- Email: [email protected]
Surveillance of Human Papilloma Virus Infection and Cervical Cancer in Kidney Transplant Recipients: Preliminary Data
Infections
Surveillance of Human Papilloma Virus Infection and Cervical Cancer in Kidney Transplant Recipients: Preliminary Data M. Veroux, D. Corona, G. Scalia, V. Garozzo, M. Gagliano, G. Giuffrida, C.M. Costanzo, A. Giaquinta, I. Palermo, D. Zappalà, T. Tallarita, D. Zerbo, R. Russo, A. Cappellani, C. Franchina, V. Scriffignano, and P. Veroux ABSTRACT Introduction. Development of cancer after transplantation has rapidly became one of the leading causes of death in kidney transplant recipients with functioning grafts. Anogenital malignant neoplasms may occur with a 14-fold increased incidence, and human papilloma virus (HPV) infection has been recently identified as the leading cause of cervical carcinoma. We report the preliminary findings of a prospective study that evaluated the incidence of HPV infection and cervical carcinoma in a population of kidney transplant recipients. Patients and Methods. The study included 35 female recipients of a deceased donor kidney with at least 6 months of follow-up. All patients underwent a cervicovaginal brushing, an HPV DNA test, and a Papanicolaou test. Results. Twenty-two patients (62.8%) were positive for HPV DNA. Thirteen of 22 HPV DNA–positive recipients (59%) demonstrated a high-risk HPV genotype. No cytologic anomalies were detected in Papanicolaou smears. Conclusions. These preliminary data demonstrated a high incidence of HPV infection in renal transplant recipients. Most of our recipients exhibited a high-risk HPV genotype, which suggests higher aggressiveness of such infection in immunosuppressed patients. The HPV test is useful to monitor patients at higher risk of anogenital malignant neoplasms by identifying the cytologic anomalies at an earlier stage. This ongoing study will investigate the rate of progression of HPV infection and the clinical patterns of HPV-positive cytologic anomalies in renal transplant recipients.
From Department of Surgical Sciences (M.V., M.G., G.G., A.G., T.T., D.Z., A.C., P.V.), Transplantation and Advanced Technologies, Vascular Surgery and Organ Transplant Units, and Department of Microbiological Sciences and Gynaecological Sciences (D.C., G.S., C.M.C., I.P., D.Z., R.R., C.F., V.S.), Virology Unit, University Hospital of Catania; and Department of
Microbiological Sciences and Gynaecological Sciences (V.G.), Gynaecology Unit, Vittorio Emanuele Hospital, Catania, Italy. Address reprint requests to Massimiliano Veroux, MD, PhD, Department of Surgical Sciences, Transplantation and Advanced Technologies, Organ Transplant Unit, University Hospital, Via S. Sofia 86, 95123 Catania, Italy. E-mail: [email protected]
© 2009 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
0041-1345/09/$–see front matter doi:10.1016/j.transproceed.2009.03.015
Transplantation Proceedings, 41, 1191–1194 (2009)
1191
1192
VEROUX, CORONA, SCALIA ET AL
IDNEY TRANSPLANTATION is the best replacement therapy in patients with end-stage renal disease (ESRD). However, long-term results have not improved in the last decade, probably as a consequence of the adverse effects of immunosuppressive drugs. Immunosuppressive medications are a leading cause of graft loss in the long term. They substantially predispose to infections and posttransplantation de novo neoplasms. Most malignant neoplasms are lymphoma and skin cancers1–3; however, many authors have also noted a high rate of anogenital tract neoplasms in renal allograft recipients.4 – 8 Penn1 identified a 14-fold increased incidence of intraepithelial carcinoma of the cervix in renal transplant recipients compared with age-matched control subjects, with an overall incidence of 11% in all women with posttransplantation malignant neoplasms. Initially it was theorized that immunosuppressive agents were the cause of carcinogenesis; however, because of their ability to induce alterations in DNA, human papilloma virus (HPV) infection was recently identified as the leading cause of cervical neoplasia. The immunosuppressed state induced to prevent graft rejection may predispose to development of HPV infection with potential to progress to cancer.4 – 8 The wider use of the polymerase chain reaction (PCR), usually followed by reverse dot blot analysis, has enabled precise identification of HPV and identification of genotypes with high vs medium to low oncogenic risk.5,7 In the first period of the viral infection, the Papanicolaou (Pap) test and colposcopy may show normal epithelium or mild atypia. Most HPV infections resolve within 2 years; however, the 10% that persist for more than 2 years are highly linked to
K
precancer. If HPV infection persists, it may evolve to cervical intraepithelial neoplasia (CIN) and finally to cancer in 5 to 7 years in immunocompetent female patients.7 While high-risk HPV genotypes are more likely to progress to cervical neoplasia, it is not known why some infections progress to cancer. The screening for cervical cancer is based on early identification of precancerous lesions. The Pap test is the first-level examination. In cases of positive Pap test results, the second-level examination is colposcopy associated with molecular biological testing. If there is suspicion of HPV infection, target biopsy of the evident lesion is performed.6,7 The incidence of HPV infections in renal transplant recipients is 17% to 45%, with a low rate of cytologic alteration found at Pap testing.4 – 6,9,10 Little is known about the rate of progression to cervical cancer and the time to progression in renal transplant recipients, probably because of the retrospective nature of most clinical reports, which do not investigate the progression of HPV infection in transplant recipients. The objective of this retrospective study was to investigate the early incidence of HPV infection and cytologic anomalies using the Pap test in a population of kidney transplant recipients.
