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256
maintain eucalcemia for as long as possible, to minimize iatrogenic
hypoparathyroidism, to minimize operative complications, all while facilitating the ease of future surgery in the setting of recurrence [3].
T. Rajwani and J. E. Gosnell
Multiple Endocrine Neoplasia 2A and2B (MEN2A
andMEN2B)
• MEN2A is an autosomal dominant syndrome that occurs as a result of muta-
tions in the RET proto-oncogene, located on chromosome 10q11.2. MEN2A
manifests with medullary thyroid cancer, pheochromocytoma, and primary
hyperparathyroidism. MEN2B manifests with medullary thyroid cancer,
pheochromocytoma, mucosal neuromas, and marfanoid habitus [4, 5].
• Specic RET mutations are associated with a particular phenotype and clinical
course. As such, the American Thyroid Association (ATA) straties these mutations based on the increasing risk of an aggressive phenotype of MTC, as well as
characterizing the relative incidence of extra-thyroidal diseases. Early thyroidectomy is recommended for medullary thyroid cancer, and timing recommendations are based on RET mutation risk categories (moderate, high, or highest risk
mutations) as depicted in Fig.28.1 [4, 5].
• The surgical management of medullary thyroid cancer when diagnosed clini-
cally involves total thyroidectomy with bilateral central neck lymph node dissection. A compartmental lateral neck dissection is carried out for biopsy-proven
lateral neck lymph node metastases [5]. For those diagnosed through genetic
testing with RET mutations, the surgical management often involves a total thyroidectomy alone, given very early and pre-clinical disease. Central and lateral
lymph node dissections are indicated based on calcitonin levels and ultrasound
ndings.
• Primary hyperparathyroidism affects 20–30% of patients with MEN2A, and
unlike in MEN1, not all glands are equally affected. The most common operative
strategy in these patients is a focused parathyroidectomy with intraoperative
parathyroid hormone monitoring [6].
• Biochemical evaluation must be performed to rule out pheochromocytoma prior
to thyroid or parathyroid surgery to prevent life-threatening intraoperative hemodynamic instability. The treatment for pheochromocytoma is adrenalectomy following adequate alpha blockade and volume expansion [7].
28 Familial Endocrine Syndromes
• Physical exam, US
of the neck, and
measurement of
serum levels of Ctn
and CEA every 6
months for one year
then annually
• Begin screening for
PHEO at 11 years
of age
• Same as above
• Follow with evalua-
tion every 6 months for
1 year, then annually
if serum Ctn remains
• If serum Ctn is
elevated but
< 150 pg/mL measure
undetectable or within
normal range
serum levels of Ctn
and CEA every 3 to 6
months to determine
• Begin screening for
PHEO at 18 years
of age
doubling times
• If serum Ctn is >150
pg/mL initiate imaging
procedures to detect
MTC metasases
• If metasases are
found, treatment
is based on site. If
systemic diseases
consider systemic
257
therapies
TTX in the first year, or
the first months of life,
based on discussions
with the endocrinolo-
gist, the surgeon, and
MEN2B
the parents. Level VI
lympy node dissection
dependent on the
ability to identify and
preserve or transplant
(ATA-HST)
the parathyroid glands
TTX at or before 5
years of age based on
serum Ctn levels
TTX to be performed
(ATA-H)
MEN2A
Children
RET Germline
when the serum Ctn
level becomes ele-
vated, or in childhood
if the parents do not
mutation
• Normal physical
wish to embark on
a lengthly period of
MEN2A
(ATA-MOD)
exam and normal US
of the neck
evaluation, which
might last for years or
decades
• Measure serum levels
of Ctn and CEA
• Annual testing. If Ctn
becomes elevated,
Normal serum Ctn
• Exclude PHEO
• TTX and dissection
of lymph node com-
partments depending
Elevated serum Ctn
Adults
on US findings and
preoperative serum
Ctn levels
Fig. 28.1 Prophylactic thyroidectomy in patients with hereditary MTC [5]
258
T. Rajwani and J. E. Gosnell
Neurobromatosis Type 1 (NF1)
• NF1 is an autosomal dominant syndrome due to mutations in the NF1 tumor sup-
pressor gene located on chromosome 17.
• The diagnosis is primarily clinical given poor genotype-phenotype correlations.
• The primary endocrine tumors seen in NF1 are pheochromocytoma/paragangli-
oma and gastroenteropancreatic neuroendocrine tumors [8].
