I. Epidemiology and risk factors
Most penile cancers are squamous cell carcinomas (SCC), while other types are rare. Penile cancer usually occurs in the inner foreskin plate and the head of the penis, and has various histological subtypes, which are pathologically similar to squamous cell carcinoma of other tissue sources.
The incidence of penile cancer in Europe and North America is low (<1 per 100,000) and increases with age. The peak age of onset is 60 years, but it also occurs in younger men. In parts of South America, Southeast Asia, and Africa, the incidence of penile cancer is high, accounting for 1 to 2 percent of malignancies in men.
In the United States, the total age-adjusted incidence rate decreased from 0.84 per 100,000 in 1973 to 0.58 per 100,000 in 2002. There are racial differences in the incidence of penile cancer, with Hispanic Americans having the highest rates. Incidence rates in Europe have been relatively flat, but have increased in Denmark and the United Kingdom.
Penile cancer incidence is higher in areas where human papillomavirus (HPV) is endemic. This phenomenon suggests that HPV may be responsible for this geographic disparity. One-third of the cases were attributed to HPV-related carcinogenic effects. HPV DNA was detected in penile cancer tissue in 30-40% of cases and varied among histologic subtypes: basal cell-like squamous cell carcinoma (76% positive), mixed verrucous-basal cell-like subtype squamous cell carcinoma (82% positive), and verrucous carcinoma (39% positive).
HPV may be a common oncogenic factor for some penile squamous cell carcinoma subtypes. The most common types of HPV in penile squamous cell carcinoma are HPV 16 (72%), HPV 6 (9%), and HPV 18 (6%). Patients with condyloma acuminatum had a higher risk of penile cancer. HPV-positive versus HPV-negative cases showed a higher tumor-specific survival rate (93% vs. 78%), but the results were inconsistent: penile cancer incidence was not significantly associated with cervical cancer.
Circumcision was significantly associated with penile cancer incidence (odds ratio [OR]: 11.4), while circumcision was not a carcinogenic factor. Other epidemiological risk factors included smoking (4.5-fold increased risk), low educational level, and poor socioeconomic status. The incidence of sclerosing moss (dry occlusive glans) was relatively high in cases of penile cancer, but was not associated with unfavorable factors Neonatal circumcision reduced the incidence of penile cancer, whereas adult circumcision did not. The lowest incidence of penile cancer has been reported in Israeli Jews (0.3/100,000). Circumcision can remove 50% of the tissue from which penile cancer originates. The protective effect of neonatal circumcision (OR: 0.41) was not effective for carcinoma in situ (CIS; OR: 1.0) and was weaker in otherwise uncircumcised men (OR: 0.79).
II. Pathology and grading
It remains unknown how many precancerous lesions of the penis transform into squamous cell carcinoma (Table 1).
Table 1- Penile cancer precancerous lesions associated with penile SCC episodic lesions・Penile skin angle・Bowen-like papulosis・Sclerosing moss (occlusive dry glans) precancerous lesions (more than 1/3 transformed into invasive SCC)・Epithelial sarcomatoid lesions grade 3・Giant acromegaly ((Buschke-Lowenstein tumor)・Kela proliferative erythema・Bowen’s disease・Peget’s disease different The histological types have different growth patterns, clinical invasiveness, and HPV associations and have been differentiated (Tables 1 and 2). A large number of mixed types exist as well.
