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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

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

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

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

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

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

Taenia coli: discontinuous muscular fibers

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

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

Normal histology of colon

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

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

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

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

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

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)

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

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; #2

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

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)

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

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

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)

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)

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

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)

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)

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)

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)

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

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

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: liquid diet (bowel rest) and oral antibiotics; surgical resection if perforation, fistula, obstruction, persistent pain, hemorrhage, repeated attacks or immunocompromise (J Clin Gastroenterol 2006;40:S145)

Micro: acute or chronic inflammatory infiltrate near base of diverticula; occasionally granulomatous inflammation

DD: Crohn’s disease (although both may coexist)

References: eMedicine #1; #2

Inflammatory bowel disease (IBD)

Inflammatory bowel disease-general

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Chronic, relapsing, inflammatory disorders of unknown origin

Incidence increasing in children (World J Gastroenterol 2006;12:3204)

Frequently have extra-intestinal manifestations (World J Gastroenterol 2005;11:7227)

Incidence increasing in Asian Pacific countries (Curr Opin Gastroenterol 2005;21:408)

15% have affected first degree relatives; 9% lifetime risk if parent or sibling is affected

Associated with HLA-B27

Often coexists with diverticular disease; the presence of Crohn’s in diverticular disease is suggested by fissuring ulcers, ulcers outside areas of active diverticulitis and fistulas other than colovesicle or colovaginal; most patients don’t develop other IBD lesions

AMACR expression is increased in dysplastic epithelium in IBD (AJSP 2006;30:871)

Possible causes: alteration in usual steady state between immune system (activated by microbes, antigens and endogenous inflammatory stimuli) and host defenses that maintain integrity of mucosa and down-regulate inflammation (Inflamm Bowel Dis 2006;12:S3, Nat Clin Pract Gastroenterol Hepatol 2006;3:390)

Diagnosis: requires clinicopathologic correlation; pathologist should convey histologic findings to clinician, who correlates with clinical history, endoscopy, radiology; disease may be difficult to classify (Histopathology 2006;48:116)

Treatment: immunosuppressive therapy

Crohn’s disease of colon

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Transmural granulomatous disease affecting GI tract from esophagus to anus but discontinuous

Also called regional enteritis because it affects sharply delineated segments, or granulomatous colitis due to granulomas

Primarily affects Western populations with prevalence of 3 per 100,000, peaks in teens/twenties and at ages 50-69

More common in whites (HLA-DR1/DQw5), Jews, smokers; monozygotic twins have 30-50% concordance

Usually involves small intestine; 40% of patients have colon involvement

Symptoms: episodic mild diarrhea, fever, pain; may be precipitated by stress; if colon affected, may have anemia

20% have abrupt onset of symptoms resembling acute appendicitis or bowel perforation

Extra-intestinal symptoms: migratory polyarthritis, sacroiliitis, ankylosing spondylitis, erythema nodosum, clubbing of fingertips, primary sclerosing cholangitis (not as common as with ulcerative colitis); occasionally uveitis, pericholangitis and renal disorders secondary to periureteral fibrosis

Complications: fibrosing strictures (common in terminal ileum); fistulas to loops of bowel, bladder, vagina and perianal skin; also protein losing enteropathy, generalized malabsorption, Vitamin B12 deficiency, bile salt malabsorption with steatorrhea, toxic megacolon (4%), carcinoma (see below)

Treatment: medical therapy (steroids, antibiotics); may need surgery eventually, although Crohn’s often recurs in pouch; involvement of resection margins doesn’t correlate with recurrence

Gross: dull and granular serosa, creeping fat (mesenteric fat wraps around bowel surface), thick/rubbery intestinal wall (due to edema, inflammation, fibrosis, hypertrophy of muscularis propria), strictures (string sign on barium enema), sharp demarcation of affected segments from uninvolved bowel (skip areas)

Aphthous mucosal ulcers coalesce into long, serpentine linear ulcers along bowel axis to acquire cobblestone appearance; fissures in mucosal folds lead to fistulas or sinus tracts

Usually rectal sparing; disease overall is less severe in distal vs. proximal colon (i.e. preferential right-sided involvement)

