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Context: Current evidence of cardiovascular (CV) risk in primary hyperparathyroidism (PHPT) is still inconsistent., Objective: To prospectively investigate changes of early atherosclerosis in patients with PHPT undergoing parathyroidectomy (PTx) or conservative management, according to consensus criteria., Methods: Biochemical parameters of PHPT, CV risk factors (systolic and diastolic blood pressure, cholesterol [total, high-density, and low-density], triglyceride, HbA1c, HOMA-IR), and carotid intima-media thickness (IMT) and plaque were assessed in 52 consecutive postmenopausal PHPT patients both at baseline and ≥ 24 months after surgery (PTx, n = 22) or conservative management (non-PTx, n = 30)., Results: At baseline, PTx and non-PTx showed comparable age, BMI, renal function, and 25(OH)D levels, and did not differ for CV risk factors, IMT and plaques, or for prevalence of smoking, diabetes mellitus, or antihypertensive or statin therapy, while all parameters characterizing PHPT differed. Follow-up duration in PTx was longer than in non-PTx (P = .004). Parameters characterizing PHPT significantly improved ≥ 24 months after surgery, whereas in non-PTx serum phosphate slightly decreased and parathyroid hormone increased. Systolic and diastolic blood pressure increased at follow-up in both groups, while other CV risk factors did not significantly vary. In PTx, IMT did not significantly vary after surgery (0.85 ± 0.14 to 0.89 ± 0.22 mm, P = .366), whereas it significantly increased in non-PTx (0.80 ± 0.18 to 0.93 ± 0.23 mm, P = .008), even adjusting for blood pressure. Plaque prevalence and incidence did not significantly differ in the 2 groups., Conclusion: Our results suggest that in postmenopausal patients with PHPT, subclinical atherosclerosis could be halted by PTx, whereas it worsens over time in nonoperated patients with milder disease., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society.)

Background: Parathyroid gland (PG) surgery is often challenging due to the small size and indistinct nature of these glands. The introduction of intraoperative near-infrared autofluorescence (NIRAF) has shown promise in localizing parathyroid tissue. However, the NIRAF features of parathyroid adenomas remain unclear. The aim of this study is to assess the NIRAF pattern of parathyroid adenomas., Methods: Patients who underwent surgery for primary hyperparathyroidism at the University Hospital of Pisa, Endocrine Surgery Unit, between December 2021 and February 2022 were enrolled in this study. Intraoperative NIRAF patterns of suspected parathyroid adenomas were evaluated, with particular attention given to the presence of a bright cap., Results: A retrospective study was conducted on 11 patients with primary hyperparathyroidism who underwent parathyroidectomy at our institution. Histopathological examination of the 15 resected specimens confirmed 14 parathyroid adenomas (12 chief cell parathyroid adenomas, 1 oxyphil cell parathyroid adenoma, and 1 mixed cell parathyroid adenoma) and one schwannoma. All adenomas exhibited a heterogeneous NIRAF pattern, distinct from the homogeneous pattern observed in the schwannoma. A bright cap was identified in 9 out of 14 (64.3%) parathyroid adenomas (all chief cell adenomas). On the contrary, all 9 macroscopically normal PGs identified during surgery presented an homogeneous pattern., Conclusion: Our findings support the integration of NIRAF into parathyroid surgical procedures. The heterogeneous NIRAF pattern observed in parathyroid adenomas, often accompanied by a bright cap, offers a promising intraoperative diagnostic tool to differentiate hyperfunctioning from normal parathyroid tissue. Larger-scale randomized trials are warranted to further validate these findings., (© 2024. The Author(s).)

Primary hyperparathyroidism represents the third most prevalent endocrine disease in the general population, consisting of an excessive secretion of parathyroid hormone from one or, more frequently, more of the parathyroid glands, leading to a dysregulation of calcium homeostasis. Schematically, its development occurs primarily by pathophysiological events with genetic mutation, at the germline and/or somatic level, that favor the neoplastic transformation of parathyroid cells and promote their aberrant proliferation, and mutations determining the shift in the PTH "set-point", thus interfering with the normal pathways of PTH secretion and leading to a "resetting" of Ca 2+ -dependent PTH secretion or to a secretion of PTH insensitive to changes in extracellular Ca 2+ levels. Familial syndromic and non-syndromic forms of primary hyperparathyroidism are responsible for approximately 2-5% of primary hyperparathyroidism cases and most of them are inherited forms. The history of the genetic/molecular studies of parathyroid tumorigenesis associated with multiple endocrine neoplasia type 1 syndrome (MEN1) represents an interesting model to understand genetic-epigenetic-molecular aspects underlying the pathophysiology of primary hyperparathyroidism, both in relation to syndromic and non-syndromic forms. This minireview aims to take a quick and simplified look at the MEN1-associated parathyroid tumorigenesis, focusing on the molecular underlying mechanisms. Clinical, epidemiological, and observational studies, as well as specific guidelines, molecular genetics studies, and reviews, have been considered. Only studies submitted to PubMed in the English language were included, without time constraints.

Purpose: The current primary hyperparathyroidism (PHPT) presents as a mild disease. We explored skeletal phenotypes in postmenopausal women affected by PHPT, focusing on fracture prevalence., Methods: PHPT women were retrospectively evaluated at four Italian centers for osteoporosis management (two centers in Milan, n = 244; Cuneo, n = 128; Pisa, n = 131). Data collected from clinical records were analyzed by hierarchical clusterization., Results: Considering the whole PHPT series [ n = 503, aged 67.0 (61.0-74.0) years], 90% had low bone mineral density (BMD) and approximately 30% reported at least one fracture. Vertebral fractures were associated with older age and lower hypophosphatemia, while women with appendicular fractures were younger with less severe hypophosphatemia. Fractures were predicted by lumbar T -score. By using a clustering approach, we identified four different skeletal phenotypes (cluster, C): C1 ( n = 53) and C2 ( n = 172) included women with lumbar and femur neck osteopenia, with low prevalence of fractures (11.3%). Osteoporotic PHPT women were grouped into C3 ( n = 142) and C4 ( n = 136); all women in C4 experienced fractures, were older, and were more frequently affected with cardiovascular diseases. In contrast, women included in C3 never experienced fractures and had a lower body mass index (BMI), though they were characterized by severe reduction in BMD at both lumbar and femur sites. Ionized and total calcium, phosphate, 25hydroxyvitamin D levels, kidney function, and stone prevalence (range, 26.4%-29.0%) were similar among clusters C1, C2, and C4, while unfractured women in C3 showed slightly higher ionized hypercalcemia, lower hypophosphatemia, and higher hypercalciuria with a trend to more frequently develop kidney stones (38.7%) than women in the remaining clusters., Conclusions: Skeletal involvement in women with PHPT presented heterogeneous phenotypes with different prevalence of fractures. Fractures were not related to PHPT severity, suggesting that other factors besides PHPT, such as age, BMI, and lumbar and femur BMD, should be considered in the evaluation of bone involvement in postmenopausal women with PHPT., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Corbetta, Gianotti, Castellano, Carrara, Raineri, Munari, Guabello, Cairoli, Chiodini, Giovanelli, Pierotti, Dinoi, Della Valentina and Cetani.)

The expression of several key molecules is altered in parathyroid tumors due to gene mutations, the loss of heterozygosity, and aberrant gene promoter methylation. A set of genes involved in parathyroid tumorigenesis has been investigated in sporadic parathyroid adenomas (PAds). Thirty-two fresh PAd tissue samples surgically removed from patients with primary hyperparathyroidism (PHPT) were collected and profiled for gene, microRNA, and lncRNA expression (n = 27). Based on a gene set including MEN1 , CDC73 , GCM2 , CASR , VDR , CCND1 , and CDKN1B , the transcriptomic profiles were analyzed using a cluster analysis. The expression levels of CDC73 and CDKN1B were the main drivers for clusterization. The samples were separated into two main clusters, C1 and C2, with the latter including two subgroups of five PAds (C2A) and nineteen PAds (C2B), both differing from C1 in terms of their lower expression of CDC73 and CDKN1B . The C2A PAd profile was also associated with the loss of TP73, an increased expression of HAR1B , HOXA-AS2 , and HOXA-AS3 lncRNAs, and a trend towards more severe PHPT compared to C1 and C2B PAds. C2B PAds were characterized by a general downregulated gene expression. Moreover, CCND1 levels were also reduced as well as the expression of the lncRNAs NEAT1 and VLDLR-AS1 . Of note, the deregulated lncRNAs are predicted to interact with the histones H3K4 and H3K27. Patients harboring C2B PAds had lower ionized and total serum calcium levels, lower PTH levels, and smaller tumor sizes than patients harboring C2A PAds. In conclusion, PAds display heterogeneous transcriptomic profiles which may contribute to the modulation of clinical and biochemical features. The general downregulated gene expression, characterizing a subgroup of PAds, suggests the tumor cells behave as quiescent resting cells, while the severity of PHPT may be associated with the loss of p73 and the lncRNA-mediated deregulation of histones.

