DOUGLAS RIEGERT JOHNSONRiegertjohnson.douglas@mayo.eduMAYO CLINIC FLORIDA

CASE DISCUSSIONS

HEREDITARY GI CANCER

SYNDROMES.

2

RESOURCESAND BACKGROUND

3

Genetics = the study of single gene disorders and genetic testing the testing of single genes.

Genomics = the study of multiple genetic disorders simultaneously and the testing of multiple genes

GENOMICS VERSUS GENETICS

BRCA1

BRCA2

ATM

BARD1*MSH2*MSH6 *MLH1

PALB2

NF1

CHEK2

CDH1TP53

RAD50

*PMS2

Genetics 2 genes $4200 12 weeks

Genomics 14 genes

$2000 ($100 out of poc)

4 weeks

Lynch syndrome associatedDNA mismatch repair genes

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GENOMIC COUNSELING AS A

SPECIALTY

Under Graduate 4 years + Post Graduate 2 years

Specialty Number

Internists 189,587

Family medicine specialists 114,000

Genomic counselors 3,200

Medical geneticists 1,509 (all time)

How do I find a genomic counselor? www.nsgc.org

Collaborative Group of the Americas on Inherited Colorectal Cancer In 1995, the Collaborative Group of the Americas on Inherited

Colorectal Cancer (CGA-ICC) was established to improve understanding of the basic science of inherited colorectal cancer and the clinical management of affected families.

The CGA focuses on families with rare forms of inherited colorectal cancer: familial adenomatous polyposis (FAP), MYH-associated polyposis, Peutz- Jeghers syndrome, juvenile polyposis, other hamartomatous polyposes, serrated polyposis, and hereditary nonpolyposis colorectal cancer (HNPCC)/Lynch syndrome.

www.polyppolyp.com - Polyposis note toolkit.

RESOURCES FOR PROVIDERS

Lynch Syndrome InternationalThe Hereditary Colon Cancer 

Foundation (FAP)Peutz Jeghers Syndrome Discussion Gro

up

PATIENTS CAN FIND SUPPORT GROUPS VALUABLE

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HEREDITARY COLON CANCER CASE

CASE FROM THE CLINIC

43 year old man presented to the ED with abdominal pain. CT showed abnormal right colon and a mass was found in the right colon on colonoscopy. No polyps were seen. The patient underwent right colon resection. Pathology was reported adenocarcinoma with lymphocytic tumor infi ltration.

The patient’s mother had a hysterectomy in her 50s for bleeding, unclear if due to endometrial cancer or not. Otherwise she has no history of cancer. Father, and a bother (45) and sister (41) are alive and well.

Which test is the most appropriate?A. Sequencing and testing for large deletions of the

APC gene.B. Tumor testing for microsatellite instability.C. Examination for peri oral pigmentation. D. Sequencing of the MSH2 gene.

CASE FROM THE CLINIC

43 year old man presented to the ED with abdominal pain. CT showed abnormal right colon and a mass was found in the right colon on colonoscopy. No polyps were seen. The patient underwent right colon resection. Pathology was reported adenocarcinoma with lymphocytic tumor infi ltration.

The patient’s mother had a hysterectomy in her 50s for bleeding. Otherwise she has no history of cancer. Father, and a bother (45) and sister (41) are alive and well.

Which test is the most appropriate?A. Sequencing and testing for large deletions of APC.

(FAP)B. Tumor testing for microsatellite instability. (Sensitive

for LS) C. Examination for peri oral pigmentation. (PJS, small

int polyp) D. Sequencing of the MSH2 gene. (Will miss mutations

in the other LS genes, MLH1, MSH6, PMS2)

Clues for Lynch syndrome

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Hereditary non polyposis colon cancer proposed by Dr. Lynch.

HNPCC no longer as cancer risks outside of the colon are also elevated in Lynch syndrome (endometrial, biliary, pancreatic, and others)

LYNCH SYNDROMEHEREDITARY NON POLYPOSIS

COLON CANCER (HNPCC)

Q: WHY IS MICRO SATELLITE INSTABILITY IMPORTANT?

