Colon and rectal cancers (CRC) combined are the third most commonly diagnosed cancer in the United States and the second deadliest. Rectal cancer has distinct environmental associations and genetic risk factors different from colon cancer. The transformation of the normal rectal epithelium to a dysplastic lesion and eventually an invasive carcinoma requires a combination of genetic mutations, either somatic (acquired) or germline (inherited), over an approximately 10 to 15 year period. Response to pre-operative therapy and pathological staging are the most important prognostic indicators of rectal cancer.
Initial workup starts with a careful history and physical examination, including a digital rectal exam. An endoscopic examination with rigid sigmoidoscopy is required; this is important to measure the distance from the lesion to the anal verge and for tissue biopsy to confirm rectal cancer. Once rectal cancer has been established pathologically, an MRI or transrectal ultrasound can accurately determine local tumor extension and node status. Baseline computed tomography of the chest, abdomen, and pelvis rules out metastatic lesions. An interdisciplinary evaluation by medical oncology, radiation oncology, and surgical oncology is important to discuss the best combination of perioperative chemo-radiotherapy (in addition to possible surgical resection) that could augment the chance of cure, particularly in high-risk patients. Oligo-metastatic disease to the liver and lung and local-recurrence patients with rectal cancer are still potentially curable with multimodality therapies. Palliative systemic therapy is reserved for non-surgical candidates to ameliorate symptoms, improve quality of life, and prolong life expectancy.
The majority of colorectal cancer, including rectal cancer, is sporadic (70%), with an average age diagnosis after 50 years old. A minority of patients (10%) show a true inheritance pattern (which carries a higher risk in patients younger than 50), and the remaining 20% of rectal cancer is seen as familial clustering in the absence of identifiable inherited syndrome. Approximately 5% of all CRC cancers are attributed to familial adenomatous polyposis (FAP) and Lynch syndrome (hereditary non-polyposis colorectal cancer [HNPCC]), the most common named cancer syndromes.
Hereditary colorectal cancer syndromes are discussed in a different StatPearls chapter. Risk factors include: personal or family history of colorectal cancer, adenomatous polyps, and polyps with villous or tubulovillous dysplasia. Patients with these features are at high risk for synchronous or metachronous colorectal primary cancer (up to 3% to 5% at five years) and require close screening. Inflammatory bowel disease (more commonly ulcerative colitis (UC) than Crohn disease) with rectal involvement increases cancer risk. For UC, there is an estimated incidence of 0.5% per year between 10 to 20 years after UC diagnosis, then 1% per year after that with up to 30% probability of colorectal cancer by the fourth decade after diagnosis. Large studies have seen an increased risk of rectal cancer associated with the history of radiation for prostate cancer (HR, 2.06; 95% CI, 1.42 to 2.99).
Epidemiologic studies indicate strong environmental and lifestyle associations for colorectal cancer, and distinct patterns between colon and rectum potentially exist. There is a modestly increased risk of colon cancer seen with risk factors such as obesity, red/processed meat, tobacco, alcohol, androgen deprivation therapy, and cholecystectomy (among others) without any increased risk of rectal cancer. On the other hand, large population studies with variable strength evidence have found protective factors - such as physical activity, diet (fruits and vegetables, fiber, resistant starch, fish), vitamin supplements (folate, folic acid, pyridoxine B6, calcium, vitamin D, magnesium), garlic and coffee, drugs (aspirin, non-steroidal anti-inflammatory drugs [NSAIDs]), hormonal replacement therapy in postmenopausal women, statins, bisphosphonate, and angiotensin inhibitors - protective for both colon and rectal cancer. Interestingly, a randomized controlled clinical trial found that 600 mg of aspirin given to patients with Lynch syndrome had a protective effect against colorectal adenomas and cancer with substantially reduced cancer incidence after 55.7 months with an HR of 0.56 (95% CI; 0.32, 0.99; p = 0.05). However, this association has not been robustly studied in the general population.
