Overview of Parathyroid Tumor
Parathyroid tumors are benign and malignant tumors originating in the parathyroid glands and manifesting as hypercalcemia, osteoporosis, pathological fractures, urinary stones, etc., accompanied by neck lumps. The etiology of the tumor is not yet clear, and may be related to genetic mutation, radioactive exposure, long-term chronic low calcium stimulation, etc. Treatment requires radical surgical resection of the tumor, internal medicine to stabilize blood calcium and inhibit parathyroid hormone secretion.
Definition
Parathyroid tumors are benign and malignant tumors originating in the parathyroid glands, which are endocrine gland tumors.
Parathyroid tumors secrete too much parathyroid hormone, resulting in primary hyperparathyroidism, referred to as primary hyperparathyroidism. It causes systemic calcium, phosphorus and bone metabolism disorders, manifested as hypercalcemia, osteoporosis, pathological fracture, urinary system stones, etc..
Some parathyroid tumors can be manifested as neck mass when they are large, and symptoms such as hoarseness and dysphagia can occur when they compress or involve peripheral nerves or organs [1-2].
Classification
In 2022, the World Health Organization (WHO) classified parathyroid tumors into three categories, including parathyroid adenoma, parathyroid carcinoma, and atypical parathyroid tumor. Of these, atypical parathyroid tumors are a new type, replacing the previous atypical parathyroid adenomas.
Parathyroid adenomas are benign lesions and account for about 80% to 90% of primary hyperparathyroidism.
Parathyroid carcinomas are malignant tumors with a risk of infiltrating blood vessels or nerves and distant metastasis. They are clinically rare, accounting for about 0.005% of all malignant tumors and 0.5% to 5% of primary hyperparathyroidism.
Atypical parathyroid tumors are a new type proposed by WHO in 2022. It specifically refers to tumors with histomorphologic features of parathyroid carcinoma, but without significant infiltrative characteristics. They are considered to be tumors of uncertain malignant potential and require long-term follow-up after treatment [3].
Morbidity
Parathyroid adenomas are more common in women, with a male to female ratio of approximately 1:3 to 4. They are most commonly seen between the ages of 40 and 60 years, with a significantly higher prevalence in postmenopausal women than in the general population, and are most prevalent in the inferior parathyroid glands.
Parathyroid carcinoma is one of the rarest cancers, accounting for about 0.005% of all malignant tumors. The overall annual incidence is less than 1 case per million people. The majority of parathyroid carcinomas develop between the ages of 45 and 55 years, and there is no significant male-female sex difference in the incidence of parathyroid carcinoma [4-6].
Causes
Pathogenesis
The etiology of parathyroid tumors has not been clearly defined, and may be related to genetic mutations, radiation exposure, and long-term chronic low calcium stimulation.
Parathyroid adenoma
Common gene mutations in parathyroid adenomas include the cell cycle protein D1/PRAD1 gene. About 20% to 40% of sporadic adenomas have overexpression of cell cycle protein D1.
About 5% of primary hyperparathyroidism is hereditary and includes multiple endocrine neoplasia (MEN) types I and IIa, and familial hypocalcemic hypercalcemia.MEN1 is an autosomal dominant syndrome, in which about 90% of patients have hyperplasia or multiple adenomas of the parathyroid glands, which are primarily caused by inactivation of the oncogene MEN1.
A history of prior radiation exposure is also thought to be associated with the development of parathyroid adenomas.
Chronic calcium deficiency leads to increased secretion of parathyroid hormone, increasing the risk of parathyroid adenomas.
Parathyroid Cancer
The etiology of the disease has not been clearly defined and may be related to genetics, history of neck radiation, and long-term chronic low-calcium stimulation. The genes associated with parathyroid carcinoma may include CD1, BRCA2, P53, Rb, PRAD1, etc., but the specific mechanism of action is not clear.
High-risk groups
It is most common in elderly patients or postmenopausal women, and those with familial hereditary parathyroid disease [1-2].
