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Preoperative risk stratification using plasma fibrinogen levels can predict lymphovascular invasion and poor prognosis in patients with upper urinary tract urothelial carcinoma

  • Authors:
    • Kenji Kuroda
    • Shinsuke Tasaki
    • Junichi Asakuma
    • Akio Horiguchi
    • Keiichi Ito
  • View Affiliations

  • Published online on: March 13, 2021     https://doi.org/10.3892/mco.2021.2264
  • Article Number: 102
  • Copyright: © Kuroda et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

It has been previously indicated that preoperative plasma fibrinogen levels can correlate with cancer progression and be used as a useful predictor of lymph node metastasis or its premetastatic status such as lymphovascular invasion (LVI). In the present study, how preoperative plasma fibrinogen levels, considered in conjunction with other clinicopathological factors, can predict the presence of LVI and prognosisin patients with upper urinary tract urothelial carcinoma (UTUC) was examined. Medical records of 145 patients with UTUC who underwent radical nephroureterectomy (RNU) were retrospectively reviewed. The current study evaluated systemic inflammatory response markers including levels of plasma fibrinogen and other clinicopathological factors in orderto determine independent predictors of LVI and prognosis. The Cox proportional hazards model indicated that positive surgical margins and LVI were independent factors for poor cancer‑specific survival (CSS) rates and extraurothelial recurrence‑free survival (ERFS) rates. In addition, positive cytology, the presence of hydronephrosis and plasma fibrinogen levels were significant preoperative predictors of LVI. Furthermore, patients exhibiting two or more of higher fibrinogen levels (≥400 mg/dl), positive urine cytology and the presence of hydronephrosis were indicated to exhibit worse CSS or ERFS rates compared with patients exhibiting only one of the aforementioned factors or those with none of the three aforementioned factors in the multivariate analysis of the Cox proportional hazards model. In conclusion, hyperfibrinogenemia can be an independent predictor of the presence of LVI, and stratifying preoperative risk using fibrinogen levels, urine cytology and hydronephrosis can serve as the basis for selecting candidates for additional therapy before and/or after RNU in patients with UTUC.

Introduction

Upper urinary tract urothelial carcinoma (UTUC) is a relatively rare malignant tumor, estimated to be approximately 10% of all renal tumors and only 5% of all urothelial carcinomas (1,2). This corresponds to an estimated annual incidence of almost two cases per 100,000 inhabitants in Western countries.

Radical nephroureterectomy (RNU) with a bladder cuff excision is the standard treatment for patients with N0M0 UTUC; however, lymphovascular invasion (LVI) as well as tumor grade and pathological stage were significantly related to cancer-specific survival (CSS) and overall survival rates in patients with UTUC who underwent open or laparoscopic RNU (3). Based on these findings, appropriate markers to monitor or predict oncologic outcomes for patients with localized UTUC are necessary.

The prognostic value of many systemic inflammatory response (SIR) markers as predictors of poor CSS or recurrence-free survival in several types of carcinoma has been reported (4-6). SIR was found to be related to shorter time to cancer progression and cancer-specific death (4-6). SIR markers include preoperative C-reactive protein (CRP), the Glasgow Prognostic Score (GPS), neutrophil to lymphocyte ratio (NLR), and platelet to lymphocyte ratio (PLR) (7-10).

Taken together, several studies have focused on the relationship between various cancers and hemostatic factors. Among such hemostatic factors, fibrinogen, an essential hemostatic factor, is converted to fibrin (a final product of the hemostatic pathway) by activated thrombin. In addition, elevated plasma fibrinogen has been reported to correlate with tumor progression in some types of cancer (11-13). Moreover, preoperative plasma fibrinogen levels were found to be a useful predictor of lymph node metastasis in earlier studies (11,12). As a result, preoperative plasma fibrinogen levels were also relevant in terms of predicting a poor prognosis in patients with several types of cancer (14-16). Based on these studies, we hypothesize that fibrinogen could be one cause of distant metastasis in patients with UTUC. Furthermore, a higher plasma fibrinogen level may also be a feasible marker of premetastatic status such as LVI; therefore, this marker mayenable us to monitor or predict oncologic outcomes of patients with localized UTUC, considered in conjunction with other clinicopathological factors. In the present study, we retrospectively examined the preoperative plasma fibrinogen levels of patients with UTUC who underwent RNU and evaluated the association of clinicopathological risk factors including preoperative plasma fibrinogen levelswith the presence of LVI and CSS and ERFS rates to establish a preoperative risk stratification model.

