# Morpho-Histo-Cytological Evaluation of Oral Tissues in Burning Mouth Syndrome: A Systematic Review

André Luís Porporatti, Ângela Graciela Deliga Schroder, Ashley Lebel, Nathan Moreau, Annabelle Réaux-Le Goazigo, Ihsène Taïhi, Heike Rittner, Tara Renton, Yves Boucher

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## To cite this version:

André Luís Porporatti, Ângela Graciela Deliga Schroder, Ashley Lebel, Nathan Moreau, Annabelle Réaux-Le Goazigo, et al. Morpho-Histo-Cytological Evaluation of Oral Tissues in Burning Mouth Syndrome: A Systematic Review. Journal of Oral Rehabilitation, 2025, 52 (12), pp.2449-2480. 10.1111/joor.70051. hal-05536554

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REVIEW

OPEN ACCESS

# Morpho-Histo-Cytological Evaluation of Oral Tissues in Burning Mouth Syndrome: A Systematic Review

André Luís Porporatti<fnref n="1" /> | Ângela Graciela Deliga Schroder² | Ashley Lebel<fnref n="1" />,³ | Nathan Moreau<fnref n="1" />,⁴ |
Annabelle Réaux-Le Goazigo⁵ | Ihsène Taïhi<fnref n="1" />,⁶ | Heike Rittner⁷ | Tara Renton⁸ | Yves Boucher<fnref n="1" />,³

**Correspondence:** André Luís Porporatti (andreporporatti@icloud.com)

**Received:** 2 July 2025 | **Revised:** 13 August 2025 | **Accepted:** 18 August 2025

**Funding:** The authors received no specific funding for this work.

**Keywords:** biopsy | burning mouth syndrome | histological | meta-analysis | morphological | systematic review

## ABSTRACT

**Background:** Burning Mouth Syndrome (BMS) is an idiopathic condition characterised by chronic oral burning pain without clinically evident lesions. Despite its prevalence and impact on quality of life, the pathophysiology of BMS remains poorly understood, limiting diagnostic and therapeutic options.

**Objective:** To systematically review histological, morphological and cytological changes in oral tissues of BMS patients, with a focus on epithelial cells and nerve fibres, to identify potential biomarkers and inform future research directions.

**Methods:** A systematic search of electronic databases and grey literature was conducted through October 2024, identifying case-control studies assessing histological or cytological features of oral tissues in adults diagnosed with BMS according to validated criteria. Risk of bias was assessed using the Joanna Briggs Institute tool, and evidence quality was evaluated with GRADE.

**Results:** Fourteen studies involving 214 BMS patients and 130 controls were included. Findings consistently reported reduced epithelial nerve fibre density and increased expression of nociceptive markers such as TRPV1, NGF and P2X3 in BMS tissues. Subepithelial alterations, including increased keratinisation and altered expression of cannabinoid receptors (CB1/CB2), were also observed. Methodological heterogeneity and risk of bias were notable, precluding meta-analysis. The overall quality of evidence was very low.

**Conclusion:** Histological evidence supports neuropathic changes in BMS, involving both neuronal and non-neuronal cells. While these biomarkers hold promise for understanding BMS pathogenesis, standardisation of techniques and further research, including development of animal models, is needed to establish diagnostic and therapeutic utility.

## 1 | Introduction

Burning Mouth Syndrome (BMS), also referred to as stomatodynia or glossodynia when limited to the tongue, is an idiopathic disorder characterised by unexplained oral burning pain [1, 2]. According to the 3rd edition of the International Classification of Headache Disorders (ICHD3) [2], BMS is defined as 'an

intraoral burning or dysaesthetic sensation, recurring daily for more than 2 hours/day over more than 3 months, without clinically evident causative lesions'. The International Classification of Orofacial Pain (ICOP) further classifies BMS as an idiopathic pain adding 'with or without somatosensory changes' to the definition [3]. Differential diagnosis includes secondary BMS for which a cause is found [4]. BMS affects approximately 1% of the

This is an open access article under the terms of the [Creative Commons Attribution-NonCommercial-NoDerivs License](https://creativecommons.org/licenses/by-nc-nd/4.0/), which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

© 2025 The Author(s). *Journal of Oral Rehabilitation* published by John Wiley & Sons Ltd.

<footnote n="1">¹Université Paris Cité and Sorbonne Paris Nord, Montrouge, France | ²NARSM (Núcleo de Revisão Sistemática e Meta-Análise), Tuiuti University, Curitiba, Brazil | ³Service Odontologie, Hôpital Pitié-Salpêtrière (AP-HP), Paris, France | ⁴Hôpital Bretonneau (AP-HP), Paris, France | ⁵Sorbonne Université, INSERM, CNRS, Institut de la Vision, Paris, France | ⁶Hopital Rothschild, APHP, Paris, France | ⁷Universitätsklinikum, University of Würtburg, Würzburg, Germany | ⁸Centre for Oral, Clinical & Translational Sciences, Kings College, London, UK</footnote>
general population worldwide, with prevalence increasing with age, particularly among post-menopausal women [5]. The condition is largely associated with comorbidities, among them anxiety-depressive conditions are the most common [6-8]. The condition significantly impairs patient's quality of life and current treatments, either topical or systemic remain largely unsatisfactory [9]. The development of new therapeutic strategies is hindered by the poorly understood etiopathogenesis [10].

Diagnosis of BMS is primarily clinical, based on patient history and physical examination, often supported by specific questionnaires. Ongoing debates persist regarding the establishment of internationally validated diagnostic criteria, with some authors even proposing a nomenclature change to 'Burning Mouth Disorder' to better reflect the idiopathic and heterogeneous nature of its presentation. Differential diagnoses must rule out secondary forms of BMS caused by nutritional deficiencies, hormonal imbalances or systemic diseases.

In this context, identifying reliable biomarkers for BMS diagnosis and management would be an important step in understanding the disease. Several approaches have been explored, including brain imaging [11-14], quantitative sensory testing (QST) [15] and liquid biopsies that is, blood or salivary tests [16]. However, each of these methods has limitations. Advanced imaging techniques, such as functional MRI, have provided valuable insights into central nervous system alterations such as higher fractional anisotropy and intracellular volume fraction in BMS but remain impractical for routine clinical use. QST results are controversial, as BMS patients may present with or without somatosensory changes, complicating interpretation [8, 17]. Liquid biopsy research has investigated various molecular biomarkers, such as neurotrophic factors, cytokines, peptides and protein hormones, in saliva or blood, but results remain inconclusive [16, 18-21]. Recent metabolomic data on saliva [16, 22, 23] point towards alterations in tyrosine pathways, echoing the hypothesis of neuronal dopamine function involvement [24]. Other hypotheses such as impaired neuronal function reflecting in levels of alpha-enolase, IL18 and KLK13 [19] need confirmation.

Histological analysis of oral tissue biopsies enables the direct observation of potential structural and cellular alterations. Such approaches have been used to investigate changes in salivary glands [25] or epithelium morphology and cytology [26]. Lauritano et al. 1998 [27] followed by Lauria et al. 2005 [28] made significant progress in the field by applying immunohistochemistry to assess neural alterations, reporting a reduction in the density of epithelial and subepithelial nerve fibres in the tongue. Based on these findings, they proposed that BMS may represent a subgroup of small-fibre neuropathies. Subsequent studies confirmed these neural alterations and identified additional biomarkers such as TRPV1, P2X3, NGF and Artemin. Morphological changes—especially those affecting peripheral nerves and epithelial tissues—have consistently been observed in BMS patients, supporting the hypothesis of underlying neuropathic and trophic abnormalities. Surgical biopsies are the most commonly used techniques for assessing biological changes in the oral tissues. However, alternative methods, such as exfoliative cytology, where cells are sampled by scraping the oral mucosa, can also provide key information, especially when combined with morphological [29] or genetic (qPCR) analysis [30].

These observations are important since they are the keystones for clinical identification and for developing an animal model of BMS that accurately reproduces human clinical evidence. Today there is no satisfying animal model of BMS available [31].

The aim of this study was therefore to systematically review the histological evidence in oral tissues of BMS patients, identify potential disease biomarkers, and provide insights for future research. Both general architecture, morphology and cytological aspects were analysed, with a special focus on epithelial cells and nerve fibres.

## 2 | Methods

### 2.1 | Protocol and Registration

This systematic review conformed to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses PRISMA Checklist [32]. The protocol was registered in the international Prospective Register of Systematic Reviews (PROSPERO) under number CRD42025638793.

### 2.2 | Eligibility Criteria

We included case-control studies that evaluated the morphological and/or histological characteristics of adults with BMS. We included studies that diagnosed BMS with validated criteria, such as clinical examinations or with international criteria, such as ICHD-3, ICOP or IASP [1-3] which state that BMS is an intraoral burning or dysaesthetic sensation, recurring daily for more than 2 h/day over more than 3 months, without clinically evident causative lesions. Morphological and histological characteristics should be assessed through tongue or oral biopsy or exfoliation. Overall, the inclusion criteria were based on the PECOS methodology [33]: Population (P): Adults; Exposure (E): BMS; Comparison (C): Healthy Subjects or other comparison group without BMS; Outcome (O): Morphological and histological characteristics; Studies (S): Case-Control. No data, sex or language restrictions were applied to the search strategy. In this review, studies could assess morphological and histological characteristics of oral tissues using surgical biopsies or exfoliative cytology. Reported histological methods could include haematoxylin-eosin staining, immunohistochemistry and immunofluorescence targeting neuronal markers (e.g., PGP9.5, β-tubulin, S100), epithelial proteins (e.g., keratins 10, 14, 16; desmogleins) and receptors/ion channels (e.g., TRPV1, CB1, CB2, NGF, P2X3, Nav1.7-1.9). Cytological approaches could comprise cytomorphometric and cytomorphological analyses, as well as molecular assays such as qPCR for specific gene expression (e.g., Nav channels, Artn).

The exclusion criteria encompassed: (1) Studies in animals; (2) Studies with burning mouth as a symptom of other diseases or secondary BMS; (3) Studies with BMS and comorbidities associated or no control group; (4) Studies where BMS was not evaluated thought a valid diagnostic criteria; (5) Not retrieved; (6) Studies where the morphological and histological were not evaluated through biopsies; (7) Literature reviews, intervention studies, letters, case reports (<10 cases) and personal opinions.
Patients with comorbidities or secondary BMS were excluded when attributable to another diagnosed condition. Secondary conditions included nutritional deficiencies, hormonal disorders, systemic diseases, local oral pathologies or other medical conditions known to cause oral burning (e.g., oral candidiasis, lichen planus, Sjögren's syndrome, diabetes mellitus). Studies including BMS with associated comorbidities were also excluded.

## 2.3 | Information Sources and Search

Detailed individual search strategies were developed, in English, for each bibliographic electronic database: EMBASE, PubMed (Including Medline), Scopus and Web of Science. A grey literature search was performed on Google Scholar and Open Grey. All database searches were conducted from the starting coverage date through October 21st, 2024. More information on the search strategies was provided in Table S1 (which can be found online). Furthermore, the authors hand-searched the reference lists of the selected articles for any additional references that might have been missed in the database searches. All references were managed, and the duplicated hits were removed by reference management software (EndNote X7 Basic-Thomson Reuters, New York, USA).

## 2.4 | Study Selection and Data Collection Process

Study selection followed a two-phase process. In phase one, two authors (A.L.P. and A.G.D.S) independently evaluated the titles and abstracts of all identified electronic database citations. In phase two, the same authors evaluated full-text data. They independently screened papers in phases one and two, applied the eligibility criteria, collected key information from the selected studies and cross-checked the information. The selection from phase two was based solely on the full-text assessment of the studies. When disagreement appeared, a third author (Y.B.) was involved to make a final decision about the inclusion or exclusion of studies.

