Transcript GI Grand Rounds

GI Grand Rounds
October 1, 2004
Yoshi Makino, M.D.
USC Department of Internal Medicine
Case Presentation
Patient F.B. is a 64 year old AfricanAmerican male, referred from an outside
M.D. for OB(+) stool and anemia. Patient
was scheduled for colonoscopy based on
the above indications.
PSH: none
PMH:
– HTN
– hyperlipidemia
Case Presentation
SH:
– EtOH: 1-2 beers/day,
6-pack on weekends x 40 years
– Tobacco: ¾ ppd x 40 years
– Drugs: Marijuana in youth; without h/o IVDA
ROS:
– Denies h/o BRBPR, melena, stool caliber
changes, nor weight loss. Without h/o GERD
or other upper GI complaints.
Case Presentation
Allergies: NKDA
Medications
–
–
–
–
–
–
–
–
Pravachol 40 mg PO daily
HCTZ 25 mg PO daily
Atenolol/Chlorthalidone 50 mg / 25 mg PO daily
Quinapril 40 mg PO daily
Norvasc 10 mg PO daily
Cardura 2 mg PO daily
EC ASA 81 mg PO daily
Darvocet or Tylenol 500 mg prn pain/HA
Laboratories
5.3
MCV
RDW
Ferr
13.0
39.1
81.6
17.6
191
TIBC
Fe
%Sat
278
Alk P
TProt
Alb
TBili
55
DBili
140
103
14
3.8
20
0.8
129
7.9
4.3
0.5
0.1
AST
ALT
78
29
18
Colonoscopy
Poor prep
Anus: small IH
Sigmoid: 2 cm flat polyp, s/p bx
Transverse colon: one diminutive polyp
and a 1.5 cm sessile polyp, s/p bx
Ascending colon: multiple 2-9mm sessile
polyp, s/p bx
Biopsy Results
8 of 11 polyps biopsied showed tubular
adenoma
Of these 8 polyps, 2 also showed areas of
focal increased glandular complexity and
high grade dysplasia
Colonoscopy Images
Colonoscopy Images
What Now?
Family History
Colon CA; Age 70’s
Colon CA; Age 68
“Bone” CA; Age 64
Unscreened
Colon CA; dx age 46;
Presently 66
1 adenomatous polyp
@ age 42, now 46
Attenuated FAP
Objectives
Overview
Clinical Features
Diagnosis
Genetics
Management
FAP Overview
Familial colorectal cancers account for
< 5% of all cases of colon cancer
Yangming et al. AJG 2002;97(7)1822-1827.
Familial Adenomatous Polyposis (FAP) was first
described by Lockhart-Mummery in 1925 as a
disease with clear dominant inheritance
Adenomatous Polyposis Coli (APC: 5q21) gene
identified by Kinzer and Groden in 1991
Attenuated FAP
In 1990, Lynch et al described two families with
“right-sided colonic flat adenomas” with more
polyps than HNPCC but fewer than FAP
Lynch also observed later age of onset of colon
cancer, and a paucity of rectal adenomas
Lynch et al. Cancer. 1990 Sep 1;66(5):909-15.
Initially called “hereditary flat adenoma
syndrome”, later called attenuated FAP
Clinical Features
Less than 100 adenomas, typically
morphologically flat
Polyps primarily located proximal to the
splenic flexure, sparing the rectum
Diagnosed at mean age of 44 years, and
cancers at a mean of 56 years
Hernegger et al. Dis Colon Rectum. 2002 Jan;45(1):127-136.
Extracolonic Manifestations
High association with gastric fundic polyps
Extracolonic cancers similar to FAP, including:
–
–
–
–
duodenal and periampullary tumors (5-10%)
pancreatic (2%)
thyroid (2%)
Gastric (0.5%)
Congenital Hypertrophic Retinal Pigment
Epithelium (CHRPE), osteomas and desmoids
are rarely seen
Hernegger et al. Dis Colon Rectum. 2002 Jan;45(1):127-136.
