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Gross, EM and immunohistochemistry images are needed for most disorders

Micro images are particularly needed for these lesions:

Congenital - intestinal neuronal dysplasia

Colitis (non-infectious) - allergic colitis, Brainerd diarrhea, diversion colitis, hemorrhagic colitis, pouchitis, radiation enterocolitis, typhlitis

Colitis (infectious) - Candida, Chagas disease, Clostridium botulinum, HIV/AIDS, HSV, Shigella, typhoid fever, Vibrio cholera, Yersinia

Non-neoplastic, non-congenital - adhesions, brown bowel, colchicine toxicity, colitis cystica profunda, gout, hyperplastic Pacinian corpuscle, idiopathic constipation, infracted epiploic appendages, reactive angioendotheliomatosis, xanthelasma

Embryology of colon

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Primitive gut is divided into foregut, midgut and hindgut

Midgut gives rise to cecum, ascending colon and right 75% of transverse colon (also distal duodenum to ileum)

Hindgut develops into remainder of transverse colon to ano-rectal line

Micro images: fetal colon-various images

References: more information, Early Hum Dev 2004;78:1

Normal anatomy of colon

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1.0 to 1.5 meters long, from terminal ileum to anal canal

Compared to small intestine, has greater diameter, fixed position, epiploic appendages, taeniae coli (discontinuous muscular fibers)

Regions: cecum, ascending (right sided) colon, transverse colon, descending (left sided) colon, sigmoid colon, rectum

Diagram: regions of colon

Cecum: in peritoneum, 6 x 9 cm; large blind pouch arising from proximal right colon; blind end directed downward, open end directed upward

Drawing: cecum and appendix; cecum and ileocecal valve #1; #2

Ascending colon: 15-20 cm long; posterior surface is in retroperitoneum, but anterior and lateral surfaces have serosa and are intraperitoneal

Hepatic flexure: junction of ascending and transverse colon

Splenic flexure: junction of transverse and descending colon

Descending colon: 10-15 cm long; posterior surface is in retroperitoneum, but anterior and lateral surfaces have serosa and are intraperitoneal

Sigmoid: descending colon at origin of mesosigmoid; from pelvic rim to S3 vertebra

Drawing: sigmoid and anal valves

Rectum: 12 cm; sigmoid colon from termination of mesosigmoid; also from opposite sacral promontory to upper border of anal canal; becomes extraperitoneal (within the pelvis) as it passes between the crura of the peritoneal muscles; has no serosa / peritoneal covering

Drawing: rectum and anal canal

Micro images: rectum; rectal folds of Morgagni

Pouch of Douglas: cul-de-sac in women made up of reflection of peritoneum from the rectum over the pelvic wall

Drawings: rectovaginal (RV) pouch

Taenia coli: discontinuous muscular fibers

Micro images: Taenia coli and lymphoid tissue; transverse section; relationship to muscularis propria

Epiploic appendages: pedunculated fat on lateral colon; lined by mesothelium

Gross images: see tip of pointer

Vasculature

Superior mesenteric artery supplies cecum to splenic flexure

Inferior mesenteric artery supplies remainder of colon to rectum

Numerous collaterals connect mesenteric circulation with celiac arterial axis proximally and pudental circulation distally

Superior hemorrhoidal branch of inferior mesenteric artery supplies upper rectum; hemorrhoidal branches of internal iliac or internal pudental artery supplies lower rectum

Venous drainage is similar; there is an anastomotic capillary bed between the superior and inferior hemorrhoidal veins, providing a connection between the portal and venous systems

Drawings: vessels of rectum

Normal histology of colon

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Composed of mucosa, submucosa, muscularis propria (externa) and serosa (perimuscular tissue in rectum)

Micro images: low power #1; #3; various images

Virtual slides: normal colon

Mucosa: epithelium, lamina propria and muscularis mucosa

Epithelium: low columnar to cuboidal cells

Tubules are tightly packed, have straight test tube shape (minimal branching), parallel to each other, straight luminal surface, rest on thin basement membrane, extend to muscularis mucosa; absorptive cells and goblet cells

Crypts open into surface epithelium or into innominate grooves

Crypts are surrounded by pericryptal fibroblast sheath (fibroblasts or myofibroblasts)

