ABSTRACT
Purpose:
To determine independent predictors of inguinal lymph node (ILN) metastasis in patients with penile cancer.
Patients and methods:
We retrospectively analyzed all patients with penile cancer who underwent surgery at our medical center in the last ten years (n=157). Using univariate and multivariate logistic-regression models, we assessed associations with age, medical-history, phimosis, onset-time, number and maximum diameter of involved ILNs measured by imaging, pathological T stage, degree of tumor differentiation and/or cornification, lymphatic vascular infiltration (LVI), nerve infiltration, and ILN metastases. Interaction and stratified analyses were used to assess age, phimosis, onset time, number of ILNs, cornification, and nerve infiltration.
Results:
A total of 110 patients were included in the study. Multiple logistic regression analysis showed that the following factors were significantly correlated with ILN metastasis: maximum diameter of enlarged ILNs, T stage, pathological differentiation, and LVI. Among patients with a maximum ILN diameter ≥1.5cm, 50% had lymph node metastasis whereas 30.6% patients with a maximum ILN diameter <1.5cm showed LNM. Among 44 patients with stage Ta/T1, 10 showed ILN metastases, while 47.0% patients with stage T2 showed ILN metastases. Among 40 patients with highly differentiated penile-cancer, eight showed ILN metastasis, while 47.1% patients with low-to-middle differentiation showed ILN metastases. The rate of LNM was 33.3% in the LVI-free group and 64.3% in the LVI group.
Conclusion:
Our single-center results suggested that maximum ILN diameter, pathological T stage, pathological differentiation, and LVI were independent risk factors for ILN metastases.
Keywords: Penile Neoplasms, Lymphatic Metastasis, Risk Factors
INTRODUCTION
Penile cancer is a rare malignancy, with an incidence of 0.081 per 100.000 in the United States and Europe (1, 2), and a prevalence of 2.3 to 8.3 per 100.000 in some developing regions, such as Asia, parts of Africa and Brazil (3, 4). Penile cancer is highly malignant and is mainly spread by lymphatic metastasis. The point of origin is the inguinal lymph nodes (ILNs), and jump metastasis rarely occurs (5, 6) ILN metastasis is the most important determinant of treatment and prognosis in patients with penile cancer (3, 7).
Pathology after lymph node biopsy or lymph node dissection remains the gold standard for the evaluation of ILN metastasis. However, it is an invasive operation that involves many postoperative complications, including poor lymph node drainage and poor wound healing (8). Therefore, researchers must explore the risk factors for ILN metastasis to determine which patients with penile cancer require ILN dissection. In so doing, patients with occult metastasis could receive prompt treatment, while patients with a lower risk of ILN metastasis could avoid excessive treatment.
Tumor stage, histological grade, lymphatic and vascular infiltration, histological subtype, and human papillomavirus have been identified as important predictors of ILN metastasis in previous studies (9, 10). However, these studies were conducted in a single center, and the sample size was small. In addition, only univariate analysis was used to explore the risk factors for ILN metastasis. In the present study, we aimed to test the independent risk factors and the role of inguinal lymph node metastasis in penile cancer in different populations, especially in China. We conducted multiple logistic and subgroup analyses, and interaction tests on all patients with penile cancer who underwent surgery in a large tertiary hospital over a 10-year period.
MATERIALS AND METHODS
This cross-sectional study was conducted between January 2010 and December 2019 at a comprehensive tertiary hospital in China. The inclusion criteria were as follows: (1) primary tumor treated surgically, (2) tumor pathology confirmed by experienced pathologists, and (3) ILN metastasis pathologically confirmed by biopsy or prophylactic inguinal lymphadenectomy. Patients with pelvic lymph node or distant metastases were excluded, as were those treated in other hospitals. All patients provided informed consent and the institutional ethics committee approved the study (IRB-032-06).
We retrieved the following clinical information from the patient's medical records: age, previous medical history (hypertension, diabetes, or cardiovascular disease), phimosis, onset time, number and maximum diameter of the involved ILNs, pathological T stage, degree of tumor differentiation and/or cornification, lymphatic vascular infiltration (LVI), and nerve infiltration. The number and maximum diameter of the ILNs were determined using ultrasound or computed tomography. Tumor stage was assessed according to the TNM Classification of Malignant Tumors (TNM) system, which was updated in 2018 (11). The pathological differentiation of tumors was evaluated according to the criteria described by Velazquez et al. (12).
