Cryoglobulinemic vasculitis in primary Sjögren's Syndrome: Clinical presentation, association with lymphoma and comparison with Hepatitis C-related disease.

OBJECTIVE: To describe the clinical spectrum of cryoglobulinemic vasculitis (CV) in primary Sjögren's syndrome (pSS), investigate its relation to lymphoma and identify the differences with hepatitis C virus (HCV) related CV. METHODS: From a multicentre study population of consecutive pSS patients, those who had been evaluated for cryoglobulins and fulfilled the 2011 classification criteria for CV were identified retrospectively. pSS-CV patients were matched with pSS patients without cryoglobulins (1:2) and HCV-CV patients (1:1). Clinical, laboratory and outcome features were analyzed. A data driven logistic regression model was applied for pSS-CV patients and their pSS cryoglobulin negative controls to identify independent features associated with lymphoma. RESULTS: 1083 pSS patients were tested for cryoglobulins. 115 (10.6%) had cryoglobulinemia and 71 (6.5%) fulfilled the classification criteria for CV. pSS-CV patients had higher frequency of extraglandular manifestations and lymphoma (OR=9.87, 95% CI: 4.7-20.9) compared to pSS patients without cryoglobulins. Purpura was the commonest vasculitic manifestation (90%), presenting at disease onset in 39% of patients. One third of pSS-CV patients developed B-cell lymphoma within the first 5 years of CV course, with cryoglobulinemia being the strongest independent lymphoma associated feature. Compared to HCV-CV patients, pSS-CV individuals displayed more frequently lymphadenopathy, type II IgMk cryoglobulins and lymphoma (OR = 6.12, 95% CI: 2.7-14.4) and less frequently C4 hypocomplementemia and peripheral neuropathy. CONCLUSION: pSS-CV has a severe clinical course, overshadowing the typical clinical manifestations of pSS and higher risk for early lymphoma development compared to HCV related CV. Though infrequent, pSS-CV constitutes a distinct severe clinical phenotype of pSS.

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.

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.

Efficacy of intravenous cyclosporine in a case of cytophagic histiocytic panniculitis complicated by haemophagocytic syndrome after visceral leishmania infection.

Cytophagic histiocytic panniculitis (CHP) is a rare panniculitis characterized by systemic features, due to histiocytic infiltration along with haemophagocytosis, which may also appear in bone marrow, spleen, lymph nodes, and liver. Haemophagocytic lymphohistiocytosis (HLH) is a group of autoinflammatory disorders, which include macrophage activation syndrome, sometimes observed in the course of systemic autoimmune diseases, such as juvenile chronic polyarthritis, systemic lupus erythematosus or vasculitis, and infection-associated haemophagocytic syndrome; if not promptly recognised and treated, HLH can be fatal. Visceral leishmaniasis (VL) is a systemic disease caused by different forms of Leishmania spp., an intracellular protozoa. VL is endemic in tropical countries such as in the Middle East and the Mediterranean. The typical clinical and laboratory features are fever, hepato-splenomegaly, hypergammaglobulinaemia and pancytopenia. The features of VL may mimic some haematologic diseases. We report a case of cytophagic histiocytic panniculitis and HLH, triggered by a previous visceral leishmania infection. Cyclosporine was quickly effective in this case, after failure of high-dose glucocorticoids, anakinra and etoposide.

Clinical and biological differences between cryoglobulinaemic and hypergammaglobulinaemic purpura in primary Sjögren's syndrome: results of a large multicentre study.

