obesity and thyroid cancer: epidemiologic associations and underlying mechanisms

Obesity Comorbidity

Obesity and thyroid cancer: epidemiologicassociations and underlying mechanisms

K. Pazaitou-Panayiotou1, S. A. Polyzos2 and C. S. Mantzoros3

1Department of Endocrinology, Theagenion

Cancer Hospital, Thessaloniki, Greece;2Second Medical Clinic, Aristotle University of

Thessaloniki, Ippokration Hospital,

Thessaloniki, Greece; 3Division of

Endocrinology, Diabetes, and Metabolism,

Beth Israel Deaconess Medical Centre,

Harvard Medical School, Boston, MA, USA

Received 2 March 2013; revised 16 July

2013; accepted 16 July 2013

Address for correspondence: Professor CS

Mantzoros, Division of Endocrinology,

Diabetes, and Metabolism, Beth Israel

Deaconess Medical Centre, Harvard Medical

School, Boston, MA 02215, USA.

E-mail: [email protected]

SummaryThe incidence of thyroid cancer has been rising over the past few decades alongwith a parallel increase in obesity.

Observational studies have provided evidence for a potential associationbetween the two. By contrast, clinical data for a link between type 2 diabetesmellitus, a condition strongly associated with obesity, and thyroid cancer arelimited and largely not supportive of such an association.

Obesity leads to hypoadiponectinemia, a pro-inflammatory state, and insulinresistance, which, in turn, leads to high circulating insulin and insulin-like growthfactor-1 levels, thereby possibly increasing the risk for thyroid cancer. Thus,insulin resistance possibly plays a pivotal role in underlying the observed asso-ciation between obesity and thyroid cancer, potentially leading to the developmentand/or progression of thyroid cancer, through its interconnections with otherfactors including insulin-like growth factor-1, adipocytokines/cytokines andthyroid-stimulating hormone.

In this review, epidemiological and clinical evidence and potential mechanismsunderlying the proposed association between obesity and thyroid cancer risk arereviewed. If the association between obesity and thyroid cancer demonstrated inobservational studies proves to be causal, targeting obesity (and/or downstreammediators of risk) could be of importance in the prevention and management ofthyroid cancer.

Keywords: Insulin resistance, obesity, thyroid cancer.

Abbreviation: AdipoR, adiponectin receptor; BEL, best evidence level; BMI, bodymass index; DTC, differentiated thyroid carcinoma; ER, oestrogen receptor; FTC,follicular thyroid cancer; GR, grade of recommendation; HOMA-IR, homeostaticmodel of assessment insulin resistance; IGF, insulin-like growth factor; IGF-1R,IGF-1 receptor; IGFBP, IGF-binding protein; IR, insulin resistance; MetS, meta-bolic syndrome; Ob-R, obesity receptor; PI3K, phosphatidylinositol 3′ kinase;PTC, papillary thyroid cancer; T2DM, type 2 diabetes mellitus; TLR, toll-likereceptor; TSH, thyroid-stimulating hormone.

obesity reviews (2013) 14, 1006–1022

obesity reviews doi: 10.1111/obr.12070

1006 © 2013 The Authorsobesity reviews © 2013 International Association for the Study of Obesity14, 1006–1022, December 2013

Introduction

The incidence of thyroid cancer is estimated to be 1.2–2.6/100,000 men and 2.0–3.8/100,000 women, but it variesamong countries (1). The incidence has been increasing inthe last decades (1,2). The exact reason remains unknown,but this increase has been partly attributed to increaseddiagnostic scrutiny resulting in ‘over-diagnosis’ of smallcarcinomas, which may have remained undiagnosed and/oruntreated in the past (1,3–5). However, an increase in inva-sive, either large or small, thyroid tumours has also beenreported by some authors (6–8), suggesting that a trueincrease in the incidence of thyroid cancer also exists.

Multiple exogenous factors have been implicated inthe pathogenesis of thyroid cancer, including radiation,imaging with iodine containing media (9,10) and evenendocrine disruptors (11), to which the exposure of thepopulation is increasing. Furthermore, the risk for differ-entiated thyroid carcinoma (DTC) has been associatedwith obesity (12–14) and possibly type 2 diabetes mellitus(T2DM) (15) in epidemiologic studies; this association hasbeen recently reviewed elsewhere (16–18). Considering therising prevalence of obesity which has reached epidemicproportions in western societies of affluence, this associa-tion may prove to be of paramount importance for theincidence and prevalence of thyroid cancer, similar to othercancer types, including colon, endometrial and breastcancer (19–21). Although the pathway(s) linking obesity orT2DM and thyroid cancer remain largely unknown, alteredadiponectin levels and the development of insulin resistance(IR) have been proposed to play a pivotal role (22).

The main aim of this review is to present evidenceon the association between obesity and thyroid cancer,and to summarize evidence for inflammation, IR, insulin-like growth factor-1 (IGF-1), adipocytokines, thyroid-stimulating hormone (TSH) and oestrogens as potentialmediators underlying the association between obesity andthyroid cancer risk, with a primary focus on clinical evi-dence. The clinical implication of this emerging associationis that targeting weight loss may reduce thyroid cancer risk.

Literature search

Computerized literature search was performed using thePubMed electronic database. The initial search was per-formed by the query: ‘((thyroid cancer) OR (thyroid carci-noma)) AND ((obesity OR overweight) OR (insulinresistance) OR (metabolic syndrome) OR (adipocytokinesOR adipokines) OR (estrogens OR oestrogens))’, whichprovided 831 possibly relevant articles (last update 31 May2013). Two reviewers (KPP, SAP) independently selectedsome of them based subsequently on a title, abstract orfull-text basis. Both agreed the final selection of cited arti-

cles. The bibliographic search was extended to the ‘RelatedArticles’ link next to each selected article in PubMed and itsreferences.

When necessary, the best evidence level (BEL) and thegrade of recommendation (GR) were attributed to the arti-cles, according to the ‘Protocol for Standardized Produc-tion of Clinical Practice Guidelines’ of the AmericanAssociation of Clinical Endocrinologists (23).

Obesity, insulin-resistance-relatedcomorbidity and thyroid cancer risk:epidemiological evidence

Obesity

There are several single cohort, case-control and prospec-tive cohort studies, two pooled analyses of case controlstudies and one pooled analysis of prospective cohortstudies providing data for the association between obesityand the risk for thyroid cancer (12–14,24–35), which arepresented in Table 1. The best to-date evidence is providedby a pooled analysis of prospective cohort studies (33), inwhich overweight and obese were at higher risk for thyroidcancer compared with normal-weighted individuals, inde-pendently from potential confounders; however, the riskfor thyroid cancer was linearly increased with the increasein body mass index (BMI) in women, but not in men(Table 1). Prior to this pooled analysis of prospectivestudies, the first strong evidence on the association ofobesity and thyroid cancer came from a pooled analysis ofcase-control studies, in which women, but not men, at thehighest tertile of BMI were at higher risk compared withthose in the lowest tertile (25) (Table 1). Similar resultswere reported for weight, but not height (25). The resultsfrom the recent EPIC study (a large European multicentre[23 research centres in 10 European countries] prospectivecohort study) validated the association between BMI (orwaist-to-hip ratio) and the risk for DTC in women, but notmen (Table 1) (34). Generally, by looking at Table 1, theassociation between obesity and thyroid cancer risk seemsto be more strongly supported in women than men. Thismay not represent a true effect or just reflect the fact thatthyroid cancer is less common in men, thereby requiringmore power to prove statistical significance. It should bealso highlighted that both obesity and thyroid cancer aremore common among women worldwide (5). According toWorld Health Organization, in 2008 the ratio of obesewomen to men was 3:2 (http://www.who.int/mediacentre/factsheets/fs311/en/). Although the above observations donot prove a causal relationship, they provide the trigger forfurther studies.

There are also two meta-analyses on the associationbetween BMI and thyroid cancer risk (BEL 2, GR B); onewas not specifically (21), while the other one was specifically

obesity reviews Insulin resistance and thyroid cancer K. Pazaitou-Panayiotou et al. 1007

© 2013 The Authorsobesity reviews © 2013 International Association for the Study of Obesity 14, 1006–1022, December 2013

Tab

le1

Sum

mar

yof

clin

ical

stud

ies

pro

vid

ing

evid

ence

for

asso

ciat

ion

bet

wee

nob

esity

and

thyr

oid

canc

erris

k

Aut

hor,

year

*C

ount

ryS

tud

yd

esig

nC

ases

(n)/

Con

trols

(n)

Follo

w-u

p(y

ears

)M

ain

find

ing

sA

dd

ition

alin

form

atio

nB

est

evid

ence

leve

l(r

ecom

men

dat

ion

gra

de)

†

Ron

,19

87(2

4)U

nite

dS

tate

sC

ross

-sec

tiona

l15

9ob

ese

285

norm

alw

eig

hted

–1.

Ob

ese

wom

en(O

R=

1.5)

athi

ghe

rris

kfo

rth

yroi

dca

ncer

2.N

od

iffer

ence

inm

en

Not

spec

ifica

llyd

esig

ned

for

thyr

oid

canc

er

3(D

)

Dal

Mas

o,20

00(2

5)E

urop

eC

hina

Jap

anU

nite

dS

tate

s

Poo

led

case

cont

rol(

12st

udie

s)

2,47

3th

yroi

dca

ncer

pat

ient

s4,

323

cont

rols

–1.

Wom

enw

ithhi

ghe

rB

MI

(OR

=1.

2;95

%C

I=1.

0−1.

4fo

rth

ehi

ghe

stvs

.lo

wes

tte

rtile

)at

hig

her

risk

for

thyr

oid

canc

er2.

No

diff

eren

cein

men

2(B

)

Irib

arre

n,20

01(2

6)U

nite

dS

tate

sP

rosp

ectiv

eco

hort

196

new

lyd

iag

nose

dp

atie

nts

with

thyr

oid

canc

erd

urin

gfo

llow

-up

of20

4,96

4in

div

idua

ls

20(m

edia

n)N

od

iffer

ence

for

thyr

oid

canc

erris

kre

gar

din

gw

eig

htor

BM

IN

otsp

ecifi

cally

des

igne

dfo

rob

esity

2(B

)

Mac

k,20

02(2

7)U

nite

dS

tate

sC

ase

cont

rol

292

pre

men

opau

salw

omen

with

thyr

oid

canc

er29

2p

rem

enop

ausa

lwom

enw

ithou

tth

yroi

dca

ncer

–W

eig

htor

BM

Iat

age

18w

asno

tre

late

dto

thyr

oid

canc

erris

kN

otsp

ecifi

cally

des

igne

dfo

rob

esity

2(C

)

Sam

anic

,20

04(2

8)U

nite

dS

tate

sC

ross

-sec

tiona

l24

6,24

9m

enve

tera

nsho

spita

lized

for

obes

ity4,

254,

451

men

vete

rans

hosp

italiz

edfo

rot

her

reas

ons

–O

bes

eW

hite

(RR

=1.

4;95

%C

I=1.

09−1

.81)

and

Bla

ckm

en(R

R=

1.92

;95

%C

I=1.

