UNIVERSITY OF JORDAN

DENTISTRY 2016

Pathology

SLIDE:

Done by  Jwana mahafza

Corrected by 
Doctor  Tareq al-adily

Date of Lecture: 00/ 00/ 2018

CONTACT US: ASNAN LAJNEH

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Slide10 from p.g6 to the end /slide11 are all included.
Sorry for the sheet length but it was a really long lecture

Inflammatory Bowel Disease (IBD):

Definition:

IBD is a chronic, lifelong condition resulting from complex

interactions between intestinal microbiota (normal flora) and host
immunity in genetically Susceptible individuals resulting in
inappropriate mucosal immune activation.
(so IBD has genetic background)

Types:
1) Crohn disease: also referred to as
Regional enteritis (because of frequent ileal involvement)
May involve any area of the gastrointestinal tract and is frequently
Transmural.
Note:crohns disease could be seen in oral cavity/buccal
mucosa/esophagus!
2) Ulcerative colitis: limited to the colon and Rectum and
extends only into the mucosa and Submucosa.

Epidemiology:
-present in adolescence or young adulthood (more common)
-small peak in fifth decade aged people(little)
-more common in whites

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IBD has been common these days especially in west,why?
According to the
Hygiene hypothesis: improved hygiene, sanitation of water and
reduced enteric infections (less exposure to bacteria) results in
inadequate development of regulatory processes that limit
mucosal immune responses.

“So less adaptation to our immune system, because there isn’t much
interaction between inflammatory cells in the gut with bacteria.”
E.g.: When someone is frequently exposed to recurrent infections, his
immunity will get used against it, not like if he has not ever exposed
to a bacteria.

Pathogenesis:

-very complicated
-Alterations in host interactions with intestinal microbiota due to
genetic factors.
- Intestinal epithelial dysfunction (epithelial cells of intestinal
mucosa).
-Aberrant (abnormal) mucosal immune responses.
-Altered composition of the gut microbiome (flora changes).

Epithelial defects:

-Defects in intestinal epithelial tight junction barrier function, in

IBD patients and first degree relatives.
-Barrier dysfunction so bacteria is allowed to enter between cells
and activates both innate and adaptive immunity.
-Paneth cell red granules, which are normally present contain
anti-microbial peptides that can affect composition of the
luminal microbiota, these paneth cells in crohn disease are
abnormal carrying ATG16L1 mutations.

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Genetic background

-Increased risk in positive history in family members, not restricted

to the 1st generation only, because we have cluster of genes.

-evidences shows the strong genetic effect in IBD ,like in identical

twins in Crohn disease 50% it shows in the other twin and its
more obvious than in ulcerative colitis, which is 16%.

The 2 important IBD related genes are:

- NOD-2 gene polymorphism: it is present in 10% of Crohn

disease.
The protein product is ineffective in preventing normal flora from
invading intestinal epithelium (so its quality is not very effective)
- ATG16L1 (autophagy-related 16–like-1) and IRGM(Immunity-
related GTPase M).
Auto phagosome for intracellular bacteria are ineffective, both
genes are related to phagocytosis.
(remember that when a macrophage engulf bacteria a
phagosome is formed then it will be taken to a lysosome for lysis).

Notes for further understanding:

Risk is not restricted to the 1st generation only, because we have cluster of
genes not single gene transmission so not all of them are known in certain
families.

Gene cluster: group of two or more genes found within an organism's DNA that
encode for similar polypeptides, or proteins, which collectively share a
generalized function. (from google)

Remember that polymorphism doesn’t mean mutation and it can be present in

people normally but not very common.

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Mucosal immune responses:

-Exaggerated polarization of T-helper lymphocytes to TH-1,TH-17

and huge increase in their numbers for unknown reason, both
have synergistic effect of inflammation and cause severe
damage.
*Remember that helper T cells with cd4 receptors give subtypes
(TH-1/TH-2/TH17)
-note: suppressing one of these subtypes can be beneficial as
therapy.
-Defects in T-regulatory cells (inhibitory cells) that produce IL-10
that has suppression function resulting in severe inflammation.

Microbiota (flora)
- Normally, 50% of dry fecal mass is composed of bacteria
- There is significant inter-individual variation in composition and
quantity of bacteria, affected by diet and disease.
-Microbiota transfer experiments from healthy people to IBD
patients has shown to reduce inflammation.
(so the conclusion is that they had different type of bacterial flora
(more virulent) than normal individuals in their gut, and that
means the microbiota type is important in development of IBD.

