Papillary Thyroid Cancer: Principles and Updates of Management

Papillary Thyroid Cancer
Principles and Updates of management
Dr. Mahmoud W. Qandeel

Outlines
• Introduction and Epidemiology • Management
– Pre-op evaluation
• Molecular genetics of thyroid tumorogenesis
– Surgical options
• Pathology
– Approach to LN dissection
• Prognostic indicators – Post-op hormonal therapy
• Staging – Indications of RAI
• PTC in thyroglossal cyst • Follow up
• Extensive disease
• PTC in pregnancy

Introduction
• In the United States, thyroid cancer accounts for <1% of all malignancies
(2% of women and 0.5% of men) and is the most rapidly increasing
cancer in women.
• Thyroid cancer is responsible for six deaths per million persons annually.
• Most patients present with a palpable swelling in the neck, which

initiates assessment through a combination of history, physical
examination, and FNAB.

• 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.
• MTC accounts for approximately 6% of thyroid cancers (20% to 30% of which

occur on a familial basis including MEN2A and MEN2B).
• Anaplastic thyroid carcinoma (ATC) is an aggressive malignancy that is

responsible for less than 1% of thyroid carcinomas.
• In the different subtypes of thyroid carcinoma, prognosis mirrors incidence in that

PTC, which is the most common thyroid malignancy, also carries an excellent
prognosis in most patients, whereas ATC is far less common and carries a dismal
prognosis.
Molecular Genetics of Thyroid Tumorigenesis
• Our knowledge of the molecular pathogenesis of benign and malignant thyroid neoplasia is
evolving.
• The molecular profiling of thyroid neoplasms is commercially available to help distinguish

benign from malignant thyroid nodules using RNA from cells obtained by fine-needle
aspiration biopsy.
• Ongoing investigations into the molecular pathogenesis of thyroid neoplasms are being
pursued aggressively and are likely to have clinically useful therapeutic implications in the
future.

• Autonomously functioning thyroid nodules are benign tumors that
produce thyroid hormone.
• Many of these tumors are caused by somatic mutations in genes that

code for the thyroid-stimulating hormone (TSH) receptor or the alpha
subunit of the guanyl nucleotide stimulatory protein (Gs).
• The most common benign thyroid tumors are the nodules of

multinodular goiters (colloid nodules) and follicular adenomas.
• The oncogene changes accounting for these benign thyroid nodules are
not well delineated.
• The RET proto-oncogene plays a significant role in the pathogenesis of
thyroid cancers.
• It is located on chromosome 10 and encodes a receptor tyrosine kinase,

which binds several growth factors such as glial-derived neurotrophic factor
and neurturin.
• The RET protein is expressed in tissues derived from the embryonic nervous
and excretory systems.
• Therefore, RET disruption can lead to developmental abnormalities in
organs derived from these systems, such as the enteric nervous system
(Hirschsprung’s disease) and kidney. !!!

• Germline mutations in the RET proto- MEN2A, MEN2B, and familial MTCs, and
somatic mutations have been demonstrated in tumors derived from the neural
crest, such as MTCs (30%) and pheochromocytomas.
• The tyrosine kinase domain of RET can fuse with other genes by rearrangement.
• These fusion products also function as oncogenes and have been implicated in the
pathogenesis of PTCs.
• At least 15 RET/PTC rearrangements have been described and appear to be early

events in tumorigenesis.
• Young age and radiation exposure seem to be independent risk factors for the
development of RET/PTC rearrangements.

• These rearrangements confer constitutive activation of the receptor tyrosine kinases.
• RET/PTC3 is associated with a solid type of PTC that appears to present at a higher stage
and to be more aggressive.
• It has now been established that RET/PTC signaling involves the mitogen activated
protein kinase (MAPK) pathway via other signaling molecules such as Ras, Raf, and MEK.
• In normal cells, physiologic activation of Raf kinases occurs via direct interaction with
guanosine triphosphate (GTP)–bound Ras, a membranebound small G protein.

