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In the treatment of penile carcinoma, the practising urologist faces a difficult decision; while oncological safety is of primary importance, radical surgical approaches are naturally associated with a significant impairment in quality of life. Sexually active men are particularly severely affected by partial or total amputation of the penis. The more mutilating a treatment, the more likely patients will suffer from the functional consequences . To overcome this therapeutic dilemma, laser therapy was first established in our centre 30 years ago as an organ-preserving method for premalignant lesions and early stages of invasive penile carcinoma . In subsequent years, laser therapy has become standard treatment in many centres, as the cosmetic and functional results were excellent [3–5]. However, the reported local recurrence rates are 3.1–48%[6,7].
The aim of the present study was to provide a long-term follow-up of patients treated with organ-preserving laser therapy for penile cancer. We also assessed lymph-node involvement (LNI) and tumour-related death in relation to local recurrence rates. We thereby intended to increase our knowledge about the natural progression of this rare disease, and thus help to improve patient selection for organ-preserving laser therapy.
PATIENTS AND METHODS
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- PATIENTS AND METHODS
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The study was approved by the local ethics committee. Patients with invasive penile carcinoma treated in our centre with the organ-preserving neodymium-doped yttrium-aluminium-garnet (Nd:YAG) laser were included in this retrospective study. Laser therapy was administered only in our institution; partial amputation during the follow-up was also performed in other hospitals. Between 1979 and 2008, 54 Caucasian patients (mean age 57.6 years, range 25–89) were included. At first diagnosis patients with invasive penile carcinoma were completely staged by a physical examination of the inguinal area, conventional chest X-ray and three-dimensional imaging pelvic and abdominal CT, MRI or positron-emission tomography with CT (PET/CT). The primary tumour was classified by preoperative biopsy according to the current TNM classification . All patients had been informed before surgery about various treatment options, including local excision, laser coagulation and partial amputation.
Premalignant lesions (e.g. erythroplasia of Queyrat or Bowen’s disease) were summarized as carcinoma in situ (Tis). Only patients with Tis (11) or T1 tumours (39) were scheduled for organ-preserving laser therapy. However, four patients with T2 tumour refused amputation despite extensive information about the risks of the organ-preserving treatment strategy, and were treated by laser therapy.
The primary tumour was treated as described previously ; briefly, the penis was examined by acetic-acid mapping after local application of 5% acetic acid for 20 min before laser coagulation. Lesions were treated with Nd:YAG laser coagulation in continuous-wave mode at 30–50 W of console power in air (1064 nm) and intermittent cooling by locally administered saline. Treatment energy depended on lesion size, with an irradiation time of 100 s (range 60–150). After treating the lesion, a safety margin of the surrounding 3 mm was coagulated. Laser energy was delivered by a 600-µm bare fibre with no tissue contact, and a fibre-to-tissue distance of 0.5–1 cm. Laser-treated areas were ablated with a scalpel or a so-called ‘ring curette’, and biopsies were taken from the tumour base and sent for frozen-section analysis. The number of biopsies taken depended on lesion size. Primary laser therapy was always combined with radical circumcision for additional safety and for better hygiene, if the patient had not been circumcised.
The oncological follow-up was documented during the visits in the outpatient clinic of our centre or by telephone interviews of the local urologists. The follow-up recommendations were adapted from the European Association of Urology (EAU) guidelines and included 2-monthly visits during the first 2 years, 3-monthly visits in the third year and 6-monthly visits from 4 years [9,10]. The mean (range) follow-up was 87 (9–366) months. Two patients were excluded, as they died within 3 month after diagnosis due to cardiovascular events.
In addition, lymph node status, time to local recurrence, number of recurrences and cause of death were assessed. The lymph nodes were classified as negative at the time of first diagnosis of penile cancer if the histopathological finding of the radical inguinal lymph-node dissection (LND)  was negative. If no inguinal LND was performed, the status of the nodes was only defined as negative when physical examination of the inguinal region was negative for palpable lymph-node metastases in at least two consecutive follow-up visits (3-monthly), and one additional second imaging procedure (conventional CT, MRI or 18F-fluorodeoxyglucose-PET/CT) was negative at ≥12 months after the initial diagnosis.
