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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

For Professionals

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, where 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 providing information on the diagnosis of the Lynch syndrome.

 

 

Modified 5/18/2014

 


Photo Courtesy of the National Institute of Health

 

Characteristics of Lynch Syndrome

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

 

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)

 

·        

 

 

 

MLH1-MSH2

1,2

MSH6

2

 

PMS2

3

Cancer

Gen Pop1

 

Risk

Avg Age

 

Risk

Avg Age

 

Risk

Avg Age

---------------

------------

 

-----------

-----

 

--------------

-----

 

----------

-----------

Colon

5.50%

 

40%-40%

44-81 yrs

 

10%-22%

54 yrs

 

15%-20%

51-66 yrs

Endometrium

2.70%

 

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

Ovaries

1.60%

 

4%-24%

42.5 yrs

 

1%-11%

46 yrs

 

6%*

42 yrs

Hepatobiliary Tract

<1%

 

1.4%-4%

50-57 yrs

 

Unk

Unk

 

6%*

Unknown

Urinary Tract

<1%

 

1%-4%

54-60 yrs

 

1%               

65 yrs

 

6%*

Unknown

Small Bowel

<1%

 

3%-8%

47-49 yrs

 

Unk

54 yrs

 

6%*

59 yrs

Brain/CNS

<1%

 

1%-3%

50 yrs

 

Unk

Unk

 

6%*

45 yrs

Sebaceous Neoplasms

<1%

 

1%-9%

Unk

 

Unk

Unk

 

Unknown

Unknown

Pancreas4

<1%

 

1%-6%

Unk

 

1%-6%

Unk

 

Unknown

Unknown

 

 

1. Kohlman, W Gruber, SB

2012

 

www.genetests.org

 

1,2 Bonatel et al

Jama 2011

 

 

 

 

3 Sentel, et al

Gastroentrology 2008

 

 

4 Kastrinos et al

Jama 2009

 

 

 

 

* Starred Cancers combined = 6% Risk.

 

 

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

 

 

Other characteristics include:

 

  • Brain/CNS (1%-3% )

Sebaceous adenomas, sebaceous carcinomas and multiple keratoacanthomas in Muir-Torre syndrome (variant of Lynch syndrome)

Subset of Breast Cancer

  • 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

 

* 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 5/18/2014

 


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Diagnostic Guidelines and Tools

 

DIAGNOSTIC GUIDELINES AND TOOLS

 

 ASSESSING FAMILY HISTORY FOR DIRECT REFERRAL FOR GENETIC SEQUENCE TESTING

 

NCCN Guidelines dramatically increased the guidelines for genetic testing of Lynch syndrome in 2014.  These changes include:

  1. The accepted use of diagnostic tools providing a quick resource to determine whether it is appropriate to prescribe genetic testing for patients who meet a five percent or greater risk threshold for Lynch syndrome have been approved by NCCN.  These include: 
  •          PREMM 1,2,6  (A very quick, 2 minute family history questionaire prediction tool to determine the clinical probability of an individual
  •          carrying a mutation of the basic Lynch cancers of MLH1, MSH2 and MSH6)
  •          MMR Pro - This assessment device developed by Johns Hopkins researchers allows medical health professionals and families to
  •          make decisions about cancer prevention screenings.  Requires download.
  •  
  •          Both tools calculates the risk of an indvidual carrying a gene defect and alleviates time necessary to assess family history and is stated
  •          to more accurately identify at risk individuals.  Download page and tool information.

2. A recommendation for panel testing for the five Lynch syndrome genes instead of sequential testing; and;

3. It acknowledged individuals with cancer may directly proceed to genetic testing without having to undergo a complicated and time intensive tissue screening algorithm.

 

 

"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)

 

Some insurance companies still insist upon the patient meeting the older standards of criteria.  It is important to ask the right questions. Most patients are not familiar with the organs of the body or medical terms determining where in the specific organ the cancer occurred.  However, they may recall some terminology, such as, "She had a whipple." or "I think it was between the kidneys and the bladder where it happened."  So, it is important to ask about age and the location of the tumors, trying to decipher where it could have occurred.  Most patients will stop the process of diagnosis if they are required to present their family's medical records.      

 

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.

 

Assess family history and determine whether or not to refer to a genetic counselor or perform the test.  In some areas, it is taking up to ten months to obtain the services of a genetic counselor, however, some insurance companies will not pay for the genetic test unless genetic counseling services are provided.  Be sure and check with the insurance company to determine their policy.

Before taking the test, be sure and provide informed consent to the patient.  

Testing can be provided through most commercial laboratories.  Make certain the laboratory is able to provide a comprehensive test for each of the genes.  Some do not.  Finally, make sure the lab is CLIA approved and positive tests are run with a second blind test to confirm the results.Be sure and ask the current delay times in providing results.  Some labs are taking up to six to twelve weeks for results to be returned.

 

                                                                             MOLECULAR TESTING OF TUMORS

 

The second prong in determining whether or not the patient meets the criteria for diagnostic testing is molecular testing of all colorectal testing of tumors to determine if characteristics of Lynch syndrome exists.  This is commonly referred to by the genetics community as "universal testing."

LSI encourages all colorectal and endometrial cancer tumors be tested for characteristics of Lynch syndrome.  This does not provide a large number of diagnoses annually, however, may identify families which do not meet the family history criteria. This is important as only approximately 50% meet Amsterdam guideline criteria.  