Symptoms
Main Symptoms
Systemic symptoms
The parathyroid glands are endocrine glands that secrete parathyroid hormone (PTH). Parathyroid tumors secrete too much PTH, resulting in primary hyperparathyroidism, or primary hyperparathyroidism for short.
In the early stage of primary hyperparathyroidism, only elevated blood calcium and PTH levels are present, and there may be no obvious clinical symptoms. As blood calcium and PTH levels continue to rise, it leads to systemic symptoms, and its clinical manifestations and severity are positively correlated. High levels of parathyroid hormone lead to changes in the target organs, mainly the bones, kidneys, cardiovascular system, nerves, and part of the digestive system.
Neuropsychomuscular system: emotional instability, depression, depression, etc.; retrograde amnesia, somnolence, loss of sense of smell, etc.; muscle fatigue and delayed tendon reflexes.
Joints and soft tissues: calcification of cartilage, joint pain, etc.
Skeletal system symptoms: cystic fibrous osteitis, bone cysts, brown tumors, osteoporosis, and pathological fractures are common.
Urinary system symptoms: hypercalciuria, urinary stones can cause upper urinary tract obstruction, secondary infections, and impaired renal function.
Digestive tract symptoms: anorexia, bloating, constipation and digestive tract ulcer.
Usually, the systemic symptoms of parathyroid cancer patients are more serious than those of parathyroid adenoma patients. Patients with parathyroid carcinoma have significantly elevated blood calcium and PTH levels at the first visit to the doctor.
Localized symptoms
Parathyroid tumors may present as a neck mass. As the mass increases in size, difficulty in swallowing and hoarseness may occur when it compresses or invades the surrounding tissues or organs.
Parathyroid cancer has the invasive property of malignant tumor, therefore, lymph node and distant metastasis can also occur.
Lymph node metastasis mostly manifests as enlarged lymph nodes in the neck.
Distant metastasis may involve lungs and cough up phlegm; involve liver and discomfort in liver area; involve bone and bone pain, etc. [5,7-8].
Medical treatment
Department of Medicine
Thyroid surgery/general surgery
If physical examination reveals elevated blood calcium, elevated parathyroid hormone (PTH), and parathyroid nodules on ultrasound, thyroid/general surgery is recommended.
Screening of parathyroid function is recommended if multiple urinary stones, pathologic fractures, or severe osteoporosis occur.
If there are symptoms such as neck lump, hoarseness, difficulty in swallowing, etc., it is recommended to consult the Thyroid/General Surgery Department promptly.
Endocrinology
If symptoms of primary hyperparathyroidism such as joint pain, kidney stones, itchy skin, moodiness, depression, etc., and secondary hyperparathyroidism due to prolonged dialysis occur, timely consultation with Endocrinology Department is recommended. After multidisciplinary discussion, appropriate treatment plan will be selected.
Preparation
Consultation: Registration, Preparation of documents, Frequently Asked Questions
Tips for Consultation: Registration, Preparation of Documents, Frequently Asked Questions
For patients with severe symptoms, it is recommended to seek timely medical treatment accompanied by family members.
Preparation List
Symptom list
Pay particular attention to the time of onset of symptoms, special manifestations, etc.
Are there symptoms such as bone pain?
Are there symptoms such as joint pain and muscle weakness in the limbs?
Are there any symptoms such as emotional instability, depression, mental depression, etc.?
Are there symptoms such as polyuria, renal colic, hematuria, etc.?
How long have these symptoms been present?
Medical History Checklist
Is there a family history of parathyroid disease.
Is there a history of neck radiation exposure.
Is there a history of fractures and urinary stones.
Checklist
Test results of the last six months, which can be carried to the doctor’s office
Laboratory tests: serum calcium, serum phosphorus, serum parathyroid hormone level, vitamin D level, 24-hour urine calcium level, adrenal hormone level, etc.
Imaging tests: neck ultrasound, neck CT, radionuclide parathyroid imaging, adrenal gland ultrasound, etc.
Bone density examination.
