Parathyroid carcinoma: Three case reports

Abstract

BACKGROUND

Parathyroid carcinoma (PC) is a rare, slow-growing malignant tumor and a rare cause of primary hyperfunctioning of the parathyroid, with a highly variable clinical course, depending on the aggressiveness of the individual tumor and the degree of hypercalcemia.

CASE SUMMARY

The aim of this report is to summarize the diagnosis and treatment of three cases of PC and to review and conclude aspects regarding the three collected cases with reference to other relevant cases to explore the value of ultrasound in the diagnosis of PC. All three patients had hypercalcemia, consisting of a high serum calcium level and a high level of parathyroid hormone that was > 2-fold (even > 30-fold) of the normal upper limit. The ultrasonographic findings of the parathyroid gland showed that the glands were all > 30 mm, and the internal echo was uneven. All patients underwent surgery. PC in three cases was confirmed by routine histopathology and immunohistochemistry.

CONCLUSION

As clinical signs and laboratory results are nonspecific, it is difficult to diagnose PC preoperatively, so imaging examinations are often needed.

Key Words: Parathyroid carcinoma, Parathyroid adenoma, Ultrasound, Parathyroid hormone, Primary parathyroid hyperfunction, Case report

Core tip: Parathyroid carcinoma (PC) is a rare malignant tumor with a highly variable clinical course, depending on the aggressiveness of the individual tumor and the degree of hypercalcemia. As clinical signs and laboratory results are nonspecific, it is difficult to diagnose PC before surgery, so relevant imaging examinations are often needed. The aim of this report is to summarize the diagnosis and treatment of three cases of PC and to review and conclude aspects regarding the three collected cases with reference to other relevant cases to explore the value of ultrasound in the diagnosis of PC.

INTRODUCTION

Parathyroid carcinoma (PC) is a rare endocrine carcinoma that accounts for approximately 0.005% of all cancers and has an annual incidence of < 0.001%[1-4]. The main clinical features are hypersecretion of parathyroid hormone (PTH) and high serum calcium. PC has no clear diagnostic criteria, lacks specific manifestations, and is difficult to distinguish from parathyroid adenoma (PA) or hyperplasia. PC should be highly suspected if the serum calcium level exceeds 3.5 mmol/L, PTH exceeds 2-5 times the upper limit of normal, or the tumor touches the neck or is accompanied by vocal cord paralysis, or bone, kidney or other related manifestations[5]. In this study, ultrasound images of three patients with pathologically confirmed PC are summarized, and related literature was reviewed to explore the value of ultrasound in the diagnosis of PC.

CASE PRESENTATION

Chief complaints

Case 1: A 59-year-old man had a neck mass detected 10 d previously.

Case 2: A 28-year-old woman presented with weakness in the left lower limb.

Case 3: A 65-year-old woman presented with a neck mass that was noticed 6 mo previously and that had recently gradually increased in size.

History of present illness

Case 1: No tenderness was observed.

History of past illness

Case 1: Blood sugar control was satisfactory, and the patient had a history of diabetes for > 3 years.

Case 2: The patient had a 3-year history of kidney stones and presented with lumbago with pain.

Case 3: None.

Laboratory examinations

Case 1: Serum calcium level was 2.78 mmol/L (normal range 2.11-2.52 mmol/L), and PTH was 207.6 pg/mL (normal range 12.3-88.3 pg/mL).

Case 2: Serum calcium was 3.47 mmol/L, and PTH was 2723 pg/mL.

Case 3: Serum calcium was 3.19 mmol/L, and PTH was 1388 pg/mL.

Imaging examinations

Case 1: Doppler ultrasound revealed a 3.9 cm × 3.5 cm × 2 cm regularly shaped complex nodule (with mixed echogenicity); that is, with solid and fluid components at the lower pole of the thyroid on the right side. The boundary between the nodule and the thyroid parenchyma was unclear (Figure 1A). Color doppler flow imaging (CDFI) indicated multiple blood flow signals in the internal solid part and around the nodule (Figure 1B). Computed tomography (CT) displayed circular shadow density at the lower pole of the right thyroid gland with a clear boundary. Mild-to-moderate enhancement was observed around the lesion, but no obvious enhancement was detected inside the lesion.

Figure 1 Parathyroid carcinoma of the lower pole of the thyroid on the right side in a 59-year-old man. A: Doppler ultrasound revealed a complex nodule (with mixed echogenicity), i.e., with solid and fluid components; B: Color doppler flow imaging indicated punctate blood flow signals were detected in the solid part of the nodule and its periphery; C: The neoplastic chief cells of the parathyroid glands were arranged in solid sheets, nests and acini, indicating diffuse infiltrative growth.

Case 2: Doppler ultrasound revealed a 5.4 cm × 4.4 cm × 2.8 cm regularly shaped solid nodule with small internal cystic foci in the lower right lobe of the thyroid gland. The nodule had a clear boundary (Figure 2A). CDFI revealed multiple blood flow signals in the solid part of the nodule (Figure 2B).

