Last updated March 30, 2023

Penile Cancer

Pathology

Summary of Evidence and Guidelines for the Pathological Assessment of Tumour Specimens

Summary of evidence

Incidence of penile cancer varies according to geographical location, race and ethnicity. (, 2a)
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Western developed countries have seen a slight increase in incidence, which may be caused by higher HPV infection rates. (, 2a)
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In analogy to other HPV-associated cancers, HPV status may influence disease-specific survival (DSS) of penile cancer, but more data is needed, underlining the importance of routine assessment of HPV status in all penile cancer patients. (, 2b)
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Recommendations

The pathological evaluation of penile carcinoma specimens must include the pTNM (see page 8: Classification Systems) stage and an assessment of tumour grade. (S, )
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The pathological evaluation of penile carcinoma specimens must include an assessment of p16 by IHC. (S, )
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The pathological evaluation of penile carcinoma specimens should follow the International Collaboration on Cancer Reporting (ICCR) dataset synoptic report. (S, )
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Classification Systems

Cancer Stage Grouping

Summary of Evidence and Guidelines for the Diagnosis and Staging of Penile Cancer

Summary of evidence
For distinguishing T1 from T2 disease, magnetic resonance imaging (MRI) does not outperform clinical staging. (, 2b)
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For predicting corporal invasion (T3 disease), MRI showed a pooled sensitivity and of 80% (95% confidence interval [CI]: 70–87%) and 96% (95% CI: 85–99%), respectively. (, 2b)
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MRI with and without artificial erection showed similar accuracy in local staging. (, 2b)
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Computed tomography (CT), positron emission tomography/computed tomography (PET/CT) and MRI imaging cannot detect micro-metastases and are therefore of limited value in clinically node-negative (cN0) patients in which the aim is to identify small sub-clinical LN metastasis. (, 2a)
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Inguinal ultrasound (US) + fine needle aspiration cytology (FNAC) of sonographically abnormal nodes can reduce the need of dynamic sentinel node biopsy (DSNB) when tumour positive, allowing for earlier therapeutic treatment of node-positive disease. (, 2a)
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For surgical staging of cN0 patients, DSNB has shown a high diagnostic accuracy. (, 2a)
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Sentinel node biopsy has been shown to lower complication rates compared to modified-, superficial-, or video-endoscopic inguinal LND. (, 2b)
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Imaging with flourine-18 fluorodeoxyglucose positron emission tomography/computed tomography (18FDG-PET/CT) in clinically node-positive (cN+) patients showed higher sensitivity/specificity than CT alone in the pre-operative staging of the pelvic LNs and distant metastasis. (, 2b)
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Recommendations
Primary tumour
Perform a detailed physical examination of the penis and external genitalia, recording morphology, size and location of the penile lesion, including extent and invasion of penile (adjacent) structures. (S, )
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Perform MRI of the penis/primary tumour (artificial erection not mandatory) when there is uncertainty regarding corporal invasion and/or the feasibility of (organ-sparing) surgery. If MRI is not available, offer US as alternative option. (W, )
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Obtain a pre-treatment biopsy of the primary lesion when malignancy is not clinically obvious, or when non-surgical treatment of the primary lesion is planned (e.g., topical agents, laser, radiotherapy). (S, )
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Inguinal LNs
Perform a physical examination of both groins. Record the number, laterality and characteristics of any palpable/suspicious inguinal nodes. (S, )
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Clinically node-negative (cN0)
If there are no palpable/suspicious nodes (cN0) at physical examination, offer surgical LN staging to all patients at high risk of having micro-metastatic disease (T1b or higher). (S, )
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In case of T1a G2 disease, also discuss surveillance as an alternative to surgical staging with patients willing to comply with strict follow-up. (W, )
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When surgical staging is indicated, offer DSNB. If DSNB is not available and referral is not feasible, or if preferred by the patient after being well informed, offer inguinal lymph node dissection (ILND) (open or video-endoscopic). (S, )
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If DSNB is planned, perform inguinal US first, with fine needle aspiration cytology (FNAC) of sonographically abnormal LNs. (S, )
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Clinically node-positive (cN+)
If there is a palpable/suspicious node at physical examination (cN+), obtain (image-guided) biopsy to confirm nodal metastasis before initiating treatment. (S, )
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In cN+ patients, stage the pelvis and exclude distant metastases with 18F-fluoro-2-deoxy-D-glucose positron emission tomography (18FDG-PET) CT or CT of the chest and abdomen before initiating treatment. (S, )
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Treatment

