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ACKNOWLEDGEMENT
In the name of Allah, the Most Gracious, the Most Merciful. First and foremost, I
would like to express my gratitude towards Allah, who has inspired me to
accomplish this noteworthy essay very well.
I owe a special gratitude to my dedicated essay supervisor, r. A!oul "heir,
#rofessor of General $urgery, Faculty of Medicine, Mansoura %niversity, for giving
me the opportunity to do the essay and providing guidance and suggestion to
complete it.
At the same time, I would also like to express my gratitude to r. &l'$aid
A!del (ady and #rofessor Alaa Mos!ah for encouragement and support through this
six and half years in learning and practicing medical and clinical knowledge.
)ot forgotten, I am grateful for my family for their endless prayers, continuous
supports and motivations in my routine undertakings and studies.
*hanks also to my fellow colleagues, for exchanges of useful tips, knowledge
and skills. May we pass this medical school with +ying colours inshaAllah. For
conclusion, I recognie that this research would not have !een possi!le without the
encouragement from my lovely family in Malaysia and from Faculty of Medicine,
Mansoura %niversity. *hank you.
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TABLE OF CONTENTS
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)o /ontent #age
AbstractAcknowledgementTable o contentsTable o a!!end"ces
#$% & 'ntrod(ct"on)$% & L"terat(re re*"ew)$# & S(rger+)$) & ,ad"oact"*e 'od"ne)$- & T.+ro/"ne S(!!ress"on)$0 & E/ternal Beam ,ad"at"on)$1 & C.emot.era!.+S(mmar+,eerences
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ABST,ACT *hyroid cancer exists in several forms. i0erentiated thyroid cancers
include papillary and follicular histologies. *hese tumors exist along a
spectrum of di0erentiation, and their incidence continues to clim!. A num!er
of advances in the diagnosis and treatment of di0erentiated thyroid cancers
now exist. *hese include molecular diagnostics and more advanced
strategies for risk stratication. *his review will focus on the treatment of
!oth papillary and follicular thyroid carcinoma.
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'NT,OD2CT'ON *he incidence of well'di0erentiated thyroid cancer has increased su!stantially
over the past three decades, and an estimated 34,55 cases were diagnosed in the
%nited $tates in 513. In fact, thyroid cancer is the fastest increasing cancer in !oth
men and women. *he !iologic !ehavior of 6*/ can vary from an indolent tumor,
incidentally detected at autopsy, to an aggressive disease with invasion into critical
structures in the neck or widespread distant metastases with a 7'year survival of
less than 75 8 91: 9:. ;f note, the increasing incidence of thyroid cancer in the
%nited $tates is predominantly due to the increased detection of small 9< cm: well'
di0erentiated cancers 92:.
Given that ma=ority of deaths from thyroid cancer are related to anaplastic or
medullary thyroid cancer, it is not surprising that this increase in the incidence of
thyroid cancer has no signicant impact on disease specic mortality. Given this
increase in detection of su!clinical thyroid cancer, it is crucial for a surgical
oncologist to understand the principles of selective surgical management of well'
di0erentiated thyroid carcinoma !ased on tumor !iological !ehavior. *reatmentrecommendations should re+ect clinical !alance !etween estimation of the
aggressiveness of the disease and e0ectiveness, as well as possi!le complications,
of the proposed intervention.
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CLASS'F'CAT'ON OF T34,O'D CA,C'NOMA
*o e0ectively treat a malignancy of the thyroid gland it is essential to
understand and document the !ehavior of the tumor. *he classications are
important in the management of thyroid cancer !ecause it often will direct
management. A histologic classication of thyroid tumors is shown in (Table 1).
