Original ResearchEndocrine Surgery

Preoperative Serum Thyrotropin to

Thyroglobulin Ratio Is Effective for
Thyroid Nodule Evaluation in Euthyroid
Patients

Otolaryngology
Head and Neck Surgery
2015, Vol. 153(1) 1519
American Academy of
OtolaryngologyHead and Neck
Surgery Foundation 2015
Reprints and permission:
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DOI: 10.1177/0194599815579877
http://otojournal.org

Lina Wang, MD1,2*, Hao Li, MD, PhD1,2*, Zhongyuan Yang, MD1,2,
Zhuming Guo, MD, PhD1,2, and Quan Zhang, MD, PhD1,2

Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.

Keywords
thyroid nodule evaluation, thyroid carcinoma, thyroid function test, thyrotropin, thyroglobulin

Abstract
Objective. This study was designed to assess the efficiency of
the serum thyrotropin to thyroglobulin ratio for thyroid
nodule evaluation in euthyroid patients.

Received December 31, 2014; revised February 20, 2015; accepted

March 11, 2015.

Study Design. Cross-sectional study.

he prevalence of palpable thyroid nodules (TNs) is 5%

to 10% in people older than 50 years and may be up to
50% to 70% in people older than 60 years on thyroid
ultrasonography.1-3 In patients with TNs, the first course of
action is to determine whether the nodule is malignant. Within
current diagnostic algorithms, measuring serum thyroidstimulating hormone (TSH) is the first and essential step.4
Previous studies have demonstrated that an elevated level of
TSH, even within the normal range, was linked to a greater
likelihood of thyroid malignancy in patients withTNs.5-7
Part of earlier studies demonstrated that the level of thyroglobulin (Tg) could be used for TN evaluation, but most
reports in recent decades present opposing conclusions.8-10
The widely accepted view is that preoperative serum Tg is
not helpful for TN evaluation but is mainly used as the
baseline to guide follow-up.11 Measuring the preoperative
serum Tg level is not included in current diagnostic
algorithms.
Numerous studies have discussed associations between
the risk of malignancy and serum TSH or Tg concentrations
in patients with TNs, but no study has explored the association between the TSH:Tg ratio and malignancy risk. The
present study was performed to investigate the efficiency of

Setting. Sun Yat-sen University Cancer Center, State Key

Laboratory of Oncology in South China.
Subjects and Methods. Retrospective analysis was performed for
400 previously untreated cases presenting with thyroid nodules.
Thyroid function was tested with commercially available radioimmunoassays. The receiver operating characteristic curves were
constructed to determine cutoff values. The efficacy of the thyrotropin:thyroglobulin ratio and thyroid-stimulating hormone for
thyroid nodule evaluation was evaluated in terms of sensitivity,
specificity, positive predictive value, positive likelihood ratio, negative likelihood ratio, and odds ratio.
Results. In receiver operating characteristic curve analysis,
the area under the curve was 0.746 for the thyrotropin:thyroglobulin ratio and 0.659 for thyroid-stimulating hormone.
With a cutoff point value of 24.97 IU/g for the thyrotropin:thyroglobulin ratio, the sensitivity, specificity, positive
predictive value, positive likelihood ratio, and negative likelihood ratio were 78.9%, 60.8%, 75.5%, 2.01, and 0.35,
respectively. The odds ratio for the thyrotropin:thyroglobulin ratio indicating malignancy was 5.80. With a cutoff point
value of 1.525 mIU/mL for thyroid-stimulating hormone, the
sensitivity, specificity, positive predictive value, positive likelihood ratio, and negative likelihood ratio were 74.0%, 53.2%,
70.8%, 1.58, and 0.49, respectively. The odds ratio indicating
malignancy for thyroid-stimulating hormone was 3.23.
Conclusion. Increasing preoperative serum thyrotropin:thyroglobulin ratio is a risk factor for thyroid carcinoma, and the
correlation of the thyrotropin:thyroglobulin ratio to malignancy is higher than that for serum thyroid-stimulating
hormone.

1
Department of Head and Neck Surgery, Sun Yat-sen University Cancer
Center, Guangzhou, China
2
State Key Laboratory of Oncology in South China, Guangzhou, China
*
These authors contributed equally to this work.

Corresponding Author:
Quan Zhang, MD, PhD, Department of Head and Neck Surgery, Sun Yatsen University Cancer Center, No. 651 Dongfeng Road East, Guangzhou,
510000, China.
Email: zhangquan@sysucc.org.cn

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OtolaryngologyHead and Neck Surgery 153(1)

Figure 1. The equation for the thyroid-stimulating hormone:thyroglobulin ratio construction.

serum the TSH:Tg ratio for TN evaluation in euthyroid subjects by comparison to that of serum TSH.

