Skip to main content
Log in

Parafibromin, Galectin-3, PGP9.5, Ki67, and Cyclin D1: Using an Immunohistochemical Panel to Aid in the Diagnosis of Parathyroid Cancer

  • Published:
World Journal of Surgery Aims and scope Submit manuscript

Abstract

Background

Parathyroid cancer is rare. Differentiating parathyroid carcinoma from degenerative changes at histopathology can be difficult and studies investigating the value of single immunohistochemical markers have had variable results. In this study we aimed to investigate whether a panel of immunohistochemistry markers could aid the diagnosis of parathyroid cancer.

Methods

All cases of parathyroid cancer at our institution from 1998 to 2012 were identified retrospectively. Cases were classified as definite cancers (those with evidence of metastatic spread) or histological cancers (those with features of carcinoma without evidence of metastasis). Controls with benign parathyroid disease were included for comparison. Immunohistochemistry for parafibromin, galectin-3, PGP9.5, Ki67, and cyclin D1 was analysed by an experienced endocrine pathologist.

Results

There were 24 cases and 14 benign adenomas. Four cases had evidence of metastatic spread and 20 were diagnosed on histological criteria alone. Sixteen of the 24 cases had further surgery with ipsilateral thyroid lobectomy and 15 also had a prophylactic level VI lymph node dissection. Apart from one patient with distant metastases at presentation, none developed recurrence at follow-up (median = 38 months). Immunohistochemistry results associated with parathyroid cancer were seen in 11/24 parafibromin, 13/24 galectin-3, 8/24 PGP9.5, 5/24 Ki67, and 2/24 cyclin D1. None of the controls had immunohistochemical staining suggestive of cancer. Nineteen of the 24 patients had at least one immunohistochemical result associated with parathyroid cancer (sensitivity 79 %, specificity 100 %). Cyclin D1 did not suggest malignancy in any case that did not already have another abnormal marker, and so did not add value to the panel in this study.

Conclusion

A panel of immunohistochemistry (PGP9.5, galectin-3, parafibromin, and Ki67) is better than any single marker and can be used to supplement classical histopathology in diagnosing parathyroid cancer.

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.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Lee PK, Jarosek SL, Virnig BA, Evasovich M, Tuttle TM (2007) Trends in the incidence and treatment of parathyroid cancer in the United States. Cancer 109(9):1736–1741

    Article  PubMed  Google Scholar 

  2. Brown S, O’Neill C, Suliburk J, Sidhu S, Sywak M, Gill A et al (2011) Parathyroid carcinoma: increasing incidence and changing presentation. ANZ J Surg 81(7–8):528–532

    Article  PubMed  Google Scholar 

  3. Talat N, Schulte KM (2010) Clinical presentation, staging and long-term evolution of parathyroid cancer. Ann Surg Oncol 17(8):2156–2174

    Article  PubMed  Google Scholar 

  4. Evangelista L, Sorgato N, Torresan F, Boschin IM, Pennelli G, Saladini G et al (2011) FDG-PET/CT and parathyroid carcinoma: review of literature and illustrative case series. World J Clin Oncol 2(10):348–354

    Article  PubMed  PubMed Central  Google Scholar 

  5. Sidhu PS, Talat N, Patel P, Mulholland NJ, Schulte KM (2011) Ultrasound features of malignancy in the preoperative diagnosis of parathyroid cancer: a retrospective analysis of parathyroid tumours larger than 15 mm. Eur Radiol 21(9):1865–1873

    Article  PubMed  Google Scholar 

  6. Horanyi J, Duffek L, Szlavik R, Takacs I, Toth M, Romics L Jr (2010) Intraoperative determination of PTH concentrations in fine needle tissue aspirates to identify parathyroid tissue during parathyroidectomy. World J Surg 34(3):538–543. doi:10.1007/s00268-009-0351-5

    Article  PubMed  Google Scholar 

  7. Wei CH, Harari A (2012) Parathyroid carcinoma: update and guidelines for management. Curr Treat Options Oncol 13(1):11–23

