rates, along with the requirement for multiple operations. More zecenly, several studies have suggested that laparoscopic lavage end diainage without bowel resection may be safe and effective even in the presence of fee perforation. Nevertheless, this epprosch remains controversial and will equi additonal prospective tnals before it canbe recommended under most ci cumstances. Obstructive symptoms occur in approximately 67% of patinls who develop acute diverticulitis, and complete cbstuc- fion occws in 10%, Patients with incomplete cbstruction offen respond oud resuscitation, nasogesic suction an gente, low- volume weterorGastogrefinexemas. Relief ofobstuctionallows fall bowel preparation end elective resection. A high-volume oral bowel preparation is contreindiceted in the presence of obstructive symptoms. Obstruction that doesnot apdly respond to medicel management mandates laparotomy. Sigmoid colee- tomy with end colostomyis the safest procedwe to perform inthis seting. However, colectomy and pamary anastomosis, with or without on-teble lavage (depending on extent of fecal lod inthe ‘poxinal colon), and prorimel diversion maybe appopnate ifthe patents stable and the proximal end distal bowel appear healthy. ‘Apuoximately 5% of patients wath complicated diverticn- litis develop fistulas between the colon and an adjacent ongen. Colovestcal fistulas exe most common, followed by colovagi- nal and coloenterc fstles. Colocutaneous fstles axe a rare complication of diverticulitis, Two key points in the evaluation of fistulas axe to define the anatomy of the fistula end exclude ether dagnoses. Contrast eneme andlor svall bowel studies axe extremely useful in defining the couse of the fistula. CT scan can identify essocited abscesses or masses. The differ. ential diagnosis includes mah gnancy, Crokn's disease, and radbation-induced fistulas. While Crohn's disease and radiation injuwy maybe suspected based on the patient's melicl history, colonoscopy or sigmoidoscopy usually is required to le out nalignancy. In edition, ina patient who has received redie- tion therapy, a fistula must be considered tobe recwzent cancer until oven otherwise. Once the natomy ofthe fistula hasbeen defined and other diagnoses excluded, operative management should include resection ofthe affected segment of the colon aavoled with diverticulitis (ually wth a pamary anastomosis) snd simple repair of the secondanly involved organ. Suspicion of carcinoma may mandate e wide, en blo resection. Hemorrhage Bleeding from a diverticulum results fim erosion of th pesdi- vertcuar arteriole and may resultin massive hemonhage. Most significant lower geshointestinal hemonage occurs in elderly pitients in whom both diverticuosis and angiodyspasia axe common. Consequently, the exact bleeding souce maybe cif ficult to identify Foxtuately, in S0% of patients, bleeding stops spontaneously. Clinic] management should focus onestzcite- tion and localization of the bleeding site as described for lower gastointestinal hemorhage. Colonoscopy may occasionally ‘entfy bleeding diverticulum that may then be teated with epinepluine injection or cautery Angiography maybe diagnos- fie and therapeutic inthis seting. Inthe me nctnce in which diverticular hemommhage persists or recus, laparotomy ae eg rental colectomy maybe required Giant Colonic Diverticulum Geant colome diverticula axe extremely rare. Most occur on the antimesenteric side of the sigmoid colon. Patients maybe (021)66485438 66485457 symptomatic or may present with vague abdominal complaints such as pain, nausea, or constipation. Plain radiographs may suggest the diagnosis. Barium enema is usually diagnostic Complications of a giant diventiculun include perforation, obstruction, and volvulus. Resection of the involved colon ani diverticulum is recommended. Right-Sided Diverticula The cecum and ascending colon infiequently are involved in divestculosis coli, Even more uncommon is a te solitary divericulum, which confain all layers of the bowel wall andl is thought to be congenital m origin. Right-sided diverticula occur mare often in younger patents than do left-sided diver. ticula and are more common in people of Asian descent than in other populations. Most patents with right-sided diverticula are symptomatic. However, diverticulitis does occur occasionally. Because patients are young and present with nght lower quad- rant pin, theyae often thought to suffer fiom acute appenic- tis, andthe chagnosis of ight sided diverticulitis svbsequently rade in the operating room. If there i e single lige divertow- Jum and minimal inflammation, a divertculectomy may be performed, but an ileocecel resection is usually the prefered operation inthis setting, Hemorshage rzely occws and should be treated in the same fashion as hemorhage from left-sided diverticulum. ADENOCARCINOMA AND POLYPS Incidence Colorectal carcinoma is the most common malignancy of the gestointestinal tact. Over 140,000 new cases are diagnosed, annually in the United States, and more than 50,000 patients die of this disease each year, making colorectal cancer the third most lethal cancer in the United States.* ‘The incidence is similar in men and women and has remained fairly constant over the past 20 yeens, however, the ‘widespread adoption of cunent nafional screening programs is gzadually decreasing the incidence of this common and lethal, disease. Barly detection and improvements in medical and swgi- cal care are thought tobe responsible for the decreasing mortal- ity of colorectal cancer observed in recent yeas, Epidemiology (Risk Factors) Identification of risk factors for development of colorectal, cancer is essential to extblih seeening and surveillance pro- gutms in apposite tngeted populations Aging. Aging is the dominant sek fctr for colorectal cancer, vwithincidence ising steely afer age 50 yes. More than 90% of cases diagnosed are in people older than ege SO yeaus, This isthe rationale for sutiatng screening tets of asympomatic patents at average tsk of developing coloectel cancer at age 50 yeaus However, individuals of enyage can develop colorec- tol cence, so symptoms such esa significant change in bowel Ibis, rectal bleeding, melena, wexplained anemia, or weight Joss require a thorough evaluation Hereditary Risk Factors. Approximately 80% of colorectal cancexs occur sporadcelly, while 20% arize in patients with a own family history of colorectal cancer. Advances in the understanding ofthese familial disondes have le to interest ently dignosis using genetic testing. Because ofthe medical, legal, anc ethical considerations that axe volved in this type www. ketabpezeshki.com 1203 SONY ONY ‘WAL234 'NO109 fTsETEL TY)1208 | SNOLLVEAOISNOD 31519348} of testing, all patients should be offered genetic counseling ife failial syndrome is suspected. Environmental and Dietary Factors. The observation that colorectal carcinoma occurs more commonly in populations that consume diets high in animal fat ancl low in fiber has led to the hypothesis that dietary factors contbute to carcinogenesis. A diet high in saturated or polyunsaturated fats increases risk of colorectal cancer, while a det high in oleic acid (olive il, coco- nut oil, fish oil) does not increase risk Animal studies suggest that fats may’be directly toxic to the colonic mucosa and thus may induce early malignant changes. In contest, a diet high in vegetable fiber appears to be protective. A conelation between alcohol intake and incidence of colorectal carcinoma has elso| been suggested. Ingestion of calcium, selenium, vitamins A, C, end E, carotenoids, and plant phenols may decrease the risk of developing colorectal cancer. Obesity and sedentary lifestyle dramatically increase cancer-related mortlity in @ number of malignancies, including colorectal carcinoma. This knowi- edge isthe basis for primary prevention strtegies to eliminate colorectal cancer by altering cht and lifestyle * Inflammatory Bowel Disease. Patients with long-standing colitis from inflammatory bowel disease are at increased risk for the development of colorectal cancer It is hypothesized that cuonic inflammation predisposes the mucosa to malignant changes, and there is some evidence that degree of inflamma- tion influences risk Ingeneral, the duration and extentof colitis comelate with isk Other factors thought to increase risk include the presence of primary sclerosing cholangitis and family his- tory of colorectal cancer Other Risk Factors. Cigarette smoking is essocited with an increased tisk of colonic adenomas, especially after more than 35 years of use. Patients with weterosigmoidostomy are also at increased risk forboth adenome end carcinoma fomnation * ‘Acromegaly, which is associated with increased levels of circulating human growth hormone and insulin-like growth factor-I, increases risk as well. Pelvic imadiation may increase the risk of developing rectal carcinoma. However, itis unclear whether this represents a diect effect of radiation damage or is instead e comelation between the development of rectal cancer and a history of another pelvic malignancy, for exemple among, patients who develop prostate cancer and are treated with radia- tion, the risk of rectal cer increases significantly * Pathogenesis of Colorectal Cancer Genetic Defects. Over the past two decades, an intense research effort has focused on elucidating the genetic defects and molecular ebnomnalities associated with the development apc KAS. Normal epithetum extins end progression of colorectal adenomas and carcinoma, Mut tions may cause activation of oncogenes (K-ras) andlorinacti- vation of tumor suppressor genes (APC, deleted in colorectal 5p. casinons [DCC p55). Colorectal carcinoma i thought > to develop from adenomatous polyps by accumulation of these mutations in what has come tobe known asthe adenoma- carcinoma sequence (Fig. 29-72) Defects inthe APC gene were fist described in patients with FAP. By investigating these families, characteristic muta- tions inthe APC gene were identified. They are nov known to be present in 80% of sporadic colorectal cancers as wel The APC gene is a tumor suppressor gene. Mutations in both alleles are necessary to initiate polyp formation. The rajorityof mutations are premature stop codons, which result in a truncated APC protein In FAP, the sie of mutation coneletes with the clinical severity ofthe