• The overwhelming majority of intestinalpolyps occur sporadically, particularly in thecolon, and increase in infrequency with age.• Non-neoplastic polyps represent 90% of allepithelial polyps in the large intestine and arefound in more than half of all persons age 60years or older.
Hyperplastic PolypsColonic hyperplastic polyps are commonepithelial proliferations that are typicallydiscovered in the sixth and seventh decades oflife.
PathogenesisThe pathogenesis of hyperplastic polyps isincompletely understood, but they are thought toresult from decreased epithelial cell turnover anddelayed shedding of surface epithelial cells,leading to a “piling up” of goblet cells andabsorptive cells.
• It is now appreciated that these lesions arewithout malignant potential. Their chiefsignificance is that they must bedistinguished from sessile serratedadenomas, histologically similar lesions thathave malignant potential.
• It is also important to remember thatepithelial hyperplasia can occur as anonspecific reaction adjacent to or overlyingany mass or inflammatory lesion and,therefore, can be a clue to the presence of anadjacent, clinically important lesion.
Hyperplastic Polyps cont.• Most common non-neoplastic polyp in the colon• Do not exhibit dysplasia• Proliferation is mainly in the basal portion of the crypt(used to distinguish from adenomas)• Typically located in the rectosigmoid and are < 5mminsize• Small left sided HP are not a significant marker ofcolon cancer risk and finding them on sigmoidoscopy isNOT a routine indication for colonoscopy
• When single, they do not have malignantpotential. Sessile serrated adenoma may havemalignant potential. They are small, nipple-like, hemispherical, smooth protrusions of themucosa. They may occur singly but are moreoften multiple. Although they may beanywhere in the colon, well over half arefound in the rectosigmoid region.
MorphologyHyperplastic polyps are most commonly found in theleft colon and are typically less than 5 mm indiameter. They are smooth, nodular protrusions ofthe mucosa, often on the crests of mucosal folds.They may occur singly but are more frequentlymultiple, particularly in the sigmoid colon andrectum.
• Histologically, hyperplastic polyps arecomposed of mature goblet and absorptivecells. The delayed shedding of these cellsleads to crowding that creates theserrated surface architecturethat is the morphologic hallmark of theselesions.
• they contain• abundant crypts• lined by well-differentiated goblet orabsorptive epithelial cells,• separated by a scant lamina propria.
Hyperplastic polyp. A, Polyp surface with irregular tufting of epithelial cells. B, Tuftingresults from epithelial overcrowding. C, Epithelial crowding produces a serrated architecturewhen glands are cut in cross-section.
Hamartomatous polyps• Hamartomatous polyps occur sporadically and inthe context of various genetically determined oracquired syndromes . Recall that hamartomas aretumor-like growths composed of mature tissuesthat are normally present at the site in which theydevelop. Although Hamartomatous polyposissyndromes are rare, they are important torecognize because of associated intestinal andextra-intestinal manifestations and the possibilitythat other family members are affected.
Juvenile Polyps• Juvenile polyps are focal malformations ofthe mucosal epithelium and lamina propria.These may be sporadic or syndromic, but themorphology of the two forms may beindistinguishable. The vast majority ofjuvenile polyps occur in children less than 5years of age. When present in adults, polypswith identical morphology are sometimesconfusingly referred to as inflammatorypolyps.
• The majority of juvenile polyps are located inthe rectum and most present with rectalbleeding. In some cases prolapse occurs andthe polyp protrudes through the analsphincter. Sporadic juvenile polyps areusually solitary lesions and may be referredto as retention polyps.
• In contrast, individuals with the autosomaldominant syndrome of juvenile polyposis havefrom 3 to as many as 100 hamartomatous polypsand may require colectomy to limit the chronicand sometimes severe hemorrhage associatedwith polyp ulceration. A minority of patients alsohave polyps in the stomach and small bowel.Pulmonary arteriovenous malformations are arecognized extra-intestinal manifestation of thesyndrome.
MorphologyMost juvenile polyps are less than 3 cm in diameter.They are typically pedunculated, smooth-surfaced,reddish lesions with characteristic cystic spacesapparent after sectioning.Microscopic examination shows these cysts to bedilated glands filled with mucin and inflammatorydebris . The remainder of the polyp is composed oflamina propria expanded by mixed inflammatoryinfiltrates. The muscularis mucosa may be normalor attenuated.
