Background

Parathyroid carcinoma is an extremely rare type of cancer that develops in the parathyroid glands. These glands are small, typically four in number, and are located behind the thyroid gland in the neck. The primary function of the parathyroid glands is to regulate calcium levels in the body. Most cases of primary hyperparathyroidism are caused by benign tumors (adenomas) rather than carcinomas.

Parathyroid carcinoma most commonly presents in individuals during their fifth decade of life, with no apparent gender preference. Diagnosing parathyroid carcinoma poses challenges as it shares clinical, radiological, and histological features with parathyroid adenoma/hyperplasia. The diagnosis hinges on clear evidence indicating local tissue invasion and metastasis.

Epidemiology

Parathyroid carcinoma is an uncommon form of cancer, constituting only a small percentage of all cases related to hyperparathyroidism. The peak incidence of parathyroid carcinoma is often reported to occur in the fifth or sixth decade of life. There doesn’t seem to be a significant gender predilection.

While most cases are sporadic, there are instances where parathyroid carcinoma is associated with genetic syndromes, such as multiple endocrine neoplasia type 1 (MEN1) and hyperparathyroidism-jaw tumor syndrome (HPT-JT). Parathyroid carcinoma is generally associated with a more guarded prognosis than benign parathyroid conditions. Parathyroid carcinoma has a relatively high recurrence rate, emphasizing the importance of long-term follow-up after initial treatment.

Anatomy

Pathophysiology

Parathyroid carcinoma originates from the epithelial cells of the parathyroid glands. These cells undergo malignant changes, leading to uncontrolled growth and division. Parathyroid carcinoma is often associated with primary hyperparathyroidism, a condition characterized by excessive secretion of parathyroid hormone (PTH).

PTH plays a crucial role in regulating calcium and phosphorus levels in the blood. Malignant parathyroid cells produce and release excessive amounts of PTH into the bloodstream. Elevated PTH levels contribute to hypercalcemia, which is a hallmark of both benign and malignant parathyroid conditions. Parathyroid carcinoma has the potential for local invasion into surrounding structures, such as adjacent tissues and organs in the neck.

Invasion into nearby structures may contribute to the challenges in surgical removal and the high recurrence rate associated with this cancer. The primary treatment for parathyroid carcinoma involves surgical removal of the tumor and affected parathyroid glands. Achieving clear margins during surgery is crucial, but it can be challenging due to local invasion.

Etiology

Genetic Factors:

While most cases of parathyroid carcinoma are sporadic, meaning they occur by chance, there may be hereditary factors that contribute to an increased susceptibility in some individuals.

Radiation Exposure:

Prolonged exposure to ionizing radiation has been suggested as a potential risk factor for parathyroid carcinoma.

Individuals undergoing radiation therapy to the head and neck region for other medical conditions may have an increased risk.

Tumor Suppressor Genes:

Mutations or inactivation of tumor suppressor genes that normally regulate cell growth and prevent cancer development may play a role in developing parathyroid carcinoma.

Genetics

Prognostic Factors

Clinical History

Patients may have a history of elevated calcium levels in the blood, leading to symptoms associated with hypercalcemia. Many cases are associated with a history of long-standing hyperparathyroidism, either primary or secondary to conditions like chronic renal failure. In some instances, there may be a family history of genetic syndromes, such as multiple endocrine neoplasia type 1 (MEN1) or hyperparathyroidism-jaw tumor syndrome (HPT-JT), indicating a possible hereditary component.

Gastrointestinal symptoms such as nausea, vomiting, constipation, and loss of appetite are present in patient. While other symptoms such as fatigue, weakness, excessive thirst, or urination may also be present. The onset of symptoms is often insidious, and patients may experience mild symptoms for an extended period before seeking medical attention.

Parathyroid carcinoma typically follows a chronic course, with symptoms developing gradually over time. The duration of symptoms can vary from months to years, depending on the rate of tumor growth and the stage at which the carcinoma is diagnosed. In advanced cases, patients may present with more severe and acute symptoms, especially if there is local invasion or distant metastasis.

