How colorectal cancer is tested on Step 1

Vignettes give iron deficiency in an older adult, a family history, or many polyps, and ask about genes or pathways.

Normal mucosaBaselineAPC lossEarly adenomaKRASGrowing adenomaTP53 lossCarcinoma
Chromosomal instability. APC normally promotes β-catenin degradation; its loss lets β-catenin drive proliferation. Aspirin use is associated with lower risk.
Right-sidedExophytic massOccult bleedingIron deficiency anemiaFatigue, weight lossOften MSI-highLeft-sidedInfiltrating, "napkin ring"ObstructionNarrow stool, changed habitsHematochezia"Apple core" on barium enemavs
Right vs left. Iron deficiency anemia in an older man or a postmenopausal woman requires evaluation for colon cancer.

Hereditary syndromes

Gene, inheritance, and associated features are frequently tested.

SyndromeGeneKey features
FAPAPC (5q), autosomal dominantHundreds to thousands of adenomas; prophylactic colectomy
Gardner syndromeAPC variantFAP plus osteomas, soft tissue tumors, desmoids, extra or impacted teeth
Turcot syndromeAPC or mismatch repairPolyposis plus brain tumors
Lynch syndrome (HNPCC)MLH1, MSH2, MSH6, PMS2Proximal colon, endometrial, ovarian cancers; few polyps
Peutz-Jeghers syndromeSTK11Hamartomatous polyps, mucocutaneous pigmentation, ↑ cancer risk
Juvenile polyposisSMAD4 or BMPR1AMultiple juvenile (hamartomatous) polyps

Lynch syndrome is the most common hereditary colorectal cancer syndrome.

Polyps

Histology and size predict malignant potential.

Colorectal polypsHyperplasticRectosigmoid;low riskTubularadenomaLower riskadenomaVillousadenomaHighest riskSessileserratedMSI pathwayHamartomatousJuvenile,Peutz-Jeghers
Polyps. Risk rises with size (> 1 cm), villous histology, and high-grade dysplasia. Large villous adenomas can secrete mucus and cause hypokalemia.

Screening and spread

Screening removes precursors before they become cancer.

  • Average-risk screening in the US begins at age 45, with options such as colonoscopy every 10 years or annual fecal immunochemical testing.
  • People with Lynch syndrome or FAP start colonoscopy much earlier and repeat it often.
  • The liver is the most common site of distant metastasis, via the portal circulation; rectal cancer can also spread to the lungs.
  • Staging depends on depth of invasion, lymph nodes, and distant metastasis (TNM).

Worked example

Recognize a hereditary pattern.

functions Worked example — young cancers in one family

A 42-year-old has a right-sided colon cancer. His mother had endometrial cancer at 48 and his uncle colon cancer at 45. Tumor testing shows microsatellite instability. What is the likely syndrome and mechanism?

  1. Several relatives with colon and endometrial cancer at young ages suggest a hereditary syndrome.
  2. Few polyps and a right-sided cancer fit Lynch syndrome rather than FAP.
  3. Microsatellite instability reflects defective DNA mismatch repair.
  4. Inheritance is autosomal dominant; relatives should be offered genetic testing.

Answer. Lynch syndrome (hereditary nonpolyposis colorectal cancer) from a germline mismatch repair gene mutation.