Predictive value of SIRI and SII for metastases in RCC: A prospective clinical study

doi:10.21203/rs.3.rs-3146361/v1

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Predictive value of SIRI and SII for metastases in RCC: A prospective clinical study

https://doi.org/10.21203/rs.3.rs-3146361/v1

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published 13 Jan, 2024

Read the published version in BMC Urology →

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Background:

Prediction of possible postoperative metastases of renal cell carcinoma is a compelling challenge for clinicians. In this prospective cross-sectional clinical study we aimed to determine the efficiency of the preoperative hematological markers namely SIRI (systemic inflammatory response index) and SII (systemic inflammatory index) for renal cell carcinoma to predict the possibility of postoperative metastases.

Methods:

72 patients who were diagnosed with RCC and underwent surgery in Urology Clinic of Istanbul Training and Research Hospital or were included in the treatment planning in the Medical Oncology Clinic of Istanbul Training and Research Hospital between July 2022 and January 2023 were included in the study. All cases with diagnoses of renal cell carcinoma were obtained from the hospital records. Patients with secondary malignancy, hematological or rhemotological disorders or ones with the recent blood product transfusion or diagnoses of infection within the 1-month-time of diagnoses were excluded. The data within complete blood counts analysed just before the time of renal biopsy or surgery were analysed for SIRI and SII calculations. A total of 22 metastatic and 50 non-metastatic RCC patients were included. SIRI and SII values were compared among groups to seek the change of values in case of meastatasis and in non-metastatic patients a cut-off value were sought to indicate malignancy before pathological diagnosis.

Results:

Mean age of non-metastatic RCC patients were 60.12+/-11.55 years and metastatic RCC patients were 60.25+/-11.72. Histological sub-types of the RCC specimens were clear cell (72%), chromophobe cell (17%), papillary cell (7%) and others (4%). Median SIRI values for non-metastatic and metastatic groups were 1.26 and 2.1 (mean+/-S.D. 1.76 +/-1.9 and 3.12+/-4.22 respectively (p<0.05). Median SII values for non-metastatic and metastatic groups were 566 and 1434 (mean+/-S.D. 870 +/-1019 and 1537+/-917) respectively(p<0.001).

Conclusions: SIRI and SII indexes seem to show a moderate efficiency to show metastases in RCC.

Trial Registration: -

Approved by the Health Sciences University Istanbul Health Practice and Research Center, Clinical Research and Ethics Committee (22.07.2022/Desicion Number: 235)

Renal cell carcinoma

SIRI

SII

Metastasis

20–25% of renal cell carcinoma (RCC) patients are metastatic at the time of diagnosis. RCC accounts for approximately 90% of all renal malignancies. The remaining 10–15% of tumors are urothelial carcinomas of the renal pelvis and other rare malignancies. It is commonly seen between the ages of 50–70. Averaging 3–5% of all cancer cases[1, 2]. In the previous decades the diagnosis has evaluated to be incidental rather than historical triad of hematuria, flank pain and palpable flank mass upon admission. RCC has been associated with high tobacco use, low socioeconomic status, obesity and NSAID [3]. Histologically, RCC has several subtypes. The clear cell type RCC, papillary type RCC and chromophobe type RCC are seen each with variying proportion [4]. Depending on the condition of the mass, radical nephrectomy or partial nephrectomy comes to fore as a treatment method in RCC confined to the kidney. In metastatic RCC, additional treatments are required.

Inflammatory cells include macrophages, mast cells, neutrophils, and T and B lymphocytes in tumor microenvironment (TME) and all of them can stimulate tumor angiogenesis and proliferation [5]. Systemic Inflammatory Response Index (SIRI) is a marker and also a trending scoring system which includes the counts of neutrophils, monocytes and lmyphocytes. Formulation of SIRI is monocyte count times neutrophil count divided by lymphocyte count. Another inflammatory scoring system is the systemic immune-inflammation index (SII) which includes the counts of lymphocyte, neutrophil and platelet. Formulation of SII is platelet count times neutrophil count divided by lymphocyte count. SII has recently been shown as a poor prognostic factor in malignancies. SII is implicated in the growth, proliferation and micrometastasis of tumor cells caused by high neutrophil, platelet and lymphocyte levels [6, 7].

