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  1. 1. NEOPLASIA Adenocarcinoma of the colon and rectum is the third most common site of new cancer cases and deaths in both men and women in the United States. The estimated incidence of new cases in 2002 is 148,300, with 56,600 deaths from the disease. The lifetime risk of developing colorectal cancer in the United States is 6%, with over 90% of cases occurring after the age of 50. The death rate from colorectal cancer decreased by 1.8% per year from 1992 to 1998.[71] Colorectal cancer occurs in hereditary, sporadic, or familial forms. Hereditary forms of colorectal cancer have been extensively described and are characterized by family history, young age at onset, and the presence of other specific tumors and defects. Familial adenomatous polyposis (FAP) and hereditary nonpolyposis colorectal cancer (HNPCC) have been the subject of many recent investigations that have provided significant insights into the pathogenesis of colorectal cancer. Sporadic colorectal cancer occurs in the absence of family history, generally affects an older population (60 to 80 years of age), and usually presents as an isolated colon or rectal lesion. Genetic mutations associated with the cancer are limited to the tumor itself, unlike hereditary disease where the specific mutation is present in all cells of the affected individual. Nevertheless, the genetics of colorectal cancer initiation and progression proceed along very similar pathways in both hereditary and sporadic forms of the disease. Studies of the relatively rare inherited models of the disease have greatly enhanced the understanding of the genetics of the far more common sporadic form of the cancer. The concept of “familial” colorectal cancer is relatively new. Lifetime risk of colorectal cancer increases for members in families in which the index case is young (younger than 50 years of age) and the relative is close (first degree). The risk increases as the number of family members with colorectal cancer rises ( Table 48–2 ). An individual who is a first-degree relative of a patient diagnosed with colorectal cancer at an age younger than 50 is twice as likely as the general population to develop the cancer. This more subtle form of inheritance is currently the subject of much investigation. Genetic polymorphisms, gene modifiers, and defects in tyrosine kinases have all been implicated in various forms of familial colorectal cancer. Table 48-2 -- Familial Risk and Colon Cancer Familial Setting Approximate Lifetime Risk of Colon Cancer General U.S. population 6% One first-degree relative * with colon cancer Two- to 3-fold increased Two first-degree relatives * with colon cancer Three- to 4-fold increased First-degree relative * with colon cancer diagnosed ≤50 yr Three- to 4-fold increased One second- or third-degree relative † ‡ with colon cancer 1.5-fold increased Two second- or third-degree relatives † ‡ with colon cancer Two- to 3-fold increased One first-degree relative * with adenomatous polyp Two-fold increased From Burt RW: Colon cancer screening. Gastroenterology 119:837–853, 2000, with permission. * First-degree relatives include parents, siblings, and children. ‡ Third-degree relatives include great-grandparents and cousins. † Second-degree relatives include grandparents, aunts, and uncles. Colorectal Cancer Genetics The field of colorectal cancer genetics was revolutionized in 1988 by the description of the genetic changes involved in the progression of a benign adenomatous polyp to invasive carcinoma.[72] Since then, there has been an explosion of additional information about the molecular and genetic pathways resulting in colorectal cancer. Tumor suppressor genes, DNA mismatch repair genes, and protooncogenes all contribute to colorectal neoplasia, both in the sporadic and inherited forms. The Fearon- Vogelstein “adenomacarcinoma” multistep model of colorectal neoplasia represents one of the best-known models of carcinogenesis ( Fig. 48–44 ).[73] This sequence of tumor progression involves damage to protooncogenes and tumor suppressor genes. The multistep carcinogenesis model can serve as a template to illustrate how certain early mutations produce accumulated defects resulting in neoplasia. The specific contributing mutations in genes such as APC have been intensely studied. It is important to view this model and others as progressive and in flux as interconnected cell cycle control pathways and new functions for well-known genes are becoming recognized ( Table 48–3 ).
  2. 2. Specific Mutations Tumor Suppressor Genes Tumor suppressor genes produce proteins that inhibit tumor formation by regulating mitotic activity and providing inhibitory cell cycle control. Tumor formation occurs when these inhibitory controls are deregulated by mutation. Point mutations, loss of heterozygosity (LOH), frame shift mutations, and promoter hypermethylation are all types of genetic changes that can cause failure of a tumor suppressor gene. These genes are often referred to as “gatekeeper” genes because they Figure 48-44 The adenoma-carcinoma sequence in sporadic and provide cell cycle inhibition and regulatory control hereditary colorectal cancer. (From Ivanovich JL, Read TE, Ciske at specific checkpoints in cell division. The failure DJ, et al: A practical approach to familial and hereditary of regulation of normal cellular function by tumor colorectal cancer. Am J Med 107:68–77, 1999.) suppressor genes is appropriately described by the term loss of function. Both alleles of the gene must be nonfunctional to initiate tumor formation. The adenomatous polyposis coli (APC) gene is a tumor suppressor gene located on chromosome 5q21. Its product is 2843 amino acids in length and forms a cytoplasmic complex with GSK-3β (a serine-threonine kinase), β-catenin, and axin. β-Catenin, a multifunctional protein, is a structural component of the epithelial cell adherens junctions and the actin cytoskeleton; it also binds in the cytoplasm to Tcf/LEF and is then transported into the nucleus where it activates transcription of genes like c-myc and others that regulate cellular growth and proliferation. APC therefore participates in cell cycle control by regulating the intracytoplasmic pool of β-catenin. The Wnt signaling proteins are closely associated with the APC/β-catenin pathway. APC also influences cell cycle proliferation by regulating Wnt expression. Wnt gene products are extracellular signaling molecules that help regulate tissue development throughout the organism. The Wnt signaling proteins are closely associated with the APC/β-catenin pathway. Under normal conditions, reduced intracytoplasmic β-catenin levels inhibit Wnt expression. When APC is mutated however, β-catenin levels rise and Wnt is activated. Overexpression of Wnt leads to activation of Wnt target genes such as cyclin D1 and MYC, which drive cell proliferation and tumor formation.[74] The earliest mutations in the adenoma-carcinoma sequence occur in the APC gene. The earliest phenotypic change present is known as “aberrant crypt formation,” and the most consistent genetic aberrations within these cells are abnormally short proteins known as APC truncations. Most clinically relevant derangements in APC are truncation mutations created by inappropriate transcription of premature termination codons.[75] A germline APC truncation mutation is responsible for the autosomal dominant inherited disease, familial adenomatous polyposis (FAP). Thirty percent of cases of FAP are de novo germline mutations, and thus patients present without a family history of the disease. FAP is rare, with an estimated incidence of 1/8000 in the United States, occurring without gender predilection. It is classically characterized by greater than 100 adenomatous polyps being present in the colon and rectum. These polyps often number in the thousands and are almost always manifest by the late second or early third decade of life ( Fig. 48– 45 ). Because some of these polyps proceed through the adenoma-carcinoma sequence, most patients with FAP will die of colon cancer by the fifth decade of life in the absence of surgical intervention. FAP is of great interest to those studying sporadic colorectal cancer because APC truncation mutations similar to those found in APC patients occur in 85% of sporadic colorectal cancers. Most APC truncation mutations occur in the “mutational cluster region” of the gene, an area responsible for β-catenin binding. However, genotype-phenotype correlations exist with mutations in other regions of the gene. For example, mutations close to the 5′ end of the gene produce a very short truncated protein that causes the syndrome known as “attenuated FAP” or AFAP. These patients usually have far less than the hundreds of polyps usually associated with FAP, and the disease has a tendency to spare the rectum. “Classic” FAP is characterized by truncation mutations occurring in the gene from codon 1250 to codon 1464. Mutations occurring farther along the gene toward the 3′ end are quite rare and most likely result in either a much attenuated phenotype or no detectable abnormality at all ( Fig. 48–46 ).
