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Solid Tumour Section
Mini Review
Penile tumors: an overview
Christopher Blick, Manit Arya, Nilay Patel, Suks Minhas, Asif Muneer
University College Hospital, London and King's College Hospital, London (CB, MA, NP, SM, AM)
Published in Atlas Database: October 2008
Online updated version : http://AtlasGeneticsOncology.org/Tumors/PenileTumorID5278.html
DOI: 10.4267/2042/44595
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2009 Atlas of Genetics and Cytogenetics in Oncology and Haematology
T1 Tumour invades subepithelial connective tissue
T2 Tumour invades corpus spongiosum or cavernosum
T3 Tumour invades urethra or prostate
T4 Tumour invades other adjacent structures
N - Regional lymph nodes
NX Regional lymph nodes cannot be assessed
N0 No evidence of lymph node metastasis
N1 Metastasis in a single inguinal lymph node
N2 Metastasis in multiple or bilateral superficial lymph
nodes
N3 Metastasis in deep inguinal or pelvic lymph nodes,
unilateral or bilateral
M - Distant metastasis
MX Distant metastases cannot be assessed
M0 No evidence of distant metastases
M1 Distant metastases
Identity
Alias
Penile Cancer
Clinics and pathology
Disease
Penile Cancer
Epidemiology
Penile carcinoma is an uncommon malignant disease,
with an incidence of 0.1-7.9 per 100,000 males. In
Europe and the USA, the incidence is 0.1-0.9 per
100,000 rising to 19 per 100 000 in some areas of Asia,
Africa and South America.
Penile cancer tends to be a disease of uncircumcised
men, with an increase in incidence of men in their
sixties; incidence peaks in men aged 80 years. The
frequency of penile carcinoma varies according to
hygienic practices, cultural and religious beliefs. Penile
cancer has been associated with the presence of herpes
virus infection and human papilloma viruses (HPV).
HPV is thought to be strongly associated with the
generation of insitu and invasive cancers of epithelial
tumours (Walboomers et al., 1999). The prevalence of
HPV DNA in penile carcinoma is 40-45%. HPV
Classification
Histologic types:
Squamous cell carcinoma (90%)
Adenocarcinoma (5%)
Melanoma (2%)
Basal cell carcinoma (2%)
Sarcoma (1%)
The 1997/2002 TNM (Tumour, Node, Metastasis)
classification of penile cancer:
T - Primary tumour
TX Primary tumour cannot be assessed
T0 No evidence of primary tumour
Tis Carcinoma in situ
Ta Non-invasive verrucous carcinoma
Atlas Genet Cytogenet Oncol Haematol. 2009; 13(10)
758
Penile tumors: an overview
Blick C, et al.
infection also correlates with penile cancer basaloid
subtypes, however verrucous tumours tend to be
negative for HPV. HPV 16 and 18 are found in 60-75%
of insitu and invasive carcinomas whereas HPV 6 and
11 are found in lower risk condylomas.
interestingly, MMP-9 immunoreactivity was shown to
be an independent predictor of disease recurrence as
was the presence of urethral infiltration and lymph
node metastasis, which had an important prognostic
role.
Clinics
Cytogenetics
Non healing ulcer, painless penile mass, phimosis.
Pathology
Cytogenetics Morphological
Grading and staging: graded by the degree of cellular
atypia (G1->G3), Staged by TNM classification (see
above).
A diploid population has been established in all
verrucous carcinomas, aneuploidy varies according to
grade of the tumour: well differentiated (5,5%),
moderately differentiated (28,8%), and poorly
differentiated (66,6%), there is a tendency towards high
DNA index correlating with increased metastatic risk,
detectable telomerase activity in has been found in
85,4% (41 of 48) of invasive penile tumours. Increased
levels of activity were also identified in adjacent skin
and corpus cavernosal tissue (Kayes et al., 2007).
Unfortunately due to the rarity and small numbers
involved complete analysis of aneuploidy and penile
cancer cannot be completed.
The evidence linking P53 expression and presence of
HPV DNA in penile cancer is contradictory and there is
no adequately proven association.
Amplifications:
Common copy-number gains included 8q24, 16p11-12,
20q11-13, 22q, 19q13, and 5p15 (Gregoire et al.,
1995).