Physical Examination

Parathyroid carcinoma may present with various physical findings on a physical examination, mainly when the tumor is advanced or if there are local complications. It’s important to note that many of these findings are not exclusive to parathyroid carcinoma and can also occur with benign parathyroid conditions. A thorough physical examination, in conjunction with other diagnostic tests, can aid in the evaluation of parathyroid carcinoma.

In some cases, a palpable neck mass or swelling may be detected, which can be attributed to the enlargement of the parathyroid gland or local tumor invasion. When the tumor invades nearby structures, it can affect the recurrent laryngeal nerve, leading to hoarseness or voice changes. The proximity of the parathyroid glands to the thyroid gland can result in changes in thyroid size, consistency, or position due to compression or infiltration.

Patients may experience localized pain or tenderness in the neck area, particularly if the tumor is causing pressure on surrounding tissues. In cases of severe hypercalcemia, physical findings may include dehydration, muscle weakness, altered mental status, and possibly cardiac arrhythmias. Examination findings may reveal signs of kidney dysfunction or complications related to kidney stones.

The presence of bone pain, fractures, or other musculoskeletal manifestations may be detected upon examination. Parathyroid carcinoma is a rare malignancy, and many of these physical findings are more commonly associated with benign parathyroid conditions such as adenomas. Therefore, a multidisciplinary approach involving endocrinologists, radiologists, and surgeons is crucial for proper diagnosis and management.

Age group

Associated comorbidity

Associated activity

Acuity of presentation

Differential Diagnoses

Parathyroid Adenoma

Parathyroid Hyperplasia

Parathyroid Cyst

Renal Hyperparathyroidism

Primary Hyperparathyroidism

Laboratory Studies

Imaging Studies

Procedures

Histologic Findings

Staging

Treatment Paradigm

The treatment approach for parathyroid carcinoma involves a multidisciplinary strategy with a primary focus on surgical intervention. Surgical removal of the tumor and affected parathyroid glands is the cornerstone of treatment, aiming for complete excision with clear margins to minimize the risk of recurrence. Postoperative monitoring of parathyroid hormone (PTH) levels is essential to assess the success of surgery.

Adjuvant therapies, such as radiation or chemotherapy, may be considered in cases of incomplete resection or when there is evidence of residual disease, although their efficacy is not well-established. Medical therapy, including calcimimetic agents and bisphosphonates, may be utilized to manage hypercalcemia and associated symptoms.

Ongoing surveillance, including imaging studies and regular follow-up, is crucial to detect recurrence or metastasis. Genetic counseling is recommended to identify hereditary factors and guide screening and preventive measures. While the rarity of parathyroid carcinoma poses challenges, a personalized and comprehensive approach involving collaboration among endocrinologists, surgeons, and other specialists is vital for optimal patient management.

by Stage

by Modality

Chemotherapy

Radiation Therapy

Surgical Interventions

Surgical removal of the tumor and affected parathyroid glands is the primary treatment for parathyroid carcinoma. The goal is to achieve en bloc resection of the tumor along with adjacent tissues and structures while preserving as much normal tissue as possible. Complete excision with clear surgical margins is crucial for reducing the risk of recurrence. In cases where there is evidence of lymph node involvement, selective lymph node dissection may be performed to remove affected nodes. Complete excision with clear surgical margins is crucial for reducing the risk of recurrence.

Adjuvant Therapy

Radiation Therapy: Radiation therapy may be considered as adjuvant treatment in cases of incomplete resection or when there is evidence of residual disease. The goal is to target and destroy any remaining cancer cells to reduce the risk of local recurrence.

Chemotherapy: Chemotherapy has shown limited efficacy in treating parathyroid carcinoma, and its use is often reserved for advanced or metastatic disease cases. Participation in clinical trials investigating new chemotherapy agents or combinations may be an option for some patients.

Hormone Therapy

Immunotherapy

Hyperthermia

Photodynamic Therapy

Stem Cell Transplant

Targeted Therapy

Palliative Care

use-of-non-pharmacological-treatment-of-parathyroid-carcinoma

Lifestyle modifications: 

Hydration: 

• Stay well-hydrated to help prevent kidney stone formation, which can be a complication of hypercalcemia. 

