Vulvo-vaginal chronic Graft-versus-Host Disease
Eva Smith Knutsson Senior doctor, clinical sexologist, Dpt of Obstetrics and Gynecology, NU Hospital Group,Trollhättan PhD student, Sahlgrenska Academy, University of Göteborg Sweden Allogeneic stem cell transplantation (alloHCT = alloSCT)
• A potentially curative procedure of hematological malignancies
• 1st Bone Marrow Transplantation (BMT) in the world 1956, New York
• To-day worldwide >32000 allogeneic stem cell transplantations per year AlloSCT • Conditioning – chemotherapy, total body irradiation (TBI) - to eradicate the malignant clone
• Infusion of donor stem cells – from bone marrow, peripheral blood, umbilical cord
• From HLA identical sibling or matched unrelated voluntary donor Graft-versus-Leukemia effect (GvL)
• An immunological anti-tumor action mainly by T-lymfocytes from the donor Graft-versus-Host Disease
• The major cause of late morbidity and non-relapse mortality
• An attack by donor immunocompetent cells on the patient´s healthy tissues
• The pathophysiology of GvHD still not completely understood Acute Graft-versus-Host Disease (aGvHD)
• Early onset
• Affects: the skin, liver and gastrointestinal tract. Chronic Graft-versus-Host Disease (cGvHD)
• Progressive inflammation and fibrosis in mucous membranes in the mouth, eyes and genitals • May affect almost any organ of the body • Extensive fibrosis e.g. scleroderma, bronchiolitis or total vaginal stenosis. My background
• I. A cross-sectional study of a population-based cohort alloSCT 1996-Nov 2005 • - assess prevalence (52%), symptoms, clinical signs and histopathological picture; n=42
Smith Knutsson et al.Biol Blood Marrow Transplant 2014;20:806-11. My background
• II. A prospective study during 3 years of a population-based cohort allotransplanted Sept 2005- Febr 2010; n=41 • - assess incidence, when and how genital cGvHD begins • - early diagnosis and intervention in order to halt progression to severe genital cGvHD.
Smith Knutsson et al. Acta Obstet Gynecol Scand 2018;97:1122-1129. Cumulative incidence of genital cGvHD
• At 1 year after alloSCT: 56 % • At 3 years after alloSCT: 66 %.
Median time to 1st confirmed sign of genital cGvHD: 6 (1-30) months Reports of very late debuts of genital GvHD up to 8 years
Smith Knutsson et al. Acta Obstet Gynecol Scand 2018;97:1122-1129 Diagnosing genital cGvHD
• National Institutes of Health (NIH):
• Diagnostic signs – sufficient to establish the diagnosis of gen cGvHD
• Distinctive signs – seen in cGvHD but insufficient to alone give the diagnosis of genital cGvHD; need extra-genital cGvHD or confirming histo-pathology Other signs
• Thin mucous membranes Diagnostic signs according to NIH • Vulvar and vaginal lichen-planus-like features: reticular white lines, erythema, teleangiectatic areas; vulvar lichen sclerosus-like features • Vulvar synechia, labial fusion and resorption, clitoral hood agglutination • Vaginal synechia, threadlike or closing the fornices, vaginal shortening circumferential fibrous vaginal banding = partial stenosis, dense sclerotic changes, complete vaginal stenosis.
• Jagasia MH et al. NIH Consensus Development Project on Criteria for clinical trials in cGvHD:I. The 2014 Diagnosis and Staging Working Group Report. BBMT 2015;21:389-401. Adhesions
Ovary Tube Uterus Cervix Synechiae Vagina Outer Inner lips
Eva Smith Knutsson Adhesions
Vaginal sore string
Eva Smith Knutsson Adhesions
Vaginal stenosis
Eva Smith Knutsson Distinctive signs according to NIH
• Erosions • Fissures • Ulcers
• Need confirming histo-pathology or extra-genital cGvHD Histopathological assessment
Few studies – false negative – false positive diagnosis
Varying picture
Shulman H M et al. Histopathologic diagnosis of chronic Graft-versus-Host Disease Biol Blood Marrow Transplant. 2015 April ; 21(4): 589–603 Self-reported symptoms at 1st diagnosis of genital cGvHD n=27 Smith Knutsson et al. Acta Obstet Gynecol Scand 2018;97:1122-1129
• Itching and dryness most common (n= 10 and 9 resp.) • Pain, burning, dyspareunia and discharge (n= 7, 6 and 6 resp.) • No symptom (n=8) = 30%!!