Losses:
Deletions were seen in 13q21-22, 4q21-32, and along
the X chromosome.
Treatment
Non surgical treatments for premalignant lesions
include laser therapy, Moh's micrographic surgery,
topical 5-FU. Penis-preserving surgery is recommended
for premalignant lesions such as carcinoma in situ and
also Ta-T1 lesions. Penis preserving surgery is suitable
for T2 lesions confined to the glans. More extensive
lesions involving the corpus cavernosum or urethra
require a partial or total amputation.
Local disease recurrence may require partial or total
amputation.
In those with a high risk of metastases and non palpable
nodes, modified or radical lymphadenectomy is
recommended, for those with an intermediate or low
risk, the options include surveillance or dynamic
sentinel node biopsy or modified inguinal
lymphadenectomy. If patients have palpable
pathological
nodes
then
radical
inguinal
lymphadenectomy is the standard recommendation.
Pelvic lymphadenectomy is performed in those patients
with greater than two positive inguinal nodes.
Genes involved and proteins
Evolution
Viral genes
Penile carcinoma is one of the few solid tumours in
which lymphadenectomy can provide a high cure rate
even when lymph nodes are involved. Most relapses
occur during the first 2 years; late recurrences, though
uncommon, may occur.
Note
E6 and E7
These viral genes are expressed in high risk types of
HPV transformed cells (Castellsague et al., 2002).
Prognosis
TP53
The mean time until death from cancer is 66.6 months
for those with CIS, 50.1 months for those with
localized disease, 32.4 months for those with regional
disease and 7.4 months for those with distant
metastases.
The most powerful prognostic factor in patients with
SCC of the penis is involvement of the lymph nodes in
the groin. 5-year cancer-specific survival probabilities
were 93% for N0 patients, 80% for N1, and 50% for
N2 patients. Mutant p53 protein has been detected in
67.6% of patients with lymph node metastases, while
only 39.6% of patients with metastases had the wildtype protein. Low levels of E-cadherin were present in
59.5% of patients with groin metastases, while high
levels of the protein were detected in 61.7% of the
patients without nodal involvement (P = 0.032). More
Location: 17p13
Note
This gene is situated on chromosome 17p13 and a
mutation in this gene can lead to either expression of a
mutant protein (90%) or absence of the protein (Leis et
al., 1998). Mutant P53 has been shown to fail to bind to
MDM2, thus, resulting in the accumulation of the
oncogenic protein in cells. There is also evidence that
overexpression of MDM2 is important in aberrant P53
down-regulation in penile cancer (Ouban et al., 2003).
There is no evidence of correlation with grade or stage
of disease. In multivariate analysis P53 was assessed as
an independent prognostic indicator and patients with a
negative P53 had significantly better 5 and 10 year
survival (Ornellas et al., 1998). Outcome was worst in
patients who were P53 and HPV positive.
Atlas Genet Cytogenet Oncol Haematol. 2009; 13(10)
759
Penile tumors: an overview
Blick C, et al.
Serine protease inhibitors
References
Note
SERPINB1 and SERPINB4 (18q21.3)
These serine protease inhibitors have been assessed in
several studies involving penile cancer, revealing that
they can provide information for detecting lymph-node
metastases in penile cancer, either at diagnosis
(sensitivity 57%; specificity 100%) or for patients
entered into surveillance programmes (Laniado et al.,
2003).
Masih AS, Stoler MH, Farrow GM, Wooldridge TN, Johansson
SL. Penile verrucous carcinoma: a clinicopathologic, human
papillomavirus typing and flow cytometric analysis. Mod Pathol.
1992 Jan;5(1):48-55
Gregoire L, Cubilla AL, Reuter VE, Haas GP, Lancaster WD.
Preferential association of human papillomavirus with highgrade histologic variants of penile-invasive squamous cell
carcinoma. J Natl Cancer Inst. 1995 Nov 15;87(22):1705-9
Leis PF, Stevens KR, Baer SC, Kadmon D, Goldberg LH,
Wang XJ. A c-rasHa mutation in the metastasis of a human
papillomavirus (HPV)-18 positive penile squamous cell
carcinoma suggests a cooperative effect between HPV-18 and
c-rasHa activation in malignant progression. Cancer. 1998 Jul
1;83(1):122-9
Proapoptotic and antiapoptotic genes
Note
BAX (19q13) and BCL-2 (18q21)
BCL-2 concentrations are significantly (Masih et al.,
1992) increased in low-grade disease compared with
verrucous cancers, whereas BAX concentrations were
comparable.
