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Programmed Death-Ligand 1, C-reactive Protein, and Neutrophil/Lymphocyte Ratio as Lymphangiogenesis Markers of Metastasis in Penile Cancer – A Systematic Review

I Wayan Yudiana
I Wayan Yudiana
, 
Stacia Novia Marta
Stacia Novia Marta
, 
Ronald Sugianto
Ronald Sugianto
 and 
Anak Agung Wiradewi Lestari
Anak Agung Wiradewi Lestari
   | Jan 01, 2024
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Article Category: Research Article
Published Online: Jan 01, 2024
Page range: -
Received: Jun 19, 2023
Accepted: Nov 06, 2023
DOI: https://doi.org/10.2478/fco-2023-0010
Keywords
© 2023 I Wayan Yudiana et al., published by Sciendo
This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.

Figure 1:

PRISMA flow chart PRISMA, Preferred Reporting Items for Systematic Review and Meta-Analysis.
PRISMA flow chart PRISMA, Preferred Reporting Items for Systematic Review and Meta-Analysis.

Summary of markers used.

Author Year PD-L1 CRP NLR and LMR Ki-67 Chemokine motif ligands miRNAs Other biomarkers
De Bacco et al.12 2020 (+) p16
Udager et al.13 2016 (+)
Ottenhof et al.14 2018 (+) HLA
Hu et al.15 2020 (+) (+)
Steffens et al.16 2013 (+)
Al Ghazal et al.17 2013 (+)
Jindal et al.18 2021 (+)
Protzel et al.19 2007 (+)
Cocks et al.20 2017 (+) CD8
Mo et al.21 2021 CXCL5
Mo et al.22 2020 CXCL13
Mo et al.23 2020 CCL20
Murta et al.24 2022 Differentially expressed miRNAs DEGs
Ayoubian et al.25 2021 miR-137 and miR-328-3p
Mohr et al.26 2022 S100A8 and S100A9; CD147
van der Fels et al.27 2020 PSMA, VEGF, EGFR, and EpCAM
Zhou et al.28 2018 sLAMC2
Fenner et al.29 2018 EF21
Zhu et al.30 2013 CA IX
Minardi et al.31 2011 D2-40
Protzel et al.32 2011 Annexins I, II, and IV

NOS risk of bias assessment.

Author Year Selection Comparability Exposure Total score
Adequate definition of patient cases Representativeness of patient cases Selection of controls Definition of controls Control for important or additional factors Ascertainment of exposure Same method of ascertainment for participants Nonresponse rate
Mohr 2022 * * * * * 5
Ayoubian 2021 * * * * * * 6
Jindal 2021 * * * * * * 6
Hu 2020 * * * * * 4
De Bacco 2020 * * * * * 5
van der Fels 2020 * * * * * * 6
Zhou 2018 * * * * * * 6
Cocks 2017 * * * * * 5
Udager 2016 * * * * * * 6
Al Ghazal 2013 * * * * * * 6
Steffens 2013 * * * * * * 6
Murta 2022 * * * * * 5
Mo 2021 * * * * * * * * 8
Mo 2020 * * * * * * * * 8
Mo (2) 2020 * * * * * * * * 8
Fenner 2018 * * * * 4
Ottenhof 2018 * * * * * * 6
Zhu 2013 * * * * * * * 7
Minardi 2011 * * * * * * * 7
Protzel 2011 * * * * * * * 7
Protzel 2007 * * * * * * * 7

Summary of eligible studies.