Primary tumors were treated surgically using either penis-sparing, partial amputation, or total excision via perineal urethrostomy. According to the EAU guidelines (2009) (13), ILN biopsy or bilateral ILN dissection is recommended for patients with stage ≥T1G2 and/or enlarged lymph nodes that have not significantly shrunk after 4-6 weeks of antibiotic treatment. Surgery was performed by three experienced urologists.
Continuous variables are presented as mean±standard deviation (SD) or median (interquartile range), while categorical variables are expressed as frequencies or percentages. To facilitate statistical analysis, all continuous variables except age were converted into categorical variables. Risk factors for penile cancer were identified using univariate logistic regression analyses, and independent predictive factors for ILN metastasis were confirmed by multivariate logistic regression analyses. The statistical packages R (The R Foundation, Vienna, Austria) was used to analyze the data. Statistical differences were considered significant when the P-value was less than 0.05.
RESULTS
A total of 157 patients were identified; 47 were excluded due to lack of follow-up data, resulting in 110 patients included in the study (Figure-1). Forty-one patients had confirmed ILN metastasis, of whom 25 were pathologically confirmed by ILN biopsy and the rest were confirmed by pathology after prophylactic inguinal lymphadenectomy. There were no signs of ILN metastasis in 69 patients. Hence, the rate of ILN metastasis was 37.3%.
Figure 1. Flowchart for the recruitment of patients in this study.
Table-1 lists the clinicopathological characteristics and univariate analysis of the variables associated with ILN metastasis in the 110 patients. The mean age was 61.6±11.8 years. Univariate analysis showed that the following factors were correlated with ILN metastasis: maximum diameter of enlarged ILNs (P=0.045), pathological stage (P=0.010), degree of pathological differentiation (P=0.009), and LVI (P=0.025).
Table 1. Clinicopathological characteristics and univariate analysis of variables associated with inguinal lymph node metastasis.
| Total | Without metastasis | With metastasis | HR(95%CI) | P-value | |
|---|---|---|---|---|---|
| N | 110 | 69 | 41 | ||
| Age(years)(Mean+SD) | 61.6 ± 11.8 | 61.0 ± 12.0 | 62.5 ± 11.5 | 0.1 (-0.3, 0.5) | 0.529 |
| HBP(N,%) | 0.0 (-0.4, 0.4) | 0.984 | |||
| no | 94 (85.5%) | 59 (85.5%) | 35 (85.4%) | ||
| yes | 16 (14.5%) | 10 (14.5%) | 6 (14.6%) | ||
| Diabetes(N,%) | 0.1 (-0.3, 0.4) | 0.799 | |||
| no | 101 (91.8%) | 63 (91.3%) | 38 (92.7%) | ||
| yes | 9 (8.2%) | 6 (8.7%) | 3 (7.3%) | ||
| CDV(N,%) | 0.1 (-0.2, 0.5) | 0.439 | |||
| no | 102 (92.7%) | 65 (94.2%) | 37 (90.2%) | ||
| yes | 8 (7.3%) | 4 (5.8%) | 4 (9.8%) | ||
| Phimosis(N,%) | 0.2 (-0.2, 0.6) | 0.347 | |||
| no | 58 (52.7%) | 34 (49.3%) | 24 (58.5%) | ||
