Sclerosing Perineuroma

Intraoral sclerosing perineurioma: a case report and review ofthe literatureWilfredo Alejandro González-Arriagada, DDS, MSc,a,b Jorge Esquiche Leon, DDS, PhD,a

Pablo Agustin Vargas, DDS, PhD,a Oslei Paes de Almeida, DDS, PhD,a andMarcio Ajudarte Lopes, DDS, PhD,a Piracicaba, BrazilORAL DIAGNOSIS DEPARTMENT, SEMIOLOGY, AND ORAL PATHOLOGY, PIRACICABA DENTAL SCHOOL,STATE UNIVERSITY OF CAMPINAS

Sclerosing perineurioma is an extraneural soft tissue lesion that has been reported in the extremities of youngadults. It is composed of oval epithelioid or plump spindled cells scattered to form ill-defined fascicles in a storiform,whorled, or trabecular pattern and dermal sclerosis represented by thickened collagen bundles in a lamellar array thatexpress epithelial membrane antigen and are negative for S-100 protein. The treatment is surgical excision, and norecurrence or metastases are expected. Herein is presented the first case of intraoral sclerosing perineurioma of the lowerlip, emphasizing its histopathologic and immunohistochemical features. (Oral Surg Oral Med Oral Pathol Oral Radiol
Endod 2010;109:e46-e52)
The perineurioma is an unusual benign soft tissue tu-mor composed of cells derived from the perineurium.Two forms of perineurioma are described: intraneuralperineurioma and soft tissue perineurioma (extraneu-ral).1-3 Sclerosing perineurioma (SP) is considered tobe a variant of the soft tissue perineurioma and was firstdescribed in 1997 by Fetsch and Miettinen2 in a clini-copathologic study of 19 cases, which showed a predi-lection for the fingers and palms of young male adults.Since then, only 22 additional cases have been reported,almost all affecting the hands.3-15 The differential di-agnosis includes fibroma of the tendon sheath, fibrosingtenosynovial giant cell tumor and Morton neuroma. SPoccurs mainly in men and in the third decade of life.The most common clinical presentation is a painlesssolitary small lesion with a long history of evolutionaffecting the extremities, particularly the fingers.2

Microscopically, it is a well circumscribed and hy-pocellular tumor surrounded by a thin fibrous pseudo-capsule which is composed of oval epithelioid orplump spindled cells forming ill-defined fascicles ina storiform, whorled, or trabecular pattern and der-mal sclerosis represented by thickened collagen bun-dles in a lamellar array.3-5 Immunohistochemicalstudies have showed positivity for EMA, CD99, vi-

aOral Diagnosis Department, Semiology and Oral Pathology, Piraci-caba Dental School, State University of Campinas (UNICAMP),Piracicaba, Sao Paulo, Brazil.bOral Pathology and Diagnosis, Dental School, University of Val-paraíso, Valparaíso, Chile.Received for publication Nov 19, 2009; returned for revision Jan 13,2010; accepted for publication Jan 26, 2010.1079-2104/$ - see front matter© 2010 Mosby, Inc. All rights reserved.
doi:10.1016/j.tripleo.2010.01.021
e46

mentin, and collagen type IV, but negativity forS-100, MART-1, factor XIIIa, CD34, muscle-spe-cific actin, alpha smooth muscle actin, desmin, Ki-67, cytokeratin, and p53.3-6,8

The treatment consists of complete local excision,and recurrence or metastases are not reported sofar.2-6,11,12 SP is extremely rare, and to the best ofour knowledge this is the first reported case affectingthe oral cavity.

CASE REPORTA 26-year-old man was referred complaining of a painless

nodule in the lower lip mucosa. The patient related that thelesion had been present for �10 years, with very slow growthin the first years and then remaining stable, without causingany inconvenience during chewing or speaking. Oral exami-nation revealed a poorly circumscribed, soft, sessile nodulewith a smooth and normal-colored surface, 2.0 � 2.0 cm in itsmaximum dimensions (Fig. 1).

