Table of Contents
- Key Points
- Background: Why This Rare Cancer Matters
- How the Expert Panel Conducted This Review
- Laboratory Models: Progress and Gaps
- Better Pathology Reporting for Accurate Diagnosis
- Imaging: Finding the Tumor and Monitoring Recurrence
- Surgery: What the Experts Recommend
- Clinical Implications: What This Means for Patients
- Limitations of the Current Evidence
- Recommendations for Patients and Clinicians
- Frequently Asked Questions
- Source Information
Key Points
- Parathyroid carcinoma is a very rare parathyroid cancer causing severe hypercalcemia; it represents about 1% of primary hyperparathyroidism cases.
- About 25% of seemingly sporadic parathyroid carcinomas carry germline CDC73 mutations, so genetic counseling and testing may be recommended.
- Preferred treatment is en bloc resection removing the tumor with the ipsilateral thyroid lobe; preserve the recurrent laryngeal nerve unless cancer surrounds it.
- After surgery, monitor calcium and intact PTH plus neck ultrasound, sestamibi, or 4D CT at 3–6 months.
- No highly effective drug therapy yet exists for recurrent or metastatic disease; targeted and radiolabeled therapies are under investigation.
Background: Why This Rare Cancer Matters
Parathyroid carcinoma (parathyroid cancer) was first described in 1933 by Sainton and Millot. It is one of the rarest causes of primary hyperparathyroidism — a condition where the parathyroid glands produce too much parathyroid hormone (PTH).
Only about 1% of patients with primary hyperparathyroidism have parathyroid carcinoma. However, this cancer tends to cause much more severe symptoms of hypercalcemia (dangerously high calcium levels in the blood) than the benign forms of parathyroid disease, such as adenomas (benign tumors) or hyperplasia (enlargement of the glands).
Parathyroid carcinoma is the least common endocrine cancer worldwide. Still, some reports have noted a higher incidence of this cancer in different parts of the world over the last few decades. The experts believe this could be due to improved diagnosis, more screening and referrals to specialized parathyroid surgery centers, or an actual increase in the number of cases.
This cancer can occur sporadically (without a family history) or in a familial form. The familial type is called hyperparathyroidism-jaw tumor (HPT-JT) syndrome, a genetic syndrome that includes:
- Primary hyperparathyroidism from parathyroid tumors (typical, adenoma, atypical adenoma, or carcinoma — carcinoma occurs in 10–15% of cases)
- Fibro-osseous jaw tumors (benign growths of the jawbone)
- Tumors of the uterus and kidney
HPT-JT syndrome is caused by mutations in the tumor suppressor gene CDC73 (formerly known as HRPT2). This gene normally helps prevent uncontrolled cell growth. When it is mutated, cells can become cancerous.
Mutations in CDC73 are also the most common genetic defect in sporadic parathyroid carcinoma. They are found in roughly 40–75% of cases, though the percentage varies widely across studies, from 9% to 100% of tumors harboring at least one mutant copy of the gene. This variability may result from small study sizes, different selection criteria, lower-quality DNA from stored tissue samples, and testing methods that can miss some mutations.
A particularly important finding for patients: about one quarter of seemingly sporadic parathyroid cancers contain germline mutations in the CDC73 gene. Germline mutations are present from birth and can be passed on to children, meaning that genetic testing may be recommended even for patients who do not have a known family history.
Only rarely has parathyroid carcinoma been linked to other inherited endocrine syndromes, such as multiple endocrine neoplasia type 1 (MEN1) or type 2 (MEN2).
How the Expert Panel Conducted This Review
The expert panel was formed by the Steering Committee of the MEN2019 conference — the 16th International Workshop on Multiple Endocrine Neoplasia, held in Houston, Texas, March 27–29, 2019.
A panel of 25 world experts with a dedicated interest in parathyroid disease met for a 2-day session. The group included genetic counselors, pathologists, nuclear medicine physicians, endocrinologists, and surgeons, along with representatives from patient advocacy groups.
Before the conference, expert panel members conducted a comprehensive literature search on key questions in parathyroid carcinoma. All presentations were based on the best peer-reviewed information available, combining historical and current literature. During the meeting, panel leaders organized active discussions across all disciplines.
The panel's goals were:
- Recap open forum discussions of interested parties from multiple disciplines
- Consult on data to be highlighted for evidence-based results
- Identify future directions for research and patient care
This report reflects the panel's synthesis of the conference material, placed in context to be useful both to clinicians and to researchers studying parathyroid carcinoma.
