Abstract
Objective
Our study tried to evaluate the prognostic utility of preoperative serum cyfra21-1 in patients with penile squamous cell carcinoma (PSCC).
Methods
This retrospective study analyzed data from 94 patients who underwent either partial or radical penectomy accompanied by bilateral inguinal or pelvic lymphadenectomy at our institution from 2010 to 2018. The median duration of follow-up was 66.5 months. Serum cyfra21-1 concentrations were quantified through enzyme-linked immunosorbent assay, with patients classified into two groups based on cyfra21-1 levels (≤ 3.30 ng/ml and > 3.30 ng/ml). The impact of cyfra21-1 levels on clinical outcomes was evaluated.
Results
Among the 94 patients, 68 (72.3%) had normal cyfra21-1 levels, while 26 (27.6%) exhibited elevated cyfra21-1 levels. During the follow-up period, 38 patients (40.4%) experienced relapse, and 35 patients (37.2%) died from PSCC. A significantly higher occurrence of advanced pathological grades was observed in the elevated cyfra21-1 group compared to the normal group (P = 0.029). Patients with elevated cyfra21-1 levels had significantly worse disease-free survival (DFS) and disease-specific survival (DSS) than those with normal levels (P < 0.001 and P < 0.001, respectively). In multivariate analysis, cyfra21-1 (HR: 3.938, 95% CI: 1.927–8.049, P < 0.001), lymph node involvement (HR: 8.277, 95% CI: 2.261–30.298, P = 0.001), pathological grade (HR: 2.789, 95% CI: 1.110–7.010, P = 0.029), and ECOG (Eastern Cooperative Oncology Group) performance status (HR: 1.751, 95% CI: 1.028–2.983, P = 0.039) were independent predictors of worse DFS. Similarly, CYFRA 21 − 1 (HR: 3.000, 95% CI: 1.462–6.156, P = 0.003), lymph node involvement (HR: 9.174, 95% CI: 2.010–41.862, P = 0.003), and ECOG performance status (HR: 1.856, 95% CI: 1.053–3.270, P = 0.032) were independent predictors of worse DSS.
Conclusions
High preoperative serum cyfra21-1 levels correlate with greater tumor aggressiveness and represent a novel, effective, and convenient prognostic biomarker for PSCC.
Keywords: Penile squamous cell carcinoma, Prognostic biomarker
Introduction
Penile cancer is a rare malignancy in Western countries but is more prevalent in Africa, Asia, and South America, where it accounts for up to 10% of all cancers in men [1–3]. Approximately 95% of penile cancers are penile squamous cell carcinomas (PSCC) [4]. PSCC predominantly affects men between the ages of 50 and 70 years [5]. The risk factors for PSCC are multifactorial, including non-circumcision in childhood, phimosis, chronic inflammation, suboptimal genital hygiene, smoking habits, immune suppression, and human papillomavirus infections [6]. Patients with PSCC, particularly those with lymph node metastasis, have a poor 5-year cancer-specific survival rate [7, 8]. While few prognostic markers, such as serum C-reactive protein (CRP) and squamous cell carcinoma antigen (SCC-Ag), have been identified for PSCC [9–13], large-scale studies are still required to improve their clinical utility. Consequently, there is a pressing need for effective, feasible, and prognostic biomarkers for patients with PSCC.
Cyfra21-1, a soluble fragment of Cytokeratin 19 (CK-19) in serum [14], was first identified in 1993 [15]. As a structural component of the cytoskeleton in epithelial cells, CK-19 is involved in maintaining cell integrity [14, 16, 17]. The quantification of Cyfra21-1 is achieved through a specific sandwich enzyme-linked immunosorbent assay (ELISA) utilizing two monoclonal antibodies, KS 19.1 and BM 19.21. During the process of epithelial malignancy, the increased breakdown of CK-19 results in elevated levels of its soluble fragment, Cyfra21-1, in the blood. This increase is particularly notable in cases where tumor cell necrosis occurs, a common feature in squamous epithelial cancers [18]. This protein is predominantly expressed in epithelial-origin tumor cells and serves as a marker for epithelial cancers [15]. Numerous studies have demonstrated that cyfra21-1 is a biomarker for squamous cell carcinoma, particularly in the lung, oropharynx, esophagus, and cervix [19–24]. However, no studies have previously investigated the correlation between serum cyfra21-1 and PSCC.