For each of the included studies, the following items were recorded: author(s), year of publication, country, sample size (n), population information, mean age and standard deviation or range, percentage of females; characteristics of BMS group; characteristics of control group, type of biopsy and method; criteria for evaluating and diagnosing BMS; main results on BMS and biopsies; and conclusions of the work. When the required data were not complete, the reviewers (A.L.P. and A.G.D.S) attempted to contact the study authors to retrieve any unpublished information. Three attempts were made in a 30-day period, by email for the first, second and last author.

## 2.5 | Risk of Bias in Individual Studies

The methodological quality of the included observational studies were evaluated through Joanna Briggs Institute (JBI) Critical Appraisal Tools to assessed risk of bias in case-control studies [34]. The answers could be ‘yes’ ‘unclear’ ‘no’ or ‘not applicable’ Decisions about scoring were agreed upon by all reviewers before beginning critical appraisal. The same two reviewers

(A.L.P. and A.G.D.S) worked out any differences regarding data analysis. A third author (Y.B.) was involved to steer decisions in case of uncertainty. Following these answers, the risk of bias was categorised as follows: (1) Low risk of bias, if all criteria were met, (2) Unclear risk of bias, if one or more criteria were not exactly described and (3) High risk of bias, if one or more criteria were not met [34].

## 2.6 | Study Outcomes and Summary Measures

We considered the results from morphological and histological evidence in oral tissues of BMS.

## 2.7 | Synthesis of Results

Statistical pooling of data using meta-analysis was planned whenever trials were considered combinable and relatively homogeneous in relation to design, interventions and outcomes. Heterogeneity between studies was evaluated either by considering clinical (differences about populations and results), methodological (design, and risk of bias) and statistical characteristics (effect of studies) or by using inconsistency indexes ($I^2$) [35].

## 2.8 | Confidence in Cumulative Evidence

A summary of the overall certainty of evidence available was presented using ‘Grading of Recommendations Assessment, Development and Evaluation’ (GRADE) Summary of Findings (SoF) tables, using GRADEpro software [35].

# 3 | Results

## 3.1 | Study Selection

The initial database search identified 2011 studies. After removing duplicates, 1486 studies remained; 1446 of them were excluded after title and abstract revision, resulting in a final number of 46 articles. Furthermore, 200 studies were found with Google Scholar, and 58 with OpenGrey. Ten of them were selected for full-text review. No additional study was selected from a search of the reference lists of the selected studies, and no studies were considered based on experts' suggestions. Consequently, 56 studies became part of phase 2. During this phase, 38 studies were excluded (reasons for exclusion may be found in Table S2). Fourteen studies were included for qualitative synthesis. A flowchart of the process of identification, inclusion and exclusion of studies is shown in Figure 1.

## 3.2 | Study Characteristics and Results of Individual Studies

Out of the 14 studies, sample size ranged from 7 to [37] to 56 BMS patients [38], and from 1 to [39] to 20 controls [29]; with a total of 214 BMS and 130 controls, mostly women, ranging from 50% to
<figure><img src="image_4.png" /><figcaption>**FIGURE 1** | PRISMA 2020 flow diagram for new systematic reviews which included searches of databases, registers and other sources. From Page et al. [36]. For more information, visit: http://www.prisma-statement.org/.</figcaption></figure>

100% of the sample. Mean age in the BMS group ranged between 57.1 [29] to 67.5 years old [40]; and from 40 to [37] to 67.4 years old [41] in the control group. Studies were conducted in Brazil [29, 42, 43], Denmark [44], Finland [41], Italy [28, 38, 40, 45], Japan [30], Spain [39] and UK [37, 46, 47]. All studies were published in English.

BMS diagnosis was based on ICHD-3 IHS, WHO, ICOP or IASP and clinical criteria of burning sensation for more than 6 months. Table 1 summarises the descriptive characteristics of the included studies.

## 3.3 | Risk of Bias in Individual Studies

Risk of bias was heterogeneous among studies. Using JBI Critical Appraisal Tools, 6 studies [29, 30, 41, 43, 45, 46] were classified as unclear risk of bias, and 08 [28, 37–40, 42, 44, 47] as high risk of bias. No study was classified as low risk of bias. The unclear risk of bias pertained to strategies to deal with confounding factors, as means of multi- or univariate regressions. The complete item list is presented in Figure 2.

## 3.4 | Results of Individual Studies

Figure 3 presents the characteristics of the studies in terms of methodology and biomarkers. Table 1 presents the main findings and conclusions of the studies, while Table 2 presents the technical aspects of the procedures and comments. Hereafter are the main results sorted according to the different aims of the study.

### 3.4.1 | Structural Epithelium Changes

Tissue architecture status has been evaluated in some studies with contrasting results. Histological alterations: Integrity of tongue mucosa remained unchanged in BMS [43, 45] as well as the oral mucosa [44].

#### 3.4.1.1 | Intraepidermal Nerve Fibre (IENF) Density.
IENF was significantly reduced in BMS patients compared to controls in four studies [28, 38, 41, 46]; but remained unchanged in one [43]. Density of innervation depended on the severity/location of symptoms in [38] that is, not altered in ‘tip only’ BMS patients but decreased in those with extended symptomatology [38].

#### 3.4.1.2 | Specific Immunoreactivity. TRPV1, NGF and P2X3-positive fibres were significantly elevated in BMS patients, correlating with pain levels [46, 47]. However, no significant changes were found in markers for other nerve fibres (e.g., Nav1.7, Nav1.9) [37, 42].

### 3.4.2 | Molecular and Cellular Changes

Increased expression of TRPV1 and CB2, along with decreased CB1 expression, was reported in the tongue epithelial cells of BMS patients [40]. Furthermore, enhanced mRNA expression for Artn was reported [30].

Cellular hypertrophy, increased keratinization and altered proteoglycan/collagen balance were observed in BMS
<table><caption>TABLE 1 | Summary of descriptive characteristics of included articles (n = 14).</caption><thead><tr><th>First author, publication date, journal, country, study design</th><th>Characteristics of BMS group, age, sex, characteristics of pain</th><th>Characteristics of control (CTRL) group, mean age ± SEM, age range, sex ratio F/M</th><th>Type of biopsy and methods</th><th>Criteria for evaluating and diagnosing BMS</th><th>Main results on BMS and biopsies</th><th>Conclusions of the work</th></tr></thead><tbody><tr><td><strong>Surgical Biopsies</strong></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Arantes, D.A.<br>2023</td><td>12 BMS,<br>67 years old ±6.1, [48–64]</td><td>11 subjects</td><td>Incisional biopsy</td><td>IASP</td><td>Similar integrity of the epithelial lining, keratin layer thickness and collagenization</td><td>Integrity and density of peripheral NF on tongue mucosa do not change in individuals with BMS and CTRL</td></tr><tr><td>Braz. Oral Res<br>Brazil</td><td>M:F: 0:12<br>VAS: 6.8 ± 1.0</td><td>Non-neoplastic tongue lesions from patients without a complaint of BMS</td><td>Cytology and IHC Biomarkers<br>S100,<br>PGP 9.5</td><td></td><td>Similar density and integrity of S-100+ and PGP 9.5+ peripheral NF and tryptase+ mast cells</td><td>Similar density of BMS and CTRL</td></tr><tr><td>Case Control</td><td>Dorsum and lateral border of the tongue.<br>Mean duration of symptoms = 45 ± 12 months range 12 to 60 months.</td><td>62 ± 7.3 years old [48–63, 65–71]<br>M:F: 3:8</td><td>Tryptase</td><td></td><td>of BMS and CTRL.</td><td>Integrity and density of peripheral NF on tongue mucosa do not depend on the density of mast cells.</td></tr><tr><td>Beneng, K.,<br>2010a,<br>Int. J. Oral<br>Maxillofac. Surg.<br>London UK</td><td>9 BMS<br>62.4 years old ±<br>M:F = 3:6<br>VAS 6.27</td><td>10 CTRL<br>Lower wisdom teeth removal<br>40.8 years old ±?</td><td>Punch biopsy<br>Morphological analysis<br>IHCnico<br>Biomarkers: P2X3</td><td>IASP</td><td>Numerous P2X3 nerve fibres in papillae, but not in epithelium. The percentage of IR area of P2X3 fibres was significantly increased in the BMS versus CTRLs., (2.51 ± 0.61 vs. 0.96 ± 0.30) (p = 0.024)</td><td>Increased P2X3 immunoreactivity in the trigeminal sensory system may play a role in the symptoms observed in BMS.</td></tr><tr><td>Case Control</td><td>Duration of symptoms not specified</td><td>M:F = 6:4</td><td>.</td><td></td><td></td><td></td></tr><tr><td>Beneng, K.<br>2010<br>BMC<br>Neuroscience<br>London UK</td><td>7 BMS<br>62 years old [48–82]<br>M:F = 5:5<br>VAS = 7.07 (range 5–10)</td><td>10 CTRL attending lower wisdom teeth removal<br>40 years old [16–35, 37–79]<br>M:F = 6:4</td><td>Tongue punch biopsies from 6 BMS patients<br>IHC:<br>Biomarkers: Nav1.7</td><td>IASP</td><td>Numerous Nav1.7 immunoreactive nerve fibres in the sub-mucosal layer of both BMS and CTRL.</td><td>No significant difference between BMS and CTRL. Trend for an increase in BMS</td></tr><tr><td>Case Control</td><td>Mean duration of symptoms = 37.6 months.</td><td></td><td></td><td></td><td></td><td></td></tr></tbody></table>

(Continues)
<table><caption>TABLE 1 | (Continued)</caption><thead><tr><th>First author, publication date, journal, country, study design</th><th>Characteristics of BMS group, age, sex, characteristics of pain</th><th>Characteristics of control (CTRL) group, mean age ± SEM, age range, sex ratio F/M</th><th>Type of biopsy and methods</th><th>Criteria for evaluating and diagnosing BMS</th><th>Main results on BMS and biopsies</th><th>Conclusions of the work</th></tr></thead><tbody><tr><td>Borsani, E.<br>2014<br>Histol<br>Histopathol<br>Italy<br>Case Control</td><td>8 BMS<br>67.5 years old ± 10.7 SD [48–64, 68–71, 75–85].<br>Duration of symptoms = 12 ± 2 months.<br>VAS score = 6 ± 2 (SD).</td><td>8 healthy CTRL<br>not age-matched</td><td>Punch biopsy at the anterolateral aspect of the tongue close to the tip.<br>IHC:<br>Biomarkers: TRPV1, CB1, CB2</td><td>IASP</td><td>Qualitative analysis: differences in IR for TRPV1, CB1 and CB2 regarding localization in the epithelium in BMS versus CTRLs.<br>Quantitative analysis: Increase of TRPV1 IR in BMS (31.85 ± 1.64) versus CTRLs (9.4 ± 0.91 SEM).<br>Decrease of the CB1 staining (24.41 ± 5.60) in BMS versus CTRL (43.23 ± 7.73 SEM).<br>Increase of CB2 IR (23.76 ± 3.84 SEM) in BMS versus CTRL (12.56 ± 1.90 SEM)</td><td>In BMS patients there was increased TRPV1, decreased CB1 and increased CB2 expression in tongue epithelial cells also associated with a change in their distribution. It would appear that these receptors are related to BMS.</td></tr><tr><td>Domaneschi, C.<br>2022<br>Braz. Oral Res.<br>Brazil<br>Case Control</td><td>12 BMS<br>61.4 ± 7.7<br>[48–71]<br>M:F: 0:12<br>Intensity of pain not specified<br>Mean duration of symptoms<br>64.8 months, range [6–324]</td><td>5 CTRL<br>63.4 ± 12.2, [48–80],<br>M:F: 1:4 matched<br>by sex and age,<br>benign tongue lesion<br>(fibrous hyperplasia)</td><td>Punch biopsy<br>qPCR<br>Biomarkers = Nav1.7,<br>Nav1.8, Nav1.9</td><td>IASP</td><td>Overexpression of Nav1.7 (×3.13) gene, and an underexpression of Nav1.9 (× 0.45) gene<br>No statistically significant<br>Differences between the BMS and CTRL regarding the expression of evaluated genes<br>Nav1.7: p = 0.52 and Nav1.9: p = 0.36.</td><td>The expression of the Nav1.8 gene was not detected in any sample analysed. No gene expression was correlated with the BMS patients' age, or duration of the burning symptoms</td></tr></tbody></table>

