11.1 Penile Cancer

11.1.1 Epidemiology, Etiology, and Pathology

Worldwide incidence of penile cancer (PC) is affected by race, ethnicity, and prevalence of HPV, resulting in an extreme variability through different geographic areas. In South America, Eastern Asia, and some parts of Africa, PC can account up to 2% of all male tumors. In USA, the higher incidence is reported in white Hispanics, followed by Native and African Americans, respectively [1,2,3]. Risk of PC increases with age, with a peak in the sixth decade. HPV infections are responsible for approximately one out of three cases [4, 5].

HPV has been found in 7–100% of intra-epithelial cancer and 30–40% of invasive penile tumor. Subtypes 16 and 18 are the most common cofactors involved in the carcinogenesis of penile squamous cell carcinoma (SCC) [6,7,8]. Other anatomical conditions, such as phimosis and chronic penile inflammation, may play a role in the tumor genesis. Smoking habit and multiple sexual partners increased the risk three to five times, although the last factor may be correlated to higher risk of sexually transmitted infections, including Papillomavirus.

HPV is responsible both for penile and cervical cancer. However, female sexual partners of penile cancer patients do not have an increased risk of developing cervical malignancy [9,10,11,12].

About 95% of PC are SCC (or variants) and usually originate from a premalignant lesion, as shown in Table 11.1.

Table 11.1 Penile cancer premalignances

SCC could exhibit a variety of growth patterns and HPV associations, resulting in different aggressiveness and prognosis [13,14,15]. Histological subtype, perineural invasion, lymphovascular invasion, depth of invasion, and grade of the primary tumor are recognized as the major pathological predictors of metastasis and prognosis of PC [16]. According to these findings, SCC should be classified into three risk groups:

11.1.2 Diagnostic Evaluation

Penile cancer can be cured in over 80% of cases if diagnosed early but is a life-threatening disease when lymphatic metastasis occurs.

Physical examination is in most of cases sufficient for a clinical diagnosis, however penile carcinoma may be hidden under a phimosis [17]. Palpation of the penis to assess the extent of local invasion and palpation of both groins to assess the lymph node status should always be performed. Local staging to provide information about infiltration of the corpora may be performed with Ultrasound (US) or magnetic resonance imaging (MRI). The sensitivity and specificity of MRI in predicting corporal or urethral invasion was reported as 82.1% and 73.6%, and 62.5% and 82.1%, respectively [18]. Penile Doppler US has been reported to have a higher staging accuracy than an MRI in detecting corporal infiltration [19]. Staging for systemic metastases using abdomino-pelvic CT and chest X-ray is recommended in patients with positive inguinal nodes [20,21,22]. PET/CT is an option [23].

11.1.3 Treatment of the Primary Tumor

The aims of the treatment of the primary tumor are complete tumor removal with as much organ preservation as possible, without compromising oncological control. Surgical treatment can be mutilating and devastating for the patient’s psychological well-being, and since local recurrence has little influence on long-term survival, organ preservation strategies are justified [24].

11.2 Treatment of Superficial Non-invasive Disease (PeIN)

Treatment of superficial non-invasive disease (PeIN) includes topical chemotherapy with imiquimod or 5-fluorouracil and laser treatment with a neodymium:yttrium-aluminum-garnet (Nd:YAG) or carbon dioxide (CO2) laser [25,26,27,28,29,30]. Circumcision is advisable prior to the use of topical agents. Due to high persistence/recurrence rates, treatment must be assessed by biopsy, and long-term surveillance is warranted. Glans resurfacing, total or partial, can be a primary treatment for PeIN or a secondary option in case of failure of the above mentioned. Additionally, patients and physician should be aware that up to 20% of patients undergoing glans resurfacing for presumed PeIN were found to have invasive disease on histopathological examination [31].

11.3 Treatment of Invasive Disease Confined to the Glans (T1–T2)

In patients with invasive penile cancer confined to the glans (T1–T2), treatment choice depends on tumor size, histology, localization (if urethral meatus is involved), and patient preference.

Small and localized invasive lesions should receive organ-sparing treatment. Additional circumcision, local excision, partial glansectomy, or total glansectomy with reconstruction are surgical options. External beam radiotherapy or brachytherapy as well as laser therapy may be an option but the risk of more invasive disease must be recognized. For a general recommendation, 3–5 mm can be considered a safe maximum [20, 32]. Conservative surgery may be performed safely in well-selected patients with discrete tumors by intraoperative frozen-section analysis.

