الفهرس 
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Abstract
RCC is the 6th leading cause of cancer-related deaths in Western world and it comprises 2-3% of all newly diagnosed malignancies in adults. It represents about 85% of all renal neoplasms. Peak incidence is in the sixth decade of life with male to female ratio about 2:1. There are many well-established risk factors, Some are modifiable as smoking, obesity and hypertension, others are non-modifiable as genetic mutations.
Nephrectomy which is performed in the early stages of the disease is considered as the only curable treatment. However, about 30-50% of patients have already metastasis at the time of presentation. In addition, one third of patients show relapse even after nephrectomy with subsequent poor response to chemotherapy and radiotherapy, lowering the 5-year survival rate to 0-20%.
There are certain populations of not fully-understood, quiescent, primitive cells existing within different human malignant tumors including RCCs. These cells possess some of stem cell properties as self-renewal and differentiation potential. They are called CSCs. These cells are not targeted during the conventional chemotherapy and radiotherapy. So they initiate treatment failure with subsequent tumor progression.
Fortunately; CSCs express a group of cell surface proteins that can be identified IHC as CXCR4 and CD105. Identification of these cells may be of great prognostic value. They also may help in developing novel therapeutic agents targeting these CSCs in order to prevent recurrence and metastasis.
The chemokine receptor CXCR4 belongs to a large superfamily of G protein-coupled receptors, and is directly involved in a number of biological processes including organogenesis, hematopoiesis, and immune response. Previous researches showed that CXCR4 expression has been detected in many human carcinomas of various origins, and its over-expression is significantly associated with poor overall survival.
CD105 is a trans-membrane protein expressed by angiogenic endothelial cells. It modulates angiogenesis by regulating proliferation and differentiation of endothelial cells. Despite being considered as a vascular marker as CD31 and CD34, CD105 expression by endothelial cells within a given tumor is more prevalent than its expression in the adjacent non neoplastic tissues.
The purpose of the current study was to evaluate the expression of CXCR4 and CD105 in RCCs, and to correlate their expression to different clinicopathological parameters; patients’ age, tumor size, coagulative necrosis, histological subtype of the tumor, capsular and perirenal fat invasion, tumor grade and stage.
The current study included a total of 52 patients with renal cell neoplasms; 49 cases of RCCs and three patients of oncocytoma. The age range of RCCs patients was 28-75 years, with mean ± SD and a median of 57.27 ± 7.5 and 58 years, respectively. They included 30 male and 19 females. Tumor size of RCCs ranged from 4 to 15 cm, with their mean ± SD and median were 7.19± 2.1 and 7 cm, respectively.
RCCs included 24/49 cases of ccRCCs, 9/49 cases of ccRCCs with focal sarcomatoid change, 11/49 cases of chromophobe carcinoma and 4/49 cases of papillary carcinoma, and one case of collecting duct carcinoma. Capsular invasion was positive in 36/49 cases, negative in 10/49 cases and couldn’t be assessed in three cases of RCCs. Perinephric fat invasion was positive in 29/49 cases, negative in 14/49 cases, and couldn’t be assessed in 6/49 cases as there was no peri-nephric fat in the submitted specimens. Coagulative necrosis was positive in 14/49 cases negative in 35/49 cases of RCCs.
The studied cases include 15/49 cases of Fuhrman’s grade 1, 18/49 of Fuhrman’s grade 2, 6/49 of Fuhrman’s grade 3 and 10/49 of Fuhrman’s grade 4. The ISUP grading system recommended by the WHO in 2016 is applicable only for the 37/49 cases of ccRCCs and papillary RCCs. Of those cases 20/37 were ISUP grade 1, 5/37 cases were ISUP grade 2, 1/37 cases were ISUP grades 3, and 3/37 cases were ISUP grade 4.
The largest tumor diameter in addition to peri-nephric fat invasion were used to broadly determine pT-stage of the tumor, due to unavailability of nodal or vascular tissues. Only one case of the 49 studied RCCs was staged as pT1a, 12/49 were staged as pT1b, 7/49 were staged as pT2a, and 29/49 cases were staged as pT3a.
