Penile cancer is the most common malignant tumor of the male reproductive system. There are significant differences in the incidence of penile cancer due to differences in countries, regions, ethnicities, religions and hygiene practices. In western countries penile cancer is relatively rare. In China, it once ranked first in the incidence rate of male genital tumors in China. In recent years, with the improvement of people’s living standard and medical and health conditions, the incidence rate has been decreasing year by year. Its incidence rate is decreasing year by year. However, it is still an important disease that endangers men’s health.
Epidemiology
Penile cancer mainly occurs in older men, the average age of patients is 60 years old, the older the patient is, the higher the possibility of incidence, and the incidence rate reaches the highest at about 70 years old. The disease also occasionally occurs in younger men.
Penile cancer often occurs in men who are not circumcised in time after birth, and is extremely rare in those who are routinely circumcised as newborns or in childhood. Even in countries with a high incidence of penile cancer, such as Nigeria and India, where some of the inhabitants are circumcised after birth due to religious beliefs, there are almost no penile cancers among men in these populations.
Causes
Some of the more recognized risk factors for penile cancer include poor hygiene practices, circumcision, prepuce and circumcision. In addition, many penile lesions may be associated with the development of penile cancer, such as penile leukoplakia. Inflammation may play an important role in the development and progression of tumors, as many penile cancers originate at the site of penile infection, chronic irritation or trauma.
Thorough circumcision can prevent most of these pathological states. This is because circumcision often leads to prolonged retention of foreskin and normally shed epithelial cells, and further leads to chronic irritation of the foreskin and glans with or without bacterial infection. A high percentage of penile cancer patients are circumcised, and circumcision is an important cause of penile cancer.
Other risk factors for penile cancer include multiple sexual partners, genital warts, or other sexually transmitted diseases. At least some of these risk factors are associated with infection with human papillomavirus (HPV).
Disease Classification
Almost 95% of penile cancers are squamous cell carcinomas, while others include basal carcinomas, verrucous carcinomas, verrucous carcinomas, and others. In principle, penile cancer can occur in any part of the penis, but clinically it is common in the epithelial tissue of the glans, coronal sulcus or foreskin, while only less than 5% of patients develop it in the body of the penis.
Penile cancer can progress from precancerous lesions of the penis. Human papillomavirus (HPV) infection can be detected in some patients. HPV-associated lesions include giant condyloma acuminata, Bowen-like papules, Bowen’s disease, and erythroplasia, while chronic inflammatory-associated lesions include genital sclerosing moss, dry occlusive glans, penile horns, mucocutaneous leukoplakia, and pseudoepitheliomatous keratosis fragilis.
Clinical Presentation
Initially, penile cancer usually presents as a small, hard-to-heal lesion at the glans penis. The exact appearance is variable and can range from a flat, hard type to a large, exophytic growth. This tumor occurs primarily in uncircumcised men, with approximately half of the tumors located on the glans, 20% on the prepuce, 20% on both the glans and the prepuce, and the remainder on the body of the penis. Sometimes there are multiple lesions.
There is often a significant delay, ranging from 8 months to 1 year, from the time the patient first identifies the lesion to the time he or she seeks treatment. The delay may be due to the patient’s reluctance to seek treatment, incorrect diagnosis, or the patient’s lack of concern for small lesions. Penile lesions may be misdiagnosed as infections and receive inappropriate treatment until a correct diagnosis is made. And because penile cancer often occurs in uncircumcised men, it is sometimes not detected until the primary lesion invades the penile foreskin or causes a foul odor due to a concomitant infection. Many patients also have difficulty performing an examination of the glans due to circumcision. This lesion generally causes little pain, even after extensive tissue destruction. The tumor may initially present as a blood-filled patch at the glans. Erythematous rash-like changes in the glans and biopsy confirmation of carcinoma in situ are also known as erythema multiforme. The lesion may also appear as a long-lasting ulcer on the foreskin. As the tumor progresses, ulcerative growth patterns can be seen and erode and destroy the surrounding normal tissue. These lesions often become infected and produce numerous foul-smelling pus.
Diagnostic Differentiation
Differential Diagnosis
Many benign lesions should be considered. These include condyloma acuminata, mucocutaneous leukoplakia, and dry occlusive glans (BXO). Mucocutaneous leukoplakia and dry occlusive glans will present with white spots and plaques. Condyloma acuminatum is a sexually transmitted disease such as genital warts as we know them, which are mostly cauliflower-like and often appear in multiple areas of the penis rather than just at the glans. Dry occlusive glans is associated with the urethra and these patients usually require long-term follow-up to prevent the development of urethral strictures. Dry occlusive glans is also considered precancerous, so patients need to be followed closely.
Biopsy remains the standard diagnostic tool for squamous cell carcinoma of the penis. Excisional biopsy can be considered for smaller, limited lesions. A negative surgical margin of deep tissue after excision is required in these patients. Biopsy provides useful information for grading and histologic classification of the disease. For small lesions, the depth of invasion may also be confirmed by biopsy. Larger lesions may be more easily determined by physical examination and imaging to determine the extent of infiltration. The combination of these fragmentary pieces of information can be useful for proper disease staging and for determining the likelihood of microscopic metastases in the absence of obvious clinical signs of tumor metastasis (i.e., palpation of metastatic lymph nodes).
