Parathyroid carcinoma is a rare endocrine malignancy that presents with parathyroid hormone-dependent hypercalcemia. There are no known risk factors for parathyroid carcinoma. The diagnosis of parathyroid carcinoma is a challenge as the clinical presentation is like primary hyperparathyroidism. It is often misdiagnosed as benign parathyroid adenoma.
Parathyroid carcinoma is often recognized intra-operatively or during histopathological testing. Often the diagnosis is made after local recurrence or distant metastasis. Here we describe a case of parathyroid carcinoma in a patient who underwent initial en bloc resection, followed by a symptom-free period without any recurrence.
A 52-year-old woman with a past medical history of morbid obesity presented for a follow-up visit after a laparoscopic sleeve gastrectomy. She was doing well and denied any active complaint. She was vitally stable, and the physical exam was unremarkable. Laboratory work showed hypercalcemia (calcium 14.4 mg/dl—normal: 8.5-10.5 mg/dl), elevated parathyroid hormone (PTH) level (200.5 pg/ml—normal: 10-55 pg/ml), low phosphorus (2 mg/dl—normal: 2.8-4.5 mg/dl), and elevated alkaline phosphatase activity. The patient underwent ultrasound of the neck, which showed a cystic lesion adjacent to the right thyroid lobe. Further investigation with sestamibi (MIBI) parathyroid scintigraphy showed increased radiopharmaceutical uptake by the right superior parathyroid gland without any enlarged or suspicious lymph nodes (Figure 1).
The patient was diagnosed with primary hyperparathyroidism and was evaluated by the surgery team. She underwent right superior parathyroidectomy along with en bloc right thyroid lobectomy due to high suspicion of parathyroid carcinoma intra-operatively. The histological examination revealed anaplastic regions with mitotic activity, giant cells with abundant cytoplasm, and polymorphous nuclei with a Ki-67 labeling index of 10%, consistent with parathyroid carcinoma. She was diagnosed with parathyroid carcinoma with local invasion of the right thyroid lobe.
She was referred for genetic testing. Hyperparathyroidism 2 gene (also known as gene HRPT2/CDC73) mutation was negative. On subsequent follow up, she underwent a PET/CT scan skull to mid-thigh, which showed increased uptake of radiotracer in the left thyroid lobe with no discrete abnormality on unenhanced CT images. There was no concern of F-fluorodeoxyglucose (FDG)-avid distant metastatic disease (Figure 2).
She was followed by endocrinology with repeat lab work for calcium, phosphorus, PTH, and vitamin D levels. All follow-up lab work was within normal limits and the patient remained asymptomatic postoperatively.
Parathyroid carcinoma is a rare endocrine malignancy with an indolent but progressive course. The incidence of parathyroid carcinoma is about 5% and it accounts for less than 1% percent of cases of sporadic primary hyperparathyroidism.1,2 Parathyroid carcinoma is usually diagnosed in the fourth or fifth decade of life and is equally distributed in both sexes.3 There are no known causes for most parathyroid tumors.
Family history of parathyroid tumor or familial isolated hyperparathyroidism, history of multiple endocrine neoplasia, or history of the hereditary hyperparathyroidism-jaw tumor syndrome increases the risk of developing parathyroid tumors and parathyroid cancer.4–7 There are some reports of increased incidence in patients with history of neck irradiation.3 There are also some reports of parathyroid carcinoma in patients with adenoma or hyperplastic parathyroid gland and in patients with hyperparathyroidism secondary to chronic renal failure and celiac disease.8,9 Some oncogenes and tumor-suppressor genes, such as retinoblastoma (Rb), breast carcinoma susceptibility (BRCA2), cyclin Dl/parathyroid adenomatosis gene 1 (PRAD1/CCND1), and HRPT2/CDC73 have been linked to parathyroid carcinoma.10,11
The clinical presentation of parathyroid carcinoma is similar to parathyroid adenoma and is characterized by signs and symptoms of severe hypercalcemia due to increased secretion of PTH. Symptoms may include fatigue, muscle weakness, weight loss, anorexia, nausea, vomiting, polydipsia, polyuria, bone pain, fractures, and renal colic. More than 70% of patients will have palpable neck mass on presentation.1 Renal involvement with impaired renal function, nephrolithiasis or nephrocalcinosis are present in 80% of patients.1 Ninety percent of patients have bone involvement with diffuse osteopenia, osteitis fibrosa cystica, or subperiosteal resorption.1 Less than 5% of patients will present with involvement of regional lymph nodes or distant metastasis.1 Rarely, parathyroid carcinoma can be nonfunctional (< 2% of cases) and can present as palpable neck mass with dysphagia or hoarseness (due to recurrent laryngeal nerve paralysis).12 It can therefore be misdiagnosed as thyroid or thymus disorder and is associated with poor prognosis.13 Parathyroid carcinoma is characterized by an elevation of calcium and PTH levels. Alkaline phosphatase is higher in patients with parathyroid carcinoma than in those with primary hyperparathyroidism.14 In summary, parathyroid carcinoma should be suspected in patients in their fifties with severe hypercalcemia (> 14mg/dl), markedly elevated PTH, with or without palpable neck mass, and renal or bone involvement.
