Abstract
Background and Purpose
Described in 2013, intraneural pseudoperineuriomatous proliferations (IPP) present perineurial cells concentrically surrounding the axon-Schwann cell complexes, forming pseudo-onion bulbs. Different from intraneural perineuriomas, rare neoplasms with differentiation of perineural cells, IPP are reactive, associated with fibrosis, and frequently diagnosed histologically as traumatic neuroma (TN). The aim of this study was to characterize IPP by exploring its clinicopathological features and differentiating it from the main neural lesions that are part of the histopathological differential diagnosis through a retrospective study in six Brazilian Oral Pathology laboratories.
Methods
Cases diagnosed as IPP, TN and intraneural perineuriomas were selected from the archives of the participating centers. Data on age, sex, race, symptoms, site, size, and clinical features and diagnosis were obtained from histopathological reports. Hematoxylin and eosin-stained slides were then re-evaluated by two examiners. Finally, statistical tests were performed to assess the association between clinical, pathological and demographic characteristics (p < 0.05).
Results
After reclassification, 152 TN, 48 IPP and no case of intraneural perineurioma were diagnosed. Clinically, IPP and TN are similar, but IPP affects younger individuals, presents less reported pain, and is more commonly found on the tongue, while TN is frequently observed on the lip, alveolar ridge, and mental foramen. Both lesions typically present as fibrous nodules, often clinically misdiagnosed as fibrous hyperplasia. IPP is fibrous in all cases, more superficial in the mucosa, less frequently associated with adipose tissue and inflammation. These features may assist clinical dentists and pathologists in differentiating lesions.
Conclusion
Although histologically similar, pathologists should note the perineural cell proliferation in IPP to avoid confusion with TN (a common reactive lesion) or intraneural perineurioma (a rare neoplastic lesion).
Supplementary Information
The online version contains supplementary material available at 10.1007/s12105-025-01771-5.
Keywords: Traumatic neuroma, Perineurioma, Pseudoperineurioma, Nerve sheath neoplasms, GLUT-1 protein
Introduction
Perineuriomas are rare tumors of the peripheral nerve sheath with perineurial cell differentiation. There are two types of perineuriomas based on their location: intraneural and extraneural. Intraneural perineuriomas usually arise within a larger peripheral nerve trunk, and histologically, are characterized by a complex concentric proliferation of perineurial cells, extending into the endoneurium and surrounding the axon-Schwann cell complexes of peripheral nerve fascicles, leading to the characteristic "pseudo-onion bulbs" [1, 2]. This term differentiates these structures from "true onion bulbs," where Schwann cells wrap around the axons, a feature seen in hereditary polyneuropathies such as Charcot-Marie-Tooth and Dejerine-Sottas [3]. Although intraneural perineuriomas were initially thought to be reactive lesions, their neoplastic nature is now supported by common TRAF7 point mutations and rare NF2 mutations [4]. This lesion rarely occurs in the oral cavity, and to the best of our knowledge, only oral 22 intraneural perineuriomas had been reported in the English-language literature [5–7].
In 2013, Koutlas and Scheithauer introduced the concept of intraneural pseudoperineuriomatous proliferation (IPP) [8], or pseudoperineurioma [9], describing it as a more common and reactive lesion, similar to intraneural perineurioma. The authors reviewed the histological slides of 500 oral peripheral nerve sheath lesions, including granular cell tumors, and identified 38 cases with "pseudo-onion bulb" formation. The lesions were reclassified as one case of true intraneural perineurioma and 37 cases of IPP. Since 2013, subsequent articles on IPP have been limited to a single case report [10] and cases of multiple pseudoperineuriomatous lesions associated with hemifacial hyperplasia, which have been linked to the PIK3CA-related overgrowth spectrum (PROS) [11, 12]. This association highlights the importance of correctly diagnosing these clinically innocuous-appearing growths when they occur in a multifocal pattern.
