This document summarizes thyroid diseases and evaluation of thyroid nodules. It discusses the peripheral action of thyroid hormones, thyroiditis conditions including Hashimoto's, subacute, and Riedel's, hyperthyroidism including Graves' disease and toxic nodular goiter, evaluation of thyroid nodules including risk factors and initial workup, and treatment options for hyperthyroidism such as antithyroid medications, radioactive iodine, and surgery.

2. THYROID DISEASES
Dr. MOHAMMAD VAZIRI-Thoracic Surgeon
Iran University of Medical Sciences
Member of The
New York Academy of Sciences
European Society of Thoracic Surgeons
International Association for the Study of Lung Cancer
European Society of Medical Oncology
Clinical Research Associate – McMaster University

3. • Peripheral Action of Thyroid Hormones
• In the periphery, T3 is significantly more bioactive than T4. Most T4 is
converted to T3
• Of circulating T3 and T4, 80% is bound to thyroxine-binding globulin (TBG)
in the periphery.T4 also is bound to albumin and prealbumin.

4. • There are many drugs that inhibit synthesis or release of thyroid hormone and
some that suppress TSH.
• Most T3 and T4 are bound to the extent that free T4 constitutes less than 1%
of peripheral hormone.
• The bound form of thyroid hormone cannot pass from the extracellular space
and must be in the free form to diffuse into extracellular tissues

5. • Most T3 is peripherally derived from the deiodination of T4, which takes place
largely in the plasma and liver.
• Other deiodination processes are found in the central nervous system,
especially the pituitary gland and brain tissues, as well as in brown adipose
tissue.
• Peripheral conversion of T4 to T3 can be impaired in overwhelming sepsis –
malnutrition- propylthiouracil [PTU]) use- high-dose corticosteroids- beta
blockers- iodinated contrast agents, and amiodarone use resulting in thyroid
imbalance

8. • The half-life of T3 is approximately 8 to 12 hours, and free levels disappear
rapidly from the peripheral circulation.
• In adults, the half-life of T4 is approximately 7 days because of the efficient
and significant degree of binding to carrier proteins.
• Thyroid hormones generally have a slow turnover time in the peripheral
circulation, and the body is ensured of at least a 7- to 10-day supply of T4
available for peripheral metabolism.

9. • Tests of Thyroid Function
• Evaluation of the Pituitary-Thyroid Feedback Loop
• Measurement of serum TSH by an ultrasensitive radioimmunoassay
• Because of its sensitivity, TSH values can detect thyroid dysfunction before
clinical manifestations are noted (e.g., subclinical hypothyroidism or
hyperthyroidism).
• Serum Triiodothyronine and Thyroxine Levels
• Accurate evaluation of thyroid function requires measurement of free T4 and
T3 levels.

10. • Calcitonin
• In patients with thyroid masses and in whom multiple endocrine neoplasia type
2 (MEN2) syndrome or isolated medullary carcinoma is suspected, a baseline
calcitonin level can be obtained.
• If there is doubt about the diagnosis, pentagastrin-stimulated or calcium-
stimulated calcitonin evaluation, which is a 4- to 5-hour test, can be performed.
• Also, calcitonin can be used as a screening test in families with MEN2
syndrome

11. • Radioactive Iodine Uptake
• Directly evaluates thyroid gland function; however, it has become less widely
used because of more precise biochemical measurements of T3, T4, and TSH
and improved thyroid ultrasonography.
• RAI uptake involves the oral administration of iodine-123 (123I) and calculated
uptake with radioscintigraphy.
• A normal result is 15% to 30% uptake of the radionuclide after approximately
24 hours.

12. • Indications for the use of Radioscintigraphy include the
• Evaluation of a solitary thyroid nodule when the initial TSH is low
• To help delineate the cause of hyperthyroidism
• Detection of functioning thyroid cancer metastases after remnant iodine
ablation.

14. • Thyroid Autoantibody Levels
• Thyroid antigens (thyroid-stimulating immunoglobulin, antimicrosomal and
antithyroid peroxidase antibodies) are produced in autoimmune thyroid
disorders, including Graves disease and Hashimoto thyroiditis.
• 95% of patients with Hashimoto thyroiditis and 80% with Graves disease have
detectable antimicrosomal antibodies.

15. •Thyroiditis
• Hashimoto Thyroiditis
• The major cause of hypothyroidism in adults is Hashimoto thyroiditis,
autoimmune-mediated destruction of thyrocytes.
• The disorder predominates in women (4 to 10 : 1).
• The presence of TSH-blocking antibodies, such as thyroid peroxidase
antibodies, can be detected.
• Ultimately, a clinical hypothyroid state can occur in patients with persistent
TSH-blocking antibodies.

16. • Acute Suppurative Thyroiditis
• Acute suppurative thyroiditis is extremely rare and is usually the result of a
severe pyogenic infection of the upper airway.
• It may be related to a pyriform sinus fistula or other congenital anomaly.
• The process results in severe localized pain and is generally unilateral.
• The most common organisms are Staphylococcus species including
methicillin-resistant Staphylococcus aureus and Streptococcus species.
• Abscess drainage followed by the administration of antibiotics is effective,
and long-term deleterious effects on thyroid function are rare.

17. • Subacute Thyroiditis
• Subacute thyroiditis occurs predominantly in women (2 : 1)
• The mean age of patients is in the 40s in most series. The exact cause is
unknown, although it is believed to have a viral or autoimmune origin.
• In most patients, a history of an upper respiratory infection before the onset of
thyroiditis can be elicited.

18. • Patients have diffuse swelling in the cervical area and a sudden increase in
pain. Approximately two thirds of patients have fever, weight loss, and severe
fatigue.
• Fine-needle aspiration (FNA) can be diagnostic if it demonstrates giant cells
of an epithelioid foreign body type, which characterize the lesion.
• Treatment with corticosteroids or nonsteroidal anti-inflammatory drugs
(NSAIDs) is effective in relieving symptoms. However, the disease process
generally continues, unaffected by these medications.

19. • Riedel Struma
• Riedel thyroiditis (struma) is a rare entity characterized by a firm thyroid
secondary to a chronic inflammatory process involving the entire gland.
• Symptoms of severe discomfort can occur because of extension into the
trachea, esophagus, and laryngeal nerve, patients may have impending airway
obstruction or dysphagia due to severe tracheal and esophageal obstruction.
• Treatment with thyroid hormone replacement, corticosteroids, or tamoxifen
may be effective.
• Immediate tracheal or esophageal obstruction may require a surgical approach
to relieve symptoms.In general, only the constricting portion of the thyroid is
removed.

20. •Hyperthyroidism
• Increased thyroid secretion can be caused by primary alterations within the
gland (e.g., Graves disease, toxic nodular goiter, toxic thyroid adenoma) or
central nervous system disorders and increased TSH-produced stimulation of
the thyroid.
• Most hyperthyroid states occur because of primary malfunction.

21. • Classic symptoms of hyperthyroidism or thyrotoxicosis include sweating,
unintentional weight loss despite increased appetite, heat intolerance, increased
thirst, menstrual disturbance, anxiety, diarrhea, palpitations, hair loss, and
sleep disturbance.
• More severe signs of thyrotoxicosis are high-output cardiac failure, congestive
heart failure with peripheral edema, and arrhythmias such as ventricular
tachycardia and atrial fibrillation.

23. • Hyperthyroid Disorders
• Graves disease.
• Graves disease is the most common cause of hyperthyroidism (diffuse toxic
goiter).
• This disease entity was originally described by Graves, an Irish physician, in
1835.
• Women between the ages of 20 and 40 years are most commonly affected.
• Hyperthyroidism in Graves disease is caused by stimulatory autoantibodies to
TSH-R.

24. • Graves disease generally manifests with the following classic triad of
complaints:
• (1) signs and symptoms of thyrotoxicosis, (2) a visibly enlarged neck mass
consistent with a goiter that may demonstrate an audible bruit secondary to
increased vascular flow, and (3) exophthalmos.
• Tracheal compression can result in symptoms of airway obstruction, although
acute compression with respiratory distress is exceedingly rare.

25. • The ocular consequences of prolonged and untreated thyrotoxicosis, such as
proptosis, supraorbital and infraorbital swelling, and conjunctival swelling and
edema, can be severe.
• The ophthalmopathy is believed to be caused by stimulation of the
overexpressed TSH-R in the retro-orbital tissues of patients with Graves
disease.
• In its most severe form, spasm of the upper eyelid, resulting in retraction and
visualization of a larger amount of sclera than normal, can lead to lid lag and
exacerbation of the already swollen conjunctiva.

