175H. Takami et al. (eds.), Treatment of Thyroid Tumor: Japanese Clinical Guidelines,DOI 10.1007/978-4-431-54049-6_41, © Springer Japan 2013

Recommendation Rating

B Prognostic factors for disease-free survival and cause-speci fi c survival are (1) patient factors (a) advanced age and (b) male gender, (2) tumor factors (c) lymph node metastasis, (d) extrathyroid extension, and (e) distant metastasis, and (3) treatment factors (f) more limited thyroidectomy than total (or near total) thyroidectomy, and (g) non-curative sur-gery. As factors preventing postoperative normalization of calcitonin, a high level of pre-operative basal calcitonin and lymph node metastasis are identi fi ed. The doubling times of serum calcitonin and CEA signi fi cantly affect the prognosis of advanced or relapsed disease.

Background

Since serum CEA and calcitonin levels are sensitive tumor markers of medullary thyroid carcinoma, they can be used not only on the evaluation of carcinoma relapse that is manifest and tangible on physical fi ndings and imaging studies, but also on biochemical relapses in which these laboratory data are the measure of treatment out-comes [ 1 , 2 ] . The literature was surveyed regarding prognostic factors for these outcomes.

S. Uchino (*) Department of Surgery , Noguchi Thyroid Clinic and Hospital Foundation , 6-33 Noguchinakamachi , Beppu, Oita 874-0932 , Japan e-mail: uchino@noguchi-med.or.jp

CQ30. What Are Prognostic Factors of Medullary Carcinoma?

Shinya Uchino, Daishu Miura, and Takahiro Okamoto

176 S. Uchino et al.

Commentary

Clear de fi nition of outcome, appropriate follow-up periods, adequate rate of follow-up, clear de fi nition of starting point of follow-up, and statistical veri fi cation for the relationship with prognosis are essential requirements to validate the evidence for prognosis [ 3 ] . Only literature that met these fi ve points was adopted. Although some reports discuss the immunohistological characteristics of tumors as prognostic factors, we limit the scope of this section to prognostic factors that can be adopted in daily medical practice. It should be noted that the purpose of this study of prog-nostic factors is not to establish causal associations, but to statistically validate the relationship between patient characteristics, intervention, and outcome.

Prognostic Factors for Carcinoma Death and Recurrence Detected on Physical Findings and Imaging Studies (Tables 1 and 2 )

The adopted literature included all retrospective cohort studies. Research objects may or may not include both initial treatment cases and recurrent cases, which is an important factor in accessing the adequacy of the studies, but few studies stipulated this point. Results from multivariate analysis were adopted as evidence. Scopi et al. reported that age 60 years or older [Hazard ratio (HR): 2.97], extension to soft tissue (HR: 7.10), and distant metastasis (HR: 3.09) were prognostic factors for carcinoma death and male gender (HR: 2.34), while extension to soft tissue (HR: 4.46) and absence of amyloid deposition (HR: 2.84) were those for carcinoma recurrence [ 4 ] in a study of 109 sporadic patients. Hyer et al. investigated the prognostic factors for cause-speci fi c survival in 162 patients (110 sporadic and 52 hereditary patients) and showed that age (if HR was set at 1.0 for less than 40 years, 1.93 for 40–49 years, 3.73 for 50–59 years, 7.2 for 60 years or older), lymph node metastasis (if HR was set at 1.0 for lack of metastasis, 2.46 for N1a and 6.06 for N1b), distant metastasis at diagnosis (HR: 4.58), and extent of thyroidectomy (if HR was set at 1.0 for limited thyroidectomy, 0.34 for total or near total thyroidectomy) signi fi cantly affected the prognosis [ 5 ] . Guiben et al. also identi fi ed non-curative surgery (HR: 4.89), extrathy-roid extension (HR: 13.68), and distant metatasis (HR: 6.19) as prognostic factors in a study of 32 sporadic patients [ 6 ] .

