25 minute Familial Polyposis and Lynch syndrome review.

1. SCAN AND FOLLOW BARCODE TO LINK OF
UPDATED PRESENTATION.

2. GENETIC COLON CANCER SYNDROMES:
ANSWERS TO FREQUENT
QUESTIONS REGARDING
FAMILIAL A. POLYPOSIS
AND
LYNCH SYNDROME
D O U G L A S R I E G E R T- J O H N S O N , M D
M AY O C L I N I C F L O R I D A
R I E G E R T J O H N S O N . D O U G L A S @ M AY O . E D

3. DISCLOSURES
None.
OFF LABEL DRUG USE.
Lovaza fish oil and celecoxib for familial
adenomatous polyposis.

5. FAP TERMINOLOGY
Attenuated FAP (aFAP)= FAP with less
than 100 adenomas in an adult. There is
a tendency to rectal sparing.
Gardner sydrome = FAP or aFAP +
extracolonic manifestations such as
osteomas, skin cysts, extra teeth
(odontogenic cysts), desmoid
tumors, and congenital hypertrophy of
the retinal pigmented epithelium
(CHRPE).
Scenario: 18 yo with 1000 adeno. polyps and 4 generation family history of
the same with osteomas, but does not have an APC mutation. Does he
still have FAP? Answer: Yes!
A gene mutation is not need for the diagnosis. For many reasons, not all
patients have a detectable APC or MUTYH mutation (could have
polymerase proofreading associated polyposis POLE, POLD1).
Patients with aFAP have a 50% chance or less of having a detectable

6. A W E B B A S E D TO O L F O R
D O C U M E N T I N G FA P PAT I E N T
V I S I T S .
D O E S N O T S TO R E O R C O L L E C T
A N Y PAT I E N T I N F O R M AT I O N .
N O C O M M E R C I A L I N T E R E S T S
I N V O LV E D .
R E C O M M E N D G O O G L E C H R O M E

8. Select text
from template
to add to note
 Review note
(plan is repeated at
top)
  Copy to
Clipboard and
paste to EMR

9. NSGC.ORG Hyperlink

11. EPA FOR CHEMOPREVENTION OF POLYPS IN
THE RETAINED RECTUM OF FAP PATIENTS
55 FAP patients
28 EPA 1000 mg bid
27 Placebo
6 months
West N J et al. Gut 2010;59:918-925. 20348368.

12. West N J et al. Gut 2010;59:918-925. 20348368.
FAP CHEMOPREVENTION STUDIES MONITOR A
TATTOOED SECTION OF THE RETAINED RECTUM

13. 22 % NET REDUCTION WITH 1 GM EPA BID.
 TO DECREASE FROM 5 TO 4 POLYPS IN OBSERVED AREA
EPA CHEMOPREVENTION EFFECT SIMILAR TO
CELECOXIB

14. Guidance in blue.

18. Spigelman
score
determines
EGD follow up

19. VIEW OF THE PAPILLA USING AN ENDOSCOPIC CAP
BIOPSY OF PAPILLA NOT REQUESTED ROUTINELY (YIELD IS LOW, RISK OF
PANCREATITIS, SEE SUPPLEMENTAL SLIDES)

20. CAP ASSISTED ENDOSCOPY OF THE PAPILLA
Choi J et al. World J Gastroenterology 2013;19:
2037-43. 23599622.
Endoscopic transparent cap. A: Short
transparent cap (Olympus distal
attachment D-201-10704, outer
diameter: 11.35 mm, length from distal
end of endoscope: 4 mm; Olympus
Tokyo, Japan); B: Long transparent
cap (Olympus distal attachment MH-
593, outer diameter: 12.9 mm, length
from distal end of endoscope: 11 mm;
Olympus);
0%
20%
40%
60%
80%
100%
Conventional
Short cap
Long cap
0.81
0.98 1
Percentage of patients were papilla was seen n =120

21. H E R E D I TA RY N O N P O LY P O S I S
C O L O N C A N C E R WA S P R E V I O U S LY
U S E D , H O W E V E R N O L O N G E R A S I T
B E C A M E A P PA R E N T T H AT T H E R E
W E R E C A N C E R R I S K S O U T S I D E O F
T H E C O L O N
( E N D O M E T R I A L , B I L I A R Y, PA N C R E AT I

22. 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 infiltration.
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.
B. Tumor testing for microsatellite instability. (Senstive for
LS)
Clues for LS

23. 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.” (Micro satellite term replaced by short tandem repeat
,STR).
Example:
Big A tract 26 (BAT 26) AAAAAAAAAAAAAAAAAAAAAAAAAA
How are they unstable?
“Instability” refers to the change of micro satillete 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
satilletes to
develop DNA
profiles for law
enforcement.

24. 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.

