Pathology of the Large Intestine

1. Pathology of the Large Intestine Aiman Zaher, MD

2. Objectives At the end of this segment, when given a clinical presentation, gross specimen, and/or photomicrograph, students will be able to: Compare and contrast the clinical presentations, etiologies, pathogenesis, and gross and microscopic changes found in developmental, inflammatory, circulatory, mechanical, and neoplastic disorders of the large intestine.

3. Objectives At the end of this segment, when given a clinical presentation, gross specimen, and/or photomicrograph students will be able to: Predict the clinical complications associated with diseases of the large intestine. Define the words in the glossary

4. Glossary Diverticulum Polyps Pedunculated Sessile

5. Structure and Function

6. Gross ~1.5 meters long Cecum, ascending colon, transverse colon, descending colon, and sigmoid colon. Sigmoid becomes rectum at the level of the third sacral vertebra. Blood Supply Ascending & proximal transverse colon – superior mesenteric artery Remainder of colon to rectum – Inferior mesenteric artery Upper rectum – Superior hemorrhoidal branch of inferior mesenteric artery Lower rectum – hemorrhoidal branches of iliac or internal pudendal artery.

7. The purpose of the colon is to reclaim water and electrolytes. Histology Mucosa is flat without villi Numerous straight tubular crypts extending to muscularis. Surface cells are columnar with numerous goblet cells. Crypts contain numerous goblet cells, endocrine cells and stem cells. Paneth cells not as abundant as in small intestine

8. Congenital Anomalies

9. Congenital Aganglionic Megacolon:Hirschsprung Disease Absence of ganglion cells (in Auerbach’s and Meissner’s plexi) in a portion of the intestinal tract Due to problems with neural crest cell migration or early death of ganglion cells Leads to functional obstruction and massive intestinal dilatation proximal to the aganglionic segment Most cases rectum and sigmoid only Complications include enterocolitis and perforation of the colon or appendix with peritonitis Manifests in newborns as failure to pass meconium and constipation Acquired megacolon: results from Chagas disease, obstruction by neoplasm or inflammation, and as complications of inflammatory bowel disease

10. Hirschsprung Disease - Morphology

11. Inflammatory Disorders

12. Antibiotic Associated Colitis(Pseudomembranous) Definition Acute colitis characterized by formation of an adherent inflammatory exudate overlying sites of mucosal injury = pseudomembrane Etiology Clostridium difficile Normal part of gut flora Toxins A and B cause host cell apoptosis May occur without antibiotic therapy: after surgery or debilitating illnesses Pathogenesis Usually occurs in patients following a course of broad-spectrum antibiotics (almost all antibacterials implicated) Toxin-producing strains flourish when normal flora disrupted

13. Antibiotic Associated Colitis(Pseudomembranous)

16. Antibiotic Associated Colitis(Pseudomembranous) Clinical Features Adults: acute or chronic diarrheal illness Diagnosis: C. difficile cytotoxin in stool Relapse occurs in up to 25% Treat with Vancomycin

17. Idiopathic Inflammatory Bowel Disease Collective term for Crohn disease and ulcerative colitis, because of their shared features Results from inappropriate and persistent activation of the mucosal immune system Distinct clinicopathologic manifestations: Crohn disease: granulomatous (50%) and can be found from the esophagus to anus, most often intestine and colon; transmural Ulcerative colitis: nongranulomatous, confined to colon and rectum, and superficial Both have extraintestinal inflammatory processes associated

19. Etiology and Pathogenesis Genetic Predisposition 15% of IBD patients have affected first-degree relatives; lifetime risk if either a parent or sibling is affected is 9% HLA-DR1/DQw5 – 27% of North American white patients w/ CD HLA-DR2 – patients w/ UC HLA-B27 – pts with IBD & ankylosing spondylitis Genetics suggest that CD and UC are distinct diseases. Infectious causes Host of organisms have been studied and none eluded; gene-knockout mice that normaly develop IBD do not develop it when they are germ free Abnormal Host Immunoreactivity Thought that there is too much T-cell activation and/or too little control by regulatory T lymphocytes Inflammation is Final Common Pathway

20. Crohn Disease

22. Crohn Disease Any region of bowel; sm. intestine (40%), small & large intestine (30%), colon (30%) Epidemiology World-wide, but most prevelant in developed Western countries Any age; peak incidence in 2nd & 3rd decades; and minor peak in 6th & 7th decades F>M; whites 2-5X >non-whites US: Jews 3-5X > non-Jews Smoking is a strong risk factor

