Parathyroid and MEN Syndromes

Dr. N Naidoo
Moderator : Mr S Chirkut /Prof Hafejee Commentators :V Pillay / F Joyalemi
5 Sept 2015
 

INTRODUCTION

Parathyroid surgery in the setting of familial disorders resulting in multiglandular disease is challenging for the surgeon.
A thorough understanding of the anatomy and embryology, and the variations that may accompany is crucial in
determining surgical success.
1
EMBRYOLOGY
The inferior parathyroid
glands
- dorsal wing of the third
pharyngeal pouch
- differentiates at
gestational weeks 5-6, with
the ventral wing becoming
the thymus.
- thymus and parathyroids
both lose their connections
to the pharynx at
gestational week 7
-thymus migrates caudally +
medially, pulling the
parathyroids with it
-The inferior parathyroid
glands usually stop at the
dorsal surface of the thyroid
gland, outside of the fibrous
capsule of the gland itself
Accessory or supernumerary parathyroid glands are found
in approximately 13% of individuals at autopsy. These glands
most likely result from tissue fragmentation occurring during
the migration of the glands rather than from an initial division of
the primordia of the glands themselves.
The superior parathyroid
glands-
- arise from the dorsal wing
of the fourth pharyngeal
pouch,
-differentiating at gestational
weeks 5-6.
-gestational week 7, the
glands lose connections
with the pharynx and attach
themselves to the thyroid
gland, which is migrating
caudally
-superior parathyroid
glands (IV) are in a more
constant location than the
inferior parathyroids
-superior parathyroids are
generally located more
posterior and medial than
the inferior parathyroids,
and their final resting point
is usually on the dorsal
surface of the thyroid gland,
outside the fibrous capsule
of the thyroid gland.

Absence of parathyroids (ie, <4 glands) is noted in approximately 3% of individuals at autopsy. This absence may result
from a failure of the primordia to differentiate into the parathyroid glands or may be the result of parathyroid gland atrophy
early in development.

Ectopic parathyroid glands occur in 15-20% of patients. The glands may be located anywhere near or even within the
thyroid or thymus. For example, if parathyroid IVs do not descend entirely, they may be located as high as the bifurcation
of the common carotid artery. Conversely, if parathyroid IVs do not release from the thymus, they may be located
intrathoracically, as low as the aortopulmonary window. Other common ectopic locations include the anterior
mediastinum, posterior mediastinum, and retroesophageal and prevertebral regions. However, even when the parathyroid
glands are in an ectopic location, they still often are symmetrical from side to side, making localization somewhat easier.

DiGeorge syndrome manifests as congenital thymic aplasia and absent parathyroid glands. This syndrome results from
failure of the third and fourth brachial pouches to differentiate. DiGeorge syndrome is also associated with facial
abnormalities from abnormal development within first arch structures. No genetic cause is known, but teratogens are the
assumed mechanism. Symptoms include neonatal tetany and impaired cellular immunity with normal humoral immunity.

  1  
 2,3,4
ANATOMY
• Usually four parathyroid glands, which lie on the posterior surface of the thyroid
• Weigh 30-50g and measure about 5mm in diameter
• The superior glands are normally located on the posteromedial aspect of the thyroid near the tracheoesophageal
groove at the level of the cricoid. They are usually 1 to 2cm cranial to the junction of the RLN with the inferior thyroid
artery and within 1cm of the entry point for the RLN into the ligament of Berry and the cricoid cartilage. They are most
often embedded in fat on posterolateral surface of upper thyroid, posterior to where the RLN enters the larynx. They are
under the thyroid superficial fascia. Ectopic positions – trachea-oesophageal groove, para-oesophageal, retro-
oesophageal, piriform fossa, intra-thyroidal.
• The inferior parathyroids are more widely distributed in the region below the inferior thyroid artery. Larger than upper
and usually more ventral (anterior to RLN). They are usually located on the posterolateral surface of the lower thyroid
pole, not more than 0.5 cm from the pole, or close to or on the upper thymus. Ectopic positions – carotid sheath,
thymus, mediastinum, intra-thyroid.
• Each parathyroid gland generally receives a single end-artery blood supply that is vulnerable to injury during surgical
manipulation. Blood supply to all 4 is usually from the inferior thyroid artery. Venous drainage is via the 3 thyroid veins
into the IJV.
• Frequency distribution (general population):
o 5 glands 6%
o 4 glands 80%
o 3 glands 13 %
o 2 glands <1
Histology

- Consists of chief cells and oxyphill cells arranged in trabeculae within stroma of adipose cells
- Chief cells secrete PTH

Physiology

- Calcium
o Most abundant cation in human beings
o Extracellular calcium important for excitation-contraction coupling in muscle tissues, synaptic transmission in
nervous system, coagulation, and secretion of other hormones
o Intracellular calcium important second messenger regulating cell division, motility, membrane trafficking, and
secretion
o Calcium absorbed from small intestine in its inorganic form
o Extracellular calcium (900 mg) 1% of body's calcium stores majority of which is in skeletal system
o 50% serum calcium is in ionized form à active component
o Remainder bound to albumin (40%) and organic anions such as phosphate and citrate (10%)
o Total serum calcium levels range 2.1 to 2.6 mmol/L and ionized calcium 1.1 to 1.3 mmol/l
o For each g/dl alteration of serum albumin above or below 4.0 mg/dL, there is a 0.8 mg/dL increase or decrease in
protein-bound calcium and in total serum calcium levels

- Calcitonin
o Produced by thyroid C cells and functions as an antihypercalcemic hormone by inhibiting osteoclast-mediated
bone resorption
o Production stimulated by calcium and pentagastrin and also by catecholamines, cholecystokinin, and glucagon
o At kidney calcitonin increases phosphate excretion by inhibiting its reabsorption
o Calcitonin plays a minimal role in regulation of calcium levels in humans
o Useful as a marker of MTC and in treating acute hypercalcemic crisis

