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Luchini C, Scarpa A. Microsatellite instability in pancreatic and ampullary carcinomas: histology, molecular pathology, and clinical implications. Hum Pathol 2023; 132:176-182. [PMID: 35714836 DOI: 10.1016/j.humpath.2022.06.009] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/01/2022] [Accepted: 06/08/2022] [Indexed: 02/07/2023]
Abstract
Microsatellite instability (MSI)/defective DNA mismatch repair (dMMR) represents an important molecular alteration with diagnostic, prognostic, and predictive value. The increasing interest toward this genetic alteration is given to the high response rate of MSI/dMMR tumors to immunotherapy. There are different cancers in the periampullary region that can harbor MSI/dMMR, and significant morphological-molecular correlates should be acknowledged in this district: (1) pancreatic ductal adenocarcinoma (PDAC): in this tumor category, the prevalence of MSI/dMMR is about 1-2%, and medullary and colloid variants are the most typically involved; (2) ampullary adenocarcinoma: here the prevalence of MSI/dMMR is up to 18%, and in this neoplastic group, MSI/dMMR is more commonly found in the intestinal subtype; (3) pancreatic acinar cell carcinoma: here the prevalence of MSI/dMMR is up to 14%; and (4) pancreatic and ampullary neuroendocrine carcinoma: in this tumor category, the prevalence of MSI/dMMR is up to 5-8%, and this molecular alteration should be assessed also in cases of mixed neuroendocrine-non-neuroendocrine neoplasms. Given the clinical importance of MSI/dMMR and its not-negligible prevalence among the different carcinomas arising in this district, its assessment should become part of the routine diagnostic workflow at least for the most typical histotypes. The test of choice is represented by immunohistochemistry for PDAC and ampullary carcinomas, and by direct molecular analyses including MSI-based polymerase chain reaction and next-generation sequencing for acinar cell and neuroendocrine carcinomas.
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Affiliation(s)
- Claudio Luchini
- Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, Verona, 37134, Italy; ARC-Net Research Center for Applied Research on Cancer, University of Verona, Verona, 37134, Italy
| | - Aldo Scarpa
- Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, Verona, 37134, Italy; ARC-Net Research Center for Applied Research on Cancer, University of Verona, Verona, 37134, Italy.
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Li Y, Sun Y, Kulke M, Hechler T, Van der Jeught K, Dong T, He B, Miller KD, Radovich M, Schneider BP, Pahl A, Zhang X, Lu X. Targeted immunotherapy for HER2-low breast cancer with 17p loss. Sci Transl Med 2021; 13:eabc6894. [PMID: 33568521 PMCID: PMC8351376 DOI: 10.1126/scitranslmed.abc6894] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2020] [Accepted: 01/13/2021] [Indexed: 12/21/2022]
Abstract
The clinical challenge for treating HER2 (human epidermal growth factor receptor 2)-low breast cancer is the paucity of actionable drug targets. HER2-targeted therapy often has poor clinical efficacy for this disease due to the low level of HER2 protein on the cancer cell surface. We analyzed breast cancer genomics in the search for potential drug targets. Heterozygous loss of chromosome 17p is one of the most frequent genomic events in breast cancer, and 17p loss involves a massive deletion of genes including the tumor suppressor TP53 Our analyses revealed that 17p loss leads to global gene expression changes and reduced tumor infiltration and cytotoxicity of T cells, resulting in immune evasion during breast tumor progression. The 17p deletion region also includes POLR2A, a gene encoding the catalytic subunit of RNA polymerase II that is essential for cell survival. Therefore, breast cancer cells with heterozygous loss of 17p are extremely sensitive to the inhibition of POLR2A via a specific small-molecule inhibitor, α-amanitin. Here, we demonstrate that α-amanitin-conjugated trastuzumab (T-Ama) potentiated the HER2-targeted therapy and exhibited superior efficacy in treating HER2-low breast cancer with 17p loss. Moreover, treatment with T-Ama induced immunogenic cell death in breast cancer cells and, thereby, delivered greater efficacy in combination with immune checkpoint blockade therapy in preclinical HER2-low breast cancer models. Collectively, 17p loss not only drives breast tumorigenesis but also confers therapeutic vulnerabilities that may be used to develop targeted precision immunotherapy.
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Affiliation(s)
- Yujing Li
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Yifan Sun
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Michael Kulke
- Heidelberg Pharma Research GmbH, Ladenburg 68526, Germany
| | | | - Kevin Van der Jeught
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Tianhan Dong
- Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Bin He
- Departments of Surgery and Urology, Immunobiology and Transplant Science Center, Houston Methodist Cancer Center, Houston Methodist Research Institute, Houston Methodist Hospital, Houston, TX 77030, USA
- Department of Medicine, Weill Cornell Medicine of Cornell University, New York, NY 10065, USA
| | - Kathy D Miller
- Indiana University Melvin and Bren Simon Cancer Center, Indiana University School of Medicine, Indianapolis, IN 46202, USA
- Division of Hematology/Oncology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Milan Radovich
- Indiana University Melvin and Bren Simon Cancer Center, Indiana University School of Medicine, Indianapolis, IN 46202, USA
- Department of Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Bryan P Schneider
- Indiana University Melvin and Bren Simon Cancer Center, Indiana University School of Medicine, Indianapolis, IN 46202, USA
- Division of Hematology/Oncology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Andreas Pahl
- Heidelberg Pharma Research GmbH, Ladenburg 68526, Germany
| | - Xinna Zhang
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
- Indiana University Melvin and Bren Simon Cancer Center, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Xiongbin Lu
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
- Indiana University Melvin and Bren Simon Cancer Center, Indiana University School of Medicine, Indianapolis, IN 46202, USA
- Indiana University Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN 46202, USA
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Gallon R, Gawthorpe P, Phelps RL, Hayes C, Borthwick GM, Santibanez-Koref M, Jackson MS, Burn J. How Should We Test for Lynch Syndrome? A Review of Current Guidelines and Future Strategies. Cancers (Basel) 2021; 13:406. [PMID: 33499123 PMCID: PMC7865939 DOI: 10.3390/cancers13030406] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Revised: 01/18/2021] [Accepted: 01/20/2021] [Indexed: 12/13/2022] Open
Abstract
International guidelines for the diagnosis of Lynch syndrome (LS) recommend molecular screening of colorectal cancers (CRCs) to identify patients for germline mismatch repair (MMR) gene testing. As our understanding of the LS phenotype and diagnostic technologies have advanced, there is a need to review these guidelines and new screening opportunities. We discuss the barriers to implementation of current guidelines, as well as guideline limitations, and highlight new technologies and knowledge that may address these. We also discuss alternative screening strategies to increase the rate of LS diagnoses. In particular, the focus of current guidance on CRCs means that approximately half of Lynch-spectrum tumours occurring in unknown male LS carriers, and only one-third in female LS carriers, will trigger testing for LS. There is increasing pressure to expand guidelines to include molecular screening of endometrial cancers, the most frequent cancer in female LS carriers. Furthermore, we collate the evidence to support MMR deficiency testing of other Lynch-spectrum tumours to screen for LS. However, a reliance on tumour tissue limits preoperative testing and, therefore, diagnosis prior to malignancy. The recent successes of functional assays to detect microsatellite instability or MMR deficiency in non-neoplastic tissues suggest that future diagnostic pipelines could become independent of tumour tissue.
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Affiliation(s)
| | | | | | | | | | | | | | - John Burn
- Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK; (P.G.); (R.L.P.); (C.H.); (G.M.B.); (M.S.-K.); (M.S.J.)