Primary Tumour

Summary of Evidence and Guidelines for Local Treatment of Penile Carcinoma

Summary of evidence
Penile intra-epithelial neoplasia progress to invasive lesions in 2.6–13% despite treatment. (, 3)
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Response and recurrence rates of topical therapies for PeIN are 40–100% and 20% for imiquimod (IQ) and 48–74% and 11% for 5-fluorouracil (5-FU). For laser therapy, response rates are 52–100% and recurrence rates 7–48%. For glans resurfacing, recurrence rates are as low as 4%. (, 3)
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A systematic review including retrospective studies on organ-sparing surgical treatment of the primary lesion shows that cumulative mean 5-year recurrence free rates (RFRs) are 82% in case series and 76.7% in non-randomized controlled trials (RCTs). For (partial) amputative surgery these are 83.9% in case series and 93.3% in non-controlled studies. The cumulative mean 5-year RFR was 69.4% for patients treated with laser therapy for invasive disease. (, 3)
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Current literature on frozen section analysis in organ-sparing surgery is heterogeneous and conflicting. (, 3)
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Tumour distance to the resection margin <1 mm resulted in higher local recurrence rates in a recent large retrospective case series from a tertiary referral centre. (, 3)
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Several retrospective series from claims databases and high-volume centres studying non-specified organ-sparing surgical and ablative techniques show no impact of local recurrence on cancer-specific survival (CSS) where case mix is pitched towards lower grade, lower stage tumours. However, a recent large retrospective series of glansectomies performed in high-volume centres showed local recurrence was a predictor of poor CSS in a cohort with a high number of T2, T3 and high-grade lesions. (, 3)
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The cumulative mean 5-year RFRs are 78.6% after brachytherapy and 55.2% after external beam radiation therapy (EBRT). (, 3)
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For neo-adjuvant chemotherapy, pooled objective response rate (ORR) was 53% (95% CI: 42–64%), the pathologically complete remissions (pCR) rate in prospective studies was 4–10% (95% CI: 5–30%) in a recent systematic review and meta-analysis. (, 2a)
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Recommendations
Offer a balanced and individualised discussion on benefits and harms of possible treatments options with the goal of shared decision making. (S, )
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Inform patients of the higher risk of local recurrence when using organ-sparing treatments compared to amputative surgery. (S, )
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Topical therapy
Clinically assess treatment effects after a treatment-free interval and in cases of doubt perform a biopsy. If topical treatment fails, it should not be repeated. (W, )
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Offer topical therapy with 5-FU or IQ to patients with biopsy-confirmed PeIN. (W, )
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Laser ablation
Offer laser ablation using carbon dioxide (CO2) or neodymium-doped yttrium aluminum garnet (Nd:YAG) laser to patients with biopsy-confirmed PeIN, Ta or T1 lesions. (W, )
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Organ-sparing treatment: surgery (circumcision, wide local excision, glansectomy and glans resurfacing)
Offer organ-sparing surgery and reconstructive techniques to patients with lesions confined to the glans and prepuce (PeIN, Ta, T1–T2) and who are willing to comply with strict follow-up. (S, )
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Perform intra-operative frozen section analysis of resection margins in cases of doubt on the completeness of resection. (W, )
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Offer salvage organ-sparing surgery to patients with small recurrences not involving the corpora cavernosa. (W, )
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Organ-sparing treatment: radiotherapy (EBRT and brachytherapy)
Offer radiotherapy to selected patients with biopsy-confirmed T1 or T2 lesions. (S, )
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Amputative surgery (partial- and total penectomy)
Offer partial penectomy, with or without reconstruction, to patients with invasion of the corpora cavernosa (T3) and those not willing to undergo organ-sparing surgery or not willing to comply with strict follow-up. (S, )
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Offer total penectomy with perineal urethrostomy to patients with large invasive tumours not amenable to partial amputation. (S, )
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Offer amputative surgery to patients with large local recurrences or corpora cavernosa involvement. (W, )
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Multimodal therapy
Offer induction chemotherapy followed by surgery to responders, or chemoradiotherapy to patients with non-resectable advanced primary lesions, or to patients with locally advanced-disease who refuse surgical management. (W, )
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Lymph Nodes

