Association Between Serum Thyrotropin Concentrationand Growth of Asymptomatic Papillary Thyroid Microcarcinoma

Iwao Sugitani • Yoshihide Fujimoto •

Keiko Yamada

Published online: 14 November 2013

� Societe Internationale de Chirurgie 2013

Abstract

Background Thyrotropin (TSH) is a known thyroid

growth factor. Several studies have suggested its potential

role in carcinogenesis and the progression of differentiated

thyroid carcinoma. We have been conducting a prospective

trial of nonsurgical observation for asymptomatic papillary

thyroid microcarcinoma (PMC) since 1995. The aim of this

study was to investigate whether serum TSH concentra-

tions can be used to predict PMC growth.

Methods This study examined 415 asymptomatic PMCs.

Three hundred twenty-two patients decided to undergo

nonsurgical observation by ultrasonography and were fol-

lowed for C2 years.

Results After a mean of 6.5 years of observation (range

2–22 years), 25 lesions (6 %) had increased in size, 377

(91 %) showed no change and 13 (3 %) had decreased in

size. Both baseline TSH and mean TSH during follow-up

for PMC that increased in size did not differ significantly

from those lesions that were unchanged or decreased in

size. Increases in size were seen in 0 of 18 (0 %), 15 of 260

(6 %), 10 of 126 (8 %), and 0 of 11 (0 %) for PMCs with

baseline TSH \ 0.50, 0.50–1.99, 2.00–3.99, and

C4.00 mIU/L, respectively. A logistic regression model

analyzing the association between baseline TSH and out-

come showed an odds ratio of 1.01 (95 % confidence

interval [CI], 0.66–1.29). No significant correlations were

apparent between mean TSH during follow-up and change

in PMC volume (r = 0.019, p = 0.70).

Conclusions No significant association between TSH and

tumor progression was verified during the nonsurgical

observation trial for PMC. TSH is not a good predictor of

PMC growth.

Introduction

Thyrotropin (thyroid-stimulating hormone, TSH) is a

known thyroid growth factor that stimulates thyroid fol-

licular cells via TSH receptors on the cellular membrane

and is said to play a key role in the initiation and pro-

gression of differentiated thyroid carcinoma (DTC). Hyper-

functioning thyroid nodules are well-known to rarely har-

bor malignancy [1]. Many recent cross-sectional studies

have compared TSH concentrations between patients with

benign and malignant thyroid nodules. A systematic review

and meta-analysis by McLeod et al. [2] reviewed 28 studies

that examined the causative role of TSH in thyroid cancer.

They concluded that higher serum TSH concentrations are

associated with increased odds of thyroid cancer in patients

with nodular thyroid disease. American Thyroid Associa-

tion (ATA) guidelines [3] also indicate that higher serum

TSH levels, even within the upper end of the reference

range, are associated with increased risk of malignancy in

thyroid nodules. Measurement of serum TSH levels is

thought to aid diagnosis in patients with thyroid nodules, in

conjunction with clinical, radiological, and cytological

findings. Moreover, several studies have shown that pre-

operative serum TSH values are higher in patients with

I. Sugitani � Y. Fujimoto

Division of Head and Neck, Cancer Institute Hospital, 3-8-31

Ariake, Koto-ku, Tokyo 135-8550, Japan

I. Sugitani (&)

Division of Endocrine Surgery, Department of Surgery, Nippon

Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8603,

Japan

e-mail: isugitani@nms.ac.jp

K. Yamada

Department of Ultrasonography, Cancer Institute Hospital, 3-8-

31 Ariake, Koto-ku, Tokyo 135-8550, Japan

123

World J Surg (2014) 38:673–678

DOI 10.1007/s00268-013-2335-8

more advanced tumors (evaluated by cancer stage, tumor

size, lymph node metastasis, extrathyroidal invasion, and

distant metastasis), suggesting a potential role of TSH in

the development and progression of DTC [4–8].

