Colorectal Cancer

Overview

Epidemiology

• 3rd most common cancer (among both men and women)
• 2nd most common cause of death due to cancer in the United States
• In the United States, incidence and mortality rates have been declining.
• The majority are adenocarcinomas.
• Most colorectal cancers (CRCs) arise from polyps (adenomatous or serrated).

Risk factors

• Age ≥ 45 (94% of new CRC cases)
• Hereditary syndromes: 
  • Familial adenomatous polyposis (FAP)
  • Hereditary non-polyposis colorectal cancer (HNPCC) or Lynch syndrome
  • Peutz-Jeghers syndrome (PJS)
  • MUTYH-associated polyposis (MAP): mutation in the base excision repair gene mutY homolog
  • Family history of CRC
• Colon pathologies:
  • Inflammatory bowel disease (IBD)
  • Large adenomatous polyps or previous CRC
• Other medical conditions:
  • Cystic fibrosis
  • Abdominopelvic radiation
  • Conditions with increased insulin or insulin-like growth factor (e.g., diabetes, acromegaly, obesity)
  • Streptococcus bovis bacteremia
  • Renal transplantation
• Lifestyle and social factors:
  • Smoking and alcohol consumption (> 4 drinks/day)
  • Diet (increased fat, red and processed meat, low fiber)
  • Low socioeconomic status

Etiology

Colorectal polyps

• Abnormal tissue outgrowths arising from the colonic mucosa and extending into the lumen
• Most common lesions from which CRC arises
• Morphology:
  • Sessile: polyp without a stalk, with growth adjacent to the mass
  • Pedunculated: polyp with a stalk
• 30% of the population has polyps by the age of 50.

Types of polyps:

• Inflammatory polyps (non-neoplastic)
• Hamartomatous polyps (↑ CRC risk if associated with PJS)
• Sessile serrated lesions:
  • Sessile serrated adenomas/polyps (SSA/Ps)
  • Traditional serrated adenomas (TSAs)
  • Hyperplastic polyps (histologically similar to SSA; non-neoplastic)
• Adenomatous polyps:
  • Tubular (> 80%)
  • Villous adenomas (majority are sessile)
  • Tubulovillous 

High-risk polyps:

• Polyps > 1 cm in size
• Adenomas with villous features (CRC risk > 3 times that of tubular adenomas) or high-grade dysplasia
• Serrated polyps/adenomas

Cancer development

Most polyps are benign. Malignant transformation is affected by a series of mutations and environmental factors.

Mutations:

• Germline mutation: 
  • Occurs before fertilization
  • Can be transmitted (from parent to offspring)
  • Found in the common inherited syndromes (e.g., FAP, Lynch syndrome), which account for < 10% of CRCs
• Somatic mutation:
  • Spontaneous mutation in sperm/ovum or zygote
  • Parent does not have the mutation, but future offspring can inherit.
  • Found in sporadic CRCs (> 70%)

APC (adenomatous polyposis coli) gene:

• Most CRCs begin with adenomatous polyposis coli (APC) gene inactivation (either by germline or somatic mutation).
• CRCs take 10–15 years to develop but can advance in a shorter time under certain conditions.
• APC protein, encoded by APC gene, promotes β-catenin degradation.
• Without APC protein: 
  • β-catenin activates T cell factor (Tcf)–dependent transcription of specific target genes.
  • These genes include MYC and cyclin D1 (oncogenes), which promote proliferation.
• APC mutations: the initiating event for adenoma formation, but multiple genetic hits are required for CRC progression

Pathophysiology

APC

Adenomatous polyposis coli is an initial gene mutation.

• Most adenomas and CRCs begin with APC gene inactivation (either by germline or somatic mutation).
• After the initiating event, CRCs take 10–15 years to develop (shorter time in certain conditions).
• APC protein, encoded by APC gene, promotes β-catenin degradation.
• Without APC protein: 
  • β-catenin (of the WnT pathway) activates Tcf–dependent transcription of specific target genes.
  • These genes include MYC and cyclin D1 (oncogenes), which promote proliferation.

