Direct healthcare costs of oral cancer: A retrospective study from a tertiary care center.

The aim of this study was to retrospectively evaluate the direct costs of OSCC treatment and postsurgical surveillance in a tertiary hospital in northeast Italy. Sixty-three consecutive patients surgically treated for primitive OSCC at S. Orsola Hospital in Bologna (Italy) between January 2018 and January 2020 were analyzed. Billing records of the Emilia Romagna healthcare system and institutional costs were used to derive specific costs for the following clinical categories: operating theatre costs, intensive and ordinary hospitalization, radiotherapy, chemotherapy, postsurgical complications, visits, and examinations during the follow-up period. The study population comprised 17 OSCC patients classified at stage I, 14 at stage II, eight at stage III, and 24 at stage IV. The estimated mean total direct cost for OSCC treatment and postsurgical surveillance was €26 338.48 per patient (stage I: €10 733, stage II: €19 642.9, stage III: €30 361.4, stage IV: €39 957.2). An advanced diagnosis (stages III and IV), complex surgical procedure, and loco-regional recurrences resulted in variables that were significantly associated with a higher cost of OSCC treatment and postsurgical surveillance. Redirection of funds used for OSCC treatment to screening measures may be an effective strategy to improve overall health outcomes and optimize national health resources.

Anxiety and depression in keratotic oral lichen planus: a multicentric study from the SIPMO.

OBJECTIVES: Oral lichen planus with exclusive keratotic reticular, papular, and/or plaque-like lesions (K-OLP) is a clinical pattern of OLP that may be associated with a complex symptomatology and psychological alteration. The aim of the study was to evaluate the prevalence of anxiety (A) and depression (D) in patients with K-OLP, analyzing the potential predictors which can affect mental health status. METHODS: Three hundred K-OLP patients versus 300 healthy controls (HC) were recruited in 15 Italian universities. The Numeric Rating Scale (NRS), Total Pain Rating Index (T-PRI), and Hamilton Rating Scales for Depression and for Anxiety (HAM-D and HAM-A) were administered. RESULTS: The K-OLP patients showed statistically higher scores in the NRS, T-PRI, HAM-D, and HAM-A compared with the HC (p-value < 0.001**). A and D were found in 158 (52.7%) and 148 (49.3%) K-OLP patients. Strong linear correlations were identified between HAM-A, HAM-D, NRS, T-PRI, and employment status and between HAM-D, HAM-A, NRS, T-PRI, employment status, and female gender. Multivariate logistic regression revealed that HAM-D and HAM-A showed the greatest increase in the R2 value for A and D in the K-OLP patients, respectively (DR2 = 55.5% p-value < 0.001**; DR2 = 56.5% p-value < 0.001**). CONCLUSIONS: The prevalence of A and D is higher in the K-OLP patients compared with the HC, also found in K-OLP subjects without pain, suggesting that the processing of pain may be in a certain way independent of the processing of mood. CLINICAL RELEVANCE: Mood disorders and pain assessment should be carefully performed in relation to K-OLP to obtain a complete analysis of the patients.

Surgical management of gingival recessions in patients with refractory gingival pemphigus vulgaris: A multidisciplinary challenge.