In our study, we were the first to analyze the prognostic value of serum cyfra21-1 in patients with PSCC. Our findings uncovered that elevated serum cyfra21-1 levels were linked to poorer disease-free survival (DFS) and disease-specific survival (DSS).
Patients and methods
In this retrospective study, we analyzed 94 patients who were diagnosed with PSCC at our institution between October 2010 and December 2018 (Fig. 1). Each patient underwent either partial or radical penectomy, coupled with bilateral inguinal or pelvic lymphadenectomy. The ethical approval for this study was granted by our ethics committee, under the protocol number B2023-618-01, and the data were recorded on the institutional website. Histopathological evaluation of the surgical specimens was done in line with established standards. Post-operative treatment decisions, including the need for adjuvant therapy, were guided by the pathological grade of the tumors. Two experienced pathologists independently reassessed the pathological TNM stage based on the 2018 American Joint Committee on Cancer guidelines for PSCC. Chemotherapy in this study consisted of a regimen of gemcitabine and cisplatin. The baseline characteristics of the patients were also reviewed, including age, presence of phimosis, T stage, pathological grade, N status, CRP, SCC-Ag, lymphadenopathy, comorbidities, Eastern Cooperative Oncology Group (ECOG) performance status, body mass index, chemotherapy, and radiotherapy. Lymphadenopathy was defined as the clinical enlargement of lymph nodes detected through physical and imaging examinations.
Fig. 1.
The inclusion and exclusion of patients to produce the final study population
Blood samples were collected within one month before surgery. The serum levels of cyfra21-1, SCC-Ag, and CRP were tested in the Department of Molecular Diagnosis before surgery. Elevated or normal levels of these markers were determined based on standard reference ranges (cyfra21-1: 3.30 ng/ml, SCC-Ag: 1.5 ng/ml, and CRP: 5.0 mg/l) [25, 26].
Serum CYFRA 21 − 1 concentrations were quantified through an ELISA employing a chemiluminescent immunoassay technique, conducted in our Department of Laboratory Medicine. Initially, 25 µl of each sample, combined with 100 µl of enzyme-linked antibody conjugate, was dispensed into designated wells of the assay plate, which were then sealed and incubated for one hour at 37 °C in a temperature-controlled environment ranging from 20 to 27 °C. Following the incubation, each well was subjected to a washing sequence involving the addition of 400 µl of a specialized cleaning solution, maintained for 10 s before being decanted and blotted out after five buffer washes. Thereafter, 100 µl of a chemiluminescent substrate was introduced to each well, which was then incubated in darkness at ambient temperature for five minutes. The resulting luminescence was promptly measured with a luminometer, capturing the intensity emitted from each microplate.
Follow-up was conducted through telephone interviews and postoperative record reviews, following generally accepted guidelines. The last follow-up was completed on September 23, 2023. In this study, DFS and DSS were the primary endpoints. DFS was defined as the interval between surgery and relapse, while DSS was defined as the interval between surgery and either the last follow-up or death from PSCC.
Statistical analysis
Comparative analyses between the two study groups were implemented utilizing the χ2 test for categorical variables and the Mann-Whitney U test for continuous variables, depending on their distribution. To assess correlations between clinical characteristics and various metrics, the Spearman rank correlation coefficient was utilized. DSS and DFS post-surgery were assessed utilizing Kaplan-Meier survival curves, with differences evaluated through the log-rank test.
