Open Access

Programmed death‑ligand 1 expression in tumor cells and tumor‑infiltrating lymphocytes are associated with depth of tumor invasion in penile cancer

  • Authors:
    • Sakkarn Sangkhamanon
    • Natcha Kotano
    • Wichien Sirithanaphol
    • Ukrit Rompsaithong
    • Pakorn Kiatsopit
    • Aumkhae Sookprasert
    • Kosin Wirasorn
    • Prin Twinprai
    • Piyakarn Watcharenwong
    • Jarin Chindaprasirt
  • View Affiliations

  • Published online on: May 29, 2023     https://doi.org/10.3892/br.2023.1627
  • Article Number: 44
  • Copyright: © Sangkhamanon et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )


Abstract

The present study aimed to demonstrate the proportion of the programmed death‑ligand 1 (PD‑L1) expression in penile cancer patients and the association with clinicopathological parameters. Formalin‑fixed paraffin‑embedded specimens were obtained from 43 patients with primary penile squamous cell carcinoma treated at Srinagarind Hospital, Faculty of Medicine, Khon Kaen University, between 2008 and 2018. PD‑L1 expression was evaluated by the immunohistochemistry using an SP263 monoclonal antibody. PD‑L1 positivity was defined as >25% tumor cell staining or >25% tumor‑associated immune cell staining. The correlation between PD‑L1 expression and clinicopathological parameters was analyzed. A total of eight of 43 patients (18.6%) were identified as positive for PD‑L1 expression in tumor cells and tumor‑infiltrating lymphocytes. In the PD‑L1 positive group, there was a significant association with pathological T stage (P=0.014) with a higher percentage of PD‑L1 positive tumors in T1 stage compared with T2‑T4 stage. In this cohort, there was a trend towards longer survival in patients with positive PD‑L1 expression (5‑year OS: 75% vs. 61.2%, P=0.19). Lymph node involvement and the location of tumor at the shaft of penis were two independent prognostic factors for survival. In conclusion, the PD‑L1 expression was detected in 18% of penile cancer patients and high expression of PD‑L1 was associated with the early T stage.

Introduction

Primary penile squamous cell carcinoma (SCC) is an uncommon neoplasm in men. In Europe and the US, the reported incidence is ~<1% per 100,000 person-year (1). By contrast, in some countries such as India or Brazil, the prevalence is high ranging from 2.3-8.3 per 100,000 person-year (2-4). In Thailand, according to data from 2008-2012, the age-standardized rate of penile cancer incidence is high (1.4 per 100,000) and ranked top three in the world (5).

Penile cancer is an aggressive tumor with limited systemic treatment options in a locally advanced and advanced stage (1,3). Therefore, identifying prognostic biomarkers is important and could be applied to predict treatment outcomes and planning.

Programmed cell death ligand-1 (PD-L1) is a T-cell regulatory protein expressed on the surface of tumor and tumor-infiltrating lymphocytes. The PD-L1/PD-1 pathway is important in cancer progression (6). The binding between PD-L1 of cancer cells with PD-1 of immune cells helps cancers evade the host immune response and prevents cancers from being killed by cytotoxic T lymphocyte (6,7). In the past few decades, major advances in immunotherapy, especially the use of immune checkpoint inhibitors of anti-PD1 or anti-PDL1 have changed the treatment paradigm in a number of types of cancer. Expression of PD-L1 by tumor cells and tumor-infiltrating lymphocytes has been described in various types of cancer, such as renal cell carcinoma, bladder, and lung cancer (8-11), and has been identified as both a prognostic and predictive marker.

Earlier studies reported high PD-L1 expression positivity in penile cancer, in endemic and non-endemic areas (12-15). However, the results for its prognostic role remain contradictory.

The present study examined the clinicopathological characteristics of PD-L1 expression in penile cancer and the association between PD-L1 expression in tumor cells and immune cells in an endemic area.

