# Radiation Oncology/Penis

* Front Page: Radiation Oncology | RTOG Trials | Randomized Trials

## 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

## 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%