Background: Although the skeleton remains a common target of primary hyperparathyroidism, the classic bone disease "osteitis fibrosa cystica" is currently rare due to early diagnosis. This case represents severe classic bone manifestations of primary hyperparathyroidism due to delayed diagnosis and delayed medical attention., Case Presentation: A 19-year-old young female was symptomatically managed for chronic back pain and nonspecific bone pain in the small joints of both hands over 2 months by a general practitioner. The patient had delayed seeking for treatment for 3 months. Later, she was evaluated for tuberculosis, hematological malignancies and rheumatic disorders following a fractured T12 vertebra and underwent pedicle screw fixation. However, clinical examination and investigations, including biochemistry, imaging and histology, ruled out the above conditions. Unfortunately, serum calcium level was not performed at the initial presentation. Later, primary hyperparathyroidism was diagnosed on the basis of moderate hypercalcaemia and elevated intact PTH levels (2064 pg/ml). She had sufficient vitamin D levels and normal kidney function. Her DXA scan revealed severe secondary osteoporosis with the lowest Z score of -8 at the total lumbar spine. Ultrasonography of the thyroid revealed a hypo echoic mass in the left lower neck, and localization studies with technetium-99 m sestamibi and 4D-CT revealed a left inferior parathyroid adenoma (1.6 × 1.5 × 1.6 cm). CT scan also revealed brown tumors in the mandible and vertebrae and diffuse bony changes in the skull, sternum, humerus and vertebrae. Her radiographs revealed subperiosteal bone resorption on the radial aspects of the middle and distal phalanges and brown tumors in both the ulna and fibula. We excluded MEN and other hereditary syndromes in our patient with a personal and family history and with a normal pituitary hormone profile because of poor resources for genetic testing. She underwent parathyroid adenoma excision, and the postoperative period was complicated with hungry bone syndrome, requiring high doses of calcium and active vitamin D supplements. These supplements were gradually weaned off over 6 months, and she recovered with normal biochemical investigations. Histology revealed parathyroid adenoma without malignant features., Conclusion: In developing countries where routine calcium screening is not available, clinicians should be aware of various manifestations of primary hyperparathyroidism to allow diagnosis as soon as possible without delay to prevent further progression, as it is a treatable condition., (© 2024. The Author(s).)

Background: Parathyroid carcinoma (PC) is a rare malignancy, often diagnosed incidentally through postoperative pathological examination. The occurrence of nodular goiter, intrathyroidal parathyroid carcinoma, contralateral parathyroid adenoma (PA), and papillary thyroid microcarcinoma (PTMC) is extremely uncommon, which prompted us to report our case experience., Case Presentation: We describe a 67-year-old male who presented with a cervical mass causing tracheal compression, which prompted him to seek medical advice. Based on preoperative auxiliary examination results from color Doppler ultrasound, SPECT parathyroid imaging, and blood tests, he was initially diagnosed with a suspected parathyroid adenoma and nodular goiter. Excision of the right lobe and isthmus of the thyroid, and left superior parathyroid gland was conducted, which were sent to intraoperative frozen pathological examination. During intraoperative observation, adhesion around the right thyroid lobe was discovered. Consequently, right central area lymph node dissection was performed due to suspicion of an aggressive malignant tumor. Histology and immunohistochemistry analysis revealed incidental intrathyroidal parathyroid carcinoma, contralateral parathyroid adenoma, classical papillary thyroid microcarcinoma, and nodular goiter., Conclusion: Parathyroid carcinoma should be highly suspected when extremely high levels of PTH and severe hypercalcemia are present, which cannot be simply explained by a preoperatively localized parathyroid adenoma, especially when suspicious malignant adhesion is found during intraoperative exploration. In cases where multifocal thyroid nodules are associated with increased uptake of 99Tc-sestamibi, the possibility of coexisting carcinomas should be considered, not only for thyroid malignancy but also for the potential presence of intrathyroidal parathyroid carcinoma., (© 2024. The Author(s).)

Primary hyperparathyroidism with parathyroid tumors is a typical manifestation of Multiple Endocrine Neoplasia Type 1 (MEN1) and is historically termed "primary hyperplasia". Whether these tumors represent a multi-glandular clonal disease or hyperplasia has not been robustly proven so far. Loss of Menin protein expression is associated with inactivation of both alleles and a good surrogate for a MEN1 gene mutation. The cyclin-dependent kinase inhibitor 1B (CDKN1B) gene is mutated in MEN4 and encodes for protein p27 whose expression is poorly studied in the syndromic MEN1 setting.Here, we analyzed histomorphology and protein expression of Menin and p27 in parathyroid adenomas of 25 patients of two independent, well-characterized MEN1 cohorts. The pattern of loss of heterozygosity (LOH) was assessed by fluorescence in situ hybridization (FISH) in one MEN1-associated parathyroid adenoma. Further, next-generation sequencing (NGS) was performed on eleven nodules of four MEN1 patients.Morphologically, the majority of MEN1 adenomas consisted of multiple distinct nodules, in which Menin expression was mostly lost and p27 protein expression reduced. FISH analysis revealed that most nodules exhibited MEN1 loss, with or without the loss of centromere 11. NGS demonstrated both subclonal evolution and the existence of clonally unrelated tumors.Syndromic MEN1 parathyroid adenomas therefore consist of multiple clones with subclones, which supports the current concept of the novel WHO classification of parathyroid tumors (2022). p27 expression was lost in a large fraction of MEN1 parathyroids and must therefore be used with caution in suggesting MEN4., (© 2024. The Author(s).)

Transient receptor potential canonical sub-family channel 3 (TRPC3) is considered to play a critical role in calcium homeostasis. However, there are no established findings in this respect with regard to TRPC6. Although the parathyroid gland is a crucial organ in calcium household regulation, little is known about the protein distribution of TRPC channels-especially TRPC3 and TRPC6-in this organ. Our aim was therefore to investigate the protein expression profile of TRPC3 and TRPC6 in healthy and diseased human parathyroid glands. Surgery samples from patients with healthy parathyroid glands and from patients suffering from primary hyperparathyroidism (pHPT) were investigated by immunohistochemistry using knockout-validated antibodies against TRPC3 and TRPC6. A software-based analysis similar to an H-score was performed. For the first time, to our knowledge, TRPC3 and TRPC6 protein expression is described here in the parathyroid glands. It is found in both chief and oxyphilic cells. Furthermore, the TRPC3 staining score in diseased tissue (pHPT) was statistically significantly lower than that in healthy tissue. In conclusion, TRPC3 and TRPC6 proteins are expressed in the human parathyroid gland. Furthermore, there is strong evidence indicating that TRPC3 plays a role in pHPT and subsequently in parathyroid hormone secretion regulation. These findings ultimately require further research in order to not only confirm our results but also to further investigate the relevance of these channels and, in particular, that of TRPC3 in the aforementioned physiological functions and pathophysiological conditions.

Multiglandular primary hyperparathyroidism (MGD) represents a rare form of primary hyperparathyroidism (PHPT). MGD is associated with hereditary PHPT, but the sporadic MGD is more common and affects a similar patient profile as single gland parathyroid disease (SGD). The distinction between SGD and MGD is of great clinical importance, especially for the strategy of parathyroidectomy. Based on the limited knowledge available, MGD is likely to be a genetically heterogeneous disease resulting from the interaction of germline and somatic DNA mutations together with epigenetic alterations. Furthermore, these events may combine and occur independently in parathyroid tumors within the same individual with MGD. Gene expression profiling has shown that SGD and MGD may represent distinct entities in parathyroid tumorigenesis. We are waiting for studies to analyze exactly which genes are different in SGD and MGD in order to identify potential biomarkers that can distinguish between the two forms of the disease.

Spontaneous or fine-needle aspiration (FNA)-induced remission of primary hyperparathyroidism (PHPT) is an extremely rare phenomenon with variable outcomes. We report a 75-year-old Male who initially presented with left ureteric calculi and was found to have PHPT. Imaging studies including ultrasound neck, parathyroid sestamibi scan and computed tomography of thorax, abdomen, and pelvis failed to identify the culprit lesion and exploratory parathyroidectomy was planned. Before surgery, he underwent FNA for cytology of a right cold thyroid nodule which was complicated with a large neck haematoma and dysphagia. The cytology of the aspirated fluid was consistent with a benign cyst. One month after the procedure, serum calcium and phosphate normalised along with resolution of haematoma. He remained in biochemical remission at 1-year follow-up with the latest ultrasound of neck showing resolution of a large colloid nodule that was previously seen occupying the right thyroid lobe., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background:  Primary hyperparathyroidism (PHPT) is an endocrine disorder characterized by excessive secretion of parathyroid hormone (PTH) with upper-normal or elevated blood calcium levels due to primary thyroid gland pathology. PHPT is a rare pathology in children, with a prevalence of 2-5:100,000 children according to the literature. Due to the non-specificity of clinical manifestations at onset (nausea, vomiting, abdominal pain, emotional lability), the disease may remain undiagnosed for a long time., Aim:  To study the features of the course and molecular genetic basis of primary hyperparathyroidism in children., Materials and Methods:  Retrospective observational study of 49 patients diagnosed with primary hyperparathyroidism. All patients underwent a comprehensive laboratory-instrumental and molecular genetic study at the Institute of Pediatric Endocrinology, Endocrinology Research Center of Russia in the period 2014-2022., Results:  The first clinical symptoms of PHPT were noted at the age of 13.8 years [10.6; 1 5.2], among which fatigue, headaches, dyspepsia, lower limb pain, and fractures were the most common. The age of diagnosis was 15.81 years [13.1; 16.8], all children were found to have high levels of PTH, total and ionized calcium, with hypophosphatemia in 93.9% of patients (n=46) and hypercalciuria in 43% (n=21). Five out of 49 patients (10.2%) were found to have ectopy of the thyroid: 3 showed an intrathyroidal location, 2 in the mediastinal region. Molecular genetic study revealed mutations in 32.7% of patients (n=16, CI (21; 47)), mutations in MEN1 being the most frequent (n=11). Pathogenic variants in CDC73 were detected in 3 patients, RET - in 2. Among the operated 39 patients, adenoma of the thyroid was detected in 84.6% of cases (n=33), hyperplasia in 7.7% (n=3), atypical adenoma in 5.1% (n=2), carcinoma in 5.1% of cases (n=2)., Conclusion:  The paper presents the peculiarities of the course and the results of molecular genetic study of pediatric PHPT. This sample is the largest among those published in the Russian Federation.

