The great masquerader: a case report of intrathyroidal hypofunctional normocalcemic parathyroid carcinoma mimicking a benign thyroid nodule

Introduction

Parathyroid carcinoma (PC) is an exceptionally rare endocrine malignancy, representing approximately 0.005% of all cancers. It is traditionally categorized into functional and non-functional variants based on parathyroid hormone (PTH) secretory activity and associated calcium levels; however, a distinct intermediate subtype of hypofunctional normocalcemic parathyroid carcinoma (HNPC) has been increasingly recognized, characterized by mild PTH elevation without hypercalcemia. The majority of PCs are functional, characterized by overt clinical signs including severe hypercalcemia, markedly elevated PTH levels, and associated skeletal or renal complications (1). Conversely, non-functional parathyroid carcinoma (NFPC), strictly defined by normal PTH levels and normocalcemia, is considerably less common, accounting for a mere 5–10% of PC cases. A closely related hypofunctional normocalcemic subtype, characterized by minimal PTH overproduction leading to mild PTH elevation without corresponding hypercalcemia, is often misclassified as non-functional due to the absence of classic hypercalcemic manifestations. Patients with both subtypes typically lack classic metabolic signs. Their clinical presentation is often limited to a neck mass or compressive symptoms (2), making HNPC a notorious diagnostic masquerader. This mimicry is particularly profound when HNPC arises within or adjacent to the thyroid gland (intrathyroidal). The considerable radiologic and cytologic overlap with common thyroid nodules renders conventional ultrasound, computed tomography (CT), and fine-needle aspiration cytology (FNAC) highly susceptible to misdiagnosis (3). Consequently, preoperative diagnosis remains a significant challenge due to its insidious presentation, rarity, and high likelihood of misinterpretation. This article presents a diagnostically challenging case of an IHNPC that perfectly mimicked a benign thyroid nodule. We incorporate a review of relevant literature to elucidate its clinicopathological characteristics, discuss the reasons for its deceptive presentation, and summarize contemporary diagnostic and management strategies. Our aim is to improve clinical awareness and preoperative diagnostic accuracy for this rare entity. We present this article in accordance with the CARE reporting checklist (available at https://gs.amegroups.com/article/view/10.21037/gs-2026-1-0110/rc).

Case presentation

A 51-year-old woman was referred for evaluation of a right-sided thyroid mass. The lesion, initially detected incidentally as a small nodule on routine examination two years earlier, had been managed conservatively with surveillance. She was asymptomatic, with no signs or symptoms of hypercalcemia or relevant family history of endocrine disorders. Physical examination revealed a firm, palpable mass in the right thyroid lobe. Laboratory investigations showed an elevated PTH level of 97.99 pg/mL (normal range: 15–65 pg/mL), with normal serum calcium (2.34 mmol/L; normal: 2.11–2.52 mmol/L), phosphorus (1.01 mmol/L; normal: 0.85–1.51 mmol/L), normal serum 25-hydroxyvitamin D (25-OHD) level of 32.6 ng/mL (normal range: 20–50 ng/mL), and normal renal function (serum creatinine 68 µmol/L; normal: 44–97 µmol/L, estimated glomerular filtration rate 92 mL/min/1.73 m²). Contrast-enhanced CT and ultrasonography identified a solid nodule in the right thyroid lobe, highly suggestive of a thyroid tumor (Figure 1). Preoperative FNAC was interpreted as a benign thyroid lesion. Notably, FNAC was performed in this case solely based on the initial clinical suspicion of a primary thyroid nodule, which is consistent with standard clinical practice; FNAC is generally contraindicated for suspected primary parathyroid neoplasms due to significant procedural risks. Based on the preoperative diagnosis of a thyroid adenoma, the patient underwent an initial limited procedure of a right thyroid lobectomy. However, intraoperative frozen section analysis raised suspicion of malignancy, prompting surgical extension to encompass isthmus resection and central compartment lymph node dissection; no evidence of lymph node metastasis was identified in the surgically dissected region. Histopathological examination of the resection specimen revealed an irregular, dark red mass measuring 4.0 cm × 2.5 cm × 2.0 cm, representing the entire surgically excised lesion including infiltrative tumor margins and adjacent adherent thyroid parenchyma. A well-circumscribed, encapsulated nodule measuring approximately 3.0 cm × 2.5 cm × 2.0 cm was identified within the resected thyroid tissue, with a solid, greyish-yellow to greyish-pink cut surface, corresponding to the main tumor mass. Microscopic examination showed nodular tumor tissue infiltrating adjacent structures with intravascular tumor thrombi. The tumor cells exhibited clear to partly eosinophilic cytoplasm with low-grade atypia. Areas of focal necrosis were surrounded by tumor cells demonstrating significant atypia and sarcomatoid features. Immunohistochemical (IHC) staining was positive for AE1/AE3, GATA3, CK19, D2-40, and CD31 (highlighting vascular invasion). Focal positivity was observed for SYN, CgA, and PTH. Staining was negative for Tg, TTF-1, PAX8, and CD56. The Ki-67 proliferation index was high at approximately 50%, and p53 showed a focal, diffuse, strong positivity pattern, suggestive of a missense mutation. Parafibromin staining was not performed as the clinical suspicion was initially directed towards a thyroid nodule. The postoperative pathology report raised the differential diagnosis between high-grade thyroid carcinoma and PC. To achieve diagnostic clarity, an external review by a specialized endocrine pathologist was requested. The external expert pathologist reviewed the slides and confirmed the presence of sarcomatoid differentiation, diffuse infiltrative growth, extensive necrosis (Figure 2A), and prominent intravascular tumor thrombi (>4 foci) (Figure 2B). Additional immunohistochemistry revealed CD61 positivity within thrombi, focal weak GATA3 expression, CD31 positivity, and diffuse moderate PTH immunoreactivity characteristic of parathyroid neoplasms, while D2-40 and INSM1 were negative (Figure 2C), CD31 positivity highlighted the intravascular thrombi (Figure 2D). The consultant rendered a final diagnosis of PC. The patient’s postoperative recovery was uneventful, with no complications observed. At the six-month outpatient follow-up, there was no evidence of local recurrence or distant metastasis. Follow-up laboratory tests revealed normal serum calcium and PTH levels, and neck ultrasonography showed no abnormalities. 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 article and any accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Figure 1 Imaging studies of the patient, with arrows indicating a neck mass. (A) Transverse view thyroid colour Doppler ultrasound reveals a 2.7 cm × 2.0 cm hypoechoic nodule within the right thyroid lobe. (B) Enhanced neck CT demonstrates a roughly circular nodular shadow within the right thyroid lobe, irregular in shape with ill-defined margins, measuring approximately 2.4 cm × 2.2 cm. CT, computed tomography.

