Eduovisual
Gastrointestinal
Hereditary colorectal cancer syndromes: Lynch and FAP
— Autosomal dominant defect in DNA mismatch repair (MMR): MLH1, MSH2, MSH6, PMS2, or EPCAM deletion silencing MSH2
— Causes microsatellite instability-high (MSI-H) tumors
— Lifetime CRC risk 20–80%; mean age at diagnosis ~45; right-sided predominance, mucinous/poorly differentiated histology, often synchronous/metachronous cancers
— Extracolonic risks: endometrial (highest in women, ~40–60%), ovarian, gastric, small bowel, urothelial (ureter/renal pelvis), pancreatobiliary, brain (Turcot variant with glioblastoma), sebaceous neoplasms (Muir-Torre)
— Autosomal dominant APC gene mutation (chromosome 5q21)
— Hundreds to thousands of adenomas by adolescence; 100% CRC risk by age ~40 if untreated
— Attenuated FAP (AFAP): <100 polyps, later onset (~50s), still high lifetime risk
— Extracolonic: duodenal/periampullary adenomas, gastric fundic gland polyps, desmoid tumors, osteomas, CHRPE (congenital hypertrophy of retinal pigment epithelium), thyroid (papillary), hepatoblastoma in children, medulloblastoma (Turcot)
— Patient <50 with CRC, or any CRC with MSI-H/dMMR on tumor testing
— Multiple primary cancers in one patient (CRC + endometrial)
— Strong family history meeting Amsterdam II (3 relatives, 2 generations, 1 <50) or revised Bethesda criteria
— Florid polyposis on screening colonoscopy
Board pearl: Universal tumor MMR/MSI testing is now recommended on every newly diagnosed CRC regardless of age — a key Step 3 systems-based practice point that drives downstream germline testing and cascade screening of relatives.
— Healthy 40-something with iron-deficiency anemia, hematochezia, or change in bowel habits → colonoscopy reveals right-sided CRC
— Woman in her 40s–50s with postmenopausal or abnormal uterine bleeding found to have endometrial cancer; family history reveals colon cancers — endometrial is often the sentinel cancer in Lynch women
— Personal history of two Lynch-spectrum cancers (e.g., colon at 42, ureteral at 55)
— Family pedigree: multiple relatives across ≥2 generations with CRC/endometrial/ovarian/gastric/urothelial cancers
— Adolescent or young adult with hematochezia, anemia, abdominal pain, or incidentally found polyps; sibling/parent with known FAP
— Asymptomatic teen referred for screening because a parent carries APC mutation
— Adult with desmoid tumor of mesentery or abdominal wall, especially post-laparotomy
— Child with hepatoblastoma (rare but classic association)
— Three-generation pedigree: ages of cancer diagnosis, tumor types, ethnicity (Ashkenazi Jewish → I1307K APC variant)
— Prior polyp counts and pathology
— Symptoms of extracolonic disease: hematuria (urothelial), bleeding (gastric/duodenal), neuro symptoms (Turcot)
— Reproductive history in women — endometrial/ovarian screening implications
— Aspirin/NSAID use (CAPP2 trial: aspirin reduces Lynch CRC)
Key distinction: Lynch tumors arise from few but rapidly progressing adenomas via accelerated carcinogenesis (3–5 yr adenoma-to-cancer, vs 10 yr sporadic), whereas FAP produces an overwhelming polyp burden where the issue is sheer numbers, not speed. This explains why Lynch screening intervals are short (1–2 yr) despite "normal-looking" colons, while FAP demands eventual colectomy because endoscopic control becomes impossible.