Micro: superficial or deep ulceration with adjacent granulation tissue extending into deep submucosa or below; transmural inflammation with lymphoid aggregates throughout bowel wall; sarcoid-like, non-caseating, poorly formed granulomas in all tissue layers (50-70% of cases, may need serial sections to detect), usually adjacent to blood vessels or lymphatics, disease is focal with intervening normal mucosa in bowel and throughout GI tract (mouth to anus); goblet cells present; initially focal neutrophils in epithelium and overlying lymphoid aggregates and plasmacytosis, then cryptitis, crypt abscesses, but usually no neutrophils in lamina propria

Mucosa and submucosa are also edematous

Often reduplication of muscularis mucosa in diseased segments, fibrosis, and thickened bowel wall; may have neuronal hyperplasia; variable Paneth cells and pyloric gland metaplasia

Aphthous ulcer: lymphoid follicle with surface erosion

Note: Crohn’s disease of colon resembles ulcerative colitis, but Crohn’s also has fistulas / sinus tracts, skip lesions, deep ulcerations, marked lymphocytic infiltration, serositis, granulomas, fewer plasma cells

Definitive diagnosis (per Sternberg): transmural lymphoid aggregates in areas not deeply ulcerated, nonnecrotizing granulomas; suggestive features are skip lesions, linear ulcers, cobblestoning, fat wrapping or terminal ileum inflammation

Often requires multiple biopsies; difficult to diagnosis without terminal ileum involvement

Other diagnostic criteria: transmural lymphoid aggregates in areas that are not deeply ulcerated or nonnecrotizing granulomas

DD: ulcerative colitis (abnormal rectal biopsy, not transmural, no fissures / fistulas, no granulomas but occasionally may have granulomas around ruptured cysts; may have patchy disease, ileal inflammation, aphthous ulcers or transmural inflammation), ischemic bowel disease, tuberculosis

References: Mod Path 2003;16:347, Wikipedia, eMedicine #1, #2

Crohn’s disease associated carcinoma in colon

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Preceded by same dysplastic changes as in ulcerative colitis

May occur in out of circuit or bypassed segments

Reported risk of colon carcinoma varies from minimal (Aliment Pharmacol Ther 2004;19:287) to less than 1% (Hepatogastroenterology 2000;47:57) to 3% (Cancer 2001;91:854); carcinoma present in 3% of colons resected for severe Crohn’s colitis (Dis Colon Rectum 2006;49:950)

Risk factors are long duration and severe disease; screening colonoscopy is recommended (Gastroenterology 2001;120:820)

Diagnosis is usually made endoscopically as a gross intraluminal lesion, usually solitary; tumor has better prognosis than ileal carcinomas, similar to other colonic carcinomas with same stage

Case reports: mixed adenocarcinoma-carcinoid tumor (J Clin Pathol 1993;46:183)

Indeterminate colitis

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Diagnosis when cannot distinguish between Crohn’s and ulcerative colitis (J Clin Pathol 1978;31:567-original designation)

Not a specific disease entity as it has no diagnostic criteria

5-15% of cases of inflammatory bowel disease; up to 30% of pediatric cases (Inflamm Bowel Dis 2006;12:258)

Originally related to fulminant colitis requiring emergent colectomy, in which classic featuresof ulcerative colitis or Crohn’s disease were obscuredby severe ulceration with early superficial fissuring,transmural lymphoid aggregates and relative rectal sparing

Currently often used when definitive diagnosis cannot be made at colonoscopy, biopsy or colectomy

Most patients evolve to a definite diagnosis at follow up

Pouch complication (43%) and removal (10%) rates are less than Crohn’s disease, more than ulcerative colitis (Dis Colon Rectum 2005;48:1542)

Pediatric cases rapidly progress to pancolitis

References: J Clin Pathol 2004;57:1233

Dysplasia in inflammatory bowel disease

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Usually detected by surveillance colonoscopy with biopsy

Multiple biopsies recommended for diagnosis of flat lesions

Precedes carcinoma in almost all cases

Incidence of dysplasia is 5% after 10 years of UC, 25% after 20 years of UC

Dysplasia is rare (less than 3%) in retained rectal segment after anastomosis

Risk may be reduced by 5-aminosalicylate use (Am J Gastroenterol 2005;100:1345)

Recommendations for biopsy interpretation: either negative for dysplasia, positive for dysplasia or indefinite for dysplasia

