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GI 3 Flashcards

1
Q

IRRITABLE BOWEL SYNDROME (IBS)

A

Condition characterised by chronic, relapsing
abdominal pain, bloating, and changes in bowel
habits

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2
Q

IRRITABLE BOWEL SYNDROME (IBS)
Epidemiology

A

Peak incidence: 20-40 yrs.; F>M

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3
Q

IRRITABLE BOWEL SYNDROME (IBS)
Pathogenesis

A

Pathogenesis:
 Interplay between psychologic stressors,
diet and abnormal GI motility
 Impairment of signaling in the brain-gut
axis => Disturbances of intestinal motility and enteric sensory function
 In some cases, onset is related to a bout (attack) of infectious gastroenteritis

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4
Q

IRRITABLE BOWEL SYNDROME (IBS)
Clinical features

A

Occurrence of:
 Abdominal pain or discomfort at least
3 days per month over 3 months
 Improvement with defecation
 Change in stool frequency or form
.

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5
Q

IRRITABLE BOWEL SYNDROME (IBS)
Other manifestations

A

Other Manifestations: Fibromyalgia, visceral hyper-sensitivity, backache, headache, urinary symptoms, dyspareunia, lethargy, and depression

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6
Q

IRRITABLE BOWEL SYNDROME (IBS)

Diarrhoeic IBS cases:

A

Microscopic colitis, coeliac disease, giardiasis,
lactose intolerance, small bowel bacterial
overgrowth, bile salt malabsorption, colon
cancer, and inflammatory bowel disease

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7
Q

IRRITABLE BOWEL SYNDROME (IBS)
.Prognosis:

A

Related to symptom duration;
Longer duration and ongoing life stressors =
Reduced likelihood of improvement

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8
Q

IRRITABLE BOWEL SYNDROME (IBS)
Treatment:

A

 Psychotherapy
 Dietary fiber supplementation
 Tricyclic antidepressants
 Selective Serotonin Reuptake Inhibitors
(SSRIs)
 Probiotics
 Antibiotics
 Chloride channel agonist (cases with
constipation)

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9
Q

INFLAMMATORY BOWEL DISEASE

A

 Chronic condition resulting from inappropriate mucosal immune activation

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10
Q

Inflammatory Bowel Disease includes two disease entities:

A

 Ulcerative Colitis: Severe ulcerating inflam-
matory disease that is limited to the colon and
rectum and extends only into the mucosa and
submucosa
 Crohn’s Disease (synonym: Regional Enteritis): May involve any area of the GI tract and is typically transmural

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11
Q

INFLAMMATORY BOWEL DISEASE
Results from a combination of defects, including:

A

Results from a combination of defects, including:
 Host interactions with intestinal microbiota
 Intestinal epithelial dysfunction and
 Aberrant (different) mucosal immune responses

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12
Q

INFLAMMATORY BOWEL DISEASE
Genetics:

A

Concordance rate for monozygotic twins:

 Crohn Disease: Approximately 50% of cases  Ulcerative Colitis: 16% of cases
 Concordance rate for dizygotic twins: <10% for both Crohn Disease and Ulcerative Colitis

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13
Q

INFLAMMATORY BOWEL DISEASE
Crohn’s Disease associated genes:

A

 NOD2 (nucleotide oligomerisation binding
domain 2):
 Specific NOD2 polymorphisms: Four-fold
increase in Crohn Disease risk
 <10% of individuals with NOD2 mutations develop disease

 ATG16L1 (autophagy-related 16-like) and IRGM (immune-related GTPase M)
 Some polymorphisms of the IL-23 receptor gene: Susceptibility to Crohn’s Disease

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14
Q

CROHN’S DISEASE
Localisation:

A

 Small intestine alone: 40% of cases
 Small intestine and colon: 30% of cases
 Colon alone: 30% of cases

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15
Q

Macroscopic findings:
 Skip lesions (multiple, separate, sharply
delineated areas of disease)
 Aphthous ulcer (earliest Crohn’s Disease lesion); progression and coalescence of multiple lesions into elongated, serpentine ulcers, oriented along the axis of the bowel
 Oedema and loss of the normal mucosal
texture
 Sparing of interspersed mucosa =>.Coarsely textured, “cobblestone appearance”
 Fissures (between mucosal folds) => Deep
extension => Fistula tracts or sites of
perforation
 Thickened and rubbery intestinal wall;
as a consequence of transmural oedema, inflammation, submucosal fibrosis, and hypertrophy of the muscularis propria
 Stricture formation
 Cases with widespread transmural disease:
Extension of mesenteric fat around the serosal surface => “Creeping” fat

