Abstract
Background:
Penile cancer is a rare malignancy which inguinal and pelvic lymph node involvement plays a major role in patients’ survival. The prognosis of patients with lymph node metastasis is poorer.
Objective:
The objective of the study was to evaluate the prognostic factors for inguinal lymph node and pelvic lymph node involvement.
Materials and Methods:
This was a retrospective analytic study of medical records between January 2010 and December 2020.
Results:
Thirty-nine patients were diagnosed with penile cancer, median age of 59 ± 14.898 (range: 32–86 years) were included in the analysis. Twenty-eight patients underwent inguinal lymph node dissection, 13 patients had inguinal lymph node metastasis (46.4%), 8 patients underwent pelvic lymph node dissection, and 5 patients had pelvic lymph node metastasis (62.5%). Inguinal lymph node metastasis was associated with tumor grading (odds ratio [OR]: 2.92, confidence interval [CI]: 0.123–0.704), lymphovascular invasion (LVI) (OR: 5.182, CI: 0.430–0.996), perineural invasion (PNI) (OR: 3.687, CI: 0.277–0.975), and fixation of inguinal node (OR: 2.463, CI: 0.078–1.195). Pelvic lymph node metastasis was associated with tumor grading (OR: 2.619, CI: 0.033–0.967).
Conclusion:
Grading, LVI and PNI of primary tumor, and fixation of inguinal node are significantly associated with inguinal lymph node metastasis. While primary tumor grading is significantly associated with pelvic lymph node metastasis. These factors are associated with poorer prognosis.
Keywords: Inguinal lymph node, pelvic lymph node, penile cancer, squamous cell carcinoma
INTRODUCTION
Penile cancer is a rare malignancy account for 0.4%–0.6% of all malignancy, but it can be differing in many countries[1] which inguinal lymph node and pelvic lymph node involvement plays a major role in patients’ survival.[2-5] Patient with inguinal and pelvic lymph node metatasis has 5 year survival rate around 50% and 90%, respectivly. Penile cancer metastasis usually spreads through penile lymphatic channel to regional nodes, especially the superficial and deep inguinal nodes, and subsequently to the pelvic lymph node.[4]
Physical examination to predict pathologically involved lymph nodes was a high false-positive rate, an average of 25% of the time (range: 11%–62%).[2,6] Clinical evaluation of regional lymph nodes in these patients is inaccurate, with 50% of those with clinically positive nodes having no tumor on histological examination due to inflammatory changes. Conversely, approximately 20% of patients with clinically negative nodes will have occult metastases from pathologic reports.[3]
Inguinal lymphadenectomy is the best treatment for inguinal lymph node metastases despite it provides high false-positive and high morbidity and mortality rates (30%–50% and 3%, respectively).[3,6]
Previous retrospective studies demonstrated the associated factor that factor that predict lymph node metastasis including stage, histological grade, lymphovascular invasion (LVI), koilocytosis, mitoses, growth pattern, DNA ploidy, and depth of invasion have been evaluated as predictors of lymph node metastasis.[2-7]
In this retrospective study, we validate the association of predictive factors for inguinal and pelvic lymph node metastasis.
Objectives
The objective of this study was to evaluate the prognostic factors for inguinal and pelvic lymph node involvement.
MATERIALS AND METHODS
Research design
This research was conducted as a retrospective analytic study.
Study population
All consecutive patients with a diagnosis of penile cancer who attended the department of urological surgery at the hospital during January 2010–December 2020 were enrolled in the study.
Inclusion criteria
All consecutive patients with a diagnosis of penile cancer during the study period were included in the study.
Exclusion criteria
Patients with benign penile lesions or consecutive patients with penile cancer with incomplete medical data or loss of follow-up were excluded from the study.
Sample size estimation
Patients who met the inclusion criteria were included in the analysis. Then, sample size calculation was made.