| yes | 52 (47.3%) | 35 (50.7%) | 17 (41.5%) | ||
| Onset_time(month) (N,%) | 0.1 (-0.2, 0.5) | 0.475 | |||
| <12 | 76 (69.1%) | 46 (66.7%) | 30 (73.2%) | ||
| >=12 | 34 (30.9%) | 23 (33.3%) | 11 (26.8%) | ||
| Number_ILN(N,%) | 0.2 (-0.2, 0.6) | 0.254 | |||
| ≥3 | 46 (41.8%) | 26 (37.7%) | 20 (48.8%) | ||
| >3 | 64 (58.2%) | 43 (62.3%) | 21 (51.2%) | ||
| Maxium_ILN(N,%) | 0.4 (0.0, 0.8) | 0.045 | |||
| >1.5cm | 72 (65.5%) | 50 (72.5%) | 22 (53.7%) | ||
| ≥1.5cm | 38 (34.5%) | 19 (27.5%) | 19 (46.3%) | ||
| T_stage(N,%) | 0.5 (0.1, 0.9) | 0.01 | |||
| Ta/T1 | 44 (40.0%) | 34 (49.3%) | 10 (24.4%) | ||
| T2 and higher | 66 (60.0%) | 35 (50.7%) | 31 (75.6%) | ||
| Differentiation(N,%) | 0.6 (0.2, 1.0) | 0.005 | |||
| lower-middle | 70 (63.6%) | 37 (53.6%) | 33 (80.5%) | ||
| higher | 40 (36.4%) | 32 (46.4%) | 8 (19.5%) | ||
| Cornification(N,%) | 0.0 (-0.3, 0.4) | 0.807 | |||
| no | 74 (67.3%) | 47 (68.1%) | 27 (65.9%) | ||
| yes | 36 (32.7%) | 22 (31.9%) | 14 (34.1%) | ||
| LVI(N,%) | 0.4 (0.0, 0.8) | 0.025 | |||
| no | 96 (87.3%) | 64 (92.8%) | 32 (78.0%) | ||
| yes | 14 (12.7%) | 5 (7.2%) | 9 (22.0%) | ||
| Nerve_infiltration(N,%) | 0.2 (-0.2, 0.6) | 0.362 | |||
| no | 92 (83.6%) | 56 (81.2%) | 36 (87.8%) | ||
| yes | 18 (16.4%) | 13 (18.8%) | 5 (12.2%) |
The P value is written in italics when it is less than 0.05
HBP, high blood pressure; CDV, cardiovascular disease; ILN, inguinal lymph node; LVI, lymphatic vascular infiltration, T stage, the TNM system of penile cancer updated in 2018; degree of tumor differentiation: According to the percentage of undifferentiated cells, the tumor was divided into middle and low differentiated groups and highly differentiated groups. CI, confidence interval; HR, hazard ratio.
Significant single factors were included in the multivariate analysis (Table-2). We applied both non-adjusted and multivariate adjusted models (adjusted for age, previous medical history, and other variables that affected the X regression coefficient by more than 10%). A two-sided significance level of 0.05 was used to evaluate statistical significance. The results showed that the following factors were independent predictors of ILN metastasis: largest diameter of enlarged ILNs, T stage of tumor, pathological differentiation, and LVI. Specifically, patients with the largest ILN diameter ≥1.5cm showed a 1.3-fold increased risk of metastasis compared to those with the largest ILN diameter <1.5cm. Those with tumor stage T2 and above showed a two-fold greater risk of ILN metastasis than those with tumor stage Ta or T1. Those with low to moderate tumor differentiation had a 2.6-fold greater risk of ILN metastasis than those with high pathological differentiation. Finally, patients with LVI had a 2.6-fold greater risk of ILN metastasis than those without LVI.
Table 2. Multiple logistic regression models assessed the correlation between risk factors and ILN metastasis.