A: ALMOST ALL LYNCH SYNDROME COLON AND ENDOMETRIAL CAS DEMONSTRATE MICRO SATELLITE

INSTABILITY.

So the presence of micro satellite instability is used as a sensitive (but not specific) screen for Lynch syndrome.

Colon Cancer

Unstable 20% of CRCs

Lynch2% of CRCs

WHAT IS MICRO SATELLITE INSTABILITY!?

What is a micro satellite? Tips of chromosomes were termed “satellites” and

later determined to be repetitive DNA. Subsequently short areas of repetitive DNA found through out the genome , these were termed “micro satellites.”

Example:Big A tract 26 (BAT 26)

AAAAAAAAAAAAAAAAAAAAAAAAAA

How are they unstable?“Instability” refers to the change of micro satellite length in tumors. Usually lengthening.Big A tract 26 (BAT 26) > 29 in the tumor tissue

AAAAAAAAAAAAAAAAAAAAAAAAAAAAA

How do they become unstable in LS?The genes that repair micro satellite errors are nonfunctional in LS tumor tissue. These are the DNA mismatch repair, Lynch syndrome, genes – MSH2>, MLH1> MSH6> PMS2> EPCAM. (Also known as the MMR genes. )

Micro satellites

length varies greatly in the population. CODIS uses

13 micro satellites to

develop DNA profiles for

law enforcement.

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Direct testing on the tumor DNA can be done from paraffi n embedded tissues. This test is clinically available.

In practice, we test for the presence of the LS DNA MMR gene proteins (MLH1, MSH2, MSH6,PMS2). This is more widely available, faster (24 hours) and less expensive ($250) than direct DNA tumor testing.

TESTING FOR MICROSATELLITE INSTABILITY

LS DX: STAINING OF TUMOR TISSUE (IHC) TO DETERMINEIF THE LYNCH SYNDROME MISMATCH REPAIR (MMR) GENES

ARE EXPRESSED: IF THE IHC SCREENING TEST STAINING IS ABNORMAL

FURTHER WORKUP IS NEEDED

Retained MLH1

Retained PMS2

Retained MSH2

Retained MSH6

EXAMPLE OF NORMAL STAINING

AN EXAMPLE OF A POSITIVE MMR-IHC LS TEST:

STAINING MLH1 AND PMS2 ABSENT. INDICATING FURTHER WORK UP POSSIBLY INCLUDING BLOOD DNA BASED TESTING OF MLH1 /

PMS2.

Loss MLH1

Loss PMS2

Retained MSH2

Retained MSH6

Colon Cancer, Second Colon Cancer, precancerous polyp

IN PATIENTS WITH LYNCH SYNDROME, MOST COMMON LOCATION OF COLORECTAL CANCER IS

IN THE ASCENDING COLON OR CECUM

Järvinen HJ, Gastroenterology 2000.

AppendixRectum

A clue for LS

Courtesy: M. Krishna

INTRA TUMORLYMPHOCYTES

1%

%Lynch

Syndrome25%

CRC 72 CRC<50 CRC<50

7%<0.2%

Mother(1st deg)

Son

50-75%

AmCriteria(3 fam mem)

PROBABILITY OF LYNCH SYNDROME RELATED TO AGE OF CANCER DX AND

FAHX

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• Primary CRC treatment • IRA preferred for LS (from historical records there is a 1-2% chance of second colon cancer per year)

• Secondary CRC Prevention (follow up)• Yearly c-scopy for LS

• Primary Prevention of CAs other than CRC• Endometrial

• Identification of other affected family members (sons, daughters)

WHY IDENTIFY PATIENTS WITH LYNCH SYNDROME?

COLONOSCOPY IS EFFECTIVE IN DECREASING CANCER IN LYNCH SYNDROME

PATIENTS

Outcome Colonoscopy No Colonoscopy

Colon Cancer 8 (18%) 19 (41%)

Colon Cancer Deaths 0 4

Total Deaths 4 (9%) 12 (26%)

Järvinen HJ, Gastroenterology 2000.