Primary hyperparathyroidism is a common endocrine disorder. Interestingly, the majority (75%) of parathyroid tumors are localized to the inferior parathyroid glands. To date, the reason for this natural bias has not been investigated. We assessed the global gene expression profile of superior and inferior glands obtained from forensic autopsies. The genes with significant differential expression between superior and inferior parathyroids were further assessed by RT-PCR in 19 pairs. As an iterative approach, additional genes with an established role in parathyroid disorders, i.e., CASR, MAFB, PAX9, TBCE, TBX1, VDR, MEN1, CCND1, and CDC73 were also evaluated by RT-PCR in all 19 pairs of superior and inferior parathyroid glands. Seven homeobox genes, namely HOXA4, HOXA5, HOXBAS3, HOXB4, HOXB6, HOXB9, IRX1, and one encoding for ALDH1A2 showed a lower expression in the inferior parathyroid glands than in the superior. Conversely, SLC6A1 showed a higher expression in the inferior glands. Of the nine genes with significant differential mRNA expression among superior and inferior glands HOXB9, HOXB4 and IRX1 could be detected by western blotting/mass spectrometry. The study is the first to show the differential expression of nine genes HOXA4, HOXA5, HOXBAS3, HOXB4, HOXB6, HOXB9, IRX1, ALDH1A2, and SLC6A1 in inferior versus the superior parathyroid glands. This could have potential implications for the preferential localization of parathyroid tumors to the inferior parathyroid glands as observed in patients with primary hyperparathyroidism., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Approximately 10% of primary hyperparathyroidism cases are hereditary, due to germline mutations in certain genes. Although clinically relevant, a systematized genetic diagnosis is missing due to a lack of firm evidence regarding individuals to test and which genes to evaluate., Methods: A customized gene panel ( AIP , AP2S1 , CASR , CDC73 , CDKN1A , CDKN1B , CDKN2B , CDKN2C , GCM2 , GNA11 , MEN1 , PTH , RET , and TRPV6 ) was performed in 40 patients from the Mediterranean area with suspected familial hyperparathyroidism (≤45 years of age, family history, high-risk histology, associated tumour, multiglandular disease, or recurrent hyperparathyroidism). We aimed to determine the prevalence of germline variants in these patients, to clinically characterize the probands and their relatives, and to compare disease severity in carriers versus those with a negative genetic test., Results: Germline variants were observed in 9/40 patients (22.5%): 2 previously unknown pathogenic/likely pathogenic variants of CDKN1B (related to MEN4), 1 novel variant of uncertain significance of CDKN2C , 4 variants of CASR (3 pathogenic/likely pathogenic variants and 1 variant of uncertain significance), and 2 novel variants of uncertain significance of TRPV6 . Familial segregation studies allowed diagnosis and early treatment of PHPT in first-degree relatives of probands., Conclusion: The observed prevalence of germline variants in the Mediterranean cohort under study was remarkable and slightly higher than that seen in other populations. Genetic screening for suspected familial hyperparathyroidism allows the early diagnosis and treatment of PHPT and other related comorbidities. We recommend genetic testing for patients with primary hyperparathyroidism who present with high-risk features., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Mazarico-Altisent, Capel, Baena, Bella-Cueto, Barcons, Guirao, Pareja, Muntean, Arsentales, Caixàs and Rigla.)

Purpose: To assess the added value of 99m Tc-MIBI single-photon emission computed tomography/computed tomography (SPECT/CT) fusion imaging over dual-phase scintigraphy in the diagnosis of secondary hyperparathyroidism (SHPT)., Methods: This retrospective study included 23 patients with SHPT. The diagnostic efficacy of 99m Tc-MIBI dual-phase scintigraphy and SPECT/CT fusion imaging was analyzed and compared based on the result of postoperative pathology and follow-up. To evaluate the diagnostic ability of 99m Tc-MIBI dual-phase scintigraphy, the volume and radioactive count of parathyroid lesions were assessed using the region of interest method., Results: A total of 79 hyperplastic parathyroid glands and two thyroid tissues were surgically removed from 23 SHPT patients and 13 normal parathyroid glands were preserved. 99m Tc-MIBI SPECT/CT fusion imaging showed higher sensitivity and accuracy than 99m Tc-MIBI dual-phase scintigraphy [sensitivity, 77.2% (61/79) vs 46.8% (37/79); accuracy, 80.4% (74/92) vs 54.3% (50/92), respectively], but comparable specificity [100% (13/13)). Among 61 positive lesions detected by 99m Tc-MIBI SPECT/CT fusion imaging, 37 were dual-phase scintigraphy positive and 24 were dual-phase scintigraphy false negative. The radioactivity counts and radioactivity per unit volume in dual-phase scintigraphy positive were higher than that in dual-phase scintigraphy false negative ( P  < 0.05), but the volume of parathyroid lesions between the two groups had no significant difference ( P  > 0.05)., Conclusion: Compared with 99m Tc-MIBI dual-phase scintigraphy, 99m Tc-MIBI SPECT/CT fusion imaging has incremental value in the diagnosis of SHPT. The low uptake of MIBI in the whole gland and low MIBI uptake per unit volume are easy to cause dual-phase scintigraphy false negative., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: The preferred nuclear medicine method for identification of hyperfunctioning parathyroid glands in hyperparathyroidism (HPT) develops continuously in relation to the technological progress. Diagnostic methods based on PET/CT have during recent years evolved with new tracer possibilities competing with traditional scintigraphic methods. This investigation is a head-to-head comparison of Tc-99m-sestamibi SPECT/CT gamma camera scintigraphy (sestamibi SPECT/CT) and C-11-L-methionin PET/CT imaging (methionine PET/CT) for preoperative identification of hyperfunctioning parathyroid glands., Procedures: The study is a prospective cohort study including 27 patients diagnosed with primary hyperparathyroidism (PHPT). Two nuclear medicine physicians assessed all examinations independently and blinded. All scanning assessments were matched to the final surgical diagnosis as confirmed by histopathology. Biochemical monitoring of the therapeutical effects was performed preoperatively by PTH-measurements and followed postoperatively for up to 12 months. Comparisons were made for differences in sensitivity and positive predictive value (PPV)., Results: Twenty-seven patients (18 females, 9 males; mean age (range): 58.9 years (34.1-79)) were enrolled into the study. The 27 patients had a total of 33 identified sites of lesions of which 28 (85%) turned out to be histopathological verified hyperfunctioning parathyroid glands. The sensitivity and PPV for sestamibi SPECT/CT were 0.71 and 0.95; that of methionine PET/CT was 0.82 and 1, respectively. Both sensitivity and PPV were slightly lower for sestamibi SPECT/CT than for methionine PET PET/CT (-0.11, 95% confidence interval (95% CI): -0.29 to 0.08; -0.05, 95% CI: -0.14 to 0.04, respectively), but not to a statistically significant extent (p=0.38 and p=0.31). The sensitivity and PPV for diagnostic CT were 0.64 (95% CI: 0.44 to 0.81) and 1 (95% CI: 0.81 to 1)., Conclusions: Methionine PET/CT performed comparable to sestamibi SPECT/CT with respect to identification and localization of hyperfunctioning parathyroid glands prior to surgery., (© 2023. The Author(s), under exclusive licence to World Molecular Imaging Society.)

Background: Hyperparathyroidism jaw-tumor syndrome (HPT-JT) is the rarest familial cause of primary hyperparathyroidism, with an incidence <1/1000000, caused by a pathogenic variant in the CDC73 (or HRPT2) gene that encodes parafibromin, a protein involved in many cellular mechanisms. Patients with HPT-JT have a 15-20% of risk of developing parathyroid carcinoma, whereas it accounts for only 1% of all cases of primary hyperparathyroidism. Patients also develop jaw tumors in 30% of cases, kidney abnormalities in 15% of cases, and uterine tumors in 50% of patients., Case Report: Here are report two atypical cases of HPT-JT with variable expressivity in the same family. In front of an isolated primary hyperparathyroidism at 28 years of age of incidental discovery following a weight gain, the propositus benefited a first-line panel by Next-Generation Sequencing of the genes involved in familial hyperparathyroidism: CaSR, CDC73, MEN1, and RET. Genetic testing revealed the presence of a pathogenic germline variation CDC73: c.687&#95;688dup; p.Val230Glufs*28, found only in nine families in the literature and allowing the diagnosis of HPT-JT. Given a history of primary hyperparathyroidism at 52 years and adenomyosis, the patient's mother also underwent a genetic analysis that found her daughter's variation and established her inherited trait., Conclusion: In view of the clinical and genotypic heterogeneity, we confirm the interest of using an extended gene panel for the diagnosis of familial primary hyperparathyroidism. CDC73 variations could be more frequent than described in the literature. The association of primary hyperparathyroidism with uterine involvement could be a new indication for analysis., (© 2023 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.)

Rationale and Objectives: Gaps in primary hyperparathyroidism diagnosis are well-documented. End-organ damage correlates with disease duration and often occurs before diagnosis. We hypothesize that opportunistic parathyroid gland assessment on routine CT could decrease existing diagnosis gaps. Our purpose is to assess for enlarged parathyroid glands on contrast-enhanced CT acquired prior to biochemical screening and subsequent development of related morbidity., Materials and Methods: This retrospective study included consecutive patients with primary hyperparathyroidism undergoing parathyroidectomy with contrast-enhanced CT including the lower neck and upper chest acquired prior to biochemical screening. One neuroradiologist retrospectively evaluated all CTs for enlarged (estimated weight greater than 60 mg) parathyroid glands. Gold standard operative and pathology reports were correlated with CT findings, and medical records were reviewed for development of primary hyperparathyroidism-related comorbidities., Results: The sample comprised 38 patients (30 women, 8 men, median age 60 years) with 70 CTs of interest. The neuroradiologist identified 32 putative enlarged parathyroid glands (median estimated weight 307 mg) in 29 (76%) patients on CTs predating biochemical screening by a median of 30 months. Putative enlarged parathyroid glands on CT corresponded to pathologically proven parathyroid lesions in 26 (90%) patients. Of 26 patients with retrospectively identified pathologically proven parathyroid lesions, 12 (46%) developed at least 1 renal, bone, or neurocognitive comorbidity between CT and subsequent biochemical screening., Conclusion: Enlarged parathyroid glands are frequently visible on routine CTs acquired years prior to primary hyperparathyroidism diagnosis. Biochemical screening based on enlarged glands could potentially prevent associated morbidity in almost half of such patients., (Copyright © 2022 The Association of University Radiologists. Published by Elsevier Inc. All rights reserved.)