Summary of Evidence and Guidelines for rILND in cN1–2 Disease

Summary of evidence

Open radical ILND is the standard for cN1–2 disease. (, 2a)
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rILND carries a significant risk of complications (21–55%). (, 2a)
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A single study reported on fsILND, fascial-sparing ILND has been reported (single study) and in cN1–2 disease which appears to offer similar oncological outcomes, and reduced complications. (, 2b)
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Lymph node yield and lymph node dissection (LND) appear related to survival, however, variance in accepted values, pathological assessment, and stage migration prevent recommendation of a specific LN count. (, 2a)
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Delay in nodal management of more than 3–6 months may affect disease-free survival (DFS). (, 3)
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Minimally-invasive approaches for ILND (video endoscopic inguinal lymph node dissection [VEIL]/robot-assisted video-endoscopic inguinal pelvic lymph node dissection [RAVEIL]) generally have longer operative times, equivalent LN yields, shorter length of hospital stay and lower wound complications when compared with open ILND. However, since current evidence is very limited in cN1–2 patients, no recommendation for minimally-invasive approaches can be provided. (, 2b)
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Recommendations

In patients with cN1 disease offer either ipsilateral:
  • Fascial-sparing inguinal lymph node dissection
  • Open radical ILND; sparing the saphenous vein, if possible
(S, )
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In patients with cN2 disease offer ipsilateral open radical ILND; sparing the saphenous vein, if possible. (S, )
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Offer minimally-invasive inguinal LN dissection to patients with cN1–2 disease only as part of a clinical trial. (S, )
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Offer chemotherapy as an alternative approach to upfront surgery in selected patients with bulky mobile inguinal nodes or bilateral disease (cN2) who are candidates for cisplatin and taxane-based chemotherapy (see page 18). (W, )
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Complete surgical inguinal and pelvic nodal management within 3 months of diagnosis (unless the patient has undergone prior neoadjuvant chemotherapy). (W, )
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Summary of Evidence and Guidelines for Prophylactic Pelvic Lymph Node Dissection

Summary of evidence

Prophylactic pelvic lymph node dissection (PLND) in most cases represents a staging procedure that can thus identify candidates for early adjuvant therapy, although in select patients it may also provide a therapeutic benefit. (, 3)
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Three or more positive inguinal nodes or ENE of cancer in inguinal nodes are associated with a significantly higher incidence of pelvic LN metastases. (, 3)
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Recommendations

Offer open or minimally-invasive prophylactic ipsilateral pelvic lymphadenectomy to patients if:
  • Three or more inguinal nodes are involved on one side on pathological examination
  • ENE is reported on pathological examination
 (W, )
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Complete surgical inguinal and pelvic nodal management within 3 months of diagnosis (unless the patient has undergone neoadjuvant chemotherapy). (W, )
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Summary of Evidence and Guidelines for the Surgical Management of cN3 Disease