- Vitamin D
o Vitamin D refers to vitamin D2 and vitamin D3
o Produced by photolysis of naturally occurring sterol precursors
o Vitamin D2 is available commercially in pharmaceutical preparations
o Vitamin D3 is most important physiologic compound and is produced from 7-dehydrocholesterol, found in skin
o Vitamin D metabolized in liver to its primary circulating form à 25-hydroxyvitamin D
o Further hydroxylation in kidney results in 1,25-dihydroxy vitamin D à most metabolically active form of vitamin D
o Stimulates absorption of calcium and phosphate from gut and resorption of calcium from bone
  2  
- Parathyroid hormone
o Regulate PTH secretion by sensing extracellular calcium level
o Secretion also stimulated by low levels of 1,25-dihydroxy vitamin D, catecholamines, and hypomagnesaemia
o Synthesized as precursor preproPTH, cleaved 1st to pro-PTH then final 84-amino-acid PTH
o Secreted PTH half-life of 2 to 4 minutes
o In liver PTH metabolized to active N-terminal component and relatively inactive C terminal fraction
o C-terminal component is excreted by the kidneys and accumulates in chronic renal failure
o PTH functions to regulate calcium levels via its actions on 3 target organs, bone, kidney, gut
o PTH increases resorption of bone by stimulating osteoclasts and promotes release of calcium and phosphate into
circulation
o At kidney, calcium is primarily absorbed in concert with sodium in proximal convoluted tubule, but fine
adjustments occur more distally
o PTH acts to limit calcium excretion at distal convoluted tubule via an active transport mechanism
o PTH also inhibits phosphate (at proximal convoluted tubule) and bicarbonate reabsorption
o Also inhibits Na+/H+ antiporter, which results in mild metabolic acidosis in hyperparathyroid states
o PTH and hypophosphatemia also enhance 1-hydroxylation of 25- hydroxyvitamin D, which is responsible for its
indirect effect of increasing intestinal calcium absorption

  3  
 5,6,7
HYPERCALCEMIA

CAUSES: SYMPTOMS
Bone: Renal
• Osteolytic bone metastases Polyuria
• Prolonged immobilisation Polydipsia
• Multiple myeloma Nephrolithiasis
• Paget’s disease Nephrocalcinosis
• Not osteoporosis Distal renal tubular acidosis
Endocrine: Hypercalciuria
• Hyperparathyroidism (Primary Nephrogenic diabetes insipidus
(adenoma, carcinoma, Acute and chronic renal insufficiency
hyperplasia), secondary, tertiary,
ectopic) Gastrointestinal
• Paraneoplastic PTH like hormone Anorexia, nausea, vomiting
• Hyperthyroidism Bowel hypomotility and constipation
Miscellaneous: Pancreatitis
• Vit D intoxication Peptic ulcer disease
• Granulomatous diseases –
Musculoskeletal
sarcoidosis and TB
Muscle weakness
• Milk alkali syndrome
Bone pain
• Drugs - Thiazide diuretics, lithium,
Osteopenia/osteoporosis
bisphosphonates
• Prolonged tourniquet when Neurologic
drawing blood
Decreased concentration
Confusion
Fatigue
Stupor, coma with increasing levels

Cardiovascular
Shortening of the QT interval
Bradycardia
Hypertension

HYPERCALCAEMIC CRISIS
• Occasionally, patients with primary HPT are
initially seen with symptoms and extremely
high serum calcium levels have developed.
• Management of a hypercalcaemic crisis
involves urgent medical and surgical
strategies
• These patients are almost always severely
dehydrated, and initial management
requires hydration with normal saline.
Sodium inhibits reabsorption of calcium
• IV fluids, preferably normal saline, are
administered at a rapid rate (200-300 ml/hr)
to reverse the intravascular volume
contraction and promote renal excretion of
calcium. Aim for urine output of 100ml/hr.
• Furosemide increases urinary calcium
excretion.

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 5,8
HYPOPARATHYROIDISM
• Results in hypocalcaemia and hyperphosphataemia

Causes
- Damage to the parathyroids –surgery
- Radiation
- Genetic mutations (Di George)
- Hypo or hypermagnasaemia – affect the secretion of PTH and the sensitivity of the CaSR
- Deposition of iron or copper in the glands e.g. Wilson’s
- Autoimmune – can be associated with other autoimmune diseases

Signs and Symptoms

• caused by neuromuscular excitability from reduced plasma ionized calcium.
• perioral numbness and tingling in the fingers.
• Anxiety or confusion
• Tetany, marked by carpopedal spasm (Trousseau’s sign), convulsions, or laryngospasm.
• Physical examination
• Chvostek sign, which is contraction of the facial muscles after tapping on the facial nerve anterior to the ear
• Can result in hypercalciuria and kidney stones

• Is the only endocrine disorder for which the missing hormone is not available as approved therapy. Subcutaneous PTH
is currently under trial with promising results
• Chronically these patients are treated with calcium and vitamin D supplementation. However, stable control of calcium
is difficult and they can get intermittent fatigue, confusion and cramps
• Hydrochlorothiazide increases calcium reabsorption in the distal tubule and is useful in patients with HT. Young patients
tend to become hypotensive and tolerate it poorly.

9,10,11,12,13,14,15,16
HYPERPARATHYRODISM

5,10,12
PRIMARY HYPERPARATHYROIDISM

• Primary hyperparathyroidism refers to increased autonomous secretion of PTH -hypercalcemia

• Its incidence increases with age and is most common in post menopausal women
• Aetiology:
• Solitary adenoma (80%)
• Hyperplasia (10%)
• Multiple adenomas
• Carcinoma
• Hyperplasia usually affects all 4 glands
• Parathyroid hyperplasia may also be part of the autosomal dominant MEN
• Diagnosis is made by demonstrating elevated serum calcium and PTH levels and normal or increased urinary
calcium in the setting of normal renal function. ALP is normal.
• PTH levels in primary are usually 8-25, whereas in secondary and tertiary it is much higher - >90.

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 11
• Indication for surgery in asymptomatic patients :
o Serum calcium concentration 0.25 mmol/L or more above the upper limit of normal
o Creatinine clearance <60 ml/min
o Bone density at the hip, lumbar spine, or distal radius that is more than 2.5 standard
deviations below peak bone mass (T score <-2.5) and/or previous fragility fracture
o Age less than 50 years
o 24hr urinary calcium >10mmol/day used to be an indication but not anymore

Preoperative (non-invasive)
• Not routinely performed
• Imperative before
primary exploration for
minimally invasive Surg
• Sestamibi combined
with SPECT= Best
Study modality
• Sestamibi retained in
abn oxyphil cells
• Limitation= false
positive due to other
reactive tissues that
may mimic parathyroid
adenomas
13,14,15
LOCALIZATION
Preoperative (Invasive) Intraoperative
• Selective arteriography in • Rapid intraoperative PTH assay
conjunction with venous • Radio guided
99m
sampling for PTH parathyroidectomy, with Tc-
• Recommended for re sestamibi
exploration in patients with • Frozen section
negative, discordant, or
non-convincing non-
invasive localization studies

Bilateral Neck Exploration

• Bilateral neck exploration with intraoperative histopathologic frozen-section examination of excised parathyroid tissue.
• Ideally, four parathyroid glands are identified, and the surgeon removes the pathologically enlarged gland or glands.
10% of primary hyperparathyroidism patients will have 2 adenomas.
• men syndromes
• famililial hyperparathyroidism
• multi gland on pre-op imaging
• concomitant thyroid and parathyroid disease requiring surgery
• where PTH remains high post min invasive approach

