Chandra SR, Shenoy RK, Karthikeyan, et al.
Rare treatable limb girdle muscle disease.
J Assoc Physicians India. 2012; 60:62-5 [PubMed]

We report two cases of Limb Girdle pattern of muscle weakness caused by hyperparathyroidism due to parathyroid adenoma. It can be easily missed as early symptoms are non specific but once diagnosed it is easily treatable and complete recovery occurs over a period of time.

Gómez-Ramírez J, Tagarro D, Bravo JM, et al.
Preoperative parathyroid harpoon localisation: a new technique helpful in reoperative patients with persistent hyperparathyroidism.
Ann R Coll Surg Engl. 2013; 95(2):e25-6 [PubMed]

Surgery for persistent primary hyperparathyroidism remains a major challenge for surgeons and these reoperative procedures require an experienced parathyroid surgeon. The goal of reoperative surgery is to excise the abnormal parathyroid gland(s) and limit exploration to help minimise the potential complications. At least two positive and concordant localising studies should be available before reoperation because the technical difficulties in these cases make an exact localisation necessary before surgery. We describe the placement of a metallic harpoon under ultrasonography guidance as a safe, simple and inexpensive technique for localisation of the enlarged gland prior to conservative surgery.

Peshev ZV, Borisov BB, Genova SN, Danev VH
Parathyroid carcinoma of the mediastinum.
Folia Med (Plovdiv). 2012 Oct-Dec; 54(4):80-3 [PubMed]

Parathyroid carcinoma accounts for about 4% of all diseases of the parathyroid glands. It usually presents as a tumor mass in the neck region. Mediastinal parathyroid carcinoma has been reported very rarely. The present paper reports an ectopic parathyroid carcinoma in the anterior mediastinum in a 54-year male that failed to be recognized antemortem. The markedly elevated serum calcium levels were repeatedly put down to laboratory errors, and the clinical features of primary hyperparathyroidism were misjudged and managed only symptomatically. The terminal cardiogenic shock was associated with myocardial infarction. Coronary plastic surgery was carried out and a stent was placed. The postmortem examination found a solid elastic tumor mass (4 cm) firmly encapsulated in the upper half of the anterior mediastinum having trabecular structure, mild nuclear and cellular polymorphism, single irregular mitoses and an area of necrosis. The mass invaded the capsule and the surrounding adipose tissue, there were tumor emboli found in the lymph and blood vessels. Immunohistochemical study showed diffuse expression of low molecular weight cytokeratin, chromogranin A and synaptophysin, and more than 20% of the tumor cells were Ki-67 positive. Glycogen granules were found in their cytoplasm. There were clearly seen metastatic calcifications in the intramural coronary vessels, the cardiomyocytes, the kidneys and the lungs. The present case report contributes considerably to the differential diagnosis of hypercalcemia.

Kotromanović Z, Birtić D, Vceva A, et al.
Non-functional parathyroid gland carcinoma, a rare malignant tumor of the head and neck.
Coll Antropol. 2012; 36 Suppl 2:23-5 [PubMed]

Carcinoma of the parathyroid gland is a very rare tumor of the head and neck. The largest number of carcinomas are discovered by chance. (intraoperatively, during surgery removal of the parathyroid gland are adenomas). Around 1% of the primary parathyreoidism is caused by the cancer of parathyroid glands. Only 10% of these rare tumors make up dysfunctional cancer of parathyroid glands. There have been 24 cases reported of this disease in the literature. The focus of our study is to present a case of this disease and to review the published literature to date.

Burke JF, Naraharisetty K, Schneider DF, et al.
Early-phase technetium-99m sestamibi scintigraphy can improve preoperative localization in primary hyperparathyroidism.
Am J Surg. 2013; 205(3):269-73; discussion 273 [PubMed] Article available free on PMC after 01/03/2014

BACKGROUND: In hyperparathyroidism, dual-phase technetium-99m sestamibi scintigraphy is important for parathyroid adenoma localization. We hypothesized that reviewing early-phase scans can increase localization in patients with primary hyperparathyroidism (PHPT).
METHODS: We reviewed our prospectively maintained database for patients with sestamibi scans before parathyroidectomy for PHPT from 2001 to 2011. Early-phase scans were read and compared with the location of the gland(s) removed at operation.
RESULTS: Of 902 patients identified, radiologists read 693 scans as positive. Of 209 negative scans, 141 (67%) were positive in the early phase; 135 (96%) correctly identified the side of the adenoma. Using radiologist reads, 35% of patients with negative scans and 41% of patients with falsely localized glands required bilateral exploration compared with 5% of patients with correctly localized glands.
CONCLUSIONS: A review of early scans in patients with negative imaging increases accurate adenoma localization and allows for minimally invasive operations in more patients.

Vysetti S, Sridhar P, Theckedath B, et al.
Synchronous papillary thyroid carcinoma and primary hyperparathyroidism: diagnosis and management issues.
Hosp Pract (1995). 2012; 40(4):16-9 [PubMed]

The occurrence of a papillary thyroid carcinoma in a patient with primary hyperparathyroidism is rare. Awareness of this condition will enable clinicians to evaluate for possible thyroid pathology in patients with primary hyperparathyroidism. Both of these endocrine conditions could then be managed with a single surgery involving concomitant resection of the thyroid and parathyroid glands. We report a case of a 53-year-old woman with a parathyroid adenoma and a unilateral papillary thyroid carcinoma, and detail the clinical features, diagnosis, and management.

