Radiol Oncol 2020; 54(1): 22-32. doi: 10.2478/raon-2020-0010 22 review Surgical options in treating patients with primary hyperparathyroidism Masa Majcen1, Marko Hocevar2 1 General Hospital Celje, Celje, Slovenia 2 Institute of Oncology Ljubljana, Ljubljana, Slovenia Radiol Oncol 2020; 54(1): 22-32. Received 5 November 2019 Accepted 15 November 2019 Correspondence to: Maša Majcen, M.D., General Hospital Celje, Oblakova 5, SI-3000 Celje, Slovenia. E-mail: masa.majcen@gmail.com Disclosure: No potential conflicts of interest were disclosed. Background. Primary hyperparathyroidism is the third most common endocrine disorder for which surgical proce- dure called parathyroidectomy is the most effective treatment. Since the early 20th century, parathyroid surgery has improved extensively. With the advances in preoperative imaging and with understanding the causes of disease, new and minimally invasive surgical approaches overrode the standard bilateral exploratory operations. Directed parathy- roidectomy is currently the standard technique for treatment of primary hyperparathyroidism worldwide. Conclusions. Surgery is the only definitive treatment of primary hyperparathyroidism. The most appropriate type of surgical procedure depends on the number and localization of the hyperactive parathyroid glands, availability of modern imaging techniques, limitation of each type of procedure and expertise. Key words: primary hyperparathyroidism; minimally invasive parathyroidectomy; directed parathyroidectomy; endo- scopic parathyroidectomy; bilateral neck exploration Introduction Primary hyperparathyroidism (PHPT) is a disease of parathyroid glands that results from their over- activity. The estimated incidence of PHPT is ap- proximately two cases per 1,000 persons per year.1 About 80% of patients have no symptoms; the disease is generally detected during random labo- ratory blood test. In countries where biochemical test are not commonly used, classical symptoms and signs tend to predominate. Surgical resection is the only potentially curative treatment and re- mains the leading treatment option for PHPT. If the patient does not meet surgical criteria or refuses surgery, specific pharmacological therapy or close monitoring is recommended.1 The evolution of parathyroid surgery Parathyroid glands were first discovered in Indian rhinoceros by English biologist Sir Richard Owen in 1850.2,3 Only 30 years later, Ivar Sandstörm from Sweden was the first person to describe the location and blood flow of glands in humans and coined the term glandulae parathyroidiae.1 It has taken many years for scientists to un- derstand the mechanism of action of parathyroid glands. With the rapid development of thyroid surgery (thyroidectomy) in the early 20th century, common occurrences of tetany were observed.2 The fact that hypocalcaemia after parathyroid surgery is the definitive cause of tetany was not wholly ac- Radiol Oncol 2020; 54(1): 22-32. Majcen M and Hocevar M / Surgical treatment of primary hyperparathyroidism 23 cepted for several decades.3 It was not until 1909 that the first evidence of the relationship between parathyroid glands and the metabolism of calcium was published by MacCallum and Voegtil.2-4 Parathyroid surgery as a possible treatment of parathyroid disease was first mentioned in 1915.5 Through the years, several scientists insisted on the connection between parathyroid disease and bone disease. Schlagenhaufer suggested the removal of a solitary tumour of the parathyroid gland in at- tempt to cure bone disease (described as osteitis fibrosa cystica).2,3 The professional public was scep- tical because of the lack of evidence on the link be- tween bone disease and the tumour. However, it took another 10 years before relationship between parathyroid disease and bone involvement was ac- cepted. The first (successful) parathyroidectomy was performed by Felix Mandl in Vienna in 1925.5,6 Prior to the surgery, he initially tried to cure his patient (who had cystic bone lesions) with animal parathyroid extracts and transplantation of four fresh parathyroid glands, taken from the street ac- cident victim. After surgical excision of the tumour with preservation of the other three parathyroid glands, the patient’s condition improved dramati- cally. The patient later died from kidney failure.2,5,6 After the first successful parathyroidectomy, the surgery became the main treatment of para- thyroid disease. Like in any other surgery, how- ever, there are potential risks and complications. In the early 1930s, many surgeons noted the oc- currence of severe, life-threatening hypocalcaemia after surgery.5,6 They (often unsuccessfully) tried to treat hypocalcaemia with a high-calcium and low- phosphate diet or intravenous calcium administra- tion.7 Churchill and Cope’s detailed description of parathyroid surgery facilitated the development of surgical treatment. They employed frozen sections and routinely performed biopsy from normal tis- sue to rule out hyperplasia.4 They also wrote rec- ommendations for the course of surgery (based on their experience in 30 observed