The diagnosis of parathyroid carcinoma is challenging, especially in the absence of local or distant metastasis. There is no definitive diagnostic marker for parathyroid carcinoma; therefore, it is often misdiagnosed as benign parathyroid adenoma. On gross pathology, parathyroid carcinomas are large (more than 3 cm), grayish-white, irregular, and hard tumors, adherent to adjacent tissues.15,16 Parathyroid adenomas in comparison are soft, oval, and brown. Schantz and Castleman have established histopathological criteria for the diagnosis of parathyroid carcinoma. These criteria include the presence of fibrous capsule or trabeculae, rosette-like cellular architecture, the presence of mitosis, and the presence of capsular or vascular invasion.17 Immunohistochemistry can aid in the diagnosis of parathyroid carcinoma. Increased expression of the cell cycle–associated antigens Ki-67 and cyclin D1, and decreased expression of inhibitor of cyclin-dependent kinase p27, and abnormal expression of galectin-3 are associated with increased likelihood of carcinoma.18–21 Genetic testing for mutation in HRPT2/CDC73 and abnormalities in the HRPT2/CDC73 gene product parafibromin can also aid in the diagnosis of parathyroid carcinoma.22,23
The only curative treatment for parathyroid carcinoma is surgery, en bloc resection of the parathyroid mass along with the ipsilateral thyroid lobe, adjacent adherent structures, and central compartment lymphadenectomy.1 Conservative resection of only the parathyroid mass is associated with high risk of capsule rupture, spillage of tumor cells, and local recurrence of the tumor.13 Chemotherapy has not shown effectiveness in the management of parathyroid carcinoma.2 Studies at the Mayo Clinic and the MD Anderson Cancer Center have demonstrated some evidence of benefits of adjuvant radiotherapy in parathyroid carcinoma.24,25 The local recurrence of parathyroid carcinoma is common after resection in up to 50% of cases. Most recurrences occur 2-3 years after the initial resection. Management of the recurrence is surgery.1 The 5-year survival rate is about 80%.26
Parathyroid carcinoma is a diagnostic challenge due to its rarity and the absence of definitive diagnostic criteria. Often it is diagnosed late, after it has locally recurred or distantly metastasized. Clinical suspicion is warranted in patients with severe hypercalcemia and markedly elevated PTH, with or without palpable neck mass, and renal or bone involvement. It is imperative to recognize parathyroid carcinoma early because the initial en bloc resection is the only curative approach. Recent attempts at early diagnosis using genetic and immunohistological testing look promising, but more needs to be done in this field.
FNU Manas: Writing—original draft
S Mandal: Writing—review and editing
B Mols-Kowalczewski: Conceptualization and supervision
The authors have no funding sources to report.
Consent to Publish
Patient details have been de-identified. Therefore, consent for publication by the patient was not required.
Disclosure of Interest
The authors declare they have no competing interests.
An abstract on this case report is appears as Mandal S, Bethala MG, Mols-Kowalczewski, B. A case report on parathyroid carcinoma - an extremely rare endocrine malignancy. J Endocr Soc. 2021;5(suppl 1):A986-A987. https://doi.org/10.1210/jendso/bvab048.2018