(American Journal of Pathology. 2001;159:1211-1218.)
© 2001 American Society for Investigative Pathology
Detection and Typing of Human Papillomavirus DNA in Penile Carcinoma
Evidence for Multiple Independent Pathways of Penile Carcinogenesis
Mark A. Rubin*,
Bernard Kleter
,
Ming Zhou*,
Gustavo Ayala
,
Antonio L. Cubilla
,
Wim G. V. Quint¶ and
Edyta C. Pirog||
From the Department of Pathology,*
University of
Michigan, Ann Arbor, Michigan; the Delft Diagnostic
Laboratory,
Delft, The Netherlands; the
Department of Pathology,
Baylor College of
Medicine, Houston, Texas; the Department of
Pathology,
Universidad Nacional de Asuncion,
Asuncion, Paraguay; the Academic Medical Center,¶
Amsterdam, The Netherlands; and the Department of
Pathology,||
Cornell University, New York, New York
 |
Abstract
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To clarify the role of human papillomavirus (HPV) in penile cancer
we evaluated the prevalence of HPV DNA in different histological
subtypes of penile carcinoma, dysplasia, and condyloma
using a novel, sensitive SPF10 HPV polymerase chain reaction
assay and a novel genotyping line probe assay, allowing
simultaneous identification of 25 different HPV types.
Formalin-fixed, paraffin-embedded tissue samples were collected
from the United States and Paraguay. HPV DNA was detected in 42% cases
of penile carcinoma, 90% cases of dysplasia, and 100%
cases of condyloma. There were significant differences in HPV
prevalence in different histological cancer subtypes. Although
keratinizing squamous cell carcinoma and verrucous carcinoma were
positive for HPV DNA in only 34.9 and 33.3% of cases,
respectively, HPV DNA was detected in 80% of basaloid and
100% of warty tumor subtypes. There was no significant difference in
HPV prevalence between cases from Paraguay and the United States. In
conclusion, the overall prevalence of HPV DNA in penile
carcinoma (42%) is lower than that in cervical carcinoma (
100%)
and similar to vulvar carcinoma (50%). In addition,
specific histological subtypes of penile cancer—basaloid and
warty—are consistently associated with HPV, however,
only a subset of keratinizing and verrucous penile carcinomas is
positive for HPV DNA, and thus these two tumor groups seem to
develop along different pathogenetic pathways.
|
Introduction
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Penile cancer (PC) is an uncommon
disease in the United States and in Europe and has a yearly incidence
of 0.29 per 100,000 among whites in the United States.1
The incidence is an order of magnitude higher in some of the African
and South American countries, such as Uganda (incidence of 4.4 per
100,000) or Paraguay (incidence 4.2 per 100,000).2,3
The
etiology of PC is not well understood. Traditionally, lack of neonatal
circumcision was considered to be the most significant risk factor for
PC, however, the causal relationship has never been established. In the
most recent detailed epidemiological study, the highest risk for PC was
associated with a history of penile rash lasting more than a month
(Bowen’s disease?) [relative risk (RR) = 9.4] and a history of
genital warts (RR = 5.9).4
As compared with these two
high-risk factors, the risk of cancer in men uncircumcised or
circumcised after the neonatal period was lower: RR = 3.2, and
RR = 3.0, respectively. Other risk factors identified in the study
included: penile tear (RR = 3.9), difficulty of foreskin
retraction (RR = 3.5), more than 30 lifetime sexual partners
(RR = 3.4), smoking (RR = 2.8), and smegma (RR =
2.1).4
The results suggest a strong association between
human papillomavirus (HPV) infection and development of PC.