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28. Crohn Disease Clinical Features Intermittent attacks of diarrhea, fever, and abdominal pain separated by weeks to months that are asymptomatic Attacks usually caused by periods of physical or emotional stress May have occult blood loss, leading to anemia, but no massive bleeds Some may have severe right lower quadrant pain

29. Crohn Disease Clinical Complications Strictures Fistulas Malabsorption and protein-losing enteropathy Extra-intestinal Manifestations Migratory polyarthritis Sacroilitis Ankylosing spondylitis Erythema nodosum Primary sclerosing cholangitis Clubbing of fingertips 5-6 fold increase in GI cancer, but less risk than in ulcerative colitis

30. Ulcerative Colitis Definition Ulceroinflammatory disease of the colon, limited to mucosa & submucosa (except in severe cases) No granulomas Involves rectum and extends continuously proximally, leading to pancolitis No skip lesions Slightly more common than Crohn Disease and affects same type of patient Associated with nonsmoking, particularly ex-smokers

38. Ulcerative Colitis Clinical Features Relapsing bouts of bloody, mucoid diarrhea, persisting for days, weeks or months. Relapse after months, years or decades. Usually accompanied by lower abdominal pain and cramps, relieved by defecation Attacks usually associated with physical or emotional stress 97% have at least one relapse during a 10-year period 30% require colectomy in first three years of onset due to uncontrollable disease Clinical Complications Cancer 20-30X risk with pancolitis of 10> years Associated carcinomas often infiltrative w/out obvious masses Actual rate of progression to dysplasia & CA is low Toxic Megacolon Extraintestinal lesions

40. Circulatory Disorders

41. Angiodysplasia Definition Tortuous dilations of submucosal and mucosal blood vessels in cecum or right colon Epidemiology < 1% of adult population, but 20% of significant lower GI bleeds (including chronic and intermittent or acute and massive bleeding) Usually after age 60 Etiology and Pathogenesis Normal distention and contraction of wall may occlude the submucosal veins ? focal dilatation LaPlace’s Law states that tension in the wall of cylinder is a function of intraluminal P & diameter; cecum has widest diameter and therefore greatest tension Vascular degenerative changes

43. Angiodysplasia Clinical Features Manifested as variable bleeding; some massive and severe. Hematochezia

44. Hemorrhoids Definition Variceal dilations of the anal and perianal venous plexuses. Microscopically, are thin-walled, dilated, submucosal vessels Types Internal: superior plexus; above anorectal line External: inferior plexus; below anorectal line Etiology and Pathogenesis 5% of general population Rarely under 30 years of age, unless pregnant Secondary to persistently elevated venous pressure within the plexi Chronic constipation and straining Pregnancy (venous stasis) Liver Cirrhosis & Portal Hypertension

46. Hemorrhoids Clinical Features Hemorrhage When traumatized ? thrombosis ? recanalization. Ulceration, fissures and infarction due to strangulation

47. Obstructions/ Dilatations

48. Diverticular Disease Definition A blind pouch lined by mucosa that communicates with lumen of gut Congenital - all three layers of bowel wall e.g Meckel diverticulum Acquired - lack or have attenuated muscularis propria

49. Diverticular Disease Epidemiology Rare < 30; In Western countries 50% incidence in age 60+ Can occur throughout the GI tract, but most commonly in the left colon (particularly sigmoid) Usually multiple present and the condition called, “diverticulosis” Etiology and Pathogenesis Focal wall weakness + ? intralumenal pressure Longitudinal muscle coat incomplete (taenia coli) in colon ? leaving regions where nerves and arterial vasa recta penetrate; connective tissue sheaths around vessels are areas for herniation ? Peristalsis ? sequester bowel segments ? ? intralumenal pressure ? ? inflammation Possibly diets low in fiber reduce stool bulk, ? peristalsis

50. 2. Microscopic - 1 slide a. thin wall with flattened or atrophic mucosa, compressed submucosa and attenuated or missing muscularis2. Microscopic - 1 slide a. thin wall with flattened or atrophic mucosa, compressed submucosa and attenuated or missing muscularis

53. Diverticular Disease Clinical Features Most asymptomatic 20% symptomatic Intermittent cramping, lower abdominal discomfort, constipation, distention, feeling like rectum won’t completely empty, alternating constipation & diarrhea, minimal chronic or intermittent blood loss or rarely massive hemorrhage Clinical Complications Obstruction ? Inflammation ? Perforation ? Pericolic abscesses ? fibrosis and/or sinus tracts ? peritonitis

55. Tumors of the Colon and Rectum

56. What is a Polyp? A tumorous mass that protrudes into the gut lumen Presumably, all polpys start as small, sessile lesions without a stalk and then devlop into stalked, pedunculated polyps.

