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Background Diagnosis of parathyroid carcinoma as a rare cause of primary hyperparathyroidism is usually very challenging, even after surgical resection. Case presentation A 45-year-old woman with a diagnosis of primary hyperparathyroidism underwent surgery three years ago. Parathyroid adenoma resection and total thyroidectomy, due to incidental intraoperative finding of papillary thyroid carcinoma, were performed. She had been asymptomatic for 2.5 years before her PTH and calcium levels rose. The second surgery was performed based on parathyroid hyperplasia diagnosis, but the patient did not recover. She was then referred to us. Imaging modalities could not localize the PTH source. Sequential bilateral neck explorations were unsuccessful. As a last attempt, mediastinal exploration was performed. By confirming no parathyroid tissue in the mediastinum, excision of some tiny pulmonary nodules (previously considered as PTC metastasis) was done, which was confirmed to be parathyroid cancer metastasis. Conclusions Diagnosing parathyroid carcinoma is difficult because of unreliable diagnostic criteria. The correct diagnosis may be determined through the follow-up for recurrent hyperparathyroidism in a previously diagnosed case of parathyroid adenoma.

Synchronous multiple parathyroid carcinoma is a rare condition within the already uncommon landscape of parathyroid malignancies, which comprise less than 1% of sporadic primary hyperparathyroidism cases. To date, only seven cases of synchronous multiple parathyroid carcinoma in sporadic primary hyperparathyroidism have been documented. This exceptional rarity complicates both the diagnostic process and therapeutic decision-making. Clinically, parathyroid carcinoma typically presents as a single mass determining severe symptoms. However, no single clinical, biochemical, or imaging feature allows for definitive preoperative diagnosis. Imaging modalities such as ultrasound and sestamibi scans exhibit variable sensitivity and may overlook multi-gland involvement. Histopathological examination remains the only reliable diagnostic method. Management strategies are also controversial: while some advocate for conservative surgery, en bloc resection is generally recommended for its association with improved local control and disease-free survival. Given the exceptional occurrence of synchronous multiple parathyroid carcinoma, there is a lack of standardized protocols for managing parathyroid carcinoma in cases of synchronous and multiple gland involvement. Early multidisciplinary evaluation and individualized treatment planning are therefore crucial. This review aims to synthesize the presently available knowledge about synchronous multiple parathyroid carcinoma, assist clinicians with the limited data available, and discuss the main challenges in the management of this rare entity.

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.

Parathyroid carcinomas are rare endocrine tumors which comprise 0.3-5.6% of all causes of hyperparathyroidism. 90% of them are hormonally active, while 10% of them may be non-functional. They mostly occur in a single parathyroid gland. Concurrent involvement of both parathyroid glands is quite rare. A 57-year-old male patient was admitted to emergency department with the complaint of dyspnea. Thorax tomography revealed a retrosternal mass. The mass was thoracoscopically excised by thoracic surgeons. Histopathological examination result of the mass was reported as parathyroid carcinoma. Parathyroid scintigraphy performed and focal activity increase in the lower pole of the left lobe. Parathyroid hormone level was 118 pg/ml and calcium level was measured as 11.4 mg/dl. The patient with these findings was operated and pathological examination of excised left lower parathyroid tissue was reported as carcinoma. In addition, micropapillary carcinoma was detected in left thyroid lobectomy specimen.Our case was also unusual in that double parathyroid carcinoma, which is a rare condition, was hormonally inactive. We aimed to present our case in the light of the literature due to its rare occurrence.