Laboratory Models: Progress and Gaps
Research into parathyroid carcinoma has been slowed by the lack of good preclinical models — laboratory systems that mimic how the disease behaves in humans. An ideal model would recreate the course of recurrent and metastatic disease, allowing scientists to study what causes the cancer to spread and to test new treatments.
The currently available models fall short of these goals. Here is what the experts discussed.
Cell Lines
Cell lines (cells grown in the lab) are useful for short-term studies and are cost-effective for prioritizing further research. However, only a few parathyroid cell lines exist, and none have been widely validated across independent laboratories.
One cell line, called PT-r, was developed from the hyperplastic (enlarged) parathyroid glands of vitamin D-deficient rats. A subclone called PTH-C1 was reported to express the parathyroid hormone gene (Pth) and maintain some calcium responsiveness.
A cell line from a patient with parathyroid carcinoma and secondary hyperparathyroidism, Pt.Kich-1, lost its ability to produce PTH or respond to calcium after the 6th–8th passage (a laboratory step of transferring cells).
Another line, sHPT-1, was developed from a hyperplastic gland of a patient with secondary hyperparathyroidism; it shows PTH expression, but it is unclear if the cells respond to calcium.
Some groups have had success in primary culture of parathyroid cells (fresh cells directly from tissue), including from parathyroid carcinoma, particularly when maintained in 3D culture. However, these systems have not been extensively evaluated.
Genetically Engineered Mouse Models (GEMMs)
Several GEMMs have been created using parathyroid tumor-driver genes.
The most common genetic change in parathyroid cancer — inactivation of CDC73 — has been modeled in mice. Mice with a homozygous germline deletion of Cdc73 (both copies of the gene missing) died by day 6.5 of embryonic development, but no parathyroid abnormality was noted initially. In a follow-up study, 68% of older mice (18 months or older) with only one copy of Cdc73 deleted developed biochemical hyperparathyroidism and/or features of parathyroid tumors under the microscope. Some tumors showed features like nuclear pleomorphism (irregularly shaped nuclei) and fibrous septation (bands of fibrous tissue) — characteristics that can suggest atypical parathyroid adenoma or carcinoma in humans. But the mice did not develop the definitive signs of malignancy: local invasion or distant metastasis.
Similar findings were seen when Cdc73 was deleted specifically in the parathyroid glands. In that model, 58% of heterozygous (one copy deleted) and 50% of homozygous null (both copies deleted) mice at least 18 months old were affected.
Another gene, CCND1, is implicated in parathyroid carcinoma. Somatic amplification (extra copies) of the CCND1 gene is seen in about 41% of parathyroid carcinomas, and cyclin D1 protein overexpression is seen in 82%. A transgenic mouse model with a PTH-CCND1 transgene (a genetic construct that turns on cyclin D1 in the parathyroid) develops chronic biochemical hyperparathyroidism and parathyroid gland overgrowth by about 8–12 months of age. However, no specific features of carcinoma were observed in these mice.
The role of MEN1 inactivation in parathyroid carcinoma remains unclear. Only a small subset of parathyroid carcinoma patients have intragenic mutations of MEN1. Also, fewer than 1% of MEN1 patients develop parathyroid carcinoma over their lifetime. In mice, homozygous knockout of Men1 is embryonic lethal. Heterozygous knockout mice develop tumors similar to human MEN1, including parathyroid adenoma. When Men1 was deleted specifically in the parathyroid, mice developed high calcium by 7 months and enlarged parathyroid glands in 80% of mice over 9 months, but no features of carcinoma were described.
Other genes recurrently mutated in parathyroid carcinoma include PIK3CA, MTOR, AKAP9, ZEB1, KDM5C, ADCK1, and PRUNE2. Mouse models exist for studying PIK3CA/MTOR in other cancers, but they are tissue-specific and not expected to produce a parathyroid phenotype. No parathyroid phenotype has been described in knockouts of AKAP9, ZEB1, or KDM5C, and GEMMs for ADCK1 or PRUNE2 have not been reported.
To make progress, the panel recommends a multipronged approach with international collaboration. Ideally, tissue from all known or suspected parathyroid carcinoma specimens would be preserved for research at the time of surgery and made accessible to investigators. Fresh tissue could be used for creating organoids (miniature organ-like structures) or patient-derived xenografts (tumors grown in mice), while frozen or formalin-fixed tissue could be used for next-generation sequencing to find relevant genetic and epigenetic changes. A biobank of such samples would help identify patients at risk of advanced disease and allow testing of new therapies before clinical trials in humans.