Bricaire L, Odou MF, Cardot-Bauters C, et al.
Frequent large germline HRPT2 deletions in a French National cohort of patients with primary hyperparathyroidism.
J Clin Endocrinol Metab. 2013; 98(2):E403-8 [PubMed]

CONTEXT: Hyperparathyroidism-jaw tumor syndrome (HPT-JT) is an autosomal dominant syndrome with incomplete penetrance that can associate in a single patient parathyroid adenoma or carcinoma, fibro-osseous jaw tumor, cystic kidney lesion, and uterine tumor. Germline mutations of the HRPT2 gene (CDC73) coding for parafibromin are identified in approximately 50%-75% of HPT-JT cases and in approximately 14% of familial isolated hyperparathyroidism. A whole deletion of this gene has recently been reported in 1 sporadic case and in a family presenting with HPT-JT.
OBJECTIVE: The objective of the study was to report molecular abnormalities of the HRPT2 gene in patients with primary hyperparathyroidism in a French National cohort from the Groupe d'Étude des Tumeurs Endocrines.
METHODS: Patients' genomic DNA was screened by PCR-based sequencing for point mutations affecting HRPT2 and real-time quantitative PCR analysis for gross deletions.
RESULTS: We report 20 index patients with a germinal HRPT2 abnormality. Median age at diagnosis of primary hyperparathyroidism was 23 years (range 14-65 years). Median serum total calcium level at diagnosis was 3.19 mmol/L (range 2.8-4.3 mmol/L). Thirteen different mutations were identified by routine sequencing, including 7 mutations never reported. Seven patients (35%) carried a gross deletion of this gene (3 complete and 4 partial deletions). No genotype-phenotype correlation could be identified. A gross deletion of the HRPT2 gene was identified in 7% of patients for whom a routine screening by direct sequencing came up as negative.
CONCLUSION: Gross deletion analysis of the HRPT2 gene is indicated for all patients negative for mutation, presenting with HPT-JT or familial isolated hyperparathyroidism, parathyroid carcinoma, or in patients with apparently sporadic parathyroid adenoma diagnosed at a young age, having a severe hypercalcemia.

Gauhar TM, Shahzad N, Mahmud T, Khwaja MA
Parathyroid carcinoma.
J Coll Physicians Surg Pak. 2012; 22(12):789-91 [PubMed]

Parathyroid carcinoma is a rare cause of hypercalcaemia due to primary hyperparathyroidism. Ninety five percent of parathyroid carcinomas are functional tumours. Surgery is the only potential curative treatment. This is a case of a 53 years lady, who presented with pathological fracture of femur, hypercalcaemia, deranged renal functions, change in voice, difficulty in swallowing and markedly raised parathormone levels. Doppler ultrasound localized an irregular mass at right lower gland. SESTAMIBI scan showed probability of adenoma in the region of right lower thyroid pole. Intra-operatively, tumour was found stuck to esophagus and right recurrent laryngeal nerve passing through it. Enlarged parathyroid gland was removed in toto along with the recurrent laryngeal nerve, right thyroid lobe and its isthmus.

Mohebati A, Shaha A, Shah J
Parathyroid carcinoma: challenges in diagnosis and treatment.
Hematol Oncol Clin North Am. 2012; 26(6):1221-38 [PubMed]

Parathyroid carcinoma is a malignant neoplasm affecting 0.5% to 5.0% of all patients with primary hyperparathyroidism. Since it was first described by De Quervain in 1904 to this day, it continues to defy diagnosis and treatment because of its rarity, overlapping features with benign parathyroid disease, and lack of distinct characteristics. En bloc surgical extirpation of the tumor with clear margins remains the best curative treatment. Although prolonged survival is possible with recurrent or metastatic disease, cure is rarely achievable. Efficacy of adjuvant therapies, such as radiotherapy and chemotherapy, in management of persistent, recurrent, or metastatic disease has been disappointing.

Andrioli M, Riganti F, Pacella CM, Valcavi R
Long-term effectiveness of ultrasound-guided laser ablation of hyperfunctioning parathyroid adenomas: present and future perspectives.
AJR Am J Roentgenol. 2012; 199(5):1164-8 [PubMed]

