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ORIGINAL ARTICLE
Year : 2019  |  Volume : 22  |  Issue : 3  |  Page : 386-392

A promising biomarker to distinguish benign and malignant renal tumors: ELABELA


1 Department of Pathology, Firat University, School of Medicine, Elazig, Turkey
2 Department of Histology and Embriology, Firat University, School of Medicine, Elazig, Turkey
3 Department of Internal Medicine and Division of Endocrinology and Metabolism, Firat University, School of Medicine, Elazig, Turkey
4 Department of Biochemistry, Firat University, School of Medicine, Elazig, Turkey
5 Department of Radiology, Firat University, School of Medicine, Elazig, Turkey
6 Department of Oncology, Dokuz Eylül University, School of Medicine, İzmir, Turkey

Date of Acceptance13-Nov-2018
Date of Web Publication6-Mar-2019

Correspondence Address:
Dr. G Artas
Firat Üniversitesi Hastanesi, Patoloji Kliniği, 23119, Elâzığ
Turkey
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/njcp.njcp_105_18

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   Abstract 


Aim: The aim of this study was to investigate ELABELA (ELA) expression in benign and malignant renal tissues and expression differences in different nuclear grades of clear cell carcinomas. Materials and Methods: Patients that underwent surgery due to renal masses between the years of 2007 and 2017 were used. Control renal tissues (n = 23), papillary RCC (n = 23), clear cell RCC (CcRCC) [Fuhrman Grade1 (n = 23), Fuhrman Grade2 (n = 23), Fuhrman Grade3 (n = 23), Fuhrman Grade4 (n = 23)], and chromophobe RCC (n = 23) were included to the study. The Independent samples t-test was used for 2-point intergroup assessments and the one-way analysis of variance and posthoctukey test was used for the others. Values of P < 0.05 were considered statistically significant. Results: ELA immunoreactivity was observed in proximal and distal tubules in the kidney, but not in glomeruli in control tissues. When compared with control kidney tissue, a statistically significant increase was observed in ELA immunoreactivity in renal oncocytoma. In the chromophobe RCC, ELA immunoreactivity was significantly lower than control kidney tissue, whereas papillary RCC did not show ELA immunoreactivity. However, compared with control kidney tissue, ELA immunoreactivity was not observed in Fuhrman Grade 1 and Grade 2 CcRCC. Also, there was a significant decrease at Fuhrman Grade 3 and Grade 4 CcRCC compared with control kidney tissues. In the statistical analysis of ELA immunoreactivity among the Fuhrman nuclear grades of CcRCCs, The ELA immunoreactivity was higher at Grade 4 CcRCC than Grade 1, Grade 2, and Grade 3. Conclusion: ELA is a usefull molecule to differentiate benign and malign renal tumors. But further broad and comprehensive studies are needed to investigate cellular and molecular mechanisms of ELAs on malign transformation.

Keywords: ELABELA, immunohistochemistry, oncocytoma, renal cell carcinoma


How to cite this article:
Artas G, Kuloglu T, Dagli A F, Ugur K, Yardim M, Aydin S, Artas H, Kocdor H. A promising biomarker to distinguish benign and malignant renal tumors: ELABELA. Niger J Clin Pract 2019;22:386-92

How to cite this URL:
Artas G, Kuloglu T, Dagli A F, Ugur K, Yardim M, Aydin S, Artas H, Kocdor H. A promising biomarker to distinguish benign and malignant renal tumors: ELABELA. Niger J Clin Pract [serial online] 2019 [cited 2019 Mar 22];22:386-92. Available from: http://www.njcponline.com/text.asp?2019/22/3/386/253441




   Introduction Top


Renal cell carcinomas (RCC) are a malignant tumor group originating from the tubule epithelium. It is usually seen in adults aged 55-60 years and accounts for about 2%–3% of adult malignancies.[1] RCC is in the top 10 cancers that affect people over 45 years old.[2] The female to male ratio is 1:2. The majority of adult kidney tumors are originated from epithelium, sarcomas, and carcinoid tumors are very rare.[3] The current cancer data suggest that 64,000 new cases of renal cancer will be diagnosed in the United States, and about 14,400 people will die from this cancer and its complications in 2017.[4]

