Hereditary upper tract urothelial carcinoma: Lynch syndrome, hereditary nonpolyposis colorectal cancer syndrome (HNPCC)

Abstract

Genetics and environment clearly both play a role in the pathogenesis of upper tract urothelial carcinoma (UTUC). This malignancy is heterogeneous in its phenotypical presentation among geographical locations in its sporadic forms, which both vary from it’s hereditary form in Lynch Syndrome (LS), also known as hereditary nonpolyposis colorectal cancer (HNPCC) (Table 9.1). Lynch syndrome is among the most common Mendelian disorders and the population incidence of LS carriers is believed to be 1:370 in the United States [14]. This autosomal dominant cancer syndrome is characterized by germline mutations in DNA mismatch repair (MMR) genes, particularly MSH-2, MLH-1, MSH-6 and PMS-2. Currently, it is estimated that LS is the responsible etiology for 2.4-3.7 % of all colorectal cancer (CRC) cases and 1.8-3.9 % of all endometrial cancer (EC) cases. The lifetime penetrance of LS genetic mutations for CRC is 25-70 % and for EC is 30-70 % [15]. Variation exists due to different penetrance rates for the possible MMR gene mutations for a given cancer type. UTUC as well as various other malignancies involving the small bowel, stomach, biliary tract, brain and skin (sebaceous neoplasms) have been shown to be part of the extra-colonic tumor spectrum in LS. LS trait carriers and patients with known MSH-2 mutations have a relative risk of 75 for UTUC development compared to the general population [16]. In addition, our group and others have observed UTUC in families with MSH-6 and MLH-1 mutations albeit less often relative to those with alterations in MSH-2. Identification of these patients and affected family members is a high priority since they ultimately may benefit from early and frequent surveillance protocols.