PARATHYROID CARCINOMA WITH LACK OF CLINICAL SYMPTOMS: A CASE REPORT AND REVIEW OF LITERATURE

Abstract

Context

Parathyroid carcinomas (PC) are rare. Imaging and laboratory tests can suggest a diagnosis of PC, but pathological examination is ultimately required to confirm the diagnosis.

Objective

The clinicopathologic data, diagnosis, and treatment of a case of PC diagnosed in our hospital in 2022 are retrospectively summarized in this case report to improve the understanding, diagnosis, and differential diagnosis of this disease.

Design

Case report.

Subjects and Methods

Herein, we present the case of a 35-year-old man who presented with imaging and laboratory findings suggestive of a parathyroid neoplasm.

Results

The patient underwent radical resection of the tumor, which was histopathologically diagnosed as PC.

Conclusion

In this case, the clinical manifestations of PC were insidious, and the histological features had to be differentiated from tumors, such as parathyroid adenoma, clear cell renal cell carcinoma, and medullary thyroid carcinoma; thus, its diagnosis was challenging.

INTRODUCTION

Parathyroid carcinoma (PC) is a very rare, low-grade malignant tumor originating from parathyroid cells (ICD-O code 8140/3), with an incidence of only 0.005% of malignant tumors (1). These tumors are responsible for 0.1–5.0% of primary hyperparathyroidism cases (2). PC can occur at all ages, with a mean age of approximately 45–55 years and no significant sex predilection (3). Patients often present with a palpable mass in the neck, accompanied by symptoms of hyperparathyroidism, such as elevated serum calcium levels, fatigue, vomiting, polyuria, and polydipsia (4).

The clinicopathologic data, diagnosis, and treatment of a case of PC diagnosed in our hospital in 2022 are retrospectively summarized in this case report to improve the understanding, diagnosis, and differential diagnosis of this disease.

CASE REPORT

Clinical data

General Information

A 35-year-old man presented at our hospital with a parathyroid nodule that had been accidentally discovered half a month prior during a color ultrasound examination in the outpatient department. The patient had not received any treatment for the nodule since its identification. The patient was otherwise healthy and denied any family history of genetic diseases or tumors. The patient had no history of nausea, vomiting, polyuria, polydipsia, or any other symptoms.

Clinical examination, investigations, and treatment

Clinical examination: the neck was found to be soft, and the trachea was midline. No significant mass was palpable in or around the thyroid gland, and no enlarged lymph nodes were palpable around the neck or in the supraclavicular or infraclavicular regions.

Laboratory investigations: blood tests revealed parathyroid hormone (PTH) levels > 1900 (reference: 12.0–65.0) pg/mL, a serum calcium level of 3.42 (reference: 2.08–2.60) mmol/L, and an alkaline phosphatase level of 534 (reference: 45.0–125.0) U/L.

Imaging: 1) Thyroid color ultrasound (Fig. 1a) showed a heterogeneous hypoechogenicity of approximately 2.5 × 2.3 cm in the lower portion of the left lobe, suggestive of a parathyroid adenoma. 2) Neck computed tomography showed a nodule on the lower side of the left lobe of the thyroid gland measuring 2.1 × 1.5 × 2.1 cm, with a computed tomography value of approximately 71 HU; therefore, a possible neoplastic lesion of parathyroid gland origin was considered.

Figure 1.

Color Doppler ultrasound, histological features, and tumor immunohistochemical detection results.

a: Color Doppler ultrasound shows irregular heterogeneous hypoechogenicity (white arrow) in the lower pole of the left lobe of the thyroid gland; b: infiltrative growth of the tumor, involving the surrounding fibroadipose tissue (H&E staining × 40); c: thick fibrous connective tissue septa in the tumor (H&E staining × 40); d: necrosis and calcification in the focal area of the tumor (H&E staining × 40); e: intravascular tumor thrombus (H&E staining × 40); f: medium-sized tumor cells with round-to-oval nuclei, rough and dense chromatin, prominent nucleoli (H&E staining × 200); g: mitotic figures (H&E staining × 400); h: Cyclin D1-positive tumor cells (EnVision staining × 100); i: GATA-3-positive tumor cells (EnVision staining × 100) H&E, hematoxylin and eosin.