patients) accord- ing to the likelihood of parathyroid hyperplasia or multiple adenomas. With the development of histology and the understanding of function of parathyroid glands, their variations in the number and location, surgical success rate slowly became higher.7 Near the end of the 20th century; high-tech diagnostic imaging techniques became powerful medical tools that allowed surgeons to operate with minimal invasion to the patient. Since then, the use of minimally invasive surgery has expand- ed widely and has almost completely replaced the conventional surgical techniques.5,6 Anatomy of parathyroid glands The anatomy of parathyroid glands is highly vari- able.7,8 A fundamental understanding of both sur- gical anatomy and embryology of parathyroid glands is key to successful parathyroid surgery. Nowadays, precise preoperative localization fa- cilitates successful surgical therapy, but a good knowledge of anatomy remains irreplaceable.7 Parathyroid glands are yellowish brown endo- crine glands, measuring about 6 × 4 × 2 mm and weighing on average 20 to 40 mg.8,9 The majority of glands are oval, bean shaped or spherical and usu- ally lie on the posterior aspect of the thyroid lateral lobes.9 Each gland is separated from the thyroid gland by a thin connective tissue capsule. Most people (85%) have four parathyroid glands7-10: ‒ Two superior glands, each of which embryo- logically arises from the fourth pharyngeal pouch. They lie 1–2 cm above the intersection of the inferior thyroid artery and the recur- rent laryngeal nerve at the level of the inferior margin of the cricoid cartilage. ‒ Two inferior glands, each of which embryo- logically arises from the third pharyngeal pouch. They are usually (in 70‒80% of peo- ple) located in the close proximity to the infe- rior margin of the thyroid gland. A small number of patients have three or even more than four glands.8 Rarely, parathyroid glands will be located elsewhere in the neck or in the chest. They are so-called ectopic parathyroid glands.9 Ectopic superior parathyroid glands can be found para- or retropharyngeal, retrotracheal or in the upper mediastinum, rarely also within the thyroid capsule.7 The location of the lower parathyroid glands is more variable due to their longer em- bryologic migration pathway. They can be found anywhere along this embryologic tract: along the thyrothymic ligament, the carotid sheath, in the an- terior mediastinum etc.7-9 The upper and lower parathyroid glands are supplied by branches of the inferior thyroid artery, which is the major blood supply for lower poles of thyroid.7,8 To preserve the vascular supply to the parathyroid glands, the ligation of branches of in- ferior thyroid artery in thyroidectomy should be done with caution as close as possible to the thy- roid capsule. Venous drainage is carried out by the inferior, middle, and superior thyroid veins, which drain into the internal jugular vein.7,8 Radiol Oncol 2020; 54(1): 22-32. Majcen M and Hocevar M / Surgical treatment of primary hyperparathyroidism24 Hyperparathyroidism Hyperparathyroidism is a common endocrine dis- order in which one or more parathyroid glands be- come overactive.1 They produce and secrete para- thyroid hormone (PTH). PTH affects several organ systems through multiple mechanisms. Its main role is regulation of calcium homeostasis but is im- portant as well in vitamin D and phosphate regula- tion (see Table 1).1,8,11-14 The most common cause of hyperparathyroidism is excessive and unregulated production of PTH by parathyroid glands, so- called PHPT. More than 80% of PHPT is caused by a single benign parathyroid neoplasm – adenoma.8 According to epidemiological research data, PHPT is the third most common endocrine disorder.11,12 It affects 2 in 1,000 people per year in western world and its incidence increases with age, with a peak incidence in the seventh decade of life. The risk of developing PHPT is 4-fold higher in women.1,8 On the other hand, secondary hyperparathyroidism refers to compensatory physiological response of parathyroid glands to chronic hypocalcaemic state due to other pathological processes (mostly kidney disease).1,8,12 Unlike PHPT, a disease outside of the parathyroids causes all of the parathyroid glands to become enlarged and hyperactive. Patients with long-standing secondary hyperparathyroidism may develop autonomous parathyroid function due to random mutation in one of the parathyroid glands called tertiary hyperparathyroidism.12 The clinical picture is usually similar and difficult to distinguish from PHPT. The following paper fo- cuses on the diagnosis and treatment of PHPT. Clinical presentation and diagnostics Nowadays, hyperparathyroidism is usually found accidentally during routine biochemical blood tests.15 Patient history and clinical presentation are often not helpful.16 Hyperparathyroidism should be considered in asymptomatic patients with elevated serum calcium levels. An atypical form of PHPT with normocalcemia and elevated PTH levels is ra- re (some authors argue that an atypical PHPT is an early form of the PHPT).1,7,15 Other possible