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Photo Courtesy of Marco Pompei
Medicine is not merely a science but an art. The character of the physician may act more powerfully upon the patient than the drugs employed.
-~ Paracelsus
Understanding the busy schedule of the professional, the following pages are quick guides for professionals to acquaint them with the basic knowledge of Lynch syndrome and how to diagnose and manage the disorder.
More detailed information to supplement these pages can be found by clicking on the LSI Library link on the Main Menu, to the left of this page, whereupon selected studies are available as well as clinical trials, registries, patient payment assistance programs, anti-discrimination laws and other resources relative to Lynch syndrome.
QUICK FACTS ABOUT LYNCH SYNDROME
- Approximately 10% of all cancers are hereditary.
- Approximately 145,000 people per year get colon cancer and one in every 35 persons with colon cancer have Lynch syndrome.
- Approximately 600,000 to 1,000,000 individuals within the United States are projected to have Lynch syndrome, however less than 10% of that number have been diagnosed.
- The first step toward diagnosis is the taking of a comprehensive family medical history.
- The only true form of diagnosis of Lynch syndrome is through genetic testing.
- Genetic testing saves lives.
LYNCH CANCERS LIFETIME RISKS
- Colon Cancer - Up to 80% General Population 2%
- Endometrial Cancer - Up to 60% General Population 1%
- Stomach - Up to 13% General Population - 1%
- Ovarian - Up to 12% General Population 1%
Those diagnosed with Lynch syndrome have a slightly elevated risk over the general population of developing cancers of the kidney/urinary tract, brain, small intestine, cervix, liver, bladder, ureter, esophagus, small bowel, pancreas, hepatobiliary tract, gall bladder duct, prostate and sebaceous adenomas (Muir Torre)
Identification, Diagnosis and Management - Excellent Immediate Resource Guide for Physicians: Lynch Syndrome by Wendy Kohlman, MS and Stephen B. Gruber, MD, PhD, revised 9/20/2012
Breast cancer has been identified as an integral component of LS based upon mismatch repair germline mutation factors in breast cancer tissues from family members who are not only at high risk, but, moreover, who had Lynch syndrome cancers, such as involving the colorectum. Breast cancer is exceedingly common in the population and, therein, its occurence in Lynch syndrome families could be due to chance, but importantly, a subset will likely be integrally related to a germline mismatch repair Lynch syndrome mutation in some LS families. Therefore, it would be prudent to mount a screening and management program for Lynch syndrome in those families where breast cancer is believed to be an integral lesion.
A detailed cost-effectiveness analysis* of screening for LS was completed after the EGAPP™ recommendation was published. The four testing approaches evaluated were found to be cost effective in the following order, from most to least cost effective:
- Preliminary screening of tumor tissue using IHC, plus BRAF
- Preliminary screening of tumor tissue using IHC only
- Preliminary screening of tumor tissue using MSI
- Genetic sequencing (DNA analysis) for all 4 MMR genes
*The Cost-Effectiveness of Genetic Testing Strategies for Lynch Syndrome Among Newly Diagnosed Patients with Colorectal Cancer, published online on January 15, 2010 in Genetics in Medicine. Authors: Mvundura M, Grosse SD, Hampel H, Palomaki GE.
Widespread Genetic Testing Appears Cost Effective published online on 1/4/2011 in Cancer Prev Res (Phila) Authors: Dinh, TA, Rosner, BL, Atwood, JC, Boland, CR, Syngal S, Vasan, HF, Gruber, SB, Burt, RW
Expert Discussion of top expert panel of the Cost Effectiveness of Genetic Testing for Lynch syndrome. The study provides a medically and cost effective method to readily identify and determine precisely who benefits from genetic testing for Lynch syndrome. A "must listen" panel discussion for all medical professionals.