A woman might have more than one symptom. Premature menopaus if not already natural
• All allo-transplanted women – premature menopause
• Ovarian recovery 5-10 % associated with young age at Tx.
Mothy M. and Apperley J.F. Long-term physiological side effects after allogeneic bone marrow transplantation. Hematology 2010: 229-236. (American Society of Hematology) Estrogen treatment
• HRT when premature menopaus • Local estrogen • Allotransplanted women need both systemic and local estrogen
• Atrophic changes might simulate cGvHD
• Faster recovery from genital cGvHD in women with estrogen therapy (Stratton el al. Vulvovaginal cGvHD with allogeneic SCT. Obstet Gynecol. 2007;110:1041-9) Treatment –cooperation with the hematologist
Medical treatment Local estrogen therapy Local immunosuppressive ointments: klobetasol (0.05%) tacrolimus (0.1-0.03%) – tacrolimus/blood test
Treatment –cooperation with the hematologist
Physical treatment Vaginal dilator – gentle painless use lubricant slow insertion wait for muscular contraction to relax 3-5 minutes in the vagina gentle extraction possibly combined with pushing
Treatment – second line
• Systemic oral corticosteroids in cooperation with the hematologist
• Surgery - acute when hematokolpos and/or hematometra - when need of ability to perform Pap smear - when wish for intercourse Sexual councelling – teaching about • Physical changes in anatomy and physiology
• Low sexual desire - less testosteron - fatigue - depression - dyspareunia - vaginismus Did early diagnosis and intervention halt progression to severe genital cGvHD?
The cross-sectional study evaluation at median 80 (13-148) months after alloHCT n=42 Vaginal total stenosis developed up to 36 months post alloSCT, n=8
The prospective study followed for 36 months post alloSCT n=41 Vaginal total stenosis, n=2 Population at risk – squamos cell carcinoma
• Allo-transplantation • cGvHD • Immunosuppressive treatment • Activation of HPV-infection
• x 5 higher risk squamos cell carcinoma (Rizzo et al. Blood 2009.)
• x13 higher risk squamos cell carcinoma of the cervix (Savani et al, J Clin Oncol 2008) Course of genital cGvHD
• Starts in either vulva, vagina or both.
• A close association between extragenital and genital cGvHD but solitary genital cGvHD exists. Course of genital cGvHD
• Pendulating
• May resolve without immunosuppressive therapy
• Lifelong active cGvHD or its sequel may impact quality of life Conclusion genital cGvHD
• Genital cGvHD is common after alloSCT • Regardless of symptoms systematic and early surveillance is important after alloSCT. • Hematologists, gynecologists and dermatologists must cooperate in balancing local and systemic corticosteroid treatments • Life-long surveillance necessary to prevent epithelial atypias from transforming into malignancies • Treatment of depression and addressing sexual function might improve sexual function and quality of life. Collaborators to the project Genital cGvHD Mats Brune (1) Karin Sundfeldt (2) Lotti Helström (3) Harald Anderson (4) Yvonne Björk (1) Anna-Karin Broman (5) Anne-Marie Levin-Jakobsen (6) Malin Nicklasson (1) Ola Nilsson Wassén (7) Kristina Stenberg (8) Eva Smith Knutsson (9) (1) Section of Hematology and Coagulation, Dpt of Medicine, Sahlgrenska University Hospital, Sahlgrenska Academy, University of Göteborg, Sweden (2) Dpt of Obstetrics and Gyneology, Sahlgrenska University Hospital, Sahlgrenska Academy, University of Göteborg, Sweden (3) Karolinska Institute, Stockholm South General Hospital, Stockholm, Sweden (4) Dpt of Cancer Epidemiology, University of Lund, Sweden (5) Dpt of Obstetrics and Gynecology, NU Hospital Group, Trollhättan, Sweden (6) Norrlands University Hospital, Umeå, Sweden (7) Dpt of Pathology, Sahlgrenska University Hospital, Sahlgrenska Academy, University of Göteborg, Sweden (8) Dpt of Ophtalmology, Sahlgrenska University Hospital, Sahlgrenska Academy, University of Göteborg, Sweden. (9) Dpt of Obstetrics and Gynecology, NU Hospital Group, Trollhättan and Sahlgrenska Academy, University of Göteborg, Sweden.