    Article  PubMed  Google Scholar 

  8. Basu A, Sistla SC, Siddaraju N, Verma SK, Iyengar KR, Jagdish S (2008) Needle tract sinus following aspiration biopsy of papillary thyroid carcinoma: a case report. Acta Cytol 52(2):211–214

    Article  PubMed  Google Scholar 

  9. Agarwal G, Dhingra S, Mishra SK, Krishnani N (2006) Implantation of parathyroid carcinoma along fine needle aspiration track. Langenbecks Arch Surg 391(6):623–626

    Article  PubMed  Google Scholar 

  10. Karakas E, Muller HH, Lyadov VK, Luz S, Schneider R, Rothmund M et al (2012) Development of a formula to predict parathyroid carcinoma in patients with primary hyperparathyroidism. World J Surg 36(11):2605–2611. doi:10.1007/s00268-012-1707-9

    Article  PubMed  Google Scholar 

  11. Ippolito G, Palazzo FF, Sebag F, De Micco C, Henry JF (2007) Intraoperative diagnosis and treatment of parathyroid cancer and atypical parathyroid adenoma. Br J Surg 94(5):566–570

    Article  PubMed  CAS  Google Scholar 

  12. Schulte KM, Talat N (2012) Diagnosis and management of parathyroid cancer. Nat Rev Endocrinol 8(10):612–622

    Article  PubMed  CAS  Google Scholar 

  13. Wang CA, Gaz RD (1985) Natural history of parathyroid carcinoma. Diagnosis, treatment, and results. Am J Surg 149(4):522–527

    Article  PubMed  CAS  Google Scholar 

  14. Schulte KM, Talat N, Miell J, Moniz C, Sinha P, Diaz-Cano S (2010) Lymph node involvement and surgical approach in parathyroid cancer. World J Surg 34(11):2611–2620. doi:10.1007/s00268-010-0722-y

    Article  PubMed  Google Scholar 

  15. Cohn K, Silverman M, Corrado J, Sedgewick C (1985) Parathyroid carcinoma: the Lahey Clinic experience. Surgery 98(6):1095–1100

    PubMed  CAS  Google Scholar 

  16. Selvan B, Paul MJ, Seshadri MS, Thomas N, Paul T, Abraham D et al (2013) High index of clinical suspicion with optimal surgical techniques and adjuvant radiotherapy is critical to reduce locoregional disease progression in parathyroid carcinoma. Am J Clin Oncol 36(1):64–69

    Article  PubMed  CAS  Google Scholar 

  17. Okamoto T, Iihara M, Obara T, Tsukada T (2009) Parathyroid carcinoma: etiology, diagnosis, and treatment. World J Surg 33(11):2343–2354. doi:10.1007/s00268-009-9999-0

    Article  PubMed  Google Scholar 

  18. Harari A, Waring A, Fernandez-Ranvier G, Hwang J, Suh I, Mitmaker E et al (2011) Parathyroid carcinoma: a 43-year outcome and survival analysis. J Clin Endocrinol Metab 96(12):3679–3686

    Article  PubMed  CAS  Google Scholar 

  19. Erovic BM, Goldstein DP, Kim D, Mete O, Brierley J, Tsang R et al (2013) Parathyroid cancer: outcome analysis of 16 patients treated at the Princess Margaret Hospital. Head Neck 35(1):35–39

    Article  PubMed  Google Scholar 

  20. Johnson SJ (2010) Changing clinicopathological practice in parathyroid disease. Histopathology 56(7):835–851

    Article  PubMed  Google Scholar 

  21. Johnson SJ, Stephenson T (2010) Dataset for parathyroid cancer histopathology reports: Royal College pathologists. Available at http://www.rcpath.org/publications-media/publications/datasets/parathyroid.htm

  22. Chang YJ, Mittal V, Remine S, Manyam H, Sabir M, Richardson T et al (2006) Correlation between clinical and histological findings in parathyroid tumors suspicious for carcinoma. Am Surg 72(5):419–426

    PubMed  Google Scholar 

  23. Smith JF, Coombs RR (1984) Histological diagnosis of carcinoma of the parathyroid gland. J Clin Pathol 37(12):1370–1378

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  24. Kameyama K, Takami H (2005) Proposal for the histological classification of parathyroid carcinoma. Endocr Pathol 16(1):49–52

