This document provides an overview of inflammatory bowel disease (IBD), including ulcerative colitis and Crohn's disease. Some key points: - IBD results from a combination of genetic and immunological factors. Several genes have been identified that increase risk of developing IBD, including NOD2 for Crohn's. - Ulcerative colitis is limited to the colon and rectum, while Crohn's can affect any part of the GI tract and is typically transmural. - Histologically, ulcerative colitis shows continuous mucosal inflammation while Crohn's is discontinuous with features like granulomas and cobblestoning. - The role of the microbiome

1. PRESENTER- Dr Shreya Prabhu
MODERATOR- Dr Nalini M
UPDATES ON PATHOLOGY
OF INFLAMMATORY
BOWEL DISEASE
1

2. 2

3. NORMAL HISTOLOGY
3

4. 4

5. 5

6. 6

7. INFLAMMATORY BOWEL
DISEASE 7

8. • Inflammatory bowel disease (IBD) is a chronic inflammatory
disorder of unknown etiology.
• The two disorders that comprise IBD are Ulcerative Colitis and
Crohn disease.
• The distinction between Ulcerative colitis and Crohn disease is
based, in large part, on the distribution of affected sites and the
morphologic expression of disease at those sites.
• ULCERATIVE COLITIS is limited to the colon and rectum and
extends only into the mucosa and submucosa.
• CROHN DISEASE/REGIONAL ENTERITIS (because of
frequent ileal involvement) may involve any area of the GI tract
and is typically transmural.
8

9. 9

10. EPIDEMOLOGY
ULCERATIVE COLITIS CROHN DISEASE
INCIDENCE / 1 LAC. 2.2-14.3 3.1-14.6
AGE OF ONSET 15-30, 60-80
MALE: FEMALE 1:1 1.1-1.8 : 1
ETHNICITY Causcasians, Jewish
SMOKING May prevent Causative
APPEDICECTOMY Protective Not
10

11. • The exact cause of IBD is unknown,
• Most investigators believe that IBD results from a combination
of
11

12. GENETIC FACTORS
• There is considerable evidence that development of both CD
and UC is determined, at least in part, by genetic factors.
• Evidence- both UC and CD cluster within families
• Having family member- risk factor for development of IBD- first
degree relatives- 10-15 fold increase
• Multiple affected family members- concordance of disease type
(in 75% cases)
12

13. • Twin studies show:
In Crohn disease, the concordance rate for monozygotic
twins is approximately 50%.
In Ulcerative colitis concordance rate for monozygotic twins
is only 15%
Concordance for dizygotic twins is <10% for both
• Population based studied identified over 160-IBD associated
genes
• Significant proportion of genes shared between UC and CD
13

14. 14

15. 15

16. • One of the gene strongly associated with CD is NOD2
(nucleotide oligomerization binding domain 2)
• <10% of individuals carrying risk associated with NOD2 variants
develop disease => any one of gene confers only a small
increase in risk of developing disease
• ATG16L1 (autophagy- related 16 like), IRGM ( immunity related
GTPase M )- CD related genes- part of autophagy pathways
critical for cellular responses to intracellular bacteria
16

17. 17

18. NADPH oxidase
• Multiple SNPs associated with increased risk of IBD are located
in coding regions of multiple NADPH oxidase complex genes.
• These mutations reduce reactive oxygen species (ROS)
formation
• Other genes associated with the NADPH oxidase pathway
included Annexin A1
18

19. • In a follow up study, Leoni and colleagues showed that
endogenous Annexin A1 can be released by intestinal epithelial
cells as a component of extracellular vesicles, which activate
wound repair process.
• Patients with IBD have higher serum levels of Annexin A1-
containing extracellular vesicles.
19

20. TETRATRICOPEPTIDE REPEAT DOMAIN
• In a study, patients with variants of the tetratricopeptide repeat
domain gene were identified within a small cohort of severe IBD
cases.
IL-10 RECEPTORS
• IL-10 receptor genes ( IL-10RA and IL-10RB ) were among the
first genes shown to be associated with early onset IBD.
• The major function of this receptor is to suppress inflammation
and tumor necrosis factor (TNF) secretion.
• AR mutations of IL-10 and IL-10 receptors genes linked to
severe, early onset IBD
20

