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Year : 2021  |  Volume : 64  |  Issue : 1  |  Page : 84-90
Correlation of cyclin D1, HER2, and AMACR expressions with histologic grade in bladder urothelial carcinomas

1 Department of Pathology, Pamukkale University, Denizli, Turkey
2 Department of Pathology, Isparta City Hospital, Isparta/, Turkey

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Date of Submission19-Dec-2019
Date of Decision20-Feb-2020
Date of Acceptance27-Jul-2020
Date of Web Publication8-Jan-2021


Background and Objective: Bladder cancer is the ninth most common type of cancer worldwide. We aimed to investigate the relationship between tumor grade, lamina propria invasion, muscularis propria invasion, and lymphovascular invasion and human epidermal growth factor receptor 2 (HER-2), cyclin D1, and alpha-methyl-CoA racemase (AMACR) expressions in bladder cancer. Materials and Methods: The study included patients who underwent complete TURBT. In total, 72 cases of bladder cancer diagnosed by two pathologists were selected. AMACR, HER-2, cyclin D1 expressions were detected immunohistochemically. Results: The study population comprised 80% (57) males and 20% (15) females (mean age, 68 years). Further, 35 cases were noninvasive and 37 invasive urothelial carcinoma and 38 patients had low-grade tumor and 34 high-grade tumor. Intense immunostaining was observed with cyclin D1 for 75% tumors, AMACR for 39%, and HER-2 for 86%. High expressions of cyclin D1 and AMACR were observed in high-grade tumors (P < 0.05 and P < 0.005, respectively). High expression of HER-2 (2 and 3 positive) was found both at low- and high-grade tumors (84% and 88%, respectively). Conclusion: Cyclin D1, AMACR expressions were found to be significant predictive factors of high-grade tumors. High Her-2 expression in patients with bladder carcinoma may indicate that they are potential targets for treatment. These markers may be important in determining prognosis of tumors and may be valuable for guiding treatment options.

Keywords: Alpha-methyl-CoA racemase, bladder cancer, cyclin D1, human epidermal growth factor receptor 2

How to cite this article:
Karakaya YA, Oral E. Correlation of cyclin D1, HER2, and AMACR expressions with histologic grade in bladder urothelial carcinomas. Indian J Pathol Microbiol 2021;64:84-90

How to cite this URL:
Karakaya YA, Oral E. Correlation of cyclin D1, HER2, and AMACR expressions with histologic grade in bladder urothelial carcinomas. Indian J Pathol Microbiol [serial online] 2021 [cited 2023 Sep 29];64:84-90. Available from:

   Introduction Top

Bladder cancer is the sixth most common malignancy in male patients worldwide and is the ninth most common malignancy in both genders; approximately 16,000 of patients with bladder cancer were expected to die due to the disease. The incidence of bladder cancer in men is four times higher than that in women, and it is two times higher in Caucasians than in blacks due to unknown reasons. The development of bladder cancer is a complex multistage process involving oncogenes, tumor suppressor genes, and genes involved in the recognition and repair of DNA damage.[1] The loss of tumor suppressor genes such as P53 or Rb is common in the early stages, but the amplification of oncoproteins is more common in advanced stages. Besides, certain mutations, which lead to bladder cancer, have not yet been fully understood and the mutation of tumor suppressor genes remains uncertain. Relatively fewer studies have been conducted on the tumor mechanisms of bladder cancer compared with that of other types of cancer. Therefore, it is critically important to set molecular targets for new therapeutic options.[2]

Cyclin D1 is a regulator of CDK4/6, which plays a role as a checkpoint in the G1/S phase transition in the cell cycle. Cyclin D1 activity is regulated by the Rb protein. Cyclin D1 and/or Rb mutations are frequently observed in many cancers including lymphoma and retinoblastoma. In a study, the hypothesis was supported that the progressive increase of cyclin D1 and p53 immunoreactivities along with the progression from hyperplasia through papilloma to carcinoma plays a role in urinary bladder carcinogenesis in rats.[3]

Alpha-methyl-CoA racemase (AMACR, p504s), a biomarker with diagnostic potential in various solid tumors, is a peroxisomal and mitochondrial enzyme involved in the oxidation of branched-chain fatty acids and cholesterol metabolites. AMACR is commonly used as a positive marker of prostate cancer and has been shown to have prognostic significance in prostatic and colorectal cancer.[4]