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Luchini C, Brosens LAA, Wood LD, Chatterjee D, Shin JI, Sciammarella C, Fiadone G, Malleo G, Salvia R, Kryklyva V, Piredda ML, Cheng L, Lawlor RT, Adsay V, Scarpa A. Comprehensive characterisation of pancreatic ductal adenocarcinoma with microsatellite instability: histology, molecular pathology and clinical implications. Gut 2021; 70:148-156. [PMID: 32350089 PMCID: PMC7211065 DOI: 10.1136/gutjnl-2020-320726] [Citation(s) in RCA: 145] [Impact Index Per Article: 36.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2020] [Revised: 04/08/2020] [Accepted: 04/10/2020] [Indexed: 12/14/2022]
Abstract
OBJECTIVE Recently, tumours with microsatellite instability (MSI)/defective DNA mismatch repair (dMMR) have gained considerable interest due to the success of immunotherapy in this molecular setting. Here, we aim to clarify clinical-pathological and/or molecular features of this tumour subgroup through a systematic review coupled with a comparative analysis with existing databases, also providing indications for a correct approach to the clinical identification of MSI/dMMR pancreatic ductal adenocarcinoma (PDAC). DESIGN PubMed, SCOPUS and Embase were searched for studies reporting data on MSI/dMMR in PDAC up to 30 November 2019. Histological and molecular data of MSI/dMMR PDAC were compared with non-MSI/dMMR PDAC and with PDAC reference cohorts (including SEER database and The Cancer Genome Atlas Research Network - TCGA project). RESULTS Overall, 34 studies with 8323 patients with PDAC were included in the systematic review. MSI/dMMR demonstrated a very low prevalence in PDAC (around 1%-2%). Compared with conventional PDAC, MSI/dMMR PDAC resulted strongly associated with medullary and mucinous/colloid histology (p<0.01) and with a KRAS/TP53 wild-type molecular background (p<0.01), with more common JAK genes mutations. Data on survival are still unclear. CONCLUSION PDAC showing typical medullary or mucinous/colloid histology should be routinely examined for MSI/dMMR status using specific tests (immunohistochemistry, followed by MSI-PCR in cases with doubtful results). Next-generation sequencing (NGS) should be adopted either where there is limited tissue or as part of NGS tumour profiling in the context of precision oncology, acknowledging that conventional histology of PDAC may rarely harbour MSI/dMMR.
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Affiliation(s)
- Claudio Luchini
- Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, Verona, Italy
| | - Lodewijk A A Brosens
- Pathology, University Medical Center, Utrecht, The Netherlands,Pathology, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Laura D Wood
- Sol Goldman Pancreatic Cancer Research Center, Department of Pathology, Johns Hopkins University, Baltimore, Maryland, USA
| | - Deyali Chatterjee
- Pathology and Immunology, Washington University in Saint Louis School of Medicine, Saint Louis, Missouri, USA
| | - Jae Il Shin
- Pediatrics, Yonsei University College of Medicine, Seoul, The Republic of Korea
| | - Concetta Sciammarella
- Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, Verona, Italy
| | - Giulia Fiadone
- Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, Verona, Italy
| | - Giuseppe Malleo
- General and Pancreatic Surgery, University and Hospital Trust of Verona, Verona, Italy
| | - Roberto Salvia
- General and Pancreatic Surgery, University and Hospital Trust of Verona, Verona, Italy
| | | | - Maria L Piredda
- Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, Verona, Italy
| | - Liang Cheng
- Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Rita T Lawlor
- ARC-Net Research Center, University and Hospital Trust of Verona, Verona, Italy
| | - Volkan Adsay
- Pathology, Koç University Hospital, Istanbul, Turkey
| | - Aldo Scarpa
- ARC-Net Research Center and Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, Verona, Italy
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Whole genome analysis identifies the association of TP53 genomic deletions with lower survival in Stage III colorectal cancer. Sci Rep 2020; 10:5009. [PMID: 32193467 PMCID: PMC7081316 DOI: 10.1038/s41598-020-61643-6] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2019] [Accepted: 02/19/2020] [Indexed: 11/13/2022] Open
Abstract
DNA copy number aberrations (CNA) are frequently observed in colorectal cancers (CRC). There is an urgent need for CNA-based biomarkers in clinics,. n For Stage III CRC, if combined with imaging or pathologic evidence, these markers promise more precise care. We conducted this Stage III specific biomarker discovery with a cohort of 134 CRCs, and with a newly developed high-efficiency CNA profiling protocol. Specifically, we developed the profiling protocol for tumor-normal matched tissue samples based on low-coverage clinical whole-genome sequencing (WGS). We demonstrated the protocol’s accuracy and robustness by a systematic benchmark with microarray, high-coverage whole-exome and -genome approaches, where the low-coverage WGS-derived CNA segments were highly accordant (PCC >0.95) with those derived from microarray, and they were substantially less variable if compared to exome-derived segments. A lasso-based model and multivariate cox regression analysis identified a chromosome 17p loss, containing the TP53 tumor suppressor gene, that was significantly associated with reduced survival (P = 0.0139, HR = 1.688, 95% CI = [1.112–2.562]), which was validated by an independent cohort of 187 Stage III CRCs. In summary, this low-coverage WGS protocol has high sensitivity, high resolution and low cost and the identified 17p-loss is an effective poor prognosis marker for Stage III patients.
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Regalla DKR, Jacob R, Manne A, Paluri RK. Therapeutic options for ampullary carcinomas. A review. Oncol Rev 2019; 13:440. [PMID: 31565197 PMCID: PMC6747019 DOI: 10.4081/oncol.2019.440] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2019] [Accepted: 08/28/2019] [Indexed: 02/08/2023] Open
Abstract
Ampullary Carcinoma arises from a histologically heterogeneous region where three different epithelia converge. Even though Ampullary Carcinoma has a superior prognosis compared to pancreatic and biliary ductal neoplasms, at least half of the patients turn up at an advanced stage that limits the treatment prospects. In addition to surgery for early-stage disease, several studies have shown that chemoradiotherapy confers additional benefits in the management of Ampullary Carcinoma. Analogously, chemotherapy plays a crucial role in treating advanced Ampullary Carcinoma with distant metastasis/recurrences. Although, stage of the disease, lymph node status, and histo-morphology are three critical prognostic variables, recently much attention is being placed on the genetic landscape of Ampullary Carcinoma. In this review, we have discussed various studies describing the role of chemoradiation and chemotherapy in the treatment of early and advanced stage Ampullary Carcinoma. Also, we have summarized the molecular landscape of Ampullary Carcinoma and the novel therapeutic strategies which could possibly target the genetic alterations involving the tumor cells.
