Clinical Guidelines for Gynecologic Care After Hematopoietic SCT

REVIEW Clinical guidelines for gynecologic care after hematopoietic SCT. Report from the international consensus project on clinical practice in chronic GVHD

B Frey Tirri1, P Häusermann2, H Bertz3, H Greinix4, A Lawitschka5, C-P Schwarze6, D Wolff7, JP Halter8, D Dörﬂer9 and R Moffat10,11

Despite similarities relevant age- and gender-speciﬁc issues exist in the care of patients after allogeneic hematopoietic SCT (HSCT). Female genital chronic GVHD (cGVHD) has been markedly underreported in the past but has a signiﬁcant impact on the patients’ health and quality of life. Data on prevention and treatment of this complication are still limited. Here we present a comprehensive review summarizing the current knowledge, which was discussed during several meetings of the German, Austrian and Swiss Consensus Project on clinical practice in cGVHD. In this report, we provide recommendations for post-transplant gynecological care of cGVHD manifestations agreed upon by all participants. This includes guidelines for diagnosis, prevention, and therapeutic options and topical treatments in female patients with genital cGVHD and hormonal replacement treatment of premature ovarian failure for adult and pediatric patients and underlines the necessity for regular gynecological care and screening programs for women after HSCT.

Bone Marrow Transplantation (2015) 50, 3–9; doi:10.1038/bmt.2014.242; published online 27 October 2014

INTRODUCTION practical guidelines for the use of supportive treatment 4,5 Complications after allogeneic hematopoietic SCT (HSCT) are modalities (summarized in Table 1). mainly due to adverse effects of cytotoxic treatment, acute and The evaluation of evidence and the subsequent recommenda- fi chronic GVHD (cGVHD), drug adverse effects or long-lasting tions were classi ed according to the rating system for ancillary immunodeficiency leading to prolonged susceptibility for therapy and supportive care published by Couriel in 2008 (ref. 27; opportunistic infections.1 To prevent permanent dysfunctions Table 2). On the basis of the National Institutes of Health (NIH) long-term follow-up programs for post-transplant patients have Consensus recommendations for clinical research in cGVHD, the focus of this report was to provide updated and more detailed been developed which address age- and gender-specific guidelines for the prevention and treatment of gender-specific characteristics.2 Despite many similarities, there are differences problems associated with cGVHD in female patients in daily in clinical symptoms, prophylaxis and treatment of post-transplant clinical routine. Strength of recommendation and evidence levels complications between female and male patients. For example, (Table 3) were based on a PubMed-based literature search with hypogonadism due to premature gonadal failure is highly subsequent rating by an expert panel approval of the recom- prevalent after intensive chemotherapy and TBI for conditioning mendations by all participants of the consensus process. Only in men and women. However, in women gonadal dysfunction is English literature was considered. Abstracts from the Bone Marrow more pronounced and occurs more often and earlier after HSCT, Transplantation Tandem meetings, the European Bone Marrow 3 and the recovery of gonadal function is less likely. This report Transplantation meetings and the American Society of Hematol- focuses on some post-transplant issues, which are important ogy meetings were cited but not included in the evidence rating. to consider in female patients after allogeneic HSCT Reference lists from the articles retrieved were also evaluated for including cGVHD. relevant information. Data on this consensus process have been presented at the German, Austrian and Swiss Consensus Conference on clinical practice in cGVHD held in Regensburg in 2009 and have been INCIDENCE AND RISK FACTORS FOR FEMALE GENITAL CGVHD updated in a workshop held in Wiesbaden 2013. Updates were The first report on female genital involvement of cGVHD discussed during the cGvHD consortia meetings in 2011 and 2013. was published in 1982.28 It took another 20 years until The consensus summarizes the currently available evidence for this problem became more widely recognized and discussed in first-line, second-line and topical therapies in cGVHD and provides the literature.29,30 Women rarely report genital symptoms to

