Colon Pathology and Polyps Overview
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Questions and Answers

What is the primary consequence of germline mutations in MMR genes in the context of colorectal carcinoma?

  • Increased apoptosis of colon cells
  • Reduced immune response to tumors
  • Increased mutation rate in microsatellite DNA (correct)
  • Enhanced DNA repair mechanisms

    • Which clinical symptom is most commonly associated with right-sided colorectal carcinoma?

  • Severe abdominal pain
  • Altered bowel habits
  • Rectal bleeding
  • Positive FOBT (correct)

    • What is a characteristic histological feature of mucinous adenocarcinoma found in MSI-positive colorectal cancer?

  • High levels of CK7 expression
  • Presence of signet ring cells (correct)
  • Extensive necrosis
  • Limited extracellular mucin pools

    • Which type of colorectal carcinoma is characterized by chromosome stability and is not significantly affected by p53 mutations?

    <p>Microsatellite instability (MSI)</p> Signup and view all the answers

    What type of tissue sample is critical for diagnosing colorectal cancer?

    <p>Histological examination from a biopsy</p> Signup and view all the answers

    What defines a neoplasm in the context of large bowel pathology?

    <p>A proliferation of cells resulting from autonomous and excessive growth.</p> Signup and view all the answers

    Which type of polyp is most commonly associated with the colon?

    <p>Hyperplastic polyps.</p> Signup and view all the answers

    What complication can arise from intussusception in relation to bowel tumors?

    <p>Obstruction of the bowel.</p> Signup and view all the answers

    What characteristic is typical of hyperplastic polyps in the colon?

    <p>Malignant potential is very rare.</p> Signup and view all the answers

    Which symptom is most likely to be observed in a patient with large polyps in the colon?

    <p>Altered bowel habit.</p> Signup and view all the answers

    In colorectal carcinoma, which of the following factors is commonly considered a risk factor?

    <p>Sedentary lifestyle.</p> Signup and view all the answers

    What type of cells characterizes an adenocarcinoma in relation to colorectal carcinoma?

    <p>Cells with invasive potential and glandular differentiation.</p> Signup and view all the answers

    What is a significant pathological feature of dysplasia?

    <p>Presence of abnormal cells with some malignant features.</p> Signup and view all the answers

    What is primarily responsible for the chromosomal instability (CIN) pathway in cancers?

    <p>Accumulation of genetic aberrations</p> Signup and view all the answers

    Which of the following proteins is NOT a mismatch repair (MMR) protein associated with the MSI pathway?

    <p>APC</p> Signup and view all the answers

    What percentage of sporadic cancers is associated with microsatellite instability (MSI)?

    <p>10-15%</p> Signup and view all the answers

    What essential molecular events are necessary in the CIN pathway leading to carcinoma development?

    <p>4-5 molecular events in key pathways</p> Signup and view all the answers

    Which of the following statements about tumors in the CIN pathway is correct?

    <p>Tumors exhibit aneuploidy and chromosomal losses</p> Signup and view all the answers

    What is the role of MMR proteins in the MSI pathway?

    <p>Proofreading DNA during replication</p> Signup and view all the answers

    What type of familial cancers is associated with microsatellite instability (MSI)?

    <p>Lynch Family Syndrome</p> Signup and view all the answers

    Which of the following best describes the morphological sequence in the CIN pathway?

    <p>Normal mucosa → adenoma → carcinoma</p> Signup and view all the answers

    Which of the following events primarily characterizes the progression of the microsatellite instability pathway?

    <p>Loss of mismatch repair protein function</p> Signup and view all the answers

    Which dietary pattern is associated with an increased risk of colorectal carcinoma?

    <p>High caloric diet with refined carbohydrates</p> Signup and view all the answers

    How does smoking relate to colorectal carcinoma risk?

    <p>It is a contributing risk factor.</p> Signup and view all the answers

    What genetic mutation is primarily associated with Familial Adenomatous Polyposis (FAP)?

    <p>APC</p> Signup and view all the answers

    What is the lifetime risk percentage of colorectal carcinoma for individuals with Lynch Syndrome?

