Parathyroid Adenoma


Article Author:
Samantha Wolfe


Article Editor:
Sandeep Sharma


Editors In Chief:
Ishwarlal Jialal


Managing Editors:
Avais Raja
Orawan Chaigasame
Khalid Alsayouri
Kyle Blair
Radia Jamil
Erin Hughes
Patrick Le
Anoosh Zafar Gondal
Saad Nazir
William Gossman
Hassam Zulfiqar
Navid Mahabadi
Hussain Sajjad
Steve Bhimji
Muhammad Hashmi
John Shell
Matthew Varacallo
Heba Mahdy
Ahmad Malik
Abbey Smiley
Sarosh Vaqar
Mark Pellegrini
James Hughes
Beenish Sohail
Hajira Basit
Phillip Hynes
Sandeep Sekhon


Updated:
3/4/2019 10:35:53 AM

Introduction

The parathyroid glands were first identified in animals in the mid-1880s. Felix Mandl performed the first parathyroidectomy in Vienna in 1925. Since then, there have been many advances in the understanding, diagnosis, and treatment of parathyroid disease.[1][2]

The parathyroid glands are small, oval-shaped structures found in close to the thyroid. Eighty-five percent of patients have 4 glands, with 2 lying superior and 2 inferior. The superior glands (developed from the fourth branchial pouch) are usually located on the posterior-lateral surface of the middle to superior thyroid lobe. The inferior glands are more variable in location due to their embryological descent with the thymus (both developing from the third branchial pouch) and can be found at any point along its path of descent. Most commonly, they are located in the inferior third of the thyroid gland.

A normal parathyroid gland is the size of an apple seed and weighs approximately 0.5 g. Microadenomas are defined as tumors that weigh less than less than 0.1 g, while a giant adenoma is over 2 g. The average weight of an adenoma is 1 g.[3][4]

Etiology

A parathyroid adenoma is part of a spectrum of parathyroid disease that also includes parathyroid hyperplasia and parathyroid carcinoma. 

The etiology of a parathyroid adenoma remains unknown for most patients. The most common genetic mutation associated with sporadic adenomas is the cyclin D1/PRAD1 gene. Alteration in the normal function of this gene affects PTH secretion. Approximately 20% to 40% of sporadic adenomas have overexpression of cyclin D1. Regarding environmental factors, some data suggest that a history radiation therapy predisposes a patient to parathyroid disease later in life. Long-term calcium deficiency may also result in parathyroid disease due to chronic stimulation of PTH.[5]

Epidemiology

A single parathyroid adenoma is responsible for 80% to 85% of hyperparathyroidism, with double adenomas the culprit in 4% to 5%, and parathyroid hyperplasia in 10% to 12%. 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; however, they can occur at any age. Women are affected 3-times as often as men.[6]

Pathophysiology

Parathyroid hormone plays a vital role in calcium and phosphorus metabolism by acting in the kidneys, intestine, and bone. Normally secreted in response to low blood calcium, PTH works to increase calcium absorption in the distal tubules and inhibit phosphate resorption. It also increases body calcium by indirectly stimulating osteoclasts, which results in bone resorption. Finally, PTH enhances intestinal absorption of calcium by increasing the activation of vitamin D. Pathological overproduction of PTH will cause inappropriate elevations in calcium with depletion of phosphate. It is derangements in these 2 elements that account for most of the symptoms classically seen in parathyroid disease.[7]

Histopathology

A parathyroid adenoma is primarily composed of chief cells, but it can also include oxyphil cells, oncocytes, transitional oncocytes, or a mixture of these cell types. There may also be a rim of normal parathyroid tissue surrounding the adenoma. Microadenomas tend to be unencapsulated; however, larger tumors may have a thin fibrous capsule present with cystic degeneration seen within the tumor. Characteristics such as thick fibrous capsule, adherence to surrounding tissues, vascular and capsular invasion, tumor necrosis, and increased mitotic activity should not be seen in benign adenoma and are more suggestive of carcinoma.

History and Physical

Many patients with a parathyroid adenoma are asymptomatic, with hypercalcemia incidentally discovered on routine lab work. Symptomatic parathyroid disease will most commonly manifest as symptoms of hypercalcemia such as bone pain, fatigue, polyuria, nephrolithiasis, constipation, and neuropsychiatric disturbance. More extreme elevations in calcium can cause complications such as cardiac arrhythmias, coma, and death. A patient is unlikely to have outward physical signs of a parathyroid adenoma. The pathologic gland itself is rarely palpable, and an obvious neck mass is more suggestive of thyroid pathology or parathyroid carcinoma.