Data collection
The research proposal was approved by the institutional review board
Permission to access the medical records was allowed by the director of the hospital
Data of the patients with diagnosis of penile cancer between January 2010 and December 2020 were collected from electronic search at the department of information technology and the radiological information system and the picture archiving and communication system. Penile cancer was diagnosed with pathologic examination of tissue from incisional biopsy, excisional biopsy, partial penectomy, and total penectomy
Patients’ demographic data, location, size, characteristics of lesion, primary treatment of tumor, grading, T staging, LVI, perineural invasion (PNI), inguinal lymph node status (palpable or nonpalpable), number of inguinal lymph nodes, fixation of inguinal lymph node enlargement, and extranodular extension were recorded. A case record form was demonstrated in the appendix
The data were processed using a statistical program.
Statistical analysis
The data were re-evaluated for correctness and recorded in data files, and then, it was statistically analyzed as follows:
Demographic data of the patients were described as range, mean, median, standard deviation, and frequency in percentage
Correlation between the inguinal lymph node involvement and the pelvic lymph node involvement was determined using Chi-square test and independent t-test
P < 0.05 was considered to indicate statistical significance
Analysis was performed using SPSS Statistics 25 (IBM Corp. Released 2017. IBM SPSS Statistics for Windows, Version 25.0. Armonk, NY: IBM Corp.).
RESULTS
Demographic data
During the study period, 39 patients were diagnosed with penile cancer, a median age of 59 ± 14.898 (range: 32–86 years) [Table 1].
Table 1.
Patients’ demographic and clinical data of primary lesion
| Variables | Statistics data, n (%) |
|---|---|
| Age, mean±SD | 59±14.898 |
| Characteristics of lesion | |
| Fungating | 36 (92.3) |
| Ulcerative | 3 (64.1) |
| Location | |
| Prepuce | 7 (17.9) |
| Glans | 25 (11.1) |
| Shaft | 7 (17.9) |
| Size (cm) | |
| 1–3 | 22 (56.4) |
| >3–6 | 14 (35.9) |
| >6 | 3 (7.7) |
| Primary treatment | |
| Partial penectomy | 32 (82.1) |
| Total penectomy | 25 (17.9) |
| Cell type | |
| SCC | 39 (100) |
| T staging | |
| Ta | 0 |
| T1a | 13 (33.3) |
| T1b | 2 (5.1) |
| T2 | 11 (28.2) |
| T3 | 13 (33.3) |
| T4 | 0 |
| Grading | |
| Well differentiation | 16 (41) |
| Moderated differentiation | 21 (53.8) |
| Poorly differentiation | 2 (5.1) |
| LVI | |
| Yes | 13 (33.3) |
| No | 26 (66.6) |
| PNI | |
| Yes | 9 (23.1) |
| No | 30 (76.9) |
SCC: Squamous cell carcinoma, SD: Standard deviation, LVI: Lymphovascular invasion, PNI: Perineural invasion
Twenty-eight patients undergo inguinal lymph node dissection (ILND), 13 patients have inguinal lymph node metastasis (46.4%), 8 patients undergo pelvic lymph node dissection (PLND), and 5 patients have pelvic lymph node metastasis (62.5%) [Figure 1 and Table 2].
Figure 1.
Management of penile cancer patients
Table 2.
Patients’ clinical data of lymph node status
| Variables | Statistics data, n (%) |
|---|---|
| Inguinal lymph node status | |
| Nonpalpable | 24 (61.5) |
| Palpable | 15 (38.5) |
| Number of inguinal nodes | |
| 1 | 5 (33.3) |
| 2 | 3 (20) |
| ≥3 | 7 (46.7) |
| Side | |
| Ipsilateral | 7 (46.7) |
| Bilateral | 8 (53.3) |
| Fixation of inguinal node | |
| No | 11 (73.3) |
| Yes | 4 (26.7) |
| ILND | |
| Modify | 13 (33.3) |
| Standard | 8 (20.5) |
| Combine | 7 (17.9) |
| Not done | 11 (28.2) |
| Inguinal lymph node metastasis | |
| None | 15 (53.6) |
| Presence | 13 (46.4) |
| ENE | |
| Presence | 13 (46.4) |
| None | 15 (53.6) |
| PLND | |
| Not done | 31 (79.5) |
| Done | 8 (20.5) |
| Pelvic lymph node metastasis | |
| Presence | 5 (62.5) |
| None | 3 (37.5) |
ILND: Inguinal lymph node dissection, PLND: Pelvic lymph node dissection, ENE: Extranodular extension
The majority of the lesions located at the glans penis followed by shaft and prepuce at 64.1%, 17.9%, and 17.9%, respectively. The size of primary tumor was measured at 1–3 cm (56.4%), >3–6 cm (35.9%), and larger than 6 cm (7.7%).
