A.

PAPILLARY THYROID CARCINOMA

1. Definition
Papillary carcinoma (PTC) is the most common form of well-differentiated
thyroid cancer, and the most common form of thyroid cancer to result from exposure
to radiation. Papillary carcinoma appears as an irregular solid or cystic mass or
nodule in a normal thyroid parenchyma. Papillary/follicular carcinoma must be
considered a variant of papillary thyroid carcinoma (mixed form) (Wreesmann VB,
Ghossein RA, Hezel M, et al. 2004).
2. Pathofhysiology
Several chromosomal rearrangements have been identified in papillary thyroid
carcinoma.The first oncogenic events identified in papillary thyroid carcinoma were
chromosomal rearrangements involving the rearranged during transfection (RET)
proto-oncogene, which arises from a paracentric inversion of chromosome 10
(Legakis I, Syrigos K, 2011). RET fusion proteins (the RET/PTC family) appear to
play an oncogenic role in approximately 20% of papillary thyroid carcinomas, with
RET/PTC1, RET/PTC2, and RET/PTC3 accounting for most cases (Prescott JD,
Zeiger MA, 2015; Legakis I, Syrigos K. 2011).
Evidence also suggests that some molecules that physiologically regulate the
growth of the thyrocytes, such as interleukin-1 and interleukin-8, or other cytokines
(eg, insulinlike growth factor-1, transforming growth factor-beta, epidermal growth
factor) could play a role in the pathogenesis of this cancer.
Mutation in the BRAF gene resulting in the BRAF V60E protein is prominent in
papillary thyroid carcinoma. A single-institution study by Mathur et al reported
increasing rates of BRAF V600E mutations in papillary thyroid cancer from 1991 to
2005, suggesting that this may be contributing to the rise in thyroid cancer rates.
[12]

The BRAF V600E mutation is associated with aggressive clinicopathological

characteristics of papillary thyroid carcinoma, including lymph node metastasis,

extrathyroidal invasion, and loss of radioiodine avidity, which may lead to failure of
radioiodine treatment and disease recurrence (Xing M, Alzahrani AS, Carson KA,
Viola D, Elisei R, et al. 2013).
There is also a clear association between radiation exposure (from radiotherapy or
fallout) and incidence of papillary thyroid carcinoma. [14] Port et al reported that
papillary thyroid cancers in patients exposed to radiation from the Chernobyl accident

could be completely distinguished from sporadic papillary thyroid cancers in patients

with no history of radiation exposure, on the basis of gene expression patterns
involving seven genes (ie, SFRP1, MMP1, ESM1, KRTAP2-1, COL13A1, BAALC,
PAGE1) (Port M, Boltze C, Wang Y, et al. 2007).
3. Clinical Symptom
The most common presentation of thyroid cancer is an asymptomatic thyroid
mass or a nodule that can be felt in the neck. For any patient with a thyroid lump that
has developed recently, record a thorough medical history to identify any risk factors
or symptoms. In particular, obtain a history regarding every prior exposure to ionizing
radiation and the lifetime duration of the radiation exposure. Consider a family
history of thyroid cancer (Keith M Baldwin, DO IMPH. 2016).
Some patients with thyroid cancer have persistent cough, difficulty breathing, or
difficulty swallowing. Pain is seldom an early warning sign of thyroid cancer. Other
symptoms (eg, pain, stridor, vocal cord paralysis, hemoptysis, rapid enlargement) are
rare, and can be caused by less serious problems (Keith M Baldwin, DO IMPH.
2016).
At the time of diagnosis, 10-15% of patients with papillary thyroid carcinoma
have distant metastases to the bones and lungs. Initially, these patiens are evaluated
for pulmonary or osteoarticular manifestations (eg, pathologic fracture, spontaneous
fracture) (Keith M Baldwin, DO IMPH. 2016).
4. Treatment
Surgery is the definitive management of papillary thyroid cancer.
Approximately 4-6 weeks after surgical thyroid removal, patients may have
radioiodine therapy to detect and destroy any metastasis and residual tissue in the
thyroid. External beam radiotherapy has been used as adjuvant therapy in patients
with papillary thyroid cancer who were older than 45 years and had locally invasive
disease. Some improvements in 10-year survival rates have been reported with this
approach. Patients require lifelong thyroid hormone replacement therapy, especially
after total thyroidectomy. Treatment consists of levothyroxine in a dosage of 2.5-3.5
mcg/kg/d (Keith M Baldwin, DO IMPH. 2016).
a. Surgical Care