— Exam is usually unremarkable; this is a "pedigree disease"
— Muir-Torre variant: sebaceous adenomas, sebaceous carcinomas, keratoacanthomas — palpable yellowish facial/trunk papules
— Café-au-lait macules and hematologic malignancies in constitutional MMR deficiency (CMMRD), biallelic — pediatric presentation
— Abdominal exam: occasionally a right-sided mass; rectal exam typically normal
— Congenital hypertrophy of retinal pigment epithelium (CHRPE) — pigmented fundus lesions on dilated eye exam; bilateral/multiple lesions are highly suggestive
— Osteomas: bony hard masses on mandible, skull, long bones — palpable
— Epidermoid/sebaceous cysts on skin, often before puberty
— Supernumerary or unerupted teeth, odontomas on dental panoramic film
— Desmoid tumors: firm, fixed abdominal wall or mesenteric masses, often post-surgical
— Gardner syndrome = FAP + osteomas + soft tissue tumors + dental anomalies (modern classification: all part of FAP spectrum)
— Turcot syndrome: FAP or Lynch + CNS tumor (medulloblastoma with APC; glioblastoma with MMR)
— Thyroid exam: cribriform-morular variant of papillary thyroid cancer — young women with FAP, palpable nodule
— Tachycardia, orthostasis from chronic GI blood loss
— Cachexia, supraclavicular adenopathy (Virchow), umbilical nodule (Sister Mary Joseph) in advanced disease
— Hepatomegaly/ascites suggest metastatic spread
Board pearl: A young adult with mandibular osteoma + epidermoid cyst + hundreds of colon polyps is the classic Gardner/FAP triad — recognize and proceed to APC germline testing plus colonoscopic confirmation. Always do a dilated eye exam looking for CHRPE in suspected FAP probands — cheap, specific, and exam-favored.
— CBC (iron-deficiency anemia), CMP (LFTs for hepatic mets), CEA as baseline tumor marker (not for screening)
— Iron studies, ferritin
— Coags if planning procedures
— Universal screening of every newly diagnosed CRC (and endometrial cancer) with either:
— IHC for MMR proteins (MLH1, MSH2, MSH6, PMS2) — loss of staining indicates dMMR
— MSI testing by PCR/NGS — MSI-H pattern
— If MLH1 loss on IHC → reflex to BRAF V600E mutation and/or MLH1 promoter hypermethylation
— Positive BRAF/methylation → likely sporadic MSI tumor (no Lynch)
— Negative → proceed to germline MMR gene testing
— MSH2, MSH6, PMS2 loss → go directly to germline testing (BRAF/methylation not informative)
— Contrast CT chest/abdomen/pelvis for CRC staging
— Pelvic MRI for rectal cancers
— PET selectively
— Lynch: typically few polyps, right-sided cancer, tumor-infiltrating lymphocytes, mucinous/signet ring/medullary histology, Crohn-like reaction
— FAP: carpet of >100 adenomas; AFAP: 10–100, right-sided predominance
— Multigene panel (APC, MUTYH, MLH1/MSH2/MSH6/PMS2/EPCAM, plus polyposis genes)
— Pre- and post-test genetic counseling required — Step 3 ethics/systems point
Step 3 management: When a 38-year-old has right-sided CRC with IHC showing loss of MSH2/MSH6, the next best step is germline MMR gene testing with genetic counseling — not BRAF testing (that's only useful when MLH1 is lost). Recognize this branch point.
— Blood or buccal sample for next-generation sequencing panel covering APC, MUTYH (biallelic = MUTYH-associated polyposis), MMR genes, EPCAM, plus emerging genes (POLE, POLD1, NTHL1)
— Cascade testing: once a pathogenic variant is identified in proband, first-degree relatives offered targeted single-site testing
— Variants of uncertain significance (VUS) should not drive clinical action — manage by phenotype
— Amsterdam II for Lynch (3-2-1 rule): ≥3 relatives with Lynch-associated cancer, spanning ≥2 generations, ≥1 diagnosed <50, one a first-degree relative of the other two, FAP excluded, tumors verified
— Revised Bethesda guidelines: triggers for tumor MSI testing — CRC <50, synchronous/metachronous Lynch tumors, MSI histology <60, family history
— Modern practice: universal tumor testing has largely replaced Bethesda
— Clinical: >100 colorectal adenomas or fewer adenomas with APC mutation/family history
— AFAP: 10–99 adenomas, often right-sided, later onset
— MUTYH-associated polyposis (MAP): autosomal recessive, biallelic MUTYH mutations, 10–100 polyps, mimics AFAP — test MUTYH if APC negative
— Upper endoscopy with side-viewing duodenoscope for Spigelman staging of duodenal polyposis in FAP
— Capsule/CT enterography for small bowel in Lynch
— Transvaginal ultrasound + endometrial biopsy considered for Lynch women
Board pearl: A patient with 20 colonic adenomas, negative APC, autosomal recessive family pattern points to MUTYH-associated polyposis — confirm with biallelic MUTYH testing. Don't anchor on FAP just because there are polyps.
