- Email: [email protected]
Subgemmal neurogenous plaque: Clinical and microscopic evaluation of 7 cases
Subgemmal neurogenous plaque: Clinical and microscopic evaluation of 7 cases Luiz Alcino Gueiros, DDS, PhD,a,b Jorge Esquiche León, DDS, PhD,a Jair Carneiro Leão, DDS, PhD,b Márcio Ajudarte Lopes, DDS, PhD,a Jacks Jorge, DDS, PhD,a and Oslei Paes de Almeida, DDS, PhD,a Piracicaba and Recife, Brazil UNIVERSITY OF CAMPINAS AND FEDERAL UNIVERSITY OF PERNAMBUCO
Subgemmal neurogenous plaques (SNPs) are biphasic neural structures found on the posterolateral border of the tongue. Fewer than 40 cases have been reported and only a few were symptomatic. The present report details the features of 7 cases of SNP retrieved from the files of a single institution. Clinical and histopathological data were reviewed and immunohistochemical analysis was performed for S100, CD56, neuron-specific enolase, epithelial membrane antigen, CK7, CK8, CK14, and CK20. All cases showed similar morphological and immunohistochemical characteristics. Neural markers highlighted the biphasic pattern and CK7, CK8, and CK20 were detected on taste buds confined to the epithelium adjacent to the SNPs. Five patients presented pain/discomfort as the main symptom. Symptomatic SNPs seems to be more common than previously reported, presenting as focal burning on the posterolateral border of the tongue. (Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2009;108:920-924)
Subgemmal neurogenous plaques (SNPs) were first described as subepithelial nerve plexuses associated with the taste buds of the tongue.1,2 Although tortuous nerve plexuses had been described close to taste buds, only recently were they recognized as a unique structure.1 Usually no clinical signs or symptoms are reported, although erythema, ulcers, white patches, and hyperplastic nodules can be associated with SNPs. There are many studies considering the taste buds, lingual foliate papillae, and lymphoid follicles present on the posterolateral border of the tongue, nevertheless little is known of the biology and clinical relevance of SNPs.2-4 Recently, we reported 2 cases of SNP associated with focal burning of the tongue, which was thought to be more than a coincidental finding.2 The present report describes the clinical, microscopic, and immunohistochemical features of 7 new cases of SNPs. MATERIAL AND METHODS Four hundred and seven biopsies of the lateral border of the tongue were reviewed from the files of the Oral Supported by The National Council for Scientific and Technological Development (CNPq) and The State of São Paulo Research Foundation (FAPESP). a Department of Oral Diagnosis, Pathology Section, Piracicaba Dental School, University of Campinas, Piracicaba, UNICAMP, Piracicaba, SP, Brazil. b Department of Clinics and Preventive Dentistry, Oral Medicine Unit, Federal University of Pernambuco, UFPE, Recife, PE, Brazil. Received for publication May 22, 2009; returned for revision Jul 7, 2009; accepted for publication Jul 20, 2009. 1079-2104/$ - see front matter © 2009 Published by Mosby, Inc. doi:10.1016/j.tripleo.2009.07.038
920
Pathology Laboratory of the Piracicaba Dental School (University of Campinas, São Paulo, Brazil), retrieved from 2001 to 2007. All specimens were fixed in 10% neutral-buffered formalin, processed for routine light microscopy, and stained with hematoxylin and eosin (H&E). After histopathological analysis, SNPs were identified in 7 cases. All 7 specimens were obtained via incisional biopsy under local anesthesia for diagnostic purposes. Clinical information regarding patients’ age, gender, signs and symptoms, and diagnosis were obtained from the clinical records (Table I). Immunohistochemical analysis The immunohistochemical analysis included S-100 (polyclonal, dilution 1:12000; Dako A/S, Glostrup, Denmark), neuron-specific enolase (NSE) (BBS/NC/YI-H14, dilution 1:800, Dako A/S), CD56 (CD56-1B6, dilution 1:50; Novocastra, Newcastle upon Tyne, UK), epithelial membrane antigen (EMA) (E29, dilution 1:400, Dako A/S), neurofilament protein (NP) (2F11, dilution 1:100, Dako A/S), CK7 (OV-TL12/30, dilution 1:400, Dako A/S), CK8 (35bH11, dilution 1:200, Dako A/S), CK14 (NCL-L-LL002, dilution 1:200, Novocastra) and CK20 (KS20,8, dilution 1:500, Dako A/S). Briefly, the slides were hydrated, and subjected to microwave antigenic retrieval in sodium citrate solution (pH 6). Next, the sections were treated with 3% H2O2 and incubated overnight with the primary antibody. This was followed by secondary antibodies conjugated with streptavidinbiotin-peroxidase (Strept ABComplex/HRP Duet, Mouse/ Rabbit, Dako A/S, Denmark), which were visualized with diaminobenzidine chromogen counterstained with Carazzi’s hematoxylin.