Evaluation

Hypercalcemia seen on routine lab work performed for other purposes is the most common initial sign of hyperparathyroidism. In most patients, this hypercalcemia is mild and may even be intermittent, and is usually less than 1.0 mg/dL above normal upper limits. Unexplained hypercalcemia on a repeated set of lab work warrants further investigation. PTH level should be subsequently measured, and it may be elevated or even within normal limits, although inappropriately so given the patient’s hypercalcemia. Twenty-four-hour urinary calcium may also be measured, but it is not essential for diagnosis.[8][9][10]

The next step in evaluation is radiographic imaging. Imaging is essential because it not only guides operative planning but distinguishes a single adenoma from a multi-gland hyperplastic disease.

Normal parathyroids are generally too small to be seen on ultrasound; therefore, visualization of this gland should raise suspicion for a pathologic process. If an adenoma identifiable on ultrasound, it should appear as homogeneously hypoechoic extrathyroidal oval mass with a fat plane separating it from normal thyroid tissue. A feeding artery may also be visualized entering the superior or inferior pole of the adenoma. Ultrasound alone has a sensitivity of only 60% to 80% because it is operator dependent. It may be used as an adjunct nuclear imaging.

The gold standard of parathyroid localization is single-radioisotope scintigraphy with technetium-99m (99mTc) combined with single photon emission computed tomography (SPECT) imaging. SPECT is a 3-dimensional sestamibi scan which improves the visualization of parathyroid glands. The combination of these methods has a 91% to 98% sensitivity for identifying parathyroid adenomas.

An alternative is dual-radioisotope imaging, in which both 99mTc pertechnetate and thallium-201 (201Tl) are given. Thallium is taken up by both the thyroid and parathyroid, while pertechnetate only has avidity for the thyroid. Subtraction imaging is then used to visualize the glands. Drawbacks to this method include the necessity of a subtraction program, long imaging times, and limited views.

Four-dimensional CT and MRI have also been used in parathyroid imaging. However, they are only 75% and 40% to 85% sensitive respectively. For that reason, nuclear imaging for preoperative localization. Four-dimensional CT and MRI may have a more beneficial role in localizing ectopic glands after failed parathyroidectomy. In a study of 45 patients who had undergone previous neck exploration, 4-dimensional CT had 88% sensitivity for abnormal parathyroid glands compared with sestamibi SPECT or neck ultrasound (54% and 21%, respectively).

Treatment / Management

Traditionally, bilateral 4-gland exploration was the procedure of choice for hyperparathyroidism. However, because a single adenoma causes 85% of the disease, minimally invasive parathyroidectomy is emerging as the gold standard for a parathyroid adenoma.[11][12][13]

Due to the short half-life of PTH, the Miami criteria dictates that the PTH level should decrease by at least 50% within 10 minutes of adenoma removal. If this value is not met, further exploration is warranted. Missing glands can be found in the retropharyngeal or retro- esophageal planes, posterior mediastinum, thymus, mediastinum, inside the thyroid capsule or gland, or in the carotid sheath.[14]

Differential Diagnosis

Perhaps the most important alternative diagnosis to be considered when a patient presents with hypercalcemia is a malignancy. Hyperparathyroid and malignancy combined account for 90% of cases of hypercalcemia. However, hypercalcemia of malignancy tends to present with much higher concentrations of the ion than a benign parathyroid disease.

Another differential diagnosis is familial hypocalciuric hypercalcemia (FHH). Up to 20% of patients with this disease will also have an elevated PTH level, which can make differentiation difficult. However, patients with FHH characteristically have a low urine calcium excretion and calcium/creatinine (Ca/Cr) clearance ratio, which is not a feature of parathyroid adenomas.

Two medications that can cause elevated calcium levels are thiazide diuretics and lithium. The medication history of any patient presenting with elevated calcium should first be checked for either of these medications.

Complications

An untreated parathyroid adenoma could cause complications related to hypercalcemia. A rare clinical phenomenon is a parathyroid crisis, which is characterized by extremely high calcium levels, usually more than 15 mg/dL. Symptoms include changes in mental status leading to nervous system failure and coma.

