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Jun SY, Lee EJ, Kim SI, An S. Tumor Microenvironment Prognostic Risk and Its Association With MUC5AC in Ampullary Carcinoma. Arch Pathol Lab Med 2023; 147:1060-1074. [PMID: 36445719 DOI: 10.5858/arpa.2022-0131-oa] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/05/2022] [Indexed: 09/01/2023]
Abstract
CONTEXT.— The tumor-host interaction in the tumor microenvironment (TME) affects the prognosis of patients with malignant tumors. TME assessed via tumor budding (BD) and tumor-infiltrating lymphocyte (TIL) had a prognostic impact in patients with nonampullary small intestinal and colorectal carcinomas. In ampullary carcinoma (AC), MUC5AC was recently revealed as a significant prognosticator, but studies about the TME have not been conducted. OBJECTIVE.— To assess TME-based prognostic risk in AC. DESIGN.— We generated a collective TME risk index based on high-grade BD at the invasive front (BD3) and high density of stromal-TIL (>5%) in 64 surgically resected ACs. We evaluated its predictive values for overall survival (OS) and recurrence-free survival (RFS). We also investigated the relationship of TME to MUC5AC expression. RESULTS.— TME prognostic risk index was classified into low-risk (BDLow/TILHigh; 26 of 64; 41%), intermediate-risk (BDLow/TILLow or BDHigh/TILHigh; 23; 36%), and high-risk (BDHigh/TILLow; 15; 23%) groups. Higher TME prognostic risk was associated with higher tumor grade (P = .03), lymphovascular invasion (P = .05), and MUC5AC immunopositivity (P = .02). TME prognostic risk index displayed better predictive ability for both OS (53.9 versus 46.1 versus 42.2) and RFS (24.8 versus 16.9 versus 15.3) than BD or TIL alone. In multivariate analysis, TME prognostic risk index was an independent prognosticator for OS (P = .003) and RFS (P = .03). CONCLUSIONS.— TME risk index in combination with BD and TIL was a stronger predictor of prognostic risk stratification than either BD or TIL alone for both OS and RFS in patients with AC. MUC5AC may modulate the interaction between tumor cells and immunity toward enhancing invasiveness in TME.
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Affiliation(s)
- Sun-Young Jun
- From the Department of Pathology (Jun, Kim, An), Incheon St Mary�s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Eui-Jin Lee
- The Clinical Research Center (Lee), Incheon St Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Sang-Il Kim
- From the Department of Pathology (Jun, Kim, An), Incheon St Mary�s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Soyeon An
- From the Department of Pathology (Jun, Kim, An), Incheon St Mary�s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
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Apurva, Abdul Sattar RS, Ali A, Nimisha, Kumar Sharma A, Kumar A, Santoshi S, Saluja SS. Molecular pathways in periampullary cancer: An overview. Cell Signal 2022; 100:110461. [PMID: 36096460 DOI: 10.1016/j.cellsig.2022.110461] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2022] [Revised: 08/19/2022] [Accepted: 08/29/2022] [Indexed: 11/22/2022]
Abstract
Molecular alterations in oncogenes and tumor suppressors in various signaling pathways are basis for personalized therapy in cancer. Periampullary carcinoma behaves differently from pancreatic carcinoma both in prognosis and outcome, therefore it needs special attention. Pancreatic cancer have higher incidence of nodal spread and perineural &lymphovascular invasion suggesting it biologically more aggressive tumor compared to periampullary cancer. Since PAC tumors consist of heterogenous tissue of origin, they might contain different mutations in tumor associated genes and other changes in tissue composition among different subgroups clubbed together. Significant progress has been made in understanding the molecular nature of PAC in the previous two decades, and a large number of mutations and other genetic changes have been identified as being responsible for the disease. This review article targets to collate and discuss the molecular evolution of PAC and their implication in its outcome. As per literature, mitogen-activated protein kinase (MAPK), phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K), and Wnt signaling are the most common pathways involved in PAC. Mutations in KRAS, TP53, CTNNB1, SMAD4 and APC genes were the most frequently reported. I-subtype resembles colorectal cancer while the morphology of PB-type shows close resemblance to pancreatic tumors. The frequency of driver gene mutations is higher in I-type compared to PB-type of PAC indicating I-type to be genetically more unstable. The genetic landscape of PAC obtained from WES data highlighted PI3/AKT pathway to be a primary target in I-type and RAS/RAF in PB-type.