32 (82.1%) patients underwent partial penectomy and 7 (17.9%) patients underwent total penectomy, which all of pathologic reports presented with squamous cell carcinoma. Tumor grading was reported that classify into well, moderated, and poorly differentiation at 41%, 53.8%, and 5.1%, respectively.
Correlation of inguinal lymph node metastasis
In a group of patients who underwent ILND (28 patients) found that 13 patients have inguinal lymph node involvement (46.4%). Inguinal lymph node involvement was associated with tumor grading (odds ratio [OR]: 2.92, confidence interval [CI]: 0.123–0.704), LVI (OR: 5.182, CI: 0.430–0.996), PNI (OR: 3.687, CI: 0.277–0.975), and fixation of inguinal node (OR: 2.463, CI: 0.078–1.195).
Patients with moderated and poorly differentiation of primary tumor were at 2.92-fold higher risk (OR: 2.92, CI: 0.123–0.704) for harboring inguinal lymph node metastasis than those with well differentiation (P = 0.007).
Patients with LVI were at 5.182-fold higher risk (OR: 5.182, CI: 0.430–0.996) for inguinal lymph node involvement than those who did not have this feature in pathologic reports (P < 0.001).
Patients with PNI were at 3.687-fold higher risk (OR: 3.687, CI: 0.277–0.975) for harboring inguinal lymph node involvement than those with no invasion to perineural areas in pathological examination (P = 0.001).
Fixed inguinal lymph node patients were at 2.463-fold higher risk (OR: 2.463, CI: 0.078–1.195) for harboring inguinal lymph node involvement than those with moveable inguinal lymph node (P = 0.029) [Table 3].
Table 3.
Correlation of inguinal lymph node metastasis
| Variables | Point with inguinal node metastasis, n (%) | Point without inguinal node metastasis, n (%) | P (95% CI) |
|---|---|---|---|
| Age, mean±SD | 66.77±14.07 | 58.60±14.33 | 0.141 (−0.023–0.004) |
| Characteristics of lesion | |||
| Fungating | 12 (42.8) | 14 (50) | 0.92 (−0.819–0.742) |
| Ulcerative | 1 (3.6) | 1 (3.6) | |
| Location | |||
| Prepuce | 6 (21.4) | 9 (32.1) | 0.76 (−0.341–0.252) |
| Glans | 6 (21.4) | 4 (14.4) | |
| Shaft | 1 (3.6) | 2 (7.1) | |
| Size (cm) | |||
| 1–3 | 3 (10.7) | 1 (3.6) | 0.065 (−0.02–0.614) |
| >3–6 | 9 (32.1) | 9 (32.1) | |
| >6 | 1 (3.6) | 5 (17.9) | |
| Primary treatment | |||
| Partial penectomy | 12 (42.8) | 10 (35.7) | 0.106 (−0.087–0.844) |
| Total penectomy | 1 (3.6) | 5 (17.9) | |
| Cell type | |||
| SCC | 13 (46.4) | 15 (53.6) | N/A |
| T staging | |||
| Ta | 0 | 0 | 0.092 (−0.32–0.025) |
| T1a | 1 (3.6) | 4 (14.4) | |
| T1b | 1 (3.6) | 1 (3.6) | |
| T2 | 3 (10.7) | 6 (21.4) | |
| T3 | 8 (28.3) | 4 (14.4) | |
| T4 | 0 | 0 | |
| Grading | |||
| Well differentiation | 2 (7.2) | 9 (32.1) | 0.007 (0.123–0.704) |
| Moderated differentiation | 9 (32.1) | 6 (21.4) | |
| Poorly differentiation | 2 (7.2) | 0 | |
| LVI | |||
| Yes | 11 (39.2) | 2 (7.2) | <0.001 (0.43–0.996) |
| No | 2 (7.2) | 13 (46.4) | |
| PNI | |||
| Yes | 8 (28.3) | 1 (3.8) | 0.001 (0.277–0.975) |
| No | 5 (17.9) | 14 (50) | |
| Inguinal lymph node status | |||
| Nonpalpable | 5 (17.8) | 8 (28.6) | 0.45 (−0.25–0.547) |
| Palpable | 8 (28.6) | 7 (25) | |
| Number of inguinal nodes | |||
| 1 | 2 (13.3) | 3 (20) | 0.291 (−0.488–0.158) |
| 2 | 1 (6.7) | 2 (13.3) | |