Clear cell renal cell carcinoma (CcRCC) is the most common subtype constituting 70-80% of RCCs, followed by papillary (10%–15%), chromophobe renal cell carcinoma (chRCC) (5%), and collecting duct RCCs (<1%).[5] Despite studies conducted in RCCs, the etiology is still unclear. Chromosome anomalies, hormones, various bacterial infections, obesity, genetic structure, environmental wastes, chemical agents, and chemical agents encountered in occupational fields were investigated in etiology. Familial history, excess of basal body mass index, hypertension, smoking, and frequent urinary tract inflammation were investigated in etiology and observed an increased carcinoma frequency with these factors.[6] ELABELA (ELA) is an endogenous peptide ligand of Apelin receptor (AR) that has a central role in zebrafish embryonic development.[7] It has been demonstrated that ELA is expressed in human embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) and adult kidney tissue. And, it has been supported that ELA is a natural hormone in human system and has functions during and after embryonic development.[8]

Herein, we aimed to investigate the ELA expression in benign and malignat renal tissues and expression differences in different nuclear grades of clear cell carcinomas which is one of the prognostic factors.


   Materials and Methods Top


Patient collection

Patients who underwent surgery due to renal masses between the years of 2007 and 2017 were included to this study. Cases were selected as control renal tissues (n = 23), papillary RCC (n = 23), CcRCC [Fuhrman Grade 1 (n = 23), Fuhrman Grade 2 (n = 23), Fuhrman Grade 3 (n = 23), Fuhrman Grade 4 (n = 23)], and chRCC (n = 23).

Immunohistochemistry

The sections were mounted on poly-l-lysine-coated slides. After deparaffining, the sections were washed in a graduated alcohol series and heated in a microwave oven (750 W) for 12 min in a citrate buffer solution, pH 6, for antigen retrieval, followed by cooling to room temperature for 20 min and washing with phosphate buffered saline (PBS) (P4417; Sigma-Aldrich) three times for 5 min each time. Hydrogen peroxide blocking solution was applied for 5 min to suppress endogenous peroxidase activity (Hydrogen Peroxide Block, TA-125-HP; Lab Vision Corp, Fremont, CA). After washing with PBS three times for 5 min each time, the sections were treated with Ultra V Block solution (TA-125-UB, Lab Vision Corp.) to prevent background staining. Sections were incubated with ELABELA primary antibody (ELA primary antibody, H-007-19, Phoenix Pharmaceutıcals, Inc., CA, USA) diluted 1:200, for 60 min in a humid chamber at room temperature. The sections then were washed with PBS three times for 5 min each time and incubated with secondary antibodies (biotinylated goat anti-polyvalent (anti-mouse/rabbit IgG), TP-125-BN; Lab Vision Corp.) for 30 min. The tissues were washed again with PBS three times for 5 min each time, incubated with streptavidin peroxidase (TS-125-HR, Lab Vision Corp.) for 30 min and left in PBS. After applying drops of 3-amino-9-ethylcarbazole (AEC) substrate + AEC chromogen (AEC Substrate, TA-015 and HAS; AEC Chromogen, TA-002-HAC; Lab Vision Corp.) solution, the tissues were washed with PBS after checking labeling by light microscopy. Sections were counterstained with Mayer's hematoxylin, rinsed in PBS and distilled water, and mounted with closure solution (Large Volume Vision Mount, TA-125-UG; Lab Vision Corp.). The preparations were examined using a Leica DM500 microscop (Leica DFC295) and photographed.

A histoscore was derived from the distribution (0.1: <25%, 0.4: 26%–50%, 0.6: 51%–75%, 0.9: 76%–100%) and intensity (0: no staining, +0.5: very little staining, +1: little staining, +2: medium, +3: very strong) of staining immunoreactivity (histoscore = distribution × intensity).

Statistical analysis

The obtained data were determined as mean ± standard deviation. SPSS version 22 program was used for statistical analysis. The Independent samples t-test was used for 2-point intergroup assessments and the one-way analysis of variance and posthoctukey test was used for the others. Values of P < 0.05 were considered statistically significant.