Author Year Location Settings Total samples Type of patients
De Bacco et al.12 2020 Porto Alegre, Brazil Prospective cohort 40 patients Penile squamous cell carcinoma
Udager et al.13 2016 Ann Arbor, USA Retrospective observational study 37 patients Penile squamous cell carcinoma
Ottenhof et al.14 2018 Amsterdam, the Netherlands Retrospective observational study (immunohistochemistry analysis) 487 patients Penile squamous cell carcinoma
Hu et al.15 2020 Changsha, China Prospective cohort 84 patients Penile squamous cell carcinoma
Steffens et al.16 2013 Hannover, Germany Retrospective cohort study 79 patients Penile cancer
Al Ghazal et al.17 2013 Ulm, Germany Retrospective cohort study 51 patients Penile cancer patients underwent radical or partial penectomy (pT1–pT4)
Jindal et al.18 2021 Bengal, India Prospective observational study 69 patients Penile cancer; pT1 (15), pT2 (37), pT3 (16), pT4 (1) with inguinal node dissection
Protzel et al.19 2007 Helios-Kliniken Schwerin, Germany Retrospective observational study (immunohistochemistry analysis) 28 patients Invasive penile squamous cell carcinoma
Cocks et al.20 2017 North America Prospective cohort 53 patients Invasive penile squamous cell carcinoma tissue
Mo et al.21 2021 Hunan, China Retrospective observational study 81 patients Penile cancer patients underwent surgery
Mo et al.22 2020 Hunan, China Retrospective observational study 76 patients Penile cancer patients underwent surgery
Mo et al.23 2020 Hunan, China Retrospective observational study 76 patients Penile cancer patients underwent surgery
Murta et al.24 2022 Sao Paulo, Brazil Prospective observational study 24 patients Penile cancer diagnosed in hospital
Ayoubian et al.25 2021 Homburg, Germany Preclinical studies (microarray analysis) 30 patients Penile squamous cell carcinoma; pT1a, pT1b, pT2, pT3; metastatic; nonmetastatic
Mohr et al.26 2022 Homburg, Germany Preclinical studies (immunohistochemistry staining analysis) Three patients HPV-positive penile cancer cell lines (primarius derived, metastasis derived)
van der Fels et al.27 2020 Groningen, the Netherlands Pilot prospective observational study 22 patients Penile squamous cell carcinoma
Zhou et al.28 2018 Guangzhou, China Prospective observational study 114 patients Penile squamous cell carcinoma cell lines (Penl1, Penl2, and 149RCa)
Fenner et al.29 2018 Rostock, Germany Preclinical study (immunohistochemistry analysis) Four patients Penile cancer cell lines
Zhu et al.30 2013 Shanghai, China Retrospective observational study (immunohistochemistry analysis) 73 patients Penile squamous cell carcinoma
Minardi et al.31 2011 Ancona, Italy Retrospective observational study (immunohistochemistry analysis) 39 patients Penile squamous cell carcinoma
Protzel et al.32 2011 Rostock, Germany Retrospective observational study 29 patients Invasive penile squamous cell carcinoma patients underwent surgical resection

Summary of the main findings on notable biomarkers as a prognostic factor.

Author Year p-value Marker used Summary of findings
De Bacco et al.12 2020 p = 0.002 PD-L1, p16 There was statistical correlation between PD-L1 and p16 expression (p = 0.002). There was a two-fold relationship in LN involvement of patients who expressed PD-L1 (69.2% of patients with LN involvement had PD-L1 expression and only 30.8% had LN involvement with PD-L1-). p16 was expressed in 38.5% of patients with LN involvement without significant difference
Udager et al.13 2016 p = 0.024 PD-L1 Twenty-three (62.2%) of 37 primary tumors were positive for PD-L1 expression, and there was strong positive correlation of PD-L1 expression in primary and metastatic samples (p = 0.72; 0.032 < p < 0.036). Primary tumor PD-L1 expression was significantly associated with regional LNM (p = 0.024)
Ottenhof et al.14 2018

p < 0.01

p = 0.02

 Nonclassical HLA class I PD-L1 Tumor PD-L1 expression was significantly associated with LNM; diffusely PD-L1–positive tumors had higher odds of LNM in comparison to tumors to marginal PD-L1 expression only (OR 4.16, p < 0.01) and tumors with combined negative/margin PD-L1 expression (OR 3.28, p < 0.01). Upregulation of nonclassical HLA class I molecules (combined score of HLA-E and HLA-G) was associated with a higher odds of LNM compared to normal expression (OR 2.28, p = 0.02). In the multivariable analysis, diffuse PD-L1 expression was the only immunological factor that remained significantly associated with LNM, although the lower limit of the confidence interval was just above 1 (OR 2.81, 95% CI [1.01–7.81], p < 0.05)
Hu et al.15 2020

