Here is a presentation made by MBChB level 3 students for the lecture series on GIT Pathology. Hope it helps you. Few typos but better will come.It includes Hirshsprung's disease, Diveticulosis, Colitis, Colorectal Carcinoma among others

1. Pathology of the Large
Intestines.
MBchB Level 3 2016
Group 8.
Dr Ancent Nzioka-Moderator
Wednesday,JUNE 8th 2016 1

2. Kenyatta University MBChB Level 3
• Orato Ogoti
• Mark Ndoria
• Wayne Kiarie
• Dennis Opondo
• Sharon Namikoye
• Angela Oruko
• Caren Akinyi
• Ikram Yusuf

3. Anatomy and Physiology
of the Large Intestines

4. NORMAL STRUCTURE
• The large intestine extends from the distal end of the ileum to the
anus
• Consists of : caecum, ascending colon, transverse colon,
descending colon sigmoid colon & rectum
• It measures c.1.5 m long, though there is considerable variation in its
length and caliber
• Caliber which is greatest at the level of the caecum, reduces towards
the mid-rectum
• It however enlarges again near its terminus, forming the rectal
ampulla that allows for fecal pooling before defecation

6. …anatomy
• What makes the typical large gut unique-
• It has a larger diameter compared to the small gut
• It is for most part, fixed to the abdominal wall
• Presence of taeniae coli- a 3-band concentrate of its longitudinal muscles*
• Appendices epiplocae- small fat projections off its wall (usually absent in caecum,
appendix, rectum)
• Haustrations- puckered sacculations along its wall demonstrable on plain
abdominal radiography(haustra appear because the taenia coli are shorter than
the intestine, hence sacculation of the colonic wall)

7. Appearance of the human colon on double contrast barium enema examination
demonstrating the transverse colon, hepatic and splenic flexures.

8. …
• Like the small intestine it is made up of-Mucosa,
Submucosa,Muscluaris propria, & serosa
• The function of the large intestine is chiefly absorption of fluid and
solutes.
• *Appreciate that most of the absorption of water will have taken
place in the small intestine
• It is also a hub for millions of commensal microbes that play a
fermentative role alongside synthesis of important molecules cite
Vitamin K

9. The caecum
• The caecum is a large blind-ending pouch of the large intestine lying in the right
iliac fossa.
• It is the first part of the large intestine
• Connects the ileum to the ascending colon.
• It is separated from the ileum by the ileocecal valve ( Bauhin valve)
• Valve serves to limit the rate of food passage into the caecum
• It also helps prevent material from returning to the small intestine.

10. …caecum
• FUNCTION: The caecum commences the process of fluid and electrolyte
reabsorption which occurs to a large extent in the ascending and transverse
colon.
• ADAPTATION: The distensible nature and 'sac-like' morphology of the caecum are
adaptations for the storage of larger volumes of semi-liquid chyme entering from
the small bowel via the ileocaecal valve.

11. Ascending colon
• It measures approximately 15cm
• It is a retroperitoneal structure, covered both anteriorly and laterally by
peritoneum
• Laterally, the peritoneum folds to form the paracolic gutter
• Loops of the ileum, the greater omentum and anterior abdominal wall are
important anterior relations
• The ascending colon possesses a narrow mesocolon for part of its course in up to
one-third of cases.

12. Transverse colon
• Is c.50 cm long, and extends from the hepatic flexure across to the splenic flexure
• It hangs down between the flexures to a variable extent, and sometimes reaches the
pelvis!
• Above it are the liver and gallbladder; the greater curvature of the stomach and the
body of the spleen.
• The transverse mesocolon permits its considerable mobility
• Occasionally the colon may be interposed between the liver and the diaphragm
(Chilaiditi syndrome)
• And may be mistaken for free intraperitoneal gas.

13. Descending colon
• Descends c 25cm to the left lumbar region
• Loops of jejunum lie anteriorly
• The descending colon is smaller in diameter compred to the
transverse
• It is also more deeply placed, and more frequently covered
posteriorly by peritoneum, than the ascending colon.

14. Sigmoid colon
• The sigmoid colon begins at the pelvic inlet and ends at the rectum.
• Characteristically it forms a mobile loop which normally lies in the
lesser pelvis
• Position and shape of the sigmoid colon vary greatly, depending on its
length; mobility of its mesocolon; the degree of distension of the
rectum, bladder and uterus *
• Clinical pearl- The sigmoid colon is an common site for acquired
diverticula formation
• Sigmoid volvulus may also occur

15. Rectum
• Group 7*
• It is part of the large intestine
• Continuous with the sigmoid colon with a few features that set it
distinct
• Features suit its specialized role in defaecation and continence in
combination with the anal canal.
• We all learn how to do a DR exam. 

16. Vascular supply
• The large intestine is supplied by branches of the superior mesenteric
artery (SMA) via its branches-Ileocolic artery, Right colic artery, Middle colic
artery
• Supply also from the Inferior mesenteric artery (IMA) through: Left colic
artery, Multiple sigmoid arteries and the Superior rectal artery
• The anorectum receives blood supply from branches of the internal iliac’s
middle rectal artery and inferior rectal artery (a branch of internal
pudendal artery)
• Venous drainage is largely by accompanying veins
• Lymphatic drainage is via the epicolic, pericolic & intermediate nodes that
subsequently drain to the main nodes

17. …concepts
• The pattern of blood supply to the intestines is not via singular
arteries but by continuing series of anastomoses that form arterial
arcades
• The terminal branches of these arcades are straight arteries called
vasa recta
• The vasa recta enter the wall of the large intestine to supply it
• These points of entry are important as sites of weakness where
diverticuli are likely to form

18. …concepts
• The arterial supply follows the embryological pattern
• WATER-SHED AREAS - these are areas of the colon that receive dual
blood supply from the most distal branches of any of the large
arteries
• CITE: The splenic flexure( SMA&IMA) and the sigmoido-rectal
area(iliac and pudendal arteries)
• These areas are highly susceptible to ischaemia in the event of
systemic hypoperfusion e.g. in DIC or heart failure
• They are however spared when atherosclerosis affects one of the two
arteries supplying the area

19. Embryology & Congenital anomalies
• The large and small intestines develop embryologically in a
dependent fashion
• The process is complex, making congenital anomalies associated with
it some of the most common
• Initially development concerns the midgut region, connected to the
yolk sac, and the hindgut region, ending at the cloacal membrane.