• Activated Raf, a serine-threonine kinase, in turn phosphorylates MEK,
another serine-threonine kinase.
• This leads to phosphorylation of ERK/MAPK, which phosphorylates

regulatory molecules in the nucleus, thereby altering gene expression.
• Aberrant activation of the MAPK pathway leads to tumorigenesis.

• Aside from RET/PTC alterations, mutations in the Ras genes can also activate
the MAPK pathway.
• Mutated RAS oncogenes have been identified in up to 20% to 40% of thyroid

follicular adenomas and carcinomas, multinodular goiters, and papillary and
anaplastic carcinomas.
• There are three Raf kinases, A-Raf, B-Raf (BRAF), and C-Raf.
• Mutations in BRAF also have been implicated in aberrant MAPK pathway
activation and tumorigenesis.

• Interestingly, BRAF mutations occur in papillary and anaplastic tumors
(average prevalence of 44% and 22%, respectively), but not in follicular
thyroid cancers, suggesting a role in the pathogenesis of these
malignancies.
• Studies also show that BRAF mutations are associated with more
aggressive clinicopathologic features, including larger tumor size,
invasion, and lymphadenopathy, and may have a role as prognostic
markers.

• The p53 gene is a tumor suppressor gene encoding a transcriptional
regulator, which causes cell cycle arrest allowing repair of damaged DNA, thus
helping to maintain genomic integrity.
• Mutations of p53 are rare in PTCs but common in undifferentiated thyroid

cancers and thyroid cancer cell lines.
• Other cell cycle regulators and tumor suppressors such as p15 and p16 are
mutated more commonly in thyroid cancer cell lines than in primary tumors.
• Thyroid cancer stem cells have also been identified; however, their role in
thyroid carcinogenesis remains to be determined.

• An oncogene resulting from the fusion of the DNA binding domain of the
thyroid-transcription factor PAX8 gene to the peroxisome proliferator-
activated receptor gamma 1 (PPARγ1) has been noted to play an important
role in the development of follicular neoplasms, including follicular cancers.
• Overexpression of normal c-myc and c-fos genes, as well as mutations of

HRAS, NRAS, and KRAS proto-oncogenes, is found in follicular adenomas,
follicular cancers, and occasionally papillary cancers.

Papillary thyroid carcinoma
• 80% of all thyroid tumors
• Predominant in children & persons exposed to radiation
• Female : Male 2:1
• Mean age 30-40 years old
• Most patients are euthyroid and painless swelling
• L.N metastasis are common ( children & young adult ) and may be
the presenting complaint.
• “Lateral aberrant thyroid” almost always denotes a cervical lymph

node that has been invaded by metastatic cancer.

• Diagnosis is established by FNAB of the thyroid mass or lymph node.
• Once thyroid cancer is diagnosed on FNAB, a complete neck ultrasound

is strongly recommended to evaluate the contralateral lobe and for
lymph node metastases in the central and lateral neck compartments.
• Distant metastases are uncommon at initial presentation, but may

ultimately develop in up to 20% of patients.
• The most common sites are lungs, followed by bone, liver, and brain.

Pathology
• Hard & white and remain flat on sectioning with a blade
• Necrosis and calcification may present
• Papillary projections or mixed ( papillary & follicular ) or pure follicular
• Characteristic nuclear cellular features are:
– Cells are cuboidal with pale abundant cytoplasm
– Crowded nuclei causing grooving
– Intranuclear cytoplasmic inclusions ( Orphan Annie nuclie )
– Psammoma bodies ( calcified deposits )
– Multifocal in 85% ( increase risk of LN mets )

Psamomma bodies seen in PAP SMEAR
• PA: PApillary thyroid cancer

• P: Pituatory adenoma
• S: Serous cystadenoma carcinoma
• ME: MEningoma
• A: Appendiceal carcinoid
• R: Renal cell carcinoma

Rare variants of PTCs
They are represent 1% but carry worse prognosis

• Tall cell
• Insular
• Columnar
• Diffuse sclerosing
• Clear cell
• Trabecular
• Poorly differentiated

