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Pseudoepitheliomatous hyperplasia. (A) Pseudoepitheliomatous hyperplasia was apparent within the inflamed granulation tissue (Goldner trichrome, ×100). (B) Epithelial nature of the proliferated epithelium was highlighted using immunohistochemistry (AE1/AE3, ×100). (C) Podoplanin expression was seen in basal and parabasal layers (D2-40, ×100).
Source publication
Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a well-characterized oral complication of systemic therapy with bisphosphonates. Pseudoepitheliomatous hyperplasia was observed in some of the lesions. Because podoplanin expression has been linked to malignant lesions of the oral mucosa, we aimed to investigate podoplanin expression in the...
Contexts in source publication
Context 1
... hyperplasia and podoplanin expression in clinical samples. Pseudoepitheliomatous hyperplasia was observed in 11 out of 17 BRONJ cases (Table I) in our study cohort and consisted of irregular squamous epithelial proliferation ( Figure 3A) associated with inflammation and formation of granulation tissue. The pseudoepithelial hyperplasia was one to several cell layers- thick and located both at the bone surface with extension into the granulation tissue and on the inner surface of the BRONJ lesion. All cases showed positive immunohistochemical reaction against pancytokeratin marker AE1/AE3 ( Figure 3B) and positive reaction of basal and parabasal keratinocytes with podoplanin ( Figure 3C) as well. Even though mitoses were found within the pseudoepithelial hyperplasia, no dysplastic changes in the epithelial cells were observed. in vivo 28: xxx-xxx (2014) ...
Context 2
... hyperplasia and podoplanin expression in clinical samples. Pseudoepitheliomatous hyperplasia was observed in 11 out of 17 BRONJ cases (Table I) in our study cohort and consisted of irregular squamous epithelial proliferation ( Figure 3A) associated with inflammation and formation of granulation tissue. The pseudoepithelial hyperplasia was one to several cell layers- thick and located both at the bone surface with extension into the granulation tissue and on the inner surface of the BRONJ lesion. All cases showed positive immunohistochemical reaction against pancytokeratin marker AE1/AE3 ( Figure 3B) and positive reaction of basal and parabasal keratinocytes with podoplanin ( Figure 3C) as well. Even though mitoses were found within the pseudoepithelial hyperplasia, no dysplastic changes in the epithelial cells were observed. in vivo 28: xxx-xxx (2014) ...
Context 3
... hyperplasia and podoplanin expression in clinical samples. Pseudoepitheliomatous hyperplasia was observed in 11 out of 17 BRONJ cases (Table I) in our study cohort and consisted of irregular squamous epithelial proliferation ( Figure 3A) associated with inflammation and formation of granulation tissue. The pseudoepithelial hyperplasia was one to several cell layers- thick and located both at the bone surface with extension into the granulation tissue and on the inner surface of the BRONJ lesion. All cases showed positive immunohistochemical reaction against pancytokeratin marker AE1/AE3 ( Figure 3B) and positive reaction of basal and parabasal keratinocytes with podoplanin ( Figure 3C) as well. Even though mitoses were found within the pseudoepithelial hyperplasia, no dysplastic changes in the epithelial cells were observed. in vivo 28: xxx-xxx (2014) ...
Citations
... To date, inflammatory cell infiltration, epithelial proliferation-called pseudoepitheliomatous hyperplasia (PEH) -and obliterated vessels with numerous spindle-shaped cells have been identified as microscopic features of the mucosa in BRONJ. [6][7][8][9] However, no further distinct histopathological findings have been reported in mucosal tissues. This study describes a novel histopathological finding in the soft tissue of a surgical specimen obtained from a patient with BRONJ. ...
... 10,11 Although knowledge regarding bone lesion has been accumulated, soft tissues have not been examined in detail as extensively. 5,8 Herein, MBFs were scattered in the subepithelial area of the oral mucosa. This finding was observed in 18/30 histological sections examined. ...
