Radiol Oncol 2023; 57(3): 380-388. doi: 10.2478/raon-2023-0034
380
research article
Treatment and outcome of patients with 
Graves’ disease and metastatic differentiated 
thyroid cancer 
Nikola Besic
1,2
, Barbara Vidergar-Kralj
3
 
1
 Institute of Oncology Ljubljana, Ljubljana, Slovenia
2
 Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
3
 Department of Nuclear Medicine, Institute of Oncology Ljubljana, Ljubljana, Slovenia
Radiol Oncol 2023; 57(3): 380-388.
Received 21 March 2023 
Accepted 19 June 2023
Correspondence to: Prof. Nikola Bešić, M.D., Ph.D., Institute of Oncology Ljubljana, Zaloška 2, SI-1000 Ljubljana, Slovenia.  
E-mail: nbesic@onko-i.si 
Disclosure: No potential conflicts of interest were disclosed.
This is an open access article distributed under the terms of the CC-BY license (https://creativecommons.org/licenses/by/4.0/).
Background. The aim of the study was to report on the experience in a single tertiary cancer center about the treat-
ment and outcome of patients with Graves’ disease (GD) and metastatic thyroid cancer as compared with patients 
without GD in our country. 
Patients and methods. Altogether, 28 patients (8 males, 20 females; 49–85 years of age; median 74 years) were 
treated because of differentiated thyroid cancer and distant metastasis at the time of diagnosis during a 10-year 
period (from 2010 to 2019) in the Republic of Slovenia. The subject of our retrospective study were four patients (three 
men, one female; 64−76 years of age, median 73 years) who had Graves’ disease and metastatic thyroid cancer. 
Results. The mean age of patients without GD and with GD was 74 years and 71 years, respectively (p = 0.36). There 
was a trend for male predominance in patients with GD (p = 0.06). There was no statistical difference in size of primary 
tumors, pT stage or pN stage between the group of patients without GD and with GD. The median length of follow-up 
was 3.33 years (range 0.04–7.83) and 5-year disease-specific survival was 51%. One of four patients with GD and 14 of 
24 patients without GD died of thyroid cancer. There was no statistical difference in disease-specific survival between 
patients’ group of without GD and with GD (p = 0.59). 
Conclusions. In our country Slovenia, 14% of patients with metastatic differentiated thyroid carcinoma at the time 
of diagnosis had Graves’ disease. There was no difference in the treatment, outcome or survival of patients with GD 
in comparison to those without GD.
Key words: differentiated thyroid cancer; metastases; Graves’ disease; treatment
Introduction
Graves’ disease (GD) is a systemic autoimmune 
disease directly caused by circulating antibodies 
against TSH receptor (anti-TSH-R) that bind to the 
thyrotropin receptor (TSH-R), subsequently induc-
ing the production and release of thyroid hormone, 
proliferation of thyrocytes, and enlargement of the 
thyroid gland.
1,2
 High serum anti-TSH-R antibod-
ies were reported to stimulate the growth of thy-
roid cancer and metastasis.
3
 A recent meta-analysis 
demonstrated an increased risk of distant metasta-
sis at the time of cancer diagnosis in patients with 
differentiated thyroid cancer and GD in compari-
son to those without GD.
4
There are only limited data in the literature 
about treatment of patients who have Graves’ 
disease and metastatic thyroid cancer, probably 
because the prevalence of GD in patients with 
thyroid cancer is very low, and the present guide-
lines do not give specific recommendations for the 
treatment of patients with differentiated thyroid 

Radiol Oncol 2023; 57(3): 380-388.
Besic N and Vidergar-Kralj B / Graves’ disease in metastatic differentiated thyroid cancer 381
cancer who have GD.
5,6
 However, Pellegriti et al.
7
 
reported increased disease-specific mortality in 
patients with GD in comparison with matched eu-
thyroid patients with thyroid cancer. Recently, we 
reported on a case report of a patient with simulta-
neous hormone-active metastatic Hürthle cell thy-
roid cancer and Graves’ disease which was treated 
by a combined multimodal treatment, but despite 
treatment, the disease rapidly progressed and the 
patient died due to distant metastases 28 months 
from diagnosis.
