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Year : 2022  |  Volume : 65  |  Issue : 3  |  Page : 604-609
Effect of HER2 and Fascin expression on muscle-invasive bladder cancers: Classification by basaloid and luminal phenotypes

1 Pathology Department, Faculty of Medicine, Tekirdağ Namık Kemal University, Tekirdağ, Turkey
2 Urology Department, Faculty of Medicine, Tekirdağ Namık Kemal University, Tekirdağ, Turkey

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Date of Submission30-May-2021
Date of Decision14-Feb-2022
Date of Acceptance15-Feb-2022
Date of Web Publication07-Jun-2022


Purpose: The present study aims to identify basaloid and luminal molecular groups and the p53-like sub-group, which is a sub-group of the luminal group, using a specific immunohistochemical panel and investigate human epithelial growth factor receptor 2 (HER2)/Neu and Fascin expression in these groups to analyze their relationship with clinicopathological features and prognosis in a cohort of cases with muscle-invasive urothelial bladder carcinoma (MIBC). Material and Methods: An immunohistochemical panel that included GATA-3, CK20, CD44, and CK5/6 was used to identify molecular sub-groups based on expression in 44 cases of MIBC. HER2/Neu and Fascin expression in basal, luminal, and p53-like groups and the relationship with clinicopathological features and prognosis were investigated. Results: The distribution of the molecular sub-groups determined by immunohistochemistry was as follows: 23 luminal cases (52.3%), 16 basal cases (36.4%), and 5 (11.4%) p53-like cases. There was a statistically significant difference in tumor size across the groups, with the greatest size in the p53-like group (p = 0.001). A statistically significant difference was observed in HER2/Neu expression between the molecular sub-groups (p = 0.017). Comparison of survival and HER2/Neu scores revealed shorter survival in patients with an HER2/Neu score of 3 + compared to those with scores of 0, 1+, and 2+ (p = 0.109). Fascin immunoreactivity was more common in the p53-like and basal groups compared to the luminal group (p = 0.036). Conclusion: Despite the limited number of cases in the MIBC group, our results support that HER2/Neu expression in the luminal sub-group and Fascin expression in basal and p53-like groups may be used as a negative prognostic marker. Multi-center studies that include large case series are warranted in this field.

Keywords: Basal, bladder cancer, fascin, HER2/Neu, immunohistochemistry, luminal, p53-like

How to cite this article:
Arslan A&, Karabağ S, Akgül M. Effect of HER2 and Fascin expression on muscle-invasive bladder cancers: Classification by basaloid and luminal phenotypes. Indian J Pathol Microbiol 2022;65:604-9

How to cite this URL:
Arslan A&, Karabağ S, Akgül M. Effect of HER2 and Fascin expression on muscle-invasive bladder cancers: Classification by basaloid and luminal phenotypes. Indian J Pathol Microbiol [serial online] 2022 [cited 2022 Aug 15];65:604-9. Available from: https://www.ijpmonline.org/text.asp?2022/65/3/604/346859

   Introduction Top

Urothelial carcinoma originates from the urothelial lining epithelium of the bladder. It is the seventh most common tumor worldwide and diagnosed at a mean age of 65–70 years, more commonly in men compared to women.[1],[2],[3] These tumors are staged with the tumor, node, and metastasis system based on their ability to invade the lamina propria and muscle layers and are graded according to their cellular histological features. Approximately 70–80% of urothelial carcinomas of the bladder exhibit lamina propria invasion (pT1) and are of a low histological grade, superficial (pTa) at the time of diagnosis. However, 30–20% of the cases are muscle-invasive (pT2) tumors with a high histological grade.[1],[2],[3] The precursor cellular lesion of muscle-invasive urothelial bladder carcinoma (MIBC) is dysplastic urothelial epithelial and urothelial carcinoma in situ. However, 15% of cases with stage pTa and pT1 at the time of diagnosis may progress to MIBC.