1Women’s Hospital, Cantonal Hospital Baselland, Bruderholz, Switzerland; 2Department of Dermatology, University Hospital Basel, Basel, Switzerland; 3Department of Hematology and Oncology, Albert Ludwigs-University Medical Center, Freiburg, Germany; 4Department of Internal Medicine I, Medical University of Vienna, Vienna, Austria; 5St Anna Children’s Hospital, Medical University of Vienna, Vienna, Austria; 6University Children’s Hospital Tuebingen, Tuebingen, Germany; 7Department of Medicine III, University of Regensburg, Regensburg, Germany; 8Department of Hematology, University Hospital Basel, Basel, Switzerland; 9Department of General Gynecology and Gynecological Oncology, Medical University of Vienna, Vienna, Austria; 10Clinic for Gynecological Endocrinology and Reproductive Medicine, University Hospital Basel, Basel, Switzerland and 11Fertisuisse, Center for Reproductive Medicine, Olten, Switzerland. Correspondence: Dr B Frey Tirri, Women’s Hospital, Cantonal Hospital Baselland, CH-4101 Bruderholz, Switzerland or Dr R Moffat, Clinic for Gynecological Endocrinology and Reproductive Medicine, University Hospital Basel, CH-4031 Basel, Switzerland. E-mail: [email protected] or [email protected] Received 30 December 2013; revised 5 September 2014; accepted 17 September 2014; published online 27 October 2014 Clinical guidelines for gynecologic care after HSCT B Frey Tirri et al 4

Table 1. Summary of recommendations

Recommendation Strength

Clinical assessment Asymptomatic women should be offered a gynecological examination once a year6 BIIa Symptomatic women should be referred to a gynecologist with experience in GVHD6 BIIIa Pediatric patients: clinical assessment should be performed by an experienced pediatric gynecologist and includes Tanner staging, AIIIb inspection of external genitalia and reevaluation every 3–6 months7

Treatment Use of water only for genital hygiene is recommended. Perfumed lotions and soaps and tight underwear and clothes should be AIIIb avoided8 In case of genital atrophy, use topical estrogen in the form of creams, capsules or estrogen-releasing rings even if the patient is using BIb HT9 In case of genital cGVHD, achieve rapid control of inﬂammation with topical class IV corticosteroids10–12 BIb Topical calcineurin inhibitors may be suitable for long-term treatment to reduce and replace topical corticosteroids. However, recent CIb meta-analyses did not detect efﬁcacy in patients with lichen planus13 and lichen sclerosus12 Regular intercourse, use of dilatators and surgery can improve vaginal narrowing14 CIIIa

Secondary malignancies of the female genital tract Regular gynecological examination including cervical cytology should be performed once a year15,16 BIIa If treatment of suspected genital cGVHD is not successful in a timely manner (6–8 weeks), biopsy of the lesion should be performed to AIIa avoid incorrect diagnosis, erroneous treatment and exclude malignancies15,17 Biopsy is recommended for all genital lesions suspicious for dysplasia or malignancy15 BIIa HPV vaccination may be offered to young women (12–26 years) after transplantation18 BIIIa

Premature ovarian failure Women with POF under the age of 40 years should be offered systemic HT irrespective of symptoms if risk factors are inexistent19–21 BIIb until the median age of natural menopause at 51 years The risk for breast cancer after allogeneic HSCT is substantially increased after TBI or local chest radiotherapy.22,23 Early mammographic AIa screening starting at the age of 25 years or 8 years after radiation of the chest or TBI24–26 is therefore recommended Abbreviations: cGVHD = chronic GVHD; HT = hormone therapy; POF = premature ovarian failure.

Table 2. Strength of recommendation

Category Deﬁnition

A Should always be offered B Should generally be offered C Evidence for efficacy is insufficient to support for or against, or evidence might not outweigh adverse consequences or cost of the approach. Optional D Moderate evidence for lack of efficacy or for adverse outcome supports a recommendation against use. Should generally not be offered E Good evidence for lack of efficacy or for adverse outcome supports a recommendation against use. Should never be offered

Table 3. Quality of evidence supporting the recommendation

Quality of evidence Deﬁnition of evidence level

I Evidence from one or more properly randomized, controlled trial(s) II Evidence from one or more well-designed clinical trial(s) without randomization, from cohort or case-controlled analytic studies (preferable from 41 center), or from multiple time series or dramatic results from uncontrolled experiments III Evidence from opinions of respected authorities on the basis of clinical experience, descriptive studies or reports from expert committees

