Potential use of optical coherence tomography in oral potentially malignant disorders: in-vivo case series study.

BACKGROUND: Evidence confirms that the use of Optical Coherence Tomography (OCT) in oral medicine can be a reliable aid for the diagnosis and management of Oral Potentially Malignant Disorders (OPMDs). Several authors described the ability of this system to detect the structural changes of the epithelia involved by the OPMDs. The purpose of this case series is to provide a suggestion for interpretation of OCT images from different OPMDs, compared to OCT images of healthy tissues. METHODS: A sample of 11 OPMDs patients was recruited and analyzed with OCT. The images obtained were then compared with an OCT repertoire image. In this work the reflectance degree was considered, together with the analysis of the increased/decreased thicknesses of the various layers. Keratin Layer (KL), Epithelial Layer (EP), Lamina Propria (LP), Basal Membrane (BM) assessment, for each lesion, was performed. RESULTS: OCT measurements of KL, EP and LP layers, together with BM assessing, should aid the physicians to recognize and describe different oral lesions, relating them to the corresponding oral pathology. CONCLUSION: More studies like this, on larger samples, are needed to validate the results and provide, in the future, a kind of manual that could guide clinicians to correctly interpret the OCT images in relation to the causing pathologies. TRIAL REGISTRATION: The present trial has been registered with ISRCTN (#17,893,224).

Population-based cohort study to assess the gingival lesions in 1319 patients with lichen planus.

AIMS: Oral lichen planus (OLP) is a chronic immune disease. In this paper, we evaluated the overall characters, clinical presentation, and outcome of gingival lesions in OLP Italian patients. METHODS AND RESULTS: A retrospective cohort study was accomplished: a total of 1319 charts were investigated, of whom 922 were female (69.9%): 617 patients (46.8%) manifested white lesions and 702 red ones (53.2%). While most patients had several oral sites of involvement, the gingiva was the unique location in 103 cases. Symptoms were reported in 480 patients (36.4%): 286 patients with erosive OLP, 103 with atrophic form, and 91 with a white form. Long-lasting surveillance showed that only 40 patients (3.03%) had a total clinical signs remission. Regarding OLP medical treatment provided, patients attending less frequently a dental office underwent more often a specific therapy. CONCLUSIONS: To the best of our knowledge, this is the biggest collections of patients with gingival OLP ever described; exclusive gingival lesions are, however, rare and unlikely to undergo a malignant transformation. Moreover, gum lesions seemed to anticipate the appearance of oral lesions and a higher rate of OLP therapy was observed in patients with less frequent dental check-ups and oral hygiene instructions.

In vivo evaluation of traumatic and malignant oral ulcers with optical coherence tomography: A comparison between histopathological and ultrastructural findings.

Ulcers in the oral mucosa is a relatively common, although challenging, entity in oral medicine, as it can arise due to a wide range of traumatic, infective, autoimmune, and neoplastic disorders. Although histopathology of lesional and peri­lesional tissues remains the gold standard for persistent oral breaching, optical coherence tomography (OCT) has been recently suggested as a potential ally to enhance the early or non-invasive diagnosis of likely causation. The aim of the present study was to provide an in-vivo OCT analysis and description from a sample of 70 patients affected by traumatic or neoplastic-related ulcers, located on the buccal mucosa, tongue or gingiva, and compare the OCT data with those of 20 patients with healthy oral mucosa. OCT dynamic scans revealed clear distinction of epithelial layer (EP), lamina propria (LP) of healthy buccal mucosa, gingiva, and tongue as well as allowing observation of the keratin layer in gingiva, and the subepithelial vascularization of each site. Traumatic lesions had an EP of reduced in thickness, with an irregular, if not disrupted surface. Interestingly, LP seemed to preserve its reflectiveness and vascularization only in the traumatic lesions. Among neoplastic lesions, regardless their site of onset, both EP integrity/homogeneity, and LP reflectiveness/vascularization were lost and unrecognizable when compared to their healthy counterparts. OCT scanning allowed some differentiation between traumatic and malignant ulcers and thus may a useful and non-invasive means of determining the need and/or urgency of histopathological examination of oral lesions.

Oral health status after hematopoietic stem cell transplantations: Outcomes from an adult Italian population.

