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Keywords:

  • penile cancer;
  • management;
  • lymph nodes;
  • surgery;
  • chemotherapy;
  • radiotherapy
Abbreviations
CIS

carcinoma in situ

HPV

human papilloma virus

BXO

balanitis xerotica obliterans

EAU

European Association of Urology

(D)SLB

(dynamic) sentinel lymph node biopsy

CBM

cisplatin, bleomycin and methotrexate.

INTRODUCTION

  1. Top of page
  2. INTRODUCTION
  3. PATHOGENESIS OF PENILE CANCER
  4. PRIMARY LESION
  5. REGIONAL LYMPH NODES
  6. MINIMALLY INVASIVE TECHNIQUES
  7. CHEMOTHERAPY
  8. RADIOTHERAPY
  9. SUMMARY
  10. CONFLICT OF INTEREST
  11. REFERENCES

The standard of treatment of penile cancer is to cure patients without functional or cosmetic compromise in most cases. In the UK, the National Institute for Clinical Excellence recommends the management of penile cancer in centres receiving 25 new cases annually, or covering a population of 4 million. Supra-regional penile cancer centres must be able to offer curative and palliative multidisciplinary treatment, including access to reconstructive surgery. In this article we review the current understanding and management of penile cancer.

PATHOGENESIS OF PENILE CANCER

  1. Top of page
  2. INTRODUCTION
  3. PATHOGENESIS OF PENILE CANCER
  4. PRIMARY LESION
  5. REGIONAL LYMPH NODES
  6. MINIMALLY INVASIVE TECHNIQUES
  7. CHEMOTHERAPY
  8. RADIOTHERAPY
  9. SUMMARY
  10. CONFLICT OF INTEREST
  11. REFERENCES

The exact pathway leading to penile carcinogenesis has yet to be clarified, but several contributing factors have been identified. Neonatal circumcision seems to be protective and there is a greater incidence of phimosis among patients presenting with penile cancer [1]. Therefore, the inner preputial environment is likely to be an important factor.

Human papilloma virus (HPV) infection and smoking are risk factors for penile cancer [1], whereas balanitis xerotica obliterans (BXO) is frequently found adjacent to the penile lesion. The commonest subtypes of HPV found in penile cancer are 16 and 18. HPV infection has a strong association with the carcinogenic processes involved in anogenital tumour formation, and is thought to be a key factor in the generation of in-situ and invasive cancers of the squamous cell type. PCR techniques have shown that the prevalence of HPV DNA in invasive penile carcinoma is 40–45%, which is similar to that for vulval cancer, but lower than that of cervical cancer. Interestingly penile carcinoma in situ (CIS) shows HPV in ≈90% of cases [2].

A key prognostic indicator in penile cancer is lymph node involvement, but the largest series examining the relationship between HPV infection and prognosis found an inverse relationship between HPV and survival, and no association with lymph node metastases [3]. In that study, the presence of high-risk HPV infection conferred an overall survival advantage (5-year survival of 93% vs 78% for patients negative for HPV), suggesting that there are other factors involved. It is conceivable that HPV could be involved in the initiation of penile malignancy, but other, as yet undetermined, factors are required for progression, invasion or metastasis.

PRIMARY LESION

  1. Top of page
  2. INTRODUCTION
  3. PATHOGENESIS OF PENILE CANCER
  4. PRIMARY LESION
  5. REGIONAL LYMPH NODES
  6. MINIMALLY INVASIVE TECHNIQUES
  7. CHEMOTHERAPY
  8. RADIOTHERAPY
  9. SUMMARY
  10. CONFLICT OF INTEREST
  11. REFERENCES

CIS can be treated by topical 5-flurouracil or imiquimod, with glans resurfacing for recurrence or if the glans is disfigured by an associated BXO. For invasive cancer the main treatments are surgery and radiotherapy. Radiotherapy has principally been used for smaller lesions for penile preservation but is associated with a high local failure rate and commonly gives rise to changes of pigmentation and telangectasia.

More recently surgery has become the main treatment, with efforts made for penile preservation, with a range of surgical options dictated by the site of the lesion (Table 1). Previously surgery involved either partial or complete amputation of the penis, removing a 2-cm margin of normal tissue. Even for small lesions on the glans penis this would usually necessitate a partial penectomy. The effects of partial penectomy on cosmesis, sexual and urinary function in patients can be devastating.

