A multicenter observational study on Medication-Related Osteonecrosis of the Jaw (MRONJ) in advanced cancer and myeloma patients of a cancer network in North-Western Italy.

BACKGROUND: Incidence of Medication-Related Osteonecrosis of the Jaw (MRONJ) related to cancer and myeloma treatments is undetermined, with scarce data varying from 2 to 7.8/million/year in limited investigated populations. A 9-years [2009-2018] regional-wide survey was conducted, deploying the North-Western Italy Cancer Network ("Rete Oncologica Piemonte e Valle d'Aosta"), to assess number and main characteristics of MRONJ cases among myeloma/cancer patients, within a population of 4.5 million inhabitants. MATERIAL AND METHODS: MRONJ cases were collected retrospectively from January 2009 to June 2015; from July 2015 to December 2018, data were collected prospectively. Number of new MRONJ cases per year, underlying disorder, drug(s) administered, treatment duration, site and onset timing of MRONJ were detailed. RESULTS: 459 MRONJ cases were identified. Primary diseases were breast cancer (46%), prostate cancer (21%), myeloma (19%), and other types of carcinoma (14%). Patients received antiresorptive treatment either alone (399; 88.47%) or in combination with biological agents (52; 11.53%); 8 patients (1.7%) received only antiangiogenic drugs. Zoledronic acid [388] and denosumab [59] were the most frequently administered drugs. Mandible was involved in 296 (64,5%) cases. Number of new MRONJ cases was stable from 2009 to 2015, with a mean of 51.3 cases per year (raw incidence: 11.6/million/year), declining in the 2016-2018 years to 33.3 cases per year (raw incidence: 7.5/million/year). CONCLUSIONS: With such discrepancy of cases overtime being partially explicable, number of new MRONJ cases per year are consistent with those observed in a previous study [2003-2008] in the same region, being instead higher than those reported in other populations.

Microbiopsy a first-level diagnostic test to rule out oral dysplasia or carcinoma in general dental practice.

OBJECTIVES: Diagnostic delay in oral oncology could be improved if general dentists had a reliable and easy-to-use first-level diagnostic test to rule out the presence of oral dysplasia or carcinoma. Microbiopsy has been proved to have high sensitivity and high negative predictive value in a clinical setting characterized by high prevalence of disease. Moreover, it has been proved to be easily performed by general dentists. This study aimed to determine the negative predictive value of microbiopsy in routine dental practice: a clinical setting characterized by low prevalence of disease. METHODS: Within the frame of a previous study, general dentists from the Metropolitan Area of Turin performed microbiopsy for each oral mucosal lesion detected during their practice. The clinical outcome of 129 lesions negative at microbiopsy was checked by a query performed through the database of the Piedmont Cancer Registry, covering the population of the Metropolitan Area of Turin, with particular reference to cancer involving the mouth (ICD-10:C03-06). This allowed us to define "true negative" cases and to calculate the negative predictive value of microbiopsy. RESULTS: In a mean follow-up of 7.5 years (range 7-9 years), with a dropout rate of 7.7%, no case of tumour involving the mouth was observed, thus revealing a negative predictive value approaching 100%. CONCLUSIONS: Microbiopsy represents an easy-to-use and reliable first-level test able to aid general dentists to select patients requiring an oral medicine assessment in a short time and definitely to avoid diagnostic delay in oncologically relevant oral mucosal lesions.

The association between burning mouth syndrome and sleep disturbance: A case-control multicentre study.

