Colon Cancer

Introduction

The colon is the segment of the GI tract most frequently affected by tumors

Polyp is any circumscribed "tumor" that projects into lumen of gut

may be pedunculated/sessile, benign/malignant

Non-neoplastic polyps

Hyperplastic polyps – <5mm diamtr; in ppl >40 yo; "hypermature" epith changes; cell renewal is normal except for longer turnover time, slow migration from crypt to surface, and slower exfoliation; pure hyperplastic have no malignant potential

Hamartomatous polyps – developmental malformations affecting the glands and lamina propria; consist of normal mucosal components arranged abnormally; increase risk of carcinomas of pancreas, breast, lung, ovary, uterus

Juvenile polyposis syndrome – autosomal dominant; no malignant potential; occur in children <5 yo; 80% occur in rectum (can be scattered thru-out colon); 1-3 cm in diameter with stalks 2cm in length

Peutz-Jeghers syndrome – autosomal dominant; scattered thru-out entire GI tract; melanotic mucosal and cutaneous pigmentation around lips, oral mucosa, face, genitalia, palms of hands; no malignant potential

Inflammatory polyps – occur in ppl with longstanding inflammatory bowel disease (commonly in chronic ulcerative colitis and rarely in Crohn’s disease); result from epithelialization of ulcers and overgrowth of overhanging margins; no distension between head and stalk (referred to as "pseudopolyps")

Lymphoid polyps – mucosal protrusion secondary to reactive hyperplasia of mucosal and submucosal lymphoid tissue

Neoplastic polyps – adenomas are benign neoplastic polyps

Tubular adenoma (adenomatous polyps) – 75% of neoplastic polyps; found mainly in distal colon and rectum; Most occur singly, sometimes 2 or more present simultaneously; The stalk is usually covered with normal colonic mucosa, but in the head of the lesion the polypoid epithelium is clearly neoplastic and composed of closely aggregated, elongated tubules and glands separated by a scant connective tissue stroma

when <1cm, 1% chance of invasive cancer; 1-2cm= 10% chance; >2cm= 45%; overall incidence of carcinoma is 3-5%

Villous adenoma – the least common, the largest, and most ominous of the epithelial polyps; occur in ppl >60 yo; majority located in rectum and rectosigmoid areas (may be scattered thru-out colon); size ranges 1-10cm in diamtr; more symptomatic than are tubular adenomas; symptoms – rectal bleeding, hypoproteinemia, hypokalemia; harbor invasive cancers in 1/3 of cases

Tubulovillous adenoma – contain features of both tubular and villous adenoma

Relationship of neoplastic polyps to carcinoma

Probability of carcinoma occurring in neoplastic polyp is related to size of polyp, relative proportion of it villous component, and presence of significant cytologic atypia (high grade dysplasia) in the neoplastic cells

Familial polyposis syndromes

Familial polyposis coli (FPC) – innumerable (1000’s) neoplastic polyps carpeting entire colon (must have >100 polyps); autosomal dominant with incomplete penetrance; deletion of chromosome 5q^- ; risk of colorectal cancer is 100% unless diseased colon is removed (10% incidence at 10yrs; 50% at 20yrs; 100% at 30yrs)

Gardner’s syndrome – exhibits familial polyposis coli, multiple osteomas, epidermal cysts and fibromatosis; autosomal dominant with incomplete penetrance; same high risk of developing colon cancer as those with FPC

Turcot’s syndrome – rare variant of polyposis coli marked by combination of multiple colonic polyposis and CNS tumors

Malignant tumors

Carcinoma – 98% of all cancers in large intestine are adenocarcinoma; slow growing tumors

malignancy produces symptoms relatively early, and at this stage are generally curable by resection

60-70% of colorectal carcinoma is located in rectum, rectosigmoid, or sigmoid colon (remainder are thru-out colon)

On the left side when discovered, they tend to become annular, encircling lesions that produce "napkin ring" constrictions of the bowel with early symptoms of obstruction

On right side, tumors tend to grow as polypoid fungating masses (bulky) that extend along one wall of the more capacious cecum and ascending colon (obstruction is uncommon on right side); begin as sessile lesions; early symptoms of bleeding

Modified Duke’s classification (Astler-Coller modification):

