Podcast
Questions and Answers
Which dietary factors are associated with an increased risk of colon cancer?
Which dietary factors are associated with an increased risk of colon cancer?
What is a characteristic feature of Lynch syndrome (HNPCC)?
What is a characteristic feature of Lynch syndrome (HNPCC)?
In which scenario is colon cancer highly suspected in an adult male?
In which scenario is colon cancer highly suspected in an adult male?
Which genetic defect is associated with Lynch syndrome?
Which genetic defect is associated with Lynch syndrome?
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What describes the growth pattern of tumors in the proximal colon?
What describes the growth pattern of tumors in the proximal colon?
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What characteristic feature is associated with the pathology of neuroendocrine tumors (carcinoid)?
What characteristic feature is associated with the pathology of neuroendocrine tumors (carcinoid)?
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Which of the following is NOT a clinical feature of carcinoid syndrome?
Which of the following is NOT a clinical feature of carcinoid syndrome?
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Which biomarker is commonly used in immunohistochemistry to identify carcinoid tumors?
Which biomarker is commonly used in immunohistochemistry to identify carcinoid tumors?
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What is the grading system for carcinoid tumors based on?
What is the grading system for carcinoid tumors based on?
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What is the most common site for gastrointestinal stromal tumors (GISTs) to arise within the GI tract?
What is the most common site for gastrointestinal stromal tumors (GISTs) to arise within the GI tract?
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What symptom is specifically associated with left-sided colorectal carcinoma?
What symptom is specifically associated with left-sided colorectal carcinoma?
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Which diagnostic method is least reliable for detecting colorectal cancer?
Which diagnostic method is least reliable for detecting colorectal cancer?
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What characteristic feature is common to well-differentiated adenocarcinoma?
What characteristic feature is common to well-differentiated adenocarcinoma?
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What is considered the most important prognostic factor in colorectal cancer staging?
What is considered the most important prognostic factor in colorectal cancer staging?
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Which monoclonal antibody is known to inhibit blood vessel growth in metastatic colon cancer?
Which monoclonal antibody is known to inhibit blood vessel growth in metastatic colon cancer?
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Which of the following genetic mutations is associated with resistance to anti-EGFR therapy in colorectal cancer?
Which of the following genetic mutations is associated with resistance to anti-EGFR therapy in colorectal cancer?
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What major complication is linked to colonic carcinoma due to its association with Streptococcus bovis?
What major complication is linked to colonic carcinoma due to its association with Streptococcus bovis?
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What type of tumour is most commonly associated with the appendix and small bowel?
What type of tumour is most commonly associated with the appendix and small bowel?
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What is the average age of onset for polyps?
What is the average age of onset for polyps?
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Which condition is associated with Gardner's syndrome?
Which condition is associated with Gardner's syndrome?
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Which genetic mutation is primarily involved in Turcot's syndrome?
Which genetic mutation is primarily involved in Turcot's syndrome?
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The adenoma-carcinoma sequence suggests that the presence of adenomatous lesions is related to which of the following?
The adenoma-carcinoma sequence suggests that the presence of adenomatous lesions is related to which of the following?
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What is the primary screening method for bowel health in the target population?
What is the primary screening method for bowel health in the target population?
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What is a common risk factor for developing colon adenocarcinoma?
What is a common risk factor for developing colon adenocarcinoma?
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Which of the following is NOT a characteristic of colon adenocarcinoma?
Which of the following is NOT a characteristic of colon adenocarcinoma?
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How are adenomatous polyps typically identified and managed?
How are adenomatous polyps typically identified and managed?
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Which type of polyp is characterized by no malignant potential but can lead to an increased risk of various cancers due to Peutz-Jeghers syndrome?
Which type of polyp is characterized by no malignant potential but can lead to an increased risk of various cancers due to Peutz-Jeghers syndrome?
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What is the primary characteristic of adenomatous polyps that makes them significant in terms of cancer risk?
What is the primary characteristic of adenomatous polyps that makes them significant in terms of cancer risk?
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Which type of polyp typically presents with cystically dilated glands in an inflamed stroma?
Which type of polyp typically presents with cystically dilated glands in an inflamed stroma?
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Which factor correlates with the risk of malignancy in adenomatous polyps?
Which factor correlates with the risk of malignancy in adenomatous polyps?
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Which of the following statements about non-neoplastic polyps is true?
Which of the following statements about non-neoplastic polyps is true?
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What characteristic differentiates sessile serrated lesions from hyperplastic polyps?
