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Vanoli A, Grillo F, De Lisi G, Guerini C, Arpa G, Klersy C, Fassan M, Parente P, Mastracci L, Biletta E, Nesi G, Macciomei MC, Lenti MV, Quaquarini E, Chiaravalli AM, Furlan D, La Rosa S, Paulli M, Di Sabatino A. Medullary carcinomas of the nonampullary small intestine: association with coeliac disease, mismatch repair deficiency, PD-L1 expression, and favourable prognosis. Histopathology 2025; 86:236-246. [PMID: 39192803 PMCID: PMC11649516 DOI: 10.1111/his.15307] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2024] [Revised: 06/20/2024] [Accepted: 08/10/2024] [Indexed: 08/29/2024]
Abstract
AIM Gastrointestinal medullary carcinoma is a rare histologic subtype of adenocarcinoma. As nonampullary small bowel medullary carcinomas (SB-MCs) are poorly characterized, we aimed to analyse their clinicopathologic and immunohistochemical features and to compare them with nonmedullary small bowel adenocarcinomas (NM-SBAs). METHODS AND RESULTS Surgically resected SBAs collected through the Small Bowel Cancer Italian Consortium were classified as SB-MCs (carcinomas with ≥50% of tumour fulfilling the typical histologic criteria of MC) or NM-SBAs. Immunohistochemistry for cytokeratin (CK)7, CK20, CDX2, programmed death-ligand 1 (PD-L1) and mismatch repair proteins was performed in both SB-MCs and NM-SBAs. SB-MCs were also tested for CK8/18, synaptophysin, SMARCB1, SMARCA2, SMARCA4, and ARID1A and for Epstein-Barr virus (EBV)-encoded RNAs by in-situ hybridization. MLH1 promoter methylation status was evaluated in MLH1-deficient cases. Eleven SB-MCs and 149 NM-SBAs were identified. One (9%) SB-MC was EBV-positive, while 10 (91%) harboured mismatch repair deficiency (dMMR). MLH1 promoter hypermethylation was found in all eight dMMR SB-MCs tested. Switch/sucrose nonfermentable deficiency was seen in two (18%) SB-MCs, both with isolated loss of ARID1A. Compared with NM-SBAs, SB-MCs exhibited an association with coeliac disease (P < 0.001), higher rates of dMMR (P < 0.001), and PD-L1 positivity by both tumour proportion score and combined positive score (P < 0.001 for both), and a lower rate of CK20 expression (P = 0.024). Survival analysis revealed a better prognosis of SB-MC patients compared to NM-SBA cases (P = 0.02). CONCLUSION SB-MCs represent a distinct histologic subtype, with peculiar features compared to NM-SBAs, including association with coeliac disease, dMMR, PD-L1 expression, and better prognosis.
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MESH Headings
- Humans
- B7-H1 Antigen/metabolism
- Female
- Male
- Aged
- Middle Aged
- Prognosis
- Celiac Disease/pathology
- Celiac Disease/complications
- Celiac Disease/metabolism
- Intestinal Neoplasms/pathology
- Intestinal Neoplasms/metabolism
- Biomarkers, Tumor/analysis
- Biomarkers, Tumor/metabolism
- Biomarkers, Tumor/genetics
- Carcinoma, Medullary/pathology
- Carcinoma, Medullary/metabolism
- Carcinoma, Medullary/genetics
- Adult
- Intestine, Small/pathology
- Intestine, Small/metabolism
- DNA Mismatch Repair
- Aged, 80 and over
- Neoplastic Syndromes, Hereditary/pathology
- Immunohistochemistry
- Adenocarcinoma/pathology
- Adenocarcinoma/metabolism
- Adenocarcinoma/genetics
- Brain Neoplasms
- Colorectal Neoplasms
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Affiliation(s)
- Alessandro Vanoli
- Department of Molecular MedicineUniversity of PaviaPaviaItaly
- Unit of Anatomic PathologyIRCCS San Matteo Hospital FoundationPaviaItaly
| | - Federica Grillo
- IRCCS Ospedale Policlinico San MartinoGenoaItaly
- Pathology Unit, Department of Surgical Sciences and Integrated Diagnostics (DISC)University of GenoaGenoaItaly
| | | | - Camilla Guerini
- Department of Molecular MedicineUniversity of PaviaPaviaItaly
| | - Giovanni Arpa
- Department of Molecular MedicineUniversity of PaviaPaviaItaly
- Anatomic Pathology Unit of Pavia InstituteIstituti Clinici Scientifici Maugeri IRCCSPaviaItaly
| | - Catherine Klersy
- Biostatistics and Clinical Trial CenterFondazione IRCCS Policlinico San MatteoPaviaItaly
| | - Matteo Fassan
- Department of Medicine (DIMED), Surgical Pathology & Cytopathology UnitUniversity of PaduaPaduaItaly
- Veneto Institute of Oncology IOV‐IRCCSPaduaItaly
| | - Paola Parente
- Unit of PathologyFondazione IRCCS Ospedale Casa Sollievo della SofferenzaSan Giovanni RotondoItaly
| | - Luca Mastracci
- IRCCS Ospedale Policlinico San MartinoGenoaItaly
- Pathology Unit, Department of Surgical Sciences and Integrated Diagnostics (DISC)University of GenoaGenoaItaly
| | - Elena Biletta
- Unit of Pathology, Department of Surgery ASL BINuovo Ospedale degli InfermiPonderanoItaly
| | - Gabriella Nesi
- Pathology Section, Department of Health SciencesUniversity of FlorenceFlorenceItaly
| | | | - Marco V Lenti
- Department of Internal Medicine and Medical TherapeuticsUniversity of PaviaPaviaItaly
- Department of Internal MedicineIRCCS San Matteo Hospital FoundationPaviaItaly
| | - Erica Quaquarini
- Medical Oncology UnitIstituti Clinici Scientifici Maugeri IRCCSPaviaItaly
| | - Anna M Chiaravalli
- Department of OncologyOspedale di Circolo, ASST‐Sette LaghiVareseItaly
- Hereditary Cancer Research CenterUniversity of InsubriaVareseItaly
| | - Daniela Furlan
- Department of OncologyOspedale di Circolo, ASST‐Sette LaghiVareseItaly
- Hereditary Cancer Research CenterUniversity of InsubriaVareseItaly
- Unit of Pathology, Department of Medicine and Technological InnovationUniversity of InsubriaVareseItaly
| | - Stefano La Rosa
- Department of OncologyOspedale di Circolo, ASST‐Sette LaghiVareseItaly
- Hereditary Cancer Research CenterUniversity of InsubriaVareseItaly
- Unit of Pathology, Department of Medicine and Technological InnovationUniversity of InsubriaVareseItaly
| | - Marco Paulli
- Department of Molecular MedicineUniversity of PaviaPaviaItaly
- Unit of Anatomic PathologyIRCCS San Matteo Hospital FoundationPaviaItaly
| | - Antonio Di Sabatino
- Department of Internal Medicine and Medical TherapeuticsUniversity of PaviaPaviaItaly
- Department of Internal MedicineIRCCS San Matteo Hospital FoundationPaviaItaly
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Christodoulidis G, Kouliou MN, Koumarelas KE. Immune signature of small bowel adenocarcinoma and the role of tumor microenvironment. World J Gastroenterol 2024; 30:794-798. [PMID: 38516246 PMCID: PMC10950647 DOI: 10.3748/wjg.v30.i8.794] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/23/2023] [Revised: 01/13/2024] [Accepted: 01/30/2024] [Indexed: 02/26/2024] Open
Abstract
In this editorial we comment on the article published "Clinical significance of programmed cell death-ligand expression in small bowel adenocarcinoma is determined by the tumor microenvironment". Small bowel adenocarcinoma (SBA) is a rare gastrointestinal neoplasm and despite the small intestine's significant surface area, SBA accounts for less than 3% of such tumors. Early detection is challenging and the reason arises from its asymptomatic nature, often leading to late-stage discovery and poor prognosis. Treatment involves platinum-based chemotherapy with a 5-fluorouracil combination, but the lack of effective chemotherapy contributes to a generally poor prognosis. SBAs are linked to genetic disorders and risk factors, including chronic inflammatory conditions. The unique characteristics of the small bowel, such as rapid cell renewal and an active immune system, contributes to the rarity of these tumors as well as the high intratumoral infiltration of immune cells is associated with a favorable prognosis. Programmed cell death-ligand 1 (PD-L1) expression varies across different cancers, with potential discrepancies in its prognostic value. Microsatellite instability (MSI) in SBA is associated with a high tumor mutational burden, affecting the prognosis and response to immunotherapy. The presence of PD-L1 and programmed cell death 1, along with tumor-infiltrating lymphocytes, plays a crucial role in the complex microenvironment of SBA and contributes to a more favorable prognosis, especially in the context of high MSI tumors. Stromal tumor-infiltrating lymphocytes are identified as independent prognostic indicators and the association between MSI status and a favorable prognosis, emphasizes the importance of evaluating the immune status of tumors for treatment decisions.
