Inherited Colorectal Cancer and the Genetics of Colorectal Cancer [Ch 165 SKF]

Overview

• Colorectal cancer (CRC) is a complex, heterogeneous disease influenced by genetic and epigenetic changes.
• Alterations in biological checks and balances can lead to malignant transformation of normal colorectal mucosa.
• Both inherited and sporadic changes affect the genotype and phenotype of CRC and its patients.
• Grouping patients based on underlying cancer pathways aids in disease understanding and precise clinical management.

Genetic Basis of Colorectal Cancer

Multistep Carcinogenesis in Colorectal Cancer

• Cancer is fundamentally a genetic disease resulting from genetic or epigenetic somatic alterations.
• Less than 5% of gastrointestinal (GI) cancers are due to highly penetrant germline mutations, leading to familial GI polyposis or cancer syndromes.
• Tumors in these syndromes follow the same evolutionary paths as sporadic tumors but with:
  • Elevated cancer risk
  • Earlier median age of onset
  • Risk for multiple metachronous tumors

Classes of Genes Involved

1. Proto-oncogenes
   • Activated through mutation, amplification, or chromosomal rearrangement.
2. Tumor Suppressor Genes
   • Inactivated through mutation, chromosomal deletion, or promoter methylation.
3. Genes Maintaining Genomic Stability
   • Dysregulation (usually inactivation) leads to genomic instability and rapid accumulation of mutations.

Pathways of Colorectal Carcinogenesis

Classic Chromosomal Instability (CIN)

• CIN is one of three broad classes of genetic or epigenetic instability in CRC.
• Proposed by Vogelstein in 1990 in the context of multistep carcinogenesis.
• Sequence of Events in CIN Pathway:
  1. Inactivation of the WNT signaling pathway
     • Often through biallelic inactivation of the APC gene.
  2. Activating mutations in growth-stimulating genes (e.g., KRAS, CDC4, PIK3CA).
  3. Disruption of TGF-β signaling (typically via inactivation of SMAD genes).
  4. Mutations and allelic losses of p53 (TP53) gene, leading to chromosomal rearrangement and aneuploidy.
• Over 50% of CRCs develop through this pathway.

Familial Adenomatous Polyposis (FAP) and CIN:

• FAP is closely linked to the CIN pathway.
• Key Concepts:
  • Germline mutation in the APC gene leads to FAP.
  • Loss of the second APC allele over time results in adenoma formation.
  • Median age for first adenoma: 16 years.
  • Median age for cancer development: 39 years.
  • Biallelic APC mutations are embryonically lethal.

CpG Island Methylator Phenotype (CIMP)

• CIMP involves inactivation of tumor suppressor genes through hypermethylation of gene promoters.
• CpG Islands:
  • Clusters of C-G dinucleotide pairs in gene promoters.
  • Hypermethylation leads to gene silencing.
• Characteristics of CIMP:
  • Occurs in about 32% of CRCs.
  • Often associated with a BRAF gene (V600E) mutation.
  • Linked to more aggressive and lethal CRCs.
• Serrated Carcinoma Pathway:
  • Tumors begin as sessile serrated adenomas (SSAs).
  • Predominantly occur in the proximal colon.
• Commonly Methylated Genes:
  • p16, CDKN2A, THBS1, HPP1, MLH1

• Role of MicroRNAs:

  • Silenced by methylation, contributing to carcinogenesis.

  

Microsatellite Instability (MSI)

• The third pathway for colorectal carcinogenesis is a secondary consequence of either CIN (in the setting of Lynch syndrome) or CIMP, and is called “microsatellite instability” or MSI.
• MSI is a consequence of defects in the DNA mismatch repair (MMR) system.
• DNA MMR System:
  • one of these is a S phase monitor
  • Monitors DNA for replication errors , particularly in microsatellites (simple repetitive sequences).
  • Repairs mutations or prevents cell replication when errors are detected.
• Absence of DNA MMR Activity:
  • Leads to a significant increase in errors in microsatellite sequences.
  • 100 fold increase in synthetic errors.
• Circumstances Leading to MSI:
  1. CIMP-Related MSI:
     • Hypermethylation of both alleles of MLH1, a DNA MMR gene.
     • Accounts for about 12% of CRCs.
  2. Lynch Syndrome (Hereditary Nonpolyposis Colorectal Cancer):
     • Germline mutations in DNA MMR genes (MLH1, MSH2, MSH6, PMS2).
     • Represents about 3% of CRCs.
     • Neoplasms may arise from adenomatous polyps developing MSI upon loss of the wild-type allele.
     • Patients are typically 15–20 years younger than other CRC patients.
  3. Lynch-like Syndrome:
     • Biallelic somatic mutations in DNA MMR genes.
     • MSI occurs after initial CIN pathway events.

Clinical Features of MSI Tumors

• CIMP-Related MSI Tumors:
  • Approximately 90% located in the proximal colon.
  • Patients are about 5 years older than those with sporadic CRCs.
• Lynch Syndrome MSI Tumors:
  • Two-thirds occur in the proximal colon.
  • Younger onset compared to sporadic cases.
• Prognosis:
  • Absence of BRAF mutation in MSI tumors is associated with a better prognosis.