disease. For example, mutations incither the 3 or 5’ end of the gene result in attenuated forms of FAP (AFAP), whereas mutations in the center of the gene resultin more virulent disease. Thus, knowledge of the specific rutation in family may help guide clinical decision making ‘APC inactivation alone does not result in carcinoma Instead, this mutation sets the stage for the accumulation of genetic damage that results in malignancy. Adlitional mutations may include activation or inactivation of a variety of genes One of the most commonly involved genes in colorectal canceris K-ras. K-ras, a signaling molecule in the epidermal growth factor receptor (EGFR) pathway, isclasified as aproto- oncogene because mutation of only one allele will pert the cell cyele. The K-ras gene product is a G-protein involved in inhcellular signal tansduction. When active, K-ras binds gua- nosine triphosphate (GTP); hytholysis of GTP to guanosine diphosphate (GDP) then inactivates the G-protein. Mutation of K-ras results in an inability to hytolyze GTP, thus leaving the G-protein pemanently inthe active form. Its thought that this then leads to uncontrolled cell division. Other EGFR signaling molecules such as BRAF have also been implicated in colorec- fal cencer pathogenesis and progression, and ongoing research is focusing on elucidating their roles in this disease Another common mutation occws in the MIF gene on chromosome 1p“ MYH is a base excision repair gene, and biallelic deletion results in changes in other downstream mol- ecules. Since its discovery, MYH mutations have been associ- ated with an AFAP phenotype in addition to sporadic cancers Unlike APC gene mutations that re expressed in an autosomal dominant pattem, the requirement forbiallelic mutation in MY results in an autosomal recessive pattem of inheritance ‘The tumor suppressor gene p53 has been well character- ized ima number of malignancies. The p53 protein appears DecmPcauvie? other changes oe Figure 29-22. Schematic showing progression fiom normal colonic epithelinm to carcinoma ofthe colon (021)66485438 66485457 www. ketabpezeshki.comto be crucial for initiating apoptosis in cells with imeparable genetic damage. Mutations in p53 are present in 75% of colorectal cancers Deletion of the tumor suppressor phosphatase and ten- sin homolog (PTEN) appears to be involved in a nunber of hamartomatous polyposis syndromes. Deletions in PTEN have been identified in juvenile polyposis, Peutz-Jeghers syndiome, Cowden’s syndrome, and PTEN hamartoma syndrome, in addi. tion to multiple endocrine neoplasia type IIB." Genetic Pathways. The mutations involved in colorectal cancer pathogenesis end progression axe now recognized to accumulate via one of three major genetic pathways: the [ose of heterozygosity (LOH; chromosomal nstabikty) pathway, the microsatellite instability (MSD pathway, and the CpG island ‘methylation (CIMP,; serrated methylated) pathway. The Loss of Heteroaygosity Pathway. The LOH pathway is characterized by chtomesomel deletions and tumor aneu- ploidy. Eighty percent of colorectal carcinomas appear to arise fiom mutations in the LOH pathway. This pathway was fist described in patients with FAP in whom mutations of the APC gene were found tobe inherited Another exemple of LOH occurs inthe region of eluemo- some 19q. This region has been found to be deleted in up to 70% of colorectal cancers. Two tumor suppressor genes, DCC and SMADS, ae located inthis region, and as such, deletion of 18q may result inthe loss of one or both of these genes. DCC. Js a tumor suppressor gene, and loss of both alleles is required, for malignant degeneration. The main role of this molecule ‘appears tobe in the cental nervous system, where itis involved, in newal differentiation and axonal migration. This observa- tion has led to the hypothesis that DCC may be involved in, differentiation and cellular adhesion in colorectal cancer, but this theory remains unproven” DCC mutations are present in more than 70% of colorectal carcinomas and may negatively impact prognosis. SMADM functions inthe signaling cascade of transforming growth factor beta and beta-catenin (also a down- stream effector of the APC gene). Loss of either ofthese genes is thought to promate cancer progression, The Microsatellite Instability Pathway. Manyof the remain- ang colorectal cazeinomas are thought to anise from mutations in the MSI pathway, which is characterized by errors in mismatch, repair duing DNA replication. These ers in mismatch repair were first descmbed in HNPCC (Lynch's syndrome), but are now recognized to be present in many sporadic tumors es wel. ‘A number of genes have been identified that appear to be ont cial for recognizing and repairing DNA replication enoss. These mismatch repar genes include MSH2, MLHI, PMS1, PMS2, and MSHO/GIBP. A mutation in one of these genes predis. poses a cell to mutations, which may occur in proto-oncogenes ox tumor suppressor genes. Accumulation of these errors then, leads to genomic instability and ultimately to carcinogenesis. ‘Microsatelites are regions of the genome in which shoxt base-pair segments axe repeated several times, regions that are particularly prone fo replication err. Consequently, a mutation ina mismatch repair gene produces variable lengths of these repetitive sequences, a finding that has been described as MSI. ‘Tumors associated with MSI appear to have different bio- logic characteristics than do tumors that result from the LOH pathway. Tumors with MSI are more likely to be in the right colon and possess diploid DNA and are associated with a better prognosis then tumors that anise from the LOH pathway that axe (021)66485438 66485457 ricrosatellite stable. Tumors arising from the LOH pathway ten to occur inthe more distal colon, often have chromosomal encuploidy, and are associated with a poorer prognosis. CpG Island Methylation Pathway. In the recently described CIMP pathway, genes do not accumulate mutations (deletions orinseitions ofbases), but insteed are activated or inactivated by methylation. This process has been called ep genetic alteration to differentiate it fiom the more traditional genetic alterations or true stations, normal cells, methylation is citcal for regulation of gene expression In cancer, aberrant methyjation (either hyper- or hypomethylation), usualy ofa promoter region results in abnor- mal activation or inactivation of genes. This gene silencing or, altematively, activation results ina phenotype similar to that pres” ent with true gene mutation. This pathway has also been called, the serrated methylated patlosay because ofthe cbservation that servated polyps often haibor aberrant methyjation in contrast to adenomatous polyps that are more offen associated with muta- tions inthe APC gene (LOH pathway). Although these classifications are useful for understanding the mechanisms underlying carcinogenesis, they are not mutt. ally exclusive, For example, a mismatch repair gene may be anwctivated by methylation. Errors in mismatch repair may then, ellow mutations to inactivate @ tumor suppressor gene. In adli- tion, there is considerable infevest in targeting molecules in each, of these pathways in order to design better anticancer agents Finally, ongoing research is focusing on the utlityof molecular profiling in predicting prognosis anclor response to treatment. Polyps Iti now well accepted thatthe majority of colorectal carcino- ras evolve fiom adenomatous polyps; this sequence of events is the adenomaccarcinoma sequence, Folyp is @ nonspecific clin cal term that desenbes any projection from the surface of the infestinal mucosa regardless ofits histologic nafure. Colorectal polyps may be classified as neoplastic (tubular adenoma, villous adenoma, tubulovllous adenomas, ervated adenomas! polyps), Iyperplastic, hamartomatous (havenile, Peut-Jeghers, Cronkte-Canada), or inflammatory (pseudepolyp, bem gn ymphexd polyp) Neoplastic Polyps. Adenomatous polyps ave commen, occtu- ring in up fo 25% of the population alder than 5O yeans of age in the United States. By definition, these lesions are dysplas- tic. The risk of malignant degeneration is elated to both the size and type of polyp. Tubular adenomas are associated with malignancy in only 5% of cases, whereas villous adenomas may habor cancer in upto 40%. Tuibulovllous adenomas are at intermediate risk (22%). Invasive carcinomas are rare in polyps smaller than | om; the inidence increases with size. The sk of carcinoma ine polyp larger than 2 em is 35% to 50%. Although rost neoplastic polyps do not evolve to cancer, mast colorectal cencexs originale esa polyp Itis his fact that formas the basis for secondary prevention strategies to eliminate colorectal cancer by targeting the neoplastic polyp for removal before malignancy develops Polyps may be pedunculated or sesale. Most pedum- culated polyps aze amenable to colonoscopic snare excision Removal of sessile polype is often more challenging. Special colonoscopic techniques, including saline lif, piecemeal snare excision and endoscopic mucosal resection facilitate success- ful removal of many sessile polype. For ectl sesile polype, transanal operative excision is preferred because it produces en www. ketabpezeshki.com 1205 SONY ONY ‘WAL234 'NO109 fTsETEL TY)1206 | SNOLLVEAOISNOD 31519348} inact, single pathology specimen that canbe used to determine the need for futher therapy. Interpretation of the precise depth, of invasion of a cancer ansing ina sessile polypafter piecemeal excision is often impossible. The site of sessile polypectomies should be marked by injection of India ink to guide follow-up colonoscopy sessions to ensure that the polyp has been com- pletely removed and to facilitate identification of the involved. ‘bowel segment should operative resection be necessary. Col- ectomy is reserved for cases in Which colonoscopie removal is ampossible, such as laxge, flat lesions, or if« focus of invasive cancer is confirmed in the specimen, Complications of polypectomy include perforation and bleeding. A small perforation (nicroperforation) ina fully pre- pated, stable patient maybe managed with bowel rest, broad spectrum antibiotics, and close observation. Signs of sepsis, petonitis, or deterioration in clinical condition are indica. tions for laparotomy. Bleeding may occur immediately after polypectomyor maybe delayed. The