Comparison of Hereditary
Colorectal Diseases
FAP
AFAP
HNPCC
Inheritance
Dominant
Dominant
Dominant
Incidence
1:10,000
1:100,000
1:2,000
Gene Defect
APC
APC / MYH ?
MMR
Colonic Polyps
Always > 100,
often >1000
10 - 100, usually
proximal
Few, sporadic
Lifetime CRC Risk
Near 100%
70-80%
> 80%
Average age of CRC
39
49
44
Adapted from Grady. Gastro. 2003;124:1574–1594
Distinguishing Flat Polyps
Eisen et al. Gastrointest Endosc 2002;55:687-94.
High-resolution Chromoendoscopy
Hyperplastic Polyp
Adenomatous Polyp
“Pit” pattern
“Grooves”
Eisen et al. Gastrointest Endosc 2002;55:687-94.
High-resolution Chromoendoscopy
Conventional dyes (e.g. 0.9% indigo carmine) or
florescent dyes used in conjunction with a highresolution endoscope (410k – 850k pixels
vs standard scopes 100k – 200k pixels)
Hyperplastic polyps
– a characteristic “pit” pattern of orderly arranged circular “dots,”
morphologically similar to surrounding normal mucosa.
Adenomatous Polyps
– surface “grooves” occasionally with a sulcus-like appearance
In a recent multicenter trial by Eisen et al.,
chromoendoscopy had a sensitivity of 82% and
specificity of 82% in distinguishing the above polyps
Eisen et al. Gastrointest Endosc 2002;55:687-94.
Gastric Fundic Gland Polyps
Fundic gland polyps account for 50% of all
gastric polyps and are observed in 0.8-1.9% of
all patients undergoing EGD
Studies estimate 52-88% of FAP patients have
gastric fundic glands polyps
Unlike colonic adenomas, the number of gastric
fundic gland polyps is not attenuated in AFAP
Burt. Gastro 2003;125:1462-1469.
Prevalence of duodenal and gastric adenomas
is unknown, varying from 93% in one series to
0% in another
Lynch. Cancer. 1995. / Rozen. Jpn J Cancer Res. 1999
Endoscopic Features
Polyps are sessile, hemispherical elevations, at
times with a “waist” but no clear stalk
1 mm to 5 mm in diameter
Color is pale, pink, resembling surrounding
mucosa
On biopsy, polyps “chunk off” or detach entirely
at the base
Usually fewer than 10 polyps in sporadic cases,
versus hundreds in FAP and AFAP
Burt. Gastro 2003;125:1462-1469.
Gastric Fundic Gland Polyps
FAP
AFAP
Burt. Gastro 2003;125:1462-1469.
Diagnostic Criteria for AFAP
Leppert et al suggest a set of diagnostic
criteria for the disease
–
A positive family history of colorectal cancer with at
least one of the following criteria
CRC at any age
> 5 colorectal adenomas
2-4 adenomas and multiple gastric fundic polyps
Leppert et al. N Engl J Med 1990; 322:9.
Later studies suggest a fourth criteria
Number of colorectal adenomas must be < 100
Knudsen et al. Familial Cancer. 2003;2:43-55
Problems with the Criteria
No consensus exists on the exact definition of
AFAP
– Cases of AFAP have been reported with
adenomatous polyps in excess of 100
– The age at which adenoma counts should be
made is undefined
Burt et al investigated 120 patients from 2
families with AFAP (5’ mutation) revealing
median number of 25 polyps, with a range of
0-470 polyps
Burt et al. Gastro. 2004;127:444-451
Extreme Phenotypic Variability
Burt et al. Gastro. 2004;127:444-451
The Genetics of AFAP
Spirio et al in 1993 identifies four mutations at
the 5’ end (exon 3) of the APC gene in seven
families with AFAP
Spirio et al. Cell. 1993; 75: 951-7.
Since then, 38 distinct mutations have been
identified
– 5’ to codon 175 (15)
– 3’ to codon 1596 (12)
– Exon 9 (10)
– Deletion of entire allele (1)
APC Gene Mutations
Nicola et al. Human Molecular Genetics. 2001.
APC Mutation Phenotypes
Colored regions = mutations / Grey areas = translated regions
Nicola et al. Human Molecular Genetics. 2001;10:7.
