Significance of oral examination in chronic graft-versus-host disease

Fourteen patients who received allogeneic bone marrow transplantation (BMT) were examined 100 to 220 days after BMT. Ten out of 14 patients were diagnosed as having chronic graft-versus-host disease (cGVHD) in skin, liver, eyes and other organs. These cGVHD patients also had objective evidence of oral involvement. Subjective xerostomia was experienced by 7 cGVHD patients and decreased whole saliva flow was observed in 4 cGVHD patients. However, no patient had a history of parotid swelling or notable abnormality in parotid sialography. Labial salivary glands (LSG) of 9 cGVHD patients showed atrophy and/or destruction in association with diffusely infiltrating lymphocytes. The infiltrating lymphocytes were mainly CD3⁺ T cells with a predominance of CD8⁺ cells over CD4⁺ cells. Lichenoid lesions on the oral mucosa were also observed in 5 cGVHD patients. Thus, this study indicated that oral examination, including LSG biopsy, is useful in the diagnosis of cGVHD.     

Immunohistopathological study of the oral lichenoid lesions of chronic GVHD

BACKGROUND: Chronic graft-vs.-host disease (cGVHD) is a common and serious complication after bone marrow transplantation (BMT). However, the detailed process of oral lichenoid lesions of cGVHD is still unknown. Therefore, we investigated the immunohistopathological features of cGVHD compared with oral lichen planus (OLP) and healthy controls. METHODS: Nineteen allogenic BMT recipients with a histopathological diagnosis of cGVHD were investigated. We investigated the immunohistopathological features of cGVHD compared with OLP and healthy controls. RESULTS: Immunohistopathological features showed that the infiltrations of CD4-positive T cells of cGVHD and OLP were significantly larger than those of the normal oral mucosa (P < 0.005). A larger number of CD8-positive T cells was infiltrated in cGVHD and OLP compared with the normal oral mucosa (P < 0.001). The difference in the number of CD4- and CD8-positive T cells between cGVHD and OLP was not significant. The infiltrations of Langerhans cells (CD1a) in cGVHD and OLP were significantly larger than those in the normal oral mucosa (P < 0.005). The difference in the number of Langerhans cells between cGVHD and OLP was not significant. CD68-positive macrophages were more frequently seen in cGVHD and OLP than in the normal oral mucosa (P < 0.0001). The difference in the number of CD68-positive macrophages between cGVHD and OLP was not significant. CONCLUSIONS: It is suggested that Langerhans cells and CD8-positive T cell may play a major role in the pathogenesis of the oral lichenoid lesions of cGVHD, and the immune response was inducted in OLP as well as the oral lichenoid lesion of cGVHD in this study.     

Vascular endothelial growth factor (VEGF) and chronic graft-versus-host disease (cGVHD) in salivary glands of bone marrow transplant (BMT) recipients

BACKGROUND: The purpose of this study was to compare the immunolocalization of vascular endothelial growth factor (VEGF) in salivary glands of bone marrow transplant (BMT) recipients with normal controls and between the different stages of chronic graft-versus-host disease (cGVHD). In addition, the impact of the immunolocalization of VEGF on the survival rate of BMT patients was investigated as well. METHODS: Labial salivary glands obtained at the day 100+ from 36 consecutive patients, who underwent BMT, were included in the study. The streptavidin-biotin-peroxidase complex stain was used to detect VEGF in the salivary glands. Time of death after BMT was displayed by means of the Kaplan-Meier method for the following parameters: age and gender of the patients, donor gender, acute GVHD, cGVHD staging at the labial salivary glands, primary disease, platelet and neutrophils counts on day of biopsy, stem cell, oral mucositis, parenteral nutrition, oral lichenoid lesions of GVHD, conditioning regimen and immunolocalization degree of VEGF in labial salivary glands. The data were initially analyzed by means of the log-rank test and then included in the Cox's proportional hazard model. RESULTS: No differences on the immunolocalization of VEGF in the labial salivary glands of BMT recipients and control group or between the different stages of glandular cGVHD were noted. Both univariate and multivariate analysis of the survival rate showed significance of 5% only for platelet count over 100 x 109/l on the day of biopsy and male donor gender. CONCLUSIONS: Platelet count over 100 x 109/l and male donor gender are positive predictive factors on the survival rate after BMT. In addition, the immunolocalization of VEGF in salivary glands is not altered in BMT recipients at day 100+ and is not influenced by the stage of cGVHD.     