20. Embryology & Congenital anomalies
• This is followed by two mechanical processes of elongation and
rotation.
• Elongation (growth in length) leaves the midgut "herniated" at the
umbilicus and external to the abdomen.
• This is attributed to the bowel loops growing at a faster rate
compared to the abdominal cavity and wall, especially the rapidity of
growth of the cranial end of the midgut (which will form the small
intestine), and the large size of the developing liver and kidneys.

21. Embryology & Congenital anomalies
• This so called “physiological herniation” occurs around 6-8 weeks
• While the bowel is within the umbilical cord, the midgut rotates 90
degrees counter-clockwise (facing the embryo).
• At approximately 10-11 weeks the abdomen has enlarged enough and
the intestines return to the abdominal cavity.
• The midgut then rotates an additional 180 degrees counter-clockwise,
fixing to the posterior retroperitoneum.

22. Embryology & Congenital anomalies
• The rotation occurs around a mesenteric axis, establishing the anatomical
position of the large intestine within the peritoneal space.

23. Embryology & Congenital anomalies
• Migration of neural crest cells into the wall of the intestines
establishes the enteric nervous system.*tier disorders
• An enteric nervous system which has a role in peristalsis and
secretion.
• Prenatally, secretions also accumulate in this region and are the first
postnatal bowel movement (meconium.)
• However, like most of the gut, this region is not fully "functional" until
after birth, when development continues besides populating it with
commensal bacteria and the establishment of the immune structures
in the wall.

25. Hirschsprung’s disease
• Also termed Congenital Aganglionic Megacolon
• Named after Harald Hirschsprung, the Danish pediatric physician who first
described the disease in 1886
• It is a developmental disorder of the enteric nervous system
• Characterized by an absence of ganglion cells in the distal colon with resultant
functional obstruction of the bowels.
• It may be isolated or occur in the light of other developmental abnormalities eg
Down’s syndrome

26. • Research studies show that it is more common in males but tends to
be more severe in females
• Patients typically present as neonates with failure to pass meconium
in the immediate postnatal period followed by obstructive
constipation and abdominal distention.

27. • Failure to pass
meconium post-
natally can also be a
feature of cystic
fibrosis
• Meconium, is
derived from
material ingested in
utero- intestinal
epithelial cells,
lanugo ,mucus,
amniotic fluid, bile,
water

28. Pathogenesis
• The enteric neuronal plexus develops from neural crest cells
• that migrate into the bowel wall during embryogenesis.
• In Hirschsprung disease, the normal migration of
• neural crest cells from cecum to rectum is disrupted.
• This produces a distal intestinal segment that lacks both the Meissner
submucosal plexus and the Auerbach myenteric plexus- hence the
term “aganglionosis”.

29. Pathogenesis
• As a result, coordinated peristaltic contractions are absent
• Subsequent functional obstruction results in dilation proximal to the
affected segment.
• Mechanisms underlying this defective neural crest cell migration
remain unknown
• However, heterozygous loss-of-function mutations in the receptor
tyrosine kinase RET account for >>
majority of familial cases and approximately 15% of sporadic cases.

30. Pathogenesis
(The RET gene codes for a protein that is involved in signaling within
cells.
• This protein appears to be essential for the normal development of
several kinds of nerve cells, including enteric neurons &the
autonomic nervous system.)
• However, mutations also occur in other genes, modifying genes
and environmental factors also play a role.

31. …pathogenesis
• Alternatively, normal migration may occur with a failure of
neuroblasts to survive, proliferate, or differentiate in the distal
aganglionic segment.
• Abnormal distribution in affected intestine of components required
for neuronal growth and development, such as fibronectin, laminin,
neural cell adhesion molecule (NCAM), and neurotrophic factors, may
be responsible for this theory.

32. Morphology
• Hirschsprung ‘s disease almost always affects the rectum, but the
length of the additional involved segments varies.
• Most cases are limited to the rectum and sigmoid colon, but severe
• disease can involve the entire colon.
• Worth noting: The aganglionic region may have a grossly normal or
contracted appearance, while the normally innervated proximal colon
may undergo progressive dilation as a result of the distal obstruction

33. Dx
• Suspect Hirschsprung's in a baby who has not passed meconium
within 48 hours of delivery.
• Recall that 90% of babies pass their first meconium within 24 hours,
and the next 9% within 48 hours.
• MORE IMPORTANTLY: Definitive diagnosis is made by suction biopsy
of the distally narrowed segment.
• Abdominal x-ray - show a lack of stool in the large intestine or near
the anus and dilated segments of the large and small intestine.
• Barium enema with x-ray of the abdomen may show strictures,
obstructions with dilated bowel portion above the obstruction.