Patients and Methods

Patients
Retrospective analysis was performed with Sun Yat-sen
University Cancer Centers institutional review board
approval. Previously untreated cases presenting with TNs,
hospitalized in the Sun Yat-sen University Cancer Center
between January 1, 2013, and December 31, 2013, were
reviewed. All cases underwent serum TSH measurement
following current guidelines. The exclusion criteria were (1)
cases without serum Tg measurement, (2) clinical or subclinical hypothyroidism or hyperthyroidism, (3) use of antithyroid drugs or with a history of thyroid hormone
replacement therapy, (4) use of any medication that could
affect thyroid function, (5) patients who underwent fineneedle aspiration biopsy within 4 weeks before blood sampling, (6) cases with an alanine aminotransferase concentration 80 IU/mL, (7) patients with an indeterminate
histological diagnosis. Four hundred cases were included in
the study. Postoperative histological diagnosis is the gold
standard for this study.

Histological Results

the gold standard. The efficacy of the ratios and TSH for
TN evaluation was evaluated in terms of sensitivity, specificity, positive predictive value (PPV), positive likelihood
ratio (PLR), negative likelihood ratio (NLR), and odds ratio
(OR). A 2-tailed P value \.05 was considered significant.

Results
The mean greatest dimension of TNs was 30.12 6 15.42
mm in patients with benign nodules and 17.19 6 11.59 mm
in those with malignancy (P \ .001). The geometric mean
of serum TSH concentration was 1.95 6 1.70 mIU/mL in
individuals with malignancy and 1.27 6 1.63 mIU/mL in
patients with benign nodules (P \ .001). The geometric
means of serum Tg concentrations were 19.54 6 1138.90
ng/mL in patients with malignant nodules and 87.91 6
746.38 ng/mL in patients with benign nodules (P = .032).
The median value of the serum TSH:Tg ratio was 86.2 IU/
g, 95% confidence interval (CI; 56.2-129.6) IU/g in patients
with malignancy and 19.9 IU/g, 95% CI (11.8-29.5) IU/g in
patients with benign nodules.
The ROC curves were constructed for TSH and TSH:Tg
ratios (Figure 2). The area under the curve (AUC) for the
TSH:Tg ratio was 0.746, 95% CI (0.697, 0.795). The AUC
for TSH was 0.659, 95% CI (0.603, 0.714). When the sum
of specificity and sensitivity was maximal, the TSH:Tg ratio

According to pathological diagnosis, nodules were benign in

158 cases and malignant in 242 cases. In cases with malignancy, 1 case presented with anaplastic thyroid cancer and
papillary thyroid cancer (PTC), 1 case presented with PTC
and medullary thyroid cancer (MTC), 2 cases presented
with MTC, and all of the other cases presented with PTC.

Laboratory Tests
Serum TSH, Tg, and thyroglobulin antibody (TgAb) levels
were measured in each case with the same blood sample.
Levels were quantified by commercially available radioimmunoassay. The reference ranges for TSH, Tg, and TgAb
were 0.27 to 4.2 mIU/mL, 1.4 to 78 ng/mL, and 0 to 115
IU/mL, respectively. The TSH:Tg ratio was calculated with
its unit transferred to IU/g (Figure 1).

Statistical Analyses
The geometric means of serum TSH and Tg concentrations
in patients with malignant and benign nodules were compared. The cutoff point values of serum TSH and TSH:Tg
ratio were determined by receiver operating characteristic
(ROC) curve analysis. A cutoff point value was selected at
which the sum of sensitivity and specificity was greatest.
With the cutoff point values, we evaluated TNs using
TSH:Tg ratios and TSH. These were then compared with

Figure 2. Receiver operating characteristic curves for the serum

thyroid-stimulating hormone:thyroglobulin ratio and thyroid-stimulating hormone concentration.

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Lina et al

17

Table 1. Comparisons of Nodule Evaluations Based on the

TSH:Tg Ratio and TSH to Histological Diagnoses.
Histological Diagnosis

Ratio-based evaluation
TSH-based evaluation

Malignant
Benign
Malignant
Benign

Malignant

Benign

191
51
179
63

62
96
74
84

Abbreviations: Tg, thyroglobulin; TSH, thyroid-stimulating hormone.