90 Lynch syndrome patients

44 Colonoscopy (every 3 years)

46 No colonoscopy

15 years

TESTING FOR LYNCH S., OR DIAGNOSING LYNCH S. BASED ON CLINICAL CRITERIA IS

INSENSITIVE (MISSES CASES).

Targeted testing (Revised Bethesda OR

AMSTERDAM)

Test if any criteria meet, • CRC before the age of 50 years;• Colorectal cancer with

Synchronous or metachronous colorectal cancer or history of LS tumors

A high-microsatellite-instability morphology (infiltrating lymphocytes) that was diagnosed before the age of 60 years

Family history. *One or more fi rst-degree relatives with colorectal cancer or other LS tumours. One of the cancers must have been diagnosed before the age of 50 years (this includes adenoma, which must have been diagnosed before the age of 40 years); Colorectal cancer with two or more relatives with colorectal cancer or other HNPCC-related tumours, regardless of age.

Universal ( or close) TUMOR testing

A) Micro satellite instability testing on all colon cancers

ORB) Micro satellite

instability testing on most colon cancers

All CRC cases less than 70

Any patient regardless of age who has any Bethesda criteria. (95% sensitive and

requires 35% fewer tests)

Moreira and others. JAMA 2012. 23073952

NOW

SCREENING ALL COLORECTAL CANCER PATIENTS FOR LS BY IHC HAS A YIELD

OF AT LEAST 2%

Of 1066 patients enrolled in the study, 208 (19.5 percent) had microsatellite instability, and 23 of these patients had a mutation causing the Lynch syndrome (2.2 percent). An additional 52 family members with Lynch syndrome were identified. Therefore, 14 patients were tested for each LS case identified.

Among the 23 probands with the Lynch syndrome, 10 were more than 50 years of age and 5 did not meet the Amsterdam criteria or the Bethesda guidelines for the diagnosis of hereditary nonpolyposis colorectal cancer.

Hampel, NEJM 2008

Mutation in the Lynch syndrome PMS2 gene (p.G559X)

Colon cancer age 59 yo

Died 86 2nd colon cancer immediately

after patient dx.

Colon cancer found to be micro satellite unstable

(lacking PMS2 gene)

THE NEW PARADIGM: PROGRAMATIC SCREENING OF ALL COLON CANCERS FOR LYNCH SYNDROME EX.

PATIENTS WITH LYNCH SYNDROME WHO HAVE COLONOSCOPIES LIVE LONGER

Outcome Colonoscopy No Colonoscopy

Colon Cancer 8 (18%) 19 (41%)

Colon Cancer Deaths 0 4

Total Deaths 4 (9%) 12 (26%)

Järvinen HJ, Gastroenterology 2000.

90 Lynch syndrome patients

44 Colonoscopy (every 3 years)

46 No colonoscopy

15 years

COLONOSCOPY FOR LYNCH SYNDROME: MISSED DEADLINES

Link to Canadian study of colonoscopy in patients with Lynch syndrome (MSH2)

68 Women with Lynch syndrome (MSH2) Colonoscopy 1-2 years

28 Colonoscopy on schedule

14% Colon CA

Age at Colon Cancer diagnosis

79 years

Median survival 80 years

40 Colonoscopy not on schedule

17% Colon CA

Age at Colon cancer diagnosis 57 years

Median survival 63 years

MISSED DEADLINES : 5 COLON CANCER > 2YR FOLLOW UP FAST GROWING: 4 COLON CANCERS IN THE 1 TO 2 YEAR INTERVAL.

M ISSED POLYPS? : 2 COLON CANCERS IN THE 1 YEAR INTERVAL . ? M ISSED RAP ID OR RAP ID GROWTH

0

1

2

3

4

5

6

7

A B C D E F G H I J K

Interval between last colonoscopy and 11 colon cancer diagnoses (years) for female patients

CASE

A 52 year old woman presented with hematochezia. She had no personal or family history of cancer. A colonoscopy 2 years ago was performed for colon cancer prevention. The preparation was good. A 4 mm tubular adenoma in the transverse colon, a 10 mm hyperplastic polyp in the ascending colon and an 5 mm hyperplastic polyp were all removed.