  3. 3. The variability of the FAP phenotype is also expressed by the presence or absence of extraintestinal manifestations of disease. In the past, the term Gardner’s syndrome was used to describe the coexpression of profuse colonic adenomatous polyps along with osteomas of the mandible and skull, desmoid tumors of the mesentery, and periampullary neoplasms. Many other associated disorders have been subsequently described, including thyroid papillary tumors, medulloblastomas, hypertrophic gastric fundic polyps, and congenital hypertrophy of the pigmented retinal epithelium of the iris (CHRPE). The expression of extraintestinal manifestations of FAP is dependent on mutation location, with the vast majority of these signs seen only when the truncation occurs in a very small area of the mutational cluster region. Table 48-3 -- Gene Mutations That Cause Colon Cancer Another APC mutation implicated in about 25% of colorectal cancers afflicting Ashkenazi Jewish descendants is the I1307 point mutation caused by substitution of a lysine for isoleucine at codon 1307. This was initially believed to be a genetic polymorphism—a substitution that does not affect the protein structure. However, it is now recognized as probably the most important cause of familial colorectal cancer in this population. The most frequently mutated tumor suppressor gene in human neoplasia is p53 (TP53), located on chromosome 17p. Mutations in p53 are present in 75% of colorectal cancers and occur rather late in the adenoma-carcinoma sequence. Under normal conditions, p53 acts by inducing apoptosis in response to cellular damage or by causing G1 cell-cycle arrest allowing DNA repair mechanisms to occur. One of the features of mutated p53 is that it is unable to activate the BAX gene to induce apoptosis. For its role in regulating apoptosis, p53 is known as the “guardian of the genome.” The minority of colon cancer patients who have intact p53 in their tumors may possess a survival advantage. Several recent studies have indicated that prognostic significance may be related to tumor p53 status.[76] A number of genes on chromosome 18q are implicated in colorectal cancer, including SMAD2, SMAD4, and DCC. SMAD proteins are involved in the TGFβ signal transduction pathway. SMAD2 and SMAD4 are mutated in 5% to 10% of sporadic colorectal cancer. DCC is encoded by a large gene and is involved in cell-cell or cell-matrix interactions. It is not clear how DCC is directly involved in colorectal neoplasia. DPC4 is a gene adjacent to DCC and may be the tumor suppressor gene deleted in 18q mutations.[76] Mismatch Repair Genes Mismatch repair genes (MMR) are called “caretaker” genes because of their important role in policing the integrity of the genome and correcting DNA replication errors. MMR genes that undergo a loss of function contribute to carcinogenesis by accelerating tumor progression. Mutations in MMR genes (including hMLH1, hMSH2, hMSH3, hPMS1, hPMS2, and hMSH6) result in the syndrome hereditary nonpolyposis colorectal cancer (HNPCC). Approximately 3% of colorectal cancers in the United States are caused by HNPCC. Mutations in MMR genes produce microsatellite instability. Microsatellites are repetitive sequences of DNA that seem to be randomly distributed throughout the genome. Stability of these sequences is a good measure of the general integrity of the genome. MMR gene mutations result in errors in S phase when DNA is newly synthesized and copied. Microsatellite instability exists in 10% to 15% of sporadic tumors and in 95% of tumors in patients with HNPCC. Even so, only 50% of patients diagnosed with HNPCC have readily identifiable MMR mutations.[75] Oncogenes Protooncogenes are genes that produce proteins that promote cellular growth and proliferation. Mutations in protooncogenes typically produce a “gain-of-function” and can be caused by mutation in only one of the two alleles. After mutation, the gene is called an “oncogene.” Overexpression of these growth-oriented genes contributes to the uncontrolled proliferation of cells associated with cancer. The products of oncogenes can be divided into categories. For example, growth factors (TGFβ, EGF, insulin-like growth factor); growth factor receptors (erbB2), signal transducers (SRC, ABL, RAS); and nuclear protooncogenes and transcription factors (MYC) are all oncogene products that appear to have a role in the development of colorectal neoplasia. The RAS protooncogene is located on chromosome 12, and mutations are believed to occur very early in the adenomacarcinoma sequence. Mutated RAS has been found to be present in aberrant crypt foci as well as adenomatous polyps. Activated RAS leads to constitutive activity of the protein that stimulates cellular growth. Fifty percent of sporadic colon cancers possess RAS mutations, and current trials of farnesyl transferase inhibitors, which block a step in RAS post-translational modification, may hold therapeutic promise.[74] The Adenoma-Carcinoma Sequence
  4. 4. The adenoma-carcinoma sequence is now recognized as the process through which most colorectal carcinomas develop. Clinical and epidemiologic observations have long been cited to support the hypothesis that colorectal carcinomas evolve through a progression of benign polyps to invasive carcinoma, and the elucidation of the genetic pathways to cancer described earlier has confirmed the validity of this hypothesis. However, before the molecular genesis of colorectal cancer was appreciated, there was considerable controversy as to whether colorectal cancer arose de novo or evolved from a polyp that was initially a benign precursor. Although there have been a few documented instances of tiny colonic cancers arising de novo from normal mucosa, these instances are rare, and the validity of the adenoma-carcinoma sequence is now accepted by virtually all authorities. The historical observations that led to the hypothesis are of interest because of the therapeutic implications implicit in an understanding of the adenoma-carcinoma sequence. Observations that provided support for the hypothesis include the following: ▪ Larger adenomas are found to harbor cancers more often than smaller ones, and the larger the polyp, the higher the risk of cancer. While the cellular characteristics of the polyp are important, with villous adenomas carrying a higher risk than tubular adenomas, the size of either polyp is also important. The risk of cancer in a tubular adenoma smaller than 1 cm in diameter is less than 5%, whereas the risk of cancer in a tubular adenoma larger than 2 cm is 35%. A villous adenoma larger than 2 cm carries a 50% chance of containing a cancer. ▪ Residual benign adenomatous tissue is found in the majority of invasive colorectal cancers, suggesting progression of the cancer from the remaining benign cells to the predominant malignant ones. ▪ Benign polyps have been observed to develop into cancers. There have been reports of the direct observation of benign polyps that were not removed progressing over time into malignancies. ▪ Colonic adenomas occur more frequently in patients who have colorectal cancer. Nearly a third of all patients with colorectal cancer will also have a benign colorectal polyp. ▪ Patients who develop adenomas have an increased lifetime risk of developing colorectal cancer. ▪ Removal of polyps decreases the incidence of cancer. Patients with small adenomas have a 2.3 times increased risk of cancer after the polyp is removed, compared with an 8-fold increased incidence of colorectal cancer in patients with polyps who do not undergo polypectomy. ▪ Populations with a high risk of colorectal cancer also have a high prevalence of colorectal polyps. ▪ Patients with familial adenomatous polyposis will develop colorectal cancer virtually 100% of the time in the absence of surgical intervention. The adenomas that characterize this syndrome are histologically the same as sporadic adenomas. ▪ The peak incidence for the discovery of benign colorectal polyps is 50 years of age. The peak incidence for the development of colorectal cancer is 60 years of age. This suggests a 10-year time span for the progression of an adenomatous polyp to a cancer. It has been estimated that a polyp larger than 1 cm has a cancer risk of 2.5% in 5 years, 8% in 10 years, and 24% in 20 years. These observations and the studies by molecular biologists document that colonic mucosa progresses through stages to the eventual development of an invasive cancer. Colonic epithelial cells lose the normal progression to maturity and cell death and begin proliferating in a more and more uncontrolled manner. With this uncontrolled proliferation the cells accumulate on the surface of the bowel lumen as a polyp. With more proliferation and increasing cellular disorganization the cells extend though the muscularis mucosae to become invasive carcinoma. Even at this advanced stage, the process of colorectal carcinogenesis generally follows an orderly sequence of invasion of the muscularis mucosae, pericolic tissue, lymph nodes, and, finally, distant metastasis ( Figs. 48–47 and 48–48 ). Colorectal Polyps A colorectal polyp is any mass projecting into the lumen of the bowel above the surface of the intestinal epithelium. Polyps arising from the intestinal mucosa are generally classified by their gross appearance as pedunculated (with a stalk) ( Fig. 48–49 ) or sessile (flat, without a stalk) ( Fig. 48–50 ). They are further classified by their histologic appearance as tubular adenoma (with branched tubular glands), villous adenoma (with long finger-like projections of the surface epithelium) ( Fig. 48–51 ), or tubulovillous adenoma (with elements of both cellular patterns). The most common benign polyp is the tubular adenoma, composing 65% to 80% of all polyps removed. Ten to 25% of polyps are tubulovillous, and 5% to 10% are villous adenomas.