OBJECTIVES: To investigate the quality of sleep and the psychological profiles of a large cohort of Italian patients with burning mouth syndrome (BMS) and to clarify the relationships between these variables and pain. METHODS: In this case-control study, 200 patients with BMS vs an equal number of age- and sex-matched healthy controls, recruited in 10 universities, were enrolled. The Pittsburgh Sleep Quality Index (PSQI), Epworth Sleepiness Scale (ESS), Hamilton Rating Scale for Depression (HAM-D), Hamilton Rating Scale for Anxiety (HAM-A), Numeric Pain Intensity Scale (NRS) and Total Pain Rating Index (T-PRI) were administered. Descriptive statistics, including the Mann-Whitney U test and hierarchical multiple linear regression analysis, were used. RESULTS: Poor sleep quality (PSQI ≥ 5) was present in 78.8% (160) patients with BMS. BMS patients had statistically higher scores in all items of the PSQI and ESS than the healthy controls (p < .001). A depressed mood and anxiety correlated positively with sleep disturbance. The Pearson correlations were 0.570 for the PSQI vs HAM-D (p < .001) and 0.549 for the PSQI vs HAM-A (p < .001). Pain intensity (NRS) poorly correlated to sleep quality; the Pearson correlation was 0.162 for the PSQI vs NRS (p = .021). CONCLUSIONS: The BMS patients showed a poor sleep quality, anxiety and depression, as compared with the controls, highlighting the relationships between oral burning, sleep and mood.

High-resolution DNA content analysis of microbiopsy samples in oral lichen planus.

OBJECTIVES: DNA aneuploidy has been reported to be a predictor of poor prognosis in both premalignant and malignant lesions. In oral lichen planus (OLP), this hypothesis remains to be proved. This study aimed to determine the rate of occurrence of DNA aneuploidy in patients with OLP by high-resolution DNA flow cytometry. METHODS: Patients with OLP were consecutively enrolled. Tissue samples were subdivided for formalin fixation and routine histological assessment and for immediate storage at -20°C for later DNA ploidy analysis, which was performed by DAPI staining of the extracted nuclei and excitation with a UV lamp. The DNA aneuploid sublines were characterized by the DNA Index. RESULTS: A DNA aneuploid status was observed in two of 77 patients with OLP (2.6%). When considering the clinical aspect of the OLP lesions, both DNA aneuploid cases had a reticular clinical aspect. CONCLUSIONS: DNA aneuploidy is an uncommon event in OLP and less frequent compared to other non-dysplastic and non-OLP oral potentially malignant disorders. The extremely low rate of DNA aneuploidy could represent an occasional finding or reflect the low rate of malignant transformation observed in patients with OLP even if the real prognostic value of DNA ploidy analysis in patients with OLP remains to be confirmed.

Time to onset of bisphosphonate-related osteonecrosis of the jaws: a multicentre retrospective cohort study.

OBJECTIVES: Osteonecrosis of the jaw (ONJ) is a potentially severe adverse effect of bisphosphonates (BP). Although the risk of ONJ increases with increasing duration of BP treatment, there are currently no reliable estimates of the ONJ time to onset (TTO). The objective of this study was to estimate the TTO and associated risk factors in BP-treated patients. SUBJECTS AND METHODS: Retrospective analysis of data from 22 secondary care centres in seven countries relevant to 349 patients who developed BP-related ONJ between 2004 and 2012. RESULTS: The median (95%CI) TTO was 6.0 years in patients treated with alendronate (n = 88) and 2.2 years in those treated with zoledronate (n = 218). Multivariable Cox regression showed that dentoalveolar surgery was inversely associated, and the use of antiangiogenics directly associated, with the TTO in patients with cancer treated with zoledronate. CONCLUSIONS: The incidence of ONJ increases with the duration of BP therapy, with notable differences observed with respect to BP type and potency, route of administration and underlying disease. When data are stratified by BP type, a time of 6.0 and 2.2 years of oral alendronate and intravenous zoledronate therapy, respectively, is required for 50% of patients to develop ONJ. After stratification by disease, a time of 5.3 and 2.2 years of BP therapy is required for 50% of patients with osteoporosis and cancer, respectively, to develop ONJ. These findings have significant implications for the design of future clinical studies and the development of risk-reduction strategies aimed at either assessing or modulating the risk of ONJ associated with BP.

Oral proliferative verrucous leucoplakia: are there particular features for such an ambiguous entity? A systematic review.