Occult micro carcinoma
• 1 cm or less in size
• No evidence of local invasions
• No LN metastasis
• Incidental findings
• 2-35% demonstrated during autopsy
• Better prognosis than large tumor

Prognostic indicators
• Excellent prognosis 95% ten years survival
• Low risk and high risk
• AGES scoring system
• MACIS scale
• AMES system
• TNM classification
• DeGroot system

• AGES scoring system, which incorporates Age, histologic Grade, Extrathyroidal
invasion, and metastases and tumor Size to predict the risk of dying from
papillary cancer.
• Low-risk patients are young, with well-differentiated tumors, no metastases, and
small primary lesions, whereas high-risk patients are older, with poorly
differentiated tumors, local invasion, distant metastases, and large primary
lesions.
• The MACIS scale is a postoperative system modified from the AGES scale.
• This scale incorporates distant Metastases, Age at presentation (<40 or >40 years
old), Completeness of original surgical resection, extrathyroidal Invasion, and
Size of original lesion (in centimeters) and classifies patients into four risk groups
based on their scores.
• Cady proposed the AMES system to classify differentiated thyroid tumors into
low- and high-risk groups using Age (men <40 years old, women <50 years old),
Metastases, Extrathyroidal spread, and Size of tumors (< or >5 cm).
• Another classification system is the TNM system (Tumor, Nodal status,

Metastases)
• A simplified system by DeGroot and associates uses four groups:

– Class I (intrathyroidal),
– Class II (cervical nodal metastases),
– Class III (extrathyroidal invasion), and
– Class IV (distant metastases)

AJCC 8th, What’s the new?

Thyroid Cancer Arising from Thyroglossal Duct Cyst
• Thyroglossal duct cysts, present in up to 7% of the adult population,

often contain an epithelial lining of stratified squamous,
pseudostratified. ciliated columnar epipthelial cells and ectopic thyroid
cells.
• More than 90-95% of PTCs arising in thyroglossal duct cysts are confined
to the cyst, without evidence of local invasion or metastatic spread, and
are usually diagnosed after surgical removal of what was presumed to
be a benign thyroglossal duct cyst.

• Following complete surgical resection (usually a Sistrunk procedure with or
without thyroidectomy), prognosis in PTCs arising in these remnants is
excellent, with very low recurrence rates and 10-year survival rates
exceeding 95%.
• Squamous cell carcinomas appear to have a significantly worse prognosis.

• Because fewer than 300 cases of thyroglossal duct remnant carcinomas
have been reported in the literature, it is difficult to confidently identify
specific prognostic features.

• However, Plaza et al. proposed classifying tumors confined to the
remnant as low-risk tumors that may be managed with a Sistrunk
procedure alone.
• Although the prognosis in thyroglossal duct remnant PTC appears to be

very similar to that of PTC arising in the thyroid primary, the pattern of
lymphatic drainage may differ, as level I lymph nodes may be involved
more commonly than would be expected in thyroid cancers arising
within the thyroid gland proper.

Management of Papillary Thyroid Cancer

IMPORTANCE OF PREOPERATIVE IMAGING
• ATA suggest preoperative ultrasound evaluation of the central and lateral neck
lymph nodes for all patients with malignant cytological findings on the fine needle
aspiration (FNA).
• Preoperative ultrasonography of the central and lateral neck identifies abnormal

lymph nodes in as many as 20 to 30 percent of patients ; these ultrasound findings
may alter the planned surgical procedure in up to 20 percent of patients.
• However, ultrasonography can miss as many as 50 percent of the involved lymph

nodes in the central neck because the overlying thyroid gland hinders adequate
visualization

• While ultrasonography is the preferred modality for evaluation of the
thyroid and cervical lymph nodes, alternative imaging modalities such as
MRI, CT with contrast, laryngoscopy, and endoscopy may be required
in patients with potentially more advanced local disease in order to
accurately define the extent of tracheal, nodal, esophageal, laryngeal, or
vascular involvement.