Surgery is the definitive management of thyroid cancer. Various types of

operations may be performed, ranging from lobectomy with isthmectomy to total
thyroidectomy. Lobectomy with isthmectomy is the minimal operation for a
potentially malignant thyroid nodule. It is an option for patients younger than 40
years who have papillary thyroid carcinoma nodules that are smaller than 1 cm,
well-defined, minimally invasive, and isolated. However, an important
consideration in considering this approach is that approximately 10% of patients
who have had only a lobectomy develop a recurrence in the contralateral lobe, and
residual tissue has the potential to dedifferentiate to anaplastic cancer.Subtotal
thyroidectomy is a near-total thyroidectomy. The argument for this form of
surgical intervention is that total thyroidectomy does not improve long-term
prognosis, and subtotal thyroidectomy has a lower incidence of complications (eg,
hypoparathyroidism, superior and/or recurrent laryngeal nerve injury) than total
thyroidectomy(Keith M Baldwin, DO IMPH. 2016).
1) Total thyroidectomy
Total thyroidectomy (removal of all thyroid tissue but preservation of the
parathyroid glands) is commonly performed for patients with papillary
carcinoma who are older than 40 years and in any patient with bilateral
disease. In addition, total thyroidectomy is used in most patients with a
thyroid nodule and a history of irradiation (Keith M Baldwin, DO IMPH.
2016).
National Comprehensive Cancer Network guidelines recommend total
thyroidectomy for patients who meet any of the following criteria [7] :
a) Radiation history
b) Known distant metastases
c) Bilateral nodularity
d) Extrathyroidal extension
e) Tumor > 4 cm in diameter
f) Cervical lymph node metastases
g) Poorly differentiated tumor

Total thyroidectomy is considered by many to be the surgical treatment

of choice for papillary tumors of the thyroid, for a number of reasons.
Papillary foci involving both lobes are found in some 60-85% of patients.
About 5-10% of patients who have had a lobectomy develop recurrences in
the remaining lobe. Also, at 20 years after initial surgery, patients who had
undergone total thyroidectomy had a recurrence rate of 8%, whereas those
who had received lobectomy only had a recurrence rate of 22%. Survival rates
were, however, comparable (Keith M Baldwin, DO IMPH. 2016).
Total thyroidectomy also facilitates earlier detection and treatment of
recurrent or metastatic carcinoma. This surgical option is mandatory in
patients with papillary carcinoma discovered on postoperative histology (ie, if
a very well-differentiated tumor is discovered) after a lobectomy, with or
without isthmectomy (Keith M Baldwin, DO IMPH. 2016).
When the primary tumor spreads outside the thyroid and involves
adjacent vital organs (eg, larynx, trachea, esophagus), these organs are
preserved at the first surgical approach. However, the surrounding soft tissues,
including the muscles and involved areas of the trachea and/or esophagus,
may be sacrificed if they are directly involved with the differentiated thyroid
carcinoma and local resection is feasible (Keith M Baldwin, DO IMPH. 2016).
Surgical techniques include video-assisted and robotic-assisted
thyroidectomy. Video-assisted thyroidectomy is rarely used to treat thyroid
cancer. A study by Lee et al found that the application of robotic technology to
endoscopic thyroidectomy may overcome the limitations of conventional
surgery, in a patient population where neck incision is considered culturally
averse. However, additional complications such as brachial plexus injury may
occur with this technique (Lee S, Ryu HR, Park JH, et al.2011).
2). Central Neck Dissection
The routine addition of central neck dissection to total thyroidectomy has
been debated over the years. Advocates cite a lower risk of later reoperation,
since reoperations for recurrence can lead to higher rates of recurrent nerve
injury. Critics cite the fact the upfront recurrent nerve injury rate may be

higher and that no survival benefit has been demonstrated over total
thyroidectomy alone.In a retrospective cohort study of 812 patients with
papillary

thyroid

carcinoma,

including

102

who underwent

total

thyroidectomy with elective central neck dissection and 478 who underwent
total thyroidectomy alone, elective central neck dissection increased the risk
for complications, but did not decrease local recurrence rates (Ywata de
Carvalho A, Chulam TC, Kowalski LP. 2015).
A study by Roh et al found that subclinical metastases are highly prevalent
in the ipsilateral central neck of patients with papillary thyroid carcinoma. The
study also revealed that although contralateral central metastases are
uncommon, they are associated with ipsilateral central metastases. The authors
conclude that these findings may suggest the necessity and extent of
prophylactic unilateral or bilateral central lymph node dissection (Roh JL,
Kim JM, Park CI. 2011).
A study by Popadich et al found that the addition of routine central lymph
node dissection in patients with cN0 papillary thyroid carcinoma reduced the
need for reoperation in the central compartment and was associated with
lower postoperative thyroglobulin levels (Popadich A, Levin O, Lee JC, et
al.2011).

b. Radioiodine Therapy
Approximately 4-6 weeks after surgical thyroid removal, patients may
have radioiodine therapy to detect and destroy any metastasis and residual tissue
in the thyroid. The decision for radioactive iodine depends on the size of the
tumors removed, the prognostic features (eg, lymphovascular invasion) and the
individual endocrinologists level of aggressiveness and interpretation of the
literature. Patients with low-risk differentiated papillary thyroid cancer have
shown excellent responses to total thyroidectomy without radioiodine remnant
ablation (Keith M Baldwin, DO IMPH. 2016).