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Affiliation(s)
| | - Rojymon Jacob
- Radiation Oncology, University of Alabama at Birmingham Hospital, Birmingham, AL
| | - Ashish Manne
- Medical Oncology, University of South Alabama Hospital, Mobile, AL
| | - Ravi Kumar Paluri
- Hematology-Oncology, University of Alabama at Birmingham Hospital, Birmingham, AL, USA
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Diagnosis, risk stratification, and management of ampullary dysplasia by DNA flow cytometric analysis of paraffin-embedded tissue. Mod Pathol 2019; 32:1291-1302. [PMID: 30976103 PMCID: PMC8549479 DOI: 10.1038/s41379-019-0272-2] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2019] [Revised: 02/27/2019] [Accepted: 03/06/2019] [Indexed: 12/20/2022]
Abstract
The limited accuracy of endoscopic biopsy in detecting high-grade dysplasia or adenocarcinoma within ampullary adenoma or dysplasia has been reported. The natural history of ampullary dysplasia is also unclear, and there are no established guidelines to determine which patients with ampullary dysplasia require resection versus surveillance endoscopy. DNA flow cytometry was performed on 47 ampullary biopsies with low-grade dysplasia, 18 high-grade dysplasia, and 23 negative for dysplasia, as well as 11 cases of ampullary adenocarcinoma. Abnormal DNA content (aneuploidy or elevated 4N fraction > 6%) was identified in 9 (82%) of adenocarcinoma, 13 (72%) of high-grade dysplasia, 7 (15%) of low-grade dysplasia, and none (0%) of non-dysplastic mucosa. One-, 2-, and 7-year detection rates of high-grade dysplasia or adenocarcinoma in low-grade dysplasia patients with abnormal DNA content were 57%, 86%, and 88%, respectively, whereas low-grade dysplasia patients in the setting of normal DNA content had 1-, 2-, and 7-year detection rates of 10%, 10%, and 10%, respectively. The univariate and multivariate hazard ratios (HRs) for subsequent detection of high-grade dysplasia or adenocarcinoma in low-grade dysplasia patients with DNA content abnormality were 16.8 (p = <0.01) and 9.8 (p = <0.01), respectively. Among the 13 high-grade dysplasia patients with DNA content abnormality, 5 patients (38%) were subsequently found to have adenocarcinoma within a mean follow-up time of 3 months, whereas only 1 (20%) of the remaining 5 patients in the setting of normal DNA content developed adenocarcinoma in a month (HR = 2.6, p = 0.39). The overall 1- and 2-year detection rates of adenocarcinoma in all high-grade dysplasia patients (regardless of flow cytometric results) were 34% (95% confidence interval = 16-63%) and 47% (95% confidence interval = 23-79%), respectively. In conclusion, the majority of low-grade dysplasia patients (86%) in the setting of abnormal DNA content developed high-grade dysplasia or adenocarcinoma within 2 years and thus may benefit from resection, whereas those with normal DNA content may be followed with surveillance endoscopy. The presence of DNA content abnormality can also confirm a morphologic suspicion of high-grade dysplasia, which should be managed with resection, as nearly 50% of the high-grade dysplasia patients were found to have adenocarcinoma within 2 years.
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Pea A, Riva G, Bernasconi R, Sereni E, Lawlor RT, Scarpa A, Luchini C. Ampulla of Vater carcinoma: Molecular landscape and clinical implications. World J Gastrointest Oncol 2018; 10:370-380. [PMID: 30487949 PMCID: PMC6247104 DOI: 10.4251/wjgo.v10.i11.370] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/01/2018] [Revised: 08/08/2018] [Accepted: 10/08/2018] [Indexed: 02/05/2023] Open
Abstract
Ampulla of Vater is a peculiar anatomical structure, characterized by the crossroad of three distinct epithelia: Intestinal, ductal pancreatic and biliary. Adenocarcinomas arising in this area represent an opportunity to understand the comparative biology of all periampullary malignancies. These neoplasms can exhibit intestinal, pancreaticobiliary or mixed features, whereas the subclassification based on morphology and immunohistochemical features failed in demonstrating a robust prognostic reliability. In the last few years, the molecular landscape of this tumor entity has been uncovered, identifying alterations that may serve as prognostic and predictive biomarkers. In this review, the histological and genetic characteristics of ampullary carcinomas are discussed, taking into account the main clinical and therapeutic implications related to this tumor type as well.
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Affiliation(s)
- Antonio Pea
- Department of Surgery, University and Hospital Trust of Verona, Verona 37134, Italy
| | - Giulio Riva
- Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, Verona 37134, Italy
| | - Riccardo Bernasconi
- Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, Verona 37134, Italy
| | - Elisabetta Sereni
- Department of Surgery, University and Hospital Trust of Verona, Verona 37134, Italy
| | - Rita Teresa Lawlor
- ARC-Net Research Center, University and Hospital Trust of Verona, Verona 37134, Italy
| | - Aldo Scarpa
- Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, Verona 37134, Italy
| | - Claudio Luchini
- Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, Verona 37134, Italy
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Heterozygous deletion of chromosome 17p renders prostate cancer vulnerable to inhibition of RNA polymerase II. Nat Commun 2018; 9:4394. [PMID: 30349055 PMCID: PMC6197287 DOI: 10.1038/s41467-018-06811-z] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2018] [Accepted: 09/11/2018] [Indexed: 12/13/2022] Open
Abstract
Heterozygous deletion of chromosome 17p (17p) is one of the most frequent genomic events in human cancers. Beyond the tumor suppressor TP53, the POLR2A gene encoding the catalytic subunit of RNA polymerase II (RNAP2) is also included in a ~20-megabase deletion region of 17p in 63% of metastatic castration-resistant prostate cancer (CRPC). Using a focused CRISPR-Cas9 screen, we discovered that heterozygous loss of 17p confers a selective dependence of CRPC cells on the ubiquitin E3 ligase Ring-Box 1 (RBX1). RBX1 activates POLR2A by the K63-linked ubiquitination and thus elevates the RNAP2-mediated mRNA synthesis. Combined inhibition of RNAP2 and RBX1 profoundly suppress the growth of CRPC in a synergistic manner, which potentiates the therapeutic effectivity of the RNAP2 inhibitor, α-amanitin-based antibody drug conjugate (ADC). Given the limited therapeutic options for CRPC, our findings identify RBX1 as a potentially therapeutic target for treating human CRPC harboring heterozygous deletion of 17p.
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Morganti AG, Macchia G, Trodella L, Valentini V, Costamagna G, Mutignani M, Tringali A, Smaniotto D, Luzi S, Cellini N. Complete Response after Chemoradiation in Ampullary Carcinoma: A Case Report. TUMORI JOURNAL 2018; 89:82-4. [PMID: 12729368 DOI: 10.1177/030089160308900117] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
Aims and Background The case of a 70-year-old patient with resectable, poorly differentiated adenocarcinoma of the ampulla of Vater is presented. Patient and Methods Due to intraoperative hemorrhagic complications, surgical resection was not feasible. The patient was treated with radiochemotherapy consisting of external beam radiotherapy (50.4 Gy; 1.8 Gy/fraction; 5 fractions/week) plus 5-FU (1000 mg/m2/day, continuous IV infusion, days 2–5, week 1 and 5 of radiotherapy) and mitomycin C (10 mg/m2 IV, day 2, week 1 of radiotherapy). Results At five years’ follow-up the patient was in good general condition, without any signs of disease according to CT scan, endoscopic retrograde cholangiopancreatography and tumor marker determination. Multiple random biopsies performed in the ampullary region were negative for tumor growth. Conclusions In patients with ampullary carcinoma the use of concurrent chemoradiation should be considered, particularly when surgical resection is unfeasible due to medical contraindications or locally advanced disease.
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Affiliation(s)
- Alessio G Morganti
- Radiation Therapy Department, Università Cattolica del Sacro Cuore, Rome, Italy
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Jayaramayya K, Balachandar V, Santhy KS. Ampullary carcinoma-A genetic perspective. MUTATION RESEARCH-REVIEWS IN MUTATION RESEARCH 2018; 776:10-22. [PMID: 29807574 DOI: 10.1016/j.mrrev.2018.03.002] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/08/2018] [Revised: 03/14/2018] [Accepted: 03/14/2018] [Indexed: 12/19/2022]
Abstract
Ampulla of vater carcinoma (AVC) is a rare gastrointestinal tumour that is associated with a high mortality rate and it's often diagnosed at later stages due to lack of clinical symptoms. Early diagnosis of this condition is essential to effectively treat patients for better prognosis. A significant amount of advancement has been made in understanding the molecular nature of cancer in the past decade. A substantial number of mutations and alterations have been detected in various tumors. Despite the occurrence of AVC across the globe, the number of studies conducted on this tumor type remains low; this is largely due to its rare occurrence. Moreover, AVC tissues are complex and contain mutations in oncogenes, tumour suppressors, apoptotic proteins, cell proliferation proteins, cell signaling proteins, transcription factors, chromosomal abnormalities and cellular adhesion proteins. The frequently mutated genes included KRAS, TP53 and SMAD4 and are associated with prognosis. Several molecules of the PI3K, Wnt signaling, TGF-beta pathway and cell cycle have also been altered in AVCs. This review comprises of all the genetic mutations, associated pathways and related prognosis that are involved in AVCs from the year 1989 to 2017. This report can be used as a stepping-stone to establish biomarkers for early diagnosis of AVC and to discover molecular targets for drug therapy.
