Excerpt for Lynch Syndrome, A Simple Guide To The Condition, Diagnosis, Treatment And Related Conditions by , available in its entirety at Smashwords

Lynch Syndrome,


A


Simple


Guide


To


The Condition,

Diagnosis,

Treatment


And


Related Conditions


By


Dr Kenneth Kee


M.B.,B.S. (Singapore)

Ph.D (Healthcare Administration)


Copyright Kenneth Kee 2017 Smashwords Edition


Published by Kenneth Kee at Smashwords.com





Dedication



This book is dedicated

To my wife Dorothy

And my children

Carolyn, Grace

And Kelvin




This book describes Lynch Syndrome, Diagnosis and Treatment and Related Diseases which is seen in some of my patients in my Family Clinic.


(What You Need to Treat Lynch Syndrome)


This eBook is licensed for the personal enjoyment only. This eBook may not be re-sold or given away to other people. If you would like to share this book with another person, please purchase an additional copy for each reader.


If you’re reading this book and did not purchase it, or it was not purchased for your use only, then please return to Smashwords.com and purchase your own copy.


Thank you for respecting the hard work of this author.




Introduction


I have been writing medical articles for my blog http://kennethkee.blogspot.com (A Simple Guide to Medical Condition) for the benefit of my patients since 2007.


My purpose in writing these simple guides was for the health education of my patients.


Health Education was also my dissertation for my Ph.D (Healthcare Administration).


I then wrote an autobiolographical account of his journey as a medical student to family doctor on his other blog http://afamilydoctorstale.blogspot.com.


This autobiolographical account “A Family Doctor’s Tale” was combined with my early “A Simple Guide to Medical Conditions” into a new Wordpress Blog “A Family Doctor’s Tale” on http://kenkee481.wordpress.com.


From which many free articles from the blog was taken and put together into 800 amazon kindle books and 200 into Smashwords.com eBooks.


Some people have complained that the simple guides are too simple.


For their information they are made simple in order to educate the patients.


The later books go into more details of medical conditions.


The first chapter is always from my earlier blogs which unfortunately tends to have typos and spelling mistakes.


Since 2013, I have tried to improve my spelling and writing.


As I tried to bring you the latest information about a condition or illness by reading the latest journals both online and offline, I find that I am learning more and improving on my own medical knowledge in diagnosis and treatment for my patients.


Just by writing all these simple guides I find that I have learned a lot from your reviews (good or bad), criticism and advice.


I am sorry for the repetitions in these simple guides as the second chapters onwards have new information as compared to my first chapter taken from my blog.


I also find repetition definitely help me and maybe some readers to remember the facts in the books more easily.


I apologize if these repetitions are irritating to some readers.



Chapter 1


Lynch syndrome


What is Lynch syndrome?


Lynch syndrome is an inherited medical disorder that confers a person a higher risk of cancers of the digestive tract, gynecologic tract, and other organs.


In Singapore Lynch syndrome has an estimated incidence of 1 in 300 in women and 1 in 500 in the general population.


People who have Lynch syndrome have a considerably higher danger of forming:

1. Colorectal cancer (CRC),

2. Endometrial (uterine) cancer,

3. Gastric (stomach) cancer,

4. Ovarian cancer,

5. Small bowel (small intestinal) cancer,

6. Pancreatic cancer,

7. Urinary tract cancer (bladder or ureter cancer),

8. Kidney cancer,

9. Bile duct cancer,

10. Certain skin tumors (sebaceous tumors of the skin or sebaceous adenomas), and

11. Brain tumors.


People with Lynch syndrome may also be at slightly higher risk of:

1. Breast cancer and

2. Prostate cancer.


The old term for Lynch syndrome was “hereditary non-polyposis colorectal cancer” (HNPCC).


There is no likelihood toward polyp formation and hence the name HNPCC.


It is the most frequent genetic syndrome linked with a higher vulnerability to Colon cancer.


