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Overview of the 2022 WHO Classification of Parathyroid Tumors

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Abstract

The 2022 WHO classification reflects increases in the knowledge of the underlying pathogenesis of parathyroid disease. In addition to the classic characteristic features of parathyroid neoplasms, subtleties in histologic features which may indicate an underlying genetic abnormality reflect increased understanding of the clinical manifestations, histologic, and genetic correlation in parathyroid disease. The importance of underlying genetic aberrancies is emphasized due to their significance to the care of the patient. Traditionally, the term “parathyroid hyperplasia” has been applied to multiglandular parathyroid disease; however, the concept of hyperplasia is generally no longer supported in the context of primary hyperparathyroidism since affected glands are usually composed of multiple “clonal” neoplastic proliferations. In light of these findings and management implications for patient care, the 2022 WHO classification endorses primary hyperparathyroidism-related multiglandular parathyroid disease (multiglandular multiple parathyroid adenomas) as a germline susceptibility-driven multiglandular parathyroid neoplasia. From such a perspective, pathologists can provide additional value to genetic triaging by recognizing morphological and immunohistochemical harbingers of MEN1, CDKN1B, MAX, and CDC73-related manifestations. In the current WHO classification, the term “parathyroid hyperplasia” is now used primarily in the setting of secondary hyperplasia which is most often caused by chronic renal failure. In addition to expansion in the histological features, including those that may be suggestive of an underlying genetic abnormality, there are additional nomenclature changes in the 2022 WHO classification reflecting increased understanding of the underlying pathogenesis of parathyroid disease. The new classification no longer endorses the use of “atypical parathyroid adenoma”. This entity is now being replaced with the term of “atypical parathyroid tumor” to reflect a parathyroid neoplasm of uncertain malignant potential. The differential diagnoses of atypical parathyroid tumor are discussed along with the details of worrisome clinical and laboratory findings, and also features that define atypical histological and immunohistochemical findings to qualify for this diagnosis. The histological definition of parathyroid carcinoma still requires one of the following findings: (i) angioinvasion (vascular invasion) characterized by tumor invading through a vessel wall and associated thrombus, or intravascular tumor cells admixed with thrombus, (ii) lymphatic invasion, (iii) perineural (intraneural) invasion, (iv) local malignant invasion into adjacent anatomic structures, or (v) histologically/cytologically documented metastatic disease. In parathyroid carcinomas, the documentation of mitotic activity (e.g., mitoses per 10mm2) and Ki67 labeling index is recommended. Furthermore, the importance of complete submission of parathyroidectomy specimens for microscopic examination, and the crucial role of multiple levels along with ancillary biomarkers have expanded the diagnostic workup of atypical parathyroid tumors and parathyroid carcinoma to ensure accurate characterization of parathyroid neoplasms. The concept of parafibromin deficiency has been expanded upon and term “parafibromin deficient parathyroid neoplasm” is applied to a parathyroid neoplasm showing complete absence of nuclear parafibromin immunoreactivity. Nucleolar loss is considered as abnormal finding that requires further molecular testing to confirm its biological significance. The 2022 WHO classification emphasizes the role of molecular immunohistochemistry in parathyroid disease. By adopting a question–answer framework, this review highlights advances in knowledge of histological features, ancillary studies, and associated genetic findings that increase the understanding of the underlying pathogenesis of parathyroid disease that are now reflected in the updated classification and new entities in the 2022 WHO classification.

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References

  1. Duan K, Gomez Hernandez K,Mete O (2015) Clinicopathological correlates of hyperparathyroidism. J Clin Pathol 68: 771-787.

    Article  CAS  PubMed  Google Scholar 

  2. Mete O,Asa SL (2013) Precursor lesions of endocrine system neoplasms. Pathology 45: 316-330.

    Article  CAS  PubMed  Google Scholar 

  3. Friedman E, Sakaguchi K, Bale AE, Falchetti A, Streeten E, Zimering MB, Weinstein LS, McBride WO, Nakamura Y, Brandi ML,et al. (1989) Clonality of parathyroid tumors in familial multiple endocrine neoplasia type 1. N Engl J Med 321: 213-218.

    Article  CAS  PubMed  Google Scholar 

  4. Thakker RV (2014) Multiple endocrine neoplasia type 1 (men1) and type 4 (men4). Mol Cell Endocrinol 386: 2-15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Schernthaner-Reiter MH, Trivellin G,Stratakis CA (2016) Men1, men4, and carney complex: pathology and molecular genetics. Neuroendocrinology 103: 18-31.

    Article  CAS  PubMed  Google Scholar 

  6. Doherty GM, Lairmore TC,DeBenedetti MK (2004) Multiple endocrine neoplasia type 1 parathyroid adenoma development over time. World J Surg 28: 1139-1142.

    Article  PubMed  Google Scholar 

  7. Duan K, Mete O (2016) Familial hyperparathyroidism syndromes. Diagnostic histopathology 22: 92-100.

    Article  Google Scholar 

  8. Seabrook AJ, Harris JE, Velosa SB, Kim E, McInerney-Leo AM, Dwight T, Hockings JI, Hockings NG, Kirk J, Leo PJ, Love AJ, Luxford C, Marshall M, Mete O, Pennisi DJ, Brown MA, Gill AJ, Hockings GI, Clifton-Bligh RJ,Duncan EL (2021) Multiple endocrine tumors associated with germline max mutations: multiple endocrine neoplasia type 5? J Clin Endocrinol Metab 106: 1163-1182.

    Article  PubMed  Google Scholar 

  9. Gill AJ, Lim G, Cheung VKY, Andrici J, Perry-Keene JL, Paik J, Sioson L, Clarkson A, Sheen A, Luxford C, Elston MS, Meyer-Rochow GY, Nano MT, Kruijff S, Engelsman AF, Sywak M, Sidhu SB, Delbridge LW, Robinson BG, Marsh DJ, Toon CW, Chou A,Clifton-Bligh RJ (2019) Parafibromin-deficient (hpt-jt type, cdc73 mutated) parathyroid tumors demonstrate distinctive morphologic features. Am J Surg Pathol 43: 35-46.