Papillary thyroid microcarcinoma (PMC), representing

papillary thyroid carcinoma (PTC) with a maximum

diameter B1 cm, generally follows a benign clinical

course. In the last few decades, the incidence of small PTC

has continuously increased worldwide [9]. This is mainly

due to the widespread use of more sensitive diagnostic

procedures, including ultrasonography. Clinical care of

patients with incidentally detected PMC has recently

become not only a management dilemma but also a public

health issue. According to our previous retrospective ana-

lysis of risk factors for patients with PMC who have

undergone surgery, the factors most significantly affecting

cancer-specific survival were clinical symptoms at pre-

sentation due to either invasion or metastasis [10]. Distant

metastasis and cancer-specific death were never seen

postoperatively for asymptomatic PMC without clinically

apparent (C1 cm) lymph node metastasis or recurrent nerve

palsy. Following those results, we have been conducting a

prospective clinical trial of nonsurgical observation for

asymptomatic PMC since 1995. As described previously

[11], nonsurgical observation for a mean of 5 years as of

2008 for 300 lesions of asymptomatic PMC revealed that

7 % had increased in size, 90 % were unchanged, and 3 %

had become smaller. Three patients (1 %) developed

apparent lymph node metastasis, but no patients showed

extrathyroidal invasion or distant metastasis. A similar trial

has been carried out at Kuma Hospital in Kobe, Japan,

since 1994. It reported almost identical results in 2003 and

2010 [12, 13]. Nonsurgical observation is recognized as an

attractive alternative to surgery for asymptomatic PMC,

and the Japanese Clinical Guidelines approved the policy

under conditions of providing an extensive explanation and

obtaining informed consent [14]. In this situation, the

ability to differentiate tumors with the potential to grow

and extend from others at the time of diagnosis would be

desirable.

The aim of this prospective cohort study was to inves-

tigate the relationship between serum TSH concentration

and outcomes of nonsurgical observation for asymptomatic

PMC and to elucidate whether serum TSH concentrations

can be used to predict PMC growth.

Materials and methods

The present study was conducted at Cancer Institute Hos-

pital, a tertiary Oncology Referral Center in Tokyo, Japan.

Since 1995, all patients with PMC diagnosed by fine needle

aspiration cytology (FNA) have been evaluated for the

presence of distant metastasis, clinically apparent lym-

phadenopathy (maximum diameter, C1 cm), or extrathy-

roidal invasion using neck ultrasonography (US), chest

computed tomography (CT), laryngoscopy, and so on. For

patients with asymptomatic PMC (clinical T1aN0M0), we

provide information regarding the option of nonsurgical

observation rather than immediate surgery, as described

previously [11]. If the patient chooses observation, the

tumor is surveyed by palpation, US, chest radiography, or

CT every 6 or 12 months. Diagnostic B-mode US (7.5-

MHz transducer) was performed by a single radiologist

(K.Y.) who specializes in thyroid US to evaluate tumor size

and cervical lymph node metastasis. Increased or decreased

tumor size was defined as a change in maximum diameter

of the tumor C3 mm on US from the start of observation,

because ±2 mm has been recognized as an observer vari-

ation. Serum thyroglobulin (Tg), anti-Tg antibody, and

TSH levels are measured at initial presentation (baseline)

and every 6 or 12 months thereafter. Anti-thyroid peroxi-

dase antibody was usually measured only at initial pre-

sentation. We recommend surgery during follow-up if the

patient meets the following criteria: (1) change in patient

preference; (2) PMC tumor has grown backward from the

thyroid, toward adjacent structures including the recurrent

laryngeal nerve, trachea, and esophagus; (3) development

of clinically evident lymph node metastasis or distant

metastasis; or (4) increased tumor size. As for extent of

surgery, when a tumor was limited to one lobe, we per-

formed lobectomy with central node dissection of the

affected side. In patients who developed clinically evident

lymph node metastasis, compartment-oriented therapeutic

neck dissection was performed. These protocols were

approved by the Ethics Committee of the Cancer Institute

Hospital. Written informed consent was obtained after

agreement based on the informed decision of the patient.

