Comparison of oral chronic graft-versus-host disease characteristics between patients with malignant and non-malignant hematopoietic disorders.

Introduction

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) represents a significant therapeutic modality for both malignant hematopoietic disorders, such as leukemia, and non-malignant hematopoietic disorders, including thalassemia major (TM). In China, the incidence of leukemia is approximately 2.76 per 100,000 individuals, making it the most prevalent malignant disorder of the hematopoietic system. Thalassemia (TH), the most common single gene inherited disease globally, is particularly prevalent in countries within the Association of Southeast Asian Nations (ASEAN) and along the Belt and Road Initiative. Guangxi province, located in southern China, is one of the regions with a high incidence of TH [ 1 ]. Advances in transplantation techniques have significantly improved transplant success rates and extended patient survival [ 2 , 3 ]. Nevertheless, chronic graft-versus-host disease (cGVHD) remains a major and severe complication following transplantation. Given that Guangxi is a region with a high incidence of thalassemia, cGVHD is also more prevalent in this area. The oral cavity is the most commonly affected organ in cGVHD cases, often being the earliest or sole site of onset, followed by the skin [ 4 ]. Previous studies have reported the prevalence of oral cGVHD in patients with cGVHD to range from 45 to 83% [ 5 – 8 ].

The clinical manifestations of oral cGVHD have been extensively documented in numerous studies. Lichenoid lesions in the oral mucosa serve as a diagnostic hallmark for oral cGVHD [ 9 ]. Other manifestations include oral ulcers, pseudomembranes, mucosal erythema, patchy hyperkeratosis, diffuse or dense flat white spots, lingual papillary atrophy, mucous cysts, and limited mouth opening [ 10 ]. In addition, involvement of the salivary glands often results in xerostomia, leading to increased tooth demineralization, severe dental caries, and recurrent secondary infections with Candida albicans. Oral mucosal ulcers cause significant pain, which adversely affects daily eating, nutritional intake, communication, and maintenance of oral hygiene. Dysesthesia, such as impaired taste and smell, along with xerostomia, can induce anxiety and mood disturbances, severely impacting patients' quality of life [ 11 , 12 ]. Oral cGVHD is a potentially malignant disorder that may progress to oral squamous cell carcinoma (OSCC) if left uncontrolled over the long term, posing a threat to patient survival [ 13 – 16 ].

However, patients with malignant hematopoietic disorders and non-malignant hematopoietic disorders exhibit distinct differences in age, occupation, and other sociological characteristics. One study demonstrated no significant differences in the cumulative incidence of cGVHD among children with malignant diseases who underwent umbilical cord hematopoietic stem cell transplantation but did not address the incidence or clinical features of oral cGVHD [ 17 ]. Consequently, whether there are differences in oral cGVHD between these two groups remains unclear, and few studies have specifically focused on this issue. A comparative analysis and summary of the clinical characteristics of oral cGVHD in two groups could facilitate the development of more personalized management strategies for patients with oral cGVHD. Additionally, the incidence of cGVHD is influenced by factors such as age, sex, primary disease diagnosis, donor type, human leukocyte antigen (HLA) disparities, acute graft-versus-host disease (aGVHD) history, and conditioning regimen type [ 18 – 20 ]. However, risk factors for cGVHD vary across different tissues and organs, and the specific risk factors for oral cGVHD remain poorly understood. Clarifying the clinical characteristics and risk factors of oral cGVHD is crucial for effectively preventing this condition and improving patients' quality of life and long-term prognosis [ 21 ].

Therefore, this study retrospectively analyzed the clinical data of 261 patients with hematopoietic disorders who underwent allo-HSCT, aiming to characterize the cohorts of patients with malignant hematopoietic disorders and non-malignant hematopoietic disorders after allo-HSCT in terms of clinical findings, and to identify risk factors of oral cGVHD, in order to provide a reference for developing more accurate and personalized clinical treatment strategies for patients with oral cGVHD.

Materials and methods

Study objects

Patients diagnosed with hematopoietic disorders who underwent allo-HSCT at the Department of Hematopathology, First Affiliated Hospital of Guangxi Medical University, and subsequently received treatment at the Department of Periodontics and Oral Medicine, Hospital of Stomatology, Guangxi Medical University, between January 2012 and December 2022 were included in this study. The exclusion criteria were as follows: 1) Patients who experienced graft failure following the initial HSCT, died within 100 days post-HSCT, or had a recurrence of the original disease; 2) Patients with pre-existing oral lichenoid lesions or those caused by other factors prior to allo-HSCT; 3) Patients with incomplete medical records or clinical examination data. This study was approved by the Ethics Committee of the Affiliated Stomatology Hospital of Guangxi Medical University (Approval Number: 2024055).

