Hereditary nonpolyposis colorectal cancer
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Maria Fernanda Villarreal, M.D. [2]Ali Akram, M.B.B.S.[3]
Synonyms and Keywords: Lynch syndrome; HNPCC; Hereditary non-polyposis colorectal carcinoma; Lynch II syndrome; Lynch I syndrome; Familial nonpolyposis colon cancer; Hereditary nonpolyposis colorectal neoplasms
Overview
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1], Associate Editor(s)-in-Chief: Maria Fernanda Villarreal, M.D. [2]
Overview
Lynch syndrome was first described by Dr. Henry T. Lynch, an American physician, in 1966. Hereditary nonpolyposis colorectal cancer may be classified into 2 types: Lynch syndrome I (familial colon cancer) and Lynch syndrome II (hereditary nonpolyposis colorectal cancer associated with other cancers). Other variants such as Muir-Torre syndrome and Turcot syndrome are considered subtypes of hereditary nonpolyposis colorectal cancer. Hereditary nonpolyposis colorectal cancer is an autosomal dominant genetic disease characterized by an early onset of colon cancer, endometrial cancer, and other malignant tumors. Development of hereditary nonpolyposis colorectal cancer is the result of multiple genetic mutations. The genes involved in the pathogenesis of hereditary nonpolyposis colorectal cancer include: MSH-2, MLH-1, MSH-6, PMS-2 , PMS-1, TGF-BR2, and MLH-3. This syndrome occurs most commonly in the proximal colon (60% to 80%). Endometrial cancer is the most common sentinel cancer among female patients with hereditary nonpolyposis colorectal cancer. Hereditary nonpolyposis colorectal cancer is caused by germline mutations in one of the four MMR genes (MLH1, MSH2, MSH6, or PMS2), that results in defective repair of DNA sequence. Deletions in the EPCAM gene also cause hereditary nonpolyposis colorectal cancer. Hereditary nonpolyposis colorectal cancer must be differentiated from other diseases that cause familial colorectal cancer, such as: juvenile polyposis, familial adenomatous polyposis, Cowden syndrome, and MYH-associated polyposis. Incidence of HNPCC is not well known but it is estimated that 0.5 to 13% of the cases of colorectal cancer are due to hereditary nonpolyposis colorectal cancer. The prevalence of hereditary nonpolyposis colorectal cancer is approximately 2 – 7% of all the diagnosed cases of colorectal cancer. Hereditary nonpolyposis colorectal cancer commonly affects young adult population. The median age of diagnosis is between 40 to 45 years. Hereditary nonpolyposis colorectal cancer affects males and females equally. Hereditary nonpolyposis colorectal cancer usually affects individuals of the white race more commonly. Ethnically-diverse individuals are less likely to develop MMR mutations related with hereditary nonpolyposis colorectal cancer. The most potent risk factor in the development of hereditary nonpolyposis colorectal cancer is gene mutations caused by defective DNA mismatch repair. According to the Bethesda guidelines and Amsterdam criteria, screening for hereditary nonpolyposis colorectal cancer by genetic testing is recommended among patients with family history or/and a confirmed diagnosis of colorectal cancer under age 50 years. If left untreated, hereditary nonpolyposis colorectal cancer progression occurs rapidly and is then followed by sentinel organ cancer or metastasis. Hereditary nonpolyposis colorectal cancer is an aggressive syndrome characterized by early onset of cancer. Affected organs include endometrium (second most common after colon), ovary, stomach, small intestine, hepatobiliary tract, upper urinary tract, brain, and skin. Complications of hereditary nonpolyposis colorectal cancer are usually related to the surgery. The 5-year relative survival of patients with hereditary nonpolyposis colorectal cancer is approximately 79.3%. A feature associated with worse prognosis is late stage diagnosis. The hallmark of hereditary nonpolyposis colorectal cancer is a first-degree relative with known MMR/EPCAM gene mutation. A positive family history of colorectal cancer and meeting Amsterdam I or II criteria or revised Bethesda guidelines is highly suggestive of hereditary nonpolyposis colorectal cancer. Some symptoms that are associated with colorectal cancer are change in bowel habits, hematochezia, and rectal pain. Patients with hereditary nonpolyposis colorectal cancer usually appear healthy. Physical examination of patients with hereditary nonpolyposis colorectal cancer may show the presence of the fordyce granules. Laboratory findings consistent with the diagnosis of hereditary nonpolyposis colorectal cancer may include positive germline testing for hereditary nonpolyposis colorectal cancer genes (MLH1, MSH2, MSH6, and PMS2), positive EPCAM gene testing, and elevated serum concentration of CEA and CA-125. There are no ECG findings associated with hereditary nonpolyposis colorectal cancer. There are no x-ray findings associated with hereditary nonpolyposis colorectal cancer. There are no echocardiography findings associated with hereditary nonpolyposis colorectal cancer. There are no ultrasound findings associated with hereditary nonpolyposis colorectal cancer. However, an ultrasound may be helpful as a screening tool for the diagnosis of endometrial cancer which is commonly found in women with this syndrome. CT scan is not routinely used for the diagnosis of hereditary nonpolyposis colorectal cancer. However, in some cases, CT scan can be useful in the detection of extracolonic lesions and also right-sided colon lesions (especially in the cecum) which are not easily seen with colonoscopy. Magnetic resonance colonography (MRC) is not routinely used for the diagnosis of hereditary nonpolyposis colorectal cancer. Although it is associated with less discomfort as compared to colonoscopy, it has poor sensitivity in detecting small polyps, limiting its utility in adenoma screening at this time. There are no associated additional imaging findings for the diagnosis of hereditary nonpolyposis colorectal cancer. According to the American College of Gastroenterology, patients with hereditary nonpolyposis colorectal cancer should undergo colonoscopy every 2 years beginning at age 20 – 25 years, until the age of 40, followed by an annual colonoscopy. Diagnostic and screening endoscopy is recommended in the case of hereditary nonpolyposis colorectal cancer. There is no medical treatment for hereditary nonpolyposis colorectal cancer. However, hereditary nonpolyposis colorectal cancer patients should consider diet optimization and pharmacological prevention. Surgery is the mainstay of treatment for hereditary nonpolyposis colorectal cancer. Surgical resection is recommended for patients with hereditary nonpolyposis colorectal cancer because of the high rate of metachronous colorectal cancer. Subtotal colectomy with ileo–rectal anastomosis and postsurgical endoscopic rectal surveillance are advised when colorectal cancer develops in the setting of hereditary nonpolyposis colorectal cancer. There is no established method for the primary prevention of hereditary nonpolyposis colorectal cancer.There are no established measures for the primary prevention of hereditary nonpolyposis colorectal cancer. Secondary prevention strategies following hereditary nonpolyposis colorectal cancer include genetic testing, colonoscopy, urine cytology, pelvic exam, and endometrial biopsy.
