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 Table of Contents  
ORIGINAL ARTICLE
Year : 2021  |  Volume : 34  |  Issue : 3  |  Page : 1087-1094

The prognostic significance of cyclin D1 expression in bladder urothelial carcinoma and correlation with clinicopathological parameters


Department of Pathology, Faculty of Medicine, Menoufia University, Menoufia, Egypt

Date of Submission03-May-2020
Date of Decision15-Jun-2020
Date of Acceptance18-Jun-2020
Date of Web Publication18-Oct-2021

Correspondence Address:
Hend A. Abdo Kassem
Shebin Elkom, Menoufia
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/mmj.mmj_138_20

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  Abstract 


Objective
To determine the expression of cell cycle protein cyclin D1 in urothelial carcinoma and to correlate it with clinicopathological parameters and overall survival.
Background
Dysregulation of the cell cycle is a key mechanism for the occurrence of various types of tumors, including urinary bladder carcinoma (UBC). Cyclin D1 critically targets the proliferative signals and has been implicated in progression of UBC.
Materials and methods
This retrospective control study was conducted on 80 cases of urothelial carcinoma, which were classified according to muscularis propria invasion into 50 cases of muscle invasive bladder carcinoma and 30 cases of non-muscle-invasive bladder carcinoma (NMIBC). Immunohistochemistry staining for cyclin D1 antibody was done for all cases.
Results
Cyclin D1 was positive in 61 (76.2%) of 80 urothelial carcinoma cases. Cyclin D1 expression is significantly associated with early stage group (P = 0.031), early lymph node staging (P = 0.001), and absent perineural invasion (P = 0.037) in infiltrating urothelial carcinoma. NMIBC cases showed significant association with cyclin D1 expression (P = 0.025) and strong intensity (P = 0.018). Moreover, high immunoreactive score of cyclin D1 was significantly associated with NMIBC group (P = 0.001).
Conclusion
Cyclin D1 expression implies a good prognostic effect in UBC, as an inverse correlation between cyclin D1 expression and poor prognostic pathologic features (muscle invasive bladder carcinoma, advanced stage, perineural invasion and lymph node involvement) was displayed in the current study.

Keywords: cyclin D1, immunoreactive score, muscle-invasive bladder carcinoma, non-muscle-invasive bladder, urothelial bladder carcinoma


How to cite this article:
Abdelwahed MM, Al-sharaky DR, Abdelnaby AS, Kassem HA. The prognostic significance of cyclin D1 expression in bladder urothelial carcinoma and correlation with clinicopathological parameters. Menoufia Med J 2021;34:1087-94

How to cite this URL:
Abdelwahed MM, Al-sharaky DR, Abdelnaby AS, Kassem HA. The prognostic significance of cyclin D1 expression in bladder urothelial carcinoma and correlation with clinicopathological parameters. Menoufia Med J [serial online] 2021 [cited 2024 Mar 29];34:1087-94. Available from: http://www.mmj.eg.net/text.asp?2021/34/3/1087/328295




  Introduction Top


Bladder cancer is the most common urinary tract malignancy and the fourth most common cancer in men, following prostate, lung, and colorectal carcinoma, with an estimated 81 400 new cases and 17 980 deaths in 2019 alone in USA [1].

In Egypt, urinary bladder carcinoma (UBC) is a common malignancy, accounting for 14.3% of total malignancies in both sexes, with 3: 1 male to female ratio. It comprises 88.3% of the total urinary system tumors and 14.31% from total malignancies, ranking it the most common urinary tract tumors according to the National Cancer Institute registry 2016 [2]. The expected new cases for urinary bladder carcinoma (UBC) will expected to be about 10.700 cases by 2020, 12.7620 cases by 2025, and 28.330 cases by 2050 [3]. Urothelial carcinoma of urinary bladder is the most predominant histological pattern of bladder carcinoma, as it accounts for more than 90% of the diagnosed cases. Traditionally, urothelial carcinoma of urinary bladder is classified into two major types based primarily on treatment planes and prognostic parameters as follows: non-muscle-invasive bladder cancer (NMIBC) (corresponding to stages pTa, T1) and muscle-invasive bladder cancer (MIBC) (corresponding to stages T2, T3, and T4) [4],[5]. UBC occasionally arises through complex, multistep processes that involve progressive disturbance of the normal mechanisms that control epithelial proliferation, inflammation, and differentiation [6]. Dysregulation of the cell cycle is a key mechanism for the occurrence of tumors. Cyclins are cell-cycle proteins that control normal cell-cycle progression and hence affect epithelial proliferation pathways. Cyclin D1 has a key role in the regulation of cell cycle and critically targets the proliferative signals in G1-S phase progression through forming a complex with different cyclin-dependent kinases [7]. Cyclin D1 is an oncogenic gene that contributes to cell-cycle dysfunction and is frequently overexpressed in numerous human malignancies [8]. Cyclin D1 overexpression has been documented in breast cancer [9], ovarian cancer [10], esophageal cancer [11], nonsmall cell lung carcinomas [12], and endometrial carcinoma [13]. Many studies proved that cyclin D1 gene is usually overexpressed in human bladder carcinoma. However, its association with pathological parameter is conflicting [14]. Therefore, the current study aims to determine the expression of cell cycle protein cyclin D1 in urothelial carcinoma and to correlate the findings with the studied clinicopathological parameters