AIM: To describe oral cavity changes in patients who underwent a hematopoietic stem cell transplantation (HSCT). METHODS AND RESULTS: A group of 32 patients was studied after a mean period of 48.8 months (±11.22) from HSCT; oral, dental, and periodontal status were collected and compared with those of healthy matched controls. Unstimulated whole salivary flow (UWS) and salivary pH were also measured. A validated questionnaire (EORTC QLQH&N-35) was used for reported quality of life. Fifty-nine percent of patients were affected by chronic graft-versus-host disease (cGVHD). Dental health and periodontal status were statistically worse than in controls (P = .003 and P = .008, respectively). Regarding the HSCT group, UWS was statistically lower, and EORTC QLQH&N-35 significantly higher than those reported in controls (P = .000 for both). There was no statistical correlation between hypo-salivation and conditioning, presence of cGVHD, type of medication used before and after transplantation, and time of follow-up. A reduction in salivary pH has been noted only for patients with erosive oral lesions. CONCLUSION: The oral cavity of HSCT patients appeared to undergo substantial modifications and the quality of life was deeply compromised.

A single-center prospective pilot open-label study to assess the efficacy of topical application of an oxygen-enriched oil for the treatment of angular cheilitis.

PURPOSE: The aim of this pilot study was to clarify the acceptability and clinical efficacy of an oxygen-enriched oil-based gel for treatment of angular cheilitis. METHODS: A class IIb medical preparation, packaged in appropriate syringes, was tested. Patients were instructed how to use the gel for 10 days: finger rub application (3 times daily) on the dried lesion after meals, without eating, drinking, or speaking for at least 30 min thereafter. The Wilcoxon signed-rank test was used to assess whether there were any differences in the distributions of reported pain and lesion dimension. A microbiological examination was also performed with oral swabs; chi-squared test was used to compare the difference in the presence of microorganisms before and after treatment. RESULTS: Thirty patients were treated. A significant improvement in reported outcome and a significant reduction in the initially measured largest dimension of the lesion were observed after use of the clinical protocol. Additionally, a significant reduction in the pathogen count was found. CONCLUSION: Even if with limitations, data showed that this medical preparation facilitated prompt recovery from reported pain, without adverse reactions. Further work with a larger study population, and possibly a randomized control medication, will be needed.

Risk of Malignant Transformation in 3173 Subjects with Histopathologically Confirmed Oral Lichen Planus: A 33-Year Cohort Study in Northern Italy.

BACKGROUND: Oral lichen planus (OLP) is considered an oral potentially malignant disorder. The aim of our study was to estimate the risk for oral cancer in patients diagnosed with OLP. METHODS: A population-based cohort study between January 1988 and December 2020 at one hospital in Northern Italy was performed. The primary endpoint of the study was that of the histopathological diagnosis of oral cancer during the follow-up period. RESULTS: The study population comprised 3173 patients. During the follow-up period, 32 men and 50 women developed an oral squamous cell carcinoma (2.58%), with a mean time of 103.61 months after the initial diagnosis of OLP, and 21 patients died because of oral cancer. Almost half of the deceased patients had the last follow-up visit before cancer diagnosis in a period of more than 12 months. Older age, having a red form of OLP and fewer sites of involvement, increased the risk of having cancer, while age and no treatment increased the risk of death. CONCLUSION: This is the largest group of OLP patients with such a long follow up ever reported. Due to the increased risk of having a malignant transformation, especially in elderly subjects, OLP patients should be regularly followed up, particularly in the Northern Italian population.

A Randomized Controlled Trial on Efficacy of Surgical Excision of Nondysplastic Leukoplakia to Prevent Oral Cancer.

The aim of this study was to evaluate the effectiveness of surgical excision to prevent cancer in patients with nondysplastic oral leukoplakia (OL). This study was the first randomized controlled clinical trial comparing surgical treatment with standard care in this group of patients. Patients were divided into two groups. The first group underwent standard care, that is smoking counseling, follow-up visits every 6 months, and control biopsy when indicated. The second group underwent surgical excision, together with standard care. Oral cancer onset was the primary outcome; secondary outcomes included healing, recurrence after surgery, onset of new lesions, and worsening of the primary lesions. The differences in distribution of the patients' and lesions' characteristics were investigated through nonparametrical tests (Wilcoxon rank-sum and Fisher exact). Univariate and multivariate logistic regressions have been performed to estimate the odds ratio of the treatment on the recurrence or worsening of the lesions. A total of 260 patients took part in the study of which 132 were women (50.8%); during the follow-up period, two subjects developed oral cancer, one for each arm. Surgical treatment, when compared with standard care, was associated with a lower probability of the treated zone to remain healed during the follow up period (OR = 7.43; 95% confidence interval, 2.96-22.66). In conclusion, it is possible to assumed that regular clinical follow-up could be considered a reliable standard of care among patients with nondysplastic OLs.Prevention Relevance: Oral white patches can transform into cancer and none has provided clinical guidelines to prevent it. For the first time ever, we have showed that the clinical follow up of non dysplastic lesions was able to provide benefits if compared with surgical excision.