| Exposure | Non-adjusted | Adjust I | Adjust II | |
|---|---|---|---|---|
| HR,95%CI P value | HR,95%CI P value | HR,95%CI P value | ||
| Maxium_ILN | ||||
| <1.5cm | 1 | 1 | 1 | |
| ≥1.5cm | 2.3 (1.0, 5.1) 0.047 | 2.4 (1.1, 5.6) 0.035 | 10.7 (2.1, 53.3) 0.004 | |
| T_stage | ||||
| Ta/T1 | 1 | 1 | 1 | |
| T2 and above | 3.0 (1.3, 7.1) 0.011 | 3.1 (1.3, 7.5) 0.010 | 7.1 (1.7, 28.9) 0.006 | |
| Differentiation | ||||
| high | 1 | 1 | 1 | |
| low-middle | 3.6 (1.4, 8.8) 0.006 | 4.0 (1.5, 10.4) 0.004 | 6.2 (1.9, 20.2) 0.003 | |
| LVI | ||||
| no | 1 | 1 | 1 | |
| yes | 3.6 (1.1, 11.6) 0.032 | 3.6 (1.1, 11.8) 0.033 | 7.4 (1.3, 40.8) 0.022 | |
The data in the table: β (95%CI) P value/OR (95%CI) P value
Outcome variable: metastasis Exposed variables:
1) Maximum_ILN
Non-adjusted model adjusted for: None
Adjust I model adjust for: age; HBP; diabetes; CDV
Adjust II model adjusted for: model1+onset_time; T_stage; differentiation; LVI; umber_ILN
2) T_stage
Non-adjusted model adjusted for: None
Adjust I model adjusted for: age; HBP; diabetes; CDV
Adjust II model adjusted for: model1+onset_time; Number_ILN; Maximum_ILN; differentiation; LVI; nerve infiltration
3) Differentiation
Non-adjusted model adjusted for: None
Adjust I model adjusted for: age; HBP; diabetes; CDV
Adjust II model adjusted for: model1+onset_time; Number_ILN; Nerve_infiltration
4) LVI
Non-adjusted model adjusted for: None
Adjust I model adjusted for: age; HBP; diabetes; CDV
Adjust II model adjusted for: model1+onset_time, Number_ILN, Maximum_ILN, T_stage, Nerve_infiltration, differentiation
ILN, inguinal lymph nodes; LVI, lymphatic vascular infiltration.
To further demonstrate the stability of our results, we performed stratified analyses and interaction tests of the four independent risk factors, as shown in the forest plot (Figure-2a-d and Table-3). The results showed that no significant interactions were observed.
Figure 2. Odds ratios for inguinal lymph node metastasis, according to baseline characteristics.
Table 3. Association between related risk factors and inguinal lymph node metastasis, according to baseline characteristics.
| Subgroud | N | OR,95%CI | P value | P for interaction | |
|---|---|---|---|---|---|
| X= Maxium_ILN | |||||
| Age, y | 0.304 | ||||
| <60 | 42 | 1.3 (0.4, 4.9) | 0.666 | ||
| >=60 | 68 | 3.2 (1.1, 9.1) | 0.029 | ||
| Onset_time, m | 0.627 | ||||
| <12 | 76 | 2.5 (1.0, 6.6) | 0.058 | ||
| >=12 | 34 | 1.6 (0.3, 7.6) | 0.54 | ||
| Phimosis | 0.164 | ||||
| no | 58 | 5.0 (1.3, 18.8) | 0.017 | ||
| yes | 52 | 1.0 (0.2, 4.1) | 0.982 | ||
| Cornification | 0.967 | ||||
| no | 74 | 2.3 (0.7, 7.9) | 0.18 | ||
| yes | 36 | 2.5 (0.5, 12.3) | 0.272 | ||
| Nerve_infiltration | 0.996 | ||||
| no | 92 | 2.2 (0.8, 6.0) | 0.132 | ||
| yes | 18 | 7.0 (0.3, 181.5) | 0.241 | ||
| X= T_stage | |||||
| Age, y | 0.98 | ||||
| <60 | 42 | 2.7 (0.5, 13.5) | 0.227 | ||
| >=60 | 68 | 3.8 (1.0, 14.5) | 0.046 | ||
| Onset_time, m | 0.971 | ||||
| <12 | 76 | 2.3 (0.7, 7.0) | 0.158 | ||
| <=12 | 34 | 4.2 (0.6, 28.8) | 0.142 | ||
| Number_ILN | 0.588 | ||||