Diagnosis
Diagnosis is based on
Medical history
Family history of parathyroid disease, history of neck radiation exposure.
Clinical manifestations
Systemic symptoms: the main manifestation is parathyroid hyperthyroidism, i.e., a series of skeletal, renal, cardiovascular, neurologic, and some gastrointestinal system changes due to hypercalcemia.
Localized symptoms: there may be a neck mass.
Laboratory examination
The main manifestations are high blood calcium, low blood phosphorus, elevated serum alkaline phosphatase and parathyroid hormone (PTH) levels, and increased 24-hour urinary calcium and phosphorus excretion.
Blood tests for calcium, phosphorus, alkaline phosphatase, and PTH suggest wearing looser clothing for ease of blood sampling. Most are done at the same time as routine biochemistry and require fasting. Different laboratories or testing methods may vary slightly, and the normal reference value of the testing organization shall prevail.
Patients should restrict a high-calcium diet before urinary calcium measurement. Prior to the test, they should not remain bedridden or engage in overly intense exercise.
Renal function tests can assess the degree of impact of primary hyperparathyroidism on renal function, thus guiding clinical medication.
Imaging examination
Neck ultrasonography
Purpose: To help identify the benign or malignant nature of parathyroid tumors.
Significance: Parathyroid adenomas are mostly solitary adenomas with oval shapes, clear borders and uniform low echogenicity inside. Parathyroid carcinoma is mostly larger in size, irregular in shape, with unclear boundary and calcification within the nodule.
Precautions: Take a light diet and pay attention to rest before the examination. Pay attention to keep the body position during the examination.
CT and MRI examination of the neck
Purpose: To understand the scope of the lesion and its relationship with the surrounding tissues and organs.
Significance: Parathyroid adenoma shows round or ovoid soft tissue density shadow with clear margin. Parathyroid adenoma may show peripheral infiltration and enlarged lymph nodes.
Precautions: Remove metal objects, such as necklaces and earrings, before the examination. During the examination, pay attention to keep the body position, do not swing freely.
Radionuclide parathyroid imaging examination
Purpose: To detect and locate parathyroid tumors.
Significance: It can show parathyroid foci, especially for ectopic parathyroid foci, which is better than other detection methods.
Precautions: Fasting before the examination. Drink plenty of water after the test and avoid contact with children and pregnant women for 24 hours.
Pathologic examination
Purpose: To clarify the benign or malignant nature of parathyroid tumors. Pathology is the gold standard for the diagnosis of parathyroid adenoma or parathyroid carcinoma.
Significance: Preoperative puncture biopsy is recommended to obtain a tumor specimen. Parathyroid adenomas have an envelope with enlarged principal cells as the main component. Parathyroid carcinomas show infiltrative growth, invade blood vessels, lymphatics, and nerves, and mitotic activity is present within the tumor. Atypical parathyroid tumors have the morphologic features of parathyroid carcinoma but do not have significant infiltrative properties.
Immunohistochemistry is also important in the diagnosis of parathyroid tumors. It includes PFIB, PGP9.5, APC, GAL3 and Ki67. When the Ki-67 index is >5%, the possibility of parathyroid cancer should be alerted.
Parathyroid gland puncture to check the PTH level of tissue eluate can also be used as a clinical diagnosis method when it is difficult to judge by conventional methods.
Grading and staging
Because the incidence of parathyroid cancer is very low, the International Union Against Cancer (UICC) has not yet developed a TNM staging system for parathyroid cancer.
Two different staging criteria have been proposed by different scholars, relying on the size of the tumor (3 cm) or the pathological features of the tumor, respectively.
It is generally accepted that invasion of the parathyroid envelope or surrounding soft tissue is considered low risk, while vascular invasion, lymph node metastasis, distant metastasis, and invasion of vital organs are considered high risk [9].
Differential diagnosis
For parathyroid tumors, the first step is to clearly identify whether it is a parathyroid adenoma, or a parathyroid carcinoma. Secondly, parathyroid tumors need to be differentiated from thyroid lesions.