OBJECTIVE: Although surgery is the first-choice treatment of primary hyperparathyroidism (pHPT), some patients present with contraindications or refuse surgery. Data from alternative nonsurgical therapies are inconclusive. To study the long-term efficacy of laser ablation in the treatment of pHPT, we retrospectively reviewed six cases of laser-treated patients.
MATERIALS AND METHODS: Six patients with pHPT were treated with laser ablation using a flat-tip technique. Energy was administered by means of one optic fiber placed into the parathyroid adenoma through a 21-gauge Chiba needle connected to a neodymium:yttrium-aluminum-garnet laser. The mean (± SD) delivered energy for all patients was 2.067 ± 1440 J (range, 1000-4200 J). Treatment was fractionated in two (n = 2 patients) or in three (n = 1 patient) ultrasound-guided sessions. Patients' serum parathyroid hormone (PTH) and calcium levels were checked periodically, with neck ultrasound performed. The mean duration of follow-up was 54 ± 34 months (range, 12-84 months).
RESULTS: Two months after laser ablation, serum PTH and calcium levels decreased in six and five patients, respectively. At the last follow-up examination, serum PTH and calcium levels were above the normal range in six and three patients, respectively. Three patients underwent surgery for persistent pHPT. Laser ablation therapy was safe and without permanent side effects. One patient reported transient dysphonia.
CONCLUSION: Laser ablation produces a transient reduction of serum PTH and calcium levels but not a lasting resolution of hyperparathyroidism. Laser cannot be proposed as the definitive therapy of pHPT. Thus, studies aiming to identify therapeutic algorithms specific for parathyroid glands are needed to verify the utility of laser ablation in pHPT.

Alvelos MI, Vinagre J, Fonseca E, et al.
MEN1 intragenic deletions may represent the most prevalent somatic event in sporadic primary hyperparathyroidism.
Eur J Endocrinol. 2013; 168(2):119-28 [PubMed]

OBJECTIVE: Primary hyperparathyroidism (pHPT) is characterised by an inappropriate over production of parathyroid hormone and it is the most frequent pathological condition of the parathyroid glands. A minority of the cases belong to familial forms, but most of them are sporadic. The genetic alterations underlying the sporadic forms of pHPT remain poorly understood. The main goal of our study is to perform the molecular characterisation of a series of sporadic pHPT cases.
DESIGN AND METHODS: We have studied matched blood and tumour from 24 patients with pHPT, who went to a medical appointment in Hospital Pedro Hispano. Informed consent was obtained from all individuals. The MEN1, RET and CDKN1B molecular study was carried out in the germline DNA by PCR/SSCP and direct sequencing. Parathyroid tumours were further analysed by the same methods for MEN1, CDKN1B and CTNNB1 genetic alterations. The multiplex ligation-dependent probe amplification technique enabled the evaluation of MEN1 gene deletions. Protein expression for menin, cyclin D1, parafibromin, p27(Kip1), β-catenin and Ki-67 was conducted by immunohistochemistry.
RESULTS: The study of parathyroid tumours detected two somatic MEN1 mutations (c.249_252delGTCT and c.115_163del49bp) and revealed the presence of MEN1 intragenic deletions in 54% (13/24) of the tumours. In RET and CDKN1B genes only previously described, non-pathogenic variants were found. Cyclin D1 protein was overexpressed in 13% (3/24) of tumours.
CONCLUSIONS: These results suggest that MEN1 alterations, remarkably intragenic deletions, may represent the most prevalent genetic alteration in sporadic parathyroid tumours.

Mazeh H, Kouniavsky G, Schneider DF, et al.
Intrathyroidal parathyroid glands: small, but mighty (a Napoleon phenomenon).
Surgery. 2012; 152(6):1193-200 [PubMed]

BACKGROUND: Intrathyroidal parathyroid adenomas (ITPAs) are a rare entity. The aim of this study is to describe the experience of 2 endocrine surgery centers and to distinguish characteristics of intrathyroidal parathyroid adenoma and nonintrathyroidal parathyroid adenomas.
METHODS: We included patients who had undergone operations for primary hyperparathyroidism who had intrathyroidal parathyroid adenomas. Patients with single intrathyroidal parathyroid adenomas were also compared to age- and sex-matched controls with nonintrathyroidal parathyroid adenomas.
RESULTS: Of 4,868 patients who underwent parathyroidectomy between January 2002 and June 2011, we identified 53 (1%) patients with intrathyroidal parathyroid adenoma. Sestamibi and ultrasound scans correctly identified the adenoma in 35 (70%) and 11 (61%) cases, respectively. Single adenomas were identified in 44 (83%) patients, double adenomas in 4 (8%) patients, and hyperplasia in 5 (9%) patients. Lobectomy was performed in 17 (32%) patients; enucleation was used in 36 (68%) patients. Cure was achieved in all patients and no patients experienced a recurrence. Patients with single intrathyroidal parathyroid adenomas had significantly smaller glands than patients with nonintrathyroidal parathyroid adenomas (325 ± 47 vs 772 ± 61 mg; P < .0001); however, no significant difference was identified between the groups with regard to demographics, symptoms, preoperative laboratory values, or outcomes.
CONCLUSION: Single intrathyroidal parathyroid adenomas are smaller than nonintrathyroidal parathyroid adenomas, but patients with intrathyroidal parathyroid adenomas present with similar laboratory values and symptoms. Recognition of this rare entity can lead to a successful surgical outcome.

