Table of Contents
Introduction (1,2)
Colorectal cancer (CRC) is currently the 4th most common cancer in the UK, although globally it has the 3rd highest rate of new cancer diagnoses (9.6%), and the 2nd highest cancer mortality (9.3%).
A combination of genetic and environmental factors drives risk of developing CRC. There has been a notable increase in the incidence of CRC in younger demographics, linked with hereditary CRC syndromes and potentially modern environmental factors.
The aetiology of CRC is outlined by the adenoma-carcinoma sequence, describing the incremental progression of cellular abnormalities underlying the development of CRC over years.
Clinical features can be vague and non-specific with many differentials, highlighting the importance of screening and early referral.
Surgery is often the mainstay of definitive management, however treatment is frequently multi-modal with chemotherapy and radiotherapy to achieve the best results.
Anatomy overview (3–7)
Anatomy of the colon. Author: https://www.cdc.gov/cancer/colorectal/basic_info/what-is-colorectal-cancer.htm. CC BY-SA 4.0. Wikimedia Commons.
General structure
Approximately 1.5m long, the colon, or the large bowel, is the distal end of the GI tract running from the ileo-caecal junction to the anal canal. The main function of the colon is to form stool and absorb remaining water in the GI tract.
It is separated into four components including (proximally to distally): Caecum, Ascending colon, Transverse colon, Descending colon, Sigmoid colon. Distally and completing the GI tract are the Rectum and Anal canal. Importantly, the Transverse colon is Intraperitoneal (enveloped within visceral peritoneum), whereas the Ascending and Descending colon are Retroperitoneal (located behind a layer of parietal peritoneum, covering their anterior surface).
At the junction between the Ascending and Transverse colon is the Hepatic flexure, closely related to the right lobe of the liver. Opposite at the junction of the Transverse and Descending colon is the Splenic flexure, closely related to the spleen.
CRC by location
- Rectum – 50%
- Colon – 50%
- Sigmoid 55%
- Caecum and ascending colon 30%
- Transverse colon 8%
- Descending colon 8%
The Mesentery is a reflection (double fold) of Parietal Peritoneum that tethers the colon and small intestine to the posterior abdominal wall and provides neurovascular and lymphatic supply and drainage. This is clinically significant in particularly in the surgical resection of rectal cancer as the section of mesentery supplying and draining the rectum (Mesorectum) is often resected to reduce local recurrence.
Mesentery. Author: https://www.scientificanimations.com/. CC BY-SA 4.0. Wikimedia Commons.
Risk factors (8–14)
Most cases of CRC are ‘sporadic,’ i.e. arising from no obvious risk factors aside from age. There are both modifiable and non-modifiable risk factors which drive CRC risk:
Non-modifiable
- Family history
- It is estimated about a third of CRC cases have a familial/inherited element, however lack of reporting on family history makes this difficult to estimate accurately
- Hereditary CRC syndromes e.g. Lynch syndrome, FAP, Peutz-Jegher’s
- Comprise around 2-5% of all cases
- Male sex
- Increasing age
- IBD
- Due to chronic inflammation. Risk increases in patients with longstanding disease, diagnosis at younger age, and greater extent of disease in the colon. Risk of CRC is 1% at 10y, 2% at 20y, and 5% after >20y disease duration.
Modifiable/Environmental
- Smoking
- Excessive alcohol
- High processed meat intake, low fibre diet
- Obesity
- Low vitamin D
Although increasing age is a significant risk factor as in many cancers, we are seeing an increasing incidence in the development of CRC in younger people. While early-onset CRC can be obviously associated with hereditary CRC syndromes such as FAP and Lynch syndrome in some cases, some studies also discuss the potential role of environmental factors, such as microplastics, and less obvious genetic contributors.
Aetiology and Pathophysiology (15,16)
As outlined by Vogelstein and Fearon, CRC carcinogenesis can be thought of as a multi-step process involving the accumulation of multiple genetic mutations in oncogenes and tumour-suppressor genes, transforming normal colorectal epithelium into adenoma, and subsequently adenocarcinoma over time.