Proliferative verrucous leucoplakia (PVL) is a distinct, particularly aggressive form of oral leucoplakia. Given the low prevalence of PVL, data are sparse and are mostly from case reports, case series and only a few case-control studies, meaning that the literature is able to provide only weak evidence. The present systematic literature review aims to collate the available evidence on the following issues: patient demographics, aetiology, lesion location(s), malignant potential, location and histopathological features of transformed lesions, disease-specific survival rates and treatment response. Electronic databases were searched for studies in the English language reporting original data from at least 10 patients with PVL on the target issues of the present review. The retrieved data were merged and a descriptive analysis performed. The 20 studies selected indicated that PVL does not seem to be correlated with the major risk factors for oral carcinoma (tobacco, alcohol and/or areca nut/betel leaf chewing). The disorder affects mainly adult/elderly women and has a very high malignant transformation rate, particular site distribution and particular location and histopathological features of transformed lesions. The present results may be limited by some articles being unintentionally excluded as they were not found during the electronic search, a lack of worldwide accepted diagnostic criteria for PVL, and overlapping data from multiple studies performed in a limited number of centres. Despite these potential drawbacks, the present results demonstrate that PVL does have particular features.

Clinical features of microinvasive stage I oral carcinoma.

BACKGROUND: This study aimed to analyse a case series of microinvasive (tumour thickness <4 mm) stage I oral squamous cell carcinoma (OSCC), with an emphasis on the clinical features of the tumours. METHODS: In total, 32 microinvasive and 67 non-microinvasive stage I lesions, which had been surgically treated, were retrospectively studied and compared. The data analysed included gender, age, risk habits, clinical appearance, lesion site, symptoms, nodal involvement and outcome. RESULTS: The clinical features of microinvasive lesions meant that, more often than not, they resembled premalignant lesions (P = 0.008), and diagnosis was mainly based on accurate clinical examination rather than the presence of symptoms (P = 0.029). During a median follow-up of 4.5 years, one nodal involvement and one cancer-related death were observed in patients with microinvasive lesions. A significantly higher (P = 0.044) level of nodal involvement was observed in the non-microinvasive lesion group. CONCLUSIONS: Stage I OSCC has a favourable prognosis overall, but nodal recurrence is more common in non-microinvasive cancers. As microinvasive lesions tend to present clinically as premalignant lesions, accurate clinical examination is essential if misdiagnosis of early lesions is to be avoided.

Course of oral lichen planus: a retrospective study of 808 northern Italian patients.

OBJECTIVES: To undertake a retrospective inspection of the general features, clinical presentation and outcome of 808 Italian patients with oral lichen planus (OLP), followed up from 6 months to 17 years. RESULTS: The mean age was 61 years for women (n = 493) and 58 years for men (n = 315). More than 20% of the total cases had liver abnormalities (n = 164) of which 83.5% infected with hepatitis C virus (n = 137). The reticular and plaque form were the predominant type, affecting almost 60% of patients. 12.3% of patients had also extraoral manifestation, taking into account the skin (n = 63) and genital (n = 24). Symptoms were present in 40% of the total patients. Only less than 2.47% of patients underwent remission, whereas 78% still had oral lesions at the end of the follow-up period. Treatment was directed towards almost 42% of the patients, mainly using topical corticosteroids. Oral squamous cell carcinoma developed in 15 patients, commonly arising on the lateral border of the tongue. CONCLUSION: This is one of the largest groups of OLP patients with such long a follow-up ever reported. We confirm the chronic nature of this disorder, rarely remissive and the treatment intend for alleviating symptoms. OLP is established to be a disease with small frequency of malignant transformation.

The prevalence of oral mucosal lesions in adults from the Turin area.