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Yu D, Wang J, Zheng B, Yuan M, Gu D, Chen R, Chen X. Comprehensive genomic profiling of small bowel adenocarcinoma by tissue and plasma biopsy. Genomics 2024; 116:110766. [PMID: 38141930 DOI: 10.1016/j.ygeno.2023.110766] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2023] [Revised: 12/14/2023] [Accepted: 12/18/2023] [Indexed: 12/25/2023]
Abstract
Small bowel adenocarcinoma (SBA) is a rare and aggressive malignancy with limited treatment options and poor prognosis. The molecular landscape and immunological characteristics of SBA are poorly understood. Here, we performed comprehensive mutation profiling of tissue and plasma biopsies from 143 and 42 patients with SBA. Analysis showed that SBA had a distinct mutation spectrum from left- and right-sided colorectal carcinoma. Plasma biopsy had high concordance with tissue biopsy for single nucleotide variants and structural variants, but low concordance for copy number variations, which showed that plasma biopsy can be an alternative to tissue biopsy. Moreover, we analyzed the association of TMB with clinical and molecular features, and found that TMB was significantly higher in tumors with DNA damage response alterations. Our findings provide valuable insights into the molecular and immunological features of SBA and demonstrate the potential of plasma biopsy as a non-invasive method for SBA diagnosis and treatment.
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Affiliation(s)
- Dan Yu
- The Second Xiangya Hospital of Central South University, Hunan 410011, China
| | - Jianzheng Wang
- Department of Oncology, the Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Henan Engineering Research Center of Precision Therapy of Gastrointestinal Cancer & Zhengzhou Key Laboratory for Precision Therapy of Gastrointestinal Cancer, Zhengzhou 450008, China
| | - Bo Zheng
- Geneplus-Beijing, Beijing 102206, China.
| | | | - Dejian Gu
- Geneplus-Beijing, Beijing 102206, China
| | | | - Xiaobing Chen
- Department of Oncology, the Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Henan Engineering Research Center of Precision Therapy of Gastrointestinal Cancer & Zhengzhou Key Laboratory for Precision Therapy of Gastrointestinal Cancer, Zhengzhou 450008, China.
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Hoshimoto A, Tatsuguchi A, Hamakubo R, Nishimoto T, Omori J, Akimoto N, Tanaka S, Fujimori S, Hatori T, Shimizu A, Iwakiri K. Clinical significance of programmed cell death-ligand expression in small bowel adenocarcinoma is determined by the tumor microenvironment. World J Gastroenterol 2023; 29:5566-5581. [PMID: 37970475 PMCID: PMC10642439 DOI: 10.3748/wjg.v29.i40.5566] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/14/2023] [Revised: 10/04/2023] [Accepted: 10/23/2023] [Indexed: 10/27/2023] Open
Abstract
BACKGROUND Comprehensive genomic analysis has shown that small bowel adenocarcinoma (SBA) has different genomic profiles from gastric and colorectal cancers. Hence, it is essential to establish chemotherapeutic regimens based on SBA characteristics. The expression of programmed cell death-ligand 1 (PD-L1) and programmed cell death-ligand 2 (PD-L2) in SBA is not fully understood. Anti-PD-L1/PD-1 therapy uses tumor-infiltrating lymphocytes (TILs); therefore, the status of TILs in the tumor microenvironment (TME) may influence their efficacy. The ratio of FoxP3+ to CD8+ T cells has been reported to be useful in predicting the prognosis of digestive system cancers. AIM To investigate the clinicopathological significance of PD-L1/2 expression according to the status of TILs in SBA tissues. METHODS We performed immunohistochemical analysis for PD-L1, PD-L2, CD8, FoxP3, and DNA mismatch repair (MMR) proteins using formalin-fixed, paraffin-embedded tissues from 50 patients diagnosed with primary SBA. The immunoreactivities of PD-L1 and PD-L2 were determined separately in tumor cells and tumor-infiltrating immune cells throughout the tumor center and invasive margins, and finally evaluated using the combined positive score (CPS). We assessed CD8+ and FoxP3+ T cells in the intratumoral and tumor-surrounding stroma. Subsequently, we calculated and summed the ratio of FoxP3 to CD8+ T cell counts. Immune-related cell densities were graded as low or high. Immunohistochemical results were compared with clinicopathological factors and patient prognosis. The distribution of cancer-specific survival (CSS) was estimated using the Kaplan-Meier method, and the log-rank test was used to test for significant differences in CSS. A Cox proportional hazard model was also used to assess the effect of tumor variables on CSS. RESULTS PD-L1 expression was positive in 34% in tumor cells (T-PD-L1) and 54% in tumor-infiltrating immune cells (I-PD-L1) of the cases examined. T-PD-L2 was positive in 34% and I-PD-L2 was positive in 42% of the cases. PD-L1 CPS ≥ 10 and PD-L2 CPS ≥ 10 were observed in 50% and 56% of the cases, respectively. Deficient MMR (dMMR) was 14% of the cases. T-PD-L1, I-PD-L1 and PD-L1 CPS ≥ 10 were all significantly associated with dMMR (P = 0.037, P = 0.009, and P = 0.005, respectively). T-PD-L1, I-PD-L1, and PD-L1 CPS ≥ 10 were all associated with deeper depth of invasion (P = 0.001, P = 0.024, and P = 0.002, respectively). I-PD-L2 expression and PD-L2 CPS ≥ 10 were significantly higher in the differentiated histological type (P = 0.015 and P = 0.030, respectively). The I-PD-L1 and I-PD-L2 levels were significantly associated with better CSS (P = 0.037 and P = 0.015, respectively). CD8-high was significantly associated with less lymph node metastasis (P = 0.047), less distant metastasis (P = 0.024), less peritoneal dissemination (P = 0.034), and earlier TNM stage (P = 0.047). The CD8-high group had better prognosis than the CD8-low group (P = 0.018). FoxP3 expression was not associated with any clinicopathological factors or prognosis. We found that patients with PD-L2 CPS ≥ 10 tended to have worse prognosis in the FoxP3/CD8-low group (P = 0.088). CONCLUSION The clinicopathological significance of PD-L1/2 expression may differ depending on the TME status. Immune checkpoint inhibitors may improve the prognosis of SBA patients with low FoxP3/CD8 ratio and PD-L2 expression.
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Affiliation(s)
- Aitoshi Hoshimoto
- Department of Gastroenterology, Nippon Medical School, Tokyo 113-8603, Japan
- Department of Analytic Human Pathology, Nippon Medical School, Tokyo 113-8603, Japan
| | - Atsushi Tatsuguchi
- Department of Gastroenterology, Nippon Medical School, Tokyo 113-8603, Japan
- Department of Analytic Human Pathology, Nippon Medical School, Tokyo 113-8603, Japan
| | - Ryohei Hamakubo
- Department of Gastroenterology, Nippon Medical School, Tokyo 113-8603, Japan
| | - Takayoshi Nishimoto
- Department of Gastroenterology, Nippon Medical School, Tokyo 113-8603, Japan
| | - Jun Omori
- Department of Gastroenterology, Nippon Medical School, Tokyo 113-8603, Japan
| | - Naohiko Akimoto
- Department of Gastroenterology, Nippon Medical School, Tokyo 113-8603, Japan
| | - Shu Tanaka
- Department of Gastroenterology, Nippon Medical School, Tokyo 113-8603, Japan
| | - Shunji Fujimori
- Department of Gastroenterology, Nippon Medical School, Tokyo 113-8603, Japan
| | - Tsutomu Hatori
- Department of Pathology, Nippon Medical School, Chiba Hokusoh Hospital, Chiba 270-1694, Japan
| | - Akira Shimizu
- Department of Analytic Human Pathology, Nippon Medical School, Tokyo 113-8603, Japan
| | - Katsuhiko Iwakiri
- Department of Gastroenterology, Nippon Medical School, Tokyo 113-8603, Japan
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Programmed death-ligand 1 expression in the immune compartment of colon carcinoma. Mod Pathol 2022; 35:1740-1748. [PMID: 35773332 DOI: 10.1038/s41379-022-01128-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2021] [Revised: 06/13/2022] [Accepted: 06/15/2022] [Indexed: 11/08/2022]
Abstract
Programmed cell death ligand 1 (PD-L1) on tumor cells is a significant prognostic biomarker for a number of malignancies, although less is known about the significance of PD-L1 positive immune cells in colon carcinoma. The purpose of this study is to evaluate the role of PD-L1 in a large cohort of colon carcinomas to identify patterns of PD-L1 expression in the tumor microenvironment and its correlation with other key immune subsets to better understand the impact of these immune cells. We assessed 1218 colon carcinomas on representative tissue microarray sections, gathered relevant clinicopathologic information, and performed immunohistochemical staining for mismatch repair proteins, CD8, CD163, LAG3, PD-L1, FoxP3, and BRAF V600E. We then performed automated quantification; manual quantification was used for PD-L1 tumor cells and immune cells. Dual PD-L1/PU.1 immunostain was also performed. The majority of PD-L1 positive cells expressed PU.1 thus representing tumor-associated macrophages. Based on the median number of PD-L1 positive immune cells (7.6/mm2), we classified tumors into two classes: (1) PD-L1 immune cell low and (2) PD-L1 immune cell high. PD-L1 immune cell high colon carcinomas showed favorable prognostic pathologic features including less frequent extramural venous invasion (p = 0.0001) and lower AJCC stage (p = 0.0001); they were also more commonly associated with deficient mismatch repair (dMMR) (p = 0.0001) and BRAF V600E reactivity. PD-LI immune cell high tumors were associated with high CD8, CD163, and FoxP3 positive cells (p = 0.0001, respectively). PD-L1 immune cell high and LAG3 high colon carcinomas were associated with improved disease-specific survival (p = 0.0001 and 0.001, respectively). PD-L1 expression on tumor cells was not associated with disease-specific survival. On multivariate analysis of chemotherapy naïve stage 2 colon carcinomas, only extramural venous invasion (p = 0.002), perineural invasion (p = 0.001) and PD-L1 immune cell expression (p = 0.032) correlated with disease-specific survival. Resected colonic carcinomas with high expression of PD-L1 and LAG3 proteins on immune cells were associated with improved prognosis in colon carcinoma. The mechanism underlying the improved prognosis of colon carcinomas bearing high numbers of immunoregulatory cells needs further investigation.