Tumor molecular sub-typing with immunohistochemical (IHC) staining, which may be easily applied in tissues during the histopathological evaluation of transurethral resection materials, may reveal neoadjuvant treatment options for patients before radical cystectomy surgery. Therefore, molecular sub-typing may prove to be useful in classifying patients and predicting prognosis and outcomes of oncological treatments.[1],[2],[4] Because cellular differentiation of the urothelium is only related to the cancer cell and stromal phenotypes[5],[6],[7] in molecular sub-types of MIBC, we focused on molecular sub-typing in MIBC cases. In molecular sub-types, it is important to investigate the molecules that predict therapeutic targets as different clinical responses would be expected in different sub-groups. Among these targets, the human epidermal growth factor receptor 2 (HER2) gene encodes a 185 kDa transmembrane receptor tyrosine kinase.[8],[9] HER2 amplification leading to overexpression of the resulting protein is the first mechanism in the development of 0–25% of urothelial bladder carcinomas.[10] Fascin is an actin-bundling protein found in cell membrane protrusions and cytoplasmic actin bundles. Fascin is thought to be a potential predictive factor in tumor cells as it appears to be effective in adhesion, motility, and invasive processes.[11],[12]

Clinical guidelines focus on cystectomy and perioperative platinum-based chemotherapy regimens in the management of localized MIBC. Cisplatin treatment provides survival longer than 24 months in 15% of patients with disease progression manifesting as distant organ metastasis after cystectomy.[13],[14],[15],[16],[17],[18] Immunotherapy with checkpoint inhibitors results in successful outcomes in patients with urothelial carcinoma.[19]

At a molecular level, muscle-invasive urothelial carcinoma of the bladder is thought to arise from urothelial dysplasia carcinoma in situ transition through deletion at 9p and 9q with inactivation of TP53 or the retinoblastoma tumor suppressor gene (RB1), followed by carcinoma in situ transition to the invasive form through inactivation of the cyclin-dependent kinase inhibitor 2A (CDKN2A) and CDKN2B genes. However, a small portion of the MIBC group is also considered to originate from low-grade non-invasive urothelial carcinoma through mutation in the fibroblast growth factor receptor (FGFR3) oncogene, 9q deletion, the tyrosine kinase receptor phosphatidylinositol 3 kinase (PI3K)/AKT/mTOR pathways, TP53 activation, and homozygous loss of CDKN2A. The CDKN2A gene encodes the p16INK4a and p14ARF proteins, which regulate the functions of RB1 and TP53. Urothelial carcinoma cells may utilize this pathway as an alternative route to inactive TP53/RB1.[20]

Choi et al.[21] classified urothelial carcinoma cases as basal, luminal, and p53-like according to the immunohistochemical GATA-3, FGFR3, FOXA1, UPK3A, PPARG, ERBB2, CK20, CK5, CK14, CK6A, CK6B, CK6C, and FGFR3 mutation analysis. In the present study, the basal sub-type was negative for GATA-3, FGFR3, FOXA1, UPK3A, PPARG, ERBB2, and CK20 and positive for CK5, CK14, CK6A, CK6B, and CK6C, with no FGFR3 mutation detected. The luminal sub-type was negative for GATA-3, FGFR3, FOXA1, UPK3A, PPARG, and ERBB2; positive for CK20; negative for CK5, CK14, CK6A, CK6B, and CK6C; and positive for GFR3 mutation. No FGFR3 mutation was detected in the p53-like group, and this type was weakly positive for GATA-3, FGFR3, FOXA1, UPK3A, PPARG, ERBB2, and CK20 and negative for CK5, CK14, CK6A, CK6B, and CK6C. These immunohistochemical staining results suggested that the p53-like group may be a luminal sub-group.[21]

Damrauer et al. stratified bladder carcinomas into basal and luminal bladder groups using immunohistochemical studies. In this study, the basal sub-group was positive for CK5/6 and CD44 and negative for CK20, whereas the luminal sub-group was negative for CK5/6 and CD44 and positive for CK20.[22]

In the present study, we stratified MIBC cases into basal, luminal, and p53-like groups based on their chosen genetic/molecular pathways to investigate the effect of these molecular sub-groups on survival, and we also evaluated Fascin and HER2/Neu expression in these molecular sub-groups to explore whether these markers may be of predictive value.