  Materials and methods Top


A retrospective study comprised formalin-fixed, paraffin-embedded blocks of tissues from patients with urothelial carcinoma retrieved from the archives of Pathology Department, Menoufia Faculty of Medicine, Menoufia University, spanning the period between 2017 and 2019. The survival data were obtained from Menoufia Cancer Institute, Menoufia University.

A total of 80 specimens of urothelial carcinoma were selected according to the availability of paraffin blocks, clinical and follow-up data. Depth of invasion and staging of the tumor were assessed according to TNM staging system/American Joint Committee on Cancer staging manual 8th edition [15].

Immunohistochemistry

One paraffin section (4 μm in thickness) was obtained from each case to be stained with a primary antibody - anti-cyclin D1 (cat# RM-9104-R7; Thermo Fisher Scientific, 168 Third Avenue, Waltham, MA USA 02451) rabbit polyclonal antibody – which was received as a ready-to-use 7-ml vial. The method used for immunostaining was streptavidin–biotin amplified system. In this system, two reagents were used: the biotinylated secondary anti-immunoglobulin, which is a purified bovine monoclonal anti-mouse IgG (NOS-3F7-B11 B5; Thermo Scientific, USA) capable of binding to the primary antibody, and the streptavidin–biotin enzyme complex.

Immunohistochemical staining was performed using the Universal Dako cytomation labeled streptavidin–biotin-2 system, Horseradish Peroxidase (LSAB-2 System, HRP Kit, Catalog No. k0679, Agilent Technologies, 5301 Stevens Creek Blvd. Santa Clara, California 95051, United States, USA). All slides were deparaffinized using xylene and then rehydrated in decreasing concentrations of ethanol. Antigen retrieval using microwave heating (20 min; 10 mmol/citrate buffer, pH 6.0) after inhibition of endogenous peroxidase activity (hydrogen peroxidase for 15 min) was used. The primary antibodies were applied on the slides and incubated overnight at room temperature in a humidity chamber. Finally, the detection of bound antibody was accomplished using a modified labeled avidin–biotin reagent for 20 min and then PBS wash. A 0.1% solution of diaminobenzidine was used for 5 min as a chromogen. Slides were counterstained with Mayer's hematoxylin for 5–10 min. Negative control slides were prepared by omitting the primary antibodies from the staining procedure. Tissue sections prepared from normal human tonsil were used as positive control for cyclin D1 [16],[17].

Immunostaining interpretation: the specimens were microscopically evaluated for cyclin D1 status in UBC cases. Each sample was first scanned with low magnification and then at least 10 fields were assessed for staining with high-power magnification.

Interpretation of cyclin D1 expression: each case was assessed for cyclin D1 immunoexpression in the whole tumor tissues.

Cyclin D1 expression was evaluated for the following: cyclin D1 staining status: nuclear staining in any number of cells for cyclin D1 was required to assign the positivity [16],[17],[18],[19]; percentage of positivity (mean, median, and range); cyclin D1 staining intensity: either mild, moderate, or strong [16],[17]; cyclin D1 subcellular localization: the slides were considered positive if it showed nuclear staining pattern [17]; cyclin D1 pattern of distribution: it was divided into diffuse and patchy pattern; and H score system (histochemical score): it was applied to evaluate the studied section according to previous studies [20],[21],[22].

H score formula = strong intensity (3) × percentage + moderate intensity (2)× percentage + mild intensity (1) × percentage.

H score ranged from 0 to 300, and it was assessed as mean ± SD, median, and range.