The human epidermal growth factor receptor 2 (HER2), which is a member of the EGF receptor family, is a type I transmembrane tyrosine kinase growth factor receptor that activates intracellular signaling pathways in response to extracellular signals. Overexpression of the HER-2 protein plays a role in oncogenesis and tumor proliferation by increased angiogenesis and cell proliferation and decreased cell–cell adhesion. The significance of overexpression of HER2 in breast cancer is well known, and patients with breast cancer are treated with trastuzumab. The overexpression of HER-2 has also been observed in certain high-grade ureteral carcinomas.[5]

So far, the knowledge about the expressions of AMACR, Her-2, and cyclin D in bladder cancer is limited. This is the first comprehensive study to correlate immunohistochemically detected AMACR expression with histopathological grading programs based on high- and low-grade bladder cancer (World Health Organization (WHO) and the WHO/International Urological Pathology Society system). The role of AMACR in the pathophysiology of bladder cancer has been disregarded so far. We conducted this study to evaluate the tumor grade, prognosis, and treatment-guiding characteristics of AMACR, Her-2, and cyclin D1 expressions.

   Materials and Methods Top

Case selection

The study population comprised patients who underwent complete TURBT. In total, 72 cases of bladder cancer (noninvasive and invasive) diagnosed by two pathologists between June 2011 and February 2017 were selected. These cases were re-evaluated and classified according to the 2016 WHO classification. All cases were rereviewed by two pathologists (YK and EO). The hospital records of each patient were retrospectively reviewed.

Clinicopathological parameters including sex, age, grade, and depth of invasion were documented. Markers of early aggressiveness including angiolymphatic and perineural invasion, depth of invasion, stage, and metastatic disease were also documented.


The ethical approval of this study was discussed by the Non-Interventional Clinical Research Ethics Committee of Pamukkale University at the Board Meeting dated 07.05.2019 and numbered 09 and accepted with the date and number of 13/05/05/E.33155.

Statistical analysis

All differences were considered statistically significant if P < 0.05; P values were two tailed. All calculations were performed using statistical software package SPSS version 20. Kaplan– Meier survival analysis, Mann–Whitney U test, and Chi-square test were used for statistical analysis.


Immunohistochemistry was performed on 5-micron sections cut from routinely processed formalin-fixed, paraffin-embedded tissue blocks. The tissue sections were deparaffinized and rehydrated, pretreated with 0.01 M citrate buffer (pH 6), and then stained for HER2 (clon CB11 Leica), cyclin D1 (clon EP12 Leica), AMACR (clon EPMU-1 Leica) by Leica Bond-Max automated immunostainer. Appropriate positive and negative controls were used throughout.

HER2 positivity was assessed using the ASCO scoring system, evaluating only membranous staining. The level of HER2 protein expression was semiquantitatively assessed by the intensity and percentage of staining and scored on a scale from 0 to 3+. Scores of 0 and 1+ were categorized as negative, and greater than 10% cells with 2+ and 3+ as positive. FISH wasn't done for cases with HER2 Score 2.

This study was completed following the guidelines of and with approval from our institutional review board. Histopathological tumor grade was according to the 2016 WHO classification of tumors of the urothelial tract.

For cyclin D1: The expression of cyclin D1 was measured in 10 successive high-power fields (x400). Cyclin D1 was expressed with a nuclear brown color. The immunostaining intensity was graded as negative = 0, weak = 1, moderate = 2, or strong = 3. The fraction of cells stained with cyclin D1 were counted as a percentage and scored (1 < 15%, 2 = 15%–50%, and 3 < 50%) Scores of 0 and 1+ were categorized as negative, and greater than 15% cells with 2+ and 3+ as positive.

