Abstract
Chronic GvHD (cGvHD) of the genital tract is an underreported and infrequently recognized complication of allogeneic hematopoietic cell transplantation in both male and female long-term survivors. Its pathophysiology, clinical manifestations and management are not well understood, and studies are limited. We thus provide a comprehensive review of genital cGvHD in both men and women, as well as discuss related issues of sexual health and viral reactivation. We further provide guidance on screening, management and long-term follow-up, as well as future priority areas of study.
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References
Shulman HM, Sullivan KM, Weiden PL, McDonald GB, Striker GE, Sale GE et al. Chronic graft-versus-host syndrome in man. A long-term clinicopathologic study of 20 Seattle patients. Am J Med 1980; 69: 204–217.
Sullivan KM, Shulman HM, Storb R, Weiden PL, Witherspoon RP, McDonald GB et al. Chronic graft-versus-host disease in 52 patients: adverse natural course and successful treatment with combination immunosuppression. Blood 1981; 57: 267–276.
Corson SL, Sullivan K, Batzer F, August C, Storb R, Thomas ED . Gynecologic manifestations of chronic graft-versus-host disease. Obstet Gynecol 1982; 60: 488–492.
Spinelli S, Chiodi S, Costantini S, Van Lint MT, Raiola AM, Ravera GB et al. Female genital tract graft-versus-host disease following allogeneic bone marrow transplantation. Haematologica 2003; 88: 1163–1168.
Spiryda LB, Laufer MR, Soiffer RJ, Antin JA . Graft-versus-host disease of the vulva and/or vagina: diagnosis and treatment. Biol Blood Marrow Transplant 2003; 9: 760–765.
Zantomio D, Grigg AP, MacGregor L, Panek-Hudson Y, Szer J, Ayton R . Female genital tract graft-versus-host disease: incidence, risk factors and recommendations for management. Bone Marrow Transplant 2006; 38: 567–572.
Flowers ME, Parker PM, Johnston LJ, Matos AV, Storer B, Bensinger WI et al. Comparison of chronic graft-versus-host disease after transplantation of peripheral blood stem cells versus bone marrow in allogeneic recipients: long-term follow-up of a randomized trial. Blood 2002; 100: 415–419.
Smith Knutsson E, Bjork Y, Broman AK, Helstrom L, Levin Jakobsen AM, Nilsson O et al. Genital chronic graft-versus-host disease in females: a cross-sectional study. Biol Blood Marrow Transplant 2014; 20: 806–811.
Mueller SM, Haeusermann P, Rovo A, Halter JP, Passweg J, Itin P et al. Genital chronic GVHD in men after hematopoietic stem cell transplantation: a single-center cross-sectional analysis of 155 patients. Biol Blood Marrow Transplant 2013; 19: 1574–1580.
Stratton P, Turner ML, Childs R, Barrett J, Bishop M, Wayne AS et al. Vulvovaginal chronic graft-versus-host disease with allogeneic hematopoietic stem cell transplantation. Obstet Gynecol 2007; 110: 1041–1049.
Filipovich AH, Weisdorf D, Pavletic S, Socie G, Wingard JR, Lee SJ et al. National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I. Diagnosis and staging working group report. Biol Blood Marrow Transplant 2005; 11: 945–956.
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.
Shulman HM, Kleiner D, Lee SJ, Morton T, Pavletic SZ, Farmer E et al. Histopathologic diagnosis of chronic graft-versus-host disease: National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: II. Pathology Working Group Report. Biol Blood Marrow Transplant 2006; 12: 31–47.
Nylander E, Wahlin YB, Lundskog B, Wahlin A . Genital graft-versus-host disease in a male following allogeneic stem cell transplantation. Acta Derma Venereol 2007; 87: 367–368.
Au WY, Yeung CK, Cheung MC, Trendell-Smith NJ . Penile lichen sclerosus after allogeneic stem cell transplantation. Br J Dermatol 2008; 159: 470–472.