Most CRCs are adenocarcinoma, however more rarely encountered types of CRC include lymphoma, neuroendocrine tumours (NETs), sarcoma, and gastrointestinal stromal tumours (GISTs).
IBD can predispose to CRC development through its chronic inflammatory state. This chronic inflammation induces oxidative stress, promoting aberrant DNA mutations and in turn favouring tumorigenesis over time.
Clinical features (8,9)
The clinical features of CRC can be vague and non-specific. In isolation they have low predictive value, however clinical suspicion may be increased with multiple co-existing symptoms or a palpable mass:
Abdominal pain
- Tends to be subacute or chronic onset unless presents as an acute complication of CRC e.g. obstruction/perforation/haemorrhage
Change in bowel habit
- Constipation/diarrhoea
- Can occasionally present with acute or subacute obstruction
- Occurs due to malignant narrowing of the bowel lumen
Rectal bleeding
Signs and symptoms of IDA
- e.g. fatigue, breathlessness, dizziness, pallor, glossitis
Weight loss
- Seen less frequently than in UGI malignancies as oral intake is not as directly affected
- Significant weight loss may indicate advanced or metastatic disease, along with abdominal distension, vomiting or ascites
Palpable mass
- On abdominal palpation or PR examination
- This should significantly raise suspicion of malignancy
Right-sided vs Left-sided
- Left-sided more likely to present with PR bleeding and tenesmus, palpable mass in the LIF or on PR exam
- Right-sided tend to present later as less likely to cause PR bleeding, may have palpable mass in the RIF, iron deficiency anaemia
Can present asymptomatically and be picked up on routine screening (see below)
Differentials
Because the clinical features of CRC can be non-specific, it can therefore be useful to think about potential differentials which can present similarly:
IBD
- Typically has a younger age of onset around 20-40y
- Can present with similar symptoms of blood/mucus in stool, change in bowel habit, weight loss and abdominal pain
- Family history can provide clues in the history
- Colonoscopy with biopsies is key to confirming diagnosis with direct visualisation and histology
Haemorrhoids
- While can present with blood in stool or on the toilet pan, would not be expected to produce constitutional symptoms or abdominal pain
Diverticular disease
- This is also a cause of blood in stool, altered bowel habit and abdominal pain in the elderly demographic
- A thorough history may reveal a previous diagnosis of diverticular disease
- CRC is typically excluded with further investigation such as sigmoidoscopy/colonoscopy and cross-sectional imaging, which can also confirm diverticular disease
Referral and Screening (17)
FIT (faecal immunochemical testing) tests for traces of blood in the stool which may not be visible, using antibodies to haemoglobin. It is widely used to guide referral for suspected CRC and in screening programmes
Current guidelines suggest FIT should be offered in the following adult patient scenarios to guide referral:
Any age
- Presence of abdominal mass
- Presence of altered bowel habits
- Presence of iron-deficiency anaemia
- >= 40y with unexplained abdominal pain AND weight loss
- < 50y PR bleeding + EITHER abdominal pain OR weight loss
- >= 50y PR bleeding OR weight loss OR abdominal pain
- >= 60y anaemia (even without iron deficiency)
– FIT positive patients should be referred using 2-week-wait pathway for suspected CRC
– FIT negative patients should be safety-netted, however consider referral if strong clinical concern
Any patients with abdominal or rectal mass should be considered for 2-week-wait referral regardless
Screening:
- Every 2y for those 50-74y in England
- Sent a FIT test in the post, dipped in bowel motion and returned by post (results within 2 weeks)
- Negative tests are returned to routine recall
- Positive tests are invited for specialist nurse assessment and colonoscopy
Faecal Immunochemical Testing. Author: Whispyhistory. CC BY-SA 4.0. Wikimedia Commons.