— Colonoscopy every 1–2 years starting age 20–25 (or 2–5 yr before earliest family CRC)
— Polypectomy of all adenomas; subtotal/total colectomy with ileorectal anastomosis considered if cancer develops or polyps unmanageable, balanced against quality of life
— Endometrial/ovarian: discuss risk-reducing hysterectomy + BSO after childbearing complete (~age 40), especially MLH1/MSH2/EPCAM carriers
— Annual urinalysis from age 30–35 (MSH2 carriers especially) for urothelial cancer
— EGD with duodenal exam every 3–5 yr from age 40
— Daily aspirin (CAPP2 trial): 600 mg/day reduced Lynch CRC; current practice uses lower dose (~100 mg) — discuss as chemoprevention
— Annual flexible sigmoidoscopy/colonoscopy starting age 10–15 in known carriers
— Prophylactic colectomy when polyp burden becomes unmanageable or high-grade dysplasia/cancer appears — typically late teens to early 20s
— Total proctocolectomy with ileal pouch–anal anastomosis (IPAA) if dense rectal polyposis
— Total abdominal colectomy with ileorectal anastomosis (IRA) if rectum sparing — easier QOL, but requires lifelong rectal surveillance every 6–12 mo
— Upper endoscopy every 1–4 yr by Spigelman stage starting age 20–25
— Annual thyroid ultrasound from late teens
— Abdominal exam/imaging for desmoids
Step 3 management: A 19-year-old FAP carrier with >1000 adenomas and high-grade dysplasia in the rectum should undergo total proctocolectomy with IPAA, not endoscopic management — the next best step is surgical referral, not "repeat colonoscopy in 6 months."
— CAPP2 trial: 600 mg daily for ≥2 years reduced CRC incidence by ~50% over 10-yr follow-up
— Current guidance: consider daily aspirin (typical 75–325 mg) in Lynch carriers, individualized for bleeding risk
— Discuss as shared decision-making — not yet universally mandated
— Sulindac and celecoxib historically shrink adenomas; do not replace colectomy
— Adjunctive role: control rectal polyps after IRA, manage duodenal polyposis, control desmoid tumors
— Celecoxib FDA approval for FAP was withdrawn; sulindac still used off-label
— Monitor for GI bleeding, renal injury, cardiovascular risk
— First-line for symptomatic/progressive desmoids: sulindac ± tamoxifen/toremifene
— Refractory: tyrosine kinase inhibitors (sorafenib), low-dose chemotherapy (methotrexate + vinblastine), or nirogacestat (gamma-secretase inhibitor, newer)
— Surgery often avoided — desmoids recur and worsen with trauma
— Stage II MSI-H tumors: do NOT benefit from 5-FU monotherapy — generally observe
— Stage III/IV: standard FOLFOX, plus immune checkpoint inhibitors (pembrolizumab, nivolumab ± ipilimumab) are highly effective in dMMR/MSI-H metastatic CRC — frontline pembrolizumab is now standard
— Combined OCPs and progestin IUDs reduce endometrial cancer risk in Lynch women
Board pearl: A patient with metastatic CRC and dMMR/MSI-H tumor — first-line systemic therapy is pembrolizumab, not FOLFOX. This is a high-yield Step 3/oncology integration point reflecting current NCCN/FDA guidance.