A second colonoscopy found a rectal mass, biopsied and found to be adenocarcinoma. The results of third colonoscopy performed with chromoendoscopy are on the next slide (2gm indigo carmine in 500 mL NS).

CASE

Mismatch repair gene immunohistochemistry showed loss of PMS2. MLH1, MSH2 and MSH6 were all present.

Germline testing identified a known disease causing mutation in PMS2.

Some interval colon cancers will be explained by Lynch syndrome.

FOLLOW UP.

Loss PMS2

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Studies suffer fromSmall numbersFew operatorsWhite light then chromoendoscopy design, so are you testing a second examination or the chromoendoscopy?

Also withdrawal time much longer from chromoendoscopy, 10 vs 20 min, so are just testing a longer withdrawal time.

CHROMOENDOSCOPY FOR LYNCH SYNDROME? DATA QUALITY IS POOR.

American J of Gastroenterology 2015. 10 French centers.

“The percentage of patients in whom at least one additional adenoma was detected during the chromoscopy was 31% (24/78).”

+Indigo carmine chromoendoscopy 45 year old female Lynch

syndrome patient (MLH1): Ascending colon polyp before injection with saline.

+Indigo carmine chromoendoscopy 45 year old female Lynch

syndrome patient (MLH1): Ascending colon polyp after injection with saline.

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LS is a hereditary colorectal, endometrial and other cancer syndrome caused by mutation in the DNA MMR genes.

First line for testing is mismatch repair gene immunohistochemistry. MMR IHC.

Universal screening for Lynch syndrome is now recommended by NCCN.

Amsterdam criteria are not sensitive or specific for Lynch syndrome

Yearly colonoscopy (?with chromoendoscopy) is recommended.

LYNCH SYNDROME SUMMARY

39

CASE

A 45 year-old man presented for medical genetics evaluation. Between the ages of 20 and 30 years, the patient had nasal polyps and several large stalked colon polyps removed. At 43 years-old, he was diagnosed with jejunal adenocarcinoma (T1N0).

Upper endoscopy following surgery showed several stomach and small bowel polyps. A genetic test for familial adenomatosis polyposis (APC gene) was negative. There was no family history of cancer.

CASE

RRIR

Arborizing smooth muscle in an intestinal polyp is almost pathognomic for PJS. Often missed in pathology!

Melanotic macules often fade and the last place they can be seen in the buccal mucosa.

Nasal Polyposis as a feature of PJS Originally published in Dutch as: Peutz J. “Very remarkable case of familial polyposis of mucous membrane of intestinal tract and nasopharynx accompanied by peculiar pigmentations of skin and mucous membrane.” Nederl Maandschr Geneesk. 1921; 10:134-146.

MELANOTIC MACULES FADE

Originally published in Dutch as: Peutz J. Very remarkable case of familial polyposis of mucous membrane of intestinal tract and nasopharynx accompanied by peculiar pigmentations of skin and mucous membrane. Nederl Maandschr Geneesk. 1921; 10:134-146.

Peutz-Jeghers syndrome is associated with melanotic macules, polyps and cancer

Died age 20 Intussusception

Connor. Archives of Surgery (London 7:290,1896).

Died age 50Breast Cancer

PEUTZ-JEGHERS

90% Adenocarcinoma / 90% Intussception Cancer surveillance tests 5 slides

SESSILE SERRATED POLYPOSIS

Douglas Riegert- Johnson, MDMayo Clinic FloridaGastroenterology and Genetics

Open access other slide sets on slideshare.net

Hyperlink

THERE ARE THREE TYPES OF SERRATED POLYPS

Classification is a relatively recent construct.HyperplasticSessile serrated adenoma/polyp (1996)

SS adenoma = SS adenoma/polypTraditional serrated adenoma (1990)

Serrated polyposis syndrome to be discussed at end of talk (WHO criteria 2000)

Burt R, Jass JR. Hyperplastic polyposis. In: Hamilton SR, Aaltonen LA, eds. Pathology and Genetics of Tumours of the Digestive System. Vol 2. Lyon, France: IARC; 2000:35–136.