Treatment: colectomy if flat high grade dysplasia (confirmed by another pathologist or another biopsy) or possibly multifocal low grade dysplasia

Adenoma: assume adenomatous changes represent inflammatory bowel disease associated dysplasia; treat with local excision and follow up only if (a) age 40+, (b) pedunculated polyp, (c) complete excision, (d) negative mucosal margin, and (e) no inflammatory polyposis in remainder of colon

Followup: negative for dysplasia - regular surveillance (annual colonoscopy after 7-10 years of disease)

indefinite for dysplasia - more frequent follow up and treatment of active colitis

low grade dysplasia - short term follow up, more frequent if suspicious lesions

high grade dysplasia - follow up needed even after colectomy

Gross: mucosa may be flat, villous or nodular

Micro:

Low grade dysplasia: basally oriented nuclei; mild nuclear enlargement, nuclear crowding and hyperchromasia; decreased intracellular mucin

High grade dysplasia: prominent nuclear stratification (compared to low grade) with many nuclei in luminal half of cell; more significant hyperchromasia and pleomorphism; may have marked architectural distortion with a villous or nodular growth pattern resembling adenoma or with cribriforming

Indefinite for dysplasia: epithelial changes in a background of active inflammation with regeneration

DD: adenoma (occurs in background of normal mucosa, no inflamed mucosa; has typical features of adenoma), reactive epithelial changes (regular nuclear contours, prominent nucleoli, adjacent cryptitis and crypt abscesses, no hyperchromasia, no pleomorphism, no nuclear stratification, no loss of nuclear polarity, no marked architectural distortions)

References: Hum Path 2000;31:288 (comparison with adenoma), J Clin Pathol 1985;38:30 (in ulcerative colitis), USCAP 2002

Ulcerative colitis

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Affects 4-12 per 100,000 in US, usually whites, peak onset ages 20-25 and 70-80 years; no gender preference

Symptoms: relapsing, bloody mucoid diarrhea (stringy mucus) with pain/cramps relieved by defecation; lasts days/months, then remission for months/years; initial attack may cause medical emergency for fluid and electrolyte imbalance

60% have mild disease; 97% have one relapse per 10 year period

30% require colectomy during first 3 years due to uncontrollable disease

Almost always rectal involvement at disease onset, but may develop rectal sparing and patchiness after treatment or chronic disease, resembling Crohn’s colitis (AJCP 2004;122:94)

Moderate to markedly active chronic cecal involvement is associated with backwash ileitis (AJCP 2006;126:1, AJSP 2005;29:1472)

Associated with increased fatty acid synthase expression in both normal and diseased bowel, suggesting that disease extension is greater than normally thought (AJCP 2006;126:113)

Extraintestinal manifestations: migratory polyarthritis, sacroiliitis, ankylosing spondylitis, pyoderma gangrenosum, clubbing of fingertips, primary sclerosing cholangitis, pericholangitis, uveitis, cholangiocarcinoma (rare)

Complications: perforation, toxic megacolon (due to toxic damage to muscularis propria and neural plexus with shutdown of neuromuscular function), iliac vein thrombosis, carcinoma, lymphoma

Skip areas: typically associated with Crohn’s disease, but occur in UC with long term oral or topical therapy; also associated with focal, appendiceal or only left sided disease; initial presentationin pediatric patients may show skip areas

Definitive diagnosis (per Sternberg): diffuse disease limited to colon, rectal involvement with continuous proximal involvement; no skip lesions; no deep fissural ulcers; no transmural sinus tracts, no transmural lymphoid aggregates or granulomas

Case reports: giant inflammatory polyposis causing obstruction (J Gastroenterol 2005;40:536)

Treatment: local or systemic steroids, infliximab (monoclonal antibody to tumor necrosis factor, N Engl J Med 2005;353:2462), total colectomy; note - steroid refractory disease is CMV+ in 25%, often detectable only by immunohistochemistry (AJSP 2004;28:365)

Gross: ulceroinflammatory disease, usually limited to colon, diffuse continuous disease from rectum proximally (pancolitis in some cases), see exceptions above; ileitis and involvement of appendix also occurs in continuity with severe colitis; anal lesions also (fissures, fistulas, skin excoriation, abscess); disease worse distally than proximally; usually no deep fissuring ulceration, no strictures or fistulas, no sinus tract formation, no small intestinal involvement, no serositis, no bowel wall thickening, no fat wrapping