— Segmental colectomy vs extended (subtotal) colectomy with ileorectal anastomosis — extended resection reduces metachronous CRC risk but with more bowel-function impact
— Shared decision-making considering age, function, fertility, surveillance feasibility
— Rectal cancer in Lynch: proctectomy + total abdominal colectomy (or proctocolectomy) often favored over isolated proctectomy
— Women: concomitant prophylactic hysterectomy + BSO if post-childbearing
— Total proctocolectomy with IPAA: gold standard when rectal polyposis is dense; eliminates CRC risk in colon/rectum but pouch surveillance still required (pouch adenomas develop)
— Total abdominal colectomy with ileorectal anastomosis (IRA): preserved rectum allows better continence/fertility but lifetime rectal surveillance every 6–12 mo; eventual completion proctectomy if rectum becomes unmanageable
— Timing: usually late teens / once polyp burden unmanageable, before cancer develops
— Spigelman staging: number, size, histology, dysplasia of duodenal polyps
— Stage IV or high-grade dysplasia → pancreas-sparing duodenectomy or pancreaticoduodenectomy
— Endoscopic ampullectomy for focal lesions
— Generally avoided — high recurrence, may worsen disease — except life-threatening obstruction
— High-definition white light + chromoendoscopy improves polyp detection in Lynch
CCS pearl: For a 22-year-old FAP patient admitted preoperatively for proctocolectomy, your CCS order set should include NPO, bowel prep, type & screen, IV access, DVT prophylaxis, smoking cessation counseling, stoma marking by enterostomal therapist, genetic counseling for siblings, preoperative EGD with Spigelman assessment, and multidisciplinary surgical/genetics consults.
— Index diagnosis of Lynch in a 70-year-old still triggers cascade testing of younger relatives — the proband may have minimal personal benefit but enormous family value
— Surveillance intensity individualized to life expectancy, functional status, comorbidities — a frail 82-year-old with multiple comorbidities may not benefit from aggressive 1-yr colonoscopy intervals
— Risk-reducing hysterectomy/BSO is typically irrelevant after natural menopause but consider if endometrial polyps/abnormal bleeding
— Discuss aspirin chemoprevention cautiously — bleeding risk rises with age, polypharmacy, CKD
— Aspirin and NSAIDs (sulindac) for chemoprevention — avoid or dose-cautiously in CKD stage ≥3, dialysis
— Contrast imaging for staging: hydrate, consider non-contrast MRI in eGFR <30
— Chemotherapy dosing: capecitabine, 5-FU require renal dose adjustment; oxaliplatin neurotoxicity may worsen
— Urothelial cancer surveillance in Lynch already concerns the urinary tract — coordinate with nephrology/urology if hematuria
— Liver mets are common; differentiate cirrhosis-related changes from metastatic disease
— Sulindac hepatotoxic — caution; avoid in advanced cirrhosis
— Irinotecan, capecitabine require hepatic dose adjustment
— Hepatoblastoma surveillance in FAP children (AFP every 3–6 mo + abdominal US to age 5)
— Optimize nutrition, anemia (IV iron preop), albumin
— DVT prophylaxis essential — cancer patients are hypercoagulable
Key distinction: Don't equate "elderly with Lynch" with "no further action" — even when the patient won't benefit personally, the ethical and clinical imperative to inform at-risk relatives persists and is a Step 3 systems-of-care point.
— Most Lynch surveillance starts age 20–25 — pediatric screening generally deferred
— Constitutional MMR deficiency (CMMRD): biallelic MMR mutations — pediatric leukemia/lymphoma, brain tumors, GI cancers in childhood; café-au-lait spots; intensive pediatric surveillance protocols
— Genetic testing of at-risk children typically offered around age 10–12 (when colonoscopy would begin) — ethics around childhood testing balanced because early surveillance is actionable
— Hepatoblastoma surveillance: AFP + abdominal ultrasound every 3–6 mo from infancy to age 5–7 in known APC carriers
— Annual sigmoidoscopy/colonoscopy from age 10–15
— Colonoscopy in pregnancy: defer if possible; if urgent (bleeding, cancer suspicion), second trimester is preferred, with anesthesia/OB coordination
— Imaging: MRI without gadolinium preferred over CT for staging
— Chemotherapy: avoid in first trimester; 5-FU/oxaliplatin can be used 2nd/3rd trimester with MFM input
— Hysterectomy/BSO discussions in Lynch deferred until childbearing complete
— Preimplantation genetic diagnosis (PGD) available for known APC or MMR mutations — IVF with embryo selection
— Counsel on autosomal dominant inheritance — 50% transmission risk
— MUTYH (recessive): partner testing changes recurrence risk
— Combined OCPs or levonorgestrel IUD reduce endometrial/ovarian cancer risk — dual benefit
Step 3 management: In a pregnant Lynch carrier with new iron-deficiency anemia and hematochezia at 22 weeks, the next best step is flexible sigmoidoscopy/colonoscopy in the second trimester with OB-coordinated sedation, not waiting until postpartum — diagnostic delay risks tumor progression.