None of the multicenter studies fi lled the above fi ve requirements, but their results were adopted as evidence because large numbers of patients were analyzed. The German MTC Registry accumulated 741 patients (559 sporadic and 182 hereditary patients) and showed that male gender (HR: 2.19) and age at diagnosis 40 years or older (HR: 2.22) were prognostic factors of carcinoma death [ 7 ] . The French Calcitonin Tumors Study Groups investigated 899 patients (515 sporadic and 384 hereditary patients), showing that the risk of carcinoma death elevated 5.9 times for each stage of advancement, 3.5% for a one year increase in age and 3.9 times for non-curative surgery [ 8 ] . Roman et al. analyzed 1,252 patients from SEER

177CQ30. What Are Prognostic Factors of Medullary Carcinoma?

Tabl

e 1

Prog

nost

ic f

acto

rs w

hen

outc

omes

are

set

at c

arci

nom

a de

ath

or r

ecur

renc

e de

tect

ed o

n ph

ysic

al e

xam

inat

ion

and

imag

ing

stud

ies

Aut

hors

No.

of

patie

nts

(spo

radi

c/he

redi

tary

) <

Initi

al s

urge

ry/r

eope

ratio

n>

Out

com

e Fo

llow

-up

peri

ods

(%)

Initi

atio

n of

fol

low

-up

Prog

nost

ic f

acto

rs o

n m

ultiv

aria

te a

naly

sis

(HR

)

Scop

si L

10

9 (1

09/0

) <

No

desc

ript

ion>

O

S, R

FS

Med

ian

5.3

year

s (1

00%

) A

t ini

tial s

urge

ry (

surg

ical

ca

ses)

or

at d

iagn

osis

(n

o su

rger

y)

Ove

rall

surv

ival

(O

S): a

ge 6

0 ye

ars

or o

lder

(2.

97),

inva

sion

to s

oft

tissu

e (7

.10)

, dis

tant

met

asta

sis

(3.0

9)

Rec

urre

nce-

free

sur

viva

l (R

FS):

mal

e (2

.34)

, inv

asio

n to

sof

t tis

sue

(4.4

6), a

bsen

ce o

f am

yloi

d de

posi

t (2.

84)

Hye

r SL

16

2 (1

10/5

2)

<N

o de

scri

ptio

n>

CSS

, OS

Med

ian

9.0

year

s (1

00%

) A

t dia

gnos

is

Age

you

nger

than

40

year

s (1

.0),

40

–49

year

s (1

.93)

, 50–

59 y

ears

(3

.73)

, old

er th

an 6

0 ye

ars

(7.2

);

abse

nce

of n

ode

met

asta

sis

(1.0

),

N1a

(2.

46),

N1b

(6.

06);

dis

tant

m

etas

tasi

s at

dia

gnos

is (

4.58

);

tota

l or

near

tota

l thy

roid

ecto

my

(0.3

4), l

imite

d th

yroi

dect

omy

(1.0

) G

ülbe

n K

32

(32

/0)

<N

o de

scri

ptio

n>

OS

Med

ian

48 m

onth

s A

t ini

tial t

hera

py

Palli

ativ

e su

rger

y (4

.89)

, ext

rath

yroi

d ex

tens

ion

(13.

68),

dis

tant

m

etas

tasi

s (6

.19)

All

are

retr

ospe

ctiv

e st

udie

s C

SS c

ause

-spe

ci fi c

sur

viva

l, O

S ov

eral

l sur

viva

l, R

FS

rela

pse-

free

sur

viva

l, H

R h

azar

d ra

tio

178 S. Uchino et al.

Tabl

e 2

Prog

nost

ic f

acto

rs w

hen

outc

omes

are

set

at c

arci

nom

a de

ath

or r

ecur

renc

e de

tect

ed o

n ph

ysic

al e

xam

inat

ion

and

imag

ing

stud

ies

(mul

ticen

tre

stud

y)

Aut

hors

St

udy

grou

p

No.

of

patie

nts

(spo

radi

c/he

redi

tary

) <

Initi

al s

urge

ry/

reop

erat

ion>

O

utco

me

Follo

w-u

p pe

riod

s (%

) In

itiat

ion

of

follo

w-u

p Pr

ogno

stic

fac

tors

on

mul

tivar

iate

ana

lysi

s (H

R)