    Article  PubMed  Google Scholar 

  25. Rodriguez C, Naderi S, Hans C, Badoual C (2012) Parathyroid carcinoma: a difficult histological diagnosis. Eur Ann Otorhinolaryngol Head Neck Dis 129(3):157–159

    Article  PubMed  CAS  Google Scholar 

  26. DeLellis RA (2004) World Health Organization classification of tumours: pathology and genetics of tumours of endocrine organs. IARC Press, Lyon

    Google Scholar 

  27. Woodard GE, Lin L, Zhang JH, Agarwal SK, Marx SJ, Simonds WF (2005) Parafibromin, product of the hyperparathyroidism-jaw tumor syndrome gene HRPT2, regulates cyclin D1/PRAD1 expression. Oncogene 24(7):1272–1276

    Article  PubMed  CAS  Google Scholar 

  28. Iwata T, Mizusawa N, Taketani Y, Itakura M, Yoshimoto K (2007) Parafibromin tumor suppressor enhances cell growth in the cells expressing SV40 large T antigen. Oncogene 26(42):6176–6183

    Article  PubMed  CAS  Google Scholar 

  29. Tan MH, Morrison C, Wang P, Yang X, Haven CJ, Zhang C et al (2004) Loss of parafibromin immunoreactivity is a distinguishing feature of parathyroid carcinoma. Clin Cancer Res 10(19):6629–6637

    Article  PubMed  CAS  Google Scholar 

  30. Haven CJ, van Puijenbroek M, Tan MH, Teh BT, Fleuren GJ, van Wezel T et al (2007) Identification of MEN1 and HRPT2 somatic mutations in paraffin-embedded (sporadic) parathyroid carcinomas. Clin Endocrinol 67(3):370–376

    Article  CAS  Google Scholar 

  31. Shattuck TM, Valimaki S, Obara T, Gaz RD, Clark OH, Shoback D et al (2003) Somatic and germ-line mutations of the HRPT2 gene in sporadic parathyroid carcinoma. N Engl J Med 349(18):1722–1729

    Article  PubMed  CAS  Google Scholar 

  32. Witteveen JE, Hamdy NA, Dekkers OM, Kievit J, van Wezel T, Teh BT et al (2011) Downregulation of CASR expression and global loss of parafibromin staining are strong negative determinants of prognosis in parathyroid carcinoma. Mod Pathol 24(5):688–697

    Article  PubMed  CAS  Google Scholar 

  33. Juhlin CC, Villablanca A, Sandelin K, Haglund F, Nordenstrom J, Forsberg L et al (2007) Parafibromin immunoreactivity: its use as an additional diagnostic marker for parathyroid tumor classification. Endocr Relat Cancer 14(2):501–512

    Article  PubMed  CAS  Google Scholar 

  34. Fernandez-Ranvier GG, Khanafshar E, Tacha D, Wong M, Kebebew E, Duh QY et al (2009) Defining a molecular phenotype for benign and malignant parathyroid tumors. Cancer 115(2):334–344

    Article  PubMed  Google Scholar 

  35. Cetani F, Ambrogini E, Viacava P, Pardi E, Fanelli G, Naccarato AG et al (2007) Should parafibromin staining replace HRTP2 gene analysis as an additional tool for histologic diagnosis of parathyroid carcinoma? Eur J Endocrinol 156(5):547–554

    Article  PubMed  CAS  Google Scholar 

  36. Gill AJ, Clarkson A, Gimm O, Keil J, Dralle H, Howell VM et al (2006) Loss of nuclear expression of parafibromin distinguishes parathyroid carcinomas and hyperparathyroidism-jaw tumor (HPT-JT) syndrome-related adenomas from sporadic parathyroid adenomas and hyperplasias. Am J Surg Pathol 30(9):1140–1149

    Article  PubMed  Google Scholar 

  37. O’Neill CJ, Chan C, Symons J, Learoyd DL, Sidhu SB, Delbridge LW et al (2011) Parathyroid carcinoma encountered after minimally invasive focused parathyroidectomy may not require further radical surgery. World J Surg 35(1):147–153. doi:10.1007/s00268-010-0826-4

