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Soonchunhyang Medical Science 20(2):123-127, December 2014
pISSN: 2233-4289 I eISSN: 2233-4297
CASE REPORT
Consideration of Discrepancy between Needle-Washout Thyroglobulin and
Serum Thyroglobulin of Recurrent Papillary Thyroid Cancer
So Ra Kim1, Mi-Kyung Kwak1, Hye Ran Kang1, Seug Yun Yoon1, Seong Soon Kwon1, Bo Young Kim1, Hoo Nam Choi1, Hye Jeong Kim1,
Jae Wook Kim2, So-Young Jin3, Hyeong Kyu Park1, Dong Won Byun1, Kyoil Suh1, Myung-Hi Yoo1
Division of Endocrinology and Metabolism, Department of Internal Medicine, Departments of 2Otorhinolaryngology-Head and Neck Surgery and 3Pathology,
Soonchunhyang University Hospital, Soonchunhyang University College of Medicine, Seoul, Korea
1
Although the prognosis of papillary thyroid cancer (PTC) is extremely good, locoregional recurrences after initial treatment occur.
Thyroglobulin (Tg) is a reliable tumor marker to detect recurrence or persistence of PTC. However, occasionally serum Tg may miss
the detection of a recurrence. We report a 54-year-old female presented with hoarseness due to cervical recurrence without concomitant elevation of serum Tg and anti-Tg antibody, in contrast to extremely increased needle-washout Tg, who had undergone a
total thyroidectomy and radioiodine ablation as initial therapies for PTC. Several factors causing such discrepancy between needlewashout Tg and serum Tg can be suggested including site of recurrence, volume of tumor, interference by some kind of plasma antibodies other than anti-Tg antibody, and any conformational defect of Tg protein. Among them, the most convincing explanation
is that any conformational defect of Tg may lead to impaired secretion of Tg to blood. We suggest that more studies are needed to
find the cause for potential mechanisms involved in PTC recurrences without increased serum Tg.
Keywords: Papillary thyroid carcinoma; Recurrence; Thyroglobulin
INTRODUCTION
CASE REPORT
Although the vast majority of patients with papillary thyroid
A 54-year-old female with suspicious malignant nodule in thy-
cancer (PTC) have an excellent prognosis, disease recurrences do
roid was referred to Soonchunhyang University Hospital. The ini-
occur. During follow-up after initial surgery and/or radioiodine
tial serum thyroid-stimulating hormone (TSH) level was 0.92 mU/
therapy, serum thyroglobulin (Tg) measurement, neck ultrasound,
L (reference range, 0.40 to 5.00 mU/L), and the preoperative levels
and/or diagnostic whole-body radioiodine scan are recommended
of serum Tg (IRMA kit; Cisbio Bioassay, Codolet, France; function-
depending on the risk for recurrence in a patient with PTC [1,2].
al sensitivity, 0.7 μg/L) and anti-Tg antibody (RIA kit; RSR Ltd.,
Particularly, serum Tg is the most sensitive biomarker of recurrence
Cardiff, UK) were 20.82 μg/L (reference range, 0 to 35 μg/L) and
for well-differentiated thyroid cancer. Since Tg is synthesized only
negative (reference range, 0 to 60 μg/L), respectively. Thyroid ultra-
by thyroid follicular cells, measurements of serum Tg provide im-
sound revealed a calcified nodule in left lobe. An ultrasound-guid-
portant information about the presence of residual, recurrent, or
ed fine needle aspiration (FNA) biopsy results showed suspicious
metastatic disease in patients with differentiated thyroid cancer [3].
for PTC. She underwent a total thyroidectomy and central neck
However, occasionally serum Tg may miss the detection of a recur-
dissection with preserving the recurrent laryngeal nerve for thyroid
rence. Here, we report a case of cervical recurrence without a con-
cancer in September 2009. In the thyroidectomy specimen, a 1.6-
comitant increase in serum Tg and anti-Tg antibody in a patient
cm tumor in the left lobe was noted. Microscopic findings showed
with PTC who had undergone a total thyroidectomy and radioio-
proliferation of papillary structures or follicles lined by cuboidal tu-
dine ablation as initial therapies.
mor cells with enlarged ground glass nuclei, irregular nuclear out-
Correspondence to: Myung-Hi Yoo
Division of Endocrinology and Metabolism, Department of Internal Medicine, Soonchunhyang University Hospital, Soonchunhyang
University College of Medicine, 59 Daesagwan-ro, Yongsan-gu, Seoul 140-743, Korea
Tel: +82-2-709-9493, Fax: +82-2-709-9083, E-mail: [email protected]
Received: Sep. 18, 2014 / Accepted after revision: Oct. 2, 2014
© 2014 Soonchunhyang Medical Research Institute
This is an Open Access article distributed under the terms of the
Creative Commons Attribution Non-Commercial License
(http://creativecommons.org/licenses/by-nc/3.0/).