8
 The aim of the study was to re-
port on experience in a single tertiary cancer center 
about the treatment and outcome of patients with 
Graves’ disease and metastatic thyroid cancer in 
comparison to those without Graves’ disease and 
metastatic thyroid cancer in our country Slovenia.
Patients and methods
Study population
There were 1524 patients (354 males and 1170 fe-
males, 11–91 years of age, median 51 years) with 
a differentiated thyroid carcinoma registered by 
The Cancer Registry of Republic of Slovenia dur-
ing a 10-year period (from 2010 to 2019). During 
this period, altogether 28 patients (eight males, 
20 females; 49–85 years of age; median 74 years) 
were treated because of differentiated thyroid 
cancer and distant metastasis at the time of di-
agnosis at our Institute. The subject of our retro-
spective study were four patients (three men, one 
female; 64–76 years of age, median 73 years) who 
had Graves’ disease and metastatic thyroid cancer. 
The Protocol Review Board and Ethics Committee 
of the Institute of Oncology on 9
th
 December 2020 
(ERID-KSOPKR-0082/2020, ERIDEK-0083/2020, 
ERIDNPVO-0040/2020) reviewed and approved 
the study, which was conducted in accordance with 
the ethical standards prescribed in the Declaration 
of Helsinki. For retrospective studies, informed 
consent is not necessary according to the nation-
al regulations. The need for consent was waived 
by the Institutional Review Board and Ethics 
Committee of the Institute of Oncology Ljubljana.
Thyrotoxicosis with concomitant thyroid can-
cer was detected in 5 of 28 patients with distant 
metastases. Anti-TSH-R antibodies were not meas-
ured in all our patients. However, anti-TSH-R anti-
bodies were measured in all patients with hyper-
functioning primary tumors or hyperfunctioning 
metastases. Elevated anti-TSH-R antibodies were 
detected in 4 of our 28 patients with distant metas-
tases. All four patients with GD had a hyperfunc-
tioning primary tumor as well as hyperfunction-
ing metastases. 
A chart review for each patient with distant me-
tastases was performed. All histological slides of 
our patients with metastatic differentiated thyroid 
cancer were examined by the pathologist experi-
enced in thyroid pathomorphology. Distant metas-
tases were diagnosed by clinical examination and 
additional diagnostic procedures, including lung 
and/or bone X-ray, ultrasonography, ultrasound 
guided fine-needle aspiration biopsy, radionuclide 
investigations with radioiodine and 
18
F-FDG PET/
CT, computed tomography, and/or nuclear mag-
netic resonance imaging. The tumor stage, pres-
ence of regional and/or distant metastases, as well 
as residual tumor after surgery were assessed by 
the 8
th
 edition of TNM clinical classification ac-
cording to the UICC criteria from 2017.
9
 Data on 
patients’ age, gender, disease history, presence of 
Graves’ disease, extent of cancer, histomorphologi-
cal characteristics, mode of cancer specific therapy, 
outcome, and survival were collected. The clinical 
and pathological characteristics of the tumors are 
presented in Table 1. The treatment of patients and 
their outcome are presented in Table 2.
The majority of patients received multimodal 
treatment. Surgery is the mainstay of the treat-
ment of primary tumors in differentiated thyroid 
cancer. All surgically treated patients had primary 
surgery and all other cancer-specific therapies 
(surgery, radioiodine (RAI) ablation of thyroid 
remnant, RAI therapy, external beam radiotherapy 
(EBRT) and/or systemic therapy) at the Institute 
of Oncology. All patients received therapy with 
L-thyroxine for TSH suppression.
Follow-up
All patients had a follow-up exam at our Institute at 
least twice per year. This consisted of obtaining med-
ical history, a physical examination, and determining 
serum Tg concentration. Imaging with radioiodine 
scintigraphy and/or 
18
F-FDG PET/CT, computed to-
mography, and/or nuclear magnetic resonance was 
conducted once a year. It was also conducted when-
ever Tg concentration increased or clinical symp-
toms suggested that the disease had progressed.
Survival
Cause-specific and overall survival was defined as 
the period from primary cancer treatment to death 
or the last follow-up. The median duration of fol-
low-up was 3.33 years (range 0.04–7.83 years).

Radiol Oncol 2023; 57(3): 380-388.