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Table I. Summary of all reported cases of subgemmal neurogenous plaques Author Triantafillou & Coulter, 2004
Age
Gender
49 60 69 42 61 77
F F M F M M
43 49
F F
78 31 68 74 70 70
M M F F F M
47 45
F F
McDaniel, 1999 (12 cases) 33 to 61
M: 7 F: 5
Val-Bernal et al., 2006 Gueiros et al., 2008
M F F F F F M M F M
Current series
66 61 34 53 46 34 51 43 52 58
Location
Presentation
Erythematous ulcer approximately 10 mm3 Exophytic lesion, present for 5 mo Raised white lesion Firm fluctuant lesion, present for 4 mo Lump, slightly increased in size, present for 2 wk Nonerythematous, nonindurated white patch, approximately 2 mm2 Right lateral border of tongue Small nodular lesion Left lateral border of tongue Papillomatous lesion approximately 3 mm3, present for 1 wk Right lateral border of tongue Localized erythematous lesion, approximately 2 mm3 Right lateral border of tongue White patch and polyp, present for 12 mo Right base of tongue Incidental finding, right neck swelling Right lateral border of tongue Erythematous area, painful Right lateral border of tongue Incidental finding, partial resection right floor of mouth Left lateral border of tongue Pus-filled lesion, history of ulceration, approximately 0.8 mm3, present for 9 mo Right lateral border of tongue Nodular lesion, soreness, present for 10 wk Right lateral border of tongue No lesion detected clinically, sore throat and tongue, present for 12 mo Lateral border of the tongue (10), Tip Not described of the tongue, anterior portion of the tongue Posterior zone of the tongue Not described Lateral border of the tongue Erythematous area Lateral border of the tongue Small red swelling Pain Candidosis/Folliate papillitis Pain Hyperplastic Lingual tonsil/Candidosis Burning/pain Folliate papillitis Hyperplastic/lingual tonsil Pain SCC Burning/pain Folliate papillitis No Symptom Hyperplastic lingual tonsil No Symptom Hyperplastic lingual tonsil Left tongue Left lateral border of tongue Right lateral border of tongue Right posterior tongue Left lingual tonsil Right lateral border of tongue
M, male; F, female; SCC, squamous cell carcinoma.
RESULTS Four (57.14%) of the 7 patients were women. The patients’ ages ranged from 34 to 58 years, with a mean age of 48.14 years. Four patients reported pain or burning sensation on the lateral border of the tongue, which was the main reason for biopsy. One patient had a clinical diagnosis of oral squamous cell carcinoma, and the other two presented with an asymptomatic swelling on the lateral border of the tongue. Microscopically, the SNPs showed a biphasic pattern, composed of a superficial circumscribed neural plexus parallel to the surface epithelium, and a deeper portion formed by small nerve fascicles intermingled with scarce mature ganglion cells, most of which were surrounded by satellite cells (Fig. 1). The superficial portion consisted of elongated and spindle wavy cells, with a variable amount of collagen in a neurofibromalike pattern. The nerve fascicles of the deeper zone showed a thin perineurium and few mature ganglion cells with a neuromalike pattern. All biopsies contained
Fig. 1. Subgemmal neurogenous plaque, showing the superficial neural component, parallel to the surface epithelium. Note the taste buds in the epithelial tissue (H&E, original magnification ⫻10).