Table 1.  Surgical options for a range of penile lesions
Site of lesionSurgical technique
ForeskinCircumcision
Premalignant lesion/superficial glansGlans resurfacing
Superficial glans with no adjacent CISWide local excision
Proximal glansPartial glansectomy +primary closure
Invading most/distal glansGlansectomy + split skin graft
Invading corpora cavernosaPartial/total penectomy as per margin

Data show that 78% of lesions arise distally, with 48% on the glans only [4], thus it was suggested that more localized excisions with a smaller resection margin might be safely undertaken whilst maintaining oncological control. Preserving penile length has functional advantages in preserving both urinary and sexual function. Furthermore, preserving length also has obvious psychological advantages.

Techniques such as laser ablation with varying types of laser have been used, but only successfully on pre-invasive and superficial tumours, with an 11.4% recurrence rate [5]. Mohs’ micrographic surgery technique has also been used to preserve penile tissue, but similarly is only suitable to treat pre-invasive and superficially invasive tumours.

For premalignant and superficial invasive lesions of the glans, glans skinning and resurfacing with a split-thickness skin graft can be done, with good cosmetic and functional results (Fig. 1). Provided a clear margin is achieved, this technique offers excellent cosmesis and function [6].

image

Figure 1. Verrucous squamous cell cancer with adjacent CIS: (a) before surgery and (b) 3 months after resurfacing.

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If the lesion is suspected to be confined to the glans, the penis should be imaged before surgery to assess invasion and plan surgery. This is best done with gadolinium-enhanced MRI after inducing an erection with intracavernosal prostaglandin E. Glansectomy was initially described for tumours of low malignant potential, but is increasingly used with split-skin grafting to the corporal heads for invasive lesions of the glans (Fig. 2). Glansectomy for invasive carcinoma appears to be oncologically safe, with a 96% recurrence-free follow-up [4]. Partial glansectomy with primary glans closure can be undertaken if the residual glanular epithelium is normal [7].

image

Figure 2. Glans excision: (a) dissection of the glans from the corporal heads; (b) glans removed intact; (c) reconstructed neoglans.

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For lesions that have involved the shaft or corporal bodies, the focus has been on what margin is safe for resection. It now appears that margins of as little as 5 mm are acceptable. The 4% recurrence can be managed with local re-resection [4].

For more advanced lesions partial penectomy might still be necessary. After closing the corpora, the urethra can be spatulated and a neoglans formed with split-skin graft, akin to the more distal procedure of glansectomy and grafting. Further apparent length can be obtained by dividing the suspensory ligament. If the patient is dissatisfied with the length after surgery, division of the suspensory ligament can be combined with a full-thickness skin graft to the unburied remnant of the shaft (Fig. 3). When the whole penis is removed, further reconstructive techniques, e.g. radial artery phalloplasty or pubic phalloplasty, can be used to create a neophallus (Fig. 4). After resection a large lesion might require the placing of a myocutaneous flap, such as those based on tensor fascia, gracilis or rectus abdominis (Fig. 5) [8].

image

Figure 3. Lengthening of the buried penile stump; (a) after partial penectomy and neoglans formation; (b) the suspensory ligament is divided and a full-thickness graft applied to the shaft.

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image

Figure 4. Radial artery phalloplasty allows normal voiding, as well as sexual intercourse, with an inflatable penile prosthesis.

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image

Figure 5. (a) Right vertical rectus abdominis myocutaneous flap that(b) covers the defect after total penectomy and excision of left inguinal skin metastases.

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REGIONAL LYMPH NODES

  1. Top of page
  2. INTRODUCTION
  3. PATHOGENESIS OF PENILE CANCER
  4. PRIMARY LESION
  5. REGIONAL LYMPH NODES
  6. MINIMALLY INVASIVE TECHNIQUES
  7. CHEMOTHERAPY
  8. RADIOTHERAPY
  9. SUMMARY
  10. CONFLICT OF INTEREST
  11. REFERENCES

In patients with clinically impalpable lymph nodes and a high-risk primary lesion, prophylactic lymphadenectomy aims to prevent the development of regional and distant metastases. If lymphadenectomy is delayed there is an inherent risk of higher morbidity and failure to control the cancer. Furthermore, as death is often due to loco-regional recurrence, control of the regional lymph nodes is crucial to reducing death rates. Men with penile cancer who undergo lymphadenectomy for palpable disease have a 33% survival rate, whereas the survival rate is 84% for those undergoing lymphadenectomy with impalpable positive nodes [9]. Guidelines published by the European Association of Urology (EAU) were set to prevent progression of any case at risk of micrometastatic disease [10]. Patients whose primary tumour is considered to be at greater risk of micrometastatic lymph node disease are recommended for inguinal lymph node dissection. Recent prospective data indicate that the guidelines succeed in preventing regional recurrence at the expense of over-treating 72% of men with impalpable lymph nodes [11]. It is clear that more accurate prognostic indicators are needed to improve case selection.