Table 2: Histologic subtypes, frequency and prognosis of penile cancer
Subtype frequency (%) Prognosis unusual SCC48-65 based on tumor location, stage, and grade basal cell-like carcinoma4-10 poor prognosis, frequent early inguinal lymphatic metastases warty carcinoma7-10 good prognosis, metastatic rare warty carcinoma3-8 good prognosis, nonmetastatic papillary carcinoma5-15 good prognosis, metastatic rare carcinosarcoma1-3 very poor prognosis, early vascular metastases mixed carcinoma9-10 Heterogeneous group of pseudoproliferative carcinoma <1< td="">palpable, associated with sclerosing moss, metastasis not reported tunneling type carcinoma <1 verrucous carcinoma variant with good prognosis, metastasis not reported pseudoglandular ductal type carcinoma <1
Highly graded tumor, early metastasis, poor prognosis mixed verrucous-basal cell carcinoma9-14 poor prognosis, high potential for metastasis (higher than verrucous-like carcinoma, lower than basal cell-like carcinoma) adenosquamous carcinoma <1< td="">highly graded tumor, high potential for metastasis but low mortality mucinous epidermal-like carcinoma <1< td="">highly invasive, poor prognosis penile carcinoma clear cell type1-2 extremely rare, associated with HPV associated with HPV, invasive, early metastasis, poor prognosis, frequent lymphatic metastasis TNM staging divided T1 into two groups based on the degree of lymphovascular infiltration and grading (Table 3). Lymph node metastases extending outside the capsule were classified as pN3. retroperitoneal lymph node metastases were classified as extra-organ distant metastases.
Table 3: Penile cancer staging Primary tumor (T) TX Primary tumor could not be assessed T0 No primary tumor found Tis carcinoma in situ Ta Non-invasive carcinoma T1 Tumor invading subcutaneous connective tissue T1a Invading subcutaneous connective tissue without lymphovascular infiltration and non-differentiated poorly or undifferentiated (T1G1-2) T1b Invading subcutaneous connective tissue combined with lymphovascular infiltration and poorly differentiated or undifferentiated ( T1G3-4)T2 tumor invasion of the corpus cavernosumT3 tumor invasion of the urethraT4 tumor invasion of adjacent tissuesLocal lymph nodes (N)NX local lymph nodes could not be assessedN0 no local lymph node metastasis was foundN1 single local lymph node metastasisN2 multiple or bilateral superficial inguinal lymph node metastasisN3 unilateral or bilateral deep inguinal or pelvic lymph node metastasisDistant metastasis (M)M0 no distant metastasisM1 distant Metastatic pathological staging pT classification was consistent with clinical T classification.
pN classification based on biopsy or surgical removal of local lymph nodes (pN) pNX local lymph nodes cannot be assessed pN0 no local lymph node metastasis pN1 single inguinal lymph node metastasis pN2 multiple or bilateral inguinal lymph node metastasis pN3 pelvic lymph node metastasis, unilateral or bilateral or extra-lymph node metastasis distant metastasis (pM) pM0 no distant metastasis pM1 distant metastasis histopathologic grading (G ) GX differentiation grading cannot be assessed G1 well differentiated G2 moderately differentiated G3-4 poorly differentiated or undifferentiated
Despite differences in local recurrence (35% vs 17%) and mortality (30% vs 21%) for invasion of the urethral corpus cavernosum and penile corpus cavernosum, both were pT2. There was no significant difference in long-term survival between T2 and T3 stage, N1 and N2 stage tumors. In addition, the prognosis was not worse for tumors with pT3 invasion of the distal urethra.
Biopsy and histology
The diagnosis of penile cancer is often unquestionable, but histological confirmation is necessary in difficult cases or when non-radical treatment is performed. All small lesions need to be removed, and at least 3 to 4 large lesions need to be removed, and all lymph nodes and surgical margins need to be sampled. The pathology report must include histologic staging, staging, perineural and vascular invasion, and surgical margins.
The average biopsy sample size is 0.1 cm, and it is difficult to assess the depth of invasion in 91% of cases. Although needle biopsy tissue is adequate, excisional biopsy is recommended. The extent of the surgical margin depends on the tumor grade and risk assessment, and the absence of tumor within 5 mm of the margin is considered adequate.