Most primary thyroid cancers are epithelial tumors that originate from thyroid
follicular cells. *hese cancers develop three main pathological types of carcinomas>
papillary thyroid carcinoma 9#*/:, follicular thyroid carcinoma 9F*/: and anaplastic
thyroid carcinoma 9A*/:. Medullary thyroid carcinoma 9M*/: arises from thyroid
parafollicular 9/: cells. #*/ and F*/ are categoried as di0erentiated thyroid cancer
9*/: !ecause of well di0erentiation and indolent tumor growth. #*/ consists of 47'
?58 of all thyroid cancer cases, followed !y F*/ 97'158: and M*/ 9a!out 8:. A*/
accounts for less than 8 of thyroid cancers and typically arises in the elder
patients. Its incidence continues to rise with age. 93: 97:
'$ 5r"mar+#$ E!"t.el"al )$ Non&e!"t.el"alA. Follicular cell derived • #rimary lymphoma and
plasmacytoma1: @enign • Angiosarcoma
• Follicular adenoma • *eratoma
: %ncertain malignant potential 9%M#: • $mooth muscle tumors
• (yaliniing tra!ecular tumor • #eripheral nerve sheath tumors
2: Malignant • #araganglioma
• #apillary carcinoma • $olitary !rous tumor
• Follicular carcinoma • Follicular dendric cell tumor
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• #oorly di0erentiated carcinoma • angerhans cell histiocytosis
• %ndi0erentiated 9Anaplastic:
carcinoma
• Bosai'orfman disease
• Granular cell tumor
@. / cell derived
• Medullary carcinoma
/. Mixed follicular and / cell derived
• Mixed medullary and follicular carcinoma
• Mixed medullary and papillary carcinoma
. &pithelial tumors of di0erent or uncertain cell derived
• Mucoepidermoid carcinoma
•
$clerosing mucoepidermoid carcinoma with eosinophilia
• $Cuamous cell carcinoma
• Mucinous carcinoma
• $pindle cell tumor with thymus'like di0erentiation9$&**&:
• /arcinoma showing thymus'like di0erentiation9/A$*&:
• &ctopic thymoma
''$ Secondar+
Table # 6 3"stolog"c Class"7cat"on O T.+ro"d T(mors
*here are also variety of classication systems that are !ased on factors such
as age, tumor sie, gender, tumor grade, multicentricity, metastatic disease, and
other varia!les. *he AG&$ system is !ased on factors including age, grade,extent,
and sie of the tumor (Table 2) 9D:. In the AG&$ system, those patients with an
aggregate score 3E are high risk and those with a score less than 3 are low risk. *he
AM&$ system considers age,distant metastasis, extent, and sie of tumor 9Table 3:
9:. Another classication system known as *)M tumor staging system endorsed !y
the American oint /ommittee on /ancer 9A//: 9Table 4: serves to provide a
uniform language when evaluating management and outcome 94:.
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Table )$ AGES Class"7cat"on S+stem
#rognostic score H 5.57 x age 9if age 35:
E1 9if grade : E2 9if grade 2 or 3: E1 9if extrathyroidal: E2 9if distant spread: E5. x tumor sie 9cm maximum diameter:
$urvival !y AG&$ score
J 2.?? H ??8 3' 3.?? H 458 7' 7.?? H D8 D H 128
Table -$ AMES Class"7cat"on S+stem
Low ,"sk
Koung patients 9menJ 31 years old, women J71 years old: without distant
metastasis.
;lder patients 9intrathyroidal papillary thyroid cancer, minor capsular invasion for
follicular lesion:
#rimary cancers < 7 cm in diameter
)o distant metastasis3"g. ,"sk
All patients with distant metastasis
&xtrathyroidal papillary
Ma=or capsular invasion for follicular
All older patients with extrathyroidal spread
All older !at"ents w"t. !r"mar+ cancer 8 1 cm "n d"ameter
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9menL 35, women L75:
$urvival !y AM&$ score
ow risk H ??8
(igh risk H D18
TNM CLASS'F'CAT'ON S4STEM
*1 *umor diameter cm. or smaller
* #rimary tumor diameter L to 3 cm.
*2 #rimary tumor diameter L3 cm. imited to the thyroid or with
minimal extracapsular extension
*3a *umor of any sie extending !eyond the thyroid capsule to
invade the
su!cutaneous soft tissues, larynx, trachea, esophagus, or
recurrentlaryngeal nerve.
*3! *umor invades preverte!ral fascia or encases carotid artery or
mediastinal nerves
*x #rimary tumor sie unknown, !ut without extrathyroid extension)5 )o metastatic nodes
)1a Metastasis to level I 9pretracheal, paratracheal, prelaryngeal:
)I! Metastasis to unilateral or !ilateral or contralateralcervical or
superior mediastinum
)x )odes not assessed at surgery
M5 )o distant metastasis
M1 istant metastasis
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Stages or D"9erent"ated T.+ro"d Cancer
#atient age < 37 years #atient age L37
years
$tage I Any *, any ), M; *1, )5, M5
$tage II Any *, any ), M1 *, )5, M5
$tage III *2, )5, M5 *2, )5, M5
*1, )1a, M5 *1, )1a, M5
*, )1a, M5 *, )1a, M5
*2, )1a, M5 *2, )1a, M5
$tage IA *3a, )5, M5 *3a, )5, M5
*3a, )1a, M5 *3a, )1a,
M5
*, )1!, M5 *, )1!, M5
*2, )1!, M5 *2, )1!, M5
*3a, )1!, M; *3a, )1!,
M5
$tage I@ Any *3!, any ), M5 Any *3!,
any ), M5
$tage I/ Any *, Any ), M1 Any *, Any ), M1
Table 0 6 TNM Class"7cat"on S+stem or D"9erent"ated T.+ro"d Carc"noma
,'SK FACTO,S
*o most accurately determine the risk of malignancy, it is essential to
consider a variety of factors (Table 5).