36. Expanded
• Hirschsprung’s disease most commonly involves the recto-sigmoid
region of the colon but can affect the entire colon and, rarely, the
small intestine.
*TRUSTED ONLINE SOURCES: Hirschsprung’s disease can be classified
into two ; “short disease” which involves rectum and sigmoid
and “long disease” involves rectum and entire colon
-Some patients present with persistent, severe constipation later in life
but a majority are diagnosed at infancy

37. Expanded
• Symptoms in infants include difficult bowel movements, poor
feeding, poor weight gain, and progressive abdominal distention
• Early diagnosis is important to prevent complications (e.g.,
enterocolitis, fluid and electrolyte disturbances, perforation, and
peritonitis.
• TREATMENT: Bowel resection of the aganglionic portion with
anastomosis

38. Intestinal Obstruction

39. INTESTINAL OBSTRUCTION
• Small intestines and colon make up the majority of GI and are
sites of a broad array of diseases.
• Obstruction of the GI occur at any level ,but the small intestines
are most often involved because of its relatively narrow lumen
• Collectively hernias ,intestinal adhesions intussusception and
volvulus account for 80% of mechanical obstruction while
tumors, infarction and other causes of strictures account for an
additional 10-15%

40. Clinical features
• Constipation
• Vomiting
• Abdominal pain and
• Abdominal distention
Surgical intervention is usually required in cases where obstruction is
associated with bowel infarction

41. .

42. Hernias
• Any weakness or defect in abdominal wall may permit protrusion of a
serosa lined pouch of peritoneus (hernia sac)
• Acquired hernias typically occur anteriorly via the inguinal or femoral
canals, umbilicus or at site of surgical scars
• Are the most frequent cause of intestinal obstruction worldwide
• Obstruction usually occurs because of visceral protrusion (external
herniation) and is most frequently associated with inguinal hernias

43. • Small bowel loops are typically involved but omentum and small or
large bowel may also protrude
• Pressure at the neck of the pouch may impair venous drainage,
resultant stasis and oedema increase the bulk of the herniated loop
leading to permanent entrapment.

44. Adhesions
• Mostly acquired but can be congenital in rare cases
• Surgical procedures, infections, endometriosis can cause localized or
generalized inflammation as peritonitis heals ,adhesion may develop
between bowel segments, abdominal wall, and surgical sites
• These fibrous bridges can create closed loops through which the
viscera may slide and frequently become trapped (intestinal
obstruction)
• This can lead to obstruction and strangulation leading to impaired
venous drainage then infarction

45. Volvulus
• Complete twisting of a loop of bowel about its mesenteric base of
attachment
• Obstruction and infarction are present
• Occurs most often in large reductant loops of sigmoid followed in
frequency by caecum, small bowel, stomach and rarely transverse
colon

46. Intussusception
• Occurs when a segment of intestine constricted by a wave peristalsis
suddenly slides into the immediately distal bowel
• Once trapped the invaginated segment is propelled further by peristalsis
into the distal segment pulling its mesentery with it
• When encountered in children there is usually no underlying lesion /defect
in bowel
• However in adults it may signify an intraluminal mass or tumor at point of
traction

47. Intestinal Vascular Disorders

48. Intro.
• The main blood supply to the intestines is by the celiac, SMA and
IMA. Upon reaching the intestinal wall, the SMA and IMA fan out to
form arcades. These arcades then anastomose with collateral supplies
from the proximal celiac, distal pudendal and iliac circulations to give
a rich blood supply to the intestines.
• This multiple blood supply to the intestines enable them to tolerate
slow progressive loss of blood supply from one of the arteries
supplying them.
• However, acute compromise of the major blood vessels can result
into intestinal infarction affecting up to several meters.

49. Ischemic Bowel Disease
• Ischemia of the intestinal wall are of 3 types:
• Mucosal infarction- extends no deeper than the muscularis
mucosa.
• Mural infarction- involves the mucosa and submucosa.
• Transmural infarction- involves all the 3 layers of the intestinal
wall.

50. Causes:
• Mucosal and mural infarcts are due to acute or chronic hypoperfusion
which may be associated with shock, dehydration, cardiac failure and
use of vasoconstrictive drugs.
• Transmural infarctions are caused by acute vascular obstruction
subject to atherosclerosis, aortic aneurysms, use of oral
contraceptives, aortic atheroma and embolism.
• Others; invasive neoplasms, cirrhosis, trauma, hypertension,
abdominal masses compressing portal system, thrombosis,
vasculitidies and infectious diseases.

51. Pathogenesis
• Occurs in two phases:
• Hypoxic injury- occurs at the onset of vascular compromise.
There’s limited damage since epithelial cells are relatively resistant
to transient hypoxia.
• Reperfusion hypoxia- occurs when blood supply is restored.
There’s greater damage e.g. organ failure. This could be due to
production of free radicals, infiltration of neutrophils and release
of inflammatory mediators.

52. • Severity depends on;
• Severity of vascular compromise
• Duration
• Vessels affected
• The distribution of ischemic damage depends on the anatomical
location’s vulnerability;
• Watershed areas(where 2 arterial circulations meet) are more
susceptible.
• Surface epithelium are more susceptible

53. Morphology
• Microscopically, there’s atrophy of surface epithelium, hypertrophic
crypts, fibrosing scaring of lamina propria and stricture formation.
• Mucosal and mural infarction- segmental and patchy distribution,
hemorrhagic ulcerated mucosa, edematous intestinal wall and
extensive mucosal/ submucosal hemorrhage and necrosis.
• Transmural infarction- more pronounced damage with blood tinged
mucus, accumulation of blood in the lumen, coagulative necrosis of
the muscularis propria, purulent serositis and perforation.

54. Clinical features
• More common in men
• Acute transmural infarctions present with sudden severe abdominal
pain and tenderness nausea, vomiting, bloody diarrhea and melaena
and in severe cases shock.
• Associated diminished peristalsis sounds and muscular spasms causes
the abdominal wall to become rigid and board-like.
• As the mucosal barrier break down bacteria enter into the circulation
leading to septicemia.