    Article  PubMed  Google Scholar 

  38. Howell VM, Gill A, Clarkson A, Nelson AE, Dunne R, Delbridge LW et al (2009) Accuracy of combined protein gene product 9.5 and parafibromin markers for immunohistochemical diagnosis of parathyroid carcinoma. J Clin Endocrinol Metab 94(2):434–441

    Article  PubMed  CAS  Google Scholar 

  39. Kim HK, Oh YL, Kim SH, Lee DY, Kang HC, Lee JI et al (2012) Parafibromin immunohistochemical staining to differentiate parathyroid carcinoma from parathyroid adenoma. Head Neck 34(2):201–206

    Article  PubMed  Google Scholar 

  40. Wang O, Wang CY, Shi J, Nie M, Xia WB, Li M et al (2012) Expression of Ki-67, galectin-3, fragile histidine triad, and parafibromin in malignant and benign parathyroid tumors. Chin Med J 125(16):2895–2901

    PubMed  CAS  Google Scholar 

  41. Cui C, Lal P, Master S, Ma Y, Baradet T, Bing Z (2012) Expression of parafibromin in major renal cell tumors. Eur J Histochem 56(4):e39

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  42. Selvarajan S, Sii LH, Lee A, Yip G, Bay BH, Tan MH et al (2008) Parafibromin expression in breast cancer: a novel marker for prognostication? J Clin Pathol 61(1):64–67

    Article  PubMed  CAS  Google Scholar 

  43. Wilson PO, Barber PC, Hamid QA, Power BF, Dhillon AP, Rode J et al (1988) The immunolocalization of protein gene product 9.5 using rabbit polyclonal and mouse monoclonal antibodies. Br J Exp Pathol 69(1):91–104

    PubMed  CAS  PubMed Central  Google Scholar 

  44. Tokumaru Y, Yamashita K, Kim MS, Park HL, Osada M, Mori M et al (2008) The role of PGP9.5 as a tumor suppressor gene in human cancer. Int J Cancer 123(4):753–759

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  45. Abbona GC, Papotti M, Gasparri G, Bussolati G (1995) Proliferative activity in parathyroid tumors as detected by Ki-67 immunostaining. Hum Pathol 26(2):135–138

    Article  PubMed  CAS  Google Scholar 

  46. Arvai K, Nagy K, Barti-Juhasz H, Petak I, Krenacs T, Micsik T et al (2012) Molecular profiling of parathyroid hyperplasia, adenoma and carcinoma. Pathol Oncol Res 18(3):607–614

    Article  PubMed  CAS  Google Scholar 

  47. Farnebo F, Auer G, Farnebo LO, Teh BT, Twigg S, Aspenblad U et al (1999) Evaluation of retinoblastoma and Ki-67 immunostaining as diagnostic markers of benign and malignant parathyroid disease. World J Surg 23(1):68–74. doi:10.1007/s002689900567

    Article  PubMed  CAS  Google Scholar 

  48. Lloyd RV, Carney JA, Ferreiro JA, Jin L, Thompson GB, Van Heerden JA et al (1995) Immunohistochemical analysis of the cell cycle-associated antigens Ki-67 and retinoblastoma protein in parathyroid carcinomas and adenomas. Endocr Pathol 6(4):279–287

    Article  PubMed  Google Scholar 

  49. Bergero N, De Pompa R, Sacerdote C, Gasparri G, Volante M, Bussolati G et al (2005) Galectin-3 expression in parathyroid carcinoma: immunohistochemical study of 26 cases. Hum Pathol 36(8):908–914

    Article  PubMed  CAS  Google Scholar 

  50. Mehrotra P, Okpokam A, Bouhaidar R, Johnson SJ, Wilson JA, Davies BR et al (2004) Galectin-3 does not reliably distinguish benign from malignant thyroid neoplasms. Histopathology 45(5):493–500

    Article  PubMed  CAS  Google Scholar 

  51. Greco C, Vona R, Cosimelli M, Matarrese P, Straface E, Scordati P et al (2004) Cell surface overexpression of galectin-3 and the presence of its ligand 90 k in the blood plasma as determinants in colon neoplastic lesions. Glycobiology 14(9):783–792