Juvenile polyposis. A, Juvenile polyp. Note the surface erosion and cysticallydilated crypts. B, Inspissated mucous, neutrophils, and inflammatory debris canaccumulate within dilated crypts.
• Although the morphogenesis of juvenile polyps isincompletely understood, some have suggestedthat mucosal hyperplasia is the initiating event.This hypothesis is consistent with the discoverythat mutations in pathways that regulate cellulargrowth cause autosomal dominant juvenilepolyposis. The most common mutation identifiedis of SMAD4, which encodes a cytoplasmicintermediate in the TGF-β signaling pathway.BMPR1A, a kinase that is a member of the TGF-βsuperfamily, may be mutated in other cases.
However, these mutations account for fewerthan half of patients, suggesting that changesin other genes can also cause juvenilepolyposis. Dysplasia occurs in a smallproportion of juvenile polyps, and thejuvenile polyposis syndrome is associatedwith an increased risk of colonicadenocarcinoma.
Hamartomatous Juvenile polyps• Hamartomatous proliferations, mainly of thelamina propria, enclosing widely spaced,dilated cystic glands. They occur mostfrequently in children younger than 5 yearsold but are also found in adults of any age; inthe latter group they may be called retentionpolyps.
large in children (1-3 cm in diameter) butsmaller in adults;they are rounded , smooth, or slightly lobulatedand sometimes have a stalk as long as 2 cm.
• In general, they occur singly and in therectum, and being Hamartomatous they haveno malignant potential.• Juvenile polyps may be the source of rectalbleeding and in some cases become twistedon their stalks to undergo painful infarction.
Peutz-Jeghers Syndrome• This rare autosomal dominant syndromepresents at a median age of 11 years withmultiple GI hamartomatous polyps andmucocutaneous hyperpigmentation. Thelatter takes the form of dark blue to brownmacules around the mouth, eyes, nostrils,buccal mucosa, palmar surfaces of the hands,genitalia, and perianal region. These lesionsare similar to freckles but are distinguishedby their presence in the buccal mucosa.
• Peutz-Jeghers polyps can initiateintussusception, which is occasionally fatal.Of greater importance, Peutz-Jegherssyndrome is associated with an increased riskof several malignancies, including cancers ofthe colon, pancreas, breast, lung, ovaries,uterus, and testicles, as well as other unusualneoplasms, such as sex cord tumors.
PathogenesisGermline heterozygous loss-of-functionmutations in the gene LKB1/STK11 arepresent in approximately half of individualswith familial Peutz-Jeghers syndrome as wellas a subset of patients with sporadicPeutzJeghers syndrome. LKB1/STK11 is akinase that regulates cell polarization,growth, and metabolism.
The function of the second “normal” copy ofLKB1/STK11 is often lost through somaticmutation in cancers occurring in Peutz-Jeghers syndrome, consistent with the viewthat LKB1/STK11 is a tumor suppressor geneand providing an explanation for the high riskof neoplasia in affected patients. The GIadenocarcinomas arise independently of thehamartomatous polyps, indicating that thehamartomas are not preneoplastic precursorlesions.
MorphologyThe polyps of Peutz-Jeghers syndrome are mostcommon in the small intestine, although theymay occur in the stomach and colon, and, withmuch lower frequecy, in the bladder and lungs.Grossly, the polyps are large and pedunculatedwith a lobulated contour. Histologicexamination demonstrates a characteristicarborizing network of connective tissue, smoothmuscle, lamina propria, and glands lined bynormal-appearing intestinal epithelium .
The arborization and presence of smoothmuscle intermixed with lamina propria arehelpful in distinguishing polyps of Peutz-Jeghers syndrome from juvenile polyps.
Peutz-Jeghers polyp. A, Polyp surface (top) overlies stroma composed of smoothmuscle bundles cutting through the lamina propria. B, Complex glandular architecture and thepresence of smooth muscle are features that distinguish Peutz-Jeghers polyps from juveni lepolyps.
Clinical FeaturesBecause the morphology of Peutz-Jegherspolyps can overlap with that of sporadichamartomatous polyps, the presence ofmultiple polyps in the small intestine,mucocutaneous hyperpigmentation, and apositive family history are key to thediagnosis. Detection of LKB1/STK11mutations can be helpful diagnostically inpatients with polyps who lackmucocutaneous hyperpigmentation.