Colorectal cancer affects approximately 135,439 estimated new patients in the United States per year. Of these cases, 39,910 (30%) are due to rectal cancer per year. Determining mortality due to rectal cancer is difficult due to the large number of deaths from rectal cancer being misclassified as colon cancer. Among all cancer sites, colorectal cancers combined are the second leading cause of death in the United States, with an estimated 50,260 deaths per year.
Approximately 18% of rectal cancer is earlier onset (age <50 years) with more advanced stage and poorer prognosis. Interestingly, the over incidence rate for colorectal cancer has been declining 3% per year since 2004 except for screened young adults for whom it is increasing by 2% per year. The increase in incidence in young adults is driven by left-sided colon cancer and rectal cancer (3.9% per year).
Colorectal cancer incidence varies worldwide, with higher rates in developed countries than in developing countries. Low socioeconomic status has an increased risk of colorectal cancer; this association is strongest in the rectum and weakest in the right colon. It is believed this is due to poor-risk behavior and access to medical care. White American lifetime average incidence of CRC is 5%; incidence is higher in men than in women and African Americans than non-Hispanic whites. From 1975 to 2014, there has been a 51% decrease in the mortality of CRC in the United States, attributed to early detection and improvement of treatment modalities. National Cancer Institute estimates that 65% of all treated patients for CRC will be alive at 5-years.
The transformation of normal rectal or colonic epithelium to a precancerous lesion (adenomas) and ultimately to invasive carcinoma requires an accumulation of genetic mutations either somatic (acquired) and/or germline (inherited). The theory of colorectal carcinogenesis features a clonal mutation evolution that gives a cell survival-immortality advantage and allows for the development of more mutations providing for cancer hallmarks such as proliferation, invasion, metastasis, and others. Clinical evidence has shown that colorectal cancer frequently arises from adenomatous polyps that typically acquire dysplastic changes over a 10 to 15 year period, leading to invasive carcinoma development. Thus, early detection and removal of polyps reduce the incidence of CRC. Alternative new evidence has demonstrated that hamartomatous and serrated polyps (in addition to adenomatous polyps) could lead to CRC.
There are three major molecular pathways linked to CRC. These are chromosomal instability, mismatch repair, and hypermethylation. The chromosomal instability pathway is an accumulation of mutations unbalancing oncogene and tumor suppressor equilibrium. This is seen in diseases such as FAP with mutations in the tumor suppressor gene adenomatous polyposis coli (APC). Cells with deficiency of DNA mismatch repair (dMMR) genes, commonly MLH1 or MSH2, accumulate errors within the genome at a more rapid rate due to the inability to correct the base mismatch. This leads to high levels of microsatellite instability (MSI-H), a hallmark of Lynch syndrome.
CpG hypermethylation of DNA could activate or silence the expression of certain genes, BRAF and MLH1, respectively. Sporadic oncogenes somatic mutations (RAS, SRC, MYC) have been implicated in CRC, RAS haveing the most clinical relevance. On the other hand, tumor suppressors genes require bi-allelic loss (“2-hit model”) and are described in loss of APC 5q21 gene (80% sporadic), TP53 17p gene (50% to 70% sporadic), and DCC/SMAD2-4 18q gene (73% sporadic). Specific MMR gene mutations could occur in hMSH2, hMLH1, hPMS1 and hPMS2, hMSH6, and hMLH3; each can interact with MLH1 and approximately found in 15% of all sporadic CRC, causing a Lynch-like syndrome with MSI-H calling for universal testing. MUTYH defects have a recessive inheritance pattern requiring bi-allelic second hit or in conjunction with APC gene mutation. Cyclooxygenase (COX-2) and peroxisome proliferator–activating receptor (PPAR) genes have been implicated in CRC tumorigenesis currently under investigation for chemo-protection.