Patients who decided to undergo nonsurgical observation

between 1995 and 2011 were enrolled in the present study

and followed for at least 2 years. Patients with autono-

mously functioning thyroid nodule, Graves’ disease, or

exogenous supplementation with thyroxine were excluded.

Data are expressed as mean ± SD. The comparison of

clinical characteristics between groups was performed

using the v2 test or Fisher’s exact test for categorical

variables and using Student’s t test or the Mann–Whitney

U test for continuous variables, as appropriate. Tumor size

progression-free survival curves were determined with the

Kaplan–Meier method and were compared by the log-rank

test. A logistic regression model was used to examine the

influence of serum TSH concentration on growth of

asymptomatic PMCs. Strength of the statistical correlation

between TSH and change in tumor volume was calculated

with the Pearson test. All analyses were performed with

JMP for Windows version 10.0.2 software (SAS Institute,

674 World J Surg (2014) 38:673–678

123

Cary, NC). Values of p \ 0.05 were considered statisti-

cally significant.

Results

Our cohort examined 415 asymptomatic patients with

PMCs. Three hundred twenty-two patients decided to be

followed by ultrasonography and declined surgical inter-

vention. The flow diagram of patients is shown in Fig. 1.

Among these patients, 43 patients were men and 279 were

women. Their age was between 23 and 84 years, with a

mean age of 54.4 ± 11.5 years. After a mean of

6.5 ± 4.0 years of observation (range 2–22 years), 25

lesions (6 %) had increased in size, 377 (91 %) showed no

change, and 13 (3 %) had decreased in size. No patients

developed extrathyroidal invasion or distant metastasis

during follow-up, although three patients (0.9 %) devel-

oped clinically apparent nodal metastasis.

The relationship between clinical characteristics and

outcomes of nonsurgical observation were investigated

(Table 1). No PMCs in male patients had increased in size,

but age, gender, duration of follow-up, maximum diameter

of the tumor at diagnosis, presence or absence of anti-

thyroglobulin (Tg) or anti-thyroid peroxidase antibodies,

and serum Tg at diagnosis were not significantly associated

Fig. 1 Flow diagram of

patients with asymptomatic

papillary thyroid

microcarcinoma (PMC)

World J Surg (2014) 38:673–678 675

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with outcomes. Both baseline TSH and mean TSH during

follow-up of lesions that increased in size did not differ

significantly from measurements for lesions that were

unchanged or that decreased in size.

When we categorized baseline TSH concentration into

four groups of\0.50, 0.50–1.99, 2.00–3.99, or C4.00 mIU/

L, increases in size of PMCs were seen in 0 of 18 (0 %), 15

of 260 (6 %), 10 of 126 (8 %), and 0 of 11 (0 %),

respectively (Table 2). No significant differences were

seen between groups with baseline TSH \ 2.0 or

C2.0 mIU/L (p = 0.55). Tumor size progression-free sur-

vival curves for patients with baseline TSH \ 2.0 and

C2.0 mIU/L are shown in Fig. 2. These two curves were

not significantly different (p = 0.67).

Logistic regression analysis of the association between

baseline TSH concentration (1 mIU/L increments) and

outcomes (increase in size, no change, or decrease in size)

showed an odds ratio (OR) of 1.01 (95 % confidence

interval [CI], 0.66–1.29).

No significant linear correlations were apparent between

TSH (either baseline or mean during follow-up) and

change in PMC volume (r = –0.0098, p = 0.84 and

r = 0.019, p = 0.70, respectively) (Figs. 3, 4).

