Familial Urothelial Carcinomas




© Springer Science+Business Media New York 2015
Cristina Magi-Galluzzi and Christopher G. Przybycin (eds.)Genitourinary Pathology10.1007/978-1-4939-2044-0_17


17. Familial Urothelial Carcinomas



Christopher G. Przybycin  and Jesse K. McKenney 


(1)
Department of Pathology, Cleveland Clinic, Robert J. Tomsich Pathology and Laboratory Medicine Institute, Cleveland, OH, USA

 



 

Christopher G. Przybycin (Corresponding author)



 

Jesse K. McKenney



Keywords
Urothelial carcinomaHereditaryFamilialLynch syndromeBladder cancerUreter cancer



Introduction


The majority of urothelial carcinomas (UCs) are considered to be sporadic, often occurring in association with environmental risk factors (e.g., smoking, exposure to aromatic amines). The past few decades, however, have seen recognition of an inherited basis for a small but increasing proportion of these tumors. Candidate gene studies have found that polymorphisms in two genes involved in metabolism of toxic compounds, N-acetyltransferase 2 (NAT2) and glutathione S-transferase μ1 (GSTM1), play a role in bladder carcinogenesis [1]. The slow-acetylator phenotype of NAT2 and the GSTM1 null phenotype are associated with a 1.4-fold and 1.5-fold increase in bladder cancer risk, respectively [2]. Subsequent genome-wide association studies have identified numerous susceptibility loci for bladder cancer [1]. In other cases, inherited UCs have been associated with one of several specific syndromes, namely, the Hereditary Non-Polyposis Colorectal Carcinoma (HNPCC)/Lynch syndrome (LS), hereditary retinoblastoma , and Costello syndrome.

It has been suggested that the proportion of UCs with a hereditary basis is underestimated. Applying a specific set of clinical criteria to define suspected hereditary UC (age at diagnosis less than 60 years with no previous history of bladder cancer, previous history of HNPCC-related cancer regardless of age, one first-degree relative with HNPCC-related cancer diagnosed before 50 years of age, or two first-degree relatives diagnosed regardless of age), one group estimates that 21 % of patients presenting with upper urinary tract UCs may have a hereditary cause (specifically HNPCC) [3].

Recognition of a familial basis for UC in a given patient has important implications not only for the patient’s family members, but also for the patient himself: he may be at risk for other malignancies for which he should be evaluated (as in HNPCC), and there is some evidence to suggest a possible difference in treatment response . Specifically, when the above-mentioned clinical criteria for suspected hereditary UC are applied to upper urinary tract UCs, one study has shown that patients with these “hereditary-like” cancers have improved overall survival and cancer specific survival after radical nephroureterectomy and adjuvant cisplatin-based chemotherapy as compared with patients with sporadic upper urinary tract UCs [4].


Familial Risk of Urothelial Carcinoma


Several case-control studies and cohort studies have examined the relative risk of UC in patients with a family history of UC. A recent review article on the subject [5] showed that most of these studies reported a relative risk between 1.4 and 1.9, with the largest case-control study reporting a relative risk of 1.5 [6] (95 % CI = 1.2–1.8). This increased risk among patients with a positive family history remains even after controlling for smoking; a large Dutch cohort reported a smoking-adjusted risk of 1.8 (95 % CI = 1.3–2.7) [7]. Thus, the increase in UC risk among patients with a family history of UC is not likely due to shared environmental exposures alone.


HNPCC (Lynch Syndrome)


LS is the most common syndrome with familial UC as a feature. Inherited in an autosomal dominant fashion, LS is caused by a germline mutation in one allele of a gene encoding one of a group of DNA mismatch repair proteins, including MSH2, MLH1, MSH6, and PMS2. When the functional allele is inactivated by mutation or epigenetic silencing, replication errors are propagated, resulting in eventual tumorigenesis [8, 9]. Lack of mismatch repair proteins can be detected by loss of immunohistochemical expression, or by observing novel alterations in microsatellite regions of DNA (microsatellite instability), an artifact of the resultant genetic instability.

Although LS is most commonly associated with colorectal carcinomas and endometrial carcinomas, UCs of the upper urinary tract are the third most common tumor subtype found in this population [10, 11]. One of the earliest studies of extra-colonic cancers in patients with LS found a relative risk of ureteral cancer of 22 times over that of the general population [12]. Upper urinary tract UC has been reported as the presenting malignancy in up to 21 % of LS patients [11]. The increased risk of upper urinary tract UC in LS patients has been shown in several studies to be more strongly associated with MSH2 mutations than MLH1 mutations [8, 11, 13].

Upper tract UCs associated with HNPCC have a slightly different epidemiologic profile than sporadically occurring tumors, with a median age at presentation of 56 years (10–15 years earlier than usual) [14]. The male-to-female ratio is closer to 1:1 as compared with 2:1 for upper tract UC in the general population, and ureteral tumors seem to predominate over renal pelvis tumors (1.3:1), in contrast to the threefold to fourfold preponderance of renal pelvis tumors over ureteral tumors in the general population [11] .

The pathologic characteristics of upper urinary tract UCs in HNPCC patients overlap substantially but not completely with those occurring sporadically. In one study of 39 HNPCC patients with upper tract UCs, the majority (88 %) were high grade, a finding compatible with that seen in sporadic tumors, and 23 % were found to be high stage (pT3 or higher) [11].

While no distinctive morphologic feature has been definitively associated with HNPCC-associated upper urinary tract UCs, the presence of an inverted growth pattern has been reported in this setting. Although it remains to be proven whether inverted growth is definitively associated with HNPCC per se, inverted growth has been shown to be predictive of microsatellite instability in upper tract UCs in general. In one study [15] of 132 upper tract UCs that were tested for microsatellite instability by PCR, 35 (26.5 %) were found to be microsatellite unstable. The majority (65.7 %) of the microsatellite unstable tumors had an inverted growth pattern accounting for at least 20 % of the tumor volume, a finding that was seen in only 17.5 % of the microsatellite stable tumors. Although microsatellite instability is not always predictive of HNPCC, given this strong association between inverted growth and microsatellite instability, it seems reasonable to consider screening patients with inverted upper urinary tract UCs for loss of mismatch repair proteins by immunohistochemistry or PCR in an effort to diagnose HNPCC, as is currently done in colonic and endometrial carcinomas with key histologic features.

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Oct 29, 2016 | Posted by in PATHOLOGY & LABORATORY MEDICINE | Comments Off on Familial Urothelial Carcinomas

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