However, the absence of LKB1/STK11mutations does not exclude the diagnosis,since mutations in other presently unknowngenes can also cause the syndrome. Becauseof the increased risk of cancer, routinesurveillance of the GI tract, pelvis, andgonads is typically recommended.
Cowden syndrome and Bannayan-Ruvalcaba-Riley syndromeare autosomal dominant hamartomatous polypsyndromes associated with loss-of-functionmutations in PTEN, a gene encoding a lipidphosphatase that inhibits signaling through thePI3K/AKT pathway. PTEN, a well-characterizedtumor suppressor, is also mutated in a smallnumber of patients presenting with juvenilepolyposis.
• The multiple syndromes associated withPTEN mutations are sometimes groupedtogether under the heading “PTENhamartoma syndrome.” The basis for thediffering presentations of these syndromes isnot understood; interaction of PTEN loss-of-function mutations with other unknownmodifying genes is suspected.
• Cowden syndrome is characterized bymacrocephaly, intestinal hamartomatous polyps,and benign skin tumors, typically trichilemmomas,papillomatous papules, and acral keratoses. Avariety of other lesions derived from all threeembryologic layers, including subcutaneouslipomas, leiomyomas, and hemangiomas, alsooccur. While individuals with Cowden syndromedo not have increased risk of GI malignancy, theyare predisposed to breast carcinoma, follicularcarcinoma of the thyroid, and endometrialcarcinoma.
• Bannayan-Ruvalcaba-Riley syndrome can bedistinguished from Cowden syndrome on clinicalgrounds; for example, mental deficiencies anddevelopmental delays are only seen with theBannayan-Ruvalcaba-Riley syndrome, which alsoseems to be associated with a lower incidence ofneoplasia than Cowden syndrome. Featuresshared by these two syndromes include GIhamartomatous polyps, lipomas, macrocephaly,hemangiomas, and, in males, pigmented maculeson the glans penis.
Cronkhite-Canada Syndrome• Cronkhite-Canada syndrome contrasts sharplywith other hamartomatous polyposis syndromesin that it is nonhereditary and most often developsin individuals over 50 years of age. The clinicalsymptoms are nonspecific and include diarrhea,weight loss, abdominal pain, and weakness. Themost characteristic feature is the presence ofhamartomatous polyps of the stomach, smallintestine, and colorectum that are histologicallyindistinguishable from juvenile polyps.
• However, the nonpolypoid interveningmucosa also shows cystic crypt dilatation andlamina propria edema and inflammation.Associated abnormalities include nailatrophy and splitting, hair loss, and areas ofcutaneous hyperpigmentation andhypopigmentation. The cause of Cronkhite-Canada syndrome is unknown, and nospecific therapies are available. Supportivenutritional therapy, which alleviates cachexiaand anemia, can occasionally induceremission. Nonetheless, as many as 50% ofcases are fatal.
Inflammatory Pseudopolyps• A projecting mass of hypertrophied mucousmembrane• Irregularly shaped islands of residual intactcolonic mucosa that are the result of themucosal ulceration and regeneration that occursin IBD (benign with no malignant potential).• Usually multiple, filiform and scatteredthroughout the colitic region of the colon(Ulcerative Colitis)
A projecting mass of hypertrophied mucous membrane (as inthe stomach or colon) resulting from local inflammation
• The polyp that forms as part of the solitaryrectal ulcer syndrome is an example of apurely inflammatory lesion. Patients presentwith a clinical triad of rectal bleeding, mucusdischarge, and an inflammatory lesion of theanterior rectal wall.
• The underlying cause is impaired relaxationof the anorectal sphincter that creates asharp angle at the anterior rectal shelf andleads to recurrent abrasion and ulceration ofthe overlying rectal mucosa. Aninflammatory polyp may ultimately form as aresult of chronic cycles of injury and healing.Entrapment of this polyp in the fecal streamleads to mucosal prolapse.
