Giant condyloma of Bushke-Löwenstein (GCBL) is a type of verrucous carcinoma first described by Buschke and Löwenstein in 1925. It is a rare form of squamous cell carcinoma (SCC) that most commonly appears on the glans penis, foreskin, or perianal regions, but can also be found on other anogenital regions e.g., the vulva, vagina or the bladder. In rare instances, GCBL has been found in the axilla. GCBL typically begins as a small keratotic growth on the penile foreskin or coronal sulcus and gradually, over several years, morphs into a cauliflower-like mass, often up to 10 to 15 cm, with cutaneous fistulas and a cobblestone surface.
GCBL is a slow-growing tumor, which in spite of its benign histopathology, is clinically malignant owing mostly to its locally destructive nature and its tendency to recur. GCBL ulcerates and invades deeper tissues, but does not generally metastasize. Malignant transformations of this tumor have been reported.
Various causative risk factors of GCBL have been described. These include long-standing phimosis, unsatisfactory penile hygiene (mostly seen in uncircumcised males), immunosuppression (human immunodeficiency virus, immunosuppressive drug intake), prolonged irritation, e.g., from ulcerative colitis or perianal fistulas, diabetes, smoking, substance abuse, pregnancy and, poor socioeconomic status.
GCBL occurs more frequently in males than in females. It is most common in uncircumcised males under the age of 50 years and rarely occurs in children. To date, no racial predilections have been reported for this tumor. Incidence rates of GCBL are higher in men who have sex with men (MSM), homosexual, and bisexual men.
Out of all the reported penile tumors in the US, GCBL constitutes about 5% to 24%. Very few cases of GCBL outside the penis have been reported. While penile cancers have a much higher incident rate outside the US, reliable epidemiological data are still lacking about the international incidence rates of GCBL.
Most studies link GCBL to the low-risk human papillomavirus (HPV) types 6 and 11. The genome of these HPV strains encodes for DNA sequences that translate to produce E (early) 6 and E7 proteins. E6 and E7 bind the tumor suppressor protein, p53, leading to an accelerated degradation of p53, which, in turn, immortalizes epithelial cells that replicate unchecked and accumulate DNA mutations, causing chromosomal instability and eventually, abnormal growth in the form of GCBL.
Similarly, chronic irritation of the penile and anogenital skin from poor hygiene, ulcerative colitis, or perianal fistulas is also postulated to produce chromosomal instability, leading to GCBL development.
GCBL lesions exhibit a densely keratinized and well-differentiated epithelium. Microscopically, it exhibits papillary structures with distinct cores of a fibrovascular nature, prominent koilocytosis, and broad pushing basis – features quite similar to those seen in condyloma acuminata. Compared to warts, however, GCBL’s histology is characterized by well-developed and distinct extrusion into the underlying tissue, often termed as an endophytic pattern by histopathologists.
Usually, GCBL tumor cells do not exhibit atypia, but, in the case of malignant transformation of GCBL, atypia may be seen on histopathological analysis. Both in situ and invasive SCC changes have been observed.
In immunocompetent individuals, GCBL will normally start as a small, often keratotic, plaque usually on the foreskin of the penis and will gradually, over up to twenty years, change into a structure typically described as a ‘cauliflower-like growth’ approximately twenty centimeters in size. The tumorous growth often forms ulcers or horns and is usually malodorous. When found on the penis, it can extend into the penile urethra or the corpus cavernous and produce fistulas. Although lymphadenopathy (usually regional) is seen with this tumor, it is most often caused by secondary spread and not because of metastasis of the tumor, which is very uncommon.
In the case of perianal GCBL, the first presenting symptoms are usually in the form of a painful mass, bleeding, fistulations, or abscesses. Perianal growth is normally circumferential, starting from the transitional zone between the anal mucosa and the cutaneous surface and slowly growing outwards, involving the anal canal in most cases.
In immunocompromised and pregnant patients, GCBL proliferates at a much more rapid pace compared to the proliferation rates seen in immunocompetent and nonpregnant individuals.
A biopsy is the diagnostic procedure of choice for GCBL. While biopsying a suspected GCBL lesion, care must be taken to go deep and far enough to look for the characteristic broad basis extruding deeply into the underlying tissue. Special attention should also be paid to look for any possible foci of SCC because these usually make recurrence and metastasis more likely.
Magnetic resonance imaging (MRI) with gadolinium contrast is used to look for tumor expansion while planning surgical removal.
Sentinel lymph node biopsy should only be considered when sufficient clinical evidence points towards its need because GCBL generally does not metastasize into lymph nodes.