AIM: To assess the prevalence of oral mucosal lesions (OML) and evaluate its association with tobacco and alcohol consumption and the wearing of removable dentures in an adult population from the Turin area, Italy. MATERIALS AND METHODS: A retrospective study, based on an invitational self-selected screening, was performed on 4098 subjects. It included clinical examination plus biopsies when necessary. Patient history included age, sex, denture wearing and risk habits. Internationally accepted criteria were adopted to classify the OMLs. RESULTS: Males were observed to have more OMLs (557/2040; 27.3%vs 471/2058; 22.89%). Overall OML prevalence was linked to risk habits and age. Tobacco was linked to leukoplakia, melanin pigmentation, smoker's palate, frictional lesions and papilloma. It was negatively related to recurrent aphthous stomatitis and oral lichen planus. Alcohol was linked to leukoplakia, frictional lesions and median rhomboid glossitis. The tobacco-alcohol association was linked to frictional lesions, leukoplakia, melanin pigmentation and smoker's palate. Denture wearers had an overall higher prevalence of OMLs, in particular candidiasis, traumatic and frictional lesions. CONCLUSIONS: The prevalence of OMLs in Turin seems to be comparable to those in other European studies and emphasize that risk habits and denture wearing have some relationship with the presence of OMLs.

Localized oral amyloidosis of the palate.

BACKGROUND: Amyloidosis is a rare disease with multifactorial pathogenesis. Localized amyloidosis affecting the head and neck region is an uncommon and benign process, which has almost no clinical consequences. The most reported characteristic features of localized oral amyloidosis appear as multiple soft nodules of the tongue, lip and cheek. METHODS: We report the case of a 68-year-old woman suffering from a primary localized amyloidosis presenting as a purple patch on the palate. CONCLUSIONS: The presence of systemic amyloidosis or underlying plasma cell dyscrasia have to be ruled out in patients presenting with a diagnosis of amyloidosis of the oral mucosa. If a primary localized amyloidosis is proven, the surgical therapy may be useful to eliminate a functional impairment.

Non-neoplastic salivary gland diseases.

A wide range of non neoplastic disorders can affect the salivary glands, although the more common are: mumps, acute suppurative sialadenitis, Sjögren's syndrome and drug-induced xerostomia. Salivary dysfunction is not a normal consequence of old age, and can be due to systemic diseases, medications or head and neck radiotherapy. Diagnosis of salivary disorders begins with a careful medical history, followed by a cautious examination. While complaints of xerostomia may be indicative of a salivary gland disorder, salivary diseases can present without symptoms. Therefore, routine examination of salivary function must be part of any head, neck, and oral examination. Health-care professionals can play a vital role in identifying patients at risk for developing salivary dysfunction, and should provide appropriate preventive and interventive techniques that will help to preserving a person's health, function, and quality of life. The present work provides an overview of most of the non neoplastic disorders of the salivary glands, in which the general presentation, pathology, and treatments are discussed.

Fibular osteofasciocutaneous flap in computer-assisted mandibular reconstruction: technical aspects in oral malignancies.

Virtual surgical planning technology in head and neck surgery is witnessing strong growth. In the literature, the validity of the method from the point of view of accuracy and clinical utility has been widely documented, especially for bone modelling. To date, however, with its increased use in head and neck oncology, and consequently the increased need for bone and soft tissue reconstruction, is important to carry out the virtual programme considering not only bone reconstruction but also all aspects related to the reconstruction of soft tissue using composite flaps. We describe our approach to virtual planning in the case of composite flaps. The study reports six consecutive patients with malignant disease requiring mandibular bone and soft tissue reconstruction using fibular osteocutaneous flaps. In all six patients, the resection and reconstruction were planned virtually focusing on the position of cutaneous perforator vessels in order to schedule fibula cutting guides. There were no complications in all six cases. The technique described allowed us to schedule composite fibula flaps in mandibular reconstruction virtually with good accuracy of the position of the bone segment in relation to the cutaneous paddle, important for soft tissue reconstruction. Despite the limited number of cases, the preliminary results of the study suggest that this protocol is useful in virtual programmes using composite flaps in mandibular reconstruction. Further investigations are needed.

Correction of a mandibular asymmetry after fibula reconstruction using a custom-made polyetheretherketone (PEEK) onlay after implant supported occlusal rehabilitation.