   Materials and Methods Top

Our study included 44 patients diagnosed with high-grade muscle-invasive bladder tumor during the initial histopathological investigation following transurethral resection performed at the urology clinic upon a provisional diagnosis of bladder tumor in 2010–2019. Clinical and follow-up information of the patients was retrieved through a retrospective review of the data in patient files. Information on age, gender, tumor diameter, the presence of metastasis, and survival was collected from these medical records. The protocols recommended in the European Association of Urology Guidelines were applied in the treatment and follow-up of patients with bladder tumors. Slides of the 44 patients were retrieved from the archive and concurrently re-assessed by two pathologists under an Olympus Bx46 light microscope to identify eligible tumor blocks without necrosis or hemorrhage.


For the IHC analysis, 3-micron sections were obtained using the paraffin blocks of these 44 patients. The sections were transferred to positive-charged microscope slides, which were allowed in an incubator at 60°C for an hour and de-paraffinized with xylene for 15 minutes. The samples were then passed through decreasing grades of alcohol for hydration and finally washed in distilled water. The slides were subsequently placed in a BenchMark XT device and stained with CD44 (IHC044), GATA-3 (IHC583), HER2/Neu (IHC042), CK20 (Ks20.8), CK5/6(COCKTAIL) (EP24/EP67), and Fascin (Ep116) antibodies. Slides were dried and coated with an appropriate coating material. Cytoplasmic, membranous staining with CD44, CK20, and CK5/6 in tumor cells was assessed as 1: positive, and no staining was considered 0: negative. Nuclear staining for GATA-3 was assessed as 1: positive, and no staining was considered 0: negative. IHC expression of basal and luminal molecular sub-groups is shown in [Figure 1]. For Fascin, immunoreactivity was scored on a scale of 0–3 based on the percentage of positive tumor cells. This scale represented 0: <25%; 1: 25–50%; 2: 50–75%; 3: >76%.[11],[12],[23],[24],[25] For HER2/Neu immunoreactivity, the scores were interpreted as follows: 0, no immunoreactivity; 1, weak immunoreactivity in <10% of tumor cells; 2, strong immunoreactivity in less than 10% of tumor cells; 3, complete membranous (also known as the “chicken wire pattern”) strong immunoreactivity in 10% of tumor cells. Accordingly, a score of 3 was considered as positive, 1–2 as suspicious, and 0 as negative.[25],[26],[27] HER2/Neu and Fascin staining scores are in [Figure 2].{Figure 1}{Figure 2}


Patient demographics and data were analyzed using the SPSS 24 program. Variables were expressed as frequency, percentage, mean (arithmetic mean, median), standard deviation (min–max), tables, and graphs. In the event of non-normal data distribution, the Mann–Whitney U test was utilized for groups of 2 and the Kruskal–Wallis test was used for groups >2, whereas Kaplan–Meier estimates were utilized for the survival analysis. A P value lower than 0.05 was considered statistically significant.


The study was approved by the Non-Interventional Clinical Trials Ethics Committee of Tekirdağ Namık Kemal University (protocol 2020.103.05.04).

