Parathyroid Cancer and the
            <i>CDC73</i>
            Tumor Suppressor Gene

Simonds, William F.

doi:10.2217/ije.14.2

Cited by 8 publications

(21 citation statements)

References 87 publications

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“…Consequently, the study and understanding of their molecular biology is important to uncover novel diagnostic, prognostic and predictive biomarkers to improve patient care. With recent advances in molecular pathology, a wide array of genetic and epigenetic alterations, as well as biomarkers, have been uncovered in parathyroid cancer 42 98 141 156 158 163 210 216…”

Section: Pathogenesis and Molecular Genetics Of Hptmentioning

confidence: 99%

Clinicopathological correlates of hyperparathyroidism

2015

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Hyperparathyroidism is a common endocrine disorder with potential complications on the skeletal, renal, neurocognitive and cardiovascular systems. While most cases (95%) occur sporadically, about 5% are associated with a hereditary syndrome: multiple endocrine neoplasia syndromes (MEN-1, MEN-2A, MEN-4), hyperparathyroidism-jaw tumour syndrome (HPT-JT), familial hypocalciuric hypercalcaemia (FHH-1, FHH-2, FHH-3), familial hypercalciuric hypercalcaemia, neonatal severe hyperparathyroidism and isolated familial hyperparathyroidism. Recently, molecular mechanisms underlying possible tumour suppressor genes (MEN1, CDC73/HRPT2, CDKIs, APC, SFRPs, GSK3β, RASSF1A, HIC1, RIZ1, WT1, CaSR, GNA11, AP2S1) and proto-oncogenes (CCND1/PRAD1, RET, ZFX, CTNNB1, EZH2) have been uncovered in the pathogenesis of hyperparathyroidism. While bi-allelic inactivation of CDC73/HRPT2 seems unique to parathyroid malignancy, aberrant activation of cyclin D1 and Wnt/β-catenin signalling has been reported in benign and malignant parathyroid tumours. Clinicopathological correlates of primary hyperparathyroidism include parathyroid adenoma (80–85%), hyperplasia (10–15%) and carcinoma (<1–5%). Secondary hyperparathyroidism generally presents with diffuse parathyroid hyperplasia, whereas tertiary hyperparathyroidism reflects the emergence of autonomous parathyroid hormone (PTH)-producing neoplasm(s) from secondary parathyroid hyperplasia. Surgical resection of abnormal parathyroid tissue remains the only curative treatment in primary hyperparathyroidism, and parathyroidectomy specimens are frequently encountered in this setting. Clinical and biochemical features, including intraoperative PTH levels, number, weight and size of the affected parathyroid gland(s), are crucial parameters to consider when rendering an accurate diagnosis of parathyroid proliferations. This review provides an update on the expanding knowledge of hyperparathyroidism and highlights the clinicopathological correlations of this prevalent disease.

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Section: Pathogenesis and Molecular Genetics Of Hptmentioning

confidence: 99%

Clinicopathological correlates of hyperparathyroidism

2015

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“…Parathyroid carcinoma is a highly aggressive endocrine tumor, with an annual incidence of less than 1 per million (1)(2)(3)(4)(5)(6)(7)(8). over 90% of patients present with excess parathyroid hormone (PTH), representing <1-5% of all patients with primary hyperparathyroidism (1,(8)(9)(10)(11).…”