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 Crohn’s disease vs ulcerative colitis
Features:

Crohns disease Ulcerative colitis

Affects any segment in GI
tract
• The most common in
terminal ileum and cecum
• 40% have disease limited to
small bowel (terminal ileum)
• 30% have involvement to
small and large bowels
• 30% have involvement in
colon
• characterized by Skip
lesions: inflammation
involves small well
circumscribed areas, away
from each other
Always involves rectum
-Extends proximally,
involving part or all colon
-Continuous lesion
-Limited to large bowel, but
minor mucosal
inflammation of terminal
ileum might occur called
(backwash ileitis)

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Grossly:

Crohns disease Ulcerative colitis

•A Transmural inflammation Inflamed mucosa appears red
starts from mucosa to serosa. only superficial
Disease begins with small ulcer - Broad based ulcers
called aphthous ulcer (circumferential ulcers)

• May enlarge and coalesce with • Regenerated mucosa appear as

other ulcers to form a linear elevated “pseudo polyps”
serpentine ulcer, parallel to the
longitudinal axis of bowel • Mucosa appear atrophic with
time, No wall enlargement or
• The alteration of normal and stricture, normal serosa.
diseases mucosa result in
“cobble stone” appearance in • Inflammatory mediators for
endoscopy. unknown reason causes damage
Deep fissures may occur, results to
in perforation neurons,smooth muscles
resulting in dilated bowel with
• Fistula tract may develop, risk of
between segment of perforation (toxic mega colon).
bowel, or between bowel and
urinary bladder showing (stool
from bladder) vagina or skin
(peri-anal fistula) releasing puss
and abccess
• Bowel appears thickened
(mucosal edema,
submucosal fibrosis, smooth
muscle hypertrophy)
all these indicate severe damage

• With time, stricture (stenosis)

develops secondary to fibrosis
• With deep inflammation, like in
fistula mesenteric fat extends
around serosa (creeping fat) and
becomes sticky

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Note: inflammation of serosa in crohns disease make it sticky
allowing it to stick with an adjacent organ forming a canal
between them called (Fistula).
Microscopy:
Crohns disease Ulcerative colitis
•Neutrophils attack epithelial • Cryptitis, crypt abscess,
cells of intestinal crypts crypt distortion
(cryptitis) which have bacteria on
them.
• Inflammation limited to
• Aggregates of neutrophils mucosa, and superficial
inside crypt lumen (crypt submucosa inflammatory
abscess) cells.
Ulceration is common
• Normally crypts are organized • NO granulomas
in arrangement/color..etc.
Here Crypts appear
disorganized (haphazard
. In endoscopy
arrangement), might find some Cobble stone /linear ulcers/pus
Branching areas with no crypts formation/pseudo polyps
Continuous inflammation
•Epithelial metaplasia: gastric
glands, Paneth cells in left
colon (normally absent)

•Sometimes: non-caseating
granulomas(which is a very
specific indication for crohn
disease, but unfortunately I does
not appear in most patients.
Remember! Caseating
granulomas are found in
tuberculosis due to the presence
of abnormal bacteria.
•Chronic inflammatory cells,
involve mucosa,
submucosa, muscularis propria

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Clinical:
Crohns disease Ulcerative colitis
• Intermittent diarrhea, abdominal Attacks of bloody diarrhea and
pain, fever. stingy mucoid,
Asymptomatic periods extends to material, purulent discharge on
months even without therapy. the wall.

• fresh Blood diarrhea abdominal pain(more painful than

(oxygenated blood) (colon
involvement), iron deficiency
Anemia due to excessive
bleeding.
• Reactivation of symptoms by
triggers :stress, certain
diets, NSAIDs, smoking
• In severe small bowel disease,
malabsorption
Syndrome (vitamin and protein
deficiencies like albumen)
in crohns)
• Symptoms may persist for a
long time
(months) before subside
• Primary sclerosing
cholangitis(bacteria reaches the
biliary tree causing
inflammation), arthritis
• Increased risk of colon
adenocarcinoma about 10 times

• Peritonitis and abscess intra- • Treatment: start by giving

abdominal (bacteria reaches the medical treatment and if no
peritoneum causing inflammation response we do colectomy
and sepsis, it’s an emergency
medical case and needs
immediate treatment)

• Arthritis in joints, uveitis in

conjunctiva, skin diseases,
because cytokines reaches these
areas and start inflammation
• Increased risk of GI
adenocarcinoma 2 times.

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Microscopic appearance of crohns disease

Cobble stone like colon in crohns disease

Slide 10 is done  ,slide 11 starts 

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Colon tumors and malignancies:

Colonic polyps
• Polyps are common in GI and most commonly in the colon but
may occur in the esophagus, oral cavity, stomach, or small
Intestine.
Polyps can be Pedunculated (with stalk) like mushroom or sessile
(without stalk).
They are several types Neoplastic (adenoma), non-neoplastic
(Inflammatory, hamartomatous, hyperplastic)
Types of colonic polyps:

1) Inflammatory Polyps
-Also called solitary rectal ulcer syndrome.

