Parathyroid adenoma

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] ; Associate Editor(s)-in-Chief: Syed Musadiq Ali M.B.B.S.[2]

A parathyroid adenoma is a benign tumor of the parathyroid gland. Parathyroid adenoma can be associated with overexpression of the cyclin D1 gene. An elevated concentration of serum calcium and serum parathyroid hormone is diagnostic of parathyroid gland. A specific test for parathyroid adenoma is sestamibi parathyroid scintigraphy, the sestamibi scan. Surgery is the mainstay of treatment for parathyroid cancer.

• A parathyroid adenoma is a benign tumor of the parathyroid gland. It generally causes hyperparathyroidism; there are very few reports of parathyroid adenomas that were not associated with hyperparathyroidism.^[1]
• A human being usually has four parathyroid glands located on the back surface of the thyroid in the neck. The parathyroids secrete parathyroid hormone (PTH), which increases the concentration of calcium in the blood by inducing the bones to release calcium into the blood and the kidneys to reabsorb it from the urine. When a parathyroid adenoma causes hyperparathyroidism, more parathyroid hormone is secreted, causing the calcium concentration of the blood to rise, resulting in hypercalcemia.^[2]

• Parathyroid adenoma can be associated with overexpression of the cyclin D1 gene.^[3]

• 
  Adenoma 01.jpg Intermediate/Low magnification micrograph of parathyroid adenoma. H&E stain. Features: Single cell population forming a single mass. Thin capsule. No adipose tissue. +/-Glandular architecture (which may lead to confusion with thyroid tissue). Normal parathyroid gland with prominent adipose tissue is seen on the right of the image.^[4]

• The following risk factors may increase a person’s chance of developing a parathyroid adenoma:

• Multiple endocrine neoplasia type 1 (MEN 1)^[5]
• Familial isolated hyperparathyroidism(FIHP)
• Hyperparathyroidism–jaw tumour (HPT-JT) syndrome
• Radiation therapy to the head or neck

Hyperparathyroidism is confirmed by blood tests such as calcium and parathormone levels.^[6]

• Fatigue
• Confusion
• Nausea
• Constipation
• Kidney stones
• Muscle aches
• Bone fracture

• CT can be very useful for localising the lesion when the site is not known. Shows increased uptake with agents such as Technetium (Tc) 99m Sestamibi (MIBI) (commonly used agent) and Tc-99m tetrofosmin. The nuclear medicine scan can be fused with the CT scan as a SPECT scan increase diagnostic accuracy.

• In the past CT was more commonly used in the setting of a failed parathyroidectomy for the detection of suspected ectopic glands (often mediastinal). However, in recent years, 4D-CT has emerged as valuable modality especially in the era of minimally invasive parathyroidectomy. This type of surgery requires precise localization with anatomical detail and a confident diagnosis of parathyroid adenoma. 4DCT has been shown to be more sensitive than sonography and scintigraphy for preoperative localisation of parathyroid adenomas.

• Enhancement on 4D-CT

• On 4D-CT parathyroid adenomas typically demonstrate intense enhancement on arterial phase, washout of contrast on delayed phase, and low attenuation on non-contrast imaging.

• Secondary signs include:

• The polar vessel which represents an enlarged feeding artery or draining vein to the hypervascular parathyroid adenoma
• A larger lesion size increases the confidence of diagnosis
• Parathyroid adenomas can also have cystic change

• MRI is infrequently utilized in initial work up because of lower spatial resolution and artifacts. Adenomas can show variable signal intensity on MRI. Reported signal characteristics include:
• T1

• Typically intermediate to low signal
• Subacute haemorrhage can cause high signal intensiy
• Fibrosis or old haemorrhage can cause low signal intensity

• T2

• Typically hyperintense
• Subacute haemorrhage can cause high signal intensity
• Fibrosis or old haemorrhage can cause low signal intensity

• Since most lesions demonstrate high T2 signal intensity, the addition of contrast for MR scanning does not significantly increase detection.

• Ultrasound is one of most commonly used initial imaging modalities.

• Greyscale

• Most nodules need to be >1cm to be confidently seen on ultrasound
• Parathyroid adenomas tend to be homogeneously hypoechoic to the overlying thyroid gland
• An echogenic thyroid capsule separating the thyroid from the parathyroid may be seen

• Doppler ultrasound

• Can commonly show a characteristic extrathyroidal feeding vessel (typically a branch off the inferior thyroidal artery), which enters the parathyroid gland at one of the poles. Internal vascularity is also commonly seen in a peripheral distribution. This feeding artery tends to branch around the periphery of the gland before penetration. This feature can give a characteristic arc or rim of vascularity. The overlying thyroid gland may also show an area of asymmetric hypervascularity that may help to locate an underlying adenoma.

