OA: Why are upper tract urothelial carcinoma two different diseases? (+Lynch Syndrome)

open access: Why are upper tract urothelial carcinoma two different diseases?

  In addition to environmental risk factors, hereditary genetic alterations may also be involved in the tumorigenesis of UTUC. Approximately 10–20% of all UTUCs have a hereditary background. It is well established that the incidence of UTUC is 8–25 fold higher in Lynch syndrome (also known as hereditary non-polyposis colorectal carcinoma; HNPCC) (23,24). The hMLH1 and hMSH2 are the most commonly damaged genes in Lynch syndrome. If both alleles of one of these genes are affected by mutation, deletion or epigenetic silencing, the mismatch-repair (MMR) function is blocked resulting in the accumulation of damaged genes ultimately leading to cancer formation with colorectal (type I) and sometimes also extra-colonic location such as ovary or upper urinary tract (type II) (24). For urothelial cancers of hereditary origin, the hMSH2 mutations are more prevalent as those of hMLH1 (25). To classify UTUC into hereditary and sporadic group the European Guidelines recommend to preform molecular analysis for UTUC patients susceptible for hereditary background based on four criteria: (I) UTUC diagnosis before the age of 60 years; (II) personal history of HNPCC-spectrum cancer; (III) at least one first-degree relative diagnosed with HNPCC under the age of 50 years; or (IV) two first-degree relatives with known HNPCC (without age restriction) (3). The molecular analysis aims to detect loss of MMR function by using immunostaining of MMR genes (hMLH1, hMSH2), DNA sequencing and microsatellite instability analysis. The loss of MMR function is associated with the resistance against chemotherapeutic agents with DNA-damaging effect (cisplatin, 5-fluorouracil, doxorubicin etc.) (26). The most frequently used radical surgical treatment of UTUC leads to the loss of kidney function that strongly limits the use of chemotherapies. Therefore, the prediction, of which patient will benefit from chemotherapy, is even more important in UTUC than in UBC.

In accordance, UTUC grade more accurately predicts survival at initial biopsy as tumor stage (35)......

Open radical surgery

For high-risk UTUC similar to UBC open radical surgery is the standard of care. However, the management of lymph nodes regarding both extent and templates are much more controversial for UTUC patients (63,65,66)....