Neoplastic vs NonNeoplastic Colon Polyps

Marianne Fahmy
Core Curriculum Lecture
September 14, 2010

Outline

Non-Neoplastic Polyps

Hamartomatous

Hyperplastic
Mucosal
Inflammatory Pseudopolyps
Submucosal (can be non-neoplastic and neoplastic)
Juvenile Polyps
Peutz-Jeghers

Inherited Family Disorders: Polyposis syndromes

Neoplastic Polyps (adenomas and carcinomas)

I. Non-Neoplastic Colon Polyps

Hyperplastic Polyps

Most common non-neoplastic polyp in the colon

Do not exhibit dysplasia
Proliferation is mainly in the basal portion of the crypt
(used to distinguish from adenomas)
Typically located in the rectosigmoid and are < 5mm in
size
Small left sided HP are not a significant marker of
colon cancer risk and finding them on sigmoidoscopy is
NOT a routine indication for colonoscopy

Inflammatory Pseudopolyps

Irregularly shaped islands of residual intact

colonic mucosa that are the result of the
mucosal ulceration and regeneration that occurs
in IBD (benign with no malignant potential).
Usually multiple, filiform and scattered
throughout the colitic region of the colon
However, their presence can complicate the
recognition of true adenomas and DALM

Submucosal Polyps

Lymphoid aggregates, lipomas, leiomyomas,

pneumatosis cystoid intestinalis, hemangiomas,
fibromas, carcinoids, and metastatic lesions
Can be neoplastic or non-neoplastic
Smooth overlying mucosa
Lipoma can be diagnosed endoscopically because of its
yellow color and softness (pillow sign)
EUS can be useful in defining the site of origin and for
biopsy of submucosal lesions if the diagnosis is in
doubt.

II. Hamartomatous Polyps

Hamartomatous Polyps

Result of faulty development, made up of a mixture of

tissues

Juvenile polyps:

consist of lamina propria and dilated cystic glands rather than

increased numbers of epithelial cells
Usually removed because of high likelihood of bleeding.
More common in childhood.

Peutz-Jeghers Polyps

Glandular epithelium supported by smooth muscle cells that is

contiguous with the muscularis mucosa.
Associated with Peutz-Jeghers syndrome
Polyps are benign- but may grow progressively and produce
symptoms or undergo malignant transformation

Inherited Disorders
I: Hamartomatous Polyposis syndrome: PeutzJeghers Syndrome and Familial Juvenile Polyposis
II: Adenomatous Polypsosis Syndrome: Familiar
Adenomatous Polyposis
III: Hyperplastic Polyposis Syndrome

Peutz-Jeghers Syndrome

Autosomal dominant hamartomatous polyposis syndrome

associated with mucocutaneous hyperpigmentation
For individuals with a histopathologically confirmed hamartoma,
a definite diagnosis of PJS requires two of the following three
findings:

Family history consistent with autosomal dominant inheritance

Mucocutaneous hyperpigmentation
Small-bowel polyposis

Variable penetrance: variable size and variable number of

hamartomatous polyps
Polyps begin to grow in first decade of life and become
symptomatic between ages of 10 and 30
Presenting symptoms include intussusception, small bowel
obstruction, bleeding, and anemia

PJS - cont

Increased risk for both GI and non-GI

malignancies: small intestine, gastric,
pancreatic, colorectal, esophageal, ovarian, lung,
endometrial, and breast
Genetic testing: only identifiable mutations
causing PJS affect the tumor suppressor gene
STK 11

Screening in PJS

From birth to age 12. In male patients: history and physical examination with
attention to the testicles. Routine blood tests annually (ultrasound of the
testicles every two years until age 12 offered as an option). For female
patients: History and physical examination with routine blood tests annually.
At age 8. For males and females: upper endoscopy and small bowel series; if
positive, continue every two to three years.
From age 18 on. In male patients: colonoscopy, upper endoscopy, and small
bowel series every two to three years. In female patients: Colonoscopy, upper
endoscopy, and small bowel series every two to three years; breast self-exam
monthly. Emerging data suggest that wireless capsule endoscopy may be an
alternative for small bowel imaging. Similarly, push-enteroscopy or doubleballoon enteroscopy may be an alternative for small bowel imaging, while also
having the benefit of permitting therapeutic intervention, although they are
more invasive.
From age 25 on. For male/female patients: endoscopic ultrasound of the
pancreas every one to two years (CT scan and/or CA19-9 offered as options).

