Eric A. Klein, MD, FACS
Samuel Haywood, MD
BASICS
DESCRIPTION
• 1st described in 1952 by Melicow and Hollowell—originally noted as Bowen’s disease of the prostatic urethra (1)
• Can occur in 1 of the 3 forms
– Primary urothelial carcinoma (UC) of the prostate
– Direct extension of bladder UC
– Nondirect extension of bladder UC
• Multiple prior staging systems
• Primary UC of the prostate—TNM staging 2001
– Tis pu—carcinoma in situ (CIS) affecting prostatic urethra
– Tis pd—CIS affecting prostatic ducts
– T1—tumor invading subepithelial connective tissue
– T2—tumor invading prostatic stroma, spongiosum body, periurethral muscle
– T3—tumor invading cavernous body prostatic capsule or bladder neck (extraprostatic extension)
– T4—tumor that invades surrounding organs
• Prostatic UC concurrent with bladder UC
– Prior TNM staging defined prostatic invasion of bladder UC as T4a disease
– However, given the heterogeneity of this classification, did not accurately predict survival
– Most recent TNM classification (2010) clarifies T4a as prostatic invasion from direct transmural or extravesical spread
– Stromal invasion from subepithelial invasion of prostatic urethra classified as organ confined disease
• Synonyms: Transitional cell carcinoma (TCC)
EPIDEMIOLOGY
Incidence
• Of all patients with bladder UC undergoing cystoprostatectomy, 12–48% will have prostatic involvement (1).
• However, underreporting of prostatic involvement likely present in radical cystectomy specimens.
• Prostatic involvement of UC is a predictor of understaging in recurrent nonmuscle invasive bladder UC (2).
• Stromal invasion of the prostate is present in 7–17% of cystectomy specimens (1).
• Primary UC of the prostate is rare malignancy—∼1–4% of all primary prostatic tumors (1).
Prevalence
N/A
RISK FACTORS
• Risk factors for prostatic involvement
– CIS of the bladder
– Multifocal disease in bladder
– High-stage bladder UC
– Previous involvement of prostate
– Tumors involving trigone or bladder neck
• Risk factors for stromal invasion—presence of CIS (odds ratio 3.2) and location of tumor at or below trigone (odds ratio 3.3) (2)
Genetics
• Genetics:
– No specific genes associated with prostatic UC
PATHOPHYSIOLOGY
• May involve any part of the prostatic urethra, prostatic duct system, or prostate stroma
• Arises from extension of bladder primary tumor, implantation of malignant cells, or transformation secondary to carcinogenic field effect
• Metastases commonly to bone, lung, liver
ASSOCIATED CONDITIONS
Almost all cases (>95%) associated with bladder UC
GENERAL PREVENTION
General Prevention: Prevention strategies similar as to bladder UC
DIAGNOSIS
HISTORY
• Risk factors similar to bladder UC—tobacco exposure, chemical/workplace exposures
• Hematuria is the most common complaint
• Other symptoms include obstructive voiding symptoms, hematospermia, or systemic symptoms (bone pain, fatigue, weight loss)
PHYSICAL EXAM
• Hematuria or bloody urethral discharge
• Lymphadenopathy
• Abnormal digital rectal exam
DIAGNOSTIC TESTS & INTERPRETATION
Lab
• PSA: Elevations rare in UC
• Urine studies: Urinalysis, urine cytology
Imaging
• Staging workup involves abdominal and chest imaging (CT vs. MRI) to identify local, regional, and distant spread
• Bone scan: UC lesions osteolytic vs. adenocarcinoma (ADC) lesions osteoblastic
Diagnostic Procedures/Surgery
• Cystoscopy—sensitivity 83.3%, specificity 95.1% (2)[C]
– Focus on macroscopic disease and concurrent bladder lesions
– Unlikely to find microscopic disease or CIS
• Transurethral biopsy (3)[C]
– No clear consensus on timing or methods
– Spectrum of sampling recommended in literature from few resectoscope swipes to complete TURP
– Pathologic analysis shows involvement most frequently observed around verumontanum
– Biopsies recommended if positive cytology and/or macroscopic lesions
• Methods of biopsy have varying accuracy (1)[C]
– Transurethral resection (TUR) biopsy is most accurate: 90% accuracy
– Fine needle aspirate (FNA) biopsies: 40% accuracy
– Transrectal needle biopsy: 20% accuracy
• Biopsies poor at accurately detecting stromal invasion—sensitivity 53%, specificity 77%, positive predictive value (PPV) 45%
• Diagnosis of primary UC of prostate requires both transrectal prostate biopsy and random biopsies of bladder to exclude concurrent UC in the bladder (4)[C].
