Colon-tumor
Last revised 16 February 2010
Last major update October 2006
Copyright (c) 2003-2010, PathologyOutlines.com, Inc.
See also Colon-nontumor, Anus and perianal area
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Table of contents
Primary references, images needed
Polyps: general, biopsies, aberrant crypt foci, adenoma, carcinoma arising in adenoma, adenoma-carcinoma sequence, atheroemboli, cap polyposis, displaced glands, diverticular, fibroblastic, flat adenoma, hyperplastic, hyperplastic polyposis, inflammatory, inflammatory fibroid, inflammatory myoglandular, juvenile, lymphoid, Peutz-Jegher, post-surgical, serrated, transitional, tubular adenoma, tubulovillous adenoma, villous adenoma
Familial polyposis syndromes: APC gene, Cowden’s, Cronkhite-Canada, familial adenomatous polyposis-classic, attenuated, Gardner’s, hereditary mixed polyposis, hyperplastic polyposis, juvenile polyposis, Lynch, Muir-Torre, MUTYH associated, Peutz-Jegher, Turcot’s
Carcinoma: general, molecular pathways, WHO classification, post-treatment changes, intramucosal, adenocarcinoma, adenosquamous, carcinosarcoma, clear cell, glassy cell, hepatoid, lymphoepithelioma-like, medullary, metastases to colon, mucinous, neuroendocrine, papillary, signet ring, small cell, small early flat, squamous cell, villous
Carcinoid tumors: rectum, not rectum
Lymphoma and hematopoietic lesions: general, Burkitt’s, follicular, HHV8, Hodgkin’s, MALT, mantle cell, mast cell sarcoma, T cell
Mesenchymal tumors: general, angiomyolipoma, angiosarcoma, endometrial stromal sarcoma, fibromatosis, ganglioneuromatosis, GANT, GIST, hemangioma, histiocytic sarcoma, idiopathic retractile mesenteritis, idiopathic retroperitoneal fibrosis, inflammatory myofibroblastic tumor, Kaposi’s sarcoma, leiomyoma, leiomyomatosis, leiomyomatosis-like lymphangioleiomyomatosis, leiomyosarcoma, lipoma, lipomatosis, liposarcoma, Mullerian adenosarcoma, perineurioma, perivascular epithelioid cell tumor, pyogenic granuloma, reactive nodular fibrous pseudotumor, schwannoma, solitary fibrous tumor
Other tumors: Langerhans cell histiocytosis, Rosai-Dorfman disease, teratoma
Other: grossing, staging, staging-neuroendocrine, features to report
Go to Colon-nontumor (normal, congenital anomalies, diverticular disease, inflammatory bowel disease, colitis (non-infectious and infectious), non-neoplastic non-congenital lesions)
Primary references
AJCC Cancer Staging Manual (7th ed)
American Journal of Clinical Pathology (AJCP), Jan 1975 to October 2006
American Journal of Surgical Pathology (AJSP), March 1977 to September 2006
Archives of Pathology and Laboratory Medicine (Archives), January 1976 to September 2006
Human Pathology (Hum Path), March 1970 to September 2006
Journal of Clinical Pathology, January 1966 to September 2006
Modern Pathology (Mod Path), January 1988 to September 2006
Biomed Center, to 8 September 2006
Mills: Sternberg's Diagnostic Surgical Pathology (4th ed), 2004
Rosai: Rosai and Ackerman's Surgical Pathology (9th ed), 2004
Websites with images: PathoPic, PEIR digital library
Please refer to these primary references for more detailed discussions and photographs
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Gross, EM and immunohistochemistry images are needed for most disorders
Micro images are particularly needed for these lesions:
Polyps - atheroemboli associated, displaced glands, fibroblastic polyp, post-surgical polyp, transitional polyp
Familial polyposis syndromes - Cowden’s syndrome, Cronkhite-Canada syndrome, familial adenomatous polyposis (classic and attenuated), hereditary mixed syndrome, Lynch syndrome, Muir-Torre, MUTYH associated, Turcot’s syndrome
Carcinoma - post-treatment changes, intramucosal carcinoma, adenosquamous, glassy cell, hepatoid, metastases to colon, neuroendocrine, squamous cell
Carcinoid - not rectum
Mesenchymal tumors - leiomyomatosis, reactive nodular fibrous pseudotumor, solitary fibrous tumor
Other tumors - hemangioma, Langerhans cell histiocytosis, Rosai-Dorfman disease, teratoma
Polyps of colon
Polyps-general of colon
Definition: mass protruding into lumen of gut
Sessile: no stalk
Pedunculated: polyp with stalk, may be due to traction on the mass
Polyps that are due to abnormal mucosal maturation, inflammation or architecture are non-neoplastic
Polyps that are due to proliferation and dysplasia are neoplastic / adenomatous
Polypoid lesions may also be due to mucosal or submucosal tumors
Clinical impression correlates poorly with neoplasia (J Gastroenterol Hepatol 2006;21:563)
Appelman recommends calling “benign mucosal polyp” unless (a) diagnosis is adenoma [the only diagnosis that causes clinicians to do anything different] or (b) you can classify it within 30 seconds
Biopsies of colon
Recommended to submit entire biopsy material and cut 3 levels
If clinically is a polyp but microscopically is normal, flipping specimen after melting paraffin block gives definitive diagnosis in 30% of cases (AJSP 2003;27:254)
Deeper levels may reveal polyps in negative biopsies (AJCP 2002;117:424)
Difficult to diagnose carcinoma (i.e. invasion into submucosa) if no submucosa is present
Can diagnose invasion if (a) marked desmoplasia, (b) infiltrative pattern, (c) ulceration or (d) clinical mass lesion
Muciphages, without other abnormalities, have no clinical significance (Histopathology 2000;36:556)
Earliest neoplastic lesion of colon
May predict future adenoma or carcinoma (Am J Gastroenterol 2006;101:1362, Am J Gastroenterol 2005;100:1283)
May be useful to monitor effects of chemoprevention agents (Clin Gastroenterol Hepatol 2005;3:S42)
Micro: crypts are 2-3x larger than normal crypts, are microscopically elevated, have slit-like openings, and have thick epithelial lining that stains darker than normal crypts (particularly with Methylene blue), with large pericryptal zone
Micro images: aberrant crypt foci #1; #2 (methylene blue)
References: Cancer Epidemiol Biomarkers Prev 1991;1:57. World J Gastroenterol 2003;9:2642, Anticancer Res 2006;26:107, summary
Adenoma-general of colon
“Adenoma” is an incorrect term - they are not benign neoplasms, but polypoid areas of epithelial dysplasia
Present in 20% (US) at age 40 years, 50% at age 60; in autopsy studies, almost all have tubular adenomas, <5% have tubulovillous or villous adenomas
Low incidence in developing countries
No gender predilection
Slow growing
Decreased risk of distal colon adenoma associated with dietary fiber intake (Lancet 2003;361:1491), fruit consumption in women (Cancer Res 2006;66:3942); folate intake (J Nutr 2005;135:2468); only weak association between fiber and adenoma recurrence (Am J Gastroenterol 2005;100:2789)
30% develop new polyps after mean 26 month follow up; higher risk if 3 or more adenomas and at least one in proximal colon (Dis Colon Rectum 2004;47:323)
Risk of invasive colorectal adenocarcinoma in the adenoma depends on size: <1% if < 1 cm vs. 10% if > 2 cm; higher risk if villous component
Risk of subsequent carcinoma is related to presence of 3 or more polyps, location at transverse colon or proximal, or [one study] presence of monotonous population of elongated cells (AJSP 2006;30:1120)
Vienna classification (1999) described at J Gastroenterol Hepatol 2006;21:1697.
Treatment: excision of a pedunculated adenoma, even with invasive carcinoma (see below), is considered adequate treatment if margin is negative, there is no vascular or lymphatic invasion and carcinoma is moderate or well differentiated; invasive adenocarcinoma in a sessile polyp requires more than polypectomy
Gross: classified as pedunculated (with stalk), sessile or flat; tubular are red (darker than surrounding mucosa); villous are shaggy with papillary fronds; true margin of resection should be inked when grossing, or can be determined by diathermy artifact
Gross images: pedunculated adenoma #1; #2; #3; #4; #5; sessile adenoma #1; #2
Micro: classify microscopically as tubular, tubulovillous (5%) or villous (1%) adenoma; all contain epithelial proliferative dysplasia; dysplasia can be classified as low grade or high grade, although some GI pathologists recommend not using high grade dysplasia terminology unless clinicians want to know
Low grade: nuclei are elongated and dysplastic, but don’t reach cell surface; apical mucin present
High grade: cytologic and architectural changes of dysplasia; nuclei are enlarged, hyperchromatic or vesicular with prominent nucleoli; nuclei are stratified and reach luminal border; cribriform or irregular budding/branching of crypts is present; prominent mitotic figures; reduced mucin; necrosis may be present; no invasion through muscularis mucosa into submucosa; high grade dysplasia present in 12% of adenomas
Intramucosal carcinoma: invasion of lamina propria only with desmoplastic response; no biologic potential for metastases
References: Am J Gastroenterol 2006;101:255 (prevalence)
Invasive carcinoma arising in a colonic adenoma
Present in 5% of adenomas (G Chir 2001;22:26)
Invasive only if cancer has invaded through muscularis mucosa into submucosa
Recommended to NOT use “carcinoma in situ” terminology in colorectum; use either high grade dysplasia or invasive carcinoma
Can diagnose invasion without identification of submucosa if (a) marked desmoplasia, (b) infiltrative pattern, (c) ulceration or (d) clinical mass lesion
Report type of carcinoma, grade, presence of angiolymphatic invasion (tumor emboli in true endothelial lined channels away from tumor, not retraction artifact), status of resection margins (close to margin is within one high power field or 1-2 mm from diathermy or at diathermy), presence of dysplasia
Sample report #1: poorly differentiated carcinoma arising within an adenoma, extending to resection margin, no angiolymphatic invasion
Sample report #2: moderately differentiated carcinoma arising with an adenoma; tumor 2.5 cm from resection margin, no angiolymphatic invasion
Case reports: adenoma with carcinoma and mixed carcinoid-adenocarcinoma (Pathol Int 2003;53:457), with sarcoid reaction in regional lymph nodes (J Clin Gastroenterol 1999;28:377), squamous cell carcinoma arising in villous adenoma (Hum Path 1988;19:362), metastatic signet ring carcinoma in adenoma (Archives 2003;127:1509)
Treatment: polypectomy probably adequate unless margin involvement, poorly differentiated or angiolymphatic invasion (J Surg Oncol 1987;36:116)
Recurrent disease, nodal metastases or residual local disease: 20% incidence if cancer is near margin, is poorly differentiated or if angiolymphatic invasion is present
Gross images: adenocarcinoma arising in villous adenoma; focal carcinoma in adenoma
Micro images: adenocarcinoma arising in tubular adenoma; arising in villous adenoma; metastatic signet ring adenocarcinoma in adenoma
Adenoma-carcinoma sequence of colon
Well characterized series of histopathologic events associated with distinct molecular alterations
There are two general pathways - chromosomal instability (abnormal number of chromosomes, not diploid) and microsatellite instability (diploid but DNA mismatch repair gene alterations)
Chromosomal instability pathway
Carcinomas arise from accumulation of mutations in various genes that initially cause adenomatous polyps (usually), some of which then acquire addition mutations and become malignant (4-10 mutations required to produce malignant phenotype)
Molecular pathway may vary in each particular tumor
Earliest event often involves APC gene (mutated in familial polyposis)
Other early events are DNA methylation changes (Genes Chromosomes Cancer 2006;45:781), which may cause oncogene activation or tumor suppression gene repression
K-ras (10% of adenomas, 50% of adenomas with severe dysplasia, 50% of carcinomas) occurs in larger but not smaller polyps
DPC4 and DCC (18q21, reduced expression in 70% of carcinomas) occur later
p53 mutations (17p, losses in 70% of carcinomas) occur late
Removing adenomas via screening colonoscopy reduces incidence of colorectal cancer (N Engl J Med 1993;329:1977)
Polyposis syndrome patients have increased risk for carcinoma (nearly 100% for familial polyposis and Gardner’s syndrome)