Table 1 6 ,"sk actors or t.+ro"d carc"noma
(istory of radiation exposure Family history of papillary thyroid carcinoma $ingle dominant solid nodule greater than 3 cm.
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Male gender Bapid growth of a nodule Kounger than 5 years old ;lder than 5 years old /ervical metastasis &vidence of invasion on imaging
CL'N'CAL 5,ESENTAT'ON
ike any newly discovered mass elsewhere in the !ody, the workup of a
thyroid nodule !egins with a thorough history and physical exam. A strong family
history of thyroid cancer or prior radiation exposure to the head and neck should
raise the suspicion of thyroid cancer. Bapid growth with compressive symptoms may
indicate that the thyroid nodule is thyroid lymphoma or a poorly di0erentiated
thyroid cancer 9?,15,11:. Koung age 9<5 years:, older age 9L5 years:, and male
gender may also represent an increased risk 9?:. *o most accurately determine the
risk of malignancy, it is essential to consider a variety of factors (Table 5).
;n physical exam, a single dominant or solitary nodule is more likely to
represent carcinoma than a single nodule within a multinodular gland, with an
incidence of malignancy from . to 258 and 1.3 to 158 respectively 915:.Ket, the
overall risk of malignancy within a gland with a solitary nodule is approximately
eCual to that of a multinodular gland due to the additive risk of each nodule 911:.
Malignant nodules are harder and xed while a nodule that is ru!!ery or soft
and moves easily with deglutition suggests a !enign nodule. #hysical exam features
alone do not ensure a !enign diagnosis. /ervical lymphadenopathy also increases
the likelihood that a thyroid nodule is malignant.
ist of #hysical examination ndings that increase the concern for malignancy
include>
• )odules larger than 3 cm in sie 91?.28 risk of malignancy: 91:
• Firmness to palpation
• Fixation of the nodule to ad=acent tissues
• /ervical lymphadenopathy
• ocal fold immo!ility
#hysical exam may !e limited !y the patientNs !ody ha!itus, as well as an
inherent variation !etween physicians and their assessment of nodules such that
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more precise measurements are o!tained through imaging 912:. #ositive predictive
values of 1558 for thyroid malignancy in the setting of a nodule have !een reported
for the physical exam ndings of cervical lymphadenopathy 9greater than 1cm: and
vocal fold immo!ility. Assessment of a patientNs voice is not adeCuately sensitive at
detecting vocal fold immo!ility when compared to +exi!le laryngoscopy 913:. A
thorough head and neck exam with visualiation of vocal fold movement is
therefore of utmost importance on initial presentation.
D'AGNOS'S
*hyroid cancer presents as a thyroid nodule detected !y palpation and more
freCuently !y neck ultrasound. 6hile thyroid nodules are freCuent 93O758
depending on the diagnostic procedures and patient age:, thyroid cancer is rare
9P78 of all thyroid nodules:. Fine needle aspiration cytology 9F)A/: should !e
performed in any thyroid nodule L1 cm and in those <1 cm if there is any clinical
9history of head and neck irradiation, positive family history of thyroid cancer,
suspicious features at palpation, presence of cervical adenopathy: or
ultrasonographic 9hypoechogenicity, microcalcications, a!sence of peripheral halo,
irregular !orders and regional lymphadenopathy: suspicion of malignancy. *he
results of F)A/ are very sensitive for the di0erential diagnosis of !enign and
malignant nodules although there are limitations> inadeCuate samples and follicular
neoplasia.
In the event of inadeCuate samples F)A/ should !e repeated while in the
case of follicular neoplasia, with normal *$( and QcoldN appearance at thyroid scan,
surgery should !e considered RIII, @S. *hyroid function test and thyroglo!ulin 9*g:
measurement are of little help in the diagnosis of thyroid cancer. (owever,
measurement of serum calcitonin is a relia!le tool for the diagnosis of the few cases
of medullary thyroid cancer 97O8 of all thyroid cancers:, and has higher sensitivitycompared with F)A/. For this reason measurement of calcitonin should !e an
integral part of the diagnostic evaluation of thyroid nodules 917:.
Bef > http>TTannonc.oxford=ournals.orgTcontentT5TsupplU3Tiv132.full
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L'TE,AT2,E ,E:'EW ; T,EATMENT OF D'FFE,ENT'ATED
T34,O'D CA,C'NOMA
*reatment of */ is multidisciplinary and involves a surgeon, endocrinologist,
nuclear medicine specialist, and, occasionally, a radiation oncologist. *his approach
!est serves patients with */ and will !e highlighted in the sections that follow.