OBJECTIVES: To determine the clinical and laboratory differences between cryoglobulinaemic and hypergammaglobulinaemic purpura in primary Sjögren's syndrome (pSS), in a large Italian multicentre cohort. METHOD: Patients were selected according to the following criteria: fulfilling the American-European classification criteria for pSS, serum cryoglobulin and gammaglobulin levels evaluated, and lack of hepatitis C virus (HCV) infection. Multinomial analyses were performed by distinguishing three groups of pSS: (i) purpura associated with cryoglobulinaemic vasculitis (CV), (ii) purpura associated with hypergammaglobulinaemic vasculitis (HGV), and (iii) pSS patients without purpura (pSS controls). Patients with purpura but without cryoglobulins or hypergammaglobulinaemia were excluded. RESULTS: A total of 652 patients were enrolled in this study. Group 1/CV comprised 23/652 patients (3.53%), group 2/HGV 40/652 patients (6.13%), and group 3/pSS controls 589/652 (90.34%). The three groups were found to be significantly different from each other (post-estimation test: group 1/CV vs. group 3/pSS controls: p < 0.0001; group 1/CV vs. group 2/HGV: p = 0.0001; group 2/HGV vs. group 3/pSS controls: p = 0.0003), thus confirming the different phenotypes of purpura in pSS.Multivariate analyses revealed that peripheral neuropathy (p < 0.001), low C4 (p < 0.001), leucopaenia (p = 0.01), serum monoclonal component (p = 0.02), and the presence of anti-SSB/La antibodies (p = 0.02) characterized CV whereas rheumatoid factor (p = 0.001), leucopaenia (p = 0.01), serum monoclonal component (p = 0.01), and anti-SSA/Ro antibodies (p = 0.049) were significantly associated with HGV. Lymphoma was associated only with CV. CONCLUSIONS: HGV is a cutaneous vasculitis, related to a benign B-cell proliferation, whereas CV is a systemic immune complex-mediated vasculitis with complement activation and a higher risk of lymphoma, thus confirming CV but not HGV as a prelymphomatous condition in pSS.

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.

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.

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.

Vascular endothelial growth factor genetic polymorphisms and haplotypes in female patients with bisphosphonate-related osteonecrosis of the jaws.

OBJECTIVE: To investigate the polymorphisms of the vascular endothelial growth factor (VEGF) gene in relation to female patients who developed bisphosphonate-related osteonecrosis of the jaws (BRONJ). METHODS: Test subjects were 30 Italian female patients with BRONJ (Group A). Control subjects were 30 female patients with a history of intravenous bisphosphonate use without any evidence of osteonecrosis (Group B) and 125 unrelated healthy volunteers (Group C). Three single-nucleotide polymorphisms were investigated: -634 G>C, occurring in 5' untranslated region (UTR); +936 C>T, occurring in 3' UTR; and -2578 C>A of the promoter region. RESULTS: The frequency of the VEGF CAC (+936/-2578/-634) haplotype was increased in patients with BRONJ, compared with female disease-negative controls [odds ratio (OR) = 2.76, 95% CI = 1.09-4.94, P = 0.039; corrected P value: P(c) = 0.117], and was also increased compared with female healthy controls (OR = 2.11, 95% CI = 1.14-3.89, P = 0.024; corrected P value: P(c) = 0.072). The CC homozygotes of -634G>C of VEGF gene and AA homozygotes of -2578C>A have also been significantly correlated in female patients who developed BRONJ compared with healthy controls (OR = 2.04, 95% CI = 1.12-3.70, P = 0.008; corrected P value: P(c) = 0.024). CONCLUSIONS: These results suggest a possible haplotype effect of VEGF polymorphisms expression in BRONJ Italian female patients. Studies with different and larger populations possibly using TagSNP to represent all haplotypes within the VEGF gene are needed to further delineate the genetic contribution of this gene to BRONJ.

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.

Periodontal status in oral mucous membrane pemphigoid: initial results of a case-control study.

OBJECTIVE: To evaluate the periodontal status of mucous membrane pemphigoid (MMP) patients and compare it with that of healthy controls. METHODS: A prospective study was undertaken to examine the impact of gingival MMP lesions on the human periodontium of 29 patients. Parameters evaluated included full mouth plaque score (FMPS), full mouth bleeding upon probing scores, probing depths (PD), gingival recession, clinical attachment level (CAL), mobility score, furcation involvement, number of missing teeth and Machtei criteria. RESULTS: All periodontal parameters recorded were increased in cases when compared to controls in univariate statistics. The mean differences between groups in PD (0.8±0.2mm, 95% CI 0.3-1.3), CAL (1.3±0.4mm, 95% CI 0.4-2.2), FMPS (41.0±6.2%, 95% CI 28.7-53.4), FMBS (16.2±6.6%, 95% CI 3.0-29.4) and tooth loss (2±1 teeth, 95% CI 1-3) were all statistically significant (P<0.01 for all). Substantial differences in domiciliary oral hygiene routines were observed (P<0.0001). In multivariate models when FMPS was included as covariate the difference between groups in all clinical periodontal parameters was no longer statistically significant. CONCLUSIONS: Our results showed that periodontal status is worse in MMP patients if compared with healthy controls due to a substantial difference in oral hygiene. Oral health should be promoted in MMP.