| <3 | 46 | 3.7 (0.9, 15.0) | 0.069 | ||
| ≥3 | 64 | 2.1 (0.5, 9.3) | 0.336 | ||
| Phimosis | 0.446 | ||||
| no | 58 | 5.4 (1.3, 21.9) | 0.017 | ||
| yes | 52 | 1.4 (0.3, 6.3) | 0.65 | ||
| Cornification | 0.069 | ||||
| no | 74 | 5.0 (1.4, 17.2) | 0.011 | ||
| yes | 36 | 0.8 (0.2, 4.0) | 0.766 | ||
| X= differention | |||||
| Age,y | 0.12 | ||||
| <60 | 42 | 0.9 (0.2, 4.5) | 0.928 | ||
| >=60 | 68 | 7.2 (1.7, 30.4) | 0.007 | ||
| Onset_time,m | 0.09 | ||||
| <12 | 76 | 5.4 (1.3, 21.7) | 0.017 | ||
| >=12 | 34 | 1.4 (0.3, 6.7) | 0.643 | ||
| Number_ILN | 0.148 | ||||
| <3 | 46 | 1.0 (0.2, 4.1) | 0.985 | ||
| ≥3 | 64 | 12.0 (1.9, 75.1) | 0.008 | ||
| Phimosis | 0.62 | ||||
| no | 58 | 2.2 (0.5, 9.0) | 0.27 | ||
| yes | 52 | 3.5 (0.9, 14.3) | 0.078 | ||
| Cornification | 0.634 | ||||
| no | 74 | 3.1 (0.9, 10.8) | 0.068 | ||
| yes | 36 | 5.4 (0.9, 34.5) | 0.072 | ||
| Nerve_infiltration | 0.551 | ||||
| no | 92 | 4.1 (1.4, 12.2) | 0.01 | ||
| yes | 18 | 0.4 (0.1, 9.4) | 0.59 | ||
| X= LVI | |||||
| Onset_time, m | 0.631 | ||||
| <12 | 76 | 2.8 (0.6, 13.2) | 0.182 | ||
| >=12 | 34 | 1.3 (0.1, 13.0) | 0.799 | ||
| Number_ILN | 0.702 | ||||
| <3 | 46 | 3.6 (0.2, 53.2) | 0.351 | ||
| ≥3 | 64 | 5.9 (1.1, 32.6) | 0.044 | ||
| Phimosis | 0.201 | ||||
| no | 58 | 1.2 (0.2, 6.2) | 0.85 | ||
| yes | 52 | 8.3 (0.7, 91.6) | 0.085 | ||
| Cornification | 0.111 | ||||
| no | 74 | 4.9 (0.8, 29.7) | 0.083 | ||
| yes | 36 | 1.1 (0.1, 11.1) | 0.933 | ||
| Nerve_infiltration | 0.138 | ||||
| no | 92 | 7.9 (0.9, 73.4) | 0.068 | ||
| yes | 18 | 3.0 (0.2, 54.2) | 0.457 | ||
OR, odds ratio; CI, confidence interval.
DISCUSSION
The most important factor affecting the prognosis of penile cancer is ILN metastasis (3, 14–16). Several studies have indicated that the rate of ILN metastasis in patients with penile cancer is 30–40% (17). The latest meta-analysis (18) selected 42 eligible studies that included a total of 4.802 patients, of whom 1.706 (36%) were diagnosed with ILN metastasis. This finding was corroborated by our results, in which 37.3% of the patients had ILN metastasis (41/110).
In our multiple regression analysis, the maximum diameter of the enlarged ILNs, pathological stage, pathological differentiation, and LVI were the only predictors of ILN metastasis. We conducted a stratified analysis and interaction tests on the four factors and found no any obvious interaction, further proving the stability of our results.
A maximum ILN diameter of >1.0cm is usually considered abnormal, while a diameter >1.5cm, with a relatively hard texture, strongly indicates tumor metastasis (19). The present study suggested that the largest diameter of enlarged ILNs was an independent risk factor, corroborating studies by Tang et al. (20) and Zhou et al. (9). However, in another study, 50% of enlarged ILNs were inflamed or reactive, rather than metastatic (17), indicating that ILN metastasis cannot be reliably detected using imaging or clinical evaluation. It is essential to predict ILNM in combination with the pathological characteristics of the primary tumor.