Better Pathology Reporting for Accurate Diagnosis
Accurate diagnosis is essential for treatment planning. Because parathyroid carcinoma is so rare, there has been a lack of standard definitions in pathology reports. The recent creation of a global nomenclature by the International Collaboration on Cancer Reporting (ICCR) is a major step toward harmonizing pathology reporting worldwide.
The ICCR dataset for parathyroid neoplasia includes reporting for both parathyroid carcinoma and atypical parathyroid neoplasms (tumors with features in between benign and malignant). The dataset includes:
- Core elements — factors agreed to be key for management and/or staging
- Non-core elements — factors that may not directly impact prognosis, are not widely available, or are awaiting further validation
The core elements require clinical information along with the surgical specimen for pathologic evaluation. Non-core elements include pre-operative biochemical evaluation and operative findings that help define the disease.
Pathologic elements to be documented include:
- Tumor site, size, and weight
- Extent of tumor invasion
- Cytologic features of necrosis (cell death), mitoses (cell division), and margin status (whether cancer cells are present at the edge of the removed tissue)
- Ancillary testing such as parafibromin (the protein product of the CDC73 gene) and the Ki67 proliferation index (a marker of how quickly cells are dividing), if available
Uniform collection of this data will allow the broader spectrum of parathyroid carcinomas to be studied and correlated with long-term clinical outcomes. The criteria for diagnosis will then be subject to validation testing.
Imaging: Finding the Tumor and Monitoring Recurrence
Imaging plays an important role in localizing parathyroid tumors, but the evidence is mostly from case reports with no systematic comparisons of different imaging methods.
Routine cervical (neck) ultrasonography is used for anatomical localization and can be suggestive of cancer if certain features are present:
- Infiltration (invasion into surrounding tissue)
- Calcification
- Heterogeneous cystic structure (mixed solid and fluid areas)
- Irregular borders
- Signs of local invasion
A sestamibi scan (using a radioactive tracer called 99mTc-sestamibi) with SPECT (single-photon emission computed tomography) provides functional information.
When cancer is suspected based on clinical presentation and ultrasound findings, cross-sectional imaging (such as CT or MRI) is used to plan surgery. Since the definitive diagnosis is usually only made by pathology after removal, there is minimal need for additional functional imaging before surgery.
After surgery, monitoring for tumor recurrence relies mainly on clinical and biochemical assessments (measuring calcium and intact parathyroid hormone, iPTH) rather than imaging alone. The experts agreed that postoperative imaging of the neck and, perhaps, chest and abdomen should be done 3–6 months after surgery along with blood tests. Although no trials prove which is best, repeat neck ultrasound and/or sestamibi or 4D CT (a specialized CT technique) can be done in that timeframe.
The role of imaging in recurrent or refractory disease is to localize disease for directed therapy. The most commonly used functional imaging agent is 99mTc-sestamibi. One older but larger series reported the sensitivity of sestamibi scans in the re-operative setting at 79%. When biochemical evidence suggests recurrence, whole-body planar imaging plus focused views of the neck are most helpful for evaluating distant metastases.
Other imaging agents were discussed:
- 18F-fluorodeoxyglucose (FDG) PET/CT — widely used in oncology, but only case reports exist for detecting parathyroid carcinoma. Research trials comparing sestamibi and FDG PET/CT are needed.
- Somatostatin receptor PET/CT (e.g., 68Ga-DOTATATE) — increasingly used for neuroendocrine tumors, and parathyroid tissue also expresses somatostatin receptors. There are anecdotal reports of false-negative scans in recurrent carcinoma, but a systematic study is warranted.
- 18F-choline PET/CT — an indicator of lipid synthesis, has shown promise in detecting benign parathyroid adenomas, but its value in carcinoma is unknown, with only case reports so far.
The experts noted that imaging without biochemical evidence of disease is unlikely to show true positive findings unless the tumor is known to have de-differentiated and become non-functional. There is no evidence on the optimal timing of imaging for surveillance or on how calcimimetics (medications that lower PTH) should be coordinated with imaging.
FDG-based imaging may provide prognostic information. Future studies should look at PET/CT with other radiopharmaceuticals that target specific receptors, using both nuclear and cytoplasmic uptake. A systemic radiotherapy approach using radiolabeled receptor ligands (e.g., 177Lutetium DOTATATE) has potential for treating recurrent or metastatic disease. These targeted therapies show a satisfying safety profile in other neuroendocrine tumors, with low rates of grade 3–4 adverse events. However, there is currently no published data on their use in parathyroid carcinoma, so prospective studies are needed.