09−3

.4)

athi

ghe

rris

kfo

rth

yroi

dca

ncer

Not

spec

ifica

llyd

esig

ned

for

thyr

oid

canc

er

3(C

)

Bor

u,20

05(2

9)Ita

lyR

etro

spec

tive

sing

leco

hort

1,33

3m

orb

idly

obes

ep

atie

nts

–Fr

eque

ncy

3.2%

for

thyr

oid

canc

er(t

hese

cond

mor

eco

mm

onaf

ter

bre

ast

canc

er)

Not

spec

ifica

llyd

esig

ned

for

thyr

oid

canc

er

4(D

)

Oh,

2005

(30)

Sou

thK

orea

Pro

spec

tive

coho

rt22

6ne

wly

dia

gno

sed

men

with

thyr

oid

canc

erd

urin

gfo

llow

-up

of78

1,28

3m

en

10(m

ean)

Ove

rwei

ght

men

athi

ghe

rris

kfo

rth

yroi

dca

ncer

(RR

=2.

00;

95%

CI=

1.38

−2.8

9an

dR

R=

2.23

;95

%C

I=1.

40−3

.55

for

BM

I25

.0−2

6.9

and

27.0

−29.

9,re

spec

tivel

y)

Not

spec

ifica

llyd

esig

ned

for

thyr

oid

canc

er

2(B

)

Eng

elan

d,

2006

(31)

Nor

way

Pro

spec

tive

coho

rt3,

046

new

lyd

iag

nose

dp

atie

nts

with

thyr

oid

canc

erd

urin

gfo

llow

-up

of2,

000,

947

ind

ivid

uals

23(m

ean)

1.O

bes

ew

omen

athi

ghe

rris

kfo

rP

TC(R

R=

1.19

;95

%C

I=1.

01−1

.41)

orFT

C(R

R=

1.63

;95

%C

I=1.

24−2

.15)

,b

utat

low

erris

kfo

rM

TC(R

R=

0.35

;95

%C

I=0.

16−0

.79)

2.N

od

iffer

ence

inm

en

2(B

)

Brin

del

,20

09(3

2)Fr

ench

Pol

ynes

iaC

ase

cont

rol

219

DTC

pat

ient

s/35

9co

ntro

ls–

1.W

eig

ht(O

R=

2.8;

95%

CI=

1.3−

6.2)

and

BM

I(O

R=

2.3;

95%

CI=

1.1−

4.7)

for

the

hig

hest

vs.

low

-qua

rtile

hig

her

risk

for

thyr

oid

canc

erin

wom

en2.

No

diff

eren

cein

men

Men

wer

eon

lya

min

ority

ofp

atie

nts/

cont

rols

2(C

)

Clé

ro,

2010

(14)

Fren

chP

olyn

esia

New

Cal

edon

ia

Poo

led

case

cont

rol(

2st

udie

s)

554

thyr

oid

canc

erp

atie

nts

776

cont

rols

–1.

73%

ofca

ses

vs.

57%

ofco

ntro

lsw

ere

over

wei

ght

orob

ese

2.B

ody

surf

ace

area

(OR

=3.

97;

95%

CI=

2.57

−6.1

5)hi

ghe

rris

kfo

rth

yroi

dca

ncer

2(B

)

1008 Insulin resistance and thyroid cancer K. Pazaitou-Panayiotou et al. obesity reviews

© 2013 The Authorsobesity reviews © 2013 International Association for the Study of Obesity14, 1006–1022, December 2013

Tab

le1

Con

tinue

d

Aut

hor,

year

*C

ount

ryS

tud

yd

esig

nC

ases

(n)/

Con

trols

(n)

Follo

w-u

p(y

ears

)M

ain

find

ing

sA

dd

ition

alin

form

atio

nB

est

evid

ence

leve

l(r

ecom

men

dat

ion

gra

de)

†

Leitz

man

n,20

10(1

3)U

nite

dS

tate

sP

rosp

ectiv

eco

hort

352

new

lyd

iag

nose

dp

atie

nts

with

thyr

oid

canc

erd

urin

gfo

llow

-up

of48

4,32

6in

div

idua

ls

8(m

ean)

1.O

verw

eig

ht(R

R=

1.59

;95

%C

I=1.

18−2

.18)

and

obes

e(R

R=

1.47

;95

%C

I=1.

03−2

.10)

athi

ghe

rris

kfo

rP

TC,

but

not

for

FTC

,M

TC,

ATC

2.B

eing

over

wei

ght

atag

e18

carr

ies

hig

her

risk

for

thyr

oid

canc

er(R

R=

1.50

;95

%C

I=0.

97−2

.33)

2(B

)

Kita

hara

,20

11(3

3)U

nite

dS

tate

sP

oole

dp

rosp

ectiv

eco

hort

s

768

wom

enan

d38

8m

enw

ithne

wly

dia

gno

sed

thyr

oid

canc

erd

urin

gfo

llow

-up

of41

3,97

9w

omen

and

434,

953

men

10.3

(mea

n)1.

Ove

rwei

ght

(HR

=1.

20;

95%

CI=

1.04

−1.3

8)an

dob

ese

(HR

=1.

53;

95%

CI=

1.31

−1.7

9)w

ere

ind

epen

den

tlyat

hig

her

risk

for

thyr

oid

canc

erth

anno

rmal

wei

ght

ed2.

Per

5kg

m−2

incr

ease

inB

MI,

the

risk

for

thyr

oid

canc

erw

aslin

early

incr

ease

din

wom

en(H

R=

1.16

;95

%C

I=1.

08−1

.24)

,b

utno

tin

men

(HR

=1.

21;

95%

CI=

0.97

−1.4

9)3.

No

sig

nific

ant

effe

ctm

odifi

catio

nb

yot

her

fact

ors

2(A

)

Alm

qui

st,

2011

(35)

Aus

tria

Nor

way

Sw

eden

Pro

spec

tive

coho

rt25

5w

omen

and

133

men

with

new

lyd

iag

nose

dth

yroi

dca

ncer

dur

ing

follo

w-u

pof

578,

500

ind

ivid

uals

12(m

ean)

1.To

tally

,hi

ghe

rB

MI

(reg

ress

ion

calib

rate

dR

R=

1.24

;95

%C

I=1.

03−1

.48)

athi

ghe

rris

kfo

rth

yroi

dca

ncer

2.N

osi

gni

fican

td

iffer

ence

sep

arat

ely

inm

enor

wom

en

Res

ults

from

the

Me-

Can

2(B

)

Rin

ald

i,20

12(3

4)E

urop

e(m

ultic

entre

)P

rosp

ectiv

eco

hort

508

wom

enan

d58

men

with

new

lyd

iag

nose

dp

atie

nts

with

DTC

dur

ing

follo

w-u

pof

343,

765

wom

enan

d14

6,82

4m

en

na‡

1.W

omen

with

hig

her

BM

I(H

R=

1.41

;95

%C

I=1.

03−1

.94

for

the

hig

hest

vs.

low

est

qui

ntile

)an

dw

aist

-to-

hip

ratio

(HR

=1.

42;

95%

CI=

1.05

−1.9

1fo

rth

ehi

ghe

stvs

.lo

wes

tte

rtile

)at

hig

her

risk

for

thyr

oid

canc

er2.

No

diff

eren

cein

men

reg

ard

ing

BM

Ian

dw

aist

-to-

hip

ratio

Res

ults

from

the

EP

ICst

udy

2(B

)

Kim

,20

13(1

2)S

outh

Kor

eaC

ross

-sec

tiona

l66

1ov

erw

eig

htan

d95

obes

eP

TCp

atie

nts

1,24

3no

rmal

-wei

ght

edP

TCp

atie

nts

1.O

verw

eig

ht(R

R=

1.41

;95

%C

I=1.

10−1

.81)

and

obes

e(R

R=

2.17

;95

%C

I=1.

23−3

.82)

athi

ghe

rris

kfo

rp

rimar

ytu

mou

rsi

ze>1

cmco

mp

ared

with

norm

alw

eig

hted

2.O

bes

e(R

R=

1.88

;95

%C

I=1.

06−3

.32)

but

not

over

wei

ght

athi

ghe

rris

kfo

rm

icro

scop

icin

vasi

on3.

No

diff

eren

cere

gar

din

gg

ross

inva

sion

,ce

rvic

ally

mp

hno

dal

met

asta

sis,

dis

tant

met

asta

sis

and

mul

tifoc

ality

3(C

)

*Dat

aar

ep

rese

nted

inp

ublic

atio

nye

aror

der

.† A

ccor

din

gto

the

‘Pro

toco

lfor

Sta

ndar

diz

edP

rod

uctio

nof

Clin

ical

Pra

ctic

eG

uid

elin

es’o

fth

eA

mer

ican

Ass

ocia

tion

ofC

linic

alE

ndoc

rinol

ogis

ts(A

AC

E).

‡ The

recr

uitm

ent

star

ted

from

1992

to19

98an

dth

ela

stfo

llow

-up

span

sfro

mD

ecem

ber

2006

toD

ecem

ber

2009

.AT

C,

anap

last

icth

yroi

dca

rcin

oma;

BM

I,b

ody

mas

sin

dex

;C

I,co

nfid

ence

inte

rval

;D

TC,

diff

eren

tiate

dth

yroi

dca

rcin

oma;

FTC

,fo

llicu

lar

thyr

oid

carc

inom

a;H

R,

haza

rdra

tio;

Me-

Can

;M

etab

olic

synd

rom

ean

dC

ance

rp

roje

ct;

MTC

,m

edul

lary

thyr

oid

carc

inom

a;na

,no

tav

aila

ble

;O

R,

odd

sra

tio;

PTC

,p

apill

ary

thyr

oid

carc

inom

a;R

R,

rela

tive

risk.



(17) designed to look into thyroid cancer risk. Based on thefour thyroid cancer-related studies included in the former(among 141 prospective studies including 282,137 cases of20 different cancer types), it was concluded that a 5 kg m−2

increase in BMI was associated with an increased thyroidcancer risk in both men (RR = 1.33; 95% CI = 1.04−1.70)and women (RR 1.14; 95% CI = 1.06−1.23) (21). In thelatter (7 cohort studies including 5,154 cases of thyroidcancer), a significant association between BMI and thyroidcancer risk, mainly papillary thyroid cancer (PTC), wasreported (RR = 1.18; 95% CI = 1.11−1.25); however, instratified analysis, this was valid for non-Asian, but not forAsian populations (17).

There are several case-control and prospective cohortstudies evaluating the potential association between dietaryfactors and thyroid cancer risk, which have recently beensystematically summarized elsewhere (BEL 2, GR B) (36).Although the extensive presentation of dietary factors isbeyond the scope of this review, briefly, it seems that there isno consistent association between thyroid cancer risk andiodine intake through fortification (risk estimate range:0.49–1.6) or fish consumption (risk estimate range: 0.6–2.2)or with diets high in cruciferous vegetables (risk estimaterange: 0.6–1.9), whereas a small number of studies showeda consistent protective effect of diets high in non-cruciferousvegetables (risk estimate range: 0.71–0.92) (36). Two previ-ously published pooled analyses of case-control studies(37,38) (n = 13 and n = 11, respectively; both BEL 2, GR B)provided similar results in general with two slight differ-ences: (i) fish and shellfish were not associated with thyroidcancer risk (OR = 0.99; 95% CI = 0.85−1.2 for moderateand OR = 0.88, 95% CI = 0.71−1.1 for high total consump-tion), but there was a protective effect in endemic goitreareas (OR = 0.65; 95% CI = 0.48−0.88) (37); (ii) cruci-ferous intake of vegetables was not associated with thyroidcancer risk (OR = 0.87; 95% CI = 0.75−1.01 for moderateand OR = 0.94; 95% CI = 0.80−1.10 for high intake). Non-cruciferous vegetable intake was protective in high con-sumption (OR = 0.82; 95% CI = 0.69−0.98), but not inmoderate consumption (OR = 1.04; 95% CI = 0.88−1.22).These results were similar in iodine-rich areas and endemicgoitre areas (38).