ContextParathyroid carcinoma (PC) is a rare endocrine malignancy with no approved systemic therapies for unresectable locally invasive or distant metastatic disease. Understanding the molecular changes in advanced PC can provide better understanding of this disease and potentially help directing targeted therapy.ObjectiveTo evaluate tumor-specific genetic changes using next-generation sequencing (NGS) panels.DesignAll patients with advanced PC were tested for hot-spot panels using NGS panels including a 50-gene panel, a 409-gene panel if the standard 50-gene panel (Ion Torrent, Life Technology) was negative or a FoundationOne panel.SettingThe University of Texas MD Anderson Cancer Center, Houston, Texas, USA.Patients or other participants11 patients with advanced PC were selected to undergo molecular testing.Main outcome measure(s)Genetic profiles of advanced PC.ResultsAmong the 11 patients, 4 patients had the 50-gene panel only, 6 had 409-gene panel after a negative 50-gene panel and 1 had FoundationOne. One patient who had 50-gene panel only also had his metastatic site (esophagus) of his tumor tested with FoundationOne. The most common mutations identified were in the PI3 K (PIK3CA, TSC1 and ATM) (4/11 patients) and TP53 (3/11) pathways. Genes not previously reported to be mutated in PC included: SDHA, TERT promoter and DICER1. Actionable mutations were found in 54% (6/11) of the patients.ConclusionsMutational profiling using NGS panels in advanced PC has yielded important potentially targetable genetic alterations. Larger studies are needed to identify commonly mutated genes in advanced PC patients. Development of novel therapies targeting these cellular pathways should be considered.

Background Parathyroidectomy has a success rate of >95 % for cure of primary hyperparathyroidism. In about 6–16 % of cases, one or more hyperfunctioning parathyroid gland(s) are found in an ectopic location. Accurate preoperative imaging can aid in detecting these ectopically located glands and allow a focused surgical approach with an even higher success rate. The objective of this study was to assess the utility of ultrasonography (US) and technetium-99m-sestamibi (MIBI) scans in locating ectopic parathyroid glands in previously unexplored patients who presented with primary hyperparathyroidism. Methods We analyzed a total of 1,562 patients who underwent surgery for hyperparathyroidism at our institution from 2000 to 2010. Ectopic parathyroid adenomas were identified in 346 of the patients (22 %). Of the 346 patients, we excluded 144 who underwent reoperations, had four-gland hyperplasia or were missing imaging details. We carefully reviewed the data, including demographics, laboratory values, preoperative localizing imaging details, and operative findings. Preoperative US and MIBI results were compared to the intraoperative findings. Results We analyzed 202 patients with ectopic glands for accuracy of preoperative localization. Of these 202 patients, a single adenoma was the most common (89 %) followed by double adenoma (11 %). The ectopic parathyroid glands were predominantly located in the thymus (38 %) followed by 31 % in the retroesophageal region; 18 % were intrathyroidal. Preoperative MIBI scans had a sensitivity of 89 % (161/197), whereas US had a sensitivity of 59 % (35/63) for detecting ectopic glands. Overall, both imaging modalities had a positive predictive value of 90 %, with MIBI correctly predicting ectopic glands best in the thymus, mediastinum, or the retroesophageal space, and US was most accurate at detecting intrathyroidal glands. Conclusions Based on the data available at our institution, MIBI has a higher sensitivity than US in correctly localizing ectopic parathyroid adenomas, but the accuracy of detection varies based on location. Both imaging techniques have a high PPV for detecting an ectopic gland. Therefore, imaging with MIBI and US can be complementary, and positive localization of an ectopic gland with either modality is highly accurate and can facilitate a more focused surgical approach.