The patient did not show signs of sensorial alteration in theaffected region, and he did not remember previous localtrauma. With the clinical diagnosis of mucocele or a benignmesenchymal tumor, an excisional biopsy was performed.Histopathologic analysis revealed, at low-power magnifica-tion, a sclerotic stroma with some cellular nests (Fig. 2, A),accompanied by nervous fascicles or twigs with evident per-ineurium at the periphery with a thin capsule (Fig. 2, B). Thelesion showed the presence of abundant vascularization withperivascular distribution of neoplastic epithelioid cells and 2different areas: a sclerotic fibrous-hypocellular area; and per-ineurial cells associated with inflammatory infiltrate (Fig. 2,C). At higher magnification, the histologic features includedinfiltration of muscular tissue by neoplastic cells and sclerotictissue. The tumor cells were isolated or were organized incellular nests, which were arranged in whorled growth patterns,similar to onion skins, and intermixed with collagen bundles.
Also, the neoplastic cells were small spindled-shaped or epithe-

Onion bulb–like structure formed by neoplastic cells (HE, original

in the lower lip.

OOOOEVolume 109, Number 5 González-Arriagada et al. e47

lioid with diffuse borders, with nuclei slightly hyperchromaticwith inconspicuous small nucleoli (Fig. 2, D). There was nocellular pleomorphism, atypical mitoses, or necrosis.

Immunohistochemical reactions were carried out using thestreptavidin-biotin-peroxidase system (Strept ABComplex/HRP Duet, Mouse/Rabbit; Dako, Copenhagen, Denmark).The tumor cells were positive for epithelial membrane anti-gen (EMA; Fig. 3, A), vimentin (Fig. 3, B), human erythro-cyte glucose transporter 1 (GLUT-1; Fig. 3, C), claudin-1(Fig. 3, D), CD10 (Fig. 4, B), CD99 (Fig. 4, C), and �-catenin(Fig. 4, D). On the other hand, the tumor cells were negativefor CD34 (Fig. 4, A), S100, D2-40, CK8, CK18, CK7, CK14,chromogranin, synaptophysin, smooth muscle actin, E-cad-herin, CD56, CD57, CD138, AE1/AE3, and NF1 (Table I).The presence of mast cells was also detected with mast cellantibody (AA1 clone; Dako; 1:10,000). According to thesemicroscopic and immunohistochemical findings, the diagno-

muscular tissue, and a dense sclerotic area with cellular nestification �25). B, Low-power magnification showing a wellmagnification �50). C, Higher magnification, displaying aated neoplastic cells (HE, original magnification �100). D,

Fig. 2. A, Low-power magnification showing minor salivary gland,of neoplastic cells (arrow) (hematoxylin-eosin [HE], original magndefined lesion with nervous twigs at the periphery (HE, originalsclerotic and cellularized area. Note the presence of nests and isol

Fig. 1. Clinical view, showing a submucosal nodule located

magnification �400).

OOOOEe48 González-Arriagada et al. May 2010

sis was SP. The patient was in follow-up for �9 months withno signs of recurrence.

DISCUSSIONSclerosing perineurioma is a rare benign tumor with

immunohistochemical and ultrastructural features sim-ilar to normal perineurial cells, and it is considered tobe a variant of the extraneural (soft tissue) perineu-rioma. The clinicopathologic features of these cases arepresented in Table II. In an extensive review of theEnglish-language literature, we did not found any caseof SP with intraoral presentation or arising on the oralmucosa. Nevertheless, we found 6 cases of intraoralperineurioma with distinct histopathologic features,which are presented in Table III.

Some atypical cases, such as cutaneous perineuriomawith features of the intraneural and sclerosing types and

Fig. 3. A, Positivity for epithelial membrane antigen, showioxidase, original magnification �400). B, Positivity for vimeperoxidase, original magnification �200). C, Strong positineoplastic cells (immunoperoxidase, original magnification �cells (immunoperoxidase, original magnification �400).

evidence of pacinian differentiation, and with the pres-

ence of adipocytic component, described respectivelyas “sclerosing pacinian-like perineurioma”8 and a “cu-taneous lipomatous sclerosing perineurioma,”12 havealso been reported. Similarly to the current case, thereare no mitoses in SP reported in the literature; however,there are other variants of soft tissue perineurioma thatpresent with mitoses.

