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Lynch syndrome in patients with upper urinary tract urothelial carcinoma: One centre study
BUCHOVÁ, Karolína
Lynch syndrome (LS) is an inherited autosomal dominant (AD) disease with predisposition for cancer development in different organs (large intestine, uterus, upper urinary tract, etc.). Typically, young or middle age individuals are affected by cancer. Presented bachelor thesis summarizes the current knowledge about LS in patients with urothelial carcinoma (UC) of the upper urinary tract. We tried to determine the frequency of LS in patients with urothelial carcinoma of the upper urinary tract and design a suitable diagnostic algorithm how to identify suspect patients appropriate for further genetic testing. In the practical part of the thesis, we searched for all patients treated on Urology department Faculty Hospital in Pilsen for UC of the upper urinary tract in the time period I/2010 - XII/2018. All cases were re-evaluated. Immunohistochemical staining of MMR proteins (MLH1, PMS2, MSH2, MSH6) was performed in selected cases. Obtained data were evaluated statistically. We found 215 examinations/biopsies from 182 patients (58 UC of the ureter, 119 UC of the renal pelvis, 5 UC of both the ureter and the renal pelvis). 121 patients were examined by immunohistochemistry (44 UC of the ureter, 73 UC of the renal pelvis, 4 UC of both the ureter and the renal pelvis). Lost expression of some MMR protein was demonstrated in 9/121 examined cases. Definitive examination of peripheral blood for detection of germline mutation was performed in only two patients (2%). One patient (male, 71 years) has confirmed germline mutation of MSH6 gene from peripheral blood. The second patient (male, 73 years) is still waiting for a definitive confirmation of the diagnosis from peripheral blood (patient has a high suspicion for Lynch syndrome, he has personal history of colorectal carcinoma, deficiency of MSH6 protein expression was found in UC of upper urinary tract even in colorectal carcinoma). Based on here presented data, we recommend routine immunohistochemical staining of MMR proteins in all patients with UC of upper urinary tract, regardless of their age or medical history. Universal immunohistochemical screening in patients with UC of upper urinary tract is a good and yielding way how to identify suspicious patients for genetic testing of LS.
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Diagnosis of Lynch syndrome based on pathologic examination
KRAUSOVÁ, Lenka
Lynch syndrome is an autosomal dominant disease predisposing to cancer development. Up to 5 % of colorectal cancers may be associated with Lynch syndrome. Due to its familial occurrence the diagnosis is important for family screening. Currently it is based on methods of modern pathology. Theoretical part describes structure of gastrointestinal tract, definition and history of Lynch syndrome, and methods of its laboratory diagnostics. The diagnosis can be based on evaluation of tumor microscopical features (Semi PREDICT score) in tissue sections, imunohistochemical investigation of MMR (mismatch repair) proteins, or molecular genetic MSI (microsatellite instability) testing. Practical part focuses mainly on correlation of immunohistochemistry and MSI testing. Randomly selected cases of colorectal cancer were organized into 2 study groups. The first group consisted of 25 cases with intact MMR immunoexpression, the second group comprised 25 cases with at least one MMR protein being deficient. For further verification molecular genetic MSI testing, along with BRAF gene analysis and MLH1 promoter methylation status to discriminate Lynch syndrome from sporadic cases, were performed. Germline analysis of MMR genes proved the diagnosis of Lynch syndrome in 5 cases of the second group. Semi PREDICT score sensitivity for MMR-deficiency prediction (and indirectly for Lynch syndrome detection) was 84 %, specificity 48 %. Sensitivity of MSI testing was 87 %, but only 50 % in Lynch syndrome subset of cases, specificity was 100 %. The results show major role of MMR immunohistochemistry in the diagnostics of MSI-H cancers, which is the cornerstone of Lynch syndrome screening.
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