Based on the clinical examination, laboratory investigations, and imaging findings, an initial clinical diagnosis of parathyroid adenoma was made. Differential diagnoses that were considered included parathyroid, metastatic, and medullary thyroid carcinomas. The patient underwent surgery for the parathyroid adenoma, during which intraoperative frozen pathological examination was performed. Intraoperative findings showed a firm, ill-defined mass measuring approximately 2.5 × 2.5 × 2.0 cm in the left lower pole of the thyroid gland. The lesion adhered significantly to the surrounding tissues and encased the recurrent laryngeal nerve. Frozen pathological examination showed evidence of malignancy; therefore, radical parathyroidectomy was performed. The patient underwent resection of the left lower parathyroid gland, left lobe of the thyroid gland, and isthmus, along with lymph node dissection of the anterior larynx, pretrachea, and left central region.

Pathological examination

Gross observation of the resected specimen showed that the tumor measured approximately 2.5 × 2.3 × 2.0 cm. Demarcation from the surrounding tissues was unclear. Capsules were observed in some areas, and the cut surface was grayish and grayish red, solid, hard in nature, and focally appeared to be lobulated. Microscopically, the tumor grew infiltratively (Fig. 1b) with thick fibrous connective tissue septa (Fig. 1c). Necrosis, calcification, and an intravascular tumor thrombus were observed in the focal area (Figs 1d, e). Tumor cells showed greater atypia and were mostly principal cells of more than moderate size with round-to-oval nuclei, rough and dense chromatin, prominent nucleoli (Fig. 1f), and presence of mitotic figures (Fig. 1g) in every 10–12 cells per 50 high-power fields (HPF), along with atypical mitotic figures. Immunohistochemistry showed that broad-spectrum cytokeratin pan (PCK), cytokeratin 7 (CK7), cytokeratin 19 (CK19), cyclin D1 (Fig. 1h), and transcription factor GATA-3 (GATA-binding factor 3, GATA-3, Fig. 1i) were positive, while thyroid transcription factor-1 (TTF-1), calcitonin (CT), paired box protein 8 (PAX 8), thyroglobulin (TG), synaptophysin (Syn), chromogranin A (CgA) were negative. Additionally, Ki-67 expression was approximately 10%. Based on the histopathological and immunohistochemistry findings, a pathological diagnosis of PC was made.

Follow-up

PTH and serum calcium and alkaline phosphatase levels returned to the reference range postoperatively. The patient was followed up for 4 months, during which he was tumor-free and did not suffer from any complications.

DISCUSSION

PC is a very rare endocrine tumor derived from parathyroid cells, accounting for approximately 0.005% of malignant tumors (1). It can occur in individuals of all ages, with a mean age of approximately 45–55 years, and has no sex predilection (3). The majority of the patients present with a palpable mass in the neck, often accompanied by hyperparathyroidism, which manifests as elevated serum calcium levels, fatigue, malignancy, vomiting, polyuria, and polydipsia (4). Patients often experience renal and skeletal complications due to hypercalcemia (4), and only 3% of patients have been reported to have insignificant clinical symptoms (5). In our case, the patient was 35 years old, which is a relatively young age, and had no clinical manifestations.

The etiology of PC remains unconfirmed. Inactivating mutations of the CDC73 gene are the most important mutations currently associated with PC. These mutations have been strongly correlated with PC-associated hyperparathyroidism-jaw tumor syndrome and approximately 70% of sporadic PCs (6). Mutations in CDC73 lead to loss of expression of the corresponding protein, which in turn promotes tumorigenesis (6). Nonaka et al. (7) reported that the Gcm2 gene has a major role in regulating parathyroid gland growth and is highly specific for normal and diseased parathyroid tissues; thus, it may be an important marker for investigating the pathogenesis of PC. With technological advancements and deepening of research in recent years, CCND1, RB1, HRPT2, and other gene mutations have also been found in some PCs (8).

Ultrasound, computed tomography, and magnetic resonance imaging are the most commonly used imaging modalities for parathyroid tumors. Signs suggestive of possible malignancy include a maximum tumor diameter >3 cm, aspect ratio >1, irregular margins, and infiltration of surrounding tissues (9). It is worth noting that some PCs have imaging features similar to those of other parathyroid tumors, including small tumor size (<3 cm) and heterogeneous parenchymal echoes, which makes it difficult to differentiate between the two. For example, in the present case, benign parathyroid tumors were considered first, based on the ultrasound and computed tomography findings of the lesion. Regarding laboratory investigations, PTH, serum calcium, and alkaline phosphatase levels are significantly increased in most cases. The possibility of PC should be considered when the tumor is >3 cm and the serum calcium level is >12 mg/dL (>3 mmol/L) (4).