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Mastracci L, Grillo F, Parente P, Gullo I, Campora M, Angerilli V, Rossi C, Sacramento ML, Pennelli G, Vanoli A, Fassan M. PD-L1 evaluation in the gastrointestinal tract: from biological rationale to its clinical application. Pathologica 2022; 114:352-364. [PMID: 36305021 PMCID: PMC9614301 DOI: 10.32074/1591-951x-803] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2022] [Accepted: 09/20/2022] [Indexed: 11/06/2022] Open
Abstract
Immune-checkpoint inhibitors targeting the PD-1/PD-L1 axis have brought significant clinical benefit in many solid cancer types, including gastrointestinal malignancies. However, it has been estimated that only 20-40% of patients respond to treatment. The pattern of expression and potential predictive value of PD-L1 as an immunohistochemical biomarker has been extensively studied in gastrointestinal neoplasms. Until now, its predictive value has been demonstrated, and is currently in use only in upper gastrointestinal malignancies (gastroesophageal adenocarcinoma and esophageal squamous cell carcinoma). In this Review, we describe the technical aspects and challenges related to PD-L1 immunohistochemical assays, the current role of PD-L1 as a biomarker in clinical practice and we outline the main studies and clinical trials analyzing the prognostic and predictive value of PD-L1 in gastrointestinal cancers.
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Affiliation(s)
- Luca Mastracci
- IRCCS Ospedale Policlinico San Martino, Genoa, Italy
- Anatomic Pathology, Department of Surgical Sciences and Integrated Diagnostics (DISC), University of Genova, Italy
| | - Federica Grillo
- IRCCS Ospedale Policlinico San Martino, Genoa, Italy
- Anatomic Pathology, Department of Surgical Sciences and Integrated Diagnostics (DISC), University of Genova, Italy
| | - Paola Parente
- Unit of Pathology, Fondazione IRCCS Ospedale Casa Sollievo della Sofferenza, San Giovanni Rotondo, FG, Italy
| | - Irene Gullo
- Department of Pathology, Centro Hospitalar Universitário de São João (CHUSJ), Porto, Portugal
- Department of Pathology, Faculty of Medicine of the University of Porto (FMUP), Portugal
- i3S - Instituto de Investigação e Inovação em Saúde da Universidade do Porto, Portugal
| | - Michela Campora
- Public Healthcare Trust of the Autonomous Province of Trento, Santa Chiara Hospital, Department of Laboratory Medicine, Pathology Unit, Trento, Italy
| | - Valentina Angerilli
- Department of Medicine (DIMED), Surgical Pathology Unit, University Hospital of Padua, Padua (PD), Italy
| | - Chiara Rossi
- Anatomic Pathology Unit, Department of Molecular Medicine, University of Pavia, and IRCCS San Matteo Hospital, Pavia, Italy
| | - Maria Luisa Sacramento
- Department of Pathology, Centro Hospitalar Universitário de São João (CHUSJ), Porto, Portugal
| | - Gianmaria Pennelli
- Department of Medicine (DIMED), Surgical Pathology Unit, University Hospital of Padua, Padua (PD), Italy
| | - Alessandro Vanoli
- Anatomic Pathology Unit, Department of Molecular Medicine, University of Pavia, and IRCCS San Matteo Hospital, Pavia, Italy
| | - Matteo Fassan
- Department of Medicine (DIMED), Surgical Pathology Unit, University Hospital of Padua, Padua (PD), Italy
- Veneto Institute of Oncology IOV - IRCCS, Padua (PD), Italy
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Cardin DB, Gilbert J, Whisenant JG, Ayers GD, Jalikis F, Dahlman KB, O'Neal JF, Revetta F, Shi C, Berlin J. Safety and Efficacy of Avelumab in Small Bowel Adenocarcinoma. Clin Colorectal Cancer 2022; 21:236-243. [DOI: 10.1016/j.clcc.2022.03.003] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2022] [Accepted: 03/17/2022] [Indexed: 11/27/2022]
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Rosenbaum MW, Gonzalez RS. Immunohistochemistry as predictive and prognostic markers for gastrointestinal malignancies. Semin Diagn Pathol 2021; 39:48-57. [PMID: 34740486 DOI: 10.1053/j.semdp.2021.10.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2021] [Accepted: 10/28/2021] [Indexed: 11/11/2022]
Abstract
Biomarkers play a key role in the comprehensive pathologic evaluation of gastrointestinal malignancies. These biomarkers can be predictive, indicating whether a tumor is likely to respond to a particular therapy, or prognostic, providing information about the likely course and outcome of a disease. This review article will discuss available immunohistochemical stains for assessing these markers, including staining rationale, scoring criteria, associated systemic therapies, and pictorial examples. PD-L1, HER2, and mismatch repair status can be evaluated via immunohistochemistry for esophageal, gastric, and colorectal carcinomas. Biomarkers currently play a more limited role in evaluation of pancreatic and small bowel malignancies. Immunohistochemistry can also be used to evaluate biomarker status in gastrointestinal stromal tumors, gastrointestinal malignancies with NTRK gene fusions, and undifferentiated carcinomas with switch-sucrose non-fermentable complex abnormalities.
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Affiliation(s)
- Matthew W Rosenbaum
- Department of Pathology, Beth Israel Deaconess Medical Center, United States
| | - Raul S Gonzalez
- Department of Pathology, Beth Israel Deaconess Medical Center, United States.
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Pedersen KS, Foster NR, Overman MJ, Boland PM, Kim SS, Arrambide KA, Jaszewski BL, Bekaii-Saab T, Graham RP, Welch J, Wilson RH, McWilliams RR. ZEBRA: A Multicenter Phase II Study of Pembrolizumab in Patients with Advanced Small-Bowel Adenocarcinoma. Clin Cancer Res 2021; 27:3641-3648. [PMID: 33883178 DOI: 10.1158/1078-0432.ccr-21-0159] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2021] [Revised: 03/10/2021] [Accepted: 04/15/2021] [Indexed: 11/16/2022]
Abstract
PURPOSE Small-bowel adenocarcinoma (SBA) is rare, and no standard of care exists for metastatic disease beyond first-line FOLFOX/CAPOX. SBA has higher rates of microsatellite instability (MSI-H) and T-lymphocyte infiltration than other gastrointestinal cancers. We hypothesize that pembrolizumab, a PD-1 inhibitor, will induce antitumor response. PATIENTS AND METHODS Patients with previously treated advanced SBA received pembrolizumab 200 mg i.v. every 3 weeks until disease progression (PD), toxicity, or 35 doses maximum. Primary endpoint was confirmed overall response rate (ORR) with secondary progression-free survival (PFS), overall survival (OS), and toxicity assessment endpoints. Outcomes were stratified by tumor location, microsatellite stability (MSS) or instability (MSI-H), and PD-L1 level. RESULTS Forty patients were treated for a median duration of four cycles (range, 1-35). All patients are off study treatment due to PD (75%), death (10%), 35 cycles completed (8%), refusal (3%), and adverse effects (AEs, 5%). Three confirmed partial responses [PRs; 8%; 95% confidence interval (CI), 2-20] did not meet predefined success criteria of ORR 30%. Median OS (7.1 months; 95% CI, 5.1-17.1) and median PFS (2.8 months; 95% CI, 2.7-4.2) were similar across primary tumor sites. One confirmed PR (3%) was seen in patients with low MSS/MSI tumors and correlated with high tumor mutation burden (TMB). Fifty percent of patients with MSI-H tumors achieved PR and remain alive without progression. Twenty-five patients (63%) had grade ≥3 AEs and 11 patients (28%) had grade 4/5 AEs. CONCLUSIONS In the largest study of SBA to date, pembrolizumab did not induce the hypothesized response rate; however, we did identify responses in key biomarker-selected cohorts.