Villous adenomas have higher malignant risk than tubular adenomas
Microsatellite instability pathway
Some carcinomas arise without a polypoid dysplastic stage (AJCP 2006;125:132); associated with DNA mismatch repair or microsatellite instability
BRAF mutations are also associated with the microsatellite instability pathway (Gut 2004;53:1137)
Polyps with no malignant risk: solitary hyperplastic polyps, juvenile polyps and Peutz-Jegher polyps
Diagrams: diagram #1; #2
References: eMedicine (#413), BMJ 2000;321:886
Atheroemboli associated polyps of colon
May be associated with rectal bleeding (AJSP 1991;15:1078)
Case reports: 68 year old man with diabetes and 2 year history of bloody diarrhea (AJSP 1993;17:1054), polypoid mass without clinical evidence of ischemia (Archives 1994;118:308), cholesterol emboli in polyp (J Clin Gastroenterol 1994;19:231)
Micro: edematous submucosa with superficial ulceration and atheroemboli in arterioles of submucosal polyps
First described in 1985 (Br J Surg 1985; 72 (Suppl) S133)
Rare
Etiology unknown, but may be associated with mucosal prolapse (Gut 1993;34:562)
Often presents with mucoid or bloody diarrhea and hypoproteinemia
Endoscopy: multiple sessile rectosigmoid polyps with adherent white flecks, with normal intervening mucosa (Endoscopy 2001;33:262)
Case reports: Case of the Week #102
Treatment: traditionally polypectomy or partial colectomy (Dis Colon Rectum 2004;47:1208); recent case reports of dramatic results from medical treatment in patients with H. pylori gastritis (Helicobacter 2004;9:651) and using infliximab, an antibody to tumor necrosis alpha (Gastroenterology 2004;126:1868)
Gross: multiple, distinctive, inflammatory rectosigmoid polyps
Gross images: multiple colonic polyps
Micro: inflamed mucosa with tortuous, elongated crypts, attenuated towards the mucosal surface, with granulation tissue ”cap” on the mucosal surface
Micro images: image #1; #2; #3; #4
inflammatory polyp of colon secondary to mucosal prolapse: #1; #2; #3
DD: amebic colitis, antibiotic associated colitis, inflammatory bowel disease
Displaced glands / pseudoinvasion of colon
Also called epithelial misplacement
Presence of dysplastic glands from an adenoma beneath the muscularis mucosa due to biopsy related torsion or other trauma
A low power diagnosis
Occurs in 3% of adenomas, usually with well-defined stalks
Resembles intramucosal carcinoma, but cytologic features resemble adenoma
See also below (hyperplastic polyp with misplaced epithelium)
Micro: submucosal glands surrounded by loose inflamed stroma and granulation tissue, but not desmoplastic stroma; glands may have atypia associated with adenoma but not carcinoma
Negative stains: p53, E-cadherin, type IV collagen (AJSP 2002;26:206)
References: AJSP 1993;17:1262, Cancer 1974;33:206
Diverticular polyp of colon
Arises in background of diverticular disease
Usually in sigmoid colon
Part of the “mucosal prolapse” syndrome (Am J Gastroenterol 2002;97:370)
Treatment: high fiber diet is usually effective (Endoscopy 1986;18:84)
Gross: redundant or polypoid mucosal folds
Micro: mucosal hemorrhage and congestion, epithelial hyperplasia with dilated and serrated crypts and bizarre nuclei in stroma, mucosal edema, fibromuscular replacement of lamina propria with thickened and splayed muscularis mucosa; no dysplastic changes
Micro images: elongated crypts without dysplasia; figure 3: epithelial hyperplasia, inflammation, congestion and fibromuscular stroma; figure 4: smooth muscle actin staining
References: AJSP 1991;15:871, Histopathology 1993;23:63
Initially described in 2004 (AJSP 2004;28:374)
May be due to exuberant response to tissue injury (J Clin Gastroenterol 2005;39:778)
May be early stage of inflammatory fibrous polyp (AJSP 2004;28:1397-letter)
Solitary, usually in sigmoid colon
Treatment: excision (benign behavior)
Gross: 2-4 mm
Micro: mucosal polyp composed of bland, plump spindle cells in lamina propria with fibroblastic features; spindle cells are associated with muscularis mucosa, cause separation and disorganization of colonic crypts; often associated with serrated / hyperplastic crypts; no atypia, no mitotic activity, no necrosis
Positive stains: vimentin; occasional weak/focal CD34 or smooth muscle actin
Negative stains: desmin, CD31, CD68, bcl2, c-kit, S100, EMA
EM: sparse cytoplasmic organelles, many intermediate filaments
References: Histopathology 2006;48:431
Flat adenoma of colon
Also called depressed adenoma
Present in asymptomatic populations (Gut 1998;43:229)
More difficult to detect during endoscopy, but targeted indigo carmine chromoscopy or other methods are useful
Diagnosis requires (a) classic endoscopic (gross) appearance of mucosal elevation with flat/rounded surface and height less than half the diameter, (b) not resembling a hyperplastic polyp, and (c) dysplastic changes
Another study defined flat as thickness of 1.3 mm or less or thickness less than twice normal mucosal thickness
Controversial if associated with higher risk for high grade dysplasia (no-Clin Gastroenterol Hepatol 2004;2:905; yes-Dis Colon Rectum 1991;34:981); risk may be higher if central depression, individual history or family history of malignancy (Dis Colon Rectum 2000;43:782), or larger lesion (Dis Colon Rectum 1985;28:847)
Endoscopic images: flat adenoma
Case reports: with deep malignant component (Virchows Arch A Pathol Anat Histopathol 1993;422:415)
Gross: flat or slightly raised plaques, often with a central depression; usually height 2 mm or less; may be multiple
Micro: plaque-like, not polypoid or exophytic; up to twice the thickness of adjacent normal epithelium; usually tubular adenomas that show superficial adenomatous changes at periphery, and centrally may extend throughout the crypt
Also associated with aberrant crypt foci (Am J Gastroenterol 2005;100:1283)
Micro images: flat adenoma; A: flat adenoma; B: MUC2+; C: MUC1+ only focally; A: flat adenoma; B: MUC2+; C: MUC1+ at base of crypts; MUC2-left; MUC1-right
Molecular: some cases have multiple APC mutations (Eur J Hum Genet 1999;7:928)
References: Hum Path 1991;22:70, Am J Gastroenterol 2006;101:172
Hyperplastic polyp of colon
90% of all polyps
Usually patients age 50+ years, often in rectosigmoid
Present in 30-50% of normal individuals (85% of adults in Western world versus 2% in third world countries)
Due to delayed shedding of surface epithelial cells
Associated with cigarette smoking (Cancer Causes Control 2005;16:1021)
Previously considered to have no/minimal malignant potential (Arch Intern Med 2005;165:382), except for those in hyperplastic polyposis syndrome
Right sided hyperplastic polyps are molecularly more similar to serrated adenomas than to left sided hyperplastic polyps, and are associated with cancers that show microsatellite instability (but see J Clin Pathol 2004;57:1089)
Intermediate (6-9 mm) sized polyps are usually right sided, and are associated with synchronous colorectal carcinoma (J Gastroenterol Hepatol 2005;20:1572)
Case reports: with small invasive carcinoma (Endoscopy 2004;36:825)
Gross: small (< 5 mm), sessile, usually on top of mucosal folds, multiple, same color as surrounding mucosa; lesions up to several cm may occur in right colon but may be serrated adenomas
Gross images: hyperplastic polyp
Micro: well formed, elongated glands and crypts with serrated (saw tooth) or star-shaped appearance resembling secretory endometrium; mixture of goblet cells (with abundant mucin) and absorptive cells; bland cytology with eosinophilic cytoplasm, well defined brush borders, basal nuclei; thickened basement membrane; Paneth cells in 8%; may have multinucleated giant cells (AJSP 2005;29:912); cells at base of crypt may have nuclear elongation, crowding and increased mitotic rate, but this is not adenomatous change; may be splaying of muscularis mucosa fibers into submucosa; large hyperplastic polyps may have adenomatous foci
Micro images: serrated crypts #1; #2; #3; #4; #5; #6; right sided vs. left sided polyps
Virtual slides: hyperplastic polyp
Molecular: limited changes, no relation to changes in coexisting adenomas (J Clin Pathol 2004;57:1084)
Hyperplastic polyp of colon with misplaced epithelium
Also called “pseudoinvasion”
Some authorities consider it synonymous to inverted hyperplastic polyp, but others consider them different
Simulates adenoma with pseudoinvasion, but benign
Arises in left colon due to local trauma (torsion or twisting of polyp, vigorous peristalsis)
Micro: colonic epithelium in lamina propria with mixed pattern (lobules and irregularly distributed crypts) or lobular pattern; continuous with mucosal portion of polyp in deeper levels; defects are present in muscularis mucosa, and muscle fibers are splayed round misplaced epithelium; often lymphoid aggregates adjacent to misplaced epithelium, fresh hemorrhage, vascular congestion, hemosiderin deposits; usually no significant inflammation, no dysplasia
Micro images: misplaced epithelium #1; #2; #3; #4; Ki67/MIB1; collagen IV
Positive stains for misplaced epithelium: Ki-67, E-cadherin, collagen IV basement membrane
References: Mod Path 2001;14:869
Inverted hyperplastic polyp of colon
More frequent in right colon
May be more common in women
Case reports: associated with adenoma (Eur J Gastroenterol Hepatol 2004;16:107), inverted hyperplastic polyposis (J Clin Pathol 1993;46:56)
Gross images: inverted polyposis
Micro: endophytic growth pattern, penetrates muscularis mucosa (AJSP 1985;9:265)
Micro images - inverted polyps #1; #2 associated with submucosal adipose; #3-large submucosal mucin cyst; #4 with epithelial displacement to lymphoid follicle; CEA+ (normal colon at upper right is CEA neg)
Hyperplastic polyposis of colon
Uncommon
Also called serrated adenomatous polyposis because polyps appear to be serrated adenomas
WHO definition: (a) at least 5 histologically diagnosed hyperplastic polyps proximal to sigmoid colon, two of which are larger than 1 cm; or (b) any number of hyperplastic polyps proximal to sigmoid colon in patients with a first-degree relative with hyperplastic polyposis; or (c) more than 30 hyperplastic polyps of any size distributed throughout colorectum (Hyperplastic polyposis. Lyon: IARC Press; 2000)
High risk for colorectal carcinoma (Dis Colon Rectum 2004;47:2101, AJSP 2001;25:177); regular surveillance is recommended (Am J Gastroenterol 2004;99:2012), including family members
Case reports: associated with two synchronous carcinomas (Am J Pathol 2000;157:385), inverted hyperplastic polyposis (J Clin Pathol. 1993;46:56)
Gross: polyps are usually sessile
Gross images: inverted polyposis
Micro images: serrated adenoma in hyperplastic polyposis #1; #2; #3; associated with synchronous carcinoma
inverted hyperplastic polyps - #1; #2 associated with submucosal adipose; #3-large submucosal mucin cyst; #4 with epithelial displacement to lymphoid follicle; CEA+ (normal colon at upper right is CEA negative)
Molecular: extensive methylation in adenomas and in normal mucosa (Gut 2006;55:1467)
Inflammatory polyp of colon
Inflamed regenerating mucosa surrounded by ulcerated tissue; also granulation tissue overlying epithelium
Associated with Crohn’s disease or ulcerative colitis; also amebiasis, schistosomiasis, ulcer, anastomotic sites
Usually asymptomatic but may cause obstruction or hemorrhage
Benign; no increased risk of dysplasia compared to surrounding mucosa, although patients with inflammatory polyposis due to ulcerative colitis have an increased risk of dysplasia, usually in flat lesions
Case reports: with ischemia (Am Surg 1993;59:315), with schistosomiasis (J Clin Gastroenterol 1983;5:169), simulating carcinoma due to multiple fused polyps (Am J Gastroenterol 1980;73:441)
Endoscopic images: inflammatory polyps in ulcerative colitis
Treatment: treat underlying inflammatory condition
Gross: smooth hyperemic or hypervascular appearance; variable surface erosion
Gross images: inflammatory pseudopolyps in ulcerative colitis #1; #2