Surgery: What the Experts Recommend
Surgery remains the mainstay of treatment for parathyroid carcinoma.
Several key surgical principles were agreed upon by the expert panel:
- No prophylactic parathyroidectomy (removing the parathyroid glands to prevent cancer) is recommended for people with germline CDC73 mutations who have no manifestation of cancer.
- For patients with a germline CDC73 mutation undergoing initial surgery for hyperparathyroidism, bilateral neck exploration (examining all four parathyroid glands) is recommended. Only glands that appear abnormal should be removed.
- Multi-gland resection (removing more than one gland) is not necessary for high-risk patients if only one gland is enlarged and/or clinically malignant.
- There was no agreement on whether unilateral parathyroid tissue clearance (removing tissue on one side) is beneficial when disease is proven to be in one gland.
- En bloc resection (removing the tumor as one piece with surrounding structures) is the preferred operation. This means comprehensive removal of all gross tumor, including adjacent involved structures, to achieve an R0 resection (no cancer cells at the margins).
- En bloc resection includes removal of the ipsilateral thyroid lobe (the thyroid lobe on the same side) and, if necessary, the overlying strap muscles (thin neck muscles) and adjacent soft tissues.
- The recurrent laryngeal nerve (the nerve that controls the vocal cord on the same side) should be left intact and functional unless it is completely surrounded by cancer.
- There is no evidence that prophylactic lymph node dissection (removing lymph nodes even when no cancer is visible) improves disease-free or overall survival.
Clinical Implications: What This Means for Patients
For patients and families affected by parathyroid carcinoma, this expert review offers several practical takeaways.
First, genetic testing matters. Because about 25% of seemingly sporadic parathyroid cancers are actually inherited (germline CDC73 mutations), patients diagnosed with parathyroid carcinoma should discuss genetic counseling and testing with their care team. This has implications for family members, who may also be at risk.
Second, a consistent pathology reporting system will improve diagnostic accuracy. Patients should expect their pathology reports to include standardized information on tumor size, invasion, margin status, and biomarkers like parafibromin and Ki67. This will enable better prediction of clinical outcomes.
Third, imaging choices are evolving. After surgery, patients can expect a combination of blood tests and imaging (ultrasound, sestamibi, or 4D CT) at 3–6 months, and then at intervals guided by symptoms and calcium/PTH levels. For recurrent disease, more sophisticated imaging with FDG or newer agents may be needed, though evidence is still limited.
Fourth, surgery should be performed at experienced centers. En bloc resection by an expert surgeon gives the best chance of cure. Patients with recurrent or metastatic disease should know that there is currently no highly effective drug therapy, but new targeted treatments and radiolabeled therapies are under investigation.
Finally, participation in research is vital. Because this cancer is so rare, collecting tissue samples (biobanking), clinical data, and patient experiences is essential for developing better models and future therapies.
Limitations of the Current Evidence
The expert panel acknowledged several important limitations in the current knowledge of parathyroid carcinoma:
- The rarity of the disease limits the size and quality of clinical studies; most published data come from small retrospective series or case reports.
- There is no widely validated preclinical model that fully mimics the clinical course of recurrent and metastatic disease, slowing drug development.
- Histopathologic diagnosis can be difficult — some tumors that are clearly malignant on pathology may behave less aggressively, while others with borderline features may recur.
- There is no consensus on the best imaging method for surveillance or for detecting recurrence, and no randomized trials exist.
- The exact benefit of additional surgery in recurrent disease has not been proven in randomized trials.
- Genetic variability in testing results makes it hard to interpret the true prevalence of CDC73 mutations.
- Data on the use of targeted therapies, including 177Lutetium DOTATATE, are not yet available for parathyroid carcinoma.
These limitations mean that patient management decisions are often based on expert opinion rather than high-level evidence. However, the panel's combined expertise provides a reliable guide for current practice.
Recommendations for Patients and Clinicians
Based on this expert review, here are actionable recommendations:
- For patients diagnosed with parathyroid carcinoma: Ask about referral to a specialized endocrine surgery center with experience in this rare tumor.
- Request genetic counseling and consider genetic testing for CDC73 mutations, especially if you are under 40 years old, have HPT-JT features, or have a family history of parathyroid or related tumors.
- Ensure your pathology report includes the standardized ICCR data elements, including tumor size, invasion status, margin status, parafibromin staining, and Ki67 index.