Materials and methods

Patients and clinicopathological data

The present study was a retrospective study. All penile SCC patients who were diagnosed and underwent surgical resection in Srinagarind Hospital between 2008 and 2018 were included. The unavailable formalin-fixed paraffin-embedded (FFPE) tissue and those surviving <30 days were excluded from the present study. Finally, the FFPE tissues from 43 patients which were all primary penile SCC, were available for the present study.

Demographic data were collected including age, performance status, and survival time of patients according to Eastern Cooperative Oncology Group (ECOG) (16). The histologic subtype, histologic grading, lymphovascular invasion (LVI) status, and perineural invasion (PNI) status were evaluated using 2016 WHO classification standard templates (17). The pathological staging was performed according to the 8th edition American Joint Committee on Cancer (AJCC) staging system (18). The pre-treatment immune profiles including hemoglobin, total white blood cells, neutrophil count, lymphocyte count, and platelet count were recorded. Neutrophil-lymphocyte ratio and platelet-lymphocyte ratio were calculated.

The present study was approved by the Institutional Review Board of the Khon Kaen University Ethics Committee for Human Research based on the Declaration of Helsinki and the ICH Good Clinical Practice Guidelines (HE611509). For this type of study, formal consent was not required in accordance with institutional guideline.

PD-L1 immunohistochemistry

For all tissue, PD-L1 immunohistochemistry was performed on a representative block of the whole slide section. Tumor sections (4 µm) were deparaffinized and stained with an anti-PD-L1 antibody (VENTANA PD-L1 clone SP263; Roche Diagnostics, cat. no. 790-4905 (prediluted). PD-L1 was stained using Ventana Benchmark XT IHC staining module (incubated at 37˚C for 1 h) and detected by OptiView DAB Detection kit. The sections were counterstained by hematoxylin followed by bluing reagent. The slides were subsequently removed and rinsed, dehydrated, cleared and mounted.

The percentage of tumor cells with membranous staining was assessed separately by two evaluators (one senior resident-in-training and one board-certified pathologist) blinded to the patient's clinicopathological parameters. The tumor and immune cells were considered PD-L1 expression status according to the interpretation guide for the VENTANA PD-L1 (SP263) Assay Scoring (Table I).

Table I

The scoring criteria of PD-L1 status.

Table I

The scoring criteria of PD-L1 status.

PD-L1 interpretationStaining description
High/positivePD-L1 status is considered high/positive if any of the following are met:
 • ≥25% of TC express membrane (any intensity above background) in invasive area; or,
 • ICP >1% and IC+ ≥25%; or,
 • ICP=1% and IC+=100%.
Low/negativePD-L1 status is considered low/negative if:
 • None of the criteria for PD-L1 high status are met.

[i] PD-L1, programmed cell death ligand-1; TC, tumor cells; ICP, Immune cells present within tumor area; IC+, Immune cells positive PD-L1 expression.

Statistical analysis

SPSS software version 27 (IBM Corp.) was used to analyze the association between PD-L1 expression and clinicopathological parameters (including tumor size, histological grading, histologic subtype, staging and survival time) with χ2 or Fisher's exact test as appropriate. The differences in continuous data between the two dependent groups were analyzed by either an independent t-test (parametric test) or Mann-Whitney test (non-parametric test). Values were presented as the mean ± SD. The survival analysis was conducted and analyzed using Kaplan-Meier estimation with Log-rank and Cox regression tests. The analysis time was restricted to a 10-year period due to the late crossover event. The present study selected a 10-year period as it is the reasonable duration to declare the cure of the disease (19). P<0.05 was considered to indicate a statistically significant difference.

Results

PD-L1 expression and clinicopathological features

The present study included 43 patients with penile SCC. No patient received neoadjuvant chemotherapy or radiotherapy before complete resection. A total of eight out of 43 cases (18.6%) were identified with positive PD-L1 expression, while 35 cases (81.4%) exhibited negative PD-L1 expression (Fig. 1). PD-L1 immunoreactivity in tumor cells (TC) >5% was found in 23 patients (53.5%).