Micro: inflamed lamina propria and distorted colonic epithelium (branched, tortuous, elongated or cystic crypts); may have surface erosion, congestion/hemorrhage or crypt abscesses; may have bizarre stromal changes in reactive fibroblasts resembling sarcoma in a fibroblastic or granulation tissue stroma, particularly underneath areas of ulceration; no/few mitotic figures, no atypical mitotic figures, often zonation
Micro images: ulcerative colitis #1; #2; #3; annotated images; bizarre stromal cells
Positive stains: vimentin
Negative stains: S100, cytokeratin, CMV
DD: pyogenic granuloma (Ann Diagn Pathol 2005;9:106)
Giant inflammatory polyp / polyposis of colon
Definition: inflammation and polyps at least 1.5 cm
Also called filiform polyposis if have long finger-like projections
Uncommon, benign
Usually associated with inflammatory bowel disease
May be diffuse (Archives 2004;128:1286)
May cause obstruction (J Gastroenterol 2005;40:536, Intern Med 1996;35:24) or intussusception (Inflamm Bowel Dis 2004;10:41),
Case reports: 40 year old man with rectal bleeding (Case of the Week #147), no history of colonic disease (Gastroenterol Clin Biol 2006;30:913, Neth J Surg 1987;39:95), with cystic fibrosis and Crohn’s disease (Pediatr Dev Pathol 2006;9:25), with Crohn’s disease (Pathol Int 2002;52:318), remission after topical budesonide (Anticancer Res 2005;25:2961)
Treatment: usually surgery (Z Gastroenterol 2000;38:845) since cannot clinically distinguish dysplastic and inflammatory polyps
Gross images: associated with protein losing enteropathy; various images
Case of the Week #147 - #1; #2
Micro images: various images; Case of the Week #147 - #1; #2; #3; #4; figure 6
EM: fibroblasts, myofibroblasts, mast cells and lymphocytes, collagen fibers, capillaries, venules and hypertrophic autonomous nerve plexuses; also remnants of original epithelium and smooth muscle cells (Dis Colon Rectum 1990;33:773)
References: AJSP 1986;10:420
Inflammatory polyp of colon secondary to mucosal prolapse
Includes inflammatory cap polyposis and diverticular polyp (AJSP 1991;15:871)
Usually rectosigmoid
Associated with chronic straining
Median age 20 years in one study; associated with rectal bleeding and mucous diarrhea (Dis Colon Rectum 2004;47:1208)
Represented 1/3 of inflammatory polyps in children in one study (Arkh Patol 2003;65:29)
Different mucins are expressed than normal colon (Gut 1998;42:135)
Case reports: Japanese woman with polyps throughout colon (Gut 2005;54:1342), associated with protein losing enteropathy (Am J Gastroenterol 2000;95:2095)
Treatment: polypectomy; patients with multiple polyps or other pathology may require resection; infliximab (Gastroenterology 2004;126:1868) and Helicobacter treatment may be useful (Helicobacter 2004;9:651)
Gross: sessile polyp covered by cap of fibrinopurulent exudate
Micro: crypts are elongated, tortuous and distended with goblet cell hypertrophy and serrated tubules; eroded surface with fibrinopurulent inflammatory cap overlying acute and chronically inflamed stroma with fibromuscular obliteration of lamina propria and proliferation of muscularis mucosa
Micro images: figure 3; staining for non-sulfated mucins
EM images: thick superficial layer of mucus
References: Am J Gastroenterol 2002;97:370, Histopathology 1993;23:63
Inflammatory fibroid polyp of colon
Uncommon in colon
Any age, no clinical associations
Benign
Treatment: endoscopic excision if small (Intern Med 2000;39:25), resection if large
Case reports: 40 year old man with positive fecal occult blood test (Dig Liver Dis 2005;37:968), causing intussusception (Dis Colon Rectum 1979;22:575), with neurofibromatosis (Ann Acad Med Singapore 2004;33:797)
Gross: mean 3-4 cm, polypoid with broad base; tan-gray-yellow; overlying mucosa may be ulcerated
Gross images: small bowel
Micro: usually limited to submucosa; spindle cell lesion in fibrovascular stroma with chronic inflammatory infiltrate including eosinophils; may be sparsely cellular with myxoid stroma; cellular areas may have up to 2 mitotic figures/HPF; may have rarefaction (zone of loose connective tissue) around muscular-walled blood vessels
Micro images: small bowel; figures 2-3; figure 2; figure 3
Positive stains: vimentin, muscle specific actin, smooth muscle actin, CD34;
variable S100
Negative stains: desmin, CD117
DD: fibromatosis (invades bowel secondarily), arteriovenous malformation (J Gastroenter 2004;39:575)
Inflammatory myoglandular polyp of colon
Mean age 53 years
Distal colon; rarely in ileum where it may cause intussusception
Associated with mucous diarrhea, tenesmus and hematochezia
Case reports: 80 year old man (Turk J Gastroenterol 2004;15:117), with rectal bleeding (Pathol Res Pract 2003;199:837)
Gross: solitary, pedunculated, red with smooth surface (Endoscopy 2003;35:363)
Micro: inflammatory granulation tissue in lamina propria, branching and dilated glands arising within proliferating smooth muscle (resembling Peutz-Jegher polyp)
Micro images: inflammatory granulation tissue and prominent smooth muscle
DD: inflammatory polyp (no abundant smooth muscle), Peutz-Jegher polyp (no prominent inflammation)
References: AJSP 1992;16:772
Juvenile (retention) polyp of colon
Most common childhood polyp
Usually children < 5 years, may occur in adults
80% in rectum
Commonly presents with rectal bleeding (Gastroenterol Jpn 1979;14:425); polyps may autoamputate (10%) due to torsion
Usually sporadic; rarely associated with juvenile polyposis syndrome (see below)
Not neoplastic by themselves, but may be associated with dysplasia (Archives 1996;120:1032)
Case reports: in esophageal colon interposition (J Pediatr Surg 1998;33:1418), with intramucosal carcinoma (Archives 1987;111:200), causing intussusception (Postgrad Med 1978;64:188)
Gross: hamartomatous, large (1-3 cm) lesions with long (1-2 cm) stalks, red granular or glistening surface; may see cystic cavities
Gross images: prolapsing through rectum; multiple polyps; cross section
Micro: granulation tissue and ulcer covering abundant cystically dilated glands filled with mucus in an edematous and inflamed stroma; 20% have hyperplastic changes; minimal epithelium or smooth muscle; no atypia; rarely osseous metaplasia, foreign-body giant cell reaction to ruptured glands
Micro images: cystically dilated glands and inflammation #1; #2; #3; #4; #5
Virtual slides: juvenile polyp
DD: inflammatory polyp
Lymphoid polyp of colon
Also called lymphoid hyperplasia
All ages; may be associated with bleeding or prolapse
Usually solitary, sessile, in rectum
Case reports: 51 year old woman (J Clin Pathol 1997;50:1034), 8 year old boy with lymphoid hyperplasia throughout bowel (Z Gastroenterol 1997;35:271), causing massive bleeding in a transplant patient (Indian J Gastroenterol 1996;15:20)
Treatment: excision
Gross: soft, superficial polyp covered by intact, smooth, gray mucosa; single or multiple
Micro: mucosal or submucosal lymphoid follicles with germinal centers that may distort muscularis mucosa or involve muscularis propria
Micro images: lymphoid follicles infiltrating throughout bowel wall; reactive germinal center
DD: lymphoma
Post-surgical polyp of colon
Develops up to 40 years after uterosigmoidostomy
Features of retention and adenomatous polyp
Case reports: Prog Urol 1996;6:590, Dis Colon Rectum 1988;31:961, Eur Urol 1986;12:360, Am J Gastroenterol 1984;79:453, Cancer 1984;53:1006
Serrated polyp / adenoma of colon
First described in 1990 (AJSP 1990;14:524)
The definition and significance of this entity is not well established
Neoplastic, 1-2% of all polyps
Combination of hyperplastic and adenomatous polyp
Usually in sigmoid colon and rectum (Anticancer Res 2000;20:1141)
Often have microsatellite-instability mutations and DNA methylation; right sided lesions may be precursor of sporadic microsatellite-unstable colorectal carcinoma, particularly if large, multiple and part of giant hyperplastic polyposis (J Natl Cancer Inst 2001;93:1282)
May be associated with attenuated (<100 polyps) familial adenomatous polyposis (Gut 2002;50:402)
Risk of subsequent carcinoma is 5-6% (AJCP 2005;123:349, World J Gastroenterol 2006;12:2770)
6% of colorectal carcinomas are associated with coexisting serrated adenomas (Pathol Int 2001;51:215)
Inhibition of apoptosis in upper and middle crypts of hyperplastic polyps and serrated adenomas may be due to reduced Fas expression and may cause serrated appearance (AJSP 2002;26:249)
Case report: developing into carcinoma within 2 years (J Gastroenterol 2002;37:467), polyp with intraepithelial carcinoma (Pathol Int 2001;51:215), associated with multiple “serrated adenocarcinomas” (J Pathol 2000;190:444)
Gross: mean 6-9 mm
Micro: variable, ranging from clearly adenomatous to resembling a hyperplastic polyp
Proposed definition: surface epithelial nuclear dysplasia (elongation, increased N/C ratio, nucleoli, atypia) and serration of 20%+ of lesional crypts (Mod Path 2003;16:417)
Left sided: have “normal proliferation” - less pronounced adenomatous features; may be vesicular cell type with prominent serration, irregular thickening of muscularis mucosa, decreased or dystrophic goblet cells, mucin in vesicular cells similar to hyperplastic polyp; also goblet cell type with less prominent serration but thick mucosa and thick basal membrane; also mucin poor type (rare) with prominent serration, no mucin
Right sided: usually large, with abundant mucin (intra/extracellular), abnormal proliferation (i.e. adenomatous changes), dilated and distorted crypts, often secondary papillae
Micro images: serrated adenoma #1; #2; #3; #4; #5; #6; #7; #8; #9; #10; #11; serrated adenoma in hyperplastic polyposis #1; #2; #3; pedunculated serrated adenoma with high grade dysplasia; case report; various images
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Virtual slides: serrated adenoma
Positive stains: CK7 and CK20 (Dig Dis Sci 2005;50:1741); similar mucin profiles as hyperplastic polyp and gastric antral mucosa (Pathol Int 2004;54:401), KI-67 (19%, intermediate between hyperplastic polyp and adenoma, proliferation in basal or intermediate [but not superficial] crypts, Pathol Int 2003;53:277); also p53 (29-50%) and hTERT (46-53%) (Scand J Gastroenterol 2002;37:1194), COX2 (Dis Colon Rectum 2001;44:1319)
Molecular: MLH1 and PMS2 is often lost in zones of dysplasia or early carcinoma (AJCP 2006;126:1); K-ras mutations in 40%, particularly in nodular and rectal lesions (Dis Colon Rectum 2003;46:327); more highly methylated than tubular adenomas (Am J Pathol 2003;162:815), often BRAF mutations (Virchows Arch 2005;447:597, Cancer Res 2003;63:4878)
DD: adenoma, hyperplastic polyp, colchicine effect (Archives 2002;126:615)
References: AJSP 2003;27:65, Batts: USCAP 2004
Serrated polyp of colon with abnormal proliferation
Also called sessile serrated adenoma
Precedes microsatellite-unstable adenocarcinoma (AJCP 2003;119:778)
MIB staining not helpful in differentiating (AJCP 2006;125:407)
Cases with focal invasive adenocarcinoma or high grade dysplasia: most of polyp is nonmalignant, with abrupt transition to malignancy; hMLH1 negative (AJCP 2006;125:132)
Micro: expanded crypt proliferative zone, exaggerated serrated architectural outline in basilar crypt region, basilar crypt dilation, inverted crypts, and predominance of dysmaturational crypts (crypts with minimal cell maturation); also horizontal extension of the crypt base along the muscularis mucosa J Clin Pathol 2004;57:682)
Micro images: sessile serrated adenoma #1; #2; #3; #4; #5; ascending colon - #6; #7; #8; cecum - #9; #10; #11
Positive stains: Ki-67, Kras, BRAF and methylation present, but this does not distinguish these polyps from traditional hyperplastic polyps (AJCP 2006;125:407) or serrated adenomas (AJSP 2004;28:1452)
Negative stains: p53 (usually); reduced expression of hMHL1 and hMSH2 (AJSP 2003;27:65)
Virtual slides: serrated adenoma with abnormal proliferation
References: Cesk Patol 2006;42:133
Only rarely described
Resemble transitional mucosa surrounding carcinoma and adenoma in the colon (Pathol Res Pract 1987;182:690)
Gross: small polypoid lesion
Micro: elongated and widened crypts, enlarged goblet cells, increased mucin
Positive stains: sialomucins
References: Endoscopy 1982;14:174
Tubular adenoma of colon
