Genital GVHD in Female Children and Adolescents: A Systematic Review of Case Reports and Case Series
Abstract
:1. Introduction
2. Materials and Methods
3. Results
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
- Majhail, N.S.; Farnia, S.H.; Carpenter, P.A.; Champlin, R.E.; Crawford, S.; Marks, D.I.; Omel, J.L.; Orchard, P.J.; Palmer, J.; Saber, W.; et al. Indications for Autologous and Allogeneic Hematopoietic Cell Transplantation: Guidelines from the American Society for Blood and Marrow Transplantation. Biol. Blood Marrow Transplant. 2015, 21, 1863–1869. [Google Scholar] [CrossRef] [PubMed]
- Shanis, D.; Merideth, M.; Pulanic, T.K.; Savani, B.N.; Battiwalla, M.; Stratton, P. Female Long-Term Survivors After Allogeneic Hematopoietic Stem Cell Transplantation: Evaluation and Management. Semin. Hematol. 2012, 49, 83–93. [Google Scholar] [CrossRef] [PubMed]
- Jacobson, M.; Wong, J.; Li, A.; Wolfman, W.L. Vulvovaginal graft-versus-host disease: A review. Climacteric 2019, 22, 603–609. [Google Scholar] [CrossRef]
- Kornik, R.I.; Rustagi, A.S. Vulvovaginal Graft-Versus-Host Disease. Obstet. Gynecol. Clin. N. Am. 2017, 44, 475–492. [Google Scholar] [CrossRef]
- Hamilton, B.K.; Goje, O.; Savani, B.N.; Majhail, N.S.; Stratton, P. Clinical management of genital chronic GVHD. Bone Marrow Transpl. 2017, 52, 803–810. [Google Scholar] [CrossRef] [PubMed]
- Tirri, B.F.; Häusermann, P.; Bertz, H.; Greinix, H.; Lawitschka, A.; Schwarze, C.-P.; Wolff, D.; Halter, J.P.; Dörfler, D.; Moffat, R. 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. [Google Scholar] [CrossRef]
- Allen, S.M.; Liang, C.S.; Chesnokova, A.E.; Childress, K.J.; Pascoe, K.F.; Dietrich, J.E. Patterns of Genital Examination and Vulvovaginal Graft-Versus-Host Disease in a Pediatric Post-Hematopoietic Stem Cell Transplant Population. J. Pediatr. Adolesc. Gynecol. 2020, 33, 658–666. [Google Scholar] [CrossRef]
- Cizek, S.M.; El-Bietar, J.; Rubinstein, J.; Dandoy, C.; Wallace, G.H.; Nelson, A.; Khandelwal, P.; Myers, K.C.; Hoefgen, H.R. Pediatric and Young Adult Vulvovaginal Graft-versus-Host Disease. Biol. Blood Marrow Transplant. 2019, 25, 2408–2415. [Google Scholar] [CrossRef] [PubMed]
- Dowlut-McElroy, T.; Shin, S.; Stepanek, E.; Jacobsohn, D.; Gomez-Lobo, V. Pediatric Vulvovaginal Graft-Versus-Host Disease: A Retrospective Cohort Study and Literature Review. J. Pediatr. Adolesc. Gynecol. 2022, 35, 552–557. [Google Scholar] [CrossRef]
- Takahashi, T.; Arora, M.; Okoev, G.; DeFor, T.E.; Weisdorf, D.J.; MacMillan, M.L. Late-Onset Acute and Chronic Graft-versus-Host Disease in Children: Clinical Features and Response to Therapy. Transplant. Cell. Ther. 2021, 27, 667.e1–667.e5. [Google Scholar] [CrossRef]
- Stratton, P.; Turner, M.L.; Childs, R.; Barrett, J.; Bishop, M.; Wayne, A.S.; Pavletic, S. Vulvovaginal Chronic Graft-Versus-Host Disease With Allogeneic Hematopoietic Stem Cell Transplantation. Obstet. Gynecol. 2007, 110, 1041–1049. [Google Scholar] [CrossRef] [PubMed]