In this study, we aimed to evaluate predictive value of SIRI and SII for metastases in RCC.

After local ethics approval of the study in accordance with the Declaration of Helsinki (Health Sciences University Istanbul Health Practice and Research Center, Clinical Research and Ethics Committee [22.07.2022/235]), patients were included in the study after informed written consent in accordance with inclusion and exclusion criteria. Inclusion criteria were diagnoses of RCC between July 2022 and January 2023, age older than 18, presence of preoperative laboratory tests and inflammatory indices.

72 patients who were diagnosed with RCC and underwent surgery in Urology Clinic of Istanbul Training and Research Hospital or were included in the treatment planning in the Medical Oncology Clinic of Istanbul Training and Research Hospital between July 2022 and January 2023 were included in the study. Male and female patients older than 18 years of age who had preoperative laboratory tests and inflammatory indices could be calculated were included in the study. 50 of the patients were male and 22 were female. Twenty-two of the patients had metastatic RCC. 50 patients had non-metastatic RCC. Patients older than 18 years of age, who underwent radical or partial nephrectomy due to kidney tumor and were diagnosed with RCC in their pathology, and patients who did not undergo surgery but were diagnosed with RCC in their pathology by biopsy and whose haematological parameter studies were performed in the last 1 week were included into the study.

Patients with another malignancy, patients who were diagnosed with or suspected of infection within 1 week before admission, patients who received steroid therapy or immunosuppressive therapy at the time of admission, patients with known autoimmune disease, and patients who received blood transfusion within the last 1 month were excluded from the study.

Laboratory results and histopathological findings of the patients included in the study were analyzed. Tumor stages and grades of the patients were recorded. The metastatic and non-metastatic groups were compared with each other by confirming the metastasis status by imaging methods of the patients whose histopathological findings were recorded. Using the laboratory results of these two groups, inflammatory indices such as SIRI and SII were calculated and their effectiveness in terms of metastasis was compared.

Shapiro-Wilk test was used to evaluate whether the data were normally distributed. Data that fit the normal distribution were presented as the mean ± standard deviation and those that did not fit were presented as the median (interquartile range). The Student-t test was used for the analysis of quantitative data that fit normally, and the Mann-Whitney-U test was used for those that did not fit the normal distribution. Chi-square or Fisher test was used for the analysis of quantitative data. For metastatic renal cell carcinoma, the area under the curve and receiver operating characteristics were calculated for the predictive value of the data. A p ≤ 0.05 was accepted as the level of significance in the comparisons.

Twenty (28%) of the patients were female and the remaining 52 (72%) were male. The mean age of the patients was 60,25 ± 11,72 years. The mean age for women was 62,35 ± 13,84 years, and the mean age for men was 59,44 ± 10,84 (p = 0.349). The mean age of metastatic patients was 60,60 ± 12,46 years, while the mean age of non-metastatic patients was 60,12 ± 11,55 (p > 0,05). Twenty-two (31%) of the patients had metastatic RCC and 50 of the patients (69%) had non-metastatic RCC. The mean body mass index (BMI) of the patients was 28,10 ± 6,18. The BMI was 30,38 ± 9,27 in women and the mean BMI in men was 27,10 ± 3,93 (p = 0,046). While the mean BMI of the metastatic patients was 30,17 ± 10,10, it was 27,49 ± 4,41 in non-metastatic patients (p > 0,05). At least 1 comorbid disease was present in 66% of the patients. According to the frequency of comorbid diseases of the patients, 44% had hypertension, 20% had diabetes mellitus, 17% had cardiovascular disease, 9% had chronic obstructive pulmonary disease and 10% had other diseases. Tumors were located unilaterally in all patients included in the study, and right and left locations (57% right and 43% left) had similar rates (p = 0,239).

