ARTICLE
Auteur(s) : Yutaka Asato, Kiyohito
Taira, Yu-ichi Yamamoto, Hiroshi Uezato
Division of Dermatology, Department of Medicine, University of
the Ryukyu, 207 Uehara, Nishiara town, Okinawa, Japan (zip code:
903-0215)
accepté le 5 Decembre 2007
Buschke-Löwenstein tumor (BLT) was first described by Buschke
and Löwenstein in 1925 [1] and was defined as “carcinoma-like
condylomata acuminata of the penis” by Löwenstein in 1938 [2]. BLT
is a slow-growing, locally destructive verrucous lesion without a
malignant appearance in histology, and may occur elsewhere in the
anogenital region.
In 1948, Ackerman reported that BLT could be regarded as a type
of verrucous carcinoma (VC), as VC resembles BLT in clinical and
histological appearance [3]. However, there are some reports that
oppose this view [4, 5]. Therefore, confusion still exists over
whether cauliflower-like tumors on the penis should be referred to
as VC or BLT.
It is not fully understood, why the conyloma acuminatum (CA)
develops into large tumors. There are many enigmatic factors in BLT
and VC. For example, the HPV typically detected in BLT, which is a
very malignant tumor, is not a high-risk type, such as genotype 16
or 18, but rather is a low-risk type, such as 6 or 11 [6, 7].
Moreover, the HPV-positivity rate in VC is lower than in common
giant conyloma acuminatum (GCA) [8, 9]. To date, these questions
remain unsolved, and several investigators have attempted to
elucidate the etiology. Here, we report a case of BLT, in which
HPV11 was observed, and discuss the possible mechanisms of BLT
oncogenesis.
Case report
A 31-year-old male reported that he had noticed small nodules on
the root of his penis when he was about 26 years of age. At that
time, he visited a nearby clinic, where he was prescribed a topical
cream that failed to relieve the condition. However, he left the
disease untreated, as there were no clinical symptoms such as
itching and pain. The nodules continued to increase in size, before
fusing and growing into a fist-sized tumor, which adversely
affected his quality of life. Although he visited another clinic
and was treated with liquid nitrogen, the size of the tumor was
unaffected. He was subsequently referred to our hospital.
On clinical examination, a giant papillary tumor on the root of
penis extending mostly throughout the frontal part was noted. The
prepuce of the penis was also infiltrated by the tumor, which
enveloped the whole of the glans (figure 1A). Magnetic
resonance imaging (MRI) revealed no invasion into the dartos fascia
or albuginea. Therefore, we decided to perform total excision of
the tumor. Under general anesthesia, the tumor was excised with
minimal margins at the deep layer of adipose tissue (figure 1B). For
reconstruction, a mesh split-thickness skin graft closure was
performed. The skin graft was taken from his thigh using an
electric dermatome and was implanted on the excised lesion.
Biological tissue adhesive (human blood factor XIII with
fibrinogen) was injected under the skin graft in order to ensure
tight adherence to the penis. The graft was successful and allowed
to the patient to be discharged at 2 weeks after surgery.
Histological examination of the pubic and prepuce parts of the
lesion was then performed. In the pubic part, the epidermis was
elongated with a saw-toothed appearance and parts of the epidermis
invaded into the deep layer of the dermis on low-power
magnification. Although the nuclei were not atypical in high-power
fields, koilocytes were observed in epidermis (figure 2A), while invasion
of epidermis was not observed in the prepuce part, despite thick
epidermal proliferation (figure 2B). On
immunohistochemistry, anti-HPV polyclonal antibody staining (Dako
Japan, Japan) was positive in koilocyte nuclei (figure 2C). Based on these
results, we diagnosed the tumor as BLT.
We also performed genetic analysis of HPV using polymerase chain
reaction (PCR) and direct sequencing methods. The L1 region of HPV
was amplified as reported by Yoshikawa et al. [10] Tumor tissue DNA
was extracted with a Tissue DNA Isolation Kit (Amersham Pharmanica
Biotech, USA) in accordance with the manufacturer’s instructions.
L1C1 (5’-CGTAAACGTTTTCCCTATTTTTTT-3’ 5609-5632 bp) and L1C2
(5’-CAATACAGAGTATTTAGGGTA-3’ 5841-5861 bp), were chosen as
consensus primers for the Ll region. PCR was performed in a total
volume of 50 μL, and each reaction mixture contained 400 ng of DNA
template, each primer at 100 pM, dNTPs at 0.2 mM each, 1.25
units of EX taq polymerase, 10 mM Tris-HCL, pH 8.3, 50 mM
KCl and 1.5 mM MgCl2 (Takara, Japan). DNA was
amplified using a Gene Amp® PCR SYSTEM 9700 (Applied Biosystems,
USA) with initial denaturation at 94 °C for 1 min followed by
40 cycles of denaturation at 94 °C for 1 min, annealing at 50
°C for 1 min and extension at 72 °C for 1 min 30 s,
with a final extension at 74 °C for 5 min. Each of PCR
products was run on a 2.5% agarose gel, stained with ethidium
bromide and visualized by UV illumination. PCR product was observed
at 240 bp (figure
3A). This product was then purified using a QIAquick Gel
Extracion Kit (Qiagen, USA), and was sequenced directly on an ABI
PRISMTM 310 automated sequencer (Applied Biosystems,
USA) using the Big Dye terminator cycle sequencing ready reaction
kit (Applied Biosystems, USA) (figure 3B). Alignment of
DNA was edited with the software Genetyx Mac.ver 11.0 (Software
Development Co. Ltd, Japan) and a homology search conducted using
NCBI Nucleotide-nucleotide BLAST
(http://www.ncbi.nlm.nih.gov/BLAST/) revealed the PCR product was
homologous to HPV type 11.