For initial variable assessment, univariate Cox regression models were utilized to identify potential prognostic factors, with those showing a P-value < 0.2 advancing to multivariate Cox regression analysis. This analysis was conducted to ascertain the independence of these factors. The results were summarized as hazard ratios (HRs) with 95% confidence intervals (CIs), indicating the relative risk associated with each variable. SPSS software version 22.0 (IBM Corporation, Armonk, NY, USA) was employed for all statistical calculations. Significance was set at a P-value of less than 0.05, and all tests were two-sided.
Results
A total of 94 PSCC patients were assessed in our study (Fig. 1). The median follow-up period was 66.5 months. Patient characteristics are summarized in Table 1. Among the patients, 43 had negative lymph nodes, while 51 had positive lymph nodes. Overall, 68 patients (72.3%) had normal cyfra21-1 levels, whereas 26 patients (27.6%) had elevated cyfra21-1 levels. Patients with elevated cyfra21-1 levels were more likely to have a lower pathological grade stage (P = 0.027) than those with normal cyfra21-1 levels. No significant differences were tested in age (P = 0.556), presence of phimosis (P = 0.718), T stage (P = 0.294), N status (P = 0.072), CRP (P = 0.359), SCC-Ag (P = 0.359), lymphadenopathy (P = 0.707), comorbidities (P = 0.925), or ECOG performance status (P = 0.753) between the two groups.
Table 1.
Association between cyfra21-1 expression level and the clinicopathologic characteristics of PSCC patients
| Variables | No. of | Cyfra21-1 | |||
|---|---|---|---|---|---|
| patients | normal | High | P-value | ||
| Total | 94 | 68 (72.3%) | 26 (27.6%) | ||
| Age | <54 | 48 | 36 | 12 | 0.556 |
| ≥ 54 | 46 | 32 | 14 | ||
| Phimosis | No | 57 | 42 | 15 | 0.718 |
| Yes | 37 | 26 | 11 | ||
| T stage | T1 | 22 | 31 | 15 | 0.294 |
| T2-4 | 46 | 37 | 11 | ||
| Pathological grade | G1 | 46 | 38 | 8 | 0.029 |
| G2 + G3 + G4 | 48 | 30 | 18 | ||
| N status | N0 | 43 | 35 | 8 | 0.072 |
| N+ | 51 | 33 | 18 | ||
| CRP | <5.0 | 57 | 43 | 14 | 0.359 |
| ≥ 5.0 | 36 | 33 | 18 | ||
| SCC-Ag | <1.5 | 53 | 40 | 13 | 0.241 |
| ≥ 1.5 | 30 | 19 | 11 | ||
| lymphadenopathy | No | 28 | 21 | 7 | 0.707 |
| Yes | 66 | 47 | 19 | ||
| Basic disease | 0 | 79 | 57 | 22 | 0.925 |
| 1 | 15 | 11 | 4 | ||
| ECOG | 0 | 89 | 65 | 24 | 0.753 |
| 1 | 3 | 2 | 1 | ||
| 3 | 2 | 1 | 1 | ||
| BMI | 0 | 70 | 50 | 20 | 0.736 |
| 1 | 24 | 18 | 6 | ||
| chemotherapy | 0 | 63 | 46 | 17 | 0.835 |
| 1 | 31 | 22 | 9 | ||
| radiotherapy | 0 | 88 | 63 | 25 | 0.534 |
| 1 | 6 | 5 | 1 | ||
Note Result of chi-squared comparisons between serum cyfra21-1 ≤ 3.3 ng/mL and > 3.3 ng/mL cohorts. Bold text indicates a statistically significant difference
In terms of prognostic outcomes, 38 patients (40.4%) experienced relapse, and 35 patients (37.2%) died from PSCC during the follow-up period. Kaplan–Meier analyses revealed that individuals with higher levels of preoperative serum cyfra21-1 had significantly poorer DFS and DSS than those with levels within the normal range (all P < 0.001; Figs. 2A and 3A). Based on these findings, a nomogram for DFS and DSS was established (Figs. 2B and 3B) and validated for accuracy through calibration analysis (Fig. 3C and C). The 1- and 3-year ROC-AUC values for DFS were 0.787 and 0.837, respectively. Similarly, the 1- and 3-year DSS ROC-AUC values were 0.814 and 0.884, demonstrating significant predictive accuracy (Figs. 2D and 3D).