(Continues)
<table><caption>TABLE 1 | (Continued)</caption><thead><tr><th>First author,<br>publication<br>date, journal,<br>country, study<br>design</th><th>Characteristics of BMS group, age,<br>sex, characteristics of pain</th><th>Characteristics<br>of control (CTRL)<br>group, mean<br>age ± SEM,<br>age range, sex<br>ratio F/M</th><th>Type of biopsy<br>and methods</th><th>Criteria for evaluating<br>and diagnosing BMS</th><th>Main results on<br>BMS and biopsies</th><th>Conclusions<br>of the work</th></tr></thead><tbody><tr><td>Lauria G.<br>2005</td><td>12 BMS<br>69 ± 9.0<br>M:F 1:11</td><td>9 CTRL<br>55 ± 16.3<br>M:F</td><td>Punch biopsy<br>IHC:</td><td>Clinical criteria</td><td>BMS showed a<br>significantly lower<br>density of ENF than<br>CTRLs (p = 0.0004)</td><td>BMS is caused by a<br>trigeminal small-fibre<br>sensory neuropathy.<br>Superficial biopsy<br>of the tongue can be<br>helpful in assessing<br>the diagnosis</td></tr><tr><td>Pain<br>Italy</td><td>Burning pain in the anterior two-<br>thirds of the tongue</td><td>Healthy subjects.<br>Not age matched</td><td></td><td></td><td>density of ENF (10.29/<br>mm; 95% confidence<br>interval [CI])</td><td></td></tr><tr><td>Case Control</td><td>Duration of symptoms: 12 ± 2 months (range 6–18).<br>VAS score 6 ± 1.8 (SD).</td><td></td><td></td><td></td><td>(15.89–5.01) than<br>controls (27.73/mm;<br>95% CI 37.71–20.35).<br>Similarly, the<br>IENFD per papilla<br>was significantly<br>lower (p = 0.03) in<br>BMS than CTRL.</td><td></td></tr></tbody></table>

(Continues)
<table><caption>TABLE 1 | (Continued)</caption><thead><tr><th>First author, publication date, journal, country, study design</th><th>Characteristics of BMS group, age, sex, characteristics of pain</th><th>Characteristics of control (CTRL) group, mean age ± SEM, age range, sex ratio F/M</th><th>Type of biopsy and methods</th><th>Criteria for evaluating and diagnosing BMS</th><th>Main results on BMS and biopsies</th><th>Conclusions of the work</th></tr></thead><tbody><tr><td>Penza, P. 2010<br>Clin J Pain Italy<br>Case Control</td><td>56 patients 65 ± 9.7 (SD)<br>M:F 6: 50<br>Tongue biopsy was performed in 51 patients.</td><td>9 healthy participants<br>Archived data<br>Age not specified</td><td>Punch Biopsy IHC<br>PGP9.5</td><td>Clinical Criteria of Burning Sensation</td><td>The density of ENF was normal (6.1 ± 2.19 SD; p > 0.05) in 25% of the patients (11 female and 2 male, mean age 62 ± 11 SD years) and significantly reduced (1.35 ± 1.46 SD; p < 0.0001) in 75% of the patients (33 female and 5 male, mean age 65.6 ± 8 SD years). The mean age of the patients with abnormal and normal tongue biopsy did not differ between groups (66 ± 8.1 SD versus 63 ± 12.4 SD years). There was a non-significant difference in the mean duration of symptoms between patients with normal (53 months, range 6 to 240) and reduced (69 months, range 12 to 238) tongue innervation density.</td><td>Compared with 9 healthy participants (4.13 ± 1.85 SD), epithelial innervation density was significantly reduced in 38 patients (1.35 ± 1.46 SD; p < 0.0001) and normal in 13 patients (6.1 ± 2.19 SD).</td><td></td></tr></tbody></table>

(Continues)
<table><caption>TABLE 1 | (Continued)</caption><thead><tr><th>First author, publication date, journal, country, study design</th><th>Characteristics of BMS group, age, sex, characteristics of pain</th><th>Characteristics of control (CTRL) group, mean age±SEM, age range, sex ratio F/M</th><th>Type of biopsy and methods</th><th>Criteria for evaluating and diagnosing BMS</th><th>Main results on BMS and biopsies</th><th>Conclusions of the work</th></tr></thead><tbody><tr><td>Puhakka, A. 2016</td><td>10 BMS 67.9 years (SD 6.4 years, range 60.0–77.5 years)</td><td>13 cadaver CTRL 6 diabetic cadaver CTRLs with no lifetime data on neuropathy CTRLs subjects 67.4 years (6.3; 58.4–75.9), Cadaver controls 64.5 years (6.4; 55.0–72.0) Cadaver diabetic CTRLs 68.8 years (7.1; 59.0–78.0).</td><td>Biconvex biopsies IHC β tubulin (TUJ1) PGP9.5</td><td>Headache Classification Subcommittee of the International Headache Society (IHS), 2013</td><td>Similar staining pattern with β-tubulin and PGP 9.5. Data on β-tubulin-staining are presented. BMS patients had significantly lower IIEFND compared to non-diabetic CTRLs when assessed both by epithelial length (EM 0.27, s.e. 0.18 mm 1 versus EM 0.92, s.e. 0.15 mm 1; p = 0.0253) and by epithelial area (EM 0.57, s.e. 0.82 mm 2 versus EM 3.6, s.e. 0.7 mm 2; p = 0.0244). IIEFND in patients with BMS was also lower than that of diabetic cadaver CTRLs (EM 0.34, s.e. 0.23 mm 1; and EM 1.64, s.e. 1.06 mm 2), but the difference was not statistically significant</td><td>Primary BMS is associated with pure peripheral small fibre damage within the tongue mucosa</td></tr></tbody></table>

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<table><caption>TABLE 1 | (Continued)</caption><thead><tr><th>First author,<br>publication<br>date, journal,<br>country, study<br>design</th><th>Characteristics of BMS group, age,<br>sex, characteristics of pain</th><th>Characteristics<br>of control (CTRL)<br>group, mean<br>age±SEM,<br>age range, sex<br>ratio F/M</th><th>Type of biopsy<br>and methods</th><th>Criteria for evaluating<br>and diagnosing BMS</th><th>Main results on<br>BMS and biopsies</th><th>Conclusions<br>of the work</th></tr></thead><tbody><tr><td>Sardella, A.<br>2012<br>Archives of Oral<br>Biology<br>Italy<br>Case Control</td><td>10 BMS<br>64.9±4.2 (SD)<br>F/M: 9/1<br>Mean duration of symptoms:<br>26.4±8.9 (SD) months.</td><td>9 CTRLS =<br>Consecutive patients<br>with asymptomatic,<br>benign lesions<br>of the tongue<br>(traumatic fibroma)<br>A tongue biopsy of<br>clinically normal<br>mucosa was taken<br>far from the lesion<br>to be excised (at<br>least 3 cm) with<br>local anaesthesia<br>62.8±4.7 SD<br>F/M: 8/1.</td><td>Punch biopsies<br>IHC<br>Desmoglein (Dsg) 1 and 3<br>Keratin (K) 10<br>K14<br>Keratin 16<br>Pepsin<br>p53<br>Caspase-3<br>Laminin</td><td>Clinical Criteria</td><td>In both groups,<br>a preserved 3D<br>architecture of the<br>tongue was observed.<br>Dsg 1 and 3 epithelial<br>distributions were<br>similar in the<br>desmosomes of<br>patients and CTRL<br>subjects. K10 IR and<br>distribution pattern of<br>K14 in the epithelial<br>compartment was<br>similar in both groups.<br>In CTRL, K16 IR was<br>scant throughout<br>the epithelium with<br>a punctuate and<br>scattered cytoplasmic<br>labelling. In contrast,<br>in all BMS patients<br>keratinocyte<br>Cytoplasm was<br>homogeneously<br>labelled for K16,<br>with a more intense<br>staining than controls.<br>Furthermore, K16<br>staining progressively<br>decreased proceeding<br>towards the<br>most superficial<br>epithelial layers</td><td>In conclusion, the<br>results of this study<br>are consistent with<br>and support the<br>clinically normal<br>features of oral<br>mucosa in BMS, and<br>suggest that K16<br>may be involved in<br>the cell mechanisms<br>underlying BMS<br>occurrence</td></tr></tbody></table>

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<table><caption>TABLE 1 | (Continued)</caption><thead><tr><th>First author, publication date, journal, country, study design</th><th>Characteristics of BMS group, age, sex, characteristics of pain</th><th>Characteristics of control (CTRL) group, mean age ± SEM, age range, sex ratio F/M</th><th>Type of biopsy and methods</th><th>Criteria for evaluating and diagnosing BMS</th><th>Main results on BMS and biopsies</th><th>Conclusions of the work</th></tr></thead><tbody><tr><td>Treldal, C. 2019</td><td>21 BMS 57.5 ± years old (38–71)</td><td>10 CTRLs 59 ± years old (55–65)</td><td>Punch biopsy Morphology IHC</td><td>Clinical Criteria</td><td>Overall, the buccal mucosa had normal appearance and no signs of inflammation.</td><td>Immunoreactivity to the oestrogen receptor (ER) was most intense in the Effect group, whereas the No effect group tended to have higher plasma levels of the pro inflammatory cytokines.</td></tr><tr><td>Oral Diseases Denmark</td><td>M:F 3:18</td><td>M:F 0–10</td><td>Oestrogen receptor, NGF</td><td>Differences were found according to the response to Local anaesthesia. (effect and non-effect groups)</td><td>The response to local anaesthesia enables subgrouping of patients with BMS according to the potential pathogenic mechanisms. Effect of local anaesthesia indicates a peripheral neuropathology involving lack of oestrogen and upregulation of ERs, and no effect indicates a systemic inflammation-induced mechanism leading to increased levels of plasma cytokines.</td><td>The response to local anaesthesia enables subgrouping of patients with BMS according to the potential pathogenic mechanisms. Effect of local anaesthesia indicates a peripheral neuropathology involving lack of oestrogen and upregulation of ERs, and no effect indicates a systemic inflammation-induced mechanism leading to increased levels of plasma cytokines.</td></tr><tr><td>Case Control</td><td>Mean intensity 5.8 or 5.3 according to bupivacaine effect group. Duration of symptoms 48 or 45 months according to the bupivacaine effect group</td><td></td><td>NGF receptor TRPV-1 IL-17F</td><td>Tissue sections from four patients (40%) in the Effect group and three patients (75%) in the No effect group (p = 0.079) displayed epithelial atrophy with flattening of epithelial ridges. Vacuolization in the epithelial layer was observed in one patient from the No effect group.</td><td></td><td></td></tr></tbody></table>