In addition to the "pseudo-onion bulb" structures, IPP show varying degrees of associated connective tissue proliferation (similar to fibrous hyperplasia/fibroma). Another key feature of IPP is their association with smaller nerves, typically showing discontinuity of the perineurium around the lesion's fascicles, with a single or double layer of perineurial cells forming the pseudo-onion bulbs. These characteristics are important for differentiating IPP from true intraneural perineuriomas. Immunohistochemically, the concentric perineurial cells forming the pseudo-onion bulb structures are positive for epithelial membrane antigen (EMA), GLUT-1, or Claudin-1 (perineurial markers) and negative for S-100 protein [8].
In the original sample from the seminal study [8], traumatic neuroma (TN) was the most assigned histological diagnosis for the newly described entity (23 cases). TN, one of the most common oral neural lesions [13, 14], is not a true neoplasm but a reactive proliferation of neural tissue following an injury to the nerve bundle. After nerve damage, the proximal portion tends to re-establish innervation to the distal segment through the growth of axons, guided by proliferating Schwann cells. When these elements encounter scar tissue or another obstacle, a lesion may develop at the site of nerve injury [15, 16].
The aim of this study was to characterize IPP, a little-known diagnosis, by exploring its clinicopathological features and differentiating it from the main neural lesions that are part of the histopathological differential diagnosis: TN and intraneural perineurioma.
Material and Methods
This study was approved by the Institutional Human Research Ethics Committee (CAAE: 48569921.4.0000.0077). It is a retrospective study based on data from reports and histopathological slides from six Oral and Maxillofacial Diagnostic Centers in Brazil: Institute of Science and Technology of São José dos Campos-UNESP (ICT-UNESP), Bauru School of Dentistry-USP (FOB-USP), São Leopoldo Mandic (SLM), Federal University of Minas Gerais School of Dentistry (UFMG), Araçatuba School of Dentistry-UNESP (FOA-UNESP), and Federal University of Rio de Janeiro School of Dentistry (UFRJ).
Cases diagnosed as intraneural perineurioma, TN (or amputation neuroma), IPP (or pseudoperineurioma) were selected from the archives of the participating centers. Information on age, sex, race, disease duration, habits, history of trauma or previous surgery, symptoms, location, primary lesion, color, consistency, lesion surface, size, clinical hypotheses, and biopsy type was extracted from the histopathological examination reports.
Hematoxylin and eosin-stained slides, as well as immunohistochemical reactions used for the initial diagnosis, were evaluated under light microscopy by two examiners. The following diagnostic criteria were used:
Intraneural Perineurioma [1, 8]: Lesions where the nerve fascicles present with more than one layer of elongated perineurial cells arranged concentrically around the axon-Schwann cell unit, with the perineurium of the affected nerve remaining intact. Although the extracellular matrix may be collagenized, nervous tissue predominates in the lesion. The concentric perineurial cells are positive for perineurial markers (EMA, Claudin-1, GLUT-1), while the central cells are negative for these markers but positive for S-100.
- TN [9] (Fig. 1): Non-encapsulated, random proliferation of mature, myelinated and non-myelinated nerve bundles within a collagenous or loose stroma, with or without an associated inflammatory infiltrate. The TN slides, based on our own observations, were subclassified into:
- Type A, characterized by nerve fascicles of varying sizes, limited by perineurium, cut in several directions, containing axons and Schwann cells, in the connective tissue.
- Type B, characterized by interwoven, disorganized, tangled and diffuse nerve fascicles and/or microfascicles embedded in connective tissue.
- Lesions containing both patterns were classified as Type AB.
IPP [8] (Fig. 2, 3): Lesion characterized by a single or rarely double layer of perineurial cells surrounding the axon-Schwann cell units, forming pseudo-onion bulbs, with varying degrees of associated connective proliferation, lacking a capsule and with discontinuity of the perineurium of the involved nerves. A collagenous component is consistently present. The concentric perineurial cells are positive for perineurial markers (EMA, Claudin-1, GLUT-1), while the central cells are negative for these markers but positive for S-100. Immunohistochemistry is a desirable aid in the diagnosis of IPP. IPP cases were classified as a serpiginous and non-serpiginous pattern.
Fig. 1.
