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ORIGINAL ARTICLE  
Year : 2023  |  Volume : 66  |  Issue : 1  |  Page : 54-57
Can CXCL13 be a prognostic marker in clear cell renal cell carcinoma?


1 Medical Student, Faculty of Medicine, Bezmialem Vakif University, Istanbul, Turkey
2 Department of Biostatistics and Medical Informatics, Bezmialem Vakif University, Istanbul, Turkey
3 Department of Pathology, Faculty of Medicine, Bezmialem Vakif University, Istanbul, Turkey

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Date of Submission07-Aug-2021
Date of Decision29-Aug-2021
Date of Acceptance30-Aug-2021
Date of Web Publication18-Jan-2023
 

   Abstract 


Background: CXCL13, B-lymphocyte chemoattractant, has been associated with many diseases and cancers. One of the malignancies that CXCL13 has been investigated is clear cell renal cell carcinomas which are the most common subtype of renal cancers. Aims and Objectives: The aim of this study is to evaluate the immunohistochemical staining patterns of CXCL13 in clear cell renal cell carcinomas and to determine its relationship with pathological tumor stage, risk factors, and prognostic parameters. Materials and Methods: In this study, 99 patients who underwent partial/radical nephrectomy diagnosed with clear cell renal cell carcinoma were included. Four micron sections were taken from paraffin embedded blocks containing sufficient tumor and kidney tissue. Samples were immunohistochemically stained with CXCL13 antibody. During microscopic examination, CXCL13 positive stained cells in ten high magnification fields were counted and evaluated using a semiquantitative H score: 3 × strongly stained + 2 × moderately stained + 1 × weakly stained. The cut-off value was set as 40 for values between 0 and 300. The low and high stained groups were compared with prognostic parameters and risk factors. Statistics: The difference of continuous variables between the two groups was examined with the t test and the distribution of categorical variables with the Chi-square test. A value of P < 0.05 was considered to be statistically significant. Results: The number of lymphocytes stained with CXCL13 in the tumor was higher than in the normal kidney parenchyma (p = 0.07). Intratumoral lymphocytes were highly stained with CXCL13 in 57.5% of pT3 cases and 31.7% of pT1 cases. The amount of intratumoral lymphocytes stained with CXCL13 increased in advanced pathological stages (p = 0.05). Nonsmoking cases were mostly in the low staining group (p = 0.06). Conclusion: The relationship we found between advanced pathological stage and intratumoral CXCL13 staining in our study suggests that CXCL13 has a prognostic value in this cancer.

Keywords: Clear cell renal cell carcinoma, CXCL13, ımmunohistochemistry, prognosis

How to cite this article:
Sayar E, Yabacı A, Coban G. Can CXCL13 be a prognostic marker in clear cell renal cell carcinoma?. Indian J Pathol Microbiol 2023;66:54-7

How to cite this URL:
Sayar E, Yabacı A, Coban G. Can CXCL13 be a prognostic marker in clear cell renal cell carcinoma?. Indian J Pathol Microbiol [serial online] 2023 [cited 2023 Feb 8];66:54-7. Available from: https://www.ijpmonline.org/text.asp?2023/66/1/54/367988





   Introduction Top


Renal cell carcinoma (RCC) encompasses a heterogeneous group of cancers derived from renal tubular epithelial cells.[1] Clear cell renal cell carcinomas (CCRCCs), the most common subtype of these cancers, are accounts for the majority of kidney cancer deaths.[1] Tumor, node, metastasis (TNM) classification and its components, which are anatomical prognostic parameters, and WHO ISUP nuclear grade, which is one of histological prognostic factors, are recommended to be used to predict prognosis in renal cell cancers.[2],[3],[4] In addition, there is a relationship between RCC and risk factors, such as smoking, hypertension, and obesity.[5] As with many tumors, recently; tumor microenvironment in RCC is one of the most popular topics, both in terms of treatment and prognosis.