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<table><caption>TABLE 1 | (Continued)</caption><thead><tr><th>First author, publication date, journal, country, study design</th><th>Characteristics of BMS group, age, sex, characteristics of pain</th><th>Characteristics of control (CTRL) group, mean age ± SEM, age range, sex ratio F/M</th><th>Type of biopsy and methods</th><th>Criteria for evaluating and diagnosing BMS</th><th>Main results on BMS and biopsies</th><th>Conclusions of the work</th></tr></thead><tbody><tr><td>Yilmaz, Z. 2007</td><td>10 BMS 62 ± years old [16–35, 37–79], M:F = 6:4</td><td>10 CTRL 40 ± years old [48–82] M:F = 5:5</td><td>Punch biopsies IHC TRPV1 NGF Nav1.8</td><td>IASP</td><td>Nerve fibres penetrating the epithelium were less abundant in BMS (p < 0.0001), indicating a small fibre neuropathy. TRPV1-positive fibres were overall significantly increased in BMS (p = 0.0011), as were NGF fibres (p < 0.0001) and basal epithelial cell NGF staining (p < 0.0147).</td><td>Our finding that TRPV1 and NGF-positive nerve fibres were significantly increased in patients with BMS, and correlated with ongoing pain, is both novel and important. There was a trend towards increase of Nav1.8 fibres, and more subjects may be needed to show a significant increase. Increased NGF levels are known to up-regulate the expression TRPV1 and Nav1.8 by nociceptor fibres, and to sensitise nociceptors.</td></tr><tr><td>J Clin Neurosci London UK Case Control</td><td>Mean intensity = 5.3 ± 0.99 Average duration of symptoms = 37.6 months.</td><td></td><td></td><td></td><td>There was a significant correlation between the baseline pain score and TRPV1 (p = 0.0143) and NGF fibres (p = 0.0252). A significant correlation was observed between baseline and post-capsaicin pain (p = 0.0006).</td><td>However, large fibre dysfunction has been reported in BMS, and so the changes we describe may contribute, but may not be exclusively responsible for, the symptomatology</td></tr></tbody></table>

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<table><caption>TABLE 1 | (Continued)</caption><thead><tr><th>First author, publication date, journal, country, study design</th><th>Characteristics of BMS group, age, sex, characteristics of pain</th><th>Characteristics of control (CTRL) group, mean age ± SEM, age range, sex ratio F/M</th><th>Type of biopsy and methods</th><th>Criteria for evaluating and diagnosing BMS</th><th>Main results on BMS and biopsies</th><th>Conclusions of the work</th></tr></thead><tbody><tr><td>Zubiate<br/>Illaramendi, I.<br/>2022</td><td>10 BMS<br/>61.5 ± years old<br/>M:F?</td><td>1 control<br/>52</td><td>Morphological and cytological observation</td><td>ICHD-3</td><td>In BMS, different parameters can be seen, such as cell hypertrophy and increased keratinization in the epithelial layers, compared to the CTRL.</td><td>The results of this study revealed histological patterns compatible with cellular hypertrophy in different layers of the epithelium as well as a greater keratinization in BMS cases.</td></tr><tr><td>J Complement<br/>Integr Med<br/>Granada Spain<br/>Case Control</td><td>80% of the patients presented BMS type 2 and 20% presented BMS type 1.</td><td></td><td></td><td></td><td></td><td>On the other hand, a lower amount of proteoglycans and a greater amount of collagen fibres were observed compared to the control. In addition, older patients had fewer reticular fibres and younger patients had fewer elastic fibres compared to the CTRL.</td></tr></tbody></table>

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<table><caption>TABLE 1 | (Continued)</caption><thead><tr><th>First author, publication date, journal, country, study design</th><th>Characteristics of BMS group, mean age ± SEM, age range, sex ratio F/M, characteristics of pain</th><th>Characteristics of control (CTRL) group, mean age ± SEM, age range, sex ratio F/M</th><th>Type of analysis and methods</th><th>Criteria for evaluating and diagnosing BMS</th><th>Main results on BMS and biopsies</th><th>Conclusions of the work</th></tr></thead><tbody><tr><td>Exfoliative cytology</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Wandeur, T. 2011</td><td>20 BMS 57.1 [37–80]</td><td>20 CTRL Healthy matched for age and gender</td><td>Cytomorphometric and cytomorphological analysis</td><td>Clinical criteria</td><td>A highly significant increase in nuclear area (NA) and reduction in Cytoplasmic area (CA) for the BMS group was found (p &lt; 0.05). The NA/CA ratio (p &lt; 0.05) was higher in the BMS group than in the CTRL group (p &lt; 0.05). There was a predominance of normal</td><td>Mean values of nuclear area (NA) for experimental and control groups were, respectively, 67.52 and 55.64 lm2 (p &lt; 0.05). Cytoplasmic area (CA) showed the following mean values: 1258.0 (experimental) and 2069.0 lm2 (control). Nucleus-to-cytoplasm area ratio for the experimental group was 0.07, besides the control group was 0.03</td></tr><tr><td>Gerodontology Brazil</td><td>M:F 0:20</td><td></td><td></td><td></td><td>epithelial cells in the smears for both BMS and CTRL groups, but no inflammatory or dysplastic alteration was noted.</td><td></td></tr><tr><td>Case Control</td><td></td><td></td><td></td><td></td><td>A predominance of intermediate cells was observed in the smears of BMS patients. The CTRL group showed higher number of smears exhibiting a predominance of nucleated superficial cells and there was a dependence between the type of predominant cell and group</td><td></td></tr></tbody></table>

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<table><caption>TABLE 1 | (Continued)</caption><thead><tr><th>First author, publication date, journal, country, study design</th><th>Characteristics of BMS group, mean age ± SEM, age range, sex ratio F/M, characteristics of pain</th><th>Characteristics of control (CTRL) group, mean age ± SEM, age range, sex ratio F/M</th><th>Type of analysis and methods</th><th>Criteria for evaluating and diagnosing BMS</th><th>Main results on BMS and biopsies</th><th>Conclusions of the work</th></tr></thead><tbody><tr><td>Shinoda M.<br>2015</td><td>9 BMS [48–64, 75–80].<br>M:F 0:9</td><td>9 CTRL<br>51–85<br>M:F 4:5</td><td>qPCR</td><td>Clinical Criteria</td><td>The mRNA expression of Artn in the tongue mucosa of patients with BMS was significantly higher than that of control subjects</td><td>There was no significant difference in the health history between patients with burning mouth syndrome and control subjects. The mRNA expression of Artn in the tongue mucosa of patients with burning mouth syndrome was significantly higher than that of control subjects</td></tr><tr><td>Pain<br>Japan<br>Case-Control</td><td></td><td></td><td></td><td></td><td></td><td></td></tr></tbody></table>

Abbreviations: BMS, burning mouth syndrome; CTRL, control; ENF, epithelial nerve fibres; IENFD, intraepidermal nerve fibre density; IR, immunoreactivity.
cases [39, 45]. Keratinocyte cytoplasm was homogeneously labelled for keratin 16 in BMS patients, with a more intense staining than controls, without differences for Desmoglein 1 and 3, CK10, CK14 [45].

### 3.4.3 | Cytological Findings

An increased nuclear-to-cytoplasmic area ratio was observed in BMS epithelial cells [29]. BMS patients exhibited a predominance of intermediate epithelial cells compared to the more superficial cells in controls [29]. Treldal et al. [44] evidenced subgroups of BMS patients with signs of epithelial atrophy [44].

Increased expression of oestrogen receptors (Era) was found in the oral mucosa in subgroups of BMS patients [44].

### 3.4.4 | Gene Expression

No statistically significant difference in sodium channel gene expression (mRNA for Nav1.7, Nav1.8, Nav1.9) was found between BMS and controls [42]. However, Artn mRNAs was significantly increased in BMS [46] compared to CTRL [30].

### 3.4.5 | Inflammatory Changes

Mast cells Tryptase: Arantes et al. [43] found no changes in mast cell density. Borsani et al. found a decreased CB1 and increased CB2 expression in tongue epithelial cells [40].

## 3.5 | Synthesis of Results

The data from the included papers were very highly? heterogeneous, making a meta-analysis infeasible. So, a qualitative description was performed. The main methodological issue pertained to strategies to deal with confounding factors such as age, sex and psychosocial status that were not always collected.

<table><thead><tr><th></th><th>Author, Year</th></tr></thead><tbody><tr><td>1.</td><td>Arantes 2023</td></tr><tr><td>2.</td><td>Beneng 2010 a</td></tr><tr><td>3.</td><td>Beneng 2010 b</td></tr><tr><td>4.</td><td>Borsani 2014</td></tr><tr><td>5.</td><td>Domaneschi 2022</td></tr><tr><td>6.</td><td>Lauria 2005</td></tr><tr><td>7.</td><td>Penza 2010</td></tr><tr><td>8.</td><td>Puhakka 2016</td></tr><tr><td>9.</td><td>Sardella 2012</td></tr><tr><td>10.</td><td>Shinoda 2015</td></tr><tr><td>11.</td><td>Treldal 2019</td></tr><tr><td>12.</td><td>Wandeur 2011</td></tr><tr><td>13.</td><td>Yilmaz 2007</td></tr><tr><td>14.</td><td>Zubiate Illaramendi 2022</td></tr></tbody></table>

## 3.6 | Confidence in Cumulative Evidence

The overall quality of evidence identified using GRADE's SoF tables was rated as very low (Table S4), because 8 of the 14 studies presented a high risk of bias, which downgraded one point; and the study design was labelled as observational studies (case-control), which downgraded two points.

# 4 | Discussion

This systematic review included fourteen studies investigating morphological, histological and cytological alterations in oral tissues of patients with Burning Mouth Syndrome (BMS). Twelve studies used surgical biopsies, while two employed exfoliative cytology. The findings provide evidence of cellular and molecular changes in epithelial cells and nerve fibres, distinguishing BMS patients from healthy controls.

These results align with those from recent reviews [15, 72] although previous analyses often focused on other diagnostic modalities such as quantitative sensory testing (QST) or neuroimaging and did not comprehensively address histological biomarkers. Furthermore, this review also provides technical insights into methodological variability, which may influence future research and clinical standardisation.