    <p>80%</p> Signup and view all the answers

    What type of cancer is NOT commonly associated with Lynch Family Syndrome?

    <p>Breast cancer</p> Signup and view all the answers

    What kind of polyposis syndrome is characterized by hamartomas?

    <p>Peutz-Jeghers syndrome</p> Signup and view all the answers

    What is a significant feature of carcinoma in patients with long-standing ulcerative colitis?

    <p>Development of multiple carcinomas without an obvious mass</p> Signup and view all the answers

    Colon cancer cases originating from familial risk typically account for what percentage of cases?

    <p>10-30%</p> Signup and view all the answers

    What type of genetic inheritance does Familial Adenomatous Polyposis (FAP) follow?

    <p>Autosomal dominant inheritance</p> Signup and view all the answers

    Which type of polyposis syndrome is associated with mutations in the MYH gene?

    <p>MYH-associated polyposis</p> Signup and view all the answers

    What is a key characteristic of sessile serrated lesions that differentiates them from adenomas?

    <p>Serrated crypts with asymmetric architecture</p> Signup and view all the answers

    Which feature is most strongly associated with the risk of an adenoma progressing to malignancy?

    <p>Size of adenoma</p> Signup and view all the answers

    Which statement accurately describes the management of tubular adenomas?

    <p>Clear margins are required if high-grade dysplasia is present</p> Signup and view all the answers

    What is a common characteristic of hamartomas?

    <p>Exhibit disorganized arrangement of normal structures</p> Signup and view all the answers

    What demographic information is associated with colorectal carcinoma onset?

    <p>Most cases occur in individuals aged 60-70s</p> Signup and view all the answers

    What is the typical growth pattern of villous adenomas?

    <p>Broad-based and sessile with finger-like projections</p> Signup and view all the answers

    In the context of colorectal carcinoma, which factor is least likely to influence outcomes?

    <p>Socioeconomic status</p> Signup and view all the answers

    Why might large villous adenomas require surgical intervention beyond colonoscopy?

    <p>They can be difficult to excise and require clear margins</p> Signup and view all the answers

    Which feature is NOT typical of hyperplastic polyps?

    <p>Presence of dysplastic epithelium</p> Signup and view all the answers

    What is true about the surveillance of adenomas?

    <p>The type, size, and number of adenomas dictate follow-up plans</p> Signup and view all the answers

    Study Notes

    Definitions

    • Polyp: A mass protruding into the lumen.
    • Neoplasm: Excessive, autonomous, and uncoordinated tissue growth.
    • Dysplasia: Abnormal cells with malignant features but no invasive or metastatic potential.
    • Adenocarcinoma: Invasive carcinoma with glandular differentiation, has metastatic potential.
    • Hamartoma: An abnormal tissue arrangement native to the site, both neoplastic and non-neoplastic forms exist.

    Normal Colon

    • The colon is comprised of several layers: mucosa, subserosa, muscularis propria, serosa, crypt, lamina propria, and muscular mucosa.

    Types of Polyps in Colon

    • Epithelial: Most common, including hyperplastic polyps, adenomas, carcinomas, and neuroendocrine tumors.
    • Non-Epithelial: Includes neoplastic (lipomas, gastrointestinal stromal tumors (GIST), neural and vascular tumors, lymphoma), inflammatory (e.g., chronic inflammatory bowel disease, rectal prolapse), and hamartomas.

    Symptoms of a Polyp

    • Asymptomatic: Many polyps have no noticeable symptoms.
    • Frank bleeding: Especially if large or located on the left side.
    • Occult bleeding: More common on the right side, detected through screening.
    • Anemia: Can be caused by chronic blood loss.
    • Metabolic changes: e.g., hypokalemia with villous adenomas (VA).
    • Large polyps: May cause altered bowel habit, obstruction, or intussusception.

    Intussusception

    • Occurs when a part of the colon telescopes into an adjacent portion, caused by a mass.
    • Leads to obstruction.

