ORIGINAL ARTICLE

p53 antibody: is it an indicator of dedifferentiated thyroid cancer?

Zekiye Hasbek • Bulent Turgut • Taner Erselcan

Received: 12 June 2013 / Accepted: 9 October 2013 / Published online: 14 November 2013

� The Japanese Society of Nuclear Medicine 2013

Abstract

Aim Radioiodine is the most effective treatment modality

in differentiated thyroid carcinoma, either in metastatic or

residual thyroid tissue. However, sometimes dedifferenti-

ation can develop and the effectiveness of radioactive I-131

decreases. The p53 is a tumor suppressor gene which plays

an important role in controlling normal cell proliferation

regulation. In the serum of healthy individuals, the pre-

sence of p53 autoantibodies is extremely rare. Mutations in

this gene cause an accumulation of non-functional proteins

and may lead to development of anti-p53 antibodies. The

aim of the present study was to devise a simple blood test

that could lead to early identification of patients with

dedifferentiation. In this respect, we investigate whether

the serum level of anti-p53 antibody is of diagnostic value

in the follow-up of patients with high levels of thyro-

globulin (Tg) and negative I-131 scan.

Materials and methods Patients who were diagnosed with

thyroid cancer, treated with total or near total thyroidec-

tomy and referred for I-131 therapy or low dose I-131

whole body scan were included in our study. Blood sam-

ples were taken before the administration of I-131 orally in

the group of patients. Besides, 28 healthy subjects were

included. We quantified the presence of p53 autoantibodies

from serums.

Results In the present study were enrolled 171 patients

with a mean age of 47.7 ± 13.5 years (range 16–80 years)

and 28 healthy subjects with an age range of 18–52 years

(mean 36.0 ± 9.8 years). One hundred and forty-eight

patients had papillary (86.5 %), 7 (4.1 %) follicular, 10

(5.8 %) thyroid tumors of uncertain malignant potential, 2

(1.2 %) Hurthle cell carcinoma, 3 (1.8 %) poor differenti-

ated, and 1 (0.6 %) undifferentiated thyroid carcinoma.

The p53 antibodies were positive in 16 (9.4 %) patients and

negative in 155 (90.6 %). The p53 antibodies were positive

in 3 (10.7 %) healthy subjects, and negative in 25 (89.3 %)

healthy subjects. In five patients with high Tg level and

negative radioiodine scan, who were accepted as dedif-

ferentiated, p53 antibodies were also negative.

Conclusion The results of the present study suggested

that the level of serum p53 antibody seems to be of limited

value in the demonstration of dedifferentiation in thyroid

cancer patients.

Keywords I-131 � Thyroid cancer � p53 �Radionuclide therapy

Introduction

Thyroid cancers are a relatively uncommon type of cancer

but are the most common cancers of the endocrine system,

and their incidence has been rapidly increasing [1]. Dif-

ferentiated thyroid cancers are biologically less aggressive

and their prognosis is good. On the other hand, patients

with poorly differentiated and undifferentiated cancers

frequently have recurrences, a poor prognosis and fatal

outcome [2]. I-131 ablation therapy is a successful form of

treatment that aims to destroy the remaining residual tissue

and/or metastatic tissue after surgical treatment in patients

with differentiated thyroid cancers. With ablation therapy,

thyroid cells do not remain. Thus, any subsequent rise in

the serum thyroglobulin (Tg) level will be a highly

ClinicalTrials.gov Identifier: NCT01954134.

Z. Hasbek (&) � B. Turgut � T. Erselcan

Department of Nuclear Medicine, Cumhuriyet University School

of Medicine, Campus, 58140 Sivas, Turkey

e-mail: hasbekz@yahoo.com

123

Ann Nucl Med (2014) 28:42–46

DOI 10.1007/s12149-013-0783-8

sensitive and specific marker of recurrent disease. Thyroid

hormone corrects hypothyroidism induced by total thy-

roidectomy, suppresses thyroid cancer tumor growth

stimulated by TSH, and reduces tumor recurrence and

death in long-term follow-up [3]. Sometimes, dedifferen-

tiation can occur in differentiated thyroid cancers, and the

tumor may grow aggressively and there may be metastatic

spread. In clinical practice patients with negative radioio-

dine scan with positive thyroglobulin are considered as

being radioiodine resistant or in another words in the

process of dedifferentiation. As a result of dedifferentiation

of thyroid cancer, the ability to accumulate radioiodine is

reduced or lost [4]. In contrast to well-differentiated thy-

roid cancers (WDTC) that have a good prognosis with

surgery and radioiodine therapy, undifferentiated thyroid

cancers (UDTC) are very resistant to chemotherapy and

their prognosis is poor [5].