Familial Juvenile Polyposis

Occurrence of 10 or more juvenile polyps

Autosomal dominant pattern of inheritance with germline
mutation in SMAD4 gene chromosome 18q21.1 or in the gene
BMPRA1A.
Associated with increased risk for the development of CRC, and
in some families, GASTRIC cancer, especially where there are
both upper and lower gastrointestinal polyps.
JPS may co-exist with Osler-Weber-Rendu syndrome which
carries a risk of aortic aneurysm and PE
Screening: colonoscopy q1-2 years beginning at age 15; EGD or
UGI with SBFT q1-2 years beginning at age 25

Familial Adenomatous Polyposis

Autosomal dominant linked to the adenomatous

polyposis coli (APC) gene located on chromosome
5q21
Large intestine contains multiple adenomatous polyps
(>100)
Disease penetrance is nearly 100% by age 40 (mean age
of death 42 if left untreated)
Treatment: Total proctocolectomy with a Brooke
ileostomy vs subtotal colectomy with ileorectal
anastomosis

FAP (cont)

Extracolonic malignances/manifestions: duodenal

ampullary carcinoma, follicular papillary thyroid cancer,
childhood hepatoblastoma, gastric carcinomas, CNS
tumors (medulloblastomas), Congenital hypertrophy of
the retinal pigment epithelium
Genetic testing: should be performed on an affected
members. If no mutation found then all at-risk family
members should undergo endoscopic screening (flex sig
or colonoscopy every year starting at age 10 to 12 and
continuing until age 35 or 40 if negative) since
commercial tests for APC mutations do not detect all
mutations that can cause FAP

Variants of FAP

Turcots syndrome

Gardners syndrome: extraintestinal lesions

Association with brain tumors (medulloblastomas and

gliomas) and FAP or HNPCC
Desmoid tumors, sebaceaous or epidermoid cysts, lipomas,
osteomas, supernumery teeth, gastric polyps, juvenile
nasopharyngeal angiofibromas

Attenuated FAP

Milder phenotypical FAP variant; < 100 adenomas

Fever extracolonic manifestions
Delayed onset of colorectal cancer (delayed by 12 years)

Screening in FAP

ASGE: Patients with FAP should undergo upper

endoscopy with both end-viewing and side-viewing
instruments. The optimal timing of initial upper
endoscopy is unknown, but could be performed around
the time the patient is considered for colectomy, or
early in the third decade of life. If no adenomas are
detected, another exam should be performed in five
years because adenomatous change may occur later in
the course of the disease
Biopsies of gastric polyps should be performed to
confirm that they are fundic glands and not adenomas
Palpation of thyroid annually (thyroid blastoma)

Hyperplastic Polyposis Syndrome

Characterized by multiple, large, proximal hyperplastic polyps

(occasionally small numbers of serrated adenomas)
Associated with increased risk of CRC
WHO criteria

At least 5 HP proximal to the sigmoid colon, of which 2 are greater than

1 cm or
Any number of HP occurring proximal to the sigmoid colon in an
individual who has a first degree relative with hyperplastic polyposis or
Greater than 30 HP distributed throughout the colon

If there are many polyps in the proximal colon may consider

colectomy
Only remaining polyposis condition for which no germline
mutation has been identified
1-3 year surveillance colonoscopies have been proposed

Neoplastic Polyps

Adenomatous Polyps

2/3 of colonic polyps are adenomas

By definition they are dysplastic and have malignant
potential
Time for development of adenomas to cancer is about
7 to 10 years.
Advanced adenoma: high grade dysplasia or adenoma that
is > 10 mm in size or with villous component
Synchronous adenoma: adenoma that is diagnosed at same
time as index colorectal neoplasm
Metachronous adenoma: diagnosed at least six months after
diagnosis of previous adenoma

Epidemiology of Adenoma

Older age is a major risk factor

More common in men
Large adenomas (> 9mm) may be more
common in African Americans
African Americans have a higher risk of rightsided colonic adenomas and may present with
cancer at a younger age (< 50 years) than
Caucasians.

Endoscopic Classification

Sessile base is attached to colon wall

Pedunculated mucosal stalk is interposed
between the polyp and the wall (small polyps <
5 mm are rarely pedunculated)
Flat height less than one-half the diameter of
the lesion.
Depressed lesions appear to be particularly likely
to harbor high-grade dysplasia or be malignant
even if small.

