Companion slideshow for polyppolyp.com (Familial adenomatous polyposis)

© 2014 DOUGLAS RIEGERT-JOHNSON
POLYPPOLYP.COM
SLIDESHOW
VERSION J. NOV 2014.
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© 2014 Douglas Riegert-Johnson MD.

Table of Contents
Topic Slide
Vocabulary
Features of FAP in the duodenum
CHPRE
Adrenal adenomas
Osteomas
Treatment of FAP with fish oil
Ileostomy site neoplasia
J pouch polyps
IPAA

VOCABULARY: FAP
Letter Word Meaning
F Familial Runs in families
A Adenomatous From the glands lining the
surface of the colon.
Adenomatous polyps are
precancerous.
P Polyposis Many polyps, at least 20 polys
in an adult.

FAP is an inherited disease. It runs from parent to
child to grandchild. It does not skip generations.
50 years old
Alive and well
28 years old
Polyposis
colon removed
10 years old.
48 years old
Polyposis
colon removed
28 years old
Alive and well
Has osteomas, assumed to have FAP.
Each child of a patient with FAP has a 1 in 2 chance of having FAP.

VOCABULARY
Attenuated FAP or aFAP=
Generally accepted to be FAP
with less than 100 adenomas
in an adult. Many attenuated
FAP patients do not have
polyps in the rectum.
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).

EXTRAINTESTINAL FEATURES OF FAP
(GARDNERS)
Pigmented spots in the back of the
eye. Technically called congenital
hypertrophy of the retinal pigmented
epithelium (CHRPE).
Dental abnormalities including
extra teeth.
Thyroid
nodule.

The Skin and FAP (Gardner’s)
• Nearly half of FAP patients will have one or more lipomas, fibromas or
epidermal cysts (general population about 30%).
Lipoma
Epidermal cyst
Fibroma

POLYPOSIS GENES
The genes for familial adenomatous polyposis are
APC and MYH. The APC gene is located on the
long arm of chromosome 5. The MUTYH gene is
located on the short arm of chromosome 1. The
MUTYH gene is sometimes called the MYH gene.

APC
From
mom
APC
From
dad
MUTYH
MUTYH From dad
From mom

Scenario. A negative genetic test does not
rule out familial polyposis.
• An 18 year old man comes to the clinic with rectal bleeding.
Colonoscopy shows 1000 polyps. Some are removed and sent
the pathology department. The pathologist reports back they
are adenomas. The patient can trace a history of polyposis
back through 4 generations of his family. Genetic testing for
polyposis is negative.
• Question: Does he still have FAP even though he has had
genetic testing?
• Answer: Yes! The genetic testing that is currently available
does not identify a mutation in about 10% of patients have FAP.
• 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 APC mutation.

Some patients
with FAP,
attenuated
(lesser FAP) and
Gardner
syndrome do not
have APC or
MUTYH
mutations.

FEATURES OF FAMILIAL
POLYPOSIS IN THE
DUODENUM
Duodenal adenomas
In the area of the papilla (ampulla)
Not associated with the papilla

VIEW OF THE PAPILLA USING AN ENDOSCOPIC CAP
BIOPSY OF PAPILLA NOT REQUESTED ROUTINELY
YIELD IS LOW, RISK OF PANCREATITIS

CAP ASSISTED ENDOSCOPY OF THE PAPILLA
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);
Choi J et al. World J Gastroenterology 2013;19:
2037-43. 23599622.
Percentage of patients were papilla was seen n =120
100%
80%
60%
40%
20%
0%
Conventional
Short cap
Long cap
0.81
0.98 1

DOUDENALADENOMA AT
THE PAPILLA (AMPULLARY
ADENOMA)
A male patient 20-30 years old presented to clinic
with abdominal pain. One year before the patient
had had his colon removed and a J pouch made.
He has a family history of polyposis and a genetic
test showed he had a mutation in the APC gene.

VIEW OF THE PAPILLA SHOWING WHAT APPEARS TO BE AN
ADENOMA

VIEW OF THE PAPILLA SHOWING THE SAME AREA AFTER THE ABNORMAL
TISSUE WAS REMOVED AND THE AREA CAUTERIZED. THE BLUE TUBE IS A
STENT GOING IN THE PANCREATIC DUCT TO PREVENT PANCREATITIS.

DUODENAL POLYPOSIS
Severity of duodenal polyposis is graded with the Spigelman
score. There are 3 steps to using the Spigelman score.
Step 1. Calculate the number of points.
Step 2. Use the number of points to determine the
stage.
Step 3. Use the stage to determine the follow up.