Historical Perspective
Lynch syndrome was first described by Dr. Henry T. Lynch, an American physician, in 1966.
Classification
Hereditary nonpolyposis colorectal cancer may be classified into 2 types: Lynch syndrome I (familial colon cancer) and Lynch syndrome II (hereditary nonpolyposis colorectal cancer associated with other cancers). Other variants such as Muir-Torre syndrome and Turcot syndrome are considered subtypes of hereditary nonpolyposis colorectal cancer.
Pathophysiology
Hereditary nonpolyposis colorectal cancer is an autosomal dominant genetic disease characterized by an early onset of colon cancer, endometrial cancer, and other malignant tumors. Development of hereditary nonpolyposis colorectal cancer is the result of multiple genetic mutations. The genes involved in the pathogenesis of hereditary nonpolyposis colorectal cancer include: MSH-2, MLH-1, MSH-6, PMS-2 , PMS-1, TGF-BR2, and MLH-3. This syndrome occurs most commonly in the proximal colon (60% to 80%). Endometrial cancer is the most common sentinel cancer among female patients with hereditary nonpolyposis colorectal cancer.
Causes
Hereditary nonpolyposis colorectal cancer is caused by germline mutations in one of the four MMR genes (MLH1, MSH2, MSH6, or PMS2), that results in defective repair of DNA sequence. Deletions in the EPCAM gene also cause hereditary nonpolyposis colorectal cancer.
Differentiating Hereditary Nonpolyposis Colorectal Cancer from other Diseases
Hereditary nonpolyposis colorectal cancer must be differentiated from other diseases that cause familial colorectal cancer, such as: juvenile polyposis, familial adenomatous polyposis, Cowden syndrome, and MYH-associated polyposis.
Epidemiology and Demographics
Incidence of HNPCC is not well known but it is estimated that 0.5 to 13% of the cases of colorectal cancer are due to hereditary nonpolyposis colorectal cancer. The prevalence of hereditary nonpolyposis colorectal cancer is approximately 2 – 7% of all the diagnosed cases of colorectal cancer. Hereditary nonpolyposis colorectal cancer commonly affects young adult population. The median age of diagnosis is between 40 to 45 years. Hereditary nonpolyposis colorectal cancer affects males and females equally. Hereditary nonpolyposis colorectal cancer usually affects individuals of the white race more commonly. Ethnically-diverse individuals are less likely to develop MMR mutations related with hereditary nonpolyposis colorectal cancer.
Risk Factors
The most potent risk factor in the development of hereditary nonpolyposis colorectal cancer is gene mutations caused by defective DNA mismatch repair.
Screening
According to the Bethesda guidelines and Amsterdam criteria, screening for hereditary nonpolyposis colorectal cancer by genetic testing is recommended among patients with family history or/and a confirmed diagnosis of colorectal cancer under age 50 years.
Natural History, Complications and Prognosis
If left untreated, hereditary nonpolyposis colorectal cancer progression occurs rapidly and is then followed by sentinel organ cancer or metastasis. Hereditary nonpolyposis colorectal cancer is an aggressive syndrome characterized by early onset of cancer. Affected organs include endometrium (second most common after colon), ovary, stomach, small intestine, hepatobiliary tract, upper urinary tract, brain, and skin. Complications of hereditary nonpolyposis colorectal cancer are usually related to the surgery. The 5-year relative survival of patients with hereditary nonpolyposis colorectal cancer is approximately 79.3%. A feature associated with worse prognosis is late stage diagnosis.
History and Symptoms
The hallmark of hereditary nonpolyposis colorectal cancer is a first-degree relative with known MMR/EPCAM gene mutation. A positive family history of colorectal cancer and meeting Amsterdam I or II criteria or revised Bethesda guidelines is highly suggestive of hereditary nonpolyposis colorectal cancer. Some symptoms that are associated with colorectal cancer are change in bowel habits, hematochezia, and rectal pain.
Physical Examination
Patients with hereditary nonpolyposis colorectal cancer usually appear healthy. Physical examination of patients with hereditary nonpolyposis colorectal cancer may show the presence of the fordyce granules.
Laboratory Findings
Laboratory findings consistent with the diagnosis of hereditary nonpolyposis colorectal cancer may include positive germline testing for hereditary nonpolyposis colorectal cancer genes (MLH1, MSH2, MSH6, and PMS2), positive EPCAM gene testing, and elevated serum concentration of CEA and CA-125.
Electrocardiogram
There are no ECG findings associated with hereditary nonpolyposis colorectal cancer.
X Ray
There are no x-ray findings associated with hereditary nonpolyposis colorectal cancer.
Echocardiography/Ultrasound
There are no echocardiography findings associated with hereditary nonpolyposis colorectal cancer. There are no ultrasound findings associated with hereditary nonpolyposis colorectal cancer. However, an ultrasound may be helpful as a screening tool for the diagnosis of endometrial cancer which is commonly found in women with this syndrome.
CT scan
CT scan is not routinely used for the diagnosis of hereditary nonpolyposis colorectal cancer. However, in some cases, CT scan can be useful in the detection of extracolonic lesions and also right-sided colon lesions (especially in the cecum) which are not easily seen with colonoscopy.
MRI
Magnetic resonance colonography (MRC) is not routinely used for the diagnosis of hereditary nonpolyposis colorectal cancer. Although it is associated with less discomfort as compared to colonoscopy, it has poor sensitivity in detecting small polyps, limiting its utility in adenoma screening at this time.
