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36
A. Tumati and B. M. Finnerty
Fig. 5.1 Computerized tomography scan of a retrosternal thyroid goiter. *: Right thyroid lobe
with a retrosternal goiter extending into the mediastinum. ξ: Trachea with a leftward deviation and
narrowing due to external compression from goiter. ∫: Lobulated and enlarged left thyroid lobe
Etiology [2–6]
• Development of goiters stems from a complex interaction between genetic and
environmental factors.
• The incidence rate of palpable thyroid nodules ranges from 0.8–1.5% and
5.3–6.4% for males and females, respectively, with 95% of all thyroid nodules
being benign.
• While iodine deciency is the most common cause of goiter worldwide, in the
United States multinodular goiter (MNG), Hashimoto’s (autoimmune) thyroiditis, and Graves’ disease are more prevalent causes of goiter formation.
• The differential diagnosis of benign goiters also includes thyroiditis, inltrative
diseases, cysts, adenomas, etc. (Table5.1).
• The most important risk factors associated with goiter development are iodine
deciency and smoking. Thiocyanate resulting from the metabolism of cyanide
in tobacco smoke is believed to be the most likely source.
5 Goiter andBenign Thyroid Nodules
Table 5.1 Differential diagnosis of benign goiters
Description Lab tests
Hyperthyroidism
Grave’s disease Auto-antibodies activate TSH receptors leading to
increased thyroid hormone production; diffusely
enlarged thyroid
Toxic multinodular
goiter
Hypothyroidism
Hashimoto’s
thyroiditis
Postpartum
thyroiditis
Subacute De
Quervain
thyroiditis
Riedel’s thyroiditis Fibrotic, painless nodule. “Hard-as-wood” nodule.
Euthyroidism
Follicular nodule Usually solitary thyroid nodule Normal TSH; Normal
Non-toxic
multinodular
goiter
Nodules distributed throughout thyroid gland Low TSH; elevated
Chronic lymphocytic inltration of thyroid.
Painless
Autoimmune destruction of thyroid following
pregnancy. Progresses from hyperthyroid to
euthyroid to hypothyroid. Painless
Usually in young females. Preceded by upper
respiratory infection. Painful nodule. Hyperthyroid
state followed by hypothyroidism
Usually hypothyroid but can present as euthyroid
Nodules distributed throughout thyroid gland Normal TSH; Normal
Low TSH; elevated
free T4 and T3; TSI
elevated
free T4 and T3; TSI
negative
High TSH; low,
normal, or high free
T4 and T
3
Variable based on
disease progression
Variable based on
disease progression
Variable
free T4 and T
free T4 and T
3
3
37
Pathogenesis [3, 7]
• Iodine deciency and chronic autoimmune thyroiditis leads to increased amount
of thyroid stimulating hormone (TSH) secretion, which then causes hyperplasia
and hypertrophy of thyroid follicular cells.
• Nodules that produce thyroid hormone independent of TSH develop in the setting of activating mutations in the TSH receptor or G proteins within follicular
cells. Note: these are classied as toxic goiters.
• Patients with sporadic non-toxic multinodular goiters can grow over time due to
several growth factors that act on follicular cells—the annual increase in goiter
volume has been estimated ~5%.
• Graves’ disease patients have auto-antibodies that stimulate the TSH receptor
leading to hyperthyroidism and diffuse enlargement of the thyroid.
• In individuals with a family history of goiters, genetic development appears to be
polygenic with various loci identied across numerous chromosomes.
38
A. Tumati and B. M. Finnerty
Evaluation
History
• Assess for pre-existing chronic autoimmune thyroiditis, iodine intake, head and
neck radiation, medication history, or family history of benign/malignant thyroid
disease.
• Evaluate for symptoms of hyperthyroidism or hypothyroidism.
• Determine the presence of compressive/obstructive symptoms (e.g., dyspnea,
shortness of breath, dysphagia, voice changes, and/or sensation of neck tightness).
