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Saudi Journal of Kidney Diseases and Transplantation
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Year : 2014  |  Volume : 25  |  Issue : 1  |  Page : 79-84
Expression of CD44 and P53 in renal cell carcinoma: Association with tumor subtypes

1 Department of Pathology, Faculty of Medicine, Urmia University of Medical Sciences, Urmia, Iran
2 Department of Community Medicine, Faculty of Medicine, Urmia University of Medical Sciences, Urmia, Iran
3 Department of Biochemistry, Faculty of Medicine, Urmia University of Medical Sciences, Urmia, Iran

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Date of Web Publication7-Jan-2014


Renal cell carcinoma (RCC) is a common malignancy of the kidney and accurate prediction of prognosis is valuable for the design of adjuvant therapy and counseling and effective scheduling of follow-up visits. Molecular genetic investigations of CD44 and P53 in RCC may be helpful in this regard. We studied the CD44 and P53 expressions semi-quantitatively on paraffin-embedded specimens of 64 RCC patients (37 male/27 female) who underwent surgery from 2003 to 2008 by immunohistochemistry and analyzed the correlation of P53 and CD44 expression in RCC and outcome. Thirteen of 64 (20.3%) specimens were P53 positive, 30/64 (46.9%) were CD44 positive and five tumors with positive P53 expressed CD44 protein (P = 0.5). A statistically significant correlation was not found between CD44 and P53 expression (P = 0.5) and age (P = 0.07), sex (P= 0.3), tumor size (P = 0.7), grade (P = 0.23), vascular invasion (P = 1.00) and ureteral invasion (P = 1.00). Furthermore, a significant correlation was not found between P53 expression with age (P = 0.3), sex (P = 0.7), tumor size (P = 0.7), grade (P = 0.1), vascular inva­sion (P = 1.00) and ureteral invasion (P = 1.00). According to our findings, only P53 expression is generally accompanied by non-conventional subtype tumor.

How to cite this article:
Noroozinia F, Fahmideh AN, Yekta Z, Rouhrazi H, Rasmi Y. Expression of CD44 and P53 in renal cell carcinoma: Association with tumor subtypes. Saudi J Kidney Dis Transpl 2014;25:79-84

How to cite this URL:
Noroozinia F, Fahmideh AN, Yekta Z, Rouhrazi H, Rasmi Y. Expression of CD44 and P53 in renal cell carcinoma: Association with tumor subtypes. Saudi J Kidney Dis Transpl [serial online] 2014 [cited 2022 Nov 26];25:79-84. Available from: https://www.sjkdt.org/text.asp?2014/25/1/79/124495

   Introduction Top

Renal cell carcinoma (RCC) is a common cancer, and the incidence of it has been rising steadily in the recent years. RCC constitutes approximately 2% of all adult cancers. [1] Because more than two-thirds of RCC patients will die of their disease, the accuracy of pathology spe­cimen assessment is very important for pa­tient follow-up. [1] Molecular genetic investiga­tions have recognized two distinctive subtypes of RCC: Conventional (clear cells) and non-conventional (papillary, chromophobe, collec­ting and unclassified). [2] It is accepted that prognosis differs according to the histological type, nuclear grade and tumor stage. [3] How­ever, in many cases of conventional RCC, staging and grading are not sufficient to pre­dict the clinical outcome of these tumors. [4] Several reports have focused on the evaluation of new markers and, accordingly, the prognostic value of P53 mutation and CD44 has been recently investigated. [5]

P53 tumor suppressor gene is located on chromosome 17p13, which encodes wild-type P53 protein. [6] This protein has a role in cell-cycle arrest after apoptosis, DNA damage and mitotic checkpoint regulation. In other words, this gene plays an important role in the control of cell proliferation. Therefore, P53 is one of the most important cancer-related genes and its mutation has been reported in a variety of cancers, such as lung, breast and prostate cancers. [7] In RCC, the role of P53 remains unde­termined and the results obtained regarding the prognostic significance of its mutation have been presented. [7],[8]

Cell adhesion molecules seem to have a role in tumor cell invasion and tumor dissemination by mediating interactions between tumor cells and their environments. [9] Altered expression of cell adhesion molecules such as CD44 on tumor cells suggests a pathogenetic mecha­nism for tumor metastasis and may provide prognostic information for particular tumors. CD44 is a surface transmembrane glycoprotein that was initially identified on lymphocytes. The extracellular domain of CD44 is the prin­cipal receptor of an extracellular matrix mole­cule, hyaluronic acid. Overexpression of hyaluronic acid has been correlated with the metastatic potential of certain human tumors, and these cell-matrix interactions of CD44 play a role in tumor cell invasion and metastasis. [10],[11]

We aimed in this study to determine the correlation of P53 protein and CD44 expres­sion in RCC subtypes. The immunohistochemical findings were subsequently correlated with multiple clinico-pathological parameters like nuclear grade and tumor size as prognostic markers in RCC.