11.4 Organ-Preserving Treatments

Organ-sparing surgery offers better outcomes in terms of quality of life (QoL) but have higher risk of local recurrence. Three years local recurrence rates range from 18% after organ-sparing surgery to 4% after amputation surgery (partial or radical) [33]. Amputation of recurrent disease may be necessary, although survival appears to be unaffected if early diagnosis and treatment are achieved. For these reasons, organ-sparing surgery should only be offered to patients compliant with a strict follow-up schedule.

11.4.1 Laser Therapy

The two most widely used laser energy sources are the CO2 and Nd:YAG, lasers. Although the CO2 laser has been widely used previously, the superficial depth of penetration (limited to 0.1 mm) makes it less than optimal for the treatment of penile carcinoma in situ or small T1 tumors.

Conversely, the Nd:YAG laser has a wavelength of 1064 nm and results in protein denaturation at a depth of up to 6 mm. Reported local recurrence rates after Nd:YAG laser treatment of T1 tumors range from 10% to 48% [27, 28]. Inguinal nodal recurrence has been reported in 21% of patients [28] and 7 years overall survival range from 85 to 95% [30].

11.4.2 Moh’s Micrographic Surgery

Moh’s micrographic surgery is a historical technique consisting of layer-by-layer resection of penile lesion with intraoperative microscopic examination of histological margins. Nowadays, Moh’s micro-surgery has been replaced by surgical excision with intraoperative frozen-section assessment of margin status.

11.4.3 Glans Resurfacing

Glans resurfacing has been proposed over the last years for management of carcinoma in situ of the glans penis. In this technique, subdermal dissection of the skin and subepithelial connective tissue of the underlying corpora spongiosa is performed. Reconstruction is then performed with a graft (split skin or buccal mucosa). Few studies have reported results of glans resurfacing in patients with PeIN or T1 with local recurrence rates of 0% and 6% respectively at a median follow-up of 30 months [34].

11.4.4 Glansectomy

Up to 80% of penile lesions are confined to the glans or prepuce [35]. Therefore, glansectomy combined with split-skin graft reconstruction of a neoglans is the preferred treatment for T1–T3 penile cancer of the glans. The skin is incised at the subcoronal level and deepened onto Buck’s fascia. Dissection is performed over or under Buck’s fascia according to clinical or MRI suspicion of tunical involvement, or when the disease is of high volume with high-risk features. The glans is excised, and the urethra is sutured to the corpora. Finally, a neoglans is created using a split-thickness skin graft. In a recent report on 172 patients undergoing glansectomy, the local recurrence rate was 9% at a median follow-up of 41.4 m [36].

11.4.5 Radiotherapy

External bean radiotherapy with a minimum dose of 60 Gy combined with brachytherapy or brachytherapy alone is a safe organ-preserving approach with good results in selected patients with T1–2 lesions <4 cm in diameter [37, 38].

11.5 Treatment Recommendations for Invasive Penile Cancer (T2–T4)

Total glansectomy with or without corpora cavernosa transection to achieve negative surgical margins is an option if patients with T2 tumors without gross cavernosum involvement [39]. Partial or total amputation is the first-line treatment in patients with T3 disease or patients with T2 disease and adverse features for organ preservation. These includes a tumors of size 4 cm or more, grade 3 lesions, and invasion into the glans urethra. Radiotherapy is an option. Partial and total amputation should also be considered in patients unfit for reconstructive surgery or non-compliant to follow-up [40].

Penile amputation remains the standard therapy for patients with deeply invasive or high-grade cancers. Partial or total penectomy should be considered in patients exhibiting adverse features for cure by organ preservation strategies such as tumors size ≥4 cm, grade 3 lesions, and invasion of the glans urethra or corpora cavernosa.

11.6 Management of Regional Lymph Nodes

11.6.1 Lymphadenectomy

Lymphatic spread of penile cancer starts with superficial and deep inguinal lymph nodes followed by the pelvic lymph nodes [24]. Pelvic nodal disease without ipsilateral inguinal lymph node metastasis and contralateral metastatic spread have never been reported. Further lymphatic spread from the pelvic nodes to retroperitoneal nodes (para-aortic and para-caval) is classified as systemic metastatic disease.