AMACR protein expression was scored as negative, no stain and weak stain (faint cytoplasmic staining or granular apical staining), moderate (diffuse granular cytoplasmic stain), and strong (diffuse intense cytoplasmic stain). Only moderate and strong staining was considered positive staining based on prior work.[6]

   Results Top

The patients were 80% (57) males and 20% (15) females (mean age, 68 years). Further, 38 patients had low-grade tumor and 34 high-grade tumor [Figure 1]a and [Figure 1]b. Intense immunostaining was observed with cyclin D1 for 75% of tumors [Figure 2], AMACR for 39% [Figure 3], and HER 2 for 86% [Figure 4]. High expressions of cyclin D1 and AMACR were observed in high-grade tumors (P < 0.05 and P < 0.005, respectively) [Table 1]. High expression of HER 2 (2 and 3 positive) was found both at low and high grade tumors (84% and 88%, respectively). AMACR and cyclin D1 showed higher expression in tumors with lamina propria invasion than in those without lamina propria invasion (P < 0.05 and P < 0.05, respectively) [Figure 5], [Figure 6]. Mortality rate was higher in males and patients with high grade tumors [Table 2]. The mean age of the surviving cases was 67 years and that of the nonsurviving cases was 73 years (P < 0.05).
Figure 1: (a) The area of high-grade urothelial carcinoma, marked nuclear atypia, and pleomorphism (H-E, x200). (b) The area of low-grade urothelial carcinoma (H-E, x100)

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Figure 2: Cyclin D1 showed high nuclear expression in high-grade tumors (IHK, x200)

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Figure 3: AMACR showed high cytoplasmic immunohistochemical expression in high-grade tumors (IHK, x100)

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Figure 4: HER-2 showed strong membranous immunohistochemical expression in high-grade tumors (IHK, x200)

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Figure 5: Ratios of staining cyclin D1, HER-2, AMACR in tumors with lamina propria, lymphovascular invasion, muscularis propria invasion

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Figure 6: Cyclin D1, HER-2, and AMACR expressions in high-grade and low-grade tumors

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Table 1: Patient characteristics in different patient groups

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Table 2: Mortality rate was higher in males and patients with high-grade tumors

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   Discussion Top

Overall 5-year survival rate was approximately 50% in all patients with muscle-invasive bladder cancer, and many progressed to metastatic disease.[7] Locally developed, non-resectable or metastatic bladder cancers have worse prognosis, and the overall 5-year survival rate is usually around 10%–15%.[8]

HER-2/neu overexpression in urothelial carcinomas has been studied by many authors because it has been shown that this protein plays a significant role in the pathogenesis of these tumors, similar to that in breast cancer. In malignant tumors, protein overexpression is a direct result of gene amplification. HER-2/neu overexpression is associated with poor prognosis in malignant breast, ovary, prostate, pancreas, and liver tumors and is significant in urothelial carcinomas of the bladder, particularly in poorly differentiated carcinomas. The expression of HER-2/neu in the bladder is variable, has an incidence ranging between 2% and 74%, and still has a controversial prognostic significance.[9] This heterogeneity is probably due to the differences in antibodies, protocols, and interpretation. The results of this study is in accordance with those obtained in previous studies and confirm the considerably heterogeneity of HER2/neu protein overexpression in high-grade urothelial carcinomas.[10]

First, a large series of studies have shown that HER-2/neu overexpression is observed in 28% of T2–T4 urothelial tumors; however, the HER-2/neu expression is not correlated with tumor stage or survival. In a study, HER-2/neu expression was observed in 70% of low- and high- grade urothelial bladder tumor each.[9]

In our study, high expression of HER-2 (2 and 3 positive) was found both in patients with low-and high-grade tumors (84% and 88%, respectively). In two different cohort studies, Belmunt et al. found HER-2 overexpression in 20% and 4% of 213 patients with metastatic urothelial carcinoma relative to a specific cohort. High protein expression rate (71%) has been reported in 39 metastatic or unresectable patients. High Her-2 rate in patients with advanced bladder cancer indicates that they are a potential target for treatment.[11]

Trastuzumab is a monoclonal antibody that targets the HER-2 receptor, mediating antibody-dependent cellular cytotoxicity of tumor cells preferably expressing HER-2.[12] It has been approved by the United States Food and Drug Administration. HER-2 expression therapy is used in adjuvant therapy and metastatic carcinomas. Moreover, it is used in breast cancer and stomach and gastroesophageal adenocarcinoma and their metastatic carcinomas. In urothelial cancer, trastuzumab and most of the other agents targeting HER-2 are used in prospectively advanced or metastatic and mostly treatment-resistant patients. The NRG Oncology RTOG 0524 study is a phase 1/2 study of muscle-invasive bladder cancer patients who do not have metastatic disease but are not eligible for cystectomy and are treated with a bladder protection strategy.[13]