Heterogeneity of Colorectal Cancers

• Different "Driver" Mutations:
  • Lead to varied clinical behaviors and tumor characteristics.
• Pathways Contributing to Heterogeneity:
  • Classic CIN Pathway:
    • Seen in FAP with germline APC mutations.
  • MSI Pathway:
    • Present in Lynch Syndrome due to germline mutations in DNA MMR genes.
    • Most MSI CRCs are sporadic, resulting from MLH1 methylation.
  • CIMP Pathway:
    • No known familial form.
• Hamartomatous Polyposis Syndromes:
  • Distinct from FAP and Lynch Syndrome.
  • Involve benign lesions with potential for various cancers due to growth dysregulation.

Recommendations for repeat colonoscopy following endoscopic removal of polyps:

It outlines guidelines based on different index colonoscopy findings and corresponding repeat colonoscopy intervals.

Key Findings and Recommendations:

1. Low-Risk Polyps:
   • Small (<10 mm) hyperplastic polyps in rectum or sigmoid:
     • Repeat colonoscopy in 10 years.
   • One to two small tubular adenomas (<10 mm) with low-grade dysplasia:
     • Repeat colonoscopy in 5–10 years (AGA guidelines) or 10 years (ESGE guidelines).
2. High-Risk Polyps:
   • Villous histology or high-grade dysplasia, or polyps ≥10 mm or ≥3 polyps:
     • Repeat colonoscopy in 3 years.
   • Piecemal removal of polyp:
     • Repeat colonoscopy in 6 months.
3. Sessile Serrated Polyps:
   • Sessile serrated polyp <10 mm:
     • Repeat colonoscopy in 5 years.
   • Sessile serrated polyp ≥10 mm or with dysplasia or traditional serrated adenoma:
     • Repeat colonoscopy in 3 years.

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Inherited Colorectal Cancer Syndromes

Polyposis Syndromes

• Polyposis: Presence of numerous colorectal polyps; defined as more than 100 polyps in one examination.
• Attenuated polyposis (oligopolyposis): 10 to 100 polyps.
• Classification based on:
  • Polyp histology (phenotype)
  • Mutated gene (genotype)

• Management Goals:

  • Prevent death from cancer
  • Maintain adequate quality of life

  

  

Familial Adenomatous Polyposis (FAP)

Epidemiology and Genetics

• Incidence: Approximately 1 in 10,000 live births.
• Prevalence: Varies from 1 in 24,000 to 1 in 60,000.
• Affects all races and genders equally.
• Caused by a germline mutation in the APC gene.
• Leads to a generalized growth disorder with both benign and malignant tumors.
• Expression varies due to genotype and modifying factors like gender.

Diagnosis

• Family history is crucial for diagnosis.
• Genetic testing is typically offered at puberty.
  • Testing in infancy is discouraged unless risk of hepatoblastoma exists.
• About 25% have no family history due to factors like adoption or de novo mutations.
  • These patients often present with symptoms: rectal bleeding, abdominal pain, diarrhea.
  • Higher chance of having colorectal cancer (CRC) at diagnosis.

Initial Evaluation and Management

• Best managed by specialized centers and registries.
• CRC is the main risk and most common cause of death in FAP.
• Prophylactic surgery considerations:
  • Timing depends on severity of polyposis and risk factors (see Table 165.3 in original context).
  • Annual colonoscopy if surgery is deferred.
• Upper GI surveillance starts at 20 to 25 years old.

Timing of Prophylactic Colectomy

• CRC is rare before 20 years old.

• Factors influencing timing:

  • Severity and location of polyps
  • Symptoms
  • Risk of desmoid disease
  • Lifestyle concerns

  

  

Choice of Surgery

• Surgical Options:
  1. Colectomy with Ileorectal Anastomosis (IRA)
     • Retains rectum; requires regular surveillance.
  2. Total Proctocolectomy with Ileal Pouch–Anal Anastomosis (IPAA)
     • Removes colon and rectum; creates ileal pouch.
  3. Total Proctocolectomy with End Ileostomy (TPC-EI)
     • Complete removal; permanent ileostomy.

• Factors Influencing Choice (see Tables 165.4 and 165.5 in original context):

  • Severity of rectal polyposis
  • Patient's age and lifestyle
  • Risk of desmoid disease
  • Desire to eliminate cancer risk entirely

  

  

Postoperative Surveillance

• IRA and IPAA patients require annual surveillance.
  • Rectum or pouch examined for adenomas and cancers.
• End ileostomy stomas should be checked once a year.
• Surveillance includes:
  • Office procedures without sedation
  • Removal of polyps as needed
  • Monitoring for anastomotic issues

Chemoprevention

• Sulindac has been studied extensively.
  • Suppresses colorectal adenomas and desmoid disease.
  • Side effects: GI distress, bleeding, renal effects.
• Not a substitute for surgery.
• May be considered for:
  • Pouch polyposis
  • Duodenal adenomas (in combination with other agents)

Desmoid Disease in FAP

• Occurs in 30% of FAP patients.
• Manifestation of APC mutation.
• Locations:
  • Abdominal wall
  • Small bowel mesentery
  • Retroperitoneum

Risk Factors

• Female gender (twice as likely)
• Family history of desmoids
• Extracolonic manifestations (e.g., Gardner syndrome features)
• Genotype: Mutations beyond codon 1400 linked to severity

Treatment

• No predictably effective treatment.
• Staging system (Table 165.5 in original context) guides management.