Summary of evidence

Surgery alone will rarely cure patients with cN3 disease. (, 3)
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Even when technically feasible, upfront surgery is associated with significant complications which may delay or prevent delivery of adjuvant therapy. (, 3)
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About half of the patients with advanced (cN2–cN3) penile cancer respond to combination chemotherapy. Responders that subsequently undergo consolidative inguinal/pelvic LND have an overall survival (OS) chance of about 50% at 5 years. (, 2a)
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Inguinal LND in cN3 patients often requires resection of overlying skin to effectively remove a fixed bulky nodal mass. (, 4)
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The available literature includes virtually no cN3 patients to assess the efficacy or safety of minimally-invasive ILND. (, 4)
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Recommendations

Offer neoadjuvant chemotherapy (NAC) using a cisplatin- and taxane-based combination to chemotherapy-fit patients with pelvic LN involvement or those with extensive inguinal involvement (cN3), in preference to up front surgery (see page 18). (W, )
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Offer surgery to patients responding to NAC in whom resection is feasible. (S, )
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Offer surgery to patients who have not progressed during NAC, but resection is feasible. See also (chemo)radiation. (W, )
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Do not offer video endoscopic inguinal lymphadenectomy. (S, )
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Summary of Evidence and Guidelines for Neoadjuvant and Adjuvant Chemotherapy

Summary of evidence

Results support the activity of NAC in patients with clinically involved regional LNs from penile SCC. However, randomized studies are lacking, and substantial concerns remain regarding the selection of patients who are best suited for a systemic therapy approach upfront. (, 2b)
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The available evidence favours a cisplatin- and taxane-based combination (doublet or triplet) as the preferred approach. (, 2b)
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Limited data support the use of adjuvant chemotherapy to improve OS following surgical resection. However, it could be offered to patients with pN3 disease post-LND if NAC has not been received, upon careful consideration of risks and benefits with the patient. (, 4)
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Recommendations

Offer neoadjuvant chemotherapy using a cisplatin- and taxane-based combination to chemotherapy-fit patients with pelvic lymph node involvement or those with extensive inguinal involvement (cN3), in preference to up front surgery. (W, )
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Offer chemotherapy as an alternative approach to upfront surgery to selected patients with bulky mobile inguinal nodes or bilateral disease (cN2) who are candidates for cisplatin and taxane-based chemotherapy. (W, )
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Have a balanced discussion of risks and benefits of adjuvant chemotherapy with high-risk patients with surgically resected disease, in particular with those with pathological pelvic LN involvement (pN3) (see page 19). (W, )
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Summary of Evidence and Guidelines for Pre- and Post-Operative Radiotherapy

Summary of evidence
Adjuvant radiotherapy results in increased OS if greater than two inguinal LN-positive and PLND-dissection negative. (, 2b)
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Adjuvant conventional radiotherapy doses are often insufficient for durable control. Increased DSS and recurrence-free survival (RFS) in penile cancer requires 54 gray (Gy) for ENE and 57–60 Gy for positive margins. (, 3)
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Peri-operative chemo-radiation
Chemo-radiation significantly improves loco-regional control over radiotherapy alone for other SCC originating in anal canal or head and neck, whilst in vulvar cancers it improves OS. The evidence is, however, sparse in penile cancer. (, 1b)
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Recommendations
Offer adjuvant radiotherapy (with or without chemo sensitisation) to patients with pN2/N3 disease, including those who received prior neoadjuvant chemotherapy. (W, )
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Offer definitive radiotherapy (with or without chemo sensitisation) to patients unwilling or unable to undergo surgery for lymph node dissection. (W, )
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Offer radiotherapy (with or without chemo sensitisation) to cN3 patients who are not candidates for multi-agent chemotherapy. (W, )
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Systemic and Palliative Therapies for Advanced Disease

Summary of Evidence and Guidelines for Systemic and Palliative Therapies for Advanced Penile Cancer