— Synchronous/metachronous CRCs — hallmark of Lynch; up to 30% risk of second primary within 10 yr if segmental resection
— Locally advanced/metastatic disease if surveillance missed — hepatic/peritoneal mets
— Bowel obstruction, perforation, GI bleeding from large polyps or tumors
— Desmoid tumors — second-leading cause of mortality after CRC in FAP; mesenteric desmoids cause bowel/ureteral obstruction, vascular compromise
— Duodenal/periampullary adenocarcinoma — major cause of post-colectomy mortality
— Thyroid cancer (cribriform-morular papillary)
— Pouchitis, pouch adenomas/cancer after IPAA
— Adhesive small-bowel obstruction post-surgery
— Endometrial cancer (often early stage with bleeding) — generally good prognosis
— Ovarian cancer — frequently advanced at diagnosis
— Urothelial cancer of upper tract — hematuria
— Pancreatic, gastric, hepatobiliary, small bowel, CNS, sebaceous tumors
— Post-colectomy: diarrhea, dehydration, electrolyte loss, vitamin B12 deficiency (terminal ileum involvement), stoma complications
— IPAA: pouchitis (treated with ciprofloxacin/metronidazole), cuffitis, fecal incontinence, reduced fertility in women (pelvic adhesions)
— Chemotherapy toxicities: oxaliplatin neuropathy, 5-FU mucositis/diarrhea, immune-related adverse events from checkpoint inhibitors (colitis, hypophysitis, pneumonitis, thyroiditis)
— Survivor guilt, anxiety, depression; impact on family relationships, insurability
Board pearl: After FAP colectomy, the two leading causes of death are duodenal/ampullary adenocarcinoma and mesenteric desmoid tumors — surveillance must extend beyond the colon. This is high-yield Step 3.
— Confirmed germline mutation → refer to genetic counselor, GI/colorectal surgery, gynecologic oncology (Lynch women), medical oncology as relevant
— New iron-deficiency anemia, hematochezia, weight loss in a known carrier → expedite colonoscopy
— Polyp burden unmanageable endoscopically → colorectal surgery for prophylactic colectomy planning
— High-grade dysplasia or invasive cancer → multidisciplinary tumor board
— Acute GI bleed from polyp/tumor — admit, resuscitate, GI consult, transfusion
— Bowel obstruction from tumor or desmoid — surgical consult, NG decompression, NPO, IVF
— Perforation — emergent surgery
— Postoperative complications: anastomotic leak (fever, peritonitis, leukocytosis post-day 3–5), pouchitis with sepsis, ileus
— Hemodynamically unstable GI bleed, septic shock from perforation/anastomotic leak, postoperative respiratory failure
— Checkpoint inhibitor severe immune-related AEs (myocarditis, pneumonitis, severe colitis)
— Genetics/genetic counseling — every proband
— Colorectal surgery — surveillance failure, prophylactic colectomy
— Gyn oncology — Lynch women, risk-reducing surgery
— Medical oncology — invasive cancer
— Endocrinology — thyroid surveillance in FAP
— Urology — hematuria in Lynch
— Ophthalmology — CHRPE confirmation
— Psychology/social work — coping, family disclosure
— Reproductive endocrinology — PGD/IVF planning
CCS pearl: When a known FAP patient presents with acute abdomen and CT shows a mesenteric mass with bowel obstruction, your CCS sequence is: NPO, NG tube, IV fluids, type & cross, surgery consult, oncology consult, CT-guided biopsy to confirm desmoid vs malignancy before committing to surgery — desmoid resection is often avoided in favor of medical therapy.