García-Talavera P, González ML, Aís G, et al.
SPECT-CT in the localization of an ectopic retropharyngeal parathyroid adenoma as a cause for persistent primary hyperparathyroidism.
Rev Esp Med Nucl Imagen Mol. 2012; 31(5):275-7 [PubMed]

A common cause for surgical failure of primary hyperparathyroidism (pHPT) is the non-detection of an ectopic adenoma during the intervention. We present a case of a patient with pHPT in whom an ectopic gland was found in the right retropharyngeal space by means of a double phase (99m)Tc-methoxy-isobutyl-isonitrile ((99m)Tc-MIBI) scintigraphy and early SPECT-CT after several surgeries and imaging tests. The addition of a tomography to the planar scintigraphy increases its sensitivity and improves pathological parathyroid glands localization. The hybrid imaging is sometimes essential to obtain surgical success, as in the case of ectopic adenomas.

Sulaiman L, Haglund F, Hashemi J, et al.
Genome-wide and locus specific alterations in CDC73/HRPT2-mutated parathyroid tumors.
PLoS One. 2012; 7(9):e46325 [PubMed] Article available free on PMC after 01/03/2014

Mutations in the hyperparathyroidism type 2 (HRPT2/CDC73) gene and alterations in the parafibromin protein have been established in the majority of parathyroid carcinomas and in subsets of parathyroid adenomas. While it is known that CDC73-mutated parathyroid tumors display specific gene expression changes compared to CDC73 wild-type cases, the molecular cytogenetic profile in CDC73-mutated cases compared to unselected adenomas (with an expected very low frequency of CDC73 mutations) remains unknown. For this purpose, nine parathyroid tumors with established CDC73 gene inactivating mutations (three carcinomas, one atypical adenoma and five adenomas) were analyzed for copy number alterations and loss of heterozygosity using array-comparative genomic hybridization (a-CGH) and single nucleotide polymorphism (SNP) microarrays, respectively. Furthermore, CDC73 gene promoter methylation levels were assessed using bisulfite Pyrosequencing. The panel included seven tumors with single mutation and three with double mutations of the CDC73 gene. The carcinomas displayed copy number alterations in agreement with previous studies, whereas the CDC73-mutated adenomas did not display the same pattern of alterations at loci frequently deleted in unselected parathyroid tumors. Furthermore, gross losses of chromosomal material at 1p and 13 were significantly (p = 0.012) associated with parathyroid carcinomas as opposed to adenomas. Quantitative PCR-based copy number loss regarding CDC73 was observed in three adenomas, while all the carcinomas were diploid or showed copy number gain for CDC73 gene. Hypermethylation of the CDC73 gene promoter was not observed. Our data could suggest that CDC73-mutated parathyroid adenomas exhibit a partly unique cytogenetic profile in addition to that of carcinomas and unselected adenomas. Furthermore, CDC73-mutated carcinomas displayed losses at 1p and 13 which are not seen in CDC73-mutated adenomas, making these regions of interest for further studies regarding malignant properties in tumors from CDC73-mutated cases. However, due to the small sample size, validation of the results in a larger cohort is warranted.

Wang O, Wang C, Nie M, et al.
Novel HRPT2/CDC73 gene mutations and loss of expression of parafibromin in Chinese patients with clinically sporadic parathyroid carcinomas.
PLoS One. 2012; 7(9):e45567 [PubMed] Article available free on PMC after 01/03/2014

OBJECTIVE: It is widely recognized that the diagnosis of parathyroid carcinoma (PC) is often difficult because of the overlap of characteristics between malignant and benign parathyroid tumors, especially at an early stage. Based on the identification of tumor suppressor gene HRPT2/CDC73 and its association with hereditary and sporadic PC, screening of gene mutations and detection of parafibromin immunoreactivity have been suggested as diagnostic instruments of PC in Whites. There is little information about HRPT2/CDC73 mutations and its corresponding protein expression in patients with sporadic PC in Chinese population, and the long-term follow-up data is scarce.
METHODS: Paraffin-embedded tissues were obtained from 13 patients with PC, 13 patients with parathyroid adenoma (PA) and 7 patients with parathyroid hyperplasia(PH), and 6 normal parathyroid (NP) tissues as controls. Peripheral blood from 11 patients with PC was collected. PCR products using Genomic DNA extracted from tumor tissues or blood as template was sequenced for HRPT2/CDC73 gene. Expression of parafibromin in tumor tissues was evaluated by immunohistochemical analysis.
RESULTS: Six mutations in 6 of 13 patients with PC were identified, with three being novel. Four of them were germ-line mutations. Patients with mutations were susceptible to recurrence of the PC. Complete (8/13, 61.5%) or partial (5/13, 38.5%) loss of parafibromin expression was observed in PC tissues. All of tissue samples from normal parathyroid or benign parathyroid tumors displayed positive immunostaining of parafibromin except one adenoma.
CONCLUSIONS: The present study supplies information on the mutations and protein expression of HRPT2/CDC73 gene and phenotypes of parathyroid carcinoma in Chinese population. And the expanded mutation database of this gene may benefit patients in the diagnosis and treatment of this disease.

