Intrathyroidal parathyroid carcinoma masquerading as a cystic thyroid nodule: a case report

Introduction

Parathyroid carcinoma (PC) is an uncommon malignancy, accounting for an estimated 0.005% of all cancers. Most data related to this pathology are limited to case series and small database studies (1). The peak incidence occurs around the fifth decade, with males having a slightly higher incidence compared to females (1). It is usually indolent and slowly progressive, with low rates of lymph node involvement and systemic metastasis (2).

Intrathyroidal PCs are even rarer, with less than 20 reported cases based on a review published recently (3). Severe hypercalcaemia (>14 mg/dL), high parathyroid hormone (PTH) level (5–10× the upper limit of normal or absolute PTH levels >500 mg/dL), and presence of a palpable neck mass with the presence of a parathyroid crisis at presentation are risk factors for PC (4). Ullah et al. reported that tumour size >4 cm, age >40 years, male sex, Caucasian race, distant spread, and poorly differentiated grade as independent risk factors for mortality. The overall 1-, 3-, and 5-year survival was 95.6%, 89.3% and 82.7% (1).

The majority of cases were diagnosed post-operatively via histopathological examination, as preoperative localization of PC can be challenging, especially in cystic lesions, where the lack of oxyphil cell predominance may reduce the sensitivity to technetium-99m (^99mTc)-methoxyisobutylisonitrile (MIBI) scans (5). In this report, we describe a case of intrathyroidal PC, whereby localization is challenging. This report aims to improve understanding and management and discuss challenges in treating this rare disease. We present this case in accordance with the CARE reporting checklist (available at https://gs.amegroups.com/article/view/10.21037/gs-2025-69/rc).

Case presentation

A 61-year-old female presented with an 8-month history of neck swelling, along with lethargy, constipation, and a 10-kg weight loss. She had no significant medical history or family history of multiple endocrine neoplasia (MEN) syndrome or thyroid disorders. Clinical examination revealed a firm mass over the right neck measuring 2 cm × 2 cm, without compressive symptoms.

Investigation was arranged and showed that calcium levels were markedly elevated (>4 mmol/L), with a raised PTH of 134.2 pmol/L (1.95–8.49 pmol/L). Her vitamin D level was low at 30 nmol/L (<50 nmol/L), and her 24-hour urine calcium was high (13.2 mmol, reference range 2.2–7.5 mmol). Thyroid function tests were normal, suggestive of primary hyperparathyroidism.

Ultrasound (USG) of the thyroid (Figure 1) showed two right thyroid nodules measuring 1.7 cm × 2.3 cm × 1.6 cm and 2.3 cm × 3.2 cm × 3.1 cm, classified as thyroid imaging, reporting and data system (TIRADS) 1, with no obvious parathyroid enlargement. Subsequently, parathyroid scintigraphy was scheduled and showed reduced tracer uptake at the lower pole of the right thyroid gland, corresponding to a hypodense thyroid nodule measuring approximately 3 cm (Figure 2). No abnormal uptake indicative of a parathyroid adenoma was noted.

Figure 1 USG of thyroid shows two well defined TIRADS 1 thyroid nodules measuring 1.7 cm × 2.3 cm × 1.6 cm (A) and 2.3 cm × 3.2 cm × 3.1 cm (B), with no worrisome features. TIRADS, thyroid imaging, reporting and data system; USG, ultrasound.

Figure 2 Parathyroid scintigraphy showed right thyroid nodule/colloid cyst, no evidence of parathyroid adenoma.

Fine-needle aspiration (FNA) of the thyroid nodule was non-diagnostic, containing only cystic fluid. A whole-body ^99mTc-MIBI scan with single-photon emission computed tomography and computed tomography (SPECT/CT) (Figure 3) showed a left parathyroid adenoma and a right thyroid nodule.

Figure 3 SPECT/CT of the neck showed increased uptake of tracer at the left upper pole of thyroid gland, measuring 0.8 cm × 0.7 cm. SPECT/CT, single-photon emission computed tomography and computed tomography.

After a multidisciplinary team (MDT) meeting with the endocrinologist, pathologist, and endocrine surgeon, a diagnostic surgery was proposed, and the patient underwent neck exploration two weeks later. Intraoperatively, a thyroglossal cyst measuring 2 cm × 2 cm was excised. The left parathyroid gland was localized and excised (1 cm × 0.6 cm), confirmed via frozen section. Preoperative PTH levels were 92 pmol/L, and intraoperative levels at T0, T5, and T10 showed 95, 107, and 107.6 pmol/L, respectively, indicating no significant reduction.

