The epidemiology of sporadic cases of UTUC has been well defined in multiple reports over the years. As with other malignant tumors, age is a major risk factor. Typically UTUC is found in persons with median age 69–70 in large published series [1, 3–6]. Involvement of the renal pelvis has been reported to be two to four times more common compared to the ureter [1, 17]. Smoking is a well-defined risk factor and carries a three to seven fold increased risk for UTUC development [18, 19]. Occupational exposure to hydrocarbons and/or petroleum products as seen by those working in the fields of chemistry, plastics, coal, tar and asphalt is thought to induce a relative risk of four to five for UTUC development [19]. Men are almost twice as likely than women to develop UTUC in most reports from western countries, similar to urothelial carcinoma of the bladder. In eastern countries plagued by Aristolochic acid nephropathy (AAN), also known as Balkan endemic nephropathy (BEN), there is a noted female predominance in large UTUC series [7–9] (Table 9.1). This trend is thought to be secondary to herbal use for weight-reduction [20] and the intermingling of Aristolochia clematitis seeds with wheat grain used to prepare home-baked bread in Balkan nations such as Croatia, Serbia, Romania, Bulgaria and Bosnia [21, 22]. Once thought to be familial in origin, BEN has since been traced to chronic exposure to herbs or seeds of all Aristolochia plants. Persons exposed to these nephrotoxic carcinogens tend to develop a progressive tubulointerstitial nephropathy culminating in UTUC in up to 50 % of cases [22].

In 1913, a published report by Dr. Aldred Warthin described a family in Michigan with multiple members suffering from colon and uterine cancers, which suggested an inheritance pattern [23]. Fifty years later, this expanded kindred was further studied by Dr. Henry Lynch and observations pointed to an autosomal dominant mode of inheritance of predominantly colorectal and endometrial carcinomas [24]. Clinical criteria, known as Amsterdam Criteria, focusing mostly on family history of colorectal cancer, emerged to better identify these individuals with HNPCC and to try to help standardize patient cohorts for study [25]. Later, human MMR genes were linked to cancer susceptibility in HNPCC families, further elucidating the molecular etiology of this cancer syndrome [26, 27]. In the early 1990s, UTUC was determined to be part of the tumor spectrum of hereditary nonpolyposis colorectal cancer (HNPCC) [28]. Given the new appreciation for extra-colonic tumors in the HNPCC spectrum, broader clinical criteria were proposed, known as Amsterdam Criteria II (Table 9.2), which aimed to include not only patients with personal or family history of CRC, but also include those individuals with UTUC, endometrial carcinoma and small bowel malignancies [29]. The association of Microsatellite Instability (MSI) with tumors in HNPCC led to the incorporating of molecular testing of surgical specimen tissue in patients presenting with known HNPCC malignancies, especially CRC. The Bethesda Criteria were proposed to determine which patients with known HNPCC tumors would qualify for MSI testing, thus providing the potential for prospective molecular screening of HNPCC-related tumor tissue and enhancing the ability to identify LS carriers [30]. Today LS patients are usually first identified by either clinical history or prospective molecular screening of tumor tissue with MSI testing and immunohistochemistry (IHC) to detect the absence of proteins made by MMR genes MSH-2, MLH-1, MSH-6 and PMS-2. In a patient meeting clinical criteria or with tumor tissues that are MSI high or demonstrating a missing MMR gene protein product on IHC, the diagnosis of LS is confirmed through germline genetic testing to detect the exact pathogenic mutation. Given the autosomal dominant inheritance pattern, family members can then be offered genetic testing to confirm or rule out their individual risk.

In 2008, members from four major LS research centers from the USA and Europe pooled their data to provide a retrospective cohort study in an effort to define the lifetime risk of developing extra-colonic and extra-endometrial cancers in LS patients and carriers [11]. This multi-institutional cohort consisted of over 6,000 individuals from 261 families with carrier or probable carrier status of a mutation in MSH-2 or MLH-1. Many first-degree relatives of these LS carriers were also included. The authors estimated an 8.4 % lifetime risk among LS carriers for the development of UTUC. Further risk stratification demonstrated the highest risk in men with MSH-2 mutations, assuming up to a 28 % lifetime UTUC risk. Women with MSH-2 mutations were noted to have a 12 % lifetime risk of UTUC development. The peak age for UTUC diagnosis was between ages 50 and 70. Prior to age 50, the risk of UTUC development was very low. There was a seven-fold higher risk for members of MSH-2 families versus those with MLH-1 mutations.

