Abstract
Many malignancies that occur in high excess in kidney transplant recipients (KTRs) are due to viruses that thrive in the setting of immunosuppression. Keratinocyte carcinoma (KC), the most frequently occurring cancer type in KTR, has been associated with skin infection by human papillomavirus (HPV) from the beta genus. In this report, we extend our previous investigation aimed at identifying the presence of active β-HPV infection in skin tumors from KTRs through detection of viral protein expression. Using a combination of antibodies raised against the E4 and L1 proteins of the β-genotypes, we were able to visualize infection in five tumors [one keratoacanthoma (KA), three actinic keratoses (AKs), and one seborrheic keratoses (SKs)] that were all removed from two patients who had been both transplanted twice, had developed multiple KCs, and presented with a long history of immunosuppression (>30 years). These infected tissues displayed intraepidermal hyperplasia and increased expression of the ΔNp63 protein, which extended into the upper epithelial layers. In addition, using a xenograft model system in nude mice displaying a humanized stromal bed in the site of grafting, we successfully engrafted three AKs, two of which were derived from the aforementioned KTRs and displayed β-HPV infection in the original tumor. Of note, one AK-derived xenograft, along with its ensuing lymph node metastasis, was diagnosed as squamous cell carcinoma (SCC). In the latter, both β-HPV infection and ΔNp63 expression were no longer detectable. Although the overall success rate of engrafting was very low, the results of this study show for the first time that β-HPV+ and ΔNp63+ intraepidermal hyperplasia can indeed progress to an aggressive SCC able to metastasize. Consistent with a series of reports attributing a causative role of β-HPV at early stages of skin carcinogenesis through ΔNp63 induction and increased keratinocytes stemness, here we provide in vivo evidence that these events are also occurring in the affected skin of KTRs. Due to these β-HPV-driven molecular pathways, the nascent tumor cell is able to acquire a high enough number of carcinogenic insults that its proliferation and survival will eventually become independent of viral gene expression.
Highlights
The prolonged use of immunosuppressive drugs in kidney transplant recipients (KTRs) is a recognized risk factor for infectious diseases and ensuing complications, including infection-related malignancies (Vajdic and van Leeuwen, 2009; Krynitz et al, 2013; Geissler, 2015)
We have recently shown β-human papillomavirus (HPV) and Skin Carcinogenesis that HPV8-induced field cancerization in a transgenic mouse model is due to Lrig1+ keratinocyte stem cell expansion, which is accompanied by aberrant nuclear p63 expression in the expanded infundibulum and adjoining interfollicular epidermis
We had already analyzed 111 formalin-fixed and paraffin-embedded blocks (FFPE) blocks obtained from 79 skin lesions of 17 patients from a cohort of KTRs for the presence of active β-HPV infection by immunostaining with anti-E4 and anti-L1 antibodies
Summary
The prolonged use of immunosuppressive drugs in kidney transplant recipients (KTRs) is a recognized risk factor for infectious diseases and ensuing complications, including infection-related malignancies (Vajdic and van Leeuwen, 2009; Krynitz et al, 2013; Geissler, 2015). Cutaneous human papillomaviruses (HPVs) from the β-genus, such as HPV5 and HPV8, have long been associated with KC in patients with a specific genetic background and in long-term immunosuppressed individuals (Genders et al, 2015; Howley and Pfister, 2015; Quint et al, 2015). Cutaneous HPVs, which are clustered in the evolutionarily distinct β-genus, can cause widespread unapparent or asymptomatic infections in the general population (Howley and Pfister, 2015; Quint et al, 2015). Β-HPV-associated wart-like lesions in EV patients are at high risk for progression to KC (Borgogna et al, 2012; Landini et al, 2014), and the ensuing tumors are positive for β-HPV DNA and protein expression (Dell’Oste et al, 2009)
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