Besic N and Vidergar-Kralj B / Graves’ disease in metastatic differentiated thyroid cancer 382
Statistical analysis
The Student t-test or the Mann–Whitney U-test 
was used according to data distribution. The asso-
ciation between categorical variables was tested by 
the chi-square test or Fisher’s exact test, as appro-
priate. All comparisons were two-sided and a p-
value <0.05 was considered statistically significant. 
The survival curves were calculated according to 
the Kaplan-Meier method. A multivariate statis-
tical analysis was not performed because of the 
small number of patients. The statistical package 
PASW 18 (SPSS Inc., Chicago, IL, USA) was used 
for the analysis.
Results
Patients with Graves’ disease
A 71-year-old patient with GD was presented to 
a surgical oncologist because of a 2.3 cm primary 
papillary thyroid cancer with lung metastases. 
He had hyperthyroidism and GD after iodine ex-
posure, heart failure, generalized arteriosclerosis, 
gangrene of the lower extremity, and type 2 diabe-
tes. He had just had a myocardial infarction with 
stented coronary arteries. Due to the poor general 
condition and accompanying diseases, we did 
not decide on surgical intervention or oncological 
treatment. He died after two months due to dete-
rioration of heart function.
A total thyroidectomy was performed on a 
76-year-old patient with hyperthyroidism due to 
GD and cytological suspicion of papillary thyroid 
cancer. Before the operation, she received thyro-
static drugs. Histologically, it was a poorly dif-
ferentiated thyroid carcinoma, 6.5 cm in diameter 
with extensive capsular invasion, but no vascular 
invasion or extrathyroidal spread. The metasta-
ses were not functionally active. After hormonal 
withdrawal she received 150 mCi of RAI, which ac-
cumulated in the lungs, skeleton, left kidney and 
right paracolic area. After six months and another 
six months, she received 152 mCi and 145 mCi of 
RAI after hormonal withdrawal, which accumu-
lated in the same places. After nine months, she 
received the 4
th
 and last 152 mCi of radioiodine and 
accumulation was less intense. After another nine 
months, there was no more accumulation in the 
metastases on RAI whole body scan, and 18F-FDG 
PET-CT showed the progression in the 5
th
 left rib 
and right iliac bone. The patient was still asymp-
tomatic. The skeletal lesions with a progression of 
disease were treated with EBRT. Anti-TSH-R levels 
were elevated all the time. The Tg value fell from 
11982 ng/mL before surgery to 9598 ng/mL before 
the first RAI therapy, and then slowly declined. 
Titres of anti-Tg antibodies were not increased. At 
the time of progression 34 months after the first 
treatment, Tg value was only 280 ng/mL, anti-Tg 
antibodies were not increased, but TPO antibodies 
were increasing. Because the patient was asympto-
matic, the medical oncologist has not yet decided 
on systemic treatment and the patient has been 
on active surveillance for seven months since pro-
gression of the disease was diagnosed.
A 75-year-old patient was operated on after 
preparation with thiamazole for a pathological 
fracture of Th2 (Figure 1) and spinal stabilization 
was performed in October 2017. Postoperatively, 
he was irradiated in the area of the thoracic spine 
with sensitization with weekly low doses of vin-
blastine and doxorubicin. In December 2017 , a total 
thyroidectomy was performed. Histological exam-
ination showed a 7 x 5.5 cm oncocytic tumor with 
regressive changes after chemotherapy. In January 
2018, T3 hyperthyroidism occurred. In February 
2018, the patient received 151 mCi of RAI, which 
accumulated in many places in the spine. In March 
2018, the RAI non-avid tumor in the sternum and 
FIGURE 1. A 75-year-old patient was operated on after preparation with 
thiamazole for a pathological fracture of Th2. Spinal stabilization was performed.

Radiol Oncol 2023; 57(3): 380-388.
Besic N and Vidergar-Kralj B / Graves’ disease in metastatic differentiated thyroid cancer 383
in the right iliac bone was treated with EBRT. 