26. • Toxic nodular goiter and toxic adenoma.
• Toxic nodular goiter, also known as Plummer disease, refers to a nodule
contained in an otherwise goitrous thyroid gland that has autonomous
function.
• The thyroid in these patients may be diffusely enlarged or associated with
retrosternal goiters. Initial symptoms are mild, peripheral thyroid hormone
levels are elevated, and TSH levels are suppressed.
• Antithyroid antibody levels are usually not detected. The diagnosis is
generally confirmed after clinical suspicion, and an RAI scan is performed to
localize one or two autonomous areas of function while the rest of the gland is
suppressed

27. • Toxic nodular goiter can be treated with thionamides, RAI therapy, or surgery;
the latter two are preferred because these nodules rarely resolve with
prolonged thionamide therapy.
• When resection is chosen for therapy, the surgical approach is lobectomy or
near-total thyroidectomy, particularly when clinical symptoms are
pronounced.
• In the case of a single hyperfunctioning adenoma, lobectomy is generally
curative.

28. Diagnosis of hyperthyroidism
• A cost-effective workup includes an extensive history, physical examination,
and thyroid function tests.
• In addition to elevated levels of T3 and T4, a decreased or undetectable level
of TSH is demonstrated. Depending on the cause of the hyperthyroidism,
thyroid antibodies may or may not be elevated.
• Ultrasound or CT scan of the neck can be performed to evaluate clinical
landmarks if needed for surgical planning, although caution is required in the
administration of intravenous contrast agents if hyperthyroidism is untreated

29. • Treatment.
• Patients with thyrotoxicosis have increased adrenergic stimulation.
• The peripheral adrenergic effects of thyrotoxicosis can be modulated by the
use of beta-blocking agents such as propranolol which should be initiated
particularly in patients with tachycardia and in elderly patients.
• Beta blockers do not directly inhibit thyroid hormone synthesis.

30. • The thionamide class of antithyroid drugs includes PTU and methimazole
(Tapazole).
• This class of drugs effectively blocks synthesis of thyroid hormone and acts by
inhibiting the organification of intrathyroid iodine as well as the coupling of
iodotyrosine molecules to form T3 and T4
• Methimazole is preferred over PTU except for during the first trimester of
pregnancy and in life-threatening thyroid storm for the treatment of
hyperthyroidism because it can reverse hyperthyroidism more quickly, can be
dosed once daily, and has fewer concerns for hepatotoxicity.
• Both drugs can cause agranulocytosis, but this occurs in less than 1% of cases.
Other side effects include rash, arthralgias, neuritis, and liver dysfunction
(potentially worse with PTU).

31. • Corticosteroids can effectively suppress the pituitary-thyroid axis.
• Also, they act in the periphery to inhibit the peripheral conversion of T4 to T3;
this effectively lowers serum T3 levels, allowing steroids to be used as a rapid
inhibitory agent for hyperthyroid conditions.
• Steroids can also lower serum TSH concentration.
• The rapid action of steroids makes them a potentially important primary
treatment of severe, previously untreated, or resistant hyperthyroidism.

32. • Iodine, given in large doses in the form of SSKI or Lugol solution after the
administration of an antithyroid medication, can inhibit thyroid hormone
release by altering the organic binding process (Wolff-Chaikoff effect).
• This effect is transient, but iodine supplementation can be used to treat
hyperactivity of the gland in preparation for surgery.

33. • Following initial medical therapy, a decision must be made about long-term
management of the hyperthyroid state.
• In conditions such as Graves disease, in which hyperthyroidism is expected to
persist, several options exist for definitive control.
• In patients treated with thionamides alone, after 1 to 2 years of treatment,
approximately one third of patients may be able to stop medication and have a
long-term remission of their Graves disease.
• However, these medications are problematic, and a more definitive ablation of
Graves disease via RAI(Radioactive Iodine) or thyroidectomy is recommended
for most patients.

34. • Patients with mild, well-tolerated hyperthyroidism can safely proceed to RAI
ablation immediately. However, patients who are older or severely thyrotoxic
may require pretreatment with a thionamide.
• RAI :exceptions include women who are pregnant or lactating or patients with
a suspicious nodule.
• Advantages of 131I therapy include avoidance of surgery and the associated
risks of RLN damage, hypoparathyroidism, or postsurgical recurrence.
• Disadvantages include exacerbation of cardiac arrhythmias, particularly in
older patients, possible fetal damage in pregnant women, worsening
ophthalmic problems, and rare but possibly life-threatening thyroid storm.

35. • Patients most typically considered candidates for thyroidetomy in the setting
of Graves disease include:
Patients with large goiters - patients who are pregnant or may become pregnant
within the next 6 months
Breastfeeding mothers - patients with a thyroid nodule concerning for
malignancy
Patients with concomitant hyperparathyroidism needing operative intervention
Patients with social factors that would expose family members to RAI.

36. • Complete ablation of thyroid tissue requires total thyroidectomy, which is
associated with the highest rates of hypoparathyroidism and RLN(Recurrent
Laryngeal Nerve) damage but also has the lowest likelihood of recurrent
Graves disease.

37. • Nonfunctioning Goiter-Multinodular Goiter
• The cause of this mass is usually iodine deficiency. Initially, the mass is
euthyroid, but with increasing size, elevations in T3 and T4 levels can occur
and gradually progress to clinical hyperthyroidism.
• The incidence of carcinoma in multinodular goiter has been reported to be 5%
to 10%.
• FNA for diagnosis and resection for suspicious lesions should be strongly
considered.
• Substernal Goiter
• A substernal goiter is an intrathoracic extension of an enlarged thyroid that
generally occurs as a result of multinodular goiter.

38. Substernal goiter is an intrathoracic extension of an enlarged thyroid

39. • EVALUATION OF A THYROID NODULE
• Palpable thyroid nodules are present in 1% of men and 5% of women, and
ultrasound-detectable thyroid nodules are present in 19% to 67% of unselected
patients.
• The frequency of palpable and nonpalpable thyroid nodules increases with
age.
• Most of these nodules are benign, but overall approximately 5% are thyroid
cancers.
• Indications for thyroid resection: (1) local compressive or inflammatory
symptoms, (2) hyperfunction, and 3) malignancy or concern for malignancy.
The structured workup systematically addresses these issues.

41. • Initial Evaluation
• The workup of a patient with a solitary nodule begins with a careful history
and physical examination.
Hyperthyroidism should be evaluated.
The physician should enquire about local symptoms including dysphagia,
subjective dyspnea, positional dyspnea, pressure or choking sensation, pain,
globus sensation, or symptoms precipitated by raising the arms over the head (a
subjective Pemberton sign).

43. • The highest risk for malignancy in a thyroid nodule exists in children, male
patients, adults younger than 30 or older than 60 years, and patients exposed to
radiation.
• Family history should be assessed for specific endocrine disorders, including
familial medullary carcinoma, MEN2, Papillary Thyroid Carcinoma, or a
history of polyposis, including Gardner syndrome or Cowden syndrome.
• In all patients with thyroid pathology, the anterior and posterior cervical
triangles should be assessed for pathologic lymphadenopathy.
• When a thyroid nodule is detected on physical examination, the size and
consistency of the nodule should be determined.

44. • Laboratory Evaluation
• If a thyroid nodule 1 cm or larger is identified, serum TSH should be tested.
• Low serum TSH denotes overt or subclinical hyperthyroidism, and a
radioisotope scan generally is indicated.
• Low serum TSH also correlates with a lower likelihood of malignancy in a
thyroid nodule
• High serum TSH suggests hypothyroidism, most commonly the result of
Hashimoto thyroiditis.
• Serum Thyroglobulin is important in the follow-up of patients after initial
treatment of thyroid cancer but should not be checked routinely in the initial
evaluation of a thyroid nodule.

46. • Thyroid Imaging-Ultrasound
• Ultrasound imaging is central to the evaluation of most thyroid nodules. All
nonthyrotoxic nodules should be evaluated with a diagnostic ultrasound scan
• Advantages of ultrasound over other imaging modalities include portability,
cost-effectiveness, and lack of ionizing radiation.
• It is extremely useful in patients who are being managed conservatively
because it can reproducibly determine whether a nodule has increased in size
or has suspicious characteristics.

47. • Ultrasound findings within a nodule that are considered suspicious for
malignancy include microcalcifications, hypervascularity, infiltrative margins,
being hypoechoic compared with surrounding parenchyma, and having a shape
that is taller than its width on transverse view
• A purely cystic lesion with no solid component may be classified as benign.
• When a thyroid nodule is detected, it also is appropriate to evaluate the central
and lateral neck sonographically for pathologic adenopathy. If pathologic
nodes are detected, biopsy may be targeted to the pathologic node.