| ≥3 | 5 (33.4) | 2 (13.3) | |
| Side | |||
| Ipsilateral | 3 (20) | 4 (26.7) | 0.483 (−0.784–0.391) |
| Bilateral | 5 (33.3) | 3 (20) | |
| Fixation of inguinal node | |||
| Yes | 4 (26.6) | 7 (46.8) | 0.029 (0.078–1.195) |
| No | 4 (26.6) | 0 |
SCC: Squamous cell carcinoma, SD: Standard deviation, CI: Confidence interval, N/A: Not available, LVI: Lymphovascular invasion, PNI: Perineural invasion
Correlation of pelvic lymph node metastasis
Eight patients underwent PLND, and five patients had lymph node metastasis (62.5%). Pelvic lymph node involvement was associated with tumor grading (OR: 2.619, CI: 0.033–0.967). Patients with moderated and poorly differentiation were 2.619-fold higher risk grading (OR: 2.619, CI: 0.033–0.967) for harboring inguinal lymph node metastasis than those with well differentiation (P = 0.04) [Table 4].
Table 4.
Correlation of pelvic lymph node metastasis
| Variables | Point with pelvic node metastasis, n (%) | Point without pelvic node metastasis, n (%) | P (95% CI) |
|---|---|---|---|
| Age, mean±SD | 65.60±15.77 | 49.67±4.04 | 0.147 (−0.490–0.009) |
| Characteristics of lesion | |||
| Fungating | 4 (50) | 3 (37.5) | 0.482 (−1.827–0.97) |
| Ulcerative | 1 (12.5) | 0 | |
| Location | |||
| Prepuce | 2 (25) | 3 (37.5) | 0.16 (−0.947–0.197) |
| Glans | 2 (25) | 0 | |
| Shaft | 1 (12.5) | 0 | |
| Size (cm) | |||
| 1–3 | 1 (12.5) | 1 (12.5) | 1 (−0.684–0.684) |
| >3–6 | 3 (37.5) | 1 (12.5) | |
| >6 | 1 (12.5) | 1 (12.5) | |
| Primary treatment | |||
| Partial penectomy | 4 (50) | 2 (25) | 0.725 (−0.938–1.271) |
| Total penectomy | 1 (12.5) | 1 (12.5) | |
| T staging | |||
| Ta | 0 | 0 | 0.532 (−0.534–0.306) |
| T1a | 0 | 1 (12.5) | |
| T1b | 1 (12.5) | 0 | |
| T2 | 0 | 0 | |
| T3 | 4 (50) | 2 (25) | |
| T4 | 0 | 0 | |
| Grading | |||
| Well differentiation | 0 | 2 (25) | 0.04 (0.033–0.967) |
| Moderated differentiation | 3 (37.5) | 1 (12.5) | |
| Poorly differentiation | 2 (25) | 0 | |
| LVI | |||
| Yes | 5 (62.5) | 2 (25) | 0.22 (−0.562–1.991) |
| No | 0 | 1 (12.5) | |
| PNI | |||
| Yes | 4 (50) | 1 (12.5) | 0.244 (−0.417–1.35) |
| No | 1 (12.5) | 2 (25) | |
| Inguinal lymph node status | |||
| Nonpalpable | 3 (37.5) | 2 (25) | 0.875 (−0.93–1.063) |
| Palpable | 2 (25) | 1 (12.5) | |
| Number of inguinal nodes | |||
| 1 | 0 | 1 (33.3) | N/A |
| 2 | 0 | 0 | |
| ≥3 | 2 (66.7) | 0 | |
| Side | |||
| Ipsilateral | 0 | 1 (33.3) | N/A |
| Bilateral | 2 (66.7) | 0 | |
| Fixation of inguinal node | |||
| Yes | 2 (66.7) | 1 (33.3) | N/A |
| No | 0 | 0 | |
| ENE | |||
| Yes | 3 (42.8) | 2 (28.6) | 0.374 (−1.454–0.654) |
| No | 2 (28.6) | 0 |
SD: Standard deviation, CI: Confidence interval, N/A: Not available, LVI: Lymphovascular invasion, PNI: Perineural invasion, ENE: Extranodular extension
DISCUSSION
Inguinal and pelvic lymph node involvement is a well-known prognostic factor in patients with penile cancer. Clinical evaluation of the inguinal region is often inaccurate with a false-negative rate of 20%–39%.[8-11] Furthermore, a pathologic report has shown no tumor in 40%–50% of patients with inguinal lymph node enlargement from physical examination. There are no reliable diagnostic methods to complement the clinical evaluation.