55. • Progression of ischemic enteritis depends on the underlying cause
and severity of the injury.
• CMV infection causes ischemic intestinal disease due to viral tropism
for and infection of endothelial cells.
• In angiodysplasia, the submucosal and mucosal blood vessels are
malformed resulting in lower Gl bleeding esp. among the elderly.
• Transmural necrosis results in necrotizing enterocolitis esp in
neonates.
• Mucosal and mural infarctions not usually fatal can progress into
transmural infarctions if blood supply is not restored.

56. Hemorrhoids
• These are collateral vessels that develop to allow resolution of venous
hypertension.
• They are dilated anal and perianal collateral vessels that connect the
portal and caval venous system to relieve elevated venous pressure
within the hemorrhoid plexus.
• Predisposing factors:
• Constipation and associated straining- these increase intra-abdominal and
venous pressures.
• Venous stasis in pregnancy
• Portal hypertension.

57. Morphology
• External hemorrhoids – the collaterals vessels within the inferior
hemorrhoid plexus are located below the anorectal line.
• Internal hemorrhoids – these result from dilation of the superior
hemorrhoid plexus within the distal rectum.
• Histologically, thin walled, dilated submucosal vessels that protrude
beneath the anal or rectal mucosa. They are subject to trauma and
ulceration due to their exposed location.

58. Clinical features
• Pain and rectal bleeding (bright red blood on the toilet tissue paper)
Treatment
• Sclerotherapy
• Rubber band ligation
• Infrared coagulation
• Hemorrhoidectomy(severe cases)

59. Diverticular Diseases

60. • Diverticular disease refers to acquired pseudodiverticular
outpouchings of the colonic mucosa and submucosa.
• Rare in persons younger than 30 years of age.
• Diverticula generally are multiple and the disease is known as
diverticulosis.

61. Pathogenesis
• They tend to develop under conditions of elevated intraluminal
pressure in the sigmoid colon. Also facilitated by unique structure of
the colonic muscularis propria where nerves, arterial vasa recta and
their connective sheaths penetrate the inner circular muscle coat
creating discontinuities in the wall.
• These gaps lack reinforcements of the longitudinal layer because in
the colon this muscle is gathered into 3 bands called taeniae coli.
• High pressures are generated by exaggerated peristaltic contractions
with spastic sequestration of bowel segments exacerbated by diets
poor in fiber, reducing stool bulk

62. Morphology
• Small, flask-like outpouchings usually 0.5-1.0 cm in diameter that
occur in a regular distribution between the taeniae coli.
• Mostly found in the sigmoid colon.
• Because they are compressible, easily emptied of fecal contents and
are often surrounded by the fat-containing epiploic appendices on
the surface of the colon.
• Have a thin wall composed of a flattened or atrophic mucosa,
compressed submucosa and attenuated muscularis propria
• Hypertrophy of the circular layer of the muscularis propria.

63. • Obstruction of the diverticula that leads to inflammatory changes
producing diverticulitis and peridiverticulitis.
• Due to the thin wall and the pressure accumulation perforation is
easy.
• With or without perforation recurrent diverticulitis may cause
segmental colitis, fibrous thickening in and around the colonic wall or
stricture formation

64. Cross-section showing the outpouching of
mucosa beneath the muscularis propria.
Low-power photomicrograph of a sigmoid
diverticulum showing protrusion of the mucosa
and submucosa through the muscularis propria.

65. Clinical Features
• Most remain asymptomatic throughout lifetime.
• Affected persons complain of:
• Intermittent cramping
• Continuous lower abdominal discomfort
• Constipation
• Diarrhea

66. Complications
Most complications of diverticular disease arise when the
outpouchings get infected and become inflamed, causing diverticulitis
which may further progress to produce the following :
• Abscess formation due to pus collection in the pouch
• Fibrous tissue formation on the mucosa that may lead to intestinal
obstruction

67. • Fistula formation between bowel sections or between the bowel and
the bladder
• Peritonitis : due to spillage of intestinal contents into the abdominal
cavity when the inflamed pouch ruptures

68. Management
• Studies have shown that while diverticula can regress early in their
development they often become more numerous and larger over
time.
• Whether a high-fiber diet prevents such progression or protects
against diverticulitis is unclear.
• Even when diverticulitis occurs, it most often resolves spontaneously
or after antibiotic treatment, and relatively few patients require
surgical intervention.

69. INFLAMMATORY BOWEL DISEASE.
• IBD is a chronic condition resulting from inappropriate mucosal
immune activation.
• It encompasses two major entities;
• Crohn disease
• Ulcerative colitis
• Distinction is based, in large part, on the distribution of affected sites
and morphological expression of disease at those sites.

70. DIFFERENCES BETWEEN CROHN AND U/C

71. Cont’d

73. EPIDEMIOLOGY
• Both are more frequent in females and frequently present in adolescence or in
young adults.
• In Western industrialized countries it is more common among whites and in the
us it occurs 3-5* more common among eastern Europe Jews (Ashkenazi). This
predilection is mostly due to genetic factors
• Geographical distribution is very variable worldwide. However incidences are on
the rise attributable to the hygiene hypothesis.

74. PATHOGENESIS
• Cause(s) still remain uncertain.
• Most investigations however believe that IBD results from a combination of
errant host interactions with intestinal microbiota, intestinal epithelial
dysfunction and aberrant mucosal immune responses.
• Genetics
• Risk is increased if there’s a member affected
• In Crohn disease the concordance rate for monozygotic twins is approximately
50% but for u/c the rate is 16%.
• NOD2 (nucleotide oligomerization binding domain 2) is a susceptibility gene
in Crohn disease.
• Other genes associated with Crohn disease are ATG16L1 and IRGM both
associated with autophagy. None of these are associated with u/c.