Qualiﬁer for categories I–III a Evidence derived directly from study(s) in GVHD b Evidence derived indirectly from study(s) in analogous or other pertinent disease

their health care providers and rather neglect genital Currently, the actual incidence of female genital cGVHD is symptoms or sexual problems in the early course of unknown. Initially it was estimated to be as low as 3% in BM the disease leading to a signiﬁcant risk of underdiagnosis recipients. However, recent publications mention incidence rates of genital cGVHD. On the other hand, health care providers of up to 49% in a mixed population of BM and PBSC recipients.31 might not speciﬁcally ask for genital symptoms. However, female Systematic gynecological care detecting also milder forms, more genital cGVHD may lead to complications associated with pain, frequent use of PBSC and better supportive care strategies for scarring and impairment of sexual life and therefore needs other post-transplant complications may explain the increase in attention. frequency of cGVHD overall32 including female genital cGVHD.

Bone Marrow Transplantation (2015) 3 – 9 © 2015 Macmillan Publishers Limited Clinical guidelines for gynecologic care after HSCT B Frey Tirri et al 5 Median time from HSCT to initial presentation of female genital genital cGVHD is challenging. Second, reporting symptoms of cGVHD is between 7 to 10 months,29 but late onset more than 1 dyspareunia and discomfort with gynecologic exam are subjec- year after HSCT is not uncommon.10,31 Indeed, the exact time of tive. Affected women usually have difficulties classifying the onset often is unclear and both, patients and physicians, especially extent of pain perceived. Third, sexually inactive women may not in sexually inactive patients, can delay detection of gynecological report symptoms like dyspareunia but might have severe signs of signs and symptoms. female genital cGVHD. Isolated female genital cGVHD is rare but does occur.6,17 In 68% cases cGVHD affects the vulva, whereas in 26%, both vulva and vagina are involved.11 Vulvar cGVHD usually precedes HISTOPATHOLOGY AND DIAGNOSIS vaginal cGVHD. In our experience, topical treatment of Histological findings of female genital cGVHD are consistent with vulvar cGVHD does not prevent the development of vaginal mucosal and skin manifestations in classic cGVHD,17,30,35 with manifestations. Often female genital cGVHD is associated with signs of chronic and acute inflammation within the subepithelial cGVHD manifestations in other organs, especially skin and other stroma and epithelium, that is, vacuolar degeneration of the basal mucosal surfaces such as mouth, eyes and gastrointestinal tract, layer, apoptotic keratinocytes and superficial perivascular lym- and may appear even a long time after the initial manifestation of phohistiocytic infiltrates. 27 cGVHD. This sequence of events underlines the need for regular According to NIH recommendations,36 biopsy is not required for gynecological care. Therefore, we recommend a gynecological diagnosis if lichen planus-like features or vaginal scarring or 6 examination once a year in asymptomatic women (BIIa). stenosis (diagnostic signs) are present. In case of vaginal erosions, Symptomatic women should be referred to a gynecologist with fissures and ulcers (distinctive signs) biopsy may be required for experience in GVHD6 (BIIIa). The risk for female genital cGVHD fi 33 diagnosing cGVHD, if cGVHD has not been con rmed at another seems to be higher after HSCT with PBSC compared with BM. organ manifestation. Shulman et al.17 recommend biopsy in Type of conditioning, donor, parity, age, GVHD prophylaxis or suspected cGVHD to avoid incorrect diagnosis and erroneous vaginal infection at the time of HSCT do not appear to have an 29,31 treatment, but acknowledges that histopathologic examination impact on incidence of genital cGVHD. However, genital