    Article  PubMed  Google Scholar 

  10. Erickson LA,Mete O (2018) Immunohistochemistry in diagnostic parathyroid pathology. Endocr Pathol 29: 113-129.

    Article  CAS  PubMed  Google Scholar 

  11. Juhlin CC, Nilsson IL, Lagerstedt-Robinson K, Stenman A, Branstrom R, Tham E,Hoog A (2019) Parafibromin immunostainings of parathyroid tumors in clinical routine: a near-decade experience from a tertiary center. Mod Pathol 32: 1082-1094.

    Article  CAS  PubMed  Google Scholar 

  12. Williams MD, DeLellis RA, Erickson LA, Gupta R, Johnson SJ, Kameyama K, Natu S, Ng T, Perren A, Perrier ND, Seethala RR,Gill AJ (2021) Pathology data set for reporting parathyroid carcinoma and atypical parathyroid neoplasm: recommendations from the international collaboration on cancer reporting. Hum Pathol 110: 73-82.

    Article  PubMed  Google Scholar 

  13. Gill AJ, Clarkson A, Gimm O, Keil J, Dralle H, Howell VM,Marsh DJ (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: 1140-1149.

    Article  PubMed  Google Scholar 

  14. Mehta A, Patel D, Rosenberg A, Boufraqech M, Ellis RJ, Nilubol N, Quezado MM, Marx SJ, Simonds WF,Kebebew E (2014) Hyperparathyroidism-jaw tumor syndrome: results of operative management. Surgery 156: 1315–1324; discussion 1324–1315.

  15. Juhlin CC, Nilsson IL, Johansson K, Haglund F, Villablanca A, Hoog A,Larsson C (2010) Parafibromin and apc as screening markers for malignant potential in atypical parathyroid adenomas. Endocr Pathol 21: 166-177.

    Article  CAS  PubMed  Google Scholar 

  16. Kruijff S, Sidhu SB, Sywak MS, Gill AJ,Delbridge LW (2014) Negative parafibromin staining predicts malignant behavior in atypical parathyroid adenomas. Ann Surg Oncol 21: 426-433.

    Article  PubMed  Google Scholar 

  17. Hosny Mohammed K, Siddiqui MT, Willis BC, Zaharieva Tsvetkova D, Mohamed A, Patel S, Sharma J, Weber C,Cohen C (2017) Parafibromin, apc, and mib-1 are useful markers for distinguishing parathyroid carcinomas from adenomas. Appl Immunohistochem Mol Morphol 25: 731-735.

    Article  CAS  PubMed  Google Scholar 

  18. Juhlin CC,Erickson LA (2021) Genomics and epigenomics in parathyroid neoplasia: from bench to surgical pathology practice. Endocr Pathol 32: 17-34.

    Article  PubMed  Google Scholar 

  19. Carpten JD, Robbins CM, Villablanca A, Forsberg L, Presciuttini S, Bailey-Wilson J, Simonds WF, Gillanders EM, Kennedy AM, Chen JD, Agarwal SK, Sood R, Jones MP, Moses TY, Haven C, Petillo D, Leotlela PD, Harding B, Cameron D, Pannett AA, Hoog A, Heath H, 3rd, James-Newton LA, Robinson B, Zarbo RJ, Cavaco BM, Wassif W, Perrier ND, Rosen IB, Kristoffersson U, Turnpenny PD, Farnebo LO, Besser GM, Jackson CE, Morreau H, Trent JM, Thakker RV, Marx SJ, Teh BT, Larsson C,Hobbs MR (2002) Hrpt2, encoding parafibromin, is mutated in hyperparathyroidism-jaw tumor syndrome. Nat Genet 32: 676-680.

    Article  CAS  PubMed  Google Scholar 

  20. Bricaire L, Odou MF, Cardot-Bauters C, Delemer B, North MO, Salenave S, Vezzosi D, Kuhn JM, Murat A, Caron P, Sadoul JL, Silve C, Chanson P, Barlier A, Clauser E, Porchet N, Groussin L,Group GTE (2013) Frequent large germline hrpt2 deletions in a french national cohort of patients with primary hyperparathyroidism. J Clin Endocrinol Metab 98: E403-408.

    Article  Google Scholar 

  21. Shattuck TM, Valimaki S, Obara T, Gaz RD, Clark OH, Shoback D, Wierman ME, Tojo K, Robbins CM, Carpten JD, Farnebo LO, Larsson C,Arnold A (2003) Somatic and germ-line mutations of the hrpt2 gene in sporadic parathyroid carcinoma. N Engl J Med 349: 1722-1729.

    Article  CAS  PubMed  Google Scholar 

  22. Cetani F, Pardi E, Borsari S, Viacava P, Dipollina G, Cianferotti L, Ambrogini E, Gazzerro E, Colussi G, Berti P, Miccoli P, Pinchera A,Marcocci C (2004) Genetic analyses of the hrpt2 gene in primary hyperparathyroidism: germline and somatic mutations in familial and sporadic parathyroid tumors. J Clin Endocrinol Metab 89: 5583-5591.

    Article  CAS  PubMed  Google Scholar 

  23. Gill AJ (2014) Understanding the genetic basis of parathyroid carcinoma. Endocr Pathol 25: 30-34.

    Article  CAS  PubMed  Google Scholar 

  24. Bollerslev J, Rejnmark L, Zahn A, Heck A, Appelman-Dijkstra NM, Cardoso L, Hannan FM, Cetani F, Sikjaer T, Formenti AM, Bjornsdottir S, Schalin-Jantti C, Belaya Z, Gibb FW, Lapauw B, Amrein K, Wicke C, Grasemann C, Krebs M, Ryhanen EM, Makay O, Minisola S, Gaujoux S, Bertocchio JP, Hassan-Smith ZK, Linglart A, Winter EM, Kollmann M, Zmierczak HG, Tsourdi E, Pilz S, Siggelkow H, Gittoes NJ, Marcocci C, Kamenicky P (2021) European expert consensus on practical management of specific aspects of parathyroid disorders in adults and in pregnancy: Recommendations of the ese educational program of parathyroid disorders. Eur J Endocrinol

  25. Aojula N, Khan S, Gittoes N,Hassan-Smith Z (2021) Normocalcaemic primary hyperparathyroidism: What is the role of parathyroid surgery? Ther Adv Endocrinol Metab 12: 2042018821995370.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Chow LS, Erickson LA, Abu-Lebdeh HS,Wermers RA (2006) Parathyroid lipoadenomas: a rare cause of primary hyperparathyroidism. Endocr Pract 12: 131-136.