## 4.1 | Interpretation of the Findings

### 4.1.1 | Morphological and Cytologic Characteristics of the Oral Epithelium

Several studies sought to identify histological or cytological markers specific to BMS, based on the hypothesis that the oral mucosa may exhibit disease-related alterations. For example, Wandeur et al. [29], using exfoliative cytology, reported normal overall epithelial cell morphology but observed significant morphometric changes in BMS patients, including nuclear and cytoplasmic alterations suggestive of epithelial atrophy and

<table><caption>**FIGURE 2** | Critical appraisal tool to assessed risk of bias summary. JBI Critical Appraisal Tools to assessed risk of bias in case-control studies.</caption><thead><tr><th>Study Design</th><th>Risk of Bias</th></tr></thead><tbody><tr><td>Case-Control</td><td>?</td></tr><tr><td>Case-Control</td><td>●</td></tr><tr><td>Case-Control</td><td>●</td></tr><tr><td>Case-Control</td><td>●</td></tr><tr><td>Case-Control</td><td>●</td></tr><tr><td>Case-Control</td><td>●</td></tr><tr><td>Case-Control</td><td>●</td></tr><tr><td>Case-Control</td><td>●</td></tr><tr><td>Case-Control</td><td>●</td></tr><tr><td>Case-Control</td><td>●</td></tr><tr><td>Case-Control</td><td>●</td></tr><tr><td>Case-Control</td><td>●</td></tr><tr><td>Case-Control</td><td>●</td></tr><tr><td>Case-Control</td><td>●</td></tr><tr><td>Case-Control</td><td>●</td></tr></tbody></table>
<figure><img src="image_5.png" /></figure>

**FIGURE 3** | Anatomical organisation and innervation of fungiform and filiform papillae on the anterior two-thirds of the human tongue. (A) Schematic dorsal views highlighting filiform (light pink), covering the whole surface of the tongue, and fungiform (dark pink) papillae located on the anterior 2/3 (within grey box), and foliate and circumvallate papillae on the posterior 1/3 (region above the grey box). (B) Crosssection through the epithelium and lamina propria of a fungiform (left) and filiform papillae (right). (C) Somatosensory fibres of the trigeminal lingual nerve (blue lines, Vth cranial nerve) innervate both papillae; gustatory fibres of the chorda tympani (orange lines, VIIth cranial nerve) selectively enter the fungiform taste buds. Glossopharyngeal (green lines, IXth cranial nerve) and chorda tympani fibres innervate the posterior. Adapted from Mistretta and Bradley [51].

disrupted cellular maturation. However, they did not explore how these changes might relate to pain perception. Jorgensen et al. (2010) [73], in a preliminary study published as an abstract, found no signs of inflammation but observed reduced epithelial thickness and flattened epithelial ridges in the tongues of BMS patients, alongside diminished oestrogen receptor expression. A subsequent study by the same group examining the buccal mucosa reported similar findings: absence of inflammation in most cases, but epithelial atrophy in approximately 50% of patients, possibly associated with upregulation of oestrogen receptors [44].

Sardella et al. [45] provided evidence of altered expression of keratin 16, a possible marker of epithelial cell injury or dysfunction, which was homogenous in the epithelial cells of BMS patients and not in CTRL subjects. Other epithelial markers (Desmogleins, cytokeratin K10 etc.) were not altered. However, the semi-quantitative methods used in the study were not well described, limiting the reliability/reproducibility of these findings. Borsani et al. [40] used immunohistochemistry to evaluate epithelial expression of specific biomarkers involved in pain and inflammation (receptors TRPV1, CB1 and CB2). They found increased expression of TRPV1 and CB2 and a decrease in CB1 receptors in BMS patients compared to CTRL subjects, suggesting that these receptors are involved in the physiopathology of BMS.

Overall, studies reported few gross architectural changes in oral tissues, suggesting that BMS is not associated with overt

epithelial pathology. Nevertheless, immunohistochemical techniques have revealed subtle but consistent cellular alterations, particularly in pain- and inflammation-related pathways.

## 4.2 | Innervation

### 4.2.1 | Total Innervation

Studies on BMS have focused so far on the density of nerve fibres in the epithelium and sub-epithelium, using different neuronal markers. The most used markers were PGP9.5 (UCH-L1) a homeostasis neuronal marker, beta-tubulin 3, Neurofilament and peripherin, which label constituents of the cytoskeleton (respectively microtubules and neurofilaments). The Schwann cell marker S100 has also been used as a surrogate marker of innervation targeting Schwann cells surrounding neurons. Several studies have reported an overall decrease in Intraepidermal nerve fibres density (IENFD) in the tongue and oral tissues of BMS patients, in particular within epithelial plexuses, while the subepithelial plexus is not affected. This supports the hypothesis of a general or peripheral fibre neuropathy underlying BMS, as suggested by Lauria et al. [28] and further supported by QST and electrophysiological findings [15, 72]. These authors found in a sample of 11 BMS patients (including 8 patients with symptoms localised at the tip of the tongue and 5 with extended symptoms) an overall decrease in IENFD, which has been confirmed in further studies [37, 46] and especially in a well-controlled study with matched age sex subject and following guidelines and
<table><caption>TABLE 2 | Technical aspects of the morpho-histo-cytological procedures and comments.</caption><thead><tr><th>Authors, year</th><th>Subjects</th><th>Method</th><th>Localization</th><th>Histology and biomarkers</th><th>Analysis</th><th>Blinded</th><th>Pain</th></tr></thead><tbody><tr><td colspan="8"><strong>Punch biopsy + histology</strong></td></tr><tr><td rowspan="2">Arantes, et al. 2023</td><td>12 BMS</td><td>Incisional biopsies (Size unknown) under local anaesthesia.</td><td rowspan="2">Symptomatic sites in the anterior region of the tongue</td><td rowspan="2">Cytology Haematoxylin eosin<br>IHC: polymer-based detection method.<br>DAB<br>Biomarkers S-100 (Schwann cells)<br>PGP 9.5 (nerve fibres)<br>Tryptase (mast cells)</td><td rowspan="2"><strong>Cytology</strong>: evaluation of the integrity of the epithelium, keratinization and thickness, inflammatory infiltrate, collagenization, keratin thickness<br><strong>IHC</strong>: density (NF/mm2), and integrity of peripheral NF<br>20 alternating fields at ×40 magnification. (density/mm [2]) on the entire slide.<br>Density of degenerate NF</td><td rowspan="2">All sections were evaluated by two examiners in a blinded fashion and disagreements were resolved by consensus.</td><td rowspan="2">NR</td></tr><tr><td>11 CTRL</td><td>Samples fixed in 10% neutral buffered formalin, and paraffin-embedded 5 µm section for cytology, 3 µm for IHC</td><td>Five random fields per tissue section were scanned and the mean value used in subsequent statistical analysis</td></tr><tr><td>Beneng et al. 2010a</td><td>9 BMS<br>10 CTRL</td><td>Punch biopsy 3×3 mm<br>Under local anaesthesia<br>Biopsies placed in liquid nitrogen and transferred to -70°C storage; Sections: 12 µm thaw mounted onto glass slides pre-coated with poly-L-lysine. Then fixed in fresh 4% paraformaldehyde in PBS for 30 min.</td><td>Location obtained from the dorsal lingual mucosa, lateral to the midline in the anterior third.<br>All BMS patients had pain at the site of the biopsy.</td><td>Cytology: Counter staining in neutral red to visualise nuclei<br>IHC: avidin-biotin peroxidase (ABC)<br>Biomarkers: Neurofilament P2X3 (receptor)</td><td></td><td></td><td>NR</td></tr><tr><td>Beneng et al. 2010b</td><td>7 BMS<br>10 CTRL (wisdom teeth extraction)</td><td>Punch biopsy<br>Same technique as Beneng et al. 2010a</td><td></td><td>Cytology and IHC same as Beneng et al. 2010a<br>Biomarkers: Nav1.7</td><td>% of nerve immuno-reactivity</td><td>The entire sub-epithelial region of the section was analysed at the same magnification of 40</td><td>NR</td></tr></tbody></table>

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<table><caption>TABLE 2 | (Continued)</caption><thead><tr><th>Authors, year</th><th>Subjects</th><th>Method</th><th>Localization</th><th>Histology and biomarkers</th><th>Analysis</th><th>Blinded</th><th>Pain</th></tr></thead><tbody><tr><td rowspan="2">Borsani et al. 2014</td><td>8 BMS</td><td>Punch biopsy, 3 mm Ø under local anaesthesia</td><td>anterolateral aspect of the tongue</td><td rowspan="2">Haematoxylin-eosin IHC: DAB IF</td><td rowspan="2">Epithelial cells Quantitative analysis</td><td rowspan="2">Researchers unaware of the group assignment calculated the percentage of positive area (per-area) measuring five fields with the same area for each section.</td><td rowspan="2">Biopsy was tolerated well and no side effects were recorded</td></tr><tr><td>8 CTRL</td><td>Specimens were immediately fixed in 2% paraformaldehyde-lysine-periodate for 24 h at 4°C, embedded in paraffin Section: 8 µm</td><td>close to the tip</td></tr><tr><td rowspan="2">Lauria et al. 2005</td><td>12 BMS</td><td>Punch biopsy (3 mm Ø). Suture was applied.</td><td>Punch biopsy at the anterolateral aspect of the tongue</td><td rowspan="2">IF Biomarkers: PGP9.5 β-Tubulin (TuJ1), MBP; PMP22</td><td rowspan="2">Epithelial innervation density per papilla</td><td rowspan="2">Two trained observers blinded to the diagnosis, counted in each section the total number of epithelial nerve fibres (ENF) arising from the sub-papillary nerve bundles under optic microscope at 40× magnification</td><td rowspan="2">Biopsy was well tolerated and no side effects were recorded</td></tr><tr><td>9 CTRLs</td><td>Specimens were immediately fixed in 2% paraformaldehyde-lysine-periodate for 24 h at 4°C, cryoprotected overnight, and serially cut with a cryostat Sections: 50 µm</td><td>close to the tip.</td></tr><tr><td rowspan="2">Penza et al. 2010</td><td>Tongue biopsy 51 patients</td><td>Punch biopsy (5mm Ø).</td><td>Anterolateral aspect of the tongue,</td><td rowspan="2">IF PGP 9.5</td><td rowspan="2">ENFD counted under an optic microscope at 40× magnification with the assistance of a microscope-mounted video camera.</td><td rowspan="2">3 sections were immunoassayed with polyclonal anti-PGP9.5 antibodies using Lauria et al. 2005 protocol If the sections did not contain at least 3 papillae in which central nerve bundles were clearly visible, further sections were immunostained. The number of ENFs per fungiform papilla was assessed blindly.</td><td rowspan="2">NR</td></tr><tr><td>9 CTRL=archive data</td><td>50 µm sections. Same method as Lauria et al. 2005 50 µm sections.</td><td>close to the tip</td></tr></tbody></table>

(Continues)
<table><caption>TABLE 2 | (Continued)</caption><thead><tr><th>Authors, year</th><th>Subjects</th><th>Method</th><th>Localization</th><th>Histology and biomarkers</th><th>Analysis</th><th>Blinded</th><th>Pain</th></tr></thead><tbody><tr><td>Puhakka et al. 2016</td><td>10 BMS<br>13<br>CTRL = cadavers<br>matched sex<br>age and 6<br>diabetic CTRL</td><td>Biconvex biopsy<br>(2×5 mm) were taken under<br>topical local anaesthesia<br>from the dorsal mucosa of the<br>anterior third of the tongue<br>of the patients with BMS.<br>Method of EFNS (Lauria et al.,<br>2005b). (i.e., section = 50 µm)</td><td>The side of the<br>biopsy coincided<br>with the side of<br>hypoesthesia findings<br>in thermal QST.<br>CTRL specimens<br>obtained from fresh<br>cadavers within 48 h<br>after death from the<br>same lingual site as<br>those of the patients.</td><td>IHC<br>Biomarkers<br>β tubulin (TUJ1)<br>PGP9.5</td><td>Quantitative analysis:<br>IENFD was calculated<br>per epithelial area<br>(mm²) and epithelial<br>length (mm²) (counted<br>with β-tubulin)</td><td>Blind-coded specimens<br>were examined</td><td>Cadaver<br>tongue<br>preferred<br>for CTRLs<br>because<br>tongue<br>biopsy,<br>even when<br>obtained<br>under topical<br>anaesthesia,<br>is a painful<br>procedure.</td></tr><tr><td>Sardella et al.</td><td>10 BMS<br>9 CTRL</td><td>Punch Biopsy<br>5 mm Ø.<br>Immediately after excision,<br>each biopsy was divided into<br>2 fragments with a scalpel,<br>and both fragments were<br>processed for light microscopy:<br>one fragment was embedded<br>in OCT, maintained at<br>-80°C, and cryostat-cut.<br>The other fragment was<br>immersion-fixed in 4%<br>formaldehyde buffered with<br>0.1 M phosphate-buffered<br>saline (PBS), pH 7.4, for 5 h at<br>room temperature, dehydrated<br>and paraffin-embedded.<br>Paraffin serial sections<br>(4 µm) were obtained with<br>a manual rotary microtome<br>and collected on 3-amino-<br>propyl triethoxysilane-<br>coated glass slides.</td><td>BMS patients:<br>anterior or lateral<br>aspect of the tongue<br>in an area where<br>burning sensations<br>were reported<br>In CTRLS: a tongue<br>biopsy of clinically<br>normal tongue<br>mucosa (anterolateral<br>aspects) was taken far<br>from the lesion to be<br>excised (at least 3 cm)<br>Under local<br>anaesthesia</td><td>IHC<br>IF:<br>Dsg1/Dsg3<br>K10<br>K14<br>K16<br>Pepsin<br>p53<br>Caspase-3<br>Laminin</td><td>Morphology<br>Semi-quantitative<br>analysis of<br>immunostaining</td><td>At least two<br>experiments/sample<br>each including two<br>slides (total of four<br>slides/sample) were<br>carried out to obtain<br>a semi-quantitative<br>analysis of K16<br>epithelial expression.</td><td></td></tr></tbody></table>