292; 72%

112; 28%

Adenomas Serrated polyps

Complete Adenoma Resection Study (CARE): Gastroenterology 2013

64; 57%

6; 5%

42; 38%

Hyperplastic

Traditional serrated ade-nomaSessile serrated adenoma/polyp

About 3 in 10 polyps are serrated polyps, about 1 in 10 are sessile

serrated adenomas

Hyperplastic polyp Sessile Serrated Adenoma

“The boot”Must have at least one

horizontally branched crypt

Traditional Serrated Adenoma

Lifetime odds of

colorectal cancer

diagnosis

Postulated lower limit (1/400 individuals have a hereditary syndrome pre disposing to rapid polyp growth eg Lynch

syndrome)

1/400

1/10

1/166

Lifetime risk with no screening

Lifetime risk for patients in colonoscopy program

All odds are approximation

WHY ARE SSAS IMPORTANT?PLUMBING THE DEPTHS OF

COLORECTAL CANCER PREVENTION

Not seen lesionsOther lesionsIncompletely resection

SSA

Risk Stratification

NOT SEEN (AND NOT CLASSIFIED) LESIONS:

THE PROPORTION OF COLOSCOPIES WITH SESSILE SERRATED ADENOMAS VARIES

BASED ON CENTER (COLONOSCOPIST AND PATHOLOGIST).

2014 USA Septin 9 trial data on SAs per center

Mean % of colonoscopies with

SSAPs = 2.8%Range (0-9.8%)

WHO CRITERIA FOR SERRATED POLYPOSIS SYNDROME

* ANY TYPE OF SERRATED POLYP.

WHO Criterion 1. At least 5 serrated polyps proximal to the sigmoid colon, of which 2 measure at least 10 mm in diameter). 5 × 2 = 10.

WHO Criterion 2. Any number of serrated polyps occurring proximal to the sigmoid colon in an individual who has a first-degree relative with SPS.

*WHO Criterion 3. >20 serrated polyps spread throughout the colon. * About 80% of patients meet this criterion.

SERRATED POLYPOSIS IS UNCOMMON (BUT NOT RARE) AND REQUIRES YEARLY FOLLOW UP

1:151 – 1:294 of patients in FIT based colorectal cancer prevention programs.

1-year surveillance interval for these patients recommended by US Multi-Society Task Force on Colorectal Cancer and the European Society of Gastrointestinal Endoscopy.

Serrated lesions: Recommendations from an expert panel.

FOR SERRATED POLYPOSIS, COLONOSCOPY OF FAMILY MEMBERS HAS HIGH YIELD BUT GENETIC TESTING

OF PATIENTS HAS A LOW YIELD

First degree relatives of SPS should have colonoscopy at age 40 or 10 years prior to proband’s diagnosis of SPS

(4/10 significant polyp, 1/7 will have serrated polyposis Reference).

Genetic evaluation recommended by the European guidelines. Yield is low. DRJ “less than 5%”. Genetic DDX includes

Lynch syndrome (mutation in the DNA mismatch repair genes) MYH associated polyposis (MAP) Mutations in the RNAF4 gene.

Patients can be referred to a genetic counselor using an online database (www.nsgc.org)

SUMMARY

SSAs represent 1 in 10 colon polyps, and have a “boot” histopathology.

Interval colon cancers are rare, SSAs may be canary signal to the causative missed lesions, new lesions, and incomplete polypectomies.

Evidence suggests that SSA themselves may not play a direct role in colorectal cancer.

Current recommendations for SSA surveillance are consensus only and similar to those for adenomas Piecemeal follow up 3 to 6 months SSA more than 10 mm in size, follow up in 3 years

Sessile serrated polyposis syndrome requires yearly follow up colonoscopy and colonoscopy is recommended for family members.