49. • Radioisotope Scanning
• Ultrasound allows anatomic evaluation, whereas radionuclide scans allow
assessment of thyroid function.
• If a dominant thyroid nodule larger than 1 cm is found to be associated with
suppressed serum TSH, a diagnostic RAI scan should be obtained to determine
whether the nodule is hyperfunctioning .

50. • In euthyroid or hypothyroid patients with thyroid nodules, radioisotope
scanning is not indicated in the initial workup of a thyroid nodule.
• Technetium 99m pertechnetate (99mTc) is taken up rapidly by the normal
activity of follicular cells.
• It is trapped by follicular cells but not organified. 99mTc has a short half-life
and low radiation dose.

51. • Iodine scintigraphy with 123I (Iodine)and 131I is also used to evaluate the
functional status of the gland.
• 123I and 131I are trapped by active follicular cells and organified. Advantages
of scanning with 123I include a low dose of radiation (30 mrad) and short half-
life (12 to 13 hours).
• 123I is a good choice for evaluating suspected lingual thyroids or substernal
goiters.
• 131I has a longer half-life (8 days) and emits higher levels of β-radiation. 131I
is optimal for imaging thyroid carcinoma and is the screening modality of
choice for the evaluation of distant metastasis.

52. • FDG-PET does not have a role in the initial evaluation of thyroid nodules.
However, 1% to 2% of PET scans obtained for other reasons identify discrete
thyroid incidentalomas
• Focal FDG-PET activity should prompt thyroid ultrasound and subsequent
FNA biopsy if an ultrasound-detectable thyroid nodule is confirmed.
• Diffuse thyroid FDG-PET activity should prompt an ultrasound scan.

53. • Computed Tomography and Magnetic Resonance Imaging
• CT or MRI is particularly appropriate for a suspicious mass (or biopsy-proven
cancer) with bulky cervical lymph nodes. either modality can be used for
postoperative follow-up, particularly for suspicion of recurrent disease.
• CT is advisable in preoperative planning for larger thyroid masses that are
believed to have a substernal component
• A typical chest or neck CT scan with iodinated contrast agent may deliver
15,000 to 30,000 mg of iodine to the patient. This iodine load is a particular
concern in a patient with hyperthyroidism.

54. • Another concern related to iodinated contrast agents is that patients must be
iodine depleted before therapeutic RAI treatment of thyroid cancer.
• The large iodine load decreases the target cell avidity for further iodine uptake
after iodinated contrast agent administration.
• In most cases, 4 weeks is adequate time for the clearance of iodine after a CT
scan.
Because RAI ablation typically is performed more than 4 weeks after
thyroidectomy, it is safe and appropriate to use CT with an intravenous contrast
agent if needed to permit appropriate operative planning to achieve safe and
complete resection of a thyroid cancer

55. • Fine-Needle Aspiration Biopsy
• FNA is a cost-effective and valuable tool and is a key diagnostic technique in
the evaluation of thyroid nodules.
• The decision to perform FNA for a thyroid nodule is made based on a
combination of patient factors, ultrasound characteristics, and size.
• In general, nodules that are less than 1 cm in greatest dimension are not
evaluated further

56. • Examples where further workup of nodules less than 1 cm may be indicated
include
• Nodules with suspicious characteristics on ultrasound
• Nodules associated with suspicious lymphadenopathy based on ultrasound or
clinical examination
• Nodules in patients with family history of PTC
• History of radiation exposure
• Prior personal history of thyroid cancer
• Lesions positive on FDG-PET.

57. • Patients with nodules with high-risk or intermediate-risk sonographic features
should undergo FNA biopsy if the nodules are 1 cm or larger in size
• Patients with nodules with low-risk sonographic features should undergo
FNA biopsy if the nodules are 1.5 cm or larger
• Patients with nodules with very low suspicion sonographic features should
undergo FNA biopsy if the nodules are 2 cm or larger.
• Purely cystic nodules do not require biopsy.

58. • Ultrasound guidance is recommended for nonpalpable, posteriorly located, or
cystic nodules and results in a lower rate of nondiagnostic cytology and
sampling error.
• Results of FNA biopsy should be reported using the Bethesda System for
Reporting Thyroid Cytology.
• Analogous to the Breast Imaging Reporting and Data System in breast
imaging, the Bethesda System standardized reporting to allow consistency in
clinical decision making and in research.

61. • the Bethesda System must be understood and used by all physicians who
manage patients with thyroid neoplasia
• The diagnosis of FTC is not made based on cellular features and instead is
based on demonstration of capsular or vascular invasion by follicular cells.
• The false-negative rate of FNA has been reported to be 1% to 6%.
• Benign nodules diagnosed based on FNA are monitored with ultrasound to
ensure that their characteristics do not change
• The most troublesome category appears to be Bethesda 3, atypia of
undetermined significance/follicular lesion of undetermined significance
(AUS/FLUS).

64. • Purely cystic lesions do not require FNA biopsy, but a needle may be used to
aspirate the cystic fluid to relieve mass effect.
• Cysts that have a residual mass after aspiration and cysts that are aspirated
with benign cytology but then recur should be considered for resection.
• Patients with multiple thyroid nodules have equivalent risk of harboring
malignancy as patients with a solitary nodule
• A reasonable approach for patients with multiple thyroid nodules larger than 1
cm is preferential FNA biopsy of nodules with suspicious ultrasound features.
• If radionuclide scanning demonstrates a hypofunctioning nodule in a patient
with multiple nodules, FNA should be considered for the cold nodules.

65. • Decision Making and Treatment
• If the patient has hyperthyroidism, a RAI uptake scan is used to guide further
diagnosis and management.
• The evaluation for malignancy is based on clinical, ultrasound, and FNA findings.
• For a patient with a thyroid goiter and local compressive symptoms, it is appropriate
to offer resection if the patient is a suitable surgical candidate.
• For patients with bilateral goiter or nodules, total thyroidectomy usually is
recommended.
• Patients with Hashimoto thyroiditis may report compressive symptoms
disproportionately to the size of the thyroid. Most of these patients experience relief
of symptoms after thyroidectomy.

66. • Patients with large goiters, substernal goiters, and Hashimoto thyroiditis also
should be cautioned that there is a marginally higher risk of technical
complications compared with thyroidectomy performed for other indications.
• A patient with a thyroid nodule with a nondiagnostic biopsy should undergo
repeat FNA under image guidance and with realtime cytologic evaluation for
sample adequacy.
• For patients with nodules with persistently nondiagnostic biopsy, either
continued close clinical and sonographic follow-up or diagnostic lobectomy
may be elected based on patient preference and concern for malignancy based
on ultrasound findings.

67. • For patients with a benign FNA biopsy finding, repeat ultrasound
should be performed.
The interval in which to pursue repeat ultrasound may be adjusted based on
ultrasound risk group
For nodules with high sonographic suspicion, repeat evaluation should be
within 3 to 6 months.
For nodules with low to intermediate suspicion, ultrasound should be repeated
in 12 to 24 months.
For nodules with very low suspicion ultrasound findings and a benign FNA
specimen, it is reasonable not to repeat ultrasound; if ultrasound is repeated, it
should be performed at least 2 years later.

68. • When a repeat ultrasound scan is performed for nodules with prior benign
biopsy, if ultrasound shows greater than 50% change in volume or a 20%
increase in two dimensions, FNA should be repeated under ultrasound
guidance.
• For thyroid nodules with Bethesda System category 3 or 4 results, mutation
testing has been explored with the hope of definitively confirming or
excluding a malignancy.
• The goal of these tests is to avoid unnecessary surgery considerations

69. • Patients with indeterminate biopsy results require careful counseling because
the only way at the present time for definitive diagnosis or exclusion of
malignancy is a diagnostic resection.
• One reasonable option for a Bethesda System category 3 lesion is repeat
biopsy, which frequently results in classification into a more definitive
cytologic category.
• Other options include close observation with ultrasound surveillance versus
diagnostic excision, typically in the form of a thyroid lobectomy.

70. • Bethesda System category 4 lesions typically are lesions with many follicular
cells, a paucity of colloid, and absent macrophages that may demonstrate
microfollicle formation and lack cytologic features of PTC.
• These lesions also may be considered for genetic testing. The more time-
tested approach is to pursue diagnostic excision of these lesions.
• For most of these lesions, an ipsilateral thyroid lobectomy is recommended.

71. • Category 4 lesions for which the standard recommendation would be total
thyroidectomy rather than lobectomy include
• Lesions that are greater than 4 cm
• Lesions with contralateral nodules
• Lesions with other concerning clinical features such as prior significant
radiation exposure.