Complications can also arise with resection of the parathyroid adenoma. Injury to the recurrent laryngeal nerve is a serious complication of endocrine surgery and has consequences of hoarseness (unilateral damage) or airway occlusion (bilateral damage). Direct trauma to the nerve due to clipping, grasping, or stretching can cause damage. Indirect deleterious effects on the nerve include skeletonization, thermal injury, or compression. The damage may be transient in cases of compression or stretching, and may resolve in 4 to 6 weeks. However, if improvement in function is not seen after 6 to 12 months, the damage should be presumed to be permanent. If the damage is recognized intra-operatively, immediate primary repair or grafting should be performed.

Postoperative and Rehabilitation Care

After parathyroidectomy, the calcium levels will drop for the next 2-4 days but few patients will develop symptoms. However, if symptoms appear, treatment with calcium gluconate may be required. if the hypocalcemic state persists, one will need to supplement with oral calcium.

Consultations

Head & Neck Surgeon

ENT

General surgeon

Endocrinologist

Enhancing Healthcare Team Outcomes

The majority of patients with a parathyroid adenoma present with hypercalcemia and complaints of bony pain, depression, and abdominal pain. The diagnosis is often made by the presence of hypercalcemia in blood, followed by an imaging test of the neck. If the condition is missed, it has very high morbidity. Thus, an interprofessional approach is recommended. A streamlined approach consisting of a radiologist, endocrinologist, surgeon, and an internist is necessary to make the diagnosis. After the surgery, the role of the pharmacist and nurse is important. The nurse must be fully aware of the symptoms of hypocalcemia which often occur within the first 24-72 hours following surgery. The other two complications that a nurse must know include hoarseness due to injury to the recurrent laryngeal nerve and a hematoma around the neck from bleeding. The latter requires an immediate call to the surgeon for evacuation of the blood as if delayed it can lead to respiratory arrest. The pharmacist plays a role in the management of hypocalcemia with either oral supplements or IV calcium gluconate. The pharmacist must educate the patient on the importance of compliance with calcium, otherwise, it can lead to significant bone wasting.[15][16] (Level V)

Evidence-Base Outcomes

The prognosis for cure of hyperparathyroidism with traditional bilateral neck exploration is over 95% with complication rates under 3%. With the advent of minimally invasive techniques, several randomized clinical trials have been conducted in the past ten years to assess if a minimally invasive technique is as efficacious as traditional treatment. These studies have shown that a minimally invasive technique has a similar cure and complication rates as traditional therapy and additionally confers decreased operative time with better cosmetic outcomes.[17][18] (level V)


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Parathyroid Adenoma - Questions

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For an intrathoracic parathyroid mass, which is the best test for localization?



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A female has been complaining of vague abdominal pain for a few weeks. She has been taking a laxative to relieve her constipation but now has severe bone pain. In the emergency room she is found to have a first-degree heart block and her stools are positive for blood. An upper gastrointestinal series reveals multiple shallow ulcers in the antrum. Further testing should be directed at which part of the body?



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Which of the following preoperative localization studies provides the greatest yield in identifying a parathyroid adenoma?



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After a detailed cervical parathyroid exploration, the two superior parathyroid glands and the right inferior gland are found to be normal and the left inferior gland cannot be located. Which of the following locations should the surgeon search?



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A 50-year-old female smoker with kidney stones is found to have a serum calcium level of 11.5 mg/dL. The serum intact parathyroid hormone (PTH) level is in the high reference range for the laboratory. There is no family history of parathyroid disease or hypercalcemia. What is the most likely diagnosis?



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You are performing a minimally invasive parathyroidectomy on a 71-year-old female that had preoperative imaging localizing an adenoma to the right superior gland. You remove what you believe to be an adenoma and promptly send it to the pathology lab for analysis. A predominance of which cell type would confirm that it was, in fact, a parathyroid adenoma you resected?



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Which of the following is the most common reason for hypercalcemia in a normal adult?



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A 55-year-old female presents with hypercalcemia and is found to have an elevated parathyroid hormone level. Parathyroid disease is suspected and imaging is done. With regard to parathyroid imaging with technetium-99m-sestamibi, which of the following statements is true of 2 to 3 hour delayed images?



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A 60-year old male presents with his third episode of ureteral stones. Work up reveals that he has hyperparathyroidism. It is suspected that he may have a parathyroid adenoma. What test is most helpful for the surgeon prior to taking the patient for surgery?