Traumatic Neuroma (TN). a Type A TN, characterized by large nerve fascicles limited by hyperplastic perineurium, cut in several directions. Bar = 500 μm. b Type A TN, characterized by smaller nerve fascicles limited by perineurium, cut in several directions in the connective tissue. Bar = 200 μm. c. Type A TN, characterized by large nerve fascicles limited by perineurium, which proliferate from an original fascicle, visible on the right. Adipose tissue is seen in association with the neural elements. Bar = 500 μm. d Type B TN characterized by interwoven, tangled nerve microfascicles embedded in connective tissue situated among salivary gland lobules and in proximity to striated muscle fibers. Bar = 100 μm. e Type B TN characterized diffuse nerve microfascicles embedded in connective tissue. Bar = 50 μm (A–E: Hematoxilin and Eosin staining). f Type B TN characterized by diffuse nerve microfascicles embedded in connective tissue, showing positive immunohistochemical staining for S100 protein. Bar = 100 μm
Fig. 2.
Intraneural pseudoperineuriomatous proliferation (IPP). a, b Lesions characterized by the proliferation of neural tissue, with serpiginous and plexiform areas visible throughout the connective tissue. Bar = 500 μm in a, Bar = 100 μm in b. c–e Pseudo-onion bulb proliferation, characterized by concentric layers of perineurial cells surrounding the axon-Schwann cell unit, sectioned in different directions. Bar = 100 μm in c, Bar = 50 μm in d, e. f Pseudo-onion bulbs among muscle fibers. Bar = 50 μm (Hematoxilin and Eosin staining)
Fig. 3.
Intraneural pseudoperineuriomatous proliferation (IPP) immunohistochemistry. a, b GLUT-1 positive perineurial cells can be seen surrounding the axon-Schwann cell unit, forming pseudo-onion bulb pattern. Bar = 50 μm in a, Bar = 200 μm in b. c The onset of IPP is visible. On the right, a normal nerve fascicle is surrounded by perineurium, while on the left, pseudo-onion bulb proliferation of GLUT-1 positive perineurial cells is seen around the axon-Schwann cell unit. Bar = 50 μm. d Only the axon-Schwann cell units are positive to S100. Bar = 50 μm
The following histological variables were also evaluated in all cases: fibrosis, inflammation near the nerve, vascular proliferation, adipose tissue, intramuscular or intraglandular lesion and presence of lining epithelium.
New 4μm-thick histological sections of all IPP with enough material in the paraffin blocks were prepared on silanized slides for immunohistochemical reaction with GLUT-1 (Santa Cruz Biotechnology, clone A-4, SC-377228, dilution 1:100, citrate pH 6.0 antigen retrieval). After these reactions, the slides were scanned (Pannoramic Desk scanner, 3D HISTECH). The freehand drawing tool in the image analysis software (Pannoramic Viewer v.1.15.4, 3D HISTECH) was employed to delineate the area where perineurial wrapping, marked positively for GLUT-1, formed pseudo-onion bulbs. The section selected for histometric analysis was the one containing the largest IPP.
Statistical Analysis
Epidemiological, clinical and histopathological data were statistically analyzed (Sphinx software, SphinxBrazil). Continuous variables were expressed as mean and standard deviation, while categorical variables were presented as absolute numbers and percentages. The chi-square test and Fisher's exact test were used to evaluate the association between clinical, pathological and demographic characteristics (p < 0.05). Continuous variables were compared using ANOVA, T-test, Kruskal–Wallis, or Mann–Whitney tests, depending on the normality of the sample.
Results
A total of 230 cases were initially diagnosed as TN (n = 223; 96.96%) or IPP (n = 7; 3.04%) by the participating institutions. No case of intraneural perineurioma was diagnosed. After reclassification (Table 1), the findings were as follows: 152 (66.1%) cases of TN, 48 (20.9%) IPP, 8 (3.5%) subgemmal neurogenic plaques, 6 (2.6%) oral neurovascular hamartomas, 8 (3.5%) solitary circumscribed neuromas, 4 (1.7%) neurofibromas, and 4 various lesions (1 incisive papilla, 1 inflammatory fibrous hyperplasia, 1 sialolipoma, 1 irritation fibroma, collectively accounting for 1.7% of the total). TN accounted for 0.115% of all lesions diagnosed in the services (132,640) during the evaluated period, while IPP accounted for 0.036%.
