Рак полового члена – редкая злокачественная опухоль половых путей мужчин, которая показывает значительные географические различия в заболеваемости. Она высоко курабельна на ранних стадиях, но из-за недостаточной осведомленности или доступа к медицинской помощи часто презентируется на распространенной и фатальной стадии. Недостаточная гигиена и инфекция вирусом папилломы человека (HPV) играют определенную роль в этиологии. Пенильно-сохраняющие подходы поощряются там, где это возможно, поскольку хирургическая ампутация может иметь разрушительные психосексуальные последствия.
Заболеваемость и смертность
The penile cancer incidence and mortality rates in the United States (US) are 0.9 new diagnoses and 0.2 deaths per 100,000 men per year. The incidence rate for men in the US increased by an average of 1.2% per year between 2004 and 2013, and the mortality rate decreased by an average of 0.6% per year during that period. The median age at diagnosis is 68 years . Approximately 2,120 men are diagnosed with penile cancer, and approximately 360 men die of this disease each year in the US .
An estimated 22,000 cases of penile cancer occur worldwide . There is wide geographical variation, with penile cancer accounting for 10–20% of cancers of men in parts of Asia, Africa, and South America. This geographic variability is related to circumcision practices and socioeconomic factors . In the developed world, penile cancer is most commonly diagnosed in the sixth decade of life, but occurs earlier in regions where the incidence is higher.
Neonatal circumcision is protective against penile cancer, with only rare reports in men circumcised in infancy . The increased risk of penile cancer in uncircumcised men is related to poor hygiene, chronic infections, greater susceptibility to HPV infection and condylomata, and phimosis, the latter being a particularly strong risk factor . Circumcision later in life does not appear to have the same protective effect, and when performed for phimosis in an adult may unmask preinvasive disease.
HPV is a family of double-stranded DNA viruses which commonly infect the squamous cells of the anogenital and orophayrngeal mucosa. HPV plays an etiologic role in 40–45% of penile cancers. The percentage of cases with detectable HPV DNA is higher among warty and basaloid types, and lower among cancers with keratinizing and verrucous histology . HPV-16. and HPV-18. are the most common subtypes identified by polymerase chain reaction DNA analysis [6,8,9]. An increased rate of penile cancer has been observed in male partners of women with cervical cancer [10,11], likely an effect of HPV.
Men with a history of genital warts have an increased risk of penile cancer, as well as cancers of the anal canal and head and neck. Blomberg et al. recently performed a large cohort study in Denmark of individuals with genital warts, and found an approximately eightfold increased risk of penile cancer . It is not clear if this is attributable to HPV subtypes responsible for the genital warts, or to other differences between men with genital warts and the population at large.
Фимоз и воспаление
Chronic inflammatory conditions also increase the risk of penile cancer, through molecular pathways unique from those associated with HPV. Phimosis often leads to retention of smegma, which is associated with chronic inflammation of the foreskin and glans. Phimosis also increases the likelihood of bacterial or fungal infections that also contribute to inflammation . Balanitis xerotica obliterans, also known as penile lichen sclerosis, is a chronic inflammatory condition that leads to the development of white plaques on the glans and foreskin.
This results in difficulty retracting the foreskin and problems with hygiene . The incidence of penile cancer in men with balanitis xerotica obliterans is 4–8% .
Disorders of the immune system can also promote the development of penile cancer, presumably through the propagation of high risk HPV infection. Men with human immunodeficiency virus infection are at high risk for HPV-associated malignancies. Research is limited examining the link between human immunodeficiency virus infection and penile cancer, though a recent study of men in Brazil has shown a high rate of preinvasive penile lesions .
Several studies reported that smoking also increases the risk of developing penile cancer, although the mechanism remains uncertain [7,15].
Treatment of psoriasis with photo chemotherapy (PUVA) in case of psoriasis also a risk factor .
Given the low incidence, neonatal circumcision is not recommended as an intervention to reduce the risk of penile cancer. Similarly, with such a low burden of penile cancer in the general population, there is no role for regular screening. Rather, emphasis should be placed on education, foreskin hygiene, and management of phimosis. Measures which reduce or prevent transmission of HPV, such as safe sexual practices (including condom use) and HPV vaccination may also reduce the incidence. There is no established role for HPV vaccination for penile cancer prevention but it is reasonable to assume that vaccination programs that reduce the burden of HPV in the population may ultimately reduce the incidence of penile cancer, in addition to cervix cancer and head neck cancers. An advisory panel of the 2009 International Consultation on Urologic Disease Consensus Publishing Group acknowledged HPV infection and lack of circumcision as important factors in the development of penile cancer, but did not recommend routine screening .
