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Buschke-Löwenstein tumors: A series of 7 case reports

Giant condyloma acuminatum (GCA), or Buschke-Löwenstein tumor (BLT), represents an infrequent sexually transmitted disease (STD), caused by human papillomavirus (HPV), especially genotype 6 or 11. There are numerous risk factors for HPV, such as multiple sexual partners, homosexuality, prostitution, chronic genital infections, as well as the lack of proper hygiene. HPV infection is a field infection, where large areas of cells at a tissue surface are affected by the HPV virus; therefore, once the GCA is excised, treatment of the whole affected genital area needs to be undertaken. The treatment is classified into topical therapy (podophyllin, 5-FU, radiotherapy, topical photodynamic therapy), excisional therapy (CO2 laser, cryotherapy, electrotherapy, surgery) and immunotherapy (imiquimod). However, the ‘gold standard’ therapy is represented by wide surgical excision without grafting, since it is considered that healing per secundam is an improved approach, because there is no risk of recurrences on fibrotic tissue. A total of 7 cases of the BLT with comorbidities and particularities are presented and it is recommended that it be taken into consideration that the incidence of the disease is increasing, emphasizing the importance of an early diagnosis, as well as an adequate treatment.

tumor characteristics and on the skills of the physician, with surgical treatment remaining as the first line therapy, with a lower recurrence risk (3,4). If the tumors are invasive, the patients could require a colostomy and nephrostomy (10).

Case reports
Case 1. A 39-year-old male patient with no notable medical history, smoker, and sexual intercourse debut at 15 years old, presented to the Department of Dermatology of Ponderas Academic Hospital for a large exophytic cauliflower-like verrucous tumor in the perianal area and smaller similar lesions localized in the genital, supra-penile, scrotal and crural areas. The patient was negative for STDs and the genotyping was positive for HPV 16. The colonoscopy revealed no rectal invasion and the patient refused a colostomy.
A reduction of the tumor volume was performed with radiosurgical excision under general anesthesia and all the smaller lesions were excised in 10 sessions of CO 2 laser under local anesthesia. The histopathological report revealed epidermal hyperplasia, hyperkeratosis, papillomatosis, koilocytes, HPV 6-positive intra-tissue and no signs of malignant transformation.
The healing occurred by secondary intention, in 60 days. The patient received systemic antibiotic therapy with levofloxacin (500 mg/day for 15 days), then cefuroxime (1 g twice a day for 3 weeks), local and intrarectal sinecatechins (twice a day for 4 months), nonspecific immune stimulation with inosine pranobex (3 tablets twice a day for 10 days per month), alternately with Coriolus versicolor (3 tablets twice a day for 4 months). The peniscopy and the microscopic examination of the anogenital region revealed residual subclinical lesions. They were excised with CO 2 laser, 3 sessions of fractional photodynamic therapy with 8% levulinic acid applied topically under occlusion for 2 h, then 20 min of 635-nm red light at 70 mJ/cm 2 fluency, followed by 10 min of 411-nm blue light at 80 mF/cm 2 fluency, and finally 10 min of 635-nm red light at 70 mJ/cm 2 fluency. A total of 3 doses of Gardasil vaccine were administered (months 0-2-6) (Figs. 1-7).

Case 2.
A 26-year-old male homosexual patient, smoker, sexual intercourse debut at 15 years old, and multiple sexual partners, presented to the Department of Dermatology of Ponderas Academic Hospital for a large exophytic cauliflower-like verrucous tumor in the perianal area. The patient had asymptomatic urethral co-infection with Haemophilus influenzae, was negative for STDs and the intra-anal and intra-urethral genotyping was positive for HPV 6 and 16. The colonoscopy revealed no rectal invasion.
The peniscopy and the microscopic examination of the anogenital region revealed 30 subclinical genital, supra-penile and crural lesions, which were excised with CO 2 laser in 4 sessions under local anesthesia. The histopathological report revealed epidermal hyperplasia, hyperkeratosis, papillomatosis, koilocytes and HPV 6-positive intra-tissue.
The patient received local and intrarectal sinecatechins (twice a day for 4 months), inosine pranobex (3 tablets twice a day, 10 days per month) alternately with Coriolus versicolor (3 tablets twice a day for 4 months). The peniscopy and the microscopic examination of the anogenital region revealed residual subclinical lesions that were excised with CO 2 laser, 3 sessions of fractional photodynamic therapy with 8% levulinic acid applied topically under occlusion for 2 h, then 20 min of 635-nm red light at 70 mJ/cm 2 fluency, followed by 10 min of 41-nm blue light at 80 mF/cm 2 fluency, and finally       Klebsiella pneumoniae. The intra-urethral genotyping was positive for HPV 16 and 52.
The peniscopy and the microscopic examination of the anogenital region revealed 10 subclinical genital lesions and 15 subclinical lesions supra-penile and perigenital, which were excised in one session of CO 2 laser under local anesthesia.
The patient received systemic antibiotherapy with levofloxacin (500 mg/day for 30 days), meloxicam (15 mg/day for 30 days), Sunvert (1 tablet twice a day for 60 days), local and intrarectal sinecatechins (twice a day for 4 months), inosine pranobex (3 tablets twice a day for 10 days per month), alternately with Coriolus versicolor (3 tablets twice a day for 4 months). The peniscopy and the microscopic examination of the anogenital region revealed residual subclinical lesions, which were excised with CO 2 laser, 2 sessions of fractional photodynamic therapy with 8% levulinic acid applied topically under occlusion for 2 h, then 20 min of 635-nm red light at 70 mJ/cm 2 fluency, followed by 10 min of 411-nm blue light at 80 mF/cm 2 fluency, and finally 10 min of 635-nm red light at 70 mJ/cm 2 fluency. A total of 3 doses of Gardasil vaccine were administered (months 0-2-6) (Fig. 13).