   Materials and Methods Top

A total of 64 renal tissue biopsies (formalin-fixed, paraffin-embedded renal tissue) from patients with RCC pathologically confirmed were collected from 2003 to 2008. Characte­ristic data for sex, age and tumor size of pa­tients were obtained from patients' medical records. The study protocol complied with the ethical guidelines of the Medical Ethics Com­mittee, Ministry of Health, Iran.

The paraffin-embedded tissue blocks were cut into 4-μm sections and mounted on slides. Sections were de-waxed in xylene and were rehydrated in descending alcohol concentra­tions. Then, they were boiled in a target re­trieval solution for 15 min and cooled to room temperature. All the slides were washed with 0.1% Tris-buffered saline (TBS) for 5 min. Later, they were kept in 0.3% hydrogen peroxidase for 5 min for the blockage of endo­genous peroxidase activity. The slides were rinsed with TBS for 5 min and then incubated with monoclonal antibody for 5 min and rinsed again with TBS for 5 min, and Envision and chromogen (Dako Co, Denmark) was added. After 30 min, the slides were rinsed under water and countered with hematoxyline, de­hydrated and mounted. They were examined regarding the P53 and CD44 protein expres­sion and evaluated regarding the vascular inva­sion and ureteral invasion. According to the latest tumor subtype classification, [2] tumors were classified to conventional (include clear cell type) and non-conventional (include pa­pillary, chromophobe, collecting and unclassi­fied types) classes. Immunostaining of tumor cells was semiquantitatively scored according to the Fuhrman's nuclear grading system [3] as follows: No positive cells (grade 1); fewer than 25% of reactive cells (grade 2); from 25% to 75% of positive cells (grade 3); and more than 75% of positive cells (grade 4).

Validation of staining scoring of all the pre­parations was carried out independently by a pathologist without prior knowledge of the samples. Tumors were classified as positive if >5% of the stained cells were positive for P53 and CD44. Negative controls by the respective deletion of primary antibody were also per­formed.

   Statistical Analysis Top

The mean values were expressed as mean ± standard deviation (SD). The Spearman rank correlation was used to correlate the immunohistochemical findings for CD44 and P53 and histopathological parameters. The chi-square test was used to evaluate the qualitative para­meters. These tests were processed with SPSS 17.0 statistical software program (SPSS Inc. Chicago, Illinois, USA). P-value <0.05 was considered as statistically significant.

   Results Top

The 64 study patients ranged in their age from 19 to 86 years (mean ± SD: 56 ± 6 years) and the male/female ratio was 37/27. The mean tumor size was 7.6 ± 4.0 cm. Of the 64 RCC cases, positivity for P53 was observed in 13 (20.3%) specimens [Figure 1], while 30 (46.9%) sections were positive for CD44 [Table 1], [Figure 2]. Thirteen of 64 (20.3%) specimens were P53 positive, 30/64 (46.9%) of specimens were CD44 positive and five tumors with positive P53 expressed CD44 protein (P = 0.5).
Figure 1: P53 immunoreactive tumor cells in a renal cell carcinoma (×400).

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Figure 2: CD44 immunoreactive tumor cells in a renal cell carcinoma (×400).

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Table 1: Relationship between immunohistochemical expression of both P53 and CD44, and age, sex, tumor size, grade, invasion and tumor subtype in RCC.

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There was no statistically significant diffe­rence in P53 expression in relation to the tumor size (P = 0.7), age (P = 0.3), sex (P = 0.7) and grade (P = 0.1). Also, there was no statistically significant difference in CD44 expression in relation to the tumor size (P = 0.7), age (P = 0.07), sex (P = 0.3) and grade (P = 0.23). Two of 13 (3.1%) P53-positive cases were conventional and 11 (17.2%) were non-conventional, which was statistically significant (P <0.05). There was no significant correlation between CD44 expression and tumor subtype: 17/30 (26.6%) were conventional and 13/30 (20.3%) were non-conventional (P = 0.6).