Гистопатология и молекулярная патология
Penile cancer is characterized using the 2004. World Health Organization classification system  which was updated to include several histologic variants . The overwhelming majority of penile cancers are well-differentiated squamous cell carcinomas which originate in the epithelium of the glans, coronal sulcus, and foreskin. Common subtypes of squamous cell carcinoma include verrucous, warty (or verruciform), and basaloid carcinoma. Sarcomatoid tumors are rare, and are typically associated with widespread nodal and distant metastases. Other rare types of carcinoma include small cell neuroendocrine type, clear cell, basaloid, papillary, Merkel cell, and sebaceous. Melanomas, lymphomas, and sarcomas can occur, as can metastases from other sites such as bladder and prostate cancers .
Premalignant lesions include Bowen disease, erythroplasia of Queyrat (EQ), and bowenoid papulosis, and are collectively defined as penile intraepithelial neoplasia. Pathologically, Bowen disease and EQ are both squamous cell carcinomas in situ; Bowen disease presents as a scaly, plaque-like lesion on the penile shaft, and EQ presents as a red-colored plaque that involves the inner prepuce or glans [16,20]. Bowenoid papulosis is commonly associated with genital HPV infection and/or immune-suppression. EQ is often observed in the setting of lichen sclerosis.
Separate molecular pathways may be responsible for HPVdependent and HPV-independent penile cancers. The prevalence of HPV DNA in the penile cancer genome, as determined using polymerase chain reaction, has been reported to be 40–45% [21,22]. HPV types 16 and 18 are most commonly associated with penile cancer. The oncogenic effects of HPV in cancer development are primarily the effect of interference with p53, a tumor suppressor gene .
There is contradictory evidence describing the prognostic effect of the presence of HPV. The presence of p53. mutations has been associated with an increased risk of nodal metastases [23,24], although other series have shown the presence of p53 mutations or HPV DNA to be associated with favorable survival outcomes [8,25]. p16 is another marker which has been used as a surrogate for high-risk HPV in other malignancies, and has been associated with improved survival in a series of Canadian men with penile cancer .
Most penile cancers arise on the glans, coronal sulcus, or the prepuce (foreskin). Early recognition and management of suspected penile cancer is important, as early-stage disease is highly curable. However, delayed presentation is common, as patients may be hesitant to seek medical attention. The average delay in seeking medical attention for these lesions is about 2 years. Men with early penile cancer typically present with an area of erythema or induration, or discharge from an unretractable foreskin. More advanced disease presents with larger or ulcerated lesions, and overlying infection is common. Pain at presentation is uncommon. Untreated, penile cancer is characterized by slow local progression to involve the shaft and corpus cavernosum, and eventually the scrotum or even the abdominal wall. Autoamputation by tumor is rare though has been reported.
Although enlarged inguinal lymph nodes as the first presenting symptom are rare, metastases to regional lymph nodes are present in 28–64% of patients at presentation . Clinical evaluation of lymph nodes can be misleading due to local tumor necrosis and infection. Palpable nodes may be histologically negative at resection, while occult metastases may be identified in clinically normal nodes. Inguinal lymph nodes are the first echelon of nodal drainage , with involvement of pelvic lymph nodes occurring subsequently. Distant metastases typically occur in patients with locoregionally advanced disease, but patients can die of penile cancer without distant metastases due to infectious complications and involvement of major blood vessels from locoregional extension.
Таблица 27.1. TNM стадийность рака полового члена.