Other Imaging Findings
There are no associated additional imaging findings for the diagnosis of hereditary nonpolyposis colorectal cancer.
Other Diagnostic Studies
According to the American College of Gastroenterology, patients with hereditary nonpolyposis colorectal cancer should undergo colonoscopy every 2 years beginning at age 20 – 25 years, until the age of 40, followed by an annual colonoscopy. Diagnostic and screening endoscopy is recommended in the case of hereditary nonpolyposis colorectal cancer.
Medical Therapy
There is no medical treatment for hereditary nonpolyposis colorectal cancer. However, hereditary nonpolyposis colorectal cancer patients should consider diet optimization and pharmacological prevention.
Surgery
Surgery is the mainstay of treatment for hereditary nonpolyposis colorectal cancer. Surgical resection is recommended for patients with hereditary nonpolyposis colorectal cancer because of the high rate of metachronous colorectal cancer. Subtotal colectomy with ileo–rectal anastomosis and postsurgical endoscopic rectal surveillance are advised when colorectal cancer develops in the setting of hereditary nonpolyposis colorectal cancer.
Primary Prevention
There is no established method for the primary prevention of hereditary nonpolyposis colorectal cancer.There are no established measures for the primary prevention of hereditary nonpolyposis colorectal cancer.
Secondary Prevention
Secondary prevention strategies following hereditary nonpolyposis colorectal cancer include genetic testing, colonoscopy, urine cytology, pelvic exam, and endometrial biopsy.
Case Studies
See also
References
Historical Perspective
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Ali Akram, M.B.B.S.[2] Maria Fernanda Villarreal, M.D. [3]
Overview
Lynch syndrome was first described by Dr. Henry T. Lynch, an American physician, in 1966.
Historical Perspective
- In 1913, Aldred Warthin, Chairman of the Department of Pathology at the University of Michigan in Ann Arbor, first reported a family which he called ‘Family G’ with features of the disease now known as Lynch syndrome. He recognized there were “cancer fraternities” and there was an influence of heredity on cancer.[1]
- In 1966, Dr. Henry T. Lynch described 2 Midwestern families whose members were affected with colon, gastric, and endometrial cancers.[2]
- In 1971, Lynch and Krush updated the studies of the family, in which they introduced the term ‘cancer family syndrome” for the disease affecting the families.[3]
- The term “Lynch syndrome” was coined in 1984 by Boland and Troncale.[4]
- Lynch named the condition “hereditary nonpolyposis colorectal cancer” in 1985. Since then the two terms have been used interchangeably. [5]
- Some sources reserve the term “Lynch syndrome” when there is a known DNA mismatch repair defect, and use the term “familial colorectal cancer type X” or “hereditary nonpolyposis colorectal cancer” when the Amsterdam criteria are met but there is no known DNA mismatch repair defect.[6]
- In 1991, the Amsterdam I Guidelines were published to help classify HNPCC.[7]
- In 1999, the updated Amsterdam II guidelines were published. [8]
- In 1997. Bethesda guidelines were published in which criteria for the identification of colorectal cancers that must be tested for microsatellite instability (MSI) were present.[9]
- The Bethesda guidelines were updated and revised in 2004.[10]
References
- â C. Richard Boland & Henry T. Lynch (2013). “The history of Lynch syndrome”. Familial cancer. 12 (2): 145â157. doi:10.1007/s10689-013-9637-8. PMIDÂ 23546821. Unknown parameter
|month=ignored (help) - â Lynch HT, Shaw MW, Magnuson CW, Larsen AL, Krush AJ (Feb 1966). “Hereditary factors in cancer. Study of two large midwestern kindreds”. Archives of Internal Medicine. 117 (2): 206â12. doi:10.1001/archinte.117.2.206. PMIDÂ 5901552.
- â H. T. Lynch & A. J. Krush (1971). “The cancer family syndrome and cancer control”. Surgery, gynecology & obstetrics. 132 (2): 247â250. PMIDÂ 5547406. Unknown parameter
|month=ignored (help) - â C. R. Boland & F. J. Troncale (1984). “Familial colonic cancer without antecedent polyposis”. Annals of internal medicine. 100 (5): 700â701. PMIDÂ 6712034. Unknown parameter
|month=ignored (help) - â Bellizzi AM, Frankel WL (Nov 2009). “Colorectal cancer due to deficiency in DNA mismatch repair function: a review”. Advances in Anatomic Pathology. 16 (6): 405â17. doi:10.1097/PAP.0b013e3181bb6bdc. PMIDÂ 19851131.
- â Lindor NM (Oct 2009). “Familial colorectal cancer type X: the other half of hereditary nonpolyposis colon cancer syndrome”. Surgical Oncology Clinics of North America. 18 (4): 637â45. doi:10.1016/j.soc.2009.07.003. PMCÂ 3454516. PMIDÂ 19793571.
- â H. F. Vasen, J. P. Mecklin, P. M. Khan & H. T. Lynch (1991). “The International Collaborative Group on Hereditary Non-Polyposis Colorectal Cancer (ICG-HNPCC)”. Diseases of the colon and rectum. 34 (5): 424â425. PMIDÂ 2022152. Unknown parameter
|month=ignored (help) - â H. F. Vasen, P. Watson, J. P. Mecklin & H. T. Lynch (1999). “New clinical criteria for hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome) proposed by the International Collaborative group on HNPCC”. Gastroenterology. 116 (6): 1453â1456. PMIDÂ 10348829. Unknown parameter
|month=ignored (help) - â M. A. Rodriguez-Bigas, C. R. Boland, S. R. Hamilton, D. E. Henson, J. R. Jass, P. M. Khan, H. Lynch, M. Perucho, T. Smyrk, L. Sobin & S. Srivastava (1997). “A National Cancer Institute Workshop on Hereditary Nonpolyposis Colorectal Cancer Syndrome: meeting highlights and Bethesda guidelines”. Journal of the National Cancer Institute. 89 (23): 1758â1762. PMIDÂ 9392616. Unknown parameter
|month=ignored (help) - â Asad Umar, C. Richard Boland, Jonathan P. Terdiman, Sapna Syngal, Albert de la Chapelle, Josef Ruschoff, Richard Fishel, Noralane M. Lindor, Lawrence J. Burgart, Richard Hamelin, Stanley R. Hamilton, Robert A. Hiatt, Jeremy Jass, Annika Lindblom, Henry T. Lynch, Paivi Peltomaki, Scott D. Ramsey, Miguel A. Rodriguez-Bigas, Hans F. A. Vasen, Ernest T. Hawk, J. Carl Barrett, Andrew N. Freedman & Sudhir Srivastava (2004). “Revised Bethesda Guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability”. Journal of the National Cancer Institute. 96 (4): 261â268. PMIDÂ 14970275. Unknown parameter
|month=ignored (help)
Classification
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Maria Fernanda Villarreal, M.D. [2]Ali Akram, M.B.B.S.[3]
Overview
Hereditary nonpolyposis colorectal cancer may be classified into 2 types: Lynch syndrome I (familial colon cancer) and Lynch syndrome II (hereditary nonpolyposis colorectal cancer associated with other cancers). Other variants such as Muir-Torre syndrome and Turcot syndrome are considered subtypes of hereditary nonpolyposis colorectal cancer.