Fig. 2.
(A) KM curves for the model in cyfra21-1 cohort, patients in the high cyfra21-1 group experienced a significantly shorter DFS time than patients in the normal group (p<0.001). (B) Nomogram based on the serum cyfra21-1 level and clinical characteristics (C) calibration curve for the nomogram (D) ROC curves for 1-, and 3-year in cyfra21-1 cohort (AUC: 0.787, 0.837)
Fig. 3.
(A) KM curves for the model in cyfra21-1 cohort, patients in the high cyfra21-1 group experienced a significantly shorter DSS time than in the nomal group (p<0.001). (B) Nomogram based on the serum cyfra21-1 level and clinical characteristics. (C) Calibration curve for the nomogram. (D) ROC curves for 1-, and 3-year in cyfra21-1 cohort (AUC: 0.814, 0.884)
When adjusting for various clinicopathological parameters, the multivariate analysis delineated several independent factors contributing to inferior DFS. Notably, elevated preoperative serum cyfra21-1 (HR: 3.938, 95% CI: 1.927–8.049, P < 0.001), presence of lymph node metastasis (HR: 8.277, 95% CI: 2.261–30.298, P = 0.001), higher pathological, grades (HR: 2.789, 95% CI: 1.110–7.010, P = 0.029), and lower ECOG performance scores (HR: 1.751, 95% CI: 1.028–2.983, P = 0.039) emerged as significant prognostic indicators (Table 2). The analysis pertaining to DSS echoed similar findings, with cyfra21-1 (HR: 3.000, 95% CI: 1.462–6.156, P = 0.003), lymph node involvement (HR: 9.174, 95% CI: 2.010–41.862, P = 0.003), and ECOG performance status (HR: 1.856, 95% CI: 1.053–3.270, P = 0.032) also identified as key predictors of adverse outcomes (Table 3).
Table 2.
Univariate and multivariate analyses for variables considered for DFS (Cox proportional hazard regression model)
| DFS univariate analysis | DFS multivariate analysis | ||||||||
|---|---|---|---|---|---|---|---|---|---|
| characteristics | 95%CIs | HR | P value | 95%CIs | HR | P value | |||
| Cyfra21-1 | (1.767–6.341) | 3.347 | <0.001 | (1.927–8.049) | 3.938 | <0.001 | |||
| Age | (0.823–2.991) | 1.569 | 0.171 | (0.360–1.800) | 0.805 | 0.597 | |||
| Phimosis | (0.241–1.025) | 0.497 | 0.058 | (0.337–1.533) | 0.719 | 0.393 | |||
| T stage | (0.840–3.088) | 1.610 | 0.152 | (1.137–4.818) | 2.34 | 0.021 | |||
| Pathological grade | (1.934–8.729) | 4.108 | <0.001 | (1.110–7.010) | 2.789 | 0.029 | |||
| N status | (5.026–53.699) | 16.428 | <0.001 | (2.261–30.298) | 8.277 | 0.001 | |||
| Lymphadenopathy | (0.625–2.812) | 1.326 | 0.462 | ||||||
| Basic disease | (0.675–3.220) | 1.475 | 0.330 | ||||||
| ECOG | (1.243–3.229) | 2.003 | 0.004 | (1.028–2.983) | 1.751 | 0.039 | |||
| BMI | (0.414–1.849) | 0.875 | 0.726 | ||||||
| Chemotherapy | (2.566–9.642) | 4.974 | <0.001 | (0.845–3.882) | 1.811 | 0.127 | |||
| Radiotherapy | (0.762–6.143) | 2.163 | 0.147 | (0.352–3.636) | 1.131 | 0.837 | |||
Table 3.