Определения AJCC TNM
|Определение первичной опухоли (T)|
|T категория||T критерий|
|TX||Первичная опухоль не может быть оценена|
|T0||Нет свидетельства первичной опухоли|
|Tis||Carcinoma in situ (penile intraepithelial neoplasia (PeIN))|
|Ta||Noninvasive localized squamous cell carcinoma|
|T1a||Tumor is without lymphovascular invasion or perineural invasion and is not high grade (i.e., grade 3 or sarcomatoid)|
|T1b||Tumor exhibits lymphovascular invasion and/or perineural invasion or is high grade (i.e., grade 3 or sarcomatoid)|
|T2||Tumor invades into corpus spongiosum (either glans or ventral shaft) with or without urethral invasion|
|T3||Tumor invades into corpora cavernosum (including tunica albuginea) with or without urethral invasion|
|T4||Tumor invades into adjacent structures (i.e., scrotum, prostate, pubic bone)|
|Определение региональных лимфатических узлов (N)|
|Клинический N (cN)|
|cN категория||cN критерий|
|cNX||Региональные лимфатические узлы не могут быть оценены|
|cN0||No palpable or visibly enlarged inguinal lymph nodes|
|cN1||Palpable mobile unilateral inguinal lymph node|
|cN2||Palpable mobile ≥2 unilateral inguinal nodes or bilateral inguinal lymph nodes|
|cN3||Palpable fixed inguinal nodal mass or pelvic lymphadenopathy unilateral or bilateral|
|Патологический N (pN)|
|pN категория||pN критерий|
|pNX||Метастазы в лимфатические узлы не могут быть установлены|
|pN0||Нет метастазов в лимфатические узлы|
|pN1||≤2 unilateral inguinal metastases, no ENE|
|pN2||≥3 unilateral inguinal metastases or bilateral metastases|
|pN3||ENE of lymph node metastases or pelvic lymph node metastases|
|Определение отдаленного метастаза (M)|
|M категория||M критерий|
|M0||Нет отдаленных метастазов|
|M1||Distant metastasis present|
AJCC прогностические стадийные группы
|Когда cT есть…||И cN есть…||И M есть…||Тогда стадийная группа есть…|
|Any T||Any N||M1||IV|
Source: Pettaway et al. . Used with permission of the American College of Surgeons, Chicago, Illinois. The original source for this information is the American Joint Committee on Cancer (AJCC) Cancer Staging Manual, 8th edn (2017), which is published by Springer Science+Business Media.
Giant condyloma acuminatum (also known as Buschke–Lowenstein tumor) is a rare, slow-growing, verruciform tumor. It typically presents as a large mass in the anogenital area, and is associated with HPV subtypes 6. and 11. Untreated, it can grow to a very large size, and eventually invades locally. It is treated with radical surgical excision.
Initial evaluation should include a description of the number, diameter, and location of lesion(s), the morphology, color, boundaries, and relationship to other structures. Penile length and the expected residual length after partial penectomy should also be estimated .
Staging uses the system of the American Joint Committee on Cancer 8th Edition (Table 27.1) . In practice, clinical staging is very subjective as evaluation of invasion of the corpora is difficult. Biopsies are often not deep enough to demonstrate corporal involvement. Thus, techniques which do not treat the full thickness of the penis should be used with caution. Magnetic resonance imaging (MRI) with induction of artificial erection using prostaglandin E1. can assess invasion, and shows a high concordance with eventual pathologic stage . Ultrasound may be helpful in settings where MRI is not available.
The presence of nodal metastases is the most powerful predictor of survival. A review of the literature by Ficarra et al. showed that 5-year cancer-specific survival for patients with pathologically negative inguinal nodes is 85–100% versus 16–45% . The prognosis depends on the number of positive nodes, unilateral versus bilateral disease, involvement of pelvic nodes, and the presence of capsular invasion . Appropriate evaluation and management of the regional nodes is paramount. Clinical examination should focus on palpable nodes, the number of enlarged nodes, unilateral versus bilateral findings, fixation, size, proximity to surrounding structures, and the presence of lower extremity edema. Computed tomography (CT) imaging should be performed in patients with grade 2 or 3 lesions, or with clinical stage T2 or higher.
For those with clinically and radiographically negative groins, the optimal strategy for inguinal management is controversial. Historically, patients managed with primary radiotherapy have not undergone inguinal node dissection. However, without surgical removal of the primary tumor, pathologic prognosticators of lymph node involvement cannot be fully appreciated.