A

CROHN’S DISEASE

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16
Q

 Microscopic features:
 Infiltration and damage of crypt epithelium
by neutrophils
 Formation of crypt abscesses (clusters of
neutrophils within a crypt)
 Commonly, ulcerations with abrupt transition
between ulcerated and adjacent normal
mucosa
 Distortion of mucosal architecture; bizarre
branching shapes of crypts and unusual
orientations to one another
 Pseudo-pyloric metaplasia (gastric antral-
appearing glands) and Paneth cell metaplasia (in the left colon)
 Non-caseating granulomas <=> Hallmark of
Crohn’s Disease (35% of cases)  Possible presence of granulomas in mesenteric
lymph nodes; Cutaneous granulomas form
nodules; referred to as metastatic Crohn’s
Disease

A

CROHN’S DISEASE

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17
Q

CROHN’S DISEASE
Clinical manifestations:

A

Variable:
 Onset with intermittent attacks of relatively
mild diarrhoea, fever, and abdominal pain
or
 Acute presentation, with right lower
quadrant pain, fever, and bloody diarrhoea
(about 20% of patients; mimics acute
appendicitis or bowel perforation)

 Alternating periods of active disease and
asymptomatic periods (last for weeks to many months)
 Disease re-activation = Association with a
variety of external triggers (e.g. physical or emotional stress, specific dietary items, and cigarette smoking)

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18
Q

CROHN’S DISEASE
Complications:

A

Complications:
 Colonic disease cases => Iron-deficiency anaemia
 Extensive small bowel disease => Serum protein loss and hypoalbuminaemia, generalised nutrient malabsorption, or malabsorption of Vitamin B12 and bile salts
 Commonly, fibrosing strictures (particularly
of the terminal ileum)
 Recurrence at the site of anastomosis =>
Requirement of additional resections
 Fistulae formation between: i. loops of bowel (entero-enteric), ii. bowel and urinary
bladder (entero-vesical), iii. bowel and vagina
(entero-vaginal) or iv. bowel and skin (entero-cutaneous)
 Perforations and peritoneal abscesses

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19
Q

CROHN’S DISEASE
Extra-Intestinal manifestations:

A

 Uveitis (inflammation of the middle layer of the eye, called the uvea or uveal tract)
 Migratory polyarthritis
 Sacroiliitis
 Ankylosing spondylitis
 Erythema nodosum
 Clubbing of the fingertips
 Pericholangitis and Primary Sclerosing
Cholangitis (occurrence in Mb. Crohn, but more common in Ulcerative Colitis)
 Increased risk of Colonic Adenocarcinoma
development<=> Cases with long-standing colonic disease

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20
Q

ULCERATIVE COLITIS
Relapsing disorder, characterised by attacks of:

A

Relapsing disorder, characterised by attacks of:
 Bloody diarrhoea with stringy, mucoid material
 Lower abdominal pain
 Cramps (temporally relieved by pain)

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21
Q

ULCERATIVE COLITIS

A

Epidemiology:
 Persistence of symptoms for days, weeks to
months before they subside
 Occasionally, initial attack may be severe enough to constitute a medical or surgical emergency
 > 50% of cases, clinically mild disease
 Almost all patients experience at least one
relapse during a 10-year period

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22
Q

ULCERATIVE COLITIS
Clinical features (Extra-Intestinal):

A

Clinical features (Extra-Intestinal):
 Uveitis
 Migratory Polyarthritis
 Sacroiliitis
 Ankylosing Spondylitis
 Skin lesions (e.g. Pyoderma Gangrenosum,
Erythema Nodosum)
 5% of patients, Sclerosing Cholangitis; Increased risk for development of Cholangiocarcinoma

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23
Q

Macroscopic features:
 Always involvement of the rectum, and
extension proximally in a continuous fashion to involve other parts or all of the colon:
- Proctitis: 30% of patients
- Distal Colitis: 30% of patients
- Left-sided Colitis: 25%
- Total Colitis: 15%

 Affected mucosa may be: Slightly red and
granular or have extensive, broad-based ulcers  Abrupt transition between diseased and
uninvolved colonic mucosa