— Autosomal recessive, biallelic MUTYH mutations
— 10–100 adenomas, often right-sided, age 40–60
— Test when APC negative; sibling recurrence ~25%, children low risk unless partner carrier
— STK11/LKB1 mutation, autosomal dominant
— Mucocutaneous pigmentation (lips, buccal mucosa, fingers) + hamartomatous polyps (small bowel predominant) → intussusception
— Increased risk: GI, breast, pancreatic, ovarian (SCTAT), testicular Sertoli cell, cervical
— SMAD4 or BMPR1A mutations
— Multiple juvenile (hamartomatous) polyps of colon, stomach, small bowel
— SMAD4 patients overlap with hereditary hemorrhagic telangiectasia (HHT) — epistaxis, AVMs
— PTEN mutation; macrocephaly, trichilemmomas, mucocutaneous papillomas
— Breast, thyroid (follicular), endometrial, CRC, renal cancers
— GI hamartomas + ganglioneuromas
— ≥5 serrated polyps proximal to sigmoid, ≥2 >10 mm, or >20 serrated polyps total
— Often non-Mendelian; BRAF-mutated; ↑ CRC risk — annual colonoscopy
— POLE/POLD1 germline mutations — oligopolyposis + CRC + endometrial
— Ultramutated/MSS tumors, often respond to checkpoint inhibitors
Key distinction: Hamartomatous (Peutz-Jeghers, JPS, Cowden) vs adenomatous (FAP, AFAP, MAP) vs mismatch repair deficient (Lynch) — the polyp histology and pattern direct the genetic workup. Mucocutaneous pigmentation → Peutz-Jeghers; carpet of adenomas → FAP; right-sided cancer with few polyps but strong family history → Lynch.
— ~70% of all CRC; older patients (>50), left-sided predominance, adenoma-carcinoma sequence over a decade
— Risk factors: age, red/processed meat, obesity, smoking, alcohol, T2DM, sedentary lifestyle
— Tumor testing may show MSI-H due to MLH1 promoter hypermethylation (sporadic), not Lynch — distinguish with BRAF V600E (positive → sporadic)
— Long-standing ulcerative colitis or Crohn colitis (>8–10 yr); dysplasia → cancer
— Surveillance colonoscopy every 1–2 yr with chromoendoscopy
— Family history of IBD, not multiple cancers
— Solitary or few; not a polyposis syndrome
— Standard post-polypectomy surveillance per number/size/histology
— Distal, small, low risk unless meeting serrated polyposis criteria
— Inflammatory pseudopolyps in chronic colitis — not neoplastic, no cancer risk per se, but underlying IBD is the risk
— Pediatric/young adult; benign; mimics polyposis on imaging
— Non-hereditary, acquired; diffuse GI polyposis + alopecia, nail dystrophy, skin hyperpigmentation, malabsorption
— Adults 50–60s; not autosomal dominant
— Meets Amsterdam I but MMR-proficient tumors — increased CRC risk but not Lynch; surveillance every 3–5 yr
Board pearl: A 65-year-old with MSI-H right-sided CRC, MLH1 loss on IHC, BRAF V600E mutated, and MLH1 promoter hypermethylated is sporadic — no germline testing needed. This branch-point logic is exam gold.
— Colonoscopy every 1–2 yr lifelong from age 20–25 (or 2–5 yr before earliest family case)
— Endometrial biopsy + transvaginal US annually from age 30–35, OR risk-reducing hysterectomy + BSO after childbearing
— EGD with duodenal exam every 3–5 yr from age 40; H. pylori test/treat
— Urinalysis annually from age 30–35 (especially MSH2)
— Skin exam annually for Muir-Torre features
— Neurologic review of systems
— Aspirin chemoprevention discussed (75–325 mg daily)
— Combined OCP or levonorgestrel IUD for endometrial/ovarian risk reduction (premenopausal)
— Lifestyle: avoid tobacco, limit red/processed meat and alcohol, maintain healthy BMI, exercise
— Annual colonoscopy (pre-colectomy) from age 10–15
— Post-colectomy: pouch/rectum surveillance every 6–12 mo
— EGD with side-viewing scope every 1–4 yr by Spigelman stage from 20–25
— Annual thyroid ultrasound from late teens
— Abdominal exam ± MRI for desmoids, especially after surgery
— Children: hepatoblastoma surveillance to age 5–7
— Skin/dental/eye exams for stigmata
— All first-degree relatives offered targeted germline testing
— Children of carriers: testing typically at age 10–15 for FAP, age 18–25 for Lynch
— Genetic Information Nondiscrimination Act (GINA) protects against health insurance and employment discrimination but not life, disability, or long-term care insurance — counsel before testing
Step 3 management: A newly diagnosed Lynch syndrome patient's next steps include cascade testing for all first-degree relatives, scheduling colonoscopy interval to 1–2 yr, referral for risk-reducing gynecologic surgery counseling, baseline EGD, and starting low-dose aspirin with shared decision-making.
