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 [1]

Staging

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%

Risk Group	Stage & Grade	LN (+)
Low	T1 G1	0%
Intermediate	T1 G2-3, T2 G1	33%
High	T2 G2-3, T3 G1-3	83%

• 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

NCI Guidelines

Stage	TNM	Recommendation
Stage 0	Tis Ta	Mohs surgery Laser, cryosurgery Iquimod, topical 5-FU
Stage 1	T1 N0	Foreskin: wide local excision Penile amputation Mohs surgery RT
Stage 2	T1 N1 T2 N0-1	Penile amputation EBRT/BT
Stage 3	T1-2 N2 T3 N-2	Penile amputation, with LN dissection if clinically LN+ Penile amputation, with nodal RT if clinically LN+ and not surgical candidate
Stage 4	T4 Any T N3 M1	Palliative surgery Palliative RT

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

EAU Guidelines

Group	Stage	Recommendation
Low Risk	Ta-1 G1	Penis conservation (Mohs or RT) Penile amputation (partial or total) in patients with poor follow-up
All Others	T1 G3 >=T2	Penile amputation (partial or total) Penis conservation (Mohs or RT) in carefully selected patients Neoadjuvant chemotherapy followed by penis conservation is investigational

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%