What characteristic differentiates sessile serrated lesions from hyperplastic polyps?
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Familial adenomatous polyposis (FAP) is primarily associated with mutations in which gene?
Familial adenomatous polyposis (FAP) is primarily associated with mutations in which gene?
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Which of the following types of polyps may present with occult bleeding and anemia?
Which of the following types of polyps may present with occult bleeding and anemia?
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Which type of polyp is often asymptomatic but may result in obstruction or protein loss?
Which type of polyp is often asymptomatic but may result in obstruction or protein loss?
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Which characteristic best describes the tumors that tend to grow in the proximal colon?
Which characteristic best describes the tumors that tend to grow in the proximal colon?
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What is a distinguishing feature of Lynch syndrome compared to familial adenomatous polyposis (FAP)?
What is a distinguishing feature of Lynch syndrome compared to familial adenomatous polyposis (FAP)?
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Which genetic repair mechanism is primarily defective in Lynch syndrome?
Which genetic repair mechanism is primarily defective in Lynch syndrome?
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What symptom is commonly linked to the presence of tumors in the distal colon?
What symptom is commonly linked to the presence of tumors in the distal colon?
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Which environmental or lifestyle factor is commonly recognized as contributing to the risk of colorectal cancer?
Which environmental or lifestyle factor is commonly recognized as contributing to the risk of colorectal cancer?
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Which clinical feature is most commonly associated with excessive serotonin production in carcinoid syndrome?
Which clinical feature is most commonly associated with excessive serotonin production in carcinoid syndrome?
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What is the appearance of neuroendocrine tumors when examined histologically?
What is the appearance of neuroendocrine tumors when examined histologically?
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Which immunohistochemical marker is least likely to be used for identifying carcinoid tumors?
Which immunohistochemical marker is least likely to be used for identifying carcinoid tumors?
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What factor is primarily used to determine the grade of carcinoid tumors?
What factor is primarily used to determine the grade of carcinoid tumors?
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What is a common location for gastrointestinal stromal tumors (GISTs) to arise?
What is a common location for gastrointestinal stromal tumors (GISTs) to arise?
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What is a key characteristic of Gardner's syndrome?
What is a key characteristic of Gardner's syndrome?
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Which genetic mutation is primarily involved in the development of colorectal adenomatous polyps?
Which genetic mutation is primarily involved in the development of colorectal adenomatous polyps?
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Which hereditary syndrome is associated with both colorectal polyps and brain tumors?
Which hereditary syndrome is associated with both colorectal polyps and brain tumors?
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At what average age does the onset of adenomatous polyps typically occur?
At what average age does the onset of adenomatous polyps typically occur?
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What is the expected consequence of a high count of adenomatous polyps over time?
What is the expected consequence of a high count of adenomatous polyps over time?
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Which screening method is primarily used for detecting colorectal issues in the target population?
Which screening method is primarily used for detecting colorectal issues in the target population?
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Which genetic alteration is commonly associated with the adenoma-carcinoma sequence?
Which genetic alteration is commonly associated with the adenoma-carcinoma sequence?
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What clinical finding is often associated with adenomatous polyps?
What clinical finding is often associated with adenomatous polyps?
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What symptom is most commonly associated with right-sided colorectal carcinoma?
What symptom is most commonly associated with right-sided colorectal carcinoma?
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Which staging component is crucial for determining the depth of invasion in colorectal cancer?
Which staging component is crucial for determining the depth of invasion in colorectal cancer?
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In the context of colorectal cancer prognosis, which tumor location is associated with a poorer outcome?
In the context of colorectal cancer prognosis, which tumor location is associated with a poorer outcome?
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What is a common feature of well-differentiated adenocarcinoma?
What is a common feature of well-differentiated adenocarcinoma?
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Which monoclonal antibody is known for blocking the EGFR signaling pathway in the treatment of metastatic colon cancer?
Which monoclonal antibody is known for blocking the EGFR signaling pathway in the treatment of metastatic colon cancer?
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Which diagnostic method provides the low sensitivity and specificity for detecting colorectal cancer?
Which diagnostic method provides the low sensitivity and specificity for detecting colorectal cancer?
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What is the primary purpose of immunohistochemistry in colorectal cancer diagnosis?
What is the primary purpose of immunohistochemistry in colorectal cancer diagnosis?
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What common feature is associated with the prognosis of colorectal cancer based on genetic factors?
What common feature is associated with the prognosis of colorectal cancer based on genetic factors?