— Maintain a lifetime surveillance log: dates, findings, pathology, next due intervals
— Use a multidisciplinary registry when available — hereditary CRC clinics improve adherence
— Stool frequency, continence, dehydration, electrolytes, B12 annually
— Pouch surveillance every 6–12 mo (FAP-IPAA); rectal stump surveillance every 6 mo (IRA)
— Stoma care if end ileostomy
— CEA every 3–6 mo for 2 yr, then every 6 mo to 5 yr
— CT chest/abdomen/pelvis annually × 3–5 yr (higher risk stages)
— Colonoscopy at 1 yr post-resection, then per syndrome interval
— Continue Lynch extracolonic surveillance
— Checkpoint inhibitors: TSH, ACTH/cortisol, glucose, LFTs, lipase periodically; symptom-based for colitis/pneumonitis
— Oxaliplatin: neuropathy assessment
— Genetic counseling at diagnosis and at major life events (marriage, pregnancy planning)
— Mental health support — anxiety, "previvor" identity
— Family disclosure: encourage proband to inform relatives; clinicians cannot directly contact relatives without consent (privacy)
— Reproductive counseling: PGD/IVF options, prenatal testing
— Lifestyle counseling: tobacco cessation, alcohol moderation, exercise, weight, diet
— Vaccination: HPV (multiple cancer risks), routine adult immunizations
— Adherence to age-appropriate colonoscopy, gyn surveillance, EGD
— Documentation of pedigree update annually
CCS pearl: At every follow-up visit for a Lynch patient, your CCS orders should include updated three-generation pedigree, symptom review across Lynch-spectrum organs, scheduled colonoscopy/EGD/UA per protocol, and reinforcement of cascade testing for relatives — these are recurring management items, not one-time tasks.
— Pre-test counseling: explain inheritance pattern, implications for relatives, insurance/employment ramifications, psychological impact, possibility of VUS
— Document shared decision-making; written consent often required
— Patients may decline — autonomy must be respected
— Predictive testing for adult-onset conditions (Lynch) generally deferred until age of consent
— Childhood-onset/actionable conditions (FAP, with hepatoblastoma and adolescent screening) justify testing at age 10–12 — directly enables surveillance
— Always include the child in age-appropriate discussion (assent)
— US ethical/legal standard: clinician's duty is to the patient, who is encouraged and supported to inform relatives
— Clinicians cannot disclose genetic information to relatives without patient consent (HIPAA) except in rare jurisdictional exceptions
— Provide family letters to facilitate disclosure
— Prohibits health insurance and employment discrimination based on genetic info
— Does NOT cover life, disability, or long-term care insurance — patients should be informed before testing
— Do not act on VUS — counsel that classification may change
— Surveillance failure is a top hereditary CRC safety event — closed-loop scheduling, registry tracking
— Handoff to adult care for pediatric FAP patients at ~18 — warm handoff with transfer of records prevents missed surveillance
— Communicate pathology and tumor MMR/MSI results clearly to PCP, surgeon, and genetics — fragmented care risks missing Lynch diagnosis
— Discuss PGD/IVF nondirectively
— Prenatal testing decisions respect patient autonomy
Board pearl: A patient with confirmed Lynch syndrome refuses to inform her siblings. You may strongly encourage and facilitate disclosure (offer a family letter, joint visit), but you cannot directly contact siblings — patient confidentiality (HIPAA) generally prevails over duty to warn in the US.
