Abstract
Study Objective:
To assess genital symptomatology, characterize findings of genital examination, and describe the incidence and treatment of vulvovaginal graft-versus-host disease (vvGvHD) in girls and adolescents after allogeneic Hematopoietic Stem Cell Transplantation (HSCT).
Design:
Retrospective cohort.
Setting:
Metropolitan area Children’s Hospital.
Participants:
Female allogeneic HSCT recipients ages 0 to 22 years.
Main Outcome Measures:
Genital symptoms, genital examination, diagnosis, and treatment of vvGvHD.
Results:
A total of 57 participants were included in the analysis. The median age at the time of HSCT was 10.0 years (range 4 months to 23 years). The majority (n= 40, 71%) underwent transplant for a non-malignant condition, most commonly sickle cell anemia (n = 19, 33%). The median time of onset of GvHD post HSCT was 62 days (IQR 42 to 151 days). The most common initial site of GvHD was skin (n= 21, 64%), followed by GI tract (n= 10, 30%). Three patients (5%) were diagnosed with vvGvHD. The time of onset of vvGvHD post HSCT ranged from 62 to 1565 days. One patient (33%) was asymptomatic at the time of diagnosis. There was no difference in diagnosis of vvGvHD when comparing race (p = 0.15), age at allogeneic HSCT (p = 0.64), non-malignant vs. malignant indication (p = 0.21), source of stem cells (p = 0.25), partial vs full HLA donor match (p = 0.34), and GvHD prophylaxis regimen (p = 0.18). None had isolated vvGvHD. vvGvHD was preceded by skin GvHD in 1 patient, by lung GvHD in 1 patient, and occurred concurrently with skin GvHD in the third patient.
Conclusions:
Pediatric vvGvHD can occur within the first 100 days post-transplant and can be asymptomatic. Routine gynecologic evaluation post allogeneic HSCT in children and adolescents should include a thorough review of vulvovaginal symptoms and a gynecologic exam for the detection and treatment of vvGvHD.
Keywords: Graft-versus-host disease, hematopoietic stem cell transplantation, vulvar disease
Introduction
Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) is indicated for the treatment of malignant and non-malignant diseases in both children and adults. Complications after allogeneic HSCT are mainly a result of disease relapse, infection, and graft-versus-host disease (GvHD). GvHD occurs in 30 to 65% of adult allogeneic HSCT recipients and is the leading cause of late non-relapse mortality 1,2. Various risk factors for GvHD have been identified including HLA mismatch, female donor to male recipient, unrelated donor, and transplants using peripheral blood stem cells (PBSC) 3. Common sites of GvHD are mucosal tissue in the mouth, conjunctiva and female genitalia 4. The diagnosis of vulvovaginal GvHD (vvGvHD) is based on symptoms and gynecologic exam findings. Histologic informationcan be obtained in the absence of diagnostic manifestations or expected response to treatment 5. Vulvovaginal GvHD in adults is well characterized in the existing literature and occurs in upwards of 66% of adult women 6. The onset of vvGvHD in adults is typically 6 to 13 months after HSCT 7-9. Symptoms of vvGvHD in adults include dysuria, dryness, burning, increased sensitivity and dyspareunia. 6-8,10-16. Various genitourinary exam findings of vvGvHD have been described including erythema on vulvar mucosal surfaces, vulvar fissures or ulcers, labial agglutination, clitoral phimosis, vaginal synechiae, vaginal shortening and complete vaginal stenosis 6-8,10-16. vvGvHD scoring systems in adults have been developed and aim to characterize the severity of disease. In 2003, Spinelli et al described a grading scale based primarily on genital exam findings 8. In 2007, Stratton et al published a modified version of the 2003 Spinelli et al scoring system to account for genital examination findings more specific to vvGvHD 8,17. This was further modified in the 2015 NIH consensus guidelines which are primarily based on signs because vulvovaginal symptoms are not specific to vvGvHD and may represent infection or primary ovarian failure 18. In these latest NIH scoring guidelines, severe genital GvHD can be diagnosed in the absence of symptoms (Table 1). Yearly gynecologic examination is recommended after HSCT for the early detection on genital involvement of GvHD in adult women 19. The treatment of vvGvHD in adults is aimed at reducing symptoms and maintaining vaginal patency. Anti-thymocyte globulin (ATG) prophylaxis is associated with decreased vvGvHD incidence 9. Topical steroids, vaginal rings (with and without hormone release), and vaginal dilators all are employed in the management of vvGvHD in adults 9,13,17.