   Results Top

The mean age of the 44 patients included in the study was 70.7 years (min: 51 years, max: 92 years). The genders of these patients were 34 (77.3%) males and 10 (22.7%) females. The histopathological grade was reported as pT2 in all 44 patients. Systemic assessment of the patients revealed distant organ metastasis in four patients (9.09%) at the time of diagnosis, which was metastasis in the lung in three patients and the liver in one patient. Radical cystectomy surgery was performed in 21 patients, whereas 11 received chemotherapy and radiotherapy, and two received chemotherapy alone. A total of ten patients refused treatment. The mean survival in the molecular sub-groups of MIBC was 14.4 ± 4.2 months in the p53-like sub-group, 18 ± 3.3 months in the basal group, and 17.5 ± 2.2 months in the luminal group. Although the shortest survival was observed in the genomic instability group, there was no statistically significant difference between the groups (p = 0.773). Survival analysis of the cases by molecular sub-group is presented in [Figure 3]. IHC profiles of the cases are shown in [Table 1]. The mean tumor size was 60 mm in the genomic instability sub-group, 57.00 mm in the basal sub-group, and 44.54 mm in the luminal sub-group. Tumor size showed a statistically significant difference among the sub-groups (p = 0.001), and the largest tumor diameter was seen in the p53-like group.{Figure 3}{Table 1}

The distribution of HER2/Neu staining scores by molecular sub-type is presented in [Table 2]. The survival was 10.7 ± 2.2 months in those with an HER2/Neu score of 3+, 18.3 months in those with score 0, 18.0 ± 16 months in those with a score of 1+, and 24.0 ± 12.0 months in those with a score of 2+ (p = 0.109). Although the difference was not statistically significant, the shortest survival was seen in the 3+ group. [Figure 4] shows Her2/Neu staining scores and survival analysis of the patients.{Figure 4}{Table 2}

There was a statistically significant difference in Fascin expression score across the molecular sub-groups (p = 0.036). The distribution of Fascin scores by molecular subtype is presented in [Table 3]. The mean survival was 22.3 ± 4.52 months, 19.3 ± 4.2 months, 17.0 ± 2.9 months, and 15.2 ± 2.9 months in those with scores of 0, 1+, 2+, and 3+, respectively. Fascin staining scores were not statistically associated with survival and distant organ metastasis (p = 0.672, P = 0.62). Positive nuclear staining was observed across all groups in all 44 cases in the GATA-3 assay.{Table 3}

   Discussion Top

HER2/Neu and Fascin expression and survival are different in molecular sub-groups determined by IHC in MIBC. HER2/Neu may offer a predictive factor in the luminal sub-group, and Fascin may offer the same in basaloid and p53-like groups. Furthermore, these markers may also be potential therapeutic targets in future studies in this field.

IHC is a convenient, inexpensive, and rapid method for qualitative purposes that has been in use for a long time in pathology labs to determine cell differentiation in routine cancer diagnosis. Therefore, IHC may be employed as an ideal method in routine practice for molecular sub-typing of urothelial carcinomas.[6],[28],[29],[30]

There are several studies that have classified genetic sub-types of urothelial carcinoma.[1],[2],[5],[6],[7],[20],[21],[22],[28],[30],[31],[32],[33],[34],[35],[36] In these studies, sub-typing has been performed with receptor tyrosine kinases, mainly FGFR3, ERBB2, EGFR, cytokeratins, and cell adhesion genes, and by mutation frequency for FGFR3, PIK3CA, and TP53. Urothelial carcinomas were stratified as basal and luminal in some of the studies, and the basal sub-type has been reported to have a more aggressive course.[6] In some studies, genomic differences between the basal, luminal, and p53-like groups[1],[2],[22] were detected using complex IHC panels. These studies suggested that molecular classification may offer a clinical predictive value and biomarkers may raise hope for potential treatment.[31]

In the present study, we stratified MIBC into three groups, that is, as basal, luminal, and p53-like using an IHC panel. We observed a larger tumor size and shorter overall survival in the p53-like group compared to basal and luminal groups. There was no difference between the groups in terms of distant organ metastasis. Consistent with the literature, these molecular differences between the MIBC sub-groups were considered associated with different clinical behaviors, and we believe that these differences may be a promising option for treatment.