S2,GE,4
*he extent of surgery for */ remains controversial. *his is especially true for
small, encapsulated, well'di0erentiated tumors, and tumors less than one
centimeter in sie 9microcarcinomas:. *he approach to microcarcinomas will !e
discussed further !elow, !ut for most */ 1 cm diagnosed preoperatively, most
clinicians recommend a total thyroidectomy 91D:. *he rationale for total
thyroidectomy is !ased on tumor !iology and current treatment modalities. */,
especially #*/, tends to !e multicentric, with up to 458 of patients having multipletumor foci and !ilateral disease in D58 when a thorough pathologic examination of
the contralateral lo!e is performed 923,33,37:.
A total thyroidectomy as the initial procedure negates the need for re'
operative surgery to remove the contralateral lo!e should a recurrence !ecome
detected. $econd, experienced thyroid surgeons can safely perform a total
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thyroidectomy with permanent complications such as recurrent laryngeal nerve
in=ury and hypoparathyroidism occurring at a rate of less than 8 91: 914:.
Badioactive iodine therapy for a!lating microscopic disease !ecomes most e0ective
when the thyroid remnant is small or a!sent. *G measurement and radioiodine
whole !ody scanning are highly sensitive modalities for detecting recurrent or
metastatic disease, !ut these two methods are most e0ective when all the thyroid
tissue has !een removed 91?: 95:. Most low'risk cancers carry an excellent
prognosis regardless of the extent of thyroidectomy, and there are no randomied
prospective trials comparing total thyroidectomy to thyroid lo!ectomy in this group
of patients. In addition, radioiodine may have limited utility in low'risk patients 91:
9:.
For these reasons, some favor thyroid lo!ectomy in low risk patients. For
example, $haha and associates have reported 5'year follow'up on 3D7 patients
with low risk */. Although the lo!ectomy group had more local recurrence
compared to the total thyroidectomy group 938 versus 18:, this was not
statistically signicant 92:. $imilarly, other groups have also failed to demonstrate
any signicant e0ect on survival 93?,75,71:. In contrast, large retrospective series
have demonstrated improvement in recurrence for total thyroidectomy compared to
lesser operations 97,72,73,77:. In a freCuently cited study, Maaferri and
colleagues reported on 1277 patients with a mean follow'up of 17. years. #atients
treated with total thyroidectomy experienced signicant improvements in
recurrence rate 9D8 vs. 358, p < 5.5: and mortality rate 9D8 vs. ?8, p H 5.5:
compared to lesser resections 93:.
6hile some have Cuestioned the accuracy of risk'stratication and
accounting for complications in these retrospective studies, current guidelines still
recommend a total or near'total thyroidectomy for small 9< 3 cm:, unifocal, well'
di0erentiated tumors with no lymph node metastases, or extrathyroidal extension
91D:. Another hotly de!ated topic related to the extent of initial surgery for */ is
the role of prophylactic central neck dissection. Although the 55D American
*hyroid Association guidelines stated that routine prophylactic central neck
dissection should !e considered for patients with */ 97: , the most recent
guidelines have !een revised to recommend that Vprophylactic central neck
dissection may !e performed, especially in patients with advanced primary tumorsW
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and Vtotal thyroidectomy without prophylactic central neck dissection may !e
appropriate for small 9*1 or *:, non'invasive, clinically node negative patientsW
91D:.
*he central neck lymph nodes are also classied as level D lymph nodes and
include the paratracheal, peri'thyroidal, and precricoid lymph nodes. *hese nodes
are found along and !ehind the recurrent laryngeal nerve and freCuently surround
the lower parathyroid gland 9Figure :.
F"g(re )$ ymph )ode /ompartments of the )eck
Although the level D lymph nodes contain macroscopic disease in 158 of
cases, when they are removed prophylactically, 2OD?8 of patients will have
microscopic metastases 97,74,7?:. #roponents of prophylactic central neck
dissection argue that the initial operation is the safest time to remove central neck
lymph nodes to prevent local recurrences and the complications associated with re'
operative surgery in the central neck. Furthermore, the central neck nodes are
diXcult to evaluate with preoperative ultrasound when the thyroid remains in place.
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6ada et al. found the recurrence rate in patients treated with therapeutic lymph
node dissection to !e 18 while patients who underwent prophylactic neck
dissection experienced a recurrence rate of only 5.328. Importantly, those patients
without clinically overt nodal disease who did not undergo prophylactic central neck
dissection also experienced a very low recurrence rate of 5.D78. (ence, the
a!solute di0erences in recurrence are miniscule 9D:.