Table 1.
Clinical score of genital graft-versus-host disease from the National Institutes of Health 2015 consensus criteria
| Score 0 | Score 1 | Score 2 | Score 3 |
|---|---|---|---|
| No signs | Mild signs and may have symptomsa WITH discomfort on
exam. Mild signs include any of the following: Erythema on vulvar mucosal surfaces, Vulvar lichen-planus, Vulvar lichen-sclerosis |
Moderate signs and may have symptoms with
discomfort on exam. Moderate signs include any of the following: Erosive inflammatory changes of the vulvar mucosa, Fissures in vulvar folds. |
Severe signs with OR WITHOUT
symptoms. Severe signs include any of the following: Labial fusion, Clitoral hood agglutination, Fibrinous vaginal adhesions, Circumferential fibrous vaginal banding, Vaginal shortening, synechia, dense sclerotic changes, Complete vaginal stenosis. |
Clinical scoring combines signs and symptoms into one of four categories (0-3).
Symptoms are not specific to GvHD and can represent premature ovarian failure or genital tract infection.
Adapted from Jagasia et al [16].
By comparison, vvGvHD in infants, children and adolescents has been relatively understudied, and, to date, there are only a few publications reporting vvGvHD exclusively in pediatric patients 20,21. In 2019, Cizek et al proposed a Pediatric Vulvar GvHD Grading Scale that may improve the classification of disease and response to treatment in pediatric vvGvHD (Table 2) 20. We seek to contribute to the paucity of data regarding pediatric vvGvHD by describing the incidence, clinical characteristics, and management of vvGvHD in a cohort of pediatric and young adults after allogeneic HSCT at our institution.
Table 2.
Pediatric Vulvar GvHD Grading Scale
| Grade | Signs |
|---|---|
| 1 | Erythema of vulvar structures with or without symptoms |
| 2 | Mild adhesive disease (thin adhesions); presence of scattered skin erosions/fissures |
| 3 | Moderate adhesive disease (thick/diffuse adhesions, distorting architecture); scattered skin erosions or fissures |
| 4 | Severe adhesive disease (partial or complete occlusion of the urethra and/or vaginal opening); diffuse skin erosions or fissures; loss of architecture of vulvar structures |
Clinical scoring combines signs and symptoms into one of four categories (1-4). Adapted from Cizek et al [20]
Materials and Methods
After institutional board review approval, we queried the clinical database of the Children’s National Hospital Blood and Bone Marrow Transplant multidisciplinary long term follow-up (LTFU) clinic for female allogeneic HSCT recipients ages 0 to 22 years who attended at least one yearly visit between 2015 and 2020. Each medical record was then reviewed to obtain demographic characteristics, diagnosis at indication for HSCT, stem cell source, conditioning regimen, GvHD prophylaxis, treatment of extragenital GvHD, and documented diagnosis and treatment of vvGVHD. As the signs and symptoms of vulvovaginal atrophy related to primary ovarian insufficiency (POI) can mimic those of vvGvHD, menarchal status, diagnosis of POI and the use of hormone replacement therapy (HRT) were also recorded. Additionally, data regarding genital symptoms, genital examination findings, treatment, and outcomes of vvGvHD were recorded. At our institution, as it was not standard practice to perform routine anogenital examination during post-transplant evaluations , only patients who reported genital symptoms were examined. The diagnosis of vvGVHD was made clinically based on symptoms and/or exam findings by medical oncologists, dermatologists or pediatric gynecologists at our institution or others from which patients transferred their care.
Statistical analysis was performed using SPSS version 22.0 (IBM Corp, Armonk, NY). Categorical variables were compared among groups using the Chi-Square test of Fishers’ exact test, as appropriate. Statistical significance was defined as P ≤ .05.
