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Grigorie TR, Potlog G, Alexandrescu ST. Lynch Syndrome-Impact of the Type of Deficient Mismatch Repair Gene Mutation on Diagnosis, Clinical Presentation, Surveillance and Therapeutic Approaches. MEDICINA (KAUNAS, LITHUANIA) 2025; 61:120. [PMID: 39859102 PMCID: PMC11766940 DOI: 10.3390/medicina61010120] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/27/2024] [Revised: 01/10/2025] [Accepted: 01/12/2025] [Indexed: 01/27/2025]
Abstract
In today's world, with its continuing advancements in genetics, the identification of Lynch syndrome (LS) increasingly relies on sophisticated genetic testing techniques. Most guidelines recommend a tailored surveillance program, as well as personalized prophylactic and therapeutic approaches, according to the type of dMMR gene mutation. Carriers of path_MLH1 and path_MSH2 genes have a higher risk of developing colorectal cancer (CRC), despite intensive colonoscopic surveillance. Conversely, carriers of path_MSH6 and path_PMS2 genes have a lower risk of developing CRC, which may be due to their lower penetrance and later age of onset. Thus, carriers of path_MLH1 or path_MSH2 would theoretically derive greater benefits from total colectomy, compared to low-risk carriers (path_MSH6 and path_PMS2), in which colonoscopic surveillance might achieve an efficient prophylaxis. Furthermore, regarding the risk of endometrial/ovarian cancer development, there is a global agreement to offer both hysterectomy and bilateral salpingo-oophorectomy to path_MLH1, path_MSH2 and path_MSH6 carriers after the age of 40. In patients with CRC, preoperative knowledge of the diagnosis of LS is of tremendous importance, due to the high risk of metachronous CRC. However, this risk depends on the type of dMMR gene mutation. For carriers of the high-risk variants (MLH1, MSH2 and EPCAM) who have already developed colon cancer, it is strongly recommended a subtotal or total colectomy is performed, while partial colectomy followed by endoscopic surveillance is an appropriate management approach to treat colon cancer in carriers of the low-risk variants (MSH6 and PMS2). On the other hand, extended surgery for index rectal cancer (such as total proctocolectomy) is less effective than extended surgery for index colon cancer from the point of view of metachronous CRC risk reduction, and is associated with a decreased quality of life.
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Affiliation(s)
- Tudor Razvan Grigorie
- Department of Surgery, Faculty of Medicine, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania;
- Department of Hepato-Bilio-Pancreatic Surgery, Emergency University Hospital Bucharest, Splaiul Independentei 169, Sector 5, 050098 Bucharest, Romania
| | - Gheorghe Potlog
- Center for Digestive Diseases and Liver Transplantation, Fundeni Clinical Institute, 022328 Bucharest, Romania;
| | - Sorin Tiberiu Alexandrescu
- Department of Surgery, Faculty of Medicine, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania;
- Department of Hepato-Bilio-Pancreatic Surgery, Emergency University Hospital Bucharest, Splaiul Independentei 169, Sector 5, 050098 Bucharest, Romania
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Trembath HE, Yeh JJ, Lopez NE. Gastrointestinal Malignancy: Genetic Implications to Clinical Applications. Cancer Treat Res 2024; 192:305-418. [PMID: 39212927 DOI: 10.1007/978-3-031-61238-1_15] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/04/2024]
Abstract
Advances in molecular genetics have revolutionized our understanding of the pathogenesis, progression, and therapeutic options for treating gastrointestinal (GI) cancers. This chapter provides a comprehensive overview of the molecular landscape of GI cancers, focusing on key genetic alterations implicated in tumorigenesis across various anatomical sites including GIST, colon and rectum, and pancreas. Emphasis is placed on critical oncogenic pathways, such as mutations in tumor suppressor genes, oncogenes, chromosomal instability, microsatellite instability, and epigenetic modifications. The role of molecular biomarkers in predicting prognosis, guiding treatment decisions, and monitoring therapeutic response is discussed, highlighting the integration of genomic profiling into clinical practice. Finally, we address the evolving landscape of precision oncology in GI cancers, considering targeted therapies and immunotherapies.
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Affiliation(s)
- Hannah E Trembath
- Division of Colon and Rectal Surgery, Department of Surgery, University of California San Diego, 4303 La Jolla Village Drive Suite 2110, San Diego, CA, 92122, USA
- Division of Surgical Oncology, Department of Surgery, University of North Carolina, 170 Manning Drive, CB#7213, 1150 Physician's Office Building, Chapel Hill, NC, 27599-7213, USA
| | - Jen Jen Yeh
- Division of Colon and Rectal Surgery, Department of Surgery, University of California San Diego, 4303 La Jolla Village Drive Suite 2110, San Diego, CA, 92122, USA
- Division of Surgical Oncology, Department of Surgery, University of North Carolina, 170 Manning Drive, CB#7213, 1150 Physician's Office Building, Chapel Hill, NC, 27599-7213, USA
| | - Nicole E Lopez
- Division of Colon and Rectal Surgery, Department of Surgery, University of California San Diego, 4303 La Jolla Village Drive Suite 2110, San Diego, CA, 92122, USA.
- Division of Surgical Oncology, Department of Surgery, University of North Carolina, 170 Manning Drive, CB#7213, 1150 Physician's Office Building, Chapel Hill, NC, 27599-7213, USA.
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Chikatani K, Ishida H, Mori Y, Nakajima T, Ueki A, Akagi K, Takao A, Yamada M, Taniguchi F, Komori K, Sasaki K, Sudo T, Miyakura Y, Chino A, Yamaguchi T, Tanakaya K, Tomita N, Ajioka Y. Risk of metachronous colorectal cancer after colectomy for first colon cancer in Lynch syndrome: multicenter retrospective study in Japan. Int J Clin Oncol 2023; 28:1633-1640. [PMID: 37752370 DOI: 10.1007/s10147-023-02412-z] [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: 03/04/2023] [Accepted: 09/01/2023] [Indexed: 09/28/2023]
Abstract
BACKGROUND We evaluated the risk of metachronous colorectal cancer (mCRC) and explored the optimal extent of colectomy in patients with Lynch syndrome (LS) and first colon cancer (fCC) in Japan, where the extent of colectomy for colon cancer (CC) is shorter than that in Western countries. METHODS The clinicopathologic and survival data of patients with LS who developed CC were collected from a nationwide database and analyzed retrospectively. The cumulative incidence of mCRC after actual segmental colectomy was compared with that of mCRC when more extensive colectomy was assumed. RESULTS There were 142 eligible patients (65 female). The median age at fCC surgery was 46.5 (range: 14-80) years. The cumulative incidence of 5-, 10-, and 20-year mCRC rate was 13.4%, 20.8%, and 53.6%, respectively. The incidence was higher in the left-sided group (splenic flexure to rectosigmoid colon, n = 54) than in the right-sided group (cecum to transvers colon, n = 88) (66.3% vs. 45.3% in 20 years, P < 0.01). Assuming that all patients would have undergone hemicolectomy or total colectomy, the estimated mCRC risk was 41.5% and 9.4% (P < 0.01, vs. actual procedures), respectively. The 20-year overall survival rate of all the patients was 83.3% without difference by fCC sidedness (P = 0.38). CONCLUSIONS To reduce the incidence of mCRC, patients with genetically diagnosed LS and fCC, preferentially located in the left-sided colon, may need to undergo more extended colectomy than that usually performed in Japan. However, such extended colectomy should be counterbalanced with favorable overall survival and actual risk of mCRC development.
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Affiliation(s)
- Kenichi Chikatani
- Department of Digestive Tract and General Surgery, Saitama Medical Center, Saitama Medical University, 1981 Kamoda, Kawagoe-City, Saitama, 350-8550, Japan.
| | - Hideyuki Ishida
- Department of Digestive Tract and General Surgery, Saitama Medical Center, Saitama Medical University, 1981 Kamoda, Kawagoe-City, Saitama, 350-8550, Japan
- The Committee of Hereditary Colorectal Cancer, Japanese Society for Cancer of the Colon and Rectum, Tokyo, Japan
| | - Yoshiko Mori
- Department of Digestive Tract and General Surgery, Saitama Medical Center, Saitama Medical University, 1981 Kamoda, Kawagoe-City, Saitama, 350-8550, Japan
| | - Takeshi Nakajima
- The Committee of Hereditary Colorectal Cancer, Japanese Society for Cancer of the Colon and Rectum, Tokyo, Japan
- Department of Clinical Genetics, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Arisa Ueki
- The Committee of Hereditary Colorectal Cancer, Japanese Society for Cancer of the Colon and Rectum, Tokyo, Japan
- Department of Clinical Genetics, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Kiwamu Akagi
- The Committee of Hereditary Colorectal Cancer, Japanese Society for Cancer of the Colon and Rectum, Tokyo, Japan
- Department of Molecular Diagnosis and Cancer Prevention, Saitama Cancer Center, Saitama, Japan
| | - Akinari Takao
- The Committee of Hereditary Colorectal Cancer, Japanese Society for Cancer of the Colon and Rectum, Tokyo, Japan
- Department of Gastroenterology, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Tokyo, Japan
| | - Masayoshi Yamada
- The Committee of Hereditary Colorectal Cancer, Japanese Society for Cancer of the Colon and Rectum, Tokyo, Japan
- Endoscopy Division, National Cancer Center Hospital, Tokyo, Japan
| | - Fumitaka Taniguchi
- The Committee of Hereditary Colorectal Cancer, Japanese Society for Cancer of the Colon and Rectum, Tokyo, Japan
- Department of Surgery, National Hospital Organization Iwakuni Clinical Center, Yamaguchi, Japan
| | - Koji Komori
- The Committee of Hereditary Colorectal Cancer, Japanese Society for Cancer of the Colon and Rectum, Tokyo, Japan
- Department of Gastroenterological Surgery, Aichi Cancer Center Hospital, Aichi, Japan
| | - Kazuhito Sasaki
- The Committee of Hereditary Colorectal Cancer, Japanese Society for Cancer of the Colon and Rectum, Tokyo, Japan
- Department of Surgical Oncology, Faculty of Medicine, The University of Tokyo, Tokyo, Japan
| | - Tomoya Sudo
- The Committee of Hereditary Colorectal Cancer, Japanese Society for Cancer of the Colon and Rectum, Tokyo, Japan
- Department of Surgery, Kurume University, Fukuoka, Japan
| | - Yasuyuki Miyakura
- The Committee of Hereditary Colorectal Cancer, Japanese Society for Cancer of the Colon and Rectum, Tokyo, Japan
- Department of Surgery, Saitama Medical Center, Jichi Medical University, Saitama, Japan
| | - Akiko Chino
- The Committee of Hereditary Colorectal Cancer, Japanese Society for Cancer of the Colon and Rectum, Tokyo, Japan
- Department of Gastroenterology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Tatsuro Yamaguchi
- The Committee of Hereditary Colorectal Cancer, Japanese Society for Cancer of the Colon and Rectum, Tokyo, Japan
- Department of Clinical Genetics, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Tokyo, Japan
| | - Kohji Tanakaya
- The Committee of Hereditary Colorectal Cancer, Japanese Society for Cancer of the Colon and Rectum, Tokyo, Japan
- Department of Surgery, National Hospital Organization Iwakuni Clinical Center, Yamaguchi, Japan
| | - Naohiro Tomita
- The Committee of Hereditary Colorectal Cancer, Japanese Society for Cancer of the Colon and Rectum, Tokyo, Japan
- Cancer Treatment Center, Toyonaka Municipal Hospital, Osaka, Japan
| | - Yoichi Ajioka
- Japanese Society for Cancer of the Colon and Rectum, Tokyo, Japan
- Division of Molecular and Diagnostic Pathology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan
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Yu J, Ding PR, Jiang W. Screening and Management of Lynch Syndrome: The Chinese Experience. Clin Colon Rectal Surg 2023; 36:369-377. [PMID: 37795465 PMCID: PMC10547539 DOI: 10.1055/s-0043-1767706] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/06/2023]
Abstract
Lynch syndrome (LS), caused by germline mutations in the mismatch repair genes, is the most common hereditary colorectal cancer. While LS is also associated with various cancers, early detection of the proband is meaningful for tumor prevention, treatment, and familial management. It has been a dramatic shift on the screening approaches for LS. As the rapid development of the molecular biological methods, a comprehensive understanding of the LS screening strategies will help to improve the clinical care for this systematic disease. The current screening strategies have been well validated but mainly by evidence derived from western population, lacking consideration of the ethnic heterogeneity, which hampers the universality and clinical application in China. Hence, this review will focus on the Chinese experience in LS screening, aiming to help better understand the ethnic diversity and further optimize the screening strategies.
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Affiliation(s)
- Jiehai Yu
- Department of Colorectal Surgery, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou Guangdong, P. R. China
| | - Pei-Rong Ding
- Department of Colorectal Surgery, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou Guangdong, P. R. China
| | - Wu Jiang
- Department of Colorectal Surgery, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou Guangdong, P. R. China
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Kudchadkar S, Ahmed S, Mukherjee T, Sagar J. Current guidelines in the surgical management of hereditary colorectal cancers. World J Gastrointest Oncol 2022; 14:833-841. [PMID: 35582097 PMCID: PMC9048527 DOI: 10.4251/wjgo.v14.i4.833] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2021] [Revised: 10/16/2021] [Accepted: 03/04/2022] [Indexed: 02/06/2023] Open
Abstract
Incidence of colorectal cancer (CRC) is on rise. While approximately 70% of all CRC cases are sporadic in nature, 20%-25% have familial aggregation and only < 5% is hereditary in origin. Identification of individuals with hereditary predilection for CRC is critical, as it has an impact on their overall surgical management including surgical timing, approach & technique and determines the role of prophylactic surgery and outcome. This review highlights the concept of hereditary CRC, provides insight into its molecular basis, possibility of its application into clinical practice and emphasizes the current treatment strategies with surgical management, based on the available international guidelines.
