Abstract
Female recipients of hematopoietic cell transplant (HCT) may develop lower genital tract (LGT) dysplasia or new malignancies. A comprehensive systematic review to delineate the occurrence and risk factors for post-HCT LGT precancer and cancer in women was conducted via electronic search of the Cochrane Library,PubMed, Embase,Wiley Online Library, from 1990 to 2018. All studies on the risk, presentation, or incidence of LGT (cervix, vulva, vagina) precancer or cancer post-HCT were included. Reviews, case reports, meta-analysis, book chapters, and studies without the relevant clinical outcomes were excluded. Post-HCT incidence and risk factors for developing LGT precancer or cancer were assessed and determined. Twenty-two out of the original 344 studies met the selection criteria. The risk of LGT cancers in allo-HCT recipients was found to be significantly higher than in the general population, with the standardized incidence ratios of 1.5–48 for cervical cancer and from 19 to 287 for dysplasia. Our review portrays an increased risk of premalignant and malignant neoplasms of female LGT, which have an incompletely described epidemiology and outcomes. Similar to other immunocompromised states, HCT recipients require specific cervical screening guidelines and can greatly benefit from HPV vaccinations. However, there is a lack of prospective data regarding optimum cervical screening in HCT recipients and limited programs offer HPV vaccinations worldwide.
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Wingard, JR, Majhail, NS, Brazauskas, R, Wang, Z, Sobocinski, KA, Jacobsohn, D, et al. Long-term survival and late deaths after allogeneic hematopoietic cell transplantation. J Clin Oncol 2011;29;2230–9.
Witherspoon, RP, Fisher, LD, Schoch, G, Martin, P, Sullivan, KM, Sanders, J, et al. Secondary cancers after bone marrow transplantation for leukemia or aplastic anemia. N Engl J Med 1989;321;784–9.
Schiffman, M, Castle, PE, Jeronimo, J, Rodriguez, AC, Wacholder, S. Human papillomavirus and cervical cancer. Lancet 2007;370;890–907.
Schiffman, M, Wentzensen, N. From human papillomavirus to cervical cancer. Obstet Gynecol 2010;116;177–85.
Ho, GYF, Bierman, R, Beardsley, L, Chang, CJ, Burk, RD. Natural history of cervicovaginal papillomavirus infection in young women. N Engl J Med 1998;338;423–8.
Winer, RL, Feng, Q, Hughes, JP, O’Reilly, S, Kiviat, NB, Koutsky, LA. Risk of female human papillomavirus acquisition associated with first male sex partner. J Infect Dis 2008;197; 279–82.
Bauer, HM, Hildesheim, A, Schiffman, MH, Glass, AG, Rush, BB, Scott, DR, et al. Determinants of genital human papillomavirus infection in low-risk women in Portland, Oregon. Sex Transm Dis 1993;20;274–8.
Doorbar, J. Latent papillomavirus infections and their regulation. Curr Opin Virol 2013;3;416–21.
Schlecht, NF, Platt, RW, Duarte-Franco, E, Costa, MC, Sobrinho, JP, Prado, JCM, et al. Human papillomavirus infection and time to progression and regression of cervical intraepithelial neoplasia. J Natl Cancer Inst 2003;95;1336–43.
Klosky, JL, Gamble, HL, Spunt, SL, Randolph, ME, Green, DM, Hudson, MM. Human papillomavirus vaccination in survivors of childhood cancer. Cancer 2009;115;5627–36.
Sheil, AG, Disney, AP, Mathew, TH, Amiss, N. De novo malignancy emerges as a major cause of morbidity and late failure in renal transplantation. Transplant Proc 1993;25;1383–4.
Bosch, FX, Manos, MM, Muñoz, N, Sherman, M, Jansen, AM, Peto, J, et al. Prevalence of human papillomavirus in cervical cancer: a worldwide perspective. International Biological Study on Cervical Cancer (IBSCC) Study Group. J Natl Cancer Inst 1995;87;796–802.
Wheeler, CM, Hunt, WC, Joste, NE, Key, CR, Quint, WGV, Castle, PE. Human papillomavirus genotype distributions: implications for vaccination and cancer screening in the United States. J Natl Cancer Inst 2009;101;475–87.
Muñoz, N, Bosch, FX, de Sanjosé, S, Herrero, R, Castellsagué, X, Shah, KV, et al. Epidemiologic classification of human papillomavirus types associated with cervical cancer. N Engl J Med 2003;348;518–27.