   Results Top


Immunohistochemical staining for ELA immunoreactivity was assessed under light microscopy. ELA immunoreactivity was observed in proximal (PT) and distal (DT) tubules in the kidney [Figure 1]a and [Figure 1]b, but not in glomeruli (G) in control tissues. When compared with control kidney tissue, a statistically significant increase was observed in ELA immunoreactivity in RO [Figure 1]c and [Figure 1]d, which is a benign tumor of the kidney (P < 0.05). In the chRCC [Figure 2]a and [Figure 2]b, which is one of the malignant tumor of the kidney, ELA immunoreactivity was significantly lower than control kidney tissue, whereas papillary RCC [Figure 2]c and [Figure 2]d did not show ELA immunoreactivity (P < 0.05). However, compared with control kidney tissue, ELA immunoreactivity was not observed in Fuhrman Grade 1 CcRCC [Figure 3]a and [Figure 3]b and Fuhrman Grade 2 CcRCC [Figure 3]c and [Figure 3]d. Also, there was a significant decrease at Fuhrman Grade 3 and Grade 4 Clear CcRCC compared with control kidney tissues (P < 0.05).
Figure 1: Control renal tissue hematoxylin eosin ve ELABELA (ELA) staining (a and b); RO hematoxylin eosin ve ELA staining (c and d)

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Figure 2: Chromophobe renal cell carcinoma (RCC) hematoxylin eosin ve ELABELA (ELA) staining (a and b); papillary RCC hematoxylin eosin ve ELA staining (c and d)

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Figure 3: Hematoxylin eosin ve ELABELA staining in different Fuhrman grade clear cell renal cell carcinoma (a and b: Grade 1; c and d: Grade 2; e and f: Grade 3; g and h: Grade 4)

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In the statistical analysis of ELA immunoreactivity among the Fuhrman nuclear grades of CcRCCs, The ELA immunoreactivity was higher at Grade 4 CcRCC than Grade 1, Grade 2, and Grade 3.

ELA immunoreactivity for all groups is summarized in [Table 1].
Table 1: ELA immunoreactivity for all groups

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   Discussion Top


Kidney cancer accounts for ~2% of all cancer diagnoses and cancer deaths worldwide, with incidence rates generally higher in developed countries.[9] RCC is the most common type cancer of the kidney and most lethal urinary malignancy.[10]

Renal cell tumors are classified as mentioned below (Pathology and Genetics of Tumours of the Urinary System and Male Genital Organs, WHO Classification of Tumours, 2004).[11]

  • Clear cell renal cell carcinoma
  • Multilocular clear cell renal cell carcinoma
  • Papillary renal cell carcinoma
  • Chromophobe renal cell carcinoma
  • Carcinoma of the collecting ducts of Bellini
  • Renal medullary carcinoma
  • Xp11 translocation carcinomas
  • Carcinoma associated with neuroblastoma
  • Mucinous tubular and spindle cell carcinoma
  • Renal cell carcinoma, unclassified
  • Papillary adenoma
  • Oncocytoma.


We included to this study most common tumor types; Oncocytoma, Clear cell renal cell carninoma (with different Fuhrman Grades), Papillary renal cell carcinoma, Chromophobe renal cell carcinoma. Herein, we will mention to the obvious histopathological features of these tumors.

Clear cell (conventional type) renal cell carcinoma

CcRCC is the most common histological subtype among RCCs and approximately 60%–70% is seen. Microscopically, the cytoplasm of the cells in clear cell carcinomas is broad and clear is because of its lipid and glycogen content. Mitotic activity varies. As the nuclear grade (Fuhrman nuclear grade) increases, the cellular pleomorphism becomes more pronounced.[12]

Papillary renal cell carcinoma

It is the second most common subtype of renal cell carcinomas. Approximately 15% is seen. Tumor usually papillary, papillary-trabecular, or papillary-solid growth pattern, as well as more than half of the cases solid, tubular, or glomeruloid growth pattern. Nuclear structure changes. Cells contain small round nucleus with indeterminate nucleoli.[12]

