Article | Published:

Parafibromin immunostainings of parathyroid tumors in clinical routine: a near-decade experience from a tertiary center


The cell division cycle 73 gene is mutated in familial and sporadic forms of primary hyperparathyroidism, and the corresponding protein product parafibromin has been proposed as an adjunct immunohistochemical marker for the identification of cell division cycle 73 mutations and parathyroid carcinoma. Here, we present data from our experiences using parafibromin immunohistochemistry in parathyroid tumors since the marker was implemented in clinical routine in 2010. A total of 2019 parathyroid adenomas, atypical adenomas, and carcinomas were diagnosed in our department, and parafibromin staining was ordered for 297 cases with an initial suspicion of malignant potential to avoid excessive numbers of false positives. The most common inclusion criteria for immunohistochemistry were marked tumor weight (146 cases) and/or fibrosis (77 cases) and/or marked pleomorphism (58 cases). In total, 238 cases were informatively stained, and partial or complete loss of nuclear parafibromin immunoreactivity was noted in 40 cases; 10 out of 182 adenomas (5%), 27 out of 46 atypical adenomas (59%), and 7 out of 10 carcinomas (70%), with positive and negative predictive values of 85 and 90%, respectively for the detection of atypical adenomas/carcinomas versus adenomas, and 18 and 98%, respectively for carcinomas versus atypical adenomas/adenomas. Male patients with high-proliferative tumors were overrepresented among cases with aberrant parafibromin immunohistochemistry, and carcinomas more frequently harbored parafibromin aberrancies than atypical adenomas and adenomas (p < 0.001). We conclude that parafibromin immunohistochemistry is a useful marker in the clinical routine when applied on a pre-selected material of cases, with positive immunoreactivity as a confident rule out marker of malignancy.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.


  1. 1.

    Quinn CE, Healy J, Lebastchi AH, Brown TC, Stein JE, Prasad ML, et al. Modern experience with aggressive parathyroid tumors in a high-volume New England referral center. J Am Coll Surg. 2015;220:1054–62.

  2. 2.

    Bondeson L, Grimelius L, DeLellis RA, Lloyd R, Åkerström G, Larsson C, et al. Parathyroid carcinoma and parathyroid adenoma. In: DeLellis RA, Lloyd RV, Heitz PU, et al., editors. Pathology and genetics of tumours of endocrine organs. Lyon: International Agency for Research on Cancer Press, 2004. p. 124–32.

  3. 3.

    DeLellis RA, Arnold A, Bilezikian JP, Eng C, Larsson C, Lloyd RV, et al. Tumours of the parathyroid glands. In: Lloyd RV, Osamura RY, Klöppel G et al., editors. WHO classification of tumours of endocrine organs. Fourth edition. Lyon: International Agency for Research on Cancer, 2017. p. 146–58.

  4. 4.

    Carpten JD, Robbins CM, Villablanca A, Forsberg L, Presciuttini S, Bailey-Wilson J, et al. HRPT2, encoding parafibromin, is mutated in hyperparathyroidism-jaw tumor syndrome. Nat Genet. 2002;32:676–80.

  5. 5.

    Shattuck TM, Välimäki S, Obara T, Gaz RD, Clark OH, Shoback D, et al. Somatic and germ-line mutations of the HRPT2 gene in sporadic parathyroid carcinoma. N Engl J Med. 2003;349:1722–9.

  6. 6.

    Juhlin CC, Villablanca A, Sandelin K, Haglund F, Nordenström J, Forsberg L, et al. Parafibromin immunoreactivity: its use as an additional diagnostic marker for parathyroid tumor classification. Endocr Relat Cancer. 2007;14:501–12.

  7. 7.

    Gill AJ, Clarkson A, Gimm O, Keil J, Dralle H, Howell VM, et al. 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. 2006;30:1140–9.

  8. 8.

    Juhlin C, Larsson C, Yakoleva T, Leibiger I, Leibiger B, Alimov A, et al. Loss of parafibromin expression in a subset of parathyroid adenomas. Endocr Relat Cancer. 2006;13:509–23.