In all statistical test significance was defined as P < 0.05; the chi-square test was used for associations between local recurrence and LNI, local recurrence and cancer-related death, and T stage and local recurrence.
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During the follow-up eight patients died, one of them from recurrent penile carcinoma, four from other malignancies and three from cardiovascular events. Sixteen of 54 patients (42%) had a local recurrence of penile carcinoma. The mean (range) time to local recurrence was 53 (9–132) months. Ten patients had one local recurrence, five had two and one had four local recurrences (mean two recurrences). Local recurrence was treated by partial amputation in six patients and repeated laser therapy in seven. Histological analysis of the amputation specimens showed a T1 tumour in four patients and a T2 tumour in two. Two patients who were sexually inactive had amputation on request, as they were psychologically affected by the local recurrence.
There was local recurrence in eight of the 16 patients after >53 months; the latest recurrences were at 104 and 132 months after initial therapy of the primary tumour. The only patients who died from causes related to penile carcinoma developed recurrent disease after 81 months and refused any further therapy.
Sixteen patients had a radical inguinal LND in addition to penile surgery, due to a high-risk stratification for LNI [9,10] at first diagnosis of penile carcinoma. In four patients at least one positive lymph node was found; of these patients, none died from penile carcinoma and all were without recurrence of disease after a mean follow-up of 105 (18–262) months. All lymph node-positive patients were diagnosed at first diagnosis of penile cancer. There were no newly developed positive lymph nodes during the follow-up in patients who were lymph-node negative at initial presentation.
As no lymph node metastases were monitored during the follow-up, and only one patient died from penile carcinoma, there was no correlation between the incidence of local recurrence with LNI (P= 0.720) or tumour-related death (P= 0.653). There was no statistically significant difference in recurrence rates for patients with Tis or invasive penile carcinoma (P= 0.574). In the group of T2 tumours at initial presentation no partial amputation was required during the follow-up and no local recurrence was monitored. However, two patients were lymph-node positive at LND; the complete patient characteristics are listed in Table 1.
Table 1. The characteristics of the patients
|No./age at diagnosis||Follow-up, months||Local recurrence||Months to local recurrence||No. of recurrences||TNM stage||Histological subtype||Partial amputation||Inguinal LND||Cause of death; penile cancer?|
|1/46||180||Yes|| 81||1||T1N0M0G1||Classic||Yes||Yes|| |
|2/50||140||No|| || ||T1N0M0G2||Classic||No||Yes|| |
|3/68|| 83||No|| || ||T1N0M0G2||Classic||No||Yes||No|
|4/53|| 85||Yes|| 81||1||TxN0M0G2||Verrucous||Yes||No||Yes|
|6/54||147||No|| || ||T1N0M0G2||Classic||No||Yes|| |
|7/48|| 28||Yes|| 12||1||T1N0M0G2||Classic||No||Yes||No|
|8/89|| 18||No|| || ||T1N0M0G3||Classic||No||No||No|
|9/59|| 79||Yes|| 69||2||T1N0M0G1||Verrucous||No||No||No|
|10/60||208||No|| || ||T1N0M0G1||Classic||No||Yes|| |
