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258
A. Nair and P. BalajiViswanath
17.8 Localization Studies
John Doppman’s skeptical comment on localization studies “the only localization study in a patient with biochemically proven Primary Hyperparathyroidism
is the localization of an experienced parathyroid surgeon” needs correction in
view of changes in imaging technology and surgical approach. No doubt we still
need a surgeon with appropriate skill to perform successful parathyroidectomy.
However, localization studies plus intraoperative adjuncts and technological
advances have helped surgeons perform minimally invasive procedures. Newer
imaging paved way for remote access procedures as well as open mini-parathyroidectomy limiting the need for extensive bilateral neck exploration for selected
patients [2].
17.8.1 Non-Invasive Localization
Ultrasound: A comprehensive imaging of parathyroid using a 5–15MHz transducer
is carried out with the patient in supine position and neck extended. Scanning is
done from the Hyoid bone to the sternal notch extending laterally to include possible ectopic gland in the carotid sheath. The thyroid gland is also scanned to look for
possible nodules and if present guided FNAC is carried out from suspicious nodules
(Fig.17.1).
This picture shows an enlarged parathyroid gland homogenous, solid hypoechoic
lesion which is less echogenic than the thyroid.
Enlarged parathyroids are usually homogenous solid, hypoechoic, and less echogenic than the thyroid. Usually, these adenomas are 8–15mm in size, oval and as
they enlarge become irregular. Cystic parathyroid adenomas present as complex
cystic lesions with internal septations, peripheral nodularity and have an echogenic
border with the thyroid gland. Parathyroid adenomas are vascular and receive blood
supply from polar vessels forming an asymmetric vascular arc around it. This helps
to differentiate from lymph nodes which have a central hilar supply. When used
alone the sensitivity of ultrasound alone is up to 80% in picking up parathyroid
lesions. The diagnostic accuracy is operator dependent and further interfered by
locations such as trachea-esophageal groove. Ultrasound imaging has a further
advantage of better availability compared to scintigraphy. Ultrasound is useful as an
adjuvant anatomical imaging for accurate localization prior to surgery and enables
mini- focused parathyroidectomy.
Parathyroid carcinoma is usually more heterogenous, multilobular and shows
evidence of invasion to surrounding structures with or without lymphadenopathy.
Ultrasound cannot fully assess ectopic locations and multiglandular disease. It also
depends on the patient’s build and body habitus.
17 Surgery oftheParathyroid Gland
Fig. 17.1 Ultrasound
imaging of inferior
parathyroid lesion
259
17.8.2 Scintigraphy
17.8.2.1 Technetium99 Sestamibi Scan
Sestamibi is a lipophilic cation that crosses passively into cells and concentrates in
the mitochondria. Adenomas and hyperplastic glands contain mitochondrial rich
oxyphil cell that concentrates and retain Sestamibi [4]. This radiotracer has afnity
to thyroid as well as to parathyroid but washes off from thyroid earlier. The afnity
to hyperactive parathyroid glands is relatively more persistent than to thyroid but
normal parathyroid glands are not lighted up with the tracer. The differential afnity
is the principle behind dual phase scintigraphy where the delayed scan is done
2–2½h after injection of tracer (Fig.17.2).
260
Fig. 17.2 Tc 99 MIBI dual phase scintigraphy
A. Nair and P. BalajiViswanath
In dual phase single isotope imaging an early image is obtained at 10–15min
after the radiotracer injection in addition to the 90–180-min post injection image.
This method utilizes different rates of washout from the thyroid tissue and retention
in abnormal parathyroid [6] (Fig.17.3).
The addition of SPECT (single photon emission computed tomography) allows
for three-dimensional imaging thereby improving visualization of abnormal parathyroid glands. This has improved sensitivity of parathyroid detection compared to
planar imaging in antero lateral and oblique views.
The sensitivity of Sestamibi dual phase scintigraphy ranges from 61.4% to 100%.