A Model for Mutation and FAP
APC gene is a classic tumor suppressor gene,
primarily down-regulating intercellular β-catenin
activity and ultimately slowing cell cycle entry
and progression
“Dominant negative model” suggests that the
mutated gene product forms homodimers with
the wild-type protein, causing lowered or
abolished tumor suppressor activity
APC, β-catenin and E-cadherin
Fearnhead et al. Hum Mol Gen. 200`;`0(7):721-733.
An Explanation for Attenuation?
5’ to codon 175
– Mutation in this region affect the homodimer forming
domain of the APC gene (amino acids 6-57)
– Interactions between mutated and wild-type proteins
are reduced
3’ to codon 1596
– Gene product not detectable by Western blot analysis
– Suggests mRNA or protein degradation
Exon 9
– Even wild-type allele undergoes significant
physiological splicing in this region
– Alternate splicing pathways may “skip over” mutation
MYH Mutations
MYH along with OGG1 and MTH1 are
proteins involved in the repair G:C to T:A
transversions due to oxidative stress from
8-hydroxyguanine
Recently, inherited variants of the MYH
gene have been associated with colorectal
polyposis with a recessive pattern of
inheritance
Al Tassan et al. Nat Genet. 2002;30:227-232.
Jones et al. Hum Mol genet. 2002;11:2961-2967.
MYH Mutation and AFAP
MYH-associated polyposis is
phenotypically similar to attenuated FAP
– Later age of onset of polyposis than FAP
– Polyps usually < 100, but counts of 500 have
also been reported
Mutations in MYH may lead to G:C to T:A
transversions in the APC gene
However, autosomal recessive pattern
Wang et al. Gastro. 2004;127:9-16.
MYH Mutation and AFAP
In a recent study, Wang et al analyzed 984
patients with high risk for genetic mutation
– 313 patients with 1-3 adenomatous polyps on colonoscopy
– 444 patients with history of CRC
– 140 patients referred for probable FAP
18 patients with biallelic mutations were
identified
– 2 patients with colorectal cancer at age > 51
– 16 patients with 20 - 500 adenomatous polyps
– No patients with polyp counts < 20 had a biallelic MYH mutaition
Wang et al. Gastro. 2004;127:9-16.
Genetic Testing for AFAP
Clinical criteria for AFAP met
– Greater than 5 to 10 and less than 100 colorectal
adenomas
– 2-4 adenomas and multiple gastric fundic polyps
First-degree relatives of a person with a known
APC mutation, regardless of polyp status
A person with multiple adenomas who is a
relative of a person with a known APC mutation
Grady. Gastro. 2003;124:1574–1594
Role of MYH Testing in AFAP
“At this time, there are insufficient clinical
data regarding the role of MYH
mutations… in people with adenomatous
polyposis to make any recommendations
regarding the use of MYH mutation
analysis in the clinical management of
these individuals.”
Grady. Genetic Testing for High-Risk Colon
Cancer Patients. Gastro 2003;124:1574–1594
Recap of Disease Course
Generally age at onset and progression to
cancer (44 and 56 years respectively) is
15 years later than that of classic FAP
Lesions usually proximal to the splenic
flexure
Rectal sparing
Gastric fundic gland polyps commonly
seen
Surveillance Recommendations
Surveillance must be by colonoscopy
– Due to lesions proximal to splenic flexure
– Contrasts with screening by flexible
sigmoidoscopy in classic FAP
Colonoscopy starting at 10–17 years,
annually
EGD starting at 30 years, every 1–3 years,
depending on polyp status in duodenum
Grady. Gastro. 2003;124:1574–1594
Management
Increased risk of colon cancer, but exact risk remains
unknown (general consensus is roughly 60-80%)
Similar to FAP, disease progression from adenoma to
carcinoma is not accelerated
Colonoscopy
– Unlike FAP, there is a sufficiently low number of
colonic polyps to make polypectomy practical
Burt et all. Gastro. 2004;127:444-451.
EGD
– Best treatment of gastric fundic gland polyps is
presently unknown
Burt. Gastro 2003;125:1462-1469.