Purpose: CDKN1B mutations were established as a cause of multiple endocrine neoplasia 4 (MEN4) syndrome in patients with MEN1 phenotype without a mutation in the MEN1 gene. In addition, variants in other cyclin-dependent kinase inhibitors (CDKIs) were found in some MEN1-like cases without the MEN1 mutation. We aimed to describe novel germline mutations of these genes in patients with primary hyperparathyroidism (PHPT)., Methods: During genetic screening for familial hyperparathyroidism, three novel CDKIs germline mutations in three unrelated cases between January 2019 and November 2021 were identified. In this report, we describe clinical features, DNA sequence analysis, and familial segregation studies based on these patients and their relatives. Genome-wide DNA study of loss of heterozygosity (LOH), copy number variation (CNV), and p27/kip immunohistochemistry was performed on tumour samples., Results: DNA screening was performed for atypical parathyroid adenomas in cases 1 and 2 and for cystic parathyroid adenoma and young age at diagnosis of PHPT in case 3. Genetic analysis identified likely pathogenic variants of CDKN1B in cases 1 and 2 and a variant of the uncertain significance of CDKN2C, with uniparental disomy in the tumour sample, in case 3. Neoplasm screening of probands showed other non-endocrine tumours in case 1 (colon adenoma with dysplasia and atypical lipomas) and case 2 (aberrant T-cell population) and a non-functional pituitary adenoma in case 3., Conclusion: Germline mutations in CDKIs should be included in gene panels for genetic testing of primary hyperparathyroidism. New germline variants here described can be added to the current knowledge., (© 2022. The Author(s).)

Introduction: Although imaging plays no role in diagnosing primary hyperparathyroidism (PHPT), preoperative localization is essential for a focused parathyroidectomy. We hypothesized that reviewing imaging obtained prior to PHPT diagnosis can identify enlarged parathyroid glands and provide information that might potentially impact the preoperative evaluation and intraoperative course of patients undergoing parathyroidectomy., Methods: We included adult patients with PHPT who underwent parathyroidectomy between October 2015 and October 2020 and had contrast-enhanced computed tomography (CT) imaging of the lower neck and upper chest obtained prior to diagnosis for unrelated indications. A radiologist reviewed the prediagnosis CTs blinded to subsequent parathyroid localization imaging and operative findings. A surgeon assessed the radiologist's findings in the context of each case to determine the potential impact of information from old imaging on surgical decision-making., Results: We identified at least one enlarged parathyroid gland on prior contrast-enhanced CT in 30 (75%) of 40 included patients. Despite old imaging enabling correct localization, 60% of these 30 underwent dedicated parathyroid imaging prior to parathyroidectomy. Knowledge of the enlarged parathyroid(s) on prior imaging might have allowed a more focused approach in 10.0% and prompted a more thorough exploration in 13.3%. In the total cohort, reviewing prior imaging could have provided information capable of changing the preoperative evaluation in 52.5% and the operative course in 17.5%., Conclusions: The identification of enlarged parathyroid glands on contrast-enhanced CT imaging that predates a diagnosis of PHPT is possible. Prospective studies might verify the impact of these findings on the preoperative evaluation and operative course of patients undergoing parathyroidectomy., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Hyperparathyroidism is a common endocrine disorder characterized by elevated levels of parathyroid hormone and hypercalcemia and is divided into 3 types: primary, secondary, and tertiary. Distinction between these types is accomplished by correlation of clinical, radiologic, and laboratory findings with pathologic features. Primary hyperparathyroidism occurs sporadically in 85% of cases with the remaining cases associated with multiple familial syndromes. The pathologic manifestations of primary hyperparathyroidism include parathyroid adenoma, parathyroid hyperplasia, and parathyroid carcinoma. Recent advances in the understanding of the pathogenesis of parathyroid disease has helped to refine the diagnosis and classification of parathyroid lesions. The identification of multiple clonal proliferations in traditional multiglandular parathyroid hyperplasia has led to the adoption by the World Health Organization (WHO) of the alternate term of primary hyperparathyroidism-related multiglandular parathyroid disease. Additional nomenclature changes include the adoption of the term atypical parathyroid tumor in lieu of atypical parathyroid adenoma to reflect the uncertain malignant potential of these neoplasms. Clinical and morphologic features characteristic of familial disease have been described that can help the practicing pathologist identify underlying familial disease and provide appropriate management. Use of ancillary immunohistochemistry and molecular studies can be helpful in classifying parathyroid neoplasms. Parafibromin has proven useful as a diagnostic and prognostic marker in atypical parathyroid tumors and parathyroid carcinomas. This review provides an update on the diagnosis and classification of parathyroid lesions considering the recent advances in the understanding of the molecular and clinical features of parathyroid disease and highlights the use of ancillary studies (immunohistochemical, and molecular) to refine the diagnosis of parathyroid lesions., Competing Interests: The authors have no funding or conflicts of interest to disclose., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Ultrasonography (US) and 99m Technetium-sestamibi scintigraphy ( 99m Tc-MIBI) are currently first-line imaging modalities to localize parathyroid adenomas with sensitivities of 80% and 84%, respectively. Therefore, finding other modalities to further improve the diagnostic accuracy for preoperative localization is critically needed., Purpose: To evaluate the application value of contrast-enhanced ultrasound (CEUS) in the preoperative localization of microwave ablation (MWA) for primary hyperparathyroidism (PHPT)., Methods: Between December 2012 and May 2021, 100 PHPT patients (34 males and 66 females; mean age, 56.31 ± 13.43 years; age range, 25-85 years) with 130 suspected parathyroid nodules were enrolled. US, CEUS, and 99m Tc-MIBI were performed for the localization of pathological parathyroid glands. All patients were performed MWA under ultrasound guidance. All the suspected parathyroid nodules underwent core needle biopsy under ultrasound guidance during MWA to confirm the pathology. The diagnostic performance of all the imaging tests was analyzed in comparison with the pathological results., Results: A total of 130 nodules suspected to be of parathyroid origin from preoperative localization images were confirmed by pathological results, of which 116 were of parathyroid origin, and 14 were not of parathyroid origin. The sensitivity, specificity, accuracy, and the area under receiver operating characteristic curve of CEUS in the localization of pathological parathyroid glands were 100%, 92.86%, 99.23%, and 0.964, which were significantly higher than those of US (93.10%, 42.86%, 87.69%, and 0.680) and 99m Tc-MIBI (81.90%, 42.86%, 77.69%, and 0.624) (p < 0.05). The sensitivity and accuracy of CEUS were 100% and 97.22%, which were higher than those of 99m Tc-MIBI (65.62% and 63.89%) or US (75.00% and 72.22%) in patients with multiple parathyroid glands (p < 0.05). For smaller parathyroid adenomas (≤2 cm in diameter), the sensitivities of CEUS in locating hyperfunctioning parathyroid glands were 100%, which was significantly higher than that of 99m Tc-MIBI (73.68% and 84.31%, p < 0.05)., Conclusions: CEUS is a valuable preoperative localization method for PHPT patients performed MWA, especially for the patients with smaller pathological parathyroid gland and multiple glandular lesions., (© 2022 The Authors. Journal of Applied Clinical Medical Physics published by Wiley Periodicals, LLC on behalf of The American Association of Physicists in Medicine.)

Purpose: Various diagnostic methods have been utilized for localizing pathologic parathyroid glands to consequently provide the possibility of avoiding bilateral neck dissection in cases of primary hyperparathyroidism. Scintigraphy, combined with ultrasound, became established as the standard method of localization in the 2000s. The aim of this study was to evaluate the role of the "before skin incision" surgeon-performed ultrasound in determining the improvement in the diagnostic accuracy in a large case series., Method: The method used in this research is a retrospective observational study (study period: between 1-2014 and 12-2020) comparing two patient groups before (control group: 31 patients) and after (study group: 70 patients) the introduction of the ultrasonography surgical protocol: combined preoperative and "before skin incision" surgeon-performed ultrasound., Results: The sensitivity of the combined preoperative "before skin incision" surgeon-performed ultrasound was 97%, and the positive predictive value was 93% in regard to detecting the number of diseased glands and the appropriate anatomic location (right versus left, upper versus lower). The sensitivity of the parathyroid scan (Tc-MIBI-scintigraphy) was 74%, and the positive predictive value was 92%. The duration of surgery was significantly shorter in the test group (84.7 vs. 66.4 min; Mann‒Whitney U: 0.006). No differences were detected between the two groups in regard to avoiding intraoperative or postoperative complications., Conclusion: The combination of the preoperative "before skin incision" surgeon-performed ultrasound could improve the efficiency of the preoperative location and anatomic classification using the standard literature-suggested diagnostic methods., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Primary hyperparathyroidism (PHPT) is third most common endocrine disorder characterized by hypercalcemia with elevated or nonsuppressed parathyroid hormone levels by parathyroid tumors. Familial PHPT, as part of multiple endocrine type-1, occurs due to the germline mutation in the MEN1 gene. The involvement and the role of germline MEN1 variations in sporadic PHPT of Indian PHPT patients are unknown. Precise classifications of different types of MEN1 variations are fundamental for determining clinical relevance and diagnostic role. This prospective cohort study was performed on 82 patients with PHPT (with no clinical or history of MEN1) who underwent screening for MEN1 variations through Sanger sequencing. Multilevel computational analysis was performed to determine the structure-function relationship of synonymous, nonsynonymous, and variants of uncertain significance (VUS). Of the 82 PHPT patients, 42 (51%) had 26 germline MEN1 variants, including eight nonsynonymous, seven synonymous, nine VUS, one splice site, and one regulatory variation. Five most common germline variations (c.1838A>G, c.1817C>T, c.1525C>A, c.-35A>T, and c.250T>C) were observed in this study. c.-35A>T (5' untranslated region [UTR]) was associated with recurrence of PHPT (odds ratio [OR] = 5.4; p = 0.04) and subsequent detection of other endocrine tumors (OR = 13.6, p = 0.035). c.1525C>A was associated with multi glandular parathyroid tumor (OR = 13.6, p = 0.035). Align-Grantham variation and Grantham deviation (Align-GVGD), functional analysis through hidden Markov MODEL (FATHMM), and MutationTaster analysis reported the disease-specific potential of VUS and synonymous variations. Significant linkage disequilibrium was observed in c.1785G>A and c.1817C>T (r 2  = 0.3859, p = 0.0001), c.1475C>G and c.1525C>A (r 2  = 0.385, p = 0.0004), and c.1569T>C and c.1838A>G (r 2  = 0.488, p = 0.0001). The detection of MEN1 variations, especially those with disease-specific potential, can prompt early screening for other MEN1-related tumors and disease recurrence. © 2022 American Society for Bone and Mineral Research (ASBMR)., (© 2022 American Society for Bone and Mineral Research (ASBMR).)