Evaluating the Suitability and Potential Efficiency of Cannabis sativa Oil for Patients with Primary Burning Mouth Syndrome: A Prospective, Open-Label, Single-Arm Pilot Study.

OBJECTIVE: To evaluate the use of a Cannabis sativa oil in the management of patients diagnosed with primary burning mouth syndrome (BMS). DESIGN: Prospective, open-label, single-arm pilot study. SETTING: University hospital. SUBJECTS: Seventeen patients with diagnosed BMS were included. METHODS: Subjects were treated for 4 weeks with a full cannabis plant extract, which was prepared from standardized plant material (cannabis flos) in specialized pharmacies by means of Romano-Hazekamp extraction and was diluted in oil (1 g of cannabis in 10 g of olive oil). The primary outcome was the change in pain intensity (assessed by the visual analog scale, Present Pain Intensity scale, McGill Pain Questionnaire, and Oral Health Impact Profiles) at the end of the protocol and during the succeeding 24 weeks; the neuropathic pain was also investigated with a specific interview questionnaire (DN4-interview [Douleur Neuropathique en 4 Questions]). Levels of anxiety and depression were considered as secondary outcomes, together with reported adverse events due to the specified treatment. RESULTS: Subjects showed a statistically significant improvement over time in terms of a clinical remission of the oral symptoms. Levels of anxiety and depression also changed statistically, displaying a favorable improvement. No serious reactions were detailed. None of the patients had to stop the treatment due to adverse events. CONCLUSIONS: In this pilot evaluation, the C. sativa oil provided was effective and well tolerated in patients with primary BMS. Further bigger and properly defined randomized controlled trials, with different therapeutic approaches or placebo control, are needed, however.

In-vivo usefulness of optical coherence tomography in atrophic-erosive oral lichen planus: Comparison between histopathological and ultrastructural findings.

Oral lichen planus (OLP) is a common premalignant chronic inflammatory disorder. Optical Coherence Tomography (OCT) provides a real-time, non-invasive, and in-situ optical signature using light of varying wavelengths to examine tissue. Aim of the present study was to assess the possible role of OCT as diagnostic tool for atrophic-erosive OLP by examining OCT scans of healthy buccal mucosa, and comparing their ultrastructural features with those of a buccal mucosa affected by atrophic-erosive OLP, using their histopathological counterparts as the gold standard. Through grayscale (enface scan) and an application in which the vascularization of the tissue is visible (dynamic scan), it was possible to distinguish the healthy from the lichenoid pattern from 20 controls (12 M; 8 F; mean age: 41.32 years) and 20 patients with histologically confirmed atrophic-erosive OLP (7 M; 13 F; mean age: 64.27 years). In detail, mean width of stratified squamous epithelium (EP) and lamina propria (LP) were evaluated. Among controls, EP and LP showed a mean width of 300 (±50) and of 600 (±50) µm respectively; among cases, disruption of membrane basement prevented from any measurement. Furthermore, a differential pattern of EP and LP emerged between the two groups: a light-grayish, hypo-reflective, homogeneous area of EP recurring in controls turned into a hyper-reflective, non-homogeneous area among cases. Dynamic scan showed a differential profile of LP vascularization, varying from a hypo-reflective red area with small blood vessels in the control group, to a hypo/hyper-reflective area, completely overrun by a denser, wider blood flow amid OLP cases. Although histopathological examination remains the gold standard for OLP diagnosis, OCT could be a potentially helpful tool for the clinician and the pathologist, since it allows analysis of the vascularization of the sample without adversely affecting histological processing.