Discussion

Our previous study [11] identified three biologically dif-

ferent types of PMC: type I, incidentally detected PMC

without any symptoms, which is harmless and has the

lowest risk cancer; type II, the early stage of the usual low-

risk PTC; and type III, clinically symptomatic PMC, rep-

resenting high-risk cancer. For patients with type I or II,

nonsurgical follow-up with US every 6 or 12 months may

be feasible. Type II tumor (approximately 5 % of all

PMCs) can then be treated safely by conservative thy-

roidectomy (lobectomy, if possible) when increasing size is

noted during the observation. The Japanese Clinical

Guidelines for Treatment of Thyroid Tumor stated that

PMC patients without clinical lymph node metastasis on

palpation or imaging studies, distant metastasis, or signif-

icant extrathyroidal extension can be candidates for

observation [14]. Any predictive marker that could differ-

entiate type II PMC from type I at the beginning would be

useful. In the previous investigation [11], PMCs in younger

patients tended to increase in size compared with those in

older patients. As for US findings, tumors with rich blood

supply showed a significantly higher incidence of increased

tumor size than tumors with poor blood supply.

Recent studies have consistently shown that the risk of

thyroid malignancy in patients with nodular thyroid disease

increases with increasing serum TSH level, even within

normal ranges [2, 4, 15–17]. Several studies have also

found a positive relationship between increasing serum

Table 1 Relationship between clinical factors and outcomes of

nonsurgical observation for asymptomatic papillary thyroid micro-

carcinoma (PMC)

Clinical

characteristics

Maximum diameter

decreased or

unchanged

(n = 390)

Maximum

diameter

increased

(n = 25)

p value

Age at diagnosis

(years)

54.8 ± 0.6 52.4 ± 2.3 0.41

Male/female ratio 54/336 0/25 0.059

Duration of

follow-up

(years)

6.5 ± 0.2 6.4 ± 0.8 0.73

Maximum

diameter of

PMC at

diagnosis (mm)

7.8 ± 0.1 7.6 ± 0.5 0.70

Anti-thyroglobulin

antibody

(absent/present)

267/123 14/11 0.27

Anti-thyroid

peroxidase

antibody

(absent/present)

289/101 15/10 0.16

Serum

thyroglobulin at

diagnosis

(ng/mla)

26.3 ± 3.0 21.5 ± 10.0 0.53

Baseline TSH at

diagnosis

(mIU/L)

1.80 ± 0.06 1.79 ± 0.25 0.47

Mean TSH during

follow-up

(mIU/L)

1.78 ± 0.05 1.91 ± 0.20 0.31

a When we evaluated serum thyroglobulin, patients with benign

nodules and/or positive anti-thyroglobulin antibody were excluded

Table 2 Baseline thyroxine (TSH) and change in maximum diameter of papillary thyroid microcarcinoma during nonsurgical observation

Baseline TSH (mIU/L) \0.50 0.50–1.99 2.00–3.99 C4.00 Total

Change in maximum tumor diameter Increase C3 mm 0 (0 %) 15 (6 %) 10 (8 %) 0 (0 %) 25 (6 %)

No change 18 (100 %) 238 (91 %) 110 (87 %) 11 (100 %) 377 (91 %)

Decrease C3 mm 0 (0 %) 7 (3 %) 6 (5 %) 0 (0 %) 13 (3 %)

Total 18 260 126 11 415

676 World J Surg (2014) 38:673–678

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TSH level and adverse prognostic indicators [4–8]. Serum

TSH is therefore thought to be a useful diagnostic tool in

thyroid cancer surveillance. However, use of a cross-sec-

tional design without follow-up data on actual prognosis

for these studies limits the ability to confirm that TSH plays

a distinctly causative role in thyroid carcinogenesis.

Reaching a definitive conclusion regarding the association

between serum TSH and thyroid cancer aggressiveness or

progression is thus difficult.

This prospective cohort study explored the effects of

serum TSH concentration on outcomes of nonsurgical

observation in asymptomatic PMC, with the expectation

that TSH would be a good predictor of PMC growth.