Data collection

Demographic information of patients, including age, sex, and diagnosis, was systematically collected. Data pertaining to HSCT, such as stem cell source, blood type compatibility, the gender combination of female donors and male recipients, donor sources, conditioning regimens, the use of anti-thymocyte globulin (ATG), graft-versus-host disease (GVHD) prophylaxis measures, and history of acute GVHD (aGVHD), were meticulously documented.

Conditioning regimens

Pre-transplantation conditioning regimens for the research subjects included the following agents, used either individually or in combination: Cytarabine (Ara-C), antithymocyte globulin (ATG), Busulfan (Bu), Lomustine (CCNU), Cyclophosphamide (Cy), total body irradiation (TBI), Fludarabine (Flu), Idarubicin (IDA), and Etoposide (VP16). And these regimens can be categorized into the following groups: myeloablative conditioning (MAC), nonmyeloablative conditioning (NMAC), reduced-intensity conditioning (RIC), MAC combined with ATG, NMAC combined with ATG, and RIC combined with ATG.

GVHD prophylaxis

Prophylactic regimens include cyclosporin A (CsA) in combination with mycophenolate mofetil (MMF) and methotrexate (MTX), or tacrolimus (FK506) in conjunction with MMF and MTX.

Oral examinations

Two oral mucosa specialists, with an inter-rater reliability Kappa value exceeding 0.9, conducted comprehensive examinations and documented the patients' oral health status. They also performed diagnoses and scoring of oral cGVHD in accordance with the 2014 National Institutes of Health (NIH) criteria (Table 1 ) [ 9 ] at the Department of Periodontics and Oral Medicine, Hospital of Stomatology, Guangxi Medical University. Table 1 Scoring criteria of oral manifestations among oral cGVHD patients Mucosal change No evidence of cGVHD Score Mild Score Moderate Score Severe Score Erythema None 0 Mild erythema or moderate erythema (< 25%) 1 Moderate (≥ 25%) or severe erythema (< 25%) 2 Severe erythema (≥ 25%) 3 Lichenoid None 0 Hyperkeratotic changes (< 25%) 1 Hyperkeratotic changes (25%−50%) 2 Hyperkeratotic changes (> 50%) 3 Ulcers None 0 None 0 Ulcers involving (≤ 20%) 3 Severe ulcers (> 20%) 6 Mucoceles None 0 1–5 mucoceles 1 5–10 mucoceles 2 Over 10 mucoceles 3

Statistical analysis

SPSS 22.0 statistical software was used for data analysis. Student t test was used to compare the transplantation age and oral cGVHD scores between malignant hematopoietic disorders and non-malignant hematopoietic disorders populations, and Chi-square test was used to compare the incidence of oral cGVHD between patients with malignant hematopoietic disorders and non-malignant hematopoietic disorders. Rank sum test was used to compare the median time from transplantation to oral cGVHD onsets between patients with malignant hematopoietic disorders and non-malignant hematopoietic disorders. And logistic regression was used to analyze the risk factors of oral cGVHD.