  5. 5. Tubular adenomas are most often pedunculated, and villous adenomas are more commonly sessile. The degree of cellular atypia is variable across the span of polyps, but there is generally less atypia in tubular adenomas, and severe atypia or dysplasia (precancerous cellular change) is found more often in villous adenomas. The incidence of invasive carcinoma being found in a polyp is dependent on the size and histologic type of the polyp. As mentioned previously, there is less than a 5% incidence of carcinoma in an adenomatous polyp less than 1 cm in size, whereas there is a 50% chance that a villous adenoma greater than 2 cm will contain a cancer. The treatment of an adenomatous or villous polyp is removal, usually by colonoscopy. The presence of any polypoid lesion is an indication for a complete colonoscopy and polypectomy, if feasible. Polyps on a stalk are often removed by a snare passed through the colonoscope, whereas sessile (flat) polyps present technical problems with this technique because of danger of perforation associated with the snare technique. Although it may be feasible to elevate the sessile polyp from the underlying muscularis with saline injection, permitting subsequent endoscopic excision, sessile lesions will often require segmental colectomy for complete removal ( Fig. 48–52 ). Figure 48-47 Model of colorectal carcinogenesis. (Modified from Corman ML [ed]: Colon & Rectal Surgery, 4th ed. Philadelphia, Lippincott-Raven, 1998, p 593; after Fearon ER, Vogelstein B: A genetic model of colorectal cancer tumorigenesis. Cell 61:759, 1990. With permission.) Figure 48-53 Anatomic landmarks of pedunculated and sessile adenomas. (From Haggitt RC, Glotzbach RE, Soffer EE, et al: Prognostic factors in colorectal carcinomas arising in adenomas: Implications for lesions removed by endoscopic polypectomy. Gastroenterology 89:328–336, 1985.) As described earlier, adenomatous polyps should be considered precursors of cancer; and when cancer arises in a polyp careful consideration needs to be given to ensure the adequacy of treatment. “Invasive carcinoma” describes the situation in which malignant cells have extended through the muscularis mucosae of the polyp, whether it is a lesion on a stalk or a sessile lesion. Carcinoma confined to the muscularis mucosae does not metastasize, and the cellular abnormalities should be described as “atypia.” Complete excision of this type of polyp is adequate treatment. If invasive carcinoma penetrates the muscularis mucosae, consideration of the risk of lymph node metastasis and local recurrence is required to determine whether a more extensive resection is required. In 1985, Haggit and associates[77] proposed a classification for polyps containing cancer according to the depth of invasion as follows ( Fig. 48–53 ):
  6. 6. Level 0: Carcinoma does not invade the muscularis mucosae (carcinoma-in-situ or intramucosal carcinoma). Level 1: Carcinoma invades through the muscularis mucosae into the submucosa but is limited to the head of the polyp. Level 2: Carcinoma invades the level of the neck of the polyp (junction between the head and the stalk). Level 3: Carcinoma invades any part of the stalk. Level 4: Carcinoma invades into the submucosa of the bowel wall below the stalk of the polyp but above the muscularis propria. By definition, all sessile polyps with invasive carcinoma are level 4 by Haggitt’s criteria. If a polyp contains a histologically poorly differentiated invasive carcinoma, or if there are cancer cells observed in the lymphovascular spaces, there is a greater than 10% chance of metastases and these lesions should be treated aggressively. A pedunculated polyp with invasion to levels 1, 2, and 3 has a low risk of lymph node metastasis or local recurrence, and complete excision of the polyp is adequate if the above mentioned poor prognostic factors are not present. A sessile polyp containing invasive cancer has at least a 10% chance of metastasis to regional lymph nodes, but if the lesion is well or moderately differentiated and there is no lymphovascular invasion noted, and the lesion can be completely excised, the depth of invasion by the cancer may provide useful prognostic information. There is a high risk of lymph node and distant metastasis associated with sessile cancers in the rectum, and these lesions should be treated aggressively. Hyperplastic polyps are the most common colonic polyps, but they are usually quite small and composed of cells showing dysmaturation and hyperplasia. The small diminutive polyps have been regarded as benign in nature with no neoplastic potential. The histologic appearance of these polyps is serrated (saw-toothed) ( Fig. 48–54 ). Ninety percent of these polyps are less than 3 mm, and these diminutive lesions are generally considered to have no malignant potential. However, adenomatous changes can be found in hyperplastic polyps, and for this reason the polyps should be excised for histologic examination. Recently, these serrated adenomas have been observed to be associated with development of cancers that predominate in the right side of the colon more frequently in elderly women and smokers. These serrated adenomas appear to be associated with the microsatellite instability characteristic of defects in DNA repair mechanisms.[78] Hereditary Cancer Syndromes ( Table 48–4 ) Peutz-Jeghers syndrome is an autosomal dominant syndrome characterized by the combination of hamartomatous polyps of the intestinal tract and hyperpigmentation of the buccal mucosa, lips, and digits. Germline defects in the tumor suppressor serine/threonine kinase 11 (STK11) gene are implicated in this rare autosomal dominant inherited disease. Although the syndrome was first described by Hutchinson in 1896, later separate descriptions by Peutz and then Jeghers in the 1940s brought recognition of the condition. The syndrome is associated with an increased (2% to 10%) risk of cancer of the intestinal tract, with cancers reported throughout the intestinal tract, from the stomach to the rectum. There is also an increased risk of extraintestinal malignancies, including cancer of the breast, ovary, cervix, fallopian tubes, thyroid, lung, gallbladder, bile ducts, pancreas, and testes. Table 48-4 -- Hereditary Cancer Syndromes Hereditary Adenomatous Polyposis Hereditary Hamartomatous Syndromes Polyposis Syndromes Ruvalcaba- Myhre-Smith Familial Syndrome Familial Adenomatous Turcot’s Cowden’s (Bannayan- Juvenile Hereditary Nonpolyposis Polyposis/Gardner’s Syndrome Disease Zonana Polyposis Colon Cancer Syndrome Peutz-Jeghers Syndrome) GI Features Colorectal polyps, Small number of Hundreds to thousands Juvenile polyps Hamartomatous GI which may be few Polyps most polyps of colorectal polyps; mostly in the polyps, usually Small number of Colorectal or resemble commonly of throughout GI duodenal adenomas colon but lipomas, polyps classic familial colon and tract but most and gastric polyps, throughout GI hemangiomas, or adenomatous stomach common in usually fundic gland tract lymphangiomas polyposis small intestine Defined by ≥ 10 juvenile polyps Other Clinical Muir-Torre variant: Osteomas, desmoid Brain tumors, Mucocutaneous Congenital Pigmented Dysmorphic facial Features sebaceous adenomas, tumors, epidermoid including lesions, thyroid abnormalities in lesions of skin; features keratoacanthomas, cysts, and congenital cerebellar adenomas and at least 20%, benign and macrocephaly,
