Optimal treatment for penile verrucous carcinoma: a systematic literature review

Verrucous carcinoma, a rare low-grade well-differentiated squamous cell carcinoma (SCC), is known for its slowly compressive expanding warty growth and rare metastasis [1‐3]. Aggressive treatment, such as penectomy, has been suggested based on the concept that penile verruca carcinoma (PVC) is malignant. In contrast, less aggressive treatment, such as local excision without preventive lymphadenectomy, has been suggested based on the concept that the biological behavior of PVC resembles that of a benign tumor. In patients who had undergone aggressive wide surgical excision of the glans penis and penile shaft, many functional, cosmetic, and psychosexual problems have been reported. To date, surgical treatment trends have been unclear regarding the use of preservation surgery. Here we reviewed the literature to determine the most effective treatment for PVC and suggest best practices for treatment guidelines.

To summarize the prevalence, causative factors, diagnostic methods, treatment methods, clinical behaviors, diagnostic imaging techniques, and prognosis of PVC, we searched PubMed for relevant studies using the keyword “penile verrucous carcinoma” without restrictions on publication year and retrieved abstracts published in English that mentioned PVC diagnosis and treatment. The abstracts were screened according to inclusion and exclusion criteria. The inclusion criteria were presented cases and the corresponding treatment methods, microscopic diagnosis of PVC, availability of full text articles, and publication in English. The exclusion criteria were lack of tumor staging information and tumor staging beyond T2 (Stage T2 penile cancers are different from penile verrucous carcinoma and defined as invasive cancers such as squamous cell carcinoma and others). To check the association between treatment method and conditions of cases, the treatments were categorized into 2 groups—the less aggressive treatment group included shaving, local excision, and no surgery and the aggressive treatment group included glansectomy, partial penectomy, and total penectomy. Individual factors included age, case history, tumor size, tumor shape, tumor location, tumor stage, adjuvant treatment, lymph node metastasis, disease-free status, recurrence, human papilloma virus (HPV) infection status, and treatment trends over time.

The statistical analysis was performed using SPSS for Windows version 25 (SPSS Inc., Chicago, IL, USA). We hypothesized that aggressive treatment is more effective and investigated the difference in efficacy between the 2 treatments. We performed a t-test, a chi-squared test, and Fisher’s exact test to ensure data accuracy and a regression analysis to examine whether the individual factors were correlated in the 2 groups.

A total of 276 articles were retrieved from PubMed. Among them, 68 abstracts that mentioned PVC diagnosis and/or treatment and were published in English were selected. The studies were published between 1969 and February 2019. Most of the studies were published in English; other publication languages included Spanish (14), Chinese (3), French (3), Japanese (2), Bulgarian (1), Israeli (1), and Italian (1). Several studies mentioned regarding PVC treatment and were simple case reports [4‐47]. Its rarity is supported by the fact that 1 case in a 10-year period and 13 cases in a 30-year period were reported [10, 48‐51]. Among the 68 studies retrieved, 28 met the inclusion criteria. Of those, 9 were excluded according to the exclusion criteria. Thus, a total of 19 studies were subjected to full-text review (Fig. 1) [4‐7, 10, 11, 20, 23, 31, 32, 35, 37‐40, 43, 45‐47].