Results

Demographic characteristics and clinical data of the study objects

A total of 261 patients who underwent allo-HSCT were included in this study. Among them, 101 patients were diagnosed with malignant hematopoietic disorders, primarily leukemia, while 160 patients were diagnosed with non-malignant hematopoietic disorders, mainly TM. The cohort comprised 162 males and 109 females, with a mean age of 17.44 ± 13.78 years (range: 2.33–59.20 years). The median follow-up duration post-transplantation was 840 days (range: 138–5110 days). Detailed clinical data, including stem cell sources, donor sources, HLA matching, conditioning regimens, GVHD prophylaxis strategies, female donor to male recipient status, and history of aGVHD, are summarized in Table 2 . Table 2 Demographic and clinical characteristics of the 261 enrolled patients Patients with oral cGVHD ( n = 108) Patients with non-oral cGVHD ( n = 153) Sex Male, n (%) 71(65.74) 91(60.67) Female, n (%) 37(34.26) 62(39.33) Age when allo-HSCT (mean ± SD, range, in yrs) 20.00 ± 14.85 (2.33–59.20) 15.22 ± 12.56 (3.00–53.00) Age ≤ 18 n (%) 58 (53.70) 108 (70.59) Age ≥ 18, n (%) 50 (46.30) 45 (29.41) Diagnoses Thalassemia major, Aplastic Anemia/Myelodysplastic Syndromes/Acute Myeloid Leukemia/Acute Lymphoblastic Leukemia/Acute Undifferentiated Leukemia, Lymphocytic Leukemia/Multiple Myeloma/Acute Monocytic Leukemia/ Chronic Granulocytic Monocytic Leukemia/Chronic Myeloid Leukemia/T-cell Lymphoblastic Lymphoma 54/2/1/24/17/1 /1/1/3/1/5/1 101/3/1/30/9/0/ 0/2/3/0/4/0 Stem cell source, n (%) BMT + PBSCT 56 (51.85) 82 (53.59) PBSCT 43 (37.96) 56 (36.60) UCBT + BMT/UCTB + BMT + PBSCT/ UCTB + PBSCT 8 (7.40) 15 (9.80) BMT 1 (0.90) 1 (0.65) Donor source, n (%) Sibling donors 79 (73.15) 104 (67.97) Matched unrelated donors 23 (21.30) 34 (22.22) Mismatched unrelated donors 2 (1.85) 4 (2.61) Haploidentical donors 4 (3.70) 11 (7.19) Blood type-match, n (%) Yes 50 (46.30) 87 (56.86) No 58 (53.70) 66 (43.14) Female donors to male recipients, n (%) Yes 35 (32.41) 31 (20.26) No 73 (67.59) 122 (79.74) Conditioning regimens, n (%) MAC 18 (16.67) 15 (9.80) RIC 2 (1.85) 4 (2.61) NMAC 11 (10.19) 10 (6.54) MAC + ATG 2 (1.85) 7 (4.58) RIC + ATG 61 (56.48) 97 (63.40) NMAC + ATG 8 (7.41) 13 (8.50) TBI 6 (5.56) 7 (4.58) GVHD prophylaxis, n (%) FK-506 + MMF + MTX 35 (32.41) 51 (33.33) CsA + MMF + MTX 73 (67.59) 102 (66.67) History of aGVHD, n (%) None 85 (78.70) 129 (84.31) I–II 15 (13.89) 18 (11.76) III–IV 8 (7.41) 6 (3.92) Presence of cGVHD in other sites, n(%) Skin 43 (39.81) 15 (9.80) Eyes 17 (15.74) 1 (0.65) Liver 25 (23.14) 7 (4.58) Gastrointestinal tract 16 (14.8) 4 (2.61) Lung 9 (8.33) 2 (1.31) Nail 4 (3.70) 1 (0.65) Arthrosis 3 (2.78) 2 (1.31) BMT Bone marrow hematopoietic stem cell transplantation, PBSCT Peripheral blood stem cell transplantation, UCBT Umbilical cord blood stem cell transplantation, HLA histocompatibility antibody, MAC Myeloablative conditioning, NMAC Nonmyeloablative conditioning, RIC Reduced-intensity conditioning, TBI Total body irradiation, ATG Human thymocyte globulin, FK-506 tacrolimus, CsA Cyclosporin A, MMF Mycophenolate mofetil, MTX Methotrexate, aGVHD Acute chronic graft-versus-host disease

The baseline characteristics of patients in the malignant disorder cohort and the non-malignant disorder cohort

Significant disparities were observed between patients in the malignant disease cohort and non-malignant disease cohort regarding transplantation age, stem cell source, and conditioning regimen. No significant differences were noted in other characteristics (Table 3 ). Table 3 The baseline characteristics of patients in the malignant disorder cohort and the non-malignant disorder cohort Characteristic Malignant diseases cohort ( n = 101) Non-malignant diseases cohort ( n = 160) P -value Sex Male, n (%) 61(60.40) 101(63.13) 0.658 Female, n (%) 40 (39.60) 59 (36.87) Age when allo-HSCT (mean ± SD, range, in yrs) 31.64 ± 10.58 (9.40–59.20) 8.48 ± 5.058 (2.33–42.50) 0.000 Stem cell Source, n (%) BMT + PBSCT 48 (47.52) 90 (56.25) 0.013 PBSCT 50 (49.50) 48 (30.00) UCBT + BMT/UCBT + BMT + PBSCT/ UCTB + PBSCT 2 (1.98) 21 (13.13) BMT 1 (0.99) 1 (0.625) Donor Source, n (%) Sibling donors 74 (73.27) 109 (68.13) 0.377 Matched unrelated donors 21 (20.79) 36 (22.50) Mismatched unrelated donors 1 (0.99) 5 (3.12) Haploidentical donors 5 (7.13) 10 (6.25)) Blood type-match, n (%) Yes 58 (57.43) 79 (49.34) 0.205 No 43 (42.57) 81(50.63) Female donors to male recipients, n (%) Yes 30 (29.70) 36 (22.50) 0.192 No 71 (70.30) 124 (77.50) Conditioning regimens n (%) MAC 33 (32.67) 0 (0) 0.000 RIC 2 (1.98) 4 (2.50) NMAC 21 (20.79) 0 (0) MAC + ATG 8 (7.92) 1 (0.62) RIC + ATG 11 (10.89) 147 (91.88) NMAC + ATG 18 (17.82) 3 (1.88) TBI 8 (5.00) 5 (3.13) GVHD prophylaxis n (%) FK-506 + MMF + MTX 41 (40.59) 58 (36.25) 0.481 CsA + MMF + MTX 60 (59.41) 102 (63.75) History of aGVHD n (%) None 79 (78.22) 135 (84.38) 0.423 I–II 16 (15.84) 17 (10.62) III–IV 6 (5.94) 8 (5.00) BMT Bone marrow hematopoietic stem cell transplantation, PBSCT Peripheral blood stem cell transplantation, UCBT Umbilical cord blood stem cell transplantation, HLA Histocompatibility antibody, MAC Myeloablative conditioning, NMAC Nonmyeloablative conditioning, RIC Reduced-intensity conditioning, TBI Total body irradiation, ATG human thymocyte globulin, FK-506:tacrolimus, CsA Cyclosporin A, MMF Mycophenolate mofetil, MTX Methotrexate, GVHD graft-versus-host disease, aGVHD acute chronic graft-versus-host disease