Patients and methods

Patients

We retrospectively reviewed and analyzed clinicopathological data from the medical records of 145 patients who underwent RNU at our institution and who were histologically diagnosed with UTUC. The study protocol (ID 2734) was approvedon June 14, 2017, by our institutional ethics committee, and we used an opt-out approach on the Web page of the National Defense Medical College instead of collecting written informed consent from all participants. The patients included 109 men and 36 women. The median follow-up period after nephroureterectomy was 54.2 months (range: 3.4 to 209.2 months). We present additional clinicopathological data in Table I.

Table I

Clinicopathological features.

Table I

Clinicopathological features.

ParametersPatients (n)
Age (median 70) 
     ≥7171
     ≤7074
Sex 
     Male109
     Female36
Urine cytology 
     Positive88
     Negative57
Histology 
     UC with other components29
     UC alone116
Pathological T stage 
     ≥T371
     ≤T274
Tumor grade 
     High101
     PUNLMP/Low44
Lymph node metastasis 
     Positive9
     Negative136
Ureteral involvement 
     Positive81
     Negative64
Surgical margins 
     Positive19
     Negative126
Lymphovascular invasion 
     Positive51
     Negative94
Carcinoma in situ 
     Present17
     Absent128
Hydronephrosis 
     Positive86
     Negative59
CRP (≥0.4 or ≤0.3) 
     ≥0.434
     ≤0.3111
Albumin (≤3.7 or ≥3.8) 
     ≤3.717
     ≥3.8128
NLR (≥1.652 or <1.652) 
     ≥1.652114
     <1.65231
PLR (≥154.122 or <154.122) 
     ≥154.12260
     <154.12285
GPS 
     ≥115
     0130
Fibrinogen (≥400 or <400) 
     ≥40023
     <400122

[i] UC, urothelial carcinoma; PUNLMP, papillary urothelial neoplasm of low malignant potential; CRP, C-reactive protein; NLR, neutrophil to lymphocyte ratio; PLR, platelet to lymphocyte ratio; GPS, glasgow prognostic score.

Extraurothelial recurrence after nephroureterectomy indicates tumor recurrence outside the bladder or distant metastasis. In this study, we defined recurrence-free survival as extraurothelial recurrence-free survival (ERFS). No patients had distant metastasis at diagnosis. Extraurothelialor intravesical recurrence was monitored for each patient every 3-6 months for the first 5 years after nephroureterectomy and 6-12 months thereafter. All surgical specimens were processed according to standard pathological procedures and were histologically confirmed to be urothelial carcinoma with or without other tumor cell types. The pathological staging of the primary tumor was determined according to the American Joint Committee on Cancer TNM Classification (17), whereas tumor grading was determined according to the 2004 World Health Organization (WHO) classification of urothelial tumors (18). Tumor specimens were evaluated by two pathologists, and the patients were categorized into two groups on the basis of the 2004 WHO classification system for tumor grading.

Inflammatory indices

Inflammatory indices were evaluated by laboratory tests. The neutrophil to lymphocyte ratio (NLR) was calculated by dividing the absolute neutrophil count by the absolute lymphocyte count (19). The platelet to lymphocyte ratio (PLR) was calculated by dividing the absolute platelet count by the absolute lymphocyte count (19). The Glasgow prognostic score (GPS) was evaluated by using the CRP and Alb values. Patients with elevated CRP levels (>1 mg/dl) in combination with hypoalbuminemia (<3.5 g/dl) were allocated 2 points. Patients with elevated CRP alone or hypoalbuminemia alone were allocated 1 point, whereas patients exhibiting these parameters within normal limits were allocated 0 points (10). In the presents study, normal limits of serum albumin, CRP levels and plasma fibrinogen levels were designated according to analyzing kits used at our institution based on the methods shown in earlier reports (11-13,20).

