Abstract
ARAB JOURNAL OF UROLOGY 2020, VOL. 18, NO. 4, 267–272 https://doi.org/10.1080/2090598X.2020.1814183 UROSCIENCE: ORIGINAL ARTICLE Human epidermal growth factor receptor 2 (HER2) gene amplification in non-muscle invasive urothelial bladder cancers: Identification of patients for targeted therapy Vinita Agrawal , Niharika Bharti and Rakesh Pandey Department of Pathology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India ABSTRACT ARTICLE HISTORY Received 6 March 2020 Objectives: To evaluate human epidermal growth factor receptor 2 (HER2) protein overexpres- Accepted 12 April 2020 sion by immunohistochemistry (IHC) and gene amplification by fluorescent in situ hybridisation (FISH) in urothelial non-muscle-invasive bladder carcinoma (NMIBC), as HER2 is a potential KEYWORDS therapeutic target in muscle-invasive bladder carcinoma (MIBC) and HER2 expression and gene Bladder carcinoma; non- amplification in low/high-grade and pTa/pT1 NMIBC is not clear. invasive bladder carcinoma; Patients and methods: The study included 93 bladder cancers; 25 MIBC and 68 NMIBC (37 HER2 oncogene; fluorescent low- and 31 high-grade). All HER2 positive (3+) and equivocal (2+) cases were subjected to FISH in situ hybridisation; immunohistochemistry; using a HER2/CEN 17 dual-colour probe kit. IHC and FISH were scored as per the American gene amplification Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) 2013 Guidelines for breast cancers. Based on the number of signals/nuclei, amplification was categorised as low (≥6–10) and high-level (≥10). Results: HER2 2–3+ expression was seen in 29% of NMIBCs (10.8% low- and 51.6% high-grade). HER2 3+ expression was seen in high-grade NMIBC (nine of 31; 29%) and MIBC (nine of 25; 36%). In all, 87% of high-grade NMIBCs were lamina invasive (pT1). Gene amplification was found in 45% (eight of 18) of 3+ tumours. None of the HER2 2+ tumours showed gene amplification. IHC and FISH results were in closest agreement when ≥50% of tumour cells showed 3+ expressions. High-level amplification correlated with increased gene expression on reverse transcriptase-polymerase chain reaction. On multivariate analysis, lower stage, grade, and HER2 expression significantly correlated with progression-free survival. HER2 3+ expression in NMIBC correlated significantly with time to recurrence and progression. Conclusion: Our present results show that HER2 FISH should not be performed for HER2 2 + and low-grade NMIBC. This contrasts with breast cancers where it is recommended for equivocal 2+ tumours. About 50% of HER2 3+ MIBC and high-grade NMIBC show HER2 gene amplification and can be potential candidates for HER2-targeted therapy. Abbreviations: ASCO/CAP: American Society of Clinical Oncology/College of American Pathologists; DAB: 3,3ʹ-diaminobenzidine; FISH: fluorescent in situ hybridisation; HER2: human epidermal growth factor receptor 2; IHC: immunohistochemistry;(N)MIBC: (non-) mus- cle-invasive bladder carcinoma; MPUC: micropapillary variant of urothelial bladder cancer; PFS: progression-free survival; TURBT: transurethral resection of bladder tumour Introduction for clinical application. Studies have shown the poten- tial prognostic value of markers including receptor Urinary bladder cancer ranks ninth in worldwide can- tyrosine kinases such as fibroblast growth factor recep- cer incidence and is the seventh most common malig- tor 3 (FGFR3), epidermal growth factor receptor (EGFR), nancy in males [1]. Clinically, non-muscle-invasive and ERBB2/human epidermal growth factor receptor 2 bladder cancers (NMIBCs) account for 70–75%, while (HER2) in invasive bladder cancers [2]. the remaining 25–30% are muscle-invasive bladder cancers (MIBCs) or metastatic lesions at the time of There are data suggesting a role of HER2 in urothe- initial presentation. Once invasive into muscle, bladder lial carcinoma and directed agents have entered clin- cancer has a poor prognosis and is responsible for ical trials as potential therapeutic targets in locally most of the bladder cancer-related deaths. Patients advanced and metastatic bladder cancer [3,4]. with NMIBC have a better prognosis and they are Encouraging preclinical results with T-DM1 (ado- treated by transurethral resection with adjuvant ther- trastuzumab emtansine), consisting of the HER2 anti- apy, but they often present later with recurrence or body trastuzumab conjugated with a cytotoxic agent, invasive unresectable