... Pseudoepitheliomatous hyperplasia is a benign reactivated epithelial lesion microscopically characterized by irregular downward epithelial projections. This relatively common feature found in the affected oral mucosa of patients with BRONJ 7,8 was also observed herein. Pseudoepitheliomatous hyperplasia is a well-known phenomenon in dermatology as a benign proliferation of the epidermis extending down into the dermis. ...
Bisphosphonate-related osteonecrosis of the jaw (BRONJ) occurs in the jawbone and interfacing oral mucosa of patients treated with bisphosphonates. Herein, we report novel histopathological findings in the oral mucosa of a surgical specimen obtained from a 61-year-old man with BRONJ. The resected jawbone and adjacent oral mucosa were separated for histological examination. The mucosal tissue was examined using Von Kossa staining and immunohistochemical (CK5/6, p63) staining of non-decalcified paraffin sections. Pseudoepitheliomatous hyperplasia (PEH), a microscopic feature of the mucosal epithelium in BRONJ, was observed in soft tissue specimens, concomitant with inflammatory cell infiltration. Von Kossa staining revealed small fragments of necrotic bone, tens to hundreds of micrometers in size, scattered within the connective tissues; the PEH forefront contacted some of the bone fragments. Immunohistochemical staining demonstrated that occasionally, the PEH not only contacted but also encompassed the bone fragments. To our knowledge, this is the first report of presence of micro bone fragments and their association with PEH in the oral mucosa in BRONJ.
... The gingival connective tissue adjacent to the necrotic bone showed dense inflammatory cell infiltration associated with epithelial hyperplasia ( Figure 3F). The bone biopsy specimens obtained from human BRONJ patients demonstrated the empty osteocytic lacunae as the definitive sign of osteonecrosis and associated with epithelial hyperplasia ( Figure 3G), reported as pseudoepitheliomatous hyperplasia (Zustin et al., 2014). ...
Bisphosphonate-related osteonecrosis of the jaw (BRONJ) presents as a morbid jawbone lesion in patients exposed to a nitrogen-containing bisphosphonate (N-BP). Although it is rare, BRONJ has caused apprehension among patients and healthcare providers and decreased acceptance of this anti-resorptive drug class to treat osteoporosis and metastatic osteolysis. We report here a novel method to elucidate the pathological mechanism of BRONJ by the selective removal of legacy N-BP from the jawbone using an intra-oral application of hydroxymethylene diphosphonate (HMDP) formulated in liposome-based deformable nanoscale vesicles (DNV). After maxillary tooth extraction, zoledronate-treated mice developed delayed gingival wound closure, delayed tooth extraction socket healing and increased jawbone osteonecrosis consistent with human BRONJ lesion. Single cell RNA sequencing of mouse gingival cells revealed oral barrier immune dysregulation and unresolved pro-inflammatory reaction. HMDP-DNV topical applications to nascent mouse BRONJ lesions resulted in accelerated gingival wound closure and bone socket healing as well as attenuation of osteonecrosis development. The gingival single cell RNA sequencing demonstrated resolution of chronic inflammation by increased anti-inflammatory signature gene expression of lymphocytes and myeloid-derived suppressor cells. This study suggests that BRONJ pathology is related to N-BP levels in jawbones and demonstrates the potential of HMDP-DNV as an effective BRONJ therapy.
... The gingival connective tissue adjacent to the necrotic bone showed dense inflammatory cell infiltration associated with epithelial hyperplasia (Fig. 3F). The bone biopsy specimens obtained from human BRONJ patients demonstrated the empty osteocytic lacunae as the definitive sign of osteonecrosis and associated with epithelial hyperplasia (Fig. 3G), reported as pseudoepitheliomatous hyperplasia (55). ...