Immunoreactivity score (IRS) was calculated depending on both intensity scoring and extent of positivity, which were graded according to the German semiquantitative scoring system as follows [23]:

Intensity scoring (IS): 0 = no staining, 1 = weak staining, 2 = moderate staining, 3 = strong staining.

Extent of positivity was scored by percent of positive cells as following: 0 = 0%, 1 = 1–10%, 2 = 11–50%, 3 = 51–80%, and 4 = more than 80%.

The IRS was determined by multiplying intensity scoring by the extent of positivity (0–12).

The cases were categorized into low and high expression scores as follows [23]: low expression score, if the score is less than 6, and high expression score, if the score is more than or equal to 6.

Statistical analysis

The χ2 test was used to assess the relationships between cyclin D1 expression and different clinicopathological parameters. The overall survival was calculated from the date of diagnosis of the primary tumor till the date of last follow-up, death, or dropout. The Student t test was used to assess survival and then data were confirmed by Kaplan–Meier survival curves to differentiate survival between compared groups using the log rank test. All P values were two-sided, and P value less than 0.05 was considered to be significant [24]. Statistical analyses were performed using SPSS 21.00 software IBM Corp. Released 2012. IBM SPSS Statistics for Windows, Version 21.0. Armonk, NY: IBM Corp.


  Results Top


The age of the patients ranged from 26 to 96 years old, with a mean ± SD of 63.5 ± 10.3 years and a median age of 65 years. A total of 66 (82.5%) cases were males, whereas 14 (17.5%) cases were females. The size of tumor in the studied cases ranged from 3 to 9 cm, with a mean ± SD of 4.7 ± 1.2 and a median of 4.7. Seventy-six (95%) cases were infiltrating urothelial carcinoma and four (5%) cases were of noninvasive papillary urothelial carcinoma. The grade of the urothelial carcinoma cases was divided into low grade in 18 (22.5%) cases and high grade in 62 (77.5%) cases. Cases were classified according to muscularis propria invasion into 50 (62.5%) cases of MIBC and 30 (37.5%) cases of NMIBC. According to TNM staging, four (5%) cases were Ta, 26 (32.5%) cases were T1, 18 (22.5%) cases T2, 28 (35%) cases T3, and four (5%) cases were T4. A total of 30 (37.5%) cases were of an early stage and 50 (62.5%) cases were of an advanced stage. Lymph node staging according to TNM staging showed the studied malignant cases were N0 in 20 (40%) cases, N1 in 11 (22%) cases and N2 in 19 (38%) cases. Moreover, 24 (30%) cases displayed bilharzial ova, whereas the rest were free. Lymphovascular invasion was presented in only 20 (25%) cases, and perineural invasion was present in only 10 (12.5%) cases. Necrosis was absent in majority of cases [52 (65%) of 80]. The stromal reaction was found to be desmoplastic in 39 (47.5%) cases and inflammatory in 29 (36.3%) cases and mixed in 13 (16.2%) cases. The mitotic count ranged from 2 to 15, with a mean ± SD of 5.8 ± 2.6 and a median of 5. The apoptotic count ranged from 3 to 31, with a mean ± SD of 15.0 ± 6.5 and a median of 14.

Cyclin D1 immunostaining results

Cyclin D1 was positive in 61 (76.2%) of 80 cases of the malignant group and negative in 19 (23.8%) cases. The percentage of cyclin D1 expression ranged from 10 to 90, with mean ± SD of 48.4 ± 21.6 and a median of 50. All the positive cases [61 (100%)] displayed nuclear staining. The intensity of expression was predominantly strong in 26 (42.6%) cases, predominantly moderate in 25 (41%) cases, and predominantly mild in 10 (16.4%) cases. IRS of cyclin D1 was of low score in 41 (67.2%) cases and high score in 20 (32.8) cases. Cyclin D1 H score ranged from 10 to 240, with mean ± SD of 111.1 ± 59.4 and a median of 120.

