Multidisciplinary approach to atypical parathyroid tumours and severe hypercalcemia: a case report

Introduction

Background

The World Health Organisation reclassified atypical parathyroid adenomas to atypical parathyroid tumours (APTs) in 2022 (1). APTs form a small subset of lesions causing primary hyperparathyroidism (PHPT) and exhibit almost identical clinical manifestations to parathyroid carcinomas. APTs demonstrate histological features concerning for parathyroid carcinoma without definitive invasion or metastases. Given uncertainty surrounding their malignant potential, APTs warrant prompt diagnosis and long-term surveillance (1).

Rationale and knowledge gap

Previous studies have compared pre-operative serum parathyroid hormone (PTH) concentrations of APTs to other types of parathyroid tumour, including parathyroid carcinomas, to identify biochemical cut-offs that distinguish between these entities (2). The lack of published caseloads has been a barrier to this process, and multiglandular disease concurrent with APTs has not been considered previously. There are also no guidelines for post-resection surveillance of APTs.

Objective

We present an additional case of APT with biochemical data while simultaneously demonstrating the multidisciplinary management of associated PHPT and severe hypercalcemia, and the importance of post-resection surveillance to identify multiglandular disease. We also highlight the challenge associated with biochemically delineating APTs from other lesions when there is multiglandular disease. We present this case in accordance with the CARE reporting checklist (available at https://acr.amegroups.com/article/view/10.21037/acr-2025-111/rc) (3).

Case presentation

All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Declaration of Helsinki and its subsequent amendments. Written informed consent was obtained from the patient for the publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal. A 66-year-old Caucasian male presented to the emergency department of a small metropolitan hospital with respiratory distress and a productive cough. He also reported a progressive history of lethargy, confusion, night sweats and diffuse bony tenderness, most severe on his shins. On examination, the patient was tachycardic and hypotensive with a productive cough. His respiratory symptoms were attributed to an exacerbation of chronic obstructive pulmonary disease due to infection, for which he received antimicrobial therapy.

Initial biochemical investigations however, revealed an incidental finding of severe hypercalcaemia (serum calcium 5.24 mmol/L and ionised calcium 2.77 mmol/L), hypoalbuminemia (29 mmol/L), hyperphosphatemia (1.63 mmol/L), and concurrent hyperparathyroidism (PTH 181.9 pmol/L). There was an associated acute on chronic kidney injury (serum creatinine 368 µmol/L from a baseline approximating 160 µmol/L). This patient was deemed to have PHPT and was immediately transferred to a major tertiary centre for further investigation and management, which included an initial four-day intensive care unit (ICU) admission with multidisciplinary input from endocrinology, nephrology, haematology, and ear, nose and throat (ENT) surgery.

Computed tomography (non-contrast due to renal impairment) of the neck, chest, abdomen, and pelvis was performed to assess for a neoplastic cause of hypercalcaemia. It revealed a heterogeneous soft tissue mass in the inferior pole of the right thyroid lobe, abutting the thoracic inlet and displacing the oesophagus to the left. Thyroid ultrasound demonstrated retrosternal extension, although it could not confirm or exclude oesophageal invasion. Magnetic resonance imaging of the neck soft tissue demonstrated a 42 mm × 30 mm × 45 mm soft tissue mass at the level of the cervical oesophagus that did not demonstrate frank invasion, although again could not confirm or exclude this (Figure 1). A technetium-99m sestamibi scan was performed and the lesion demonstrated intense tracer uptake with early phase images, alongside persistent activity in delayed phase images. No uptake was identified at other locations at this time. No metastatic spread was found on this scan or subsequent fluorodeoxyglucose (FDG) positron emission tomography (Figure 1). Bilateral leg X-rays revealed multiple poorly defined bony lytic lesions (Figure 2) in both tibias consistent with osteitis fibrosa cystica secondary to PHPT. Multiple myeloma was excluded with an urgent bone marrow biopsy performed by Haematology.