causes of hypercalcaemia should always be ruled out.15 Occasionally, non-specific symptoms are found in presumed asymptomatic patients with a more detailed questioning (for example fatigue, depres- sion, neuromuscular symptoms). In the past, the disease was diagnosed in the more advanced phase TABLE 1. Biological actions of parathyroid hormone (PTH) in the body. PTH increases the serum calcium concentration and lowers the serum phosphate concentration Organ system Function of PTH Kidneys (leading role) It increases calcium and decreases phosphate reabsorption, stimulates calcitriol production by increasing the synthesis of the enzyme 1-α hydroxylase in proximal tubules. Skeletal It raises calcium levels in blood by increasing bone destruction (via osteoblast-mediated activation of osteoclasts) and decreasing the formation of new bone. Gastrointestinal system It increases calcium absorption by stimulating the production of 1,25-dihydroxycholecalciferol. Other (minor role, experimental) Metabolic effects (reduced glucose tolerance, changes in fat metabolism), effects on the liver, adipose tissue, cardiovascular system, neuromuscular function. TABLE 2. Clinical presentation of developed primary hyperparathyroidism (PHPT). Symptoms and clinical signs are associated with an elevated serum calcium concentration and/or increased secretion of parathyroid hormone (PTH) Organ system Symptoms and clinical signs General anorexia, polyuria, polydipsia, weight gain, anaemia Skeletal osteitis fibrosa cystica (bone pain, decreased bone density or generalized osteoporosis, pathological fractures) Kidney kidney stones, renal parenchymal calcifications, nephrocalcinosis, chronic renal impairment Neuromuscular proximal muscle weakness, depression, decline in cognitive ability, psychosis Cardiovascular arterial hypertension, arrhythmias, left ventricular hypertrophy, vascular wall and myocardial calcification Gastrointestinal nausea, vomiting, constipation, ulcer disease, pancreatitis Rheumatological gout, pseudogout Radiol Oncol 2020; 54(1): 22-32. Majcen M and Hocevar M / Surgical treatment of primary hyperparathyroidism 25 or so-called classical form, which is less commonly seen today.16 The developed clinical picture is very diverse due to the broad action of PTH and differ- ent calcium concentrations (Table 2).1,12,14-16 Laboratory measurement of serum calcium concentrations should be obtained on at least two separate occasions. Hypercalcemia with concomi- tant elevated PTH levels confirms the diagnosis of PHPT.1,15 Some patients have atypical form of hyperparathyroidism with elevated PHT levels in the absence of hypercalcemia.16 This pheno- type of PHPT is called normocalcemia with ab- normally high PTH. Different secondary causes need to be excluded before diagnosis of atypical PTH is made.15 At least the serum concentration of phosphate, chlorine, alkaline phosphatase, vita- min D and the patient’s acid-base balance must be checked, as well as basic examination of urine and urinary sediment.1,15,16 All patients with diagnosis of PHPT (including asymptomatic patients) should undergo a urinary tract ultrasound.15 Other diagnostic procedures (dual-energy x-ray absorptiometry, bone x-ray, bone biopsy) should be performed only if there is reasonable clinical suspicion.1,15 After the diagnosis of PHPT is established, lo- calization studies need to be done to determine if minimally invasive surgical treatment can be per- formed.13 The localization studies should not be used to diagnose the disease. Parathyroid glands can be imaged with multiple modalities. The neck ultrasound, CT, scintigraphy or newer hybrid imaging PET/CT and SPECT/CT can be used.17-20 99mTc-sestamibi scan (complemented with neck ul- trasound) is still the most commonly used method in many countries.18 Sestamibi is a small protein la- belled with the radio-pharmaceutical technetium- 99m. The scan is performed by injecting small amount of radioactive material, which is then ab- sorbed by overactive parathyroid gland. The gam- ma camera detects radioactive material and shows position of parathyroid glands. Different studies reported the sensitivity of 99mTc-sestamibi between 77% and 89%, but up to one-third of patients with adenomas could be sestamibi negative.18 PET/CT is a newer and promising tool for lo- calization of parathyroid adenomas. Different PET tracers can be used (18F-fluorodeoxyglucose, 18F-fluorocholine (FCH) etc.).19,21 Many studies are comparing FCH PET/CT with conventional imag- ing modalities. Behera and Damle reported the incremental role of PET/CT over sestamibi scan in 2016 because of better spacial resolution, pos- sible detection of smaller adenomas and reduced scanning time.18,20 Retrospective study by Hočevar et al. analysed the results of preoperative localiza- tion with FCH PET/CT in 151 patients with PHPT.21 Choline is a precursor molecule for a major com- ponent of the cell membrane and is taken up by hyperfunctioning parathyroid cells and neoplastic cells. They concluded that FCH PET/CT is a reli- able preoperative localization test prior to directed