- Dyer, G.; Gilroy, N.; Bradford, J.; Brice, L.; Kabir, M.; Greenwood, M.; Larsen, S.R.; Moore, J.; Hertzberg, M.; Kwan, J.; 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. [Google Scholar] [CrossRef] [PubMed]
- Flowers, M.E.D.; Parker, P.M.; Johnston, L.J.; Matos, A.V.B.; Storer, B.; Bensinger, W.I.; Storb, R.; Appelbaum, F.R.; Forman, S.J.; Blume, K.G.; 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. [Google Scholar] [CrossRef] [PubMed]
- Hirsch, P.; Leclerc, M.; Rybojad, M.; Petropoulou, A.D.; Robin, M.; Ribaud, P.; de la Tour, R.P.; Cavelier-Balloy, B.; Socié, G.; Vexiau-Robert, D. Female Genital Chronic Graft-Versus-Host Disease: Importance of early diagnosis to avoid severe complications. Transplantation 2012, 93, 1265–1269. [Google Scholar] [CrossRef]
- Lev-Sagie, A.; Adar-Walling, E.; Gumer, A.; Grisariu, S.; Avni, B. Management and long-term consequences of genital graft versus host disease following hematopoietic stem cell transplantation. Bone Marrow Transplant. 2020, 55, 2234–2243. [Google Scholar] [CrossRef] [PubMed]
- Knutsson, E.S.; Björk, Y.; Broman, A.-K.; Helström, L.; Nicklasson, M.; Brune, M.; Sundfeldt, K. A prospective study of female genital chronic graft-versus-host disease symptoms, signs, diagnosis and treatment. Acta Obstet. Gynecol. Scand. 2018, 97, 1122–1129. [Google Scholar] [CrossRef]
- Spinelli, S.; Chiodi, S.; Costantini, S.; Van Lint, M.T.; Raiola, A.M.; Ravera, G.B.; Bacigalupo, A. Female genital tract graft-versus-host disease following allogeneic bone marrow transplantation. Haematologica 2003, 88, 1163–1168. [Google Scholar] [PubMed]
- Zantomio, D.; Grigg, A.P.; 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. [Google Scholar] [CrossRef]
- Michala, L.; Vlachopapadopoulou, E.; Tsimaris, P.; Papaioannou, G.; Paisiou, A.; Peristeri, I.; Michalacos, S.; Kitra, V. Resolution of Hematocolpos in Adolescents Affected with Graft vs Host Disease. J. Pediatr. Adolesc. Gynecol. 2018, 31, 536–539. [Google Scholar] [CrossRef]
- Childress, K.; Swanson, K.; Gossett, D. Vulvovaginal Graft-vs-Host Disease. J. Pediatr. Adolesc. Gynecol. 2015, 28, e61. [Google Scholar] [CrossRef]
- Choi, K.H.; Lee, J.Y.; Cho, B.K.; Cho, B.; Park, H.J. Labial fusion after chronic graft-vs.-host disease. Int. J. Dermatol. 2009, 48, 1028–1029. [Google Scholar] [CrossRef] [PubMed]
Study | Patient | Diagnosis | Age at HSCT | Stem Cell Source | Related/Unrelated Donor; Match | Conditioning Regimen | GVHD Prophylaxis | Acute GVHD Site | Chronic GVHD Severity/Site | Non-Genital GVHD Treatment at Diagnosis of Vulvovaginal GVHD | Symptoms | Clinical Findings | Treatment of Genital GVHD | Long-Term Follow-Up/Response | Time of vvGVHD Diagnosis after HSCT | Genital GVHD Grading |
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Dowlut-McElroy et al., 2022 [9] | 1 | Infantile osteopetrosis | 1.4 | BM | N/A | N/A | Sirol | None | Lungs | Sirol | Unknown | Unknown | Premarin cream | Unknown | N/A | Unknown |