The correlation of PD-L1 status with clinic-pathological characteristics is shown in Table II. Briefly, the median age was 58 years. The PD-L1 expression showed no significant difference between primary tumor locations including tip and shaft (P=0.390).

Table II

Clinicopathological characteristics of PD-L1 positive and negative in tumors.

Table II

Clinicopathological characteristics of PD-L1 positive and negative in tumors.

FeaturesAll patientsPD-L1 positive (n=8)PD-L1 negative (n=35)P-value
Age, median (range)58 (26-84)58; 48-8458; 26-800.490
ECOG, n (%)    
     036 (83.7)6(75)30 (85.7)0.390
     17 (16.3)2(25)5 (14.3) 
Location    
     Tip33 (76.7)7 (87.5)26 (74.3)0.390
     Shaft10 (23.3)1 (12.5)9 (25.7) 
Histological grade    
     136 (83.7)6(75)30 (85.7)0.390
     2-37 (16.3)2(25)5 (14.3) 
LVI positive5 (11.6)05 (14.3)0.340
PNI positive3(7)03 (8.6)0.530
T stage    
     T114 (32.6)6(75)8 (22.9)0.014
     T2-429 (67.4)2(25)27 (77.1) 
Lymph node metastasis (N stage)    
     Negative27 (62.8)4(50)23 (65.7)0.330
     Positive16 (37.2)4(50)12 (34.3) 
Stage    
     I-II24 (55.8)4(50)20 (57.1)0.510
     III-IV19 (44.2)4(50)15 (42.9) 

[i] PD-L1, programmed cell death ligand-1; ECOG, Eastern Cooperative Oncology Group; LVI, Lymphovascular invasion; PNI, Perineural invasion; HR, hazard ratio; CI, confidence interval.

PD-L1 expression was not significantly correlated with histological grade (P=0.390), lymphovascular or perineural invasion (P=0.340 and 0.530, respectively). Moreover, no association was observed between PD-L1 expression and nodal involvement (P=0.330). Notably, the present study found that pathological T staging, which represented the depth of primary tumor invasion, displayed a statically significant correlation with PD-L1 positivity; 75% of pT1 stage SCC patients were PD-L1 positive, while only 25% of patients with pT2-pT4 were positive for PD-L1 expression (P=0.014; Table II).

Univariate and multivariate analysis of PD-L1 expression and clinicopathological features in the survival of penile SCC patients

At the time of data analysis, 24 patients (55.8%) had succumbed and the median follow-up time was 89.7 months. The median survival time was 7.4 years (95% Confidence Interval 3.7-9.7). The 1, 5, and 10-year OS rates were 78.6, 63.6, and 25% respectively.

The survival rate was analyzed using Kaplan-Meier estimation with a log-rank test. There was a statistically significant difference in clinicopathological features such as tumor location [Hazard ratio (HR)=4.76, P=0.003], histological grade (HR=4.25, P=0.005), LVI (HR=4.89, P=0.002), PNI (HR=4.75, P=0.02), T category (HR=4.31, P=0.002) and lymph node metastasis (HR=3.56, P=0.003) compared with their references. While there was no statistical significance in the patient's age, ECOG score and PD-L1 expression. The significant clinicopathological features of survival analysis were further analyzed to identify independent prognostic factors using the Cox regression test. The result showed that tumor at shaft and positive lymph node metastasis were independent factors for poor survival of SCC patients (HR=4.81 and 2.59, P=0.015 and 0.009, respectively; Table III and Fig. 2).

Table III

Univariate and multivariate analysis for overall survival.

Table III

Univariate and multivariate analysis for overall survival.