Exercise: 

• Engage in regular, low-impact exercise to support bone health and maintain overall fitness. 

Vitamin D Intake: 

• Vitamin D plays a important role in calcium absorption and bone health. 

Alcohol and Caffeine Consumption: 

• Limit alcohol and caffeine intake, as these substances can contribute to dehydration, which might exacerbate hypercalcemia. 

Medication Adherence: 

• If prescribed medications to manage hypercalcemia or bone health, adhere to your healthcare provider’s recommendations. 

Stress Management: 

• Engage in stress-reducing activities such as mindfulness, meditation, yoga, or deep breathing exercises. 

Use of Calcimimetic Agent in the treatment of Parathyroid Carcinoma

Cinacalcet (Sensipar): 

• Calcimimetic agents, including Cinacalcet (brand name Sensipar), are medications used in the management of hyperparathyroidism, including primary hyperparathyroidism and certain cases of secondary hyperparathyroidism. However, their use in parathyroid carcinoma is limited and not considered a primary treatment option due to the aggressive and malignant nature of the carcinoma. 
• Cinacalcet works by increasing the sensitivity of calcium-sensing receptors on the parathyroid glands, leading to a decrease in parathyroid hormone (PTH) secretion. This, in turn, can help lower calcium levels in the blood, which is particularly useful for managing hypercalcemia associated with benign parathyroid disorders. 
• In parathyroid carcinoma, characterized by a malignant tumor in the parathyroid glands, treatment strategies typically focus on surgical resection of the tumor and addressing the potential complications of hypercalcemia. Cinacalcet may not be as effective in managing hypercalcemia caused by parathyroid carcinoma compared to its use in benign conditions. 

Use of Bisphosphonate in the treatment of Parathyroid Carcinoma

Bisphosphonates are a class of medications commonly used to manage conditions involving abnormal bone metabolism, such as hypercalcemia and bone-related complications.

While bisphosphonates can play a role in managing certain aspects of parathyroid carcinoma, it is important to note that their use is typically secondary to surgical and other treatment approaches.  

1. Pamidronate (Aredia): Used to manage hypercalcemia of malignancy, including that associated with parathyroid carcinoma.

Mechanism of Action: 

• Inhibits bone resorption by suppressing the osteoclasts activity, cells responsible for breaking down the bone tissue. 

Administration: 

• Administered intravenously (IV). 

Use in Parathyroid Carcinoma: 

• Used to lower elevated calcium levels in the blood associated with parathyroid carcinoma. 
• Helps reduce the risk of bone-related complications caused by hypercalcemia. 

2. Alendronate (Fosamax):

• Commonly used to treat osteoporosis and other bone-related conditions. 

Mechanism of Action: 

• Like other bisphosphonates, alendronate inhibits osteoclast activity, slowing bone resorption. 

Administration: 

• Usually taken orally. 

Use in Parathyroid Carcinoma: 

• May be considered to manage bone health and prevent fractures associated with long-term hypercalcemia. 
• Addresses the potential effects of hyperparathyroidism on bone density. 

3. Etidronate Disodium (Didronel):

• Primarily used in the treatment of conditions like Paget’s disease, a disorder affecting bone remodeling. 

Mechanism of Action: 

• Suppresses bone resorption by inhibiting osteoclast activity. 

Administration: 

• Typically taken orally. 

Use in Parathyroid Carcinoma: 

• Limited evidence of its use in the context of parathyroid carcinoma. 
• May be considered for bone health management in specific cases. 

4. Zoledronic Acid (Zometa):

• Often prescribed for patients with cancer to prevent bone-related complications. 

Mechanism of Action: 

• A potent bisphosphonate that inhibits osteoclast function and bone resorption. 

Administration: 

• Administered intravenously (IV). 

Use in Parathyroid Carcinoma: 

• May be used to manage bone health & reduce the risk of fractures related to hypercalcemia. 
• Could be considered as part of a comprehensive treatment plan for patients with advanced parathyroid carcinoma. 

