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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 Cover

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

Open Access
|Jan 2024

Figures & Tables

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_

AuthorYearPD-L1CRPNLR and LMRKi-67Chemokine motif ligandsmiRNAsOther biomarkers
De Bacco et al.122020(+) p16
Udager et al.132016(+)
Ottenhof et al.142018(+) HLA
Hu et al.152020(+) (+)
Steffens et al.162013 (+)
Al Ghazal et al.172013 (+)
Jindal et al.182021 (+)
Protzel et al.192007 (+)
Cocks et al.202017 (+) CD8
Mo et al.212021 CXCL5
Mo et al.222020 CXCL13
Mo et al.232020 CCL20
Murta et al.242022 Differentially expressed miRNAsDEGs
Ayoubian et al.252021 miR-137 and miR-328-3p
Mohr et al.262022 S100A8 and S100A9; CD147
van der Fels et al.272020 PSMA, VEGF, EGFR, and EpCAM
Zhou et al.282018 sLAMC2
Fenner et al.292018 EF21
Zhu et al.302013 CA IX
Minardi et al.312011 D2-40
Protzel et al.322011 Annexins I, II, and IV

NOS risk of bias assessment_

AuthorYearSelectionComparabilityExposureTotal score
Adequate definition of patient casesRepresentativeness of patient casesSelection of controlsDefinition of controlsControl for important or additional factorsAscertainment of exposureSame method of ascertainment for participantsNonresponse rate
Mohr2022* ****5
Ayoubian2021** ****6
Jindal2021** ****6
Hu2020* ****4
De Bacco2020* ****5
van der Fels2020** ****6
Zhou2018** ****6
Cocks2017* ****5
Udager2016** ****6
Al Ghazal2013** ****6
Steffens2013** ****6
Murta2022 * ****5
Mo2021********8
Mo2020********8
Mo (2)2020********8
Fenner2018 ****4
Ottenhof2018** ****6
Zhu2013 *******7
Minardi2011 *******7
Protzel2011 *******7
Protzel2007 *******7

Summary of eligible studies_

AuthorYearLocationSettingsTotal samplesType of patients
De Bacco et al.122020Porto Alegre, BrazilProspective cohort40 patientsPenile squamous cell carcinoma
Udager et al.132016Ann Arbor, USARetrospective observational study37 patientsPenile squamous cell carcinoma
Ottenhof et al.142018Amsterdam, the NetherlandsRetrospective observational study (immunohistochemistry analysis)487 patientsPenile squamous cell carcinoma
Hu et al.152020Changsha, ChinaProspective cohort84 patientsPenile squamous cell carcinoma
Steffens et al.162013Hannover, GermanyRetrospective cohort study79 patientsPenile cancer
Al Ghazal et al.172013Ulm, GermanyRetrospective cohort study51 patientsPenile cancer patients underwent radical or partial penectomy (pT1–pT4)
Jindal et al.182021Bengal, IndiaProspective observational study69 patientsPenile cancer; pT1 (15), pT2 (37), pT3 (16), pT4 (1) with inguinal node dissection
Protzel et al.192007Helios-Kliniken Schwerin, GermanyRetrospective observational study (immunohistochemistry analysis)28 patientsInvasive penile squamous cell carcinoma
Cocks et al.202017North AmericaProspective cohort53 patientsInvasive penile squamous cell carcinoma tissue
Mo et al.212021Hunan, ChinaRetrospective observational study81 patientsPenile cancer patients underwent surgery
Mo et al.222020Hunan, ChinaRetrospective observational study76 patientsPenile cancer patients underwent surgery
Mo et al.232020Hunan, ChinaRetrospective observational study76 patientsPenile cancer patients underwent surgery
Murta et al.242022Sao Paulo, BrazilProspective observational study24 patientsPenile cancer diagnosed in hospital
Ayoubian et al.252021Homburg, GermanyPreclinical studies (microarray analysis)30 patientsPenile squamous cell carcinoma; pT1a, pT1b, pT2, pT3; metastatic; nonmetastatic
Mohr et al.262022Homburg, GermanyPreclinical studies (immunohistochemistry staining analysis)Three patientsHPV-positive penile cancer cell lines (primarius derived, metastasis derived)
van der Fels et al.272020Groningen, the NetherlandsPilot prospective observational study22 patientsPenile squamous cell carcinoma
Zhou et al.282018Guangzhou, ChinaProspective observational study114 patientsPenile squamous cell carcinoma cell lines (Penl1, Penl2, and 149RCa)
Fenner et al.292018Rostock, GermanyPreclinical study (immunohistochemistry analysis)Four patientsPenile cancer cell lines
Zhu et al.302013Shanghai, ChinaRetrospective observational study (immunohistochemistry analysis)73 patientsPenile squamous cell carcinoma
Minardi et al.312011Ancona, ItalyRetrospective observational study (immunohistochemistry analysis)39 patientsPenile squamous cell carcinoma
Protzel et al.322011Rostock, GermanyRetrospective observational study29 patientsInvasive penile squamous cell carcinoma patients underwent surgical resection

Summary of the main findings on notable biomarkers as a prognostic factor_

AuthorYearp-valueMarker usedSummary of findings
De Bacco et al.122020p = 0.002PD-L1, p16There 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.132016p = 0.024PD-L1Twenty-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.142018
  • p < 0.01

  • p = 0.02

Nonclassical HLA class I PD-L1Tumor 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.152020
  • 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.162013p = 0.007CRPA 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.172013p = 0.04CRPThe 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.182021p = 0.001NLR, LMRNLR >3 and LMR ≤3 were significantly associated with the presence of inguinal LN involvement (p = 0.001 and 0.026, respectively)
Protzel et al.192007p = 0.005Ki-67None 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.202017p = 0.0057CD8, Ki-67CD8 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.212021p = 0.018CXCL5Preoperative serum CXCL5 levels were significantly associated with pelvic LNM (p = 0.018).
Mo et al.222020p < 0.001CXCL13Higher preoperative serum CXCL13 level was detected in PC cohorts than in healthy male controls (p < 0.001)
Mo et al.232020p = 0.007CCL20Preoperative serum CCL20 level was significantly associated with pelvic LNM (p = 0.007)
Murta et al.242022n/aDEmiRs and DEGsUpregulation of miR-421 and miR-744-5p is associated with metastasis of LN in penile cancer patients (based on total cohort)
Ayoubian et al.252021
  • p = 0.004

  • p = 0.007

miR-137 miR-328-3pLower 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.262022n/aS100A8 and S100A9; CD147All 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.272020n/aThe monoclonal antibodies PSMA, VEGF, EGFR, and EpCAM expressionHigh 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.282018n/asLAMC2LAMC2 was overexpressed in PSCC tissues, and the LAMC2 expression level was higher in metastatic LN tissues than in primary cancer tissues
Fenner et al.292018p < 0.001EF21
  • 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.302013p = 0.85CA IXThe 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.312011p = 0.326D2-40All 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.322011
  • 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)
DOI: https://doi.org/10.2478/fco-2023-0010 | Journal eISSN: 1792-362X | Journal ISSN: 1792-345X
Language: English
Page range: 25 - 34
Submitted on: Jun 19, 2023
Accepted on: Nov 6, 2023
Published on: Jan 1, 2024
Published by: Helenic Society of Medical Oncology
In partnership with: Paradigm Publishing Services
Publication frequency: 2 issues per year

© 2024 I Wayan Yudiana, Stacia Novia Marta, Ronald Sugianto, Anak Agung Wiradewi Lestari, published by Helenic Society of Medical Oncology
This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 License.