Results
Demographics and HSCT characteristics
A total of 57 female pediatric patients were actively attending the LTFU clinic at our institution during the study period. The demographic characteristics of the cohort are presented in Table 3. The median age at the time of HSCT was 10.0 years (range 4 months to 23 years). The majority (n= 46, 81%) were 15 years old and under at the time of transplant. The majority (n= 40, 71%) underwent transplant for a non-malignant condition, most commonly sickle cell anemia (n = 19, 33%). The majority (n = 49, 86%) received transplants from an HLA-matched source, either related (n = 25, 44%) or unrelated (n = 24, 42%), exclusive of 4 patients with missing information. Of those with a non-malignant condition, most received reduced-intensity conditioning regimens (n = 22, 55%).
Table 3.
Demographics and HSCT characteristics
| Demographics | Value |
|---|---|
| Age at HSCT, yr, median (IQR) | 10.0 (4.0 – 14.0) |
| Race, n (%) | |
| White (Non-Latina) | 11 (19%) |
| Black/African American | 20 (35 %) |
| Asian | 3 (5 %) |
| Other | 16 (28 %) |
| Unknown | 6 (11 %) |
| Indication for HSCT, n (%) | |
| Malignant Condition | 17 (30 %) |
| Acute myeloid leukemia | 10 (18%) |
| Acute lymphoblastic leukemia | 5 (9%) |
| Myelodysplastic syndrome | 2(4%) |
| Benign Diagnosis | 40 (70 %) |
| Sickle cell anemia | 19 (33%) |
| Severe aplastic anemia | 6 (11%) |
| Primary immunodeficiency disordera | 5 (9%) |
| Thalassemia | 3 (5%) |
| Inherited marrow failure syndromesb | 2 (4%) |
| Other nonmalignant disordersc | 5 (9%) |
| Type of transplant, n (%) | |
| Bone marrow | 38 (67%) |
| Peripheral blood stem cells | 7 (12%) |
| Umbilical Cord Blood | 6 (11%) |
| Bone marrow and umbilical cord blood | 2 (4%) |
| Source of transplant | |
| Matched related donord | 25 (44%) |
| Matched unrelated donore | 24 (42%) |
| Mismatched related donord | 0 (0%) |
| Mismatched unrelated donore | 4 (7%) |
Data are presented as n(%) unless otherwise indicated
Primary immunodeficiency disorder included chronic granulomatous disease, severe combined immune deficiency (SCID), leukocyte adhesion defect, dedicator of cytokinesis 8 (DOCK8), and GATA2, NFKB2 Haploinsufficiency, Mevalonic Kinase Deficiency.
Inherited marrow failure syndromes included Fanconi anemia, Diamond-Blackfan anemia, dyskeratosis congenital, severe congenital neutropenia, and Shwachman-Diamond syndrome.
Other nonmalignant disorders included Hurler syndrome, hemophagocytic lymphohistiocytosis/X-linked lymphoproliferative syndrome, Glanzmann’s thrombasthenia, cerebral adrenoleukodystrophy, osteopetrosis, and chronic active Epstein-Barr virus infection.
Includes the following degrees of HLA matching: 6/6, 8/8, 10/10
Includes the following degrees of HLA matching: 5/6, 7/8
GvHD
Of the 57 patients who underwent allogeneic HSCT, all but one patient (with missing information) received GvHD prophylaxis with 1 or more medications (Table 4). Most (n= 43, 75%) received a regimen including cyclosporine (CSA). More than half (n = 33, 58%) developed GvHD. Those with a malignant diagnosis were more likely to develop GvHD (82% vs. 48%, p= .02). Those who received a reduced-intensity conditioning regimen were less likely to be diagnosed with GvHD (41% vs. 59%, p = 0.48). The median time of onset of GvHD post HSCT was 62 days (IQR 42 to 151 days). The most common initial site of GvHD was skin (n= 21, 64%), followed by GI tract (n= 10, 30%).
Table 4.