Pathologic Classification

Low grade dysplasia: characterized by branching crypts

lined by cells with long, thin nuclei that begin to stratify,
resulting in increased nucleus-to-cytoplasm ratio and a
loss of normal goblet cells.
High grade dysplasia: do not contain invasive
malignancy, which is defined by breach of the
muscularis mucosa by neoplastic cells.

Represents an intermediate step in the evolution from lowgrade adenomatous polyp to cancer
Not associated with metastasis since there are no lymphatic
vessels in the lamina propria..

Pathology cont.

Tubular: account for more than 80 percent of colonic

adenomas. Characterized by a complex network of
branching adenomatous glands.
Villous: account for 5 to 15 percent of adenomas. They
are characterized by glands that are long and extend
straight down from the surface to the center of the
polyp, creating finger-like projections.
TVA: having 26 to 75 percent villous component
account for 5 to 15 percent of adenomas; combination
of above.

Serrated Polyps

Display features of both hyperplastic and adenoma

Were classified in past as HP and benign but new
evidence shows that they may behave as adenomas
No guidelines for management; it is generally
recommended that surveillance intervals should follow
that of other adenomas
Two types

Sessile serrated adenoma precursors to large HP in

proximal colon of patients with hyperplastic polyposis
Traditional serrated adenoma look and behave as
conventional adenomas; often pedunculated found more
often in distal colon

Risk Factors for High grade

dysplasia and cancer

Adenomatous polyps > 1 cm in diameter are risk factor

for containing CRC
Villous histology adenomatous polyps with > 25
percent villous histology are a risk factor for developing
CRC
High-grade dysplasia adenomas with high-grade
dysplasia often coexist with areas of invasive cancer in
the polyp.
Number of polyps: three or more is a risk factor for
development of metachronous adenomas with
advanced pathologic features.

Molecular Basis of Colorectal Cancer

Colorectal cancer is the second leading cause of

death from cancer among adults.
benign adenomatous polyp advanced
adenoma with high grade dysplasia invasive
cancer

Genomic Instability

Chromosomal Instability most common type of

genomic instability in CRC; changes in chromosomal
copy number and structure.

DNA-Repair Defects Inactivation of genes required

for repair of base-base mismatches in DNA

Loss of tumor suppressor genes: APC, P53, SMAD4

Inherited inactivation: HNPCC (lynch syndrome) germ line

defects in mismatch-repair genes (MLH1 and MSH2); high
risk of second cancers (endometrial, ovarian, small intestine)
Acquired inactivation

Aberrant DNA Methylation causes epigenetic

silencing of genes

Mutational Inactivation of Tumor

Supressor Genes

CRC acquire many genetic changes

Changes in the Wnt signaling pathway, is
regarded as the initiating event in colorectal
cancer
The most common mutation in CRC inactives the
gene that encodes the APC protein
In the absence of functional APC the brake on Bcatenin Wnt signaling is inappropriately and
constitutively activated.

Growth Factor Pathways

Increased levels of COX-2 are found in

approximately two thirds of CRC
Loss of 15-PGDH in 80% of colorectal
adenomas and cancers
Clinical trials have shown that the inhibition of
Cox-2 by NSAIDS prevents the development of
new adenomas and mediates regression of
established adenomas
(Steinbach et al. The effect of celecoxib, a coxcox-2 inhibitor, in FAP N

Engl J Med 2000;342:19462000;342:1946-52)

A 60 year old male presents with recurrent pancreatitis and weight loss. He denies
alcohol use and take no medications. On CT, a cystic mass is found in the head of
the pancreas as well as a dilated pancreatic duct. A follow up ERCP reveals a
mucus protruding from the ampulla. He undergoes a colonoscopy as part of his
work-up, as he also has iron deficiency anemia.
What type of polyps are associated with this presentation

A. Serrated Adenomas
B. Hamartomatous polyps
C. Hyperplastic polyps
D. Villous Adenomas
E. Glandular hyperplasia

Answer is B

The patient shows features typical of intraductal

mucinous neoplasms (IPMN). The final
diagnosis would be strengthened by cytology
and positive mucin stain.
One third of patients with IPMN harbor an
inactivated Peutz-Jeghers gene STK 11/LKB1,
which is associated with hamartomatous polyps
and increase in colon cancer risk.