Discussion
BLT is regarded as a cauliflower-like exophytic giant tumor in the
genital or peri-anal regions, and is often misdiagnosed as squamous
cell carcinoma (SCC). Originally, Buschke and Löwenstein noted that
BLT was distinct from the condyloma acuminate in that BLT invaded
into the deep tissues [2]. On the other hand, Ackermann reported in
1948 [3] that VC is a well-differentiated squamous carcinoma in the
oral cavity that lacked metastatic tendencies. Because VC resembled
BLT in clinical appearance and histology, BLT is generally
considered to be VC in genital regions.
However, there is still some confusion between BLT and VC. Some
reports regard these lesions as distinct entities [4, 5]. In fact,
the HPV-positivity rate of VC is lower than that of general GCA [8,
9], with some reports stating that only 12% of cases (3/26) are
positive [8, 9, 11, 12]. Another report found that VC of the vulva
is a rare HPV-negative neoplasm [13]. As BLT was originally
reported as a type of GCA, it should be an HPV-associated tumor.
These results are thus inconsistent with BLT. Therefore, Clare et
al. believed that BLT was a low-risk HPV (type 6 or 11)-positive
tumor, and considered that the presence of HPV may be useful in
differentiating BLT from VC [14]. As HPV type 11 was also detected
in the present patient, we diagnosed BLT rather than VC.
It is unclear why CA grows into giant tumors such as BLT, but
there are three hypotheses. The first hypothesis relates to
oncogenic viruses. Some reports have suggested that the presence of
high-risk HPV type 16 or 18 within a condyloma already containing
HPV type 6 or 11 may be important for the development of BLT;
however, PCR did not detect high-risk HPV in our case [15]. Other
reports postulated that mutations within the E6 and E7 coding
regions of low-risk HPV (oncogenes in high-risk HPV) may alter the
oncoproteins and be related to oncogenesis [16]. Heck et al.
revealed that the substitution of a single amino acid at position
22 in HPV type 6 (replacing glycine with aspartic acid) was
responsible for enhanced pRB binding affinity and increased
potential to cooperate with ras in the transformation of primary
rodent cells [17]. Sang et al. also reported that subtle amino acid
changes in HPV type 6 E7 proteins may result in HPV type 16
oncoprotein-like transforming activities in vitro [16].These
reports demonstrate the possibility that viral mutations are
related to carcinogenesis. On the other hand, Grassmann et al.
attempted to perform sequencing of the E6 and E7 regions from a
number of clinical samples in order to detect specific mutations
for oncogenesis, but identified few unique codes in individual
samples, although several amino acid substations were noted,
particularly in the E6 protein.
The second hypothesis relates to host immunity. Cuesta et al.
reported that VC in human immunodeficiency virus (HIV)-infected
patients is associated with HPV [18]. This supports the notion that
concurrent immune deficiency resulting from HIV infection may play
a role in promoting the effects of HPV in the pathogenesis of
genito-anal cancer. Our patient was negative for HIV and human
T-lymphotropic virus 1 (HTLV-1). HTLV-1 is a similar retrovirus to
HIV and is endemic in South America, Central Africa and
southwestern parts of Japan, including Okinawa. These two human
retroviruses (HIV and HTLV-1) differ greatly. HIV vigorously
replicates in vivo, while HTLV-1 has long resided in the human
body. It is unclear whether HTLV-1 may have influenced
tumorigenesis in our patient. However, other virus-associated
tumors, such as Kaposi’s sarcoma (KS) caused by human herpes virus
8 (HHV-8), which is ordinarily observed in AIDS patients, are
frequently reported in Okinawa, even in patients who are not HIV
carriers [19]. At least one report has suggested that that HTLV-1
infection may be related to HHV-8 infection and raises the risk of
KS [20]. Such reports suggest the need for further research into
HPV.
The third hypothesis relates to penile hygiene. Some reports
have suggested that uncircumcised males are inclined to higher
rates of BLT when compared with circumcised males, and that a
higher incidence of circumcision is a factor in the prevention of
BLT [20]. The present patient exhibited phimosis, and thus penile
hygiene may have played a role in oncogenesis.
Unfortunately, there was insufficient data to conclusively
identify the pathogenesis of BLT. However, we were able to discuss
the roles of various possible factors in oncogenesis. We need to
follow future reports more closely.
Acknowledgements
Financial support: none. Conflict of interest: none.
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