Introduction
Thyroid cancer is the most common among endocrine
cancers, and its incidence is 3 times higher in women
than in men (21 and 7/100,000 population, respectively).[] Estimated incidence of thyroid cancer by
age and sex has increased in both sexes and all ethnicities
compared to other malignancies in recent years.
[,] Differentiated thyroid cancer (DTC) accounts for
80-90% of all thyroid cancer diagnoses. Papillary, follicular,
and poorly differentiated types of thyroid cancer
are considered as DTC. DTC subtypes are treated
similarly despite numerous biological differences.
Serum thyroglobulin (Tg) level is used for recurrent
disease follow-up in patients with DTC after initial treatment.
However, serum Tg measurements in patients
with serum anti-thyroglobulin antibody (TgAb) positive
can be misleading. TgAb can be detected in 20% of
patients with DTC and in 10% of the general population.
[-] Following total thyroidectomy and subsequent radioactive
iodine (RAI) treatment, serum TgAb levels
generally reach undetectable levels within 3-5 years.
The decrease in TgAb level has prognostic significance.
The decrease in TgAb level above 50% in the first 3 years
of the follow-up is associated with the risk of recurrence
<3%.[,] Stable values at the TgAb level are associated
with an approximately 20% risk of recurrence, while increasing
values at the TgAb level are associated with an
approximately 40% risk of recurrence.
Although there are many studies in the literature
investigating the relationship between post-operative
TgAb level and DTC stage, metastasis, and recurrence
risk, there are limited number of studies investigating
the relationship between pre-operative TgAb level and
these parameters.
In this study, we aimed to determine the relationship
between the positivity and level of pre-operative
TgAb and the cancer stage, metastasis status, and recurrence
risk in subjects who underwent total thyroidectomy
and had TgAb results measured in the pre-operative
period.
Methods
The study enrolled 331 patients who underwent total
thyroidectomy and those who had TgAb results measured
in the pre-operative and post-operative period
between January 2012 and May 2019. Ethical committee
approval was obtained for the study from the Local
Ethics Committee. The study was carried out in accordance
with the Principles of Helsinki Declaration. İnformed consent was obtained from all participants.
Laboratory and clinicopathological data of the patients
such as sex, age at the diagnosis, TgAb positivity and
level in the pre-operative period, histopathological
subtype of thyroid cancer, lymph node metastasis status,
tumor volume, tumor size, TNM stage, risk stratification
according to the American thyroid association
(ATA), tumor focus number, whether recurrence occurred
during follow-up, whether surgical treatment or
RAI treatment was performed in those who developed
recurrence, TSH levels at the time of diagnosis and
TgAb levels in the post-operative period were recorded
from the patient files.
TgAb positivity status: Those with a TgAb level above
the reference value were considered positive and those
within the reference value range were considered negative
(TGAb normal range: 0-115 U/mL). Tumor volume
was calculated by the formula [width (mm)×length
(mm) × thickness (mm)] ×∏/6. The largest tumor size
was recorded in those given two diameters of the tumor.
Those whose tumor diameter could not be calculated
were recorded as separate groups. TNM stage: Tumors
were stratified according to 8th AJCC TNM classification
system. ATA risk stratification: Patients were classified
according to the ATA risk stratification (low, moderate,
and high risk). Tumor focus number: Single-focus tumors
are grouped as single-focus, and those with more
than one focus are grouped as multifocal tumors. Postoperative
TgAb level: TgAb values in the 2nd year after
thyroidectomy, and the last TgAb values if there was no
value in the 2nd year were recorded.
Statistical Analysis
Statistical analysis was carried out by the Statistical Package
for the Social Sciences 22.0 program. According to
the distrubition characteristics of varieables, continuous
varieables were given as mean±standard deviation or
median (min-max). To compare the differences of independent
groups, Independent samples t-test, Mann-
Whitney U-test, and Chi-square test were used. Pearson
and Spearman test were used for correlation analysis.
P<0.05 value was considered statistically significant.