Figure 2 Histopathological and immunohistochemical features of the parathyroid carcinoma. (A) H&E staining showing extensive necrosis. (B) H&E staining demonstrating tumor cells invading vascular walls with an intravascular thrombus. (C) Immunohistochemistry for PTH showing diffuse moderate positivity in tumor cells, consistent with the immunophenotype of parathyroid neoplasms. (D) Immunohistochemistry for CD31 highlighting an intravascular cancer thrombus. A, ×40; B, ×100; C, ×40; D, ×100. H&E, hematoxylin and eosin; PTH, parathyroid hormone.

Discussion

PC represents one of the rarest endocrine malignancies. Among these, NFPC, strictly defined by normal PTH levels and normocalcemia, accounts for approximately 5–10% of all cases, while HNPC, characterized by mild PTH elevation without hypercalcemia, represents an underrecognized intermediate subtype. Both subtypes act as clinical “great masqueraders”. Unlike its functional counterpart, HNPC secretes only minimally excessive PTH, which is insufficient to induce hypercalcemia, and NFPC secretes little to no PTH. Consequently, patients typically lack hypercalcemic symptoms and often present with only a neck mass (4), as exemplified in our case by mildly elevated PTH levels alongside normal serum calcium. Our patient presented with a PTH level of 97.99 pg/mL, which is 1.5 times the upper limit of the normal range, indicating preserved but dysregulated PTH secretion that was insufficient to overcome calcium homeostatic mechanisms and cause hypercalcemia. This clinical phenotype fits the emerging category of HNPC, which represents a distinct biological entity between fully functional (hypercalcemic) and truly non-functional (normocalcemic with normal PTH) parathyroid carcinomas. This revised terminology more accurately reflects the tumor’s secretory status and aligns with the 2022 WHO Classification of Parathyroid Tumors’ emphasis on integrating biochemical and pathological features for precise classification. Importantly, isolated mild PTH elevation with normocalcemia is most commonly caused by secondary hyperparathyroidism, with vitamin D deficiency being the leading global etiology, affecting approximately 1 billion people worldwide. Therefore, vitamin D deficiency must be systematically excluded as the first-line differential diagnosis in all patients presenting with this biochemical profile before considering a primary parathyroid neoplasm. In our case, the serum 25-OHD level was within the optimal reference range (32.6 ng/mL), effectively ruling out vitamin D deficiency as the cause of elevated PTH. Other secondary causes of elevated PTH, including chronic kidney disease, were also excluded based on normal serum creatinine and eGFR values. The absence of identifiable secondary etiologies, combined with the presence of a solid intrathyroidal mass with ill-defined borders on imaging, raised suspicion for a primary parathyroid lesion despite the initial misdiagnosis as a benign thyroid nodule. This case highlights the critical importance of measuring serum 25-OHD levels in all patients with thyroid nodules and any degree of PTH elevation to avoid misattributing primary parathyroid carcinoma to a reversible secondary cause. The IHNPC further accentuates its diagnostic elusiveness; to date, only two cases of intrathyroidal normocalcemic parathyroid carcinoma have been documented in the global literature (5), underscoring its extreme rarity. Given the non-specific clinical presentation, imaging plays a crucial yet often inconclusive role. Imaging features of PC and thyroid nodules significantly overlap. Ultrasound often shows a hypoechoic mass with ill-defined borders, while CT may reveal an irregular, heterogeneously enhancing mass, yet neither can definitively confirm a parathyroid origin (6). To address this limitation, four-dimensional computed tomography (4D-CT) with multiphase enhancement can aid in localization. In HNPC with partial function, 99mTc-MIBI scintigraphy might still show delayed uptake. Thus, combining these modalities may improve preoperative localization accuracy (7,8). However, even when localized, cytological confirmation remains challenging. Parathyroid lesions are often misdiagnosed as thyroid pathologies on FNAC due to their cytomorphological similarities, and FNAC has a sensitivity of only 30–50% for the diagnosis of PC. Crucially, FNAC is generally contraindicated for suspected primary parathyroid carcinomas or adenomas, as it carries a well-documented risk of needle tract seeding, tumor capsule disruption, and peritumoral adhesion formation, which can compromise the success of subsequent en bloc resection and increase local recurrence rates. Therefore, FNAC combined with PTH washout testing or immunohistochemistry (e.g., PTH, GATA3) should only be considered as an absolute last resort, exclusively when all non-invasive multimodal imaging modalities (ultrasound, shear wave elastography, 4D-CT, 99mTc-MIBI scintigraphy) have failed to establish a definitive diagnosis, and the results would be absolutely essential to guide surgical decision-making. In all other cases, surgical exploration with intraoperative frozen section analysis is the preferred diagnostic and therapeutic approach for suspected parathyroid neoplasms (3). Ultimately, the definitive diagnosis of PC relies on histology. WHO criteria require evidence of vascular invasion, local tissue infiltration, or metastasis. It is important to note that intraoperative frozen section has low diagnostic yield due to sampling limitations, making postoperative pathology combined with immunohistochemistry (e.g., focal PTH positivity) crucial for confirmation (9). Immunohistochemical analysis of parafibromin (CDC73-encoded) serves as a key diagnostic marker, showing complete loss of nuclear expression in most PCs but retained expression in thyroid carcinomas, thereby offering a critical molecular basis for their differentiation. Parafibromin expression loss is strongly associated with inactivating mutations of the CDC73 gene, which not only confirms the diagnosis of parathyroid carcinoma but also has important prognostic implications, as patients with CDC73-mutated tumors have a significantly higher risk of local recurrence and distant metastasis. Additionally, germline CDC73 mutations are responsible for hyperparathyroidism-jaw tumor syndrome (HPT-JT), an autosomal dominant disorder characterized by parathyroid tumors, ossifying fibromas of the jaw, and increased risk of other malignancies, necessitating genetic counseling and lifelong surveillance for affected patients and their family members. In this case, parafibromin testing was omitted initially due to preoperative suspicion of a primary thyroid lesion, which led to the exclusion of parathyroid-specific markers from the initial immunohistochemical panel. Postoperatively, although the diagnosis of parathyroid carcinoma was confirmed, parafibromin staining and germline CDC73 gene testing were not performed for several reasons: first, parafibromin immunohistochemistry was not a routine diagnostic test in our institution at the time of this patient’s treatment; second, the patient had an uneventful postoperative recovery with no evidence of recurrence or metastasis at the six-month follow-up; and third, the patient and her family declined further molecular testing after being informed of the potential benefits and limitations of these assays. This experience emphasizes the critical need to consider IHNPC in the differential diagnosis of thyroid nodules with abnormal PTH levels and to include parathyroid-specific markers such as parafibromin in the immunohistochemical panel for suspicious cases, as well as to offer appropriate genetic testing for patients with confirmed parathyroid carcinoma. Once diagnosed, surgical management is the cornerstone of treatment (10). This involves en bloc resection, including the ipsilateral thyroid lobe and involved tissues, to reduce recurrence. Prophylactic central neck dissection is not recommended unless metastasis is evident (11). Owing to frequent diagnostic delays, NFPC may have a worse prognosis, with a 5-year overall survival (OS) rate of 70% to 91%. Consequently, establishing a standardized postoperative surveillance protocol is essential. We recommend monitoring serum calcium and PTH levels at 3- to 6-month intervals for the first 5 years after surgery, which can be transitioned to annual assessments thereafter. Concurrent annual neck ultrasonography should be performed to facilitate early detection of recurrence. However, as a single case report, this study has inherent limitations, including the inability to generalize findings to broader populations and the absence of long-term follow-up data to assess late recurrence or survival outcomes. In summary, although rare, delayed diagnosis of INFPC directly impacts prognosis. Our case underscores that clinicians should maintain a high index of suspicion, include INFPC in the differential diagnosis for patients with elevated PTH and a neck mass, and employ multimodal imaging, molecular pathology, and multidisciplinary collaboration to achieve early diagnosis and treatment, ultimately improving patient outcomes. However, as a single case report, this study has several important inherent limitations. First, the inability to generalize findings to broader populations remains a key constraint, and the current follow-up duration of only six months is insufficient to assess late recurrence or long-term survival outcomes. Second, preoperative fine-needle aspiration (FNA) may have induced reactive histopathological changes that could potentially confound the interpretation of malignant features; previous studies have demonstrated that FNA can cause necrosis, hemorrhage, and even sarcomatoid morphological changes in parathyroid lesions, which may mimic true malignant transformation. Third, the immunohistochemical panel was incomplete: parafibromin (a key diagnostic marker for parathyroid carcinoma), BCL2, Rb, galectin-3, and p27 were not evaluated, and Ki-67 proliferation index was not specifically assessed in areas distant from potential FNA-induced reactive changes, which limits the definitive confirmation of malignant biological behavior. Finally, the absence of lymph node or distant metastasis at six-month follow-up, while reassuring, does not definitively exclude the malignant potential of the lesion given the indolent course of some parathyroid carcinomas. In summary, although rare, delayed diagnosis of IHNPC directly impacts prognosis.