Sentinel lymph node biopsy (SLB) might have a role in reducing the rate of negative lymphadenectomy. The pioneering group in the Netherlands describe 10 years of experience with dynamic SLB (DSLB) [12]. The technique was applied to 140 patients, of whom 31 were found to have the disease and had an inguinal lymphadenectomy. Interestingly, 78% of these with positive sentinel lymph nodes had no further cancer identified in their lymph nodes. Those with sentinel nodes negative for cancer were observed. Of these, six patients (16%) subsequently developed nodal disease at a median (range) of 7 (3–27) months, four of whom have since died. A false-negative rate of 16% needs to be compared with the rate of micrometastatic disease of 18% in a large prospective series from one institution [11]. Most of cases with a false-negative sentinel node were earlier in the series, and modifications in the technique, e.g. preoperative ultrasonography of the inguinal region, might reduce the false-negative rate.

The preferred method of studying DSLB is to use the technique and then continue to an inguinal lymph node dissection at the same session (completion dissection). Several groups have reported using this approach, but with few patients. With this method no patient is exposed to the risk of false-negative biopsy and the true accuracy of the technique is immediately known. This strategy could confirm the benefits of the refinements described above [12].

The clear advantage of DSLB is the reduced morbidity, reported at 8%, vs almost 88% for standard inguinal lymphadenectomy [13]. There are several potential disadvantages to DSLB. First and most importantly, a false-negative rate of more than zero is too high. Second, it requires considerable expertise, with coordination of the surgeon, department of nuclear medicine and being able to predict when the patient will be in theatre. Third, the technique takes time to learn and to gain experience [12]. If in future DSLB is shown to be better than standard management, it will require careful planning, teaching and mentoring for its safe introduction. Finally, the estimated cost per case is up to 11 000 Euro. This must be balanced against the reduced cost of avoiding unnecessary formal lymph node dissection, with its high rates of morbidity. A randomized study of DSLB against standard management according to EAU guidelines might clarify the role of DSLB. The primary endpoint needs to remain the control of cancer, whereas a secondary endpoint ought to be reduced morbidity. We look forward to the further reports from the group in the Netherlands.

MINIMALLY INVASIVE TECHNIQUES

  1. Top of page
  2. INTRODUCTION
  3. PATHOGENESIS OF PENILE CANCER
  4. PRIMARY LESION
  5. REGIONAL LYMPH NODES
  6. MINIMALLY INVASIVE TECHNIQUES
  7. CHEMOTHERAPY
  8. RADIOTHERAPY
  9. SUMMARY
  10. CONFLICT OF INTEREST
  11. REFERENCES

Much of the morbidity of inguinal lymphadenectomy is related to the incision. This has prompted several centres to develop minimally invasive techniques. Sotelo et al.[14] describe a bilateral endoscopic lymphadenectomy for penile carcinoma in eight patients, with no wound complications. The long-term follow-up is awaited to confirm regional control using these promising innovations.

CHEMOTHERAPY

  1. Top of page
  2. INTRODUCTION
  3. PATHOGENESIS OF PENILE CANCER
  4. PRIMARY LESION
  5. REGIONAL LYMPH NODES
  6. MINIMALLY INVASIVE TECHNIQUES
  7. CHEMOTHERAPY
  8. RADIOTHERAPY
  9. SUMMARY
  10. CONFLICT OF INTEREST
  11. REFERENCES

Up to 30% of patients with penile cancer can present with advanced disease, and patients can develop regional or distant metastases after initial surgical treatment. There is therefore a need for effective systemic therapies to deal with the surgically incurable patient. Studies to date show that squamous cell carcinoma of the penis is relatively responsive to chemotherapy. However, partly due to the rarity of the disease, there are no randomized controlled trials of chemotherapeutic agents in penile cancer, and most reports to date have too few patients to achieve statistical significance. Several agents have been examined both as single agents and in combination, and in both the adjuvant and neoadjuvant settings.

Cisplatin/5-fluorouracil

Reports in the early 1990s described the effectiveness of a combination of cisplatin and 5-fluorouracil for recurrent or unresectable disease, although the doses and regimens varied among studies. Hussein et al.[15] achieved partial responses in all five patients with penile cancer, and a complete remission in a case of urethral squamous carcinoma. Selected patients then had surgery or radiotherapy. However, all patients eventually progressed, at a mean duration of 12 months, resulting in a median survival of 16 months.