Given the preoperative ultrasound findings of a right thyroid cyst, aspiration of the contralateral right thyroid cyst fluid was performed and sent for IOPTH assay, revealing a markedly high PTH level (>1,060 pmol/L). The patient subsequently underwent a right hemithyroidectomy (Figure 4). IOPTH levels showed a 78% reduction post-surgery.

Figure 4 Gross specimen of right hemithyroidectomy, weighing 6.5 g, measuring 3.5 cm × 3.5 cm.

Histological examination (Figures 5,6) confirmed intrathyroidal PC within a background of benign thyroid follicles with a clear margin of 1 mm. Postoperatively, the patient’s serum PTH level normalized to 1.1 pmol/L. She was discharged in stable condition on postoperative day four and has since been monitored with annual neck ultrasound and biannual serum PTH surveillance. No adjuvant chemotherapy or radiotherapy was suggested due to a lack of data available; hence opted for active surveillance as per MDT, in view of it being a localised malignancy. Follow-up assessments to date have demonstrated no evidence of local recurrence, with PTH levels remaining stable at <1 pmol/L. Upon discharge, she was prescribed calcium carbonate 1,000 mg twice daily and calcitriol 0.25 mcg twice daily; over two years of follow-up, the calcium dosage was reduced to 500 mg twice daily while maintaining the same calcitriol dose. The patient has consistently expressed gratitude and a positive outlook during each follow-up visit.

Figure 5 Hematoxylin and eosin stain demonstrates invasion of neoplastic cells into adjacent thyroid follicles (10× magnification).

Figure 6 Hematoxylin and eosin stain shows monomorphic neoplastic chief cells arranged in trabecular and solid patterns, interspersed with thin, incomplete fibrous septa (40× magnification).

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 Helsinki Declaration 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.

Discussion

PC is a rare malignant neoplasm of the parathyroid gland. It accounts for less than 5% of primary hyperparathyroidism. Parathyroid glands are located posterior to the thyroid gland, with a more variable location towards the inferior parathyroid due to the embryological development from a third branchial pouch. Histologically, the major functional cells of the glands are chief cells, which contain cytoplasmic secretory granules, which are responsible for producing PTH. Oxyphil cell is another cell type that makes up the parathyroid parenchyma (6). Mutation of HRPT2 (CDC73), a tumour suppressor gene, has been described by Simonds et al. as playing a role in the molecular pathogenesis of PC. This mutation is found in hyperparathyroidism-jaw tumour syndrome and sporadic PC (7). Although most patients are hypercalcemic, some may remain normocalcemic due to a non-functioning PC (8).

Schaapveld et al. in his population-based study in The Netherlands showed that a PTH level more than 3 times upper normal limits was suspicious and levels more than 10 times carries a positive predictive value of 84% for carcinoma, in which our patient has a serum PTH value of (134 pmol) which is more than 10 times (8.4 pmol) of normal value (9). The serum PTH levels are expected to reduce by more than 50% from the highest pre-excision level, measured 10 minutes after gland removal (10). Pre-operative imaging showed uptake of left parathyroid adenoma, which was excised intra-operatively, but which does not show a reduction in serum PTH level in our patient. A decision was made to aspirate fluid from the contralateral right thyroid cyst, which was shown to be TIRADS 1 from imaging, and sent for PTH assay, which came back as a result of >100 times higher than the upper limit. Aspiration of cystic fluid from parathyroid has been shown to differentiate parathyroid cyst from other neck masses from a literature review, however, none were used to diagnose parathyroid cancer (11). This could be explained due to the rarity of intrathyroidal PC, which is only less than 20 cases reported in the literature. Initial scintigraphy for our patient did not show any uptake at the right parathyroid, this could be explained by rapid washout similar to that of thyroid tissue; therefore, any avid foci seen on early images should be considered suspicious despite potential washout (12). Multiple factors can affect the sensitivity of the scan, including the lesion size, cellularity, and the presence of P-glycoprotein. Modification of the imaging protocol may help to avoid false-positive or false-negative results in certain cases (13).

Surgery remains the mainstay of therapy for resectable disease. According to Lee et al., in the Surveillance, Epidemiology, and End Results (SEER) registry, 96% of patients underwent parathyroidectomy, with 78.6% of patients underwent simple parathyroidectomy and 12.5% underwent en-bloc resection (which include lymph node and surrounding tissue). No difference in postoperative morbidity and mortality or survival rate between these two approaches. However, data were limited by the relatively small number of patients who underwent en-bloc resection (14). A systematic review by McInerney et al. showed that these two approaches had no difference in morbidity and mortality as well. Patients who underwent either form of surgery had longer overall survival than those managed conservatively (15). When the tumour is no longer amenable to surgical intervention, symptomatic control becomes a focus—control of hypercalcemia with the best medical therapy. Limited data can be obtained for treatment with radiotherapy and chemotherapy, due to rarity of disease.