Minimally Invasive Parathyroidectomy

• With improved methods for preoperative localization and the use of intraoperative PTH monitoring (IPM), less invasive
parathyroidectomy has been described with similar or better outcomes. These less invasive procedures include
unilateral neck exploration (UNE), focused parathyroidectomy (exploring and resecting only the diseased gland), and
minimally invasive video-assisted methods
• Today, MIP requires preoperative localization (typically with sestamibi combined with SPECT) followed by limited
exploration, often using cervical block anaesthesia and the intraoperative PTH assay to confirm the adequacy of
resection
• Patients with known multigland hyperplasia are not generally offered MIP
• The skin incision is small, typically 2 to 4 cm over the gland which can also be localised with U/S. A superficial cervical
block is administered posterior and deep to the sternocleidomastoid muscle on the ipsilateral side of the sestamibi-
localized adenoma. Possible problems with this technique include bleeding and difficulty getting into surgical planes.
• Endoscopic parathyroidectomy can be done

Postoperative Complications

• High-volume endocrine surgeons have higher cure rates and lower complication rates.
• Persistent HPT - can be as high as 30% in less experienced hands.
• Recurrent laryngeal nerve injury
• Superior laryngeal nerve injury
  6  
• Hypoparathyroidism - from injury to or removal/devascularization of the remaining parathyroids can occur and result in
transient postoperative hypocalcaemia is not uncommon.
o Risk factors include subtotal or three and a half gland parathyroidectomy, bilateral neck exploration,
removal of the parathyroids together with the thyroid gland, or a history of previous neck dissection.
o Calcium gluconate infusion may be needed diluting 4 ampoules of calcium gluconate in 200ml of dextrose
saline. This can be increased to 8 amps if needed. The initial rate of infusion is 10 ml/hr, which needs to
be titrated according to symptoms and serial serum calcium levels
o Oral calcium supplements used

Medical Alternatives

• There are no long-term medical therapies for which data are convincing regarding either their efficacy or safety in the
treatment of primary HPT
• Bisphosphonates
o Limitations of long-term treatment include
§ poor gastrointestinal drug absorption
§ a rise in PTH levels with increased renal tubular resorption and gastrointestinal absorption of
calcium
§ expense
• Discovery of the calcium sensing receptor (receptor on parathyroid and C-cells) and its molecular role in mineral
metabolism represents a major scientific advance during the past decade
• The CaSR became the target for the development of compounds that enhance the affinity of the CaSR for calcium and
reduce PTH secretion.
• The long-term role of calcimimetic agents such as cinacalcet has yet to be determined for the treatment of primary HPT,
but it has rapidly become established as a mainstay in the management of secondary HPT

5,9
SECONDARY HYPERPARATHYROIDISM

• This is due to an outside defect resulting in diffuse glandular

hyperplasia
• Most commonly caused by Chronic Renal Failure. Mechanisms
involved include:
• Decreased 1,25 Vit D production
• Skeletal resistance to PTH
• Reduced intestinal calcium absorption
• Renal phosphate retention
• Non-renal causes include calcium & vit D deficiency

Indications
o Calciphylaxis
o SHPT refractory to medical therapy consistent with the following:
+2 −4
§ PTH >600 pg/mL; (Ca × PO ) >55, High-turnover bone disease
o SHPT consistent with the above conditions and associated with one of the following à subperiosteal resorption,
bone pain, pathologic fractures, severe pruritus, persistent anemia, renal osteodystrophy, hypercalcemia,
hyperphosphatemia, extra skeletal non-vascular calcification

Medical management:

• Administration of vitamin D analogues has been used to treat secondary HPT and to correct the endogenous deficiency
of chronic renal failure.
• The calcimimetic agents (e.g., cinacalcet) have revolutionized the medical management of secondary HPT in chronic
renal failure patients undergoing dialysis.
• The drugs directly lower PTH levels by increasing the sensitivity of the Calcium sensing receptor to extracellular
calcium

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Surgical Strategies

• Comprehensive medical workup to ensure good surgical candidate

• Timed with haemodialysis
• Preoperative imaging is not indicated because bilateral neck exploration is required for identification of all glands, given
that the underlying pathology is parathyroid hyperplasia
• When performing subtotal parathyroidectomy, it is well advised to choose the most easily accessible gland for the
vascularised remnant.
• Most often this will be an inferior gland because of its more anterior location.
• If the remnant appears ischemic, a second gland is chosen.
• Surgery consists of removal of three (or more, if supernumerary glands are identified) glands and 50% to 75% removal
of one gland with preservation of a viable, histologically confirmed remnant.
• Marking the remnant with a titanium clip enables later identification if recurrence develops in the remnant.
• Use of intraoperative PTH measurements can help ensure that adequate tissue has been resected.
• Cervical thymectomy is considered in all patients undergoing surgery for secondary HPT because supernumerary,
intrathymic parathyroid glands are a common cause of persistent or recurrent disease.
• Total parathyroidectomy with autotransplantation removes all identified glands and uses an easily accessible area,
most commonly the forearm or the sternocleidomastoid muscle, as the site for implantation.
• The gland to be transplanted is minced into 1-mm pieces, and 12 to 18 pieces are embedded in well-vascularised
muscle and marked with a stitch or clip. The remaining glands must be cryopreserved in case the transplanted gland
fails.
• Subtotal parathyroidectomy seems to be the preferred surgical approach in most, but not all patients
• A third option is total parathyroidectomy which is not favoured by many. The advantage is the low rate of recurrence,
and a large number of patients have recordable PTH levels post-op, probably due to ectopic parathyroid tissue.
• 3,5 parathyroidectomy without transcervical thymectomy is done.

5,10
TERTIARY HYPERPARATHYROIDISM

• Tertiary HPT can occur in 2 settings:

o Elevated PTH levels and spontaneous hypercalcaemia (i.e. not due to treatment with calcium and vitamin
D analogues) or patients with persistent and progressive elevations of serum PTH that cannot be lowered
to levels less than 300 pg/ml despite treatment with vitamin D analogues and cinacalcet (180 mg/day)
o Prolonged stimulation of the parathyroids in secondary hyperparathyroidism in which autonomous
hyperfunction develops post transplantation and the parathyroids no longer respond to calcium feedback
inhibition, which results in hypercalcaemia.
o Indications for parathyroidectomy for THPT after kidney transplant
§ Subacute severe hypercalcemia (CA >12.4mg/dl)
§ Persistent hypercalcemia 2 years post-transplant associated with the following
Decline in renal function, nephrolithiasis, acute pancreatitis, progressive bone disease
5,9
PARATHYROID CARCINOMA

• Parathyroid carcinoma is rare.

Genetics :The molecular and genetics events underlying hyperparathy- roidism and its associated pathology are complex
and overlapping.