Thyroiditis and thyroid neoplastic nodules retain Sestamibi and can result in false
positive scans. Sometimes early washout from pathological parathyroid tissue can
give false negative results. This underscores the use of SPECT and CT.Size of the
adenoma and serum calcium levels also have a bearing on Sestamibi scans. Large
adenomas with high PTH values and higher calcium levels are more likely to be
lighted up on Sestamibi scans.
Deciency in vitamin D seems to be a predictive for a positive scan. Calcium
channel blockers interfere with the uptake of Sestamibi. Oxyphil cells have higher
mitochondrial content than chief cells and hence oxyphil adenomas have a higher
positive scan rate.
17.8.2.2 Positron Emission Tomography
It has a sensitivity of 86% and a specicity of 78%. FDG—PET has not been widely
used. Recently PET with 11-C methionine that detects amino acid metabolism is
being evaluated. The recent introduction Fluro-choline PET has promising results
inlocalization studies od otherwise obscure lesions.
17 Surgery oftheParathyroid Gland
261
Fig. 17.3 SPECT imaging of right inferior parathyroid adenoma
17.8.3 Computed Tomography
4D CT scan is showing great promise as an imaging modality for locating abnormal
parathyroid glands. The advantages of 4 D CT are that precise anatomical information from CT scan is easy to interpret and can direct surgical exploration. Also,
ectopic locations are fully assessed (Fig.17.4).
17.8.4 Magnetic Resonance Imaging
This is less sensitive than other imaging modalities. The primary advantage of MRI
is no exposure to radiation and therefore can be used in a pregnant woman with
primary hyperparathyroidism (Fig.17.5).
262
Fig. 17.4 Four D CT
showing left inferior
parathyroid adenoma
Fig. 17.5 MRI image of
left inferior parathyroid
adenoma
17.8.5 Invasive Localization
A. Nair and P. BalajiViswanath
Catheter based localization with arteriography and venous sampling is reserved for
remedial patients who fail to localize with noninvasive imaging, discordant imaging, unusual anatomy, or prior neck surgery.
Ultrasound or CT guided FNA combined with rapid PTH assay is a useful
adjunct for patients with equivocal imaging in the setting of prior neck surgery or
for conrmation of glands in ectopic locations.
17.8.6 Intraoperative Localization
17.8.6.1 Radio Guided Surgery
Patients are injected 10mci of Sestamibi, 1–2h prior to surgery. A gamma probe is
used to direct surgery. Radio guidance has been reported to provide several advantages during surgery including facilitating speedy identication of glands, especially in ectopic locations.
17.8.6.2 Intraoperative Ultrasound
Intraoperative ultrasound can be a helpful imaging adjunct for identication of
abnormal parathyroid glands with equivocal pre-operative imaging and in remedial
surgery.
17 Surgery oftheParathyroid Gland
263
Intra-operative parathyroid aspiration: Aspiration of suspicious lesion and estimation of PTH in the aspirate is suggested as an alternate technique of excision and
frozen section biopsy. But this technique needs more validation to estimate the
cut off.
17.8.6.3 Methylene Blue
Methylene blue infusion at 7.5 mg/kg is infused over 15min once the incision is
made. Parathyroid gland retains the dye. False positive staining was noted in normal
parathyroid glands, thyroid tissue, and lymph nodes. All secretions including saliva,
urine will turn blue. Methylene blue is no longer used routinely.
Parathyroid carcinoma (PC): PC is a rare etiology of PHPT and generally considered <1% of all parathyroid lesions. Most of PC are hormonally very active and
shows high disease severity indices like serum calcium and serum PTH. Many
patients present in metabolic crisis and a palpable neck nodule is not rare. There are
no conclusive clinical or biochemical evidences indicating the diagnosis. During
surgical procedure a rm or hard adherent lesion is always found but these observations are seldom unique to PC.Similar features are not uncommon in atypical adenoma and even in adenoma. Since only effective treatment with curative intend is
complete excision without residual malignancy, wide excision is recommended in
patients with suspicious features.