$everal other studies also support the concept that microscopically positive
lymph nodes rarely progress to recurrence, especially after postoperative
radioactive iodine a!lation 9D1,D,D2:. *herefore, the de!ate regarding prophylactic
central neck dissection is closely tied to the utility of radioactive iodine. /linically
evident lymph node metastases place patients at higher risk for recurrence, and
these patients !enet from therapeutic lymph node dissection. #rophylactic central
neck dissection modestly reduces an already low recurrence rate, potentially
eliminates or reduces the need for radioactive iodine, !ut is also associated with its
own risks such as hypoparathyroidism. *he risk !enet ratio may favor prophylactic
central neck dissection in a su!set of patients, !ut the putative risk factors that
dene such a su!set remains unknown 923,D3,D7,DD:. $ome groups are currently
using molecular markers to preoperatively risk stratify patients, and decide who
might !enet from more aggressive surgery up front 9: 94:.
*hyroidectomy still involves the same !asic steps historically descri!ed, !ut
newer technology and attention to cosmetics account for some more recent
modications of the !asic techniCue. *raditionally, a "ocher collar incision was
utilied, !ut this reCuires a very large dissection superiorly to reach the upper pole
of the thyroid, placing the patient at risk for postoperative seroma. Intraoperative
ultrasound can help assess the upper extent of the gland and place the incision
appropriately. ;ften, the incision can !e placed higher in the neck !ut hidden in a
neck crease to allow a smaller !ut still cosmetically pleasing incision. $uperior and
inferior su!'platysmal +aps are raised to create a working space around the thyroid.
Instead of traditional clamps and ties, most of the vasculature feeding the thyroid
can now !e managed using energy devices such as the (armonic scalpel or
igasureY 9?: 925:, !ut larger vessels still may reCuire clips andTor ties.
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@efore dividing any structures along the medial !order of the gland, the
recurrent laryngeal nerve must !e identied and its course dissected. *he nerve is
found medial to the upper parathyroid gland and lateral to the lower parathyroid.
*he parathyroid glands must also !e identied and dissected free from the thyroid
on an intact vascular pedicle. ;nce the recurrent laryngeal nerve is identied, the
!ranches of the inferior thyroid artery can !e divided along the thyroid capsule. In
recent years, nerve monitoring devices have ena!led surgeons to test the
functionality of the recurrent laryngeal nerve intraoperatively. Beported rates of
permanent recurrent laryngeal nerve in=ury when the surgeon visually identies the
nerve is less than 8 921: 92:. &ven the largest trials have failed to show any
signicant prevention of nerve in=ury 922: 923:.
A multi'institutional prospective non'randomied study of 1D,334 patients
9?,??4 nerves at risk: found no statistical di0erence in nerve in=ury rates when
comparing patients treated with visual identication of the nerve alone compared to
those treated with a com!ination of visual identication and nerve monitoring 927:.
;ne of the few prospective studies, *homusch and colleagues reported on 4,723
patients 917,352 nerves at risk:. *hey compared direct stimulation of the recurrent
laryngeal nerve to indirect stimulation of the vagus nerve 9the recurrent nerve is a
distal !ranch of the vagus:, and found that direct stimulation had a much lower
sensitivity of predicting nerve palsy compared to indirect stimulation 937.?8 vs.
??.D8: 92D:. Although nerve monitoring does not prevent nerve in=ury, many
surgeons still use this technology to identify nerve palsies when they do occur. *his
last study suggests that when nerve monitoring is used in this fashion, it should not
simply !e used to stimulate the recurrent laryngeal nerve directly.
*he use of nerve monitoring remains Cuite controversial. Many experts feel
that nerve stimulation is generally not necessary for the primary surgery on the
thyroid, and may !e more useful for reoperations. @efore passing the specimen o0
the eld, the surgeon should examine it to make sure that there is no parathyroid
tissue adherent to the gland. Any inadvertently removed parathyroid tissue can !e
nely minced and re'implanted into either the sternocleidomastoid or the strap
muscles. Froen section of a !iopsy of this tissue can distinguish !etween fat,
parathyroid, or lymph nodeZ this will also avoid auto'transplanting cancer'!earing
lymph nodes !ack into the patient. *wo to three pockets are created within the
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muscle, and the minced parathyroid tissue is divided !etween these pockets. &ach
pocket should !e marked with permanent suture so that it can easily !e found in a
re'operative setting. #reoperative F)A or intraoperative froen section can conrm
that enlarged lymph nodes seen on ultrasound har!or metastatic disease.
