Advances in the management of parathyroid carcinoma

modalities, surgical innovations, adjuvant therapies, and emerging targeted treatments. Recently published manuscripts (between 2022 and 2023) were obtained from Medical Literature Analysis and Retrieval System Online (Medline), Excerpta Medica (Embase), Cochrane Central Register of Controlled Trials (CENTRAL), and European Union Drug Regulating Authorities Clinical Trials (EudraCT). These were assessed for their relevance in terms of the diagnosis and management of patients with PCA. This manuscript explores the role of genetic profiling and presents case studies illustrating successful management strategies. The manuscript also discusses the ongoing challenges in the management of parathyroid carcinoma, suggesting future research directions and potential therapeutic avenues.


Aim
Parathyroid Carcinoma (PCA) is extremely rare and accounts for approximately 1% of cases of primary hyperparathyroidism.The clinical presentation of PCA mimics primary hyperparathyroidism and includes hypercalcaemia-derived signs and symptoms such as fatigue, bone & joint pain, nephrolithiasis, decreased glomerular filtration rate, osteoporosis, fragility fractures and neurocognitive dysfunction.The purpose of this review is to summarise recent developments in the diagnosis, management and treatment of PCA (see Figs. 1 and 2).

Background
The parathyroid glands, located on the dorsal surface of the thyroid gland, produce and secrete parathyroid hormone (PTH).This hormone plays a crucial role in maintaining calcium homeostasis.PTH helps control the levels of calcium in the blood by acting on the bones, kidneys, and intestines.Overall, PTH acts to increase blood calcium levels when they are low.This is accomplished in part by mobilising calcium from the bones.This is achieved through promoting osteoclast activity thus releasing mineralised calcium into the blood.PTH also increases calcium reabsorption in the distal convoluted tubule of the kidney nephrons.Furthermore, PTH indirectly promotes calcium absorption from the intestine.Simultaneously, PTH also decreases blood phosphate by preventing reabsorption in the proximal convoluted tubule.
Diagnosing PCA can be challenging due to its rarity and the similarity of symptoms to benign parathyroid disorders, principally benign parathyroid adenomas (BPA).Imaging techniques such as ultrasound, computed tomography (CT), and magnetic resonance imaging (MRI) can help locate the tumour.However, distinguishing between benign and malignant tumours using these methods is not 100% accurate: fineneedle aspiration (FNA) biopsy is often inconclusive and not recommended, so definitive diagnosis is usually confirmed after surgical removal and pathological examination of the tumour.
PCA is characterised by its aggressive behaviour with a tendency to metastasise to other organs, particularly the lungs, bones and liver.This occurs via the lymph or blood vessels, or by infiltrating nearby structures.This renders complete resection challenging.Moreover, complications involving the recurrent laryngeal nerve are not uncommon.Patients often experience recurrences leading to subsequent operations making it not only a difficult disease for the clinician to manage but is also an arduous mental ordeal for the patient.Specifically, the excessive amounts of PTH leads to severe hypercalcaemia and associated complications which may be difficult to control.The 5-year survival rate for PCA has been estimated to be 82.7%,yet in patients who have received radiation therapy alone this number falls to 72.2% (Ullah et al., 2022), and the tumour often requires multimodal treatment approaches.Due to its diagnostic challenges, PCA should be managed by a multidisciplinary team of experts with experience in parathyroid disorders.Prompt diagnosis, surgical resection, and close follow-up are crucial for optimizing outcomes in patients with PCA.

Materials and methods
This narrative review assessed papers from January 2022 to December 2023, expanding on a recent and comprehensive systematic review (Roser et al., 2023).This specific time frame was selected for this study to prevent potential overlap and redundancy with the findings of a recently published comprehensive systematic review which appraised publications until January 2022.Some papers prior to this time frame were also analysed to compare and assess if changes have occurred.Manuscripts were obtained from Medical Literature Analysis and Retrieval System Online (Medline), Excerpta Medica (Embase), Cochrane Central Register of Controlled Trials (CENTRAL), European Union Drug Regulating Authorities Clinical Trials (EudraCT).These were assessed for their relevance in terms of the diagnosis and management of patients with PCA.The papers listed in Table 1 were chosen as eligible with key findings outlined.For utility of inspection, each paper listed in Table 1 has a focus assigned to it to depict the stage of the PCA patient pathway to which they applied.We have assessed real-world applications of the papers and how each development could be applied to a clinical scenario (see Table 2).

