Grading of minor salivary gland immuno-histopathology post-allogenic hematopoietic cell transplantation.

The oral cavity commonly displays mucosal lichenoid lesions and salivary gland dysfunction, which are considered different chronic Graft-versus-Host Disease (cGVHD) pathophysiology's. However, diagnostics of salivary gland (sg-)cGVHD are limited. The objectives of the current study are to evaluate the minor salivary gland (MSG) histo-immunopathological profiles post allogenic hematopoietic cell transplantation based on sg-cGVHD criteria. Design: Histopathology was characterized according to two published grading strategies. Firstly, the National Institute of Health (NIH) assessed peri-ductal/acinar infiltration, exocytosis, damage, and fibrosis, and a points-based grading scheme was established (0-16 points, Grade (G) 0 to IV). Second, a modified Sjögren's Syndrome focus-score with parenchymal damage was also adapted, (0-10 points, Score 0 to 2). 146 MSG biopsies from 79 patients were compared, using the histopathological specific criteria for sg-cGVHD pathology. Quantitative immunohistochemistry for T-cells (CD4, CD8), B-cells (CD19, CD20), monocytic cells (CD68) and dendritic cells (CD1a) were also assessed. Results: The large-scale cohort validated the use of both grading schemes. GIII-GIV and score 2 signified a histopathological diagnosis of "likely" sg-cGVHD. Immunopathological severity was associated with increased T-cells (CD4 and CD8) and monocytic (CD68) infiltrate, with minimal involvement of B-cells (CD19 and CD20), and Langerhans cells (CD1a). Conclusions: Both schemes were verified as being suitable for histological grading to improve assessment and diagnosis of sg-cGVHD. The NIH cGVHD grading appears to be more beneficial for research purposes, including final diagnostics of "no/inactive", "possible" or "likely" cGVHD. The study highlights the intricacies of sg-cGVHD pathology; and the need for standardized assessment to improve patient management associated to sg-cGVHD.

Complications after minor salivary gland biopsy: a retrospective study of 630 patients from two Swedish centres.

OBJECTIVES: The aims of the study were to investigate the prevalence of impaired sensation after minor salivary gland biopsy (MSGB) in two Swedish centres [Karolinska University Hospital (KUH) and Skåne University Hospital (SUH)] and to assess its impact on quality of life (QoL) and associated risk factors. METHOD: A questionnaire including questions regarding the presence of impaired sensation, impact on QoL, and impact on everyday life was sent to patients who had undergone MSGB between 2007 and 2016, and their medical notes were scrutinized. RESULTS: The study included 630 patients (505 from KUH and 125 from SUH). In KUH the biopsies were performed by rheumatologists and in SUH by dentists or oral and maxillofacial surgeons (OMSs). Long-standing, probably permanent, impaired sensation after MSGB was reported by 21% of patients, and was associated with lower age and absence of anti-SSA antibodies. Patients with long-standing impaired sensation reported the inconvenience (1-10) of impaired sensation as 4.0 (2.0-7.0) [median (interquartile range)], and 32% reported an influence on their QoL, the reported influence (1-10) on everyday life being 3.0 (1.0-5.0). When comparing the outcomes from KUH and SUH, patients from SUH reported a significantly lower frequency of long-standing impaired sensation (14% vs 23%; p = 0.02). CONCLUSION: A high frequency of long-standing impaired sensation after MSGB was found among patients who had undergone MSGB, although it had a low impact on everyday life. The complication frequency was less pronounced when a dentist or an OMS had performed the biopsy.

The Mutational Profile of Unicystic Ameloblastoma.