Crypts also contain precursor cells, endocrine cells and Paneth cells in right sided colon

Positive stains: CDX2 (sensitive and specific for colon), CK8, CK18, CK19

Micro images: mucosa #1; #2; #3; #4; #5; #6; crypts

pericryptal fibroblast sheath - #1 (figures C/D); #2-A: sheath is positive for high molecular weight caldesmon; #3-A: sheath is positive for alpha smooth muscle actin;

CDX2 #1; #2; #3; CK18

References: J Clin Pathol 1999;52:785 (pericryptal fibroblasts)

Innominate grooves: mucosal area where several crypts open into one central crypt

Lamina propria: capillaries (uniform), lymphatics just above muscularis mucosa; inflammatory cells present (see below)

Muscularis mucosa: thin and regular

Micro images: mucosa and muscularis mucosa #1; #2; #3

Submucosa: loose connective tissue with submucosal plexus of Meissner; minimal inflammatory infiltrate; younger patients may have intramucosal lymphoid aggregates that disrupt muscularis mucosa

Micro images: mucosa and submucosa #1; #2; submucosal plexus of Meissner

Muscularis propria: inner circular layer, myenteric plexus of Auerbach, outer longitudinal layer

Micro images: muscularis propria #1; #2; myenteric plexus of Auerbach #1; #2; #3

Serosa: single layer of flat to low cuboidal mesothelial cells and adjacent fibroelastic tissue

Types of cells

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Absorptive cells: basal nuclei, eosinophilic cytoplasm, no mucin, shorter microvilli than small intestinal cells

Endocrine cells: usually at base of crypts; similar to cells in pancreas, lung, thyroid, urethra; contain fine eosinophilic granules with secretory proteins; nuclei are not basal but on luminal side of granules

Secretory granules are released at BASAL surface of endocrine cell or along lateral surface; NOT apical; products modulate digestive functions

Ganglion cells: nerve cell body (perikarya) common in normal and abnormal mucosa; may resemble microgranulomas or CMV (AJCP 2005;124:269)

Goblet cells: contain ovoid mucoid vacuole

Inflammatory cells: lymphocytes (B & T), intraepithelial lymphocytes only rarely, plasma cells, histiocytes (may contain hemosiderin, mucin or “pseudomelanin” from laxatives), mast cells, occasional eosinophils (vary by geography, Mod Path 1997;10:363); lymphoglandular complexes when lymphoid follicles surround deep crypt epithelium extending into submucosa; neutrophils not normally present

Interstitial cells of Cajal: associated with myenteric (Auerbach/intramuscular) plexus between circular and longitudinal muscle layers; have pacemaker function which facilitates active propagation of electrical events and mediates neurotransmission; have unique ultrastructure on EM with gap junctions between each other and smooth muscle cells; have surface tyrosine kinase receptor c-Kit (CD117) which is essential for their development; kit ligand provided by neuronal cells or smooth muscle cells

Reference: AJSP 2003;27:228

M cells: flattened surface cells overlying lymphoid aggregates; associated with mononuclear inflammation and epithelial cells with reduced cells; deliver intact foreign macromolecules and commensal bacteria from lumen to mucosal lymphoid tissue to trigger immune responses; also site of adhesion and invasion for enteric pathogens (Histopathology 1987;11:941), including HIV (Pathobiology 1998;66:141) and Shigella (Ann NY Acad Sci 1994;730:197)

M cells have cytoplasmic microvilli, enfold lymphocytes and plasma cells (Dig Dis Sci 1992;37:1089)

Drawings: M cells; in small intestine

Micro images: small intestine

Paneth cells: secretory epithelial cells at base of crypts in cecum and ascending colon; considered metaplastic if present elsewhere in colon; granules contain antimicrobial peptides (Trends Microbiol 2004;12:394)

Micro: basophilic cytoplasm (due to rough ER) and numerous eosinophilic granules, larger than those in endocrine cells

Micro images: Paneth cells #1; #2; #3; #4; #5

Undifferentiated crypt cells: at base of crypts; precursor to other noninflammatory cells; migration from crypts to surface takes 3-8 days; process allows for rapid repair, but also makes cells sensitive to radiation and cancer chemotherapy

Normal physiology of colon

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Reclaims water and electrolytes