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Affiliation(s)
| | - Nathan R Foster
- Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota
| | - Michael J Overman
- Department of Gastrointestinal Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Patrick M Boland
- Department of GI Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, New York
| | - Sunnie S Kim
- Department of Oncology, Georgetown University, Washington, D.C
| | | | - Brandy L Jaszewski
- Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota
| | | | - Rondell P Graham
- Division of Anatomic Pathology, Mayo Clinic, Rochester, Minnesota
| | - Jack Welch
- National Cancer Institute, Bethesda, Maryland
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Vanoli A, Grillo F, Guerini C, Neri G, Arpa G, Klersy C, Nesi G, Giuffrida P, Sampietro G, Ardizzone S, Fociani P, Fiocca R, Latella G, Sessa F, D'Errico A, Malvi D, Mescoli C, Rugge M, Ferrero S, Poggioli G, Rizzello F, Macciomei MC, Santini D, Volta U, De Giorgio R, Caio G, Calabrò A, Ciacci C, D'Armiento M, Rizzo A, Solina G, Martino M, Tonelli F, Villanacci V, Cannizzaro R, Canzonieri V, Florena AM, Biancone L, Monteleone G, Caronna R, Ciardi A, Elli L, Caprioli F, Vecchi M, D'Incà R, Zingone F, D'Odorico A, Lenti MV, Oreggia B, Reggiani Bonetti L, Giannone AG, Orlandi A, Barresi V, Ciccocioppo R, Amodeo G, Biletta E, Luinetti O, Pedrazzoli P, Pietrabissa A, Corazza GR, Solcia E, Paulli M, Di Sabatino A. Prognostic Role of Mismatch Repair Status, Histotype and High-Risk Pathologic Features in Stage II Small Bowel Adenocarcinomas. Ann Surg Oncol 2021; 28:1167-1177. [PMID: 32761330 PMCID: PMC7801310 DOI: 10.1245/s10434-020-08926-4] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2020] [Accepted: 07/04/2020] [Indexed: 12/15/2022]
Abstract
BACKGROUND Small bowel adenocarcinoma is a relatively rare cancer, often diagnosed in an advanced stage. In localized and resectable disease, surgery alone or in combination with adjuvant chemotherapy is the mainstay of treatment. In the recently published National Comprehensive Cancer Network Clinical Practice guidelines, criteria for selecting patients with stage II small bowel adenocarcinoma to receive adjuvant chemotherapy are provided, and they are mainly extrapolated from studies on colorectal cancer. PATIENTS AND METHODS In the present study, we aimed to verify whether mismatch repair deficiency phenotype, high-risk pathologic features (including T4, positive resection margins and a low number of lymph nodes harvested), as well as tumor histologic subtype, were associated with cancer-specific survival in 66 stage II non-ampullary small bowel adenocarcinoma patients, collected through the Small Bowel Cancer Italian Consortium. A central histopathology review was performed. Mismatch repair deficiency was tested by immunohistochemistry for MLH1, MSH2, MSH6 and PMS2, and confirmed by polymerase chain reaction for microsatellite instability. RESULTS We identified mismatch repair deficiency, glandular/medullary histologic subtype, and celiac disease as significant predictors of favorable cancer-specific survival using univariable analysis with retained significance in bivariable models adjusted for pT stage. Among the high-risk features, only T4 showed a significant association with an increased risk of death; however, its prognostic value was not independent of mismatch repair status. CONCLUSIONS Mismatch repair protein expression, histologic subtype, association with celiac disease, and, in the mismatch repair proficient subset only, T stage, may help identify patients who may benefit from adjuvant chemotherapy.
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Affiliation(s)
- Alessandro Vanoli
- Anatomic Pathology Unit, Department of Molecular Medicine, University of Pavia and Fondazione IRCCS San Matteo Hospital, Pavia, Italy.
| | - Federica Grillo
- Pathology Unit, Department of Surgical and Diagnostic Sciences, University of Genoa and Ospedale Policlinico San Martino University Hospital, Genoa, Italy
| | - Camilla Guerini
- Anatomic Pathology Unit, Department of Molecular Medicine, University of Pavia and Fondazione IRCCS San Matteo Hospital, Pavia, Italy
| | - Giuseppe Neri
- Anatomic Pathology Unit, Department of Molecular Medicine, University of Pavia and Fondazione IRCCS San Matteo Hospital, Pavia, Italy
| | - Giovanni Arpa
- Anatomic Pathology Unit, Department of Molecular Medicine, University of Pavia and Fondazione IRCCS San Matteo Hospital, Pavia, Italy
| | - Catherine Klersy
- Clinical Epidemiology and Biometry Unit, Fondazione IRCCS San Matteo Hospital, Pavia, Italy
| | - Gabriella Nesi
- Division of Pathological Anatomy, Department of Surgery and Translational Medicine, University of Florence, Florence, Italy
| | - Paolo Giuffrida
- Department of Internal Medicine, University of Pavia and Fondazione IRCCS San Matteo Hospital, Pavia, Italy
| | - Gianluca Sampietro
- Unit of General Surgery, ASST Rhodense, Rho Hospital, University of Milan, Milan, Italy
| | - Sandro Ardizzone
- Gastroenterology Unit, Luigi Sacco University Hospital, Milan, Italy
| | - Paolo Fociani
- Anatomic Pathology Unit, ASST Ovest Milanese, Milan, Italy
| | - Roberto Fiocca
- Pathology Unit, Department of Surgical and Diagnostic Sciences, University of Genoa and Ospedale Policlinico San Martino University Hospital, Genoa, Italy
| | - Giovanni Latella
- Gastroenterology Unit, Department of Life and Environmental Sciences, University of L'Aquila, L'Aquila, Italy
| | - Fausto Sessa
- Pathology Unit, Department of Medicine and Surgery, University of Insubria, Varese, Italy
| | - Antonietta D'Errico
- Department of Experimental, Diagnostic and Specialty Medicine (DIMES), Institute of Oncology and Transplant Pathology, St. Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy
| | - Deborah Malvi
- Department of Experimental, Diagnostic and Specialty Medicine (DIMES), Institute of Oncology and Transplant Pathology, St. Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy
| | - Claudia Mescoli
- Pathology Unit, Department of Medicine, University of Padua, Padua, Italy
| | - Massimo Rugge
- Pathology Unit, Department of Medicine, University of Padua, Padua, Italy
| | - Stefano Ferrero
- Division of Pathology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Department of Biomedical, Surgical and Dental Sciences, University of Milan, Milan, Italy
| | - Gilberto Poggioli
- Surgery of the Alimentary Tract, Department of Medical and Surgical Sciences, Sant'Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy
| | - Fernando Rizzello
- Intestinal Chronic Bowel Disease Unit, Department of Medical and Surgical Sciences, Sant'Orsola-Malpighi Hospital, Alma Mater Studiorum University of Bologna, Bologna, Italy
| | | | - Donatella Santini
- Department of Experimental, Diagnostic and Specialty Medicine (DIMES), Institute of Oncology and Transplant Pathology, St. Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy
| | - Umberto Volta
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - Roberto De Giorgio
- Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy
| | - Giacomo Caio
- Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy
| | - Antonio Calabrò
- Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy
| | - Carolina Ciacci
- Department of Medicine and Surgery, University of Salerno, Salerno, Italy
| | - Maria D'Armiento
- Public Health Department, Federico II University of Naples, Naples, Italy
| | - Aroldo Rizzo
- Unit of Pathology, Cervello Hospital, Palermo, Italy
| | - Gaspare Solina
- Units of General Surgery, Cervello Hospital, Palermo, Italy
| | - Michele Martino
- Department of Internal Medicine, University of Pavia and Fondazione IRCCS San Matteo Hospital, Pavia, Italy
| | - Francesco Tonelli
- Surgery and Translational Medicine, University of Florence, Florence, Italy
| | | | - Renato Cannizzaro
- Department of Gastroenterology, Centro di Riferimento Oncologico (CRO) di Aviano IRCCS, Aviano, Italy
| | - Vincenzo Canzonieri
- Pathology Unit, Centro di Riferimento Oncologico (CRO) di Aviano IRCCS, Aviano, Italy
- Department of Medical, Surgical and Health Sciences, University of Trieste, Trieste, Italy
| | - Ada Maria Florena
- Pathologic Anatomy Unit, Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties, University of Palermo, Palermo, Italy
| | - Livia Biancone
- Department of Systems Medicine, University of Tor Vergata, Rome, Italy
| | | | - Roberto Caronna
- Department of Surgical Sciences, La Sapienza University, Rome, Italy
| | - Antonio Ciardi
- Department of Radiological, Oncological, Pathological Sciences, Umberto I Hospital, La Sapienza University, Rome, Italy
| | - Luca Elli
- Gastroenterology and Endoscopy Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Flavio Caprioli
- Gastroenterology and Endoscopy Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Maurizio Vecchi
- Gastroenterology and Endoscopy Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Renata D'Incà
- Gastroenterology Section, Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy
| | - Fabiana Zingone
- Gastroenterology Section, Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy
| | - Anna D'Odorico
- Gastroenterology Section, Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy
| | - Marco Vincenzo Lenti
- Department of Internal Medicine, University of Pavia and Fondazione IRCCS San Matteo Hospital, Pavia, Italy
| | - Barbara Oreggia
- General Surgery Unit, Ca' Granda-Ospedale Maggiore Policlinico, Milan, Italy
| | - Luca Reggiani Bonetti
- Section of Pathology, Department of Diagnostic Medicine and Public Health, University of Modena and Reggio Emilia, Modena, Italy
| | - Antonino Giulio Giannone
- Pathologic Anatomy Unit, Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties, University of Palermo, Palermo, Italy
| | - Augusto Orlandi
- Department of Biopathology and Image Diagnostics, University of Tor Vergata, Rome, Italy
| | - Valeria Barresi
- Section of Anatomical Pathology, Department of Diagnostics and Public Health, University and Hospital Trust of Verona, Verona, Italy
| | - Rachele Ciccocioppo
- Gastroenterology Unit, Department of Medicine, AOUI Policlinico G.B. Rossi, University of Verona, Verona, Italy
| | - Giuseppe Amodeo
- Gastroenterology Unit, Department of Medicine, AOUI Policlinico G.B. Rossi, University of Verona, Verona, Italy
| | | | - Ombretta Luinetti
- Anatomic Pathology Unit, Department of Molecular Medicine, University of Pavia and Fondazione IRCCS San Matteo Hospital, Pavia, Italy
| | - Paolo Pedrazzoli
- Department of Internal Medicine, University of Pavia and Fondazione IRCCS San Matteo Hospital, Pavia, Italy
- Oncology Unit, IRCCS San Matteo Hospital, Pavia, Italy
| | - Andrea Pietrabissa
- Department of Surgery, General Surgery II, University of Pavia and Fondazione IRCCS San Matteo Hospital, Pavia, Italy
| | - Gino Roberto Corazza
- Department of Internal Medicine, University of Pavia and Fondazione IRCCS San Matteo Hospital, Pavia, Italy
| | - Enrico Solcia
- Anatomic Pathology Unit, Department of Molecular Medicine, University of Pavia and Fondazione IRCCS San Matteo Hospital, Pavia, Italy
| | - Marco Paulli
- Anatomic Pathology Unit, Department of Molecular Medicine, University of Pavia and Fondazione IRCCS San Matteo Hospital, Pavia, Italy
| | - Antonio Di Sabatino
- Department of Internal Medicine, University of Pavia and Fondazione IRCCS San Matteo Hospital, Pavia, Italy
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Ishikawa E, Nakaguro M, Nakamura M, Yamamura T, Sawada T, Mizutani Y, Maeda K, Furukawa K, Shimoyama Y, Kawashima H, Fujishiro M. Gastrointestinal tract metastasis of lung cancer: The PD-L1 expression and correlated clinicopathological variables. Pathol Int 2021; 71:33-41. [PMID: 33259707 DOI: 10.1111/pin.13048] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2020] [Revised: 10/27/2020] [Accepted: 10/28/2020] [Indexed: 11/30/2022]
Abstract
The gastrointestinal tract is a rare site for metastatic lung cancer. Programmed cell death-ligand 1 (PD-L1) expression in lung cancer is a biomarker for the response to anti-PD-1/PD-L1 therapy. We investigated clinicopathological features and PD-L1 expression in 25 gastrointestinal metastatic tumors from the lung and primary adenocarcinoma of the small bowel. The small bowel was the most common site (16/25; 64%) of gastrointestinal tract lung cancer metastasis. A total of 19 (76%) of the gastrointestinal metastasis showed PD-L1 expression in ≥5% of tumor cells, with 14 (56%) showing high expression levels (≥50%). In contrast, 21 (84%) expressed PD-L1 in ≥5% immune cells, including 4 (16%) showing a high expression levels (≥50%). The PD-L1 expression on tumor cells and immune cells in primary lung cancer and corresponding gastrointestinal metastasis was concordant in 13 (68%) and 11 (58%) of the 19 paired cases, respectively. Small-bowel metastasis of lung cancer was characterized by a higher incidence of perforation (31% vs. 0%), ulcerated mass (83% vs. 60%), and neoplastic PD-L1 expression (75% vs. 0%) compared to primary small-bowel adenocarcinoma. Gastrointestinal metastasis from lung cancer might be a potential target for immune checkpoint inhibitor therapy, given its high expression of PD-L1.