Statistical analysis

Cox proportional hazards model was used in the examination of independent factors for worse CSS and ERFS rates in multivariate analysis. A receiver operator characteristic (ROC) analysis was performed to determine the cut-off values of NLR and PLR according to the method shown in previous reports (21,22). Fisher's exact probability test was performed to examine the relationship between clinicopathological factors and the presence of LVI. Multiple logistic regression analysis was performed to detect predictors of LVI. The effect of independent markers for worse CSS and ERFS rates was evaluated with Kaplan-Meier plots and the log-rank test. The statistical analysis was undertaken using JMP version 14 (SAS Institute, Inc.). P<0.05 was considered to indicate a statistically significant difference.

Results

Independent factors for poor CSS rate and ERFS rate

The Cox proportional hazards model indicated that tumor histology, pathological T stage, tumor grade, lymph node metastasis, positive surgical margins, LVI, and the presence of hydronephrosis were independent factors for poor CSS and ERFS ratesin univariate analysis, and positive surgical margins and LVI were independent predictors of worse CSS (P=0.035, P=0.001, respectively) and ERFS (P<0.001, P=0.003, respectively) rates in multivariate analysis among pathological factors (Tables II and III). Finally, cancer-specific mortality and extraurothelial recurrence were found in 37 and 41 patients, respectively.

Table II

Univariate and multivariate analyses of independent factors for cancer-specific survival.

Table II

Univariate and multivariate analyses of independent factors for cancer-specific survival.

 UnivariateMultivariate
Pathological parametersHRP-valueHR95% CIP-value
Age (≥71 or ≤70)1.4360.272     
Sex (male or female)0.8360.623     
Urine cytology (positive or negative)1.4160.313     
Tumor histology (UC with other components or UC alone)3.0990.0031.7620.738-3.9690.195
Pathological T stage (≥T3 or ≤T2)4.275<0.0011.6240.710-4.0170.258
Tumor grade (high or PUNLMP/low)4.824<0.0012.5490.926-9.0120.072
Lymph node metastasis (positive or negative)4.3200.0060.7200.230-2.0290.544
Ureter involvement (positive or negative)1.6520.143     
Surgical margins (positive or negative)3.2810.0032.3881.064-5.0830.035
Lymphovascular invasion (positive or negative)7.570<0.0013.9651.688-9.9030.001
Carcinoma in situ (positive or negative)0.5820.333     
Hydronephrosis (positive or negative)2.1440.0351.2270.562-2.9030.618

[i] HR, hazard ratio; CI, confidence interval; UC, urothelial carcinoma; PUNLMP, papillary urothelial neoplasm of low malignant potential.

Table III

Univariate and multivariate analyses of independent factors for recurrence-free survival.

Table III

Univariate and multivariate analyses of independent factors for recurrence-free survival.

 UnivariateMultivariate
Pathological parametersHRP-valueHR95% CIP-value
Age (≥71 or ≤70)1.4990.197     
Sex (men or women)0.6980.295     
Urine cytology (positive or negative)1.1500.664     
Tumor histology (UC with other components or UC alone)3.625<0.0012.1780.993-4.6430.052
Pathological T stage (≥T3 or ≤T2)4.461<0.0012.0930.965-4.8590.062
Tumor grade (high or PUNLMP/low)5.426<0.0013.1821.162-11.2230.023
Lymph node metastasis (positive or negative)6.713<0.0011.3380.495-3.2830.547
Ureter involvement (positive or negative)1.7510.086     
Surgical margins (positive or negative)3776<0.0015.1022.318-10.833<0.001
Lymphovascular invasion (positive or negative)6.822<0.0013.1471.480-7.0000.003
Carcinoma in situ (positive or negative)0.5410.263     
Hydronephrosis (positive or negative)2.2880.0161.4380.685-3.2400.345

[i] HR, hazard ratio; CI, confidence interval; UC, urothelial carcinoma; PUNLMP, papillary urothelial neoplasm of low malignant potential.