• Treatment Options:
  • Sulindac and estrogen-modifying agents for early stages.
  • Chemotherapy (e.g., methotrexate, vinorelbine, doxorubicin) for advanced stages.
  • Surgery reserved for symptom relief or complication prevention.

Upper Gastrointestinal Tract in FAP

• Fundic gland polyps:
  • Present in almost all patients.
  • Usually nonneoplastic but can hide carcinoma.
• Duodenal adenomas:
  • Nearly 100% incidence.
  • Risk of progression to duodenal cancer.

• Surveillance:

  • Starts at 20 to 25 years old.
  • Esophagogastroduodenoscopy (EGD) with side-viewing duodenoscope.
  • Spigelman staging system (Table 165.7 in original context) assesses severity.

  

Other Extracolonic Manifestations

• Gardner Syndrome features:
  • Osteomas, epidermoid cysts, extra teeth
• Thyroid cancer:
  • Increased risk (especially papillary type)
  • Annual thyroid ultrasound recommended
• Adrenal adenomas:
  • Often asymptomatic; monitor if <5 cm
• Turcot Syndrome:
  • Association with brain tumors (e.g., medulloblastoma)
• Hepatoblastoma:
  • Risk in infants; consider screening with ultrasound and alpha-fetoprotein until age 7

Attenuated Familial Adenomatous Polyposis (aFAP)

• Characterized by <100 synchronous colorectal adenomas.
• Later onset of CRC (10–20 years older than classic FAP).
• APC mutations typically at the extremities of the gene.
• Similar risk of upper GI polyposis and desmoid disease as classic FAP.
• Management:
  • Colectomy with IRA is common.
  • Annual colonoscopy may suffice for very mild cases.

MutYH-Associated Polyposis (MAP) and NTHL1-Associated Polyposis (NAP)

Genetics

• Caused by biallelic mutations in MutYH or NTHL1 genes.
• Recessive inheritance pattern.
• Carrier frequency: Approximately 2% in the population.

Clinical Features

• Resembles attenuated FAP.
• Variable presentations:
  • Early or late onset
  • With or without polyposis
  • Family history may be recessive or appear dominant
• CRC risk in biallelic MutYH carriers: Approximately 75%
• Phenotype of NAP is still being defined.

Extracolonic Manifestations

• Similar to FAP:
  • Gastric and duodenal adenomas
  • Small bowel carcinomas
  • Desmoid tumors
  • Thyroid cancer

Clinical Management

• Colonoscopy:
  • High-quality exams with excellent preparation.
  • Remove all adenomas >5 mm.
  • Surveillance intervals based on polyp burden.
• Surgery:
  • Colectomy for uncontrolled polyposis or CRC.
  • Extended colectomy with IRA recommended if CRC is present.
• Extracolonic surveillance:
  • Thyroid ultrasound
  • EGD starting at presentation; repeat every 3–5 years if normal.

Polymerase Proofreading-Associated Polyposis

Genetics

• Caused by germline mutations in POLD1 and POLE genes.
• Affect DNA polymerase proofreading domains.
• Leads to a mutator phenotype with increased replication errors.

Clinical Features

• Dominantly inherited syndrome.
• Characterized by:
  • Oligoadenomatous polyposis
  • Early-onset CRC
  • Endometrial cancer in POLE mutation carriers
• Can present with both microsatellite stable (MSS) and microsatellite unstable (MSI) CRCs.

Clinical Management

• Management tailored to presentation.
• Extended surgery may be considered for early-onset CRC with multiple adenomas.
• Phenotype is still being defined due to the small number of reported families.

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Key Terms:

• Polyposis Syndromes
• Familial Adenomatous Polyposis (FAP)
• Attenuated FAP (aFAP)
• APC Gene Mutation
• Colectomy
• Ileorectal Anastomosis (IRA)
• Ileal Pouch–Anal Anastomosis (IPAA)
• Desmoid Disease
• Gardner Syndrome
• Spigelman Staging System
• MutYH-Associated Polyposis (MAP)
• NTHL1-Associated Polyposis (NAP)
• Polymerase Proofreading-Associated Polyposis
• POLD1 and POLE Genes

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Hamartomatous Polyposis Syndromes

Overview

• Hamartomatous polyps: Benign overgrowths of mature epithelial cells.
• Syndromes include:
  • Juvenile Polyposis Syndrome (JPS)
  • Peutz-Jeghers Syndrome (PJS)
  • PTEN Hamartoma Tumor Syndromes (PHTS)
    • Cowden Syndrome (CS)
    • Bannayan-Riley-Ruvalcaba Syndrome (BRRS)
  • Hereditary Mixed Polyposis Syndrome (HMPS)
• Less than 1% of all colorectal cancers (CRCs) are associated with these syndromes.
• Importance of knowledge:
  • Genetic counseling and testing
  • Assessment of cancer risk
  • Screening recommendations

Juvenile Polyposis Syndrome (JPS)

Diagnosis and Genetics

• Diagnostic criteria:
  • Any juvenile polyp in a patient with a family history of juvenile polyposis.
  • More than 4 synchronous juvenile polyps in the large intestine.
• Polyp distribution:
  • Mostly in the colon and rectum, can also involve the stomach and small intestine.
• Incidence: 1 in 50,000 to 1 in 100,000.
• Genetics:
  • Germline mutations in SMAD4 and BMPR1A genes (TGF-β superfamily).
  • Autosomal dominant inheritance with variable penetrance.
  • 20%–50% have a family history.