 UnivariateMultivariate
CharacteristicMedian survival (years)HR (95%CI)P-valueHR (95%CI)P-value
Age     
     <588.07Reference - 
     >586.641.33 (0.58-3.03)0.5--
ECOG     
     07.40Reference - 
     10.744.18 (0.92-19.0)0.06--
Histological Grade     
     18.07Reference Reference 
     2-30.794.25 (1.54-11.75)0.005a1.37 (0.27-6.84)0.70
Location     
     Tip8.07Reference Reference 
     Shaft1.004.76 (1.69-13.39)0.003a4.81 (1.35-17.16)0.015a
T stage     
     T1-29.23Reference Reference 
     T3-41.324.31 (1.71-10.85)0.002a2.39 (0.67-8.46)0.18
Lymph node metastasis (N)     
     Node negative9.68Reference Reference 
     Node positive0.793.56 (1.54-8.23)0.003a2.59 (0.87-7.73)0.09a
LVI     
     Negative8.07Reference Reference 
     Positive1.254.89 (1.62-14.81)0.005a1.40 (0.31-6.41)0.66
PNI     
     Negative8.07Reference Reference 
     Positive1.004.73 (1.29-17.41)0.02a2.06 (0.43-9.86)0.37
PD-L1 status     
     Negative6.72Reference - 
     PositiveNR0.41 (0.09-1.76)b0.23--

[i] aP<0.05.

[ii] bEstimation by Cox regression test; HR, hazard ratio; CI, confidence interval; NR, not reached.

Expression of PD-L1 in tumor cells and immune cells

The immune profile and inflammatory markers were compared among PD-L1 positive and negative tumors as shown in Table IV. The number of peripheral white blood cell count, total lymphocytes, neutrophil-lymphocyte ratio, and platelet-lymphocyte ratio were comparable. No statistically significant difference was observed in the immune profile and inflammatory markers between PD-L1 positive and negative.

Table IV

Comparison of immune profile between the PD-L1 expression status of SCC patients.

Table IV

Comparison of immune profile between the PD-L1 expression status of SCC patients.

Immune profilePD-L1 positive (n=8)PD-L1 negative (n=35)P-value
PD-L1 expression on tumor cells (%) median, IQR57.5, 35-67.53, 0.5-15 <0.001a
PD-L1 expression on immune cells (%) median, IQR12.5, 4-18.73, 0.5-7.50.012a
Percent of tumor-associated immune cells in the tumor area (%) median, IQR52.5, 28.7-6525, 12.5-500.091
Hb (g/dl) median, IQR13.5, 11.7-1412.5, 11-13.60.250
White blood cells (103/µl) median, IQR10.8, 7.8-17.99.2, 7.2-12.40.430
Total PMN (103/µl) median, IQR5.6, 4.4-13.85.8, 4.2-9.00.640
Total lymphocyte (103/µl) median, IQR2.4, 1.8-2.82.1, 1.4-2.90.640
Platelet (103/µl) median, IQR274, 217-356297, 249-3910.280
Neutrophil-lymphocyte ratio median, IQR2.6, 1.9-8.22.7, 2.0-5.20.840
Platelet-lymphocyte ratio median, IQR111.1, 69.4-395.5133, 86.8-241.50.660

[i] aP<0.05. PD-L1, programmed cell death ligand-1; SCC, squamous cell carcinoma; IQR, interquartile range.

Comparing PD-L1 positive and negative cases, the percentage of PD-L1 expression was higher in both tumor cells (57.5 vs. 3%; P=0.0001) and immune cells (12.5 vs. 3%; P=0.012) (Table IV and Fig. 3). Moreover, the correlation analysis between PD-L1 expression in tumor and immune cells has shown that there was a high positive correlation between tumor cells and immune cells PD-L1 expression, R2=0.55, P<0.001 as in Fig. 4.

Discussion

Immune checkpoint inhibitors have been shown to possess significant benefits in various types of cancer (6). The percentage of PD-L1 expression in tumor and immune cells is the prognostic and predictive biomarker for PD-1/PD-L1 blockade agents in several tumors including non-small cell lung cancer and gastric carcinoma (9,20). However, in certain types of cancer, such as renal cell carcinoma, bladder cancer and melanoma, PD-L1 expression does not predict the benefit of an anti-PD1 agent (21-23). Even patients identified as PD-L1 negative may derive benefits from therapy.

