Voriconazole exposure and risk of cutaneous squamous cell carcinoma among lung or hematopoietic cell transplant patients: A systematic review and meta-analysis

Published:August 18, 2018DOI:https://doi.org/10.1016/j.jaad.2018.08.010


      Current evidence about the association between voriconazole and risk of cutaneous squamous cell carcinoma (SCC) remains inconsistent.


      To assess the association between voriconazole use and risk of SCC.


      We systematically searched PubMed and Embase and performed a random effects model meta-analysis to calculate the pooled relative risk (RR) with a 95% confidence interval (CI).


      Of the 8 studies involving a total of 3710 individuals with a lung transplant or hematopoietic cell transplant that were included in the qualitative analysis, 5 were included in the meta-analysis. Use of voriconazole was significantly associated with increased risk of SCC (RR, 1.86; 95% CI, 1.36-2.55). The increased risk did not differ according to type of transplantation or adjustment for sun exposure. Longer duration of voriconazole use was found to be positively associated with risk of SCC (RR, 1.72; 95% CI, 1.09-2.72). Voriconazole use was not associated with increased risk of basal cell carcinoma (RR, 0.84; 95% CI, 0.41-1.71).


      There were some heterogeneities in the retrospective observational studies.


      Our findings support an increased risk of SCC associated with voriconazole in individuals with a lung transplant or hematopoietic cell transplant. Routine dermatologic surveillance should be performed, especially among individuals at high risk of developing SCC.

      Key words

      Abbreviations used:

      BCC ( basal cell carcinoma), CI ( confidence interval), HCT ( hematopoietic cell transplant), LT ( lung transplant), NMSC ( nonmelanoma skin cancer), RR ( relative risk), SCC ( squamous cell carcinoma), UV ( ultraviolet), VNO ( voriconazole N-oxide)
      To read this article in full you will need to make a payment
      AAD Member Login
      AAD Members, full access to the journal is a member benefit. Use your society credentials to access all journal content and features
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Madeleine M.M.
        • Patel N.S.
        • Plasmeijer E.I.
        • et al.
        Epidemiology of keratinocyte carcinomas after organ transplantation.
        Br J Dermatol. 2017; 177: 1208-1216
        • Omland S.H.
        • Gniadecki R.
        • Haedersdal M.
        • Helweg-Larsen J.
        • Omland L.H.
        Skin cancer risk in hematopoietic stem-cell transplant recipients compared with background population and renal transplant recipients: a population-based cohort study.
        JAMA Dermatol. 2016; 152: 177-183
        • Leisenring W.
        • Friedman D.L.
        • Flowers M.E.
        • Schwartz J.L.
        • Deeg H.J.
        Nonmelanoma skin and mucosal cancers after hematopoietic cell transplantation.
        J Clin Oncol. 2006; 24: 1119-1126
        • Ulrich C.
        • Kanitakis J.
        • Stockfleth E.
        • Euvrard S.
        Skin cancer in organ transplant recipients–where do we stand today?.
        Am J Transplant. 2008; 8: 2192-2198
        • Zwald F.O.
        • Brown M.
        Skin cancer in solid organ transplant recipients: advances in therapy and management: part I. Epidemiology of skin cancer in solid organ transplant recipients.
        J Am Acad Dermatol. 2011; 65 (quiz 262): 253-261
        • Rizvi S.M.H.
        • Aagnes B.
        • Holdaas H.
        • et al.
        Long-term change in the risk of skin cancer after organ transplantation: a population-based nationwide cohort study.
        JAMA Dermatol. 2017; 153: 1270-1277
        • Rashtak S.
        • Dierkhising R.A.
        • Kremers W.K.
        • Peters S.G.
        • Cassivi S.D.
        • Otley C.C.
        Incidence and risk factors for skin cancer following lung transplantation.
        J Am Acad Dermatol. 2015; 72: 92-98
        • Euvrard S.
        • Kanitakis J.
        • Claudy A.
        Skin cancers after organ transplantation.
        N Engl J Med. 2003; 348: 1681-1691
        • Garrett G.L.
        • Lowenstein S.E.
        • Singer J.P.
        • He S.Y.
        • Arron S.T.
        Trends of skin cancer mortality after transplantation in the United States: 1987 to 2013.
        J Am Acad Dermatol. 2016; 75: 106-112
        • Vajdic C.M.
        • van Leeuwen M.T.
        Cancer incidence and risk factors after solid organ transplantation.
        Int J Cancer. 2009; 125: 1747-1754
        • Mudigonda T.
        • Levender M.M.
        • O'Neill J.L.
        • West C.E.
        • Pearce D.J.
        • Feldman S.R.
        Incidence, risk factors, and preventative management of skin cancers in organ transplant recipients: a review of single- and multicenter retrospective studies from 2006 to 2010.
        Dermatol Surg. 2013; 39: 345-364
        • Garrett G.L.
        • Blanc P.D.
        • Boscardin J.
        • et al.
        Incidence of and risk factors for skin cancer in organ transplant recipients in the United States.
        JAMA Dermatol. 2017; 153: 296-303
        • Goncalves C.P.
        • Trope B.M.
        • Ramos E.S.M.
        Non-melanoma skin cancer in renal transplant recipients: a study in a Brazilian reference center.
        Clin Cosmet Investig Dermatol. 2015; 8: 339-344
        • Gogia R.
        • Binstock M.
        • Hirose R.
        • Boscardin W.J.
        • Chren M.M.
        • Arron S.T.
        Fitzpatrick skin phototype is an independent predictor of squamous cell carcinoma risk after solid organ transplantation.
        J Am Acad Dermatol. 2013; 68: 585-591
        • Silveira F.P.
        • Husain S.
        Fungal infections in solid organ transplantation.
        Med Mycol. 2007; 45: 305-320
        • Marr K.A.
        Fungal infections in hematopoietic stem cell transplant recipients.
        Med Mycol. 2008; 46: 293-302
        • Levine M.T.
        • Chandrasekar P.H.
        Adverse effects of voriconazole: over a decade of use.
        Clin Transplant. 2016; 30: 1377-1386
        • Ona K.
        • Oh D.H.
        Voriconazole N-oxide and its ultraviolet B photoproduct sensitize keratinocytes to ultraviolet A.
        Br J Dermatol. 2015; 173: 751-759
        • Wojenski D.J.
        • Bartoo G.T.
        • Merten J.A.
        • et al.
        Voriconazole exposure and the risk of cutaneous squamous cell carcinoma in allogeneic hematopoietic stem cell transplant patients.