90% of GI tubular adenomas occur in colon; also stomach and small intestine
50% are single
Prevalence of 30% in adults at autopsy, increasing with age
Risk of subsequent adenomas or colorectal carcinoma is related to size; higher risk if 6-10 mm or larger, multiple adenomas or family history (Ann Intern Med 1998;129:273, Gut 2002;51:424)
May bleed due to twisting; large polyps may cause change in bowel habits or intussusception
Associated with hypertriglyceridemia (World J Gastroenterol 2006;12:1261)
Case reports: osseous metaplasia (J Clin Pathol 2005;58:220), metastatic signet ring cell carcinoma in adenoma (Pathol Res Pract 2004;200:707, Archives 2003;127:1509), metastatic melanoma in adenoma (Dis Colon Rectum 2002;45:1681)
Gross: usually < 1 cm and pedunculated, but may be sessile; darker color than surrounding mucosa; multiple polyps tend to cluster
Gross images: tubular adenoma #1; #2; hemorrhagic surface; multiple cecal polyps
Micro: increased number of glands and cells per unit area compared to normal mucosa; cells are crowded with hyperchromatic nuclei, increased mitoses (some atypical); mucin production usually decreased; changes first affect superficial portion of glands; dysplasia from mild to severe (carcinoma in situ); rarely biotin-containing clear nuclei, squamous metaplasia (J Surg Oncol 1984;26:130), Paneth cells, cytoplasmic clear cells (Histopathology 1999;34:250), endocrine cells, malakoplakia
Micro images: tubular adenoma #1; #2; #3; compared to normal mucosa; with osseous metaplasia
Virtual slides: tubular adenoma #1; #2; #3
Positive stains: bcl2 (almost all cases), increased CEA (in atypical areas)
Negative stains: p53 (usually)
Molecular: 1/3 are aneuploid
Tubulovillous adenoma of colon
At least 25% of each component; some define as approximately equal amounts of both components
May present with liver abscess (World J Gastroenterol 2006;12:990)
Case reports: causing intussusception (World J Gastroenterol 2006;12:146, Surg Today 2000;30:441), associated with malakoplakia (Ann Diagn Pathol 2004;8:364), with metastatic epithelioid angiosarcoma (Tumori 2005;91:210), overlying small cell carcinoma (Archives 2005;129:412), with gastric heterotopia (N J Med 1995;92:512)
Gross images: tubulovillous adenoma #1
Micro images: tubulovillous adenoma #1; #2; #3; #4; #5; #6; #7; #8; with high grade dysplasia
Villous adenoma of colon
Older adults, commonly in rectum or rectosigmoid
Less frequent than tubular adenoma
May invade directly into colon wall since no stalk is present to serve as buffer zone
Higher risk of malignancy than tubular adenoma; 40% risk if sessile and > 4 cm
Case reports: mimicking carcinoma (Turk J Gastroenterol 2004;15:270), associated with fluid and electrolyte imbalances (Ugeskr Laeger 2000;162:4272, Ann Surg 1964;159:604), associated with bowel perforation (Dis Colon Rectum 1997;40:244)
Treatment: local excision if small; may need larger surgery to completely excise, even if benign
Endoscopy: video
Gross: soft, usually large and sessile with papillary villous projections, large base and no stalk, may encircle the bowel
Gross images: villous adenoma #1; #2; #3-flat; #4-with associated adenocarcinoma
Micro: long fronds of papillary / villous projections arising directly from mucosal surface
Micro images: villous adenoma #1; #2; #3; #4; #5; various images; high power #1; #2
Virtual slides: villous adenoma
References: eMedicine
Familial polyposis syndromes of colon
Adenomatous polyposis coli (APC) gene and colon
Tumor suppressor gene with important role in familial adenomatous polyposis and Gardner syndromes
Mutated in most non-familial colon cancers; most colon tumors without APC mutations show mutations in beta-catenin
APC is a gatekeeper gene since it directs the downstream activity of different pathways
APC antagonizes the Wnt effector beta-catenin by promoting its proteosomal destruction, which directs beta-catenin away from the Tcf-Lef pathway (Dev Cell 2004;7:677)
Mutations in APC promote the Tcf-Lef pathway, and also inhibit the cellular adhesion complex; overall, this stimulates cell proliferation (Mol Cancer 2003;2:41)
Drawings: APC pathway
References: Entrez Gene, University of Washington
Cowden's syndrome and colon
Also known as multiple hamartoma syndrome and PTEN hamartoma-tumor syndrome
Bannayan-Riley-Ruvalcaba syndrome (OMIM 153480) is also associated with PTEN mutations
Autosomal dominant (with incomplete penetrance and variable expressivity) with facial tricholemmomas, acral keratoses, oral mucosal papillomas and colorectal polyps (Clin Genet 1986;29:222)
Patients have increased risk of malignancy (breast and thyroid cancer), but low rate of GI adenomatous polyps or GI malignancy (J Clin Gastroenterol 1986;8:576)
Micro: hamartomatous features with disorganization, proliferation and splaying of muscularis mucosa; polyps have same histology as mucosal prolapse syndromes (colitis cystica profunda)
Molecular: germline PTEN mutations in 70-80%
DD: Peutz-Jeghers
References: eMedicine, OMIM 158350, J Clin Oncol 2004;22:2954 (PTEN)
Cronkhite-Canada syndrome and colon
Rare, non-hereditary disorder of multiple GI juvenile type polyps, usually colonic, associated with ectodermal changes (alopecia, nail atrophy, hyperpigmentation), protein losing enteropathy with associated diarrhea, weight loss, abdominal pain, weakness and anorexia
Polyps affect stomach, colorectum, small intestine
Usually age 50-60 years
Poor prognosis due to GI polyposis and nutritional complications; up to 50% may have remissions
15% develop colon carcinoma (Surg Today 1997;27:345)
Case reports: with adenoma containing focus of carcinoma (Indian J Gastroenterol 2003;22:189), with p53 but not APC or K-ras mutations (Z Gastroenterol 2001;39:365), use of nuclear medicine scan to locate areas of protein losing enteropathy (Dis Colon Rectum 2005;48:870), acute brain syndrome due to malabsorption (Psychiatr Danub 2005;17:90), 17 year old (Eur J Gastroenterol Hepatol 2005;17:1139)
Micro: multiple juvenile-type polyps with broad sessile base, cystically dilated glands filled with proteinaceous fluid or inspissated mucus, expanded edematous lamina propria (Am J Gastroenterol 1988;83:772); often are serrated adenomas (Digestion 2004;69:57); may have surface erosions and eosinophilic infiltrate; typically no dysplasia (AJSP 1989;13:940); mucosa between polyps also has dilated glands, edema, congestion and inflammation
Micro images: esophagus-stomach - (1) polyp on left resembles hyperplastic polyp; two polyps on right have smooth surfaces like juvenile polyps; (2) smooth surface with expanded and cellular lamina propria; (3) smooth surface with residual clustered glands, lamina propria is expanded and edematous with apparent smooth muscle cells and fibroblasts, inflammatory cells and distorted and dilated pits
duodenum / small intestine - elongated, irregular and cystic crypts lined by attenuated epithelium; lamina propria has mixed inflammatory cell infiltrate; eosinophilic infiltrate
References: eMedicine #1; #2
Familial adenomatous polyposis of colon-classic
Also known as familial polyposis coli
Due to defect in APC gene at 5q21
Autosomal dominant trait with high degree of penetrance
Polyposis patients without APC mutations often have mutations in MYH gene (see below)
Incidence of 1 per 8-30,000 individuals, 20% represent a new mutation
100% progress to colonic adenocarcinoma, often in teens, most by thirties
Patients have >100 colon polyps (usually thousands), beginning as teenagers; most are tubular adenomas
Polyps in children may have severe dysplasia (J Pediatr Surg 2006;41:658)
Polyps may also occur in stomach (fundic gland polyps) and small intestine, although most ileal lesions are lymphoid hyperplasia not adenomas
May also develop carcinoma of thyroid gland, gallbladder and adrenal gland; also desmoid tumors (10-25%)
APC mutations may cause expansion of crypt base cell population, including crypt stem cells; mutant crypt stem cells may clonally expand to form adenomas and carcinomas (Am J Pathol 2004;165:1489)
Diagnostic criteria: (a) 100+ colorectal polyps, (b) germ line mutation in APC gene, (c) family history of APC and (d) at least one of epidermoid cyst, osteoma or desmoid tumor
Case reports: cancer in 11 and 12 year old brothers (Eur J Pediatr 2005;164:306)
Treatment: prophylactic colectomy by age 20-25, must monitor rectal stump (if preserved) and possibly upper GI tract; screening of relatives
Gross: small to large adenomas involve entire bowel; may be flat or depressed (Int J Surg Pathol 2006;14:133)
Gross images: extensive polyposis #1; #2; #3
Micro: tubular adenomas that progress to carcinoma; adenomatous epithelium may be present in only a single crypt taken from flat, endoscopically unremarkable mucosa
Gross/micro images: image1
References: eMedicine #769, OMIM 175100, Am J Gastroenterol 2006;101:385
Familial adenomatous polyposis of colon-attenuated FAP (AFAP)
Previously called hereditary flat adenoma syndrome (Dis Colon Rectum 1992;35:411
Usually less than 100 polyps, but high risk for colorectal carcinoma (69% cumulative risk by age 80, Gastroenterology 2004;127:444)
Phenotypically and genetically heterogeneous (Gut 2006;55:1440)
Polyps usually more proximal (i.e. right sided) than in classic FAP; often rectal polyp sparing
Cancers usually develop at age 50-55 years, 15 years later than classic FAP
May develop stomach fundic gland polyps, gastric or small bowel flat adenomas and stomach / duodenal carcinomas (Cancer 1993;71:2709)
Diagnosis: genetic testing is important
Case reports: 60 flat adenomas in proximal colon (Int J Gastrointest Cancer 2003;33:117), 2 early cases (Cancer 1990;66:909), 42 year old presenting with ampullary adenoma
Gross: polyps are flat or slightly raised or plaque-like
Micro images: tubular adenoma
Molecular: germline mutations in 5' and 3' end and exon 9 of APC gene (also biallelic MUTYH mutations, Int J Cancer 2006;119:807)
DD: hereditary nonpolyposis colon cancer (Am J Gastroenterol 2002;97:1822)
References: Fam Cancer 2003;2:43
Gardner’s syndrome and colon
A variant of familial adenomatous polyposis
Incidence of 1 per million in US
Colonic adenomatous polyps plus extraintestinal features of multiple osteomas (skull, mandible, long bones), epidermal cysts, fibromatosis (10%, usually intraabdominal after surgery, aggressive, may cause death), fibromas, lipomas, impacted and supernumerary teeth, dental cysts, congenital hypertrophy of retinal pigment epithelium; also lymphoid polyps of terminal ileum
100% develop colon carcinomas
Due to mutations of APC gene, but with variable penetrance, so all extracolonic features may not be present
Case reports: 11 year old girl presenting with fibromatosis (World J Gastroenterol 2005;11:5408)
Treatment: similar to familial adenomatous polyposis
Gross images: 11 year old girl; mucosa studded with polyps
Micro images: adenoma #1; #2
References: eMedicine #2712, eMedicine #163
Hereditary mixed polyposis syndrome and colon
Uncommon
Autosomal dominant
May be a variant of juvenile polyposis syndrome
Micro: polyps of mixed histologic types (tubular adenomas, villous adenomas, flat adenomas, hyperplastic polyps and atypical juvenile polyps), totaling <15 per patient; most polyps are adenomas
Molecular: due to mutation in bone morphogenesis protein receptor 1A (OMIM 601299) in one family study (J Med Genet 2006;43:e13); 15q13-14 in Ashkenazi Jews (Am J Gastroenterol 2003;98:2317, Am J Hum Genet 2003;72:1261), different haplotype in Singapore (Zhonghua Wei Chang Wai Ke Za Zhi 2005;8:312)
References: OMIM 601228
Hyperplastic polyposis syndrome and colon
See above
Juvenile polyposis syndrome and colon
Also called juvenile polyposis coli
Autosomal dominant with incomplete penetrance
Associated with adenomatous polyps and adenocarcinoma of colon (30-40%), duodenum, stomach and pancreas
Diagnostic criteria: (a) 6 or more colorectal juvenile polyps, (b) juvenile polyps throughout entire GI tract, or (c) any number of polyps in a patient with a family history of juvenile polyposis (Histopathology 1988;13:619)