A

‘ULCERATIVE COLITIS

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24
Q

Macroscopic features (cont.):
 Isolated islands of regenerating mucosa=>
Bulging into the lumen => Pseudo-polyps => Fusion of the polyps’ tips => Mucosal bridges
 Ulcers aligned along the long axis of the colon
 Chronic disease: Mucosal atrophy with flat and smooth mucosal surface
 Inflammation and inflammatory mediators =>Damage of the muscularis propria and
disturbance of the neuro-muscular function =>
Colonic dilation and Toxic Megacolon =>
Increased risk of penetration

A

ULCERATIVE COLITIS

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25
Microscopic findings:  Inflammatory infiltrates, crypt abscesses, architectural crypt distortion, and epithelial metaplasia  Inflammatory process: Diffuse but limited to the mucosa and superficial submucosa  Severe cases: Extensive mucosal destruction => Ulcers => Deep extension into the submucosa (rare involvement of the muscularis propria)  Residua of healed disease: i. Submucosal fibrosis, ii. Mucosal atrophy, and iii. Distorted mucosal architecture; after prolonged remission => Restoration of the normal histology  Absent granulomas
ULCERATIVE COLITIS
26
Complications of long-standing Ulcerative Colitis:
 Development of inflammatory polyps ' (“PseudoPolyps”): - Composed of inflammatory tissue - No dysplastic features (= No premalignant)  Increased risk of ColorectalAdenocarcinoma; development through the process of Dysplasia
27
ULCERATIVE COLITIS The risk of Dysplasia is related to several Factors
 Increased risk, 8 to 10 years after disease onset  Greater risk for patients with Pancolitis than those with only left-sided disease  Higher risk, in cases with greater frequency and severity of active inflammation
28
ULCERATIVE COLITIS , Histological Classification of IBD-associated Dysplasia: Low Grade Dysplasia:
Low Grade Dysplasia:  Decreased intracellular mucin  Nuclear enlargement  Nuclear crowding  Nuclear hyperchromasia  Maintenance of the basilar orientation of the nuclei
29
ULCERATIVE COLITIS Histological Classification of IBD-associated Dysplasia: High Grade Dysplasia:
High Grade Dysplasia:  Irregular nuclear crowding  Pleomorphic nuclei  Variable nuclear hyperchromasia  Markedly irregular external nuclear contours  Increased nuclear stratification (many nuclei located in the luminal half of the cell)
30
ULCERATIVE COLITIS Management:
Management:  Colectomy requirement in up to 30% of patients within the first three years after presentation, because of uncontrollable symptoms  Colectomy: Effective cure of intestinal disease in Ulcerative Colitis, but persistence of extra-intestinal manifestations
31
-TOXIC MEGACOLON Causes
'Causes: Most commonly, a complication of IBD; but also other aetiologic factors responsible (Table)
32
—TOXIC MEGACOLON Pathogenesis
'Pathogenesis:  Association between inflammatory conditions of the colon and decreased smooth muscle contractility .  Penetration of the muscularis propria by the inflammatory process (in UC); Depth of inflam- mation correlated with the extent of colonic dilatation  Detection of high iNOS levels in muscularis propria of patients with Toxic Megacolon  NO (non-adrenergic, non-cholinergic neuro- transmitter) => Induction of colonic smooth muscle relaxation
33
'TOXIC MEGACOLON . Clinical findings:
Clinical findings:  Signs of systemic toxicity  Abdominal tenderness  Reduced bowel sounds  Signs of Peritonitis <=> Indicative of colon perforation  Fever  Tachycardia
34
TOXIC MEGACOLON . Laboratory studies:
'Laboratory studies:  Anaemia and Leukocytosis  Increased ESR and Elevated CRP  Hypokalaemia and Hypoalbuminaemia  Toxin detection <=> C. difficile infection
35
TOXIC MEGACOLON . Imaging studies:
Colonic dilatation in plain abdominal radiographs of >6cm; ascending and transverse colon, most dilated
36
. TOXIC MEGACOLON Management:
-Medical therapy:  High-dose intravenous steroids <=> Patients with Ulcerative Colitis  Metronidazole or Vancomycin  Gancyclovir (CMV cases) -Surgery '
37
'MICROSCOPIC COLITIS . two entities:
-1. Collagenous Colitis 2. Lymphocytic Colitis
38
-MICROSCOPIC COLITIS Cause
