First described by Buschke and Löwenstein in 1925, the giant condyloma of Buschke and Löwenstein (GCBL) is a slow-growing, locally destructive verrucous plaque that typically appears on the penis but may occur elsewhere in the anogenital region. It most commonly is considered to be a regional variant of verrucous carcinoma, together with oral florid papillomatosis and epithelioma cuniculatum.
Related Medscape Drugs & Diseases articles of possible interest include Head and Neck Cutaneous Squamous Cell Carcinoma and Human Papillomavirus.
GCBL is slow growing, highly destructive to contiguous tissue, and seldom metastasizes. Most commonly located on the glans penis, GCBL can be found on any anogenital mucosal surface, including the vulva, vagina, rectum, scrotum, and bladder.[1]
Co-localization with human papillomavirus (HPV) types 6 and 11[2, 3, 4] ; occasionally HPV types 16 and 18; and, on one occasion, HPV-54 has been shown. In a study of various types of verrucous carcinomas, the presence of low-risk HPV serotypes 6 and 11 was confirmed in all three giant condylomas analyzed. Two anal lesions showed HPV-6, while a vulvar giant condyloma demonstrated the presence of HPV-11. Although a causal role of these HPV strains in carcinogenesis was not directly supported, the authors recommend the testing for HPV-6 and HPV-11 as a tool to improve the differential diagnosis of giant condylomas from other verrucous carcinomas.[4]
The E6 protein of HPV-6 and HPV-11 binds p53 tumor suppressor protein less efficiently than that of HPV-16 and HPV-18 but, theoretically, could lead to accelerated degradation of the p53 protein. The E6 protein also inhibits p53 transcription.
Alternatively, a mutation may occur in the p53 protein, leading to clonal proliferation. Several reports have shown some overexpression of p53 in genital warts and squamous cell carcinomas (SCCs), but it appears that p53 mutations were not present. Other implicated agents are chronic chemical exposure, chronic irritation, and poor hygiene.
Chronic phimosis and poor penile hygiene have been postulated as inciting or contributing events. This may account for the higher incidence in males who are uncircumcised. Populations with a higher incidence of circumcision have a lower rate of GCBL. In general, newborn circumcision has been estimated to be 99.9% effective in eliminating cancer of the penis. Chronic irritation, produced by a perianal fistula and ulcerative colitis, has been implicated as a causative factor. Immunosuppression secondary to HIV disease or due to immunosuppressive medication may be a predisposing factor.
Other risk factors for GCBL are low socioeconomic status, drug abuse, use of oral contraceptives, presence of other sexually transmitted diseases, diabetes, smoking, and, possibly, pregnancy,[5] which may be associated with an impaired immune response.[6] The dependency of Buschke-Löwenstein tumor growth to a state of decreased immune responsiveness is exemplified by the development of new penile and perianal lesions in a male with chronic lymphocytic leukemia at the time he received chemotherapy.[7]
GCBL is rare. Estimates of incidence show that GCBL accounts for 5-24% of penile cancers, which, in turn, are 0.3-0.5% of male malignancies. Another review assessed that verrucous carcinoma accounted for approximately 50% of all low-grade SCCs of the penis. GCBL located outside the penis is much more infrequent. Fewer than 50 cases of perianal tumors and only 20-30 cases of vulvar or bladder GCBL have been reported. The bladder lesions have been associated with schistosomiasis (ie, Schistosoma haematobium).
International
SCC of the penis is much more common elsewhere in the world compared with the United States. No specific data are available in the English literature regarding international incidence.
Race
No racial predilection is reported.
Sex
Most cases of GCBL occur in males on the glans penis. This condition is more common in males who are uncircumcised. The male-to-female ratio is 3.5:1.
Age
Two thirds of cases of GCBL occur in persons younger than 50 years. It is rarely reported in children. A recent trend toward a younger reported age at presentation is recognized, with a mean age of presentation of 44 years.
If untreated, GCBL can be locally very destructive, extending into the pelvic organs and bony structures. Even with treatment, morbidity rates can be high because recurrences are very common with all treatment modalities.
Inadequately treated GCBL has a relentless progression and is fatal by direct spread to pelvic organs. By definition, adequately treated GCBL has a low recurrence rate and, therefore, an excellent prognosis. However, one study of perianal/anogenital GCBL, with treatments ranging variously from podophyllin to pelvic exenteration, showed a 68% recurrence rate with a 21% mortality rate.