21. IMMUNOLOGIC FACTORS
• Several observations support a role for mucosal immune
responses in the pathogenesis of IBD.
• Both CD and UC at least in part disorders of both innate and
acquired immunity
• T helper cells are activated in Crohn disease and the response
is polarized to the TH1 type
• TH17 T cells most likely contribute to disease pathogenesis.
21

22. • Many other pro-inflammatory cytokines, including TNF,
interferon-γ and IL-13, as well as immunoregulatory molecules
such as IL-10 and TGF-β, appear to be play a role the
pathogenesis of IBD.
• Activation of cytotoxic T Cells and cytokine release result in
generation of activated matrix metalloproteinases
• Because of all these mucosa becomees heavily infiltrated by
inflammatory cells
22

23. 23

24. 24

25. 25

26. EPITHELIAL DEFECTS
• Defects in intestinal epithelial tight junction barrier function are
present in CD
• This barrier dysfunction is associated with specific disease-
associated NOD2 polymorphisms
• Some polymorphisms, such as those involving ECM1
(extracellular matrix protein 1), which inhibits matrix
metalloproteinase 9, are linked to ulcerative colitis
• Certain polymorphisms in the transcription factor HNFA are
associated with ulcerative colitis but not Crohn disease.
26

27. MICROBIOTA
• There is abundance of microbiota in the GI lumen
• In total, these organisms greatly out number human cells in our
bodies
Microbiota play a role in the evolution of IBD follows:
• Linkage to NOD2, points to the involvement of microbes in the
causation of Crohn disease.
• The presence of antibodies against the bacterial protein flagellin
are most common in Crohn disease patients who have disease
associated NOD2 variants, stricture formation, perforation, and
small-bowel involvement.
27

28. 28

29. MICROBIOTA
29

30. • Recent studies of the microbiota in IBD patients have advanced
understanding of IBD pathogenesis.
• In a sttudy examining the fecal microbiota from CD patients
showed that unaffected relatives of CD patients also have a
different composition of microbiota compared to healthy controls
 Including less Escherichia coli-Shigella group bacterias
 More Ruminococcus torques
30

31. • They found that the microbiome of CD patients contained
An increased abundance in enterobacteriaceae,
pasteurellacaea, veillonellacea, and fusobacteriaceae
Decreased abundance in erysipelotrichales, bacteroidales,
and clostridiales.
• It was found that the degree of mucosal dysbiosis was greater in
patients who had previous exposure to antibiotics, suggesting
that the dysbiosis status may be affected by antibiotics usage.
31

32. 32

33. CROHN DISEASE
34

34. • It is the chronic recurrent disease characterised by patchy
transmural inflammation involving any segment of GIT from
mouth to anus
 Ileocecal region > terminal ileum > diffuse SI > colon
• 2 forms-
 Inherently indolent
 Inherently aggressive
• Cigarette smoking is strongly associated with the development
of CD
35

35. • 30-40% of patients have small bowel disease alone
• 40-55% of patients have both small and large intestines disease
• 15-25% of patients have colitis alone
• In 75% of patients with small intestinal disease the terminal
ileum is involved in 90%
36

36. GI FORMS OF CROHN DISEASE
37

37. SYMPTOMS:
• Mild diarrhea
• Fever
• Abdominal pain
• Iron deficiency anemia
• Extensive small bowel disease may result in serum
protein loss -generalized nutrient malabsorption (vit
B12 and bile salts )
38

38. CLINICAL FEATURES OF CROHN DISEASE
RELATED TO SITE OF BOWEL INVOLVEMENT
39

39. GROSS FEATURES
40

40. UNOPENED ILEOCOLECTOMY SPECIMEN. DISTAL ILEUM IS COVERED WITH SHAGGY
EXUDATES AND PORTIONS OF TRANSECTED ADHESIONS
41

41. 42

42. 43

43. 44

44. 45

45. COBBLESTONE
APPEARANCE TO
MUCOSA
46

46. 47

47. LUMEN OF ILEUM OCCLUDED BY DISEASE AND STENOTIC
AREA SEEN (ARROW)
48

48. 49

49. 50

50. 51

51. 52

52. 53

53. HISTOLOGICAL FEATURES
54

54. 55

55. 56

56. 57

57. 58

58. 61

59. TERMINAL ILEUM WITH PRESENCE OF PROMINENT GRANULOMA JUST
BENEATH MUSCULARIS MUCOSA
62

60. 63

61. 64

62. 65

63. 66

64. 67

65. FEATURES THAT SUGGEST DIAGNOSIS OF
CROHN DISEASE
68

66. ULCERATIVE COLITIS
69

67. • Is an inflammatory disease of the large intestine
• 40-50% of patients have disease limited to the rectum
• 30-40% of patients have disease extending beyond the sigmoid
(left sided colitis)
• 20% of patients have a total /extensive colitis
• Proctosigmoditis > pancolitis > left sided colitis
70