After thyroidectomy, patients are given thyroid replacement therapy for

approximately 4-6 weeks. Thyroid replacement is then discontinued, to induce a
hypothyroid state and promote high serum thyroid-stimulating hormone (TSH)
levels.
A diagnostic dose of radioiodine (131I or 123I) is then given, and a wholebody scintiscan is performed to detect any tissue taking up radioiodine. If any
normal thyroid remnant or metastatic disease is detected, a therapeutic dose of 131 I
is administered to ablate the tissue. The patient is then placed back on thyroid
hormone replacement (levothyroxine) therapy (Keith M Baldwin, DO IMPH.
2016).
Therapy is administered until radioiodine uptake is completely absent.
Radioiodine treatment may be used again 6-12 months after initial treatment of
metastatic disease, for cases in which disease recurs or has not fully responded.
Some patients have elevated stimulated thyroglobulin concentrations after
reoperation for recurrent or persistent papillary thyroid cancer. Yim and
colleagues found that in such patients, adjuvant radioiodine therapy resulted in no
significant differences compared with no additional radioiodine therapy (Yim JH,
Kim WB, Kim EY, et al. 2011).
Patients receiving radioiodine therapy need to follow radiation
precautions, to maintain the safety of themselves, their familes, and the public.
The American Thyroid Association Taskforce on Radioiodine Safety released
recommendations to help guide physicians and patients in safe practices after
treatment, including reminders in the form of a checklist (Sisson JC, Freitas J,
McDougall IR, et al. 2011).

1. Legakis I, Syrigos K. Recent advances in molecular diagnosis of thyroid cancer. J

Thyroid Res. 2011. 2011:384213.
2. Prescott JD, Zeiger MA. The RET oncogene in papillary thyroid carcinoma. Cancer.
2015 Mar 2.

3. Xing M, Alzahrani AS, Carson KA, Viola D, Elisei R, et al. Association between BRAF
V600E mutation and mortality in patients with papillary thyroid cancer. JAMA. 2013 Apr
10. 309 (14):1493-501.
4. Wreesmann VB, Ghossein RA, Hezel M, et al. Follicular variant of papillary thyroid
carcinoma: genome-wide appraisal of a controversial entity. Genes Chromosomes
Cancer. 2004 Aug. 40(4):355-64.
5. Port M, Boltze C, Wang Y, et al. A radiation-induced gene signature distinguishes postChernobyl from sporadic papillary thyroid cancers. Radiat Res. 2007 Dec. 168(6):63949.
6. Keith M Baldwin, DO IMPH. 2016. Papillary Thyroid Carcinoma. Assistant Professor of
Surgery, Boston University School of Medicine; Endocrine and Surgical Oncologist,
Department of General Surgery, Roger Williams Cancer Center. Received in December
27, 2016 from: http://emedicine.medscape.com/article/282276-clinical#b1
7. Lee S, Ryu HR, Park JH, et al. Excellence in robotic thyroid surgery: a comparative study
of robot-assisted versus conventional endoscopic thyroidectomy in papillary thyroid
microcarcinoma patients. Ann Surg. 2011 Jun. 253(6):1060-6.
8. Ywata de Carvalho A, Chulam TC, Kowalski LP. Long-term Results of Observation vs
Prophylactic Selective Level VI Neck Dissection for Papillary Thyroid Carcinoma at a
Cancer Center. JAMA Otolaryngol Head Neck Surg. 2015 Jul. 141 (7):599-606.
9. Roh JL, Kim JM, Park CI. Central lymph node metastasis of unilateral papillary thyroid
carcinoma: patterns and factors predictive of nodal metastasis, morbidity, and
recurrence. Ann Surg Oncol. 2011 Aug. 18(8):2245-50.
10. Popadich A, Levin O, Lee JC, et al. A multicenter cohort study of total thyroidectomy and
routine central lymph node dissection for cN0 papillary thyroid cancer. Surgery. 2011
Dec. 150(6):1048-57.
11. Yim JH, Kim WB, Kim EY, et al. Adjuvant radioactive therapy after reoperation for
locoregionally recurrent papillary thyroid cancer in patients who initially underwent total
thyroidectomy and high-dose remnant ablation. J Clin Endocrinol Metab. 2011 Dec.
96(12):3695-700.

12. Sisson JC, Freitas J, McDougall IR, et al. Radiation safety in the treatment of patients
with thyroid diseases by radioiodine i: practice recommendations of the american
thyroid association. Thyroid. 2011 Apr. 21(4):335-46.