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123
Kim SR, et al. • Recurrent PTC without Increased Serum Tg
line, nuclear grooves, and occasional intranuclear inclusion on the
the immunoassay used is protected against potential interferences
sclerotic stroma, consistent with typical type of papillary carcinoma.
like human anti-mouse antibodies by adding a protection in the
It spread to the perithyroidal soft tissue (Fig. 1A). Dissected lymph
tracer, it cannot be guaranteed that there will never be detection of
nodes showed reactive hyperplasia without tumor metastasis. In
December 2009, she received radioiodine ablation with 150 mCi of
‘false positive’ or ‘false negative’ due to the presence of interferences
like heterophile antibodies (HAB) in the patient samples. So, to de-
131
I. A post-therapy whole-body scan showed only focal uptake in
termine whether HAB to Tg were present in our patient’s serum, we
the neck (Fig. 2). Stimulated serum Tg level obtained after thyroxine
performed test by two methods. First, precipitation method using
withdrawal was 9.56 μg/L and serum TSH level was 64.81 mU/L.
serum of the patient and four euthyroid controls was performed.
She was followed by clinical examination, assessment of serum Tg
The amount of 100 μL of each serum was incubated at 37°C for 1
levels and anti-Tg antibody, and ultrasound of the neck every 6 to 12
months without evidence of disease. TSH suppression therapy by levothyroxine was maintained to achieve a serum TSH less than 0.10
mU/L (Table 1).
At 3 years after surgery, she complained of hoarseness for the past
6 weeks. Laryngoscopic examination showed left vocal cord palsy.
Thyroid ultrasound revealed two small lymph nodes at right level
IV and a 1.2-cm sized mass at left level VI suspicious for lymph node
metastasis. The ultrasound-guided FNA was performed, and the
needle-washout fluid was analyzed both cytological examination
and Tg assay. The cytology specimen showed PTC recurrence. The
level of needle-washout Tg was 3,825.3 μg/L in right level IV and
3,355.7 μg/L in left level VI. Serum TSH level was 0.02 mU/L, Tg was
0.09 μg/L, and anti-Tg antibody was negative at that time. Although
A
Fig. 2. A post-therapeutic radioactive iodine scan showed focal increased uptake in the neck.
B
Fig. 1. Microscopic findings of primary tumor and metastatic lesions. It shows follicular to papillary proliferation of tumor cells on the sclerotic background. (A) Their
nuclei have enlarged characteristic ground glass nuclei and nuclear grooves (H&E, × 100). (B) The recurrent tumor nodules of the neck are lymph nodes involved by
metastatic papillary carcinoma of the thyroid (H&E, × 40).
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Soonchunhyang Medical Science 20(2):123-127
Recurrent PTC without Increased Serum Tg • Kim SR, et al.
hour with 500 μL of the 125I-labelled Tg analog. The 1 mL of 20%
immediately recovered from hoarseness and vocal cords are fully
polyethylene glycol (PEG) was added. Then, that was centrifuged at
adducted on laryngoscopic examination. Three months later, a dose
3,000 rpm for 30 minutes. Radioactivity of the precipitate were mea-
of 150 mCi of 131I was administered and post-therapy whole-body
sured using gamma counter. When the radioactivity of the precipi-
scan demonstrated no abnormal increased uptake. Stimulated se-
tate was expressed as a percentage of total radioactivity, there were
rum Tg level obtained after thyroxine withdrawal was 0.63 μg/L and
no significant differences between the patient and controls. Second,
serum TSH level was 25.75 mU/L. She is receiving TSH suppression
50 μL of each serum and 1 mL of I-labelled Tg analog were mixed
therapy and followed without evidence of disease until now.