has limitations. atrophy due to estrogen deficiency seems to be a confounding 29 We prefer a trial of treatment after exclusion of infection, drug or factor for female genital cGVHD. allergic reactions and dysplasia in cases with distinctive signs (corresponding to moderate genital cGVHD in Stratton’sscoring).If SYMPTOMS AND CLINICAL PRESENTATION OF GENITAL the treatment is not successful in a timely manner (6–8 weeks), we 15 CGVHD perform a biopsy of the lesions to exclude malignancies (AIIa). Pain or burning, dysuria, a feeling of redness and swelling, perineal and perianal soreness, dryness and dyspareunia despite DIFFERENTIAL DIAGNOSES adequate systemic and/or topical hormone therapy (HT) are Genital infections produce signs of inflammation such as redness nonspecific symptoms of female genital cGVHD. Patients, who are and soreness as in mild cGVHD but typically cause vaginal sexually active, may recognize symptoms earlier. Female genital discharge and alter vaginal pH. Leukocytes, clue cells or yeast can cGVHD causing complete vaginal obstruction resulting in hema- be identified by microscopy in wet mounts of vaginal fluid tocolpos or hematometra can manifest as cyclic pain and 34,35 samples and cultures should be obtained to identify the amenorrhea in women taking HT or as difficulty while voiding in case of vulvar adhesions. pathogen. HSV and VZV infection typically cause vesicular and In 2005, NIH recommendations for diagnosing and staging of ulcerative lesions of the external genitalia. Viral culture and female genital cGVHD were published.36 According to these, molecular assays are validated methods for direct diagnosis of lichen planus-like features and vaginal scarring or stenosis are HSV and other viral infections. Allergic reactions to topical diagnostic signs of genital cGVHD that do not require biopsy. remedies and sanitary products and eczema can cause vulvar Erosions, fissures and ulcers are distinctive signs requiring erythema resembling cGVHD. Early stages of genital lichen exclusion of infection, drug effects, malignancy or other causes. sclerosus often cause erythema and edema that usually begin The NIH recommendations include a score (Table 4) on the basis of severity of symptoms and clinical signs, ranging from score 0 for asymptomatic women to score 3 for women with severe Table 5. Severity scoring for female genital cGVHD disease according symptoms. to Stratton10 The score published by Stratton10 (Table 5) grades female genital cGVHD on the basis of clinical signs but not symptoms. Severity score Findings on clinical examination One of the limitations of the NIH recommendations is that genital atrophy caused by premature ovarian failure (POF) is a common Grade I (minimal) Generalized erythema and edema of vulvar finding and distinguishing atrophic vaginitis from mild female structures Patchy erythema of mucosa and glandular structures of vulvar vestibule Erythema around openings of vestibular Table 4. Scoring for female genital chronic GVHD (cGVHD) according (Bartholin’s and Skene’s) glands to NIH recommendations for diagnosis and staging of female genital Grade II Grade I findings plus cGVHD36 (moderate) Erosions of mucosal surfaces of the vulva Score 0 No symptoms Fissures in vulvar folds (that is, interlabial Score 1 Symptomatic with mild signs on exam and no effect on sulci; fourchette) coitus and minimal discomfort with gynecologic exam Grade III (severe) Grade II findings plus Score 2 Symptomatic with moderate signs on exam and with mild Agglutination of clitoral hood dysparunia or discomfort with gynecologic exam Introital stenosis Score 3 Symptomatic with advanced signs (stricture, labial Vaginal synechiae agglutination or severe ulceration) and severe pain with Hematocolpos or complete vaginal closure coitus or inability to insert vaginal speculum Fasciitis or spasticity of levator sling