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Affiliation(s)
- Kaavya Jayaramayya
- Department of Zoology, Avinashilingam Institute for Home Science and Higher Education for Women - Avinashilingam University for Women, Coimbatore 641 043, Tamil Nadu, India.
| | - Vellingiri Balachandar
- Human Molecular Cytogenetics and Stem Cell Laboratory, Department of Human Genetics and Molecular Biology, Bharathiar University, Coimbatore 641 046, Tamil Nadu, India
| | - Kumaran Sivanandan Santhy
- Department of Zoology, Avinashilingam Institute for Home Science and Higher Education for Women - Avinashilingam University for Women, Coimbatore 641 043, Tamil Nadu, India
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Ampulla of Vater Carcinoma: Sequencing Analysis Identifies TP53 Status as a Novel Independent Prognostic Factor and Potentially Actionable ERBB, PI3K, and WNT Pathways Gene Mutations. Ann Surg 2017; 267:149-156. [PMID: 27611608 DOI: 10.1097/sla.0000000000001999] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
OBJECTIVE To identify molecular prognostic factors and potentially actionable mutations in ampulla of Vater cancer (AVC). BACKGROUND The largely variable outcomes of AVCs make clinical decisions difficult regarding the need of postsurgical therapy, which is based on morphological and immunohistochemical classification that do not adequately consider the varying degrees of heterogeneity present in many AVCs. No approved targeted therapies for AVC exist, but some show promising results requiring better molecular characterization to identify potential responders. METHODS We assessed 80 AVCs for the prognostic value of mutations of kirsten rat sarcoma (KRAS), neuroblastoma RAS (NRAS), B rapidly accelerated fibrosarcoma (BRAF), TP53, and 4 membrane erythroblastosis oncogene B (ERBB) receptor tyrosine kinases (EGFR-ERBB1, HER2-ERBB2, HER3-ERBB3, HER4-ERBB4) amenable to pharmacological inhibition. Moreover, we evaluated mutations in 16 key components of rat sarcoma (RAS), phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K), protein 53 (P53), transforming growth factor beta (TGF-β), and wingless/integrated (WNT) pathways, recently associated to AVC by whole-exome sequencing. RESULTS TP53 and KRAS were mutated in 41% and 35% of cases, respectively, and emerged as independent prognostic factors together with tumor stage and regardless of the histotype (TP53: P = 0.0006; KRAS: P = 0.0018; stage IIB: P = 0.0117; stage III-IV: P = 0.0020). ERBB, WNT and PI3K pathway genes were mutated in 37.5% of cases. CONCLUSIONS KRAS and TP53 mutations are negative predictors of survival in AVCs, regardless of histotype. Potentially actionable mutations in ERBB, WNT, and PI3K signaling pathway genes are present in 37.5% of all cases. These might be amenable to target therapy using available drugs like Everolimus in PI3K-mutated cases or compounds under active screening against ERBB and WNT signaling.
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Differentiation and prognostic markers in ampullary cancer: Role of p53, MDM2, CDX2, mucins and cytokeratins. Pathol Res Pract 2016; 212:1039-1047. [DOI: 10.1016/j.prp.2016.09.004] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2016] [Revised: 09/01/2016] [Accepted: 09/09/2016] [Indexed: 12/23/2022]
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Ahmad SR, Adler DG. Cancer of the ampulla of vater: current evaluation and therapy. Hosp Pract (1995) 2015; 42:45-61. [PMID: 25485917 DOI: 10.3810/hp.2014.12.1158] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Ampullary cancer is a relatively rare cancer of the digestive tract. In contrast to pancreatic cancer, ampullary cancer is often curable if detected at an early stage. The evaluation and management of ampullary cancer is similar to, but distinct from, that of other pancreaticobiliary tumors. This manuscript will review the current evaluation, diagnosis, and therapy of patients with ampullary cancer. The diagnosis of ampullary cancer is complicated by its similar clinical presentation to pancreatic cancer as well as its nonspecific laboratory findings. Diagnostic modalities such as ERCP, EUS, and biopsy are necessary for differentiating the 2 cancers, and noninvasive imaging techniques such as MRI and CT may be used for tumor staging. Although pancreaticoduodenectomy is considered the primary curative surgical option, consensus guidelines regarding adjuvant and neoadjuvant chemoradiation therapies are lacking.
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Affiliation(s)
- Sarah R Ahmad
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of Utah School of Medicine, Salt Lake City, UT
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15
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The analysis of microsatellite instability in extracolonic gastrointestinal malignancy. Pathology 2014; 45:540-52. [PMID: 24018804 DOI: 10.1097/pat.0b013e3283653307] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Microsatellite instability (MSI) is a genetic feature of sporadic and familial cancers of multiple sites and is related to defective mismatch repair (MMR) protein function. Lynch syndrome (LS) is a familial form of MMR deficiency that may present with a spectrum of MSI positive cancers including gastrointestinal (GI) malignancies. The incidence of high level MSI (MSI-H) in colorectal carcinoma is well defined in both familial and sporadic cases and these tumours portend a better overall prognosis in colorectal carcinoma (CRC). There are certain morphological features that suggest MSI-H CRC and international guidelines have been established for the evaluation of MSI in CRC. The prevalence and morphological features of extracolonic GI MSI-H tumours are less well documented. Furthermore, it is unclear whether the guidelines for the assessment of MSI in CRC are appropriate for application to extracolonic GI malignancies. This review aims to summarise the recent literature on MSI in extracolonic LS-related GI tract malignancies with special attention to the assessment of the MMR system by evaluation of specific microsatellite markers and/or immunohistochemical evaluation of MMR protein expression. The reported prevalence of sporadic and LS-related MSI-H tumours along with their associated unique morphological patterns and related prognostic or therapeutic implications will be discussed.
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Perysinakis I, Margaris I, Kouraklis G. Ampullary cancer--a separate clinical entity? Histopathology 2014; 64:759-68. [PMID: 24456259 DOI: 10.1111/his.12324] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
AIMS Ampullary cancer is a relatively uncommon tumour, with a better prognosis than pancreatic cancer. The purpose of this study was to review the recent literature on ampullary adenocarcinoma, focusing on histological types and prognostic factors. METHODS AND RESULTS Using PubMed, we carried out a comprehensive search of the literature, which was extended to April 2013 to retrieve all additional publications. Ampullary cancer comprises two main histological subtypes, the pancreatobiliary type and the intestinal type. These subtypes have different pathogenetic and clinical characteristics. Clinical and histological parameters as well as immunohistochemical markers have been identified as significant prognostic factors in ampullary cancer. Moreover, several immunohistochemical markers have been studied, not only as prognostic factors but as a means of differentiating ampullary from other peri-ampullary tumours, and of identifying the exact histological subtype. CONCLUSIONS The considerable differences in the frequencies of the two subtypes of ampullary tumours reported in literature reinforce the necessity to define molecular markers to distinguish them. Until then, the significance of the histological subtype as a prognostic factor should be evaluated cautiously. Future research on the pathogenesis of ampullary cancer will possibly suggest that we should stop treating this type of cancer as a separate entity.