• A specific test for parathyroid adenoma is sestamibi parathyroid scintigraphy, the sestamibi scan. This nuclear imaging technique reveals the presence and location of pathological parathyroid tissue.^[7]

• 
  Sharply marginated, hypoechogenic lesion at the dorsal lower pole of the left thyroid lobe.^[8]
• 
  High magnification micrograph of a parathyroid adenoma. H&E stain. Features: Single cell population forming a single mass. Thin capsule. No adipose tissue. +/-Glandular architecture (which may lead to confusion with thyroid tissue). Normal parathyroid gland with prominent adipose tissue is seen on the right of the image^[8]
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  Parathyroid adenoma^[8]
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  Parathyroid adenoma^[8]
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  Parathyroid adenoma^[8]
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  Parathyroid adenoma^[8]
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  Parathyroid adenoma^[8]

• Surgery is the only cure for parathyroid adenomas.^[9] It is successful about 95% of the time. Parathyroidectomy is the removal of the affected gland(s). The standard of treatment of primary hyperparathyroidism was formerly a surgical technique called bilateral neck exploration, in which the neck was opened on both sides, the parathyroids were identified, and the affected tissue was removed.^[10] By the 1980s, unilateral exploration became more common.^[10] Parathyroidectomy can now be performed in a minimally invasive fashion, mainly because imaging techniques can pinpoint the location of the tissue.^[10] Minimally invasive techniques include smaller open procedures, radio-guided and video-assisted procedures, and totally endoscopic surgery.^[10]
• Before surgery is attempted, the affected glandular tissue must be located. Though the parathyroid glands are usually located on the back of the thyroid, their position is variable. Some people have one or more parathyroid glands elsewhere in the neck anatomy or in the chest. About 10% of parathyroid adenomas are ectopic, located not along the back of the thyroid but elsewhere in the body, sometimes in the mediastinum of the chest.^[9] This can make them difficult to locate, so various imaging techniques are used, such as the sestamibi scan, single-photon emission computed tomography (SPECT), ultrasound, MRI,^[9] and CT scans.^[9][11]

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Anmol Pitliya, M.B.B.S. M.D.[2]

The oldest known case of hyperparathyroidism was found in a cadaver from a Early Neolithic cemetery in southwest Germany. In 1880, Ivar Sandström, a Swedish anatomist, described parathyroids in human following 50 autopsies. He found two parathyroid glands bilaterally in 43 out of 50 autopsies. In 1925, Felix Mandl, a viennese surgeon, was the first who performed parathyroidectomy to treat a patient suffering from osteitis fibrosa cystica.

• The oldest known case of hyperparathyroidism was found in a cadaver from a Early Neolithic cemetery in southwest Germany.^[1]
• In 1852, Sir Richard Owen, Hunterian Professor and Conservator of the Museum in the Royal College of Surgeons of England, described parathyroids in rhinoceros.^[2]
• In 1880, Ivar Sandström, a Swedish anatomist, described parathyroids in human following 50 autopsies. He found two parathyroid glands bilaterally in 43 out of 50 autopsies.^[3]
• In 1891, Friedrich van Rechlinghausen, a German pathologist described ‘osteitis fibrosa cystica‘ (the parathyroid cystic bone disease).^[3]

• In 1925, Felix Mandl, a viennese surgeon, was the first who performed parathyroidectomy to treat a patient suffering from osteitis fibrosa cystica.^[4]

• Garry Shandling, a famous comedian suffered from hyperparathyroidism.^[5]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Anmol Pitliya, M.B.B.S. M.D.[2]

Parathyroid adenoma may be classified according to location into 7 subtypes from type A gland to type G gland.