72. • Bethesda System category 5 lesions typically are managed surgically
• The practice of using exogenous thyroid replacement to suppress TSH with
the goal of suppressing a thyroid nodule is losing favor.
• 20% to 30% of nodules shrink on suppressive therapy, and up to 13% of
proven papillary cancers in one series decreased in size on suppressive
therapy.
• Suppressive therapy is not considered appropriate treatment for thyroid
nodules.

73. • The finding of a thyroid nodule in a child or a pregnant woman can be of
particular concern to the patient.
• Although the frequency of malignancy may be higher in children than in
adults, the evaluation should generally proceed in the same fashion as for an
adult.
• This approach also generally holds true in pregnant patients

74. • THYROID MALIGNANCIES
• Thyroid carcinoma represents 4% of all malignancies
• Greater than 75% of cases occur in women making this the fifth most common
malignancy in women.
• Although less than 25% of thyroid carcinomas occur in men, men account for
45% of mortality from thyroid carcinoma.
• The incidence of PTC has been increasing rapidly in men and women
• Of thyroid carcinomas, 90% to 95% are categorized as DTCs that arise from
follicular cells. Papillary, follicular, and Hürthle cell carcinomas are included
in this category.

75. • Thyroid Oncogenesis
• Genetic Alterations
• Most of these genetic abnormalities are acquired, but 5% to 10% of PTCs are
thought to be familial.
• Genetic alterations that lead to constitutive activation of mitogen-activated
protein kinase (MAPK) and phosphatidylinositol-3′-kinase (PI3K)/AKT are
causative in the most common forms of thyroid carcinoma.
• This is a downstream effect of a pathway that includes the RET

76. • The PTC/RET proto-oncogene perhaps has received the most attention in
thyroid tumorigenesis studies.
• The PTC/RET proto-oncogene encodes for a membrane receptor tyrosine
kinase and is the most frequent genetic alteration in PTC despite the absence of
the RET protein product in normal thyroid follicular cells.
• This proto-oncogene may be involved in the normal differentiation of
neuronal cells. Cells of neural crest origin appear to have increased expression
of this gene because it has been found in neuroblastoma, pheochromocytoma,
and MTC tissue.
• Thyroid malignancies expressing this oncogene may have a predilection for
distant metastasis.

77. • The downstream pathway of the RET and NTRK1 mutations includes RAS,
BRAF, MEK, and ultimately activation of MAPK.
• Of all the isoforms of RAF kinase, the B type (BRAF) is the most potent
stimulator of MAPK signaling.
• BRAF is implicated in PTC and has been seen in ATC, but not FTC.
• The BRAFV600E mutation is the most common in thyroid malignancy and is
present in 40% to 50% of PTCs, including 60% of classic PTCs, 10% to 15%
of follicular variant PTCs, greater than 90% of tall cell variant PTCs, and
25% of ATCs.

78. • The ras gene family encodes signal transduction G proteins that play an
important role in the regulation of cell growth and differentiation.
• Mutational activation of this oncogene results in the production of an
inactive form of an enzyme (guanosine triphosphatase) that is ineffective in
inactivating protein degradation.
• Of thyroid tumors, 40% may have one of three ras gene point mutations (H-
ras, K-ras, or N-ras), and ras mutations may occur in benign and malignant
thyroid neoplasms, including follicular adenomas, FTCs, and follicular
variant PTCs.

79. • K-ras mutations appear more frequently in radiation-induced PTCs.
• FTCs with ras mutations are more aggressive than FTCs without ras
mutations, and ras mutations may be found in undifferentiated thyroid
carcinomas and ATCs.
• Tumor suppressor genes also play a role in thyroid malignancy.
• Loss of function of the p53 tumor suppressor gene is one of the most
common genetic alterations seen across all human cancer and is associated
with radiation exposure.

80. • Ionizing Radiation
• Ionizing radiation can cause genetic mutations leading to malignant
transformation.
• This association is much stronger for thyroid cancer than for other
malignancies, and radiation is the only clearly established environmental risk
factor for thyroid malignancy.
• The risk of developing thyroid cancer after exposure to radiation is greater in
people exposed during childhood and increases with higher doses of radiation
delivered to the thyroid
• This is true for exposure to ionizing radiation given for medical purposes as
well as environmental exposures. The association with radiation is much
stronger for papillary than for follicular carcinoma.

81. •Papillary Thyroid Carcinoma
• PTC is the most common thyroid malignancy and usually is associated with
an excellent prognosis, particularly in young female patients .
• Of thyroid carcinomas diagnosed, 70% to 80% are PTC. PTC may occur
much more commonly than it is diagnosed, with autopsy series finding small
(<1 cm) PTCs in 30% of people who died of other causes.
• The most important risk factor for PTC is childhood radiation exposure from
either medical or environmental sources.

82. • Other important risk factors for PTC include a history of thyroid carcinoma
in a first-degree relative and the presence of a familial syndrome that
includes thyroid carcinoma, such as Werner syndrome, Cowden syndrome,
Carney complex, and familial polyposis.
• PTC occurs in a 2.5 : 1 female-to-male ratio, and the peak incidence occurs
between ages 30 and 50 years

83. • Pathologic Classification-Papillary Thyroid Carcinoma
• Diagnosis may be made definitively based on FNA cytology. Findings of
intranuclear inclusion bodies and nuclear grooving on the FNA specimen
confirm the diagnosis of PTC .Additionally, the finding of calcified clumps of
cells, known as psammoma bodies, is diagnostic of PTC.
• follicular variant of PTC constitutes approximately 10% of PTCs. Classic PTC
and the follicular variant of PTC have similar prognostic implications.

84. • Other subtypes of papillary carcinoma include columnar, hobnail, and tall
cell carcinomas, which are more aggressive in their biologic behavior.
• Although these subtypes are rare, they tend to occur in older patients, and the
prognosis is less favorable.
• These latter groups represent perhaps less than 1% of all PTCs The solid
variant and the diffuse sclerosing variants of PTC have less clear prognostic
implications but likely have more aggressive biologic behavior than classic
PTC.

85. • Clinical Features
• PTC most typically manifests either as a palpable thyroid nodule or as an
incidental imaging finding .
• Occasionally, a metastatic PTC manifests as a painless lateral neck mass that
is clinically detected before detecting the primary thyroid lesion.
• The FNA diagnosis of PTC has an almost 100% correlation to a diagnosis of
PTC on final pathology.
• Most patients with PTC can expect an excellent prognosis, with the 10-year
survival rate greater than 95% for the most favorable stages

87. • The AMES clinical scoring system, is based on patient age, distant metastasis,
extent of primary tumor, and size of primary tumor.
•
• The AGES clinical scoring system, is based on patient age, pathologic grade
of tumor, extent of primary tumor, and size of primary tumor.
• The Age at diagnosis is the most important prognostic factor in DTC.
• Patients with distant spread to the lungs still have significant survival of up
to 50% at 10 years; however, patients with brain metastases have a median 1-
year survival.

88. • The impact of lymphatic metastases on prognosis depends on patient age.
• In a large series in younger patients (<45 years old), the presence of lymph
node metastases had no effect on the excellent overall survival
• Multicentricity can be anticipated in 70% of patients with PTC and may
represent either intraglandular metastasis or multiple primary tumors.
• Cervical lymph node metastases are common, particularly in children, who
may have a 50% incidence

89. • If there is gross or microscopic extension of a primary PTC through the
thyroid capsule, a poor prognosis and possibly a higher rate of lymph node
metastasis may be anticipated.
• Although PTC typically disseminates via lymphatic spread, distant metastases
can occur and are present in 3% to 5% of patients at the time of diagnosis. The
two most common sites of spread are to the lungs and bones.
• The unique role of age in the TNM staging of thyroid carcinoma reflects the
overwhelming implications of age on disease prognosis.
• A patient who presents at younger than 45 years old is stage 1 regardless of T
stage and N stage as long as there are no distant metastases.

91. • Follicular Thyroid Carcinoma
• FTC is the second category of DTC and constitutes approximately 10% of all
thyroid malignancies.
• FTC is a disease of an older population compared with PTC, with a peak
incidence between ages 40 and 60 years. It occurs more commonly in women,
with a ratio of approximately 3 : 1.
• There appears to be an increased incidence of FTC in geographic distributions
associated with iodine deficiency.
• In contrast to PTC, FTC is not strongly associated with radiation exposure.