MATERIALS AND METHODS This study included 35 women with ESRD who received a deceased donor kidney transplant in a 2-year period and had at least 6 months of follow-up posttransplantation. Data on personal history, original disease, immunosuppressive drugs, and duration of dialysis were collected from each patient (Table 1). Every 6 months, all
Table 1. Clinical Characteristics of HPV-Positive Renal Transplant Recipients Patient
Age, y
Time Receiving Dialysis, mo
Primary Disease
Donor Age, y
Immunosuppressive Therapy
HPV Subtype
Papanicolaou Test Result
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22
31 43 56 64 51 51 30 49 51 40 58 63 45 35 45 44 36 29 46 41 30 28
24 36 42 212 65 64 18 12 100 50 17 131 126 6 15 17 52 38 50 70 30 50
Chronic pyelonephritis Chronic glomerulonephritis Chronic glomerulonephritis Chronic glomerulonephritis Polycystic kidney Chronic glomerulonephritis Chronic glomerulonephritis Membranous glomerulonephritis Chronic glomerulonephritis Chronic glomerulonephritis Polycystic kidney Polycystic kidney Chronic glomerulonephritis Diabetic nephropathy Chronic glomerulonephritis Mesangial nephritis Chronic pyelonephritis Chronic glomerulonephritis Chronic glomerulonephritis Chronic glomerulonephritis Postactnic nephropathy Chronic glomerulonephritis
48 48 46 26 63 78 62 60 52 57 68 59 42 20 72 36 33 49 82 33 52 75
Tac, AZA, Steroids Tac, MMF, Steroids Tac, MMF, Steroids Tac, MMF, Steroids Tac, MMF, Steroids CyA, MMF, Steroids Tac, MMF, Steroids CyA, MMF, Steroids Tac, MMF, Steroids Tac, MMF, Steroids CyA, MMF, Steroids Tac, MMF, Steroids Tac, MMF, Steroids Sir, MMF, Steroids CyA, MMF, Steroids Sir, MMF, Steroids Sir, MMF, Steroids Sir, MMF, Steroids Sir, Tac, Steroids Sir, MMF, Steroids CyA, MMF, Steroids Tac, MMF, Steroids
16 53 16 53, 61, 16, 31 53, 16 16 52 16 56 16, 26 16, 26, 66 16 53 16 33 ND 33 ND ND 43, 61, 70 ND 16
Negative Negative Fungal infection Bacterial infection Fungal infection Negative Negative Negative Fungal infection Bacterial infection Bacterial infection Fungal infection Negative Negative Bacterial infection Bacterial infection Bacterial infection Bacterial infection Bacterial infection Negative Bacterial infection Bacterial infection
Abbreviations: AZA, azathioprine; CyA, cyclosporine A; MMF, mycophenolate mophetil; ND, not determined; Sir, sirolimus; Tac, tacrolimus.