Another recent piece of evidence, which also needsfurther investigation, is that the operation time is longer inobese than non-obese patients subjected to standardizedrobotic thyroidectomy for PTC (BEL 3, GR C); however,post-operative complications were similar between obeseand non-obese (39).

Other insulin-resistance-related comorbidity

The association between T2DM and thyroid cancer has beenreviewed recently (18). Eight studies were included in thatreview: five prospective cohort studies, one retrospective

cohort, one case control not specifically designed to assessthe association between T2DM and thyroid cancer, and onepooled analysis of five prospective cohort studies designed toassess the association between T2DM and thyroid cancer.The best to-date evidence is provided by the pooled analysisof five prospective cohort studies (312,149 women and362,342 men followed up for 10.5 years [median]; BEL 2,GR A), in which the thyroid cancer risk was similar betweenmen (HR = 0.96; 95% CI = 0.65−1.42) and women (HR =1.19; 95% CI = 0.84−1.69) with or without T2DM (40).Only in one of them (the NIH-AARP Diet and Health Study;200,556 women and 295,992 men followed for a meanof 10 years) (15), diabetic women, but not men, were athigher risk to develop thyroid cancer (HR = 1.54; 95%CI = 1.08−2.20). In general, existing data, which are ratherless for T2DM than obesity (Table 1), do not provide robustevidence for an association between T2DM and thyroidcancer and, therefore, more studies are needed to shed lighton a potential association between these entities. Studiescomparing obese diabetic vs. non-obese diabetic individualsin terms of thyroid cancer are currently lacking, but wouldbe of importance.

Notably, in articles derived from the Metabolic syn-drome and Cancer project (BEL 2, GR B) (35,41,42), therewas paradoxically an inverse association between glucoseand thyroid cancer risk in women (35), but a positiveassociation in men (35,42). No association was shownamong serum triglycerides, cholesterol or blood pressureand thyroid cancer risk (35,41). However, the largest(1,298,385 Koreans) prospective cohort study to date (BEL2, GR B) did not report any association between bloodglucose and thyroid cancer risk (43), whereas other pro-spective cohort studies (both BEL 2, GR B) reported apositive association between blood glucose and thyroidcancer risk in women (44) or in sum of men and women(45). More studies are needed to highlight the associationof glucose levels with the long-term risk for thyroid cancer.

To our knowledge, there are currently no data regardingany association between thyroid cancer and polycysticovary syndrome or non-alcoholic fatty liver disease, com-monly regarded as the ovarian and hepatic manifestation ofIR, respectively.

Obesity and thyroid cancer risk:potential mediators

There is a variety of potential mechanisms linking obesitywith thyroid cancer: IR, IGF-1, adipocytokines, TSH andoestrogens may represent only some pieces of the underly-ing puzzle. These parameters may not act independently,but in combination (46,47): (i) there is an interplaybetween obesity and adipocytokine profile and inflamma-tion, leading to IR and certain metabolic consequences; (ii)altered adipocytokines due to central obesity, especially



low serum adiponectin, may lead to IR and abnormalitiesof hormones increasing malignant cell proliferation; (iii) IRand TSH are increased in obesity and both may have agrowth and proliferative effect on thyroid cells; in vitro, themitogenic effect of TSH in thyroid cell lines was decreasedin the absence of other growth factors (48,49); (iv) theeffect of IR is mediated through hyperinsulinaemia, and theaccompanying higher levels of bioactive IGF-1.

As mentioned above, IR also favours a low-grade butchronic and systemic inflammatory state, which worsensIR. Although the initial mechanistic event is practicallyunknown, it appears that there is a vicious cycle among IR,adipocytokines and inflammation in obesity. By lookinginto the adiponectin paradigm, hypoadiponectinemia dueto central obesity aggravates IR and is being aggravated byIR, resulting in a vicious cycle with metabolic, inflamma-tory and, possibly, oncogenic consequences (50) (Fig. 1).

Inflammation

BackgroundThe potential role of inflammation in thyroid cancerdevelopment and progression has been reviewed in detailelsewhere (51,52). Briefly, chronic systemic subclinicalinflammation favours the development of different cancertypes, including thyroid cancer (53,54), through increasedformation of reactive oxygen species, increased cell cyclerate and loss of tumour suppressor function (20).

Inflammatory cells usually infiltrate malignant lesions,and thus an inflammatory microenvironment is almostalways present in the majority of malignant lesions.Macrophages accumulate in tumoral stroma of PTC, and

their presence has been associated with decreased survival inadvanced PTC (55). Lymphocytic infiltrates are also signifi-cantly higher in patients with PTC than those with benignthyroid lesions (56). Furthermore, evidence suggests thatcancer-related inflammation promotes genetic instability.

Apart from local thyroid inflammation, systemic inflam-mation may contribute to thyroid cancer developmentand/or progression. By adipose tissue expansion, the infil-tration of inflammatory cells increases and triggers produc-tion of pro-inflammatory cytokines (50). This chronicsubclinical inflammation of the adipose tissue furtherworsens IR and may have systematic consequences withboth metabolic and oncogenic components (50).

Clinical evidenceThe association of Hashimoto’s thyroiditis with DTC iswell established, as reviewed in detail elsewhere (57,58).Many studies have reported a significant associationbetween PTC and Hashimoto’s thyroiditis. Furthermore,anti-thyroglobulin antibodies are detected in approxi-mately 20% of DTC patients and this has been proposed asa more specific thyroid tumour marker than the titre ofanti-thyroid peroxidase antibodies (58). Primary thyroidlymphoma, which is also reviewed in detail elsewhere(59,60), has also been closely associated with Hashimoto’sthyroiditis, and thus it has been proposed that Hashimoto’sthyroiditis may be a prerequisite for its development.

There are also many clinical studies, some of which areselectively described below, that provide more specific evi-dence on the association between inflammation and thyroidcancer. In an Italian cross-sectional study of PTC patients(128 with vs. 215 without associated thyroiditis), RET/PTC1 rearrangement was higher in the former (31%) thanthe latter (13%) group, showing a different genetic back-ground in PTC with and without autoimmunity (BEL 3,GR C). Furthermore, higher expression of genes encodingthe chemotactic factors chemokine (C-C motif) ligand20 and interleukin-8 was shown in PTC lesions comparedwith either normal tissue or thyroiditis alone. The strongassociation between RET/PTC1 and thyroiditis points to apotential critical role of this oncoprotein in the modulationof the autoimmune response. Moreover, enhanced expres-sion of inflammatory molecules in PTC suggests a possiblepro-inflammatory relationship between thyroiditis andthyroid cancer (61).

In another Italian cross-sectional study of patients withfollicular variant of PTC (n = 91) vs. patients with thyroidadenomas (n = 44), higher presence of immunologic cellswas shown in carcinomas than adenomas (BEL 3, GR C).More specifically, in the intratumoral and peritumoralareas, the expression of CD1a (specific for dentritic cells),tryptase (specific for mast cells) and CD68 (specific formacrophages) was higher in patients with carcinomasthan adenomas. Notably, non-encapsulated carcinomas

AdipocytokinesAlterations

Inflammation

Thyroid InsulinCancerObesity

Resistance

?

TSH

ÁH

ÁH

ÁH

ÁH IGF-1

Figure 1 Factors linking obesity with thyroid cancer. IR may be acentral mediator of risk. Expanding adipose tissue leads to IR,abnormal adipocytokine/cytokine profile and inflammation. IR,adipocytokines and inflammation influence each other, thereby creatinga vicious cycle, and may contribute to the pathogenesis of thyroidcancer. IR may also act, at least in part, through increases of insulinand free IGF-1 levels. Furthermore, elevated TSH may also contributeto the pathogenesis of thyroid carcinoma. IGF-1, insulin-like growthfactor-1; IR, insulin resistance; TSH, thyroid-stimulating hormone.



were more positive to tryptase. Regarding extratumoralareas, the expression of CD1a and tryptase was similarbetween groups, whereas CD68 was higher in patients withcarcinomas than adenomas (62).

In a Norwegian cohort study of patients with follicularthyroid cancer (FTC), including oxyphilic neoplasms(n = 127), the degree of peritumoral chronic inflammation,as assessed by the number of CD45+ lymphocytes,was lower for metastasized carcinomas than for non-metastasized ones (BEL 3, GR C). Furthermore, eitherhigher toll-like receptor (TLR)-4 expression or lack ofTLR-4 expression in FTC was associated with metastaticand aggressive disease. TLR-2 expression was stronger inadenomas than carcinomas, but it was not correlated withclinical variables. TLRs take part in adaptive and innateimmunity and may have both apoptotic and anti-apoptoticeffects (63).

Insulin resistance

BackgroundIR is a condition characterized by decreased, generalizedor, more frequently, selective sensitivity of target tissues toinsulin action. Pancreatic β-cells up-regulate insulin pro-duction to counteract decreased insulin sensitivity and tocontrol serum glucose levels, thereby resulting in hyper-insulinaemia. However, long-term hyperinsulinaemia hasmultiple undesirable consequences, collectively described asIR syndrome or metabolic syndrome (MetS). Under the termMetS are described several clustered pathologic componentsthat share IR as a common pathogenetic mechanism, includ-ing obesity, T2DM, dyslipidemia, hypertension, polycysticovary syndrome, non-alcoholic fatty liver disease andendothelial dysfunction, all of which increase the risk forcardiovascular disease and mortality, the end points of MetS(50). Thyroid nodular disease has been proposed to be thethyroid manifestation of MetS (64,65) and patients withdiabetes have increased prevalence of thyroid nodules com-pared with controls (66). In line, IR has also been associatedwith thyroid cancer in few clinical studies. IR may affect thethyroid cells directly, through hyperinsulinaemia, or indi-rectly, through increased IGF-1 and/or through its interac-tion with TSH, inflammation or oxidative stress. Apart fromits metabolic effects on glucose and lipid metabolism, insulinacts as a mitogen and has been associated with several cancertypes, including breast, prostate and colorectal cancer(67). Mitogenic insulin action is mediated mainly throughthe mitogen-activated protein kinase pathway and thephosphoinositide-3 kinase/Akt pathway (68).

The tumorigenic effects of insulin in the target cells aremediated by either insulin receptors, which exist in twoisoforms -A and -B, or the closely related IGF-1 receptors(IGF-1Rs), which seem to play a major role in the regulationof cell proliferation (69). Although isoform A has been

proposed to be more closely related to mitogenic signalling,whereas isoform B to metabolic signalling (68), there iscurrently no specific evidence related to thyroid cancerdevelopment. Insulin receptors were overexpressed incancer compared with normal thyroid cell lines and thyroidtissue specimens showing their potential implication in thedevelopment of thyroid cancer (70). Moreover, the expres-sion of insulin receptors was higher in less differentiated andanaplastic compared with well DTCs (71), but the exactsignificance of these findings remains to be elucidated.