Rau

e F

Ger

man

MT

C

Reg

istr

y 74

1 (5

59/1

82)

<N

o de

scri

ptio

n>

Surv

ival

M

edia

n 14

.4 y

ears

(1

00%

) N

o de

scri

ptio

n M

ale

(2.1

9), 4

0 ye

ars

or o

lder

at d

iagn

osis

(2

.22)

M

odig

liani

E

Fren

ch C

alci

toni

n T

umor

s St

udy

Gro

up

899

(515

/384

) <

No

desc

ript

ion>

Su

rviv

al

Med

ian

3.2

year

s (1

00%

) N

o de

scri

ptio

n 5.

9 tim

es f

or o

ne u

psta

ging

, 3.5

% f

or o

lder

at

1 ye

ar, 3

.9 ti

mes

for

pal

liativ

e su

rger

y

Rom

an S

SE

ER

Reg

istr

y 1,

252

(1,

252

/0)

<N

o de

scri

ptio

n>

OS

No

desc

ript

ion

At d

iagn

osis

A

ge y

oung

er th

an 4

0 ye

ars

(1.0

), 4

0–64

yea

rs

(2.3

5), o

lder

than

65

year

s (6

.55)

; lim

ited

in th

e th

yroi

d (1

.0),

ext

ensi

on to

the

loca

l le

sion

(2.

69),

dis

tant

met

asta

sis

(4.4

7); n

o su

rger

y (1

.0),

hem

ithyr

oide

ctom

y (0

.47)

, to

tal o

r ne

ar to

tal t

hyro

idec

tom

y w

ithou

t no

de d

isec

tion

(0.2

9), t

otal

or

near

tota

l th

yroi

dect

omy

with

lim

ited

diss

ectio

n (0

.17)

, tot

al th

yroi

dect

omy

with

sys

tem

atic

di

ssec

tion

(0.2

5), n

o ex

tern

al b

eam

ra

diot

hera

py (

1.0)

, ext

erna

l bea

m

radi

othe

rapy

(1.

65)

HR

haz

ard

ratio

, MT

C m

edul

lary

thyr

oid

carc

inom

a, S

EE

R S

urve

illan

ce, E

pide

mio

logy

, and

End

Res

ults

(U

SA)

179CQ30. What Are Prognostic Factors of Medullary Carcinoma?

(Surveillance, Epidemiology, and End Results) in the United States and reported that age (younger than 40 years HR: 1.0, 40–64 years HR: 2.35, 65 years or older HR: 6.55), carcinoma progression (limited to the thyroid HR; 1.0, extension to the local tissues HR: 2.69, distant metastasis HR: 4.47), surgical treatment (no surgery HR: 1.0, lobectomy HR: 0.47, total or near total thyroidectomy without node dis-section HR: 0.29, total or near total thyroidectomy with limited dissection HR: 0.17 and total thyroidectomy with systematic node dissection HR: 0.25), and external beam radiotherapy (no HR: 1.0, yes HR: 1.65) were all prognostic factors [ 9 ] .

Prognostic Factors for Biochemical Cure (Normalization of Postoperative Calcitonin Levels)

Four studied from the literature were adopted (Table 3 ). Here, results of univariate analysis were also adopted as evidence. Fleming et al. analyzed 40 patients (23 sporadic and 17 hereditary patients) and showed that the incidences of postoperative calcitonin normalization were signi fi cantly lower in patients with preoperative basal calcitonin level > 835 pg/ml, lymph node metastasis, extrathyroid extension, and more than 2 years after initial surgery [ 10 ] . A multivariate analysis (logistic model) analyzing 36 patients (16 sporadic and 20 hereditary patients, including no recur-rent cases) by Weber et al. showed that only lymph node metastasis was a prognos-tic factor [odds ratio (OR): 19.0] [ 11 ] . Scolo et al. investigated the relationship of 101 patients (54 sporadic and 47 hereditary patients, including no recurrent cases) with lymph node metastasis, and reported that the incidences of normalization of postoperative basal calcitonin levels were 57% for patients having 10 or less node metastases, but were only 4% for those having 11 or more metastases [ 12 ] . Machens et al. showed that the incidences of postoperative calcitonin normalization were signi fi cantly lower in recurrent cases, patients with high preoperative basal calci-tonin levels, large tumor size, extrathyroid extension, lymph node metastasis, and distant metastasis on univariate analysis for 224 patients, including 127 recurrent cases. In a subset of N0 patients without preoperative clinical node metastasis, less than 50% of patients with preoperative basal calcitonin level > 300 pg/ml or tumor size > 10 mm showed postoerpative calcitonin normalization. Furthermore, multi-variate logistic analysis indicated that preoperative basal calcitonin level (100 pg/ml or less OR: 1.0, 500–1,000 pg/ml OR: 19.7, >1,000 pg/ml OR: 4.2) and lymph node metastasis (no OR: 1.0, yes OR: 5.9) were signi fi cant prognostic factors [ 13 ] .