was 24.97 IU/g. Taking 24.97 IU/g as the cutoff point value
for the TSH:Tg ratio, we predicted cases with ratios 24.97
IU/g to be malignant, whereas cases with ratios \24.97 IU/
g were taken to be benign. The TSH was 1.525 mIU/mL
when the sum of specificity and sensitivity was the largest.
We predicted cases with TSH 1.525 mIU/mL to be malignant, whereas cases with less than this level were predicted
to be benign. Comparisons of predictive results to histological diagnoses are displayed in Table 1.
The accuracy of the TSH:Tg ratio was 71.8%, with sensitivity = 78.9%, specificity = 60.8%, PPV = 75.5%, PLR =
2.01, and NLR = 0.35. The OR indicating malignancy for the
TSH:Tg ratio was 5.80. The accuracy for TSH was 65.8%,
with sensitivity = 74.0%, specificity = 53.2%, PPV = 70.8%,
PLR = 1.58, and NLR = 0.49. The OR indicating malignancy
for TSH was 3.23.
TgAb was elevated in 21.1% (51/242) of cases in patients
with malignancy and in 6.3% (10/158) of cases with benign
nodules. The geometric mean of serum Tg concentration was
52.64 6 1089.62 ng/mL in patients with normal TgAb and
3.90 6 42.31 ng/mL in patients with elevated TgAb (P =
.069). Comparisons of predictive results to histological diagnoses are displayed in Table 2. The accuracy of the TSH:Tg
ratio in patients with normal TgAb was 68.7% with sensitivity = 74.3%, specificity = 61.5%, PPV = 71.4%, PLR = 1.93,
and NLR = 0.42. In patients with elevated TgAb, the accuracy was 88.5% with sensitivity = 96.1%, specificity =
50.0%, PPV = 90.7%, PLR = 1.92, and NPR = 0.08. The OR
indicating malignancy was 4.63 in patients with normal
TgAb and 24.50 in patients with elevated TgAb.

Discussion
TSH is a main regulator of thyroid hormone production by
thyroid follicular cells and plays a critical role in normal
thyroid function and in disorders.12-14 Differentiated thyroid
cancer expresses the TSH receptor on cell membranes and
responds to TSH stimulation by increasing the expression of
several thyroid-specific proteins and by elevating cell growth
rates.4,15,16 Furthermore, data demonstrate that serum TSH
concentration in patients with malignant nodules is higher
than that of patients with benign nodules.5-7 Taken together,
it is believed that TSH plays a role in thyroid cancer development and progression and as a growth factor in thyroid
tumors, and it is a link within a complex signaling network
that modulates thyroid cell growth and function.17,18
Produced by thyroid follicular cells, the synthesis and
secretion of Tg is an active process requiring stimulation by
TSH. Without TSH, little or no Tg would be released into
the circulation. Although TSH concentration is not the only
factor affecting serum Tg level, Tg concentration is supposed to be correlated with serum TSH level. In fact, the Tg
level does not vary in accordance with TSH level. In our
study, the geometric mean Tg level in patients with malignancy was significantly lower than that in patients with
benign nodules. The large standard deviation indicated that
Tg levels vary tremendously between cases and can be elevated in patients with benign nodules and in patients with
malignancy. Therefore, Tg cannot be independently used as
an effective marker for TN status, which accords with previous reports.9
To our knowledge, this is the first study designed to evaluate the efficiency of the TSH:Tg ratio for TN evaluation. Our
data showed that the median serum TSH:Tg ratio differed
significantly between malignant and benign thyroids. The OR
of the TSH:Tg ratio was 5.80. This indicates that when the
ratio is in the higher range, the risk of malignancy is elevated
5.80-fold in comparison to absence of malignancy. When the
TSH level is in the higher range, the risk of a malignancy is
increased 3.23-fold compared with nonmalignant cases. The
OR indicating a malignancy of TSH:Tg ratio is apparently
higher than that of TSH. These data reinforce that both high
TSH level and high TSH:Tg ratio are risk factors for thyroid
carcinoma.5,6 Furthermore, the correlation of TSH:Tg ratio to
a malignant state is higher than that of serum TSH.

Table 2. Comparisons of Nodule Evaluations Based on the TSH:Tg Ratio and TSH to Histological Diagnoses in Normal and Elevated TgAb
Subgroups.
Histological Diagnosis

Normal TgAb subgroup

Ratio-based evaluations

Elevated TgAb subgroup

Ratio-based evaluations

Malignant
Benign
Malignant
Benign

Abbreviations: Tg, thyroglobulin; TgAb, thyroglobulin antibody; TSH, thyroid-stimulating hormone.