Abstract Context Atypical parathyroid tumor (APT) represents a neoplasm characterized by histological features typical of parathyroid carcinoma (PC) but lacking local infiltration and/or distant metastasis, leading to uncertainty regarding its malignant potential. Objective To characterize the molecular landscape and deregulated pathways in APT. Methods Whole-exome sequencing (WES) was conducted on 16 APTs. DNA from tumors and matched peripheral blood underwent WES using Illumina HiSeq3000. Results A total of 192 nonsynonymous variants were identified. The median number of protein-altering mutations was 9. The most frequently mutated genes included BCOR, CLMN, EZH1, JAM2, KRTAP13-3, MUC16, MUC19, and OR1S1. Seventeen mutated genes belong to the Cancer Gene Census list. The most consistent hub genes identified through STRING network analysis were ATM, COL4A5, EZH2, MED12, MEN1, MTOR, PI3, PIK3CA, PIK3CB, and UBR5. Deregulated pathways included the PI3 K/AKT/mTOR pathway, Wnt signaling, and extracellular matrix organization. Variants in genes such as MEN1, CDC73, EZH2, PIK3CA, and MTOR, previously reported as established or putative/candidate driver genes in benign adenoma (PA) and/or PC, were also identified in APT. Conclusion APT does not appear to have a specific molecular signature but shares genomic alterations with both PA and PC. The incidence of CDC73 mutations is low, and it remains unclear whether these mutations are associated with a higher risk of recurrence. Our study confirms that PI3 K/AKT/mTOR and Wnt signaling represents the pivotal pathways in parathyroid tumorigenesis and also revealed mutations in key epigenetic modifier genes (BCOR, KDM2A, MBD4, and EZH2) involved in chromatin remodeling, DNA, and histone methylation.

Purpose Parathyroid carcinoma (PC) is an endocrine malignancy with a poor prognosis. However, the diagnosis of PC is still a difficult problem. A model with immunohistochemical (IHC) staining of 5 biomarkers has been reported from limited samples for the differential diagnosis of PC. In the present study, a series of IHC markers was applied in relatively large samples to optimize the diagnostic model for PC. Methods In this study, 44 patients with PC, 6 patients with atypical parathyroid tumors and 57 patients with parathyroid adenomas were included. IHC staining for parafibromin, Ki-67, galectin-3, protein-encoding gene product 9.5 (PGP9.5), E-cadherin, and enhancer of zeste homolog 2 (EZH2) was performed on formalin-fixed, paraffin-embedded tissue samples. The effects of clinical characteristics, surgical procedure, and IHC staining results of tumor tissues on the diagnosis and prognosis of PC were evaluated retrospectively. Results A logistic regression model with IHC results of parafibromin, Ki-67, and E-cadherin was created to differentiate PC with an area under the curve of 0.843. Cox proportional hazards analysis showed that negative parafibromin staining (hazard ratio: 3.26, 95% confidence interval: 1.28–8.34, P  = 0.013) was related to the recurrence of PC. Conclusion An IHC panel of parafibromin, Ki-67 and E-cadherin may help to distinguish PC from parathyroid neoplasms. Among the 6 IHC markers and clinical features examined, the risk factor related to PC recurrence was parafibromin staining loss.

Purpose Ectopic parathyroid carcinoma (EPC) is a rare clinical entity with multiple diagnostic pitfalls, making surgical cures challenging. We assessed the clinicopathological spectrum and outcome of EPCs. Methods In this retrospective cohort study, 24 EPCs were identified from 133 PC patients treated at a tertiary referral center. The relationship between clinicopathological findings and locations was analyzed. Results The locations of EPCs were predominantly intrathyroidal (62.5%), followed by 16.7% in the mediastinum, 8.3% in the retropharyngeal space, 8.3% in the carotid sheath, and 4.2% in the upper neck. Intrathyroidal EPC patients experienced higher serum calcium ( p  = 0.020), a higher rate of vascular invasion ( p  = 0.040), and a slightly higher incidence of non-R0 initial resection ( p  = 0.092) than those in other ectopic locations. Intrathyroidal EPC patients also suffered a trend of higher upper aerodigestive tract (UAT) invasion rate ( p  = 0.070) and higher risks of distant metastasis ( p  = 0.037) than the other PC patients. The 5-year disease-free survival rate after surgery was slightly compromised at 41.5% in intrathyroidal EPC patients compared with 77.8% among those in other ectopic locations ( p  = 0.143) and 59.7% among the other PC patients (log-rank = 3.194; p  = 0.074), though without statistical significance. Conclusion Intrathyroidal EPC might cause a more biochemically and invasively distinct PC picture compared with other PCs. Special caution should be exercised in the preoperative diagnosis and management of such cases.

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.