INTRODUCTION

Parathyroid carcinoma (PC) is a rare neoplasm, with fewer than 1000 cases reported in the literature since its description by De Quervain in 1904. With an estimated prevalence of 0.005% of all cancers, PC is the rarest endocrine cancer, representing 0.5 to 5% of all cases of primary hyperparathyroidism¹.

Parathyroid carcinoma occurs equally in both sexes, with an average age of onset between 54 and 56 years². PC typically presents as an indolent and slowly progressive course. Most patients present with signs and symptoms of primary hyperparathyroidism and hypercalcemia, including nephrolithiasis, nephrocalcinosis, osteopenia, pathological fractures, gastrointestinal disturbances, fatigue, and depression³. Most cases of parathyroid carcinoma are unilateral. Bilateral cases are exceptionally rare, especially in patients without a history of long-term hemodialysis^1-2. We present a case of bilateral parathyroid carcinoma without a history of hemodialysis.

CLINICAL CASE

A 63-year-old male patient presented with recurrent nephrolithiasis and renal colic for 3 years prior to consultation. Laboratory data showed PTH 522 pg/ml, total calcium: 13 mg/dl, and calciumuria of 650 mg/24h. Cervical ultrasound revealed two mixed nodular images with cystic areas located behind and below the lower pole of each thyroid lobe, suggestive of parathyroid adenomas. The right side measured 4.5 x 2.5 x 1.6 cm, and the left side measured 4.4 x 2.3 x 2.3 cm. Thyroid nodules classified as Thyroid Imaging Reporting and Data System (TI-RADS) 3 were detected in the right thyroid lobe. The patient expressed a preference for a less invasive method than surgery and received percutaneous ethanol injection for both parathyroid glands. Two months later, laboratory data showed PTH 504 pg/ml, total calcium 12.4 mg/dl, and calciuria 858 mg/24h.

A single-photon emission computed tomography (SPECT) scan with sestamibi revealed a positive gammagraphic pattern for two lower left parathyroid adenomas. (Figure 1)

Figure 1.  SPECT with sestamibi 

An ultrasound study indicated an enlarged right thyroid lobe. Additionally, a mixed cystic nodule with regular borders measuring 28 x 21 mm was observed, along with a hypoechoic solid nodule with irregular borders (29 x 17 mm) in the postero-inferior zone and delimited by the thyroid, compatible with a parathyroid nodule. The left thyroid lobe exhibited a mixed nodule measuring 13 mm with regular borders. In the left postero-inferior zone, delimited by the thyroid, another mixed hypoechoic nodule with regular borders measuring 47 x 21 mm was observed, also compatible with a parathyroid nodule. The diagnosis was multinodular goiter and bilateral lower parathyroid nodules. Total thyroidectomy with bilateral parathyroidectomy and resection of bilateral macroscopically lymph nodes at level VI was performed.

Pathological findings showed: 1) Solid right parathyroid tumor measuring 2.5 cm. Microscopically, it was a low-grade infiltrative parathyroid carcinoma, adhered to the thyroid, with extensive stromal fibrosis and capsular invasion (Figures 2 and 3). 2) Solid left parathyroid tumor measuring 1.1 cm. Microscopically, it was a low-grade parathyroid carcinoma with fibrosis and capsular invasion (Figures 4 and 5).

Figure 2.  Low-grade parathyroid carcinoma. On the left, solid tumor composed of small cells. In the center and on the left, a thick fibrous capsule with nests of infiltrating carcinoma. 

Figure 3.  Nest of well-differentiated low-grade carcinoma, round non-atypical cells, without mitosis, indistinguishable from an adenoma except for its infiltrative nature. 

Figure 4.  Low-grade parathyroid carcinoma. On the left, solid tumor composed of small cells with irregular borders. In the center and on the left, a thick fibrous capsule with infiltrative nests. 

Figure 5.  Infiltrative nests of carcinoma, with minimal nuclear atypia, absence of mitosis, peritumoral fibrosis. 

The thyroid gland showed changes consistent with benign multinodular goiter. Regional left (4) and right (2) lymph nodes showed no evidence of metastatic carcinoma.