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What type of polyp is associated with multiple hamartomatous polyps throughout the gastrointestinal tract and an increased risk of non-GI cancers?
What type of polyp is associated with multiple hamartomatous polyps throughout the gastrointestinal tract and an increased risk of non-GI cancers?
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Which type of adenomatous polyp is most typically characterized by a villous architecture and has a higher risk of malignancy?
Which type of adenomatous polyp is most typically characterized by a villous architecture and has a higher risk of malignancy?
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What is the primary genetic mutation associated with Familial Adenomatous Polyposis (FAP)?
What is the primary genetic mutation associated with Familial Adenomatous Polyposis (FAP)?
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Which type of non-neoplastic polyp can present alongside longstanding inflammatory bowel disease?
Which type of non-neoplastic polyp can present alongside longstanding inflammatory bowel disease?
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What is a significant feature of sessile serrated lesions compared to hyperplastic polyps?
What is a significant feature of sessile serrated lesions compared to hyperplastic polyps?
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Which symptom is most commonly associated with juvenile polyps?
Which symptom is most commonly associated with juvenile polyps?
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In which polyps is the risk of malignancy strongly correlated with size and histological type?
In which polyps is the risk of malignancy strongly correlated with size and histological type?
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Which type of polyp is classified under hamartomatous syndromes and not typically malignant?
Which type of polyp is classified under hamartomatous syndromes and not typically malignant?
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What characterizes hyperplastic polyps in adults over the age of 60?
What characterizes hyperplastic polyps in adults over the age of 60?
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Study Notes
Tumours of the Small & Large Bowel
- More common in the large bowel than in the small bowel.
- Can be primary, arising from different tissue types, or secondary, which are rare.
- Primary tumours include:
- Non-neoplastic polyps
- Epithelial neoplasms (benign or malignant)
- Benign adenomatous polyps
- Malignant (Adenocarcinoma, Carcinoid)
- Mesenchymal neoplasms
- Lymphoma
Polyps
- Mass protruding into the lumen of the gut.
- Can be non-neoplastic or neoplastic (adenomas).
- Classified as pedunculated (with a stalk) or sessile (flat).
Non-Neoplastic Polyps
- Include:
- Hyperplastic (metaplastic) polyps
- Hamartomatous polyps (juvenile and Peutz-Jeghers)
- Inflammatory polyps
- Lymphoid polyps
Hyperplastic Polyps
- Common, especially in people over 60.
- Found frequently in the recto-sigmoid region.
- Usually less than 5mm and can be single or multiple.
- Asymptomatic.
- Composed of non-neoplastic glands with a serrated appearance.
- Results from delayed shedding of surface epithelial cells.
- Very low malignant potential.
Juvenile Polyps
- Hamartomatous malformations of the bowel mucosa occurring in children younger than 5 years.
- Can be encountered in adults, primarily in the rectum
- Can be large (1-3cm).
- Characterized by cystically dilated glands in an inflamed stroma.
- No malignant potential.
- Multiple juvenile polyps + adenomas = Juvenile polyposis.
Peutz-Jeghers Polyps
- Hamartomatous polyps found in the small intestine and colon.
- Single or multiple (Peutz-Jeghers syndrome).
- Composed of glands and connective tissue with smooth muscle.
- Peutz-Jeghers syndrome
- Autosomal dominant inheritance.
- Mucocutaneous pigmentation (around lips, oral mucosa, genitalia, and hands).
- Multiple hamartomatous polyps throughout the GI tract.
- No malignant potential but patients have an increased risk of developing GI and non-GI cancers (pancreas, breast, lung, ovary, and uterus).
Hamartomatous Syndromes
- Include other syndromes besides Peutz-Jeghers:
- Cowden syndrome:
- Autosomal dominant inheritance.
- Multiple hamartomatous polyps and trichoepitheliomas.
- Increased risk of thyroid and breast cancer.
- Cronkhite-Canada syndrome:
- Hamartomatous polyps, nail atrophy, and skin pigmentation.
- Cowden syndrome:
Inflammatory and Lymphoid Polyps
- Inflammatory (pseudo) polyps:
- Inflamed regenerative mucosa surrounded by ulcerated tissue.
- Seen in individuals with longstanding inflammatory bowel disease.
- Lymphoid polyp:
- Intramucosal lymphoid tissue.
Adenomatous Polyps (Neoplastic Polyps)
- Common lesions.
- Proliferation of dysplastic epithelium (mild to severe).
- Precursors of carcinoma.