75. Path.. Cont’d
• Mucosal immune responses.
• Mechanisms are still being deciphered.
• Immunosuppressive and immunomodulators are the mainstays of IBD
therapy.
• Polarization of helper T cells to TH1 type is a well known in Crohn disease also
TH 17 also contributes to pathogenesis
• Polymorphisms of IL-23 receptor confer protection from Crohn disease and
U/C.
• U/C includes a significant TH2 component.IL-13 is increased in U/C and to a
lesser degree in Crohn disease.
• Polymorphisms in IL-10 gene as well as the receptor is linked to U/C.

76. Path…Cont’d
• Epithelial defects
• A variety have been described in crohn disease, ulcerative colitis or both. For
example defects in intestinal epithelial tight junction barrier function and a
subset of their healthy first degree relatives.
• This barrier function is associated with the nod2 gene polymorphism. This
dysfunction can activate innate and adaptive immunity and sensitize subjects
to disease.
• Paneth cell granules that contain antimicrobial peptides that affect
composition of luminal microbial are abnormal in patients with crohn disease.

77. Path… Cont’d
• Microbiota
• Quantity of gastrointestinal lumen is enormous amounting to as many as 1012
organism/mL of fecal material in the colon.
• There’s an increase in data that microbiota are involved in IBD pathogenesis
• In this view therefore, some antibiotics can such as metronidazole can be
helpful in preventing remission in crohn disease

78. Crohn Disease
• Also known as regional enteritis.
• May occur in any area of the gastrointestinal tract.
Morphology
• Most common sites are the terminal ileum, ileocecal valve and
cecum.
• Limited to the small intestines in 40% of cases, both the small and the
colon in 30%, and the rest in colonic involvement alone.

79. • There are multiple, separate, sharply delineated areas of disease
resulting in skip lesions. This is characteristic for Crohn disease.
• Earliest lesion is the aphthous ulcer. These may progress and coalesce
into long serpentine ulcers along the axis of the bowel.
• There’s edema and loss of normal mucosal folds.
• Sparing of interspersed mucosa results in coarsely textured
cobblestone appearance where the diseased part is depressed below
normal tissue.
• Fissures may develop and become sites of perforation or fistula tracts.

80. • Intestinal edema causes thickening, inflammation, submucosal
fibrosis, hypertrophy of the muscularis propia resulting in stricture
formation.
• Creeping fat: with extensive transmural disease, mesenteric fat will
extend around serosal surface.
• Microscopically:
• Numerous neutrophils that infiltrate and damage crypt epithelium (crypt
absess)
• Distortion of mucosal architecture.
• Epithelial metaplasia
• Noncaseating granulomas (35%)

81. Clinical features
• Extremely variable
• Starts with intermittent attacks of relatively mild diarrhea, fever and
bloody diarrhea
• RLQ abdominal pain (20%) mimicking acute appendicitis or
perforation.
• Episodes are interrupted by asymptomatic intervals lasting weeks to
months. Reactivation associated with stress, dietary items and
cigarette smoking.

82. • IDA may develop in colonic diseases. Also may occur with
malabsorption.
• Fibrosing strictures are common and need surgical invention.
Anastomoses can be affected by recurrences.
• Fistulas are common
• Extra intestinal manifestations include uveitis, polyarthritis, sacrolitis,
ankylosing spondylitis, erythema nodosum and clubbing of fingertips.
Pericholangitis and primary sclerosing cholangitis occur.
• Risk of colonic adenocarcinoma is increased in Crohn disease.

83. ULCERATIVE COLITIS
• Closely related to Crohn disease.
• However it is limited to the colon and the rectum
• Extra intestinal manifestations of U/C overlap with those of Crohn
disease.
Morphology
• Always involves the rectum and progresses proximally in a continuous
fashion to involve all parts of the colon.
• Skip lesions not seen in U/C. so it is referred to as pancolitis
• When limited to the rectum and sigmoid colon it is called ulcerative
proctitis or proctosigmoditis.

84. • Backwash ileitis: the small intestines are rarely affected but
sometimes the distal ileum is caught up in the disease.
• Grossly the involved mucosa maybe slightly red and granular
appearing or exhibit extensive broad based ulcers. The transition
from diseased part to normal colon maybe abrupt.
• Ulcers are along the long axis of the colon and not in a serpentine
manner as in Crohn disease.
• Isolated bulges of healing mucosa called pseudopolyps.
• Chronicity may lead to mucosal atrophy and a flat smooth mucosa
lacking folds.

85. • Mucosal thickening is absent, serosal surface is normal and stricture
formation is not present.
• Inflammation and its mediators may cause damage to the muscularis
propria leading to colonic dilation and toxic megacolon.
• Microscopically:
• Similar to Crohn disease but skip lesions are absent and inflammation is
largely confined to mucosa and submucosa.
• Granulomas are absent.
• May remit and the contour to be normal again.

86. Clinical features
• Relapsing disorder characterized by attacks of bloody diarrhea with
expulsion of stringy mucoid material, lower abdominal pain and
cramps momentarily relieved by defecation.
• Colectomy cures the disease.
• Infectious enteritis usually precedes the disease entity.

87. Other Forms of Colitis

88. Indeterminate Colitis
• A term used when there is overlap between pathological and clinical
features of both Ulcerative Colitis and Crohn Disease.
• Usually in about 10% of IBD patients.
• These cases do not involve the small bowel and have colonic disease
in a continuous pattern that indicates ulcerative colitis .
• However , patchy histological disease ,a family Hx of Crohn Disease ,
perianal lesions ,onset after initiation of cigarette smoking or other
features that are not typical of ulcerative colitis may prompt
endoscopic , radiographic ,and histological examination.

