Immunohistochemical Screening of Upper Tract Urothelial Carcinomas for Lynch Syndrome Diagnostics: A Systematic Review

Rasmussen, Maria; Madsen, Mia Gebauer; Therkildsen, Christina

doi:10.1016/j.urology.2022.02.006

Cited by 11 publications

(9 citation statements)

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“…Molecular studies investigating urothelial cancer primarily aim to screen for Lynch syndrome patients in large, unselected cohorts using immunohistochemistry and/or MSI analysis and germline MMR test a selected subgroup. Thus only few Lynch syndrome cases are included and often Lynch syndrome tumors with retained MMR protein and/MSS tumors will not be MMR germline tested ( 37 , 38 ). Hence, the proportion of Lynch syndrome patients with retained immunohistochemical MMR protein expression and/or MSS status remains uncertain.…”

Section: Discussionmentioning

confidence: 99%

“…The concordance between the MSI assays and immunohistochemical MMR protein expression was highest for the 54-marker assay (90.3%) and lowest for the Promega assay (70.6%). A systematic review of universal screening of upper tract urothelial cancer, found a concordance of 58.7% (range 40%-100%) between immunohistochemical MMR protein expression and (primarily) the Bethesda panel ( 38 ). In total, 57 samples gave evaluable results by all three MSI assays, of which the sequencing-based method performed better than the Promega MSI assay.…”

Section: Discussionmentioning

confidence: 99%

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Mismatch repair deficiency testing in Lynch syndrome-associated urothelial tumors

et al. 2023

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IntroductionLynch syndrome-associated cancer develops due to germline pathogenic variants in one of the mismatch repair (MMR) genes, MLH1, MSH2, MSH6 or PMS2. Somatic second hits in tumors cause MMR deficiency, testing for which is used to screen for Lynch syndrome in colorectal cancer and to guide selection for immunotherapy. Both MMR protein immunohistochemistry and microsatellite instability (MSI) analysis can be used. However, concordance between methods can vary for different tumor types. Therefore, we aimed to compare methods of MMR deficiency testing in Lynch syndrome-associated urothelial cancers.MethodsNinety-seven urothelial (61 upper tract and 28 bladder) tumors diagnosed from 1980 to 2017 in carriers of Lynch syndrome-associated pathogenic MMR variants and their first-degree relatives (FDR) were analyzed by MMR protein immunohistochemistry, the MSI Analysis System v1.2 (Promega), and an amplicon sequencing-based MSI assay. Two sets of MSI markers were used in sequencing-based MSI analysis: a panel of 24 and 54 markers developed for colorectal cancer and blood MSI analysis, respectively.ResultsAmong the 97 urothelial tumors, 86 (88.7%) showed immunohistochemical MMR loss and 68 were successfully analyzed by the Promega MSI assay, of which 48 (70.6%) were MSI-high and 20 (29.4%) were MSI-low/microsatellite stable. Seventy-two samples had sufficient DNA for the sequencing-based MSI assay, of which 55 (76.4%) and 61 (84.7%) scored as MSI-high using the 24-marker and 54-marker panels, respectively. The concordance between the MSI assays and immunohistochemistry was 70.6% (p = 0.003), 87.5% (p = 0.039), and 90.3% (p = 1.00) for the Promega assay, the 24-marker assay, and the 54-marker assay, respectively. Of the 11 tumors with retained MMR protein expression, four were MSI-low/MSI-high or MSI-high by the Promega assay or one of the sequencing-based assays.ConclusionOur results show that Lynch syndrome-associated urothelial cancers frequently had loss of MMR protein expression. The Promega MSI assay was significantly less sensitive, but the 54-marker sequencing-based MSI analysis showed no significant difference compared to immunohistochemistry. Data from this study alongside previous studies, suggest that universal MMR deficiency testing of newly diagnosed urothelial cancers, using immunohistochemistry and/or sequencing-based MSI analysis of sensitive markers, offer a potentially useful approach to identification of Lynch syndrome cases.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Mismatch repair deficiency testing in Lynch syndrome-associated urothelial tumors

et al. 2023

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“…One systemic review reported that, among 1087 patients with upper urinary tract UC, 51 (4.7%) assumed or verified Lynch syndrome patients were identified. 10 Results from the phase II KEYNOTE‐158 study of pembrolizumab in patients with previously treated, advanced non‐colorectal MSI‐H/dMMR cancer were reported. For the seven tumor types with greatest enrollment, which included endometrial ( n = 49), gastric ( n = 24), cholangiocarcinoma ( n = 22), pancreatic ( n = 22), small intestine ( n = 19), ovarian ( n = 15), and brain cancers ( n = 13), complete responses occurred most frequently in patients with endometrial ( n = 8) and gastric cancers ( n = 4).…”