- Benign but may progress to adenocarcinoma.
- Three types:
- Tubular
- Villous
- Tubulovillous
Adenomatous Polyps (Neoplastic Polyps) - Continued
- Can be pedunculated or sessile.
- Covered by dysplastic epithelium.
- Risk of malignancy correlates with:
- Size (>2cm)
- Histologic type (villous component)
- Degree of dysplasia
- All adenomatous polyps should be removed due to their pre-malignant nature.
Adenomatous Polyps (Neoplastic Polyps) - Presentation
- May be asymptomatic.
- Can present with occult bleeding, anaemia, protein loss, and obstruction.
- Treatment involves complete excision.
Sessile Serrated Lesions
- Overlap with hyperplastic polyps but have a serrated architecture in the crypt base.
- Lack cytologic features of dysplasia, found predominantly in the right colon.
- May be asymptomatic or present with occult bleeding, anaemia, protein loss and obstruction.
- Should be completely excised.
Familial Adenomatous Polyposis (FAP)
- Autosomal dominant inheritance.
- Mutations of the APC gene on 5q21.
- Numerous adenomatous polyps throughout the GI tract (especially the large bowel).
- Average age of onset in teens to twenties.
- Bleeding and anaemia are common symptoms.
- Virtually 100% risk of carcinoma within 10 to 15 years.
- Prophylactic total colectomy is recommended.
Gardner’s Syndrome
- A variation of FAP.
- Mutations of the APC gene.
- Autosomal dominant inheritance.
- Presents with multiple adenomas, epidermoid cysts (skin), fibromatosis (soft tissue), osteomas (bone), and abnormal dentition.
- Individuals have an increased risk of duodenal and thyroid cancer.
Turcot’s Syndrome
- A variation of FAP.
- Mutations of the APC gene.
- Autosomal dominant inheritance.
- Colorectal adenomatous polyps and brain tumours (gliomas, medulloblastoma).
Adenoma-Carcinoma Sequence
- Describes the development of carcinoma from an adenomatous lesion.
- It involves multiple genetic alterations:
- APC mutations (germline in FAP, sporadic in adenomas).
- Inactivation of the other APC allele.
- Activation of K-ras (12p).
- Loss of DCC gene (18q).
- Loss of p53 (17p).
- Increased COX expression.
- Activation of telomerase.
Bowel Screening
- Targeted for individuals aged 59 to 69 years.
- Screening conducted using home test kits (FIT - Faecal Immunochemical Test) every 2 years.
- Aims to detect and remove adenomatous polyps before they develop into carcinoma.
- All polyps are removed and examined microscopically during colonoscopy.
Colon Adenocarcinoma
- Disease of the western world.
- Peak incidence in the 7th decade of life.
- Occurrence in young individuals suggests a genetic predisposition or inflammatory bowel disease (ulcerative colitis).
Risk Factors for Colon Adenocarcinoma
- Increasing age.
- Adenomatous polyps.
- Hereditary syndromes.
- Inflammatory bowel disease (especially UC).
- Diet (low fiber, high fat, high carbohydrates, high intake of red meat, and decreased intake of micronutrients like vitamins A, C, and E).
- Obesity.
- Physical inactivity.
Hereditary Colon Cancer Syndromes
- Include:
- Familial adenomatous polyposis (FAP)
- Hereditary nonpolyposis colorectal cancer (HNPCC) (Lynch syndrome)
Colon Adenocarcinoma - Cumulative Genetic Alterations
- Two major pathways:
- Adenoma-carcinoma sequence: Involves APC mutations and other genetic alterations.
- Microsatellite instability: Associated with HNPCC and serrated lesions.
Lynch Syndrome
- Autosomal dominant familial syndrome.
- Colon cancer is not associated with pre-existing adenomas and usually affects the right side of the colon.
- Fewer polyps than in FAP.
- Defects in mismatch DNA repair genes:
- MSH2
- MLH1
- MLH6
- PMS1
- PMS2
- Lynch syndrome 1: Increased risk of colon cancer.
- Lynch syndrome 2: Increased risk of colon cancer and non-GI cancers (endometrial, ovarian).
Colorectal Carcinoma
- Tumours in the proximal colon tend to grow as polypoid lesions (cauliflower-like) and may ulcerate, leading to occult bleeding.
- Iron deficiency anaemia in adults (especially males) is a red flag for colon cancer.
- Tumours in the distal colon tend to be annular, encircling lesions ("napkin-ring") causing obstruction.