Parathyroidectomy: Parathyroidectomy is the curative surgical procedure for
PHPT.Focused parathyroidectomy through a well-planned small incision is the procedure of choice when localization is successful. The operation is planned as a day
case procedure in mildly symptomatic or asymptomatic PHPT.The scenario is different in many symptomatic patients with high disease severity indices especially
when bone loss is severe. These patients may require early admission and measures
to lower serum calcium levels before operation. Vitamin D deciency is corrected
cautiously. Patients with severe bone loss, severe vitamin D deciency, and advanced
age are likely to develop hungry bone syndrome and a few require parenteral supplementation to severe symptoms of hypocalcemia.
References
1. Akerström G, Malmaeus J, Bergström R. Surgical anatomy of human parathyroid glands.
Surgery. 1984;95(1):14–21.
2. NIH Conference. Diagnosis and management of asymptomatic primary hyperparathyroidism:
consensus development conference statement. Ann Intern Med. 1991;114(7):593–7. https://
doi.org/10.7326/0003- 4819- 114- 7- 593.
3. Cusano NE, Silverberg SJ, Bilezikian JP.Normocalcemic primary hyperparathyroidism. J Clin
Densitom. 2013;16(1):33–9. https://doi.org/10.1016/j.jocd.2012.12.001.
4. Cheung K, Wang TS, Farrokhyar F, Roman SA, Sosa JA.A meta-analysis of preoperative
localization techniques for patients with primary hyperparathyroidism. Ann Surg Oncol.
2012;19(2):577–83. https://doi.org/10.1245/s10434- 011- 1870- 5.
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5. Chan RK, Ibrahim SI, Pil P, Tanasijevic M, Moore FD.Validation of a method to replace frozen
section during parathyroid exploration by using the rapid parathyroid hormone assay on parathyroid aspirates. Arch Surg. 2005;140(4):371–3. https://doi.org/10.1001/archsurg.140.4.371.
6. Coakley AJ, Kettle AG, Wells CP, O’Doherty MJ, Collins RE. 99Tcm sestamibi—a new
agent for parathyroid imaging. Nucl Med Commun. 1989;10(11):791–4. https://doi.
org/10.1097/00006231- 198911000- 00003.
A. Nair and P. BalajiViswanath
Management ofPHPT inMEN 1 andMEN
2 Syndrome
18
SabaretnamMayilvaganan andP.R.K.Bhargav
18.1 Introduction
Primary hyperparathyroidism (PHPT) is a common endocrine disease, and a few
have syndromic associations with Multiple Endocrine Syndrome Neoplasia Type 1
and Multiple Endocrine Neoplasia Type 2. Multiple Endocrine Neoplasia Type 1
(MEN 1) is characterised by neoplasms of parathyroid glands, pituitary, and gastropancreatic endocrine cells with phenotype expression of two or more organs. The
PHPT is the commonest presentation of MEN 1. MEN 2 is the association of medullary thyroid cancer, pheochromocytoma, and neoplasms parathyroid. Usually,
hyperparathyroidism associated with MEN 2 is mild and asymptomatic. PHPT is
frequently encountered as expression mutations in exon II, codon 634 of MEN 2.
The treatment of choice is excision of the enlarged parathyroid gland [1, 2].
18.2 MEN 1
Multiple endocrine neoplasia Type 1 is a rare hereditary syndrome with a wide
range of expressions, including about 20 types of endocrine and non-endocrine
tumours. The principal organs are the anterior pituitary gland, parathyroid, and
entero-pancreatic endocrine tissue, and phenotype expressions occur in two or more
of these locations. The genetic changes in MEN 1 was identied in 1997 and was
found positive in about 90% of patients. Genetic testing is now recommended and
helps identify asymptomatic carriers who remain on biochemical screening.