Figure 1 Magnetic resonance imaging (left, middle); demonstrates a 42 mm × 30 mm × 45 mm soft tissue mass which is predominantly solid but displays a heterogenous signal with small fluid filled spaces in the lower section. The soft tissue mass epicentres at the level of the lower cervical oesophagus and displaces the oesophagus to the left. There is no evidence of frank tracheal invasion. Positron emission tomography (right); diffusely increased FDG activity in the paraoesophageal space with a soft tissue mass that displaces the oesophagus to the left. FDG, fluorodeoxyglucose.

Figure 2 Bilateral leg X-rays were performed to evaluate the initial presenting symptom of shin pain. The image (right tibia, lateral view) demonstrates innumerable poorly defined lucencies best appreciable at the anterior aspect of the tibia.

Given the risk of complications from severe hypercalcemia, Endocrinology input was sought and the patient received intravenous zoledronic acid 4 mg, intravenous calcitonin 100 IU, and cholecalciferol 2,000 IU daily given concurrent vitamin D deficiency (23 nmol/L). Due to expected rebound tachyphylaxis with prolonged calcitonin use, the patient was prepared for urgent surgical resection of the tumour, suspected to be a parathyroid carcinoma due to the constitutional symptoms, severe hypercalcaemia, and potential oesophageal invasion.

The patient was again transferred to a different tertiary centre with a specialised head and neck surgery unit. Surgical resection was performed by an experienced ENT head and neck surgeon. The resection involved a focused right parathyroidectomy with a curved neck incision and elevation of subplatysmal flaps with division of the omohyoid and strap muscles. The tumour was dissected off the surrounding tissue bed using a bipolar with preservation of the recurrent laryngeal nerve. Rigid esophagoscopy immediately prior to surgical resection confirmed no invasion into the oesophageal lumen. The lesion was a tan-coloured nodular mass, of 50 mm × 34 mm × 25 mm, weighing 21 g (Figure 3). Histology confirmed parathyroid glandular tissue with expanded trabeculae and predominantly uniform chief cells, although some oncocytic variants were present. The lesion also demonstrated necrosis, variable sized nuclei, prominent nucleoli and up to 5 mitoses/mm². Parafibromin immunohistochemistry demonstrated retained nuclear staining (Figure 4). No capsular, perineural or vascular invasion was identified. This specimen was classified as an APT.

Figure 3 Tan coloured, nodular specimen, that was surgically resected. Dimensions are 50 mm × 34 mm × 25 mm with weight of 21 g.

Figure 4 Histological images of the resected specimen, demonstrating parathyroid glandular tissue with uniform chief cells and oncocytic variants. Necrosis is evident (left) with up to five mitoses per millimetre squared (right). Stain: haematoxylin and eosin. Magnification: ×40 (left) and ×200 (right).

On the day of excision, preoperative PTH was 325 pmol/L. At 10 minutes post-resection, serum PTH concentrations reduced to 60.3 pmol/L using the rapid PTH protocol assay. Post-resection, PTH and serum calcium levels respectively, were 37.3 pmol/L and 2.19 mmol/L at 4 hours, and 44.5 pmol/L and 2.04 mmol/L at 10 hours. Postoperative recovery was complicated by rapid, severe hypocalcaemia with a nadir serum calcium of 1.70 mmol/L and ionised calcium of 0.91 mmol/L at day 13. This was attributed to a combination of hungry bone syndrome and vitamin D deficiency. The patient required ICU re-admission with Endocrinology guidance for management, involving intravenous calcium gluconate, twice daily calcitriol 0.25 µg, a single 50,000 IU dose of cholecalciferol, and ongoing daily 1,000 IU cholecalciferol supplementation. Serum calcium concentrations gradually normalised to 2.54 mmol/L and PTH concentrations stabilised at 34.2 pmol/L at day 15.