parathyroidectomy, with operative confirmation of location and therapy success rate above 95%.21 Indications and contraindications for surgical treatment The surgery is indicated in all patients with clinical symptoms of PHPT who agree to be treated with TABLE 3. The 2014 Fourth International Guidelines for the Management of Asymptomatic PHPT. Patients need to meet at least one of the following criteria to be advised to have surgery Measurement Criteria Age of patient < 50 years Serum calcium concentration (above the upper reference value) > 0.25 mmol/L (1.0 mg/dL) Skeletal injury bone mineral density (DXA): T-score < -2.5 SD* spinal fracture (proven by XR, CT, MRI or VFA) Renal impairment creatinine clearance < 60 mL/min kidney stones or nephrocalcinosis (proven by XR, US or CT) 24-hour calcium in urine > 10 mmol/L (400 mg/day) or increased risk for kidney stones based on biochemical analysis * measured on the lumbar spine, hip, femoral neck or distal third of the radius CT = computed tomography; DXA = dual-energy x-ray absorptiometry; MRI = magnetic resonance imaging; SD = standard deviation; US = ultrasound; VFA = vertebral fracture assessment; XR = x-ray imaging Radiol Oncol 2020; 54(1): 22-32. Majcen M and Hocevar M / Surgical treatment of primary hyperparathyroidism26 surgery.22 Successful surgical intervention can com- pletely cure the disease.15 On the other hand, not all authors agree that surgery is beneficial for asymp- tomatic patients with PHPT. Differences in opinion arise mainly due to poor knowledge of the natural course of the disease, benefits of the surgical pro- cedure and appropriate timing of surgery.1,16,22 The indications for surgery in asymptomatic patient with PHPT according to the Fourth International Guidelines for the Management of Asymptomatic PHPT are presented in Table 3.23 If the patient is a suitable candidate for surgery according to the guidelines, possible contraindica- tions for surgery must be considered.23,24 Surgery is absolutely contraindicated in patients with famil- ial hypocalciuric hypercalcemia (FHH), because it does not result in cure.25 FHH is an autosomal dominant disorder that is often confused with PHPT due to similar laboratory findings (normo- or hypercalcemia with elevated PTH). The ma- jor feature that distinguishes FHH from PHPT is 24-hour urinary calcium excretion. Urinary calci- um concentration below 100 mg in 24-hour urine is diagnostic for FHH.12,24.25 The relative contrain- dications are prior vocal cord injury, contralateral laryngeal nerve injury and symptomatic cervical disc herniation (parathyroid surgery is performed in neck hyperextension, which may worsen the condition).25 The contraindications listed above are common and apply to all types of surgical proce- dures on the parathyroid glands. Each surgical ap- proach also has specific contraindications, which are mentioned in the descriptions of individual ap- proaches. Preoperative management of patients Once the diagnosis of PHPT has been confirmed, determining the best approach for surgery depends on several factors. Before making any decision, the surgeon checks and evaluates the patient’s medi- cal history, family medical history, patient’s regu- lar treatment, the most recent laboratory results, etc.24,25 Specific tests (if not already performed) based on clinical symptoms may need to be done to check for the involvement of individual organs (kidney, bone, etc.). The preoperative examination should include at least the following1,24,25: ‒ serum calcium levels and intact parathyroid hormone (iPTH); ‒ serum value of 25-hydroxy vitamin D; ‒ serum creatinine concentration; ‒ 24-hour urinary calcium concentration and creatinine values and ‒ serum thyroid-stimulating hormone (TSH) and thyroxine levels. Accurate preoperative localization is crucial for successful surgical outcomes (particularly for minimally invasive parathyroidectomy). It helps to determine the location and number of hyper- functioning parathyroid glands and it is very im- portant in the case of recurrent neck procedures.18 In some western Europe countries conventional imaging with 99mTc-sestamibi was successfully re- placed by neck ultrasound and FCH PET-CT imag- ing (Figure 1).21 In some cases, additional imaging (e.g. CT, MRI) is required. Invasive procedures (se- lective venous sampling, selective arteriography) are reserved for patients who have had prior neck surgery and require reoperative surgery18,23 Due to the frequent concomitant thyroid and parathy- roid disease, preventive preoperative analysis of the thyroid gland is performed to avoid increased complications from reoperations.26 Types of surgical treatment of primary hyperparathyroidism The surgeon decides on the type of surgical pro- cedure based on the patient’s anamnesis, clinical status and results of preoperative examinations.24 The patient should be informed of the procedure that is indicated, possible surgical complications FIGURE 1. 