89. • Serological studies may be useful in such cases because perinuclear
anti-neutrophil cytoplasmic antibodies are found in 75% of individuals
with UC and only 11% those with CD.
• In contrast ,UC patients tend to lack antibodies to Saccromyces
cerevisiae which is often present in those with CD.
• Serological results can also be ambiguous in cases in which clinical
features are indeterminate.
• Indeterminate colitis can be a diagnosis and thus can be treated
effectively.

90. Colitis Associated Neoplasia
• One of the most feared complication of Ulcerative Colitis and colonic
Crohn Disease is development of neoplasia.
• The risk of dysplasia is related to several factor;
• Duration of disease. After 8 to 10 years of onset, the risks increase
markedly.
• Extent of Disease. Patients with pan colitis are at greater risk than
those with only left-sided disease.
• Nature of the inflammatory response. Greater frequency and
severity of active inflammation confers increased risk.

91. • To facilitate early detection of neoplasia, patients are enrolled in
surveillance programs approx. 8 years after diagnosis of IBD.
• The goal of surveillance is to identify dysplastic epithelium which is a
precursor to colitis-associated carcinoma.
• IBD-associated dysplasia can be classified histologically as low or high
grade. High-grade dysplasia are associated with invasive carcinoma at
the same site or else where in the colon and prompts colectomy. Low
grade dysplasia on the other hand can be treated with colectomy or
followed closely.
• Colonic adenomas can sometimes be difficult to differentiate from
polypoid focus of IBD-associated dysplasia.

92. Pseudomembranous colitis
• Pseudomembranous colitis, generally caused by Clostridium difficile,
is also known as antibiotic-associated colitis orantibiotic-associated
diarrhea.
• The latter terms apply to diarrhea developing during or after a course
of antibiotic therapy
• It may be due to C. difficile as well as Salmonella, C. perfringens type
A, or S. aureus.
• However, the latter two organisms produce enterotoxins and are
common agents of food poisoning(They do not cause
pseudomembranes)

93. Pathogenesis
• Disruption of the normal colonic microbiota by antibiotics allows C.
difficile overgrowth.
• Toxins released by C. difficile cause the ribosylation of small GTPases,
such as Rho
• This leads to disruption of the epithelial cytoskeleton, tight junction
barrier loss, cytokine release, and apoptosis

94. Morphology
• Fully developed C. difficile–associated colitis is accompanied by
formation of pseudomembranes
• The membranes are made up of an adherent layer of inflammatory
cells and debris at sites of colonic mucosal injury.
• The surface epithelium is denuded, and the superficial lamina propria
contains a dense infiltrate of neutrophils and occasional fibrin
thrombi within capillaries.
• Damaged crypts are distended by a mucopurulent exudate that
“erupts” to the surface in a fashion comparable to a volcano

95. Close-up & Endoscopic view of
‘pseudomembrane’

96. Risk factors
• In addition to antibiotic exposure, risk factors for C. difficile–
associated colitis include advanced age, hospitalization,and
immunosuppression.
• The organism is particularly prevalent in hospitals; as many as 20% of
hospitalized adults are colonized with C. difficile (a rate 10 times
higher than in the general population)
• Interestingly, most colonized patients are free of the disease.

97. Clinical presentation
• Persons with C. difficile–associated colitis present with fever,
leukocytosis, abdominal pain, cramps, hypoalbuminemia, watery
diarrhea, and dehydration.
• Fecal leukocytes and occult blood may be present, but grossly bloody
diarrhea is rare.
• Diagnosis of C. difficile–associated colitis is accomplished by detection
of C. difficile toxin, rather than culture
• This is supported by the characteristic histopathologic findings.

98. Rx
• Metronidazole is the drug of choice for treatment
• Vancomycin may be used as well, but antibiotic-resistant and
hypervirulent C. difficile strains are increasingly common
• The infection may recur in high risk patients.

99. Diversion Colitis
• Surgical treatment of U/C, Hirschsprung disease and other intestinal
disorders sometimes require creation of a temporary or permanent
ostomy and a blind distal segment of the colon from which the
normal faecal flow is diverted. Colitis may develop in the diverted
segment especially in U/C patients.

100. Morphology:
• Besides mucosal Erythema and friability, the most striking feature of
diversion colitis is the development of numerous mucosal lymphoid
follicles.
• Increased number of lamina propria lymphocytes, monocytes
,macrophages and plasma cells may also be present.
• Severe cases ,histopathology may resemble IBD and include: crypt
abscesses, mucosal architectural distortion or rarely granulomas.

101. Microscopic Colitis
• Encompasses two entities:
• Collagenous colitis
• Lymphocytic colitis
• They both present with chronic ,non-bloody, watery diarrhoea
without weight loss. Radiologic and Endoscopic studies are typically
normal.
• Collagenous colitis ,which occurs primarily in ,middle-aged and older
women, is characterised by;
• Presence of dense sub epithelial collagen layer,
• Increased number of intraepithelial lymphocytes and
• Mixed inflammatory infiltrates within the lamina propria.

102. • Lymphocytic Colitis is histologically similar ,but the sub epithelial
collagen layer is of normal thickness and increase in intraepithelial
lymphocytes is greater ,frequently exceeding one T-lymphocyte per
five colonocyte.
• Lymphocytic Colitis shows a strong association with celiac disease and
autoimmune disease including Graves disease ,Rheumatoid arthritis
and autoimmune or Lymphocytic Gastritis.