/ytologic or pathologic conrmation of lymph node metastases should
prompt the surgeon to perform a compartment'oriented lymph node dissection.
ymph node sampling or V!erry'pickingW should !e avoided as this leaves !ehind
lymph nodes that likely contain microscopic disease which then !ecome more
diXcult to excise in a re'operative setting. Although VskipW metastases directly to
the lateral compartment can occur in #*/, the central neck nodes 9level I: are
usually the rst nodes to receive drainage from the thyroid 9Figure :. *he
!oundaries of the central neck are the carotid sheathes laterally, the hyoid !one
superiorly, and the innominate artery inferiorly 92:. ymphadenectomy in this area
reCuires skeletoniing the recurrent laryngeal nerve along its entire cervical course,
and removing all the !ro'fatty tissue along the trachea. FreCuently the lower
parathyroid is invested in this tissue and !ecomes devascularied with this
dissection 924:. A lateral neck dissection usually involves dissection of levels II, III,
and I 9Figure :.
*his dissection puts the spinal accessory, phrenic, vagus, cervical sensory,
sympathetic trunk, hypoglossal, greater auricular, and the marginal mandi!ular
!ranch of the facial nerves at risk. *he extent of node dissection should !e guided
!y preoperative and intraoperative ultrasound ndings. %sually, the great vessels
can !e preserved, !ut more aggressive tumors can invade the internal =ugular vein,
and it should !e sacriced in this scenario. In addition, to nerve in=ury, chyle leak is
another complication from performing lateral neck dissection 92?: 935:. In recent
years, transaxillary approaches to thyroidectomy have !een developed. *here are
several variations of these techniCues including, trans'axillary endoscopic, ro!otic,
and axillo'!reast techniCues 931:. All of these techniCues avoid a neck incision, and
instead hide the incision in the crease !etween the axilla and the !reast. ong'term
data on the adeCuacy of resection using these approaches is lacking, and these
techniCues come with added complication risk such as !rachial plexus in=ury 93:.
,AD'OACT':E 'OD'NE
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Bemnant a!lation with radioactive iodine is the standard ad=uvant treatment
for selected patients with */. It can only !e administered after a total or neartotal
thyroidectomy, otherwise the radioactive isotope will !e a!sor!ed !y the remnant
thyroid and not destroy any micro'metastatic disease as intended. Badioactive
iodine is administered 1O2 months postoperatively as 121I as sodium iodide in an
oral form whose half'life is O4 days. /onsensus guidelines recommend a dose of
25O155 m/i for patients with low risk tumors and higher doses 9155O55 m/i: for
patients with residual disease, suspected microscopic disease, or more aggressive
histologic su!types 9i.e., tall cell, columnar cell, or insular variants: 91D:. In order to
stimulate intracellular uptake of the isotope, the *$( concentration should !e at
least as high as 25 m%T. *here are two methods for achieving such an elevation in
*$(. *he traditional method reCuires the patient to withdraw from thyroid hormone
replacement over 3OD weeks 91?:.
A newer method is to administer recom!inant human *$( 9rh*$(:. rh*$( is
administered in the form of intramuscular in=ections on two consecutive days
followed !y radioactive iodine on the third day. *he advantage of this method is that
the patient does not experience an extended period of hypothyroidism as with
hormone withdrawal. (owever, long'term data on the e0ectiveness of rh*$(
compared to traditional withdrawal are not esta!lished, although it appears
e0ective for low'risk patients. *he %.$. Food and rug Administration 9FA:
approved rh*$( for thyroid remnant a!lation in patients who do not have evidence
of metastatic disease 932:. In addition to making the *$( rise, clinicians should also
prepare patients !y instructing them to follow a low'iodine diet for 1O weeks prior
to radioactive iodine treatment. *his diet reCuires patients to avoid foods that
contain iodied salt, dairy products, eggs, seafood, soy!eans or soy'containing
products, and foods colored with red dye [2 933:.
Its important to note that rh*$( is not approved for use in children. 6hile
some studies show no !enet to radioactive iodine therapy 937:, other studies
demonstrate a reduction in locoregional recurrences and distant metastases 93:.
As with the controversy over the extent of thyroidectomy, the !enet of radioactive
iodine for low risk patients remains unclear 93D:. *he most recent A*A guidelines
recommend remnant a!lation for patients with *2 tumors or nodal disease.
$elective use is recommended for 1O cm intrathyroidal tumors or * tumors. It is
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not recommended for intrathyroidal tumors less than or eCual to 1 cm in sie 91D:.