The perivascular distribution of neoplastic cells is acommon histologic aspect, and it likely occurs becauseof the nutrition supply given by the blood vessel. Thepresent case was associated with inflammatory cellsand infiltration of muscular tissue by the neoplasticcells and sclerotic tissue. The neoplastic cells may befound isolated or arranged in cellular nests with onionbulb–like structures or presenting a whorled growthpattern. These onion bulb–like structures are helpful forthe diagnosis of perineurioma affecting the oral cavity.

whorled growth pattern similar to onion skins (immunoper-the neoplastic cells, showing a storiform pattern (immuno-

r human erythrocyte glucose transporter 1 in the nests of, Positivity for claudin-1 in a membrane pattern of neoplastic

ng thentin in

vity fo400). D

These cells are small, plump, and spindle-shaped or


epithelioid with indistinct cell borders. The abundantcollagen fibers in the stroma and the nuclear and nu-cleolar features and the absence of cellular pleomor-phism, atypical mitoses, or necrosis are observed in theextraoral cases.3,5 The present case showed very similarhistologic features.

The main histologic differential diagnoses includedcollagenized neurofibroma, myoepithelioma, submu-cous nevus, giant cell angiofibroma, collagenized fi-broma, and sclerotic fibroma. The differential diagnosisin extremities includes fibroma of the tendon sheath,fibrosing tenosynovial giant cell tumor, and Mortonneuroma. However, because the present case was in-traoral, the differential diagnosis also included glomustumor, epithelioid neurofibroma, traumatic neuroma,schwannoma, epithelioid hemangioendothelioma, pleo-morphic fibroma, myofibroma, melanocytic nevus, des-

Fig.4. A, Positivity for CD34 in the stromal fusiform cells; ncells (immunoperoxidase, original magnification �200). B, Postromal cells (immunoperoxidase, original magnification �40(immunoperoxidase, original magnification �400). D, Positiv(immunoperoxidase, original magnification �400).

moplastic fibroblastoma, and sclerosing pyogenic gran-

uloma3-6,21,23 Because these tumors may have similarhistologic features, immunohistochemistry is essentialto establish the diagnosis. Collagenized and epithelioidneurofibroma, traumatic neuroma, schwannoma, sub-mucous, and melanocytic nevus are S-100 positive.Myoepithelioma is positive for cytokeratin and smoothmuscle actin. Glomus tumor and myofibroma are alsopositive for smooth muscle actin. In giant cell angiofi-bromas, in addition to the presence of giant cells, theneoplastic cells are immunoreactive for CD34. Epithe-lioid hemangioendothelioma is also positive for CD34.Desmoplastic fibroblastoma, and collagenized, scle-rotic and pleomorphic fibroma are not immunoreactivefor EMA. The perineurial cells show a characteristicpattern of positivity for EMA and negativity for S-100.The immunoprofile of the neoplastic cells seen in thepresent case is consistent with perineurial differentia-

internal control and the negativity in the nests of neoplasticy for CD10 in the neoplastic cells; note the positivity in somePositivity for CD99 in fusiform stromal and neoplastic cells�-catenin in a membrane pattern only in the neoplastic cells

ote thesitivit0). C,ity for

tion.3-6,8,24

NF1 2F11 Dako 1:100 �

Present case, 2010 1 26

Present case, 2010 26/M Lower li


However, because EMA and S-100 expression canbe found in other mesenchymal neoplasms, staining for2 additional recently reported markers, claudin-1 andGLUT-1, might be useful in supporting the diagnosis ofperineurioma.4,24,25 Yamaguchi et al. used GLUT-1 inthe immunohistochemical panel of 5 cases of SP, andaffirmed that this maker is helpful for diagnosing SP.Although positivity for CD10 was observed in all cases,they reported that it is not very specific for the diagno-sis of SP.4 Brock et al. reported positivity for GLUT-1in all types of perineurioma with strong cytoplasmicmembrane staining.10 Another marker used in the immu-nohistochemical characterization of perineuriomas is clau-din-1 with a diffuse membranous staining.10,14,25,26 Im-munoreactivity for CD99 was also demonstrated in somecases, which confirms the perineurial differentiation of theneoplastic cells.15 The present case had similar results,showing positivity for GLUT-1, claudin-1, CD10, andCD99.