• Additional imaging beyond routine preoperative neck ultrasonography should be
obtained in patients presenting with locally advanced disease, as manifested by:
• Clinically palpable metastatic lymphadenopathy or other evidence of extensive lymph
node involvement identified preoperatively
• Signs or symptoms of locally invasive disease:
– Dysphagia
– Respiratory compromise
– Hemoptysis
– Rapid tumor enlargement
– Changes in voice
– Vocal cord paralysis
– Tumor fixed to surrounding structures
– Ultrasonographic evidence of macroscopic extrathyroidal extension

• In these locally advanced cases, we routinely obtain preoperative CT of
the neck and chest with intravenous contrast to evaluate these lymph
node chains and optimize surgical planning.
• In such cases, the benefit of accurate surgical planning outweighs the

delay in radioiodine administration that is necessary after the use of
iodinated contrast.
• FDG-PET scanning is seldom used in preoperative surgical planning.

APPROACH TO THYROIDECTOMY
• Types of procedures — There are two potential surgical approaches to differentiated
thyroid cancer: total (or near-total) thyroidectomy and unilateral lobectomy and
isthmusectomy.
• A third option, subtotal thyroidectomy, is considered to be an inadequate procedure and
is not recommended.
– Total thyroidectomy involves removal of all thyroid tissue while attempting to identify
and preserve the recurrent laryngeal nerve (RLN), the superior laryngeal nerve (SLN),
and the vascular supply to the parathyroid glands.
– Near-total thyroidectomy is identical except for a slightly more conservative
approach to preserving the posterior thyroid capsule of the lobe contralateral to the
thyroid tumor.
– A unilateral lobectomy and isthmusectomy involves removal of one entire lobe and
the isthmus, without entering the contralateral neck.
Proponents of total thyroidectomy
• Enables the use of RAI effectively

• Makes serum Tg. More sensitive
• Eliminates contralateral occult ca.
• Reduce the risk of recurrence & survival
• Reduces the need to repeated
• Decrease the risk of progression to anaplastic or undiff.

Those who favor lobectomy
• Total has higher complication rate
• Recurrence in the remaining tissue 5%
• Multicentricity have little prognostic effect
• Patient with lobectomy still have good prognosis

Choice of procedure
Tumor <1 cm without extrathyroidal extension and no lymph nodes
• When surgery is planned for unilateral intrathyroidal differentiated

thyroid cancer <1 cm, a thyroid lobectomy is the preferred approach
unless there are clear indications to remove the contralateral lobe eg,
– clinically evident thyroid cancer in the contralateral lobe,
– Previous history of head and neck radiation,
– Strong family history of thyroid cancer, or
– Imaging abnormalities that will make follow-up difficult

Tumor 1 to 4 cm without extrathyroidal extension and no lymph nodes
• For intrathyroidal tumors between 1 and 4 cm, the initial surgical procedure can
either be a total thyroidectomy or thyroid lobectomy.
• Total thyroidectomy would be chosen either based on

– Patient preference,
– The presence of ultrasonographic abnormalities in the contralateral lobe
(nodules, thyroiditis in the contralateral lobe, or non-specific lymphadenopathy
which will make follow-up difficult), or
– On a decision by the treatment team that radioiodine therapy may be beneficial
either as adjuvant therapy or to facilitate follow-up

Tumor ≥4 cm, extrathyroidal extension, or metastases
• Total thyroidectomy is recommended if the primary tumor is 4 cm in

diameter or greater, there is extrathyroidal extension of tumor, or there
are metastases to lymph nodes or distant sites.

Any tumor size and history of childhood head and neck radiation
• Total thyroidectomy should also be performed in all patients with thyroid

cancer who have a history of exposure to ionizing radiation of the head
and neck, given the high rate of tumor recurrence with lesser operations
in these patients

Multifocal papillary microcarcinoma (fewer than five foci)
• Unilateral lobectomy and isthmusectomy is an appropriate procedure

for patients whose pathology reports subsequently show multifocal
papillary microcarcinomas with fewer than five foci.