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Affiliation(s)
- Iraklis Perysinakis
- Third Department of Surgery, 'George Gennimatas' General Hospital, Athens, Greece
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17
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Histopathologic features and microsatellite instability of cancers of the papilla of vater and their precursor lesions. Am J Surg Pathol 2009; 33:691-704. [PMID: 19252434 DOI: 10.1097/pas.0b013e3181983ef7] [Citation(s) in RCA: 97] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
The prevalence and development of microsatellite instability (MSI) and underlying mismatch repair (MMR) deficiency in the carcinogenesis of adenocarcinomas of the papilla of Vater and their precursor lesions are not well established. We analyzed 120 ampullary adenomas (31 pure adenomas and 89 carcinoma-associated adenomas) and 170 pure adenocarcinomas for MSI, immunohistochemical expression of MMR proteins and specific histopathologic features. The most common histologic subtype was intestinal (46.5%), followed by pancreatobiliary (23.5%), poorly differentiated adenocarcinomas (12.9%), intestinal-mucinous (8.2%), and invasive papillary carcinomas (5.3%). Eight of 89 adenomas (9%) and 15/144 carcinomas (10%) showed high microsatellite instability (MSI-H), 10/89 adenomas (11%) and 5/144 carcinomas (4%) showed low microsatellite instability (MSI-L), and 71/89 adenomas (80%) and 124/144 carcinomas (86%) were microsatellite stable (MSS). MSI analysis from carcinomas contiguous with an adenomatous component (n=54) exhibited concordant results in 6/8 (75%) MSI-H and 42/46 (91.3%) MSS tumors. Of 14 carcinomas with MSI-H, 7 showed loss of MLH1 and 5/6 (83%) MLH1 promoter methylation, and 2 carcinomas showed simultaneous loss of MSH2 and MSH6. Two carcinomas and 3 adenomas with MSI-H revealed exclusive loss of MSH6. MSI-H cancers were significantly associated with intestinal mucinous subtype (P<0.001), high tumor grade (P=0.003), expansive growth pattern (P=0.044), and marked lymphoid host response (P=0.004). Patients with MSI-H carcinoma had a significantly longer overall survival (P=0.0082) than those with MSI-L or MSS tumors. Our findings indicate that the MSI-phenotype is an early event, which develops at the stage of adenoma and is reliably detectable in the precursor lesion. The MMR deficient molecular pathway of carcinogenesis is associated with a histopathologic phenotype in ampullary cancer, similar to the one that has been well described in colon cancer.
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Vincenzi B, Santini D, Perrone G, Russo A, Adamo V, Rizzo S, Castri F, Antinori A, Alloni R, Crucitti P, Morini S, Rabitti C, Vecchio F, Magistrelli P, Coppola R, Tonini G. Promyelocytic leukemia (PML) gene expression is a prognostic factor in ampullary cancer patients. Ann Oncol 2009; 20:78-83. [DOI: 10.1093/annonc/mdn558] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
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Sessa F, Furlan D, Zampatti C, Carnevali I, Franzi F, Capella C. Prognostic factors for ampullary adenocarcinomas: tumor stage, tumor histology, tumor location, immunohistochemistry and microsatellite instability. Virchows Arch 2007; 451:649-57. [PMID: 17653761 DOI: 10.1007/s00428-007-0444-1] [Citation(s) in RCA: 59] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2007] [Revised: 06/05/2007] [Accepted: 06/06/2007] [Indexed: 12/15/2022]
Abstract
Prognostic factors for ampullary carcinomas (ACs) are poorly defined. Fifty three resected ACs were analyzed for CDX2, MUC1, MUC5AC, MUC6, MUC2, and for mismatch repair proteins (hMLH1, hMSH2, PMS2, hMSH6) using immunohistochemistry. Microsatellite instability (MSI) status was evaluated by fluorescently labeled PCR using an automated sequencer. Univariate and multivariate analysis was performed for clinicopathological, immunohistochemical and molecular parameters. CDX2 was found in 32 out of 53 (60%) ACs with a significantly higher frequency among intestinal ACs compared with biliopancreatic (BP) ACs. The MUC1, MUC5AC, MUC6, MUC2 apomucins were expressed in 75, 43, 39, and 28% of ACs, respectively, with a significantly higher coexpression of MUC1/MUC5AC in BP ACs. MSI and loss of expression of hMLH1/PMS2 or hMSH2/hMSH6 proteins were observed only in intestinal ACs. Factors significantly correlated with improved survival in the univariate analysis were: low stage, absence of lymph nodes metastases, negative surgical margins (R0 status), and presence of MSI. In the multivariate analysis, stage was the only independent prognostic factor of survival. We conclude that stage is the only independent prognostic factor of survival in the multivariate analysis, whereas histological criteria and the immunohistochemical expression of apomucins and CDX2 are helpful in the classification and understanding of the histogenesis of ACs.
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Affiliation(s)
- Fausto Sessa
- Division of Anatomic Pathology, Department of Human Morphology, University of Insubria, Varese, Italy.
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20
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Fitzsimmons D, Osmond C, George S, Johnson CD. Trends in stomach and pancreatic cancer incidence and mortality in England and Wales, 1951–2000. Br J Surg 2007; 94:1162-71. [PMID: 17520709 DOI: 10.1002/bjs.5751] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
Abstract
Background
The aim of this study was to describe period and cohort effects in incidence and mortality of stomach and pancreatic cancer in England and Wales.
Methods
National figures for mortality (1951–2000) and incidence (1971–2000) were analysed using log-linear Poisson regression models to obtain relative risks (RR) for period (year of incidence or death) and cohort (year of birth).
Results
Stomach cancer shows a pronounced cohort effect in mortality with a decline in RR in men from 2·20 (1876) to 0·47 (1946) and a reduction from 2·79 to 0·41 for women. Mortality to incidence ratios are now less than 0·70. Pancreatic cancer mortality (men) RR rose from 0·91 (1951–1955) to a peak 1·11 (1976–1980) and then declined to 0·90 (1996–2000). Women showed a similar pattern. Cohort RR (men) increased to a peak of 1·14 in 1916 and declined to 1·01 in 1946, and continued to fall; the peak occurred slightly later in women. Mortality to incidence ratios were near 1 in the first 20 years, declining to 0·95 in the last 10 years.
Conclusion
Stomach cancer incidence has fallen continuously from 19th century birth cohorts onwards. Incidence of pancreatic cancer has fallen in successive birth cohorts after 1920; peak period risk was 1976–1990. Age-standardized mortality and case mortality for pancreatic cancer are declining.