Physical Examination [8]
• Steps to perform a comprehensive thyroid exam:
– Observe for external signs of obvious neck masses, tracheal deviation, or
dilated veins over the anterior chest wall and neck.
– Stand behind the patient, reach both hands around the patient’s neck to nd
the cricoid cartilage, which is the rst cartilaginous ring below the thyroid
cartilage.
– Then move your ngertips laterally to assess the thyroid lobes, checking for
symmetry.
– To assess the right lobe, press down on the left thyroid lobe to rotate the right
thyroid lobe anteriorly. Repeat this process to assess the left lobe.
– Next, ask the patient to swallow (tip: ask the patient to drink water) to evalu-
ate for any nodules that may be retrosternal.
– Ask the patient to elevate both their hands above their head for 60s. Any sign
of facial fullness, cyanosis, or inability to swallow (i.e., Pemberton’s sign)
following this maneuver suggests retrosternal extension and obstruction of
the thoracic inlet of the goiter.
– Finally, palpate the lateral neck bilaterally to examine for cervical
lymphadenopathy.
• Thyroid goiters palpated on physical exam should further be characterized by
size, distribution (solitary or diffuse), consistency (rm/xed, rubbery, or soft),
and pain (tender or non-tender).
• Evaluate the quality of upper airway breathing and phonation, for example,
assessing for stridor or overt hoarseness.
• Assess for signs of Graves’ hyperthyroidism, such as exophthalmos and pretibial
myxedema.
5 Goiter andBenign Thyroid Nodules
39
Laboratory Tests [9]
• Any patient with a goiter can be euthyroid, hyperthyroid, or hypothyroid. As
such, the initial test in these patients is to check their serum TSH level.
• If the TSH level is abnormal, then measure the serum-free thyroxine (T4) and
total triiodothyronine (T3).
• In patients with elevated or normal serum TSH levels, check serum thyroid peroxidase (TPO) antibodies to evaluate for Hashimoto’s thyroiditis.
• In patients with below normal TSH levels check thyroid stimulating immunoglobulin (TSI) and/or thyrotropin receptor antibody levels to assess for the presence of Graves’ disease. If negative, toxic multinodular goiter and other forms of
thyroiditis should be considered.
Imaging [3, 10]
• Neck ultrasound is the initial imaging test employed in patients found to have a
goiter, thyroid asymmetry, rm nodule, or tenderness on physical examination.
• Sonographic features seen on ultrasonography delineate malignancy risk of nodules and guide decision-making on which should undergo ne-needle aspiration
(FNA) biopsy (see section below).
• A radioactive iodine uptake (RAIU) scan can be performed in hyperthyroid
patients with a goiter on physical exam without obvious signs and symptoms of
Graves’ disease (e.g., exophthalmos, pretibial myxedema).
– RAIU scans may show varying levels of radioactive iodine uptake based on
the underlying etiology:
Diffuse uptake suggests Graves’ disease.
An area(s) of intense uptake (i.e., hot nodules) without any excess uptake
by the rest of the thyroid gland suggests a toxic adenoma or toxic (multi)
nodular goiter.
Reduced or no uptake is found in various forms of thyroiditis (e.g., subacute or postpartum thyroiditis).
• For goiters with retrosternal extension or obstructive symptoms, a non-contrast
CT scan can be obtained to gauge the goiter’s effect on adjacent structures and
determine the extent of mediastinal growth (Fig.5.1).
40
A. Tumati and B. M. Finnerty
Biopsy [11]
• FNA biopsy is the gold standard for assessing the risk of malignancy in thyroid
nodules. It helps guide decision-making on which thyroid nodules require operative intervention versus observation.
• Indications for FNA biopsy include:
– Nodules ≥1cm with high-risk sonographic features (Table5.2).
– Nodules ≥1cm with intermediate-risk sonographic features (Table5.2).