This study describes an unusual case of mandibular asymmetry after fibula free flap reconstruction in a young man following major facial trauma that was corrected using a custom-made polyetheretherketone prosthesis. There is little information in the literature on the use of alloplasts to correct mandibular asymmetry as interest in 'aesthetic re-modelling' has traditionally focused on nasal, zygomatic and chin regions. This report demonstrates that this technique can be used successfully to address selected cases of mandibular asymmetry.

Osteonecrosis of the jaw in a patient receiving cabozantinib.

Since the discovery of bisphosphonate-related osteonecrosis of the jaw, there has been increasing evidence in recent years of osteonecrosis induced by drugs other than bisphosphonates, mainly agents with antiangiogenic and antiosteoclastic activity. Mandibular osteonecrosis was observed in a 51-year-old female with medullary thyroid cancer receiving cabozantinib, a new tyrosine kinase inhibitor having antiangiogenic activity. The bone necrosis appeared after a dental extraction. The clinical, radiographic and histologic picture of a chronic non-healing extraction socket was consistent with drug-induced osteonecrosis of the jaw. Healing was achieved by segmental ostectomy. The osteonecrosis was likely associated with a vascular endothelial growth factor (VEGF) pathway inhibition, implying inhibition of angiogenesis and hampering of the local host defence mechanisms.

Proliferative verrucous vs conventional leukoplakia: no significantly increased risk of HPV infection.

Proliferative verrucous leukoplakia (PVL) is a very aggressive form of oral leukoplakia (OL) with high morbidity and mortality rates, hypothesised to be linked to HPV infection. This study aimed to determine the presence of HPV DNA in PVL in comparison with OL, and in relation to social-demographical variables (age, gender, smoking and drinking habits) in an Italian multi-centric hospital-based study. The study group consisted of 58 cases of PVL and 90 cases of OL as controls (47 homogeneous (H) and 43 non-homogeneous (non-H) form), both recruited from four Italian cohorts. HPV DNA was identified in exfoliated mucosal cells by nested PCR (nPCR) with MY09/MY11 and GP5+/GP6+ primer pairs and the HPV genotype determined by direct DNA sequencing. HPV DNA was found in 24.1% (14/58)of PVL and in 25.5% (23/90) of OL; there was thus no significant difference found between PVL and OL (both forms) for risk of HPV infection (OR=0.93; 95% IC:0.432-1.985). Similarly, in both groups of PVL and OL lesions, no statistic association was found between any demographical variable considered and HPV infection. HPV-18 was the most frequently detected genotype in all tissues, being found in 78.5% and 60.8% of HPV+ve PVL and OL, respectively. Other more rarely detected genotypes were HPV-16 (28.6% in PVL and 13% in OL), HPV-6 (17.4% in OL) and HPV-53 (8.8% in OL). PVL does not appear more likely to be associated to HPV infection than conventional OL lesions.

Malacoplakia of the tongue. A case report and review of the literature.

Our aim is to present a singular case of malacoplakia of the tongue and a review of the literature. Malacoplakia (from the Greek "malacos", soft, and "placos", plaque) is a granulomatosis initially described in 1902. It has the clinical aspect of a yellow-brown, soft plaque of variable size, characterized by a central navel or ulcer and an intense peripheral hyperaemia, usually located in the urogenital and gastrointestinal tract. The mortality rate is higher than 50% if vital organs are involved. In the world literature there are 16 cases of the head and neck region and particularly only 2 of them are located on the tongue. In these 2 cases the lesion caused some distress to the patients who referred to a medical observation for this motive. Conversely we report a case of asymptomatic lingual malacoplakia occurring in a 57-year-old woman, diagnosed by chance during a stomatological examination in the Department of Oral Medicine and Periodontology of Turin University. In this case the outcome was quite plain and our patient did not need any supporting medical therapy. Nevertheless the potential danger of malacoplakia should underline the importance of a more careful histological assessment of submucosal nodules of the oro-pharyngeal region. Moreover the histopathological characteristic, the present etiopathogenetic hypothesis and the therapeutic pattern of malacoplakia suggested in the literature are discussed.

[Usefulness of oral exfoliative cytology for the diagnosis of oral squamous dysplasia and carcinoma]. / Utilità della citologia esfoliativa orale per la diagnosi di displasia e carcinoma squamoso orale.

