Evaluation of Female Chronic Genital GVHD after Hematopoietic Stem Cell Transplantation in Patients Referring to Shariati Hospital of Tehran: A Cross Sectional Study

Received: 26-May-2020, Manuscript No. IJMRHS-20-11653; Editor assigned: 29-May-2020, Pre QC No. IJMRHS-20-11653(PQ); Reviewed: 12-Jun-2020, QC No. IJMRHS-20-11653; Revised: 18-Nov-2022, Manuscript No. IJMRHS-20-11653(R); Published: 16-Dec-2022

Introduction

An important complication of Bone marrow transplantation (Hematopoietic Stem Cell Transplant, HPSCT) is Graft Versus Host Disease (GVHD). GVHD is an immunologic process in which donor T-cells recognize the recipient as foreign and attacks the host tissues. While most of the cases of severe GVHD reactions are seen in incompatible HLA transplantation, can frequently present in the transplantation of siblings with the same HLA or autologous transplantation. Acute GVHD occurs most often in the first 100 days after transplantation therefore; all patients undergoing HPSCT will receive immunosuppressive prophylaxis for that. Without such prevention, the incidence and severity of GVHD will be high even in the identical HLA conditions. Chronic GVHD is an immune system disorder and the most common late complication of HPSCT especially in allogeneic transplant. Chronic GVHD is becoming increasingly common due to improved overall survival and increased use of peripheral blood stem cells sources, which may be associated with an increased risk of chronic GVHD. However, it shows a two-edged sword, which its occurrence is associated with lower recurrence rates and better control of underlying malignancies. It’s duration and severity varies widely. In many patients, chronic GVHD improves desirable and can stop all immunosuppressive therapy, while others have severe and refractory manifestations [1].

Chronic genital GVHD is seen in both males and females after BMT but is more prominent and debilitating in women. It is often ignored in patients, while it's may be the only manifestation of chronic GVHD, and can impair sexual function of patients and can influence quality of life after transplantation. Women with genital GVHD often complain of disturbing symptoms such as dryness, itching, burning, tenderness, dysuria and dyspareunia [2]. Even if these symptoms significantly affect the quality of life and affect the capacity of sexual functions, women rarely meet a physician and complaint of genital complications is less examined, this can be responsible for misdiagnosis and a low prevalence of it. However, chronic genital GVHD is the most common cause of vulvar and vaginal symptoms after HPSCT, even in children [3].

This study was designed to investigate post transplantation chronic genital GVHD in Shariati hospital, because there wasn’t such a study and women's examination is not routine for follow-up visits during post-transplant visits in Iran [4].

Materials and Methods

Female patients aged 20 to 60 years old, who had undergone BMT in Shari'ati Hospital and met the inclusion criteria (age, gender, at least 3 months after transplant, being in remission) were recruited during their transplantation follow-up visits in oncology and hematology clinic. Startup of study was on April 21, 2015 and end was on October 22, 2017 (last patient follow up) [5].

Three visits were scheduled for each patient by a 6-8 weeks interval. In the 1^st visit; transplant information, ongoing immunosuppressive drugs, reproductive history, symptoms and genital complaint were obtained according to the prepared questionnaire. Laboratory hormonal tests such as LH, FSH and Estradiol were requested and vaginal Estradiol (0.625%) was prescribed for 4-6 weeks. During the medical visits, genital examination including vaginal observation, palpation and speculum insertion was performed by a gynecologist and signs and symptoms of chronic GVHD were recorded. In the second visit, if lesions were observed, a biopsy was taken and otherwise a blinded biopsy was performed from the vaginal mucosa or posterior fourchette under local anesthesia [6]. Local hydrocortisone cream (1%) was prescribed for 4-6 weeks later and recommended to continue local vaginal estrogen at least 2-3 times per week. Biopsy specimen was taken by punch and collected in formalin box distinct for each patient and delivered to pathology department. After preparation of paraffin fixed specimen and staining by hematoxylin and eosin, slides were assessed by an expert pathologist. Based on a previous study and existence of inflammation, lymphocyte infiltration, fibrosis and apoptosis findings were categorized into 4 groups and 1 none other specified. A) No GVHD, B) Possible chronic GVHD, C) Consistent with chronic GVHD, D) Chronic GVHD [7].