68. SIGNS AND SYMPTOMS
The most common are :
• Diarrhea with blood or pus
• Abdominal discomfort
• An urgent need to have a bowel movement
• Feeling tired
• Nausea or loss of appetite
• Weight loss
• Fever
• Anemia
71

69. GROSS FEATURES
72

70. 73

71. 74

72. 75

73. 76

74. 77

75. 78

76. 79

77. HISTOLOGICAL FEATURES
80

78. 81

79. 82

80. 83

81. 84

82. 85

83. 86

84. 87

85. 88

86. 89

87. EXTRAINTESTINAL MANIFESTATION OF IBD
91

88. 92

89. 93

90. UPDATE ON DIAGNOSTIC AND MANAGEMENT
ISSUES OF IBD PATHOLOGY
94

91. IMPORTANCE OF MACROSCOPIC PATHOLOGY
• Certain features pathognomonic or highly characteristic of the
two major types
• Really assessable at the time of macroscopic pathological
assessment
95

92. ULCERATIVE COLITIS CROHN DISEASE
DISEASE In continuity Discontinuous
RECTUM Always involved In 50%
TERMINAL ILEUM In 10% In 30%
MUCOSA Granular, ulcerated Ulcerated, cobblestone
appearance, fissuring
VASULARITY Intense Seldom
SEROSA Normal Serositis
STRICTURES Rare Common
FISTULAE Never Enterocutaneous or intestinal
INFLAMMATORY
POLYPOSIS
Common and extensive Less prominent and extensive
DYSPLASIA AND
MALIGNANT CHANGE
Well recognised Less common
ANAL LESIONS <25% In 75%
96

93. CIBD VERSUS INFECTION IN BIOPSY MATERIAL
• CIBD needs to be differentiated from other causes of colorectal
inflammation
• Main DD is INFECTIVE COLITIS
SPECIFIC COLORECTAL INFECTIONS THAT CAN RESEMBLE
CIBD:
• Chronic proctocolitis secondary to LGV and Syphilis
• Chronic or recurrent infections with Clostridium difficle
• Amoebic Colitis
• TB, Yersinia infection (granulomas have central
necrosis/lymphoid cuff or if there is stellate abscesses)
97

94. Important predictors of CIBD:
BASAL PLASMACYTOSIS
ARCHITECTURAL CHANGES
GRANULOMA
PANETH CELL METAPLASIA (marker of chronic
colorectal inflammation)
• Changes favoring infective colitis over CIBD are less well
defined
• Absence of CIBD like abnormalities favor Infective colitis
• Combination of clinical features, endoscopic information,
histological features from multiple biopsy site useful
98

95. UPPER GASTRO INTESTINAL TRACT AND
SMALL INTESTINE IN CIBD
ILEUM:
• Involvement more common in CD
• Increasing rates of involvement in UC- more easily detected in
resections than in biopsies
99

96. ILEAL FEATURES FAVOURING CD RESECTION (R) OR
BIOPSY (B)
Granulomas B & R
Giant cells B
Mild active inflammation B
Patchy LP oedema with crypt disarray B
Transmural lymphoid aggregates in absence of deep ulcers R
Transmural inflammation with granulomas R
Submucosal inflammation R
Fissure ulcers R
Extensive ileal disease R
Neural hyperplasia R
100

97. ILEAL FEATURES FAVOURING UC RESECTION (R) OR
BIOPSY (B)
Mild ileal mucosal injury with moderate/ markedly active caecal
colitis
B
Active inflammation and oedema of villus tips B
OTHER FEATURES OBSERVED IN CIBD
Ulcer associated cell lineage/ pyloric metaplasia/ mucoid gland
metaplasia
Both
Disturbed villous architecture B
Disturbed crypt architecture B
Increased goblet cells in villi B
Jejunalisation B
Patchy cryptitis and crypt abscesses R
101