Approximately 20% of men with clinically negative nodes will have microscopic nodal disease which is curable by lymphadenectomy. Surgical series have demonstrated improved survival for patients with clinically occult but pathologically involved groin nodes, as compared with those undergoing therapeutic lymph node dissection at the time of recurrence [32,33]. However, since lymphadenectomy may represent overtreatment in many men and is associated with substantial risk of complications including lymphedema, wound infection, and lymphocele formation, lymph node dissection should be selectively applied.
For grade 1, T1. disease, the rate of failure in inguinal lymph nodes after treatment of the primary site is sufficiently low that inguinal nodal dissection is not required [28,34]. For patients with grade 2. or 3. disease, lymphovascular invasion on biopsy, or clinical stage T2 (or higher), prophylactic inguinal node dissection is indicated. Dynamic sentinel lymph node mapping can be considered in high volume centers where expertise exists, with completion inguinal dissection for positive sentinel nodes. The risk of a false negative result with dynamic sentinel lymph node biopsy is about 5%, and the morbidity is sufficiently low compared with modified lymph node dissection that this risk of a false negative result is considered acceptable. In centers where sentinel lymph node biopsy is not available, or when the nodes are clinically positive, bilateral modified inguinal nodal dissection is the appropriate surgical staging. Although approximately 50% of patients with palpable lymph nodes at diagnosis will prove to have benign reactive adenopathy, delayed management with a 6-week course of antibiotics is no longer recommended . CT imaging of the abdomen and pelvis should be performed to determine if there are enlarged pelvic and/or paraaortic lymph nodes. Fine-needle aspiration (FNA) can determine whether clinically suspicious nodes contain malignancy. Clinically suspicious nodes with negative initial FNA should be considered for repeat FNA or excisional biopsy to guide definitive management. Node positive disease is discussed further below.
Biopsy of the primary tumor is required before definitive therapy. This confirms the diagnosis and provides vital information on grade and histology to direct further therapy and assist with evaluation of the risk of lymph node involvement. All patients undergoing penile preserving treatment should undergo circumcision as a first step. This allows complete evaluation of the extent of disease, and reduces complications like balanitis and phimosis after radiotherapy. It also facilitates follow-up as these patients are at risk for local recurrence in the long term. Circumcision may incidentally provide definitive management of small, preinvasive lesions confined to the foreskin.
Болезнь ранней стадии (Tis, T1, T2)
Penile-preserving approaches are recommended for stage Tis, T1a, T1b and T2 lesions <4. cm (Figure 27.1).
Topical therapies, like 5-fluorouracil and imiquod, are commonly used for superficial preinvasive lesions (Tis, Ta, T1a). Evidence is limited to small retrospective series but topical therapies appear to be effective, at least as an initial treatment . The rates of long-term control are not well documented, and patients should be closely monitored.
Although external radiotherapy is not often used for superficial lesions, orthovoltage photon beams have been used for well-lateralized in situ lesions. Neither is brachytherapy typically delivered for this stage of disease, except in the setting of recurrence.
Figure 27.1. Squamous carcinoma of the penis in a 58-year-old male. Clinical stage T2 Involvement of adjacent face of retracted foreskin evident.
There are several penile-preserving surgical approaches that can be considered for men with small preinvasive or superficially invasive tumors. Traditionally, the surgical approach aimed for 2. cm resection margins, limiting the likelihood of preserving penile function. More recent reports have shown that this appears unnecessary . Margins of 5–10. mm are now considered adequate  as local recurrences can be salvaged with further therapy.
Mohs surgery involves intraoperative assessment of margin status, with removal of successive layers of tissue until clear margins are obtained . Local recurrence rates appear to be higher than with more extensive surgery, though many recurrences can be salvaged with repeat procedures . Thus, survival and regional progression rates are favorable. Resection with carbon dioxide or neodymium:yttrium-aluminum-garnet (Nd:YAG) laser can be considered for small, superficial lesions . As with Mohs surgery, close surveillance is required. Schlenker et al. have reported a 42% rate of local recurrence in 54. patients with mostly in situ and T1 disease . Meijer et al. have also reported a relatively high local recurrence rate in a series of patients with long-term follow-up . For patients with early-stage disease, recurrences may be salvageable with repeat resection, and survival is not likely to be compromised.