Effect of two different alcohol-free chlorhexidine formulations in mouthrinses on the immediate postoperative period for oral mucosal biopsies.

Oral biopsy is a common surgical practice. To date, few authors have described the healing of mucosal wounds following oral biopsy. The aim of the present single-center, prospective, randomized, controlled study is to evaluate the differences between two chlorhexidine (CHX) mouthrinses and a treatment-free approach in the immediate postoperative period following oral mucosal biopsy. 354 patients were included in this study and were randomly allocated to three groups: A) CHX 0.12% mouthrinse (twice daily, 10 mL rinse for 30 s), B) CHX 0.20% mouthrinse (twice daily, 10 mL rinse for 30 s), and C) no topical treatment. 118 patients were treated in group A and 115 in group B; 121 received no therapy in group C, reporting the greatest improvement in related symptoms. Outcome variables included the age, gender, site and size of lesions, visual analog score (VAS), Oral Health Impact Profile questionnaire (OHIP-14), and number of painkillers taken during the first week post-surgery. Use of a CHX 0.12% mouthrinse exhibited the poorest outcome. On the other hand, best clinical healing was found for patients treated with CHX 0.20%. These findings suggest that regardless of its concentration, CHX was found to be ineffective in reducing related symptoms, whereas CHX 0.20% can be recommended to facilitate enhanced healing.

Treatment Outcome of Oral Leukoplakia with Er:YAG Laser: A 5-Year Follow-Up Prospective Comparative Study.

Objective: The purpose of this prospective analysis was to evaluate the efficacy of erbium-substituted yttrium aluminum garnet (Er:YAG) laser compared with that of conventional surgery, regarding the long-term outcome of nondysplastic oral leukoplakias (OL). Background: To date, this comparison has never been performed. Methods: Patients were randomly allocated to two different groups: some underwent surgical excision with traditional scalpel (Group TrSc) and others underwent an ablative session with Er:YAG laser (Group Las), with these modalities: 1.5-W power, 150-mJ pulse energy, 10-Hz frequency, 500-µs pulse duration, and 0.9-mm spot size. During the follow-up period, the evolution of the OL was listed as (1) healing: if novel lesions did not appear in the same place of the surgery and (2) recurrence: if a new mucosal change has been detailed in the equivalent place of the primary disease. Results: One hundred seventeen lesions were treated. Fifty-eight lesions underwent surgery with traditional scalpel, whereas 59 underwent laser surgery. Follow-up ranged from 24 to 108 months (median of 58). Healing was detailed for 52.99% (n = 62) of the 117 OL, with no statistical differences between the two randomized groups. Conclusions: It seems reasonable to consider the Er:YAG laser as effective as traditional scalpel in terms of healing for OL, with the same rate of recurrences in a period of almost 5 years.

Salivary extracellular vesicle-associated miRNAs as potential biomarkers in oral squamous cell carcinoma.

BACKGROUND: Several studies in the past have investigated the expression of micro RNAs (miRNAs) in saliva as potential biomarkers. Since miRNAs associated with extracellular vesicles (EVs) are known to be protected from enzymatic degradation, we evaluated whether salivary EVs from patients with oral squamous cell carcinoma (OSCC) were enriched with specific subsets of miRNAs. METHODS: OSCC patients and controls were matched with regards to age, gender and risk factors. Total RNA was extracted from salivary EVs and the differential expression of miRNAs was evaluated by qRT-PCR array and qRT-PCR. The discrimination power of up-regulated miRNAs as biomarkers in OSCC patients versus controls was evaluated by the Receiver Operating Characteristic (ROC) curves. RESULTS: A preliminary qRT-PCR array was performed on samples from 5 OSCC patients and 5 healthy controls whereby a subset of miRNAs were identified that were differentially expressed. On the basis of these results, a cohort of additional 16 patients and 6 controls were analyzed to further confirm the miRNAs that were up-regulated or selectively expressed in the previous pilot study. The following miRNAs: miR-302b-3p and miR-517b-3p were expressed only in EVs from OSCC patients and miR-512-3p and miR-412-3p were up-regulated in salivary EVs from OSCC patients compared to controls with the ROC curve showing a good discrimination power for OSCC diagnosis. The Kyoto Encyclopedia of Gene and Genomes (KEGG) pathway analysis suggested the possible involvement of the miRNAs identified in pathways activated in OSCC. CONCLUSIONS: In this work, we suggest that salivary EVs isolated by a simple charge-based precipitation technique can be exploited as a non-invasive source of miRNAs for OSCC diagnosis. Moreover, we have identified a subset of miRNAs selectively enriched in EVs of OSCC patients that could be potential biomarkers.