Two of thirteen (3.1%) P53-positive spe­cimens and six of 51 (9.4%) P53-negative spe­cimens revealed vascular invasion. Also, four of 30 (6.3%) CD44-positive cases and four of 34 (6.3%) CD44-negative specimens showed vascular invasion. On the other hand, one of 13 (1.6%) P53-positive cases and three of 51 (4.7%) P53-negative specimens had ureteral invasion. In addition, two of 30 (3.1%) CD44-positive cases and two of 34 (3.1%) CD44-negative specimens showed ureteral invasion. There were no statistically significant correla­tions between ureteral and vascular invasion and both P53 and CD44 expression (P = 1.000)

   Discussion Top

RCC constitutes 1-3% of visceral cancers in humans and about 85% of primary malignant tumors of the kidney in adults. [12] In many cases, efforts such as grading and staging are not sufficient to define the behavior and prog­nosis of these tumors. Thus, several studies have focused on the evaluation of new markers. The most common mutated gene in human malig­nancies is P53. The mutation of this gene is reported in most of human malignancies such as astrocytoma, mesothelioma, sarcoma, leu­kemia and colon, bladder, lung and breast carcinomas. [13],[14] The relationship between the increased expression of this protein and urogenital cancers (bladder and prostate carcinomas) has been well demonstrated; [13],[15],[16] while its rela­tionship with RCC is still a matter of debate.

Studies have shown that the standard form of CD44 or one or more of its variants are over-expressed in many human malignancies, inclu­ding breast, stomach, colorectal, lung, bladder, non-Hodgkin lymphoma, certain squamous cell carcinomas, melanoma and RCC. [10] The en­hanced metastatic potential for tumor cells that overexpress CD44 has been well documented. CD44 overexpression in RCC has shown an association with tumor progression, recurrence, survival, aggressiveness and, perhaps, pathogenesis. [10],[11]

It was demonstrated that positive P53 immunostaining in RCC is associated with metastatic carcinomas and poor survival in patients with early-stage disease [17] It was claimed by Mombini et al that increased expression of P53 protein is rather prevalent in RCC. This factor is associated with tumor grade and subtype. According to their findings, P53 was generally associated with non-conventional subtypes and higher tumor grades. [18]

Nuclear grade and tumor size were found to be independent predictors of survival in locally confined clear cell (conventional) RCC, as has been shown previously for locally confined RCC in general, but P53 expression did not contribute additional prognostic information. [5] In the Zigeuner et al report, [6] P53 overexpression for papillary, chromophobe and conven­tional RCC was 70.0%, 27.3% and 11.9%, respectively (P <0.0001). They concluded that overexpression of P53 was significantly more frequent in "nonconventional" RCC subtypes, especially papillary RCC, compared with con­ventional RCC in their study. Terpe et al. [19] showed that expression of variant CD44 isoforms was strongly correlated with grading and appeared to mediate a more aggressive phenotype to renal cell tumors, but they could not interpret the clinical data.

In a study on 91 patients with locally con­fined conventional RCCs, CD44 was found to be a useful prognostic parameter in conven­tional RCC. [20] In another study, the expression of CD44 was immunohistochemically eva­luated in 173 conventional RCCs, and was compared with the usual clinico-pathological parameters such as tumor size, histological grade and pathological stage. The study con­cluded that CD44 molecules may play a role in the progression of conventional RCC and may be used in the evaluation of disease outcome. [21]

In our study, we examined the immunohistochemical staining patterns of P53 and CD44 in archival tissue from patients who had undergone partial or radical nephrectomy for RCC. We found the expression of P53 protein in 20.3% of the specimens similar to previous studies (20-30%). [18] The most important fin­ding in our study was the correlation between expression of P53 protein and non-conven­tional types of RCC, especially the papillary type, which was similar to that in the study of Zigeuner et al. [6]

We conclude that of the markers of RCC, only P53 was found in our study, helpful in staging of conventional tumor. A further study of other markers may be more helpful in this regard.