GvHD prophylaxis regimens
| Medication(s) | n (%) |
|---|---|
| Unknown | 1 (2%) |
| Sirolimus (SIR) | 7 (13%) |
| Cyclosporine (CSA) | 6 (11%) |
| TAC/MMF | 1 (2%) |
| TAC/MTX | 3 (5%) |
| CSA/MTX | 21 (37%) |
| CSA/MMF | 6 (11%) |
| CSA/MTX/TAC | 2 (4%) |
| CSA/MTX/MMF | 1 (2%) |
| CSA/MTX/methylprednisolone (MP) | 3(5%) |
| CSA/MTX/ATG | 2 (4%) |
| CSA/MTX/abatacept | 2 (4%) |
| TAC/MTX/MP | 1 (2%) |
| SIR/MTX/MMF | 1 (2%) |
ATG, anti-thymocyte globulin
CSA, cyclosporine
MMF, mycophenolate mofetil
MP, methylprednisolone
MTX, methotrexate
SIR, sirolimus
TAC, tracrolimus
Three patients (5%) in our cohort were diagnosed with vvGvHD (Table 5). There was no difference in diagnosis of vvGvHD when comparing race (p = 0.15), age at allogeneic HSCT (p = 0.64), non-malignant vs. malignant indication (p = 0.21), source of stem cells (p = 0.25), partial vs full HLA donor match (p = 0.34), and GvHD prophylaxis regimen (p = 0.18). None had diagnosed isolated vvGvHD. vvGvHD was preceded by skin GvHD in 1 patient, by lung GvHD in 1 patient, and occurred concurrently with skin GvHD in the third patient. Although the patients who received anti-thymocyte globulin prophylaxis did not develop vvGvHD, the difference was not statistically significant (p= .18). The time of onset of vvGvHD post HSCT ranged from 62 to 1565 days. For one patient, although her records indicated that the primary site of GvHD was lung, the exact date of diagnosis of vvGvHD could not be determined due to missing data. Although no standard method of vvGvHD classification was documented, both the NIH Genital GvHD Score and Pediatric Vulvar GvHD Grading Scale were used to classify disease severity in the 2 patients whose symptoms and signs were available in their medical records (Table 5). One patient with no genital symptoms was found to have vaginal introital erythema and both mild interlabial and clitoral adhesions on exam, consistent with NIH genital GvHD score of 3 and a Pediatric Vulvar GvHD Grading Scale of 2. Treatment initially with betamethasone dipropionate cream 0.05% followed by Protopic ointment 0.1% (after she developed telangiectasias and thinning of her perianal skin consistent with steroid atrophy) resulted in resolution of vaginal introital erythema but not adhesions. The other patient presented with dysuria and had labial erythema on exam consistent NIH genital GvHD score of 1 and a Pediatric Vulvar GvHD Grading Scale of 1. Due to a concurrent flare of skin GvHD, she was treated with a 5-day course of oral prednisone which resulted in the resolution of labial erythema. All three patents were diagnosed with vvGvHD prior to the onset of puberty and subsequently developed POI. Two were treated with systemic hormone replacement therapy (HRT). The third was 10 years old at the time of her last endocrinology assessment when plans to begin HRT at approximately age 12 years were discussed.
Table 5.
Characteristics of patients with vvGvHD*
| Patient 1 | Patient 2 | Patient 3 | |
|---|---|---|---|
| Indication Diagnosis | Infantile osteopetrosis | AML | AML |
| Age at HSCT (years) | 1.4 | 12 | 4 |
| Stem cell source | BM (MUD) | PB (MUD) | UC (MUD) |
| Primary GvHD site(s) | Lungs | Skin/Vulva | Skin |
| Onset of nongenital GvHD post HSCT (days) | 1553 | 62 | 41 |
| Age at vvGvHD diagnosis (years) | unknown** | 12 | 8 |
| Onset of vvGVHD post HSCT (days) | unknown** | 62 | 1565 |
| Genital symptoms | unknown** | None (diagnosed prior to transfer to our institution) | dysuria |
| Genital examination | unknown** | erythematous vaginal introitus, mild adhesions between labia majora and clitoral hood. | Labial erythema |
| NIH genital GvHD score | unknown** | 3 | 1 |
| Pediatric vulvar GvHD scale | unknown** | 2 | 1 |
| Non-genital GvHD treatment | Sirolimus | Sirolimus | Sirolimus, prednisone for 5 days for skin GvHD flare |
| Topical vvGvHD treatment | Premarin cream | Betamethasone dipropionate cream 0.05%, Protopic ointment 0.1% | None |
| Result of topical treatment of vvGvHD | unknown** | Yes. Resolution of introital erythema. Labial adhesions persist. | Yes. Resolution of labial erythema. |
| Developed POI | Yes | Yes | Yes |
| Hormone replacement therapy | Transdermal estradiol for pubertal
induction. Transdermal estradiol 0.1 mg + medroxyprogesterone acetate 10 mg for 10 days each month. |
Transdermal estradiol for pubertal
induction. Transferred care thereafter due to medical insurance carrier. |
Has not yet started pubertal induction (was 10 years old at time of last endocrinology evaluation) |
All were prepubertal at the time of allogeneic HSCT and diagnosis of vvGvHD
Diagnosed prior to transferring care to our facility. Records not available for detailed review.