Table 1.
TN and IPP clinical features
| TN | IPP | Statistical test | |
|---|---|---|---|
| Total | 152 | 48 | |
| Institution | |||
| UFMG | 26 (17.1%) | 8 (16.7%) |
χ2(5, n = 200) = 8.08 p = .15 |
| SLM | 33 (21.7%) | 17 (35.4%) | |
| UFRJ | 13 (8.6%) | 4 (8.3%) | |
| FOA UNESP | 24 (15.8%) | 4 (8.3%) | |
| FOB USP | 31 (20.4%) | 4 (8.3%) | |
| ICT UNESP | 25 (16.4%) | 11 (22.9%) | |
| Sex | |||
| Female | 107 (70.4%) | 29 (60.4%) |
χ2(1, n = 199) = 1.84 p = .18 |
| Male | 44 (28.9%) | 19 (39.6%) | |
| NI | 1 (0.7%) | 0 (0%) | |
| Race | |||
| White | 100 (65.8%) | 32 (66.7%) |
χ2(1, n = 188) = 0.01 p = .91 |
| Non-White | 42 (27.6%) | 14 (27.6%) | |
| NI | 10 (6.6%) | 2 (4.2%) | |
| Age | |||
| Less than 20 years-old | 18 (11.8%) | 12 (25%)* |
χ2(3, n = 187) = 9.8452 p = .019 |
| 20–40 | 31 (20.4%) | 13 (27.1%) | |
| 41–60 | 53 (34.9%) | 17 (35.4%) | |
| Over 60 | 39 (25.7%) | 4 (8.3%)# | |
| NI | 11 (7.2%) | 2 (4.2%) | |
| Mean ± standard deviation | 45.84 ± 19.25 (n = 141) | 35.50 ± 18.77 (n = 46) | t(185) = 3.184, p = .0017 |
| Disease duration | |||
| Up to 1 year | 27 (17.8%) | 7 (14.6%) |
χ2(1, n = 76) = 1.04 p = .31 |
| More than 1 year | 29 (19.1%) | 13 (27.1%) | |
| NI | 96 (63.2%) | 28 (58.3%) | |
| Habits | |||
| Smoking | 1 (0.7%) | 1 (2.1%) |
Fisher's Exact Test p = 1, n = 6 |
| Alcohol | 1(0.7%) | 3 (6.3%) | |
| Others | 2 (1.3%) | 0 (0%) | |
| NI | 148(97.4%) | 45 (93.8%) | |
| Reported trauma | |||
| Yes | 20 (13.2%) | 8 (16.7%) |
χ2(2, n = 200) = 0.37 p = .54 |
| No | 132 (86.8%) | 40 (83.3%) | |
| Previous surgery | |||
| Yes | 14 (9.2%) | 1 (2.1%) |
Fisher's Exact Test p = .1249, n = 200 |
| No | 138 (90.8%) | 47 (90.8%) | |
| Pain | |||
| Yes | 31 (20.39%) | 1 (2.08%)# |
χ2(1, n = 113) = 9.96 p = .02 |
| No | 56 (36.84%) | 25 (52.08%)* | |
| NI | 65 (42.76%) | 22 (45.83%) | |
| Site | |||
| Tongue | 33 (21.71%)# | 37 (77.08%)* |
χ2(4, n = 190) = 57.44 p = .0001 |
| Lip | 44 (28.94%) | 4 (8.33%) | |
| Lower alveolar ridge/mental foramen | 40 (26.32%) | 0 (0%) | |
| Buccal Mucosa | 9 (5.92%) | 5 (10.41%) | |
| Other | 18 (11.84%) | 0 (0%) | |
| NI | 8 (5.26%) | 2 (4.16%) | |
| Primary lesion | |||
| Nodule/papule | 76 (50%) | 22 (45.83%) |
Fisher's Exact Test p = 1, n = 106 |
| Other | 7 (4.60%) | 1 (2.08%) | |
| NI | 69 (45.39%) | 25 (52.08%) | |
| Lesion color | |||
| Similar to normal mucosa | 52 (34.21%) | 22 (45.83%) |
χ2(1, n = 107) = 1.58 p = .209 |
| Different from normal mucosa | 27 (17.76%) | 6 (12.5%) | |
| NI | 73 (48.02%) | 20 (41.66%) | |
| Consistency | |||
| Soft/elastic | 19 (12.5%) | 4 (8.3%) |
χ2(2, n = 97) = 0.48 p = .79 |
| Firm/fibrous | 57 (37.5%) | 16 (33.33%) | |
| Other | 1 (0.07%) | 0 (0%) | |
| NI | 75 (49.34%) | 28 (58.33%) | |
| Surface | |||
| Smooth | 23 (15.13%) | 13 (27.08%) * |
χ2(1, n = 71) = 4.47 p = .03 |
| Non-smooth | 30 (19.73%) | 5 (10.41%)# | |
| NI | 99 (65.13%) | 30 (62.5%) | |
