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Conditions

Parathyroid carcinoma

Parathyroid carcinoma is a rare endocrine malignancy that usually occurs sporadically, though it is sometimes part of a wider hereditary condition.

Overview

Parathyroid carcinoma is a rare endocrine malignancy and accounts for less than 1% of cases of primary hyperparathyroidism (PHPT). The majority of cases of parathyroid carcinoma present sporadically, but it can also occur as part of a hereditary condition, most frequently due to constitutional (germline) pathogenic variants in the CDC73 gene.

Clinical features

Parathyroid carcinoma frequently presents with signs and symptoms related to marked hypercalcaemia and PHPT. Asymptomatic presentations are very rare. Typical features may include:

  • bone and muscle pain;
  • weakness;
  • renal colic due to kidney stones and/or nephrocalcinosis;
  • fractures due to osteoporosis; and
  • features related to marked hypercalcaemia, including neuropsychiatric features or acute pancreatitis, which can lead to an acute presentation.

In addition, the finding of a palpable neck mass with biochemical features of severe PHPT should raise a suspicion of parathyroid carcinoma.

In contrast to sporadic PHPT due to benign parathyroid adenoma or hyperplasia, in which a marked female predominance is observed, parathyroid carcinoma is reported to have an equal sex distribution.

Biochemical findings

  • The biochemical findings of parathyroid carcinoma are typically that of marked hypercalcaemia (for example, albumin adjusted serum calcium over 3.0mmol/l and often over 3.4mmol/l) and marked elevation in parathyroid hormone (PTH) (for example, over four times the upper limit of normal).
  • Elevations in alkaline phosphatase may also be observed.

Imaging

  • Pre-operative imaging with ultrasound, 99mTc-sestamibi imaging SPECT/CT scans (MIBI) and/or 4D-CT scans are used for localisation studies.
  • Large tumour size (for example, over 3cm) increases the probability of parathyroid carcinoma (although a significant proportion of parathyroid carcinomas are smaller than 3cm), while specific radiological features (such as calcification, or evidence of local invasion or infiltration of adjacent tissue) may be suggestive of parathyroid carcinoma.

Diagnosis

  • There remains considerable overlap in clinical presentation between benign causes of PHPT (such as parathyroid adenoma) and parathyroid carcinoma – such that establishing a diagnosis pre-operatively is frequently not possible (unless, for example, there is evidence of local invasion, metastases on preoperative imaging).
  • The diagnosis of parathyroid carcinoma is made on histopathological grounds, with evidence of capsular and adjacent soft tissue invasion, or clinically in the presence of local or distant metastases.

Clinical associations

  • Parathyroid carcinoma most commonly occurs as an apparently sporadic condition affecting a single parathyroid gland.
  • Hereditary forms of parathyroid carcinoma relating to constitutional (germline) CDC73 pathogenic variants (see below) include a small percentage of individuals with familial isolated hyperparathyroidism (FIHP) and 10%–15% of patients with hyperparathyroidism jaw tumour (HPT-JT) syndrome who then develop parathyroid carcinoma.
  • HPT-JT is a rare multiple-tumour condition characterised by PHPT (including benign parathyroid adenoma and parathyroid carcinoma), ossifying fibromas of the jaw and/or mandible and additional benign and malignant tumours including renal and uterine lesions.
  • Very rare instances of parathyroid carcinoma have been reported in patients with multiple endocrine neoplasia type 1 and multiple endocrine neoplasia type 2a, and cases have been reported in FIHP kindreds associated with apparent pathogenic GCM2 variants, although further evidence is required to support this association.

Genetics

Inactivation of the gene CDC73 is the major known genetic driver of parathyroid carcinoma. Constitutional (germline) heterozygous CDC73 pathogenic variants account for individuals and kindreds with HPT-JT syndrome as well as those with CDC73-associated FIHP. In addition, 20%–40% of patients with apparently sporadic parathyroid carcinoma are observed to carry constitutional (germline) pathogenic CDC73 variants.

