Neoplastic vs Non- Neoplastic Colon Polyps

Neoplastic vs Non- Non
Neoplastic Colon Polyps
Marianne Fahmy
Core Curriculum Lecture
September 14, 2010

�� Non-Neoplastic Non Polyps
�� Hamartomatous
Outline
Neoplastic Polyps
�� Hyperplastic
�� Mucosal
�� Inflammatory Pseudopolyps
�� Submucosal (can be non-neoplastic non neoplastic and neoplastic)
Hamartomatous
�� Juvenile Polyps
�� Peutz-Jeghers
Peutz Jeghers
�� Inherited Family Disorders: Polyposis syndromes
�� Neoplastic Polyps (adenomas and carcinomas)

I. Non-Neoplastic Non Neoplastic Colon Polyps

Hyperplastic Polyps
�� Most common non-neoplastic 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
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 Peutz Jeghers Polyps
�� Glandular epithelium supported by smooth muscle cells that is
contiguous with the muscularis mucosa.
�� Associated with Peutz-Jeghers Peutz Jeghers syndrome
�� Polyps are benign- benign but may grow progressively and produce
symptoms or undergo malignant transformation

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

Peutz-Jeghers 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 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 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 examination
with
attention to the testicles. Routine blood tests annually (ultrasound (ultrasound
of the
testicles every two years until age 12 offered as an option). For For
female
patients: History and physical examination with routine blood tests 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, Colonoscopy,
upper
endoscopy, and small bowel series every two to three years; breast breast
self-exam self exam
monthly. Emerging data suggest that wireless capsule endoscopy may may
be an
alternative for small bowel imaging. Similarly, push-enteroscopy
push enteroscopy or double-
balloon enteroscopy may be an alternative for small bowel imaging, imaging,
while also
having the benefit of permitting therapeutic intervention, although 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 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 co exist with Osler-Weber
Osler Weber-Rendu Rendu syndrome which
carries a risk of aortic aneurysm and PE
�� Screening: colonoscopy q1-2 q1 2 years beginning at age 15; EGD or
UGI with SBFT q1-2 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 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

�� Turcot’s Turcot s syndrome
Variants of FAP
�� Association with brain tumors (medulloblastomas and
gliomas) and FAP or HNPCC
�� Gardner’s Gardner s syndrome: extraintestinal lesions
�� 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 end viewing and side-viewing 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 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 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 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: adenoma:
high grade dysplasia or adenoma that
is > 10 mm in size or with villous component
�� Synchronous adenoma: adenoma:
adenoma that is diagnosed at same
time as index colorectal neoplasm
�� Metachronous adenoma: 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 right-
sided 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 one half the diameter of
the lesion.
�� Depressed lesions appear to be particularly likely
to harbor high-grade 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 nucleus to-cytoplasm 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 low-
grade 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 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 High grade dysplasia – adenomas with high-grade 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 invasive
cancer

Genomic Instability
�� Chromosomal Instability – most common type of
genomic instability in CRC; changes in chromosomal
copy number and structure.
�� Loss of tumor suppressor genes: APC, P53, SMAD4
�� DNA-Repair DNA Repair Defects – Inactivation of genes required
for repair of base-base base base mismatches in DNA
�� Inherited inactivation: HNPCC (lynch syndrome) – germ line
defects in mismatch-repair 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 B-
catenin – Wnt signaling is inappropriately and
constitutively activated.

Growth Factor Pathways
�� Increased levels of COX-2 COX 2 are found in
approximately two thirds of CRC
�� Loss of 15-PGDH 15 PGDH in 80% of colorectal
adenomas and cancers
�� Clinical trials have shown that the inhibition of
Cox-2 Cox 2 by NSAIDS prevents the development of
new adenomas and mediates regression of
established adenomas (Steinbach et al. The effect of celecoxib, a cox-2 cox 2 inhibitor, in FAP N
Engl J Med 2000;342:1946-52)
2000;342:1946 52)

A 60 year old male presents with recurrent pancreatitis and weight weight
loss. He denies
alcohol use and take no medications. On CT, a cystic mass is found 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 as
part of his
work-up, 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 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 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 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 K RAS mutations.

A 35 year old male with no significant family history presents with with
iron deficiency anemia. A
colonoscopy was performed as part of his work up and revealed approximately 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.