In the present study in an endemic area, the PD-L1 status of tumor cells and immune cells in a cohort of primary SCC of the penis was evaluated using the SP263 antibody. It was found that 18.6% of the tumors were identified as PD-L1 positive. The PD-L1 positive rate in penile cancer varies greatly according to the type of antibody and the cut-off value. Studies have validated PD-L1 in penile cancer and report a positive rate ranging from 7.3-87% (12,15). Udager et al (15) were among the first to report the PD-L1 expression in 37 patients with penile SCC and the PD-L1 expression was positive in 62.2% of cases. The lower reported positive rates in this study could be the higher cut-off point in tumor cells; TC ≥25% in this study vs. TC ≥1-5% in other studies. When the cut-off value to TC >5% was re-examined in the present study, the PD-L1 positive rate was 53.5% which is comparable to the results from China and Brazil (4,13).

Montella et al (24) demonstrated the highest proportion of positive PD-L1 expression in tumor cells and immune cells using either SP142 or SP263 antibody in T1 stage and lower PD-L1 positivity in T2, T3, and T4 accordingly. Similarly the present study also found a statistically significant correlation between PD-L1 expression and pT staging in which 75% of SCC patients with PD-L1 positive correlated with pT1 stage.

PD-L1 expression has been associated with regional lymph node metastasis and decreased cancer-specific survival in several studies (12,15,25,26). By contrast, in this cohort, PD-L1 positivity did not show worse survival outcomes when compared with negative patients. The present study further examined the PD-L1 expression by tumor cells at the cut-off value of 1 and 5%, but no survival difference was found between those with positive or negative PD-L1.

In a recent meta-analysis, higher PD-L1 expression was associated with shorter cancer-specific survival in Caucasians but not in Asians (Chinese study). Furthermore, it was not associated with overall survival (27). The different races of patients and etiology of penile cancer along with different PD-L1 antibody, detection technique and cut-off level could explain the variations of the results. Further standardization of the technique designated for penile cancer is warranted.

With limited data, immune checkpoint inhibitors, either single agent anti PD-1 or a combination of anti PD-1/anti CTLA4, did not provide an impressive outcome compared with other types of tumor (28,29). PD-L1 expression as a predictive biomarker for ICIs in advanced penile cancer remains controversial. However, more data regarding ICI combined with chemotherapy or radiotherapy in the future is expected (30).

The major strength of the present study included the use of whole tissue sections, which has significant advantages over tissue microarray (TMA), as whole tissue sections allow a more comprehensive assessment of tumor protein expression. This is especially important for PD-L1 immunochemistry, which can reduce interpretative bias from tumor heterogeneity compared with the tissue microarray technique. Moreover, the present study was the first conducted in the high incidence area of southeast Asia. The present study had a long follow up period and a high proportion of node positive disease.

There are a few limitations in the present study. First, the number of PD-L1 positive cases was small and only single PD-L1 antibody was used. Second, in vitro experiments for PD-L1 positivity were not performed. Third, the present study did not evaluate the HPV status of p16 expression in the samples. Larger number of tumor samples and in vitro validations are needed in future studies.

In summary, PD-L1 expression was found in 18% of primary penile SCC and PD-L1 positivity (high expression) was more common in the early pT stage (pT1).

Acknowledgements

Not applicable.

Funding

Funding: The present study was supported by the Faculty of Medicine, Khon Kaen University, Thailand (grant no. IN63132).

Authors' contributions

SS and JC conceived the present study. SS, NK, WS, UR, PK, AS, KW, PT, PW and JC were responsible for data curation. SS, NK, WS, UR, PK, AS, KW, PT, PW and JC were responsible for experiments. SS, NK, WS, UR, PK, AS, KW, PT, PW and JC were responsible for methodology. JC and SS confirm the authenticity of all the raw data. SS, NK, WS and JC were responsible for writing, reviewing and editing the manuscript. All authors read and approved the final manuscript.