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Affiliation(s)
- Shantata Kudchadkar
- Department of Colorectal Surgery, Luton & Dunstable University Hospital NHS Foundation Trust, Luton LU4 0DZ, United Kingdom
| | - Safia Ahmed
- Department of Colorectal Surgery, Luton & Dunstable University Hospital NHS Foundation Trust, Luton LU4 0DZ, United Kingdom
| | - Tanmoy Mukherjee
- Department of Colorectal Surgery, Luton & Dunstable University Hospital NHS Foundation Trust, Luton LU4 0DZ, United Kingdom
| | - Jayesh Sagar
- Department of Colorectal Surgery, Luton & Dunstable University Hospital NHS Foundation Trust, Luton LU4 0DZ, United Kingdom
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Liao CK, Lin YC, Hsu YJ, Chern YJ, You JF, Chiang JM. Deciding the operation type according to mismatch repair status among hereditary nonpolyposis colorectal cancer patients: should a tailored approach be applied, or does one size fit all? Hered Cancer Clin Pract 2021; 19:29. [PMID: 34187536 PMCID: PMC8243908 DOI: 10.1186/s13053-021-00186-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2021] [Accepted: 06/09/2021] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Although extended colectomy (EC) was recommended for HNPCC patients, previous studies did not show significantly improved overall survival. Immunohistochemical (IHC) stain of mismatch repair (MMR) gene protein expression is now a feasible and reliable test clinically. Therefore, we tried to investigate whether we could use MMR IHC stain to select operation types in HNPCC patients. PATIENTS AND METHODS Between 1995 and 2013, 186 HNPCC patients were collected. Status of MMR protein expression, perioperative clinic-pathological variables and post-operative follow up status were analyzed by multivariate analyses. RESULTS Sixty-five percent (121 of 186) patients of these HNPCC patients demonstrated loss of at least one MMR protein. There were several significant differences existing between deficient MMR (dMMR) and proficient MMR (pMMR) subgroups in terms of clinic-pathological characteristics. With the average follow-up duration of 93.9 months, we observed significantly high risk of developing metachronous CRC between SC and EC subgroups (crude rate 8.5% vs. 0%, p = 0.035). However, no significant difference was observed among the presence of extra-colonic tumors (12.4% vs. 5.8%, p = 0.284). The positive and negative prediction rate of metachronous CRC in dMMR subgroup was 12.8 and 87.2% while 1.9 and 98.1% in the pMMR subgroup. Survival outcomes were significantly affected by MMR status and resection types by multivariate analysis. Significantly better OS in dMMR subgroup (HR = 0.479, 95% CI: 0.257-0.894, p = 0.021) comparing with pMMR subgroup was observed. However, significant improved DFS (HR = 0.367, 95% CI: 0.172-.0787, p = 0.010) but not significant for OS (HR = 0.510, 95% CI: 0.219-1.150, p = 0.103) for EC subgroup compared with SC subgroup. Differences existing among different subgroups by combing extent of resection and MMR status. In dMMR subgroup, SC, compared with EC, demonstrated significantly worse DFS by multivariate analyses (HR = 3.526, 95% CI: 1.346-9.236, p = 0.010) but not for OS (HR = 2.387, 95% CI: 0.788-7.229, p = 0.124), however, no significantly differences of OS and DFS in pMMR subgroup between SC and EC were found. CONCLUSIONS Significantly better overall survival and higher rate of metachronous CRC exist in dMMR subgroup of HNPCC patients comparing with pMMR subgroup. Extended colectomy significantly improved DFS and was thus recommended for dMMR subgroup but not pMMR subgroup of HNPCC patients.
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Affiliation(s)
- Chun-Kai Liao
- Colorectal Section, Department of Surgery, Chang Gung Memorial Hospital, No. 5, Fuxing St., Guishan Dist,, Taoyuan, Taiwan, 33305
| | - Yueh-Chen Lin
- Colorectal Section, Department of Surgery, Chang Gung Memorial Hospital, No. 5, Fuxing St., Guishan Dist,, Taoyuan, Taiwan, 33305
| | - Yu-Jen Hsu
- Colorectal Section, Department of Surgery, Chang Gung Memorial Hospital, No. 5, Fuxing St., Guishan Dist,, Taoyuan, Taiwan, 33305
| | - Yih-Jong Chern
- Colorectal Section, Department of Surgery, Chang Gung Memorial Hospital, No. 5, Fuxing St., Guishan Dist,, Taoyuan, Taiwan, 33305
| | - Jeng-Fu You
- Colorectal Section, Department of Surgery, Chang Gung Memorial Hospital, No. 5, Fuxing St., Guishan Dist,, Taoyuan, Taiwan, 33305
| | - Jy-Ming Chiang
- Colorectal Section, Department of Surgery, Chang Gung Memorial Hospital, No. 5, Fuxing St., Guishan Dist,, Taoyuan, Taiwan, 33305. .,College of Medicine, Chang Gung University, Taoyuan, Taiwan.
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Abstract
Lynch syndrome is one of the most common hereditary cancer syndromes and is characterized by the development of many cancers, such as colorectal cancer (CRC), endometrial cancer, ovarian cancer, stomach cancer and many other cancers. Lynch syndrome is caused by pathogenic germline variants in one of four DNA mismatch repair genes (MLH1, MSH2, MSH6, or PMS2) or by an EPCAM deletion. The MLH1 variant is correlated with the highest risk of CRC, while the MSH2 variant is correlated with the highest risk of other cancers. CRC is the most common cancer type that develops in individuals with Lynch syndrome, followed by endometrial cancer. Recent advances have been made to help us further understand the molecular pathogenesis of this disease and help improve diagnostic testing efficiency and surveillance strategies. Moreover, recent advances in immunotherapy provided by clinical trials also provide clinicians with more chances to better treat Lynch syndrome. This study aims to review many advances in the molecular genetics, clinical features, diagnosis, surveillance and treatment of Lynch syndrome.
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Affiliation(s)
- Xi Li
- Department of Geriatric Surgery, Xiangya Hospital, Central South University, Changsha, 410008, China.,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, China.,Department of General Surgery, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Guodong Liu
- Department of Geriatric Surgery, Xiangya Hospital, Central South University, Changsha, 410008, China. .,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, China. .,Department of General Surgery, Xiangya Hospital, Central South University, Changsha, 410008, China.
| | - Wei Wu
- Department of Geriatric Surgery, Xiangya Hospital, Central South University, Changsha, 410008, China. .,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, China. .,Department of General Surgery, Xiangya Hospital, Central South University, Changsha, 410008, China.
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Ykema BLM, Nagtegaal ID, Kuhlmann K, van Berkel AM, van Leerdam ME. Compliance with mismatch repair testing in pT1 colorectal cancer diagnosed before the age of 70 years. Virchows Arch 2021; 479:451-457. [PMID: 33718978 DOI: 10.1007/s00428-021-03074-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2021] [Revised: 02/12/2021] [Accepted: 03/01/2021] [Indexed: 11/28/2022]
Abstract
Mismatch repair (MMR) testing is recommended in the Netherlands for all patients under 70 years of age with newly diagnosed colorectal cancer (CRC) in order to identify Lynch syndrome. T1 CRC can be removed by local excision or oncological surgical resection. We evaluated the frequency of MMR testing in pT1 lesions within the Dutch CRC screening cohort. pT1 CRC diagnosed within the Dutch population-based screening program from 2016-2018 were identified by the Dutch pathology registry (PALGA). Pathology reports were evaluated, including registration of MMR testing (by immunohistochemistry and/or microsatellite instability PCR). Frequency of MMR testing was compared between pT1 tumors that were treated by local (endoscopic or transanal) excision and oncological surgical resections. A total of 3.692 pT1 CRCs were diagnosed (median age 63 years, 61.4% males). MMR testing was performed in 83% and uptake increased over time (71% in 2016 to 92% in 2018, p<0.01). MMR testing was significantly more often performed in younger patients and in academic hospitals. When pT1 CRC was treated by oncological surgical resection (n=1.132), MMR testing was performed in 89% of cases and was known prior to oncological resection in 51% of cases. MMR testing occurred significantly less often in case of local excision (80% of n=2.560) compared to oncological surgical resection (p<0.01). MMR testing was performed in 83% of T1 CRCs and uptake increased over time. MMR testing was more frequently performed in pT1 CRC resected by oncological surgical resection compared with local excision.
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Affiliation(s)
- Berbel L M Ykema
- Department of Gastroenterology and Hepatology, Netherlands Cancer Institute, Amsterdam, the Netherlands
| | - Iris D Nagtegaal
- Department of Pathology, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Koert Kuhlmann
- Department of Surgery, Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Annemarie M van Berkel
- Department of Gastroenterology and Hepatology, Noordwest Ziekenhuisgroep, Alkmaar, The Netherlands
| | - Monique E van Leerdam
- Department of Gastroenterology and Hepatology, Netherlands Cancer Institute, Amsterdam, the Netherlands. .,Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands.
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Prophylactic Gynecologic Surgery at Time of Colectomy Benefits Women with Lynch Syndrome and Colon Cancer: A Markov Cost-Effectiveness Analysis. Dis Colon Rectum 2020; 63:1393-1402. [PMID: 32969882 DOI: 10.1097/dcr.0000000000001681] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
BACKGROUND Women with Lynch syndrome who have completed childbearing should be offered prophylactic hysterectomy and bilateral salpingo-oophorectomy for gynecologic cancer prevention. The benefit of prophylactic gynecologic surgery at the time of colon cancer resection is unclear. OBJECTIVE This study aimed to compare the cost, quality of life, and likelihood of being alive and free from colon, endometrial, and ovarian cancer between operative choices for patients with Lynch syndrome undergoing surgery for colon cancer. DESIGN A Markov decision tree spanning 40 years was constructed for a hypothetical cohort of 30-year-old women with Lynch syndrome who had been diagnosed with colon cancer. Outcomes of 6 surgical strategies were compared, including segmental or total abdominal colectomy with or without hysterectomy alone or combined with bilateral salpingo-oophorectomy. SETTINGS A Markov cost-effectiveness analysis was performed at a single center. PATIENTS A literature search was performed identifying studies of patients with genetically diagnosed Lynch syndrome that described cost, risk of mortality, and quality of life after colon cancer resection and prophylactic gynecologic surgery. MAIN OUTCOME MEASURES The primary outcomes measured were quality-adjusted life-years and the likelihood of being alive and free from colon, endometrial, and ovarian cancer 40 years after surgery. RESULTS Women with Lynch syndrome who underwent a total abdominal colectomy and hysterectomy with bilateral salpingo-oophorectomy had the highest likelihood of being alive and cancer free. Total abdominal colectomy with hysterectomy was a close second, but yielded the largest amount of quality-adjusted life-years and lowest cost. LIMITATIONS This study is limited by the statistical method and quality of studies used. CONCLUSIONS Total abdominal colectomy with prophylactic hysterectomy at 30 years of age was the most cost-effective surgical choice in women with Lynch syndrome and colon cancer. The addition of bilateral salpingo-oophorectomy offered the highest event-free survival and lowest mortality. However, the additional morbidity of premature menopause of prophylactic salpingo-oophorectomy for younger women outweighed the benefit of ovarian cancer prevention. See Video Abstract at http://links.lww.com/DCR/B287. LA CIRUGÍA GINECOLÓGICA PROFILÁCTICA EN EL MOMENTO DE LA COLECTOMÍA BENEFICIA A LAS MUJERES CON SÍNDROME DE LYNCH Y CÁNCER DE COLON: UN ANÁLISIS DE COSTO-EFECTIVIDAD DE MARKOV: Las mujeres con síndrome de Lynch que han completado la maternidad deberían recibir histerectomía profiláctica y salpingooforectomía bilateral para la prevención del cáncer ginecológico. El beneficio de la cirugía ginecológica profiláctica en el momento de la resección del cáncer de colon no está claro.Comparar el costo, la calidad de vida y la probabilidad de estar viva y libre de cáncer de colon, endometrio y ovario entre las opciones quirúrgicas para pacientes con síndrome de Lynch sometidos a cirugía por cáncer de colon.Se construyó un árbol de decisión de Markov que abarca cuarenta años para una cohorte hipotética de mujeres de 30 años con síndrome de Lynch diagnosticadas con cáncer de colon. Se compararon los resultados de seis estrategias quirúrgicas, incluida la colectomía abdominal segmentaria o total con o sin histerectomía sola o combinada con salpingooforectomía bilateral.Se realizó un análisis de costo-efectividad de Markov en un solo centro.se realizó una búsqueda bibliográfica para identificar estudios de pacientes con síndrome de Lynch con diagnóstico genético que describieron el costo, el riesgo de mortalidad y la calidad de vida después de la resección del cáncer de colon y la cirugía ginecológica profiláctica.años de vida ajustados por calidad y probabilidad de estar vivo y libre de cáncer de colon, endometrio y ovario 40 años después de la cirugía.Las mujeres con síndrome de Lynch que se sometieron a una colectomía e histerectomía abdominal total con salpingooforectomía bilateral tuvieron la mayor probabilidad de estar vivas y libres de cáncer. La colectomía abdominal total con histerectomía fue un segundo lugar cercano, pero produjo la mayor cantidad de años de vida ajustados por calidad y el costo más bajo.Este estudio está limitado por el método estadístico y la calidad de los estudios utilizados.La colectomía abdominal total con histerectomía profiláctica a los 30 años fue la opción quirúrgica más rentable en mujeres con síndrome de Lynch y cáncer de colon. La adición de salpingooforectomía bilateral ofreció la mayor supervivencia libre de eventos y la menor mortalidad. Sin embargo, la morbilidad adicional de la menopausia prematura de la salpingooforectomía profiláctica para las mujeres más jóvenes superó el beneficio de la prevención del cáncer de ovario. Consulte Video Resumen en http://links.lww.com/DCR/B287. (Traducción-Dr. Yesenia Rojas-Khalil).
