Download Inflammatory bowel disease and familial adenomatous polyposis

Journal of Crohn's and Colitis (2013) 7, e103–e107
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SHORT REPORT
Inflammatory bowel disease and familial
adenomatous polyposis☆
N. Jewel Samadder a,⁎, Michele Gornick b , Jessica Everett b ,
Joel K. Greenson c , Stephen B. Gruber a, b, d,1
a
Department of Internal Medicine, University of Michigan Medical School, USA
Department of Human Genetics, University of Michigan Medical School, USA
c
Department of Pathology, University of Michigan Medical School, USA
d
Department of Epidemiology, School of Public Health, Ann Arbor, MI, USA
b
Received 5 May 2012; received in revised form 28 June 2012; accepted 29 June 2012
KEYWORDS
Familial adenomatous
polyposis (FAP);
Ulcerative colitis;
Inflammatory bowel
disease (IBD)
Abstract
Background: Inflammatory bowel disease (IBD) and familial adenomatous polyposis (FAP) are
uncommon diseases and both are associated with marked increased risk of colorectal cancer.
Methods: We present a patient diagnosed in parallel with ulcerative colitis and FAP. Mutational
analysis of the APC germline and somatic DNA was performed by sequencing.
Results: This patient's phenotype consisted of polyps only on the right side of the colon (cecum
and ascending colon) whereas the area affected by ulcerative colitis (descending colon and
rectum) was free of polyps on endoscopy and microscopic adenomas on histology. This raises the
possibility that mosaicism or inflammation in the presence of active ulcerative colitis modified
the phenotypic expression of adenomatous polyposis in the left colon. Mosaicism was excluded
by DNA analysis.
Discussion: This case of a patient diagnosed with both inflammatory bowel disease and familial
adenomatous polyposis offers potential insights into the distinct pathogenesis of cancer
susceptibility within these syndromes, and suggests that a collision of phenotypes may influence
their mutual presentation. Both of these conditions independently increase the risk of colorectal
cancer.
© 2012 European Crohn's and Colitis Organisation. Published by Elsevier B.V. All rights reserved.
☆
Grant support: This work was supported in part by the National Cancer Institute RO1 CA81488 (Dr. Gruber), and the University of Michigan's
Cancer Center Support Grant (5 P30 CA465920).
⁎ Corresponding author at: Division of Gastroenterology, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA. Tel.: + 1
801 585 2357; fax: + 1 801 581 7476.
E-mail address: [email protected] (N.J. Samadder).
1
Current affiliation: Norris Cancer, University of Southern California, Los Angeles, CA, USA.
1873-9946/$ - see front matter © 2012 European Crohn's and Colitis Organisation. Published by Elsevier B.V. All rights reserved.
doi:10.1016/j.crohns.2012.06.021
e104
1. Introduction
Ulcerative colitis (UC) is a relapsing inflammatory bowel
disease, associated with an increased risk of colorectal cancer
of approximately two to five fold over general population. 1
This increased risk of cancer is associated with disease
severity, extent and duration. 2
About 5 to 10% of colorectal cancer is due to an identifiable
genetic cause. Familial adenomatous polyposis (FAP) is a
genetic condition which predisposes individuals to 100 s to
1000 s of colorectal polyps, with an average age of onset at
16 years. FAP is caused by mutations in the APC gene and is
inherited in an autosomal dominant fashion. 3 Without appropriate intervention, risk of colorectal cancer in individuals
with FAP is virtually 100%. 3,4
2. Case presentation
A 59 year old male was referred to the outpatient gastroenterology clinic for assessment of diarrhea for 5 months. He
described having greater than five watery bowel movements
per day associated with urgency and occasional rectal
bleeding. This was a change from previous bowel frequency
of one well formed stool per day. There was no history of
infectious risk factors such as travel or sick contacts. He did
not report any previous history of rectal bleeding, chronic
diarrhea, extra-intestinal features such as arthritis, erythema
nodosum or oral aphthous ulceration.
His only medications were ranitidine and ibuprofen as
needed (less than one dose per week). His only medical
history was that of gastro-esophageal reflux, dyslipidemia
and benign positional vertigo. He did not have a personal or
family history of inflammatory bowel disease or microscopic
colitis. However, the family history was significant for his
father having died from metastatic colorectal cancer at age
77 and his sister having a clinical diagnosis of familial
polyposis at age 50 without confirmatory genetic testing,
treated with colectomy (Fig. 1a).
His bloodwork was normal, including erythrocyte sedimentation rate, C-reactive protein, celiac serology and infectious
stool studies.
Upper endoscopy with random biopsies of the duodenum
revealed multiple sessile polyps in the fundus along with a
single flat polyp located at the ampulla. Biopsies of the
stomach revealed fundic gland polyps, two of which had
histologic evidence of low grade dysplasia. One gastric polyp
was an adenoma (Fig. 1b), as was the ampullary polyp.