Availability of data and materials

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

Ethics approval and consent to participate

The present study was approved by the Institutional Review Board of the Khon Kaen University Ethics Committee for Human Research based on the Declaration of Helsinki and the ICH Good Clinical Practice Guidelines (HE611509). For this type of study, formal consent was not required in accordance with institutional guideline.

Patient consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

References

1 

Hakenberg OW, Comperat EM, Minhas S, Necchi A, Protzel C and Watkin N: EAU guidelines on penile cancer: 2014 Update. Eur Urol. 67:142–150. 2015.PubMed/NCBI View Article : Google Scholar

2 

Christodoulidou M, Sahdev V, Houssein S and Muneer A: Epidemiology of penile cancer. Curr Probl Cancer. 39:126–136. 2015.PubMed/NCBI View Article : Google Scholar

3 

Deng X, Liu Y, Zhan X, Chen T, Jiang M, Jiang X, Chen L and Fu B: Trends in incidence, mortality, and survival of penile cancer in the United States: A population-based study. Front Oncol. 12(891623)2022.PubMed/NCBI View Article : Google Scholar

4 

Vieira CB, Feitoza L, Pinho J, Teixeira-Júnior A, Lages J, Calixto J, Coelho R, Nogueira L, Cunha I, Soares F and Silva GEB: Profile of patients with penile cancer in the region with the highest worldwide incidence. Sci Rep. 10(2965)2020.PubMed/NCBI View Article : Google Scholar

5 

Fu L, Tian T, Yao K, Chen XF, Luo G, Gao Y, Lin YF, Wang B, Sun Y, Zheng W, et al: Global pattern and trends in penile cancer incidence: Population-based study. JMIR Public Health Surveill. 8(e34874)2022.PubMed/NCBI View Article : Google Scholar

6 

Boussiotis VA: Molecular and biochemical aspects of the PD-1 checkpoint pathway. N Engl J Med. 375:1767–1778. 2016.PubMed/NCBI View Article : Google Scholar

7 

Ribas A: Tumor immunotherapy directed at PD-1. N Engl J Med. 366:2517–2519. 2012.PubMed/NCBI View Article : Google Scholar

8 

Huang Y, Zhang SD, McCrudden C, Chan KW, Lin Y and Kwok HF: The prognostic significance of PD-L1 in bladder cancer. Oncol Rep. 33:3075–3084. 2015.PubMed/NCBI View Article : Google Scholar

9 

Mok TSK, Wu YL, Kudaba I, Kowalski DM, Cho BC, Turna HZ, Castro G Jr, Srimuninnimit V, Laktionov KK, Bondarenko I, et al: Pembrolizumab versus chemotherapy for previously untreated, PD-L1-expressing, locally advanced or metastatic non-small-cell lung cancer (KEYNOTE-042): A randomised, open-label, controlled, phase 3 trial. Lancet. 393:1819–1830. 2019.PubMed/NCBI View Article : Google Scholar

10 

Ueda K, Suekane S, Kurose H, Chikui K, Nakiri M, Nishihara K, Matsuo M, Kawahara A, Yano H and Igawa T: Prognostic value of PD-1 and PD-L1 expression in patients with metastatic clear cell renal cell carcinoma. Urol Oncol. 36:499.e9–499.e16. 2018.PubMed/NCBI View Article : Google Scholar

11 

Zhu L, Sun J, Wang L and Li Z, Wang L and Li Z: Prognostic and clinicopathological significance of PD-L1 in patients with bladder cancer: A meta-analysis. Front Pharmacol. 10(962)2019.PubMed/NCBI View Article : Google Scholar

12 

Davidsson S, Carlsson J, Giunchi F, Harlow A, Kirrander P, Rider J, Fiorentino M and Andrén O: PD-L1 expression in men with penile cancer and its association with clinical outcomes. Eur Urol Oncol. 2:214–221. 2019.PubMed/NCBI View Article : Google Scholar