Squamous carcinoma of the penis spreads primarily via the lymphatic drainage route, and this spread progresses progressively along a predictable chain of inguinal lymph nodes. Therefore, assessing the status of these lymph nodes not only helps in the staging of penile cancer, but can also determine the best treatment options. The current challenge is that many patients have inguinal lymph node enlargement that may not be related to metastasis, but rather reactive and inflammatory enlargement. Our current experience is to re-evaluate the patient’s lymph nodes after the primary site has been treated and the wound has healed for 4-6 weeks.
Both CT and MRI are viable imaging modalities to evaluate enlarged lymph nodes. The criteria for determining metastasis by both methods are defined as a lesion larger than 1 cm. This dictates that these two tools are unable to diagnose early microscopic lymph node metastases. The sensitivity of determining metastases based on size is 40-60%, while the specificity is much better, approaching 100%. Some studies using positron emission computed tomography (PET/CT) for diagnosis show a promising sensitivity that can be increased to 88%. However, PET/CT also has limitations for lymph nodes smaller than 7 mm.
Clinical staging
Clinical staging of penile cancer is important for the selection of surgical approach and prognosis assessment, therefore, accurate clinical staging of penile cancer patients is required before surgery. Currently, the commonly used clinical staging is the TNM staging (2002) of the International Anti-Cancer Society (UICC).
TNM staging of penile cancer (2002)
Table 3-1 1997/2002 AJCC TNM staging system for penile cancer:
Primary tumor (T)
TX: Primary tumor could not be evaluated
T0: No primary tumor found
Tis: Carcinoma in situ
Ta papillary non-invasive carcinoma
T1: Tumor invades subepithelial connective tissue
T2: Tumor invades the corpus cavernosum of the penis or the urethral surface
T3: Tumor invades urethra or prostate
T4: Tumor invades other adjacent structures
Clinical staging of regional lymph nodes (cN)
cNX: Local lymph nodes cannot be evaluated
cN0: No local lymph node metastasis detected
cN1: single superficial inguinal lymph node metastasis
cN2: Multiple or bilateral superficial inguinal lymph node metastases
cN3: Deep inguinal or pelvic lymph node metastasis, unilateral or bilateral
Regional lymph node pathological staging (pN)
pNX: Local lymph nodes cannot be evaluated
pN0: No local lymph node metastasis found
pN1: single superficial inguinal lymph node metastasis
pN2: Multiple or bilateral superficial inguinal lymph node metastases
pN3: Deep inguinal or pelvic lymph node metastasis, unilateral or bilateral
Distant metastases (M)
MX: distant metastases cannot be assessed
M0: No distant metastases
M1: with distant metastases [3][4][1]
Disease treatment
The treatment of penile cancer is mainly based on surgery, which can be combined with radiotherapy, chemotherapy and laser therapy.
According to the tumor site and stage, different surgical methods are chosen clinically. For small superficial tumors, local excision and circumcision can be adopted, especially for young patients, this treatment can not only effectively control the lesion but also preserve the physiological function of the penis. In cases where the cancer is large or invades the cavernous body, partial or total penile excision is required.
For patients with inguinal enlarged lymph node biopsy or inguinal anterior lymph node suggesting lymph node metastasis, inguinal lymph node dissection should be performed. For patients with fixed inguinal lymph nodes: neoadjuvant therapy may be considered before surgery.
Disease prevention
Circumcision
Circumcision during neonatal period is an effective measure to prevent penile cancer. This is because, firstly, circumcision is likely to lead to long-term retention of foreskin scale. According to statistics, men who are circumcised rarely suffer from penile cancer. In addition, circumcision is a very effective treatment for circumcised patients, but penile cancer may recur in the scar after circumcision. Whether circumcision in the elderly can have preventive effect is still inconclusive. Third, male circumcision will help reduce the risk of human papilloma virus infection.
HPV vaccine
To date, two vaccines against HPV registered by the European Medicines Evaluation Agency (EMEA) and the US FDA. Both vaccines were found to be highly effective in preventing long-term HPV infection or incidental high-grade cervical lesions in a population of women who tested negative for HPV. The HPV vaccine for men has been marketed in some countries after clinical trials demonstrated the safety and efficacy of the vaccine. We speculate that the HPV vaccine may also prevent HPV-positive penile cancer, but the true effectiveness needs to be verified in future clinical trials.
Condom use
Although not 100% effective, the role of condom use in the prevention and treatment of sexually transmitted diseases is extremely clear. A related clinical study is underway in which condoms were given randomly between sexual partners and found that the time to cure of HPV-associated genital lesions was significantly shorter in the condom-use group.
Smoking cessation
Although the specific role of smoking in the development of penile cancer is unclear, there is no doubt that smoking is a risk factor for penile cancer. Smokers are much more likely to develop penile cancer than nonsmokers; therefore, active smoking cessation campaigns are one of the measures to prevent penile cancer.
Other measures
Other preventive measures include prevention of circumcision, treatment of chronic inflammatory diseases of genitalia, and improvement of hygiene, etc.
Prognosis of the disease
Penile cancer is one of the solid tumors that can be cured with high rate through surgical treatment. After partial or total penile excision, the local recurrence rate of penile cancer is less than 10%, while the recurrence rate of conservative treatment is 50%. The postoperative survival rate of patients with single lymph node metastasis is close to 80%, while the survival rate of patients with multiple lymph node metastasis or extra-lymph node dissemination decreases to less than 30%.
Postoperative follow-up
Follow-up is every 3 months for the first 2 years, every 6 months for 2-5 years, and annually for life after 5 years.