A: tumor limited to the mucosa
B: tumor extends to the entire thickness of the wall
C: tumor with metastases to lymph nodes
D: tumor with distant metastases

Other malignant tumors of the colon-anus: carcinoid, malignant lymphoma, malignant melanoma, Paget’s disease, sarcoma, squamous cell carcinoma, transitional cell carcinoma

Principles of Cancer Genetics

All cancers are genetic diseases resulting from sequential mutations in genes that regulate cellular growth and proliferation (proto-oncogenes, tumor supressor genes) or the rate of cellular mutations (DNA repair genes)

normal Þ preneoplastic Þ malignant

All cancers are the product of a clonal expansion of a single cell that acquires a selective growth advantage due to a somatic mutation in the genome

further growth and subsequent mutations in abnormal clones gives rise to a cell population with new biologic properties

Mutations occur as somatic, non-random and sequential events during the process of carcinogenesis

Some gene mutations occur in the germline and will cause inherited forms of cancer

Knudson’s "two-hit hypothesis" for retinoblastoma: Inactivating mutations in both alleles of Rb gene were necessary for retinoblastoma to develop; First mutation is germline or somatic while the second mutation is always somatic
Some cancers (like CRC) are more complex and require additional mutations in other genes

Molecular Steps in Colon Cancer Carcinogenesis

Stages range from aberrant crypt foci to adenomas to malignant tumors due to a series of genetic mutations in proto-oncogenes and tumor supressor genes

Four important genetic events occur in most cases of CRC Þ activation of the ras proto-oncogene and the inactivation of the tumor supressor genes on chromosomes 5q, 17p and 18q

Activation of the K- or N-ras proto-oncogene: occurs during the intermediate to late adenoma stage; occurs in 50% of adenomas >1cm; ras proto-oncogenes encode small proteins similar to G proteins that can bind GTP (alters GTPase activity) resulting in a growth advantage for this clone; all ras mutations are somatic mutations

Inactivation of the tumor supressor genes (identified on basis of chromosomal deletions):

adenomatous polyposis coli (APC) gene is located on 5q – early step in initiation of CRC since found to be in most small adenomas and aberrant crypts; 80% of sporadic cancers carry APC mutations; mutations in the APC gene can occur in inherited and sporadic forms of CRC
p53 gene is located on 17p
DCC gene is located on 18q

Mutations in mismatch repair genes can also cause CRC (identified on basis of genomic instability of polymorphic microsatellite markers) – referred to as MSI (microsatellite instability)

found in 10 to 15% of sporadic cases of CRC and up to 90% of cases from a form of familial CRC (HNPCC)
MSI leads to an unstable hypermutable phenotype in the colon epithelial cell where the cells develop additional mutations 100 to 700 times the normal rate
5 separate genes have been identified with 4 of them identified in the germline (leading to sporadic or HNPCC CRC):

hMSH2 located on 2p15-16; hMLH1 located on 3p21; hPMST1 located on 2q31; hPMST2 located on 7p22

see figure below: Kinzler and Vogelstein prot-oncogene model (top) and Markowitz and Wilson MSI model (bottom)

Inherited Predisposition to Colo-rectal Cancer

Familial Adenomatous Polyposis (FAP) – autosomal dominant; predisposition for polyposis, CRC and other cancers; accounts for <1% of all CRC cases; Gardner syndrome (allelic to FAP; polyposis, CRC plus extra-colonic manifestations)

affected individuals carry a germline mutation in one allele of the APC gene from birth

Hereditary Non-Polyposis Colorectal Cancer (HNPCC) – name is a misnomer since affected ppl can develop several polyps throughout the bowel; syndrome not as rare as FAP (accounts for 5 to 10% of all CRC); autosomal dominant; was initially called Lynch syndrome; germline mutations can occur in one of the 4 separate DNA repair (MSI) genes

clinical criteria: developed CRC before the age of 50, and who has 2 first degree relatives with CRC at any age. One of the 3 affected cases must be a first degree relative of the other 2 (hint: 1 with CRC <50; 2 generations; 3 close relatives)

Genetics and the importance of a family history

Genetic factors may predispose to and heighten the risk of colon cancer (FAP, HNPCC)