Clinical characterization of patients with oral cGVHD

Among the 261 patients, 108 were diagnosed with oral cGVHD, while 153 did not develop this condition during follow-up, resulting in an overall oral cGVHD incidence rate of 41.37%. All 108 patients with oral cGVHD exhibited reticular white striated lesions on the oral mucosa. The most common clinical manifestations included oral mucosal ulcers and erosions, followed by xerostomia, pseudomembranes, and erythematous lesions. Other observed symptoms comprised oral mucosal blisters, atrophy of the tongue papillae, chapped lips, mucoceles, and limited mouth opening. The affected areas of the oral mucosa included the buccal mucosa, tongue, lip, palate, gingiva, floor of the mouth, and oral commissures. The buccal mucosa was the most frequently affected site, followed by the tongue, lip, and palatal mucosa. Over 84.6% of patients experienced involvement of more than two oral regions simultaneously. During follow-up, one patient was diagnosed with papillary epithelioma, and two patients developed secondary OSCC. These cases have been previously reported [ 13 , 14 ]. All three patients had a history of leukemia prior to allo-HSCT, were over 30 years old at the time of transplantation, and had oral cGVHD for more than 24 months. According to the NIH-modified Oral Mucosa Rating Scale (OMRS), the oral characterization scores for patients with oral cGVHD were predominantly distributed between 2 and 6 points, with a mean score of 3.82 ± 1.89 (range: 1–9 points). The median time from transplantation to the onset of oral cGVHD was 6 months (range: 3–28 months).