Chemokines are small molecular weight proteins that are involved in the migration of immune cells to specific organs with their chemoattractant effects.[6] According to their structures, they are divided into four families: CXC, CC, CX3C, and C chemokines.[6] CXCL13, known as a B-lymphocyte chemoattractant, is a chemokine belonging to the CXC family that affects the CXCR5 receptor and has been associated with various autoimmune, infectious, lymphoproliferative diseases, and malignancies.[7] The CXCL13:CXCR5 axis is a key element in B-cell and tumor cell responses.[8] The chemokine CXCL13, acting on the CXCR5, promotes chemotaxis, germinal center formation, and the differentiation to plasma cells and B-memory lymphocytes.[8] CXCL13 also target cancer cells to promote proliferation, migration, and invasion.[8] CXCL13 is thought to have dual effects on tumor development, both antitumoral and protumoral.[9] In previous studies in CCRCCs, it was stated that CXCL13 increases cancer proliferation and migration and this chemokine may be a prognostic marker in CCRCC.[10],[11],[12],[13]

The aim of our study is to evaluate the immunohistochemical staining patterns of CXCL13 in CCRCCs and to determine its relationship with pathological tumor stage, risk factors, and prognostic parameters.


   Materials and Methods Top


Patient's data

In our study, 99 patients who underwent partial/radical nephrectomy at Bezmialem Vakif University Hospital between January 2012 and January 2019 and were diagnosed with clear cell renal cell cancer were included. We evaluated the prognostic parameters for CCRCCs as pathological T stage, WHO ISUP nuclear grade, tumor diameter, perirenal adipose tissue invasion, lymph node metastasis, distant metastasis, and risk factors, such as smoking and hypertension. We obtained these data through a retrospective archive research over our hospital information system. All experiments were undertaken, following the approval by the Non-invasive Ethical Committee of the University of Bezmialem Vakif University protocol 02/34 (21- Jan-2020).

CXCL13 immunohistochemical staining and evaluation

All the hematoxylin-eosin stained samples belonging to the tumors were removed from the archive. Slides containing sufficient tumor and kidney parenchyma with normal histology were selected. Sections of four microns were taken from the paraffin blocks of these slides and stained with CXCL13 antibody (1:100 dilution, Genetex, USA) immunohistochemically in the Ventana Benchmark Ultra device.

While the tumor and intrarenal lymphocytes were evaluated in microscopic examination, the most intensely stained areas at low magnification were selected and CXCL13 positive staining cells were counted in ten high magnification areas. The H score for these cells was calculated with the formula = (3× strongly stained + 2× moderately stained + 1× weakly stained). For values between 0 and 300, the limit value was set as 40. Two groups were obtained as high and low staining, depending on whether it was above or below the cut-off value. In addition, staining of CXCL13 in tumor and kidney tissue was evaluated by dividing them into two groups in terms of the presence of staining.

The groups with low and high CXCL13 staining were compared with prognostic parameters, such as pT stage, WHO ISUP nuclear grade, tumor diameter, perirenal adipose tissue invasion, lymph node metastasis, distant metastasis, and risk factors, such as smoking and hypertension.

Statistical analysis

All statistical analyses were performed with IBM SPSS Statistics 22.0 package program. The difference of continuous variables between the two groups was examined with the t test and the distribution of categorical variables with the Chi-square test. Frequency, percentage, mean, and standard deviation values were given as descriptive statistics. P value < 0.05 was considered statistically significant.


   Result Top


Patient characteristics

In this study, there were 99 patients [68 male (68,7%), 31 female (31,3%)] with age ranging from 23 to 86 (mean ± SD, 55,66 ± 13,21). Demographic and clinicopathological data of the patients were grouped according to T stages and summarized in [Table 1].
Table 1: Demographic and clinicopathological data of the patients

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Comparison of CXCL13 expression with clinicopathological features

As a result of the evaluation of lymphocytes stained with CXCL13 within the tumor, 68.3% of pT1 cases had low staining and 31.7% of them had high staining. In pT3 cases, the rate of low staining is 42.5% and the rate of high staining is 57.5%. The rate of high staining was higher in pT3 tumors than in pT1 (p = 0.05). Perirenal invasion rate was higher in the high staining group than in the low staining group (p = 0.12). There were five cases with lymph node metastasis and all were in the low staining group (p = 0.05). Nonsmokers were mostly in the low group (p = 0.06). There was no statistically significant difference between the two groups between prognostic parameters such as WHO ISUP nuclear grade, tumor diameter and distant metastasis, and risk factors such as hypertension [Table 2] [Figure 1].
Table 2: Comparison of intratumoral CXCL13 positive lymphocytes with prognostic parameters

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Figure 1: (a) Clear-cell renal cell carcinoma (H & E, ×200). (b) Presence of CXCL13-positive colored lymphocytes in the tumor (arrow) (×200)

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The number of lymphocytes stained with CXCL13 in the tumor was higher than the number of lymphocytes stained positive with CXCL13 in the kidney (p = 0.07). In addition, no statistically significant difference was found between the low and high staining groups in the kidney in terms of prognostic parameters such as WHO ISUP nuclear grade, tumor diameter, lymph node metastasis, distant metastasis, and risk factors, such as smoking and hypertension.