Association between clinicopathological factors and the presence of LVI

Out of these two pathological factors, LVI was expected to be more frequently seen in surgical specimens unless pathological T stage was equal to or higher than 3. Therefore, we investigated the association between preoperative factors and the presence of LVI. Positive cytology, the presence of hydronephrosis, C-reactive protein levels, NLR, PLR, and plasma fibrinogen levels were significantly associated with the presence of LVI among preoperative factors in Fisher's exact probability test (Table IV). Among these related factors, positive cytology, the presence of hydronephrosis, and plasma fibrinogen levels were significant preoperative predictors of the presence of LVI (P=0.008, P=0.010, P<0.001, respectively) (Table V). In fact, patients with higher fibrinogen levels (≥400 mg/dl) had worse CSS and ERFS rates (both P<0.001) (Fig. 1). Patients with positive urine cytology did not have poor CSS or ERFS rates when compared with those with negative cytology (P=0.319, P=0.666, respectively) (Fig. 2). Patients with hydronephrosis had worse CSS and ERFS rates than those without hydronephrosis (P=0.042, P=0.019, respectively) (Fig. 3).

Table IV

Association between preoperative parameters and LVI.

Table IV

Association between preoperative parameters and LVI.

A, Clinicopathological parameters
 LVI 
ParameterTotal(%)Positive(%)Negative(%)P-value
Age (median 70)      0.492
     ≥7171(49.0)23(32.4)48(67.6) 
     ≤7074(51.0)28(37.8)46(62.2) 
Sex      0.085
     Male109(75.2)34(31.2)75(68.8) 
     Female36(24.8)17(47.2)19(52.8) 
Urine cytology      0.029
     Positive88(60.7)37(42.1)51(57.9) 
     Negative57(39.3)14(24.6)43(75.4) 
Hydronephrosis      0.005
     Positive86(59.3)38(44.2)48(55.8) 
     Negative59(40.7)13(22.0)46(78.0) 
B, Laboratory parameters
 LVI 
ParameterTotal(%)Positive(%)Negative(%)P-value
Laboratory parameters       
CRP (≥0.4 or ≤0.3)      0.015
     ≥0.434(23.5)18(52.9)16(47.1) 
     ≤0.3111(76.5)33(29.7)78(70.3) 
Albumin (≤3.7 or ≥3.8)      0.110
     ≤3.717(11.7)9(52.9)8(47.1) 
     ≥3.8128(88.3)42(32.8)86(67.2) 
NLR (≥1.652 or <1.652)      <0.001
     ≥1.652114(78.6)48(42.1)66(57.9) 
     <1.65231(21.4)3(9.7)28(90.3) 
PLR (≥154.122 or <154.122)      0.005
     ≥154.12260(41.4)29(48.3)31(51.7) 
     <154.12285(58.6)22(25.9)63(74.1) 
GPS (≥1 or 0)      0.128
     ≥115(10.3)8(53.3)7(46.7) 
     0130(89.7)43(33.1)87(66.9) 
Fibrinogen (≥400 or <400)      <0.001
     ≥40023(15.9)19(82.6)4(17.4) 
     <400122(84.1)32(26.2)90(73.8) 

[i] LVI, lymphovascular invasion; CRP, C-reactive protein; NLR, neutrophil to lymphocyte ratio; PLR, platelet to lymphocyte ratio; GPS, glasgow prognostic score.

Table V

Univariate and multivariate analyses of preoperative factors for the presence of LVI.

Table V

Univariate and multivariate analyses of preoperative factors for the presence of LVI.

 UnivariateMultivariate
Preoperative parametersORP-valueOR95% CIP-value
Urine cytology (positive or negative)2.2280.0333.4391.373-8.6130.008
Hydronephrosis (present or absent)2.8010.0073.3981.334-8.6540.010
CRP (≥0.4 or ≤0.3)2.6590.0150.8420.286-2.4790.756
Albumin (≤3.7 or ≥3.8)2.3040.110     
NLR (≥1.652 or <1.652)6.7880.0034.1580.971-17.7940.055
PLR (≥154.122 or <154.122)2.6790.0061.1310.479-2.6730.778
GPS (≥1 or 0)2.3120.128     
Fibrinogen (≥400 or <400)13.359<0.00114.7023.799-56.900<0.001

[i] LVI, lymphovascular invasion; OR, odds ratio; CI, confidence interval; CRP, C-reactive protein; NLR, neutrophil to lymphocyte ratio; PLR, platelet to lymphocyte ratio; GPS, glasgow prognostic score.