Among the 108 patients with oral cGVHD, 52 patients had been diagnosed with malignant hematopoietic disorders prior to allo-HSCT, while 56 patients were diagnosed with non-malignant hematopoietic disorders. The incidence of oral cGVHD was significantly higher in patients with malignant hematopoietic disorders compared to those with non-malignant hematopoietic disorders (51.49% vs 35.00%, P = 0.01). However, pseudomembranous lesions of the oral mucosa were more frequently observed in patients with non-malignant hematopoietic disorders (13/52 vs 26/56, P = 0.027). Regarding the affected sites within the oral cavity, no significant differences were noted between the two groups. In terms of the mean OMRS, there was no overall significant difference between patients with malignant hematopoietic disorders and those with non-malignant hematopoietic disorders. Nevertheless, a significantly higher proportion of patients with malignant hematopoietic disorders exhibited an oral lesion score greater than 5 compared to those with non-malignant hematopoietic disorders (17/52 vs 7/56, P < 0.0001). The median time from transplantation to the onset of oral cGVHD was earlier in patients with malignant hematopoietic disorders compared to those with non-malignant hematopoietic disorders (6 months vs 7 months, P = 0.001). These findings are summarized in Table 4 . Additionally, the typical clinical manifestations of oral cGVHD in patients with TM are illustrated in Fig. 1 . Table 4 Clinical manifestations and characteristics of patients with oral cGVHD ( n = 108) Total Malignant hematopoietic disorders ( n = 52) Non-malignant hematopoietic disorders ( n = 56) P -value oral cGVHD rate 41.37% (108/261) 51.49% (52/101) 35.00% (56/160) 0.01 Oral manifestations of cGVHD (n, %) White reticular stripe lesion 108 (100) 52 56 Ulcer/ erosion 76 (70.37) 35 (67.31) 41 (73.21) 0.533 Dry mouth 40 (37.03) 24 (46.15) 16 (28.57) 0.074 Pseudomembrane 39 (36.11) 13 (25.00) 26 (46.43) 0.027 Erythematous lesions 20 (18.5) 8 (15.38) 12 (21.43) 0.466 Blister 15 (13.83) 4 (7.69) 11 (19.64) 0.096 Mucocele 10 (11.11) 4 (7.69) 6 (10.71) 0.058 Lingual papillary atrophy 10 (9.26) 4 (7.69) 6 (10.71) 0.058 Chapped mouth and lip 9 (8.33) 3 (5.77) 6 (10.71) 0.492 Limitation of mouth opening 6 (5.55) 4 (7.69) 2 (3.57) 0.425 Affected sites(n, %) Buccal 95 (87.96) 47 (90.38) 48 (85.71) 0.560 Tongue 77 (71.30) 37 (71.15) 40 (71.43) 1.00 Lip 43 (39.81) 20 (38.46) 23 (41.07) 0.843 Palate 39 (36.11) 21 (40.38) 18 (32.14) 0.551 Gingiva 20 (18.52) 9 (17.31) 11 (19.64) 0.808 Floor of mouth 4 (3.70) 2 (3.85) 2 (3.57) 1.00 Corner of the mouth 8 (7.40) 3 (5.77) 5 (8.93) 0.718 Secondary oral tumor Papillary epithelioma 1(0.93) 1(1.92) 0 OSCC 2(1.85) 2(3.85) 0 NIH-modified OMRS (n, %) 1 12 (11.11) 8 (15.38) 4 (7.14) 2 22 (20.37) 10 (19.23) 12 (21.43) 3 15 (14.81) 7 (13.46) 8 (14.29) 4 16 (14.81) 5 (9.62) 11 (19.64) 5 19 (17.59) 5 (9.62) 14 (25.00) 6 19 (17.59) 13 (25.00) 6 (10.71) 7 2 (1.85) 1 (1.92) 1 (1.79) 8 2 (1.85) 2 (3.85) 0 9 1 (0.93) 1 (1.92) 0 Mean ± SD 3.82 ± 1.89 4.19 ± 2.07 3.63 ± 1.48 0.604 ≤ 5 35 (67.31) 49 (87.50) < 0.0001 > 5 17 (32.69) 7 (12.50) Median number of months from transplant to enrollment (Median, range) 6 (3–28) 6 (3–24) 7(3–28) 0.001 Involved organs (n, %) Oral 108 52 56 Skin 43 (39.81) 21 (40.38) 22 (39.29) 1.00 Eyes 17 (15.74) 11 (21.15) 6 (10.71) 0.187 Liver 25 (23.14) 13 (25.00) 12 (21.43) 0.820 Gastrointestinal tract 16 (14.8) 6 (11.54) 10 (17.86) 0.423 Lung 9 (8.33) 8 (19.23) 1 (1.79) 0.014 Nail 4 (3.70) 2 (3.85) 2 (3.57) 1.00 Arthrosis 3 (2.78) 1 (1.92) 2 (3.57) 1.00 OSCC Oral squamous cell carcinoma, OMRS NIH-modified Oral Mucosa Rating Scale Fig. 1 Clinical manifestations of oral cGVHD in patients following allo-HSCT. A White reticulated striated lesion on the buccal mucosa of the oral cavity; B : Ulceration on the buccal mucosa; C : Erosion on the buccal mucosa; D : Grayish yellow pseudomembrane on the buccal mucosa; E : White pseudomembrane on the upper lip mucosa; F : Erythematous lesions on the buccal mucosa. G Blisters on the palate (black arrows); H : Mucous cysts on the floor of the mouth (black arrow); I : Lingual papillary atrophy J : Xerostomia and chapped corner of the mouth. K Submucosal fibrosis on the buccal mucosa; L : limitation of mouth opening

Involvement of other cGVHD target organs in oral cGVHD patients

Oral cGVHD may occur in isolation or concurrently with cGVHD affecting other organs and tissues. Among the 108 patients diagnosed with oral cGVHD, 26 exhibited involvements limited to the oral cavity, while the remaining cases also affected additional target organs and tissues. The most frequent co-occurrence was with cutaneous cGVHD, followed by ocular and hepatic cGVHD. In terms of organ involvement, more than two target organs were commonly affected. Furthermore, the incidence of pulmonary cGVHD was significantly higher in patients with malignant hematopoietic disorders compared to those with non-malignant hematopoietic disorders. No significant differences were observed in the involvement of other target organs between patients with malignant hematopoietic disorders and those with non-malignant hematopoietic disorders (Table 4 ).