BM, bone marrow
PB, peripheral blood
UC, umbilical cord
MUD, matched unrelated donor
Genital Symptomatology and Exam Findings
In 12 (21%) of patients in our cohort, there was no documentation of genitourinary (GU) review of symptoms and a GU exam was not performed. Of the remaining 45, 11 with labial or mucosal erythema and 1 with fissures were not given a diagnosis of vvGvHD. Although more patients who were not diagnosed with vvGvHD had genital symptoms, the difference between those with a vvGvHD diagnosis was not significant (Table 6). There were 11 patients with labial or mucosa erythema and 1 with fissures who were not diagnosed with vvGvHD but were given a variety of diagnoses including diaper rash, non-specific vulvovaginitis, "possible fungal disease" and hypoestrogenism due to POI. Six were not given any diagnosis.There was a significant association between the presence of labial and clitoral adhesions and the diagnosis of vvGVHD (p=0.05
Table 6.
Genitourinary symptomatology and exam findings
| Symptom/Exam Finding (n=number of patients assessed) |
vvGvHD Diagnosed n (%) |
vvGvHD Not Diagnosed n (%) |
p |
|---|---|---|---|
| Dysuria (n =37) | 1 (33%) | 15 (36%) | 0.52 |
| Burning (n=14) | 0 | 4 (10%) | 0.22 |
| Dryness (n= 6) | 0 | 1(2%) | 0.41 |
| Sensitivity to touch (n=16) | 0 | 1 (2%) | 1.0 |
| Itching (n=24) | 0 | 6 (14%) | 0.35 |
| Dyspareunia (n=4) | 0 | 1 (2%) | 1.0 |
| Vaginal discharge (n=33) | 0 | 5 (12%) | 1.0 |
| Erythema labia majora (n=25) | 2 (67%) | 7 (17%) | 0.14 |
| Erythema mucosa (n=20) | 1 (33%) | 4 (10%) | 0.34 |
| Hypopigmentation (n=16) | 0 | 1 (2%) | 0.31 |
| Fissures (n=29) | 0 | 1 (2%) | 0.33 |
| Petechiae (n=29) | 0 | 0 | -- |
| Erosions (n=29) | 0 | 0 | -- |
| Clitoral adhesion (n=14) | 1 (33%) | 0 | 0.05 |
| Labial adhesion (n=14) | 1 (33%) | 0 | 0.05 |
| Labial resorption (exclusive of prepubertal patients, n=10) | 0 | 0 | -- |
| Vaginal scarring (n=4) | 0 | 0 | -- |
Discussion
An important objective of the long-term care of children who undergo allogeneic HSCT is the treatment of complications that can negatively affect their quality of life. Genitourinary complications include hemorrhagic cystitis, POI and vvGvHD. Hemorrhagic cystitis triggered by viral replication and acute GvHD is a well-recognized cause of increased urologic morbidity.22,23 Although POI is routinely recognized as a potential gynecological complication, there is less emphasis on the diagnosis and treatment of vvGvHD. Our retrospective study was primarily undertaken to assess genital symptomatology, characterize findings of genital examination, and describe the incidence and treatment of vvGvHD in girls and adolescents after allogeneic HSCT. That only those patients who reported genital symptoms underwent genital examinations reflect practice patterns at our institution during the study period.