Section: Discussionmentioning

confidence: 99%

“…Without investigation into the MSI status, patients with mUC undergo pembrolizumab therapy in clinical practice. One systemic review reported that, among 1087 patients with upper urinary tract UC, 51 (4.7%) assumed or verified Lynch syndrome patients were identified 10 . Results from the phase II KEYNOTE‐158 study of pembrolizumab in patients with previously treated, advanced non‐colorectal MSI‐H/dMMR cancer were reported.…”

Section: Discussionmentioning

confidence: 99%

A radiological complete response to pembrolizumab in a patient with metastatic upper urinary tract urothelial cancer and Lynch syndrome

et al. 2022

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Introduction In Lynch syndrome, urothelial cancer is the third most common cancer, following colorectal and endometrial cancers. Little is known, however, about the efficacy of immune checkpoint inhibitors in the treatment of metastatic urothelial cancer in Lynch syndrome. Case presentation A 49‐year‐old patient with metastatic urothelial cancer underwent pembrolizumab therapy after platinum‐containing chemotherapy. The efficacy of the pembrolizumab therapy was good. Her lung and bone metastatic lesions disappeared in imaging studies and her back pain decreased dramatically. Pathogenic mutations of MSH2 and BRCA2 were found in the DNA extracted from her tumor, and subsequent genetic analysis confirmed the germline pathogenic variant of MSH2. As such, this case was genetically diagnosed as Lynch syndrome. Conclusion We report metastatic urothelial cancer in a patient with Lynch syndrome who demonstrated a radiological complete response to pembrolizumab therapy. Accurate genetic diagnosis can provide useful information to both the patient and their relatives.

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“…[39][40][41][42] There are two screening methods: immunohistochemistry (IHC) for mismatch repair proteins (MLH1, MSH2, MSH6, and PMS2) and microsatellite instability analysis. 39,43 The IHC method has been widely utilized by pathologists as a cost-effective procedure. A positive screening result should prompt subsequent testing for germline DNA mutations.…”

Section: Upper Urinary Tract Urothelial Carcinoma and Lynch Syndromementioning

confidence: 99%

Contemporary Issues in Urothelial Carcinoma of Upper Urinary Tract

Zhao,

Guo,

Rao

2023

Advances in Anatomic Pathology

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Upper urinary tract urothelial carcinoma (UTUC) is an uncommon malignancy involving the renal pelvis and ureter. Careful pathologic analysis plays a critical role in the diagnosis and clinical management of UTUC. In combination with clinical and radiologic evaluation, pathologic features can be used to stratify patients into low-risk and high-risk groups. This risk stratification can help clinicians select the optimal treatment for patients with UTUC, such as kidney-sparing (conservative) treatment, radical nephroureterectomy or ureterectomy, and perioperative systemic therapy. However, due to the technical difficulty of obtaining sufficient tissue from the upper urinary tract, it is often challenging for pathologists to accurately grade the tumor and assess tumor invasion in small biopsy specimens. Although the majority of UTUCs are pure urothelial carcinoma, a considerable subset of UTUCs show histologic subtypes or divergent differentiation. Recent studies have identified genetically distinct molecular subtypes of UTUC by examining DNA, RNA, and protein expression profiles. The prognosis of pT3 UTUC, particularly renal pelvic UC, remains controversial, and several studies have proposed subclassification of pT3 UTUC. Lynch syndrome is a significant risk factor for UTUC, and screening tests may be considered in young patients and those with familial histories of the disease. Despite significant progress in recent years, several issues remain to be addressed in the pathologic diagnosis, molecular classification, and treatment of UTUC.

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Immunohistochemical Screening of Upper Tract Urothelial Carcinomas for Lynch Syndrome Diagnostics: A Systematic Review

Cited by 11 publications

References 40 publications

Mismatch repair deficiency testing in Lynch syndrome-associated urothelial tumors

Mismatch repair deficiency testing in Lynch syndrome-associated urothelial tumors

A radiological complete response to pembrolizumab in a patient with metastatic upper urinary tract urothelial cancer and Lynch syndrome

Contemporary Issues in Urothelial Carcinoma of Upper Urinary Tract

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