2 | Acute myelogenous leukemia | 12 | PBSC | N/A | N/A | Sirol | Skin/Vulva | Skin | Sirol | None | Erythema | Cream Betamethasone, ointment pimecrolimus | CR | 62 | 3 | |
3 | Acute myelogenous leukemia | 4 | UC | N/A | N/A | Sirol | Skin | Skin | Sirol | Dysuria | Erythema, mild adhesions | None | CR | 1565 | 1 | |
Cicek et al., 2019 [8] | 4 | Acute myelogenous leukemia | 2.4 | BM | Unrelated | ATG/BU/CY | CSA/MTX | Skin | Skin, eyes | Pred | Vulvar pruritus, dysuria | Not specified for each case. Clinical findings of the whole Study: vulvar adhesions/ agglutination (89%), loss of vulvar architecture (42%), vulvar skin erosions/ fissures (37%), vestibular pain to palpation (11%), vaginal atrophy (16%), abnormal vaginal discharge (5%), vulvar skin hyperpigmentation, (5%) and vulvar skin dryness/scaling (5%) | Beclomethasone 0.05%, tacrolimus topical, estradiol cream, betamethasone | PR with relapse | 287 | 3 |
5 | Severe combined immunodeficiency | 3.8 | BM | Unrelated | Cam/Flu/Mel | CSA/Pred | None | MS | None | No symptoms | Betamethasone cream | Unknown | 2966 | 3 | ||
6 | Chronic myelogenous leukemia | 8.7 | BM | Unrelated | ATG/CY/TBI | CSA/Pred | None | Intestine, liver, oral mucosa | Pred | Vulvar pain/Pruritus, dysuria | Betamethasone dipropionate ointment 0.1% | PR | 452 | 3 | ||
7 | Dyskeratosis congenita | 9.3 | BM | Unrelated | Cam/Flu/Mel | CSA/MMF | Skin | Oral mucosa, skin | Rituximab, MP, MMF | Vulvar pain, dysuria | Triamcinolone 0.1% ointment, hydrocortisone 1% ointment, estradiol cream | PR | 71 | 2 | ||
8 | Fanconi anemia | 10.2 | UC | Unrelated | ATG/CY/Flu/TBI | CSA/Pred | None | Skin, oral mucosa, MS | Tac | Abnormal vaginal discharge | Triamcinolone 0.1% ointment, clobetasol 0.05% ointment, estradiol cream | PR with relapse | 1811 | 3 | ||
9 | Dyskeratosis congenita | 11.9 | BM | Unrelated | Cam/Flu/Mel | CSA/Pred | Skin | Skin, oral mucosa | Hydrocortisone, Pred | Vulvar pain/pruritis, abnormal vaginal discharge, dysuria, urge urinary incontinence | Clobetasol 0.05% cream, triamcinolone 0.1% ointment, estradiol cream, surgical lysis of adhesions | PR | 690 | 3 | ||
10 | Beta thalassemia | 12.2 | BM | Unrelated | BU/Flu/Thio | Aba/Pred | None | Skin, lung | Infliximab, Ruxolitinib, tac, pred, MP, phototherapy | Vulvar pain/pruritus, abnormal vaginal discharge, dysuria | Clotrimazole, betamethasone 0.5% ointment | CR | 600 | 3 | ||
11 | Acute lymphoblastic leukemia | 12.8 | PBSC | Unrelated | CY/TBI | CSA/MTX | Skin | Oral mucosa | Bud po | No symptoms | Estradiol cream | CR | 226 | 3 | ||
12 | Beta thalassemia | 13.2 | BM | Related | BU/Flu/Thio | CSA/Mar/Pred | None | Oral mucosa, lung | MMF, pred, bud po | Vulvar pain, dysuria | Triamcinolone 0.1% ointment, betamethasone 0.1% ointment | CR | 313 | 3 | ||