Biochemistry
Main biochemical abnormalities observed in parathyroid carcinoma (PC) include markedly elevated corrected calcium and parathyroid hormone (PTH) concentrations.However, a subset of PC patients, termed non-functional PCs, present with PTH and corrected calcium concentrations within the normal range, predominantly observed in patients in their 70's.Chen et al. ( 2003) reported significantly higher concentrations of both biomarkers as well as alkaline phosphatase (ALP) in PC compared to benign primary hyperthyroidism.Similarly, a cohort study from Seoul, South Korea, demonstrated 83% sensitivity and 97% specificity for PC when ALP levels exceeded 285 IU/L.
In a retrospective cohort study by Robert et al. (2005), no patient with PC had PTH concentrations below four times the upper normal range.However, solely focusing on PTH values for PC diagnosis is arbitrary, as demonstrated by Cavalier et al. (2014), who found excessive production of amino-PTH, a N-terminal-extended form of PTH, in PCs but not in benign primary adenomas (BPA).They recommend utilising the third/second-generation PTH ratio to assess excessive amino-PTH, as only the third generation PTH assay can measure it.A ratio >1 for third/second-generation PTH has a sensitivity of 82% and specificity of 97% as a marker for PC in patients with primary hyperparathyroidism

(PHPT).
Human chorionic gonadotrophin (hCG) has also been investigated as a marker for PC; Rubin et al. (2008) demonstrated higher hCG concentrations among PC patients compared to those with PHPT of other causes.
In conclusion, there is no singular biomarker capable of determining a PC diagnosis alone.Therefore, other investigative modalities, including imaging, are utilised to aid in PC diagnosis.Continued research in this area holds promise for enhancing early detection, optimizing patient outcomes, and facilitating personalised therapeutics based on individual molecular profiles.

Imaging
In the first instance, a patient with biochemical hyperparathyroidism (PHPT) being considered for surgery will undergo some form of imaging.
PET/CT can improve the detection of the smallest pathological glands which cannot be visualised by SPECT/CT (Petranović et al., 2021).The sensitivity of 18 FDG-PET/CT for the detection of PC is high in all disease phases (Evangelista et al.). 11C-methionine (MET) PET/CT has been previously used as second-line imaging after negative or inconclusive conventional imaging.Preoperative 11 C-MET PET/CT can localise hyperfunctioning parathyroid glands in 74% of patients with a negative 99m Tc-MIBI.However, 18 F-fluorocholine (FCH) PET/CT, which has higher sensitivity than other SPECT/CT radionuclides for locating lesions responsible for PHPT (Thanseer et al., 2017), might be an alternative method to diagnose PC.This modality is better than 11 C-MET PET/CT for the detection of pathologic parathyroid tissue in patients with biochemical evidence of PHPT and negative or inconclusive 99m Tc-MIBI imaging (Mathey et al.), although further prospective studies are warranted (Treglia et al.).
CT and magnetic resonance imaging (MRI) are useful in the localisation of parathyroid tumours, and to some extent can indicate the possibility of malignancy.Such features will include local invasion and distant spread.CT features suggesting malignancy include a high shortto-long axis ratio, irregular shape, peritumoral infiltration and calcification, and minimal contrast enhancement (Takumi et al., 2021).Four-dimensional CT can also be utilised for PC and is generally considered when radionuclide imaging is negative or in patients with distorted neck anatomy.Recent data suggest that a 4D-CT has a specificity of 90.4% and even 100% in some studies in the location of a PC.Christakis et al. (2017) suggests that the combination of ultrasonography along with 99M Tc-MIBI and 4D-CT are beneficial in localising the PC as opposed to using a singular modality: reporting the combination has a sensitivity of 100%.On MRI, parathyroid hyperplasia or adenoma lesions are usually small in size, homogeneous, and well-defined.Signal intensity is low on T1-weighted sequences and high on T2-weighted sequences; contrast enhancement is high.In contrast, PCA tend to be large, ill-defined, and very heterogeneous on MRI, including diffusion-weighted imaging sequences (Yildiz et al., 2019).
In the context of discerning benign from malignant parathyroid lesions, Bae et al. ( 2012) identified a tumour size of 3 cm or greater to be indicative of PC in patients with PHPT, exhibiting a sensitivity and specificity of 91% and 92%, respectively.Despite this, data from a nationwide US cohort, as reported by Lo et al. (2018), demonstrated that around one-third of parathyroid carcinomas within a population of 520 individuals manifested tumour sizes below this size threshold.Considering disease severity, Calapkulu et al. ( 2021) posited that tumour volume may offer advantageous diagnostic utility compared to tumour size alone.