Cisplatin, bleomycin and methotrexate (CBM)

The combination of CBM in genital tract malignancy showed promising initial results. Corral et al.[16] found a 55% response rate in 29 patients, with a median response duration of 4.7 months and overall survival of 11 months. For the nine patients who were disease-free the median survival increased to 34.4 months, which was significantly greater than that of patients who did not become disease-free (7.0 months). However, there was pulmonary toxicity due to bleomycin in a third of the patients. In what is the largest chemotherapy trial in penile cancer to date, the Southwest Oncology Group subsequently evaluated the effects of CBM in 45 patients, with an overall response rate of 32.5%[17]. However, there were six treatment-related deaths and a further five life-threatening toxic episodes, emphasizing the significant toxicity of this regimen.

Vincristine, bleomycin and methotrexate

This combination was examined by the Milan National Tumour Institute [18]; 25 patients with high-risk disease, as defined by extranodal growth and pelvic or bilateral nodal involvement, were treated with adjuvant chemotherapy. The 5-year survival was 82%, compared to 37% of 31 patients treated with surgery alone.

Ifosfamide/cisplatin, paclitaxel

Paclitaxel, a taxane, has also been shown to be effective in combination with other agents, including carboplatin and ifosfamide/cisplatin [19]. The latter combination was used in the neoadjuvant setting for 10 patients with positive lymph nodes. Four of five patients had a complete response after consolidative lymphadenectomy, with the fifth remaining stable. The three patients who had three or more positive nodes at the time of surgery all died from the disease.

Neoadjuvant chemotherapy might affect the outcome of subsequent inguinal surgery, with myocutaneous flaps often being necessary to limit morbidity.

In summary, chemotherapy can induce responses in metastatic penile cancer, although they are typically partial and of short duration. There is some evidence of a benefit for survival, but randomized controlled trials are awaited.

RADIOTHERAPY

  1. Top of page
  2. INTRODUCTION
  3. PATHOGENESIS OF PENILE CANCER
  4. PRIMARY LESION
  5. REGIONAL LYMPH NODES
  6. MINIMALLY INVASIVE TECHNIQUES
  7. CHEMOTHERAPY
  8. RADIOTHERAPY
  9. SUMMARY
  10. CONFLICT OF INTEREST
  11. REFERENCES

The inguinal region does not tolerate radiotherapy well, and the local cutaneous and soft-tissue effects might compromise subsequent clinical examination, imaging or surgery. In addition, primary radiotherapy does not allow for histological analysis, and therefore accurate staging. Consequently there has not been widespread uptake of this treatment. Several studies examining the effects of prophylactic radiotherapy in patients with impalpable nodes have failed to show an advantage with reference to nodal recurrence or survival.

Ravi et al.[20] used neoadjuvant radiotherapy in patients presenting with nodal metastases of >4 cm, and on subsequent lymphadenectomy found that perinodal infiltration was reduced from 33 to 9% when compared with unirradiated groins. While radiation is not as effective as surgery in the treatment of inguinal lymph nodes, it might be useful in the downsizing or palliation of inoperable nodes.

SUMMARY

  1. Top of page
  2. INTRODUCTION
  3. PATHOGENESIS OF PENILE CANCER
  4. PRIMARY LESION
  5. REGIONAL LYMPH NODES
  6. MINIMALLY INVASIVE TECHNIQUES
  7. CHEMOTHERAPY
  8. RADIOTHERAPY
  9. SUMMARY
  10. CONFLICT OF INTEREST
  11. REFERENCES

All patients need multidisciplinary management in cancer centres. Most cases are amenable to conservative surgery without oncological compromise. Inguinal lymph nodes are best managed according to the EAU guidelines. DSLB will hopefully be shown to match its promise of regional control with reduced morbidity, although this has yet to be realized. Randomized controlled trials are necessary to define the indications and timing of adjuvant therapy for high-risk and advanced cases. The rarity of the disease suggests that trials should be international, using consistent management strategies.

REFERENCES

  1. Top of page
  2. INTRODUCTION
  3. PATHOGENESIS OF PENILE CANCER
  4. PRIMARY LESION
  5. REGIONAL LYMPH NODES
  6. MINIMALLY INVASIVE TECHNIQUES
  7. CHEMOTHERAPY
  8. RADIOTHERAPY
  9. SUMMARY
  10. CONFLICT OF INTEREST
  11. REFERENCES