*he )ational /omprehensive /ancer )etwork 9)//): guidelines reCuire a more
thorough evaluation for the extent of remaining disease after thyroidectomy with a
radioiodine scan 1O1 weeks postoperatively. Badioactive iodine a!lation is not
recommended if the stimulated *g is less than 1 ngTm and the radioiodine scan is
negative 93:. Becently, some studies have shown an increase in the risk of
developing secondary malignancies after radioactive iodine therapy.
*his has !een examined using the )ational /ancer Institute\s $urveillance,
&pidemiology, and &nd Besults 9$&&B: data!ase. @rown and colleagues found that
patients treated for */ had signicantly higher rates of nonthyroid second primary
malignancies than expected in the general population. Although the excess risk was
relatively small, it was greater in the su!set of patients who were treated with
radioactive iodine 934:. Iyer and associates specically examined low risk patients
9*1)5: treated with radioactive iodine and found that their excess a!solute risk was
3.D excess cases per 15,555 person years at risk 93?: .
As discussed a!ove, radioactive iodine clearly !enets patients with larger
tumors and metastatic disease, !ut the increased risk of secondary malignancies in
low risk patients where the long'term !enet of radioactive iodine is Cuestiona!le
means that careful patient selection is necessary. (ematologic malignancies are the
most common secondary malignancies after radioactive iodine, !ut there is also an
association with kidney, !reast, !ladder, skin, and salivary gland cancers 975:. *he
more commonly noted side e0ects after radioiodine treatment include dry mouth,
mouth pain, salivary gland swelling 9sialadenitis:, altered smell and taste,
con=unctivitis, and fatigue. 6omen should not !e pregnant at the time of treatment
nor should they !ecome pregnant for at least D months following treatment.
$imilarly, men should avoid conception for at least D months following treatment
971:.
T34,O<'NE S255,ESS'ON
$ince all cells of follicular origin depend on *$( for growth, *$( suppression
through the administration of supraphysiologic doses of levothyroxine 9*3: remains
an important strategy for maintaining disease'free survival and overall survival 97:.
For high'risk patients with incomplete resection, tumor invasion into ad=acent
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structures, or distant metastases, their physician should initially titrate
levothyroxine dosing to a *$( < 5.1m%T. ower risk patients should !e dosed to a
*$( at or slightly !elow the lower limit of normal 95.1 O 5.7 m%T: 91D: 9??, 171:.
;nce patients remain disease'free for at least two years, their *$( suppression can
!e li!eralied to within the reference range. #atients with persistent disease should
!e kept at a *$( <5.1 m%T indenitely. *$( suppression carries risks of
arrhythmias, anxiety, and osteoporosis. *he risks and !enets should !e carefully
considered, particularly in older patients. ue to the risk of !one loss, the )//)
guidelines recommend daily calcium and vitamin supplementation for patients on
*$( suppression 93:.
E<TE,NAL BEAM ,AD'AT'ON
Although 121I is the preferred ad=uvant therapy for thyroid carcinoma,
external'!eam radiation sometimes plays a role in treating this disease. #ersistent,
recurrent, anaplastic, or poorly di0erentiated tumors may fail to take up 121I.
*reatment of anaplastic thyroid tumors almost always includes external !eam
radiation since these tumors often cannot !e completely resected and do not
concentrate iodine. Although no improvement in overall survival has ever !een
documented, external !eam radiation is often given after resection of poorly
di0erentiated tumors to reduce the risk of local relapse 972:. *he group at Memorial
$loan "ettering /ancer /enter has found that up to 478 of poorly di0erentiated
tumors display some iodine avidity, and therefore treatment with radioactive iodine
may remain worthwhile. #atients with incompletely resected tumors, unresecta!le
disease, and locoregional recurrence in a previously operated eld may !enet from
external !eam radiation 973:. &xternal !eam radiation is typically reserved as a last
resort, after surgery and BAI have !een exhausted.
C3EMOT3E,A534
$ince radioactive iodine often can !e e0ective treatment for
welldi0erentiated tumors that have metastasied, cytotoxic chemotherapy has not
!een extensively evaluated for metastatic thyroid cancers. For large !urden of
disease, anaplastic cancers, or poorly di0erentiated tumors that are not iodine avid,
chemotherapy !ecomes an important treatment component after surgery or if the
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tumor is not resecta!le. In these rare situations, chemotherapy confers minimal
e0ects as these tumors hold a very poor prognosis. (istorically, doxoru!icin was the
most e0ective single agent. /om!ination therapy with doxoru!icin and cisplatin
resulted in modest o!=ective response rates 977:. )ewer, targeted therapies have
shown some promise. $mall molecule tyrosine kinase inhi!itors 9such as sorafeni!
or sunitini!: and anti!odies 9anti'&GF: should !e considered in the context of
ongoing clinical trials 93:. Mitogen'activated protein kinase 9MA#": inhi!itors target
specic oncogenic pathways in */ progression.