Molecular mechanisms of tumorigenesis

Multiple genetic hits are required for CRC progression.

Accumulation of mutations and molecular events:

Accumulation of mutations and molecular events (e.g., genetic alteration, DNA methylation, overexpression) contributes to carcinogenesis.

• Chromosomal instability (CIN):
  • Structural chromosomal aberrations (deletions or loss of heterozygosity)
  • Results in either promotion of oncogenes or reduction of tumor suppressor genes (TSGs)
  • Seen in genetic alterations of APC
  • Other genes: DCC, TP53/p53, and SMAD4 (tumor suppressor genes) or KRAS (a proto-oncogene)
  • 85% of CRCs develop through this mechanism.
• Microsatellite instability (MSI):
  • Also called mutator phenotype/mismatch repair pathway
  • Microsatellites: repeated, abnormal, short sequences of nucleotide bases caused by mismatch repair deficiency
  • Cause: germline mutation of genes MLH1, MSH2, or PMS2 leading to dysfunctional DNA mismatch repair (MMR) enzymes
  • Microsatellite accumulation: found in MSI-high (MSI-H) tumors
  • Biologic hallmark of Lynch syndrome
  • Seen in up to 15% of sporadic CRCs
• CpG island methylator phenotype (CIMP+) pathway:
  • DNA hypo- or hypermethylation can change gene expression.
  • High methylation of CpG islands (cytosine followed by a guanine base, linked by phosphodiester bond) occurs in TSG.
  • Methylation inactivates TSG, leading to tumor progression.
  •  Found in CIMP+ tumors

Cyclooxygenase (COX)-2 overexpression: 

• COX-2: overexpressed in 43% of adenomas and 86% of carcinomas
• COX-2 inhibition reduces the number of intestinal polyps.

Morphologic mechanisms of tumorigenesis

Adenoma-carcinoma sequence:

• Sequence followed by most CRCs
• Progression: early adenoma (tubular or tubulovillous) → advanced adenoma (villous) → adenocarcinoma
• Adenomatous polyps: 
  • Develop with disrupted epithelial renewal
  • Replacement of surface cell lining becomes dysplastic as the adenomas increase in size.
• APC mutation common
• Associated molecular pathway(s): CIN

Serrated polyp pathway:

• Serrated polyps: also have malignant potential 
• Seen in 10%–20% of cases
• Progression: sessile serrated polyp/adenoma → adenocarcinoma
• BRAF oncogene activation with KRAS mutations noted
• Associated molecular pathway/s: 
  • CIMP (major mechanism that drives the serrated pathway toward CRC)
  • MSI

Clinical Presentation

General clinical findings

• Often asymptomatic, with CRC detected on screening colonoscopy
• Symptomatic:
  • Systemic features: weakness, anemia, weight loss
  • Iron deficiency anemia in an elderly patient indicates colon cancer until proven otherwise.
  • Dependent on location

Right-sided carcinomas

• Obstructive symptoms are not common:
  • Stool in the area (ileocecal valve to ascending colon) is still liquid.
  • Lumen is larger (than left side).
• Lesions can grow, ulcerate, and lead to occult blood loss:
  • Iron deficiency anemia: fatigue, angina, palpitations
  • Melena 

Left-sided carcinomas

• From the transverse to the descending colon, stool becomes formed.
• Thus, cancerous lesions can impede passage of stool, causing:
  • Abdominal cramping or colicky pain
  • Changes in bowel habits (constipation alternating with loose stools)
  • Blood-streaked stools or hematochezia
  • Decreased stool caliber due to obstruction

Rectal cancers

• Palpable ulcerating mass on rectal exam
• Tenesmus 
• Rectal bleeding
• Obstruction

Metastasis

• CRCs metastasize by direct extension or via hematogenous and lymphatic route. 
• Sites of metastasis: 
  • Liver (1st site for intestinal tumors): abdominal distention, jaundice, ascites, hepatomegaly
  • Lungs (1st site for distal rectal tumors): cough, dyspnea (may be from pleural effusion), hemoptysis