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Affiliation(s)
- Apurva
- Central Molecular Lab, GovindBallabhPant Institute of Postgraduate Medical Education and Research (GIPMER), New Delhi, India; Amity University, Noida, India
| | - Real Sumayya Abdul Sattar
- Central Molecular Lab, GovindBallabhPant Institute of Postgraduate Medical Education and Research (GIPMER), New Delhi, India
| | - Asgar Ali
- Central Molecular Lab, GovindBallabhPant Institute of Postgraduate Medical Education and Research (GIPMER), New Delhi, India
| | - Nimisha
- Central Molecular Lab, GovindBallabhPant Institute of Postgraduate Medical Education and Research (GIPMER), New Delhi, India
| | - Abhay Kumar Sharma
- Central Molecular Lab, GovindBallabhPant Institute of Postgraduate Medical Education and Research (GIPMER), New Delhi, India
| | - Arun Kumar
- Central Molecular Lab, GovindBallabhPant Institute of Postgraduate Medical Education and Research (GIPMER), New Delhi, India
| | | | - Sundeep Singh Saluja
- Central Molecular Lab, GovindBallabhPant Institute of Postgraduate Medical Education and Research (GIPMER), New Delhi, India; Department of GI Surgery, GovindBallabh Pant Institute of Postgraduate Medical Education and Research (GIPMER), New Delhi, India.
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Fernandez-Placencia RM, Montenegro P, Guerrero M, Serrano M, Ortega E, Bravo M, Huanca L, Bertani S, Trejo JM, Webb P, Malca-Vasquez J, Taxa L, Lachos-Davila A, Celis-Zapata J, Luque-Vasquez C, Payet E, Ruiz E, Berrospi F. Survival after curative pancreaticoduodenectomy for ampullary adenocarcinoma in a South American population: A retrospective cohort study. World J Gastrointest Surg 2022; 14:24-35. [PMID: 35126860 PMCID: PMC8790327 DOI: 10.4240/wjgs.v14.i1.24] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/10/2021] [Revised: 09/28/2021] [Accepted: 01/13/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Ampullary adenocarcinoma (AAC) is a rare neoplasm that accounts for only 0.2% of all gastrointestinal cancers. Its incidence rate is lower than 6 cases per million people. Different prognostic factors have been described for AAC and are associated with a wide range of survival rates. However, these studies have been exclusively conducted in patients originating from Asian, European, and North American countries. AIM To evaluate the histopathologic predictors of overall survival (OS) in South American patients with AAC treated with curative pancreaticoduodenectomy (PD). METHODS We analyzed retrospective data from 83 AAC patients who underwent curative (R0) PD at the National Cancer Institute of Peru between January 2010 and October 2020 to identify histopathologic predictors of OS. RESULTS Sixty-nine percent of patients had developed intestinal-type AAC (69%), 23% had pancreatobiliary-type AAC, and 8% had other subtypes. Forty-one percent of patients were classified as Stage I, according to the AJCC 8th Edition. Recurrence occurred primarily in the liver (n = 8), peritoneum (n = 4), and lung (n = 4). Statistical analyses indicated that T3 tumour stage [hazard ratio (HR) of 6.4, 95% confidence interval (CI) of 2.5-16.3, P < 0.001], lymph node metastasis (HR: 4.5, 95%CI: 1.8-11.3, P = 0.001), and pancreatobiliary type (HR: 2.7, 95%CI: 1.2-6.2, P = 0.025) were independent predictors of OS. CONCLUSION Extended tumour stage (T3), pancreatobiliary type, and positive lymph node metastasis represent independent predictors of a lower OS rate in South American AAC patients who underwent curative PD.