HUMAN PAPILLOMA VIRUS AND CERVICAL CANCER patients underwent Pap and HPV testing while awaiting transplantation, with negative findings. Six months after transplantation, all patients underwent a pelvic examination and HPV testing performed using cervicovaginal brushing. The cellular material was pelleted using centrifugation, and total genomic DNA was extracted using a commercially available kit (DNA Assay Blood and Tissue Kit; Qiagen Gmb, Wilden, Germany). The HPV DNA detection was performed using a commercial nested PCR kit (AlphaStrip II HPV; Alphagenics Diaco Biotechnologies S.r.L., Trieste, Italy). Each amplification also included HPV-16 DNA positive and negative controls. Positive samples were detected using 2% agarose gel electrophoresis (Fig 1). Reverse dot blot analysis was performed for genotyping; each positive sample utilized the same kit used for nested PCR. All patients with positive HPV DNA test results underwent a Pap test and cytologic examination. In our protocol, colposcopy was performed in all HPV-positive patients with cytologic anomalies at Pap testing, with eventual cervical biopsy and endocervical curettage. Patients with negative HPV DNA test results were followed up yearly, and HPV-positive patients with no cytologic anomalies were followed up every 6 months with a HPV DNA test and a Pap test. All patients with negative Papanicolaou and HPV DNA test results before transplantation had well-functioning grafts at examination.
RESULTS
Twenty-two patients (62.8%) were positive for HPV DNA (Table 1). Their median age was 47 years, with a median time receiving dialysis of 50 months. Thirteen of 22 HPV DNA–positive recipients (59%) exhibited a high-risk HPV
1193
genotype; however, no HPV-18 infection was detected, which confirms the low prevalence of this genotype in Italy. The Pap test revealed no cytologic anomalies; 4 patients had a fungal infection, and 10 patients had a bacterial infection. DISCUSSION
The chronic use of maintenance immunosuppressive agents to prevent allograft rejection increases the long-term risk of malignancy in renal transplant recipients. An increased incidence of cancer of the cervix and the body of the uterus has been reported in young patients with functioning grafts,11 whereas other reports have demonstrated a lower incidence of CIN in older kidney transplant recipients.4 The association of HPV infection with anogenital carcinogenesis has led to extensive analysis of this pathogen; however, the incidence of HPV infection in renal transplant recipients is not well known. Morrison et al4 reported a low incidence (5%) of HPV infection in a cohort of 21 renal transplant recipients, with no patients having CIN. In contrast, others have reported a greater incidence of HPV infection.5,6,10 These differences may be due to the quality of the analyzed specimens (biopsy tissue vs brushings). Although posttransplantation malignancies are believed to be a late complication of immunosuppressive agents, a recent report demonstrated a higher incidence of cervical carcinoma within 2 years after transplantation.12 Screening methods have been extensively applied in kidney transplant
Fig 1. Agarose gel electrophoresis of nested polymerase chain reaction amplification products. Lanes 1, 9, and 17, 50 base pair (bp) ladder; lanes 2 through 6, clinical sample amplifications; lanes 10 through 14, samples (nested); lanes 7 and 15, positive controls; lanes 8 and 16, negative controls.
1194
recipients because anogenital malignant neoplasms may be easily screened before and after grafting. We prospectively analyzed for at least 6 months 35 female recipients with a functioning graft to evaluate the incidence of HPV infection and cytologic anomalies in the early posttransplantation follow-up. Our analysis demonstrated a high incidence of HPV infection in this population (62.8%), particularly including high-risk HPV genotypes. However, there were no cytologic anomalies at Pap testing, probably as a consequence of the short follow-up. Our clinical observations demonstrated that HPV infection may develop early during follow-up, even in patients with no cytologic anomalies at Pap testing. While most HPV infections in immunocompetent patients resolve within 5 to 7 years,7 there are currently no data about the rate of resolution or time to progression in renal transplant recipients. Early screening seems mandatory in these patients. An HPV screening test together with a Pap test should be the first step, reserving colposcopy for patients with positive Pap test results. The HPV test may be considered an early screening test by selecting a group of patients who may benefit from more intensive follow-up. In patients with an HPV infection, 6-month follow-up with an HPV test and a Pap test is recommended, whereas HPV-negative patients should be followed up annually. In conclusion, these preliminary data demonstrate a high incidence of HPV infection in renal transplant recipients even in the absence of cytologic anomalies at Pap testing. Most of our recipients exhibited a high-risk HPV genotype, which suggests possibly higher aggressiveness of these infections in immunosuppressed patients. The HPV test is useful to monitor patients at higher risk of anogenital malignancies by enabling identification of the cytologic anomalies at an earlier stage. This ongoing study will be useful to investigate the rate of progression of HPV infec-