All normal parathyroid glands and most adenomas and hy- perplasias are diploid. Parathyroid carcinomas show diploidy
or aneuploidy, with aneuploidy suggesting more aggressive bio- logical behaviour. Parathyroid carcinomas show higher
proliferation than adenomas but proliferation rates are low in all parathyroid pathologies and there is overlap between
entities. Regarding clonality, most parathyroid adenomas and carcinomas are monoclonal. Although diffuse hyperplasia
tends to be poly- clonal, the nodules of nodular hyperplasia may be monoclonal.

There are a few genes that appear to play important roles, mainly:

_ PRAD1 (parathyroid adenoma oncogene 1)

_ MEN1 gene (encodes menin)

  8  
 _ HRPT2 gene (encodes parafibromin)

_ CASR (calcium-sensing receptor) gene. The aetiology of parathyroid carcinoma is unknown; some cases are
associated with various types of hereditary predisposition, particularly HPT-JT syndrome. Case reports suggest
5
that sec- ondary parathyroid hyperplasia and neck irradiation may be possible risk factors.

Rare endocrine malignancy prevalence of 0.005%

Uncommon cause of hypercalcemia 0.5- 1% of PHPT
Sex distribution is equal
Median age 44–54 years and rarely affects children
5-year survival 20-85% and 10-year survival 15-80%

AETIOLOGY PRESENTS
- with prior history of neck • Hypercalcaemia >3.5
irradiation, o muscle weakness
- end-stage renal disease, o fatigue
o depression
- familial isolated HPT
• Hypercalcemic crisis
- HPT-jaw tumor syndrome • extremely high PTH
• palpable neck mass
• Hoarseness secondary to RLN palsy
• pulmonary or osseous metastases
• significant uptake on sestamibi scan

- Some benign adenomas mimic a cancer à definitive diagnosis on clinical or biochemical impossible
- FNAC
o Can confirm a palpable lesion to be parathyroid in origin
o To arrive at a diagnosis of malignancy based on cytology is difficult
o Needle track seeding poses a potential problem
- Intraoperative findings of gross tumor invasion to adjacent strap muscles, thyroid gland, recurrent laryngeal nerve, or
esophagus may help to distinguish a benign adenoma from a carcinoma
- Frozen section examination is of little value, and distinction between adenomas and cancers is difficult even with
histologic examinations
- Efforts to look for a reliable molecular marker using immunohistochemical and genetic techniques
- Testing of HRPT2 germ-line mutation should be considered for patients who have parathyroid carcinoma, and
appropriate genetic counseling should be made

- Imaging
o Preoperative diagnosis or staging and detection of recurrences or metastases during follow-up
o Role of preoperative localization for cancer less well defined than it is benign adenoma
o For patients who have a palpable neck mass or are suspected to have a carcinoma, preoperative localization not
necessary because 4-gland exploration with a wide en-bloc resection performed
o Noninvasive localization studies useful adjuncts for diagnosis and searching for presence of nodal or distant
metastases
o Ultrasonography
§ Useful, noninvasive, and inexpensive imaging
§ Tool of choice for patients who have pHPT undergoing preoperative localization
§ Sensitivity and specificity rates for locating abnormal glands vary between 34%-92% and 90%-97%

  9  
 § Characteristic signs such as invasion to surrounding structures, irregular margins, and suspicious cervical
nodal enlargement aid in the diagnosis of cancer
§ Classic large, heterogeneous, hypoechoic parathyroid masses with irregular borders as shown by
ultrasonography should be suspected to be parathyroid cancer
o 99m Tc sestamibi scintigraphy
§ Most sensitive noninvasive imaging modality used for localizing abnormal parathyroid tissue
§ Overall accuracy of 90%
§ Uptake and retention by functioning carcinoma should not differ from a benign adenoma to account for any
difference in scintigraphy appearance unless there are multiple areas of increased activity to suggest nodal or
distant metastases

o CT and MRI
§ May be of value in assessing the invasiveness of locally advanced cancer
§ Both imaging modalities can provide additional information with reference to the presence of cervical and
mediastinal lymph nodes and pulmonary metastases
§ A combined approach using different imaging modalities in patients who have suspected parathyroid cancer
can improve the diagnostic accuracy, evaluate invasiveness of the carcinoma, and detect associated distant
metastases

o Recurrence or metastases after surgical treatment

§ Noninvasive imaging modalities considered first after confirmation of the biochemical diagnosis
§ US is most accurate in detecting local tumor bed or cervical nodal recurrence, sensitivity of 69%
99m
§ Tc sestamibi scintigraphy useful in locating locoregional and distant metastases sensitivity 70%-80%
§ CT and MRI value in imaging mediastinal or intrathoracic recurrences and in anatomically correlating with a
positive scintigraphy image
§ If all noninvasive modalities turn out to be negative or equivocal, then an invasive study such as selective
venous catheterization with PTH measurement may be considered
§ Similar to imaging for primary cancer, a combined approach using various imaging modalities appears to be
the most effective method for identifying recurrences or metastases

o Intraoperative radio-guided localization

o Intraoperative parathyroid hormone assay

- Role of cinacalcet hydrochloride (Sensipar) for unresectable disease

o Optimal treatment complete removal of localized tumor by surgical resection
o Loco-regional recurrence or distant metastases 33%-78% despite a potentially curative resection
o Delayed recurrence occur up to 20 years after initial surgery, life-long follow-up is recommended
o After recurrence or metastasis is confirmed biochemically and localized radiologically
o Surgical resection should considered but may not be feasible based on its anatomic location and extent
o For resectable diseases, options including wide local excision, modified radical neck dissection, and
metastectomy should be considered
o For unresectable disease, surgical debulking attempted (with a palliative intent) and can facilitate subsequent
medical therapy for refractory hypercalcemia
o Uncommon for advanced, recurrent, or metastatic parathyroid carcinoma to die of malignant cachexia
o Most die of metabolic complications arising from refractory hypercalcemia
o Chemotherapy or radiotherapy does not appear to produce a consistent response or satisfactory outcome in
controlling hypercalcemia
o A new therapeutic agent has shown promise in effectively treating refractory parathyroid carcinoma
o Cinacalcet hydrochloride belongs to a group of second-generation calcium-lowering therapeutic agents, the
calcimimetics, which are capable of reducing serum PTH by 60% to 70% within 2 hours of administration
  10  
 o Its direct action involves binding directly to the calcium-sensing receptor on the cells of the parathyroid gland;
increasing the receptor’s sensitivity to calcium; and reducing PTH, serum calcium, and phosphorus levels
o Preliminary studies show that patients who had refractory parathyroid carcinoma responded favorably
o Drug safety à safety profile well documented in several double-blind, placebo-controlled clinical trials
o Well tolerated with nausea (31%) and vomiting (27%) most commonly reported adverse effects
o Hypocalcemia may be potential adverse effect close monitoring of serum calcium at regular intervals
o For unresectable disease, recommended starting dose 30 mg orally twice daily and should be titrated based on
serum calcium levels
o Dosage adjustment should not be made more frequently than every 2 to 4 weeks
o Because metabolized in liver, many potential drug interactions can occur, and in cases of concurrent therapy with
medications metabolized by liver such as ketoconazole, itraconazole, and vinblastine, the patient should be
monitored even more closely