Duodenal f/u for FAP is determined by the Spigelman score
Criterion One point Two points Three points
Polyp number 1-4 5-20 >20
Polyp size (mm) 1-4 5-10 >10
Histology Tubular Tubulovillous Villous
Dysplasia Mild Moderate* Severe**
Stage (points) Follow up (yrs)
Vasan, Gut, 2008. Bülow, Gut 2004.
*A low degree of
dysplasia according
to current
classification.
**A high degree of
dysplasia.
0 (0) 5
I (1-4) 5
II (5-6) 3
III (7-8) 1-2
IV (9-12) EUS ? surgery
S
t
t
p

S
t
e
p


Spigelman
stage IV
duodenal
polyposis

EXTRACOLONIC
MANIFESTATIONS OF FAP
A PRESENTATION FOR WWW.POLYPPOLYP.COM
AVAILABLE ON WWW.SLIDESHARE.NET
Douglas Riegert-Johnson, MD
Mayo Clinic

Extracolonic
manifestations of
Familial
Adenomatous
Polyposis
Extraintestinal
(CHRPE)
Intestinal
(Doudenum)

Large CHRPE in posterior pole. The Duke Elder Lecture 2001 Eye (2002) 16, 325–346. Things that
go bump in the light. The differential diagnosis of posterior uveal melanomas. I G Rennie.

CHRPE
(Congenital Hypertrophy Of the Retinal Pigmented Epithelium)
• Hyperpigmented areas in the eyes are common. Not all
are CHRPE. Also, not all patients with CHRPE have FAP.
• Best seen with a dilated eye examination.
• No malignant transformation has been reported.
• CHRPE seen in FAP patients is usually present in both
eyes. They often have a depigmented halo (Berk type A).

General
population
Feature
Retinal
hyperpigmentation
Specific
Feature
CHRPE
Highly specific
FAP variant of
specific feature
CHRPE,
posterior pole,
fish tail shaped
hypopigmentati
on, bilateral
Odds
of
FAP
CHRPE as paradigm for FAP extra intestinal manifestations

Importance of FAP extra colonic features
for diagnosis and screening
• SCENERIO 1 – Known
adenomatous colon polyp.
The presence of extra
colonic features can be
useful in making the
diagnosis.
• SCENRIO 2 – Patient has
not had colonoscopy. The
feature prompts the
evaluation and diagnosis.

CHRPE, osteomas and skin cysts associated with
mutations after exon 9
CHRPE coefficient = no small CHRPE + (3 large CHRPE)
Cell. 1993 Dec 3;75(5):959-68. Restriction of ocular fundus lesions to a specific subgroup of APC mutations in adenomatous
polyposis coli patients. Olschwang S1, Tiret A, Laurent-Puig P, Muleris M, Parc R, Thomas G.
Am J Med Genet A. 2006 Feb 1;140(3):200-4.Familial adenomatous polyposis (FAP): genotype correlation to FAP phenotype with
osteomas and sebaceous cysts. Bisgaard ML1, Bülow S.

Dental abnormalities
Abnormality FAP General population
Super nummary teeth
(extra teeth)
11-27% 0-4%
Impacted teeth
(teeth that do not erupt)
4 to 38% Less than 1%
Odontomas
(well-defined encapsulated
hard tissue
growths with an odontogenic
appearance)
9.4% to 89% 1-4%
A scoring system has been developed for panoramic x-rays to predict if the
patient has FAP (Thakker)
J Med Genet. 1995 Jun;32(6):458-64. The dental phenotype in familial adenomatous polyposis: diagnostic application of a weighted scoring system for changes on dental
panoramic radiographs. Thakker N1, Davies R, Horner K, Armstrong J, Clancy T, Guy S, Harris R, Sloan P, Evans G. Oral Dis. 2007 Jul;13(4):360-5. Oral and maxillofacial
manifestations of familial adenomatous polyposis. Wijn MA1, Keller JJ, Giardiello FM, Brand HS.

“Part of dental panoramic radiograph of a female familial adenomatous polyposis
patient. An impacted 34 as well as odontomas are visible: one distal from 35 and one
between 26 and 27.”

The Skin and FAP
• Nearly half of FAP patients will have one or more lipomas, fibromas or
epidermal cysts (general population about 30%). Lipomas are the
most common skin finding in FAP patients.
Lipoma
Epidermal cyst (Soft, “sub-skin”)
(often able to express material)
Oncologist. 2011;16(12):1698-705. doi: 10.1634/theoncologist.2011-0244. Epub 2011 Dec 1.
Prevalence of skin lesions in familial adenomatous polyposis: a marker for presymptomatic diagnosis?
Fibroma
Burger B1, Cattani N, Trueb S, de Lorenzo R, Albertini M, Bontognali E, Itin C, Schaub N, Itin PH, Heinimann K.

