Subgemmal Neurogenous Plaque: Report of Two Cases and a Review of the Literature

Brandon Veremis, D.D.S and Naomi Ramer, D.D.S.Introduction

Originally described as a “hyperplastic subepithelial (subgemmal) nerve plexus” by McDaniel (1999),1 the subgemmal neurogenous plaque (SNP) is a subepithelial proliferation of nerve fibers likely associated with the overlying taste buds. Prior to the description of the SNP, the normal neural structures of the taste buds were well-described.2,3 It consists of a subepithelial nerve plexus with intergemmal (between taste buds) and intragemmal (within taste buds) branches of nerves. The proposed etiology of the SNP is that the nervous tissue structures become hyperplastic following chronic irritation and subsequent inflammation, though this is disputed, with other authors suggesting that it may merely be a normal structure of the taste buds.

The diagnosis of subgemmal neurogenous plaque was recently rendered in two cases at our institution. We present these cases as well as a review of the literature on the subject.

MethodsWe reviewed recent cases of diagnosed SNP at our institution (the Mount Sinai Hospital, New York, New York). For these cases, immunohistochemistry was performed: S100 (Ventana, 10 µg/mL) and neuron-specific enolase (NSE, Cell Marque/Sigma, 1 µg/mL) were utilized. We also searched PubMed for all relevant articles (using the phrases “subgemmal neurogenous plaque” and “subepithelial nerve plexus”) that discuss the SNP in the oral cavity of humans.

Results

The taste bud is a structure that transmits sensory information about chemicals in the oral environment to the brain; in order to do so, it must have neural structures present. It is reasonable to expect that biopsies in areas where taste buds are predominant will have at least a minor degree of neural tissue present. One article found what they called “pseudoganglioneuromas” in the pharynx, which they described as traumatic neuromas with ganglion cells (similar to the SNP), hypothesizing that these were traumatic neuromas occurring in areas with pre-existing pharyngeal ganglion cells.4

McDaniel was the first to describe the presence of hyperplastic (but otherwise normal) neural structures in the tongue. He referred to the normal structure as a “subepithelial nerve plexus” that existed under the taste buds and often showed ganglion cells, and suggested that when these structures were hyperplastic, they be called “hyperplastic subepithelial (subgemmal) nerve plexus”.1

However, the etiological underpinnings of this lesion are not fully understood. With the reasoning that these lesions are not definitively hyperplastic in nature (as McDaniel suggested with his nomenclature), Triantafyllou and Coulter published an article describing this lesion as the “subgemmal neurogenous plaque.” The etiology of this lesion, indeed, is still under debate. It seems unlikely that it is a neoplastic tumor, since neural neoplasms are typically deeper and do not show such a marked predilection for a particular site. There are arguments to be made for a reactive

Case 1: A 64-year-old female presented to an oral surgeon for a biopsy of a painful ulcer on the lateral tongue that had not resolved over the course of the previous three months. Histopathologic examination showed multiple tongue papillae, each exhibiting multiple taste buds. Some papillae had a proliferation of neural-appearing tissue that stained positively with S100. The taste buds and ganglion cells (located deep to the taste buds) showed strongly positive staining for NSE. Other areas of the lesion showed a pseudoinvasive inflammatory component composed of eosinophils, plasma cells, lymphocytes, and occasional neutrophils; this inflammatory component was diagnosed as a traumatic ulcerative granuloma with stromal eosinophilia, and primary cutaneous CD30+ lymphoproliferative disorder was ruled out with the demonstration of CD30 negativity. Selected images of this case are presented in Figure 2.

Discussion

hyperplasia of neural tissue—they occur in a frequently traumatized site, and the lesions frequently have some degree of inflammation that could cause an increase of cytokines and growth factors to cause such a proliferation—but there are a lack of Ki67- and Bcl1-positive cells, which could indicate that these cells are not actively proliferating. Triantafyllou and Coulter also note that there a possibility that this could be a dysplastic or developmental malformation5, though there isn’t enough data to definitively support or refute those ideas. Their theory is that there is a progressive expansion of postganglionic gustatory nerves with axonal branching and endoneurial fibroblasts, which eventually disappear, resulting in a loose mixture of Schwann cells, axons, and basement membrane material.5 Alternatively, other authors suggest that this entity may merely be a normal neural structure of the taste buds.6

Under this moniker, only a few studies have reviewed this entity. Collectively, they tend to agree that the subgemmal neurogenous plaque tends to appear as a hyperplastic taste bud1,5 or an erythematous plaque,6 if it has an evident clinical appearance at all. Most commonly, it affects patients aged 30-60 (mean: 51 years), and has a slight female predominance (1:1.4 male:female), though these numbers may not be completely accurate since relatively few cases have been published.