Background: Intraoperative parathyroid gland identification can be challenging. Parathyroid glands have an intrinsic autofluorescence when excited by wavelengths in the near-infrared region. Studies using near-infrared cameras to detect parathyroid gland near-infrared autofluorescence have suggested improved identification. The pathologic parathyroid glands in primary hyperparathyroidism have variable near-infrared autofluorescence intensity, but how this correlates with different characteristics of hyperparathyroidism is unknown. Our objective was to correlate the fluorescent intensity of excited glands with clinical variables to enhance a surgeon's ability to identify parathyroid glands., Methods: The data on patients undergoing surgery for primary hyperparathyroidism were collected. The images were collected intraoperatively with a handheld near-infrared device and analyzed. The data consisted of the ratio of mean parathyroid gland near-infrared autofluorescence over background (white gauze) near-infrared autofluorescence. The variables assessed for correlation with autofluorescence intensity were gland volume and weight, preoperative serum calcium and parathyroid hormone, age, body mass index, and sex. The images were quantified by Image J software (National Institutes of Health, Bethesda, MD). The lasso regression was analyzed by R version 4.1.3 to calculate adjusted P values (R Foundation for Statistical Computing, Vienna, Austria)., Results: From 2017 to 2021, 131 patients with primary hyperparathyroidism underwent parathyroidectomies of 151 parathyroid glands. The mean near-infrared autofluorescence intensity of parathyroid glands had a negative correlation with weight with lighter glands fluorescing more (P = .019) and a positive correlation with age with glands from older patients fluorescing more (P = .013). There were no significant correlations with preoperative serum calcium and parathyroid hormone, body mass index, and sex (P > .05)., Conclusion: In patients with primary hyperparathyroidism, we found that autofluorescence intensity correlated with parathyroid gland weight and patient age. This suggested that near-infrared camera use may be particularly helpful in identifying smaller adenomas and in older patients., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Objective: Preoperative location of hyperfunctioning parathyroid glands (HPGs) is vital when planning minimally invasive surgery in patients with primary hyperparathyroidism (PHPT). Dual-isotope subtraction scintigraphy with 99m Tc-MIBI/ 123 Iodide using SPECT/CT and planar pinhole imaging (Di-SPECT) has shown high sensitivity, but is challenged by high radiation dose, time consumption and cost. 11 C-Choline PET/CT (faster with a lower radiation dose) is non-inferior to Di-SPECT. We aim to clarify to what extent the two are interchangeable and how often there are discrepancies., Design: This is a prospective, GCP-controlled cohort study., Patients and Measurements: One hundred patients diagnosed with PHPT were included and underwent both imaging modalities before parathyroidectomy. Clinical implications of differences between imaging findings and negative imaging results were assessed. Surgical findings confirmed by biochemistry and pathology served as reference standard., Results: Among the 90 patients cured by parathyroidectomy, sensitivity was 82% (95% confidence interval [CI]: 74%-88%) and 87% (95% CI: 79%-92%) for Choline PET and Di-SPECT, respectively, p = .88. In seven cases at least one imaging modality found no HPG. Of these, neither modality found any true HPGs and only two were cured by surgery. When a positive finding in one modality was incorrect, the alternative modality was correct in approximately half of the cases., Conclusion: Choline PET and Di-SPECT performed equally well and are both appropriate as first-line imaging modalities for preoperative imaging of PHPT. When the first-line modality fails to locate an HPG, additional preoperative imaging with the alternate modality offers no benefit. However, if parathyroidectomy is unsuccessful, additional imaging with the alternate modality has merit before repeat surgery., (© 2022 The Authors. Clinical Endocrinology published by John Wiley & Sons Ltd.)

Childhood and adolescent primary hyperparathyroidism (PHPT) is a very rare disease. Data on its molecular genetics are scarce. We performed a retrospective analysis (January 2000-January 2021) to determine the deleterious germline variants and genotype-phenotype correlations in children and adolescents < 20 years diagnosed with PHPT from a single referral center. Clinical features, biochemistry, imaging, management, and genetics (clinical exome analyzed for 11 PHPT and 7 pancreatitis-associated genes, MLPA for CDC73) were recorded. Thirty-six patients (20 males; median age 17 years) were classified into those with familial and/or syndromic (F/S) or apparently sporadic (AS) presentation. Sixteen (44.4%) harbored pathogenic/likely pathogenic germline variants in PHPT-associated genes. The genetic yield in F/S group was 90% (MEN1:8/10; CDC73:1/10), and AS group was 26.9% (CDC73:4/26; CASR:3/26). F/S group had frequent asymptomatic presentation (60% vs none; P < 0.001), lower serum PTH (237.5 vs 1369.1 pg/mL; P = 0.001), and maximum parathyroid dimension (0.9 vs 2.2 cm; P = 0.01) than AS group. Among the AS group, renal involvement was higher in those with molecular diagnoses (71.4% vs 10.5%; P = 0.01). All those with novel CASR variants (including one homozygous) had hypercalciuria and histology-proven parathyroid adenoma/carcinoma. A missense CTRC VUS occurred in one patient with chronic pancreatitis. In summary, Asian Indian children and adolescents with PHPT have high genetic yield, even with apparently sporadic presentation. The phenotypic spectrum of CASR variants is expanded to include childhood/adolescent PHPT with hypercalciuria and single gland neoplasia. The proposed roles for renal involvement to predict molecular diagnosis among those with apparently sporadic presentation require further elucidation., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Primary hyperparathyroidism (pHPT) is well treatable surgically. Sonography (US) and sestamibi scintigraphy (MIBI) are used routinely, but it is unclear how valuable they are in determining Parathyroid glands' different locations. This study aimed to evaluate the prognostic value of US and MIBI in relation to the different localization of parathyroid adenomas in one of the largest study populations analyzed to date., Methods: 1089 patients with pHPT who had treatment in one tertiary referral center between 2007 and 2016 were analyzed. Preoperative US and MIBI reports were compared with the parathyroid adenoma's intraoperative localization. All parathyroid glands were confirmed by histological diagnosis., Results: No gland was detectable in 22.5% and 27.7% of all patients, by US or by MIBI, respectively. In relation to the different adenoma locations, the sensitivity of US ranged from 21.3% (upper right) to 68.9% (lower left) and of MIBI ranged from 23.5% (upper right) to 72% (lower left). The specificity for US ranged from 85% (lower right) to 99.2% (upper right) and for MIBI ranged from 86.1% (lower right) to 99.1% (upper right. Positive predictive values for all gland sites were 54% and 59% for MIBI and US, respectively. The value increased for side-only prediction to 73% and 78%, respectively. Neither the parathyroid hormone level nor the calcium value level influenced the sensitivity or specificity of the two test methods., Conclusions: The validity of preoperative US and MIBI depends crucially on the specific localization of adenomas. This should be considered when planning the extent of parathyroid surgery., (© 2022. The Author(s) under exclusive licence to Société Internationale de Chirurgie.)

Background: Parathyroid lesions are identified by subjective enhancement and washout patterns on computed tomography (CT). We have previously proposed "percentage arterial enhancement" (PAE) as an objective index and now aim to validate its performance prospectively., Methods: Dual-phase CT was performed in 40 consecutive primary hyperparathyroidism patients. PAE was calculated as [{arterial phase Hounsfield unit (HU)-unenhanced phase HU}/unenhanced phase HU] × 100. PAE > 128.9% was considered parathyroid., Results: PAE had 94.2% sensitivity, 100% positive predictive value (PPV) in lateralization, and sensitivity and PPV of 93.9% in quadrant localization of single-gland disease. PAE failed to identify two lesions: an intrathyroidal parathyroid carcinoma in the background of multinodular goiter and another lower enhancing cystic parathyroid adenoma. PAE had 60% sensitivity, and 100% PPV to identify multigland disease. The mean effective dose was 2.74 mSV., Conclusions: PAE is a specific CT index for parathyroid lesions with less radiation exposure. Areas of caution include intrathyroidal and cystic lesions., (© 2022 Wiley Periodicals LLC.)

Context: Germline CDKN1B pathogenic variants result in multiple endocrine neoplasia type 4 (MEN4), an autosomal dominant hereditary tumor syndrome variably associated with primary hyperparathyroidism, pituitary adenoma, and duodenopancreatic neuroendocrine tumors., Objective: To report the phenotype of 3 unrelated cases each with a unique germline CDKN1B variant (of which 2 are novel) and compare these cases with those described in the current literature., Design/methods: Three case studies, including clinical presentation, germline, and tumor genetic analysis and family history., Setting: Two tertiary University Hospitals in Sydney, New South Wales, and 1 tertiary University Hospital in Canberra, Australian Capital Territory, Australia., Outcome: Phenotype of the 3 cases and their kindred; molecular analysis and tumor p27kip1 immunohistochemistry., Results: Family A: The proband developed multiglandular primary hyperparathyroidism, a microprolactinoma and a multifocal nonfunctioning duodenopancreatic neuroendocrine tumor. Family B: The proband was diagnosed with primary hyperparathyroidism from a single parathyroid adenoma. Family C: The proband was diagnosed with a nonfunctioning pituitary microadenoma and ectopic Cushing's syndrome from an atypical thymic carcinoid tumor. Germline sequencing in each patient identified a unique variant in CDKN1B, 2 of which are novel (c.179G > A, p.Trp60*; c.475G > A, p.Asp159Asn) and 1 previously reported (c.374&#95;375delCT, p.Ser125*)., Conclusions: Germline CDKN1B pathogenic variants cause the syndrome MEN4. The phenotype resulting from the 3 pathogenic variants described in this series highlights the heterogenous nature of this syndrome, ranging from isolated primary hyperparathyroidism to the full spectrum of endocrine manifestations. We report the first described cases of a prolactinoma and an atypical thymic carcinoid tumor in MEN4., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society.)