The pathological stage of the primary tumor is generally considered the most important parameter for predicting ILN metastasis in patients with penile cancer (21). Depending on whether there is infiltration of the urethra or corpus cavernosum, the tumor stage can be classified as T1, T2, or higher (11). In the present study, the rate of ILN metastasis in patients with T1 stage was 22.7% (10/44), while it was 47.0% (31/66) in those with T2 stage and above. The ILN metastasis rate in patients with T2 stage disease was significantly higher than that in patients with T1 stage disease. Several researchers have suggested that if the corpus cavernosum is infiltrated, ILN dissection should be performed, even if there are no obvious enlarged ILNs (22, 23). However, deciding to perform ILN dissection in all patients with T2 and above based only in tumor stage will lead to overtreatment (24). In the present study, 53.0% of patients with T2 stage disease and above showed no obvious signs of ILN metastasis. Therefore, other factors should be considered when screening for high-risk patients.
The degree of tumor differentiation under pathological conditions is negatively correlated with tumor pathological grade or malignancy, with lower tumor differentiation indicating higher grade, higher malignancy, and greater risk of metastasis (18). Solsona et al. (25) found that the grade of tumor differentiation correlates well with ILN metastasis, corroborating our multiple regression analysis (HR=3.0, 95% CI: 1.3-7.1). According to Horenblas et al. (26), the lymph node metastasis rates of G1, G2, and G3 were 29%, 46%, and 82%, respectively. Our results were similar to these, with 20% (8/40), 45% (30/66), and 75% (3/4), respectively. Theodoresu et al. (27) asserted that tumor grade is the only predictor of ILN metastasis, and they recommended ILN dissection in patients with G2 and G3, which coincides with our point of view.
The existing literature has different opinions on whether LVI is a predictor of ILN metastasis. Some studies have ranked LVI as one of the most important factors of metastasis (28–31), while others have not (32). Our findings suggest that LVI is significantly associated with ILN metastasis (HR=3.6, 95% CI: 1.1-11.6) among patients with penile cancer.
The present study had several strengths. First, although some potential confounding factors were unavoidable, we used strict statistical adjustments to minimize residual confounding. Second, the effect modifier factor analysis took full advantage of the data; no interaction was found, indicating that the results were more stable.
However, there were some limitations to our study. Patients with penile cancer were recruited from a large single medical center. Therefore, an external validation of the results is required. The study was cross-sectional, and no information was available about the degree of risk factors prior to ILN metastasis, because the earlier pathology reports contained no such data. Moreover, no data were available regarding lymph node extranodal transfer and the growth pattern of tumors in some patients (papillary, ulcerated, invasive,) therefore, we could not consider these variables in the final results, although there was evidence that these factors had prognostic significance. Despite these limitations, the findings of this study have implications for clinicians when formulating further treatment plans for patients with penile cancer who have undergone surgery. However, prospective studies with a larger sample size are required.
CONCLUSION
In conclusion, the maximum diameter of the enlarged ILN, pathological stage, pathological differentiation, and LVI were independent predictive factors that worsened the prognosis of patients with penile cancer. Specifically, patients with enlarged lymph nodes >1.5cm in diameter, pathological stage T2 and above, low-to-middle differentiation, and LVI are more likely to develop ILN metastasis. Prophylactic ILN dissection is recommended for these patients. Prospective studies with larger sample sizes are required to support our findings.
ABBREVIATIONS
- ILN
inguinal lymph node;
- LVI
lymphatic vascular infiltration;
- SD
standard deviation;
- HBP
high blood pressure;
- CDV
cardiovascular disease;
- CI
confidence interval;
- HR
hazard ratio.
Footnotes
ETHICS APPROVAL AND CONSENT TO PARTICIPATE
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Informed consent was obtained from all participants included in the study.
