Carcinoma Colon

Detailed Outline of the Content in the PDF "Carcinoma Colon"

1. Introduction

• Overview of carcinoma colon
• Importance of understanding the multistep carcinogenesis

2. Multistep Carcinogenesis

• Chromosomal Instability Pathway (CIN)
  • Proposed by Vogelstein
  • Sporadic CRC arises from precursor dysplastic adenoma
  • Adenoma-Carcinoma Sequence (60% of patients with CRC)
  • Order: APC → KRAS → DCC → p53
  • Genomic Changes:
    • Activation of Proto-Oncogenes: KRAS, c-myc, c-Src
    • Inactivation of Tumor Suppressor Genes: APC, TP53, 18q LOH
  • APC Gene:
    • Tumor Suppressor Gene
    • Binds to Beta-Catenin
    • WNT Signaling Pathway
    • Mutations and their implications
  • Classic Chromosomal Instability (CIN) and Multistep Carcinogenesis
• CpG Island Methylator Phenotype (CIMP) Pathway
  • 2nd most common pathway (30% of sporadic CRC)
  • Hypermethylation of Promoter Sequence of Tumor Suppressor Genes (P16, CDKN2A, MLH1)
  • Associated with BRAF Mutation
  • More aggressive, lethal CRC
  • Occurs in Proximal Colon
• Microsatellite Instability Pathway (MSI)
  • Combination of CIMP and CIN Pathway
  • Lynch Syndrome

3. Polyp Characteristics

• Types and Risk of Malignancy
  • Pedunculated, Sessile
  • Tubular, Villous, Tubulovillous
• Classification and Risk Assessment
  • Haggitt Classification for Carcinoma
  • Kikuchi Classification for Sessile Polyps
• Malignant Polyps and Indications for Completion Colectomy
  • Risk considerations and management strategies

4. Gastrointestinal Polyposis Syndromes

• Adenomatous Polyposis Syndromes
  • FAP (Familial Adenomatous Polyposis)
  • AFAP (Attenuated Familial Adenomatous Polyposis)
  • MAP (MUTYH-Associated Polyposis)
  • NTHL1 Associated Polyposis
  • Lynch Syndrome
  • Familial CRC Type X
• Hamartomatous Polyposis Syndromes
  • Juvenile Polyposis Syndrome
  • Peutz-Jeghers Syndrome
  • PTEN Hamartoma Tumor Syndrome
  • Cronkhite-Canada Syndrome
• Hyperplastic/Serrated Polyposis Syndrome
  • Serrated Polyposis Syndrome (CIMP pathway)
• Mixed Polyposis Syndrome
  • Hereditary Mixed Polyposis Syndrome

5. Familial Adenomatous Polyposis (FAP)

• General Information
  • Autosomal dominant transmission
  • Clinical features and manifestations
  • Desmoid tumors in FAP
• Staging and Surveillance
  • Spigelman Staging System for Duodenal Adenomas
  • Surveillance recommendations
• Surgical Options and Management
  • Indications for Ileorectal Anastomosis (IRA)
  • Analysis of surgical options: IRA, IPAA

6. Lynch Syndrome and Related Conditions

• Definition and Criteria
  • Lynch Syndrome: Mutation in MMR genes
  • Amsterdam II Criteria
  • Bethesda Criteria for testing colorectal tumors for MSI
• Pathology and Genetic Testing
  • Tumor characteristics
  • Protocol for genetic testing
• Surveillance and Management
  • Recommendations for various associated cancers
  • Surgical management options

7. Colorectal Cancer (CRC) Characteristics

• Right-Sided vs. Left-Sided Tumors
  • Histology and prognosis
  • Response to treatment

8. Screening and Staging

• Screening Recommendations
  • Guidelines for colonoscopy and other screening methods
• AJCC Staging of CRC
  • Criteria for classification based on tumor characteristics

9. Management of CRC

• Chemotherapy for Stage 2 and Stage 3 CRC
  • Clinical scenarios and treatment recommendations
• Complete Mesocolic Excision with Central Vascular Ligation
  • Surgical technique and its benefits

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Multistep Carcinogenesis

1. CIN (Chromosomal Instability Pathway)
   • Proposed by Vogelstein
   • Sporadic CRC arises from precursor dysplastic adenoma
   • Adenoma-Carcinoma Sequence (60% of patients with CRC)
2. Second Most Common Pathway: CpG Island Methylator Cancer (35%)
3. 5% (Microsatellite Instability)

• Answer: A

1. CIN Pathway:

• Adenoma-Carcinoma Sequence Model
• Genomic Changes:
  • Activation of Proto-Oncogenes: KRAS, c-myc, c-Src
  • Inactivation of at least 3 Tumor Suppressor Genes:
    • Adenomatous Polyposis Coli (APC) Gene
    • Tumor Suppressor p53 (TP53) Gene
    • Heterozygosity for the Long Arm of Chromosome 18 (18q LOH)

• APC Gene:

  • Tumor Suppressor Gene
  • Both Alleles Have to Be Inactivated (Loss of Function)
  • Location: 5q21
  • Binds to Beta-Catenin
  • Regulates Intracytoplasmic Pool of Beta-Catenin
  • WNT Signaling Pathway: Regulate Cyclin D1 and MYC, Cell Proliferation

  APC Gene Mutations:

  • Earliest Mutation: APC Gene
  • Earliest Phenotypic Change: Aberrant Crypt Formation
  • Most Consistent Mutation: Truncation Mutation (Inappropriate Transcription of Premature Terminating Codons)
    • Codon 1250 to Codon 1464
    • Mutation in 5" End Causes FAP
    • Mutation in 3" End is Rare
    • Point Mutation 1307: Lysine for Isoleucine, 25% of CRC in Ashkenazi Jews