Multifocal papillary microcarcinoma (more than five foci)
• When multifocal papillary cancer is appreciated preoperatively, particularly when a

large number of microcarcinoma are suspected (eg, greater than five foci, especially
if the foci are in the 8 to 9 mm size range), we are more likely to perform a total
thyroidectomy.
• For patients whose initial procedure was a lobectomy and in whom pathology
shows multifocal papillary microcarcinomas with more than five foci, especially if
the foci are in the 8 to 9 mm range, we typically refer patients for completion
thyroidectomy.

Indeterminate or suspicious thyroid nodules
• For patients with a cytologically indeterminate nodule, a unilateral lobectomy and

isthmusectomy is usually performed.
• Because as many as 60 percent of these patients may prove to have benign disease,
total thyroidectomy is usually not required as the initial procedure.
• If the final pathologic diagnosis is cancer, and if a completion thyroidectomy is

needed (for example, to administer radioiodine), it can be performed without
significant increased risk because the second surgery would avoid the first
operative field.

APPROACH TO LYMPH NODE DISSECTION

• In patients with differentiated thyroid cancer, preoperative assessment
of nodal status with ultrasound is necessary.
• A neck dissection for differentiated thyroid cancer (papillary and

follicular) should be performed as a therapeutic procedure when nodal
disease is identified or suspected based upon the clinical examination or
ultrasound evaluation.

• A prophylactic central neck dissection (level VI) for patients with thyroid
cancer is controversial.
• It is not necessary for small, noninvasive papillary and most follicular cancers.
• However, for patients with advanced primary tumors (>4 cm and/or with
extrathyroidal invasion), clinically involved lateral lymph nodes, or if the
information will contribute to the planning of further therapy, perform
prophylactic central lymph node dissection.
• BRAF mutation ??
• There are no data to show that routine prophylactic lateral neck dissection
benefits patients’ long-term survival [and therefore we do not perform this
procedure.

Therapeutic lymph node dissection
• Therapeutic lymph node dissection should be performed if there is

clinical evidence (on exam or ultrasound) of central or lateral node
metastases due to the increased risk of neck recurrence and mortality.
• This approach is consistent with the National Comprehensive Cancer

Network (NCCN) and American Thyroid Association (ATA) guidelines,
which recommend central and/or lateral neck dissection only in the
presence of grossly positive metastases

• During the operation, the lymph nodes should be inspected, and any suspected of
containing cancer should be biopsied.
• If nodes in the central compartment (level VI, the region bounded by the jugular
veins, the hyoid bone, and the upper mediastinum) are found to contain cancer,
dissection of all lymphatic and surrounding tissue in that compartment should be
performed.
• If any nodes in the upper, middle, or lower jugular nodal groups (levels II, III, IV) are
found to contain cancer, complete dissection of nodal tissue along the jugular and
carotid vessels should be done.
• Radical dissection, with removal of the internal jugular vein, spinal accessory
nerve, and sternocleidomastoid muscle, is rarely necessary.

• There is general agreement that therapeutic node dissection should be performed in
patients with papillary cancer who have visibly involved nodes.
• We perform lateral node dissection based upon intraoperative gross involvement or
preoperative ultrasound detection.
• Lateral compartment nodes containing metastases detectable by ultrasound are

associated with a shortened relapse-free survival, whereas those only found by
histologic examination do not predict altered outcomes.
• Although cervical nodal metastases are rare in patients with follicular cancer, patients
with the Hürthle cell variant may have nodal disease (which predicts a worse
outcome) and should have a therapeutic neck dissection if metastatic lymph nodes
are identified

• Microscopic regional lymph node metastases of papillary cancer occur in up to
80 percent of patients.
• However, only about 35 percent have cervical or mediastinal node metastases
that are detected at the time of initial surgery.
• Because microscopic nodal disease is rarely of clinical importance or subsequent

radioiodine administration ablates these occult foci, and observational studies
have not shown a clear benefit in reducing locoregional recurrence rates, many
authors argue that prophylactic neck dissection of microscopic lymph node
metastases that are not clinically identifiable at the time of surgery may not
improve long-term outcome and could subject patients to more risk than
benefit

SURGERY FOR INVASIVE DISEASE
• The primary tumor or local and regional metastases may invade the strap muscles, trachea,
recurrent laryngeal nerves (RLNs), larynx, esophagus, thoracic duct, or carotid sheath.
• Careful preoperative and intraoperative evaluation, including laryngoscopy and symptom-

guided imaging studies, is essential.
• Conservative procedures, such as vertical hemilaryngectomy for unilateral laryngeal

cartilage invasion or circumferential tracheal resection for subglottic invasion, may allow
maintenance of function.
• However, extensive intraluminal invasion may occasionally necessitate total laryngectomy.