The risk factors of oral cGVHD

Univariate analysis was performed to analyze sex, age at transplantation, hematologic diagnosis (malignant or non-malignant), donor sources, HLA-match, blood type-match, female donors to male recipients or not, stem cell sources, donor sources, GVHD prevention, using ATG or not and history of aGVHD. The results showed that age at transplantation, malignant hematologic diagnosis and female donors to male recipients had statistically significant impact on oral cGVHD, while there were no statistically significant differences in other factors. Furthermore, the results of logistic regression analysis showed that only female donors to male recipients [OR = 1.926, 95% CI (1.078, 3.442), P = 0.027] is the independent risk factor of oral cGVHD. Malignant hematopoietic disorder does not independently serve as a risk factor for the development of oral cGVHD (Table 5 ). Table 5 Analysis of risk factors of oral cGVHD ( n = 261) t/X2 P -value for single factor analysis P-value for single logistic regression analysis OR 95% CI of OR lower limit upper limit Sex 1.055 0.304 Age at transplantation −3.073 0.002 0.062 1.031 0.998 1.065 Age ≤ 18 verse age ≥ 18 7.78 0.005 0.903 1.082 0.305 3.840 Hematologic diagnosis (malignant or non-malignant) 6.937 0.008 0.858 0.910 0.326 2.543 Female donors to male recipients 4.944 0.026 0.027 1.926 1.078 3.442 HLA-match 1.525 0.217 Blood type-match 2.834 0.092 Using ATG or not 2.040 0.153 History of aGVHD 1.903 0.386 GVHD prophylaxis 0.025 0.875 Stem cell sources 0.322 0.606 Donor Source 0.099 0.754 ATG human thymocyte globulin, OR Odd ratio, CI Confidence interval

Discussion

Oral cGVHD is a heterogeneous disorder that affects both the oral mucosa and salivary glands, significantly impacting patients' quality of life and, in severe cases, posing a substantial threat to their survival. This study constitutes the inaugural in-depth analysis and comparison of the clinical features of oral GVHD in patients with malignant and non-malignant hematopoietic disorders following allo-HSCT in Guangxi, China. Our findings provide valuable clinical insights for developing personalized management strategies for patients with oral cGVHD resulting from diverse hematopoietic disorders.

In this study, oral cGVHD manifestations were diverse and predominantly characterized by lichenoid lesions. Besides the typical lichenoid changes, the most prevalent oral features included ulcerative erosion (68.57%), followed by xerostomia (37.14%), pseudomembranous lesions (35.24%), and erythematous lesions (18.1%). Additionally, other manifestations observed were mucosal blisters (13.33%), lingual and papillary atrophy (8.57%), oral hyperkeratosis (7.62%), cheilitis (7.62%), superficial mucous cysts (7.62%), and trismus (4.76%). The buccal mucosa was the most frequently affected site and exhibited the most severe lesions, followed by the tongue mucosa. These clinical features of oral cGVHD are consistent with those reported in previous studies [ 22 – 24 ].

The incidence rates of cGVHD among thalassemia patients vary across different populations: 21.67% in the Thai population [ 25 ], 28% in the Egyptian population [ 26 ], and 8.3% in the Turkish population [ 27 ]. To date, there has been no reported data on the incidence rate of oral cGVHD in patients with non-malignant hematopoietic disorders. This study represents the first comprehensive analysis of the incidence and clinical characteristics of oral cGVHD in patients with non-malignant hematopoietic disorders. Our findings indicate that the prevalence of oral cGVHD in patients with non-malignant hematopoietic disorders was 41.37%, which is significantly lower than the 51.49% observed in patients with malignant hematopoietic disorders, while being higher than the 35.00% prevalence in patients with non-malignant hematopoietic disorders. The onset time of oral cGVHD in patients with non-malignant hematopoietic disorders was significantly later compared to patients with malignant hematopoietic disorders, potentially due to earlier discontinuation of anti-rejection drugs in patients with non-malignant hematopoietic disorders. In terms of average oral cGVHD scores, no significant difference was found between the two groups; however, patients with malignant hematopoietic disorders exhibited a wider distribution of scores and a higher proportion of severe cases (more than 5 points). These results suggest that oral cGVHD in patients with malignant hematopoietic disorders tend to have a faster onset and a higher likelihood of severe manifestations. Conversely, oral mucosal pseudomembranes were more prevalent in patients with non-malignant hematopoietic disorders. Additionally, we observed poorer oral hygiene in non-malignant hematopoietic disorders patients compared to patients with malignant hematopoietic disorders, possibly because most of patients with malignant hematopoietic disorders are younger minors for whom maintaining oral hygiene is more challenging. This may lead to a more complex oral microbial composition and a higher risk of infection and exudation when oral mucosal lesions occur. The presence of oral mucosal pseudomembranes can affect the efficacy of local treatments, indicating that dentists should pay closer attention to and enhance oral hygiene management measures for these patients.

