Skip to main content

Advertisement

Log in

Diagnostic value of neutrophil gelatinase-associated lipocalin (NGAL) immunoexpression in follicular-patterned lesions of the thyroid gland

  • Original Article
  • Published:
Virchows Archiv Aims and scope Submit manuscript

Abstract

Neutrophil gelatinase-associated lipocalin (NGAL) is a protein which participates in iron trafficking and which is involved in cancerogenesis and cancer progression. Since its over-expression has been documented in thyroid malignancies in comparison to thyroid normal gland, in the present study, we aimed to determine whether the evaluation of NGAL immunoexpression may be of help in the differential diagnosis of follicular-patterned thyroid lesions. Our additional aim was to test the possible interference of endogenous biotin on the immunohistochemical findings. Thus, all the immunohistochemical procedures, carried out with labeled streptavidin biotin method, were doubly performed, with or without the preliminary inhibition of endogenous biotin. No NGAL staining was found in the normal thyroid gland nor in the nodular colloid goiters or in Hashimoto's thyroiditis. NGAL expression appeared to be significantly more frequent in the malignant tumors in comparison to benign ones (P < 0.000001). Even more, NGAL expression appeared to be specific (specificity 93%) for carcinoma and represented a sensitive method (sensitivity 84%), with high negative (88%) and positive (94%) predictive values, as well as high diagnostic accuracy (88%), in the identification of follicular-patterned thyroid malignant tumors. The specificity, positive predictive value and diagnostic accuracy lowered when biotin was not preliminary inhibited, due to the presence of false positives among benign Hürthle cell tumors. In conclusion, the immunohistochemical detection of NGAL may be helpful in the differential diagnosis between malignant and benign follicular-patterned lesions of the thyroid. The use of biotin free system or the preliminary biotin inhibition is warranted for the detection of NGAL in thyroid samples, especially when dealing with Hürthle cell tumors.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Yang J, Goetz D, Li JY et al (2002) An iron delivery pathway mediated by a lipocalin. Mol Cell 10:1045–1056

    Article  PubMed  CAS  Google Scholar 

  2. Goetz DH, Willie ST, Arme RS et al (2000) Ligand preference inferred from the structure of neutrophil gelatinase associated lipocalin. Biochemistry 39:1935–1941

    Article  PubMed  CAS  Google Scholar 

  3. Bauer M, Eickhoff JC, Gould MN et al (2008) Neutrophil gelatinase- associated lipocalin (NGAL) is a predictor of poor prognosis in human primary breast cancer. Breast Cancer Res Treat 108:389–397

    Article  PubMed  CAS  Google Scholar 

  4. Iannetti A, Pacifico F, Acquaviva R et al (2008) The neutrophil gelatinase-associated lipocalin (NGAL), a NF-kappaB-regulated gene, is a survival factor for thyroid neoplastic cells. Proc Natl Acad Sci U S A 105:14058–14063

    Article  PubMed  CAS  Google Scholar 

  5. Barresi V, Ieni A, Bolignano D et al (2010) Neutrophil gelatinase-associated lipocalin immunoexpression in renal tumors: correlation with histotype and histological grade. Oncol Rep 24:305–310

    Article  PubMed  Google Scholar 

  6. Barresi V, Lucianò R, Vitarelli E et al (2010) Neutrophil gelatinase-associated lipocalin immunoexpression in colorectal carcinoma: a stage-specific prognostic factor? Oncol Lett 1:1089–1096

    Article  Google Scholar 

  7. Barresi V, Tuccari G, Barresi G (2010) NGAL immunohistochemical expression in brain primary and metastatic tumors. Clin Neuropathol 29:317–322

    PubMed  CAS  Google Scholar 

  8. Barresi V, Di Gregorio C, Regiani-Bonetti L et al (2011) Neutrophil gelatinase-associated lipocalin (NGAL): a new prognostic marker in stage I colorectal carcinoma? Hum Pathol 42:1720–1726

    Article  PubMed  CAS  Google Scholar 

  9. Bratt T (2000) Lipocalins and cancer. Biochim Biophys Acta 1482:318–326

    Article  PubMed  CAS  Google Scholar 

  10. Devireddy LR, Gazin C, Zhu X et al (2005) A cell-surface receptor for lipocalin 24p3 selectively mediates apoptosis and iron uptake. Cell 23:1293–1305

    Article  Google Scholar 

  11. Le NT, Richardson DR (2002) The role of iron in cell cycle progression and the proliferation of neoplastic cells. Biochim Biophys Acta 1603:3146

    Google Scholar 

  12. Yan L, Borregaard N, Kjeldsen L et al (2001) The high molecular weight urinary matrix metalloproteinase (MMP) activity is a complex of gelatinase B/MMP-9 and neutrophil gelatinase-associated lipocalin (NGAL). Modulation of MMP-9 activity by NGAL. J Biol Chem 276:37258–37265

    Article  PubMed  CAS  Google Scholar 

  13. Hu L, Hittelman W, Lu T et al (2009) NGAL decreases E-cadherin-mediated cell–cell adhesion and increases cell motility and invasion through Rac1 in colon carcinoma cells. Lab Invest 89:531–548

    Article  PubMed  CAS  Google Scholar 

  14. Barresi V, Ieni A, Tuccari G et al (2012) Neutrophil gelatinase-associated lipocalin (NGAL) immunohistochemical expression in follicular cell-derived thyroid tumors: a novel diagnostic tool? Histol Histopathol (in press)

  15. Bussolati G, Gugliotta P, Volante M et al (1997) Retrieved endogenous biotin: a novel marker and a potential pitfall in diagnostic immunohistochemistry. Histopathology 31:400–407