Intestinal immune system

Composed of Peyer’s patches in ileum, M cells (membranous) in small intestine and colon which transfer antigen macromolecules from lumen to lymphocytes, T cells and B cells, and mucosal associated lymphoid tissue - lymphoid nodules, mucosal lymphocytes, appendix lymphoid follicles and mesenteric nodes

Neuromuscular function

Anterograde and retrograde peristalsis mixes food, promotes maximal contact of nutrients with mucosa

Colonic peristalsis prolongs contact with mucosa

Peristalsis mediated via enteric nervous system, smooth muscle layers and interstitial cells of Cajal

Gut innervation has complex 3D structure

Bowel preparation associated changes

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Micro: reduced intracellular mucin, epithelial apoptosis and sloughing, increase in mitotic figures; may have erosion of superficial epithelium, consistent with clinical impression of aphthoid ulcer; also increased lymphocytes and neutrophils (Dis Colon Rectum 2006;49:109); rarely lamina propria edema or extravasated red blood cells

DD: Crohn’s disease

References: Hum Path 1998;29:972

Congenital anomalies

Atresia of colon

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Imperforate mucosal diaphragm or stringlike segment of bowel

Very rare (1 per 20,000 live births)

Associated with other congenital anomalies, including Hirschsprung’s disease

May have genetic (J Pediatr Surg 2005;40:390) or vascular cause

Type 1: bowel and mesentery are intact, but bowel lumen is interrupted by a complete membrane

Type 2: bowel is discontinuous, connected by a fibrous cord

Type 3: bowel ends are completely separated and mesentery has a gap

Case reports: #1

Treatment: segmental resection and anastomosis; good prognosis with prompt treatment (J Pediatr Surg 2005;40:1258)

Gross images: atretic and dilated segments

References: eMedicine

Chronic intestinal pseudo-obstruction

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Syndrome of intestinal obstruction without mechanical obstruction

Usually a small bowel disorder but can occur anywhere in GI tract

Gut motility depends on sympathetic (thoracolumbar) and parasympathetic (vagal) innervation to the ganglionated plexi; also enteric nervous system, smooth muscle cells and interstitial cells of Cajal

Usually congenital in children; in adults due to systemic disease (diabetes, myxedema, dermato/polymyositis, amyloid, Chagas disease, myotonic dystrophy, muscular dystrophy, scleroderma), drugs (antiParkinson, clonidine, ganglionic blockers, tricyclic antidepressants, phenothiazines) or idiopathic (ceroidosis, cathartic colon, Hirschsprung’s disease, visceral myopathies, visceral neuropathies)

May be due to loss of interstitial cells of Cajal in small and large bowel (AJSP 2003;27:228)

Often poor long-term outcome (Clin Gastroenterol Hepatol 2005;3:449); high mortality if perforation or ischemia

Ogilvie's syndrome (acute colonic pseudo-obstruction): abrupt onset of abdominal distension (Radiol Med (Torino) 2005;109:370)

Treatment: diet, octreotide, surgery, transplant

Micro: visceral myopathy - vacuolar degeneration with swelling and loss of muscle cells, fibrosis of outer longitudinal muscle layer; other cases show cytoplasmic vacuoles, marked nuclear enlargement and irregularity and interstitial fibrosis (AJSP 1987;11:846)

Micro images: familial autonomic visceral myopathy - muscularis propria degeneration #1-especially inner layer; #2-with muscle fiber loss and degenerative changes and collagen replacement; muscularis mucosa shows degenerative changes of fibers (vacuolation and pyknotic nuclei)

DD: ischemic colitis (hemosiderin deposits, fibrous stricture), tuberculosis (stricture, necrotizing granulomas), scleroderma (patchy bowel involvement, dense fibrosis affecting inner or all muscle layers, no vacuolar change)

References: J Clin Pathol 1988;41:424-inherited, Eur J Pediatr Surg 2003;13:201-mitochondrial myopathies

Cyst of retrorectal space

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Also called tailgut cyst

Retrorectal space is loose areolar tissue plane between fascia propria of rectum and presacral space

Rare; often misdiagnosed clinically (J Am Coll Surg 2003;196:880)

Dermoid cyst: unilocular, lined by squamous epithelium and skin adnexae, no smooth muscle