© 2015 Macmillan Publishers Limited Bone Marrow Transplantation (2015) 3 – 9 Clinical guidelines for gynecologic care after HSCT B Frey Tirri et al 6 around the periclitoral hood accompanied by the typical SECONDARY MALIGNANCIES OF THE FEMALE GENITAL TRACT porcelain-white lesions that are easily distinguishable from genital AFTER HSCT 37 cGVHD. Genital lichen simplex chronicus is considered an atopic Secondary solid tumors are a well-known severe post-transplant disorder caused by excessive scratching leading to lichenification complication.24,41 Prolonged use of immunosuppressive drugs to of the vulva. The skin is leathery and thickened. Fissures can occur treat cGVHD and severity of cGVHD are major risk factors for the 38 in severe cases. Intraepithelial dysplasia and squamous cell development of human papillomavirus (HPV)-related dysplasia15 carcinoma, which is by far the most common cancer of the female and squamous cell carcinoma of the female genital tract.42 genital tract, can be detected by visual inspection after application We recommend performing regular gynecological examination of acetic acid.39 Paget’s disease, melanoma and basal cell including cervical cytology once a year15,16 (BIIa). In the case of carcinoma are rare malignancies of the female genital tract. suspicious genital lesions, colposcopy and biopsy are recom- Biopsy is recommended for all lesions suspicious for dysplasia or mended (BIIa).15 Given the relevance of HPV infection in the malignancy. pathogenesis of cervical cancer, HPV vaccination may be offered Burning, dryness, tenderness and pruritus are common to young women after transplantation43,44 (BIIIa).The Advisory symptoms of both genital cGVHD and genital atrophy due to Committee on Immunization Practices recommends HPV vaccina- estrogen deficiency. In both, sexual activity is often compromised tion for immunocompromised persons aged 12–26 years if they and physical examination may be painful. Typical signs of mild have not already received any or all vaccine doses.18 However, cGVHD are generalized patchy erythema, edema of vulvar efficacy data are not yet available. structures and reticulated leukoplakia. In contrast to cGVHD, atrophic epithelium is shiny, pale and frail and tends to bleed on contact. The vaginal pH is alkaline. Clinical signs of atrophic POF, SEXUAL DYSFUNCTION AND FERTILITY ISSUES vaginitis are very similar to those of mild cGVHD.8 Atrophy often After allogeneic HSCT many women suffer from POF depending accompanies genital cGVHD but in contrast to cGVHD, local on conditioning regimen, pretransplant chemotherapy, the age at estrogen treatment alone is effective in these patients. HSCT and post-transplant complications.45,46 Only a minority (o5%) of these patients recover ovarian function after HSCT for a limited period of time before entering early menopause.47,48 TREATMENT Toxicity-reduced conditioning regimens applied in younger Treatment of female genital cGvHD is based on the following patients may reduce the incidence of POF but systematic review principles: is currently pending.49 (1) Reduce mechanical or chemical irritation of the genital skin POF is associated with symptoms of estrogen deficiency, such by using only warm water for genital hygiene. Avoid perfumed as hot flushes, night sweats, mood disorders, sleep disorders, lack lotions, soaps and tight underwear and clothes8 (AIIIb). of concentration, arthralgia, impaired sexual function50 and loss of (2) Use topical estrogen in form of creams, capsules or estrogen- reproductive potential, all of which negatively impact quality of releasing rings even if the patient is using systemic HT9 (BIb). life.51,52 Lack of estrogen at an early age prevents the develop- Topical estrogen treatment increases epithelial thickness and ment of secondary sex characteristics, increases the risk for makes the vaginal epithelium more resilient. osteoporosis,53 cognitive impairment54 and cardiovascular (3) Achieve control of GvHD-related inflammation with topical disease55–58 that are frequently observed in women after class IV corticosteroids (BIb). We suggest the use of clobetasol HSCT.59,60 However, attributing these diseases to POF is difficult propionate (Dermovate) ointment once daily at bedtime for because their occurrence are influenced by other factors, such as 4 weeks as first-line therapy in newly diagnosed cGVHD and in the use of steroids, calcineurin inhibitors, selective serotonin case of flare-ups. receptor inhibitors and proton pump inhibitors, hyperlipidemia or (4) Topical calcineurin inhibitors, such as tacrolimus (Protopic) vitamin D deficiency. Estrogen replacement significantly alleviates and pimecrolimus (Elidel) may be suitable for long-term treatment postmenopausal vasomotor symptoms,61 improves vaginal muco- – to reduce and replace topical corticosteroids10 12 (CIb). However, sal architecture9 and bone density,62 thus increasing quality of life. recent meta-analyses did not detect efficacy in patients with Women with POF under the age of 40 years should be offered lichen planus13 and lichen sclerosus.12 systemic HT irrespective of symptoms until the median age of (5) Regular intercourse or use of dilators can prevent vaginal natural menopause at 51 years provided there are no contra- narrowing and stenosis14 (CIIIa). Prevention of vaginal stenosis is indications, such as history of breast or endometrial cancer, important to facilitate cervical cytology screening. On the basis of thromboembolic disorders, cardiovascular disease, porphyria or our experience, it is better to avoid intercourse, dilation or surgical severe liver disease (BIIb).19–21 Symptomatic women older than 40 lysis of synechiae when inflammation is acute because this may years may benefit from HT as well. HT has been viewed negatively result in aggravation of inflammation. Patients hardly tolerate after publication of the results of the women’s health initiative.63 vaginal examination and dilation in this situation. Successful However, the results of the women’s health initiative may not be control of inflammation results in significant reduction of pain, representative for young women with POF after high-dose redness and swelling, thus enabling gentle intercourse or use of chemotherapy. Benefits and risks of HT should be discussed dilators. Persistent vaginal synechiae in spite of intercourse or use individually with each patient preferably by a gynecological of dilators are easily separated manually under anesthesia, incision endocrinologist to prevent complications. is rarely necessary.40 However, recurrence of synechiae is The risk for breast cancer after allogeneic HSCT is substantially common, especially after surgery. Therefore, we encourage increased after TBI or local chest radiotherapy.22,23 Therefore, early patients to perform digital self-examinations several times a week. mammography screening starting at the age of 25 years or 8 years Regular intercourse, the use of dilators or estrogen-releasing rings after radiation of the chest or TBI16,25,26 (AIa) is recommended. (not available in all countries) can prevent recurrence as well. In In the absence of guidelines on the basis of randomized trials our experience the patients appreciate if either their gynecologist for women with chemotherapy-induced POF, transdermal (50 μg provides the dilator set or if they can order it anonymously by estradiol/24 h) or oral estrogen (2 mg estradiol) can be given. If the internet. However, some patients might be reluctant to perform uterus is present, cyclic or continuous progesterone (for example, self-examinations or dilation. 170 μg norethisterone acetate/24 h by transdermal route or (6) Photodocumentation is an easy and painless way of 0.5 mg norethisterone acetate per day by oral route) should be monitoring response to treatment. added. Alternatively, low-dose combined oral contraceptives may