Case Report: Sporadic Burkitt lymphoma misdiagnosed as dental abscess in a 15-year-old girl.

Background: Burkitt lymphoma (BL) is a non-Hodgkin's B-cell tumor that can be classified into three variants, based on clinical characteristics and epidemiology: endemic, human immunodeficiency-related and sporadic. Oral sporadic BL is quite an unusual entity, with the gastrointestinal trait being often the first site of appearance. Clinical finding: A 15-year-old patient that presented a symptomatic swelling of the right maxilla, unsuccessfully treated as a primary endodontic disease, displaying solid tissue on CT scan, "starry sky" pattern on oral biopsy, multifocal bone and lymph node uptake on PET. Diagnoses, interventions, and outcomes: A diagnosis of stage IV BL was formulated; Rituximab was then administered for three months according to Inter-B-NHL ritux 2010 protocol and CYM (cytarabine and methotrexate) chemotherapy. The patient was followed-up for three years, with no recurrence. Conclusion: It is important for general dental practitioners to suspect a malignancy in the differential diagnosis of unresponsive odontogenic infections in young healthy patients.

Evidence of earlier thyroid dysfunction in newly diagnosed oral lichen planus patients: a hint for endocrinologists.

The association between oral lichen planus (OLP) and hypothyroidism has been debated with conflicting results: some authors detected a statistically significant association between these two, while others did not confirm it. The aim of this study was to evaluate the thyroid status in patients with newly diagnosed OLP to test the null hypothesis that thyroid disease is not associated with an increased incidence of oral lesions, with a prospective case-control approach. A total of 549 patients have been evaluated, of whom 355 were female. Odds ratio (OR) and 95% confidence intervals (CIs) were obtained. Patients suffering from thyroid diseases were associated with an almost 3-fold increased odds of having OLP (OR 2.85, 95% CI: 1.65-4.94), after adjusting this analysis for age, gender, body mass index, smoking status, diabetes, hypertension and hepatitis C infection. It would be appropriate to further investigate the possible concomitance of OLP among patients with thyroid disorder; endocrinologists should be aware of this association, especially because OLP is considered a potentially malignant oral disorder.

Laser Photobiomodulation for a Complex Patient with Severe Hydroxyurea-Induced Oral Ulcerations.

Patients affected by polycythemia vera (PV), a myeloproliferative neoplasm characterized by an elevated red blood cell mass, are at high risk of vascular and thrombotic complications. Conventional therapeutic options aim at reducing vascular and thrombotic risk; low-dose aspirin and phlebotomy are first-line recommendations, for patients at low risk of thrombotic events, whereas cytoreductive therapy, usually hydroxyurea (HU) or interferon alpha, is recommended for high-risk patients. In the present study, we report the case of a patient with persistent oral ulcerations, possibly related to long-lasting HU treatment, firstly treated with topic and systemic corticosteroids and then more effectively with the addition of low-level laser therapy. Laser photobiomodulation has achieved pain control and has contributed to the healing of oral ulcers without any adverse effect; this has permitted a reduction in the dose of systemic corticosteroids and the suspension of the use of the topic ones, due to the long-term stability of oral health, even after the interruption of low-level laser therapy sessions.

A randomized pilot study to assess the safety and the value of low-level laser therapy versus clonazepam in patients with burning mouth syndrome.

