Transcript villous adenoma - University of Illinois at Chicago

Pathology of the Gastrointestinal Tract III
and IV
Part 2
Small and Large Intestines
Grace Guzman, M.D.
The Department of Pathology
University of Illinois at Chicago
Neoplasms of the Intestines
Colorectal cancer ranks #2 as a cancer
killer
Lung cancer #1 cancer killer
Adenocarcinoma constitutes 70% of
malignant tumors of the GI tract
Neoplasms of the
small intestines
 Perplexingly uncommon
compared to tumors in other
segments of GI tract
 3-6% of GI tumors
 Benign
-Adenomas
-”Leiomyomas”
-Lipomas
-Angiomas
 Malignant
-Adenocarcinoma
-Primary lymphoma
-Carcinoids
-GISTS
Adenoma
-25% of SI benign tumors
-mostly in ampulla of vater
-familial polyposis coli
prone to amp of v adenoma
-30-60 yrs
-pancreatoduodenectomy
Maligmant
-rare
-annual death rate: <1000
-1% of all GI malignancies
-5 YSR: 70% if rected en bloc
-jejunum and ileum
-40-60 years
-napkin ring like growth
-n,v, wt loss, pain anemia
-tumor lead pt in intussuception
Malignant
-Adenocarcinoma
-Primary lymphoma
-Carcinoids
-Gastrointestinal stromal
tumors (GISTS)
 Primary lymphoma
 Arises from lymphoid
aggregates in the wall
with no evidence of
other primary sites
 Gastric lymphomas
are most common and
have better prognosis
than SI or LI if early
 refractory (celiac)
sprue associated with
TCL; mostly in
jejunum
Overall, most intestinal lymphomas are B cell type (> 95%)
Rare T cell tumors (Refractory sprue)
Have better outcome than lymphomas from other sites
10 YSR: 85% if limitted to mucosa and submucosa
PX: depend on depth, local invasion, size, grade of tumor, mets
GI lymphomas: sporadic but occur more
frequently on certain populations:
1. pxs with H. pylori
2. natives of Mediterranean region
3. pxs with immunodeficiency states
4. HIV infected individuals
5. pxs in immunosuppressive therapy
6. patients with refractory sprue 30-40 yrs
Location in:
Stomach: 50-60%
SI: 25-30%
Distal colon: up to 10%
Due to random changes brought about by t(11;18)
H. pylori reactive T helper cells produces cytokine
that allows growth of monoclonal B cell population
Therefore Tx: H.pylori
Lymphomas
-40% extranodal
-GI primary extranodal site
-1-4% of all GI malignancies
MALT lymphoma
-arise in B cells of GUT
Mucosal Associated Lymphoid
Tissue (MALT)
-occur focally or early stages
-relapses exclusively in GI
-unique t(11;18)
-no sex predilection
Malignant
-Adenocarcinoma
-Primary lymphoma
-Carcinoids
-Gastrointestinal stromal tumors (GISTS)
Carcinoids
 arise from NE cells
 may secrete bioactive
amines (serotonin: diarrhea,
flushing of face,
bronchospasm, cyanosis carcinoid syndrome)
 common in SI (50% of SI
malignancies; 2% of
colorectal malignancies)
 5 YSR: 90%
 5 YSR with liver mets: 50%
 if widespread - death
Most common
sites in the order
of frequency:
Appendix
Ileum (SI)
Rectum
Stomach
Colon
Appendiceal and rectal
carcinoids almost never
metastasize.
90% of ileal, gastric and
colon carcinoids
have already met to LNs
at time of diagnosis
Electron microscopy:
neurosecretory
granules
Carcinoid syndrome occurs in about 1% of all patients with carcinoid
and 20% of those with widespread metastasis. Excess elaboration of
serotonin 5HT and 5 HIAA; present in blood and urine. 5 HIAA is
deactivated in the liver. Therefore in GI carcinoids, liver mets have to
be present for the development of the syndrome. Not true for ovary and
lung carcinoids. Other products: Histamine, bradykinin and prostaglandins
Malignant
-Adenocarcinoma
-Primary lymphoma
-Carcinoids
-Gastrointestinal stromal
tumors (GISTS)
-all are potentially malignant
-may be low risk or high risk
-high risk if > 5 cm in size and
mitosis >10/10 hpf
 Gastrointestinal stromal tumor
(GIST)
 uncommon
 arise in wall of bowel (interstitial
Interstital cells of Cajal stained for c-kit
cells of Cajal)
 portrude into lumen; ulcerate; GI
bleed
 mostly slow growing; cured by
surgery
 30% recurrence/liver mets within 10
years
 may progress to high grade sarcoma Correct notes:
should read
 c-kit proto-oncogene, receptor type
“high grade
sarcoma”
tyrosine kinase
Types of intestinal polyps
-Occassionally seen
- long standing IBD: UC > Crohn
Pseudopolyp
Hamartomatous polyp
*Polyps with no malignant
-Juvenile inflammatory polyp potential: Non-neoplastic
-Peutz Jeghers polyp
Hyperplastic polyps
Lymphoid polyps
(rare)
Very common
90% of all epithelial polyps found in
>1/2 of all persons over the age of 60
 Adenomatous polyps Preneoplastic polyps
-tubular adenoma (very common)
-tubulovillous adenoma (seen less than TA)
-villous adenoma (occasionally seen)
Neoplasms of the colon