Diagnosis

Colonoscopy

• Diagnostic test of choice
• Visualization of lesion(s) and tissue sampling (biopsy or lesion removal) can be performed.
• Screening colonoscopy:
  • Asymptomatic patients
  • For the population with average risk: performed at age 50 years and above
  • Screening at a younger age depends on conditions and risks.
• Diagnostic colonoscopy:
  • Performed in symptomatic patients
  • Indicated for those with abnormal imaging studies
• Findings:
  • Polyps 
  • Carcinoma:
    • Bulky exophytic masses
    • Annular constricting lesions

Computed tomography (CT) colonography

• Virtual colonoscopy 
• Requires mechanical preparation
• Can be used in incomplete colonoscopy (e.g., obstruction, tortuous colon) or as an initial diagnostic test
• Colonoscopy remains the gold standard.
• Limitations:
  • Patients should be able to pass flatus.
  • Cannot perform biopsy or lesion removal

PILLCam 2

• Colon capsule endoscopy: Patient swallows a capsule-sized endoscope.
• Considered in patients with incomplete colonoscopy
• Patients should have no obstruction.

Further imaging studies

• Air contrast barium enema may show apple core lesion.
• CT scan:
  • For preoperative staging
  • Detects associated complications (e.g., obstruction, perforation, fistula)
  • Detects metastasis
• Pelvic magnetic resonance imaging (MRI) or transrectal endoscopic ultrasonography (US):
  • For rectal cancers 
  • For assessment of cancer depth through the rectal wall and perirectal lymph nodes

Laboratory tests

• Carcinoembryonic antigen (CEA):
  • Tumor marker for CRC; obtained with proven CRC
  • Not used for screening or diagnostic test
  • Prognostic value: preoperative CEA > 5 ng/mL has worse prognosis.
  • Non-normalization of values after surgery: indicative of persistent disease
• Complete blood count (CBC): may show anemia
• Metabolic panel:
  • May show additional metabolic abnormalities
  • Elevated alkaline phosphatase: most common liver abnormality associated with liver metastasis

Staging

After establishing the diagnosis of CRC, staging the disease is needed for appropriate management.

TNM (tumor, node, metastasis) staging system: 

• Determines disease extent
• Findings based on: 
  • Preoperative examination (e.g., ascites, lymph nodes)
  • Imaging results: 
    • CT scan (chest/abdomen/pelvis)
    • MRI (identifies more metastatic hepatic lesions)
    • Transrectal endoscopic US (for rectal cancer)
  • Endoscopy (with biopsy) and lymph node biopsy

Prevention

• Adults (50–59 years of age):
  • United States Preventive Services Taskforce: daily low-dose aspirin for primary prevention of CRC
  • Individuals should have:
    • No bleeding risk 
    • At least 10 years of life expectancy
    • ≥ 10% of 10-year CVD risk
• Individuals with average risk:
  • Initiated at 50 years of age (45 years of age for African Americans)
  • Options for screening:
    • Annual high-sensitivity guaiac-based fecal occult blood test (HSgFOBT)
    • Annual fecal immunochemical test (FIT)
    • sDNA-FIT test every 3 years
    • Flexible sigmoidoscopy every 5 years (limited to distal part of the colon)
    • Colonoscopy every 10 years
    • CT colonography every 5 years
  • A positive screening stool-based test, CT colonography, or sigmoidoscopy warrants a colonoscopy. 
  • Screening generally not recommended after age 75
• Individuals with a family history of CRC/advanced adenoma/advanced serrated lesion:
  • Colonoscopy at age 40 or 10 years earlier than the age of diagnosis of the 1st-degree relative (whichever comes first)
  • Repeat every 5 years

Management

General principles

• Resection of primary cancer:
  • Treatment of choice for almost all patients with resectable lesions
  • Can be laparoscopic or open surgery
• Regional lymph node dissection (at least 12 lymph nodes) is performed with resection (aids in determining additional adjuvant therapy).
• Chemotherapy:
  • Adjuvant chemotherapy: given depending on stage of colon carcinoma
  • Neoadjuvant chemotherapy and/or radiotherapy: given for patients with rectal carcinoma (T3 or higher, node-positive cancers) 
  • Chemotherapy regimens:
    • FOLFOX (5-fluorouracil/5-FU + folinic acid/leucovorin + oxaliplatin) regimen
    • FOLFIRI (5-fluorouracil + folinic acid + irinotecan)
    • CAPOX/XELOX: oral capecitabine (Xeloda) used with oxaliplatin

The stage of CRC and molecular biology (in the case of targeted therapy) dictate the roles of surgical and pharmacologic treatments.

