Thesis Complete Edit Diagnosis New - Copy

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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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1

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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1

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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1

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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1

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.

2 - # a g e



1

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3 - # a g e



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