Key Components in the Evaluation and Management of Primary Urethral Carcinoma

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Journal of MedVerse Research & Practice

nurexus.com

Key Components in the Evaluation and Management of Primary

Urethral Carcinoma

Dr. Deshmuk

, Dr. Varma

, Dr. Yuvi

Assistant Professor, Department of Urology

Saveetha Medical College & Research Institute, Thandalam, Kanchipuram

Email ID: deshmukdr@gmail.com

Submission Date: 20.11.2023

Accepted Date: 16.12.2023

Published Date: 31.12.2023

article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits

unrestricted use, distribution, and reproduction in any medium, provided the original author(s) and source are credited.

Abstract

Primary urethral carcinoma (PUC) is an uncommon cancer with few therapeutic alternatives. This overview aims

to summarize current approaches for managing this condition. The majority of existing research consists of

retrospective analyses with limited sample sizes and unclear treatment guidelines. Diagnosing this ailment

presents significant challenges. Tumors located in the proximal (posterior) region may go undetected until the

disease has progressed, as they are challenging to detect through physical examination. Additionally, early-stage

tumors in distant areas might be mistaken for infections, leading to delayed treatment and potentially worse

outcomes. In our case, the patient received a diagnosis of primary urethral cancer at the First Clinical Hospital of

Yichang, confirmed through cystoscopy and biopsy procedures. Given her elderly status, compromised health,

and financial constraints, she opted against undergoing extensive surgical intervention. The absence of a

standardized protocol for treating primary urethral cancer in clinical settings has led to variations in surgical

approaches and post-operative adjuvant therapies across different medical institutions, resulting in diverse

prognostic outcomes. Further research, ideally in the form of randomized prospective controlled trials, is

necessary to establish uniform treatment strategies for patients.

Keywords: Primary, cystoscopy, urethral carcinoma

Introduction

Primary urethral carcinoma represents a neoplastic entity, constituting less than 1% of all malignancies

(1,2). PUC can be categorized histologically into three principal types: urothelial carcinoma (UC),

squamous cell carcinoma (SCC), and adenocarcinoma (AC) (3). The optimal therapeutic strategies for

PUC remain inadequately delineated, necessitating consensus regarding the most efficacious treatment

modalities (4). In male patients, Squamous cell carcinoma constitutes 12-30% of cases, while

adenocarcinoma represents 5-16% [5,6,7].

Among female patients with primary urethral carcinomas (PUCs), urothelial carcinoma (UC) similarly

predominates, comprising approximately 45% of cases. However, adenocarcinoma is diagnosed more

frequently than squamous cell carcinoma, with incidence rates of 29% and 19%, respectively [8].

Dirksen et al. also identified adenocarcinoma as the most aggressive variant of malignancy, followed by

carcinoma in terms of severity [8]. The emergence of adenocarcinoma as a lymph node metastasis likely

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elucidates this observation, further contributing to disease progression [8]. Early detection of PUC is

imperative for effective intervention, as this malignancy often manifests without overt symptoms and

lacks specific screening biomarkers. During intermediate and advanced stages, patients may report

significant symptoms, including urinary obstruction, dyspareunia, irritation, and hematuria. Although

various diagnostic modalities, including MRI scan and CT scan, are utilized for PUC detection,

cystoscopy and biopsy are regarded as the most definitive diagnostic techniques. Primary urethral

carcinomas (PUC) are infrequent malignancies, representing less than 1% of all cancer diagnoses.

The rarity of this cancer type has culminated in the absence of standardized management protocols.

Various medical institutions implement diverse strategies predicated on the specific histological

subtypes of PUC. The limited case numbers have resulted in a lack of consensus on optimal therapeutic

approaches for this rare urological malignancy. Among different racial demographics, African

Americans demonstrate the highest incidence rate (3.33/1,000,000), followed by Caucasians

(1.72/1,000,000), while Hispanics and other racial groups reflect an equivalent rate (1.57/1,000,000)