In another series of 42 patients, the median number of recurrences of giant condyloma acuminatum was 2 years (range, 1-7 y), and the median time to first recurrence was 10 months. A high rate of recurrence correlates with a long duration of disease.[8]
One case report noted recurrent lesions in the ischial tuberosities that required pelvic exenteration.
Malignant transformation is reported in 30-56% of patients.
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Giant condyloma of Buschke and Löwenstein (GCBL) typically starts on the prepuce as a keratotic plaque and slowly expands into a cauliflowerlike mass, as large as 15 cm. The slow growth of the tumor, which may span as long as 20 years, is typical for immune competent individuals. The lesion may ulcerate or form a penile horn and typically is associated with a foul odor. Expansion to the corpus cavernosum and urethra may occur, with subsequent fistulation. Regional lymphadenopathy is common, primarily due to secondary infection, not metastases.
Similar slow progression is noted on perianal lesions, where it disseminates circumferentially from the mucocutaneous transitional zone to the perianal area. The anal canal itself is commonly, but not universally, uninvolved. Presenting symptoms of perirectal GCBL include perianal mass (47%),[9] fistula or abscess (32%), and bleeding (18%).The more recent advent of acquired and iatrogenic immune suppression tends to shift the occurrence of Buschke-Löwenstein tumor more towards immune-suppressed individuals, in whom the growth is commonly more rapid.
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Giant condylomata acuminata of Buschke and Lowenstein of the perianal region, consisting of a slow-growing, ulcerated, cauliflowerlike mass.
During pregnancy, giant condyloma has a tendency to proliferate, which represents a treatment challenge owing to the limited therapeutic options. Successful management was obtained in one case by surgical excision alone, which was performed one month after childbirth. In rare cases, an evolution from HPV-induced vulvoperineal lesions into Buschke-Löwenstein tumor has been noted.[10]
Unusual locations, such as axillary areas, have been described.
Giant condyloma of Buschke and Löwenstein (GCBL) has shown mild, heterogenous enhancement with gadolinium-diethylenetriamine pentaacetic acid (DTPA) contrast on MRI. This study may be useful in delineating the expansion of the lesion when planning for removal.[14]
Biopsy is the diagnostic procedure necessary for evaluation. It must be sufficiently deep and generous to evaluate for possible foci of SCC because lesions with these changes have been shown to have a higher recurrence rate and to metastasize. Vacuolar change is not a reliable differentiator between GCBL and condyloma, and visualizing the base of the lesion and the characteristic broad, blunt, deeply penetrating rete pegs is necessary to make the diagnosis.
Although the rate of regional lymph node involvement is low, sentinel lymph node biopsy should be considered if clinical findings suggest the need for it.
GCBL characteristically has massive epidermal hyperplasia, hyperkeratosis, and parakeratosis and is markedly exophytic. Granular vacuolization may be present, and individual keratinocytes have large cytoplasm and a nucleus with prominent nucleoli.
Blunt-shaped masses of tumor project deeply into the dermis and contiguous structures. The tumor cells have little evidence of atypia and are not found inside blood vessels or lymphatics. Individual keratinocytes may show keratinization, but no horn pearls are seen. Lymphohistiocytic inflammation is usually present.
Giant condyloma acuminatum is differentiated histologically from ordinary condyloma acuminata by its thicker stratum corneum and the presence of an endophytic downgrowth, along with a tendency to invade deeper. Because the distinction of GCBL from verrucous carcinoma can be difficult, GCBL has been regarded by some as a variant of verrucous carcinoma.[15]
The treatment of choice for giant condyloma of Buschke and Löwenstein (GCBL) is considered wide surgical excision. Surgery alone has resulted in a disease-free status in 45.5% of patients.[16] However, controlled trials comparing treatments are currently lacking.[17]
Several factors need to be considered in the selection of treatment, including the thickness and size of the lesions, quantity and anatomic location of the lesions, HPV classification, immunocompromised or immunocompetent status, preferences of the patient and provider, cost, and availability. No current treatment achieves complete eradication the HPV.[17]
In addition, oral and topical chemotherapeutic modalities have been used with mixed success as adjuvants to surgery or as treatment for recurrences. Topical therapy alone, such as with 5-fluorouracil,[18] podophyllin, or interferon (IFN), are generally insufficient to control disease or prevent progression of the giant lesions. One case report noted that intralesional bleomycin in the wound bed of an incompletely resected tumor was effective, with no recurrence at 2 years. Topical cidofovir gel 1.5% used for several months produced clinical improvement, even in cases refractory to conventional treatment.[19, 20]
The postulated viral origin of these tumors has led to the use of IFN with moderate success. One case of vaginal GCBL responded to 6 months of IFN 2-alfa, with apparent complete resolution. Although topical IFN lacked clinical efficacy, intralesional administration[21] has produced complete responses in 47-62% of cases; however, the recurrence rate is 40%. Large lesions may be candidates for systemic IFN. A deeply infiltrating giant condyloma acuminatum experienced a major response after 9 months of continuous IFN administration at 10 MU thrice weekly, although no change in the tumor could be observed in the first several months.