PTEN Hamartoma Tumor Syndrome
• This syndrome arises as a result of germline mutations in the PTEN tumor sup-
pressor gene, and encompasses the clinical phenotypes of Cowden syndrome
(CS), Bannayan-Riley-Ruvalcaba syndrome, PTEN-related Proteus syndrome,
and Proteus-like syndrome.
• Cowden syndrome is the most common phenotype, presenting with multiple
hamartomas, endometrial tumors, breast tumors, and benign and malignant thyroid tumors [9, 10].
• The lifetime risk of thyroid cancer in patients with PTEN mutations has histori-
cally been estimated around 3–10%, however, more recent studies estimate the
risk to be as high as 35% [11].
• Papillary thyroid cancer, including its follicular variant, accounts for the major-
ity of thyroid cancers in patients with PTEN mutations.
Li-Fraumeni Syndrome
• Inherited in an autosomal dominant manner, Li-Fraumeni syndrome involves
germline mutations in the P53 tumor suppressor gene.
• Patients develop soft tissue and bone sarcomas, leukemias, breast cancers, adre-
nocortical carcinomas, and brain tumors.
• The adrenal cortex is the third most common site of neoplasia in patients with
Li-Fraumeni syndrome [12, 13].
APC-Associated Polyposis
• APC-associated polyposis disorders result from germline mutations in the APC
tumor suppressor gene and include the syndromes familial adenomatous polyposis (FAP), attenuated FAP, Gardner syndrome, and Turcot syndrome.
• These patients are at an increased risk of developing functional and non-
functional adrenal gland tumors, and rarely adrenocortical carcinoma.
28 Familial Endocrine Syndromes
• Patients with APC-associated polyposis have a 1–2% lifetime risk of thyroid
cancer. Unique to FAP is the cribriform-morular variant of papillary thyroid cancer [14].
259
Von Hippel-Lindau Syndrome (VHL)
• VHL is an autosomal dominant condition associated with inactivating mutations
of the VHL gene located on chromosome 3.
• Patients with VHL are at an increased risk of developing hemangioblastomas of
the CNS, renal cell carcinoma, pancreatic neuroendocrine tumors, pheochromocytoma, endolymphatic sac tumors, and visceral cysts [15].
Hereditary Pheochromocytoma/Paraganglioma Syndromes (SDH Mutations)
• Pheochromocytomas and paragangliomas (PCC/PGL) are neuroendocrine
tumors derived from the adrenal medulla and extra-adrenal sympathetic or parasympathetic ganglia, respectively.
• Approximately 30–40% of PCC/PGL are associated with a germline mutation in
a known susceptibility gene [16].
• Approximately 20% of all patients with PCC/PGL have mutations in one of the
succinate dehydrogenase (SDH) genes, with SDHB and SDHD mutations being
the most common. Most of the SDH-related PCC/PGL have a normetanephrine
and/or dopamine-predominant production [17]. SDHD mutations are most commonly associated with head and neck PGL. SDHB mutations are most commonly associated with abdominal and pelvic PCC/PGL [18].
Familial Non-Medullary Thyroid Cancer (FNMTC)-Non Syndromic
• Familial thyroid cancer may occur as a part of a syndrome, as described earlier
in the chapter, or may be non-syndromic where thyroid cancer is the major feature of the disease.
• FNMTC is diagnosed when at least two rst-degree relatives are diagnosed with
a non-medullary thyroid carcinoma [19]. However, there is a 95% probability
that a patient has FNMTC when ≥3 rst-degree relatives are affected, compared
to 31–38% when only two rst-degree relatives are affected.
• Whether FNMTC is more aggressive than sporadic disease is a matter of debate.
It is believed that patients with FNMTC present at a younger age, and have
higher rates of bilateral disease, extrathyroidal extension, and lymph node and
distant metastases [20].
260
T. Rajwani and J. E. Gosnell
References
1. Thakker RV.Multiple endocrine neoplasia type 1 (MEN1). Best Pract Res Clin Endocrinol
Metab. 2010;24:355–70.
2. Schneider DF, Mazeh H, Chen H, etal. Predictors of recurrence in primary hyperparathyroidism: an analysis of 1386 cases. Ann Surg. 2014;259:563–8.
3. Nobecourt PF, Zagzag J, Asare EA, etal. Intraoperative decision-making and technical aspects
of parathyroidectomy in young patients with MEN1 related hyperparathyroidism. Front
Endocrinol (Lausanne). 2018;9:618.
4. Raue F, Frank-Raue K.Update on multiple endocrine neoplasia type 2: focus on medullary
thyroid carcinoma. J Endocr Soc. 2018;2:933–43.