bleeding will usually stop, spontaneously, but colonoscopy maybe required to resnare @ bleeding stalk or cauterize the lesion. Occasionally angiography and infusion of vasopressin may be necessary. Rarely, colec- tomyis required, Hyperplastic Polyps. Hyperplastic polyps are extremely common in the colon, These polyps are usually small (<5 mm) and show histologic characteristics of hyperplasia without any dysplasia. They aze not considered premalignant, but cannot be distinguished from adenomatous polyps colonoscopically and ae therefore often removed. In contrast, lange hyperplastic polyps (>2 em) may have a slight rsk of malignant degenera- tion. Moreover, lage polyps may harbor foci of adenomatous tissue and dysplasia. Hiperplastic polypoas isa rae disorder in, which multiple lage hyperplastic polype occur in young adults. ‘These patients are at sightly increased nek forthe development of colorectal cancer Serrated Polyps. Serrated polyps are a recently recognized, histologicelly distinct group of neoplastic polyps. These lesions were long thought to be simular to hyperplastic polype with rinimel malignant potential. However, thas become clear that some of these polyps wall developinto invasive cancess. In ad tion, « familial serrated polyposis syndrome has recently been descrived. Seneted polype should be rested lke adenomatous nis Hamartomatous Polyps (Juvenile Polyps). In contrast to adenomatous end serated polyps, hamertomatous polyps (jwve- rule polyps) uruelly ae not premalignant. These lesions are the characteristic polype of childhood but may occur at any age Bleeding is a common symptom, and intussusception andor obstruction may occur. Because the gross appearance of these polype is identical to adenomatous polyps, these lesions should also be treated by polypectomy. In contast to adenomatous pol- yposis syndromes, these conditions are often associated with rutation in PTEN. Fatal jwertle poyposis is en autosomal dominant is- onder in which patients develop hundeds of polyps in the colon nd rectum. Unlike solitary juvenile polyps, these lesions may degenerate into adenomas and eventually carcinoma. Annual screening should begin between the ages of 10 and 12 years ‘Treatment is surgical andl depends in paston the degree ofectal involvement. Ifthe rectum is relatively spared, a total abdom- nal colectomy with ileorectal anastomosis may be performed with subsequent close surveillance ofthe retained ectum. If the (021)66485438 66485457 rectum is carpeted with polyps, total proctocolectomy is the more appropriate operation. These patients are candidates for ileel pouch-anal reconstruction to avoid a permanent stoma PeulzJeghers syndrome is chaxecterized by polyposis of the small intestine and, to a lesser extent, polyposis of the colon and rectum, Characteristic melanin spots are often noted on the buccal mucosa and lips of these patents. The polyps of Peutz-Jeghers syndrome are genetally considered to be hamer- tomas and are not thought tobe at significant risk for malignant degeneration. However, carcinoma may occasionally develop. Because the entize length of the gestrointestnal tect may be affected, sugery is reseived for symptoms such es obstruction or bleeding or for patients in whom polyps develop edezoma- tous features. Screening consists ofa baseline colonoscopy and upper endoscopy at age 20 years, followed by annual flexible sigmoidoscopy thereafter Cronltte-Cnada syndrome is a disorder in which patients develop gastrointestinal polyposis in association with elopzcia, cutaneous pigmentation, and etrophy of the fingernails and toenails. Diarrhea is @ prominent symptom, and vomiting, malab- sonption, and protein losing enferopathymay occur Most patients die ofthis disease despite maximal medical therapy, and sugery is eserved for complications of polyposis such as obstruction. Cowsden’s syndrome is en autosomal dominant disorder with hamartomas of ell tree embryonal cell layers. Facial trich- ilemmomas, breast cancer, thyroid disease, and gastrointestinal polyps are typical ofthe syndiome. Patients shouldbe screened for cancers. Treatment is otherwise based on symptoms Inflammatory Polyps (Pseudopolyps). Inflammatory polyps occur most commonly in the context of inflammatory bowel disease, but may aso occurafter amebic colitis, ischemic colitis, and schistosomal colitis. These lesions re not premalig- nant, but they cannotbe distinguished fiom adenomatous polyps based on gross appearance end therefore should be removed. Microscopic examination shows islands of nome, egeneret- ing mucosa (the polyp) sumounded by areas of mucosal loss. Polyposis may be extensive, especially in patents with severe colts, and may mimic FAP Inherited Colorectal Carcinoma ‘Many of the genetic defects originally descxibed in hereditary cancers have subsequently been found in sporadic tumors. ‘Although the majority of colorectal cancer is sporadic, several hereditary syndromes provide paradigms for the study of this disease. Insight gained from studying inherited colorectal cancer syndromes has led to better understanding of the genetics of colorectal carcinoma, Familial Adenomatous Polyposis. This rere autosomal dominant condition accounts for only about 1% of all colorec- tal adenocarcinomas. Nevertheless, this syndrome has provided, tremendous insight into the molecular mechanisms underlying colorectal carcinogenesis. The genetic dbnomality in FAP is ‘mutation in the APC gene, located on chromosome Sq. Of ptients with FAP, APC mutation testing is positive in 75% of cases. While most patients with FAP will have a known family history of the disease, up to 25% present without ather affected, family menibers. Clinically, patients develop hundreds to thou- sands of adenomatous polyps shortly after puberty. The lifetime risk of colorectal cancer in FAP patients approaches 100% by age 50 yeass Flexible sigmoidoscopy of first-degree relatives of FAP patients beginning at age 10 to 15 yeaus has been the traditional www. ketabpezeshki.commainstay of screening. Today, following genetic counseling, APC gene testing maybe used to screen family members, pro- viding an APC mutation has been identified. If APC testing is positive in relative of a patient with a known APC mutation, nna flexible sigmoidoscopy beginning at age 10 to 15 years is done until polyps are identified. If APC testing is negative, the relative canbe screened starting atage 5O years per average risk guidelines. IF APC testing is refused or unavailable, or fe rutation cannot be identified, annual flexible sigmoidoscopy beginning at age 10 to 15 yeas is performed until ege 24 years. Screening flexible sigmoidoscopy is then done every 2 years until age 34 years, every 3 years until age 44 years, and then every’ to 5 years, FAP patients are also at isk forthe development of edeno- ras anywhere in the gastrointestinal tract, particularly in the duodenum. Periampullary carcinoma is a particular concern. Upper endoscopy is therefore recommended for surveillance every | to 3 yeats beginning at age 25 to 30 years (Once the diagnosis of FAP has been made and polyps are developing, treatment is sugical. Four factors affect the choice of operation: age of the patient, presence and severity of symp- toms; extent of rectal polyposis, and presence end location of cancer or desmoid tumors. Three operative procedures can be considered: total proctocolectomy with an end (Brooke) ilos- tomy, total ebdominal colectomy with leorectal anastomosis, and restorative proctocolectomy with ileal pouch-anal anas- tomosis with or without a temporary ileostomy. Mist patients elect to have an ileal pouch-anal anastomosis inthe absence of a distal rectal cancer, e mesenteric desmoid tumor that prevents the ileum fiom reaching the anus, or poor sphincter function. ‘Mucosectomy has been advocated in patients with FAP under- going ileal pouch-anal anastomosis because of the risk of neo- plasia in the anal transition zone, but the requirement for this procedure remains controversial. Although patient satisfaction with tis procedure remains high, function may not be ideal, end up to 50% of patients experience some degree of incontinence Total ebdominal colectomy with an ileorectl anastomosis is also an option in these patients, but equires vigilant suveil- lance of the retained rectum for development of rectal cancer ‘There is increasing data suggesting that the administration of cyelooxygenase-? (COX.2) mhibitos (celecoxib, sulindac) may slow or prevent the development of polyp FAP may be associated with extraintestinal manifeste- tions such as congenital hypertrophy of the retinal pigmented epithelium, desmoid tumors, epidermoid cysts, mandibular osteomas (Gardner's syndrome), and central ne1vous system tumors (Tucot's syncome). Desimoid tumors in particular, can make sugical management difficult and are a souce of mejor morbidity and mortality in these patients. Desmoidl tumors are offen hormone responsive, andl growth maybe inhibited in some patients with tamoxifen, COX-2 inhibitors and nonsteroidal, ant-inflammatory drugs may also be beneficial inthis setting Attenuated Familial Adenomatous Polyposis. AFAP is a recognized variant of FAP. Patients present later in life with fewer polyps (usually 10-100) predominantly located in the right colon, when compared to classic FAP. Colorectal carci- noma develops in more than 50% of these patents, but occurs Inter (average age, 55 years) Patients are also at rsk for duo- denal polyposis. However, in contrst to FAP, APC gene muta- tions are resent in only ebout 30% of patients with AFAP ‘When present, these mutations are expressed in an autosomal dominant pattem, (021)66485438 66485457 ‘Mutations in MPH also result inthe AFAP phenatype but axe expressed in an autosomal recessive pattem It has been sug- gested that MYH mutations may be responsible for AFAP in patients who do not have e detectable APC gene mutation." Genetic testing is offen offered to patients with suspected AFAP. When positive, genetic counseling and testing may be ‘wed to screen at-risk family members. Ifthe family mutation is unlnown, screening colonoscopyis recommended beginning at age 13 to 15 yeas, ten every 4 yeas to age 28 yeaxs, and then every 3 yeaus. These patents aze often candidates for a total stodominal colectomy with ieorectl anastomosis because the limited polyposis