Radiation Oncology/Penis

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Epidemiology

US - 1500 cases annually, <2% of GU cancers
Incidence rises dramatically in 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

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

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%

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