Pathology
As a new term to the Overview of the 2022 (2022) WHO classification, an 'atypical parathyroid tumour' should be in consideration when PCA is diagnosed.It has similar histologic features often seen in PCA, but they do not show unequivocal invasion which is required for the diagnosis of PCA (Erickson et al., 2022).PCA is classified as low grade, or minimally-invasive PCA (MIPC), and high grade, or widely-invasive PCA (WIPC), based on the degree of microscopic infiltration (Kameyama et al., 2005).
Due to the variety of presentations of PCA, differentiation between PCA and its benign counterpart benign parathyroid adenoma (BPA) can be problematic.One paper identified measuring patients' levels of intact PTH (iPTH).This value was found to be elevated 8 times above the  normal value in over half the patients with confirmed PC (Kawai et al., 2023).Further investigations need to be done with a wider sample size to ascertain the validity of iPTH concentration but it has the potential to be utilised to outline a threshold value for the diagnosis of malignant disease.
A case series of 39 patients showed variation in the values of Ki-67 in patients with PCA compared to a group which had atypical adenomas (AA).Ki-67 is a proliferation marker and its index represents the percentage of cells within a tumour that are currently dividing, with higher values indicating increased proliferation.Whilst critical Ki-67 thresholds for differentiating between PC and adenomas have been proposed, there is a degree of overlap between the two entities.Studies have suggested thresholds of 5-10% to delineate between the two entities.PCs tend to exhibit higher Ki-67 indices, surpassing these thresholds, reflecting their malignant nature and increased cellular proliferation.Conversely, parathyroid adenomas usually present with lower indices, typically below 5%.However, it is important to acknowledge the potential overlap in Ki-67 expression between the two, underscoring the complexity of their differentiation.In fact, a descriptive study conducted by Thanveer et al. ( 2023) revealed intriguing finings among 38 postsurgical lesions categorised as parathyroid adenoma (31), hyperplasia (5) and carcinoma (2).Notably, the mean Ki-67 index was determined to be 0.49% in adenomas and 5.84% in carcinomas.It is also worth pointing out that a heightened index was not confined solely to carcinoma, as it was also discerned in a minority of atypical adenomas; this demonstrates that Ki-67 expression cannot serve as an absolute discriminator between benign and malignant parathyroid lesions, but may still be useful.