Typical Features of Lynch syndrome


Patients with Lynch syndrome have a 60%-80% risk for Colorectal Cancer (CRC), as well as a higher risk for cancers, most conspicuously endometrial cancer


Endometrial cancer is the second most frequent malignancy in Lynch syndrome with a lifetime danger between 40% and 60%, often happening before Colorectal Cancer (CRC) in females.


Lynch syndrome is also linked with a higher relative danger for cancer in the stomach, ovary, small bowel, pancreas, ureter, renal pelvis, biliary tract, and brain


One of the major features (phenotype) of Lynch syndrome carriers is that cancer often forms at an earlier age than in the normal population


The average age of start for colorectal cancer and endometrial cancer for patients with Lynch syndrome is about 44 and 48 years, respectively, compared to 65 years for colorectal and 60 years for endometrial sporadic carcinomas in the normal population


The incidence of synchronous (multiple primary cancers happening simultaneously) and metachronous (multiple cancers happening at intervals) CRCs happen in up to 50% of individuals with Lynch syndrome, compared to less than 20% risk in patients with sporadic CRC


Also, CRC in Lynch syndrome patients often happens in the right or proximal colon in contrast to predominance of sigmoid or distal carcinomas in sporadic disease


Pathologic features of Lynch syndrome-linked CRC often are:

1. Tumor-infiltrating lymphocytes,

2. Crohn's like reactions,

3. Signet ring cells, and

4. Mucinous adenocarcinoma.


These pathologic features of Lynch syndrome are less normally found in sporadic CRC and often are red flags for Lynch syndrome


There is a contentious link between Lynch syndrome and breast cancer.


Evidence showed 50% of breast cancers occurring in Lynch syndrome mutation carriers had a loss of mismatch repair proteins


Lynch syndrome is a probable diagnosis when multiple people on the same side of the family diagnosed with colorectal cancer.


Also, cancer tends more likely to be diagnosed at a young age.


The average age for colorectal cancer to be diagnosed in a person with Lynch syndrome is 45 in contrast with the average age of 72 for a new diagnosis of colorectal cancer in the general population.


In Lynch syndrome, colorectal cancer is rather more likely to form on the right side of the colon.


ASCO advises tumor testing for Lynch syndrome in all patients with colorectal cancer.


As another option, tumor testing is advised for people who develop colorectal cancer in patients younger than 70 or those who are older than 70 and have any of the revised Bethesda guidelines.


There is also a higher danger of a person with Lynch syndrome to form multiple cancers during his or her lifetime


What are the causes of Lynch syndrome?


Cause:


Lynch syndrome is a genetic disorder, indicating that the cancer risk can be passed from generation to generation in a family.


Several genes have been identified that are linked to Lynch syndrome.


They are MLH1, MSH2, MSH6, PMS2, and EPCAM.


A mutation (modification) in any of these genes causes the person to have a higher lifetime danger of forming colorectal cancer and other related cancers.


Women also have a higher risk of forming endometrial and ovarian cancers.


Most mutations that cause Lynch syndrome are present in the MLH1 or MSH2 genes.


Not all families that seem to have Lynch syndrome will have mutations in MLH1, MSH2, MSH6, PMS2, or EPCAM.


Some people will have alterations in these genes that are not passed on in the family, but are linked to the increasing age progression and other causes that are not well known.


If a tumor is discovered to have changes in these genes, the person’s blood will also be tested for that abnormal gene.


If the blood and tumor both have the changed gene, the disorder is inherited rather than acquired, meaning other family members could be involved; testing is required.


How is Lynch syndrome inherited?


Normally, every cell has two copies of each gene: one inherited from the mother and one inherited from the father.


Lynch syndrome stays on an autosomal dominant inheritance pattern, in which a mutation needs to happen in only one copy of the gene for the person to have a higher risk of getting that disease.


This indicates that a parent with a gene mutation may transmit along a copy of their normal gene or a copy of the gene with the mutation.