Preoperative localization of pathologic parathyroids is crucial for minimally invasive treatment of primary hyperparathyroidism (PHPT). This study compared contrast-enhanced 18 F-fluorocholine PET/CT, cervical ultrasonography (CU), and conventional scintigraphic imaging modalities (MIBI scintigraphy, consisting of 99m Tc-sestamibi/ 123 I-sodium iodide SPECT/CT, 99m Tc-sestamibi/ 123 I-sodium iodide planar subtraction imaging, and 99m Tc-sestamibi planar dual-phase imaging), combined and individually, for preoperative localization of hyperfunctional parathyroids in PHPT. The gold standard was histologic examination. Methods: Data from consecutive patients with clinically suspected PHPT were retrospectively collected. All 3 imaging modalities were systematically performed. The ability of 18 F-fluorocholine PET/CT, CU, and MIBI scintigraphy to identify a hyperfunctional parathyroid and specify the side or identify an ectopic location was noted. Patients underwent surgical exploration if at least 1 examination was positive. The findings of CU + MIBI scintigraphy combined were considered positive if CU and MIBI scintigraphy separately showed a hyperfunctional parathyroid gland on the same side or in the same ectopic location; any findings other than these were considered negative. The composite judgment criterion for pathologic parathyroid was a combination of histologic analysis and normalization of parathyroid hormone and calcium levels. Results: In total, 149 pathologic parathyroids were found in 143 of the 144 included patients. 18 F-fluorocholine PET/CT diagnosed 148 of 149 pathologic parathyroids. Only 4 false-positives and 1 false-negative were found. The 18 F-fluorocholine PET/CT sensitivity of 99.3% was superior to that of CU, at 75.2% ( P < 0.0001); MIBI scintigraphy, at 65.1% ( P < 0.0001); and CU + MIBI scintigraphy, at 89.9%, ( P = 0.0009). Five of the 5 ectopic locations were diagnosed by 18 F-fluorocholine PET/CT, 2 of the 5 by MIBI scintigraphy, and none by CU. Accuracy was better for 18 F-fluorocholine PET/CT, at 98%, than for CU, at 84% ( P < 0.0001); MIBI scintigraphy, at 81% ( P < 0.0001); or CU + MIBI scintigraphy, at 91% ( P < 0.0001). Among the 72 (50%) patients who had a negative CU + MIBI scintigraphy result, 18 F-fluorocholine PET/CT correctly identified hyperfunctional thyroids in 70 (97.2%). Average uptake in the 18 F-fluorocholine PET/CT hyperfunctional parathyroid was higher than that in the adjacent thyroid (SUV max adjusted for lean body mass, 6.45 vs. 2.15) ( P < 0.0001). Conclusion: The accuracy of 18 F-fluorocholine PET/CT is higher than that of CU and MIBI scintigraphy for localization of hyperfunctional parathyroids, justifying the systematic use of 18 F-fluorocholine PET/CT as the first-line method for PHPT diagnosis., (© 2022 by the Society of Nuclear Medicine and Molecular Imaging.)

Parathyroidectomy is the only cure for primary hyperparathyroidism and is effective in more than 95% of cases at initial surgical intervention. However, 2.5-5% of cases have recurrent or persistent disease. Pre-operative imaging is recommended in patients undergoing redo parathyroidectomy to localize the diseased gland. Parathyroid 4D CT scan is now widely used for localization and has been reported to have improved accuracy when compared to other imaging modalities. We conducted a retrospective study of all redo parathyroidectomies from 2017 to 2021 at a single tertiary parathyroid referral center. We evaluated pre-operative 4D CT scan results and compared them to intra-operative findings to determine if 4D CT scan correctly predicted the location of the diseased gland. 4D CT scan had a concordance of 87% with intra-operative findings. 4D CT scan is highly effective identifying parathyroid pathology in re-operative cases and can be used as a pre-operative tool to guide surgical management.

Objective: To study the protein and mRNA expressions of regulator of G-protein signaling 5 (RGS5) in the pathogenesis of hyperparathyroidism., Methods: The expression of RGS5 protein in 20 primary hyperparathyroidism (PHPT), 31 secondary hyperparathyroidism (SHPT), and 20 control cases were studied by immunohistochemistry (IHC). The expression of RGS5 mRNA in 15 PHPT, 102 SHPT, and 7 normal parathyroid tissue were measured by quantitative real-time PCR (qRT-PCR) method., Results: The expressions of RGS5 in PHPT tissues were significantly higher than that in SHPT and normal parathyroid tissues (P < 0.05). While the differences in RGS5 protein expressions between SHPT and respective control samples were not statistically significant (P > 0.05). Likewise, the RGS5 mRNA expression in PHPT was significantly higher than that in SHPT (P < 0.05) and normal parathyroid (P < 0.05) samples. In a similar line, the differences in RGS5 gene expressions between SHPT and control tissues were not statistically significant (P > 0.05)., Conclusions: The characteristic RGS5 protein and mRNA levels in hyperparathyroidism might be helpful in discovering the pathomechanism of hyperparathyroidism and novel therapeutic targets as well., (© 2022. The Author(s).)

Objective: Multiple endocrine neoplasia type 1 (MEN1) is a rare genetic syndrome characterized by parathyroid, anterior pituitary, and/or duodenopancreatic neuroendocrine tumors. Studies have indicated that investigating primary hyperparathyroidism (pHPT) with subsequent genetic screening may be an essential tool for the early diagnosis of MEN1 in patients with pituitary tumors (PTs). This study aimed to investigate the presence of pHPT in patients with PTs and, subsequently, to screen for genetic mutations and related tumors in patients with MEN1 syndrome., Methods: This study included 255 patients with PTs who were assessed for the presence of MEN1 by serum calcium and parathyroid hormone measurements. Mutation screening of the MEN1, CDKN1B, and AIP genes was performed in the index cases showing the MEN1 phenotype., Results: Five patients with PTs presented a clinical condition compatible with MEN1. These patients had a younger age of onset and a more severe clinical condition. Genetic analysis identified a frameshift mutation in the MEN1 gene in one of the cases with the MEN1 phenotype, but point mutations in CDKN1B and AIP were not detected in any of these patients., Conclusion: Our results show that periodic screening for pHPT in patients with PTs may be useful to detect MEN1 syndrome; thus, it is recommended in those patients with both findings a genetic analysis of MEN1 gene and an additional search of related tumors. By contrast, our data suggest that CDKN1B and AIP mutations do not seem to play a relevant role in the pathogenesis of MEN1., (Copyright © 2022 AACE. Published by Elsevier Inc. All rights reserved.)

Preoperative molecular imaging is paramount to direct surgery in primary hyperparathyroidism (pHPT). We investigated the diagnostic performance of 18 F-fluorocholine ( 18 F-FCH) PET/CT compared with 11 C-methionine ( 11 C-MET) PET/CT for localization of hyperfunctioning parathyroid tissue in patients with pHPT and negative or inconclusive 99m Tc-sestaMIBI ( 99m Tc-MIBI) SPECT findings. Methods: Fifty-eight patients with biochemical evidence of pHPT and negative or inconclusive 99m Tc-MIBI SPECT findings were referred for presurgical detection and localization of hyperfunctioning parathyroid tissue by 11 C-MET and 18 F-FCH PET/CT. The PET/CT results were classified into 3 categories (positive, inconclusive, or negative) based on the nodular aspect of tracer uptake and the visualization of corresponding nodules on CT. The PET/CT results were correlated with the surgical and histopathologic findings, which were used as the gold standard. Results: Fifty-three patients were included for analysis. 18 F-FCH PET/CT was positive in 39 patients (74%), inconclusive in 5 (9%), and negative in 9 (17%), compared with 25 (47%), 12 (23%), and 16 (30%), respectively, for 11 C-MET PET/CT. 18 F-FCH localized 11 additional foci (6 positive and 5 inconclusive), compared with 11 C-MET. Twenty-six patients (sex ratio, 10/16 M/F) underwent surgery, with resection of 31 lesions (22 adenomas, 6 hyperplastic glands, and 3 carcinomas) and 1 normal gland. At follow-up, 21 patients (81%) were considered cured after surgery, whereas 3 patients (12%) had persistence of hypercalcemia. With inconclusive cases being considered negative, 18 F-FCH PET/CT correctly localized 26 lesions in 24 of 26 patients (92%), compared with 16 lesions in 15 of 26 patients (58%) localized by 11 C-MET PET/CT. Per-patient-based sensitivity and positive predictive value were 96% and 96%, respectively, for 18 F-FCH and 60% and 94%, respectively, for 11 C-MET ( P < 0.0001). Per-lesion-based sensitivity and positive predictive value were 84% and 90%, respectively, for 18 F-FCH and 52% and 94%, respectively, for 11 C-MET ( P < 0.0001). Conclusion: In the presence of biochemical evidence of pHPT with negative or inconclusive 99m Tc-MIBI SPECT findings, 18 F-FCH PET/CT performs better than 11 C-MET PET/CT for the detection of pathologic parathyroid tissue, allowing localization of parathyroid adenoma or hyperplasia in 96% of patients., (© 2022 by the Society of Nuclear Medicine and Molecular Imaging.)

