A 44-year-old man attended our sexually transmitted disease outpatient clinic. He presented with large, painless, smelling mass on his glans conditioning anuria from the previous night due to meatal obstruction. On detailed history, the patient revealed the occurrence of papular lesions on the penis and scrotum about 6 months before. He had been prescribed by his general physician a 4-month treatment of topical betamethasone twice a day. He was not known to have any previous medical illness. He denied any sexual exposure except for monogamous relationship with his wife. Physical examination revealed a big verruciform glans mass in the exposed portion through the preputial rim that appeared to be stenotic. Squeezing the glans, a purulent material could be appreciated. Ulceration was present at one side of the prepuce with multiple warty papules on the scrotum (Fig. 1). Inguinal lymph nodes were enlarged on palpation. Swabs from prepuce ulceration and glans for common bacteria were sent for testing. HIV antibody and serological tests for syphilis were sent to the laboratory. A presumptive diagnosis of Buschke-Löwenstein tumor (BLT) was made, 1 g ceftriaxone was injected, and the patient was sent to surgery department to perform urgent circumcision and suprapubic catheterization to prevent acute renal failure. Serology for HIV and syphilis was negative and culture from the glans and ulceration was positive for multiple gram-positive bacteria.
An incisional biopsy confirmed the diagnosis of infiltrating verrucous squamous cell carcinoma (BLT), associated with an in situ component. For human papillomavirus (HPV) genotyping, we extracted genomic DNA from formalin-fixed and paraffin-embedded block of the biopsy using the QIAamp DNA FFPE Tissue Kit (Qiagen), a kit especially designed for the purification of genomic DNA from tissue sections fixed in formalin and embedded in paraffin and that allows to obtain a rapid purification of DNA ready to use, eliminating the effects of crosslinking caused by formalin. Once the DNA was extracted, we proceeded with the polymerase chain reaction to amplify the L1 region of HPV DNA which is the most conserved gene of the entire HPV genome integrated in the human DNA during the infection. Polymerase chain reaction was performed with the INNO-LiPA HPV Genotyping Extra Amp kit (Innogenetics), designed to amplify the HPV's L1 region. Human papillomavirus genotyping was finally obtained with the INNO-LiPA HPV Genotyping Extra (Innogenetics) kit, which allows for the identification of 28 different HPV genotypes by detection of specific sequences in the L1 region of the virus genome. Human papillomavirus genotyping identified the presence of HPV6 (low-risk HPV) and HPV52 (high-risk HPV) in the bioptic sample, which included both the infiltrating and the in situ component of the tumor. Computed tomographic scan of the thorax and abdomen was performed and did not reveal distant metastasis; only inguinal inflammatory reactive lymph nodes were present. The patient underwent a full-thickness excision with intraoperatory tumor-free margin controls. A complete penectomy was performed with a perineal urethrotomy.
Intraoperatory and definitive histological examination of the specimen confirmed the presence of a large infiltrating squamous cell carcinoma arising from the squamous mucosa of the glans, deeply invading the subepithelial chorion with kerating pearl formation, associated with in situ squamous cell carcinoma of the adjacent mucosa showing various degrees of dysplasia. In addition, numerous intraurethral condylomas were found, with parakeratosis and the characteristic nuclear changes typical of HPV infections (Fig. 2). To identify which HPV genotype caused the invasive carcinoma, we selected the infiltrating component from a representative paraffin block and we performed molecular analysis only on the selected part of the corresponding slide (so-called macrodissection). The results of the analysis, performed with the same molecular techniques described above, showed only the presence of HPV52 genotype in the infiltrating part of the lesion. Scrotum warts were removed by diathermocoagulation. The patient continued to be monitored and sent to the oncology department to undergo adjuvant chemotherapy and follow-up. We advised the patient's partner to visit the gynecologist to have a vulvovaginal examination, a Papanicolaou test, and an HPV test.
Buschke-Löwenstein tumor, or giant condyloma acuminatum, is a rare, sexually transmitted disease. In 1925, Buschke and Löwenstein1 described the disease and classified it as a potential malign condyloma acuminatum. In 1979, this disorder was included into the verrucous carcinoma category.2 The clinical presentation is one or various prominent-sized vegetant mass that usually ulcerate. It is characterized by slow progression and adjacent tissue infiltration. Men are most affected (ratio, 2.7:1), but some cases in women and children have also been highlighted.3 The disease is considered to be caused by HPV (types 6 and 11 are the most common) infection.4 Other possible risk agents are smoking, multiple sexual relations, anaerobic infections, local chronic inflammation, and immune deficiency.5 Peculiar characteristics are the high recurrence rate (60%–70% variation),6 reduced metastasis tendency, and 30% to 56% rate of malignant development.7 Buschke-Löwenstein was histologically differentiated by Knoblich from simple condyloma, the first presenting increased mitotic activity, important papillomatosis, thickened tumor edges, acanthosis, and the tendency to penetrate and infiltrate the adjacent tissues.8 Preoperative imagistic investigations (computed tomography, magnetic resonance imaging) are required to evaluate the local and systemic disease extension and to select the best treatment approach. Multiple treatment approaches are available and described in the literature as classical surgery excision, photodynamic therapy, cryotherapy, laser, Mohs micrographic surgery, systemic immunotherapy with α-interferon or imiquimod, and topic treatment (podophyllin, 5-fluorouracil, bleomycin associated with cisplatin and methotrexate, trichloride and bichloride acetic acid, imiquimod, and interferon).3 The surgical treatment represents the “gold-standard” therapy and consists in full-thickness excision and tumor-free margins control.3 Chemotherapy and radiotherapy should be used as adjuvant treatments because when used as single forms of therapy, the results are not encouraging.9
Male vaccination with the quadrivalent HPV vaccine that protects against HPV6/11/16/18 has been shown to significantly reduce HPV-associated anogenital infection and disease in men and could prevent also this kind of disease.10
Our case represents a unique BLT with HPV types 6 and 52. To our knowledge, HPV52 has never been described to be associated with BLT and, in our case report, can be considered the oncogenic causative virus type in consideration to its presence in the infiltrative part of neoplasia. In addition, a key feature of this case was the highly aggressive behavior of the tumor with infiltration into the deep structures of the penis that could have been accelerated also by the steroid application. This report reconfirms the importance of male HPV vaccination and HPV high oncogenic potential in men too.
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