tumours. exemplifies a new potential treatment for HER2- With improvements in knowledge about its patho- positive bladder cancers. Studies have shown that genesis, the greater challenge is to identify biomarkers HER2-positivity rates can differ between different CONTACT Vinita Agrawal vinita.agrawal15@gmail.com Department of Pathology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226014, India © 2020 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 268 V. AGRAWAL ET AL. populations [5]. An accurate assessment of HER2 status [9]. HER2-positive (3+) and equivocal (2+) cases is important for proper patient selection. There are were subjected to FISH. limited studies evaluating the correlation of HER2 2/3 + protein expression by immunohistochemistry (IHC) FISH with HER2 gene amplification in NMIBC [6,7]. The third (2004) and the fourth (2016) WHO Classification of FISH was performed in bladder cancers showing tumours of the urothelial tract recommends classifying 2/3+ HER2 immunohistochemical protein expres- non-invasive papillary urothelial carcinoma as low- and sion using a HER2/CEN 17 dual-colour probe kit high-grade [8]. (ZytoLight Spec, Bremerhaven, Germany). To determine the utility and identify patients who Formalin-fixed paraffin-embedded tissue sections could benefit from HER2-targeted therapy in low- and of 3–4 µm thickness were used and the area in high-grade NMIBC, we analysed HER2 protein overex- the slide showing strongest expression for HER2 pression by IHC and gene amplification by fluorescent by IHC in the maximum number of tumour cells in situ hybridization (FISH) according to the American was marked for probe application. Society of Clinical Oncology/College of American A signal ratio of HER2 to chromosome 17 was Pathologists (ASCO/CAP) 2013 Guidelines for breast recorded in a count of a minimum of 30 tumour cells cancer. and a ratio of ≥2 was regarded as HER2 gene amplifica - tion. This was further categorised as low (≥6–10 HER2 signals/nuclei) and high-level amplification (≥10 HER2 Patients and methods signals/nuclei). Breast cancer with HER2 amplification Retrospective analysis of consecutive urothelial was taken as a positive control. MIBCs (n = 25) and NMIBCs (n = 68) diagnosed on histology of transurethral resection of bladder Validation of FISH results by reverse transcriptase tumour (TURBT) at the Department of Pathology, (RT)-PCR Sanjay Gandhi Postgraduate Institute of Medical Sciences (SGPGIMS), Lucknow, over a period of HER2 gene expression by quantitative RT-PCR was per- 3 years was performed. The TURBT tissues in formed in 10 bladder tumours with HER2 3+ over- which detrusor muscle was not included in the expression by IHC. The RNA was extracted from 10- biopsy were excluded. Mesenchymal and non- µm thick formalin-fixed paraffin-embedded tissue sec- urothelial bladder tumours were not included in tions using an RNA extraction kit from Chromous the study. All patients with <2 years of follow-up Biotech (Bangalore, India). Primers were designed and were also excluded, except for patients who died of synthesised for human glyceraldehyde 3-phosphate the disease in <2 years of diagnosis. The study was dehydrogenase (GAPDH; housekeeping gene) and approved by the Institutional Ethics Committee. HER2 gene. First-strand complementary DNA synthesis Clinical and pathological data, including histolo- reactions were performed using Oligo dT primer. PCR gical grade and extent of invasion of the tumour, was standardised to obtain amplification of the genes. were recorded. The histological grading was done All reactions were run in triplicate on an ABI Step-one according to the International Society of Urological real-time PCR machine. The output from the real-time Pathology (ISUP) WHO/ISUP (2004) system and the software was analysed. WHO 2016 classification of urothelial tract can- cers [8]. Follow-up data included information about recur- Statistical analysis rence, time to recurrence, number of recurrences, pro- gression documented on histology, time to Continuous variables between different groups of progression, and disease-free survival. bladder carcinoma were compared using ANOVA and the categorical data was analysed by chi-square test. Survival analysis was done using Kaplan–Meier IHC curves and differences in survival between groups The IHC for HER2 was performed in all bladder were tested using the log-rank test. The survival end- cancers using rabbit