Case 4.
A 32-year-old uncircumcised male patient presented to the Department of Dermatology of Ponderas Academic Hospital for multiple, giant flesh-colored, cauliflower-like growths involving the penis, the supra-penile and the right inguinal region. The patient denied experiencing pain, bleeding or dysuria. The patient had been sexually active since 16 years old and provided history of multiple sexual partners. Laboratory tests were performed in order to verify the status of the patient for STDs and the patient tested positive for an asymptomatic urethral coinfection with Mycoplasma hominis. The HPV genotyping revealed HPV 6, 11 and 54.
The treatment consisted of 5 sessions of CO 2 laser with local anesthesia, followed by 2 daily applications of sinecatechins ointment for 4 consecutive months in the affected areas. In addition, the patient was prescribed inosine pranobex   (500 mg x 6/day, 10 days/month for 4 months), alternating with Coriolus versicolor (6 cps/day 20 days/month for 4 months). The patient was advised to get vaccinated against HPV with 3 shots of Gardasil 9 vaccine.
At the follow-up visit, the microscopic analysis of the genital skin revealed certain persistent subclinical lesions, for which the patient underwent 2 sessions of topical photodynamic therapy. Briefly, 8% aminolevulinic acid (ALA) was applied and after 2 h, the dressing was removed and the lesions were irradiated using a red light for 20 min (the peak emission of 635 nm was used and the total dose was 70 mJ/cm 2 ), then a blue light was used for another 10 min (80 mJ/cm 2 ), followed again by a red light (635 nm, 70 mJ/cm 2 ) (Figs. 14-16).  The PCR test conducted on the vaginal brushing revealed the presence of HPV 6, 16 and 18. The tumor was excised with radiosurgery under general anesthesia. The biopsy of the lesion identified HPV 6 and 16 genotypes and revealed moderately differentiated squamous cell carcinoma. Therefore, the patient underwent pelvectomy with nephrostomy, followed by radiotherapy (Fig. 22).