Clinical evidenceThere are some clinical studies linking IR or MetS withthyroid nodular disease and/or cancer (64,65,72,73).Although most of these studies are cross-sectional, therebynot proving a cause – effect relationship, they raise hypoth-eses to be tested in relation to an association between IR orMetS and thyroid nodular disease and/or cancer. Cross-sectional studies providing evidence for potential associa-tion between thyroid nodular disease and thyroid cancerare presented in Table 2.

Interestingly, when patients (n = 66) with benign thyroidnodules < 2 cm were assigned to metformin alone,levothyroxine alone, metformin plus levothyroxine or notreatment in a 6-month prospective open-label study, inthose receiving metformin alone or metformin pluslevothyroxine, nodule size was significantly reduced byapproximately 30 and 55%, respectively, together with thenormalization of IR. On the other hand, nodule sizeremained essentially unchanged in patients assigned tolevothyroxine alone or no treatment (74).

According to the above-mentioned studies (Table 2), anassociation between IR and thyroid nodular disease mightpossibly exist; however, more and larger studies are needed.Furthermore, in our opinion, it is too early to consider thethyroid gland as another ‘victim’ of MetS and/or to subjectpatients meeting the criteria for MetS to screening formultinodular goitre, as other authors have proposed(64,73).

In addition, data regarding IR and thyroid carcinoma arecurrently fewer. To our knowledge, the first case linking IRwith thyroid carcinoma was reported in 1992 in an ado-lescent girl with severe IR and acanthosis nigricans (BEL 3,GR D) (75). In an Argentinean cross-sectional study ofpatients with DTC (n = 22) vs. euthyroid controls (n = 20),IR was reported in 50% of the former group, whereas 10%of the latter (BEL 3, GR C). When patients with BMI > 25were selected (n = 10 in each subgroup), IR was reportedin 70% of DTC patients vs. 20% of the control group.Regarding DTC subtype, IR was reported in 56% ofpatients with PTC, whereas 25% with FTC; however, thisfinding should be cautiously interpreted because of the verysmall number of patients with follicular carcinoma (22).



Insulin receptors are expressed in normal thyroid cells andaffect thyroid cell proliferation and differentiation. In anItalian cross-sectional study of patients with DTC (n = 22)vs. benign scintigraphically ‘cold’ adenomas (n = 13) vs.toxic adenomas (n = 9), insulin receptors were outnumberedin the specimens of patients with DTC or ‘cold’ adenomascompared with those with toxic adenomas, being similarbetween patients with DTC or ‘cold’ adenomas (BEL 3,GR C). Furthermore, within patients with DTC or ‘cold’adenomas, insulin receptor expression was higher in theselesions compared with the adjacent normal thyroid tissue ofthe same patients, whereas within patients with toxicadenomas, insulin receptors were similar in the lesionscompared with the adjacent normal thyroid tissue. Thisstudy suggests that the up-regulation of insulin receptors isnot restricted to the thyroid malignant lesions, but is alreadypresent in the ‘cold’ adenomas, which carry a certain risk formalignancy. Therefore, this may represent an early eventthat gives a selective growth advantage to transformedthyroid cells, thereby possibly contributing to thyroidtumorigenesis (76).

Insulin and insulin-like growth factor-1

BackgroundLong-term hyperinsulinaemia results in a decrease of thehepatic synthesis of IGF-binding proteins (IGFBPs), leading

to increased circulating free IGF-1. Insulin and IGF-1 areboth important determinants of cell proliferation andapoptosis and their elevated serum levels are responsiblefor the increased risk of various cancers, including thyroidcancer, as reviewed elsewhere (70).

In short, evidence from experimental studies supports therole of IGF-1 in the pathogenesis of different cancer celltypes. In vitro, the increase in IGF-1 concentrations resultsin a dose-dependent enhancement in the proliferation ofbreast cancer cells (77). IGF-1Rs, similar to insulin recep-tors, were overexpressed in cancer compared with normalthyroid cell lines and thyroid tissue specimens, therebyshowing a potential implication of the IGF system inthe development of thyroid cancer (70). Insulin receptoroverexpression, which was also found to be significantlyhigher in thyroid cancer, is considered as the key point foractivation of the IGFs and the formation of hybrids withIGF-1Rs. Large quantities of hybrid receptors are expressedin thyroid cancer, thereby expanding the pool of IGF-1binding sites (71).

Clinical evidenceThere are a few small clinical studies linking IGF-1 withthyroid nodular disease and/or cancer, which are indicativeof a potential association. However, the association ofacromegaly with thyroid nodular disease and/or cancer is

Table 2 Summary of cross-sectional studies providing evidence for association between insulin resistance and thyroid nodular disease

Author, year* Country Study design Cases (n)/Controls (n) Main findings Best evidence level(recommendationgrade)†

Rezzonico,2008 (64)

Argentina Cross-sectional 111 euthyroid womendivided in 4 groups

Higher rates of thyroid nodular disease (US), nodulenumber and nodules greater than 10 mm in IR thannon-IR individuals (either obese or non-obese)

3 (C)

Ayturk,2009 (72)

Turkey Cross-sectional 278 individuals withMetS261 individuals withoutMetS

1. Higher rates of thyroid nodular disease (US) inMetS individuals (50.4% vs. 14.6%)

2. Higher rates of thyroid nodular disease (48.3% vs.22.6%) and thyroid volume in individuals withhigher HOMA-IR

3. IR as independent predictor for thyroid nodules(OR = 1.87; 95% CI = 1.21−2.88)

3 (C)

Yasar,2011 (65)

Turkey Cross-sectional 63 euthyroid patientswith thyroid nodulardisease/83 controls

1. Higher rates of HOMA-IR and thyroid volume inpatients

2. HOMA-IR was positively correlated with thyroidvolume, but not thyroid nodule number

3 (C)

Rendina,2012 (73)

Italy Cross-sectional 277 with multinodulargoitre/261 patientssolitary thyroidnodules/884 controls

1. Higher rates of MetS (48%) in patients withmultinodular goitre than either patients withsolitary nodules (31%) or controls (28%).

2. The presence of Mets was independentlyassociated with multinodular goitre.

3 (C)

*Data are presented in publication year order.†According to the ‘Protocol for Standardized Production of Clinical Practice Guidelines’ of the American Association of Clinical Endocrinologists(AACE).HOMA-IR, homeostatic model of assessment insulin resistance; US, ultrasonography.



regarded as established, with IGF-1 considered to be thelink between these conditions, as reviewed in detail else-where (78).

In a Chinese cross-sectional study of patients with solid‘cold’ (n = 18) vs. cystic ‘cold’ (n = 20) vs. ‘hot’ nodules(n = 18) vs. controls (n = 18), serum IGF-1 levels werehigher in patients with thyroid nodules compared withcontrols (BEL 3, GR C). However, there were differenceswithin patients: higher serum IGF-1 was reported inpatients with solid ‘cold’ nodules compared with ‘hot’nodules, whereas lower in patients with cystic ‘cold’nodules compared with the controls. The authors con-cluded that IGF-1 may play a role in the pathogenesis ofthyroid nodules, especially solid ‘cold’ ones (79).

In a Greek cross-sectional study of patients with thyroidcancer (n = 175) vs. healthy controls (n = 106), individualsbeing in the highest tertile of IGF-1 levels had higher riskfor PTC, but not FTC, Hurtle cell or medullary carcinoma,compared with those in the lowest tertile (OR = 2.25; 95%CI = 1.14−4.42; BEL 3, GR C). However, IGF-1 was notdifferent between groups after adjustment for age, gender,height, weight, T2DM, thyroid hormones and smokingstatus, suggesting that higher IGF-1 levels may mediate theeffects of these actors, mainly body weight. No significantdifferences on serum IGFBP-3 levels were found betweengroups for any thyroid cancer type (80).

In a population-based German cross-sectional study ofpatients with goitre or thyroid nodular disease (n = 423) vs.controls (n = 3,239), serum IGF-1 levels above the uppertertile were shown to be independently associated withincreased goitre risk compared with subjects with serumIGF-I levels below the lower tertile in both genders(OR = 1.67; 95% CI = 1.24−2.26 in women; OR = 2.04;95% CI = 1.55−2.68 in men) (BEL 3, GR C). A similarassociation was present for thyroid nodules in men(OR = 1.64; 95% CI = 1.17−2.32), but not in women. Onthe other hand, serum IGFBP-3 levels were not associatedwith thyroid disorders (81).

The well-established association of acromegaly withthyroid nodules and cancer and the possible role of IGF-1 asa link between these conditions are elsewhere reviewed indetails (78). Selectively, in a Polish retrospective study ofpatients with acromegaly (n = 86; newly diagnosed n = 41;previously diagnosed n = 46), thyroid nodular disease wasobserved in 65 (75.6%) patients, diffuse goitre in 10 (11.6%)and thyroid carcinoma in 5 (5.8%), the latter being PTC(n = 3) and follicular variants of PTC (n = 2) (BEL 3, GR C).This study confirmed the common coexistence of acromegalyand thyroid lesions and the relatively higher risk for thyroidcarcinoma in patients with acromegaly, thereby suggesting apotential role of IGF-1 in the pathogenesis of both benign andmalignant thyroid nodules (82). Similar was the percentage ofthyroid nodular disease (74%) in another recent retrospectivestudy (n = 115) (BEL 3, GR C) (83).

Adipocytokines

Adipocytokines and cytokines are peptides produced byadipocytes or by inflammatory cells infiltrating adiposetissue, respectively. They are secreted into the bloodstreamand contribute to the pathogenesis of IR and relatedmorbidities in the obesity state. Adipocytokines are gener-ally up-regulated with increasing fat mass, except foradiponectin, which is down-regulated (50). As adiposetissue is emerging as an endocrine organ, approximately 50molecules are now considered to be secreted by the adiposetissue. Several adipokines, including two among the mostabundant and most investigated adipocytokines, i.e. leptinand adiponectin, have also been studied as potential media-tors of the effects of obesity on cancer development, aboveand beyond their traditional roles in energy homeostasis(84). Although the role of leptin and adiponectin in thepathogenesis of thyroid cancer has not been fully elucidated,data are emerging and are mainly null for leptin but essen-tially rather strongly supportive for adiponectin.

Leptin

Background. Leptin plays a critical role in the homeosta-sis and energy balance and its secretion increases withincreasing fat mass. It acts centrally, as an anti-appetiteand neuroendocrine regulator (85), mainly through spe-cific membrane receptor, the obesity receptor (Ob-R),which belongs to the cytokine receptor family. Thyroidcancer in vitro studies, usually utilizing very high,supraphysiologic doses of leptin, have shown that (i)leptin stimulated cell proliferation and inhibited apoptosisvia activation of phosphatidylinositol 3’ kinase (PI3K)/Aktsignalling pathway (86); (ii) leptin enhanced the migratoryactivity of thyroid cell lines through the same pathway(PI3k/Akt) in a dose-dependent manner (87); (iii) Ob-Rexpression in PTC cells was down-regulated by bothdecitabine, a DNA methyltransferase inhibitor, andtrichostatin A, a histone deacetylase inhibitor, whereasup-regulated by insulin (88). Whether these data have rel-evance in human physiology where circulating leptin levelsare much lower than those usually used in vitro studiesand thus whether the above studies can be interpreted aspossibly enhancing cancer progression remains to be clari-fied, but seems unlikely on the basis of available evidencefrom studies in humans.