Preoperative risk stratification using plasma fibrinogen levels and other risk factors to predict worse CSS and ERFS rates

Based on these findings, we stratified patients into three groups. Group A was comprised by patients exhibiting two or more of higher fibrinogen levels (≥400 mg/dl), positive urine cytology, and the presence of hydronephrosis. Group B consisted of patients with only one of those factors, and Group C consisted of those with none of the three factors. Group A patients showed worse CSS and ERFS rates than those in Groups B and C (both P<0.001, Fig. 4). Moreover, we further divided patients into those with renal pelvic cancer alone and those with renal pelvic and/or ureteral cancer. Kaplan-Meier curves revealed that in both patients with renal pelvic cancer alone and those with renal pelvic and/or ureteral cancer, patients of Group A had significantly worse CSS (P=0.025, P=0.018, respectively) and ERFS (P=0.046, P=0.039, respectively) rates than those in Groups B and C (Figs. 5 and 6).

Discussion

In this study, a Cox proportional hazards model demonstrated that positive surgical margins and LVI were independent predictors of shorter CSS and ERFS time (Tables II and III). In addition, we found that fibrinogen levels, positive urine cytology, and the presence of hydronephrosis were significant factors associated with the presence of LVI (Tables IV and V). In fact, patients exhibiting two or more of these factors showed worse CSS or ERFS rates than those exhibiting only one factor or those exhibiting none of the three factors (Fig. 4). These results were also consistent in patients with renal pelvic cancer alone and those with renal pelvic and/or ureteral canceras seen in all patients (Figs. 5 and 6). In addition, plasma fibrinogen levels are associated with other diseases (e.g., atherosclerosis, hypertension, and stroke). However, histories of such severe diseases were not found in patients enrolled in the present study. It is speculated that plasma fibrinogen levels were only predictors of worse CSS and ERFS in this study.

Several studies have indicated the association between elevated preoperative plasma fibrinogen levels and poor prognosis in a number of cancers by using meta-analyses (23-25). Earlier studies have also revealed that the metastatic status can potentiallyoccur in the environment of circulating tumor cells which may be caused by high plasma fibrinogen levels (26). Furthermore, preoperative plasma fibrinogen levels may berelated to tumor volume and may provide favorable conditions for circulating tumor cells to metastasize through the lymphatic drainage orvascular flow (12,23). A preliminary study showed that mice lacking fibrinogen had a remarkably decreased level of lymphatic and hematogenous metastases compared to that observed in wild-type mice. They suggested that an increase in plasma fibrinogen levels can play an important role in cancer metastasis (26). Tanaka et al especially showed that patients with malignant tumors and preoperative high plasma fibrinogen levels have a higher risk for a worse prognosis than those with low fibrinogen levels in patients with UTUC (20). Hence, the results of the present study concur with the results reported by Tanaka et al and others.

The prognostic value of chronic kidney disease and positive surgical margins in UTUC patients undergoing RNU was previously reported (27). However, preoperative plasma fibrinogen levels were not independent predictors of worse CSS or ERFS because the patient group of the previous study was different from that of the present study. In addition, the cut-off value of plasma fibrinogen levels also differed from that used in the present study (27).

Questions remain on how fibrinogen can influence the progression and metastatic possibility ofmalignant tumors. Several tentative theories have been reported on this. First, fibrinogen may aggregate around cancer cells to work as a structure for cancer cell proliferation. Fibrinogen can also serve as a basement to sustain some growth factors, such as vascular endothelial growth factor and fibroblast growth factor, to promote tumor angiogenesis (25). Second, tumor cells retain fibrinogen receptors, which play a role in bridging fibrinogen molecules to tumor cells and thus enhance the endothelial adhesion of tumor cell emboli in a target organ's vasculature. This mechanism appears to enable metastasis and successively increase the survival rates of metastatic cells (24). Third, fibrinogen can enhance the adhesion of platelets to tumor cells, mediated by β3-integrin which was expressed by tumor cells. The aggregation of fibrinogen can be proceeded by platelet migration to the tumor cell environment; a thick layer of fibrin may then be formed to provide protection of the tumor cells against natural killer cell cytotoxicity, resulting in a higher possibility of distant metastasis (28). Moreover, fibrinogen can be integrated by cancer cells endogenously. This event can lead to the proliferation of cancer cells and angiogenesis, caused by fibroblast growth factor-2, which induces cancer progression and metastasis (29).

