Colon Cancer in the Setting of Polyposis
Case: Mrs. W is a 64-year-old woman with a past history of multiple colon polyps who underwent diagnostic colonoscopy because of anemia. Colonoscopy revealed an ulcerated cecal tumor, with biopsy confirming a moderately differentiated invasive adenocarcinoma. At 50 years of age, initial screening colonoscopy had revealed multiple polyps of differing types: six tubular adenomas, one villous adenoma, and three hyperplastic polyps. Subsequent intermittent colonoscopies identified several polyps each time. At 58 years of age, she was found to have a large villous adenoma requiring a segmental resection of the transverse colon. In light of her history of polyposis and colon cancer, you refer her to genetics.
Pedigree of Mrs. W's Family
Genetics evaluation: Apart from her mother’s history of a solitary polyp, there is no other known history of polyps in the family (Figure 7). Syndromes in which there is a predisposition for fewer than 100 adenomatous polyps include the autosomal dominant syndrome of attentuated familial adenomatous polyposis (AFAP) and the recessive syndrome of MYH-associated polyposis (MAP). Because of her history of cecal cancer, Lynch syndrome is also in the differential diagnosis. If there had been more than 100 polyps, familial adenomatous polyposis (FAP) would have been more likely, and if the polyps had not been defined, one might have considered looking for signs of other polyposis conditions, such as Peutz-Jeghers, Cowden syndrome, juvenile polyposis, neurofibromatosis, multiple endocrine neoplasia type I, and tuberous sclerosis.
FAP is an autosomal dominant syndrome that occurs in 1 of every 7000 to 22,000 individuals and is caused by germline mutations in the APC gene.[49] Twenty-five percent of mutations are de novo,[49] while a small fraction of cases result from somatic mosaicism,[50] explaining the lack of family history in a proportion of cases. The classic syndrome is characterized by adenomatous polyps carpeting the colon by young adulthood,[51] with the risk of colorectal cancer being virtually 100% (mean age at diagnosis, 40 years). Screening recommendations for classic FAP include annual flexible sigmoidoscopy beginning at age 10 to 15 years—or earlier if symptoms develop. Once polyps are identified, it is recommended that screening be switched to colonoscopy. For classic FAP, prophylactic colectomy is the treatment of choice. Upper gastrointestinal polyposis in FAP is common. Fundic gland polyps occur in the stomach and show focal dysplasia.[52] Although uncommon, there are reports of gastric cancer associated with FAP.[53,54] There is also a 95% risk of duodenal polyps, with an associated 5% risk of malignant progression.[55] When studied in a prospective manner, surveillance for duodenal adenocarcinoma and subsequent early referral for curative surgery does not demonstrate efficacy[55]; thus, recommendations exist for prophylactic surgery, dependent on the polyp burden.[32]
Other cancers associated with the syndrome include pancreatic, papillary thyroid, biliary tract, and brain (usually medulloblastoma)—and in children there is a risk of hepatoblastoma. Other benign extraintestinal manifestations include fibromas, lipomas, sebaceous and epidermoid cysts, nasopharyngeal angiofibromas, osteomas of the jaw, desmoid tumors, dental anomalies, and congenital hypertrophy of the retinal pigment epithelium [56].
Variations of classical FAP include AFAP, which is usually caused by mutations in the 3' or 5' regions of the APC gene, and which either gives rise to fewer polyps (< 100) or has a later age at onset of polyposis. AFAP rarely displays the extraintestinal manifestations of FAP. The average age for CRC in AFAP is 54 years.[57]
Mrs. W was tested for germline APC mutations and was found to be negative by sequencing and rearrangement testing. Subsequently, she was tested for biallelic mutations in MUTYH and was found to be positive. MYH-associated polyposis is inherited in an autosomal recessive manner. Thus far, the reported spectrum of disease has been mainly confined to the colon and upper gastrointestinal tract, where duodenal polyposis occurs relatively frequently. Recom-mendations for screening include colonoscopy beginning at age 25 to 30 years and repeated every 3 to 5 years until polyps are detected. Once adenomatous polyps are identified, the colonoscopy and polypectomy surveillance intervals are decreased to every 1 to 2 years. In order to detect duodenal malignancy, upper endoscopy with side viewing of the duodenum should be performed every 3 to 5 years beginning at age 30 to 35 years.[32] With regard to other potential cancers, the full spectrum of disease is still being defined. Prophylactic colectomy is undertaken depending on patient age, disease location, and polyp burden.
Mrs. W’s clinical picture could easily have been classified as AFAP, which has a 50% chance of being passed to each of her children. Fortunately, genetic testing revealed the underlying cause to be MAP, which is autosomal recessive. This means that her children will be obligate carriers of either one of her MYH mutations; however, the chance that they would be affected by the syndrome is very low—less than 1%, based on an MYH mutation–carrier frequency of 1% to 2% in the general population. While still not completely elucidated, the risk of CRC in monoallelic MYH mutation carriers may be moderately increased.[58] This case demonstrates that in APC-negative polyposis cases, an evaluation for MYH mutations should be pursued. Moreover, when unselected APC-negative index cases of FAP or AFAP were screened, regardless of polyposis subtype (typical, atypical, attenuated), the detection rate for biallelic MYH mutations was significant—17% (55 of 329 patients), and even higher ( 27%) when the denominator included only cases with the attenuated phenotype.[58] In general, the feature that more often characterized cases as attenuated was older age at onset and not necessarily a lower number of polyps.[58]
It was recently shown that homozygous BUB1B mutations previously thought to cause only the rare multivariegated aneuploidy syndrome (characterized by microcephaly, intellectual disability, and predisposition to multiple solid and hematologic cancers), predisposed a healthy adult to gastrointestinal polyps and colorectal cancer.[59] Detection of the patient’s underlying syndrome was only possible by karyotype analysis, which demonstrated mosaic aneuploidies, structural rearrangements, and premature chromatid separation secondary to the patient’s underlying genetic defect in mitosis. Investigation of these phenomena requires karyotype analysis of dividing cells and therefore can be performed using lymphocytes from blood, or alternatively, skin fibroblasts.[59]
Future Directions
In this review, we have focused on the strategy of targeted testing of genes known to be associated with particular gastrointestinal malignancies. This has been proven to be an effective strategy and has enabled the implementation of surveillance and life-prolonging risk-reduction surgeries in those at highest risk. However, clinical genetics is changing. Along with the advent of cheaper sequencing technologies will come the era of personalized medicine, which will give rise to the discovery of new cancer predisposition genes and the rediscovery of known genes, either in milder forms of the classic disease or in different roles. Thus, the unknown portions of the familial clustering wedges that are currently unaccounted for will start to fill. Furthermore, as we gain a higher-resolution picture of rare genetic events through sequencing of individuals or families, the collective impact of the rare variants and the common low-risk variants found in genome-wide association studies may explain the variable presentations seen within and between families.
Just as important as identifying a patient’s germline susceptibility is the ability to use that information to help the patient and his or her family make decisions about management, surveillance, and potential interventions. The information we give patients depends on our knowledge of the natural history of the cancer syndromes; therefore, recruitment into research protocols continues to be essential. Such research will allow us to capture the genotype-phenotype correlations that will help us determine the triggers of hereditary cancer and improve risk stratification within affected families.
Financial Disclosure: The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.
A 47-year-old male with complaints of chronic abdominal pain and episodes of flushing presents for evaluation. What is your diagnosis?