Rare lethal form occurs in infancy, associated with diarrhea, anemia, hypoalbuminemia
Rarely presents with GI hemorrhage (Am J Gastroenterol 2000;95:543)
Treatment: repeated endoscopic polypectomies and surgery; screening of family members
Micro: polyps have juvenile and adenomatous features; often complex glandular structures
Micro images: dilated glands and inflammatory cells; dilated glands and hyperplastic features; adenomatous changes
Positive stains: often p53 and Ki-67 >50% (Arkh Patol 2004;66:28)
Molecular: often mutations in PTEN, SMAD4/DPC4/MADH4 (19%, J Mol Diagn 2006;8:84), BMPR1A (11%); also deletions in PTEN and BMPR1A (Am J Hum Genet 2006;78:1066); no loss of APC (Pediatr Res 2005;57:4)
References: GeneTests, OMIM 174900
Lynch syndrome and colon
Also known as hereditary non-polyposis colon cancer (HNPCC), because patients have hereditary colon carcinoma but fewer polyps than familial adenomatous polyposis; “HNPCC” terminology has been criticized (World J Gastroenterol 2006;12:4943)
Hereditary disorder due to mutation in mismatch repair gene (see JAMA 2005;294:2195 for report on family tracked for 100 years)
Most common hereditary colorectal carcinoma syndrome (2-5% of all colorectal carcinomas)
Autosomal dominant
80% develop colorectal carcinoma; also increased risk of endometrial carcinoma (33%), ovarian carcinoma (5%), cancers of small bowel, stomach, urinary tract, and brain (Fam Cancer 2005;4:245)
Risk of endometrial carcinoma (33%) and ovarian carcinoma (5%) is reduced by prophylactic surgery (N Engl J Med 2006;354:261)
Molecular: defect in mismatch repair genes (caretaker genes) MLH1 or MSH2 (90%), MSH6 (7-10%) or PMS2 (less common, Gastroenterology 2006;130:312), which proofread DNA replication; associated with microsatellite instability (MSI, microsatellites are dinucleotide repeat sequences, such as (CA)n, normally present in human genome), although MSI is not specific (World J Gastroenterol 2006;12:4745)
MSI is detected by instability at 2 or more of 5 microsatellite markers (MSH2, MLH1 are most common)
Defective mismatch repair genes can be reliably detected (negative staining) by immunohistochemistry (AJCP 2004;122:389, N Engl J Med 2005;352:1851)
Amsterdam I screening criteria (all 4 must be met): 3 or more family members with a confirmed diagnosis of colorectal cancer, one of whom is a first degree (parent, child, sibling) relative of the other two; two successive affected generations; one or more colon cancers diagnosed before age 50; familial adenomatous polyposis has been excluded (Dis Colon Rectum 1991;34:424); these criteria are relatively sensitive but not specific for Lynch syndrome since these patients may lack mismatch repair gene mutations
Amsterdam II criteria (all 4 must be met): 3 or more family members with HNPCC-related cancers, one of whom is a first degree relative of the other two; two successive affected generations; one or more HNPCC-related cancers diagnosed before age 50; familial adenomatous polyposis has been excluded (Gastroenterology 1999;116:1453)
Table of Amsterdam I and II criteria
Revised Bethesda criteria (any criteria must be met): colorectal cancer diagnosed before age 50 years; presence of synchronous or metachronous colorectal cancers or other HNPCC-associated tumors, regardless of age; colorectal cancer with the MSI-H histology diagnosed before age 60 years; colorectal cancer diagnosed in one or more first degree relatives with an HNPCC-related tumor, with one of the cancers being diagnosed before age 50 years; or colorectal cancer diagnosed in 2 or more first or second degree relatives with HNPCC-related tumors, regardless of age, table (J Natl Cancer Inst 2004;96:261)
Screening: full colonoscopy every 1-2 years beginning at age 20-25 years, annual screening for endometrial cancer beginning at age 25-35, annual urinalysis and cytologic examination beginning at age 25, annual skin surveillance, and upper GI endoscopy beginning at age 35 when gastric cancer is part of the family spectrum (JAMA 2006;296:1507)
At colonscopic screening, have similar rate of adenomas as non syndrome patients, but much higher incidence of carcinoma (Gastroenterology 2006;130:1995)
Case reports: colorectal carcinoma and duodenal follicular lymphoma (Mod Path 2000;13:586), urothelial carcinoma of ureter (Archives 2003;127:E60)
Prognosis/treatment: better survival than other adenocarcinomas; 5 FU chemotherapy does not appear to be helpful (Isr Med Assoc J 2005;7:520, Eur J Cancer 2009;45:1890)
Gross: usually proximal colon, 18% multiple, 40% metachronous (multiple separate occurrences)
Micro: tumors tend to be poorly differentiated with abundant mucin and marked lymphocytic infiltration
References: GeneReviews, OMIM 120435
Muir-Torre syndrome and colon
Also called Torre-Muir syndrome
Clinical variant of Lynch syndrome
Rare autosomal dominant disorder with < 100 adenomas, usually in proximal colon
Multiple colorectal tumors associated with multiple sebaceous tumors, keratoacanthomas and basal cell carcinoma
15% of women develop endometrial cancer
Molecular: mutations in MSH2, MLH1 and MSH6
Negative stains: MSH2 and MSH6 in colonic polyps (Arch Dermatol 2006;142:1039), CK15 and MSH2 in sebaceous neoplasms (J Cutan Pathol 2006;33:634, Dermatol Online J 2006;12:4)
References: Hum Path 1995;26:422, eMedicine #275, OMIM 158320
MUTYH/MYH associated polyposis and colon
Gene is at 1p; protein is base excision repair enzyme (Ned Tijdschr Geneeskd 2005;149:2970)
Autosomal recessive
Biallelic patients (mutations in both genes) have multiple adenomas (Hum Mutat 2006;27:1064), 93x excess risk of colorectal carcinoma compared to normal controls, but account for <1% of all cases (Am J Hum Genet 2005;77:112)
Overlaps with familial adenomatous polyposis, although MUTYH patients often had attenuated or atypical phenotype (Int J Cancer 2006;119:807)
Case reports: with duodenal carcinoma (J Clin Pathol 2006 Aug 30; [Epub ahead of print])
References: OMIM 604933
Peutz-Jeghers syndrome and colon
Rare; autosomal dominant with variable penetrance, usually diagnosed in 20’s
Diagnostic criteria: (a) 3+ histologically confirmed Peutz-Jeghers polyps, (b) any Peutz-Jeghers polyp with a family history, (c) characteristic melanotic mucocutaneous pigmentation (lips, oral mucosa, genitalia, digits, palms, soles) with a family history or (d) Peutz-Jegher polyp and characteristic mucocutaneous pigmentation
Hamartomatous polyps are present throughout GI tract excluding esophagus
All patients have small intestinal polyps; 25% involve stomach and colon
Increased risk of cancer from adenomatous polyps other than classic Peutz-Jeghers polyps; however, no apparent increased risk from solitary polyps (Int J Colorectal Dis 2003;18:33)
Very high risk of cancer overall (Gastroenterology 2000;119:1447), with half dying of cancer by age 60
Almost all patients have sex-cord tumor / tumorlet with annular tubules in ovary or testis
Also associated with mucinous tumors, adenoma malignum of cervix and carcinomas of breast, pancreas, lung and uterus
Large polyps may cause intussusception and GI bleeding
Gross: large, lobulated, pedunculated polyps resembling adenomas
Gross images: various images-pages 3, 7, 9-11
Micro: polyps have broad bands of muscularis mucosa smooth muscle fibers in superficial mucosa, thicker centrally than peripherally, with “Christmas tree” appearance at low power; disorganized glands resemble epithelium adjacent to polyp; also Paneth cells; epithelial structures may herniate into bowel wall (pseudoinvasion, more common in small intestine); no atypia
Micro images: figure 1: CT of small intestine shows multiple masses and intussusception; 2/3: core of smooth muscle arising from muscularis mucosa with extensive treelike branching; 4: smooth muscle actin; from small intestine; page 3
Molecular: mutation at 19p13.3 (STK11/LKB1 gene) in 60%
References: eMedicine #1807, GeneReviews, OMIM 175200
Turcot’s syndrome and colon
Pronounced with silent second t (Turcot was French Canadian)
Rare; autosomal recessive variant of familial adenomatous polyposis
CNS tumors (gliomas or glioblastomas) and later familial adenomatous polyposis
May be 2 types - (a) gliomas plus nonpolyposis adenomas with mismatch repair gene mutations and (b) medulloblastomas plus adenomatous polyposis with APC mutations
Case reports: colon carcinoma and astrocytoma (Neurol Med Chir (Tokyo) 2004;44:124), colonic adenocarcinoma and astrocytoma (Neurol Med Chir (Tokyo) 1989;29:606).
Molecular: MLH1, MSH2 and PMS2 germline mutations; also APC (N Engl J Med 1995;332:839)
References: OMIM 276300
Carcinoma of colon
Carcinoma-general of colon
98% of colonic cancers are adenocarcinomas
#2 cause of cancer deaths in US after lung cancer with 185,000 new cases and 55,000 deaths/year
Affects 5% of US population during their lifetime
Most common GI tumor in US; less common in Africa, Asia, parts of South America
Peak age 60-79 years; < 20% before age 50
Note: lymph nodes in rectal carcinoma patients may be involved by prostate cancer as an occult second primary
Risk factors: older age, obesity, physical inactivity, ulcerative colitis, Crohn’s disease, schistosomiasis, polyposis syndrome, family history of colorectal neoplasia, diet
Polyposis syndromes: familial adenomatous polyposis and variants (APC gene), juvenile polyposis (DPC4, PTEN genes), Peutz-Jeghers syndrome (STK11 gene), Lynch syndrome and variants (MSH2, MLH1, PMS1, PMS2, MSH3 and MSH6 genes)
Diet risk factors: low vegetable fiber, high refined carbohydrates, increased beef consumption, decreased Vitamins A, C, E
Low fiber prolongs transit time (toxic oxidative byproducts are in longer contact with colonic mucosa) and alters bacterial flora; beef consumption enhances synthesis of bile acids by liver, which may be converted into carcinogens by bile acid
Screening: endoscopy, guaiac stool examination; serum CEA (elevated levels associated with various carcinomas or liver disease, useful for monitoring recurrences but not sensitive for early tumors)
Symptoms: rectal bleeding, change in bowel habits (alternating diarrhea and constipation), anemia due to blood loss, vague abdominal pain; cecal tumors may mimic appendicitis
Metastases: most commonly to regional lymph nodes and liver; also peritoneum, lung, ovaries; metastases may simulate primary tumors of affected organs
Prognosis: 5 year survival 40-60%; most recurrences are within 2 years
Poor prognostic factors: high stage; high grade / poorly differentiated tumors, positive margins (particularly rectal carcinoma); small cell, mucinous, anaplastic or signet ring subtypes; flat or ulcerative carcinomas tend to invade deeper (and have higher stage) than polypoid carcinomas; also highly infiltrative growth pattern at margin, extensive tumor budding, undifferentiated cells; free tumor cells in peritoneal space (AJCP 2003;119:108), angiolymphatic invasion (particularly outside of bowel wall); perineurial invasion, very young or very old patients; male patients; perforation; elevated serum CEA > 5 ng/ml, reduced claudin 1 expression in Stage II tumors (Mod Path 2005;18:511)
Treatment: resection with endoscopic follow up; local excision for small rectal carcinomas; surgical excision of isolated distant metastases; radiation therapy or chemotherapy
References: Wikipedia
Molecular pathways of colorectal carcinoma
(1) Chromosome instability pathway
80% of carcinomas
Mutations in oncogenes and tumor suppressor genes, including APC, beta catenin, KRAS, BRAF, SMAD4, PTEN, P53 and bax
Have altered total DNA content, cytogenetics aneuploidy and numerous allelic gains and losses
Important in familial adenomatous polyposis and variants (APC gene) and juvenile polyposis (DPC4, PTEN genes)
Alterations in beta catenin pathway appear to be important in ulcerative colitis related and sporadic colon carcinomas (Mod Path 2001;14:29)
RAS signaling pathway (Kras, BRAF, NF1 and RASSF1A) shows dysregulation in at least one gene in 70%+ of colorectal carcinomas (Neoplasia 2008;10:680)