Parathyroid adenoma may be classified according to location into 7 subtypes: ^[1][1][2][3]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Anmol Pitliya, M.B.B.S. M.D.[2], Preeti Singh, M.B.B.S.[3]

Parathyroid adenoma results in an increase in parathyroid hormone secretion. Calcium-sensing receptor expression in reduced in parathyroid adenoma resulting in an increase in calcium sensing set point.The development of parathyroid adenoma is the result of multiple genetic mutations in minority of cases. Genes involved in the pathogenesis of parathyroid adenoma include calcium-sensing receptor gene, HRPT2 gene (CDC73 gene), Cyclin D1 gene (CCND1)/PRAD1 gene, MEN1 gene, and RET gene. Familial hypocalciuric hypercalcemia (FHH) and neonatal severe hyperparathyroidism are transmitted in autosomal dominant pattern. On gross pathology, parathyroid adenoma is a soft, tan nodule which is well-circumscribed by a delicate capsule. It is most commonly present in single gland. Some times multiple glands are involved.The tissue of parathyroid gland that is not involved in parathyroid adenoma is typically atrophied and compressed.

The effect of parathyroid hormone on mineral metabolism is as follows:^[1][2]

• Effect of parathyroid hormone on inorganic phosphate metabolism:
  • Increases excretion of inorganic phosphate from kidney resulting in decreased serum concentration of phosphate.
• Effect on parathyroid hormone on calcium metabolism:
  • Direct effect:
    • Increased resorption of bones.
    • Decreases excretion from kidney.
  • Indirect effect:
    • Increases conversion of inactive 25-hydroxy vitamin D to the active 1,25-dihydroxy vitamin D which increases absorption of calcium from gut. Decreased phosphate concentration also increases this conversion process. Vitamin D shows synergism with parathyroid hormone action on bone.
    • Decreased serum inorganic phosphate concentration prevents precipitation of calcium phosphate in bones.
  • Both these direct and indirect mechanism results in an increased serum calcium concentration.
• Effect of parathyroid hormone on magnesium concentration:
  • Decreases excretion of magnesium resulting in increased serum magnesium concentretion.

Effect of minerals and vitamin D on parathyroid hormone:

• Decrease in serum calcium concentration stimulates parathyroid hormone.
• Calcium provides negative feedback on parathyroid hormone.
• Magnesium provides negative feedback on parathyroid hormone.
• Vitamin D decreases the concentration of parathyroid hormone.

• Parathyroid adenoma results in an increase in parathyroid hormone secretion.^[3]
• Calcium-sensing receptor expression in reduced in parathyroid adenoma resulting in an increase in calcium sensing set point.^[4][5]

• Calcium-sensing receptors are present on parathyroid glands. They are a type of 7-transmembrane receptors in G-protein coupled receptors superfamily of receptors.^[6]
• Calcium-sensing receptors sense change in extracellular concentration of ionized calcium.^[7]
• Calcium-sensing receptor expression in reduced in primary hyperparathyroidism (parathyroid adenoma) and secondary hyperparathyroidism.^[4]
• This reduced expression of receptor causes an increases in calcium sensing set point.^[5]
• This in turn leads to increase in secretion of parathyroid hormone in presence on normal serum concentration of extracellular ionized calcium.

The development of parathyroid adenoma is the result of multiple genetic mutations in minority of cases. Genes involved in the pathogenesis of parathyroid adenoma include calcium-sensing receptor gene, HRPT2 gene (CDC73 gene), Cyclin D1 gene (CCND1)/PRAD1 gene, MEN1 gene, and RET gene.

• Calcium-sensing receptor gene mutation:^[8]
  • Calcium-sensing receptor (CSR) gene is present on chromosome 3q.
  • Few individuals carries an inherited mutation in the extracellular calcium-sensing receptor gene.
  • The first identified mutation in CSR gene is a point mutation in which phenylalanine is replaced with leucine at codon 881 of CSR gene.^[9]
  • This mutation reduces the activity of calcium-sensing receptor.
  • This mutation can be heterozygous or homozygous.
  • Individuals carrying heterozygous mutation have familial hypocalciuric hypercalcemia (FHH) or familial benign hypercalcemia. FHH is characterized by parathyroid dependent hypercalcemia and decreased responsiveness of parathyroid and kidney to hypercalcemia.
  • Individuals carrying homozygous mutation have neonatal severe hyperparathyroidism. Neonatal severe hyperparathyroidism is characterized by marked parathyroid hyperplasia.
• Familial hypocalciuric hypercalcemia (FHH) and neonatal severe hyperparathyroidism are transmitted in autosomal dominant pattern.
• HRPT2 gene(CDC73 gene) mutations:^[10]
  • HRPT2 gene code for parafibromin protein.
  • HRPT2 gene mutations are found in a type of familial hyperparathyroidism, hyperparathyroidism-jaw tumor (HPT-JT) syndrome.
  • HRTP2 gene mutations increases risk of parathyroid carcinoma.
• Cyclin D1 gene (CCND1)/PRAD1 gene:^[11][12]
  • PRAD1 (parathyroid adenoma 1) is a protooncogene located on chromosome 11q13.
  • Cyclin D1 gene translocation and oncogene action observed in 8% of adenomas.
  • Cyclin D1 gene overexpression is observed in 20% to 40% of parathyroid adenomas.
• MEN1 gene:^[11][13]
  • MEN 1 ics a tumor supressor gene on chromosome 11q13.
  • Somatic loss of single MEN1 allele is observed in 25% to 40% of sporadic parathyroid adenomas.
• RET gene:^[14]
  • RET gene is a proto-oncogene.
  • RET proto-oncogene is associated with multiple endocrine neoplasia type 2 (MEN 2).
  • MEN2A caries increased risk of parathyroid adenoma and/or parathyroid hyperplasia.
• CDNK1B gene:^[15]
  • CDNK1B mutation causes Multiple endocrine neoplasia type 4 (MEN 4).
  • Parathyroid tumors are found along with anterior pituitary, gonadal, adrenal, and renal tumors in MEN 4 syndrome.
  • CDNK1B encodes for the cyclin-dependent kinase inhibitor p27kip1.