  7. 7. Hereditary Adenomatous Polyposis Hereditary Hamartomatous Syndromes Polyposis Syndromes Ruvalcaba- Myhre-Smith Familial Syndrome Familial Adenomatous Turcot’s Cowden’s (Bannayan- Juvenile Hereditary Nonpolyposis Polyposis/Gardner’s Syndrome Disease Zonana Polyposis Colon Cancer Syndrome Peutz-Jeghers Syndrome) GI Features Colorectal polyps, Small number of Hundreds to thousands Juvenile polyps Hamartomatous GI which may be few Polyps most polyps of colorectal polyps; mostly in the polyps, usually Small number of Colorectal or resemble commonly of throughout GI duodenal adenomas colon but lipomas, polyps classic familial colon and tract but most and gastric polyps, throughout GI hemangiomas, or adenomatous stomach common in usually fundic gland tract lymphangiomas polyposis small intestine Defined by ≥ 10 juvenile polyps including goiter, malrotation, seizures, fibroadenomas hydrocephalus, intellectual and fibrocystic sebaceous epitheliomas, and hypertrophy of retinal medulloblastoma cardiac lesions, malignant impairment, and disease of the basal cell epitheliomas epithelium and glioblastomas Meckel’s genital tumors pigmented macules breast, uterine diverticulum, of shaft and glans leiomyomas, and and mesenteric of penis macrocephaly lymphangioma 70%-80% lifetime risk of ↑ Risk of GI Colorectal cancer risk colorectal cancer; 30%-60% 10% risk of 9% to 25% risk malignancy and approaches 100%; ↑ lifetime risk of endometrial thyroid cancer of colorectal pancreatic Malignant GI risk of periampullary cancer; ↑ risk of ovarian Colorectal and up to 50% cancer; ↑ risk of cancer and tumors identified malignancy, thyroid Malignancy Risk cancer, gastric carcinoma, carcinoma and risk of gastric, adenoma but lifetime risk for carcinoma, central transitional cell carcinoma of brain tumors adenocarcinoma duodenal, and malignum of malignancy nervous system the ureters and renal pelvis, of breast in pancreatic cervix; unknown unknown tumors, and small bowel cancer, and affected women cancer. risk of breast hepatoblastoma sebaceous carcinomas cancer Screening Upper GI Recommendations endoscopy, small bowel radiography, and colonoscopy every 2 yr; pancreatic ultrasound and hemoglobin levels annually; gynecologic Flexible examination, proctosigmoidoscopy Same as for Annual physical Screening by cervical smear, No known Colonoscopy at age 20–25 at age 10–12 yr; repeat familial exam with age 12 yr if and pelvic published yr; repeat every 1–2 yr every 1–2 yr until age adenomatous special attention symptoms have ultrasound recommendations 35; after age 35 repeat polyposis to thyroid not yet arisen annually; clinical every 3 yr breast exam and mammography at age 25 yr; clinical testicular exam and testicular ultrasound in males with feminizing features (expert opinion only) Colonoscopy Mammography Transvaginal ultrasound or Upper GI endoscopy with multiple Also consider at age 30 or 5 yr endometrial aspirate at age every 1–3 yr starting random biopsies imaging of the before earliest 20–25 yr; repeat annually when polyps first every several brain breast cancer (expert opinion only) identified years (expert case in the family opinion only) Routine colon cancer surveillance (expert opinion only)
  8. 8. Hereditary Adenomatous Polyposis Hereditary Hamartomatous Syndromes Polyposis Syndromes Ruvalcaba- Myhre-Smith Familial Syndrome Familial Adenomatous Turcot’s Cowden’s (Bannayan- Juvenile Hereditary Nonpolyposis Polyposis/Gardner’s Syndrome Disease Zonana Polyposis Colon Cancer Syndrome Peutz-Jeghers Syndrome) GI Features Colorectal polyps, Small number of Hundreds to thousands Juvenile polyps Hamartomatous GI which may be few Polyps most polyps of colorectal polyps; mostly in the polyps, usually Small number of Colorectal or resemble commonly of throughout GI duodenal adenomas colon but lipomas, polyps classic familial colon and tract but most and gastric polyps, throughout GI hemangiomas, or adenomatous stomach common in usually fundic gland tract lymphangiomas polyposis small intestine Defined by ≥ 10 juvenile polyps Genetic Basis AD inheritance AD AD AD AD AD AD in some families Subset of APC mutations families with identified PTEN mutation in STK11 PTEN predominantly in MLHI (chromosome 3p APC (chromosome 5p (chromosome SMAD4 (chromosome (chromosome 10q) families with 10q (DRC4) 19q) in some families cerebellar (chromosome medulloblastoma 10q) hMLH1, PMS2 Mutation Type identified in MSH2 (chromosome 2q) families with predominance of glioblastomas MSH6/GTMP(chromosome 10q) PMS1(chromosome 2q) PMS2(chromosome 7q) Families being Clinical testing of Research testing Research testing Research testing of Clinical testing of MLH1 and Clinical testing of collected for Genetic Testing APC and MLH1 of PTEN gene of STK11 gene PTEN gene MSH2 gene available APC gene available research studies genes available available available available only GI, gastrointestinal; AD, autosomal dominant; ↑, increased. The polyps may cause bleeding or intestinal obstruction (from intussusception). If surgery is required for these symptoms, an attempt should be made to remove as many polyps as possible with the aid of intraoperative endoscopy and polypectomy. Any polyp that is larger than 1.5 cm should be removed if possible. It is reasonable to survey the colon endoscopically every 2 years, and patients should be screened periodically for malignancies of the breast, cervix, ovary, testis, stomach, and pancreas. Juvenile polyps are benign polyps composed of cystic dilatations of glandular structures within the fibroblastic stroma of the lamina propria. They are relatively uncommon, yet may cause bleeding or intussusception. For these reasons the polyps should be treated by endoscopic removal. Multiple polyposis coli is an autosomal dominant syndrome with high penetrance that carries an increased risk of both gastrointestinal and extraintestinal cancer. The syndrome is usually discovered because of GI bleeding, intussusception, or hypoalbuminemia associated with protein loss through the intestine. The juvenile polyps in this syndrome are predominately hamartomas, but the hamartomas may contain adenomatous elements and adenomatous polyps also are common. There is an increased cancer risk in the afflicted individuals, with a malignant potential of at least 10% in patients with multiple juvenile polyps. Mutations in the tumor suppressor gene SMAD4 are believed to cause up to 50% of reported cases. In patients with a relatively small number of juvenile polyps, endoscopic polypectomy should be done. However, patients with numerous polyps should be treated with abdominal colectomy, ileorectal anastomosis, and frequent endoscopic surveillance of the rectum. If the diffuse form of polyposis involves the rectal mucosa, consideration should be given to restorative proctocolectomy with ileal pouch anal anastomosis. FAP is the prototypical hereditary polyposis syndrome. The discovery of the gene responsible for the transmission of the disease, the APC (adenomatosis polyposis coli) gene, located on chromosome 5q21, lagged behind the first descriptions of cases
  9. 9. of FAP by an entire century. In 1863, Virchow reported a 15-year-old boy with multiple colonic polyps. In 1882, Cripps described the occurrence of numerous colonic polyps in multiple family members. In 1927, Cockayne demonstrated that FAP was genetically transmitted in an autosomal dominant fashion. Dukes was the first to establish some form of a familial tumor registry, which he reported with Lockhart-Mummery in 1930. Throughout the 20th century many reports described various extraintestinal manifestations associated with FAP. In 1986, Lemuel Herrera demonstrated that the underlying genetic abnormality was a mutation in the APC gene. The common expression of the syndrome is the invariable presence of multiple colonic polyps, the frequent occurrence of gastric, duodenal, and periampullary polyps, and the occasional association of extraintestinal manifestations, including epidermoid cysts, desmoid tumors in the abdomen, osteomas, and brain tumors. Gastric and duodenal polyps will occur in about half of affected individuals. Most of the gastric polyps represent fundic gland hyperplasia, rather than adenomatous polyps, and have limited malignant potential. However, duodenal polyps are adenomatous and should be considered to be premalignant. Patients with FAP have an increased risk of ampullary cancer. Adenomatous polyps and cancer have also been found in the jejunum and ileum of patients with FAP. Rare extraintestinal malignancies in FAP patients include cancers of the extrahepatic bile ducts, gallbladder, pancreas, adrenals, thyroid, and liver. An interesting marker for FAP is congenital hypertrophy of the retinal pigmented epithelium (CHRPE), which can be detected by indirect ophthalmoscopy in about 75% of affected individuals. The gene is expressed in 100% of patients with the mutation. Autosomal dominance results in expression