-7 expression.
METHODS: Using immunohistochemistry, we examined the expression of β-catenin, cyclinD1, c-myc and MMP-7 in 47 pancreatic adenocarcinoma tissues, 12 pancreatic intraepithelial neoplasia (PanIN) and 10 normal pancreases, respectively. Proliferation cell nuclear antigen was also tested as the index of proliferative activity of pancreatic cancer cells.
RESULTS: In 10 cases of normal pancreatic tissues, epithelial cells showed equally strong membranous expression of β-catenin protein at the cell-cell boundaries, but the expression of cyclinD1, c-myc and MMP-7 was negative. The expression of β-catenin, cyclinD1, c-myc and MMP-7 in PanIN and pancreatic adenocarcinoma tissues had no significant difference [6/12 and 32/47 (68.1%), 6/12 and 35/47 (74.5%), 5/12 and 33/47 (70.2%), 7/12 and 30/47 (63.8%), respectively]. The abnormal expression of β-catenin was significantly correlated to metastasis and one-year survival rate of pancreatic cancer, but had no relation with size, differentiation and cell proliferation. The expression of cyclinD1 was correlated with cell proliferation and extent of differentiation, but not with size, metastasis and one-year survival rate of the pancreatic cancer. The expression of c-myc was not correlated with size, extent of differentiation, metastasis and 1-year survival rate, but closely with cell proliferation of pancreatic cancer. The overexpression of MMP-7 was significantly associated with metastasis and 1-year survival rate of pancreatic cancer, but not with size, extent of differentiation and cell proliferation. There was a highly significant positive association between abnormal expression of β-catenin and overexpression of cyclinD1, c-myc and MMP-7 not only in PanIN (r = 1.000, 0.845, 0.845), but also in pancreatic cancer (r = 0.437, 0.452, 0.435).
CONCLUSION: The abnormal expression of β-catenin plays a key role in the carcinogenesis and progression of human pancreatic carcinoma by up-regulating the expression of cyclinD1, c-myc and MMP-7, resulting in the degradation of extracellular matrix and uncontrolled cell proliferation and differentiation. β-catenin abnormal expression and MMP-7 overexpression may be considered as two useful markers for determining metastasis and prognosis of human pancreatic cancer.
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Affiliation(s)
- Yu-Jun Li
- Department of Pathology, The Affiliated Hospital of Medical College, Qingdao University, Qingdao 266003, Shandong Province, China.
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Kitada T, Seki S, Sakaguchi H, Sawada T, Hirakawa K, Wakasa K. Clinicopathological significance of hypoxia-inducible factor-1alpha expression in human pancreatic carcinoma. Histopathology 2004; 43:550-5. [PMID: 14636255 DOI: 10.1111/j.1365-2559.2003.01733.x] [Citation(s) in RCA: 48] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
AIMS The transcription factor hypoxia-inducible factor-1alpha (HIF-1alpha) plays a key role in the cellular adaptation to hypoxia and the activation of several genes that have been implicated in tumour growth. The aim of this study was to investigate the clinicopathological significance of HIF-1alpha expression in pancreatic carcinoma. METHODS AND RESULTS We investigated HIF-1alpha expression immunohistochemically in pancreatic carcinoma tissues and regional lymph node metastasis. In cases of pancreatic ductal carcinoma, the relationship between HIF-1alpha expression and various clinicopathological parameters including cellular proliferation, apoptosis, and microvessel density, was also examined. Over-expression of HIF-1alpha was frequently (29 of 49 cases, 59.2%) detected in pancreatic carcinoma and regional lymph node metastasis (19 of 25 cases, 76.0%), whereas HIF-1alpha expression was almost absent in non-cancerous pancreatic tissues. HIF-1alpha expression was significantly associated with tumour size (P = 0.023) and advanced TNM stage (stage I/II versus stage III, P = 0.039; stage I/II versus stage IV, P = 0.027). Moreover, HIF-1alpha expression positively correlated with cellular proliferation (P = 0.024) and microvessel density/neo-angiogenesis (P = 0.038), but not with apoptosis. CONCLUSIONS HIF-1alpha may play a critical role in the progression of pancreatic carcinoma.