  Classic Chromosomal Instability (CIN) and Multistep Carcinogenesis:

  • The initial step is the disruption of WNT signaling, either by loss of adenomatous polyposis coli (APC) or a downstream event that achieves the same result.
  • The adenoma can remain small indefinitely, but if it acquires additional mutations that activate proto-oncogenes, they become larger and more dysplastic.
  • The loss of p53 is the most common event at the adenoma-to-carcinoma transition.
  • Initially, colorectal cancers (CRCs) may have minimal ability to metastasize, but the accumulation of additional mutations or other alterations eventually permits tumor cells to escape the primary tumor mass and grow at a distant site.
  • TGF-β (Transforming Growth Factor Beta): Provides insights into tumor evolution.

2. CIMP Pathway in Colonic Carcinogenesis

• Answer: C

CIMP Pathway:

• 2nd Most Common Pathway, 30% of Sporadic CRC
• Hypermethylation of Promoter Sequence of Tumor Suppressor Gene:
  • P16
  • CDKN2A
  • MLH1
• Associated with BRAF Mutation
• More Aggressive, Lethal CRC
• Begin as Sessile Serrated Adenoma Rather Than Adenomatous Polyp
• Occur in Proximal Colon
• MSI-H (Due to Hypermethylation of MLH1 Gene)

3. Microsatellite Instability Pathway

• Combination of CIMP and CIN Pathway
• CIMP:
  • 90% in Proximal Colon
  • 5 Years Older than Those of Sporadic CRC
• Lynch Syndrome:
  • Proximal Colon
  • 15-20 Years Younger
• CIN:
  • Masquerades as Lynch Syndrome

Polyp Characteristics

Polyp:

• Mass Projecting into the Lumen Above Surface of Epithelium

• Types:

  • Pedunculated
  • Sessile

• Subtypes:

  • Tubular
  • Villous

• Highest Risk of Malignancy:

  • Sessile
  • Villous
• Most Common Type:
  • Tubular Adenoma (65-80%)
  • 10-25% are Tubulovillous
  • Villous Adenoma
• Villous Adenoma >2 cm: Risk of Malignancy is 50%
• Peak Incidence of Polyp: 50 Years
• Peak Incidence of CRC Malignancy: 60 Years

Haggitt Classification for Carcinoma

• Level 0: Carcinoma limited to the mucosa, carcinoma in situ.
• Level 1: Carcinoma invading into the submucosa, limited to the head of the polyp.
• Level 2: Carcinoma invading to the level of the neck (junction of the head and stalk).
• Level 3: Carcinoma invading any part of the stalk.
• Level 4: Carcinoma invading into the submucosa of the colon wall, below the level of the stalk, but above the muscularis propria.

Sessile Polyps and Kikuchi Classification

Sessile Polyps:

• Invasion of the muscularis mucosa is seen and are by definition Haggitt level 4.

Kikuchi Classification:

• Sm1: Invasion into the upper third of the submucosa.
• Sm2: Invasion into the middle third of the submucosa.
• Sm3: Penetration into the lower third of the submucosa.

Malignant Polyps and Indications for Completion Colectomy

Malignant Polyps:

• Commonly referred for completion colectomy in cases of:
  • Pedunculated Haggitt level 4
  • Sessile Kikuchi level Sm2 and Sm3
  • Histologic poor differentiation
  • Lymphovascular invasion
  • Incomplete removal or close resection margins

Risk Considerations:

• In these cases, the risk of residual cancer and lymph node metastasis is higher than 10%.

GI Polyposis Syndromes

1. Adenomatous Polyposis Syndromes:
   1. FAP (Familial Adenomatous Polyposis)
   2. AFAP (Attenuated Familial Adenomatous Polyposis)
   3. MAP (MUTYH-Associated Polyposis) = AR
   4. NTHL1 associated polyposis = AR
   5. Lynch Syndrome
   6. Familial CRC Type X
2. Hamartomatous Polyposis Syndromes:
   1. Juvenile Polyposis Syndrome
   2. Peutz-Jeghers Syndrome
   3. PTEN Hamartoma Tumor Syndrome
   4. Cronkhite-Canada Syndrome
3. Hyperplastic/Serrated Polyposis Syndrome:
   • Serrated Polyposis Syndrome = CIMP pathway
4. Mixed Polyposis Syndrome:
   • Hereditary Mixed Polyposis Syndrome

FAP (Familial Adenomatous Polyposis)

General Information:

• Autosomal dominant transmission, M=F, 100% penetrance
• 1% of all CRC, 2nd most common inherited syndrome
• 25-30% do not have positive family history (de novo mutation)
• Lemuel Herrera: underlying genetic abnormality in the APC gene
• More than 100 polyps in colon and rectum
• CHRPE (Congenital Hypertrophy of the Retinal Pigment Epithelium) in 75% of individuals (non-malignant)
• Age of onset for polyps: 16 years
• Age of onset for malignancy: 39 years
• Gastric and duodenal polyps in 50% of affected individuals
  • Gastric polyps: fundic gland polyps (benign)
  • Duodenal polyps: adenomatous polyps (premalignant)
• Upper GI and small bowel evaluation recommended at 25-30 years of age
• Most common cause of death: Colon cancer > Desmoid tumors > Duodenal cancer

Desmoids in FAP:

• Found in 30% of patients
• Common locations: abdominal wall, mesentery, retroperitoneum
• Risk factors:
  • Female gender
  • Family history
  • Gardner syndrome
  • Genotype (predicts severity, 3' greater severity)