anti-human c-erbB2 oncopro- point was taken as death due to disease or progres- tein (SP3, Dako, Glostrup, Denmark) after heat- sion. Cox regression analysis was done to look for induced epitope retrieval. Polymer-based techni- factors predicting time to recurrence and progression que with 3,3ʹ-diaminobenzidine (DAB) as the chro- of bladder carcinoma in different groups. The mogen was used for detection of the bound Statistical Package for the Social Sciences (SPSS®), antibody. HER2 expression was scored according version 17 (SPSS Inc., Chicago, IL, USA), was used for to ASCO 2013 HER2 test guidelines for immunohis- statistical analysis and a P < 0.05 was considered as tochemical expression as 0–3+ for breast cancers statistically significant. ARAB JOURNAL OF UROLOGY 269 HER2 3+ staining correlated with amplification by Results FISH (P < 0.05). High-level amplification seen in three The present study included 93 bladder tumours com- tumours correlated with increased gene expression on posed of 25 MIBCs and 68 NMIBCs. Of the 68 NMIBCs, RT-PCR. 37 were low- and 31 were high-grade tumours. Lamina The mean overall survival in low- and high-grade invasion (pT1) was found in most (27/31; 87%) of the NMIBC, and MIBC was 135 and 99, and 61.7 months, high-grade non-invasive tumours, while most (27/37; respectively. 73%) of the low-grade non-invasive tumours were not Kaplan–Meier analysis showed significantly lamina invasive (pTa). On follow-up, recurrence was (P < 0.05) better progression-free survival (PFS) in low- seen in 29 (42.6%; 17 low-grade and 12 high-grade) grade NMIBC followed by high-grade NMIBC and then patients with NMIBC. Progression in Stage/Grade was MIBC. The log-rank test showed that PFS significantly found in 16 (55%; seven low-grade and nine high- correlated with stage, grade and HER2 3+ expression. grade) of these 29 recurrences. Most of the patients In the NMIBC group, low-grade tumours had better were in their sixth and seventh decade of life, with patient survival than high-grade tumours. High-grade a male predominance (n = 82; 88%). There was no NMIBC had a significantly higher HER2 protein expres- significant difference in age at presentation or gender sion (P < 0.05), incidence of progression (P < 0.05), and between the different groups. lamina invasion (P < 0.05). However, there was no On IHC for HER2, 33% (31/93) of bladder cancers correlation with age at presentation, gender, recur- showed 2/3+ expression (Figure 1A and B). HER2 3 rence, and history of prior recurrence. + expression was found in 19% (18/93) of the bladder As described by Chen et al. [6], IHC and FISH results cancers, comprised of 29% (nine of 31) high-grade were in closest agreement when over-expression was NMIBCs and 36% (nine of 25) MIBCs (Table 1). All the defined as 50% of tumour cells showing strong high-grade NMIBCs showing HER2 3+ expression were immunoreactivity. lamina-invasive (pT1). The HER2 protein expression by IHC correlated with the stage (P < 0.05) and grade (P < 0.05) of bladder carcinoma. Discussion All tumours with 2/3+ expression by IHC were sub- Bladder carcinoma is characterised by the presence of jected to FISH to evaluate for the presence of HER2 two different clinical and prognostic subtypes: NMIBCs gene amplification. None of the HER2 2+ tumours had and MIBCs. MIBC has a poor outcome with common HER2 gene amplification by FISH. By contrast, 44.5% progression to metastasis, while NMIBC shows fre- (eight of 18) of the tumours with HER2 3+ expression quent recurrences. by IHC showed gene amplification (Figure 1C) and HER2 is a member of the epidermal growth factor these comprised 8.6% (eight of 93) of all the bladder receptor family having tyrosine kinase activity. carcinomas. Figure 1. IHC for HER2 showing 2+ (A, DAB ×200) and 3+ (B, DAB ×400) expression in NMIBCs; HER2 gene amplification by FISH was seen only in 3+ tumours (C; green signal HER2, red signal CEP17). Table 1. IHC expression of HER2 oncoprotein and correlation with HER2 amplification by FISH according to the ASCO/CAP 2013 Guidelines on bladder urothelial carcinoma [8]. HER2 (2+) HER2 (3+) Amplification by FISH Amplification by FISH Category HER2 (0, 1+), n (%) Cases, n (%) Yes No Cases, n (%) Yes No LG-NMIBC (n = 37) 33 (89.2) 4 (10.8) 0 4 0 - - HG-NMIBC (n = 31) 15 (48.4) 7 (22.5) 0 7 9 (29) 4 5 MIBC (n = 25) 14 (56) 2 (8) 0 2 9 (36) 4 5 LG: low grade; HG: high grade. 