Following these rules, treatment of regional lymph nodes is performed step by step based on the clinical inguinal lymph node status. If clinical lymph nodes appear negative on palpation and are not enlarged (cN0), micro-metastatic disease occurs in up to 25% of cases and invasive lymph node staging is required since no imaging technique can reliably detect or exclude micro-metastatic disease. In clinically positive lymph nodes (cN1/cN2), metastatic disease is highly likely and lymph node surgery with histology is required.

Enlarged fixed inguinal lymph nodes (cN3) require neoadjuvant chemotherapy and surgery.

11.7 Andrological Aspects of Penile Cancer

11.7.1 Consequences after Penile Cancer Treatment

Over the last 15 years, the management of penile cancer shifted from a model based on oncologic control to a more balanced approach, taking into account patients’ quality of life in terms of sexual function, voiding while standing up, and cosmesis.

Few comparative studies in the literature reported that local excision led to better sexual outcomes than glansectomy. Similarly, men after partial penectomy reported significantly more problems with orgasm, cosmesis, life interference, and urinary function than those who had undergone penile-sparing surgery (83% vs. 43%, p < 0.0001). Interestingly, there were no differences in erectile function, sexual desire, intercourse satisfaction, or overall sexual satisfaction [41].

11.7.2 Sexual Activity and Quality of Life After Treatment for Penile Cancer

Laser and topical treatments have no impact on quality of life and sexuality [42]. Similarly, patients undergoing glans resurfacing reported that the sensation at the tip of their penis was no different or better after surgery [34]. In patients undergoing glansectomy, spontaneous erection, rigidity, and penetrative capacity decline in up to 21% with 25% of patients unable to orgasm [43, 44]. Patients’ satisfaction after partial and total penectomy is much lower. Indeed, only 55.6% of patients had erectile function that allowed sexual intercourse after partial penectomy and only 33.3% were satisfied with their sex life. After total amputation, a significant effect on sexual life and overall QoL, although there were no negative implications in terms of partner relationships, self-assessment or the evaluation of masculinity [45]. Even if the evidence is very limited, total phallic reconstruction following full or near-total penile amputation is possible, with cosmetically acceptable results [46,47,48].

11.8 Testicular Cancer

11.8.1 Epidemiology, Etiology, and Pathology

With an estimated worldwide incidence of 75,000 new cases per year [49], testicular cancer (TC) represents 1% of all neoplasms and 5% of urological tumors. Its incidence is constantly increasing, especially in Western Countries, with a peak in the third and fourth decade of life.

Germ cell tumor is the predominant histotype which can be found in 90–95% of all TCs. At diagnosis, 1–2% of tumors are bilateral and 5% of GCTs have a primary extragonadal location [50, 51].

TC recognizes a series of morphological and functional risk factors enclosed in the so-called “Testicular dysgenesis syndrome,” including cryptorchidism, hypospadias, sub- or infertility, and hypogonadism. Other risk factors include a familiar history of TC and presence of contralateral tumor [52, 53]. A genetic predisposition is often responsible for advanced stage tumors. Specifically, an isochromosome found on the short arm of chromosome 12 (i12p) is overexpressed in the GCT related to germ cell neoplasia in situ (GCNIS), while a cKIT mutations is often present in seminoma. These mutations play a major role in pathological upgrade and invasiveness [54].

The 2016 World Health Organization (WHO) histological classification of TC [55, 56] and the 2016 TNM classification [57], are presented in Table 11.2. About 75–80% of seminoma and 55–64% non-seminoma patients exhibit stage I at diagnosis [58]. Serum tumor marker levels are strong predictors of metastasis and prognosis representing an essential selection tool for adjuvant therapies.

Table 11.2 The 2016 World Health Organization (WHO) histological classification of TC and the 2016 TNM classification Diagnostic Evaluation

Testicular cancer usually present as a scrotal mass or diffuse enlargement detected by patient’s self-examination or it may be an incidental finding during testicular ultrasonography (US) [59] (Fig. 11.1). Physical examination may reveal bulky retroperitoneal disease or supraclavicular, scalene and inguinale nodes involvement. Gynecomastia may be present [60]; back and flank plain can be reported because of retroperitoneal metastasis.