Recently, the development of genetic tests in parallel

with technological developments, as well as other cancers,

the genetic structure of thyroid cancers has been examined

better and, both prognosis and treatment monitoring has

enabled the use of various prognostic parameters. p53 is a

tumor suppressor gene which plays an important role in

controlling normal cell proliferation regulation that is

encoded by the TP53 gene located on the short arm of

chromosome 17. It is the most common goal of genetic

alteration in many tumors. p53 is effective in the nucleus

and inhibits cell the cycle. When cells are exposed to

carcinogens, normal p53 protein accumulates rapidly in the

nucleus and the cell remains constantly in the G1 phase and

saves time for DNA repair. If such repair does not occur,

p53 stops the division of mutant cells and stimulates

apoptosis. It is not seen in normal cells but when DNA is

damaged by a carcinogen then it occurs. Mutations in the

p53 tumor suppressor gene are the most frequent known

genetic alterations in all human cancers [6]. Some studies

have reported that p53 mutations are highly common in

leukemia, lymphoma, lung, esophagus, stomach, liver,

bone, bladder, ovarian, and brain cancers [7–9]. Particu-

larly, p53 mutations have been found at high rates in head

and neck cancers (50 %), while this rate is lower in thyroid

cancer (10 %). More rarely, mutant p53 allele is inherited.

The p53 mutation causes the development of dedifferenti-

ation in thyroid cancer [10]. Serum p53 protein is present

in normal healthy individuals. However, p53 antibody is

extremely rare. Mutations in this gene cause an accumu-

lation of non-functional proteins and development of anti-

p53 antibodies, which can be detected in tissues, sloughed

cells, blood, and other body fluids [11].

The purpose of the present study was to investigate

serum anti-p53 antibody as a tumor marker, together with

thyroglobulin (Tg) in patients with thyroid cancer before

pre-ablation therapy or during routine follow-up. It is

known that the effectiveness of radioactive I-131 decreases

in poorly and undifferentiated thyroid cancers. We aimed

to test whether a simple blood test could lead to early

identification of patients with dedifferentiation. In addition,

we intended to investigate whether the serum level of anti-

p53 antibody has any diagnostic value in the follow-up of

patients with high values of Tg and radioactive I-131 scan-

negative.

Materials and methods

Patients who were diagnosed with DTC, treated with total

and/or near-total thyroidectomy and referred for I-131

ablation therapy or low dose I-131 whole body scan (WBS)

between December 2010 and January 2013 were included

in our study. This study was performed in accordance with

the principles of the Declaration of Helsinki. This study

was approved by the Cumhuriyet University Research

Ethics Committee. Oral and written consent of the patients

was obtained. Exclusion criteria were: dose 131-I given in

another hospital and radioiodine treatment more than

1 year after thyroidectomy. After ablation, Diagnostic

WBS with I-131 was applied to the patients in 8–10th

months. Patients with undetectable thyroid-stimulating

hormone-stimulated serum thyroglobulin concentrations,

normal physical examination, negative results on whole

body scan, and no evidence of neck lymph node metastases

at ultrasound were defined as free of disease. After diag-

nostic WBS, the next follow up of patients with complete

ablation was applied with neck US and serum Tg and anti-

Tg. Age, gender, tumor type, the presence of tumor capsule

and thyroid capsule invasion, tumor size, number of

tumors, the presence of lymph node and distant metastasis,

pre-ablation thyroglobulin, anti-thyroglobulin and TSH

values, the administered dose were recorded. Apart from

this, post ablation 131-I whole body scan, and diagnostic

131-I WBS, neck ultrasonography, serum Tg and anti-Tg

level results in 8–10th months and Tg and anti-Tg in their

next follow-up were recorded. Scintigraphic images were

obtained with the use of a single-headed gamma camera

(Toshiba GCA-7100A) that was equipped with a ‘‘high

energy parallel hole’’ collimator and interfaced to a dedi-

cated computer. For image acquisition, a peak energy set-

ting at 364 keV with a 20 % window was used. Diagnostic

WBS was performed 24–48 h after administration of I-131.