Cause: Idiopathic diseases
39
MICROSCOPIC COLITIS Radiologic and Endoscopic Studies:
Radiologic and Endoscopic Studies: Normal
40
MICROSCOPIC COLITIS 1. Collagenous Colitis: Epidemiology
-Epidemiology: Middle-aged and older women
41
Microscopic findings: i. Dense sub-epithelial collagen layer ii. Increased numbers of intra-epithelial lymphocytes iii. A mixed inflammatory infiltrate within the lamina propria
'. MICROSCOPIC COLITIS
42
. 2. Lymphocytic Colitis:
 Strong association with Coeliac disease and auto- immune diseases (e.g. Thyroiditis, Arthritis, and Autoimmune or Lymphocytic Gastritis)  Similar histologic picture with Collagenous Colitis, but a. Normal thickness of sub-epithelial collagen layer b. Greater increase in intraepithelial lympho- cytes; >1 T-lymphocyte per 5 colonocytes
43
'DIVERTICULAR DISEASE
Development of Diverticula, mainly in the Sigmoid Colon
44
DIVERTICULAR DISEASE Epidemiology:
Epidemiology:  Common in Western world  50% of people over 60 years; increased incidence with age
45
DIVERTICULAR DISEASE Diverticulum
-Diverticulum: Pouch of colonic mucosa herniated through the muscularis propria and found in sub-serosal (pericolic) fat
46
-DIVERTICULAR DISEASE Important Factors for Diverticula formation:
 Area of weakness in colonic wall (natural defects in circular muscle wall, where blood vessels pass through to supply the submucosa and mucosa)  Raised intraluminal pressure, due to insufficient dietary fibers: - Binding of fibers to NaCl and H2O => Bulky, moist faeces => Easily propelled through colon - Low-fiber diet => Difficulty in the movement of feces => Muscle hypertrophy and increased intraluminal pressure  Sigmoid Colon: Smallest diameter and highest intraluminal pressure
47
Macroscopic Features:  Small, flask-like out-pouchings (0.5-1.0 cm)  Regular distribution in between the taeniae coli of the Sigmoid Colon Microscopic Findings: Thin wall, composed of: Flattened or atrophic mucosa Compressed submucosa Attenuated (or absent) muscularis propria  Hypertrophy of the circular layer of the muscularis propria
DIVERTICULA & DIVERTICULOSIS
48
DIVERTICULAR DISEASE Clinical features: (+ acute diverticulitis)
.  Diverticulosis: Asymptomatic in 70-90% of patients Acute Diverticulitis: Pathogenesis: Impaction and obstruction of diverticulum’s neck with faecal matter => Rubbing to the mucosa by faecolith => Mucosal injury => Acute inflammatory response Clinical features: Abdominal pain in the left iliac fossa, malaise, fever and localised tenderness
49
PERICOLIC ABSCESS
Extension of acute inflammatory infiltrate beyond the Diverticulum in the surrounding subserosal tissue => ' Pericolic abscess  Abscess: Localised collection of pus within a newly formed cavity in a tissue  Pus: Neutrophils, cellular debris, fibrin and oedema fluid
50
' 'PERFORATION -> PERITONITIS
 Perforation of a pericolic abscess into the abdominal cavity => Peritonitis
51
'DIVERTICULAR DISEASE -Complications
' Stricture: Consequence of diverticular disease, because of:  Smooth muscle hypertrophy and hyperplasia (due to low fiber diet)  Fibrosis around Diverticula  Consequence of the above conditions => Stricture => Reduction in lumen diameter => Clinically manifested as bowel obstruction  Lower GI tract bleeding: Painless and spontaneous bleeding (small amount of blood)
52
'MECKEL DIVERTICULUM
'Outpouching on the anti-mesenteric border of the Terminal Ileum that represents the persistence of the embryologic omphalo-mesenteric (vitelline) duct
53
-MECKEL DIVERTICULUM Localisation + epidemiology
Localisation: Approximately 20 cm from the ileocaecal valve , Epidemiology: Most common intestinal congenital anomaly; 1% to 2% of the general population
54
MECKEL DIVERTICULUM Clinical manifestations:
'Clinical manifestations: Intestinal obstruction, ulcer with haemorrhage, perforation, or diverticulitis
55
Microscopic findings:  Small intestinal mucosa, in 50% to 70% of cases  Ectopic gastric or pancreatic tissues; the rest
-MECKEL DIVERTICULUM
56
HIRSCHSPRUNG DISEASE . Synonym
Synonym: Congenital Aganglionic Megacolon
57
HIRSCHSPRUNG DISEASE - Cause:
Cause: Heterozygous loss of function mutations in receptor tyrosine kinase RET; Congenital defect in colonic innervation
58
HIRSCHSPRUNG DISEASE Epidemiology
Epidemiology:  More common in males; More severe in females
59
'HIRSCHSPRUNG DISEASE . Pathogenesis
'Pathogenesis:  Disrupted neural crest cells migration from Caecum to Rectum =>?Distal intestinal segment without both Meissner submucosal plexus and Auerbach myenteric plexus => Absent coordinated peristalsis=> Functional obstruction => Dilatation proximal to the affected segment
60
Macroscopic features:  Aganglionic region: Normal or contracted appearance -  Normal innervated proximal colon => Progressive dilatation, due to distal obstruction Microscopic findings:  Absence of ganglion cells in the affected segment
HIRSCHSPRUNG DISEASE
61
'HIRSCHSPRUNG DISEASE Clinical manifestations
Clinical manifestations:  Failure to pass meconium in immediate postnatal period  Obstructive constipation  Fluid and electrolyte disturbances  Perforation  Peritonitis
62
HIRSCHSPRUNG DISEASE Management
-Management: Surgical resection of the aganglionic segment, with anastomosis of the proximal normal colon to the rectum
63
NECROTISING ENTEROCOLITIS
Condition primarily affecting infants who either are premature or have had exchange transfusions
64
NECROTISING ENTEROCOLITIS Other causes
Other causes:  Appearance of some cases, after thrombosis of the abdominal aorta (suggestive of ischaemia as an important risk factor)  Complication of Hirschprung Disease
65
NECROTISING ENTEROCOLITIS  Clinical manifestations (majority of cases, onset in the first week of life):
 Abdominal distention  Disappearance of bowel sounds  Passage of small amounts of blood-stained stool
66
NECROTISING ENTEROCOLITIS Localisation:
. Localisation: Terminal Ileum and Ascending Colon
67
-Microscopic findings:  Necrotic mucosa that may partially slough off  Small submucosal gas-filled cysts
'. NECROTISING ENTEROCOLITIS
68
NECROTISING ENTEROCOLITIS Diagnostic sign:
-Diagnostic sign: Radiographically observed submucosal cysts
69
NECROTISING ENTEROCOLITIS Complication + management
-Complication: Bowel perforation => Management: Resection of the perforated and necrotic bowel
70
ACUTE APPENDICITIS Epidemiology
Epidemiology: Most common in adolescents and young adults; Lifetime risk: 7%
71
ACUTE APPENDICITIS Pathogenesis
 Progressive increases in intraluminal pressure=> Impairment of venous outflow  50-80% of cases: Luminal obstruction (by faecalith, gallstone, tumour, mass of worms)  Ischaemic injury and stasis of luminal contents => Bacterial proliferation => Inflammatory response (tissue oedema, neutrophilic infiltration of the lumen, muscular wall and peri-appendiceal soft tissues)
72
Macroscopic Features:  Dull, granular-appearing, erythematous surface Microscopic Findings:  Congested sub-serosal vessels  Transmural, modest, perivasc. neutroph. infiltrate  Neutrophilic infiltration of the muscularis propria (key-point for the diagnosis)  Formation of focal abscesses within the wall <=> Acute suppurative appendicitis  Haemorrhagic ulceration and gangrenous necrosis, extending to serosa => Acute gangrenous appendicitis => Rupture and suppurative peritonitis
ACUTE APPENDICITIS
73
-ACUTE APPENDICITIS Clinical Features:
, Clinical Features:  Pain; Peri-umbilical region => Right lower quadrant  Nausea and Vomiting  Low-grade Fever  Mild elevation of WBC  Characteristic McBurney’s sign (deep tender- ness at a point located two thirds of the distance from the umbilicus to the right anterior superior iliac spine)
74
ACUTE APPENDICITIS . DD:
DD: Mesenteric lymphadenitis, acute salpingitis, ectopic pregnancy, Meckel diverticulitis
75
-INFLAMMATORY POLYPS
'. Polypoid mass made up of inflamed and reactive mucosal tissue Present as a part of the solitary rectal ulcer syndrome
76
INFLAMMATORY POLYPS Cause/Pathogenesis:
Cause/Pathogenesis: Impaired relaxation of the anorectal sphincter => Sharp angle at the anterior rectal shelf => Recurrent abrasion and ulceration of the overlying rectal mucosa => Chronic process of injury and repair => Inflammatory polyp
77
INFLAMMATORY POLYPS Patients with characteristic Clinical Triad:
-Patients with characteristic Clinical Triad: 1. Rectal bleeding 2. Mucus discharge 3. Inflammatory lesion of the anterior rectal wall
78
HAMARTOMATOUS POLYPS
 Sporadic occurrence  Components of hereditary or acquired syndromes: - Peutz-Jeghers syndrome - Juvenile polyposis - Cowden syn., Bannayan-Ruvalcaba-Riley syn. - Cronkhite-Canada syndrome - Tuberous sclerosis - Familial Adenomatous Polyposis (FAP)
79
HAMARTOMATOUS POLYPS Hamartomas
Hamartomas: Disorganised, tumour-like growths composed of mature cell types, normally present at the site of polyp’s development
80
JUVENILE POLYPS Epidemiology
 Most common type of hamartomatous polyps  Sporadic or syndromic type Epidemiology: Children ≤ 5years
81
JUVENILE POLYPS Localisation
Localisation: Rectum - Sporadic juvenile polyps <=> Solitary polyps - Juvenile polyposis syndrome <=> 3-100 polyps
82
JUVENILE POLYPS Clinical manifestations:
Clinical manifestations:  Rectal bleeding  Rectal prolapse with polyp’s protrusion through the anal sphincter
83
JUVENILE POLYPS Management
-Management: Colectomy; to limit haemorrhage associated with polyp ulceration
84
PEUTZ-JEGHERS SYNDROME Synonym
Synonym: Intestinal Polyposis-Cutaneous Pigmentation Syndrome  Autosomal dominant disorder
85
PEUTZ-JEGHERS SYNDROME Causes:
Causes: Germline heterozygous mutations in LKB1/STK11 gene
86
PEUTZ-JEGHERS SYNDROME Characterised by:
 Multiple gastro-intestinal hamartomatous polyps and  Muco-cutaneous hyperpigmentation
87
. PEUTZ-JEGHERS SYNDROME Localisation of Polyps:
Localisation of Polyps: Small intestine, stomach, colon; rarely in bladder and lungs
88
Macroscopic features:  Large and pedunculated lesions  Lobulated contour (outline) Microscopic findings:  Characteristic arborising network of connective tissue, smooth muscle, lamina propria, and glands with normal intestinal- epithelium lining
PEUTZ-JEGHERS SYNDROME
89
HYPERPLASTIC POLYPS
Common epithelial proliferations
90
HYPERPLASTIC POLYPS Hypothetical Pathogenetic mechanism:
Hypothetical Pathogenetic mechanism:  Decreased epithelial cell turnover  Delayed shedding of surface epithelial cells => “Pileup” of goblet cells
91
HYPERPLASTIC POLYPS Localisation:
Commonly, in the left colon
92
Macroscopic features: Smooth nodular protrusions of the mucosa (on crests of mucosal folds) Microscopic Findings:  Mature goblet and absorptive cells  Irregular tufting (due to overcrowding) of epithelial cells => Serrated architecture in cross-section
HYPERPLASTIC POLYPS
93
'HYPERPLASTIC POLYPS Prognosis + DD
Prognosis: Benign lesions without malignant potential DD: Sessile serrated adenomas (with malignant potential)
94
COLONIC ADENOMAS
Dysplastic (pre-malignant) lesions that give rise to majority of colorectal Adeno-CAs
95
-COLONIC ADENOMAS Epidemiology
'Epidemiology:  Most common neoplastic polyps  50% of adult population, ≥ 50 years
96
Macroscopic features:  Pedunculated or sessile lesions; 0.3-10cm  Surface: Velvet- or raspberry-like texture Microscopic findings:  Characteristics of epithelial Dysplasia:  Nuclear hyperchromasia (Appreciated at Adenoma’s surface)  Cellular elongation (“ “)  Stratification (“”)
COLONIC ADENOMAS
97
COLONIC ADENOMAS
-Invasion of Adenoma cells into submucosa <=> Invasive Adeno-CA
98
'COLONIC ADENOMAS Risk factors ( (for progression of an Adenoma to Adeno-Ca):
Risk factors (for progression of an Adenoma to Adeno-Ca):  Increasing size  High grade of Dysplasia  Histological type (Villous > Tubular)
99
Microscopic findings (cont.):  Classification of Adenomas, depending on morphology:  Tubular: Small, pedunculated polyps with small, rounded or tubular glands  Villous: Large and sessile, covered by slender villi (invasive growth more frequent than in tubular adenoma)
COLONIC ADENOMAS
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Microscopic findings (cont.): Classification of Adenomas, depending on morphology:  Tubulo-villous: Mixture of tubular and villous elements  Sessile serrated adenomas vs. Hyperplastic polyps: Serrated architecture throughout gland’s length (including crypt base)  Size <=> Risk factor of malignant transformation
COLONIC ADENOMAS