Data analysis was performed using STATA ver.12. The Kolmogorov-Smirnov test was used to examine the normal distribution of variables. Chi-square and Fisher’s exact test were used for analysis. For all cases, the significance level of p-values<0.05 was considered [8].

Results

In total, 79 female patients were enrolled. The median age of patients was 35 years. The mean time from transplantation to biopsy at second visit was 29.11 ± 2.07 months. Diseases that resulted in transplantation according to their frequency were AML 57%, ALL 20.3%, Aplastic anemia and myelodysplastic syndrome 5% each one. Sixty three patients at the end of study were in complete remission, three had relapsed and underwent chemotherapy and one had GVHD Flare after tapering of immunosuppressant drugs and received systemic corticosteroid. Also 10 patients were dead due to recurrence of disease, GVHD or infectious complications [9].

Nineteen patients were virgin and one patient got married after BMT. 68 (86.1%) of them had regular menstruation before the transplantation, but after transplantation, only 8 (10.1%) had regular menstruation and the number of cases with amenorrhea increased from 6 (7.6%) to 65 (82.3%) patients after transplantation and chemotherapy [10].

Forty one patients (51.9%) continued to have intercourse after transplantation. Thirty eight patients (48.1%) had no sexual intercourse from the time of illness, primary chemotherapy, and transplantation. Among all patients after transplantation, 40 (50.6%) patients reported no libido and 30 (38%) reported decreased libido after BMT and only 9 had normal libido [11].

Of all patients, in 10 cases there was no reported symptoms of acute GVHD within 3 months after transplantation, and the rest (69 cases) had some degrees of acute GVHD (21 mild, 31 moderate and 17 of them showed sever symptoms) [12]. In addition, in post-transplant follow-up 3 cases had no symptoms of chronic GVHD and in the rest (21 mild, 38 moderate and 17 severe) chronic GVHD was observed in other organs except genital. Severity evaluation was calculated according to NIH scoring system for chronic GVHD [13].

In evaluating the status of ovarian function, mean levels of serum LH, FSH and Estradiol were (66.3 ± 30.5), (99.4 ± 43.0) and (26.0 ± 38.1) respectively that indicated ovarian failure in most patients (Table 1).

In assessment of genital symptoms, 17 patients (21.5%) reported no burning, 54 patients (68.4%) had no complaints of spontaneous or after intercourse bleeding also, 42 (53.16%) patients complained of vaginal dryness [14]. In addition, 42 (53.16%) patients had dyspareunia during intercourse (undetectable in 23 patients due to virginity or lack of intercourse after transplantation). Regarding signs observed during examinations by gynecologist; 73 (92.4%) patients had some degrees of vaginal dryness and 35 patients (44.3%) had some degrees of erythema [15].

Also, 46 (58.2%) patients had some degrees of erosion during the examination. In examining the stenosis, it was not possible to evaluate 19 patients due to virginity, but examination of rest of patients with speculum showed that 43 patients had no stenosis, 21 had mild, 11 had moderate and 4 had severe stenosis, so that vaginal examination and speculum insertion was not possible [16]. In addition, 48 (60.8%) patients had no adhesion in labia or Commissure, and 31 (39.2%) had some degrees of adhesion, which were severe in 5 (6.3%) cases. Evaluation of pain was not possible in 19 patients due to virginity and was mild in 16, moderate in 11 and severe in 19 patients (Table 2).

Summing up the genital scores in the first and second visits showed that 9 cases (12.9%) did not had a chronic genital GVHD, 21 (30.0%) had mild, 19 (27.1%) had moderate and 21 (30.0%) had severe (Table 3) [17]. In 4 cases, the genital scores slightly changed in three visits, but there was no significant difference (p>0.05) as shown in Table 4, association between genital GVHD score based on NIH scoring system and acute GVHD was not significant (p=0.32), but with a chronic form of GVHD in other organs except genital was significant (p=0.009).