WBS with anterior and posterior views was acquired.

Baseline data and sera were collected from identified

cases and controls. Blood samples were taken before the

administration of I-131 orally in the group of patients. All

sera were obtained after complete clotting by centrifuga-

tion, immediately frozen and stored at -40 �C. Detection

of serum anti-p53 antibodies by ELISA (enzyme-linked

Ann Nucl Med (2014) 28:42–46 43

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immuno sorbent assay) [micro-plate reader (CA-2000)/

Diagnostics Pasteur LP35 Microplate Washer]. We quan-

tified the presence of p53 autoantibodies from the sera of

all patients by using the p53 auto-antibody ELISA kit. The

kit was designed to measure circulating p53 antibodies in

human serum samples. In the control group, 28 healthy

subjects with no systemic or chronic disease, no history of

cancer, no drug use, were included in the study. Positivity

was defined as (sample OD450value)/(negative control

OD450 value) C2 [11].

Statistical analysis

SPSS 15.0 software was used for the statistical analysis.

The Chi square test was applied to evaluate the statistical

significance of the parameters, significance levels were

presented as p values. It was assumed that the observed

differences were statistically significant at the p B 0.05

level.

Results

A total of 171 patients with an age range of 16–80 years

(mean 47.7 ± 13.5 years) and a total of 28 healthy subjects

with an age range of 18–52 years (mean 36.0 ± 9.8 years)

were included in this study. Demographic and clinico-

pathologic characteristics are listed in Table 1. According

to the histopathological results, 148 (86.5 %) papillary, 7

(4.1 %) follicular, 10 (5.8 %) thyroid tumors of uncertain

malignant potential, 2 (1.2 %) Hurthle cell carcinoma, 3

(1.8 %) poor differentiated and 1 (0.6 %) undifferentiated

thyroid carcinoma. In the papillary cancer group, 80

(54.1 %) had classic type, 52 (35.1 %) had follicular var-

iant, 15 (10.1 %) patients had oncocytic cell variant and

one (0.7 %) had tall cell variant. Patients were given doses

of I-131 ranging from 100 to 250 mCi (mean

114 ± 24 mCi) orally. 134 patients (78.4 %) were female

and 37 (21.6 %) were male. In the control group, 18

(64.3 %) healthy subjects were female and 10 (35.7 %)

were male. Sixty-five patients (38 %) were under 45 years

of age, whereas 106 (62 %) were 45 years and older. The

mean tumor size was 18 ± 15 mm (range 1–90). Fourteen

(10.8 %) patients had lymph node metastases, 17 (10.3 %)

patients had tumor capsular invasion, 14 (8.6 %) patients

had thyroid capsular invasion and 9 (5.3 %) patients had

distant metastases at the time of diagnosis. p53 antibodies

were positive in 16 (9.4 %) patients and negative in 155

(90.6 %). p53 antibodies were positive in 3 (10.7 %)

healthy subjects, and negative in 25 (89.3 %). These rates

were not statistically significant. p53 antibody was negative

in all patients with distant metastases at the time of diag-

nosis. There was no statistical relation between serum p53

antibodies and lymph node metastases, thyroid capsular

invasion, or tumor capsular invasion (p [ 0.05). There was

no statistical relation between serum p53 antibodies and

any of the histopathological sub-groups (p [ 0.05)

(Table 2). Eleven patients did not come to control for

follow up. There were no elevated anti-Tg in any patient.

Among the patients followed up, p53 antibodies were

negative in 127 of 141 (90.1 %) with low Tg level (\2 ng/

ml), while positive in 14 patients (14 %). While p53 anti-

bodies were negative in 17 patients of 19 (89.5 %) with

high Tg level ([2 ng/ml), they were positive in 2 patients

(10.5 %) (Table 3).