98. UPPER GI TRACT:
• Involvement more common in CD, children>adults
• Poses difficulty in diagnosing GERD and inflammation caused
by H pylori
• Granuloma in oesophagus – CD
• Recent attention on ‘LYMPHOCYTIC OESOPHAGITIS’ (LE)-
pattern might represent Crohn’s oesophagitis
102

99. DEFINITION OF LE:
• Marked oesophageal lymphocytosis with no or only rare
intraepithealial granulocytes (IEG): >50 IEL/hpf and a ratio of
>50:1 IEL to IEG
• Oesophageal inflammation with >20 Lymphocytes and sparse
neutrophil and eosinophil
• Dense peripapillary lymphocytic infiltrates and peripapillary
spongiosis involving the lower two thirds of the epithelium
103

100. STOMACH
104
• FOCALLY ENHANCED GASTRITIS- described as feature of CD
has been demonstrated in other conditions
• Detailed study of gastric histology in UC- 3 characteristic
patterns
 Focal gastritis (FEG)
 Patchy mixed basal inflammation with loose collections of
inflammatory cells in LP
 Superficial plasmacytosis

101. IN DUODENUM-
 Granulomas
 Duodenal cryptitis (CD>UC)
 IEL (UC>CD)
 Diffuse chronic duodenitis (UC)
• New diagnosis of CIBD rarely made but suggested if
granulomas/FEG present
• Classification into subtypes rarely helped by upper GI histology
• GI biopsies greater value in children, undertaken at time of
colonoscopic assessment in this group
105

102. POUCHITIS AND PREPOUCH ILEITIS:
• Pouchitis, complicating ileal pouch anal anastomosis (IPAA),
example of small bowel involvement by UC
• Prepouch ileitis- diffuse inflammation extending from pouch into
neoterminal ileum
CHANGES-
• Chronic inflammation
• Ulceration
• Fistulae
• Submucosal fibrosis
• Cryptolytic granuloma
106

103. THE APPENDIX AND CIBD
• Assessment of appendix- important in assessment and D/D
• Recognised to be one of the ‘skip lesions’ of UC
• There is considerable evidence that previous appendicectomy
protects patients against subsequent UC
 Removal of immunocompetent tissue of appendix
 ? removal of influence of fecal stasis on generation of mucin
changes that lead to UC
• Florid transmural inflammation in form of lymphoid aggregates
with focal active inflammation with/without ulceration- suggest
CD
107

104. GRANULOMAS AND CIBD
• Not specific to CD
• Location of granuloma important-
In mucosa / submucosa- CD more common as one descends
down GIT- implies oeso+stomach- CD granuloma uncommon
• 40% CD patients have Granuloma, MC in younger with short
presenting history
• Characteristic of CD granuloma- adjacent to or within lymphatic
vessels
• Granulomatous vasculits- characteristic of CD
• Granuloma also seen in a transmural distribution, often subserosal
108

105. • Granulomas and active inflammation at resected margin- does
not influence recurrence
• Granuloma normal feature in the pelvic ileal reservoir mucosa,
especially within lymphoid aggregates and peyer’s pathches.
• Granuloma + focal active inflammation + transmural
inflammation + fissuring ulceration + fistulae – mimic CD in
complicated Diverticular disease
109

106. 110

107. 111

108. NEOPLASIA AND CIBD
COLORECTAL CARCINOMA
• Risk of CRC increase higher in patients with CIBD ( CD=UC)
• Risk of small bowel carcinoma increased in CD
• Risk of CRC depends on
 Time, duration, extent
 Severity of histological inflammation, endoscopic
inflammation
 Presence of dysplasia, PSC
 Family history
112

109. • CIBD-CRC occurs at younger age than non-IBD CRC
• Has pathological features in common with both LS-related CRC
and sporadic MSI CRC
• Compared with sporadic CRC, APC gene mutation in CIBD CRC
occurs less frequently
• Clinical and pathological similarities between CIBD- related
CRC and non- IBD MSI CRC have raised the possibility that MSI
and serrated pathway are important for the pathogenesis of
CIBD related CRC
113

110. DYSPLASIA IN THE COLORECTUM
• Detection of dysplasia is the basis for CIBD surveillance
programes
• British Society of Gastroenterology (BSG) guidelines advise
initial colonoscopy 10 years after onset of symptoms, with
screening every 5, 3 or 1 year(s)
• Pancolonic dye spraying and targeted biopsy of endoscopically
abnormal areas- recommended- higher rate of detection of
dysplasia
114