BRAF V600E is the most common mutation in conventional ameloblastoma (AM) of the mandible. In contrast, maxillary AMs appear to harbor more frequently RAS, FGFR2, or SMO mutations. Unicystic ameloblastoma (UAM) is considered a less aggressive variant of ameloblastoma, amenable to more conservative treatment, and classified as a distinct entity. The aim of this study was to characterize the mutation profile of UAM ( n = 39) and to compare it to conventional AM ( n = 39). The associations between mutation status and recurrence probability were also analyzed. In the mandible, 94% of UAMs (29/31, including 8/8 luminal, 6/8 intraluminal, and 15/15 mural subtypes) and 74% of AMs (28/38) revealed BRAF V600E mutations. Among the BRAF wild-type cases, 1 UAM showed a missense SMO mutation (p.L412F), whereas 2 NRAS (p.Q61R), 2 HRAS (p.Q61R), and 2 FGFR2 (p.C383R) activating mutations were identified in AM. Of the 3 maxillary UAMs, only 1 revealed a BRAF V600E mutation. Taken together, our findings demonstrate high frequency of activating BRAF V600E mutations in both UAM and AM of the mandible. In maxillary UAMs, the BRAF V600E mutation prevalence appears to be lower as was shown for AM previously. It could therefore be argued that UAM and AM are part of the spectrum of the same disease. AMs without BRAF V600E mutations were associated with an increased rate of local recurrence ( P = 0.0003), which might indicate that routine mutation testing also has an impact on prognosis.

Quantitative chromogenic immunohistochemical image analysis in cellprofiler software.

Visual grading of chromogenically stained immunohistochemical (IHC) samples is subjective, time consuming, and predisposed to considerable inter- and intra-observer variations. The open-source digital analysis software, CellProfiler has been extensively used for fluorescently stained cells/tissues; however, chromogenic IHC staining is routinely used in both pathological and research diagnostics. The current investigation aimed to compare CellProfiler quantitative chromogenic IHC analyses against the gold standard manual counting. Oral mucosal biopsies from patients with chronic graft-versus-host disease were stained for CD4. Digitized images were manually counted and subjected to image analysis in CellProfiler. Inter-observer and inter-platform agreements were assessed by scatterplots with linear regression and Bland-Altman plots. Validation comparisons between the manual counters demonstrated strong intra-observer concordance (r2 = 0.979), particularly when cell numbers were less than 100. Scatterplots and Bland-Altman plots demonstrated strong agreement between the manual counters and CellProfiler, with the number of positively stained cells robustly correlating (r2 = 0.938). Furthermore, CellProfiler allowed the determination of multiple variables simultaneously, such as area stained and masking to remove any nonstained tissue and white gaps, which also demonstrated reliable agreement (r2 = >0.9). CellProfiler demonstrated versatility with the ability to assess large numbers of images and allowed additional parameters to be quantified. CellProfiler allowed rapid high processing capacity of chromogenically stained chronic inflammatory tissue that was reliable, accurate, and reproducible and highlights potential applications in research diagnostics.

A mechanistic linkage between oral lichen planus and autoimmune thyroid disease.

OBJECTIVE: To determine the levels of antithyroid antibodies and thyroid hormones in the sera of patients with oral lichen planus (OLP), and to quantify the expression of thyroid proteins in OLP lesions. SUBJECTS AND METHODS: Venous blood samples were drawn from 110 patients with OLP who had no history of thyroid disease or levothyroxine supplementation (OLP+/LT4 -). A random population sample of 657 healthy subjects was used as the control group. Two additional groups were used as comparators. Immunohistochemical and qPCR analyses were performed on tissue specimens collected from the patients with OLP and thyroid disease and healthy subjects. RESULTS: No association was found between the presence of antithyroid antibodies and OLP. More patients in the OLP+/LT4 - group showed high levels of thyroid-stimulating hormone and low levels of free thyroxine than were seen in the control group. Thyroid-stimulating hormone receptor was more highly expressed in the OLP lesions of patients with thyroid disease than in the healthy oral mucosa. CONCLUSIONS: A significant number of patients with OLP who are not previously diagnosed with thyroid disease have thyroid parameters that are compatible with hypothyroidism. The expression of thyroid-stimulating hormone receptor in OLP lesions suggests that mechanisms related to autoimmune thyroid disease are involved in the aetiology of OLP.

Oral psoriasis-a diagnostic dilemma: a report of two cases and a review of the literature.

