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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.
     Simply follow the links on the top right to review the basic steps toward diagnosis of the
Lynch syndrome.

 

                                                                            INTRODUCTION

 

    Lynch syndrome is part of a syndrome known as hereditary nonpolyposis colorectal cancer (HNPCC).  This syndrome includes individuals individuals having Familial Colorectal Cancer Type X, who display no evidence of DNA mismatch repair gene deficiency as well as those who have Lynch syndrome, which is indicated by a defect in mismatch repair genes.

     Approximately 10% of all cancers are hereditary.  Thirty five percent (35%) of colorectal cancers have been stated to be the result of a familial or hereditary condition.  

     The American Cancer Society reports about 145,000 people per year contract colorectal cancer and studies conducted by the James Cancer Center at Ohio State University indicate one in every 35 of those persons are affected with  Lynch syndrome.  

     Geneticists predict approximately 800,000 individuals within the United States, alone, are affected by Lynch syndrome, however it is believed less than 5% of that number have been diagnosed.  It is thought one in every 440 to 550 persons is affected by Lynch syndrome.  

      Relying upon these numbers, it can be reasonably assumed each physician whose practice provides care for 3,000 to 4,000 persons, has five to ten patients affected by Lynch syndrome, and each patient has an average of three to five direct family members and most likely over a dozen second degree family members affected.

      The only way to diagnose these patients is either by taking a family history, to assess risk and arrange for the genetic testing of those patients, or when those patients present with colorectal and endometrial tumors, arrange for pathological testing of those tumors for the characteristics of Lynch syndrome.

  •  

The only true form of diagnosis of Lynch syndrome is through genetic testing. During the process, DNA is sequenced seeking out defects in four primary mismatch repair genes, MLH1, MSH2, MSH6, PMS2 as well as within another gene, TACSTD1 ( Epcam) which eits to the right or to the front of the MSH2 gene.  Deletions in the EPCAM gene have been found to silence or turn off the MSH2 gene and in doing so, predisposes the individual to cancers of the Lynch syndrome.

  

LYNCH CANCERS LIFETIME RISKS (Source NCCN Guidelines 1.2013)

 

  •    MLH1-MSH2 1,2MSH62 PMS2 3
    CancerGen Pop1 RiskAvg Age RiskAvg Age RiskAvg Age
    --------------------------- ---------------- ------------------- ---------------------
    Colon5.50% 40%-40%44-81 yrs 10%-22%54 yrs 15%-20%51-66 yrs
    Endometrium2.70% 25%-60%48-62 yrs 16%-28%55 yrs 15%               49 yrs
    Stomach<1% 1%-13%56 yrs <3%63 yrs 6%*70-73 yrs
    Ovaries1.60% 4%-24%42.5 yrs 1%-11%46 yrs 6%*42 yrs
    Hepatobiliary Tract<1% 1.4%-4%50-57 yrs UnkUnk 6%*Unknown
    Urinary Tract<1% 1%-4%54-60 yrs 

    1%               

    65 yrs 6%*Unknown
    Small Bowel<1% 3%-8%47-49 yrs Unk54 yrs 6%*59 yrs
    Brain/CNS<1% 1%-3%50 yrs UnkUnk 6%*45 yrs
    Sebaceous Neoplasms<1% 1%-9%Unk UnkUnk UnknownUnknown
    Pancreas<1% 1%-6%Unk 1%-6%Unk UnknownUnknown

 

 

1. Kohlman, W Gruber, SB2012 www.genetests.org 
1,2 Bonatel et al Jama 2011    
3 Sentel, et alGastroentrology 2008  
4 Kastrinos et al Jama 2009    

* Starred Cancers combined = 6% Risk.

 

     More detailed information on the diagnosis and management of Lynch syndrome is below.  

 

The Basics of Identification, Diagnosis and Management of Lynch Syndrome

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

     

Is Breast Cancer A Part of the Lynch Syndrome?

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.

 

What Is The Cost Effectiveness Of Genetic Testing?