18F-fluorocholine (FCH) PET-CT fusion images of patient with pathologic uptake in the right lower parathyroid gland (solitary adenoma). Radiol Oncol 2020; 54(1): 22-32. Majcen M and Hocevar M / Surgical treatment of primary hyperparathyroidism 27 and the overall course of treatment.25 Today, there are several different surgical approaches that are further described below. With the development of medicine, classical surgical procedures are increas- ingly being replaced by new approaches that seek to minimize interventions into the human body.7 There are many different tools/procedures avail- able today to perform surgery as accurately as possible, reduce the number of surgical complica- tions and surgery repetitions, e.g. intraoperative neuromonitoring for identification of the recurrent laryngeal nerve, intraoperative iPTH assay, intra- operative frozen section when malignant tissue is suspected etc.7,24,25,27 Bilateral neck exploration Bilateral neck exploration (also standard, open, conventional parathyroidectomy) is a traditional surgical approach for the treatment of PHPT. Due to the development of less invasive procedures, its application is decreasing.7 During the operation, the surgeon exposes all four parathyroid glands, therefore precise preoperative localization is not re- quired (but it may be helpful). Parathyroid glands identification can be challenging even for a skilled surgeon due to their unpredictable location.22,25 According to literature data the success rate of surgery is 95% in experienced hands (the success of the procedure depends directly on the experi- ence of the surgeon).8,25 In the past, a biopsy of all four parathyroid glands was used to histologically prove pathological parathyroid tissue.28 Due to the high risk of bleeding and postoperative hypopar- athyroidism, it is no longer recommended.25,28 Current indications for bilateral parathyroidec- tomy include25,28-30: ‒ unreliable or inaccessible preoperative imag- ing; ‒ preoperative imaging is contraindicated (pregnancy etc.); ‒ multiple parathyroid lesions; ‒ ectopic parathyroid glands location (inac- cessibility with minimally invasive interven- tion), ‒ familial PHPT; ‒ concurrent thyroid surgery and ‒ other contraindications for minimally inva- sive intervention (measurement of iPTH is not available etc.). The surgical approach has not changed signifi- cantly since the first bilateral parathyroidectomy in 1925.7 Surgery is usually performed under gen- eral anaesthesia, local anaesthesia is rarely used (depending on the experience of the surgical and anaesthesia team).30.31 The patient is lying on the operating room table in a supine position with his upper body at 30 degrees.25 The surgeon makes a 3 to 5 cm transverse incision (initially the inci- sion was longer) about 2 cm above the collarbone. Subcutaneous fat and platysma are divided and the infrahyoid strap muscles are retracted for optimal exposure of thyroid. Using upward and medial digital retraction of the thyroid gland, the surgeon enters the “parathyroid” space.7,25 Once the impor- tant structures come into view (inferior thyroid artery and recurrent laryngeal nerve), the surgeon continues with the identification of the parathyroid glands.31 Caution should be used when removing the parathyroid tissue and during connective tis- sue manipulation, because the rupture of the para- thyroid capsule can result in parathyromatosis.25 The surgeon must identify all four parathyroid glands but remove only the abnormal ones.31 When in any doubt, frozen section can be done to confirm that the tissue excised is parathyroid in origin. In the event of accidental removal of healthy parathy- roid tissue, reimplantation of the tissue should be considered (usually into the brachioradial forearm muscle).7,25 After successful removal of pathologi- cal glands and proper haemostasis, the surgeon ap- proximates the retracted infrahyoid strap muscles and closes the wound with a continuous intrader- mal suture.25,28-31 The most common complication of bilateral neck exploration is recurrent or persistent hyper- parathyroidism that results from missed adenoma or parathyromatosis. Rarely, the cause of recurrent hyperparathyroidism is new neoplasia (most com- monly in previously unrecognized familial PHPT or multiglandular disease, for example multiple endocrine neoplasia [MEN syndrome]).25 As well as the success of the operation, the rate of compli- cation depends directly on the experience of the surgeon (to be considered experienced, surgeon should perform at least 50 procedures per year).25 During the procedure, the superior or recur- rent laryngeal nerves on either side can be dam- aged.8 Damage can cause long-term hoarseness or voice loss. According to the literature, permanent nerve injury occurs in less than 1% of patients.8,33 Transient nerve injuries (neuropraxia) are more common and have different recovery times, com- plete recovery generally occurs within the first six months. Postoperative hypocalcaemia is usu- ally transient and occurs in 25% of patients.25,33 It is most often due to slow reactivation of healthy parathyroid glands, which have been suppressed Radiol Oncol 2020; 54(1): 22-32. Majcen M and Hocevar M / Surgical treatment of primary hyperparathyroidism28 