Ornellas AA, Ornellas MH, Simões F, Soares R, Campos MM,
Harab RC, Silva ML. Cytogenetic analysis of an invasive,
poorly differentiated squamous cell carcinoma of the penis.
Cancer Genet Cytogenet. 1998 Feb;101(1):78-9
Walboomers JM, Jacobs MV, Manos MM, Bosch FX, Kummer
JA, Shah KV, Snijders PJ, Peto J, Meijer CJ, Muñoz N. Human
papillomavirus is a necessary cause of invasive cervical cancer
worldwide. J Pathol. 1999 Sep;189(1):12-9
E-cadherin
Location
16q22
Note
There
is
evidence
that
low
E-cadherin
immunoreactivity is associated with a greater risk of
lymph-node metastases (Campos et al., 2006).
Castellsagué X, Bosch FX, Muñoz N, Meijer CJ, Shah KV, de
Sanjose S, Eluf-Neto J, Ngelangel CA, Chichareon S, Smith
JS, Herrero R, Moreno V, Franceschi S. Male circumcision,
penile human papillomavirus infection, and cervical cancer in
female partners. N Engl J Med. 2002 Apr 11;346(15):1105-12
MMP genes
Ferreux E, Lont AP, Horenblas S, Gallee MP, Raaphorst FM,
von Knebel Doeberitz M, Meijer CJ, Snijders PJ. Evidence for
at least three alternative mechanisms targeting the
p16INK4A/cyclin D/Rb pathway in penile carcinoma, one of
which is mediated by high-risk human papillomavirus. J Pathol.
2003 Sep;201(1):109-18
Note
MMP-2 (16q12.2) and MMP-9 (20q13.12)
High MMP-9 expression was an independent risk
factor for disease recurrence (Campos et al., 2006).
Laniado ME, Lowdell C, Mitchell H, Christmas TJ. Squamous
cell carcinoma antigen: a role in the early identification of nodal
metastases in men with squamous cell carcinoma of the penis.
BJU Int. 2003 Aug;92(3):248-50
P16INK4a [A50]/cyclin D/retinoblastoma
pathway
Note
This pathway can be disrupted by three independent
mechanisms in penile cancer. Analysis of 52 cases of
invasive penile cancer were scrutinised for P16INK4a
and BMI1 using immunohistochemical techniques.
HPV-16 E6 and E7 mRNA and P16INK4a methylation
were assessed using polymerase chain reaction. HPV
presence was also investigated using in-situ
hybridisation (Ferreux et al., 2003). The authors
described HPV-dependent and HPV-independent
mechanisms affecting the normal functioning of this
important signalling pathway. p16INK4a might act as a
potential prognostic marker and that these results have
strong implications on the potential effectiveness of
prophylactic HPV vaccines for this tumour.
Ouban A, Dellis J, Salup R, Morgan M. Immunohistochemical
expression of Mdm2 and p53 in penile verrucous carcinoma.
Ann Clin Lab Sci. 2003 Winter;33(1):101-6
Gross G, Pfister H. Role of human papillomavirus in penile
cancer, penile intraepithelial squamous cell neoplasias and in
genital warts. Med Microbiol Immunol. 2004 Feb;193(1):35-44
Campos RS, Lopes A, Guimarães GC, Carvalho AL, Soares
FA. E-cadherin, MMP-2, and MMP-9 as prognostic markers in
penile cancer: analysis of 125 patients. Urology. 2006
Apr;67(4):797-802
Kayes O, Ahmed HU, Arya M, Minhas S. Molecular and
genetic pathways in penile cancer. Lancet Oncol. 2007
May;8(5):420-9
This article should be referenced as such:
Blick C, Arya M, Patel N, Minhas S, Muneer A. Penile tumors:
an overview. Atlas Genet Cytogenet Oncol Haematol. 2009;
13(10):758-760.
Atlas Genet Cytogenet Oncol Haematol. 2009; 13(10)
760