Utility of Nestin immunohistochemistry in the diagnosis of granular cell tumor

Abstract

Aim: Granular cell tumors (GCTs) show neuroectodermal differentiation. Morphologically, a wide variety of mesencymal tumors may have granular cell appearance. Nestin, which is an intermediate filament protein expressed in undifferentiated cells during central nerves system development and its tumors. We aim to determine the diagnostic utility of Nestin in diagnosis of GCTs. 

Methods:  Nestin immunohistochemistry applied to GCT cases and other mesenchymal tumors which may have granular cytoplasm and the major differential diagnostic consideration of GCT.  A total of 21 GCT from different tissues (including 7 in the esophagus, 8 originating from skin tissues, 4 in the tongue, 2 in the vocal cord), 17 gastrointestinal stromal tumor  in the gastrointestinal tract, 8 leiomyoma (5 in the esophagus and 3 originating from skin tissues), 4 schwannoma (1 in the esophagus and 3 originating from skin tissues),  subcutaneous mesenchymal tumors ( including 7 neurofibroma, 5 fibroma, 15 dermatofibroma), 20 melanocytic nevi, 15 gastric xanthomas and 15 xanthalesma of the skin were included the study.

Results: Nestin positivity was detected in all GCTs. Additionally, strong Nestin positivity was seen in all gastrointestinal stromal tumors, schwannoma and neurofibroma cases. However, Nestin was negative in all leiomyoma, fibroma, dermatofibroma, melanocytic nevi, gastric xanthoma and xanthalesma cases. 

Conclusion:  The study showed that Nestin immunohistochemistry has limitation in distinction of GCT from tumors arising from neural cell lineage such as gastrointestinal stromal tumor, schwannoma and neurofibroma; however, Nestin as a neural marker provides an evidence to neural origin of GCT and could be useful in distinction GCT from other mesenchymal tumors with granular cytoplasm such as leiomyoma, dermatofibroma and melanocytic nevi.

Keywords

• Nestin,granular cell tumor,neural origin

Granüler hücreli tümör tanısında Nestin immunhistokimyasının kullanımı

Öz

Amaç: Granüler hücreli tümorler (GCTs) nöroektodermal diferansiasyon gösterirler. Morfolojik olarak pek çok mezenkimal tümor, granüler hücreli görünüme sahip olabilir. Nestin, santral sinir sistemi gelişimi boyunca undiferansiye hücrelerde ve santral sinir sistemi tümörlerinde eksprese edilen bir intermediate filament proteindir. Çalışmamızda Nestin proteininin granüler hücreli tümör ayırıcı tanısında kullanılabilirliğinin belirlenmesi amaçlanmıştır.

Yöntemler: Çalışmamızda GCT tümör olguları ve granüler sitoplazmaya sahip olabilecek ve granüler hücreli tümör ayırıcı tanısında başlıca ele alınan mezenkimal tümörlere immunhistokimyasal olarak Nestin antikoru uygulanmıştır.  Farklı dokulardan köken alan 21 GCT (7’si özofagus, 8’i deri,  4’ü dil,  2’si vokal korddan gelişen ) , 17 GIST (gastrointestinal stromal tumor- gastrointestinal kanaldan gelişen) , 8 leiomyoma ( 5’i özofagus,  3’ü deriden gelişen), 4 schwannoma  (1’i özofagus, 3’ü deri yerleşimli) ve subkutan yerleşimli mesenkimal tümörler (7 nörofibroma, 5 fibroma, 15 dermatofibroma)  ile 20 melanositik nevüs,  15 gastrik ksantom ve 15 ksantalezma olgusu çalışmamıza dahil edilmiştir.

Bulgular: GCT’lerin tamamında Nestin pozitifliği görüldü. Ayrıca tüm GIST’ler,  schwannoma ve nörofibromada Nestin pozitif olarak izlendi.   Bununla birlikte tüm leiomyoma, fibroma,  dermatofibroma,  melanositik nevüs, gastrik ksantom ve  ksantalezmada  olgularında  Nestin ekspresyonu görülmedi.