Several prognostic factors have been evaluated as predictive factors for occult metastasis in inguinal lymph nodes such as tumor grade, stage, presence of LVI, PNI, clinically palpable inguinal lymph node, and fixation of inguinal lymph node.
Our study shows that four parameters (tumor grade, LVI, PNI, and fixation of inguinal node) are independently associated with the presence of inguinal lymph node involvement by cancer.
Specifically, tumor grade is related to the incidence of positive inguinal lymph nodes . Patients with Grade 1 (well differentiation) have lower incidence of inguinal node metastasis compared to patients with Grade 2–3 tumor (moderated and poorly differentiation) (12.5%, 42.8%, and 100%, respectively). Furthermore, Fraley et al. noted a 4% lymph node metastasis in Grade 1 tumors and 88.6% in Grades 2–3 tumors. Horenblas et al. reported that the rate of positive lymph nodes was 17% for Grades 1–2 and 64% for Grade 3 primary tumors. Theodorescu et al. observed lymph node involvement in 66.7% of all patients and increasing to 80.8% with disease that has higher grade than Grade 1.
Vascular invasion by cancerous cells was a significant prognostic factor in the studies by Slaton et al. and Lopes et al. In the large multi-institutional study by Ficarra et al.[12], venous and lymphatic invasion were independent predictors of lymph node metastasis on multivariate analysis. In our study, LVI and PNI correlated with inguinal lymph node metastasis and proved to be an independent predictive variable of inguinal lymph node involvement. LVI and PNI should be considered an important parameter for determining which patients with negative lymph nodes on physical examination should undergo inguinal lymphadenectomy.
Approximately 50% of the inguinal lymph nodes considered clinically positive for metastasis have no metastasis from pathological examination. Clinically, palpable inguinal lymph node can be explained by inflammatory process and consequently a greater number of false-positive results. Only fixed node status was a significant prognostic factor in our study.
About 20%–25% of patients with inguinal lymph node involvement from penile cancer have pelvic lymph node involvement. This proportion is not negligible, but it indicates that most patients with inguinal lymph node involvement may be spared pelvic lymph node surgery. Pelvic lymph node involvement is a well-known prognostic factor in patients with penile cancer. Historical reports of sparse data indicate only 10% 5-year survival. Two more recent series described no survivors of 21 patients at 5 years and a 16% rate of long-term survival in 25 patients with pelvic lymph node metastasis.[13-15]
Several prognostic factors have been evaluated as predictive factors for pelvic lymph node metastasis, such as inguinal metastases of more than 3 nodes, a pathologic lymph node >30 mm, and extranodular extension. Our study has a limitation due to the low number of pelvic lymph node metastases but shows that tumor grading is independently associated with the presence of inguinal lymph node metastasis.
CONCLUSION
Grading, LVI, PNI, and fixation of inguinal node are significantly associated with inguinal lymph node metastasis.
While grading of primary tumor is significantly associated with pelvic lymph node metastasis.
These factors are associated with poorer prognosis and should be considered in predicting inguinal and pelvic lymph node involvement.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
Acknowledgment
I would like to extend my appreciation to my advisor Col. Asst. Prof. Satit Siriboonrid, M.D., for his guidance and time in making this research a possibility.
Second, I would also like to express my sincerest gratitude to my family who has always been the most important support in any of my achievements.
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