— Genes: MLH1, MSH2, MSH6, PMS2, EPCAM
— Tumor signature: MSI-H, dMMR
— Right-sided, mucinous, TILs, medullary histology
— Top extracolonic cancer in women: endometrial (often the sentinel cancer)
— MSH2 carriers: highest urothelial risk
— MLH1 sporadic mimics: BRAF V600E + promoter hypermethylation
— CAPP2: aspirin reduces CRC ~50%
— Pembrolizumab: first-line for dMMR/MSI-H metastatic CRC
— Amsterdam II (3-2-1 rule); revised Bethesda — largely replaced by universal tumor testing
— Gene: APC (5q21), autosomal dominant
— >100 adenomas, 100% CRC by ~40 untreated
— AFAP: <100 polyps, right-sided, later
— CHRPE, osteomas, epidermoid cysts, supernumerary teeth, desmoids, duodenal polyps, thyroid (cribriform-morular), hepatoblastoma
— Gardner = FAP + bones/skin; Turcot = FAP + medulloblastoma (vs Lynch + glioblastoma)
— Surgery: proctocolectomy + IPAA vs TAC + IRA
— Post-colectomy mortality: duodenal cancer and desmoids
— Spigelman staging guides duodenal surveillance
— Autosomal recessive, biallelic MUTYH
— Mimics AFAP
— FAP child: hepatoblastoma surveillance with AFP + US to age 5
— GINA: protects health insurance/employment only
— Universal tumor MMR/MSI testing recommended in all CRC and endometrial cancers
Key distinction: FAP polyps = adenomas (carpet, 100% cancer); Lynch polyps = few adenomas but accelerated; Peutz-Jeghers = hamartomas + pigmentation; JPS = juvenile hamartomas; MAP = recessive adenomatous mimic of AFAP. Memorize the polyp histology + inheritance pattern + pathognomonic stigma — that triad solves most exam stems.
— 38-year-old with right-sided CRC; tumor IHC shows loss of MSH2 and MSH6 → next step: germline MMR gene testing with genetic counseling (not BRAF, not MLH1 methylation)
— 68-year-old with MSI-H CRC, MLH1 loss, BRAF V600E positive → sporadic MSI tumor, no germline testing needed
— Teen with hundreds of colon polyps, mandibular osteoma, epidermoid cyst, CHRPE on dilated exam → APC germline testing; plan prophylactic colectomy
— 45-year-old with 30 right-sided adenomas, parents unaffected, sibling affected → autosomal recessive pattern → MUTYH testing
— Lynch carrier woman age 50, hasn't had gyn exam → next step: endometrial sampling + transvaginal US, discuss risk-reducing hysterectomy + BSO
— Stage IV dMMR/MSI-H CRC → first-line pembrolizumab, not FOLFOX
— Patient post-IRA at 40 with new anemia and weight loss → next: EGD with side-viewing scope (duodenal/ampullary cancer) and proctoscopy (rectal stump)
— Post-colectomy patient with abdominal wall mass → biopsy/MRI → desmoid; manage medically (sulindac ± tamoxifen), avoid resection
— Proband with known APC mutation; next best step for asymptomatic 12-year-old child → targeted APC germline testing + initiate sigmoidoscopy at 10–15
— Lynch patient refuses to inform siblings → encourage disclosure, offer family letter; do not breach confidentiality
— Lynch carrier asks about prevention → daily aspirin (CAPP2 evidence), shared decision-making
Step 3 management: Recognize the three branch points that dominate exam stems: (1) tumor MMR/MSI result → germline pathway, (2) MLH1 loss → BRAF/methylation reflex, (3) polyp count + inheritance pattern → APC vs MUTYH vs MMR testing.
Lynch syndrome and FAP are the two pillars of hereditary colorectal cancer — Lynch (autosomal dominant MMR gene defects causing MSI-H tumors with right-sided CRC and extracolonic risks led by endometrial cancer, managed by 1–2 year colonoscopy, risk-reducing hysterectomy/BSO, aspirin chemoprevention, and pembrolizumab for metastatic dMMR disease) and FAP (autosomal dominant APC mutation producing carpet polyposis with 100% CRC risk requiring prophylactic colectomy, lifelong duodenal/thyroid surveillance, and recognition of desmoids and CHRPE) — both demand universal tumor MMR/MSI testing of CRC, germline confirmation with counseling, and cascade testing of relatives.