However, serum TSH concentration (both baseline and

mean during follow-up) for PMCs that increased in size did

not differ significantly from those lesions that were

unchanged or decreased in size. Logistic regression model

analysis indicated an OR of 1.01 for TSH increments of

1 mIU/L on the outcomes of nonsurgical observation for

asymptomatic PMC (increase in size, no change or

decrease in size). The 95 %CI (0.66–1.29) contained 1.00

and the association between TSH and outcomes was not

significant. Likewise, no significant correlations were

apparent between serum TSH and change in PMC volume.

In addition, three patients developed clinically evident

nodal metastasis during the observation. Baseline and mean

TSH during follow-up were 1.20 ± 0.73 and

1.74 ± 0.59 mIU/L for these patients, respectively. These

values were not significantly different from other patients

(baseline, 1.80 ± 0.07 mIU/L, p = 0.30; mean,

1.78 ± 0.06 mIU/L, p = 0.67, respectively). As a result,

no significant association between TSH and tumor pro-

gression in the natural course of PMC could be verified.

The TSH level is thus not useful for predicting growth of

PMC.

Debate about the relationship between thyroid autoim-

munity and DTC incidence and aggressiveness is ongoing.

A meta-analysis showed increased incidence of thyroid

cancer in patients with positive thyroid antibodies, com-

pared with control populations [18]. In another study, Fiore

and Vitti [16] reported that the frequency of DTC did not

differ significantly between antibody-positive and anti-

body-negative patients, and higher serum TSH concentra-

tions were found in patients with PTC when compared with

subjects with benign disease, regardless of antibody status.

We excluded patients with positive anti-Tg and/or anti-

thyroid peroxidase antibodies in our study, and the results

were not significantly changed (logistic regression model:

Fig. 2 Tumor size progression and baseline thyroxine (TSH) levels

Fig. 3 Correlation between baseline TSH and change in tumor

volume

Fig. 4 Correlation between mean TSH during follow-up and change

in tumor volume

World J Surg (2014) 38:673–678 677

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OR, 1.05; 95 %CI, 049–1.34). No significant correlations

were seen between TSH (either baseline or mean during

follow-up) and change in PMC volume (r = –0.0049,

p = 0.43 and r = –0.025, p = 0.70, respectively).

Long-term suppression of TSH using supraphysiological

doses of levothyroxine has been used in an attempt to

decrease the risk of thyroid cancer recurrence and even

cancer-related mortality. However, formal validation of the

effects of this therapy through studies guaranteeing a high

level of evidence is still lacking [19]. We conducted a

randomized controlled trial (RCT) to investigate the effi-

cacy of TSH-suppression therapy on disease-free survival

(DFS) after surgery for patients with PTC [20]. The find-

ings indicated that DFS in patients without TSH-suppres-

sion therapy was not inferior to that in patients with TSH

suppression. Moreover, according to the observational trial

for PMC by Ito et al [13], whether TSH-suppression was

carried out or not was not related to enlargement of tumors.

Although some investigators have recommended TSH-

suppression therapy for all patients with nodular thyroid

disease for the purpose of reducing the risk of thyroid

malignancy [16], long-term administration of supraphysi-

ological doses of levothyroxine could cause serious side

effects, including thyrotoxicosis, osteoporosis, angina, and

cardiac arrhythmias [21]. Taken together, we do not cur-

rently recommend TSH-suppression for patients with

asymptomatic PMC. However, verification by RCT would

be necessary to settle a dispute whether TSH-suppression

can prevent PMC progression.

Unique to the present study is its prospective design, but

some limitations must be considered when interpreting the

findings. The number of patients was relatively small and

the duration of follow-up was insufficient. In particular,

events of increased tumor size and development of lymph

node metastasis were rare. The statistical power to reach

conclusions was thus relatively weak. Further studies with

longer follow-up and a much greater number of subjects

are necessary. At the same time, we should try to find

reliable predictors for evaluating the biological aggres-

siveness of PMC, such as uptake values of 18F-fluorode-

oxyglucose on positron emission tomography or presence

of the BRAF gene mutation.

Conflict of interest The authors have no conflicts of interest.

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