5. Wells SA Jr, Asa SL, Dralle H, Elisei R, Evans DB, Gagel RF, Lee N, Machens A, Moley JF,
Pacini F, Raue F, Frank-Raue K, Robinson B, Rosenthal MS, Santoro M, Schlumberger M,
Shah M, Waguespack SG.American Thyroid Association guidelines task force on medullary
thyroid carcinoma. Revised American Thyroid Association guidelines for the management of
medullary thyroid carcinoma. Thyroid. 2015;25(6):567–610.
6. Alevizaki M, Saltiki K.Primary hyperparathyroidism in MEN2 syndromes. Recent Results
Cancer Res. 2015;204:179–86.
7. Kiernan CM, Du L, Chen X, etal. Predictors of hemodynamic instability during surgery for
pheochromocytomachromocytoma. Ann Surg Oncol. 2014;21:3865–71.
8. Anon. National Institutes of Health consensus development conference statement:
Neurobromatosis. Bethesda, 1987. Neurobromatosis. 1988;1:172–8.
9. Liaw D, Marsh DJ, Li J, Dahia PL, Wang SI, Zheng Z, Bose S, Call KM, Tsou HC, Peacocke
M, Eng C, Parsons R.Germline mutations of the pten gene in Cowden disease, an inherited
breast and thyroid cancer syndrome. Nat Genet. 1997;16:64–7.
10. Harach HR, Soubeyran I, Brown A, Bonneau D, Longy M.Thyroid pathologic ndings in
patients with Cowden disease. Ann Diagn Pathol. 1999;3:331–40.
11. Bubien V, Bonnet F, Brouste V, Hoppe S, Barouk-Simonet E, David A, Edery P, Bottani A,
Layet V, Caron O, et al. High cumulative risks of cancer in patients with PTEN hamartoma
tumour syndrome. J Med Genet. 2013;50:255–63.
12. Malkin D, Li FP, Strong LC, Fraumeni JF Jr, Nelson CE, Kim DH, Kassel J, Gryka MA,
Bischoff FZ, Tainsky MA, etal. Germ line p53 mutations in a familial syndrome of breast
cancer, sarcomas, and other neoplasms. Science. 1990;250:1233–8.
13. Gonzalez KD, Noltner KA, Buzin CH, Gu D, Wen-Fong CY, Nguyen VQ, Han JH, Lowstuter
K, Longmate J, Sommer SS, Weitzel JN.Beyond Li Fraumeni syndrome: clinical characteristics of families with p53 germline mutations. J Clin Oncol. 2009;27:1250–6.
14. Groen EJ, Roos A, Muntinghe FL, Enting RH, de Vries J, Kleibeuker JH, Witjes MJ, Links
TP, van Beek AP.Extra-intestinal manifestations of familial adenomatous polyposis. Ann Surg
Oncol. 2008;15:2439–50.
15. Maher ER, Kaelin WG Jr. von Hippel-Lindau disease. Medicine (Baltimore). 1997;76:381–91.
16. Fishbein L, Merrill S, Fraker DL, Cohen DL, Nathanson KL.Inherited mutations in pheochromocytoma and paraganglioma: why all patients should be offered genetic testing. Ann Surg
Oncol. 2013;20:1444–50.
17. Eisenhofer G, Lenders JW, Timmers H, Mannelli M, Grebe SK, Hofbauer LC, Bornstein
SR, Tiebel O, Adams K, Bratslavsky G, etal. Measurements of plasma methoxytyramine,
normetanephrine, and metanephrine as discriminators of different hereditary forms of pheochromocytoma. Clin Chem. 2011;57:411–20.
18. Jochmanova I, Wolf KI, King KS, Nambuba J, Wesley R, Martucci V, Raygada M, Adams KT,
Prodanov T, Fojo AT, etal. SDHB-related pheochromocytoma and paraganglioma penetrance
and genotype-phenotype correlations. J Cancer Res Clin Oncol. 2017;143:1421–35.
19. Malchoff CD, Malchoff DM. Familial nonmedullary thyroid carcinoma. Cancer Control.
2006;13:106–10.
20. Wang X, etal. Endocrine tumours: familial nonmedullary thyroid carcinoma is a more aggressive disease: a systematic review and meta-analysis. Eur J Endocrinol. 2015;172:253–62.
