LITERATURE - 2017, Journal of Hungarian Obstetricians and Gynaecologists
Genital chronic graft versus host disease in females
Summary of the lecture held at the 25th EBCOG conference in Antalya 19th May 2017
Author: Brigitte Frey Tirri
Woman’s Hospital, Cantonal Hospital Baselland, Liestal, Switzerland
Nowadays, haematopoietic stem cell transplantation (HSCT) is a recognized therapy for patients with severe innate or acquired diseases of the haematopoietic system. Autologous and allogeneic stem cells from either the bone marrow, peripheral blood or umbilical cord blood are used to treat a multiplicity of diseases. Complications after allogeneic HSCT are due to adverse effects of cytotoxic treatment, acute and chronic graft versus host disease (GvHD). GvHD is an immunologic reaction where the T-cells of the graft react versus the host organs. Prophylactic treatment of the graft before allogeneic HSCT minimizes this reaction. GvHD may be acute, when the reaction occurs in the first 100 days after HSCT and chronic GvHD (>100 days). Chronic GvHD (cGvHD) affects mostly the skin and the mucous membranes but may affect all other organs as well. Men and women need special care after HSCT.
In these women, lifetime gynaecological care has to focus on screening for breast cancer, as there is a known, increased risk of breast cancer , on the treatment of premature ovarian failure, and on the sequel of genital cGvHD . This paper is focused on female genital chronic GvHD. It is based on the review about the clinical guidelines for gynaecological care after HSCT, a report from the international consensus project on clinical practice in chronic GvHD .
Up to 49% of all female survivors of allogenic HSCT will face genital cGvHD . The median time to onset was 10 months in this study, but it can occur even after 12 to 24 months as well. It often affects the vulva, but can also affect both the vulva and the vagina. The grade of genital GvHD does not necessarily correlate with the severity of systemic GvHD and can appear only in the vulva and vagina without affecting other organs. Some studies suggest that genital GvHD is more common after transplantations that use peripheral blood stem cells as a source compared to bone marrow .
Keywords: genital disease, stem cell transplantation
Symptoms include dryness, burning, itching, vulvodynia, and dyspareunia. Signs include erythematous patches, redness, vulvar fissures, erosions, retiform leukokeratosis (lichen planus like lesions), vaginal synechiae and adhesions, and complete vaginal stenosis.
Several recommendations for diagnosing and staging female genital cGvHD have been published. The 2005 NIH’ recommendations consider not only the signs but also the symptoms . Nevertheless, it has different limitations. First, mild signs of female genital cGvHD are difficult to differentiate from atrophy caused by premature ovarian failure (POF). Second, reporting symptoms of dyspareunia and discomfort with gynaecological examination is subjective. Affected women usually have difficulty classifying the extent of pain perceived. Third, sexually inactive women may not report symptoms like dyspareunia but might have severe signs of female genital cGvHD .
For these reasons, the score published by Stratton  is more useful in describing the extent of female genital cGvHD. Severity scoring for female genital cGvHD according to Stratton shows the 1. table.
Histological findings of female genital cGvHD are consistent with mucosal and skin manifestations in classic cGvHD with signs of chronic and acute inflammation within the subepithelial stroma and epithelium, that is, vacuolar degeneration of the basal layer, apoptotic keratinocytes, and superficial perivascular lymphohistiocytic infiltrates. No biopsy is mandatory in every case. In our clinic, we prefer a trial of treatment after the exclusion of infection, drug or allergic reactions, and dysplasia in cases with distinctive signs (corresponding to moderate genital cGvHD in Stratton’s scoring). If the treatment is not successful in a timely manner (6–8 weeks), we perform a biopsy of the lesions to exclude malignancies .
|1. table: Severity scoring for female genital cGvHD according to Stratton |
|Severity score||Findings on clinical examination|
|Grade I (minimal)||Generalized erythema and oedema of vulvar structures |
Patchy erythema of mucosa and glandular structures of vulvar vestibule
Erythema around openings of vestibular (Bartholini’s and Skene’s) glands
|Grade II (moderate)||Grade I findings plus |
Erosions of mucosal surfaces of the vulva
Fissures in vulvar folds (that is, interlabial sulci; fourchette)
|Grade III (severe)||Grade II findings plus |
Agglutination of clitoral hood
Haematocolpos or complete vaginal closure
Fasciitis or spasticity of the levator sling
For genital hygiene, only the use of water is recommended. Perfumed lotions and soaps and tight underwear and clothes should be avoided. In case of genital atrophy, the use of topical oestrogen in the form of creams, capsules or oestrogen-releasing rings is reasonable even if the patient is using hormone therapy (HT). In case of genital cGvHD, rapid control of inflammation with topical class IV corticosteroids should be used. In our clinic, we use clobetasol propionate (Dermovate®) ointment once daily at bedtime for 4 weeks as first-line therapy in newly diagnosed cGvHD and in case of flare-ups. If it is effective, the clobetasol ointment shall be reduced to 3 times weekly for 4 weeks, and then to once to twice a week, depending on the therapeutic success. Regular intercourse or use of dilators can prevent vaginal narrowing and stenosis. Empirically, this latter therapy should be initiated only when inflammation is under control; otherwise, mechanical skin irritation can produce a flare-up of the inflammation. Photodocumentation is an easy and painless way of monitoring response to treatment. 