- Symptoms of obstruction: rectal bleeding, changing bowel habits.
Left-Sided vs Right-Sided Carcinoma
- Left-sided carcinomas:
- Decreased stool calibre.
- Left lower quadrant pain.
- Blood-streaked stool.
- Right-sided carcinomas:
- Iron deficiency anaemia.
- Vague abdominal pain.
Microscopic Features
- Adenocarcinoma is the most common type.
- Can be well, moderately, or poorly differentiated.
- May produce mucin.
- Invade through the bowel wall.
- Metastasize to lymph nodes and then to the liver and lungs.
Diagnosis
- Colonoscopy and biopsy.
- Barium enema.
- Occult blood testing.
- Digital rectal examination.
- CEA (carcinoembryonic antigen) - tumour marker with low sensitivity and specificity.
- Used to assess the adequacy of resection and detect early recurrence.
- Radiology for staging.
Prognosis
- Key prognostic factors:
- Stage of the tumour.
- Tumour grade (degree of differentiation).
- Tumour location (left-sided lesions have a poorer prognosis).
- Adequacy of excision (margins).
- Genetic mutations and MSI.
Staging for Colorectal Carcinoma
- TNM system is the most important prognostic factor.
- T: Depth of invasion. Tumours limited to the mucosa generally do not spread due to the lack of lymphatics in the mucosa.
- N: Spread to regional lymph nodes.
- M: Distant spread, most commonly involves the liver.
Ancillary Tests
- Immunohistochemistry for mismatch repair proteins:
- MSH2
- MLH1
- PMS1
- MPS2
- MSI (microsatellite instability) by PCR.
- Gene mutation testing: KRAS, NRAS, BRAF.
- BRAF testing (if IHC deficient or MSI-high).
- MLH1 promoter methylation (if MSI high or deficient MLH1).
Monoclonal Antibodies for Metastatic Colon Cancer
- Erbitux (cetuximab) and Vectibix (panitumumab) block EGFR signalling pathway.
- Effectiveness depends on downstream mutations: KRAS, BRAF, and NRAS mutations are associated with EGFR therapy resistance.
- Avastin (bevacizumab) blocks the growth of blood vessels to the tumour.
Neuroendocrine Tumours (Carcinoid)
- Tumours of neuroendocrine cells.
- Present throughout the GI tract, most common sites: appendix, small bowel, rectum, stomach, colon.
- May secrete bioactive hormones (especially serotonin).
- Low-grade malignant tumours.
- Behaviour is determined by size, location, and depth of penetration.
Neuroendocrine Tumours (Carcinoid)- Pathology
- Solitary or multicentric firm, yellow-tan nodules.
- Usually submucosal masses, sometimes with ulceration.
- Cause a desmoplastic response.
- Form islands, trabeculae, glands, or sheets.
- Monotonous, speckled nuclei, and abundant pink cytoplasm.
- Contain cytoplasmic secretory dense-core granules.
Immunohistochemistry for Carcinoid Tumours
- Chromogranin.
- Synaptophysin.
- CD56.
- Proliferation index Ki67.
Grading of Neuroendocrine Tumours (Carcinoid)
- Grades 1, 2, and 3 are determined by the number of mitoses and Ki67%.
Clinical Features of Carcinoid Tumours
- Can be Asymptomatic.
- May cause Obstruction, Bleeding.
- Can release bioactive hormones:
- Zollinger-Ellison syndrome (Gastrin).
- Cushing syndrome (adrenocorticotropic hormone).
- Hypoglycemia (insulin).
- Carcinoid syndrome is a result of excess serotonin production.
Carcinoid Syndrome
- Occurs only with massive liver metastases (liver degrades 5-HT).
- Excess serotonin detected in blood and urine.
- Symptoms:
- Vasomotor disturbances (skin flushing).
- Intestinal hypermotility (diarrhoea/cramps).
- Bronchospasm (wheezing, cough).
- Systemic fibrosis (with cardiac involvement: right ventricular subendocardial fibrosis, pulmonary and tricuspid valve).
- Hepatomegaly (metastasis).
- Symptoms can be triggered by alcohol or emotional stress.
Mesenchymal Tumours
- Benign: Lipoma, leiomyoma, schwannoma.
- Gastrointestinal stromal tumours (GISTs)
Gastrointestinal Stromal Tumours (GISTs)
- Mesenchymal neoplasms of the GI tract.
- Arise from the pacemaker cells (ICC) of the GIT.
- 2/3 occur in the stomach.