    Article  PubMed  Google Scholar 

  27. Hyrcza MD, Sargin P,Mete O (2016) Parathyroid lipoadenoma: a clinicopathological diagnosis and possible trap for the unaware pathologist. Endocr Pathol 27: 34-41.

    Article  PubMed  Google Scholar 

  28. Kong SH, Kim JH, Park MY, Kim SW,Shin CS (2021) Epidemiology and prognosis of parathyroid carcinoma: Real-world data using nationwide cohort. J Cancer Res Clin Oncol 147: 3091-3097.

    Article  CAS  PubMed  Google Scholar 

  29. Wang P, Xue S, Wang S, Lv Z, Meng X, Wang G, Meng W, Liu J,Chen G (2017) Clinical characteristics and treatment outcomes of parathyroid carcinoma: a retrospective review of 234 cases. Oncol Lett 14: 7276-7282.

    PubMed  PubMed Central  Google Scholar 

  30. Ryhanen EM, Leijon H, Metso S, Eloranta E, Korsoff P, Ahtiainen P, Kekalainen P, Tamminen M, Ristamaki R, Knutar O, Loyttyniemi E, Niskanen L, Vaisanen M, Heiskanen I, Valimaki MJ, Laakso M, Haglund C, Arola J,Schalin-Jantti C (2017) A nationwide study on parathyroid carcinoma. Acta Oncol 56: 991-1003.

    Article  PubMed  Google Scholar 

  31. Brown S, O'Neill C, Suliburk J, Sidhu S, Sywak M, Gill A, Robinson B,Delbridge L (2011) Parathyroid carcinoma: increasing incidence and changing presentation. ANZ J Surg 81: 528-532.

    Article  PubMed  Google Scholar 

  32. 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: 1736-1741.

    Article  PubMed  Google Scholar 

  33. Cappellacci F, Medas F, Canu GL, Lai ML, Conzo G, Erdas E,Calo PG (2020) Parathyroid carcinoma in the setting of tertiary hyperparathyroidism: case report and review of the literature. Case Rep Endocrinol 2020: 5710468.

    PubMed  PubMed Central  Google Scholar 

  34. Nasrallah MP, Fraker DL,LiVolsi VA (2014) Parathyroid carcinoma in the setting of tertiaryhyperparathyroidism after renal transplant. Endocr Pathol 25: 433-435.

    Article  PubMed  Google Scholar 

  35. Duan K,Mete O (2015) Parathyroid carcinoma: diagnosis and clinical implications. Turk Patoloji Derg 31 Suppl 1: 80-97.

    PubMed  Google Scholar 

  36. Asare EA, Silva-Figueroa A, Hess KR, Busaidy N, Graham PH, Grubbs EG, Lee JE, Williams MD,Perrier ND (2019) Risk of distant metastasis in parathyroid carcinoma and its effect on survival: a retrospective review from a high-volume center. Ann Surg Oncol 26: 3593-3599.

    Article  PubMed  Google Scholar 

  37. Cavalier E, Betea D, Schleck ML, Gadisseur R, Vroonen L, Delanaye P, Daly AF,Beckers A (2014) The third/second generation pth assay ratio as a marker for parathyroid carcinoma: evaluation using an automated platform. J Clin Endocrinol Metab 99: E453-457.

    Article  CAS  PubMed  Google Scholar 

  38. Erovic BM, Goldstein DP, Kim D, Mete O, Brierley J, Tsang R, Freeman JL, Asa SL, Rotstein L,Irish JC (2013) Parathyroid cancer: outcome analysis of 16 patients treated at the princess margaret hospital. Head Neck 35: 35-39.

    Article  PubMed  Google Scholar 

  39. Harari A, Waring A, Fernandez-Ranvier G, Hwang J, Suh I, Mitmaker E, Shen W, Gosnell J, Duh QY,Clark O (2011) Parathyroid carcinoma: a 43-year outcome and survival analysis. J Clin Endocrinol Metab 96: 3679-3686.

    Article  CAS  PubMed  Google Scholar 

  40. Schaapveld M, Jorna FH, Aben KK, Haak HR, Plukker JT,Links TP (2011) Incidence and prognosis of parathyroid gland carcinoma: a population-based study in the netherlands estimating the preoperative diagnosis. Am J Surg 202: 590-597.

    Article  PubMed  Google Scholar 

  41. Cavalier E, Daly AF, Betea D, Pruteanu-Apetrii PN, Delanaye P, Stubbs P, Bradwell AR, Chapelle JP,Beckers A (2010) The ratio of parathyroid hormone as measured by third- and second-generation assays as a marker for parathyroid carcinoma. J Clin Endocrinol Metab 95: 3745-3749.

    Article  CAS  PubMed  Google Scholar 

  42. Caron P, Maiza JC, Renaud C, Cormier C, Barres BH,Souberbielle JC (2009) High third generation/second generation pth ratio in a patient with parathyroid carcinoma: clinical utility of third generation/second generation pth ratio in patients with primary hyperparathyroidism. Clin Endocrinol (Oxf) 70: 533-538.

    Article  CAS  Google Scholar 

  43. Busaidy NL, Jimenez C, Habra MA, Schultz PN, El-Naggar AK, Clayman GL, Asper JA, Diaz EM, Jr., Evans DB, Gagel RF, Garden A, Hoff AO, Lee JE, Morrison WH, Rosenthal DI, Sherman SI, Sturgis EM, Waguespack SG, Weber RS, Wirfel K,Vassilopoulou-Sellin R (2004) Parathyroid carcinoma: a 22-year experience. Head Neck 26: 716-726.

    Article  PubMed  Google Scholar 

  44. Wynne AG, van Heerden J, Carney JA,Fitzpatrick LA (1992) Parathyroid carcinoma: clinical and pathologic features in 43 patients. Medicine (Baltimore) 71: 197-205.

    Article  CAS  Google Scholar 

  45. Fraser WD (2009) Hyperparathyroidism. Lancet 374: 145-158.

    Article  CAS  PubMed  Google Scholar 

  46. Lin X, Fan Y, Zhang Z,Yue H (2021) Clinical characteristics of primary hyperparathyroidism: 15-year experience of 457 patients in a single center in China. Front Endocrinol (Lausanne) 12: 602221.

  47. Lundgren E, Hagstrom EG, Lundin J, Winnerback K, Roos J, Ljunghall S,Rastad J (2002) Primary hyperparathyroidism revisited in menopausal women with serum calcium in the upper normal range at population-based screening 8 years ago. World J Surg 26: 931-936.