De Vuyst, H, Gichangi, P, Estambale, B, Njuguna, E, Franceschi, S, Temmerman, M. Human papillomavirus types in women with invasive cervical carcinoma by HIV status in Kenya. Int J Cancer 2008;122;244–6.
World Health Organization International Agency for Research on Cancer. IARC. n.d.;90 https://monographs.iarc.fr/iarcmonographs-on-the-evaluation-of-carcinogenic-risks-tohumans-31/
Rodriguez, AC, Schiffman, M, Herrero, R, Hildesheim, A, Bratti, C, Sherman, ME, et al. Longitudinal study of human papillomavirus persistence and cervical intraepithelial neoplasia grade 2/3: critical role of duration of infection. JNCI J Natl Cancer Inst 2010;102;315–24.
Schiffman, M, Clifford, G, Buonaguro, FM. Classification of weakly carcinogenic human papillomavirus types: addressing the limits of epidemiology at the borderline. Infect Agent Cancer 2009;4;8.
Holcomb, K, Maiman, M, Dimaio, T, Gates, J. Rapid progression to invasive cervix cancer in a woman infected with the human immunodeficiency virus. Obstet Gynecol 1998;91;848–50.
Sri, T, Merideth, MA, Pulanic, TK, Childs, R, Stratton, P. Human papillomavirus reactivation following treatment of genital graftversus- host disease. Transpl Infect Dis 2013;15;E148–51.
Sasadeusz, J, Kelly, H, Szer, J, Schwarer, A, Mitchell, H, Grigg, A. Abnormal cervical cytology in bone marrow transplant recipients. Bone Marrow Transplant 2001;28;393–7.
Savani, BN, Stratton, P, Shenoy, A, Kozanas, E, Goodman, S, Barrett, AJ. Increased risk of cervical dysplasia in long-term survivors of allogeneic stem cell transplantation—implications for screening and HPV vaccination. Biol Blood Marrow Transplant 2008;14;1072–5.
Wang, Y, Brinch, L, Jebsen, P, Tanbo, T, Kirschner, R. A clinical study of cervical dysplasia in long-term survivors of allogeneic stem cell transplantation. Biol Blood Marrow Transplant 2012;18;747–53.
Shanis, DL, Pophali, P, Koklanaris, E, Savani, BN, Battiwalla, M, Barrett, J, et al. High rates of genital tract dysplasia in long-term survivors of allogeneic stem cell transplantation and associated risk factors. Biol Blood Marrow Transplant 2012;18;S282.
Yu, S-C, Huang, H-H, Li, C-C, Tang, J-L, Lee, Y-H, Mao, T-L, et al. Cervical papanicolaou smears in hematopoietic stem cell transplant recipients: high prevalence of therapy-related atypia during the acute phase. Biol Blood Marrow Transplant 2017;23; 1367–73.
Negri, G, Herz, M, Deola, S, Piccin, A, Casini, M, Babich, B, et al. Abnormal cervical cytology after allogeneic bone marrow transplantation. Am J Clin Pathol 2014;142;222–6.
Curtis, RE, Rowlings, PA, Deeg, HJ, Shriner, DA, Socíe, G, Travis, LB, et al. Solid cancers after bone marrow transplantation. N Engl J Med 1997;336;897–904.
Lowsky, R, Lipton, J, Fyles, G, Minden, M, Meharchand, J, Tejpar, I, et al. Secondary malignancies after bone marrow transplantation in adults. J Clin Oncol 1994;12;2187–92.
Danner-Koptik, KE, Majhail, NS, Brazauskas, R, Wang, Z, Buchbinder, D, Cahn, J-Y, et al. Second malignancies after autologous hematopoietic cell transplantation in children. Bone Marrow Transplant 2013;48;363–8.
Ringdén, O, Brazauskas, R, Wang, Z, Ahmed, I, Atsuta, Y, Buchbinder, D, et al. Second solid cancers after allogeneic hematopoietic cell transplantation using reduced-intensity conditioning. Biol Blood Marrow Transplant 2014;20;1777–84.
Atsuta, Y, Suzuki, R, Yamashita, T, Fukuda, T, Miyamura, K, Taniguchi, S, et al. Continuing increased risk of oral/esophageal cancer after allogeneic hematopoietic stem cell transplantation in adults in association with chronic graft-versus-host disease. Ann Oncol 2014;25;435–41.