REFERENCES
- 1.Hernandez BY, Barnholtz-Sloan J, German RR, Giuliano A, Goodman MT, King JB, et al. Burden of invasive squamous cell carcinoma of the penis in the United States, 1998-2003. Cancer. 2008; 113 (10 Suppl):2883-91. [DOI] [PMC free article] [PubMed]
- 2.Douglawi A, Masterson TA. Updates on the epidemiology and risk factors for penile cancer. Transl Androl Urol. 2017; 6:785-90. [DOI] [PMC free article] [PubMed]
- 3.Wen S, Ren W, Xue B, Fan Y, Jiang Y, Zeng C, et al. Prognostic factors in patients with penile cancer after surgical management. World J Urol. 2018; 36:435-40. [DOI] [PubMed]
- 4.Favorito LA, Nardi AC, Ronalsa M, Zequi SC, Sampaio FJ, Glina S. Epidemiologic study on penile cancer in Brazil. Int Braz J Urol. 2008; 34:587-91. [DOI] [PubMed]
- 5.Leijte JA, Valdés Olmos RA, Nieweg OE, Horenblas S. Anatomical mapping of lymphatic drainage in penile carcinoma with SPECT-CT: implications for the extent of inguinal lymph node dissection. Eur Urol. 2008; 54:885-90. [DOI] [PubMed]
- 6.Azevedo RA, Roxo AC, Alvares SHB, Baptista DP, Favorito LA. Use of flaps in inguinal lymphadenectomy in metastatic penile cancer. Int Braz J Urol. 2021; 47:1108-19. [DOI] [PMC free article] [PubMed]
- 7.Koifman L, Hampl D, Ginsberg M, Castro RB, Koifman N, Ornellas P, et al. The role of primary inguinal surgical debulking for locally advanced penile cancer followed by reconstruction with myocutaneous flap. Int Braz J Urol. 2021; 47:1162-75. [DOI] [PMC free article] [PubMed]
- 8.Yuan P, Zhao C, Liu Z, Ou Z, He W, Cai Y, et al. Comparative Study of Video Endoscopic Inguinal Lymphadenectomy Through a Hypogastric vs Leg Subcutaneous Approach for Penile Cancer. J Endourol. 2018; 32:66-72. [DOI] [PubMed]
- 9.Zhou X, Zhong Y, Song L, Wang Y, Wang Y, Zhang Q, et al. Nomograms to predict the presence and extent of inguinal lymph node metastasis in penile cancer patients with clinically positive lymph nodes. Transl Androl Urol. 2020; 9:621-8. [DOI] [PMC free article] [PubMed]
- 10.Nascimento ADMTD, Pinho JD, Júnior AALT, Larges JS, Soares FM, Calixto JRR, et al. Angiolymphatic invasion and absence of koilocytosis predict lymph node metastasis in penile cancer patients and might justify prophylactic lymphadenectomy. Medicine (Baltimore). 2020; 99:e19128. [DOI] [PMC free article] [PubMed]
- 11.Paner GP, Stadler WM, Hansel DE, Montironi R, Lin DW, Amin MB. Updates in the Eighth Edition of the Tumor-Node-Metastasis Staging Classification for Urologic Cancers. Eur Urol. 2018; 73:560-9. [DOI] [PubMed]
- 12.Velazquez EF, Ayala G, Liu H, Chaux A, Zanotti M, Torres J, et al. Histologic grade and perineural invasion are more important than tumor thickness as predictor of nodal metastasis in penile squamous cell carcinoma invading 5 to 10 mm. Am J Surg Pathol. 2008; 32:974-9. [DOI] [PubMed]
- 13.Pizzocaro G, Algaba F, Horenblas S, Solsona E, Tana S, Van Der Poel H, et al. EAU penile cancer guidelines 2009. Eur Urol. 2010; 57:1002-12. [DOI] [PubMed]
- 14.Hakenberg OW, Compérat EM, Minhas S, Necchi A, Protzel C, Watkin N. EAU guidelines on penile cancer: 2014 update. Eur Urol. 2015; 67:142-50. [DOI] [PubMed]
- 15.Zhu Y, Ye DW. Lymph node metastases and prognosis in penile cancer. Chin J Cancer Res. 2012; 24:90-6. [DOI] [PMC free article] [PubMed]
- 16.Hughes B, Leijte J, Shabbir M, Watkin N, Horenblas S. Non-invasive and minimally invasive staging of regional lymph nodes in penile cancer. World J Urol. 2009; 27:197-203. [DOI] [PubMed]