Conclusions

PC remains rare and poses a great challenge to diagnose pre-operatively. A combination of laboratory parameters, imaging, tissue sampling, and a multidisciplinary team will aid in improving overall management. Furthermore, aspiration of parathyroid fluid for PTH assay may be incorporated in standard treatment, however, more evidence is needed.

Acknowledgments

We would like to thank the Department of Pathology, Faculty of Medicine, Dr Chiew Seow Fan, for providing HPE pictures for this report.

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://gs.amegroups.com/article/view/10.21037/gs-2025-69/rc

Peer Review File: Available at https://gs.amegroups.com/article/view/10.21037/gs-2025-69/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://gs.amegroups.com/article/view/10.21037/gs-2025-69/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 Helsinki Declaration 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/.

References

1. Ullah A, Khan J, Waheed A, et al. Parathyroid Carcinoma: Incidence, Survival Analysis, and Management: A Study from the SEER Database and Insights into Future Therapeutic Perspectives. Cancers (Basel) 2022;14:1426. [Crossref] [PubMed]
2. Schulte KM, Talat N, Miell J, et al. Lymph node involvement and surgical approach in parathyroid cancer. World J Surg 2010;34:2611-20. [Crossref] [PubMed]
3. Benali K, Aarab J, Benmessaoud H, et al. Intrathyroidal parathyroid carcinoma: a case report and literature review. Radiat Oncol J 2021;39:145-51. [Crossref] [PubMed]
4. Machado NN, Wilhelm SM. Parathyroid Cancer: A Review. Cancers (Basel) 2019;11:1676. [Crossref] [PubMed]
5. Xu T, Zheng X, Wei T. Incidental synchronous intrathyroidal parathyroid carcinomas and papillary thyroid microcarcinoma with compressive neck mass and primary hyperparathyroidism: case report and literature review. BMC Endocr Disord 2024;24:125. [Crossref] [PubMed]
6. Byrd C, Kashyap S, Kwartowitz G. Parathyroid Cancer. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025. Available online: https://www.ncbi.nlm.nih.gov/books/NBK519038/
7. Simonds WF, Robbins CM, Agarwal SK, et al. Familial isolated hyperparathyroidism is rarely caused by germline mutation in HRPT2, the gene for the hyperparathyroidism-jaw tumor syndrome. J Clin Endocrinol Metab 2004;89:96-102. [Crossref] [PubMed]
8. Messerer CL, Bugis SP, Baliski C, et al. Normocalcemic parathyroid carcinoma: an unusual clinical presentation. World J Surg Oncol 2006;4:10. [Crossref] [PubMed]
9. Schaapveld M, Jorna FH, Aben KK, et al. Incidence and prognosis of parathyroid gland carcinoma: a population-based study in The Netherlands estimating the preoperative diagnosis. Am J Surg 2011;202:590-7. [Crossref] [PubMed]
10. Khan ZF, Lew JI. Intraoperative Parathyroid Hormone Monitoring in the Surgical Management of Sporadic Primary Hyperparathyroidism. Endocrinol Metab (Seoul) 2019;34:327-39. [Crossref] [PubMed]
11. Ginsberg J, Young JE, Walfish PG. Parathyroid cysts. Medical diagnosis and management. JAMA 1978;240:1506-7. [Crossref] [PubMed]
12. Strauss SB, Roytman M, Phillips CD. Parathyroid Imaging: Four-dimensional Computed Tomography, Sestamibi, and Ultrasonography. Neuroimaging Clin N Am 2021;31:379-95. [Crossref] [PubMed]
13. Alenezi SA, Saqr MA, Elgazzar AH. Scintigraphic parathyroid imaging: concepts and new developments. Research and Reports in Nuclear Medicine 2015;5:9-18.
14. Lee PK, Jarosek SL, Virnig BA, et al. Trends in the incidence and treatment of parathyroid cancer in the United States. Cancer 2007;109:1736-41. [Crossref] [PubMed]
15. McInerney NJ, Moran T, O’Duffy F. Parathyroid carcinoma: Current management and outcomes-A systematic review. Am J Otolaryngol 2023;44:103843. [Crossref] [PubMed]