Results
Of the 331 patients enrolled in the study, 253 (76.4%)
were female and 78 (23.6) were male, and the age at
diagnosis was 46.7±15.4. The age was 44.9 in the DTC
group and 48.0 in the benign group. Ninety-seven of
126 patients in the DTC group and 154 of 205 patients in the benign group were women. We found no difference
between the DTC group and the benign group
in terms of gender and age (p=0.473 and p=0.076,
respectively). The final histopathology results of patients
who underwent total thyroidectomy were DTC
in 126 (38.1%) patients and benign in 205 (61.9%)
patients. In DTC group, papillary thyroid cancer was found in 72 (57.1%) patients, thyroid papillary microcarcinoma
in 49 (38.9%) patients, follicular type thyroid
cancer in 4 (3.2%) patients, and poorly DTC in
one patient (0.8%). When the tumor stages of DTC
patients were examined, it was detected as Stage I in
115 patients (91.3%), Stage II in seven patients (5.6%),
Stage III in three patients (2.4%), and Stage IVb in one patient (0.8%). According to the current ATA stratification
system, in the DTC group, 32 patients (25.4%)
were in low risk, 88 patients (69.8%) were in moderate
risk, and six patients (4.8%) were in high-risk group.
In the DTC group, 91 (72.2) patients received RAI
treatment, and 35 patients (27.8%) did not receive RAI
treatment. During follow-up, recurrence occurred in
14 (11.1%) of 126 patients in the DTC group. It was
determined that 11 (78.6%) of the patients with recurrence
were re-operated and 6 (42.9%) patients received
RAI treatment again due to recurrence. Multifocal
tumor foci were detected in 48 patients (38.1%)
and single tumor focus in 78 patients (61.9%) in the
DTC group. Lymph node metastasis was detected in
35 patients (27.8%) in the DTC group (Table 1).
Table 1 Demographic, pathological, and laboratory features of patients who underwent thyroidectomy
At the diagnosis of DTC, the mean TSH level of all
patients was 1.41±1.54, the mean values of TSH in the
DTC group was 1.76±1.45, the mean values of TSH in
the benign group were 1.19±1.58, and TSH value at
the diagnosis was found to be higher in DTC group
(p<0.001). In the pre-operative period, TgAb values
were negative in 276 patients (83.4%) and positive in
55 patients (16.6%). While TgAb was positive in 26
(20.6%) of 126 patients in the DTC group, TgAb was
positive in 29 (14.1%) of 205 patients in the benign
group (p=0.117). In the TgAb positive group, pre-operative
mean TgAb level was 743.88±978.11 IU/ml in
the DTC group, 880.63±1053.30 IU/ml in the benign
group, and we did not find any difference between the
groups (p=0.577) (Table 2).
Table 2 Comparison of demographic and laboratory
parameters of DTC group and benign group
We did not find any relationship between pre-operative
TgAb positivity and parameters such as TNM stage
(p=0.119), lymph node metastasis (p=0.416), receiving
RAI treatment (p=0.868), recurrence (p=0.732), surgical
treatment due to recurrence (p=0.396), RAI treatment
due to recurrence (p=0.165), and tumor focus
number (p=0.947) (Table 3).
Table 3 Relationship between pre-operative TgAb positivity
and clinicopathological parameters
In the TgAb positive group, there were no lymph
node metastases in 17 of 26 patients with DTC, and
nine of 26 patients with DTC have had lymph node
metastases. In the group with lymph node metastasis,
we found that the mean value of TgAb was
higher than the group without lymph node metastasis
(1356.20±1163.77 IU/ml, 419.71±703.64 IU/ml, respectively,
p=0.043). No recurrence was observed in 24 of 26
patients with DTC, and two of them had recurrence.
Mean TgAb level was higher in patients with recurrent
disease than those without recurrence (2492.00±718.42
IU/ml, 598.20±854.15 IU/ml, respectively, p=0.043).
According to the current ATA stratification system of 26
patients with DTC, nine were in the low-risk group and 17 were in the moderate risk group. We did not find any
difference between the intermediate risk group and the
low-risk group in terms of TgAb level (847.97±1007.37
IU/ml, 547.26±945.27 IU/ml, respectively, p=0.374). Of
the 26 patients with DTC, 19 received RAI treatment,
seven did not receive RAI treatment. In patients who
received RAI treatment, mean TgAb level was found to
be significantly higher than those who did not receive
RAI treatment (959.35±1068.51 IU/ml, 159.02±122.37
IU/ml, respectively, p=0.022). Of the 26 patients with
DTC, ten had multifocal tumors and 16 had single focus
tumors. We found no difference between the groups
in terms of mean TgAb level (463.66±530.41 IU/ml,
919.02±1157.85 IU/ml, respectively, p=0.562) (Table 4).