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Affiliation(s)
- Eri Ishikawa
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Japan
- Department of Pathology and Laboratory Medicine, Nagoya University Hospital, Nagoya, Japan
| | - Masato Nakaguro
- Department of Pathology and Laboratory Medicine, Nagoya University Hospital, Nagoya, Japan
| | - Masanao Nakamura
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Takeshi Yamamura
- Department of Pathology and Laboratory Medicine, Nagoya University Hospital, Nagoya, Japan
| | - Tsunaki Sawada
- Department of Endoscopy, Nagoya University Hospital, Nagoya, Japan
| | - Yasuyuki Mizutani
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Keiko Maeda
- Department of Endoscopy, Nagoya University Hospital, Nagoya, Japan
| | - Kazuhiro Furukawa
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Yoshie Shimoyama
- Department of Pathology and Laboratory Medicine, Nagoya University Hospital, Nagoya, Japan
| | - Hiroki Kawashima
- Department of Endoscopy, Nagoya University Hospital, Nagoya, Japan
| | - Mitsuhiro Fujishiro
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Japan
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Prognostic Value of Immune Environment Analysis in Small Bowel Adenocarcinomas with Verified Mutational Landscape and Predisposing Conditions. Cancers (Basel) 2020; 12:cancers12082018. [PMID: 32718028 PMCID: PMC7463640 DOI: 10.3390/cancers12082018] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2020] [Revised: 07/20/2020] [Accepted: 07/22/2020] [Indexed: 12/12/2022] Open
Abstract
Background: Small bowel adenocarcinoma (SBA) is a rare yet insidious cancer with poor survival. The abundance of tumour-infiltrating lymphocytes is associated with improved survival, but the role of the programmed death-1/programmed death ligand-1 (PD-1/PD-L1) pathway in tumour escape is controversial. We evaluated immune cell infiltration, PD1/PD-L1 expression and their prognostic value in a series of SBAs with previously verified predisposing conditions and exome-wide somatic mutation characterization. Methods: Formalin-fixed paraffin-embedded tissue sections stained for CD3, CD8, PD-L1 and PD-1 were analysed from 94 SBAs. An immune cell score (ICS) was formed from the amount of the CD3 and CD8 positive lymphocytes from the tumour centre and invasive margin. The PD-L1 and PD-1 positive immune cells (ICs) and ICS were combined into a variable called Immunoprofile. Results: High ICS, PD-L1IC and PD-1, individually and combined as Immunoprofile, were prognostic for better patient outcome. Sixty-five (69%) SBAs expressed ≥1% positive PD-L1IC. A high tumour mutation burden was common (19%) and associated with immune markers. Immunoprofile, adjusted for TNM stage, mismatch repair status, tumour location, sex and age were independent prognostic markers for disease-specific and overall survival. Conclusions: Analysing tumoral immune contexture provides prognostic information in SBA. Combining ICS, PD-1 and PD-L1IC as Immunoprofile enhanced the prognostic performance.
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13
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Giuffrida P, Arpa G, Grillo F, Klersy C, Sampietro G, Ardizzone S, Fociani P, Fiocca R, Latella G, Sessa F, D'Errico A, Malvi D, Mescoli C, Rugge M, Nesi G, Ferrero S, Furlan D, Poggioli G, Rizzello F, Macciomei MC, Santini D, Volta U, De Giorgio R, Caio G, Calabrò A, Ciacci C, D'Armiento M, Rizzo A, Solina G, Martino M, Tonelli F, Villanacci V, Cannizzaro R, Canzonieri V, Florena AM, Biancone L, Monteleone G, Caronna R, Ciardi A, Elli L, Caprioli F, Vecchi M, D'Incà R, Zingone F, D'Odorico A, Lenti MV, Oreggia B, Reggiani Bonetti L, Astegiano M, Biletta E, Cantoro L, Giannone AG, Orlandi A, Papi C, Perfetti V, Quaquarini E, Sandri G, Silano M, Usai P, Barresi V, Ciccocioppo R, Luinetti O, Pedrazzoli P, Pietrabissa A, Viglio A, Paulli M, Corazza GR, Solcia E, Vanoli A, Di Sabatino A. PD-L1 in small bowel adenocarcinoma is associated with etiology and tumor-infiltrating lymphocytes, in addition to microsatellite instability. Mod Pathol 2020; 33:1398-1409. [PMID: 32066859 DOI: 10.1038/s41379-020-0497-0] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2019] [Revised: 01/25/2020] [Accepted: 01/27/2020] [Indexed: 12/13/2022]
Abstract
Small bowel adenocarcinomas (SBAs) are often associated with poor prognosis and have limited therapeutic options. Programmed cell death protein-1 (PD-1)/programmed cell death ligand 1 (PD-L1) pathway blockade is an effective treatment in many microsatellite instability-high (MSI-H) solid tumors. We aimed at investigating PD-L1 and PD-1 expression in non-hereditary, non-ampullary SBAs, associated with celiac disease (CeD), Crohn's disease (CrD), or sporadic, recruited through the Small Bowel Cancer Italian Consortium. We assessed PD-L1 and PD-1 by immunohistochemistry in a series of 121 surgically resected SBAs, including 34 CeD-SBAs, 49 CrD-SBAs, and 38 sporadic SBAs. PD-L1 and PD-1 expression was correlated with several clinico-pathological features, such as the etiology, microsatellite instability status, and tumor-infiltrating lymphocyte (TIL) density. The prevalence of PD-L1 positivity according to combined positive score (CPS) was 26% in the whole cohort of SBAs, with significantly (p = 0.001) higher percentage (35%) in both CeD-SBAs and CrD-SBAs in comparison with sporadic SBAs (5%). CPS ≥ 1 SBAs were significantly (p = 0.013) more frequent in MSI-H cases (41%) than in non-MSI-H ones (18%); however, 15 CPS ≥ 1 microsatellite stable SBAs were also identified. CPS ≥ 1 SBAs showed higher TIL and PD-1+ immune cell density, more frequently medullary histotype, as well as a better outcome in comparison with CPS < 1 cases. This study demonstrates an increased proportion of PD-L1+ cases in both CeD-SBAs and CrD-SBAs in comparison with sporadic SBAs. In addition, the identification of a subset of PD-L1+ microsatellite stable SBAs supports the need to ascertain additional biomarkers of response to immune checkpoint inhibitors along with MSI-H.
