Primary Squamous Cell Carcinoma of the Male Proximal Urethra

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Primary Squamous Cell Carcinoma of the Male Proximal Urethra:

Outcomes from a Single Centre

a,d,e a a a

Fabio Castiglione , Hussain M. Alnajjar , Michelle Christodoulidou , Maarten Albersen ,

a b b c a a

Arie Parnham , Alex Freeman , Charles Jameson , Anita Mitra , Raj Nigam , Peter Malone , a,d,e,

Asif Muneer *,

on behalf of the Trauma and Reconstructive Urology Working Party of the European Association

of Urology Young Academic Urologists

a b

Department of Urology, University College London Hospital, London, UK; Department of Pathology, University College London Hospital, London, UK;

c d

Department of Oncology, University College London Hospital, London, UK; NIHR Biomedical Research Centre, University College London Hospital, London,

UK; Division of Surgery and Interventional Science, University College London, London, UK

Article info Abstract

Article history: Background: Primary squamous cell carcinoma (SCC) of the male proximal urethra is an

aggressive and rare urogenital malignancy.

Accepted February 25, 2019

Objective: To review the surgical management and outcomes for male proximal urethral

SCCs within a single centre and to suggest an algorithm for the surgical management of

Associate Editor: Malte Rieken

these rare tumours.

Design, setting, and participants: This was a retrospective study of patients undergoing

Keywords: surgery for male proximal urethral SCC within a single tertiary academic centre

Primary urethral cancer managing rare genital tumours. Ten patients with a histological diagnosis of proximal

urethral SCC were identiﬁed from an institutional database over a period of 10 yr with a

Urethral tumour

median follow-up of 22.5 mo (standard deviation Æ 25.77 mo).

Proximal urethral cancer

Outcome measurements and statistical analysis: Pathological staging, surgical treat-

Urethra

ment, and neoadjuvant and adjuvant treatment were recorded. Complications according

Squamous cell carcinoma to the Clavien-Dindo classiﬁcation and overall survival rates were recorded. Kaplan-

Meier curves were used for overall survival.

Results and limitations: A total of 10 patients were identiﬁed of whom eight underwent

panurethrectomy and radical prostatectomy. Radical inguinal lymphadenectomy was

performed in ﬁve patients, which conﬁrmed bilateral metastatic disease. Perioperative

complicationswere reportedin six patients (Clavien I and II). Within6 moof surgery, 90% of

patients developed distant metastatic disease. Nine patients died of urethra cancer during

the follow-up. One patient is still on follow-up. The median overall follow-up was 13.92 mo

(range: 5–91 mo).At 5 yr, cancer-speciﬁc/overall survivalwas10%. A limitationof thisstudy

is the retrospective design, which is unavoidable for such a rare disease.

Conclusions: Radical surgery allows local disease control, but despite neo/adjuvant

treatment, proximal urethral SCC is associated with poor survival outcomes and

progression to distant metastatic disease within 6 mo.

Patient summary: Proximal urethral squamous cell carcinoma is a rare cancer in men

which is often detected late. Patients often present with problems such as voiding,

urethral bleeding, or a palpable mass. Aggressive surgery allows local control, but

despite this the overall survival is poor. Adjuvant and neoadjuvant radiochemotherapy

can improve survival. Multicentric randomised trials are needed to identify the correct

treatment modality.

* Corresponding author. University College London Hospital, London, UK. Tel. +44(0)7779652389.

E-mail address: [email protected] (A. Muneer).

https://doi.org/10.1016/j.euf.2019.02.016

Please cite this article in press as: Castiglione F, et al. Primary Squamous Cell Carcinoma of the Male Proximal Urethra: Outcomes

from a Single Centre.DownloadedEur forUrol AnonymousFocus User(2019), (n/a) athttps://doi.org/10.1016/j.euf.2019.02.016 University of Wisconsin Madison from ClinicalKey.com by Elsevier on June 12, 2019. For personal use only. No other uses without permission. Copyright ©2019. Elsevier Inc. All rights reserved.