Imiquimod was effective in combination with carbon dioxide laser ablation in a patient unable to tolerate surgery, whose tumor was positive for HPV-6.[22]
Traditional systemic antitumor agents have also been used. One report described the use of bleomycin, cisplatin, methotrexate, and leucovorin in a patient with recurrence after multiple surgeries for GCBL.[23] An autopsy 1 year later showed no evidence of active disease. A separate report noted tumor shrinkage with mitomycin-C and 5-fluorouracil combined with fractionated radiotherapy; unfortunately, this patient manifested pulmonary metastases.[24] Etretinate and photodynamic therapy with intravenous porphyrins have been used with some success in vaginal GCBL.
Radiation therapy remains controversial. Extensive evidence supports anaplastic transformation in oral/plantar verrucous carcinoma, but data in GCBL are mixed. While some studies show evidence of new aggressive behavior after radiation therapy, more than a few case reports document resolution of small tumors after radiation.[25] One review recommended the avoidance of radiation if possible; but, if necessary, the use of a large dose of radiation to minimize chances of further mutation may be effective in a candidate who is a poor surgical risk.[24] To support this view, one report describes successful treatment of a recurrent tumor with radiation at 4500 cGy in 25 fractions; the patient remained disease free when reevaluated at 20 months.
Bulky tumors have been shrunk with preoperative chemoradiation, followed by radical surgery, in some instances followed by reconstructive surgery. One regimen that lead to a complete response consists of mitomycin C and 5-fluorouracil administered concomitantly with radiation therapy 50.4 Gy to the tumor bed and prophylactic irradiation of the regional nodes.
Autologous vaccination with a preparation of condyloma cells was well tolerated clinically and produced good responses in an initial and recurrent giant condyloma acuminata. After more than 1 year of follow-up in this series, recurrence rates with various treatments were 50% for excision alone and bichloracetic acid, 85% for podophyllin and IFN alfa, and only 4.6% after excision and vaccination. Mean follow-up was 13 months (range, 6-23 mo).[26]
Refractory disease that relapsed despite cryotherapy, imiquimod, topical sinecatechins, and surgical debulking was successfully treated with a combination of systemic interleukin 2 and topical cidifovir.[7]
Another biological treatment combination consisting of oral retinoid plus intramuscular interferon-gamma resulted in the complete clearance within 3 months of a GCBL in a 16-year-old girl. No recurrence was noted during two years of follow-up. The authors propose this treatment option in light of it being nonscarring and relatively painless.[27]
Surgical excision is the treatment of choice. Its main advantage is the ability to histologically examine the entire specimen to ensure clear margins and to evaluate for foci of SCC. As a drawback, it typically requires at least a partial penectomy, but one series successfully used glansectomy only, with excellent functional and therapeutic results.[28, 29] Mohs surgery appears to be the most efficacious surgical treatment, allowing specimen examination and sparing most of the tissue.