    Hyperplastic Polyp

    • Common, primarily in the recto-sigmoid region.
    • Usually under 0.5 cm.
    • Asymptomatic.
    • Hyperplastic mucosa.
    • Rarely has malignant potential.
    • Removed at colonoscopy.

    Sessile Serrated Lesion

    • Type of hyperplastic polyp, found mainly on the right side.
    • Serrated crypts with an asymmetric architecture at the base.
    • No dysplasia present.
    • May be a precursor for sporadic carcinomas.
    • Removed at colonoscopy, no need for clear margins.

    Adenomas

    • Common in middle-aged adults.
    • More frequently found on the left side of the colon.
    • Contain dysplastic epithelium.
    • Can be pedunculated or sessile.

    Tubular Adenomas (TA)

    • Pedunculated tubular adenoma is a common type.

    Villous (Sessile) Adenomas

    • Broad-based, sessile villous adenoma.

    Villous Adenomas (VA)

    • Characterized by finger-like projections.

    Risk of Adenoma Progressing to Malignancy

    • Increased size: Risk increases with size, especially for adenomas greater than 40 mm.
    • High-grade dysplasia: Presence of high-grade dysplasia significantly increases the risk.
    • Villous growth: Higher proportion of villous growth increases risk.
    • Number of adenomas: Multiple adenomas increase risk.
    • Molecular profile: Emerging importance in future risk prediction.

    Management of Adenomas

    • Removal at colonoscopy: TAs often completely excised, complete excision not always necessary for TAs without high-grade dysplasia (HGD).
    • Clear margins: HGD necessitates complete excision with clear margins, large VAs may require surgery to obtain clear margins.
    • Surveillance: Regular follow-up based on risk factors (e.g., number, type, and size of adenomas).

    Hamartoma

    • Uncommon, found throughout the gastrointestinal tract.
    • Disorganized arrangement of normal structures.
    • Typically solitary.
    • Removed at colonoscopy.
    • Can be part of a syndrome if multiple.

    Colorectal Carcinoma: Epidemiology

    • Third most common cancer and cause of cancer mortality.
    • Peak age of diagnosis is 60-70s.
    • Data available for Ireland shows cases, rates, and deaths between 2018-2020, broken down by gender.
    • Prevalence varies based on age group for both males and females.

    Colorectal Carcinoma: Risk Factors

    • Dietary: High caloric diet, high fat and refined carbohydrates, low vegetable and fiber intake.
    • Smoking: Increases risk.
    • Sedentary lifestyle: Increases risk.
    • Aspirin: Shown to be protective.
    • Sporadic adenomas: Presence of adenomas increases risk.
    • Family history: Risk increased with relatives with adenomas or CRC.
    • Strong family history Risk x 2-3 with one first-degree relative with CRC, x 3-4 with multiple family members affected, and x 4 if cancer diagnosed at a young age (45-59 years).

    ### Carcinoma and CIBD

    • Increased risk in long-standing ulcerative colitis with pancolitis.
    • Overall incidence is low.
    • Symptoms may be masked by underlying disease.
    • Multiple carcinomas can occur without obvious masses.
    • Mechanisms not fully understood, potentially involving oxidative stress.

    Colon Cancer Cases Arising in Various Family Risk Settings

    • Sporadic cases: Majority of cases.
    • Familial risk: 10% to 30% of cases.
    • Lynch Syndrome: 2% to 3% of cases.
    • Hamartomatous polyposis syndromes: Less than 0.1% of cases.
    • Familial adenomatous polyposis: Less than 1% of cases.

    Common Polyposis Syndromes

    • Adenomas: FAP, Attenuated FAP, Gardner, Turcot, MYH-associated Polyposis (MAP).
    • Hamartomas: Peutz-Jeghers, Juvenile Polyposis.

    Polyposis Syndromes: FAP

    • Autosomal dominant inheritance.
    • Germline mutation in the APC gene.
    • APC is a tumor suppressor gene.
    • More than 100 adenomas in the large bowel.
    • Adenomas and carcinoma in the small bowel and stomach.
    • 100% risk of progression to colorectal carcinoma.
    • Extra-GI manifestations: fibromatosis, cysts, CHRPE, carcinoma of thyroid, adrenal, pancreas, bile duct, etc.