    Article  PubMed  CAS  Google Scholar 

  52. Saggiorato E, Bergero N, Volante M, Bacillo E, Rosas R, Gasparri G et al (2006) Galectin-3 and Ki-67 expression in multiglandular parathyroid lesions. Am J Clin Pathol 126(1):59–66

    Article  PubMed  CAS  Google Scholar 

  53. Vasef MA, Brynes RK, Sturm M, Bromley C, Robinson RA (1999) Expression of cyclin D1 in parathyroid carcinomas, adenomas, and hyperplasias: a paraffin immunohistochemical study. Mod Pathol 12(4):412–416

    PubMed  CAS  Google Scholar 

  54. Hadar T, Shvero J, Yaniv E, Ram E, Shvili I, Koren R (2005) Expression of p53, Ki-67 and Bcl-2 in parathyroid adenoma and residual normal tissue. Pathol Oncol Res 11(1):45–49

    Article  PubMed  Google Scholar 

  55. Juhlin CC, Haglund F, Villablanca A, Forsberg L, Sandelin K, Branstrom R et al (2009) Loss of expression for the Wnt pathway components adenomatous polyposis coli and glycogen synthase kinase 3-beta in parathyroid carcinomas. Int J Oncol 34(2):481–492

    PubMed  CAS  Google Scholar 

  56. Juhlin CC, Nilsson IL, Johansson K, Haglund F, Villablanca A, Hoog A et al (2010) Parafibromin and APC as screening markers for malignant potential in atypical parathyroid adenomas. Endocr Pathol 21(3):166–177

    Article  PubMed  CAS  Google Scholar 

  57. Osawa N, Onoda N, Kawajiri H, Tezuka K, Takashima T, Ishikawa T et al (2009) Diagnosis of parathyroid carcinoma using immunohistochemical staining against hTERT. Int J Mol Med 24(6):733–741

    PubMed  CAS  Google Scholar 

  58. Onoda N, Ogisawa K, Ishikawa T, Takenaka C, Tahara H, Inaba M et al (2004) Telomerase activation and expression of its catalytic subunits in benign and malignant tumors of the parathyroid. Surg Today 34(5):389–393

    Article  PubMed  CAS  Google Scholar 

  59. Kammori M, Nakamura K, Ogawa T, Mafune K, Tatutomi Y, Obara T et al (2003) Demonstration of human telomerase reverse transcriptase (hTERT) in human parathyroid tumours by in situ hybridization with a new oligonucleotide probe. Clin Endocrinol 58(1):43–48

    Article  CAS  Google Scholar 

  60. McCourt CM, Boyle D, James J, Salto-Tellez M (2013) Immunohistochemistry in the era of personalised medicine. J Clin Pathol 66(1):58–61

    Article  PubMed  CAS  Google Scholar 

  61. Solcia E, Klöppel G, Sobin LH, Capella C, DeLellis RA, Heitz PU, Horvath E, Kovacs K, Lack E et al (2000) World Health Organization International Histological Classification of Tumours: histological typing of endocrine tumours, 2nd edn. Springer, New York

    Google Scholar 

  62. Kameyama K, Takami H, Umemura S, Osamura YR, Wada N, Sugino K et al (2000) PCNA and Ki-67 as prognostic markers in human parathyroid carcinomas. Ann Surg Oncol 7(4):301–304

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We are indebted to Anna Long for performing the immunohistochemical staining. This project was funded by the British Association of Endocrine and Thyroid Surgeons. Roche Diagnostics Limited provided the reagents without charge for 28 of the 195 stains performed to prevent the project from going over budget.

Conflict of interest

None

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Peter P. Truran.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Truran, P.P., Johnson, S.J., Bliss, R.D. et al. Parafibromin, Galectin-3, PGP9.5, Ki67, and Cyclin D1: Using an Immunohistochemical Panel to Aid in the Diagnosis of Parathyroid Cancer. World J Surg 38, 2845–2854 (2014). https://doi.org/10.1007/s00268-014-2700-2

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00268-014-2700-2

Keywords

Navigation