Even in 5 patients with high Tg level and negative

radioiodine scan, p53 antibodies were negative. One

patient had brain metastases, 3 patients had lymph node

metastases, and 1 patient had recurrence in the thyroid bed.

These patients were accepted as dedifferentiated. However,

p53 antibodies were negative in these patients.

Table 1 Demographic and clinico-histopathologic characteristics

Characteristics n (%)

Age

Mean age at diagnosis (years) (range)

47 ± 13 years, range 16–80 years

\45 years 65 (38 %)

C45 years 106 (62 %)

Sex

Female 134 (78.4 %)

Male 37 (21.6 %)

Pathological classification

Papillary 148 (86.5 %)

Follicular 7 (4.1 %)

Thyroid tumors of uncertain malignant potential 10 (5.8 %)

Hurthle cell 2 (1.2 %)

Poorly differentiated 3 (1.8 %)

Undifferentiated 1 (0.6)

Table 2 The positive rates of serum p53 antibodies in histopathol-

ogical classification (p [ 0.05)

Histopathological type p53 antibody Total

Positive Negative

Papillary thyroid cancer 16 (10.8 %) 132 (89.2 %) 148

Follicular thyroid cancer 0 7 (100 %) 7

Thyroid tumors of uncertain

malignant potential

0 10 (100 %) 10

Hurthle cell carcinoma 0 2 (100 %) 2

Poorly differentiated thyroid

cancer

0 3 (100 %) 3

Undifferentiated thyroid cancer 0 1 (100 %) 1

Total 16 155 171

44 Ann Nucl Med (2014) 28:42–46

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One patient had both undifferentiated thyroid carcinoma

and papillary cancer. This patient was treated with radio-

iodine due to papillary cancer. Similarly, there was another

patient who had medullary and papillary cancer. This

patient was treated with radioiodine due to papillary cancer

too. The p53 antibodies were also negative in these

patients.

Three patients had poorly differentiated thyroid cancer

but serum p53 antibody was negative. Two patients had

Hurthle cell thyroid carcinoma but serum p53 antibody was

negative, too. In one patient, during both ablation therapy

and follow-up, serum p53 antibodies were studied. The first

time p53 antibody was normal. During follow-up, lung

metastases developed. The second time p53 antibody was

again normal.

Tissue p53 was studied in only three patients and was

negative in all.

Discussion

Serum p53 protein is present in normal healthy individuals.

In the serum of healthy individuals the presence of p53

autoantibodies is extremely rare. In 1982, Crawford et al.

[12] first described antibodies against human p53 protein.

Mutations in this gene cause an accumulation of non-

functional proteins and development of anti-p53 antibod-

ies, which can be detected in tissues, sloughed cells, blood

and other body fluids [11]. Muller et al. [13] analyzed 1874

serum samples, including 591 patients with various types

of cancer, esophageal, gastric, colorectal, pancreatic,

hepatocellular, breast and urogenital cancer, and 436 con-

trol individuals, for the presence of p53 mutations. They

found no anti-p53 antibodies in the sera of the patients in

the control group but did find them in 23.4 % of the sera of

patients with malignant disease. Therefore, they concluded

that the serum anti-p53 antibodies have low sensitivity but

100 % specificity for malignancy. Min Wu et al. [11]

compared 569 patients and 879 healthy subjects with dif-

ferent types of malignancy, serum p53 protein and serum

anti-p53 antibody. They found, the presence of p53 protein

in 4.22 % of the patients with malignant disease and

0.34 % of the healthy individuals. Likewise they found, the

presence of p53 antibody in 14.5 % of the patients with

malignant disease and 1.02 % of healthy individuals.

Eventually they said that serum p53 protein and p53 anti-

body can be associated with an increased cancer risk and

can be used as early serological markers in the diagnosis of

many malignant tumors except bladder cancer (such as

leukemia, lymphoma, osteosarcoma, nasopharyngeal, lung,

hepatocellular, esophageal, gastric, colorectal, biliary,

pancreatic, breast). In contrast p53 antibodies were nega-

tive in 90.6 % of patients in our study. Also, p53 antibodies

were negative in patients with dedifferentiated thyroid

cancer.