Prognostic Factors for Advanced or Relapsed Cases

In advanced or relapsed cases showing higher serum calcitonin levels and/or CEA levels than the normal range, the doubling time (DT) of these markers re fl ects the

180 S. Uchino et al.

Tabl

e 3

Prog

nost

ic f

acto

rs w

hen

outc

omes

are

set

at p

osto

pera

tive

calc

itoni

n no

rmal

izat

ion

(bio

chem

ical

cur

e)

Aut

hors

No.

of

patie

nts

(spo

radi

c/he

redi

tary

) <

initi

al s

urge

ry/

reop

erat

ion>

Fo

llow

-up

peri

ods

(%)

Initi

atio

n of

fol

low

-up

Prog

nost

ic f

acto

rs o

n un

ivar

iate

ana

lysi

s Pr

ogno

stic

fac

tors

on

mul

tivar

iate

ana

lysi

s

Flem

ing

JB

40 (

23/1

7)

<N

o de

scri

ptio

n>

Med

ian

35 m

onth

s (1

00%

) A

t sur

gery

Pr

eope

rativ

e ba

sal c

alci

noni

n >

835

pg/m

l Ly

mph

nod

e m

etas

tasi

s E

xtra

thyr

oid

exte

nsio

n L

onge

r th

an 2

yea

rs a

fter

in

itial

sur

gery

No

anal

ysis

Web

er T

36

(16

/20)

<

36/0

>

Med

ian

3.7

year

s (1

00%

) A

t sur

gery

Ly

mph

nod

e m

etas

tasi

s (O

R

19.0

) Sc

ollo

C

101

(54/

47)

<10

1/0>

6

wee

ks to

3

mon

ths

At s

urge

ry

Post

oper

ativ

e ca

lcito

nin

norm

aliz

atio

n ra

tes,

57%

fo

r 10

or

few

er n

ode

met

asta

ses,

4%

for

mor

e th

an 1

0 m

etas

tase

s

No

anal

ysis

Mac

hens

A

224

<97

/127

>

Med

ian

6 da

ys

At s

urge

ry

Preo

pera

tive

basa

l cal

cito

nin

>30

0 pg

/ml

Rat

e of

pos

tope

rativ

e ca

lcito

nin

norm

aliz

atio

n w

as 5

0% o

r le

ss f

or tu

mor

s m

easu

ring

10

mm

or

larg

er

Preo

pera

tive

basa

l cal

cito

nin

(OR

): 5

00 o

r le

ss (

1.0)

, 50

0–1,

000

(19.

7), >

1,00

0 (4

.2)

Lym

ph n

ode

met

asta

asis

(O

R):

abs

ent (

1.0)

, pr

esen

t (5.

9)

181CQ30. What Are Prognostic Factors of Medullary Carcinoma?

prognosis thereafter [ 14– 16 ] . Five-year cause speci fi c survival rates of patients with DT less than 6 months, 6 months or longer but shorter than 2 years, and 2 years or longer were 25%, 92%, 100%, respectively [ 15 ] .

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16. Giraudet AL, Ghulzan AA, Aupérin A et al (2008) Progression of medullary thyroid carci-noma: assessment with calcitonin and carcinoembryonic antigen doubling times. Eur J Endocrinol 158:239–246 (RS)