The diagnosis was made by percutaneous renal biopsy in 8 of the patients (11%), while the diagnosis was made by surgical excision (radical nephrectomy/partial nephrectomy) in 64 cases (89%). As the surgical approach in surgical excision, laparoscopic surgery was used in 89% (57 patients) and open surgery in 11% (7 patients). Radical total nephrectomy was performed in 38% of patients (n = 24) and partial nephrectomy was performed in 62% of the remaining (n = 40) patients. Renal ischemia was performed in 75% of the patients who underwent partial nephrectomy, and the remaining 25% did not. Simultaneous lymph node dissection was performed in 9% (6/64) of the patients who underwent surgical excision. Surgical complication developed as pleural injury in 1.5% of the patients.

The histological subtypes of RCC specimens in our study consisted of 72% clear cell, 17% chromophobe cell, 7% papillary type and 4% other subtypes which are shown in Table 1.

Table 1

RCC histological subtypes of the patients in the study
Histopathologic subtype	Frequency	Percentage
Clear cell	52	72.2
Chromophobe	12	16.7
Papillary type	5	6.9
Others	3	4.2
Total	72	100

T stages of the patients in our study consisted of 29% pT1a, 33% pT1b, 6% pT2a and 32% pT3a which are shown in Table 2.

Table 2

T stages of the patients in the study
T-stages of patients	Frequency	Percentage
pT1a	18	28.6
pT1b	21	33.3
pT2a	4	6.3
pT3a	20	31.7
Total	63	100

When the metastatic and non-metastatic groups were compared, statistically significant differences were observed between the two groups in terms of lymphocyte and platelet counts (p < 0.01) which are shown in Table 3.

Table 3

Comparison of patients’ blood parameter values between metastatic and non-metastatic groups
	Neutrophil count	Monocyte count	Lymphocyte count*	Leukocyte count	Thrombocyte Count*
Non-metastatic	5.73 ± 3.36	0.54 ± 0.13	2.23 ± 0.83	8.75 ± 3.64	263.19 ± 83.08
Metastatic	5.80 ± 2.04	0.65 ± 0.39	1.52 ± 0.57	8.29 ± 2.16	357.45 ± 124.47
*: p < 0.01

When the metastatic and non-metastatic groups were compared, statistically significant differences were observed between the two groups in terms of SIRI and SII values (p < 0.05 for SIRI, p < 0.001 for SII).

Median SIRI values for non-metastatic and metastatic groups were 1.26 and 2.1, respectively (mean ± standart deviation 1.76 ± 1.9 and 3.12 ± 4.22 respectively (p < 0.05)). Median SII values for non-metastatic and metastatic groups were 566 and 1434, respectively (mean ± standart deviation 870 ± 1019 and 1537 ± 917 respectively (p < 0.001)) which are shown in Table 4.

Table 4

Comparison of SIRI and SII metastatic and non-metastatic groups from the blood parameter values of the patients
	SIRI*	SII**
Non-metastatic	1.75 ± 1.92	869.59 ± 1018.95
Metastatic	3.12 ± 4.22	1537.80 ± 916.82
*: p < 0.05
**: p < 0.001

The area under the curve in metastatic patients was 0.809 for SII and 0.737 for SIRI. The ROC curve is shown in the Fig. 1.

Approximately one-third of patients have metastatic RCC at presentation. RCC is one of the cancers in which the immune system is most activated [8]. In order to better evaluate the outcomes of the patients, it is necessary to identify some predictive factors for reliable prognostic and metastasis prediction. In this study, thrombocyte, lymphocyte, SIRI and SII were found to be independent predictive factors in predicting metastasis from the blood parameters of the patients at the time of admission.

Local and systemic inflammation associated with cancer is a defined feature of malignant tumors. The critical role of inflammation in malignancy formation, progression and metastasis has been investigated and accepted in recent studies. Tumor microenvironment and selectin and chemokine receptors of tumor cells are implicated in neoplastic and metastatic processes [9].

Numerous studies have investigated the relationship between inflammation and cancer. Studies have reported the relationship of inflammation with tumor invasion, progression and metastasis. The body’s systemic response to inflammation affects many hematological parameters through myeloid growth factors such as IL-1, IL-6, TNF-alpha, granulocyte stimulating factor (G-CSF), granulocyte macrophage stimulating factor (GM-CSF). Many studies have been conducted on the number of neutrophils, lmyphocytes and platelets from peripheral circulating inflammatory cells. As a result, especially in metastatic patients, considering these mechanisms, treatments were planned using immune checkpoint treatments and future treatment planning will be based on the immune system [10].