Epidermoid cyst: unilocular, lined by squamous epithelium without adnexa

Rectal duplication cyst: unilocular, lined by colonic, gastric or respiratory epithelium with organized smooth muscle similar to muscularis propria

Cystic hamartoma: multilocular with squamous, transitional or glandular lining, disorganized smooth muscle, occasionally foreign body granulomatous inflammation; case report diagnosed as ovarian tumor (Arch Gynecol Obstet 2005;272:301)

Treatment: complete excision recommended to prevent malignant transformation (AJCP 1988;89:139)

Gross: multilocular, variable solid areas

Micro images: cystic hamartomas; dermoid cyst; epidermoid cyst; tailcut cyst

References: Radiographics 2001;21:575-adults, Archives 2000;124:725-cystic hamartoma

Duplication of colon

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Rare; partial or complete doubling of a variable length of bowel

Saccular to long, cystic structures

Often present in mesentery of normal bowel without communication with lumen

Associated with complex GU abnormalities

May rarely present in adults with rectal bleeding (World J Gastroenterol 2005;11:5072)

May not require treatment (Yonsei Med J 2005;46:189)

Gross images: double colonic lumen; various images

Courtesy of Dr. Celso Rubens Vieira e Silva, Brazil: cystic congenital duplication - gross; micro

DD: enteric cysts (less organized smooth muscle, no nerve plexus)

References: eMedicine (GI duplications)

Epidermolysis bullosa dystrophica in colon

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Commonly causes constipation

Case reports: fecal impaction causing toxic megacolon and death from perforation (BMC Dermatol 2006;6:2)

Gastroschisis

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Portion of abdominal wall fails to form together, with extrusion of intestines, but NOT through the umbilical cord

Intestines are exposed, not covered by a membranous sac, as in omphalocele

Associated with intestinal atresia, Hirschsprung’s disease

References: eMedicine

Heterotopia of colon

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Pancreatic or gastric mucosa appear as nodules (usually small) in aberrant gut location

Case reports: gastric heterotopia associated with adenoma in elderly patient (NJ Med 1995;92:512), gastric heteropia #1 with hemorrhage (Gut 1988;29:848), #2 in rectum (Archives 1999;123:222), child with heterotopic renal tissue in colonic wall associated with congenital anomalies (Pediatr Dev Pathol 2002;5:587), skin heterotopia in polyps, associated with trauma (Dis Colon Rectum 1995;38:219)

Micro images: gastric and colonic mucosa; prominent parietal cells

Hirschsprung’s disease of colon

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Also called congenital aganglionic megacolon

No parasympathetic ganglion cells in submucosal and myenteric plexus of affected colon, causing functional obstruction and colonic dilation proximal to affected segment

80% male; usually sporadic (1 per 5,000 live births); in 3.6% of affected siblings

10% have Down’s syndrome; another 5% have other serious neurologic impairment

Normally, neural crest cells migrate into bowel, forming intestinal neural plexus; in Hirschsprung’s, usually are heterogeneous defects in genes regulating migration and survival of neuroblasts (endothelin 3 and its receptor), glial cell-derived growth factor (neurogenesis) and receptor tyrosine kinase activity (RET, Ann Med 2006;38:11)

Always affects rectum, usually also sigmoid, not other segments; anus and rectum usually small and devoid of stool

Symptoms: failure to pass meconium, obstructive constipation; may have occasional passage of stool or diarrhea if only a short segment of rectum is affected

Complications: proximal innervated colon may become massively distended (15 cm in diameter) with muscular wall hypertrophy and rupture/perforation, usually near cecum or appendix; also acute intestinal obstruction, enterocolitis with fluid and electrolyte imbalance

Mortality: currently 5-10%

Classic: aganglionic portion begins in distal colorectum and extends a considerable distance proximally

Ultrashort segment: less than 2 cm affected in rectum and sigmoid; more common in boys; difficult to document because this portion of rectum typically lacks ganglion cells even in normals

Short segment: aganglionic portion involves rectum and rectosigmoid for only a few cm

Long segment: 10% of cases; involves 40 cm or more of colon, and may extend into small bowel; patients have obstruction without megacolon; more common in girls; may lack hypertrophied nerve trunks, but do have increase in acetylcholinesterase+ nerve abnormalities