Discussion
In 1925, Buschke and Löwenstein described BLT for the first time. They examined a penile lesion, which resembled both common condyloma acuminata and squamous cell carcinoma from a clinical point of view; however, it presented differences from both of these diseases concerning the biological behavior and the histopathological findings (9).
BLT represents an infrequent STD, caused by HPV, mostly genotype 6 or 11. There are numerous risk factors for HPV, such as multiple sexual partners, homosexuality, prostitution, chronic genital infections, as well as the lack of proper hygiene (4,9).
BLT is invariably preceded by condyloma acuminatum and it is more common in individuals with a suppressed immune system caused by AIDS, chemotherapy with immunosuppressive therapy alcoholism or diabetes. HPV screening for HIV-positive and immunocompromised patients should always be a priority in this category of patients (1,4).
A high prevalence of GCA has been reported in the homosexual and bisexual communities. Recurrent aggressive GCA has been reported in HIV-positive patients. BLT could occur at any age, particularly following puberty. However, the elderly should also be tested for HPV infection. Men are more affected than women, and the main affected areas are the penis, the anorectal area and the urethra in males, and the vulva in females (4,11).
From a clinical view, it presents as a voluminous cauliflower-like, flesh-colored tumor of papillomatous and irregular surface, ultimately surpassing 10 cm 2 in size (4).
From a histopathological point of view, BLT is characterized by papillomatosis and severe acanthosis. Generally, the hyperplastic epithelium is well-differentiated; nevertheless, the vacuolated epidermal cells reveal clear cytoplasm and hyperchromatic nuclei. The basal membrane is undamaged and there is a lymphohistiocytic inflammatory infiltrate present in the upper dermis. When a biopsy is performed, it should be deep enough to contain the whole tumor, particularly the epidermal/dermal interface (4).
The multiplication cycle of HPV needs stratified squamous epithelium (the junction between it and the columnar   or cuboid epithelium being the election site), explaining the HPV-associated cancers on the lips, oral cavity, cervix, prostate, penis, scrotum and rectum. The first structure infected is the basal keratinocyte nucleus and if the host defense mechanism is overcome, the virus multiplies and the DNA copies, during cell division, are distributed to daughter cells, which are hard to identify if the viral gene expression is low. The risk of malignant transformation of infected cells is high if the infection persists more than 6 months; however, ~90% of the cases have a self-limited evolution of 2 years. There are numerous co-factors participating in HPV-related    carcinogenesis. The oncogenes E6 and E7 are the key viral oncogenes from HPV 16 and other high-risk HPVs that inactivate p53 and members of the retinoblastoma protein family leading to inhibition of apoptosis, progression of the cellular cycle and accumulation of genetic alterations, viral integration and uncontrolled cell proliferation. The tumor-induced inflammation promotes the proliferation, the survival of the malignant cells and the alteration of the response to chemotherapy. The HPV infection requires either intact skin tissue or wound healing and an active inflammatory process in the skin in order to multiply. This theory has a great impact on the treatment plan, healing per secundam being an improved approach in comparison with grafting after excision, since there is no risk for recurrences on fibrotic    tissue (as aforementioned HPV requires stratified squamous epithelium for replication) (12)(13)(14).
It is very difficult to differentiate between BLT and verrucous carcinoma. There are authors who consider these lesions to have numerous similarities. Nevertheless, other authors have strongly suggested that BLT is the midway lesion between condyloma acuminatum and verrucous carcinoma, considering it a condyloma-like precancerous lesion (4).
The most frequent complications of BLT include superinfection, fistulae or necrosis (15). Spontaneous regression is extremely rare, while recurrence following an incomplete excision is very frequent. In the case of GCA, histology does not reveal any evidence of malignancy, such as infiltration of the basement membrane, lymphatic invasion, angioinvasion or distant metastases. Bleeding, infiltration of the tumor basis or lymph node enlargement may lead to the suspicion of a malignant transformation into micro-invasive carcinoma or into well-differentiated squamous cell carcinoma, occurring in 30-50% of the cases (4,5,15).
The incidence of perianal GCA has slightly increased during the last few years, but it remains very hard to differentiate GCA from common condylomas or well-differentiated squamous cell carcinomas. There is a well-known association between HPV 16, 18, 31 and 33 and anogenital squamous cell carcinoma (5,16).
Numerous factors need to be considered when deciding on the most appropriate type of treatment, such as the size, the location of the giant condyloma, as well as previous therapies that have proven unsuccessful. The microscopic analysis of the genital skin for subclinical HPV lesions has a crucial role for an early detection of HPV lesions or recurrences and for selecting the best treatment plan (8).
The 'gold standard' therapy is represented by surgical treatment, which consists of full thickness excision and tumor-free margin control. According to the clinical condition of the patient, extensive abdominopelvic surgery may be recommended in cases of visceral involvement.
Preoperative imagistic investigations (CT and MRI) are required before surgery in order to assess the extensiveness of local and systemic disease, and to select the optimal treatment approach. Temporary colostomy followed by reintegration in cases of rectum involvement is also recommended. Despite the fact that numerous authors consider wide local excision followed by split-thickness skin grafts the mainstay of therapy, it is considered that healing per secundam is an improved approach, since grafting represents a risk factor for HPV (6)(7)(8).
HPV infection is a field infection, where large areas of cells at a tissue surface are affected by the HPV virus; therefore, once the GCA is excised, focus on treating the whole affected genital area is required. In literature, certain treatment methods for BLT are stated, but the risk of recurrence is very high (podophyllotoxin, usually used for common condyloma acuminata; 5-FU, with improved results for the intraurethral BLT; imiquimod, very aggressive therapy with numerous side effects; cryotherapy, CO 2 laser and sinecatechins, very effective with less side effects; and topical photodynamic therapy using both red and blue lights, which was successfully used in our cases) (11,17). However, the best specific immunostimulation is the HPV vaccination with Gardasil 9. In case of verrucous carcinoma, chemotherapy needs to be added to the treatment plan. Radiotherapy, however, appears to be responsible for the alteration of BLT into anaplastic carcinoma (8,18).
In conclusion, despite the fact that numerous authors consider wide local excision followed by split-thickness skin grafts the mainstay of therapy, it is considered in the present study that healing per secundam is an improved approach, since there is no risk for recurrences on fibrotic tissue. For an improved understanding of this phenomenon, further studies are required.
Microscopic analysis of the genital skin for subclinical HPV lesions has a crucial role for an early detection of HPV lesions/recurrences and an improved outcome for the health and social life of the patient.
In case of BLT, there are cases that exceed the qualifications of the dermatologist; therefore, there may be a need for a multidisciplinary approach: Colonoscopy/proctoscopy for rectal invasion, cystoscopy and gynecological exam. The importance of gynecological examination and HPV screening for every female patient should not be overlooked, regardless of age (case 7), nor the importance of HPV screening for HIV-positive and immunocompromised patients (cases 5 and 6) (17,19).
Most importantly, a set of complete STD tests should be performed for all young male patients, as well as smokers and patients who have started their sexual activities early in life. In addition, non-specific immune stimulation and HPV vaccination with Gardasil 9 should be integrated in the treatment plan for every patient with an HPV infection.

Patient consent for publication
A written informed consent for clinical examination, surgery, treatment and obtaining images for publication was obtained from the patients.