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)