and rectum
Benign non-neoplastic
polyps
-Hyperplastic polyps
-very common (we see
it every day)
-proliferation of mature
goblet cells; size <0.5
cm
-commonly found in
adults > 60 years old
Gross-nipple like
-hemispheric
-smooth moist
protrusions of the
mucosa
-often multiple
-> 1/2 in rectosigmoid
Micro-well formed glands
-crypts lined by non-neoplastic cells
-goblet cell/absorptive cell differentiation
-serrated lumen
Juvenile Polyps or
inflammatory polyps
-Rare; focal
hamartomatous
polyps
-virtually no
malignant potential
(exception: Juvenile
polyposis syndrome)
-commonly found in
children younger than
age 5
•usually solitary
-most frequently in
rectum
-JP tend to be large: 1-3
cm.
-isolated IP may be found
in adults:
“retention polyp”
which are smaller < 1 cm.
with stalks
up to 2 cm
-Lamina propria is the
bulk of the
polyp with cystically
dilated glands, surface
ulceration
-Rare autosomal
dominant JP syndrome
does carry a risk of
adenoma and
hence adenocarcinoma
Hamartomatous Polyp:
Peutz Jeghers polyp
 Rare
 Large polyp with
arborizing (tree-like)
projections with smooth
muscle present at the
mucosal surface
 Polyps with no malignant
potential, but patients at
risk for other
malignancies: pancreas,
breast, lung, ovary, and
uterus
Adenomas
 All adenomas show
dysplastic epithelium
 All are precancerous
 May proceed to intramucosal
or invasive carcinoma
 May occur anywhere in the
LI, most occur in the left
colon, specifically,
rectosigmoid
 Risk of malignant
transformation is dependent
on polyp size, architecture,
severity of dysplasia
Corless
-Cancer is rare in TA <1cm in size
-The risk of cancer is high (approximately 40%) in sessile villous lesions > 4cm
-Severe dysplasia when present is often seen in villous areas
Severe dysplasia when present is often seen in villous areas
Intramucosal
Adenocarcinoma
Old terminology: severe
dysplasia/carcinoma in situ
Submucosal stalk
rich in lymphatic channel
Tubulovillous adenoma with intramucosal adenocarcinoma
 Carcinoma arising in a
tubular adenoma that has
not invaded into the
submucosa
 little or no metastatic
potential
 if 1.) no lymphatic
invasion, 2.) not poorly
differentiated, and 3.)
superficial with margin is
free of ca, then
polypectomy is an
adequate procedure
 because this has no
propensity to metastasize
at this point
Invasive
adenocarcinoma
Most worrisome lesions are villous adenoma > 4 cm.
When invasive carcinoma occurs, there is no stalk as a buffer zone
and invasion is directly into the wall of the colon (submucosa or deeper).
Invasive adenocarcinoma arising in villous adenoma
The tumor has
invaded through the
mucosa, into
submucosa (in this
case it is seen to the
level of the
muscularis propria)
The submucosa
contains large
lymphatics which are
conduits for
metastases
Quiz time
Submucosal stalk
 Question: What if the
cancer is in the stalk of a
pedunculated polyp - is
this an invasive
carcinoma?
 Answer: Yes,
carcinomatous invasion
into the submucosal stalk
of a pedunculated polyp
constitutes an invasive
adenocarcinoma.
 Question: What is the
treatment, polypectomy
or colectomy?
 Answer: Colectomy,
invasive carcinoma can
not be adequately treated
by polypectomy.
Tubular
adenoma
Pedunculated, composed Adenomatous polyps
of branching round/
-tubular adenoma
-tubulovillous adenoma
tubular glands on a stalk
-villous adenoma
Can grow up to 4 cm in
diameter
The larger the polyp the
greater the chance of
harboring carcinoma
Common; we see it every day
-90% in the colon; rarely in the stomach and SI
-solitary in 50%
-2 or more in the remaing 50%
VILLOUS
ADENOMA
 VILLOUS ADENOMA (occassionally seen)
-Sessile, broad base rather
than a stalk
-Composed of numerous ,
finger-like projections of
epithelium
-Greater than 50% villous
-More than 40% harbor
carcinoma
 TUBULOVILLOUS (not as common as TA)
ADENOMA
-features of both adenomas
-25-50% (30%) villous
Adenomatous polyps
-tubular adenoma
-tubulovillous adenoma
-villous adenoma
Familial
syndromes
Familial syndromes
-Familial adenomatous polyposis
-Gardner syndrome
-Hereditary nonpolyposis colorectal cancer
FAP - Cancer preventive measures:
prophylactic colectomy as soon as possible
early detection of disease in siblings and
first degree relatives at risk
Average onset of polyps in each of these adenomatous polyp syndromes is the teens and twenties,
followed by cancer in 10-15 years unless surgical resections interrupt the natural progression.
 Familial adenomatous
polyposis (FAP)
 Rare, autosomal dominant;
genetic defect is in the APC
gene on Ch 5q21
 Patients with 500-2500
polyps (min 100 polyps)