Person has 2-3x risk of developing colon cancer with 1^st degree relative with colon cancer and 8x risk with two 1^st degree relatives; risk is even higher if an affected 1^st degree relative was diagnosed with the disease before age 55

Person with 1^st degree relative with colonic polyps has greater risk of developing other colorectal adenomas and colon cancer

Environment

autosomal dominant genetic programming accounts for only 6 to 8% of colon cancers (FAP, HNPCC), thus most colon cancers develop when environmental factors influence colons that are genetically predisposed to colon cancer
a number of colorectal cancers occur without evolving thru a polyp cancer sequence (10-20% of colorectal cancers); patients who have these cancers lack a family history of cancer or adenomas
Intake of animal fat increases the risk of colon cancer (theory- dietary fat increases bile synthesis by liver and increases amount of sterols presented to colon where colonic bacteria convert the sterols to secondary bile acids; both bile acids and FFA’s increase proliferative activity in the epithelium)
Inflammation in colonic mucosa increases the risk of colorectal cancer

Age and ethnicity

Patients >70 are more likely to present with Dukes’ A or B colorectal cancer; younger patients present more often with D
Older patients fare worse regarding comorbid conditions and complications of surgery such as abscess and sepsis; yet the 3 and 5 year survival for stage specific older and younger groups is the same
African american men and women have a higher mortality rate from colon cancer than others – this is associated with later stages at diagnosis than those of the same age in other ethnic groups are, also limited access to care and delay in diagnosis are responsible for the higher death rate in minorities (Boring showed the incidence of colorectal cancer as being higher in white men and women than african american counterparts when stratified in same socioeconomic groups)

Clinical Presentation

Symptoms and Signs

Obstruction – less likely in cecum and ascending colon cancers; tumor becomes so large it obliterates colonic lumen

Pain – develops as tumor obstructs the colonic lumen or invades surrounding organs; can usually palpate a mass

Wasting – "cancer cachexia"; avoidance of food due to obstruction or pain

Bleeding – occurs more chronically and profoundly in right colon lesions and more frequently on the surface of the stool in left colon lesions; only GI bleeding is an early sign of colorectal cancer

Taking a thorough history is the best clinical tool for preventing colon cancer

Removal of polyps will decrease predicted mortality from colon cancer

Diagnosis and Screening

Hemoccult – done once yearly in ppl 50-80 yo decreased the cumulative mortality of colorectal cancer by 33%; Although the cumulative incidence was identical in all groups screened, there was a higher incidence of Dukes’ stage D cancer in the control group than the screened group; results in colon cancer being detected at an earlier stage

Sigmoidoscopy – improves surveillance for the disease; no randomized control studies addressing effectiveness of this test; case control studies show a 60% reduction in mortality from cancer in parts of the colon reached by the sigmoidoscope; Use is recommended at age 50 and 51 then every 3yrs there-after

Colonoscopy – preferred diagnostic procedure for patient with colorectal bleeding and anemia; indications: hemoccult positive stools, hematochezia, prior polyps or cancers, family history of colon cancer or variety of tumors, ulcerative colitis of long-standing duration, unexplained weight loss and abdominal pain; Use is recommended at age 60

Air contrast barium enema

Screening High-Risk Groups for Colon Cancer

75% of colorectal cancer occurs in people who are at higher risk

Special screening is indicated for people with: Colon polyps, previous polyps and previous colon cancer; Family members of patients with sporadic colorectal cancer or colon polyps; Familial adenomatous polyposis; Familial non-polyposis cancer syndrome; Inflammatory bowel disease

Treatment

Surgery is treatment of choice for patients with colorectal cancer

Surgical treatment, prognosis and type of adjuvant therapy are markedly different between colon and rectal cancer

Radiation therapy has little use in colon cancers above the rectum

Adjuvant chemotherapy is useful in cases that have spread to lymph nodes and beyond

Chemotherapy, vaccine therapy and immunotherapy are being tested for colon cancers that haven’t spread to lymph node

Chemoprevention – Diet may contribute to colon cancer in ppl whose colons are genetically predisposed to it

Fiber – shown to NOT be effective in 1999 study
Calcium – shown to be effective in preventing adenomas in 1999 study
Aspirin – shown to be effective in multiple studies
COX-2 inhibitors – shown to be very promising in 1999 preliminary studies