Activating Kras mutations found in 30-40%, associated with poor response to anti-EGFR therapies in primary (Virchows Arch 2008;453:417, N Engl J Med 2008;359:1757) or metastatic disease (J Clin Oncol 2008;26:1626, J Clin Oncol 2008;26:374)
High rate of concordance for Kras status between primaries and metastases (Oncologist 2008 Dec 4 [Epub ahead of print])
Patterns of Kras mutation vary based on germline mismatch repair defects and hMLH1 methylation status (Hum Mol Genet 2004;13:2303)
Updated National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology for Colon Cancer now recommend that tumors from all patients with stage IV disease be tested for the Kras gene; only patients whose tumors have normal (wild-type) Kras should receive cetuximab and panitumumab (news item)
Sources for testing (advertisements): Genzyme (Kras mutation analysis)
(2) Microsatellite instability pathway
15% of carcinomas
Have high (MSI-H) or low levels of instability (MSI-L)
Includes alterations in mismatch repair genes MSH2, MSH6, MLH1, PMS2 and genes whose alterations cause gross chromosomal abnormalities (BUB1, BUBR1, CDC4, Cancer Metastasis Rev 2004;23:11)
Inactivation of both alleles of nucleotide mismatch repair, usually hMSH2 or hMLH1, promotes tumorigenesis
Tumors have numerous nucleotide substitutions and insertion/deletion mutations in repeated nucleotide sequences (microsatellites), normal total DNA content and relatively normal cytogenetics with only infrequent allelic gains/losses
Either germline mutations (Lynch syndrome and variants) or sporadic due to promotion methylation
Includes medullary, mucinous and signet ring carcinoma subtypes
Often present at earlier stage than other colon carcinomas (AJSP 2003;27:1393)
Frequent present in colon/stomach double primaries (Mod Path 2001;14:543
Gross: usually right sided, expansive growth
Micro: tumor infiltrating lymphocytes, peritumoral lymphocytes, no “dirty” necrosis; may be associated with serrated adenomas
(3) MYH pathway
Mutations in both copies of MUTYH / MYH repair gene; not well understood
Biallelic patients (mutations in both genes) have multiple adenomas (Hum Mutat 2006;27:1064), 93x excess risk of colorectal carcinoma compared to normal controls, but account for <1% of all cases (Am J Hum Genet 2005;77:112)
(4) CpG island methylation pathway
30% of carcinomas
Important mechanism of inactivating tumor suppressor genes in chromosomal instability pathway above (Curr Mol Med 2006;6:401, Cancer Metastasis Rev 2004;23:29)
CpG islands are 500 to 2000 base regions rich in cytosine-guanosine dinucleotide repeats present at 5’ region in 50% of human genes; methylation of cytosine residues in promoter regions and proximal exons of these islands represses transcription; may also have methylation of MLH1
Sources for testing (advertisements): Genzyme (colorectal cancer profiles)
References: Howard Hughes Medical Institute
World Health Organization (WHO) classification of colorectal carcinoma
Adenocarcinoma
Adenosquamous carcinoma
Mucinous (colloid) adenocarcinoma
Signet ring cell carcinoma
Small cell carcinoma (oat cell)
Squamous cell carcinoma
Undifferentiated carcinoma
Medullary carcinoma
Other
Post-treatment changes of colonic carcinoma
Preoperative (neoadjuvant) radiation therapy, with or without chemotherapy, is often used to treat rectal adenocarcinoma
Presence of acellular mucin reflects pretreatment tumor
Gross: flat firm mass with central ulceration; may be no identifiable lesion
Micro: regenerated mucosa at edge of ulcer; tumor cells with variable tumor effects of fibrosis, mucin pools, inflammation, necrosis
Positive stains: cytokeratin to detect rare residual tumor cells
Intramucosal carcinoma of colon
Stage Tis
Some of these lesions are also called small flat carcinomas
Controversial terminology - may reflect differing thresholds for malignancy between West (higher threshold) and Japan (lower threshold), as Japanese pathologists diagnose as malignant what West calls high grade dysplastic lesions
Definition: malignant change confined to mucosa; for adenomas, no invasion into submucosal stalk, no undifferentiated carcinoma, no vascular invasion, no desmoplastic stroma
Rosai suggests calling these lesions polyps with severe atypia
Little metastatic potential as there are minimal lymphatic channels in colonic mucosa, so resection is not indicated
If tumor invades stalk of polyp, then bowel resection may be justified
Case reports: juvenile polyp with intramucosal carcinoma (Archives 1987;111:200)
Adenocarcinoma of colon
98% of colonic cancers are adenocarcinomas
Rarely associated with endometriosis and unopposed estrogen therapy (AJSP 2000;24:513); these cases usually involve serosa and spare mucosa, have endometrioid histology and squamous differentiation; important to differentiate since staging and treatment may be different
Only rarely produces pseudomyxoma peritonei, even if mucinous
Right colon tumors: polypoid exophytic masses; anemia, weakness and fatigue are common, but obstruction is uncommon; iron deficiency anemia in older man is presumed to be a GI carcinoma unless proven otherwise
Left sided tumors: annular, encircling lesions (napkin ring constrictions of bowel); diarrhea, obstructive symptoms
Rectosigmoid tumors: usually more advanced at presentation
Poor prognostic factors: high grade, possibly intramural venous invasion (identify with elastic stain, J Clin Pathol 2002;55:17)
Case reports: metastases - cervix in 17 year old girl (J Reprod Med 2005;50:793), ear (Ear Nose Throat J 2005;84:36), kidney (Int J Urol. 2005;12:93), larynx (Acta Otolaryngol 2006;126:661), mandible (Head Neck 2005;27:729), perianal fistula (Int Semin Surg Oncol 2006;3:25), skin (Ann Acad Med Singapore 2006;35:585, Int Semin Surg Oncol 2006;3:2), sphenoid sinus (Otolaryngol Pol 2005;59:429), thyroid gland (Tumori 2006;92:252, Endocr J 2006;53:339),
other - coexistent mantle cell lymphoma (Archives 2003;127:E64), coexisting GIST (Int J Colorectal Dis 2006 Apr 26 [Epub ahead of print]), with enteroliths (Actas Urol Esp 2006;30:206), with hypercalcemia (Surg Today 2005;35:692), with urinary diversion for exstrophy (World J Surg Oncol 2004;2:20)
Gross: usually single; polypoid or ulcerative; may have serosal puckering if muscularis propria involved
Gross images: napkin ring lesion #1; #2; invasion through muscularis propria; exophytic tumor; superficial tumor; rectal tumor; heaped up edges and central ulceration; tattooed sigmoid colon #1; #2; #3; ascending colon #1; #2
Micro: well to poorly differentiated tumor cells with marked desmoplasia, particularly at edge of tumor, often mucin producing; glands often filled with necrotic debris (“dirty necrosis”); inflammatory cells and scattered neuroendocrine cells common (Pol J Pathol 2005;56:89); rarely germ cell elements (Archives 2001;125:558)
Low grade (grade 1): well differentiated, 15-20% of all carcinomas; well formed glands or simple tubules with uniform, basally oriented nuclei, resembles adenomatous epithelium
Moderately differentiated (grade 2): 60-70% of all carcinomas; tubules may be simple, complex or slightly irregular; loss of nuclear polarity
High grade (grade 3): poorly differentiated in 50% or more of tumor (i.e. less than 50% gland formation), 15-20% all of carcinomas; majority of tumor (excluding advancing edge of tumor) is sheets of cells without gland formation; usually right sided (Hepatogastroenterology 2004;51:1698)
Note: preoperative histologic grading is not accurate (J Med Assoc Thai 2005;88:1535)
Micro images: moderately differentiated tumor #1; #2; glands filled with necrotic debris; serosal involvement; venous invasion #1; #2 with elastic stain; #3; mucinous and undifferentiated areas; colloid carcinoma-like area; CEA (figure 2C); CEA, AFP, HCG stains; p53; whole mount scan; signet ring cells; metastatic to lymph node
Virtual slides: adenocarcinoma
Positive stains: CK20, mucin (MUC1 and MUC3), CEA, B72.3, CDX2 (sensitive but not that specific, Hum Path 2006 Aug 10 [Epub ahead of print], AJSP 2003;27:303); also hCG (often), p53, P504S (AJSP 2002;26:926), CD10 (stromal cells), estrogen receptor (Hum Path 2001;32:940 but see AJCP 2000;113:364), villin; may have scattered endocrine cells
Negative stains: CK7, HepPar1, DPC4 (SMAD4), PR (AJCP 2000;113:364), MUC2, MUC5AC
EM: prominent microfilaments perpendicular to cell membrane and entering the brush border
References: Archives 2001;125:1074 (keratin stains), Mod Path 2000;13:962 (CK7, CK20), Hum Path 2002;33:806 (CD10), Clin Cancer Res 2005;11:3766 (algorithm for adenocarcinoma of unknown primary-figure 1C), eMedicine #413, eMedicine #182
Adenosquamous carcinoma of colon
Rare ( 0.1 to 0.2% of colon carcinomas, AJSP 1978;2:47)
Associated with ulcerative colitis
Aggressive behavior (Dis Colon Rectum 1996;39:1265)
Poorer prognosis with advanced disease than adenocarcinoma (Dis Colon Rectum 1999;42:258)
Case reports: tumor of rectosigmoid junction (Am Surg 2006;72:754), with nodal metastases (J Exp Clin Cancer Res 2001;20:293), with hypercalcemia (Int J Clin Oncol 2005;10:144)
Micro: malignant glandular and squamous components
Positive stains: CD44 (squamous component, Archives 2000;124:212)
References: Dis Colon Rectum 2001;44:341
Carcinosarcoma of colon
Also called sarcomatoid carcinoma
Very rare
Aggressive
Case reports: 81 year old man with ascending colon tumor and liver metastases (BMC Cancer 2006;6:185), invading mesentery and omentum (Clin Imaging 2005;29:259), 80 year old woman with recurrent tumor (Surg Today 2003;33:545)
Micro: typical adenocarcinoma plus malignant spindle cells with bony or cartilaginous differentiation
Micro images: various images-PDF file
Positive stains: cytokeratin for both components
Clear cell carcinoma of colon
A minor morphologic variant of adenocarcinoma with intracytoplasmic glycogen
Usually left colon
Usually elderly men
Case reports: associated with endometriosis (J Clin Pathol 2001;54:76), death due to liver metastases (J Clin Pathol 1995;48:1142), 89 year old woman (Int J Colorectal Dis 2004;19:264)
Micro images: glandular arrangement of clear cells #1; #2 with vesicular nuclei and prominent nucleoli
Positive stains: PAS, CEA
Negative stains: mucin
DD: metastatic renal cell carcinoma (CEA-)
Glassy cell carcinoma of colon
Rare in colon; more common in cervix
Considered a poorly differentiated adenosquamous carcinoma
Case reports: hCG production (AJSP 1996;20:187)
Micro: moderate ground glass or finely granular cytoplasm; cell wall is PAS+ and distinct; enlarged nuclei with prominent nucleoli
Micro images: cervix - low power; high power
DD: focal hCG producing adenocarcinoma (more common)
Hepatoid carcinoma of colon
Rare
Elevated serum AFP
Metastases may mimic hepatocellular carcinoma (AJSP 2003;27:1302)
Case reports: tumor with adenocarcinoma and hepatoid areas (Dis Colon Rectum 2003;46:826), with ulcerative colitis (Dis Colon Rectum 2000;43:105), AFP producing tumor (Pathology 1995;27:277)
Micro: adenocarcinoma plus hepatocellular-like carcinoma composed of trabecular or solid pattern of large polygonal cells with abundant eosinophilic or clear cytoplasm; often vascular invasion
Micro images: stomach - cords of liver-like cells separated by sinuses
Positive stains: mucin, polyclonal CEA (cytoplasmic staining in adenocarcinoma and canalicular staining in hepatoid areas)
References: Histopathology 1997;31:47
Lymphoepithelioma-like carcinoma of colon
Very rare in colon
Case reports: rectal tumor associated with EBV (Pathol Res Pract 2001;197:577), in Lynch syndrome with colonic mucinous and well-differentiated adenocarcinomas (Archives 1999;123:720), with tumors at other sites (Dis Colon Rectum 1998;41:925)
Micro: syncytial growth pattern of undifferentiated pleomorphic malignant epithelial cells with ill-defined borders, prominent nucleoli, brisk mitotic activity, prominent stromal and intratumoral lymphoid infiltrate; focal necrosis; infiltrative margins
Micro images: various images; CAM 5.2
bladder - low power; high power
lung - pale islands of tumor cells surrounded by lymphocytes; tumor cells and infiltrating lymphocytes; tumor cells have pale, vesicular nuclei
Positive stains: cytokeratin (AE1/AE3, CAM 5.2), EBV (often), p53 (10% of tumor cells)