92. • Pathologic Classification
• Histologic diagnosis of FTC depends on the demonstration of follicular cells
occupying abnormal positions, including capsular or vascular invasion
Because this diagnosis depends on defining the lesion architecture, the
diagnosis cannot be made on FNA biopsy.
• Using these criteria, two types of FTC are usually described: minimally
invasive and widely invasive. microscopic angioinvasion is an important
prognostic finding.
• Lymph node involvement is unusual in FTC occurring in less than 10% of
cases. In patients with widely invasive FTC, distant spread is more common,
and lung, bone, and other solid organs are often involved

93. • A subtype of FTC, known as Hürthle cell carcinoma, consists of oxyphilic
cells and tends to occur in older patients, usually 60 to 75 years old.
• Hürthle cell cancers have a greater likelihood of having local recurrence and
are less avid to absorb RAI, leading to more aggressive biologic behavior

94. • Clinical Features
• Similar to PTC, FTC typically manifests as a painless thyroid mass that is
evaluated as described earlier. FTC and multinodular goiter coexist in 10% of
cases.
• FNA cytology is of limited value in the preoperative diagnosis of FTC.
Additionally, intraoperative frozen section has been notoriously ineffective in
making a definitive diagnosis of FTC.
• In contrast to PTC, FTC typically spreads via hematogenous routes, which
occurs in 10% to 15% of cases. The most common sites for metastatic deposits
are lytic bone lesions and lung
•

95. • As with papillary cancer, age is the most important predictor of survival with
a 95% 10-year survival in patients younger than 40 years and an 80% 10-year
survival in patients between 40 and 60 years old.
• FTCs in older patients also are less likely to respond to RAI therapy. Size of
the primary tumor is an important prognostic indicator, although in contrast to
PTC, even small FTCs should be considered clinically significant.
• TNM staging for FTC is the same as for PTC

97. • Treatment of Differentiated Thyroid Carcinoma
• (Papillary and Follicular)
• The primary treatment of DTC, is surgical ablation. The other mainstays of
therapy are RAI ablation and TSH suppression.
• Persistent and recurrent disease also is primarily addressed using the same
three modalities.
• External-beam radiation and systemic adjuvant chemotherapy play a role in a
few cases of DTC.

98. • Targeted therapy with tyrosine kinase inhibitors may play a role in the setting
of a clinical trial to manage advanced cases of metastatic DTC that are
refractory to RAI.
• Although DTCs generally have a good prognosis, there are high rates of
multicentricity within the thyroid and high rates of lymph node metastases, and
recurrence is frequent.

99. • The objectives of initial therapy include the following:
• (1) remove the primary tumor and clinically significant cervical lymph nodes
• (2) minimize treatment-related morbidity
• (3) accurately stage the disease
• (4) facilitate postoperative RAI therapy if appropriate
• (5) permit accurate long-term surveillance
• (6) minimize risk of recurrence or metastasis.

100. • Extent of Thyroid Resection
• Appropriate surgical options and terminology for known or suspected thyroid
malignancy include the following:
• (1)Hemithyroidectomy/thyroid lobectomy with or without isthmusectomy
• (2) Near-total thyroidectomy, defined by leaving less than 1 g of tissue
adjacent to the RLN at the ligament of Berry on one side
• (3) Total thyroidectomy, defined by removal of all visible thyroid tissue.
• Nodulectomy and leaving greater than 1 g of thyroid tissue in a “subtotal”
thyroidectomy are not considered appropriate surgical options

101. • There are several rationales to consider total thyroidectomy, including
• (1) facilitation of RAI ablation, which is much less effective and requires a
larger dosage if residual thyroid exists
• (2) the frequent presence of occult multifocal Disease
• (3) facilitating the use of Tg as a tumor marker, which is most useful if there
is no remaining normal thyroid.

102. • DTCs less than 1 cm in diameter are defined as microcarcinomas.
• Surgery is not clearly required for these lesions if there are no clinically
involved cervical lymph nodes, no extrathyroidal extension, and no history of
head and neck irradiation.
• Similarly, if a DTC less than 1 cm is diagnosed after thyroid lobectomy,
completion thyroidectomy is not required if there are no clinically involved
cervical lymph nodes, no extrathyroidal extension, and no history of head and
neck irradiation.

103. • For DTCs that are 1 cm or larger, a total thyroidectomy is indicated in
situations in which RAI therapy is planned.
• These situations include DTCs greater than 4 cm in size, DTCs with
extrathyroidal extension, and DTCs with regional or distant metastases.
• Other factors that may make total thyroidectomy an appropriate consideration
are patient and physician preference, age older than 45 years, contralateral
nodules, prior irradiation, and familial DTC.
• DTCs that are 1 to 4 cm: offer RAI for many of these cancers, and many of
these patients receive total thyroidectomy.

104. • Lymph Node Dissection
• Distinctions should be made between the central neck (level VI) and the lateral
neck and between therapeutic dissection and prophylactic dissection.
• A prophylactic dissection is the clearance of a clinically uninvolved nodal
basin, whereas therapeutic dissection is lymph node dissection in the setting of
proven nodal metastasis.
• The anatomically defined nodal regions of the central and lateral neck are
demonstrated in the next Figure .

106. Lymph node compartments separated into levels and sublevels.
Level VI contains the thyroid gland and the adjacent nodes bordered superiorly
by the hyoid bone, inferiorly by the innominate artery, and laterally on each side
by the carotid sheaths.
Level II, III, and IV nodes are arrayed along the jugular veins on each side,
bordered anteromedially by level VI and laterally by the posterior border of the
sternocleidomastoid muscle.
Level III nodes are bounded superiorly by the level of the hyoid bone and
inferiorly by the inferior aspect of the cricoid cartilage; levels II and IV are
above and below level III, respectively.

107. The level I node compartment includes the submental and submandibular
nodes, above the hyoid bone and anterior to the posterior edge of the
submandibular gland.
Level V nodes are in the posterior triangle, lateral to the lateral edge of the
sternocleidomastoid muscle.
Levels I, II, and V can be further subdivided as noted in the figure. The inferior
extent of level VI is defined as the suprasternal notch.
Many authors also include the pretracheal and paratracheal superior mediastinal
lymph nodes above the level of the innominate artery (sometimes referred to as
level VII) in central neck dissection.

108. • The central compartment nodes should be assessed at the time of
thyroidectomy by visual inspection and palpation, in addition to preoperative
ultrasound.
• In the setting of clinically negative central compartment nodes, a prophylactic
dissection is more clearly indicated in higher risk situations, such as tumors
that are larger than 4 cm, tumors with gross extrathyroidal extension, and
tumors with lateral neck nodal disease.
• The management of lateral neck lymph node basins must be considered
separately from the central neck.

109. • In the course of thyroidectomy, the lateral compartment of the neck is not
entered, and these nodes are not evaluated intraoperatively. Therefore, the
lateral neck should be evaluated for malignancy before thyroidectomy.
• If pathologic appearing nodes are found, FNA biopsy should be performed. In
the presence of pathologically confirmed lateral neck nodal disease, an
ipsilateral therapeutic lateral neck dissection is indicated.
• Despite a nearly 30% rate of micrometastases in lateral lymph nodes, there is
little benefit to prophylactic lateral neck dissection for clinically negative
nodes

110. • Radioactive Iodine Therapy
• RAI has several particular purposes in the treatment of DTC after
thyroidectomy, including
• (1) Ablation of remnant thyroid tissue to facilitate detection of later disease
recurrence by imaging and Tg assay
• (2) Adjuvant therapy with the intention of targeting occult metastatic disease
• (3) Primary treatment of known persistent disease.
• There has been a general trend toward being more selective in recommending
RAI and toward giving lower doses of RAI.

111. • Patients with gross extrathyroidal extension or M1 disease lesions have
improved disease-specific and recurrence-free survival with RAI and that RAI
should routinely be recommended to these patients.
• For patients with tumors that are larger than 4 cm, with microscopic
extrathyroidal extension, or with central or lateral compartment nodal
metastasis, RAI should be considered

112. • For patients with tumors that are between 1 and 4 cm, are confined to the
thyroid, and do not have nodal or distant metastasis, RAI is not routinely
recommended
• But it should be more strongly considered in the setting of an adverse
histologic subtype (e.g., tall cell) or if there is vascular invasion.
• RAI should not be given to patients with low-risk DTCs that are less than 1
cm without any direct extrathyroidal extension or metastases.

113. • When RAI is recommended, several steps must be taken to ensure that the
targeted cells have active uptake of the RAI.
• These steps include making the cells iodine avid by maintaining a low iodine
diet for 1 to 2 weeks before RAI administration.
• Urine iodine may be measured to ensure that the patient is iodine depleted,
particularly if there was a recent large iodine exposure such as iodinated
contrast agent or amiodarone.

114. • High levels of TSH are needed before administration of RAI.
• The optimal TSH level is unknown, but a goal TSH greater than 30 mIU/liter
has been generally adopted.
• This TSH elevation may be achieved either by withdrawal of thyroid hormone
or by the administration of exogenous recombinant human thyroid stimulating
hormone (rhTSH).
• If thyroid hormone withdrawal is used, levothyroxine should be held for 3 to 4
weeks before a planned RAI therapy.