[11]. An analysis conducted by the SEER program indicated that the incidence of PUC peaked in

individuals aged over 75. The study from the SEER program established that the highest rate of PUC

was observed in the cohort exceeding 75 years (7.6 per million),

Diagnostic assessment

Clinical history

Initially, PUC may not display any specific symptoms, leading to potential misdiagnosis as common

urethral strictures, especially in females. More than 70% of women experience recurrent urinary tract

infections, symptoms of irritable voiding, or discomfort during sexual intercourse. When diagnosed, the

majority of female patients are identified as having T3-4N0M0 stage disease (29%), whereas most male

patients are found to have T1N0M0 stage disease (32%) [13]. Of greater significance, patients with

penile urethral cancer (PUC) typically present with symptoms such as visible blood in the urine or

bloody discharge from the urethra. In cases of locally advanced PUC (T3 / T4)(45 %e57 %), patients

may experience additional symptoms, including an extra-urethral mass, obstruction of the bladder outlet,

pain in the pelvic region, formation of a urethrocutaneous fistula, development of an abscess, or pain

during sexual intercourse[ 14].

Clinical examination

For male patients, evaluation included a digital rectal examination, while female patients underwent a

pelvic exam that involved palpation of the urethra.. In male patients, potential induration of the external

genitalia can be detected through manual examination, using a finger inserted into the rectum. For

female patients, a thorough examination of both inguinal regions should be conducted through palpation

to evaluate the local clinical stage and detect any enlarged lymph nodes (LN). This assessment should

include noting the position, dimensions, and movability of the nodes [20]. Additionally, a two-handed

examination is necessary to determine the local clinical stage and rule out the possibility cancers [21].

Urinary cytology

Urine specimen evaluation can be employed to identify PUC with a sensitivity range of 50% to 80%

[22]. The effectiveness of urinary cytology in detecting cancer varies based on the pathological type.

Studies revealed that male patients showed sensitivity rates of 80% for urothelial carcinoma (UC) and

50% for squamous cell carcinoma (SCC). Conversely, female patients demonstrated sensitivity rates of

50% for UC and 77% for SCC [23].

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Cytological assessment of urine specimens

To evaluate, Physicians can employ cystoscopy and urethral biopsy techniques [23]. When obtaining

biopsy samples, it is important to mark the sites (proximal or distal) and provide this information, along

with clinical details, to the pathologist. Additionally, urethral cystoscopy serves as a method to exclude

the presence of associated bladder tumors, as urethral cancer may originate in the bladder through micro

metastases [24]. For histological diagnosis, larger lesions can be removed through transurethral

resection. When ulcerative urethritis or prostatic ducts are suspected, a resectoscope biopsy of the

prostatic urethra may be beneficial in identifying ulcerative prostatitis. This procedure is elaborated on

in subsequent sections.

Diagnosis of UC of the prostate

Table 1: Reproduced with authorization from the American Joint Committee on Cancer TNM staging

system for urethral carcinoma (15). The T category indicates the degree of tumor penetration, the N

category denotes the extent of lymph node involvement, and the M category signifies the presence of

distant metastases.

Stages

Details

T stage

The tumor cannot be assessed

Tis

Carcinoma in situ

Non-invasive carcinoma

Lamina propria invasion

Spongiosum, prostate, or periurethral muscle invasion

Cavernosum, vagina, or bladder neck invasion

All regional nodes are negative

N stage

All regional nodes are negative

Single positive node <2 cm

Single positive node >2 cm or multiple nodes

M stage

No metastasis

Distant metastasis

Grading of urothelial urethral carcinoma

PUNLMP

Papillary urothelial neoplasm of low malignant potential

Low grade

Well differentiated

High grade

Poorly differentiated

Grading of nonurothelial urethral carcinoma

Tumor grade not assessable

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Well differentiated

Moderately differentiated

Poorly differentiated

TNM = tumor-node-metastasis; WHO = World Health Organization.

Primary urethral cancer (PUC) is characterized by its irregular nature and difficulty in detection, often

leading to late-stage diagnosis [18]. The primary methods for identifying PUC include physical

examination, cystoscopy followed by tissue biopsy for confirmation, and imaging techniques. Due to

its scarcity and elusive nature, this malignancy may go unnoticed until advanced stages, resulting in

delayed treatment initiation. This postponement in intervention allows the disease to progress to a more

complex state, ultimately reducing overall patient survival rates. Considering that better outcomes are

linked to early identification and asymptomatic PUC [18,19], it is essential to detect these tumors

before symptoms appear. To evaluate local clinical staging and exclude the possibility of colorectal or

gynecological cancers, a bimanual physical examination should be performed [21].