Which of the following statements is true regarding the

pathogenesis of colorectal cancer?

A. Colorectal cancers that demonstrate chromosomal

instability tend to be diploid
B. Colorectal cancers that demonstrate microsatellite
instability often have p53 mutations
C. Colorectal cancers from familial adenomatous
polyposis patients tend to follow the chromosomal
instability pathway
D. Colorectal cancers that demonstrate microsatellite
instability often lack mucin within their tumors.
E. Colorectal cancers that arise in patients with IBD
follow the chromosomal instability pathway.

Answer is C

The chromosomal instability pathway is observed in 80 to 85%

of sporadic colorectal cancers and also familial adenomatous
polyposis cancers. It is mainly characterized by aneuploidy, with
loss of heterozygosity at key tumor suppressor gene loci,
including APC, chromosome 18q, and p53. Tumors that
demonstrate microsatellite instability have a different genetic
pattern that does not involve p53 and tend to be right-sided
colon location, poorly differentiated, and more likely to be
mucinous. IBD associated colorectal cancers demonstrate a
different timing and pattern of molecular alterations than the
CIN and MSI pathways, with p53 mutations occurring early but
with rare APC and K-RAS mutations.

A 35 year old male with no significant family history presents with iron deficiency anemia. A
colonoscopy was performed as part of his work up and revealed approximately 200 polyps
distributed throughout the entire colon. Histology of the polyp reveals them to be adenomas.
What is the appropriate next step?

A. Perform total colectomy with mucosal proctectomy, then

genetic counseling and testing for APC germline mutation.
B. Perform surveillance colonoscopies annually, with segmental
resection of cancers.
C. Perform total colectomy with mucosal proctectomy, then
genetic counseling and testing for hMLH1 and hMSH2 germline
mutations.
D. Perform total colectomy with mucosal proctectomy, then
genetic counseling and testing for SMAD4 and BMPR1A
germline mutations.
E. Perform total colectomy with mucosal proctectomy, then
genetic counseling and testing for PTEN germline mutations.

Answer is A.

This patient has multiple adenomas, which makes it

most likely that the patient carries a germ line mutation
in APC or has biallelic mutations in the MYH gene.
Thus, this patient has either an attenuated form of FAP
or MYH polyposis. The risk for colorectal cancer
development is nearly 100% and the patient should
undergo a total abdominal colectomy and subsequently
be referred to genetic counseling and appropriate
testing. Additionally, the patient should contact family
members for screening and potentially genetic testing
purposes.

1118 A 50-year-old woman presents for colorectal cancer screening. Her father had
colon cancer at age 45 and her sister at age 55. Her colonoscopy reveals a cecal
adenocarcinoma. Which of the following statements regarding this syndrome is true?

A. It is inherited in an autosomal recessive

fashion.
B. It causes less than 1% of all colorectal
cancers.
C. There is increased frequency of cancer of the
female genital tract.
D. Germline mutations in the hMSH2 or
hMLH1 genes do not occur.
E. There is a predominance of distal tumors.

1118 C (S&F, ch123)

This family meets the Amsterdam criteria for
HNPCC. This syndrome is inherited in an
autosomal dominant
fashion. There is a predominance of proximal
tumors. Germline mutations in the hMSH2 or
hMLH1 gene
are present in 80% of colon cancers. There is an
increased frequency of cancers of the female
genital tract.
This syndrome accounts for approximately 6%
of all the colorectal cancers, whereas FAP
accounts for less
than 1% (see three tables at end of chapter).

1134 A statistician consults you and wants to know precisely which

test can prevent him from dying of colon
cancer. Which of the following has been shown to decrease
mortality from colorectal cancer?
A. Yearly FOBT
B. Double-contrast barium enema
C. Virtual colonoscopy
D. Yearly digital rectal examination

1134 A (S&F, ch123)

FOBT has been shown in large-scale,
randomized, controlled studies to decrease
mortality from colorectal
cancer with yearly and biannual testing. A
decrease in colorectal cancer mortality has been
demonstrated
with sigmoidoscopy. The National Polyp Study
suggests that removal of adenomatous polyps
reduces the
mortality from colorectal cancer. Thus, it has
been inferred that colonoscopy should have the
same effect.