Overall, 60% of patients treated with paclitaxel/trastuzumab and 74% of patients treated with paclitaxel monotherapy have completed trastuzumab therapy, and it has been suggested to have better clinical efficacy in advanced urothelial cancer based on reports on case series.[14],[15] A prospective clinical trial was conducted to further investigate the effectiveness of trastuzumab in HER2-overexpressing urothelial cancer and published in 2007.[16] In this multicenter phase-II study involving HER2 overexpression (IHC 2+ or 3+, FISH-positive patients), platinum-resistant, HER2-positive (HER2 amplification or gene sequence, FISH or IHC), metastatic urothelial cancers received standard doses of pertuzumab and trastuzumab until progression or toxicity occurred. Among 109 initially screened patients without prior chemotherapy for metastatic disease, 57 were found to be HER2–positive by at least one method (most by IHC or FISH). Patients with HER2 positive disease had more metastatic sites and more visceral metastases. Trastuzumab was administered at initial. Patients also received carboplatin and paclitaxel and gemcitabine (non-cisplatin regimen). Objective response rate was 70% (31 of 44 patients) including 5 complete and 26 partial responses, while 57% of responses were confirmed. HER2-targeted agents have been shown to play a potentially important role in combination with monotherapy or immune checkpoint inhibitors and/or other agents.[11]

The trend toward the use of a molecular targeted approach in the treatment of this heterogeneous disease, abandoning uniform treatment, is recommended in bladder cancer. Given the prevalence of HER-2 changes, we hope that a molecular approach for HER-2-targeted agents will be introduced in advanced bladder cancer. With the discovery and validation of suitable biomarkers and well-designed clinical trials, anti-HER2 treatment may contribute to increasing the number of the strategies that might be used for urothelial cancer in the near future.

In a study by Nedjadi et al., Her-2/neu status was significantly correlated with primary tumor-lymph node metastasis of urothelial bladder cancer. This observation shows that Her-2/neu is a valuable biomarker associated with the metastatic potential of tumor cells and the studies on targeted Her-2/neu therapy in patients with metastatic bladder cancer will be significant.[17]

Going forward, optimized selection of patients whose tumors have HER2 amplification or mutation, cell-free circulating tumor DNA next-generation sequencing may be relevant in the peri-operative (neoadjuvant, adjuvant) and advanced disease settings, and/or in bladder preservation approach.[11]

In cases where cyclin D1 gene is active, high expression of cyclin D1 is observed. G1 phase then shortens and cyclin D1 enters phase S early, leading to uncontrolled cell proliferation and tumor formation.[18]

A significant proportion of bladder cancer cases have shown that increased cyclin D1 expression and gene overexpression are associated with poor prognosis and decreased postoperative patient survival. Heterozygous loss of cyclin D1 is observed in approximately 50% of muscle-invasive bladder cancers. Therefore, the identification of a new anticancer drug that regulates cyclin D1 expression and function is one of the first priorities in anticancer studies.[19]

In our study, cyclin D1 was found to have a higher rate of positivity in patients with high-grade tumors (P < 0.05). Strong cyclin D1 expression was observed in 65% patients with low-grade tumors and 85% with high-grade tumors (P < 0.05).

Cyclin D1 is active in the nucleus; however, it can be found in the cytoplasm where ubiquitin-dependent degradation occurs. Thus, the antibody may stain the cytoplasm in tissues such as those in urothelial carcinomas of the urinary tract. However, the comparisons are only based on nuclear staining, not cytoplasmic staining. Cyclin D1 staining has been more commonly observed in carcinomas than in normal bladder, hyperplasias, and papillomas.[3]

In a study by Shan et al., cyclin D1 expression was not observed in cystitis tissues. Furthermore, 48 cases (68.6%) of urothelial bladder carcinoma showed positive cyclin D1 expression. Mean density and positive area ratio were significantly different between urothelial bladder cancer and cystitis tissues.[19]