Additionally, among the 108 patients with oral cGVHD, 26 (24.07%) patients exhibited localized cGVHD affecting only the oral cavity. In patients with multi-organ cGVHD, the most frequently affected sites associated with the oral cavity were the skin and eyes, in that order. The oral cavity may be one of the earliest organs involved in cGVHD [ 28 ], potentially indicating a correlation with cGVHD in other organs. Jeppesen et al. demonstrated a significant correlation between oral cGVHD scores and progressive damage to the eyes and skin [ 29 , 30 ]. From an embryological perspective, the oral cavity, eyes, skin, nails, and genitals all originate from the ectoderm, suggesting potential similarities in pathogenesis. Therefore, patients with oral cGVHD should be vigilant for the development of skin and eye cGVHD. Previous studies have shown that histological changes in the lips, oral mucosa, and salivary glands, along with clinical manifestations of oral mucosal lesions, can serve as indicators of systemic cGVHD [ 31 ], This implies that optimizing the clinical management of oral cGVHD may positively impact the prevention and treatment of cGVHD in other organs. In our study, patients with malignant hematopoietic disorders had a higher likelihood of developing pulmonary cGVHD post-transplantation compared to those with non-malignant hematopoietic disorders.

For oral cGVHD, studies have demonstrated that malignant hematopoietic disorders, a history of aGVHD, total body irradiation (TBI), peripheral blood stem cell transplantation (PBSCT) [ 32 ], and female donors to male recipients were risk factors of oral cGVHD [ 33 , 34 ]. In our study, logistic regression analysis revealed that only female donors to male recipients was an independent risk factor for oral cGVHD. Female donors to male recipients may increase the risk of cGVHD because the immune system of female donors can recognize H-Y and non-maternal genetic antigens specific to male recipients, thereby inducing an immune response [ 35 ]. No significant association was found between the history of aGVHD and the incidence of oral cGVHD. Regarding the tissue involvement of aGVHD, studies have shown that aGVHD rarely affects oral tissues [ 5 , 36 ]. Mechanistically, there is no clear correlation between aGVHD and the pathogenesis of cGVHD, indicating that cGVHD is not a continuation or transformation of aGVHD [ 18 ]. Gabriel suggested that whether aGVHD could become an independent risk factor for cGVHD might be related to patients receiving different myeloablative regimens [ 37 ]. Regarding donor sources, prior studies have demonstrated that patients undergoing PBSCT experienced lower rates of graft rejection and exhibited higher overall survival and disease-free survival rates compared to those who received bone marrow transplantation (BMT). However, the incidence of cGVHD was elevated in recipients who underwent PBSCT [ 38 – 40 ]. However, in this study, no correlation was found between donor source and the incidence of oral cGVHD. These discrepancies may be influenced by differences in population and transplantation techniques. Besides HSCT-related factors, Picardi found that poor oral hygiene and inadequate oral care may be local risk factors for oral lesions caused by cGVHD [ 41 ]. The oral cavity serves as a natural bacterial carrier environment, suggesting that microbial imbalance may also be a risk factor for oral cGVHD. Existing studies have shown that professional oral treatment reduced the incidence of oral mucositis, and preoperative oral preventive measures could shorten the time required for mucositis improvement in patients with oral cGVHD [ 42 – 44 ]. Managing the overall oral health status of patients before, during, and after transplantation positively impacts the prevention and treatment of oral cGVHD. In our study, we observed that the prevalence of oral cGVHD following allo-HSCT was higher among patients with malignant hematopoietic disorders compared to those with non-malignant hematopoietic disorders. However, neither benign nor malignant hematopoietic disorders were identified as independent risk factors for oral cGVHD. Instead, female donors to male recipients emerged as an independent risk factor for oral cGVHD. This suggests that the observed difference in prevalence is not attributable to the type of hematologic disease but may be influenced by the varying proportions of female-to-male transplants between the two groups.