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included in the study. Patients with a diagnosis of non-SCC (eg, mela-

1. Introduction

noma, lymphoma of the urethra), prostatic adenocarcinoma, and pri-

mary bladder TCC with urethral involvement (at presentation or later)

Primary male urethral cancer (PUC) is a rare and aggres-

were excluded from the cohort. Patients with missing clinical informa-

sive tumour accounting for <1% of all genitourinary malig-

tion were also excluded. OS was calculated from the date of diagnosis to

nancies [1] and 0.02% of all cancers [2,3]. Risk factors

the date of death or last follow-up. Kaplan-Meier curves were used to

include a history of urethral strictures, chronic irritation

show the OS.

following intermittent self-catheterisation, previous ure- All statistical tests were performed using the R Studio graphical

throplasty, external-beam radiation therapy (EBRT), radio- interface v.0.98 for R software environment v.3.0.2.

active seed implantation, and chronic urethral inflamma-

tion/urethritis following sexually transmitted diseases [4–

3. Results

11]. Patients can present with urinary obstruction, irrita-

tive voiding symptoms, haematuria, or a penile discharge

A total of 10 cases with histologically proven proximal

that is often associated with a palpable lump in the penis

urethral SCC were treated within a single centre. Fifteen

or perineum [10,11].

patients were excluded from the study because they did not

PUCs present as variable histological subtypes. The most

meet the inclusion criteria. Patient characteristics are

common histological subtypes reported in the Surveillance,

shown in Table 1. The median follow-up was 21.8 mo (stan-

Epidemiology, and End Results (SEER) review of

dard deviation Æ 25.5 mo).

1615 patients were transitional cell carcinoma (TCC) repre-

senting 55%, squamous cell carcinoma (SCC) representing

3.1. Clinical presentation

21.5%, and adenocarcinoma accounting for 16.4% [12]. Of all

the urethral tumours, anterior urethral tumours have a

The mean age at presentation was 55 yr (range: 46–64 yr).

higher incidence than posterior urethral tumours

Two patients had distant metastasis (pulmonary) at the time

[10,11]. SCC is the predominant subtype in the fossa navi-

of diagnosis. Three patients presented with proximal urethral

cularis and the anterior urethra. TCCs account for 80–90% of

posterior urethral tumours [10–12].

–

Clinical management and prognosis are related to the Table 1 Patient characteristics.

clinical stage and location of the tumour at presentation

Variable Overall (n = 10)

[10–14]. Conventionally, the anterior urethra includes the

Age at surgery (yr)

penile and the bulbar urethra, and the posterior urethra

Median 55

includes the prostatic and the membranous urethra.

Range 43–64

Proximal PUCs refer to tumours in the prostatic, mem-

Follow-up (mo)

branous, and bulbar urethra, whereas distal tumours Median 22

Range 6–90

involve the penile urethra and fossa navicularis. Although

Race (n)

this is a nonspecific nomenclature, it is now increasingly

White 8

used within the literature [10,11]. Black 2

In men, proximal PUCs are usually more aggressive than Other 0

Pathological grade (n)

distal PUCs. Distal urethral tumours tend to be of low stage,

G1 0

with reported cure rates of 70–90% following local surgical

G2 2

–

excision and radiotherapy [10 14]. Most cases (66%) of G3 8

proximal PUC are at an advanced stage at presentation. Pathological tumour stage (n)

T1–2 3

The optimal multidisciplinary treatment strategy for proxi-

T3–4 7

mal urethral cancer is still unclear. Owing to the small

Inguinal lymph node status (n)

number of patients who develop these proximal urethral pNx 5

pN0 0

SCC, standardised treatment options are lacking with cases

pN1 2

often treated along local protocols on a case-by-case basis

pN2 3

[10–14].

Pelvic lymph node status (n)

The aim of this study was to analyse the data regarding pNx 9

pN0 0

treatment responses and survival outcomes for patients

pN1 1

with advanced proximal urethral SCC managed within a

PNI (n)

single institution.