    Article  PubMed  CAS  Google Scholar 

  16. Nikiel B, Chekan M, Jarzab M et al (2009) Endogenous avidin biotin activity (EABA) in thyroid pathology: immunohistochemical study. Thyroid Res 2:5

    Article  PubMed  Google Scholar 

  17. De Lellis RA, Lloyd RV, Heitz PU et al (2004) Pathology and genetics of tumours of endocrine organs. IARC Press, Lyon

    Google Scholar 

  18. Livolsi VA, Baloch ZW (2011) Follicular-patterned tumors of the thyroid: the battle of benign vs. malignant vs. so-called uncertain. Endocr Pathol 22:184–189

    Article  PubMed  Google Scholar 

  19. Hirokawa M, Carney JA, Goellner JR et al (2002) Observer variation of encapsulated follicular lesions of the thyroid gland. Am J Surg Pathol 26:1508–1514

    Article  PubMed  Google Scholar 

  20. Elsheikh TM, Asa SL, Chan JK et al (2008) Interobserver and intraobserver variation among experts in the diagnosis of thyroid follicular lesions with borderline nuclear features of papillary carcinoma. Am J Clin Pathol 130:736–744

    Article  PubMed  Google Scholar 

  21. Sahoo S, Hoda SA, Rosai J et al (2001) Cytokeratin 19 immunoreactivity in the diagnosis of papillary thyroid carcinoma: a note of caution. Am J Clin Pathol 116:696–702

    Article  PubMed  CAS  Google Scholar 

  22. Herrmann ME, LiVolsi VA, Pasha TL et al (2002) Immunohistochemical expression of galectin-3 in benign and malignant thyroid lesions. Arch Pathol Lab Med 126:710–713

    PubMed  CAS  Google Scholar 

  23. Erickson LA, Lloyd RV (2004) Practical markers used in the diagnosis of endocrine tumors. Adv Anat Pathol 11:175–189

    Article  PubMed  CAS  Google Scholar 

  24. Prasad ML, Pellegata NS, Huang Y et al (2005) Galectin-3, fibronectin-1, CITED-1, HBME1 and cytokeratin-19 immunohistochemistry is useful for the differential diagnosis of thyroid tumors. Mod Pathol 18:48–57

    Article  PubMed  CAS  Google Scholar 

  25. Cho Mar K, Eimoto T, Tateyama H et al (2006) Expression of matrix metalloproteinases in benign and malignant follicular thyroid lesions. Histopathology 48:286–294

    Article  PubMed  CAS  Google Scholar 

  26. Cho Mar K, Eimoto T, Nagaya S et al (2006) Cell proliferation marker MCM2, but not Ki67, is helpful for distinguishing between minimally invasive follicular carcinoma and follicular adenoma of the thyroid. Histopathology 48:801–807

    Article  PubMed  CAS  Google Scholar 

  27. Barroeta JE, Baloch ZW, Lal P et al (2006) Diagnostic value of differential expression of CK19, Galectin-3, HBME-1, ERK, RET, and p16 in benign and malignant follicular-derived lesions of the thyroid: an immunohistochemical tissue microarray analysis. Endocr Pathol 17:225–234

    Article  PubMed  CAS  Google Scholar 

  28. El Demellawy D, Nasr A, Alowami S (2008) Application of CD56, P63 and CK19 immunohistochemistry in the diagnosis of papillary carcinoma of the thyroid. Diagn Pathol 3:5

    Article  PubMed  Google Scholar 

  29. Buergy D, Weber T, Maurer GD et al (2009) Urokinase receptor, MMP-1 and MMP-9 are markers to differentiate prognosis, adenoma and carcinoma in thyroid malignancies. Int J Cancer 125:894–901

    Article  PubMed  CAS  Google Scholar 

  30. Saleh HA, Jin B, Barnwell J et al (2010) Utility of immunohistochemical markers in differentiating benign from malignant follicular-derived thyroid nodules. Diagn Pathol 26:5–9

    Google Scholar 

  31. Fernandez CA, Yan L, Louis G et al (2005) The matrix metallo-proteinase-9/neutrophil gelatinase associated lipocalin complex plays a role in breast tumor growth and is present in the urine of breast cancer patients. Clin Cancer Res 11:5390–5395

    Article  PubMed  CAS  Google Scholar 

  32. Lee S, Jilani SM, Nikolova GV et al (2005) Processing of VEGF-A by matrix metalloproteinases regulates bioavailability and vascular patterning in tumors. J Cell Biol 169:681–691

    Article  PubMed  CAS  Google Scholar 

  33. Kim SH, Jung KC, Shin YK et al (2002) The enhanced reactivity of endogenous biotin-like molecules by antigen retrieval procedures and signal amplification with tyramine. Histochem J 34:97–103

    Article  PubMed  CAS  Google Scholar 

  34. Rosai J, Kuhn E, Carcangiu ML (2006) Pitfalls in thyroid tumour pathology. Histopathology 49:107–120

    Article  PubMed  CAS  Google Scholar 

Download references

Conflict of interest statement

We declare that we have no conflict of interest.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Valeria Barresi.

Additional information

Dedicated to my father, Gaetano Barresi, who left us on the 14th of February 2012, a great researcher, but above all a great man.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Barresi, V., Vitarelli, E., Reggiani Bonetti, L. et al. Diagnostic value of neutrophil gelatinase-associated lipocalin (NGAL) immunoexpression in follicular-patterned lesions of the thyroid gland. Virchows Arch 460, 319–325 (2012). https://doi.org/10.1007/s00428-012-1208-0

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00428-012-1208-0

Keywords

Navigation