VEROUX, CORONA, SCALIA ET AL
tion and the clinical patterns of HPV-positive cytologic anomalies in renal transplant recipients. REFERENCES 1. Penn I: Cancer is a complication of severe immunosuppression. Surg Gynecol Obstet 162:603, 1986 2. Blohme I, Brynger H: Malignant disease in renal transplant patients. Transplantation 39:23, 1985 3. Veroux M, Puliatti C, Fiamingo P, et al: Early de novo malignancies after kidney transplantation. Transplant Proc 36:718, 2004 4. Morrison EAB, Dole P, Sun XW, et al: Low prevalence of human papillomavirus infection of the cervix in renal transplant patients. Nephrol Dial Transplant 11:1603, 1996 5. Brown MR, Noffsinger A, First MR, et al: HPV subtype analysis in lower genital tract neoplasms of female renal transplant recipients. Gynecol Oncol 79:220, 2000 6. Paternoster DM, Cester M, Resente C, et al: Human papilloma virus infection and cervical intraepithelial neoplasia in transplanted patients. Transplant Proc 40:1877, 2008 7. Schiffman M, Castle PE, Jeronimo J, et al: Human papillomavirus and cervical cancer. Lancet 370:890, 2007 8. Ghazizadeh S, Lessan-Pezeshki M, Einollahi B, et al: Uterine cervical intraepithelial neoplasia in renal transplantation. Transplant Proc 33:2817, 2001 9. Alloub MI, Barr BB, Mclaren KM, et al: Human papillomavirus infection and cervical intraepithelial neoplasia in women with renal allografts. Br Med J 298:153, 1989 10. Fairley CK, Chen S, Tabrizi SN, et al: Prevalence of HPV DNA in cervical specimens in women with renal transplants: a comparison with dialysis-dependent patients and patients with renal impairment. Nephrol Dial Transplant 9:416, 1994 11. Brunner FP, Landais P, Selwood NH; European Dialysis and Transplantation Association–European Renal Association: Malignancies after renal transplantation the EDTA-ERA registry experience. Nephrol Dial Transplant 10(suppl 1):74, 1995 12. Kim MS, Chang HK, Ju MK, et al: Chronologically different incidences of post-transplant malignancy in renal transplant recipients: 25 years’ experience in Korean single center. Abstract 1125, American Transplant Congress. Am J Transplant 8(suppl 2):478, 2008
Surveillance of Human Papilloma Virus Infection and Cervical Cancer in Kidney Transplant Recipients: Preliminary Data M. Veroux, D. Corona, G. Scalia, V. Garozzo, M. Gagliano, G. Giuffrida, C.M. Costanzo, A. Giaquinta, I. Palermo, D. Zappalà, T. Tallarita, D. Zerbo, R. Russo, A. Cappellani, C. Franchina, V. Scriffignano, and P. Veroux ABSTRACT Introduction. Development of cancer after transplantation has rapidly became one of the leading causes of death in kidney transplant recipients with functioning grafts. Anogenital malignant neoplasms may occur with a 14-fold increased incidence, and human papilloma virus (HPV) infection has been recently identified as the leading cause of cervical carcinoma. We report the preliminary findings of a prospective study that evaluated the incidence of HPV infection and cervical carcinoma in a population of kidney transplant recipients. Patients and Methods. The study included 35 female recipients of a deceased donor kidney with at least 6 months of follow-up. All patients underwent a cervicovaginal brushing, an HPV DNA test, and a Papanicolaou test. Results. Twenty-two patients (62.8%) were positive for HPV DNA. Thirteen of 22 HPV DNA–positive recipients (59%) demonstrated a high-risk HPV genotype. No cytologic anomalies were detected in Papanicolaou smears. Conclusions. These preliminary data demonstrated a high incidence of HPV infection in renal transplant recipients. Most of our recipients exhibited a high-risk HPV genotype, which suggests higher aggressiveness of such infection in immunosuppressed patients. The HPV test is useful to monitor patients at higher risk of anogenital malignant neoplasms by identifying the cytologic anomalies at an earlier stage. This ongoing study will investigate the rate of progression of HPV infection and the clinical patterns of HPV-positive cytologic anomalies in renal transplant recipients.
