Immunohistochemical assessment of basal and luminal markers in non-muscle invasive urothelial carcinoma of bladder

Peña, Maria Del Carmen Rodriguez; Chaux, Alcides; Eich, Marie‐Lisa; Tregnago, Aline C.; Taheri, Diana; Borhan, Walaa; Sharma, Rajni; Rezaei, M. Katayoon; Netto, George J.

doi:10.1007/s00428-019-02618-5

Cited by 42 publications

(19 citation statements)

References 19 publications

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“…As a result, the fraction of CK5 negative and of strongly positive cases increased markedly with bladder cancer grade and stage. A link between CK5 expression and bladder cancer progression was earlier reported by several authors [38][39][40][41]. Most of these studies have employed antibodies against CK5/6 and it has been assumed that CK5/6 positivity reflects a "basal-type" molecular subgroup of urothelial carcinoma [42,43].…”

Section: Discussionmentioning

confidence: 84%

Cytokeratin 5 and cytokeratin 6 expressions are unconnected in normal and cancerous tissues and have separate diagnostic implications

et al. 2021

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Cytokeratins (CKs) 5 and 6 are functionally unrelated but often analyzed together using bispecific antibodies in diagnostic immunohistochemistry. To better understand the diagnostic utility of CK5 or CK6 alone, tissue microarrays with > 15,000 samples from 120 different tumor types as well as 608 samples of 76 different normal tissues were analyzed by immunohistochemistry. In normal tissues, both CKs occurred in the squamous epithelium; CK5 dominated in basal and CK6 in suprabasal layers. CK5 (not CK6) stained basal cells in various other organs. Within tumors, both CK5 and CK6 were seen in > 95% of squamous cell carcinomas, but other tumor entities showed different results: CK5 predominated in urothelial carcinoma and mesothelioma, but CK6 in adenocarcinomas. Joint analysis of both CK5 and CK6 obscured the discrimination of epithelioid mesothelioma (100% positive for CK5 alone and for CK5/6) from adenocarcinoma of the lung (12.8% positive for CK5 alone; 23.7% positive for CK5/6). CK5 and CK6 expressions were both linked to high grade, estrogen receptor, and progesterone receptor negativity in breast cancer (p < 0.0001 each), grade/stage progression in urothelial cancer (p < 0.0001), and RAS mutations in colorectal cancer (p < 0.01). Useful diagnostic properties which are commonly attributed to CK5/6 antibodies such as basal cell staining in the prostate, distinction of adenocarcinoma of the lung from squamous cell carcinoma and epithelioid mesothelioma, and identification of basal-type features in urothelial cancer are solely driven by CK5. At least for the purpose of distinguishing thoracic tumors, monospecific CK5 antibodies may be better suited than bispecific CK5/6 antibodies.

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Section: Discussionmentioning

confidence: 84%

Cytokeratin 5 and cytokeratin 6 expressions are unconnected in normal and cancerous tissues and have separate diagnostic implications

et al. 2021

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“…Furthermore, using complex methodologies, MIBC has been classified into two wide molecular subtypes, luminal and basal, following the categorization currently in use in breast cancer [21][22][23][24][25][26][27][28]. Reportedly, these two wide categories present differences in prognosis and sensitivity to the current therapies, with the basal subtype being more aggressive than luminal [22,25,27,29,30].…”

Section: Introductionmentioning

confidence: 99%

Molecular Classification of Bladder Urothelial Carcinoma Using NanoString-Based Gene Expression Analysis

López-Beltrán

Blanca

Cimadamore

et al. 2021

Cancers

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Molecular classification of bladder carcinoma is a relevant topic in modern bladder cancer oncology due to its potential to improve oncological outcomes. The available molecular classifications are generally based on transcriptomic profiles, generating highly diverse categories with limited correlation. Implementation of molecular classification in practice is typically limited due to the high complexity of the required technology, the elevated costs, and the limited availability of this technology worldwide. We have conducted a gene expression analysis using a four-gene panel related to luminal and basal subtypes in a series of 91 bladder cancer cases. NanoString-based gene expression analysis using typically luminal (GATA3+/KRT20+) and basal markers (KRT14+/KRT5+/GATA3low/-/KRT20low/-) classified urothelial bladder carcinoma samples as luminal, basal, and a third category (KRT14-/KRT5-/GATA3-/KRT20-), null/double negative (non-luminal/non-basal). These three categories were meaningful in terms of overall cancer-specific survival (p < 0.0001) or when classified as conventional urothelial carcinoma and variant histology urothelial carcinoma (p < 0.0001), NMIBC vs. MIBC (p < 0.001), or by AJCC stage category Ta (p = 0.0012) and T1 (p < 0.0001) but did not reach significance in T2-T4 (p = 0.563). PD-L1 expression (low vs. high) was also different according to molecular subtype, with high PD-L1 expression mostly seen in basal and null subtypes and carcinomas with variant histology (p = 0.002). Additionally, the luminal subtype was enriched in NMIBC with favorable cancer-specific survival (p < 0.0001). In contrast, basal and null subtypes resulted in aggressive MIBC tumors with shorter cancer-specific survival (p < 0.0001), some of which presented variant histology. In conclusion, a comprehensive evaluation of a gene classifier related to molecular taxonomy using NanoString technology is feasible. Therefore, it might represent an accessible and affordable tool in this rapidly expanding area of precision genomics.