The conditions associated with parathyroid adenoma include:^{[16][17][18][8][10][13][19][20][21][22][23][24]}

• Brown tumor
• Chronic renal failure
• Depression
• Familial hypocalciuric hypercalcemia
• Hyperparathyroid-jaw tumor syndrome
• Hypertension
• Multiple endocrine neoplasia type 1
• Multiple endocrine neoplasia type 2A
• Multiple endocrine neoplasia type 4
• Neonatal severe hyperparathyroidism
• Osteitis fibrosa cystica
• Osteoporosis
• Osteomalacia
• Osteoarthritis
• Pancreatitis

• On gross pathology, parathyroid adenoma is a soft, tan nodule which is well-circumscribed by a delicate capsule.^[25]
• Most commonly, parathyroid adenoma is present in single gland. Some times multiple glands are involved.
• If single gland is involved, the other glands may shrink due to negative feedback.
• Majority of times, parathyroid adenoma weight ranges between 0.5 gram to 5 gram.
• Typically, cut surface of parathyroid adenoma is smooth, soft, and reddish brown in color. It should be differentiated from normal parathyroid gland tissue which is yellow-brown color.^[26]
• The tissue of parathyroid gland that is not involved in parathyroid adenoma is typically atrophied and compressed. Fat component of normal parathyroid tissue is also observed.
• On rare occasion, parathyroid adenoma may be cystic.

• Chief cells are predominant in parathyroid adenoma on microcopy.
• In majority of cases, a few nests of larger oxyphil cells are also present.
• Adenoma is seperated from a rim of non-neoplastic tissue on the edge by a fibrous capsule.
• Chief cells present in adenoma larger than normal chief cells and shows greater variability on nuclear size.
• Endocrine atypia (cells with bizarre and pleomorphic nuclei) is often seen in parathyroid adenoma. It should not be mistaken as a sign of malignancy.
• Mitotic figures are rarely present.
• Parathyroid adenoma has incospicuous adipose tissue when compared with normal parathyroid gland.

• 
  Intermediate/Low magnification micrograph of parathyroid adenoma. H&E stain. Features: Single cell population forming a single mass. Thin capsule. No adipose tissue. +/-Glandular architecture (which may lead to confusion with thyroid tissue). Normal parathyroid gland with prominent adipose tissue is seen on the right of the image. – Source: Wikipedia
• 
  High magnification micrograph of a parathyroid adenoma. H&E stain. Features: Single cell population forming a single mass. Thin capsule. No adipose tissue. +/-Glandular architecture (which may lead to confusion with thyroid tissue). Normal parathyroid gland with prominent adipose tissue is seen on the right of the image. – Source:wikipeida
• 
  Histopatholgical image of parathyroid adenoma in a patient with primary hyperparathyroidism. Hematoxylin and eosin stain. – Source: Wikipedia
• 
  Histopatholgical image of parathyroid adenoma in a patient with primary hyperparathyroidism. Hematoxylin and eosin stain. – Source: Wikipedia
• 
  Histopatholgical image of parathyroid adenoma in a patient with primary hyperparathyroidism. – Source: Wikipedia

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Preeti Singh, M.B.B.S.[2], Anmol Pitliya, M.B.B.S. M.D.[3]

The cause of most parathyroid adenomas is unknown. However, about 10% are said to be hereditary. It can be the result of multiple genetic mutations in genes such as the calcium-sensing receptor gene, HRPT2 gene (CDC73 gene), Cyclin D1 gene (CCND1)/PRAD1 gene, MEN1 gene, and RET gene.