From Department of Surgical Sciences (M.V., M.G., G.G., A.G., T.T., D.Z., A.C., P.V.), Transplantation and Advanced Technologies, Vascular Surgery and Organ Transplant Units, and Department of Microbiological Sciences and Gynaecological Sciences (D.C., G.S., C.M.C., I.P., D.Z., R.R., C.F., V.S.), Virology Unit, University Hospital of Catania; and Department of
Microbiological Sciences and Gynaecological Sciences (V.G.), Gynaecology Unit, Vittorio Emanuele Hospital, Catania, Italy. Address reprint requests to Massimiliano Veroux, MD, PhD, Department of Surgical Sciences, Transplantation and Advanced Technologies, Organ Transplant Unit, University Hospital, Via S. Sofia 86, 95123 Catania, Italy. E-mail: [email protected]
© 2009 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
0041-1345/09/$–see front matter doi:10.1016/j.transproceed.2009.03.015
Transplantation Proceedings, 41, 1191–1194 (2009)
1191
1192
VEROUX, CORONA, SCALIA ET AL
IDNEY TRANSPLANTATION is the best replacement therapy in patients with end-stage renal disease (ESRD). However, long-term results have not improved in the last decade, probably as a consequence of the adverse effects of immunosuppressive drugs. Immunosuppressive medications are a leading cause of graft loss in the long term. They substantially predispose to infections and posttransplantation de novo neoplasms. Most malignant neoplasms are lymphoma and skin cancers1–3; however, many authors have also noted a high rate of anogenital tract neoplasms in renal allograft recipients.4 – 8 Penn1 identified a 14-fold increased incidence of intraepithelial carcinoma of the cervix in renal transplant recipients compared with age-matched control subjects, with an overall incidence of 11% in all women with posttransplantation malignant neoplasms. Initially it was theorized that immunosuppressive agents were the cause of carcinogenesis; however, because of their ability to induce alterations in DNA, human papilloma virus (HPV) infection was recently identified as the leading cause of cervical neoplasia. The immunosuppressed state induced to prevent graft rejection may predispose to development of HPV infection with potential to progress to cancer.4 – 8 The wider use of the polymerase chain reaction (PCR), usually followed by reverse dot blot analysis, has enabled precise identification of HPV and identification of genotypes with high vs medium to low oncogenic risk.5,7 In the first period of the viral infection, the Papanicolaou (Pap) test and colposcopy may show normal epithelium or mild atypia. Most HPV infections resolve within 2 years; however, the 10% that persist for more than 2 years are highly linked to
K
precancer. If HPV infection persists, it may evolve to cervical intraepithelial neoplasia (CIN) and finally to cancer in 5 to 7 years in immunocompetent female patients.7 While high-risk HPV genotypes are more likely to progress to cervical neoplasia, it is not known why some infections progress to cancer. The screening for cervical cancer is based on early identification of precancerous lesions. The Pap test is the first-level examination. In cases of positive Pap test results, the second-level examination is colposcopy associated with molecular biological testing. If there is suspicion of HPV infection, target biopsy of the evident lesion is performed.6,7 The incidence of HPV infections in renal transplant recipients is 17% to 45%, with a low rate of cytologic alteration found at Pap testing.4 – 6,9,10 Little is known about the rate of progression to cervical cancer and the time to progression in renal transplant recipients, probably because of the retrospective nature of most clinical reports, which do not investigate the progression of HPV infection in transplant recipients. The objective of this retrospective study was to investigate the early incidence of HPV infection and cytologic anomalies using the Pap test in a population of kidney transplant recipients.