�-Catenin binds to membrane-associated E-cadherinthat maintains intercellular adhesiveness. �-Catenin is

resent case)rs) Gender(s) Location(s) Size range (mm)

14M/5F Finger/palm 7-33F Finger 8F Finger 5F Finger 10M Finger/palm 10-251M/1F Finger 7-104M/1F Finger/palm 12-40F Axilla 653F Finger/palm/foot 3-401M/1F Finger 7-101M/1F Finger/palm NAF Finger 10F Finger 14F Palm/forearm 3-6M Oral mucosa 20

ing the oral cavityite Size (mm) Histologic subtype

e 25 Unknown40 Extraneural, reticular variant7.5 Intraneural

ial area 20 Extraneurale 20 Intraneural

6 Intraneural10 Intraneural

p 5 Intraneural

Table I. Immunohistochemical informationPrimary antibody Clone Company Dilution Result

EMA E 29 Dako 1:400 �Vimentin Vim3B4 Dako 1:400 �GLUT-1 Polyclonal DBS 1:100 �Claudin-1 Polyclonal DBS 1:100 �CD10 56C6 DBS 1:20 �CD99 12E7 Dako 1:100 ��-Catenin 17C2 Novocastra 1:200 �CD34 QBEnd 10 Dako 1:50 �S-100 Polyclonal Dako 1:100,000 �D2-40 D2-40 Dako 1:100 �CK8 35 �H11 Dako 1:200 �CK18 DC10 Dako 1:200 �CK7 OV-TL12/30 Dako 1:300 �CK14 LL002 Novocastra 1:200 �Chromogranin Polyclonal Dako 1:80 �Synaptophysin SY38-1 Dako 1:100 �Smooth muscle actin 1A4 Dako 1:400 �E-Cadherin NCH-38 Dako 1:200 �CD56 CD56-1B6 Novocastra 1:50 �CD57 NK1 Dako 1:1,300 �CD138 My15 Dako 1:100 �AE1/AE3 AE1/AE3 Dako 1:50 �

Table II. Sclerosing perineuriomas (n � 42, including the pAuthor, year No. of cases Age range (y

Fetsch and Miettinen, 19972 19 9-55Sciot et al., 19999 1 15Robson and Calonje, 200011 1 67Burgues et al., 20018 1 21Huang and Sung, 20023 1 16Canales-Ibarra et al., 200315 2 9-18Yamaguchi et al., 20034 5 11-49Lee at al., 20047 1 36Rankine et al., 200414 3 42-58Brock et al., 200510 2 7-15Miyake et al., 20066 2 11-16Nakamura et al., 200613 1 11Macarenco and Macarenco, 200812 1 39Rubin et al., 20095 1 21

Table III. Previously reported cases of perineuriomas affectAuthor, year Age (yrs)/gender S

Kusama et al., 198116 31/F MandiblGraadt van Roggen et al., 200117 42/F GingivaDamm et al., 200318 26/F TongueMeer et al., 200319 46/F NasolabHuguet et al., 200420 64/M MandiblPerez et al., 200621 12/M TongueRocha et al., 200922 47/F Tongue

37/M Lower li
p mucosa 20 Extraneural, sclerosing variant


the major effector of the canonical Wnt signaling path-way. Mutations in components of Wnt signaling path-way stabilize �-catenin, which dislocates to the nu-cleus and causes the constitutive activation of TCF/LEF1 gene transcription and expression of c-myc,tcf1, and cyclin D1 genes.27,28 In the present case,�-catenin was positive only at the membrane, whichprobably indicates that this molecule is not impli-cated in the tumorigenesis of SP.27 To our knowl-edge, the expression of �-catenin in perineuriomahas not been described.

The positive staining for CD34 in fibroblastic cells inthe stroma of peripheral nerve sheath tumors is similarto the staining pattern of the present case. The immu-noreactive cells for CD34 are often seen and wereidentified as mesenchymal cells or endoneurial fibro-blasts at the periphery of the lesion and in sclerotic ar-eas.24,26,29 CD10 was originally a specific marker foracute lymphoblastic leukemia, but its expression has beendescribed in other tumors, including mesenchymal skintumors, such as dermatofibroma, dermatofibrosarcomaprotuberans, neurofibroma, and atypical fibroma.29-31