by overactive pathological parathyroid glands. After removal of the adenoma, the remaining sup- pressed glands will eventually regain their func- tional capacity.8,25,32 Patients with low blood cal- cium levels complain of numbness and tingling in their fingertips and toes, very low concentrations can result in involuntary movements and severe muscle spasms.25,33 Postoperative bleeding is a rare but dangerous complication, which may lead to respiratory problems and wound infection.25,33 Minimally invasive parathyroidectomy The term minimally invasive parathyroidectomy (also focal, selective parathyroidectomy) has been used since the 1990s to describe newer types of sur- geries on parathyroid glands.34,35 There is no exact definition of the term, but some experts define it as a procedure with minimal dissection (excision of the adenoma without the removal of non-patholog- ical parathyroid glands) and a wound smaller than 2.5 cm.7 Worldwide, the term currently includes the following procedures: directed parathyroidec- tomy, endoscopic parathyroidectomy (total endo- scopic, video-assisted and robotic parathyroidec- tomy) and isotope-guided parathyroidectomy.34 In 2009, the European Society of Endocrine Surgeons (ESES) confirmed that in keeping with prescribed indications and contraindications, minimally inva- sive parathyroidectomy is a safe and reliable pro- cedure.35 Directed parathyroidectomy With the development and improvement of preop- erative imaging diagnostics, parathyroid surgery is focused on minimally invasive surgery.5,6 Accurate preoperative localization (with neck ultrasound, sestamibi scan and/or FCH PET-CT) is critical to the success of this type of surgery.17-20 Directed par- athyroidectomy is a procedure recommended for patients with solitary adenoma.7 Worldwide, this type of surgery accounts for 70% of all minimally invasive procedures.34 The operation is usually performed under general anaesthesia but can be al- so performed under regional anaesthesia (usually deep cervical block). Regional anaesthesia prevents side effects of general anaesthesia and at the same time allows for intraoperative testing of superior and recurrent laryngeal nerve (by evaluating the patient’s speech).36 Depending on the location of the adenoma, a central or lateral 2 to 4 cm long in- cision is made at the neck (see Figure 2).7,13 The sur- geon identifies and removes only the pathological parathyroid gland (or solitary adenoma).25 Other parathyroid glands are not exposed. Since preop- erative imaging is not completely reliable, majority of surgeons use iPTH to determine the surgery’s success.13 iPTH levels are determined at anaesthe- sia induction (general or regional) and 5–10 min after adenoma removal. According to Miami crite- ria, successful parathyroidectomy was defined as a > 50% decrease of iPTH level compared to the level measured before removal. The half-life of iPTH in plasma is 3–5 min.37,38 Directed approach reduces the invasiveness of the surgery and shortens the surgery and hospitalization time.13,32,35 Published research also demonstrates a lower risk of opera- tive complications (postoperative hypocalcaemia, recurrent laryngeal nerve damage) and death, com- pared to bilateral neck exploration.7,13,25 The patient recovers faster, with less pain and a better aesthetic result (smaller postoperative scar) (Figure 3).25,32 The procedure is not appropriate for patients with multiglandular disease, thyroid disease that also requires surgery or a family history of MEN syn- drome.13,25,27,28 FIGURE 2. Directed parathyroidectomy. The image shows the incision site and the removed parathyroid tissue. FIGURE 3. Appearance of the incision and surrounding skin 10 days after performing directed parathyroidectomy. Radiol Oncol 2020; 54(1): 22-32. Majcen M and Hocevar M / Surgical treatment of primary hyperparathyroidism 29 In the last five years, FCH PET-CT has proven to be the most sensitive and specific method in pre- operative localization of pathologically changed parathyroid glands.39 Its reliability to exclude mul- tiglandular disease is so high that iPTH monitoring can be safely abandoned.40 This shortens the sur- gery time by 30 minutes, which is very significant given that the average duration of directed parath- yroidectomy is less than 20 minutes. According to a 2007 analysis by Westerdahl et al., the long-term results of directed parathyroid- ectomy with iPTH monitoring are comparable to bilateral neck exploration.41 Due to the benefits of this procedure primarily in the early postoperative period and the comparable risk of PHPT recur- rence, this procedure is (with the patient’s consent and the absence of contraindications) indicated as the procedure of choice for removing preoperative- ly proven solitary adenoma.41 Endoscopic parathyroidectomy Endoscopic parathyroidectomy is a surgical tech- nique using an endoscope.7 It is divided into two types, depending on the course: total endoscopic and video-assisted parathyroidectomy, which is a combination of endoscopic intervention and open surgical approach.34 In addition to a directed