13 | Acute myelogenous leukemia | 13.3 | BM | Unrelated | Flu/Mel | CSA/MTX | Skin | Intestine, skin | Infliximab, pred, CSA, bud po | Vulvovaginal pain | Betamethasone 0.1% ointment, betamethasone 0.05% ointment | NR | 132 | 1 | ||
14 | Acute lymphoblastic leukemia | 13.8 | BM | Unrelated | CY/TBI | Aba/CSA/Pred | Skin | Skin | Ruxolitinib, bud po | No symptoms | None | n/a | 593 | 3 | ||
15 | Fanconi anemia | 14.6 | BM | Unrelated | ATG/BU/CY/Flu | CSA/Pred | Skin | Oral mucosa | None | No symptoms | Betamethasone 0.05% ointment, estradiol cream | PR | 677 | 3 | ||
16 | Acute lymphoblastic leukemia | 12.9 | BM | Related | ATG/CY/TBI | MTX/Sirol/TAC | None | Skin | None | No symptoms | Clobetasol 0.05% ointment, estradiol cream | PR | 381 | 3 | ||
17 | Fanconi anemia | 10.6 | PBSC | Unrelated | ATG/BU/CY/Flu | CSA/TCD | None | None | None | No symptoms | Clobetasol 0.05% ointment | CR | 2453 | 3 | ||
18 | Fanconi anemia | 6.5 | BM | Related | ATG/CY/Flu | ATG/CSA/MP | Gut | Lung | None | Vulvar pain/pruritus, dysuria | Clobetasol 0.05% ointment | PR | 2286 | 3 | ||
19 | Acute myelogenous leukemia | 10.2 | BM | Unrelated | BU/CY/ATG | CSA/MTX | Skin | Oral mucosa | Oral bud | Unknown | None (declined) | Unknown | 290 | 3 | ||
20 | Acute lymphoblastic leukemia | 5.0 | PBSC | Related; fully matched | TBI-based | Unknown | None | Skin, joints, eyes, lungs, oral mucosa | MMF, pred | No symptoms | Triamcinolone 0.1% ointment | PR | 77 | 3 | ||
Michala et al., 2018 [19] | 21 | Fanconi anemia | 10.5 | BM | Unrelated | BU/CY, no TBI | ATG/CSA/MTX | None | Mild cGVHD skin/mucosa, conjunctivitis, stomatitis, | None (symptomatically) | No symptoms, | Hematocolpos, vulvar atrophy, clitoral phimosis | Oral estradiol, hydrocortisone foam, estriol gel, dilator | CR | 1278 | 3 |
22 | Myelodysplastic syndrome | 13.0 | BM | Unrelated; fully matched | Be/Mel/Flu | ATG/CSA/MTX | None | Skin | Oral steroids | No symptoms, | Hematocolpos, vaginal stenosis, | Oral estradiol, hydrocortisone foam, estriol gel, Vaginal dilator | CR | 456 | 3 | |
Allen et al., 2020 [7] | 23 | Griscelli Syndrome and Hemophagocytic Lymphohistiocytosis | 2.0 | BM | Unrelated; matched | N/A | CSA, MP, Tac | None | Intestine, skin | Tac, etanercept, bud, MP, topical tac and triamcinolone | Vulvar pruritus, | Labial scar tissue | Barrier cream | PR | 2207 | 3 |
24 | Acute myelogenous leukemia/myelodysplastic syndrome | 7 | PBSC | Haploidentical matched | N/A | Unknown | Skin | Skin | Steroids | Dysurea, vulvar pain, rash, | White plaque on labia | Topical triamcinolone and tacrolimus, transdermal estradiol | PR | 88 | 1 | |
25 | Acute myelogenous leukemia | 17 | BM, PBSC | 1. Matched unrelated; 2. Haploidentical | N/A | Tac, steroids after BMT; tac, mycophenolic, CY | Gut | Intestine, skin, liver, | MP, Tocilizumab, rituximab, etanercept, basiliximab and topical clobetasol | Vaginal pain, labial hypopigmentation, mons and labia tightness | Labial hypopigmentation, tenderness to palpation | Topical clobetasol and mometasone | PR | 284 | 2 | |