CD99 has been reported in Ewing sarcoma, peripheralneuroectodermal tumors, and some lymphomas, and it hasbeen used as mesenchymal stem cell marker.32,33 Mutualassociations between nerves and mast cells have beenobserved. The positivity for mast cells could be attrib-uted to their participation in signaling pathways be-tween neoplastic and inflammatory cells. Mast cellshave been also associated with angiogenesis and tumorgrowth.34

There are studies that noted membranous immuno-reactivity for collagen type IV around the perineurialcells and positivity for CD10.4 Abnormalities of chro-mosomes 10 and 22 have been observed in SP.9,10

Ultrastructural study could be useful for diagnosing SP,but it has been used only in a few cases.4 Although SPis a poorly recognized tumor and its occurrence in theoral cavity has not been described, the present caseindicates that the clinicians should consider SP as apossible differential diagnosis for a nontender nodule inoral mucosa with histopathologic features of a benigntumor presenting perineurial cells.

REFERENCES1. Lazarus SS, Trombetta LD. Ultrastructural identification of a

benign perineural cell tumor. Cancer 1978;41:1823-9.2. Fetsch JF, Miettinen M. Sclerosing perineurioma: a clinicopath-

ologic study of 19 cases of a distinctive soft tissue lesion with apredilection for the fingers and palms of young adults. Am J SurgPathol 1997;21:1433-42.

3. Huang HY, Sung MT. Sclerosing perineuriomas affecting bilat-eral hands. Br J Dermatol 2002;146:129-33.

4. Yamaguchi U, Hasegawa T, Hirose T, Fugo K, Mitsuhashi T,
Shimizu M, et al. Sclerosing perineurioma: a clinicopathological
study of five cases and diagnostic utility of immunohistochemicalstaining for GLUT1. Virchows Arch 2003;443:159-63.

5. Rubin AI, Yassaee M, Johnson W, Elenitsas R, Zaladonis J Jr,Seykora JT. Multiple cutaneous sclerosing perineuriomas: anextensive presentation with involvement of the bilateral upperextremities. J Cutan Pathol 2009;36:60-5.

6. Miyake M, Tateishi U, Maeda T, Arai Y, Seki K, Hasegawa T,et al. Sclerosing perineurioma: tumor of the hand with a short T2.Skeletal Radiol 2006;35:543-6.

7. Lee LH, Bos GD, Marsh WL Jr, Wakely PE Jr. Fine-needleaspiration cytology of sclerosing perineurioma. Ann DiagnPathol 2004;8:80-6.

8. Burgues O, Monteagudo C, Noguera R, Revert A, Molina I,Llombart-Bosch A. Cutaneous sclerosing pacinian-like perineu-rioma. Histopathology 2001;39:498-502.

9. Sciot R, Cin PD, Hagemeijer A, De Smet L, Van Damme B, Vanden Berghe H. Cutaneous sclerosing perineurioma with crypticNF2 gene deletion. Am J Surg Pathol 1999;23:849-53.

10. Brock JE, Perez-Atayde AR, Kozakewich HP, Richkind KE,Fletcher JA, Vargas SO. Cytogenetic aberrations in perineurioma:variation with subtype. Am J Surg Pathol 2005;29:1164-9.

11. Robson AM, Calonje E. Cutaneous perineurioma: a poorly rec-ognized tumour often misdiagnosed as epithelioid histiocytoma.Histopathology 2000;37:332-9.

12. Macarenco AC, Macarenco RS. Cutaneous lipomatous scleros-ing perineurioma. Am J Dermatopathol 2008;30:291-4.

13. Nakamura T, Kawamura T, Nariya S, Fujiwara M. Cutaneoussclerosing perineurioma of the digit. Int J Dermatol 2006;45:1086-8.

14. Rankine AJ, Filion PR, Platten MA, Spagnolo DV. Perineu-rioma: a clinicopathological study of eight cases. Pathology2004;36:309-15.

15. Canales-Ibarra C, Magarinos G, Olsoff-Pagovich P, Ortiz-Hidalgo C. Cutaneous sclerosing perineurioma of the digits: anuncommon soft-tissue neoplasm. Report of two cases with im-munohistochemical analysis. J Cutan Pathol 2003;30:577-81.

16. Kusama K, Iwamoto A, Mikuni M, Komagamine M, Suzuki T,Yamamura J, et al. A case of central perineurioma (Lazarus andTrombetta) of the mandible. J Nihon Univ Sch Dent 1981;23:10-7.