|11/58|| 114||No|| || ||T1N0M0G2||Classic||No||Yes|| |
|12/60||102||No|| || ||T1N1MXG3||Classic||No||Yes|| |
|13/69||104||No|| || ||TxN0M0G3||Classic||No||No|| |
|14/60||107||No|| || ||TxN0M0G2||Classic||No||No|| |
|15/61||107||No|| || ||TxN0M0GX||Verrucous||No||No|| |
|16/60||261||Yes|| 43||2||T1N0M0G2||Classic||Yes||Yes|| |
|17/69||171||Yes|| 70||4||TisN0M0|| ||No||No|| |
|18/48|| 96||Yes|| 61||1||T1N0M0G2||Classic||Yes||Yes|| |
|19/64|| 93||No|| || ||TisN0M0|| ||No||No|| |
|20/30|| 116||No|| || ||TisN0M0|| ||No||No|| |
|21/50||262||No|| || ||T2N1M0G2||Classic||No||Yes|| |
|22/49|| 84||Yes|| 41||2||T1N1M0G2||Classic||No||Yes|| |
|23/31||366||Yes||132||2||TisN0M0|| ||No||No|| |
|24/56|| 73||No|| || ||T1N0M0G1||Warty type||No||No|| |
|25/62|| 77||No|| || ||T1N0M0G2||Classic||No||No|| |
|26/57|| 44||No|| || ||T1N0M0GX||Classic||No||No||No|
|27/65|| 63||No|| || ||T1N0M0G2||Classic||No||No|| |
|28/67||207||No|| || ||T1N0M0G1||Classic||No||No||No|
|29/75|| 58||Yes|| 53||2||T1N0M0G2||Classic||No||No|| |
|30/53|| 67||No|| || ||T1N0M0G2||Classic||No||No|| |
|31/59|| 55||No|| || ||T1N0M0G1||Classic||No||No|| |
|32/25|| 57||No|| || ||T1N0M0G2||Classic||No||No|| |
|33/49|| 57||No|| || ||T2N1M0G2||Classic||No||Yes|| |
|34/52|| 53||No|| || ||T1N0M0G2||Classic||No||No|| |
|35/70|| 89||No|| || ||TisN0M0|| ||No||No|| |
|36/64|| 56||Yes|| 17||1||T1N0M0G2||Verrucous||Yes||Yes|| |
|37/64|| 51||No|| || ||T1N0M0G2||Classic||No||No|| |
|38/83|| 53||No|| || ||T1N0M0G2||Classic||No||No|| |
|39/36|| 42||No|| || ||T2N0M0G3||Classic||No||Yes|| |
|40/65|| 50||Yes|| 12||1||T1N0M0G1||Classic||No||No|| |
|41/67|| 46||No|| || ||TisN0M0|| ||No||No|| |
|42/59|| 39||No|| || ||T1N0M0G1||Classic||No||Yes|| |
|43/70|| 42||Yes|| 25||1||T1N0M0G2||Verrucous||No||No|| |
|44/48|| 32||No|| || ||TisN0M0|| ||No||No|| |
|45/30|| 37||No|| || ||TisN0M0|| ||No||No|| |
|46/36|| 36||No|| || ||TisN0M0|| ||No||No|| |
|47/73|| 42||Yes|| 41||1||T1N0M0G1||Classic||No||No|| |
|48/77|| 38||No|| || ||TisN0M0|| ||No||No|| |
|49/54|| 36||No|| || ||T1N0M0G3||Classic||No||No|| |
|50/65|| 41||No|| || ||TisN0M0|| ||No||No|| |
|51/81|| 18||No|| || ||T1N0M0G1||Verrucous||No||No||No|
|52/62|| 13||Yes|| 9||1||T1N0M0G2||Classic||No||No|| |
|53/55|| 9||No|| || ||T2N0M0G2||Classic||No||No|| |
|54/48|| 11||No|| || ||T1N0M0G2||Classic||No||No|| |
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In the present series the recurrence rate was 42% overall, which is comparable to other reports with a long-term follow-up. Due to the long follow-up of up to 366 months it was possible to document that half of late local recurrences occurred only after >53 months. From our perspective these late recurrences are ‘de novo’ carcinomas rather than failure of primary treatment. Many patients had congenital phimosis and over time a variety of carcinogenic factors might lead to Tis . Consequently, larger dysplastic lesions or Tis areas on the glans and foreskin develop and might finally lead to invasive carcinoma. This might explain why even many years after treatment of the primary tumour, ‘de novo’ carcinoma develops in an initially untreated area or close to a treated area. Therefore, especially late recurrences are not regarded as a failure of primary treatment but natural carcinogenesis of pre-damaged skin.