103. Neoplasia of the Large
Intestines

104. Benign Lesions

105. • Most common polyps in the colon and occur in the esophagus,
stomach and small intestine.
• Sessile are those with stalks and enlargement of cells adjacent to
polyp combine to form stalks (pedunculated).
1) Inflammatory polyps
• The solitary rectal ulcer syndrome is an example of an inflammatory
lesion caused by impaired relation of anorectal sphincter ,that creates
a sharp angle at anterior rectal shelf.
• This leads to abrasion and ulceration presenting with rectal bleeding
and mucus discharge.

106. 2) Harmatomatous polyps
• Occur sporadically and components of various genetically and
acquired syndromes.
• A rare disorganized tumor like growth composed of mature cell types
a) Juvenile polyps
• Most common type of harmatomous polyps
• Either syndromic or sporadic where the sporadic is referred to as
inflammatory and usually in persons with autosomal dominant
syndrome of juvenile polyposis.
• Occur in children less than 5yrs and manifest as rectal bleeding.

107. Morphology
• Sporadic and syndromic are indistinguishable.
• Are typically pedunculated smooth surfaced reddish lesions less than 3cm
and have cystic spaces.
• Micro: shows the spaced areas to be dilated glands filled with mucin and
inflammatory debris.
b) Peutz-jeghers syndrome
• Rare autosomal dominant disorder defined by presence of multiple GIT
hamartomas and mucocutaneus hyperpigmentation that has high risk to
malignancy.
• Germ line heterozygous loss of function mutation in the gene LKB1/5TK11
in familial form.

108. • Gross: polyps are large and pedunculated with lobulated contour.
• Micro: characteristic of arborizing network of connective tissue,
lamina propria and glands.
3) Hyperplastic polyps
• Common epithelial proliferation that typically discovered in the 6th
and 7th decades of life.
• Formation of these lesions thought to result from decreased
epithelial cell turnover and delayed shedding of surface epithelial
cells.

109. Morphology
• Found in left colon and less than 5mm in diameter.
• Are smooth nodular protrusions of mucosa on crests of mucosal
folds.
• Micro: composed of mature goblet cells and absorptive cells.

110. Adenomas
• Any neoplastic mass lesion in the GIT that may produce mucosal
protrusion /polyp. Most commonly the colonic adenomas that are
benign polyps that give rise to a majority of colorectal
adenocarcinomas.
• Characterized by epithelial dysplasia and growth range from small
pedunculated to large sessile lesions.

111. • Adults in US undergo colonoscopy starting age 50 and persons with familial
history have high risk for developing colon cancer in life typically screened
at least 10yrs before youngest age at which a relative was diagnosed.
Morphology
• Can be pedunculated or sessile with the surface of both types having a
texture resembling velvet or raspberry.
• Cytologic hallmark of epithelial dysplasia is nuclear hyperchromasia
elongation and stratification.
• Pedunculated adenomas have slender fibromuscular stalks containing
prominent blood vessels derived from the submucosa.

112. Tubulovillous
• Small pedunculated polyps composed of small rounded or tubular
glands. Have a mixture of tubular and villous elements. Villous types
have high risk of foci invasion.
Sessile serrated adenomas
• Overlap with those of hyperplastic polyps and cytologic features of
dysplasia are lacking. The most useful histologic feature that
distinguishes sessile serrated adenomas and hyperplastic polyps is the
presence of serrated architecture.

113. FAMILIAL SYNDROMES

114. FAMILIAL ADENOMATOUS POLPS(FAP)
• Autosomal dominant disorder
• Marked by appearance of numerous colorectal adenomas by the
teenage years
• Caused by mutations of the adenomatous polyposis coli gene(APC)
• A count of at least 100 polyps is necessary for a diagnosis of classic
FAP, as many as several thousand may be present
• The growths are morphologically indistinguishable from sporadic
adenomas
• Colorectal adenocarcinoma develops in 100% of patients with
untreated FAP, often before age 30

115. • Thus prophylactic colectomy is standard therapy for persons carrying
APC mutations
• They however still remain at risk of extra intestinal manifestations,
including neoplasia at other sites
• In addition to intestinal polyps, clinical features of Gardner syndrome
and Turcot syndrome, variants of FAP ,may include osteomas of
mandible, skull, and long bones; epidermal cysts; desmoid and
thyroid tumors; and dental abnormalities including unerupted and
supernumerary teeth

116. • Turcot syndrome is rarer and is characterized by intestinal adenomas
and tumors of CNS.
• 2/3 of patients with Turcot syndrome have APC gene mutations and
develop medulloblastomas.
• The remaining 1/3 have mutations in one of the genes involved in
DNA repair and develop glioblastomas.
• Some patients who have FAP without APC loss have mutations of the
base repair gene MUTYH.

117. HEREDITARY NON POLYPOSIS COLORECTAL
CANCER(HNPCC)/LYNCH SYNDROME
• Originally described as familial clustering of cancers at several sites
including colo-rectum, brain, ovary, small bowel, etc.
• Colon cancers in these patients tend to occur at younger ages than for
sporadic colon cancers and often are located in the right colon

118. Etiology
• Caused by inherited germline mutations in genes that encode for the
detection ,excision and repair of errors that occur during DNA replication
• Majority of HNPCC cases involve either MSH2 or MLH1 repair genes
• Patients with HNPCC inherit one mutated DNA repair gene and one
normal allele
• When the second copy is lost through mutation or epigenetic silencing
,defects in mismatch repair lead to the accumulation of mutations at
rates up to 1000x higher than normal, mostly in regions containing short
repeating DNA sequences referred to as microsatellite DNA
• The human genome contains approx 50,000-100,000 microsatellites,
which are prone to undergo expansion during DNA replication and
represent the most frequent sites of mutations in HNPCC

119. Malignant Lesions

120. Adenocarcinoma
• Adenocarcinoma of colon is the most common malignancy of GIT, and
major contributor to morbidity and mortality worldwide

