Novel PRUNE2 Germline Mutations in Aggressive and Benign Parathyroid Neoplasms.

Parathyroid tumors are mostly sporadic but can also occur in familial forms, including different kinds of genetic syndromes with varying phenotypes and penetrance. Recently, somatic mutations of the tumor suppressor gene PRUNE2 were found to be frequent in parathyroid cancer (PC). The germline mutation status of PRUNE2 was investigated in a large cohort of patients with parathyroid tumors from the genetically homogenous Finnish population, 15 of which had PC, 16 atypical parathyroid tumors (APT), and 6 benign parathyroid adenomas (PA). Mutations in previously established hyperparathyroidism-related genes were screened with a targeted gene panel analysis. Nine PRUNE2 germline mutations with a minor allele frequency (MAF) of <0.05 were found in our cohort. Five of these were predicted to be potentially damaging and were identified in two patients with PC, two with APT, and three with PA. The mutational status was not associated with the tumor group nor related to the clinical picture or severity of the disease. Still, the frequent finding of rare germline mutations of PRUNE2 may point to the gene playing a role in the pathogenesis of parathyroid neoplasms.

Filamin A and parafibromin expression in parathyroid carcinoma.

OBJECTIVE: Parathyroid carcinoma (PC), atypical parathyroid tumours (APT) and parathyroid adenoma (PA), all present with hypercalcemia. Diminished calcium-sensing receptor (CaSR) expression is reported in PC but is rare in benign tumours. Filamin A (FLNA) binds to the CaSR and activates the mitogen-activated protein kinase (MAPK) signalling pathway. FLNA is related to tumour aggressiveness in several cancers, but its role in parathyroid neoplasia is unknown. DESIGN: We examined FLNA, CaSR and parafibromin expression in PCs (n = 32), APTs (n = 44) and PAs (n = 77) and investigated their potential as diagnostic and/or prognostic markers. METHODS: Tissue microarray slides were immunohistochemically stained with antibodies for FLNA, CaSR and parafibromin. Staining results were correlated with detailed clinical data. RESULTS: All tumours stained positively for CaSR, with two tumours (one PC and one APT) showing diminished expression. Carcinomas were characterized by increased cytoplasmic FLNA expression compared to APTs and PAs (P = 0.004). FLNA expression was not correlated with Ki-67 proliferation index or loss of parafibromin expression. Cytoplasmic FLNA expression was also associated with higher serum calcium, PTH concentrations and male sex (P = 0.014, P = 0.017 and P = 0.049 respectively). Using a combined marker score, we found that parathyroid tumours with low FLNA expression and positive parafibromin staining were extremely likely to be benign (P < 0.001). CONCLUSION: Cytoplasmic and membranous FLNA expression is increased in parathyroid carcinomas compared to benign tumours. A combined FLNA and parafibromin expression score shows potential as a prognostic predictor of indolent behaviour in parathyroid neoplasms.

MGMT Promoter Methylation and Parathyroid Carcinoma.

CONTEXT: Parathyroid carcinoma (PC) is extremely rare. Prognosis is poor, with no known evidence-based systemic therapies. We previously reported complete remission in a patient with metastasized parathyroid carcinoma and high tumor MGMT promoter methylation status who was treated with temozolomide. OBJECTIVE: To study MGMT promoter methylation status in an additional set of aggressive parathyroid tumors. DESIGN/SETTING: The study included 12 patients: 7 with sporadic and 5 with familial primary hyperparathyroidism (two of the latter carried a CDC73 gross deletion). Patient 9 is the previously described patient with PC and high MGMT methylation status. Her daughter (patient 12) had surgery for severe primary hyperparathyroidism due to atypical parathyroid adenoma during pregnancy. Eleven patients thus had PC and one had atypical parathyroid adenoma. MGMT promoter methylation status was determined from DNA extracted from primary (n = 10) or metastatic (n = 2) tumors. A mean methylation level >20% was considered high. Patient 11 had metastatic PC and received temozolomide cycles. RESULTS: Only the previously published patient (patient 9) had high tumor MGMT promoter methylation status. This was not a characteristic of the atypical parathyroid adenoma of the daughter (patient 12). Patient 11 (CDC73 intragenic deletion) has disseminated PC, low MGMT promoter methylation, and stable disease on follow-up after temozolomide treatment. CONCLUSION: High MGMT promoter methylation status seems rare in PC. However, as demonstrated in other neuroendocrine tumors, some patients with disseminated PC might benefit from temozolomide. Demonstration of high methylation status could be a predictor of positive response to temozolomide treatment.

Somatostatin receptor expression in parathyroid neoplasms.