To clarify if the relatively high recurrence rate justified the organ-preserving approach in penile carcinoma, we compared our data for local recurrence with other published data and examined the effect of local recurrence on LNI and tumour-related death. To our knowledge there are few series with a comparable follow-up for laser treatment of penile carcinoma. Meijer et al. published long-term data from 44 patients with premalignant lesions and invasive carcinoma treated with a laser. According to their data, the overall recurrence rate was 48% with a mean follow-up of 52 months. Especially patients with T2 tumour developed lymph node metastasis during the follow-up and died because of the tumour. The authors concluded that laser therapy should not routinely be used in patients with T2 tumours. Another group published data on the long-term follow up of 44 patients treated with the carbon dioxide, potassium-titanyl phosphate or Nd:YAG laser . After a mean follow-up of 58 months the local recurrence rate was only 11.4% and one patient died from tumour-associated disease. However, up to 40% of the lesions were premalignant. Windahl et al. reported a prospective study including 67 patients, with a recurrence rate of 19% during a median follow-up of 42 months. However, 12% of patients died from tumour-associated causes due to recurrent cancer. This local recurrence rate is comparable to our data for the first 53 months, while in the present patients only one (2%) died from tumour-associated causes during the follow-up. In our patients with T2 tumour there were no recurrences or late development of positive lymph nodes. As the group of patients with T2 tumour was very small, it is likely that this trend would not be maintained in a larger population. We therefore do not recommend using organ-preserving laser therapy as standard treatment for T2 tumours, and suggest limiting the indication for organ-preserving therapy to only to selected cases (e.g. patients refusing partial amputation).
Most other reports include only a few patients or a relative short follow-up, a shortcoming because late recurrence is a major concern in laser therapy; Table 2[3,4,6,13–17] shows the reported recurrence rates after organ-preserving laser therapy.
Table 2. Recurrence rates after organ-preserving laser therapy
|Study||Mean follow-up, months||N patients||Recurrence rate, %|
||| 7||15|| 6.6|
The EAU guidelines on penile cancer  recommend wide local excision (plus reconstructive surgery) or glansectomy (plus split skin graft) for treating invasive penile carcinoma as alternative to laser therapy. The reported recurrence rate is 3–30% for local excision [7,18,19] and 0–4% for glansectomy [20,21]. While the recurrence rates for glansectomy are excellent, the technique is not organ-preserving as the glans penis is completely removed.
Lymph node status has been repeatedly shown to be the most important prognostic factor for survival . In the present study there was no effect of local recurrence on lymph node status and disease-related death. This is in accordance with published data, which suggest that lymph node status is more predictive for survival than local recurrence [23,24]. Nevertheless we are aware that the relatively few patients in the present study might bias our data, and that local recurrence in general might have an influence on lymph node status and therefore survival. The one patient who died from carcinoma refused any further therapy due to psychological problems, and could otherwise probably have been cured. In the present study, of the four patients who were lymph node-positive, two were T1 and two were T2. By contrast, Meijer et al. found significantly more nodal metastases in patients classified at T2 than as T1. Therefore, those authors did not recommend routine laser therapy for T2 tumours. In all, 18% of patients developed lymph node metastases after primary treatment. According to the results of Windahl et al. the death rate from penile carcinoma and concurrent disease was 11.9%. Tewari et al. reported, in a small group of 32 patients with a long mean follow-up of 70 months, that there were no tumour-related deaths or positive lymph nodes. The evident high variability in local recurrence rates with lymph node status and tumour-related death might be a result of the relatively small series from which they were derived. We therefore suggest risk stratification for LNI and subsequent therapy according to the EAU guidelines .
As shown before by our group and others, laser therapy provides excellent cosmetic and functional results [3–5]. Cosmetic results are considered to be satisfying in up to 80% of patients. In addition, up to 60% of sexually active patients before surgery are still active after laser treatment [25,26]. Compared with other treatments, laser therapy can preserve sexual function in a higher percentage of patients . In our patients the self-reported sensitivity of the glans penis was not or only a little impaired by laser therapy. The effect of maintaining glans sensitivity on sexual life was not the subject of the study and was therefore not assessed. Figure 1 shows an example for successful treatment and a good cosmetic result.
Figure 1. Views of a 65-year-old patient with a T1 G2 tumour of glans penis and foreskin: (A) At initial presentation; (B) 4 weeks after Nd:YAG laser therapy and circumcision; (C) 7 weeks after Nd:YAG laser therapy and circumcision.
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In conclusion, despite a relatively high recurrence rate, organ-preserving laser therapy appears to be a suitable treatment for premalignant lesions and early stages of penile carcinoma, as the oncological outcome and survival were not compromised by local recurrence. Patient information about late recurrence is crucial. In organ-preserving therapy for penile carcinoma, the therapeutic strategy must include risk-adapted management of the lymph nodes (e.g. dynamic sentinel node biopsy if available, or radical LND).