High oncogenic risk HPVs have been detected in virtually 100% of
carcinomas of the uterine cervix and the role of HPV in malignant
transformation of the cervical epithelium has been well
established.5,6
In contrast to the consistent finding of
HPV in the cervical tumors, the reported prevalence of HPV in PC is
highly variable, from 15 to 71%, depending on the sensitivity of the
detection method and the selection of the tumor type.4,7
Penile carcinomas include several different histological subtypes. The
majority of tumors are well-differentiated, keratinizing squamous cell
carcinomas (SCCs) (Figure 1A)
that
resemble SCCs arising in nongenital skin. The second most common tumor
subtype, verrucous carcinoma (Figure 1B)
, and the less prevalent
variants, namely, basaloid carcinoma (Figure 1C)
and warty carcinoma
(Figure 1D)
arise most frequently on the mucosal surfaces of the
anogenital and oropharyngeal regions, and on the penis these tumors
most often involve the glans.8-10
The histological
subtypes of PC are identical to those described in the vulva and it is
plausible that penile carcinogenesis parallels the pathogenetic
mechanisms of malignant transformation of the vulvar epithelium. The
current concept of vulvar carcinogenesis includes at least two
independent pathways: one, HPV-related and the other, not associated
with HPV infection.11
Tumors associated with HPV tend to
occur in younger women with past history of genital warts or cervical
dysplasia and arise from the in situ lesions similar to
those found in the cervix. The carcinomas are frequently of basaloid or
warty type.12
The prevalence of HPV in these tumors ranges
from 75 to 100%.13,14
Tumors not associated with HPV
occur in older women and are typically well-differentiated keratinizing
SCCs arising in a background of differentiated vulvar intraepithelial
neoplasia and/or lichen sclerosus.13
The risk factors are
unknown.
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Figure 1. Main histological subtypes of penile carcinoma analyzed in the study.
A: Keratinizing SCC: infiltrating tumor characterized by
nests and tongues of malignant squamous epithelium with prominent
central keratin pearls. B: Verrucous carcinoma: exophytic
tumor characterized by papillary architecture and pushing invasive
border; malignant squamous epithelium is well differentiated and no
koilocytic atypia is present. C: Basaloid carcinoma:
infiltrating tumor characterized by nests and cords of immature
malignant squamous epithelium with areas of central necrosis; foci of
keratin pearls may be also present. D: Warty carcinoma:
exophytic/infiltrating tumor characterized by papillary architecture
and marked cytological atypia with prominent koilocytic features.
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Few studies of PC have analyzed the different histological subtypes
separately. This lack of separation of histological types may have
confounded both the results of the HPV studies and the epidemiological
findings. The goal of this study was to further investigate the
relationship between HPV and PC, by examining the prevalence of HPV DNA
in a large series of tumors encompassing a spectrum of histological
differentiation. In addition we wanted to analyze the prevalence and
the distribution of HPV types in the premalignant penile lesions
(penile dysplasia). Benign penile condylomas were included in the study
as the HPV-positive control group.
The specific questions that we wanted to answer in this study were: 1)
are there one or many pathways of penile carcinogenesis?; 2) are the
various histological subtypes of penile carcinoma etiologically
related?; 3) are there differences in frequency of various histological
tumor subtypes between the high-risk and low-risk geographical regions
(Paraguay versus the United States)?; 4) are there
differences in HPV prevalence in the tumors from the high-risk and
low-risk geographical regions (Paraguay versus the United
States)?
HPV DNA amplification was performed using a novel, sensitive,
broad-spectrum HPV polymerase chain reaction (PCR) assay (SPF 10 PCR),
which permits general HPV DNA amplification of at least 43 known HPV
types.15,16
HPV genotyping was performed using a novel
line probe assay (LiPA). LiPA assay enables simultaneous identification
of 25 individual HPV genotypes, allowing efficient detection of single
and/or multiple HPV infection.16
High sensitivity of the
assays used in this study was confirmed in a previous investigation in
which HPV DNA was detected in 100% of cases of cervical
carcinoma.6
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Materials and Methods
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Clinical Specimens
Cases of penile condyloma, dysplasia (including Bowenoid papulosis
and Bowen’s disease), and carcinoma were retrieved from the archives
of the Pathology Departments at University of Michigan (Ann Arbor, MI),
Baylor College of Medicine (Houston, TX), Yale University (New Haven,
CT), Universidad Nacional de Asuncion, (Asuncion, Paraguay), and the
Weill Medical College of Cornell University (New York, NY). Twelve
cases of condyloma, 30 cases of dysplasia, and 155 cases of PC were
collected. All cases were reviewed and diagnostic groups were assigned
and graded according to standard histological criteria.17
A representative tissue block from each case was selected for HPV
analysis. Clinicopathological parameters were obtained from the
pathology reports.
DNA Extraction and ß-Globin Amplification
Three, 5-µm thick sections of formalin-fixed, paraffin-embedded
tissue were placed on glass slides after cutting deep into the block.