Section: Introductionmentioning

confidence: 99%

Parathyroid carcinoma: diagnosis and clinical implications

Duan¹,

Mete²

2015

TJPATH

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Parathyroid carcinoma is a rare type of endocrine cancer, with significant morbidity and mortality associated with parathyroid hormone (PTH)-mediated hypercalcemia. Concerning clinical features for parathyroid cancer include severe hypercalcemia (albumin-corrected calcium > 3 mmol/L), a palpable neck mass ( > 3 cm), 3rd/2nd generation PTH assay ratio ( > 1), and intraoperative suspicion of local invasion or regional metastasis. A definite diagnosis of malignancy is rendered when a parathyroid tumor presents one of the following clinicopathological features: (1) vascular invasion, (2) perineural invasion, (3) gross invasion into adjacent anatomical structures, and/or (4) metastasis. In difficult cases, the use of ancillary biomarkers is critical to establish an accurate diagnosis. Recent advances in molecular pathology have uncovered the important role of CDC73/HRPT2, a tumor suppressor gene deregulated in parathyroid carcinomas. Loss of nuclear and/or nucleolar expression of parafibromin (the gene product of CDC73/HRPT2) is now regarded as a diagnostic, prognostic and predictive biomarker for parathyroid carcinoma. Furthermore, over 15-20% of seemingly sporadic parathyroid carcinomas have underlying germline CDC73/HRPT2 mutations. As a result, many centers have integrated the use of ancillary biomarkers, notably parafibromin staining, in their routine practise. Radical surgery with en bloc resection has emerged as a primary treatment modality in parathyroid cancer, achieving cure in some patients. However, in those with inoperable disease, there remains a dire need for new therapies, as current treatments are largely ineffective. This review provides an update on the current knowledge of parathyroid carcinoma and highlights its exciting changes in endocrine practice.

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“…HPT-JT is a rare syndrome that was not widely-recognized until the 1990s [1,88,89]. The expressions among adults are PHPT (80 %), cemento-ossifying fibromas of the jaw (30 %), renal cysts (20 %), renal hamartoma, Wilms tumor, and uterine tumor in women [90].…”

Section: Clinical Traits Of Hpt-jtmentioning

confidence: 99%

“…Parathyroid or extra-parathyroid cancer is prominent (greater than 20 % penetrance by age 50 years) with substantial lethal potential in three syndromes (MEN1, MEN2A, HPT-JT) [50,89,118]. The possibilities for prevention or cure of cancer are specific around each syndrome (▶table 2) [49,99,119].…”

Section: Treatment Of Phpt or Cancer In Fhmentioning

confidence: 99%

Familial Hyperparathyroidism – Disorders of Growth and Secretion in Hormone-Secretory Tissue

Marx

Lourenço

2017

Horm Metab Res

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Six syndromes of familial hyperparathyroidism are compared: 1) Familial hypocalciuric hypercalcemia (FHH) expresses primary hyperparathyroidism (PHPT) beginning at birth with lifelong hypercalcemia. There is nonsuppressed PTH secretion from outwardly normal parathyroid glands. It reflects germline heterozygous mutation in or. 2) Neonatal severe primary hyperparathyroidism is severest of the six syndromes. It requires urgent total parathyroidectomy in infancy. It usually reflects biallelic inactivation of the 3) Multiple endocrine neoplasia type 1 (MEN1) is most frequently expressed as PHPT with asymmetric enlargement of 3-4 parathyroids. Benign or malignant tumors may occur among 30 other tissues. It is predisposed by germline inactivation of or rarely by inactivation of a cyclin dependent kinase inhibitor, and then termed MEN4. 4) Multiple endocrine neoplasia type 2A from activating mutation rarely presents as familial hyperparathyroidism, because medullary thyroid cancer and pheochromocytoma are more prominent. 5) Hyperparathyroidism-jaw tumor syndrome (HPT-JT) has frequent PHPT and benign jaw tumors. Twenty percent develop parathyroid cancer. It is predisposed by inactivating mutation in. 6) Familial isolated hyperparathyroidism causes multiple parathyroid tumors. It can be an incomplete expression of FHH, MEN1, HPT-JT or even of relatives without a shared driver mutation. However, in 20% of families it reflects activating mutation. Five of the PHPT syndromes reflect overgrowth of parathyroid tissue; in contrast, familial hypocalciuric hypercalcemia reflects dysregulation of PTH secretion with little or no parathyroid overgrowth. These differences underlie major differences in clinical expression.

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Parathyroid Cancer and the CDC73 Tumor Suppressor Gene

Cited by 8 publications

References 87 publications

Clinicopathological correlates of hyperparathyroidism

Clinicopathological correlates of hyperparathyroidism

Parathyroid carcinoma: diagnosis and clinical implications

Familial Hyperparathyroidism – Disorders of Growth and Secretion in Hormone-Secretory Tissue

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