The majority of all Rca are adenocarcinomas (90%), and others not frequently seen are adenosquamous, spindle, squamous and undifferentiated. RCA adenocarcinoma can be further differentiated in cribriform comedo-type, medullary, micropapillary, serrated, mucinous, and signet-ring cell. Adenocarcinomas are categorized by the percentage of gland formation into well (greater than 95%), moderately (greater than 50%), and poorly (less than 49%) differentiated, but further divided into a 2-tier low grade (well-moderate)/high grade (poor) with prognostic significance. Mucinous or signet ring cells pathological description denotes that more than half of the stained cells possess that particular characteristic. Differential clinicopathological diagnoses include neuroendocrine, hamartomas, mesenchymal, and lymphomas. Cytokeratin 20 (CK20) and caudal-type homeobox 2 (CDX2) immunohistochemistry (IHC) can accurately identify CRC adenocarcinoma origin, except medullary carcinoma with MSI-H expressing other markers such calretinin, CK7, SABT2, and CDH17.
The tumor, node, metastasis (TNM) staging system of the American Joint Committee on Cancer/Union for International Cancer Control (AJCC/UICC) 2017 is the preferred staging system for CRC. Of note, peritoneal carcinomatosis (M1c) and nodal micrometastases (cluster greater than 0.2 mm) are included as poor prognostic factors. Other prognostic indicators that the classification continues to exclude are extramural deposits, lymphovascular invasion (LVI), perineural invasion (PNI), poor histological grade, diagnostic serum carcinoembryonic antigen (CEA), MSI-H, and RAS/BRAF mutation status. The most important prognostic indicator is the pathological stage at presentation supported by data from the SEER observed overall survival (OS) at 5-year rates for rectum in Stage I includes 74%; Stage IIA, 64%; Stage IIB, 51%; Stage IIC, 32%; Stage IIIA, 74%; Stage IIIB, 45%; Stage IIIC, 33%; and Stage IV, 6%. Complete, intermediate, and poor tumor regression grade (TRG) at resection after neoadjuvant CRT in the German Rectal Cancer study group showed improved disease-free survival (DFS) with 90%, 74%, and 63% at 10 years, respectively. Surgical pathology specimens with neoadjuvant treatment effects are reported with “upstage and TRG” to more accurately reflect outcomes.
Complete mesorectal resection (R0) with all negative circumferential resection margins (CRM) is an important goal to avoid local-distant recurrence (38% CRM+ versus 10% CRM-) and increase survival. Lymph node involvement is the strongest outcome predictor, and the total number resected directly influences prognosis on Stage II (node-negative) and Stage III (node-positive) disease. Current guidelines by the American Society of Clinical Oncology (ASCO), National Comprehensive Cancer Network (NCCN), and European Society for Medical Oncology (ESMO) recommend a minimum of 12 nodes surgical resection, although the numbers of lymph nodes are significantly less on rectal cancer treated with neoadjuvant therapy related to a higher TRG. Lymph node ratio from the INT-0089 trial showed a 5-year OS of 80% with less than 0.05 LNR versus 50% greater than 0.4 ratios depending on the total of node retrieved.
The NCCN and the College of American pathologists, among other associations, recommend universal MMR/MSI status (15 to 20% sporadic CRC), BRAF p.V600 E (less than 10% sporadic CRC), and RAS mutational (12 to 75% sporadic CRC) testing for prognostic and predictive of chemotherapy efficacy. hMLH1 and hMSH2 IHC provides a high sensitive (92.3%), and specific (100%) method, and positive (96.7%) / negative (100%) predictive value method for screening for MMR/MSI status. MSI-H is synonymous with dMMR, and MSI-stable will refer to proficient MMR state. The prevalence of MSI-H in CRC is about 15% in stage II, 8% in stage III, and 4% to 5% in stage IV. BRAF gene mutation testing is indicated after a negative MLH1 IHC, indicating MLH1 gene down-regulation through somatic methylation. Recently, 6 independent classification systems coalesced into 4 consensus molecular subtypes (CMSs) with distinguishing features: CMS1 (MSI-immune, 14%), hypermutated burden, dMMR, microsatellite unstable and strong immune activation; CMS2 (canonical, 37%), high chromosomal instability, epithelial, marked WNT and MYC signaling activation; CMS3 (metabolic, 13%), epithelial and evident metabolic dysregulation, KRAS mutation; and CMS4 (mesenchymal, 23%), CpG hyper-methylation, prominent transforming growth factor-beta activation, stromal invasion, and angiogenesis. CMS classification had a prognostic value, CMS1 good, CMS4 poor, and CMS2/3 intermediate.