• If a large, gray-white, locally invasive parathyroid carcinoma is suspected on exploration

o an initial aggressive surgical approach involving en bloc tumour resection
o ipsilateral thyroid lobectomy
o resection of adjacent soft tissues is performed because this is the only potentially curative treatment

• En bloc resection is associated with an 8% local recurrence rate and an overall survival rate of 89%
• Simple parathyroidectomy, in contrast, is associated with a 51% local recurrence rate and a 53% long-term survival rate
• Parathyroid carcinomas tend to recur locally after incomplete excision.
• Distant metastases generally develop in the lungs, liver, and bone; they can occasionally be treated by resection of
individual tumour deposits
• There are no effective chemotherapeutic agents
• In selected patients, adjuvant external beam radiation appears to decrease the rate of local recurrence and may
improve disease-free survival, particularly in high-risk patients

5,13
HUNGRY BONE DISEASE

• Hypocalcemia is a common problem after parathyroidectomy or thyroidectomy. The fall in serum calcium is primarily
due to functional or relative hypoparathyroidism, leading to reductions in bone reabsorption and intestinal calcium
absorption and, in patients without end-stage renal disease, increased calcium excretion.
• The hypocalcemia is generally transient because the degree of bone disease is typically mild and normal parathyroid
tissue recovers function quickly (usually within one week), even after long-term suppression.
• In some cases, however, the postoperative hypocalcemia is severe and prolonged despite normal or even elevated
levels of PTH. This phenomenon, called the hungry bone syndrome, most often occurs in patients who have developed
bone disease preoperatively due to a chronic increase in bone resorption induced by high levels of PTH (osteitis
fibrosa). The underlying hyperparathyroidism can either be primary or secondary due to end-stage renal disease. In
addition to parathyroidectomy, a similar syndrome can occur in patients with end-stage renal disease who are treated
with calcimimetics, which reduce PTH secretion by modulating the calcium-sensing receptor in the parathyroid glands.
• Hungry bone syndrome has also been described after thyroidectomy in patients with hyperthyroidism. In such patients,
the preoperative bone disease is due to high bone turnover induced by excess thyroid hormone.

  11  
 5,18,19,20
MEN SYNDROMES

- Introduced in 1968
- Rare inherited autosomal dominant conditions
- Characterized by synchronous or metanchronous neoplasm in 2 or
more different hormone producing tissue
- Predispose to benign and malignant tumors of pituitary, thyroid,
parathyroids, adrenals, endocrine pancreas, paraganglia, or non-
endocrine organs
- MEN type 1 (MEN1) and MEN type 2 (MEN2)
- Several other hereditary conditions should also be considered in
category of MEN: von Hippel-Lindau syndrome (VHL), familial
paragangliomas syndromes, Cowden syndrome, Carney complex,
hyperparathyroidism jaw-tumor syndrome
- MEN syndromes differ from other hereditary cancer syndromes in that most tumor growth occurs in hormone-
secreting glands
- This has two primary consequences of clinical importance à Excess hormone production
o results in well-defined hormonal syndromes with characteristic symptoms and medical sequelae
o serves as sensitive tumor marker for diagnosis, determining response to therapy and screening asymptomatic
patient

Overview of Endocrine Neoplasia Syndromes

Syndrome Mutated Gene Manifestations

MEN1
MEN subtype2A
MEN subtype2B
Familial medullary thyroid cancer
Hyperparathyroidism-jaw tumor syndrome
Familial isolated hyperparathyroidism
Familial hypocalciuric hypercalcemia
MEN1 Primary hyperparathyroidism (usually four-gland
hyperplasia),anterior pituitary adenomas, tumors of
endocrine pancreas and duodenum, foregut
carcinoids
RET proto- Medullary thyroid cancer, pheochromocytoma,
oncogene primary hyperparathyroidism(usually single
adenoma),cutaneous lichen amyloidosis,
Hirschsprung disease
RET proto- Medullary thyroid cancer, pheochromocytoma,
oncogene marfanoid body habitus, facial features resulting from
mucosal neuromas, ganglio-neruomatosis of the
gastrointestinal tract
RET proto- Medullary thyroid cancer in at least four family
oncogene members, with documented absence of other
endocrinopathies
HRPT2 Primary hyperparathyroidism (usually single
adenoma), ossifying fibromas of maxilla or mandible,
renal cysts and hamartomas, 15%risk of parathyroid
carcinoma
MEN1, HRPT2, Nonsyndromic primary hyperparathyroidism
CASR, other
CASR Benign hypercalcemia; medical management only

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MEN 1

- Tumors in parathyroid, anterior pituitary, endocrine pancreas, duodenum

- Defined as 2 target endocrine tissue affected in an individual
- Occurs as a result of inactivating mutations of MEN 1 gene (MEN1), located on chromosome 11q13
- Menin gene appears to be a tumor suppressor gene
- Autosomal-dominant condition
- Female and male affected equally , females have sporadic HPT more commonly
- Prevalence estimated to be 1 in 20,000 to 40,000 individuals
- MEN1 variable in terms of number of organ systems involved and age at onset of tumors and symptoms
- Most individuals are diagnosed with their first tumors in late adolescence or early adulthood
5
MEN1 Screening Guidelines

- Risk assessment and surveillance

o Should be considered in patients
§ Diagnosed with primary hyperparathyroidism under age 30 years
§ Primary hyperparathyroidism resulting from multi gland involvement
§ Familial primary hyperparathyroidism
§ Zollinger-Ellison syndrome, multifocal pancreatic endocrine tumors, > 2 MEN1-related tumors

o Clinical diagnosis of MEN1 ( remember the PPP)

§ Tumors in 2 of most commonly affected endocrine organs (parathyroid, pituitary, pancreatic/duodenal
endocrine tumors)
§ Patients with 1 such tumor and a family history of MEN1

o Genetic testing for MEN 1

§ Offered to patients in whom a diagnosis of MEN 1 is being considered
§ Benefit is that diagnosis of MEN 1 at early age allows patients to be monitored for development of subsequent
MEN1-related tumors
§ Sensitivity varies depending on combination of affected organs and whether patient is an index or familial
case
§ Mutations can be identified in only 75-90% of patients with a clinical diagnosis of MEN1
§ Negative test result cannot definitively rule out risk for further MEN1-related tumors
o Patients with known MEN 1, family hx of MEN 1 or clinical suspicion following tests are done