17. Graadt van Roggen JF, McMenamin ME, Belchis DA, NielsenGP, Rosenberg AE, Fletcher CD. Reticular perineurioma: a dis-tinctive variant of soft tissue perineurioma. Am J Surg Pathol2001;25:485-93.

18. Damm DD, White DK, Merrell JD. Intraneural perineurioma—not restricted to major nerves. Oral Surg Oral Med Oral PatholOral Radiol Endod 2003;96:192-6.

19. Meer S, Coleman H, Altini M. Intraoral perineurioma: report ofa case with a review of the literature. Oral Dis 2003;9:99-103.

20. Huguet P, de la Torre J, Pallarès J, Carrera M, Soler F, EspinetB, et al. Intraosseous intraneural perineurioma: report of a casewith morphological, immunohistochemical and FISH study. MedOral 2004;9:64-8.

21. Perez DAC, Aguiar FCA, Leon JE, Graner E, Paes de AlmeidaO, Vargas PA. Intraneural Perineurioma of the tongue: a casereport. J Oral Maxillofac Surg 2006;64:1140-2.

22. Rocha LA, Lopes SM, Silva AR, Lopes MA, Vargas PA. Oralintraneural perineurioma. Report of two cases. Clinics2009;64:1037-9.

23. de Andrade CR, Lopes MA, de Almeida OP, León JE, Mistro F,Kignel S. Giant cell angiofibroma of the oral cavity: a case reportand review of the literature. Med Oral Patol Oral Cir Bucal 2008;13:E540-3.

24. Hirose T, Tani T, Shimada T, Ishizawa K, Shimada S, Sano T.Immunohistochemical demonstration of EMA/Glut1-positiveperineurial cells and CD34-positive fibroblastic cells in periph-
eral nerve sheath tumors. Mod Pathol 2003;16:293-8.


25. Folpe AL, Billings SD, McKenney JK. Walsh SV, Nusrat A, WeissSW. Expression of claudin-1, a recently described tight junction-associated protein, distinguishes soft tissue perineurioma from po-tential mimics. Am J Surg Pathol 2002;26:1620-6.

26. Hornick JL, Fletcher CD. Soft tissue perineurioma: clinicopath-ologic analysis of 81 cases including those with atypical histo-logic features. Am J Surg Pathol 2005;29:845-58.

27. Kumamoto H, Ooya K. Immunohistochemical detection of beta-catenin and adenomatous polyposis coli in ameloblastomas.J Oral Pathol Med 2005;34:401-6.

28. Montgomery E, Folpe AL. The diagnostic value of beta-cateninimmunohistochemistry. Adv Anat Pathol 2005;12:350-6.

29. Poblet E, Jiménez F. CD10 and CD34 in fetal and adult humanhair follicles: dynamic changes in their immunohistochemicalexpression during embryogenesis and hair cycling. Br J Dermatol2008;159:646-52.

30. Perna AG, Smith MJ, Krishnan B, Reed JA. CD10 is expressedin cutaneous clear cell lesions of different histogenesis. J CutanPathol 2005;32:348-51.

31. Hultgren TL, DiMaio DJ. Immunohistochemical staining of
CD10 in atypical fibroxanthomas. J Cutan Pathol 2007;34:415-9.
32. Kovar H, Bernard A. CD99-positive “Ewing’s sarcoma” frommouse-bone marrow-derived mesenchymal progenitor cells?Cancer Res 2005;65:11459-68.

33. Burns JS, Abdallah BM, Schrøder HD, Kassem M. The histopa-thology of a human mesenchymal stem cell experimental tumormodel: support for an hMSC origin for Ewing’s sarcoma? HistolHistopathol 2008;23:1229-40.

34. Ribatti D, Crivellato E, Roccaro AM, Ria R, Vacca A. Mast cellcontribution to angiogenesis related to tumour progression. ClinExp Allergy 2004;34:1660-4.

Reprint requests:

Márcio Ajudarte LopesÁrea de SemiologiaFaculdade de Odontologia de Piracicaba–UNICAMPAv. Limeira, 901, Bairro AreãoPiracicaba, São PauloBrazilCEP: 13.414-903
[email protected]
mailto:[email protected]

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