115. • Some centers prefer to use T3 (liothyronine in the early weeks of withdrawal,
which allows a shorter period off of thyroid hormone until an adequate TSH
is reached.
• The advantage of using rhTSH is that hypothyroidism may be avoided
completely.

116. • Thyroid-Stimulating Hormone Suppression
• Suppression of TSH is another element of therapy for DTCs.
• For patients with high-risk DTC, initial TSH suppression should be to less than 0.1
mIU/liter.
• For patients with intermediate-risk lesions, the initial TSH goal is 0.1 to 0.5
mIU/liter.
• For patients with low-risk DTC, the initial TSH goal is to be within the low half of
the reference range (0.5 to 2.0 mIU/liter).
• Consideration also must be given to the health of the patient, such as the increased
risk of atrial fibrillation and osteoporosis in older patients with suppressed TSH

117. • Medullary Thyroid Carcinoma
• MTC accounts for 4% to 10% of thyroid carcinomas. The malignancy
originates in the parafollicular cells, or C cells, which are of neural crest
origin.
• MTC occurs most commonly in a sporadic form (80%).It occurs less
commonly as an autosomal dominant inherited disorder such as MEN2A,
MEN2B, and familial medullary thyroid carcinoma (FMTC).
• FMTC is a variant of MEN2A that includes MTC but not the other features of
MEN2A.
• MTC arising in MEN2A usually has a more favorable long-term outcome
than MTC arising in MEN2B or sporadic MTC.

118. • Clinical Features
• A patient with a sporadic MTC typically has one of two manifestations:
• (1) a palpable mass in the thyroid that is present in most cases and for which a
diagnosis can be made with FNA with immunohistochemistry or (2) the
finding of an elevated calcitonin level.
• The presence of a mass and an elevated calcitonin level is virtually diagnostic
of MTC.
• The finding of an elevated basal calcitonin level in the absence of a thyroid
mass might require further workup, including repeat basal calcitonin
measurement and a calcium-stimulated or gastrin-stimulated test.
• Carcinoembryonic antigen may also be elevated in MTC.

119. • 40% to 50% of sporadic MTC specimens have acquired RET mutations.
• Patients with inherited MTC syndromes initially develop C cell hyperplasia,
which is a preneoplastic lesion in these patients, although C cell hyperplasia
has little to no malignant potential in patients without RET mutations.
• Family members of patients with MEN2 should be screened at an early age
for the RET proto-oncogene.
• RET testing should be performed shortly after birth in MEN2B kindreds and
before age 5 years in FMTC and MEN2A kindreds.

120. • Pheochromocytoma in particular must be excluded before considering
interventions in patients with MTC.
• The consensus is that the workup of MTC should include serum calcitonin,
carcinoembryonic antigen, thorough ultrasound scanning of the lateral neck
including lateral compartment, genetic testing for germline RET mutation, and
biochemical evaluation for pheochromocytoma.

121. • Treatment
• MTC can be cured only by complete resection of the primary tumor and local
and regional metastases. They should undergo at least total thyroidectomy
• Patients with the MEN2B RET mutation are advised to undergo prophylactic
total thyroidectomy within the first year of life or at the time of diagnosis.
• Even in the absence of germline RET mutations, patients with known or
suspected MTC without evidence of advanced disease should undergo total
thyroidectomy with prophylactic level VI nodal dissection.
• The presence of clinically detectable or ultrasound-detectable disease in the
lateral neck warrants total thyroidectomy and level VI and lateral
compartment nodal dissection.

122. • If MTC is diagnosed postoperatively in a patient undergoing less than total
thyroidectomy, further operative intervention is indicated to complete therapy
• An exception is a patient with an incidental finding of MTC in a thyroid
lobectomy where the MTC is sporadic and unifocal
• There is no C cell hyperplasia
• An otherwise normal ultrasound scan of the neck
• Negative surgical margin, and
• Normal serum calcitonin all are confirmed.

123. • Use basal and stimulated calcitonin tests to monitor for recurrence because
stimulated calcitonin values may increase before basal calcitonin levels do.
• Documentation of recurrent MTC by biochemical means is often associated
with unresectable recurrence in distant metastatic locations, including the lung
and liver.
• Because MTC is not of follicular cell origin, TSH suppression and RAI
scanning and therapy have no role in MTC, unless there is a concomitant PTC
or FTC.

126. • Poorly Differentiated Thyroid Carcinoma
• Poorly DTC describes a lesion that previously was known as “insular”
thyroid cancer.
• Poorly DTC may be thought of as occupying a middle ground between DTC
and ATC, which is completely dedifferentiated. Poorly DTCs have a
significantly worse outcome than DTCs
• Many, but not all, poorly DTCs absorb RAI, including many M1 tumors.it is
appropriate to offer it until better data are available.

127. •Anaplastic Thyroid Carcinoma
• ATC accounts for approximately 1% of all thyroid malignancies.
• ATC is the most aggressive form of thyroid carcinoma with a disease-specific
mortality approaching 100%.
• A typical manifestation is an older patient with dysphagia, cervical
tenderness, and a painful, rapidly enlarging neck mass.
• Patients frequently have a history of prior or coexistent DTC, and up to 50%
have history of goiter.

128. • Findings may also include superior vena cava syndrome.
• The clinical situation deteriorates rapidly into tracheal obstruction and rapid
local invasion of surrounding structures.
• Three types of cell populations have been classified:
small spindle cell, giant cell, and squamous.
• All have a poor prognosis. p53 mutations are found in 15% of tumors, a much
higher rate than noted with DTCs.

129. • Treatment
• The results of any surgical treatment of ATC are tempered by its rapidly
progressive clinical course.
• Distant spread is present in 90% of patients at the time of diagnosis most
commonly to the lungs, and most reports of resection are not optimistic.
• FNA is accurate in 90% of cases, making open biopsy an uncommon surgical
indication.
• If ATC is initially thought to be resectable based on imaging, some small
improvement in survival may be seen after resection.

130. • The finding of distant metastasis or invasion into locally unresectable
structures, such as the trachea or vasculature of the anterior mediastinum,
leads to a more conservative surgical approach, such as tracheostomy.
• Postoperative external beam irradiation or adjunctive chemotherapy adds little
to the overall prognosis but should be considered.
• Because the prognosis is so grim in this disease, end-of-life planning and
consideration of palliation must be part of very early management and
counseling of these patients.

131. •Thyroid Lymphoma
• Primary thyroid lymphoma, although rare, is being recognized more
frequently.
• The diagnosis is considered in patients with a goiter, especially one that has
apparently grown significantly in a short period.
• Other initial symptoms include hoarseness, dysphagia, and fever.
• Thyroid lymphoma occurs four times more frequently in women than in men.
Approximately half of primary thyroid lymphomas occur in the setting of
preexisting Hashimoto thyroiditis.

132. • Workup and Diagnosis
• Suspicious signs are rapid enlargement and diffuse pain. Physical examination
demonstrates a firm, slightly tender, fixed mass, frequently with substernal
extension. There may be local symptoms including vocal cord paralysis.
• A few patients have “B” symptoms of lymphoma.
• Ultrasound may demonstrate a classic pseudocystic pattern.
• FNA can be diagnostic in this situation using flow cytometry for
monoclonality to confirm the diagnosis.

133. • Thyroid lymphomas are almost all non-Hodgkin lymphomas, and most are B
cell in origin.
• A subgroup of mucosa-associated lymphoid tissue (MALT) lymphomas occur
in 6% to 27% of patients in some series.
• If FNA is nondiagnostic, core needle biopsy or open biopsy can be considered.
• If the diagnosis is confirmed or highly suspicious, additional evaluation
includes neck, chest, and abdominal CT or MRI to assess for extrathyroidal
disease and may demonstrate disease completely encircling the trachea.

134. • Treatment
• Patients with impending airway compromise frequently have very rapid results
with the initiation of chemotherapy, particularly the glucocorticoid component,
potentially avoiding the need for a surgical airway.
• Use of the CHOP regimen (cyclophosphamide, hydroxydaunomycin
[doxorubicin], Oncovin [vincristine], and prednisolone) has been associated
with excellent survival.

135. • Surgical resection, including near-total or total thyroidectomy, is thought by
some authors to enhance these results, particularly for MALT lymphomas, but
likely has little role in patients with extrathyroidal disease and is not pursued
in most centers.
• For MALT lymphomas, 5-year survival rates approach 100%, whereas rates
for large cell and mixed large cell lymphomas are 71% and 78%, respectively.

