Teaching pack: Parathyroid carcinoma

Parathyroid carcinoma is a malignant neoplasm of parathyroid chief cells that presents with severe primary hyperparathyroidism: calcium and parathyroid hormone far above adenoma levels, bone disease, kidney stones and renal impairment, and often a palpable neck mass, in contrast to the mild disease of parathyroid adenoma. About a quarter of sporadic cases and nearly all cases in the hyperparathyroidism-jaw tumour syndrome carry inactivating mutations in CDC73 (HRPT2), whose product parafibromin is lost on immunohistochemistry; germline testing is recommended for all patients because of the syndromic association. Preoperative distinction from adenoma is unreliable, so the diagnosis is often made at surgery or pathology.

The only curative treatment is en bloc resection of the tumour with the ipsilateral thyroid lobe and any adherent tissue, avoiding capsular rupture; incomplete initial surgery is the main cause of recurrence, which is usually loco-regional and can be re-resected repeatedly. Radiotherapy and chemotherapy have little proven activity. Because morbidity and death come from hypercalcaemia rather than tumour mass, medical control matters: cinacalcet (a calcimimetic, approved for hypercalcaemia of parathyroid carcinoma), denosumab or bisphosphonates for bone resorption, hydration and, in crisis, dialysis. Rare durable responses to PD-1 inhibitors have been reported in tumours with high mutation burden, and case series describe activity of multikinase inhibitors, but there is no approved systemic anticancer therapy.

• Cinacalcet and denosumab have turned uncontrollable hypercalcaemia, historically the cause of death, into a manageable problem for most patients.
• CDC73 testing identifies the hereditary syndrome and allows surveillance of relatives.
• Reports of checkpoint inhibitor response in high-mutation-burden tumours and of multikinase inhibitor activity point towards genomically guided treatment, no drug is approved for the carcinoma itself, so tumour sequencing and a tumour-agnostic or basket trial are the route to one.
• The WHO 2022 classification tightened histological criteria, separating carcinoma from atypical parathyroid tumours.

1. 1933First clear description of parathyroid carcinoma (Sainton and Millot)
2. 2002HRPT2 (CDC73) identified as the hyperparathyroidism-jaw tumour syndrome gene
3. 2003Somatic and germline CDC73 mutations in sporadic parathyroid carcinoma
4. 2004Cinacalcet approved
5. 2022WHO classification refines carcinoma criteria

• Bone-modifying agents (bisphosphonates, denosumab) (technology)
• Immune checkpoint inhibitors (technology)

• Preoperative diagnosis: no reliable imaging or biochemical threshold, so many patients have inadequate first surgery.
• No effective systemic anticancer therapy for metastatic disease; genomic profiling for actionable alterations and immunotherapy case series are the current approach.
• Rarity precludes randomised trials; international registries are the evidence base.

1. What questions should someone newly diagnosed with triple-negative breast cancer ask before surgery?
   Answer

   Whether chemo-immunotherapy before surgery (KEYNOTE-522) is planned and why; germline BRCA testing; PD-L1 and HER2-low status; TIL score; clinical trial options; fertility preservation; breast-conserving versus mastectomy and sentinel node approach; what response (pCR/RCB) will mean for treatment afterwards.
2. What are the main side effects of checkpoint inhibitors and how are they handled?
   Answer

   Immune-related adverse events such as colitis, thyroid problems, rash, hepatitis, and pneumonitis, most common with CTLA-4 plus PD-1 combinations; treated with steroids and sometimes other immunosuppressants, some endocrine effects are permanent.
3. Who should have germline genetic testing when diagnosed with cancer?
   Answer

   All patients with TNBC, ovarian, pancreatic, or metastatic prostate cancer, increasingly all breast cancer, and anyone with suggestive family history; results change surgery, drug choice (PARP inhibitors), and family screening.

• NCI PDQ: parathyroid cancer: https://www.cancer.gov/types/parathyroid
• NCCN Neuroendocrine and Adrenal Tumors: https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1448
• CDC73 in parathyroid carcinoma (NEJM 2003): https://doi.org/10.1056/NEJMoa031237
• Wikipedia: https://en.wikipedia.org/wiki/Parathyroid_carcinoma
• Guideline: https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1448