Diagnostic imaging

In patients with urethral carcinoma, radiography can be employed to evaluate the extent of local tumor

growth, identify lymphatic spread, and detect distant metastases. Identifying and categorizing urethral

cancer can be accomplished through the use of several diagnostic methods, including a biopsy of the

tumor, as well as imaging techniques such as MRI scan and CT scan. [25]. For imaging studies, it is

strongly advised to conduct CT scans of the thorax, abdominal region, and pelvic area. These imaging

techniques are essential for evaluating soft tissue and lymph node involvement, as well as detecting any

remote metastases. A thorough CT examination should include both pre-contrast and post-contrast

imaging and delayed-phase scans to enable a thorough evaluation of the entire urinary system. Recent

studies have demonstrated that MRI surpasses other imaging techniques in detecting disease onset,

owing to its exceptional sensitivity in evaluating local tumor involvement and monitoring responses to

chemoradiotherapy [26,27].

Treatment of PUC

The male urethra has anterior and posterior sections, with lymphatic drainage differing between the two.

Anterior lymph flows to the inguinal nodes before reaching the pelvic nodes, while posterior lymph

drains directly to the pelvic nodes. Urethral tumours with cell type, with the bubo membranous urethra

most commonly affected (60%), followed by the penile urethra and prostate. Urothelial carcinoma is the

predominant type (77.6%), with histological variations based on location. Symptoms include dysuria,

urinary retention, and perineal pain.

The female urethra, shorter at 3-4 cm, is divided into anterior and posterior sections with distinct

lymphatic pathways. Urothelial cancer is highly prevalent, with adenocarcinoma more frequent in

younger women. Adenocarcinoma from paraurethral glands has clear cell and columnar/mucinous

variants, with distinct immunohistochemical markers. Most women with PUC present with urinary

symptoms or recurrent infections.

Treatment of PUC in males

No specific treatment guidelines exist for urethral CIS, which resembles bladder CIS more than penile

CIS. Without treatment, urethral CIS leads to lymph node involvement in 50% of cases. Surgical

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urethral removal to achieve clear margins is a key approach, and lymph node dissection is recommended

for lymphadenopathy or high-grade disease to improve survival outcomes.

Distal urethral tumours have better survival rates than proximal ones. Penis-preserving surgery for distal

urethral carcinoma has shown no local recurrence with margins under 5 mm in select cases, though risks

increase with positive proximal margins or lymphatic invasion. Organ-sparing treatments should be

reserved for carefully selected patients.

For men with urethral tumours, treatment includes urethral resection, with or without

cystoprostatectomy. Low-grade lesions may undergo transurethral resection, while T2 lesions often

require penectomy and pelvic lymphadenectomy. Proximal tumours generally result in poor outcomes

and may necessitate chemoradiotherapy.

Treatment of PUC in females & Anterior Urethra

Treatment strategies for anterior female PUC are determined by the extent of the tumor. For small

tumors located in the distal urethra, laser therapy or endoscopic resection may be employed. Exophytic

tumors can be addressed through partial urethrectomy. Nevertheless, there is limited research

supporting the effectiveness of urethral-sparing approaches for local control. A study conducted by

DiMarco et al. revealed five-year survival rates ranging from 64% to 66%. Common post-treatment

complications included urinary incontinence (42%) and retention (8%).

For advanced cases, bladder-preserving surgeries, such as transvaginal radical urethrectomy, offer local

cure potential. Radical urethrectomy provides the best outcomes for brachytherapy and alternative,

achieving a five-year survival rate of 71-74%. However, complications like radiation cystitis and

urethral strictures occur in 16-49% of cases.

Posterior Urethra

When comparing primary urethral carcinoma (PUC) of the anterior and posterior female urethra, patients

receiving surgical, radiotherapy, or combinatory treatments exhibited significantly inferior outcomes for

posterior PUC. Specifically, the five-year 25% versus 54%, and disease-specific survival rates were 46%

against 69%. The surgical protocol for anterior pelvic exenteration necessitates extensive pelvic lymph node

dissection and resection of multiple organs; however, evaluating aggressive surgical outcomes is

complicated by concurrent therapies. A study by Dalbagni et al. indicated a median post-cystectomy

survival of 36 months, with another investigation revealing five-year survival rates of 39% and 52%

respectively. Alternatively, Milosevic et al. examined radiation therapy alone, reporting a 37% relapse-free

rate and a 20% cause-specific survival rate over 7.6 years, with brachytherapy not enhancing outcomes in

advanced cases. Complications from radiation therapy were prevalent, with a significant percentage of

patients experiencing adverse effects, highlighting the necessity for multimodal treatment strategies to

optimize outcomes in advanced PUC.

