Friday, July 19, 2019

No Evidence for Role of Cutavirus in Malignant Melanoma - Volume 25, Number 8—August 2019 - Emerging Infectious Diseases journal - CDC

No Evidence for Role of Cutavirus in Malignant Melanoma - Volume 25, Number 8—August 2019 - Emerging Infectious Diseases journal - CDC

Issue Cover for Volume 25, Number 8—August 2019

Volume 25, Number 8—August 2019
Research Letter

No Evidence for Role of Cutavirus in Malignant Melanoma

Ulrike WielandComments to Author , Steffi Silling, Martin Hufbauer, Cornelia Mauch, Paola Zigrino, Frank Oellig, Alexander Kreuter, and Baki Akgül
Author affiliations: University of Cologne, Cologne, Germany (U. Wieland, S. Silling, M. Hufbauer, C. Mauch, P. Zigrino, B. Akgül)Institute of Pathology, Mülheim an der Ruhr, Germany (F. Oellig)Helios St. Elisabeth Hospital Oberhausen, University Witten/Herdecke, Witten, Germany (A. Kreuter)

Abstract

Cutavirus was previously found in cutaneous melanoma. We detected cutavirus DNA in only 2/185 melanoma biopsies and in 0/52 melanoma metastases from patients in Germany. Viral DNA was localized in the upper epidermal layers. Swab specimens from healthy skin were cutavirus positive for 3.8% (9/237) of immunocompetent and 17.1% (35/205) of HIV-positive men.
Cutavirus, a novel human protoparvovirus with linear single-stranded DNA, has been detected in fecal samples from children with diarrhea and in cutaneous T-cell lymphomas (CTCL) (1,2). Recently, Mollerup et al. reported the identification of cutavirus in 1 of 10 cutaneous malignant melanomas using viral enrichment methods with high-throughput sequencing and real-time PCR (3). This discovery raised questions concerning tropism and pathogenicity of cutavirus in human skin. We performed a retrospective study to determine cutavirus DNA prevalence and viral load in a large collection of formalin-fixed paraffin-embedded tissue biopsy specimens of malignant melanomas and in forehead swabs of healthy skin of immunocompetent and HIV-positive persons in Germany.
We used 185 cutaneous malignant melanoma biopsy specimens from 179 patients and 52 melanoma metastases from 42 patients from Germany for analyses with cutavirus real-time PCR (Appendix). We detected cutavirus DNA only in 2 nodular malignant melanomas, located on the abdomen of a 64-year-old man (MM-A) and on the cheek of an 85-year-old woman (MM-B). Viral DNA loads in these biopsies were 0.3 (MM-A) and 2.8 (MM-B) cutavirus DNA copies per β-globin gene copy. None of the 52 analyzed metastases carried cutavirus DNA (Table). The cutavirus PCR results of the 2 melanomas could be confirmed by sequencing and by in situ hybridization. In both melanomas, the cutavirus DNA–specific signals could be detected only in the superficial layers and on the surface of the skin but not in the tumor cells (AppendixFigure).
To analyze the prevalence of cutavirus on healthy nonlesional skin, we used 442 forehead swab specimens from 237 immunocompetent men and 205 HIV-positive men that were available from a previous study (4) (Appendix). We found cutavirus DNA significantly more frequently on the skin of HIV-positive men than on the skin of healthy controls (17.1% vs. 3.8%; p<0.001 by 2-sided χ2 test; Table). Among HIV-positive men, we found a trend for a higher cutavirus prevalence in patients with AIDS compared with those without AIDS (14/59 [23.7%; 95% CI 14.7–36.0] vs. 19/140 [13.6%; 95% CI 8.9–20.2]; p = 0.078 by 2-sided χ2 test). The range of viral DNA loads found in the 44 cutavirus-positive skin swabs was 0.004–268.75 (median 0.41; interquartile range [IQR] 0.0–3.57); there was no significant difference between HIV-negative and HIV-positive men (p = 0.389 by Mann-Whitney-U test; Table).
Mollerup et al. found cutavirus DNA in 1 of 10 melanomas from Denmark and suggested investigating the role of cutavirus in cutaneous cancer (3). We detected cutavirus DNA in only 2 of 185 melanoma biopsy specimens and in none of 52 metastases. In situ hybridization localized the viral DNA on the surface of the 2 cutavirus-positive melanomas and not within the malignant cells. Our data therefore argue against an oncogenic role of cutavirus in malignant melanoma.
Väisänen et al. found cutavirus DNA in 2.9% of 136 skin biopsy specimens from 123 organ transplant recipients and in none of 159 skin biopsy specimens of 98 healthy adults (5). In accordance with Väisänen et al., we also found cutavirus more frequently in immunosuppressed patients than in healthy (immunocompetent) adults. Their finding related to healthy adults is in contrast to our results; however, we analyzed not skin biopsy specimens but widespread skin swab specimens covering ≈10 cm2 of forehead skin (4). Our cutavirus DNA prevalence data on normal skin of immunocompetent adults (3.8%) are in line with cutavirus IgG seroprevalence rates reported for adults in Finland, Iran, and Kenya (4.2%–5.6%). Lower cutavirus IgG seroprevalence rates have been found in the United States (0%) and Iraq (1%) (6).
A pathogenic role of cutavirus has been investigated in further malignancies. Concerning CTCL, conflicting results have been reported. Phan et al. have found cutavirus DNA in 23.5% (4/17) (1) and Väisänen et al. in 16% (4/25) of CTCL of the mycosis fungoides type (5). Our group recently analyzed 189 biopsies of various cutaneous B- and T-cell lymphoma types and detected cutavirus DNA only in 5.8% of 104 mycosis fungoides biopsy specimens (7). In contrast, Bergallo et al. could not detect cutavirus in 55 CTCL samples (8). The in situ hybridization results of a cutavirus-positive mycosis fungoides sample analyzed by Phan et al. pointed to a localization of the viral DNA in the superficial parts of the lesion (1), similar to the results we show. Therefore, it remains unclear whether cutavirus plays a role in the development of CTCL. Recently, Dickinson et al. could not detect cutavirus in oropharyngeal and oral cavity squamous cell carcinomas (9).
In summary, our data on cutavirus DNA prevalence and localization argue against an oncogenic role of cutavirus in malignant melanoma. However, oncolytic properties of this virus or viral hit-and-run oncogenesis cannot be excluded (10). Cutavirus seems to be more frequent on healthy skin of immunosuppressed patients than on the skin of immunocompetent persons and could be part of the human skin virome. It is possible that cutavirus is an apathogenic virus shed from human skin.
Dr. Wieland is a professor of virology at the Institute of Virology of the University of Cologne, Germany. Her research interests include diagnosis and epidemiology of viral diseases.