Although positive staining with CXCL13 was detected in tumor and kidney tissue, no statistically significant difference was found in between the stained and unstained groups in terms of the evaluated parameters.


   Discussion Top


CXCL13 expression is thought to have a dual effect on tumorigenesis, which has been evaluated in tumors of various organs.[9] While it is thought that CXCL13 has a role in tumor progression by increasing tumor growth, metastasis capacity, and invasion, it has been observed that it acts by increasing antitumoral immunity in some studies.[9] In a study evaluating intratumoral CXCL13 expression in gastric cancers, larger tumor diameters and shorter survival times were found in cases with high expression.[14] In colorectal cancers, both CXCR5 and CXCL13 were associated with poor prognosis in terms of overall survival and recurrence-free survival.[15] In addition, higher CXCL13 expression was associated with a better disease-free survival rate in triple-negative breast cancer patients treated with neoadjuvant chemotherapy.[16] In addition to these tumors, studies are also available in CCRCCs, and it is suggested that CXCL13 is associated with poor prognosis.[10],[11],[12],[13] In the study of Zheng et al.[10] it has been shown that CXCL13 binds to the CXCR5 receptor and increases the proliferation and migration of CCRCCs via the PI3K/AKT/mTOR signaling pathway. In our study, the higher staining of intratumoral lymphocytes with CXCL13 in advanced stages compared to low stages supports the studies that this chemokine may have a prognostic value for clear cell renal cell cancers. In another study, a strong correlation was found between tumor infiltrating immune cells and CXCL13 expression, and it was stated that CXCL13 increased the migration ability by acting on the motility of renal cell cancers.[11] The fact that the group with high staining is slightly higher in those with perirenal invasion and the higher staining in the advanced stage may indicate the increase in migration noted in previous studies. In another study with CCRCCs, it was reported that infiltration with intratumoral CXCL13+ CD8+ T cells was more common in advanced tumor stages, and high infiltration with intratumoral CXCL13+ CD8+ T cells was associated with shorter survival and recurrence-free survival compared to low infiltration.[13] In addition, it is stated that CXCL13 may be a prognostic marker in renal cell cancers.[10],[11],[12],[13]

In our study based on immunohistochemical staining of nephrectomy materials, we found a difference between the groups with low and high staining in lymphocytes in tumor and healthy tissue, especially in terms of tumor stage and smoking. The presence of lymph node metastases in our data group in the low staining group and the absence of a significant difference in terms of metastasis may be due to the low number of metastasized cases and the short follow-up period. Since metastases can be seen years after nephrectomy in renal cell cancers, studies with longer follow-up periods and larger case groups are needed. Due to the increase in imaging methods, tumors with a lower pathological tumor stage are detected.

We had limitations in our study, such as the absence of pT4 cases, the low number of lymph nodes and distant metastases, and short follow-up times.


   Conclusion Top


In our study with CXCL13 immunohistochemical staining in nephrectomy materials diagnosed with CCRCC, we grouped intratumoral and intrarenal lymphocyte staining as high and low and compared them with pathological prognostic parameters and risk factors. The high staining rate of intratumoral CXCL13 staining in advanced pathological tumor stages compared to low stages supports that CXCL13 is associated with a poor prognosis.

Financial support and sponsorship

This study was approved by Bezmialem Vakif University ethical board under decision number 54022451-050.05.04. And, this study was supported by Bezmialem Vakif University Scientific Research Projects Unit (BAP Project Number: 20200202E).

Conflicts of interest

There are no conflicts of interest.