ap- proach, the endoscope also allows us to perform the entire procedure through small incision wound and with small tissue damage. PHPT is a disease that is otherwise an “ideal disease” for endoscopic surgery, since34,42-44: ‒ in most cases, the cause is a benign tumour, ‒ the tumour is mostly smaller than 3 cm and ‒ there is no need for surgical reconstruction af- ter removal of small amount of tissue. Endoscopic surgery has similar advantages to bilateral parathyroidectomy as other minimally invasive procedures. Compared to directed par- athyroidectomy, it is less invasive, it results in less postoperative pain and a better aesthetic result, but surgery is longer, technically more demand- ing, and requires more expensive surgical equip- ment.45 General anaesthesia is always required.34 Endoscopic intervention is indicated in patients with sporadic PHPT and solitary adenoma, which should be confirmed by preoperative imaging.43 The procedure is not appropriate in the case of intrathyroid parathyroid adenoma, multiple para- thyroid involvement, previous neck surgery, sus- pected parathyroid cancer, familial PHPT, second- ary and tertiary hyperparathyroidism, goitre and in the obese patients.25,34,43,45 Total endoscopic parathyroidectomy Total endoscopic parathyroidectomy was first men- tioned by Gagner et al. in 1996.46 Initial technique was carried out entirely under a steady gas flow, introduced through a central trocar. Nowadays, due to the limited exposure of structures, the cen- tral approach is used only for the more anteriorly located adenomas.46 A more frequently used tech- nique is the lateral approach. The intervention be- gins with the insertion of three working channels for endoscopic instruments (sizes 2, 3 and 10 mm) along the upper anterior margin of the sterno- cleidomastoid muscle (Figure 4). Carbon dioxide is insufflated to help the surgeon expose the area of work and show up the main structures (lateral bor- der of the thyroid gland, recurrent laryngeal nerve, and both ipsilateral parathyroid glands) with lat- eral displacement of the infrahyoid muscles and remove the adenoma through a 10 mm trocar.47 According to the data, the conversion from en- doscopic to traditional ‘open’ surgery is between 13.4% and 28%.46,47 The causes are different, most often due to difficult dissection, bleeding or per- sistence of elevated iPTH after removal of the suspected solitary adenoma.25,46,47 The success of the endoscopic approach is very favourable in the short term (with the exception of a large number of conversion to the open mode), but the results of long-term studies are not yet available (inter- mediate results are encouraging).46,47 Fouyuet et al. operated on 200 patients with PHPT, 28% were converted to open parathyroidectomy. After an av- erage 13 months after endoscopic surgery, 197 pa- tients (98%) were reported to be cured.47 In another prospective study Vidal-Perez et al. performed 28 endoscopic lateral parathyroidectomies with no in- FIGURE 4. Total endoscopic parathyroidectomy. Radiol Oncol 2020; 54(1): 22-32. Majcen M and Hocevar M / Surgical treatment of primary hyperparathyroidism30 traoperative complications. They reported favour- able outcome in 27 of the 28 patients (96%) after an average of 22 months after procedure.48 The major limitation of the approach represents simultaneous bilateral adenomas, since the approach only allows simultaneous removal of the ipsilateral adenomas. Video-assisted parathyroidectomy Video-assisted parathyroidectomy is a combina- tion of endoscopic and open surgery. It was first described in 1999 by Miccoli et al.35,49 The endo- scope, with a smaller incision than used in other open procedures, allows the operator to visualize the operative field equally or better. This results in a smaller postoperative scar. The use of two to three times magnification of the operative field makes identification of anatomical structures easier and the risk of damage to the laryngeal recurrent nerve and other important structures is lower. The ad- vantage is seen especially in the case of very poste- riorly located parathyroid glands.25,34,35,50According to data from Barczynski et al. from 2006, patients have less pain after this procedure compared with directed parathyroidectomy. There is reduced need for postoperative analgesia, a shorter incision wound and better cosmetic results, but at the cost of a longer intervention duration and higher inter- vention costs. The number of video-assisted par- athyroidectomy conversions to the open-surgery and the length of hospitalization (compared to directed parathyroidectomy) were not statistically significantly different. There are no data available on long-term outcomes and effectiveness of the in- tervention.50 Video-assisted parathyroidectomy can be per- formed under local or general anaesthesia.49,50 The procedure is performed via a central incision locat- ed centrally above the collarbone. The endoscope of 5 mm in size is introduced (without a trocar) at an angle of 30 degrees via a lateral incision on the side of the pathological parathyroid gland.35 Gas