(Continues)
<table><caption>TABLE 2 | (Continued)</caption><thead><tr><th>Authors, year</th><th>Subjects</th><th>Method</th><th>Localization</th><th>Histology and biomarkers</th><th>Analysis</th><th>Blinded</th><th>Pain</th></tr></thead><tbody><tr><td>Teldal et al. 2019</td><td>21 BMS 10 CTRL</td><td>Biopsy 5×7 mm immediately divided into 2 parts. One part was fixed in 10% phosphate-buffered neutral formalin (pH 7.3, 24h at 20°C), and the other part was embedded in Tissue-Tek OCT compound, snap-frozen in isopentane/dry ice and stored at -80°C until analysis.<br>4 µm sections stained with haematoxylin and eosin (H&E) for routine histological examination.</td><td>Right buccal mucosa Under regional anaesthesia</td><td>Semi quantitative analysis of the IHC labelling<br>Oestrogen receptor, NGF<br>NGF receptor TRPV-1<br>IL-17F</td><td>Morphology<br>The presence and distribution of IR were evaluated semi-quantitatively</td><td>Analysis by a trained histopathologist blinded regarding patient data.</td><td>NR</td></tr><tr><td>Yilmaz et al. 2007</td><td>10 BMS 10 CTRLs</td><td>Punch biopsy 3×3 mm Under local analgesia<br>Suturing of the biopsy site was not necessary.<br>The mucosal<br>Biopsies were immediately placed on a sterile suture card, then in liquid nitrogen and subsequently transferred to 70°C storage until used for IHC analysis.<br>12 µm frozen sections were collected onto poly-L-lysine coated glass slides and post-fixed in freshly prepared, 4% w/v paraformaldehyde in 0.15 mol phosphate buffered saline (PBS) for 30 min.</td><td>Human tongue (lingual dorsal mucosa 1-2 cm from the tip of the tongue).<br>All BMS patients had pain at the site of the biopsy.<br>This was an additional procedure in the CTRL subjects undergoing planned wisdom tooth surgery, with no additional local analgesia.</td><td>IHC TRPV1, NGF, Nav1.8 TRPV1<br>Neurofilament Peripherin</td><td>Morphology<br>Descriptive and quantitative analysis of sub epithelial and epithelial nerve fibres</td><td></td><td>NR</td></tr></tbody></table>

(Continues)
<table><caption>TABLE 2 | (Continued)</caption><thead><tr><th>Authors, year</th><th>Subjects</th><th>Method</th><th>Localization</th><th>Histology and biomarkers</th><th>Analysis</th><th>Blinded</th><th>Pain</th></tr></thead><tbody><tr><td>Zubiate Illaramendi et al. 2022</td><td>10 BMS<br>1CTRL</td><td>Punch biopsy<br>6 mm fixed in<br>4% buffered formalin<br>Hematoxilin Eosin Alcian blue (proteoglycans) Picrosirius, Gomori Reticulin (collagen) and Verhoeff. (reticular fibres)</td><td>Lingual mucosa on the right lateral lingual border, on the dorsal side.</td><td></td><td>Descriptive and quantitative analysis of the extracellular matrix of the connective tissue</td><td></td><td>NR</td></tr><tr><td>Domaneschi et al.</td><td>12 BMS<br>5 CTRL</td><td>Punch biopsy (5 mm Ø, 5 mm deep) under local anaesthesia<br>All the samples were immediately frozen in liquid nitrogen, and stored in a freezer at 80°C, awaiting further laboratory procedures<br>qPCR</td><td>tongue dorsum affected by the burning symptom<br>CTRL: tongue dorsum after excision of the fibrous hyperplasia from 5 patients.</td><td>Real-time qPCR (mRNA)<br>Biomarkers<br>Nav1.7<br>Nav1.8<br>Nav1.9</td><td>Differential expression levels of the genes studied in the case and control groups<br>Correlations between the clinical and gene expression data</td><td></td><td>NR</td></tr><tr><td>Shinoda et al. 2015</td><td>9 BMS<br>9 CTRL</td><td>Samples were obtained by scraping the tongue mucosa, 5 times using the lid of a 1.5 mL centrifuge tube.</td><td>Sample including the area with focal chronic pain</td><td>qPCR<br>Artemin (Artn)</td><td>Relative expression levels of Artn were determined after normalisation to the corresponding sample expression level of b-Actin. Amplified PCR products were analysed by DNA sequencing to confirm their sequences</td><td></td><td>NR</td></tr></tbody></table>

(Continues)
<table><caption>TABLE 2 | (Continued)</caption><thead><tr><th>Authors, year</th><th>Subjects</th><th>Method</th><th>Localization</th><th>Histology and biomarkers</th><th>Analysis</th><th>Blinded</th><th>Pain</th></tr></thead><tbody><tr><td>Wandeur et al. 2011</td><td>20 BMS 20 CTRL</td><td>The squamous epithelial cells were collected using a cytobrush and kit Universal Collection Medium</td><td>The collection of cells at the location of pain for BMS and at the same corresponding anatomical region for CTRL</td><td>Cytomorphology and Cytomorphometry of epithelial cells (EC)</td><td>All smears were analysed and classified according to the EC features (normal EC; normal EC associated with inflammatory changes; or EC exhibiting dysplastic alterations), Additionally, the type of predominant cell (enucleated superficial cells, nucleated superficial cells, intermediate and para- basal cells) in each smear was also evaluated</td><td></td><td>NR</td></tr></tbody></table>

Abbreviations: CTRL, control; ENFD, DAB, DiaminoBenzidine; epithelial nerve fibre density; IENFD, intraepithelial nerve fibre density; IF, immunofluorescence; IHC, immuno histo chemistry; NF, nerve fibre; NR, not reported; qPCR, quantitative polymerase chain reaction.
criteria for inclusion [41]. However, a more complex and some-
how contradictory picture seems to emerge from the work of
Penza et al. [38] who identified an overall difference in IENFD
when examining their whole sample of 51 BMS patients com-
pared to 9 control subjects from a previous study, but found dif-
ferences according to the location of the pain: patients with ‘Tip
only’ BMS had normal IENFD, whereas patients with ‘extended’
symptoms showed a decrease in IENFD. Despite methodolog-
cal issues in the definition and comparison of the subgroups, this
difference might reflect a clinical feature and raises the question
of whether the location of the symptoms is related to a step of
the disease or a different physio-pathological process. In addi-
tion, one study by Arantes et al. [43] found no change in nerve
density in BMS patients compared with CTRL. Another finding
of this review is the heterogeneity in the methods between the
different studies to calculate IENFD, regarding the tissues ex-
amined. Except for Treldal et al. [44] who examined another site
of the oral mucosa, all the biopsies examined the anterior tongue
surface, including epithelium and sub-epithelium. However, the
surface of the anterior tongue is covered with filiform papillae
(FilP) and fungiform papillae (FunP) which have a different pat-
tern and density of innervation [74] and can both participate in
painful sensations. Lauria (2005) [28] and Penza (2010) [38], for
example, examined only the innervation of fungiform papillae,
while others do not specify the presence of fungiform papillae
[41, 46] refer to papillae only in the results section, without pre-
cising FunP or FilP. This can make a difference since the FunP
display the highest density of nerve fibres in the tongue epithe-
lium. In addition, for calculating IENFD, several authors refer
to the method of Lauria et al. (European guidelines) [65] for
skin biopsy in order to normalise the procedure of counting and
preparation, but it should be noticed that the skin does not con-
tain papillae, either FunP nor FiP, making the method difficult
to implement for the tongue surface.

4.3 | Specific Nerve Labelling

While the total amount of nerve fibres measured as IENFD is
an important measure, it does not indicate which type of nerve
fibres are affected in BMS. Some studies looked at this qualita-
tive aspect of innervation through the presence of *neurotrophic*
*factors* conditioning nerve growth and homeostasis such as NGF
and Artemin (Artn) and their receptors, or through *ion chan-
nels* (Nav1.7, Nav1.8, Nav1.9) known to be expressed in primary
afferent nociceptors. Both NGF, the ligand of the NGF receptor
TrkA [46] and Artn, a ligand of the GDNF receptor [30] were
increased. NGF and GDNF control different neuronal subpopu-
lations [66]. Only Nav1.8 expression was significantly increased
at the protein level but not at the gene level, when Nav1.7 and
1.9 were unchanged [37, 42, 46]. Some receptors involved in
pain and thermo-sensation were searched: *TRPV1*, a receptor
activated by heat, acidity and inflammatory mediators such
as oxidised lipids [67] and external ligands such as capsaicin,
was found to be increased in nerves of BMS patients, as was the
pronociceptive neurotrophin NGF, compatible with the burning
sensation associated to TRPV1 activation [46]. This is especially
interesting since a correlation has been found with the expres-
sion of TRPV1 and NGF and the intensity of pain in BMS [46]. It
should, however, be noticed that, even if some studies using cap-
saicin, an agonist of the TRPV1 receptors, suggest that TRPV1

is responsible for the burning sensation [68, 69], no study yet
has clearly proven this hypothesis. Other pain-related receptors
such as TRPA1 (implicated in the production of inflammatory
and neuropathic pain) [70] or ASIC (acid sensor ionic channel)
could also be candidates, especially since BMS patients avoid
acids and spicy food. The lack of clinically available antagonists
for humans explains this lack of knowledge. TRPV1 immuno-
reactivity was also increased in epithelial cells, suggesting that
not only nerve fibres contribute to the etiopathogenesis of BMS.
P2X3 immunoreactivity was also increased in epithelial nerve
fibres. The P2X purinergic receptor is activated by extracellular
adenosine triphosphate (ATP), which is released during tissue
injury or inflammation and chronic pain including OFP [71]; in
addition, P2X3 expression, as that of TRPV1, is regulated by oes-
trogens [48] possibly involved in BMS.