Prognostic factors
The degree of perineural and lymphatic invasion and pathological grade are all prognostic factors for penile cancer. The tumor grade is highly dependent on the observer. Some penile cancers have good prognosis, such as verrucous, papillary, verrucous, pseudoproliferative and tunnel type cancers. These types of penile cancers cause local damage but rarely metastasize. High-risk penile cancers are basal cell-like, sarcomatoid, adenosquamous, and hypofractionated types, which can metastasize early. Intermediate-risk penile cancers include common squamous carcinoma, mixed type and pleomorphic verrucous carcinoma. Penile cancer confined to the foreskin has a better prognosis.
V. Molecular biology
Few data link chromosomal aberrations to the biological behavior of penile squamous cell carcinoma. DNA copy number alterations in penile squamous carcinoma are similar to those in other tissue squamous carcinomas. Low copy number changes are associated with low survival rates. Genetic alterations located at the 8q24 locus play an important role.
Epigenetic alterations due to CDKN2A methylation on CpG island, which encodes two tumor suppressor proteins (p16INK4A and p14ARF), have been identified. 62% of invasive penile cancers have deletion of the p16 allele, an alteration associated with lymph node metastasis and prognosis; deletion of the p53 allele is seen in 42% of invasive penile cancer cases and suggests poor prognosis.
Diagnosis and staging
Physical examination includes palpation of the penis and groin area. Ultrasound or magnetic resonance imaging (MRI) under artificial erection can provide information on the extent of tumor infiltration. The clinical manifestations of penile cancer are often obvious but may be masked by encopresis.
The likelihood of micrometastases in normal inguinal lymph nodes is approximately 25%. Current imaging techniques have low confidence in detecting such micrometastases. Ultrasound (7.5 MHz), CT, MRI and 18F-fluorodeoxyglucose PET-CT imaging (18F-FDG-PET/CT) do not accurately detect such occult metastases, with the only exception being in obese patients with no positive findings on palpation.
Diagnostic treatment of normal inguinal lymph nodes needs to be based on pathologic risk factors, including lymphovascular infiltration, staging and grading, and columnar maps are not reliable. For patients with intermediate or high risk of lymphatic metastasis, the stage of lymphatic infiltration needs to be clarified.
In patients with large inguinal lymph nodes, the likelihood of lymphatic metastasis is high. The number of lymph nodes should be noted on physical examination regardless of whether they are mobile or not. Staging of pelvic lymph nodes and systemic disease is determined by abdominopelvic CT and chest X-ray or CT. For palpable inguinal lymph nodes, 18F-FDG-PET/CT can confirm the presence or absence of metastasis.
No tumor markers are available for penile cancer. SCC antigen is increased in less than 25% of cases and does not predict the development of metastatic disease, but may indicate tumor-free survival in lymph node positive patients.
VII. Treatment of primary tumor
The goal of treatment is to completely remove tumor tissue and preserve as many organs as possible. Its local recurrence has almost no effect on long-term survival, so the organ preservation approach is reasonable.
Controlled clinical trials of different therapies are still lacking and the overall level of available evidence is low. The penis preservation approach is better in terms of preserving function and aesthetics. When non-surgical treatment is considered, local staging with a histological diagnosis is mandatory.
In treatment, the primary tumor and local lymph nodes are important for surgical staging.
7.1 Treatment of epidermal non-invasive carcinoma
For carcinoma in situ, local chemotherapy with imiquimod or 5-fluorouracil (5-FU) is preferred; this therapy has low toxicity and a high complete response rate of 57%. Close follow-up is required and chemotherapy cannot be repeated in case of treatment failure. Other therapies include laser treatment, complete or partial glans epidermal reconstruction (complete removal of the cephalic epidermis with bladed thick skin grafts). 20% of cases have aggressive tumors, so histological confirmation is required.
For low-grade invasive damage (Ta/T1a), preservation of the penis is recommended. For tumors confined to the foreskin, only circumcision is required. Intraoperative frozen section pathology of the cut edge is recommended. For smaller penile cancers, foreskin and head excision has the lowest local recurrence rate (2%) of all approaches, and a negative margin within 5 mm is considered adequate.