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Affiliation(s)
- Paolo Giuffrida
- Department of Internal Medicine, University of Pavia and Fondazione IRCCS San Matteo Hospital, Pavia, Italy
| | - Giovanni Arpa
- Anatomic Pathology Unit, Department of Molecular Medicine, University of Pavia and Fondazione IRCCS San Matteo Hospital, Pavia, Italy
| | - Federica Grillo
- Pathology Unit, Department of Surgical and Diagnostic Sciences, University of Genoa and San Martino/IST University Hospital, Genoa, Italy
| | - Catherine Klersy
- Biometry and Statistics Service, Fondazione IRCCS San Matteo Hospital, Pavia, Italy
| | | | - Sandro Ardizzone
- Gastroenterology Unit, Luigi Sacco University Hospital, Milan, Italy
| | - Paolo Fociani
- Pathology Unit, Luigi Sacco University Hospital, Milan, Italy
| | - Roberto Fiocca
- Pathology Unit, Department of Surgical and Diagnostic Sciences, University of Genoa and San Martino/IST University Hospital, Genoa, Italy
| | - Giovanni Latella
- Gastroenterology Unit, Department of Life and Enviromental Sciences, University of L'Aquila, L'Aquila, Italy
| | - Fausto Sessa
- Pathology Unit, Department of Medicine and Surgery, University of Insubria, Varese, Italy
| | - Antonietta D'Errico
- Department of Experimental, Diagnostic and Specialty Medicine (DIMES), Institute of Oncology and Transplant Pathology, University of Bologna, St. Orsola-Malpighi Hospital, Bologna, Italy
| | - Deborah Malvi
- Department of Experimental, Diagnostic and Specialty Medicine (DIMES), Institute of Oncology and Transplant Pathology, University of Bologna, St. Orsola-Malpighi Hospital, Bologna, Italy
| | - Claudia Mescoli
- Pathology Unit, Department of Medicine, University of Padua, Padua, Italy
| | - Massimo Rugge
- Pathology Unit, Department of Medicine, University of Padua, Padua, Italy
| | - Gabriella Nesi
- Division of Pathological Anatomy, Department of Surgery and Translational Medicine, University of Florence, Florence, Italy
| | - Stefano Ferrero
- Division of Pathology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Department of Biomedical, Surgical and Dental Sciences, University of Milan, Milan, Italy
| | - Daniela Furlan
- Pathology Unit, Department of Medicine and Surgery, University of Insubria, Varese, Italy
| | - Gilberto Poggioli
- Surgery of the Alimentary Tract, Department of Medical and Surgical Sciences, Sant'Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy
| | - Fernando Rizzello
- Intestinal Chronic Bowel Disease Unit, Department of Medical and Surgical Sciences, Sant'Orsola-Malpighi Hospital, Alma Mater Studiorum University of Bologna, Bologna, Italy
| | | | - Donatella Santini
- Department of Experimental, Diagnostic and Specialty Medicine (DIMES), Institute of Oncology and Transplant Pathology, University of Bologna, St. Orsola-Malpighi Hospital, Bologna, Italy
| | - Umberto Volta
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | | | - Giacomo Caio
- Department of Medical Sciences, University of Ferrara, Ferrara, Italy
| | - Antonio Calabrò
- Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy
| | - Carolina Ciacci
- Department of Medicine and Surgery, University of Salerno, Salerno, Italy
| | - Maria D'Armiento
- Public Health Department, Federico II University of Naples, Naples, Italy
| | - Aroldo Rizzo
- Units of Pathology, Cervello Hospital, Palermo, Italy
| | - Gaspare Solina
- Units of General Surgery, Cervello Hospital, Palermo, Italy
| | - Michele Martino
- Department of Internal Medicine, University of Pavia and Fondazione IRCCS San Matteo Hospital, Pavia, Italy
| | - Francesco Tonelli
- Surgery and Translational Medicine, University of Florence, Florence, Italy
| | | | - Renato Cannizzaro
- Department of Gastroenterology, Centro di Riferimento Oncologico (CRO) di Aviano IRCCS, Aviano, Italy
| | - Vincenzo Canzonieri
- Pathology Unit, Centro di Riferimento Oncologico (CRO) di Aviano IRCCS, Aviano, Italy
- Department of Medical, Surgical and Health Sciences, University of Trieste, Trieste, Italy
| | - Ada M Florena
- Pathologic Anatomy Unit, Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties, University of Palermo, Palermo, Italy
| | - Livia Biancone
- Department of Systems Medicine, University of Tor Vergata, Rome, Italy
| | | | - Roberto Caronna
- Department of Surgical Sciences, La Sapienza University, Rome, Italy
| | - Antonio Ciardi
- Department of Radiological, Oncological, Pathological Sciences, Umberto I Hospital, La Sapienza University, Rome, Italy
| | - Luca Elli
- Gastroenterology and Endoscopy Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Flavio Caprioli
- Gastroenterology and Endoscopy Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Maurizio Vecchi
- Gastroenterology and Endoscopy Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Renata D'Incà
- Gastroenterology Section, Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy
| | - Fabiana Zingone
- Gastroenterology Section, Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy
| | - Anna D'Odorico
- Gastroenterology Section, Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy
| | - Marco Vincenzo Lenti
- Department of Internal Medicine, University of Pavia and Fondazione IRCCS San Matteo Hospital, Pavia, Italy
| | - Barbara Oreggia
- General Surgery Unit, Ca' Granda-Ospedale Maggiore Policlinico, Milan, Italy
| | - Luca Reggiani Bonetti
- Section of Pathology, Department of Diagnostic Medicine and Public Health, University of Modena and Reggio Emilia, Modena, Italy
| | - Marco Astegiano
- General and Specialistic Surgery, Città della Salute e della Scienza-Molinette Hospital, Turin, Italy
| | | | | | - Antonino G Giannone
- Pathologic Anatomy Unit, Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties, University of Palermo, Palermo, Italy
| | - Augusto Orlandi
- Department of Biopathology and Image Diagnostics, University of Tor Vergata, Rome, Italy
| | - Claudio Papi
- IBD Unit, San Filippo Neri Hospital, Rome, Italy
| | - Vittorio Perfetti
- Internal Medicine Unit, S.S. Annunziata Hospital, ASST-Pavia, Varzi, Italy
| | - Erica Quaquarini
- Medical Oncology Unit, IRCCS ICS Maugeri and Department of Internal Medicine and Therapeutics, University of Pavia, Pavia, Italy
| | | | - Marco Silano
- Unit of Human Nutrition and Health, Istituto Superiore di Sanità, Rome, Italy
| | - Paolo Usai
- Department of Internal Medicine, University of Cagliari, Cagliari, Italy
| | - Valeria Barresi
- Department of Diagnostics and Public Health, Section of Anatomical Pathology, University and Hospital Trust of Verona, Verona, Italy
| | - Rachele Ciccocioppo
- Gastroenterology Unit, Department of Medicine, AOUI Policlinico G.B. Rossi, University of Verona, Verona, Italy
| | - Ombretta Luinetti
- Department of Internal Medicine, University of Pavia and Fondazione IRCCS San Matteo Hospital, Pavia, Italy
| | - Paolo Pedrazzoli
- Department of Internal Medicine, University of Pavia and Fondazione IRCCS San Matteo Hospital, Pavia, Italy
- Oncology Unit, IRCCS San Matteo Hospital, Pavia, Italy
| | - Andrea Pietrabissa
- Department of Surgery, General Surgery II, University of Pavia and Fondazione IRCCS San Matteo Hospital, Pavia, Italy
| | - Alessandra Viglio
- Anatomic Pathology Unit, Department of Molecular Medicine, University of Pavia and Fondazione IRCCS San Matteo Hospital, Pavia, Italy
| | - Marco Paulli
- Anatomic Pathology Unit, Department of Molecular Medicine, University of Pavia and Fondazione IRCCS San Matteo Hospital, Pavia, Italy
| | - Gino R Corazza
- Department of Internal Medicine, University of Pavia and Fondazione IRCCS San Matteo Hospital, Pavia, Italy
| | - Enrico Solcia
- Anatomic Pathology Unit, Department of Molecular Medicine, University of Pavia and Fondazione IRCCS San Matteo Hospital, Pavia, Italy
| | - Alessandro Vanoli
- Anatomic Pathology Unit, Department of Molecular Medicine, University of Pavia and Fondazione IRCCS San Matteo Hospital, Pavia, Italy
| | - Antonio Di Sabatino
- Department of Internal Medicine, University of Pavia and Fondazione IRCCS San Matteo Hospital, Pavia, Italy.
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Klose J, Lasitschka F, Horsch C, Strowitzki MJ, Bruckner T, Volz C, Schmidt T, Schneider M. Prognostic relevance of programmed death-ligand 1 expression and microsatellite status in small bowel adenocarcinoma. Scand J Gastroenterol 2020; 55:321-329. [PMID: 32191146 DOI: 10.1080/00365521.2020.1734073] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Background: Small bowel adenocarcinoma (SBA) is a dreadful disease. Patient prognosis is limited due to late presentation and ineffective chemotherapy. PD-1/PD-L1 checkpoint immunotherapy is regarded as a promising approach in several cancer entities. The association of PD-1/PD-L1 expression and its impact on patient prognosis with SBA is unclear. Material and methods: Seventy-five consecutive patients who underwent surgery for SBA were retrospectively analyzed and stained for PD-L1 expression in the tumour or the stroma. Analysis of mismatch repair genes was performed to determine microsatellite status. Kaplan-Meier estimate was used to analyze patient survival. Univariate and multivariable Cox regression-analyses were used to assess the impact of PD-L1 expression and microsatellite status on patient survival.Results: PD-L1 was weakly upregulated within the tumour or the stroma and associated with prolonged survival (p = .0071 and p = .0472, respectively). Fifty-one tumours (68%) revealed microsatellite stability (MSS) and 24 tumours (32%) were microsatellite instable (MSI) without correlating with patient survival (p = .611). Neither PD-L1 expression in the tumour nor in the stroma was identified as an independent risk factor influencing survival (p = .572 and p = .3055).Conclusion: Although PD-L1 expression is associated with prolonged survival, it was not identified as an independent prognostic marker. Microsatellite status did not influence long-term survival.