Conclusions

IHNPC should be considered for thyroid nodules with indistinct borders and mildly abnormal PTH levels, even with normocalcemia. Routine measurement of serum 25-OHD to exclude vitamin D deficiency is an essential first step in the diagnostic workup. Proactive use of multimodal imaging and cautious, highly restricted use of FNAC only as a last resort is essential to reduce misdiagnosis and procedural complications.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://gs.amegroups.com/article/view/10.21037/gs-2026-1-0110/rc

Peer Review File: Available at https://gs.amegroups.com/article/view/10.21037/gs-2026-1-0110/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-2026-1-0110/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 article and any 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. Yin Z, Xu X, Cheng L, et al. Functional and nonfunctional parathyroid carcinoma: two case reports and literature review. Discov Oncol 2023;14:216. [Crossref] [PubMed]
2. Wang L, Han D, Chen W, et al. Non-functional parathyroid carcinoma: a case report and review of the literature. Cancer Biol Ther 2015;16:1569-76. [Crossref] [PubMed]
3. Gowrishankar SV, Bidaye R, Das T, et al. Intrathyroidal parathyroid adenomas: Scoping review on clinical presentation, preoperative localization, and surgical treatment. Head Neck 2023;45:706-20. [Crossref] [PubMed]
4. Sawhney S, Vaish R, Jain S, et al. Parathyroid Carcinoma: a Review. Indian J Surg Oncol 2022;13:133-42. [Crossref] [PubMed]
5. Jo HG, Moore JG, Harnoor AV, et al. First Case of a Biochemically Normal Intrathyroidal Parathyroid Carcinoma: Case Report and Literature Review. Clin Case Rep 2025;13:e71390. [Crossref] [PubMed]
6. Liu J, Zhan WW, Zhou JQ, et al. Role of ultrasound in the differentiation of parathyroid carcinoma and benign parathyroid lesions. Clin Radiol 2020;75:179-84. [Crossref] [PubMed]
7. Kurian KE, Hamdi O, Roecker ZA, et al. Surgeon Review of 4D CT for Identification of Parathyroid Adenomas. Head Neck 2025;47:839-46. [Crossref] [PubMed]
8. Viswanath A, Drakou EE, Lajeunesse-Trempe F, et al. Parathyroid carcinoma: New insights. Best Pract Res Clin Endocrinol Metab 2025;39:101966. [Crossref] [PubMed]
9. Erickson LA, Mete O, Juhlin CC, et al. Overview of the 2022 WHO Classification of Parathyroid Tumors. Endocr Pathol 2022;33:64-89. [Crossref] [PubMed]
10. Guilmette J, Sadow PM. Parathyroid Pathology. Surgical Pathology Clinics 2019;12:1007-19.
11. Kubal M, Lech M, Lajeunesse-Trempe F, et al. Advances in the management of parathyroid carcinoma. Mol Cell Endocrinol 2024;592:112329. [Crossref] [PubMed]