    Article  PubMed  Google Scholar 

  48. Dawood NB, Yan KL, Shieh A, Livhits MJ, Yeh MW,Leung AM (2020) Normocalcaemic primary hyperparathyroidism: an update on diagnostic and management challenges. Clin Endocrinol (Oxf) 93: 519-527.

    Article  CAS  Google Scholar 

  49. Goasguen N, Chirica M, Roger N, Munoz-Bongrand N, Zohar S, Noullet S, de Roquancourt A, Cattan P,Sarfati E (2010) Primary hyperparathyroidism from parathyroid microadenoma: specific features and implications for a surgical strategy in the era of minimally invasive parathyroidectomy. J Am Coll Surg 210: 456-462.

    Article  PubMed  Google Scholar 

  50. Sala TD, Muresan S, Roman R, Lazar A, Ion R,Pascanu I (2019) Hypercalcaemic crisis due to primary hyperparathyroidism: report of two cases. J Crit Care Med (Targu Mures) 5: 34-39.

    Article  Google Scholar 

  51. Mantzoros I, Kyriakidou D, Galanos-Demiris K, Chatzakis C, Parpoudi S, Sapidis N, Loutzidou L, Ioannidis O, Angelopoulos S,Tsalis KG (2018) A rare case of primary hyperparathyroidism caused by a giant solitary parathyroid adenoma. Am J Case Rep 19: 1334-1337.

    Article  PubMed  PubMed Central  Google Scholar 

  52. Akerstrom G, Malmaeus J,Bergstrom R (1984) Surgical anatomy of human parathyroid glands. Surgery 95: 14-21.

    CAS  PubMed  Google Scholar 

  53. Howson P, Kruijff S, Aniss A, Pennington T, Gill AJ, Dodds T, Delbridge LW, Sidhu SB,Sywak MS (2015) Oxyphil cell parathyroid adenomas causing primary hyperparathyroidism: a clinico-pathological correlation. Endocr Pathol 26: 250-254.

    Article  CAS  PubMed  Google Scholar 

  54. Erickson LA, Jin L, Papotti M,Lloyd RV (2002) Oxyphil parathyroid carcinomas: a clinicopathologic and immunohistochemical study of 10 cases. Am J Surg Pathol 26: 344-349.

    Article  PubMed  Google Scholar 

  55. Durmus ET, Atmaca A, Kefeli M, Mete O, Canbaz Tosun F, Baycelebi D, Polat C,Colak R (2021) Clinicopathological variables that correlate with sestamibi positivity in uniglandular parathyroid disease: a retrospective analysis of 378 parathyroid adenomas. Ann Nucl Med

  56. Hu Y, Cui M, Xia Y, Su Z, Zhang X, Liao Q, Jiang Y,Zhao Y (2018) The clinical features of cystic parathyroid adenoma in chinese population: a single-center experience. Int J Endocrinol 2018: 3745239.

    Article  PubMed  PubMed Central  Google Scholar 

  57. El Hussein S,Poppiti R (2017) Water clear cell adenoma of the parathyroid gland: a forgotten cause of primary hyperparathyroidism. Int J Surg Pathol 25: 384-388.

    Article  PubMed  Google Scholar 

  58. Pirela D, Treitl D, El Hussein S, Poppiti R, Mesko T,Manzano A (2016) Intrathyroidal clear cell tumor of parathyroid origin with review of literature. Case Rep Pathol 2016: 7169564.

    PubMed  PubMed Central  Google Scholar 

  59. Roth SI (1970) The ultrastructure of primary water-clear cell hyperplasia of the parathyroid glands. Am J Pathol 61: 233-248.

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Juhlin CC, Nilsson IL, Falhammar H,Zedenius J (2021) Institutional characterisation of water clear cell parathyroid adenoma: a rare entity often unrecognised by tc-99m-sestamibi scintigraphy. Pathology 53: 852-859.

    Article  PubMed  Google Scholar 

  61. Chandramohan A, Sathyakumar K, John RA, Manipadam MT, Abraham D, Paul TV, Thomas N,Paul MJ (2014) Atypical ultrasound features of parathyroid tumours may bear a relationship to their clinical and biochemical presentation. Insights Imaging 5: 103-111.

    Article  PubMed  Google Scholar 

  62. Krawitz R, Glover A, Koneru S, Jiang J, Di Marco A, Gill AJ, Aniss A, Sywak M, Delbridge L,Sidhu S (2020) The significance of histologically “large normal” parathyroid glands in primary hyperparathyroidism. World J Surg 44: 1149-1155.

    Article  PubMed  Google Scholar 

  63. Milas M, Wagner K, Easley KA, Siperstein A,Weber CJ (2003) Double adenomas revisited: nonuniform distribution favors enlarged superior parathyroids (fourth pouch disease). Surgery 134: 995–1003; discussion 1003–1004.

  64. El Lakis M, Nockel P, Gaitanidis A, Guan B, Agarwal S, Welch J, Simonds WF, Weinstein L, Marx S, Nilubol N, Patel D, Merkel R, Tirosh A,Kebebew E (2018) Probability of positive genetic testing results in patients with family history of primary hyperparathyroidism. J Am Coll Surg 226: 933-938.

    Article  PubMed  PubMed Central  Google Scholar 

  65. Juhlin C, Larsson C, Yakoleva T, Leibiger I, Leibiger B, Alimov A, Weber G, Hoog A,Villablanca A (2006) Loss of parafibromin expression in a subset of parathyroid adenomas. Endocr Relat Cancer 13: 509-523.

    Article  CAS  PubMed  Google Scholar 

  66. Erovic BM, Harris L, Jamali M, Goldstein DP, Irish JC, Asa SL,Mete O (2012) Biomarkers of parathyroid carcinoma. Endocr Pathol 23: 221-231.

    Article  CAS  PubMed  Google Scholar 

  67. Hirokawa M, Suzuki A, Higuchi M, Hayashi T, Kuma S, Miya A,Miyauchi A (2021) Histological alterations following fine-needle aspiration for parathyroid adenoma: incidence and diagnostic problems. Pathol Int 71: 400-405.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Schulte JJ, Pease G, Taxy JB, Hall C,Cipriani NA (2021) Distinguishing parathyromatosis, atypical parathyroid adenomas, and parathyroid carcinomas utilizing histologic and clinical features. Head Neck Pathol 15: 727-736.