Acknowledgments

We thank Monika Junk for excellent technical assistance.
The study was supported by intramural funds of the Faculty of Medicine of the University of Cologne (Koeln Fortune no. 2680-9067-01 and 2680-9159-01) and by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation, project no. 73111208–SFB 829 [Z4 project to C.M.]).

References

  1. Phan  TGDreno  Bda Costa  ACLi  LOrlandi  PDeng  Xet al. A new protoparvovirus in human fecal samples and cutaneous T cell lymphomas (mycosis fungoides). Virology2016;496:299305DOIExternal LinkPubMedExternal Link
  2. Väisänen  EFu  YHedman  KSöderlund-Venermo  MHuman protoparvoviruses. Viruses2017;9:E354DOIExternal LinkPubMedExternal Link
  3. Mollerup  SFridholm  HVinner  LKjartansdóttir  KRFriis-Nielsen  JAsplund  Met al. Cutavirus in cutaneous malignant melanoma.Emerg Infect Dis2017;23:3635DOIExternal LinkPubMedExternal Link
  4. Wieland  USilling  SScola  NPotthoff  AGambichler  TBrockmeyer  NHet al. Merkel cell polyomavirus infection in HIV-positive men.Arch Dermatol2011;147:4016DOIExternal LinkPubMedExternal Link
  5. Väisänen  EFu  YKoskenmies  SFyhrquist  NWang  YKeinonen  Aet al. Cutavirus DNA in malignant and non-malignant skin of cutaneous T-cell lymphoma and organ transplant patients but not of healthy adults. Clin Infect Dis2019;68:190410DOIExternal LinkPubMedExternal Link
  6. Väisänen  EMohanraj  UKinnunen  PMJokelainen  PAl-Hello  HBarakat  AMet al. Global distribution of human protoparvoviruses.Emerg Infect Dis2018;24:12929DOIExternal LinkPubMedExternal Link
  7. Kreuter  ANasserani  NTigges  COellig  FSilling  SAkgül  Bet al. Cutavirus infection in primary cutaneous B- and T-cell lymphoma.JAMA Dermatol2018;154:9657DOIExternal LinkPubMedExternal Link
  8. Bergallo  MDaprà  VFava  PPonti  RCalvi  CFierro  MTet al. Lack of detection of cutavirus DNA using PCR real time in cutaneous T-cell lymphomas (CTCL). G Ital Dermatol Venereol2018;•••DOIExternal LinkPubMedExternal Link
  9. Dickinson  AXu  MSilén  SWang  YFu  YSadeghi  Met al. Newly detected DNA viruses in juvenile nasopharyngeal angiofibroma (JNA) and oral and oropharyngeal squamous cell carcinoma (OSCC/OPSCC). Eur Arch Otorhinolaryngol2019;276:6137DOIExternal LinkPubMedExternal Link
  10. Hufbauer  MAkgül  BMolecular mechanisms of human papillomavirus induced skin carcinogenesis. Viruses2017;9:E187DOIExternal LinkPubMedExternal Link
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Cite This Article

DOI: 10.3201/eid2508.190096
Original Publication Date: 7/6/2019

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