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Sun CY, Chiang JM, Chen TC, Hung HY, You JF. Different surgical outcome and follow-up status between dMMR and pMMR colorectal cancer patients who fulfilled with Amsterdam-II criteria. World J Surg Oncol 2020; 18:195. [PMID: 32767993 PMCID: PMC7414700 DOI: 10.1186/s12957-020-01976-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2020] [Accepted: 07/30/2020] [Indexed: 11/17/2022] Open
Abstract
Background Although hereditary non-polyposis colorectal cancer (HNPCC) could be subtyped into proficient or deficient mismatch repair gene expression (pMMR or dMMR), distinct clinical features between these two subgroups patients were rarely reported. Methods We retrospectively analyzed 175 hereditary non-polyposis colorectal cancer (HNPCC) patients between January 1995 and December 2012. Cox proportional hazards model was used to compare the differences between two subgroups. Results Significant differences of disease free survival (DFS) and overall survival (OS) exist between dMMR and pMMR. In addition to other factors including younger mean age of diagnosis for dMMR patients (48.6 years vs. 54.3 years), operation type (more extended colectomy for dMMR 35.8% vs. 14.5%), tumor location (right colon predominance for dMMR 61.7% vs. 27.3% and more rectum cases for pMMR 41.8% vs. 11.7%), tumor differentiation (more poor differentiation for dMMR 23.3% vs. 9.0%), N staging (more N0 cases for dMMR 70.8% vs. 50.9%), more frequently presence of extra-colonic tumors for dMMR (16.7% vs.1.8%), and lower recurrence rates (9.1% vs.35.3%). Significantly different cumulative incidences of developing metachronous colorectal cancer were observed with 6.18 for pMMR patients and 20.57 person-years for dMMR patients (p < 0.001). Conclusions Distinct clinicopathological features significantly exist between dMMR and pMMR subtypes patient, MMR status should be consider to tailor operation types and follow up surveillance between these two subgroups patients who all fulfilled with Amsterdam-II criteria.
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Affiliation(s)
- Ci-Yuan Sun
- Division of Colon and Rectal Surgery, Department of Surgery, Chang Gung Memorial Hospital, Lin-Kou Medical Center, Tao-Yuan, Taiwan. .,College of Medicine, Chang Gung University, No. 5, Fu-Hsing Rd. Kuei-Shan, Tao-Yuan, 333, Taiwan.
| | - Jy-Ming Chiang
- Division of Colon and Rectal Surgery, Department of Surgery, Chang Gung Memorial Hospital, Lin-Kou Medical Center, Tao-Yuan, Taiwan.,Chang Gung University, College of Medicine, Tao-Yuan, Taiwan
| | - Tse-Ching Chen
- Chang Gung University, College of Medicine, Tao-Yuan, Taiwan.,Department of Pathology, Chang Gung Memorial Hospital, Lin-Kou Medical Center, Tao-Yuan, Taiwan
| | - Hsin-Yun Hung
- Division of Colon and Rectal Surgery, Department of Surgery, Chang Gung Memorial Hospital, Lin-Kou Medical Center, Tao-Yuan, Taiwan
| | - Jeng-Fu You
- Division of Colon and Rectal Surgery, Department of Surgery, Chang Gung Memorial Hospital, Lin-Kou Medical Center, Tao-Yuan, Taiwan
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11
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Zhou X, Ding X, Li H, Yang C, Ma Z, Xu G, Yang S, Zhang D, Xie X, Xin L, Luo X. Upregulation of TIGIT and PD-1 in Colorectal Cancer with Mismatch-repair Deficiency. Immunol Invest 2020; 50:338-355. [PMID: 32397769 DOI: 10.1080/08820139.2020.1758130] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Affiliation(s)
- Xuebing Zhou
- Department of Medical Laboratory, School of Clinical Medicine, Ningxia Medical University, Yinchuan, China
- Department of General Surgery Center, People's Hospital of Ningxia Hui Autonomous region, Yinchuan, China
| | - Xiaoling Ding
- Department of Gastroenterology, People's Hospital of Ningxia Hui Autonomous region, Yinchuan, China
| | - Hai Li
- Department of Anal-Colorectal Surgery, General Hospital of Ningxia Medical University, Yinchuan, China
| | - Chun Yang
- Department of Anal-Colorectal Surgery, General Hospital of Ningxia Medical University, Yinchuan, China
| | - Zhanbing Ma
- Department of Medical Genetics and Cell Biology, Ningxia Medical University, Yinchuan, China
| | - Guangxian Xu
- Ningxia Key Laboratory of Clinical and Pathogenic Microbiology, General Hospital of Ningxia Medical University, Yinchuan, China
| | - Shaoqi Yang
- Department of Gastroenterology, General Hospital of Ningxia Medical University, Yinchuan, China
| | - Dong Zhang
- Department of Anal-Colorectal Surgery, General Hospital of Ningxia Medical University, Yinchuan, China
| | - Xiaoliang Xie
- Department of Anal-Colorectal Surgery, General Hospital of Ningxia Medical University, Yinchuan, China
| | - Lei Xin
- Department of Medical Laboratory, School of Clinical Medicine, Ningxia Medical University, Yinchuan, China
| | - Xiaoli Luo
- Department of Anal-Colorectal Surgery, General Hospital of Ningxia Medical University, Yinchuan, China
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12
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Monahan KJ, Bradshaw N, Dolwani S, Desouza B, Dunlop MG, East JE, Ilyas M, Kaur A, Lalloo F, Latchford A, Rutter MD, Tomlinson I, Thomas HJW, Hill J. Guidelines for the management of hereditary colorectal cancer from the British Society of Gastroenterology (BSG)/Association of Coloproctology of Great Britain and Ireland (ACPGBI)/United Kingdom Cancer Genetics Group (UKCGG). Gut 2020; 69:411-444. [PMID: 31780574 PMCID: PMC7034349 DOI: 10.1136/gutjnl-2019-319915] [Citation(s) in RCA: 287] [Impact Index Per Article: 57.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2019] [Revised: 10/25/2019] [Accepted: 11/05/2019] [Indexed: 12/12/2022]
Abstract
Heritable factors account for approximately 35% of colorectal cancer (CRC) risk, and almost 30% of the population in the UK have a family history of CRC. The quantification of an individual's lifetime risk of gastrointestinal cancer may incorporate clinical and molecular data, and depends on accurate phenotypic assessment and genetic diagnosis. In turn this may facilitate targeted risk-reducing interventions, including endoscopic surveillance, preventative surgery and chemoprophylaxis, which provide opportunities for cancer prevention. This guideline is an update from the 2010 British Society of Gastroenterology/Association of Coloproctology of Great Britain and Ireland (BSG/ACPGBI) guidelines for colorectal screening and surveillance in moderate and high-risk groups; however, this guideline is concerned specifically with people who have increased lifetime risk of CRC due to hereditary factors, including those with Lynch syndrome, polyposis or a family history of CRC. On this occasion we invited the UK Cancer Genetics Group (UKCGG), a subgroup within the British Society of Genetic Medicine (BSGM), as a partner to BSG and ACPGBI in the multidisciplinary guideline development process. We also invited external review through the Delphi process by members of the public as well as the steering committees of the European Hereditary Tumour Group (EHTG) and the European Society of Gastrointestinal Endoscopy (ESGE). A systematic review of 10 189 publications was undertaken to develop 67 evidence and expert opinion-based recommendations for the management of hereditary CRC risk. Ten research recommendations are also prioritised to inform clinical management of people at hereditary CRC risk.
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Affiliation(s)
- Kevin J Monahan
- Family Cancer Clinic, St Mark's Hospital, London, UK
- Faculty of Medicine, Imperial College, London, UK
| | - Nicola Bradshaw
- Clinical Genetics, West of Scotland Genetics Services, Glasgow, Glasgow, UK
| | - Sunil Dolwani
- Gastroenterology, Cardiff and Vale NHS Trust, Cardiff, UK
| | - Bianca Desouza
- Clinical Genetics, Guy's and St Thomas' NHS Foundation Trust, London, UK
| | | | - James E East
- Translational Gastroenterology Unit, John Radcliffe Hospital, Oxford, UK
- Oxford NIHR Biomedical Research Centre, University of Oxford, Oxford, UK
| | - Mohammad Ilyas
- Faculty of Medicine & Health Sciences, Nottingham University, Nottingham, UK
| | - Asha Kaur
- Head of Policy and Campaigns, Bowel Cancer UK, London, UK
| | - Fiona Lalloo
- Genetic Medicine, Central Manchester University Hospitals Foundation Trust, Manchester, UK
| | | | - Matthew D Rutter
- Gastroenterology, University Hospital of North Tees, Stockton-on-Tees, UK
- Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK
| | - Ian Tomlinson
- Nuffield Department of Clinical Medicine, Wellcome Trust Centre for Human Genetics, Birmingham, UK
- Cancer Research Centre, University of Edinburgh, Edinburgh, UK
| | - Huw J W Thomas
- Family Cancer Clinic, St Mark's Hospital, London, UK
- Faculty of Medicine, Imperial College, London, UK
| | - James Hill
- Genetic Medicine, Central Manchester University Hospitals Foundation Trust, Manchester, UK
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13
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Quezada-Diaz FF, Hameed I, von Mueffling A, Salo-Mullen EE, Catalano JD, Smith JJ, Weiser MR, Garcia-Aguilar J, Stadler ZK, Guillem JG. Risk of Metachronous Colorectal Neoplasm after a Segmental Colectomy in Lynch Syndrome Patients According to Mismatch Repair Gene Status. J Am Coll Surg 2020; 230:669-675. [PMID: 32007537 DOI: 10.1016/j.jamcollsurg.2020.01.005] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2019] [Accepted: 01/16/2020] [Indexed: 12/12/2022]
Abstract
BACKGROUND Because of increased risk of metachronous colorectal cancer (CRC), all patients with Lynch syndrome (LS) are offered a total colectomy. However, because metachronous CRC rate by mismatch repair (MMR) gene is uncertain, and total colectomy negatively impacts quality of life, it remains unclear whether segmental resection is indicated for lower penetrance MMR genes. We evaluated metachronous CRC incidence according to MMR gene in LS patients who underwent a segmental colectomy. STUDY DESIGN Single-center, retrospective cohort study in patients with an earlier colectomy for CRC and an MMR germline mutation in MLH1, MSH2, MSH6, or PMS2 followed prospectively in a hereditary CRC family registry. All patients underwent surveillance colonoscopy. Metachronous CRC was defined as one detected more than 1 year after index resection. Primary end point was cumulative incidence of metachronous CRC overall and by MMR gene. RESULTS One hundred and ten patients were included: 35 with MLH1 likely pathogenic/pathogenic (LP/P) variants (32%), 42 MSH2 (38%), 20 MSH6 (18%), and 13 PMS2 (12%). Median follow-up 4.26 years (range 0.53 to 19.92 years). Overall, metachronous CRC developed in 22 patients (20%). At 10-year follow-up, incidence was 12% (95% CI 6% to 23%), with no metachronous CRC detected in patients with a PMS2 or MSH6 LP/P variant. CONCLUSIONS After index segmental resection, metachronous CRC is less likely to develop in LS patients with MSH6 or PMS2 LP/P variant than in MLH1 or MSH2 carriers. Our data support segmental resection and long-term colonoscopic surveillance rather than total colectomy in carefully selected, well-informed LS patients with MSH6 or PMS2 LP/P variant.
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Affiliation(s)
- Felipe F Quezada-Diaz
- Colorectal Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Irbaz Hameed
- Colorectal Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Alexa von Mueffling
- Colorectal Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Erin E Salo-Mullen
- Clinical Genetics Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
| | - John D Catalano
- Colorectal Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY
| | - J Joshua Smith
- Colorectal Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Martin R Weiser
- Colorectal Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Julio Garcia-Aguilar
- Colorectal Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Zsofia K Stadler
- Clinical Genetics Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Jose G Guillem
- Colorectal Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY.
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14
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Menahem B, Alves A, Regimbeau J, Sabbagh C. Lynch Syndrome: Current management In 2019. J Visc Surg 2019; 156:507-514. [DOI: 10.1016/j.jviscsurg.2019.07.009] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
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15
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Langers AMJ, Boonstra JJ, Hardwick JCH, van der Kraan J, Farina Sarasqueta A, Vasen HFA. Endoscopic full thickness resection for early colon cancer in Lynch syndrome. Fam Cancer 2019; 18:349-352. [PMID: 31111311 PMCID: PMC6559999 DOI: 10.1007/s10689-019-00132-w] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Subtotal colectomy is usually the therapy of choice in Lynch syndrome patients diagnosed with colon cancer. In patients who develop cancer after the age of 50-60 years, segmental colectomy is considered a good alternative. Although the endoscopic treatment of early colorectal cancer in non-Lynch patients has increased in the last decades, almost all patients with a Lynch syndrome-associated colorectal malignancy undergo surgery, even if the tumour is diagnosed in a (very) early stage. One of the endoscopic treatment options for early colorectal cancer is an endoscopic full thickness resection (eFTR). This treatment modality allows optimal pathological examination of the resection specimen, as a transmural resection is performed with optimal T-staging of the tumour. We report a case of a 62 year old man, diagnosed with MSH2-Lynch syndrome, who underwent successful eFTR treatment of an early (pT1) colon cancer located in the ascending colon, with no signs of recurrence 12 months after treatment. We discuss the pros and cons of endoscopic resection of early colorectal carcinoma in Lynch syndrome patients.