270 V. AGRAWAL ET AL. Dimerisation of the receptor results in the autopho- amplification was seen only in high-grade NMIBC. All of sphorylation of tyrosine residues within the cytoplas- these tumours were lamina-invasive (pT1). Soria et al. mic domain of the receptors and initiates a variety of [24], showed 2/3+ HER2 expression in 126 (36%) of 354 signalling pathways leading to cell proliferation and patients with MIBC and high-risk NMIBC refractory to tumorigenesis. The introduction of HER2-directed intravesical chemotherapy/immunotherapy. In the pre- therapies has dramatically influenced the outcome of sent study, we found higher HER2 2/3+ expression patients with HER2-positive breast and gastric/gastro- (46%) in MIBC and high-grade NMIBC. oesophageal cancers. There have been attempts to Studies have shown variable results regarding the translate HER2 over-expression in MIBC into prognostic significance of HER2 expression in urothe- a therapeutic paradigm. However, the results have lial carcinomas, Jimenez et al. [25] studied HER2 not been as promising as in breast cancer, possibly expression by IHC in MIBC and found that irrespective because HER2 over-expression in many urothelial car- of primary or nodal involvement, it was not predictive cinomas occurs without underlying genetic amplifica - of survival. In contrast, other studies have shown that tion [10]. Next-generation sequencing of advanced HER2 immunoreactivity is significantly associated with urothelial bladder cancers has revealed a diverse spec- shorter PFS and recurrence-free survival and disease- trum of actionable genomic alterations in 83% of cases, specific overall survival in urothelial carcinoma including HER2 mutations in 6% of tumours [11]. [3,6,7,26]. We also found a correlation of HER2 protein Most of the studies of HER2 expression in bladder expression and gene amplification with PFS. Patients carcinoma have been performed on MIBC and show with MPUC having HER2 amplification had a worse varying expression ranging between 9% and 81% [12]. cancer-specific survival than those who do not [18]. In In a study on metastatic urothelial bladder carcinoma non-invasive tumours, HER2 over-expression has been treated with platinum-based chemotherapy, Bellmunt found to correlate with the incidence of recurrence et al. [5] reported that HER2 status varies in different and progression [27]. However, the authors considered populations. HER2 3+ staining and FISH amplification HER2 expression as positive if membranous staining in was seen in 22% of Spanish and 4% of Greek cohorts >20% of tumour cells was seen, irrespective of the with no association with overall survival in univariate pattern and intensity, and they found no correlation or multivariate analysis in any of the cohorts. In a study of expression with a higher stage at presentation. of 1005 invasive bladder cancers, Lae et al. [13] found Variable degrees of correlation between HER2 protein lower HER2 2/3+ expression (9%) and gene amplifica - over-expression and amplification have been reported in tion (5%). Other studies have reported HER2 gene different studies. In a study of micropapillary and non- amplification in 10–12% of muscle-invasive and meta- micropapillary urothelial carcinoma, HER2 IHC correlated static tumours [14,15]. In the present study from the with HER2 amplification [17]. There are studies that did Indian subcontinent, we found higher HER 2/3+ expres- not identify a strong association between HER2 protein sion (44%), HER2 3+ expression (36%) and amplifica - over-expression and gene amplification in high-grade tion (16%) in MIBCs. This variability could be due to the invasive urothelial carcinomas [5,28]. Some studies have different populations studied, methods and cut-offs shown that HER2 amplification by FISH is seen only in used, antibodies, as well as tumour heterogeneity HER2 3+ tumours with no amplification in 2+ tumours and advanced stage at diagnosis. [13,29]. We also found HER2 gene amplification by in situ MIBCs with a luminal molecular subtype have been hybridisation only in tumours showing 3+ protein shown to have a significantly higher rate of HER2 expressions by IHC. A recent study found that when alterations than those of the basal subtype, suggesting scored according to the 2013 ASCO/CAP Guidelines, that HER2 activity is also associated with subtype sta- 67% of HER2 3+ expressing advanced urothelial tumours tus [16]. Authors have observed higher HER2 amplifica - were