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Affiliation(s)
- D Fitzsimmons
- School of Health Science, University of Wales-Swansea, Swansea, UK
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21
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Iacono C, Verlato G, Zamboni G, Scarpa A, Montresor E, Capelli P, Bortolasi L, Serio G. Adenocarcinoma of the ampulla of Vater: T-stage, chromosome 17p allelic loss, and extended pancreaticoduodenectomy are relevant prognostic factors. J Gastrointest Surg 2007; 11:578-88. [PMID: 17468917 DOI: 10.1007/s11605-007-0136-9] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
OBJECTIVE To evaluate the prognostic significance of different clinico-pathological and molecular factors, and to compare survival after standard and extended pancreaticoduodenectomy (PD) in ampulla of Vater adenocarcinoma (AVAC). There are discordant data on factors affecting prognosis, and hence therapeutic choices, in AVAC. PATIENTS AND METHODS Clinical-pathological factors were evaluated in 59 patients, subjected to PD for AVAC; in 42 subjects information on chromosome 17p and 18q allelic losses (LOH) and microsatellite instability (MSI) was also available. The association between survival and type of PD was investigated in the 25 patients operated between 1990 and 2001 (16 standard and nine extended). RESULTS The overall 5- and 10-year tumor-related survival rates were 46% and 33%, respectively. Sixteen patients had T-stages 1-2, 14 T-stage 3, and 29 T-stage 4 cancers. Chromosome 17p and 18q LOH were detected in 23 (55%) and 15 cases (36%), respectively, and in 12 cases (29%) coexisted. Five cases were MSI-positive (12%). At univariate analysis, poor survival was associated with cancer ulceration (P = 0.051), poor differentiation (P = 0.008), T-stage 4 (P < 0.001), nodal metastases (P = 0.004), chromosome 17p (P < 0.001) and 18q LOH (P = 0.002), and absence of MSI (P = 0.009). At multivariate analysis, only T-stage (P = 0.002) and 17p LOH (P = 0.001) were independent predictors of survival. All patients with MSI-positive cancers were long-survivors (>12 yrs), whereas only 30% of MSI-negative cancer patients survived at 5 years. Extended pancreaticoduodenectomy was associated with a 3-year disease-related survival higher than standard resection (83% vs 31%; P = 0.018). CONCLUSION MSI and chromosome 17p status allow to better define prognosis within ampullary cancers at the same stage. Surgery alone resulted curative in MSI-positive cancer patients, whereas it was inadequate in patients showing allelic losses, who might benefit from adjuvant therapy. In this observational study, extended PD was associated with increased survival compared to standard procedures.
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Affiliation(s)
- Calogero Iacono
- Department of Surgery and Gastroenterology, University of Verona Medical School, Verona, Italy.
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Santini D, Vincenzi B, Tonini G, Scarpa S, Vasaturo F, Malacrino C, Vecchio F, Borzomati D, Valeri S, Coppola R, Magistrelli P, Nuzzo G, Picciocchi A. Cyclooxygenase-2 overexpression is associated with a poor outcome in resected ampullary cancer patients. Clin Cancer Res 2005; 11:3784-9. [PMID: 15897577 DOI: 10.1158/1078-0432.ccr-04-2136] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
PURPOSE To identify potential prognostic molecular factors in ampullary adenocarcinoma that could be of significant importance. To this end, we examined the possible prognostic significance of cyclooxygenase-2 (Cox-2) and Survivin expression and the apoptotic index in a cohort of uniformly treated patients with ampullary cancer treated with radical surgical excision. EXPERIMENTAL DESIGN The entry criteria were that the patients have a pathologic diagnosis of ampullary cancer which had been resected. Expression analysis for Cox-2 and Survivin was done by immunohistochemical staining. Apoptotic cells were identified by the terminal deoxyribonucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) method. RESULTS Thirty-nine tumor specimens from resected ampullary adenocarcinoma patients were included. By univariate analysis, overall survival was affected by Cox-2 expression and TUNEL staining (respectively, P = 0.0003 and 0.03). Survivin expression did not influence the overall survival in our patient population (P = 0.123). Patients' clinicopathologic features (gender, age, and T and N factors) did not influence outcome. In multivariate Cox regression analysis, Cox-2 expression (relative risk, 4.330; P = 0.005) was the only variable that significantly affected overall survival. CONCLUSIONS The results of the present article provide, for the first time, evidence that Cox-2 expression, but not Survivin expression, may represent a significant prognostic factor after surgical resection in patients affected by cancer of the ampulla of Vater. Further studies are required to determine whether Cox-2 inhibitors may be useful for the therapy or prevention of ampullary carcinoma.
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Santini D, Tonini G, Vecchio FM, Borzomati D, Vincenzi B, Valeri S, Antinori A, Castri F, Coppola R, Magistrelli P, Nuzzo G, Picciocchi A. Prognostic value of Bax, Bcl-2, p53, and TUNEL staining in patients with radically resected ampullary carcinoma. J Clin Pathol 2005; 58:159-65. [PMID: 15677536 PMCID: PMC1770581 DOI: 10.1136/jcp.2004.018887] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Abstract
BACKGROUND There is a lack of data in the literature concerning the identification of potential prognostic factors in ampullary adenocarcinoma. AIMS To examine the prognostic significance of Bax, Bcl-2, and p53 protein expression and the apoptotic index in a large cohort of uniformly treated patients with radically resected ampullary cancer. METHODS All patients with a pathological diagnosis of ampullary cancer and radical resection were evaluated. Expression analysis for p53, Bax, and Bcl-2 was performed by immunohistochemistry. Apoptotic cells were identified by terminal deoxynucleotidyl transferase mediated dUTP nick end labelling (TUNEL). RESULTS Thirty nine tumour specimens from patients with radically resected ampullary adenocarcinoma were studied. A positive significant correlation between Bax and p53 expression was found by rank correlation matrix (p < 0.001). A trend towards a positive correlation was found between the apoptotic index and p53 expression (p = 0.059). By univariate analysis, overall survival was influenced by Bax expression, p53 expression, and TUNEL staining (p = 0.001, p = 0.01, and p = 0.03, respectively). Bcl-2 expression did not influence overall survival in these patients (p = 0.55). By multivariate Cox regression analysis, the only immunohistochemical parameter that influenced overall survival was Bax expression (p = 0.020). CONCLUSIONS These results provide evidence that apoptosis may be an important prognostic factor in patients with radically resected ampullary cancer. This study is the first to assess the clinical usefulness of Bax expression in radically resected ampullary cancer.
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Affiliation(s)
- D Santini
- University Campus Bio-Medico University, Via Emilio Longoni, 83, 00155 Rome, Italy.
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Gürbüz Y, Klöppel G. Differentiation pathways in duodenal and ampullary carcinomas: a comparative study on mucin and trefoil peptide expression, including gastric and colon carcinomas. Virchows Arch 2004; 444:536-41. [PMID: 15071739 DOI: 10.1007/s00428-004-1008-2] [Citation(s) in RCA: 19] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2003] [Accepted: 02/04/2004] [Indexed: 12/19/2022]
Abstract
Duodenal carcinomas, such as ampullary tumors, may be a heterogeneous group of neoplasms that share differentiation features with gastric or colorectal carcinomas. Because of the cell- and tissue-specific expression patterns of mucins and trefoil peptides, these markers were used to investigate the differentiation status of duodenal and ampullary carcinomas in comparison with gastric and colorectal carcinomas. Adenocarcinomas (14 duodenal, 10 gastric, 11 ampullary and 10 colorectal) were examined immunohistochemically for the mucin gene products MUC1, MUC2, MUC5AC, MUC6 and the trefoil peptides TFF1 and TFF2. The tumors' expression profile for MUC5AC, MUC6 and TFF1 was used to distinguish between gastric- and intestinal-directed differentiation. The mucins that were most often expressed in the individual tumor types were MUC1 (duodenal and ampullary carcinomas), MUC2 (colorectal carcinomas) and MUC5AC (gastric carcinomas). Further classification focusing on the expression profile for MUC5AC, MUC6 and TFF1 revealed that 21% of the duodenal and 45% of the ampullary carcinomas demonstrated mainly gastric differentiation (positivity for all three markers or only two of them). The remaining duodenal and ampullary carcinomas showed nongastric, i.e., intestinal differentiation (all three markers negative or only one marker positive). The gastric differentiation pattern characterized 60% of gastric carcinomas. Colorectal carcinomas showed intestinal differentiation in 100% of cases. Duodenal carcinomas have a heterogeneous mucin expression pattern that is mainly related to either gastric differentiation or intestinal differentiation. This also holds for ampullary carcinomas. Among the markers used, MUC5AC, MUC6 and TFF1 are most useful for revealing differentiation pathways in duodenal and ampullary carcinoma.