        Transpl Infect Dis. 2015; 17: 250-258
        • Vadnerkar A.
        • Nguyen M.H.
        • Mitsani D.
        • et al.
        Voriconazole exposure and geographic location are independent risk factors for squamous cell carcinoma of the skin among lung transplant recipients.
        J Heart Lung Transplant. 2010; 29: 1240-1244
        • Singer J.P.
        • Boker A.
        • Metchnikoff C.
        • et al.
        High cumulative dose exposure to voriconazole is associated with cutaneous squamous cell carcinoma in lung transplant recipients.
        J Heart Lung Transplant. 2012; 31: 694-699
        • Mansh M.
        • Binstock M.
        • Williams K.
        • et al.
        Voriconazole exposure and risk of cutaneous squamous cell carcinoma, aspergillus colonization, invasive aspergillosis and death in lung transplant recipients.
        Am J Transplant. 2016; 16: 262-270
        • Kuklinski L.F.
        • Li S.
        • Karagas M.R.
        • Weng W.K.
        • Kwong B.Y.
        Effect of voriconazole on risk of nonmelanoma skin cancer after hematopoietic cell transplantation.
        J Am Acad Dermatol. 2017; 77: 706-712
        • Kolaitis N.A.
        • Duffy E.
        • Zhang A.
        • et al.
        Voriconazole increases the risk for cutaneous squamous cell carcinoma after lung transplantation.
        Transpl Int. 2017; 30: 41-48
        • Hamandi B.
        • Fegbeutel C.
        • Silveira F.P.
        • et al.
        Voriconazole and squamous cell carcinoma after lung transplantation: a multicenter study.
        Am J Transplant. 2018; 18: 113-124
        • Feist A.
        • Lee R.
        • Osborne S.
        • Lane J.
        • Yung G.
        Increased incidence of cutaneous squamous cell carcinoma in lung transplant recipients taking long-term voriconazole.
        J Heart Lung Transplant. 2012; 31: 1177-1181
        • Stroup D.F.
        • Berlin J.A.
        • Morton S.C.
        • et al.
        Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis Of Observational Studies in Epidemiology (MOOSE) group.
        JAMA. 2000; 283: 2008-2012
        • De La Cruz O.
        • Silveira F.P.
        Respiratory fungal infections in solid organ and hematopoietic stem cell transplantation.
        Clin Chest Med. 2017; 38: 727-739
        • Higgins J.P.
        • Thompson S.G.
        Quantifying heterogeneity in a meta-analysis.
        Stat Med. 2002; 21: 1539-1558
        • Williams K.
        • Mansh M.
        • Chin-Hong P.
        • Singer J.
        • Arron S.T.
        Voriconazole-associated cutaneous malignancy: a literature review on photocarcinogenesis in organ transplant recipients.
        Clin Infect Dis. 2014; 58: 997-1002
        • Angeles J.G.C.
        • Cleaver J.E.
        • Feeney L.
        • Oh D.H.
        • Arron S.T.
        Voriconazole does not potentiate photo damage from UVB exposure.
        J Clin Exp Dermatol Res. 2013; 4: 173
        • Mansh M.
        • Ing L.
        • Dimon M.
        • Celli A.
        • Mauro T.M.
        • Arron S.T.
        Voriconazole exposure regulates distinct cell-cycle and terminal differentiation pathways in primary human keratinocytes.
        Br J Dermatol. 2017; 176: 816-820
        • Ikeya S.
        • Sakabe J.I.
        • Yamada T.
        • Naito T.
        Voriconazole-induced photocarcinogenesis is promoted by aryl hydrocarbon receptor-dependent COX-2 upregulation.
        Sci Rep. 2018; 8: 5050
        • Swanson H.I.
        Cytochrome P450 expression in human keratinocytes: an aryl hydrocarbon receptor perspective.
        Chem Biol Interact. 2004; 149: 69-79
        • Armstrong B.K.
        • Kricker A.
        The epidemiology of UV induced skin cancer.
        J Photochem Photobiol B. 2001; 63: 8-18
        • Tang H.
        • Fu S.
        • Zhai S.
        • Song Y.
        • Asgari M.M.
        • Han J.
        Use of antihypertensive drugs and risk of keratinocyte carcinoma: a meta-analysis of observational studies.
        Pharmacoepidemiol Drug Saf. 2018; 27: 279-288
        • Jiyad Z.
        • Olsen C.M.
        • Burke M.T.
        • Isbel N.M.
        • Green A.C.
        Azathioprine and risk of skin cancer in organ transplant recipients: systematic review and meta-analysis.
        Am J Transplant. 2016; 16: 3490-3503
        • Coghill A.E.
        • Johnson L.G.
        • Berg D.
        • Resler A.J.
        • Leca N.
        • Madeleine M.M.
        Immunosuppressive medications and squamous cell skin carcinoma: nested case-control study within the Skin Cancer after Organ Transplant (SCOT) cohort.
        Am J Transplant. 2016; 16: 565-573
        • Zwald F.O.
        • Spratt M.
        • Lemos B.D.
        • et al.
        Duration of voriconazole exposure: an independent risk factor for skin cancer after lung transplantation.
        Dermatol Surg. 2012; 38: 1369-1374