 

*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

LSI recommends a two pronged approach toward identifying those with the Lynch syndrome to include 

NCCN Guidelines of January, 2014 recommend all patients who meet a five percent or greter risk threshold for Lynch syndrome are appropriate for testing. (PREMM Model), a recommendation against sequential testing for the five Lynch syndrome genes in lieu of panel testing, and individuals with cancer can proceed directly to sequenced teseting without a complicated tissue screening algorithm.

 

Modified 3/7/2014

 


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:

 

  1.  Autosomal dominant inheritance pattern
  2.  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)
  3. Proximal (right sided) colonic cancer predilection (70%-85% of colorectal cancers in Lynch syndrome are proximal to the splenic flexure)
  4. Accelerated carcinogenesis (tiny adenomas can develop carcinoma within 2-3 years in Lynch syndrome v. 8-10 years in the general population)
  5.  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%
  6. Increased risk of malignant disease at certain extracolonic sites
  7.  Pathology of colorectal cancer is more often poorly differentiated, with an excess of mucoid and signet cell features, a
  8.  Crohn-like reaction and an excess of infiltrating lymphocites within the tumor
  9.  Increased survival from colorectal cancer
  10. Penetrance in individual families is dependent upon the specific mutation and perhaps other factors.

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.

 

To learn more about Lynch syndrome and the specific risks by mutation, visit the LSI Library.  The key is on the left of this page.

 

Modified 4/12/2014

 


 

 

 

"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 Update  Henry 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

 

Endometrial and Ovarian Cancer Screening For Women With the Lynch Syndrome

 

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 

 

Revised Guidelines for the Clinical Management of Lynch Syndrome (HNPCC) by a Group of European Experts (Mallorca Group)

 

 

Modified 1/25/2014

 


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DIAGNOSTIC GUIDELINES

 

Amsterdam Criteria I for HNPCC  (Also known as the 3-2-1 Rule)

The following must be met in order to make a diagnosis of Lynch syndrome:

 

  • 3. Three affected relatives with verified colorectal cancer- One is a first-degree relative of the other two
  • 2. Two successive generations affected
  • 1. One of the relatives with colorectal cancer diagnosed under age fifty
  •  
  • Familial Adenamomatus Polyposis (FAP) should be ruled out.

 

 

Amsterdam Criteria II for Lynch Syndrome  (Practiced Today)

The following must be met in order to make a diagnosis of Lynch syndrome:

 

  • 3. Three affected relatives with an Lynch syndrome-associated cancer -One is a first-degree relative of the other two
  • 2. Two successive generations affected
  • 3. One of the relatives with Lynch syndrome-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 all of

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
  • 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.

 

Diagnostic Codes For Lynch Syndrome  (Be advised Tri-Care has eliminated all codes, at this time, and is not furnishing genetic testing.  LSI is monitoring the situation and addressing it.)

 

Guidelines: Guidelines For The Clinical Management of Lynch Syndrome, Vasen, et. al. 2007

NCCN Guidelines Have Been Revised 1/2014  - Are Listed Under NCCN Guidelines, Version 1.2014 Updates, Genetic Familial High Risk Assessment: Colorectal  

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

Revised Guidelines For the Clinical Management of Lynch Syndrome by a Group of European Experts (Mallorca Group)

 

 

Reviewed 3/10/2014

 

 

 

 

 


 

 

 

 

"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.  These tools are recommended by NCCN Guidelines 1/2014.  "Consider testing individuals with >5% risk of LS on any mutation prediction model MMR Pro, PREMM 1,2,6 MMR Predict."

 

PREMM Prediction Model for MLH1, MSH2 and MSH6 - 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. Other tools for genetic risk are also available upon this page.

 

Reviewed 4/10/2014

 


 

 

RECOMMENDED SCREENING  (European Screening Guidelines To Be Added Soon)

 

Colonoscopy: Annually, beginning at age 20-25, or ten years younger than the earliest age of diagnosis in the family, whichever comes first for those with MLH1 and hMSH2 mutations.  For MSH6 and PMS2 patients, NCCN guidelines recommend colonoscopy testing beginning at the age of 25-30 or 2-5 years prior to the youngest age of presentation of colorection cancer in the family if diagnosed under the age of 30, and repeat every one to two years.  

European Guidelines recommend every 1-2 years for persons with all affected faulty genes.