New NCCN guidelines recommend "MMR protein testing should strongly be considered for ALL colon cancer patients <50 years of age based upon an increased likelihood of Lynch syndrome in this population. Some centers, however, now perform IHC (and sometimes MSI) testing on all colorectal tumors to determine which patients should have genetic testing for Lynch syndrome. The cost effectiveness of this so-called " reflex testing" approach has been confirmed for colorectal cancer and this approch was endorsed by the Evaluation of Genomic Applications in Prevention and Practice. (EGAPP) working group at the Centers For Disease Control (CDC)."
Modified 01/13/2013
Photo Courtesy of the National Institute of Health
For those of us who have been diagnosed with cancer, time is a precious commodity. The time and distance from the scientist's lab bench to the patient's bedside must be shortened. ~ Larry Lucchino
Characteristics of Lynch Syndrome:
Autosomal dominant inheritance pattern
Earlier average age of onset of colorectal cancer than in the general population (45 years in Lynch syndrome v. 63 years in the general population)
- Proximal (right sided) colonic cancer predilection (70%-85% of colorectal cancers in Lynch syndrome are proximal to the splenic flexure)
Accelerated carcinogenesis (tiny adenomas can develop carcinoma within 2-3 years in Lynch syndrome v. 8-10 years in the general population)
- High risk of additional colorectal cancers (25%-30% of patients who have surgery for a Lynch syndrome-associated colorectal cancer within 10 years of surgical resection if they received a less than subtotal colectomy) Starts at an earlier age than the general population. Average onset is 44 years old. Lifetime risk is 60% to over 80%.
Increased risk of malignant disease at certain extracolonic sites
- Endometrium (20-60% lifetime risk for female mutation carriers)
Ovary (9%-12% lifetime risk for female mutation carriers)
- Stomach (11% - 19% lifetime risk. Higher risk in individuals of Asian descent. Average age of presentation at 56)
Small Bowel ( Lifetime risk is 1% to 4%.)
- Hepitobilliary Tract ( Lifetime risk is 2% to 7% )
Pancreas ( Lifetime risk is 4%)
- Upper Uroepithelial Tract (transitional cell carcinoma of ureter and renal pelvis. Lifetime risk is 4% to 10%. )
Prostate (European Studies)
- Brain/CNS (1%-3% )
Sebaceous adenomas, sebaceous carcinomas and multiple keratoacanthomas in Muir-Torre syndrome (variant of Lynch syndrome)
- Pathology of colorectal cancer is more often poorly differentiated, with an excess of mucoid and signet cell features, a Crohn-like reaction and an excess of infiltrating lymphocites within the tumor.
Increased survival from colorectal cancer
Germline mutation in a mismatch repair gene (most commonly MLH1, MSH2 or MSH6) that segregates in the patient's family (i.e., members who carry the mutation show a high rate of syndrome-related cancers than those who do not carry the mutation.)
In the MSH-6 mutation, most individuals have colorectal cancers located on the left side of the colon; including the descending colon, the sigmoid colon and the rectum, different from many of those with Lynch syndrome in which the cancers are proximal. There are more cases of endometrial cancer within those with an MSH-6 mutation.
Modified 7/19/2012
"Like with every form of cancer, early detection is what it is all about. ..It can be prevented with testing, and it can be beaten if caught early!"
~ Rod Stewart
Diagnosis and management of hereditary colorectal cancer syndromes: Lynch syndrome as a model
Henry T. Lynch, MD, Jane F. Lynch, BSN and Thomas A. Attard, MD
What the Physician Needs to Know About Lynch Syndrome - An UpdateHenry T. Lynch
Guidelines for the Clinical Management of Lynch Syndrome by Dr H F A Vasen Department of Gastroenterology, Leiden University Medical Centre and The Netherlands Foundation for the Detection of Hereditary Tumours
Lynch Syndrome Wendy Kohlmann, MS and Stephen Gruber, MD, Phd 9/20/2012 Excellent immediate resource guide
Risk Assessment, Genetic Testing and Management of Lynch Syndrome by Shilpa Grover, MD, MPH and Sapna Syngal, MD, MPH, Boston, Massachusetts
Diagnostic Approach and Management of Lynch Syndrome by the American Cancer Society
INSIGHT - International Society for Gastrointestinal Hereditary Tumours - International organization that performs research, educates professionals and maintains databases on hereditary gastrointestinal conditions.