Manifestations of Germline APC Mutation in FAP:

Organ	Benign	Malignant
Colon and rectum	Adenoma	Carcinoma
Stomach	Adenoma, Fundic gland polyp	Carcinoma
Small intestine	Adenoma	Carcinoma
Thyroid	—	Papillary carcinoma
Adrenal gland	Adenoma	Carcinoma
Bone	Osteoma	—
Skin	Epidermoid cyst	—
Teeth	Extra teeth	—
Fibroblasts	Desmoid disease	—
Brain	—	Medulloblastoma
Liver	—	Hepatoblastoma

A Staging System for Intraabdominal Desmoid Disease:

Stage	Size	Symptoms	Growth
I	<10 cm	None	None
II	<10 cm	Mild	<25% in 6 months
III	11-20 cm	Moderate	25% to 50% in 6 months
IV	>20 cm	Severe	>50% in 6 months

Note: Many patients have multiple desmoids. The worst stage is taken for treatment planning.

Treatment of Intraabdominal Desmoid Disease in FAP, According to Stage:

Stage	Treatment	Surveillance
I	Nothing, or sulindac 150-200 mg by mouth twice a day	Repeat scan in 1 year
II	Sulindac 150-200 mg twice a day with raloxifene 60 mg by mouth twice a day	Repeat scan in 6 months
III	Methotrexate/vinorelbine or sorafenib	Repeat scan in 3 months
IV	Doxil, Adriamycin	Repeat scan in 3 months

Spigelman Staging System for Duodenal Adenomas:

Criterion	1 Point	2 Points	3 Points
Polyp number	1-4	5-20	>20
Polyp size (mm)	1-4	5-10	>10
Polyp histology	Tubular	Tubulovillous	Villous
Degree of dysplasia	Low	Moderate*	High

*Now combined with low-grade dysplasia.

Stage 0 = 0 points; stage I = 1-4 points; stage II = 5-6 points; stage III = 7-8 points; stage IV = 9-12 points.

Spigelman Staging Surveillance:

• Stage I: Survey every 3 years
• Stage II: Survey every 1 year
• Stage III: Survey every 6 months
• Stage IV: Surgery (Pancreas-preserving duodenectomy or Whipple's procedure)

Attenuated FAP (aFAP)

• Answer: C

aFAP:

• Less than 100 polyps
• APC mutation at extremities
• Same risk of upper GI polyposis
• 3' end: Increased risk of desmoid disease
• Treatment: Colectomy + IRA
• Mild polyposis: Can be observed

MUTYH-Associated Polyposis (MAP)

MAP:

• Autosomal recessive
• Resembles aFAP
• Two-fold increase in CRC
• Rectal studding
• Extracolonic manifestations seen
• Treatment: Colectomy + IRA

Familial Adenomatous Polyposis (FAP) Surgical Options

Timing of Sugery in FAP:

MCQ - Indications for Ileorectal Anastomosis in FAP

Answer: C

Explanation:

Indications for Ileorectal Anastomosis (IRA):

• <20 rectal adenomas: Indicated when there are fewer than 20 rectal adenomas.
• <1000 colonic adenomas: Suitable when there are fewer than 1000 colonic adenomas.
• Low desmoid risk: Preferred in patients with a low risk of desmoid tumors.
• Not indicated for: High-grade dysplasia in rectal adenoma, as this requires more aggressive management to prevent cancer.

Analysis of the Advantages and Disadvantages, Indications and Contraindications of the Three Main Colorectal Surgical Options of Patients With Familial Adenomatous Polyposis

Advantages and Disadvantages of Surgical Options for FAP

Ileorectal Anastomosis (IRA):

• Advantages:
  • Quick, safe, and uncomplicated.
  • Good quality of life.
  • Acceptable bowel function.
  • Controls colonic polyposis.
  • Avoids any ileostomy.
  • Easy surveillance.
• Disadvantages:
  • Risk of rectal cancer.
  • Continuous surveillance required.
• Indications:
  • <20 rectal adenomas.
  • <1000 colonic adenomas.
• Contraindications:
  • Rectal cancer.

Ileal Pouch-Anal Anastomosis (IPAA):

• Advantages:
  • Controls most colorectal polyposis.
  • Risk of pouchitis is less compared to UC
  • Avoids permanent ileostomy.
  • Reasonable quality of life.
• Disadvantages:
  • High complication rate. [High incidence of leak, stricture in hand sewn]
  • Unpredictable bowel function.
  • Ileostomy may be needed.
  • Risk of pouch polyposis and ATZ cancer.
  • Difficult surveillance.
• Indications:
  • 20 rectal adenomas.
  • Rectal cancer.
• Contraindications:
  • High desmoid risk.
  • Lack of surgical expertise.
  • <20 rectal adenomas.
• Note:
  • Staped / Hand sewn with mucosectomy ( S pouch)
  • Diverting stoma can be avoided if:
    • stapler donuts are intact
    • leak test is negative
    • stapled anastomosis

Lynch Syndrome and Related Conditions

Variations of Lynch Syndrome:

Lynch Syndrome:

• Definition: Presence of a heritable genetic variant in one of the MMR genes regardless of clinical context or family history.
• Most common inherited syndrome: Accounts for 3% of all colorectal cancers (CRC).
• Inheritance: Autosomal dominant (AD).
• Germline mutations: Occur in DNA mismatch repair (MMR) genes, including MLH1, MSH2, MSH6, PMS2, and EPCAM.
• Most common mutations: MLH1 and MSH2.
• Amsterdam Criteria: 50% of patients with Lynch syndrome do not meet the Amsterdam criteria.