Von Ebner’s glands and a discrete to moderate amount of subepithelial inflammatory lymphoid infiltrate. Lymphoid follicles were associated with SNP in 4 cases,
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Fig. 2. Immunohistochemistry of SNP. The spindle cells of the superficial component were positive for S-100 (A) and neuron-specific enolase (B); the latter also highlighted mature ganglion cells of the deeper portion (IHC, original magnification ⫻5). C, Intense fibrillar staining was observed for CD56 (IHC, original magnification ⫻20). D, EMA was detected in the nerve fascicle sheath (IHC, original magnification ⫻20).
and 3 corresponded to secondary follicles. Two cases showed complete resolution of the symptoms following biopsy, and it was not possible to retrieve information regarding the remaining cases. The spindle cells of the superficial component of the SNP were positive for S-100 and NSE; the latter also highlighted mature ganglion cells of the deeper portions (Fig. 2, A and B). Intense fibrillar staining was observed for CD56, which was also detected on the membranes of ganglion cells (Fig. 2, C). EMA was detected in the nerve fascicles sheath (Fig. 2, D). NP showed a uniform staining in the neuromalike and neurofibromalike areas, as well as in the taste buds (Fig. 3). Intense CK7 staining was observed on the basal cells of the taste buds (Fig. 4, A). Slight CK8 staining was observed on the basal cells of the stratified epithelium, but it was intensely expressed on the taste buds (Fig. 4, B). CK14 staining was found in the stratified epithelium, but it was not observed in taste buds (Fig. 4, C). All cases showed numerous taste buds adjacent to the SNPs, and these were strongly positive for CK20. Merkel cells were not detected in any of the CK20-stained preparations (Fig. 4, D). DISCUSSION SNPs have been described previously by Squier and Finkelstein1 but only recently were they recognized as a unique structure of the lateral border of the tongue. Studies considering the SNPs are scarce,2-5 and only one described in detail their microscopic characteristics.4 It is important to recognize this neural structure to
Fig. 3. Immunohistochemistry of neurofilament protein in SNP. Deeper neuromalike areas were intensely positive for neurofilament protein (IHC, original magnification ⫻20). Mature ganglion cells were also positive (inset—IHC, original magnification ⫻40).
avoid misdiagnosis with other neural proliferations, such as ganglioneuroma, pseudo-ganglioneurofibroma, neurofibroma, traumatic neuroma, and mucosal neuroma.3 Localization on the lateral border of the tongue and the unique biphasic pattern, with superficial neurofibromalike plaques and deeper neuromalike areas, permit the identification of SNPs. In fact, they should be considered as normal structures associated with taste buds.
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Fig. 4. A, Immunohistochemistry of SNP. Intense CK7 staining was observed on taste bud cells. B, CK8 showed slight staining on the basal cells of the stratified epithelium and intense staining on the taste buds. C, CK14 stained the basal layer of the stratified epithelium, but not the taste buds. D, Intense CK20 staining the taste buds, but no Merkel cells were found in this area (IHC, original magnification ⫻20).