4.4 | Implications and Integrative Interpretation

First, BMS is associated with neuropathic changes, which help to decipher the etiopathogenesis; considering QST, imagery and saliva studies together with these neuropathic changes result in a complex picture of generalised changes involving nervous, glial and epithelial cells. Second, these changes are not 'all or none'. There is yet no specific marker for BMS that would be found only in CTRL subjects, pointing out that clinical diagnosis is still the standard of diagnosis. Only quantitative changes for innervation or other biomarkers have been evidenced along with discrete qualitative cytologic changes. This raises the question of whether there is a continuum of changes [38] or a discontinuous evolution as evoked in the first part of the discussion. Tip only might relate to stress-induced BMS [49] when extended BMS might relate to advanced neuropathy. In the first case, BMS pain would be caused by a central sensitisation caused by stress as described in the concept of stress-induced sensitization [50] and in the second case would be the result of the histopathological changes observed in the tongue, reflecting general changes (see further discussion). This raises the question of the mechanism of pain in BMS. Since no correlation was evidenced in the reviewed studies between the severity of the symptoms and the magnitude of the histological changes, the pain cannot be solely assigned to the decrease of epithelial nerve fibres. Third, our knowledge is still very limited, and the available studies looked at small parts of the whole picture. A better understanding of the innervation of the human tongue is necessary and the following points need to be discussed:

4.4.1 | Origin of the Labelled Nerves

*Trigeminal* versus *Chorda tympani (CT)*: The anterior part of the tongue, covered with FilP and FunP, is innervated, for the sensory nerves, by the trigeminal (V) and CT-VII nerves. The V conveys tactile and interoceptive (temperature, pain, pruriception, chemoception etc.). The VII relays taste information. Filiform papillae (FilP) are innervated by the V and fungiform papillae (FunP) by the V and VII; in addition, as shown in animal studies, in the FunP, nerve fibres of the VII are distributed inside the taste bud and V afferents outside the TB [51]. FilP and FunP convey tactile innervation when taste is only processed in FunP. In rodents, as well as in humans, both FilP and FunP are
innervated by interoceptive nerve fibres [52, 53, 74]. In this regard, the FunP is a special sensory organ, crucial for oral perceptions integrating at the first step taste, tactile and interoceptive information [51]. In the articles reviewed in this study, the data are difficult to interpret, especially for FunP, since the innervation and the bulk of innervation arising from the subepithelial plexus can belong either to CT or V. Therefore, the meaning of the P2X3 increase [37] is difficult to embrace since purinergic (P2X3) labelling is, in animals, mainly found within taste buds (intragemmal) [54] originating from CT fibres when perigemmal innervation is mainly composed of peptidergic nerve fibres of trigeminal origin, suggesting a role in taste rather than in pain. Many studies report an association between dysgeusia and BMS [55] although a recent well-controlled study challenged this view [56]. Autonomic innervation: In addition to the sensory innervation, animal studies evidenced an autonomic innervation in the tongue [57, 58] which can be labelled with nerve biomarkers such as the enzyme Tyrosine Hydroxylase (TH). The presence of autonomic nerve fibres has not been searched in the human tongue with BMS, but autonomic symptoms such as xerostomia are frequently reported. In addition, autonomic alterations have been evidenced in BMS patients [59]. Therefore, it cannot be excluded that the decrease in IENFD might involve autonomic nerve fibres.

### 4.4.2 | Subtypes of Nerves

If pain in BMS is supposed to come from trigeminal nerve dysfunction, deciphering the origin of the signal is more complex and requires identifying the subtypes of nerves involved. The view of interoceptive versus exteroceptive sensory pathways conveying respectively by small neurons with unmyelinated nerve fibres and large neurons with myelinated fibres has challenged our understanding of nociception and pain as well as that of touch and homeostasis function [60]. Nociception arises from two categories of neurons: small unmyelinated neurons connected to amyelinic fibres (C-Neurons), and small to medium-sized neurons connected to thinly myelinated nerve fibres (Aδ Neurons); the C-fibre neurons are broadly divided into peptidergic neurons containing neuropeptides such as substance P and calcitonin gene-related peptide (CGRP) and non-peptidergic neurons expressing IB4 (isolectin B4)-binding protein. NGF controls the survival, differentiation and target innervation of both peptidergic and non-peptidergic sensory neurons in dorsal root/trigeminal ganglion neurons [61]. Non-peptidergic primary afferents are firstly dependent on NGF and later on GDNF (glial cell-derived neurotrophic factor) [62]. Based on scRNA-seq (single-cell RNA sequencing) obtained in rodent studies, this knowledge has been updated recently [63, 64] as follows: type C including C-Cold (TRPM8<sup>high</sup>, expressing TRPM8), C-Nociceptors MH (=PEP1, including 4 subtypes, expressing among other TRPV1, TRPA1, TRPM3 and Piezzo2), type Aδ H nociceptors (PEP2, expressing TRPV1, ASIC1), for the main types [64]. Recent studies on tongue innervation in mice fit with this classification [75] and can be useful for BMS studies.

Although each sensory neuron subtype expresses a repertoire of receptors, there is an overlap between the neurons; for example,

in rodents, TRPV1 is found in both C-fibres and Aδ fibres and in C-fibres some receptors such as Piezzo 2 are expressed in different subtypes [75, 76]. Temperature-sensitive afferents, which express TRPV1, not only respond to noxious heat and capsaicin but are also modulated by the acidity of the chemical milieu of inflammation, a frequent clinical feature of BMS patients avoiding spicy and acidic foods. TRPA1, thought to be restricted to a subset of TRPV1 afferents of the peptidergic subclass, has a wider distribution than does TRPV1, is expressed by all neuronal sizes in the sensory ganglion of mice [77] and is found in the human tongue [74]. Therefore, the use of TRPV1 labelling is interesting for understanding the mechanism of the pain but is not sufficient to determine the precise neuronal subtype involved. Shinoda et al. [30] found an upregulation of artemin, a ligand of the GDNF family receptor α3 (GFRα3) in BMS patients and a mirror increased artemin protein expression in the keratinized epithelium of the tongue, in a mouse model of BMS, pointing to a role of non-peptidergic sensory neurons in BMS. However, this mouse model of BMS is closer to a chemical neuropathy than to a true clinical representation of BMS.

### 4.4.3 | Non-Nociceptive Neurons

Recent animal studies [52, 53] also evidenced mechanical innervation of fungiform and filiform papillae indicating that not all the nerve fibres are dedicated to pain or interoceptive information, raising the question of the origin of the decreased IENFD in BMS. Fungiform papillae are convergently innervated by multiple Piezo2+ trigeminal afferents, whereas single trigeminal afferents branched into multiple adjacent filiform papillae. Although the neuronal mechanical sensor Piezo2 is expressed in non-nociceptive neurons, it also plays a role in pain. For example, capsaicin inhibits Piezo2 function [78] and Piezo2 upregulation in pain-afferent neurons following trigeminal nerve injury contributes to neuropathic pain development. Moreover, its upregulation may be modulated by proinflammatory cytokines such as IL-6 [79], suggesting a link between mechanical transduction, inflammation and changes in sensory function in BMS patients.

### 4.4.4 | Non-Neuronal Cells

In addition, Schwann cells, labelled in some BMS studies with S100 marker [43], can participate in nociception, as evidenced in animal studies [80], raising the question of which type is important for pain in BMS. Other cell types such as epithelial cells may modulate neuronal sensitivity and play a role in the etiopathogenesis of BMS: for example, Borsani et al. [40] found an increased expression of TRPV1 in epithelial cells in BMS versus CTRL, along with its translocation to the plasma membrane. TRPV1 is not limited to pain but contributes in humans to several other cellular functions such as cell proliferation, barrier function and inflammation [81], and interestingly in concert with TRPA1 [82]. The same group also evidenced a decrease in CB1 and an increase in CB2 receptors in epithelial cells, which are known modulators of nerve function [83]. Taken together, this suggests that not only neurons, but also non-neuronal cells may participate in the burning sensation experienced by BMS patients.
4.4.5 | The Pain Is Not Always the Result of Increased Nociception

Pain sensation is mainly a cerebral construct resulting from the integration of neuronal activities [84]. Both the network configuration [85], as well as the context of the perception, is important as illustrated respectively by the gate control model [86] and the thermal grid paradigm [85]. According to the gate control theory, nociceptive inputs from small fibres are inhibited at the spinal cord level by non-nociceptive tactile inputs. These are supposed to be Aδ fibres but recent evidence in animals indicates that C-LTMR expressing TAFA 4 peptide can do the same [87]. Then, a decrease in nerve fibre density might translate to a pain sensation. It has been suggested that a relative reduction in the activity of Aδ fibres mediating cooling that in normal conditions inhibits the polymodal C-fibre nociceptor system results in unmasking or disinhibition of the system and consequent burning pain [60]. Jaaskelainen 2012 [88] suggested that according to some thermal QST results, hypofunction within the Aδ fibre class mediating innocuous cooling may be relatively more frequent than C-fibre hypofunction in primary BMS. This disinhibition phenomenon occurs irrespective of the level of the lesion within the cool fibre mediated system; damage either within the peripheral or central nervous system will lead to clinically similar representation In addition, although a recent study using Conditioned Pain Modulation (CPM) evidenced ascending dysfunction with QST [89], another study showed alteration of descending controls although [90], suggesting that BMS pain might be due to altered central controls [85, 86].

4.4.6 | Symptoms

Studies found no significant correlation neither between IENFD and intensity of the pain (Lauria et al.; 2007, Penza et al.2010), nor between IENFD and duration of the symptoms, though Lauria et al. observed a trend towards significance. There is only one study linking pain symptoms and histological findings. Yilmaz et al. (2007) [46] found a positive correlation between the baseline pain score and TRPV1 (p = 0.0143) and NGF fibres (p = 0.0252) but no correlation with global IENFD. Additionally, they found a significant correlation between baseline and post-capsaicin pain (p = 0.0006). The study was performed in a small sample of patients (N = 10 in each group). Beneng et al. 2010 [46, 47] observed a trend but an insignificant correlation between pain symptoms and P2X labelling also in a small sample lacking statistical power. Treldal et al. [44] evidenced a link between pain symptoms and the presence of biomarkers: immunoreactivity to the oestrogen receptor was most intense in the group of patients relieved by local anaesthetic application, whereas the patients who were not tended to have higher plasma levels of proinflammatory cytokines. They did not, however, assess IENFD. This approach echoes the idea of using local anaesthesia to sort BMS patients according to distinct pathogenic mechanisms: peripheral neuropathy versus systemic inflammation [91]. It also echoes attempts to phenotype BMS patients with QST, and may help to find subgroups of patients and disconnect out different types of BMS. The value of QST has been already discussed elsewhere [8, 15, 92] and will not be here, but overall results indicate that thermal sensitivity seems to

be significantly altered in patients with BMS compared to controls, suggesting a small-fibre neuropathy. In addition, the variability in QST results suggests that small fibre neuropathy may not be present in all BMS patients and study protocols were highly variable and heterogeneous. Combining biopsy with response to treatment biomarkers and QST is interesting although difficult to implement in clinics.

4.4.7 | Tissues Biopsies vs. Other Procedures

Biopsies need to prove their innocuity. The procedure is painful and, for example, Puhakka et al. [41] used biopsies from cadavers in order to limit the number of CTRLs subjects. It can also be questioned, especially in patients with a neuropathic condition such as BMS, if biopsies can be harmful, leading to additional persistent pain. We did not find an answer in the BMS literature and looked at other diseases using biopsies procedures. Salivary accessory glands biopsy used for Sjögren disease diagnosis seems innocuous [93] but delayed effects can be misevaluated. It would be interesting to recall the patients from BMS studies for a long-term follow-up to evaluate pain over time, since the baseline data are already available. In this regard, exfoliative cytology [29, 30], by avoiding surgical lesions, emerges as a promising non-invasive alternative to surgical biopsy. This method, easy to perform, allows for providing different information at the cellular and molecular levels, offering a useful tool to evaluate neuroinflammatory changes and identify neuropathic biomarkers.