| Clinical size | |||
| Mean ± standard deviation (mm) | 8.55 ± 9.14 (n = 84) | 8.67 ± 7.23 (n = 23) | Mann Whitney U = 947, p = .8863 |
| Gross size | |||
| Mean ± standard deviation (mm) | 10.14 ± 6.63 (n = 71) | 7.78 ± 4.99 (n = 18) |
Mann Whitney U = 488, p = .1230 |
| Clinical diagnosis | |||
| Fibrous hyperplasia/fibroma | 68 (44.16% of 154 diagnostic hypothesis) | 37 (62.71% of 59 diagnostic hypothesis) |
χ2(4, n = 213) = 27.77 p < .0001 (more than one hypothesis/case is possible, n = total number of hypothesis) |
| Mucocele | 15 (9.74%) | 2 (3.4%) | |
| Squamous papilloma | 6 (3.9%) | 10 (16.95%)* | |
| TN | 33 (21.43%)* | 0 (0%)# | |
| Other | 32 (20.77%) | 10 (16.95%) | |
| NI | 17 (11.18% of 152 cases) | 0 (0%) | |
| Biopsy | |||
| Excisional | 77 (50.7%) | 23 (47.9%) |
Fisher's Exact Test p = .067, n = 113 |
| Incisional | 13 (8.6%) | 0 (0%) | |
| NI | 62 (40.8%) | 25 (52.1%) | |
| Original histological diagnosis | |||
| TN | 152 (100%) | 41 (85.42%) |
Fisher's Exact Test p < .0001, n = 200 |
| IPP | 0 (0%) | 7* (14.6%) |
Bold values indicate statistical significance (p < 0.05)
*Indicates that the actual frequency is significantly higher than the expected frequency
#Indicates that the actual frequency is significantly lower than the expected frequency
NI not informed
Clinical Features
Both TN and IPP were more common in females and white individuals. The mean age of diagnosis of IPP was 10 years less than TN. In addition, IPP was more common in individuals under 20 years old and less prevalent in individuals over 60 compared to TN (Table 1).
The most frequently reported disease duration was over one year, though this information was missing in many requests. Only 8 (4%) reports included information on habits, with no significant differences between the lesions. In most cases, there was no reported history of trauma or previous surgery. The percentage of patients experiencing pain was ten times higher in cases of TN than IPP.
The tongue was the most common location for IPP, with no cases found in the mental foramen. TN occurred more frequently in the lip, tongue, and lower alveolar ridge/ mental foramen. Both lesions typically presented as nodules with color similar to the normal mucosa and a firm and/or fibrous consistency on palpation. While the surface of TN was similarly likely to be smooth or irregular, IPP typically had a smooth surface (Table 1). Inflammatory fibrous hyperplasia and fibroma were the most common diagnostic hypotheses for both lesions. However, the clinical diagnosis of TN was more common in cases with a final diagnosis of TN (21.43%) compared to those with IPP (0%). Papilloma was more frequently cited as a clinical diagnosis in lesions with a final diagnosis of IPP than TN.
Excisional biopsy was the decision made in most cases. Only 14.6% of IPP cases were initially diagnosed as IPP, with all other cases initially diagnosed as TN.