Figure 2 Parathyroid adenocarcinoma of the lower right lobe of the thyroid gland in a 28-year-old woman. A: Doppler ultrasound revealed a solid nodule with small internal cystic foci; B: Color doppler flow imaging indicated multiple streaks of blood flow signals were observed in the solid part of the nodule; C: Parathyroid chief cells with neoplastic hyperplasia; some of the tumor cells were atypical, and the tumor capsule was of different thicknesses with focal capsule invasion.

Case 3: Doppler ultrasound revealed a 3.2 cm × 2.6 cm × 2.4 cm, irregularly shaped, solid nodule with an inhomogeneous echo-structure at the lower right lobe of the thyroid gland. The boundary was unclear, and the internal echo was uneven (Figure 3A). CDFI indicated multiple blood flow signals within the nodule (Figure 3B). Several lymph nodes were detected on the right side of the neck; the larger lymph node was 1.3 cm × 0.5 cm, with poorly defined boundaries and no tenderness. A CT scan revealed an oval low-density lesion with a clear boundary in the middle and lower lobes of the right thyroid gland.

Figure 3 Parathyroid adenocarcinoma of the lower right lobe of the thyroid gland in a 65-year-old woman. A: Doppler ultrasound revealed a solid nodule with an inhomogeneous echostructure; B: Color doppler flow imaging indicated multiple spots and strips of blood flow signals were observed in the nodules; C: Parathyroid tumor with an unclear local capsule. A vascular tumor thrombus can be seen.

Intraoperative findings and immunohistochemistry

Case 1: A 3.5 cm × 3.0 cm × 2 cm mass was observed under the right thyroid gland, which was closely associated with the surrounding tissues. The mass surface was smooth, and the envelope was complete with a variable thickness. The section was a solid cyst. The cystic part was multilocular, the inner wall of the sac was smooth, and the solid part was grayish-red, soft and brittle. The parathyroid neoplastic master cells were arranged in a solid flaky-like, nest-like, acinar pattern with diffuse infiltrating growth that invaded a nerve and locally infiltrated but did not penetrate the capsule. A small amount of thyroid tissue was seen in the tumor margin focus (Figure 1C). Immunohistochemistry revealed PTH (+), calcitonin (-), carcinoembryonic antigen (-), chromogranin A (CgA) (+), synaptophysin (Syn) (-), thyroid transcription factor-1 (TTF-1) (-), thyroglobulin (Tg) (-) and Ki67 (1%).

Case 2: An enlarged parathyroid gland (6 cm × 4 cm × 3 cm) was observed below the right thyroid gland during the operation. The general surface of the nodule was smooth, the capsule was intact, and the section surface was dark red, multinodular and soft. The main cells of the parathyroid gland were neoplastic and hyperplastic, and coarse fiber segmentation was seen in the tumor. Some tumor cells were atypical, with mitotic images of approximately 2/50 per high-power field (HPF). The tumor envelope was of different thicknesses, and the tumor had invaded the envelope. The blood vessels had invaded the thyroid, and a tumor plug was seen in the blood vessels (Figure 2C). Immunohistochemistry revealed PTH (+) and Ki67 (4%).

Case 3: A 3.4 cm × 2.4 cm × 2.2 cm mass was found at the lower pole of the right thyroid gland, which had adhered to the surrounding esophageal and recurrent laryngeal nerves. The general surface was smooth, the envelope was relatively complete, and the section surface was grayish-brown, soft and slightly brittle. The local envelope of the tumor was not obvious, there were visible mitoses (< 2/10 HPF), and the tumor had invaded the thyroid tissue (Figure 3C). Immunohistochemistry revealed PTH (+), calcitonin (-), cytokeratin pan (+), cytokeratin19 (+), CgA (+), neural cell adhesion molecule (NCAM; CD56) (-), Syn (weak +), TTF-1 (-), Tg (-) and Ki67 (5%).

FINAL DIAGNOSIS

Case 1: The patient was pathologically diagnosed with highly differentiated PC (low grade).

Case 2: The pathological diagnosis was parathyroid adenocarcinoma.

Case 3: The lesion was pathologically diagnosed as parathyroid adenocarcinoma.

TREATMENT

Case 1: The right inferior pole of the parathyroid and the right thyroid were resected.

Case 2: The right parathyroid lesion was resected.

Case 3: The right parathyroid gland was explored, the right parathyroid lesion, the right thyroid and the isthmus were resected, and a regional lymphadenectomy was performed.

OUTCOME AND FOLLOW-UP

Case 1: The 5-year follow-up did not show residual–recurrent disease.

Case 2: The 1-year follow-up did not show residual–recurrent disease.

Case 3: The 1-year follow-up did not show residual–recurrent disease.