THE END

ADDENDUM

Neoplastic polyps, n (%) 346 (82.8)

 Adenomas 292 (69.9)

  Tubular adenomas 260 (62.2)

  Tubulovillous adenomas 21 (5.0)  Villous adenomas 5 (1.2)  Traditional serrated adenomas 6 (1.4)

 Sessile serrated adenomas/polyps 42 (10.1)

  Cancer 1 (0.2)

 Hyperplastic polyps 64 (15.3)

Complete Adenoma Resection Study (CARE): Gastroenterology 2013

HYPERPLASTIC POLYP FOLLOW UP

Lesion Size Number Location Follow up

HP <10 mm Any numberb Rectosigmoid 10c

HP ≤5 mm ≤3 Proximal to sigmoid 10

HP Any ≥4 Proximal to sigmoid 5

HP >5 mm ≥1 Proximal to sigmoid 5

4 years old. Alive and well.

28 years oldAlive and well

48 years oldThyroid disease

50 years oldAlive and well

25 yo dx with transverse CRC.

25 tubular adenomas in left colon (right colon not seen due to obstruction).A few stomach polyps. At 22 yo dx left temporal lobe glioblastoma.“Freckles in Eye”.

CASE

4 years old. Alive and well.

28 years oldAlive and well

48 years oldThyroid disease

50 years oldAlive and well

25 yo dx with transverse CRC, 25 tubular adenomas in left colon (right colon not seen due to obstruction)A few stomach polyps. At 22 yo dx left temporal lobe glioblastoma.“Freckles in Eye”.DX: ? FAP NEW MUTATION TURCOT

FAP + brain tumor (usually meduloblastoma) = Turcot syndrome

LS + brain tumor (usually glioblastoma) = Turcot syndrome

TERM “TURCOT SYNDROME” AS CURRENTLY USED

Numerous CAL macules

PHYSICAL EXAMINATION

4 years old. Alive and well.

28 years oldAlive and well

48 years oldThyroid disease

50 years oldAlive and well

PMS2 gene mutation (Pro246Cysfsx3)

PMS2 gene mutation (Ile611Asnfsx3)

PMS2 gene wildtype(normal)

25 yo dx with

transverse CRC.

or

GENETIC TEST RESULTS: “DOUBLE LYNCH” ONE LYNCH SYNDROME

MUTATION FROM EACH PARENT

First described in 1999 in two simultaneously publishedreports (Ricciardone et al. 1999; Wang et al. 1999)

Synonyms.Childhood cancer syndrome (CCS)

Lynch III syndrome ‘‘CoLoN’’, Colon tumours or/and Leukaemia/Lymphoma

CONSTITUTIONAL MISMATCH REPAIR DEFICIENCY“DOUBLE LYNCH”

Constitutional mismatch repair-deficiency syndrome:have we so far seen only the tip of an iceberg?

All CMMRD patients with available clinical data (n = 18) had café-au-lait spots (>6 spots) and three patients had hypopigmentation. Three individuals had axil lary freckles, and one had a plexiform neurofi broma; meeting the criteria for NF-1, but lacked germline NF-1 mutations.

CMMR OVERLAPS WITH NF1: CASE 2 WITH 50 CALM.

Genetic and clinical determinants of constitutional mismatch repair deficiency syndrome: Report from the constitutional mismatch repair deficiency consortium.. 24440087.

Cancer Number Median age (range) of diagnosis

Hematological 30 6 (0.4-17)

Brain tumor 44 8 (2-35)

Colorectal cancer

37 16 (8-35)

Small bowel 9 26 (11-42)

TUMOR SPECTRUM OF CMMRD IN 92 PATIENTS

2010 CMMRD Review of 92 patients.

SUPPLEMENTAL SLIDES

Described in 1959 by Jacques Turcot in Diseases of the Colon and Rectum

Hôtel Dieu de Quebec hospital (1640) and the Laval University2 teenage siblings with numerous colorectal polyps. The brother (15 years old) with meduloblastoma of the spinal cord and adenocarcinomas of the sigmoid colon and rectum. The sister (13 years old) with cerebral glioblastoma and pituitary adenoma.Mckusick and Osler communicated that parents were third cousins.