13 

De Bacco MW, Carvalhal GF, MacGregor B, Marcal JMB, Wagner MB, Sonpavde GP and Fay AP: PD-L1 and p16 expression in penile squamous cell carcinoma from an endemic region. Clin Genitourin Cancer. 18:e254–e259. 2020.PubMed/NCBI View Article : Google Scholar

14 

Müller T, Demes M, Lehn A, Köllermann J, Vallo S, Wild PJ and Winkelmann R: The peri- and intratumoral immune cell infiltrate and PD-L1 status in invasive squamous cell carcinomas of the penis. Clin Transl Oncol. 24:331–341. 2022.PubMed/NCBI View Article : Google Scholar

15 

Udager AM, Liu TY, Skala SL, Magers MJ, McDaniel AS, Spratt DE, Feng FY, Siddiqui J, Cao X, Fields KL, et al: Frequent PD-L1 expression in primary and metastatic penile squamous cell carcinoma: Potential opportunities for immunotherapeutic approaches. Ann Oncol. 27:1706–1712. 2016.PubMed/NCBI View Article : Google Scholar

16 

Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET and Carbone PP: Toxicity and response criteria of the eastern cooperative oncology group. Am J Clin Oncol. 5:649–655. 1982.PubMed/NCBI

17 

Moch H, Cubilla AL, Humphrey PA, Reuter VE and Ulbright TM: The 2016 WHO classification of tumours of the urinary system and male genital organs-part A: Renal, penile, and testicular tumours. Eur Urol. 70:93–105. 2016.PubMed/NCBI View Article : Google Scholar

18 

Amin MB, Edge S, Greene F, Byrd DR, Brookland RK, Washington MK, Gershenwald JE, Compton CC, Hess KR, Sullivan DC (eds), et al: AJCC cancer staging manual (8th edition). Springer International Publishing: American Joint Commission on Cancer, 2017.

19 

Tai P, Yu E, Cserni G, Vlastos G, Royce M, Kunkler I and Vinh-Hung V: Minimum follow-up time required for the estimation of statistical cure of cancer patients: Verification using data from 42 cancer sites in the SEER database. BMC Cancer. 5(48)2005.PubMed/NCBI View Article : Google Scholar

20 

Shitara K, Ajani JA, Moehler M, Garrido M, Gallardo C, Shen L, Yamaguchi K, Wyrwicz L, Skoczylas T, Bragagnoli AC, et al: Nivolumab plus chemotherapy or ipilimumab in gastro-oesophageal cancer. Nature. 603:942–948. 2022.PubMed/NCBI View Article : Google Scholar

21 

Fradet Y, Bellmunt J, Vaughn DJ, Lee JL, Fong L, Vogelzang NJ, Climent MA, Petrylak DP, Choueiri TK, Necchi A, et al: Randomized phase III KEYNOTE-045 trial of pembrolizumab versus paclitaxel, docetaxel, or vinflunine in recurrent advanced urothelial cancer: Results of >2 years of follow-up. Ann Oncol. 30:970–976. 2019.PubMed/NCBI View Article : Google Scholar

22 

Munhoz RR and Postow MA: Clinical development of PD-1 in advanced melanoma. Cancer J. 24:7–14. 2018.PubMed/NCBI View Article : Google Scholar

23 

Powles T, Plimack ER, Soulières D, Waddell T, Stus V, Gafanov R, Nosov D, Pouliot F, Melichar B, Vynnychenko I, et al: Pembrolizumab plus axitinib versus sunitinib monotherapy as first-line treatment of advanced renal cell carcinoma (KEYNOTE-426): Extended follow-up from a randomised, open-label, phase 3 trial. Lancet Oncol. 21:1563–1573. 2020.PubMed/NCBI View Article : Google Scholar

