Squamous Neoplasia of the Scrotum

Abstract

The current epidemiology and clinicopathologic features of squamous cell carcinoma (SCC) of the scrotum are largely unknown because of its low incidence. We describe the histopathologic features, immunohistochemistry, and human papillomavirus (HPV) status of 29 patients with scrotal SCC. The mean age at presentation was 55 years (range, 30 to 74 y). White to black ratio was 1.9:1. There was no predominant occupation, with the majority being white-collar professionals. Clinical history of condylomas was present in 5 patients, and 7 patients had a history of multiple skin cancers including melanoma, basal cell carcinoma, and other SCCs. Other comorbidities included human immunodeficiency virus infection (n=2), kidney transplant (n=1), leukemia/lymphoma (n=2), hidradenitis suppurativa (n=1), chronic scrotal infections with abscess (n=1), inflamed epidermal inclusion cyst (n=1), and lichen planus (n=1). One patient had a history of regular tanning bed use. Morphologically, the majority was usual type (n=17), followed by basaloid (n=7) and warty (n=5). Nineteen cases were in situ, and 10 were invasive. Three patients had inguinal lymphadenopathy; in 1, metastasis was confirmed. Suprabasal nuclear staining for Ki67 was considered positive. For p16, a continuous band of nuclear and cytoplasmic staining was considered positive, and a noncontinuous or absence of staining was considered negative. p16 was positive in 10 cases; high-risk HPV was confirmed in 7 cases. Ki67 was positive in 8/17 (47%) usual, 6/7 (85.7%) basaloid, and 3/5 (60%) warty type. p53 was positive in 5/17 (29.4%) usual, 2/7 (28.6%) basaloid, and 1/5 (20%) warty type. All patients were treated with local excision only; 13 had positive margins. Three patients were treated with imiquimod after local excision. The median follow-up was 30 months. Three patients recurred and were treated with re-excision; 1 patient received radiotherapy. Overall, the morphologic, immunohistochemical, and HPV studies show that, similar to SCC of the vulva or penis, the SCC of the scrotum can be divided into 2 major groups. Group 1 (38.5%): positive for p16 and elevated Ki67. This group is associated with HPV infection and displays predominantly a basaloid or warty morphology, although a number of them are of usual type. Group 2 (61.5%): negative for p16. This group has variable Ki67 expression, is consistently negative for HPV, and displays predominantly usual-type morphology. SCC of the scrotum in the United States currently affects primarily white-collar professionals. The majority present with in situ lesions, and the high rate of positive margins at first excision suggests that they are clinically ill-defined lesions. No longer are occupational exposures to carcinogens the major etiology of scrotal SCC. Rather in contemporary times, common risk factors include HPV infection, immunocompromised states, and chronic scrotal inflammatory conditions.

HPV Carcinomas in Immunocompromised Patients

“…However, there are several case reports of scrotal SCCs associated with HPV [38,39]. Reports of patients with scrotal carcinoma have included a history of genital warts or condylomas (17%), a history of multiple skin cancers (31%), and immunocompromise (17%) [38].…”

“…This study proposed the use of p16 antigen screening for HPV-related carcinomas, which has been shown to have higher sensitivity than in situ hybridization techniques, the current gold standard for HPV detection. However, this study may be too underpowered (29 patients) to have significant impact on the diagnosis and of anogenital lesions [39]. …”

“…Multiple studies have reported the success of topical imiquimod, including the treatment of scrotal carcinoma (after local excision) [39], Bowen’s disease of the penis [102,103], Buschke-Lowenstein tumor [104], vulvar intraepithelial neoplasia [105], penile intraepithelial neoplasia [106,107], and anal intraepithelial neoplasia [108]. Significant success has been seen in AIN with one study showing regression of the tumor by at least two grades, which corresponded to normal epidermis in most patients [109].…”

Human papillomavirus 16 is an aetiological factor of scrotal cancer

“…The specific localisation of HPV16 to SCSC tumour cells required the use of LCM-PCR, which excluded potential contamination from adjacent tissue as has been described in studies of cervical cancer and precancer and of penile cancer (Quint et al , 2012; Guimera et al , 2013; María José Fernández-Nestosa et al , 2017). The very sensitive and specific methodology for HPV-DNA detection (Kleter et al , 1998, 1999; Quint et al , 2012), employed in this study together with more specific data on viral transcriptional activity than p16 INK4a staining provides new definitive evidence confirming the oncogenic role of HPV16 in some histological types of SCSC (Orihuela et al , 1995; Guran and Pak, 1999; Matoso et al , 2014, 2016). …”

“…Human papillomavirus-DNA has been found in tissue sections containing SCSC, precancers and normal scrotum, but biological evidence is missing that directly demonstrates type-specific HPV-DNA in tumour cells, producing oncogenic RNA transcripts (Guran and Pak, 1999; Nielson et al , 2009; Matoso et al , 2014, 2016). We tested 6 cases for 72 mucosal and cutaneous HPV-genotypes.…”