Thick fibrous septa are common histopathological findings in the tumor, and the cells are arranged in solid and patchy patterns. Most principal cells show rough and hyperchromatic nuclei, prominent nucleoli, increased mitotic figures, and atypical mitotic figures. Eosinophils predominate in a few cases (10). Definitive invasive growth or distant metastasis is necessary for the diagnosis of PC (11). Infiltrative growth includes tumor invasion of surrounding tissues and organs or invasion of capsules, extracapsular vessels, and nerves (11). In addition, tumor necrosis, increased cellular atypia, increased mitotic figures (>5/50 HPF), and the presence of atypical mitotic figures suggest the possibility of PC (12). However, cancer cannot be directly diagnosed, and adequate sampling must be performed to identify the presence of invasive growth or metastasis in such cases.

Immunohistochemically, PC shows positive expression of PCK, CK19, PAX 8, PTH, and GATA-3, along with upregulation of Ki-67. Positive expression of neuroendocrine markers, such as Syn and CgA, but not TG, CT, and TTF-1, has also been reported in some cases. Among these markers, positive expression of GATA-3 and Ki-67 expression >5% are suggestive of malignancy (13). In addition, PC can result in high levels of cyclin D1 expression due to CCND1 gene mutations (8). In the present case, PTH, GATA-3, and cyclin D1 were positive, and Ki-67 expression was >10%, which was consistent with the previous reports.

Based on the clinical manifestations and histological features of PC, the entities that must be differentiated from PC include the following: 1) parathyroid adenoma: PTH, serum calcium, and alkaline phosphatase levels are elevated in most parathyroid tumors, like PC (11). Histologically, atypical parathyroid tumors, which are a subtype of parathyroid tumors, have similar morphological characteristics to those of PC, including increased atypia of tumor cells, thickened chromatin, prominent nucleoli, and atypical mitotic figures (11). These clinical and pathological features make differentiation between the two entities very challenging. Distinction is focused on clear infiltrative growth or metastasis of PC, which is not characteristic of parathyroid adenoma. In addition, GATA-3 positivity, increased Ki-67 expression (>5%), and loss of CDC73 suggest PC. 2) Metastatic clear cell renal cell carcinoma: the cytoplasm of tumor cells in PC may be weakly eosinophilic to hyaline, similar to findings in clear cell renal cell carcinoma. Partially clear cell renal cell carcinoma has been reported to metastasize to the parathyroid gland (14). Both PC and clear cell renal cell carcinoma express PAX 8 and renal cell carcinoma marker (15). However, renal cell carcinoma specifically expresses carbonic anhydrase IX. Moreover, PTH and serum calcium levels are not elevated in renal cell carcinoma, which can aid in distinguishing this entity from PC. 3) Medullary thyroid carcinoma: a malignant tumor originating from C cells with diverse histological morphology (16). These tumors are often immersed in the surrounding organs and tissues, and some cells have eosinophilic or clear cytoplasm, which must be differentiated from PC (10, 16). Differentiating features include the presence of amyloid deposits in the stroma of the medullary thyroid carcinoma and CT positivity, whereas PC is PTH-positive (16, 17).

Surgical treatment is preferred for PC; if necessary, the ipsilateral thyroid gland can be removed to prevent tumor dissemination; the key to performing this surgery lies in achieving negative margins (17). Lymph node metastasis is 7.5 times more likely to occur in PCs with a maximum diameter >3 cm compared to other PCs, but lymph node metastasis is not significantly associated with patient prognosis (18). The 5- and 10-year survival rates of PC have been reported to range from 77–100% and 49–91%, respectively (19). A 36-year study reported that factors associated with PC prognosis include age (>65 years), serum calcium level (>15 mg/dL), and vascular invasion (20). In our case, the patient underwent removal of a parathyroid tumor and ipsilateral thyroidectomy, along with lymph node dissection. After a 4-month follow-up, PTH and serum calcium levels returned to normal, and the patient reported no complications.

In conclusion, PC is a very rare, low-grade malignancy. Clinical signs, imaging, and laboratory findings may suggest a diagnosis of PC, but the final diagnosis needs to be confirmed based on the characteristic histological morphology (invasive growth or metastasis). PC progresses slowly, and surgical resection is the preferred treatment. The main cause of death in patients with PC is severe renal and cardiac diseases caused by hypercalcemia (4). The etiology of PC remains unclear, and more cases need to be collected for systematic review and analysis in the future.

Conflict of interest

The authors declare that they have no conflict of interest.