DISCUSSION

PC is a rare, slow-growing malignant tumor and a rare cause of primary hyperfunctioning of the parathyroid (PHPT), with an incidence of 0.5%-7.0%[6,7]. Approximately 95% of PC tumors are functional and clinically manifested by various symptoms and signs caused by excessive secretion of PTH and hypercalcemia, including moderate to severe hypercalcemia (a parathyroid crisis may occur in some patients), kidney stones, renal calcinosis, osteoporosis, osteitis cystic fibrosis, brown tumors, fractures, constipation, abdominal pain, peptic ulcers and pancreatitis[8,9]. The PTH and serum calcium were increased in these three patients, and PTH was 2.35, 30.84 and 15.72 times the upper limit of normal, respectively. Case 2 presented with osteoporosis and recurrent kidney stones. Cases 1 and 3 presented at the clinic for painless anterior neck masses. It has been reported that 30%-76% of patients with PC have a palpable mass in the neck[10], which is uncommon in patients with PA. PC is considered a slow-growing malignant tumor with a highly variable clinical course, depending on the aggressiveness of the individual tumor and the degree of hypercalcemia. As clinical signs and laboratory results are nonspecific, it is difficult to diagnose PC before surgery, so relevant imaging examinations are often needed.

A variety of techniques can be used to image the parathyroid gland, including ultrasound, methoxy isobutyl isonitrile (MIBI) imaging, CT and magnetic resonance imaging (MRI). Ultrasound is the first choice to accurately assess the size of a tumor without radiation and at a low cost and has significant value for detecting parathyroid disease. Studies have shown that ultrasound has a sensitivity of 67%-96% and a positive predictive value of 82%-98% in patients undergoing PHPT surgery[11-14]. The ultrasonographic findings of normal parathyroid glands are oval hypoechoic or hyperechoic nodules with a maximum diameter of 4-7 mm, clear boundaries and a uniform echo. PC is usually larger, lobulated, hypoechoic, heterogeneous and ill-defined compared with PA. A high positive predictive value is obtained when the parathyroid lesion is > 30 mm, calcified, and has an unclear boundary with the surrounding tissue[15,16]. In this group of three patients, the tumors were > 30 mm, and the internal echo was uneven. In cases 1 and 2, the tumors were cystic and solid, and in cases 1 and 3, the tumors had unclear boundaries with the surrounding tissue, which was consistent with malignant signs. However, ultrasound has some limitations. Parathyroid diseases can be difficult to distinguish from thyroid nodules and lymph nodes, so the clinical manifestations and a laboratory examination should be combined for identification. In addition, when the parathyroid lesion is cystic, it should be distinguished from other cystic neck lesions. For cystic neck lesions, close attention should be paid to the age of presentation, lesion location, and association with surrounding structures[17,18]. If located on the midline, the differential diagnosis narrows to thyroglossal duct cysts, ranulas or dermoid cysts. Off-midline lesions can be, instead, branchial cleft cysts or lymphangiomas[17]. Due to interference by the sternum and clavicle, ultrasound examination of hypolocated parathyroid tumors or ectopic parathyroid tumors in the retropharyngeal space or mediastinum is limited, so other imaging examinations are needed. Tc-99 m-MIBI is widely used to localize parathyroid tumors, but there is no significant specificity between benign and malignant parathyroid diseases. CT and MRI have limited diagnostic value in patients with parathyroid disease but can be used to assess cervical lymph node status, detect ectopic parathyroid tumors and assess preoperative risk[19].

There are some difficulties when preoperatively and intraoperatively diagnosing PC. Fine-needle aspiration can be used to distinguish thyroid from parathyroid tissues, but it has limited value in the differential diagnosis of benign and malignant parathyroid tumors and may cause local dissemination and implantation of tumors, so it is not recommended[20,21]. Because the histopathological features of PC may overlap with PA, an intraoperative rapid frozen pathological examination has been demonstrated to lack reliability. Therefore, postoperative pathological examination of the lesion is the gold standard for diagnosing PC. PC is pathologically diagnosed if the tumor is invasive, such as in the capsule, blood vessels or nerves, or has local or distant metastasis[22].

Surgical excision is an effective method to treat PC, and the standard of treatment is total excision of the tumor and surrounding tissues[20]. Selective cervical lymph node dissection is also necessary when the cervical lymph nodes are involved. However, the necessity of prophylactic septal lymphadenectomy remains controversial[23]. In this study, all three patients underwent surgical resection of the diseased parathyroid gland combined with resection of the affected thyroid gland. PC is an indolent, slowly progressive cancer since the tumor has a low malignant potential. Few patients initially present with regional lymph node involvement (< 5%) or with distant metastatic disease (< 2%)[24]. PC can recur 2-5 years after the initial operation, and the local recurrence rate within 5 years is 33%-82%[25]. The prognosis mainly depends on whether the tumor is completely removed during the first operation. Most patients do not die from the tumor disease burden since it is slow growing. Instead, most patients with metastatic disease die from complications of hypercalcemia[26,27]. Consequently, postoperative serum calcium and PTH monitoring are also important to detect whether the tumor was completely removed and whether there is early recurrence and metastasis. This especially applies to serum calcium levels, since most of these patients are highly susceptible to hungry bone syndrome. They require regular monitoring of their calcium and PTH levels every 3 mo for up to 1 year to evaluate for recurrence[28]. If the levels remain stable at this point, the duration between laboratory assessments can gradually be increased.

CONCLUSION

PC is a rare head and neck malignant tumor. Significant increases in serum calcium and PTH should be warning signs of a mass in the neck. The best surgical method should be selected to improve the survival rate of patients.