Clinical Features

• Polyp growth starts in the first decade of life.
• Number of polyps: Usually between 50 and 200.
• Polyp characteristics:
  • Size: 5–50 mm
  • Appearance: Red to brown, pedunculated, sometimes ulcerated.
  • Histology: Dilated cystic glands, inflammatory infiltrate.
• Polyp distribution:
  • Colorectum: 98%
  • Stomach: 13.6%
  • Small intestine: 6.5%
• Subtypes (Sachatello classification):
  1. Juvenile polyposis of infancy: Entire GI tract affected, poor prognosis.
  2. Juvenile polyposis coli: Polyps limited to colon and rectum.
  3. Generalized juvenile polyposis: Polyps throughout GI tract.
• Symptoms:
  • Rectal bleeding, anemia, abdominal pain, diarrhea, rectal prolapse.
• Extraintestinal anomalies:
  • Macrocephaly, cardiac anomalies, telangiectasia, among others.

Genotype-Phenotype Correlations

• SMAD4 mutations:
  • Associated with generalized JPS.
  • Higher risk of upper GI polyps.
  • Linked to hereditary hemorrhagic telangiectasia (HHT).
• BMPR1A mutations:
  • More likely to present with juvenile polyposis coli.

Malignant Potential

• Increased risk of colorectal cancer (CRC) and other GI cancers.
• Mean age of cancer diagnosis: Around 35 years.
• Sequence of progression:
  • Hamartoma → Adenoma → Dysplasia → Carcinoma.
• Dysplasia prevalence:
  • Higher in multilobulated or villous polyps (47%).

Clinical Management

Screening and Surveillance

• Genetic testing for known mutations.
• Colonoscopy:
  • Start at age 12–15.
  • Repeat every 2–3 years if no polyps; annually if polyps are present.
• Upper GI screening:
  • Esophagogastroduodenoscopy (EGD) starting between 15–25 years.

Surgical Management

• Indications:
  • Symptomatic patients (bleeding, anemia, failure to thrive).
  • Dysplasia or cancer detected.
  • Multiple polyps not manageable endoscopically.
• Procedures:
  • Colectomy with ileorectal anastomosis (IRA) if rectum is manageable.
  • Total proctocolectomy if extensive disease.
• Postoperative Surveillance:
  • Continued upper and lower GI examinations.
  • Polypectomy for residual or new polyps.

Peutz-Jeghers Syndrome (PJS)

Diagnosis and Genetics

• Diagnostic criteria:
  • ≥2 Peutz-Jeghers polyps.
  • One polyp with a family history or mucocutaneous pigmentation.
• Inheritance: Autosomal dominant.
• Incidence: 1 in 120,000 live births.
• Genetics:
  • Mutations in STK11 (LKB1) gene on chromosome 19.
  • Found in up to 69% of individuals.

Clinical Features

• Hamartomatous polyps:
  • Can occur anywhere; most common in the small intestine (>75%).
• Mucocutaneous pigmentation:
  • Present in >95% of patients.
  • Common sites: Lips, perioral area, hands, feet, buccal mucosa.
• Symptoms:
  • Abdominal pain, distension.
  • Intussusception leading to small bowel obstruction.
  • GI bleeding, anemia.

Risk of Cancer

• High lifetime risk of various cancers (up to 93% by age 65).
• GI cancers:
  • Colon: 39%
  • Pancreas: 36%
  • Stomach: 29%
  • Small bowel: 13%
• Non-GI cancers:
  • Breast: 54%
  • Ovary: 21%
  • Lung: 15%
  • Uterus: 9%
• Unique tumors:
  • Adenoma malignum of the cervix.
  • Sex cord tumors with annular tubules (SCTAT).
  • Large cell calcifying Sertoli cell tumors in testes.

Clinical Management

• Surveillance:
  • Upper GI endoscopy, small bowel evaluation, and colonoscopy.
  • Begin upper GI and small bowel exams at age 10 years.
  • Colonoscopy every 2–3 years starting at age 25.
• Polyp Management:
  • Endoscopic polypectomy for polyps >1 cm.
  • Intraoperative endoscopy for small bowel polyp removal.
  • Use of capsule endoscopy for small bowel screening.
• Extraintestinal Screening (NCCN recommendations):
  • Testicular exams annually from age 10.
  • Pelvic exams and Pap smears for women starting at 18–20.
  • Breast screening with exams, mammograms, and MRI from age 25.
  • Pancreatic cancer screening with imaging and CA19-9 levels starting at 25–30.

PTEN Hamartoma Tumor Syndromes (PHTS)

Overview

• Includes:
  • Cowden Syndrome (CS)
  • Bannayan-Riley-Ruvalcaba Syndrome (BRRS)
• Genetics:
  • Mutations in the PTEN gene (tumor suppressor in the PI3K/AKT pathway).
  • Autosomal dominant inheritance.
  • PTEN mutations in ~80% of CS and ~60% of BRRS patients.