Clinical evidence. Only a limited number of studies with arather small number of subjects have focused on thyroidcancer. Thus, the relevant data need to be interpreted withcaution, especially given the publication bias favouring posi-tive data and the fact that most studies have not adjusted forfat mass, a strong predictor of circulating leptin; an associa-tion between thyroid cancer and leptin, a hormone closely



associated with fat mass, and thus obesity, could simplyreflect an underlying association with obesity and fat mass(not leptin) in the studies below.

The first clinical study evaluating the associationbetween leptin and DTC was a Taiwanese cross-sectionalstudy (BEL 3, GR C) in athyreotic patients operated due toDTC (n = 65) vs. controls (n = 38), in which similar serumleptin levels were reported between controls and patients,when in the euthyroid state (89).

In a Turkish cross-sectional study (BEL 3, GR C) inwomen with PTC (n = 43) vs. controls (n = 30), serumleptin levels were higher in the former. Furthermore, leptinlevels decreased in patients 20 days after total thyroidec-tomy although remained significantly higher than thecontrol group (90). Similarly, in an Iranian cross-sectionalstudy (BEL 3, GR C) of patients with PTC (n = 83) vs.controls (n = 90), serum leptin levels were higher in theformer (91). Lack of adjustment for potential confoundersand the relatively small number of subjects in these studiescasts doubt about the reliability and/or generalizability oftheir results, which need to be confirmed or refuted byfuture studies.

In a Saudi Arabian single-cohort study (BEL 3, GR C) ofpatients with PTC (n = 536), Ob-R overexpression wasseen in 80% of PTCs and in 37% of adjacent non-neoplastic thyroid tissue (n = 304). The presence of Ob-Rwas significantly associated with more aggressive pheno-type, characterized by older age, extrathyroid extension,larger tumour size, lymph node metastasis, advanced stage,tall cell variant histological subtype and a poor disease-freesurvival; however, Ob-R was not independently associatedwith the disease-free survival in multivariate analysis (86),indicating the potential presence of confounding.

In a Taiwanese single-cohort study (BEL 3, GR C) ofpatients with PTC (n = 49), leptin and Ob-R wereexpressed in 37 and 51% of primary lesions and lymphnode metastases (n = 15), respectively. Neither leptin norOb-R was expressed in normal follicles. Expression ofeither leptin or Ob-R was associated with greater neoplasmsize (92), but it remains to be shown whether one causes theother and/or both are due to a third underlying factor. In aChinese single-cohort study (BEL 3, GR C) of patients withPTC (n = 76), leptin and Ob-R were expressed in 72 and74% of primary lesions, respectively. The expression ofeither was associated with greater tumour size but notmultifocality or lymph node metastasis (93). In summary,no conclusive evidence exists on any potential role of leptinin thyroid carcinogenesis.

Adiponectin

Background. Adiponectin is a collagen-like polypeptidethat circulates at relatively high serum concentrations(5–30 μg mL−1), thereby being the most abundant

adipocytokine. It is predominantly expressed by theadipocytes and acts through two transmembrane recep-tors (AdipoR1, AdipoR2), which are similar but notidentical to G-protein coupled receptors, and possiblythrough TLR-4 and T-cadherin. Most of the effects ofadiponectin are mediated through the AMP-activatedprotein kinase pathway. Adiponectin acts as an insulin-sensitizing, anti-inflammatory and anti-tumour agent, thelatter by inhibiting cell proliferation and angiogenesis andincreasing apoptosis. It has been directly or indirectlyimplicated in the pathogenesis of IR-related morbidity,including obesity, T2DM and non-alcoholic fatty liverdisease; circulating adiponectin levels are generallydecreased by increasing the severity of IR or IR-relatedmorbidity (94).

Clinical evidence. In the first small observational studyevaluating adiponectin in Taiwanese athyreotic patientswith thyroid cancer (single cohort; n = 28), adiponectinand free thyroxine levels after a 4-week thyroid hormonewithdrawal were positively correlated after adjustment forpotential covariates, including age, gender and homeostaticmodel of assessment insulin resistance (HOMA-IR) (BEL 3,GR C) (95). In a Korean prospective cohort study of non-diabetic patients with end-stage renal disease under perito-neal dialysis (n = 106) followed up for a mean of 47months, malignancy was observed in 15 patients, with thethyroid cancer being the second more common (13.3%;n = 2) after kidney cancer (BEL 2, GR C). Interestingly,adiponectin levels were significantly lower in patients whodeveloped malignancy, being together with HOMA-IRindependent predictors of malignancy in a cox propor-tional hazard model (96).

In a Greek cross-sectional study of patients with thyroidcancer (n = 175) vs. healthy controls (n = 106), lowerserum adiponectin levels were observed in the former(BEL 3, GR C). Individuals being in the highest tertile ofadiponectin levels had lower risk for thyroid carcinoma(OR = 0.29; 95% CI = 0.14−0.55) after adjustment forpotential cofounders. However, although both AdipoR1and AdipoR2 were observed in thyroid carcinoma tissuesand cell lines, recombinant adiponectin did not exerta significant direct effect on cell cycle, proliferation orapoptosis in thyroid cancer cell lines in vitro. The authorshypothesized that, in the absence of a direct effect ofadiponectin on thyroid cancer cell lines in vitro, the nega-tive association between adiponectin and thyroid cancer invivo might be possibly attributed to indirect effects ofadiponectin, possibly through its anti-inflammatory andinsulin-sensitizing properties (80).

In a Taiwanese single-cohort study of patients withPTC (n = 49), adiponectin receptors AdipoR1 and AdipoR2were expressed in 27 and 47%, respectively, of primarylesions (n = 49). The absence of expression of both



adiponectin receptors was associated with extrathyroidalinvasion, multicentricity and higher tumor size, nodesinvolvement, metastasis (TNM) stage, but not lymphnodal metastasis (BEL 3, GR D). Notably, AdipoR1expression was correlated with serum leptin and Ob-R,whereas AdipoR2 with serum leptin, but not Ob-R (97).These correlations are indicative of interplay betweenadipocytokines, but may also reflect uncontrolled con-founding by obesity and thus cannot be interpreted atface value.

Thyroid-stimulating hormone

BackgroundBy binding to the TSH receptor, TSH is the most importanthormone regulating the growth and function of the thyroid.DTCs express TSH receptors on their cell membranes.Higher levels of TSH were associated with higher cell pro-liferation and possibly increased probability for mutationsand development of thyroid cancer (98), which are likely tobe mediated by TSH receptors (99,100). TSH suppressionin a rat model exposed to radioiodine prevented the for-mation of thyroid cancer (101). Similarly in human, thy-roxin treatment for TSH suppression after thyroidectomyfor DTCs is independently associated with reduced recur-rence and mortality (102).

Clinical evidenceThere is increasing number of clinical studies suggestingserum TSH levels as a predictor of thyroid malignancy.Apparently, the first article (BEL 3, GR C) in which theprevalence of thyroid malignancy increased with increasingTSH concentrations at presentation was published in 2006;this may happen even within the normal range of TSH, butthe association was stronger for TSH between 1.8 and5.5 mU L−1 and for TSH greater than 5.5 mU L−1 comparedwith TSH < 0.4 mU L−1 (P = 0.006 and P < 0.001, respec-tively) (103). Subsequently, many other authors havevalidated these results (104–107). Notably, some authorsreported improved survival after treatment with suppres-sive (of TSH levels) doses of levothyroxine (106). Recently,a meta-analysis of 28 relevant studies (BEL 2, GR B),including 42,032 individuals and 5,786 thyroid cancercases, established a non-linear relationship between TSHand thyroid cancer. Among the studies included, six hadassessed serum TSH in relation to markers of poor prog-nosis, with three showing significantly positive associations(108).

Apart from the above-mentioned results linking TSH andthyroid malignancy, there are clinical studies linking IR andMetS with higher TSH levels. For example, in the previ-ously mentioned cross-sectional study (72) of individualswith MetS (n = 278) vs. without MetS (n = 261), serum

TSH levels and thyroid volume were higher in the former,although within the normal range (BEL 3, GR C). Inanother cross-sectional study of premenopausal euthyroidobese (n = 98) vs. non-obese (n = 31) women, serum TSHlevels were significantly higher in the former, although stillwithin the normal range; thyroid volume was also signifi-cantly higher (BEL 3, GR C). Positive correlations wereobserved between thyroid volume and body weight, BMI,body fat percentage, body fat weight or waist circumfer-ence. Interestingly, 6 months after treatment for obesity,thyroid volume and TSH levels decreased only in obesewomen who lost >10% body weight; furthermore, positivecorrelations were observed between the changes ofthyroid volume and the change of body weight or bodyfat (109).

In a Greek cross-sectional study of 78 morbidly obeseeuthyroid patients vs. 77 normal-weighted euthyroid con-trols, serum TSH, T3 and T4 levels were significantlyhigher in the former, although within the normal range(BEL 3, GR C). Interestingly, in the same study, 19.5% of144 morbidly obese patients had subclinical or overthypothyroidism. Serum TSH levels were associated withfasting serum insulin levels and IR, but not with serumleptin levels, BMI, fat mass or lean body mass (110).

The association between hypothyroidism and obesityhas been reviewed elsewhere (111). Existing data cannotestablish the direction of causality. Taken data together, itseems that hypothyroidism may be a common determi-nant for both obesity and thyroid carcinoma (Fig. 1);the role of increasing TSH levels, as well as the directionof causality, in the observed associations remains to beelucidated.

Oestrogens

BackgroundThyroid cancer occurs three to four times more frequentlyin females than males; in females the incidence is higherduring the reproductive years and decreases after meno-pause (112,113). Adipose tissue plays a role in the synthesisor conversion of endogenous sex steroids. This role ismore prominent after menopause, when the function ofovaries ceases. Obese postmenopausal women have highercirculating oestradiol than normal-weight women (114).Expression of oestrogen receptors (ERs) is established inhuman DTC cell lines and may have modulatory effect onthyroid cancer cells (115); in vitro oestradiol increasedcell proliferation in PTC cell lines, whereas tamoxifen, ananti-oestrogen factor, prevented proliferation (116,117).However, it seems that there is an ER-subtype specificresponse: overexpression of ER-α induces proliferative andanti-apoptotic responses, whereas overexpression of ER-βdecreases proliferation and promotes apoptosis of thyroidcells (113); thus, ERα positivity and ERβ negativity are



reported to be associated with a more aggressive phenotypeof small DTC (118).

Clinical evidenceClinical data for the association between oestrogens andthyroid cancer risk could be indirectly derived from studiesinvestigating various reproductive factors implying longerexposure to endogenous oestrogens (i.e. age at menarche ormenopause, age at last birth, parity, use of contraceptivepills and number of abortions). However, existing clinicaldata, as they have been recently summarized in a systematicreview (36), vary and are rather inconclusive. We herebypresent three large cohort studies and two pooled analysesof case-control studies.