The choice of treatment is based on tumor size, histology, staging, location relative to the urethral orifice, and patient preference. Laser therapy can be performed with neodymium-doped-yttrium aluminum garnet laser (Nd:YAG) or carbon dioxide laser, which can enhance tumor visibility through photodynamic diagnosis. The local recurrence rate for CIS/T1 with CO2 laser is 14-23% and for Nd:YAG laser is 10-48%. The local recurrence rate is 0-6% for complete or partial epidermal reconstruction of the penile head and 7-8% for penile head excision.
There is insufficient evidence as to whether the prognosis of different procedures for penile preservation differs. Treatment of organ preservation, including reconstructive surgery, may improve quality of life but has a higher risk of recurrence than partial penectomy (5-12% vs 5%). Local recurrence of organ-preserving surgery has only a small impact on long-term survival.
7.2 Radiotherapy for stage T1/T2
For stage T1-2 tumors <4 cm in diameter, external radiation radiotherapy given in combination with brachytherapy or brachytherapy alone is more effective. The local control rate of brachytherapy is
70-90%. Although the local recurrence rate is higher than that of partial penectomy, recurrence can be controlled by remedial surgery. Complications are more common, with urethral stricture in 20-35% of cases and 10-20%
The head of the penis is necrotic; metal-induced strictures occur in more than 40% of brachytherapy applications.
7.3 Local lymph node dissection
Local lymph node dissection determines the long-term survival of the patient. Local lymph node metastases can be cured. Radical inguinal lymph node dissection (ILND) may be one of the treatment options, but multimodal chemotherapy is commonly used.
Lymphatic spread of any primary penile cancer can be unilateral or bilateral. It spreads first to superficial and deep inguinal lymph node groups, with the superior and intermediate sites being most frequently involved. Next, it spreads to the ipsilateral pelvic lymph nodes. No cross metastatic spread has been reported, and pelvic lymph nodes are unaffected in the absence of ipsilateral inguinal lymph node invasion. Invasion of the para-abdominal aortic and para-ventricular lymph nodes is indicative of systemic metastasis.
Patients with negative lymph nodes who underwent prophylactic ILND had a higher survival rate compared to those who underwent curative ILND for local tumor recurrence (>90%, <40%, respectively). Comparing the results of treating lymph node-negative patients with ILND with inguinal zone radiation and conservative therapy, respectively, the highest overall survival rates were found for surgical treatment (74%, 66%, 63%, respectively). Because 25% of patients had occult metastases, conservative treatment of clinically normal lymph nodes carries a risk of recurrence.
Normal lymph node dissection is based on pathologic staging and the presence of lymphovascular infiltration. pTa/pTis stage and low-grade cancers are at low risk of metastasis. In contrast, well-differentiated pT1 has a moderate risk. pT2 or higher and all G3 stage cancers are at high risk. Therefore, conservative treatment is only indicated for patients with low-risk penile cancer and normal lymph nodes. Needle aspiration cytology results are unreliable except for occult metastases.
For patients at intermediate to high risk with hard-to-reach lymph nodes, two invasive diagnostic methods are available: modified ILND and dynamic sentinel lymph node biopsy (DSNB). DSNB is based on the hypothesis that penile lymphatic drainage always introduces an inguinal lymph node that is anatomically separate from the others. In 97% of cases, the sentinel lymph node can be detected by injecting technetium 99-labeled colloid or a gamma probe into the tumor area. A high sensitivity of 90-94% has been reported for this method. In a mixed Meta-analysis of 18 studies, the sensitivity was 88% with this method alone and 90% with the addition of patent blue.
Both methods can miss occult metastatic cancer. Even in experienced medical centers, the DSNB false-negative rate can be as high as 12-15%, while the modified ILND false-negative rate is not known. The detection of lymphatic metastases by either method requires ipsilateral radical ILND.