The microtome blade was changed after each case. The tissue sections
were deparaffinized in xylene and stained with hematoxylin. Tumor
tissue was dissected from the adjacent squamous epithelium and stroma
using a sterile scalpel blade. The samples were digested with
proteinase K (1 mg/ml) in a volume of 0.25 ml at 56°C for 18 hours.
Proteinase K was heat inactivated at 95°C for 10 minutes and 10 µl
of DNA aliquot was used directly for PCR. To ensure adequate DNA
quality, PCR amplification of the ß-globin gene was performed in a
separate reaction using primers PC03 and PC04, resulting in a 96-bp
product.18
In 13 of 155 (8%) cancer cases no ß-globin
amplification was achieved. Repeated digestion was ineffective in these
cases. These results indicated marked DNA degradation and the cases
were excluded from further analysis (11 keratinizing, 1 basaloid, and 1
verrucous carcinoma).
HPV DNA Detection and Typing
Broad-spectrum HPV DNA amplification was performed using the short
PCR fragment (SPF10) primer set.15
The SPF10 primers
amplify a 65-bp fragment from the L1 region of the HPV
genome.16
The primer sequences and exact HPV PCR
conditions were described previously.15
The PCR products
were run on a 3% agarose gel and the 65-bp product was visualized with
ethidium bromide staining. Additional confirmation of the presence of
amplified HPV-specific sequences was performed using HPV DNA enzyme
immunoassay, a microtiter plate-based hybridization assay. The exact
HPV DNA enzyme immunoassay conditions were described
previously.15
All HPV-negative cases were confirmed by the
second PCR assay using standard DNA concentration as well as 10x
diluted DNA sample to exclude the presence of PCR inhibitors.
Appropriate positive and negative PCR controls were run with all
reactions.
Samples identified as positive for HPV DNA were genotyped with the
INNO-LiPA HPV prototype research assay (LiPA).16
Twenty-five individual HPV genotypes (high-risk HPV: 16, 18, 31, 33,
35, 39, 45, 51, 52, 56, 58, 59, 66, 68, 70, and low-risk HPV: 6, 11,
34, 40, 42–44, 53, 54, 74) can be identified simultaneously in a
single assay. In this assay, 10 µl of denatured HPV PCR product was
hybridized to the genotype-specific probes immobilized as parallel
lines on a nitrocellulose strip. After the washing step, the products
of hybridization were detected by a color reaction with alkaline
phosphatase-streptavidin conjugate and substrate
(5-bromo-4-chloro-3-indolylphosphate and nitroblue tetrazolium),
which results in a purple precipitate. The exact assay conditions were
described previously.16
The results of hybridization were
assessed visually by comparing to the standard grid (Figure 2)
.
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Figure 2. Identification of HPV genotypes using LiPA. LiPA strips with
hybridization bands indicating a single HPV type infection: lane
1 = HPV 16; lane 2 = HPV 18; and a multiple HPV type
infection: lane 3 = HPV 45 and 70. Note: HPV 18 is reactive
with two probes, 18 and c68, and HPV 45 with probes 45 and 45/68.
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Results
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Clinicopathological Data
The study group included 106 cases of keratinizing SCC (33% grade
1 tumors, 48% grade 2 tumors, and 18% grade 3 tumors), 12 cases of
verrucous SCC, 15 cases of basaloid SCC, 5 cases of warty SCC, 2 cases
of clear cell SCC, 1 case of sarcomatoid SCC, and 1 case of a
metastatic penile SCC in which the primary lesion was not available for
a review. Benign cases consisted of a group of penile dysplasia
(n = 30) and penile condylomas
(n = 12). The average age of patients with
cancer was 61.2 years (range, 31 to 94 years), with dysplasia was 58.1
years (range, 27 to 85 years), and with condyloma was 50.6 years
(range, 34 to 82 years).
There was no significant difference in the distribution of tumor
subtypes between the cases from Paraguay and the United States (Table 1)
.
HPV DNA Detection and Typing
Only the cases with positive ß-globin DNA amplification were
included in the study. HPV DNA was amplified in 99 of 182 benign and
malignant cases, some of which were stored in the paraffin blocks for
as long as 20 years. HPV DNA amplification was confirmed with the HPV
DNA enzyme immunoassay and the individual HPV genotypes were
subsequently identified with the LiPA. The cases, in which HPV DNA was
not detected, were of various storage ages.