    Article  PubMed  PubMed Central  Google Scholar 

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

    Article  PubMed  PubMed Central  Google Scholar 

  70. Norman J, Politz D,Browarsky I (2007) Diagnostic aspiration of parathyroid adenomas causes severe fibrosis complicating surgery and final histologic diagnosis. Thyroid 17: 1251-1255.

    Article  PubMed  Google Scholar 

  71. Fernandez-Ranvier GG, Khanafshar E, Jensen K, Zarnegar R, Lee J, Kebebew E, Duh QY,Clark OH (2007) Parathyroid carcinoma, atypical parathyroid adenoma, or parathyromatosis? Cancer 110: 255-264.

    Article  PubMed  Google Scholar 

  72. Alwaheeb S, Rambaldini G, Boerner S, Coire C, Fiser J,Asa SL (2006) Worrisome histologic alterations following fine-needle aspiration of the parathyroid. J Clin Pathol 59: 1094-1096.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Fraker DL, Travis WD, Merendino JJ, Jr., Zimering MB, Streeten EA, Weinstein LS, Marx SJ, Spiegel AM, Aurbach GD, Doppman JL,et al. (1991) Locally recurrent parathyroid neoplasms as a cause for recurrent and persistent primary hyperparathyroidism. Ann Surg 213: 58-65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Fitko R, Roth SI, Hines JR, Roxe DM,Cahill E (1990) Parathyromatosis in hyperparathyroidism. Hum Pathol 21: 234-237.

    Article  CAS  PubMed  Google Scholar 

  75. Sarquis MS, Silveira LG, Pimenta FJ, Dias EP, Teh BT, Friedman E, Gomez RS, Tavares GC, Eng C,De Marco L (2008) Familial hyperparathyroidism: surgical outcome after 30 years of follow-up in three families with germline hrpt2 mutations. Surgery 143: 630-640.

    Article  PubMed  Google Scholar 

  76. Iacobone M, Masi G, Barzon L, Porzionato A, Macchi V, Ciarleglio FA, Palu G, De Caro R, Viel G,Favia G (2009) Hyperparathyroidism-jaw tumor syndrome: a report of three large kindred. Langenbecks Arch Surg 394: 817-825.

    Article  PubMed  Google Scholar 

  77. Korpi-Hyovalti E, Cranston T, Ryhanen E, Arola J, Aittomaki K, Sane T, Thakker RV,Schalin-Jantti C (2014) Cdc73 intragenic deletion in familial primary hyperparathyroidism associated with parathyroid carcinoma. J Clin Endocrinol Metab 99: 3044-3048.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Simonds WF, Robbins CM, Agarwal SK, Hendy GN, Carpten JD,Marx SJ (2004) Familial isolated hyperparathyroidism is rarely caused by germline mutation in hrpt2, the gene for the hyperparathyroidism-jaw tumor syndrome. J Clin Endocrinol Metab 89: 96-102.

    Article  CAS  PubMed  Google Scholar 

  79. Howell VM, Haven CJ, Kahnoski K, Khoo SK, Petillo D, Chen J, Fleuren GJ, Robinson BG, Delbridge LW, Philips J, Nelson AE, Krause U, Hammje K, Dralle H, Hoang-Vu C, Gimm O, Marsh DJ, Morreau H,Teh BT (2003) Hrpt2 mutations are associated with malignancy in sporadic parathyroid tumours. J Med Genet 40: 657-663.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Haven CJ, van Puijenbroek M, Karperien M, Fleuren GJ,Morreau H (2004) Differential expression of the calcium sensing receptor and combined loss of chromosomes 1q and 11q in parathyroid carcinoma. J Pathol 202: 86-94.

    Article  CAS  PubMed  Google Scholar 

  81. Hunt JL, Carty SE, Yim JH, Murphy J,Barnes L (2005) Allelic loss in parathyroid neoplasia can help characterize malignancy. Am J Surg Pathol 29: 1049-1055.

    Article  PubMed  Google Scholar 

  82. Cetani F, Ambrogini E, Viacava P, Pardi E, Fanelli G, Naccarato AG, Borsari S, Lemmi M, Berti P, Miccoli P, Pinchera A,Marcocci C (2007) Should parafibromin staining replace hrtp2 gene analysis as an additional tool for histologic diagnosis of parathyroid carcinoma? Eur J Endocrinol 156: 547-554.

    Article  CAS  PubMed  Google Scholar 

  83. Cavaco BM, Santos R, Felix A, Carvalho D, Lopes JM, Domingues R, Sirgado M, Rei N, Fonseca F, Santos JR, Sobrinho L,Leite V (2011) Identification of de novo germline mutations in the hrpt2 gene in two apparently sporadic cases with challenging parathyroid tumor diagnoses. Endocr Pathol 22: 44-52.

    Article  CAS  PubMed  Google Scholar 

  84. Erickson LA, Jin L, Wollan P, Thompson GB, van Heerden JA,Lloyd RV (1999) Parathyroid hyperplasia, adenomas, and carcinomas: differential expression of p27kip1 protein. Am J Surg Pathol 23: 288-295.

    Article  CAS  PubMed  Google Scholar 

  85. Stojadinovic A, Hoos A, Nissan A, Dudas ME, Cordon-Cardo C, Shaha AR, Brennan MF, Singh B,Ghossein RA (2003) Parathyroid neoplasms: clinical, histopathological, and tissue microarray-based molecular analysis. Hum Pathol 34: 54-64.

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  87. Howell VM, Gill A, Clarkson A, Nelson AE, Dunne R, Delbridge LW, Robinson BG, Teh BT, Gimm O,Marsh DJ (2009) Accuracy of combined protein gene product 9.5 and parafibromin markers for immunohistochemical diagnosis of parathyroid carcinoma. J Clin Endocrinol Metab 94: 434-441.

    Article  CAS  PubMed  Google Scholar 

  88. Osawa N, Onoda N, Kawajiri H, Tezuka K, Takashima T, Ishikawa T, Miyauchi A, Hirokawa M, Wakasa K,Hirakawa K (2009) Diagnosis of parathyroid carcinoma using immunohistochemical staining against htert. Int J Mol Med 24: 733-741.

    CAS  PubMed  Google Scholar 

  89. Truran PP, Johnson SJ, Bliss RD, Lennard TW,Aspinall SR (2014) 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.