Use of Human calcitonin analogs in the treatment of Parathyroid Carcinoma

Calcitonin (Miacalcin, Osteocalcin): 

Mechanism of Action: 

• Calcitonin is a hormone that regulates calcium metabolism by inhibiting osteoclast activity, thereby reducing bone resorption and lowering blood calcium levels. 

Administration: 

• Available as a nasal spray, injectable form, and sometimes as an intravenous infusion. 

Use in Parathyroid Carcinoma: 

• Calcitonin can be considered for short-term management of severe hypercalcemia caused by parathyroid carcinoma. 
• It acts quickly to lower blood calcium levels by inhibiting bone resorption. 
• Generally used as an adjunctive therapy alongside other measures. 

Use of Denosumab in the treatment of Parathyroid Carcinoma

Denosumab (Xgeva, Prolia): 

• Denosumab inhibits bone resorption by targeting a protein called RANK ligand (RANKL), which is involved in the regulation of osteoclast activity. I It is administered as a subcutaneous injection. 
• Denosumab may be considered in cases of severe hypercalcemia and bone-related complications. 
• Denosumab can help lower blood calcium levels by reducing bone resorption, which can be particularly relevant in managing hypercalcemia associated with parathyroid carcinoma. 
• In cases where parathyroid carcinoma has led to bone-related complications such as fractures, Denosumab could be considered to strengthen bones and prevent further complications. 

surgical-resection-in-the-treatment-of-parathyroid-carcinoma

• Surgical resection involves removing the entire tumor, often along with adjacent tissue and affected lymph nodes, to achieve clear margins and prevent recurrence. 
• The specific procedure may remove the malignant tissue to control hypercalcemia and reduce the risk of complications. 
• Achieving clear margins is crucial to prevent local recurrence. 
• Parathyroid carcinoma can be invasive and challenging to differentiate from surrounding tissues, which can make achieving clear margins difficult. 

neck-dissection-in-the-treatment-of-parathyroid-carcinoma

• In cases where there’s evidence of lymph node involvement or metastasis, neck dissection may be performed to remove affected lymph nodes. 
• Neck dissection involves removing lymph nodes from the neck region to reduce the risk of recurrence and spread. 
• Reducing the risk of regional lymph node metastasis and recurrence of carcinoma. 

adjuvant-radiation-therapy-in-the-treatment-of-parathyroid-carcinoma

• In cases where there is a high risk of local recurrence or if complete surgical resection was not possible, adjuvant radiation therapy may be considered. 
• Radiation therapy involves targeting the tumor site with focused radiation to destroy any remaining cancer cells. 
• Radiation therapy can be administered postoperatively to target any residual tumor cells that might be left after surgery. 

management-of-parathyroid-carcinoma

Acute Phase: 

Hypercalcemia Management: 

• In the acute phase, one of the primary goals is to control severe hypercalcemia, which can lead to life-threatening complications. 
• Intravenous hydration, loop diuretics, calcitonin, and bisphosphonates might be used to rapidly lower blood calcium levels. 

Stabilization for Surgery: 

• If surgery is planned, the patient may undergo stabilization measures to optimize their overall condition before surgery. 
• This might involve controlling hypercalcemia and addressing any other medical issues that could impact the surgical outcome. 

Surgical Resection: 

• Surgical intervention aims to achieve complete resection with clear margins to reduce the risk of recurrence. 
• Depending on the extent of the tumor, nearby lymph nodes might also be removed. 

Chronic Phase: 

Long-Term Follow-Up: 

• After surgery, patients enter the chronic phase of management, which involves regular follow-up appointments and monitoring. 
• Blood calcium levels and parathyroid hormone (PTH) levels are monitored to detect recurrence or hypercalcemia. 

Adjuvant Therapies: 

• In cases where there is a high risk of recurrence, adjuvant therapies like radiation therapy might be considered. 
• Adjuvant therapies are aimed at targeting any remaining cancer cells and reducing the risk of local recurrence. 

Long-Term Surveillance: 

• Long-term follow-up is crucial due to the potential for recurrence even after successful initial treatment. 

Medication

Future Trends

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References

Parathyroid Cancer. nlm.nih.gov