Sonuç: Çalışmamız Nestin immunhistokimyasının GCT’ün ayırıcı tanısında özellikle GIST, Schwannoma ve nörofibroma gibi nöral orijinli tümörlerde sınırlı olduğunu göstermektedir. Bununla birlikte nöral bir marker olan Nestin GCT’ün nöral kökenine dair bir kanıt sunmaktadır.  Nestin, GCT ‘ün granüler sitoplazmaya sahip leiomyoma, dermatofibroma gibi diğer mezenkimal tümörler ve melanositik nevüsden ayırımında kullanılabilir.

Anahtar Kelimeler

• nestin,granüler hücreli tümör,nöral orijin

Kaynakça

1. 1- Di Tommaso L, Magrini E, Consales A, Poppi M, Pasquinelli G, Dorji T, et al. Malignant granular cell tumor of the lateral femoral cutaneous nerve: report of a case with cytogenetic analysis. Hum Pathol. 2002;33:1237-40.
2. 2- Cardis MA, Ni J, Bhawan J. Granular cell differentiation: A review of the published work.J Dermatol. 2017;44:251-58.
3. 3-Stefansson K, Wollmann RL.S-100 protein in granular cell tumors (granular cell myoblastomas). Cancer. 1982;49:1834-8.
4. 4-Armin A, Connelly EM, Rowden G.An immunoperoxidase investigation of S-100 protein in granular cell myoblastomas: evidence for Schwann cell derivation. Am J Clin Pathol. 1983;79:37-44.
5. 5- Filie AC, Lage JM, Azumi N, Immunoreactivity of S100 protein, alpha-1-antitrypsin, and CD68 in adult and congenital granular cell tumors. Mod Pathol.1996;9:888-92.
6. 6- Parfitt JR, McLean CA, Joseph MG, Streutker CJ, Al-Haddad S, Driman DK. Granular cell tumours of the gastrointestinal tract: expression of Nestin and clinicopathological evaluation of 11 patients. Histopathology. 2006;48:424-30
7. 7- Singhi AD, Montgomery EA. Colorectal granular cell tumour: a clinicopathologic study of 26 cases. Am J Surg Pathol. 2010;34:1186-92.
8. 8-Kishaba Y, Matsubara D, Niki T. Heterogeneous expression of nestin in myofibroblasts of various human tissues. Pathol Int. 2010;60:378-85.