MATERIALS AND METHODS This study included 35 women with ESRD who received a deceased donor kidney transplant in a 2-year period and had at least 6 months of follow-up posttransplantation. Data on personal history, original disease, immunosuppressive drugs, and duration of dialysis were collected from each patient (Table 1). Every 6 months, all
Table 1. Clinical Characteristics of HPV-Positive Renal Transplant Recipients Patient
Age, y
Time Receiving Dialysis, mo
Primary Disease
Donor Age, y
Immunosuppressive Therapy
HPV Subtype
Papanicolaou Test Result
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22
31 43 56 64 51 51 30 49 51 40 58 63 45 35 45 44 36 29 46 41 30 28
24 36 42 212 65 64 18 12 100 50 17 131 126 6 15 17 52 38 50 70 30 50
Chronic pyelonephritis Chronic glomerulonephritis Chronic glomerulonephritis Chronic glomerulonephritis Polycystic kidney Chronic glomerulonephritis Chronic glomerulonephritis Membranous glomerulonephritis Chronic glomerulonephritis Chronic glomerulonephritis Polycystic kidney Polycystic kidney Chronic glomerulonephritis Diabetic nephropathy Chronic glomerulonephritis Mesangial nephritis Chronic pyelonephritis Chronic glomerulonephritis Chronic glomerulonephritis Chronic glomerulonephritis Postactnic nephropathy Chronic glomerulonephritis
48 48 46 26 63 78 62 60 52 57 68 59 42 20 72 36 33 49 82 33 52 75
Tac, AZA, Steroids Tac, MMF, Steroids Tac, MMF, Steroids Tac, MMF, Steroids Tac, MMF, Steroids CyA, MMF, Steroids Tac, MMF, Steroids CyA, MMF, Steroids Tac, MMF, Steroids Tac, MMF, Steroids CyA, MMF, Steroids Tac, MMF, Steroids Tac, MMF, Steroids Sir, MMF, Steroids CyA, MMF, Steroids Sir, MMF, Steroids Sir, MMF, Steroids Sir, MMF, Steroids Sir, Tac, Steroids Sir, MMF, Steroids CyA, MMF, Steroids Tac, MMF, Steroids
16 53 16 53, 61, 16, 31 53, 16 16 52 16 56 16, 26 16, 26, 66 16 53 16 33 ND 33 ND ND 43, 61, 70 ND 16
Negative Negative Fungal infection Bacterial infection Fungal infection Negative Negative Negative Fungal infection Bacterial infection Bacterial infection Fungal infection Negative Negative Bacterial infection Bacterial infection Bacterial infection Bacterial infection Bacterial infection Negative Bacterial infection Bacterial infection
Abbreviations: AZA, azathioprine; CyA, cyclosporine A; MMF, mycophenolate mophetil; ND, not determined; Sir, sirolimus; Tac, tacrolimus.
HUMAN PAPILLOMA VIRUS AND CERVICAL CANCER patients underwent Pap and HPV testing while awaiting transplantation, with negative findings. Six months after transplantation, all patients underwent a pelvic examination and HPV testing performed using cervicovaginal brushing. The cellular material was pelleted using centrifugation, and total genomic DNA was extracted using a commercially available kit (DNA Assay Blood and Tissue Kit; Qiagen Gmb, Wilden, Germany). The HPV DNA detection was performed using a commercial nested PCR kit (AlphaStrip II HPV; Alphagenics Diaco Biotechnologies S.r.L., Trieste, Italy). Each amplification also included HPV-16 DNA positive and negative controls. Positive samples were detected using 2% agarose gel electrophoresis (Fig 1). Reverse dot blot analysis was performed for genotyping; each positive sample utilized the same kit used for nested PCR. All patients with positive HPV DNA test results underwent a Pap test and cytologic examination. In our protocol, colposcopy was performed in all HPV-positive patients with cytologic anomalies at Pap testing, with eventual cervical biopsy and endocervical curettage. Patients with negative HPV DNA test results were followed up yearly, and HPV-positive patients with no cytologic anomalies were followed up every 6 months with a HPV DNA test and a Pap test. All patients with negative Papanicolaou and HPV DNA test results before transplantation had well-functioning grafts at examination.
RESULTS
Twenty-two patients (62.8%) were positive for HPV DNA (Table 1). Their median age was 47 years, with a median time receiving dialysis of 50 months. Thirteen of 22 HPV DNA–positive recipients (59%) exhibited a high-risk HPV
1193
genotype; however, no HPV-18 infection was detected, which confirms the low prevalence of this genotype in Italy. The Pap test revealed no cytologic anomalies; 4 patients had a fungal infection, and 10 patients had a bacterial infection. DISCUSSION
The chronic use of maintenance immunosuppressive agents to prevent allograft rejection increases the long-term risk of malignancy in renal transplant recipients. An increased incidence of cancer of the cervix and the body of the uterus has been reported in young patients with functioning grafts,11 whereas other reports have demonstrated a lower incidence of CIN in older kidney transplant recipients.4 The association of HPV infection with anogenital carcinogenesis has led to extensive analysis of this pathogen; however, the incidence of HPV infection in renal transplant recipients is not well known. Morrison et al4 reported a low incidence (5%) of HPV infection in a cohort of 21 renal transplant recipients, with no patients having CIN. In contrast, others have reported a greater incidence of HPV infection.5,6,10 These differences may be due to the quality of the analyzed specimens (biopsy tissue vs brushings). Although posttransplantation malignancies are believed to be a late complication of immunosuppressive agents, a recent report demonstrated a higher incidence of cervical carcinoma within 2 years after transplantation.12 Screening methods have been extensively applied in kidney transplant
Fig 1. Agarose gel electrophoresis of nested polymerase chain reaction amplification products. Lanes 1, 9, and 17, 50 base pair (bp) ladder; lanes 2 through 6, clinical sample amplifications; lanes 10 through 14, samples (nested); lanes 7 and 15, positive controls; lanes 8 and 16, negative controls.