Osteomas
• Osteomas are abnormal growths of bone. They are not
bone cancer and are not know to change into cancer.
• About 1 or 2 out of 10 patients with FAP will have an
osteoma.They are more common in women with FAP
• Most commonly located on the mandible or maxilla. A few
patients with osteomas will have symptoms from nerve or
eye compression.
• More common in patients with CHRPE.
Int J Med Sci. 2012;9(2):137-41. Epub 2012 Jan 7. Oral and maxillofacial considerations in Gardner's Syndrome. Cankaya AB1,
Erdem MA, Isler SC, Cifter M, Olgac V, Kasapoglu C, Oral CK.
Familial adenomatous polyposis (FAP): genotype correlation to FAP phenotype with osteomas and sebaceous cysts.
Bisgaard ML, Bülow S.Am J Med Genet A. 2006 Feb 1;140(3):200-

Osteoma on the mandible of a patient with FAP
Int J Med Sci. 2012;9(2):137-41. Epub 2012 Jan 7. Oral and maxillofacial considerations in Gardner's Syndrome. Cankaya AB1,
Erdem MA, Isler SC, Cifter M, Olgac V, Kasapoglu C, Oral CK.

OSTEOMA
CASE SCENERIO
30-40 year old female patient with familial
adenomatous polyposis and arm pain.
Radiograph shows osteoma of the left humerus.
The osteoma was compressing the radial nerve.
Following removal of the osteoma the pain
resolved.

Radiograph of the left humerus
Osteoma

ADRENAL ADENOMA
These are growths of the adrenal gland. They
occur in about 13 out of 100 patients with
FAP. They rarely require removal but do need
monitoring.
Smith TG, Clark SK, Katz DE, Reznek RH, Phillips RK. Adrenal masses are associated
with familial adenomatous polyposis. Dis Colon Rectum 2000;43:1739–42

The adrenal glands
Although the adrenal glands are small, they produce several hormones
that affect almost every system in the body. Hormones are substances
carried through the bloodstream to Many parts of the body where they
regulate various body functions. Hormones produced by the adrenal
glands include:
• Aldosterone
• Androgens
• Catecholamines:
• Epinephrine (adrenaline),
• dopamine, and
• Norepinephrine (noradrenaline)
• Cortisol
• Estrogens
You need only about one-half of one adrenal gland for adequate
hormone function.

MR scan of the abdomen
Lung Lung
Liver
Normal right
adrenal gland
Left adrenal gland with
adenoma
Kidney Kidney

CT scan of the abdomen

Spleen
Normal right
adrenal gland
Left adrenal gland
with adenoma
Liver
Front of the abdominal wall.
Spine

Follow up of adrenal adenoma
• Often called incidentaloma as they are often found
incidentally when testing it performed for another reason.
• Most complete long term data comes from St. Mark’s
hospital (UK)
30 patients with adrenal
adenomas
3 had adrenal
gland removal
2 had adrenal
cancer
Adrenal incidentaloma in familial adenomatous polyposis: a long-term follow-up study and schema for management.
Will OC, Hansmann A, Phillips RK, Palazzo FF, Meeran K, Marshall M, Clark SK.
Dis Colon Rectum. 2009 Sep;52(9):1637-44.

An adrenal gland
can be removed
laparoscopically
through small “key
hole” incisions.

Initial management of adrenal incidentaloma
Signs of cancer?
Dense (10 HU), calcification
> 3.5 cm or rapid growth
Yes
Refer to specialist
No
Exclude hormone production
(see appendix)
Follow up CT MR in one year

Case
• 54 year old man with familial polyposis to clinic.
• MRI for other reasons shows 20 mm left adrenal
adenoma.
• Review of records shows adrenal adenoma present for
since 2006 with it was 16 mm.
• In 10 years has increase in size 4 mm.

DESMOID TUMORS
AGGRESSIVE FIBROMATOSIS
• From “desmos” meaning band or tendon like.
• Tumors of connective tissue.
• “Locally malignant” – cause local complications
(obstruction, abscesses) but do not metastasize.
• Spontaneous regression seen in 20% or more of
cases.
• Risk factors include family history and surgery.