It was classified as a bilateral low-grade parathyroid carcinoma. TNM staging (8th AJCC edition): Right side T2N0M0 and left side T1N0M0.

One month postoperatively, PTH was 4 pg/ml, total calcium was 8.8 mg/dl, no calcium was detected in urine; at the 10-month follow-up, PTH was 3 pg/ml, total calcium was 9.2 mg/dl (January 2023). The patient remains under active surveillance with no evidence of recurrence.

DISCUSSION

Diagnosis of CP is challenging due to its clinical, radiological, and histological overlap with parathyroid adenoma/hyperplasia, and only unequivocal evidence of local tissue invasion and/or metastasis confirms the diagnosis. However, a higher frequency of hypercalcemia symptoms; palpable neck mass; PTH levels exceeding 500 pg/ml; and total calcium levels above 14 mg/dl are suggestive of carcinoma⁴. The preferred imaging studies for localization are neck ultrasound and sestamibi scintigraphy.⁴

The etiology of CP remains unknown, and there is no evidence of transformation from pre-existing lesions. Nonetheless, there is an increased risk of parathyroid carcinoma in patients with other endocrine neoplasms such as isolated familial hyperparathyroidism and multiple endocrine neoplasia type 1. Several genetic mutations have been proposed in CP, including retinoblastoma (RB), P53, cyclin D1/gene 1 of parathyroid adenomatosis (PRAD1), and BRCA2⁵.

Surgery remains the only intervention offering the potential for curing parathyroid carcinoma. The primary goal of treatment should be complete removal of parathyroid cancer with negative margins. This includes en bloc resection of the primary lesion, ipsilateral thyroid lobectomy, isthmectomy, tracheal skeletonization, and excision of any adherent muscles. Central lymph node dissection is not indicated prophylactically⁶.

Ultrasound-guided percutaneous ethanol injection therapy can reduce calcium and PTH levels by up to 45% in parathyroid adenomas, although studies in carcinomas are not well-established⁷.

While parathyroid adenomas tend to be soft, oval, and reddish-brown in appearance, carcinomas tend to be larger (> 3 cm), white-gray, lobulated, and have a dense fibrous capsule. Adherence or invasion of adjacent structures suggests malignancy. Histological characteristics of parathyroid carcinoma described by Shanz and Castelman include sheets or lobules of tumor cells separated by dense fibrous bands, mitotic figures, necrosis, capsular invasion, and vascular invasion⁸.

Unfortunately, these classical pathological features are not always present in parathyroid carcinoma. Additionally, some of these characteristics, particularly mitotic figures and trabecular architecture, can also be observed in parathyroid adenomas⁹. They are categorized as low or high grade based on pleomorphism, nuclear size variation, prominent nuclear membranes, features closer to or distant from adenomas¹⁰.

Recent reports have recommended postoperative radiation therapy as a strategy to optimize local control, as it appears to effectively reduce local recurrence rates and improve disease-free intervals. However, due to the rarity of the disease, there are no prospective randomized trials, and most of the knowledge so far comes from case reports and small retrospective series, making the role of adjuvant radiotherapy after surgery still unclear^1,11.

Chemotherapy has not been shown to improve survival, disease-free period, or correct hypercalcemia in patients with disseminated or unresectable disease¹².

The AJCC 8th edition tumor classification uses the TNM system for staging; however, there is no specific clinical staging. Complete en bloc tumor resection can achieve survival rates of up to 90% at 5 years and 67% at 10 years¹¹. Negative prognostic factors include lymph node metastasis at the time of diagnosis, distant metastasis, non-functioning carcinomas, tumor size, high mitotic rate¹⁰.

Despite the best efforts, a significant proportion of patients experience recurrence. Recurrence rates of 33% to 78% have been reported in published studies. Most recurrences will manifest within the first 3 years, but recurrences up to 20 years have been reported. Once the disease has recurred, chances of cure are remote¹³.

To our knowledge, this is the first reported case of synchronous bilateral parathyroid cancer in Paraguay.