121. Epidemiology
• >130,000 new cases and 55,000 deaths from colorectal
adenocarcinoma in the US yearly.
• 15% of all cancer deaths.2nd only to lung cancer
• Peaks at 60-70 yrs.<20% occurs before 50 yrs
• M>F
• Dietary factors most closely related to increased incidence
• low intake of absorbable vegetable fiber, high intake of refined
carbohydrates and fat

122. • Several epidemiologic studies suggest that aspirin/other NSAIDS have
a protective effect.
• This effect is suspected to be mediated by inhibition of COX2,which is
highly expressed in 90% of colorectal carcinomas and 40-90% of
adenomas and is known to promote epithelial proliferation, esp. in
response to injury

123. Pathogenesis
• The combination of molecular events that lead to colonic
adenocarcinoma is heterogeneous and includes genetic and
epigenetic abnormalities
• APC/B-catenin pathway
• Microsatellite instability pathway
• Epigenetic events may enhance progression along both pathways eg
methyl-induced gene silencing

124. 1)APC/B-catenin pathway
• The classic adenocarcinoma sequence, which accounts for as much as
80% of sporadic colon tumors, typically involves mutation of the APC
tumor suppressor early in the neoplastic process
• Both copies of APC gene must be functionally inactivated, either by
mutation or epigenetic events for adenomas to develop
• APC is a key negative regulator of B-CATENIN, a component of the
WNT signaling pathway

125. • The APC protein normally binds to and promotes degradation of B-
catenin.
• With loss of APC function, B-catenin accumulates and translocate to
the nucleus, where it activates the transcription of genes, e.g. those
encoding MYC and cyclin DI, which promote proliferation.
• This is followed by additional mutations, including activating mutation
in KRAs, which promote growth and or event apoptosis.

126. • The conclusion that mutation of KRAs is a late event is supported by
the observation that mutations are present in <10% of adenomas less
than 1 cm in diameter, in 50% of adenomas .11 cm diameter, and in
50% of invasive adenocarcinoma.
• Neoplastic progression also is associated with mutations in tumor
suppressor gene e.g. those encoding SMAO2 & SMAD4,which re
effectors of TGF-B signaling.

127. • TGF-B signaling normally inhibits the cell cycle thus loss of this gene
may allow unrestrained cell growth.
• Tp53 gene is mutated in 70-80% of colon cancers but is uncommonly
affected in adenomas, suggesting that Tp53 mutation also occurs at
late stage of tumor progression.

128. • Loss of function of Tp53 and other tumor suppressor genes is often
caused by chromosomal deletions.
• Hence chromosomal instability is hallmark of APC/B-catenin pathway.
• Alternatively, tumor suppressor genes may be silenced by
methylation of CpG islands, a 5’ region of some genes that frequently
includes the promoter and transcriptional start site.
• Expression of telomerase also increases as lesions become more
advanced.

129. 2)Microsatellite pathway
• In patients with DNA mismatch repair deficiency ,mutations
accumulate in microsatellite repeats i.e. microsatellite instability
• This mutations are generally silent, because microsatellites typically
are located in non-coding regions, but other microsatellite sequence
are located in the coding/promoter region of genes involved in
regulation of cell growth e.g. those encoding type2 TGF-B receptor,
and the pro-apoptotic BAX

130. • Because TGF-B inhibits colonic epithelial cell proliferation, type 2 TGF-
B receptor mutants can contribute to uncontrolled cell growth, while
loss of BAX may enhance survival of genetically abnormal clones.
• Mutations in oncogenes BRAF and silencing of distinct groups of
genes due to CpG island hyper methylation also are common in
cancers that develop through DNA mismatch repair defects.

131. • By contrast KRAs and Tp53 typically are not mutated.
• Thus the combination of microsatellite instability, BRAF mutation, and
methylation of specific targets e.g. MLHI, is the signature of this
pathway of carcinogenesis.

132. Morphology
• Adenocarcinoma are overally distributed approx equally over entire
length of colon.
• Tumors in proximal colon often grow as polypoid, exophytic masses
and rarely cause obstruction.
• Whereas carcinoma, a in distal colon tend to be annular lesions that
produce ‘napkin ring’ constrictions and luminal narrowing sometimes
to the point of obstruction.
• Both forms grow into the bowel wall over time and may be palpable
as firm masses.

133. • General microscopic characteristics of right and left sided colonic
adenocarcinoma are similar.
• Most tumors are composed of tall columnar cells that resemble
dysplastic epithelium found in adenomas.
• The invasive component of this tumors elicits a strong stromal
desmoplastic response, which is responsible for their characteristic
firm consistency.
• Some poorly differentiated tumors form few glands, others may
produce abundant mucin that accumulates within the intestinal wall,
and this carry a poor prognosis.
• Tumors may also be composed of signet ring cells that are similar to
those in gastric cancer.

134. Clinical features
• Develops insidiously thus may go undetected for long periods.
• Cecal and other right sided colon cancers-fatigue and weakness due
to iron deficiency anemia.
• Hence clinical maxim that underlying cause of Iron deficiency in an
elderly man/post menopausal woman is GITal cancer until proven
otherwise.
• Left side colorectal carcinomas-occult bleeding changes in bowel
habits or cramping left lower quadrant discomfort.

135. • The 2 most important prognostic factors are;
1. depth of invasion
2. presence/absence of LN metastasis
• Regardless of stage, however, some patients do well for years after
resection of distant tumor nodules
• This observation once again emphasizes the clinical and molecular
heterogeneity of colorectal tumors

136. • Metastases may involve regional LNs, lungs, and bones, but because
of the portal drainage, the liver is the most common site of metastatic
lesions
• The rectum does not drain by way of portal circulation, and
metastases from anal region often circumventing the liver

137. END