1194
recipients because anogenital malignant neoplasms may be easily screened before and after grafting. We prospectively analyzed for at least 6 months 35 female recipients with a functioning graft to evaluate the incidence of HPV infection and cytologic anomalies in the early posttransplantation follow-up. Our analysis demonstrated a high incidence of HPV infection in this population (62.8%), particularly including high-risk HPV genotypes. However, there were no cytologic anomalies at Pap testing, probably as a consequence of the short follow-up. Our clinical observations demonstrated that HPV infection may develop early during follow-up, even in patients with no cytologic anomalies at Pap testing. While most HPV infections in immunocompetent patients resolve within 5 to 7 years,7 there are currently no data about the rate of resolution or time to progression in renal transplant recipients. Early screening seems mandatory in these patients. An HPV screening test together with a Pap test should be the first step, reserving colposcopy for patients with positive Pap test results. The HPV test may be considered an early screening test by selecting a group of patients who may benefit from more intensive follow-up. In patients with an HPV infection, 6-month follow-up with an HPV test and a Pap test is recommended, whereas HPV-negative patients should be followed up annually. In conclusion, these preliminary data demonstrate a high incidence of HPV infection in renal transplant recipients even in the absence of cytologic anomalies at Pap testing. Most of our recipients exhibited a high-risk HPV genotype, which suggests possibly higher aggressiveness of these infections in immunosuppressed patients. The HPV test is useful to monitor patients at higher risk of anogenital malignancies by enabling identification of the cytologic anomalies at an earlier stage. This ongoing study will be useful to investigate the rate of progression of HPV infec-
VEROUX, CORONA, SCALIA ET AL
tion and the clinical patterns of HPV-positive cytologic anomalies in renal transplant recipients. REFERENCES 1. Penn I: Cancer is a complication of severe immunosuppression. Surg Gynecol Obstet 162:603, 1986 2. Blohme I, Brynger H: Malignant disease in renal transplant patients. Transplantation 39:23, 1985 3. Veroux M, Puliatti C, Fiamingo P, et al: Early de novo malignancies after kidney transplantation. Transplant Proc 36:718, 2004 4. Morrison EAB, Dole P, Sun XW, et al: Low prevalence of human papillomavirus infection of the cervix in renal transplant patients. Nephrol Dial Transplant 11:1603, 1996 5. Brown MR, Noffsinger A, First MR, et al: HPV subtype analysis in lower genital tract neoplasms of female renal transplant recipients. Gynecol Oncol 79:220, 2000 6. Paternoster DM, Cester M, Resente C, et al: Human papilloma virus infection and cervical intraepithelial neoplasia in transplanted patients. Transplant Proc 40:1877, 2008 7. Schiffman M, Castle PE, Jeronimo J, et al: Human papillomavirus and cervical cancer. Lancet 370:890, 2007 8. Ghazizadeh S, Lessan-Pezeshki M, Einollahi B, et al: Uterine cervical intraepithelial neoplasia in renal transplantation. Transplant Proc 33:2817, 2001 9. Alloub MI, Barr BB, Mclaren KM, et al: Human papillomavirus infection and cervical intraepithelial neoplasia in women with renal allografts. Br Med J 298:153, 1989 10. Fairley CK, Chen S, Tabrizi SN, et al: Prevalence of HPV DNA in cervical specimens in women with renal transplants: a comparison with dialysis-dependent patients and patients with renal impairment. Nephrol Dial Transplant 9:416, 1994 11. Brunner FP, Landais P, Selwood NH; European Dialysis and Transplantation Association–European Renal Association: Malignancies after renal transplantation the EDTA-ERA registry experience. Nephrol Dial Transplant 10(suppl 1):74, 1995 12. Kim MS, Chang HK, Ju MK, et al: Chronologically different incidences of post-transplant malignancy in renal transplant recipients: 25 years’ experience in Korean single center. Abstract 1125, American Transplant Congress. Am J Transplant 8(suppl 2):478, 2008