In our study 3 (5%) patients were diagnosed with vvGvHD after allogeneic HSCT. The development of vvGvHD could not be predicted by race, age at HSCT, indication (non-malignant vs. malignant), source of stem cells, degree of HLA match with donor cells (partial vs complete), or GvHD prophylaxis regimen. We found only 2 other publications describing vvGvHD limited to a pediatric and young adult population. Cizek et al reported a 5.9% incidence of vvGvHD over an 8-year period in their cohort of children and young adults (age range 2.4 years to 21.9 years) at a pediatric HSCT center 20. In contrast, Allen at et al reported a much lower incidence of 1.2% of vvGvHD in female patients 21 years and younger who had undergone allogeneic HSCT 21. As with our institution, routine post-transplant evaluation for vvGvHD was not standard practice at these institutions at the time of publication. In our study, the time of onset of vvGvHD post HSCT ranged from 62 to 1565 days. vvGVHD has previously been diagnosed 2966 days (8.1 years) after HSCT 20. These findings highlight the both the possibility of onset of disease both within the first 100 days post-transplantation as well as beyond the first year post-transplantation in children.
Symptoms associated with vvGvHD in the pediatric population include vulvar pain, pruritus, dysuria, sensitivity, dryness, and vaginal pain 20,21. Although in our series genitourinary symptoms commonly associated with vvGvHD were not uniformly assessed and genitourinary exams were not uniformly performed after allogeneic HSCT, 79% of our pediatric cohort were evaluated for genital symptoms. Dysuria was reported by 1 patient diagnosed with vvGvHD. Erythema of the labia and vaginal introitus were observed in 19% and 9% of the entire cohort respectively. However, labial and clitoral adhesions were only found in those with a diagnosis of vvGvHD. Labial adhesions (interlabial between labia minora and majora, and involving labia to clitoral hood), skin erosions (including at the posterior vaginal vestibule, labia majora and minora and clitoral hood), tenderness to palpation, and severe anatomical changes including loss of appreciable tissue of the glans clitoris have previously been reported as findings on genital examination of children and adolescents with vvGvHD 20,21. Neither these exam findings nor symptoms are specific to vvGvHD. Adolescents and adults who develop post-transplantation POI may describe vaginal dryness and dyspareunia and have exam findings of labial resorption and vaginal atrophy. The use of topical estrogen when not contraindicated, i.e., in post-pubertal patients, may minimize the confounding effects of hypoestrogenism in these cases and help diagnose vvGvHD in early stages 24.
Vulvovaginal GvHD can also be asymptomatic in both adults and children. In our series, one (33%) asymptomatic patient was diagnosed with vvGvHD prior to transfer of care to our institution. However, this is likely an underrepresentation of asymptomatic cases given the 12 patients (21%) in our cohort without a documented genital exam. In a previous series of pediatric and young adult patients, 42% were without vulvar or vaginal complaints at the time of diagnosis 20. As post-HSCT surveillance in children and adolescents has not included routine gynecological examination (in the absence of genital symptoms), the incidence of vvGvHD of 1.2 to 5.9% limited to pediatric populations is likely an underestimation. The much higher reported incidence of vvGvHD in adults of upwards of 66% is inclusive of a large number of asymptomatic women. In a prospective study of 41 women median age 46 years (range 17 to 66 years), of the 17 (66%) who were diagnosed with genital GvHD, 8 (47%) were asymptomatic 6. In a retrospective analysis of 64 women followed for 9 years after allogeneic HSCT, 56% were diagnosed with vvGVHD of whom 8 (23%) did not report any genital symptoms 9. Recent recommendations for routine gynecologic examinations after allogeneic HSCT in children will likely result in a more accurate estimation of the true incidence of vvGvHD in the pediatric population 20,21.