Yes 7

No 3

LNI, n (%)

2. Patients and methods

Yes 8

No 2

We retrospectively collected data of patients diagnosed with proximal ECE, n (%)

urethral SCC from an institutional database. Yes 3

No 2

Data were recorded on a standardised pro forma and included patient

age, histological subtypes, surgical management, postoperative compli-

ECE = extracapsular extension; LNI = lymph node involvement;

cations, use of chemoradiotherapy, and overall survival (OS) rates. Only

PNI = perineural invasion.

patients >18 yr old with SCC located in the proximal urethra were

Please cite this article in press as: Castiglione F, et al. Primary Squamous Cell Carcinoma of the Male Proximal Urethra: Outcomes

from a Single Centre.DownloadedEur forUrol AnonymousFocus (2019), User (n/a)https://doi.org/10.1016/j.euf.2019.02.016 at University of Wisconsin Madison from ClinicalKey.com by Elsevier on June 12, 2019. For personal use only. No other uses without permission. Copyright ©2019. Elsevier Inc. All rights reserved.

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Fig. 1 – (A) Sagittal MRI showing extensive posterior urethral tumour with bilateral testicular involvement and infiltration of the corpora. (B)

Descending urethrogram demonstrating fistula between the scrotum and the urethra. MRI = magnetic resonance imaging.

stricture disease, obstructive lower urinary tract symptoms scrotum, a urethrogram was performed to check the extent

(LUTS),andbleeding fromthe urethralmeatus.Threepatients of the tumour and urethral involvement (Fig. 1B).

presented to the emergency department with urethral bleed-

ing and penile pain. A further two patients presented with 3.3. Surgery

either a urethral or a scrotal abscess and pain, and one patient

presented with a palpable penile lump. In this cohort, nine patients underwent panurethrectomy

combined with a radical prostatectomy, bladder neck clo-

3.2. Diagnosis sure, and urinary diversion (either suprapubic drainage or

Mitrofanoff). Of this cohort, one patient underwent excision

Preoperative imaging using pelvic and penile magnetic of a large perineal-scrotal mass combined with a bilateral

resonance imaging showed the extent of the tumour and orchidectomy and a total penectomy due to the extensive

allowed surgical planning (Fig. 1A). Staging with computed local invasion of the tumour, and the resulting perineal

tomography (CT) was performed preoperatively combined defect was covered using a pedicled gracilis flap (Fig. 2).

with ultrasound fine needle aspiration cytology (FNAC) of One patient underwent a total urethrectomy combined with

the inguinal lymph nodes. All patients underwent a cystos- a cystoprostatectomy, and one patient underwent a ure-

copy and biopsy of the lesion for confirmation of the pri- threctomy sparing the prostatic urethra and perineal ure-

mary lesion. Where a cystoscopy was not possible due to the throstomy alone without excision of the prostatic urethra

extensive nature of the tumour or fistulation through the because he refused to undergo a prostatectomy.

Fig. 2 – (A) Panurethrectomy combined with radical prostatectomy and bilateral radical inguinal lymphadenectomy. (B) The defect is covered with a

pedicled gracilis.

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3.4. Perioperative complication Table 2). However, one patient discontinued before the

completion of chemotherapy owing to side effects. Addi-

A total of six patients developed perioperative complica- tional chemotherapy with cisplatin and 5-FU or gemcita-

tions following the surgery. Complications included post- bine was offered as a palliative treatment option in three

operative ileus (n = 1; Clavien grade: II), wound infection patients who developed lung metastases postoperatively.

(n = 1; Clavien grade: I), and sepsis (n = 2; Clavien grade: II), Of these patients, two also underwent palliative pelvic EBRT

and perioperative transfusion was required in two patients for local disease control. One patient underwent EBRT and

(Clavien grade: II). Severe complications related to urinary one cycle of paclitaxel.

derivations did not happen.