  9. 9.

    Cetani F, Ambrogini E, Viacava P, Pardi E, Fanelli G, Naccarato AG, et al. Should parafibromin staining replace HRTP2 gene analysis as an additional tool for histologic diagnosis of parathyroid carcinoma? Eur J Endocrinol. 2007;156:547–54.

  10. 10.

    Tan M-H, Morrison C, Wang P, Yang X, Haven CJ, Zhang C, et al. Loss of parafibromin immunoreactivity is a distinguishing feature of parathyroid carcinoma. Clin Cancer Res. 2004;10:6629–37.

  11. 11.

    Marcocci C, Cetani F. Parafibromin as a tool for the diagnosis of parathyroid tumors. Adv Anat Pathol. 2008;15:179. author reply179-180.

  12. 12.

    Juhlin CC, Höög A. Parafibromin as a diagnostic instrument for parathyroid carcinoma-lone ranger or part of the posse? Int J Endocrinol. 2010;2010:324964.

  13. 13.

    Hu Y, Liao Q, Cao S, Gao X, Zhao Y. Diagnostic performance of parafibromin immunohistochemical staining for sporadic parathyroid carcinoma: a meta-analysis. Endocrine. 2016;54:612–9.

  14. 14.

    Juhlin CC, Nilsson I-L, Johansson K, Haglund F, Villablanca A, Höög A, et al. Parafibromin and APC as screening markers for malignant potential in atypical parathyroid adenomas. Endocr Pathol. 2010;21:166–77.

  15. 15.

    Kruijff S, Sidhu SB, Sywak MS, Gill AJ, Delbridge LW. Negative parafibromin staining predicts malignant behavior in atypical parathyroid adenomas. Ann Surg Oncol. 2014;21:426–33.

  16. 16.

    Yang Y-J, Han J-W, Youn H-D, Cho E-J. The tumor suppressor, parafibromin, mediates histone H3 K9 methylation for cyclin D1 repression. Nucleic Acids Res. 2010;38:382–90.

  17. 17.

    Woodard GE, Lin L, Zhang J-H, Agarwal SK, Marx SJ, Simonds WF. Parafibromin, product of the hyperparathyroidism-jaw tumor syndrome gene HRPT2, regulates cyclin D1/PRAD1 expression. Oncogene. 2005;24:1272–6.

  18. 18.

    Takahashi A, Tsutsumi R, Kikuchi I, Obuse C, Saito Y, Seidi A, et al. SHP2 tyrosine phosphatase converts parafibromin/Cdc73 from a tumor suppressor to an oncogenic driver. Mol Cell. 2011;43:45–56.

  19. 19.

    Mosimann C, Hausmann G, Basler K. Parafibromin/Hyrax activates Wnt/Wg target gene transcription by direct association with beta-catenin/Armadillo. Cell. 2006;125:327–41.

  20. 20.

    Kikuchi I, Takahashi-Kanemitsu A, Sakiyama N, Tang C, Tang P-J, Noda S, et al. Dephosphorylated parafibromin is a transcriptional coactivator of the Wnt/Hedgehog/Notch pathways. Nat Commun. 2016;7:12887.

  21. 21.

    Juhlin CC, Haglund F, Villablanca A, Forsberg L, Sandelin K, Bränström R, et al. Loss of expression for the Wnt pathway components adenomatous polyposis coli and glycogen synthase kinase 3-beta in parathyroid carcinomas. Int J Oncol. 2009;34:481–92.

  22. 22.

    Witteveen JE, Hamdy NA, Dekkers OM, Kievit J, van Wezel T, Teh BT, et al. Downregulation of CASR expression and global loss of parafibromin staining are strong negative determinants of prognosis in parathyroid carcinoma. Mod Pathol. 2011;24:688–97.

  23. 23.

    Truran PP, Johnson SJ, Bliss RD, Lennard TW, Aspinall SR. Parafibromin, galectin-3, PGP9.5, Ki67, and cyclin D1: using an immunohistochemical panel to aid in the diagnosis of parathyroid cancer. World J Surg. 2014;38:2845–54.