The treatment of pediatric vvGvHD has been directed towards the resolution of symptoms, largely due to the lack of routine examination of children and adolescents without genital symptoms. Although vvGvHD in most adults and children is typically preceded by GvHD at one or more other sites (skin, mouth, GI), genital manifestations as the only site of GvHD has been reported in both adults and children 8-10,14,20. Systemic treatment of GvHD has not been shown to effectively prevent or treat vvGvHD in adults 6,9,17. However, in both the adult and pediatric literature, an association between the progression or relapse of vvGvHD with lowering systemic oral corticosteroids has been observed 6,20. Topical immunosuppressive ointments are the first-line treatment of vvGvHD. Various regimens of ultra-high potency corticosteroids have been reported in adults and children with improvement within 4 weeks 5,6,9,20,21. Topical calcineurin inhibitors can be used if response to topical steroids is inadequate or in the setting of side-effects as a result of prolong use of topical steroids 5. In our series, one patient with asymptomatic vvGvHD was treated with topical betamethasone which was switched to topical tacrolimus after she developed steroid atrophy of the skin. Though there was a resolution of her vaginal introital erythema, her labial/clitoral adhesions persisted. The lack of complete resolution of vulvar adhesions after treatment of vvGvHD in children has been observed by other investigators 20. That the treatment of vvGvHD may not prevent or reverse vulvar adhesions has also been reported in adults. Lev-Sagie at al reported that although treatment with topical steroids alleviated vulvar symptoms within 1 to 2 weeks, anatomical vulvar changes continued despite continuous treatment and was irreversible in all patients in their cohort 9. However, local treatment may prevent the development of severe vaginal adhesions 6,9.
Our study has several limitations. This is a retrospective study with a small sample size. Follow-up intervals of patients varied and the approach to the evaluation of genital symptoms, gynecologic examinations and treatment recommendations were not standardized. That the majority of patients underwent allogeneic HSCT for non-malignant conditions and received reduced-intensity conditioning regimen may have resulted in a decreased incidence of GvHD. Other potential contributors to a decreased incidence of vvGvHD include misdiagnosis in symptomatic patients diagnosed with other conditions such as diaper rash or nonspecific vulvovaginitis and the lack of routine GU examination of asymptomatic patients who may have had signs of the disease. In addition, missing data did not allow for the inclusion of various aspects of the care of one patient with vvGvHD to the statistical analysis. Despite these limitations, our study reinforces the need for an increased emphasis on the diagnosis and treatment of vvGvHD in the pediatric population and serves as a reminder of the importance of routine gynecological examination including of asymptomatic patients following allogeneic HSCT.
In conclusion, the recognition that vvGvHD in adults can present within the first 100 days after allogeneic HSCT and can persist as many 16 years after has led to the recommendation to begin regular gynecologic examinations 3 months post-transplant and to continue at least yearly thereafter17 6,9,19. In children and adolescents, gynecologic assessment for vvGvHD after HSCT is not routine at all institutions and severe complications including vaginal stenosis with the subsequent development of hematocolpos have been reported 25. The true incidence of pediatric vvGvHD is unknown and is likely higher that what has been reported so far. We describe in this third cohort of pediatric vvGvHD that disease onset can occur within the first 100 days post-transplant and can be asymptomatic. The inclusion of an assessment for vvGvHD with a thorough review of vulvovaginal symptoms and a gynecologic exam as part of the routine interdisciplinary care of children and adolescents who undergo allogeneic HSCT may improve the detection and treatment of pediatric vvGvHD.
Acknowledgments
This study was supported by NICHD grant Z1A HD008985.
Footnotes
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References
- 1.Arai S, Arora M, Wang T, et al. Increasing incidence of chronic graft-versus-host disease in allogeneic transplantation: a report from the Center for International Blood and Marrow Transplant Research. Biol Blood Marrow Transplant. 2015;21(2):266–274. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Arora M, Cutler CS, Jagasia MH, et al. Late Acute and Chronic Graft-versus-Host Disease after Allogeneic Hematopoietic Cell Transplantation. Biol Blood Marrow Transplant. 2016;22(3):449–455. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Gratwohl A, Sureda A, Cornelissen J, et al. Alloreactivity: the Janus-face of hematopoietic stem cell transplantation. Leukemia. 2017;31(8):1752–1759. [DOI] [PubMed] [Google Scholar]