S. Mayilvaganan (*)
Department of Endocrine Surgery, SGPGI, Lucknow, Uttar Pradesh, India
P. R. K. Bhargav
Department of Endocrine & Breast Surgery, Sanjay Gandhi Postgraduate Institute of Medical
Sciences (SGPGIMS), Lucknow, Uttar Pradesh, India
© The Author(s), under exclusive license to Springer Nature Singapore Pte
Ltd. 2024
C. G. Nair, S. J. Abraham (eds.), Surgical Management of Thyroid and
Parathyroid Diseases, https://doi.org/10.1007/978-981-97-3774-1_18
265
266
S. Mayilvaganan and P. R. K. Bhargav
18.2.1 Primary Hyperparathyroidism inMEN 1
Primary hyperparathyroidism is the most common form of endocrinopathy in MEN
1 and accounts for 2–4% of all forms of primary hyperparathyroidism. In most
occasions, hyperparathyroidism is the earliest occurring endocrine expression of
MEN 1. It manifests between 20–25 years of age, about a decade or two earlier than
the non-syndromic PHPT.Patients with proven PHPT at a younger age with a positive family history should be screened for MEN 1 syndrome. However, the genotypephenotype correlation for transmission of PHPT in MEN 1 has yet to be identied.
Nodular hyperplasia involving multiple parathyroid glands is typical of MEN 1;
however, adenomas are seen rarely. There is no symmetry in volume or size, volume, and weight. However, each gland expresses a monoclonal lesion. Supernumerary
glands can be found in 20% of MEN 1 patients. Rarely parathyroid adenomas
located in ectopic locations and parathyroid remnants in the thymus assume great
signicance.
The treatment is essentially surgery, but the optimal extent of removal is disputed
[3, 4]. Subtotal parathyroidectomy is the excision of 3–3½ glands, and total
Parathyroidectomy is the removal of all parathyroid glands and autologous parathyroid tissue graft [5, 6]. After total parathyroidectomy, a portion of relatively normallooking parathyroid is implanted in the brachioradialis muscle of the non-dominant
arm. Cervical thymectomy is generally combined with subtotal or total parathyroidectomy to ensure the removal of accessary parathyroid remnants. The so-called total
parathyroidectomy may not be a curative procedure, and recurrence is inevitable, so
the surgery is aimed at preventing the complications of hyperparathyroidism [7, 8]
(Algorithm, Box 18.1 and Fig.18.1).
Fig. 18.1 Total
parathyroidectomy with
auto transplantation for
MEN 1
Algorithm
cS
l
IOPTH role not clear
Ex
18 Management ofPHPT inMEN 1 andMEN 2 Syndrome
Hypercalcemia
PTH
Primary Hyperparathyroidism
Age, Calcium levels, family
History, genetic tests
Sporadic or Syndromic
267
Sporadi
MIP/ UNE / BNE
cision of enlarged
gland
IOPTH useful
MEN 1
No Imaging
BNE
Subtotal
Total Parathyroidectomy
Vs
yndromic
MEN 2AUSG + MIBI
USG+ MIBI
MIP
Excision
IOPTH usefu
18.3 MEN 2
Multiple endocrine neoplasia Type 2A is an autosomal dominant syndrome [9] the
phenotype includes Pheochromocytoma (usually bilateral synchronous), medullary
thyroid carcinoma, and PHPT.The majority of patients have medullary thyroid carcinoma as the initial manifestation, and the pheochromocytoma may be diagnosed
at a later stage. PHPT is seen in 15% of MEN 2A and is asymptomatic. Mutations
of the Rearranged During Transfection (RET) proto-oncogene have been documented in MEN 2, and the mutation analysis should be considered in suspected
MEN 2 patients. The clinical expression developing each of the three pathognomonic tumours in MEN 2A is based on the codon-specic variant, and it is most
penetrant in the highest and high-risk groups.
MEN 2B phenotype includes pheochromocytoma, MTC, mucosal neuromas,
thickened corneal nerves, intestinal ganglioneuromas, and marfanoid body habitus.
PHPT is usually not present in these individuals. MEN 2B is primarily associated
with mutations in codon 918 [10].