Kolb, HJ, Socié, G, Duell, T, Van Lint, MT, Tichelli A, Apperley JF, et al. Malignant neoplasms in long-term survivors of bone marrow transplantation. Late effects working party of the European Cooperative Group for Blood and Marrow Transplantation and the European Late Effect Project Group. Ann Intern Med 1999;131;738–44.
Bhatia, S, Louie, AD, Bhatia, R, O’Donnell, MR, Fung, H, Kashyap, A, et al. Solid cancers after bone marrow transplantation. J Clin Oncol 2001;19;464–71.
Brown, JR, Yeckes, H, Friedberg, JW, Neuberg, D, Kim, H, Nadler, LM, et al. Increasing incidence of late second malignancies after conditioning with cyclophosphamide and total-body irradiation and autologous bone marrow transplantation for non-Hodgkin’s lymphoma. J Clin Oncol 2005;23; 2208–14.
Shimada, K, Yokozawa, T, Atsuta, Y, Kohno, A, Maruyama, F, Yano, K, et al. Solid tumors after hematopoietic stem cell transplantation in Japan: incidence, risk factors and prognosis. Blood Marrow Transplant 2005;36;115–21.
Ruiz-Soto, R, Sergent, G, Gisselbrecht, C, Larghero, J, Ertault, M, Hennequin, C, et al. Estimating late adverse events using competing risks after autologous stem-cell transplantation in aggressive non-Hodgkin lymphoma patients. Cancer 2005;104; 2735–42.
Rizzo, JD, Curtis, RE, Socie, G, Sobocinski, KA, Gilbert, E, Landgren, O, et al. Solid cancers after allogeneic hematopoietic cell transplantation. Blood 2008;113;1175–83.
Seshadri, T, Pintilie, M, Kuruvilla, J, Keating, A, Tsang, R, Zadeh, S, et al. Incidence and risk factors for second cancers after autologous hematopoietic cell transplantation for aggressive non- Hodgkin lymphoma. Leuk Lymphoma 2009;50;380–6.
Majhail, NS, Brazauskas, R, Rizzo, JD, Sobecks, RM, Wang, Z, Horowitz, MM, et al. Secondary solid cancers after allogeneic hematopoietic cell transplantation using busulfancyclophosphamide conditioning. Blood 2011;117;316–22.
Holowaty, P, Miller, AB, Rohan, T, To, T. Natural history of dysplasia of the uterine cervix. J Natl Cancer Inst 1999;91;252–8.
Halpert, R, Fruchter, RG, Sedlis, A, Butt, K, Boyce, JG, Sillman, FH. Human papillomavirus and lower genital neoplasia in renal transplant patients. Obstet Gynecol 1986;68;251–8.
Han, CS, Miller, W, Haake, R, Weisdorf, D. Varicella zoster infection after bone marrow transplantation: incidence, risk factors and complications. Bone Marrow Transplant 1994;13;277–83.
Stockfleth, E, Nindl, I, Sterry, W, Ulrich, C, Schmook, T, Meyer, T. Human papillomaviruses in transplant-associated skin cancers. Dermatologic Surg 2004;30;604–9.
Berkhout, RJ, Bouwes Bavinck, JN, ter Schegget, J. Persistence of human papillomavirus DNA in benign and (pre)malignant skin lesions from renal transplant recipients. J Clin Microbiol 2000;38;2087–96.
Deeg, H, Socie, G, Schoch, G, Henry-Amar, M, Witherspoon, R, Devergie, A, et al. Malignancies after marrow transplantation for aplastic anemia and fanconi anemia: a joint Seattle and Paris analysis of results in 700 patients. Blood 1996;87;386–92.
Oddou, S, Vey, N, Viens, P, Bardou, VJ, Faucher, C, Stoppa, AM, et al. Second neoplasms following high-dose chemotherapy and autologous stem cell transplantation for malignant lymphomas: a report of six cases in a cohort of 171 patients from a single institution. Leuk Lymphoma 1998;31;187–94.
Gallagher, G, Forrest, DL. Second solid cancers after allogeneic hematopoietic stem cell transplantation. Cancer 2006;109;84–92.
Shimoni, A, Shem-Tov, N, Chetrit, A, Volchek, Y, Tallis, E, Avigdor, A, et al. Secondary malignancies after allogeneic stem-cell transplantation in the era of reduced-intensity conditioning; the incidence is not reduced. Leukemia 2013;27; 829–35.