Univariate and multivariate analyses for variables considered for DSS (Cox proportional hazard regression model)
| OS univariate analysis | OS multivariate analysis | ||||||||
|---|---|---|---|---|---|---|---|---|---|
| characteristics | 95%CIs | HR | P value | 95%CIs | HR | P value | |||
| Cyfra21-1 | (1.647–6.215) | 3.199 | 0.001 | (1.462–6.156) | 3.000 | 0.003 | |||
| Age | (0.779–2.982) | 1.524 | 0.218 | ||||||
| Phimosis | (0.217–0.992) | 0.464 | 0.048 | (0.314–1.599) | 0.709 | 0.407 | |||
| T stage | (0.910–3.594) | 1.808 | 0.091 | (1.271–6.139) | 2.793 | 0.011 | |||
| Pathological grade | (1.890–9.305) | 4.194 | <0.001 | (0.914–5.389) | 2.219 | 0.078 | |||
| N status | (5.537–97.199) | 23.199 | <0.001 | (2.010-41.862) | 9.174 | 0.004 | |||
| Lymphadenopathy | (0.628–3.073) | 1.389 | 0.417 | ||||||
| Basic disease | (0.545–2.859) | 1.248 | 0.601 | ||||||
| ECOG | (1.302–3.683) | 2.189 | 0.003 | (1.053–3.270) | 1.856 | 0.032 | |||
| BMI | (0.362–1.753) | 0.796 | 0.571 | ||||||
| Chemotherapy | (2.602–10.253) | 5.165 | <0.001 | (1.151–5.961) | 2.619 | 0.022 | |||
| Radiotherapy | (0.804–6.557) | 2.296 | 0.121 | (0.348–3.055) | 1.031 | 0.956 | |||
Discussion
PSCC is a relatively rare malignancy, but its incidence has been increasing in certain regions [1–3]. Despite advances in detection techniques and treatment options, PSCC remains associated with high mortality rates [7, 8, 11]. While serum CRP and SCC-Ag levels show promise in PSCC but lack robust validation and thus require further investigation in larger cohorts [9–13]. Therefore, there is a pressing need to identify more effective prognostic factors for PSCC to enable timely intervention. In epithelial malignancies, cyfra21-1, a fragment of CK-19, is released into circulation through the action of cleaving enzymes like caspase-3 during apoptosis [27]. Thus, a higher tumor burden leads to increased levels of cyfra21-1 in the bloodstream. Historically, Serum cyfra21-1 has been an established marker for diagnosing and predicting outcomes in lung squamous cell carcinoma [20, 28] and has been pivotal in managing other squamous carcinomas. It plays an important role in the diagnosis and recurrence monitoring of esophageal, and oropharynx squamous cell carcinoma [19–24].
While several studies have established a link between elevated levels of cyfra21-1 and adverse outcomes in various squamous cell carcinomas, its impact on PSCC prognosis has not been previously determined. In our study, we were the first to demonstrate that elevated serum cyfra21-1 levels indicated a poor prognosis in PSCC patients and served as an independent prognostic indicator for both DSS and DFS. The serum cyfra21-1 level reflects the tumor burden in PSCC. The prognostic model performed well for DFS (ROC-AUC values: 1-year 0.787, 3-year 0.837) and DSS (ROC-AUC values: 1-year 0.814, 3-year 0.884). These results suggest that the model may effectively predict relapse and survival in patients with elevated cyfra21-1. Therefore, PSCC patients with elevated cyfra21-1 levels should be considered for more aggressive and individualized treatment plans. For diagnostic purposes in new patients, an elevated serum cyfra21-1 level indicates a high risk in PSCC. These patients should undergo more comprehensive imaging examinations and pathological diagnoses to better predict their prognosis.