Pathologic Findings
• Urothelial cancer in situ (CIS) of the prostate:
– Can involve the prostatic urethra, the prostatic ducts, and the prostatic acini.
– Most prostate urothelial CIS arises along with bladder urothelial neoplasia or from pagetoid spread from the bladder into the prostate.
– Partial or complete replacement of urethra or duct by atypical urothelial cells with pleomorphic nuclei, coarse chromatin, and frequent mitoses. Fibrosis and chronic inflammation may be seen.
• Invasive UC into prostatic stroma consists of irregular nests, clusters, or single atypical cells that infiltrate prostatic tissue. There are 2 distinct pathways that invade the prostate:
– Invasive carcinoma arising from the prostatic urethra and duct, which is often associated with CIS within the prostatic duct or acini.
– Prostatic stroma invasion, in which bladder cancer penetrates from posterior periprostatic soft tissue or the bladder neck.
• Immunohistochemistry (IHC) of prostatic urethral carcinoma is identical to bladder UC: Positive for cytokeratin (CK) 7 (90%), and high–molecular-weight CK (HMWCK) 34βE12 (59%), and do not stain positive for PSA or PAP.
DIFFERENTIAL DIAGNOSIS
• High-grade prostatic intraepithelial neoplasia (HGPIN)
• Prostatic adenocarcinoma
• Other uncommon prostatic tumors
TREATMENT
GENERAL MEASURES
• Risk reduction
• Assessment of the degree of invasion is imperative—management decision strongly dependent on this
MEDICATION
First Line
• Bacille Calmette–Guerin (BCG)
– As with primary bladder UC, BCG efficacious for prostatic urethra CIS
– Evidence regarding depth of penetration of BCG into prostatic stroma is unclear
– CIS of prostatic urethra has response rates to BCG of ∼70–100%. Response rate when combined with bladder primary decreases to 47–72% (1)[C].
– Response rate of bladder CIS of prostatic urethra to BCG immunotherapy is ∼70–100%.
– Some propose TUR prior to BCG therapy to increase exposure—improved prevention of recurrence compared to TUR alone (5)[C].
– Absolute contraindications to BCG: Active urinary infection, gross hematuria, traumatic catheterization.
Second Line
N/A
SURGERY/OTHER PROCEDURES
• Options include TUR alone, TUR with BCG (as in “First line" above), and radical cystoprostatectomy
• Radical cystoprostatectomy is the treatment of choice for stromal-invasive prostatic UC. It should also be recommended for patients with progression or recurrence after nonsurgical therapies. (1,2,5)[C]
• Cystoprostatectomy may also be considered as treatment for prostatic UC involving the prostatic ducts.
• Pelvic lymphadenectomy should be performed as with primary bladder UC.
• Options for diversion similar to bladder UC. While debated, prostatic urethral involvement of UC is not an absolute contraindication to orthotopic diversion (1).