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“…Of the 83 studies included in the qualitative analysis, 24 were excluded after full-text analysis due to insufficient data, duplicated report of same sample cohort, contradictory data between text and tables, and lack of information about antibody used (Table S1), resulting in 58 studies included. Three studies reported ERa and GATA3 in the same tumour sample cohort (35,45,46).…”

Section: Eligibility and Data Collectionmentioning

confidence: 99%

“…Network meta-analysis was performed to assess a possible relationship between the expression of ERa, ERb and GATA3 (Table 5). The model was based on direct evidence pooled from studies evaluating at least two of the proteins in the same study: 3 studies for ERa and GATA3 (35,45,46), 2 studies for ERa and ERb (27,32) and 1 study for ERb and GATA3 (86). The model showed that both ERb (0.014; 95%; CI: 0.007-0.030) and GATA3 (0.002; 95%CI: 0.001-0.005) positive cases negatively correlate with ERa-positivity.…”

Section: Association Between Era Erb and Gata3mentioning

confidence: 99%

“…Six studies analysed the association between ERa and patients' prognosis, with no significant association between ERa expression and tumour recurrence/progression or survival observed in each individual study (27,33,34,39,40). An exception was Pena et al that showed less likelihood for tumour recurrence in ERa -positive cases using unadjusted logistic regression (46). Due to differences in the methodology and information reported, it was not possible to carry out a metaanalysis.…”

Section: Prognostic Valuementioning

confidence: 99%

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Association Between Estrogen Receptors and GATA3 in Bladder Cancer: A Systematic Review and Meta-Analysis of Their Clinicopathological Significance

et al. 2021

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BackgroundEstrogen receptors alpha (ERα) and beta (ERβ) and the cooperating protein GATA-binding factor 3 (GATA3) have been implicated in bladder carcinogenesis and tumour progression. GATA3 and ER have been functionally linked in the establishment of luminal fate in breast tissue, but to date their relationship in bladder cancer has not been established. This information will be useful to advance diagnostic and prognostic markers.AimTo determine the relationship between the expression of ERα, ERβ and GATA3 in bladder cancer, disclose their prognostic and diagnostic value and their association with clinicopathological characteristics.MethodsA comprehensive literature search in PubMed database was performed for all immunohistochemical studies of ERα, ERβ and/or GATA3 in bladder cancer patients. We selected eligible studies in accordance with the PRISMA guidelines and evaluated methodological quality and risk of bias based on quality criteria from the reporting recommendations for tumour MARKer (REMARK) prognostic studies. Risk of bias assessment was performed using Review Manager 5. R software was used for all statistical analysis, the packages used were meta and dmetar for the standard meta-analysis, and netmeta for the network meta-analysis.ResultsThirteen studies were eligible for ERα, 5 for ERβ and 58 for GATA3 meta-analysis. Low grade tumours showed significantly lower ERα expression. GATA3 was widely expressed in bladder tumours, especially urothelial carcinomas, with higher expression of GATA3 in low grade and low stage tumours. Data was insufficient to determine the prognostic value of either ERα or ERβ, but GATA3-positivity was associated with higher recurrence free survival. A negative correlation between ERα or ERβ positivity and GATA3 expression was disclosed. Additionally, several sources of heterogeneity were identified, which can be used to improve future studies.ConclusionThe clinicopathological value of ERα and ERβ was inconclusive due to low availability of studies using validated antibodies. Still, this meta-analysis supports GATA3 as good prognostic marker. On the contrary, ERα-positivity was associated to higher grade tumours; while ERα and ERβ were inversely correlated with GATA3 expression. Considering that it has previously been shown that bladder cancer cell lines have functional ERs, this suggests that ERα could be activated in less differentiated cells and independently of GATA3. Therefore, a comprehensive analysis of ERα and ERβ expression in BlaCa supported by complete patient clinical history is required for the identification of BlaCa subtypes and subgroups of patients expressing ERα, to investigate if they could benefit from treatment with hormonal therapy.Systematic Review RegistrationProspero, CRD42021226836.

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Immunohistochemical assessment of basal and luminal markers in non-muscle invasive urothelial carcinoma of bladder

Cited by 42 publications

References 19 publications

Cytokeratin 5 and cytokeratin 6 expressions are unconnected in normal and cancerous tissues and have separate diagnostic implications

Cytokeratin 5 and cytokeratin 6 expressions are unconnected in normal and cancerous tissues and have separate diagnostic implications

Molecular Classification of Bladder Urothelial Carcinoma Using NanoString-Based Gene Expression Analysis

Association Between Estrogen Receptors and GATA3 in Bladder Cancer: A Systematic Review and Meta-Analysis of Their Clinicopathological Significance

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