Histological Features
Among the 48 IPP, 28 (58.3%) presented serpiginous pattern. In addition to the characteristic areas of IPP, 85.41% of IPP presented nerve bundles cut in various directions, especially at the base of the lesions. 25.7% of TN were present in association with one or more other lesions/characteristics as hyperkeratosis (8.6%), fibrous hyperplasia/fibroma (6.6%), mucocele (3.9%), and others (7.2%). Type A corresponded to 27% of all TN, Type B to 37.5%, and Type AB to 35.5%.
A significantly higher percentage of IPP lacked associated fatty tissue and inflammation near the affected nerve. All IPP had epithelial lining, often more atrophic than in TN, and fibrosis, which was absent in more than a quarter of TN cases. There was no statistically significant difference between the lesions regarding vascular proliferation, intramuscular or intraglandular location (Table 2).
Table 2.
Histopathological features of TN and IPP
| TN | IPP | Statistical test | |
|---|---|---|---|
| Total | 152 | 48 | |
| Fibrosis | |||
| Yes | 110 (72.4%) | 48 (100%) |
Fisher's Exact Test p < .0001, n = 200 |
| No | 42 (27.6%) | 0 (0%)# | |
| Inflammation near neural tissue | |||
| Yes | 66 (43.4%) | 11 (22.9%)# |
Fisher's Exact Test p = .0111, n = 200 |
| No | 86 (56.6%) | 37 (77.1%)* | |
| Vascular proliferation | |||
| Yes | 98 (64.5%) | 24 (50%) |
Fisher's Exact Test p = .0898, n = 200 |
| No | 54 (35.5%) | 24 (50%) | |
| Adipose tissue | |||
| Yes | 62 (40.8%) | 7 (14.6%)# |
Fisher's Exact Test p = .0008, n = 200 |
| No | 90 (59.2%) | 41 (85.4%)* | |
| Intramuscular lesion | |||
| Yes | 52 (34.2%) | 21 (43.8%) |
Fisher's Exact Test p = .2348, n = 200 |
| No | 100 (65.8%) | 27 (56.2%) | |
| Intraglandular lesion | |||
| Yes | 6 (3.9%) | 0 (0%) |
Fisher's Exact Test p = .3389, n = 200 |
| No | 146 (96.1%) | 48 (100%) | |
| Epithelium | |||
| Hyperplastic | 64 (42.1%) | 23 (47.9%) |
χ2(4, n = 200) = 32.34 p = .0001 |
| Atrophic | 9 (5.9%) | 14 (29.2%)* | |
| Normal | 18 (11.8%) | 6 (12.5%) | |
| Hyperplastic and atrophic in different areas | 14 (9.2%) | 5 (10.4%) | |
| Absence | 47 (30.9%) | 0 (0%)# |
Bold values indicate statistical significance (p < 0.05)
*Indicates that the actual frequency is significantly higher than the expected frequency
#Indicates that the actual frequency is significantly lower than the expected frequency
TN Subtypes
To evaluate if TN histological subtype would be associated with clinical and histological features, we compared the subtypes regarding the same variables used previously (Supplementary Tables 1 and 2). There was no difference among subtypes regarding sex, race, age, reported trauma or previous surgery, primary lesion, surface, gross size, color or disease duration (Supplementary Table 1).
Painful symptoms varied between TN types: 39.02% of Type A patients presented with pain, compared to only 5.26% of those with Type B. The tongue was the most common location in Type B (38.6%) and less frequent in Type A (4.88%), whereas Type A was predominantly found in the lower ridge/mental foramen (56.10%). Inflammatory fibrous hyperplasia and fibroma were the most common diagnostic hypotheses for Types B and AB (61.67% and 44.44%, respectively), with TN being most common in Type A (45%). Excisional biopsy was performed in most cases, and of the 13 incisional biopsies, 61.5% involved Type A (Supplementary Table 1).
Type A presented more adipose tissue (75.61%) and absence of epithelium (63.41%). Conversely, Type B exhibited more vascular proliferation (77.19%). Type AB was more commonly found in intramuscular regions (48.15%), and out of the 6 intraglandular cases, 5 were of Type AB (83.3%) (Supplementary Table 2). Although TN Type A presented more painful symptoms, there was no significant dependance between pain and inflammation among all TN [χ2(2, n = 152) = 1.32, p = 0.5168] or only Type A [χ2 (2, n = 41) = 2, p = 0.3687].