Cowden Syndrome (CS)

Clinical Features

• Multiple hamartomas and increased risk of benign and malignant tumors.
• Diagnostic criteria (International Cowden Consortium):
  • Major criteria: Breast cancer, thyroid cancer (follicular), macrocephaly, endometrial cancer, Lhermitte-Duclos disease.
  • Minor criteria: Benign thyroid disease, mental retardation, hamartomatous polyps, lipomas, fibromas.
• Common features:
  • Skin lesions: Trichilemmomas, papillomatous papules.
  • Macrocephaly
• Colorectal polyps:
  • Varied histology: Hamartomas, adenomas, serrated polyps, ganglioneuromas.
• Cancer Risks:
  • Breast cancer: 50% lifetime risk.
  • Endometrial cancer: 5%–10% lifetime risk.
  • Thyroid cancer: 10% lifetime risk.
  • Increased risk of CRC (9%–16% lifetime risk).

Clinical Management

• Surveillance recommendations:
  • Physical exam starting at age 18.
  • Breast screening with exams, mammograms, and MRI from age 30.
  • Thyroid ultrasound every 1–2 years from age 18.
  • Colonoscopy starting at age 20, every 1–3 years.
  • EGD starting at age 30, every 3–5 years.
  • Endometrial cancer screening from age 35–40.
  • Dermatologic exams for melanoma screening.

Bannayan-Riley-Ruvalcaba Syndrome (BRRS)

Clinical Features

• Characteristics:
  • Macrocephaly
  • Hamartomatous polyps in the colon
  • Lipomas
  • Pigmented penile macules
• Other features:
  • Hashimoto thyroiditis
  • Vascular malformations
  • Mental retardation
• Cancer Risk:
  • Less well-defined; surgery for CRC is rare.
• Management:
  • Similar surveillance as CS due to polyp burden.

Hereditary Mixed Polyposis Syndrome (HMPS)

Overview

• Autosomal dominant inheritance.
• Polyps with mixed histology:
  • Adenomas
  • Serrated polyps
  • Juvenile hamartomas
• Increased CRC risk.
• Genetics:
  • Mutation in the GREM1 gene.
• Initial reports in Ashkenazi Jewish families.

Clinical Management

• Goal: Control CRC risk with minimal invasiveness.
• Management:
  • Colonoscopy and polypectomy.
  • Extended resection if cancer is diagnosed.
• Surveillance:
  • Regular colonoscopic exams due to CRC risk.

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Key Terms:

• Hamartomatous Polyps
• Juvenile Polyposis Syndrome (JPS)
• SMAD4 and BMPR1A Genes
• Hereditary Hemorrhagic Telangiectasia (HHT)
• Peutz-Jeghers Syndrome (PJS)
• STK11 (LKB1) Gene
• Mucocutaneous Pigmentation
• PTEN Hamartoma Tumor Syndromes (PHTS)
• Cowden Syndrome (CS)
• Bannayan-Riley-Ruvalcaba Syndrome (BRRS)
• PTEN Gene
• Hereditary Mixed Polyposis Syndrome (HMPS)
• GREM1 Gene

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Nonpolyposis Colorectal Cancer

Overview

• Nonpolyposis colorectal cancer syndromes were introduced to distinguish from polyposis syndromes.
• Historically called Hereditary Nonpolyposis Colorectal Cancer (HNPCC).
• HNPCC is a clinical diagnosis based on the Amsterdam II criteria.

Amsterdam II Criteria

To fulfill the criteria:

1. At least three relatives with an HNPCC-associated cancer:
   • Cancers include: colorectum, endometrium, ovaries, small bowel, stomach, ureter or renal pelvis, pancreas, brain, skin.
2. One should be a first-degree relative of the other two.
3. At least two successive generations should be affected.
4. At least one cancer diagnosed before age 50.
5. Familial Adenomatous Polyposis (FAP) is excluded.
6. Patients with a germline mutation in one of the Mismatch Repair (MMR) genes are defined as having Lynch syndrome, regardless of family history.
7. Approximately 93% of patients with Lynch syndrome have microsatellite unstable (MSI-H) tumors.
8. Patients meeting Amsterdam criteria but with microsatellite stable (MSS) tumors are diagnosed with Familial Colorectal Cancer Type X (FCC X).
9. 50% of patients with Lynch syndrome do not meet Amsterdam criteria.
10. Lynch-like syndrome refers to patients with MSI-H tumors and loss of MMR protein expression but no identifiable MMR gene germline defect.
11. Each classification has unique risk profiles and different management recommendations.

Bethesda Criteria for Testing Colorectal Tumors for MSI:

1. Colorectal cancer diagnosed in a patient before age 50.
2. Presence of synchronous/metachronous colorectal or other HNPCC-related tumors (including endometrial, stomach, ovarian, pancreas, ureter and renal pelvis, biliary tract, brain, sebaceous gland adenomas, and keratoacanthomas, or carcinoma of the small bowel), regardless of age.
3. Colorectal cancer with 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 a 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.

Lynch Syndrome

Definition and Genetics

• Lynch syndrome is caused by a germline mutation in one of the MMR genes:
  • MLH1
  • MSH2
  • MSH6
  • PMS2
• Also caused by germline deletions of EPCAM.
• Autosomal dominant inheritance.
• Accounts for approximately 3% of all CRCs and 10%–19% of CRCs diagnosed before age 50.
• First-degree relatives have a 50% chance of carrying the mutation.