Haglund F, Ma R, Huss M, et al.
Evidence of a functional estrogen receptor in parathyroid adenomas.
J Clin Endocrinol Metab. 2012; 97(12):4631-9 [PubMed]

CONTEXT: Primary hyperparathyroidism (PHPT) is most frequently present in postmenopausal women. Although the involvement of estrogen has been suggested, current literature indicates that parathyroid tumors are estrogen receptor (ER) α negative.
OBJECTIVE: The aim of the study was to evaluate the expression of ERs and their putative function in parathyroid tumors.
DESIGN: A panel of 37 parathyroid tumors was analyzed for expression and promoter methylation of the ESR1 and ESR2 genes as well as expression of the ERα and ERβ1/ERβ2 proteins. Transcriptome changes in primary cultures of parathyroid adenoma cells after treatment with the selective ERβ1 agonist diarylpropionitrile (DPN) and 4-hydroxytamoxifen were identified using next-generation RNA sequencing.
RESULTS: Immunohistochemistry revealed very low expression of ERα, whereas all informative tumors expressed ERβ1 (n = 35) and ERβ2 (n = 34). Decreased nuclear staining intensity and mosaic pattern of positive and negative nuclei of ERβ1 were significantly associated with larger tumor size. Tumor ESR2 levels were significantly higher in female vs. male cases. In cultured cells, significantly increased numbers of genes with modified expression were detected after 48 h, compared to 24-h treatments with DPN or 4-hydroxytamoxifen, including the parathyroid-related genes CASR, VDR, JUN, CALR, and ORAI2. Bioinformatic analysis of transcriptome changes after DPN treatment revealed significant enrichment in gene sets coupled to ER activation, and a highly significant similarity to tumor cells undergoing apoptosis.
CONCLUSIONS: Parathyroid tumors express ERβ1 and ERβ2. Transcriptional changes after ERβ1 activation and correlation to clinical features point to a role of estrogen signaling in parathyroid function and disease.

Singer MC, Pucar D, Mathew M, Terris DJ
Improved localization of sestamibi imaging at high-volume centers.
Laryngoscope. 2013; 123(1):298-301 [PubMed]

OBJECTIVES/HYPOTHESIS: Sestamibi imaging can provide critical information regarding the location of suspected parathyroid adenomas. However, this modality can be challenging to perform and interpret reliably. The impact of experience on the localizing efficacy of sestamibi scanning was assessed.
STUDY DESIGN: Prospective analysis of a consecutive series of patients undergoing parathyroidectomy was undertaken after institutional review board approval was obtained.
METHODS: Patients undergoing parathyroid surgery from October 2003 through June 2011 were considered. Inclusion criteria represented primary surgery for primary hyperparathyroidism, in which a single adenoma was excised and cure obtained. Sestamibi scan results, performed at our institution and at outside imaging centers, were compared to intraoperative findings.
RESULTS: There were 389 parathyroidectomies performed; 188 patients met inclusion criteria. Fifty-four patients had sestamibi scans performed at outside institutions; 36 (67%) were localizing and 18 (33%) were nonlocalizing. Among localizing studies, half identified the correct quadrant and half recognized the correct side. At our institution, 147 patients underwent sestamibi imaging; 121 (82%) localized and 26 (18%) did not. Among localizing studies, the correct quadrant was reported in 64% and the correct side in 36%. Of the 147 scans performed at our institution, 13 represented repeat scans of patients with nonlocalizing outside scans. All 13 of these localized; six identified the correct quadrant and seven the side of the adenoma.
CONCLUSIONS: A high volume of experience may improve the yield of sestamibi imaging. Repeating this study at a high-volume center when it was nonlocalizing elsewhere may provide useful additional information.

Butt WT, Azim A, Abbas A, et al.
Parathyroid carcinoma.
J Coll Physicians Surg Pak. 2012; 22(9):588-90 [PubMed]

Parathyroid carcinoma is a rare endocrine malignancy accounting for less than 1% of all cases of hyperparathyroidism. We present a case of a middle-aged woman who was undiagnosed for 3 years before presenting with renal stones and advanced musculoskeletal disease. Investigations revealed primary hyperparathyroidism. Focused cervical exploration and left inferior parathyroidectomy was carried out based on the pre-operative localization studies. Parathyroid carcinoma was diagnosed on histopathology postoperatively. Subsequent en bloc resection was not performed and the patient is being monitored with serial parathyroid hormone levels which have not shown any increase in 6 months of follow-up. Only two previous cases of parathyroid carcinoma have been reported from Pakistan.

Ghervan C, Silaghi A, Nemeş C
Parathyroid incidentaloma detected during thyroid sonography - prevalence and significance beyond images.
Med Ultrason. 2012; 14(3):187-91 [PubMed]

INTRODUCTION: Parathyroid incidentaloma (PTI) designates a nodule discovered incidentally during thyroid sonography, and whose location and aspect suggests an abnormal parathyroid. Our aim was to assess the prevalence of PTI, their functional characteristics and to identify the factors correlated with their presence.
PATIENTS AND METHODS: We recorded all patients detected with PTI between January 2009 and December 2011, in our department. Serum calcium, parathyroid hormone (PTH), thyroid stimulating hormone (TSH), free thyroine (FT4) and anti thyroid peroxidase antibodies (anti-TPO Ab) were measured.
RESULTS: From a total of 2662 thyroid ultrasounds, 32 patients were identified with PTI (prevalence 1.2%). The diagnosis of a functional parathyroid adenoma was confirmed in 12 patients (37.5%). There was no significant difference in size, location, echogenicity or vascular pattern between the functioning adenomas and the other PTI. The only parameter correlated with the non functioning lesion was the multinodular pattern of the thyroid (multinodular goiter or macronodular autoimmune thyroiditis).
CONCLUSIONS: Although rare, the ultrasound identification of an image suggestive for a pathological parathyroid gland requires the evaluation of the functioning character of the lesion, more than one third PTI being hyperfunctional. The concomitance of a nodular goiter decreases the probability of a primary hyperparathyroidism.