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Affiliation(s)
- Johannes Klose
- Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany
| | - Felix Lasitschka
- Institute of Pathology, University of Heidelberg, Heidelberg, Germany.,Institute for Pathology, Ludwigshafen, Germany
| | - Cornelia Horsch
- Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany
| | - Moritz J Strowitzki
- Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany
| | - Thomas Bruckner
- Institute for Medical Biometry and Informatics, University of Heidelberg, Heidelberg, Germany
| | - Claudia Volz
- Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany
| | - Thomas Schmidt
- Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany
| | - Martin Schneider
- Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany
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15
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Prognostic implications of immune classification in a multicentre cohort of patients with small intestinal adenocarcinoma. Pathology 2020; 52:228-235. [DOI: 10.1016/j.pathol.2019.09.004] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2019] [Revised: 09/08/2019] [Accepted: 09/15/2019] [Indexed: 01/03/2023]
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16
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Immune classification for the PD-L1 expression and tumour-infiltrating lymphocytes in colorectal adenocarcinoma. BMC Cancer 2020; 20:58. [PMID: 31992245 PMCID: PMC6986059 DOI: 10.1186/s12885-020-6553-9] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2019] [Accepted: 01/17/2020] [Indexed: 12/21/2022] Open
Abstract
Background Colorectal adenocarcinoma is the third most common cancer worldwide and a leading cause of cancer-related death. The recent emergence of diverse immunotherapeutic agents has made it crucial to interpret a complex tumour microenvironment intermingled with tumour-infiltrating immune cells to predict the immunotherapeutic response rate. However, in colorectal adenocarcinoma, studies are lacking that provide detailed analyses of programmed death-ligand 1 (PD-L1) and tumour-infiltrating lymphocytes (TIL) to elucidate their prognostic values and to identify immunotherapy-targetable subgroups, preferably with multiple immune-related biomarkers. In the present study, we categorize colorectal adenocarcinomas into four types of tumour immune microenvironments according to PD-L1 expression and TIL, analyse their prognostic values, and propose an immunotherapy-targetable subgroup. Methods Formalin-fixed, paraffin-embedded tissue samples of surgically resected primary colorectal adenocarcinomas (n = 489) were obtained and arrayed on tissue microarray blocks. Immunohistochemical stains for PD-L1, programmed cell death protein 1 (PD-1), cluster of differentiation 8 (CD8), and deficient mismatch repair (dMMR) were performed and evaluated. Results Tumour microenvironment immune type (TMIT) I (PD-L1-positive tumour cells and CD8-high TIL) and type II (PD-L1-negative tumour cells and CD8-low TIL) showed the best and worst prognoses, respectively. PD-L1 overexpression was significantly associated with dMMR status. PD-L1 immunoreactivity was positively correlated with TIL having CD8 or PD-1 overexpression. Conclusions TMIT I subgroup showed stronger CD8/PD-L1/PD-1 signalling interaction compared to the other TMIT. Therefore, we propose that the TMIT I subgroup is a candidate TMIT to predict effective response rate for existing immune checkpoint inhibitors and determine targetable subgroups for emerging therapies.
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17
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Roberts J, Salaria SN, Cates J, Wang Y, Vnencak-Jones C, Berlin J, Shi C. PD-L1 Expression Patterns in Microsatellite Instability-High Intestinal Adenocarcinoma Subtypes. Am J Clin Pathol 2019; 152:384-391. [PMID: 31152546 DOI: 10.1093/ajcp/aqz052] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
OBJECTIVES To investigate patterns of programmed death protein-1 (PD-L1) expression in microsatellite instability (MSI)-high intestinal carcinomas and correlate them with pathologic and molecular features. METHODS One hundred and fifteen MSI-high and 41 microsatellite stable carcinomas were included. Tumor sections were immunohistochemically labeled for PD-L1. The results were correlated with histologic subtypes, MSI, and BRAF status. RESULTS As expected, MSI status was associated with PD-L1 expression. Among 115 MSI-high tumors, PD-L1 expression was observed on tumor cells in 28 tumors and on tumor-associated inflammatory cells in 77 tumors. Medullary carcinoma demonstrated more frequent PD-L1 expression on tumor cells than mucinous and typical adenocarcinoma. PD-L1 expression was more frequent in medullary and typical adenocarcinoma than in mucinous adenocarcinoma based on combined positive scores. Tumors with more nucleotide shifts by PCR-based MSI testing were more likely to express PD-L1. CONCLUSIONS Expression of PD-L1 is different among different histologic subtypes of MSI-high intestinal carcinomas.
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Affiliation(s)
- Jordan Roberts
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN
| | - Safia N Salaria
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN
| | - Justin Cates
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN
| | - Yang Wang
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN
| | - Cindy Vnencak-Jones
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN
| | - Jordan Berlin
- Department of Hematology/Oncology, Vanderbilt University Medical Center, Nashville, TN
| | - Chanjuan Shi
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN
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18
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Huffman BM, Jin Z, Yadav S, Patel S, Nagorney DM, Truty MJ, McWilliams RR, Halfdanarson TR, Mahipal A. Novel Prognostic Factors in Resected Small Bowel Adenocarcinoma. Clin Colorectal Cancer 2019; 18:218-225. [PMID: 31178274 DOI: 10.1016/j.clcc.2019.05.002] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2019] [Accepted: 05/08/2019] [Indexed: 12/18/2022]
Abstract
BACKGROUND Small bowel adenocarcinoma (SBA) is a rare malignancy affecting approximately 3000 patients per year in the United States, and there is limited evidence prognosticating patients with resected SBA. We aimed to evaluate prognostic factors and the role of adjuvant therapy in patients with resected SBA. PATIENTS AND METHODS Two hundred forty-one patients who had resected stage I-III SBA were retrospectively identified at a single tertiary referral institution. Overall survival (OS) analysis was performed by the Kaplan-Meier method, and Wilcoxon tests were used for statistical comparisons. Cox proportional hazards were performed to identify significant variables by univariate and multivariate analysis. RESULTS Median OS for the entire group was 54.5 months (95% confidence interval [CI], 37.2-81.2 months), with 5- and 10-year OS of 48% and 35%. Median follow-up was 113.7 months (95% CI, 97.9-126.6 months). For patients with stage III disease who received adjuvant therapy, the median OS was 33.8 months (95% CI, 27.8-78.8) compared to 24.7 months (95% CI, 11.5-37.8) for patients with no adjuvant therapy (P < .01). Male sex, advanced T stage, advanced N stage, increased positive lymph node ratio, lymphocyte-to-monocyte ratio < 1.56, presence of residual disease, and earlier date of diagnosis predicted worse survival on univariate analysis. Age > 60 years, lymphocyte-to-monocyte ratio < 1.56, and advanced T stage were identified as independent negative predictors of OS for all patients by multivariate analysis. CONCLUSION Advanced age, advanced T stage, and lymphocyte-to-monocyte ratio < 1.56 independently predicted survival in resected SBA. Adjuvant therapy is associated with improved survival in patients with resected stage III SBA.
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Affiliation(s)
| | - Zhaohui Jin
- Division of Medical Oncology, Mayo Clinic, Rochester, MN
| | | | - Shruti Patel
- Department of Internal Medicine, Mayo Clinic, Rochester, MN
| | - David M Nagorney
- Division of Hepatobiliary and Pancreas Surgery, Mayo Clinic, Rochester, MN
| | - Mark J Truty
- Division of Hepatobiliary and Pancreas Surgery, Mayo Clinic, Rochester, MN
| | | | | | - Amit Mahipal
- Division of Medical Oncology, Mayo Clinic, Rochester, MN.
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19
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Zhang Y, Zulfiqar M, Bluth MH, Bhalla A, Beydoun R. Molecular Diagnostics in the Neoplasms of Small Intestine and Appendix: 2018 Update. Clin Lab Med 2019; 38:343-355. [PMID: 29776634 DOI: 10.1016/j.cll.2018.03.002] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Neoplasms of the small intestine are rare in comparison with colorectal tumors. The most common tumor types arising in the small intestine are adenocarcinomas, well-differentiated neuroendocrine tumors, gastrointestinal stromal tumors, and lymphoma. Primary appendiceal neoplasms are rare and found in less than 2% of appendectomy specimens with an incidence of approximately 1.2 cases per 100,000 people per year in the United States. This article explores molecular diagnostics in the neoplasms of small intestine and appendix.