Carcinoma in a polyp

• Endoscopic removal or polypectomy
• When invasive cancer is suspected, tattooing is done (for localization if an invasive lesion is found or if additional therapy/surgery is needed).
• Factors indicating high risk for residual cancer or nodal metastasis (consider radical surgery):
  • Poorly differentiated histology
  • Cancer at stalk margin
  • Lymphovascular invasion
  • T2 lesion
  • Invasive carcinoma in a sessile polyp

Colon cancer stage I–III

• Wide resection of the lesion with regional lymphadenectomy is performed.
• Surgical options:
  • Right hemicolectomy: lesion(s) in the cecum and right colon (can be extended to include transverse colon)
  • Left hemicolectomy: lesion(s) in the splenic flexure and left colon (can be extended to include transverse colon)
  • Sigmoid colectomy: sigmoid colon 
  • Total abdominal colectomy:
    • Synchronous colon cancers
    • FAP
    • HNPCC
• Multivisceral resection with negative margins of the involved structure is recommended in patients who have an invasion of the contiguous organs or adhesions with adjacent structures.
• Chemotherapy options:
  • Stage I: no adjuvant therapy
  • Stage II: controversial; those at high risk of recurrence may benefit from adjuvant therapy
  • Stage III (node-positive disease): 
    • Significant benefit from adjuvant therapy
    • MSI-H tumors: do not benefit from 5-FU based chemotherapy

Metastatic disease or stage IV

• The majority do not have a resectable (curable) disease.
• Chemotherapy: standard treatment and can slow tumor progression
• Isolated liver/lung lesions: Metastatic lesions confined to the liver or lung can be resected.
• The addition of biologic agents/targeted therapy improves survival in suitable patients.
• Unresectable metastatic disease: 
  • Address the associated complication(s) (obstruction, perforation).
  • Local ablative techniques (cryosurgery, radiofrequency coagulation, embolization, hepatic intra-arterial chemotherapy) or radiation

Rectal cancer

• Preoperative (neoadjuvant) chemotherapy and/or radiotherapy: 
  • In T3 or greater tumors
  • Recommended in all node-positive tumors
• Operative approach post-chemotherapy depends on:
  • Level of the tumor above the anal verge
  • Size and depth of penetration
  • Patient’s overall clinical status
• For minimally invasive, small (less than 3 cm), well-differentiated T1 rectal tumors: transanal excision
• Most stage II–III:
  • Low anterior resection (LAR): 
    • Sphincter-preserving surgery
    • Moderately or well-differentiated tumors within 2 cm of the anal sphincter 
    • Poorly differentiated tumors within 5 cm of the anal sphincter
  • Abdominoperineal resection (APR): 
    • Total rectal excision with a permanent colostomy
    • Moderately or well-differentiated tumors < 2 cm from the anal sphincter
    • Poorly differentiated tumors < 5 cm from the anal sphincter
• Unresectable rectal cancer: palliative treatment with a diverting colostomy

Role of targeted therapy

• Gene profiling of tumor tissue: performed to find specific molecular abnormalities and determine treatment options 
• Used with chemotherapy or on its own when cancer has progressed on chemotherapy
  • Anti-VEGF (vascular epidermal growth factor):
    • Bevacizumab (added to 1st-line chemotherapy)
    • Ramucirumab (2nd-line treatment) 
    • VEGF trap or aflibercept (2nd-line treatment) 
  • Anti-EGFR (epidermal growth factor receptor) (added to chemotherapy in stage IV tumors with specific mutations): cetuximab, panitumumab 
  • BRAF inhibitor (for metastatic CRC that progressed with prior chemotherapy): encorafenib
  • Immune checkpoint inhibitors (for MSI-H or deficient mismatch repair (dMMR) CRC): pembrolizumab, nivolumab
  • Multi-targeted kinase inhibitor (for metastatic, refractory CRC after progression on standard regimens): regorafenib
  • Trifluridine/tipiracil (refractory CRC after progression on standard regimens) 