Screening and Diagnosis

• Use of Amsterdam criteria and Bethesda criteria to identify at-risk patients.
• Histologic features associated with Lynch syndrome:
  • Poor differentiation
  • Signet cell histology
  • Extracellular mucin
  • Tumor-infiltrating lymphocytes
  • Lymphoid host response
• These features should prompt testing for Microsatellite Instability (MSI) or MMR protein expression via Immunohistochemistry (IHC).
• Lynch syndrome-associated CRC:
  • Up to 91% exhibit MSI-H.
  • Approximately 83% show loss of one MMR protein.
• Universal screening of all CRCs is recommended:
  • EGAPP Working Group: All newly diagnosed CRCs should undergo MSI and/or IHC testing.
  • NCCN: Universal screening for all CRCs under age 70 and those over 70 meeting Bethesda guidelines.
• MLH1 loss requires further analysis:
  • BRAF mutation and/or MLH1 promoter methylation testing.
  • Presence of BRAF mutation or MLH1 methylation suggests a sporadic MSI-H cancer.
• Loss of MSH2, MSH6, or PMS2 suggests Lynch syndrome and warrants germline testing.
• Predictive models (e.g., PREMM1,2,6, MMRpro) can aid in risk assessment.

Cancer Risks

Colorectal Cancer Risk

• Lifetime risk varies by gene:
  • MLH1, MSH2, PMS2: 30%–74%
  • MSH6: 10%–22%
• Mean age at diagnosis: 44–61 years

Extracolonic Cancer Risks

• Endometrial cancer:
  • Highest extracolonic risk.
  • Up to 44% in women with MSH2 and MSH6 mutations.
  • PMS2 mutation carriers: 15%–20% lifetime risk.
  • Mean age at diagnosis: 48–62 years
• Synchronous endometrial and ovarian cancers in 7%–21% of women.
• Other increased cancer risks:
  • Urinary tract
  • Stomach
  • Small bowel
  • Brain
  • Skin
  • Pancreas
  • Prostate
  • Breast
• Prostate and breast cancer risks are still under study.

Clinical Management

Surveillance

• Colonoscopy:
  • Reduces CRC incidence by 62% and mortality by 72%.
  • Recommended every 1–2 years starting at age 20–25.
• Endometrial cancer screening:
  • Annual pelvic exam, transvaginal ultrasound, and endometrial biopsy.
  • Awareness of symptoms like abnormal bleeding or pelvic pain.
  • Consider prophylactic hysterectomy and bilateral salpingo-oophorectomy after childbearing.
• Screening for other cancers:
  • Urinalysis and cytology for urothelial cancers.
  • Upper endoscopy for gastric and small bowel cancers (evidence for cost-effectiveness lacking).
  • Annual or biannual dermatologic exams for skin neoplasms.

Chemoprevention

• CAPP2 Trial:
  • 600 mg aspirin daily for at least 2 years reduced CRC incidence by 60% after 10 years.
  • Reduced other Lynch-associated cancers by 55%.
• Current recommendations:
  • Routine use of high-dose aspirin not yet established.
  • CAPP3 Trial ongoing to determine optimal dose and duration.

Surgical Management for Colorectal Cancer

• Extended resection recommended due to high risk of metachronous CRC.
  • Total colectomy with ileorectal anastomosis (IRA) preferred.
• Metachronous CRC risk after surgery:
  • Segmental colectomy: 16% at 10 years, 41% at 20 years, 62% at 30 years.
  • Colectomy and IRA: 3%–12% risk of rectal cancer at 10–12 years.
• Surveillance of remaining rectum:
  • Annual flexible proctoscopy recommended.
• Balancing surgery and quality of life:
  • Extended colectomy may result in higher stool frequency and social impact but similar quality of life.
  • Patient counseling is essential to make informed decisions.

Rectal Cancer Management

• Options:
  1. Proctectomy (LAR or APR)
  2. Total proctocolectomy (TPC) with:
     • End ileostomy (EI)
     • Ileal pouch–anal anastomosis (IPAA)
• Metachronous colon cancer risk after proctectomy:
  • 19% at 10 years
  • 47% at 20 years
  • 69% at 30 years
• Functional outcomes:
  • TPC with IPAA may affect bowel function.
  • IPAA can have good functional results.
• Recommendation:
  • Many experts favor TPC with IPAA for rectal cancer in Lynch syndrome.

Variations of Lynch Syndrome

Muir-Torre Syndrome

• Characteristics:
  • Skin sebaceous gland neoplasms (adenomas and carcinomas)
  • Hair follicle neoplasms (keratoacanthomas)
  • Associated with other Lynch-associated tumors.
• Genetics:
  • Most commonly associated with MSH2 mutation.
• Clinical note:
  • Presence of sebaceous adenomas should prompt evaluation for Muir-Torre syndrome.

Turcot Syndrome

• Characteristics:
  • Combination of CRC and brain tumors.
• Genetics:
  • Can be associated with MMR gene mutations (Lynch syndrome) or APC mutations.
• Associations:
  • MMR mutations: Commonly linked to glioblastoma.
  • APC mutations: Linked to anaplastic astrocytoma, ependymoma, or medulloblastoma.