Follow-up

Managing PUC patients necessitates individualized follow-up based on each patient's specific risk factors.

Nevertheless, comprehensive guidelines for surveillance protocols are currently lacking. The European

Association of Urology recommendations only indicate that patients who undergo urethra-preserving

procedures should receive more intensive follow-up care [38].In one research, the PUC monitoring protocol

encompassed outpatient consultations, urine cytology examinations, urethrocystoscopy procedures,

uroflowmetry, and cross-sectional imaging. These were conducted 3-6 months after surgery and

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subsequently every 6 months for a minimum of 2 years [39]. A separate investigation monitored PUC

patients initially every 2-4 weeks in an outpatient setting, followed by biannual check-ups. For patients who

underwent extensive urethral reconstruction, a comprehensive follow-up regimen was implemented. This

included laboratory assessments, uroflowmetry, regressive urethrography, and annual urine cytology tests

[40].

Summary

Primary urethral carcinoma (PUC) is an exceptionally rare malignancy, representing less than 1% of all

cancers. It encompasses three major histological subtypes: urothelial carcinoma (UC), squamous cell

carcinoma (SCC), and adenocarcinoma (AC). In males, SCC accounts for 12–30% of cases and AC for 5–

16%, whereas in females, UC predominates (45%), followed by AC (29%) and SCC (19%).

Adenocarcinoma is identified as the most aggressive subtype, often linked to lymph node metastasis and

poorer outcomes. The disease typically presents in individuals above 60 years of age, with a slightly higher

incidence among African Americans.

Early-stage PUC is often asymptomatic, leading to delayed diagnosis and advanced-stage presentation.

Common symptoms include haematuria, urinary obstruction, pain during intercourse, and recurrent urinary

tract infections. Clinical evaluation involves physical examination (digital rectal or pelvic exam),

cystoscopy, and biopsy. Urinary cytology demonstrates variable sensitivity depending on tumor histology,

being more effective for UC than SCC. Imaging modalities such as CT and MRI are crucial for assessing

local invasion, lymph node involvement, and distant metastasis. MRI is particularly advantageous for

evaluating tumour extent and treatment response.

PUC staging follows the TNM system, with grading based on histological differentiation. Management

depends on tumour location, stage, and patient sex. In men, distal urethral tumours may be managed with

organ-sparing surgery if margins are clear, while proximal tumours often necessitate penectomy or

chemoradiotherapy. In women, treatment varies according to tumour site: anterior urethral tumours may be

treated with laser ablation or partial urethrectomy, whereas advanced or posterior tumours often require

radical urethrectomy or exenteration. Radiation therapy may serve as a primary or adjunctive treatment but

carries risks of complications such as cystitis and strictures.

Prognosis is influenced by tumour stage, location, and histological type. Generally, anterior urethral tumours

have better outcomes than posterior ones. Five-year survival rates range between 25% and 70%, depending

on the treatment modality and stage. Post-treatment follow-up is essential due to the risk of recurrence.

Although no standardized surveillance protocol exists, periodic cystoscopy, urine cytology, uroflowmetry,

and imaging every 3–6 months are commonly recommended.

Overall, the rarity of PUC has limited large-scale research, resulting in non-uniform treatment strategies.

Early detection through vigilant clinical evaluation and multimodal management involving surgery,

radiotherapy, and chemotherapy can improve survival outcomes. Multicentric collaborative studies are

needed to establish standardized diagnostic and therapeutic guidelines for this uncommon urological

malignancy.

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Conclusion

When addressing PUC, it is essential to consider the tumour’s gravity, clinical characteristics, and site. In

contrast, those with more advanced conditions should receive an optimal combination of treatments. To

explore more effective PUC management strategies, increased collaboration among multiple institutions is

necessary in the future.

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