Bisphosphonate-related osteonecrosis of the jaw (BRONJ) presents as a morbid jawbone lesion in patients exposed to a nitrogen-containing bisphosphonate (N-BP). Although it is rare, BRONJ has caused apprehension among patients and healthcare providers and decreased acceptance of this anti-resorptive drug class to treat osteoporosis and metastatic osteolysis. We report here a novel method to elucidate the pathological mechanism of BRONJ by the selective removal of legacy N-BP from the jawbone using an intra-oral application of hydroxymethylene diphosphonate (HMDP) formulated in deformable nanoscale vesicles (DNV). After maxillary tooth extraction, zoledronate-treated mice developed delayed gingival wound closure, delayed tooth extraction socket healing and increased jawbone osteonecrosis consistent with human BRONJ lesion. Single cell RNA sequencing of mouse gingival cells revealed oral barrier immune dysregulation and unresolved pro-inflammatory reaction. HMDP-DNV topical applications to nascent mouse BRONJ lesions resulted in accelerated gingival wound closure and bone socket healing as well as attenuation of osteonecrosis development. The gingival single cell RNA sequencing demonstrated resolution of chronic inflammation by increased anti-inflammatory signature gene expression of lymphocytes and myeloid-derived suppressor cells. This study suggests that BRONJ pathology was predominantly induced by the oral N-BP and demonstrates the potential of HMDP-DNV as an effective BRONJ therapy.
Brief Summary
The targeted removal of legacy bisphosphonate from the jawbone by competitive equilibrium therapy elucidated the pathological mechanism of aberrant oral barrier immunity and bisphosphonate-related osteonecrosis of the jaw (BRONJ)
... An interesting finding, however, was that the granulation tissue was covered by inflammatory-altered squamous epithelium. This epithelial lining resembled pseudoepitheliomatous hyperplasia that has been observed in other oral pathologies such as bisphosphonate-related osteonecrosis of the jaw (10). The source of these epithelial cells is unclear but it is possible that they originate from the gingival epithelium or from epithelial remnants within the periodontal ligament (i.e. ...
Background:
Internal root resorption is an endodontic disease characterized by progressive resorption of dentin from the inside of the pulp chamber. It is a comparatively rare finding in the permanent dentition, and the underlying pathology is not fully understood.
Case report:
A 45-year-old patient was referred to our Department for the evaluation of the lower right canine and the upper left wisdom tooth. Pulp sensitivity tests, cone-beam tomography, and magnetic resonance imaging were used to determine the extent of lesions of the affected teeth. The teeth were subsequently extracted due the extent of the lesions. The same was the case for the upper right canine, which developed a severe internal resorption 10 months later. Micro-computed tomography of the extracted teeth revealed that all lesions had a well-defined border with no evidence of sclerosis or hypomineralization. Pulp stones were evident inside the pulp chamber. Ground sectioning of the upper right canine revealed pulp necrosis and an acute infection that had gradually moved in the apical direction. Large multi-nucleated resorbing cells were found on the dentin surface. Importantly, the apical half of the pulp exhibited comparatively normal tissue without substantial inflammatory changes. Decalcified histology of the upper left wisdom tooth demonstrated a completely different histopathological appearance characterized by chronically inflamed granulation tissue with pseudoepitheliomatous hyperplasia and massive bacterial colonization.
Conclusion:
Our analyses demonstrate that internal root resorption is a multifaceted dental disease with considerable variability in the rate of the underlying inflammatory changes. Oral surgeons should take this into consideration when evaluating the need for extraction of teeth with internal root resorption.
... Furthermore, our previously reported BRONJ mouse model [26,32,33] and the current refined model (Fig. 5D and S3) similarly exhibited oral epithelial hyperplasia albeit at different frequencies and severities. Pseudoepitheliomatous hyperplasia (PEH) has been reported in a high percentage of BRONJ biopsy specimens [19,42]. Both epithelial hyperplasia in our mouse model and PEH of human BRONJ pathologically establish the contact between epithelial cells and necrotic bone surface. ...