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 § Serum calcium, serum gastrin and pancreatic polypeptides, fasting blood glucose, prolactin and head MRI/CT
to investigate for pituitary adenoma

o Routine surveillance of pre-symptomatic patients and treated patients who are currently without evidence of
disease
§ Annual biochemical testing for all tumor types
§ Imaging studies (CT or MRI) every 1 to 3 years

- Diagnosis and management of component tumors

o Parathyroid tumors
§ Primary hyperparathyroidism resulting from benign four-gland hyperplasia
§ Most common presentation of parathyroid disease in MEN1 patients
§ Usually present in 20s and virtually all MEN1 patients are affected by age 50
§ Parathyroidectomy is the cornerstone of the management of primary hyperparathyroidism in MEN1 patients
§ Transcervical thymectomy should always be performed during the first neck operation because MEN1
patients have an increased risk of supernumerary parathyroid glands
§ MEN1patients have an increased incidence of developing carcinoid tumors in the thymus

o Pancreatic and duodenal tumors

§ 75% develop neuroendocrine tumors of the pancreatic islet cells or duodenum
§ Pancreatic endocrine tumors are the most significant source of MEN1-specific morbidity and mortality, mainly
• Potential for malignant transformation but also from complications of hormone overproduction
§ MEN1-associated pancreatic endocrine tumors develop earlier, are multifocal, occur throughout the pancreas
§ Timing and extent of pancreatic resection for MEN1-related pancreatic endocrine tumors remain controversial

o Pituitary tumors
§ 20-60% develop pituitary adenomas
§ Initial manifestation of MEN1 in 10% to 20% of cases
§ Typical onset at age 40, are rare in children
§ Common functioning tumors produce prolactin, growth hormone, or corticotropin
§ Approximately 15% of tumors are non-functioning
§ MEN 1- associated pituitary tumors are usually not malignant or multifocal
§ Most are macroadenomas, 1/3 are invasive and cause morbidity because of mass effects
§ The preferred imaging modality for suspected pituitary tumors is MRI
§ The functional status is determined by biochemical evaluation of basal hormone levels

o Gastrinoma (Zollinger-Ellison syndrome)

§ 40% with MEN1 and may present as abdominal pain, esophagitis, and peptic ulcer disease
§ Patients with ulcers that are multiple, found in atypical locations, fail to respond to medical therapy, recur after
adequate therapy, or are discovered in association with diarrhea or hyperparathyroidism should undergo
evaluation for Gastrinoma
§ Serum gastrin level drawn when patient has discontinued PPI for at least 2 weeks
§ The gastrin level is usually greater than 1000 pg/mL in a patient with Gastrinoma
§ If gastrin level equivocal, secretin stimulation test can be performed, rise in the gastrin > 200 pg/mL
§ Multiple in patients with MEN1 and can occur both within gastrinoma triangle and in body of pancreas and
distal duodenum
§ Gastrinoma management controversial, no consensus achieved regarding surgical management
§ Some investigators have advocated an aggressive approach, which involves early surgical intervention for
any MEN 1 patient with biochemical or radiographic evidence of gastrinoma
§ Other investigators recommend medical management until tumors reach 2.5 to 3 cm in diameter
§ Rationale for conservative approach is that the risk of distant metastasis is small for gastrinomas less than 2.5
to 3 cm and pancreatic resection carries a high incidence of morbidity
§ A reasonable surgical approach includes distal pancreatectomy, enucleation of lesions in the pancreatic head
and uncinate process that are palpable or visible with intraoperative ultrasonography, regional
lymphadenectomy, and duodenotomy with local resection of any tumors found in the duodenum

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 o Insulinoma
§ 10% of MEN 1 patients
§ Classically presents as ‘‘Whipple’s triad’’ of fasting or exercise-induced hypoglycemia, plasma glucose level
less than 50 mg/dL, and reversal of symptoms with administration of glucose
§ The diagnosis is confirmed with a monitored 72-hour fast in which plasma glucose and insulin levels are
measured every 4 to 6 hours
§ An inappropriately high insulin level in the presence of a low glucose level (insulin-to-glucose ratio >0.4) is
indicative of Insulinoma
§ CT and endoscopic ultrasonography are the best tests for localization
§ Unlike other pancreatic endocrine tumors, Insulinoma are usually benign
§ Should be managed surgically
§ Distal pancreatectomy with enucleation of any disease in the pancreatic head or uncinate process that is
palpable or visible by intraoperative ultrasonography

o The other functioning pancreatic endocrine tumors

§ Affect < 5% of patients with MEN1
§ Glucagonoma, VIPomas, somatostatinoma

o Non- functioning pancreatic endocrine tumors

§ Represent up to 71% of surgically treated MEN1-associated pancreatic endocrine tumors
§ Symptoms can arise as a result of local growth or metastatic disease
§ Diagnosis is made with CT, endoscopic ultrasonography, or MRI
§ These tumors are often malignant, metastasizing both to the lymph nodes and to the liver
§ Pancreatic polypeptidoma is considered together with the nonfunctioning pancreatic endocrine tumors
because oversecretion of pancreatic polypeptide does not produce a clinical syndrome

o Other manifestations of multiple endocrine neoplasia type 1

§ Over 40 different tumor types have been reported in patients with MEN 1
§ Not part of diagnostic criteria but support the diagnosis
§ Foregut (thymic, bronchial, orgastric) carcinoid tumors occur in 5%-10%
§ Tend to be non-functional and do not produce carcinoid syndrome
§ Carcinoids typically develop after age 50 years and are usually detected incidentally
§ Carcinoid tumors represent the second leading MEN1-specific cause of death
§ ½ of MEN1 patients develop adenomas, hyperplasia, or ‘‘fullness’’ of the adrenal cortex
§ Rarely, pheochromocytoma, hyperaldosteronism, hypercortisolism, or adrenocortical carcinomas reported
§ 25% of patients à Thyroid tumors, such as follicular adenomas, goiters, occasionally, non-medullary thyroid
carcinoma, patients

MEN 2A

- Manifestations
o Medullary Thyroid Carcinoma
§ Almost all patients with MEN 2A develop MTC
§ These tumors are usually multicentric and preceded by C-cell hyperplasia
§ Occur at a younger age than the sporadic MTC
§ Aggressiveness differs among MEN 2A kindred and appears to depend on the specific ret germline mutation
o Pheochromocytoma
§ Over 70% of patients with MEN 2A develop pheochromocytoma
§ These are frequently bilateral, or are multiple and extra adrenal, but rarely malignant
§ They usually develop in the third to fourth decade of life.
o Hyperparathyroidism
§ Hyperparathyroidism develops in about 50% of patients and may involve multiple parathyroid glands
§ It occurs independently of medullary thyroid carcinoma.
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- Diagnostic Evaluation and Family Screening
o The best screening test to determine whether a family member has inherited MEN 2 is a test for germline ret
proto-oncogene mutation
o The genetic screening test is more than 95% sensitive
o Basal or pentagastrin-stimulated plasma calcitonin level is less sensitive and specific as a screening test, but is
useful for follow-up of patients with MTC
o Metaiodobenzoguanidine (MIBG) is a useful localization study if the patient has biochemical evidence of
pheochromocytoma by urinary or plasma levels of catecholamines and metabolites
o MIBG can identify multiple and extra adrenal pheochromocytomas