- 25% occur in the small intestine.
Tumours of the Large Bowel
-
Tumours of the large bowel are more common than tumours of the small bowel.
-
Polyps are mass arising from the mucosal epithelium or submucosal connective tissue protruding into the gut lumen.
- Non-neoplastic polyps
- Neoplastic polyps are known as adenomas
-
Non-neoplastic polyps
-
Hyperplastic (metaplastic) polyps
- Common lesions, found in more than 50% of individuals over 60 years of age.
- Often found in the recto-sigmoid.
- Less than 5 mm in size and can be single or multiple.
- Asymptomatic.
- Composed of non-neoplastic glands with goblet cell differentiation and a serrated appearance.
- Result from delayed shedding of surface epithelial cells.
- Virtually no malignant potential.
-
Hamartomatous polyps
-
Juvenile polyps
- Malformations of bowel mucosa.
- Most common in children under 5 but can be encountered in adults.
- Found in the rectum.
- Can be large, ranging from 1 to 3 cm in size.
- Cystically dilated glands are present within an inflamed stroma.
- No malignant potential.
- Juvenile polyposis is a condition characterized by multiple juvenile polyps and adenomas.
-
Peutz-Jeghers polyps
- Hamartomatous polyps of the small intestine and colon.
- Single or multiple polyps can occur (Peutz-Jeghers syndrome).
- Consist of glands and connective tissue with smooth muscle.
- Peutz-Jeghers syndrome is an autosomal dominant syndrome.
- Characterized by mucocutaneous pigmentation around the lips, oral mucosa, genitalia, and palmar surfaces of the hand.
- Multiple hamartomatous polyps throughout the GI tract are present.
- No malignant potential, but patients have an increased risk of developing GI and non-GI cancers (pancreas, breast, lung, ovary, and uterus).
-
Juvenile polyps
-
Inflammatory polyps
- Inflamed regenerative mucosa surrounded by ulcerated tissue.
- Observed in individuals with long-standing inflammatory bowel disease.
-
Lymphoid polyps
- Composed of intramucosal lymphoid tissue.
-
Hyperplastic (metaplastic) polyps
Hamartomatous Syndromes
-
Cowden syndrome
- Autosomal dominant syndrome caused by a mutation in the PTEN gene.
- Characterized by multiple hamartomatous polyps and trichoepitheliomas.
- No malignant potential, but patients have an increased risk of developing thyroid and breast cancer.
-
Cronkhite-Canada syndrome
- Characterized by hamartomatous polyps, nail atrophy, and skin pigmentation.
Adenomatous Polyps = Neoplastic Polyps
- Common lesions with a prevalence of 50% at the age of 60.
- Proliferation of dysplastic epithelium ranging from mild to severe.
- Precursors of carcinoma.
- Considered benign but have the potential to progress to adenocarcinoma through the adenoma-carcinoma sequence.
Adenomatous Polyps
-
Three types:
- Tubular (consist of tubular glands)
- Villous (characterized by villous projections)
- Tubulovillous (mixture of tubular and villous features)
-
Can be:
- Pedunculated (most typical of tubular adenoma)
- Sessile (most typical of villous adenoma)
Adenomatous Polyps
-
Covered by dysplastic epithelium.
-
The risk of malignancy is correlated with the following factors:
- Size (greater than 2 cm)
- Histologic type (villous component)
- Degree of dysplasia
-
Since they are considered pre-malignant, all adenomatous polyps should be removed.
Adenomatous Polyps
- May be asymptomatic.
- Can present with occult bleeding, anemia, protein loss, and obstruction.
- Treatment: Complete excision.
Sessile Serrated Lesions
- Overlap with hyperplastic polyps, but have a serrated architecture in the crypt base.
- Lack cytologic features of dysplasia.
- Commonly found in the right colon.
- May be asymptomatic.
- Can present with occult bleeding, anemia, protein loss, and obstruction.
- Treatment: Complete excision.
Familial Adenomatous Polyposis (FAP)
- Autosomal dominant inheritance.
- Caused by mutations in the APC gene located on chromosome 5q21.
- Numerous adenomatous polyps throughout the GI tract (especially the large bowel) are present.
- A minimum of 100 but may be greater than 2000 polyps.
- Average age of onset of polyps is in the teens to twenties, presenting with bleeding and anemia.
- Virtually a 100% risk of carcinoma developing within 10 to 15 years.
- Prophylactic total colectomy is indicated.
Gardner’s Syndrome
- A variation of FAP.