inthe rectum can usuallybe treated by colo- noscopic mate excision “Prophylaxis with COX.2 inhibitors also may be appropriate. Because of the more subtle pheno- type in these pabent, its important to rule out other femal syndromes such as HNPCC (Lynch's synciome) end the more common familial colorectal cancer Hereditary Nonpolyposis Colon Cancer (Lynch's Syndrome). HNPCC (Lynch’s syndrome) is more common than FAP, but is still extremely rre (1%-3% of all colon c cers). The genetic defects associated with HNPCC arise fiom emors in mismatch repair, the phenotypic result being MSI HNPCC is inherited in an autosomal dominant pattem and is characterized by the development of colorectal carcinoma at an early age (average age, 40-45 years). Approximately 70% of affected individuals will develop colorectal cancer. C cers appear inthe proximal colon more often than in sporadic colorectl cancerand have abetter prognosis regardless of sage The risk of synchronous or metechronous colorectal carcinoma is 40% HNPCC may also be associated with extacolonic malignancies, including endometrial cercinoma, which is most common, and ovarian, pancreas, stomach, small bowel, biliary, end winery tact carcinomas. The diagnosis of HNPCC is made based on family history. The Amsterdam criteria for clinical diagnosis of HNPCC are three affected relatives with histologi- cally verified edenocercinoma of the large bowel (one must be a first-degree relative of one of the others) in two successive generations of a family with one patient diagnosed before age 5D years. The presence of other HNPCC- related carcinomas should raise the suspicion of this syndrome. In patient with an estab- lished diagnosis of colorectal cancer, tumor testing for presence of mismatch repair gene products (immunohistochemistry) andl or MSI can sometimes serve as screening for this syndrome “| HNPCC results fiom mutations in mismatch repair genes, nd like FAP, specific mutations are associated with different phenotypes For example, mutations in PMS? or MSH result in ‘a more attenuated form of HNPCC when compared to mutations nother genes, MSHS inactivation also appeats tobe associated with « higher risk for endometrial cancer. Further significance ofthese specific mutations remains to'be determined Screening colonoscopy is recommended annually for at- risk patients beginning at either age 20 to 25 years or 10 years younger than the youngest age a diagnosis in the family, which- ever comes first Because of the high sk of endometrial carci- znom, tnsvaginal ultrasound or endomettil aspiration biopsy is also recommended annually after age 25to 35 years. Because there is 0 40% risk of developing a second colon cancer, total colectomy with ileorectal anastomosis is recommended once adenomas or a colon carcinoma is diagnosed. Annual proctos- copy is necessary because the risk of developing rectal cancer remains high Similarly, prophylactic hysterectomy andlbilaterl www. ketabpezeshki.com 1207 SONY ONY ‘WAL234 'NO109 fTsETEL TY)1208 | SNOLLVEAOISNOD 31519348} salpingo-oophorectomy should be considered in women who have completed childbearing Familial Colorectal Cancer. Nonsyndromic familial coloree- tal cancer accounts for 10% to 15% of patients with colorec- tal cancer. The lifetime risk of developing colorectal cancer increases with a family history ofthe disease. The lifetime risk. of colorectal cancer ina patient with no family history of this disease (everage-tisk population) is approximately 6%, but rises to 12% ifone fst-degree relative is affected and to 35% if two fist-degree relatives are affected. Age of onset also impacts risk, and a diagnosis before the age of 50 years is associated with @ higher incidence in family members. Screening colonoscopy is recommended every 5 years beginning at age 40 years or begin- ning 10 years before the age ofthe eatliest diagnosed patient in the pedigree. While there are no specific genetic abnormalities that are associated with familial colorectal cancer, any of the defects found in either the LOH pathway or MSI pathway may bbe present in these patients Prevention: Screening and Surveillance Because the majority of colorectal cancers are thought to azise fiom adenomatous polyps, preventive measwes focus on denti- fication and removal of these premalignant lesions. In addition, many cencers are asymptomatic, and screening may detect these tumors at an early and cweble stage (Table 29-1). Although, screening for colorectal cancer decreases the incidence of cancer and cancer-related mortality, the optimal method of screening remains controversial. Screening guidelines aze meant for asymptomatic patients.“ Any patient with a gastointes- tinal complaint (bleeding, change in bowel habits, pain, ete) requires a complete evaluation, usuallyby colonoscopy. Fecal Occult Blood Testing. FOBT is known to reduce colorectal cancer mortality by 33% and metastatic disease by 50%. However, FOBT is relatively insensitive, missing up to ‘50% of cancers ancl the majority of adenomas Its specificity is lowbecause 90% of patients with postive tests do not have colorectal cancer. Compliance with annual testing is low ancl costs are significant if one includes the colonoscopy examina- tions done to evaluate patients with positive FOBT. Nonethe- less, the dixect evidence that FOBT screening is efficacious and decreases both the incidence and mortality of colorectal cancer 4s s0 sting that national guidelines recommend anual FOBT. screening for asymptomatic, average-risk Americans older than, ‘5D yeaus of age as one of several accepted strategies. Newer ‘mununohistochemical methods for detecting human globin may prove to be more sensitive and specific.” A positive FOBT test should be followed by colonoscopy. Flexible Sigmoidoscopy. Screening by flexible sigmoidos- copy every 5 years may lead toa 60% to 70% reduction in mor- tality from calorectal cancer, chiefly by identifying high-risk individuals with adenomas. However, itis important to recog- nize that Isione inthe roximal colon cannot be identified, and, for this reason, flexible sigmoidoscopy has often been paired, with air-contrast barium enema to detect transverse and right colon lesions. Patients found to have a polyp, cancer, or other lesion on flexible sigmoidoscopy will zequte colonoscopy.” Fecal Occult Blood Testing and Flexible Sigmoidoscopy. Seven] tials have shown that FOBT screening is least effec- tive at detecting rectosigmoid cancers” This is recisely the area screened by flexible sigmoidoscopy, thus, the combination, of the two tests has been suggested as @ reasonable screening Advantages and disadvantages of screening modalities for asymptomatic individuals ADVANTA‘ DISADVANTAGES Fecal occult blood testing ase of use and noninvasive ‘May not detect most polyps Low cost Low specificity Good sensitivity with repeat testing Colonascopy required for positive result Poor compliance with serial testing ‘Sigmoidescopy ‘Examines colon most at isk Invasive ‘Very sensitive for polypdetection in left colon | Uncomfortable Does not require full bowel preparation Slight risk of perforation or bleeding (enemas only) ‘May miss proximal lesions Colonoscopy required if polyp identified Colonoscopy Examines enfize colon ‘Most iwvasive Highly sensitive and specific ‘Uncomfortable and requires sedation ‘Therapeutic ‘Requires bowel preparation ‘Risk of perforation or bleeding Costly ‘Double-contast barium enema Examines enfize colon ‘Requites bowel preparation. Good sensitivity for polyps >1 om Less sensitivity for polyps <1 cm. Examines entze colon ‘May miss lesions inthe sigmoid colon Colonoscopy required for positive result ‘Computed tomography colonography | Noninvasive ‘Requites bowel preparation (virtual colonoscopy) Sensitivity maybe as good as colonoscopy _ Insensitive for small polyps ‘Minimal experience and data Colonoscopy required for positive result (021)66485438 66485457 www. ketabpezeshki.comstrategy. Winawer and colleagues, in study of 12,479 subjects, slowed thatthe combination of FOBT annually wit flexible sigmoidoscopy every 5 yee resulted in lower mortality fiom colorectal cancer and better survival in patents with colorectal cancer” Such deta led to the American Cancer Society recom- rendatons that one of the acceptable screening regimens for average-rsk Americans isthe combination of FOBT annually and flexible sigmoidoscopy every 5 yeass, this combination was prefered over either tet elone. The addition of ar-contast Dbrium enema to asses the proximal colon may imgrove sen- sitivity es wel Colonoscopy. Colonoscopy s cunently the most acute and rostconplete method forexansning the lage bowel, This woce- dime ishighly sensitive fordetecting even small polype («lem») and ellows biopry, polypectomy, control of hemorthage, and dilation of stictues. However, colonoscopy does require rechanicel bowel preperation, andthe discomfort associated with the procedizerequtes conscious sedation in most patients Colonoscopy i also considerably moze expensive than other screening mnodalites and requires a well-tained endoscopst The rsh of¢ major complication after colonoscopy (perforation anal hemonage) is extemely low (0.2%-0 3%) Nevertheless, deaths Ive been reported Alr-Contrast BariumEnema, As-contastbariun enemas alo gh sensitive for detecting polyp greater than {cm indameter (00% sensitivity). Unfortunately, there ze no stuies proving its efficeey for scieening Inge populations. Accuracy is greatest the proximal colonbutmaybe compromised in the sigmoid colon if there iz significant diverticulosis The major disadvantages of ‘bamum enema are the eed for mecbanical bowel preperation and the requizement fr colonoscopy fa lesion i discovered Computed Tomography Colonography (Virtual Colonos- copy). Adtances in imaging technology have czeated a num- ber of less invasive, but highly accurte tools for seeening, CT colonography males use of Ielicel CT techaology and thee- dimensional reconstruction to image the intaluninal colon, A reent, ptentsrequze a mechanicel bowel preparation The Colon i then insulted witha, a spiel CT is peaformed, and both two-dimensional and tee-dimensional images are genes- ated Inthe bands ofe qualified reiologist, sensitivity appears toe as good as colonoszopy for colorectal cancers end polyp gueater than | cm in siz.” Colonoscopy is requzed if lesion 3 identified, CT