3.8. Metastatic disease

3.5. Histology

Distant metastasis at the time of diagnosis was found in two

The histopathology is summarised in Table 1. Of the patients (lung). However, distant metastases developed in

patients, 80% were affected by poorly differentiated G3 90% of patients on follow-up, with six developing lung

–

SCC and 70% by T3 4 disease (Table 2). Both perivascular metastasis and a further four developing pelvic recurrence

and perineural invasion were positive in 60% of the patients. (Table 1).

One patient, who underwent a urethrectomy and peri-

3.6. Lymph node involvement neal urethrostomy alone without the excision of the pros-

tatic urethra because he refused a prostatectomy, devel-

A total of five patients underwent bilateral inguinal oped local recurrence at the site of the perineal

lymphadenectomy. Of these patients, three had SCC diag- urethrostomy.

nosed preoperatively following inguinal ultrasound and

FNAC. The other two had clinically suspicious inguinal 3.9. Surveillance

lymph nodes on cross-sectional imaging (Table 2).

The mean number of lymph nodes removed was 13.2 The median overall follow-up was 13.92 mo (range: 5–91

–

(range: 11 19). Four patients undergoing inguinal mo). Nine patients died due to cancer progression (90%) and

lymphadenectomy were found to harbour SCC within the one is still under clinical follow-up. At 5 yr, cancer-specific

lymph nodes, with the mean number of metastatic lymph survival/OS was 10%. In the subgroup of patients who had

–

nodes being 2 (range: 2 4), and three patients had extra- received platinum-based neoadjuvant or additional chemo-

capsular extension noted on pathological review of the therapy (n = 6), the median survival time from diagnosis

lymph nodes. Only one patient had a pelvic lymph node was 28.1 mo (range: 15–91 mo); for patients who had not

dissection due to enlarged pelvic nodes on preoperative CT received chemotherapy (n = 4), the median survival was

imaging. In this case, one out of 19 pelvic lymph nodes was 6.3 mo (range: 5–10 mo).

positive for metastatic SCC.

3.10. Treatment algorithm

3.7. Adjuvant, neoadjuvant, and additional therapy

Based on our cohort, we have developed our own algorithm

Three patients were deemed suitable for neoadjuvant che- for the management of proximal urethral SCC for our centre

motherapy (cisplatin/5-fluorouracil [5-FU]/gemcitabine; (Fig. 3).

Table 2 – Adjuvant and neoadjuvant treatment according to the patient’s TNM stage.

Patient Age Stage at diagnosis Neoadjuvant therapy Additional therapy Time to last follow-up/death (mo)

1 46 T3N1M0 No No 10 (Death)

2 56 T3N2M1 No Yes 7 (Death)

Cisplatin/gemcitabine

3 61 T3NxM0 No Yes 11 (Death)

Cisplatin/ﬂuorouracil

4 43 T2NxM0 Yes Yes 91 (Follow-up)

Cisplatin/ﬂuorouracil RT

5 55 T3NxMo No Yes 6 (Death)

6 56 T3NxM0 No No 15 (Death)

7 65 T4NxM0 No No 5 (Death)

8 45 T2NxM0 Yes Yes RT Paclitaxe—palliative 17 (Death)

Cisplatin/ﬂuorouracil

9 47 T4N1M0 No No 38 (Death)

Cisplatin/ﬂuorouracil

10 65 T2NxM1 Yes Yes RT 15 (Death)

Cisplatin/gemcitabine

RT = radiotherapy; TNM = tumour, node, metastasis.