- Caused by mutations in the APC gene.
- Autosomal dominant inheritance.
- Characterized by multiple adenomas, epidermoid cyst (skin), fibromatosis (soft tissue), osteomas (bone), and abnormal dentition (teeth).
- Increased risk of duodenal cancer and thyroid cancer.
Turcot’s Syndrome
- A variation of FAP.
- Caused by mutations in the APC gene.
- Autosomal dominant inheritance.
- Characterized by colorectal adenomatous polyps and brain tumors (gliomas, medulloblastoma).
Adenoma-Carcinoma Sequence
- The development of carcinoma from an adenomatous lesion.
- Populations with a high prevalence of adenomas also have a high prevalence of colorectal cancer.
- The distribution of adenomas is comparable to that of colorectal cancer.
- The peak incidence of adenomatous polyps precedes the peak incidence of cancer by several years.
- The risk of cancer is related to the number of adenomas.
- Adenomatous lesions are often seen in association with invasive carcinoma.
Adenoma-Carcinoma Sequence
-
Genetic alterations involved:
- APC mutations (FAP-germline, Adenoma-sporadic)
- Inactivation/mutation of the other allele of APC
- Activation of K-ras (12p)
- Loss of DCC gene (18q)
- Loss of p53 (17p)
- Increased expression of COX
- Activation of telomerase
Bowel Screen
- Target population: Individuals aged 59 to 69 years.
- Target individuals: Offered screening every 2 years.
-
Screening conducted using a home test kit:
- Faecal Immunochemical Test (FIT)
- Aim: To remove adenomatous polyps before progression to carcinoma.
- Method: Colonoscopy for polyp removal and microscopic examination.
Colon Adenocarcinoma
- Common in Westernized societies.
- Peak incidence occurs in the 7th decade.
- Carcinoma in a young individual is associated with genetic predisposition or ulcerative colitis (UC).
Risk Factors
- Increasing age
- Adenomatous polyps
- Hereditary syndromes
- Inflammatory bowel disease (especially UC)
- Diet (low fiber, high fat, high carbohydrates, high intake of red meat, and decreased intake of micronutrients, vitamins A, C, and E)
- Obesity
- Physical inactivity
Hereditary Colon Cancer Syndromes
- Familial adenomatous polyposis (FAP)
- Hereditary nonpolyposis colorectal cancer (HNPCC)
Colon Adenocarcinoma - Cumulative Genetic Alterations or “Multi-Hit” Hypothesis
- Two pathways:
- Adenoma-carcinoma sequence: APC mutations (FAP-germline, Adenoma-sporadic)
- Microsatellite instability (MSI): HNPCC, serrated lesions
Lynch Syndrome
-
HNPCC (Lynch syndrome) is an autosomal dominant familial syndrome.
- Colonic cancer development is not associated with pre-existing adenomas and is usually located on the right side.
- Fewer polyps than FAP are present.
- Lynch syndrome 1: Increased risk of colon cancer.
- Lynch syndrome 2: Increased risk of colon cancer and non-GI cancers (endometrial, ovarian).
- Defect in the mismatch DNA repair genes, including:
- MSH2
- MLH1
- MLH6
- PMS1
- PMS2
Colorectal Carcinoma
- Tumors in the proximal colon tend to grow as polypoid lesions, resembling a "cauliflower," and may ulcerate, leading to occult bleeding.
- Iron deficiency anemia in an adult (especially a male) should be considered suggestive of colon cancer until proven otherwise.
- Distal colon tumors tend to be annular, encircling lesions, resembling a "napkin-ring," resulting in constriction and symptoms/signs of obstruction (rectal bleeding and changes in bowel habits).
Why Do Tumors of the Left Side Present with Obstruction?
- Annular tumors.
- Lumen is narrower than the right side.
- Solid fecal material.
Symptoms of Colorectal Cancer
- Change in bowel habits
- Blood in stool
- Iron deficiency anemia
- Abdominal discomfort/pain
- Note: Colonic carcinoma is associated with an increased risk of Streptococcus bovis endocarditis.
Colorectal Carcinoma Symptoms (by Location)
-
Left-sided carcinoma:
- Decreased stool caliber, left lower quadrant pain, blood-streaked stool
-
Right-sided carcinoma:
- Iron deficiency anemia and vague pain
Microscopic Features
-
Adenocarcinoma:
- Well, moderately, or poorly differentiated
- Can produce mucin
- Invade through the bowel wall
- Metastasize to lymph nodes and then to the liver and lungs
-
Diagnosis
- Colonoscopy and biopsy
- Barium enema
- Occult blood test
- Digital rectal examination
- Carcinoembryonic antigen (CEA)- a tumor marker, but has low sensitivity and specificity.