After the transplantation, the patient should present to our clinic every three months in the first year, and providing that there are no complaints that need more frequent evaluation, we will see the patient every year.
The aim of the follow-up visits is to treat the patient for the symptoms of premature ovarian failures (POF), sexual dysfunction and fertility issues, and to prevent secondary malignancies of the breast and the female genital tract.
Women with POF under the age of 40 years should be offered systemic hormone therapy irrespective of the symptoms if there are no risk factors  until the median age of natural menopause at 51 years.
The risk for breast cancer after allogenic HSCT is substantially increased after total body irradiation (TBI) or local chest radiotherapy. The screening may include self- and provider examination, mammography, or breast magnetic resonance imaging (MRI) . The risk of dysplasia and HPV-related genital cancer is high in patients after allogenic HSCT [7, 8]. Prolonged systemic immunosuppressive treatment for cGvHD is a main risk factor.
It is of great importance to refer these women to a gynaecologist with experience in GvHD, colposcopy and genital dysplasia. It is often difficult to interpret colposcopy findings due to the changes of genital cGvHD. Screening for HPV related genital dysplasia can be performed by cytology or preferably by high risk HPV–DNA test (hrHPV test). A negative hrHPV test result more reliably suggests low CIN3+ risk than a negative cytology result. In case of a positive hrHPV test result, cytology and colposcopy should be performed .
For prevention of HPV related diseases, the administration of the HPV vaccination may be an option. Limited information is available about the immunogenicity of HPV vaccines in people who are immunocompromised. Data on the use of HPV vaccines in a 3-dose schedule in HIV infected children, women and men are reassuring in terms of safety . There are results of a four-year follow-up in children with well-controlled HIV infection after having received 3 doses of the qHPV vaccine. Seropositivity and antibody levels are similar to those of children of the same age who are not HIV infected . At our clinic, we vaccinate women 6 to 12 months after HSCT.
Women with allogenic HSCT rarely present to a general gynaecological practice. Therefore, it is very important that gynaecologists be aware of the special difficulties these women face, and that they need special care, if possible by a gynaecologist trained in this field and having access to the stem cell transplantation centres.
- Friedman DL, Rovo A, Leisenring W. Increased risk of breast cancer among survivors of allogeneic hematopoietic cell transplantation: a report from the FHCRC and the EBMT-Late Effect working Party. Blood 2008; 11: 939–944.
- Frey Tirri B, Häusermann P, Bertz H. Clinical guidelines for gynecologic care after hepatopoietic SCT. Report from the international consensus project on clinical pratice in chronic GVHD. Bone Marrow Transplantation 2015; 50: 3–9.
- Zantomio D, Grigg AP, MacGregor L, Panek-Hudson Y, Szer J, Ayton R. Female genital tract graft-versus-host disease: incidenc, riskfactors and recommendations for management. Bone Marrow Transplantation 2006; 38: 567–572.
- Filipovich AH, Weisdorf D, Pavletic S. National Institutes of Health consensus development on criteria for clinical trials in chronic graft-versus-host disease: I. Diagnosis and staging working group report. Biol Blood Marrow Transplant 2005; 11: 869–873.
- Stratton P, Turner ML, Childs R, Barrett J, Bishop M, Wayne AS, Pavletic S. Vulvovaginal Chronic Graft-Versus-Host Disease With Allogeneic Hematopoietic Stem Cell Transplantation. Obstet Gynecol 2007; 110: 1041–9.
- Ng AK, Garber JE, Diller LR, et al. Prospective study of the efficacy of breast magnetic resonance imaging and mammographic screening in surviviors of Hodgkin lymphoma. J Clin Oncol 2013; 31(18): 2282–8.
- Grulich AE, van Leeuwen MT, Falster MO, VAjdic CM. Incidence of cancers in People with HIV/AIDS compared with immunosuppressed transplant recipients: a meta-analysis. Lancet 2007; 370: 59–67.
- 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 transplantationimplications for screening and HPV vaccination. Biol Blood Marrow Transplant 2008; 14: 1072–1075.
- Huh WK, Ault KA, Chelmow D, et al. Use of Primar High-Risk Human Papillomavirus Testin for Cervical Cancer Screening: Interim Clinical Guidance. J Lower Gen Tract Dis 2015; 19: 91–96.
- WHO weekly epidemiological record. 2017; 19: 241–268. http://www.who.int/wer.
- Levin MJ, Huang S, Moscicki AB, et al. Four-year persistence of type-specific immunity after quadrivalent human papillomavirus vaccination in HIV-infected children: Effect of a fourth dose of vaccine. Vaccine 2017; 35: 1712–1720.
Download Full Article
- Brigitte Frey Tirri: Genital chronic graft versus host disease in females (2017, Journal of Hungarian Obstetricians and Gynaecologists, PDF, 4 pages, English/Hungarian, 3MB)