137. • THYROID DISEASE IN PREGNANCY
• Physiologic Changes of the Thyroid Gland During Pregnancy
• hCG is secreted by the placenta, has significant homology with TSH, and is
active at the TSH receptor.
• Pregnancy also results in elevated levels of serum TBG, requiring greater
levels of total T4 and T3 to maintain adequate levels of free hormone.
• Overall, anticipated normal ranges of TSH concentration are lower during
pregnancy with the lowest levels seen during the first trimester.
• Recommended ranges for TSH are 0.1 to 2.5 mIU/liter in the first trimester,
0.2 to 3.0 mIU/liter in the second trimester, and 0.3 to 3.0 mIU/liter in the
third trimester.

138. •Hypothyroidism in Pregnancy
• The fetus depends entirely on maternal thyroid hormone until 10 weeks’
gestation, when the fetal thyroid gland begins producing small amounts of
thyroid hormone.
• Maternal hypothyroidism is associated with a wide range of poor pregnancy
outcomes, including spontaneous abortion, fetal death, preterm delivery,
pregnancy-induced hypertension, gestational diabetes, anemia, postpartum
hemorrhage, placental abruption and preterm labor, preeclampsia, cesarean
section, and very early embryo loss.

139. • Subclinical hypothyroidism has been associated with a threefold increased
risk of placental abruption and an almost twofold increased risk of preterm
labor.
• It is recommended that thyroid function tests be measured in all women
within 30 to 40 days of the first positive pregnancy test and then every 4 to 6
weeks throughout pregnancy.

140. •Hyperthyroidism in Pregnancy
• The most common cause of biochemical hyperthyroidism in pregnancy is hCG
mediated.
• Hyperthyroidism usually is mild and resolves spontaneously, and treatment
with antithyroid drugs is not recommended.
• Graves disease accounts for 85% to 90% of overt hyperthyroidism in pregnant
women.
• Untreated overt maternal hyperthyroidism has been associated with the risk of
low birth weight, severe preeclampsia, miscarriages, maternal congestive heart
failure, stillbirth, and fetal growth restriction.

141. • RAI at diagnostic and therapeutic doses is contraindicated in pregnancy.
• For medical treatment of hyperthyroidism in pregnancy, different medications
are appropriate at different points in pregnancy.
• Methimazole should not be used in the first trimester because of associated
teratogenicity.
• PTU is recommended in the first trimester, PTU is associated with
hepatotoxicity and methimazole is recommended in the second and third
trimesters.

142. • Pregnant women being treated with antithyroid drugs should have free T4 and
TSH measured every 2 to 6 weeks during pregnancy.
• Thyroidectomy may be performed if rapid control of hyperthyroidism is
needed and antithyroid medications cannot be used because of allergies or
noncompliance.
• If thyroidectomy is necessary during pregnancy, it is preferentially performed
during the second trimester because of the risks of teratogenicity and fetal loss
in the first trimester and of preterm labor in the third trimester.
• Preoperative treatment of pregnant women may include 10 to 14 days of
iodine, antithyroid medications, and beta blockers.

143. • Thyroid Nodules and Thyroid Carcinoma in Pregnancy
• If a thyroid nodule is discovered during pregnancy, a thyroid ultrasound scan
and FNA can be performed safely at any time during pregnancy.
• All pregnant women with a thyroid nodule should have TSH and free T4
measured.
• Radionuclide scanning is contraindicated during pregnancy; however,
inadvertent scanning during the first trimester does not appear to damage the
fetal thyroid.
•

144. • If thyroid carcinoma is diagnosed during pregnancy, a sometimes emotionally
difficult decision must be made in regard to performing a thyroidectomy
during pregnancy or postponing thyroidectomy until after delivery.
• Surgery usually is not required during gestation, as deferring surgery for DTC
until postpartum is not associated with a worse prognosis.

145. • If surgery is deferred for FNA biopsy diagnostic of DTC, suppressive doses of
thyroid hormone may be considered with a goal TSH of 0.1 to 0.5 mIU/ liter.
• Ultrasound scans of the neck should be performed during each trimester to
assess for rapid growth, which could indicate the need for surgery.
• Extensive local, nodal, or distant disease also may indicate the need for more
urgent intervention.
• Thyroid nodules that are either benign or indeterminate and do not have rapid
growth do not require levothyroxine suppressive therapy during pregnancy.

146. • SURGICAL APPROACHES TO THE THYROID
• Total thyroidectomy involves excision of all visible thyroid tissue.
• Near-total thyroidectomy is complete resection on one side while leaving a
remnant of thyroid tissue on the contralateral side, leaving less than 1 g of
tissue adjacent to the RLN at the ligament of Berry.
• Subtotal thyroidectomy leaves a remnant of thyroid tissue bilaterally.
• The typical reason to leave a remnant at the ligament of Berry is the pursuit of
preservation of the RLN and blood supply to the parathyroids.
• Thyroid lobectomy typically includes removal of the thyroid isthmus and
pyramidal lobe (if present).

147. • When general anesthesia is used, paralysis is contraindicated if intraoperative
neuromonitoring is planned.
• Prophylactic antibiotics and chemoprophylaxis for venous thrombosis are not
indicated
• Incision overlies the isthmus of the thyroid and usually lies somewhere
between two finger-breadths above the clavicular heads and the level of the
cricoid cartilage.

148. • The incision should be centered on the midline even for an asymmetrical
goiter or unilateral lobectomy unless lateral neck dissection also is required.
• The anterior jugular veins are identified, and any that are crossing or running
along the midline can be divided.

149. • In the case of complicated lateral thyroid masses, lymphadenopathy, or
previous surgery, it may be necessary to gain exposure laterally by dividing
the sternohyoid and sternothyroid muscles.
• it is done superiorly to minimize denervation because both of these muscle
groups are innervated from a caudal direction through the ansa cervicalis
nerves.

150. • Inferior and lateral traction on the upper pole of the thyroid facilitates
identification of the avascular medial thyroid space of Reeves between the
upper pole of the thyroid and the cricothyroid muscle.
• With this space well defined and the lateral upper pole well cleared, the
adjacent sternothyroid muscle and the external branch of the superior
laryngeal nerve may be swept off of the superior thyroid vascular pedicle
leaving well-defined superior thyroid artery and vein.
• After mobilizing the upper pole vessels, in this area the superior parathyroids
are usually found lying in small deposits of fat within the thyroid sheath.

151. • For patients with large goiters and substernal goiters, it usually is impossible to
mobilize the goiter into the cervical wound until after the superior pole vessels
have been divided because these are an important point of fixation.
Continued medial retraction of the thyroid lobe allows the posterior aspect of the
thyroid lobe to be visualized, and larger goiters may be brought out through the
wound.
• The upper and lower parathyroids may become evident at this point. Minimal
dissection of the lower vessels entering the thyroid is undertaken, and no
division is done until the RLN is seen

152. • Useful landmarks for RLN identification include the following:
• (1) Palpation of the tracheoesophageal groove is facilitated by having a tube
such as an esophageal stethoscope in the esophagus.
• (2) The RLN crosses the inferior thyroid artery medial, lateral, or between
branches.
• (3) The superior parathyroid is posterior to the RLN, and the inferior
parathyroid is anterior to the RLN.

153. • Useful landmarks for RLN identification include the following:
• (4) The RLN frequently passes immediately medial to a tubercle of
Zuckerkandl.
• (5) The RLN enters the cricothyroid 2 cm posterior to the anterior border of
the trachea at approximately the level of the cricoid ring.

154. In rare situations, such as ATC or aggressive DTC, the nerve may be sacrificed.
• If the RLN is found to have been injured during the course of an otherwise
uncomplicated operation, every attempt is made to repair it initially with
microscope-aided visualization and microvascular technique (8-0 or 9-0
monofilament sutures).

155. • Continued medial traction on the lobe identifies the cephalad course of the
nerve to the point at which it disappears under the ligament of Berry or into its
final destination, the caudal border of the cricothyroid muscle.
• The ligament of Berry is in a position just anterior and slightly medial to the
entrance of the nerve underneath the cricothyroid muscle.
• Slowing the dissection again at this area and carefully separating the RLN
from the ligament of Berry permits a more complete thyroidectomy. A traction
injury to the RLN is most likely at this time

156. • If central compartment lymph node dissection is planned, level VI should be
cleared
• This is bounded superiorly by the hyoid bone, laterally by the carotid arteries,
and inferiorly by the level of the innominate artery on the right and lies
between the superficial and deep layers of the deep cervical fascia.

157. • Level VI lymph node dissection should include the prelaryngeal or delphian
nodes superiorly, the pretracheal nodes inferiorly, and the paratracheal nodes
laterally in the tracheoesophageal groove on one or both sides.
• On the right side, particular attention must be paid to clearing the nodes
posterolateral to the RLN. The upper paratracheal region typically is devoid
of lymphatic tissue

158. • Lateral Neck Dissection
• Biopsy is used routinely for definitive demonstration of lateral neck metastatic
spread before recommending lateral neck dissection.
• Prophylactic lateral neck dissection is not typically indicated, and “berry
picking” of nodes from the lateral compartment should not be performed.
• Excellent exposure is provided by extending the thyroidectomy incision
superiorly and laterally along the anterior border of the sternocleidomastoid
muscle.