Histometric Analysis—IPP
Twenty-one IPP cases could not be used for GLUT-1 immunohistochemistry due to the absence of paraffin blocks or insufficient material. The mean total area of the 27 lesions analyzed was 11.00 ± 8.66 mm2 (range: 1.43–32.86 mm2), with a mean IPP area of 0.55 ± 0.45 mm2 (range: 0.05–1.89 mm2) and a mean connective tissue area of 10.44 ± 8.46 mm2 (range: 0.98–31.41 mm2). On average, IPP comprised 8.26 ± 9.40% (range: 0.75–36.74%) of the total lesion area, with the remainder corresponding to connective tissue.
Discussion
Oral neural tumors are rare, accounting for less than 1% of the lesions sent to oral and maxillofacial pathology laboratories [17] and can pose a challenge in histological diagnosis. Among benign neural lesions in the oral cavity, the most common are neurofibromas, TN, and schwannomas [13, 14]. The frequency of TN varies in the literature, with values ranging from 0.07 to 0.34% [13, 14, 17–19]. In our sample, we observed a frequency of 0.1%, and even when considering TN and IPP cases together, we remain within the reported range.
Almost one third (31.83%) of lesions initially diagnosed as TN were reclassified. Among the reclassified lesions, the most common diagnosis was IPP, which was an expected result, consistent with previous study [8]. However, we identified 8 subgemmal neurogenic plaques, 6 oral neurovascular hamartomas, and 8 solitary circumscribed neuromas. Subgemmal neurogenic plaque and neurovascular hamartoma were more recently described [20, 21], which may explain their relative lack of recognition.
Clinically, IPP and TN are very similar, with the main differences involving younger individuals being affected, a lower prevalence of pain, and a more common location on the tongue in the first. In contrast, TN is more frequently found on the lip and lower alveolar ridge/mental foramen. The causes of oral TN include traumatic events, such as tooth extractions, other surgeries and poorly fitting dentures [16, 18]. In most cases in our sample, however, there was no reported history of trauma or prior surgery, indicating that trauma may go unnoticed by the patient or unreported by the clinical dentist. A major limitation of this study is that clinical data, including patient history, symptoms, and risk factors, were only available from histology reports and were incomplete in most cases.
The most common clinical hypothesis for both TN and IPP (fibrous hyperplasia/fibroma) does not match the final diagnosis but highlights the common fibrotic appearance observed in the histopathology of both lesions. The second most common diagnostic hypothesis in TN cases was TN itself, which may be associated with symptomatology and the submucosal location in the mental foramen, commonly found in TN type A and uncommon features in lesions such as fibrous hyperplasia/fibroma. We subdivided TN into three groups based on histological characteristics, with subtypes A and B being clearly distinct. Clinically, these two subtypes also showed some differences. Subtype A had a higher frequency of pain, was more commonly located on the alveolar ridge and mental foramen, and TN was the primary clinical hypothesis. In contrast, subtype B was more frequently diagnosed as a fibrous lesion. Other histological characteristics accompanied subtype A, such as less fibrosis and more adipose tissue, which typically surrounds thicker nerve bundles.
When a nerve is transected, the distal axons undergo Wallerian degeneration, while the axons and Schwann cells in the proximal stump begin to proliferate. If a barrier forms between the proximal and distal stumps or if the distal stump is lost, the nerve continues to proliferate from the proximal end, resulting in a disorganized mass of neural fibers and connective tissue that extends into the surrounding soft tissues [22]. To further explain the development of the lesion, there is the hypothesis that the contraction of wound and scar myofibroblasts would then compress the regenerating nerve fibers, thereby stimulating the overgrowth of perineurial cells as a protective response. This ongoing process would result in the gradual enlargement of the proliferating mass, leading to the characteristic histological appearance of a TN, where numerous interwoven nerve fascicles are surrounded by dense fibrous tissue [22].