in 50% of offspring. There is a negative family history in 10% to 20% of affected individuals who apparently acquire the syndrome as the result of a spontaneous mutation. All patients with the defective gene will develop cancer of the colon if left untreated. The average age of discovery of a new patient with FAP is 29 years. The average age of a patient who is newly discovered to have colorectal cancer related to FAP is 39 years. Eponymous polyposis syndromes now recognized to belong to the general disorder of FAP include Gardner’s syndrome (colonic polyps, epidermal inclusion cysts, osteomas) and Turcot’s syndrome (colonic polyps and brain tumors). Osteomas usually present as visible and palpable prominences in the skull, mandible, and tibia of individuals with FAP. They are virtually always benign. Radiographs of the maxilla and mandible may reveal bone cysts, supernumerary and impacted molars, or congenitally absent teeth. Desmoid tumors can present in the retroperitoneum and abdominal wall of affected patients, usually after surgery. These tumors seldom metastasize but are often locally invasive, and direct invasion of the mesenteric vessels, ureters, or walls of the small intestine can result in death. Surgical treatment of patients with FAP is directed at removal of all affected colonic and rectal mucosa. Restorative proctocolectomy with ileal pouch anal anastomosis (IPAA) has become the most commonly recommended operation. The procedure is usually accompanied by a distal rectal mucosectomy to ensure that all premalignant colonic mucosa is removed, and the IPAA is fashioned between the ileal pouch and the dentate line of the anal canal. Patients who undergo this procedure for FAP have a better functional result than patients similarly treated for ulcerative colitis, in that the incidence of inflammation in the ileal pouch (pouchitis) is much lower in patients with FAP than in patients with ulcerative colitis. An alternative approach, total abdominal colectomy with ileorectal anastomosis, was used extensively before the development of the technique of IPAA, and has certain advantages to be considered. If a FAP patient has relatively few polyps in the rectum, consideration may be given to this option. The abdominal colon is resected, and an anastomosis fashioned between the ileum and rectum. It is technically a simpler operation to perform, and the pelvic dissection is avoided. This eliminates the potential complication of injury to the autonomic nerves that could result in impotence. In addition, there is theoretically less of a risk of anastomotic leak from the relatively simple ileorectal anastomosis fashioned in the peritoneal cavity, compared with the long suture (or staple) lines required to form the ileal pouch and then fashion the anastomosis between the ileal pouch and the anus. An additional argument in favor of abdominal colectomy and ileorectal anastomosis is the observation that sulindac and celecoxib have been observed to cause the regression of adenomatous polyps in some patients with FAP.[79] The disadvantages are that the rectum remains at high risk for the formation of new precancerous polyps, a proctoscopic examination is required every 6 months to detect and destroy any new polyps, and there is a definite increased risk of cancer arising in the rectum with the passage of time. It has been suggested that genetic testing may help make a decision between restorative proctocolectomy with IPAA and abdominal colectomy with ileorectal anastomosis. It has been observed that the risk of rectal cancer is almost three times higher in FAP patients with a mutation after codon 1250 than in patients with mutations before this codon. This fact may influence the decision to offer abdominal colectomy with ileorectal anastomosis to patients whose mutation occurs proximal to codon 1250 if proctoscopic examination should reveal no or few polyps in the rectum.[80] Patients who choose to be treated by abdominal colectomy with ileorectal anastomosis should realize that the risk of developing rectal cancer is real and has been shown to be 4%, 5.6%, 7.9%, and 25% at 5, 10, 15, and 20 years after the operation, respectively.[81] Even though sulindac and celecoxib can produce partial regression of polyps, semiannual surveillance of the
  10. 10. rectal mucosa is required, and about one third of patients treated by abdominal colectomy and ileorectal anastomosis will develop florid polyposis of the rectum that will require proctectomy (and either ileostomy or IPAA) within 20 years. As discussed earlier, polyps of the stomach and duodenum are not uncommon in patients with FAP. The gastric polyps are usually hyperplastic and do not require surgical removal. However, the duodenal and ampullary polyps are usually neoplastic and require attention. A reasonable surveillance program is for upper gastrointestinal surveillance every 2 years after the age of 30 and endoscopic polypectomy, if possible, to remove all large adenomas from the duodenum. If numerous polyps are identified, the endoscopy obviously should be repeated at greater frequency. If an ampullary cancer is discovered at an early stage, pancreatoduodenectomy (Whipple’s procedure) is indicated. The abdominal desmoid tumor can be an especially vexing and difficult extraintestinal manifestation of FAP. After surgical procedures, dense fibrous tissue forms in the mesentery of the small intestine or within the abdominal wall in some patients with FAP. If the mesentery is involved, the intestine can be tethered or invaded directly by the tumor. The locally invasive tumor can also encroach on the vascular supply to the intestine. Small desmoid tumors confined to the abdominal wall are appropriately treated by resection, but the surgical treatment of mesenteric desmoids is dangerous and generally futile. There have been sporadic reports of regression of desmoid tumors after treatment with sulindac, tamoxifen, radiation, and various types of chemotherapy. The initial treatment is usually with sulindac or tamoxifen.[82] The ability to identify the genetic mutation in most patients with FAP (although the mutation may not be identified in as many as 20% of patients with a welldocumented, transmissible FAP syndrome) permits a method of screening family members that are at risk of inheriting the mutation. It is imperative that the APC mutation is clearly identified in the DNA of a family member known to have the disease. The DNA of other family members can then be directly analyzed, requiring only a venipuncture. If the analysis demonstrates noninheritance of a mutated APC gene, the individual can avoid yearly endoscopic screening and should require only occasional colonoscopy. HNPCC is the most frequently occurring hereditary colorectal cancer syndrome in the United States and Western Europe. It accounts for approximately 3% of all cases of colorectal cancer and for approximately 15% of such cancers in patients with a family history of colorectal cancer. Dr. Aldred S. Warthin, chairman of pathology at the University of Michigan, initially recognized this hereditary syndrome in 1985. Dr. Warthin’s seamstress prophesied that she would die of cancer because of her strong family history of endometrial, gastric, and colon cancer. Dr. Warthin’s investigations of her family’s medical records revealed a pattern of autosomal dominant transmission of the cancer risk. This family (Family G) has been further studied and characterized by Dr. Henry Lynch, who described the prominent features of the syndrome, including onset of cancer at a relatively young age (mean of 44 years), proximal distribution (70% of cancers located in the right colon), predominance of mucinous or poorly differentiated (signet cell) adenocarcinoma, an increased number of synchronous and metachronous cancers, and, despite all of these poor prognostic indicators, a relatively good outcome after surgery. Two hereditary syndromes were initially described. Lynch I syndrome is characterized by cancer of the proximal colon occurring at a relatively young age, whereas Lynch II syndrome is characterized by families at risk for both colorectal cancer and extracolonic cancers, including cancers of endometrial, ovarian, gastric, small intestinal, pancreatic, and ureteral and renal pelvic origin. Before the genetic mechanisms underlying the Lynch syndromes were understood, the syndrome was defined by the Amsterdam criteria, which required three criteria for the diagnosis: (1) colorectal cancer in three family members (first-degree relatives), (2) involvement of at least two generations, and (3) at least one affected individual being younger than the age of 50 at the time of diagnosis. These requirements were recognized as being too restrictive, and the modified Amsterdam criteria expanded the cancers to be included to not only colorectal but also endometrial, ovarian, gastric, pancreatic, small intestinal, ureteral, and renal pelvic cancers. Further liberalization for identifying patients with HNPCC occurred with the introduction of the Bethesda criteria ( Box 48–4 ). Box 48-4
