pathology of the gastrointestinal tract iii and iv part 2 small and large intestines
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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 - PowerPoint PPT PresentationTRANSCRIPT
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 killerAdenocarcinoma 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 coliprone 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
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
Malignant-Adenocarcinoma-Primary lymphoma-Carcinoids-Gastrointestinal stromal tumors (GISTS)
MALT lymphoma-arise in B cells of GUTMucosal Associated Lymphoid Tissue (MALT)-occur focally or early stages-relapses exclusively in GI-unique t(11;18)-no sex predilection
GI lymphomas: sporadic but occur more frequently on certain populations:1. pxs with H. pylori2. natives of Mediterranean region3. pxs with immunodeficiency states4. HIV infected individuals5. pxs in immunosuppressive therapy6. patients with refractory sprue
Due to random changes brought about by t(11;18)H. pylori reactive T helper cells produces cytokinethat allows growth of monoclonal B cell populationTherefore Tx: H.pylori
Location in:Stomach: 50-60%SI: 25-30%Distal colon: up to 10%
Overall, most intestinal lymphomas are B cell type (> 95%)Rare T cell tumors (Refractory sprue)Have better outcome than lymphomas from other sites10 YSR: 85% if limitted to mucosa and submucosaPX: depend on depth, local invasion, size, grade of tumor, mets
30-40 yrs
Lymphomas-40% extranodal-GI primary extranodal site-1-4% of all GI malignancies
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
Electron microscopy: neurosecretory granules
Carcinoid syndrome occurs in about 1% of all patients with carcinoidand 20% of those with widespread metastasis. Excess elaboration ofserotonin 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 andlung carcinoids. Other products: Histamine, bradykinin and prostaglandins
Appendiceal and rectal carcinoids almost nevermetastasize.
90% of ileal, gastric andcolon carcinoidshave already met to LNs at time of diagnosis
Most common sites in the order of frequency:AppendixIleum (SI)RectumStomachColon
Malignant-Adenocarcinoma-Primary lymphoma-Carcinoids-Gastrointestinal stromal tumors (GISTS)
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
-all are potentially malignant-may be low risk or high risk-high risk if > 5 cm in size andmitosis >10/10 hpf
Correct notes:should read“high gradesarcoma”
Types of intestinal polyps
PseudopolypHamartomatous polyp (rare) -Juvenile inflammatory polyp-Peutz Jeghers polypHyperplastic polypsLymphoid polyps Adenomatous polyps -tubular adenoma (very common)
-tubulovillous adenoma (seen less
than TA)
-villous adenoma (occasionally seen)
-Occassionally seen- long standing IBD: UC > Crohn
Very common90% of all epithelial polyps found in >1/2 of all persons over the age of 60
*Polyps with no malignantpotential: Non-neoplastic
Preneoplastic polyps
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
Micro-well formed glands-crypts lined by non-neoplastic cells-goblet cell/absorptive cell differentiation-serrated lumen
Gross-nipple like-hemispheric-smooth moistprotrusions of themucosa-often multiple-> 1/2 in rectosigmoid
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 cysticallydilated 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
-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
Corless
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
Severe dysplasia when present is often seen in villous areas
Submucosal stalkrich in lymphatic channel
Tubulovillous adenoma with intramucosal adenocarcinoma
Old terminology: severe dysplasia/carcinoma in situ
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
Invasive adenocarcinoma arising in villous adenoma
Most worrisome lesions are villous adenoma > 4 cm.When invasive carcinoma occurs, there is no stalk as a buffer zoneand invasion is directly into the wall of the colon (submucosa or deeper).
Quiz 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
Tubular 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
-90% in the colon; rarely in the stomach and SI-solitary in 50%-2 or more in the remaing 50%
Common; we see it every day
VILLOUS 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
Adenomatous polyps -tubular adenoma -tubulovillous adenoma -villous adenoma
(occassionally seen)
(not as common as TA)
Familial syndromes
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
Familial syndromes-Familial adenomatous polyposis-Gardner syndrome-Hereditary nonpolyposis colorectal cancer
FAP - Cancer preventive measures:prophylactic colectomy as soon as possibleearly 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.
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
•Multiple synchronous or metachronous colorectal cancers not always associated with pre-existing adenomas•Association with sebaceous tumors of skin ; Muir-Torre syndrome
Familial syndromes-Familial adenomatous polyposis-Gardner syndrome-Hereditary nonpolyposis colorectal cancer
Inherited mutations in any of four genes that are involved in DNA
repair are putatively responsible for familial syndrome of HNPCC.
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.
These human mismatch repair genes are involved in genetic proofreading during DNA replication and are referred to as “caretaker” 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
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 toone gene copy. The second gene copy is then later deleted.
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 theroad to an adenoma.
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
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
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 andpossibly 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
•Loss of methyl groups in DNA(hypomethylation)•early change in colonic neoplasm
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 - mucosaB - submucosa or muscularis propria B1; serosa B2C - B1 + lymph node met C1; B2 + lymph node met C2D - Distant mets to lung and liver
A: 5YSR - 100%
B1: 67% B2: 54%
C1: 43%; C2: 23%
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
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
Polypoid, fungatingnon-obstructing rt colon ca
Cancer narrows lumen
Colorectal 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
Neoplasms of appendix
Mucocele _ benign dilatation of the lumen by mucinous secretions Mucinous cystadenoma-proliferation of benign neoplastic cells-dilatation by mucinous material -may rupture
Mucinous cystadenocarcinoma -invasion of neoplastic cells-Pseudomyxoma peritonei - term
describing distention of the peritoneal
cavity by the presence of semisolid, mucin containing adenocarcinoma cells
(normal appendix mucosa)
(The mucosa is altered by mucinous cells)
Peritoneum Inflammation1. Sterile peritonitis due to
bile or pancreatic juices2. Surgical procedures3. Endometriosis4. Rupture of GI tract
(Ruptured appendicitis, acute salphingitis, or diverticulitis)
Neoplasms
1. Primary mesothelioma -rare
2. Secondary malignancies -extension, seeding, or implantation (more common)