Follow-up

Carcinoembryonic antigen:

• Monitored for 5 years after the completion of treatment (every 6 months). 
• Serial values after surgery/treatment: 
  • Elevation of CEA should be retested.
  • When confirmed, testing may include CT scan, positron emission tomography (PET), and/or colonoscopy looking for disease recurrence.

Colonoscopy:

• Within a few months after surgical resection, then 1 year after surgery
• Every 3–5 years thereafter

Imaging:

• Annual CT scan (chest and abdomen) for at least 3 years
• Annual CT scan (pelvis) for rectal cancer if pelvic radiation was not given

Familial Colon Cancer Syndromes

Familial adenomatous polyposis

• Autosomal dominant
• Occurs due to a mutation in the APC gene
• Hundreds of colorectal adenomas develop (seen in colonoscopy) by age 15 years.
• Risk of CRC: 100%, often detected by age 40 years
• Screening for cancer: colonoscopy starting at 10–15 years of age
• Treatment: prophylactic colectomy (proctocolectomy or total colectomy), usually by age 20
• Indications for colectomy in FAP: 
  • Elective
  • Suspected CRC
  • Presence of colonic dysplasia or neoplasia 
  • Significant increase in polyp number during screening

Hereditary non-polyposis colorectal cancer/Lynch syndrome

• Autosomal dominant
• Occurs due to mutation of 1 of the DNA mismatch repair genes (MSH2, MSH6, MLH1) resulting in MSI, or the EPCAM gene.
• Risks of CRC: 75%
• At-risk individuals who meet the Amsterdam II criteria (“3-2-1 rule”):
  • 3 or more relatives with CRC, 1 of whom must be a first-degree relative of the other 2
  • Involvement of 2 or more generations
  • At least 1 cancer must have been diagnosed < 50 years of age.
  • FAP has been excluded.
  • Tumors verified by pathologic examination
• Confirmatory test: DNA sequencing
• CRC screening: annual screening colonoscopy at 20–25 years of age
• Management: 
  • Surveillance generally preferred
  • Aspirin (may reduce risk of CRC)
  • Surgery if surveillance not feasible/confirmed mutations/when advanced adenoma/CRC found

Peutz-Jeghers syndrome

• Autosomal dominant
• STK11 mutation
• Development of hamartomas of the small and large intestines
• Associated with hyperpigmentation of the mouth, hands, and feet
• Risk of developing CRC: 40%
• Malignancies:
  • Gastrointestinal (GI) malignancies (stomach, small bowel, and colon) develop in 40%–60% of cases.
  • Breast cancer in 30%–50% of cases
  • Nonintestinal organs (gonads, pancreas)

Differential Diagnosis

• IBD: also presents with changes in bowel habits, abdominal pain, and weight loss, but colonoscopy findings and extraintestinal manifestations of IBD help differentiate this disease from CRC. Fecal calprotectin is a highly sensitive test for intestinal inflammation that can be used to distinguish IBD.
• Hemorrhoids: also presents with blood per rectum and changes in bowel habits. Hemorrhoids may cause rectal pain and can be identified on physical exam or anoscopic exam. Bleeding per rectum in a patient > 50 years of age with hemorrhoids still needs to be investigated for CRC.
• Diverticular disease: diverticulosis is the presence of sac-like protrusions in the colon. Complications include diverticular bleeding and diverticulitis, which also present with blood per rectum and changes in bowel habits. Colonoscopic findings differentiate diverticular disease from CRC.
• Small bowel neoplasms: also present with blood in stool and obstructive symptoms. To differentiate these neoplasms from CRC, upper and lower endoscopy may be required.
• Neuroendocrine tumors: affect the right colon in the majority of cases. These lesions have characteristic symptoms of carcinoid syndrome (diarrhea, flushing, and wheezing).