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Fig. 3 – Algorithm for the management of proximal urethral SCC. CT = computed tomography; FNAC = fine needle aspiration cytology; MRI = magnetic

resonance imaging; SCC = squamous cell carcinoma; SPC = suprapubic catheterisation.

and histology, proximal urethral SCC is one of the most

4. Discussion

aggressive urethral tumours [10–15]. More importantly,

In this series, we present a single-centre experience of diagnosis of early proximal urethral cancer is difficult,

managing rare proximal urethral SCC. Owing to the location and the presentation is often delayed by which time the

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tumour causes bothersome LUTS. In our cohort, all the pattern of lymphatic drainage. Although prophylactic

patients developed obstructive LUTS or infection due to lymph node dissection was initially considered controver-

locally advanced disease. Owing to these nonspecific symp- sial for urethral cancers, it is now accepted that urethral SCC

toms, diagnosis of PUC is usually delayed, which then should be managed along similar guidelines to those offered

impacts the commencement of treatment. Presentation for penile SCC with respect to the management of inguinal

with urethral bleeding is a sign that often leads to investi- lymph nodes [13]. When there are metastatic inguinal

gation and diagnosis. Unfortunately, this sign often occurs lymph nodes, the risk of metastatic pelvic lymph nodes

at the stage of advanced disease [14–16]. increases and often a pelvic lymphadenectomy is performed

Our cohort included patients with advanced disease with [10,11]. In this cohort, five patients underwent bilateral

80% presenting with pT3–4 G3 disease, and two patients inguinal lymphadenectomy because of suspicious lymph

had distant metastases at diagnosis. Our cohort reported a nodes found on imaging or positive preoperative FNAC,

very high mortality rate (90%) of the patients who died and only one patient underwent a pelvic lymphadenectomy.

within 13 mo of diagnosis. This is in line with the published The small number of patients in the cohort does not allow a

literature on PUC. According to a SEER database analysis, the comparison between patients treated with or without

median 5- and 10-yr OS rates of PUC are 46% and 29%, lymphadenectomy. However, based on our data, we can

respectively, whereas the cancer-specific survival rates are see that radical inguinal lymphadenectomy may be required

68% and 60%, respectively [12]. more often than anticipated based on the perceived drain-

Management of proximal PUC is still unclear owing to age of proximal lesions directly to the pelvic nodes.

the lack of randomised controlled studies, which is often Data regarding the role of adjuvant systemic chemother-

seen with rare cancers [13]. apy in urethral cancer are scarce and derived from small

In 1994, Dinney et al [15] reported on a series of 23 men retrospective case series. It has been suggested that adju-

suffering from PUC. A squamous cell tumour was found in vant chemotherapy has a role in locally advanced disease,

19 patients (83%). Three patients (13%) had TCC and one and this multimodality approach has been associated with

patient (4%) had an endodermal sinus tumour of the penile promising results. Selection of chemotherapy regimens is

urethra. The penile urethra was involved in 15 patients determined by the tumour histology. SCCs have tradition-

(65%) and the bulbomembranous urethra in eight patients ally been treated with cisplatin/5-FU or mitomycin C/5-FU

(35%) [15]. The study proposed that posterior urethral chemotherapy [13,18]. Within our cohort, four patients

tumours required an en bloc resection of the penis, scrotum, were treated with adjuvant cisplatin/5-FU or cisplatin/gem-

prostate, bladder, and inferior pubic rami. This study citabine chemotherapy. A comparison of the outcomes

reported that for proximal urethral cancers, the survival between surgery and surgery plus adjuvant therapy in this

rate was below 30% at 31 mo. Similar results were published series is not possible owing to the small number of patients.

from the Memorial Sloan-Kettering Hospital by Dalbagni However, in previous studies, local recurrence rates are

et al [17]. In this retrospective study, 46 patients had pri- high, ranging from 50% to 57% [18]. Even aggressive surgical

mary carcinoma of the bulbar (n = 28) and anterior (n = 18) resection with pelvic exenteration with or without pelvic

urethra. The median follow-up was 125 mo. The OS rate was lymph node dissection resulted in a 63% local recurrence

83% for superficial disease versus 36% for invasive tumours. rate [15,19]. Likewise, survival rates for surgical monother-

The OS rate was 26% for tumours of the bulbar urethra apy for proximal PUC have been reported between 0% and

versus 69% for tumours of the anterior urethra. 38% [20–22].