4.5 | Prospective

4.5.1 | Call for an Animal Model

This review summarises the knowledge relative to tissue
changes focusing particularly on the innervation. However,
the information is scarce and focused on a few biomarkers
when many other candidates could also be informative. This
emphasises the need for an animal model of BMS. As pointed
out in a recent review, there have been few attempts to develop
an animal model of BMS [31] which consists mainly of dry
tongue models, overexpression of artemin, and CT transsection.
Dry-tongue models based on hyposalivation cannot be taken
as models since BMS patients report generally normal values;
genetically engineered overexpression of artemin, as a putative
agent of sensitisation [94] after Shinoda's observations [30] is
rather a model of chemical neuropathy than BMS. Boucher et al.
[95, 96] tested the hypothesis of CT transsection disinhibiting
trigeminal pathways after Bartoshuk's hypothesis [97], but not
all BMS patients display taste alterations [88]. Interestingly, in
their study, the ovariectomised group displayed increased oral
sensitivity to capsaicin, in line with previous observations [98]
and reflecting human conditions, that is, increased aversion to
spicy food [99] and capsaicin [46, 68]. In line with these obser-
vations, Kobayashi et al. [100] reported recently an increased
sensitivity to capsaicin in ovariectomised rats associated with a
decrease of IENFD in the tongue, mimicking some of the pheno-
typic characteristics of BMS; however, with a short-term obser-
vation period (14 days). Further studies are needed to propose a
valid animal model of BMS integrating the key features of BMS,
that is, hormonal deprivation and anxio-depressive conditions
possibly related to stress [100]. Such a model should reflect yet
known biomarkers of BMS, as pointed out in this review, and
allow the exploration of others such as TRPA1 and ASICs re-
ceptors, but many others such as specific neuron enolase, AchR,
and other TRP receptors, etc. expressed in sensory neurons in-
nervating the tongue and epithelial cells [101, 102].

**4.5.2 | Standardisation of Procedures**

Lauria et al. proposed for skin biopsies a standardisation of the procedures [65], however, this was not followed by further authors, and many elements differ from study to study: (1) the surgical piece: the punch biopsy [3mm-6mm] diameter was the most used technique for the tongue. But other formats have been used. (2) Thickness of sections: the guidelines for skin biopsies are 50µm but many authors use different thickness, range [7-50µm]. (3) the histological technique and biomarkers: some use immunohistochemistry, others immunofluorescence. Some authors used, for example, the neuronal markers PGP9.5 [28, 37, 38] or B tubulin [41] or others, single or mixed [46] (4) the area of observation in the tongue, especially the inclusion of fungiform papillae in the biopsy. This review suggests differentiating counting in FunP and FilP areas since they are both important and may reveal differences. (5) Other areas than the tongue might also be important. For example, the retroincisal palate is also frequently reported but contains no FunP nor FilP. (6) Types of nerve fibres altered in BMS, using specific biomarkers and new classification [63], as pointed out in the discussion with specific biomarkers.

**4.5.3 | Improving Evidence From Studies**

The high variability across studies included in this review
limited the feasibility of statistical pooling, and therefore the
I² statistic was not calculated. Several clinical and method-
ological factors likely contributed to inter-study discrepancies.
Clinically, heterogeneity arose from differences in diagnostic
criteria for BMS (e.g., ICHD-3, ICOP, IASP or author-defined),
wide variation in symptom duration (ranging from 6 months
to over 20 years), demographic differences such as age and sex
distribution, and subgroup classifications (e.g., 'tip only' vs.
'extended' BMS). Methodological variability included differ-
ences in tissue sampling (punch vs. incisional biopsies, buccal
vs. lingual mucosa, inclusion or exclusion of fungiform papil-
lae), histological techniques employed (haematoxylin-eosin,
immunohistochemistry, immunofluorescence, qPCR), and the
range of biomarkers assessed (e.g., PGP9.5, β-tubulin, TRPV1,
NGF, CB1/CB2, Nav1.7-1.9). Additional variation in section
thickness, staining protocols and quantification methods (per
mm of epithelial length, per papilla or per epithelial area) fur-
ther complicates direct comparison. These factors should be
considered when interpreting the findings, as they may partly
explain the conflicting results observed between studies.

Most of the studies included in this review were biopsy-based
case-control studies with small sample sizes—typically 9 to 12
participants per group—except for Treldal (N=21) and Penza
et al., who included 56 patients in the BMS group. However,
their control group was derived from a previous study with

a small sample size (N=9). Given the variability in results
highlighted in this review, larger-scale studies are clearly war-
ranted. Such studies would not only bolster evidence-based
knowledge of the disease but also facilitate better control
over symptom homogeneity. Indeed, many studies indicate
that BMS exhibits clinical heterogeneity and may encompass
distinct conditions [4, 10]. Although progress has been made
through the use of more stringent inclusion criteria [103–105]
access to well-characterised cohorts—including quantitative
sensory testing (QST), biopsies and comprehensive clinical
data—would improve control over key parameters such as age,
symptom location and duration. For example, the duration of
symptoms at the time of biopsy was not always documented,
and ranged widely—from 6 months to 27 years. Since many
neurological changes associated with BMS, such as decreased
nerve fibre density and phenotypic alterations in nociceptors,
evolve slowly, this variability could introduce significant bias.
A recent study, for instance, suggests that acute stress can
trigger BMS within a timeframe where more profound neu-
rological changes may not have had sufficient time to develop
[49]. Therefore, performing biopsies on patients who exhibit
BMS clinical features but before the 3-month period specified
in the diagnostic criteria could be insightful. Notably, none
of the patients included in this review had symptoms lasting
less than 6 months. Additionally, conducting biopsies at dif-
ferent time points could reveal histological changes and their
relationship to pain symptoms, particularly in patients who
experience remission.

Improved matching of controls to BMS patients would also en-
hance our understanding of disease pathogenesis. Although
most studies match participants by sex, this is often not done
for age. In the reviewed biopsy studies, BMS patients were on
average more than 12years older than controls, with only two
studies matching for age [41, 42]. This age difference is espe-
cially relevant around menopause, as gonadal hormone levels
are known to influence peripheral nerve density [106].

*Promising role for exfoliative surgery?* Exfoliative studies provide no information related to nerve changes unless they translate as neuroinflammatory changes in tissues that can be evidenced. An interesting biomarker could be NGF and its receptors TrkA and P75NTR, which are expressed both in neuronal cells and epithelial cells and are implicated both in cellular trophism and neuronal function.

**5 | Conclusion**

This reviewed aimed at helping to synthetize the evidence
regarding histological changes in peripheral tissues in BMS,
in order to have a better understanding of the disease and
propose future directions for research. Although the exact
pathophysiology of primary BMS is still under investigation,
there is numerous clinical, histological, neurophysiological,
neurochemical and connectomic evidence suggesting neuro-
pathic and possibly nociplastic mechanisms at play. The clas-
sical clinical presentation of BMS (burning, subjective dryness
sensation and dysgueusia) is coherent with a neuropathic
condition, notably a small fibre neuropathy [107], further sup-
ported by positive scores in several neuropathic pain detection
questionnaires [108–112]. Histological alterations, as reviewed in the present paper, show—among other things—changes in nerve fibre density [41] and receptor expression [46] in BMS patients, in association with neurophysiological changes evidenced using QST [113, 114] or the blink reflex [115]. The arguments towards a neuropathic component in BMS have been reviewed [15, 92, 115, 116]. Recently, some authors have raised the question of the possible nociplastic nature of burning mouth syndrome [117] after the recent conceptualization and definition of nociplastic pain, that can be briefly summarised as ‘pain that arises from altered nociception despite no clear evidence of nociceptive or neuropathic pain mechanisms’ [118]. Although the question is quite complex, especially considering the still recent definition of nociplastic pain, there are arguments suggesting dysfunctional nociception that does not imply nociceptor activation or somatosensory nervous system lesion or disease. For example, dysfunctional central processing of pain in BMS patients has been evidenced using TEP scan imaging of nigrostriatal dopaminergic pathways [119], further supported by genetic studies of D2 dopamine receptor polymorphisms that predispose to developing burning mouth syndrome [115]. Functional MRI studies have also suggested altered cortical activation patterns during pain processing in BMS patients (as compared to healthy controls) [11, 120, 121]. The connectomic data related to BMS has recently been reviewed [122]. Nevertheless, from a clinical standpoint, it seems that other nociplastic pain conditions such as fibromyalgia, surprisingly, do not predispose to developing burning mouth syndrome [123]. Considering the diversity in the clinical presentations of BMS [124] it is most probable that neuropathic and/or nociplastic pain mechanisms are at play, the nature and extent of which may vary from case to case, as with other nociplastic conditions [118].

## 6 | Bullet Points

- Biopsies provided interesting information related to the etiopathogenesis of BMS and raise numerous questions.

- They evidenced neuronal alterations in terms of density and expression of biomarkers.

- The main findings indicate a decrease of nerve fibre density in tongue epithelium and quantitative alteration of several biomarkers such as TRPV1 in nerve and epithelial cells.

- The observed changes have yet no diagnostic value since no cut-off in the observation can be inferred from these analyses.

- The idea of observing changes in subgroups does not seem well suited for diagnosis but remains interesting for tailoring treatments.

- The techniques used in the studies do not address the question of the origin of the nerves.

* Chorda tympani versus Trigeminal nerve and SNA

* The types of sensory nerve fibres: non-nociceptive (C-LTMR, A-β) versus nociceptive

* The subtypes of nociceptors (C PEP1-3, A-δ, CH etc.)

- There is a need for standardisation of techniques

- There is a need for randomised controlled trials and large-scale cohorts.

- There is a need for an animal model to validate these changes and explore other markers with diagnostic value.

## Author Contributions

André Luís Porporatti worked on study conceptualisation, design, data collection, data analysis, drafted the initial manuscript and approved the final manuscript as submitted. He was the first reviewer. Ângela Graciela Deliga Schroder worked on study conceptualisation, design, data collection, data analysis and approved the final manuscript as submitted. She was the second reviewer. Ashley Lebel worked on study conceptualisation, design, data collection, data analysis and approved the final manuscript as submitted. Nathan Moreau worked on study conceptualisation, design, data collection, data analysis and approved the final manuscript as submitted. Annabelle Réaux-Le Goazigo critically reviewed the manuscript and approved the final manuscript as submitted. Ihsène Taïhi critically reviewed the manuscript and approved the final manuscript as submitted. Heike Rittner critically reviewed the manuscript and approved the final manuscript as submitted. Tara Renton critically reviewed the manuscript and approved the final manuscript as submitted. Yves Boucher worked on study conceptualisation, design, data analysis, drafted the initial manuscript and approved the final manuscript as submitted.

## Ethics Statement

The authors have nothing to report.

## Consent

The authors have nothing to report.

## Conflicts of Interest

The authors declare no conflicts of interest.

## Data Availability Statement

All the data, material and methods which support the results can be found in the article or appendices.

## Peer Review

The peer review history for this article is available at https://www.webofscience.com/api/gateway/wos/peer-review/10.1111/joor.70051.

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## Supporting Information

Additional supporting information can be found online in the Supporting Information section. **Table S1:** Database search strategy (October 21st 2024). **Table S2:** Articles excluded and the reasons for exclusion (n=32). **Table S3:** JBI Critical Appraisal Tools to assessed risk of bias in case-control studies (n=14). **Table S4:** Grading of Recommendations Assessment, Development and Evaluation (GRADE) Summary of Findings (SoF) tables, using GRADEpro software.