Oral cGVHD screening tests in the diagnosis of systemic chronic graft-versus-host disease

To determine the diagnostic properties of oral manifestations and histological features of graft-versus-host disease (GVHD) screening tests in the diagnosis of systemic chronic graft-versus-host disease (cGVHD). Sixty patients having undergone allogeneic haematopoietic stem cell transplantation were selected. The patients were submitted to a clinical oral examination to assess symptoms and clinical changes in the oral mucosa. Histopathologic analysis of the lower lip oral mucosa (LLOM) and salivary glands (SG) was also performed. Systemic cGVHD was used for a comparison to oral cGVHD. The accuracy of oral cGVHD tests was low for all methods (58.4% and 52.6% for white lesions and white/red lesions, respectively, in the clinical analysis; 50.4% for the presence of oral pain; and 66.8% and 55.1% for LLOM and SG histopathologic tests, respectively). However, the presence of oral pain had good diagnostic properties [specificity: 100.0, 95% confidence interval (CI): 88.0–100.0; positive predictive value (PPV): 100.0, 95% CI: 94.4–100.0; and negative predictive value (NPV): 72.0, 95% CI: 57.3–83.3]. Moreover, SG alterations revealed by the histopathological analysis also exhibited good diagnostic properties (sensitivity: 98.6, 95% CI: 81.5–99.8; PPV: 71.1, 95% CI: 62.1–79.7; NPV: 85.9 95% CI: 32.9–99.4). The clinical severity of oral lesions and histophatological changes in the LLOM did not exhibit adequate diagnostic properties, whereas both oral pain and SG histopathological analysis exhibited adequate properties for the diagnosis of systemic cGVHD. Histological changes in lip oral mucosa and salivary glands together with a clinical manifestation of the disease in the oral mucosa can be useful to determining the systemic cGVHD.     

Late effects of chronic graft-vs.-host disease in minor salivary glands

BACKGROUND: The established pathologic criteria for minor salivary gland (MSG) involvement in chronic graft-vs.-host disease (cGVHD) could play a role in monitoring response to therapy. METHODS: We evaluated MSG sequential biopsies during cGVHD therapy in 14 allogeneic bone marrow transplantation (BMT) patients. Nine patients that did not develop GVHD after BMT entered the control group. Biopsies were examined using hematoxylin-eosin, Periodic acid-Schiff (PAS) and leukocyte common antigen staining. RESULTS: A significant loss of PAS+ acinar volume was observed at the diagnosis of cGVHD as much as at the end of treatment when compared with the control group. In the second evaluation, the inflammatory infiltrate was still greater than control group. CONCLUSIONS: The results suggest that persistent xerostomia after cGVHD treatment is because of maintenance of lymphocytic infiltrate and consequent absence of MSG secretory unit recovery. This data may be useful to provide improved insight into the histopathology of this organ involvement.     

Immunoprofile of focal lymphocytic infiltration in minor salivary glands of healthy individuals

Aim: To characterize the immunohistochemical profile of the inflammatory cells included in the focal lymphocytic infiltration in the minor salivary glands of healthy individuals. Materials and Methods: Tissue samples of the labial and palatal salivary glands from 46 postmortem subjects, demonstrating the presence of focal lymphocytic infiltration were quantitatively evaluated for the presence of T‐ and B‐cell lymphocytes, plasma cells and macrophages by immunohistochemical and morphometric methods. Results: B‐cell lymphocytes, the predominant cell population in labial (67.5%) and palatal salivary glands (60.8%), were more frequent than T‐cell lymphocytes in both glands (P < 0.001). Among the T‐cell lymphocytes, CD₄‐positive cells were significantly more prevalent than the CD₈‐positive cells (P < 0.001). Plasma cells were almost absent, comprising only 0.01% of the focal lymphocytic infiltration cells of the labial and palatal salivary glands. Conclusions: Focal lymphocytic infiltration in the samples of the salivary glands obtained from healthy individuals is devoid of plasma cells. This can serve as an additional means to differentiate between focal lymphocytic infiltration in patients with Sjögren's syndrome, in which plasma cells are abundant, and focal lymphocytic infiltration in individuals with other causes of focal sialadenitis.     