– Nodules ≥1.5cm with low-risk sonographic features (Table5.2).
– Nodules ≥2cm with very low-risk sonographic features (Table5.2).
– History of rapid nodular growth or change in nodular quality (pain or
rmness).
• FNA biopsy results are classied according to the Bethesda classication system
(Table5.3).
• Bethesda II category nodules are characterized as benign nodules.
Table 5.2 Sonographic features of thyroid nodules and associated risk of malignancy [11]
Estimated risk of
Risk level Sonographic features
Benign • Cystic nodules without any solid component <1
Very low risk • Either spongiform or partially cystic nodules without any
concomitant features described in the risk levels below
Low risk • Mostly cystic (>50%) nodules with solid areas at the
periphery
• Isoechoic or hyperechoic solid nodules
• Note: low-risk nodules CANNOT have
microcalcications, irregular margins, extrathyroidal
extension, or taller than wide morphology
Intermediate
risk
High risk Classied as solid hypoechoic nodules or partially cystic
• Hypoechoic solid nodule with regular margins
• Note: intermediate risk nodules CANNOT have
microcalcications, extrathyroidal extension, or taller than
wide morphology
nodules with a solid hypoechoic portion harboring at least
one of the following features:
• Microcalcications
• Rim calcications involving soft tissue
• Irregular margins
• Taller-than-wide morphology
• Evidence of extrathyroidal extension
malignancy (%)
<3
5–10
10–20
>70–90
5 Goiter andBenign Thyroid Nodules
Table 5.3 Bethesda classication [11]
Risk of
malignancy
Category Description Management
I Non-diagnostic Repeat FNA biopsy 1–4
II Benign Clinical and sonographic
surveillance
III Atypia of undetermined signicance
(AUS) or follicular lesion of
undetermined signicance (FLUS)
IV Follicular neoplasm or suspicious for
follicular neoplasm
V Suspicious for malignancy Surgery 60–75
VI Malignant Surgery 97–99
Repeat FNA biopsy,
molecular testing, or
surgery
Molecular testing,
surgery
(%)
0–3
5–15
15–30
Treatment
Expectant Management [9, 12]
• Indications:
– For patients with goiters that have minimal symptoms or remain asymptomatic.
– Absence of malignancy (conrmed through ultrasound or FNA biopsy).
– Absence of compressive symptoms.
41
• 90% of goiters either do not grow at all or do so very slowly.
• Patients meeting the above indications can be observed and followed with yearly
ultrasounds.
• If there has been no interval growth in size and the patient remains asymptomatic, then surveillance ultrasounds can be discontinued.
• Graves’ disease is typically initially managed medically with anti-thyroidal medications (e.g., methimazole, propylthiouracil); radioactive iodine ablation can
also be considered.
Surgical Management [9, 13]
• Indications:
– Symptomatic patients (e.g., compressive symptoms), toxic goiter, rapid
growth of nodule, tracheal deviation, retrosternal goiters, cosmetic concerns,
or if malignancy cannot be ruled out.
• Hemithyroidectomy.
42
A. Tumati and B. M. Finnerty
– Approach for patients with multinodular goiter conned to or predominantly
involving a single thyroid lobe.
• Total Thyroidectomy.
– Bilateral non-toxic or toxic goiter.
– Graves’ disease (e.g., refractory to medical management, suspicious nodules,
exophthalmos, or patient preference).
Non-Surgical Management [14]
• Options include thermal ablation (e.g., laser, microwave, high-intensity focused
ultrasound, or radiofrequency ablation) and radio-iodine therapy (
131
I).
• Could be considered in patients with a previous history of neck/thyroid surgery
or severe co-morbidities precluding safe anesthesia.
• Could be considered for symptomatic patients due to abnormal thyroid hormone
production or patients with compressive symptoms.
• To undergo any of the treatment options above, malignancy must be excluded!