Even extensive perineal giant condylomata acuminata can be successfully treated by extended surgical procedures, including colostomy and plastic reconstruction of resulting defects upon resection.[30]
In another report, very large lesions such as the one measuring 30 × 10 cm on each side of the vulva/perineum can be still excised and defects reconstructed.[31]
Excision of large genital lesions can be followed by long-term treatment with topical podophyllin. This approach, which was successfully used in one case by Akhavizadehan, allowed preservation of sexual function by limiting the depth of surgical resection.[32]
However, other experts favor conservative surgery, considering the patient’s quality of life.[33]
Recurrences of giant condyloma acuminatum can be successfully addressed with radical surgery. The cure rate with radical surgery reportedly is 61%, versus only 25% with chemoradiotherapy with or without local excision. Some authors recommend radical electrocautery surgical resection whenever possible.[34]
The substantial efficiency of surgery alone on patients in whom conservative measures failed was recently demonstrated in a series of 27 patients. The method of treatment consisted of radical excision with subsequent split-thickness skin graft. The advantages of this method consist of allowing a complete histological examination and having a rapid healing, which translates to an improvement in the patient’s quality of life.[35]
Resection with the carbon dioxide laser has also been effective, with the advantage of permitting a bloodless field, and it has been used effectively in a pregnant patient. Carbon dioxide and argon lasers are used for relapsing cases or as an alternative first-line therapy.[36] Cryosurgery has been effective in several case reports, primarily on small lesions, with normal anatomy resulting after tumor resolution. Close monitoring is required because destruction of the entire tumor cannot be ensured.
A combination of radiofrequency surgical dissection and oral acitretin (used for the treatment of erythrodermic psoriasis) was successfully used in the treatment of perianal Buschke-Löwenstein tumor, achieving an impressive disease-free status 26 months after the end of the treatment. The use of acitretin resulted in elimination of all the residual disease that was not removed by surgery.[37]
Most complications of GCBL are the result of the growth of the tumor or of the treatment. As the lesion progresses, fistulization, foul odor, and secondary infections are common. Extensive lesions, particularly leading to complex fistulous tracts and discharge, may require a temporary colostomy. Less radical approaches may lead to local recurrence. Therefore, abdominoperineal resection has been recommended for patients with rectal sphincter involvement. Malignant transformation to SCC occurs usually after several years.
Early circumcision has been found to be extremely effective in preventing penile carcinoma. Given the association with HPV, condom use would probably be effective in decreasing the incidence of GCBL. The 9-valent HPV vaccine (9vHPV, Gardasil 9) is indicated for the prevention of condyloma acuminata caused by HPV subtypes 6 and 11. The 9vHPV vaccine is indicated to prevent HPV-associated dysplasias and neoplasias in males and females aged 9-45 years.[38] The vaccine is administered as three separate doses administered at 0, 2, and 6 months. In children aged 9-14 years, a two-dose regimen may be given. The availability of vaccinations against HPV infection is contributing to the decreasing incidence of this disease.[17]
Catharine Lisa Kauffman, MD, FACP, Georgetown Dermatology and Georgetown Dermpath
Disclosure: Nothing to disclose.
Coauthor(s)
Doru Traian Alexandrescu, MD, Assistant Professor of Medicine, Georgetown University
Disclosure: Nothing to disclose.
Specialty Editors
David F Butler, MD, Former Section Chief of Dermatology, Central Texas Veterans Healthcare System; Professor of Dermatology, Texas A&M University College of Medicine; Founding Chair, Department of Dermatology, Scott and White Clinic
Disclosure: Nothing to disclose.
Edward F Chan, MD, Clinical Assistant Professor, Department of Dermatology, University of Pennsylvania School of Medicine
Disclosure: Nothing to disclose.
Chief Editor
Dirk M Elston, MD, Professor and Chairman, Department of Dermatology and Dermatologic Surgery, Medical University of South Carolina College of Medicine
Disclosure: Nothing to disclose.
Additional Contributors
Mark W Cobb, MD, Consulting Staff, WNC Dermatological Associates
Disclosure: Nothing to disclose.
Acknowledgements
The authors and editors of Medscape Reference gratefully acknowledge the contributions of previous authors, Christopher Norwood, MD, and Mary K. Mather, MD, to the development and writing of this article.
US Food and Drug Administration. FDA approves expanded use of Gardasil 9 to include individuals 27 through 45 years old. FDA News Release. October 5, 2018. Available at https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm622715.htm
Giant condylomata acuminata of Buschke and Lowenstein of the perianal region, consisting of a slow-growing, ulcerated, cauliflowerlike mass.
Giant condylomata acuminata of Buschke and Lowenstein of the perianal region, consisting of a slow-growing, ulcerated, cauliflowerlike mass.
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