Table 4 The association between the level of TgAb and
clinicopathological parameters in patients with
positive pre-operative TgAb
In the correlation analysis, we found significant correlations
between pre-operative TgAb level and recurrence
(p=0.032) and lymph node metastasis (p=0.023).
Discussion
In our study, pre-operative TgAb levels were found to
be significantly higher in DTC patients with lymph
node metastasis or recurrence. We found that preoperative
TgAb level significantly correlated with
recurrence and lymph node metastasis. In addition,
TSH value at the diagnosis was found to be higher in
the DTC group than in the benign group. No significant
relationship was found between the positivity or
level of pre-operative TgAb and parameters such as
tumor focus number, stage, ATA risk classification,
and RAI treatment.
In the present study, the number of male patients
was less than the number of female patients in both
the DTC group and among all patients who underwent
thyroidectomy. In studies with patients who underwent
thyroidectomy, it was determined that the majority of
patients were women.[,] In some studies, the age of
the patients was lower in the malignant group,[] while
in some studies, there was no difference in age in the
malignant and benign groups.[]
In our study, the mean TSH value at the diagnosis
was higher in the DTC patients than in the benign
group. In the previous studies with patients who underwent
total thyroidectomy, TSH values were found
to be higher in patients whose histopathology results
were malignant compared to those whose histopathology
results were benign.[,-] It is thought
that one of the reasons for this high TSH level in those
with malignant histopathology results is that TSH itself
has a trophic effect on the growth of thyroid cancer
and this condition is mediated by the TSH receptors on thyeroid cancer cells. As another reason, it is
thought that patients who have low concentrations of
TSH may be developing autonomic function associated
with lower malignancy rates.
In our study, although positivity of TgAb was more
frequent and the mean TgAb level was higher in the
malignant group, these findings were not statistically
significant. We think that this may be due to the relatively
small sample size of our study population. In
several studies, it has been shown that positivity of
pre-operative TgAb is more frequent in patients who
have malignancy than those with benign histopathology.[,] Liu et al.[] found that TgAb positivity is
an independent predictor for malignancy. Hosseini et
al.[] showed that patients with a pre-operative TgAb
level ≥30 IU/ml had higher malignancy rate compared
to patients with a pre-operative TgAb level <30 IU/ml.
In some studies, it has been demonstrated that the
risk of recurrent or persistent disease is not associated
with pre-operative TgAb positivity,[] but rather with
the change in post-operative TgAb levels.[] Qin et
al.[] did not find any significant difference between
TgAb positive DTC patients and TgAb negative DTC
patients in terms of lymph node metastasis and stage.
In our study, similar results were found in terms of the
pre-operative TgAb positivity.
In our study, it was found that there was a relationship
between pre-operative TgAb level and both
lymph node metastasis and recurrence. Li et al.[] showed that pre-operative TgAb positivity was associated
with the primary tumor diameter greater than
1 cm, and TgAb level and TSH level were associated
with central lymph node metastasis. Seo et al.[] reported
that tumor recurrence frequency was higher in
patients with TgAb >140 U/mL than in DTC patients
with TgAb <140 U/mL.
Our study has some limitations. One of them is that
the study population is small, and another is that the
presence of autoimmune thyroid disease before thyroidectomy
was not taken into consideration.
Conclusion
In conclusion, measuring the pre-operative TgAb of
patients with clinical and ultrasonographic suspicious
findings in terms of malignancy may provide information
about which patients have a high risk of recurrence
and lymph node metastasis. In this context, more
comprehensive studies are needed.
Peer-review: Externally peer-reviewed.
Conflict of Interest: All authors declared no conflict of interest.
Ethics Committee Approval: The study was approved
by the Necmettin Erbakan University Faculty of Medicine
Ethics Committee (no: 2019/1998, date: 12/07/2019).
Financial Support: None declared.
Authorship contributions: Concept - H.K., M.Ka., M.Ku.;
Design - H.K., F.K., M.Ku.; Supervision - M.Ko., İ.Ç.; Funding
- H.K., M.C., M.Ka.; Materials - H.K., İ.Ç.; Data collection
and/or processing - M.Ko., M.C., F.K.; Data analysis and/or
interpretation - H.K., M.C., M.Ku.; Literature search - M.Ko.,
İ.Ç., M.Ka.; Writing - M.Ko., F.K.; Critical review - M.Ku.
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