Abstract
Approximately one-third of individuals diagnosed with colorectal cancer have a family history of cancer, suggesting that CRCs may result from a heritable component. Despite the availability of current gene-identification techniques, only 5% of all CRCs emerge from well-identifiable inherited causes for predisposition, including polyposis and nonpolyposis syndromes. Hereditary nonpolyposis colorectal cancer represents a large proportion of cases, and robustly affected patients are at increased risk for early onset, synchronous, and metachronous colorectal malignancies and extracolonic malignancies. HNPCC encompasses several cancer syndromes, such as Lynch syndrome, Lynch-like syndrome, and familial colorectal cancer type X, which have remarkable clinical presentations and overlapping genetic profiles that make clinical diagnosis a challenging task. Therefore, distinguishing between the HNPCC disorders is crucial for physicians as an approach to tailor different recommendations for patients and their at-risk family members according to the risks for colonic and extracolonic cancer associated with each syndrome. Identification of these potential patients through epidemiological characteristics and new genetic testing can estimate the individual risk, which informs appropriate cancer screening, surveillance, and/or treatment strategies. In the past three years, many appealing and important advances have been made in our understanding of the relationship between HNPCC and CRC-associated syndromes. The knowledge from the genetic profile of cancer syndromes and unique genotype-phenotype profiles in the different syndromes has changed our cognition. Therefore, this review presents and discusses HNPCC and several common nonpolyposis syndromes with respect to molecular phenotype, histopathologic features, and clinical presentation.
Highlights
Colorectal cancers (CRCs) are one of the most common malignancies and represent the third most common cancer in men and the second in women worldwide
This paper provides a comprehensive literature review on the most common hereditary nonpolyposis colorectal cancer (HNPCC) and HNPCC-associated cancer syndromes that present distinguishing molecular phenotypes, histopathologic features, and clinical presentations among different subtypes (Figure 1)
Many guidelines suggest two possible approaches to screen out Lynch syndrome: a universal one, that is, to test every patient with CRC, and a selective one (Jerusalem guidelines), which broadens the indications for microsatellite instability (MSI) or IHC testing to every individual with CRC diagnosed prior to age 70 plus patients diagnosed at older ages who meet the Bethesda criteria [16], with the latter approach missing more than a quarter of patients with Lynch syndrome (Figure 2)
Summary
Colorectal cancers (CRCs) are one of the most common malignancies and represent the third most common cancer in men and the second in women worldwide. The “nonpolyposis” label of HNPCC can be misleading and confusing to physicians, because adenomas typically present a villous growth characteristic and have different degrees of cell dysplasia [10]. Identification of these individuals is critical for early intervention and treatment of associated malignancies to reduce HNPCC-associated morbidity and mortality. Cancer-free individuals whose family history indicates suspicion for a hereditary cancer syndrome should undertake clinical genetic evaluation and receive genetic counseling. This paper provides a comprehensive literature review on the most common HNPCC and HNPCC-associated cancer syndromes (including Lynch syndrome, Lynch-like syndrome, and familial colorectal cancer type X) that present distinguishing molecular phenotypes, histopathologic features, and clinical presentations among different subtypes (Figure 1)
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