Hereditary Nonpolyposis Colorectal Cancer (HNPCC):

• Clinical diagnosis: Based on the cancer pattern in a family as defined by Amsterdam II criteria.

Familial Colorectal Cancer Type X:

• Criteria: Meet Amsterdam criteria but have microsatellite stable (MSS) tumors (negative gene mutation).

Lynch-like Syndrome:

• Tumor Characteristics: Microsatellite instability (MSI) but no identifiable MMR gene germline defect. ⇒ CIMP pathway

MCQ - Variations of Lynch Syndrome

Answer: C

Explanation:

• HNPCC: Correctly matched with fulfilling Amsterdam II criteria.
• Lynch syndrome: Correctly matched with a mutation in MMR gene irrespective of family history.
• FCC X: Incorrectly matched; FCC X meets Amsterdam criteria but has microsatellite stable (MSS) tumors.
• Lynch-like: Correctly matched with microsatellite unstable (MSI) tumors with no MMR gene germline defect.

Pathology of Lynch Syndrome:

• Poor differentiation, medullary growth, cribriform pattern.
• Signet cell histology.
• Abundance of extracellular mucin.
• Tumor-infiltrating lymphocytes.
• Crohn’s-like histology.
• Often right-sided with a good prognosis. [ even with poor differentiation and signet cell histology]

Amsterdam II Criteria:

Three or more relatives with hereditary nonpolyposis colorectal cancer-associated cancer (colorectal cancer or cancer of the endometrium, small bowel, ureter, or renal pelvis) plus all of the following:

1. One affected patient is a first-degree relative of the other two.
2. Two or more successive generations are affected.
3. Cancer in one or more affected relatives is diagnosed before the age of 50 years.
4. Familial adenomatous polyposis is excluded.
5. Pathologic diagnosis of cancer is verified.

Bethesda criteria for testing colorectal tumors for microsatellite instability (MSI)

Tumors from individuals in the following situations should be tested for MSI:

1. Colorectal cancer diagnosed in a patient before age 50.
2. Presence of synchronous/ metachronous colorectal or other hereditary non polyposis colorectal cancer (HNPCC)-related tumors (including endometrial, stomach, ovarian, pancreas, ureter and renal pelvis, biliary tract, brain (usually glioblastoma), sebaceous gland adenomas and keratoacanthomas, and carcinoma of the small bowel), regardless of age.
3. Colorectal cancer with the MSI histology (defined by the presence of tumor infiltrating lymphocytes, Crohn-like lymphocytic reaction, mucinous/signet ring differentiation, or medullary growth pattern) diagnosed in a patient before age 60.
4. Colorectal cancer diagnosed in at least one first-degree relative with an HNPCC-related tumor in which one cancer was diagnosed before age 50.
5. Colorectal cancer diagnosed in at least two first- or second-degree relatives with HNPCC-related tumors, regardless of age.

Key Points related to Lynch and its variants:

• NCCN recommends to check for MSI testing if pt has CRC diagnosed before age of 70 years
• Most Common Brain tumor associated with HNPCC is Glioblastoma
• MSI-H or loss of MMR protein expression do not confirm Lynch syndrome diagnosis
• Majority of sporadic MSI-H CRC arise via acquired methylation of the MLH1 promotor sequence
• Non Lynch MLH1 deficient tumor have BRAF mutation
• Wild type BRAF or methylated MLH1 promotor suggest sporadic MSI-H cancer

Protocol for genetic testing of patients with suspected Lynch Syndrome?

Lynch Syndrome Surveillance

1. Colorectal Cancer Risk:
   • Lifetime Risk:
     • MLH1, MSH2, PMS2: 30% to 74%
     • MSH6: 10-22%
   • Mean Age of Onset: 44-61 years
   • Screening: Colonoscopy every 1-2 years starting at age 20-25 years
2. Endometrial Cancer:
   • Highest Risk with Extracolonic Cancers:
     • MSH6 and MSH2 mutation: 44% risk
   • Mean Age of Onset: 48-62 years
   • Annual Screening:
     • Transvaginal ultrasound (TVS)
     • Endometrial biopsy
   • Prophylactic Surgery: Total abdominal hysterectomy (TAH) + bilateral salpingo-oophorectomy (BSO) for those who have completed childbearing

3. Other Tumors Associated with Lynch Syndrome:

   • Urinary Tract: Annual urinalysis recommended by NCCN starting at age 25-30 years
   • Stomach, Small Bowel: Surveillance with EGD (esophagogastroduodenoscopy) with extended duodenoscopy every 3-5 years starting at age 30-35 years
   • Brain, Skin, Pancreas, Prostate, and Breast
   • Muir-Torre Syndrome:
     • Sebaceous skin neoplasms, keratoacanthomas;
     • associated with MSH2 mutation
   • Turcot Syndrome:
     • APC mutation: Medulloblastoma, astrocytoma, ependymoma
     • MMR mutation: Glioblastoma
   • Possible Elevated Risk of Breast Cancer

   Additional Notes:

   • Surveillance Procedures:
     • MRI/EUS for pancreas surveillance starting at age 30-35 years.
     • Annual urinalysis for urinary tract surveillance starting at age 25-30 years as per NCCN recommendations.
     • EGD with extended duodenoscopy for small bowel and gastric surveillance every 3-5 years starting at age 30-35 years.