In a Canadian prospective cohort study (89,835 women;mean follow-up 15.9 years; 169 thyroid cancer cases; BEL2, GR B), no menstrual or reproductive factor (age atmenarche, parity, age at first birth, menopause, use ofcontraceptives or hormonal replacement therapy) wasassociated with thyroid cancer risk (119). In anotherNorwegian prospective cohort study (63,090 women, meanfollow-up 29 years; 124 thyroid cancer cases, BEL 2, GR B),later menarche (≥15 vs. ≤13) was related to marginallydecreased risk PTC (OR = 0.50; 95% CI = 0.25−1.00);however, age at menopause, parity, age at last birth andnumber of abortions were not significantly associated withthyroid cancer risk (120).

In a more recent U.S. prospective cohort study (117,646women; median follow-up 7 years; 233 invasive PTC; BEL2, GR B), in younger (<45 years at baseline), but not olderwomen, later age at menarche (≥14 years; RR = 1.88, 95%CI = 1.13−3.13) and longer menstrual cycles (>30 d;RR = 1.78; 95% CI = 1.01−3.14) were associated withincreased risk for invasive PTC. However, the variablesever use of contraceptives or hormonal replacementtherapy, parity, number of miscarriages or abortions, andage at first or last therapy were not associated with invasivePTC risk (121).

In a pooled analysis of 14 case-control studies (2,247women with thyroid cancer and 3,699 controls; BEL 2, GRB), no menstrual or reproductive factor (age at menarche ormenopause, menopausal status, parity, number of births ormiscarriages or abortions, age at first or last birth) wassignificantly associated with thyroid cancer risk (122). Inanother pooled analysis of 13 case-control studies (2,132women with thyroid cancer and 3,301 controls; BEL 2, GRB) performed by the same investigators, a marginally sig-nificant increase in PTC risk was reported in currentusers of oral contraceptives (OR = 1.6; 95% CI = 1.1−2.4),but the risk declined with increasing time since stopping.Lactation suppression treatment also increased the overallrisk for thyroid cancer (OD = 1.5: 95% CI = 1.1−2.1).Hormone replacement therapy or fertility drugs did notincrease the risk (123).

Closing remarks

The increasing incidence of thyroid cancer during the lastdecades (1,2,4) has been attributed to increased diagnosticability and increase in lifespan, but also to other factors suchas the increased exposure to radiation, imaging with iodinecontaining media and even endocrine disruptors. There isalso increasing evidence that the rising prevalence of obesity,which has been previously associated with other cancertypes, including colon, endometrial and breast cancer (19–21), may be partly accounted for the increasing incidenceof thyroid cancer. Importantly, the increasing incidenceof thyroid cancer is related mainly to increasing incidence ofDTC, and more specifically PTC, whereas the incidence ofmedullary or anaplastic thyroid carcinoma has remainedessentially unchanged.

Summary of existing evidence

Many observational studies provide evidence for a poten-tial association between thyroid cancer and obesity, whoseprevalence is rapidly increasing globally during the lastdecades. To date, the best level of evidence for an associa-tion between obesity and thyroid cancer risk is provided bya pooled analysis of prospective cohort studies (33). Thenotion that obesity may possibly represent a risk factorfor thyroid cancer, similar to other cancer types (i.e. breastand colon), should be interpreted with caution becausethe design of the above-mentioned observational studiescannot support a causative relationship, and because thereare discrepancies between studies, possibly related to meth-odological and population differences.

In contrast, the limited clinical data on the associationbetween T2DM and thyroid cancer do not generallysupport such an association, while there are currentlyessentially no data regarding the association betweenthyroid cancer and other IR-related morbidities, includingpolycystic ovary syndrome or non-alcoholic fatty liverdisease.

Several mechanisms have been proposed to explain theassociation between obesity and thyroid cancer, with IRpossibly playing a central role. IR is associated with otherrisk factors including IGF-1, adipocytokines/cytokines andTSH in a dynamic relationship with a potential for devel-opment and/or progression of thyroid cancer (Fig. 1). Anintriguing speculation would also be the following: obesityleads to hypoadiponectinemia, which is upstream of thechanges in adipose tissue or systematic inflammation andIR, and which, in turn, leads to high insulin and IGF-1,thereby increasing thyroid cancer risk (80,124).

Data on an association between obesity and medullary oranaplastic thyroid carcinomas are lacking; the pathogenesisof medullary carcinoma is rather distinct from that of DTCand possibly not related to obesity and IR. However, an



association, if any, between medullary or anaplastic thyroidcarcinoma and obesity would be rather difficult to be estab-lished due to their rarity, which would necessitate verylarge-scale epidemiologic studies.

Clinical implications

Understanding the pathogenetic mechanisms linkingobesity and IR with thyroid cancer could have therapeuticimplications; by targeting obesity, or mechanisms underly-ing its association with thyroid cancer, thyroid cancermight be more effectively prevented and managed. If IR isproven as an underlying mechanism, traditional insulinsensitizers such as metformin may represent potentialmedications for reducing the risk for thyroid cancer.Whereas metformin would be a non-expensive choice,thiazolinediones have the advantage of up-regulatingadiponectin; however, the latter should be critically consid-ered because of their weight-increasing properties alongwith other undesirable effects. In order to avoid the typicalthiazolinediones’ side effects, the development of selectiveperoxisome proliferator-activated receptor-γ modulators(such as INT131) (125), which have been developed for thetreatment of T2DM, might probably be of certain valuebecause they have been reported to ameliorate IR, withoutthe typical thiazolinedione side effects, in preclinical studiesand clinical trials. Finally, new therapeutic approaches maybe developed, i.e. recombinant adiponectin or adiponectinanalogues, which would combine insulin-sensitizing, anti-inflammatory and anti-tumoral properties (126).

Areas for future research

The design of randomized controlled trials to study theassociation between obesity and thyroid cancer couldpossibly never overcome ethical considerations, given thatnobody could randomly allocate normal-weight individualsto a long-term high-caloric diet to assess the risk for thyroidcancer in relation to control diets. Alternatively, the reversecould be investigated in the future: obese individuals wholose weight (by lifestyle changes or pharmacological inter-ventions or bariatric surgery) without regaining it on along-term basis might be compared with those who failedto lose weight in terms of the thyroid cancer incidence.Large clinical trials, such as the Look Ahead study, provideopportunities to potentially run such studies.

Moreover, randomized controlled trials are needed toinvestigate whether targeting obesity itself (by lifestylechanges, pharmacologically or by bariatric surgery) orits potential mediators (i.e. inflammation, IR, IGF-1,hypoadiponectinemia, TSH) would have any effect on theprevention of thyroid cancer. Such studies would requirethe recruitment of a large sample size (possibly in amulticentre basis) and a long-term follow-up.

In conclusion, most epidemiological studies havereported an association between obesity and thyroidcancer, which may be mediated by IR and its interplaywith IGF-1, adipocytokines/cytokines, local and systematicinflammation, and TSH. Although this association wouldhave important implications in terms of prevention andtreatment of thyroid cancer, many future studies would beneeded to fully prove this notion and implement preventiveor therapeutic strategies that would capitalize on suchnewly acquired knowledge to provide tangible benefits toour patients.

Conflict of interest statement

No conflicts of interest.

References

1. Agate L, Lorusso L, Elisei R. New and old knowledge ondifferentiated thyroid cancer epidemiology and risk factors. JEndocrinol Invest 2012; 35(6 Suppl.): 3–9.2. Davies L, Welch HG. Increasing incidence of thyroid cancer inthe United States, 1973–2002. JAMA 2006; 295: 2164–2167.3. Davies L, Ouellette M, Hunter M, Welch HG. The increasingincidence of small thyroid cancers: where are the cases comingfrom? Laryngoscope 2010; 120: 2446–2451.4. Alevizaki M, Papageorgiou G, Rentziou G et al. Increasingprevalence of papillary thyroid carcinoma in recent years inGreece: the majority are incidental. Thyroid 2009; 19: 749–754.5. Polyzos SA, Kita M, Avramidis A. Thyroid nodules – stepwisediagnosis and management. Hormones (Athens) 2007; 6: 101–119.6. Gomez Segovia I, Gallowitsch HJ, Kresnik E et al. Descriptiveepidemiology of thyroid carcinoma in Carinthia, Austria: 1984–2001. Histopathologic features and tumor classification of 734cases under elevated general iodination of table salt since 1990:population-based age-stratified analysis on thyroid carcinoma inci-dence. Thyroid 2004; 14: 277–286.7. Enewold L, Zhu K, Ron E et al. Rising thyroid cancer incidencein the United States by demographic and tumor characteristics,1980–2005. Cancer Epidemiol Biomarkers Prev 2009; 18: 784–791.8. Pazaitou-Panayiotou K, Iliadou PK, Chrisoulidou A et al. Theincrease in thyroid cancer incidence is not only due to papillarymicrocarcinomas: a 40-year study in 1.778 patients. Exp ClinEndocrinol Diabetes 2013; 121: 397–401.9. Mangano JJ. Geographic variation in U.S. thyroid cancer inci-dence and a cluster near nuclear reactors in New Jersey, New York,and Pennsylvania. Int J Health Serv 2009; 39: 643–661.10. How J, Tabah R. Explaining the increasing incidence of dif-ferentiated thyroid cancer. CMAJ 2007; 177: 1383–1384.11. Soto AM, Sonnenschein C. Environmental causes of cancer:endocrine disruptors as carcinogens. Nat Rev Endocrinol 2010; 6:363–370.12. Kim HJ, Kim NK, Choi JH et al. Associations between bodymass index and clinico-pathological characteristics of papillarythyroid cancer. Clin Endocrinol (Oxf) 2013; 78: 134–140.13. Leitzmann MF, Brenner A, Moore SC et al. Prospective studyof body mass index, physical activity and thyroid cancer. Int JCancer 2010; 126: 2947–2956.