Factors like lesion size, number and location, immune status of the patient, personal preferences of the patient, and the type of treatment available at a particular healthcare facility dictate the chosen treatment. Broadly speaking, a wide surgical excision is the treatment of choice for GCBL. According to most experts, Mohs surgery is the preferred technique as it allows tissue sparing while simultaneously enabling the surgeon to ensure tumor-free margins and spotting any SCC foci. If necessary, surgical defects can later be surgically reconstructed e.g., by using delayed split-thickness grafts. In most cases, GCBL recurrences are dealt with by radical surgery. Carbon dioxide/argon laser resection has also been used for recurrences.
Topical, intralesional, or oral chemotherapy with fluorouracil (5-FU), podophyllin, cidofovir, interferon, and imiquimod, as well as systemic chemotherapeutic drugs e.g., bleomycin, cisplatin, and leucovorin have been used as neoadjuvant or adjuvant therapy and for treating tumor recurrences after surgery. Chemotherapy alone, however, has not shown promising results.
Radiation therapy, in spite of its neoadjuvant application in a limited number of GCBL cases, has largely been avoided, mostly because of the fear of causing further anaplastic transformations.
Autologous vaccination therapy as a treatment for GCBL has also shown promising results.
Treatment for giant condyloma of Bushke-Löwenstein (GCBL) often requires large excisions of the affected areas. This may pose a challenge for the reconstruction of tissue. Reconstructive surgery with a flap has been described in case reports to cover the defect left after the excision of GCBL.
Untreated or inadequately treated GCBL has an invariably fatal course due to its locally destructive nature. It extends into and erodes pelvic organs and skeletal structures. Even with adequate treatment, the mortality rate is 21%, and the recurrence rate is approximately 68%.
Up to 56% of GCBL lesions exhibit malignant transformations.
Complications of GCBL, including treatment complications, are many. These include fistula formation, secondary infections, malodorous discharge, frequent recurrences, and malignant transformations.
Given the high prevalence rate of GCBL among uncircumcised males, it is imperative to educate parents about the important role of newborn circumcision in preventing the development of GCBL and other penile lesions.
Patients should be counseled about condom use as it diminishes the transmission of HPV, which is associated with GCBL.
Similarly, the HPV vaccine should be given to individuals between nine and twenty-six years of age as it protects against infection with both HPV 9 and 11 – strains most strongly associated with GCBL.
Giant condylomata acuminata of Bushke-Löwenstein (GCBL) frequently poses a diagnostic dilemma. These patients may exhibit non-specific signs and symptoms such as pain, bleeding, abscesses, and a penile/anogenital mass. The cause of such a mass may be a myriad of lesions, including condyloma acuminatum, cutaneous SCC (including papillary carcinoma, warty carcinoma, and carcinoma cuniculatum), primary rectal adenocarcinoma, Bowenoid papulosis, and lymphangiomas. While the physical exam may reveal that the patient has a cauliflower-like mass with fistulization, the cause is difficult to know with certainty without proper histopathological and imaging studies. [Level V]
While the general surgeon is almost always involved in the care of patients with GCBL, it is important to consult with an interprofessional team of specialists that includes a primary care clinician, a radiologist, a histopathologist, and an oncologist. The nurses are also vital members of the interprofessional group as they will monitor the patient's vital signs and assist with the education of the patient and family. The radiologist and histopathologist play a vital role in determining the cause. Without the patient providing a proper history, the radiologist and histopathologist may not be sure what to look for or what additional radiologic exams may be needed. This problem gets even more complex when immunocompromised or pregnant patients present with a GCBL lesion, in which case an OB/GYN specialist and/or an immunologist will also be an integral part of the healthcare team.
To derive good outcomes, the goals and objectives of GCBL excision surgery have to be defined prior to taking the patient to the operating room. In some cases, a chronic infection may preclude definitive repair in a single stage - thus, the importance of incorporating assistance from an infectious disease specialist. As with any other complex procedure, the preoperative workup must be thorough, and the patient should be seen by a pulmonologist and cardiologist to optimize lung and cardiac function. Sometimes the lesion may be too extensive or involving the underlying soft tissues or bone, and an oncology consult may be required for neoadjuvant chemotherapy. When GCBL is extending into the penile urethra or the anal canal, a urology or colorectal consult is recommended. Plastic surgery may be consulted to reconstruct any surgical defects. [Level V] In the postoperative period for pain and wound infection, the pharmacist will ensure that the patient is on the right analgesics and appropriate antibiotics.
With the ongoing and evolving debate about the best approach to GCBL management, there is no disputing the fact that with each attempt at GCBL treatment, there is presently a 68% risk of recurrence. Thus, further emphasizing the need for an interprofessional approach to the management of GCBL lesions. The need for meticulous planning and discussion with other professionals involved in the management of the patient is highly recommended to lower the morbidity and improve outcomes. At the same time, the role of a primary care clinician in educating patients about consistent condom use, newborn circumcision, and immunization against HPV as potential preventative strategies against giant condylomata acuminata of Bushke-Löwenstein must be emphasized. [Level V]
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