25. TESTING FOR LYNCH S., OR DIAGNOSING LYNCH S.
BASED ON CLINICAL CRITERIA IS INSENSITIVE
(MISSES CASES).T A R G E T E D T E S T I N G
( R E V I S E D B E T H E S D A
( B E L O W )
O R A M S T E R D A M )
Test if any criteria meet,
• Diagnosed with colorectal cancer 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 first-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.
U N I V E R S A L
M S S T U M O R
T E S T I N G
( O R C L O S E TO
I T )
A) Micro satellite
instability testing on
all colon cancers
OR
B) 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
NO
W

26. 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.

28. NEXT GENERATION SEQUENCING
Generic term for parallel testing of numerous genes relatively quickly and
inexpensively in panels. Current MC panel has 14 genes. Was >$14,000 -> Now
$3,500 with NextGen.
APC
EPCAM MSH6
MSH2
MLH1MUTYH
PMS2
STK11
TP53
PTEN
CDH1
SMAD4AXIN2
CHEK2
MLH3 GREM1
BMPR1
A

29. SUMMARY
For familial polyposis,
FAP is a clinical dx. Many patient will not have a APC
or MUTYH mutation. Testing for new described genes not
yet available (eg polymerase proofreading associated polyposis
PPAP).
Consider chemoprevention with Lovaza (EPA fish oil).
Fundic gland polyps dysplasia not clinically
significant.
Lower endoscopy fu for most FAP patients is q 6
months.
For Lynch syndrome,
The emerging standard of care is programatic micro
satellite instability testing on all or a large subset of
colon caners.

32. IRON AND B12 DEFICIENCY COMMON IN FAP
AND LS PATIENTS.
About 1/3 of patients will have hypoferritinemia or hypovitaminosis
B12.
All patients have ferritin and vitamin B12 measured annually.

33. THYROID, ADRENAL AND DESMOID TUMOR
Thyroid
About 3% lifetime risk for papillary thyroid cancer.
Mostly female [89% female (96 F: 11 M)]
Mostly young [mean age dx 29.2 (+/− 10.3) years.]
Seth Septer and others. Hereditary Cancer in Clin Practice 2013;11:13. 24093640.

35. BENEFIT AND RISK OF AMPULLARY BX
What is the reason for the biopsy?
To prevent ampullary cancer by detecting premalignant precursors.
What is the benefit?
Normal ampulla: Information yield low in normal appearing ampulla, 75%
of patients have histologic ampullary adenoma .
Abnormal ampulla: Unlikely to progress. 1 of 69 patients with untreated
histologically proven adenoma progressed to CA. Interval for that patient
was 39 months.
What is the risk?
Pancreatitis. (St Mark’s halted routine ampullary bx in 1992.)
CONSIDER: Enlarged ampulla >10 mm refer to ERCP for evaluation for
ampullary bx and or ampullary bx. (Assumption cancer risk associated
with size).
Carol Burke and others. Gastrointestinal Endoscopy 1999. 10049420.
T Matsumoto and others. Am J Gastroenterology 2000. 10894596.
KP Nugent and others. Gut 1999. 8406166.
CJ Groves and others. Gut 2002. 11950808.
Bleau and others. Clinical J Gastroenterology 1996. 8724267.

36. RETROFLEXED VIEW OF THE ANUS IN FAP PT S/P
PROCOTOCOLECTOMY/J POUCH

37. Subtotal Colectomy
(Ileal Rectal Anastamosis, IRA)
• 3 BM/day Mean
• 4% night time incontinence
• 5% need a pad for continence
• Laproscopic and no impact on
fertility
•Followup every 6 mo flexible
sigmoidoscopy required. If advanced
neoplasia interval decreases to every
3 months
•Rectal loss rate quoted as
10%, decreasing with improved follow
up.
BACKGROUND: SUBTOTAL COLECTOMY IS THE
SURGICAL TREATMENT FOR MOST PATIENTS WITH
FAP (80%)
A. Sinha, Britsh Journal of Surgery, 2010.

38. 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. The
patient underwent right colon resection. Pathology
was reported adenocarcinoma with lymphocytic
tumor infiltration.
The patient’s mother had a hysterectomy in her 50s for
bleeding. Otherwise she has no history of cancer.
Father (73), brother (45) and sister (41) are alive and
well.
Which test is the most appropriate?
A. Sequencing and testing for large deletions of APC.
B. Tumor testing for microsatellite instability

40. Micro satellite
Status of Tumor
Normal Tumor
Stable AAAA AAAA
Unstable AAAA AAAAAAA

41. HNPCC Tumor Tissue
MLH1 MLH1
Inactivation
MLH1
HNPCC Normal Tissues
MLH1
AAAAAAAAAAAAAAAAAAAAAAAAAAA
AAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA
Normal
Tumor
Unstable micro satellite
Protein
DNA
“Downstream” Mutations
Micro Satellites – small repetitive DNA sequences
Normal
MLH1MLH1
100%
50%
0%
100%
50%
0%
IHC IHCFXN FXN
100%
50%
0%
IHCFXN