    Article  PubMed  Google Scholar 

  90. Barazeghi E, Gill AJ, Sidhu S, Norlen O, Dina R, Palazzo FF, Hellman P, Stalberg P,Westin G (2017) A role for tet2 in parathyroid carcinoma. Endocr Relat Cancer 24: 329-338.

    Article  CAS  PubMed  Google Scholar 

  91. Akirov A, Asa SL, Larouche V, Mete O, Sawka AM, Jang R,Ezzat S (2019) The clinicopathological spectrum of parathyroid carcinoma. Front Endocrinol (Lausanne) 10: 731.

    Article  Google Scholar 

  92. Davies MP, John Evans TW, Tahir F,Balasubramanian SP (2021) Parathyroid cancer: a systematic review of diagnostic biomarkers. Surgeon 19: e536-e548.

    Article  PubMed  Google Scholar 

  93. Silva-Figueroa AM, Bassett R, Jr., Christakis I, Moreno P, Clarke CN, Busaidy NL, Grubbs EG, Lee JE, Perrier ND,Williams MD (2019) Using a novel diagnostic nomogram to differentiate malignant from benign parathyroid neoplasms. Endocr Pathol 30: 285-296.

    Article  CAS  PubMed  Google Scholar 

  94. Cetani F, Marcocci C, Torregrossa L,Pardi E (2019) Atypical parathyroid adenomas: challenging lesions in the differential diagnosis of endocrine tumors. Endocr Relat Cancer 26: R441-R464.

    Article  CAS  PubMed  Google Scholar 

  95. Bondeson L, Sandelin K,Grimelius L (1993) Histopathological variables and DNA cytometry in parathyroid carcinoma. Am J Surg Pathol 17: 820-829.

    Article  CAS  PubMed  Google Scholar 

  96. Schneider R, Bartsch-Herzog S, Ramaswamy A, Bartsch DK,Karakas E (2015) Immunohistochemical expression of e-cadherin in atypical parathyroid adenoma. World J Surg 39: 2477-2483.

    Article  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  98. Arribas B, Cristobal E, Alcazar JA, Tardio J, Matinez-Montero JC, Polo JR, Carrion R, Gil L, Azanedo M, Rojas JM,Menarguez J (2000) P53/mdm2 pathway aberrations in parathyroid tumors: P21(waf-1) and mdm2 are frequently overexpressed in parathyroid adenomas. Endocr Pathol 11: 251-257.

    Article  CAS  PubMed  Google Scholar 

  99. Juhlin CC, Zedenius J,Hoog A (2020) Clinical routine application of the second-generation neuroendocrine markers isl1, insm1, and secretagogin in neuroendocrine neoplasia: staining outcomes and potential clues for determining tumor origin. Endocr Pathol 31: 401-410.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Yu Q, Hardin H, Chu YH, Rehrauer W,Lloyd RV (2019) Parathyroid neoplasms: immunohistochemical characterization and long noncoding rna (lncrna) expression. Endocr Pathol 30: 96-105.

    Article  CAS  PubMed  Google Scholar 

  101. O'Connor DT,Deftos LJ (1986) Secretion of chromogranin a by peptide-producing endocrine neoplasms. N Engl J Med 314: 1145-1151.

    Article  CAS  PubMed  Google Scholar 

  102. Altinay S, Erozgur B, Dural AC, Volante M,Papotti MG (2021) Monoclonal/polyclonal pax-8, pth and gata3 immunohistochemistry in parathyroid lesions. J Endocrinol Invest 44: 1997-2008.

    Article  CAS  PubMed  Google Scholar 

  103. Juhlin CC, Haglund F, Villablanca A, Forsberg L, Sandelin K, Branstrom R, Larsson C,Hoog A (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: 481-492.

    CAS  PubMed  Google Scholar 

  104. Cryns VL, Rubio MP, Thor AD, Louis DN,Arnold A (1994) P53 abnormalities in human parathyroid carcinoma. J Clin Endocrinol Metab 78: 1320-1324.

    CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  106. Lloyd RV, Carney JA, Ferreiro JA, Jin L, Thompson GB, Van Heerden JA, Grant CS,Wollan PC (1995) Immunohistochemical analysis of the cell cycle-associated antigens ki-67 and retinoblastoma protein in parathyroid carcinomas and adenomas. Endocr Pathol 6: 279-287.

    Article  PubMed  Google Scholar 

  107. Farnebo F, Auer G, Farnebo LO, Teh BT, Twigg S, Aspenblad U, Thompson NW, Grimelius L, Larsson C,Sandelin K (1999) Evaluation of retinoblastoma and ki-67 immunostaining as diagnostic markers of benign and malignant parathyroid disease. World J Surg 23: 68-74.

    Article  CAS  PubMed  Google Scholar 

  108. 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: 412-416.

    CAS  PubMed  Google Scholar 

  109. Hsi ED, Zukerberg LR, Yang WI,Arnold A (1996) Cyclin d1/prad1 expression in parathyroid adenomas: an immunohistochemical study. J Clin Endocrinol Metab 81: 1736-1739.

    CAS  PubMed  Google Scholar 

  110. Cryns VL, Thor A, Xu HJ, Hu SX, Wierman ME, Vickery AL, Jr., Benedict WF,Arnold A (1994) Loss of the retinoblastoma tumor-suppressor gene in parathyroid carcinoma. N Engl J Med 330: 757-761.

    Article  CAS  PubMed  Google Scholar 

  111. Vargas MP, Vargas HI, Kleiner DE,Merino MJ (1997) The role of prognostic markers (mib-1, rb, and bcl-2) in the diagnosis of parathyroid tumors. Mod Pathol 10: 12-17.

    CAS  PubMed  Google Scholar 

  112. Sulaiman L, Juhlin CC, Nilsson IL, Fotouhi O, Larsson C,Hashemi J (2013) Global and gene-specific promoter methylation analysis in primary hyperparathyroidism. Epigenetics 8: 646-655.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Hahn MA, Howell VM, Gill AJ, Clarkson A, Weaire-Buchanan G, Robinson BG, Delbridge L, Gimm O, Schmitt WD, Teh BT,Marsh DJ (2010) Cdc73/hrpt2 cpg island hypermethylation and mutation of 5'-untranslated sequence are uncommon mechanisms of silencing parafibromin in parathyroid tumors. Endocr Relat Cancer 17: 273-282.