Constitutional Mismatch Repair Deficiency (CMMRD)

• Cause:
  • Biallelic inheritance of MMR gene mutations.
• Clinical features:
  • CRC at very young ages (before 20 years)
  • Multiple adenomatous polyps (10–100)
  • Café-au-lait skin lesions
  • Hematologic malignancies
  • Brain tumors
• Mean age of first cancer diagnosis: 16 years

Familial Colorectal Cancer Type X (FCC X)

• Definition:
  • Patients meeting Amsterdam criteria but with MSS tumors and no MMR gene mutation.
• Prevalence:
  • 40% of patients meeting Amsterdam I criteria.
• Cancer risk:
  • Twofold increased CRC risk compared to general population.
  • Mean age at diagnosis: 61 years
• Management:
  • Colonoscopy starting at age 45, or 10 years younger than youngest case in family.
  • Repeat colonoscopy every 5 years if normal.
  • Segmental colectomy recommended for CRC.
• Extracolonic cancers:
  • No increased risk; extracolonic screening not recommended.

Lynch-like Syndrome (Tumor-Lynch)

• Definition:
  • Patients with MSI-H tumors and MMR protein deficiency but no germline mutation found.
• Possible causes:
  • Biallelic somatic mutations within the tumor (up to 69% of cases).
• Cancer risk:
  • Do not have Lynch syndrome; no increased genetic risk for individual or family.
• Management:
  • Based on family history and other risk factors.
  • If Lynch syndrome cannot be excluded, manage as Lynch syndrome, especially with suspicious family history.
• Current status:
  • 50% of cases remain undefined.
  • Ongoing research to clarify risk assessments.

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Key Terms:

• Hereditary Nonpolyposis Colorectal Cancer (HNPCC)
• Amsterdam II Criteria
• Lynch Syndrome
• Mismatch Repair (MMR) Genes: MLH1, MSH2, MSH6, PMS2
• Microsatellite Instability (MSI-H)
• Familial Colorectal Cancer Type X (FCC X)
• Lynch-like Syndrome (Tumor-Lynch)
• Colonoscopy Surveillance
• CAPP2 Trial
• Total Colectomy with Ileorectal Anastomosis (IRA)
• Proctectomy
• Ileal Pouch–Anal Anastomosis (IPAA)
• Muir-Torre Syndrome
• Turcot Syndrome
• Constitutional Mismatch Repair Deficiency (CMMRD)

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Screening protocols for colorectal cancer (CRC)

Pathology/Syndrome	Screening Protocol
Familial Adenomatous Polyposis (FAP)	**- Annual colonoscopy starting in late adolescence.
- Upper GI surveillance begins at age 20–25 years.**
Attenuated FAP (aFAP)	**- Annual colonoscopy may suffice for very mild cases.
- Upper GI surveillance starting at age 20–25 years.**
MutYH-Associated Polyposis (MAP)	**- High-quality colonoscopy with adenoma removal.
- Surveillance intervals based on polyp burden.**
NTHL1-Associated Polyposis (NAP)	**- Colonoscopy starting at presentation.
- EGD starting at presentation, repeated every 3–5 years if normal.**
Peutz-Jeghers Syndrome (PJS)	**- Colonoscopy every 2–3 years starting at age 25.
- Upper GI and small bowel exams starting at age 10 years.**
Juvenile Polyposis Syndrome (JPS)	**- Colonoscopy starting at age 12–15.
- Upper GI screening with EGD starting between age 15–25 years.**
Cowden Syndrome (CS)	**- Colonoscopy starting at age 20, repeated every 1–3 years.
- EGD starting at age 30, repeated every 3–5 years.**
Bannayan-Riley-Ruvalcaba Syndrome (BRRS)	**- Similar to Cowden Syndrome: Colonoscopy every 1–3 years starting at age 20.
- Upper GI screening as needed.**
Lynch Syndrome (Hereditary Nonpolyposis CRC)	**- Colonoscopy every 1–2 years starting at age 20–25.
- Endometrial cancer screening annually.**
Hereditary Mixed Polyposis Syndrome (HMPS)	**- Regular colonoscopic exams.
- Polypectomy for polyp control.**
Lynch-like Syndrome	- Management based on family history and other risk factors; colonoscopy as appropriate.
Constitutional Mismatch Repair Deficiency (CMMRD)	**- Colonoscopy starting very early, before age 20.
- Surveillance for extracolonic malignancies.**

Screening protocols for other pathologies (non-colonoscopy-related)