colonogzephy is also weful for imaging the ori colon in cases of cbstuction or ifacolonoszopy can rot be completed. Limitations of this technique include false- postive results fiom retained stool, diverticular disease, haustal folds, motion axtifcts, and an inability to detect fat adenomas Guidelines for Screening. Cuzent American Cancer Society guidelines advocete screening fr the average-risk population (asymptomatic, no family history of colorectal canon, 20 personal history of polype or colorectal cinoma, no fanil- Jal syndrome) beginning at age SO years, Recomended pro- cedutes include yeelly FOBT, flexible sigmoidoscopy every 5 yeats, FOBT and flexible sigmoidoscopy in combination, air-contast barium enema every 5 yeas, o colonoscopy every 10 yeas Patents with other risk factors should be screened, earlier and more fiequenily (Teble 29-2) Routes of Spread and Natural History Corcinoms of the colon and rectum arses inthe mucosa. The tumor subsequently invades the bowel wall and eventuelly (021)66485438 66485457 adjacent tissues and other viscera, Tumors maybecome bulky snd cixcunferential, leading fo colon obstruction. Local exten- sion (especiallyin the rectum) may occasionally cause obstuc- tion of other organs such asthe weter Regional lymph node involvement i the most common form of szreed of colorectal carcinoma and urwally precedes distant metastasis othe development of carcinomsetosis. The lielihoodof nodal metastasis increases with tur size, poorly differentiated histology, Iymphovascuar invasion, and depth of invasion The T stage (depth of invasion) is the single most significant redctor of lymph node sjweed. Caeinoma in sit (Ts) in which there is no penetation ofthe moscuazis mucosa (basement membrane) has also been called It gi grade dyspla- sia and should cary no risk of lymph node metastasis. Stall lesions confined to the bowel wall (Tl and T2) are associated with Iymph node metastasis in 5% to 20% of cases, whereas Jager tumors that invade huough the bowel well or into a) cent oxgens (T3 and T4) are likely to have lymph node metas- fazis in more than 50% of eases. The nunber of lymph nodes with metastases conelates with the presence of distant disease andlinvessely with survival. Fou or more involved lymph nodes edit poor prognosis In colon cancer, lymphatic reed uru- ally follows the major venous outflow from the involved seg rent of the colon. Lymphtic seed fiom the rectum follows two routes. In the upper rectum, drainage ascends along the superior rectal vessel othe inferior mesenteric nodes. Inthe lower rectum, lymphatic drainage may couse along the mile rectal vesels, Nodal spead elong the inferior ctl vessels © the internal ie nades or groin see unless the tuner wolves the anal canal or the proximal lymphatics axe blocked with tumor Fig. 29-23) “The most commonsite of distant metastasis from colorec- tal cancer is the liver. These metastases ari fiom hematog- enous seed vie the portal venous system, Like lymph node retatais, the nsk of hepatic metastasis increases with tumor size and funor grade. However, even small tumors may pro- dice distant metastasis. The lung is lzo a site of hematogenous spread, but this raely occur in isolation, Cazcinomsatosis (Giffuse poitoneel metastases) occwsby peritoneal seeding end Inga dismal prognosis Staging and Preoperative Evaluation Clinical Presentation, Symploms of colon and rectal cancers axe nonspecific and generally develop when the cancers locally advanced The clasic ust symptoms aze a change in bowel Ibis and rectal bleeding. Abdornnal ain bloating, and other signs of obstruction typicelly occur with lager hunor an sug gest more advanced disease, Because of the caliber ofthe bowel tnd the consistency of the stool, left-sided tumors are more likely to cause obstruction than ave sightsided tuors. Rectal ttmors may cause bleeding, tenesmus, and pein, Allematvely, patents maybe asymptomatic and/or resent with unexplained sense, weight loss, or oor appetite Staging, Colorectal cancer staging is based on tumor depth and the presence or absence of nodal or distant metastases Older staging systems, suchas the Dukes" Classification and ts Astles-Coller modification, have been replaced by the tumer- node-metastasis (TNM) staging system (Table 29-3). Stage I disease includes adenocarcinomas that ee invasive though the muscularis mucosa but are confined to the submucosa (T1) or the muscularis ropa (T2) inthe sbsence of nodel metestases Stage II disease consists of tumors that invede through the www. ketabpezeshki.com 1209 SONY ONY ‘WAL234 'NO109 fTsETEL TY)Screening guidelines for colorectal cancer | SNOLLVEAOISNOD 31519348} LATION INTIAL AGE MEN ING TEST ‘Average risk soy ‘Annual FOBT or Flexible sigmoidoscopy every 5 yor ‘Annual FOBT and flexible sigmoidoscopy every 5 yor ‘Air-contast barium enema every 5 yor Colonoscopy every 10.y ‘Adenomatous polyps soy Colonoscopy at fast detection; then colonoscopy in3 y Ifno funther polyps, colonoscopy every 5 y Ifpolyps, colonoscopy every3 y Annual colonoscopy for >5 adenomas Colorectal cancer ‘At diagnosis Pretreatment colonoscopy, then at 12 mo after cwative resection, ‘then colonoscopy after 3 y, then colonoscopy every 5, ifn new lesions ‘Ulcerative colitis, Crohn's | Atdiagnosis; then after y | Colonoscopy with multiple biopsies every 1-2 y colitis for pancolitis, after 15 y for left-sided colitis FAP 1eDy ‘Annual flexible sigmoidoscopy ‘Upper endoscopy every 1-3 yafter polyps appear ‘Attenuated FAP ay ‘Annual flexible sigmoidoscopy ‘Upper endoscopy every 1-3 yafter polyps appear HNPCC 225 y Colonoscopy every 1-2 y Endometrial aspiration biopry every 1-2 y Familial colorectal cancer | 40 yor 10 ybefore the age of Colonoscopy every Sy fast-degree relative the youngest affected relative | Increase fiequency if multiple family members are affected, ‘especiallybefore 50 y [FAP =f dmmustoue pobpori; FOBT ~fecal occ blood tetng: HNPCC ~haredzary nenpobypris cola cancer. Sources: Data adapted fem Saath ee Pignane el" end Levin etl” ‘Superior. reetal a Inferior mesenteic 3 Common ise a Figure 29-23. Lymphatic drainage ofthe rectum a = artery. (021)66485438 66485457 ‘bowel wall into the subserose or nonpzrtonealized pericolic or petirectl tissues (T3) or into other orgens or tissues or through the viscerl peritoneum (T4) without nodal metastases. Stage II disease includes any T stage with nodal metastases, and stage IV disease denotes distant metastases ‘The preoperative evaluation usually identifies stage IV disease. In colon cancer, differentiating stages I, II, end IIL depends on examination of the resected spzcimen. In rectal cancer, endorectal ultrasound or MRI may predict the stage (ltrasound stage, uTxNx) preoperatively, but the final determi- nation depends on pathologic examination ofthe resected tumor and adjacent lymph nodes (pathologic stage, pTxNx). Disease stage comelates with 5-year survival. Patients with stages I end TI disease can expzct excellent survival rates. The presence of nodal metastases (stage IID) decreases suvival (Table 29-4) ‘The 5-year survival rate with stage IV disease is less than 16%. However, in wel-selected patients, metastesectomy, especially of isolated liver orlung lesions, can result in cue. In recta can- cer, staging has been futher refined, and outcomes suggest that subgroups of patients within each stage may have very differ- ent prognoses (Teble 29-5). If the mesonectum around @ rectal cancer is involved or fhueatened (only 1-2 mm of clearance), there is @ very high likelihood of local recumence and a poor www. ketabpezeshki.comTNM staging of colorectal carcinoma ‘American Joint Committee on Cancer staging DEFINITION Loca SUR “Tumor stage (T) Nu STAGE | RECURRENCE (96) | (%) x J m2N0 II 3 0 a BN 0A 8 14 TaND 0B 15 65 a TI2NL TIA 6 81 Tl Tumor invades abmucosa oe o nR Tumor ivades muscularis ropa TN [mB (il 61 us ‘Tumor invades tnough musculais propria TN? [mic (15 a info subsea or info nonpenitonealized TaNi2 {MIC [19-22 36 pticoicorpenzectal tissues ee 74 Tunardieetly invades oter ongensortssuss Sout: arn Gdn o> Cy ve or pefortes the visceral pentoneum of specimen prognosis. This cixcunferentil or radial margin is probably D NX Regional lymph nodes cannotbe assessed NO ‘No lymph node metastasis, NI ‘Metastasis to one to three pericolic or erizectal lymph nodes N2 ‘Metastasis to four or more pericolic or erizectal lymph nodes NB ‘Metastasis to anylymph node along a major named vascular trunk Distant metastasis (MD MK Presence of distant metastasis canmot be assessed MD No distant metastasis MI Distant metastasis present ‘TM -pmernodeawtacasis Source: Used wih the pissin of the Americ Joint Conmtee ox (Cancer (AJCC), Chicag, nos. The ergmal soe forthicmateria ‘he AICC Cancer Sugg Meal, Sevath Eition (2010)publshed by ‘Sprniger Science nd Burmese Media LLC, mm prnge com. TNM staging of colorectal carcinoma and 5-year survival stage | TNW 5-Y SURVIVAL (%) I T12,NO 932 Ta 73,NO 847 Tb 74,NO na Ie T12,NI 34 Ib 73,N1 641 Me T3,N2orT4NI-2 |443 Vv ‘Tany, Nany, ML 81 TM -nmnernode atta Source: Data som OConnl et ab” (021)66485438 66485457 best assessed meoperatvely by MRI. Although nodal invalve- rentis the single most impotent prognostic fectorin colorectal carcinoma, tumor charecteriscs, suchas degree of ifferentie- tion, mucinous or signe.zng cell histology, vascular invasion, end DNA aneuploidy, also adversely affect prognosis. Molecw- Jar profiling is ewnently being studied in an effort to further improve prognostic indicators Preoperative Evaluation. Once a colon or rectal carcinoma has been diagnosed, a staging evaluation shouldbe undertaken The colon must be evaluated for synchronous tumors, usally by colonoscopy. Synchronous disease will be present in up to ‘SY of patients. Forvectl cancers, digital ectal examination and nigid or flexible roctoscopy with biopsy shouldbe pesforned to assess tumor size, location, morphology, histology, ane fixe- tion. Endorectal ultrasound or MRI can be invaluable in stag- ing rectal cancer en is wed to classify the ultrasound T and N stage of rectal cencens (Fig. 29.24). A chestlebdominel/pelvic Figure 29-24. Endorectal ultrasonography chewing a TS zectal carcinoma, The dotted line is being used to measure the diameter of te lesion. (Used vith permission of Charles O. Firme IIL MD. Momeapolis, MN) www. ketabpezeshki.com 1211 SONY