Kami M, Kanda Y, Sasaki M, Takeda N, Tanaka Y, Saito T et al. Phimosis as a manifestation of chronic graft-versus-host disease after allogeneic bone marrow transplantation. Bone Marrow Transplant 1998; 21: 721–723.
Grigg AP, Underhill C, Russell J, Sale G . Peyronie's disease as a complication of chronic graft versus host disease. Hematology 2002; 7: 165–168.
Yared J, Gojo I, Akpek G . Glans penis involvement: an under-recognized manifestation of chronic GVHD. Bone Marrow Transplant 2012; 47: 1006–1007.
Patel ST, Woodward MN, Williams M, O'Brien M, Chandran H, Parashar K . Graft-versus-host disease and phimosis. J Pediatr Urol 2008; 4: 165–166.
Thomas LJ, Shim TN, Borysiewicz C, Dinneen M, Fawcett H, Roy A et al. Male genital lichen sclerosus in recipients of bone marrow transplants. Clin Exp Dermatol 2016; 41: 495–497.
Jain NA, Venkatesan K, Anandi P, Ito S, Kumar D, Lu K et al. A rare consequence of chronic graft versus host disease - peyronie's disease. Arch Cancer Res 2015; 3: 18.
Marks CL, Leiber C, Bertz H, Finke J, Marks R . Genital mucosa in men is a target of chronic graft-versus-host disease with serious impact on quality of life. Bone Marrow Transplant 2011; 46(Suppl 1): S66.
Couriel D, Carpenter PA, Cutler C, Bolanos-Meade J, Treister NS, Gea-Banacloche J et al. Ancillary therapy and supportive care of chronic graft-versus-host disease: national institutes of health consensus development project on criteria for clinical trials in chronic Graft-versus-host disease: V. Ancillary Therapy and Supportive Care Working Group Report. Biol Blood Marrow Transplant 2006; 12: 375–396.
Carpenter PA, Kitko CL, Elad S, Flowers ME, Gea-Banacloche JC, Halter JP et al. National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: V. The 2014 Ancillary Therapy and Supportive Care Working Group Report. Biol Blood Marrow Transplant 2015; 21: 1167–1187.
Frey Tirri B, Hausermann P, Bertz H, Greinix H, Lawitschka A, Schwarze CP et al. Clinical guidelines for gynecologic care after hematopoietic SCT. Report from the international consensus project on clinical practice in chronic GVHD. Bone Marrow Transplant 2015; 50: 3–9.
Norian JM, Stratton P . Labial fusion: a rare complication of chronic graft-versus-host disease. Obstet Gynecol 2008; 112 (2 Pt 2): 437–439.
Shanis D, Merideth M, Pulanic TK, Savani BN, Battiwalla M, Stratton P . Female long-term survivors after allogeneic hematopoietic stem cell transplantation: evaluation and management. Sem Hematol 2012; 49: 83–93.
Humphreys CT, Tallman B, Altmaier EM, Barnette V . Sexual functioning in patients undergoing bone marrow transplantation: a longitudinal study. Bone Marrow Transplant 2007; 39: 491–496.
Scanlon M, Blaes A, Geller M, Majhail NS, Lindgren B, Haddad T . Patient satisfaction with physician discussions of treatment impact on fertility, menopause and sexual health among pre-menopausal women with cancer. J Cancer 2012; 3: 217–225.
Dyer G, Gilroy N, Bradford J, Brice L, Kabir M, Greenwood M et al. A survey of fertility and sexual health following allogeneic haematopoietic stem cell transplantation in New South Wales, Australia. Br J Haematol 2016; 172: 592–601.
Syrjala KL, Kurland BF, Abrams JR, Sanders JE, Heiman JR . Sexual function changes during the 5 years after high-dose treatment and hematopoietic cell transplantation for malignancy, with case-matched controls at 5 years. Blood 2008; 111: 989–996.
Wong FL, Francisco L, Togawa K, Kim H, Bosworth A, Atencio L et al. Longitudinal trajectory of sexual functioning after hematopoietic cell transplantation: impact of chronic graft-versus-host disease and total body irradiation. Blood 2013; 122: 3973–3981.