Differentiation between parathyroid adenoma and parathyroid carcinoma
Similarities: Parathyroid adenoma and parathyroid carcinoma are both causes of primary hyperparathyroidism, and therefore both have symptoms of hypercalcemia, systemic symptoms such as skeletal system and urinary system, and localized symptoms such as neck mass.
Differences: The systemic and local symptoms of parathyroid carcinoma are usually more serious than those of parathyroid adenoma, which are manifested by the obvious elevation of parathyroid hormone (PTH) level, which can be more than 3-10 times of the upper limit of the normal level; the blood calcium level is often more than 14mg/dl; and the larger neck mass. Pathology is the gold standard for definitive diagnosis.
Thyroid lesions
The thyroid gland is located in front of the parathyroid glands. Common thyroid lesions include nodular goiter, thyroid adenoma, and thyroid cancer.
Similarities: Both may present with localized symptoms such as neck lumps and hoarseness.
Differences: Parathyroid tumors and thyroid lesions cause different systemic symptoms because of the different hormones secreted. In addition, imaging can help to distinguish the origin of the mass, and pathology can clarify the diagnosis [5,9-10].
Treatment
Aim of treatment: to remove lesions, stabilize blood calcium, and relieve systemic symptoms.
Treatment principle: The treatment of parathyroid tumors is based on surgery, and very few patients with parathyroid cancer can benefit from radiotherapy and chemotherapy.
Some patients should be treated with internal medicine for hyperparathyroidism before and after surgical treatment, and it runs through the whole treatment. Before surgical treatment, blood calcium needs to be lowered and stabilized to create conditions for surgery. After surgical treatment there is a rapid drop in PTH and blood calcium due to removal of the tumor, requiring prevention of hypocalcemia and repair of existing damage.
Tumor Treatment
Surgery
Radical removal of parathyroid tumors is the basic principle of surgical treatment.
Removal of the adenoma is sufficient for parathyroid adenomas.
The scope of resection for parathyroid carcinoma should conform to the principle of resection of malignant tumors. In addition to the affected parathyroid glands, the lobes and isthmus of the thyroid glands on the same side should be resected, the surrounding soft tissues and even the recurrent laryngeal nerves should be involved, and the lymph nodes of the central group on the same side should be cleared. Preoperative confirmation of cervical lymph node metastasis also requires therapeutic clearance.
Recurrent patients may be reoperated on as conditions permit. Reducing the tumor load may help relieve systemic symptoms, prolong survival time, and improve quality of life. Once the atypical parathyroid tumor recurs, reoperation is required according to the surgical principles of parathyroid carcinoma.
Radiotherapy
Studies have shown that parathyroid cancer is not sensitive to radiotherapy.
Adjuvant radiotherapy after surgery is only used for parathyroid cancer patients at high risk of recurrence.
Chemotherapy
Chemotherapy is usually ineffective in the treatment of parathyroid cancer, and success has been reported only in isolated cases.
Other treatments
Some studies have shown some benefit from sorafenib-targeted therapy in patients with recurrent/metastatic parathyroid cancer.
For distant metastases of parathyroid cancer, such as lung metastases and bone metastases, there have been attempts of treatments such as radiofrequency ablation.
Treatment of primary hyperparathyroidism due to tumor
Volume expansion
Ask the patient to drink more water and supplement saline intravenously.
Pay attention to potassium supplementation to correct hypokalemia.
Limit calcium intake before surgery, promote urinary calcium excretion
Limit the intake of calcium in food before surgery.
Use labeled diuretics, such as furosemide, to promote urinary calcium excretion. Thiazide diuretics, such as hydrochlorothiazide, are prohibited. Encourage appropriate exercise in patients with conditions.
Inhibit bone resorption and suppress parathyroid hormone (PTH) secretion
Calcitonin: salmon calcitonin, eel calcitonin
Used 2~3 times a day depending on patient’s blood calcium level.
Fast-acting, but the effect will be weakened after several injections.
Diphosphonates: zoledronic acid, pamidronate sodium
Should be applied as early as possible, especially if severe hypercalcemia is present.