Kurinczuk, JJ, Burton, P. Cervical intraepithelial neoplasia in women with renal allografts. BMJ 1989;298;598–9.
Jagasia, MH, Greinix, HT, Arora, M, Williams, KM, Wolff, D, Cowen, EW, et al. National Institutes Of Health Consensus Development Project on criteria for clinical trials in chronic graft-versus-host disease: I. The 2014 Diagnosis and Staging Working Group report. Biol Blood Marrow Transplant 2015;21; 389–401.e1.
Hamilton, BK, Goje, O, Savani, BN, Majhail, NS, Stratton, P. Clinical management of genital chronic GvHD. Bone Marrow Transplant 2017;52;803–10.
Aldabagh, B, Angeles, JGC, Cardones, AR, Arron, ST. Cutaneous squamous cell carcinoma and human papillomavirus: is there an association? Dermatologic Surg 2013;39;1–23.
Inamoto, Y, Shah, NN, Savani, BN, Shaw, BE, Abraham, AA, Ahmed, IA, et al. Secondary solid cancer screening following hematopoietic cell transplantation. Bone Marrow Transplant 2015;50;1013–23.
Morton, LM, Saber, W, Baker, KS, Barrett, AJ, Bhatia, S, Engels, EA, et al. National Institutes of Health Hematopoietic Cell Transplantation Late Effects Initiative: The Subsequent Neoplasms Working Group report. Biol Blood Marrow Transplant 2017;23;367–78.
Matzinger, P. The Danger model: a renewed sense of self. Science 2002;296;301–5.
Buchan, A, Merideth, MA, Childs, RW, Stratton, P. Novel management of vaginal chronic graft-versus-host disease causing haematometra and haematocolpos. BMJ Case Rep 2018;2018;bcr- 2017-222720.
Forman, D, de Martel, C, Lacey, CJ, Soerjomataram, I, Lortet- Tieulent, J, Bruni, L, et al. Global burden of human papillomavirus and related diseases. Vaccine 2012;30;F12–F23.
World Health Organization.WHO meeting of the Strategic Advisory Group of Experts on immunization, April 2014 – conclusions and recommendations.WHO 2014;89;221–36.
Kumar, D, Unger, ER, Panicker, G, Medvedev, P, Wilson, L, Humar, A. Immunogenicity of quadrivalent human papillomavirus vaccine in organ transplant recipients. Am J Transplant 2013; 13;2411–17.
Esposito, S, Corona, F, Barzon, L, Cuoco, F, Squarzon, L, Marcati, G, et al. Immunogenicity, safety and tolerability of a bivalent human papillomavirus vaccine in adolescents with juvenile idiopathic arthritis. Expert Rev Vaccines 2014;13;1387–93.
Heijstek, MW, Scherpenisse, M, Groot, N, Tacke, C, Schepp, RM, Buisman, A-M, et al. Immunogenicity and safety of the bivalent HPV vaccine in female patients with juvenile idiopathic arthritis: a prospective controlled observational cohort study. Ann Rheum Dis 2014;73;1500–7.
Mok, CC, Ho, LY, Fong, LS, To, CH. Immunogenicity and safety of a quadrivalent human papillomavirus vaccine in patients with systemic lupus erythematosus: a case-control study. Ann Rheum Dis 2013;72;659–64.
Grönlund, O, Herweijer, E, Sundström, K, Arnheim-Dahlström, L. Incidence of new-onset autoimmune disease in girls and women with pre-existing autoimmune disease after quadrivalent human papillomavirus vaccination: a cohort study. J Intern Med 2016;280;618–26.
Grimaldi-Bensouda, L, Rossignol, M, Koné-Paut, I, Krivitzky, A, Lebrun-Frenay, C, Clet, J, et al. Risk of autoimmune diseases and human papilloma virus (HPV) vaccines: six years of case-referent surveillance. J Autoimmun 2017;79;84–90.
Majhail, NS, Rizzo, JD, Lee, SJ, Aljurf, M, Atsuta, Y, Bonfim, C, et al. [Recommended screening and preventive practices for longterm survivors after hematopoietic cell transplantation]. Rinsho Ketsueki 2014;55;607–32.
Stratton, P, Battiwalla, M, Abdelazim, S, Barrett, AJ, Cantilena, CR, Childs, RW, et al. Immunogenicity of HPV quadrivalent vaccine in women after allogeneic HCT is comparable to healthy volunteers. Biol Blood Marrow Transplant 2018;24;S85–6.