Molecular diagnosis of PC
The CDC73 gene encodes a ubiquitously expressed, evolutionarily conserved, protein, parafibromin.In normal parathyroid cells, parafibromin is located in the nucleus.Loss of nuclear immunostaining of parafibromin is a common hallmark of PCA cells (Ciuffi et al., 2019).Furthermore, evidence from recent studies indicates that variations in CDC73 could be more common than seen in the literature.Currently, it is identified that 80% of patients with PCA have a somatic CDC73 mutation with 30% of the total being germline mutations (Cetani et al., 2023).Variations could indicate cases of hyperparathyroidism caused by PC could be genetically linked.(Garrigues et al., 2023).On top of this, screening of the CDC73 gene could provide a marker for this tumour.Studies also indicate an autosomal dominant pattern of inheritance of the CDC73 gene, and it is therefore important that genetic counselling is offered to patients diagnosed with this germline gene mutation as well as pre-implantation genetic testing for future offspring.There are three main conditions linked with the CDC73 gene: Hyperparathyroidism-jaw tumour (HPT-JT) syndrome, PCA, and familial isolated hyperparathyroidism (FIHP).What links all three of these is an increased susceptibility to PC and related hyperparathyroidism, illustrating how possible screening methods for this gene could help us to detect PCA earlier (Marini, et al. 2023).
Activating mutations in the PIK3CA gene and inactivating mutations in the PTEN gene commonly occur in diverse human tumours, resulting in constitutive activation of the PI3K/AKT/mTOR signalling and being a key pathway in carcinogenesis (Marin et al. 2023).A recent study by (Riccardi et al., 2020) found somatic, heterozygous, activating mutations of the PIK3CA gene in only 1% of the 391 analysed typical, sporadic PAs, suggesting that tumorigenic activation of the enzyme PIK3CA could be strongly associated with malignant PC rather than benign PA.Storvall et al. (2019) analysed the state of MGMT promoter methylation in tumour specimens from 11 PCs.The presence of high MGMT promoter methylation was found only in one patient, while all the other cases showed a low methylation status, indicating that the hypermethylation of the MGMT promoter is an extremely rare event in PCA.However, despite the results of this study, the authors recommended MGMT promoter methylation testing in recurrent PCAs, not curable by surgery, since, even if extremely rare, the presence of a high methylation status could pharmaco-epigenetically predict a good treatment response to chemotherapy with temozolomide.
The role of Long non-coding RNAs (lncRNAs) as prognostic and diagnostic biomarkers in parathyroid cancer has also been explored by Morotti et al. (2022), suggesting that human parathyroid tumours are characterised by a different lncRNAs signature, with the lncRNA BC200/BCYRN1 representing a candidate biomarker for PCA and its possible use in the postoperative setting for the patient's follow-up.
Work has been done to identify differentially expressed proteins (DEPs) between PCA and BPA: the most enriched pathways in these studies were the glycoprotein 6 and mTOR.The differential expressions of these proteins could help define molecular guidelines for PCA diagnosis (Sung et al. 2023), but this is not as yet in routine clinical practice.Zafereo, et al. (2019) surgical eradication is the first-choice therapy, and currently remains the primary and most effective management modality in the treatment of PCA, either for primary tumours or recurrent disease.Parathyroidectomy is the mainstay treatment to remove malignancy and has a good prognosis.En bloc resection can also be performed alongside the removal of the adjacent thyroid lobe in more complex cases.This is favoured as it can prevent the rupture of the tumour capsule (McIenerney et al. 2023).This is especially emphasised in the case described by Yuquan et al. (2023), which shows that the surgeons who simply excised the tumour split the capsule.Subsequently, there is thought to have been a leak of cells causing a 'chimney' effect resulting in localised PCA lesions around the pneumoperitoneum; the paper also describes how high-resolution ultrasound is sensitive and should be used to aid surgeons in such scenarios.Severe hypercalcaemia should be controlled before surgery.Intra-operative recognition of malignancy is extremely important to optimise surgery and decide the extension of neck exploration and surgical resection, since PCA treatment requires more radical surgery than the benign counterpart.