Note that screening in patients with hereditary CRC syndromes may differ significantly, starting much earlier with regular colonoscopic surveillance
Investigations (8,9,18)
Bloods
- FBC and iron studies – may show anaemia and/or iron deficiency
- LFTs – may be deranged with liver metastases
- Clotting screen – useful in the presence of bleeding or for operative planning
- Carcinoembryonic antigen (CEA) – not used in diagnosis due to poor sensitivity and specificity, however should be measured as a baseline to monitor for response to treatment, disease progression and potential recurrence
Endoscopy
- Colonoscopy is the preferred investigation, allowing direct visualisation of the entire colon with biopsies of suspicious lesions for histopathology, as well as removal of incidental polyps
- If detected on flexible sigmoidoscopy, complete visualisation of the bowel should be performed with colonoscopy. This is because synchronous CRC (>1 primary CRC detected at initial presentation) is present in approximately 3.5% of CRCs
Circumferential colon carcinoma causing stricture. Author: డా. గన్నవరపు నరసింహమూర్తి. CC BY-SA 4.0. Wikimedia Commons.
Endoscopic images of polyps. https://www.doctorchristodoulou.com/content/colorectal-cancer-diagnosis.
Tubulovillous polyp of the colon. Author: Ed Uthman. Wikimedia Commons. Public Domain.
Imaging
- CT colonography/virtual colonoscopy if colonoscopy is contraindicated or not tolerated:
- After bowel prep with laxatives, the bowel is insufflated with air or CO2 to distend the lumen for optimal views of the bowel
- Images can be reconstructed in a 3D virtual model of the colon
- Has good sensitivity but less specificity than colonoscopy, i.e. worse at identifying those without CRC
- Suspicious lesions should undergo biopsy for tissue diagnosis
CT virtual colonoscopy. Case courtesy of Dalia Ibrahim, Radiopaedia.org, rID: 29923.
‘Apple core’ sign with constriction of hepatic flexure lumen indicative of stenosis CRC. CT confirmed neoplastic soft tissue mass. Case courtesy of Dalia Ibrahim, Radiopaedia.org, rID: 28747.
- CT CAP for staging once diagnosis confirmed to detect potential metastases. Can also detect local complications e.g. fistulation
- MRI rectum is a key investigation in rectal cancers to locally assess T and N stages, thereby directing management strategy. Also used in the assessment of potentially resectable liver metastases
Comparative images in the sagittal plane with gross pathology specimen. CT/MRI shows circumferential thickening of mid and upper rectum. Pathology: tumour (white) extending through rectal wall into mesorectal fat (yellow). T3, N2, M1 (liver). Case courtesy of Ian Bickle, Radiopaedia.org, rID: 32623.
- Trans-rectal US can be used if MRI contraindicated
- Occasionally PET-CT can be used to detect extra-hepatic metastases in patients being considered for surgery (metastectomy can be an option in patients with metastases limited to the liver)
Staging (19)(20)
Staging is highly influential in planning management for CRC, for example whether to include chemotherapy in addition to surgical resection, or opt for palliative management
Table showing TNM staging of colorectal cancer, adapted from TNM Classification of Malignant Tumours (19).
Schematic of layers of bowel wall and corresponding T-stage of colorectal tumours. From CRUK website (20).
Although complete staging is largely carried out using the TNM system, some centres may use the traditional Dukes staging classification:
Stage A – tumour confined to mucosa
Stage B – tumour invades through muscularis propria
Stage C – involvement of locoregional lymph nodes
Stage D – distant metastases
Management (8,9,21–28)
Surgery
- Surgical resection of the tumour is the mainstay of curative treatment.
- This is usually in the form of a regional colectomy to ensure adequate local margins, depending on the tumour location (see below). Resection of rectal cancer uses Total Mesorectal Excision (TME) to reduce the likelihood of local recurrence, removing the mesentery containing local blood supply, lymph nodes and venous drainage.