Thus, a child who has a parent with a mutation has a 50% chance of getting that mutation.


A brother, sister, or parent of a person who has a mutation also has a 50% chance of getting the same mutation.


There are alternatives for couples who wish to have a child when they know that one of them has a gene mutation that raises the danger for this hereditary cancer syndrome.


Pre-implantation genetic diagnosis (PGD) is a medical test done in conjunction with in-vitro fertilization (IVF).


It permits people who carry a specific known genetic mutation to have children who do not have the mutation.


A woman’s eggs are taken and fertilized in a laboratory.


When the embryos reach a certain size, one cell is taken out and is tested for the hereditary disorder in question.


The parents can then choose to implant embryos that do not have the mutation.


PGD has been in use for over ten years, and more recently has been done for several hereditary cancer predisposition syndromes.


It is a complicated procedure with financial, physical, and emotional factors for couples to note before starting


Lynch syndrome is a genetic disorder caused by germ line mutations or alterations in any one of the four genes known as mismatch repair (MMR) genes


MMR genes are necessary to maintain the integrity of the DNA, examining for and correcting mistakes that if not repaired have the possibility for tumor formation and cancer development


The four MMR genes indicated in the Lynch syndrome are MLH1, MSH2, MSH6, and PMS2


Lynch syndrome is transmitted in a Mendelian autosomal-dominant (AD) pattern of inheritance whereby individuals with Lynch syndrome have a 50% chance of transmitting the genetic mutation to each of their offspring.


Patients with Lynch syndrome are born with a normal functioning gene (wild type allele) on one chromosome and a mutated gene on the other chromosome


In spite of the presence of a Lynch syndrome-linked gene mutation at birth (the first hit), cancer does not occur unless there is a loss of function (or acquired somatic mutation) on the remaining chromosomal gene or allele (second hit)


This acquired mutation tends to be likely because of gene or environment interaction and results in a second hit that immobilizes the remaining wild-type allele.


The second hit leads to the development of cancer due to the loss of the protective repair mechanisms of the MMR genes


The need for the second hit demonstrates why some patients with the genetic mutation might not form Lynch syndrome-linked cancers


Patients with a high risk of Lynch Syndrome should be presented with annual or biannual colonoscopies from the age of 25 years


How common is Lynch syndrome?


Most colorectal cancer is sporadic, meaning it occurs by chance with no known cause.


Lynch syndrome is responsible for about 2% to 5% of all cases of CRC (colorectal cancer).


What are the symptoms and signs of Lynch syndrome?


Symptoms:


One set of criteria used to recognize Lynch syndrome is called the revised Bethesda guidelines:


1. Developing colorectal cancer younger than age 50


2. Forming colorectal and other cancers linked with Lynch syndrome individually or together (colorectal cancer, endometrial cancer, small bowel, and ureter, or renal pelvis cancer, ovarian cancer)


3. Developing colorectal cancer with tumor features linked to Lynch syndrome at an age younger than 60


4. Colorectal cancer presence in one or more first-degree relatives who also has or has had another Lynch syndrome-linked cancer, with one of these cancers forming before age 50.


5. Colorectal cancer in two or more first- or second-degree relatives with another Lynch syndrome-related cancer.


The definition of Lynch syndrome is still developing.


A family may still have Lynch syndrome even if the revised Bethesda guidelines do not fully comply with the family history.


Consultation with a doctor who has training in genetic diseases and disorders, such as a genetic counselor or medical geneticist, is advised for people who have a family history that indicates Lynch syndrome.


There are two different forms of Lynch syndrome called Muir-Torre syndrome and Turcot syndrome.


How is Lynch syndrome diagnosed?


Diagnosis:


Lynch syndrome tends to be likely if a family history meets the revised Bethesda guidelines above.


Lynch syndrome can also be established through a blood test.


The test can detect if someone has a mutation in one of the genes linked with Lynch syndrome.