Chromophobe renal cell carcinoma

It accounts for 5% of all renal cell carcinomas. Although seen in adult ages, the average is around 55 years.[3] The tumor is separated by thin fibrovascular septa and has as well as tubular, trabecular, cystic, papillary, or sarcomatoid growth patterns. Two types of chromophobe renal cell carcinomas are described as classical and eosinophilic. Classical type is composed of large polygonal cells with eosinophilic cytoplasm and medium-sized nuclei. The nucleolus is too small. Very fewmitosis can be observed. Eosinophilictype's cells are eosinophilic and cytoplasm is granular. There is a perinuclear halo around the nucleus.[13]

Oncocytoma

Oncocytoma is benign renal tumor and has classic gross and histological features as mass with central scar, nested architecture, and round-regular nuclei with prominent central nucleoli.[14] Gross appearance of oncocytomais generally similar to normal renal parenchyma. Central scar is quite characteristic but it is not specific for RO and can be detected in all tumors such as chRCC.[15]

With its gross appearance and cellular features, sometimes it can be difficult to differentiate RO fromrenal malignancies and especially from eosinophilic variant chRCC. Also, RO organizes in nests and tubular structures lined by cells with eosinophilic, granular cytoplasm. Occasionally, other patterns are present, highly compact nested architecture, resulting in a solid appearance, or small papillary structures protrude into cystic spaces, which can create a problem with the differential diagnosis with an eosinophilic variant of papillary renal cell carcinoma. Mitotic activity is rare, and a single mitotic figure may be compatible with the diagnosis. However, more than one mitotic figure is potentially incompatible with a diagnosis of RO.[16]

Renal cell carcinomas have a 5-year survival rate of 70%. Surgical excision is the primary treatment. Radical nephrectomy; along with the kidney, the surrounding fat tissue, Gerota fascia and adrenal gland are removed. Many clinicopathological parameters are important in prognosis: age, gender, stage, distant metastasis, tumor size, renal ven invasion, renal pelvis invasion, nuclear grade (Fuhrman), etc.[3]

Immunohistochemistry and special stains can be helpfull in the differential diagnosis of renal masses. Oncocytomas show minimal staining for cytokeratin 7 (CK7), whereas chRCC shows diffusely positive staining in a membranous distribution. In a recent study of urologic pathologists, CK7 is the most commonly utilized staining technique for diagnosing RO, but positive staining threshold not compatible with RO was not well determined.[17] As mentioned in the literature, eosinophilic chRCC may exhibit less extensive CK7 labeling.[18] Other markers, such as kidney-specific cadherin and S100A1, are less widely used by some laboratories.[17] Colloidal iron staining (Hale or modified Mowry) is also often used as a histochemical technique. But variations in staining techniques between laboratories can make interpretation challenging and lead diffuculties in the diagnosis.[19]

In the differential diagnosis of RO and chRCC from other RCC subtypes, KIT (CD117) and vimentin may be helpful. Oncocytoma and chRCC show membranous positivity for KIT and negative staining for vimentin. CcRCC and papillary RCC are negative for KIT and often positive for vimentin.[18]

However, as discussed, these immunohistochemical and histochemical markers still have their pitfalls in distinguishing between chRCCs and ROs. Ensuring accurate diagnosis of RO and chRCC by nonsurgical routes is important in the proper management of care.

Generally, in the diagnosis of renal masses, core needle biopsies are used. Especially, oncocytic lesions can be troublesome, becasue a limited biopsyshould not represent the entire lesion.[20] In clinical practice, RO often represents a diagnostic challenge, due to its similarity in appearance to RCC on both pathology and imaging.[21]

Oncocytomas closely resemble primary renal malignancies on imaging, particularly other oncocytic renal neoplasms such as chRCCand type 2 papillary RCC. They can be difficult to distinguish even with active surveillance, as RO have been shown to demonstrate preoperative growth rates similar to RCC.[22] Pathologists use the designation of “oncocytic neoplasm” if they cannot differentiate chRCC and RO.[23]