Surveillance Table for HNPCC / Lynch Sx:

Site	Age to Begin Surveillance (years)	Surveillance Interval (years)	Surveillance Procedures
Colon	20-25 (MLH1/MSH2 mutation) 25-30 (MSH6/PMS2 mutation)	1-2	Colonoscopy
Endometrial and Ovarian	30-35	1	Annual pelvis examination
Annual endometrial biopsy and Transvaginal ultrasound
TAH/BSO for those who have completed childbearing
Pancreas	30-35	1-2	MRI/EUS
Urinary Tract	25-30	1	NCCN recommends considering an annual urinalysis
Small Bowel and Gastric	30-35	3-5	EGD with extended duodenoscopy

Surgical Management of HNPCC (Lynch Syndrome):

Answer: B (Total proctocolectomy + IPAA)

Explanation:

Appropriate Surgical Options:

1. Segmental Colectomy:
   • Suitable for localized cancer.
   • Follow-up surveillance is necessary due to the risk of metachronous cancers.
2. Total Abdominal Colectomy + IRA (Ileorectal Anastomosis):
   • Offers extensive protection by removing the entire colon, thereby significantly reducing the risk of developing subsequent colorectal cancer.
   • Cumulative risk of metachronous colorectal cancer after surgery:
     • 16% at 10 years
     • 41% at 20 years
     • 62% at 30 years
   • Cumulative risk of colon cancer after proctectomy:
     • 19% at 10 years
     • 47% at 20 years
     • 69% at 30 years
3. Anterior Resection:
   • Indicated for cancers located in the rectosigmoid area.
   • Preserves anal function, making it a viable option for appropriate cases.
4. Left Hemicolectomy:
   • Suitable for cancers located in the descending colon and part of the transverse colon.

Inappropriate Surgical Option:

• Total Proctocolectomy + IPAA (Ileal Pouch-Anal Anastomosis):
  • Generally not recommended for isolated colon cancer in Lynch Syndrome unless there is significant rectal involvement or a high risk of rectal cancer.
  • This procedure is more invasive and reserved for specific conditions involving the rectum or high risk of rectal cancer, which is not indicated in this scenario.

Further Explanation:

• Follow-up and Surveillance:
  • Patients who undergo segmental colectomy require stringent follow-up surveillance because there is a significant risk of developing metachronous colorectal cancers.
  • 20-30% of patients may develop rectal cancer over time.

• Prophylactic Measures:

  The CAPP2 trial showed that high-dose aspirin (600 mg) is effective in preventing cancer in individuals with Lynch Syndrome.

FCC X (Familial Colorectal Cancer Type X):

• Characteristics:
  • These patients meet the Amsterdam criteria but have microsatellite stable (MSS) tumors.
  • 40% of amsterdam criteria
  • There is no increased risk of extracolonic malignancies.
  • The mean age of diagnosis is around 60 years.
  • Segmental colectomy is often sufficient as there is no significant risk of metachronous tumors or extracolonic cancers.
  • Less risk of CRC than lynch syndrome.

Summary:

For a 35-year-old female with Lynch Syndrome presenting with adenocarcinoma in the sigmoid colon, the preferred surgical options are Total Abdominal Colectomy + IRA, Segmental Colectomy, Anterior Resection, and Left Hemicolectomy. Total Proctocolectomy + IPAA is generally not recommended unless there is significant rectal involvement or a high risk of rectal cancer. Regular follow-up and surveillance are crucial to monitor for potential metachronous

Hamartomatous Polyposis Syndromes

• < 1% of CRC

Includes:

• Juvenile Polyposis Syndrome (JPS)
• Peutz-Jeghers Syndrome (PJS)
• Cronkhite-Canada Syndrome
• PTEN Hamartoma Tumor Syndrome (PHTS)
  • Cowden Syndrome (CS)
  • Bannayan-Riley-Ruvalcaba Syndrome (BRRS)

Peutz-Jeghers Syndrome (PJS)

• Ans: C

Explanation:

Peutz-Jeghers Syndrome (PJS):

• PJS is an autosomal dominant hereditary cancer syndrome.
• Cancer Risks:
  • Lifetime risk of colorectal cancer (CRC): 39%
  • Highest risk of cancer is in the colon (39%), not the pancreas.
  • Other cancer risks include:
    • Pancreas (36%)
    • Stomach (29%)
    • Small bowel (13%)
    • Cervix (adenoma malignum)
    • Sertoli cell tumors of the testes (SCTAT)

Clinical Features:

• Polyp Characteristics:
  • Benign hamartomatous polyps.
  • Most common site of polyp: Small intestine.
• Most common clinical presentation: Small bowel obstruction.
• Mucocutaneous Pigmentation:
  • Found on the vermillion border of the lip, buccal mucosa, hands, and feet.
• Genetic Mutation:
  • STK11/LKB1 gene mutation on chromosome 19p.

Diagnosis:

• Clinical diagnosis based on WHO criteria:
  1. Three or more histologically confirmed Peutz-Jeghers polyps.
  2. Any number of polyps with a family history of PJS.
  3. Mucocutaneous pigmentation.
  4. Polyp with mucocutaneous pigmentation.

Management:

• Polypectomy:
  • Cornerstone of management.
  • Small bowel polyps larger than 1 to 1.5 cm should be removed.
  • Asymptomatic gastric or colonic polyps larger than 1 cm should be removed.
• Investigation:
  • Investigation of choice for small bowel polyps: Capsule endoscopy.
• Surgical Approach:
  • At laparotomy, clearance of all small bowel polyps should be attempted.
  • Intraoperative enteroscopy may be required.