Summary of evidence
Low-level data support the use of platinum-based chemotherapy as first-line systemic therapy in advanced disease. (, 3)
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Effective second-line palliative chemotherapy regimens are lacking. Secondline chemotherapy in multiple studies was associated with median OS of 6 months or less. (, 3)
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Initial phase II or basket studies assessed anti-epidermal growth factor receptor (EGFR) therapy or checkpoint inhibition, as monotherapy or combination therapy, in advanced disease. Early evidence of promising clinical activity has been reported in patients with penile cancer. (, 2b)
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Recommendations
Systemic therapies
Offer patients with distant metastatic disease, platinum-based chemotherapy as the preferred approach to first-line palliative systemic therapy. (W, )
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Do not offer bleomycin because of the pulmonary toxicity risk. (S, )
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Offer patients with progressive disease under platinum chemotherapy the opportunity to enroll in clinical trials, including experimental therapies within phase I or basket trials. (S, )
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Radiotherapy
Offer radiotherapy for symptom control (palliation) in advanced disease. (S, )
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Follow-Up and Quality of Life (QoL)

Summary of Evidence and Guidelines for Follow-up and QoL

Summary of evidence
Follow-up surveillance is important as early detection of recurrence may increase the likelihood of curative treatment. (, 3)
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Local or regional nodal recurrences usually occur within two years of primary treatment. (, 3)
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Penile cancer has a significant impact on QoL in many ways and there remain many unmet needs to address. (, 4)
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There is very little data on QoL after treatment for penile cancer. In particular, there is heterogeneity of the psychometric tools used to assess QoL outcomes and further research is needed to develop disease-specific patient reported outcome measures (PROMS) for penile cancer. (, 3)
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Generally, penile-preserving surgery preserves erectile function, although glans sensation and orgasm can be affected. Overall, partial penectomy is associated with poorer sexual outcomes. (, 2b)
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Access to psychological support, counselling and psychosexual therapy are critical components of a holistic and multi-disciplinary patient support service. (, 4)
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Ideally, following nodal surgery, patients would be referred to specialist lymphoedema services for assessment and management before any significant lymphoedema occurs. (, 4)
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In one United Kingdom (UK) specialist penile cancer centre (referral population approximately 11 million), 5-year CSS rates were observed to improve by up to 12% to 85% following centralisation. (, 3)
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Recommendations
Deliver penile cancer care as part of an extended multi-disciplinary team comprising of urologists specialising in penile cancer, specialist nurses, pathologists, uro-radiologists, nuclear medicine specialists, medical and radiation oncologists, lymphoedema therapists, psychologists, counsellors, palliative care teams for early symptom control, reconstructive surgeons, vascular surgeons, sex therapists. (S, )
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Follow-up men after penile cancer treatment, initially three-monthly for 2 years then less frequently to assess for recurrent disease and to offer patient support services through the extended multi-disciplinary team. At discharge, recommend self-examination with easy access back to the clinic as local recurrence can occur late. (S, )
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Discuss the psychological impact of penile cancer and its treatments with the patient and offer psychological support and counselling services. (S, )
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Discuss the negative impact of treatments for the primary tumour on penile appearance, sensation, urinary and sexual function so that the patient is better prepared for the challenges he may face. (S, )
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Discuss the potential impact of lymphoedema as a consequence of inguinal and pelvic lymph node treatment with the patient and assess patients for it at follow-up and refer to lymphoedema therapists early. (S, )
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Recommendation Grading

Disclaimer

The information in this patient summary should not be used as a substitute for professional medical care or advice. Contact a health care provider if you have questions about your health.

Overview

Title

Penile Cancer

Authoring Organizations

Publication Month/Year

March 10, 2023

Document Type

Guideline

Country of Publication

US

Inclusion Criteria

Male, Adult, Older adult

Intended Users

Nurse, nurse practitioner, physician, physician assistant

Scope

Diagnosis, Assessment and screening, Treatment, Management

Diseases/Conditions (MeSH)

D010412 - Penile Neoplasms

Keywords

penile cancer

Source Citation

Brouwer OR, et al. ASCO-EAU Collaborative Guidelines on Penile Cancer. Eur Urol. 2023 March 10. doi:10.1016/j.eururo.2023.02.027.

Supplemental Methodology Resources

Evidence Tables