159. • The anterior border of the sternocleidomastoid muscle is completely dissected,
and the plane is entered between the strap muscles and the
sternocleidomastoid, which is retracted laterally.
• The omohyoid muscle typically is divided.
• Nodes lying anterior to the carotid artery and vein at the level of the thyroid
cartilage may be resected at this time or later in the operation. The carotid
sheath contents are exposed.
• The carotid sheath is opened, and the lateral border of the internal jugular vein
is dissected, starting several centimeters above the clavicles.

160. • With retraction of the internal jugular vein medially and dissecting down to
the floor of the neck on the anterior scalene, the phrenic nerve may be found
running along the anterior scalene.
• The transverse cervical artery passes anterior to the phrenic nerve and usually
does not need to be sacrificed.
• The carotid artery and vagus nerve should then be well identified and cleared
of nodal tissue. With these structures identified, the nodal packet should be
cleared from these structures down to the base of the neck.
• On the left side, the thoracic duct is encountered looping up from posterior to
the internal jugular vein and passing from medial to lateral to enter the
subclavian vein at the junction with the internal jugular vein.

161. • By dissecting laterally across the base of the neck, the nodal packet may be
separated and swept superiorly off of the scalene.
• The brachial plexus may be identified passing between the anterior and
middle scalene. The sensory branches of the cervical plexus frequently may be
preserved by dissecting them out of the nodal specimen.
• The spinal accessory nerve is sought superiorly to this as it courses obliquely
across level II.
• The contents inferior and medial to this nerve are included in a typical
dissection for papillary cancer (level IIA), but the nodes superior and medial
typically are not (level IIB).

162. Substernal Goiter
• Characteristics that might predict an inability to mobilize a thoracic goiter into
a cervical incision include
• Reoperative field
• Invasive substernal thyroid malignancy
• Goiters that extend below the inferior margin of the aortic arch
• Goiters that reach the carina
• Goiters that extend into the posterior mediastinum, and true ectopic
mediastinal thyroid tissue.

163. • Maneuvers that may help to mobilize the mediastinal component into the
cervical incision include
• Division of the superior thyroid vascular pedicle
• Division of the thyroid isthmus, and opening of the midline raphe all the way
to the manubrium.

164. • The RLN is usually displaced posteriorly and inferiorly; however, it can be
draped anteriorly over the mass and damaged in that position.
• Great care must be exercised in mobilization of the mass until the nerve is
identified.
• In the unusual case in which a median sternotomy is required, a partial sternal
split of just the manubrium or of only the cephalad portion of the sternum,
usually provides excellent exposure and avoids the instability associated with
full sternotomy.

165. • Intraoperative Neuromonitoring
• Primary utility of IONM lies in the ability of a normal reading to rule out
injury. The clinical implications of an abnormal reading are less consistent.
• Visual identification of the RLN was the gold standard of care and that IONM
may have an adjunctive role in special cases as a “promising tool” for nerve
identification and protection in extended thyroid resection procedures.
• Important risk factors of permanent RLN paralysis appear to include recurrent
goiters, thyroid malignancies, and lobectomies.

166. • In the largest single-institution study published so far, Calo and colleagues
reported results from 2034 patients who underwent thyroidectomy,
approximately half of whom were assigned IONM in a nonrandom fashion.
• Noting a 2.2% injury rate in patients who received IONM and a 2.8% injury
rate in patients with no neuromonitoring, the study showed no significant
difference

167. • Taken in aggregate, direct anatomic identification and protection of the RLN is
the gold standard.
• IONM is a technology that should be within the armamentarium of the thyroid
surgeon. Some surgeons use this technology routinely; others never use it
• And others use it selectively for cases with expected distorted or aberrant
anatomy, cases with a preexisting deficit in vocal cord movement, and cases in
which the nerve lies in a scarred surgical field. All these practices are within
accepted standard of care.

168. • Postoperative Care
• One protocol that we have used involves routine over the-counter calcium
carbonate with vitamin D given at a dose of 1 g three times a day for 1 week
and then 1 g two times a day for the subsequent 2 weeks. This is a low-cost
approach, and the adverse effects are minimal

169. • Previously euthyroid patients scheduled to undergo thyroid lobectomy should
be informed of their risk of becoming hypothyroid despite leaving one lobe in
situ; the likelihood of this occurring is related to their preoperative TSH level.
• Of patients with a preoperative TSH less than 1 mIU/liter, approximately 20%
require postoperative thyroid supplementation

170. • Of patients with a preoperative TSH between 1 and 2 mIU/liter, approximately
40% require postoperative thyroid supplementation
• Of patients with a preoperative TSH between 2 and 3 mIU/liter, approximately
70% require postoperative thyroid supplementation
• And of patients with a preoperative TSH between 3 and 4 mIU/liter,
approximately 90% require postoperative thyroid supplementation.

171. • For patients undergoing total thyroidectomy a typical physiologic replacement
dose of levothyroxine is 1.6 μg/ kg/day. In a 70-kg adult, this correlates to a
dose of 112 μg, which is administered as a once-daily dose.
• Adipose tissue does not require the same degree of supplementation as lean
body mass, and the weight-based dose may be adjusted in obese patients, for
which several formulas are available.
• One method involves using the following formula:
• μg kg day = (−0.018 × body mass index) + 2.13

172. • Older patients also should be started at a lower dose. Although clinical
hypothyroidism does not develop immediately, thyroid hormone
supplementation typically is started on the day after surgery
• In a patient with previous hyperthyroidism, supplementation may be deferred
for several days.
• Calculated values for thyroid hormone replacement are imperfect, and dose
monitoring and adjustment are necessary.

173. • After initiating thyroid hormone therapy or a dose adjustment, a TSH level
should be checked approximately 6 weeks later.
• If the patient is clearly clinically hypothyroid or hyperthyroid before 6 weeks,
an earlier TSH level at 2 to 3 weeks is appropriate.
• It is mandatory to involve the endocrinologist, who will manage the
subsequent treatment in the decision for initial thyroid hormone dosing in the
setting of known or suspected thyroid carcinoma.

174. • Complications of Thyroid Surgery
• Hypocalcemia and Hypoparathyroidism
• Rates of postprocedure hypocalcemia are approximately 5%, and it resolves in
80% of cases in approximately 12 months.
• Every effort is made to evaluate the parathyroid tissue intraoperatively.
• For glands that appear to be devascularized, the use of immediate parathyroid
autotransplantation of 1-mm fragments of saline-chilled tissue into pockets
made in the sternocleidomastoid muscle or the brachioradialis muscle is
extremely effective in avoiding permanent hypocalcemia.

175. • Nerve Injury
• All patients should undergo voice assessment before thyroid surgery
including at least a description of the preoperative voice by the patient and the
physician.
• Perform preoperative laryngoscopy in patients with preoperative onset of
voice changes, patients with bulky tumor or nodal disease in the
tracheoesophageal groove, and patients with a history of cervical or upper
thoracic surgical intervention

176. • Superior Laryngeal Nerve
• The superior laryngeal nerve has two branches: an internal branch that
supplies sensory fibers to the larynx and an external branch that supplies
motor fibers to the cricothyroid muscles and tenses the vocal cords.
• The external branch can run closely adherent to the superior thyroid artery,
and care must be exercised during dissection in this area.
• Injury to the external branch causes voice changes, huskiness, poor volume
and projection, voice fatigue, and inability to sing at higher ranges.

177. • Recurrent Laryngeal Nerve
• the RLN arises from the vagus and is a mixed motor, sensory, and autonomous
nerve that innervates the adductor and abductor muscles.
• Unilateral injury is classically described as a paralyzed vocal cord with loss
of movement from the midline.
• A wide spectrum of injuries to the voice or swallowing mechanisms, or both,
can occur because of the mixed fibers contained within the nerve.
• Temporary or permanent voice change can result and is extremely distressing
to the patient.

178. • Bleeding
• Wound hematoma occurs in less than 1% of patients
• If the patient has impending loss of airway, if the patient has lost the airway,
or endotracheal intubation cannot be achieved, the wound should be opened
immediately, even if this occurs at the bedside.
• Complication rates appear to be affected by a surgeon’s experience.
• A study in Maryland comprising 5860 patients reported the lowest
complication rates in patients operated on by surgeons who performed more
than 100 neck explorations annually, and other studies confirmed these
results.