Ezzat T, Paramesawaran R, Phillips B, Sadler G
MEN 2 syndrome masquerading as MEN 1.
Ann R Coll Surg Engl. 2012; 94(6):e206-7 [PubMed]

Patients with multiple endocrine neoplasia (MEN) type 2A develop medullary thyroid cancer, which is associated with poor prognosis in its metastatic stage. Hyperparathyroidism is a common finding in both MEN 1 and 2. We report a 68-year-old patient diagnosed clinically with MEN 1 based on the presence of hyperparathyroidism and pituitary Cushing's disease with no supporting genetic evidence. The hyperparathyroidism was later found to be part of MEN 2A with underlying metastatic medullary thyroid cancer. We highlight the importance of genetic confirmation before a diagnosis of MEN 1 is made as other more serious pathologies might be overlooked.

Javadi H, Jallalat S, Farrokhi S, et al.
Concurrent papillary thyroid cancer and parathyroid adenoma as a rare condition: a case report.
Nucl Med Rev Cent East Eur. 2012; 15(2):153-5 [PubMed]

Although the pathological relationship between parathyroid and thyroid diseases is common, an association between parathyroid adenoma and thyroid cancer is rare. Concomitant thyroid cancer in patients with primary hyperparathyroidism (pHPT) has been reported at varying frequencies. WE present here a 23-year-old man who had papillary thyroid carcinoma in the right thyroid lobe and a parathyroid adenoma in the left thyroid lobe, which were confirmed surgically.

Wang O, Wang CY, Shi J, et al.
Expression of Ki-67, galectin-3, fragile histidine triad, and parafibromin in malignant and benign parathyroid tumors.
Chin Med J (Engl). 2012; 125(16):2895-901 [PubMed]

BACKGROUND: It is widely recognized that the diagnosis of parathyroid carcinoma (PC) is often difficult because of the overlap of characteristics between malignant and benign parathyroid tumors, especially at an early stage. Our study aimed to investigate the differential expression of Ki-67, galectin-3, fragile histidine triad (FHIT) gene, and parafibromin in PC, parathyroid adenoma (PA), parathyroid hyperplasia (PH), and normal parathyroid (NP) tissues; then to assess these expression values for use in differential diagnosis of malignant and benign parathyroid tumors.
METHODS: Data of 15 cases with PC, 19 PAs, and 8 PHs were retrospectively analyzed for their clinical characteristics. The expression of Ki-67, galectin-3, FHIT, and parafibromin were detected via immunohistochemistry in the above-mentioned specimens and 6 NPs as control.
RESULTS: Complete loss of parafibromin expression was seen in 9 of 15 (60%) carcinomas, and all normal parathyroid tissues and parathyroid benign tumors stained positive for parafibromin except for one (4%) adenoma. Galectin-3 staining was positive in 11 of 15 (73%) carcinomas, 5 of 19 (26%) adenomas, 1 of 8 (12%) hyperplasias, and 0 of 6 normal tissues. The Ki-67 proliferative index was high in 4 of 15 (27%) carcinomas, 1 of 19 (5%) adenomas, and none of the hyperplasia or normal tissues. FHIT expression did not differ appreciably among the tumor types. The combination of overexpression of galectin-3 or loss of parafibromin increased sensitivity for PC to 87%, while the specificity of both positive galectin-3 and positive Ki-67 could reach 100%.
CONCLUSIONS: These data suggested that loss of parafibromin and overexpression of galectin-3 and Ki-67 might help to distinguish parathyroid carcinoma from other parathyroid tumors. And the combination of two or three of these markers might produce better sensitivity and/or specificity for the diagnosis of parathyroid carcinoma.

Stack BC, Moore ER, Belcher RH, et al.
Hormone, relationships of parathyroid gamma counts, and adenoma mass in minimally invasive parathyroidectomy.
Otolaryngol Head Neck Surg. 2012; 147(6):1035-40 [PubMed]

OBJECTIVE: To better understand relationships of parathyroid hormone (PTH) production, adenoma gamma counts, and adenoma mass in patients undergoing minimally radioguided invasive parathyroidectomy for primary hyperparathyroidism from single-gland disease.
STUDY DESIGN: A prospective review of 104 patients operated on by a single surgeon.
SETTING: University tertiary hospital.
SUBJECTS: Adults who have primary hyperparathyroidism due to a single gland.
RESULTS: There were 23 men and 81 women with an average age of 63 years. The mean (SD) adenoma mass was 0.78 (0.69) g (median, 0.57 g). The mean (SD) percent of background for the adenoma was 120.2 (90.5). Preoperative PTH and percent of background gamma count of the adenoma showed a likely correlation with a Spearman ρ value of 0.2039 and a P value of .037. There were significant correlations between both percent of background of the adenoma and adenoma mass (Spearman ρ = 0.4991 and P < .0001). Preoperative PTH and adenoma mass also showed a significant positive correlation (Spearman ρ = 0.308 and P = .002).
CONCLUSION: There exist correlations between gland mass, radioactivity, and PTH level. Adenoma radiation counts do not appear to be a proxy for changes in PTH levels measured during surgery as has been reported. Intraoperative PTH has been shown by others not to be necessary when doing radioguided parathyroid surgery if the Norman rule is observed. However, a radioguided technique and intraoperative PTH can provide complementary information in making an assessment of completion of parathyroid procedures.