Secondary tumors represent a significant late complication associated with long-term cGVHD and immunosuppression. The two most common solid tumors are cutaneous and OSCC [ 45 ]. In 2020, the World Health Organization (WHO) classified oral cGVHD as a potential precursor to oral malignancy [ 46 ]. The severity of oral cGVHD is correlated with an increased risk of secondary oral cancer, particularly when the duration of oral cGVHD exceeds 15 months, which is considered an independent risk factor due to target tissue damage and prolonged immunosuppressive therapy [ 47 – 49 ]. Study has shown that the tongue is the most frequent site of secondary oral tumors following allo-HSCT, accounting for 28.24% of cases, followed by the buccal mucosa (10.64%) and lip (5.56%) [ 50 ]. In this study, three patients with oral cGVHD who developed secondary oral tumors had leukemia as their primary disease, were over 30 years old at the time of transplantation, and experienced oral cGVHD for more than 24 months. The tongue was the predominant site of involvement, consistent with previous reports. Given the rising incidence of OSCC in patients with cGVHD, the NIH recommends annual oral examinations for patients surviving more than a year post-allo-HSCT [ 51 – 54 ]. Consequently, patients with oral cGVHD should undergo more frequent evaluations and extended follow-up periods, especially those with a disease course exceeding one year or a history of malignant hematopoietic disorders before allo-HSCT. Enhancing dentists' awareness of the association between oral cGVHD and OSCC can facilitate early diagnosis, improve clinical management, and enhance patient survival and quality of life.

Conclusion

In summary, we have systematically compared and analyzed the clinical characteristics of oral cGVHD following allo-HSCT in patients with both malignant and non-malignant hematopoietic disorders. Our findings indicate that the clinical manifestations of oral cGVHD differ significantly between these two patient populations. Specifically, patients with malignant hematopoietic disorders exhibit a higher incidence rate, more rapid onset, and greater likelihood of developing severe oral cGVHD post-transplantation. Conversely, oral mucosal pseudomembranes are more frequently observed in patients with non-malignant hematopoietic disorders. Additionally, female donors to male recipients represent a significant risk factor for oral cGVHD. This association is not observed in patients diagnosed with benign or malignant blood disorders. However, it is also important to note that oral cGVHD has the potential to undergo malignant transformation, particularly in patients with malignant hematopoietic disorders.

Abbreviations

Allogeneic hematopoietic stem cell transplantation

Acute graft-versus-host disease

Chronic Graft-versus-host Disease

Oral Mucosa Rating Scale

Oral potential malignant disorders;

β-Thalassemia Major

Aplastic Anemia

Myelodysplastic Syndrome

Acute Myelocytic Leukemia

Acute Lymphoblastic Leukemia

Acute uncategorized leukemia

Lymphomatocytic leukemia

Multiple myeloma

Acute monocytic leukemia

Chronic granular monocytic leukemia

Chronic Myelocytic Leukemia

T lymphoblastoma

Bone marrow hematopoietic stem cell transplantation

Peripheral Blood Stem Cell Transplantation

Umbilical Cord Blood Stem Cell Transplantation

Histocompatibility antibody

Human thymocyte globulin

Tacrolimus

Cyclosporin A

Acute chronic graft-versus-host disease

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Acknowledgements

We are grateful to Mr. Richards in Seattle, WA, USA, for his critical reading and language polishing in this paper.

Clinical trial number

Not applicable.

Consent to publish declaration

A written consent for publication was obtained from the patient to publish all clinical details and any accompanying images. And the authors all agreed to publish this work.

Authors’ contributions

Qiaozhi Jiang, Guocheng Mei and Renchuan Tao contributed to conception and design, data analysis and interpretation, and drafted and critically revised the manuscript. Xiangzhi Yong and Zhenmin Liu contributed to data analysis, interpretation, and critically revised the manuscript. Yuxi Zhou, Tiantian Wu, Yan Peng, Xinyu Chen, Jiaqi Huang and Zhongming Zhang contributed to data collection and analysis. Qiaozhi Jiang and Renchuan Tao contribute to fund acquirement.

Funding

This study was funded by National Natural Science Foundation of China (82370959, 82160180), Youth Science Foundation Project of Guangxi Natural Science Foundation (2024GXNSFBA010284), Key Project of Guangxi Natural Science Foundation (2023GXNSFDA026018),Youth Science Foundation Project of Guangxi Medical University Natural Science Foundation (GXMUYSF202431), First-class discipline innovation-driven talent program of Guangxi Medical University and Innovation Project of Guangxi Graduate Education (YCBZ2022097).

Data availability

The data used to support the findings of this study are available from the corresponding author upon request.

Declarations

Ethics approval and consent to participate

This study received approval from the Ethics Committee of the Affiliated Stomatology Hospital of Guangxi Medical University (Approval Number: 2024055). Written informed consent was obtained from all participants for the publication of this study, including all associated data and accompanying images.

Consent for publication

A written consent for publication was obtained from patients to publish all clinical details and any accompanying images.

Competing interests

The authors declare no competing interests.

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