BACKGROUND: Mucogingival surgery for root coverage of gingival recessions (GRs) is usually performed in patients with unremarkable periodontal and systemic health. However, the predictable results of surgical procedures and increasingly high aesthetic expectations of patients necessitate optimal management of GR also in patients with systemic conditions that affect the oral cavity. In patients with pemphigus vulgaris (PV), mucosal fragility and complicated surgical management of inflamed soft tissues are major challenges. METHODS AND RESULTS: A 36-year-old female patient with PV and deep GR on the mandibular incisors is presented. After initial unresponsiveness to steroids and immunosuppressants, complete clinical remission was achieved through repeated rituximab infusions and topical platelet-rich plasma. After > 1 year of stable clinical remission off therapy the patient successfully underwent surgical procedures for vertically coronally advanced flap with connective tissue graft. CONCLUSIONS: To the best of our knowledge, no studies have described the surgical management of GR in PV patients. Although controlled studies are required to confirm present results, complete and stable clinical remission is necessary to avoid complications. Collaboration among dermatologists, oral medicine specialists, and periodontologists is essential to determine whether mucogingival surgery for root surface exposure is indicated for PV patients. KEY POINTS: Why are these cases new information? This is the first report of root coverage in a patient with oral PV What are the keys to the successful management of these cases? The achievement of complete and stable clinical remission from oral PV Multidisciplinary collaboration among dermatologists, oral medicine specialists, and periodontologists What are the primary limitations to success in these cases? The refractoriness of gingival lesions induced by PV Poor mucogingival conditions of inflamed gingival tissues exacerbated by PV.

Where do you live? North versus Central-South differences in relation to Italian patients with oral lichen planus: a cross-sectional study from the SIPMO (Italian Society of Oral Pathology and Medicine).

BACKGROUND: Oral lichen planus (OLP) is an immune-mediated inflammatory chronic disease of the oral mucosa, with different patterns of clinical manifestations which range from keratotic manifestations (K-OLP) to predominantly non-keratotic lesions (nK-OLP). The aim of the study was to analyze the differences in the clinical, psychological profile and symptoms between Italian patients of the North and Central-South with K-OLP and nK-OLP. METHODS: 270 K-OLP and 270 nK-OLP patients were recruited in 15 Italian universities. The Numeric Rating Scale (NRS), Total Pain Rating Index (T-PRI), Hamilton Rating Scales for Depression and for Anxiety (HAM-D and HAM-A), Pittsburgh Sleep Quality Index (PSQI), and Epworth Sleepiness Scale (ESS) were administered. RESULTS: The Central-South K-OLP (CS-K-OLP) patients reported a higher frequency of pain/burning compared with the K-OLP patients of the North (N-K-OLP) with higher scores in the NRS and T-PRI (p value < 0.001**). The CS-K-OLP and the CS-nK-OLP patients showed higher scores in the HAM-D, HAM-A, PSQI and ESS compared with the Northern patients (p value < 0.001**). Multivariate logistic regression revealed that the NRS and T-PRI showed the greatest increase in the R2 value for the CS-K-OLP (DR2 = 9.6%; p value < 0.001**; DR2 = 9.7% p value < 0.001**; respectively) and that the oral symptoms (globus, itching and intraoral foreign body sensation) and PSQI showed the greatest increase in the R2 value for the CS-nK-OLP (DR2 = 5.6%; p value < 0.001**; DR2 = 4.5% p value < 0.001** respectively). CONCLUSIONS: Pain and mood disorders are predominant in patients with OLP in the Central-South of Italy. Clinicians should consider that the geographical living area may explain the differences in oral symptoms and psychological profile in OLP.

Assessment of sleep disturbance in oral lichen planus and validation of PSQI: A case-control multicenter study from the SIPMO (Italian Society of Oral Pathology and Medicine).