*hese small molecules are generally well'tolerated with low toxicity proles.
As discussed a!ove, the @BAF gene is commonly mutated in thyroid cancer, and
therefore, many of the targeted MA#" drugs !lock the Baf kinases for patients with
B&* or @BAF mutations 97D:. $orafeni! is an orally administered multi'kinase
inhi!itor targeting @BAF, &GF, B&*, and c'kit. *wo di0erent phase II clinical trials
enrolled patients with radioiodine resistant metastatic */, and reported that
sorafeni! sta!ilied disease progression and lowered serum thyroglo!ulin with
minimal toxicity 97:. &merging therapies specically target angiogenesis !ecause
*/ tumors express high levels of vascular endothelial growth factor 9&GF:
receptors 974: . Multi'kinase inhi!itors such as motesani!, vandetani!, sunitini!, and
axitini! have shown early promise in patients with */ 97?: .*hese drugs often
target multiple &GF receptors in addition to other signaling pathways such as c'"it,
B&*, and #GF.
Another mechanism targeted in anti'cancer therapy is the acetylation of )'
terminal lysine residues on histones. (istone acetylation results in a more open
chromatin conguration and gene transcription. Many di0erent types of cancer cells
have !een found to have dysregulated histone acetyltransferase or histone
deactylase 9(A/: enymes 9D5:. $everal (A/ inhi!itors including vorinostat,
depsipeptide, and valproic acid have !een shown to have an e0ect on thyroid
cancer cells 9D1:. For example, in thyroid carcinoma cell lines, valproic acid
increased expression of the sodium'iodide symporter and radioiodine uptake 9D:.
Many of these results come from in'vitro studies or early phase clinical trials, !ut do
represent promising novel therapies with much lower toxicity than traditional
chemotherapeutic agents.
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S2MMA,4
*hyroid cancer is the fastest increasing cancer in !oth men and women. *he
!iologic !ehavior of 6*/ can vary from an indolent tumor, incidentally detected at
autopsy, to an aggressive disease with invasion into critical structures in the neck or
widespread distant metastases with a 7'year survival of less than 75 8. *o
e0ectively treat a malignancy of the thyroid gland it is essential to understand and
document the !ehavior of the tumor. *he classications are important in the
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management of thyroid cancer !ecause it often will direct management for example
> (istological, AG&$, AM&$ and *M) $taging classications. Furthermore, risk
factors are also essential for determining the risk of malignancy.
*he workup of a thyroid nodule !egins with a thorough history and physical
exam. *he list of important investigations would include > F)A !iopsy, thyroid
radionuclide scanning, serum thyroglo!ulin, %ltarsound, /* scan and molecular
markers.
*reatment of */ is multidisciplinary and involves a surgeon, endocrinologist,
nuclear medicine specialist, and, occasionally, a radiation oncologist. *he extent of
surgery for */ remains controversial. *his is especially true for small,
encapsulated, well'di0erentiated tumors, and tumors less than one centimeter in
sie 9microcarcinomas:. *he approach to microcarcinomas will !e discussed further
!elow, !ut for most */ 1 cm diagnosed preoperatively, most clinicians
recommend a total thyroidectomy 91D:. *he rationale for total thyroidectomy is
!ased on tumor !iology and current treatment modalities. */, especially #*/,
tends to !e multicentric, with up to 458 of patients having multiple tumor foci and
!ilateral disease in D58 when a thorough pathologic examination of the
contralateral lo!e is performed 95: 91: 9:.
Bemnant a!lation with radioactive iodine is the standard ad=uvant treatment
for selected patients with */. It can only !e administered after a total or neartotal
thyroidectomy, otherwise the radioactive isotope will !e a!sor!ed !y the remnant
thyroid and not destroy any micro'metastatic disease as intended. *$( suppression
through the administration of supraphysiologic doses of levothyroxine 9*3: remains
an important strategy for maintaining disease'free survival and overall survival 97:.
Although 121I is the preferred ad=uvant therapy for thyroid carcinoma, external'
!eam radiation sometimes plays a role in treating this disease.
$ince radioactive iodine often can !e e0ective treatment forwelldi0erentiated tumors that have metastasied, cytotoxic chemotherapy has not
!een extensively evaluated for metastatic thyroid cancers. For large !urden of
disease, anaplastic cancers, or poorly di0erentiated tumors that are not iodine avid,
chemotherapy !ecomes an important treatment component after surgery or if the
tumor is not resecta!le.
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)$ Fort(nat" N= Catalano MG= Arena K= et al$ :al!ro"c ac"d "nd(ces t.e
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