24 

Montella M, Sabetta R, Ronchi A, De Sio M, Arcaniolo D, De Vita F, Tirino G, Caputo A, D'Antonio A, Fiorentino F, et al: Immunotherapy in penile squamous cell carcinoma: Present or future? Multi-target analysis of programmed cell death ligand 1 expression and microsatellite instability. Front Med (Lausanne). 9(874213)2022.PubMed/NCBI View Article : Google Scholar

25 

Joshi VB, Spiess PE, Necchi A, Pettaway CA and Chahoud J: Immune-based therapies in penile cancer. Nat Rev Urol. 19:457–474. 2022.PubMed/NCBI View Article : Google Scholar

26 

Ottenhof SR, Djajadiningrat RS, de Jong J, Thygesen HH, Horenblas S and Jordanova ES: Expression of programmed death ligand 1 in penile cancer is of prognostic value and associated with HPV status. J Urol. 197:690–697. 2017.PubMed/NCBI View Article : Google Scholar

27 

Lu Y, Wang Y, Su H and Li H: PD-L1 is associated with the prognosis of penile cancer: A systematic review and meta-analysis. Front Oncol. 12(1013806)2022.PubMed/NCBI View Article : Google Scholar

28 

Buonerba C, Scafuri L, Costabile F, D'Ambrosio B, Gatani S, Verolino P, Trolio RD, Cosimato V, Verde A and Lorenzo GD: Immune checkpoint inhibitors in penile cancer. Future Sci OA. 7(FSO714)2021.PubMed/NCBI View Article : Google Scholar

29 

Tang Y, Hu X, Wu K and Li X: Immune landscape and immunotherapy for penile cancer. Front Immunol. 13(1055235)2022.PubMed/NCBI View Article : Google Scholar

30 

Long XY, Zhang S, Tang LS, Li X and Liu JY: Conversion therapy for advanced penile cancer with tislelizumab combined with chemotherapy: A case report and review of literature. World J Clin Cases. 10:12305–12312. 2022.PubMed/NCBI View Article : Google Scholar

Related Articles

Journal Cover

July-2023
Volume 19 Issue 1

Print ISSN: 2049-9434
Online ISSN:2049-9442

Sign up for eToc alerts

Recommend to Library

Copy and paste a formatted citation
x
Spandidos Publications style
Sangkhamanon S, Kotano N, Sirithanaphol W, Rompsaithong U, Kiatsopit P, Sookprasert A, Wirasorn K, Twinprai P, Watcharenwong P, Chindaprasirt J, Chindaprasirt J, et al: Programmed death‑ligand 1 expression in tumor cells and tumor‑infiltrating lymphocytes are associated with depth of tumor invasion in penile cancer. Biomed Rep 19: 44, 2023
APA
Sangkhamanon, S., Kotano, N., Sirithanaphol, W., Rompsaithong, U., Kiatsopit, P., Sookprasert, A. ... Chindaprasirt, J. (2023). Programmed death‑ligand 1 expression in tumor cells and tumor‑infiltrating lymphocytes are associated with depth of tumor invasion in penile cancer. Biomedical Reports, 19, 44. https://doi.org/10.3892/br.2023.1627
MLA
Sangkhamanon, S., Kotano, N., Sirithanaphol, W., Rompsaithong, U., Kiatsopit, P., Sookprasert, A., Wirasorn, K., Twinprai, P., Watcharenwong, P., Chindaprasirt, J."Programmed death‑ligand 1 expression in tumor cells and tumor‑infiltrating lymphocytes are associated with depth of tumor invasion in penile cancer". Biomedical Reports 19.1 (2023): 44.
Chicago
Sangkhamanon, S., Kotano, N., Sirithanaphol, W., Rompsaithong, U., Kiatsopit, P., Sookprasert, A., Wirasorn, K., Twinprai, P., Watcharenwong, P., Chindaprasirt, J."Programmed death‑ligand 1 expression in tumor cells and tumor‑infiltrating lymphocytes are associated with depth of tumor invasion in penile cancer". Biomedical Reports 19, no. 1 (2023): 44. https://doi.org/10.3892/br.2023.1627