57. How are polyps formed? Non-neoplastic (hyperplastic polyps) Abnormal mucosal maturation Inflammation Architecture Neoplastic Proliferation and Dysplasia (adenomatous polyps, adenomas) These are precursors to carcinoma! Submucosal or mural tumors give rise to polypoid lesions *Unless otherwise specified, polyps are epithelial and arise from mucosa.

58. Benign Lesions

59. Non-Neoplastic Polyps

60. Hyperplastic Polyps Patients 60+ Nipple-like protrusions into lumen; often multiple Histology - well-formed glands and crypts lined by non-neoplastic cells Virtually no malignant potential

61. Hyperplastic Polyps - Morphology

62. Juvenile Polyps Focal hamartomatous malformations in mucosa and lamina propria Sporadic and majority in children < 5 yrs Large (1-3 cm), round, smooth and lobulated with up to 2 cm stalks No malignant potential except for a rare autosomal dominant juvenile polyposis syndrome 50-100 juvenile polyps in GI tract

63. Juvenile Polyps - Morphology

64. Juvenile Polyps - Morphology

65. Peutz-Jeghers Polyps Hamartomatous polpys of mucosa, lamina propria, and muscularis mucosa Either single or Multiple throughout GI tract, as in P-J Syndrome melanotic mucosal and cutaneous pigmentation around oral mucosa, lips, face, genitalia, and palmer surface of hands risk of intussusception, causing death The polyps have no malignant potential, but patients with syndrome have increased risk of carcinoma of pancreas, breast, lung, ovary and uterus

66. Adenomas Epidemiology Small pedunculated to large neoplasms that are sessile Prevalence is 20-30% < 40 yrs to 40-50% > 60 yrs Familial predisposition for sporadic adenomas (4X risk for 1st degree relatives and 4X risk for colorectal cancer)

67. Adenomas Classification Tubular adenomas Most common >75% tubular architecture, small & pedunculated Villous adenomas: Least common >50% villous architecture Tubulovillous adenoma Mixture of the other two 25-50% villous architecture

68. Adenomas Malignant Risk Adenomas arise from proliferative dysplasia that varies in severity; they are precursors to invasive colorectal adenocarcinoma Polyp size, histologic architecture, & severity of dysplasia determines risk of malignancy Rare in tubular adenomas <1 cm Up to 40% of villous adenomas > 4cm Usually contains severe dysplasia

77. Adenomas Clinical Features Regardless of whether carcinoma is present, the only adequate treatment for a pedunculated or sessile adenoma is complete resection. If adenomatous tissue is left behind, the patient still has a premalignant lesion.

78. Familial Syndromes Onset in teens to twenties in all syndromes and cancer 10-15 years later Autosomal dominant diseases Familial adenomatous polyposis (FAP) Archetype familial adenomatous polyposis syndrome Caused by mutations of the adenomatous polyposis coli (APC) gene on chromosome 5 Exhibits innumerable adenomatous polyps that carpet the mucosa 100% frequency of progression to adenocarcinoma Gardner syndrome Variation of FAP Addition of osteomas (mandible, skull & lung bones), epidermal cysts, and fibromatosis Turcot syndrome Rare Adenomatous colonic polyposis + CNS tumors (gliomas)

80. Malignant Lesions

81. Adenocarcinoma Epidemiology Adenocarcinomas (98% of cancer in colon) 10% of all cancer related deaths in US Peak incident 60-79 years Highest death rates in US and Eastern European countries -high refined CHO ? toxic oxidative products held in slow moving small bulk stools against mucosa - red meat e.g. ?cholesterol? synth bile acids ?bact ? carcinogens? -decreased protective micronutrients e.g. Vit A,C,E -high refined CHO ? toxic oxidative products held in slow moving small bulk stools against mucosa - red meat e.g. ?cholesterol? synth bile acids ?bact ? carcinogens? -decreased protective micronutrients e.g. Vit A,C,E

82. Adenocarcinoma Etiology and Pathogenesis Must suspect preexisting UC or Polyposis Syndrome if found in young person Diet implicated Excess caloric intake relative to requirements Low unabsorbable vegetable fiber ? reduces transit time & yields scanty stool Large quantities of refined carbohydrates ? toxic oxidative products held in contact with mucosa by slow-moving stools Red meat High cholesterol ? synthesizes bile acids ? converted into carcinogens by bacteria Decreased intake of protective micronutrients, e.g. Vit A,C,E

86. Adenocarcinoma Clinical Features Asymptomatic for years and then insidious onset Right sided Fatigue, weakness, iron deficiency anemia Lesions are bulky and bleed easily Left sided Occult blood in stool Alternating constipation and diarrhea Crampy discomfort in left lower quadrant Rectum & sigmoid more infiltrative at time of diagnosis ? poorer prognosis Iron deficiency anemia in an older man is GI cancer until proven otherwise.