Santoni et al. showed that the presence of a large number of tumor associated macrophages in the RCC microenvironment promotes tumor progression and metastasis by stimulating angiogenesis, tumor growth and cell migration. Tumor-associated macrophages are thought to mediate angiogenesis and tumor proliferation by increasing vascular endothelial growth factor (VEGF) secretion [11].

Neutrophils are the blood cells that first response to tissue damage. It has been shown in many studies that neutrophils play a role in cancer formation and proliferation through many mechanisms, especially inflammation, angiogenesis and immunsupression. It regulates the functions of other immune cells, especially cytotoxic T cells, in the tumor microenvironment. It also stimulates tumor vascularization via VEGF and fibroblast growth factor (FGF-2) [12]. In animal experiments on mice, it has been defined that circulating tumor cells and neutrophil clusters from cell-cell junction and cytokine receptor pairs during metastatic RCC development. This described relationship has been shown to promote circulating cell turnover and increase the metastatic potential of circulating cancer cells [13].

Lymphocytes play an important role in the balance between body defense and harmful agents that play a role in a number of diseases, including cancer. They induce cytotoxic cell death, inhibit tumor proliferation and migration, improve the prognosis of cancer [14].

Thrombocytosis is an indicator of the tumor gaining a more aggressive character and is an indicator of poor prognosis as it increases the risk of metastasis [15].

Increasing evidence suggests a complex interaction between leukocytes and various types of cancer, including RCC. SIRI, which is an indicator of inflammation and mainly based on peripheral neutrophil, lymphocyte and monocyte counts, was first suggested to be a reliable prognostic factor in a study conducted by Qi et al. in 2016 including 177 patients with pancreatic cancer [16].

In the meta-analysis of patients with urological cancer, which included 14 studies with 3744 patients, it was shown that high SII value is associated with poor prognosis [17]. On the other hand, there is no study in the literature investigating the effectiveness of inflammation biomarkers in predicting metastasis in patient with RCC. In this sense, we hope that our study will contribute to the literature.

Aktepe et al., in a retrospective review of the data of 150 people with metastatic RCC who received tyrosine kinase inhibitor, showed that the platelet/lymphocyte ratio (PLR) was superior to the neutrophil/lymphocyte ratio (NLR) in terms of assesing overall survival [18]. In our study, when compared with the non-metastatic group, especially high platelet and low lymphocyte levels were observed in the metastatic group. In this case, it is seen that the rate of PLR is higher in the metastatic group. Therefore, high platelet count and low lymphocyte count can guide us about the risk of metastasis.

In a study by Takuya et al., in which the records of 268 nephrectomized patients were examined, it was shown that reactive thrombocytosis in renal cell carcinomas developed due to hypercytocinemia. It has also been reported that the presence of IL-6 and high CRP in the liver triggers thrombocytosis and IL-6 induces differentiation from megakaryocytes to platelets and leads to an abnormal inflammatory response. In addition, it has been stated that the tumor itself triggers thrombocytosis. It has been reported that thrombocytosis and tumor progression may also be a marker [19]. When the platelet counts were compared in our study, a statistically significant difference was observed between the metastatic and non-metastatic groups, and it is thought that it may contribute to the prediction of metastasis.

Zheng et al. investigated the relationship of SIRI with lymph node metastasis in patients with upper system urothelial carcinoma who underwent radical nephrectomy between 2003 and 2016. SIRI value was found to be associated with lymphovascular invasion and lymph node metastasis [20]. Chen et al. also investigated the association of SIRI with 3-year and 5-year survival and prognosis in clear cell RCC. They found that other inflammatory parameters, NLR, were statistically more significant than PLR values in both 3-year and 5-year follow-up [21]. In our study, we have not done any research on the comparison of SIRI, NLR and PLR values.