“Every case of familial polyposis should be followed and explored, not only looking for new occurrences of polyps in the colon and rectum, when they are not removed by also for the appearance of other tissue tumors elsewhere in the body.”

Colon Cancer, Second Colon Cancer, precancerous polyp

IN PATIENTS WITH LYNCH SYNDROME THE PREDOMINANCE OF COLON POLYPS AND

CANCERS ARE LOCATED IN THE RIGHT COLON.

Järvinen HJ, Gastroenterology 2000.

Appendix

Rectum

Cancer Surveillance strategy

Children  

Colon Colonoscopy annuallya

Upper GI tract and small bowel

EGD annuallya, video capsule endoscopy annuallya

Brainb Ultrasound at birth then MRI brain every 6 months

Leukemiab, Lymphomab Complete blood count, erythrocyte sedimentation rate, lactate dehydrogenase every 4 months

Adults  

Colon Colonoscopy annuallya

Upper GI tract and small bowel

EGD annuallya, video capsule endoscopy annuallya

Brainb Ultrasound at birth then MRI brain every 6 months

Leukemiab, Lymphomab Complete blood count, erythrocyte sedimentation rate, lactate dehydrogenase every 4 months

Uterus Ultrasound annually

Upper urinary tract Ultrasound and urine cytology annually

 

Surveil lance protocol for patient with for Bial lel ic MMR mutations.

EGD-esophagogastroduodenoscopy. a To start at 3 years of age or at diagnosis;

b Brain, leukemia/lymphoma screening should commence at birth if diagnosed prenatally.

Genetic and clinical determinants of constitutional mismatch repair deficiency syndrome: Report from the constitutional mismatch repair deficiency consortium. 24440087.

PMS2 dominates, followed by MSH6 and MLH1.“MSH2 mutations which are most commonly found

in Lynch syndrome are less common to absent in CMMRD, while PMS2 and MSH6 are more commonly observed in the syndrome. A possible explanation for this phenomenon is low penetrance of heterozygous mutations in MSH6 and PMS2 found in CMMRD and the deleterious functional consequence of homozygous mutations. Highly penetrant mutations in MSH2, may be embryonically lethal when homozygous leading to the lower prevalence observed in CMMRD.”

CMMRD MUTATION SPECTRUM

There were several cafr-au-lait spots on theskin of the chest, back, abdomen, and extremities,but there were no nodules on the body surface.

H Itoh and others, Gut 1979. Kyushu University Faculty of Medicine, Fukuoka, Japan.“There were several cafe-au-lait spots on theskin of the chest, back, abdomen, and extremities, but there were no nodules on the body surface.”

Proband. 13 yo from Brazil. Youngest in a family of 7 children.

No gastric or extracolonic features

of FAP.

Compared with familial polyposis coli, colonic polyps in Turcot’s syndrome are fewer in number and larger in size.

(1)In Turcot's syndrome the manifestations of brain tumour and colonic polyposis are signifi cantly associated and are not merely coincidental, although the association of brain tumour is only incidental in the few cases of famil ial polyposis coli .

(2)Moreover, an autosomal recessive mode of transmission is most l ikely in this syndrome.

(3)The number of colonic polyps in Turcot's syndrome was frequently less than 100, in contrast with the study of Bussey (1975) who noted that the average number of polyps in famil ial polyposis coli was about 1000 and rarely less than 200. The analysis of macroscopic fi ndings of colonic polyps showed that they were fewer in number and larger in size in Turcot's syndrome compared with famil ial polyposis coli .

(4)Therefore, we present the hypothesis that Turcot's syndrome is genetical ly dist inct from famil ial polyposis col i .

FEATURES OF TURCOT BY ITOH AND OTHERS

Turcot syndrome and its characteristic colonic manifestations.Itoh H, Ohsato K. Dis Colon Rectum. 1985 Jun;28(6):399-402.