• Thus, the distinctive histologic features arethose of a typical inflammatory polyp withsuperimposed mucosal prolapse and includelamina propria fibromuscular hyperplasia,mixed inflammatory infiltrates, erosion, andepithelial hyperplasia
Solitary rectal ulcer syndrome. A, The dilated glands, proliferative epithelium,superficial erosions, and inflammatory infiltrate are typical of an inflamatory polyp.However, the smooth muscle hyperplasia within the lamina propria suggeststhat mucosal prolapse has also occurred. B, Epithelial hyperplasia. C, Granulationtissue-like capillary proliferation within the lamina propria caused by repeatederosion and re-epithelialization.
Submucosal Polyps• Lymphoid aggregates, lipomas, leiomyomas,pneumatosis cystoid intestinalis, hemangiomas,fibromas, carcinoids, and metastatic lesions• Can be neoplastic or non-neoplastic• Smooth overlying mucosa• Lipoma can be diagnosed endoscopically becauseof its yellow color and softness (pillow sign)• EUS can be useful in defining the site of origin andfor biopsy of submucosal lesions if the diagnosis isin doubt.
Adenomatous Polyps2/3 of colonic polyps are adenomasBy definition they are dysplastic and havemalignant potentialTime for development of adenomas to cancer isabout 7 to 10 years.Adenomas
Advanced adenomahigh grade dysplasia oradenoma that is > 10 mm in size orwith villous component.
Synchronous adenomaadenoma that is diagnosed at same time asindex colorectal neoplasm
Metachronous adenomadiagnosed at least six months after diagnosis ofprevious adenoma.
Epidemiology of AdenomaOlder age is a major risk factorMore common in menLarge adenomas (> 9mm) may be morecommon in African AmericansAfrican Americans have a higher risk of right-sided colonic adenomas and may present withcancer at a younger age (< 50 years) thanCaucasians.
• The prevalence of colonic adenoma is 20% to30% before age 40, rising to 40 to 60 % afterage 60. Males and females are affectedequally???.
• There is a well-defined familial predispositionto sporadic adenomas, accounting for about afourfold greater risk for adenomas among firstdegree relatives, and also a fourfold greaterrisk of colorectal carcinoma in any person withadenomas.
• All adenomatous lesions arise as the result ofepithelial proliferation and dysplasia, whichmay range from mild to severe as to representtransformation to carcinoma. Furthermore,there is strong evidence that most sporadicinvasive colorectal adenocarcinomas arise inpreexisting adenomatous lesions.
Types of adenomas on the basis of the epithelial architecture• 1. Tubular adenomas• 2. Villous adenomas• 3. Tubulovillous adenomas• 4. Sessile Serrated adenomas
Endoscopic Classification1. Sessile – base is attached to colon wall usuallylarge2. Pedunculated – mucosal stalk is interposedbetween the polyp and the wall3. Flat – height less than one-half the diameter ofthe lesion.Depressed lesions appear to be particularly likelyto harbor high-grade dysplasia or be malignanteven if small.
Pathologic ClassificationI. Low grade dysplasia: characterized bybranching cryptslined by cells with long, thin nuclei that begin tostratify, resulting inincreased nucleus-to-cytoplasm ratio anda loss of normal goblet cells.
II. High grade dysplasia: do not contain invasivemalignancy, which is defined by breach of themuscularis mucosa by neoplastic cells.Represents an intermediate step in theevolution from low grade adenomatous polypto cancerNot associated with metastasis since there areno lymphatic vessels in the lamina propria..
Tubular AdenomaThe most common, account for more than 80percent of colonic adenomas.Characterized by a complex network of branchingadenomatous glands.Most TA are small and pedunculated.
Morphology of TAMay arise anywhere in the colon, but about halfare found in the rectosigmoid, theproportion increasing with age.In about half of the instances they occur singly,but in the remainder two or more lesions aredistributed at random.
• The smallest adenomas are sessile; lesions0.3 cm in size can be identified at endoscopy.Among the larger tubular adenomas up to 2.5cm in diameter, most have slender stalks 1 to2 cm long and raspberry –like heads.
• Histologically the stalk is covered by normalcolonic mucosa, but the head is composed ofneoplastic epithelium, forming branchingglands lined by tall, hyperchromatic,somewhat disorderly cell, which may or maynot show mucin secretion.
• In some instances there are small foci ofvillous architecture.• In the clearly benign lesion, the branchingglands are well separated by lamina propria,and the level of dysplasia or cytologic atypia isslight.