NCCN does not provide management guidelines for the extracolonic cancers of those with MSH-6.  They advise prophylactic hysterectomy and oopherectomy following childbearing years.

NCCN Guidelines reflects:  There are data to suggest that aspirin may decrease the risk of colon cancer in LS, however, at this time, the data are not sufficiently robust to make a recommendation for its standard use.

 

Endometrial and Ovarian Cancer Screening:

NCCN Guidelines reflect "Prophylactic hysterectomy and bilateral oopherectomy, (BSO) is a risk reducing option that should be considered by women who have completed childbearing;

Patients must be aware that dysfunctional uterine bleeding warrants evaluation;

There is no clear evidence to support screening for endometrial cancer for LS.  However annual endometrial sampling is an option.

Where there may be circumstances in which clinicians find screening helpful, data do not support routine ovarian screening for LS.  Transvaginal ultrasound for ovarian and endometrial cancer has not shown to be sufficiently sensitive or specific as to support a positive recommendation, but may be considered at the clinician's discretion." 

Serum CA-125 is an additional ovarian cancer test with caveats similar to transvaginal ultrasound.

 

Extra Colonic Cancers for MLH6 and PMS2:  The risk of other LS cancers is reportedly low, however due to limited data no screening recommendation is possible at this time.

 

Extra Colonic Cancer Screenings for MLH1 and MSH2

 

Gastric and Small Bowel Cancer:  "There is no clear evidence to support screening for gastric, duodenal, and small bowel cancer for LS.  Selected individuals or families of those of Asian descent  may consider EGD with extended duodenoscopy (to distal duodenum or into the jejunum) every 3-5 years beginning at 30-35 years.

 

Urothelial Cancer:  Consider annual urinalysis starting at 25-30 years.

 

Central Nervous System Cancer:  Annual physical/neuological examination starting at 25-30 years, no additional screening recommendations have been made.

 

Pancreatic Cancer:  Despite data indicating an increased risk for pancreatic cancer, no effective screening techniques have been identified; therefore, no screening recommendation is possible at this time;

 

Breast Cancer:  There have been suggestions there is an increased risk for breast cancer in LS patients, however due to limited data, no screening recommendation is possible at this time.   

 

Prostate Cancer:

European studies have evidenced prostate cancers as an integral component of Lynch syndrome, though the experts believe there is need for more evidence.  LSI recommends annual PSA screenings and prostate exams are a prudent choice for the screening of individuals with the Lynch syndrome.

European Guidelines:  "Until more studies are available, the Mallorca group does not recommend surveillance for prostate cancer in  LS families outside of appropriate research studies (see http://impact-study.co.uk)."

 LSI Recommendation:  Examination and Review: Family History Review, Discussion of LS - Annually

 

LSI Recommendation:   Dermatological Examination for those with a family history of sebaceous or the following cancers of Muir Torre if a family history exists, or a personal history of sebaceous or other tumors as noted below: 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.)

 

LSI Recommendation:  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. 

 

LSI Recommendation: Any Other Screening As Deemed Appropriate By the Physician:

 

LSI Recommendation:  Breast Cancer:

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.

 

Modified 4/10/2014

 

 


 

 

 

DATABASES 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. (Currently Genetests is down, however is expected to return)

 

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.

 

The NCBI offers a database which lists labs and information on the specific gene mutations.

 

InSight, an organization of the top gastro cancer researchers in the world, maintains a database on the mutations and lists some of the cancers of the specific mutations.

 

The Memorial University of Newfoundland has a terrific database of specific mutations and articles directly addressing those mutations.

 

 

 

Reviewed 6/7/2013


 

 

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%

 

EPCAM


PMS1 2Q32.2 chromosome Rare


MSH3 5q14.1 chromosome Rare


EXO1 1q1q43 chromosome Rare

 

Other Genes Not Yet Discovered 20-25% prev

 

 


 

 

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IT'S JUST THE TIP OF THE ICEBERG

 

Approximately ten percent (10%) of all cancers are hereditary. It is estimated many more are familial and 35% of all colorectal cancer is hereditary and/or familial. These patients need to be identified and receive more extensive cancer screenings. FIT testing (testing for blood in the stool) is not effective for them. 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 Gardner'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.

Reviewed: 4/10/2014

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

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