- 4.Mohty M, Apperley JF. Long-term physiological side effects after allogeneic bone marrow transplantation. Hematology Am Soc Hematol Educ Program. 2010;2010:229–236. [DOI] [PubMed] [Google Scholar]
- 5.Ciavattini A, Clemente N. Female genital tract chronic graft-versus-host disease: review of the literature. Anticancer Res. 2015;35(1):13–17. [PubMed] [Google Scholar]
- 6.Smith Knutsson E, Bjork Y, Broman AK, et al. A prospective study of female genital chronic graft-versus-host disease symptoms, signs, diagnosis and treatment. Acta Obstet Gynecol Scand. 2018;97(9):1122–1129. [DOI] [PubMed] [Google Scholar]
- 7.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(12):760–765. [DOI] [PubMed] [Google Scholar]
- 8.Spinelli S, Chiodi S, Costantini S, et al. Female genital tract graft-versus-host disease following allogeneic bone marrow transplantation. Haematologica. 2003;88(10):1163–1168. [PubMed] [Google Scholar]
- 9.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(12):2234–2243. [DOI] [PubMed] [Google Scholar]
- 10.Corson SL, Sullivan K, Batzer F, August C, Storb R, Thomas ED. Gynecologic manifestations of chronic graft-versus-host disease. Obstet Gynecol. 1982;60(4):488–492. [PubMed] [Google Scholar]
- 11.Frey Tirri B, Hausermann P, Bertz H, 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(1):3–9. [DOI] [PubMed] [Google Scholar]
- 12.Hirsch P, Leclerc M, Rybojad M, et al. Female genital chronic graft-versus-host disease: importance of early diagnosis to avoid severe complications. Transplantation. 2012;93(12):1265–1269. [DOI] [PubMed] [Google Scholar]
- 13.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. Semin Hematol. 2012;49(1):83–93. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Schubert MA, Sullivan KM, Schubert MM, et al. Gynecological abnormalities following allogeneic bone marrow transplantation. Bone Marrow Transplant. 1990;5(6):425–430. [PubMed] [Google Scholar]
- 15.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(8):567–572. [DOI] [PubMed] [Google Scholar]
- 16.Chung CP, Sargent RE, Chung NT, Lacey JV Jr, Wakabayashi MT. Graft-versus-Host Disease-Associated Vulvovaginal Symptoms after Bone Marrow Transplantation. Biol Blood Marrow Transplant. 2016;22(2):378–379. [DOI] [PubMed] [Google Scholar]
- 17.Stratton P, Turner ML, Childs R, et al. Vulvovaginal chronic graft-versus-host disease with allogeneic hematopoietic stem cell transplantation. Obstet Gynecol. 2007;110(5):1041–1049. [DOI] [PubMed] [Google Scholar]
- 18.Jagasia MH, Greinix HT, Arora M, 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(3):389–401 e381. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Majhail NS, Rizzo JD, Lee SJ, et al. Recommended screening and preventive practices for long-term survivors after hematopoietic cell transplantation. Bone Marrow Transplant. 2012;47(3):337–341. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Cizek SM, El-Bietar J, Rubinstein J, et al. Pediatric and Young Adult Vulvovaginal Graft-versus-Host Disease. Biol Blood Marrow Transplant. 2019;25(12):2408–2415. [DOI] [PubMed] [Google Scholar]
- 21.Allen SM, Liang CS, Chesnokova AE, Childress KJ, Pascoe KF, Dietrich JE. Patterns of Genital Examination and Vulvovaginal Graft-Versus-Host Disease in a Pediatric Post-Hematopoietic Stem Cell Transplant Population. J Pediatr Adolesc Gynecol. 2020. [DOI] [PubMed] [Google Scholar]
- 22.Gorczynska E, Turkiewicz D, Rybka K, et al. Incidence, clinical outcome, and management of virus-induced hemorrhagic cystitis in children and adolescents after allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2005;11(10):797–804. [DOI] [PubMed] [Google Scholar]
- 23.Cesaro S, Tridello G, Pillon M, et al. A Prospective Study on the Predictive Value of Plasma BK Virus-DNA Load for Hemorrhagic Cystitis in Pediatric Patients After Stem Cell Transplantation. J Pediatric Infect Dis Soc. 2015;4(2):134–142. [DOI] [PubMed] [Google Scholar]
- 24.Klasa L, Sadowska-Klasa A, Piekarska A, Wydra D, Zaucha JM. The management of gynecological complications in long-term survivors after allogeneic hematopoietic cell transplantation-a single-center real-life experience. Ann Hematol. 2020;99(6):1361–1368. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25.Michala L, Vlachopapadopoulou E, Tsimaris P, et al. Resolution of Hematocolpos in Adolescents Affected with Graft vs Host Disease. J Pediatr Adolesc Gynecol. 2018;31(5):536–539. [DOI] [PubMed] [Google Scholar]