Special Considerations
Retrosternal Goiter [15]
• Most common symptoms include compressive symptoms such as dyspnea, dysphagia, cough, stridor, and/or rarely superior vena cava syndrome.
• See above for work-up of goiters. Uniquely, CT scan is an important pre-op diagnostic step to assess relevant anatomy for operative planning (Fig.5.1).
• FNA can be obtained in the setting of a cervical component but is not recommended for retrosternal goiters due to the heightened risk of damaging vital
structures.
• Surgical management is the gold standard for treating retrosternal goiters (e.g.,
hemi-thyroidectomy vs total thyroidectomy is dependent on the case).
• Pre-operatively, ensure the patient does not have hyperthyroidism which would
need to be medically managed rst to prevent the development of thyroid storm
intraoperatively.
5 Goiter andBenign Thyroid Nodules
43
References
1. Berghout A, Wiersinga WM, Smits NJ, Touber JL.Determinants of thyroid volume as measured by ultrasonography in healthy adults in a non-iodine decient area. Clin Endocrinol
(Oxf). 1987;26(3):273–80.
2. Knudsen N, Perrild H, Christiansen E, Rasmussen S, Dige-Petersen H, Jorgensen T.Thyroid
structure and size and two-year follow-up of solitary cold thyroid nodules in an unselected
population with borderline iodine deciency. Eur J Endocrinol. 2000;142(3):224–30.
3. Scott-Coombes D, Sinclair C. Non-toxic thyroid nodules and multinodular goitre. In:
Endocrine surgery comprehensive board exam guide. 1st ed. Cham: Springer; 2022. p.33–52.
4. Tunbridge WM, Evered DC, Hall R, Appleton D, Brewis M, Clark F, etal. The spectrum of thyroid disease in a community: the Whickham survey. Clin Endocrinol (Oxf). 1977;7(6):481–93.
5. Holzheimer RG.Benign nodular thyroid disease. In: Holzheimer RG, Mannick JA, editors.
Surgical treatment: evidence-based and problem-oriented. Munich: Zuckschwerdt; 2001.
6. Knudsen N, Brix TH.Genetic and non-iodine-related factors in the aetiology of nodular goitre.
Best Pract Res Clin Endocrinol Metab. 2014;28(4):495–506.
7. Berghout A, Wiersinga WM, Smits NJ, Touber JL. Interrelationships between age, thyroid
volume, thyroid nodularity, and thyroid function in patients with sporadic nontoxic goiter. Am
J Med. 1990;89(5):602–8.
8. Smith TJ. Neck and thyroid examination. In: Walker HK, Hall WD, Hurst JW, editors. Clinical methods: the history, physical, and laboratory examinations. 3rd ed. Boston:
Butterworths; 1990.
9. Bahn RS, Castro MR. Approach to the patient with nontoxic multinodular goiter. J Clin
Endocrinol Metab. 2011;96(5):1202–12.
10. Giovanella L, Avram AM, Iakovou I, Kwak J, Lawson SA, Lulaj E, etal. EANM practice
guideline/SNMMI procedure standard for RAIU and thyroid scintigraphy. Eur J Nucl Med
Mol Imaging. 2019;46(12):2514–25.
11. Haugen BR, Alexander EK, Bible KC, Doherty GM, Mandel SJ, Nikiforov YE, etal. 2015
American Thyroid Association management guidelines for adult patients with thyroid nodules
and differentiated thyroid cancer: the American Thyroid Association guidelines task force on
thyroid nodules and differentiated thyroid cancer. Thyroid. 2016;26(1):1–133.
12. Durante C, Costante G, Lucisano G, Bruno R, Meringolo D, Paciaroni A, etal. The natural
history of benign thyroid nodules. JAMA. 2015;313(9):926–35.
13. Mishra A, Agarwal A, Agarwal G, Mishra SK.Total thyroidectomy for benign thyroid disorders in an endemic region. World J Surg. 2001;25(3):307–10.