Early - mucosa is hemorrhagic, granular, friable; changes usually diffuse (similar intensity throughout)

Late - extensive ulceration along bowel axis but usually not serpentine as in Crohn’s; have pseudopolyps (isolated islands of regenerating mucosa) and flat mucosa; usually normal wall thickness and normal serosa; severe cases may have megacolon or fibrotic, narrow or shortened colon

Ulcerative colitis of colon - continued

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Micro: affects primarily mucosa and submucosa, except in most severe cases

Active changes include diffuse mononuclear inflammatory infiltrate in lamina propria, crypt abscesses (neutrophils in glandular lumen) and cryptitis but usually no neutrophils in lamina propria and reduced intraepithelial mucin; plasma cells are common at base of crypts (basal plasmacytosis), muscularis mucosa may be exposed by ulceration or be covered by granulation tissue and reepithelialization; submucosal fibrosis present

Chronic changes include architectural glandular disarray (branching and irregular glands, not parallel and not evenly spaced, irregular luminal border; also present in recently diagnosed ulcerative colitis) with reactive epithelial changes (nuclear enlargement, mitotic activity, reduced mucin), glandular atrophy (glands don’t reach muscularis mucosa), hypertrophic muscularis mucosa, mast cells at border with normal mucosa, Paneth cells, hyperplastic endocrine cells, mucosal capillary thrombi; pseudopolyps are composed of granulation tissue, inflamed and hyperemic mucosa, may have multinucleated stromal giant cells (J Clin Pathol 1993;46:874)

Endarteritis obliterans in submucosal arteries (10%)

No granulomas, no fissures, no transmural inflammation (except in fulminant cases), no submucosal edema or inflammation, no neuronal hyperplasia

Definitive diagnostic criteria: diffuse disease limited to colon, involvement of rectum, no transmural lymphoid aggregates or granulomas

Chronic ulcerative colitis in remission: architectural glandular disarray (branching and irregular glands, not parallel, not evenly spaced, irregular luminal border) with reactive epithelial changes (nuclear enlargement, mitotic activity, reduced mucin), glandular atrophy (glands don’t reach muscularis mucosa, reduced number of crypts), hypertrophic muscularis mucosa, Paneth cells; these findings are not specific, must be interpreted with clinical and endoscopic findings

Children: initial rectal biopsies show diffuse architectural abnormalities in fewer (32%) cases, have shorter duration of symptoms (mean 17 weeks) than adults (mean 55 weeks, AJSP 2002;26:1441)

Stomas/pouches: may develop colonic metaplasia and ulcerative colitis-like lesions, including inflammatory polyps

DD: Crohn’s disease of colorectum (often strictures, fistulas and fissures; longitudinal and transverse ulcers, colitis more focal than diffuse, epithelium has straight colonic crypts with cytoplasmic mucin and lymphoid aggregates but no crypt abscesses and minimal mucosal atrophy; inflammation primarily involves submucosa with marked edema, submucosal nonnecrotizing granulomas in 60%, often adjacent to vessels; usually poor response to steroids), indeterminate colitis, normal rectal mucosa (normally some crypt shortening and loss of parallelism but no active colitis), acute self-limited colitis (neutrophils are present in lamina propria but no crypt distortion and no basal plasmacytosis), diverticular disease (rectal sparing, colitis only present in areas of diverticula), eosinophilic colitis (Turk J Gastroenterol 2006;17:53)

References: Mod Path 2003;16:347, Wikipedia, eMedicine #1, #2

Pediatric ulcerative colitis

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More likely than adults to have patchiness of microscopic chronicity (21%), relative or absolute (23%/3%) rectal sparing, relatively normal rectal biopsies; more likely to have initial pancolitis (42%, AJSP 2004;28:190)

Ulcerative colitis associated carcinoma

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Regular colonoscopy with biopsy recommended in patients with long-standing extensive colitis to detect precancerous dysplastic changes

Overall risk of carcinoma is 3-5% at 20 years, 8% at 30 years and 11% at 40 years (Gastroenterology 2006;130:1030, Inflamm Bowel Dis 2006;12:205)

10-20% have multiple tumors (more common in younger individuals)

Usually arises from flat mucosa

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

Crohn’s disease of colon