Negative stains: mucin (may be focal), neuroendocrine markers, S100
DD: medullary carcinoma (lymphocytic infiltrates are peritumoral, not intratumoral; pushing not infiltrative margins, monomorphic tumor cells)
Medullary carcinoma of colon
Also called undifferentiated carcinoma; a subtype of poorly differentiated adenocarcinoma
<1% of colorectal neoplasms
Often elderly women, right sided tumors
Strongly associated with high degree of microsatellite instability (MSI), indicative of loss of normal DNA repair gene function
Often better clinical outcome independent of stage than microsatellite stable tumors or tumors with low levels of microsatellite instability; usually no/few nodal metastases; may be more sensitive to 5 FU chemotherapy; may have more metachronous colonic carcinomas
Case reports: 79 year old woman with ulcerated cecal tumor (Archives 2005;129:113)
Gross: large with invasion into adjacent organs
Micro: expansive growth pattern of well circumscribed sheets of tumor cells; also nested, organoid, or trabecular patterns, but no/minimal mucin production and no tubule formation; pushing border with prominent lymphocytic infiltration; cells are uniform, polygonal to round, small to medium sized with variable eosinophilic cytoplasm, small/medium nuclei with open chromatin and prominent nucleoli, frequent mitotic activity; neuroendocrine features but negative for neuroendocrine markers
Micro images: large cells with abundant eosinophilic cytoplasm, vesicular nuclei and prominent nucleoli; figure 1-tar black tumor with ulceration, 2-sheets of tumor cells with extensive necrosis, 3-cells have prominent nucleoli, 4-CK+; loss of MSH2 expression;
breast - high grade tumor cells in syncytial pattern #1; #3
Positive stains: keratin, CEA, EMA
Negative stains: neuroendocrine markers, MLH1 and MSH2 (Mod Path 2002;15:741), p53
Flow cytometry: diploid
DD: lymphoepithelioma-like carcinoma
References: AJCP 2005;123:56, Hum Path 1999;30:843
Metastases to colon
Common primaries are lung (large cell), melanoma, prostate (by extension), breast, stomach, ovary
Gross: central ulceration extending towards mucosa, but often sparing it
Micro: no in situ or mucosal malignancy
Primary sites of metastases to colon
Bladder: case report of signet ring carcinoma (Dig Liver Dis 2006;38:609)
Breast: rare (Tech Coloproctol 2004;8 Suppl 1:s135)
Endometrial stromal sarcoma: may resemble GIST but plump spindle cells with invasive tongues at periphery and angiovascular invasion; also CD10+, CD117-
Endometrioid adenocarcinoma: associated with endometriosis
Leukemia: usually involves right colon and terminal ileum; polypoid or transmural infiltrates
Melanoma
May have long time interval between primary and metastases
Case report: unknown primary site (The Internet Journal of Gastroenterology 2006;4: Number 2)
Micro: usually multiple submucosal metastases with normal overlying mucosa; undifferentiated epithelial neoplasm with discohesive cells with pink cytoplasm, large nucleoli
Micro images: melanoma cells in submucosa
Positive stains: HMB45, MelanA/Mart1, S100
Prostate: infiltrative into submucosa; no in situ or intramucosal carcinoma; classic prostate histology; resections for rectal cancer rarely contain nodes with metastatic prostate carcinoma
Stomach: linitis plastica type metastases may resemble poorly differentiated carcinoma (Kaohsiung J Med Sci 2004;20:552)
Mucinous (colloid) carcinoma of colon
Relatively common (10% of all colorectal carcinomas), usually in rectum
Note: this entity is defined as having mucin lakes comprising 50% or more of tumor mass
Associated with microsatellite instability (Cancer 2005;103:2023)
Associated with villous adenomas, ulcerative colitis or other colitis, prior pelvic radiation (Cancer 1976;37:1891)
Usually presents with more advanced stage (Dis Colon Rectum 1993;36:49), greater nodal involvement (Gastroenterol Hepatol 2002;25:534) than nonmucinous tumors, but see J Med Assoc Thai 2006;89:25
Similar prognosis by stage as other carcinomas
Case reports: with perianal fistula (Dig Surg 2003;20:69), 11 year old girl (J Postgrad Med 1993;39:218)
Gross: exophytic, gelatinous
Gross images: cecal tumor #1; #2
Micro: bland tumor cells floating in large extracellular mucin lakes comprising 50%+ of tumor mass; may have signet ring cells (with intracellular mucin)
Micro images: large mucin pools containing tumor cells; various images from breast
DD: signet ring carcinoma (no mucin lakes)
References: Dis Colon Rectum 2005;48:1161
Neuroendocrine carcinoma of colon
Discussion excludes carcinoid tumors and small cell carcinoma (see below)
Rare; highly aggressive with nodal metastases (AJSP 1990;14:1010)
Often high stage at diagnosis (Dis Colon Rectum 2004;47:163)
Mixed neuroendocrine carcinoma-adenocarcinoma also occurs (Virchows Arch 2006;448:644)
Micro: organoid appearance, larger cells than small cell carcinoma, marked nuclear pleomorphism, large irregular hyperchromatic nuclei with prominent nucleoli, frequent mitotic activity, tumor necrosis
Micro images: various images (article in Korean but captions in English); rectal tumor
ampulla of Vater - H&E, chromogranin
cervix - trabecular pattern with mitotic activity #1; #2
Positive stains: cytokeratin, usually EMA, NSE, chromogranin and synaptophysin; c-kit/CD117 in 23% but not associated with activating mutations (AJSP 2003;27:1551)
DD: focal neuroendocrine cells in adenocarcinoma (more common)
References: Korean J Gastroenterol 2006;48:97
Papillary adenocarcinoma of colon
Not in WHO classification; may not be a distinct histologic variant
7% incidence in recent study (Zhonghua Nei Ke Za Zhi 2006;45:9)
Case reports: with psammoma bodies (Jpn J Clin Oncol 1997;27:193, full text), with Paneth cells (Histopathology 1979;3:489)
Gross images: fungated tumor with central ulceration
Micro: arise in polyps, have distinct invasive papillary component
Micro images: (1) left-infolded papillary growth in irregularly arranged glands; right-neoplastic cells have basophilic cytoplasm and large, pleomorphic nuclei; (2) psammoma bodies; (3) hyaline globules
Negative stains: p53, p27 (limited number of cases)
References: Hum Path 2002;33:372
Signet ring carcinoma of colon
Also known as linitis plastica type carcinoma
1% of colonic carcinoma
May affect younger patients than classic colorectal carcinoma (Am J Gastroenterol 1996;91:2195)
Metastases to lymph nodes, peritoneal surface (malignant ascites) and ovary; liver less commonly (ANZ J Surg 2001;71:703)
Usually high stage/poor prognosis (Dis Colon Rectum 2005;48:1161, Dis Colon Rectum 1999;42:1176)
Case reports: foci within adenoma #1 (Archives 1999;123:957), #2 (Archives 2003;127:1509); with metastases to stomach (Mod Path 1989;2:265), early stage (World J Gastroenterol 2006;12:3446), mimicking inflammatory bowel disease (Dig Liver Dis 2005;37:537), incidentally detected with ulcerative colitis (Hepatogastroenterology 1999;46:236), with peritoneal dissemination (J Gastroenterol 2002;37:550), with multiple skin metastases (Kaohsiung J Med Sci 2002;18:359)
Gross: diffuse infiltration of bowel wall; rarely presents as polyp
Micro: diffuse growth of signet ring cells (>50% of tumor cells) with little glandular formation; cells have intracellular mucin that displaces nucleus to side; often linitis plastica appearance
Micro images: various images #1; #2; figure 2; figure 4
Positive stains: CK20, MUC2, villin, CDX2, MUC5AC; variable MUC1 and HepPar1
Negative stains: CK7, ER
DD: metastatic gastric, breast or bladder carcinoma (Dig Liver Dis 2006;38:609), metastatic mucinous carcinoma (Pathol Res Pract 2004;200:707), benign signet ring change with pseudomembranous colitis (Pathol Res Pract 1998;194:197, AJSP 1996;20:599)
References: AJCP 2004;121:884 (immunostains), Appl Immunohistochem Mol Morphol 2000;8:183 (immunostains), Rev Gastroenterol Peru 2004;24:234
Small cell carcinoma of colon
Usually in right colon or cecum
30% arise from villous or other adenoma
Mean age 63 years
<1% of colorectal carcinomas
Poor prognosis due to early metastases to lymph nodes and liver, poor response to therapy
FNA may identify metastatic disease before known primary (Diagn Cytopathol 1996;15:54)
2/3 dead at 5 months historically (AJCP 1991;95:315)
Case reports: with overlying villous adenoma (Archives 2005;129:412), with coexisting adenocarcinoma (Chirurg 2002;73:859), rapid growth after resection (Tohoku J Exp Med 2006;209:361), cecal tumor (Ann Diagn Pathol 2006;10:162), with ulcerative colitis (South Med J 1996;89:921)
Micro: resembles pulmonary tumor; sheets and nests of small round/ovoid cells with minimal cytoplasm, hyperchromatic nuclei with stippled chromatin, nuclear molding with peripheral palisading, usually brisk mitotic activity, apoptotic cells, necrosis and vascular invasion, may have Azzopardi effect (encrustation of nuclear material around blood vessels); adenoma present in 30-40%; may have foci of glandular differentiation with variable mucin production or squamous differentiation; no prominent nucleoli, no pleomorphism
Micro images: H&E, synaptophysin; left-H&E, right-synaptophysin; with overlying villous adenoma (D: synaptophysin+)
Positive stains: neuron-specific enolase (84%), synaptophysin (50%), chromogranin (37%), Leu7 (CD57, 18%)
EM: few dense-core secretory granules
References: Archives 2001;125:1251
Small early flat carcinoma of colon
Controversial entity
In Japan, represents 6-10% of colonic cancers
In US, small flat tumors are usually hyperplastic polyps (AJR Am J Roentgenol 2000;175:747), although adenocarcinomas do occur (Gut 2002;51:550)
May develop from flat adenomas
May be an important precursor of advanced malignancies (Ann Acad Med Singapore 2003;32:263)
Tend to invade submucosa at a smaller size than polypoid lesions (Ann Pathol 2002;22:18)
Tumors with central depression tend to rapidly invade submucosa (Société Internationale de Chirurgie 2000)
Case reports: submucosal tumor (Int J Gastrointest Cancer 2005;36:177), with extensive nodal metastases (Int J Colorectal Dis 2001;16:262)
Gross: flat, plaque like, often with central depression; 1 cm or less; easier to detect with dye spraying of mucosa
Gross images: top-flat lesion with slightly concaved surface
Micro: limited to mucosa or invasive only to submucosa, by definition; height is usually less than twice the height of adjacent normal mucosa; has cytologic features of high grade dysplasia with mild architectural changes
Micro images: invasion of submucosa; bottom-marked submucosal invasion #1; #2; minute focus of submucosal invasion (arrow)
Molecular: frequently early multiple loss of heterozygosity of 17p, 18p, 18q and 22q, coupled with LOH of other loci either simultaneously or in the early clonal progression phase (Ann Oncol 2006;17:43)
Squamous cell carcinoma of colon
Extremely rare
Diagnosis of primary colonic tumor requires no involvement of cloacogenic or squamous lined mucosa, no squamous cell carcinoma elsewhere in body, and generous sampling to exclude adenosquamous carcinoma (Surg Today 1994;24:75)
Associated with ulcerative colitis (J Surg Oncol 1995;59:48), radiation therapy, schistosomiasis
Aggressive (Saudi Med J 2006;27:874); often metastatic to liver, peritoneum or lung
Favorable survival if node negative at presentation (Dis Colon Rectum 2001;44:341
May cause hypercalcemia (Dig Surg 2005;22:371)
Case reports: in villous adenoma (Hum Path 1988;19:362), from colocutaneous fistula (World J Gastroenterol 2005;11:5251), in colon duplication (Cancer 1981;47:602), with elevated serum squamous cell carcinoma antigen (Clin Colorectal Cancer 2001;1:55)
Negative stains: HPV (Eur J Surg Oncol 2002;28:657)
DD: extension or metastasis from anal or other carcinomas (Eur J Cardiothorac Surg 2001;19:719)
Villous adenocarcinoma of colon
5% incidence in one study (World J Gastroenterol 1998;4:527)
Pre-resection biopsies may not be diagnosed as carcinoma
Appear to have a good prognosis
Associated with profound electrolyte disturbance (Ann Surg 1962;156:318)
Gross images: villous tumor with central ulceration