POSTOPERATIVE THYROID HORMONE THERAPY
• After thyroid surgery, all patients (except selected low-risk patients

undergoing lobectomy) require postoperative thyroid hormone therapy
(T4 levothyroxine) to replace normal hormone production and/or to
suppress regrowth of tumor.

Lobectomy
• For low-risk patients whose initial surgery was a lobectomy, we do not

begin thyroid hormone (T4) immediately postoperatively (unless the
patient has Hashimoto’s thyroiditis and the preoperative thyroid-
stimulating hormone [TSH] was high normal).
• Instead, we measure serum TSH six weeks after surgery and determine
the need for T4 based upon the TSH and evaluation of postoperative
disease status

Total thyroidectomy
• For patients whose initial surgery was total thyroidectomy, the initial dose and type
of thyroid hormone (T4 or T3 [liothyronine]) depend upon the likelihood of needing
radioiodine scanning/ablation and the method of preparation for radioiodine
scanning.
• These decisions are based upon the estimated risk of persistent/recurrent disease.
• In the immediate postoperative period, complete clinicopathologic findings may be
unavailable to fully estimate these risks, and the clinician may need to modify dosing
four to six weeks postoperatively.

• T4 (usually 1.6 to 2 mcg/kg per day) can be started immediately
postoperatively in the following patients:
• ATA low and intermediate-risk patients who are unlikely to need radioiodine
scanning or ablation.
• Selected ATA intermediate and high-risk patients in whom radioiodine
scanning and ablation will be done using recombinant human TSH (rhTSH
[thyrotropin alfa]).

• The higher doses are used in selected intermediate and high-risk patients,
modified by age and other comorbid conditions.
• TSH is measured four to six weeks postoperatively, and the dose is adjusted
as needed to achieve goal TSH.
• The initial TSH goal is based upon the risk of recurrence as determined by
clinicopathologic findings and postoperative Tg.
• The long-term TSH goals depend upon structural and biochemical response
to initial therapy, which is determined by ongoing assessment and risk
stratification.

• For patients in whom radioiodine scanning and ablation will be done
using thyroid hormone withdrawal (typically ATA high-risk patients),
short-term thyroid hormone replacement can be initiated
postoperatively with T3, 25 mcg two to three times daily.
• After two to three weeks, T3 is discontinued and imaging is performed
once the patient's serum TSH concentration is above 25 to 30 mU/L.
• Postoperative evaluation:
• ATA guidelines that the optimal cutoff value for either a stimulated or non-stimulated
postoperative Tg four to six weeks after surgery is not clearly established , we expect
non-stimulated Tg values of:
– <5 ng/mL after a total thyroidectomy
– <30 ng/mL after thyroid lobectomy
• Serum Tg values above these cutoffs should prompt re-evaluation of the completeness
of the initial surgery (usually with neck ultrasonography) and consideration of the
possibility of persistent metastatic disease.

Response to therapy

RAI indications

Initial monitoring during year 1
• For the detection of possible persistent/recurrent disease during the first year after
thyroidectomy or lobectomy, we monitor:
• Neck ultrasound
• Thyroid-stimulating hormone (TSH)
• Serum Tg levels on thyroid hormone suppression
• Serum Tg on thyroid hormone suppression is generally measured every three to six

months for the first year, with ultrasound at 6 to 12-month intervals depending on
initial risk assessment.

