Abstract
Parathyroid neoplasms encompass a spectrum of proliferative lesions that include adenomas, atypical adenomas, and carcinomas. While the diagnosis of adenomas is usually straightforward, parathyroid carcinomas (PTCAs) often present considerable diagnostic challenges. Fibrosis and mitotic activity are common in PTCAs, but these features are not specific for malignancy. An unequivocal diagnosis of PTCA should be restricted to those tumors that invade adjacent soft tissues, thyroid gland, blood vessels, or perineural spaces or to those cases with documented metastases. Atypical adenomas include those tumors that share some of the features of PTCA but lack evidence of invasive growth. A variety of genetic abnormalities, including HRPT2 mutations, occur in PTCAs. Mutations of the HRPT2 gene, which encodes parafibromin, are responsible for the development of the hyperparathyroidism–jaw tumor syndrome and have also been implicated in the development of a high proportion of sporadic PTCAs. Correlative immunohistochemical studies have revealed nuclear parafibromin immunoreactivity in adenomas but absence or partial loss of staining in PTCAs. While parafibromin immunohistochemistry represents an important step in the ability to diagnose PTCA, additional studies will be required to test the validity of this approach and to determine the roles of other genes in the development of these tumors.
Similar content being viewed by others
References
DeLellis RA, Mazzalia P, Mangray S. Primary hyperparathyroidism: a current perspective. Arch Pathol Lab Med 132:1251–62, 2008.
Bondeson L, Grimeluis L, DeLellis RA, et al. Parathyroid carcinoma. In: DeLellis RA, Lloyd RV, Heitz PN, Eng C, eds. Pathology and genetics of tumours of endocrine organs (WHO classification). Lyon: IARC, pp. 224–7, 2004.
DeLellis RA. Parathyroid carcinoma. An overview. Adv Anat Pathol 12:53–1, 2005. doi:10.1097/01.pap.0000151319.42376.d4.
Norris EH. Collective review. Carcinoma of the parathyroid glands with a preliminary report of 3 cases. Int Abstracts of Surg 86:1–21, 1948.
Castleman B. Tumors of the Parathyroid Glands. Atlas of Tumor Pathology. Section IV—Fascicle 15. Armed Forces Institute of Pathology. Washington, DC 1952.
Schantz A, Castleman B. Parathyroid carcinoma. A study of 70 cases. Cancer 31:600–5, 1973. doi:10.1002/1097-0142(197303)31:3<600::AID-CNCR2820310316>3.0.CO;2-0.
Snover D, Foucar K. Mitotic activity in benign thyroid diseases. Am J Clin Pathol 75:345–7, 1981.
DeLellis RA. Tumors of the parathyroid glands. Atlas of tumor pathology, 3rd series, fascicle 6. Washington DC: Armed Forces Institute of Pathology, 1993.
Reddick RL, Costa J, Marx SJ. Parathyroid hyperplasia and parathyromatosis. Lancet 1:549, 1977. doi:10.1016/S0140-6736(77)91414-3.
Levin KE, Chew KL, Ljung BM. Deoxyribonucleic acid cytometry helps identify parathyroid carcinomas. J Clin Endocrinol Metab 67:770–4, 1988.
Bondeson L, Sandelin K, Grimeluis L. Histopathological variables and DNA cytometry in parathyroid carcinoma. Am J Surg Pathol 17:820–9, 1993. doi:10.1097/00000478-199308000-00007.
Guiter GE, DeLellis RA. Risk of recurrence or metastasis in atypical parathyroid adenoma. Mod Pathol 15:115A, 2002, (Abstract).
Abbona GC, Papotti M, Gasparri G, Bussolati G. Proliferative activity in parathyroid tumors as detected by KI-67 immunostaining. Hum Pathol 26:135–8, 1995. doi:10.1016/0046-8177(95)90028-4.
Erickson LA, Jin L, Wollan P, Thompson GB, van Heerden LA, Lloyd RV. Parathyroid hyperplasia, adenomas and carcinoma: differential expression of p27kip1 protein. Am J Surg Pathol 23:288–5, 1999. doi:10.1097/00000478-199903000-00007.
Stojadinovic A, Hoos A, Nissan A, et al. Parathyroid neoplasms; clinical, histopathological and tissue microarray-based molecular analysis. Hum Pathol 34:54–4, 2003. doi:10.1053/hupa.2003.55.
Kytola S, Farnebo F, Obara T, et al. Patterns of chromosomal imbalances in parathyroid carcinomas. Am J Pathol 157:570–6, 2000.
Erickson LA, Jalal SM, Harwood A, Sherer B, Jin L, Lloyd RV. Analysis of parathyroid neoplasms by interphase fluorescence in situ hybridization. Am J Surg Pathol 38:578–4, 2004. doi:10.1097/00000478-200405000-00003.
Haven CJ, van Puijenbroek M, Karperien M, Fleuren GJ, Morreau H. Differential expression of the calcium sensing receptor and combined loss of chromosome 1p and 11q in parathyroid carcinoma. J Pathol 202:86–4, 2004. doi:10.1002/path.1489.