Aggressive fibromatosis.
Fisher, Cyril; Thway, Khin
Pathology. 46(2):135-140, February 2014.
DOI: 10.1097/PAT.0000000000000045
Microscopic view of dermoid tumor
Fig. 1 . This core needle biopsy of typical desmoid fibromatosis
illustrates sweeping fascicles of slender spindle cells evenly
arranged within a uniform collagenous stroma.
© 2014 Royal College of Pathologists of Australasia. Published by Royal College of Pathologists of Australasia.

FRONT
Umbilicus
BACK
Skin

Desmoid tumors are categorized by their location.
Abdominal wall
Subcutaneous
Intra abdominal
Treatment for desmoid tumor is highly individualized. Treatments include
observation, NSAIDs, anti estrogens, surgery, traditional chemotherapy.

ABDOMINAL WALL
DESMOID TUMOR
30-40 year old female patient with familial
polyposis. The patient has a family history of
desmoid tumor in her brother and father.
Following single incision subtotal colectomy the
patent developed an abdominal wall desmoid
tumor while taking sulindac and raloxifene.

FRONT
Umbilicus
BACK

ABDOMINAL WALL
DESMOID TUMOR
Patient did not opt for surgery. She continued
treatment with Sulindac and raloxifene. The patient
sought out a specialist center and was enrolled in a
trial of the chemotherapeutic drug sorafenib. Follow
up six months later shows no change or slight
decrease in size of the desmoid tumor.

REGRESSION OF
INTRA ABDOMINAL
DESMOID TUMOR
A male patient with attenuated familial polyposis
between the ages of 50 and 60.
Desmoid tumor regressed while treated with
sulindac 150 mg by mouth once a day, curcumin
and fish oil.

Day 1

Day 1
Desmoid tumor

Day 386

Day 1094

THE THYROID GLAND
AND FAP
50 FAP patients had thyroid U/S
• 7 (21%) patients with different textures in their
thyroids (heterogeneous)
• 27 (79%) with thyroid nodules.
• Of the 52 nodules found, 12 (19%) nodules were at least
10 mm (range 2 to 35).

Cribriform – Morular variant
of PTC is associated with FAP
Int J Med Sci 2004;
1(1):43-49.
doi:10.7150/ijms.1.43
Cribriform-Morular
Variant of Papillary
Carcinoma:
Association with
Familial Adenomatous
Polyposis - Report of
Three Cases and
Review of Literature
Shylashree
Chikkamuniyappa ,
Jaishree Jagirdar

Thyroid Cancer and FAP
• About 5 out of 100 FAP patients will have papillary thyroid
cancer (PTC) on a one time screen (general population
less than 1 in 1000).
• Much more common in young female patients than males
(17 females:1 male)
• Very few recurrences of PTC in FAP patients and only one
death possibly related to FAP-associated PTC.
• No widely accepted recommendations for screening.
• DRJ recommends all patients have at least 1 thyroid
ultrasound.
Am J Surg. 2014. Results of a prospective thyroid ultrasound screening program in adenomatous polyposis patients.
Steinhagen E1, Hui VW1, Levy RA1, Markowitz AJ2, Fish S3, Wong RJ4, Sood R1, Ochman SM1, Guillem JG5.
Ann Surg. 2014 Jan 2. Screening for Thyroid Cancer in Patients With Familial Adenomatous Polyposis.
Cetta F1, Ugolini G, Martellucci J, Gotti G.

Hepatoblastoma in FAP
• Most patients with hepatoblastoma do not have FAP
(10%, 5 of 50).
• Risk about 1 in 200 (Population risk 1 in 100,000), study
2/470 (0.42%).
• Screening would be AFP and U/s every 3 months until the
age of 4.
• Screening be offered with caveats
• 1/200 risk
• 75% hepatoblastoma patients cured without screening, so screening for
25%
Am J Med Genet. 1992 Aug 1;43(6):1023-5. Risk of hepatoblastoma in familial adenomatous polyposis. Hughes LJ1, Michels VV.
Pediatr Blood Cancer. 2006 Nov;47(6):811-8.
Should children at risk for familial adenomatous polyposis be screened for hepatoblastoma and children with apparently sporadic
hepatoblastoma be screened for APC germline mutations?Aretz S1, Koch A, Uhlhaas S, Friedl W, Propping P, von Schweinitz D, Pietsch T.

Duodenal polyposis
• Almost all FAP patients will have duodenal polyps.
• 1/3 of patients will progress to severe disease (Spigelman
stage IV) and require surgery to remove the doudenum.
• Median age of stage IV disease is 45 years old.
Ann Surg. 2014 Jun 19. Progression and Management of Duodenal Neoplasia in Familial Adenomatous Polyposis: A Cohort Study.
Serrano PE1, Grant RC, Berk TC, Kim D, Al-Ali H, Cohen Z, Pollett A, Riddell R, Silverberg MS, Kortan P, May GR, Gallinger S.