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Affiliation(s)
- Alexandra M J Langers
- Department of Gastroenterology and Hepatology, Leiden University Medical Centre, PO Box 9600, 2300 RC, Leiden, The Netherlands.
| | - Jurjen J Boonstra
- Department of Gastroenterology and Hepatology, Leiden University Medical Centre, PO Box 9600, 2300 RC, Leiden, The Netherlands
| | - James C H Hardwick
- Department of Gastroenterology and Hepatology, Leiden University Medical Centre, PO Box 9600, 2300 RC, Leiden, The Netherlands
| | - Jolein van der Kraan
- Department of Gastroenterology and Hepatology, Leiden University Medical Centre, PO Box 9600, 2300 RC, Leiden, The Netherlands
| | | | - Hans F A Vasen
- Department of Gastroenterology and Hepatology, Leiden University Medical Centre, PO Box 9600, 2300 RC, Leiden, The Netherlands
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16
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Clark SK. Management of genetically determined colorectal cancer. Surgeon 2019; 17:165-171. [PMID: 30935877 DOI: 10.1016/j.surge.2019.03.003] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2019] [Accepted: 03/05/2019] [Indexed: 02/01/2023]
Abstract
Surgeons are increasingly treating patients for colorectal cancer who are known to have a genetic predisposition to develop the disease; this may modify the surgical and oncological management of the patient. In this review the approach to the patient with colorectal cancer on a background of Lynch syndrome or familial adenomatous polyposis is explored.
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Affiliation(s)
- S K Clark
- St. Mark's Hospital, Harrow, UK; Department of Surgery and Cancer, Imperial College, London, UK.
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17
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Total abdominal colectomy is cost-effective in treating colorectal cancer in patients with genetically diagnosed Lynch Syndrome. Am J Surg 2019; 218:928-933. [PMID: 30904142 DOI: 10.1016/j.amjsurg.2019.03.011] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2019] [Revised: 03/10/2019] [Accepted: 03/13/2019] [Indexed: 11/21/2022]
Abstract
BACKGROUND Lynch syndrome (LS) has a 80% lifetime risk of developing colorectal cancer and metachronous cancer. No studies have examined the quality adjusted life expectancy after SEG or TAC for LS patients, which this study was aiming for. If TAC offers a higher quality adjusted life year (QALY) to SEG in LS patients, preoperative diagnosis of LS is critical as it alters the recommended surgical procedure. METHODS A Markov decision tree was constructed using Treeage software to compare QALY of LS patients following SEG or TAC. Probabilities, cost, and utility were obtained from literature. Cost-effectiveness analyses were performed. RESULTS TAC dominates SEG as both the life-saving and cost-saving strategy. TAC dominated SEG on QALY (17.80 vs 17.13 QALY) for a cohort of LS patients diagnosed at an average of 30 year old and followed every 2 years after initial surgery. CONCLUSIONS We conclude that TAC as the primary surgical option for LS patients diagnosed with Stage I-III colon cancer is cost-effective. Further cost-effectiveness study is recommended to include extra-colonic malignancies in LS patients.
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18
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Danys D, Stratilatovas E, Cereska V, Poskus T. Lynch syndrome and sextuple primary malignancies. Acta Chir Belg 2018; 118:326-330. [PMID: 28938854 DOI: 10.1080/00015458.2017.1379801] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2017] [Accepted: 09/10/2017] [Indexed: 12/12/2022]
Abstract
Lynch syndrome or hereditary nonpolyposis colorectal cancer is the most common of hereditary colorectal cancer and accounts for 1-3%. Lynch and Chapelle estimated that it accounts 5-8% for all colorectal cancers. It is an autosomal dominant syndrome characterized by predisposition of various cancers (colorectal, stomach, endometrial, ovarian, renal, small bowel, and hepatobiliary tract) at earlier age than in general population and occurs as a result of mutation in DNA mismatch repair genes. This article presents a rare clinical of a 61-year-old female diagnosed with extracolonic Lynch syndrome with six metachronous tumours acquiring in digestive tract during the period from 1993 to 2014 (over 21 years). No other cases of six primary malignancies in patient with Lynch syndrome have been reported in literature. Upon diagnosis of Lynch syndrome, it is important to screen patient for malignancies of different localization as this syndrome predisposes appearance of various cancers at earlier age than in general population.
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Affiliation(s)
- Donatas Danys
- a Center of Abdominal Surgery , Vilnius University Hospital Santariskiu Clinics , Vilnius , Lithuania
| | - Eugenijus Stratilatovas
- a Center of Abdominal Surgery , Vilnius University Hospital Santariskiu Clinics , Vilnius , Lithuania
| | - Vaidas Cereska
- b Medical Faculty , Vilnius University , Vilnius , Lithuania
| | - Tomas Poskus
- a Center of Abdominal Surgery , Vilnius University Hospital Santariskiu Clinics , Vilnius , Lithuania
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19
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Noll A, J Parekh P, Zhou M, Weber TK, Ahnen D, Wu XC, Karlitz JJ. Barriers to Lynch Syndrome Testing and Preoperative Result Availability in Early-onset Colorectal Cancer: A National Physician Survey Study. Clin Transl Gastroenterol 2018; 9:185. [PMID: 30237431 PMCID: PMC6148048 DOI: 10.1038/s41424-018-0047-y] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2018] [Revised: 07/17/2018] [Accepted: 07/19/2018] [Indexed: 01/07/2023] Open
Abstract
Objective Although widely recommended, Lynch syndrome (LS) testing with tumor microsatellite instability (MSI) and/or immunohistochemistry (IHC) is infrequently performed in early-onset colorectal cancer (CRC), and CRC generally. Reasons are poorly understood. Hence, we conducted a national survey focusing on gastroenterologists, as they are frequently first to diagnose CRC, assessing testing barriers and which specialist is felt responsible for ordering MSI/IHC. Additionally, we assessed factors influencing timing of MSI/IHC ordering; testing on colonoscopy biopsy, opposed to post-operative surgical specimens, assists decisions on preoperative germline genetic testing and extent of colonic resection (ECR). Methods A 21-question web-based survey was distributed through an American College of Gastroenterology email listing. Results In total 509 completed the survey. 442 confirmed gastroenterologists were analyzed. Only 33.4% felt gastroenterologists were responsible for MSI/IHC ordering; pathologists were believed most responsible (38.6%). Cost, unfamiliarity interpreting results and unavailable genetic counseling most commonly prevented routine ordering (33.3%, 29.2%, 24.9%, respectively). In multivariable analysis, non-academic and rural settings were associated with cost and genetic counseling barriers. Only 46.1% felt MSI/IHC should always be performed on colonoscopy biopsy. Guideline familiarity predicted whether respondents felt surgical resection should be delayed until results returned given potential effect on ECR decisions. Conclusion Inconsistencies in who is felt should order MSI/IHC may lead to diffusion of responsibility, preventing consistent testing, including preoperatively. Assuring institutional universal testing protocols are in place, with focus on timing of testing, can optimize care. Strategies addressing cost barriers and genomic service availability in rural and non-academic settings can enhance testing. Greater emphasis on guideline familiarity is required.
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Affiliation(s)
- Alan Noll
- Tulane University School of Medicine, New Orleans, LA, USA;, Emory University School of Medicine, Atlanta, GA, USA
| | - Parth J Parekh
- Tulane University School of Medicine, New Orleans, LA, USA;, Eastern Virginia Medical School, Norfolk, VA, USA
| | - Meijiao Zhou
- Louisiana Tumor Registry and Epidemiology, School of Public Health, Louisiana State University Health Sciences Center, New Orleans, LA, USA
| | - Thomas K Weber
- Zucker School of Medicine, Hofstra Northwell, Northwell Health Cancer Institute, Hempstead, NY, USA
| | - Dennis Ahnen
- Gastroenterology of the Rockies, University of Colorado School of Medicine, Aurora, CO, USA
| | - Xiao-Cheng Wu
- Louisiana Tumor Registry and Epidemiology, School of Public Health, Louisiana State University Health Sciences Center, New Orleans, LA, USA
| | - Jordan J Karlitz
- Tulane University School of Medicine, Division of Gastroenterology. Staff Gastroenterologist Southeast Louisiana Veteran Health Care System, New Orleans, LA, USA.
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20
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Sun J, Dong M, Xiao X. Efficacy, functional outcome and post-operative complications of total abdominal colectomy with ileorectal anastomosis vs. segmental colectomy in hereditary non-polyposis colorectal cancer. Exp Ther Med 2018; 16:1603-1612. [PMID: 30186378 PMCID: PMC6122142 DOI: 10.3892/etm.2018.6380] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2017] [Accepted: 02/16/2018] [Indexed: 01/07/2023] Open
Abstract
The primary objective of the present study was to compare the choice of colectomy, i.e. total vs. segmental colectomy, in cases of hereditary non-polyposis colorectal cancer (HNPCC/lynch syndrome), and to assess the efficacy, oncological safety, functional outcome and post-operative complications of total abdominal colectomy with ileorectal anastomosis vs. segmental colectomy in HNPCC. A total of 289 patients who fulfilled the Amsterdam I and II criteria for HNPCC were included in the present study. The criteria for confirmation of the diagnosis were five micro-satellite markers, namely BAT25, BAT26, D2s123, d5S346 and D17S250. Group 1 included those patients who received their diagnosis in the years 2011–2013 and those in group 2 had been diagnosed in the years 2014–2016. The cohort had been subjected to two different types of surgery: i) Standard and extended surgery including total colectomy with ileal pouch anal anastomosis and subtotal colectomy and ii) segmental resection of the colon. Analysis of patient data indicated that in group 1, the extended resection was performed more frequently than in group 2 (68 vs. 34% of cases) and accordingly, segmental resection was less frequent (32 vs. 66%; P<0.001). In conclusion, the extensive rather than the segmental resection has been commonly performed several years ago, but at present, the surgical method of choice in cases of lynch syndrome is segmental resection. Trial registry no. QU/MR2011/CRC5, dated 21 March 2011.
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Affiliation(s)
- Jie Sun
- Department of Gastrointestinal Surgery, Qilu Hospital of Shandong University, Jinan 250012, P.R. China.,Department of General Surgery, Affiliated Weihai Second Municipal Hospital of Qingdao University, Weihai, Shandong 264200, P.R. China
| | - Mingjie Dong
- Department of General Surgery, Affiliated Weihai Second Municipal Hospital of Qingdao University, Weihai, Shandong 264200, P.R. China
| | - Xiaoping Xiao
- Department of General Surgery, Affiliated Weihai Second Municipal Hospital of Qingdao University, Weihai, Shandong 264200, P.R. China
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21
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Leicher LW, Lammertink MHA, Offerman SR, Morreau H, de Jong MM, de Groot JWB, van Westreenen HL, Vasen HFA, de Vos Tot Nederveen Cappel WH. Consequences of testing for mismatch repair deficiency of colorectal cancer in clinical practice. Scand J Gastroenterol 2018; 53:632-636. [PMID: 29161904 DOI: 10.1080/00365521.2017.1406534] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
INTRODUCTION Mismatch repair deficiency (dMMR) can be found in Lynch syndrome (LS)-associated colorectal carcinoma and in 15% of sporadic colorectal cancer (CRC). Outcome of MMR-deficiency testing is important for surgical decisions as extended colectomy is recommended in young LS-patients with CRC. Moreover, the finding of a dMMR tumour has consequences for the choices of adjuvant chemotherapy as MMR-deficient CRC is resistant to 5-fluorouracil (5-FU) monotherapy. Aims of our study are to evaluate whether MMR-deficiency testing leads to (1) identification of LS, (2) change in surgical treatment and (3) adjustment of systemic therapy in patients with dMMR CRC. METHODS We performed a multicentre, retrospective study, in a community hospital and a University Medical Centre. We included all CRC-patients between 2012 and 2016 who were tested for microsatellite instability. We collected clinical data such as gender, age, referral to clinical geneticist, surgical procedure and choice of chemotherapy. RESULTS We analysed 225 CRCs. Twenty-four (10.7%) of 225 CRC were MMR-deficient. Of the 24 patients with dMMR CRC, 18 (75%) were referred to the clinical geneticist and in nine (37%) patients a MMR mutation was identified. In one (4%) of the 24 patients, a subtotal colectomy was performed. In seven (35%) out of 20 MMR deficient patients, the chemotherapy regimen was adjusted. CONCLUSIONS The finding of a dMMR CRC had consequences for decisions on chemotherapy in a relative high proportion of patients. We recommend testing in all patients with CRC independent of age at diagnosis, as proper treatment decisions and genetic counselling are very important.