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MESH Headings
- Adenocarcinoma, Papillary/metabolism
- Adenocarcinoma, Papillary/pathology
- Antigens, CD34/analysis
- Apoptosis
- Blood Vessels/chemistry
- Blood Vessels/pathology
- Carcinoma, Acinar Cell/metabolism
- Carcinoma, Acinar Cell/pathology
- Carcinoma, Pancreatic Ductal/metabolism
- Carcinoma, Pancreatic Ductal/pathology
- Cell Division
- Cystadenocarcinoma, Mucinous/metabolism
- Cystadenocarcinoma, Mucinous/pathology
- Female
- Humans
- Hypoxia-Inducible Factor 1, alpha Subunit
- Immunohistochemistry
- In Situ Nick-End Labeling
- Ki-67 Antigen/analysis
- Lymphatic Metastasis
- Male
- Middle Aged
- Neoplasm Staging
- Pancreatic Neoplasms/metabolism
- Pancreatic Neoplasms/pathology
- Single-Blind Method
- Transcription Factors/biosynthesis
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Affiliation(s)
- T Kitada
- Third Department of Internal Medicine, Osaka City University Medical School, Osaka, Japan
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Li YJ, Ji XR. Relationship between expression of E-cadherin-catenin complex and clinicopathologic characteristics of pancreatic cancer. World J Gastroenterol 2003; 9:368-72. [PMID: 12532469 PMCID: PMC4611349 DOI: 10.3748/wjg.v9.i2.368] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the expression of E-cadherin and alpha-catenin and beta-catenin in pancreatic carcinoma and its relationship with the clinicopathologic characteristics, and clarify the mechanism of invasion and metastasis of pancreatic cancer.
METHODS: The expression of E-cadherin and alpha-, beta-catenin was examined in 47 cases of infiltrative ductal adenocarcinoma of pancreas and 12 adult normal pancreatic tissues by immunohistochemical technique.
RESULTS: The immunoreactivity of E-cadherin and alpha-, beta-catenin was expressed by normal ductal and acinar cells with strong membranous staining at the intercellular border in 12 cases of adult normal pancreatic tissues. Abnormal expression of E-cadherin and alpha-, beta-catenin in 47 pancreatic carcinoma tissues was demonstrated in 53.2%, 61.7% and 68.1%, respectively. Both abnormal expression of E-cadherin and alpha-catenin significantly correlated with differentiation, lymph node and liver metastases (P < 0.05, respectively), whereas aberrant beta-catenin expression only correlated with lymph node and liver metastases (P < 0.001). Abnormal E-cadherin and alpha-, beta-catenin expression was not associated with tumor size, invasion and survival time of patients (P > 0.05, all).
CONCLUSION: Pancreatic cancer likely occurs in case of E-cadherin-catenin complex genes mutations or deletions and abnormal expression of proteins, which significantly correlate with the biologic character of the tumor and lymph node and liver metastases. It is suggested that the abnormal E-cadherin-catenin complex expression plays an important role in the development and progression of tumor, and thus may become a new marker in pancreatic cancer metastasis.
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Affiliation(s)
- Yu-Jun Li
- Department of Pathology, the Affiliated Hospital of Medical College, Qingdao University, 16 Jiangsu Rd, Qingdao 266003, China.
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Campani D, Esposito I, Boggi U, Cecchetti D, Menicagli M, De Negri F, Colizzi L, Del Chiaro M, Mosca F, Fornaciari G, Bevilacqua G. Bcl-2 expression in pancreas development and pancreatic cancer progression. J Pathol 2001; 194:444-50. [PMID: 11523052 DOI: 10.1002/path.925] [Citation(s) in RCA: 48] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Apoptosis is important for both tissue development and differentiation; its deregulation may contribute to tumourigenesis. In order to clarify the role of Bcl-2, an apoptosis-inhibiting protein, in pancreatic morphogenesis and tumour progression, its immunohistochemical expression was evaluated in 12 samples of fetal pancreas, in 10 samples of adult pancreas with ductal hyperplastic lesions, in 120 cases of primary pancreatic ductal adenocarcinoma, and in 43 synchronous metastatic lymph nodes. To evaluate the role of apoptosis in pancreatic cancer, p53 expression was also studied in tumour samples. Bcl-2 cytoplasmic acinar and ductal immunostaining was found in all fetal and adult tissue samples; ductal hyperplastic lesions were constantly negative. Thirty out of 120 (25%) tumours and 3 out of 43 (7%) lymph nodes expressed Bcl-2, whereas 67 out of 120 (56%) expressed nuclear p53. Well-differentiated tumours (G1) were more frequently Bcl-2-positive (p=0.002); furthermore, there was an inverse correlation between Bcl-2 and p53 expression in primary tumours (p=0.02). Neither Bcl-2 nor p53 influenced patients' prognosis, which was instead affected by N (p=0.02) and M (p<0.0001) status and stage of the disease (p=0.002). It is concluded that Bcl-2 regulates pancreatic morphogenesis and tissue homeostasis from early fetal to adult life and can be considered a phenotypic marker of normal exocrine pancreas. On the other hand, the lack of expression in preneoplastic lesions and the low positivity found in primary tumours and lymph node metastases suggest that Bcl-2 does not play a centralrole in pancreatic tumourigenesis and cancer progression.