Hereditary Non-Polyposis Colon Cancer (Excellent Resource) by Dr. Steve Gruber and Wendy Kohlman, MS, Cancer Genetics Clinic, University of Michigan, Ann Arbor, Michigan
NCCN Guidelines (See Page 8 for Lynch syndrome)
Value of MLH1 and MSH2 In the Appearance of Muir-Torre Syndrome Phenotype in HNPCC Patients Presenting Sebaceous Gland Tumors or Keratoacanthomas; http://www.nature.com/jid/journal/v126/n10/full/5700475a.html Giovanni Ponti, Lorena Losi, Monica Pedroni, Emanuela Lucci-Cordisco, Carmela di Gregorio, Giovanni Pelicani and Stephania Seidenari,
- 1Department of Internal Medicine, Division of Dermatology, University of Modena and Reggio Emilia, Modena, Italy
- 2Department of Pathology, University of Modena and Reggio Emilia, Modena, Italy
- 3Department of Internal Medicine, Division of Internal Medicine, University of Modena and Reggio Emilia, Modena, Italy
- 4Department of Clinical Pathophysiology, Section of Medical Genetics, University of Florence, Firenze, Italy
- 5Division of Pathology, Carpi General Hospital, Carpi, Modena, Italy
Journal of Investigative Dermatology (2006) 126, 2302–2307. doi:10.1038/sj.jid.5700475; published online 6 July 2006
For More Information, Publications and Resources, visit the LSI Library by clicking the key on the main menu.
Modified 1/13/2013
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DIAGNOSTIC GUIDELINES
Amsterdam Criteria I for HNPCC
The following must be met in order to make a diagnosis of Lynch syndrome:
- Three affected relatives with verified colorectal cancer
- One is a first-degree relative of the other two
- Two successive generations affected
- One of the relatives with colorectal cancer diagnosed under age fifty
- Familial Adenamomatus Polyposis (FAP) should be ruled out.
Amsterdam Criteria II for HNPCC
The following must be met in order to make a diagnosis of Lynch syndrome:
- Three affected relatives with an HNPCC-associated cancer
- One is a first-degree relative of the other two
- Two successive generations affected
- One of the relatives with HNPCC-associated cancer diagnosed under age fifty
- Familial Adenamomatus Polyposis (FAP) should be ruled out.
Approximately 50% of those meeting the Amsterdam II criteria will have Lynch syndrome.
Revised Bethesda Guidelines - testing of tumors for microsatellite instability (MSI)
Preliminary MSI testing of tumors should occur in the following situations:
- Colorectal cancer diagnosed in individuals under the age of 50
- Presence of synchronous, metachronous colorectal, or other HNPCC-associated tumors, regardless of age
- Colorectal cancer with the MSI-H histology diagnosed in a patient <60 years of age
- Colorectal cancer diagnosed in a patient with one or more first-degree relatives with an HNPCC-related tumor, and one of the cancers being diagnosed <age 50 years
- Colorectal cancer diagnosed in two or more first-degree or second-degree relatives with HNPCC-related tumors, regardless of age
† MSI-H = high microsatellite instability in tumors refers to changes in two or more of the five NCI-recommended panels of microsatellite markers. MSI-L = low microsatellite instability in tumors refers to changes in only one of the five NCI-recommended panels of microsatellite markers.
Hereditary Nonpolyposis Colorectal Cancer (HNPCC)-related tumors include colorectal, endometrial, stomach, ovarian, pancreas, bladder, ureter and renal pelvis, biliary tract, brain (usually glioblastoma as seen in Turcot Syndrome), prostate, sebaceous gland adenomas and keratoacanthomas in Muir-Torre syndrome, and carcinoma of the small bowel.