- It starts as ulcer then grows into polyp.

Due to injury in the ulcer site Rectal, bleeding starts locally,
mucus discharge, and an inflammatory lesion of the anterior rectal
wall
-Occurs Secondary to impaired relaxation of anorectal sphincter.
(which means, the sphincter goes deep to the mucosa of rectum
and with stool movement projections in mucosa cause sharp
angle elevation of anterior rectal wall, ulcerations and with
repeated episodes of ulceration and tissue repair it becomes
inflammatory polyps.

-inflammatory polyps are diagnosed by hemorrhoid, and if its not

present they do endoscopy
*note: hemorrhoids are swollen veins in your anus and lower
rectum, similar to varicose veins. from (mayoclinic.org)

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2) Hamartomatous Polyps
-It can be Sporadic (individual) or syndromic (multiple, with other
anomalies)
-Hamartoma: means disorganization of normal tissue, so here we
can see all types of GI tissues(glands,smooth muscles, blood
vessels, inflammatory cells), However neoplasms arises from
single type of cells for example in glandular cells, so we notice the
infiltration of glands everywhere.

-So hamartomatous polyps are disorganized growth of normal

tissue with multiple components
-“Juvenile”)‫( طفولي‬polyps present early in life but seen in both
adults and children, and they are the most common type of
hamartomatous polyps.
-They are Solitary(single) in sporadic cases, multiple in syndromic
-Also called inflammatory polyp (especially in adults,
with severe inflammation)
-could find Numerous glands, some are cystically dilated with
stromal inflammation.
- Patients present with bleeding and Increased risk of
adenocarcinoma, but still it’s a small risk.

3)Peutz-Jeghers Syndrome (hereditary)

-Rare autosomal dominant
- Multiple hamartomatous GI polyps and mucocutaneous
Hyperpigmentation, the patient may show pigmentation in his oral
cavity.
- Increased risk of GI and extra-GI malignancies
- LKB1/STK11 gene is a tumor suppressor gene and a mutation in
it leads to a high susceptibility for malignancies.
- Most common in small intestine,but it may arise on other areas.
- Morphology: glands, inflammatory cells with very thick smooth
muscles(the last feature help in differentiation between peutz-
jeghers and the hamartomatous polyps.

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4) Hyperplastic polyps
-It’s Very common in people above age of 60.
Epithelial cells normal life span is about 3-4 days and if shedding
decrease, epithelial cells, will accumulate and make a serrated
surface so decreased shedding of epithelial cells and
accumulation of goblet cells, results in serrated morphology
- Single or multiple growths
- More common in left colon
- small in size <5 mm
--they are not malignant or scary.

Hyperplastic polyp.
• (A) Polyp surface with irregular tufting of
epithelial cells (not all are goblet cells)
• (B) Tufting results from epithelial
overcrowding.
• (C) Epithelial crowding produces a
serrated architecture when glands are cut
in cross-section.

5) Adenoma
- Benign polyp that has mutation and can progress to
Adenocarcinoma
- Defined by presence of epithelial dysplasia in histological
diagnosis
(Nuclear elongation “cigar like nucleus”, stratification,
Hyperchromatic)
- Present in 50% of adults older than 50 in the west
- Pedunculated or sessile
- Size is variable from small to large 0.3-10

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Adenoma is classified into 3 types:
1- Tubular: round to tubular glands, commonly small and
pedunculated.
2- Villous: covered by villi, commonly large and sessile.
3- Tubulovillous: mixture of both.
*villous adenoma was thought to be the worst type of them but
studies proved that the Size of polyp is most important risk factor
for invasion and malignancy (rare if <1cm)
- Sometimes the lumen is serrated.

Familial Adenomatous Polyps

- Autosomal dominant
- Multiple adenomas in GI tract (>100)
- Mutation in adenomatous polyposis coli (APC),which is a tumor
suppressor gene
- Morphology similar to adenomas
- Always develop carcinoma if not treated so in early detection
doctors do (colectomy) as prophylactic treatment.

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6) Hereditary non polyposis colorectal carcinoma
- Lynch syndrome
- Familial clustering of cancer in GI, gynecologic, brain and skin
cancer
- Younger age of presentation
*Note: colon cancer is mostly common in elderly, so if a 20 year
old patient comes with colon cancer and a family history, we
suspect hereditary non polyposis colorectal carcinoma.
- Cancer more common on right colon
-Adenomas develop, but no numerous polyps
- Germ-line mutation in one allele of genes are responsible for
DNA repair so if the (MSH2, MLH1) genes are mutant incorrect
transcription occurs which leads to cancer.