Whether psoriasis can manifest itself in the oral mucosa has been a matter of debate for many years. If an oral version of psoriasis exists, most researchers regard this manifestation as rare. The present report describes two patients who presented with lesions possibly related to cutaneous psoriasis. One patient had patchy erythematous lesions on the gingiva, and one had serpiginous lesions in the hard palate. We discuss these cases in relation to the existing literature, with special emphasis on the clinical and histopathologic criteria for the diagnosis of oral psoriasis.

Maxillary sinus augmentation with iliac autograft - a health-economic analysis.

PURPOSE: To estimate and compare the costs of maxillary sinus augmentation performed with autologous bone graft either from the iliac crest or from local bone harvested from the mandibula. To evaluate post-operative health-related quality-of-life parameters for patients subjected to sinus augmentation and iliac bone surgery. MATERIAL AND METHODS: The hospital records of 14 patients subjected to sinus augmentation with iliac autograft, and 14 patients treated with local autograft, were analysed with regard to costs related to surgery, hospitalization and sick leave. Post-operative health parameters were assessed with a questionnaire. RESULTS: Mean hospital costs, administration excluded, for sinus augmentation with iliac autograft was €3447. Policlinic treatment alternatives e.g. local bone autograft with or without bone substitutes, rendered costs of approximately 42% thereof. The loss of production for a worker was 41% of the total cost (€9285). With regard to health-related quality-of-life and post-operative morbidity, most of the patients had recovered 14 days after the iliac graft surgery. CONCLUSION: The cost for a sinus augmentation with iliac surgery exceeds that of a policlinic procedure manifold. Provided that a policlinic operation with local bone, with or without bone substitute, renders an adequate end result, the economic gain would be substantial and post-operative morbidity would be greatly reduced.

Scandinavian Fellowship for Oral Pathology and Oral Medicine: guidelines for oral pathology and oral medicine in the dental curriculum.

In Scandinavia, as in many European countries, most patients consult their general dentist once a year or more. This gives the dentist a unique opportunity and an obligation to make an early diagnosis of oral diseases, which is beneficial for both the patient and the society. Thus, the dentist must have knowledge of clinical symptoms, local and systemic signs and clinical differential diagnoses to make an accurate diagnosis. The dentist must be competent in selecting appropriate diagnostic tests, for example, tissue biopsy and microbiological samples, and conducting them correctly, as well as in interpreting test results and taking appropriate action accordingly. Furthermore, the dentist must be aware of diseases demanding multidisciplinary cooperation and be able to recognise his/her professional limitation, and to refer to other specialists when required. The dental curriculum changes over time as new approaches, treatments and diagnostic possibilities develop. Likewise, the role of the dentist in the community changes and may vary in different countries. As members of the Scandinavian Fellowship for Oral Pathology and Oral Medicine and subject representatives of oral pathology and oral medicine, we feel obliged to contribute to the discussion of how the guidelines of the dental curriculum support the highest possible standards of dental education. This article is meant to delineate a reasonable standard of oral pathology and oral medicine in the European dental curriculum and to guide subject representatives in curriculum development and planning. We have created an advisory topic list in oral pathology and oral medicine.

Mandibular osteomyelitis associated with paroxysmal nocturnal hemoglobinuria.

A case of osteomyelitis in a 71-year-old woman with paroxysmal nocturnal hemoglobinuria (PNH) is reported. Osteomyelitis of the jaw is a well known condition of the oral and maxillofacial region that may cause severe morbidity. It is well documented that vaso-occlusive crises in sickle cell anaemia, a hemolytic blood disorder, can make the jaw bone susceptible to osteomyelitis. The authors report a case proposing an association between PNH and osteomyelitis of the mandible.

Cartilage changes link retrognathic mandibular growth to TMJ disc displacement in a rabbit model.