HPV DNA was detected in 100% of condylomas, 90% cases of dysplasia,
and 42% of penile carcinomas. The results of HPV DNA detection in the
different histological categories are summarized in Tables 2 and 3
.
All but one case of condyloma were associated with the low-risk viral
types, with HPV 6 being the most prevalent type. In contrast, penile
dysplasia was associated with high-risk HPVs in 81.5% of cases, and
HPV 16 was most frequently detected. In PC, there were significant
differences in HPV prevalence among the different histological tumor
subtypes. Keratinizing and verrucous carcinoma were positive for HPV
DNA in 34.9 and 33.3% of the cases, respectively. Basaloid and warty
PCs were positive for HPV DNA in 80 and 100% of the cases,
respectively. The difference in HPV prevalence between these two groups
was statistically significant (chi-square test, P <
0.05).
HPV 16 was the most common viral type identified in PC (60% of HPV+
cases) and was detected in 29 tumors as a single HPV type (48.3%) and
as multiple-type infection in 7 tumors (11.6%) (Table 3
and Figure 2
).
Other HPV types were relatively less common. The types that were
detected as a single viral infection included: HPV 45
(n = 4), HPV 35 (n = 3),
HPV 18 (n = 2), HPV 52 (n
= 2), HPV 68 (n = 2), HPV 31
(n = 1), HPV 53 (n = 1),
and HPV 6 (n = 1). Other high-risk HPVs (51, 54,
and 70) were detected in multiple-type infections with HPV 16.
Undetermined HPVs (X types) were present in 7.8% of the cases.
Multiple viral types were detected in 16.6% of HPV-positive tumors
(Table 2)
. There was no statistically significant difference in HPV
prevalence/type distribution between the cases from Paraguay and the
United States (Table 4)
.
The average age of the patients with HPV DNA-positive versus
HPV DNA-negative tumors (58.3 years versus 61.2 years) was
not significantly different (Student’s t-test,
P > 0.05). No association between the tumor grade and
HPV positivity was identified.
|
Discussion
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The present report is the largest multicenter study of HPV DNA
prevalence in PC. In this study, HPV DNA amplification was performed
using a novel, currently the most sensitive, broad-spectrum HPV PCR
assay (SPF 10), which allows for the detection of at least 43 known HPV
types. The SPF 10 assay significantly diminishes the problems of HPV
detection in formalin-fixed tissue by amplifying only a 65-bp fragment
located within the L1 region of the HPV genome. The amplification
product is much shorter than the products obtained with other
frequently used general primer sets such as My11/09 (450 bp) or GP
5+/6+ (150 bp).19,20
The kinetics of the PCR reaction
favors amplification of shorter DNA sequences and consequently, the SPF
assay has been shown to be more sensitive than amplification systems
using My11/09 or GP 5+/6+ primers.15
In addition, a short
target sequence is statistically less likely to be affected by either
DNA fragmentation or loss during viral integration. High sensitivity of
this technique was confirmed in the previous investigation in which HPV
DNA was detected in 100% of cases of cervical carcinoma.6
The overall prevalence of HPV DNA in PC detected in this study was
42.2%. This result is similar to the results of previously published
studies (Table 5)
. However, we have
observed great differences in HPV prevalence depending on the
histological subtype of PC. And although basaloid and warty carcinomas
were found to be consistently associated with HPV presence, only a
subset of keratinizing and verrucous PCs was positive for HPV DNA. The
most common viral type identified in PC was HPV 16, which was detected
in 60% of HPV+ cancers. This result is similar to those reported by
other investigators in which HPV 16 was found in 65 to 74% of
HPV-positive tumors.4,21,22
In this study we did not find
a significant difference between HPV prevalence in tumors from Paraguay
and the United States; further, no significant difference in the
distribution of the histological tumor subtypes was found. We therefore
conclude, that pathogenetic pathways of penile carcinogenesis are
likely to be similar in the high-risk and the low-risk geographical
regions.