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Affiliation(s)
- Yesim Gürbüz
- Department of Pathology, University of Kocaeli, Turkey
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Sorio C, Moore PS, Ennas MG, Tecchio C, Bonora A, Sartoris S, Balzarini P, Grigolato P, Scarpa A. A novel cell line and xenograft model of ampulla of Vater adenocarcinoma. Virchows Arch 2003; 444:269-77. [PMID: 14677066 DOI: 10.1007/s00428-003-0936-6] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2003] [Accepted: 10/31/2003] [Indexed: 01/23/2023]
Abstract
Ampulla of Vater cancers (AVC) are of clinical relevance, as they represent more than one-third of patients undergoing surgery for pancreaticoduodenal malignancies and have a better prognosis than periampullary cancers of pancreaticobiliary origin. The availability of cellular models is crucial to perform cell biology and pharmacological studies and clarify the relationship between AVC and pancreatic and biliary cancers. Numerous cell lines are available for pancreatic and biliary adenocarcinomas, while only two have been reported recently for AVC. These were derived from a poor and a well-differentiated AVC, and both had wild-type K- ras and mutated p53. We report the establishment of a novel AVC cell line (AVC1) derived from a moderately differentiated cancer, having a mutated K- ras, wild-type p53, and methylated p16. Thus, our cell line adds to the spectrum of available in vitro models representative of the different morphological and molecular presentations of primary AVC. We further characterized AVC1 for the expression of relevant cell surface molecules and sensitivity to chemotherapeutic agents of common clinical use. It expresses MHC-I and CD95/Fas, while HLA-DR, CD40, CD80, CD86, MUC-1, MUC-2, and ICAM-1/CD54 are absent. It has a low to moderate sensitivity to both 5-FU and gemcitabine, at variance with much higher sensitivity displayed by two pancreatic ductal carcinoma cell lines. Lastly, AVC1 can be readily xenografted in immunodeficient mice, making it a suitable model for pre-clinical studies.
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Affiliation(s)
- Claudio Sorio
- Dipartimento di Patologia, Università di Verona, Strada Le Grazie, 37134, Verona, Italy
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Kim SG, Chan AOO, Wu TT, Issa JPJ, Hamilton SR, Rashid A. Epigenetic and genetic alterations in duodenal carcinomas are distinct from biliary and ampullary carcinomas. Gastroenterology 2003; 124:1300-10. [PMID: 12730870 DOI: 10.1016/s0016-5085(03)00278-6] [Citation(s) in RCA: 38] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
BACKGROUND & AIMS Carcinomas of the extrahepatic bile ducts, ampulla of Vater, and duodenum are uncommon, and their epigenetic and genetic alterations are not well characterized. METHODS We therefore compared the methylation profile and genetic alterations in 18 extrahepatic biliary, 9 ampullary, and 12 duodenal carcinomas. We evaluated methylation at p16, p14, and human Mut L homologue (hMLH1) by methylation- specific PCR (MSP), and at cyclooxygenase 2 (COX2), O(6)-methyl-guanine methyltransferase (MGMT), estrogen receptor (ER), retinoic acid receptor beta 2 (RAR beta), and T-type calcium channel (CACNA1G) genes, and methylated in tumor 1 (MINT1), MINT2, MINT25, MINT27, and MINT31 loci by combined bisulfite restriction analysis (COBRA); mutation of K-ras, p53, p16, and p14 genes by sequencing; loss of heterozygosity of chromosome 9p; and microsatellite instability (MSI). RESULTS Duodenal carcinomas were methylated more frequently or had increased methylation densities than biliary carcinomas at p14 (P = 0.04), hMLH1 (P = 0.04), MGMT (P = 0.01), MINT1 (P = 0.01), MINT25 (P = 0.01), MINT27 (P = 0.001), RAR beta (P = 0.03), and ER (P = 0.001), and than ampullary carcinomas at RAR beta (P = 0.02) and ER (P = 0.03). In contrast, the methylation profiles of biliary and ampullary carcinomas were not statistically different. Simultaneous methylation of 3 or more CpG islands (CpG island methylator phenotype-high) was more common in duodenal cancers (P = 0.004). MGMT methylation was associated with G-to-A mutation in K-ras (P = 0.006), and hMLH1 methylation was associated with MSI-high (P = 0.01). CONCLUSIONS Our findings indicate that the methylation profile and genetic alterations of duodenal carcinomas are distinct from biliary and ampullary carcinomas, and that tumor-specific methylation is associated with gene mutation and MSI.
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Affiliation(s)
- Sang Geol Kim
- Department of Pathology, the University of Texas M. D. Anderson Cancer Center, Houston, 77030, USA
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Moore PS, Beghelli S, Zamboni G, Scarpa A. Genetic abnormalities in pancreatic cancer. Mol Cancer 2003; 2:7. [PMID: 12537585 PMCID: PMC149421 DOI: 10.1186/1476-4598-2-7] [Citation(s) in RCA: 58] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2002] [Accepted: 01/07/2003] [Indexed: 01/30/2023] Open
Abstract
The incidence and mortality of pancreatic adenocarcinoma are nearly coincident having a five-year survival of less than 5%. Enormous advances have been made in our knowledge of the molecular alterations commonly present in ductal cancer and other pancreatic malignancies. One significant outcome of these studies is the recognition that common ductal cancers have a distinct molecular fingerprint compared to other nonductal or endocrine tumors. Ductal carcinomas typically show alteration of K-ras, p53, p16INK4, DPC4 and FHIT, while other pancreatic tumor types show different aberrations. Among those tumors arising from the exocrine pancreas, only ampullary cancers have a molecular fingerprint that may involve some of the same genes most frequently altered in common ductal cancers. Significant molecular heterogeneity also exists among pancreatic endocrine tumors. Nonfunctioning pancreatic endocrine tumors have frequent mutations in MEN-1 and may be further subdivided into two clinically relevant subgroups based on the amount of chromosomal alterations. The present review will provide a brief overview of the genetic alterations that have been identified in the various subgroups of pancreatic tumors. These results have important implications for the development of genetic screening tests, early diagnosis, and prognostic genetic markers.
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Affiliation(s)
- Patrick S Moore
- Dipartimento di Patologia, Università di Verona, Strada Le Grazie, 37134, Verona, Italy
| | - Stefania Beghelli
- Dipartimento di Patologia, Università di Verona, Strada Le Grazie, 37134, Verona, Italy
| | - Giuseppe Zamboni
- Dipartimento di Patologia, Università di Verona, Strada Le Grazie, 37134, Verona, Italy
| | - Aldo Scarpa
- Dipartimento di Patologia, Università di Verona, Strada Le Grazie, 37134, Verona, Italy
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Gumbs AA, Moore PS, Falconi M, Bassi C, Beghelli S, Modlin I, Scarpa A. Review of the clinical, histological, and molecular aspects of pancreatic endocrine neoplasms. J Surg Oncol 2002; 81:45-53; discussion 54. [PMID: 12210027 DOI: 10.1002/jso.10142] [Citation(s) in RCA: 74] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Pancreatic endocrine neoplasms (PENs) are rare tumors, and little is known about their genetic and chromosomal alterations. Elucidation of the molecular events involved in PEN carcinogenesis has been hindered by the fact that PENs have been considered a single disease entity. The emergence of novel molecular characterization strategies has, however, made it apparent that these lesions exhibit diverse molecular fingerprints, which will facilitate the precise delineation of PEN prognosis, histopathology, and carcinogenesis.