insufflation is not used in comparison with total endoscopic surgery.50 The endoscope is more mobile, but it requires an additional assistant to manage it. The procedure is performed in the same way as directed parathyroidectomy.35,50 Some au- thors also use endoscopes for bilateral exploratory parathyroidectomy in patients with multiglandu- lar disease.25,31,35 Radioguided parathyroidectomy Radioguided parathyroidectomy is a type of mini- mally invasive surgery, during which the gamma probe is used to guide the surgeon towards the location of the pathological parathyroid gland.35 As with all minimally invasive procedures, good preoperative imaging plays an important role.17-20 Good interaction between the entire surgical team and nuclear medicine experts is a prerequisite for this type of surgical intervention. The patient is given an intravenous dose of 99mTc-sestamibi ap- proximately 2 to 4 hours before the surgery.35 The uptake of sestamibi into the parathyroid adenoma cells depends on their activity.20 Intraoperatively, a gamma probe is then used to trace the location with the highest radioactivity (which must be at least 20% higher than background neck activity). The surgeon thus determines the best incision site.35 However, the use of radioactivity to deter- mine the location has its limitations. The thyroid pathology, which can have increased sestamibi uptake, may be mistaken for an abnormal parathy- roid gland. When searching for radioactive ectopic parathyroids in the chest, high concentration of the isotope in the myocardium can be mistakenly de- tected. If the tissue resected is radioactive and the neck shows equal radioactivity after excision, the patient can be assumed cured.51 Nonetheless, iPTH assay is used to determine the complete excision of all hyperfunctioning tissue.21,51 The method described above is used only by few experienced surgeons.35 It is mostly used as an al- ternative method or just as an aid for the surgery. According to Burkey et al., the reliability of the gamma probe is only 66% and therefore is not a consistently reliable tool for routine use.51 Robotic parathyroidectomy Robotic-assisted parathyroidectomy is a modern technique and it represents the new generation in the evolution of minimally invasive parathyroid- ectomy techniques.52 The beginnings of telerobotic surgical technology go back to the early 21st centu- ry when a new established idea of robotic-assisted surgery offered solutions in overcoming the limita- tions associated with endoscopic techniques (two- dimensional view of the operative filed, limited manipulation with surgical instruments, need for carbon dioxide insufflation and assistants during surgery).52,53 In 2011, Tolley et al. introduced and performed the first robotic-assisted parathyroidec- Radiol Oncol 2020; 54(1): 22-32. Majcen M and Hocevar M / Surgical treatment of primary hyperparathyroidism 31 tomy without the scar in the neck (by infraclavicu- lar incision), using the da Vinci® surgical system.53 As for every other minimal invasive surgical ap- proach, preoperative imaging studies that assist in the localization of lesions have been key elements in patients’ selection for targeted robotic-assisted parathyroid surgeries.17-20,54 Before robotic-assisted parathyroidectomy is preformed, parathyroid ad- enoma should be properly localized.54 Tolley et al. preformed first robotic-assisted surgery (RAS) for parathyroidectomy in which they made an in- cision in infraclavicular region on the side of the lesion. Following that, three other small incisions had been performed in the axillary line on the ip- silateral side without using insufflation. Adenoma was successfully removed in all 11 patients that were represented in this pilot study for evaluating robotic parathyroidectomy; although it should be noted that during one of the RAS procedures the surgeon had to switch to the conventional open approach due to unsuitable habitus of the patient. Nevertheless, the robotic procedure took an aver- age of 61 minutes.53 Many improvements and up- grades have since been introduced into this mini- mal invasive surgical technique. Nowadays, only one small incision is necessary for RAS.52 However, due to high prices of robotic systems and other equipment, robotic-assisted surgical technique in parathyroidectomy has been an alternative proce- dure only in selected medical centres in the USA and Great Britain.53,54 There are only few known studies about RAS in parathyroidectomy, yet all the known data supports robotic-assisted par- athyroidectomy as an equally successful and safe approach for treatment of PHPT as conventional open or endoscopic assisted parathyroidectomy (level 2 and 3 diagnostic evidence).52 Despite an excellent cosmetic outcome due to small incision and a safe approach to the surgery, high expenses, limited equipment, long duration of the procedure and technical difficulties represent limitations in choosing ideal candidates for RAS.52-54 Conclusions Parathyroid surgery is the only potentially cura- tive treatment of PHPT. 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