CXCR4 showed nuclear, cytoplasmic and/ or membranous expression within renal tumor cells with variable proportions. In the current study the three sub-cellular locations of CXCR4 within RCC cells were evaluated in order to obtain the best sub-cellular expression that seems to be of good prognostic value.
RCCs showed nuclear expression of CXCR4 in all 49 studied cases; 42/49 cases showed diffuse nuclear expression, while 7/49 cases showed focal nuclear expression. There was an association between nuclear expression of CXCR4 and ISUP grading (p=0.024). However, nuclear expression of CXCR4 didn’t show any significant association with other studied clinicopathological parameters; tumor size, histological type, associated coagulative necrosis, tumor stage and different grading systems of RCCs.
Cytoplasmic expression of CXCR4 as was evaluated by IRS score; was positive in 30/49 cases and negative in 19/49 cases. A statistically significant association was found between cytoplasmic expression of CXCR4 and histological subtype of RCCs (p<0.0001). All cytoplasmic CXCR4 negative cases were of ccRCC subtype. All cases of chromophobe and papillary RCCs showed positive cytoplasmic CXCR4. Loss of cytoplasmic CXCR4 was associated with capsular and peri-nephric fat invasion and peri-nephric fat invasion (p= 0.038 & p= 0.037 respectively).
Applying H Score; 43/49 cases of RCCs showed low cytoplasmic expression, and 6/49 showed high cytoplasmic expression of CXCR4. There was a significant association between cytoplasmic expression of CXCR4 and histological subtype (p= 0.052). Most ccRCCs cases (32/33) showed low cytoplasmic expression of CXCR4. A significant relationship was found between cytoplasmic CXCR4 and Fuhrman grading system (p= 0.008).
Membranous CXCR4 expression was positive in 33/49 cases of RCCs and negative in 16/49 cases of RCCs. All cases of chromophobe RCCs showed positive membranous expression of CXCR4, while all cases of ccRCCs with sarcomatoid change showed negative membranous expression of CXCR4 and this difference was statistically significant (p˂0.0001). Membranous expression of CXCR4 was significantly associated with Fuhrman grading (p˂0.0001) and pT stage of RCCs (p= 0.035); as membranous CXCR4 expression was lost with increasing grade and/ or stage of the resected RCCs in the studied cases.
CD105/Endoglin expression as assessed by MVD was Low in 25/49 cases, moderate in 19/49 cases, and negative in 5/49 cases of RCCs. CD105 didn’t show any significant association with the studied parameters; patients’ age, tumor size, coagulative necrosis, histological subtype of the tumor, capsular and perirenal fat invasion, tumor grade and stage of RCCs.
A weak correlation was found between CD105 and both cytoplasmic and nuclear expression of CXCR4. A moderate correlation was found between CD105 and membranous expression of CXCR4.
The three cases of renal oncocytoma included in the current study occurred in male patients, with age ranged from 65 to 69 years old. Tumor sizes ranged from 4.5 to 8 cm. The three cases didn’t show any capsular invasion and only one of them showed peri-nephric fat invasion. All studied renal oncocytomas showed diffuse nuclear and negative membranous expression of CXCR4. Two cases showed high cytoplasmic expression of CXCR4, while the third one showed low cytoplasmic expression. All included cases of renal oncocytomas showed low expression of CD105.
Conclusions
• Evaluation of IHC expression of CXCR4 showed be evaluated at nuclear, cytoplasmic and membranous locations separately.
• Both cytoplasmic and membranous expression of CXCR4 were associated with histological subtype and Fuhrman grading of RCCs.
• Loss of cytoplasmic CXCR4 is associated with capsular and perinephric fat invasion.
• Loss of membranous CXCR4 expression could be accompanied by increasing grade or stage of RCCs.
• CD105 didn’t show any significant association with any studied clinicopathological parameters.
• Renal oncocytoma; despite its benign course, may show some confusing features simulating RCCs as bizarre nuclei or fat invasion.
Recommendations
• Studying the expression of CXCR4 and CD105 should be applied on large number of patients with RCCs with considerable presentation of each histological subtype in order to obtain more reliable results.
• Nodal and distant metastasis should be asked in each case with RCCs in order to be correlated to the expression of the studied markers for obtaining more accurate results about their prognostic significance.