In these settings, parathyroid carcinoma typically demonstrates bi-allelic inactivation of the CDC73 locus, with a constitutional (germline) variant accounting for inactivation of one allele and a somatic event (such as a large-scale deletion or an inactivating variant) resulting in loss of function of the second allele. Bi-allelic somatic inactivation of the CDC73 gene is reported in 40%–60% of sporadic parathyroid carcinomas.

The CDC73 gene encodes the tumour suppressor parafibromin, a ubiquitously expressed protein implicated in transcriptional or epigenetic regulation through membership of the human RNA polymerase II-associated factor (PAF) complex, as well as an important modulator of several cell signalling pathways.

For information about genomic testing, see Presentation: Patient with parathyroid carcinoma.

Inheritance and genomic counselling

  • FIHP and HPT-JT are inherited in an autosomal dominant pattern.
  • Patients with apparently sporadic parathyroid carcinoma or FIHP identified as carrying pathogenic CDC73 variants should be followed up as per recommendations for individuals with HPT-JT (that is, surveillance for HPT-JT-associated tumours).
  • It is important to note that while the penetrance of PHPT in those with constitutional (germline) pathogenic variants in the CDC73 gene is 60%–90%, only 10%–15% will develop parathyroid carcinoma.
  • The penetrance of the other clinical features in HPT-JT is variable (for example, 30% for ossifying fibromas of the jaw or mandible) – such that affected kindreds may be labelled as FIHP, or there may be an absence of relevant family history.
  • Recent studies indicate that high-impact CDC73 constitutional (germline) pathogenic variants (that is, those predicting marked conformational change in parafibromin and/or loss of parafibromin expression) are associated with an increased risk of parathyroid carcinoma.

Management

Surgery is the mainstay of treatment for parathyroid carcinoma.

  • If a diagnosis of parathyroid carcinoma is suspected or known pre-operatively, radical en bloc resection has been recommended as the gold standard of management, although the extent of surgery is debated.
  • If parathyroid carcinoma is identified in patients undergoing lesser surgical approaches (for example, minimally invasive surgery for presumed benign disease), further surgery should be considered, although the timing and extent of further resection is also debated.
  • Surgery should be performed by a surgeon and/or at a centre with significant experience in parathyroid disease.
  • Surgical debulking of large metastatic lesions has occasionally been employed to assist with control of parathyroid carcinoma-associated hypercalcaemia.

Management of severe hypercalcaemia

  • This requires treatment with intravenous fluids. Diuretics and bisphosphonates may also have a role.
  • Cinacalcet may be effective in reducing PTH and serum calcium levels in some patients with parathyroid carcinoma-associated hypercalcaemia (although not all parathyroid carcinomas express the calcium-sensing receptor).

Other therapies

  • Radiotherapy is not reported to be particularly effective for parathyroid carcinoma and is not widely employed, although a consensus on its use has not been established due to lack of randomised trials.
  • Chemotherapy and immunotherapy have not yet been demonstrated to be effective for treating locally advanced or metastatic parathyroid carcinoma. However, responses to specific molecular- and immune-based treatments are reported in metastatic parathyroid carcinoma, and further studies are required to assess the role of molecular profiling in predicting response to such therapies.

Follow up

  • Patients identified as having parathyroid carcinoma should be followed up indefinitely as there is a risk of recurrence, which is typically characterised by hypercalcaemia.
  • Recurrence typically arises slowly (median time to recurrence is three years, but is sometimes much longer).
  • Subsequent morbidity and mortality are frequently associated with refractory hypercalcaemia.
  • Patients identified as carrying pathogenic constitutional (germline) CDC73 variants should be followed up according to surveillance guidance for HPT-JT syndrome.

Resources

For clinicians

References:

For patients

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  • Last reviewed: 17/08/2023
  • Next review due: 17/08/2025
  • Authors: Dr Paul Newey
  • Reviewers: Dr Ellen Copson, Dr Louise Izatt, Professor Márta Korbonits, Dr Terri McVeigh