positive by FISH [30]. We found this correlation in tion (15–40%) in micropapillary variant of urothelial 45% of HER2 3+ tumours. This difference could be attrib- bladder cancer (MPUC) compared with non-MPUC uted to the fact that our cohort includes both invasive [17–19]. HER2 over-expression has also been reported and less aggressive non-invasive tumours. in plasmacytoid and lipid cell variants of urothelial Reports suggest that the closest agreement bladder cancers [20,21]. between IHC and FISH exists when over-expression is However, reports of HER2 status in NMIBC are lim- defined as 50% of tumour cells showing immunoreac- ited. A few studies have shown HER2 protein over- tivity [6]. We also observed that IHC and FISH results expression and gene amplification in 4–12% and were in closest agreement when HER2 over-expression 3–8% of NMIBCs, respectively [7,22,23]. Except for an is defined as 50% of tumour cells showing strong occasional study, there is no clear data for HER2 expres- complete membranous immunoreactivity. sion and amplification in the two groups namely, low- A limitation of the present study was that none of our and high-grade NMIBC [6]. In the present study, we patients received HER2-targeted therapy and secondly, found HER2 3+ expression in 13% and gene amplifica - a relatively small sample size due to the exclusion of tion in 6% of NMIBCs. HER2 3+ expression and gene patients in whom follow-up data was <2 years. The ARAB JOURNAL OF UROLOGY 271 approved HER2-targeted therapies for HER2-positive [5] Bellmunt J, Werner L, Bamias A, et al. HER2 as a target in invasive urothelial carcinoma. Cancer Med. breast cancer include two antibodies (trastuzumab and 2015;4:844–852. pertuzumab), an antibody-drug conjugate (ado- [6] Chen PC, Yu HJ, Chang YH, et al. Her2 amplification trastuzumab emtansine), and a small molecule kinase distinguishes a subset of non-muscle-invasive bladder inhibitor (lapatinib). cancers with a high risk of progression. J Clin Pathol. 2013;66:113–119. [7] Lim SD, Cho YM, Choi GS, et al. Clinical significance of substaging and HER2 expression in papillary Conclusion non-muscle invasive urothelial cancers of the urinary Our present study shows that about one-half of non- bladder. J Korean Med Sci. 2015;30:1068–1077. [8] Humphrey PA, Moch H, Cubilla AL, et al. The 2016 invasive tumours show high-grade histology and HER2 WHO classification of tumours of the urinary system 3+ protein expression on IHC Therefore, confirmation and male genital organs-part B: prostate and bladder of HER2 gene amplification by FISH should be per- tumours. Eur Urol. 2016;70:106–119. formed in all HER2 3+ high-grade NMIBC. However, [9] Wolff AC, Hammond ME, Hicks DG, et al. FISH is not recommended for HER2 2+ and low-grade Recommendations for human epidermal growth fac- tor receptor 2 testing in breast cancer: American NMIBC. This contrasts with breast cancers where FISH is society of clinical oncology/college of American recommended for equivocal 2+ tumours. pathologists clinical practice guideline update. Arch HER2 IHC may thus be recommended as part of the Pathol Lab Med. 2014;138:241–256. management protocol in invasive and high-grade [10] Dreicer R. The future of drug development in urothe- NMIBCs. HER2-targeted therapy may be a used as lial cancer. J Clin Oncol. 2012;30:473–475. a treatment modality in such patients. Further studies [11] Ross JS, Wang K, Al-Rohil RN, et al. Advanced urothelial carcinoma: next-generation sequencing reveals are required to understand the molecular mechanisms, diverse genomic alterations and targets of therapy. other than gene amplification that account for the Mod Pathol. 2014;27:271–280. high rates of HER2 protein over-expression in bladder [12] Grivas PD, Day M, Hussain M. Urothelial carcinomas: cancers. a focus on human epidermal receptors signaling. Am J Transl Res. 2011;3:362–373. [13] Lae M, Couturier J, Oudard S, et al. Assessing HER2 gene amplification as a potential target for therapy in Acknowledgments invasive urothelial bladder cancer with a standardized The authors acknowledge the technical support of Ms methodology: results in 1005 patients. Ann Oncol. Madhulika Tewari and Mr Vishwakarma for IHC and FISH 2010;21:815–819. experiments. [14] Millis SZ, Bryant D, Basu G, et al. Molecular profiling of infiltrating urothelial carcinoma of bladder and non- bladder origin. Clin Genitourin Cancer. 