BACKGROUND: The wellbeing of oral lichen planus patients (OLPs) may be strongly influenced by a poor quality of sleep (QoS) and psychological impairment. The aims were to analyze the prevalence of sleep disturbance, anxiety, and depression in OLPs and to validate the Pittsburgh Sleep Quality Index (PSQI) in OLPs. METHODS: Three hundred keratotic OLPs (K-OLPs), 300 with predominant non-keratotic OLP (nK-OLPs), and 300 controls were recruited in 15 Italian universities. The PSQI, Epworth Sleepiness Scale (ESS), Hamilton Rating Scales for Depression and Anxiety (HAM-D and HAM-A), Numeric Rating Scale (NRS), and Total Pain Rating Index (T-PRI) were administered. RESULTS: Oral lichen planus patients had statistically higher scores than the controls in the majority of the PSQI sub-items (p-values < 0.001**). Moreover, OLPs had higher scores in the HAM-D, HAM-A, NRS, and T-PRI (p-values < 0.001**). No differences in the PSQI sub-items' scores were found between the K-OLPs and nK-OLPs, although nK-OLPs suffered from higher levels of anxiety, depression, and pain (p-values: HAM-A, 0.007**, HAM-D, 0.009**, NRS, <0.001**, T-PRI, <0.001**). The female gender, anxiety, depression (p-value: 0.007**, 0.001**, 0.020*) and the intensity of pain, anxiety, and depression (p-value: 0.006**, <0.001**, 0.014*) were independent predictors of poor sleep (PSQI > 5) in K-OLPs and nK-OLPs, respectively. The PSQI's validation demonstrated good internal consistency and reliability of both the total and subscale of the PSQI. CONCLUSIONS: The OLPs reported an overall impaired QoS, which seemed to be an independent parameter according to the regression analysis. Hence, clinicians should assess QoS in OLPs and treat sleep disturbances in order to improve OLPs management.

Prognostic impact of intra-field heterogeneity in oral squamous cell carcinoma.

Genetic heterogeneity displayed by tumour cells (intratumoural heterogeneity, ITH) represents a diagnostic challenge when assessing tumour mutational profile. In oral squamous cell carcinoma (OSCC), ITH may be found both in tumour cells and in adjacent mucosa. Genetic heterogeneity of the adjacent mucosa can be interpreted as evidence of the field cancerization (field heterogeneity, FH). The aim of the study was to investigate the impact of intratumoural and intrafield heterogeneity on locoregional control. Ten OSCC patients (5 recurrent and 5 nonrecurrent) were studied. Multiple areas were sampled from the bulk of the tumour and the adjacent nonneoplastic mucosa. A panel of 10 tumour-specific OSCC driver genes was analysed for each sample and was used to calculate heterogeneity. Values were compared among recurrent and nonrecurrent OSCC. Mutational analysis highlighted that a single tumour sample has limited accuracy in assessing the genetic profiles of tumours. High values of ITH considering shared mutations between specimens were found in both recurrent and non-recurrent OSCC (p = 0.095). On the contrary, the intrafield genetic heterogeneity was significantly less frequently in the non-recurrent OSCC group (p = 0.032). Heterogeneity within each specimen calculated with variant allele frequency confirmed that there was better discrimination between recurrent and nonrecurrent groups using nonneoplastic adjacent mucosa than tumour tissue (p value 0.0006 and 0.0048 respectively). In agreement with the theory of field cancerization, intrafield genetic heterogeneity correlates with a higher risk of developing loco-regional recurrences and second primaries. In order to reduce the ITH effects, analysis of multiple tumour areas should be encouraged.

Multi-Region Sequence Analysis of a Pregnancy-Related Oral Squamous Cell Carcinoma Exhibiting Low-Level Aggressive Behavior.

We analyzed the genetic and epigenetic profiles of an oral squamous cell carcinoma affecting a 41-year-old pregnant female. The patient presented with an oral mass located at the hard and soft palate with bone involvement and lymph node metastases (T4N1M0). She had been treated with multimodal radiotherapy and chemotherapy, and she is currently alive with no evidence of disease 8 years after treatment. DNA methylation and DNA mutation analyses were used to analyze multiple samples from the tumor mass and from the non-neoplastic mucosa to verify tumor heterogeneity. Genetic and epigenetic analyses revealed the presence of one shared TP53 driver mutation with the same DNA methylation profile in each of the 3 areas of the tumor mass; only 2 additional passenger mutations were detected, suggesting a simple clonal homogeneous carcinoma, which usually is associated with low-level aggressive behavior. Additionally, no genetic or epigenetic alteration in the non-neoplastic oral mucosa was detected, demonstrating the absence of field cancerization. The low aggressiveness of the lesion was confirmed by the patient being free of disease at a long-term follow-up examination. These data suggest a different molecular transformation pathway in pregnancy-related oral squamous cell carcinomas, providing new perspectives for further investigation.