History and Physical
Most all CRC will present either by diagnostic colonoscopy for suspicious signs and symptoms (80%), asymptomatic, routine screening (11%), or incidental finding at an acute abdomen emergent admission (7%). Patients diagnosed through routine cancer screening are frequently at an earlier stage compared to the advanced disease seen in incidental surgical findings. Diagnostic colonoscopy’s triggers are blood per rectum (37%), abdominal pain (34%), and anemia (23%). The most common indications of emergent surgery are obstruction (57%), peritonitis (25%), and perforation (18%).
Symptoms according to tumor location on the clinical presentation of rectosigmoid are more frequently associated with a change in bowel habits (diminish stool caliber), bright red blood per rectum (hematochezia), pain (tenesmus), leakage diarrhea (mucus discharge), and constipation (obstruction). Late symptomatic presentation of metastatic disease at diagnosis will depend on the affected organ according to the dissemination route. Physical examination should explore signs of ascites, hepatomegaly, and lymphadenopathy and must extend to a digital rectal exam for fixed mass. A thorough family history is of great relevance in identifying familial clusters and inherited patterns that would change the surveillance and therapy of a high-risk patient.
All newly diagnosed patients with rectal cancer should be universally screened for DNA mismatch repair/microsatellite status present in up to 13% of all sporadic rectal cancer cases.
The initial evaluation may involve barium enema or computed tomography (CT) colonography, but endoscopy is ultimately required for tissue biopsy. Flexible sigmoidoscopy is no replacement for a complete diagnostic colonoscopy; still, it is a screening modality that reduces CRC mortality. The Federal Drug Administration (FDA) has approved PILLCAM 2 for those non-obstructed patients with incomplete colonoscopy, and not for routine screening. CRC screening modalities and recommendations for average and high-risk patients are discussed in a different StatPearls article. Routine laboratory workups with complete blood count (CBC), iron panel, basic metabolic panel, liver function test, and coagulation tests are not diagnostic but often useful for management. CEA greater than five ng/mL has a poor prognostic value when present but lacks diagnostic sensitivity 46% (95% CI 0.45 to 0.47) and has limited specificity 89% (95% CI 0.88 to 0.92). Pre-operative CEA is indicated on all newly diagnosed CRC, normalization after surgical resection expected, and serial assays monitor on follow-ups.
Baseline CT of the chest, abdomen, and pelvis with intravenous (IV) and oral contrast is the preferred cost-effective staging imaging study before surgical resection. CT abdomen and pelvis provides a moderate specificity for initial assessment of accurately staging T (50%) and N (73%) but rather provide immediate high screening sensitivity for distant metastasis (87%). CT chest remains controversial, as 9% will show indeterminate lesions, of that 11% represent metastatic lesions. MRI and CT triple-phase imaging have improved the detection of liver metastasis. Positron emission tomography (PET) is not routinely indicated in the preoperative staging of CRC. A biopsy of a suspicious metastatic site should be performed to confirm the diagnosis.