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Affiliation(s)
| | - Paola Montenegro
- Department of Medical Oncology, Instituto Nacional de Enfermedades Neoplasicas, Lima 15038, Peru
| | - Melvy Guerrero
- Department of Pathology, Instituto Nacional de Enfermedades Neoplasicas, Lima 15038, Peru
| | - Mariana Serrano
- Department of Medical Oncology, Instituto Nacional de Enfermedades Neoplasicas, Lima 15038, Peru
| | - Emperatriz Ortega
- Department of Medical Oncology, Instituto Nacional de Enfermedades Neoplasicas, Lima 15038, Peru
| | - Mercedes Bravo
- Department of Pathology, Instituto Nacional de Enfermedades Neoplasicas, Lima 15038, Peru
| | - Lourdes Huanca
- Department of Pathology, Instituto Nacional de Enfermedades Neoplasicas, Lima 15038, Peru
| | - Stéphane Bertani
- International Joint Laboratory of Molecular Anthopological Oncology, Instituto Nacional de Enfermedades Neoplasicas, Lima 15038, Peru
- Unite Pharmacochim & Pharmacol Dev, UMR152, F-31062 Toulouse, France
| | - Juan Manuel Trejo
- Department of Radiation Oncology, Instituto Nacional de Enfermedades Neoplasicas, Lima 15038, Peru
| | - Patricia Webb
- Department of Pathology, Instituto Nacional de Enfermedades Neoplasicas, Lima 15038, Peru
| | - Jenny Malca-Vasquez
- Department of Radiation Oncology, Instituto Nacional de Enfermedades Neoplasicas, Lima 15038, Peru
| | - Luis Taxa
- Department of Pathology, Instituto Nacional de Enfermedades Neoplasicas, Lima 15038, Peru
| | - Alberto Lachos-Davila
- Department of Radiation Oncology, Instituto Nacional de Enfermedades Neoplasicas, Lima 15038, Peru
| | - Juan Celis-Zapata
- Hepato-Pancreato-Biliary Section, Department of Abdominal Surgery, Instituto Nacional de Enfermedades Neoplasicas, Lima 15038, Peru
| | - Carlos Luque-Vasquez
- Department of Abdominal Surgery, Instituto Nacional de Enfermedades Neoplasicas, Lima 15038, Peru
| | - Eduardo Payet
- Department of Abdominal Surgery, Instituto Nacional de Enfermedades Neoplasicas, Lima 15038, Peru
| | - Eloy Ruiz
- Hepato-Pancreato-Biliary Section, Department of Abdominal Surgery, Instituto Nacional de Enfermedades Neoplasicas, Lima 15038, Peru
| | - Francisco Berrospi
- Hepato-Pancreato-Biliary Section, Department of Abdominal Surgery, Instituto Nacional de Enfermedades Neoplasicas, Lima 15038, Peru
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Rare Orbital Metastasis Originating from Ampullary Adenocarcinoma. MEDICINA (KAUNAS, LITHUANIA) 2021; 57:medicina57111238. [PMID: 34833456 PMCID: PMC8624159 DOI: 10.3390/medicina57111238] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/14/2021] [Accepted: 11/12/2021] [Indexed: 12/13/2022]
Abstract
Background: Orbital metastasis from ampullary carcinoma is rare, with no previously reported cases. Case presentation: We report the case of a 60-year-old man who complained of a right-sided headache, blurred vision, progressive proptosis, ptosis, and right eye pain for 3 months. His past medical history included an ampullary adenocarcinoma stage IIIA treated via the Whipple procedure and adjuvant chemoradiotherapy 1 year ago. However, he was lost to follow-up. Computed tomography of the orbit showed a soft tissue lesion in the right orbital fossa measuring 3.3 × 2 × 2 cm. An orbital mass biopsy demonstrated an intestinal-type adenocarcinoma that tested positive for cytokeratins 7 and 20 and CDX2 on immunohistochemical staining. The pathologic diagnosis was metastatic adenocarcinoma from the ampulla of Vater. Despite oncological treatment, the patient’s illness progressed. He received palliative treatment and died 1 month later. Conclusions: We presented a rare case of orbital metastasis from ampullary adenocarcinoma. This should be considered in the differential diagnosis of patients with a history of ampullary adenocarcinoma who present with symptoms referring to the relevant locations.
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Hong SM. Histologic subtyping of ampullary carcinoma for targeted therapy. J Pathol Transl Med 2021; 55:235. [PMID: 34015888 PMCID: PMC8141967 DOI: 10.4132/jptm.2021.04.28] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2021] [Accepted: 04/29/2021] [Indexed: 11/17/2022] Open
Affiliation(s)
- Seung-Mo Hong
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
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Zhu M, Jin Z, Hubbard JM. Management of Non-Colorectal Digestive Cancers with Microsatellite Instability. Cancers (Basel) 2021; 13:651. [PMID: 33561950 PMCID: PMC7915546 DOI: 10.3390/cancers13040651] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2021] [Revised: 01/26/2021] [Accepted: 02/03/2021] [Indexed: 02/08/2023] Open
Abstract
Microsatellite instability (MSI) is a hallmark of genetic predisposition to DNA damage. It arises from either germline or somatic events leading to impaired function of the mismatch repair system. It can be detected via genetic sequencing or immunohistochemistry with relatively high concordance rates. The presence of MSI in a tumor reflects a high neoantigen load and predicts favorable treatment response to immune checkpoint inhibitors (ICIs). In gastrointestinal cancers, MSI is a predictive biomarker for ICIs with potential prognostic impact but its clinical utility varies widely depending on tumor type. This may be explained by the complexity of tumor microenvironment as highlighted by recent translational studies. In this review, we will discuss the predictive and prognostic value of MSI status in non-colorectal cancers of the digestive system, important clinical trials involving ICIs and potential strategies to overcome resistance to immunotherapy.