Following discharge, the patient was monitored in an Endocrinology outpatient clinic. Postoperatively, persistent hyperparathyroidism (serum PTH 58 pmol/L) was noted from resection to 6 months after. While chronic kidney disease, previous vitamin D deficiency and hungry bone syndrome may have contributed to this, investigations were performed to exclude residual or recurrent parathyroid disease. A neck ultrasound was performed at 7 months postoperatively and identified a solitary lesion inferior to the left lobe of the thyroid of 17 mm × 13 mm × 10 mm dimensions, with central echogenic regions and peripheral hypoechogenicity. CT neck and techtenium-99m sestamibi scan were subsequently performed and demonstrated a sestamibi-avid lesion suggestive of a left parathyroid adenoma with no right-sided avidity to suggest residual APT. The left parathyroid adenoma was suspected to have been missed in previous imaging due to the relatively high sestamibi avidity of the previously resected right APT. The patient subsequently underwent a left parathyroidectomy at 9 months following the initial right parathyroidectomy. At 5 months following left parathyroidectomy (14 months after the initial right APT resection), the PTH concentration was 20.2 pmol/L. A bone densitometry scan was performed and yielded a left radius bone T-score of −2.6 with a Z-score of −1.9, consistent with osteoporosis. The patient was tolerant of and adherent to all treatment and surveillance and remains alive and well at the time of this report. Genetic testing did not identify any genetic change associated with parathyroid neoplasms. The sequence of events during this patient’s care is summarised in Figure 5.

Figure 5 Timeline of chronological sequence of events during the patient’s care, from presentation until most recent surveillance. APT, atypical parathyroid tumour; Ca, calcium; CT, computed tomography; ENT, ear, nose and throat; FDG, fluorodeoxyglucose; ICU, intensive care unit; iCa, ionised calcium; IV, intravenous; MRI, magnetic resonance imaging; PET, positron emission tomography; PHPT, primary hyperparathyroidism; PTH, parathyroid hormone; US, ultrasound; XR, X-ray.

Discussion

Key findings

This case demonstrated the challenge of preoperatively differentiating APTs and parathyroid carcinomas. The presence of severe hypercalcaemia, PHPT, constitutional symptoms, and radiological features that could not exclude invasion were concerning for a parathyroid carcinoma, yet the causative lesions were an APT and a parathyroid adenoma. Additionally, this case highlights the importance of multidisciplinary management of such neoplasms, as the complications of parathyroid lesions and their resection are medically complex. Furthermore, the presence of a previously unidentified parathyroid adenoma highlights a key indication for ongoing surveillance post-resection of APTs, and unidentified multiglandular disease as a differential diagnosis for persistently elevated serum PTH post-resection.

Strengths and limitations

This case demonstrates the importance of the appropriate hospital setting for multidisciplinary management of APTs, given their potential to present with complex airway, surgical and endocrine pathology. It also demonstrates that patients are provided the maximal likelihood of safe, holistic and patient-centred care through tailored management plans (4). While guidelines exist for the evaluation and management of parathyroid carcinomas and PHPT, APTs are a rare subset without specific guidelines, including for postoperative surveillance. The presence of a previously unidentified left parathyroid adenoma emphasises the importance of this, especially when post-resection serum PTH concentrations remain elevated. Nevertheless, a key limitation of this report is the provision of a single case and limited generalisability. Furthermore, the PTH trends demonstrated in this case were from multiglandular disease. While this highlights a unique clinical presentation of PHPT, it also limits biochemical comparability between other cases.