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Affiliation(s)
- L W Leicher
- a Department of Gastroenterology and Hepatology , Isala , Zwolle , The Netherlands
| | - M H A Lammertink
- a Department of Gastroenterology and Hepatology , Isala , Zwolle , The Netherlands
| | - S R Offerman
- b Department of Pathology , Isala , Zwolle , The Netherlands
| | - H Morreau
- c Department of Pathology , Leiden University Medical Centre , Leiden , The Netherlands
| | - M M de Jong
- d Department of Genetics , University Medical Centre Groningen , Groningen , The Netherlands
| | - J W B de Groot
- e Department of Oncology , Isala , Zwolle , The Netherlands
| | | | - H F A Vasen
- g Department of Gastroenterology , Leiden University Medical Centre , Leiden , The Netherlands.,h The Netherlands Foundation for the Detection of Hereditary Tumors , Leiden , The Netherlands
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22
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O'Kane GM, Ryan É, McVeigh TP, Creavin B, Hyland JM, O'Donoghue DP, Keegan D, Geraghty R, Flannery D, Nolan C, Donovan E, Mehigan BJ, McCormick P, Muldoon C, Farrell M, Shields C, Mulligan N, Kennedy MJ, Green AJ, Winter DC, MacMathuna P, Sheahan K, Gallagher DJ. Screening for mismatch repair deficiency in colorectal cancer: data from three academic medical centers. Cancer Med 2017; 6:1465-1472. [PMID: 28470797 PMCID: PMC5463076 DOI: 10.1002/cam4.1025] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2016] [Revised: 01/03/2017] [Accepted: 01/04/2017] [Indexed: 12/23/2022] Open
Abstract
Reflex immunohistochemistry (rIHC) for mismatch repair (MMR) protein expression can be used as a screening tool to detect Lynch Syndrome (LS). Increasingly the mismatch repair-deficient (dMMR) phenotype has therapeutic implications. We investigated the pattern and consequence of testing for dMMR in three Irish Cancer Centres (CCs). CRC databases were analyzed from January 2005-December 2013. CC1 performs IHC upon physician request, CC2 implemented rIHC in November 2008, and CC3 has been performing rIHC since 2004. The number of eligible patients referred to clinical genetic services (CGS), and the number of LS patients per center was determined. 3906 patients were included over a 9-year period. dMMR CRCs were found in 32/153 (21%) of patients at CC1 and 55/536 (10%) at CC2, accounting for 3% and 5% of the CRC population, respectively. At CC3, 182/1737 patients (10%) had dMMR CRCs (P < 0.001). Additional testing for the BRAF V600E mutation, was performed in 49 patients at CC3 prior to CGS referral, of which 29 were positive and considered sporadic CRC. Referrals to CGS were made in 66%, 33%, and 30% of eligible patients at CC1, CC2, and CC3, respectively. LS accounted for CRC in eight patients (0.8%) at CC1, eight patients (0.7%) at CC2, and 20 patients (1.2%) at CC3. Cascade testing of patients with dMMR CRC was not completed in 56%. Universal screening increases the detection of dMMR tumors and LS kindreds. Successful implementation of this approach requires adequate resources for appropriate downstream management of these patients.
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Affiliation(s)
| | - Éanna Ryan
- Centre for Colorectal Disease, St. Vincent's University Hospital, Dublin 4, Ireland
| | - Terri P McVeigh
- Department of Clinical Genetics, Our Lady's Children's Hospital, Dublin 12, Ireland
| | - Ben Creavin
- Centre for Colorectal Disease, St. Vincent's University Hospital, Dublin 4, Ireland
| | - John Mp Hyland
- Centre for Colorectal Disease, St. Vincent's University Hospital, Dublin 4, Ireland
| | | | - Denise Keegan
- Centre for Colorectal Disease, St. Vincent's University Hospital, Dublin 4, Ireland
| | - Robert Geraghty
- Centre for Colorectal Disease, St. Vincent's University Hospital, Dublin 4, Ireland
| | | | | | | | | | | | | | | | - Conor Shields
- Mater Misericordiae University Hospital, Dublin 7, Ireland
| | - Niall Mulligan
- Mater Misericordiae University Hospital, Dublin 7, Ireland
| | | | - Andrew J Green
- Department of Clinical Genetics, Our Lady's Children's Hospital, Dublin 12, Ireland
| | - Desmond C Winter
- Centre for Colorectal Disease, St. Vincent's University Hospital, Dublin 4, Ireland
| | | | - Kieran Sheahan
- Centre for Colorectal Disease, St. Vincent's University Hospital, Dublin 4, Ireland
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23
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Bui QM, Lin D, Ho W. Approach to Lynch Syndrome for the Gastroenterologist. Dig Dis Sci 2017; 62:299-304. [PMID: 27990589 DOI: 10.1007/s10620-016-4346-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2016] [Accepted: 10/11/2016] [Indexed: 12/18/2022]
Abstract
Lynch syndrome is an autosomal-dominant hereditary cancer syndrome. Mutations in mismatch repair genes, including MLH1, MSH2, MSH6, and PMS2, are implicated in the pathogenesis of the syndrome through microsatellite instability (MSI) and a rapid adenoma-carcinoma sequence. The primary methodologies for diagnosis include clinical criteria (Amsterdam I/II, Revised Bethesda Guidelines), computational models, and genetic testing (MSI, immunohistochemistry, germline testing). Universal genetic testing of colorectal cancers has gained popularity as a method to identify high-risk individuals and to offer appropriate cancer surveillance, psychological reassurance, and family planning. Management includes short-interval surveillance with colonoscopy in those without colorectal cancer and colectomy for those with cancer. Long-term chemoprevention with aspirin may improve mortality.
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Affiliation(s)
- Quan M Bui
- Department of Internal Medicine, University of California, San Diego, 330 Lewis St., San Diego, CA, 92103, USA
| | - David Lin
- Vatche and Tamar Manoukian Division of Digestive Diseases, David Geffen School of Medicine at UCLA, 100 UCLA Medical Plaza, Suite 205, Los Angeles, CA, 90095, USA
| | - Wendy Ho
- Vatche and Tamar Manoukian Division of Digestive Diseases, David Geffen School of Medicine at UCLA, 100 UCLA Medical Plaza, Suite 205, Los Angeles, CA, 90095, USA.
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24
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Kim TJ, Kim ER, Hong SN, Kim YH, Huh JW, Park YA, Cho YB, Yun SH, Kim HC, Lee WY, Kim K, Kim K, Chang DK. Survival Outcome and Risk of Metachronous Colorectal Cancer After Surgery in Lynch Syndrome. Ann Surg Oncol 2016; 24:1085-1092. [PMID: 27766559 DOI: 10.1245/s10434-016-5633-1] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2016] [Indexed: 01/13/2023]
Abstract
BACKGROUND The survival benefit of extensive colectomy is controversial in Lynch syndrome, and risk factors for metachronous colorectal cancer (CRC) after segmental colectomy are unclear. OBJECTIVE The aim of this study was to investigate the survival outcome and risk of metachronous CRC after surgery in Lynch syndrome patients diagnosed with their first CRC. METHODS Overall, 106 patients with Lynch syndrome who underwent surgery for CRC were included in the study. The demographics, genotype, clinicopathological characteristics of the index CRC, and follow-up data were reviewed from a single-institution Lynch syndrome database. RESULTS Of 30 patients who underwent extensive surgery, no metachronous CRC was developed during a mean follow-up of 68.1 months. Of 76 patients who underwent segmental colectomy, 13 (17.1 %) developed metachronous CRC during a mean follow-up of 77.2 months. The cumulative risk of metachronous CRC was 8.4 % at 5 years and 20.4 % at 10 years after segmental colectomy. No difference in overall and CRC-specific survival was observed between segmental colectomy and extensive colectomy (p = 0.277 and p = 0.659, respectively). A 25 cm or longer resection of bowel decreased the risk of metachronous CRC after segmental colectomy compared with less extensive resection (hazard ratio 0.10, 95 % confidence interval 0.01-0.86). Annual surveillance colonoscopy did not decrease the risk of metachronous CRC compared with less frequent surveillance colonoscopy. Although not statistically significant, none of the MSH6 gene mutation carriers were diagnosed with metachronous CRC. CONCLUSIONS Although no survival benefit was identified, surgeons and patients might consider extensive colectomy to prevent metachronous CRC in Lynch syndrome patients regardless of their clinicopathological characteristics.
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Affiliation(s)
- Tae Jun Kim
- Division of Gastroenterology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Eun Ran Kim
- Division of Gastroenterology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Sung Noh Hong
- Division of Gastroenterology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Young-Ho Kim
- Division of Gastroenterology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Jung Wook Huh
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Yoon Ah Park
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Yong Beom Cho
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Seong Hyeon Yun
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Hee Cheol Kim
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Woo Yong Lee
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Kiyoun Kim
- Biostatistics and Clinical Epidemiology Center, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Kyunga Kim
- Biostatistics and Clinical Epidemiology Center, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Dong Kyung Chang
- Division of Gastroenterology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
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25
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Jayasekara H, Reece JC, Buchanan DD, Rosty C, Dashti SG, Ouakrim DA, Winship IM, Macrae FA, Boussioutas A, Giles GG, Ahnen DJ, Lowery J, Casey G, Haile RW, Gallinger S, Le Marchand L, Newcomb PA, Lindor NM, Hopper JL, Parry S, Jenkins MA, Win AK. Risk factors for metachronous colorectal cancer following a primary colorectal cancer: A prospective cohort study. Int J Cancer 2016; 139:1081-1090. [PMID: 27098183 PMCID: PMC4911232 DOI: 10.1002/ijc.30153] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2016] [Revised: 03/24/2016] [Accepted: 04/01/2016] [Indexed: 01/07/2023]
Abstract
Individuals diagnosed with colorectal cancer (CRC) are at risk of developing a metachronous CRC. We examined the associations between personal, tumour-related and lifestyle risk factors, and risk of metachronous CRC. A total of 7,863 participants with incident colon or rectal cancer who were recruited in the USA, Canada and Australia to the Colon Cancer Family Registry during 1997-2012, except those identified as high-risk, for example, Lynch syndrome, were followed up approximately every 5 years. We estimated the risk of metachronous CRC, defined as the first new primary CRC following an interval of at least one year after the initial CRC diagnosis. Observation time started at the age at diagnosis of the initial CRC and ended at the age at diagnosis of the metachronous CRC, last contact or death whichever occurred earliest, or were censored at the age at diagnosis of any metachronous colorectal adenoma. Cox regression was used to derive hazard ratios (HRs) and 95% confidence intervals (CIs). During a mean follow-up of 6.6 years, 142 (1.81%) metachronous CRCs were diagnosed (mean age at diagnosis 59.8; incidence 2.7/1,000 person-years). An increased risk of metachronous CRC was associated with the presence of a synchronous CRC (HR = 2.73; 95% CI: 1.30-5.72) and the location of cancer in the proximal colon at initial diagnosis (compared with distal colon or rectum, HR = 4.16; 95% CI: 2.80-6.18). The presence of a synchronous CRC and the location of the initial CRC might be useful for deciding the intensity of surveillance colonoscopy for individuals diagnosed with CRC.