Di Cosimo C, Metere A, Chiesa C, et al.
Mediastinal parathyroid adenoma: a case report.
Eur Rev Med Pharmacol Sci. 2012; 16(6):845-7 [PubMed]

Ectopic parathyroid adenomas represent a diagnostic challenge, since they are quite rare in clinical practice. We present a case of a 61 years old man with symptomatic hypercalcemia due to an ectopic parathyroid adenoma in the upper-anterior mediastinum that was not localized by the scintigraphy. Ultrasonography identified a nodule on the left upper-superior lobe of the thyroid gland, consistent with a parathyroid adenoma; scintigraphy showed two focuses of abnormal tracer uptake, one on the left upper-superior lobe of the gland and the other on the right inferior lobe of the gland. Patient underwent surgery to remove the adenoma on the left side, but postoperatively PTH and serum calcium level were still elevated. CT scan showed a mass of 27 x 22 mm in the upper anterior mediastinum, in front of the right emisoma of D2. The final surgery allowed us to remove the adenoma with a laterocervical approach. The histopathology was consistent with parathyroid adenoma.

Li L, Chen L, Yang Y, et al.
Giant anterior mediastinal parathyroid adenoma.
Clin Nucl Med. 2012; 37(9):889-91 [PubMed]

A 57-year-old woman with type 2 diabetes was admitted to our hospital presenting with generalized bone pains, hypercalcemia, and elevated parathyroid hormone level. Enhanced CT scan demonstrated a large soft tissue mass in the right anterior mediastinum. Tc-MIBI scintigraphy revealed the focal accumulation of radiotracer uptake in the anterior mediastinum. Tc-MIBI SPECT/CT imaging also corroborated the same finding. The patient underwent surgery to have a giant ectopic parathyroid adenoma (7 × 4.5 × 1.5 cm) removed. The patient has been observed for 2 years, with normal parathyroid hormone and calcium levels.

Bae JH, Choi HJ, Lee Y, et al.
Preoperative predictive factors for parathyroid carcinoma in patients with primary hyperparathyroidism.
J Korean Med Sci. 2012; 27(8):890-5 [PubMed] Article available free on PMC after 01/03/2014

This study was conducted to review the clinical characteristics of parathyroid carcinoma (PC) and to evaluate potential preoperative predictive factors for PC in patients with primary hyperparathyroidism (PHPT). We performed a retrospective review of electronic medical records of 194 patients with pathologically confirmed PHPT in affiliated teaching hospitals of Seoul National University from January 2000 to March 2011. Adenoma was diagnosed in 171 patients, hyperplasia in 12, and carcinoma in 11. Several biochemical measurements were higher in patients with PC than in patients with benign disease, including serum total calcium (P < 0.001), intact parathyroid hormone (P = 0.003), and alkaline phosphatase (ALP) (P < 0.001). Tumors were larger in PC than in benign disease (P < 0.001). Multivariate analysis revealed that serum ALP level (P < 0.001) and tumor size were associated with PC (P = 0.03). Tumor size and serum ALP level were evaluated as preoperative predictive factors for PC using ROC analyses: a tumor size of 3.0 cm (sensitivity 90.9%, specificity 92.1%) and serum ALP level of 285 IU/L (83.3%, 97.0%) had predictive value for the diagnosis of PC in patients with PHPT. In conclusion, elevated serum ALP and a large parathyroid mass at the time of diagnosis can be helpful to predict PC in patients with PHPT.

Newey PJ, Nesbit MA, Rimmer AJ, et al.
Whole-exome sequencing studies of nonhereditary (sporadic) parathyroid adenomas.
J Clin Endocrinol Metab. 2012; 97(10):E1995-2005 [PubMed]

CONTEXT: Genetic abnormalities, such as those of multiple endocrine neoplasia type 1 (MEN1) and Cyclin D1 (CCND1) genes, occur in <50% of nonhereditary (sporadic) parathyroid adenomas.
OBJECTIVE: To identify genetic abnormalities in nonhereditary parathyroid adenomas by whole-exome sequence analysis.
DESIGN: Whole-exome sequence analysis was performed on parathyroid adenomas and leukocyte DNA samples from 16 postmenopausal women without a family history of parathyroid tumors or MEN1 and in whom primary hyperparathyroidism due to single-gland disease was cured by surgery. Somatic variants confirmed in this discovery set were assessed in 24 other parathyroid adenomas.
RESULTS: Over 90% of targeted exons were captured and represented by more than 10 base reads. Analysis identified 212 somatic variants (median eight per tumor; range, 2-110), with the majority being heterozygous nonsynonymous single-nucleotide variants that predicted missense amino acid substitutions. Somatic MEN1 mutations occurred in six of 16 (∼35%) parathyroid adenomas, in association with loss of heterozygosity on chromosome 11. However, no other gene was mutated in more than one tumor. Mutations in several genes that may represent low-frequency driver mutations were identified, including a protection of telomeres 1 (POT1) mutation that resulted in exon skipping and disruption to the single-stranded DNA-binding domain, which may contribute to increased genomic instability and the observed high mutation rate in one tumor.
CONCLUSIONS: Parathyroid adenomas typically harbor few somatic variants, consistent with their low proliferation rates. MEN1 mutation represents the major driver in sporadic parathyroid tumorigenesis although multiple low-frequency driver mutations likely account for tumors not harboring somatic MEN1 mutations.