Classification
Lynch Syndrome I
- Site-specific colonic cancer.
Lynch Syndrome II
- Includes extracolonic cancer.
- The most common cancer that develops among such patients is endometrial carcinoma.
Variants
MuirâTorre Syndrome[1][2][3]
- Hereditary autosomal dominant syndrome.
- Considered a subtype of hereditary nonpolyposis colorectal cancer.
- Affected individuals are prone to develop cancers of the colon, breast, and genitourinary tract along with skin lesions such as keratoacanthomas and sebaceous tumors.
- Genes affected are MLH1, MSH2, and MSH6, which are involved in the DNA mismatch repair.
- Hereditary autosomal recessive syndrome.
- Considered a sub-type of hereditary nonpolyposis colorectal cancer.
- Individuals are prone to develop intestinal polyposis in addition to CNS tumors such as glioblastoma or medulloblastoma.
References
- â Mintsoulis D, Beecker J (2016). “Muir-Torre syndrome”. CMAJ. 188 (5): E95. doi:10.1503/cmaj.150171. PMCÂ 4786404. PMIDÂ 26527831.
- â John AM, Schwartz RA (2016). “Muir-Torre syndrome (MTS): An update and approach to diagnosis and management”. J Am Acad Dermatol. 74 (3): 558â66. doi:10.1016/j.jaad.2015.09.074. PMIDÂ 26892655.
- â 3.0 3.1 Velter C, Caussade P, Fricker JP, Cribier B (2017). “[Muir-Torre syndrome and Turcot syndrome]”. Ann Dermatol Venereol. 144 (8â9): 525â529. doi:10.1016/j.annder.2017.01.017. PMIDÂ 28256262.
- â Dipro S, Al-Otaibi F, Alzahrani A, Ulhaq A, Al Shail E (2012). “Turcot syndrome: a synchronous clinical presentation of glioblastoma multiforme and adenocarcinoma of the colon”. Case Rep Oncol Med. 2012: 720273. doi:10.1155/2012/720273. PMCÂ 3479943. PMIDÂ 23119205.
Pathophysiology
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Maria Fernanda Villarreal, M.D. [2] Ali Akram, M.B.B.S.[3]
Overview
Hereditary nonpolyposis colorectal cancer is an autosomal dominant genetic disease characterized by an early onset of colon cancer, endometrial cancer, and other malignant tumors. Development of hereditary nonpolyposis colorectal cancer is the result of multiple genetic mutations. The genes involved in the pathogenesis of hereditary nonpolyposis colorectal cancer include: MSH-2, MLH-1, MSH-6, PMS-2 , PMS-1, TGF-BR2, and MLH-3. This syndrome occurs most commonly in the proximal colon (60% to 80%). Endometrial cancer is the most common sentinel cancer among female patients with hereditary nonpolyposis colorectal cancer.
Pathogenesis
- Hereditary nonpolyposis colorectal cancer results from a defect in the DNA mismatch repair mechanism that leads to microsatellite instability (MSI), which is a hallmark of the disease.
- Most cases result in changes in the lengths of dinucleotide repeats of the nucleobases cytosine and adenine.[1]
- Microsatellite instability (MSI) is a surrogate marker for DNA mismatch repair gene dysfunction.[2][3]
- In hereditary nonpolyposis colorectal cancer, colon malignancies usually occur from a single or multiple adenomas, and mostly in the proximal colon.
Genetics
- Hereditary nonpolyposis colorectal cancer is inherited in an autosomal dominant manner.
- Development of hereditary nonpolyposis colorectal cancer is the result of multiple genetic mutations.[4]
- Most mutations (90%) that cause hereditary nonpolyposis colorectal cancer are found in the MLH1 or MSH2 genes.[5]
- MSH6 and PMS2 account for the other 10% of mutations.[6]
- Endometrial cancer is the most common distant cancer among female patients with hereditary nonpolyposis colorectal cancer.
- MSH2 mutations have an increased risk of urothelial carcinoma relative to MLH1 and MSH6 mutations.[7]
The table below lists the genes involved in the pathogenesis of hereditary nonpolyposis colorectal cancer:
| Genes implicated in hereditary nonpolyposis colorectal cancer | Frequency of mutations in hereditary nonpolyposis colorectal cancer families | Locus |
|---|---|---|
| MSH2 | Approximately 60% | 2p22 |
| MLH1 | Approximately 30% | 3p21 |
| MSH6 | 7 – 10% | 2p16 |
| PMS2 | Relatively infrequent | 7p22 |
| PMS1 | Case report | 2q31-q33 |
| TGFBR2 | Case report | 3p22 |
| MLH3 | Disputed | 14q24.3 |
Associated Conditions
- Stomach carcinoma (intestinal type)[11][12]
- Biliary tree carcinoma[11]
- Pancreatic carcinoma
- Urinary system carcinoma
Gross Pathology
- On gross pathology, there are no characteristic findings of hereditary nonpolyposis colorectal cancer.[4]
Microscopic Pathology
- On microscopic histopathological analysis, hereditary nonpolyposis colorectal cancer is more likely to be poorly differentiated, abundant in extracellular mucin, and distinguished by a lymphoid (peritumoral lymphocytes) host response to the tumor.[4]
- Three major groups of MSI-H cancers can be recognized by histopathological criteria, which include:[13][14]
- Right-sided poorly differentiated cancers
- Right-sided mucinous cancers
- Adenocarcinomas in any location showing any measurable level of intraepithelial lymphocyte
References
- â Oki E, Oda S, Maehara Y, Sugimachi K (Mar 1999). “Mutated gene-specific phenotypes of dinucleotide repeat instability in human colorectal carcinoma cell lines deficient in DNA mismatch repair”. Oncogene. 18 (12): 2143â7. doi:10.1038/sj.onc.1202583. PMIDÂ 10321739.