Recent experimental research demonstrated that non-reducing temporomandibular joint (TMJ) disc displacement in growing rabbits impaired mandibular growth. TMJ disc displacement is also shown to induce histological changes of the condylar cartilage. The authors hypothesized that the severity of these changes would correlate to the magnitude of mandibular growth. Bilateral non-reducing TMJ disc displacement was surgically created in 10 growing New Zealand White rabbits. Ten additional rabbits constituted a sham operated control group. Aided by tantalum implants, growth was cephalometrically determined for each mandibular side during a period equivalent to childhood and adolescence in man. At the end of the growth period, histologically classified cartilage features were correlated with the assessed ipsilateral mandibular growth. Non-reducing displacement of the TMJ disc during the growth period induced histological reactions of the condylar cartilage in the rabbit model. The severity of cartilage changes was inversely correlated to the magnitude and the direction of mandibular growth, which resulted in a retrognathic growth pattern.

Oral pigmentation in the hard palate associated with imatinib mesylate therapy: a report of three cases.

Imatinib mesylate is a tyrosine kinase inhibitor which targets Bcr-Abl-protein, c-Kit, and platelet-derived growth factor receptor. The drug was originally developed for treatment of chronic myeloid leukemia but is also regarded as first-line treatment of patients with metastatic gastrointestinal stromal tumours (GIST). Dermatologic side effects are common, with superficial edema and rash as the most frequent. In addition, imatinib mesylate treatment is often associated with hypopigmentation. Intraoral side effects are very rare. The present paper demonstrates 1 patient with GIST and 2 patients with chronic myeloid leukemia treated with imatinib mesylate for 5-6 years. All 3 patients presented with diffuse solitary bluish-brown pigmentations in the hard palate. The lesions persisted at follow-ups. There were no other pigmentations in the oral mucosa. The histopathologic examination showed depositions of melanin pigment in the lamina propria. The possible relationship between the observed melanotic maculae and imatinib mesylate treatment is discussed.

Scandinavian Fellowship for Oral Pathology and Oral Medicine: statement on oral pathology and oral medicine in the European Dental Curriculum.

BACKGROUND: For many years, dentists have migrated between the Scandinavian countries without an intentionally harmonized dental education. The free movement of the workforce in the European Union has clarified that a certain degree of standardization or harmonization of the European higher education acts, including the dental education, is required. As a result of the Bologna process, the Association for Dental Education in Europe and the thematic network DentEd have generated guidelines in the document 'Profile and Competences for the European Dentist' (PCD). This document is meant to act as the leading source in revisions of dental curricula throughout Europe converging towards a European Dental Curriculum. In order to render the best conditions for future curriculum revisions providing the best quality dentist we feel obliged to analyse and comment the outlines of oral pathology and oral medicine in the PCD. METHODS: The representatives agreed upon definitions of oral pathology and oral medicine, and competences in oral pathology and oral medicine that a contemporary European dentist should master. The competences directly related to oral pathology and oral medicine were identified, within the PCD. RESULTS: The subject representatives suggested eighteen additions and two rewordings of the PCD, which all were substantiated by thorough argumentation. PERSPECTIVES: Hopefully, this contribution will find support in future revisions of the PCD in order to secure the best quality dental education.

Bone substitute as an on-lay graft on rat tibia.

OBJECTIVES: To investigate the capacity of Cerament, an injectable bone substitute, to guide bone generation from a cortical surface. MATERIALS AND METHOD: Cerament was applied to the cortical surface of rat tibiae and investigated histologically after 3, 6 and 12 weeks, using a procedure similar to that performed in sham-operated rats. RESULTS: In both groups, the thickness of the bone cortex increased significantly from 473 + or - 58 microm (mean + or - SD) at day 0 to 1193 + or - 255 microm (Cerament) and 942 + or - 323 microm (sham) after 3 weeks. In the Cerament group, the new bone thickness remained constant (1258 + or - 288 microm) until the end of the experiment at 12 weeks, while the sham group demonstrated a return to initial cortical thickness (591 + or - 73 microm) at 12 weeks. The newly formed bone in the Cerament group was highly trabecular after 3 weeks but attained a normal trabecular structure of the cortex after 12 weeks. CONCLUSION: Cerament may guide bone generation from an intact cortical bone surface. Although bone remodeling speed may differ between rats and humans, our study indicates that Cerament may become a useful alternative to autologous bone, both to fill defects and to increase bone volume by cortical augmentation.