2015;13:e37–49. [15] Hansel DE, Swain E, Dreicer R, et al. HER2 overexpres- Funding sion and amplification in urothelial carcinoma of the bladder is associated with MYC co-amplification in This work was supported by the Sanjay Gandhi Postgraduate a subset of cases. Am J Clin Pathol. 2008;130:274–281. Institute of Medical Sciences (SGPGIMS) [PGI/DIR/RC/800/ [16] Kiss B, Wyatt AW, Douglas J, et al. Her2 alterations in 2013]. muscle-invasive bladder cancer: patient selection beyond protein expression for targeted therapy. Sci Rep. 2017;7:42713. ORCID [17] Bertz S, Wach S, Taubert H, et al. Micropapillary mor- phology is an indicator of poor prognosis in patients Vinita Agrawal http://orcid.org/0000-0003-1806-7142 with urothelial carcinoma treated with transurethral resection and radiochemotherapy. Virchows Arch. 2016;469:339–344. References [18] Schneider SA, Sukov WR, Frank I, et al. Outcome of patients with micropapillary urothelial carcinoma fol- [1] Ploeg M, Aben KK, Kiemeney LA. The present and lowing radical cystectomy: ERBB2 (HER2) amplification future burden of urinary bladder cancer in the world. identifies patients with poor outcome. Mod Pathol. World J Urol. 2009;27:289–293. 2014;27:758–764. [2] Netto GJ. Molecular diagnostics in urologic malignan- [19] Ching CB, Amin MB, Tubbs RR, et al. HER2 gene ampli- cies, a work in progress. Arch Pathol Lab Med. fication occurs frequently in the micropapillary variant 2011;135:610–621. of urothelial carcinoma: analysis by dual-color in situ [3] Kruger S, Weitsch G, Buttner H, et al. HER2 hybridization. Mod Pathol. 2011;24:1111–1119. over-expression in muscle-invasive urothelial carci- [20] Kim B, Kim G, Song B, et al. HER2 protein overexpres- noma of the bladder: prognostic implications. sion and gene amplification in plasmacytoid urothelial Int J Cancer. 2002;102:514–518. carcinoma of the urinary bladder. Dis Markers. [4] Kruger S, Weitsch G, Buttner H, et al. Overexpression of 2016;2016:8463731. c-erbB-2 oncoprotein in muscle-invasive bladder car- [21] Miyama Y, Morikawa T, Nakagawa T, et al. Lipid cell cinoma: relationship with gene amplification, clinico- and micropapillary variants of urothelial carcinoma of pathological parameters and prognostic outcome. the ureter. Case Rep Oncol. 2015;8:515–519. Int J Oncol. 2002;21:981–987. 272 V. AGRAWAL ET AL. [22] Kruger S, Lange I, Kausch I, et al. Protein expression urothelial carcinoma patients receiving adjuvant and gene copy number analysis of topoisomerase M-VEC chemotherapy? Urol Int. 2007;79:210–216. 2alpha, HER2 and P53 in minimally invasive urothelial [27] Hegazy R, Kamel M, Salem EA, et al. The prognostic carcinoma of the urinary bladder–a multitissue array significance of p53, p63 and her2 expression in study with prognostic implications. Anticancer Res. non-muscle-invasive bladder cancer in relation to 2005;25:263–271. treatment with bacilli Calmette-Guerin. Arab J Urol. [23] Olsson H, Fyhr IM, Hultman P, et al. HER2 status in 2015;13:225–230. primary stage T1 urothelial cell carcinoma of the urin- [28] Caner V, Turk NS, Duzcan F, et al. No strong association ary bladder. Scand J Urol Nephrol. 2012;46:102–107. between HER-2/neu protein overexpression and gene [24] Soria F, Moschini M, Haitel A, et al. The effect of HER2 amplification in high-grade invasive urothelial status on oncological outcomes of patients with inva- carcinomas. Pathol Oncol Res. 2008;14:261–266. sive bladder cancer. Urol Oncol. 2016;34(533):e1–10. [29] 5Li J, Jackson CL, Yang D, et al. Comparison of tyrosine [25] Jimenez RE, Hussain M, Bianco FJ Jr, et al. Her-2/neu kinase receptors HER2, EGFR, and VEGFR expression in overexpression in muscle-invasive urothelial carci- micropapillary urothelial carcinoma with invasive noma of the bladder: prognostic significance and com- urothelial carcinoma. Target Oncol. 2015;10:355–363. parative analysis in primary and metastatic tumors. [30] Moktefi A, Pouessel D, Liu J, et al. Reappraisal of HER2 Clin Cancer Res. 2001;7:2440–2447. statusin the spectrum of advanced urothelial carci- [26] Tsai YS, Tzai TS, Chow NH. Does HER2 immunoreactiv- noma: a need of guidelines for treatment eligibility. ity provide prognostic information in locally advanced Mod Pathol. 2018;31(8):1270–1281.
Journal
Arab Journal of Urology
– Taylor & Francis
Published: Oct 1, 2020
Keywords: Bladder carcinoma; non-invasive bladder carcinoma; HER2 oncogene; fluorescent in situ hybridisation; immunohistochemistry; gene amplification