9. 9-Sugawara K, Kurihara H, Negishi M, Saito N, Nakazato Y, Sasaki T, et al. Nestin as a marker for proliferative endothelium in gliomas. Lab Invest. 2002;82:345-51.
10. 10- Bhattacharyya I, Summerlin DJ, Cohen DM, Ellis GL, Bavitz JB, Gillham LL. Granular cell leiomyoma of the oral cavity. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2006;102:353–9.
11. 11- Sarlomo-Rikala M, Tsujimura T, Lendahl U, Miettinen M, Patterns of Nestin and other intermediate filament expression distinguish between gastrointestinal stromal tumors, leiomyomas and schwannomas. APMIS. 2002;110:499-507.
12. 12- Shintaku M. Immunohistochemical localization of autophagosomal membrane-associated protein LC3 in granular cell tumor and schwannoma. Virchows Arch. 2011;459:315–9
13. 13-Mentzel T, Wadden C, Fletcher CD. Granular cell change in smooth muscle tumours of skin and soft tissue. Histopathology. 1994;24:223-31.
14. 14-Dobashi Y, Iwabuchi K, Nakahata J, Yanagimoto K, Kameya T. Combined clear and granular cell leiomyoma of soft tissue: evidence of transformation to a histiocytic phenotype. Histopathology. 1999;34:526-31.
15. 15- El-Gamal HM, Robinson-Bostom L, Saddler KD, Pan T, Mihm MC. Compound melanocytic nevi with granular cell changes. Am Acad Dermatol. 2004;50:765–6
16. 16- Tsujimura T, Makiishi-Shimobayashi C, Lundkvist J, Lendahl U, Nakasho K, Sugihara A, et al.Expression of the intermediate filament nestin in gastrointestinal stromal tumors and interstitial cells of Cajal. Am J Pathol. 2001;158:817-23.
17. 17-Hou YY, Tan YS, Xu JF, Wang XN, Lu SH, Ji Y, et al. Schwannoma of the gastrointestinal tract: a clinicopathological, immunohistochemical and ultrastructural study of 33 cases. Histopathology. 2006;48:536-45.
18. 18- Shimada S, Tsuzuki T, Kuroda M, Nagasaka T, Hara K, Takahashi E, et al. Nestin expression as a new marker in malignant peripheral nerve sheath tumors. Pathol Int. 2007;57:60-7.
19. 19- Zimmerman L, Parr B, Lendahl U, Cunningham M, McKay R, Gavin B, et al. Independent regulatory elements in the nestin gene direct transgene expression to neural stem cells or muscle precursors. Neuron. 1994;12:11–24.
20. 20- Kachinsky AM, Dominov JA, Miller JB. Myogenesis and the intermediate filament protein, nestin. Dev Biol. 1994;165:216–28.
21. 21- Sejersen T, Lendahl U. Transient expression of the intermediate filament nestin during skeletal muscle development. J Cell Sci.1993;106:1291–300.
22. 22- Brychtova S, Fiuraskova M, Hlobilková A, Brychta T, Hirnak J. Nestin expression in cutaneous melanomas and melanocytic nevi. J Cutan Pathol. 2007;34:370-5.
23. 23- Laga AC, Zhan Q, Weishaupt C, Ma J, Frank MH, Murphy GF. SOX2 and nestin expression in human melanoma: an immunohistochemical and experimental study. Exp Dermatol. 2011;20:339-45.
24. 24- Mori T, Misago N, Yamamoto O, Toda S, Narisawa Y.Expression of nestin in dermatofibrosarcoma protuberans in comparison to dermatofibroma. J Dermatol. 2008;35:419-25.
25. 25- Bellezza G, Colella R, Sidoni A, Del Sordo R, Ferri I, Cioccoloni C, et al. Immunohistochemical expression of Galectin-3 and HBME-1 in granular cell tumors: a new finding. Histol Histopathol. 2008;23:1127-30.
26. 26- Bigotti G, Coli A, Del Vecchio M, Massi G. Evaluation of Galectin-3 expression by sarcomas, pseudosarcomatous and benign lesions of the soft tissues. Preliminary results of an immunohistochemical study. J Exp Clin Cancer Res. 2003;22:255-64.
27. 27- Fine SW, Li M. Expression of calretinin and the alphasubunit of inhibin in granular cell tumors. Am J Clin Pathol. 2003;119:259-64.
28. 28- Le BH, Boyer PJ, Lewis JE, Kapadia SB. Granular cell tumor: immunohistochemical assessment of inhibin-alpha, protein gene product 9.5, S100 protein, CD68, and Ki-67 proliferative index with clinical correlation. Arch Pathol Lab Med. 2004;128:771-75.
29. 29- Andressen C, Blumcke I, Celio MR. Calcium-binding proteins: selective markers of nerve cells. Cell Tissue Res.1993;271:181-208.
30. 30- Hoang MP, Sinkre P, Albores-Saavedra J. Expression of protein gene product 9.5 in epithelioid and conventional malignant peripheral nerve sheath tumors. Arch Pathol Lab Med. 2001;125:1321-25.
31. 31- Mahalingam M, LoPiccolo D, Byers HR. Expression of PGP 9.5 in granular cell nerve sheath tumors. J Cutan Pathol. 2001;28:282-86.
32. 32- Heerema MG, Suurmeijer AJ. Sox10 immunohistochemistry allows the pathologist to differentiate between prototypical granular cell tumors and other granular cell lesions. Histopathology. 2012;61:997-9.
33. 33- Campbell LK, Thomas JR, Lamps LW, Smoller BR, Folpe AL. Protein gene product 9.5 (PGP 9.5) is not a specific marker of neural and nerve sheath tumors: an immunohistochemical study of 95 mesenchymal neoplasms. Mod Pathol. 2003;16:963-69.