Intraoperative consultation for assessment of parathyroid tissue is a controversial area of endocrine pathology. This assessment often follows historical institutional and individual surgical practitioner practices rather than documented utility data and adjuvant intraoperative testing data, including intraoperative parathyroid hormone level testing by clinical pathologists and the use of Oil Red O vital stain on frozen tissue sections by anatomic pathologists, as a means of conferring etiology of parathyroid disease. The American Association of Endocrine Surgeons (AAES), in 2016, proposed guidelines for the management of primary hyperparathyroidism, including recommendations for intraoperative consultation, recommending against the use of intraoperative frozen section to determine parathyroid functional status but in support for its use for parathyroid identification. In this series, we review a one-year, retrospective cohort of consecutive parathyroid surgeries at Massachusetts General Hospital, including over 200 cases meeting inclusion criteria for which primary hyperparathyroidism was the indication for surgery, discussing outcomes, compliance with AAES guidelines, and overall utility of intraoperative consultation and adjuvant testing., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Purpose: The purpose of this study was to assess the diagnostic capabilities of preoperative conventional imaging ( 99m Tc-MIBI scintigraphy, cervical ultrasonography [CUS]) and 18 F-fluorocholine PET/CT (FCH PET/CT) in the detection of hyperfunctioning parathyroid gland in patients with primary hyperparathyroidism (PHPT) used alone or as a single imaging set., Materials and Methods: A total of 51 consecutive patients (6 men, 45 women; mean age, 62 ± 11.6 [SD] years; age range: 28-86 years) with biochemically confirmed PHPT who underwent CUS, single-tracer dual phase 99m Tc-MIBI scintigraphy and FCH PET/CT were retrospectively included. 99m Tc-MIBI scintigraphy were performed immediately after CUS and interpreted by the same operators. FCH PET/CT examinations were interpreted independently by two nuclear medicine physicians. An additional reading session integrating the three imaging modalities read in consensus as a combined imaging set was performed., Results: At surgery, 74 lesions were removed (32 parathyroid adenomas, 38 parathyroid hyperplasia and 4 subnormal glands). Thirty-six patients (71%) had single-gland disease and 15 patients (29%) had multiglandular disease at histopathological analysis. On a patient basis, sensitivity and accuracy of FCH PET/CT, CUS and 99m Tc-MIBI scintigraphy for the detection of abnormal parathyroid glands were 76% (95% CI: 63-87%) and 76% (95% CI: 63-87%), 71% (95% CI: 56-83%) and 71% (95% CI: 56-83%), 33% (95% CI: 21-48%) and 33% (95% CI: 21-48%), respectively. The sensitivity of the combined imaging set was 94% (95% CI: 84-99%) and greater than the sensitivity of each individual imaging technique (P ≤ 0.001 for all)., Conclusion: Our results suggest that CUS, 99m Tc-MIBI scintigraphy and FCH PET/CT interpreted as a single imaging set could be the ideal practice to precisely localize parathyroid lesion in patients with PHPT before surgery., Competing Interests: Disclosure of Interest The authors have no conflict of interests to declare in relation to this manuscript., (Copyright © 2022 Société française de radiologie. Published by Elsevier Masson SAS. All rights reserved.)

Objective: It is important to detect parathyroid adenomas by parathyroid scintigraphy with 99m-technetium sestamibi ( 99m Tc-MIBI) before surgery. This study aimed to develop and validate deep learning (DL)-based models to detect parathyroid adenoma in patients with primary hyperparathyroidism, from parathyroid scintigrams with 99m Tc-MIBI., Methods: DL-based models for detecting parathyroid adenoma in early- and late-phase parathyroid scintigrams were, respectively, developed and evaluated. The training dataset used to train the models was collected from 192 patients (165 adenoma cases, mean age: 64 years ± 13, 145 women) and the validation dataset used to tune the models was collected from 45 patients (30 adenoma cases, mean age: 67 years ± 12, 37 women). The images were collected from patients who were pathologically diagnosed with parathyroid adenomas or in whom no lesions could be detected by either parathyroid scintigraphy or ultrasonography at our institution from June 2010 to March 2019. The models were tested on a dataset collected from 44 patients (30 adenoma cases, mean age: 67 years ± 12, 38 women) who took scintigraphy from April 2019 to March 2020. The models' lesion-based sensitivity and mean false positive indications per image (mFPI) were assessed with the test dataset., Results: The sensitivity was 82% [95% confidence interval 72-92%] with mFPI of 0.44 for the scintigrams of the early-phase model and 83% [73-92%] with mFPI of 0.31 for the scintigrams of the delayed-phase model in the test dataset, respectively., Conclusions: The DL-based models were able to detect parathyroid adenomas with a high sensitivity using parathyroid scintigraphy with 99m-technetium sestamibi., (© 2022. The Author(s) under exclusive licence to The Japanese Society of Nuclear Medicine.)

Inconclusive preoperative imaging is a strong predictor of multiglandular parathyroid disease (MGD) in patients with primary hyperparathyroidism (PHPT). MGD was investigated in a cohort of 17 patients with PHPT (mean age 64.9 years, total calcium 2.75 mmol/l and parathyroid hormone (PTH) 113.3 ng/l) who underwent 18F-fluorocholine PET/CT (FCH) imaging before surgery. The initial MIBI SPECT scintigraphy (MIBI) and/or neck ultrasound were not conclusive or did not localize all pathological parathyroid glands, and PHPT persisted after surgery. Sporadic MGD was present in 4 of 17 patients with PHPT (24 %). In 3 of 4 patients with MGD, FCH correctly localized 6 pathological parathyroid glands and surgery was successful. Excised parathyroid glands were smaller (p <0.02) and often hyperplastic in MGD than in single gland disease. In two individuals with MGD, excision of a hyperplastic parathyroid gland led to a false positive decline in intraoperative PTH and/or postoperative serum calcium. Although in one patient it was associated with partial false negativity, parathyroid imaging with FCH seemed to be superior to neck ultrasound and/or MIBI scintigraphy in MGD.

Preoperative localisation studies are essential for parathyroidectomy in patients with primary hyperparathyroidism. If the location of abnormal parathyroid glands cannot be identified through non-invasive studies, parathyroid venous sampling (PVS) may be employed. In this study, we evaluated the utility of preoperative PVS in parathyroid surgery. Patients with primary hyperparathyroidism who underwent preoperative PVS at Severance Hospital between January 2015 and June 2020 were identified. Patients for whom the results of non-invasive imaging studies were inconsistent or negative underwent PVS. The results of PVS were compared with operative findings and pathologic results. For 14 patients, the results of preoperative ultrasonography and 99m Tc-sestamibi single-photon emission computed tomography (SPECT) were negative; for 20 patients, either the result of only one test was positive, or the results of the two tests were inconsistent. With respect to the lateralisation of diseased adenoma, the results of PVS and pathological examination were inconsistent only for one patient in either group (total: 2/34 patients). This study showed that PVS could be used effectively for preoperative localisation in patients with primary hyperparathyroidism in whom the location of diseased parathyroid glands cannot be determined through non-invasive image studies., (© 2022. The Author(s).)

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 10mm 2 ) 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., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objective: Near-infrared imaging for intraoperative parathyroid gland (PG) detection has recently commanded significant attention. The PTeye (Medtronic, Minneapolis, MN) is a probe-based system for near-infrared autofluorescent evaluation of PGs. This study was designed to evaluate the capabilities of the PTeye in the setting of surgery for primary hyperparathyroidism., Study Design: Prospective, Cohort study., Methods: This single-institution, prospective cohort study included all patients undergoing parathyroidectomy for primary hyperparathyroidism with presumed single gland disease from June 2020 to December 2020. Absolute intensity and intensity ratios, with the thyroid as the control tissue, were obtained for the adenoma, ipsilateral normal PG, and adjacent tissue. The ability of the PTeye to function when not in direct contact with tissue was measured., Results: Twenty-two patients were included. The median intensity ratio for the in situ adenomas was 4.38 (interquartile range [IQR]: 2.03-5.87), ipsilateral normal PGs 6.17 (IQR: 3.83-7.67), strap muscle 0.47 (IQR: 0.30-0.60), and fat 0.20 (IQR: 0.17-0.47). All normal PGs and 21/22 adenomas demonstrated autofluorescence above the detection threshold. The PTeye functioned at a maximum distance of separation of 10 mm through saline medium and 6 mm through clear solid medium., Conclusion: This study confirms the PTeye's ability to recognize PGs with a high degree of precision. The device was found to function properly even with the probe not in direct contact with the tissue. Although adenomatous PGs appear to demonstrate altered autofluorescent properties from normal PGs, additional research is required to determine if these differences are clinically useful., Level of Evidence: 3 Laryngoscope, 132:715-721, 2022., (© 2021 The American Laryngological, Rhinological and Otological Society, Inc.)