- â Lynch syndrome.Ganfyd.http://www.ganfyd.org/index.php?title=Lynch_syndrome Accessed on December 01, 2015
- â Vasen HF, Watson P, Mecklin JP, Lynch HT (1999). “New clinical criteria for hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome) proposed by the International Collaborative group on HNPCC”. Gastroenterology. 116 (6): 1453â6. PMIDÂ 10348829.
- â 4.0 4.1 4.2 Si JW, Wang L, Ba XJ, Zhang X, Dong Y, Zhang JX, Li WT, Li T (2015). “[Clinicopathological screening of Lynch syndrome: a report of 2 cases and literature review]”. Beijing Da Xue Xue Bao (in Chinese). 47 (5): 858â64. PMIDÂ 26474631.
- â Lynch Syndrome. Canadian Cancer Society http://www.cancer.ca/en/cancer-information/cancer-101/what-is-a-risk-factor/genetic-risk/lynch-syndrome/?region=ab#ixzz3t69IQ9M7 Accessed on December 01 2015
- â Lynch Syndrome. Canadian Cancer Society http://www.cancer.ca/en/cancer-information/cancer-101/what-is-a-risk-factor/genetic-risk/lynch-syndrome/?region=ab#ixzz3t69IQ9M7 Accessed on December 01 2015
- â van der Post, RS.; Kiemeney, LA.; Ligtenberg, MJ.; Witjes, JA.; Hulsbergen-van de Kaa, CA.; Bodmer, D.; Schaap, L.; Kets, CM.; van Krieken, JH. (2010). “Risk of urothelial bladder cancer in Lynch syndrome is increased, in particular among MSH2 mutation carriers”. J Med Genet. 47 (7): 464â70. doi:10.1136/jmg.2010.076992. PMIDÂ 20591884. Unknown parameter
|month=ignored (help) - â Okuda T, Sekizawa A, Purwosunu Y; et al. (2010). “Genetics of endometrial cancers”. Obstet Gynecol Int. 2010: 984013. doi:10.1155/2010/984013. PMCÂ 2852605. PMIDÂ 20396392.
- â Garg, K.; Soslow, RA. (2009). “Lynch syndrome (hereditary non-polyposis colorectal cancer) and endometrial carcinoma”. J Clin Pathol. 62 (8): 679â84. doi:10.1136/jcp.2009.064949. PMIDÂ 19638537. Unknown parameter
|month=ignored (help) - â Lax, SF. (2002). “[Dualistic model of molecular pathogenesis in endometrial carcinoma]”. Zentralbl Gynakol. 124 (1): 10â6. doi:10.1055/s-2002-20303. PMIDÂ 11873308. Unknown parameter
|month=ignored (help) - â 11.0 11.1 Online Mendelian Inheritance in Man (OMIM) 120435
- â Cristofaro, G.; Lynch, HT.; Caruso, ML.; Attolini, A.; DiMatteo, G.; Giorgio, P.; Senatore, S.; Argentieri, A.; Sbano, E. (1987). “New phenotypic aspects in a family with Lynch syndrome II”. Cancer. 60 (1): 51â8. PMIDÂ 3581033. Unknown parameter
|month=ignored (help) - â Lynch HT, Lynch PM, Lanspa SJ, Snyder CL, Lynch JF, Boland CR (2009). “Review of the Lynch syndrome: history, molecular genetics, screening, differential diagnosis, and medicolegal ramifications”. Clin Genet. 76 (1): 1â18. doi:10.1111/j.1399-0004.2009.01230.x. PMCÂ 2846640. PMIDÂ 19659756.
- â Ma H, Brosens LAA, Offerhaus GJA, Giardiello FM, de Leng WWJ, Montgomery EA (2018). “Pathology and genetics of hereditary colorectal cancer”. Pathology. 50 (1): 49â59. doi:10.1016/j.pathol.2017.09.004. PMIDÂ 29169633.
Causes
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Maria Fernanda Villarreal, M.D. [2]Ali Akram, M.B.B.S.[3]
Overview
Hereditary nonpolyposis colorectal cancer is caused by germline mutations in one of the four MMR genes (MLH1, MSH2, MSH6, or PMS2), that results in defective repair of DNA sequence. Deletions in the EPCAM gene also cause hereditary nonpolyposis colorectal cancer.