Given the distinct historical behavior of CRC in LS compared to sporadic CRC, it is not surprising that LS patients with UTUC would have some diverse features from sporadic UTUC patients. The most common manifestation of LS is CRC and these cases have many interesting differences clinically and pathologically when compared to sporadic CRC cases. Patients with LS present with CRC at significantly younger ages compared to sporadic CRC cases (45 years versus 64 years, respectively) [31]. LS patients with CRC tend to have predominantly right-sided colon lesions, specifically proximal to the splenic flexure, and usually are more prone to multiple lesions presenting either simultaneously or over time [32]. Even though colon polyps are not necessarily more common in LS patients, polyps do occur at younger ages, tend to be larger in size, demonstrate more villous features and are more likely to contain contiguous adenocarcinoma when compared to patients with sporadic colon polyps [33]. Interestingly, multiple studies have shown that LS patients with CRC have a superior overall survival rate versus sporadic CRC cases when controlled for age and stage [34, 35]. Unfortunately, not as much information is yet available when comparing sporadic UTUC patients with those having UTUC and LS. This is mostly due to smaller numbers, lack of awareness and likely unrecognized cases.

The first descriptions of UTUC in Lynch syndrome came out of retrospective studies by medical oncology groups. Many factors make it difficult to draw any solid conclusions about the unique characteristics of UTUC in LS cases based on these early studies. These factors include how patient cohorts were picked for study inclusion, data organization and the limited amount of retrospective data available. Prior to the availability of genetic mutation analysis to provide for LS carrier designation, patient cohorts were initially identified by the use of Amsterdam Criteria I, which relies solely on the presence of family history of colon cancer [28, 36]. Not until the later introduction of Amsterdam Criteria II [29] and the Bethesda Criteria [37] did patients with extra-colonic malignancies get full consideration for inclusion. Therefore these early studies likely excluded some number of UTUC cases with LS. Additionally, the early cohort studies were sometimes lacking pathology report information and loosely characterized UTUC cases in the broad category of “GU malignancy” having them lumped together with urothelial carcinomas of the bladder or renal cell carcinomas. No mention was ever made about the presence or absence of synchronous or metachronous bilateral UTUC in these patients.

In order to highlight the characteristics of UTUC in LS, Crockett et al. presented a retrospective case-control study providing a formal comparison of UTUC in LS patients against a well-established cohort of sporadic UTUC cases from Sweden [12]. The LS patients were extracted from Creighton University’s HNPCC database, which comprises a 42-year experience worth of data from patients with LS from 1964 to 2006. From the Creighton registry, a total of 39 patients were identified as having met Amsterdam Criteria II and having a diagnosis of UTUC. A total of 33/39 (85 %) of these patients had available genetic mutational analysis verifying MSH-2 or MLH-1 mutations and 26/39 (66 %) had formal pathological grading and staging of their UTUC specimen on record. Thus, for a retrospective study, reasonably strict inclusion criteria for the LS cohort were met. For comparison, 783 patients from western Sweden with UTUC diagnosis served as the control group, representing sporadic cases. The two cohorts were statistically compared. Upon initial presentation, the LS/UTUC group was on average 8 years younger than the sporadic UTUC group (62 years and 70 years, respectfully). LS patients had a higher proportion of primary UTUC in the ureter (51 %) compared to the intrarenal collecting system (39 %). By contrast, sporadic UTUC patients had more intrarenal tumors (65 %) compared to ureteral lesions (28 %). Based on the 2004 WHO grading system for urothelial carcinoma, there were similar numbers of high-grade cases between LS and sporadic cases (88 % and 74 %, respectively). Interestingly, in the LS cohort, the male/female ratio was 0.95 while in the sporadic group it was 1.52. No statistically significant differences were noted in tumor staging or the subsequent development of de novo urothelial carcinomas of the bladder. Survival data and the presence of bilateral UTUC were not specifically addressed in this report. The authors noted that their study did not provide conclusive evidence to forgo nephroureterectomy (NU) for treatment of UTUC in LS, but nevertheless, they advised “considerable caution” should still be exercised prior to considering complete NU in these patients due to the potentially higher risk of later UTUC development in the contralateral renal unit.

Another retrospective study recently reported the effectiveness of ureteroscopic laser ablative treatment in LS patients with UTUC and also suggested the increased risk for bilateral upper tract disease in this unique population [13]. Thirteen patients were identified with UTUC and had documented MSH-2 mutations by germline mutation analysis. Similarly to the Crockett study, patients were relatively young at time of presentation with UTUC at mean age 56.5 years (range 38–73) and a greater tendency for ureteral tumor location was noted (66 %) compared to the intrarenal collecting system (33 %). Unlike Crockett’s study, the majority of patients had low-grade disease (73 %) according to the 2004 WHO grading system for urothelial carcinoma. When considering each patient’s complete urological history, bilateral UTUC was noted in 6/13 (46 %). All six of these patients had metachronous disease presentation with a mean time of 49 months until bilateral UTUC development. The authors were careful to point out that selection bias obviously must be taken into consideration given that four of the six patients had extirpative surgery for UTUC prior to presentation to a tertiary care center which specializes in conservative endoscopic management for UTUC. Nevertheless, the potential for bilateral disease development in this special group must be considered when making treatment decisions and deserves future study. In general, UTUC cases in LS patients tend to present at younger ages, more often involve a primary tumor in the ureter versus the intrarenal collecting system and may have a tendency towards bilateral upper tract involvement more often when compared to sporadic UTUC cases (Table 9.3).