111. • Dysplastic lesions endoscopically- categorised raised or flat
• Lesions outside the area of colitis managed in same way as
sporadic lesions
• If raised dysplastic lesion in the area of colitis is endoscopically
resected and no dysplasia in perilesional biopsies, colectomy is
unnecessary
• Unresectable raised lesions- risk of carcinoma- requries
colectomy
• Flat high grade dysplasia- colectomy
115

112. • Difficulty distinguish complicating UC from adenomatous
dysplasia
• Advent of newer endoscopic detection techniques (EMR, ESD)-
less requirement for pathological classification on biopsy
• Some dysplastic lesions resemble hyperplastic polyps, rarely
dysplasia occurs within an inflammatory polyp
116

113. POUCH CANCER
• IPAA offered patients with UC after Colectomy- associated with
reduced risk of CRC
• Carcinoma in pouch itself is rare
• Likely if there was preoperative colorectal neoplasia/ PSC
• Likely to arise from in the columnar cuff at the pouch- anal
junction
• Likely to have a Crohn’s- like peritumoral reaction
117

114. LYMPHOMA
• Intestinal and extraintestinal lymphoma increased in long
standing CIBD-not supported by population studies
• Increased frequency in CIBD patients on immunosuppressive
therapy (? EBV)
• GI lymphomas more common in men, often large B cell type,
likely in large bowel
• Possibilty of lymphoma should be considered when assessing
CIBD biopsies, especially if mucosa is heavily inflammed
118

115. APPENDICEAL NEOPLASIA
• Involvement is common
• Chronic mucosal inflammation can be a risk factor for
development of neoplasia
• CIBD + CRC- 15 fold increase in prevalance of appendiceal
cystadenoma and 8 fold increase compared with those with
uncomplicated CIBD
• Appendiceal neuroendocrine tumors have same prevalance in
CIBD and general population
119

116. 120

117. 121

118. 122

119. SUMMARY
• Microscopic features favoring CIBD over Infective colitis in
biopsies include basal plasmacytosis and mucosal architectural
changes
• Macroscopic assessment of CIBD resections often provides as
much information as histological assessment
• Ileal inflammation favors CD over UC in biopsies
• Ileal granulomas favor CD
• LE, FEG, duodenal cryptitis and UC- like duodenal changes
might suggest CIBD
123

120. • Pathological assessment of the appendix is increasingly useful
for the differentiation of UC from CD
• CIBD related CRC shares clinical and pathological features with
hereditary and sporadic MSI tumors
• Dysplastic lesions in CIBD are initially managed on the basis of
their resectability rather than grade
• Prelesional biopsies help to confirm resectability
124

121. CONCLUSION
• IBD results from a continuum of complex interactions between a
host-derived and external elements.
• Recent studies into the complexity of these arrangements
increasingly support the syndromic nature of this disorder.
• Studies of the microbiota, immune system, and genetics have
revealed more similarities than differences between these two
extreme phenotypes
125

122. • Genetic studies increasingly support the concept of familial and
sporadic forms of IBD whose inheritance ranges from
monogenic to polygenic
• Finally, given these comments, it can be anticipated that
environmental factors that modify the risk for development of
IBD have the common attribute of affecting the relationship
between the commensal microbiota and the immune system in a
manner that intersects with the functionally relevant
immunogenetic pathway.
126

123. REFERENCES
127
1. Alpers C E, Chang A. gastrointestinal tract . In: Kumar V, Abbas A K, Fausto
N, editors. Robbins & Cotran pathologic basis of disease. 9th ed. New Delhi;
Reed Elsevier India Pvt Ltd;2015.p897-958
2. Small intestine In: Juan Rosai, editors. Rosai & Ackerman’s Surgical
Pathology.10th ed Vol 2.New Delhi:Elsevier; 2
3. Gastrointestinal pathology, atlas and text, Cecilia M Fenoglio Preser
4. Annu rev Pathol 2016;11:127-148
5. chapter 9, 23rd edition Recent advances in histopathology, Massimo
Pignatelli

124. THANK YOU

‘I HAVE FINALLY COME TO THE CONCLUSION
THAT A GOOD SET OF BOWELS IS WORTH MORE
TO A MAN THAN ANY QUANTITY OF BRAINS’
- Josh Billings
128