Ellerbrock, TV, Chiasson, MA, Bush, TJ, Sun, XW, Sawo, D, Brudney, K, et al. Incidence of cervical squamous intraepithelial lesions in HIV-infected women. JAMA 2000;283;1031–7.
Hawes, SE, Critchlow, CW, Faye Niang,MA, Diouf, MB, Diop, A, Touré, P, et al. Increased risk of high‐grade cervical squamous intraepithelial lesions and invasive cervical cancer among african women with human immunodeficiency virus type 1 and 2 infections. J Infect Dis 2003;188;555–63.
Schuman, P, Ohmit, SE, Klein, RS, Duerr, A, Cu‐Uvin, S, Jamieson, DJ, et al. Longitudinal study of cervical squamous intraepithelial lesions in Human Immunodeficiency Virus (HIV)–seropositive and at‐risk HIV‐seronegative women. J Infect Dis 2003;188;128–36.
Moscicki, A, Ellenberg, JH, Crowley‐Nowick, P, Darragh, TM, Xu, J, Fahrat, S. Risk of high‐grade squamous intraepithelial lesion in HIV‐infected adolescents. J Infect Dis 2004;190;1413–21.
Conley, LJ, Ellerbrock, TV, Bush, TJ, Chiasson, MA, Sawo, D, Wright, TC. HIV-1 infection and risk of vulvovaginal and perianal condylomata acuminata and intraepithelial neoplasia: a prospective cohort study. Lancet 2002;359;108–13.
Jamieson, DJ, Paramsothy, P, Cu-Uvin, S, Duerr, A. HIV Epidemiology Research Study Group. Vulvar, vaginal, and perianal intraepithelial neoplasia in women with or at risk for human immunodeficiency virus. Obstet Gynecol 2006;107;1023–8.
Kaplan, JE, Kaplan, C, Holmes, KK, Brooks, JT, Pau, A, Masur, H, et al. Guidelines for prevention and treatment of opportunistic infections in HIV-infected adults and adolescents: recommendations from CDC, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America. MMWR Recomm Rep 2009;58;1–207. quiz CE1-4.
Nguyen, ML, Flowers, L. Cervical cancer screening in immunocompromised women. Obstet Gynecol Clin North Am 2013;40;339–57.
Bhatia, S, Armenian, SH, Landier, W. How I monitor long-term and late effects after blood or marrow transplantation. blood 2017;130;1302–14.
Majhail, NS, Rizzo, JD, Lee, SJ, Aljurf, M, Atsuta, Y, Bonfim, C, et al. Recommended screening and preventive practices for long-term survivors after hematopoietic cell transplantation. Biol Blood Marrow Transplant 2012;18;348–71.
Daling, JR, Madeleine, MM, Schwartz, SM, Shera, KA, Carter, JJ, McKnight, B, et al. A population-based study of squamous cell vaginal cancer: HPV and cofactors. Gynecol Oncol 2002;84; 263–70.
Woolfrey, A, Lee, SJ, Gooley, TA, Malkki, M, Martin, PJ, Pagel, JM, et al. HLA-allele matched unrelated donors compared to HLAmatched sibling donors: role of cell source and disease risk category. Biol Blood Marrow Transplant 2010;16;1382–7.
Jeronimo, J, Castle, PE, Temin, S, Denny, L, Gupta, V, Kim, JJ, et al. Secondary prevention of cervical cancer: ASCO resourcestratified clinical practice guideline. J Glob Oncol 2017;3;635–57.
GOV.UK. Cervical screening: professional guidance. 2004. https://www.gov.uk/government/collections/cervical-screeningprofessional-guidance.
Arbyn, M, Anttila, A, Jordan, J, Ronco, G, Schenck, U, Segnan, N, et al. European Guidelines for Quality Assurance in Cervical Cancer Screening. Second edition–summary document. Ann Oncol Off J Eur Soc Med Oncol 2010;21;448–58.
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Tanweer, M.S., Aljurf, M., Savani, B.N. et al. Lower Genital Tract Precancer and Cancer in Hematopoietic Cell Transplant Survivors and the Role of HPV: A Systematic Review and Future Perspectives. Clin Hematol Int 1, 142–153 (2019). https://doi.org/10.2991/chi.d.190519.001
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DOI: https://doi.org/10.2991/chi.d.190519.001