Pathology/Syndrome	Screening Protocol (Non-Colonoscopy)
Familial Adenomatous Polyposis (FAP)	- Upper GI surveillance with EGD starting at age 20–25.
- Annual thyroid ultrasound to monitor for thyroid cancer.
Attenuated FAP (aFAP)	- Upper GI surveillance starting at age 20–25.
- Thyroid ultrasound annually for thyroid cancer risk.
MutYH-Associated Polyposis (MAP)	- EGD starting at presentation, repeated every 3–5 years if normal.
- Thyroid ultrasound annually.
Peutz-Jeghers Syndrome (PJS)	- Upper GI and small bowel screening starting at age 10 years.
- Breast screening with mammograms and MRIs starting at age 25.
- Pancreatic cancer screening with imaging and CA19-9 levels starting at age 25–30.
- Pelvic exams and Pap smears annually starting at age 18–20.
Juvenile Polyposis Syndrome (JPS)	- Upper GI screening with EGD starting between ages 15–25 years.
Cowden Syndrome (CS)	- Breast screening with mammograms and MRIs starting at age 30.
- Thyroid ultrasound every 1–2 years starting at age 18.
- Endometrial cancer screening starting at age 35–40.
Bannayan-Riley-Ruvalcaba Syndrome (BRRS)	- Thyroid ultrasound as needed due to similar recommendations as Cowden Syndrome.
- Breast screening starting at age 30.
Lynch Syndrome (Hereditary Nonpolyposis CRC)	- Endometrial cancer screening with annual pelvic exams, transvaginal ultrasound, and endometrial biopsy.
- Screening for urothelial cancers with annual urinalysis and cytology.
- Dermatologic exams annually or biannually for skin neoplasms.
- Upper endoscopy for gastric and small bowel cancers (based on clinical judgment).
Hereditary Mixed Polyposis Syndrome (HMPS)	- No specific non-colonoscopy-related screening provided beyond regular colonoscopic exams.
Constitutional Mismatch Repair Deficiency (CMMRD)	- Surveillance for extracolonic malignancies including skin lesions and brain tumors.

This table provides a summary of screening protocols for pathologies other than colonoscopy, highlighting upper GI, thyroid, breast, endometrial, and other specific screenings based on different hereditary syndromes associated with colorectal cancer.

Comparison of Polyp Histology in Colorectal Cancer Syndromes

Syndrome	Polyp Histology	Additional Features
Familial Adenomatous Polyposis (FAP)	- Numerous adenomatous polyps in the colon and rectum.
- Polyps are typically adenomas with a high risk of malignant transformation.
- Polyps can be more than 1000 in number.	- Polyps develop in teenage years.
- Median age for first adenoma: 16 years.
- Median age for cancer development: 39 years.
Attenuated FAP (aFAP)	- Fewer adenomatous polyps (<100 synchronous polyps).
- Polyps are similar histologically to those in classic FAP but fewer in number.	- Later onset of polyps and CRC (10–20 years later than classic FAP).
- Increased risk of upper GI polyposis and desmoid tumors.
MUTYH-Associated Polyposis (MAP)	- Adenomas, can include serrated polyps.
- Phenotypically resembles attenuated FAP with fewer than 100 polyps.
- Polyps may have features of both adenomatous and serrated histology.	- Recessive inheritance pattern.
- Variable presentations: early or late onset.
- Increased risk of CRC (~75% in biallelic carriers).
Juvenile Polyposis Syndrome (JPS)	- Juvenile polyps characterized by:
- Dilated cystic glands lined by tall columnar epithelium.
- Expanded lamina propria with an inflammatory infiltrate (neutrophils, eosinophils, lymphocytes).
- Large mucus-filled spaces.	- Polyps are 5–50 mm, red to brown, spherical or lobulated, often pedunculated.
- Polyps distributed throughout the GI tract, mostly colon.
Peutz-Jeghers Syndrome (PJS)	- Peutz-Jeghers polyps characterized by:
- Smooth muscle bundles within the lamina propria of the stalk and head of the polyp. - Lack of dilated cystic spaces seen in juvenile polyps.	- Polyps can arise anywhere in the GI tract, most common in the small intestine (>75%).
- Associated with mucocutaneous pigmentation.
Cowden Syndrome (CS)	- Variety of polyp histologies including:
- Hamartomas.
- Serrated or hyperplastic polyps.
- Inflammatory polyps.
- Adenomas.
- Ganglioneuromas.	- Polyps can be numerous but rarely carpet the colon.
- Associated with other manifestations like skin lesions and macrocephaly.
Bannayan-Riley-Ruvalcaba Syndrome (BRRS)	- Juvenile polyps, which may contain adenomatous dysplasia.
- Polyps develop early in life.
- Similar histology to juvenile polyps in JPS.	- Features include macrocephaly, lipomas, and pigmented macules of the glans penis.
- Possible adenomatous changes within polyps.
Hereditary Mixed Polyposis Syndrome (HMPS)	- Multiple polyp histologies within the same colon, including: - Adenomas.
- Serrated polyps.
- Juvenile hamartomas.	- Typically less than 15 polyps.
- Increased risk for CRC.
- Initially reported in Ashkenazi Jewish families.

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Notes:

• FAP polyps are adenomatous and numerous, leading to a high risk of CRC at a young age.
• aFAP presents with fewer adenomatous polyps and a later onset of CRC.
• MAP polyps are adenomatous, may include serrated features, and resemble aFAP phenotypically.
• JPS polyps are juvenile hamartomatous polyps with characteristic cystic gland dilation and inflammatory infiltrate.
• PJS polyps are hamartomatous with smooth muscle core, distinct from juvenile polyps, and commonly found in the small intestine.
• CS polyps have varied histology, including hamartomas and adenomas, and are associated with PTEN mutations.
• BRRS features juvenile polyps that may show adenomatous dysplasia, developing early in life.
• HMPS is characterized by mixed polyp types within the same colon, increasing CRC risk.