SNP has also been associated with the following conditions, often discovered as an incidental finding: • Pseudoepitheliomatous hyperplasia7

• Lymphoid hyperplasia, foliate papillitis, or lingual tonsillar tissue1,5

• Lymphoepithelial cysts1,5,7

• Burning tongue6

Most publications on the subject agree that the SNP should have the following histopathologic features: • Circumscription and non-encapsulation5

• Composed of eosinophilic cellular and fibrous structures, including Schwann cells (which stain with S100 and laminin) and axons (which stain with PGP9.5 and NFP)5

• Somewhat rectangular in shape, roughly 0.5-3.5 mm in diameter5

• Often, a focal lymphoplasmacytic inflammatory infiltrate1,5

• Can be located in foliate papillae (usually one plaque per papilla, but can have two separated by a groove in the papilla, forming a “mirror image” of itself, perhaps because it is forming an annular structure)5,7

Triantafyllou and Coulter, in their review of 16 cases on the subject, developed a useful description of the “progressive and subtle” zonal pattern in these lesions:5 • Superficial: primary component of the plaque; nerve fascicles are inconspicuous and set in a loose background of fibrillary collagen. • Intermediate: composed of nerve fascicles, but with attenuated perineurial sheaths and increased endoneurial components that are both growing less organized as they progress to the superficial regions. • Deep: sometimes stem-like, composed of small nerve fascicles, often with myelinated axons and occasionally with ganglion cells.

Gueiros et al.8 and Brito et al.9 considered this to be a biphasic lesion, categorizing the histological patterns as “superficial” and “deep,” though the descriptions for each are functionally similar to Triantafyllou and Coulter’s descriptions, with the latter authors preferring to have a transitional area in their description.

It is important that these lesions are not be confused with other hyperplastic neural entities, such as a neuroma, neurofibroma, or ganglioneuroma. This is particularly true in the case of neurofibroma, wherein multiple misdiagnosed SNPs could potentially lead to an erroneous diagnosis of neurofibromatosis. The superior portions of the subgemmal plaque, being a hyperplasia of collagenous fibers and neural cells, may appear very similar to a neurofibroma. However, the subgemmal neurogenous plaque tends to be more well-defined, has the aforementioned zonal distribution of features, and lacks the feature of continuous growth that the neurofibroma more often demonstrates. The identification of the ganglion cells near a neurofibroma-like area may give the suspicion of a ganglioneuroma, though these are very uncommon in the head and neck, usually appear in those aged 10-30, are usually encapsulated, and often display alterations in the ganglion cells, such as ballooning degeneration and multinucleation. Because this is likely either a normal structure or a hyperplasia of a normal structure, conservative excision with histologic examination to rule out other entities in the list of differential diagnoses should be adequate therapy. According to the study that identified two cases possibly associated with burning mouth syndrome, while initial efforts to remove irritants and rule out systemic causes of burning tongue were ineffective, removal of the subgemmal plaque resulted in a complete resolution of symptoms in both cases.6

1. McDaniel RK. Subepithelial nerve plexus (with ganglion cells) associated with taste buds. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1999;87(5):605-609.2. Mikhail Y, El-Rahman SA, Morris L. Observations on the structure of the subepithelial nerve plexus in the tongue. Acta Anat (Basel). 1980;107(3):311-317.3. Tizzano M, Grigereit L, Shultz N, Clary MS, Finger TE. Immunohistochemical Analysis of Human Vallate Taste Buds. Chem Senses. 2015;40(9):655-660.4. Daneshvar A. Pharyngeal traumatic neuromas and traumatic neuromas with mature ganglion cells (pseudoganglioneuromas). Am J Surg Pathol. 1990;14(6):565-570.5. Triantafyllou A, Coulter P. Structural organization of subgemmal neurogenous plaques in foliate papillae of tongue. Hum Pathol. 2004;35(8):991-999.6. Gueiros L a, Leon JE, Lopes M a, de Almeida OP, Jorge J. Subgemmal neurogenous plaque associated with burning tongue: report of two cases and review of the literature. Int J Oral Maxillofac Surg. 2008;37(8):773-776.7. Val-Bernal JF, Rivadulla I, Garijo MF. Lingual subgemmal neurogenous plaques with pseudoepitheliomatous hyperplasia: incidental pseudomalignant condition. Pathol Int. 2006;56(8):462-465.8. Gueiros LA, León JE, Leão JC, Lopes MA, Jorge J, de Almeida OP. Subgemmal neurogenous plaque: clinical and microscopic evaluation of 7 cases. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2009;108(6):920-924.9. Brito JAR, de Souza FTA, de Lacerda JCT, Bernardes VF, Gomes CC, Gomez RS. Asymptomatic nodule in the tongue. Oral Surg Oral Med Oral Pathol Oral Radiol. 2012;114(3):281-283.