TN can be classified as Neuromas-in-Continuity (NIC), where the proximal and distal ends of the damaged nerve are connected, and Nerve-End Neuromas (NEN), where the nerve ends are completely separated, resulting in swelling of the proximal stump [15]. In our sample, NIC features were clear in some TN cases involving larger nerves, such as the inferior alveolar nerve near the mental foramen. However, in most TN and IPP cases in other locations, this assessment was not possible, suggesting that most oral cases are NEN in smaller nerves, or close to nerve ending, with connective tissue predominating over nerve tissue. In frequently traumatized areas, it is difficult to determine whether nerve injury preceded or followed fibrous proliferation.
Pain is an important feature, observed in 20.39% of NT cases in our sample. Other studies have reported prevalence rates between one-third and one-quarter of cases [16, 18], with inflammation significantly more present in painful cases, which was not observed in our sample. The association between inflammation and pain was also not confirmed by other authors [23]. However, other mechanisms may explain the symptomatology of NT as structural changes in neuroma tissue can alter the electrophysiologic properties of trapped axons, making them abnormally sensitive to various stimuli and causing spontaneous firing. Contributing factors include superficial location, compression, incorporation into a scar, infection, inflammation, ischemia, demyelination, axon crosstalk, sympathetic-sensory interactions, and changes in neuropeptide and ion-channel levels, as reviewed previously [15].
The proposed mechanism to explain IPP development also begins with a traumatic mechanical injury, such as chronic nerve compression and ischemia, or by focal loss of perineurial ensheathment without nerve transection. Trauma-induced loss of the perineurial barrier can trigger endoneurial fibroblasts to transform into perineurial cells, leading to the formation of a new protective barrier around individual Schwann cell-axon units [8, 24, 25]. Collagen deposition between the cell layers forming pseudo-onion bulbs appears to result from secretion by perineurial cells, leading to fascicular enlargement without significant axonal loss [8].
No IPP case was clinically diagnosed as TN. Histologically, in addition to the essential diagnostic features, IPP presented as a superficial connective tissue hyperplasia (thus always exhibiting a covering epithelium), with a low frequency of association with adipose tissue and minimal inflammation near the nerve, like Type B NT. After histometric analysis, we observed that the average percentage of the area composed of pseudo-onion bulbs in lesions classified as IPP was only 8.26% ± 9.40%, with the remainder occupied by fibrous tissue. This characteristic highlights the fibrous nature of the lesion, where areas of IPP are present. Therefore, in the majority of analyzed cases, the term IPP, associated or not with a fibrous lesion, may be more appropriate than pseudoperineurioma. Although histologically similar, pathologists should note the perineural cell proliferation in IPP to avoid confusion with TN (a common reactive lesion) or perineurioma (a rare neoplastic lesion).
Supplementary Information
Below is the link to the electronic supplementary material.
Acknowledgements
To the National Council for Scientific and Technological Development (CNPq)/PIBIC Program, for financing the scholarship for scientific initiation to JEG.
Author Contributions
Authorship: All the authors contributed to this study. VAMM, LAA, TCA, KTB, ACA, MJR, SLVO, NLMA, VSL, FAF, PCC, LGA, RAM, CF ALA initially interpreted the H&E staining and immunohistochemical findings of the cases and reviewed the final manuscript. JEG and ALA revised the slides and data, performed formal analysis, statistical analysis, prepared the original draft, reviewed and edited it. JEG performed the immunohistochemical staining and histometrical measurements. ALA conceptualized the manuscript and supervised the research.
Funding
The National Council for Scientific and Technological Development (CNPq)/PIBIC Program financed the scholarship for scientific initiation to JEG.
Data Availability
The data that is used in this study is available with the corresponding author on reasonable request.
Code Availability
Not applicable.
Declarations
Conflict of interest
The authors declare that they have no conflict of interest. This study was presented at the 48th Brazilian Congress of Stomatology and Oral Pathology (2023).
Ethical Approval
This study was approved by the Institutional Ethics Committee (CAAE: 48569921.4.0000.0077).
Consent to Participate
For this type of study formal consent is not required.
Consent to Publish
For this type of study consent for publication is not required.
Footnotes
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Data Availability Statement
The data that is used in this study is available with the corresponding author on reasonable request.
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