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.

Topical clobetasol in the treatment of atrophic-erosive oral lichen planus: a randomized controlled trial to compare two preparations with different concentrations.

Oral lichen planus (OLP) is a chronic inflammatory disease that can be painful, mainly in the atrophic and erosive forms. Numerous drugs have been used with dissimilar results, but most treatments are empirical and do not have adequate control groups or correct study designs. However, to date, the most commonly employed and useful agents for the treatment of LP are topical corticosteroids. A randomized, double-blind, placebo-controlled trial has been designed to compare the efficacy and safety of two different formulations of clobetasol, a very potent topical steroid, in the topical management of OLP and to evaluate which gives the longest remission from signs and symptoms. Thirty-five consecutive patients were divided into two groups: the first received clobetasol propionate 0.025% and the second was given clobetasol propionate 0.05%. Both drugs were placed in 4% hydroxyethyl cellulose bioadhesive gel. Anti-mycotic prophylaxis was also added. After the end of therapy, patients received a 2-month follow-up. In all, 14 of the 15 clobetasol 0.025% patients (93%) and 13 of the 15 clobetasol 0.05% patients (87%), had symptoms improvement after 2 months of therapy (P = 0.001 in both groups). Also, 13 of the 15 clobetasol 0.025% patients (87%) and 11 of the 15 clobetasol 0.05% patients (73%) had clinical improvement after 2 months of therapy (P < 0.05 in both groups). No statistical differences were found in comparing the two different formulations. A larger concentration of the active molecules cannot further improve the therapeutic findings or optimize the obtained results in a significant manner.

Verrucous oral carcinoma: clinical findings and treatment outcomes in 74 patients in Northwest Italy.

AIM: Oral squamous cell carcinoma (OSCC) is an extremely invasive tumour of stratified squamous epithelium that spreads throughout degradation of the basement membrane (BM) and extracellular matrix (ECM). Oral verrucous carcinoma (VC) is a rare low-grade variant of OSCC. VC has a different clinical behaviour from classical OSCC and the optimal treatment is controversial. This report analyses the clinical features and outcomes in patients undergoing treatment for oral VC. METHODS: A group of 74 Northern Italian patients were studied; for each patient, agreement of histological diagnosis, age and gender, risk factors, tumor site, T classification, treatment, outcome and survival rate were examined and analysed statistically. RESULTS: The survival rate was 93.65% at 5 years and 83.44% at 10 years. Retrospective analysis showed no risk of cervical lymph node metastasis and surgical treatment results were good. CONCLUSION: Our survival rates showed a good prognosis, with no risk of cervical lymph node metastases, suggesting that most cases can be controlled by surgery alone.

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.

Implant supported prostheses with Bone System implant system: a retrospective study with follow-up period up to 13-years about 1021 fixtures.

AIM: To analyze the data collected in 13 years of clinical controls in patients with oral rehabilitation on Bone System dental implant systems and to evaluate the success, failure and complications in daily implant dentistry, without strict inclusion criteria, in order to define the success or survival or failure of dental implants. METHODS: A total of 477 patients (231 men and 246 women) received dental implants for oral rehabilitation in 3 different private dental offices in Piedmont, Italy. A total of 1 021 fixtures were implanted from 1992 to 2004; patients were followed up for a maximum of 13 years. Surgery was performed by the same operator using the same dental implant system (Bone System, Italy), with manufacturer modifications and improvements to the system as it evolved during the study period. Treatment planning and oral reconstruction on the inserted implants were carried out by 3 different specialists in prosthesis dentistry and 4 dental laboratory technicians. In the follow-up period, clinical success was defined as the degree of patient satisfaction and as the survival of restorations on dental implants. RESULTS: The survival rate of the fixtures was 95.9%; the clinical effectiveness was 92.8%; the failure rate was 4.1%. Complications included peri-implantitis, implant fractures and technical complications related to implant components and prostheses. Long-term implant survival and clinical success were not influenced by anatomic site (maxilla or mandible). CONCLUSION: Dental implant therapy is a viable option for oral rehabilitation; if correctly managed, it may provide predictable results.