Zonal colonic aganglionosis: involvement of short segment of bowel; ganglion cells are present above and below this segment

Diagnosis: mucosal rectal biopsy with serial sections to detect ganglion cells (more irregular in submucosal plexus but process is less invasive than full thickness rectal biopsy [classic method below]); further identify in frozen section stained with acetylcholinesterase (see below); other diagnostic tests are contrast enema and anorectal manometry (J Pediatr Gastroenterol Nutr 2006;42:496)

Classic method: biopsy muscular wall of rectum and examine for ganglion cells in myenteric plexus; should biopsy 2+ cm above anal valve in infants, 3+ cm in older children; if squamous epithelium present, must biopsy higher

Frozen sections: to document absence of ganglion cells and determine level of bowel transaction at surgery; also for acetylcholinesterase staining

Treatment: proctectomy with pull-through of ganglionic bowel to anus; some patients have persistent bowel dysfunction (enterocolitis, constipation, incontinence)

Gross: normal anus but small rectum and anal canal without stool, dilated proximal bowel

Gross images: dilated bowel #1; #2; #3

Micro: no ganglion cells in submucosal or myenteric plexus; thickening and hypertrophy of nonmyelinated nerve fibers and muscularis mucosa; stercoral ulcers (sharply demarcated shallow ulcers with mucosal inflammation due to pressure of feces on obstructed colon); fibromuscular dysplasia of arteries between normal and diseased colon; no/reduced myenteric and muscular interstitial cells of Cajal in rectosigmoid colon

Hypoganglionosis - arises between normal and aganglionic bowel; reduced number of ganglion cells (such as 10% of normal)

Micro images: lack of ganglion cells #1; #2; hyperplastic nerves but no ganglion cells #1; #2; increased acetylcholine positive nerve fibers #1; #2; reduced interstitial cells of Cajal

normal ganglion cells - sympathetic ganglion cells; dorsal root of spinal cord #1; #2

Virtual slides: Hirschsprung’s disease

Positive stains: acetylcholinesterase (increase in staining in lamina propria and muscularis mucosa reflects increase in nerve fibers (Pediatr Surg Int 2005;21:255)

Negative stains: neuron specific enolase (stains ganglion cells), RET (detects ganglion cells, AJCP 2006;126:49)

EM: altered cytoskeletal proteins in affected colon

References: Archives 2002;126:928, Archives 2002;126:692, eMedicine, OMIM 142623 and 600155

Intestinal neuronal dysplasia

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Also known as neuronal colonic dysplasia, hyperganglionosis, pseudo- or variant Hirschsprung’s disease

Type A: hypoplastic or aplastic sympathetic innervation

Type B: hypoplastic or plastic parasympathetic innervation (Virchows Arch A Pathol Anat Histopathol 1992;420:171)

Associated with neurofibromatosis 1 and MEN2b syndromes

Associated with hypoganglionosis of myenteric plexus or aganglionosis of rectum

A controversial entity; should diagnose only if no other diagnosis, no obstruction, and multiple adequate biopsies (30 sections) of submucosa and muscularis propria available; may be due to delayed maturity of enteric nervous system as 95% have normal gut motility within 1 year

Diagnostic criteria in two studies: (1) biopsies 8-10 cm above dentate line, sufficient submucosa, 15-20% of ganglia are giant ganglia with more than 8 nerve cells in submucosa of 30 serial sections (Eur J Pediatr Surg 2004;14:384); (2) hyperganglionosis of submucous plexus, giant ganglia and rectal biopsies show either ectopic ganglia, increased acetylcholinesterase activity in lamina propria or increased acetylcholinesterase in nerve fibers around submucosal blood vessels (J Pediatr Surg 2001;36:777)

Case reports: coexisting congenital interstitial cell of Cajal hyperplasia (AJSP 2000;24:1568)

Micro: resembles Hirschsprung’s disease with hyperplasia of myenteric nerves and increased acetylcholinesterase staining, but with occasional (15-20%) submucosal giant ganglia (containing 7-10 neurons vs. 3-5 normally) and isolated ganglion cells in submucosa

Note: giant ganglia by themselves are not specific (Virchows Arch 1998;432:103)