Presently testing is provided for the MLH1, MSH2, MSH6, and EPCAM genes.


The PMS2 gene is tested for in some medical trials (research studies) and cancer centers that specialize in Lynch syndrome.


Not all families with Lynch syndrome will have a mutation in one of these genes.


For patients who have a family history that indicates Lynch syndrome, screening tests can be done on tumor (cancer) tissue to help detect if Lynch syndrome is possible.


The two screening tests indicated are micro-satellite instability testing (MSI) and immuno-histo-chemistry testing (IHC).


The results of these tests can show whether more specific genetic testing should be done.


Since most colorectal cancer is sporadic, genetic testing is only advised for people who have a family history that indicates Lynch syndrome.


Testing for mutations in the Lynch syndrome genes may not be advantageous for the average person.


What is the evaluated cancer risks linked with Lynch syndrome?


General cancer risks for people with Lynch syndrome are:


1. Colorectal cancer: *Up to 80%

2. Stomach cancer: 11% to 19%

3. Hepatobiliary tract cancer (liver/bile duct): 2% to 7%

4. Urinary tract cancer: 4% to 5%

5. Small bowel cancer (intestines): 1% to 4%

6. Brain or central nervous system tumor: 1% to 3%

*The estimated lifetime risk of colorectal cancer in people with Lynch syndrome has a wide range, with 80% being the very upper limit of that range.


Colorectal cancer danger evaluations are for people with Lynch syndrome who do not have regular colonoscopy screenings.


Regular screenings with colonoscopy considerably decreases this risk.


Cancer dangers for women with Lynch syndrome are:

1. Endometrial cancer 20% to 60%

2. Ovarian cancer 9% to 12%


Lynch syndrome has been linked to higher risk of other types of cancer as well, such as pancreatic, prostate, kidney, and breast cancers.


General screening guidelines


1. Colonoscopy every 1 to 2 years, beginning between the ages of 20 to 25 or 2 to 5 years younger than the youngest age at diagnosis of CRC in the family, whichever is sooner


2. Testing and treatment for Helicobacter pylori is advised if a person has been diagnosed with Lynch syndrome


Screening for other cancers linked with Lynch syndrome may be advised depending on a person’s family history.


Screening for women is:


1. Yearly pelvic examination, transvaginal ultrasound, endometrial biopsy, from age 30 to 35


Women who do not wish to have any more children may want to think having preventive surgery to remove the uterus and ovaries.


Screening methods may change over time as new technological procedures are developed and more is known about Lynch syndrome.


It is important to talk with the doctor about suitable screening tests.


What is the treatment for Lynch Syndrome?


Surgical Care


Removal of the entire colon is the only way to completely avoid the development of colon cancer or to treat a present colon cancer.


Several different surgeries are presently present for the treatment of Lynch Syndrome.


The 3 most often performed surgeries are:


1. Subtotal colectomy with ileorectal anastomosis

2. Total colectomy with ileoanal pull-through (pouch procedure)

3. Total colectomy with ileostomy


Subtotal colectomy with ileo-rectal anastomosis and post-surgical rectal surveillance are advised when colorectal cancer forms in patients with Lynch Syndrome.


This surgery may be regarded for prevention in selected mismatch repair (MMR) gene mutation carriers.


Subtotal colectomy with ileo-rectal anastomosis is favored over segmental resection or hemicolectomy for Lynch Syndrome-linked cancers that occur proximal to the peritoneal reflection.


Even though total procto-colectomy with ileo-anal anastomosis and total procto-colectomy with ileostomy remove the need for endoscopic surveillance, these interventions are normally reserved for patients with Lynch Syndrome who manifest with rectal cancers, mainly because of concerns about post-surgical morbidity and quality of life

What is the prognosis of Lynch Syndrome?


Prognosis:


The 5-year survival rate in patients with Lynch Syndrome is evaluated to be about 60%, compared with 40-50% for sporadic cases.