    Article  CAS  PubMed  Google Scholar 

  114. Tan MH, Morrison C, Wang P, Yang X, Haven CJ, Zhang C, Zhao P, Tretiakova MS, Korpi-Hyovalti E, Burgess JR, Soo KC, Cheah WK, Cao B, Resau J, Morreau H,Teh BT (2004) Loss of parafibromin immunoreactivity is a distinguishing feature of parathyroid carcinoma. Clin Cancer Res 10: 6629-6637.

    Article  CAS  PubMed  Google Scholar 

  115. Hodgson A, Pakbaz S, Tayyari F, Young JEM,Mete O (2019) Diagnostic pitfall: parathyroid carcinoma expands the spectrum of calcitonin and calcitonin gene-related peptide expressing neuroendocrine neoplasms. Endocr Pathol 30: 168-172.

    Article  PubMed  Google Scholar 

  116. Juhlin CC, Haglund F, Obara T, Arnold A, Larsson C,Hoog A (2011) Absence of nucleolar parafibromin immunoreactivity in subsets of parathyroid malignant tumours. Virchows Arch 459: 47-53.

    Article  CAS  PubMed  Google Scholar 

  117. Panicker LM, Zhang JH, Dagur PK, Gastinger MJ,Simonds WF (2010) Defective nucleolar localization and dominant interfering properties of a parafibromin l95p missense mutant causing the hyperparathyroidism-jaw tumor syndrome. Endocr Relat Cancer 17: 513-524.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Quinn CE, Healy J, Lebastchi AH, Brown TC, Stein JE, Prasad ML, Callender GG, Carling T,Udelsman R (2015) Modern experience with aggressive parathyroid tumors in a high-volume new england referral center. J Am Coll Surg 220: 1054-1062.

    Article  PubMed  Google Scholar 

  119. Heppner C, Kester MB, Agarwal SK, Debelenko LV, Emmert-Buck MR, Guru SC, Manickam P, Olufemi SE, Skarulis MC, Doppman JL, Alexander RH, Kim YS, Saggar SK, Lubensky IA, Zhuang Z, Liotta LA, Chandrasekharappa SC, Collins FS, Spiegel AM, Burns AL,Marx SJ (1997) Somatic mutation of the men1 gene in parathyroid tumours. Nat Genet 16: 375-378.

    Article  CAS  PubMed  Google Scholar 

  120. Thakker RV, Bouloux P, Wooding C, Chotai K, Broad PM, Spurr NK, Besser GM,O'Riordan JL (1989) Association of parathyroid tumors in multiple endocrine neoplasia type 1 with loss of alleles on chromosome 11. N Engl J Med 321: 218-224.

    Article  CAS  PubMed  Google Scholar 

  121. Nakamura Y, Larsson C, Julier C, Bystrom C, Skogseid B, Wells S, Oberg K, Carlson M, Taggart T, O'Connell P,et al. (1989) Localization of the genetic defect in multiple endocrine neoplasia type 1 within a small region of chromosome 11. Am J Hum Genet 44: 751-755.

    CAS  PubMed  PubMed Central  Google Scholar 

  122. Larsson C, Skogseid B, Oberg K, Nakamura Y,Nordenskjold M (1988) Multiple endocrine neoplasia type 1 gene maps to chromosome 11 and is lost in insulinoma. Nature 332: 85-87.

    Article  CAS  PubMed  Google Scholar 

  123. Agarwal SK, Guru SC, Heppner C, Erdos MR, Collins RM, Park SY, Saggar S, Chandrasekharappa SC, Collins FS, Spiegel AM, Marx SJ,Burns AL (1999) Menin interacts with the ap1 transcription factor jund and represses jund-activated transcription. Cell 96: 143-152.

    Article  CAS  PubMed  Google Scholar 

  124. Hughes CM, Rozenblatt-Rosen O, Milne TA, Copeland TD, Levine SS, Lee JC, Hayes DN, Shanmugam KS, Bhattacharjee A, Biondi CA, Kay GF, Hayward NK, Hess JL,Meyerson M (2004) Menin associates with a trithorax family histone methyltransferase complex and with the hoxc8 locus. Mol Cell 13: 587-597.

    Article  CAS  PubMed  Google Scholar 

  125. Hong YA, Park KC, Kim BK, Lee J, Sun WY, Sul HJ, Hwang KA, Choi WJ, Chang YK, Kim SY, Shin S,Park J (2021) Analyzing genetic differences between sporadic primary and secondary/tertiary hyperparathyroidism by targeted next-generation panel sequencing. Endocr Pathol 32: 501-512.

    Article  CAS  PubMed  Google Scholar 

  126. Cromer MK, Starker LF, Choi M, Udelsman R, Nelson-Williams C, Lifton RP,Carling T (2012) Identification of somatic mutations in parathyroid tumors using whole-exome sequencing. J Clin Endocrinol Metab 97: E1774-1781.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Costa-Guda J, Marinoni I, Molatore S, Pellegata NS,Arnold A (2011) Somatic mutation and germline sequence abnormalities in cdkn1b, encoding p27kip1, in sporadic parathyroid adenomas. J Clin Endocrinol Metab 96: E701-706.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Arnold A, Kim HG, Gaz RD, Eddy RL, Fukushima Y, Byers MG, Shows TB,Kronenberg HM (1989) Molecular cloning and chromosomal mapping of DNA rearranged with the parathyroid hormone gene in a parathyroid adenoma. J Clin Invest 83: 2034-2040.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Arya AK, Bhadada SK, Singh P, Sachdeva N, Saikia UN, Dahiya D, Behera A, Bhansali A,Rao SD (2017) Promoter hypermethylation inactivates cdkn2a, cdkn2b and rassf1a genes in sporadic parathyroid adenomas. Sci Rep 7: 3123.

    Article  PubMed  PubMed Central  Google Scholar 

  130. Kato J, Matsushime H, Hiebert SW, Ewen ME,Sherr CJ (1993) Direct binding of cyclin d to the retinoblastoma gene product (prb) and prb phosphorylation by the cyclin d-dependent kinase cdk4. Genes Dev 7: 331-342.

    Article  CAS  PubMed  Google Scholar 

  131. Brewer K, Costa-Guda J,Arnold A (2019) Molecular genetic insights into sporadic primary hyperparathyroidism. Endocr Relat Cancer 26: R53-R72.

