Radiation Oncology/Penis

Epidemiology

 * US - 1500 cases annually, <2% of GU cancers
 * Incidence is dramatically higher in the developing world
 * US - 0.2 / 100,000
 * Bombay - 1.8 / 100,000 (10-fold increase)
 * Sao Paolo - 28 / 100,000 (another 15-fold increase)
 * Uganda - most common male malignancy
 * Risk factors
 * Phimosis - narrowed opening of the prepuce resulting in non-retractile foreskin. Odds ratio 10
 * Smegma
 * Circumcision - in Uganda, circumcised tribes 0.5 vs. uncircumcised tribes 2.9 / 100,000
 * HPV - primarily 16, prevalence 30-70%
 * Age - meadian age at diagnosis in US is 60
 * Tobacco
 * Premalignant lesions

HPV16
 * Amsterdam; 2007 PMID 17925550 -- "Human papillomavirus-16 is the predominant type etiologically involved in penile squamous cell carcinoma." (Heideman DA, J Clin Oncol. 2007 Oct 10;25(29):4550-6.)
 * Molecular and serologic analysis of HPV on 83 penile SCC vs. age-matched controls
 * Outcome: HPV DNA in 55% samples - HPV16 75%. HPV18 and HPV6 seropositivity associated, but not by molecular findings
 * Conclusion: HPV16 is the main HPV type associated with penile SCC

Histology

 * Squamous cell (95%)
 * Papillary
 * Basaloid
 * Warty
 * Sarcomatoid
 * Verrucous (up to 25%)
 * Melanoma
 * Lymphoma
 * Basal cell
 * Urethral

Grading
Differentiation grading systems for SCC
 * Broder's grading system
 * I - well differentiated with keratinization, prominent intercellular bridges, and keratin pearls
 * II to III - greater nuclear atypia, increased mitotic activity, and decreased keratin pearls
 * IV - deeply invasive, marked nuclear pleomorphism, nuclear mitoses, necrosis, lymphatic and perineural invasion, and no keratin pearls


 * Maiche’s system score
 * currently seems to be the most suitable staging system

AJCC Current Staging
AJCC 7th Edition (2009) Primary Tumor:
 * Tis - carcinoma in situ
 * Ta - non-invasive verrucous carcinoma
 * T1
 * T1a - invades subepithelial connective tissue without lymphovascular invasion and is not poorly differentiated (i.e. tumor is grade 1-2 of 4)
 * T1b - invades subepithelial connective tissue with lymphovascular invasion or is poorly differentiated (i.e. tumor is grade 3-4 of 4)
 * T2 - invades corpus spongiosum or cavernosum
 * T3 - invades urethra
 * T4 - invades other adjuacent structures (including prostate)

Regional Lymph Nodes: include superficial and deep inguinal, internal and external iliac, pelvic lymph nodes
 * Clinical assessment (based on palpation or imaging):


 * cN0 - none
 * cN1 - palpable mobile unilateral inguinal LN
 * cN2 - palpable mobile multiple or bilateral inguinal LN
 * cN3 - fixed inguinal nodal mass or pelvic lymphadenopathy


 * Regional Lymph Nodes (pathologic assessment):


 * pN0 - none
 * pN1 - metastasis in single inguinal LN
 * pN2 - multiple or bilateral inguinal lymph nodes
 * pN3 - extranodal extension or pelvic lymph node involvement

Distant Metastases:
 * M0 - no
 * M1 - yes

Stage Grouping:
 * 0 - Tis or Ta
 * I - T1a N0
 * II - T1b-T3 N0
 * IIIA - T1-3 N1
 * IIIB - T1-3 N2
 * IV - T4, N3, M1

Changes from 6th Edition:
 * T1 subdivided into T1a and T1b based on LVI and grade
 * Prostate invasion moved from T3 to T4. T3 limited to urethral invasion
 * Added new schemes for clinical vs pathologic lymph node assessment
 * T1b (new subdivision) becomes Stage II and T1a remains Stage I
 * Any LN+ is now at least Stage III. Divided into IIIA and IIIB.