14. Cléro E, Leux C, Brindel P et al. Pooled analysis of twocase-control studies in New Caledonia and French Polynesia ofbody mass index and differentiated thyroid cancer: the importanceof body surface area. Thyroid 2010; 20: 1285–1293.15. Aschebrook-Kilfoy B, Sabra MN, Brenner A et al. Diabetesand thyroid cancer risk in the National Institutes of Health-AARPDiet and Health Study. Thyroid 2011; 21: 957–963.16. Mijovic T, How J, Payne RJ. Obesity and thyroid cancer.Front Biosci(Schol Ed) 2011; 3: 555–564.17. Zhao ZG, Guo XG, Ba CX et al. Overweight, obesity andthyroid cancer risk: a meta-analysis of cohort studies. J Int MedRes 2012; 40: 2041–2050.18. Shih SR, Chiu WY, Chang TC, Tseng CH. Diabetes andthyroid cancer risk: literature review. Exp Diabetes Res 2012;2012: 578285.19. Wolk A, Gridley G, Svensson M et al. A prospective study ofobesity and cancer risk (Sweden). Cancer Causes Control 2001;12: 13–21.20. Pothiwala P, Jain SK, Yaturu S. Metabolic syndrome andcancer. Metab Syndr Relat Disord 2009; 7: 279–287.21. Renehan AG, Tyson M, Egger M, Heller RF, Zwahlen M.Body mass index and incidence of cancer: a systematic review andmeta analysis of prospective observational studies. Lancet 2008;371: 569–578.22. Rezzonico JN, Rezzonico M, Pusiol E, Pitoia F,Niepomniszcze H. Increased prevalence of insulin resistance inpatients with differentiated thyroid carcinoma. Metab Syndr RelatDisord 2009; 7: 375–380.23. Mechanick JI, Camacho PM, Cobin RH et al.; AmericanAssociation of Clinical Endocrinologists. American Association ofClinical Endocrinologists protocol for standardized production ofclinical practice guidelines – 2010 update. Endocr Pract 2010; 16:270–283.24. Ron E, Kleinerman RA, Boice JD Jr, LiVolsi VA, Flannery JT,Fraumeni JF Jr. A population-based case-control study of thyroidcancer. J Natl Cancer Inst 1987; 79: 1–12.25. Dal Maso L, La Vecchia C, Franceschi S et al. A pooledanalysis of thyroid cancer studies. V. Anthropometric factors.Cancer Causes Control 2000; 11: 137–144.26. Iribarren C, Haselkorn T, Tekawa IS, Friedman GD. Cohortstudy of thyroid cancer in a San Francisco Bay area population. IntJ Cancer 2001; 93: 745–750.27. Mack W, Preston-Martin S, Bernstein L, Qian D. Lifestyle andother risk factors for thyroid cancer in Los Angeles Countyfemales. Ann Epidemiol 2002; 12: 395–401.28. Samanic C, Gridley G, Chow WH, Lubin J, Hoover RN,Fraumeni JF Jr. Obesity and cancer risk among white andblack United States veterans. Cancer Causes Control 2004; 15:35–43.29. Boru C, Silecchia G, Pecchia A et al. Prevalence of cancer inItalian obese patients referred for bariatric surgery. Obes Surg2005; 15: 1171–1176.30. Oh SW, Yoon YS, Shin SA. Effects of excess weight on cancerincidences depending on cancer sites and histologic findings amongmen: Korea National Health Insurance Corporation Study. J ClinOncol 2005; 23: 4742–4754.31. Engeland A, Tretli S, Akslen LA, Bjørge T. Body size andthyroid cancer in two million Norwegian men and women. Br JCancer 2006; 95: 366–370.32. Brindel P, Doyon F, Rachedi F et al. Anthropometric factors indifferentiated thyroid cancer in French Polynesia: a case-controlstudy. Cancer Causes Control 2009; 20: 581–590.33. Kitahara CM, Platz EA, Freeman LE et al. Obesity andthyroid cancer risk among U.S. men and women: a pooled analysis

of five prospective studies. Cancer Epidemiol Biomarkers Prev2011; 20: 464–472.34. Rinaldi S, Lise M, Clavel-Chapelon F et al. Body size and riskof differentiated thyroid carcinomas: findings from the EPIC study.Int J Cancer 2012; 131: E1004–E1014.35. Almquist M, Johansen D, Björge T et al. Metabolic factorsand risk of thyroid cancer in the Metabolic syndrome and Cancerproject (Me-Can). Cancer Causes Control 2011; 22: 743–751.36. Peterson E, De P, Nutall R. BMI, diet and female reproductivefactors as risks for thyroid cancer: a systematic review. PLoS ONE2012; 7: e29177.37. Bosetti C, Kolonel L, Negri E et al. A pooled analysis ofcase-control studies of thyroid cancer. VI. Fish and shellfish con-sumption. Cancer Causes Control 2001; 12: 375–382.38. Bosetti C, Negri E, Colonel L et al. A pooled analysis ofcase-control studies of thyroid cancer. VII. Cruciferous and othervegetables (International). Cancer Causes Control 2002; 13: 765–775.39. Lee S, Park S, Lee CR et al. The impact of body habitus on thesurgical outcomes of transaxillary single-incision robotic thyroid-ectomy in papillary thyroid carcinoma patients. Surg Endosc 2013;27: 2407–2414.40. Kitahara CM, Platz EA, Beane Freeman LE et al. Physicalactivity, diabetes, and thyroid cancer risk: a pooled analysis offive prospective studies. Cancer Causes Control 2012; 23: 463–471.41. Borena W, Stocks T, Jonsson H et al. Serum triglyceridesand cancer risk in the Metabolic syndrome and Cancer (Me-Can)collaborative study. Cancer Causes Control 2011; 22: 291–299.42. Stocks T, Rapp K, Biorge T et al. Blood glucose and risk ofincident and fatal cancer in the Metabolic syndrome and Cancerproject (Me-Can): analysis of six prospective cohorts. PLoS Med2009; 6: e1000201.43. Jee SH, Ohrr H, Sull JW, Yun JE, Ji M, Samet JM. Fastingserum glucose level and cancer risk in Korean men and women.JAMA 2005; 93: 194–202.44. Tulinius H, Sigfússon N, Sigvaldason H, Bjarnadóttir K,Tryggvadóttir L. Risk factors for malignant diseases: a cohortstudy on a population of 22,946 Icelanders. Cancer EpidemiolBiomarkers Prev 1997; 6: 863–873.45. Rapp K, Schroeder J, Klenk J et al. Fasting blood glucose andcancer risk in a cohort of more than 140,000 adults in Austria.Diabetologia 2006; 49: 945–952.46. Deleu S, Pirson I, Coulonval K et al. IGF-1 or insulin, and theTSH cyclic AMP cascade separately control dog and humanthyroid cell growth and DNA synthesis, and complement eachother in inducing mitogenesis. Mol Cell Endocrinol 1999; 149:41–51.47. Van Keymeulen A, Dumont JE, Roger PP. TSH induces insulinreceptors that mediate insulin costimulation of growth in normalhuman thyroid cells. Biochem Biophys Res Commun 2000; 279:202–207.48. Dumont JE, Lamy F, Roger P, Maenhaut C. Physiological andpathological regulation of thyroid cell proliferation and differen-tiation by thyrotropin and other factors. Physiol Rev 1992; 72:667–697.49. Milazzo G, La Rosa GL, Catalfamo R, Vigneri R, Belfiore A.Effect of TSH in human thyroid cells: evidence for both mito-genic and antimitogenic effects. J Cell Biochem 1992; 49: 231–238.50. Polyzos SA, Kountouras J, Zavos C. Nonalcoholic fattyliver disease: the pathogenetic roles of insulin resistance andadipocytokines. Curr Mol Med 2009; 9: 299–314.



51. Bozec A, Lassalle S, Hofman V, Ilie M, Santini J, Hofman P.The thyroid gland: a crossroad in inflammation-induced carci-noma? An ongoing debate with new therapeutic potential. CurrMed Chem 2010; 17: 3449–3461.52. Guarino V, Castellone MD, Avilla E, Melillo RM. Thyroidcancer and inflammation. Mol Cell Endocrinol 2010; 321:94–102.53. Coussens LM, Werb Z. Inflammation and cancer. Nature2002; 420: 860–867.54. Mantovani A, Allavena P, Sica A, Balkwill F. Cancer-relatedinflammation. Nature 2008; 454: 436–444.55. Ryder M, Ghossein RA, Ricarte-Filho JC, Knauf JA, Fagin JA.Increased density of tumor associated macrophages is associatedwith decreased survival in advanced thyroid cancer. Endocr RelatCancer 2008; 15: 1069–1074.56. Okayasu I. The relationship of lymphocytic thyroiditis to thedevelopment of thyroid carcinoma. Endocr Pathol 1997; 8: 225–230.57. Antonaci A, Consorti F, Mardente S, Giovannone G. Clinicaland biological relationship between chronic lymphocytic thyroidi-tis and papillary thyroid carcinoma. Oncol Res 2009; 17: 495–503.58. Spencer CA. Clinical review: clinical utility of thyroglobulinantibody (TgAb) measurements for patients with differentiatedthyroid cancers (DTC). J Clin Endocrinol Metab 2011; 96: 3615–3627.59. Ahmed R, Al-Shaikh S, Akhtar M. Hashimoto thyroiditis: acentury later. Adv Anat Pathol 2012; 19: 181–186.60. Graff-Baker A, Sosa JA, Roman SA. Primary thyroidlymphoma: a review of recent developments in diagnosis andhistology-driven treatment. Curr Opin Oncol 2010; 22: 17–22.61. Muzza M, Degl’Innocenti D, Colombo C et al. The tightrelationship between papillary thyroid cancer, autoimmunity andinflammation: clinical and molecular studies. Clin Endocrinol(Oxf) 2010; 72: 702–708.62. Proietti A, Ugolini C, Melillo RM et al. Higher intratumoralexpression of CD1a, tryptase, and CD68 in a follicular variant ofpapillary thyroid carcinoma compared to adenomas: correlationwith clinical and pathological parameters. Thyroid 2011; 21:1209–1215.63. Hagström J, Heikkilä A, Siironen P et al. TLR-4 expressionand decrease in chronic inflammation: indicators of aggressivefollicular thyroid carcinoma. J Clin Pathol 2012; 65: 333–338.64. Rezzonico J, Rezzonico M, Pusiol E, Pitoia F, NiepomniszczeH. Introducing the thyroid gland as another victim of the insulinresistance syndrome. Thyroid 2008; 18: 461–464.65. Yasar HY, Ertugrul O, Ertugrul B, Ertugrul D, Sahin M.Insulin resistance in nodular thyroid disease. Endocr Res 2011; 36:167–174.66. Anil C, Akkurt A, Ayturk S, Kut A, Gursoy A. Impairedglucose metabolism is a risk factor for increased thyroid volumeand nodule prevalence in a mild-to-moderate iodine deficientarea. Metabolism 2013; 62: 970–975.67. Inoue M, Tsugane S. Insulin resistance and cancer: epidemio-logical evidence. Endocr Relat Cancer 2012; 19: F1–F8.68. Braun S, Bitton-Worms K, LeRoith D. The link between themetabolic syndrome and cancer. Int J Biol Sci 2011; 7: 1003–1015.69. Cheatham B, Kahn CR. Insulin action and the insulin signal-ing network. Endocr Rev 1995; 16: 117–142.70. Vella V, Sciacca L, Pandini G et al. The IGF system inthyroid cancer: new concepts. Clin Pathol Mol Pathol 2001; 54:121–125.