Parathyroid adenoma is idiopathic in approximately 90% of the individuals. However, approximately 10% of parathyroid adenoma are caused by mutation in genes.^[1]

• Parathyroid adenoma can be caused by a mutation of the following genes.

• Calcium-sensing receptor gene^[2][3]
• HRPT2 gene (CDC73 gene)^[4]
• Cyclin D1 gene (CCND1)/PRAD1 gene^[5][6]
• MEN1 gene^[7][8]
• RET gene^[9]
• CDNK1B gene^[10]

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Anmol Pitliya, M.B.B.S. M.D.[2]

Majority of parathyroid adenoma are asymptomatic. However, most common presentation of a parathyroid adenoma is hypercalcemia. So, parathyroid adenoma shall be differentiated from other conditions presenting pimarily as hypercalcemia.

• Majority of parathyroid adenoma are asymptomatic.
• However, most common presentation of a parathyroid adenoma is hypercalcemia.
• So, parathyroid adenoma shall be differentiated from other conditions presenting primarily as hypercalcemia.^[1]
• Common conditions presenting as hypercalcemia include:
  • Parathyroid adenoma (primary hyperparathyroidism)
  • Secondary hyperthyroidism (long term)
  • Tertiary hyperparathyroidism
  • Familial hypocalceuric hypercalcemia
  • Hypercalcemia due to malignancy
    • Humoral hypercalcemia of malignancy
    • Osteolytic tumors
    • Production of calcitriol
    • Ectopic parathyroid gland
  • Medication induced
    • Lithium
    • Thiazide diuretics
  • Nutritional
    • Milk alkali syndrome
    • Vitamin D toxicity
  • Granulomatous disease
    • Sarcoidosis

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Syed Musadiq Ali M.B.B.S.[2]

A single parathyroid adenoma is responsible for 80% to 85% of hyperparathyroidism^[1]. A double adenomas the culprit in 4% to 5%, and parathyroid hyperplasia in 10% to 12%^[2]. Parathyroid carcinomas are very rare causes of hyperparathyroidism and account for less than 1% of disease. Adenomas are most common in patients 50 to 70 years old.They can occur at any age. Women are affected 3-times as often as men

• A parathyroid adenoma is a benign tumor of the parathyroid gland. It generally causes hyperparathyroidism^[3].
• Approximately 100,000 Americans develop primary hyperparathyroidism each year from parathyroid adenoma^[4].

• A single parathyroid adenoma is responsible for 80% to 85% of hyperparathyroidism.
• Parathyroid carcinomas are very rare causes of hyperparathyroidism and account for less than 1% of disease.

• They can occur at any age^[5].

• Women are affected 3-times as often as men

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Syed Musadiq Ali M.B.B.S.[2]

There are no established risk factors for Parathyroid adenoma.

There are no established risk factors for Parathyroid adenoma.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Anmol Pitliya, M.B.B.S. M.D.[2] Syed Musadiq Ali M.B.B.S.[3]

There is insufficient evidence to recommend routine screening for parathyroid adenoma.

There is insufficient evidence to recommend routine screening for parathyroid adenoma.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Anmol Pitliya, M.B.B.S. M.D.[2] Syed Musadiq Ali M.B.B.S.[3]

Parathyroid adenoma usually presents as asymptomatic hypercalcemia in presence of increased parathyroid hormone. If left untreated, some of the patients with parathyroid adenoma may develop marked hypercalcemia, hypercalciuria, cortical bone demineralization and nephrolithiasis. Prognosis of parathyroid adenoma is generally excellent after parathyroidectomy.

• Parathyroid adenoma usually presents as asymptomatic hypercalcemia in presence of increased parathyroid hormone.
• If left untreated, some of the patients with parathyroid adenoma may develop marked hypercalcemia, hypercalciuria, cortical bone demineralization and nephrolithiasis.^[1][2]

Organ system specific complication caused by primary hyperparathyroidism due to parathyroid adenoma include:

• Prognosis of parathyroid adenoma is generally excellent after parathyroidectomy.
• The complications of parathyroid adenoma resolves after the treatment.
• Untreated complication of parathyroid adenoma may be fatal.^[33]

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