26 | Acute myelogenous leukemia | 17 | BM | Unrelated; matched | N/A | CSA, steroids | Gut | Intestine, skin, mucosa, lung | MP, pred, etanercept, ruxolitiab, oral bud, imatinib, topical Tac, unspecified steroids (IV, topical) | Vulvar pain, sensitivity, dryness | Hypoestrogenic vulva, labial adhesions/agglutination | Hormone replacement, topical estrogen and zinc oxide barrier creams | NR | 512 | 3 | |
Choi et al., 2009 [21] | 27 | Acute myelogenous leukemia | 14 | PBSC | Matched unrelated | N/A | N/A | Skin, gut | None | Pred, CSA | Not reported | Labial fusion, adhesions, vulvar skin erosions | Topical steroid, | PR | 730 | 3 |
Stratton et al., 2007 [11] | 28 | Hodgkin’s lymphoma | 16 | PBSC | Matched related | Flu/CY | N/A | Not specified, though all patients in the study had some manifestation of extra-genital acute or chronic GVHD | None | Yes. Not specified | Not specified for each case. Clinical findings of the whole study: vulvar erythema (93.1%), tender gland openings (89.7%), vulvar fissures or erosions (51.2%), clitoral agglutination (10.3%), vaginal synechiae (17.2%), vaginal fascitis (3.4%) | Not specified; 22 out of 29 pts were treated with 0.5%clobetasol propionate; the others were prescribed 0.025% fluocinolone acetonide or 0.01% tacrolimus | Not specified, but mentioned that all patients had some response | 312 | 3 | |
29 | Acute lymphoblastic leukemia | 9 | PBSC | Matched related | Flu/CY | N/A | Mycophenolate, pred, extracorporeal photophoresis | Yes. Not specified | 374 | . | ||||||
30 | Myelodysplastic syndrome/Ewing Sarcoma | 20 | PBSC | Unrelated; cord blood | Bu/Cy/ATG | N/A | Pred, CSA | Yes. Not specified | 224 | . | ||||||
31 | Ewing Sarcoma | 19 | PBSC | Matched related | Flu/CY | N/A | None | Yes. Not specified | 80 | 3 | ||||||
Childress et al., 2015 * [20] | 32 | Aplastic anemia | 12 | N/A | N/A | N/A | N/A | N/A | N/A | N/A | Discharge | Erythema and erosions, discharge, adhesions, ematocolpos | Topical clobetasol, surgical, topical estrogen | NR, then PR | 365 | 3 |
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Tsimeki, M.; Tsimpidakis, A.; Roidi, S.; Gregoriadis, T.; Soldatou, A.; Kitra, V.; Michala, L. Genital GVHD in Female Children and Adolescents: A Systematic Review of Case Reports and Case Series. Children 2023, 10, 1463. https://doi.org/10.3390/children10091463
Tsimeki M, Tsimpidakis A, Roidi S, Gregoriadis T, Soldatou A, Kitra V, Michala L. Genital GVHD in Female Children and Adolescents: A Systematic Review of Case Reports and Case Series. Children. 2023; 10(9):1463. https://doi.org/10.3390/children10091463
Chicago/Turabian StyleTsimeki, Maria, Antonios Tsimpidakis, Stella Roidi, Themos Gregoriadis, Alexandra Soldatou, Vasiliki Kitra, and Lina Michala. 2023. "Genital GVHD in Female Children and Adolescents: A Systematic Review of Case Reports and Case Series" Children 10, no. 9: 1463. https://doi.org/10.3390/children10091463