71. Belfiore A, Pandini G, Vella V et al. Insulin/IGF-I hybrid recep-tors play a major role in IGF-I signaling in thyroid cancer.Biochemie 1999; 81: 403–417.72. Ayturk S, Gursoy A, Kut A, Anil C, Nar A, Tutuncu NB.Metabolic syndrome and its components are associated withincreased thyroid volume and nodule prevalence in a mild-to-moderate iodine-deficient area. Eur J Endocrinol 2009; 161: 599–605.73. Rendina D, De Filippo G, Mossetti G et al. Relationshipbetween metabolic syndrome and multinodular non-toxic goiter inan inpatient population from a geographic area with moderateiodine deficiency. J Endocrinol Invest 2012; 35: 407–412.74. Rezzónico J, Rezzónico M, Pusiol E, Pitoia F, NiepomniszczeH. Metformin treatment for small benign thyroid nodules inpatients with insulin resistance. Metab Syndr Relat Disord 2011;9: 69–75.75. Vassilopoulou-Sellin R, Cangir A, Samaan NA. Acanthosisnigricans and severe insulin resistance in an adolescent girl withthyroid cancer: clinical response to antineoplastic therapy. Am JClin Oncol 1992; 15: 273–276.76. Frittitta L, Sciacca L, Catalfamo R et al. Functional insulinreceptors are overexpressed in thyroid tumors: is this an earlyevent in thyroid tumorigenesis? Cancer 1999; 85: 492–498.77. Myal Y, Shiu RP, Bhaumick B, Bala M. Receptor binding andgrowth-promoting activity of insulin-like growth factors in humanbreast cancer cells (T-47D) in culture. Cancer Res 1984; 44: 5486–5490.78. Siegel G, Tomer Y. Is there an association between acromegalyand thyroid carcinoma? A critical review of the literature. EndocrRes 2005; 3: 51–58.79. Liu YJ, Qiang W, Liu XJ et al. Association of insulin-likegrowth factor-1 with thyroid nodules. Oncol Lett 2011; 2: 1297–1301.80. Mitsiades N, Pazaitou-Panayiotou K, Aronis KN et al. Circu-lating adiponectin is inversely associated with risk of thyroidcancer: in vivo and in vitro studies. J Clin Endocrinol Metab 2011;96: 2023–2028.81. Völzke H, Friedrich N, Schipf S et al. Association betweenserum insulin-like growth factor-I levels and thyroid disorders in apopulation-based study. J Clin Endocrinol Metab 2007; 92: 4039–4045.82. Ruchala M, Skiba A, Gurgul E, Uruski P, Wasko R, SowinskiJ. The occurrence of thyroid focal lesions and a need for fine needleaspiration biopsy in patients with acromegaly due to an increasedrisk of thyroid cancer. J Neuro Endocrinol Lett 2009; 30: 382–386.83. Anagnostis P, Efstathiadou ZA, Polyzos SA et al. Acromegaly:presentation, morbidity and treatment outcomes at a single centre.Int J Clin Pract 2011; 65: 896–902.84. Paz-Filho G, Lim EL, Wong ML, Licinio J. Associationsbetween adipokines and obesity-related cancer. Front Biosci 2011;16: 1634–1650.85. Mantzoros CS, Moschos SJ. Leptin: in search of role(s) inhuman physiology and pathophysiology. Clin Endocrinol (Oxf)1998; 49: 551–567.86. Uddin S, Bavi P, Siraj AK et al. Leptin-R and its associationwith PI3K/AKT signaling pathway in papillary thyroid carcinoma.Endocr Relat Cancer 2010; 17: 191–202.87. Cheng SP, Yin PH, Hsu YC et al. Leptin enhances migrationof human papillary thyroid cancer cells through the PI3K/AKT andMEK/ERK signaling pathways. Oncol Rep 2011; 26: 1265–1271.88. Cheng SP, Liu CL, Hsu YC, Chang YC, Huang SY, Lee JJ.Regulation of leptin receptor expression in human papillarythyroid cancer cells. Biomed Pharmacother 2012; 66: 469–473.



89. Hsieh CJ, Wang PW, Wang ST et al. Serum leptin concentra-tions of patients with sequential thyroid function changes. ClinEndocrinol (Oxf) 2002; 57: 29–34.90. Akinci M, Kosova F, Cetin B, Aslan S, Ari Z, Cetin A. Leptinlevels in thyroid cancer. Asian J Surg 2009; 32: 216–223.91. Hedayati M, Yaghmaei P, Pooyamanesh Z, Zarif Yeganeh M,Hoghooghi Rad L. Leptin: a correlated peptide to papillary thyroidcarcinoma? J Thyroid Res 2011; 2011: 832163.92. Cheng SP, Chi CW, Tzen CY et al. Clinicopathologic signifi-cance of leptin and leptin receptor expressions in papillary thyroidcarcinoma. Surgery 2010; 147: 847–853.93. Zhang GA, Hou S, Han S, Zhou J, Wang X, Cui W.Clinicopathological implications of leptin and leptin receptorexpression in papillary thyroid cancer. Oncol Lett 2013; 5: 797–800.94. Polyzos SA. Editorial: adiponectin in health and disease:current evidence and therapeutic perspectives. Curr Med Chem2012; 19: 5425–5426.95. Lin SY, Huang SC, Sheu WH. Circulating adiponectin con-centrations were related to free thyroxine levels in thyroid cancerpatients after thyroid hormone withdrawal. Metabolism 2010; 59:195–199.96. Park JT, Yoo TH, Chang TI et al. Insulin resistance and lowerplasma adiponectin increase malignancy risk in nondiabetic con-tinuous ambulatory peritoneal dialysis patients. Metabolism 2011;60: 121–126.97. Cheng SP, Liu CL, Hsu YC, Chang YC, Huang SY, Lee JJ.Expression and biologic significance of adiponectin receptors inpapillary thyroid carcinoma. Cell Biochem Biophys 2013; 65:203–210.98. Roger PP, Dumont JE. Thyrotropin is a potent growth factorfor normal human thyroid cells in primary culture. BiochemBiophys Res Commun 1987; 149: 707–711.99. Carayon P, Thomas-Morvan C, Castanas E, Tubiana M.Human thyroid cancer: membrane thyrotropin binding andadenylate cyclase activity. J Clin Endocrinol Metab 1980; 51:915–920.100. Chang TC, Kuo SH, Liaw KY, Chang CC, Chen FW. Cellkinetics, DNA content and TSH receptor–adenylate cyclase systemin differentiated thyroid cancer. Clin Endocrinol (Oxf) 1988; 29:477–484.101. Goldberg RC, Lindsay S, Nichols CW, ChaikoV IL. Induc-tion of neoplasms in thyroid glands of rats by subtotal thyroidec-tomy and by the injection of one microcurie of I-131. Cancer Res1964; 24: 35–43.102. Pujol P, Daures JP, Nsakala N, Baldet L, Bringer J, JaViol C.Degree of thyrotropin suppression as a prognostic determinant indifferentiated thyroid cancer. J Clin Endocrinol Metab 1996; 81:4318–4323.103. Boelaert K, Horacek J, Holder RL, Watkinson JC, SheppardMC, Franklyn JA. Serum thyrotropin concentration as a novelpredictor of malignancy in thyroid nodules investigated byfine-needle aspiration. J Clin Endocrinol Metab 2006; 91: 4295–4301.104. Polyzos SA, Kita M, Efstathiadou Z et al. Serum thyrotropinconcentration as a biochemical predictor of thyroid malignancy inpatients presenting with thyroid nodules. J Cancer Res Clin Oncol2008; 134: 953–960.105. Haymart MR, Repplinger DJ, Leverson GE et al. Higherserum thyroid stimulating hormone level in thyroid nodulepatients is associated with greater risks of differentiated thyroidcancer and advanced tumor stage. Clin Endocrinol Metab 2008;93: 809–814.

106. Jonklaas J, Nsouli-Maktabi H, Soldin SJ. Endogenousthyrotropin and triiodothyronine concentrations in individualswith thyroid cancer. Thyroid 2008; 18: 943–952.107. Fiore E, Rago T, Provenzale MA et al. Lower levels of TSHare associated with a lower risk of papillary thyroid cancer inpatients with thyroid nodular disease: thyroid autonomy mayplay a protective role. Endocr Relat Cancer 2009; 16: 1251–1260.108. McLeod DS, Watters KF, Carpenter AD, Ladenson PW,Cooper DS, Ding EL. Thyrotropin and thyroid cancer diagnosis: asystematic review and dose-response meta-analysis. J ClinEndocrinol Metab 2012; 97: 2682–2692.109. Sari R, Balci MK, Altunbas H, Karayalcin U. The effect ofbody weight and weight loss on thyroid volume and function inobese women. Clin Endocrinol (Oxf) 2003; 59: 258–262.110. Michalaki MA, Vagenakis AG, Leonardou AS et al. Thyroidfunction in humans with morbid obesity. Thyroid 2006; 16:73–78.111. Pearce EN. Thyroid hormone and obesity. Curr OpinEndocrinol Diabetes Obes 2012; 19: 408–413.112. Horner MJ, Ries LAG, Krapcho M, Neyman N, Aminou R,Howlader N. SEER Cancer Statistics Review, 1975–2006. 2012.[WWW document]. URL http://seer.cancer.gov/csr/1975_2006/(accessed 2012).113. Chen G, Vlantis AC, Zeng Q, van Hasselt CA. Regulation ofcell growth by estrogen signaling and potential targets in thyroidcancer. Curr Cancer Drug Targets 2008; 8: 367–377.114. Freeman EW, Sammel MD, Lin H, Gracia CR. Obesity andreproductive hormone levels in the transition to menopause.Menopause 2010; 17: 718–726.115. Kansakar E, Chang YJ, Mehrabi M, Mittal V. Expression ofestrogen receptor, progesterone receptor, and vascular endothelialgrowth factor-A in thyroid cancer. Am Surg 2009; 75: 785–789;discussion 789.116. Lee ML, Chen GG, Vlantis AC, Tse GMK, Leung BCH, vanHasselt CA. Induction of thyroid papillary carcinoma cell prolif-eration by estrogen is associated with an altered expression ofBcl-xL. Cancer J 2005; 11: 113–121.117. Kumar A, Klinge CM, Goldstein RE. Estradiol-induced pro-liferation of papillary and follicular thyroid cancer cells is medi-ated by estrogen receptors alpha and beta. Int J Oncol 2010; 36:1067–1080.118. Magri F, Capelli V, Rotondi M et al. Expression of estrogenand androgen receptors in differentiated thyroid cancer: an addi-tional criterion to assess the patient’s risk. Endocr Relat Cancer2012; 19: 463–471.119. Navarro Silvera SA, Miller AB, Rohan TE. Risk factors forthyroid cancer: a prospective cohort study. Int J Cancer 2005; 1:433–438.120. Akslen LA, Nilssen S, Kvåle G. Reproductive factors and riskof thyroid cancer. A prospective study of 63,090 women fromNorway. Br J Cancer 1992; 65: 772–774.121. Horn-Ross PL, Canchola AJ, Ma H, Reynolds P, Bernstein L.Hormonal factors and the risk of papillary thyroid cancer in theCalifornia teachers study cohort. Cancer Epidemiol BiomarkersPrev 2011; 20: 1751–1759.122. Negri E, Dal Maso L, Ron E et al. A pooled analysis ofcase-control studies of thyroid cancer. II. Menstrual and reproduc-tive factors. Cancer Causes Control 1999; 10: 143–155.123. La Vecchia C, Ron E, Franceschi S et al. A pooled analysis ofcase-control studies of thyroid cancer III. Oral contraceptives,menopausal replacement therapy and other female hormones.Cancer Causes Control 1999; 10: 157–166.



124. Dalamaga M, Diakopoulos KN, Mantzoros CS. The role ofadiponectin in cancer: a review of current evidence. Endocr Rev2012; 33: 547–594.125. Lee DH, Huang H, Choi K, Mantzoros C, Kim YB. SelectivePPARγ modulator INT131 normalizes insulin signaling defects and

improves bone mass in diet-induced obese mice. Am J PhysiolEndocrinol Metab 2012; 302: E552–E560.126. Polyzos SA, Toulis KA, Goulis DG, Zavos C, Kountouras J.Serum total adiponectin in nonalcoholic fatty liver disease: a sys-tematic review and meta-analysis. Metabolism 2011; 60: 313–326.



obesity and thyroid cancer: epidemiologic associations and underlying mechanisms

Documents