Beyond Head and Neck Cancer: The Relationship Between Oral Microbiota and Tumour Development in Distant Organs.

An altered oral microbiota has been linked with the development of several oral diseases, such as dental caries, periodontal disease, and oral stomatitis. Moreover, poor oral health has been linked to head and neck cancer, particularly oral cancer. In recent years a growing number of studies indicate that oral microbiota could be involved in the development of primary tumours outside of head and neck region. The aim of this article is to review the recent studies based on high-throughput technology to present evidences of a relationship between oral microbiota and "non-head and neck tumours." Oral dysbiosis seem to be more pronounced in patients with tumours of gastrointestinal tract, in particular oesophageal, gastric, pancreatic, and colorectal cancers, paving the way for developing specific oral microbiota test to allow early cancer detection. Regarding other tumour types, the results are promising but highly preliminary and still debated. Currently, there are several factors that limit the generalization of the results, such as the small sample size, the lack of adequate clinical information about patients, the different sequencing techniques used, and biological sample heterogeneity. Although only at the beginning, the analysis of oral microbiota could be the next step in the evolution of cancer therapy and will help clinicians to develop individualised approaches to cancer prevention and treatment.

Intratumoral Heterogeneity in Recurrent Metastatic Squamous Cell Carcinoma of the Oral Cavity: New Perspectives Afforded by Multiregion DNA Sequencing and mtDNA Analysis.

PURPOSE: Improvements in sequencing technologies have shown that genetic differences among neoplastic cells can reflect clonal expansion. Intratumor heterogeneity (ITH) has been suggested to explain differences in prognosis and treatment response, indicating that personalized medicine is the goal of the future. This study evaluated ITH in 5 patients with recurrent metastatic oral squamous cell carcinoma (OSCC) and tracked the evolution from non-neoplastic tissue to neoplastic events developing after primary tumor formation. PATIENTS AND METHODS: Representative regions were macrodissected from specimens obtained from patients with OSCC of the tongue (n = 4) and floor of the mouth (n = 1). ITH and tumor evolution were explored by analyzing DNA mutations disclosed by next-generation sequencing of specific driver genes combined with changes in the mtDNA D-loop hypervariable region. Phylogenetic trees were generated employing MAFFT tool with UPGMA/Jukes-Cantor serving as the substitute model. RESULTS: High levels of heterogeneity were observed within and among tumors. ITH emerged as metastatic and recurrent events progressed, but the evolutionary patterns differed. In some patients, specific subclones persisted during tumor relapse. Neighboring tissue also was heterogeneous at the premalignant level. CONCLUSIONS: A multiregion approach yielded more representative data than did single samples when tumors were subjected to molecular investigation. Persistent mutations that might be targeted by individualized medicine were thus exposed. Mitochondrial DNA is a useful adjunct tool when studying the phylogenetic evolution of subclones. The clinical implications of "field" heterogeneity should be studied in depth.

Podoplanin expression as a predictive marker of dysplasia in oral leukoplakia.

PURPOSE: Recent studies have emphasized the role of podoplanin in oral lesions at risk of malignant transformation. We investigated a group of oral leukoplakias (OLs) to determine a possible relation between altered podoplanin expression and dysplasia, and to compare the results with those obtained by other, widely used biomarkers. MATERIALS AND METHODS: The population consisted of 40 consecutive patients with a clinical and histological diagnosis of OL. Thirty-two OLs did not show dysplasia, whereas eight lesions presented with dysplasia. Immunohistochemical expression of podoplanin, p53 and Ki67 was analyzed in all samples. RESULTS: All three biomarkers were positive in seven of eight dysplastic OLs. Among the 32 OLs without dysplasia, Ki67 and p53 showed positive values in 21 and 10 samples respectively, whereas podoplanin was positive in only one case. Multiple logistic regression showed that podoplanin was the most powerful variable (Chi square 9.77; p < .01) statistically related to the presence of dysplasia. In addition, podoplanin showed a higher specificity value (96.87%) than Ki67 (34.37%) and p53 (68.75%). CONCLUSION: Podoplanin seems to be a reliable means of discriminating lesions with epithelial dysplasia and could be introduced in routine practice as a marker to discriminate OLs at risk of developing cancer.