Chapter 29
Re-operative Thyroid andParathyroid
Surgery
SaraAbou Azar andPeterAngelos
Re-operative Parathyroid Surgery
Incidence of hyperparathyroidism in the United States is approximately 1–4in 1000
(incidence increases with age>55) [1]. Hyperparathyroidism is divided into primary, secondary, and tertiary. Surgical management of this disease is dependent on
establishing the diagnosis and ensuring an indication for surgery, before conrming
localization of the abnormal gland(s). Since the risks of surgery are higher in reoperative parathyroid surgery, careful assessment of the patient’s comorbidities is
essential when deciding if the benets outweigh the risks [2].
It is important to distinguish two different indications for re-operation:
– Persistent hyperparathyroidism occurs within 6months of primary parathyroid-
ectomy and is often due to failure to nd and remove the offending gland or
glands [1, 3].
– Recurrent hyperparathyroidism occurs when cure was initially achieved after a
prior operation; however, elevated values are noted more than 6months after
primary resection [1, 3].
Once surgical intervention is planned, two main approaches can be offered
depending on pre-operative imaging: focused parathyroidectomy and/or 4 gland
exploration in conjunction with the use of intraoperative PTH.Cure is conrmed
with a drop to at least 50% of baseline and to with in normal range [4]. It is
S. Abou Azar (*)
Department of Surgery, University of Chicago, Chicago, IL, USA
e-mail: sara.abouazar@uchicagomedicine.org
P. Angelos
Endocrine Surgery, MacLean Center for Clinical Medical Ethics, University of Chicago,
Chicago, IL, USA
e-mail: pangelos@bsd.uchicago.edu
Switzerland AG 2024
R. M. Gartland, J. A. Lee (eds.), Endocrine Surgery Clerkship, Contemporary
Surgical Clerkships, https://doi.org/10.1007/978-3-031-62091-1_29
261© The Author(s), under exclusive license to Springer Nature
262
S. Abou Azar and P. Angelos
acceptable to proceed with surgery despite non-localizing studies when performing
the rst operation. However, when re-operation is indicated, it is essential to localize the abnormal parathyroid gland pre-operatively to increase cure rates and
decrease complications associated with re-operation [5]. In general, it is best to
avoid surgery in the re-operative setting without positive localization. It is important
to note that if a patient previously had a neck operation such as a thyroidectomy
which inevitably causes scarring in the region of the parathyroid glands, such a
patient should be treated as undergoing a re-operative parathyroidectomy rather
than as a primary parathyroidectomy patient.
During pre-operative evaluation, the surgeon should ask themselves the
following:
– What was the indication for the primary surgery and does the patient still fulll
the criteria for surgical intervention?
– Is the operative note from prior surgeries available for review? Finding out
exactly which planes have been violated and which glands were removed, if any,
is important in future surgical planning.
– What does the pathology report say and is it concordant with the operative nd-
ings as described in the operative report?
Any patient who has had prior neck operations, especially thyroid/parathyroid
operations, should undergo a pre-operative vocal cord exam. This is done by undergoing an ofce laryngoscopy to assess for mobility of the vocal cords and any
abnormalities. Laryngoscopy may also be indicated for other prior neck operations
such as carotid endarterectomy or cervical spine operations through an anterior
approach.
Key points in re-operative parathyroidectomy:
– Be exible regarding prior parathyroid gland excision labeling.
– No harm in waiting longer to re-operate while proper imaging studies are
obtained.
– Ensure adequate localization and identication of the abnormal gland prior to
deciding on surgery.
Localization studies:
– Start with ultrasound and Sestamibi scan (99mTc-sestamibi parathyroid scintig-
raphy with SPECT/CT) (Fig.29.1a, b). These studies are more widely available
and less costly. Although ultrasound is an excellent modality for imaging, there
are drawbacks namely:
It can be operator-dependent.
It can be difcult to nd very posterior glands and/or glands in ectopic locations.
– Even if a parathyroid gland is identied on an ultrasound, correlation of the nd-
ing on Sestamibi scan is important in the re-operative setting due to the higher
risks of the operation and the increased difculty in looking at additional glands
29 Re-operative Thyroid andParathyroid Surgery
263
a
b
Fig. 29.1 (a) 99mTc-sestamibi with SPECT/CT, arrow indicates localized right-sided abnormal
parathyroid gland. (b) US thyroid with yellow arrow indicating corresponding right-sided abnormal parathyroid gland in the same patient
if the gland identied on the ultrasound proves to not be the abnormal parathy-
roid gland [3, 5].
– If an abnormal parathyroid gland is not clearly localized on ultrasound and
Sestamibi scan, obtain a 4D CT scan of the neck and chest [3]. Of note, some
institutions may choose to obtain a 4D CT initially rather than a Sestamibi scan.
The 4D CT incorporates the added dimension of time and contrast perfusion,
where parathyroid glands have rapid uptake and washout.