Palpable inguinal lymph nodes (cN1/cN2) are at high risk for metastasis. Instead of prophylactic antibiotics, ultrasound-guided needle aspiration cytology should be performed. It is also helpful to stage the pelvic lymph nodes. In patients with positive lymph nodes, 18F-FDG-PET/CT can identify tumor metastases. In patients with enlarged lymph nodes, dynamic anterior lymph node biopsy is unreliable and should not be used.
Patients with positive lymph nodes should undergo radical ILND, which has a high incidence of lymphatic drainage and wound healing complications. The incidence is as high as 50% and the high body mass index is an important risk factor, with recent reports showing a complication rate of approximately 25%. Radical ILND treatment is effective, but the high incidence of complications may lead to a decrease in its use. Lymph node density size can be a predictor of complications. Surgical manipulation of tissue resection and lymphatic vessel dissection requires caution.
Lymphatic vessel truncation cannot be performed using electrofusion and should be performed as a ligation or using a clip. In addition, such as pressure bandaging of the inguinal region, vacuum suction and the use of prophylactic antibiotics may reduce the incidence of postoperative complications. The most common complications reported were wound infection (1.2-1.4%), flap necrosis (0.6-4.7%), lymphedema (5-13.9%) and lymphoid cyst formation (2.1-4%). The use of laparoscopic and robot-assisted ILND has been reported, but whether it is better is unclear. The finding of two or more positive lymph nodes or one extracapsularly extended lymph node (pN3) requires ipsilateral pelvic lymph node dissection.
Pelvic lymph nodes are positive in 23% of cases with more than 2 positive inguinal lymph nodes and in 56% of cases with 3 positive inguinal lymph nodes or extracapsular metastases.
If the pelvic lymph nodes are positive, the prognosis is worse than that of inguinal lymph node metastasis alone (5-year tumor-specific survival rates of 71.0% and 33.2%, respectively), and pelvic lymph node dissection may be performed concurrently or later. If surgery is decided, unnecessary waiting time should be avoided if possible.
In patients with stage pN2/pN3, adjuvant chemotherapy is recommended. This conclusion is based on a retrospective study that showed a higher survival rate with adjuvant chemotherapy than with historical controls without adjuvant chemotherapy (84% vs. 39%).
The presence of large, fixed inguinal lymph nodes leaves no doubt that metastases are present, and a concomitant biopsy for histological confirmation is not necessary. Suspected cases require excisional biopsy or central puncture biopsy. The prognosis for these patients is poor and a cure is difficult to achieve. Direct surgery is not recommended. Radical ILND after neoadjuvant chemotherapy is recommended and has a long-term survival rate of 37%.
7.4 Management of lymph node recurrence
Treatment of local recurrence is the same as primary cN1/cN2 stage cancer. Patients with this type of local recurrence and non-invasive stage have a disturbed lymphatic structure and are at high risk of irregular metastasis. The prognosis is poor if inguinal lymph nodes recur after curative radical ILND, with a 5-year survival rate of 16%. There is no optimal therapy and new adjuvant chemotherapy and radical lymph node dissection are still recommended.
7.4.1 Radiotherapy for lymph node metastases
Radiotherapy for inguinal lymph node metastases is not recommended due to the lack of reliable evidence. No oncologic improvement has been reported with adjuvant radiotherapy or neoadjuvant radiotherapy in patients with positive lymph nodes. A prospective trial comparing inguinal radiotherapy with radical ILND showed that surgery was more effective. Another retrospective case study showed that adjuvant chemotherapy was superior to adjuvant radiotherapy in lymph node-positive patients.
An analysis of epidemiologic testing and final results including 2458 patients showed that adjuvant radiotherapy was not considered to improve tumor-specific survival, either with surgical treatment alone or with surgery combined with radiotherapy. Adjuvant radiotherapy to the groin may be an option for palliative treatment in cases where surgical resection is not possible.