Causes
- Hereditary nonpolyposis colorectal cancer is caused by a genetic mutation in MMR gene, that results in defective repair of DNA sequence.[1][2]
- Deletions in the EPCAM gene, which can lead to MSH2 silencing, also cause hereditary nonpolyposis colorectal cancer.[3][4]
References
- â C. Richard Boland & Ajay Goel (2010). “Microsatellite instability in colorectal cancer”. Gastroenterology. 138 (6): 2073â2087. doi:10.1053/j.gastro.2009.12.064. PMIDÂ 20420947. Unknown parameter
|month=ignored (help) - â Jing-wen Si, Li Wang, Xiao-jun Ba, Xu Zhang, Ying Dong, Ji-xin Zhang, Wen-ting Li & Ting Li (2015). “[Clinicopathological screening of Lynch syndrome: a report of 2 cases and literature review]”. Beijing da xue xue bao. Yi xue ban = Journal of Peking University. Health sciences. 47 (5): 858â864. PMIDÂ 26474631. Unknown parameter
|month=ignored (help) - â Kandelaria Rumilla, Karen V. Schowalter, Noralane M. Lindor, Brittany C. Thomas, Kara A. Mensink, Steven Gallinger, Spring Holter, Polly A. Newcomb, John D. Potter, Mark A. Jenkins, John L. Hopper, Tiffany I. Long, Daniel J. Weisenberger, Robert W. Haile, Graham Casey, Peter W. Laird, Loic Le Marchand & Stephen N. Thibodeau (2011). “Frequency of deletions of EPCAM (TACSTD1) in MSH2-associated Lynch syndrome cases”. The Journal of molecular diagnostics : JMD. 13 (1): 93â99. doi:10.1016/j.jmoldx.2010.11.011. PMID 21227399. Unknown parameter
|month=ignored (help) - â Marlies J. E. Kempers, Roland P. Kuiper, Charlotte W. Ockeloen, Pierre O. Chappuis, Pierre Hutter, Nils Rahner, Hans K. Schackert, Verena Steinke, Elke Holinski-Feder, Monika Morak, Matthias Kloor, Reinhard Buttner, Eugene T. P. Verwiel, J. Han van Krieken, Iris D. Nagtegaal, Monique Goossens, Rachel S. van der Post, Renee C. Niessen, Rolf H. Sijmons, Irma Kluijt, Frans B. L. Hogervorst, Edward M. Leter, Johan J. P. Gille, Cora M. Aalfs, Egbert J. W. Redeker, Frederik J. Hes, Carli M. J. Tops, Bernadette P. M. van Nesselrooij, Marielle E. van Gijn, Encarna B. Gomez Garcia, Diana M. Eccles, David J. Bunyan, Sapna Syngal, Elena M. Stoffel, Julie O. Culver, Melanie R. Palomares, Tracy Graham, Lea Velsher, Janos Papp, Edith Olah, Tsun L. Chan, Suet Y. Leung, Ad Geurts van Kessel, Lambertus A. L. M. Kiemeney, Nicoline Hoogerbrugge & Marjolijn J. L. Ligtenberg (2011). “Risk of colorectal and endometrial cancers in EPCAM deletion-positive Lynch syndrome: a cohort study”. The Lancet. Oncology. 12 (1): 49â55. doi:10.1016/S1470-2045(10)70265-5. PMIDÂ 21145788. Unknown parameter
|month=ignored (help)
Differentiating Hereditary Nonpolyposis Colorectal Cancer from Other Diseases
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Maria Fernanda Villarreal, M.D. [2]Ali Akram, M.B.B.S.[3]
Overview
Hereditary nonpolyposis colorectal cancer must be differentiated from other diseases that cause familial colorectal cancer, such as: juvenile polyposis, familial adenomatous polyposis, Cowden syndrome, and MYH-associated polyposis.
Differentiating Hereditary Nonpolyposis Colorectal Cancer from other Diseases
HNPCC must be differentiated from other diseases, such as:[1]
| Diseases | History and Symptoms | Physical Examination | Laboratory Findings | Other Findings | ||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Abdominal Pain | Rectal Bleeding | Fatigue | Abdominal Tenderness | Hyperpigmentation | Anemia | Gene(s) | Gastrointestinal Tumors | Cancers | ||
| Hereditary NonâPolyposis Colon Cancer | â | + | + | +/â | â | + | ||||
| Carney Syndrome | â | â | â | â | â | |||||
| Familial Adenomatous Polyposis | + | + | + | +/â | â | + |
|
|||
| PeutzâJeghers syndrome | + | + | + | + | + | + | ||||
| Juvenile Polyposis Syndrome | + | + | â | â | â |
|
||||
| Cowden Syndrome | â | â | â | â | â | |||||
| Differential Diagnosis | Similar Features | Differentiating Features |
|---|---|---|
| Familial adenomatous polyposis |
|
|
| Juvenile polyposis |
|
|
| Cowden syndrome |
|
|
References
- â Kladny J, Lubinski J. Lynch syndrome (HNPCC). Hered Cancer Clin Pract. 2008;6(2):99-102.
Epidemiology and Demographics
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Maria Fernanda Villarreal, M.D. [2]Ali Akram, M.B.B.S.[3]
Overview
Incidence of HNPCC is not well known but it is estimated that 0.5 to 13% of the cases of colorectal cancer are due to hereditary nonpolyposis colorectal cancer. The prevalence of hereditary nonpolyposis colorectal cancer is approximately 2 – 7% of all the diagnosed cases of colorectal cancer. Hereditary nonpolyposis colorectal cancer commonly affects young adult population. The median age of diagnosis is between 40 to 45 years. Hereditary nonpolyposis colorectal cancer affects males and females equally. Hereditary nonpolyposis colorectal cancer usually affects individuals of the white race more commonly. Ethnically-diverse individuals are less likely to develop MMR mutations related with hereditary nonpolyposis colorectal cancer.
Epidemiology and Demographics
Incidence
- Incidence of HNPCC is not well known but it is estimated that 0.5 to 13% of the cases of colorectal cancer are due to hereditary nonpolyposis colorectal cancer.[1][2]
Prevalence
- The prevalence of hereditary nonpolyposis colorectal cancer is approximately 2 – 7% of all the diagnosed cases of colorectal cancer.[3]
Age
- Hereditary nonpolyposis colorectal cancer commonly affects young adult population.
- The median age of diagnosis is often less than 45 years.[3]
Gender
- Hereditary nonpolyposis colorectal cancer affects males and females equally.
- In some particular genetic mutations such as MLH1, males have significantly higher risk than females at all ages.[3]
Race
- Hereditary nonpolyposis colorectal cancer usually affects individuals of the white race more commonly.
- Ethnically-diverse individuals are less likely to develop MMR mutations related with hereditary nonpolyposis colorectal cancer.
References
- â Aaltonen LA, Sankila R, Mecklin JP, JĂ€rvinen H, Pukkala E, PeltomĂ€ki P; et al. (1994). “A novel approach to estimate the proportion of hereditary nonpolyposis colorectal cancer of total colorectal cancer burden”. Cancer Detect Prev. 18 (1): 57â63. PMID 8162607.