• Additional imaging (MRI,CT,FDG-PET) is usually reserved only for :
• ATA high-risk patients who typically have either a biochemical or structural

incomplete response to therapy.
• ATA low/intermediate-risk patients who demonstrate a structural or biochemical
incomplete response to therapy during the first year of follow-up.
• These patients require further evaluation to identify residual disease, with

consideration for additional therapies.

Diagnostic whole-body scan
• Diagnostic whole-body radioiodine scanning may have a role in the follow-up

of patients with high or intermediate risk (with higher-risk features) of
persistent disease.
• However, ATA guidelines agree that routine follow-up diagnostic whole-body

scanning one year after radioiodine ablation is not required in low and
intermediate-risk (with lower-risk features) patients

Ongoing monitoring after year 1
• Most recurrences of differentiated thyroid cancer occur within the first five years after initial
treatment, but recurrences may occur many years or even decades later, particularly in patients
with papillary cancer.
• A serum TSH is measured annually and six to eight weeks after any dose adjustments of T4.
• Although the serum TSH should be maintained <0.1 mU/L in patients with a structurally
incomplete response, patients with a better response to therapy can have their TSH goal raised.
– For patients who initially presented with high-risk disease but who have an excellent or
indeterminate clinical response to therapy, a TSH goal of 0.1 to 0.5 mU/L for up to five years is
acceptable, after which time the degree of suppression can be further relaxed (with continued
surveillance for recurrence).
– For patients who initially presented with low-risk disease and who have an excellent clinical
response to therapy, a TSH goal of 0.5 to 2 mU/L is acceptable.
– For patients with a biochemically incomplete response, the serum TSH should be maintained
between 0.1 and 0.5 mU/L.
Extensive disease
• Recurrence within the thyroid bed may be associated with soft-tissue, laryngeal, tracheal,
or esophageal invasion, which may require more extensive resection.
Other options for treating recurrent/metastatic disease include the following :

• Radioiodine, if scans demonstrate uptake.
• Systemic chemotherapy (eg, kinase inhibitors).
• External radiotherapy.
• Percutaneous ethanol injection of cervical nodal metastases.
• Radiofrequency ablation of cervical, osseous, and pulmonary metastases – This is an
alternative for patients who are poor surgical candidates and whose metastases do not
concentrate radioiodine, but expertise in this treatment modality is not widely available.
• Palliative embolization of bone metastases – Palliative embolization may reduce symptoms
or be used prior to surgery.
• Pamidronate may reduce bone pain from skeletal metastases and improve quality of life,
and in one study, resulted in partial radiologic improvement in 2 of 10 patients.
• Zoledronic acid can also be used, although its greater potency may increase risk of
hypocalcemia and osteonecrosis of the jaw (ONJ) (although this remains a rare
complication).
• Denosumab (a RANK ligand inhibitor) is also available for the prevention of skeletal related
events (pathologic fracture, need for surgery or external bean irradiation to a bone
metastasis, or spinal cord compression) in patients with bone metastases from solid
tumors.
• Thus, denosumab is an alternative to bisphosphonate therapy in the management of
thyroid cancer patients with bone metastases.
• Systemic chemotherapy or palliative external radiotherapy may be considered for patients
with either local or distant recurrence or when radioiodine fails to control local growth and
spread of disease.

ATA guidelines for Thyroid cancer in Pregnancy
• The 2017 ATA guidelines recommend that a nodule with cytology indicating papillary
thyroid carcinoma discovered early in pregnancy should be monitored
sonographically and, if either it grows substantially by 24 weeks gestation (50% in
volume and 20% in diameter in two dimensions), or if metastatic cervical lymph
nodes are present, surgery should be considered in the second trimester.
• However, if it remains stable by midgestation, or if it is diagnosed in the second half

of pregnancy, surgery may be performed after delivery.
• Surgery in the second trimester is an option if the DTC is advanced stage at diagnosis
or if the cytology indicates medullary or anaplastic carcinoma.