7.4.2 Chemotherapy
Adjuvant chemotherapy for lymph node metastases may improve survival. If it is a curative measure, a drug triple therapy including cisplatin needs to be applied. Vincristine, bleomycin and methotrexate (VBM therapy) can be used, while cisplatin and 5-FU can be used with similar efficacy and lower toxicity.
Paclitaxel-based therapies (cisplatin, 5-FU in combination with paclitaxel and doxorubicin) have resulted in tumor-free survival rates of up to 52%, as have paclitaxel-cisplatin regimens. There is no evidence to support the use of adjuvant chemotherapy in the pN1 phase, and its use is limited to clinical trials.
Novel adjuvant therapy for larger inguinal lymph nodes (cN3) is recommended as a triple combination therapy including cisplatin and paclitaxel. Its median survival time has been reported to be 17 months.
In cases with progressive tumors, the presence of visceral tumor metastases and a systemic functional status score ≥1, as proposed by the Eastern U.S. Oncology Collaborative Group, were independent prognostic factors. Cisplatin-based therapies had better efficacy than cisplatin-free therapies and were enhanced by paclitaxel analogs. Only one report suggested that a second-line regimen with a single application of paclitaxel resulted in a 30% response rate rather than a survival rate.
The epidermal growth factor receptor (EGFR) is expressed in almost all penile SCC, and anti-EGFR-targeted therapy with pamucizumab and cetuximab has been successful. The same results have been achieved with tyrosine and enzyme inhibitors.
7.5 Follow-up
Seventy-four percent of relapses frequently occurred within two years of initial treatment, as did 66% of local relapses, 86% of local relapses, and 100% of distant relapses. Overall, 92.2% of recurrences occurred within the first 5 years of treatment, with local recurrences or new primary foci after 5 years.
Close follow-up within the first two years of treatment is essential and should be followed for at least another five years. Follow-up should also continue thereafter, but may be waived for patients who have frequent physical examinations.
In patients with negative lymph nodes, follow-up should include penile and inguinal physical examinations; imaging is not indicated. After laser treatment or local chemotherapy, histologic results need to be obtained to determine anaplastic status. Patients with therapeutic inguinal lymph node metastases require CT or MRI every 3 months for 2 years after surgery.
7.5.1 Recurrence
Organ-preserving surgery is more likely to result in local recurrence, and the recurrence rate is as high as 27% at 2 years postoperatively. Partial penectomy has a local recurrence rate of 4-5%. Patients should be educated to have frequent physical examinations.
Conservative treatment has the highest rate of local recurrence (9%) and the lowest rate in cases with lymph node invasion but negative lymph nodes (2.3%). The application of ultrasound and needle aspiration cytology in doubtful cases may improve the early detection of local recurrence. For cases with positive lymph nodes applying ILND and no adjuvant therapy, the local recurrence rate was 19%.
7.6 Quality of life
Sexual dysfunction, urinary problems and aesthetic problems are all post-treatment challenges for patients with long-term viability. One of the studies on the results of laser treatment showed a significant reduction in sexual behavior but a generally satisfactory quality of life; another reported that no patients reported erectile or sexual dysfunction.
After phallopexy, 79% of patients reported no difference in spontaneous erection, hardness, or ability to penetrate. After partial phallopexy, 55.6% of patients had fair erectile function during intercourse, but decreased satisfaction. After total or partial penectomy, complete penile reconstruction is feasible in some cases.
VIII. Conclusion
About 80% of penile cancers can be cured. Partial penectomy has a negative impact on patients’ self-esteem and sexual function. With advances in treatment, organ preservation options have been recognized for their advantages in improving quality of life and sexual function. If conditions allow, organ preservation options should be recommended. Referral to an experienced treatment center is recommended and psychological support for the patient is important.