- â Houlston RS, Collins A, Slack J, Morton NE (1992). “Dominant genes for colorectal cancer are not rare”. Ann Hum Genet. 56 (Pt 2): 99â103. PMIDÂ 1503398.
- â 3.0 3.1 3.2 Aaltonen LA, Salovaara R, Kristo P, Canzian F, Hemminki A, PeltomĂ€ki P, Chadwick RB, KÀÀriĂ€inen H, Eskelinen M, JĂ€rvinen H, Mecklin JP, de la Chapelle A (1998). “Incidence of hereditary nonpolyposis colorectal cancer and the feasibility of molecular screening for the disease”. N. Engl. J. Med. 338 (21): 1481â7. doi:10.1056/NEJM199805213382101. PMID 9593786.
Risk Factors
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Maria Fernanda Villarreal, M.D. [2]Ali Akram, M.B.B.S.[3]
Overview
Incidence of HNPCC is not well known but it is estimated that 0.5 to 13% of the cases of colorectal cancer are due to hereditary nonpolyposis colorectal cancer. The prevalence of hereditary nonpolyposis colorectal cancer is approximately 2 – 7% of all the diagnosed cases of colorectal cancer. Hereditary nonpolyposis colorectal cancer commonly affects young adult population. The median age of diagnosis is between 40 to 45 years. Hereditary nonpolyposis colorectal cancer affects males and females equally. Hereditary nonpolyposis colorectal cancer usually affects individuals of the white race more commonly. Ethnically-diverse individuals are less likely to develop MMR mutations related with hereditary nonpolyposis colorectal cancer.
Epidemiology and Demographics
Incidence
- Incidence of HNPCC is not well known but it is estimated that 0.5 to 13% of the cases of colorectal cancer are due to hereditary nonpolyposis colorectal cancer.[1][2]
Prevalence
- The prevalence of hereditary nonpolyposis colorectal cancer is approximately 2 – 7% of all the diagnosed cases of colorectal cancer.[3]
Age
- Hereditary nonpolyposis colorectal cancer commonly affects young adult population.
- The median age of diagnosis is often less than 45 years.[3]
Gender
- Hereditary nonpolyposis colorectal cancer affects males and females equally.
- In some particular genetic mutations such as MLH1, males have significantly higher risk than females at all ages.[3]
Race
- Hereditary nonpolyposis colorectal cancer usually affects individuals of the white race more commonly.
- Ethnically-diverse individuals are less likely to develop MMR mutations related with hereditary nonpolyposis colorectal cancer.
References
- â Aaltonen LA, Sankila R, Mecklin JP, JĂ€rvinen H, Pukkala E, PeltomĂ€ki P; et al. (1994). “A novel approach to estimate the proportion of hereditary nonpolyposis colorectal cancer of total colorectal cancer burden”. Cancer Detect Prev. 18 (1): 57â63. PMID 8162607.
- â Houlston RS, Collins A, Slack J, Morton NE (1992). “Dominant genes for colorectal cancer are not rare”. Ann Hum Genet. 56 (Pt 2): 99â103. PMIDÂ 1503398.
- â 3.0 3.1 3.2 Aaltonen LA, Salovaara R, Kristo P, Canzian F, Hemminki A, PeltomĂ€ki P, Chadwick RB, KÀÀriĂ€inen H, Eskelinen M, JĂ€rvinen H, Mecklin JP, de la Chapelle A (1998). “Incidence of hereditary nonpolyposis colorectal cancer and the feasibility of molecular screening for the disease”. N. Engl. J. Med. 338 (21): 1481â7. doi:10.1056/NEJM199805213382101. PMID 9593786.
Screening
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Maria Fernanda Villarreal, M.D. [2]
Overview
According to the Bethesda guidelines and Amsterdam criteria, screening for hereditary nonpolyposis colorectal cancer by genetic testing is recommended among patients with family history or/and a confirmed diagnosis of colorectal cancer under age 50 years.
Screening
- According to the Bethesda guidelines and Amsterdam criteria, screening for hereditary nonpolyposis colorectal cancer by genetic testing is recommended among patients with family history or/and a confirmed diagnosis of colorectal cancer under age 50 years.[1][2]
- The Amsterdam and Bethesda guidelines are useful for identifying cancer patients who are most likely to be hereditary nonpolyposis colorectal carriers as ideal candidates for genetic testing.
- Genetic testing for mutations in DNA mismatch repair genes is expensive and time-consuming.
- Microsatellite instability can be observed in the majority of patients with colorectal cancer.
- Immunohistochemistry and microsatellite instability profiling strategy is the most advanced way of identifying candidates for genetic testing for the hereditary nonpolyposis colorectal cancer.
- The Amsterdam Criteria I and II identify patients for colonoscopic screening and approximately 40 – 80% of the patients meet these criteria.
- The revised Bethesda criteria are used to identify patients for molecular screening of hereditary nonpolyposis colorectal cancer.
