Lynch Syndrome: Its Impact on Urothelial Carcinoma

Abstract

Lynch syndrome, known as hereditary nonpolyposis colorectal cancer (HNPCC), is an autosomal-dominant familial cancer syndrome with an increased risk for urothelial cancer (UC). Mismatch repair (MMR) deficiency, due to pathogenic variants in MLH1, MSH2, MSH6, and PMS2, and microsatellite instability, are known for development of Lynch syndrome (LS) associated carcinogenesis. UC is the third most common cancer type in LS-associated tumors. The diversity of germline variants in the affected MMR genes and their following subsequent function loss might be responsible for the variation in cancer risk, suggesting an increased risk of developing UC in MSH2 mutation carriers. In this review, we will focus on LS-associated UC of the upper urinary tract (UUT) and bladder, their germline profiles, and outcomes compared to sporadic UC, the impact of genetic testing, as well as urological follow-up strategies in LS. In addition, we present a case of metastatic LS-associated UC of the UUT and bladder, achieving complete response during checkpoint inhibition since more than 2 years.

Keywords: DNA mismatch repair genes; Lynch syndrome; MMR; checkpoint inhibitor; immunotherapy; microsatellite instability; upper urinary tract; urothelial cancer.

Figure 1

Workflow giving an overview of our literature search structure.

Figure 2

Sequence of protein synthesis. Four DNA mismatch repair genes are responsible for Lynch syndrome-related cancer development. MSH2 could bind mismatched nucleotides together with MSH6. MLH1 complexes with PMS2, thus forming the MutLα complex, which is responsible for excision of the mismatched locus. Defects in these proteins may increase the percentage of mutations and diminish effectiveness of tumor suppressors. Adapted from Peltomäk et al. [21].

Figure 3

Incidence rate of Lynch syndrome (LS)-associated cancers depending on the involved mismatch repair (MMR) gene mutation up to the age of 75 years [28].

Figure 4

Immunohistochemical analysis of mismatch repair protein complexes in gastric biopsy. Gastric mucosa staining positive for MLH1 (A), PMS2 (B), and MSH6 (C), and lost expression of MSH2 (D). Scale bar indicates 100 µm.

Figure 5

Frequent computed tomography (CT) scans of a patient diagnosed with LS during intravenously administered therapy with pembrolizumab. (A) Axial CT scan with an enlarged mass of the right renal pelvis (red arrow) in first diagnosis. (B) Axial CT scan prior to electroresection of the bladder, showing an enhancing mass (red arrow) at the region of the right ureter ostium. (C) Retroperitoneal lymph node bulk (red arrow) occurring three months after cystoprostatectomy. (D) CT-guided biopsy of the interaortocaval lymph nodes (red arrow). (E) Normal sized lymph nodes (red arrow) after five cycles of pembrolizumab 200 mg. (F) Remaining normal sized lymph nodes (red arrow) after 28 cycles pembrolizumab 200 mg with no other signs of regional or local metastasis.

Figure 6

Immunohistochemical analysis of the mismatch repair protein complexes in the radical cystectomy specimen: Urothelial mucosa staining positive for MLH1, PMS2, MSH6, and MSH2 (arrow in (A–D)) versus lost expression of MSH6 (C) and MSH2 (D) in the urothelial carcinoma (asterisk).