When to Perform Colectomy?
The exact risk of colon cancer is unknown in AFAP, but
estimated between 60 – 80%
In FAP patients, The American Society of Colon and
Rectal Surgeons recommends colectomy between ages
15 to 18
Church and Simmang. Dis Colon Rectum, August 2003.
No clear consensus exists for AFAP
– 15 year delay in onset of disease would suggest
colectomy at age 30
– In a series of 120 patient with AFAP by Burt et al., first
CRC was at a mean age of 58 years (range of ages
29 to 81), with 12 patients over the age of 60 with
intact colons
Burt et all. Gastro. 2004;127:444-451.
Type of Surgery
Three main surgical options
– Colectomy and ileorectal anastomosis (IRA),
– Proctocolectomy with ileostomy (TPC)
– Proctocolectomy with ileal pouch-anal anastomosis
(IPAA)
As AFAP almost always spares the rectum,
present consensus is for IRA, with subsequent
surveillance by flexible sigmoidoscopy annually
Bülow et al. Gastro. 2000;119:1454–1460.
Church and Simmang. Dis Colon Rectum, August 2003.
Pharmacologic Therapy
Treatment with sulindac and celecoxib may also
reduce polyp burden
Giardiello et al. N Engl J Med 1993;328:1313-1316.
Steinbach et al. N Engl J Med 2000;342:1946–52.
In 1999, FDA approves celecoxib as a treatment
for patients with FAP
– Dosage: celecoxib 400 mg PO BID
– “To reduce the number of adenomatous colorectal
polyps in familial adenomatous polyposis (FAP), as
an adjunct to usual care (e.g., endoscopic
surveillance, surgery).”
FDA Application NDA 21-156 & 20-998/S007
Celecoxib and FAP
Steinbach et al. N Engl J Med 2000;342:1946–52.
Sulindac and FAP
15 case series and at least 4 randomized, controlled
trials have proven the efficacy of NSAIDs (primarily
sulindac) in reducing the adenoma burden of
persons with FAP
However, in a recent trial by Giardiello, sulindac did
not significantly reduce or delay the emergence of
colorectal adenomas in prephenotypic FAP patients
Definitive clinical outcomes (e.g., reductions in CRC
morbidity and mortality or changes in surveillance
practices) have yet to be proven.
Hawk et al. Gatro. 204;126:1423–1447.
Giardiello et al.N Engl J Med 2002;346:1054–1059.
Conclusions
Attenuated FAP is a rare cause of CRC, accounting for
<0.1% annually
However, distinguishing AFAP from sporadic polyps is
critical as the lifetime risk for CRC may be as high as 6080%
Suspicion for AFAP should be heightened in:
– the presence of > 5-10 colonic polyps (especially proximal
distribution)
– 2-4 adenomas and multiple gastric fundic polyps
Family history should be obtained, and genetic testing
should be offered to all first degree relatives
Conclusions
Annual colonoscopy with polypectomy
may be sufficient to prevent progression of
disease
Pharmacologic therapy with celecoxib/
sulindac may further aid in reducing polyp
burden
No consensus yet regarding need for
colectomy, however when required, IRA is
believed to be sufficient
The Future of AFAP
AFAP remains a poorly defined entity
– While most literature associates AFAP with specific
APC mutations, recent literature suggest MYH
mutations may also be seen in this disease
Wang et al. Gastro. 2004;127:9-16.
– Consensus on a gold-standard test for AFAP is
required to reliably report and follow the course of this
disease
Cumulative lifetime polyp counts
– To better understand progression of disease
– To reach a consensus regarding age that polyp count
should be made
Patient Follow-up
Patient had an EGD on 9/20/2004 to
evaluate for gastric fundic gland polyps
and periampullary disease
– No significant lesions found
Patient underwent genetic counseling at
Norris Comprehensive Cancer Center on
9/24/2004, and is presently pending
results of genetic testing
Acknowledgements
Dr. Laurie DeLeve
Dr. Mark Ewing
GI Consult Team
This presentation is available at:
http://www.makino.net/gastro
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