Ранняя стадия, неповерхностная
For T1b and T2 lesions <4. cm, there are several penile-preserving options. For clinical stage T2 disease and higher, the rates of local and nodal recurrence are sufficiently high that laser therapy is not recommended . Likewise, Mohs surgery is not a suitable approach. Glansectomy is preferable to partial penectomy, and multiple single institution studies have shown the feasibility of this approach [42–46]. Glansectomy appears to provide a better functional and cosmetic result than amputative surgery. This involves stripping of the epithelium of the glans with coverage of the surgical defect with a skin graft. Local recurrences are still possible, though they can often be salvaged with partial or total penectomy without compromising longterm survival. In the series reported by Veeratterapillay et al., 85% of men maintained erectile function at 1. year postsurgery . A small number of patients were noted to develop contacture of the glans in follow-up requiring repeat surgery. Patients with extension onto the penile shaft are not candidates for glansectomy. When glansectomy cannot be performed, a partial penectomy is indicated.
Radiotherapy is an organ-preserving approach that provides favorable oncologic and functional outcomes. Radiotherapy can be delivered as external beam radiotherapy (EBRT) or brachytherapy, which involves interstitial placement of radioactive sources into the penis. In suitable patients, brachytherapy provides a high likelihood of local control and maintenance of erectile and urinary function, though it requires considerable specialized expertise. EBRT is more widely available and may be preferred for larger tumors over 4. cm and those extending onto the penile shaft. Published radiotherapy series extend over decades with a variety of treatment techniques and dose prescriptions, which do not reflect recent technical improvements in radiotherapy delivery. Outcomes from selected radiotherapy series are shown in Table 27.2.
Радиотерапия внешними лучами
EBRT is commonly used in the definitive management of penile cancer. It is widely available and does not require specific technical expertise. As the results for early-stage disease are less favorable for EBRT than for brachytherapy, it is not the preferred option in these patients; however, EBRT is a reasonable alternative where brachytherapy expertise is not available.
EBRT requires the penis to be positioned such that incidental irradiation to the surrounding tissues is avoided. Typically, the patient is treated supine with the penis encased in a 10. х 10. cm block of tissue equivalent material such as wax or Perspex. This allows reproducibility of set up and full radiation dose delivery to the penile surface. A central cylindrical space houses the penis within the block and a “cork” of tissue equivalent material is placed on the distal end to close the cylinder. Over the course of radiotherapy, the central cylinder may need to be enlarged, as edema and skin reaction develop. Perspex has the advantage of being transparent, allowing easy verification of the penile position within the central cylinder. Shielding of the testicles should be considered for patients who wish to maintain fertility.
The most commonly used fractionation schedule is 60–66. Gy in 2. Gy daily fractions, over 6–6.5. weeks. Two opposed low energy photon beams will treat the entire thickness of the penis to a therapeutic dose with full dose to the skin surface.
EBRT is an effective form of penile preservation. Local control rates of 57–62% at 5. years have been reported [47–50], but there are no reports of outcomes after longer follow-up. Causespecific survival rates are satisfactory as salvage surgery is often effective for local recurrence. This usually involves either partial or total penectomy, depending on the extent of recurrence and length of penile shaft which has been irradiated.
Brachytherapy is a highly effective treatment for men with localized penile cancer stageT1b, T2 tumors <4. cm and selected T3 cases. There is limited awareness of this procedure in the uro-oncologic community, given the rarity of penile cancer and the fact that brachytherapy is delivered in specialized centers. There is considerable published experience supporting its use, and referral for an opinion to an appropriate center should be considered.
Brachytherapy delivers a high dose of radiotherapy in a very accurate fashion. Crook et al. have described the penile brachytherapy technique in detail [51,52]. It involves the placement of two to three parallel planes of hollow, thin needles within the penis (four to nine needles in total), spaced 12–18. mm apart. The needles are held together with two Lucite plates which “sandwich” the penis (Figure 27.2). The procedure is performed under either general anesthesia or a local penile block with sedation. A radiotherapy plan is generated based on needle position and the size and location of the tumor. As the depth of invasion of the cancer is difficult to assess clinically, sufficient margin is required at a depth to account for potential subclinical invasion. The needles are loaded with the radiation sources either manually or using an automated afterloading machine commonly available in radiotherapy departments. The appropriate dose of radiation is delivered through the needles over a period of 4–5. days. The patient is hospitalized over the course of treatment, and bed rest is recommended. In general, the treatment is well tolerated and sufficient analgesia is achieved with acetaminophen +/– codeine. At completion of treatment, the needles can be removed at the bedside with appropriate premedication.