  11. 11. Clinical Criteria for Hereditary Nonpolyposis Colorectal Cancer (HNPCC) Molecular biologists have demonstrated that the increased cancer risk in these syndromes is due to malfunction of the DNA repair mechanism. Specific genes that have been Amsterdam Criteria shown to be responsible for the syndrome include hMSH2 (located on chromosome 2p21), hMLH1 (3p21), hMSH6 At least three relatives with colon cancer and all of the following: (2p16–21), and hPMS2 (7p21). A mutation in hMSH2 has One affected person is a first-degree relative of the other two affected been shown to be responsible for the cancer prevalence in persons Cancer Family G. Mutations in hMSH2 or hMLH1 account Two successive generations affected for over 90% of identifiable mutations in patients with HNPCC. The initially reported difference in types of At least one case of colon cancer diagnosed before age 50 years cancers occurring in Lynch I and Lynch II syndromes Familial adenomatous polyposis excluded cannot be accounted for by mutations in specific mismatch Modified Amsterdam Criteria repair genes. The cancer family syndrome involving hMSH6 is characterized by an increased incidence of Same as the Amsterdam criteria, except that cancer must be associated endometrial carcinoma. with HNPCC (colon, endometrium, small bowel, ureter, renal pelvis) instead of specifically colon cancer The mainstay of the diagnosis of HNPCC is a detailed Bethesda Criteria family history. Still, it should be remembered that as many as 20% of newly discovered cases of HNPCC are caused The Amsterdam criteria or one of the following: by spontaneous germline mutations, so a family history Two cases of HNPCC-associated cancer in one patient, including may not accurately reflect the genetic nature of the synchronous or metachronous cancer syndrome. Colorectal cancer, or an HNPCC-related Colon cancer and a first-degree relative with HNPCC-associated cancer cancer, arising in a person younger than the age of 50 and/or colonic adenoma (one case of cancer diagnosed before age 45 years and adenoma diagnosed before age 40 years) should raise the suspicion of this syndrome. Genetic counseling and genetic testing can be offered. If the Colon or endometrial cancer diagnosed before age 45 years individual proves to have HNPCC by identification of a Right-sided colon cancer that has an undifferentiated pattern (solid- mutation in one of the known mismatch repair genes, then cribriform) or signet-cell histopathologic characteristics diagnosed before age 45 years other family members can be tested after obtaining genetic counseling. However, failure to identify a causative Adenomas diagnosed before age 40 years mismatch repair gene mutation in a patient with a suggestive history does not exclude the diagnosis of HNPCC. In as many as 50% of patients with a family history that clearly demonstrates HNPCC type transmission of cancer susceptibility, DNA testing will fail to identify the causative gene. The management of patients with HNPCC is somewhat controversial, but the need for close surveillance in patients known to carry the mutation is obvious. It is usually recommended that a program of surveillance colonoscopy should begin at the age of 20. Colonoscopy is repeated every 2 years until the age of 35 and then annually thereafter. In women, periodic vacuum curettage is begun at age 25, as well as pelvic ultrasound and determination of CA-125 levels. Annual tests for occult blood in the urine should also be obtained, because of the risk of ureteral and renal pelvic cancer ( Table 48–5 ). It has been shown that annual colonoscopy and removal of polyps when found will decrease the incidence of colon cancer in patients with HNPCC. However, there have been well-documented cases of invasive colon cancers occurring 1 year after a negative colonoscopy. It is obvious that the slow evolution from benign polyp to invasive cancer is not a feature of pathogenesis in HNPCC patients, and this phenomenon of accelerated carcinogenesis mandates frequent (annual) colonoscopic examinations. Even with annual colonoscopic examinations there is a documented risk of colon cancer, but should a cancer arise while the patient is under a vigorous surveillance program the cancer stage is usually favorable ( Fig. 48–55 ). When a colon cancer is detected in a patient with HNPCC, an abdominal colectomy and ileorectal anastomosis is the procedure of choice. If the patient is a woman with no further plans for childbearing, a prophylactic total abdominal hysterectomy and bilateral salpingo-oophorectomy is recommended. The rectum remains at risk for development of cancer, and annual proctoscopic examinations are mandatory after abdominal colectomy. Other forms of cancer associated with HNPCC are treated according to the same criteria as in nonhereditary cases. The role of prophylactic colectomy for patients with HNPCC has been considered in some instances, but this concept has not received universal acceptance. It is an interesting but well-documented fact that the prognosis is better for cancer patients with HNPCC than for non-HNPCC patients with cancer of the same stage. Table 48-5 -- Screening Recommendations for FAP and HNPCC Lifetime Cancer Risk Screening Recommendations Familial Adenomatous Polyposis (FAP)
  12. 12. Lifetime Cancer Risk Screening Recommendations Colorectal cancer 100% Colonoscopy annually, beginning age 10–12 Duodenal or periampullary cancer 5%-10% Upper GI endoscopy every 1 to 3 yr, beginning age 20–25 Pancreatic cancer 2% Possible periodic abdominal ultrasound Thyroid cancer 2% Annual thyroid examination Gastric cancer <1% Upper GI endoscopy as for duodenal and periampullary Central nervous system cancer <1% Annual physical examination Hereditary Nonpolyposis Colorectal Cancer (HNPCC) Colorectal cancer 80% Colonoscopy, every 2 yr beginning age 20, annually after age 40 or 10 years younger than earliest case in family Endometrial cancer 40%-60% Pelvic exam, transvaginal ultrasound, endometrial aspirate every 1–2 yr, beginning age 25–35 Upper urinary tract cancer 4%-10% Ultrasound and urinalysis every 1–2 yr; start at age 30 to 35 yr Gallbladder and biliary cancer 2%-18% No recommendation Central nervous system cancer <5% No recommendation Small bowel cancer <5% No recommendation Sporadic Colon Cancer It is important to recognize the increased risk of cancer in patients with hereditary cancer syndromes, but by far the most common form of colorectal cancer is sporadic, without an associated strong family history. Although the cause and pathogenesis of adenocarcinoma are similar throughout the large bowel, significant differences in the use of diagnostic and therapeutic modalities separate colonic from rectal cancers. This distinction is largely due to the confinement of the rectum by the bony pelvis. The limited mobility of the rectum allows MRI to generate better images and increases its sensitivity. In addition, the proximity of the rectum to the anus permits easy access of ultrasound probes for more accurate assessment of the extent of penetration of the bowel wall and the involvement of adjacent lymph nodes. The limited accessibility of the rectum, the proximity to the anal sphincter, and the close association with the autonomic nerves supplying the bladder Figure 48-55 