Discussion

Giant condyloma acuminata (GCA), also known as Buschke-Löwenstein tumor, is a rare and aggressive form of condyloma acuminata, characterized by benign histology, which belies its persistent and locally destructive growth, high risk of recurrence, and potential for malignant transformation.^{1, 2} Although associated with low-risk HPV (HPV-6 and HPV-11) and characterized by benign histological appearance, GCA can exhibit clinical behavior akin to malignant tumors, including aggressive tissue infiltration and destruction, a high rate of recurrence, and a mortality rate of up to 20%-30% in historical series.^{3, 4}

Genomic characteristics of GCA have rarely been reported, and the biological underpinnings of its pathogenesis are poorly understood.¹ Among the alterations found via NGS in this case, KMT2B and KMT2D are mutations that affect histone methyltransferases, which may contribute to epigenetic dysregulation and have been reported in many cancer types, notably in squamous cell carcinomas of the lung, esophagus, anus, and head and neck.⁵ An activating TERT promoter hotspot mutation was also seen; activating TERT promoter mutations have been identified frequently in many cancer types and in pre-cancerous settings.⁶ The NGS also revealed few large-scale chromosomal losses or gains, which are much more commonly seen in anal squamous cell carcinomas.⁷

Traditionally, GCA is managed through locoregional therapies, including topical therapies, wide local excision, or APR. A literature review of 42 cases of surgically managed GCA found that up to 56% of these tumors were associated with histologically confirmed malignancy, underlining the high malignant risk of these tumors.³ Moreover, GCA were frequently associated with deep infiltration of surrounding structures and formation of fistulas filled with condylomas. Our case highlights the utility of FDG PET in delineating the full extent of involvement with GCA as condylomatous involvement of the deep pelvis and fistulous tracts had not been suspected, but was evident on the pre-radiation therapy FDG PET. Indeed, intense FDG avidity within condyloma acuminata has previously been described in case reports, but the use of FDG PET for GCA has not, to our knowledge, been reported on before.^{8 - 10}

Reports of definitive radiation therapy for GCA remain rare, but the existing examples suggest that radiation therapy is a viable treatment option for managing refractory GCA and condyloma acuminata. Moodley and Govender reported on 54 HIV-positive patients with unresectable vulvar GCA treated with 30 Gy in 10 fractions, resulting in a 30% complete response and 61% partial response rate.¹¹ Partial responders received further local therapies, and 52 of 54 (96%) of patients were recurrence free at 5 years. Dhadda et al reported complete regression of extensive genital warts incidentally within a postoperative vulvar radiation field treated with 40 Gy in 15 fractions.¹² Sobrado et al reported complete response to 45 Gy in 25 fractions of a large recurrent perianal GCA with fistulous involvement, with the patient remaining disease free through 20 months of follow-up.¹³ Kim et al describe a case of a giant perianal condyloma recurrent after APR, successfully treated with 45 Gy in 15 fractions with apparent complete clinical response at 6 weeks post-radiation therapy.¹⁴ Sivapalan et al reported complete clinical response to 50.4 Gy in 28 fractions of a perianal GCA with deep pelvic infiltration extending into the mesorectal and periprostatic space, with the patient remaining disease free at 6 months of follow-up.¹⁵ They also provided a literature review of 8 cases of GCA associated with histologically confirmed malignancy and 3 cases of GCA without histologic confirmation of malignancy, treated with definitive chemoradiation. Of these 11 cases, 3 developed recurrences, an outcome similar to that of anal squamous cell carcinoma. These data and the present case suggest that radiation therapy may be an effective therapy for GCA in cases where traditional treatments are inadequate, providing effective local control and potential disease regression, particularly in cases with clearly benign histology of condyloma acuminata. The effectiveness of radiation therapy in the definitive setting also lends support to its efficacy in the neoadjuvant setting, which may be particularly important in maximizing the opportunities for avoidance of permanent colostomy. Multidisciplinary discussion is essential to improve outcomes of patients with this rare and often complex condition.

Key takeaways from the present case include the utility of FDG PET in delineating the true extent of pelvic involvement of GCA, and the unexpectedly extensive imaging findings identified during workup of this case underlines the potential of GCA to infiltrate insidiously within the pelvis, particularly along surgical and fistulous tracts. Additionally, the GCA in the present case was extensively sampled and examined by pathology over time, including with an NGS panel, without evidence of malignant transformation, which provided equipoise regarding treatment with definitive radiation therapy or chemoradiotherapy and patient-centered decision-making.