- After surgery, follow your doctor's plan for monitoring calcium and PTH levels every 3–6 months, along with neck ultrasound or other imaging as recommended.
- If recurrence is detected, discuss all options with your multidisciplinary team — including reoperation, imaging-guided interventions, and potential enrollment in clinical trials.
- Consider participating in a tissue biobank or registry, which can help future research and the development of new therapies.
For clinicians, the panel emphasizes the importance of collaboration across institutions, standardizing pathological and imaging reporting, and prioritizing research into preclinical models and targeted therapies.
Frequently Asked Questions
What is parathyroid carcinoma?
Parathyroid carcinoma is an extremely rare cancer of the four tiny parathyroid glands in the neck that control blood calcium levels. It accounts for about 1% of primary hyperparathyroidism cases but can cause dangerously high calcium levels. It may occur sporadically or as part of the inherited hyperparathyroidism-jaw tumor syndrome.
Should I get genetic testing if I have parathyroid carcinoma?
Yes, discuss it. About one quarter of seemingly sporadic parathyroid cancers contain germline CDC73 mutations, which are present from birth and can be passed to children. Genetic testing is especially suggested if you are under 40, have features of HPT-JT syndrome, or have a family history of related tumors.
What surgery is recommended for parathyroid carcinoma?
The preferred operation is en bloc resection, removing the tumor as one piece with the ipsilateral thyroid lobe and, if needed, adjacent strap muscles and soft tissues. The recurrent laryngeal nerve should be left intact unless completely surrounded by cancer. No prophylactic parathyroidectomy is recommended for germline CDC73 carriers without cancer.
What imaging will I need after surgery?
After surgery, you can expect blood tests for calcium and intact PTH, along with neck ultrasound, sestamibi scan, or 4D CT at 3–6 months. Imaging without biochemical evidence of disease is unlikely to show true positive findings. Repeat imaging is guided by symptoms and calcium/PTH levels.
How is recurrence of parathyroid carcinoma monitored?
Monitoring relies mainly on clinical and biochemical assessments—measuring calcium and intact parathyroid hormone—rather than imaging alone. Postoperative imaging of the neck and possibly chest and abdomen is done 3–6 months after surgery. When recurrence is suspected, whole-body sestamibi plus focused neck views help evaluate distant metastases.
Are there effective drug treatments for recurrent or metastatic parathyroid carcinoma?
There is currently no highly effective drug therapy proven for parathyroid carcinoma. New targeted treatments and radiolabeled therapies, such as 177Lutetium DOTATATE, are under investigation, but no published data yet exist for their use in this cancer. Discuss clinical trials with your multidisciplinary team.
What should my pathology report include?
Your report should follow standardized ICCR elements: tumor site, size, and weight; extent of invasion; cytologic features like necrosis and mitoses; margin status; and, if available, ancillary tests such as parafibromin staining and the Ki67 proliferation index. This helps predict outcomes and guides treatment decisions.
I was just diagnosed with parathyroid carcinoma. Should I get a second opinion to confirm the pathology and review the surgery plan?
Because this cancer is extremely rare and histopathologic diagnosis can be difficult, expert review of the pathology is valuable. Standardized reports should include tumor size, invasion, margin status, parafibromin staining, and Ki67 index. Genetic testing is also relevant, since about one quarter of seemingly sporadic parathyroid cancers carry germline CDC73 mutations. En bloc resection by a surgeon experienced with this rare tumor is the preferred approach. A second opinion can review both the pathology and the surgical plan. Diagnostic Detectives Network provides independent expert second opinions.
Source Information
This patient-friendly article is based on the following peer-reviewed research article:
Original title: "New and future perspectives for parathyroid carcinoma"
Authors: Nancy D Perrier, Andrew Arnold, Jessica Costa-Guda, Naifa L Busaidy, Ha Nguyen, Hubert H Chuang, and Maria Luisa Brandi
Journal: Endocrine-Related Cancer (2020) 27, T53–T63
DOI: 10.1530/ERC-20-0018
Publication details: Published by Bioscientifica Ltd. © 2020 Society for Endocrinology. This article is part of a thematic review on "Hereditary Endocrine Tumours: Current State-of-the-Art and Research Opportunities," based on the MEN2019: 16th International Workshop on Multiple Endocrine Neoplasia, held 27–29 March 2019, in Houston, TX, USA.
This patient-friendly article was created to help readers understand the original scientific review. It preserves all key data, findings, and conclusions from the source paper while explaining medical terms in plain language.