Comparison of the development of cancer in patients with and genitalia require special and unique consideration when planning treatment for familial adenomatous polyposis (FAP) cancer of the rectum. Therefore, colon and rectal adenocarcinomas are discussed and hereditary nonpolyposis colon separately. cancer (HNPCC). The signs and symptoms of colon cancer are varied, nonspecific, and somewhat dependent on the location of the tumor in the colon as well as the extent of constriction of the lumen caused by the cancer. Over the past several decades the incidence of cancer in the right colon has increased in comparison to cancer arising in the left colon and rectum. This is an important consideration, in that at least half of all colon cancers are located proximal to the area that can be visualized by the flexible sigmoidoscope. Colorectal cancers can bleed, causing red blood to appear in the stool (hematochezia). Bleeding from right-sided colon tumors can cause dark, tarry stools (melena). Often the bleeding may be asymptomatic and detected only by anemia discovered by a routine hemoglobin determination. Iron-deficiency anemia in any male or nonmenstruating female should lead to a search for a source of bleeding from the gastrointestinal tract. Bleeding is often associated with colon cancer, but in approximately one third of patients with a proven colon cancer the hemoglobin will be normal and the stool will test negative for occult blood. Cancers located in the left colon are often constrictive. Patients with left-sided colon cancers may notice a change in bowel habit, most often reported as increasing constipation. Sigmoid cancers can mimic diverticulitis, presenting as pain, fever, and obstructive symptoms. At least 20% of patients with sigmoid cancer will also have diverticular disease, making the correct diagnosis difficult at times. Sigmoid cancers can also cause colovesical or colovaginal fistulas. Such fistulas are more commonly caused by diverticulitis, but it is imperative that the correct diagnosis be established, because the treatment of colon cancer is substantially different than the treatment for diverticulitis.
  13. 13. Cancers in the right colon more often present as melena, fatigue associated with anemia, or, if the tumor is advanced, abdominal pain. Although obstructive symptoms are more commonly associated with cancers of the left colon, any advanced colorectal cancer can cause a change in bowel habits and intestinal obstruction ( Figs. 48–56 and 48–57 ). Colonoscopy is the gold standard for establishing the diagnosis of colon cancer. It permits biopsy of the tumor to verify the diagnosis while allowing inspection of the entire colon to exclude metachronous polyps or cancers (the incidence of a metachronous cancer is approximately 3%). Colonoscopy is generally performed even after a cancer is detected by barium enema to obtain a biopsy and to detect (and remove) small polyps that may be missed by the contrast study ( Fig. 48–58 ). In patients with tumors causing complete obstruction the diagnosis is most properly established by resection of the tumor without the benefit of preoperative colonoscopy. A water-soluble contrast enema is often useful in such circumstances to establish the anatomic level of the obstruction. Primary anastomosis between the proximal colon and the colon distal to the tumor has been avoided in the past in the presence of obstruction because of a high risk of anastomotic leak associated with such an approach. Thus such patients were usually treated by resection of the segment of colon containing the obstructing cancer, suture closure of the distal sigmoid or rectum, and construction of a colostomy (Hartmann’s operation). Intestinal continuity could be reestablished later after the colon had been cleansed with purgatives by taking down the colostomy and fashioning a colorectal anastomosis. Alternatives to this approach have been to resect the segment of left colon containing the cancer and then cleanse the remaining colon with saline lavage by inserting a catheter through the appendix or ileum into the cecum and irrigating the contents from the colon. A primary anastomosis between the prepared colon and the rectum can then be fashioned without the need for a temporary colostomy. A third approach occasionally used for obstructing cancers of the sigmoid colon is to resect the tumor and the entire colon proximal to the tumor and fashion an anastomosis between the ileum and the distal sigmoid colon (subtotal colectomy and ileosigmoid anastomosis). This approach has the advantage of avoiding a temporary colostomy and eliminating the need to search for synchronous lesions in the colon proximal to the cancer. However, patients treated by this approach may have more frequent bowel movements. More recently endoscopic techniques have been developed that permit the placement of a stent introduced with the aid of a colonoscope that traverses the obstructed tumor and expands, re-creating a lumen, relieving the obstruction, and permitting a bowel prep and elective operation with primary colorectal anastomosis.[83] The approaches just discussed concern obstruction of the left colon. Complete obstruction of the right colon or cecum by cancer occurs less frequently. These patients present with signs and symptoms of a small bowel obstruction. If an obstruction of the proximal colon is suspected, a water-soluble contrast study is useful to verify the diagnosis and evaluate the distal colon for the presence of a synchronous lesion. Obstructing cancer of the proximal colon is treated by right colectomy with primary anastomosis between the ileum and the transverse colon. Patients with tumors that are not obstructing should undergo a thorough evaluation for metastatic disease. This includes a thorough physical examination, chest radiograph, liver function tests, and carcinoembryonic antigen (CEA) level. Most surgeons now order CT or MRI to more thoroughly inspect the liver for metastases and to search for other intra-abdominal pathologic processes. The presence of hepatic metastatic disease does not preclude the surgical excision of the primary tumor. Unless the hepatic metastatic disease is extensive, excising the primary cancer can provide excellent palliation. Bleeding and obstruction caused by the tumor can be avoided, and if the metastatic disease in the liver is resectable, the patient may yet be cured. The objective of surgery for colon adenocarcinoma is the removal of the primary cancer with adequate margins, regional lymphadenectomy, and restoration of the continuity of the gastrointestinal tract by anastomosis. The extent of resection is determined by the location of the cancer, its blood supply and draining lymphatic system, and the presence or absence of direct extension into adjacent organs. It is important to resect the lymphatics (which parallel the arterial supply) to the greatest extent possible, to render the abdomen free of lymphatic metastases if possible. Should hepatic metastases subsequently be detected, they may still be resected for cure in some instances if the abdominal disease has been completely eradicated ( Fig. 48–59 ). To restore the continuity of the gastrointestinal tract, an anastomosis is fashioned with either sutures or staples, joining the ends of the intestine (small or large). It is important that both segments of the intestine used for the anastomosis have excellent blood supply and that there be no tension on the anastomosis. For lesions involving the cecum, ascending colon, and hepatic flexure, a right hemicolectomy is the procedure of choice. This involves removal of the bowel from 4 to 6 cm proximal to the ileocecal valve to the portion of the transverse colon supplied by the right branch of the middle colic artery.An anastomosis is fashioned between the terminal ileum and the transverse colon. An extended right hemicolectomy is the procedure of choice for most transverse colon lesions and involves division of the right and middle colic arteries at their origin, with removal of the right and transverse colon supplied by these vessels. The anastomosis is fashioned between the terminal ileum and the proximal left colon.