Micro images: various images

Malrotation of colon

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From improper embryologic rotation of gut

Symptoms may first occur in women during pregnancy (Obstet Gynecol 1993;81:817)

Drawings: Netter drawings; various drawings and text

References: eMedicine

Omphalocele

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Abdominal musculature fails to form

Infant is born with herniated abdominal contents into ventral membranous sac through the umbilical cord

Case reports: with colonic atresia and Hirschsprung’s disease (Pediatr Surg Int 2001;17:218)

Gross images: omphalocele #1; #2; various images

DD: gastroschisis (not through umbilical cord, no membranous sac covering intestines)

References: eMedicine #1; #2

Diverticular disease of colon

Diverticulosis

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Diverticulum: blind pouch leading off alimentary tract, lined by mucosa that communicates with gut lumen

Congenital: have all 3 layers of bowel wall (includes Meckel’s diverticulum)

Acquired: lack or have attenuated muscularis propria due to focal weakness in wall and increased intraluminal pressure

Note: colonic longitudinal layer is gathered into taeniae coli; focal defects occur where nerves and arterial vasa recta penetrate inner circular muscle wall

Associated with Western diets (low fiber causes prolonged transit time and increased intraluminal pressure associated with low volume stools); rare in Asia, Africa, South America where high residue diet is common, and may diminish colonic segmentation and associated mucosal herniation

Rare before age 30, 50% of cases are in patients age 60+; only 20% develop symptoms

May regress early in development or become more numerous/prominent over time

May coexist with inflammatory bowel disease in some patients

Left sided disease: common in West, affects sigmoid but not rectum, older individuals

Right sided disease: more common in Far East, may mimic appendicitis; in Japan, has similar features to left-sided disease (Int J Colorectal Dis 2002;17:365); other reports indicate patients may be younger with fewer clinical problems (Dis Colon Rectum 1995;38:755)

Symptoms: cramping, discomfort, constipation, distention, sensation of inability to completely empty rectum; alternating constipation and diarrhea; motor abnormalities may be due to loss of interstitial cells of Cajal and glial cells (J Clin Pathol 2005;58:973)

Complications: hemorrhage (may be massive), perforation with abscess resembling a mass or forming a sinus tract, diverticulitis / peritonitis, fistula into bowel or bladder, obstruction, adhesions

Treatment: high fiber diet and poorly absorbed antibiotics (Digestion 2006;73 Suppl 1:58), resection for perforation and peritonitis and for repeated attacks of diverticulitis

Grossing: fix intact specimen with formalin for 24 hours before dissection

Gross: multiple, small, flasklike invaginations present along prominent taeniae coli, filled with mucin or stool but easily emptied, may bulge into serosa; thick and corrugated circular muscle with prominent accordion-like mucosal folds; in severe cases, bowel is segmented and shortened

Gross images: multiple diverticula #1; #2; #3; #4; #5; #6; #7; with bowel wall stenosis; blue-gray diverticula #1; #2

Micro: no muscle layer around diverticula except for residual bundles of muscularis mucosa; inflammation due to obstruction or perforation, may dissect into adjacent pericolic fat, causing fibrotic thickening resembling colon carcinoma; may have Paneth cells

Micro images: mucosal herniation through thinned muscularis propria; central lumen with surrounding mucosa #1; #2; #3; Paneth cells #1; #2

Virtual slides: diverticulum

DD: Crohn’s disease if fistulas present (has mucosal ulceration, lymphoid aggregates distant from inflamed diverticula)

References: AJCP 1997;107:438

Diverticulitis

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Radiologically may resemble carcinoma

Clinically may resemble appendicitis

May be more aggressive in younger patients (World J Gastroenterol 2006;12:2932)

Treatment:

Table of contents

Non-neoplastic, non-congenital - adhesions, brown bowel, colchicine toxicity, colitis cystica profunda, gout, hyperplastic Pacinian corpuscle, idiopathic constipation, infracted epiploic appendages, reactive angioendotheliomatosis, xanthelasma

Normal anatomy of colon

Vasculature

Normal histology of colon

Normal physiology of colon

Atresia of colon

Duplication of colon

Heterotopia of colon

Hirschsprung’s disease of colon

Malrotation of colon

Diverticular disease of colon