    Article  CAS  PubMed  Google Scholar 

  132. Bradley KJ, Bowl MR, Williams SE, Ahmad BN, Partridge CJ, Patmanidi AL, Kennedy AM, Loh NY,Thakker RV (2007) Parafibromin is a nuclear protein with a functional monopartite nuclear localization signal. Oncogene 26: 1213-1221.

    Article  CAS  PubMed  Google Scholar 

  133. Hahn MA,Marsh DJ (2005) Identification of a functional bipartite nuclear localization signal in the tumor suppressor parafibromin. Oncogene 24: 6241-6248.

    Article  CAS  PubMed  Google Scholar 

  134. Yart A, Gstaiger M, Wirbelauer C, Pecnik M, Anastasiou D, Hess D,Krek W (2005) The hrpt2 tumor suppressor gene product parafibromin associates with human paf1 and rna polymerase ii. Mol Cell Biol 25: 5052-5060.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Rozenblatt-Rosen O, Hughes CM, Nannepaga SJ, Shanmugam KS, Copeland TD, Guszczynski T, Resau JH,Meyerson M (2005) The parafibromin tumor suppressor protein is part of a human paf1 complex. Mol Cell Biol 25: 612-620.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Yang YJ, Han JW, Youn HD,Cho EJ (2010) The tumor suppressor, parafibromin, mediates histone h3 k9 methylation for cyclin d1 repression. Nucleic Acids Res 38: 382-390.

    Article  CAS  PubMed  Google Scholar 

  137. Lin L, Zhang JH, Panicker LM,Simonds WF (2008) The parafibromin tumor suppressor protein inhibits cell proliferation by repression of the c-myc proto-oncogene. Proc Natl Acad Sci U S A 105: 17420-17425.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Mosimann C, Hausmann G,Basler K (2006) Parafibromin/hyrax activates wnt/wg target gene transcription by direct association with beta-catenin/armadillo. Cell 125: 327-341.

    Article  CAS  PubMed  Google Scholar 

  139. Kutahyalioglu M, Nguyen HT, Kwatampora L, Clarke C, Silva A, Ibrahim E, Waguespack SG, Cabanillas ME, Jimenez C, Hu MI, Sherman SI, Kopetz S, Broaddus R, Dadu R, Wanland K, Williams M, Zafereo M, Perrier N,Busaidy NL (2019) Genetic profiling as a clinical tool in advanced parathyroid carcinoma. J Cancer Res Clin Oncol 145: 1977-1986.

    Article  PubMed  Google Scholar 

  140. Starker LF, Svedlund J, Udelsman R, Dralle H, Akerstrom G, Westin G, Lifton RP, Bjorklund P,Carling T (2011) The DNA methylome of benign and malignant parathyroid tumors. Genes Chromosomes Cancer 50: 735-745.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Svedlund J, Auren M, Sundstrom M, Dralle H, Akerstrom G, Bjorklund P,Westin G (2010) Aberrant wnt/beta-catenin signaling in parathyroid carcinoma. Mol Cancer 9: 294.

    Article  PubMed  PubMed Central  Google Scholar 

  142. Barazeghi E, Gill AJ, Sidhu S, Norlen O, Dina R, Palazzo FF, Hellman P, Stalberg P,Westin G (2016) 5-hydroxymethylcytosine discriminates between parathyroid adenoma and carcinoma. Clin Epigenetics 8: 31.

    Article  PubMed  PubMed Central  Google Scholar 

  143. Mao X, Wu Y, Yu S,Chen J (2021) Genetic alteration profiles and clinicopathological associations in atypical parathyroid adenoma. Int J Genomics 2021: 6666257.

    Article  PubMed  PubMed Central  Google Scholar 

  144. Haven CJ, Howell VM, Eilers PH, Dunne R, Takahashi M, van Puijenbroek M, Furge K, Kievit J, Tan MH, Fleuren GJ, Robinson BG, Delbridge LW, Philips J, Nelson AE, Krause U, Dralle H, Hoang-Vu C, Gimm O, Morreau H, Marsh DJ,Teh BT (2004) Gene expression of parathyroid tumors: Molecular subclassification and identification of the potential malignant phenotype. Cancer Res 64: 7405-7411.

    Article  CAS  PubMed  Google Scholar 

  145. Sulaiman L, Haglund F, Hashemi J, Obara T, Nordenstrom J, Larsson C,Juhlin CC (2012) Genome-wide and locus specific alterations in cdc73/hrpt2-mutated parathyroid tumors. PLoS One 7: e46325.

  146. Hu Y, Zhang X, Wang O, Bi Y, Xing X, Cui M, Wang M, Tao W, Liao Q,Zhao Y (2020) The genomic profile of parathyroid carcinoma based on whole-genome sequencing. Int J Cancer 147: 2446-2457.

    Article  CAS  PubMed  Google Scholar 

  147. Kang H, Pettinga D, Schubert AD, Ladenson PW, Ball DW, Chung JH, Schrock AB, Madison R, Frampton GM, Stephens PJ, Ross JS, Miller VA,Ali SM (2019) Genomic profiling of parathyroid carcinoma reveals genomic alterations suggesting benefit from therapy. Oncologist 24: 791-797.

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Laboratory Medicine and Pathology, Mayo Clinic, 200 First St SW, Rochester, MN, 55901, USA

    Lori A. Erickson

  2. Department of Pathology, University Health Network, Toronto, ON, Canada

    Ozgur Mete

  3. Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada

    Ozgur Mete

  4. Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden

    C. Christofer Juhlin

  5. Department of Pathology and Cancer Diagnostics, Karolinska University Hospital, Stockholm, Sweden

    C. Christofer Juhlin

  6. Institute of Pathology, University of Bern, Bern, Switzerland

    Aurel Perren

  7. Department of Anatomical Pathology, NSW Health Pathology, Royal North Shore Hospital, St Leonards, Sydney, NSW, Australia

    Anthony J. Gill

  8. Cancer Diagnosis and Pathology Research Group, Kolling Institute of Medical Research, Royal North Shore Hospital, St Leonards, Sydney, NSW, Australia

    Anthony J. Gill

  9. University of Sydney, Sydney, NSW, Australia

    Anthony J. Gill

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Erickson, L.A., Mete, O., Juhlin, C.C. et al. Overview of the 2022 WHO Classification of Parathyroid Tumors. Endocr Pathol 33, 64–89 (2022). https://doi.org/10.1007/s12022-022-09709-1

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