Gardner syndrome
a variant of FAP
also autosomal dominant
polyps similar to FAP but
with multiple bone lesions
and skin lesions particularly
mandible, skull, long bones, epidermal cysts and
fibromatosis
 Turcot syndrome: rare variant, GI
polyps and CNS tumors, mostly gliomas
Hereditary nonpolyposis
colorectal cancer (HNPCC)
 Autosomal dominant
 lower number of polyps
 occur earlier than the
general adult population
(peak 40-55 years)
 cancer often right sided
(70%)
 more often poorly
differentiated
 prognosis is better
 women at increase risk of
endometrial
adenocarcinoma
 caused by mutation in
DNA mismatch repair
genes
Familial syndromes
-Familial adenomatous polyposis
-Gardner syndrome
-Hereditary nonpolyposis colorectal cancer
•Multiple synchronous or
metachronous colorectal cancers
not always associated with preexisting adenomas
•Association with sebaceous
tumors of skin ; Muir-Torre
syndrome
Inherited mutations in any of four genes that are involved in DNA
repair are putatively responsible for familial syndrome of HNPCC.
These human mismatch repair genes are involved in genetic proofreading during DNA replication and are referred to as “caretaker” genes.
There are 50,000 to 100,000 dinucleotide repeat sequences in the human
genome. And mutations in mismatch repair genes can be detected by the
presence of widespread alterations in these repeats; this is referred to as
microsatellite instability. Patients who inherit a mutant DNA repair gene
have normal repair activity because of the normal remaining allele.
Mutation rates up to 1000X normal ensue, such that most of the
HNPCC tumors show microsatellite instability. About 10-15% sporadic
colon cancers have mutations in similar caretaker DNA repair genes.
Adenocarcinoma
 Accounts for 10% of all cancer related deaths
 peak incidence: 60-79 years (<20%: before 50)
 worldwide: environment, diet, obesity, physical activity; no
causal relationship
FAP patients either inherit one defective copy of APC (one hit) or else
acquire it during embryogenesis. Deletion of the remaining good APC
gene in the colonic stem cell is all that is necessary to start down the
road to an adenoma.
Two genetic “hits” are necessary to compromise both copies of APC gene with in
colonic stem cells in normal individuals. The first hit is usually a point mutation to
one gene copy. The second gene copy is then later deleted.
Genetic Alterations:






the path from normal to cancer
APC at Ch 5q21
APC- B catenin
K-ras at Ch 12p12
p53 at Ch 17p13
or loss of
heterozygosity
 Adenoma-carcinoma sequence
 a. germline or somatic mutations of cancer suppressor genes (first hit)
 b. methylation abnormalities and inactivation of normal alleles
(second hit)
 c. proto-oncogene mutation
 d. homozygous loss of additional cancer gene
 e. additional mutations with gross chromozomal alterations
•Loss of methyl groups in DNA
(hypomethylation)
•early change in colonic neoplasm
 K-ras-most frequently
observed oncogene in
adenomas and colon
carcinomas
 Ch12p12; intracellular
transduction
 mutated in fewer than 10%
of adenomas less than 1 cm
and 50% of carcinomas
 DCC-common allelic loss in
colon ca is on 18q21
 deleted in colon cancer
 a cell adhesion molecule
normally expressed in normal
colon mucosa
 reduced or absent in 70-75%
of colon ca
 LOH in 18q
 recently it’s role has been
questioned, is it DCC or
neighboring gene?
•P53 losses at 17p found in
70-80% of colon cancers
•infrequent in adenomas
•mutations in p53 occur late
in colon carcinogenesis
•APC gene “gate keeper gene”
•APCmutations is usually the earliest and
possibly the initiating event in about 80%
of sporadic colon ca
•less role of fromDNA mismatch repair
• genes
•alterations in genome lead to progressive
increases in size, level of dysplasia, and
invasive potential of neoplastic lesions
Adenocarcinoma
-tumor will infiltrate wall of colon and metastasize to
lymph nodes and liver
-prognosis is related to size and spread of the lesion
Astler Coller System - pathologic staging of
colorectal cancer:
A: 5YSR - 100%
A - mucosa
B - submucosa or muscularis propria B1;
serosa B2
B1: 67% B2: 54%
C - B1 + lymph node met C1; B2 + lymph
node met C2
C1: 43%; C2: 23%
D - Distant mets to lung and liver
Adenocarcinoma
 Right colon adenocarcinoma
 -usually -asymptomatic for a
long period of time
 -signs and symptoms of iron
deficiency anemia due to
surface ulceration and
resulting blood loss
Polypoid, fungating
non-obstructing
rt colon ca
Left colon adenocarcinoma
-generally annular
-narrow the lumen
-change in bowel habits or
obstruction
 -blood in stool (maybe
obvious/bright red or
occult)
 -originating from ruptured
vessels at the edge of the
ulceration




Cancer narrows lumen
Colorectal Adenocarcinoma
Summary

Approximately 5% of all colon cancers are related to a
hereditary predisposition



Among sporadic colon cancers




Majority are related to APC mutations (FAP)
Some are due to mismatch repair defects (Lynch Syndrome)
75% are related to acquired APC mutations
15% are related to acquired mismatched repair defects
Dietary factors play an important role in both the
origin and progression of colon cancers
Screening for adenomatous polyps can prevent colon
cancer
Neoplasms of appendix
 Mucocele _ benign normal appendix mucosa)
dilatation of the lumen by
mucinous secretions
Mucinous cystadenomaproliferation of benign
neoplastic cells-dilatation
by mucinous material -may
rupture (The mucosa is altered by mucinous cells)
 Mucinous
cystadenocarcinoma invasion of neoplastic cells
(
-Pseudomyxoma peritonei - term
describing distention of the peritoneal
cavity by the presence of semisolid,
mucin containing adenocarcinoma
cells
Peritoneum
 Inflammation
1. Sterile peritonitis due to
bile or pancreatic juices
2. Surgical procedures
3. Endometriosis
4. Rupture of GI tract
(Ruptured appendicitis,
acute salphingitis, or
diverticulitis)
 Neoplasms
1. Primary mesothelioma rare
2. Secondary malignancies extension, seeding, or
implantation (more
common)