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Affiliation(s)
- A A Gumbs
- Department of Surgery, University of Verona, Verona, Italy
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Moore PS, Missiaglia E, Antonello D, Zamò A, Zamboni G, Corleto V, Falconi M, Scarpa A. Role of disease-causing genes in sporadic pancreatic endocrine tumors: MEN1 and VHL. Genes Chromosomes Cancer 2001; 32:177-81. [PMID: 11550286 DOI: 10.1002/gcc.1180] [Citation(s) in RCA: 78] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022] Open
Abstract
Pancreatic endocrine tumors (PETs) occur in association with multiple endocrine neoplasia type 1 (MEN1) and von Hippel-Lindau (VHL) syndromes caused by germline alterations in MEN1 and VHL, respectively. It is thus expected that these genes will also be altered in a proportion of sporadic PETs. Indeed, MEN1 is altered in about 25% of nonfamilial PETs, although no mutations have been found in VHL. For all clinical subtypes, the frequency of allelic loss on chromosome arm 11q mirrors observed mutational frequencies, with the exception of nonfunctional tumors (NF-PETs), in which mutations have been reported in only 8% of cases. As allelic loss on 11q is the most frequent event found in these neoplasms, this low frequency is somewhat puzzling, particularly in light of the fact that most MEN1-associated PETs are nonfunctioning. To clarify the role of these genes in sporadic PETs, we analyzed 31 sporadic NF-PETs, nine insulinomas, and one VIPoma for alterations in MEN1 and VHL. As somatic mutations were observed in eight (26%) of the NF tumors and in one insulinoma, it would therefore appear unlikely that an additional tumor suppressor gene related to sporadic PET pathogenesis is located on 11q. One insulinoma also had a somatic mutation in VHL, and thus this gene may also be altered in these neoplasms, albeit in a small proportion of cases.
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Affiliation(s)
- P S Moore
- Department of Pathology, Università di Verona, Strada le Grazie 8, I-37134 Verona, Italy
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de Manzoni G, Tomezzoli A, Di Leo A, Moore PS, Talamini G, Scarpa A. Clinical significance of mutator phenotype and chromosome 17p and 18q allelic loss in gastric cancer. Br J Surg 2001; 88:419-25. [PMID: 11260110 DOI: 10.1046/j.1365-2168.2001.01667.x] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
BACKGROUND Tumour stage is the only reliable prognostic factor for gastric cancer. The molecular anomalies involved in this process have the potential to serve as additional prognostic markers. METHODS Forty-four gastric cancers, treated by surgery alone, have been analysed for chromosome 17p and 18q allelic loss and for the presence of microsatellite instability (MSI), using microsatellite markers and DNA from paraffin-embedded tumours. RESULTS Eight cancers showed a MSI-positive (MSI+) phenotype. Among the 36 MSI-negative cancers, chromosome 17p and 18q allelic losses were found in 22 of 34 and 19 of 33 informative cases respectively. Multivariate survival analysis indicated MSI status to be an independent prognostic factor along with the tumour stage. MSI+ cancers were associated with longer patient survival, whereas MSI-negative cancers had a significantly poorer prognosis (P = 0.007), with a median actuarial survival of 24 months. CONCLUSION MSI status is an independent prognostic factor among gastric cancers at the same stage. Chromosome 17p and 18q status added no additional prognostic information to that of tumour stage. The combined use of tumour stage and MSI status may help in deciding whether patients with advanced gastric cancer require additional therapy other than surgery alone.
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Affiliation(s)
- G de Manzoni
- Istituto di Semeiotica Chirurgica, Dipartimento di Patologia, Università di Verona, Verona, Italy
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Moore PS, Orlandini S, Zamboni G, Capelli P, Rigaud G, Falconi M, Bassi C, Lemoine NR, Scarpa A. Pancreatic tumours: molecular pathways implicated in ductal cancer are involved in ampullary but not in exocrine nonductal or endocrine tumorigenesis. Br J Cancer 2001; 84:253-62. [PMID: 11161385 PMCID: PMC2363700 DOI: 10.1054/bjoc.2000.1567] [Citation(s) in RCA: 153] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023] Open
Abstract
Alterations of K- ras, p53, p16 and DPC4/Smad4 characterize pancreatic ductal cancer (PDC). Reports of inactivation of these latter two genes in pancreatic endocrine tumours (PET) suggest that common molecular pathways are involved in the tumorigenesis of pancreatic exocrine and endocrine epithelia. We characterized 112 primary pancreatic tumours for alterations in p16 and DPC4 and immunohistochemical expression of DPC4. The cases included 34 PDC, 10 intraductal papillary-mucinous tumours (IPMT), 6 acinar carcinomas (PAC), 5 solid-pseudopapillary tumours (SPT), 16 ampulla of Vater cancers (AVC) and 41 PET. All tumours were also presently or previously analysed for K- ras and p53 mutations and allelic loss at 9p, 17p and 18q. Alterations in K- ras, p53, p16 and DPC4 were found in 82%, 53%, 38% and 9% of PDC, respectively and in 47%, 60%, 25% and 6% of AVC. Alterations in these genes were virtually absent in PET, PAC or SPT, while in IPMT only K- ras mutations were present (30%). Positive immunostaining confirmed the absence of DPC4 alterations in all IPMT, SPT, PAC and PET, while 47% of PDC and 38% of AVC were immunonegative. These data suggest that pancreatic exocrine and endocrine tumourigenesis involves different genetic targets and that among exocrine pancreatic neoplasms, only ductal and ampullary cancers share common molecular events.
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MESH Headings
- Adenocarcinoma, Mucinous/genetics
- Adenocarcinoma, Mucinous/metabolism
- Adenocarcinoma, Mucinous/pathology
- Ampulla of Vater/metabolism
- Ampulla of Vater/pathology
- Base Sequence
- Carcinoma, Acinar Cell/genetics
- Carcinoma, Acinar Cell/metabolism
- Carcinoma, Acinar Cell/pathology
- Carcinoma, Ductal, Breast/genetics
- Carcinoma, Ductal, Breast/metabolism
- Carcinoma, Ductal, Breast/pathology
- Carcinoma, Pancreatic Ductal/genetics
- Carcinoma, Pancreatic Ductal/metabolism
- Carcinoma, Pancreatic Ductal/pathology
- Carcinoma, Papillary/genetics
- Carcinoma, Papillary/metabolism
- Carcinoma, Papillary/pathology
- Common Bile Duct Neoplasms/genetics
- Common Bile Duct Neoplasms/metabolism
- Common Bile Duct Neoplasms/pathology
- Cyclin-Dependent Kinase Inhibitor p16/analysis
- Cyclin-Dependent Kinase Inhibitor p16/genetics
- DNA/chemistry
- DNA/genetics
- DNA Mutational Analysis
- DNA-Binding Proteins/analysis
- DNA-Binding Proteins/genetics
- Endocrine Gland Neoplasms/genetics
- Endocrine Gland Neoplasms/metabolism
- Endocrine Gland Neoplasms/pathology
- Endocrine Glands/metabolism
- Endocrine Glands/pathology
- Exocrine Glands/metabolism
- Exocrine Glands/pathology
- Humans
- Immunohistochemistry
- Loss of Heterozygosity
- Mutation
- Pancreatic Neoplasms/genetics
- Pancreatic Neoplasms/metabolism
- Pancreatic Neoplasms/pathology
- Polymorphism, Single-Stranded Conformational
- Smad4 Protein
- Trans-Activators/analysis
- Trans-Activators/genetics
- Tumor Suppressor Protein p53/analysis
- Tumor Suppressor Protein p53/genetics
- ras Proteins/analysis
- ras Proteins/genetics
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Affiliation(s)
- P S Moore
- Department of Pathology, Università di Verona, Italy
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