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Affiliation(s)
- Harindra Jayasekara
- Centre for Epidemiology and Biostatistics, Melbourne School of
Population and Global Health, The University of Melbourne, Parkville, Victoria,
Australia
- Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne,
Victoria, Australia
| | - Jeanette C. Reece
- Centre for Epidemiology and Biostatistics, Melbourne School of
Population and Global Health, The University of Melbourne, Parkville, Victoria,
Australia
| | - Daniel D. Buchanan
- Centre for Epidemiology and Biostatistics, Melbourne School of
Population and Global Health, The University of Melbourne, Parkville, Victoria,
Australia
- Colorectal Oncogenomics Group, Genetic Epidemiology Laboratory,
Department of Pathology, The University of Melbourne, Parkville, Victoria,
Australia
| | - Christophe Rosty
- Colorectal Oncogenomics Group, Genetic Epidemiology Laboratory,
Department of Pathology, The University of Melbourne, Parkville, Victoria,
Australia
- University of Queensland, School of Medicine, Herston, Queensland,
Australia
| | - S. Ghazaleh Dashti
- Centre for Epidemiology and Biostatistics, Melbourne School of
Population and Global Health, The University of Melbourne, Parkville, Victoria,
Australia
| | - Driss Ait Ouakrim
- Centre for Epidemiology and Biostatistics, Melbourne School of
Population and Global Health, The University of Melbourne, Parkville, Victoria,
Australia
| | - Ingrid M. Winship
- Department of Medicine, Royal Melbourne Hospital, The University of
Melbourne, Parkville, Victoria, Australia
- Genetic Medicine and Family Cancer Clinic, Royal Melbourne Hospital,
Parkville, Australia
| | - Finlay A. Macrae
- Department of Medicine, Royal Melbourne Hospital, The University of
Melbourne, Parkville, Victoria, Australia
- Genetic Medicine and Family Cancer Clinic, Royal Melbourne Hospital,
Parkville, Australia
- Colorectal Medicine and Genetics, Royal Melbourne Hospital,
Parkville, Victoria, Australia
| | - Alex Boussioutas
- Department of Medicine, Royal Melbourne Hospital, The University of
Melbourne, Parkville, Victoria, Australia
- Cancer Genomics and Predictive Medicine, Peter MacCallum Cancer
Centre, East Melbourne, Victoria, Australia
| | - Graham G. Giles
- Centre for Epidemiology and Biostatistics, Melbourne School of
Population and Global Health, The University of Melbourne, Parkville, Victoria,
Australia
- Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne,
Victoria, Australia
| | - Dennis J. Ahnen
- Department of Medicine, University of Colorado School of Medicine,
Denver, Colorado, USA
| | - Jan Lowery
- Department of Epidemiology, University of Colorado School of Public
Health, Denver, Colorado, USA
| | - Graham Casey
- Department of Preventive Medicine, Keck School of Medicine and
Norris Comprehensive Cancer Center, University of Southern California, Los Angeles,
California, USA
| | - Robert W. Haile
- Department of Medicine, Division of Oncology, Stanford Cancer
Institute, Stanford University, California, USA
| | - Steven Gallinger
- Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital,
University of Toronto, Toronto, Ontario, Canada
| | | | - Polly A. Newcomb
- Public Health Sciences Division, Fred Hutchinson Cancer Research
Center, Seattle, Washington, USA
- School of Public Health, University of Washington, Seattle,
Washington, USA
| | - Noralane M. Lindor
- Department of Health Science Research, Mayo Clinic Arizona,
Scottsdale, Arizona, USA
| | - John L. Hopper
- Centre for Epidemiology and Biostatistics, Melbourne School of
Population and Global Health, The University of Melbourne, Parkville, Victoria,
Australia
| | - Susan Parry
- New Zealand Familial Gastrointestinal Cancer Service, Auckland, New
Zealand
| | - Mark A. Jenkins
- Centre for Epidemiology and Biostatistics, Melbourne School of
Population and Global Health, The University of Melbourne, Parkville, Victoria,
Australia
| | - Aung Ko Win
- Centre for Epidemiology and Biostatistics, Melbourne School of
Population and Global Health, The University of Melbourne, Parkville, Victoria,
Australia
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26
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Validation of an online questionnaire for identifying people at risk of familial and hereditary colorectal cancer. Fam Cancer 2016; 14:401-10. [PMID: 25800523 PMCID: PMC4559103 DOI: 10.1007/s10689-015-9792-1] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
We developed and validated an online questionnaire to document familial cancer history, in order to facilitate the detection of persons with a familial or hereditary colorectal cancer (CRC) risk. The development of the self-administered online questionnaire for the assessment of familial and hereditary CRC risk was based on nationwide criteria for referral to genetic specialists due to a Lynch syndrome suspicion, as well as existing criteria for surveillance colonoscopies because of an increased risk of familial CRC. The questionnaire was validated at a private colonoscopy center. Patients scheduled for colonoscopy were enrolled (n = 150). Performance of the questionnaire was assessed by comparing referrals based on questionnaire data against referral decisions based on full pedigree data. In a second validation phase, referrals based on questionnaire data were compared with referrals based on data collected in a telephone interview. We also calculated inter-observer agreement in referral decisions. In the first validation phase, the questionnaire had a sensitivity of 90 % (95 % CI 55–98 %) at a specificity of 98 % (95 % CI 87–100 %) in identifying persons qualifying for referral. In the second validation phase, sensitivity was 100 % (95 % CI 63–100) at a specificity of 97 % (95 % CI 91–99 %). In both validation phases an inter-observer agreement of 100 % in referral decisions was achieved. The online questionnaire has a high sensitivity and specificity in identifying persons qualifying for referral because of suspected Lynch syndrome or familial CRC. Implementation of this tool in colonoscopy clinics can facilitate the detection of patients with hereditary or familial CRC.
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27
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Karlitz JJ, Sherrill MR, DiGiacomo DV, Hsieh MC, Schmidt B, Wu XC, Chen VW. Factors Associated With the Performance of Extended Colonic Resection vs. Segmental Resection in Early-Onset Colorectal Cancer: A Population-Based Study. Clin Transl Gastroenterol 2016; 7:e163. [PMID: 27077958 PMCID: PMC4855160 DOI: 10.1038/ctg.2016.17] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2016] [Accepted: 02/22/2016] [Indexed: 02/07/2023] Open
Abstract
OBJECTIVES: Early-onset colorectal cancer (CRC) incidence rates are rising. This group is susceptible to heritable conditions (i.e., Lynch syndrome (LS)) and inflammatory bowel disease (IBD) with high metachronous CRC rates after segmental resection. Hence, extended colonic resection (ECR) is often performed and considered generally in young patients. As there are no population-based studies analyzing resection extent in early-onset CRC, we used CDC Comparative Effectiveness Research (CER) data to assess state-wide operative practices. METHODS: Using CER and Louisiana Tumor Registry data, all CRC patients aged ≤50 years, diagnosed in Louisiana in 2011, who underwent surgery in 2011–2012 were retrospectively analyzed. Prevalence of, and the factors associated with operation type (ECR including subtotal/total/proctocolectomy vs. segmental resection) were evaluated. RESULTS: Of 2,427 CRC patients, 274 were aged ≤50 years. In all, 234 underwent surgery at 53 unique facilities and 6.8% underwent ECR. Statistically significant ECR-associated factors included age ≤45 years, polyposis, synchronous/metachronous LS-associated cancers, and IBD. Abnormal microsatellite instability (MSI) was not ECR-associated. ECR was not performed in sporadic CRC. CONCLUSIONS: ECR is performed in the setting of clinically obvious associated high-risk features (polyposis, IBD, synchronous/metachronous cancers) but not in isolated/sporadic CRC. However, attention must be paid to patients with seemingly lower risk characteristics (isolated CRC, no polyposis), as LS can still be present. In addition, the presumed sporadic group requires further study as metachronous CRC risk in early-onset sporadic CRC has not been well-defined, and some may harbor undefined/undiagnosed hereditary conditions. Abnormal MSI (LS risk) is not associated with ECR; abnormal MSI results often return postoperatively after segmental resection has already occurred, which is a contributing factor.
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Affiliation(s)
- Jordan J Karlitz
- Department of Medicine, Division of Gastroenterology, Tulane University School of Medicine, New Orleans, Louisiana, USA
| | - Meredith R Sherrill
- Department of Medicine, Tulane University School of Medicine, New Orleans, Louisiana, USA
| | - Daniel V DiGiacomo
- Department of Medicine, Tulane University School of Medicine, New Orleans, Louisiana, USA
| | - Mei-Chin Hsieh
- Epidemiology Program, Louisiana Tumor Registry, LSU Health Sciences Center School of Public Health, New Orleans, Louisiana, USA
| | - Beth Schmidt
- Epidemiology Program, Louisiana Tumor Registry, LSU Health Sciences Center School of Public Health, New Orleans, Louisiana, USA
| | - Xiao-Cheng Wu
- Epidemiology Program, Louisiana Tumor Registry, LSU Health Sciences Center School of Public Health, New Orleans, Louisiana, USA
| | - Vivien W Chen
- Epidemiology Program, Louisiana Tumor Registry, LSU Health Sciences Center School of Public Health, New Orleans, Louisiana, USA
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28
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Karlitz JJ, Hsieh MC, Liu Y, Blanton C, Schmidt B, Jessup JM, Wu XC, Chen VW. Population-Based Lynch Syndrome Screening by Microsatellite Instability in Patients ≤50: Prevalence, Testing Determinants, and Result Availability Prior to Colon Surgery. Am J Gastroenterol 2015; 110:948-55. [PMID: 25601013 DOI: 10.1038/ajg.2014.417] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVES As there are no US population-based studies examining Lynch syndrome (LS) screening frequency by microsatellite instability (MSI) and immunohistochemistry (IHC), we seek to quantitate statewide rates in patients aged ≤50 years using data from a Centers for Disease Control and Prevention-funded Comparative Effectiveness Research (CER) project and identify factors associated with testing. Screening rates in this young, high-risk population may provide a best-case scenario as older patients, potentially deemed lower risk, may undergo testing less frequently. We also seek to determine how frequently MSI/IHC results are available preoperatively, as this may assist with decisions regarding colonic resection extent. METHODS Data from all Louisiana colorectal cancer (CRC) patients aged ≤50 years diagnosed in 2011 were obtained from the Louisiana Tumor Registry CER project. Registry researchers and physicians analyzed data, including pathology and MSI/IHC. RESULTS Of the 2,427 statewide all-age CRC patients, there were 274 patients aged ≤50 years, representing health care at 61 distinct facilities. MSI and/or IHC were performed in 23.0% of patients. Testing-associated factors included CRC family history (P<0.0045), urban location (P<0.0370), and care at comprehensive cancer centers (P<0.0020) but not synchronous/metachronous CRC or MSI-like histology. Public hospital screening was disproportionately low (P<0.0217). Of those tested, MSI and/or IHC was abnormal in 21.7%. Of those with abnormal IHC, staining patterns were consistent with LS in 87.5%. MSI/IHC results were available preoperatively in 16.9% of cases. CONCLUSIONS Despite frequently abnormal MSI/IHC results, LS screening in young, high-risk patients is low. Provider education and disparities in access to specialized services, particularly in underserved populations, are possible contributors. MSI/IHC results are infrequently available preoperatively.
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Affiliation(s)
- Jordan J Karlitz
- Division of Gastroenterology, Tulane University School of Medicine, New Orleans, Louisiana, USA
| | - Mei-Chin Hsieh
- Louisiana Tumor Registry, Epidemiology Program, LSU Health Sciences Center School of Public Health, New Orleans, Louisiana, USA
| | - Yong Liu
- Department of Medicine, Tulane University School of Medicine, New Orleans, Louisiana, USA
| | - Christine Blanton
- Division of Gastroenterology, Tulane University School of Medicine, New Orleans, Louisiana, USA
| | - Beth Schmidt
- Louisiana Tumor Registry, LSU Health Sciences Center School of Public Health, New Orleans, Louisiana, USA
| | - J Milburn Jessup
- Cancer Diagnosis Program-National Cancer Institute (NCI), Division of Cancer Treatment and Diagnosis (DCTD), National Institute of Health (NIH), Rockville, Maryland, USA
| | - Xiao-Cheng Wu
- Louisiana Tumor Registry, Epidemiology Program, LSU Health Sciences Center School of Public Health, New Orleans, Louisiana, USA
| | - Vivien W Chen
- Louisiana Tumor Registry, Epidemiology Program, LSU Health Sciences Center School of Public Health, New Orleans, Louisiana, USA
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29
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Snowsill T, Huxley N, Hoyle M, Jones-Hughes T, Coelho H, Cooper C, Frayling I, Hyde C. A systematic review and economic evaluation of diagnostic strategies for Lynch syndrome. Health Technol Assess 2015; 18:1-406. [PMID: 25244061 DOI: 10.3310/hta18580] [Citation(s) in RCA: 88] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND Lynch syndrome (LS) is an inherited autosomal dominant disorder characterised by an increased risk of colorectal cancer (CRC) and other cancers, and caused by mutations in the deoxyribonucleic acid (DNA) mismatch repair genes. OBJECTIVE To evaluate the accuracy and cost-effectiveness of strategies to identify LS in newly diagnosed early-onset CRC patients (aged < 50 years). Cascade testing of relatives is employed in all strategies for individuals in whom LS is identified. DATA SOURCES AND METHODS Systematic reviews were conducted of the test accuracy of microsatellite instability (MSI) testing or immunohistochemistry (IHC) in individuals with CRC at risk of LS, and of economic evidence relating to diagnostic strategies for LS. Reviews were carried out in April 2012 (test accuracy); and in February 2012, repeated in February 2013 (economic evaluations). Databases searched included MEDLINE (1946 to April week 3, 2012), EMBASE (1980 to week 17, 2012) and Web of Science (inception to 30 April 2012), and risk of bias for test accuracy was assessed using the Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) quality appraisal tool. A de novo economic model of diagnostic strategies for LS was developed. RESULTS Inconsistencies in study designs precluded pooling of diagnostic test accuracy results from a previous systematic review and nine subsequent primary studies. These were of mixed quality, with significant methodological concerns identified for most. IHC and MSI can both play a part in diagnosing LS but neither is gold standard. No UK studies evaluated the cost-effectiveness of diagnosing and managing LS, although studies from other countries generally found some strategies to be cost-effective compared with no testing. The de novo model demonstrated that all strategies were cost-effective compared with no testing at a threshold of £20,000 per quality-adjusted life-year (QALY), with the most cost-effective strategy utilising MSI and BRAF testing [incremental cost-effectiveness ratio (ICER) = £5491 per QALY]. The maximum health benefit to the population of interest would be obtained using universal germline testing, but this would not be a cost-effective use of NHS resources compared with the next best strategy. When the age limit was raised from 50 to 60 and 70 years, the ICERs compared with no testing increased but remained below £20,000 per QALY (except for universal germline testing with an age limit of 70 years). The total net health benefit increased with the age limit as more individuals with LS were identified. Uncertainty was evaluated through univariate sensitivity analyses, which suggested that the parameters substantially affecting cost-effectiveness: were the risk of CRC for individuals with LS; the average number of relatives identified per index patient; the effectiveness of colonoscopy in preventing metachronous CRC; the cost of colonoscopy; the duration of the psychological impact of genetic testing on health-related quality of life (HRQoL); and the impact of prophylactic hysterectomy and bilateral salpingo-oophorectomy on HRQoL (this had the potential to make all testing strategies more expensive and less effective than no testing). LIMITATIONS The absence of high-quality data for the impact of prophylactic gynaecological surgery and the psychological impact of genetic testing on HRQoL is an acknowledged limitation. CONCLUSIONS Results suggest that reflex testing for LS in newly diagnosed CRC patients aged < 50 years is cost-effective. Such testing may also be cost-effective in newly diagnosed CRC patients aged < 60 or < 70 years. Results are subject to uncertainty due to a number of parameters, for some of which good estimates were not identified. We recommend future research to estimate the cost-effectiveness of testing for LS in individuals with newly diagnosed endometrial or ovarian cancer, and the inclusion of aspirin chemoprevention. Further research is required to accurately estimate the impact of interventions on HRQoL. STUDY REGISTRATION This study is registered as PROSPERO CRD42012002436. FUNDING The National Institute for Health Research Health Technology Assessment programme.