HER2/Neu score 3 + expression detected by IHC was particularly positive, and overall survival was shorter in the luminal sub-group among the molecular sub-groups.[9],[26],[27] The absence of such a relationship in patients with an HER2/Neu score of 1+ or 2+ was associated with tumor heterogeneity. Therefore, we believe that a score of 3+ based on IHC should be recognized as significant, whereas patients interpreted as scores 1+ and 2+ should certainly be re-assessed by in situ hybridization to be assigned to a negative or positive group to allow improved estimates of survival. Furthermore, we believe that a drug molecule used for the treatment of breast carcinoma in the HER2/Neu 3+ group may also be a treatment option for these patients.[9],[10],[26],[34]

Yorozu et al.[28] performed basaloid/luminal sub-typing by IHC in 83 patients with renal pelvis carcinoma and 65 with urothelial carcinoma located in the ureter. They evaluated the HER2 protein by fluorescent in situ hybridization (FISH) in basal/luminal sub-types and compared the results with clinicopathological findings. Reporting distribution of their cases as 46% basal and 54% luminal, they detected overexpression of the HER2 protein in 14% of the study cohort. They found an increased rate of HER2 protein expression in the luminal sub-group compared to the basal sub-group (22% vs 4%; P < 0.030). Finally, the authors reported shorter survival in HER2-positive patients.[28] In the present study, HER2-positive patients were more common in the luminal group, and we observed shorter survival in these patients compared to the other sub-groups (p = 0.036).

Karasawidou F. et al.[24] evaluated the intensity of Fascin expression in patients with MIBC and non-muscle invasive bladder cancer and compared the expression between these groups. They detected stronger reactivity in the invasive group (p = 0.001).

To the best of our knowledge, no study has investigated and compared Fascin expression in molecular MIBC sub-groups to date. We aimed to sub-type MIBC, a group of tumors with an aggressive clinical course, and determine the difference in Fascin expression across these sub-types. Our results revealed greater Fascin expression in basal and p53-like groups. Comparison of survival data showed that the p53-like group had the shortest survival with 14.40 ± 4.23 months. Therefore, Fascin expression may be associated with aggressive behavior in molecular sub-groups.[35] Fascin immunoreactivity reflecting migration was more common in p53-like and basaloid sub-groups than in the luminal sub-group. In our MIBC cohort, 38 (86.36%) out of the 44 cases were Fascin-positive. Fascin may be considered as an important predictive factor for invasion; however, we were unable to establish a statistical association between Fascin immunoreactivity and survival or distant organ metastasis. The fact that metastasis was present in only four patients out of the 44 cases included in our study may explain the lack of a statistical association between Fascin expression and metastasis. The differences in HER2/Neu and Fascin expression noted in basal and p53-like groups compared to the luminal group may be resulting from the neuroendocrine, squamous, and mesenchymal-like genetic characteristics, intra-tumoral heterogeneity, and differences in the differentiation stages of the originating tumoral stem cells.

Our study has certain limitations that limit interpretation of the data, which mainly include the small study sample, heterogeneous demographics of the cases, and the fact that not all subjects were treated with cystectomy or the same chemotherapy regimen, including 11 patients who refused all treatment options. Furthermore, we believe that the staining patterns may not be optimal in the paraffin-block sections retrieved retrospectively from the 10-year archive.

   Conclusion Top

Our results support the presence of significant differences in MIBC sub-groups in terms of clinical behavior as well as HER2/Neu and Fascin expression. HER2/Neu scores of 3 + detected by IHC may be used as a negative predictive marker in the luminal sub-group. In addition, Fascin expression may offer a negative predictive value in basal and p53-like groups. Our study might highlight the comprehensive, multi-center studies with case series that reflect the clinical course of disease through the mixed sub-molecular pathways, and their reflection at a cellular level in MIBC may shed light on individualized treatment modalities.

Financial support and sponsorship

The financial support for this study was provided by the investigators.

Conflicts of interest

There are no conflicts of interest.

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Correspondence Address:
Ayşegül İ Arslan
Tekirdağ Namık Kemal University, Faculty of Medicine, Pathology Department, Tekirdağ
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ijpm.ijpm_537_21

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