Cyclin D1 protein expression is much higher in invasive carcinoma than in superficial carcinoma; the higher the pathological stage and the positivity rate, the more pronounced the positivity rate of cyclin D1 in patients with palindromic bladder cancer. Cyclin D1 expression may be associated with the progression of bladder cancer. In many cancer patients, it was found that cyclin D1 overexpression is associated with poor prognosis. It has been shown that a significantly poorer prognosis is observed in patients with high cyclin D1 expression than in those with low cyclin D1 expression. Cyclin D1 expression is useful in the diagnosis of bladder cancer and in the evaluation of the prognosis of patients. Abnormal cyclin D1 expression has been observed in various malignancies. However, the related literature has not provided consistent results regarding its role and clinical significance in tumorigenesis for bladder urothelial carcinomas. Some studies have shown that cyclin D1 overexpression tends to be higher in pTa and pT1 tumors and lower in more aggressive high-grade tumors. Experimental data showing cyclin D1 expression have suggested that urothelial tissue plays a role in triggering cell proliferation and autonomic growth in early-stage bladder tumors.[19]

The study by Tarek Aboushousha et al. showed that cyclin D1 expression was significantly correlated with low-grade and papillary tumor growth.[20] Levidou et al. (2010),[21] Kopparapu et al. (2013),[22] and Khabaz et al. (2017)[23] reported that high cyclin D1 immunoreactivity was more frequent in low-grade tumors and NMIBC (Ta/Tis/T1C) and lower cyclin D1 scores were found in high-grade and advanced-stage tumors, muscle-invasive bladder cancer (MIBC) (T2-T4), and tumors with vascular invasion and lymph node involvement. A negative correlation of cyclin D1 expression with tumor grade and stage is consistent with experimental data showing that cyclin D1 expression in urothelial tissue promotes cell proliferation and cell differentiation.[24]

The significance of AMACR positivity has been emphasized in high-grade tumors in terms of tumor progression and recurrence. As reported in a study by Aron et al., AMACR expression is very useful in CIS variants with concentric normal/reactive urothelium, although it does not appear to affect immunohistochemical results in CIS. It was found that AMACR immunoexpression is positive in neoplastic cells and negative in normal cells.[25]

AMACR is considered a therapeutic target in the treatment of cancer. AMACR overexpression is most commonly observed in prostate and colorectal carcinomas with positive staining of 92% and 83%, respectively. AMACR expression was observed in 44% of breast cancer cases and was found to be negative in peripheral normal tissues. Thus, AMACR may be a potentially significant tumor marker for many cancers and precursor lesions, particularly in patients fed with high-fat diets, and AMACR antibody or enzyme inhibitors may be used in cancer treatment.[6]

Gunia et al. found a significant positive correlation between AMACR expression and higher tumor grade. These new findings include high-grade noninvasive bladder carcinomas in the

AMACR-positive neoplasm group and may shed light on the unknown role of AMACR in the pathobiology of tumor presence and tumor cell energy metabolism.[26]

They exemplfy a new trend of using a molecularly targeted approach in treating this heterogeneous disease, and a departure from a “one size fits all” approach that has been generally used in bladder cancer until the present time.[11]

The treatment results are inadequate in advanced bladder cancer patients receiving radiotherapy or chemotherapy. The lack of more effective treatments for bladder cancer necessitates the development of new therapies for specific molecular targets and molecular mechanisms underlying bladder tumorigenesis.[27]

   Conclusion Top

Cyclin D1 and AMACR expressions were found to be high in high-grade urothelial carcinomas, and Her-2 expression was found to be high in both high- and low-grade urothelial carcinomas. High Her-2 expression in patients with bladder carcinoma indicates that they are potential targets for treatment. In addition, the detection of AMACR and cyclin D1 may be useful in the diagnosis of bladder cancer and in the evaluation of the prognosis of patients. Tumorigenesis and progression mechanisms in bladder urothelial carcinomas involving AMACR and cyclin D1 should be investigated to reveal new targets for gene therapy. Further studies including detailed follow-up data for tumor progression and recurrence are needed to address prognosis in bladder cancer.

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Conflicts of interest

There are no conflicts of interest.

   References Top

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Correspondence Address:
Yeliz Arman Karakaya
Department of Pathology, Pamukkale University Medical School, Denizli
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/IJPM.IJPM_980_19

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  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]

  [Table 1], [Table 2]


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