If blood calcium is not reduced satisfactorily, it may be reapplied 7 days after the initial dose.
There are certain requirements for renal function, and diphosphonates should not be used in severe renal insufficiency. Multiple uses need to be alerted to the possibility of mandibular necrosis.
Calcium mimetics: cinacalcet
It can inhibit the secretion of PTH and lower blood calcium.
GI adverse effects such as nausea and vomiting may occur in some patients and not be tolerated.
RANKL inhibitor: disulizumab
Inhibit bone resorption and reduce blood calcium.
Its application has no special requirements for renal function. Long-term use needs to be alert to the possibility of osteonecrosis of the jaw.
Postoperative repair of bone and other injuries
After surgery to effectively remove the thyroid tumor, there is no longer an overproduction of PTH. transient or persistent hypocalcemia may occur, requiring timely supplementation with calcium carbonate and vitamin D. If the blood calcium is normal after calcium supplementation and symptoms such as convulsions remain, magnesium supplementation should also be considered.
When supplementing calcium and vitamin D, it is important to closely monitor the indicators.
Postoperative bone disease patients should be high protein, high calcium and phosphorus diet. Patients with urinary stones should have active stone removal and surgical removal if necessary.
Other treatments
In some patients with persistent or renal insufficiency with hypercalcemia crisis, peritoneal dialysis or hemodialysis with low or no calcium dialysis solution should be used to rapidly reduce blood calcium [1,5,7].
Prognosis
Cure
Parathyroid adenoma
Parathyroid adenomas have a good prognosis and can be cured after surgical removal of the adenoma.
Parathyroid carcinoma
The prognosis is good for those who are diagnosed early and have the lesions completely removed by early surgery. Some studies report that the recurrence rate of parathyroid cancer is 23%~51%.
Patients with recurrence can be operated again if conditions permit. As the disease progresses, the systemic symptoms caused by severe hypercalcemia are more serious than the local symptoms caused by tumor recurrence.
Atypical parathyroid tumors
The prognosis of atypical parathyroid tumors is better than that of parathyroid carcinoma. However, long-term follow-up is needed.
Prognostic factors
Early diagnosis and early treatment of parathyroid tumors should be emphasized.
The prognosis of parathyroid adenoma is better than that of parathyroid carcinoma.
In addition, the severity of primary hyperparathyroidism due to parathyroid tumor also has a certain impact on the prognosis of patients.
Hazards
Prolonged hypercalcemia leading to neurological symptoms, generalized bone pain, and renal insufficiency can affect daily life and even lead to irreversible organ damage.
Daily
Daily Management
Dietary management
After complete resection of parathyroid tumors, patients can appropriately supplement a high protein, high calcium and phosphorus diet.
Usually, blood calcium and phosphorus levels will return to normal in about one week after surgery. At this time, patients can return to normal dietary habits.
Living Habits
After parathyroid tumor surgery, patients with bone disease or urinary stones need to receive follow-up treatment so as to gradually restore labor.
Under the guidance of the doctor, moderate intensity physical activities are carried out to return to society as soon as possible.
Psychological support
When hypercalcemia is present, patients may experience symptoms such as mental depression and depression, and need to be accompanied by family and friends. With the decrease and stabilization of blood calcium level, most of the above symptoms can be relieved.
Patients with atypical parathyroid tumors and parathyroid carcinoma need long-term follow-up and are encouraged to maintain a good state of mind.
Follow-up examination
Importance of follow-up: Regular follow-up is helpful to detect tumor recurrence or metastasis in time, especially parathyroid cancer.
Follow-up time: according to the type of tumor, follow the doctor’s instruction for follow-up.
Examinations needed for follow-up: ultrasound of the neck, CT of the neck and other imaging examinations, as well as tests of serum calcium, serum phosphorus and parathyroid hormone levels.
Prevention
Avoid exposure to radiation. People with family history of parathyroid disease should have regular monitoring of parathyroid function and relevant imaging tests when necessary.