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Affiliation(s)
- D Campani
- Department of Oncology, Division of Pathology, University of Pisa, Via Roma 57, 56126 Pisa, Italy.
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Lüttges J, Schemm S, Vogel I, Hedderich J, Kremer B, Klöppel G. The grade of pancreatic ductal carcinoma is an independent prognostic factor and is superior to the immunohistochemical assessment of proliferation. J Pathol 2000. [PMID: 10861575 DOI: 10.1002/(sici)1096-9896(200006)191:2%3c154::aid-path603%3e3.0.co;2-c] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Tumour grade is one of the prognostic factors in pancreatic ductal adenocarcinoma, but its value is controversial. In this study, the predictive value and the reproducibility of the WHO grading system were reconsidered and the possibility of supplementing it with the immunohistochemically assessed proliferative activity was investigated. Seventy resected ductal adenocarcinomas of the head of the pancreas were evaluated. A total of 60 HPF fields on two to four sections per tumour were screened for glandular differentiation, mucin production, mitosis, and nuclear atypia by two observers with different degrees of experience. Each criterion was scored and the grade was calculated from the mean value of all single scores. Corresponding slides were immunohistochemically stained with the proliferation marker Ki-S5. The percentage of positive nuclei was assessed and a proliferation index (PI) assigned (<10%=1; 10-50%=2; >50%=3). Multivariate analysis (Cox regression) identified grade and R stage as the most significant factors for predicting survival. The PI determined on the basis of Ki-S5 staining did not prove to be an independent prognostic factor. In 30 of 70 carcinomas, it correlated with the tumour grade. Within a given tumour grade, the cases with the least favourable prognosis could be distinguished on the basis of their PI. The inter-observer variability was considerable, with the main differences occurring in the group of G1 tumours. According to the refined WHO criteria, the histopathological grade of pancreatic ductal carcinoma is an important independent prognostic factor, but reproducibility depends on the expertise of the observer. Criteria that relate to cellular and structural differentiation seem to be more predictive than those related to proliferation.
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Affiliation(s)
- J Lüttges
- Department of Pathology, University of Kiel, Germany.
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Lüttges J, Schemm S, Vogel I, Hedderich J, Kremer B, Klöppel G. The grade of pancreatic ductal carcinoma is an independent prognostic factor and is superior to the immunohistochemical assessment of proliferation. J Pathol 2000; 191:154-61. [PMID: 10861575 DOI: 10.1002/(sici)1096-9896(200006)191:2<154::aid-path603>3.0.co;2-c] [Citation(s) in RCA: 121] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Tumour grade is one of the prognostic factors in pancreatic ductal adenocarcinoma, but its value is controversial. In this study, the predictive value and the reproducibility of the WHO grading system were reconsidered and the possibility of supplementing it with the immunohistochemically assessed proliferative activity was investigated. Seventy resected ductal adenocarcinomas of the head of the pancreas were evaluated. A total of 60 HPF fields on two to four sections per tumour were screened for glandular differentiation, mucin production, mitosis, and nuclear atypia by two observers with different degrees of experience. Each criterion was scored and the grade was calculated from the mean value of all single scores. Corresponding slides were immunohistochemically stained with the proliferation marker Ki-S5. The percentage of positive nuclei was assessed and a proliferation index (PI) assigned (<10%=1; 10-50%=2; >50%=3). Multivariate analysis (Cox regression) identified grade and R stage as the most significant factors for predicting survival. The PI determined on the basis of Ki-S5 staining did not prove to be an independent prognostic factor. In 30 of 70 carcinomas, it correlated with the tumour grade. Within a given tumour grade, the cases with the least favourable prognosis could be distinguished on the basis of their PI. The inter-observer variability was considerable, with the main differences occurring in the group of G1 tumours. According to the refined WHO criteria, the histopathological grade of pancreatic ductal carcinoma is an important independent prognostic factor, but reproducibility depends on the expertise of the observer. Criteria that relate to cellular and structural differentiation seem to be more predictive than those related to proliferation.
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Affiliation(s)
- J Lüttges
- Department of Pathology, University of Kiel, Germany.
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