Table 27.2. Selected results from brachytherapy and external beam radiotherapy series (of at least 50. patients).
CSS, cause-specific survival; LC, local control; LDR, low-dose rate.
Figure 27.2. Brachytherapy implant. Urinary catheter in situ.
The majority of the reported experience for penile brachytherapy has used low-dose rate or pulse-dose rate radiotherapy, delivering 60. Gy over 4–5. days at a rate of 50–60. cGy per hour. High-dose rate treatment is now more commonly available in radiotherapy departments but the total dose and schedule for high-dose rate are not well established. There is little published literature on high-dose rate penile brachytherapy. Unpublished experience suggests that the delivery of 38–45. Gy total dose over multiple fractions (twice daily with a minimum 6. hours between) over 6. days may be effective. Homogeneity and volume considerations still need to be worked out before recommending any prescription as the risk of subsequent soft tissue necrosis is considerable.
Two large series have recently been published on long-term outcomes in patients treated at single institutions with low-dose rate penile brachytherapy. De Crevoisier et al. reported the rates of local recurrence-free and cause-specific survival to be 80% and 92% respectively for 144. men . Crook et al. reported actuarial local control and penile preservation rates after penile brachytherapy to be 87% and 88% at 5. years, and 72% and 67% at 10. years . Late local recurrence can occur up to 8–10. years after treatment, so prolonged follow-up is mandatory. Local recurrences are highly salvageable with surgery (either partial or total penectomy).
As with other penile-preserving therapies, appropriate patient selection is paramount. Brachytherapy is ideally reserved for men with clinical stage T1, T2, and selected T3 disease, with tumors under 4. cm and located on the glans. This population represents most of those treated in the studies discussed above. Brachytherapy is also effective in moderatelyor poorly-differentiated tumors, although these patients also require surgical staging of the inguinal lymph nodes. Size of the primary tumor >4. cm is a relative contraindication imparting an increased risk of recurrence and radiotherapy-related complications.
Figure 27.3. Cosmetic result 7. years after brachytherapy showing a pale flat scar and mild telangiectasia
Patients treated for local disease require appropriate management of the inguinal lymph nodes. In the series by Crook et al. tumors with moderate or poor differentiation had a high rate of regional or distant recurrence at 31%, compared to 4% in those that were well differentiated . For this reason patients with moderately or poorly differentiated tumors or T3 disease should undergo surgical staging of the lymph nodes, regardless of whether they are clinically and radiographically (CT staging) node-negative. This is reflected in the 2009. European Association of Urology guidelines for the management of penile cancer .
Moist desquamation in the treated area peaks about 2–3. weeks after treatment and takes 2–3. months to resolve. Healing is delayed by smoking, poor hygiene, and diabetes. The most common late sequelae of brachytherapy are soft-tissue ulceration or necrosis, and meatal stenosis. Soft tissue ulceration is reported in 6–26% of patients. The likelihood depends on dose, radiation technique, tumor stage, and treated volume. The peak time for occurrence of soft tissue ulceration is 7–18. months, although it can occur later . Conservative management is recommended, with good hygiene, antibiotic creams, and avoidance of trauma and cold exposure. Hyperbaric oxygen therapy can be effective if conservative measures fail . Debridement should be undertaken cautiously as it can worsen necrosis; amputative surgery should only be performed as a last resort.
Meatal stenosis has been reported in up to 45% of patients, and tends to occur later in follow-up . This can be managed with self-dilatation using a meatal dilator as required. Dilatation is more successful if initiated early, and routine provision of a dilator at the 3-month follow-up visit may prevent subsequent clinical issues. Urethroplasty or meatoplasty may be considered in severe cases but is rarely required.
Cosmesis after brachytherapy is usually good, with some degree of hypopigmentation and telangiectasia in the irradiated area (Figure 27.3). Fibrosis is usually subtle and is limited to the irradiated area. More deeply invading tumors may leave a tissue defect in the treated area which re-epithelializes slowly.