Considering approximately 149,00 cases of colorectal cancer occur annually and 3% may be a result of Lynch syndrome, the maximum of only 4,470 persons tested as a result of colorectal cancer each year hardly puts a dent into the need to diagnose the approximate 700,000 persons in the U.S. alone, believed to be at risk for Lynch syndrome. The likely number of the effect of universal testing resulting in genetic testing is approximately fifty percent or 2,270 persons per year, which would result in approximately 11,350 diagnosed annually if four other family members would consent to genetic testing, as well.

Asking each patient their family history of cancer and aggressively molecularly testing each tumor will significantly reduce the above number of individuals yet to be diagnosed.  The answer and resolution of protecting families with hereditary cancers rests with our physicians to either test our families or refer those who meet the criteria for testing to genetic counselors.

Below is the Bethesda criteria to determine if this testing is necessary as a precursor test for genetic sequencing.  Some insurance companies may require it, so be certain to contact the insurance companies first for their guidelines and obtain approval for genetic testing prior to providing the test.  The input of a genetic counselor is beneficial when performing molecular testing.

 

 

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, one cancer 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 (Codes Are In The Process Of Change)

 

NCCN Guidelines Have Been Revised 2014 for Lynch Syndrome HNPCC Cancers  Sign Up and Log In

Revised European Guidelines June 2013

EGAPP Recommendations for Preliminary Screening And Genetic Testing

American Society of Breast Surgeon Guidelines

American Society of Clinical Oncologists Guidelines

ACMG Guidelines 9/17/2013

Society of Gynecological Oncologists Statement on Prophylactic Surgery

AMA Activity For Medical Professionals To Identify High Risk Individuals

National Society of Genetic Counselors

 

 

Reviewed 5/18/2014

 

 

 


 

Screening and Management

RECOMMENDED SCREENING AND MANAGEMENT

 

This year, differing from that of last year, NCCN Guidelines included the same screening protocol for all Lynch syndrome patients, regardless of mutation. The NCCN protocol is a minimum standard.  As noted, physicians may add other screenings as they feel necessary.  The guidelines are basic, due to limited research into the cancers and care of those with Lynch syndrome.

 

COLONOSCOPY: 

Annually, beginning at age 20-25, or two to five years younger than the earliest age of diagnosis in the family, whichever comes first.

 (NCCN ) state colonoscopy to be administered  two to five years prior to the earliest age of diagnosis in the family, and to repeat every 1-2 years.

There is data to suggest 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.

 

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 Sampling: Annually, beginning between ages 30-35

NCCN states, "There is no clear evidence to support screening for endometrial cancer for LS.  However annual office endometrial sampling may be an option."  Hysterectomy and bilateral salpingo-oopherectomy is a risk reducing option by women who have completed childbirth.

 

CA-125: For Ovarian Cancer

NCCN Guidelines state, "However while there may be circumstances where clinicians may find screening helpful, data do not support routine ovarian screening for LS. 

 

Transvaginal Ultrasound/Endometrial Biopsy : For Endometrial and Ovarian Cancer: Annually beginning ages 30-35

NCCN Guidelines state, "Transvaginal ultrasound for ovarian and endometrial cancer has not been shown to be sufficiently sensitive or specific as to support a reommendation, but may be consideration at the Clinician's discretion.  Serum Ovarian 125 is an additional screening test with caveats similar to transvaginal ultrasound." 

 

Ultrasonography With Cytology: Annually, beginning at age 25-35

NCCN Guidelines state, "Consider urinalysis starting at 25-30 years old."

 

Gastroscopy: Annually for individuals with family history of Lynch gastric cancers.

NCCN Guidelines state, "There is no clear evidence to support screening for gastric, duodenal, and small bowel cancer for LS.  Selected individuals or families or those of Asian descent may consider EGD with extended duodenoscopy (to distal duodenum or small jejunum.)"

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

NCCN did not address annual family history review or discussion of Lynch syndrome.

 

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.)

NCCN did not address skin cancers.

 

Prostate Cancer:  NCCN Guidelines did not address any screening measures.

 

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) 

 

Full Abdominal Hysterectomy and Bilateral Salpingo Oopherectomy: Discuss as an option after childbearing years to deter the high risk of gynecological cancers. (Recommended by NCCN)

 

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.

NCCN Guidelines stated,  "There have been suggestions that there has been an increased risk for breast cancer in LS, however due to limited data, no effective screening techniques have been identified, therefore, no recommendation is possible at this time." 

In respect to pancreatic cancers, NCCN Guidelines state:  "Despite data reading an increased risk for pancreatic cancer, no effective screening techniques have been identified, therefore, no screening." 

Finally, NCCN addressed CNS cancer with:  "Annual physical exam starting at 25-30 yrs; no additional screening recommendations have been made. 

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 5/18/2014

 


Databases and Laboratories

 

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.

 

 

 

 


 

alt

Specific Mutated Genes

IT'S JUST THE TIP OF THE ICEBERG

 

Approximately ten percent (10%) of all cancers are hereditary. It is estimated many more are familial. Finally, 35% of all colorectal cancer is hereditary and familial. These patients need to be identified and receive more extensive cancer screenings. FIT testing is not effective for those with familial conditions. 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: 5/18/2014

 


 

Diagnostics and Management Publications

"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

 

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 (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,

  1. 1Department of Internal Medicine, Division of Dermatology, University of Modena and Reggio Emilia, Modena, Italy
  2. 2Department of Pathology, University of Modena and Reggio Emilia, Modena, Italy
  3. 3Department of Internal Medicine, Division of Internal Medicine, University of Modena and Reggio Emilia, Modena, Italy
  4. 4Department of Clinical Pathophysiology, Section of Medical Genetics, University of Florence, Firenze, Italy
  5. 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 5/18/2014