ONY ‘WAL234 'NO109 fTsETEL TY)1212 | SNOLLVEAOISNOD 31519348} CT scan should be obtained to evaluate for distant metastases. Pelvic CT scan, and sometimes MRI, can be useful in large rectal tumors end in recent disease to determine the extent of locel invasion. Among patients with obstructive symptoms, ‘a water-soluble contrast study (Gastrografin enema) may be ‘useful for delineating the degree of obstruction. [tis important to avoid mechanical bowel preparation (for either colonos- copy or sugery) in a patient who appeaas to be obstructed. PET scan maybe useful im evaluating lesions seen on CT scan, ‘and in patients in whom a risky or highly morbid operation, is planned (pelvic exenteration, sacrectomy). Preoperative CEA is often obtained and may be useful for postoperative follow-up, Therapy for Colonic Carcinoma Principles of Resection. The jective in teatment of car- cinoma of the colon is to remove the primary tuner along with its Iymphovascular supply. Because the Iymphetics of the colon accompany the main eteiel supply, the length of bowel resected depends on which vessels are supplying the segitent involved with the cancer. Any adjacent organ or tis- sue, such as the omentum, that has been invaded should be resected en bloc with the tumor If all ofthe tumor cannot be removed, a palliative procedure should be considered, although it suportnt to note that “debulking” is azelyeffec- tive in colorectal adenocarcinoma ‘The presence of synchronous cancers or adenomas or & strong family history of colorectal neoplasms suggests that the ene colon is at sk for carcinoma (often celled afield defect), anal a mbtotl or total colectomy should be considered, Mete- eluonous tumors (a second primary colon eancer) identified ding follow-up studies shouldbe treated sinilerly. Howeves, the sugeon must be awaze of which mesenteric vessels have been ligetedat the inital coleslomybecause that may niluence the choice of procedue ‘The aumber of lymph nodes recovered in the sugi- cal specimen has long served as a proxy for the oncologic adequacy of resection A number of studies previously have ruggested tht a minimum of 12 lymph nodes in the resected specimen aze necessary for adequate staging. In addition, patients in whom mare nodes aze harvested have better long fem outcome.” As such, a 12-node minimum has been sug- gested as an appropriate benclanark for assessing quality of care, However, several investigatozs recently have called this ino question, noting thet the number of lymph nodes exam- ined does not comelate with staging, use of adjuvant che- rotherapy, or ptient suvivel” Others have suggested that the number of negative Lymph nodes andlor the lymph node rao (positive lymph nodes to totl lymph nodes) may futher improve staging Tf unexpected metastatic diese is encountered at the time of lapeotomy, the decision about whether to proceed with resection of the primary tumor depends on the volume of distant disease, location and sizeof the mary tumor, the operation zuzed to remave the pmry funor, and the opeze- tive approach Ifthe metastatic diseese is low volume (oated or potentially resectable liver lesions) and the resection of the puinary tumor is straightforward (seguienal ebdomsnalcolec- tomy), itt robebly reasonable to proceed wath resection, On the other hand ifthe metastatic disease is high volume (carci xnomatosis), especially ifthe primary tumor is minimally symp- tomatic the operetion should be aborted in order to facilitate, (021)66485438 66485457 early systemic chemotherapy. Some centers fevor starting the operation with diagnostic laparoscopy in cases where nsk of discovering metastasis is high inorder to minimize the magni- tude of the operation should surgery be aborted. With recent advances in chemotherapy, many of these patients will never developa complication from the primary tumor requiring surgi- cal intervention." Other palliative approaches include a bypass or proximal stoma for obstructing lesions, Stage-Specific Therapy Stage 0 (Tis, N0, MO). Polyps containing carcinoma in stu (high-grade dysplasia) camry no risk of lymph node metastasis However, the presence of high-grade dysplasia increases the risk of finding an invasive carcinoma within the polyp. For this reason, these polyps should be excised completely, and pxtho- logic margins should be fiee of dysplasia. Most pedunculated polyps and many sessile polyps may be completely removed endoscopically. These patients shouldbe followed with frequent colonoscopy to ensure thet the polyp has not recured and that an invasive carcinoma has not developed. In cases where the polyp cannot be remove entirely, «segmental resection i 1¢- ommended Stage I: The Malignant Polyp (T1, NO, MO). Occasionally « polyp that was thought to be benign willbe found to hexbor invasive carcinoma affer polypectomy. Treatment of @ maiig- nant polyp is based on the risk of locel recumrence and the risk of lymph node metastasis * The risk of lymph node metastases depends primarily onthe depth of invasion. Invasive carcinoma in the head of a pedunculated polyp with no stalk involvement came a low risk of metasiass (<1%) and maybe completely resected endoscopically. However, lymphovascular invasion, poorly differentiated histology, or tumor within 1 mm of the resection margin greatly increases the risk of local recunence and metastatic spread. Segmental colectomy is then indiceted Invasive cercinoma arising in a sessile polyp extends into the sibmucosa and is usuallybest teated with segmental colectomy ig. 29-25). Stages I and II: Localized Colon Carcinoma (T1-3, NO, (MO). The majority of patients with tages I and II colon cancer will be cued with surgical resection. Few patients with com- pletely resected stage I disease will develop either local or dis- fant ecumence, end adjuvant chemotherapy does not improve Pedunculated polyp Musculai Figure 29.25. Levels of invasive cazeinoma in pedunculated and sessile polyps. ca = carcinoma www. ketabpezeshki.comsurvival in these patients. However, upto 46% of patients with completely resected stage II disease will ultimately die from colon cancer For this reason, adjuvant chemotherapy has been suggested for selected patients with stage II disease (young patients, tumors with “high-1sk” histologic findings). Itremains contoversial as to whether chemotherapy improves suvivel rates in these patients, Molecular profiling holds promise for Improving patient selection in these early cancers ‘Stage I1I- Lymph Node Metastasis (Tany, NJ, MO). Patients with lymph node involvement are at significant sk forboth locel end distant recunence, and adjuvant chemotherapy has been recommended routinely in these patients. 5-Fluorouracil-based regimens (with leucovorin) and oxaliplatin (FOLFOX) reduce recuences and improve survival in this patient population” It is important to note, however, that a subgroup of patents with stage II disease will do well without chemotherapy. MSI status in particular predicts good prognosis. Subset analysis fiom the CRYSTAL thal has shown that patients with MST-tigh stage IIT disease do not benefit from 5-fluorourecil-besed chemotherapy. Mblecular profiling, therefore, may be helpful in determining ‘hich stage II patents cen safely aveid systemic chemotherapy Stage IV. Distant Metastasis (Tany, Nany, M1). Suvival is extremely limited in stage IV colon carcinoma, However, unlike many other malignancies, highly selected patents with isolated, resectable metastases may benefit fiom resection (inetastasectomy). The most common site of metastasis isthe liver. Of patients with systemic disease, approximately 15% will have metastases limited to the liver. Of these, 20% are poten- tially resectable for cue. Survival is improved in these patients (20% ~0% 5-year survival) when compared to patients who do not undergo resection. Hepatic resection of synchronous metas- tases fiom colorectal carcinoma maybe performed as a com- bined procectue or in two stages. All patients require edjuvant chemotherapy. The second most common site of metastasis is the Img, occurring in approximately 20% of patients with colorectal carcinoma. Although very few of these patients will be potentially resectable, among those who ere (ebout 1%4-2% ofall colorectal cancer patients), long-term survival benefit is approximately 30% to 40% ® There ae limited reports of suc- cessful resection of metastases in other sites (ovary end 1eto- penitoncum are most common) ‘The remainder of patients with sage IV disease cannotbe cumed sugicelly, and therefore, the focus of treatment should be palliation * Methods such as colonic stenting for obstract- ing lesions of the left colon also provide good palliation. More limited sumgical intervention suchas a diverting stoma or bypass proceciure maybe appropriate in patents with stage IV disease who developobstuction Hemombage in en unsesectable tumor can sometimes be controlled with angiographic embolization. Exfemal beam radiation also has been used for palliation Therapy for Rectal Carcinoma Principles of Resection. The biology of rectal adenocesci- xonin is thought fo be identical tothe biology of colonic adeno- carcitoms, end the operative principles of complete resection of the primary tuo, its lymphatic bed, and anyother involved ongen apply to sugicel resection of ecelcercitoma. Howeves, the anatomy of the pelvis and proximity of other structures (eters, bladder, prostate, vagina ne vessels, and sacrum) rake resection more challenging and often zequie a ciferent approtch thn for colonic adenocarcinome. Moreover itis more difficult to achieve negative redial mazgine in zectal cancers that (021)66485438 66485457 extend through the bowel wall because of the anatomic limite- tions of the pelvis. Therefore, local recurrence is higher than with similar stage colon cancers. However, unlike the intaperi- ‘oneal colon, the relative paucity of small bowel and other radi- ation-sensitive structures in the pelvis makes it easier to treat rectal tumors with radietion. Therapeutic decisions, therefore, are based on the location and depth of the tumor and its elation. ship to other structures inthe pelvis. Local Therapy. The distal 10 cm of the rectum are accessible transanally, For this reason, severllocel approaches have been proposed for treating rectal neoplasms. Transanal exon (full thickness or mucosal) is an excellent