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Affiliation(s)
- Yingtao Zhang
- PGY-3 Department of Pathology and Anatomical Sciences, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo General Hospital, A-701, 100 High Street, Buffalo, NY 14203, USA
| | - Muhammad Zulfiqar
- Southeastern Pathology Associates (SEPA Labs), 203 Indigo Drive, Brunswick, GA 31525, USA
| | - Martin H Bluth
- Department of Pathology, Wayne State University, School of Medicine, 540 East Canfield Street, Detroit, MI 48201, USA; Pathology Laboratories, Michigan Surgical Hospital, 21230 Dequindre Road, Warren, MI 48091, USA
| | - Amarpreet Bhalla
- PGY-3 Department of Pathology and Anatomical Sciences, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo General Hospital, A-701, 100 High Street, Buffalo, NY 14203, USA.
| | - Rafic Beydoun
- Department of Pathology, Harper University Hospital, Detroit Medical Center, 3990 John R Street, Detroit, MI 48201, USA
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20
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Giuffrida P, Vanoli A, Arpa G, Bonometti A, Luinetti O, Solcia E, Corazza GR, Paulli M, Di Sabatino A. Small Bowel Carcinomas Associated with Immune-Mediated Intestinal Disorders: The Current Knowledge. Cancers (Basel) 2018; 11:31. [PMID: 30597986 PMCID: PMC6356995 DOI: 10.3390/cancers11010031] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2018] [Revised: 12/10/2018] [Accepted: 12/24/2018] [Indexed: 12/14/2022] Open
Abstract
Small bowel carcinomas (SBC) are uncommon neoplasms, whose predisposing conditions include hereditary syndromes and immune-mediated intestinal disorders including coeliac disease (CD) and Crohn's disease (CrD). Although both CD-associated SBC (CD-SBC) and CrD-associated SBC (CrD-SBC) arise from an inflammatory background, they differ substantially in tumour cell phenotype, frequency of microsatellite instability and nuclear β-catenin expression, as well as in prognosis. For these patients, high tumour-infiltrating lymphocyte density and glandular/medullary histotype represent independent positive prognostic factors. Dysplasia adjacent to SBC is rare and characterized by intestinal phenotype and nuclear β-catenin in CD, while it is frequent and typified by gastro-pancreatobiliary marker expression and preserved membranous β-catenin in CrD. Recent evidence suggests that Epstein-Barr virus-positive dysplasia and SBC, albeit exceptional, do exist and are associated with CrD. In this review, we summarize the novel pathological and molecular insights of clinical and therapeutic interest to guide the care of CD-SBC and CrD-SBC.
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Affiliation(s)
- Paolo Giuffrida
- First Department of Internal Medicine, University of Pavia and Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy.
| | - Alessandro Vanoli
- Anatomic Pathology Unit, Department of Molecular Medicine, University of Pavia and Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy.
| | - Giovanni Arpa
- Anatomic Pathology Unit, Department of Molecular Medicine, University of Pavia and Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy.
| | - Arturo Bonometti
- Anatomic Pathology Unit, Department of Molecular Medicine, University of Pavia and Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy.
| | - Ombretta Luinetti
- Anatomic Pathology Unit, Department of Molecular Medicine, University of Pavia and Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy.
| | - Enrico Solcia
- Anatomic Pathology Unit, Department of Molecular Medicine, University of Pavia and Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy.
| | - Gino Roberto Corazza
- First Department of Internal Medicine, University of Pavia and Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy.
| | - Marco Paulli
- Anatomic Pathology Unit, Department of Molecular Medicine, University of Pavia and Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy.
| | - Antonio Di Sabatino
- First Department of Internal Medicine, University of Pavia and Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy.
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21
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Abstract
OPINION STATEMENT Small bower cancer is a rare disease, despite its incidence is increasing in the last decade. Both benign and malignant tumors can arise from the small intestine. The main histological cancer types are adenocarcinomas, neuroendocrine tumors, sarcomas, gastrointestinal stromal tumors (GISTs), and lymphomas. Due to the rarity of these malignances, all the currently available data are based on small studies or retrospective series, although recent breakthroughs are redirecting our approach to these patients. Immunotherapy for small bowel adenocarcinomas, several multikinase inhibitors in resistant GIST patients, as well as everolimus and 177Lu-DOTATATE in neuroendocrine tumors are only few of the novel therapeutic options that have changed, or may change in the future, the therapeutic landscape of these rare cancers. Larger and more powerful studies on the molecular profile of these tumors may lead to a better design of clinical trials, which eventually would provide our patients with more efficacious treatments to improve both overall survival and quality of life.
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Affiliation(s)
- Alberto Puccini
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, 1441 Eastlake Avenue, Suite 3456, Los Angeles, CA, 90033, USA.,Department of Medical Oncology, Ospedale Policlinico San Martino, Genoa, Italy
| | - Francesca Battaglin
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, 1441 Eastlake Avenue, Suite 3456, Los Angeles, CA, 90033, USA.,Medical Oncology Unit 1, Clinical and Experimental Oncology Department, Veneto Institute of Oncology IOV-IRCCS, 35128, Padua, Italy
| | - Heinz-Josef Lenz
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, 1441 Eastlake Avenue, Suite 3456, Los Angeles, CA, 90033, USA.
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22
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de Bree E, Rovers KP, Stamatiou D, Souglakos J, Michelakis D, de Hingh IH. The evolving management of small bowel adenocarcinoma. Acta Oncol 2018; 57:712-722. [PMID: 29381126 DOI: 10.1080/0284186x.2018.1433321] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2017] [Accepted: 01/22/2018] [Indexed: 02/06/2023]
Abstract
BACKGROUND Small bowel adenocarcinoma (SBA) is rare despite the fact that the small bowel represents the longest part and has the largest surface of all alimentary tract sections. Its incidence is 50-fold lower than that of colorectal carcinoma. It is often diagnosed at an advanced stage due to atypical and late symptoms, its low index of suspicion, difficult endoscopic access and poor detection by radiological imaging, resulting in impaired outcome. Due to its rarity and being molecularly a unique intestinal cancer, data regarding its optimal management are relatively sparse. MATERIAL AND METHODS A PubMed search was performed to identify relevant manuscripts that were recently published. Emerging data regarding the pathogenesis, the diagnosis and the treatment of SBA that resulted from recent research are discussed in this comprehensive review. RESULTS Genomic analysis has demonstrated that SBA is a molecularly unique intestinal cancer. Double balloon enteroscopy and capsule endoscopy are novel techniques which may result in earlier diagnosis and consequently in improvement of the generally poor prognosis. For clinically localized disease, the quality of surgery has recently been defined, with removal of at least 8-10 lymph nodes correlating with improved prognosis. Moreover, adjuvant chemotherapy seems to improve outcome of stage III disease. The combination of a fluoropyrimidine and oxaliplatin appears to be the most effective systemic chemotherapy for disseminated disease. Genomic profiling can identify potentially targetable genomic alterations in a significant proportion of SBA patients. The role of administration of targeted agents or immune checkpoint inhibitors is still unknown and subject of ongoing clinical trials. In the common case of peritoneal metastases, recent studies have shown that cytoreductive surgery and intraoperative hyperthermic intraperitoneal chemotherapy may be an attractive treatment option in selected patients. CONCLUSIONS SBA is a rare and unique malignancy, whose diagnostic approach and treatment are evolving, resulting in improved outcome.
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Affiliation(s)
- Eelco de Bree
- a Department of Surgical Oncology , Medical School of Crete University Hospital , Heraklion , Greece
| | - Koen P Rovers
- b Department of Surgical Oncology , Catharina Hospital , Eindhoven , The Netherlands
| | - Dimitris Stamatiou
- a Department of Surgical Oncology , Medical School of Crete University Hospital , Heraklion , Greece
| | - John Souglakos
- c Department of Medical Oncology and Laboratory of Translational Oncology , Medical School of Crete University Hospital , Heraklion , Greece
| | - Dimosthenis Michelakis
- a Department of Surgical Oncology , Medical School of Crete University Hospital , Heraklion , Greece
| | - Ignace H de Hingh
- b Department of Surgical Oncology , Catharina Hospital , Eindhoven , The Netherlands
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23
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Expression of PD-1 and PD-L1 in poorly differentiated neuroendocrine carcinomas of the digestive system: a potential target for anti-PD-1/PD-L1 therapy. Hum Pathol 2017; 70:49-54. [PMID: 29037958 DOI: 10.1016/j.humpath.2017.10.003] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2017] [Revised: 09/20/2017] [Accepted: 10/04/2017] [Indexed: 12/31/2022]
Abstract
Poorly differentiated neuroendocrine carcinoma of the digestive system has a dismal prognosis with limited treatment options. This study aimed to investigate expression of the PD-1/PD-L1 pathway in these tumors. Thirty-seven patients with a poorly differentiated neuroendocrine carcinoma of the digestive system were identified. Their electronic medical records, pathology reports, and pathology slides were reviewed for demographics, clinical history, and pathologic features. Tumor sections were immunohistochemically labeled for PD-1 and PD-L1, and expression of PD-1 and PD-L1 on tumor and tumor-associated immune cells was analyzed and compared between small cell and large cell neuroendocrine carcinomas. The mean age of patients was 61 years old with 18 men and 19 women. The colorectum (n=20) was the most common primary site; other primary sites included the pancreaticobiliary system, esophagus, stomach, duodenum, and ampulla. Expression of PD-1 was detected on tumor cells (n=6, 16%) as well as on tumor-associated immune cells (n=23, 63%). The 6 cases with PD-1 expression on tumor cells also had the expression on immune cells. Expression of PD-L1 was visualized on tumor cells in 5 cases (14%) and on tumor-associated immune cells in 10 cases (27%). There was no difference in PD-1 and PD-L1 expression between small cell and large cell neuroendocrine carcinomas. In conclusion, PD-1/PD-L1 expression is a frequent occurrence in poorly differentiated neuroendocrine carcinomas of the digestive system. Checkpoint blockade targeting the PD-1/PD-L1 pathway may have a potential role in treating patients with this disease.
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