Urethral Cancer

URETHRAL CANCER

URETHRAL CANCER

Epidemiology

–          1% of GU malignancies

–          Female urethral cancer is 3x more prevalent than male urethral cancer

Etiology

–          Nothing definitive

–          Chronic inflammation and infection: HPV 16,18; HSV

–          Urethral diverticula (clear cell carcinomas)

–          Urethral strictures (25-70% of urethral cancer patients)

Anatomy: FEMALE

–          Transitional epithelium proximal third; squamous in distal two thirds

–          Lymph drainage, distal third urethra: medial superficial inguinal nodes –> deep inguinal nodes –> external iliac nodes

–          Lymph drainage, proximal 2/3rds: obturator, hypogastric, and external iliac nodes (all three LN chains freely anastomose)

Anatomy: MALE

–          Transitional epithelium in posterior urethra (prostatic and membranous)

–          Pseudostratisfied epithelium in bulbar and penile urethra

–          Nonkeratinized stratified squamous epithelium in fossa

–          Lymph: penile urethra: presymphyseal plexus nodes –> inguinal nodes –> external iliac nodes

–          Lymph: bulbar and membranous urethra –> external iliac nodes

–          Lymph: prostatic urethra has three routes: 1) obturator and internal iliac nodes; 2) external iliac nodes; 3) sacral nodes

Symptoms

–          Female: frequency, dysuria, hematuria, blood spotting (rarely retention)

  • Can erode into vagina
  • 98% symptomatic at time of diagnosis

–          Male: obstructive urinary sx, perineal mass, rarely fistula, abscess, hematuria, spotting, discharge, pain

  • New onset stricture in a middle-aged man who has not undergone prior urethral instrumentation should arouse suspicion

Pathology: FEMALE

–          Squamous: 50-65% of primary cancers

–          Transitional: 15%

–          Adenocarcinoma: 10-12% (Skene’s glands can sometimes make PSA)

  • Clear cell adenocarcinoma: urethral diverticula; comprise 40% of adenoCAs
  • Mucinous/columnar or colloid cancers: resemble colorectal or endometrial CA

–          Neuroendocrine tumors: rare

  • Carcinoid, small cell

–          Carcinosarcoma, NHL, Hodgkin’s lymphoma, plasmacytoma

–          Melanoma: insensitive to radiation and chemo; very aggressive and presents late

Pathology: MALE

–          Squamous cell carcinoma: 50-90%; penile and bulbar urethra

–          Transitional: 2nd most common; prostatic urethra, membranous urethra

  • But could be found in penile urethra via urothelial metaplasia

–          AdenoCA: 3rd; metaplasia from periurethral glands or direct extension from rectal CA

  • Same prognosis as other types stage for stage
  • Cowper’s gland; next to membranous urethra; homolog to Bartholin glans in women
    • Cancer of Cowper’s extremely rare
    • Perineal pain and mass with LUTS
    • Poor prognosis; propensity to metastasize
    • Adenoid cystic carcinoma arises from Cowper’s

–          Location breakdown of tumor origination:

  • Membranous and bulbar urethra: 60%
  • Penile urethra: 30%
  • Prostatic urethra: 10%

Evaluation and Staging: FEMALE

–          H and P: pelvic and LN exam, speculum, cysto

  • LNs: 10-30% of women will have clinically suspicious groin nodes at time of diagnosis
  • LNs can be inflammatory or malignant; needle biopsy can confirm spread

–          Mets hematogenous to lungs, bones liver (lungs most common)

–          X rays: CXR, vaginal u/s, CT, MRI

  • MRI gadolinium enhanced good for assessing local invasion

Evaluation and Staging: MALE

–          Dx: TUR biopsy; occasional needle bx

–          H and P: palpate nodes, perineum

–          X rays: CT contrast enhanced or MRI to evaluate pelvic and paraaortic nodes

Primary Tumor
T0 No evidence of tumor
Ta Noninvasive papillary, polypoid, or verrucous carcinoma
Tis CIS
T1 Tumor invades subepithelial connective tissue
T2 Tumor invades any of the following:-          Corpus spongiosum

–          Prostate

–          Periurethral muscle

T3 Tumor invades any of the following:-          Corpus cavernosum

–          Beyond prostatic capsule

–          Anterior vagina

–          Bladder neck

T4 Tumor invades other adjacent organs
Lymph Nodes
N0 No node mets
N1 Mets to a single LN 2cm or less
N2 Mets to a single node > 2cm ORMultiple nodes
Metastasis
M1 Distant mets

MSKCC pathologic stage breakdown

–          pT2 30%

–          pT3 37%

–          pT4 11%

–          LN positive 22%

TREATMENT: overview

–          Women: because of proximity to functionally important structures (bladder, vagina, vulva, clitoris) treatment is often multimodal

–          Men: surgery is the primary therapy for most

  • Penile preserving chemoradiation alone or coordinated with conservative surgery may be appropriate in select patients with squamous or epidermoid carcinomas

SURGERY FEMALE

–          Distal tumors:

  • distal urethrectomy (for small volume with minimal extension (T1, T2, minimal T3 with clinically negative groin nodes)
  • electrofulguration or laser ablation can be used to treat small superficial cancers, esp of the meatus

–          LN groin mets: surgery as monotherapy not enough

  • Pre or postop radiation required after surgical LN removal
  • LN surgery: should be a limited resection since complete inguinal femoral (superficial and deep) LN dissection with radiation can lead to debilitating leg lymphedema

–          Proximal 2/3 urethral tumor

  • Anterior exenteration or total urethrectomy with continent conduit connected to the bladder; rarely appropriate as initial therapy
    • reserved for salvage of local radiation failure
    • Exception: total urinary incontinence from fistula
  • Radiation/chemo is first line

–          Vulvar invasion from distal urethra

  • Conservative local surgical therapy ok if sexual function (clitoris) can be preserved
  • Chemoradiation would be first line followed by limited surgical resection if tumor near clitoris

–          Results of surgery as monotherapy

  • Low stage disease: 80% 5 yr survival
  • Locally advanced disease: < 20% at 5 years
  • Most treatment plans: combination of surgery with adjuvant radiation

SURGERY MALE

–          Posterior urethra: bad prognosis

  • Radical surgery –> 30% 5 yr disease free survival VS 3% who did not undergo radical surgery

–          Anterior urethra: better prognosis (lower stage, better local control)

–          TUR and fulguration: good for superficial papillary tumors

–          Partial/total penectomy: invasive carcinoma of pendulous urethra

  • Excellent local control

–          Inguinal mets: B inguinal LNadenectomy can be therapeutic

  • Prophylactic LNadenectomy is controversial
  • There is high incidence of undetected microscopic positive LNs –> bilateral inguinal LNadenectomy with BPLND is appropriate for pts with invasive carcinoma of the pendulous urethra

–          Bulbomembranous urethra:

  • TUR or segmental resection adequate, but these tumors are rare since most pts present at advanced stage
  • Radical excision is the treatment of choice for most of these tumors: total penectomy and radical cystectomy, inferior pubectomy
    • 5 yr disease free survival is 30%
    • Primary cause of failure: lack of local control
    • Tumors here tend to be locally invasive and are apt to recur
    • Mets are a late event
    • Consider neoadjuvant chemoradiation for bulky tumors
      • One series, 2 of 4 patients rendered disease free
      • MSKCC data: 58% disease free survival when radical resection combined with preoperative radiation and excision of the inferior pubic rami

–          Prostatic urethra

  • Superficial tumor: good prognosis and treated with TUR
  • Very important to distinguish between primary carcinoma of the prostatic urethra VS primary TCC of the prostate (this carries poor prognosis)
  • Primary carcinoma of prostatic urethra symptoms: gross hematuria, LUTS
  • Surgery: cystoprostatectomy and urethrectomy
    • Most cases, tumor involves bulk of the prostate with variable extension to the bulbomembranous urethra or to the bladder neck and trigone

Radiation: FEMALE

–          Adjuvant good for local control and LN treatment

–          Combo surgery with modest dose adj radiation (45-50Gy) allows for more conservative resection

–          Can be given pre or post dependent on extent of invasion

  • MSKCC suggested data for preop radiation

–          Radiation should target inguinal and pelvic LNs and the primary tumor site

  • Reduces incidence of groin failure from 52% to 10 % (80% reduction)

–          Brachytherapy also an option

  • Allows potential higher doses of radiation to tumor than XRT
  • Ok for small distal  urethral tumors that are well defined (c.f. more extensive tumors extending to the bladder outlet are better suited to XRT)

–          Combo brachy + XRT may have better local control and survival

–          Complications:

  • Urethral stenosis stricture
  • Necrosis with fistula
  • Radiation cystitis

Radiation: MALE

–          General: not effective as sole modality and may result in stricture and chronic edema

–          XRT over 5-6 weeks common

–          Chemo radiation: 5FU, MMC, radiation to genitals, perineum, internal and external nodes

  • 5 yr overall survival 60%, disease specific survival 83%
  • 5 yr disease free survival after chemoradiation: 54%
  • 5 yr disease free survival after chemoradiation and surgery: 72%

–          Squamous cell CA can be treated with penile-sparing chemo radiation

  • Not tried in TCC

Chemotherapy:

–          Cisplatin: best single agent

–          MVAC regimen: methotrexate, vinblastine, doxorubicin, cisplatin

–          Female: carboplatin and paclitaxel

–          Radiation sensitizers: 5FU, cisplatin

–          Neoadjuvant theoretically helpful, but no evidence

Results:

–          Predictors of survival: primary stage, nodal status, site of disease (anterior vs posterior)

–          Overall survival 5 to 10 yrs: 30-40%

–          Prognosis:

  • Overall survival 83% for superficial < T1 disease
  • 36% for invasive tumors T3 and T4
  • 26% for bulbmembranous urethra
  • 69% for anterior urethral tumors

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