Penile tumors: an overview

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Penile tumors: an overview

Written	2008-10	Christopher Blick, Manit Arya, Nilay Patel, Suks Minhas, Asif Muneer
		University College Hospital, London, King's College Hospital, London

(Note : for Links provided by Atlas : click)

Identity

ICD-Topo C600-C602,C608-C609,C632 PENIS & SCROTUM

Atlas_Id 5278

Phylum Male organs: Penis::Penis tumor
WHO/OMS Classification Male organs

Other names Penile Cancer

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
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

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 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.

Clinics Non healing ulcer, painless penile mass, phimosis.

Pathology Grading and staging: graded by the degree of cellular atypia (G1->G3), Staged by TNM classification (see above).

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.

Evolution 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.

Prognosis 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 wild-type 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 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.

Cytogenetics

Cytogenetics
Morphological 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.

Genes involved and Proteins

Gene Name Viral genes

Note E6 and E7
These viral genes are expressed in high risk types of HPV transformed cells (Castellsague et al., 2002).

Gene Name TP53 (Tumour protein p53 (Li-Fraumeni syndrome))

Location 17p13.1

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.

Gene Name Serine protease inhibitors

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).

Gene Name 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.

Gene Name CDH1 (cadherin 1, type 1, E-cadherin (epithelial))

Location 16q22.1

Note There is evidence that low E-cadherin immunoreactivity is associated with a greater risk of lymph-node metastases (Campos et al., 2006).

Gene Name MMP genes

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).

Gene Name CDKN2A (cyclin dependent kinase 2a / p16)

Location 9p21.3

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.

Bibliography

E-cadherin, MMP-2, and MMP-9 as prognostic markers in penile cancer: analysis of 125 patients.

Campos RS, Lopes A, Guimaraes GC, Carvalho AL, Soares FA.

Urology. 2006 Apr;67(4):797-802. Epub 2006 Mar 29.

PMID 16566971

Male circumcision, penile human papillomavirus infection, and cervical cancer in female partners.

Castellsague X, Bosch FX, Munoz N, Meijer CJ, Shah KV, de Sanjose S, Eluf-Neto J, Ngelangel CA, Chichareon S, Smith JS, Herrero R, Moreno V, Franceschi S; International Agency for Research on Cancer Multicenter Cervical Cancer Study Group.

N Engl J Med. 2002 Apr 11;346(15):1105-12.

PMID 11948269

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.

Ferreux E, Lont AP, Horenblas S, Gallee MP, Raaphorst FM, von Knebel Doeberitz M, Meijer CJ, Snijders PJ.

J Pathol. 2003 Sep;201(1):109-18.

PMID 12950023

Preferential association of human papillomavirus with high-grade histologic variants of penile-invasive squamous cell carcinoma.

Gregoire L, Cubilla AL, Reuter VE, Haas GP, Lancaster WD.

J Natl Cancer Inst. 1995 Nov 15;87(22):1705-9.

PMID 7473819

Role of human papillomavirus in penile cancer, penile intraepithelial squamous cell neoplasias and in genital warts.

Gross G, Pfister H.

Med Microbiol Immunol. 2004 Feb;193(1):35-44. Epub 2003 Jun 28.

PMID 12838415

Molecular and genetic pathways in penile cancer.

Kayes O, Ahmed HU, Arya M, Minhas S.

Lancet Oncol. 2007 May;8(5):420-9.

PMID 17466899

Squamous cell carcinoma antigen: a role in the early identification of nodal metastases in men with squamous cell carcinoma of the penis.

Laniado ME, Lowdell C, Mitchell H, Christmas TJ.

BJU Int. 2003 Aug;92(3):248-50.

PMID 12887477

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.

Leis PF, Stevens KR, Baer SC, Kadmon D, Goldberg LH, Wang XJ.

Cancer. 1998 Jul 1;83(1):122-9.

PMID 9655301

Penile verrucous carcinoma: a clinicopathologic, human papillomavirus typing and flow cytometric analysis.

Masih AS, Stoler MH, Farrow GM, Wooldridge TN, Johansson SL.

Mod Pathol. 1992 Jan;5(1):48-55.

PMID 1311839

Cytogenetic analysis of an invasive, poorly differentiated squamous cell carcinoma of the penis.

Ornellas AA, Ornellas MH, Simoes F, Soares R, Campos MM, Harab RC, Silva ML.

Cancer Genet Cytogenet. 1998 Feb;101(1):78-9.

PMID 9460507

Immunohistochemical expression of Mdm2 and p53 in penile verrucous carcinoma.

Ouban A, Dellis J, Salup R, Morgan M.

Ann Clin Lab Sci. 2003 Winter;33(1):101-6.

PMID 12661905

Human papillomavirus is a necessary cause of invasive cervical cancer worldwide.

Walboomers JM, Jacobs MV, Manos MM, Bosch FX, Kummer JA, Shah KV, Snijders PJ, Peto J, Meijer CJ, Munoz N.

J Pathol. 1999 Sep;189(1):12-9.

PMID 10451482

Citation

This paper 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.

Free journal version : [ pdf ] [ DOI ]

On line version : http://AtlasGeneticsOncology.org/Tumors/PenileTumorID5278.html

Other genes implicated (Data extracted from papers in the Atlas) [ 3 ]

Genes APAF1 CEACAM19 MKI67

External links

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For comments and suggestions or contributions, please contact us
jlhuret@AtlasGeneticsOncology.org.

ICD-Topo	C600-C602,C608-C609,C632 PENIS & SCROTUM
Atlas_Id	5278
Phylum	Male organs: Penis::Penis tumor
WHO/OMS Classification	Male organs

Other names	Penile Cancer

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 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.
Clinics	Non healing ulcer, painless penile mass, phimosis.
Pathology	Grading and staging: graded by the degree of cellular atypia (G1->G3), Staged by TNM classification (see above).
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.
Evolution	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.
Prognosis	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 wild-type 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 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.

Gene Name	Viral genes
Note	E6 and E7 These viral genes are expressed in high risk types of HPV transformed cells (Castellsague et al., 2002).

Gene Name	TP53 (Tumour protein p53 (Li-Fraumeni syndrome))
Location	17p13.1
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.

Gene Name	Serine protease inhibitors
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).

Gene Name	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.

Gene Name	CDH1 (cadherin 1, type 1, E-cadherin (epithelial))
Location	16q22.1
Note	There is evidence that low E-cadherin immunoreactivity is associated with a greater risk of lymph-node metastases (Campos et al., 2006).

Gene Name	MMP genes
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).

Gene Name	CDKN2A (cyclin dependent kinase 2a / p16)
Location	9p21.3
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.