Two Unusual Cases of Oral Lichen Planus Arising After Oral Squamous Cell Carcinoma: Can Oral Cancer Trigger Autoimmunity?

Autoimmune diseases occur when the immune system fails to recognize self-antigens expressed on the body's own cells and attacks them. Oral lichen planus (OLP) is a chronic autoimmune mucocutaneous disease of the oral cavity characterized by white/red lesions. Considered a potentially malignant disorder, OLP evolution into oral squamous cell carcinoma (OSCC) is still a matter of debate. While chronic autoimmune inflammation is considered a potential risk factor for malignant transformation in many solid tumors, the opposite idea that cancer may trigger autoimmune responses remains controversial. We describe 2 patients who developed lesions clinically suggestive of OLP with histological evidence of lichenoid infiltration some time after OSCC removal, even in areas far from the neoplastic site. Neither patient had OLP before the diagnosis of OSCC, or reported exposure to OLP-associated etiologic factors, and neither. experienced tumor recurrence during follow-up. Our findings suggest that oral cancer remission may be linked to OLP development, but further studies are necessary to unveil the underlying mechanisms and possible prognostic implications.

Ki67 Overexpression in mucosa distant from oral carcinoma: A poor prognostic factor in patients with long-term follow-up.

PURPOSE: The aggressive behavior of oral squamous cell carcinoma (OSCC) has recently been related to the mucosa surrounding the primary mass, consisting of genetically altered cells that might be responsible for cancer progression. The aim of the study was to determine whether an abnormal cell turnover in clinically and histologically "normal" mucosa distant from the primary tumor is associated with a poor prognosis in terms of locoregional control (LRC) of disease and disease-specific survival (DSS). MATERIAL AND METHODS: This prospective study monitored 55 OSCC patients. Cell turnover in areas clinically and histologically distant from the tumor mass was evaluated by immunohistochemical expression of Ki67. A Ki67 value >20% was considered "high." RESULTS: The mean follow-up period of the population studied was 53.7 ± 32.4 months (range 12-110 months). Multivariate analysis showed that the Ki67 value in distant mucosa was a powerful independent prognostic factor for LRC. In addition, high Ki67 expression in distant mucosa was the only variable statistically related to worse LRC (χ(2) = 9.5; p = 0.002) and DSS (χ(2) = 5.51; p = 0.02) in T1-2N0 OSCCs. CONCLUSIONS: The present study confirmed the role of Ki67 in tumor-distant areas as a prognostic marker for OSCC patients.

Unusual Histological Evidence of Dysplasia in a Case of Oral Pemphigus Vulgaris: A Potential Diagnostic Challenge.

This report describes the management of an unusual case of oral pemphigus vulgaris (PV). The patient was referred for a painful single bullous lesion together with a small proliferative area localized in the soft palate. Histology and direct immunofluorescence data were consistent for PV but disclosed unusual signs of high-grade dysplasia in the proliferative area. At surgical removal of the dysplastic area 1 week after the start of cortisone therapy there was no evidence of dysplasia. Histological signs of high-grade dysplasia in oral mucosa are often associated with concurrent or subsequent carcinoma. However, severe inflammation may induce reactive epithelial cell changes and hence mimic histologic dysplasia. Pathologic evaluation of dysplasia in an inflammatory disease like PV may be a diagnostic challenge and a careful pathological evaluation is advisable before choosing between surgical and medical approach.

Laser evaporation versus laser excision of oral leukoplakia: A retrospective study with long-term follow-up.