In total cases of urothelial carcinoma, cyclin D1 expression was significantly in favor of early stage group (27 cases) (90%), as 16/19 (32%) cases of negative cyclin D1 expression were of advanced stage (P = 0.031). Moreover, cyclin D1 expression was significantly associated with absent perineural invasion (P = 0.037) and absence of lymph node involvement (P = 0.001). Cyclin D1 high IRS was correlated with early stage group (P = 0.001), absence of lymph node involvement (P = 0.001), and low mitotic count (P = 0.007). Moreover, all high IRS cyclin D1 cases (20/20) displayed absence of Bilharzial infestation (P = 0.001) [Table 1], [Table 2].
Table 1: Relationship between cyclin D1 expression and different clinicopathological parameters in malignant cases

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Table 2: Relationship between cyclin D1 immunoreactive score and the studied clinicopathological parameters in malignant cases

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Comparison between MIBC and NMIBC revealed that cyclin D1 expression (P = 0.025), predominantly strong intensity (P = 0.018), higher percentage (P = 0.001), and diffuse pattern of expression (P = 0.023) were significantly in favor of NMIBC in comparison with MIBC. High IRS (P = 0.001) and higher H score of cyclin D1 expression (P = 0.001) were significantly in favor of NMIBC in comparison with MIBC [Table 3] and [Figure 1].
Table 3: Comparison between muscle invasive bladder carcinoma and non-muscle invasive bladder carcinoma regarding the immunohistochemical profile of cyclin D1

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Figure 1: Nuclear cyclin D1 expression pattern in urothelial bladder carcinoma, strong diffuse expression in a case of high-grade non-muscle-invasive urothelial carcinoma (a, IHC × 200; b, IHC × 400), and mild to moderate patchy expression in a case of muscle-invasive urothelial carcinoma (c, IHC × 200); (d, ×400).

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Data regarding survival were available for 44 (40%) of the studied 80 cases of primary UBC. Mean ± SD of overall survival time was 16.75 ± 11.739 months. Of the available 44 cases, 16 died. Unfortunately, our study failed to reveal significant association between the cyclin D1 immunoreactivity and patient's overall survival (P > 0.05).

Univariate survival analysis for studied bladder carcinoma cases: univariate analysis of overall survival showed the bad prognostic impact with advanced pathological T stage (P = 0.003), presence of nodal invasion (P = 0.006), presence of bilharziasis (P = 0.044) on patient's outcome. By multivariate COX-regression analysis, pathological T stage was the most independent prognostic factor affecting patient's overall survival (P = 0.027) [Figure 2].
Figure 2: Kaplan–Meier survival curve demonstrating the effect of (a) pathological T stage in primary bladder carcinoma cases on overall survival, (b) lymph node invasion in primary bladder carcinoma cases on overall survival, and (c) bilharziasis in primary bladder carcinoma cases on overall survival. (d) COX regression curve demonstrating that the pathological T stage was the most independent prognostic factor in primary bladder carcinoma cases.

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  Discussion Top


Cyclin D1 regulates the G0–G1 phase and promotes cell growth and proliferation. It is considered a proto-oncogene located on chromosome 11q13 that modulates a critical step in cell cycle control progression. Conflicting data on the significance of cyclin D1 has been reported in urinary bladder tumors. Thus, the prognostic role of this protein remains controversial [17].

In this study, the percentage of cyclin D1 expression in UBC (67.2%) was close to Amer and Eid [17], who reported cyclin D1 expression in 62.22% (56/90), and slightly higher than reported by Khabaz et al. [16], who reported that cyclin D1 was expressed in 55.4% (56/101). On the contrary, a higher expression was reported by Levidou et al., [25], who demonstrated 99.36% positive expression.

Cyclin D1 staining was observed only in the nucleus of tumor cells, and this result was in agreement with Khabaz et al. [16] and Amer and Eid [17]. However, Guang and Tian [7] and Betticher et al. [26] found that cyclin D1 was present only in cytoplasm of tumor cells. Lukas et al. [27] suggested that intracellular localization of cyclin D1 is changed during progress through the cell cycle, and from the G1-S transition, the protein becomes more soluble, reflecting the loss of nuclear cyclin D1 proteins, which also explains the nuclear localization of cyclin D1 in our study.

In UBC, strong nuclear immunostaining of cyclin D1 was found in 26 (42.6%) cases, slightly near to that reported by Khabaz et al. [16] (55.4%). Moreover, 32.8% showed high IRS for cyclin D1. Higher levels (51.6, 56.5, 68.6, and 62.22%) were observed Guang and Tian [7], Khabaz et al. [16], Xu et al. [28], and Amer and Eid [17], respectively. These differences may be attributed to variations in the size of samples, difference in evaluation techniques, patient's circumstances, and included tumor variables.