- 17.Chaux A, Velazquez EF, Algaba F, Ayala G, Cubilla AL. Developments in the pathology of penile squamous cell carcinomas. Urology. 2010; 76 (2 Suppl 1):S7-S14. [DOI] [PubMed]
- 18.Hu J, Cui Y, Liu P, Zhou X, Ren W, Chen J, et al. Predictors of inguinal lymph node metastasis in penile cancer patients: a meta-analysis of retrospective studies. Cancer Manag Res. 2019; 11:6425-41. [DOI] [PMC free article] [PubMed]
- 19.Zhu Y, Zhang SL, Ye DW, Yao XD, Jiang ZX, Zhou XY. Predicting pelvic lymph node metastases in penile cancer patients: a comparison of computed tomography, Cloquet's node, and disease burden of inguinal lymph nodes. Onkologie. 2008; 31:37-41. [DOI] [PubMed]
- 20.Tang Y, Rao S, Yang C, Hu Y, Sheng R, Zeng M. Value of MRI morphologic features with pT1-2 rectal cancer in determining lymph node metastasis. J Surg Oncol. 2018; 118:544-50. [DOI] [PubMed]
- 21.Fraley EE, Zhang G, Manivel C, Niehans GA. The role of ilioinguinal lymphadenectomy and significance of histological differentiation in treatment of carcinoma of the penis. J Urol. 1989; 142:1478-82. [DOI] [PubMed]
- 22.Ornellas AA, Nóbrega BL, Wei Kin Chin E, Wisnescky A, da Silva PC, de Santos Schwindt AB. Prognostic factors in invasive squamous cell carcinoma of the penis: analysis of 196 patients treated at the Brazilian National Cancer Institute. J Urol. 2008; 180:1354-9. [DOI] [PubMed]
- 23.Ornellas AA, Kinchin EW, Nóbrega BL, Wisnescky A, Koifman N, Quirino R. Surgical treatment of invasive squamous cell carcinoma of the penis: Brazilian National Cancer Institute long-term experience. J Surg Oncol. 2008; 97:487-95. [DOI] [PubMed]
- 24.Maciel CVM, Machado RD, Morini MA, Mattos PAL, Dos Reis R, Dos Reis RB, et al. External validation of nomogram to predict inguinal lymph node metastasis in patients with penile cancer and clinically negative lymph nodes. Int Braz J Urol. 2019; 45:671-8. [DOI] [PMC free article] [PubMed]
- 25.Solsona E, Iborra I, Rubio J, Casanova JL, Ricós JV, Calabuig C. Prospective validation of the association of local tumor stage and grade as a predictive factor for occult lymph node micrometastasis in patients with penile carcinoma and clinically negative inguinal lymph nodes. J Urol. 2001; 165:1506-9. [PubMed]
- 26.Horenblas S, van Tinteren H. Squamous cell carcinoma of the penis. IV. Prognostic factors of survival: analysis of tumor, nodes and metastasis classification system. J Urol. 1994; 151:1239-43. [DOI] [PubMed]
- 27.Theodorescu D, Russo P, Zhang ZF, Morash C, Fair WR. Outcomes of initial surveillance of invasive squamous cell carcinoma of the penis and negative nodes. J Urol. 1996; 155:1626-31. [PubMed]
- 28.Peak TC, Russell GB, Dutta R, Rothberg MB, Chapple AG, Hemal AK. A National Cancer Database-based nomogram to predict lymph node metastasis in penile cancer. BJU Int. 2019; 123:1005-10. [DOI] [PubMed]
- 29.Diorio GJ, Leone AR, Spiess PE. Management of Penile Cancer. Urology. 2016; 96:15-21. [DOI] [PubMed]
- 30.Hughes BE, Leijte JA, Kroon BK, Shabbir MA, Swallow TW, Heenan SD, et al. Lymph node metastasis in intermediate-risk penile squamous cell cancer: a two-centre experience. Eur Urol. 2010; 57:688-92. [DOI] [PubMed]
- 31.Bhagat SK, Gopalakrishnan G, Kekre NS, Chacko NK, Kumar S, Manipadam MT, et al. Factors predicting inguinal node metastasis in squamous cell cancer of penis. World J Urol. 2010; 28:93-8. [DOI] [PubMed]
- 32.de Paula AA, Netto JC, Freitas R Jr, de Paula LP, Mota ED, Alencar RC. Penile carcinoma: the role of koilocytosis in groin metastasis and the association with disease specific survival. J Urol. 2007; 177:1339-43. [DOI] [PubMed]