Colorectal tumors that have micro-satellite instability (MSI)-positive have specific features, such as a tendency to arise in the proximal colon, lymphocytic infiltrated, and a poorly differentiated, mucinous or signet ring appearance.


Doctors have found that MSI-positive tumors are linked with better survival rates.


Based on the stage of the cancer, patients with colorectal cancer from families with a history of Lynch Syndrome have a better prognosis than patients with colorectal cancer in the general population (sporadic colon cancer), which may be enlightened by immunological factors.


Immunological studies with colon cancer have shown that tumors affect the host immune response by changing host T-cell receptors


The defective T-cell response was seen only in animals with chronic tumors, indicating that rapid tumor growth, as observed in Lynch Syndrome, may preserve immune response.


Colorectal cancer was decreased by 62% in the screened group versus the unscreened group.


The decrease was believed to be due to polypectomies in the intervention group.




Chapter 2


Causes


Hereditary non-polyposis colorectal cancer (Lynch Syndrome) is the most frequent form of hereditary colorectal cancer.


It is passed on in the family as an autosomal dominant syndrome as a result of defective mismatch repair (MMR) proteins.


Lynch Syndrome is responsible for 2-5% of all colorectal carcinomas.


Over 90% of all colorectal cancers in Lynch Syndrome patients show a high micro-satellite instability (MSI-H), which indicates at least 2 or more genes have been mutated (modified) in Lynch Syndrome families or atypical Lynch Syndrome families.


Colorectal cancer in patients with Lynch Syndrome occurs at a younger age than in the general population and is featured by:


1. A higher danger of other cancers, such as endometrial cancer and,

2. In a lesser extent, cancers of the ovary,

3. Stomach,

4. Small intestine,

5. Hepatobiliary tract,

6. Pancreas,

7. Upper urinary tract,

8. Prostrate,

9. Brain, and

10. Skin.


Lynch Syndrome is classified into:


1. Lynch syndrome I (familial colon cancer) and


2. Lynch syndrome II (HNPCC linked with other cancers of the gastrointestinal [GI] or reproductive system).


The higher cancer risk is due to inherited mutations that corrupt the self-repair capability of DNA.


The tumor testing (i.e., immuno-histo-chemistry, MSI, germ-line testing, and BRAF mutation testing), screening, and prophylactic surgery all assist to decrease the risk of death in patients with HNPCC or Lynch syndrome.


The advantages of all methods of tests mainly affect relatives with a mutation linked with HNPCC or Lynch syndrome.


The frequent application of colorectal tumor testing helps to recognize families with HNPCC or Lynch syndrome.


Colorectal tumor testing could produce considerable advantages at reasonable cost.


1. Mainly in females with a mutation linked with HNPCC or Lynch syndrome that begin regular screening and have reducing surgery.


2. The cost-effectiveness of such testing is dependent on an increased rate in relatives at danger for HNPCC or Lynch syndrome.


Pathophysiology


An inherited mutation in one of the DNA mismatch repair (MMR) genes appears to be a critical factor in Lynch Syndrome.


MMR genes normally form proteins that recognize and correct sequence mismatches that may happen during DNA replication.


In Lynch Syndrome, an abnormality that stops activation of an MMR gene leads to the collection of cell mutations and largely raises the tendency of malignant transformation and cancer.


Doctors have recognized 7 distinct MMR genes, such as:


1. hMLH1 on band 3p22 - 20%


2. hMSH2 on band 2p16 - 45-50%


3. hMSH6 on band 2p16: 10%


4. hPMS1 on band 3p32 - Rare


5. hPMS2 on band 7q22 - 1%


Other mutations are:


5. hMSH3 on band 5q14.1 - Rare


6. EXO1 on band 1q43 - Rare


Mutations of hMLH1 and hMSH2 are responsible for about 70% of MMR mutations in Lynch Syndrome.


10% affect hMSH6.



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