OBJECTIVES: The study makes a comparison between two surgical approaches for the treatment of oral leukoplakia (OL) in terms of recurrence in a well-defined cohort of patients with a long-term follow-up period. METHODS: The cohort consisted of 77 OL patients divided into 2 groups. Group 1: 47 patients treated with laser evaporation using a Nd:YAG laser. Group 2: 30 patients treated with a CO2 laser for excision. Clinical and histological examinations were performed for the diagnosis of OL before treatment. We included OLs with or without dysplasia. The mean follow-up period was 60 ± 32.49 months. RESULTS: Of the 77 patients, 22 (28.5%) showed recurrence during the follow-up period. No significant difference was found between the two treatments (χ(2) = 2.6; p = 0.2). However, CO2 laser excision resulted in better results than the Nd:YAG laser evaporation, considering the non-homogeneous OLs (χ(2) = 3.9; p = 0.04) and OLs with mild dysplasia (χ(2) = 4.6; p = 0.03). DISCUSSION: The study makes a comparison between our results and articles from the literature, and suggests when each of the two surgical approaches is most appropriate.

Clinicopathologic parameters related to recurrence and locoregional metastasis in 180 oral squamous cell carcinomas.

Lymph node metastasis (LNm), local recurrence (LR), and second primary tumor (SPT) after primary surgery for oral squamous cell carcinoma (OSCC) have been considered poor prognostic entities in terms of survival rate. The purpose of this study was to identify the clinicopathologic parameters significantly related to LNm, LR, and SPT. Records from 180 patients who underwent radical surgery for OSCC were retrospectively reviewed. Perineural invasion was significantly related to LNm (18% vs 8%) and LR (15% vs 5%), while the status of the surgical margin (10% in case of clear margins, 18% close margins, and 24% involved margins), namely epithelial precursor lesions (43%) was an independent factor influencing SPT. Perineural invasion proved a good prognostic factor for early events, either LNm or LR, while a surgical margin width less than 5 mm or with epithelial precursor lesions may be considered a risk factor for late events such as SPT.

Genetic relationship between multiple squamous cell carcinomas arising in the oral cavity.

BACKGROUND: Histological and clinical criteria are generally used to differentiate second primary tumors (SPTs) from local recurrences. The purpose of the present study was to apply mitochondrial DNA (mtDNA) D-loop analysis to differentiate SPTs from local recurrences and to validate the clinical classification. METHODS: The study population consisted of 20 consecutive patients presenting multiple oral neoplastic lesions for a total of 25 paired lesions. The mtDNA D-loop analysis was performed by direct sequencing and phylogenetic clusterization. RESULTS: Agreement between mtDNA analysis and clinical classification was found in 19 cases. Discrepancies arose in 6 cases in which the clinical criteria based only on the spatial or temporal distance of the second lesion from the index tumor had led to a diagnosis of SPT (2 cases) or local recurrence (4 cases). CONCLUSION: The present data highlight the value of mtDNA analysis in establishing the clonal relationship between the index tumor and the second neoplastic lesion.

Paraneoplastic pemphigus presenting with a single oral lesion.

Paraneoplastic pemphigus (PNP) is recognised in most cases after diagnosis of malignant and benign haematological tumours. PNP usually presents with severe and diffuse oral ulcerations, ocular lesions, lichen planus-like skin lesions and frequently genital ulcerations. We describe the uncommon case of a patient unaware of any neoplasia with a unique ulcerated oral lesion with histological (acantholysis of the basal epithelial layer, necrotic keratinocytes and pronounced regenerative hyperplasia) and immunofluorescent (direct immunofluorescence test exhibited immunoglobulin IgG, fibrinogen and C3 deposition in intercellular areas and along the basement membrane; indirect immunofluorescence test performed on rat bladder showed bright fluorescence) features suggestive of PNP. Diagnosis of PNP was strengthened by the subsequent discovery of monoclonal gammopathy. The reported case is quite unusual if we consider the clinical appearance of the oral lesions and the patient's negative medical history. Following serological examinations, the patient proved to have monoclonal gammopathy of undetermined significance (MGUS), one of the most common premalignant plasma cell disorders.