Additionally, we found that pathological grade, N stage, and ECOG performance status were independent predictors of worse DFS and DSS, consistent with previous research findings [2, 6–8, 11, 29]. While no significant correlation was noted between N status and serum cyfra21-1 levels (P = 0.072), the P-value was very close to 0.05, which may be attributed to the small sample size. Furthermore, our research also revealed a correlation between elevated preoperative serum cyfra21-1 levels and higher pathological grades, a novel finding in this context.
When penile squamous cell carcinomas emerge and advance, tumor cells disintegrate and necrosis ensues, generating a substantial amount of CK-19 protein. Once this protein dissolves in the blood, serum cyfra21-1 escalates, which can mirror the malignancy grade of the tumor and tumor burden. This serum marker is readily accessible and detectable in practice. Our research discovered that this indicator can precisely predict the prognosis of penile cancer. Indeed, cyfra21-1 is an ideal tumor marker for PSCC.
Despite efforts to minimize confounding factors, our study has some limitations. First, the data were retrospective, and the small sample size may introduce bias. No prospective randomized trials were conducted. Second, all patients in this study were from China, which may limit the generalizability of the findings. Third, we did not perform Cox analysis for SCC-Ag and CRP due to missing data in some patients. Lastly, we did not analyze post-therapy serum cyfra21-1 levels to monitor treatment progress, which requires further investigation with more comprehensive data.
Conclusions
Our study suggests that serum cyfra21-1 is a novel, effective, feasible, and prognostic biomarker for PSCC patients. It is associated with tumor biological aggressiveness and reflects tumor burden. Based on our results, serum cyfra21-1 levels may also have the potential for monitoring treatment efficacy. To establish the robustness of serum cyfra21-1 as a clinical biomarker, further validation through large-scale, multi-center, and prospective studies on an international level is imperative.
Acknowledgements
We thank all authors, reviewers, and editor for their critical discussion of this manuscript and apologize to those not mentioned due to space limitations.
Abbreviations
- PSCC
Penile squamous cell carcinoma
- CRP
C-reactive protein
- SCC-Ag
Squamous cell carcinoma antigen
- CK-19
Cytokeratin 19
- ELISA
Enzyme-linked immunosorbent assay
- DFS
Disease-free survival
- DSS
Disease-specific survival
- ECOG
Eastern Cooperative Oncology Group
- HR
Hazard ratios
- CI
Confidence interval
Author contributions
Conceived and designed study: HTL, ZYL, YLY Performed surgery：HH, FJZ, ZKQ, KY Collected and Analyzed the data: HTL, QYZ, ZYL, JLL, TNC, Wrote or revised the manuscript: HTL, QYZ, YLY, FJZ, KY, HH, ZKQ Prepared figures and tables: HTL, JLL, TNC, QYZ Final approval of the version: HTL, ZYL, JLL, KY, QYZ, TNC, HH, FJZ, YLY, ZKQ All authors reviewed the manuscript.
Funding
Not applicable.
Data availability
Raw data had registered in the website: https://www.medicalresearch.org.cn/. The major data and materials in this study are shown in the article. All raw data including the imaging data can be provided upon reasonable request to the corresponding author.
Declarations
Ethics approval and consent to participate
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. For its retrospective limitation, writing informed consent from the patients was not available, ethics approval from the Sun Yat-sen University Cancer Center Institute Research Ethics Committee (approval number: B2023-618-01 ) was obtained.
Informed consent
Informed consents were obtained from the patients or legal guardian.
Consent for publication
Not applicable.
Competing interests
The authors declare no competing interests.
Footnotes
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Haitao Liang, Qiuyue Zheng, Jiangli Lu and Zhiyong Li contributed equally to this work.
Contributor Information
Kai Yao, Email: yaokai@sysucc.org.cn.
Yunlin Ye, Email: yeyunl@sysucc.org.cn.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
Raw data had registered in the website: https://www.medicalresearch.org.cn/. The major data and materials in this study are shown in the article. All raw data including the imaging data can be provided upon reasonable request to the corresponding author.