Li Z, Mewawalla P, Stratton P, Yong AS, Shaw BE, Hashmi S et al. Sexual health in hematopoietic stem cell transplant recipients. Cancer 2015; 121: 4124–4131.
Rizzo JD, Curtis RE, Socie G, Sobocinski KA, Gilbert E, Landgren O et al. Solid cancers after allogeneic hematopoietic cell transplantation. Blood 2009; 113: 1175–1183.
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: 1072–1075.
Curtis RE, Metayer C, Rizzo JD, Socie G, Sobocinski KA, Flowers ME et al. Impact of chronic GVHD therapy on the development of squamous-cell cancers after hematopoietic stem-cell transplantation: an international case-control study. Blood 2005; 105: 3802–3811.
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: 464–471.
Sri T, Merideth MA, Pulanic TK, Childs R, Stratton P . Human papillomavirus reactivation following treatment of genital graft-versus-host disease. Transpl Infect Dis 2013; 15: E148–E151.
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: 348–371.
Wang SH, Chi CC, Wong YW, Salim A, Manek S, Wojnarowska F . Genital verrucous carcinoma is associated with lichen sclerosus: a retrospective study and review of the literature. J Eur Acad Dermatol Venereol 2010; 24: 815–819.
Powell JJ, Wojnarowska F . Lichen sclerosus. Lancet 1999; 353: 1777–1783.
Renaud-Vilmer C, Cavelier-Balloy B, Verola O, Morel P, Servant JM, Desgrandchamps F et al. Analysis of alterations adjacent to invasive squamous cell carcinoma of the penis and their relationship with associated carcinoma. J Am Acad Dermatol 2010; 62: 284–290.
Micali G, Nasca MR, Innocenzi D . Lichen sclerosus of the glans is significantly associated with penile carcinoma. Sex Transm Infect 2001; 77: 226.
Petrosky E, Bocchini JA Jr, Hariri S, Chesson H, Curtis CR, Saraiya M et al. Use of 9-valent human papillomavirus (HPV) vaccine: updated HPV vaccination recommendations of the advisory committee on immunization practices. MMWR Morb Mortal Wkly Rep 2015; 64: 300–304.
Joura EA, Giuliano AR, Iversen OE, Bouchard C, Mao C, Mehlsen J et al. A 9-valent HPV vaccine against infection and intraepithelial neoplasia in women. N Engl J Med 2015; 372: 711–723.
Van Damme P, Olsson SE, Block S, Castellsague X, Gray GE, Herrera T et al. Immunogenicity and Safety of a 9-Valent HPV Vaccine. Pediatrics 2015; 136: e28–e39.
Levin MJ, Moscicki AB, Song LY, Fenton T, Meyer WA 3rd, Read JS et al. Safety and immunogenicity of a quadrivalent human papillomavirus (types 6, 11, 16, and 18) vaccine in HIV-infected children 7 to 12 years old. J Acquir Immune Def Syndr 2010; 55: 197–204.
Tedeschi SK, Savani BN, Jagasia M, Engelhardt B, Anasetti C, Barrett AJ et al. Time to consider HPV vaccination after allogeneic stem cell transplantation. Biol Blood Marrow Transplant 2010; 16: 1033–1036.
Turnbaugh PJ, Ley RE, Hamady M, Fraser-Liggett CM, Knight R, Gordon JI . The human microbiome project. Nature 2007; 449: 804–810.
Martin DH . The microbiota of the vagina and its influence on women's health and disease. Am J Med Sci 2012; 343: 2–9.
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This paper was funded in part by the Intramural Program of the National Institutes of Health and the National Institute of Child Health and Human Development.
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Hamilton, B., Goje, O., Savani, B. et al. Clinical management of genital chronic GvHD. Bone Marrow Transplant 52, 803–810 (2017). https://doi.org/10.1038/bmt.2016.315
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DOI: https://doi.org/10.1038/bmt.2016.315
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