Three phases: non-contrast phase, arterial phase, venous phase.
Provides anatomical and functional information.
Drawbacks: unavailable in certain institutions, contrast and radiation
exposure.
– Other adjuncts to consider that are potentially valuable in the re-operative set-
ting, some with the ability to look at all parathyroid glands in the operating room,
are the following:
Selective venous sampling for PTH levels [6] (Fig.29.2).
Performed by interventional neuroradiology via femoral venous access.
Selective sampling of PTH levels from bilateral neck and upper chest
venous drainage constructing a road map of PTH levels.
264
Fig. 29.2 Selective
parathyroid venous
sampling. Elevated intact
PTH levels at the inferior
thyroid vein (357)
compared to the remaining
values indicate a potential
left inferior abnormal
parathyroid gland (red star)
The closer the sample is to the venous drainage of an abnormal gland, the
higher the level of PTH.
S. Abou Azar and P. Angelos
FDG PET/CT (18F-uorocholine positron emission tomography/computed
tomography) or choline PET/CT [3, 5].
Intraoperative radionuclear mapping: a pre-operative injection similar to what
is given for a Sestamibi scan is given right before the start of the procedure.
Intraoperatively, a gamma detection probe is used during exploration to identify abnormal uptake.
Intraoperative use of near-infrared uorescence imaging [7, 8].
Intraoperative nerve monitoring.
Surgical scenarios in re-operative parathyroidectomy include the following:
– If one gland is abnormal, proceed with removal of the offending single adenoma.
– If several glands are abnormal, consider subtotal parathyroidectomy vs total
parathyroidectomy and auto-transplantation.
– If three glands have already been removed and one remaining adenoma is identi-
ed, it may be necessary to proceed with total resection of the gland and auto-
transplantation of a small portion of that gland.
29 Re-operative Thyroid andParathyroid Surgery
265
Re-operative Thyroidectomy andLymph Node Dissection
Re-operative thyroidectomy is often performed in cases following thyroid lobectomy where pathology reveals thyroid cancer with high-risk features requiring postoperative radioactive iodine. As such, completion thyroidectomy is indicated. Other
instances include recurrence in the thyroid bed though this is less common. It is also
quite important to understand the biology of the different types of thyroid cancer.
Well-differentiated tumors such as papillary, follicular, and Hurthle cell cancers
behave differently than other, more aggressive types. For example, in recurrent
medullary thyroid cancer, rule out distant disease rst as re-operative surgery may
not necessarily improve survival and may be of less value in the face of distant
metastases.
Pre-operative workup of redo thyroid surgery includes the following:
– Obtain slides, operative notes, and pathology reports from previous operations to
help identify any prior injuries, challenges, or extent of disease. Know the
anatomy.
– Perform a pre-operative laryngoscopy to assess vocal cords.
– Review US imaging and perform an FNA biopsy of any suspicious lesions.
– Pre-operative surgical planning is key to avoid complications in a scarred opera-
tive eld. Consider the possibility that the recurrent laryngeal nerve may be
involved and might need to be sacriced. Such a possibility must be discussed
with patients prior to surgery.
– Discuss thyroid cancer cases in a multidisciplinary tumor board. Do the risks of
re-operation outweigh the possibility of progression of disease or recurrence?
How will re-operation affect survival and prognosis?
– Assess lymph node status. Ensure adequate imaging via ultrasound or CT scan-
ning if necessary. PET scans may be of value for less well-differentiated tumors.
In general, attempt to rst remove abnormal lymph nodes surgically. RAI is
rarely effective in ablating grossly abnormal nodes. Other options include percu-
taneous ethanol ablation, external beam radiation, microwave ablation, or radio-
frequency ablation [9]. Identify if bilateral central neck dissection is indicated
versus unilateral, and evaluate the need for lateral neck dissection.
Intraoperative considerations in re-operative neck dissection:
– If lateral lymph node recurrence is identied and no prior central neck dissection
was performed, consider proceeding with central neck dissection (CND). If
CND was done in the initial operation, do not proceed unless pre-operative imag-
ing conrms recurrent disease in the central neck.
– Balance benets of extensive surgery and lymph node harvesting with risks of
injury to parathyroid glands and recurrent laryngeal nerve, which are 3–4 times
higher in re-operative cases than in initial surgery.
– Consider use of intraoperative ultrasound-guided methylene blue dye injections
to help identify abnormal nodes in the lateral neck when there is scarring from
prior surgery [7, 10]. Do not use methylene blue dye injection in the central neck