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URETHRAL CANCEREpidemiology1% of GU malignanciesFemale urethral cancer is 3x more prevalent than male urethral cancerEtiologyNothing definitiveChronic inflammation and infection: HPV 16,18; HSVUrethral diverticula (clear cell carcinomas)Urethral strictures (25-70% of urethral cancer patients)Anatomy: FEMALETransitional epithelium proximal third; squamous in distal two thirdsLymph drainage: distal third urethra medial superficial inguinal nodes deep inguinal nodes external iliac nodesLymph drainage: proximal 2/3rds obturator, hypogastric, and external iliac nodes (all three LN chains freely anastomose)Anatomy: MALETransitional epithelium in posterior urethra (prostatic and membranous)Pseudostratisfied epithelium in bulbar and penile urethraNonkeratinized stratified squamous epithelium in fossaLymph: penile urethra presymphyseal plexus nodes inguinal nodes external iliac nodesLymph: bulbar and membranous urethra external iliac nodesLymph: prostatic urethra has three routes: 1) obturator and internal iliac nodes; 2) external iliac nodes; 3) sacral nodesSymptomsFemale: frequency, dysuria, hematuria, blood spotting (rarely retention)Can erode into vagina98% symptomatic at time of diagnosisMale: obstructive urinary sx, perineal mass, rarely fistula, abscess, hematuria, spotting, discharge, painNew onset stricture in a middle-aged man who has not undergone prior urethral instrumentation should arouse suspicionPathology: FEMALESquamous: 50-65% of primary cancersTransitional: 15%Adenocarcinoma: 10-12% (Skene’s glands can sometimes make PSA)Clear cell adenocarcinoma: urethral diverticula; comprise 40% of adenoCAsMucinous/columnar or colloid cancers: resemble colorectal or endometrial CANeuroendocrine tumors: rareCarcinoid, small cellCarcinosarcoma, NHL, Hodgkin’s lymphoma, plasmacytomaMelanoma: insensitive to radiation and chemo; very aggressive and presents latePathology: MALESquamous cell carcinoma: 50-90%; penile and bulbar urethraTransitional: 2nd most common; prostatic urethra, membranous urethraBut could be found in penile urethra via urothelial metaplasiaAdenoca: 3rd; metaplasia from periurethral glands or direct extension from rectal CASame prognosis as other types stage for stageCowper’s gland; next to membranous urethra; homolog to Bartholin glans in womenCancer of Cowper’s extremely rarePerineal pain and mass with LUTSPoor prognosis; propensity to metastasizeAdenoid cystic carcinoma arises from Cowper’sLocation breakdown of tumor origination:Membranous and bulbar urethra: 60%Penile urethra: 30%Prostatic urethra: 10%Evaluation and Staging: FEMALEH and P: pelvic and LN exam, speculum, cystoLNs: 10-30% of women will have clinically suspicious groin nodes at time of diagnosisLNs can be inflammatory or malignant; needle biopsy can confirm spreadMets hematogenous to lungs, bones liver (lungs most common)X rays: CXR, vaginal u/s, CT, MRIMRI gadolinium enhanced good for assessing local invasionEvaluation and Staging: MALEDx: TUR biopsy; occasional needle bxH and P: palpate nodes, perineumX rays: CT contrast enhanced or MRI to evaluate pelvic and paraaortic nodesPrimary TumorT0No evidence of tumorTaNoninvasive papillary, polypoid, or verrucous carcinomaTisCIST1Tumor invades subepithelial connective tissueT2Tumor invades any of the following:Corpus spongiosumProstatePeriurethral muscleT3Tumor invades any of the following:Corpus cavernosumBeyond prostatic capsuleAnterior vaginaBladder neckT4Tumor invades other adjacent organsLymph NodesN0No node metsN1Mets to a single LN 2cm or less N2Mets to a single node > 2cm ORMultiple nodesMetastasisM1Distant metsMSKCC pathologic stage breakdownpT2 30%pT3 37%pT4 11%LN positive 22%TREATMENT: overviewWomen: because of proximity to functionally important structures (bladder, vagina, vulva, clitoris) treatment is often multimodalMen: surgery is the primary therapy for mostPenile preserving chemoradiation alone or coordinated with conservative surgery may be appropriate in select patients with squamous or epidermoid carcinomasSURGERY FEMALEDistal 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 meatusLN groin mets: surgery as monotherapy not enoughPre or postop radiation required after surgical LN removalLN surgery: should be a limited resection since complete inguinal femoral (superficial and deep) LN dissection with radiation can lead to debilitating leg lymphedemaProximal 2/3 urethral tumorAnterior exenteration or total urethrectomy with continent conduit connected to the bladder; rarely appropriate as initial therapyreserved for salvage of local radiation failureException: total urinary incontinence from fistulaRadiation/chemo is first lineVulvar invasion from distal urethraConservative local surgical therapy ok if sexual function (clitoris) can be preservedChemoradiation would be first line followed by limited surgical resection if tumor near clitorisResults of surgery as monotherapyLow stage disease: 80% 5 yr survivalLocally advanced disease: < 20% at 5 yearsMost treatment plans: combination of surgery with adjuvant radiationSURGERY MALEPosterior urethra: bad prognosisRadial surgery 30% 5 yr disease free survival VS 3% who did not undergo radical surgeryAnterior urethra: better prognosis (lower stage, better local control)TUR and fulguration: good for superficial papillary tumorsPartial/total penectomy: invasive carcinoma of pendulous urethraExcellent local controlInguinal mets: B inguinal LNadenectomy can be therapeuticProphylactic LNadenectomy is controversialThere is high incidence of undetected microscopic positive LNs bilateral inguinal LNadenectomy with BPLND is appropriate for pts with invasive carcinoma of the pendulous urethraBulbomembranous urethra:TUR or segmental resection adequate, but these tumors are rare since most pts present at advanced stageRadical excision is the treatment of choice for most of these tumors: total penectomy and radical cystectomy, inferior pubectomy5 yr disease free survival is 30%Primary cause of failure: lack of local controlTumors here tend to be locally invasive and are apt to recurMets are a late eventConsider neoadjuvant chemoradiation for bulky tumorsOne 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 ramiProstatic urethraSuperficial tumor: good prognosis and treated with TURVery 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, LUTSSurgery: cystoprostatectomy and urethrectomyMost cases, tumor involves bulk of the prostate with variable extension to the bulbomembranous urethra or to the bladder neck and trigoneRadiation: FEMALEAdjuvant good for local control and LN treatmentCombo surgery with modest dose adj radiation (45-50Gy) allows for more conservative resectionCan be given pre or post dependent on extent of invasionMSKCC suggested data for preop radiationRadiation should target inguinal and pelvic LNs and the primary tumor siteReduces incidence of groin failure from 52% to 10 % (80% reduction)Brachytherapy also an optionAllows potential higher doses of radiation to tumor than XRTOk 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 survivalComplications:Urethral stenosis strictureNecrosis with fistulaRadiation cystitisRadiation: MALEGeneral: not effective as sole modality and may result in stricture and chronic edemaXRT over 5-6 weeks commonChemo radiation: 5FU, MMC, radiation to genitals, perineum, internal and external nodes5 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 radiationNot tried in TCCChemotherapy:Cisplatin: best single agentMVAC regimen: methotrexate, vinblastine, doxorubicin, cisplatinFemale: carboplatin and paclitaxelRadiation sensitizers: 5FU, cisplatinNeoadjuvant theoretically helpful, but no evidenceResults: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 disease36% for invasive tumors T3 and T426% for bulbmembranous urethra69% for anterior urethral tumors ................
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