Локально распространенная болезнь (T3, T4, узел позитивная, метастатическая)
Patients with early-stage primary tumors and clinically involved lymph nodes can still be managed with penile-sparing approaches. In this situation, local control at the primary site can be achieved and the nodes managed surgically. However, for patients with larger tumors or extension on to the shaft, more radical surgery is required. Partial penectomy can be considered if adequate margins can be obtained, leaving enough penile shaft to allow direction of the urinary stream. Otherwise, total penectomy with perineal urethrostomy is recommended. Postoperative radiotherapy should be considered for positive surgical margins.
For clinically negative nodes with high-risk primary tumor features (G2. or 3, T2 or greater disease, and lymphovascular invasion), a superficial inguinal node dissection anterior to the fascia lata of the thigh can be performed with saphenous vein sparing. This is associated with a low risk of chronic lymphedema. These nodes will have to be sampled real time and if positive, one or both sides with superficial positive nodes will have to undergo deep dissection, skeletonizing the anterior surface of the femoral vessel. Lymphedema is almost guaranteed. If the deep nodes are positive, then a pelvic lymph node dissection is indicated. Positive pelvic lymph nodes impart a poor prognosis. Inguinal lymphadenectomy is recommended in all patients with involved lymph nodes. If clinically suspicious nodes are present, ultrasound-guided FNA may precede pathological assessment. A modified inguinal lymphadenectomy reduces the volume of surgical dissection, and is associated with less morbidity than a radical lymphadenectomy but should include the central and superior zones of the inguinal region . Prophylactic radiotherapy for clinically negative groins is not routinely recommended as an alternative for surgical staging, although may be considered in cases where there is an increased risk of nodal involvement, but inguinal lymphadenectomy is not possible.
Direct lymphatic drainage from the penis to pelvic lymph nodes is rare . Pelvic lymphadenectomy is recommended in patients with more than two involved inguinal lymph nodes and/or with extracapsular extension. Postoperative adjuvant radiotherapy to the nodal regions should be considered in patients with more than one positive node or if there is extracapsular extension. There is little direct evidence to guide decisions in this setting but adjuvant radiotherapy is routinely offered to patients with high risk cancers of the anal canal and vulva [22,59,60]. The treatment fields typically include the groins and pelvis bilaterally, treating to a dose of 45–50. Gy over 5. weeks. A boost can be considered for extracapsular disease. The pelvis can be omitted if pelvic lymph node dissection is negative. The primary site is typically not treated postoperatively unless there are positive surgical margins. A recent study by Franks et al. suggested a benefit in a small population of men receiving adjuvant radiotherapy, with 8. of 14. patients treated being alive and free of locoregional relapse after a median follow-up of 27. months .
Preoperative therapy can be considered for unresectable nodal disease. Various preoperative chemotherapy regimens have been used in the setting of locally advanced disease. A recent phase II study from MD Anderson Cancer Center used a regimen of paclitaxel, ifosfamide, and cisplatin (TIP) in patients with N2 or N3 penile cancer. Twenty-two of 30. patients completed the protocol therapy and went on to receive lymphadenectomy, and nine of 30. were alive without evidence of disease at last follow-up (median follow-up 34. months) . A Southwest Oncology Group study used cisplatin, methotrexate, and bleomycin (BMP), showing encouraging response rates. However, there was a higher rate of toxicity than in the MD Anderson study, with five treatment-related deaths in 40. patients . If chemotherapy does not render surgery possible, palliative radiotherapy can be considered to optimize local control.
There is very little published data on combined chemotherapy and radiotherapy either as an alternative to surgery in locally advanced disease, or as preoperative treatment. The addition of surgery should be considered if chemoradiotherapy renders the disease resectable. Experience in cancer of the vulva and anal canal has demonstrated that long-term local control and survival can be achieved in patients with unresectable, locally advanced disease. Preoperative chemoradiotherapy has also been described in vulvar cancer, and a recent Gynecologic Oncology Group study reported high rates of complete clinical and pathologic response in patients who received preoperative radiotherapy and concurrent weekly cisplatin . A similar approach is under development as an international initiative. The International Penile Advanced Cancer Trial (InPACT: NCT02305654), sponsored by the International Rare Cancers Initiative, the Institute of Cancer Research, Cancer Research UK, and the National Cancer Institute will test this approach in the neoadjuvant scenario against surgery alone or neoadjuvant chemotherapy (TIP regimen: paclitaxel, ifosfamide, and platinum) for men with pathologically involved inguinal nodes, and for those men with high-risk groin pathology in an adjuvant postoperative setting or in place of pelvic node surgery. Four hundred patients are to be randomized in the UK and North America. Results will provide important insights into optimal management of this disease .