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Affiliation(s)
- Tristan Snowsill
- Peninsula Technology Assessment Group (PenTAG), University of Exeter Medical School, Exeter, UK
| | - Nicola Huxley
- Peninsula Technology Assessment Group (PenTAG), University of Exeter Medical School, Exeter, UK
| | - Martin Hoyle
- Peninsula Technology Assessment Group (PenTAG), University of Exeter Medical School, Exeter, UK
| | - Tracey Jones-Hughes
- Peninsula Technology Assessment Group (PenTAG), University of Exeter Medical School, Exeter, UK
| | - Helen Coelho
- Peninsula Technology Assessment Group (PenTAG), University of Exeter Medical School, Exeter, UK
| | - Chris Cooper
- Peninsula Technology Assessment Group (PenTAG), University of Exeter Medical School, Exeter, UK
| | - Ian Frayling
- Institute of Medical Genetics, Cardiff University, Cardiff, UK
| | - Chris Hyde
- Peninsula Technology Assessment Group (PenTAG), University of Exeter Medical School, Exeter, UK
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30
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Brosens LAA, Offerhaus GJA, Giardiello FM. Hereditary Colorectal Cancer: Genetics and Screening. Surg Clin North Am 2015; 95:1067-80. [PMID: 26315524 DOI: 10.1016/j.suc.2015.05.004] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Colorectal cancer (CRC) is the third most common cancer and the third leading cause of cancer death in men and women in the United States. About 30% of patients with CRC report a family history of CRC. However, only 5% of CRCs arise in the setting of a well-established mendelian inherited disorder. In addition, serrated polyposis is a clinically defined syndrome with multiple serrated polyps in the colorectum and an increased CRC risk for which the genetics are unknown. This article focuses on genetic and clinical aspects of Lynch syndrome, familial adenomatous polyposis, and MUTYH-associated polyposis.
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Affiliation(s)
- Lodewijk A A Brosens
- Department of Pathology, University Medical Center Utrecht (H04-312), Heidelberglaan 100, Utrecht 3584 CX, The Netherlands; Department of Pathology, The Johns Hopkins University School of Medicine, CRB 2, Room 345, 1550 Orleans Street, Baltimore, MD 21231, USA.
| | - G Johan A Offerhaus
- Department of Pathology, University Medical Center Utrecht (H04-312), Heidelberglaan 100, Utrecht 3584 CX, The Netherlands
| | - Francis M Giardiello
- Department of Medicine, Oncology Center, The Johns Hopkins University School of Medicine, 1830 East Monument Street, Room 431, Baltimore, MD 21205, USA; Department of Pathology, The Johns Hopkins University School of Medicine, 1830 East Monument Street, Room 431, Baltimore, MD 21205, USA.
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Guillem JG, Bertelsen C. Total proctocolectomy for rectal cancer in Lynch syndrome: indications and considerations. COLORECTAL CANCER 2015. [DOI: 10.2217/crc.15.16] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
SUMMARY Patients with Lynch syndrome and rectal cancer present a unique clinical challenge. Management of the primary rectal cancer and prophylactic removal of the colon should be considered. In patients requiring a mesorectal excision, a combined prophylactic colon removal can be considered. Although surveillance of the colon with frequent colonoscopies is an alternative, concerns of metachronous colon cancer development support prophylactic removal of the colon as an alternative. Since data are not available to confirm superiority of either approach, the final decision is greatly dependent upon a patient's wishes and preferences. Patients interested in pursuing simultaneous prophylactic colon removal can be offered total proctocolectomy with either ileal pouch anal-anastomosis as a sphincter-preserving alternative or a total proctocolectomy with end ileostomy.
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Affiliation(s)
- Jose G Guillem
- Memorial Sloan Kettering Cancer Center, Department of Surgery, Colorectal Service, 1275 York Avenue, C1077, New York, NY 10065, USA
| | - Corinna Bertelsen
- Memorial Sloan Kettering Cancer Center, Department of Surgery, Colorectal Service, 633 3rd Avenue, 1584A, New York, NY 10017, USA
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Hereditary Non-polyposis Colorectal Cancer: Prevention and Therapeutic Options. CURRENT COLORECTAL CANCER REPORTS 2015. [DOI: 10.1007/s11888-015-0265-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
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Liska D, Kalady MF. Colorectal Surgery in Lynch Syndrome Patients: When and How? CURRENT COLORECTAL CANCER REPORTS 2015. [DOI: 10.1007/s11888-015-0262-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
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Abstract
Treatment of colorectal cancer is becoming more uniform, with wider acceptance of standardized guidelines. However, areas of controversy exist where the appropriate treatment is not clear, including: should a segmental colectomy or a more extensive resection be performed in hereditary nonpolyposis colorectal cancer? should an asymptomatic primary cancer be resected in the presence of unresectable metastatic disease? what is the role of extended lymph node resection in colon and rectal cancer? are there clinically significant benefits for a robotic approach to colorectal resection versus a laparoscopic approach? This chapter will examine these issues and discuss how they may be resolved.
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Giardiello FM, Allen JI, Axilbund JE, Boland CR, Burke CA, Burt RW, Church JM, Dominitz JA, Johnson DA, Kaltenbach T, Levin TR, Lieberman DA, Robertson DJ, Syngal S, Rex DK. Guidelines on genetic evaluation and management of Lynch syndrome: a consensus statement by the US Multi-Society Task Force on colorectal cancer. Gastroenterology 2014; 147:502-26. [PMID: 25043945 DOI: 10.1053/j.gastro.2014.04.001] [Citation(s) in RCA: 352] [Impact Index Per Article: 32.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
The Multi-Society Task Force, in collaboration with invited experts, developed guidelines to assist health care providers with the appropriate provision of genetic testing and management of patients at risk for and affected with Lynch syndrome as follows: Figure 1 provides a colorectal cancer risk assessment tool to screen individuals in the office or endoscopy setting; Figure 2 illustrates a strategy for universal screening for Lynch syndrome by tumor testing of patients diagnosed with colorectal cancer; Figures 3-6 provide algorithms for genetic evaluation of affected and at-risk family members of pedigrees with Lynch syndrome; Table 10 provides guidelines for screening at-risk and affected persons with Lynch syndrome; and Table 12 lists the guidelines for the management of patients with Lynch syndrome. A detailed explanation of Lynch syndrome and the methodology utilized to derive these guidelines, as well as an explanation of, and supporting literature for, these guidelines are provided.
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Affiliation(s)
| | - John I Allen
- Yale University School of Medicine, New Haven, Connecticut
| | | | | | | | | | | | - Jason A Dominitz
- VA Puget Sound Health Care System, Seattle, Washington; University of Washington, Seattle, Washington
| | | | | | | | | | - Douglas J Robertson
- White River Junction VA Medical Center, White River Junction, Vermont; Geisel School of Medicine at Dartmouth, White River Junction, Vermont
| | - Sapna Syngal
- Brigham and Women's Hospital, Boston, Massachusetts; Dana Farber Cancer Institute, Boston, Massachusetts; Harvard Medical School, Boston, Massachusetts
| | - Douglas K Rex
- Indiana University School of Medicine, Indianapolis, Indiana
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36
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Giardiello FM, Allen JI, Axilbund JE, Boland CR, Burke CA, Burt RW, Church JM, Dominitz JA, Johnson DA, Kaltenbach T, Levin TR, Lieberman DA, Robertson DJ, Syngal S, Rex DK. Guidelines on genetic evaluation and management of Lynch syndrome: a consensus statement by the U.S. Multi-Society Task Force on Colorectal Cancer. Gastrointest Endosc 2014; 80:197-220. [PMID: 25034835 DOI: 10.1016/j.gie.2014.06.006] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
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Giardiello FM, Allen JI, Axilbund JE, Boland CR, Burke CA, Burt RW, Church JM, Dominitz JA, Johnson DA, Kaltenbach T, Levin TR, Lieberman DA, Robertson DJ, Syngal S, Rex DK. Guidelines on genetic evaluation and management of Lynch syndrome: a consensus statement by the US Multi-society Task Force on colorectal cancer. Am J Gastroenterol 2014; 109:1159-79. [PMID: 25070057 DOI: 10.1038/ajg.2014.186] [Citation(s) in RCA: 308] [Impact Index Per Article: 28.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
The Multi-Society Task Force, in collaboration with invited experts, developed guidelines to assist health care providers with the appropriate provision of genetic testing and management of patients at risk for and affected with Lynch syndrome as follows: Figure 1 provides a colorectal cancer risk assessment tool to screen individuals in the office or endoscopy setting; Figure 2 illustrates a strategy for universal screening for Lynch syndrome by tumor testing of patients diagnosed with colorectal cancer; Figures 3,4,5,6 provide algorithms for genetic evaluation of affected and at-risk family members of pedigrees with Lynch syndrome; Table 10 provides guidelines for screening at-risk and affected persons with Lynch syndrome; and Table 12 lists the guidelines for the management of patients with Lynch syndrome. A detailed explanation of Lynch syndrome and the methodology utilized to derive these guidelines, as well as an explanation of, and supporting literature for, these guidelines are provided.
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Affiliation(s)
| | - John I Allen
- Yale University School of Medicine, New Haven, Connecticut, USA
| | | | | | | | | | | | - Jason A Dominitz
- 1] VA Puget Sound Health Care System, Seattle, Washington, USA [2] University of Washington, Seattle, Washington, USA
| | | | | | | | | | - Douglas J Robertson
- 1] White River Junction VA Medical Center, White River Junction, Vermont, USA [2] Geisel School of Medicine at Dartmouth, White River Junction, Vermont, USA
| | - Sapna Syngal
- 1] Brigham and Women's Hospital, Boston, Massachusetts, USA [2] Dana Farber Cancer Institute, Boston, Massachusetts, USA [3] Harvard Medical School, Boston, Massachusetts, USA
| | - Douglas K Rex
- Indiana University School of Medicine, Indianapolis, Indiana, USA
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38
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Sie AS, Mensenkamp AR, Adang EMM, Ligtenberg MJL, Hoogerbrugge N. Fourfold increased detection of Lynch syndrome by raising age limit for tumour genetic testing from 50 to 70 years is cost-effective. Ann Oncol 2014; 25:2001-2007. [PMID: 25081898 DOI: 10.1093/annonc/mdu361] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Recognising colorectal cancer (CRC) patients with Lynch syndrome (LS) can increase life expectancy of these patients and their close relatives. To improve identification of this under-diagnosed disease, experts suggested raising the age limit for CRC tumour genetic testing from 50 to 70 years. The present study evaluates the efficacy and cost-effectiveness of this strategy. METHODS Probabilistic efficacy and cost-effectiveness analyses were carried out comparing tumour genetic testing of CRC diagnosed at age 70 or below (experimental strategy) versus CRC diagnosed at age 50 or below (current practice). The proportions of LS patients identified and cost-effectiveness including cascade screening of relatives, were calculated by decision analytic models based on real-life data. RESULTS Using the experimental strategy, four times more LS patients can be identified among CRC patients when compared with current practice. Both the costs to detect one LS patient (€9437/carrier versus €4837/carrier), and the number needed to test for detecting one LS patient (42 versus 19) doubled. When family cascade screening was included, the experimental strategy was found to be highly cost-effective according to Dutch standards, resulting in an overall ratio of €2703 per extra life-year gained in additionally tested patients. CONCLUSION Testing all CRC tumours diagnosed at or below age 70 for LS is cost-effective. Implementation is important as relatives from the large number of LS patients that are missed by current practice, can benefit from life-saving surveillance.
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Affiliation(s)
- A S Sie
- Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands
| | - A R Mensenkamp
- Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands
| | - E M M Adang
- Department of Health Evidence, Radboud University Medical Center, Nijmegen, The Netherlands
| | - M J L Ligtenberg
- Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands; Department of Pathology, Radboud University Medical Center, Nijmegen, The Netherlands
| | - N Hoogerbrugge
- Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
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Abstract
Lynch Syndrome, or hereditary non-polyposis colorectal cancer (HNPCC) is an autosomal dominant cancer predisposition syndrome caused by inactivating mutations in DNA mismatch repair genes. It accounts for 2-4 % of all incident colorectal cancers. Mutation carriers are at risk of early onset colorectal cancer, endometrial cancer, and a spectrum of other tumours. Accurate estimation of cancer risk for mutation carriers is essential for counselling, and establishing appropriate screening guidelines. This study reviews the current data on cancer risk, and emerging risk reduction strategies.
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Affiliation(s)
- Emma Barrow
- Department of General Surgery, University of Manchester and Central Manchester University Hospitals NHS Foundation Trust, Manchester Royal Infirmary, Oxford Road, Manchester, UK.
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40
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Rodriguez-Bigas MA, Möeslein G. Surgical treatment of hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome). Fam Cancer 2014; 12:295-300. [PMID: 23508345 DOI: 10.1007/s10689-013-9626-y] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The surgical management of the Lynch syndrome patient with colorectal cancer needs to be individualized. Because of the increased incidence of synchronous and metachronous colorectal neoplasms, most favor an extended resection at the time of diagnosis of colorectal cancer. Age of diagnosis, stage of the tumor, co-morbidities, surgical expertise, surgical morbidity, and patient wishes should be taken into account when considering a surgical procedure. There are no prospective randomized trials or retrospective trials suggesting that patients undergoing an extended procedure have a survival advantage compared to those undergoing segmental resection. In retrospective studies it has been demonstrated that patients undergoing extended procedures will develop less metachronous colorectal neoplasms and will undergo less subsequent surgical procedures related to colorectal cancer. In females abdominal hysterectomy and bilateral salpingoophorectomy should be considered at the time of surgery for colorectal cancer.