An associated burning or pain sensation appears to be uncommon, except in our series. We found that 5 of 7 cases described on this study were associated with focal pain or burning, and that was the main reason for biopsy in 4 cases. Although few pathological conditions may also be associated with focal pain in the lateral border of the tongue, such as contact allergy, transient lingual papillitis, burning mouth syndrome, and Candida-associated atrophic glossitis, surgical removal is not the first option for their management.3 Therefore, if conventional treatments do not help to improve focal pain or burning on the lateral border of the tongue, a biopsy may be useful to obtain the correct diagnosis and eventual improvement of the symptoms. In our view, it is reasonable to consider that some cases of painful or burning sensation in the tongue may be associated with SNP. In fact, we speculate that chronic trauma may stimulate the nerve fibers of the SNP directly or via inflammatory mediators. In addition, there are only 4 reports describing a total of 31 cases of SNPs, most of which are considered as incidental findings (Table I); with only 6 cases related with pain or discomfort.3,4 It would be intriguing to evaluate larger series to better estimate the prevalence of symptomatic cases. The reported prevalence of SNPs in biopsies of the lateral border of the tongue is approximately 4.0%,4 and in our sample of 407 cases, we found 7 SNPs (1.7%). There is no evaluation of the prevalence of SNPs in the general population, and postmortem studies of normal tongues could be helpful. We examined tongues removed during autopsies for
studies of infectious diseases, but the posterior border of the tongue was invariably lacerated and inadequate for microscopic studies. Furthermore, we recently reported 2 cases of focal burning of the tongue associated with SNPs, and both patients reported complete relief after the area was biopsied.3 The largest series of SNPs reported includes 16 cases, of which only 4 were associated with pain.4 Case 4 was biopsied because of a clinical suspicion of squamous cell carcinoma and in fact SNPs have been found adjacent to tumors on the lateral border of the tongue. However, the presence of SNPs in these cases was considered coincidental and not related with clinical symptoms.4 Triantafyllou and Coulter4 also reported SNP associated with lymphoid cyst, which is common on the lateral border of the tongue. It is unknown whether the involvement of SNPs by an associated lesion, such as a carcinoma or lymphoid cyst, can produce symptoms.6 Under routine H&E staining, SNPs typically show a biphasic pattern. As reported previously, spindle cells organized in cords parallel to the superficial epithelium account for a large proportion of the plaque.4 Some mature ganglion cells may be intermingled with the nerve fascicles. To better characterize these structures, we performed immunohistochemical analysis to detect expression of S-100, NP, NSE, EMA, and CD56. The IHC findings highlighted the biphasic pattern of the plaque, facilitating its recognition.2-5 NP also stained the mature ganglion cells, as seen in Fig. 3. CK20 staining was observed on taste buds, which were numerous in the area above the plaque, but absent in the
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Gueiros et al.
adjacent regions.8 Interestingly, no Merkel cells were observed in the area rich in taste buds, similar to what was reported by Barrett et al.7 CK7, CK8, and CK14 expression also was similar to previous reports.9 CK14 was strongly expressed in the stratified epithelium, but it was not observed in the taste buds, which instead showed strong CK20 staining. In summary, SNPs are normal neural structures found in the posterior third of the lateral border of the tongue, frequently associated with lymphoid follicles, forming a morphological and physiological complex with taste buds. Although pain or discomfort has rarely been described in association with these plaques, painful or symptomatic SNPs appear to be more common than previously considered. Nevertheless, further studies are necessary to better understand the biology and clinical relevance of SNPs.
4.
5.
6.
7.
8.
9.
mal neurogenous plaque associated with burning tongue: report of two cases and review of the literature. Int J Oral Maxillofac Surg 2008;37:773-6. Triantafyllou A, Coulter P. Structural organization of subgemmal neurogenous plaque in the foliate papillae of tongue. Hum Pathol 2004;35:991-9. Val-Bernal JF, Rivadulla I, Garijo MF. Lingual subgemmal neurogenous plaque with pseudoepithelial hyperplasia: incidental pseudomalignant condition. Pathol Int 2006;56:462-5. Cuffari L, Siqueira JT, Nemr K, Rapaport A. Pain complaint as the first symptom of oral cancer: a descriptive study. Oral Surg Oral Med Oral Pathol Oral Radio Endod 2006;102:56-61. Barrett AW, Cort EM, Patel P, Berkovitz BK. An immunohistological study of cytokeratin 20 in human and mammalian oral epithelium. Arch Oral Biol 2000;45:879-87. Witt M, Reutter K, Ganchrow D, Ganchrow JR. Fingerprintering taste buds: intermediate filaments and their implication for taste bud formation. Phil Trans R Soc Lon B 2000;355:1233-7. Witt M, Kasper M. Distribution of cytokeratin filaments and vimentin in developing human taste buds. Anat Embryol 1999; 199:291-9.