   References Top

1.Lin ZH, Han EM, Lee ES, et al. A distinct expression pattern and point mutation of c-kit in papillary renal cell carcinomas. Mod Pathol 2004;17:611-6.  Back to cited text no. 1
2.Störkel S, Eble JN, Adlakha K, et al. Classification of renal cell carcinoma: Workgroup No. 1. Cancer, 1997;80:987-9.  Back to cited text no. 2
3.Fuhrman SA, Lasky LC, Limas C. Prognostic significance of morphologic parameters in renal cell carcinoma. Am J Surg Pathol 1982; 6:655-63.  Back to cited text no. 3
4.Shvarts O, Seligson D, Lam J, et al. p53 is an independent predictor of tumor recurrence and progression after nephrectomy in patients with localized RCC. Urology 2005;173:725-8.  Back to cited text no. 4
5.Gelb AB, Sudilovsky D, Wu CD, Weiss LM, Medeiros LJ. Appraisal of intratumoral micro-vessel density, MIB-1 score, DNA content, and p53 protein expression as prognostic indicators in patients with locally confined renal cell carcinoma. Cancer 1997;80:1768-75.  Back to cited text no. 5
6.Zigeuner R, Ratschek M, Rehak P, Schips L, Langner C. Value of p53 as a prognostic marker in histologic subtypes of renal cell carcinoma: A systematic analysis of primary and metastatic tumor tissue. Urology 2004;63: 651-5.  Back to cited text no. 6
7.Ljungberg B, Bozoky B, Kovacs G, et al. p53 expression in correlation to clinical outcome in patients with renal cell carcinoma. Scand J Urol Nephrol 2001;35:15-20.  Back to cited text no. 7
8.Kabiri MM, Mohajery MR, Taheri D, Chehrei A. Prognostic value of p53 in renal cell carci­noma. Iran J Pathol 2006;2:75-80.  Back to cited text no. 8
9.Ruoslahti E. The Walter Herbert Lecture. Control of cell motility and tumour invasion by extracellular matrix interactions. Br J Cancer 1992;66:239-42.  Back to cited text no. 9
10.Rioux-Leclercq N, Epstein JI, Bansard JY, et al. Clinical significance of cell proliferation, microvessel density, and CD44 adhesion mole­cule expression in renal cell carcinoma. Hum Pathol 2001;32:1209-15.  Back to cited text no. 10
11.Tawfik OW, Kramer B, Shideler B, Danley M, Kimler BF, Holzbeierlein J. Prognostic signi­ficance of CD44, platelet-derived growth factor receptor alpha, and cyclooxygenase 2 expression in renal cell carcinoma. Arch Pathol Lab Med 2007;131:261-7.  Back to cited text no. 11
12.Medeiros LJ, Gelb AB, Weiss LM. Renal cell carcinoma. Prognostic significance of morpho­logic parameters in 121 cases. Cancer 1988;61: 1639-51.  Back to cited text no. 12
13.Cote RJ, Jhanwar SC, Novick S, Pellicer A. Genetic alterations of the p53 gene are a feature of malignant mesotheliomas. Cancer Res 1991;51:5410-6.  Back to cited text no. 13
14.Fujimoto K, Yamada Y, Okajima E, et al. Frequent association of p53 gene mutation in invasive bladder cancer. Cancer Res 1992;52: 1393-8.  Back to cited text no. 14
15.Isaacs WB, Carter BS, Ewing CM. Wild-type p53 suppresses growth of human prostate cancer cells containing mutant p53 alleles. Cancer Res 1991;51:4716-20.  Back to cited text no. 15
16.Sidransky D, Von Eschenbach A, Tsai YC, et al. Identification of p53 gene mutations in bladder cancers and urine samples. Science 1991;252:706-9.  Back to cited text no. 16
17.Uhlman DL, Nguyen PL, Manivel JC, et al. Association of immunohistochemical staining for p53 with metastatic progression and poor survival in patients with renal cell carcinoma. J Natl Cancer Inst 1994;86:1470-5.  Back to cited text no. 17
18.Mombini H, Givi M, Rashidi I. Relationship between expression of p53 protein and tumor subtype and grade in renal cell carcinoma. Urol J 2006;3:79-81.  Back to cited text no. 18
19.Terpe HJ, Störkel S, Zimmer U, et al. Expres­sion of CD44 isoforms in renal cell tumors. Positive correlation to tumor differentiation. Am J Pathol 1996;148:453-63.  Back to cited text no. 19
20.Paradis V, Ferlicot S, Ghannam E, et al. CD44 is an independent prognostic factor in conven­tional renal cell carcinomas. J Urol 1999;161: 1984-7.  Back to cited text no. 20
21.Lucin K, Matusan K, Dordeviæ G, Stipiæ D. Prognostic significance of CD44 molecule in renal cell carcinoma. Croat Med J 2004;45: 703-8.  Back to cited text no. 21

Correspondence Address:
Yousef Rasmi
Department of Biochemistry, Faculty of Medicine, Urmia University of Medical Sciences, Urmia
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/1319-2442.124495

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  [Figure 1], [Figure 2]

  [Table 1]

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