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41
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Guillén-Ponce C, Molina-Garrido MJ, Carrato A. Follow-up recommendations and risk-reduction initiatives for Lynch syndrome. Expert Rev Anticancer Ther 2014; 12:1359-67. [DOI: 10.1586/era.12.114] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
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42
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Pollett WG, Marion K, Moeslein G, Schneider C, Parry S, Veysey K, Bissett IP, Jones I, Macrae F. Quality of life after surgery in individuals with familial colorectal cancer: does extended surgery have an adverse impact? ANZ J Surg 2013; 84:359-64. [DOI: 10.1111/ans.12336] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/23/2013] [Indexed: 11/30/2022]
Affiliation(s)
- William G. Pollett
- Department of Surgery; St. Clare's Mercy Hospital; St. John's Newfoundland Canada
| | - Kaye Marion
- School of Mathematical and Geospatial Sciences; RMIT University; Melbourne Victoria Australia
| | - Gabriela Moeslein
- Department of Surgery; HELIOS St. Josefs-Hospital Bochum-Linden; Bochum Germany
| | - Claudia Schneider
- Department of Surgery; HELIOS St. Josefs-Hospital Bochum-Linden; Bochum Germany
| | - Susan Parry
- Department of Gastroenterology; NZ Familial GI Cancer Service; Auckland New Zealand
| | - Katrina Veysey
- Department of Surgery; University of Auckland; Auckland New Zealand
| | - Ian P. Bissett
- Department of Surgery; University of Auckland; Auckland New Zealand
| | - Ian Jones
- Department of Surgery; The Royal Melbourne Hospital; Parkville Victoria Australia
| | - Finlay Macrae
- Department of Colorectal Medicine and Genetics; The Royal Melbourne Hospital; Parkville Victoria Australia
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43
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Evans DGR, Ingham SL. Reduced life expectancy seen in hereditary diseases which predispose to early-onset tumors. APPLICATION OF CLINICAL GENETICS 2013; 6:53-61. [PMID: 23935382 PMCID: PMC3735038 DOI: 10.2147/tacg.s35605] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
There are several hereditary diseases that are a predisposition to early-onset tumors. These include syndromic conditions like neurofibromatosis 1 and 2, von Hippel-Lindau syndrome, Gorlin syndrome, multiple endocrine neoplasia, and familial adenomatous polyposis; and conditions which are usually not possible to diagnose clinically in a single individual, such as Lynch syndrome and BRCA1/2. Understanding of the mortality in hereditary cancer predisposing diseases is important for developing effective disease treatment programs. A number of studies have been undertaken to investigate the genetic predictors, prevalence and incidence, and treatment outcomes of these diseases; however, the majority examine only the most common of these diseases (eg, neurofibromatosis or BRCA), or look into postoperative survival. The mortality of individuals who are diagnosed with one of these hereditary diseases remains an area for investigation. This review is the first to attempt identification of studies investigating life expectancy in hereditary diseases which predispose to early-onset tumors.
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Affiliation(s)
- D Gareth R Evans
- Genetic Medicine, Manchester Academic Health Science Centre, Central Manchester Foundation Trust, St Mary's Hospital, Manchester, UK
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44
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Baucom RB, Wise PE. Endoscopic and surgical management of hereditary nonpolyposis colorectal cancer. Clin Colon Rectal Surg 2013; 25:90-6. [PMID: 23730223 DOI: 10.1055/s-0032-1313779] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Hereditary nonpolyposis colorectal cancer (HNPCC) or Lynch syndrome is a disease characterized by autosomal dominant clustering of colorectal cancer (CRC) as well as other cancers. It is critical for clinicians and surgeons caring for patients with HNPCC to be familiar with their management related to CRC. Based on retrospective studies, screening colonoscopy is recommended every 1 to 2 years beginning at age 20 to 25, or 10 years younger than the earliest CRC in the family (whichever is earlier). HNPCC patients with colon cancer should be considered for total abdominal colectomy rather than a more limited segmental colon resection due to the increased risk of metachronous neoplasia associated with the condition. Rectal cancer in HNPCC has not been well studied, but discussions with the patient regarding surgical management should weigh the risks of metachronous CRC with the morbidity and quality of life issues associated with proctocolectomy. Regardless of the procedure, a patient with HNPCC requires close postoperative endoscopic surveillance of any remaining at-risk mucosa. In terms of chemoprevention, aspirin has been shown to be effective in preventing colorectal neoplasia in prospective trials and should be considered in patients who do not have a contraindication to the drug. Trials for other chemopreventative agents in HNPCC are ongoing. As more is learned about particular genotype-phenotype correlations with Lynch syndrome, this will likely affect surgical decision making. Despite all of these efforts in the management of patients with HNPCC or Lynch syndrome, incident CRCs still occur, thus reinforcing the need for further studies to better understand the optimal management of these patients.
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Affiliation(s)
- Rebeccah B Baucom
- Section of Surgical Sciences, Vanderbilt University Medical Center, Nashville, Tennessee
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45
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Quality of life after surgery for colon cancer in patients with Lynch syndrome: partial versus subtotal colectomy. Dis Colon Rectum 2012; 55:653-9. [PMID: 22595844 DOI: 10.1097/dcr.0b013e31824f5392] [Citation(s) in RCA: 71] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Lynch syndrome is a disorder caused by mismatch repair gene mutations. Mutation carriers have a high risk of developing colorectal cancer. In patients with Lynch syndrome in whom colon cancer has been diagnosed, in general, subtotal colectomy instead of partial colectomy is recommended because of the substantial risk of metachronous colorectal cancer. However, the effect of more extensive surgery on quality of life and functional outcome is unknown. OBJECTIVE The aim of this study was to investigate quality of life and functional outcome in patients with Lynch syndrome after partial colectomy and subtotal colectomy. DESIGN This is a nationwide cross-sectional study in the Netherlands. SETTINGS Two quality-of-life questionnaires (Short Form-36 and The European Organization for Research and Treatment of Cancer Colorectal Cancer-specific Quality of Life Questionnaire Module) and a functional outcome questionnaire (Colorectal Functional Outcome) were used. PATIENTS Patients with Lynch syndrome who underwent surgery for colon cancer were included. MAIN OUTCOME MEASURES The primary outcomes measured were quality of life and functional outcome. RESULTS Questionnaires were sent to 192 patients with Lynch syndrome who underwent surgery for colorectal cancer. A total of 136 patients returned the questionnaire (response rate, 71%). Eighteen patients with rectal cancer, 9 patients with a permanent ileostomy, and 5 patients with an IPAA were excluded. Fifty-one patients underwent partial colectomy, and 53 underwent subtotal colectomy. None of the scales of the Short Form-36 survey showed a significant difference. Analysis of the Colorectal Functional Outcome questionnaire revealed that, after subtotal colectomy, patients have a significantly higher stool frequency (p ≤ 0.01) and a significantly higher score on stool-related aspects (p = 0.06) and social impact (p = 0.03). The European Organization for Research and Treatment of Cancer Colorectal Cancer-specific Quality of Life Questionnaire Module presented more problems with defecation after subtotal colectomy (p ≤ 0.01). LIMITATIONS Certain selection bias cannot be ruled out. CONCLUSIONS Although functional outcome is worse after subtotal colectomy than after partial colectomy, generic quality of life does not differ after the 2 types of surgery in Lynch syndrome. When discussing the options for surgery with the patient, all advantages and disadvantages of both surgical procedures, including quality of life and functional outcome, should be discussed.
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Stupart DA, Goldberg PA, Baigrie RJ, Algar U, Ramesar R. Surgery for colonic cancer in HNPCC: total vs segmental colectomy. Colorectal Dis 2011; 13:1395-9. [PMID: 20969713 DOI: 10.1111/j.1463-1318.2010.02467.x] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
AIM The high reported risk of metachronous colon cancer (MCC) in hereditary nonpolyposis colorectal cancer (HNPCC) has led some authors to recommend total colectomy (TC) as the preferred operation for primary colon cancer, but this remains controversial. No previous study has compared survival after TC with segmental colectomy (SC) in HNPCC. The aim of this study was to determine the risk of developing MCC in patients with genetically proven HNPCC after SC or TC for cancer, and to compare their long-term survival. METHOD This is a prospective cohort study of all patients referred to our unit between 1995 and 2009 with a proven germline mismatch repair gene defect, who had undergone a resection for adenocarcinoma of the colon with curative intent. All patients were offered annual endoscopic surveillance. RESULTS Of 60 patients in the study, 39 had TC as their initial surgery and 21 had SC. After 6 years follow up, MCC occurred in eight (21%) SC patients and in none of the TC patients (P = 0.048). The risk of developing MCC after SC was 20% at 5 years. Colorectal cancer-specific survival was better in TC patients (P = 0.048) but overall survival of the two groups was similar (P = 0.29). CONCLUSION Patients with HNPCC have a significant risk of MCC after SC. This is eliminated by performing TC as the primary operation for colonic cancer.
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Affiliation(s)
- D A Stupart
- Colorectal Unit, Department of Surgery, University of Cape Town and Groote Schuur Hospital, Cape Town, South Africa.
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47
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Parry S, Win AK, Parry B, Macrae FA, Gurrin LC, Church JM, Baron JA, Giles GG, Leggett BA, Winship I, Lipton L, Young GP, Young JP, Lodge CJ, Southey MC, Newcomb PA, Le Marchand L, Haile RW, Lindor NM, Gallinger S, Hopper JL, Jenkins MA. Metachronous colorectal cancer risk for mismatch repair gene mutation carriers: the advantage of more extensive colon surgery. Gut 2011; 60:950-7. [PMID: 21193451 PMCID: PMC3848416 DOI: 10.1136/gut.2010.228056] [Citation(s) in RCA: 191] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND Surgical management of colon cancer for patients with Lynch syndrome who carry a mismatch repair (MMR) gene mutation is controversial. The decision to remove more or less of the colon involves the consideration of a relatively high risk of metachronous colorectal cancer (CRC) with the impact of more extensive surgery. OBJECTIVE To estimate and compare the risks of metachronous CRC for patients with Lynch syndrome undergoing either segmental or extensive (subtotal or total) resection for first colon cancer. DESIGN Risk of metachronous CRC was estimated for 382 MMR gene mutation carriers (172 MLH1, 167 MSH2, 23 MSH6 and 20 PMS2) from the Colon Cancer Family Registry, who had surgery for their first colon cancer, using retrospective cohort analysis. Age-dependent cumulative risks of metachronous CRC were calculated using the Kaplan-Meier method. Risk factors for metachronous CRC were assessed by a Cox proportional hazards regression. RESULTS None of 50 subjects who had extensive colectomy was diagnosed with metachronous CRC (incidence rate 0.0; 95% CI 0.0 to 7.2 per 1000 person-years). Of 332 subjects who had segmental resections, 74 (22%) were diagnosed with metachronous CRC (incidence rate 23.6; 95% CI 18.8 to 29.7 per 1000 person-years). For those who had segmental resections, incidence was statistically higher than for those who had extensive surgery (P <0.001). Cumulative risk of metachronous CRC was 16% (95% CI 10% to 25%) at 10 years, 41% (95% CI 30% to 52%) at 20 years and 62% (95% CI 50% to 77%) at 30 years after segmental colectomy. Risk of metachronous CRC reduced by 31% (95% CI 12% to 46%; p=0.002) for every 10 cm of bowel removed. CONCLUSIONS Patients with Lynch syndrome with first colon cancer treated with more extensive colonic resection have a lower risk of metachronous CRC than those receiving less extensive surgery. This finding will better inform decision-making about the extent of primary surgical resection.
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Affiliation(s)
- Susan Parry
- New Zealand Familial GI Cancer Registry, Auckland City Hospital, New Zealand.
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[HNPCC (hereditary non-polyposis colorectal cancer) or Lynch syndrome: a syndrome related to a failure of DNA repair system]. Bull Cancer 2011; 98:323-36. [PMID: 21459714 DOI: 10.1684/bdc.2011.1328] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
The HNPCC syndrome (hereditary non polyposis colon cancer) or Lynch syndrome stands for an autosomic dominant condition leading to the most prevalent hereditary colo-rectal cancers (CCR). MMR (mismatch repair)'s genes are involved in carcinogenesis as they play a role in ADNA mismatch repair. Microsatellite instability (MSI+ phenotype) induced by germline mutations is characteristic of such tumors and is necessary to assert the diagnosis. The HNPCC syndrome is associated with a significant increased risk of CCR altogether with endometrium, upper urinary tract and small bowel carcinomas as well as ovarian, biliary system and gastric cancers although of lesser extent. It is of importance to diagnose HNPCC syndrome prior to the treatment starts because it may influence patient's (as well as her/his relatives) disease management (type of surgery, surveillance and screening exams). New French recommendations, developed in 2009, about prophylactic colo-rectal and gynecologic surgeries and monitoring update latest ones published on 2004.
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Dudukgian H, Cintron JR. Indication and Extent of Surgery in Hereditary Nonpolyposis Colorectal Cancer. SEMINARS IN COLON AND RECTAL SURGERY 2011. [DOI: 10.1053/j.scrs.2010.12.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
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50
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Cannom RR, Kaiser AM. Management of Young Amsterdam- and Marker-Negative Patients with Colorectal Cancer. SEMINARS IN COLON AND RECTAL SURGERY 2011; 22:127-130. [DOI: 10.1053/j.scrs.2010.12.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
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