According to the results of the meta-analysis, which included 30 retrospective studies published between 2016 and 2020, although it was found to be associated with SIRI value, TNM stage and lymphovascular invasion, its relationship with metastasis was not evaluated. This meta-analysis study includes cohort studies of different numbers of gastrointestinal cancers, lung cancer, cervical cancer, breast cancer, urological cancer and soft tissue cancers [22]. Our study shows that SIRI can be a parameter that can be used to predict metastasis.

In a study by Özbek et al., 176 patients with radical nephrectomy were included and the relationship of SII value with TNM stage and poor prognosis was investigated. High SII value was found to be associated with advanced TNM stage and poor prognosis [23]. In our study, it was shown that the level of SII is associated with the risk of metastasis.

Renal cell carcinoma is usually a disease of advanced age. The incidence and metastasis rate increase with increasing age. It peaks between the ages of 60–70. In our study, the mean age of the patients was 60.25 ± 11.72 years. The mean age of metastatic patients was 60.60 ± 12.46 years, while the mean age of non-metastatic patients was 60.12 ± 11.55 years [24].

In the studies, there is a male predominance in all age groups in patients with RCC. This ratio is 1.5:1 in epidemiological studies. In our study, there were 52 male patients and 20 female patients, and there was a male gender predominance similar to the literature [24].

This study has several limitations. More compherensive results and possible mechanisms can be revealed by evaluating the results of more patients that can be done in this regard. First of all, carrying out our study with a larger group and in a wider time period will contribute more to the results.

As a result of our study, inflammation parameters obtained from venous blood samples taken from patients can be used to predict metastasis. Low lymphocyte, high platelet count, increased SIRI and SII values indicate a high probability of metastasis. We think that it would be beneficial to conduct more comprehensive studies based on repeated measurement results by evaluating the results of more patients.

According to the results of this study, it is seen that the risk of metastasis may be higher in patients with RCC who have high SIRI and SII values, low lymphocyte count and increased platelet count, which are among the inflammatory parameters obtained from the venous blood sample at the time of diagnosis of patients with RCC. For this reason, it is thought that determining the prognosis and metastasis risk at the time of diagnosis from the inflammatory parameters of patients diagnosed with RCC may be useful in treatment planning and follow up.

AUC Area under the ROC Curve

BMI Body Mass Index

CBC Complete Blood Counts

CT Computed Tomography

FGF-2 Fibroblast Growth Factor

G-CSF Granulocyte Colony Stimulating Factor

GM-CSF Granulocyte-Macrophage Colony Stimulating Factor

MRI Magnetic Resonance Imaging

MSKCC Memorial Sloan Kettering Cancer Center

NLR Neutrophil/Lymphocyte Ratio

PLR Platelet/Lymphocyte Ratio

RCC Renal Cell Carcinoma

SII Systemic Inflammatory Index

SIRI Systemic Inflammatory Response Index

TME Tumor Microenviroment

VEGF Vascular Endothelial Growth Factor

Ethics approval and consent to participate - All methods were carried out in accordance with relevant guidelines and regulations.

Consent for publication - Not applicable

After local ethics approval of the study in accordance with the Declaration of Helsinki (Health Sciences University Istanbul Health Practice and Research Center, Clinical Research and Ethics Committee [Decision number: 22.07.2022/235]), patients were included in the study after informed written consent in accordance with inclusion and exclusion criteria.

Availability of data and materials - The datasets used during the current study available from the corresponding author on request.

Competing interests - The authors declare that they have no conflicts of interest.

Funding - Not applicable

Authors' contributions - All authors contributed to the study of conception and design. Hikmet Köseoğlu coordinated and managed all parts of the study. Tolga Eroğlu carried out the literature search. All authors conducted data collection and performed preliminary data preparations. Hikmet Köseoğlu conducted data analyses and all the authors contributed to the interpretation of data. Emre Arı wrote the draft of the paper and all authors provided substantive feedback on the paper and contributed to the final manuscript. All authors read and approved the final manuscript.

Acknowledgements - Not applicable

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No competing interests reported.

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You are reading this latest preprint version

Predictive value of SIRI and SII for metastases in RCC: A prospective clinical study

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Abstract

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Background

Materials and Methods

Results

Discussion

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