 
   References Top

1.
Hsieh JJ, Purdue MP, Signoretti S, Swanton C, Albiges L, Schmidinger M, et al. Renal cell carcinoma. Nat Rev Dis Primers 2017;3:17009.  Back to cited text no. 1
    
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Klatte T, Rossi SH, Stewart GD. Prognostic factors and prognostic models for renal cell carcinoma: A literature review. World J Urol 2018;36:1943-52.  Back to cited text no. 2
    
3.
Moch H, Amin MB, Argani P, Cheville J, Delahunt B, et al. Renal cell tumours Introduction İn: WHO Classification of Tumors of the Urinary System and Male Genital Organs. 4th ed. Lyon;IARC;2016,p.14-17.  Back to cited text no. 3
    
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Amin MB, Edge SB, Greene FL, Byrd DR, Brookland RK, Wahington MK, et al. AJCC Cancer Staging Manual. 8th ed. New York:Springer; 2017.  Back to cited text no. 4
    
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Capitanio U, Bensalah K, Bex A, Boorjian SA, Bray F, Coleman J, et al. Epidemiology of renal cell carcinoma. Eur Urol 2019;75:74-84.  Back to cited text no. 5
    
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Vilgelm AE, Richmond A. Chemokines modulate immune surveillance in tumorigenesis, metastasis, and response to immunotherapy. Front Immunol 2019;10:333.  Back to cited text no. 6
    
7.
Hussain M, Adah D, Tariq M, Lu Y, Zhang J, Liu J. CXCL13/CXCR5 signaling axis in cancer. Life Sci 2019;227:175-86.  Back to cited text no. 7
    
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Kazanietz MG, Durando M, Cooke M. CXCL13 and its receptor CXCR5 in cancer: Inflammation, immune response, and beyond. Front Endocrinol (Lausanne) 2019;10:471.  Back to cited text no. 8
    
9.
Rubio AJ, Porter T, Zhong X. Duality of B cell-CXCL13 axis in tumor immunology. Front Immunol 2020;11:521110.  Back to cited text no. 9
    
10.
Zheng Z, Cai Y, Chen H, Chen Z, Zhu D, Zhong Q, et al. CXCL13/CXCR5 axis predicts poor prognosis and promotes progression through PI3K/AKT/mTOR pathway in clear cell renal cell carcinoma. Front Oncol 2019;8:682.  Back to cited text no. 10
    
11.
Jiao F, Sun H, Yang Q, Sun H, Wang Z, Liu M, et al. Association of CXCL13 and immune cell infiltration signature in clear cell renal cell carcinoma. Int J Med Sci 2020;17:1610-24.  Back to cited text no. 11
    
12.
Xu T, Ruan H, Song Z, Cao Q, Wang K, Bao L, et al. Identification of CXCL13 as a potential biomarker in clear cell renal cell carcinoma via comprehensive bioinformatics analysis. Biomed Pharmacother 2019;118:109264.  Back to cited text no. 12
    
13.
Dai S, Zeng H, Liu Z, Jin K, Jiang W, Wang Z, et al. Intratumoral CXCL13+CD8+T cell infiltration determines poor clinical outcomes and immunoevasive contexture in patients with clear cell renal cell carcinoma. J Immunother Cancer 2021;9:e001823.  Back to cited text no. 13
    
14.
Wei Y, Lin C, Li H, Xu Z, Wang J, Li R, et al. CXCL13 expression is prognostic and predictive for postoperative adjuvant chemotherapy benefit in patients with gastric cancer. Cancer Immunol Immunother 2018;67:261-9.  Back to cited text no. 14
    
15.
Qi XW, Xia SH, Yin Y, Jin LF, Pu Y, Hua D, et al. Expression features of CXCR5 and its ligand, CXCL13 associated with poor prognosis of advanced colorectal cancer. Eur Rev Med Pharmacol Sci 2014;18:1916-24.  Back to cited text no. 15
    
16.
Song IH, Heo SH, Bang WS, Park HS, Park IA, Kim YA, et al. Predictive value of tertiary lymphoid structures assessed by high endothelial venule counts in the neoadjuvant setting of triple-negative breast cancer. Cancer Res Treat 2017;49:399-407.  Back to cited text no. 16
    

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Correspondence Address:
Ganime Coban
Department of Pathology, Bezmialem Vakif University, Adnan Menderes Boulevard P.C. 34093 Fatih, Istanbul
Turkey
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijpm.ijpm_796_21

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