REFERENCES
Reprint requests:
1. Squier CA, Finkelstein MW. Oral mucosa. In: Nanci A, editor. Ten Cate’s oral histology. Development, structure and function. 6th ed. St. Louis: Mosby; 2003. p. 329-75. 2. McDaniel K. Subepithelial nerve plexus (with ganglion cells) associated with taste buds. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1999;87:605-9. 3. Gueiros LA, Leon JE, Lopes MA, Almeida OP, Jorge J. Subgem-
Luiz Alcino Gueiros, DDS, MSc, PhD Oral Pathology Section Piracicaba Dental School University of Campinas – UNICAMP Av. Limeira 901, Caixa Postal 52 Piracicaba – SP, Brasil CEP: 13414-903 [email protected]
Subgemmal neurogenous plaques (SNPs) are biphasic neural structures found on the posterolateral border of the tongue. Fewer than 40 cases have been reported and only a few were symptomatic. The present report details the features of 7 cases of SNP retrieved from the files of a single institution. Clinical and histopathological data were reviewed and immunohistochemical analysis was performed for S100, CD56, neuron-specific enolase, epithelial membrane antigen, CK7, CK8, CK14, and CK20. All cases showed similar morphological and immunohistochemical characteristics. Neural markers highlighted the biphasic pattern and CK7, CK8, and CK20 were detected on taste buds confined to the epithelium adjacent to the SNPs. Five patients presented pain/discomfort as the main symptom. Symptomatic SNPs seems to be more common than previously reported, presenting as focal burning on the posterolateral border of the tongue. (Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2009;108:920-924)
Subgemmal neurogenous plaques (SNPs) were first described as subepithelial nerve plexuses associated with the taste buds of the tongue.1,2 Although tortuous nerve plexuses had been described close to taste buds, only recently were they recognized as a unique structure.1 Usually no clinical signs or symptoms are reported, although erythema, ulcers, white patches, and hyperplastic nodules can be associated with SNPs. There are many studies considering the taste buds, lingual foliate papillae, and lymphoid follicles present on the posterolateral border of the tongue, nevertheless little is known of the biology and clinical relevance of SNPs.2-4 Recently, we reported 2 cases of SNP associated with focal burning of the tongue, which was thought to be more than a coincidental finding.2 The present report describes the clinical, microscopic, and immunohistochemical features of 7 new cases of SNPs. MATERIAL AND METHODS Four hundred and seven biopsies of the lateral border of the tongue were reviewed from the files of the Oral Supported by The National Council for Scientific and Technological Development (CNPq) and The State of São Paulo Research Foundation (FAPESP). a Department of Oral Diagnosis, Pathology Section, Piracicaba Dental School, University of Campinas, Piracicaba, UNICAMP, Piracicaba, SP, Brazil. b Department of Clinics and Preventive Dentistry, Oral Medicine Unit, Federal University of Pernambuco, UFPE, Recife, PE, Brazil. Received for publication May 22, 2009; returned for revision Jul 7, 2009; accepted for publication Jul 20, 2009. 1079-2104/$ - see front matter © 2009 Published by Mosby, Inc. doi:10.1016/j.tripleo.2009.07.038
920
Pathology Laboratory of the Piracicaba Dental School (University of Campinas, São Paulo, Brazil), retrieved from 2001 to 2007. All specimens were fixed in 10% neutral-buffered formalin, processed for routine light microscopy, and stained with hematoxylin and eosin (H&E). After histopathological analysis, SNPs were identified in 7 cases. All 7 specimens were obtained via incisional biopsy under local anesthesia for diagnostic purposes. Clinical information regarding patients’ age, gender, signs and symptoms, and diagnosis were obtained from the clinical records (Table I). Immunohistochemical analysis The immunohistochemical analysis included S-100 (polyclonal, dilution 1:12000; Dako A/S, Glostrup, Denmark), neuron-specific enolase (NSE) (BBS/NC/YI-H14, dilution 1:800, Dako A/S), CD56 (CD56-1B6, dilution 1:50; Novocastra, Newcastle upon Tyne, UK), epithelial membrane antigen (EMA) (E29, dilution 1:400, Dako A/S), neurofilament protein (NP) (2F11, dilution 1:100, Dako A/S), CK7 (OV-TL12/30, dilution 1:400, Dako A/S), CK8 (35bH11, dilution 1:200, Dako A/S), CK14 (NCL-L-LL002, dilution 1:200, Novocastra) and CK20 (KS20,8, dilution 1:500, Dako A/S). Briefly, the slides were hydrated, and subjected to microwave antigenic retrieval in sodium citrate solution (pH 6). Next, the sections were treated with 3% H2O2 and incubated overnight with the primary antibody. This was followed by secondary antibodies conjugated with streptavidinbiotin-peroxidase (Strept ABComplex/HRP Duet, Mouse/ Rabbit, Dako A/S, Denmark), which were visualized with diaminobenzidine chromogen counterstained with Carazzi’s hematoxylin.
