Improved detection reveals active β-papillomavirus infection in skin lesions from kidney transplant recipients

Abstract

The aim of this study was to determine whether detection of b-HPV gene products, as defined in epidermodysplasia verruciformis skin cancer, could also be observed in lesions from kidney transplant recipients alongside the viral DNA. A total of 111 samples, corresponding to 79 skin lesions abscised from 17 kidney transplant recipients, have been analyzed. The initial PCR analysis demonstrated that b-HPV-DNA was highly present in our tumor series (85%). Using a combination of antibodies raised against the E4 and L1 proteins of the b-genotypes, we were able to visualize productive infection in 4 out of 19 actinic keratoses, and in the pathological borders of 1 out of 14 squamous cell carcinomas and 1 out of 31 basal cell carcinomas. Increased expression of the cellular proliferation marker minichromosome maintenance protein 7 (MCM7), that extended into the upper epithelial layers, was a common feature of all the E4-positive areas, indicating that cells were driven into the cell cycle in areas of productive viral infections. Although the present study does not directly demonstrate a causal role of these viruses, the detection of E4 and L1 positivity in actinic keratosis and the adjacent pathological epithelium of skin cancer, clearly shows that b-HPV are actively replicating in the intraepidermal precursor lesions of kidney transplant recipients and can therefore cooperate with other carcinogenic agents, such as UVB, favoring skin cancer promotion. Modern Pathology (2014) 27, 1101-1115; doi:10.1038/modpathol.2013.240; published online 3 January 2014Keywords: b-HPV; immunosuppression; kidney transplant recipients; skin cancer; viral life cycle Solid organ transplantation is a treatment offered to an increasing number of patients with end-stage organ diseases. Although lifesaving, organ transplantation is associated with an overall three-to fivefold increased risk of malignancies. 1-4 Most of these cancers are caused by reactivated viruses whose oncogenic potential is suppressed by immunological reactions in healthy individuals, like Epstein-Barr virus-associated B-cell lymphomas, Kaposi's sarcoma, caused by the reactivation of human herpesvirus type 8, and Merkel cell carcinoma of the skin, associated with Merkel cell polyomavirus. [5][6][7][8][9] Of the cancers presenting in organ transplant recipients that have no established infectious etiology, skin cancer is the most frequent form (95%), including squamous and basal cell carcinomas. [10][11][12][13] The incidence of skin cancer, the most common cancer in fair-skinned populations, is at least 50-fold higher in organ transplant recipients. 14-16 Large numbers of skin tumors (often more than 10) tend to develop over time in these at-risk subjects, thus

Characterization of skin lesions induced by skin-tropic α- and β-papillomaviruses in a patient with epidermodysplasia verruciformis

“…e,f), positive for HPV20. As already reported, E4 staining was absent in the adjacent normal epithelium . The late protein L1 was not observed in this tumour (data not shown).…”

Beta genus papillomaviruses and skin cancer

“…The prevalence of beta HPV-DNA in precancerous actinic keratosis is higher than in SCCs and higher HPV-DNA loads (up to 50 copies/cell) are compatible with a carcinogenic role of the beta HPVs in early phases of skin cancer development (Weissenborn et al, 2005). Active replication and expression of beta HPVs has been demonstrated in actinic keratosis lesions as well as in the adjacent pathological epithelium of SCCs in renal transplant patients, where beta HPV expression is also associated with increased expression of the cellular proliferation marker MCM7 (Borgogna et al, 2014). …”

Human papilloma virus infection in basal cell carcinoma of the skin: a systematic review and meta-analysis study

“…Fifteen studies were case-control and 30 studies were cross-sectional studies. Twenty-four studies did polymerase chain reaction (PCR) [1,2,12,14,19,20,21,25,28,29,31,32,35,36,37,39,40,41,42,43,44,46,47,49,50], 2 in situ hybridization (ISH) [15,18], 3 serology [16,48,24], 7 nested PCR [5,8,11,26,27,34,43], one loop-mediated isothermal amplification assay (LAMP)/PCR [30], 4 multiplex serology [17,22,38,45], 2 immunohistochemistry (IHC) [9,33] Meta-analysis Figure 2 shows the incidence of number of HPVs in the BCC patients and controls. Some studies reported this incidence in the BCC patients and controls (case-control studies) and other studies only reported in BCC patients (cross-sectional and cohort studies).…”

“…Out of 45 studies reported during 1991 to 2017; two studies were reported in Australia [12,13], one Romania [14], ten USA [15,16,17,18,19,20,21,22,23,24], one Argentina [1], four Netherlands [25,26,27,28], two Spain [8,11], one Brazil [29], one China [30], one UK [31], one Croatia [2], four Iran [9,32,33,34], one North Africa/France [35], one Germany/USA [36], two Greece [37,38], one Sweden/Austria [39], two Germany [40,41], five Italy [5,42,43,44,45], one Russia [46], one Germany/Poland [47], one Norway/Sweden [48] and two Sweden [49,50] (Table I). Fifteen studies were case-control and 30 studies were cross-sectional studies.…”