- Treatment
o MTC
§ Total thyroidectomy is indicated
§ Central neck and ipsilateral neck lymph node dissection indicated if lymph node metastasis likely
§ MTC is not responsive to postoperative radioiodine treatment or TSH suppression
§ For MEN 2A family members diagnosed genetically with no palpable thyroid tumor or elevated serum
calcitonin, a prophylactic total thyroidectomy alone without lymph node dissection may not be sufficient, since
5-10% of these patients will already have central neck node metastases
§ Patients with MEN2A have variably aggressive MTC
§ Mutations in codons 634, 620, 618, and 611 are considered high risk (level II)
§ Patients with level II mutations should undergo a total thyroidectomy at 5 to 6 years of age
§ Evidence that risk of lymph node metastasis is very low in MEN2A patients < 8 years with normal calcitonin
§ CLND associated with a higher risk of hypoparathyroidism and recurrent laryngeal nerve injury and should be
reserved for patients with elevated calcitonin
§ A larger subset of RET mutations are considered lowest risk (level I) à mutations at codons 768, 790, 791,
804, and 891.30
§ For patients with low-risk level I mutations, total thyroidectomy before age 5 to 10 years appropriate

o Pheochromocytoma
§ Bilateral adrenalectomy is recommended if the patient has bilateral pheochromocytomas
§ Unilateral adrenalectomy with careful follow up is an acceptable option for patients with only a unilateral lesion
by imaging studies
§ The risk of Addisonian crisis after a bilateral adrenalectomy needs to be weighed against the risk of
developing pheochromocytoma in the contralateral adrenal gland
§ Laparoscopic adrenalectomy is the procedure of choice if pheochromocytomas are limited to one or both
adrenal glands
§ In patients with other synchronous tumors, pheochromocytoma should be resected first to avoid hypertensive
crisis when treating other tumors

o Hyperparathyroidism
§ Some endocrine surgeons advocate total parathyroidectomy and auto transplantation for patients with MEN
2A at the time of thyroidectomy
§ The parathyroids are moved from the neck, where reoperations may be necessary
§ Others resect only obviously enlarged parathyroid tumors, arguing that recurrent hyperparathyroidism is rare
and the risk of hypoparathyroidism is high in MEN 2A patients

o Familial medullary thyroid carcinoma (FMTC)

§ The FMTC subtype makes up 5% to 35% of MEN2 cases
§ Defined as families with four or more cases of MTC in absence of pheochromocytoma or parathyroid
adenoma/hyperplasia
§ Families with two or three cases of MTC and incompletely documented screening for pheochromocytoma and
parathyroid disease may actually represent MEN2A; it has been suggested that these families should be
considered unclassified
§ Misclassification of families with MEN2A as having FMTC (because of too-small family size or later onset of
other manifestations of MEN2A) may result in overlooking the risk of pheochromocytoma, a disease with
significant morbidity and mortality
§ For this reason, there is debate about whether FMTC represents a separate entity or is a variation of MEN2A

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MEN 2B

- Manifestations
o Medullary thyroid carcinoma 95%
o pheochromocytoma 50%
o Multiple neuromas 100%
o Marfanoid habitus 70%

- Neuromas and Habitus

o Patients with MEN 2B have unique physical characteristics
o Almost all have marfanoid habitus and multiple neuromas
o The neuromas are especially common on the lips, eyelids, and tongue, producing the “lumpy lips” appearance
o The corneal nerves are thickened
o These physical characteristics may be recognizable even in infancy, before the development of MTC or
pheochromocytoma

- Medullary Thyroid Carcinoma

o If early diagnosis is not made based on phenotype, MTC is usually the first endocrine tumor discovered
o MTC develops at a significantly younger age in patients with MEN 2B
o 15 years earlier than patients with MEN 2A or sporadic MTC
o The clinical course in patients with MEN 2B is also more virulent than in patients with MEN 2A or sporadic MTC
o Metastases are usually present at the time of initial diagnosis

- Pheochromocytoma
o Pheochromocytomas develop in about 50% of patients with MEN 2B
o They are similar to those found in patients with MEN 2A.

- Diagnostic Evaluation and Family Screening

o The characteristic features of patients with MEN 2B can usually be recognized on physical exam
o Genetic diagnosis for ret oncogene mutation should be made as for MEN 2A

- Treatment
o Surgical treatment for MTC and pheochromocytoma is the same as for patients with MEN 2A
o Because MEN 2B is more virulent, prophylactic total thyroidectomy is indicated as soon as the diagnosis is made
even in young children

- Genetic testing
o MEN2 is a well-defined hereditary cancer syndrome for which genetic testing is considered an important part of
the management for at-risk family members
o It meets the criteria related to indications for genetic testing for cancer susceptibility outlined by the American
Society of Clinical Oncology
o At-risk individuals are defined as first-degree relatives (parents, siblings, and children) of a person known to have
MEN2
o Testing allows the identification of people with asymptomatic MEN2 who can be offered risk-reducing
thyroidectomy and biochemical screening as preventive measures
o A negative mutation analysis in at-risk relatives, however, is informative only after a disease-causing mutation has
been identified in an affected relative
o Because early detection of at-risk individuals affects medical management, testing of children who have no
symptoms is considered beneficial

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- Risk-reducing thyroidectomy
o Risk-reducing thyroidectomy and parathyroidectomy with reimplantation of one or more parathyroid glands into
the neck or non-dominant forearm is a preventive option for all subtypes of MEN2
o To implement this management strategy, biochemical screening to identify CCH and/or genetic testing to identify
persons who carry causative RET mutations is needed to identify candidates for risk-reducing surgery
o The optimal timing of surgery, however, is controversial
o Current recommendations are based on clinical experience and vary for different MEN2 subtypes

- Screening of at-risk individuals for pheochromocytoma

o The presence of a functioning pheochromocytoma should be excluded by appropriate biochemical screening
o Childhood pheochromocytomas are rare in MEN2
o ATA has recommended that annual screening for pheochromocytoma be considered after the age of 8 years in
patients with RET mutations in codons 630 and 634 and in patients with RET mutations associated with MEN2B
o In carriers of other MEN2A RET mutations, ATA recommends that annual screening begin by age 20 years.
o Patients with RET mutations associated only with FMTC should have periodic screening for pheochromocytoma
beginning at age 20 years
o MRI or other imaging tests should be ordered only if the biochemical results are abnormal
o Measurement of catecholamine metabolites, specifically plasma-free metanephrines and/or urinary fractionated
metanephrines, provides a higher diagnostic sensitivity than urinary catecholamines because of the episodic
nature of catecholamine excretion
o Pregnant patients who are found to have catecholamine excess require appropriate pharmacotherapy before
delivery