  14. 14. A left hemicolectomy (i.e., resection from the splenic flexure to the rectosigmoid junction) is the procedure of choice for tumors of the descending colon, whereas a sigmoidectomy is appropriate for tumors of the sigmoid colon. Most surgeons prefer to avoid incorporating the proximal sigmoid colon into an anastomosis because of the often-tenuous blood supply from the IMA and the frequent involvement of the sigmoid with diverticular disease. Abdominal colectomy (sometimes called subtotal colectomy or total colectomy) entails removal of the entire colon from the ileum to the rectum, with continuity restored by an ileorectal anastomosis. Owing to loss of the absorptive and storage capacity of the colon, this procedure causes an increase in stool frequency. Patients younger than the age of 60 years generally tolerate this well, with gradual adaptation of the small bowel mucosa, increased water absorption, and an acceptable stool frequency of one to three bowel movements daily. In older individuals, however, abdominal colectomy may result in significant chronic diarrhea. Abdominal colectomy is indicated for patients with multiple primary tumors, for individuals with HNPCC, and occasionally for patients with completely obstructing sigmoid cancers. The chances that the patient has been cured by an operation performed to remove a colorectal cancer is dependent on several factors, including technical aspects of the operation, such as the complete removal of all tumor, certain biologic properties of the cancer that are poorly understood, and the stage of the disease. Staging may be defined as the process by which objective data are assembled to try to define the state of progression of the disease.[84] Separate items of data are summated to provide a designated stage for an individual patient’s disease, from which inferences may be drawn regarding the relative likelihood of residual disease and hence the chance of cure without further treatment and the advisability of considering further treatment. The ideal staging system would provide one ultimately important and simple item of information: Has the operation cured the patient or will he or she die unless further intervention prevents it? Thus, there would be just two categories: the cured and those destined to die of their disease.[85] Unfortunately, no system extant even remotely approaches that goal. Still, every attempt should be made to accurately assess the extent of the disease to provide guidance for prognosis and the need for further treatment. At the present time the stage of the tumor is assessed by indicating the depth of penetration of the tumor into the bowel wall (T stage), the extent of lymph node involvement (N stage), and the presence or absence of distant metastases (M stage). For most of the last half century the standard staging system was based on a system developed and modified by Cuthbert Dukes, a pathologist at St. Mark’s Hospital in London.[86] The classification was developed for rectal cancer, but it was generally used to also describe the stage of colon cancer. The Dukes’ classification is simple to remember and still frequently used. Dukes’ stage A cancer is confined to the bowel wall. Stage B cancer penetrates the bowel wall, and stage C cancer indicates lymph nodal metastases. Kirklin and colleagues, from the Mayo Clinic, established a distinction between tumors that partially penetrated the muscularis propria (B1) and those that fully penetrated this layer (B2). Astler and Coller further separated the tumors that had invaded lymph nodes but did not penetrate the entire bowel wall (C1) from tumors that invaded lymph nodes and did penetrate the entire wall (C2).[87] Turnbull and associates from the Cleveland Clinic added stage D for tumors with distant metastasis. All of these modifications in various combinations are still in use and often called the modified Dukes classifications. The classification in use by most hospitals in the United States was developed by the American Joint Committee on Cancer (AJCC) and was approved by the International Union Against Cancer (UICC).[88] This classification, known as the TNM (Tumor, Node, Metastasis) system, Figure 48-59 Operative procedures for right-sided combines clinical information obtained preoperatively with data obtained colon cancer, sigmoid diverticulitis, and low-lying during surgery and after histologic examination of the specimen. There have rectal cancer. A right hemicolectomy (A) involves been some modifications in the system since its introduction in 1987. The resection of a few centimeters of terminal ileum and surgeon is now encouraged to score the completeness of the resection as colon up to the division of the middle colic vessels into right and left. A sigmoidectomy (B) consists of follows: R0 for complete tumor resection with all margins negative; R1 for removing the colon between the partially incomplete tumor resection with microscopic involvement of a margin, and retroperitoneal descending colon and the rectum. An R2 for incomplete tumor resection with gross residual tumor not resected ( abdominoperineal resection of the rectum (C) is Table 48–6 ). performed in a combined approach through the abdomen and through the perineum for the resection of the entire rectum and anus.
  15. 15. Table 48-6 -- AJCC TNM Staging System for Colorectal Cancer Primary Tumor (T) TX Primary tumor cannot be assessed T0 No evidence of primary tumor Tis Carcinoma in situ: intraepithelial or invasion of lamina propria * T1 Tumor invades submucosa T2 Tumor invades muscularis propria T3 Tumor invades through the muscularis propria into the subserosa, or into nonperitonealized pericolic or perirectal tissues T4 Tumor directly invades other organs or structures and/or perforates visceral peritoneum † Regional Lymph Nodes (N) ‡ NX Regional lymph nodes cannot be assessed N0 No regional lymph node metastasis N1 Metastasis in 1 to 3 regional lymph nodes N2 Metastasis in 4 or more regional lymph nodes Distant Metastasis (M) MX Distant metastasis cannot be assessed M0 No distant metastasis M1 Distant metastasis Stage Grouping Stage T N M Dukes § MAC § 0 Tis N0 M0 I T1 N0 M0 A A T2 N0 M0 A B1 IIA T3 N0 M0 B B2 IIB T4 N0 M0 B B3 IIIA T1-T2 N1 M0 C C1 IIIB T3-T4 N1 M0 C C2/C3 IIIC Any T N2 M0 C C1/C2/C3 IV Any T Any N M1 D Histologic Grade (G) GX Grade cannot be assessed G1 Well differentiated G2 Moderately differentiated G3 Poorly differentiated G4 Undifferentiated Note: The y prefix is to be used for those cancers that are classified after pretreatment, whereas the r prefix is to be used for those cancers that have recurred. * Tis includes cancer cells confined within the glandular basement membrane (intraepithelial) or lamina propria (intramucosal) with no extension through the muscularis mucosae into the submucosa. † Direct invasion in T4 includes invasion of other segments of the colorectum by way of the serosa: for example, invasion of the sigmoid colon by a carcinoma of the cecum. Tumor that is adherent to other organs or structures macroscopically is classified T4. However, if no tumor is present in the adhesion microscopically the classification should be pT3. The V and L substaging should be used to identify the presence or absence of vascular or lymphatic invasion. ‡ A tumor nodule in the pericolorectal adipose tissue of a primary carcinoma without histologic evidence of residual lymph node in the nodule is classified in the pN category as a regional lymph node metastasis if the nodule has the form and smooth contour of a lymph node. If the nodule has an irregular contour, it should be classified in the T category and also coded as V1 (microscopic venous invasion) or as V2 (if it was grossly evident), because there is a strong likelihood that it represents venous invasion. § Dukes B is a composite of better (T3N0M0) and worse (T4N0M0) prognostic groups, as is Dukes C (Any TN1M0 and Any TN2M0). MAC is the modified Astler-Coller classification.