Fig. 11.1
figure 1

Testicular cancer detected by US: you may see the hypervascular testicular lesion

Valuation of symptoms is also important. Urethral and irritative symptoms and testicular pain of acute onset may help in differential diagnosis with epididymitis or epididymitis-related orchitis.

Transillumination of scrotum may reveal the presence of hydrocele. Even if testicular cancer is evident by testicular examination, high frequency US is mandatory. Other differential diagnosis includes spermatocele, hematocele, granulomatous orchitis, and varicocele. International guidelines recommend chest, abdomen, and pelvis computerized tomography (TC) for M staging.

Finally, serum tumor markers are of pivotal for diagnosis and treatment of testicular cancer. AFP (alpha-fetoprotein), β-HCG (human chorionic gonadotropin), and lactic acid dehydrogenase (LDH) should always be determined before and during follow-up after orchidectomy. Normal serum markers may not exclude tumor, while persistence of high levels after surgical treatment indicates a probability of disease progression. Disease Management

Gold standard for management of testicular tumor is inguinal exploration with cross-clamping of spermatic cord vasculature and eventual orchifunicolectomy. Scrotal approaches and open biopsy of testis must be avoided. If testicular cancer cannot be excluded, radical orchiectomy must be performed [61]. Testing sparing surgery must be considered for small tumors, in case of solitary testis, when benign pathology is suspected or in patients with synchronous/metachronous tumor [62]. Further treatments depends on histology of tumor and its clinical stage.

11.8.2 GCNIS (Germinal Cell Neoplasia In Situ)

If GCNIS is diagnosed and contralateral testis is healthy, we can perform the following:

  • Radical orchiectomy.

  • Close observation (as the 5-years risk of developing TC is 50%) if patient is compliant [63].

  • Radiotherapy (18–20 Gy in fractions of 2 Gy), which is the gold standard in case solitary testis. It can turn out in infertility and Leydig cells insufficiency. Stage I Germ Cell Tumors Seminoma: Clinical Stage I

After radical orchiectomy, the options for management are as follows:

  • Surveillance: low-stage seminoma has a very positive survival rate (almost 90%) and can be treated with radical orchiectomy alone. Surveillance is the preferred option, because radiotherapy and chemotherapy are associated with important morbidity and risk of secondary malignancy [64]. It consists of 10-years follow-up, which includes physical examination, serum markers (every 3–6 months for year 1, 6–12 months for years 2–3, then annually until year 10). Imaging includes abdominal and pelvic TC, chest X-ray.

  • Radiotherapy (usually 2500–3000 cGy): this low dose of radiation is well-tolerated [65], and can be offered to patients that cannot make surveillance, and with contraindications to perform chest-abdomen CT.

  • Carboplatin chemotherapy: adjuvant therapy with carboplatin must be taken in consideration as a salvage therapy after irradiation or if risk of occult metastasis is present (tumor >4 cm; involvement of testis). NSGCT (Non-seminoma Germ Cell Tumors): Clinical Stage I

NSGCT: CS I tumors are classified according to risk of development of occult metastasis. All treatment options must be discussed with individual patients, to let them make an informed decision about further treatment. The risk-adapted strategy takes into consideration the lymphovascular probability of invasion:

  • Low risk (no vascular invasion):

    • Standard option: surveillance.

    • If patients cannot agree surveillance protocol: 1 cycle of BEP (bleomycin, etoposide, and cisplatin) as adjuvant therapy [66].

    • If remains conditions against surveillance or chemotherapy is not proposed: nerve-sparing retroperitoneal lymph node dissection [67].

  • High risk (vascular invasion present):

    • Standard option: 1 cycle of BEP (bleomycin, etoposide, and cisplatin) as adjuvant therapy.

    • If chemotherapy is not chosen, nerve-sparing retroperitoneal lymph node dissection or surveillance (the last option, if any other curative option is unavailable) (Fig. 11.2).