p = 0.02

p < 0.01

PD-L1

NLR

 PD-L1 and NLR increased the predictive accuracy of the clinical model. PD-1 and NLR were considered independent predictors of LNM; NLR model risk analysis: OR = 10.93 (2.81–42.53, p-value <0.01); PD-L1 model risk analysis: OR = 5.16 (1.29–20.58, p-value 0.02)
Steffens et al.16 2013 p = 0.007 CRP A significantly elevated CRP level (>15 vs. ≤15 mg/l) was found more often in patients with nodal disease at diagnosis (50.0 vs. 14.6%, p = 0.007)
Al Ghazal et al.17 2013 p = 0.04 CRP The mean CRP value was significantly higher in patients with nodal disease than in those without it: 24.7 versus 12.4 mg/dl (p = 0.04)
Jindal et al.18 2021 p = 0.001 NLR, LMR NLR >3 and LMR ≤3 were significantly associated with the presence of inguinal LN involvement (p = 0.001 and 0.026, respectively)
Protzel et al.19 2007 p = 0.005 Ki-67 None of the patients with weak Ki-67 expression had LNM, whereas eight patients with moderate Ki-67 staining (47%) and all seven patients with a strong Ki-67 expression displayed LNMs (p = 0.005). The statistical analyses revealed that Ki-67 labeling index is related to distant metastasis (p = 0.026)
Cocks et al.20 2017 p = 0.0057 CD8, Ki-67 CD8 and Ki-67 expression in stromal immune cells correlated with distant metastasis (p = 0.0057). Tumors with higher CD8 and Ki-67 expression in the stromal immune cells were more likely to metastasize
Mo et al.21 2021 p = 0.018 CXCL5 Preoperative serum CXCL5 levels were significantly associated with pelvic LNM (p = 0.018).
Mo et al.22 2020 p < 0.001 CXCL13 Higher preoperative serum CXCL13 level was detected in PC cohorts than in healthy male controls (p < 0.001)
Mo et al.23 2020 p = 0.007 CCL20 Preoperative serum CCL20 level was significantly associated with pelvic LNM (p = 0.007)
Murta et al.24 2022 n/a DEmiRs and DEGs Upregulation of miR-421 and miR-744-5p is associated with metastasis of LN in penile cancer patients (based on total cohort)
Ayoubian et al.25 2021

p = 0.004

p = 0.007

 miR-137 miR-328-3p Lower fold value in miR-137 (−3.7 [p = 0.004] and −8.54 [p = 0.004]) and miR-328-3p (−2.7 [p = 0.007] and −1.98 [p = 0.032]) in metastatic cells with negative HPV, implying lower expression
Mohr et al.26 2022 n/a S100A8 and S100A9; CD147 All metastasis cell lines were stained positive for S100A8 and S100A9 (100%). All HPV+ metastasis cell lines (LM) were also positive for CD147 marker
van der Fels et al.27 2020 n/a The monoclonal antibodies PSMA, VEGF, EGFR, and EpCAM expression High immunoreactivity score of VEGF and EGFR expression in metastatic LN involvement and primary tumor; however, EGFR is not expressed in tumor without metastasis. PSMA and EpCAM ae not expressed in the tumor cell at all
Zhou et al.28 2018 n/a sLAMC2 LAMC2 was overexpressed in PSCC tissues, and the LAMC2 expression level was higher in metastatic LN tissues than in primary cancer tissues
Fenner et al.29 2018 p < 0.001 EF21

E2F1 is critical in promoting PC invasiveness, with significant cell migratory and invasive capacity.

E2F1 expression was significantly higher in metastatic PC primary tumor and LN metastases than in nonmetastatic tumors
Zhu et al.30 2013 p = 0.85 CA IX The probability of LNM was 38.1% and 45.2% in CA IX low- and high-expression categories, respectively. CA IX was associated with LNM with OR 1.149 (p = 0.85) despite not being significant
Minardi et al.31 2011 p = 0.326 D2-40 All patients whose intratumoral cells were D2-40 negative were N0, whereas all N+ patients were positive, with 66.7% strongly so. All deceased patients had high-level cell D2-40 expression. N+ patients accounted for 16.7% and 35.7% of samples with moderate and strong D2-40 reactivity, respectively (p = 0.326, χ2 test)
Protzel et al.32 2011

p = 0.001

n/a

p = 0.019

Annexins I

Annexins II

Annexins IV

 There was a significant correlation between strong ANX AI expression at the invasion front and the occurrence of LNM (p = 0.001). Analysis of ANX AII expression showed no significant correlation with clinical data. Strong expression of ANX AIV at the invasion front was significantly associated with LNM (p = 0.019)
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