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A client has a parathyroid adenoma resulting in an increase of parathyroid hormone. Which of the following laboratory would be expected to be abnormal? Select all that apply.



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Parathyroid Adenoma - References

References

Pamathy G,Jayarajah U,Wangmo T,Banagala ASK, Lithium-induced Symptomatic Hypercalcemia and Hyperparathyroidism in a Patient with Bipolar Affective Disorder: A Case Report and Review of Literature. Indian journal of psychological medicine. 2018 Jul-Aug     [PubMed]
Wolfe SA,Fingeret A, Parathyroid, Minimally Invasive Surgery null. 2018 Jan     [PubMed]
Gupta M,Singhal L,Kumar A, Hyperparathyroidism Mimicking Metastatic Bone Disease: A Case Report and Review of Literature. Journal of adolescent and young adult oncology. 2018 Jun     [PubMed]
Allen E,Bhimji SS, Anatomy, Neck, Thyroid null. 2018 Jan     [PubMed]
Sahli ZT,Karipineni F,Zeiger MA, A garden of parathyroid adenomas. BMJ case reports. 2017 Aug 3     [PubMed]
Edafe O,Collins EE,Ubhi CS,Balasubramanian SP, Current predictive models do not accurately differentiate between single and multi gland disease in primary hyperparathyroidism: a retrospective cohort study of two endocrine surgery units. Annals of the Royal College of Surgeons of England. 2018 Feb     [PubMed]
Mizamtsidi M,Nastos C,Mastorakos G,Dina R,Vassiliou I,Gazouli M,Palazzo F, Diagnosis, management, histology and genetics of sporadic primary hyperparathyroidism: old knowledge with new tricks. Endocrine connections. 2018 Feb     [PubMed]
Raruenrom Y,Theerakulpisut D,Wongsurawat N,Somboonporn C, Diagnostic accuracy of planar, SPECT, and SPECT/CT parathyroid scintigraphy protocols in patients with hyperparathyroidism. Nuclear medicine review. Central     [PubMed]
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Parikh AM,Suliburk JW,Morón FE, IMAGING LOCALIZATION AND SURGICAL APPROACH IN THE MANAGEMENT OF ECTOPIC PARATHYROID ADENOMAS. Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists. 2018 Jun     [PubMed]
Komarowska H,Bromińska B,Luftmann B,Ruchała M, Primary hyperparathyroidism in pregnancy - a review of literature. Ginekologia polska. 2017     [PubMed]
Leere JS,Karmisholt J,Robaczyk M,Vestergaard P, Contemporary Medical Management of Primary Hyperparathyroidism: A Systematic Review. Frontiers in endocrinology. 2017     [PubMed]
Bilezikian JP,Cusano NE,Khan AA,Liu JM,Marcocci C,Bandeira F, Primary hyperparathyroidism. Nature reviews. Disease primers. 2016 May 19     [PubMed]
Mourad M,Buemi A,Darius T,Maiter D, Surgical options for primary hyperparathyroidism. Annales d'endocrinologie. 2015 Oct     [PubMed]
Al-Thani H,El-Matbouly M,Al-Sulaiti M,Asim M,Majzoub A,Tabeb A,El-Menyar A, Management and outcomes of hyperparathyroidism: a case series from a single institution over two decades. Therapeutics and clinical risk management. 2018     [PubMed]
Hancox SH,Sinnott JD,Kirkland P,Lipscomb D,Owens E,Howlett DC, Setting up a parathyroid multidisciplinary team meeting: one year's experience, outcomes and learning points. The Journal of laryngology and otology. 2018 Mar     [PubMed]
Mallikarjuna VJ,Mathew V,Ayyar V,Bantwal G,Ganesh V,George B,Hemanth GN,Vinotha P, Five-year Retrospective Study on Primary Hyperparathyroidism in South India: Emerging Roles of Minimally Invasive Parathyroidectomy and Preoperative Localization with Methionine Positron Emission Tomography-Computed Tomography Scan. Indian journal of endocrinology and metabolism. 2018 May-Jun     [PubMed]
Neychev VK,Ghanem M,Blackwood SL,Aragon Han P,Fazeli R,Schneider E,Najafian A,Bloch DC,Bard MC,Klarsfeld JH,Zeiger MA,Lipton RJ, Parathyroid surgery can be safely performed in a community hospital by experienced parathyroid surgeons: A retrospective cohort study. International journal of surgery (London, England). 2016 Mar     [PubMed]

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