Men who are symptomatic with locoregionally advanced disease may benefit from palliative radiotherapy for local symptoms such as pain, bleeding, and edema. Those with symptoms from distant metastatic disease to bone, lung, or other sites may also benefit. Typical doses of palliative radiotherapy include 8. Gy in a single fraction, 20. Gy in five fractions, and 30. Gy in 10. fractions.
Palliative chemotherapy can be considered in patients with recurrent or metastatic disease. Cisplatin-based regimens appear to be most effective and are typically used as first-line therapy in medically fit patients. The Southwest Oncology Group study, previously discussed, evaluating BMP chemotherapy included patients with metastatic disease; the toxicity was such that bleomycin should be avoided in palliative regimens. TIP chemotherapy, as described above, is reasonable as firstline treatment for metastatic disease in medically fit patients. Five-fluorouracil and cisplatin have also been used. Paclitaxel may also be of benefit as a second-line agent . Epidermal growth factor receptor activity has been noted in penile cancer, and recent reports have demonstrated activity of anti-epidermal growth factor receptor monoclonal antibodies (including cetuximab) in patients with advanced disease [67,68].
Patients who have undergone penile-preserving therapies require prolonged follow-up, as local recurrences can be salvaged. At present, there is no clear role for routine imaging investigations; CT, MRI, and PET should be directed at investigating symptoms of disease recurrence. Local recurrence in the penis is best detected on physical examination. Most local recurrences occur in the first 2. years, though recurrences as late as 10. years are reported. Men should be taught to monitor the treated area for erythema, induration, and ulceration. Similarly, most recurrences in inguinal lymph nodes occur within the first 2. years. Biannual CT or ultrasound of the pelvis and inguinal areas may supplement physical examination in the initial follow-up period.
The impact of penile cancer and its therapies on sexual function has not been well documented. With partial penectomy, many men are able to maintain some degree of sexual function, though in general, achieve less satisfaction from their sexual relationships . Windahl et al. conducted face-to-face interviews following laser surgery for penile cancer, reporting that most men who were sexually active prior to therapy maintained function afterwards, and were satisfied with their penile cosmesis . Reconstructive surgery may be considered using skin grafts and tissue flaps, cutting of the suspensory ligament, or removal of fat. Erectile function after brachytherapy appears to be well maintained. In a series of 49. men undergoing brachytherapy, 22. of 27 who reported normal potency at baseline maintained adequate erectile function in follow-up . Other smaller series have reported similar findings [48,55,72]. There are no prospective studies documenting erectile function after external radiotherapy.
Urinary function can be compromised, particularly in men who have undergone total penectomy. Patients undergoing partial penectomy should have enough residual penis to allow direction of the urinary stream. Men undergoing total penectomy typically have a perineal urethrostomy, which requires one to sit to urinate. Continence should be maintained in all patients. Men who develop meatal stenosis after brachytherapy may require periodic dilatation.
The effects of penile cancer and its treatment on psychological wellbeing are substantial. A recent systematic review of quality of life and psychosexual health reported psychiatric symptoms in about 50% of men, with two-thirds reporting detrimental effects on sexual function . Patients with penile cancer should be screened for depression and offered referral to mental health services for counseling as appropriate.
Men who have undergone inguinal lymph node dissection, with or without EBRT, are at risk for developing lymphedema of the lower extremities. Recurrent disease in the groins should be ruled out. Referral to a lymphedema clinic can be helpful to assist with management.
Penile cancer is a rare and challenging disease to treat. The psychologic and sexual effects of treatment can be devastating, and these potential consequences need to be discussed at the time of initial evaluation in all patients. Early stage disease is highly curable, and all efforts should be made to minimize the potential effects on psychosexual quality of life. Morbidity and mortality are much higher in patients with advanced-stage disease, and cooperative group trials are necessary to evaluate new treatment paradigms in this population.
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