Differentiated thyroid cancers are usually curable, with

a good prognosis and slow progression. However, ana-

plastic thyroid cancers are very aggressive. Most anaplastic

carcinomas develop as a result of dedifferentiation or

progression of well-differentiated thyroid cancer, and sur-

vival is very short after the diagnosis [14–16]. Poorly dif-

ferentiated thyroid carcinomas are associated with

advanced age and large tumor size. Usually, this state is

accompanied by a loss of ability to take up iodine and

metastatic spread [17, 18]. Oncogene gain of function is the

most frequent molecular alteration described in thyroid

cancer. Loss of function of tumor suppressor proteins may

also occur in thyroid cancer and includes PAX-8/PPARcrearrangement, PTEN down-regulation, b-catenin, and p53

mutations [19]. According to a study on mice, loss of

functional p53 is the cause of anaplasia and invasiveness of

thyroid carcinomas [20]. p53 stimulates apoptosis by

stopping the division of mutant cells and when DNA is

damaged by carcinogenic would be effective. p53 expres-

sion in papillary and follicular cancers is lower than in

poorly differentiate and anaplastic cancers [6, 21, 22].

Miyake et al. [23] did not find p53 expression in 19 patients

with thyroid follicular adenoma. Hamzany et al. [24] did

not determine the p53 mutation in any of the patients with

PTC who died early (within 10 years after diagnosis).

Fagin et al. [8] reported that p53 mutations may cause a

loss of differentiated function and development of ATC. In

contrast, according to Donghi et al. [7] p53 gene alterations

do not represent a common genetic hallmark of thyroid

cancers. But, its relationship is high with PDTC and UTC

and most likely associated with tumor progression. Iodine

can induce apoptosis by induction of p21 and Bcl-xL and/

or reduction of mutant p53 in human thyroid cells [25].

According to immunohistochemical studies performed by

Zafon et al. [22] on 61 patients, p53 is seen more frequently

in tumors with RET/PTC? and extrathyroidal spread is

more frequent in papillary thyroid cancers with RET/

PTC?. In a study done by Kim et al. [26] in 86 patients

with thyroid cancer, p53 was detected in six of seven

(82.5 %) cases of anaplastic carcinoma, in one of nine

cases of poorly differentiated carcinoma and in one of

Table 3 The comparison of the positive rates of serum p53 anti-

bodies and the levels of serum Tg

p53 antibody

Positive Negative Total

Serum Tg \2 ng/ml 14 (19.9 %) 127 (90.1 %) 141

Serum Tg [2 ng/ml 2 (10.5 %) 17 (89.5 %) 19

16 144 160

Ann Nucl Med (2014) 28:42–46 45

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twenty cases of follicular carcinoma. In papillary (n = 40)

and medullary (n = 10) carcinomas, p53 was not detected.

Likewise, in the study of Quiros et al. [27] p53 mutation

was detected in eight of eight cases of ATC and BRAF

mutation in five of eight of cases ATC, whereas p53

mutation was not detected in PTC cells. Sobrinho-Simoes

et al. [28] found in their study that, there is p53 gene

mutation in approximately 26 % of PDTC and more than

60 % of UTC, whereas p53 gene is normal in more than

98 % of WDTC. BRAF and RAS mutations are common in

WDTC but p53 mutation is rare [19].

Differentiated thyroid cancers usually progress slowly.

So, dedifferentiation is a rare condition. The limitation of

our study was the limited number of patients with dedif-

ferentiated thyroid cancer. There was no statistically sig-

nificant relation between healthy individuals and thyroid

cancer patients in serum p53 antibodies rates. While

positive serum p53 antibodies are evaluated as evidence of

malignancy in the literature, we think that for the demon-

stration of dedifferentiation, the diagnostic value of serum

p53 antibody is low.

Acknowledgments The work was supported by grants from

Cumhuriyet University Scientific Research Project Unit (T-485).

Ethical standard The presented study had been submitted to

Cumhuriyet University Ethical Committee in order to be approved

and at same time for the registration to the national registry. We have

mentioned the registry number of the study as; ‘‘Ethical Commitee

registry number of the study: 28 December 2010-10/27/2010-03/03’’.

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