7)Adenocarcinoma
Colon is the most common site of carcinoma in GI
system
- Second most common cancer in men and women
in Jordan and 1st are prostate for men and breast for women.
- Major cause of morbidity and mortality
- Peak incidence between 60—70 years old, except familial which
appears in young age.
- Risk factors: sedentary life-style, low intake of
dietary fibers, high dietary sugar and fat, obesity
- COX-2 inhibitors and aspirin are protective against colon
carcinoma for an unknown reason, but excessive use cause
gastroenteritis.

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Pathogenesis
Colon cancer has been studied thoroughly and it was noticed that
it has several pathways in mutations
- 70% of sporadic adenocarcinoma, are caused by APC/β-catenin
pathways
How? It occurs in 4 levels of mutations
1-APC which is a tumor suppressor normally inhibits β-catenin
(an activator to the cell cycle)
and if it becomes mutated and both copies of APC are
inactivated, β-catenin accumulates and translocate into nucleus,
activating transcription factors and cyclin D1 to promote cell
proliferation
-until this stage only dysplasia is evident
2- K-RAS gene (cell cycle activator) is mutated, becomes more
active and promote cell survival and prevents apoptosis
-at this stage the disease start to appear grossly.
3- SMAD gene mutation, normally inhibits cell cycle
4- TP53 mutation, the last mutation to occur and by then
countless mutations are accumulated in the cell and reaches
invasive carcinoma state.

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Pathogenesis

30% of adenocarcinoma si due toThe microsatellite instability

pathway
- (LSH/MSH)genes mutation result in mismatch repair failure
- Accumulation of short nucleotide repeats in a high number
- Most repeats are located in non-coding genome,if they are
located there nothing will happen, however, some are located in
promotors areas of TGF-β and BAX genes (proapoptotic
proteins) and apoptosis will be stopped.

Pathogenesis
- similar to (LSH/MSH)CpG island hypermethylation phenotype
(CIMP)
-Indirect gene mutation in MLH1 gene,methyl group binds to the
(C,G)nucleotides and cause inactivation.
- Instead, hyper methylation occurs in promotor
region, results in decreased transcription
- BRAF oncogene is commonly mutated
- No mutation in TP53 or KRAS,but it will reach cancer at the end.
*Note: nowadays medicine is directed toward genome studying by
analyzing these genes mutations, so they can predict cancers
before they occur and advice these people to do frequently check
up by colonoscopy.

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Morphology
• Proximal tumors(right side) tend to be exophytic, polypoid, rarely
cause obstruction.
• Distal tumors tend to be annular, constricting (napkin
ring)appearance, causing intestinal obstruction.
• Microscopy: malignant invading glands,
Desmoplasia (fibrosis)”reactive fibroblast proliferation.

Clinical features
- Firstly diagnosed as Iron deficiency anemia,mostly occur in
elderly.
- Alteration in bowel habit (timing for going to bathroom changes)
- Abdominal pain, blood in stool
-• Depth of invasion, lymph node involvement and distant
metastasis are the most important prognostic factors.
So old personiron deficiency anemiamust check their colon

8)ACUTE APPENDICITIS (focus on symptoms and pathogenises)

- very common,it’s the Most common in adolescents and young
adults
- May affect any age
- Pre-operative diagnosis is sometimes difficult,because
symptoms are variable between patients.
-confused with lymphadenitis and gynecologic
Disease(especially ovarian diseases in women)

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Pathogenesis
- Progressive increase in intraluminal pressure
by fecolith (small piece of hard stool), causing
venous obstruction,might cause ischemia and inflammation.
- Other less common causes are tumors, gall stones, worms
- Next, bacterial overgrowth
- Neutrophilic infiltration into lumen, appendix wall and peri-
appendiceal fat,and deep inflammation results.

Morphology
-Appendix appears erythematous(because of the inflammation),
granular serosa (instead of smooth)
- Neutrophil infiltration into mucosa and muscularis propria
- in severe inflammation neutrophils and dead tissue form abscess,
called acute suppurative appendicitis
- If extensive ulceration develops, obstruction and infarction,called
acute gangrenous appendicitis.
Clinical presentation
- Begins as peri-umbilical pain,at the center.
- Sometimes fever, nausea, anorexia, not always present.
- Pain then shifts to right lower quadrant
- Typical symptoms are typically absent, so doctors when aren’t
certain usually open and check if its inflamed or not.

9)Appendix tumors
-Not adenocarcinoma, Most common appendix tumor is carcinoid
-carcinoid: is a well differentiated neuro endocrine glands.
Remember in stomach they produce gastrin/hormones/peptides,,.
- Commonly asymptomatic
-At tip of appendix
- Well-differentiated neuroendocrine glands
- Benign behavior
- Mucocele: thin dilated appendix filled with mucin,produced by goblet
cells commonly secondary to mechanical
obstruction, or rarely from tumors,it might appear as lare tumor but it’s
a completely normal process.

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