Inherited CRC syndromes Table

*Remember the risk of CRC

Colorectal Cancer (CRC): Right-Sided vs. Left-Sided Tumors

• Ans: A

Explanation:

Differences Between Right-Sided and Left-Sided Colorectal Tumors:

Right-Sided Colorectal Cancer:

• Histology:
  • Often mucinous adenocarcinomas, sessile serrated adenomas.
  • Frequently have flat-like morphology.
  • Typically MSI-high (microsatellite instability-high) and mismatch repair deficient tumors.
• Immunogenicity:
  • Highly immunogenic with high T-cell infiltration.
• Metastasis:
  • Metastasizes in the peritoneal region.
• Demographics:
  • Occurs in older ages.
  • Predominantly occurs in females.
• Prognosis:
  • Better prognosis at early stages (Stage I and II).
• Response to Treatment:
  • Responds well to immunotherapy.

Left-Sided Colorectal Cancer:

• Histology:
  • Usually tubular, villous adenocarcinomas.
  • Often have polypoid-like morphology.
  • Typically CIN-high (chromosomal instability-high) tumors.
• Immunogenicity:
  • Low immunogenicity.
• Metastasis:
  • Metastasizes in the liver and lungs.
• Demographics:
  • Occurs in younger ages.
  • Predominantly occurs in males.
• Prognosis:
  • Better prognosis at late stages (Stage III and IV).
• Response to Treatment:
  • Responds well to adjuvant chemotherapies, including standard chemotherapies and targeted therapies.

Key Points on Right vs Left CRC:

1. Prognosis:
   • Right colon does not necessarily have a better prognosis than the left colon.
   • Right-sided CRC generally has a better prognosis at early stages but worse prognosis at later stages compared to left-sided CRC.
2. Histology:
   • Right-sided CRCs are more likely to be MSI-high and have mismatch repair deficiencies.
   • Left-sided CRCs are more likely to have chromosomal instability.
3. Age and Gender:
   • Right-sided CRCs occur more in older individuals and females.
   • Left-sided CRCs occur more in younger individuals and males.
4. Treatment Response:
   • Right-sided CRCs respond well to immunotherapy.
   • Left-sided CRCs respond well to adjuvant chemotherapies, including standard and targeted therapies.

MCQ: Screening of CRC

Answer: B. 3 years

Explanation:

The recommendations for repeat colonoscopy following endoscopic removal of polyps are based on the type, size, and histological features of the polyps identified during the initial colonoscopy. The provided table outlines these recommendations clearly.

Detailed Recommendations:

Index Colonoscopy Findings and Repeat Colonoscopy Intervals:

1. Small (<10 mm) Hyperplastic Polyps in Rectum or Sigmoid:
   • Repeat Colonoscopy: 10 years
2. Low Risk (One to two small tubular adenomas <10 mm, with low-grade dysplasia):
   • Repeat Colonoscopy:
     • 5–10 years (AGA guidelines)
     • 10 years (ESGE guidelines)
3. High Risk (Villous histology or high-grade dysplasia or size ≥10 mm or ≥3 polyps):
   • Repeat Colonoscopy: 3 years
4. Piecemeal Removal of Polyp:
   • Repeat Colonoscopy: 6 months
5. Sessile Serrated Polyp <10 mm:
   • Repeat Colonoscopy: 5 years
6. Sessile Serrated Polyp ≥10 mm or with dysplasia or traditional serrated adenoma:
   • Repeat Colonoscopy: 3 years

Explanation for Answer:

The patient has three tubular adenomas, each measuring 7 mm, with low-grade dysplasia, which categorizes him under the high-risk group. Therefore, the recommended interval for the next colonoscopy is 3 years.

Recommendations for repeat colonoscopy following endoscopic removal of polyps.

General Screening Recommendations for CRC:

1. Colonoscopy:
   • Start at age 50 years (every 10 years).
   • Start at age 45 years for African American race (AGA recommendation).
2. Sigmoidoscopy:
   • Every 5 years.
3. Sigmoidoscopy + FIT:
   • Annually.
4. CT Colonography:
   • Screening option for patients at average risk.
5. Multitarget Stool DNA Testing:
   • Screening option for patients at average risk.
6. Fecal Immunochemical Testing (FIT):
   • Annually.
7. Capsule Colonoscopy:
   • Used when conventional colonoscopy is not feasible.
8. FIT vs gFOBT:
   • FIT: Only one sample required, no dietary modifications needed.
   • gFOBT: Requires three samples, dietary modifications necessary.

These recommendations help ensure appropriate follow-up and early detection of potential malignancies in patients with a history of polyps or other risk factors for colorectal cancer.

MCQ: AJCC staging of CRC

Answer: C. N1c

Explanation:

The AJCC staging system provides detailed criteria for classifying colorectal cancer based on the extent of the primary tumor, regional lymph node involvement, and the presence of distant metastasis.

Regional Lymph Nodes (pN) Staging:

1. pNX: Cannot be assessed.
2. pN0: No regional lymph node metastasis.
3. pN1: Metastasis in 1 - 3 regional lymph nodes.
   • N1a: Metastasis in 1 regional lymph node.
   • N1b: Metastasis in 2 - 3 regional lymph nodes.
   • N1c: No regional lymph nodes are positive, but there are tumor deposits in the subserosa, mesentery, or nonperitonealized pericolic or perirectal/mesorectal tissues.
4. pN2: Metastasis in 4 or more regional lymph nodes.
   • N2a: Metastasis in 4 - 6 regional lymph nodes.
   • N2b: Metastasis in 7 or more regional lymph nodes.