ELA is a peptide that contains 54 amino acids including a secretory signal with a mature form containing 32 amino acids and its transcripts are found in human pluripotent stem cells.[7] ELA is an endogenous peptide ligand of AR that is a G-protein coupled receptor.[24] Both apelin and its receptors are expressed in a wide range of eukaryotes, including humans, animal models, in cells, or tissue cultures. High levels of apelin have been detected in the central nervous system, and both receptor and its ligands are widely present throughout the peripheral tissue.[25],[26],[27] Both apelin and AR are expressed in heart, lung, vascular endothelium, kidney, and brain. Studies have demonstrated that the apelinergic system has of biological functions, such as homeostasis of the cardiovascular system and fluid metabolism.[28],[29] Chng et al. suggest that loss of ELA or its receptor APJ affects lateral cardiac mesoderm progenitors and leads to variable and severe heart and posterior malformations in zebrafish.[7]

In a study, Lena et al. reported that ELA is necessary to activate the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/AKT pathway that is required for Human pluripotent embryonic stem cells (hESC) growth and protect against cellular stress.[30] PI3K/AKT has anti-apoptotic properties in both normal and cancer cells [31] and important in tumor growth and development.[32] ELA has been showed to act through the PI3K/AKT pathway in hESCs to potentiate growth by promoting cell-cycle progression and benefit protein translation. Also, ELA inhibition by CRISPR/Cas9-mediated deletion, shRNA, or neutralizing antibodies causes reduced hESC growth, cell death, and loss of pluripotency. These data suggest that ELA is essential for protecting the cells' spontaneous apoptosis inherent to hESC cultures.[30] Apelin effectively prevented cardiomyocyte apoptosis by inhibiting the release of cytochrome C and subsequent activation of the caspase-9 - caspase-3 cascade. In their study, they all observed that hypoxia-induced mitochondrial fission and cardiomyocyte apoptosis could be suppressed by Apelin. Apelin might inhibit the opening of mitochondrial permeability transition pore and stimulate the reperfusion injury RISK pathway by inactivating GSK-3β to activate PI3K/Akt.[33] Interestingly, Tickoo et al. have reported that the hallmark of renal oncocytomas is the accumulation of mitochondria. They have reported that cells in RO have uniform and round mitochondria closely packed in the cytoplasm. Their mean size was slightly larger than those of chRCC. The mitochondrias in the chRCC were diffusely distributed and admixed with other organelles at the cytoplasm.[34]

In our study, ELA immunoreactivity showed a significant increase in renal oncocytoma when compared with control kidney tissue (P < 0.05). In the chRCC which is one of the malignant tumors of the kidney, ELA immunoreactivity was significantly lower than control kidney tissue and RO. ELA immunoreactivity was not observed in Fuhrman Grade 1 CcRCC [Figure 3]a and [Figure 3]b and Fuhrman Grade 2 CcRCC [Figure 3]c and [Figure 3]d and papillary RCC. Also, there was a significant decrease at Fuhrman Grade 3 [Figure 3]e and [Figure 3]f and Grade 4 [Figure 3]g and [Figure 3]h Clear CcRCC compared with control kidney tissues. ELA immunoreactivity among the Fuhrman nuclear grades of CcRCCs was higher at Grade 4 Clear Cell RCC than Grade 1, Grade 2, and Grade 3.

Renal masses are generally diagnosed by core biopsy. Sometimes small tissue samples can cause diagnostic confusion. In order to differentiate renal masses and make a correct diagnosis, immunohistochemistry is necessary. In our study, ELA immunoreactivity was higher at RO then all types of RCC. Especially, the difference between RO and ChRCC was important, because both two tumor types can have similar appearance in biopsy. We suggest that different expression of ELA in RO and ChRCC should be resulted from the cells mitochondrial shape, size, and number. Also, we observed that ELA expression in benign control renal tissue and RO, which is a benign tumor of kidney, is higher than renal malignant tumors. We believe that ELA protects the cells from the apoptosis and ELA realize this effect through the PI3K/AKT pathway. ELA is a nowelpeptid and we have few data about it and its effects. The reason why ELA expression reduces with malign transformation is unclear. By its effects over apoptosis, we believe that ELA may have been consumed extensively to prevent malign transformation. We conclude that ELA is an usefull molecule to differentiate benign and malign renal tumors. But further broad and comprehensive studies are needed to investigate the cellular and molecular mechanisms of ELAs on malign transformation.

Acknowledgement

No support, financial or otherwise, was sought or granted for this study.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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