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'SERRATED PATHWAY
30% of cancers arise from serrated polyps  Serrated polyps: Due to their microscopic appearance  Serrated adenomas can progress to carcinomas, after mutations in specific genes:  Activation of BRAF  Silencing of mismatch repair genes (e.g. hMLH1, hMSH2) due to promotor hypermethylation > Microsatellite instability > Insertions or deletions of nucleotides within repeated sequences of DNA
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Microscopic features:  Serrated epithelium at the surface and deep in the crypts - Saw-tooth appearance, epithelium has jagged appearing edge  Crypt dilation at base with serrations  "Boot"-shape or "L"-shaped glands - Shape may be similar to a hockey stick  Horizontal crypts = Crypt long axis parallel to the muscularis mucosae  Crypt branching
SESSILE SERRATED ADENOMAS
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FAMILIAL ADENOMATOUS POLYPOSIS (FAP)
-Autosomal dominant disorder - Characterised by the appearance of numerous colorectal adenomas in teenagers
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FAMILIAL ADENOMATOUS POLYPOSIS (FAP) Causes
Causes: Mutations in Adenomatous Polyposis Coli (APC) gene
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FAMILIAL ADENOMATOUS POLYPOSIS (FAP) Diagnosis
'Diagnosis: A number of more than 100 polyps, necessary for classic FAP
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FAMILIAL ADENOMATOUS POLYPOSIS (FAP) . Treatment
'Treatment: Prophylactic colectomy (in individuals with APC mutations); Untreated FAP > Colorectal Adeno-CA (100% of patients, before 30 years of age)
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FAMILIAL ADENOMATOUS POLYPOSIS (FAP) Gardner syndrome:
Gardner syndrome:  Variant of FAP  Apart from intestinal polyps, also the following:  Osteomas of mandible, skull and long bones  Epidermal cysts  Desmoid and thyroid tumours  Dental abnormalities (unerupted and supernumerary teeth)
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FAMILIAL ADENOMATOUS POLYPOSIS (FAP) Turcot syndrome:
' Apart from intestinal adenomas, also tumours ' of the Central Nervous System  2/3 of patients, APC gene mutations > Medulloblastomas  1/3 of patients, Mutations in DNA repair genes >Glioblastomas
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HEREDITARY NON-POLYPOSIS COLORECTAL CANCER (HNPCC) +Synonym
'Synonym: Lynch syndrome Familial clustering of cancers at several sites including the colorectum, endometrium, stomach, ovary, ureters, brain, small bowel, hepatobiliary tract, and skin
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-HEREDITARY NON-POLYPOSIS COLORECTAL CANCER (HNPCC) Epidemiology
Epidemiology: Occurrence of colon cancers in HNPCC patients, at younger ages than sporadic colon cancers
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HEREDITARY NON-POLYPOSIS COLORECTAL CANCER (HNPCC) , Localisation + causes
Localisation: Most often in the right colon  Causes: Inherited mutations in genes, encoding proteins responsible for the detection, excision, and repair of errors that occur during DNA replication
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HEREDITARY NON-POLYPOSIS COLORECTAL CANCER (HNPCC) Majority of HNPCC cases
Majority of HNPCC cases: Mutations in two such mismatch repair genes, namely MSH2 and MLH1; Inheritance of one mutated DNA repair gene and one normal allele > Loss of the second copy through mutation or epigenetic silencing > Defects in mismatch repair > Accumulation of mutations at rates up to 1000 times higher than normal, mostly in regions containing short repeating DNA sequences, referred as microsatellite DNA (Microsatellite instability)
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COLON ADENOCARCINOMA Epidemiology
Epidemiology: ''  Most common malignancy of GI tract  15% of cancer-related deaths; Second to lung CA  Dietary factors responsible for the development of colorectal cancer: i. Low intake of unabsorbable vegetable fiber and ii. High intake of refined carbohydrates and fat