Bisphosphonate (BP)-related osteonecrosis of the jaw, previously known as BRONJ, now referred to more broadly as medication-related osteonecrosis of the jaw (MRONJ), is a morbid condition that represents a significant risk for oncology patients who have received high dose intravenous (IV) infusion of a potent nitrogen containing BP (N-BP) drug. At present, no clinical procedure is available to prevent or effectively treat MRONJ. Although the pathophysiological basis is not yet fully understood, legacy adsorbed N-BP in jawbone has been proposed to be associated with BRONJ by one or more mechanisms. We hypothesized that removal of the pre-adsorbed N-BP drug common to these pathological mechanisms from alveolar bone could be an effective preventative/therapeutic strategy. This study demonstrates that fluorescently labeled BP pre-adsorbed on the surface of murine maxillo-cranial bone in vivo can be displaced by subsequent application of other BPs. We previously described rodent BRONJ models involving the combination of N-BP treatment such as zoledronate (ZOL) and dental initiating factors such as tooth extraction. We further refined our mouse model by using gel food during the first 7 days of the tooth extraction wound healing period, which decreased confounding food pellet impaction problems in the open boney socket. This refined mouse model does not manifest BRONJ-like severe jawbone exposure, but development of osteonecrosis around the extraction socket and chronic gingival inflammation are clearly exhibited. In this study, we examined the effect of benign BP displacement of legacy N-BP on tooth extraction wound healing in the in vivo model. Systemic IV administration of a low potency BP (lpBP: defined as inactive at 100 μM in a standard protein anti-prenylation assay) did not significantly attenuate jawbone osteonecrosis. We then developed an intra-oral formulation of lpBP, which when injected into the gingiva adjacent to the tooth prior to extraction, dramatically reduced the osteocyte necrosis area. Furthermore, the tooth extraction wound healing pattern was normalized, as evidenced by timely closure of oral soft tissue without epithelial hyperplasia, significantly reduced gingival inflammation and increased new bone filling in the extraction socket. Our results are consistent with the hypothesis that local application of a rescue BP prior to dental surgery can decrease the amount of a legacy N-BP drug in proximate jawbone surfaces below the threshold that promotes osteocyte necrosis. This observation should provide a conceptual basis for a novel strategy to improve socket healing in patients treated with BPs while preserving therapeutic benefit from anti-resorptive N-BP drug in vertebral and appendicular bones.
... Oral soft tissue adjacent to affected bone may demonstrate acute and/or chronic infl ammatory cell infi ltration. Pseudoepitheliomatous hyperplasia of adjacent mucosa may also be observed, but should not be considered a sign of malignancy [ 59 ]. More advanced microscopic evaluation with tools such as confocal scanning laser microscopy or scanning electron microscopy has identifi ed multispecies microbial biofi lms in association with affected bone. ...
... Oral soft tissue adjacent to affected bone may demonstrate acute and/or chronic infl ammatory cell infi ltration. Pseudoepitheliomatous hyperplasia of adjacent mucosa may also be observed, but should not be considered a sign of malignancy [ 59 ]. More advanced microscopic evaluation with tools such as confocal scanning laser microscopy or scanning electron microscopy has identifi ed multispecies microbial biofi lms in association with affected bone. ...
ARONJ is defined as the persistence of exposed necrotic jawbone in the oral cavity for 8 weeks, despite adequate treatment, in a patient with current or previous history of ART and without local evidence of malignancy or prior radiotherapy to the affected region. The pathogenesis of ARONJ is multifactorial, and many risk factors have been associated with disease development and progression. Clinically, patients with ARONJ can be asymptomatic or may present with a wide range of signs and symptoms that are often inflammatory in nature. Radiologic examination is essential for accurate diagnosis and staging of ARONJ and for assessing the extent of disease. Many conditions can resemble ARONJ clinically, radiographically, and histopathologically; therefore, accurate clinical diagnosis should be predicated on careful correlation of medical and dental history, medication history, risk factors, presenting signs and symptoms, and examination and radiologic findings.