Rigid sigmoidoscopy measures the distal extension of the tumor from the anal verge and is further divided into low (less than 5 cm), middle (less than 10 cm), or high (less than 15 cm) rectal cancer. Loco staging of Rca will require optimal imaging by transrectal ultrasonography (TRUS) and pelvic magnetic resonance imaging (MRI) to accurately determine T, N and predicting CRM optimal candidates for upfront surgery, radiation therapy, or CRT. TRUS accuracy for T ranges from 80% to 95% and N from 70% to 75%; however, it carries CRM limitations on posterior tumors. MRI accuracy ranges are as follows: T from 81% to 92%, N from 69% to 84%, and CRM 57% to 90%. In clinical practice, the information obtained with TRUS and MRI is often complementary and center-dependent directed. Although TRUS may be comparable to MRI for initial stating, it has shown significant limitations evaluating pre-operative treatment tumor response (re-stage) whereas MRI has greater post-treatment anatomical accuracy with the newer acquisition methods (sensitivity 88%), allowing a more precise surgical plan.
- Inflammatory bowel disease
- Irritable bowel syndrome (IBS)
When found early, colorectal cancer treatment is highly successful. The overall 5-year survival rate for rectal cancer is 67%, but this is affected significantly by various factors, most notably the stage of cancer. If the cancer is diagnosed when it is in the localized stage, the survival rate jumps to89%. The 5-year survival rate is 71% if cancer has metastasized to surrounding tissues or organs and/or the regional lymph nodes. However, with metastatic spread to distant areas of the body, the 5-year survival rate drops to 15%.
Complications of rectal cancer include bowel obstruction, recurring cancer/developing another colo-rectal cancer, and metastatic disease.
Deterrence and Patient Education
Prevention and early detection are the keys in colo-rectal cancers. Risk factors include age and genetics. Recommendations are that people over 50 obtain colorectal cancer screening every 10 years.
Pearls and Other Issues
Utilize CRC screening guidelines to guide and avoid repeating other screening modalities after a high-quality colonoscopy for ten years or with less than ten years of life expectancy.
Do not use epidermal growth factor targeted-therapy against colorectal cancer unless the patient has a tumor biomarker (RAS/BRAF or MMR/MSI) that predicts effective response, advanced non-surgical stage, and satisfactory performance status.
Offer early palliative care for all CRC patients with uncontrolled physical symptoms or psychosocial stress even during oncological disease treatment, and encourage early conversations of the end of life of those with the metastatic stage.
All CRC patients should be supported for survivorship care after completion of treatment. A discussion on lifestyle changes, including following a healthy diet, obtain and maintain ideal body weight, establish an active exercise routine, minimize alcohol consumption, and quit smoking, should be encouraged.
Establish a route for preventing and detecting new or recurrent CRC to minimize psychological stress, offer genetic risk assessment when appropriate, and manage long-term effects of cancer treatment.
Enhancing Healthcare Team Outcomes
Colon and rectal cancer (CRC) is a relatively common cancer in the US. Because of its varied presentation, the malignancy is managed by an interprofessional team. All newly diagnosed patients with rectal cancer should be universally screened for DNA mismatch repair/microsatellite status present in up to 13% of all sporadic rectal cancer cases. A careful history and physical examination, including a digital rectal exam, are paramount on clinical suspicion. An endoscopy examination with rigid sigmoidoscopy is required to measure the distance from the lesion to the anal verge (less than 15 cm) and for tissue biopsy for pathological confirmation of rectal cancer. Baseline computed tomography of the chest, abdomen, and pelvis may initially grossly rule out metastatic stage disease. Nevertheless, a combined approach by magnetic resonance imaging or transrectal ultrasound will accurately determine tumor extension and node status of the local rectal disease at diagnosis.
An interprofessional evaluation by medical oncology, radiation oncology, and surgical oncology should discuss the best peri-operative chemo-radiotherapy route that could augment the chance of cure on high-risk patients. Oligo-metastatic, liver and lung, and local-recurrence patients with rectal cancer are potentially curable with multimodality therapies. It is important to involve the dietitian early on in the care of these patients. The pharmacist should educate the patient on the different chemotherapeutic agents, their benefits, and adverse effects. The Palliative nurse team should consult with non-surgical candidates to ameliorate symptoms, improve quality of life, inform patients about the right to die, DNR, and ways to improve the quality of life.