• If surgery is not performed, the utility of thyroid hormone therapy
targeted to lower serum TSH levels to improve the prognosis of DTC
diagnosed during gestation is not known.
• Because higher serum TSH levels may be correlated with a more

advanced stage of cancer at surgery , if the patient’s serum TSH is >2
mU/L, it may be reasonable to initiate thyroid hormone therapy to
maintain the TSH between 0.3 and 2.0 mU/L for the remainder of
gestation

• The impact of pregnancy on women with newly diagnosed medullary
carcinoma or anaplastic cancer is unknown.
• However, a delay in treatment is likely to adversely affect outcome.
• Therefore, surgery should be strongly considered, following assessment
of all clinical factors.

References
• American Thyroid Association Guidelines 2012, 2015, 2016

and 2017.
• AJCC 8th Edition
• Sabiston Textbook of Surgery, The Biological Basis of Modern
Surgical Practice, 20th Edition 2016.
• Schwartz’s Principles of Surgery, 10th Edition 2015.
• UpToDate 2017, 2018.

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Papillary Thyroid Cancer

Principles and Updates of management

Dr. Mahmoud W. Qandeel

Dr. Mahmoud W. Qandeel

• Most patients present with a palpable swelling in the neck, which

Dr. Mahmoud W. Qandeel

• MTC accounts for approximately 6% of thyroid cancers (20% to 30% of which

• Anaplastic thyroid carcinoma (ATC) is an aggressive malignancy that is

• In the different subtypes of thyroid carcinoma, prognosis mirrors incidence in that

• The molecular profiling of thyroid neoplasms is commercially available to help distinguish

Dr. Mahmoud W. Qandeel

• Many of these tumors are caused by somatic mutations in genes that

• The most common benign thyroid tumors are the nodules of

• It is located on chromosome 10 and encodes a receptor tyrosine kinase,

Dr. Mahmoud W. Qandeel

• At least 15 RET/PTC rearrangements have been described and appear to be early

Dr. Mahmoud W. Qandeel

Dr. Mahmoud W. Qandeel

• This leads to phosphorylation of ERK/MAPK, which phosphorylates

• Aberrant activation of the MAPK pathway leads to tumorigenesis.

Dr. Mahmoud W. Qandeel

• Mutated RAS oncogenes have been identified in up to 20% to 40% of thyroid

Dr. Mahmoud W. Qandeel

Dr. Mahmoud W. Qandeel

• Mutations of p53 are rare in PTCs but common in undifferentiated thyroid

Dr. Mahmoud W. Qandeel

• Overexpression of normal c-myc and c-fos genes, as well as mutations of

Dr. Mahmoud W. Qandeel

• “Lateral aberrant thyroid” almost always denotes a cervical lymph

Dr. Mahmoud W. Qandeel

• Once thyroid cancer is diagnosed on FNAB, a complete neck ultrasound

• Distant metastases are uncommon at initial presentation, but may

Dr. Mahmoud W. Qandeel

Dr. Mahmoud W. Qandeel

• PA: PApillary thyroid cancer

Dr. Mahmoud W. Qandeel

They are represent 1% but carry worse prognosis

Dr. Mahmoud W. Qandeel

• No evidence of local invasions

• 2-35% demonstrated during autopsy

• Better prognosis than large tumor

Dr. Mahmoud W. Qandeel

Dr. Mahmoud W. Qandeel

• Another classification system is the TNM system (Tumor, Nodal status,

• A simplified system by DeGroot and associates uses four groups:

Dr. Mahmoud W. Qandeel

Dr. Mahmoud W. Qandeel

• Thyroglossal duct cysts, present in up to 7% of the adult population,

Dr. Mahmoud W. Qandeel

• Squamous cell carcinomas appear to have a significantly worse prognosis.

Dr. Mahmoud W. Qandeel

• Although the prognosis in thyroglossal duct remnant PTC appears to be

Dr. Mahmoud W. Qandeel

Dr. Mahmoud W. Qandeel

• Preoperative ultrasonography of the central and lateral neck identifies abnormal

• However, ultrasonography can miss as many as 50 percent of the involved lymph

Dr. Mahmoud W. Qandeel

Dr. Mahmoud W. Qandeel