approach for noncizcum- ferential, benign, villous adenomas of the rectum. Transanal endoscopic merosurgery (TEM) end transanal minamally inva save surgery (TAMIS) make use of a specially designed yroc- toscope, magnifying system, and instruments simular to those used in laparoscopy to ellow local excision of lesions higher an the rectum (up 15 em). Although this technique has been ‘wed for selected TI, and some T2, carcinomas, local excision does not allow pathologic examination ofthe lymph nodes end night therefore uderstge patents, Moreover, local recunence rates ere high after tensanal excision, and selvage sugery, while often ewative, is associated with poorer survival then with initial radical stagery. Local excision of any rectal neo- plasm should be considered an excizonal opsy beceuse final pathologic examination of the specimen may reveal an invasive carcinoma thet then mandates more radical therapy. Ablative techniques, such as electrocautery ox endocavi- tary radiation, elso hve been used. The disadvantage of these techniquesis thatno pathologic specimen s retrieved to confi the tumor stage. Fulguration is generally eserved for extremely high-risk patents with e limited life span who cannot tolerate nore radical suger. Radical Resection. Radical resection is preferred to local therapy for most rectal carcinomas. Radical resection involves removal of the involved segment of the rectum along withts Iym- phovascular supply. Although any microscopically negative mar- gin hasbeen suggested tobe adequate, most swgeons still atempt fo obtaina 2-cm distal mural maxgin for cwative resections Total mesorectal excision (TME) isa technique that uses sharp dissection along anatomic planes to ensure complete resec- tion of the rectal mesentery cuzing low andl extended low ante- rior resections. For upper rectal or rectosigmoid resections, @ partial mesorectal excision of at least 5 cm distal to the tumor appears adequate. TIME both decreases local ecwrence rates and ngpoves long-term suvival mites. Moreover, this technique is associated with less blood loss and less risk to the pelvic nerves and presacral plexus than is blunt dissection. The principles of| ‘TME should be applied to all radical resections for rectal cancer. Recunence of rectal cancer generally has a poor prog- nosis. Extensive volvement of other pelvic oxgans (usually occurring inthe setting of tumor zecwnence) may require a pel- Me exenteration. The rectal and perineal postions of this opera- tion are simular to an APR, but en bloc resection of the wreters, bladder, and prostate or uterus and vagina are also pexformed, ‘A pemnanent colostomy and an ileal conduit to drein the unary tract maybe necessary. The sacrum may also be resected ifnec- essary (sacrectonp) up to the level of the $2-S3 junction. These operations are best performed in tertiary centers with multidisei- plinary teams consisting of a colonand rectal sugeon, wologist, newoswgeon, and plastic sugeon, www. ketabpezeshki.com 1213 SONY ONY ‘WAL234 'NO109 fTsETEL TY)1218 3 8 EI 2 Sry pores No metastases ay ner pee meany ens chemoradiation Radical Radical ry feed No metastases ‘Asymptomatic | Symptomatic Eo Restage rere rmutiple metastatic Rezectable/single metastatio site Continue cy ablation, stoma, eed Figure 29-26. Diagnostic algorithm for rectal cancer. CT = computed tomography; MRI = magnetic resonance imaging; UIS = ultrasound Stage-Specific Therapy (Fig. 29-26). Pretreatment stag- ing of rectal carcinoma often relies on endorectal ullesound to determine the T and N status of e rectal cancer. Ultrasound is highly accurate at assessing tumor depth, but less accurate in diagnosing nodal involvement. Ultrasound evaluation can fruide choice of therapy in most patients. MRI is useful to assess mesorectal involvement. When the radial margin is tneatened or involved, neoadjuvant chemoradiation is recommended. Stage 0 (Tis, NO, MO). Villous adenomas harboring carci- znome inst (high-grade dysplasia) are ideally treated with local excision. A I-cm margin should be obtained. Rarely, radical resection will be necessary if transanal excision is not techni- cally possible (large circumferential lesions). ‘Stage I Localized Rectal Carcinoma (T1-2,NQ.MO). Although local excision has been used for small, favorable sessile wTINO end wT2N0 rectal cancers, local ecunrence rates may? as high 5 20% andl 0%, respectively. For this reason, raicel resection is strongly recommenced in all good-risk patients. Lesions with unfavorable histologic characteristics and those located in the distal third of the rectum, in particular, are prone fo recuzence In high-risk patients and in patients who refuse radical sugery because of the risk of need for a permanent colostomy, local excision may be adequate, but sting consideration should be given to adjuvant or neoadjuvant chemoradiation to improve local contol. The efficacy of adjuvant or neoadjuvant chemo- rediation followed by transanal excision in patients who can (021)66485438 66485457 tolerate radical sugery has been controversial. Early results from ACOSOG 26041, in which patients with TD rectal c cers received neoadjuvant chemoradiation followed by transanal excision, showed a pathologic complete response rate of 44% Long-term outcomes, however, are nat yet known Locally Advanced Rectal Cancer (Stages II and I) Stage I Localized Rectal Carcinoma (T3-4, NO, MO). Larger rectal tumors, especially if located in the distal ectum, axe more Likely to recur locally. There are two schools of thought, each differing in their approach to contol local recunences. Acvo- cates of total mesorectal resection suggest that optimization of operative technique will obviate the need for any adjuvant chemoradiation to contol local recurence after resection of | stages I, I, andl rectal cancers, The opposing school suggests that stages II and III rectal cancers will benefit from chemo- rediation. They argue that such therapy reduces locel recur- rences and prolongs survival whether given preoperatively or postopztively The advantages of preoperative chemoradiation include tumor shrinkage, increased likelihood of resection end ofa sphincter-sparing procedure, tumor downstaging by eating locally involved lymph nodes, and decreased nsk fo the small intestine. Disadvantages include possible overtreatment of eanly.siage tumors, impaired wound healing, and pelvic fibro- sis mereesing the risk of operative complications. Postopera- tive radiation allows accurate pathologic staging of the resected tumorand lymph nodes and avoids the wound healing problems www. ketabpezeshki.comsssociated with preoperative radiation However, bulky tumors, tunoss involving edjacent ongens, and very low zectal humors raybe much more cifiulto resect without preoperative radi ation and may require a mare extensive opezation. Stage I: Lymph Node Metastasis (Tay, N41, MO). Many sugeons now lecommend chemotherapy and radiation either re or postoperatively for node-positive rectal canceas. The advantages and disadvantages aze similar to those listed for stage II disease, except thatthe likelihood of averteating en ccaly.stge lesion is considerably Iss (ver the past two decades, e wide variety of studies have acdessed the issue of adjuvant end neoadjuvant therepy for locally advanced rectal cancer. Many of these studies demon- strated both improved local contol and prolonged suvival and renulted inthe 1990 National Institutes of Health (NIH) con- sensus conference recommendation for postoperative chemo- radiation therapy in these patents There is litle contoversy regarding chemoradiation therapy for stage III (node-positive) disease However, advances in suicel technique, suches TNE, for locally advanced node-negative cancers (3-4, NO, stage II) Inve improved local contol with sugery lone, romping some to abendonedjuvant chemoradiation in these paints, especially for those with cancers in the proximel rectum. Although the dita from these studies are intriguing other reports have shown that chemoradiation improves local contol and survivel even in patients who undergo TME. Thus, most colorectal sugeons in the United States confine to recommend adjuvant oF neo- adjuvant therepy for patients with locelly advanced disease Many Ewopsen sugeons now rely heavily on MRI staging to determine the need for neoadjwent chemoradiation. They se xeoadjuvant chemoradiation if the radial margin is thetened or involved by the cancer or if anal sphincter or other local ongen invasion is present. In the United States, chemoredie- tion therapy is tll ecommenced forall patients with stage IL disease and the majority of patients with stage II disease. In select patients with T3 tumors, favorable histology, end nege- tive radial margins, chemoradiation may not be necessary, but Javger prospective studies ae requzed before this approach can be recommended ‘Apgroprat ining of chemoradiation for loclly advanced rectal cancer has been debated. Historically, preoperative chemoradiation has been advocated based on tua shuinkage! downstaging, improved xsectablty and the possibilty of pex foming « sphincter-spering operation in some patients. In add tion, the absence of small bowel adhesions inthe pelvis may decrease toxicity. However, preoperative radiation therapy rayincteese operative complicetions and impaits wound healing Although preoperative endorectal ultrsound end MRI have improved our ability to stage rectal cance, clinical “ovestag- ing” can be problemetic, and neoadjuvant therapy may there- fore overeat patients with pT1-2, NO tumors. Advocates of postoperative rediation therapy cite more accurate pathologic staging endl fewer operative/postoperative complications. How. eve, lange, bulky tanors maybe uesecable cr equiree more extensive opzration (APR, pelvic exenteration) without preop- exative therapy. In addition, postoperative pelvic radiation may compromise Function of the neorectum Compasisons of perioperative toxicity and oncologic out- come have been advessed by the German CAOIAROIAIO.94 tual. In this study, pre-and postoperative chemoradiation were essociatedl with equivalent ecute toxicity and equivalent post operative complication rates. Postoperative chemoradiation, (021)66485438 66485457 however, doubled the risk of postoperative stricture formation Inaction, preoperative chemoradiation halved the risk of local recumence (6% vs. 12%). Based on these data, most surgeons consider reoperative chemoradiation tobe the most apgropriate therapy for locally advanced rectal cancer * ‘Stage IV: Distant Metastasis (Tany, Nany, 11). Like stage IV colon carcinoma, survival is limited in patients with distant retastass fiom recfal carcinoma. Isolated hepatic andlor pul- monary metastases are rare, but when present maybe resected for cure in selected patents." Some patients will equixe pal- liatve procedures. Radical resection may be required to con- tnol pain, bleeding, or tenesmus, but highly morbid procedures such es pelvic exenteration and sacrectomy should generally be avoided inthis setting. Local therapy using cautery, enlo- cavitary radiation, or laser ablation maybe adequate to con- trol bleeding or prevent obstruction. Intraluminal stents maybe ‘sefl in the uppermost rectum but often cause pain and tenes- rus lower in the rectum. Occasionally, « proximal diverting colostomy will be required to alleviate obstruction. A mucus fistula should be created if possible to vent the distal colon. It is critical that the morbidity of any procedure be realistically weighed against potential benefit in these patents with limited life expectancy. The assistance ofa palliative care team can be invaluable in this setting * Follow-Up and Surveillance Patients who have been treated for one colorectal cancer axe at risk for the development of recurzent disease (either locally or systemically) or metachronous disease (a second primary tumor). In theory, metachzonous cancers should be preventable by using suveillance colonoscopy to detect and remove polyps before they progress to invasive cancer. For most patients, & colonoscopy should be performed within 12 months after the diagnosis ofthe original cancer (or sooner if the colon was not examined in its entzety prior to the original resection). If that study is normal, colonoscopy should be repeated every 3 to 5 years thereafter. ‘The optimal method of following patients for recwnent cancer remains controversial. The goal of close follow- up observation is to detect resectable recurrence and to improve surival. Re-resection of local recuzence and resection of dis- tant metastasis to liver, lung, or other sites axe often technically challenging and highly moxbid, with only a limited chance of achieving long-term survival. Thus, only selected patients who ‘would tolerate such an approach shouldbe followed intensively. Because most recurences occur within 2 yeaas of the original diagnosis, surveillance focuses on this tine period. Patients who have undergone local resection of rectal tumors probably also should be followed with frequent endoscopic examinations (every 3-6 months for 3 yeas, then every 6 months for 2 yea) CEA is often followed every3 to 6 months for 2 years. CT scans ave often performed annually for 5 years, but there are few date to support this prectice. More intensive suveillance is appro- piste in high-risk patients such as those with possible HNPCC syndrome or T3, N+ cancers. Although intensive surveillance improves detection of resectable recumences, i i important to note thet a suvival benefit has never been proven, Therefore, the risks and benefits of intensive swveillance mustbe weighed, and treatment individualized Treatment of Recurrent Colorectal Carcinoma Between 20% and 40% of patients who have undergone cura- tive intent surgery for colorectal cazcinoma will eventually www. ketabpezeshki.com 1215 SONY ONY ‘WAL234 'NO109 fTsETEL TY)1216 | SNOLLVEAOISNOD 31519348} develop recunent disease. Most recuences occur within the fast 2 years after the inital diegnosis, but preoperative chemo- nediation therapy may delay recunence. While most of these patients wil present with distant metastases, a small proportion vil have isolated local recunence and maybe considered for salvage surgery. Recunence after colon cancer resection use ally ocets at the local site within the abdomen or inthe liver or hugs. Resection of other involved organs maybe necessary. Recuence of rectal cancer can be considerably more difficult to manage because of the proximity of other pelvic structures. If the patient hes not received chemotherapy and radiation, then adjuvant therapy should be administered prior to salvage sugery. Radical resection may require extensive resection of pelvic organs (pelvic exenteration with or without secrectomy). Ideally, the aim of a salvage operation should be to resect all, of the tumor with negative maxgins. However, if the ability to achieve a negative margin is in question, the addition of intaoperative radiation therepy (usually brachytherapy) can, help improve local contol, Pelvic MRI is useful for identify- ing tumor extension that would prevent successful resection (extension of tumor into the pelvic sidewall, nrvolvement of the aligc vessels or bilateral sacral nerves, sacral invasion above the 52-83 junction). Patients should also widergo a thorough pre- operative evaluation to identify distant metastases (CT of chest, abdomen, and pelvis, and PET scan) before undergoing suchan, extensive procedure Nevertheless, radical salvage sugery can, prolong survival in selected patients Minimally Invasive Techniques For Resection Lapmroscopie colectomy for cancer has been controversial Early reports of high pot site recuence dampened enthusi- asm for this tecnugue The silty to perform an adequate oncologic resection for cancer has also been questioned. Sev- eral ties have laid to rest many ofthese feats. The Clnicl, Gp Outcomes of Sugicel Therapy Study Group (COST), the Colon Carcinoma Laparoscopic or Open Resection (COLOR) triel, and the United Kingdom Medical Research Council Conventional versus Laparoscopic-Aaristed Suugery in Colorectal Cancer (CLASSICC) trial all have shown onco- logic equivalence between open and lapeoscopie techniques In these mult-insttutional studies, the rates of cancer recar- rence, survival, and quality of life were similar, suggesting that, inthe hands of an eppropsitely tained swgeon, laposcopic colectomy is approprite for cancer." The recent noduc- tion of robotic surgery offers an aditionl minimally invasive approech. Early studies suggest that robotic sugery my be the oncologic equivalent to laproscopic sugery for colorectal cancer. A prospective randomized, mulbcenter tal, Robotic venus Laparoscopic Reseoton for Rectal Cancer (ROLARR) is under way in hopes of enswening this question.” OTHER NEOPLASMS Rare Colorectal Tumors Carcinoid Tumors, Carcinoid tumors occur most commonly in the gastrointestinal tact, and up to 25% of these tumors axe found in the rectum, Most stall rectal carcinoids are benign, and. overall survival is greater than 90%, However, the isk of malig- nancy increases with size, end more then 60% of tumors greeter than 2 cm in diameter are associated with distant metastases. Rectal carcinoids appear to be less likely to secrete vasoactive substances then carcinoids in other locations, and carcinoid, (021)66485438 66485457 syndrome is uncommon inthe absence of hepatic metastases Small carcinoids can be locally resected transanally. Larger tumors or tumors with obvious invasion into the muscularis require more radical swgery. Cazeinoidl tumors in the proximal colon are less common and are more likely tobe malignant. Size also conelates with risk of malignancy, and tumors less than, 2em im diameter rarely metastasize. However, the majority of carcinoid tumors in the proximal colon present as bulky lesions, ‘and upto two this of patients will have metastatic spread atthe time of diagnosis, These tumors should urually be treated with rdical resection, Because carcinoid tumors axe typically slow growing, patients with distant metastases may expect reason- ably long swvival. Symptons of carcinoid syndrome can offen, be alleviated with somatostatin analogues (octreotide) andlor interferon-c. Tumor debulking can offer effective palliation in, selected patients Carcinoid Carcinomas. Composite carcinoid carcinomas (ade- nocarcinoids) have histologic features of both carcinoid tumors and adenocarcinomas. The natural history ofthese tumors more closely parllels that of adenocarcinomas than cercinoid tumors, ‘and regional and systemic metastases axe common, Carcinoid, carcinoma of the colon and rectum should be treated according to the same oncologic principles as followed for management of adenocarcinoma, Lipomas. Ligomas occur most commonly in the submucosa of the colon and rectum. They are benign lesions, but rarely may cause bleeding, obstruction, or intussusception, especially hen gveater than? em in diameter. Small asymptomatic lesions do not requie resection. Langer lipomas should be resected by colonascopic techniques or by a colotomy and enucleation or limuted colectomy. Lymphoma. Lymphoma involving the colon and yectum is axe Dut accounts for about 10% of all gastrointestinal lymphomas. The cecum is most often involved, probebly as a result of spreed from the temninal ileum, Symptoms include bleeding and obstruction, and these tumors may be clinically indistinguish- able from adenocarcinomas. Bowel resection is the treatment of choice for isolated colorectal lymphoma. Adjuvant therapy may be givenbased on the stage of disease Leiomyoma and Leiomyosarcoma, Leiomyomas are benign tumors of the sinooth muscle of the bowel wall and occur most commonly in the upper gastrointestinal tact. Most patients are symptomatic, but lage lesions can cause bleeding or obstruc- tion. Because itis difficult to differentiate a benign leiomy- oma fiom @ malignant leiomyosarcoma, these lesions should. be resected. Recurrence is common after local resection, but most small eiomyomas canbe adequately treated with limited, resection. Lesions laxger than 5 cm shouldbe treated with redi- cal resection because the risk of malignancy is high. Leiomyosarcoma is rare inthe gastrointestinal trac. When, this malignancy occws in the lauge intestine, the rectum is the most common ite. Symptoms include bleeding and obstruction ‘A radical resection is indicated for these tumors. Gastrointestinal Stromal Tumor. These rare tumors occur most commonly in the stomach and small intestine, but 5% to 10% arise in the colon or rectum, They ave often mistaken, for leiomyomas. Thisty percent to 50% axe malignant, thus all, lesions should be resected www. ketabpezeshki.com