ADDITIONAL TREATMENT
Radiation Therapy
Radiotherapy has insufficient data to make recommendations (1)[C]
Additional Therapies
• Chemotherapy
• Data not sufficient to evaluate use of neoadjuvant/adjuvant chemotherapy with respect to prostatic UC (1)[C]. Data from bladder UC shows ∼5% survival advantage with neoadjuvant chemotherapy
Complementary & Alternative Therapies
N/A
ONGOING CARE
PROGNOSIS
• Degree of prostatic invasion has prognostic implications with respect to 5-yr survival rates (1)
– Involvement of the urethral mucosa: 100%
– Ductal/acinar involvement: 50%
– Stromal invasion: 40%
• In addition, the path of invasion from concurrent bladder UC also has significant prognostic role on 5-yr survival rate (1)
– Contiguous from bladder: 7% survival
– Noncontiguous from bladder: 46%
• Prostatic stromal invasion is associated with higher rates of node-positive disease as well as decreased survival (3)[C]
• Decreased survival associated with prostatic stromal invasion persists regardless of concurrent bladder UC stage (4) or surgical resection (3)[C]
COMPLICATIONS
• Adverse reactions to BCG therapy
– Local reactions include hematuria, fever, dysuria
– BCG infectious complications include fevers and/or sepsis, and are managed with hospitalization and antibiotics (eg, isoniazid, rifampin, ethambutol, and fluoroquinolones)
• Erectile dysfunction may occur after cystoprostatectomy
• Bowel diversion risks include electrolyte abnormalities, nutritional deficiencies, bowel obstruction, and ureteral strictures
FOLLOW-UP
Patient Monitoring
• Detection of prostatic relapse can be difficult, requiring frequent and/or lifelong biopsies of bladder, neck, and prostate.
• Surveillance of prostatic urethra recommended with high-risk bladder UC or prior prostatic involvement.
• Monitor with urine cytology, cystoscopy, and transurethral prostate biopsies.
• Biopsy is surveillance of choice with positive cytology and no identifiable bladder lesion. (1)
• Random biopsies occasionally recommended given frequent microscopic disease.
Patient Resources
N/A
REFERENCES
1. Walsh DL, Chang SS. Dilemmas in the treatment of urothelial cancers of the prostate. Urol Oncol. 2009;27(4):352–357.
2. Roupret M, Wood D, Bochner BH, et al. ICUD-EAU International Consultation on Bladder Cancer 2012: Urothelial carcinoma of the prostate. Eur Urol. 2013;63(1):81–87.
3. Liedberg F, Chebil G, Månsson W. Urothelial carcinoma in the prostatic urethra and prostate: Current controversies. Expert Rev Anticancer Ther. 2007;7(3):383–390.
4. Esrig D, Freeman JA, Elmajian DA, et al. Transitional cell carcinoma involving the prostate with a proposed staging classification for stromal invasion. J Urol. 1996;156(3):1071–1076.
5. Palou J, Baniel J, Klotz L, et al. Urothelial carcinoma of the prostate. Urology. 2007;69(1 suppl):50–61.
ADDITIONAL READING
Patel AR, Cohn JA, Abd El Latif A, et al. Validation of new AJCC exclusion criteria for subepithelial prostatic stromal invasion from pT4a bladder urothelial carcinoma. J Urol. 2013;189(1):53–58.
See Also (Topic, Algorithm, Media)
• Bladder Cancer, Urothelial, Invasive (T2/3/4)
• Bladder Cancer, Urothelial, Superficial (CIS, Ta, T1)
• Prostate Cancer, General
• Prostate Cancer, Urothelial Images 
CODES
ICD9
• 185 Malignant neoplasm of prostate
• 198.1 Secondary malignant neoplasm of other urinary organs
• 233.6 Carcinoma in situ of other and unspecified male genital organs
ICD10
• C61 Malignant neoplasm of prostate
• C79.11 Secondary malignant neoplasm of bladder
• D09.19 Carcinoma in situ of other urinary organs
CLINICAL/SURGICAL PEARLS
• Incidental prostatic involvement frequently found at cystoprostatectomy.
• Detecting stromal invasion important for determination of appropriate therapy.
• Involvement of prostatic urethra only may be treated with BCG therapy.
• Stromal invasion of prostate necessitates radical cystoprostatectomy.
• Prognosis highly dependent on degree of prostatic invasion.