Breast cancer has been identified as an integral component of LS based upon mismatch repair germline mutation factors in breast cancer tissues from family members who are not only at high risk, but, moreover, who had Lynch syndrome cancers, such as involving the colorectum. Breast cancer is exceedingly common in the population and, therein, its occurence in Lynch syndrome families could be due to chance, but importantly, a subset will likely be integrally related to a germline mismatch repair Lynch syndrome mutation is some LS families. Therefore, it would be prudent to mount a screening and management program for Lynch syndrome in those families where breast cancer is believed to be an integral lesion.
Guidelines: Guidelines For The Clinical Management of Lynch Syndrome, Vasen, et. al. 2007
NCCN Guidelines Have Been Revised 11/2011 for Lynch Syndrome HNPCC Cancers
EGAPP Recommendations for Preliminary Screening And Genetic Testing
American Society of Breast Surgeon Guidelines
American Society of Clinical Oncologists Guidelines
Society of Gynecological Oncologists Statement on Prophylactic Surgery
AMA Activity For Medical Professionals To Identify High Risk Individuals
National Society of Genetic Counselors
Reviewed 7/19/2012
"If you don't ask the right questions, you do not get the right answers. A question asked in the right way often points to its own answer. Asking questions is the A-B-C of diagnosis. Only the inquiring mind solves problems.
-Edward Hodnett (1841-1920)
PROFESSIONAL TOOLS
Diagnostic Identification Tools: Essential and effective tools available to medical professionals to calculate the risk for Lynch syndrome.
PREMM Prediction Model for MLH1 or MSH2 - An easy qustionaire clinical prediction designed to determine the clinical probability of an individual carrying a mutation of the basic Lynch cancers.
MMR Pro- This assessment device developed by Johns Hopkins researchers allows medical health professionals and families to make decisions about cancer prevention screenings and calculates the risk of an individual carrying a gene defect. It alleviates the time necessary to assess a family history and is stated to accurately identify more at risk individuals. Download page and Tool Information.
Reviewed 1/31/2011
RECOMMENDED SCREENING
Colonoscopy: Annually, beginning at age 20-25, or ten years younger than the earliest age of diagnosis in the family, whichever comes first.
Endometrial Sampling: Annually, beginning between ages 30-35
CA-125: For Ovarian Cancer
Transvaginal Ultrasound: For Endometrial and Ovarian Cancer: Annually beginning ages 30-35
Ultrasonography With Cytology: Annually, beginning at age 25-35
Gastroscopy: Annually for individuals with family history of Lynch gastric cancers.
Examination and Review: Family History Review, Discussion of LS - Annually
Dermatological Examination: Including Muir-Torre lesions characterized including, but not all inclusive of sebaceous adenomas, sebaceous epithelioma, basal cell epithelioma with sebaceous differentiation, sebaceous carcinoma and squamous cell cancer (keratoacanthoma type.)
Colon Resection: For individuals with active colon cancer that cannot be removed by colonoscopy. Subtotal colectomy favored with preferences of patient actively elicited. Consider more extensive colectomy for patients with a strong family history of colon cancer or young age. (<50) NCCN 2.2012
Full Abdominal Hysterectomy and Bilateral Salpingo Oopherectomy: Discuss as an option after childbearing years to deter the high risk of gynecological cancers.
Any Other Screening As Deemed Appropriate By the Physician:
Breast cancer has been identified as an integral component of LS based upon mismatch repair germline mutation factors in breast cancer tissues from family members who are not only at high risk, but, moreover, who had Lynch syndrome cancers, such as involving the colorectum. Breast cancer is exceedingly common in the population and, therein, its occurence in Lynch syndrome families could be due to chance, but importantly, a subset will likely be integrally related to a germline mismatch repair Lynch syndrome mutation is some LS families. Therefore, it would be prudent to mount a screening and management program for Lynch syndrome in those families where breast cancer is believed to be an integral lesion.
European studies have evidenced prostate cancer as an integral component of LS based upon mismatch repair germline mutation factors. Annual PSA screenings and prostate examinations are a prudent approach for screening of individuals with the Lynch syndrome.