In the cervix, all main histological subtypes of carcinoma: SCC,
adenocarcinoma, and adenosquamous carcinoma are associated with HPV
infection.6,23
In contrast, SCCs of the vulva seem to have
multiple pathogenetic pathways. Basaloid and warty carcinomas are
consistently associated with high-risk HPVs.12-14
Well-differentiated keratinizing SCCs and verrucous carcinomas have a
low prevalence of HPV DNA.12-14
Rare cases of verrucous
carcinoma of the vulva have been described to be associated with low
oncogenic risk HPVs.24,25
The results of our current study
and previously published reports indicate that the etiology and the
pathogenetic pathways of PC may parallel the pathogenetic pathways of
vulvar, but not cervical carcinoma. First, the overall prevalence of
HPV DNA in PC (42.2%) is lower than that in cervical carcinoma
(100%)5,6
and similar to that reported for vulvar
carcinoma (50%).14
Second, the correlation between HPV
DNA detection and histological tumor subtypes is similar in vulvar and
PC. In our study two histological subtypes of PC: basaloid and warty
were found to be positive for HPV DNA in almost 100% of cases and
associated with HPV 16. This result is consistent with previously
published reports. Cubilla and colleagues8
reported
detection of HPV 16 in 9 of 11 (81%) cases of basaloid and 3 of 5
(60%) cases of warty SCC of the penis.9
Interestingly,
basaloid carcinomas of the anus and the head and neck mucosa were also
described as the specific histological tumor subtypes with high
prevalence of HPV.26-28
Verrucous carcinomas of the penis
analyzed in this study were most commonly HPV-negative and of a total
of 26 cases reported in the multiple publications only 3 were found
to be positive for HPV DNA (12%), and all were positive for low-risk
HPVs.10,21,29-32
The reported prevalence of HPV DNA in penile dysplasia or penile
intraepithelial neoplasia ranges from 75 to 100%.33
Results of our study (90% HPV +) are consistent with the previous
reports. High-risk HPVs were detected in 81.5% of these cases, with
HPV 16 being the most prevalent viral type. These findings suggest that
penile intraepithelial neoplasia or penile dysplasia, as defined
currently, is a precursor lesion to only a subset of tumors, which
include basaloid and warty carcinomas. The precursor lesion for
keratinizing SCC or verrucous carcinoma is not well established.
Squamous cell hyperplasia and/or lichen sclerosus frequently coexist
with keratinizing SCC and verrucous carcinoma, however the significance
of this association remains to be determined.17
Table 6
summarizes the hypothetical pathways of
penile carcinogenesis after combining the results of the current and
previous investigations. There are still multiple unknowns that await
further research.
Numerous molecular genetic studies have provided strong evidence that
HPV is an oncogenic virus. HPV was found to inactivate some of the
mechanisms regulating the cellular mitotic cycle. By doing this, the
virus launches a cascade of uncontrolled genetic events that may lead
to malignant transformation of the host cell. Specifically, HPV has
been shown to interfere with the functions of retinoblastoma protein
and p53 tumor suppressor protein. Inactivation of retinoblastoma
protein keeps the cell in a perpetual proliferative state. The fidelity
of cellular DNA replication is maintained by p53. Alteration of p53
expression by HPV renders cellular DNA susceptible to carcinogenic
effects of mutagens (eg, cigarette carcinogens). In time, the unchecked
replication of damaged DNA may result in malignant transformation of
the cell because of accumulation and propagation of DNA errors.
However, as the cell cycle is maintained by redundant, multilevel
mechanisms, it is thought that more than five different alterations of
the major regulatory proteins are required before the cell acquires
full malignant potential. And thus, although HPV has been firmly
established as a causative factor of many cancers, HPV infection alone
is insufficient to cause malignancy. The results of the epidemiological
studies clearly indicate that numerous factors, including lack of
neonatal circumcision, foreskin injuries, and cigarette smoking
contribute to penile carcinogenesis. The exact molecular mechanisms by
which these factors increase the risk of PC remain to be determined.
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Footnotes
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Address reprint requests to Dr. Edyta C. Pirog, Department of Pathology, Weill Medical College of Cornell University, 525 E 68th St., F-766, New York, NY 10021. E-mail: ecpirog{at}mail.med.cornell.edu
Accepted for publication June 21, 2001.
|
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Top
Abstract
Introduction