Table 1. Patient characteristics from these cases and the literature review.

Publication Number of Cases

Age Sex Location Clinical Signs/Symptoms Clinical Diagnosis

McDaniel 19991 12 Mean: 46

7 male, 5 female

10 lateral tongue, 2 anterior tongue

N/A

Triantafyllou and Coulter 20045

16 49 F Left tongue Erythematous ulcer approximately 10 mm2; occasional discomfort

Traumatic keratosis/foliate papillitis

60 F Lateral tongue Exophytic lesion, present for 5 months Foliate papillitis/fibroepithelial polyp

69 M Lateral tongue Raised white lesion Lingual tonsil42 F Right posterior

tongueFirm fluctuant lesion, present for 4 months Lingual tonsil/infection/

neoplasia61 M Left lingual

tonsilLump, slightly increased in size, present for 2 weeks

Hyperplastic lingual tonsil

77 M Lateral tongue Nonerythematous, nonindurated white patch, approximately 2 mm2

Foliate papilla/sebaceous gland

43 F Lateral tongue Small nodular lesion Dysplasia/smoker’s keratosis49 F Lateral tongue Papillomatous lesion approximately 3 mm2,

present for 1 weekSquamous cell carcinoma

78 M Lateral tongue Localized erythematous lesion, approximately 2 mm2

N/A

31 M Lateral tongue White patch and polyp, present for 12 months

Lichen planus/fibroepithelial polyp

68 F Right base of tongue

Incidental finding, right neck swelling Squamous cell carcinoma

74 F Lateral tongue Erythematous area, painful N/A70 F Lateral tongue Incidental finding, partial resection right floor

of mouthSquamous cell carcinoma

70 M Lateral tongue Pus-filled lesion, history of ulceration, approximately 0.8 mm2, present for 9 months

N/A

47 F Lateral tongue Nodular lesion, soreness, present for 10 weeks

Lingual tonsil/malignancy

45 F Lateral tongue No lesion detected clinically, sore throat and tongue, present for 12 months

Confirm normal mucosa

Val-Bernal et al. 20067

1 66 M Posterior zone of tongue

Autopsy; patient succumbed to SCCA of the lung

N/A

Gueiros et al. 20086

2 61 F Lateral tongue Burning tongue for 12 months; resolved after excision of the plaque. No evidence of other causes of burning tongue (diabetes, anemia, nutritional/vitamin deficiencies, sensitivity to toothpaste/diet).

Transient lingual papillitis/contact allergy

34 F Lateral tongue Burning tongue for 4 months. Small red swelling was noted. CBC, B12, folate, and glucose plasmatic levels were normal. No symptoms at three-month follow-up.

Foliate papillitis

Gueiros et al. 20098ǂ

7 53 F Lateral tongue Pain Candidosis/foliate papillitis

46 F Lateral tongue Pain Hyperplastic lingual tonsil/candidosis

34 F Lateral tongue Burning/pain Foliate papillitis/hyperplastic lingual tonsil

51 M Lateral tongue Pain SCC43 M Lateral tongue Burning/pain Foliate papillitis52 F Lateral tongue Asymptomatic swelling Hyperplastic lingual tonsil58 M Lateral tongue Asymptomatic swelling Hyperplastic lingual tonsil

Brito et al. 20129 1 28 F Posterior dorsum, anterior to circumvellate papillae

Asymptomatic nodule for six months N/A

This report 2 64 F Lateral tongue Painful non-healing ulceration for 3 months SCC, traumatic ulcer75 M Base of tongue Mass N/A

TOTAL 41 52 18 male, 25 female (1:1.4)

32 lateral tongue, 9 in other lingual sites

ǂThis publication exclusively assessed lateral tongue sites.

References

Case 2: A 75-year-old male with a base of tongue mass. Like the previous case, the histopathologic findings involved the presence of taste buds with an increased density of neural tissue in the submucosa. In this case, S100 demonstrated diffusely positive staining, as did NSE, particularly in deeper ganglion cells. No other substantial secondary features were noted. Selected images of this case are presented in Figure 3.

Literature review: Six articles were identified that directly discussed this entity in the oral cavity. The results from this review are included in Table 1, along with our own cases.

Figure 2. 2A: Low-power view of two annular structures containing SNPs. 2B: Higher power of taste buds with subepithelial neural tissue. 2C: Nearby area of traumatic ulcerative granuloma with stromal eosinophilia with pseudoepitheliomatous hyperplasia. 2D: S-100. 2E: Neuron-specific enolase. 2F: NSE, higher power noting the presence of ganglion cells deeper in the lesion.

A B

C D

E F

Figure 3 (Case 2). 3A: Low-power view of the lesion. 3B: Higher power of taste buds with subepithelial neural tissue. 3C: S-100. 3D: Neuron-specific enolase.

A B

C D