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Table I. Summary of all reported cases of subgemmal neurogenous plaques Author Triantafillou & Coulter, 2004
Age
Gender
49 60 69 42 61 77
F F M F M M
43 49
F F
78 31 68 74 70 70
M M F F F M
47 45
F F
McDaniel, 1999 (12 cases) 33 to 61
M: 7 F: 5
Val-Bernal et al., 2006 Gueiros et al., 2008
M F F F F F M M F M
Current series
66 61 34 53 46 34 51 43 52 58
Location
Presentation
Erythematous ulcer approximately 10 mm3 Exophytic lesion, present for 5 mo Raised white lesion Firm fluctuant lesion, present for 4 mo Lump, slightly increased in size, present for 2 wk Nonerythematous, nonindurated white patch, approximately 2 mm2 Right lateral border of tongue Small nodular lesion Left lateral border of tongue Papillomatous lesion approximately 3 mm3, present for 1 wk Right lateral border of tongue Localized erythematous lesion, approximately 2 mm3 Right lateral border of tongue White patch and polyp, present for 12 mo Right base of tongue Incidental finding, right neck swelling Right lateral border of tongue Erythematous area, painful Right lateral border of tongue Incidental finding, partial resection right floor of mouth Left lateral border of tongue Pus-filled lesion, history of ulceration, approximately 0.8 mm3, present for 9 mo Right lateral border of tongue Nodular lesion, soreness, present for 10 wk Right lateral border of tongue No lesion detected clinically, sore throat and tongue, present for 12 mo Lateral border of the tongue (10), Tip Not described of the tongue, anterior portion of the tongue Posterior zone of the tongue Not described Lateral border of the tongue Erythematous area Lateral border of the tongue Small red swelling Pain Candidosis/Folliate papillitis Pain Hyperplastic Lingual tonsil/Candidosis Burning/pain Folliate papillitis Hyperplastic/lingual tonsil Pain SCC Burning/pain Folliate papillitis No Symptom Hyperplastic lingual tonsil No Symptom Hyperplastic lingual tonsil Left tongue Left lateral border of tongue Right lateral border of tongue Right posterior tongue Left lingual tonsil Right lateral border of tongue
M, male; F, female; SCC, squamous cell carcinoma.
RESULTS Four (57.14%) of the 7 patients were women. The patients’ ages ranged from 34 to 58 years, with a mean age of 48.14 years. Four patients reported pain or burning sensation on the lateral border of the tongue, which was the main reason for biopsy. One patient had a clinical diagnosis of oral squamous cell carcinoma, and the other two presented with an asymptomatic swelling on the lateral border of the tongue. Microscopically, the SNPs showed a biphasic pattern, composed of a superficial circumscribed neural plexus parallel to the surface epithelium, and a deeper portion formed by small nerve fascicles intermingled with scarce mature ganglion cells, most of which were surrounded by satellite cells (Fig. 1). The superficial portion consisted of elongated and spindle wavy cells, with a variable amount of collagen in a neurofibromalike pattern. The nerve fascicles of the deeper zone showed a thin perineurium and few mature ganglion cells with a neuromalike pattern. All biopsies contained
Fig. 1. Subgemmal neurogenous plaque, showing the superficial neural component, parallel to the surface epithelium. Note the taste buds in the epithelial tissue (H&E, original magnification ⫻10).