AIM: It is well known that diagnostic oral exfoliative cytology, even if a useful, economical and practical tool in the diagnosis of oral dysplasia and carcinoma, is not yet used so extensively as is cervico-vaginal cytology. METHODS: Exfoliative cytology was used for the diagnosis of oral dysplasia and carcinoma, and the results compared to the histological examination. Cytological smears were taken from 89 patients with oral lesions suspicious for neoplasia (in particular erythro- and leukoplakia and lichen). All patients were also subjected to oral biopsy and histological examination. RESULTS: Out of 89 cases studied, histology showed the presence of an invasive squamous carcinoma in 32, dysplasia in 17, phlogosis in 15 and other types of lesions (2 of which malignant non-epithelial tumours) in 25. The cytological smear was inadequate for diagnosis in 11/89 cases (12.4%). In cytologically adequate and histologically positive cases, cytology confirmed the histological diagnosis of dysplasia and/or carcinoma in 38/45 cases (sensitivity 86.5%, accuracy 89.6%). Moreover, 1 case which was histologically negative at the onset, proved positive at cytology. There were 2 false-positive cytology results (specificity 94.3%, predictive positive value 95.7%). CONCLUSIONS: Despite the small number of cases in the cohort, oral cytology can improve the accuracy of histology, and may be a useful screening tool for the diagnosis of oral neoplasia/dysplasia.

Genomic aberrations in normal appearing mucosa fields distal from oral potentially malignant lesions.

OBJECTIVES: Oral fields of visually normal and non-dysplastic mucosa (ODFs) may represent the precursors of oral potentially malignant lesions (OPMLs). Aim of the study was to provide new evidence for the concept of the "field carcinogenesis" model by comparing the ODF and OPML genomic aberration profiles obtained by high resolution DNA flow cytometry (hr DNA-FCM) and array-Comparative Genomic Hybridization (a-CGH). A second aim was to investigate if specific CGH aberrations were associated with DNA aneuploidy. METHODS: Nineteen patients with single OPMLs were recruited for the study. In parallel with obtaining samples of OPML tissue from 11 leukoplakias without dysplasia (nd-OPMLs) and 8 with dysplasia (d-OPMLs), we also obtained samples from distant ODFs. DNA aneuploid nuclei detected by hr DNA-FCM were physically separated, based on DNA content, from the DNA diploid components with a DNA-FCM-Sorter. These relatively pure subpopulations of epithelial nuclei were then submitted to DNA extraction and a-CGH for a genome-wide analysis of DNA copy number aberrations (CNAs). RESULTS: The frequencies of DNA aneuploidy (DI ≠ 1) among ODFs and OPMLs were respectively 5.3% and 32%. The DI aneuploid values of ODFs and nd-OPMLs were all near-diploid (DI ≠ 1 and DI ≤ 1.4), while for d-OPMLs were high-aneuploid (DI > 1.4) in 40% of the cases. CNA averages were 1.9 in ODFs and 6.5 in OPMLs. The gain of the chromosomal region 20q13.33-qter was observed in 37% of both ODFs and corresponding OPMLs. Additional common regions included 7p22.2-pter, 11p15.5-pter and 16p13.3-pter where gains were observed. Furthermore, gains of 20q13.31-q13.33 and of 5p13.33-pter and loss of 9p21.3 were detected at high frequency (respectively, at 62.5%, 50% and 50%) only in d-OPMLs. In particular, loss at 9p21.3, gain at 5p13.33-pter and gain of 20q13.31-q13.33 were associated with DNA aneuploidy (p = 0.00004; p = 0.0005; p = 0.01). CONCLUSIONS: ODFs and OPMLs showed common CNAs in specific chromosomal regions suggesting that they may represent early events of the natural history of oral carcinogenesis according to the field effect cancerization and may contribute to the ODF-OPML transition. In addition, loss at 9p21.3 and gains at 5p13.33-pter and 20q13.31-q13.33 may contribute to DNA aneuploidization.