The studies comprised a total of 58 cases of PVC (Table 1). The patients were 28–86 years of age. The case histories were 1–204 months long. The tumor sizes were 0.8–10 cm. Fifty-4 of the cases included a description of tumor shape: papillary cauliflower in 30, keratotic hornlike in 3, and warty verrucous in 21. The tumors involved the glans in 33 cases, coronoid sulcus in 4, shaft in 4, prepuce in 7, prepuce and glans in 4, glans and coronoid sulcus and shaft in 1, prepuce and coronoid sulcus in 2, glans and coronoid sulcus in 2, and coronoid sulcus and shaft in 1. A total of 10 cases involved the coronoid sulcus, an area in which penile carcinoma would more rapidly infiltrate the penile fascia. Regarding staging, 52 cases were classified as stage Ta, 4 were classified as T1, and 2 were classified as T1a. Regarding treatment, no surgery was performed in 4 cases, local excision was performed in 10, shaving in 3, Mohs surgery was performed in 2, circumcision was performed in 1, glansectomy was performed in 3, partial penectomy was performed in 29, and total penectomy was performed in 6. Thus, 20 cases involved less aggressive treatment and 38 cases involved aggressive treatment. Fifteen cases of adjuvant treatment were reported, including 1 of radiotherapy, 6 of chemotherapy, 2 of chemoradiotherapy, and 6 of local therapy (CO₂ laser, cryotherapy, intralesional interferon, and topical fluorouracil). There was only 1 case of lymph node metastasis. The reported lymphadenopathies were revealed as inflammation without metastasis [4‐6]. One case of bilateral lymph node metastasis, which was suspected as a mixed tumor condition with moderately differentiated SCC, was reported [35]. The follow-up period was 6–228 months (19 years). There were 7 cases of tumor recurrence: 5 in the less aggressive treatment group and 2 in the aggressive treatment group. All cases except 2 achieved tumor-free status. The other 2 patients died due to other malignant conditions [35, 47]. Six cases were associated with the following diseases: anaplastic spindle cell carcinoma suggestive of malignant transformation after radiotherapy, hybrid verrucous SCC, moderately differentiated SCC, lichen sclerosis, pseudoepitheliomatous keratotic and micaceous balanitis, and human immunodeficiency virus infection. HPV infection status was described as negative in 8 cases; the others were not specified. The reported cases following the year of issue categorized in 10-year increments: 1 in the 1970s, 14 in the 1980s, 2 in the 1990s, 15 in the 2000s, and 26 in the 2010s. The main diagnostic method was biopsy. Chest x-ray, HPV polymerase chain reaction (PCR), ultrasonography, and computed tomography were optional. The best diagnostic method was biopsy and HPV PCR. Ultrasonography, computed tomography, and magnetic resonance imaging (MRI) offered more precise information about tumor anatomy and regional lymphadenopathy. Two reports mentioned surgical treatment guidelines according to tumor size [8] and depth [17]. Concerning surgical excision, the main treatment was radical surgery, including at least partial penectomy [4‐47], even with the relatively small tumor size (< 3 cm) [8]. The surgical margins were 2 cm in cases of partial penectomy and 0.3–1 cm in cases of local excision (Table 2) [5, 6]. In contrast, some studies have emphasized the good clinical results of local excision because of the favorable clinical behavior of PVC [5, 6, 11, 15, 17, 31, 32, 37, 39, 40, 43, 45‐47].

The results of the t-test using categories of age, case history, and tumor size and the result of the cross-sectional analysis of the categories of tumor shape, disease-free status, and HPV status were excluded since some individual data for each case were missing (data n ot shown). In the cross-sectional analysis, tumor location, tumor stage, and recurrence were not significantly associated with either treatment. Regarding the clinical results, all but 2 patients (who died of other malignant conditions) achieved disease-free status. Regarding treatment efficacy, the recurrence rates did not differ significantly between the less aggressive and aggressive treatments. Patients who received adjuvant therapy tended to ultimately receive less aggressive treatment. Regarding the test statistics, the X² was 21.926 and the probability was 0.000. Thus, the results were statistically significant. Regarding differences in treatment trends over time, the X² was 12.549 and the probability was 0.005. Thus, the result was statistically significant (Table 3).

According to the regression analysis of age, case history, tumor size, tumor shape, tumor location, tumor stage, adjuvant treatment, tumor recurrence, and treatment trends over time did not appear to have a significant negative or positive effect (data not shown).

In summary, the associations between tumor location and treatment method and tumor depth and treatment method were not statistically significant. Adjuvant therapy tended to be performed alone or with local excision preventing a penectomy or glansectomy. Partial penectomy cases (aggressive treatment group) were predominantly reported in the 2010s. No intergroup differences were seen in clinical results. Therefore, our hypothesis that aggressive treatment is more effective was rejected.

The review performed here revealed that PVC tends not to recur or metastasize after resection but that surgical treatment tends to remove too much tissue. However, in most cases of local excision, the wound heals well and local recurrence rarely occurs. Therefore, considering the ability of local excision with minimal surgical margins to spare the functional and cosmetic aspects of the penile shaft and glans penis, we recommend it as the first-line choice of treatment with observation, especially for tumors measuring < 3 cm and classified as stage T1 according to the 2016 tumor node metastasis clinical and pathological classification for penile cancer.