In the current study, we found that cyclin D1 expression was associated with NMIBC, as positive expression (P = 0.018), predominant strong intensity (P = 0.025), overexpression (P = 0.001), and diffuse pattern of expression (P = 0.023) were in favor of NMIBC. These findings were in agreement with other studies [6],[16],[17],[18],[29], which reported that cyclin D1 expression was significantly higher in NMIBC than in MIBC. They observed that nuclear cyclin D1 expression was absent from most invasive tumors and from lymph node metastasis within MIBC.

In contrast to our results, Xu et al. [28] noted that cyclin D1 expression was much higher in invasive carcinoma than superficially located tumor, suggesting that higher expression of cyclin D1 is closely related to the progression of bladder carcinoma.

Regarding histologic type, there was no statistical correlation between histological type of tumor and expression of cyclin D1. Our results are in concordance with Lee K et al. [30] and in disagreement with Lee CCR et al. [29] who demonstrated that positive cyclin D1 staining was observed only in papillary urothelial carcinoma (111/161), and all the nonpapillary tumors were negative.

Regarding the grade, our results displayed a near significant association between high cyclin D1 IRS and low-grade tumors (P = 0.062). This is near similar to Khabaz et al. [16], Amer and Eid [17], and Tut et al. [18] who demonstrated that the majority of low-grade tumors displayed strong cyclin D1 immunostaining, whereas low level of cyclin D1 immunoreactivity was more common in tumors with high grade. On the contrary, Lee et al. [30] found that cyclin D1 was significantly higher with high-grade UBC. However, others failed to find any significant association between cyclin D1 expression and tumor grade [7],[31],[32].

In the current study, cyclin D1 overexpression was reported in early stage group (P = 0.031), tumors with absent perineural invasion (P = 0.037), and absence of lymph node involvement (P = 0.001). These results were in agreement with Amer and Eid [17], Galmozzi et al. [33], and Lenz et al. [34], who stated that low level of cyclin D1 is observed in advanced stage, poorly differentiated tumors, and tumors with vascular invasion, as well as lymph node involvement. However, Rekan SA et al. [32] found that cyclin D1 was significantly higher with advanced stage and MIBC. On the contrary, Ioachim et al. [35], Shariat et al. [36], Seiler et al. [37], and Guang and Tian [7] reported no significant correlation between cyclin D1 expression and grade, stage, and invasion. Moreover, all high IRS cyclin D1 cases (20/20) displayed absence of bilharzial infestation (P = 0.001). This is explained by Zaghloul [38] who demonstrated that schistosomiasis-associated UBC presented in more advanced stage than schistosomiasis non-associated UBC.

Our results support that cyclin D1 expression is evident in the initial stages where cell proliferation is a necessary step, involving no tumor invasion or metastasis as suggested by Guang and Tian [7]. Moreover, Suwa et al. [39] explained the association between low expression of cyclin D1 and poor prognostic factors by that low cyclin D1 expression might be a surrogate of other genetic events in the same cells, which ultimately drives cell growth and leads to worse prognosis.

The inverse correlation between cyclin D1 expression and poor prognostic parameters was not only reported in urothelial carcinoma but also among other tumors, such as in gastric carcinoma [40], laryngeal squamous cell carcinoma [41] and in invasive breast carcinoma [42]. This is in contrary to Zhao et al. [43], Xu et al. [44], and Ramos et al. [45], which demonstrated that cyclin D1 overexpression was associated with worst clinicopathological features for esophageal squamous cell carcinoma, ER-positive breast cancer, and colorectal carcinoma, respectively.

Our study failed to reveal significant association between the cyclin D1 immunoreactivity and patient's overall survival. This was similar to Sgambato et al. [19], and contrary to Khabaz et al. [16], who found that decreased expression of cyclin D1 was associated with poor prognosis.

It has been accepted that high-grade neoplasms of bladder have higher progression and invasiveness rate more than low-grade tumors [46]. Hence, the phenotype of cyclin D1 was correlated with the degree of cancer progression and invasiveness. Altered expression of cyclin D1 may lead to changes in the biological behavior of transformed cells, for instance growth, proliferation, invasion, and metastasis [17].


  Conclusion Top


Cyclin D1 expression implies a good prognostic effect in UBC, as an inverse correlation between cyclin D1 expression and poor prognostic pathologic features (MIBC, advanced stage, perineural invasion, and lymph node involvement) was displayed in the current study. Further studies on a large scale are highly recommended to confirm the role of cyclin D1 in diagnosis and prognosis of NMIBC.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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