Comparison between low-level laser therapy (LLLT) and clonazepam for treating burning mouth syndrome (BMS) patients has never been documented; the aim of this study was to assess the effects of LLLT photobiomodulation versus medical therapy with clonazepam on BMS. Thirty-three patients (25 female, 8 male, mean age = 67.12) were randomly allocated to two different groups: the first one (group A, 18 patients) underwent two laser irradiation sessions weekly for 5 weeks, whereas the second one (group B, 15 patients) received topical clonazepam therapy [half a tablet (2 mg) in the mouth without swallowing for 3 min, three times a day for 21 days]. LLLT was delivered with a continuous wave 980-nm aluminum gallium arsenide (AlGaAs) diode laser and the output of 300 mW, delivering a Fluence of 10 J/cm(2), using a "spot technique," with an average power density of about 1 W/cm(2). The laser probe was held perpendicularly at a distance of about 2 mm from the mucosa. Visual analogue scale (VAS), McGill Pain Questionnaire, present pain intensity (PPI), and Oral Health Impact Profile (OHIP-49) assessed sensation of pain. Hospital Anxiety and Depression Scale and Geriatric Depression Scale assessed levels of anxiety and depression. Twelve weeks after the end of treatment, patients treated with LLLT experienced a decrease in pain sensation reported for all the parameters analyzed: VAS (P = 0.004), McGill Pain Questionnaire (P = 0.002), PPI (P = 0.002), and OHIP-49 (P = 0.010). The group treated with clonazepam had less favorable results for VAS (P = 0.33), McGill Pain Questionnaire (P = 0.005), PPI (P = 0.013), and OHIP-49 (P = 0.25). Levels of anxiety and depression did not change statistically in any groups (P > 0.05). Comparing the two groups, LLLT appeared to be superior in improving pain perception, but statistically only at 8 weeks after the end of the protocol proposed (P = 0.026). Based on this preliminary trial, LLLT is capable of reducing the symptoms of patients with BMS with a constant and long-lasting effect, experienced since the end of the first applications.

Er:YAG Laser Versus Cold Knife Excision in the Treatment of Nondysplastic Oral Lesions: A Randomized Comparative Study for the Postoperative Period.

OBJECTIVE: The aim of this prospective study was to estimate the effects of Erbium substituted: Yttrium Aluminium Garnet (Er:YAG) laser, compared with traditional scalpel, on the early postoperative sequelae of nondysplastic oral lesion removal. BACKGROUND DATA: There is limited evidence that laser surgery could exhibit advantages over scalpel in oral mucosal surgery. METHODS: The investigators studied a cohort of 344 patients; 394 lesions were randomized and treated. Outcome statistically evaluated variables were: age, gender, the site and size of investigated lesions, visual analogue score (VAS) of pain, the Oral Health Impact Profile questionnaire (OHIP-14) and the Quality of Life test (QOL), and number of analgesics taken in the 1st week after surgery. RESULTS: Significant differences were found if considering the surgical time, VAS, and QOL and OHIP-14 questionnaires; regarding those data, the Er:YAG laser appeared to be faster and less painful than traditional scalpel (p < 0.05). For bigger lesions, patients statistically took more painkillers if they had undergone traditional surgery. Considering the site of the treated lesions, Er:YAG laser was less painful, especially in the gingiva and palate (p < 0.05). CONCLUSIONS: This is the first randomized controlled surgical trial reported for the management of nondysplastic oral lesions with the use of an Er:YAG laser. With many limitations, the present report identifies significant difference in the immediate postoperative surgical period between the two treatments, meaning that the Er:YAG laser seemed to be less painful, and better accepted by patients, than traditional scalpel.

Clinical features and histological description of tongue lesions in a large Northern Italian population.

BACKGROUND: Only few studies on tongue lesions considered sizable populations, and contemporary literature does not provide a valid report regarding the epidemiology of tongue lesions within the Italian population. In this report, the histopathological and clinical appearance of 1.106 tongue lesions from northern Italians are described and discussed. MATERIAL AND METHODS: The case records of patients referred for the diagnosis and management of tongue lesions, from October 1993 to October 2013, were reviewed. Histological data were also obtained and blindly re-examined. RESULTS: For instance, a biopsy performed on a lingual ulcer has a strong predicting association with a carcinoma, whereas a biopsy on a white lesion predicts for a leukoplakia or oral lichen planus. Moreover, a biopsy of erosion is representative of bullous diseases, whereas a biopsy on a verrucous-papillary lesion is significant for fibroma. Furthermore, carcinomas occur in the majority of cases on the lingual edge or pelvis, oral lichen planus is mainly seen on the edge, and fibromas mostly on the lingual tip. CONCLUSIONS: The high frequency of tongue involvement of such different diseases emphasizes the importance of histological characterization and that some diseases occur more frequently than others, with a peculiar clinical aspect and a more common area. In fact our survey can help the clinician in advancing diagnostic hypothesis, on the basis of the elementary lesion and its site of involvement.