Bone Marrow Transplantation (2015) 3 – 9 © 2015 Macmillan Publishers Limited Clinical guidelines for gynecologic care after HSCT B Frey Tirri et al 7 be used for HT. To avoid menopausal symptoms during the 7-day Table 6. HT in pediatric patients for the induction of menarche hormone-free break, combined oral contraceptives can be given continuously. Time from onset Drug Dose Women suffering from diminished libido, presumably due to estrogen and androgen deficiency, might benefit from testoster- Month 1–6 Estradiol valerate 0.25 mg/day oral one therapy. Low-dose transdermal testosterone (300 μg/day) Month 7–12 Estradiol valerate 0.50 mg/day oral added to an estrogen/progesterone hormone therapy has been Month 13–18 Estradiol valerate 1.00 mg/day oral shown to improve hypoactive sexual desire disorder in surgically Month 19–24 Estradiol valerate 1.50 mg/day oral, menopausal women.64 Reliable data on long-term safety and cyclic 3 weeks 1 week discontinued fi After month 25 Combined therapy ef cacy of treatments improving sexual dysfunction in women with Estradiol valerate/Dihydrogesteron with chemotherapy-induced POF are lacking. Selective estrogen receptor modulators (for example, tamoxifen, raloxifene) prevent- ing bone loss may be an option in women with POF after urinating, frequently changing the diapers and avoiding transplantation who prefer not to take estrogens or who have a constipation.76,77 high risk for breast cancer.65 Notably, selective estrogen receptor In 70 percent of cases hypogonadism is a consequence of stem modulators can aggravate genital atrophy and vasomotor cell therapy in girls. This is predominantly due to damaged symptoms.66 There are no data to support the efficacy of ovaries, resulting in primary hypergonadotropic hypogonadism. In 67 68 phytoestrogens and black cohosh to relieve menopausal some cases, central hypogonadotrophic hypogonadism can result symptoms. Therefore, this treatment cannot be recommended from cranial radiation. Therefore a high percentage of girls will as an alternative for HT. Selective serotonin receptor inhibitors benefit from HT. Starting at age 8 pubertal status, growth and alleviate vasomotor symptoms and improve sleep disorders and 69 serum levels of luteinizing hormone, follicule stimulating hormone can be used instead of HT. and estradiol of the girl should be evaluated every 6 months. Fertility is clearly impaired after HSCT and the reported overall Estrogen therapy for induction of puberty, maximizing growth and conception rate is o1%.70 Some women achieve pregnancy and development of secondary sex characteristics should begin no live birth even after high-dose chemotherapy and TBI and pregnancies are likely to have successful outcomes.71 In fact, later than age 15 and not before age 12 (refs 7,78; AIIIb). In pregnancies have been reported despite the presence of cGVHD, pubertal girls, the starting dose of HT depends on the volume of indicating that cGVHD and its therapy does not always impair the uterus and the Tanner stage. A possible treatment scheme is fertility.70,71 Nonetheless, data on spontaneous and assisted shown in Table 6. After the end of puberty, a short discontinuation conception are scarce. Women and girls facing HSCT should have of HT is encouraged to monitor if ovarian function has recovered. fertility preservation counseling.72 Once contraception is needed or desired, oral contraceptives can be given instead of HT. PEDIATRIC ASPECTS CONCLUSIONS Lesions of genital cGVHD in children and adolescents may be similar to those of adults but systematic reviews of incidence, risk Female genital cGVHD, secondary genital malignancies, POF and factors, treatment and outcome of genital cGVHD in children and loss of fertility are frequent complications after HSCT. Genital adolescents are lacking. Underdiagnosis may be higher because symptoms are rarely reported spontaneously by patients. There- symptoms like genital irritation, dryness and pain are rarely fore health care workers should ask patients for symptoms. Local mentioned by children. Young girls after HSCT are particularly corticosteroids are the mainstay of treatment of genital cGVHD. vulnerable to vulvar or vaginal irritation and infection because of Careful surgical interventions may become necessary to improve poor local immune system and thin genital epithelium due to the severe forms of genital cGVHD. Women with genital cGVHD are at lack of estrogen. Frequent contact with irritants (bubble bath, wet an increased risk of developing squamous cell carcinoma and fi wipes and soaps), the fact that the vaginal ori ce is less well need regular pap smears and meticulous examinations of protected by the labia,73 its proximity to the anus and poor suspicious genital lesions by experts. Almost all women will hygiene add to the risk of vulvovaginitis. Microbiological and viral experience POF and infertility after HSCT. Estrogen/progesterone findings may be A/B beta hemolytic Streptococcus, Staphylococcus fl replacement should be considered for women younger than 40 aureus, Haemophilus in uenzae, Escherichia coli, Enteroccus faecalis, fi Yersinia and Shigella and Pseudomonas aeruginosa, Chlamydia, years. Women between 40 and 50 years might bene t from HT Gardnerella, Mycoplasma hominis and Ureaplasma, Candida depending on their individual risk for breast cancer and vascular albicans (often) and glabrata, BK Virus, HSV 1/2, HPV, VZV, complications. Women and girls facing HSCT should be offered Pinworms (Enterobius vermicularis).74,75 fertility preservation counseling. More prospective studies are Clinical assessment should be performed by an experienced needed to improve our knowledge on genital cGVHD and POF. pediatric gynecologist/endocrinologist and includes Tanner staging, inspection of external genitalia and reevaluation every 3–6 CONFLICT OF INTEREST months7 (AIIIb). Appropriate patient history should include genital hygiene practices and previous treatments. Vaginal swabs for The authors declare no conflict of interest. cultures and virus isolation should be taken from the lower vagina. Genital cGvHD lesions may be similar to those of adults. Late REFERENCES onset of symptoms such as vaginal obstruction causing hematocolpos at the time of menarche illustrates the importance of long- 1 Khera N, Storer B, Flowers ME, Carpenter PA, Inamoto Y, Sandmaier BM et al. Nonmalignant late effects and compromised functional status in survivors of term follow-up. 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