Micro: villous architecture in 50% or more; presence of epithelial islands in desmoplastic stroma is specific and 67% sensitive for carcinoma vs. adenoma (AJSP 2004;28:1460)
Micro images: abrupt transition from benign to malignant mucosa #1; #2
Carcinoid tumors of colon
Most common site of colonic carcinoid is rectum
Annual incidence in USA: 10 per million vs. 500 for adenocarcinoma (Int J Colorectal Dis 2006 Jul 15 [Epub ahead of print])
Rarely is familial (Tech Coloproctol 2006;10:143)
5 year survival is 90% (Cancer 2003;97:934)
Poor prognosis (malignant potential): 2 cm or larger (associated with nodal metastases), invasion of muscularis propria, 2+ mitotic figures/HPF, angiolymphatic invasion, anaplasia
Case reports: liver metastases from tumor less than 5 mm (Hepatogastroenterology 2004;51:1330), atypical carcinoid associated with ulcerative colitis (J Clin Path 1986;39:913)
Treatment: local excision (J Laparoendosc Adv Surg Tech A 2006;16:435); partial colectomy if malignant potential (see above)
Gross: usually 5 mm or less, round, no ulceration
Micro: islands, trabeculae, glands or sheets of monotonous cells with scant, pink granular cytoplasm and round-oval stippled nuclei, small nucleoli, minimal pleomorphism, minimal mitotic activity; rarely mucin secretion or anaplasia; no necrosis
Micro images: submucosal tumor #1; #2; various images #1; #2; #3; #4; figures 2-3; chromogranin+ in a few cells
atypical carcinoid - H&E; angiolymphatic and perineural invasion; synaptophysin
Positive stains: chromogranin, synaptophysin, neuron specific enolase; also PAP (80%), CEA, hCG
Negative stains: PSA
EM: cytoplasmic, well formed membrane bound secretory granules with dense (osmophilic) cores
Molecular: diploid if nonmetastasizing, aneuploid if metastatic
DD: prostate carcinoma (PSA+, neuroendocrine markers-)
References: eMedicine #271
Carcinoid-colon but not rectum
Uncommon
Usually large, penetrate muscularis propria and involve regional lymph nodes
Not associated with carcinoid syndrome
Case reports: with adenoma (AJSP 1988;12:607)
Gross: flat or depressed plaque or polypoid lesion; yellow-tan, particularly after formalin fixation
Gross images: large tumor
Micro: islands, trabeculae, glands or sheets of monotonous cells with scant, pink granular cytoplasm and round-oval stippled nuclei, small nucleoli, minimal pleomorphism, minimal mitotic activity, no necrosis; rarely mucin secretion and anaplasia
Positive stains: chromogranin, synaptophysin, neuron specific enolase
EM: cytoplasmic, well formed membrane bound secretory granules with dense (osmophilic) cores
References: eMedicine #126
Lymphoma and hematopoietic lesions of colon
Lymphoma-general of colon
Less common in colon than small bowel or stomach
Usually B cell lineage in Western countries; 18-30% are T cell lineage in Korea (Dig Dis Sci 2005;50:2243) and China (Zhonghua Bing Li Xue Za Zhi 2004;33:445); T cell patients are younger, associated with perforation and poorer prognosis
Risk factors: transplants, ulcerative colitis, AIDS
Regional lymph nodes involved in 50% of cases
Advanced lesions may impair gut motility by destroying muscle wall
10 year survival is 85% if localized to submucosa
Gross: plaque like expansion of mucosa/submucosa, bowel wall thickening, polyps (“multiple lymphomatoid polyposis” if multiple polyps throughout colon) or ulceration
Burkitt’s lymphoma of colon
See also Lymphoma-B cell chapter
Sporadic cases in Western world and Middle East may present with ileocecal involvement and pain or obstruction
Endemic cases in Africa usually don’t present with GI involvement
Case reports: with Crohn’s colitis (J Clin Gastroenterol 2003;36:332), presenting as wide-based polyp (Zhonghua Min Guo Xiao Er Ke Yi Xue Hui Za Zhi 1996;37:373)
Micro: small, noncleaved, monomorphic cells with basophilic cytoplasm, round nuclei, prominent multiple nucleoli; starry sky appearance on low power
Micro images: not necessarily colon - various images; starry sky; touch prep; Ki-67
Cytology: vacuoles
Positive stains: CD20, CD10; Ki-67 staining in >90% of cells
Negative stains: CD5, CD23
Molecular: c-myc translocations [t(8;14) and others]
References: Pathologist’s perspective
Follicular lymphoma of colon
See also Lymphoma-B cell chapter
Rare in colon; more common in small intestine (Am J Pathol 1992;140:1327)
Resemble mucosal polyps
Case reports: rectal tumor with FISH (World J Gastroenterol 2004;10:2602), 10 cm tumor of splenic flexure (J Clin Oncol 1999;17:3684)
Micro images: H&E #1; #2; CD20; bcl2; rectal tumor-left: H&E, upper right: CD20, lower right: bcl2
small bowel - H&E and stains
Positive stains: CD20, bcl2; also CD10
Negative stains: CD5, T cell markers (in tumor cells)
Molecular: bcl-2 - IgH translocation
HHV8 positive lymphoma of colon
Case reports: HIV negative patient with Kaposi’s sarcoma (J Surg Oncol 2001;76:197); 2 HIV+ men with EBV+ tumors but no primary effusion lymphoma (Hum Path 2002;33:846), primary tumors with secondary effusions (AJSP 1997;21:719)
Micro: markedly pleomorphic cells resembling immunoblasts, somewhat similar to anaplastic large lymphoma
Hodgkin’s lymphoma of colon
Rare in colon
Associated with inflammatory bowel disease (Leuk Lymphoma 2001;42:521), chronic inflammation or chronic immunosuppression; all may cause EBV mediated lymphoproliferation (AJSP 2000;24:66)
Stringent diagnostic criteria necessary due to rarity of primary disease and possible confusion with secondary spread
Case reports: 42 year old woman with inflammatory bowel disease (Archives 2000;124:1824), 62 year old man with acute appendicitis (Clin Transl Oncol 2006;8:450), presenting as polyp (Clin Colorectal Cancer 2001;1:185), with diverticular disease (Archives 1997;121:528), causing splenic vein obstruction (Indian J Gastroenterol 1994;13:70)
Treatment: discontinuation of immunosuppressive therapy may be helpful
Gross: transmural involvement of bowel wall, often multifocal, associated with fissuring ulcers, diverticula with abscesses
Micro: Reed-Sternberg cells in background of lymphoid hyperplasia, occasional granulomas
Micro images: various images
Positive stains: CD15, CD30, EBER1, LMP1
Negative stains: CD45 (LCA)
MALT lymphoma of colon
Rare in colon
Usually adults
Often relapse, but usually only in GI tract
Case reports: 75 year old woman (World J Gastroenterol 2006;12:5573), with lymphomatoid polyposis (Am J Gastroenterol 1999;94:2540)
Treatment: early tumors are focal and curable by surgery; antibiotics may cause regression (J Gastroenterol 2005;40:843, Endoscopy 2002;34:343)
Micro: small atypical lymphocytes with irregular nuclei, lymphoepithelial lesions; reactive germinal centers and plasmacytic cells are common
Micro images: figures A-D; figures 2, 4, 5
Molecular: usually trisomy 3 or 18; less commonly t(1;14);(p22;q32) (Gut 2006;55:1581); t(11;18)(q21;q21) in 15% (Mod Path 2003;16:1232)
Mantle cell lymphoma of colon
Uncommon in colon
Often presents as multiple lymphomatoid polyposis
Often present in benign appearing mucosa (Curr Opin Gastroenterol 2005;21:80)
88% males, mean age 61 years
Also involves stomach and small intestine
Mean survival historically less than 3 years; may be improving with newer treatments
Rarely coexists as incidental finding with adenocarcinoma (Archives 2003;127:E64, Mod Path 2001;14:811, free full text)
Case reports: diffuse involvement of GI tract without polyposis (J Gastroenterol 2004;39:995), associated with ulcerative colitis (AJSP 1996;20:1024), rectal tumor (Hepatogastroenterology 2001;48:675), University of Pittsburgh Case #441
Gross: nodular, sessile or polypoid lesions, widely spaced, confluent studded or cobblestone appearance; each polyp 2 mm to 2 cm; may be dominant tumor mass in ileocecum; endoscopically normal mucosa may have small tumor infiltrates also
Gross images: lymphomatoid polyposis #1
Micro: mantle cells (small lymphocytes with pale cytoplasm and cleaved nuclei), often invasion of submucosa, proliferation around germinal centers, sparing of mucosa; late - epithelial invasion and ulceration
Note: may also be minute lymphoid infiltrates in known mantle cell patients
Micro images: various images #1; #2; incidental tumor #1; #2; #3; figures 2, 3A-3D
Positive stains: CD20, CD5, cyclin D1/bcl1; immunohistochemistry for cyclin D1 may be more sensitive than FISH for t(11;14) or PCR for IgH (AJSP 2006;30:1274)
Negative stains: CD3, CD10, CD23
DD: nodular lymphoid hyperplasia (benign, associated with common variable immunodeficiency syndrome), multiple lymphoid polyps (benign germinal centers in children, patients with Gardner’s syndrome), MALT lymphoma (may present as multiple lymphomatoid polyposis, but has lymphoepithelial lesions, is negative for CD5 and cyclin D1), inflammatory bowel disease (may need immunostains to differentiate, Dig Dis Sci 1992;37:934)
Rare
Case reports: 32 year old woman with ascending colon tumor (Mod Path 1999;12:739)
Micro: cells have abundant granular or clear cytoplasm; oval, lobulated or indented nuclei; numerous eosinophils
Positive stains: CD68, tryptase, CD45RB
T cell lymphoma of colon
Rare in West, but 18% of colorectal lymphomas in Korea (Dig Dis Sci 2005;50:2243)
Usually EBV+ in China (Chin Med J (Engl) 2005;118:1542)
Often multifocal ulcerative lesions in relatively young patients; may resemble Crohn’s disease (Hepatogastroenterology 2002;49:950)
Poor prognosis, even if localized
Case reports: adult T cell leukemia/lymphoma (J Gastroenterol 2004;39:788), cytotoxic/suppressor phenotype #1 (AJSP 2000;24:296), #2 (Int J Hematol 2000;71:379), #3 with ulcerative colitis (J Gastroenterol 2003;38:376), gamma-delta phenotype causing lymphomatoid polyposis (Dig Liver Dis 2004;36:218), intravascular T cell lymphoma involving colonic vessels (Am J Hematol 2005;78:207), peripheral T cell lymphoma #1 in AIDS patient (Oncologist 2005;10:292), #2 with colonic adenocarcinoma (Pathol Oncol Res 2003;9:188), #3 with Crohn’s disease (Korean J Gastroenterol 2006;47:233), #4 with Crohn’s disease (Korean J Intern Med 1997;12:238), post-transplant tumor in child (AJSP 2004;28:967), T/NK cell lymphoma (J Gastroenterol 2002;37:939), lymphoma causing colojejunal fistula (Dis Colon Rectum 2005;48:158), with diffuse GI tract involvement (Korean J Intern Med 2000;15:245)
Micro images: peripheral T cell lymphoma #1; #2; #3
Mesenchymal tumors of colon
Recommended that all stromal tumors be stained with CD117
Case reports: usually no association with tuberous sclerosis (Mod Path 1999;12:1132, Z Gastroenterol 2003;41:715, Dis Colon Rectum 2003;46:547, Gastroenterol Jpn 1989;24:407); may be HMB45 negative (Am J Gastroenterol 1996;91:1852), monotypic (J Clin Path 2005;58:1107) or pleomorphic (also called PEComa, Int J Surg Pathol 2000;8:67)
Positive stains: HMB45, CD68, vimentin, desmin, smooth muscle actin
Negative stains: CD34
Very rare in GI tract as primary or metastasis
In GI series, median age 57 years (range 25-85 years, AJSP 2004;28:298)
Often death due to disease
Case reports: associated with retained surgical sponge (AJCP 1992;97:416), associated with prior surgery (World J Surg Oncol 2005;3:60), with rectal bleeding and obstruction (Dis Colon Rectum 2004;47:2202), in teenage boy (Acta Chir Belg 2004;104:465), cecal tumor (Indian J Gastroenterol 1995;14:31), metastatic from liver (Archives 2001;125:968), metastatic into tubular adenoma (Tumori 2005;91:210)
Micro: sheets of malignant appearing epithelioid cells with subtle areas of cleft-like spaces suggestive of vascular differentiation
Micro images: associated with prior surgery; metastases - A: FNA; B: AE1-3; C: H&E of liver primary; D: CD31
Positive stains: CD31, CD34, Factor VIII, AE1-AE3; variable Cam 5.2/CK8, CK19, CK7
Negative stains: CK20, S100, EMA (usually)
DD: primary or metastatic carcinoma, melanoma, florid vascular proliferation due to prolapse or intussusception (Mod Path 2001;14:1114)
Endometrial stromal sarcoma of colon
Rare complication of endometriosis and unopposed estrogen therapy (AJSP 2000;24:513)
Uterine primary tumors may also recur in colon (World J Gastroenterol 2005;11:2367, Eur J Gynaecol Oncol 2006;27:297)
Typically no death from disease (J Korean Med Sci 2002;17:412)