INTRODUCTION: Parathyroid carcinoma represents a rare cause of primary hyperparathyroidism. Distinguishing carcinoma from the benign tumors underlying primary hyperparathyroidism remains challenging. The diagnostic criteria for parathyroid carcinoma are local and/or metastatic spreading. Atypical parathyroid adenomas share other histological features with carcinomas but lack invasive growth. Somatostatin receptors are commonly expressed in different neuroendocrine tumors, but whether this also holds for parathyroid tumors remains unknown. AIM: Our aim is to examine the immunohistochemical expression of somatostatin receptor 1-5 in parathyroid typical adenomas, atypical adenomas and carcinomas. METHODS: We used a tissue microarray construct from a nationwide cohort of parathyroid carcinomas (n = 32), age- and gender-matched typical parathyroid adenomas (n = 72) and atypical parathyroid adenomas (n = 27) for immunohistochemistry of somatostatin receptor subtypes 1-5. We separately assessed cytoplasmic, membrane and nuclear expression and also investigated the associations with histological, biochemical and clinical characteristics. RESULTS: All parathyroid tumor subgroups expressed somatostatin receptors, although membrane expression appeared negligible. Except for somatostatin receptor 1, expression patterns differed between the three tumor types. Adenomas exhibited the weakest and carcinomas the strongest expression of somatostatin receptor 2, 3, 4 and 5. We observed the largest difference for cytoplasmic somatostatin receptor 5 expression. CONCLUSIONS: Parathyroid adenomas, atypical adenomas and carcinomas all express somatostatin receptor subtypes 1-5. Somatostatin receptor 5 may serve as a potential tumor marker for malignancy. Studies exploring the role of somatostatin receptor imaging and receptor-specific therapies in patients with parathyroid carcinomas are needed.

Recurrent Metastasized Parathyroid Carcinoma-Long-Term Remission After Combined Treatments With Surgery, Radiotherapy, Cinacalcet, Zoledronic Acid, and Temozolomide.

Parathyroid carcinoma is a rare cause of primary hyperparathyroidism with rather poor prognosis. Apart from surgery, no evidence-based treatments exist. A 48-year-old woman presented with weight loss, nausea, constipation, hypercalcemic crisis, and a recurrent neck tumor 5 years after primary surgery of a parathyroid tumor that primarily was classified as an adenoma. Histopathological reevaluation of the original tumor revealed the correct diagnosis to be parathyroid carcinoma (PC). The patient underwent surgery of the recurrent tumor, which was locally invasive with metastatic spread to the mediastinum and neck lymph nodes. Computed tomography demonstrated large lytic bone lesions in both iliac bones including, on the right, a soft tissue mass compatible with bone metastasis. The patient was treated with cinacalcet, repeated zoledronic acid infusions, and temozolomide cycles for 1 year. She underwent two additional neck surgeries for PC and sternotomy for resection of mediastinal metastases. Massive osteolytic lesions in both femoral necks caused imminent fracture risk and therefore both femurs were prophylactically stabilized by intramedullary nail. Serum calcium normalized after the third neck surgery, cinacalcet was discontinued, and parathyroid hormone gradually normalized during continued treatments with temozolomide, adjuvant radiotherapy, and zoledronic acid, with no signs of active disease on imaging and normal biochemistry. The patient remains in remission 17 years after successful combined treatments for recurrent, metastasized PC. The parathyroid tumor tissue demonstrated high O6-methylguanine DNA methyltransferase (MGMT) promoter methylation status, a known predictor of positive temozolomide treatment response in other tumors. In addition, synergistic effects of multiple treatments may have accounted for the favorable response. © 2018 The Authors. JBMR Plus is published by Wiley Periodicals, Inc. on behalf of the American Society for Bone and Mineral Research.

Surgery Significantly Improves Neurocognition, Sleep, and Blood Pressure in Primary Hyperparathyroidism: A 3-Year Prospective Follow-Up Study.

Surgery for primary hyperparathyroidism (PHPT) improves health-related quality of life (HRQoL), but it is unclear whether the effects are sustained after medium-term (>2 years) follow-up, and whether the results on some or all dimensions of HRQoL will reach that of the general population. We performed a follow-up of HRQoL on average 3.3 years after surgery for PHPT using the 15D in our patient cohort (n=124) and compared the results to those of an age- and gender-standardized general population (n=1099). We studied self-reported blood pressure and current medications; new comorbidities were retrieved from electronic patient records. A total of 104 (83%) patients [eight with serum calcium (1.34-1.46 mmol/l)] returned the questionnaires. After a follow-up of 3.3 years (range 23 to 55 months), systolic and diastolic blood pressure had decreased significantly compared to baseline (the situation before surgery, p<0.001). Thirty-four (33%) had acquired a new diagnosis (range 1-7), the most common being cardiovascular disease and cancer. Mean 15D score was significantly better compared to baseline (p<0.001), the dimensions of sleeping, mental function, discomfort and symptoms, and depression had further improved (p<0.01), and no longer differed from that of the general population. In PHPT, after >2 years follow-up, surgery improves blood pressure and restores neurocognitive function and sleep to the level of the general population. The improvements observed in overall HRQoL at one year after surgery are sustained, but overall HRQoL does not reach that of the general population.