- Tumours in the ascending colon may be managed with a right hemicolectomy, whilst tumours in the descending colon may require a left hemicolectomy. Tumours in the sigmoid colon and rectum can be excised with anterior resection or sigmoid colectomy. Tumours that are particularly low and close to the anus may require abdomino-perineal resection (APR), in which the sigmoid colon, rectum and anus are removed.
- Following resection, the remaining bowel is either joined through primary anastomosis, or a stoma is formed.
Emergency presentations of CRC e.g. obstruction/perforation may be managed differently and are outwith the scope of this article.
Open vs Laparoscopic/Robotic
- Laparoscopic colectomy for colon cancer offers an alternative to open surgery with similar oncological and mortality outcomes. Advantages include enhanced post-operative outcomes such as reduced length of hospital stay, lower complication rate, improved pain and speed of recovery. The main drawback is increased operating time.
- Laparoscopic surgery for rectal cancer has ongoing debate regarding outcomes compared with open surgery, with some studies failing to demonstrate non-inferiority.
- Robotic surgery is increasingly used for pelvic organ surgery such as in rectal cancer, due to superior ergonomics and vision, and potentially lower rates of urinary and sexual complications, which are important complications seen in pelvic surgery. It is limited, however, by longer operating times and significant financial cost.
Chemotherapy and Radiotherapy
Chemotherapy can be adjuvant (following resection) or neoadjuvant (prior to resection). It is generally considered in more advanced and high-risk local disease (e.g. Dukes C) and metastatic disease. Decisions regarding chemotherapy and precise regimes are decided on a case-by-case basis by the multidisciplinary team, taking into consideration patient factors and tumour factors, including potential side-effects of treatment.
The rationale behind adjuvant chemotherapy is to target unresected micrometastases which, left unaddressed, may lead to recurrent disease. This risk is higher in more advanced disease, and adjuvant chemotherapy in these patients can significantly increase survival and reduce risk of recurrence.
Neoadjuvant chemo-radiotherapy is typically seen in the treatment of rectal cancers, and may also be utilised in advanced disease. It can both reduce risk of recurrence while reducing the size of the tumour in some cases, facilitating more complete surgical resection. Radiotherapy may be given alone or alongside chemotherapy in rectal cancer, however radiotherapy is not typically used in colon cancer due to the many other target organs in the vicinity which may be damaged. Side effects of pelvic radiotherapy can include inflammation/irritation of the bladder (cystitis), rectum (proctitis), and sexual dysfunction.
Palliative
In some cases of advanced or metastatic cancer, disease may not be curable and the focus shifts to reducing burden of disease and symptom control, which may be achieved with controlled use of chemo-radiotherapy. This may also be the case in patients with significant frailty or comorbidities who are not fit for surgery. Care is coordinated by a team including oncologists, palliative team members and surgeons.
Hereditary colorectal cancer syndromes (11,29)
CRC has a relatively high proportion of familial association. There are several known familial syndromes associated with high risk of developing CRC, including Lynch syndrome (A.K.A Hereditary non-polyposis coli or HNPCC), Familial adenomatous polyposis (FAP), Peutz-Jeghers syndrome, Cowden syndrome and others. Lynch and FAP are the generally the most examined:
Table comparing characteristics and management of Lynch syndrome and FAP. TAH = total abdominal hysterectomy. BSO = bilateral salpingo-oophorectomy. From the Mind The Bleep General Surgery Series.
FAP on sigmoidoscopy. Author: Samir at English Wikipedia. Wikimedia Commons. CC BY-SA 3.0. People with FAP often have hundreds or even thousands of colonic polyps which can be seen on colonoscopy.
Prognosis (30)
According to Cancer Research UK, overall survival for bowel cancer is:
- around 80 out of 100 people (around 80%) for 1 year or more
- almost 60 out of 100 people (almost 60%) for 5 years or more
- almost 55 out of 100 people (almost 55%) for 10 years or more
Clearly individual prognosis is a case-by-case estimate and varies greatly depending on patient factors (age, general health, frailty and comorbidities, patient choice) and tumour factors (stage, high-risk biological features, response to treatment).
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