Untch BR, Adam MA, Danko ME, et al.
Tumor proximity to the recurrent laryngeal nerve in patients with primary hyperparathyroidism undergoing parathyroidectomy.
Ann Surg Oncol. 2012; 19(12):3823-6 [PubMed]

BACKGROUND: Recurrent laryngeal nerve (RLN) injury is a rare complication for patients undergoing neck exploration for primary hyperparathyroidism (pHPT). Distances between RLNs and parathyroid adenomas have not been previously published. In this study we used a RLN monitor to identify the RLN and to measure the proximity to parathyroid tumors.
METHODS: Patients with pHPT (n = 136) underwent neck exploration and had the clinical data recorded prospectively. Adenomas were recorded in 1 of 4 locations (right upper, right lower, left upper, left lower). Measurement of RLN to adenoma distances were recorded intraoperatively with the gland in situ. The RLN location was confirmed with a RLN monitor.
RESULTS: The average RLN to adenoma distance was 0.52 ± 0.52 cm. Adenomas in the right upper position were significantly closer to the nerve (0.25 ± 0.39 cm) compared with adenomas in the left upper (0.48 ± 0.61 cm, p = .03), left lower (0.70 ± 0.53 cm, p < .001), and right lower position (1.02 ± 0.56 cm, p < .001). Left upper adenomas were also significantly closer to the nerve compared with right lower adenomas (p < .001). Adenomas in the right upper position abutted the nerve more often (47 %) compared with adenomas in other positions (p = .001). There were no perioperative characteristics that predicted tumor abutment. There were no permanent RLN injuries.
CONCLUSION: In patients with sporadic pHPT, parathyroid adenomas in the right upper location have, on average, greater proximity to the RLN and are more often directly abutting compared with adenomas in other locations.

Mahmoodzadeh H, Harirchi I, Hassan Esfehani M, Alibakhshi A
Papillary thyroid carcinoma associated with parathyroid adenoma.
Acta Med Iran. 2012; 50(5):353-4 [PubMed]

Concomitant papillary thyroid cancer and parathyroid adenoma is rare. We report a 55 years old female with papillary cancer admitted for surgery. Preoperative laboratory findings revealed hypercalcemia and then primary hyperparathyroidism. Thyroidectomy, neck dissection and excision of parathyroid adenoma were performed. Histological examination revealed parathyroid adenoma. Serum calcium returned to normal range after surgery. We recommend preoperative check of calcium in patients with thyroid cancer.

Morris LF, Loh C, Ro K, et al.
Non-super-selective venous sampling for persistent hyperparathyroidism using a systemic hypocalcemic challenge.
J Vasc Interv Radiol. 2012; 23(9):1191-9 [PubMed]

PURPOSE: To describe a new protocol employing an acute systemic hypocalcemic challenge (SHC) aimed at augmenting the parathyroid hormone (PTH) gradient to enable non-super-selective venous sampling (VS) in patients with persistent primary hyperparathyroidism (PHPT).
MATERIALS AND METHODS: In a retrospective study, 37 patients (39 studies-20 SHC, 19 super-selective VS) who underwent VS for persistent or recurrent PHPT were examined. Study patients were pretreated with intravenous hydration, diuretics, and bicarbonate to induce temporary relative hypocalcemia and then underwent non-super-selective VS targeted at large vessels within the neck and chest with rapid PTH testing. The traditional VS protocol involved super-selective VS with arteriography.
RESULTS: SHC decreased ionized calcium by 0.098 mmol/L ± 0.18 (P = .07) and increased peripheral PTH by 10.2 pg/mL (P = .58). Positive VS gradients, defined as a ≥ 1.4-fold difference from baseline to after SHC, were detected in 95% of patients. VS findings guided successful surgery in 77% of SHC cases and 90% of super-selective VS cases; the peak gradient site was concordant with operative findings in 46% of SHC cases and 80% of super-selective VS cases. Avoidance of super-selective sampling decreased mean fluoroscopy time from 91 minutes to 33 minutes and decreased contrast material administered from 204 mL to 63 mL (both P < .0001).
CONCLUSIONS: The SHC protocol to enable non-super-selective VS in patients with persistent PHPT had the same ability as super-selective VS to detect a positive (≥ 1.4-fold) PTH gradient, was associated with decreased accuracy in identifying the site of the adenoma compared with super-selective VS, and significantly decreased contrast material used and fluoroscopy time.