Valimaki S, Forsberg L, Farnebo LO, Larsson C. Distinct target regions for chromosome 1p deletions in parathyroid adenomas and carcinomas. Int J Oncol 21:727–5, 2002.
Cryns VT, Thor A, Xu HJ. Loss of the retinoblastoma tumor suppressor gene in parathyroid carcinoma. N Engl J Med 330:757–1, 1994. doi:10.1056/NEJM199403173301105.
Pearce SH, Trump D, Wooding C, Sheppard MN, Clayton RN, Thakker RV. Loss of heterozygosity studies at the retinoblastoma and breast cancer susceptibility BRCA2 loci in pituitary, parathyroid, pancreatic and carcinoid tumors. Clin Endocrinol (Oxf) 45:195–200, 1996. doi:10.1046/j.1365-2265.1996.d01-1561.x.
Cetani F, Pardi E, Viacava P, et al. A reappraisal of the Rb1 gene abnormalities in the diagnosis of parathyroid carcinoma. Clin Endocrinol (Oxf) 60:99–106, 2004. doi:10.1111/j.1365-2265.2004.01954.x.
Shattuck TM, Kim TS, Costa J, et al. Mutational analysis of RB and BRCA2 as candidate tumor suppressor genes in parathyroid carcinomas. Clin Endocrinol (Oxf) 59:180–9, 2003. doi:10.1046/j.1365-2265.2003.01814.x.
Carpten JD, Robbins CM, Villablanca A, et al. HRPT2 encoding parafibromin is mutated in hyperparathyroidism–jaw tumor syndrome. Nat Genet 32:676–80, 2002. doi:10.1038/ng1048.
Teh BT, Sweet KM, Morrison CD. Hyperparathyroidism–jaw tumor syndromeIn: DeLellis RA, Lloyd RV, Heitz PN, Eng C, eds. Pathology and genetics of tumours of endocrine organs (WHO classification).. Lyon: IARC, pp. 228–9, 2004.
Howell VM, Haven CJ, Kahnoski K, et al. HRPT2 mutations are associated with malignancy in sporadic parathyroid tumors. J Med Genet 40:657–3, 2003. doi:10.1136/jmg.40.9.657.
Shattuck TM, Valimaki S, Obara T, et al. somatic and germline mutations of the HRPT2 gene in sporadic parathyroid carcinoma. N Engl J Med 349:1722–29, 2003. doi:10.1056/NEJMoa031237.
Tan MH, Morrison C, Wang P, et al. Loss of parafibromin immunoreactivity is a distinguishing feature of parathyroid carcinoma. Clin Cancer Res 10:6629–7, 2004. doi:10.1158/1078-0432.CCR-04-0493.
Juhlin C, Larsson C, Yakoleva T, et al. Loss of parafibromin expression in a subset of parathyroid adenomas. Endocr Relat Cancer 13:509–3, 2006. doi:10.1677/erc.1.01058.
Gill AJ, Clarkson A, Gimm O, et al. Loss of nuclear expression of parafibromin distinguishes parathyroid carcinomas and hyperparathyroidism–jaw tumor associated adenomas from sporadic parathyroid adenomas and hyperplasias. Am J Surg Pathol 30:1140–49, 2006. doi:10.1097/01.pas.0000209827.39477.4f.
Cetani F, Ambrogini E, Viacava P, et al. Should parafibromin staining replace HRPT2 gene analysis as an additional tool for histologic diagnosis of parathyroid carcinoma. Europ J Endocrinol 156:547–4, 2007. doi:10.1530/EJE-06-0720.
Juhlin CC, Villablanca A, Sandelin K, et al. Parafibromin immunoreactivity; its use as an additional diagnostic marker for parathyroid tumor classification. Endocr Relat Cancer 14:501–2, 2007. doi:10.1677/ERC-07-0021.
Tominaga Y, Tsuzuki T, Matsuoka A, et al. Expression of parafibromin in distant metastatic parathyroid tumors in patients with advanced secondary hyperparathyroidism due to chronic kidney disease. World J Surg 32:815–1, 2008. doi:10.1007/s00268-007-9458-8.
Mangray S, Kurek KC, Sabo E, DeLellis RA. Immunohistochemical expression of parafibromin is of limited value in distinguishing parathyroid carcinoma from adenoma. Mod Pathol 21:108A, 2008, (abstract).
Mangray S, DeLellis RA. Parafibromin s a tool for the diagnosis of parathyroid tumors (letter). Adv Anat Pathol 15:179, 2008. doi:10.1097/PAP.0b013e3181709f83.
Author information
Authors and Affiliations
Corresponding author
Additional information
This paper was presented in part at the Annual Meeting of the Endocrine Pathology Society in March, 2008.
Rights and permissions
About this article
Cite this article
DeLellis, R.A. Challenging Lesions in the Differential Diagnosis of Endocrine Tumors: Parathryoid Carcinoma. Endocr Pathol 19, 221–225 (2008). https://doi.org/10.1007/s12022-008-9050-2
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12022-008-9050-2