Von Ebner’s glands and a discrete to moderate amount of subepithelial inflammatory lymphoid infiltrate. Lymphoid follicles were associated with SNP in 4 cases,
922
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OOOOE December 2009
Fig. 2. Immunohistochemistry of SNP. The spindle cells of the superficial component were positive for S-100 (A) and neuron-specific enolase (B); the latter also highlighted mature ganglion cells of the deeper portion (IHC, original magnification ⫻5). C, Intense fibrillar staining was observed for CD56 (IHC, original magnification ⫻20). D, EMA was detected in the nerve fascicle sheath (IHC, original magnification ⫻20).
and 3 corresponded to secondary follicles. Two cases showed complete resolution of the symptoms following biopsy, and it was not possible to retrieve information regarding the remaining cases. The spindle cells of the superficial component of the SNP were positive for S-100 and NSE; the latter also highlighted mature ganglion cells of the deeper portions (Fig. 2, A and B). Intense fibrillar staining was observed for CD56, which was also detected on the membranes of ganglion cells (Fig. 2, C). EMA was detected in the nerve fascicles sheath (Fig. 2, D). NP showed a uniform staining in the neuromalike and neurofibromalike areas, as well as in the taste buds (Fig. 3). Intense CK7 staining was observed on the basal cells of the taste buds (Fig. 4, A). Slight CK8 staining was observed on the basal cells of the stratified epithelium, but it was intensely expressed on the taste buds (Fig. 4, B). CK14 staining was found in the stratified epithelium, but it was not observed in taste buds (Fig. 4, C). All cases showed numerous taste buds adjacent to the SNPs, and these were strongly positive for CK20. Merkel cells were not detected in any of the CK20-stained preparations (Fig. 4, D). DISCUSSION SNPs have been described previously by Squier and Finkelstein1 but only recently were they recognized as a unique structure of the lateral border of the tongue. Studies considering the SNPs are scarce,2-5 and only one described in detail their microscopic characteristics.4 It is important to recognize this neural structure to
Fig. 3. Immunohistochemistry of neurofilament protein in SNP. Deeper neuromalike areas were intensely positive for neurofilament protein (IHC, original magnification ⫻20). Mature ganglion cells were also positive (inset—IHC, original magnification ⫻40).
avoid misdiagnosis with other neural proliferations, such as ganglioneuroma, pseudo-ganglioneurofibroma, neurofibroma, traumatic neuroma, and mucosal neuroma.3 Localization on the lateral border of the tongue and the unique biphasic pattern, with superficial neurofibromalike plaques and deeper neuromalike areas, permit the identification of SNPs. In fact, they should be considered as normal structures associated with taste buds.
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Fig. 4. A, Immunohistochemistry of SNP. Intense CK7 staining was observed on taste bud cells. B, CK8 showed slight staining on the basal cells of the stratified epithelium and intense staining on the taste buds. C, CK14 stained the basal layer of the stratified epithelium, but not the taste buds. D, Intense CK20 staining the taste buds, but no Merkel cells were found in this area (IHC, original magnification ⫻20).
An associated burning or pain sensation appears to be uncommon, except in our series. We found that 5 of 7 cases described on this study were associated with focal pain or burning, and that was the main reason for biopsy in 4 cases. Although few pathological conditions may also be associated with focal pain in the lateral border of the tongue, such as contact allergy, transient lingual papillitis, burning mouth syndrome, and Candida-associated atrophic glossitis, surgical removal is not the first option for their management.3 Therefore, if conventional treatments do not help to improve focal pain or burning on the lateral border of the tongue, a biopsy may be useful to obtain the correct diagnosis and eventual improvement of the symptoms. In our view, it is reasonable to consider that some cases of painful or burning sensation in the tongue may be associated with SNP. In fact, we speculate that chronic trauma may stimulate the nerve fibers of the SNP directly or via inflammatory mediators. In addition, there are only 4 reports describing a total of 31 cases of SNPs, most of which are considered as incidental findings (Table I); with only 6 cases related with pain or discomfort.3,4 It would be intriguing to evaluate larger series to better estimate the prevalence of symptomatic cases. The reported prevalence of SNPs in biopsies of the lateral border of the tongue is approximately 4.0%,4 and in our sample of 407 cases, we found 7 SNPs (1.7%). There is no evaluation of the prevalence of SNPs in the general population, and postmortem studies of normal tongues could be helpful. We examined tongues removed during autopsies for
