Colonic Cancer Notes

COLONIC CANCER

Introduction

  • Colorectal cancer (CRC) is the most common malignancy of the gastrointestinal tract (GIT).
  • Over 150,000 new cases are diagnosed annually.
  • More than 52,000 patients die from it yearly.

Aetiology

  1. Aging
    • A dominant risk factor.
    • Incidence rises steadily after age 50 years.
    • More than 90% of cases are diagnosed in people older than 50 years of age.
    • This is the basis for commencing screening tests at age 50 years for average-risk Americans.
  2. Hereditary Risk Factor
    • Approximately 80% of CRC cases are sporadic, while 20% arise in patients with a known family history.
    • Hereditary CRC cancer syndrome is broadly divided into two categories:
      • Hereditary Adenomatous Polyposis Syndrome
      • Hereditary Non-polyposis Colon Cancer [HNPCC]

Hereditary Non-Polyposis Colon Cancer (HNPCC)

  • HNPCC is the most frequently occurring hereditary CRC syndrome in the USA and Western Europe.
  • Accounts for about 3% of all cases of CRC and approximately 15% of hereditary CRC.
  • Cancer occurs at a relatively young age (mean = 44 years).
  • Proximal distribution: 70% of cancers are located in the right colon.
  • Predominantly mucinous or poorly differentiated (signet ring) adenocarcinoma.
  • Increased number of synchronous and metachronous cancers.
  • Relatively good outcome after surgery despite the above poor prognostic indicators.
  • Two hereditary syndromes were described:
    • Lynch I: cancer of the proximal colon occurring at a relatively young age.
    • Lynch II: families at risk for both CRC and extracolonic cancers, including cancers of the endometrial, ovarian, gastric, small intestine, pancreatic, ureteral, and pelvic origin.
  • Before the genetic mechanisms underlying Lynch syndrome were understood, the syndromes were defined by the Amsterdam Criteria and later by Modified Amsterdam Criteria.
Components of “Amsterdam Criteria”
  • CRC in 3 family members (first-degree relatives).
  • Involvement of at least 2 generations.
  • At least one affected individual being younger than 50 years at the time of presentation, and FAP excluded.
Modified Amsterdam Criteria
  • Same as Amsterdam criteria, except that cancer must be associated with HNPCC (colon, endometrium, small bowel, ureter, renal pelvis) instead of specifically colon cancer.
  • Further liberalization for identifying patients with HNPCC occurred with the introduction of the “Bethesda Criteria.”
  • HNPCC is inherited in an autosomal dominant fashion.
  • HNPCC results from mutations in mismatch repair [MMR] genes.
  • A small number of colorectal polyps are present.
  • 70-80% lifetime risk for CRC.
Muir-Tore Variant
  • A variant of HNPCC.
  • Sebaceous adenomas, keratoacanthomas, basal cell carcinoma, and sebaceous epitheliomas occur as extracolonic manifestations.

Familial Adenomatous Polyposis (FAP) / Gardner’s Syndrome

  • Hundreds to thousands of colorectal polyps.
  • Osteomas, desmoid tumors, epidermoid cysts, and Congenital Hyperplasia of Retinal Pigmented Epithelium [CHRPE].
  • CRC risk is approximately 100%.
  • Risk also increases for periampullary malignancy, thyroid, CNS, hepatoblastomas, gastric, and duodenal tumors.
  • Inheritance is autosomal dominance.
  • The defect is APC gene mutation [5q21], from codon 1250 to codon 1464 for classic FAP.
  • FAP is the prototypical hereditary polyposis syndrome and accounts for about 1% of all CRCs.
  • There is a negative family history in 10-20% of patients who apparently acquire the syndrome by spontaneous mutation.
  • 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 CRC related to FAP is 39 years.
  • Genetic testing is positive in 75% of cases.

