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Radiation Oncology/Penis

< Radiation Oncology
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Epidemiology

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  • 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

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

Grading

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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

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AJCC Current Staging

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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

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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

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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

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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

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  • 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

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  • 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

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  • 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

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  • 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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