Conventional therapies
While surgical extirpation is the surgical ideal, this may not always be possible, and one is then left with hypercalcaemia which may be intractable.In the first instance, acutely, rehydration with normal saline is essential, but for longer-term control a variety of different agents can be used.Most commonly, bisphosphonates are first-line therapy, usually intravenously and at frequent intervals depending on the level of calcium and the duration of control.Monthly denosumab is also an option.Calcitonin has been used but is not often effective.Calcimimetic agents have also been used with varying efficacy.Cinacalcet, in particular, has shown promise in reducing serum calcium concentrations in inoperable parathyroid carcinoma cases, and has been approved for the management of PC-associated hypercalcaemia.Guise and Wysolmerski (2022) found that cinacalcet can reduce calcium levels by 1 mg/dl at a minimum with no reduction noted in PTH levels in approximately 60% of patients with PC.Predictably, the greatest benefit in terms of calcium reduction was seen in those with the highest initial calcium levels.Similar results were expressed by Silverberg et al. (2007), in which 29 patients with parathyroid carcinoma were administered cinacalcet (titrated up to 90 mg QDS) for 16 weeks, with the primary end point being a minimum of 1 mg/dl reduction in serum calcium at the end of the titration phase.Eighteen out of the 29 patients successfully achieved the primary endpoint, with the greatest effect in calcium reduction seen in those with the highest baseline calcium levels.Furthermore, there was no statistically significant reduction in PTH concentrations.A possible method of management before surgery was discovered during the COVID-19 pandemic.A patient with severe hypercalcaemia was managed with IV corticosteroids which normalised serum calcium after other therapeutics such as bisphosphonates had failed.The patient was weaned off 'steroids' and surgical resection was performed.This could indicate that pre-operative management in patients with PCA-induced hyperparathyroidism can be managed with IV corticosteroids (Mathew et al., 2023).
The recent development of the drug etelcalcetide, which acts as a direct agonist for the calcium-sensing receptor CaSR, enhances receptor sensitivity to plasma calcium and can decrease levels of PTH secretion.Its predecessor cinacalcet is an allosteric modulator for the same receptor and the potency of the newer drug is higher.Currently, the drug is recommended for use in patients diagnosed with secondary hyperparathyroidism and chronic kidney disease.However, from an assessment of the mechanism of action, there is a possibility to control calcium levels prior to PCA surgery, or in recalcitrant cases post-surgery.Currently, etelcalcetide is recommended for secondary hyperparathyroidism due to end-stage renal failure but there is no literature trialling its use in PCA patients (Hamano et al., 2017).
Radiofrequency ablation (RFA) represents a promising component in the multimodal treatment of PC.Although studies are limited for PC cases, the work of Ebrahiminik et al. (2022).has shown how RFA can be utilised for patients with BPA.The study identified that the implementation of RFA showed a significant reduction in serum PTH by 13.8% and serum calcium levels by 8.2%.Moreover, this treatment modality showed no complications in the patient cohort.Although this work relates to BPA, due to its minimal invasiveness could provide improved outcomes for patients diagnosed with PCA.Nevertheless, further research will be required to ensure its effectiveness and safety in this patient population.
The main locations for PCA secondary deposits include the lungs, liver and bones (Alberti et al., 2022).Metastasis to the liver has been researched more extensively by Su et al. (2022).They included 11 patients of which 9 underwent surgery, RFA or trans-arterial embolisation.Using these methods they demonstrated improved survival up to a follow-up of 60 months in 88.9% of patients.The paper highlights the effectiveness of RFA, and how it can alleviate symptoms.The sample size of this work is relatively small and therefore the effectiveness of such techniques to tackle metastatic disease will need to be scaled up in larger trials studying additional metastatic deposits.

Targeted therapies
Therapies utilising mTOR inhibitors have been used to reduce the high mTOR signalling levels in various cancer types (Lazaris et al., 2006).Somatic gene mutations that constitutively activate the PI3K/AKT/mTOR pathway were found in about up to 20% of PCA cases (Erickson et al., 2022), and thus the use of mTOR inhibitors could potentially be an effective therapy in PCA patients having these mutations.Currently, only one study (Kutahyalioglu et al., 2019) reported systemic therapy with everolimus, an mTOR inhibitor, in association with vandetanib (an anti-angiogenic tyrosine kinase inhibitor) in a patient with metastatic PCA and recurrent severe hypercalcaemia following two non-curative operations (a unilateral parathyroidectomy and a neck dissection), which was positive for two somatic mutations in the TSC1 gene (Arg228X and Val25Met), a known regulator of the PI3K/AKT/mTOR pathway.After two and a half months of treatment, the patient showed improved control of hypercalcaemia (dropping from 12.6 to 13.7 mg/dl before treatment to 10-11 mg/dl), with stable disease both in the neck and the liver metastases.
A study by (Kang et al., 2019) found mutations in the KDR gene, encoding the pro-angiogenic VEGF-R2 protein, in 13% of PCA cases analysed, and mutations in other genes involved in the regulation of angiogenesis have been reported in PCs (i.e., EPHB4, PTPRB, and VCAN).Recently, Shen et al. reported that somatic mutations in KDM5C, a gene encoding a lysine histone demethylase and found mutated in PCAs by three different studies, correlated with high angiogenesis (Shen, et al. 2021).Results of off-label treatment with specific anti-angiogenic inhibitors, the tyrosine kinase inhibitors (TKIs), were published in six PCA case reports, one with a somatic mutation of the KDR gene and one with a somatic mutation of the KDM5C gene, all 6 showing a positive response to therapy in terms of better control of hypercalcaemia, stabilisation of cancer, and/or reduction in the size of metastases (Fulgenzi, et al. 2022).TKIs appear to be a suitable medical therapy for PCA since they not only are effective in suppressing angiogenesis and growth in solid tumours but also effectively control hypercalcaemia and inhibit bone resorption (Rozhinskaya et al., 2017).
The potential development of new peptide radioreceptor therapies for other neuroendocrine tumours such as medullary thyroid carcinoma, neuroblastoma, primary phaeochromocytoma and abdominal paraganglioma (Fortunati et al., 2022), has identified an area that could be beneficial to PC treatments.These new peptides have been shown to have a favourable distribution and may be beneficial in targeting the tumours directly.Further research will be required to develop such peptides specifically for PC, principally in identifying the most useful ligands.