    Lynch Family Syndrome (HNPCC)

    • Autosomal dominant.
    • Mutations in DNA mismatch repair (MMR) genes.
    • 80% lifetime risk of CRC.
    • Onset around 45 years.
    • Rapid growth.
    • Predominantly on the right side, multiple tumors, mucinous subtype, dense lymphocytic infiltrate.
    • Also linked to carcinoma of the small bowel and endometrium.

    Molecular basis of CRC: Pathways that Drive Colonic Neoplasia

    • Chromosomal Instability (CIN): Sporadic and hereditary (e.g., FAP).
    • Microsatellite Instability (MSI): Sporadic methylation and Lynch Family/HNPHCC.

    Chromosomal Instability (CIN) Pathway

    • Mechanism for cancers arising in FAP and 80% of sporadic carcinomas.
    • Stepwise accumulation of genetic aberrations.
    • Number of mutations is more important than the sequence, generally 4-5 molecular events in key pathways are needed.
    • Tumors show aneuploidy and chromosomal losses.
    • CIN effectively leads to the loss of wild-type alleles of tumor suppressor genes.

    CIN (APC) Pathway

    • Shows the progression from normal epithelium to small adenoma, large adenoma, and carcinoma.
    • Key genes involved are APC, RAS, PI3K, Cell Cycle/Apoptosis, and TGF-β.

    Microsatellite Instability (MSI) Pathway

    • Found in 10-15% of sporadic cancers and tumors arising in HNPCC/Lynch Family Syndrome.
    • Loss of mismatch repair (MMR) protein function.
    • Morphological sequence not fully understood compared to CIN pathway.

    Microsatellite Instability (MSI) Pathway Role of Mismatch Repair Proteins

    • Shows MMR proteins (MLH1, PMS2, MSH2, MSH6) involved in DNA mismatch repair during replication.
    • MMR proteins form heterodimer pairs.

    Role of Mismatch Repair Proteins in CRC

    • Epigenetic hypermethylation in sporadic cases.
    • Defects in MMR coding genes lead to reduced repair of specific DNA damage.
    • Germline mutations in MMR genes (Lynch Syndrome/HNPCC) drastically increase mutation rate in microsatellite DNA, leading to colorectal carcinoma.

    Microsatellite Instability (MSI) Pathway

    • Germline or somatic mutations in mismatch repair genes.
    • Alteration of the second allele by LOH, mutation, or promoter methylation.
    • Microsatellite instability ("mutator phenotype").
    • Accumulated mutations in genes regulating growth, differentiation, and/or apoptosis.
    • TGFbR, BAX, BRAF are often affected (not p53, KRAS).

    Classic Presentation: Right-Sided carcinoma

    • Symptoms: Subtle, related to occult blood loss (fatigue, pallor, iron deficiency anemia).
    • Signs: Vague mass in the right iliac fossa, possible altered bowel habit.
    • FOB test: Positive.
    • Differential Diagnosis: Other causes of IDA, appendiceal mass, adenoma or other tumor, ovarian mass.

    Classic Presentation: left-sided tumor

    • Symptoms: Altered bowel habit (constipation or diarrhea), rectal bleeding, possible abdominal pain.
    • Signs: Left iliac fossa mass.
    • Differential Diagnosis: Adenoma, colitis (e.g., CIBD), diverticular disease, rectal prolapse, other tumors.

    Diagnosis of CRC requires tissue obtained at colonoscopy

    • Microscopy: Biopsy shows adenocarcinoma in over 90% of cases.
    • Cytokeratin Profile Characteristic profile of CK20+, CK7-, CDX2+.

    Mucinous adenocarcinoma is more common in MSI-positive CRC

    • Shows microscopic images of colonic adenocarcinoma including pools of extra-cellular mucin and intra-cellular mucin (signet ring cells).

    Staging

    • CRC spreads through direct extension, lymphatics, and blood.
    • Staging is performed by radiology.

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