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COLON ADENOCARCINOMA Pathogenesis
Pathogenesis:  Two genetic pathways involved in colorectal carcinogenesis: 1. APC β-Catenin/WNT signaling pathway 2. Microsatellite instability pathway Epigenetic events: Most common, methylation-induced gene silencing
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COLON ADENOCARCINOMA  Pathogenesis (cont.): 1. APC/β-Catenin pathway
1. APC/β-Catenin pathway  80% of sporadic colon tumours  Early event: Mutation of APC  Prerequisite for Adenoma development: Functional inactivation of both APC gene copies, either by mutation or epigenetic events  APC: Negative regulator of β-Catenin  Normally, APC binds to β-Catenin and promotes its degradation  Loss of APC function > Accumulation and translocation of β-Catenin to the nucleus > Activation of gene transcription (MYC, Cyclin D1)  Additional mutations in KRAS gene (promotes growth and prevents apoptosis)  Mutations in other tumour suppressor genes (SMAD2 and SMAD4)  Loss of TP53 (either through chromosomal deletions or silencing by methylation of CpG islands)
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COLON ADENOCARCINOMA Pathogenesis (cont.): 2. Microsatellite instability pathway
2. Microsatellite instability pathway • Germline (inherited) or somatic (acquired) mutations of mismatch-repair genes > • > Mutations in microsatellite repeats (Microsatellite instability) • Mutations located in coding or promoter regions of genes involved in cell growth (TGFβRII and BAX) • Mutations in BRAF oncogene • NO Mutations in KRAS and TP53
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Macroscopic Features:  Proximal Colon (Caecum & Ascending Colon): Polypoid, exophytic lesions; Rarely lumen obstruction  Distal Colon: Annular lesions (“napkin ring”) > Constrictions and luminal narrowing
-COLON ADENOCARCINOMA
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--Microscopic findings:  Tall columnar cells  Invasive growth with intense desmoplastic reaction  Amount and morphology of glandular structures, depending on grade of differentiation (Grade I-III)  Some tumours characterised by abundant mucin production <=> Mucinous Adeno-CAs  Others with presence of “signet ring” cells
COLON ADENOCARCINOMA
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COLON ADENOCARCINOMA Clinical features:
 Right-sided colon cancers:  Fatigue and weakness (iron-deficiency anaemia)  Left-sided colorectal Adeno-CAs: - Occult bleeding - Changes in bowel habits - Cramping  Complications related to metastases (most commonly, liver)
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COLON ADENOCARCINOMA  Prognostic factors:
 Mucinous & poorly differentiated histologic patterns (Grading of tumour)  Depth of wall invasion (T staging)  Presence or absence of lymph node metastases (N staging)
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-HAEMORRHOIDS
.  Definition: Dilated anal and perianal colateral vessels that connect the portal and caval venous systems, to relieve elevated venous pressure within the haemorrhoid plexus
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, HAEMORRHOIDS Causes:
Causes:  Constipation > Straining during defecation > Increase in intra-abdominal and venous pressures  Venous stasis of pregnancy  Portal hypertension
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Macroscopic features:  Collateral vessels within inferior haemorrhoidal plexus <=> External haemorrhoids (below anorectal line)  Dilated vessels of superior haemorrhoidal plexus <=> Internal haemorrhoids (distal rectum) Microscopic findings:  Thin-walled, dilated, sub-mucosal vessels that protrude beneath the anal or rectal mucosa  Inflammatory infiltrates  Thrombosis with recanalisation  Superficial ulceration
HAEMORRHOIDS
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HAEMORRHOIDS  Clinical features:
Pain and Rectal bleeding (bright red blood)
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'HAEMORRHOIDS Management:
Management:  Sclerotherapy  Rubber band ligation  Infrared coagulation  Haemorrhoidectomy

Pathology 1 (4 decks)

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