125
in anti-Tg antibody coated tube and shaken for 2 hours. The 1 mL of
30% PEG was added, then, centrifuged and measured radioactivity
DISCUSSION
of each tube. There were no significant differences of radioactivity
between the patient and controls. Selective neck dissection was per-
According to recent Korean [1] and American [2] management
formed for right lateral and left central neck. Pathology specimens
guideline for patients with thyroid cancer, measurements of serum
were confirmed PTC at right level IV and left level VI, and histolog-
Tg, anti-Tg antibody and TSH at 6- to 12-month intervals and neck
ic features are same as the initial mass (Fig. 1B). After surgery, she
ultrasound 6 to 12 months postoperatively and then periodically
depending on the patient’s risk for recurrent disease are recommended. Tg is a highly sensitive and specific marker for detection
Table 1. Serum TSH, Tg, and anti-Tg antibody levels during follow-up
Date
April 2010
December 2010
June 2011
June 2012
September 2012
At recurrence
Months
TSH (mU/L) Tg (μg/L)
since thyroidectomy
7 months
1 year and 3 months
1 year and 9 months
2 years and 9 months
2 years and 11 months
3 years
0.07
0.05
0.03
0.02
0.04
0.02
0.13
0.24
0.26
0.10
0.28
0.09
Anti-Tg
antibody
of recurrent or residual disease after initial therapy [3]. After total
Negative
Negative
Negative
Negative
Negative
Negative
expected to be very low (< 1 to 2 μg/L), either on TSH suppression
thyroidectomy and radioiodine ablation, serum Tg levels would be
therapy or after thyroid hormone withdrawal, if the patient is cured
[4]. As a single investigation, serum Tg measurement is more sensitive than radioiodine uptake scanning [5-9]. Previous studies suggested that patients with low levels of serum Tg during suppression
therapy may have a high probability of being free of disease [10,11].
TSH, thyroid-stimulating hormone; Tg, thyroglobulin.
A
B
Fig. 3. Immunohistologic findings. (A) The primary and (B) the metastatic tumors are strongly positive for thyroglobulin in the both cytoplasm of tumor cells and colloid
(thyroglobulin, × 100).
Soonchunhyang Medical Science 20(2):123-127
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125
Kim SR, et al. • Recurrent PTC without Increased Serum Tg
The present case represented PTC recurrences despite the ab-
may lead to false decreases and increases in Tg concentrations [19].
sence of detectable serum Tg and the negativity of anti-Tg antibody
HAB interference is relatively prevalent (range, 1.5% to 3%) in a
contradictory to high needle-washout Tg level. There are several
commonly used automated Tg assay, so HAB interference should
potential mechanisms that might be involved in PTC recurrence
be suspected if Tg results do not fit the clinical picture [19]. HAB
with such discrepancy between needle-washout Tg and serum Tg.
did not significantly interfere with Tg measurement in FNA wash-
First, tumor cells might be ‘poor secretor.’ It means tumor could
out fluid, probably because of the very high Tg concentrations in
have synthesized Tg but had some defects on secretion process. To
the needle-washout fluids [20]. However, we could not identify
date, 43 inactivating mutations have been reported in the human
HAB interference in patient’s serum.
TG gene [12]. Some Tg mutants have defective intracellular trans-
The present case has some limitations. Most of all, serum Tg level
port and accumulate within the rough endoplasmic reticulum, so
after thyroid hormone withdrawal were not measured. However, it
cannot be released into the follicle lumen [12-16]. We performed
is usually adopted measuring of serum Tg on thyroxine because of
immunostaining for Tg from primary mass and recurrent lymph
its high sensitivity and the inconvenience of withdrawal of thyroid
nodes specimens. Immunohistochemical stains demonstrated
hormone. Furthermore, patients with a TSH-suppressed serum Tg
strong positive staining for Tg in the tumor cells and colloid of the
concentration < 0.1 μg/L were unlikely to have an stimulated Tg
both initial mass and metastatic nodule (Fig. 3). So it is less likely
above 2.0 μg/L [21].
that tumor cells had some defect of intracellular transport of Tg to
In summary, we report an unusual case of PTC recurrence with-
colloid. Instead, Tg protein may had any conformational change
out a concomitant increase in serum Tg and anti-Tg antibody, in
leading to failure of secretion from colloid to blood. It also may be
contrast to extremely increased needle-washout Tg, in a patient
the reason of negative serum Tg versus positive needle-washout Tg.
who had undergone a total thyroidectomy and radioiodine ablation
Further pathologic examination by electron microscope may be
as initial therapies. It is important that PTC patients need to be fol-
needed. Second, the site of recurrence may influence serum Tg lev-
lowed by clinical examination and ultrasound of the neck as well as
el. Patients with distant metastases to lung or bone have higher Tg
assessment of serum Tg levels and anti-Tg antibodies. We suggest
levels than those with lymph node metastases [11]. Our patient had
that more studies are needed to find the cause for potential mecha-
metastases only to cervical lymph nodes and no distant metastases.
nisms involved in PTC recurrences without concomitant elevation
However, this fact may explain the result of negative serum Tg, but
of serum Tg levels in the absence anti-Tg antibody.
not that of high needle-washout Tg level. Third, the volume of metastatic tumor may be too small to increase serum Tg level enough
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