Comparison with similar research

Given the recent reclassification of atypical parathyroid adenomas to APTs, there is comparably little evidence pertaining to the clinical and biochemical manifestations of APTs compared to other parathyroid neoplasms, and factors that can reliably distinguish APTs from parathyroid carcinomas. Further biochemical data pertaining to APTs may assist in this process, although the rarity of both lesions, the occasional presence of multiglandular disease, and variable serum calcium and PTH concentrations are key barriers to this. Di Filippo et al. compared 451 histologically confirmed APT cases and reported a mean calcium concentration of 3.72 mmol/L and a mean PTH of 100 pmol/L at diagnosis (5). In contrast, Chen et al. reported a mean calcium concentration of 3.17 mmol/L (12.7 mg/dL) and PTH of 42.1 pmol/L (397 pg/mL) at diagnosis of 20 histologically confirmed parathyroid carcinomas. These concentrations were significantly higher than for parathyroid adenomas, although this difference appears less distinct when comparing parathyroid carcinomas and APTs (6). Further research assessing the reliability of novel biochemical differences would be useful for preoperative differentiation.

Our case demonstrated multiglandular disease, whereby the majority of PTH elevation was attributed to the APT. This limits comparisons between other cases of APTs without multiglandular disease. However, in a retrospective analysis of APT cases with PHPT that underwent parathyroidectomy, Napolitano et al. identified a significantly (P<0.05) higher pre- and post-operative mean PTH concentration in solitary APTs compared to a second group consisting of both solitary typical adenomas and multiglandular parathyroid disease in the same category. Preoperative concentrations for APTs were 118.7 pmol/L (1,119.09 pg/mL) versus 31.4 pmol/L (296.00 pg/mL) for the latter category. Post-operative concentrations for APTs were 8.67 pmol/L (81.1 pg/mL) versus 4.37 pmol/L (41.22 pg/mL) for the latter category (2). This markedly higher PTH concentration in the APT group supports the observation from this case, whereby PTH elevation was predominantly due to the APT, with a preoperative and postoperative serum PTH of 325 and 44.5 pmol/L, respectively (before parathyroid adenoma resection).

Beyond calcium and PTH, other studies are assessing novel immunohistochemical markers to aid differentiation, such as parafibromin and galectin-3 (7). A reliable biochemical marker would have particular use in cases of equivocal diagnosis and optimise pre-operative management. For example, Ki-67, a marker of cellular proliferation, demonstrates higher concentrations in parathyroid carcinomas than APTs, whereby a 5% cut-off may delineate parathyroid carcinomas from APTs, although further validation is required (8).

Explanations of findings

Importantly, this patient was discharged with an elevated PTH concentration (34.2 pmol/L) despite complete APT resection. In some instances, this may relate to preoperative findings of vitamin D deficiency and high bone turnover markers, which are features of hungry bone syndrome (9). However, in this case, persistently elevated PTH levels were attributed to a left parathyroid adenoma that was subsequently identified through outpatient Endocrinology surveillance. Subsequent removal of the left parathyroid adenoma yielded a further reduction of serum PTH levels.

Implications and actions needed

This case highlights the challenges in distinguishing between APTs and parathyroid carcinomas. Clinical, biochemical and histological features have significant overlap with both entities. Parathyroid carcinomas can present without vascular and perineural invasion, which further complicates histological differentiation of these diseases (10). This case demonstrated high PTH levels in an APT, concordant with prior data, yet these biochemical differences are not yet proven reliable in delineating between APT and parathyroid carcinomas (2). Furthermore, this case highlights the importance of considering occult multiglandular disease as a cause of PHPT alongside APT.

Conclusions

APTs and parathyroid carcinomas are both uncommon yet serious neoplasms that are difficult to reliably distinguish and can manifest as severe PHPT and hypercalcemia. Although initial management can be similar, the management and surveillance requirements may differ. Given the complexity of APT complications, this case highlights the critical need for a multidisciplinary management approach. Further research is required to assess the reliability of biochemical markers in differentiating these entities.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://acr.amegroups.com/article/view/10.21037/acr-2025-111/rc

Peer Review File: Available at https://acr.amegroups.com/article/view/10.21037/acr-2025-111/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://acr.amegroups.com/article/view/10.21037/acr-2025-111/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Declaration of Helsinki and its subsequent amendments. Written informed consent was obtained from the patient for the publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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