Post-operative management
It is vitally important to follow up all patients with any suggestion of their parathyroid tumour being a carcinoma.As previously mentioned, PCA has a high rate of recurrence post-treatment therefore posttreatment management is of utmost importance to pick up residual disease.In addition, it is important to monitor the quality of life (QoL) in patients who who have had a parathyroidectomy (Ionova et al., 2023).In this latter study, two measurements were taken one prior to treatment assessing QoL and one after.The SF-36 scoring system was utilised with patients having a significantly lower QoL prior to treatment compared to a control group.After treatment, surveys were repeated at 3, 12 and 24 months with there being a significant increase in QoL scores.Patients had fewer complaints of symptomatic issues as well as a decrease in reporting of cognitive behavioural changes.What this tells us is that parathyroidectomy as a treatment protocol is well tolerated by patients and is effective in improving QoL.
A case series by (Mani et al., 2023) highlighted some significant key points concerning follow-up in patients who have been treated for PCA.In the three individuals suffering from PCA, all of them were regularly investigated with scanning to check for recurrent hyperparathyroidism and metastases, plus symptoms which could indicate recurrence.It was also stated that a visibly swollen neck, PTH levels greater than 400 IU/L and serum calcium greater than 15 mg/dL could be used to identify recurrence.
Prognostically, there is a good proportion of patients that live cancerfree for many years with 5-year survival rates being high after initial treatment.However, studies have shown that the disease can lie indolent for several years but those who have recurrences within 36 months have lower survival rates.The work of Magnabosco et al. (2023) shows us that free-margin diameter has the greatest effect on the survival rate.

Discussion and conclusions
Parathyroid carcinoma is a rare disease while parathyroid adenomas are very frequently seen by most endocrinologists.As the outcomes for the two disorders are so different, it is important to diagnose such carcinomas as soon as possible as their lifetime follow-up is so different.There are certain biochemical and imaging characteristics which should increase suspicion of a carcinoma, but ultimately the histopathology is the only sure diagnostic criterion, with immunostaining for parafibromin being extremely useful.Surgery should be complete with an en bloc resection.In the case of metastatic or residual disease, these tumours can often be very indolent and slow-growing, and there is no reliable chemotherapy.However, the major concern is usually persisting or recurrent hypercalcaemia, which may require bisphosphonates, denosumab, or calcium receptor antagonists.Newer agents under trial include tyrosine kinase inhibitors, but more research is needed on molecular targeted agents, and other therapies such as immunotherapy.

Fig. 1 .
Fig. 1.Illustrative representation of the normal functioning of parathyroid hormone on different organ systems of the human body and how this affects calcium and phosphate balance.Created with Biorender.com(Insert line 28, page 3).

Fig. 2 .
Fig. 2. Illustrative representation of differing biomarkers in PC and BPA yet this leads to similarities in the presentation of symptoms.The figure also highlights the actions of drugs in reducing the effects of these symptoms.Created with Biorender.com(Insert line 22, page 6).

Table 1
Differences in clinical, biochemical, imaging, histopathological and molecular features between parathyroid adenoma and carcinoma.

Table 2
Key study details with major findings (01/2022 to 12/2023) included in this narrative review