The oral manifestations of chronic graft-versus-host disease (cGVHD) in paediatric allogeneic bone marrow transplant recipients

The oral manifestations of chronic graft-versus-host disease (cGVHD) in eight allogeneic bone marrow transplant (BMT) paediatric recipients were studied clinically, and lip biopsies were performed in seven of them. A prominent lichenoid reaction was observed in four patients, two with accompanying ulceration. Superficial mucoceles were present in three children. Clinically obvious xerostomia was seen in seven patients. Lip biopsies were positive and correlated with the clinical manifestations. Both clinical and histological findings confirmed the diagnosis of cGVHD. In three additional children, with systemic manifestations indicating cGVHD, the oral mucosa was clinically and histologically normal, and the systemic manifestations were, thus, attributed to drug reactions. The above findings indicate the high value of oral examination in diagnosing or confirming paediatric cGVHD. Superficial mucoceles, reported for the first time in paediatric recipients, seem to be important in the early diagnosis of cGVHD.     

Histopathological analysis and demonstration of EBV and HIV p-24 antigen but not CMV expression in labial minor salivary glands of HIV patients affected by diffuse infiltrative lymphocytosis syndrome

BACKGROUND: The diffuse infiltrative lymphocytosis syndrome (DILS) in HIV patients is characterized by the persistence of CD8-circulating lymphocytes and lymphocytic infiltration, predominantly in salivary glands. METHODS: We examined seven HIV-positive patients with bilateral parotid enlargement and sicca symptoms. Minor labial salivary gland biopsies were performed in all patients and submitted for histopathological analysis and immunohistochemistry for CD4, CD8, cytomegalovirus (CMV), LMP-EBV protein, and HIV p-24 protein. RESULTS: In all cases, lymphocytic infiltration of the minor salivary glands, mainly periductal, was found. Acinar atrophy, ductal ectasia, and mild to moderate fibrosis were also observed. We noticed strong immunohistochemical reaction for LMP-EBV and p-24 proteins in ductal cells in all cases, while staining for CMV was consistently negative. The lymphocytes were positive for CD8, but consistently negative for CD4. CONCLUSIONS: A role of Epstein-Barr virus (EBV) and HIV, but not CMV, in the pathogenesis of DILS, is suggested by our immunohistochemical findings.     

Keratin proteins identified in epithelial fragments of salivary mucoceles

Immunohistochemically detected keratin proteins in mucoceles of oral mucosa were used to served as markers to identify epithelial-derived cells of minor salivary glands. Normal ducts of minor salivary glands showed an intense keratin staining. Epithelial lining and or epithelial fragments in cystic walls of mucoceles displayed a strong reaction to keratin proteins too, whereas granulation tissue or connective tissue fibers of the walls were not seen. Foamy macrophages present in cystic cavities signify higher staining with the use of keratin proteins. Mucoceles in oral minor salivary glands are probably caused by ductal obstructions leading to continuous mucous secretion. Keratin proteins were used as an epithelial marker of ductal segments.     

Focal lymphocytic infiltration in the human labial salivary glands: a postmortem study

Focal lymphocytic infiltration in the human labial salivary glands was examined in a series of 190 postmortem subjects after suitable exclusion had been made. Focal lymphocytic infiltration, with or without a slight degree of parenchymal atrophic change, was found in 22.4% of the males and in 35.7% of the females. Of these, 9.0% (12 subjects) of the males and 10.7% (6 subjects) of the females with focal lymphocytic infiltration did not show any atrophic changes of the parenchyma. In the series reported here, the prevalence of focal lymphocytic infiltration apparently differs from the results of earlier investigators who had reported that none of the postmortem subjects without autoimmune diseases or connective tissue diseases showed focal lymphocytic infiltration in minor salivary glands. Although the pathological significance of focal lymphocytic infiltration in the minor salivary glands remains obscure, its diagnostic value for Sjögren's syndrome is discussed.     