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Affiliation(s)
- Mojun Zhu
- Department of Medical Oncology, Mayo Clinic, Rochester, MN 55905, USA; (Z.J.); (J.M.H.)
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Palmeri M, Funel N, Franco GD, Furbetta N, Gianardi D, Guadagni S, Bianchini M, Pollina LE, Ricci C, Chiaro MD, Candio GD, Morelli L. Tissue microarray-chip featuring computerized immunophenotypical characterization more accurately subtypes ampullary adenocarcinoma than routine histology. World J Gastroenterol 2020; 26:6822-6836. [PMID: 33268964 PMCID: PMC7684454 DOI: 10.3748/wjg.v26.i43.6822] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/29/2020] [Revised: 06/24/2020] [Accepted: 08/27/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Ampullary adenocarcinomas (AACs) are heterogeneous tumors currently classified into three important sub-classes (SC): Intestinal (INT), Pancreato-Biliary (PB) and Mixed-Type (MT). The different subgroups have similar clinical presentation and are treated by pancreatoduodenectomy with curative intent. However, they respond differently to chemotherapy and have different prognostic outcomes. The SC are often difficult to identify with conventional histology alone. The clinical outcome of all three remains unclear, particularly for MT. AIM To identify two main subtypes of AACs, using an immunohistochemical (IHC) score based on CDX2, CK7 and CK20. METHODS Tissue samples from 21 patients who had undergone resection of AAC were classified by HE histology and IHC expression of CDX2, CK7 and CK 20. An IHC score was obtained for each marker by counting the number of positive cells (0 = no stained cells; 1 < 25%; 2 < 50% and 3 > 50%) and their intensity (1 = weak; 2 = moderate and 3 = strong). A global score (GS) was then obtained by summation of the IHC scores of each marker. The MT tumors were grouped either with the INT or PB group based on the predominant immuno-molecular phenotype, obtaining only two AACs subtypes. The overall survival in INT and PB patients was obtained by Kaplan-Meier methods. RESULTS Histological parameters defined the AACs subtypes as follows: 15% INT, 45% PB and 40% MT. Using IHC expression and the GS, 75% and 25% of MT samples were assigned to either the INT or the PB group. The mean value of the GS was 9.5 (range 4-16). All INT samples had a GS above the average, distinct from the PB samples which had a GS score significantly below the average (P = 0.0011). The INT samples were identified by high expression of CDX2 and CK20, whereas PB samples exhibited high expression of CK7 and no expression of CK20 (P = 0.0008). The INT group had a statistically significant higher overall survival than in the PB group (85.7 mo vs 20.3 mo, HR: 8.39; 95%CI: 1.38 to 18.90; P = 0.0152). CONCLUSION The combination of histopathological and molecular criteria enables the classification of AACs into two clinically relevant histo-molecular phenotypes, which appear to represent distinct disorders with potentially significant changes to the current therapeutic strategies.
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Affiliation(s)
- Matteo Palmeri
- General Surgery Unit, Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa 56124, Italy
| | - Niccola Funel
- Division of Surgical Pathology, University-Hospital of Pisa, Pisa 56124, Italy
| | - Gregorio Di Franco
- General Surgery Unit, Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa 56124, Italy
| | - Niccolò Furbetta
- General Surgery Unit, Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa 56124, Italy
| | - Desirée Gianardi
- General Surgery Unit, Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa 56124, Italy
| | - Simone Guadagni
- General Surgery Unit, Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa 56124, Italy
| | - Matteo Bianchini
- General Surgery Unit, Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa 56124, Italy
| | - Luca E Pollina
- Division of Surgical Pathology, University-Hospital of Pisa, Pisa 56124, Italy
| | - Claudio Ricci
- Department of Surgical, Medical, Molecular Pathology and Critical Area, University of Pisa, Pisa 56124, Italy
| | - Marco Del Chiaro
- Department of Surgery, University of Colorado, Denver, CO 80045, United States
| | - Giulio Di Candio
- General Surgery Unit, Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa 56124, Italy
| | - Luca Morelli
- General Surgery Unit, Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa 56124, Italy
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