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Malignant

Benign

142
49
49
2

57
91
5
5

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OtolaryngologyHead and Neck Surgery 153(1)

It is reported that approximately 20% of patients with

thyroid cancer have elevated TgAb, which reinforces our
data.19 In our cohort, only 6.3% patients with benign
nodules presented with elevated TgAb. As reported, TgAb
levels interfere with Tg measurement irrespective of the
assay used.20 However, most reports propose that TgAb
should be taken into consideration only in cases with significantly elevated TgAb levels.21,22 In this study, the geometric means of serum Tg concentration in patients with
normal TgAb were higher than those in patients with elevated TgAb, but the difference was not statistically significant. However, this difference should be further explored
because of insufficient cases in the TgAb-elevated subgroup. The OR for the TSH:Tg ratio indicating a malignancy was 24.50 in the TgAb-elevated subgroup and 4.63 in
the TgAb-normal subgroup. This result indicates that the
efficiency of the TSH:Tg ratio is better in patients with elevated TgAb. The OR of the TSH:Tg ratio in the subgroup
with normal TgAb is still higher than the OR for TSH
alone. This demonstrates that the TSH:Tg ratio is more
effective than TSH alone for TN evaluation regardless of
TgAb level. Considering the assays used for Tg measurement, when the ratio is referred to, the cutoff point value of
TSH:Tg ratio may differ.
The present data showed that the TSH:Tg ratio is higher
in histologically confirmed carcinoma than in benign
nodules. Compared with TSH, the sensitivity, specificity,
PPV, and PLR of TSH:Tg ratios were higher, while the
NLR was smaller. This demonstrates that more patients
with a malignancy would be identified. In the meantime,
fewer benign nodules would be misdiagnosed as malignant.
The OR indicating a malignancy of TSH:Tg ratio was
higher than that of TSH alone. Overall, the serum TSH:Tg
ratio is more effective than TSH for the evaluation of TN.
An elevated TSH:Tg ratio was linked with a greater likelihood of thyroid malignancy in patients with TNs. We speculate that findings in this study could contribute to a TN
evaluation algorithm. Serum TSH:Tg ratios could be used
for TN evaluation instead of serum TSH. Comprehensively
considering clinical factors, TSH:Tg ratios, and ultrasound
features, clinicians determine whether fine-needle aspirate
(FNA) is indicated or follow-up needs to be conducted.
FNA biopsy is the preoperative gold standard diagnostic
method. Most cases can be diagnosed with a combination of
FNA, ultrasonography, laboratory findings, and clinical
data. Some patients still cannot obtain definitive diagnoses,
especially those with micronodules or large (.4 cm) cystic
nodules. Ten percent to 25% of TNs are categorized as
indeterminate.23 A median of 34% (range, 14%-48%) of
patients with indeterminate cytology findings who underwent surgery were found to have a malignancy.1,11,24-27
Furthermore, the false-negative rate for nodules larger than
4 cm is approximately 10% to 15%, and some cystic
nodules remain undiagnosed despite repeated biopsies.11 As
the gold standard in the study, a definitive pathological
diagnosis of each case was required. For these reasons, we
used postoperative histological diagnosis as the gold

standard instead of FNA results. We performed this study

with data from patients who underwent surgery. The indications of thyroidectomy for malignant and benign TNs were
different. As a result, selection bias was caused in this
study. Our data showed that the mean greatest dimension of
TNs in the benign group was significantly larger than that
in the malignant group. This is an evidence of selection
bias. As a result of the limitation of a retrospective analysis
and selection bias, we cannot accurately evaluate how many
patients with benign nodules would be suggested to undergo
further confirmatory tests or how many patients with malignancy would be missed. Consequentially, the efficiency of
the TSH:Tg ratio for nodule evaluation needs to be confirmed with prospective studies.

Conclusion
Increased preoperative serum TSH:Tg ratio is a risk factor
for thyroid carcinoma, and the correlation of TSH:Tg ratio
to malignancy is higher than that of serum TSH.
Acknowledgments
Thank Liu Qing, MD, PhD, and Liang Huiying, MD, for consultation in selection of statistical analysis methods.

Author Contributions
Lina Wang, drafting, data analysis, interpretation of data, final
approval accountability for all aspects of the work; Hao Li, revising, data analysis, interpretation of data, final approval, accountability for all aspects of the work; Zhongyuan Yang, drafting,
acquisition of data, final approval, accountability for all aspects of
the work; Zhuming Guo, revising, interpretation of data, final
approval, accountability for all aspects of the work; Quan Zhang,
design, revising, final approval, accountability for all aspects of the
work.

Disclosures
Competing interests: None.
Sponsorships: Guangdong Provincial Department of Science
Technology. The sponsor is a governmental agency. It does
participate in study design and conduct; collection, analysis,
interpretation of the data; and writing or approval of
manuscript.

and
not
and
the

Funding source: Government finance: funding from government

finance approved by Guangdong Provincial Department of Science
and Technology, with program series 2012A020602001.

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