Attenuated FAP (AFAP)

  • A variant of FAP associated with mutations in the 3’ or 5’ end of the APC gene.
  • Patients present later in life with fewer polyps (usually 10-100), dominantly located in the right colon when compared to FAP.
  • CRC develops in more than 50% of these patients.
  • APC gene mutation is present in only 30% of patients with AFAP (autosomal dominance).
  • Mutations in MYH also result in the AFAP phenotype, but this expressed in an autosomal recessive pattern.

Turcot’s Syndrome

  • Colorectal polyps which may be few or resemble that of classic FAP.
  • Brain tumors including cerebellar medulloblastomas and glioblastomas.
  • Inheritance is autosomal dominance in APC gene.

Hereditary Hamartomatous Polyposis Syndrome

Cowden Disease
  • Mucocutaneous lesions, thyroid adenomas, goiters, fibroadenomas, BMD, uterine fibroid, macrocephaly.
  • Mutation occurs in the PTEN gene.
  • Inherited in an autosomal dominant pattern.
Familial Juvenile Polyposis
  • Defined by greater than or equal to 10 juvenile polyps.
  • Congenital abnormalities in at least 20%.
  • These include malrotation, hydrocephalus, cardiac lesions, Meckel’s diverticulum & mesenteric lymphangiomas.
  • 9-25% risk of CRC.
  • Autosomal inheritance.
  • SMAD4 gene mutation at 10q.
Peutz-Jegher’s Syndrome
  • A small number of polyps throughout the GIT but more common in the small intestine.
  • Pigmented lesions of skin; benign and malignant genital tumors.
  • Increased risk of GIT malignancy, pancreatic cancer.
  • Autosomal dominant inheritance.
  • Mutation in STK11 gene at 19q.
Ruvalcaba-Myre-Smith Syndrome (Bannayan-Zonana Syndrome)
  • GI polyps usually lipomas, hemangiomas, lymphangiomas.
  • Dysmorphic facial features, macrocephaly, seizures, pigmented macules.
  • Autosomal dominant inheritance.
  • PTEN gene mutation at 10q.
Cronkite-Canada Syndrome
  • GI polyposis in addition to alopecia, cutaneous pigmentation, and atrophy of fingernails and toenails.
  • Diarrhea is prominent.
  • Vomiting, malabsorption, and protein-losing enteropathy may occur.

  1. Adenomas

    • Most CRCs arise from adenomas
    • Adenoma-cancer sequence may take 5-15 years to develop.
    • Cancer most frequently arises from adenomas 2cm in diameter, villous in pathology, sessile in type, and with a high degree of dysplasia.
    • Approximately 40% of villous adenomas may be carcinoma in-situ or frankly invasive.
    • In about 30% of CRC, there are synchronous adenomatous polyps.

  2. Inflammatory Polyps

    • Occur most commonly in the context of inflammatory bowel disease (Ulcerative colitis, Crohn’s disease), but may also occur after amoebic colitis, ischemic colitis, and schistosomal colitis.
    • CRC is 30x greater and multiple cancers are 8x commoner in patients with ulcerative disease.
    • There is about a 20-fold risk of cancer developing in Crohn’s disease of the colon.

  3. Diet

    • Red meat increases risk
    • Vegetables, fruits, whole-grain cereals, and fish are protective
    • High-fat intake, especially saturated fat, increases risk
    • High fat/meat enhances the activities of certain anaerobic organisms - degradation of primary bile acids into secondary bile acids and other bile acid metabolites which are carcinogenic.

  4. Radiation

    • Radiation treatment of prostate cancer moderately increases the risk of rectal cancer.

  5. Familial CRC

    • First-degree relatives of patients with CRC have a 3-4 fold increased risk.
    • If the cancer develops at <55 years, the increased risk is 4-8 fold.
    • About 10-20% of cases are of this origin.

  6. Sporadic Cancers

    • Most cancers are sporadic and develop in average-risk patients.

  7. Others

    • Cigarette smoking increases risk.
    • Uterosigmoidoscopy increases risk.
    • Acromegaly also increases risk.
    • Obesity increases risk.