14. Nygaard B, Hegedus L, Ulriksen P, Nielsen KG, Hansen JM. Radioiodine therapy for multinodular toxic goiter. Arch Intern Med. 1999;159(12):1364–8.
15. Knobel M.An overview of retrosternal goiter. J Endocrinol Invest. 2021;44(4):679–91.
Chapter 6
Differentiated Thyroid Cancer
RebeccaL.Williams-Karnesky andDavidF.Schneider
Introduction
Thyroid cancers are classied by cells of origin [1]. Those derived from follicular
epithelial cells include well-differentiated thyroid carcinoma (DTC), poorly differentiated thyroid carcinoma (PDTC), and anaplastic thyroid carcinoma (ATC) [2].
Well-differentiated thyroid carcinomas can be further classied as papillary thyroid
cancer (PTC), follicular thyroid carcinoma (FTC), and Hürthle cell carcinoma (HCTC).
Classication of Differentiated Thyroid Cancers
– Papillary thyroid carcinoma is the most common subtype of DTC, and accounts
for approximately 85–90% of all DTCs [3, 4]. Of this subtype, 75–80% are classical variant [2]. Aggressive variants of PTC include tall cell, columnar cell,
hobnail, and diffuse sclerosing. Less clinically aggressive variants of PTC
include follicular variant papillary thyroid cancer and Warthin-like.
– Follicular thyroid carcinoma accounts for approximately 8% of DTCs. FTC is
subdivided into widely invasive (i.e., gross invasion) and minimally invasive.
Minimally invasive FTC is further stratied by the degree of microscopic capsular and vascular invasion.
– Hürthle cell carcinoma accounts for approximately 2% of all DTCs.
R. L. Williams-Karnesky (*) · D. F. Schneider
Division of Endocrine Surgery, Department of Surgery, University of Wisconsin School of
Medicine and Public Health, Madison, WI, USA
e-mail: rebecca.williams1@nm.org; schneiderd@surgery.wisc.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_6
45© The Author(s), under exclusive license to Springer Nature
46
R. L. Williams-Karnesky and D. F. Schneider
Presentation
Epidemiology andScreening
– Differentiated thyroid cancers make up >95% of the thyroid cancers diagnosed
annually [3, 5].
– 5–10% of all DTCs have a familial occurrence [6]. Patients with familial DTC
should have routine annual focused neck examination and targeted history.
– Syndromes associated with DTC include PTEN hamartoma tumor syndrome
(Cowden’s disease), familial adenomatous polyposis (FAP), Carney complex,
and Werner syndrome/progeria, and may warrant enhanced screening.
Initial Workup
– After identication of a DTC, patients should have a complete history and physi-
cal exam, focused on the thyroid gland and cervical lymph nodes.
– Pertinent history related to thyroid malignancy includes childhood exposure to
ionizing radiation, childhood exposure to head and neck radiation, whole-body
exposure to radiation for bone marrow transplant, and familial thyroid carcinoma
or cancer syndromes.
– History features concerning for malignancy include rapid nodule growth and
hoarseness.
– Physical exam features concerning for malignancy include xation of the nodule
to surrounding tissues, vocal cord paralysis, and cervical lymphadenopathy.
– A serum thyrotropin (TSH) should be obtained for any nodule >1cm to assess
for functionality [6].
– Routine measurement of serum thyroglobulin (Tg) is not recommended as this
test is insensitive and nonspecic in the setting of thyroid cancer and does not
change disease management [7].
Imaging
Neck US
– Cervical lymph node metastasis is present in up to 20–50% of patients with DTC
at the time of presentation [6].
– Bilateral central and lateral neck ultrasound should be used to evaluate for patho-
logic lymph nodes in patients with DTC [2, 6].
– US-guided biopsy of sonographically suspicious lymph nodes >8–10mm should
be performed to conrm malignancy [6].