Fig. 11.2
figure 2

NSGCT CS I—treatment according to the EAU guidelines 2021©

In patients with elevated serum markers or relapsing during surveillance, according to the IGCCC Group Classification of prognosis, the therapy may include 3–4 cycles of BEP followed by resection in case of residual tumour [67]. Metastatic Germ Cell Cancer (Stage IIA–IIB) Stage IIA-IIB Seminoma

Nowadays, chemotherapy is the preferred alternative to radiotherapy for stage II seminoma. It consists of three cycles of BEP or four cycles of EP (etoposide and cisplatin) in case of contraindications to bleomycin for older patients. Radiotherapy may be considered in elderly selected patients who difficulty tolerate systemic therapy [68]. Acute toxicity is reported almost exclusively from chemotherapy, while long-term toxicity derives from the irradiation following RT, with bowel damage and risk for secondary tumors [69]. Stage IIA-IIB NSGCT

All patients with elevated serum markers (Marker +) at Stage IIA-IIB NGCS tumors require three cycles of primary chemotherapy (BEP) according to IGCCCG risk-group. Nerve-sparing (NS) retroperitoneal lymph node resection (RPLND) can be performed in patients with II A NGCS stage (Marker -) in specialized centers by an experienced surgeon. Surveillance may be considered in the same stage in patients with normal markers and lymph nodes <2 cm in greatest axial diameter, and re-evaluation after six weeks is mandatory.

Relapse of tumor occurs in almost 30% of patients with pathological stage II treated with RPLND, with specifical further therapy according to prognosis risk-group (Fig. 11.3).

Fig. 11.3
figure 3

NSGCT CS IIA-IIB—treatment according to the EAU guidelines 2021©

11.9 Andrological Aspects of Testicular Cancer

11.9.1 Testicular Cancer and Gonadal Function

Sperm abnormalities and Leydig cell’s dysfunction in patient with testicular cancer are very common before orchidectomy. Histopathological studies have shown a very high incidence of abnormalities in the contralateral testis of patients with unilateral TC. These abnormalities result in poor semen quality [70]. Additionally, reproductive function may decrease after treatment [71]; for this reason, semen preservation should be offered to all patients [61].

The association between testicular cancer, cryptorchidism/small testis, endocrine, and andrological aspects has been widely investigated.Lower sperm concentration and total sperm count, and increased levels of FSH were found in patients with testicular cancer before treatment. No differences were found in the level of testosterone and estradiol, while man with testicular cancer who had increased level of HCG had very low LH levels [72]. A possible explanation for the lower LH-levels could be the altered secretion of LH-RH by hypothalamus because of the cancer. The increased levels of HCG in some patients could explain the normal level of testosterone and estradiol, and the lower LH-level too (in fact, HCG may stimulate production of testosterone and estradiol by Leydig cells, exerting LH-like effects) [70].

11.9.2 Fertility and Sexual Disfunction After Treatment for Testicular Cancer

Because of the high cure rate of patients with testicular cancer, their quality life after treatment is an important point to discuss. Fertility and sexual aspects are known to condition QoL.

Previous studies have confirmed the impairment of fertility in these patients even before orchidectomy and diagnosis; moreover, gonadal function is affected by surgical treatment, radiotherapy, and chemotherapy in patients with TC.

Leydig cells are more resistant than germinal cells to chemotherapy; however, endocrine disfunction commonly happen during follow-up [72]. Postoperative serum measurement of LH and testosterone must be performed, and the patients might be asked about symptoms and signs of androgen deficiency, to assess the need of androgen therapy. High postoperative FSH levels (≥24 IU/l) are associated with persistent infertility.

Even if a new pregnancy is unlike during cytotoxic treatment and the first year after treatment, contraception is recommended in this period because of the high risk of teratogenic effects induced by radio-chemotherapy. This risk is higher during the first period after treatment, because the patient may still have some sperm exposed to DNA damage.

Additionally, adjuvant therapies and the associated psychological distress may lead to sexual disfunction affecting partner relationship. Orchidectomy itself do not impact erectile function but nerve-sparing retroperitoneal lymph node dissection that may be necessary in some advanced cases may lead to dry ejaculation.

In this scenario, it is very important to counsel patients about cryopreservation, eventual testicular sperm extraction, fertility after treatment, and need for androgen replacement therapies.

Every patient with testicular cancer should be managed by a multidisciplinary team including urologist, oncologist, radiologist, endocrinologist, pathologist, phycologist, and fertility experts. Patients should not be encouraged with false hopes, and alternative plans should be discussed. Indeed, although modern techniques of assisted fecundation (e.g., ICSI-intracytoplasmic sperm injection) can be performed even in a very poor quality, semen [73] and the benefits of cryopreservation are clear, outcomes of fertility treatments are in most of cases unpredictable.