Notes on Tumor Deposits:

• Tumor deposits are discrete tumor nodules of any shape, contour, or size found within the lymph drainage area of the primary carcinoma, lacking associated lymphoid tissue, vascular structures, or neural structures.
• N1c is specifically used when there are tumor deposits in the absence of unequivocal lymph node metastases. If lymph node metastasis is present, the number of tumor deposits is not added to the number of positive lymph nodes.

Summary of AJCC TNM Staging for Colorectal Cancer:

Primary Tumor (pT):

• pTX: Cannot be assessed.
• pT0: No evidence of primary tumor.
• pTis: Carcinoma in situ.
• pT1: Tumor invades submucosa.
• pT2: Tumor invades muscularis propria.
• pT3: Tumor invades through the muscularis propria into pericolorectal tissues.
• pT4:
  • pT4a: Tumor invades through the visceral peritoneum.
  • pT4b: Tumor directly invades or adheres to other adjacent organs or structures.

Regional Lymph Nodes (pN):

• pNX: Cannot be assessed.
• pN0: No regional lymph node metastasis.
• pN1: Metastasis in 1 - 3 regional lymph nodes or tumor deposits without nodal metastasis (N1c).
• pN2: Metastasis in 4 or more regional lymph nodes.

Distant Metastasis (pM):

• pM0: No distant metastasis by imaging.
• pM1: Distant metastasis.
  • M1a: Metastasis confined to 1 organ or site without peritoneal metastasis.
  • M1b: Metastasis to 2 or more sites or organs without peritoneal metastasis.
  • M1c: Metastasis to the peritoneal surface alone or with other site or organ metastases.

MCQ: Management options of CRC based on Staging:

1. Staging according to AJCC 8th Edition:

Answer: A. M1a

Explanation:

• M1a: Metastasis confined to one organ or site (e.g., liver) without peritoneal metastasis.
• M1b: Metastasis to two or more sites or organs without peritoneal metastasis.
• M1c: Metastasis to the peritoneal surface alone or with other site or organ metastases.

Since the patient has a liver metastasis confined to one organ, the appropriate staging is M1a.

2. Appropriate Management:

Answer: B. Abort procedure and give palliative chemotherapy

Explanation:

• Left hemicolectomy + Liver metastatectomy: This option is appropriate for a potentially curative approach, especially if the metastasis is resectable.
• Abort procedure and give palliative chemotherapy: This option is not appropriate for a resectable liver metastasis in the context of potentially curative surgery.
• Left hemicolectomy followed by NACT followed by liver metastatectomy: This staged approach can be considered depending on the patient's overall condition and response to chemotherapy.
• NACT followed by liver metastatectomy followed by left hemicolectomy: This option is also viable, focusing on reducing the tumor burden before surgical resection.

Discussion:

Staging and Management of Colorectal Cancer with Liver Metastasis:

Staging (AJCC 8th Edition):

• M0: No distant metastasis.
• M1: Distant metastasis present.
  • M1a: Metastasis confined to one organ or site (e.g., liver).
  • M1b: Metastasis to two or more sites or organs.
  • M1c: Metastasis to the peritoneal surface alone or with other site or organ metastases.

Management:

• Surgical Resection: The primary treatment for resectable liver metastases involves surgical resection. The goal is to achieve R0 resection (complete resection with negative margins).
• Neoadjuvant Chemotherapy (NACT): Chemotherapy before surgery can help shrink the metastasis, making it easier to resect and potentially improving outcomes.
• Sequential Approach: Depending on the tumor burden and patient’s condition, a staged approach with chemotherapy followed by surgery can be effective.
• Palliative Chemotherapy: For patients with unresectable metastases or those who are not surgical candidates, systemic chemotherapy is the mainstay of treatment.

MCQ: Chemotherapy for Stage 2 and Stage 3 CRC

Clinical Scenario:

MCQ:

Answer: C. Adjuvant 5-FU for 6 months

Explanation:

Management of Stage II Colon Cancer:

• Adjuvant Chemotherapy:
  • No Adjuvant Chemotherapy: Generally indicated for low-risk Stage II patients without adverse features.
  • Consider Adjuvant Chemotherapy: For high-risk Stage II patients with adverse features including T4 tumors, obstruction, perforation, perineural invasion (PNI), lymphovascular invasion (LVI), or inadequate lymph node sampling (<12 nodes).
  • No Adjuvant Therapy in MSI-H: Patients with high microsatellite instability (MSI-H) tumors typically do not benefit from adjuvant chemotherapy and may even experience detrimental effects.
• Chemotherapy Regimen:
  • 5-FU/LV: For Stage II patients requiring adjuvant chemotherapy, 5-FU (5-Fluorouracil) with leucovorin (LV) is the standard regimen.
  • Oxaliplatin Addition: Can be considered in very high-risk cases (e.g., high-risk MSI-H histology).

Differences Between Stage II and Stage III Colon Cancer:

• Stage II Colon Cancer:
  • Tumor Characteristics: Invades through the muscularis propria into pericolorectal tissues (T3) or invades through the serosa (T4a) or directly invades other organs (T4b).
  • Lymph Nodes: No regional lymph node involvement (N0).
  • Adjuvant Therapy: Generally not required unless high-risk features are present.
• Stage III Colon Cancer:
  • Tumor Characteristics: Can be any T stage (T1-T4).
  • Lymph Nodes: Involves 1-3 regional lymph nodes (N1) or 4 or more regional lymph nodes (N2).
  • Adjuvant Therapy: Adjuvant chemotherapy is standard of care. FOLFOX (5-FU, leucovorin, and oxaliplatin) or CAPEOX (capecitabine and oxaliplatin) regimens are commonly used.