Purpose: Hyperparathyroidism (HPT) is a common disorder. A cure can only be achieved by removing all diseased glands. It is critical to localize the hyperfunctioning glands exactly to prevent extensive surgical exploration. The number of false negative/inconclusive results in standard imaging techniques is high. We aimed to evaluate the diagnostic accuracy of 18 F-Fluorocholine-PET in combination with contrast-enhanced CT (FCH-PET/CT) and its sensitivity in patients with primary, secondary/tertiary, and familial HPT with negative and/or discordant findings in ultrasound and/or 99m Tc-sestamibi scintigraphy/SPECT/CT., Methods: A total of 96 patients with HPT and negative/equivocal conventional imaging were referred for FCH-PET/CT. In this retrospective, single institution study, 69 patients, who have undergone surgery and histopathologic workup, were analyzed. Of the 69 patients included, 60 patients suffered from primary HPT, four from secondary or tertiary HPT, and five from familial HPT. Sensitivities, positive predictive values, and accuracies were calculated., Results: Sensitivity/positive predictive value (PPV) per lesion was 87.5/98.3% for primary HPT, 75/100% for secondary/tertiary HPT and 25/66.7% for familial HPT. Sensitivity/PPV per patient was 91.5/98.2% for primary HPT, 100/100% for secondary/tertiary HPT and 50/100% for familial HPT. All patients showed normalized serum calcium levels in the postoperative period. The follow-up rate was 97%. Of the patients included in the study, 58 of 60 patients with primary HPT, and four of four patients with secondary/tertiary HPT showed normal calcium and parathyroid hormone (PTH) levels after six months and were cured. Of the patients with familial HPT, four of five patients were cured., Conclusion: Diagnostic accuracy of 18 F-Fluorocholine-PET/CT for patients with pHPT is excellent. 18 F-Fluorocholine-PET/CT is a valuable tool for endocrine surgeons to optimize the surgical treatment of patients with hyperparathyroidism., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: Calcium sensing receptor (CaSR), on the surface of normal parathyroid cells, is essential for maintaining serum calcium levels. The normal pattern of CaSR immunostaining remains undefined and is presumptively circumferential. Given the physiological variation in serum calcium, we postulated that CaSR expression could not be uniformly circumferential. Also, cytoplasmic expression has not been evaluated either in normal or pathological tissues. We studied normal parathyroid tissues derived from forensic autopsies and those rimming parathyroid adenomas for membranous and cytoplasmic CaSR immunoexpression. Results were compared with primary hyperparathyroidism (PHPT) to look for any pathogenetic implications., Materials and Methods: We evaluated 34 normal parathyroid tissues from 11 autopsies, 30 normal rims, 45 parathyroid adenoma, 10 hyperplasia, and 7 carcinoma cases. Membranous expression was categorized complete/incomplete and weak/moderate/strong; scored using Her2/Neu and Histo-scores; predominant pattern noted. Cytoplasmic expression was categorized negative/weak/moderate/strong; predominant intensity noted., Results: Normal autopsy-derived parathyroid tissues were Her2/Neu 3 + , but incomplete membranous staining predominated in 85%. Their immune-scores were significantly more than the cases (p <  < 0.05). The mean histo-score of normal rims was intermediate between the two (p <  < 0.05). Cytoplasmic expression was strong in all autopsy-derived tissues, weak/negative in hyperplasia (100%), moderate in 16% adenomas, and 43% carcinomas., Conclusions: Normal autopsy-derived parathyroid tissues showed strong but predominantly incomplete membranous expression. Surface CaSR expression decreased in PHPT and is probably an early event in parathyroid adenoma, seen even in normal rims. Whether there is a defect in CaSR trafficking from the cytoplasm to the cell surface in adenoma and carcinoma needs further evaluation., (© 2021. Italian Society of Endocrinology (SIE).)

Background: In total, ∼15% of patients with sporadic primary hyperparathyroidism have multiglandular disease, which may be suspected preoperatively but can only be confirmed intra or postoperatively. The study aim is to determine how and when patients are diagnosed with multiglandular disease and to what extent different modalities contribute., Methods: Consecutive cases of sporadic primary hyperparathyroidism (2013-2019) undergoing initial exploration were reviewed from a single-institution prospective database. Preoperative single-photon emission tomography/computed tomography and neck ultrasound were routinely performed to help direct either bilateral or unilateral exploration guided by intraoperative parathyroid hormone monitoring using the dual criteria. Multiglandular disease was defined as either resection of >1 enlarged parathyroid or hypercalcemia at ≥6 months after single gland resection., Results: Of 1,890 patients with sporadic primary hyperparathyroidism, multiglandular disease was identified in 254 (13.4%); 244 (96.1%) were diagnosed intraoperatively and 10 (3.9%) postoperatively. In these multiglandular disease patients, single gland disease was suggested on single-photon emission tomography/computed tomography in 54.0%, ultrasound in 49.2%, and both were concordant for single gland disease in 29.4%. Intraoperative multiglandular disease diagnosis was prompted by an inadequate intraoperative parathyroid hormone monitoring drop in 38.5%, by surgeon interpretation of imaging in 38.1%, by observing ipsilateral gland enlargement in 11.0%, by finding an initial gland <200 mg in 10.3%, and 2.0% had unexpected multiglandular disease during thyroidectomy. Multiglandular disease was diagnosed by postoperative hypercalcemia in 10 of 254 patients (4.9%)., Conclusion: To avoid failure at parathyroidectomy for primary hyperparathyroidism, expert surgeons use multiple approaches to diagnose and manage multiglandular disease. Preoperative localization studies alone are insufficient, missing multiglandular disease in at least 30% of cases. All examined adjuncts are informative, including intraoperative parathyroid hormone monitoring, imaging, and intraoperative visual cues., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Preoperative parathyroid imaging guides surgeons during parathyroidectomy. This study evaluates the clinical impact of 18 F-fluorocholine positron emission tomography for preoperative parathyroid localization on patients with primary hyperparathyroidism., Methods: Patients with primary hyperparathyroidism and indications for parathyroidectomy had simultaneous 18 F-fluorocholine positron emission tomography imaging/magnetic resonance imaging. In patients who underwent subsequent parathyroidectomy, cure was based on lab values at least 6 months after surgery. Location-based sensitivity and specificity of 18 F-fluorocholine positron emission tomography imaging was assessed using 3 anatomic locations (left neck, right neck, and mediastinum), with surgery as the gold standard., Results: In 101 patients, 18 F-fluorocholine positron emission tomography localized at least 1 candidate lesion in 93% of patients overall and in 91% of patients with previously negative imaging, leading to a change in preoperative strategy in 60% of patients. Of 76 patients who underwent parathyroidectomy, 58 (77%) had laboratory data at least 6 months postoperatively, with 55/58 patients (95%) demonstrating cure. 18 F-fluorocholine positron emission tomography successfully guided curative surgery in 48/58 (83%) patients, compared with 20/57 (35%) based on ultrasound and 13/55 (24%) based on sestamibi. In a location-based analysis, sensitivity of 18 F-fluorocholine positron emission tomography (88.9%) outperformed both ultrasound (37.1%) and sestamibi (27.5%), as well as ultrasound and sestamibi combined (47.8%)., Conclusion: Long-term results in the first cohort in the United States to use 18 F-fluorocholine positron emission tomography for parathyroid localization confirm its utility in a challenging cohort, with better sensitivity than ultrasound or sestamibi., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Parathyroid lesions exhibiting a water clear cell morphology are exceedingly rare manifestations in primary hyperparathyroidism (PHPT), and the phenomenon has been reported both for uniglandular (water clear cell adenoma; WCCA) and multiglandular disease (water clear cell hyperplasia; WCCH). In all, only 24 previous descriptions of WCCA exist in the literature. Herein, we present seven cases with water clear cell morphology (6 WCCAs and 1 case of WCCH) in an institutional series of approximately 4000 parathyroid lesions spanning 29 years in a tertiary centre setting. Major histological attributes and clinical parameters associated with this morphological subtype were reviewed, and a literature search was conducted. WCCA and WCHH exhibited an institutional prevalence of 0.15% and 0.025%, respectively. All cases displayed histological hallmarks of water clear cell morphology, with cells exhibiting abundant cytoplasm filled with vacuoles. Atypical findings or unequivocal evidence of invasive behaviour were not observed. The gender distribution was 6:1 (F:M), patients were generally symptomatic with mild hypercalcaemia, and the median age at surgery was 53 years (range 38-78). The preoperative localisation was inconclusive in four of seven, and neck exploration of all four glands was undertaken in five cases. The excised WCCAs exhibited an average weight of 1215 mg, markedly higher than conventional adenomas, and all patients were cured of PHPT following parathyroidectomy. Interestingly, previous reports mirror our observations that these lesions often are large, in relation to their sizes biochemically fairly indolent, and indecisively localised using scintigraphy, providing correlations of possible clinical value when pre-operatively assessing these rare lesions., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

The advent of new insights into phosphate metabolism must urge the endocrinologist to rethink the pathophysiology of widespread disorders, such as primary hyperparathyroidism, and also of rarer endocrine metabolic bone diseases, such as hypoparathyroidism and tumor-induced hypophosphatemia. These rare diseases of mineral metabolism have been and will be a precious source of new information about phosphate and other minerals in the coming years. The parathyroid glands, the kidneys, and the intestine are the main organs affecting phosphate levels in the blood and urine. Parathyroid disorders, renal tubule defects, or phosphatonin-producing tumors might be unveiled from alterations of such a simple and inexpensive mineral as serum phosphate. This review will present all these disorders from a 'phosphate perspective'.

Context: Primary hyperparathyroidism (PHPT), a leading cause of hypercalcemia and secondary osteoporosis, is underdiagnosed., Objective: This work aims to establish a foundation for an electronic medical record-based intervention that would prompt serum parathyroid hormone (PTH) assessment in patients with persistent hypercalcemia and identify care gaps in their management., Methods: A retrospective cohort study was conducted in a tertiary academic health system of outpatients with persistent hypercalcemia, who were categorized as having classic or normohormonal PHPT. Main outcome measures included the frequencies of serum PTH measurement in patients with persistent hypercalcemia, and their subsequent workup with bone mineral density (BMD) assessment, and ultimately, medical therapy or parathyroidectomy., Results: Among 3151 patients with persistent hypercalcemia, 1526 (48%) had PTH measured, of whom 1377 (90%) were confirmed to have classic (49%) or normohormonal (41%) PHPT. PTH was measured in 65% of hypercalcemic patients with osteopenia or osteoporosis (P < .001). At median 2-year follow-up, bone density was assessed in 275 (20%) patients with either variant of PHPT (P = .003). Of women aged 50 years or older with classic PHPT, 95 (19%) underwent BMD assessment. Of patients with classic or normohormonal PHPT, 919 patients (67%) met consensus criteria for surgical intervention, though only 143 (15%) underwent parathyroidectomy., Conclusion: Within a large academic health system, more than half of patients with confirmed hypercalcemia were not assessed for PHPT, including many patients with preexisting bone disease. Care gaps in BMD assessment and medical or surgical therapy represent missed opportunities to avoid skeletal and other complications of PHPT., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)