Effect of ambient light and monitor brightness and contrast settings on the detection of approximal caries in digital radiographs: an in vitro study.

OBJECTIVES: The aim of this study was to investigate how brightness and contrast settings of the display monitor and ambient light level (illuminance) in the viewing room affect the clinician's ability to diagnose carious lesions in digital radiographs. METHODS: Standardized radiographs were taken of 100 extracted teeth. Seven observers evaluated the images for approximal carious lesions twice, once under 50 lux and once under 1000 lux room illumination. Monitor brightness and contrast were varied +/-50% and +/-6%, respectively, to mimic the normal limits of monitor adjustment by an inexperienced user and one optimal setting. This was done by adjusting radiograph brightness and contrast by +/-25%. Thus, five radiographs of each tooth were evaluated. Receiver operating characteristic (ROC) analyses were performed. Histological examinations of the teeth served as the criterion standard. A paired t-test was used to evaluate whether differences in the areas under the ROC curves were significant and kappa was used to evaluate intraobserver agreement. RESULTS: When a monitor with optimal brightness and contrast settings was used to detect approximal carious lesions, ambient light levels less than 50 lux were significantly better than levels above 1000 lux (dentin and enamel lesions, P < 0.01; dentin lesions, P < 0.02). Increasing the contrast setting of the monitor by 6% did not change these results; 50 lux was still significantly better than 1000 lux (enamel lesions, P < 0.01; dentin and enamel lesions, P < 0.02) for evaluating radiographs. Intraobserver agreement differed from fair to good. CONCLUSIONS: Reducing ambient light to less than 50 lux significantly increased the accuracy of diagnosing approximal carious lesions on a monitor with an optimal brightness setting and an optimal or slightly higher than optimal contrast setting.

Oral lichenoid contact reactions may occasionally transform into malignancy.

The purpose was to identify cases of squamous cell carcinoma (SCC) of the tongue, in which a biopsy taken at the site preceding the cancer could be verified to show a lichenoid contact type of reaction (LCR). We retrieved all 724 SCC of the tongue from the Swedish Cancer Registry in the period 1995-2000. These cases were cross-searched with our own oral biopsy data files from 1988 to 1994, in order to identify biopsies with LCR-type lesions preceding the cancer. We found four verified and some additional tentative cases. The study demonstrated that there is a low incidence of malignant transformation in LCR-type oral lesions, not much different from what has been previously reported in oral lichen planus.

Solitary fibrous tumour of the oral cavity: clinicopathological and immunohistochemical characterization of three cases.

Solitary fibrous tumour (SFT) is an uncommon mesenchymal neoplasm rarely located in the oral cavity. To characterize further oral SFT, we describe three new cases. Each tumour originated in the buccal mucosa of a middle-aged/elderly patient. Histological examination showed well-circumscribed tumours with densely cellular areas alternating with hypocellular areas in a variedly collagenous, vascular stroma. Mast cells were abundant. The spindle-shaped, neoplastic cells immunostained strongly for CD34 antigen and vimentin and weakly for bcl-2, but not for epithelial cell markers, alpha-smooth muscle actin, or neurofilament or S-100 proteins. Compatible with the virtual absence of mitoses and of marked nuclear atypia, the overall frequency of proliferating cells expressing Ki-67 was low. The expression of CD34 was useful in the differential diagnosis. The consistent location in the cheek and expansion of one tumour after local trauma does not preclude a traumatic element in the development of oral SFT.

Immunohistochemistry of 'tertiary lymphoid follicles' in oral amalgam-associated lichenoid lesions.