Positive urine cytology and the presence of hydronephrosis have been associated with the presence of LVI. Sakano et al showed that positive urine cytology and hydronephrosis were significantly associated with the presence of LVI (30). Ito et al also indicated that a higher hydronephrosis grade had a significant correlation with the presence of ureteral tumors, a higher pT stage, and the presence of LVI (31). Another study also showed that patients with positive voided urine cytology had higher incidences of high-grade tumors and positive LVI in UTUC patients treated with RNU (32). These findings are consistent with those of the present study, although neither positive urine cytology nor hydronephrosis was found as an independent factor for worse CSS or ERFS rates. However, using plasma fibrinogen levels in conjunction with these clinicopathological factors couldmore accurately predict LVI and a poorer prognosis in UTUC, as described in an earlier study evaluating the effectiveness of a two-factor risk stratification model (33).

This study had some limitations. First, it was retrospective in nature, and our sample size was relatively small; however, the median follow-up period after RNU was more than four years, and so our observation time to cancer-specific death and extraurothelial recurrence was long enough to support our findings. Second, the underlying mechanism explaining the association of positive urine cytology or hydronephrosis with the presence of LVI remains unclear. As to hydronephrosis, its presence may imply tumoral extension to the outer urothelial layers, which may be an indicator of cancer cells spreading to the reginal nodes or distant organs. Considering that the urothelial lumen under hydronephrosis is thinner than normal lumen, the spreading of urothelial carcinoma cells beyond the urothelial layers is possible. The increased pressure in the urothelial lumen may also lead to counterflow in lymphatics and blood vessels, increasing the possibility of cancer cell migration (34). Furthermore, we could not validate the efficacy of positive urine cytology as an independent predictor of the presence of LVI, although several reports suggest a significant relationship between positive urine cytology and the presence of LVI (30,32). Despite these limitations, our data suggests that a high plasma fibrinogen level can be an independent prognosticator for worse CSS and ERFS in patients with UTUC undergoing RNU.

In conclusion, stratifying preoperative risk using fibrinogen levels, positive urine cytology, and the presence of hydronephrosis before RNU can provide additional information aboutthe possibility of worse CSS and ERFS rates in patients with localized UTUC. This finding can serve as a basis for selecting candidates for additional therapy before and/or after RNU in patients with UTUC.

Acknowledgements

Not applicable.

Availability of data and materials

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Authors' contributions

KK, ST, JA, AH and KI were involved in the conception and design of the study. KK collected and analyzed the data. KK drafted the manuscript. The authenticity of all the raw data was assessed by KK and KI. KK and KI reviewed and edited the manuscript. All authors read and approved the final manuscript.

Ethics approval and consent to participate

All procedures performed in this study were approved bythe National Defense Medical College (Saitama, Japan; approval no. 2734). All procedures were conducted in accordance with the 1964 Declaration of Helsinki and its later amendments.

Patient consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

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May-2021
Volume 14 Issue 5

Print ISSN: 2049-9450
Online ISSN:2049-9469

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Spandidos Publications style
Kuroda K, Tasaki S, Asakuma J, Horiguchi A and Ito K: Preoperative risk stratification using plasma fibrinogen levels can predict lymphovascular invasion and poor prognosis in patients with upper urinary tract urothelial carcinoma. Mol Clin Oncol 14: 102, 2021
APA
Kuroda, K., Tasaki, S., Asakuma, J., Horiguchi, A., & Ito, K. (2021). Preoperative risk stratification using plasma fibrinogen levels can predict lymphovascular invasion and poor prognosis in patients with upper urinary tract urothelial carcinoma. Molecular and Clinical Oncology, 14, 102. https://doi.org/10.3892/mco.2021.2264
MLA
Kuroda, K., Tasaki, S., Asakuma, J., Horiguchi, A., Ito, K."Preoperative risk stratification using plasma fibrinogen levels can predict lymphovascular invasion and poor prognosis in patients with upper urinary tract urothelial carcinoma". Molecular and Clinical Oncology 14.5 (2021): 102.
Chicago
Kuroda, K., Tasaki, S., Asakuma, J., Horiguchi, A., Ito, K."Preoperative risk stratification using plasma fibrinogen levels can predict lymphovascular invasion and poor prognosis in patients with upper urinary tract urothelial carcinoma". Molecular and Clinical Oncology 14, no. 5 (2021): 102. https://doi.org/10.3892/mco.2021.2264