studies of infectious diseases, but the posterior border of the tongue was invariably lacerated and inadequate for microscopic studies. Furthermore, we recently reported 2 cases of focal burning of the tongue associated with SNPs, and both patients reported complete relief after the area was biopsied.3 The largest series of SNPs reported includes 16 cases, of which only 4 were associated with pain.4 Case 4 was biopsied because of a clinical suspicion of squamous cell carcinoma and in fact SNPs have been found adjacent to tumors on the lateral border of the tongue. However, the presence of SNPs in these cases was considered coincidental and not related with clinical symptoms.4 Triantafyllou and Coulter4 also reported SNP associated with lymphoid cyst, which is common on the lateral border of the tongue. It is unknown whether the involvement of SNPs by an associated lesion, such as a carcinoma or lymphoid cyst, can produce symptoms.6 Under routine H&E staining, SNPs typically show a biphasic pattern. As reported previously, spindle cells organized in cords parallel to the superficial epithelium account for a large proportion of the plaque.4 Some mature ganglion cells may be intermingled with the nerve fascicles. To better characterize these structures, we performed immunohistochemical analysis to detect expression of S-100, NP, NSE, EMA, and CD56. The IHC findings highlighted the biphasic pattern of the plaque, facilitating its recognition.2-5 NP also stained the mature ganglion cells, as seen in Fig. 3. CK20 staining was observed on taste buds, which were numerous in the area above the plaque, but absent in the
924
OOOOE December 2009
Gueiros et al.
adjacent regions.8 Interestingly, no Merkel cells were observed in the area rich in taste buds, similar to what was reported by Barrett et al.7 CK7, CK8, and CK14 expression also was similar to previous reports.9 CK14 was strongly expressed in the stratified epithelium, but it was not observed in the taste buds, which instead showed strong CK20 staining. In summary, SNPs are normal neural structures found in the posterior third of the lateral border of the tongue, frequently associated with lymphoid follicles, forming a morphological and physiological complex with taste buds. Although pain or discomfort has rarely been described in association with these plaques, painful or symptomatic SNPs appear to be more common than previously considered. Nevertheless, further studies are necessary to better understand the biology and clinical relevance of SNPs.
4.
5.
6.
7.
8.
9.
mal neurogenous plaque associated with burning tongue: report of two cases and review of the literature. Int J Oral Maxillofac Surg 2008;37:773-6. Triantafyllou A, Coulter P. Structural organization of subgemmal neurogenous plaque in the foliate papillae of tongue. Hum Pathol 2004;35:991-9. Val-Bernal JF, Rivadulla I, Garijo MF. Lingual subgemmal neurogenous plaque with pseudoepithelial hyperplasia: incidental pseudomalignant condition. Pathol Int 2006;56:462-5. Cuffari L, Siqueira JT, Nemr K, Rapaport A. Pain complaint as the first symptom of oral cancer: a descriptive study. Oral Surg Oral Med Oral Pathol Oral Radio Endod 2006;102:56-61. Barrett AW, Cort EM, Patel P, Berkovitz BK. An immunohistological study of cytokeratin 20 in human and mammalian oral epithelium. Arch Oral Biol 2000;45:879-87. Witt M, Reutter K, Ganchrow D, Ganchrow JR. Fingerprintering taste buds: intermediate filaments and their implication for taste bud formation. Phil Trans R Soc Lon B 2000;355:1233-7. Witt M, Kasper M. Distribution of cytokeratin filaments and vimentin in developing human taste buds. Anat Embryol 1999; 199:291-9.
REFERENCES
Reprint requests:
1. Squier CA, Finkelstein MW. Oral mucosa. In: Nanci A, editor. Ten Cate’s oral histology. Development, structure and function. 6th ed. St. Louis: Mosby; 2003. p. 329-75. 2. McDaniel K. Subepithelial nerve plexus (with ganglion cells) associated with taste buds. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1999;87:605-9. 3. Gueiros LA, Leon JE, Lopes MA, Almeida OP, Jorge J. Subgem-
Luiz Alcino Gueiros, DDS, MSc, PhD Oral Pathology Section Piracicaba Dental School University of Campinas – UNICAMP Av. Limeira 901, Caixa Postal 52 Piracicaba – SP, Brasil CEP: 13414-903 [email protected]