- Used to assess resection adequacy and detect early recurrence
-
Radiology for staging
Prognosis
- The most important prognostic factor is the stage of the tumor.
-
Factors influencing prognosis:
- Stage of the tumor
- Tumor grade (degree of differentiation)
- Tumor location (left-sided lesions have a poorer prognosis due to increased invasiveness)
- Adequacy of excision (margins)
- Genetic mutations and MSI
Staging: TNM
- T - Depth of invasion: Tumors confined to the mucosa generally do not spread due to lack of lymphatics in the mucosa.
- N - Spread to regional nodes.
- M - Distant spread: Most commonly involves the liver.
Ancillary Tests
-
Immunohistochemistry for mismatch repair proteins:
- MSH2
- MLH1
- PMS1
- MPS2
- Microsatellite instability (MSI) by PCR.
-
Gene mutation testing: KRAS, NRAS, BRAF
- BRAF testing (if IHC deficient or MSI-High)
- MLH1 promoter methylation (if MSI high or deficient MLH1)
Monoclonal Antibodies Approved to Treat Metastatic Colon Cancer
-
Erbitux® (cetuximab) and Vectibix® (panitumumab): Block the EGFR signaling pathway.
- Effectiveness of EGFR inhibition depends on downstream mutations.
- KRAS, BRAF, and NRAS mutations are associated with resistance to anti-EGFR therapy.
- Avastin® (bevacizumab): Blocks the growth of blood vessels to the tumor.
Neuroendocrine Tumors (Carcinoid)
- Tumors of neuroendocrine cells.
- Found throughout the GI tract, with the most common sites being:
- Appendix
- Small bowel
- Rectum
- Stomach
- Colon
- May secrete numerous bioactive hormones, especially serotonin.
- Low-grade malignant tumors.
- Tumor behavior correlates with size, location, and depth of penetration.
Neuroendocrine Tumors (Carcinoid) – Pathology
- Solitary or multicentric firm, yellow-tan nodules.
- Usually submucosal masses, sometimes with ulceration.
- Cause a striking desmoplastic response.
- Form islands, trabeculae, glands, or sheets.
- Monotonous, speckled nuclei and abundant pink cytoplasm.
- Contain cytoplasmic secretory dense-core granules.
Immunohistochemistry for Carcinoid Tumors
- Chromogranin
- Synaptophysin
- CD56
- Proliferation index Ki67
Grade Carcinoid Tumors (Neuroendocrine Tumors)
- Graded as 1, 2, or 3 depending on the number of mitoses and the Ki67 percentage.
Clinical Features of Carcinoid Tumors
- Asymptomatic.
- Obstruction.
- Bleeding.
- May release their products into circulation, potentially leading to:
- Zollinger-Ellison syndrome (Gastrin)
- Cushing syndrome (adrenocorticotropic hormone)
- Hypoglycemia (insulin)
- Carcinoid syndrome: Production of serotonin.
Carcinoid Syndrome
-
Occurs only with massive liver metastases.
- 5-HT (serotonin) is degraded in the liver.
- Hepatic metastasis is not required for extra GI carcinoids.
- Excess elaboration of serotonin is detected in the blood and urine.
-
Symptoms:
- Vasomotor disturbances (skin flushing)
- Intestinal hypermotility (diarrhea/cramps)
- Bronchospasm (wheezing, cough)
- Systemic fibrosis (with cardiac involvement, right ventricular subendocardial fibrosis, pulmonary and tricuspid valve)
- Hepatomegaly (metastasis)
- Symptoms can be triggered by alcohol or emotional stress.
Mesenchymal Tumors
- Benign: Lipoma, leiomyoma, schwannoma
- Gastrointestinal stromal tumors (GISTs)
Gastrointestinal Stromal Tumors (GISTs)
- Mesenchymal neoplasms of the GI tract.
- Arise from the pacemaker cells of the GIT (ICC).
- Approximately two-thirds occur in the stomach.
- 25% occur in the small intestine.
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Description
This quiz focuses on the various types of tumours affecting the small and large bowel, including their classifications and characteristics. It covers primary and secondary tumours, non-neoplastic polyps, and the specific types of epithelial neoplasms and hyperplastic polyps. Test your knowledge on the pathology of gastrointestinal tumours!