• However all degrees of dysplasia may beencountered, ranging up to cancer confined tothe mucosa (intramucosal carcinoma) orinvasive carcinoma extending into the mucosaof the stalk.• A frequent finding in any adenoma issuperficial erosion of the epithelium, theresult of mechanical trauma.
Villous adenomasVillous: account for 5 to 15 percent ofadenomas. They are characterized by glandsthat are long and extend straight down fromthe surface to the center of the polyp,creating finger-like projections. Villousadenomas tend to be large and sessile.
• Morphology of VA: Villous adenomas are thelarger and more ominous of the epithelialpolyps. They tend to occur in older persons,most commonly in the rectum andrectosigmoid, but they may be locatedelsewhere. They generally are sessile, up to 10cm in diameter, velvety or cauliflower-likemasses projecting 1 to 3 cm above thesurrounding mucosa.
• The histology is that of frondlike villiformextensions of the mucosa covered bydysplastic, sometimes very disorderly,sometimes piled-up, columnar epithelium. Alldegrees of dysplasia may be encountered, andinvasive carcinoma is found in as many as 40%of these lesions, the frequency beingcorrelated with the size of the polyp.
Tubulovillous adenomasTVA: having 26 to 75 percent villous componentaccount for 5 to 15 percent of adenomas;combination of above. Tubulovillous adenomas arecomposed of a broad mix of tubular and villousareas. They are intermediate between the tubularand the villous lesions in their frequency of having astalk or being sessile, their size, the degree ofdysplasia, and the risk of harboring intramucosal orinvasive carcinoma.
Serrated PolypsDisplay features of both hyperplastic andadenoma Were classified in past as HP andbenign but new evidence shows that they maybehave as adenomasNo guidelines for management; it is generallyrecommended that surveillance intervals shouldfollow that of other adenomas
Two typesSessile serrated adenoma – precursors to largeHP in proximal colon of patients withhyperplastic polyposisTraditional serrated adenoma – look and behaveas conventional adenomas; oftenpedunculated found more often in distal colon
Clinical features of adenomas• The smaller adenomas are usuallyasymptomatic, until such time that occultbleeding leads to clinically significant anemia.• Villous adenomas are much more frequentlysymptomatic because of overt or occult rectalbleeding. The most distal villous adenomasmay secrete sufficient amounts of mucosalmaterial rich in protein and potassium toproduce hypoproteinemia or hypokalemia.
• On discovery, all adenomas, regardless oftheir location in the alimentary tract, are to beconsidered potentially malignant; thus, inpractical terms, prompt and adequate excisionis mandated.
• Familial polyposis syndromes are uncommon• Autosomal dominant disorders. Theirimportance lies in the propensity formalignant transformation and in the insightsthat such transformation has provided inunraveling the molecular basis of colorectalcancer.
• Individuals with familial adenomatouspolyposis (FAP) typically develop 500 to 2500colonic adenomas that carpet the mucosalsurface; a minimum number of 100 is requiredfor the diagnosis.
• Multiple adenomas may also be presentelsewhere in the alimentary tract, includingalmost a 100 % lifetime incidence of duodenaladenomas.
• Most polyps are tubular adenomas; occasionalpolyps have villous features.
• Polyps usually become evident in adolescenceor early adulthood. The risk of colonic canceris virtually 100% by midlife, unless aprophylactic colectomy is performed.
Risk Factors for High grade dysplasia and cancerAdenomatous polyps > 1 cm in diameter are riskfactor for containing CRCVillous histology – adenomatous polyps with > 25percent villous histology are a risk factor fordeveloping CRCHigh-grade dysplasia – adenomas with high-gradedysplasia often coexist with areas of invasive cancerin the polyp.Number of polyps: three or more is a risk factor fordevelopment of metachronous adenomas withadvanced pathologic features.