Pathogenesis of CRC

  • CRC occurs in a hereditary, sporadic, or familial form.
  • Genetic mutations associated with sporadic cancers are limited to the tumor itself, unlike hereditary disease, in which the specific mutation is present in all cells of the affected individual.
  • Nevertheless, the genetics of CRC initiation and progression proceed along similar pathways in the hereditary and sporadic forms.
  • The “Fearon-Vogelstein Adenoma-Carcinoma multistep model” of colorectal neoplasia represents one of the best-known models of carcinogenesis.
  • Tumor suppressor genes, DNA mismatch repair genes, and proto-oncogenes all contribute to colorectal neoplasia in the inherited and sporadic forms.
  • This sequence of tumor progression involves damage to proto-oncogenes and tumor suppressor genes.
  • 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.’
  • Classic FAP is characterized by APC truncation in the mutational cluster region of the gene, from codon 1250 to codon 1464, an area responsible for B-catenin binding.

Adenoma-Carcinoma Sequence

  • Normal colonic epithelium --(APC)--> Dysplastic aberrant crypt foci --> Early adenoma --(K-RAS)--> Intermediate adenoma --(DCC)--> Late adenoma --(P53)--> Carcinoma --(Other changes)--> Metastasis
  • From Dysplastic aberrant crypt foci to early adenoma = Tumor initiation
  • From intermediate adenoma to late adenoma = Tumor progression
  • Carcinoma = Neoplasia
  • In FAP, tumor initiation is accelerated (due to germline APC mutation), while the duration of tumor progression is normal [5-10 years].
  • In HNPCC, tumor initiation is normal, while tumor progression is accelerated [1-3 years]; the HNPCC patient with normal index colonoscopic findings may present with florid malignancy before the next endoscopy is due.

Pathology

Macroscopic Types

  1. Proliferative or cauliflower type

    • Bulky fungating tumor that projects into the lumen of the gut.
    • It is the usual tumor in the right colon.
    • It may become necrotic and ulcerates as it grows.

  2. Malignant Ulcer

    • It grows in the transverse axis of the bowel.
    • Are found commonly in the rectum and rectosigmoid.
    • Generally, CRC starts as a thickening of the mucosa which may proliferate and become bulky. It may invade the submucosa and muscle and obstruct blood vessels with consequent necrosis and ulceration.

  3. Annular, scirrhous, or string stricture type

    • This probably starts as a malignant ulcer that grows slowly in the transverse direction to encircle the lumen as if a string has been tied around it.
    • It occurs most commonly in the left colon.

  4. Tubular or infiltrative type

    • The annular type may spread longitudinally and involves a segment 5cm or more long. It is then tubular or infiltrative in type.

  5. Microscopic Types

    • Over 80% are adenocarcinomas, the rest being colloid or anaplastic carcinomas.

Spread

  • Direct.
  • Via lymphatic.
  • Via the bloodstream.
  • Transperitoneal seedlings.

Staging and Grading

  • Colorectal cancer staging is based upon the tumor depth and the presence or absence of nodal or distant metastasis.
  • Older staging systems such as the Duke’s classification and its Astler-Coller modification have been largely replaced by the AJCC based on TNM staging system.
AJCC
  • Stage I: T1-2, N0, M0 (5-year survival = 70-95%)
  • Stage II: T3-4, N0, M0 (5-year survival = 54-65%)
  • Stage III: Tany, N1-3, M0 (5yr survival = 39-60%)
  • Stage IV: Tany, Nany, M1 (5-year survival = 0-16%)

Complications of CRC

  • Intestinal obstruction.
  • Perforation.
  • Internal fistulae.
  • Anemia.