Older staging systems
AJCC 6th Edition (2002) Primary Tumor:
 * Tis - carcinoma in situ
 * Ta - non-invasive verrucous carcinoma
 * T1 - invades subepithelial connective tissue
 * T2 - invades corpus spongiosum or cavernosum
 * T3 - invades urethra or prostate
 * T4 - invades other adjuacent structures

Regional Lymph Nodes:
 * N0 - none
 * N1 - single superficial inguinal lymph node
 * N2 - multiple or bilateral superficial inguinal lymph nodes
 * N3 - deep inguinal or pelvic lymph nodes (unilateral or bilateral)

Distant Metastases:
 * M0 - no
 * M1 - yes

Stage Grouping:
 * I - T1 N0
 * II - T1 N1, T2 N0-1
 * III - T1-2 N2, T3 N0-2
 * IV - T4, N3, M1

Other staging systems
Jackson's Staging


 * Stage I (A) - tumor is confined to glans, prepuce or both
 * Stage II (B) - tumor extends onto shaft of penis; no nodal or distant metastases
 * Stage III (C) - tumor has inguinal nodal metastases that are operable
 * Stage IV (D) - tumor involves adjacent structures and is associated with inoperable inguinal metastasis or distant metastasis

Spread
Lymph Nodes
 * Drainage to superficial inguinal -> deep inguinal -> external iliac
 * At presentation
 * 50% clinically enlarged
 * 50% disease
 * 50% reactive - so should treat first with a course of ABX
 * 50% clinically negative
 * 20% occult disease
 * Decision on who should undergo inguinal dissection one of the hardest in penile CA management. Sentinel LN reasonable option
 * Highly correlates with T-stage and grade (PMID 11342906)
 * T1 11%, T2 63%, T3 63%
 * G1 15%, G2 67%, G3 75%


 * LN+ correlates with 5-year survival:
 * N0 - 80-90%
 * N1 - 70%
 * N2-3 inguinal - 35%
 * N3 pelvic - 20%
 * Overall N+ 40-50%

Mets
 * <10% M+ at presentation

Sentinel Lymph Node

 * Netherlands Cancer Institute; 2009 PMID 19414668 -- "Two-center evaluation of dynamic sentinel node biopsy for squamous cell carcinoma of the penis." (Leijte JA, J Clin Oncol. 2009 Jul 10;27(20):3325-9. Epub 2009 May 4.)
 * Prospective. 323 patients (from 611 cN0 patients).
 * Outcome: Technical success rate 97%. LN+ in 24%. Inguinal recurrences (false-negative SLNB) 7%
 * Toxicity: 5% (mostly seroma/lymphocele and infections)
 * Conclusion: SLNB suitable procedure to stage clinically N0 penile cancer

Treatment Guidelines

 * NCI Guidelines are driven by TNM staging


 * European Association of Urologists guidelines are driven by TNM and by lesion grade

Surgery vs. RT

 * Lausanne, 2006 (Switzerland) PMID 16949770 -- "Treatment of penile carcinoma: To cut or not to cut?" (Ozsahin M, Int J Radiat Oncol Biol Phys. 2006 Nov 1;66(3):674-9.)
 * Retrospective. 60 patients, 5 surgery, 22 surgery + adjuvant RT, 29 primary RT. Mean F/U 62 months
 * 5-year OS: surgery 53% vs. RT 56% (NS). RT failures underwent surgical salvage
 * Local failure: Median time to LR failure 14 months; Surgery (+/- RT) 13% vs. RT 56% (SS)
 * Patients treated with RT: penis preservation 52%. 5-year probability of intact penis 43%
 * Conclusion: Surgery better LR rate, RT better penile preservation, OS same

Brachytherapy

 * Princess Margaret, 2005 (Canada) 1989-2003 PMID 15890588 -- "Penile brachytherapy: results for 49 patients." (Crook JM, Int J Radiat Oncol Biol Phys. 2005 Jun 1;62(2):460-7.)
 * Retrospective. 49 patients. T1 51%, T2 33%. G1 31%, G2 45%. RT treated 23 with PDR BT, 22 Iridium BT, 4 seeds BT to 60 Gy. Medium F/U 2.7 years
 * 5-year OS: 78%, CSS 90%
 * Local failure: 15%, all salvaged by surgery. Regional failure 20%. Distant failure 10%
 * 5-year penile preservation: 86%
 * Side effects: soft tissue necrosis 16%, urethral stenosis 12%