Focal lymphocytic infiltration in the human labial salivary glands: a postmortem study

Focal lymphocytic infiltration in the human labial salivary glands was examined in a series of 190 postmortem subjects after suitable exclusion had been made. Focal lymphocytic infiltration, with or without a slight degree of parenchymal atrophic change, was found in 22.4% of the males and in 35.7% of the females. Of these, 9.0% (12 subjects) of the males and 10.7% (6 subjects) of the females with focal lymphocytic infiltration did not show any atrophic changes of the parenchyma. In the series reported here, the prevalence of focal lymphocytic infiltration apparently differs from the results of earlier investigators who had reported that none of the postmortem subjects without autoimmune diseases or connective tissue diseases showed focal lymphocytic infiltration in minor salivary glands. Although the pathological significance of focal lymphocytic infiltration in the minor salivary glands remains obscure, its diagnostic value for Sj?gren's syndrome is discussed.     

Characterization of peripheral blood and salivary gland lymphocytes in secondary Sj?gren's syndrome.

Secondary Sj?gren's syndrome (SS) is defined as a condition of patients with sicca symptoms in association with a connective tissue disease such as rheumatoid arthritis. This study was designed to investigate the peripheral blood and affected minor salivary gland (SG) tissue lymphocytes with monoclonal antibodies in patients with secondary SS having rheumatoid arthritis. Minor SG lymphocytes of the patients and normals were determined in the fresh-frozen sections of the minor SG biopsy samples using monoclonal antibodies with immunoperoxidase technique. Peripheral blood of secondary SS patients revealed significant reduction in CD3+ and CD8+ cells. CD4/CD8 radio, HLA-DR+ cells, and B-cells were unchanged. SG biopsies showed varying degrees of lymphocytic infiltration with predominance of CD3+CD4+ cells located at the periductal areas. CD8+ cells were found to be in low numbers within the infiltrates. IgG- and IgA-producing plasma cells were both numerous in the biopsy samples. Our findings suggest that there is an alteration of lymphocyte subpopulations at the local site of inflammation in the salivary glands without, however, a corresponding alteration in the peripheral blood.     

Carcinoembryonic antigen in mucoceles of oral mucosa

Immunohistochemical detection of carcinoembryonic antigen (CEA) was reported in mucocele and associated minor salivary glands of oral mucosa. Higher levels of staining for CEA occurred in salivary glands with attached mucoceles, in which acinar cells and ductal segments in the gland displayed concentrations of CEA higher than those in normal minor salivary glands. Floating cells also gave positive CEA staining, whereas epithelial fragments and connective tissue in the mucocele wall were lacking in CEA. It was suggested that mucoceles in oral mucosa accumulated CEA in associated minor salivary glands.     

Quantitative analysis of Langerhans' cells in oral chronic graft-vs.-host disease

Background:  The Langerhans cells (LCs) are scattered throughout the epithelium of skin and mucosa and have been associated with the graft-vs.-host disease (GVHD), which is the highest cause of morbidity and mortality in patients who underwent bone marrow transplant (BMT). This study aims at quantifying the LCs in the oral chronic GVHD (cGVHD).
Methods:  Microscopic sections from biopsies carried out in the buccal mucosa of 40 patients who underwent allogenic BMT and developed (20) or not (20) oral cGVHD (Groups 1 and 2, respectively) were utilised. For the control group, free surgical margins of 20 biopsies of non-inflammatory lesions in the buccal mucosa (Group 3) were used. The sections were studied in routine colouration and immunostained for CD1a.
Results:  Group 1 (with cGVHD) presented a greater number of Langerhans' cells/mm² (50.6 ± 37.2) when compared with the other groups (Group 2, 23.11 ± 19.7; Group 3, 16.6 ± 17.3).
Conclusion:  Our results suggest a greater recruitment of LCs in patients transplanted with cGVHD, probably as a result of cytokines secreted by the inflammatory cells.     

Oral graft vs host disease: An immune system disorder in hematopoietic cell transplantation

Graft vs host disease (GVHD) is a complication of patients who are treated by hematopoietic cell transplantation. National Institutes of Health in 2005 by Working Group on Diagnosis and Staging Consensus Development Project on Criteria for Clinical Trials in Chronic GVHD (cGVHD) established 2 principal categories of oral GVHD, acute and chronic. The oral mucosa may be the first site of manifestation of the disease. Clinical diagnosis needs to be confirmed by a biopsy of oral mucosa and minor salivary glands. Microscopic results have played a major role in the diagnosis and management of acute and chronic oral GVHD. Development of second malignancies is the greatest risk of oral cGVHD patients, mostly regarding squamous cell carcinoma. The focus of oral GVHD therapy is to improve symptoms and maintain oral function. The aim of this review article is to update the information on the oral GVHD in its clinical, microscopic features and their complications.     