Colonoscopy showed many sessile 2–10 mm polyps in cecum,
ascending colon and transverse colon that were too numerous
to resect completely (Fig. 1c). Also, a diffuse area of granular,
erythematous mucosa with loss of vascularity was noted
extending from anus to descending colon (40 cm from anal
verge) (Fig. 1d). Biopsies of cecal polyps were consistent with
adenomas (Fig. 1e). Biopsies from the descending colon and
rectum showed active ulcerative colitis without dysplasia
(Fig. 1f). Though his laboratory parameters were normal
(including ESR and CRP) his acute onset symptoms of diarrhea
and hematochezia and endoscopic findings of left sided colitis
were consistent with a flare of ulcerative colitis.
His constellation of findings was consistent with a clinical
diagnosis of FAP and he was referred to Cancer Genetics.
N.J. Samadder et al.
DNA sequence analysis of APC was performed on a blood
sample in a CLIA-certified lab. Independent verification of the
identified mutation was performed in our research lab from a
second tube of blood. Adenomas from right colon and areas of
ulcerative colitis from left colon were obtained at the time of
surgical resection through the University of Michigan Tissue
Core. Frozen sections of affected areas were evaluated
by routine hematoxylin and eosin (H&E) stains by a surgical
pathologist. Areas of at least 70% cellularity within the
adenomas and areas of ulcerative colitis, as well as adjacent
normal tissue were microdissected, and DNA was extracted
using a TRIzol Reagent (Life Technologies, Gaithersburg, MD).
PCR and capillary sequencing confirmed a deletion in exon 4,
of adenosine and thymidine residues at position 426_427of
APC in the genomic DNA. The mutation was also identified in
DNA from samples of adenoma, ulcerative colitis and adjacent
normal tissue (Fig. 2). This mutation is predicted to result in
a premature protein truncation and confirms a molecular
genetic diagnosis of FAP.
Bilateral or multiple congenital hypertrophy of the
retinal pigment epithelium (CHRPE) is another finding seen
in association with FAP, this patient did not undergo an
indirect ophthalmoscope exam through a dilated pupil since
genetic testing confirmed a molecular diagnosis of FAP.
With molecular confirmation of FAP and histologic
confirmation of ulcerative colitis the patient was referred
to colorectal surgery and underwent total abdominal
colectomy with J-pouch creation and ileo-anal anastamosis
as a single procedure. This was intended to be a curative
treatment for both FAP and ulcerative colitis.
3. Discussion
The risk of intestinal cancer in IBD has been identified in both
referral center 5,6 and population-based studies 1,7 and ranges
between a 2.5 and 5 fold elevation over the general population.
Treatment of UC is divided into medical and surgical management. Medical treatment includes anti-inflammatory medications such as amino-salicylates, immunomodulators such as
imuran and prednisone along with anti-TNF biologic agents such
as infliximab. 8 There is debate whether these medications can
decrease the risk of colorectal cancer. 9 Surgical management
of UC includes total abdominal or procto-colectomy, which is
believed to be curative.
About 5 to 10% of colorectal cancer diagnosis is due to an
identifiable genetic cause. The differential diagnosis for
these genetic causes includes Lynch Syndrome (formerly
described as HNPCC) which accounts for 2–3%, FAP which
accounts for 1% and other rare conditions which account for
approximately 1%. 10 This patient's personal and family
history of polyps and colon cancer led to a clinical diagnosis
of FAP. FAP is caused by mutations in the APC gene, located
on chromosome 5. 3,4 FAP can present with a “classical” or
“attenuated” phenotype. While the “classical” phenotype
displays N 1000 polyps and frequently presents early in life,
the “attenuated” phenotype often has b 100 polyps and can
present much later in age. Mutations in the APC gene that
have been described to cause the “attenuated” phenotype
are typically located in the 5′ or 3′ regions of the gene. 11,12
The risk of colorectal cancer in classic FAP is virtually 100%.
These patients are also at risk of developing duodenal,
Inflammatory bowel disease and familial adenomatous polyposis
e105
Figure 1 a. Family pedigree. b. Esophogastroduodenoscopy showing multiple fundic gland polyps, 2 of which had histologic
evidence of low grade dysplasia and one gastric polyp was an adenoma. c. Colonoscopy showing cecum covered in innumerable small
adenomatous polyps. d. Colonoscopy showing granularity and erythema in descending colon, endoscopic and histologically consistent
with ulcerative colitis. e. Medium-power view of the right colon showing a small (microscopic) tubular adenoma (arrows). Multiple tiny
adenomas such as this as well as larger macroscopically visible adenomas were scattered throughout the right colon. f. Medium-power
view of the left colon showing active ulcerative colitis. Note the crypt abscess (arrow) and dense lamina propria inflammation. No
adenomas were seen in the areas involved with colitis.