OBJECTIVES: To characterise lymphoid follicle-like aggregates incidentally found to occur in biopsies of oral lichenoid reactions (OLR) and to correlate the findings to hyperplastic tonsil follicles. DESIGN: An immunocytochemical analysis of archival material. SUBJECTS AND METHODS: In an arbitrarily selected period 1992-1994 with a total of 13,924 oral biopsies, 2407 cases were signed out as OLR or lichen planus. These were microscopically reviewed, with the purpose to retrieve all cases showing histologic changes resembling secondary lymphoid follicles. RESULTS: 87 cases showed lymphoid follicle-like changes and 82 of these were in oral regions known to constitutively lack 'organised MALT'. Unexpectedly, all of the 82 were found retrospectively to be in close or direct contact with amalgam fillings. Immunocytochemically, using antibodies to B and T cells, macrophages, follicular dendritic cells and proliferation and apoptosis markers, the mucosal follicles stained similar to tonsillar secondary follicles. In several of an additional 11 OLR cases with histologic changes suggestive of primary follicles, we also found immunocytochemical evidence of such changes. CONCLUSIONS: 'Tertiary lymphoid follicles' may occasionally develop in OLR at sites of the oral mucosa constitutively lacking organised lymphoid tissue. The microenvironment of the OLR T cell infiltrate may occasionally favour such follicle development and amalgam constituents may causally be involved in an unknown way.

Oral, perioral and systemic pathosis in HgCl2-induced autoimmunity in the BN rat.

Male BN rats were repeatedly skin-injected with HgCl2 solution and sacrificed after 6, 9, 14, 21, 28 or 24 days. Mononuclear cell infiltrates were observed in the oral mucosa and in lacrimal, salivary and thyroid glands from 6-9 days onwards, with a peak at 14-21 days. Immunohistochemistry identified these cells as predominantly T cells with some NK cells but very few B cells. Reversible parenchymal changes were observed but there was no obvious persistent tissue destruction. Serum titers of IgE, IgG1, anti-laminin and anti-DNP, but not IgG2a antibodies, were raised and peaked at 14-21 days. However, there was no correlation, within animals, between these titers and the extent of mononuclear cell infiltration. Mercury was histochemically detected within dendritic cells/macrophages in the connective tissue stroma of the glands and in the oral mucosa, but no correlation was found between the distribution of mercury and the degree of inflammation. We conclude that the accumulation of mononuclear cells in oral and perioral tissues of HgCl2-treated BN rats does not represent a local immune response to tissue-retained Hg. Instead, we propose that the extravasation represents an epiphenomenon that is not necessarily deleterious to the infiltrated organ.

Experimental graft versus host disease in the (BN x LEW) F1 rat hybrid: an immunohistochemical study of early disease in oral mucosa.

OBJECTIVE: To study the initial cellular events in oral mucosa (tongue) of experimental hyperplastic GVHD, in order to increase our understanding of the possible pathogenic mechanisms that may be shared with eg mercury (and other drug)-induced immunological reactions. MATERIALS AND METHODS: GVHD was induced by one i.v. injection of 0.5-1 x 10(8) BN spleen cells into (BNxLEW)F1 hybrid rats. The pre-onset stages of the developing semiallogeneic GVHD were investigated in tongue mucosa by immunohistochemistry and monoclonal antibodies. RESULTS: No detectable tissue infiltrates were found 24 h post induction. The pioneer cells appeared at day 3 and were RTIB+/CD2+ and RTIB1-/CD45 (240 kD)-/ EDI-/CD45RC-. At day 3, there was also a visible increase in spleen and lymph node size. Between day 3 and 7, there was a statistically significant increase of CD2+, RTIB+, TCR-alpha beta+, CD4+ and CD8+ cells, but no increase of NKR-PI+ cells. At day 10 there were focal accumulations of CD8+ and NKR-PI+ cells in subepithelial c.t. and in the basal parts of the adjacent epithelium. Animals not sacrificed earlier, showed signs of disease onset at day 11-14. CONCLUSIONS: The early inflammatory infiltrate in this GVHD model consists of activated T cells of donor origin. We suggest, that these originally 'naive' cells migrate initially into lymphoid tissue and following an activation (day 3) enter host's peripheral tissue. Here, (allo-) antigen in constitutively RTIB1 (and EDI) expressing connective tissue dendritic cells may be immune targets of the primed T cells. Such interaction may lead to focal inflammation (increase of CD2+, RTIB+, TCR-alpha beta+, CD4+ and CD8+ cells) and to secondary epithelial damage executed by CD8+ and NKR-PI+ lymphocytes.