Title: Pathology of the Gastrointestinal Tract III and IV Part 2 Small and Large Intestines
1Pathology of the Gastrointestinal Tract III and
IV Part 2Small and Large Intestines
- Grace Guzman, M.D.
- The Department of Pathology
- University of Illinois at Chicago
2Neoplasms 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
3Neoplasms of the small intestines
Adenoma -25 of SI benign tumors -mostly in
ampulla of vater -familial polyposis coli prone
to amp of v adenoma -30-60 yrs -pancreatoduodenect
omy
- 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
Maligmant -rare -annual death rate lt1000 -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
4Malignant-Adenocarcinoma-Primary
lymphoma-Carcinoids-Gastrointestinal stromal
tumors (GISTS)
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
- 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
30-40 yrs
Due to random changes brought about by
t(1118) H. pylori reactive T helper cells
produces cytokine that allows growth of
monoclonal B cell population Therefore Tx
H.pylori
Location in Stomach 50-60 SI 25-30 Distal
colon up to 10
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(1118) -no sex predilection
Overall, most intestinal lymphomas are B cell
type (gt 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
5Malignant-Adenocarcinoma-Primary
lymphoma-Carcinoids-Gastrointestinal stromal
tumors (GISTS)
Appendiceal and rectal carcinoids almost
never metastasize. 90 of ileal, gastric
and colon carcinoids have already met to LNs at
time of diagnosis
- 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 Colo
n
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
6Malignant-Adenocarcinoma-Primary
lymphoma-Carcinoids-Gastrointestinal stromal
tumors (GISTS)
-all are potentially malignant -may be low risk
or high risk -high risk if gt 5 cm in size
and mitosis gt10/10 hpf
- Gastrointestinal stromal tumor (GIST)
- uncommon
- arise in wall of bowel (interstitial 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
- c-kit proto-oncogene, receptor type tyrosine
kinase
Interstital cells of Cajal stained for c-kit
Correct notes should readhigh grade sarcoma
7Types of intestinal polyps
-Occassionally seen - long standing IBD UC gt
Crohn
- Pseudopolyp
- Hamartomatous polyp (rare)
- -Juvenile inflammatory polyp
- -Peutz Jeghers polyp
- Hyperplastic polyps
- Lymphoid polyps
- Adenomatous polyps
- -tubular adenoma (very common)
- -tubulovillous adenoma (seen less than TA)
- -villous adenoma (occasionally seen)
Polyps with no malignant potential
Non-neoplastic
Very common 90 of all epithelial polyps found
in gt1/2 of all persons over the age of 60
Preneoplastic polyps
8Neoplasms of the colon and rectum
- Benign non-neoplastic polyps
- -Hyperplastic polyps
- -very common (we see it every day)
- -proliferation of mature goblet cells size lt0.5
cm - -commonly found in adults gt 60 years old
Gross-nipple like -hemispheric -smooth
moist protrusions of the mucosa -often
multiple -gt 1/2 in rectosigmoid
Micro-well formed glands -crypts lined by
non-neoplastic cells -goblet cell/absorptive cell
differentiation -serrated lumen
9Juvenile Polyps or inflammatory polyps
- 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 lt 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
- -Rare focal hamartomatous polyps
- -virtually no malignant potential (exception
Juvenile polyposis syndrome) - -commonly found in children younger than age 5
10Hamartomatous 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
11Adenomas
- 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 lt1cm in size -The risk of
cancer is high (approximately 40) in sessile
villous lesions gt 4cm -Severe dysplasia when
present is often seen in villous areas
12Severe dysplasia when present is often seen in
villous areas
- 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
- Old terminology severe
- dysplasia/carcinoma in situ
Submucosal stalk rich in lymphatic channel
Tubulovillous adenoma with intramucosal
adenocarcinoma
13- Invasive adenocarcinoma
- 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
Most worrisome lesions are villous adenoma gt 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
14Quiz time
- 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.
Submucosal stalk
15Tubular adenoma
- Pedunculated, composed of branching round/
tubular glands on a stalk - Can grow up to 4 cm in diameter
- The larger the polyp the greater the chance of
harboring carcinoma
Adenomatous polyps -tubular adenoma
-tubulovillous adenoma -villous adenoma
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
16VILLOUS ADENOMA
- VILLOUS ADENOMA
- -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 ADENOMA
- -features of both adenomas
- -25-50 (30) villous
(occassionally seen)
Adenomatous polyps -tubular adenoma
-tubulovillous adenoma -villous adenoma
(not as common as TA)
17Familial 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
18Hereditary 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 pre-existing
adenomas Association with sebaceous tumors of
skin Muir-Torre syndrome
19Inherited mutations in any of four genes that are
involved in DNA repair are putatively responsible
for familial syndrome of HNPCC.
20These 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.
21Adenocarcinoma
- Accounts for 10 of all cancer related deaths
- peak incidence 60-79 years (lt20 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.
22Genetic 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
23- 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 its role has been questioned, is it DCC
or neighboring gene?
- 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
- 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
24Adenocarcinoma -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 - mucosa B - submucosa or
muscularis propria B1 serosa B2 C - B1 lymph
node met C1 B2 lymph node met C2 D - Distant
mets to lung and liver
A 5YSR - 100
B1 67 B2 54
C1 43 C2 23
25Adenocarcinoma
- 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
- 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
Cancer narrows lumen
26Colorectal Adenocarcinoma Summary
- Approximately 5 of all colon cancers are related
to a hereditary predisposition - Majority are related to APC mutations (FAP)
- Some are due to mismatch repair defects (Lynch
Syndrome) - Among sporadic colon cancers
- 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
27Neoplasms of appendix
- Mucocele _ benign dilatation of the lumen by
mucinous secretions Mucinous cystadenoma-prolifera
tion of benign neoplastic cells-dilatation by
mucinous material -may rupture - Mucinous cystadenocarcinoma -invasion of
neoplastic cells
(normal appendix mucosa)
(The mucosa is altered by mucinous cells)
-Pseudomyxoma peritonei - term describing
distention of the peritoneal cavity by the
presence of semisolid, mucin containing
adenocarcinoma cells
28Peritoneum
- 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)