- Screening of at-risk individuals for hyperparathyroidism

o MEN2-related hyperparathyroidism is generally associated with mild, often asymptomatic hypercalcemia early in
the natural history of the disease, which, if left untreated, may become symptomatic
o Childhood hyperparathyroidism is rare in MEN2
o The ATA provides recommendations for annual screening for hyperparathyroidism
o Annual screening should begin at age 8 years in carriers of mutations in codons 630 and 634 and at age 20 years
for carriers of other MEN2A RET mutations
o Patients with mutations associated only with FMTC should have periodic testing after the age of 20 years
o Testing should include albumin-corrected calcium or ionized serum calcium with/without intact PTH measurement

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 2,5,13
OPERATIVE PROCEDURE
POSITION
The patient is usually placed in a supine position, and the neck is extended either by placing the head on a ring or by
placing a rolled towel beneath the shoulders. The neck and the upper thorax are scrubbed, prepped, and draped in the
usual manner. The patient is placed in reverse Trendelenburg position.
INCISION
A curvilinear transverse skin-crease incision is marked with an indelible pen approximately two fingers-breadth above the
clavicle. The skin at the proposed site of incision is infiltrated with 1% lidocaine with epinephrine. The skin incision is
made and deepened with electrocautery until the platysma is identified.
EXPOSURE AND OPERATIVE TECHNIQUE
The platysma is divided with electrocautery, and subplatysmal flaps are developed superiorly and inferiorly. The midline is
identified and the cervical fascia incised. The strap muscles are dissected off the thyroid gland and retracted laterally.
Beginning on either the right or the left side or the side indicated by preoperative imaging, the thyroid lobe is elevated and
rotated medially. The areolar tissue is carefully cleared from around the lobe, and the inferior thyroid artery and the
recurrent laryngeal nerves are identified. It is important to expose the nerve from its entrance into the operative field to the
level of the larynx. As a rule, it is safer to expose vital structures so that they are identified and preserved rather than
avoiding their exposure and iatrogenically damaging them. It is essential to avoid unnecessary bleeding in the operative
field because it can make the identification of parathyroid glands difficult. The parathyroid glands characteristically are
yellowish brown and vary in shape and dimension. The parathyroid gland is also identified by observing a single small
artery entering its hilus and radiating out over the capsule.
The usual number of parathyroid glands is four, although five parathyroid glands can be found in 4% of cases, three in 5%
of cases, and two in less than 1%. The anatomic location of the parathyroid glands is reasonably constant .In
approximately 80% of the cases, the glands are situated symmetrically on opposite sides of the neck. The superior
parathyroid glands are invariably found behind the upper pole of the thyroid gland or at the cricothyroid junction. The
inferior parathyroid glands can be variable in location due to embryologic mobility but are generally found in the immediate
vicinity of the lower pole of the thyroid. The surgeon should identify all parathyroid glands before removing any of them,
however; some surgeons perform preoperative localization and explore and resect only the enlarged parathyroid gland(s).
If an inferior parathyroid gland cannot be found after an extensive search in the operative area, the thymus should be
gently elevated from the mediastinum. If the parathyroid gland still cannot be located, in addition
to examining the thyrothymic ligament, the surgeon should examine the
tracheoesophageal groove, retroesophageal space, and carotid sheath to
locate an ectopic parathyroid gland. The key anatomic structures are the
inferior thyroid artery and its branches, which will often guide the surgeon to
the parathyroid glands If three parathyroid glands have been identified and
one is enlarged and the other two are of normal size, an extensive search is
undertaken. If the fourth gland cannot be found, the procedure may be
terminated because the chance of leaving behind a second hyperfunctioning
parathyroid gland is approximately 5% to 10%. If, on the other hand, two or
more enlarged parathyroid glands have been identified and the fourth gland
cannot be found, a diligent search is necessary because the likelihood that
the remaining fourth gland is enlarged is greater than 50%.
If the retroesophageal and retropharyngeal spaces and the carotid sheath
have been explored and the fourth gland still has not been identified, an
ipsilateral thyroid lobectomy should be considered if the diagnosis of parathyroid hyperplasia is considered. At the initial
exploration, one should not proceed with a sternotomy but should terminate the cervical exploration and then proceed to
confirm the diagnosis by performing localizing studies before undertaking a mediastinal dissection. Once the surgeon has
identified the parathyroid glands, the extent of resection is based on the operative findings. When an adenoma is found
and normal glands are identified, only the adenoma needs to be removed to cure hyperparathyroidism. Biopsy of all three
remaining glands is unnecessary and undesirable because it can lead to ischemic injury.
If four hyperplastic glands are identified, the surgeon has the option of performing a subtotal parathyroidectomy, in which
approximately 35 to 50 mg of one parathyroid gland is left in situ. Alternatively, a total parathyroidectomy with immediate
transplantation of the parathyroid tissue in either the sternocleidomastoid or the forearm muscles may be performed. The
remaining parathyroid gland, whether in the neck or in the forearm, should be marked with hemoclips for subsequent
  19  
 identification if hyperparathyroidism recurs. If four normal parathyroid glands are found, the surgeon has to diligently
search for an adenoma of a supernumerary gland elsewhere in the neck, as described earlier, or within the thyrothymic
ligament or thymus itself.If at the time of surgery the enlarged parathyroid gland feels hard and appears grayish in color
and is firmly fixed to surrounding tissue, the possibility of parathyroid carcinoma should be entertained. In this situation it
is often necessary to perform an ipsilateral thyroid lobectomy and resection of the parathyroid tumor and the adjacent
invading structures. If there are enlarged lymph nodes, a neck dissection may also be needed.
CLOSURE
The wound is irrigated and hemostasis is secured. Routine drainage is usually unnecessary. The platysma is carefully re-
approximated with interrupted 3-0 absorbable sutures. The dermis is closed with interrupted 3-0 absorbable sutures and
the skin is approximated with 4-0 subcuticular nonabsorbable monofilament or absorbable sutures. Steri-Strips are
applied longitudinally, which can act as a dressing as well.

CONCLUSION

The success of minimally invasive parathyroidectomy is dependent upon both preoperative localization studies that limit
the operative field to the region where a presumed single adenoma has been localized, and the use of intraoperative PTH
monitoring to confirm that no other hyperfunctioning gland remains in situ. Guidelines for surgical intervention were
developed based upon risk for end-organ effects and for disease progression. Parathyroidectomy should be performed
only by surgeons who are highly experienced and skilled in the operation.

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