ampullary and rarely gastric tumors. 3 Neklason et al. describe
two large American kindreds with the identical FAP mutation
to our patient (426_427delAT). 13 They describe a highly
variable phenotype in affected individuals with this mutation
and estimate a cumulative risk of colorectal cancer by age 80
of 69% with a corresponding standardized incidence ratio of
17.9 (95% CI, 8.4–24.7). 13 Management of FAP includes annual
surveillance colonoscopy to remove polyps until the polyp
burden makes endoscopic removal not feasible. Colectomy is
recommended for extensive polyposis. Since the risk of rectal
cancer developing after subtotal colectomy in FAP is high,
most experts advise total proctocolectomy with ileal pouch
anal anastamosis. If rectal tissue is left intact at time of
surgery, then yearly flexible sigmoidoscopy must continue to
prevent the appearance of neoplasia in this area. Periampullary
and duodenal tumors are surveyed with the use of annual
forward and side-viewing esophogastroduodenoscopy (EGD). 14
The hereditary flat adenoma syndrome (HFAS) is an
autosomally dominant inherited condition with multiple
colonic adenomas (usually less than 100) with a tendency for
proximal location that would be consistent with the presentation in our patient. Given its linkage to the FAP locus on 5q
e106
N.J. Samadder et al.
Reference sequence:
5’ T
T
T
T
T
A
T
C
C
A
G
Genomic DNA sequence:
5’ T
T
T
T
T
A
T
C
C
A
G
T
A
A
C
G
A
A
G
A
A
C 3’
A
C
G
A
A
G
A
A
C 3’
Figure 2 Chromatogram showing a deletion in exon 4, of adenosine and thymidine residues at position 426_427of APC in reference
(ceph) and genomic DNA.
and the phenotypic parallels between HFAS and FAP researchers have concluded that HFAS is a variant of FAP. Though
our patients' presentation would be consistent with HFAS, this
would not change the diagnosis of FAP, since a mutation was
found in APC (confirming a molecular diagnosis of FAP) and
HFAS is likely a variant of FAP, similar to the usage of the
term Gardner syndrome to reflect a variant of FAP with
extra-intestinal manifestations. 15
Though attenuated FAP can present with b 100 polyps,
adenomas are typically distributed throughout the entire
colon. In fact, the majority of patients with FAP begin to
develop polyps during their childhood, mostly in the distal
colon (rectosigmoid). 16 Also, the polyps seen in the right
colon of this patient were not consistent with inflammatory
pseudopolyps since they were adenomatous. This patient's
phenotype consisted of polyps only on the right side of the
colon (cecum and ascending colon) whereas the area
affected by ulcerative colitis (descending colon and rectum)
was free of polyps on endoscopy and microscopic adenomas
on histology. This raises the possibility that either mosaicism
or inflammation accompanying active ulcerative colitis
modified the phenotypic expression of adenomatous polyposis in the left colon.
There have been several reports in the literature of
somatic mosaicism in patients with FAP. These patients have
a wide spectrum of colonic and extra-colonic phenotype
depending on the cellular level of mosaicism. 17,18 In this case,
we have demonstrated the presence of the APC 426-427delAT
mutation in genomic, polyposis-affected right colon and
non-polyposis, inflamed left colon, therefore eliminating
mosaicism as a cause of the observed phenotype. Expert
pathology review confirmed the lack of microscopic adenomas
and aberrant crypt foci (ACF) in the left colon. This may
suggest that inflammation associated with UC suppresses
polyposis at a very early stage leading to the lack of even ACF.
All of these findings further strengthen our argument that the
UC-inflammation modifies the expression of FAP in this
patient. To further investigate whether mucosal inflammation
acts to suppress polyposis there are several animal models of
UC 19 that could be introduced into the APCmin + mice 20 to
model the patient's symptoms. However, these animal models
are limited, as the chemical colitis induced in the UC models
differs histologically and in neoplasia development then
human disease. 19 Most APCmin + mouse models also have a
different colonic phenotype then human FAP, with most of the
intestinal tumors occurring in the small bowel. 20,21 Other
reports of inflammatory bowel disease with colonic inflammation (UC or Crohn's colitis) in patients with FAP may also
shed further light on our hypothesis.
This case of a patient diagnosed with both inflammatory
bowel disease (ulcerative colitis) and familial adenomatous
polyposis offers potential insights into the distinct pathogenesis
of cancer susceptibility within these syndromes, and suggests
that a collision of phenotypes may influence their mutual
presentation. Both of these conditions markedly increase the
risk of colorectal cancer independently. Treatment of both
conditions was accomplished with total colectomy with ileoanal
anastamosis. The clinical expression of FAP in this case (right
sided polyposis without accompanying left-sided polyposis)
suggests the hypothesis that mucosal inflammation secondary
to UC may alter the formation or expression of adenomas.
Conflict of interest
Guarantor of the article: Stephen B. Gruber, MD, PhD.
Specific author contributions: All authors approved
the final draft submitted. Study concept and design, data
collection, analysis, interpretation, article preparation and
manuscript review: Stephen B. Gruber; study concept and
design, data analysis and interpretation, and article preparation: N. Jewel Samadder; data analysis and manuscript
review: Jessica Everett and Michele Gornick; data interpretation and manuscript review: Joel K. Greenson.
Financial support: NCI R01 CA81488, NCI P30 CA465920.
Potential competing interests: No authors have conflicts
of interest to declare.
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