Modified 11/22/2011
GENETIC COUNSELORS AND LABORATORIES:
GeneTests from the University of Washington provides a list of genetics clinics in the United States and internationally. The list can be accessed by clicking on “Clinic Directory” at the top of the GeneTests home page. Clinics can be chosen by state or country, by service, and/or by specialty. State maps can assist in locating a clinic in your area.
The National Society of Genetic Counselors offers a searchable directory of genetic counselors in the United States. Search by location, name, area of practice/specialization, and/or ZIP Code.
The National Cancer Institute provides a Cancer Genetics Services Directory, which lists professionals who provide services related to cancer genetics. You can search by type of cancer or syndrome, location, and/or provider name.
Reviewed 2/14/2011
LYNCH SYNDROME MUTATED GENES
Lynch syndrome cancers are caused by mutations in seven mismatch repair genes, specifically:
MSH2 2p16 chromosome 45-50%
MLH1 3p22.3/A> chromosome 20%
MSH6 2p16 chromosome 10%
PMS2 7P22.1 chromosome 1%
PMS1 2Q32.2 chromosome Rare
MSH3 5q14.1 chromosome Rare
EXO1 1q1q43 chromosome Rare
Other Genes Not Yet Discovered 20-25% prev
IT'S JUST THE TIP OF THE ICEBERG
Approximately ten percent (10%) of all cancers are hereditary. Many more are familial and we have most likely only touched the tip of the iceberg in respect to hereditary and familial cancers.
The field of genetics is pioneering and modern medical technology changes daily. What we do know, today, is with early detection and a good screening management program, coupled with prophylactic treatment, many affected by genetic defects, resulting in a high predisposition to cancer, can be saved as a number of the cancers are preventable and treatable before becoming life threatening.
Li Fraumeini Syndrome - Breast cancer before the age of 50, soft tissue sarcoma, osteosarcoma, brain tumors, lung cancer, adrenal gland cancer, leukemia and other cancers. Genetic defect in the TP-53 gene
Hereditary Breast and Ovarian Cancer Syndrome - HBOC High lifetime risk of breast cancer and of ovarian cancers. Prostate cancer in men.
Cowden Syndrome - Also known as PTEN, Creates a 10% risk to thyroid and a higher than average risk to breast and uterine cancers. It hasn't been extensively studied...
Familial Adenomatous Polyposis (FAP) or Gradner's Syndrome is a colon cancer predisposition syndrome in which hundreds to thousands of precancerous colon polyps (called adenomas) develop throughout the gastrointestinal tract (mostly in the colon and rectum but also in the stomach and small intestine). Attenuated FAP (AFAP) is a milder form of FAP and is associated with increased risk for colon cancer but fewer number of colon polyps. Gardner's Syndrome is associated with the typical number of polyps as in FAP, but also osteomas (benign tumors of the bone) and soft tissue tumors (called desmoids). A second variant, called Turcot Syndrome, is associated with certain brain tumors (different than in HNPCC-Lynch Syndrome). All forms of FAP are associated with mutations in the APC gene.
Von Hippel-Lindau Von Hippel-Lindau Disease (VHL) is a multisystem disorder characterized by abnormal growth of blood vessels (called hemangioblastomas or angiomas). Hemagioblastomas may develop in the retina, certain areas of the brain, the spinal cord and other parts of the nervous system. Other types of tumors can develop in the adrenal gland, kidney and pancreas. Individuals with VHL also have a higher risk to develop certain types of cancer, especially kidney cancer. Nearly all individuals with VHL are found to have mutations in the VHL gene.
Multiple Endocrine Neoplasias Multiple endocrine neoplasia (MEN) syndromes received their name because they predispose people to develop tumors of the endocrine glands. The endocrine system is comprised of glands that secrete hormones into the bloodstream that control numerous processes within the body. The endocrine system is instrumental in regulating mood, growth and development and metabolism, as well as sexual function and reproductive processes.
The major glands of the endocrine system affected by the MEN syndromes are the pituitary, thyroid, parathyroids, adrenals and pancreas. Currently, there are two distinct MEN syndromes: MEN1 and MEN2. In some ways, the two syndromes are similar, but there are important differences.