Clinical Features

Insidious Presentation (75%)

  • The most common and important symptoms in colonic cancer are a change in bowel habit and abdominal pain. This may be constipation, diarrhea, or alternating constipation and diarrhea.
  • Passage of blood or mucus in stool.
  • Noises in the abdomen (audible borborygmi).
  • Dyspepsia and abdominal distension.
  • Lump in the abdomen, especially in cancer of the cecum.
  • Anemia, weight loss.
  • Cancer of the right colon often presents with vague dyspepsia because of the gastrocolic reflex, anemia from necrosis and bleeding, weight loss, or a mass. Change in bowel habit is unusual, but diarrhea may occur occasionally.
  • Tumor of the left colon usually presents with a change in bowel habit due to obstruction.
  • Tumors of the rectum and rectosigmoid present with rectal bleeding. There is associated spurious diarrhea and often tenesmus.
  • Obstruction of any of the tributaries of the superior rectal vein by the tumor may give rise to hemorrhoids. Patients over 40 years presenting with hemorrhoids must be carefully evaluated.
  • Involvement of contiguous structures: vesico-colonic fistula, sciatic pain.

Emergency Presentation

  • Acute on chronic intestinal obstruction.
  • Perforation and subsequent general peritonitis.
  • Paracolic abscess.
  • Acute bleeding.

Investigations

  1. Colonoscopy and Biopsy
  2. Sigmoidoscopy + Barium enema and biopsy
    • Barium enema if facility or expertise for endoscopy is lacking.
  3. CT abdomen.
  4. MRI.
  5. FBC, SEUCr, CxR, Abdominopelvic U/S

Differential Diagnosis

Cancer of the Cecum or ascending colon

  • Appendix abscess.
  • Amoeboma of the cecum or ascending colon.
  • Crohn’s disease.
  • Ileocaecal TB.
  • Actinomycosis.
  • Ovarian cyst, renal swelling.
  • Pedunculated myoma uteri.

Cancer of the Left Colon

  • Diverticulitis.
  • Amoeboma.
  • Schistosoma of the colon.
  • Renal swelling.
  • Ovarian cyst.
  • Pedunculated leiomyoma uteri.

Cancer of the Transverse Colon and Flexures

  • Cancer of the stomach.
  • Cancer of the gallbladder.
  • Hepatic enlargement.
  • Splenomegaly.
  • Secondary deposit in the omentum.

Treatment

  1. Resuscitation with fluid, blood, N-G tube decompression, Urethral catheterization, antibiotics, analgesics.
  2. Bowel preparation
    • Obstruction must be excluded.
    • Commonly for left-sided colon cancers.
    • Polyethylene glycol [PEG] and sodium phosphate are common agents used for mechanical bowel preparation.
  3. Operative treatment
    • The extent of resection depends on the stage of the disease, location of the cancer, and area of the bowel supplied by the main colic vessels along which the regional lymph nodes are located.
    • (a) Cecum, ascending colon, and hepatic flexure: Radical right hemicolectomy is done.
    • (b) Transverse colon: Resection of transverse colon and both flexures.
    • (c) Splenic Flexure: Radical Left Hemicolectomy-resection of the descending colon and distal two-thirds of the transverse colon.
    • (d) Descending colon
      • As for splenic flexure, but a more radical resection with removal of the pelvic colon is preferable.
    • (e) Pelvic colon
      • Pelvic colectomy with or without left hemicolectomy.
  4. Adjuvant Chemotherapy
    • (a) A subset of Stage II may benefit from a 5-Flurouracil-based regimen.
    • (b) Stage III clearly benefits from adjuvant chemotherapy like FOLFOX. FOLFIRI can also be used.
    • (c) Stage IV requires chemotherapy-FOLFOX or FOLFIRI.
    • (d) Monoclonal antibodies effective for metastatic (stage IV) disease are:
      • Bevacizumab (Avastin): vascular endothelial growth factor inhibitor. Can be combined with FOLFOX or FOLFIRI.
      • Cetuximab (Erbitux).
      • Panitumumab.

Follow-up/Surveillance

  • Colonoscopy.
  • Carcino-embryonic antigen [CEA].
  • CT and MRI of the abdomen and chest commonly if CEA is elevated.