Duodenal f/u for FAP is determined by the Spigelman score
Criterion One point Two points Three points
Polyp number 1-4 5-20 >20
Polyp size (mm) 1-4 5-10 >10
Histology Tubular Tubulovillous Villous
Dysplasia Mild Moderate* Severe**
Vasan, Gut, 2008. Bülow, Gut 2004.
*A low degree of
dysplasia
according to
current
classification.
**A high degree
of dysplasia.
Stage (points) Follow up (yrs)
0 (0) 5
I (1-4) 5
II (5-6) 3
III (7-8) 1-2
IV (9-12) EUS ? surgery
V Adenocarcinoma
S
t
t
p

S
t
e
p


Stomach polyps in FAP
• Supportive of the diagnosis.
• Seen about 50% of patients.

EPA TYPE FISH OIL FOR THE PREVENTION
OF POLYPS IN THE RETAINED RECTUM
OF FAP PATIENTS
55 FAP patients
6 months
28 EPA 1000 mg twice a day
27 Placebo
West N J et al. Gut 2010;59:918-925. 20348368.

EPA is a subtype of fish oil.

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

EPA FISH OIL POLYP PREVENTION EFFECT
SIMILAR TO CELECOXIB
22 % NET REDUCTION WITH 1 GM EPA BID.
 TO DECREASE FROM 5 TO 4 POLYPS IN OBSERVED AREA

Summary slide
• Extracolonic features can prompt evaluation for FAP or
aid in the diagnosis.
• Two extracolonic features are the major causes of
morbidity and mortality in FAP
• Desmoid tumors
• Duodenal polyposis
• Referral to specialist centers
• All patients with
• Spigelman stage IV duodenal polyposis
• Intra abdominal desmoid
• Referral should be considered for
• All patients with desmoid tumors
• Fish oil (EPA) has been shown to be effective for FAP in a
randomized blinded study.

END

TABLE 1
Mortality of Intra-Abdominal Desmoid Tumors in
Patients With Familial Adenomatous Polyposis: A Single
Center Review of 154 Patients.
Quintini, Cristiano; Ward, Gregory; Shatnawei, Abdullah;
Xhaja, Xhileta; Hashimoto, Koji; MD, PhD; Steiger, Ezra;
Hammel, Jeffrey; Diago Uso, Teresa; Burke, Carol;
Church, James; MBChB, FRACS
Annals of Surgery. 255(3):511-516, March 2012.
DOI: 10.1097/SLA.0b013e31824682d4
TABLE 1 . Desmoid Tumor Staging System
© 2012 Lippincott Williams & Wilkins, Inc. Published by Lippincott Williams & Wilkins, Inc. 2

FIGURE 2
Mortality of Intra-Abdominal Desmoid Tumors in
Patients With Familial Adenomatous Polyposis: A Single
Center Review of 154 Patients.
Quintini, Cristiano; Ward, Gregory; Shatnawei, Abdullah;
Xhaja, Xhileta; Hashimoto, Koji; MD, PhD; Steiger, Ezra;
Hammel, Jeffrey; Diago Uso, Teresa; Burke, Carol;
Church, James; MBChB, FRACS
Annals of Surgery. 255(3):511-516, March 2012.
DOI: 10.1097/SLA.0b013e31824682d4
FIGURE 2 . Desmoid tumor patients. Survival by stage.
© 2012 Lippincott Williams & Wilkins, Inc. Published by Lippincott Williams & Wilkins, Inc. 2

ILEOSTOMY SITE
NEOPLASIA

PROLAPSING POLYP
FROM PATIENT WITH J
POUCH

TREATMENT OF FAP
WITH FISH OIL

POLYP PROLAPSING
THROUGH ANUS OF
PATIENT WITH J POUCH
Patients with FAP who have a J pouch should
have a pouchoscopy (endoscopic
examination of the pouch) at least every 12
months.

+
Adrenal incidental work up
• Exclude hyperfunction by once-off screen:
• 1. Check and record BP
• 2. History and examination for Phaeo ,
• Cushings, or Conns:
• - Headache, sweating, palpitations
• - Centripetal obesity, striae, bruising
• - Occasionally muscle tiredness, polyuria
• 3. 24-hour acidified urine collection for free
• catecholamines (via GP if necessary)
• 4. Blood tests: ACTH, U&E (ACTH to exclude
• subclinical Cushings; although lab range 0-80nM,
• most normals 30-50. REFER If undetectable)

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