Intestinal tumorsNon-neoplastic PolypsHyperplastic polypsHamartomatous polypsJuvenile polypsPeutz-Jeghers polypsInflammatory polypsLymphoid polypsNeoplastic Epithelial LesionsBenign polypsAdenomasMalignant lesionsAdenocarcinomaSquamous cell carcinoma of the anusOther TumorsGastrointestinal stromal tumorsCarcinoid tumorLymphomaEpithelial tumors of the intestines:major cause of morbidity and mortality worldwideColon, including rectum:host to more primary neoplasms than any otherorgan in the body
AdenocarcinomaAdenocarcinoma is a cancer of an epithelium thatoriginates in glandular tissue, adeno means gland.• 98% of all cancers in large intestine almost alwaysarise in adenomatous polyps, generallycurable by resection
Epidemiology• peak incidence: 60 to 70 years of age• < 20% cases before age of 50• adenomas – presumed precursor lesionsfor most tumors• males affected ≈ 20% more often thanfemales
Epidemiology• worldwide distribution• highest incidence rates in United States,Canada, Australia, New Zealand, Denmark,Sweden, and other developed countries
Etiology• genetic influences:– preexisting ulcerative colitis or polyposissyndrome– hereditary nonpolyposis colorectal cancersyndrome (HNPCC, Lynch syndrome) → germ-linemutations of DNA mismatch repair genes
Etiology• environmental influences:– dietary practices• low content of unabsorbable vegetable fiber• corresponding high content of refined carbohydrates• high fat content• decreased intake of protective micronutrients (vitaminsA, C, and E)– use of Aspirin®and other NSAIDs: protective effectagainst colon cancer?• cyclooxygenase-2 & prostaglandin E2
Morphology• 25% of colorectal carcinomas: in cecum orascending colon• similar proportion: in rectum and distalsigmoid• 25%: in descending colon and proximalsigmoid• remainder scattered elsewhere• multiple carcinomas present → often atwidely disparate sites in the colon
Morphology• all colorectal carcinomas begin as in situ lesions• tumors in the proximal colon: polypoid, exophyticmasses that extend along one wall of the cecum andascending colon
Morphology• in the distal colon: annular, encircling lesions thatproduce “napkin-ring” constrictions of the bowel andnarrowing of the lumen• both forms of neoplasm eventually penetrate the bowelwall and may appear as firm masses on the serosalsurface
Morphology• all colon carcinomas - microscopically similar• almost all - adenocarcinomas• range from well-differentiated to undifferentiated,frankly anaplastic masses• many tumors produce mucin• secretions dissect through the gut wall, facilitateextension of the cancer and worsen the prognosis• cancers of the anal zone are predominantly squamouscell in origin
Clinical Features• may remain asymptomatic for years• symptoms develop insidiously• cecal and right colonic cancers:– fatigue– weakness– iron deficiency anemia• left-sided lesions:– occult bleeding– changes in bowel habit– crampy left lower quadrant discomfort• anemia in females may arise from gynecologic causes, but it is aclinical maxim that iron deficiency anemia in an older man meansgastrointestinal cancer until proved otherwise
Clinical Features• spread by direct extension intoadjacent structures and bymetastasis through lymphatics andblood vessels• favored sites for metastasis:– regional lymph nodes– liver– lungs– bones– other sites including serosalmembrane of the peritonealcavity• carcinomas of the anal region →locally invasive, metastasize toregional lymph nodes and distantsitesTNM Staging of Colon CancerTumor (T)T0 = none evidentTis = in situ (limited to mucosa)T1 = invasion of lamina propria or submucosaT2 = invasion of muscularis propriaT3 = invasion through muscularis propria intosubserosa or nonperitonealized perimusculartissueT4 = invasion of other organs or structuresLymph Nodes (N)0 = none evident1 = 1 to 3 positive pericolic nodes2 = 4 or more positive pericolic nodes3 = any positive node along a named blood vesselDistant Metastases (M)0 = none evident1 = any distant metastasis5-Year Survival RatesT1 = 97%T2 = 90%T3 = 78%T4 = 63%Any T; N1; M0 = 66%Any T; N2; M0 = 37%Any T; N3; M0 = data not availableAny M1 = 4%
Clinical Features• detection and diagnosis:– digital rectal examination– fecal testing for occult blood loss– barium enema, sigmoidoscopy andcolonoscopy– confirmatory biopsy– computed tomography and otherradiographic studies– serum markers (elevated bloodlevels of carcinoembryonicantigen)– molecular detection of APCmutations in epithelial cells,isolated from stools– tests under development:detection of abnormal patterns ofmethylation in DNA isolated fromstool cells