87. Adenocarcinoma Complications Weight loss, malaise, & weakness are ominous signs Metastasis by lymph and blood In order of metastatic spread: regional nodes, liver, lungs and bone Extent of tumor at time of diagnosis (stage) is the most important prognostic indicator.

89. Carcinoid Tumors Source Endocrine cells throughout GI tract can generate bioactive compounds that coordinate gut function (gastrin, vasoactive amines, somatostatin & insulin) Epithelial cells that functionally and morphologically resemble endocrine cells Epidemiology Most located in GI tract Peak incidence in 50s < 2% of colorectal malignancies, 50% of small intestinal malignancies Site is important in terms of biologic behavior because there is no reliable histological difference between benign & malignant carcinoids

93. Carcinoid Tumors Clinical Features Many asymptomatic May obstruct May be functional e.g. hyperinsulinemia, Cushing Syndrome, Zollinger-Ellison Syndrome May have Carcinoid Syndrome 1% of all patients; 20% with widespread metastases Excess elaboration of serotonin; 5-HT and its metabolite (5-HIAA) are present in the blood and urine of patients Symptoms: flushing, intestinal hypermotility, bronchoconstriction, hepatomegaly, and systemic fibrosis

94. Carcinoid Tumors Clinical Complications Liver metastasis 5 year survival 90% (excluding appendiceal) 50% if small bowel tumor with liver metastasis Wide spread disease will usually cause death

95. Gastrointestinal Lymphoma Definition Primary GI lymphomas exhibit no evidence of liver, spleen, mediastinal lymph node, or bone marrow involvement at the time of diagnosis Regional lymph node involvement may be present Who gets them? Sporadic, H. pylori gastritis, Mediterranean population, congenital immunodeficiency, HIV, Celiac sprue, immunosuppressive therapy

96. Gastrointestinal Lymphoma Clinical Features Tumors start as plaques then become exophytic or infiltrative Symptoms vague to prominent: weakness and weight loss Ulcerate leading to bleeding Tumors invade and perforate Obstruction Complications Depth of invasion, size of tumor, histologic grade and extension determine prognosis 85% 10-year survival if localized to mucosa or submucosa

97. Appendix

98. Acute Appendicitis Epidemiology Mainly adolescents and young adults Males slight more often than females Etiology and Pathogenesis Obstruction by fecoliths (most common), gallstones, tumors or parasites Obstruction ? mucous secretion ? ? intralumenal pressure ? collapse of draining veins ? ischemia ? bacterial proliferation ? further inflammation with edema ? ?blood flow Some have an unknown cause

101. Acute Appendicitis Clinical Features Classic signs are periumbilical pain to lower right quadrant, nausea and/or vomiting, abdominal tenderness in the region of the appendix, mild fever and leukocytosis (15-20 thousand) Classic signs absent more than present, especially in young children and elderly Surgical false positives 20-25% of the time, but significant mortality rate (2% w/ perforation) outweighs this fact. Clinical Complications Perforation leading to periumbilical abscess local peritonitis

102. Peritonitis

103. Peritonitis Common Causes Sterile peritonitis from leakage of bile or pancreatic enzymes Perforation or rupture of biliary system Acute hemorrhagic pancreatitis Surgical procedures Gynecologic conditions (endometriosis & ruptured dermoid cysts)

104. Neoplasms Mesotheliomas Extremely rare Same as those found in pleural cavity and pericardium Associated with asbestos exposure in 80% Secondary tumors (Metastatic) Common Diffuse serosal implantation e.g ovarian and pancreatic tumors Mucinous cystadenocarcinomas of appendix implant peritoneum ? mucin = pseudomyxoma peritoneii

105. References Kumar, Abbas, and Fausto: ROBBINS AND COTRAN PATHOLOGIC BASIS OF DISEASE, 7th Edition, pp.828-870.