The management of colorectal cancer has progressed over the past two decades because of many advances, including those in genetics, pathology, imaging, medical oncology, radiation oncology, and surgery. Within genetics, a number of mutations have been identified that play a causative role in colon carcinogenesis and have led to developments in targeted therapies and genetic testing for familial syndromes. Currently, most patients presenting with an inherited form of colorectal neoplasm can be classified as having adenomatous (familial adenomatous polyposis [FAP], attenuated FAP [AFAP], MUTYH-associated polyposis [MAP], Lynch syndrome, and familial colorectal cancer type X [FCC X])1 or hamartomatous [juvenile polyposis syndrome [JPS] and Peutz-Jeghers syndrome [PJS]) polyps. With the exception of FCC X, genetic testing can now diagnose all of the aforementioned syndromes, thereby making prophylactic risk-reducing surgery a practical option.
MAP, a recently characterized hereditary adenomatous polyposis syndrome, should be suspected in patients who have greater than 10 colorectal adenomas and have a weak or negative family history of colorectal cancer. The seemingly negative family history is due to MAP's autosomal recessive inheritance and its low (~2%) carrier frequency.2,3 While the vertical transmission rate is low, the siblings of biallelic carriers have a 25% risk of being biallelic carriers.3
FCC X describes a subset of patients who meet Amsterdam criteria II (at least three relatives with colorectal, endometrial, small bowel, ureteral, or renal pelvis cancer; one a first-degree relative of the other two; at least two successive generations affected; at least one diagnosed before age 50; FAP excluded; and tumors verified by pathologic examination) but lack an identifiable mismatch repair (MMR) gene mutation.4 Patients with FCC X have been found to have a lower incidence of colonic and extracolonic cancers than those with Lynch syndrome.5 Patients with Lynch syndrome are generally recommended to undergo colonoscopy every 1–2 years, endometrial cancer screening annually, urinalysis annually, and to consider prophylactic colectomy or hysterectomy.6 Patients with the apparently less virulent phenotype of FCC X may require a less thorough approach.5,7 Until more is known about the condition, patients with FCC X are recommended to undergo screening colonoscopy every 1–2 years.
Patients who meet Amsterdam criteria should be tested for MMR gene mutations either through immunohistochemistry (IHC) for loss of MMR protein expression or through molecular analysis for microsatellite instability (MSI). IHC may be the preferred test as it is less expensive, its sensitivity is comparable to MSI testing, and it allows for targeted germline testing by identifying a specific MMR protein loss. The routine testing of colorectal cancer patients younger than 50 years for loss of MMR protein expression via IHC can help identify Lynch syndrome in otherwise unsuspected cases.8
Within the field of pathology, sessile-serrated adenomas have received a lot of recent attention. They are characterized by saw-toothed crypt epithelial folds and are associated with MSI-high sporadic colorectal cancers.9 These lesions are particularly ...