- Approximately 80% of patients are identified using the Bethesda criteria, although the specificity is low.[3][4]
Amsterdam Criteria
The following are the Amsterdam criteria in identifying high-risk candidates for molecular genetic testing:[1]
Amsterdam Criteria I:
- Three or more family members with a confirmed diagnosis of colorectal cancer, one of whom is a first degree (parent, child, or sibling) relative of the other two
- Two successive affected generations
- One or more colon cancers diagnosed under age 50 years
- Familial adenomatous polyposis (FAP) has been excluded
Amsterdam Criteria II:
- Three or more family members with HNPCC-related cancers, one of whom is a first degree relative of the other two
- Two successive affected generations
- One or more of the HNPCC-related cancers diagnosed under age 50 years
- Familial adenomatous polyposis (FAP) has been excluded
Bethesda Guidelines
The revised Bethesda Guidelines are designed for identifying individuals at risk for hereditary nonpolyposis colorectal cancer, and therefore recommend microsatellite instability testing.[5]
Revised Bethesda guidelines:
- Colorectal cancer diagnosed in a patient aged < 50â years
- Presence of synchronous, metachronous colorectal or other Lynch syndromeârelated tumors, regardless of age
- Patient with colorectal cancer and a firstâdegree relative with a Lynch syndromeârelated tumor, with one of the cancers diagnosed at age < 50â years
- Patient with colorectal cancer with two or more firstâdegree or secondâdegree relatives with a Lynch syndromeârelated tumor, regardless of age
- Lynch syndromeârelated tumors include colorectal, endometrial, stomach, ovarian, pancreas, ureter, renal pelvis, biliary tract and brain tumors, sebaceous gland adenomas and keratoacanthomas, and carcinoma of the small bowel
Surveillance
- According to Netherlands Surveillance Protocol for Carriers of an MMR-gene mutation, there is sufficient evidence to recommend routine screening for HNPCC-related cancers.[6][7]
- Recommended annual screening for patients with hereditary nonpolyposis colorectal cancer (age 25 onwards or beginning no later than 5 years before the lowest age of onset in family) should include:[7]
- Physical examination
- Abdominal ultrasound
- Colonoscopy
- Upper gastrointestinal endoscopy (age 35 onwards)
- Gynecological examination including transvaginal ultrasound
- Endometrial pipelle biopsy (age 35 onwards)
- Skin surveillance
- Urinalysis
References
- â 1.0 1.1 Vasen HF, Watson P, Mecklin JP, Lynch HT (Jun 1999). “New clinical criteria for hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome) proposed by the International Collaborative group on HNPCC”. Gastroenterology. 116 (6): 1453â6. doi:10.1016/S0016-5085(99)70510-X. PMIDÂ 10348829.
- â Hampel H, de la Chapelle A (2011). “The search for unaffected individuals with Lynch syndrome: do the ends justify the means?”. Cancer Prev Res (Phila). 4 (1): 1â5. doi:10.1158/1940-6207.CAPR-10-0345. PMCÂ 3076593. PMIDÂ 21205737.
- â Lynch syndrome.Ganfyd.http://www.ganfyd.org/index.php?title=Lynch_syndrome Accessed on December 01, 2015
- â Vasen HF, Watson P, Mecklin JP, Lynch HT (1999). “New clinical criteria for hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome) proposed by the International Collaborative group on HNPCC”. Gastroenterology. 116 (6): 1453â6. PMIDÂ 10348829.
- â Umar A, Boland CR, Terdiman JP, Syngal S, de la Chapelle A, RĂŒschoff J, Fishel R, Lindor NM, Burgart LJ, Hamelin R, Hamilton SR, Hiatt RA, Jass J, Lindblom A, Lynch HT, Peltomaki P, Ramsey SD, Rodriguez-Bigas MA, Vasen HF, Hawk ET, Barrett JC, Freedman AN, Srivastava S (2004). “Revised Bethesda Guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability”. J. Natl. Cancer Inst. 96 (4): 261â8. PMCÂ 2933058. PMIDÂ 14970275.
- â Vasen HF, Möslein G, Alonso A, Bernstein I, Bertario L, Blanco I, Burn J, Capella G, Engel C, Frayling I, Friedl W, Hes FJ, Hodgson S, Mecklin JP, MĂžller P, Nagengast F, Parc Y, Renkonen-Sinisalo L, Sampson JR, Stormorken A, Wijnen J (2007). “Guidelines for the clinical management of Lynch syndrome (hereditary non-polyposis cancer)”. J. Med. Genet. 44 (6): 353â62. doi:10.1136/jmg.2007.048991. PMC 2740877. PMID 17327285.
- â 7.0 7.1 Lindor NM, Petersen GM, Hadley DW, Kinney AY, Miesfeldt S, Lu KH, Lynch P, Burke W, Press N (2006). “Recommendations for the care of individuals with an inherited predisposition to Lynch syndrome: a systematic review”. JAMA. 296 (12): 1507â17. doi:10.1001/jama.296.12.1507. PMIDÂ 17003399.
Natural History, Complications and Prognosis
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Maria Fernanda Villarreal, M.D. [2]
Overview
If left untreated, hereditary nonpolyposis colorectal cancer progression occurs rapidly and is then followed by sentinel organ cancer or metastasis. Hereditary nonpolyposis colorectal cancer is an aggressive syndrome characterized by early onset of cancer. Affected organs include endometrium (second most common after colon), ovary, stomach, small intestine, hepatobiliary tract, upper urinary tract, brain, and skin. Complications of hereditary nonpolyposis colorectal cancer are usually related to the surgery. The 5-year relative survival of patients with hereditary nonpolyposis colorectal cancer is approximately 79.3%. A feature associated with worse prognosis is late stage diagnosis.
Natural History, Complications, and Prognosis
Natural History
- If left untreated, hereditary nonpolyposis colorectal cancer progression occurs rapidly and is then followed by sentinel organ cancers or metastasis.
- Other organ cancers include:[1]
- Genitourinary tract malignancies
- Endometrial carcinoma: 30 – 50% lifetime risk
- Ovarian tumors
- Urinary tract cancer
- Small bowel cancer: lifetime risk ~5%
- Duodenum 45%
- Jejunum 29%
- Ileum 12%
- Not specified 14%
- Gastric cancer
- CNS tumors (glioblastoma)
- More advanced stages are characterized by multiple organ metastasis.
Prognosis
- The 5-year relative survival of patients with hereditary nonpolyposis colorectal cancer is approximately 79.3%.[2]
Complications
- Complications that can develop as a result of hereditary nonpolyposis colorectal cancer are sentinel organ tumors, such as:
- Other complications of hereditary nonpolyposis colorectal cancer are usually related to the colorectal surgery.
References
- â Hereditary nonpolyposis colorectal cancer. Dr Amir Rezaee. Radiopedia. http://radiopaedia.org/articles/hereditary-non-polyposis-colorectal-cancer-1 Accessed on December 3, 2015
- â Vasen HF, Watson P, Mecklin JP, Lynch HT (1999). “New clinical criteria for hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome) proposed by the International Collaborative group on HNPCC”. Gastroenterology. 116 (6): 1453â6. PMIDÂ 10348829.
Diagnosis
Diagnosis
Staging | History and Symptoms | Physical Examination | Laboratory Findings | Chest X Ray | CT | MRI | Ultrasound | Other Imaging Findings | Other diagnostic studies
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