In our cohort, all the patients underwent radical surgery, EBRT and brachytherapy implants, or a combination of

and our preference was to offer a panurethrectomy with both has been used in the management of urethral tumours

radical prostatectomy and bladder neck closure combined [10–14]. Historically, EBRT has been used in the adjuvant

with urinary diversion using either a suprapubic catheter or setting following surgery for male urethral cancer. In our

a Mitrofanoff. Patients with a suprapubic catheter who cohort, two patients underwent pelvic EBRTafter chemother-

remained disease free for 12 mo were then offered conver- apy and two patients after surgery for pelvic recurrences.

sion to a Mitrofanoff. This offered local disease control in all Based on our small cohort, we have developed a new

the patients. algorithm for the management of proximal urethral SCC

Where there was a large disease burden at presentation, (Fig. 3). For those without metastatic disease on presenta-

neoadjuvant chemotherapy was used for several reasons: tion, FNAC of the inguinal lymph nodes is required before

preoperative chemotherapy may downsize the tumour and offering a panurethrectomy. Depending on the performance

therefore allow a complete resection [13], and possible status of the patient, we would either offer a temporary

complications from surgery might impair the administra- suprapubic catheterisation (SPC) with a delayed Mitrofanoff

tion of adjuvant chemotherapy. Four of our patients under- or construct a Mitrofanoff at the time of surgery. For those

went neoadjuvant chemotherapy, with one patient discon- with advanced disease or distant metastases on presenta-

tinuing treatment due to chemotherapy-related side effects. tion, neoadjuvant chemotherapy should be offered before

However, the disease burden is extensive, and patient per- proceeding to surgical resection.

formance status and symptoms dictate the need for early This study has some limitations, mainly a result of the

surgery even if it is on a palliative basis. fact that it is a retrospective review of a small case series.

The lymphatic spread of anterior urethral SCC is similar Unfortunately, the rare nature of this disease makes it very

to that of conventional penile SCC as they share the same difficult to perform large, randomised prospective studies.

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study and takes responsibility for the integrity of the data and the

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accuracy of the data analysis.

Clin North Am 2016;43:505–13.

Study concept and design: Castiglione, Muneer.

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Acquisition of data: Alnajjar, Christodoulidou.

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Analysis and interpretation of data: Castiglione. 503.

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Muneer, Freeman, Jameson, Mitra, Nigam, Malone.

[13] Gakis G, Witjes JA, Compérat E, et al. EAU guidelines on primary

Statistical analysis: Parnham, Castiglione.

urethral carcinoma. Eur Urol 2013;64:823–30.

Obtaining funding: Muneer.

[14] Grivas PD, Davenport M, Montie JE, Kunju LP, Feng F, Weizer AZ.

Administrative, technical, or material support: Castiglione, Muneer.

Urethral cancer. Hematol Oncol Clin North Am 2012;26:1291–314.

Supervision: Muneer.

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Other: None.

AC. Therapy and prognosis for male anterior urethral carcinoma: an

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Financial disclosures: Asif Muneer certiﬁes that all conﬂicts of interest,

[16] Johnson EK, Daignault S, Zhang Y, Lee CT. Patterns of hematuria

including specific financial interests and relationships and affiliations

referral to urologists: does a gender disparity exist? Urology

relevant to the subject matter or materials discussed in the manuscript

2008;72:498–502, discussion 502–3.

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stock ownership or options, expert testimony, royalties, or patents ﬁled,

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received, or pending), are the following: None.

[18] Dayyani F, Pettaway CA, Kamat AM, Munsell MF, Sircar K, Pagliaro

LC. Retrospective analysis of survival outcomes and the role of

Funding/Support and role of the sponsor: This study was supported by

cisplatin-based chemotherapy in patients with urethral carcinomas

the NIHR Biomedical Research Centre, University College London Hospital.

referred to medical oncologists. Urol Oncol 2013;31:1171–7.

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