High-Risk Factors in Stage II Colon Cancer:

• Clinical Pathologic Factors:

  • T4 Tumor: Indicates higher risk of recurrence.
  • Obstruction/Perforation: Poor prognostic factors necessitating adjuvant therapy.
  • PNI/LVI: Presence indicates aggressive disease.
  • Inadequate Lymph Node Sampling: Less than 12 lymph nodes examined.

  

Adjuvant Chemotherapy Considerations:

• Stage II, Low-Risk: Observation or 5-FU/LV.
• Stage II, High-Risk: 5-FU/LV, considering oxaliplatin in specific high-risk cases.
• MSI-H Tumors: Avoid adjuvant chemotherapy unless high-risk factors dictate otherwise

MCQ: Complete Mesocolic Excision with Central Vascular Ligation

Answer: A. Hemicolectomy with removal of nodes along SMV and SMA

Explanation: Complete mesocolic excision (CME) is a surgical technique used in the treatment of colon cancer that involves meticulous dissection and removal of the mesocolon along with the central vascular ligation (CVL). This approach aims to remove the entire mesocolon enveloping the tumor-bearing bowel segment, which includes all the lymphatic drainage pathways to ensure a comprehensive oncological resection. The goal is to achieve clear margins and maximize lymph node retrieval for accurate staging and improved survival outcomes.

Complete Mesocolic Excision (CME) and Central Vascular Ligation (CVL):

1. CME Technique:

   • Involves the dissection of the mesocolon intact, leaving behind toldt’s fascia, ensuring that it remains covered by its peritoneal envelope.

   • Ensures the removal of the tumor along with the entire lymphatic drainage.

     

2. CVL Technique:

   • Involves ligating the supplying vessels (such as the superior mesenteric artery (SMA) and vein (SMV)) at their origins to ensure the removal of all associated lymph nodes.

Illustration from Image:

• The diagram shows the levels of lymph node dissection (D1, D2, D3).
• D2 Dissection: Involves the removal of pericolic and intermediate lymph nodes.
• D3 Dissection: Extends to the main lymph nodes along the SMA and SMV, providing a more radical clearance compared to D2.
• The study results indicate the benefits and risks associated with D3 dissection, showing increased node positivity and the importance of comprehensive nodal retrieval.

Comparison Table:

• The table compares short-term outcomes between D2 and D3 dissection approaches, highlighting the increased node retrieval and positivity with D3 dissection.

Conclusion: The concept of CME with CVL emphasizes the importance of a thorough surgical approach in colorectal cancer surgery to improve oncological outcomes. This technique is considered superior in ensuring complete removal of potentially affected lymph nodes and minimizing the risk of cancer recurrence.

MCQ: Adjuvant Therapy for Colon Cancer

Answer: C. T4bN2bM0; Adjuvant CAPEOX for 6 months

Explanation:

Staging:

• Tumor (T): The tumor infiltrates the serosa, which classifies it as T4b.
• Nodes (N): There are 8 positive lymph nodes, which classifies it as N2b.
• Metastasis (M): No distant metastasis, so M0.

The correct staging is T4bN2bM0.

Adjuvant Therapy for Stage 3/4 CRC:

• High-Risk Features: T4 status, poorly differentiated histology, LVI, PNI, and multiple positive lymph nodes.
• MSI-H Status: MSI-H tumors typically do not benefit from fluorouracil (5-FU)-based chemotherapy alone but do respond well to combination therapies.
• Wild-Type KRAS: This indicates no mutation in the KRAS gene, making the tumor potentially responsive to EGFR inhibitors in metastatic settings. However, targeted therapies like cetuximab or panitumumab are not used in non-metastatic (localized) colon cancer.

Adjuvant Therapy Recommendations:

1. For High-Risk Stage III (T4bN2bM0):
   • CAPEOX (Capecitabine and Oxaliplatin) for 6 months: This regimen is recommended for its effectiveness in high-risk cases.
2. Short-term vs. Long-term Regimens:
   • High Risk (T4/N2):
     • Six months of FOLFOX (Oxaliplatin, 5-FU, and Leucovorin)
     • Six months of CAPEOX
   • Low Risk (T3/N1):
     • Three months of CAPEOX: Non-inferior to 6 months of CAPEOX.
     • Three months of FOLFOX: Inferior to 6 months of FOLFOX.

Adjuvant Therapy in Metastatic Cancer:

• Wild-Type Pan-Ras (KRAS, NRAS): Panitumumab and cetuximab are used.
• BRAF Mutation (worst prognosis): FOLFOXIRI (Oxaliplatin, Irinotecan, 5-FU) + Bevacizumab.
• Right-Sided Colon Cancer:
  • Anti-EGFR antibodies (e.g., Cetuximab, Panitumumab) are not useful.
  • Preferred Regimen: FOLFOX/FOLFIRI + Bevacizumab.
• Left-Sided Colon Cancer:
  • Anti-EGFR antibodies can be used.
  • No more than 6 cycles of neoadjuvant chemotherapy (NACT) for liver metastases.

Key Points:

1. Staging:
   • T4b: Tumor invades through the visceral peritoneum or directly invades/adheres to other organs/structures.
   • N2b: Metastasis in 7 or more regional lymph nodes.
   • M0: No distant metastasis.
2. Adjuvant Therapy:
   • High-Risk Features: Poor differentiation, LVI, PNI, high lymph node involvement (N2b).
   • Chemotherapy Regimen: CAPEOX for 6 months for stage III high-risk colon cancer.
3. Targeted Therapy: Not recommended for localized colon cancer but used in metastatic settings based on specific mutations and tumor locations.