Cytomegalovirus shedding in the oral cavity of allogeneic haematopoietic stem cell transplant patients

OBJECTIVE: This study was designed to investigate the effect of allogeneic haematopoietic stem cell transplantation (HSCT) on cytomegalovirus (CMV) shedding in the saliva by nested polymerase chain reaction (nested PCR) and its impact on patient survival. PATIENTS AND METHODS: One hundred and twenty-four HSCT patients and 124 healthy volunteers were included in the study. Oral swabs were taken before, after 100 days and 1 year of HSCT at the buccal mucosa. Nested PCR was used to detect CMV in the saliva. Time of death after HSCT was displayed, by means of the Kaplan-Meier method, for the following parameters: age and gender of the patient, donor gender, primary disease, stem cell source, platelet number, chronic graft vs host disease (cGVHD) of salivary glands and oral mucosa, and oral CMV shedding. Cox proportional hazards model was used for multivariate survival analysis. RESULTS: While none of the individuals in the control group showed positive swabs for CMV, the frequency of positive CMV oral swabs in patients at day + 100 after HSCT (45.2%) was statistically higher than before (7.2%) and 1 year after HSCT (17.5%). The presence of CMV was not associated with cGVHD and did not have any impact on post-transplant survival. CONCLUSIONS: The present study shows that oral CMV shedding occurs after HSCT, especially at day +100 post-transplant. Identification of CMV in the saliva might be important for the early diagnosis of CMV infection in allo-HSTC.     

Severe oral manifestations of chronic graft-vs.-host disease

BACKGROUND: Graft-vs.-host-disease, or GVHD, is the main cause of morbidity in patients who have received bone marrow transplants. Chronic GVHD, or cGVHD, occurs 100 days or more after the transplant procedure and may take the form of various oral manifestations. CASE DESCRIPTION: A 23-year-old woman received an allogeneic bone marrow transplant. Although prophylactic therapy was provided, the patient developed cGVHD. Appropriate therapy was initiated, and it received a good clinical response at all sites affected by cGVHD, except in the oral cavity. The patient received complete symptomatic relief through revised systemic therapy, improved oral hygiene, use of topical medications and a monitored diet. CLINICAL IMPLICATIONS: Effective intervention by dentists is an important part of increasing treatment effectiveness and improving quality of life in patients who received bone marrow transplants.     

Oral chronic graft-versus-host disease: What the general dental practitioner needs to know

BackgroundLong-term survivors of allogeneic hematopoietic cell transplantation will increasingly seek care from dental providers.MethodsThe authors highlight the importance of minimizing oral symptoms and complications associated with oral chronic graft-versus-host-disease (cGVHD).ResultsChronic GVHD is the result of an immune response of donor-derived cells against recipient tissues. Oral cGVHD can affect the mucosa and damage salivary glands and cause sclerotic changes. Symptoms include sensitivity and pain, dry mouth, taste changes, and limited mouth opening. Risk of developing caries and oral cancer is increased. Food intake, oral hygiene, and dental interventions can represent challenges. Oral cGVHD manifestations and dental interventions should be managed in close consultation with the medical team, as systemic treatment for cGVHD can have implications for dental management.ConclusionsGeneral dental practitioners can contribute substantially to alleviating oral cGVHD involvement and preventing additional oral health deterioration.Practical ImplicationsFrequent examinations, patient education, oral hygiene reinforcement, dry mouth management, caries prevention, and management of dental needs are indicated. In addition, oral physical therapy might be needed. Invasive dental interventions should be coordinated with the transplantation team. Screening for oral malignancies is important even years after resolution of GVHD symptoms. Management of the oral manifestations of cGVHD might require referral to an oral medicine professional.     

广西地区异基因造血干细胞移植后患者口腔黏膜健康状况研究

目的:了解广西地区异基因造血干细胞移植后患者的口腔黏膜健康状况,尤其是对慢性移植物抗宿主病(chronic graft-versus-host disease,cGVHD)的口腔表征进行深入分析.方法:调查于广西医科大学一附院行异基因外周血干细胞移植成功并存活的患者69例,以复诊的方式进行病史采集、口腔专科检查,详细记...