  24. 24.

    Hosny Mohammed K, Siddiqui MT, Willis BC, Zaharieva Tsvetkova D, Mohamed A, Patel S, et al. Parafibromin, APC, and MIB-1 are useful markers for distinguishing parathyroid carcinomas from adenomas. Appl Immunohistochem Mol Morphol. 2017;25:731–5.

  25. 25.

    Howell VM, Gill A, Clarkson A, Nelson AE, Dunne R, Delbridge LW, et al. Accuracy of combined protein gene product 9.5 and parafibromin markers for immunohistochemical diagnosis of parathyroid carcinoma. J Clin Endocrinol Metab. 2009;94:434–41.

  26. 26.

    Juhlin CC, Kiss NB, Villablanca A, Haglund F, Nordenström J, Höög A, et al. Frequent promoter hypermethylation of the APC and RASSF1A tumour suppressors in parathyroid tumours. PLoS ONE. 2010;5:e9472.

  27. 27.

    Svedlund J, Aurén M, Sundström M, Dralle H, Åkerström G, Björklund P, et al. Aberrant WNT/β-catenin signaling in parathyroid carcinoma. Mol Cancer. 2010;9:294.

  28. 28.

    Alwaheeb S, Rambaldini G, Boerner S, Coiré C, Fiser J, Asa S. Worrisome histologic alterations following fine-needle aspiration of the parathyroid. J Clin Pathol. 2006;59:1094–6.

  29. 29.

    Kim J, Horowitz G, Hong M, Orsini M, Asa SL, Higgins K. The dangers of parathyroid biopsy. J Otolaryngol Head Neck Surg. 2017;46:4.

  30. 30.

    Hahn MA, Marsh DJ. Nucleolar localization of parafibromin is mediated by three nucleolar localization signals. FEBS Lett. 2007;581:5070–4.

  31. 31.

    Masi G, Iacobone M, Sinigaglia A, Mantelli B, Pennelli G, Castagliuolo I, et al. Characterization of a new CDC73 missense mutation that impairs Parafibromin expression and nucleolar localization. PLoS ONE. 2014;9:e97994.

  32. 32.

    Panicker LM, Zhang J-H, Dagur PK, Gastinger MJ, Simonds WF. Defective nucleolar localization and dominant interfering properties of a parafibromin L95P missense mutant causing the hyperparathyroidism-jaw tumor syndrome. Endocr Relat Cancer. 2010;17:513–24.

  33. 33.

    Juhlin CC, Haglund F, Obara T, Arnold A, Larsson C, Höög A. Absence of nucleolar parafibromin immunoreactivity in subsets of parathyroid malignant tumours. Virchows Arch. 2011;459:47–53.

  34. 34.

    Gill AJ. Understanding the genetic basis of parathyroid carcinoma. Endocr Pathol. 2014;25:30–34.

  35. 35.

    Gill AJ, Lim G, Cheung VKY, Andrici J, Perry-Keene JL, Paik J, et al. Parafibromin-deficient (HPT-JT Type, CDC73 mutated) parathyroid tumors demonstrate distinctive morphologic features. Am J Surg Pathol. 2019;43:35–46.

  36. 36.

    Guarnieri V, Battista C, Muscarella LA, Bisceglia M, de Martino D, Baorda F, et al. CDC73 mutations and parafibromin immunohistochemistry in parathyroid tumors: clinical correlations in a single-centre patient cohort. Cell Oncol (Dordr). 2012;35:411–22.

Download references


The authors are indebted to Ms. Lisa Ånfalk for acquisition of subsets of the clinical data as well as tumor samples for genetic analysis. The study was supported by grants provided from the Swedish Cancer Society and The Swedish Society for Medical Research.

Author information

Conflict of interest

The authors declare that they have no conflict of interest.

Correspondence to C. Christofer Juhlin.

Supplementary information

  1. Supplementary Table 1

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Further reading

Fig. 1
Fig. 2
Fig. 3