DIFFERENCES IN TUMOR SPECTRUM BASED ON GENOTYPE IN CMMRD

PMS2/MSH6>

MLH1/MSH2

n 65 24

Median age of dx 9 years 4 years

Hematological (#1 Non Hodgkins Lymphoma Tcell)

29% 46%

Brain 35% 8%

Lynch syndrome cancer(colon, endometrial)

68% 29%

Described in 1959 by Jacques Turcot in Diseases of the Colon and Rectum Hôtel Dieu de Quebec hospital (1640) and the Laval

University 2 teenage siblings with numerous colorectal polyps. The

brother (15 years old) with meduloblastoma of the spinal cord and adenocarcinomas of the sigmoid colon and rectum. The sister (13 years old) with cerebral glioblastoma and pituitary adenoma.

Mckusick and Osler communicated that parents were third cousins.

Crail Syndrome case report (1949) Adenomatous polyposis, mebullastoma of the brain stem,

and papillary thyroid cancer.

TURCOT SYNDROME

New England Journal Medicine article describing molecular phenotype.Turcot original report 1959. 13839882.

Normal Staining of PMS2 in tumor.Both copies of PMS2 present.

Lynch syndrome. No staining in tumor. (Both copies of PMS2 inactivated, one inherited, one acquired in tumor) Staining

in tumor lymphocytes and normal tissue.

Patient Results: Constitutional mismatch repair deficiency. No staining in tumor and normal tissue.

(Both copies of PMS2 inactivated in tumor and normal by inherited mutations.)

DNA measurements of microsatellite instability based on comparing normal and tumor tissue MS. In LS, the tumor MS change, so a difference can be seen. (I think) in CMMRD normal and tumor both change so no difference can be seen.

Only one out of the 14 brain tumours

exhibited an MSI-high genotype.

MICRO SATELLITE INSTABILITY UNRELIABLE IN CMMRD

Genetic and clinical determinants of constitutional mismatch repair deficiency syndrome: Report from the constitutional mismatch repair deficiency consortium. 24440087.

87

SSAS

TRADITIONAL SERRATED ADENOMA SHOULD BE RENAMED AS CONFUSED WITH SSA

Much higher rate of high grade dysplasia or carcinoma compared to SSA. About 1 in 5 associated with advanced neoplasia (19%).

Are rare, large (mean size 16 mm)

mostly located in the sigmoid or rectum (71%) in older men and women (mean age 64 with equal male to female ratio).

A clinicopathological and molecular analysis of 200 traditional serrated adenomas.

THE GOOD NEWS: SUSTAINED AND NOTABLE DOWNWARD TREND IN

COLON CANCER AND DEATHS FROM COLON CANCER ( P E R 1 0 0 , 0 0 0 )

1975

1977

1979

1981

1983

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1989

1991

1993

1995

1997

1999

2001

2003

2005

2007

2009

2011

0

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Number of new cases Number of deaths

CASE

91

60 year old man with juvenile polyposis and family history of the same presents for endoscopy.

CASE

92

93

JP STOMACH VIDEO

94

ARE THERE ANY ENDOSCOPIC

OPTIONS FOR THE ADVANCED JP

STOAMCH?

95

JP is caused by mutations in the SMAD4 and BMPR1A genes. Patients with mutations in the last portion SMAD4 have HHT features as well.

JP OVERLAP WITH HHT

96

97

33 year old man with juvenile polyposis and family history of the same presents for endoscopy.

CASE

98

How many polyps is too many?

“Approx 25 6 to 15 mm polyps in the ascending colon and in the cecum. Resected and retrieved.”

Colon

HOW MANY POLYPS UNTIL SURGERY?

99

AGITATED SALINE INJECTION INTO A PERIPHERAL VEIN WILL NORMALY ONLY BE SEEN IN RIGHT HEART UNLESS THERE IS A

SHUNT

Right Atrium

Small pulmonary AVMs in a patient with JP/HHT (SMAD4 mutation)

CASE