In the second visit, 70 patients were visited (9 were dead), and then 30 received a biopsy. Based on the results of previous studies, pathological findings were classified into four groups:

A: No satisfied criteria of chronic GVHD (No GVHD).

B: Inflammatory infiltrate of mostly lymphocytes accompanied by epithelial changes (possible chronic GVHD).

C: B+ and a band like inflammation or apoptotic bodies (consistent with Chronic GVHD).

D: B+ and a band like inflammation or apoptotic bodies (chronic GVHD).

NOS: Ulceration with granulation tissue formation.

The pathological findings of biopsy are presented in Table 5.

There was no significant relationship between pathologic findings groups and GVHD symptoms and signs and libido of the patients (Table 6).

Discussion

GVHD is one of the major problems after the HSCT, but is less detectable due to specific features of genital involvement. Genital GVHD was first described by Corson in five women with sclerosing vaginitis and vaginal stenosis. Vaginal stenosis prevents Pap smear test and normal sexual functions. Several therapeutic methods have been proposed including topical estrogen, surgical release and vaginal dilatators, but all had limitations. Most of the patients in this study reported decreased or no libido after transplantation and did not have any sexual activity or rarely did that, which could be one of the reasons for a lower diagnosis of genital GVHD in patients undergoing HSCT [18].

Previous studies have assessed symptoms of hypo-estrogenism due to ovarian failure, which can mimic symptoms of genital GVHD including thick and palemucosa, dryness and dyspareunia and concluded that the use of topical estrogen dramatically reduces the symptoms but in genital GVHD hormonal treatment has been reported to be ineffective and cannot be attributed to estrogen deficiency [19]. In addition, in our study, the examined women had obvious signs and symptoms including burning, bleeding, erythema, erosion, pain, stenosis and adhesion that cannot be attributed only to hypoestrogenism. Particularly adhesion and stenosis that can never be seen in postmenopausal women, although vagina may somewhat lose its elasticity, but it’s never covered by scar tissue and cervix visualization does not affect. In our study 14 patients were under hormone therapy, but there was no significant difference in their signs and symptoms, this is consistent with other studies including Lisa, Spinelli and Jane and Henry. And demonstrates that GVHD is a completely separated entity from estrogen deficiency [20].

The study of Zantomio has found the source of stem cells as the most important risk factor for the development of genital GVHD, which has been associated with a higher risk for peripheral blood stem cells than bone marrow’s.

Schmitz and Flowers also showed that the use of peripheral blood stem cells for allogeneic transplantation has a higher risk of developing GVHD than using bone marrow stem cells. In this study, the source of the stem cells was peripheral blood in all cases therefore we cannot comment about the effect of source of BMT on genital GVHD [21-22].

Histologically, there is no specific characteristic specifically indicative of a chronic genetinal GVHD. The findings in hematoxylin and eosin staining are the same as the findings in chronic GVHD of other tissues accordingly; in the absence of genital signs and symptoms may be helpful for a definitive diagnosis.

In our study, 30 patients underwent biopsy during the second visit, with the most pathologic findings associated with the infiltration with lymphocytes and epithelial changes, which reported a possible chronic genital GVHD.

Pathological findings were not significantly correlated with total genital scores. Similarly, there was lack of a correlation between pathologic findings and symptoms including bleeding, burning, dryness, loss of libido and dyspareunia which was consistent with other studies like a cross-sectional study by Smith regarding chronic genital GVHD, which there wasn’t significant relationship between clinical signs and pathologic findings, so that the biopsy specimen was confirmatory only in patients without clinical signs of GVHD. These results should be taken with caution because biopsy is not available in all patients.

Conclusion

Our evaluation of the prevalence, clinical signs and symptoms of chronic genital GVHD in a cross-sectional study using NIH criteria showed that in most cases the diagnosis were missed and findings of genital biopsy were nonspecific and weren’t consistent with clinical signs and symptoms of GVHD. Most patients were young and in reproductive age. Soit may be necessary to use a regular follow-up program with post-transplantation gynecologic examinations to diagnose genital GVHD. Treatment with topical medications in early stages was much better than the next stages and leads to improvement of patient’s sexual life quality.

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