Because of side effects of bisphosphonates therapy, 
the patient discontinued this therapy. In August 
2018, he had T3 hyperthyroidism again. After 
preparation with thiamazole, he received 160 mCi 
of RAI in October 2018. It accumulated in the skel-
etal metastases. Due to poor accumulation of RAI 
in Th5, he was referred to a medical oncologist, 
who did not decide on systemic therapy. In March 
2019, he received 161 mCi RAI, the accumulation 
of RAI in metastases was less intense. In February 
2020, he was asymptomatic, but 18F-FDG PET-CT 
showed a progression of metastases, so therapy 
with 166 mCi of RAI was administered. Only 
some metastases accumulated RAI. In April 2020, 
MRI showed progression of metastasis in Th5 and 
again T3 hyperthyroidism was diagnosed, there-
fore therapy with sorafenib (200 mg + 400 mg) was 
initiated. Because of the side effects, the dose was 
reduced to half, which he tolerated better. But after 
four months, the patient stopped this therapy due 
to side effects. He was asymptomatic until April 
2022. At that time 18F-FDG PET-CT showed new 
metastases in the skeleton and T3 hyperthyroid-
ism recurred. Therapy with lenvatinib was initi-
ated on May 2022. For the first time since the be-
ginning of cancer treatment, anti-TSH-R levels fell 
to the normal level three months after initiation 
of treatment with lenvatinib. The level of Tg also 
dropped from 5838 ng/mL in May 2020 to 2360 ng/
mL in August 2022.
A 64-year-old male patient had clinical signs of 
hyperthyroidism and a tumor measuring 9 cm in 
diameter of the left thyroid lobe, metastatic neck 
lymph node and metastases in the lungs, mediasti-
num, and in the 8
th
 right rib measuring 20 x 5.6 x 
4.5 cm, in the left acetabulum measuring 9 x 9 x 3 
cm and in the skull measuring 5 x 4 x 2 cm.
8
 The 
TABLE 1. Clinical characteristics and pathological characteristics of tumors
Factor Subgroup
All patients
(N = 28)
Without Graves’ disease
 (N = 24)
With Graves’ disease
(N =4 )
p-value
Mean age of patients
(year)
73.86 74.25 71.50 0.359
Mean primary tumor size (cm) 5.604 5.483 6.325 0.355
Gender
Female
Male
20
8
19
5
1
3
0.058
Age
(years)
54 or less
55 or more
1
27
1
23
0
4
1.00
Hyperthyreosis at presentation
No
Yes
23
5
23
1
0
4
0.001
Functional metastases
No
Yes
26
2
24
0
2
2
0.016
Tumor diameter
(cm)
0-4
4.01 and more
9
19
8
16
1
3
1.00
pT tumor stage
pTx, pT1 or pT2
pT3
pT4
7
7
14
6
5
13
1
2
1
0.522
N stage
N0
N1 or N2
20
8
17
7
3
1
1.00
M stage
M0
M1
0
28
0
24
0
4
-
Type of metastases
Lung only
Bones and others
Lungs and others 
without bones
11
12
5
10
9
5
1
3
0
0.759
Single organ metastases
No
Yes
14
14
11
13
3
1
0.596
Tumor type
Papillary
Hürthle
Follicular
Poorly differentiated
14
6
5
3
12
4
5
3
1
2
0
1
0.279
Tumor differentiation
(N = 19)
Well
Moderate or poor
6
13
5
12
1
1
1.00

Radiol Oncol 2023; 57(3): 380-388.
Besic N and Vidergar-Kralj B / Graves’ disease in metastatic differentiated thyroid cancer 384
region of the left hip had been irradiated with con-
comitant doxorubicin 20 mg once weekly. When 
hyperthyroidism was controlled with thiamazole, 
a total thyroidectomy was performed. Persistent 
T3 hyperthyroidism, most likely caused by anti-
TSH-R stimulated T3 production in a large metas-
tasis in the 8
th
 right rib, was cured by rib resection. 
The patient was treated with three RAI therapies. 
But after a short interval, the disease progressed 
despite treatment with RAI and therapy with 
sorafenib. The patient died due to distant metas-
tases 28 months from the beginning of treatment.
Histology, age of patients and type of 
metastases
At presentation, 5 of 28 patients had hyperthyroid-
ism and four of them had GD. Two patients with 
GD had functional metastases.
Papillary carcinoma, Hürthle cell carcinoma, 
follicular and poorly differentiated thyroid car-
cinoma were diagnosed in 13, 6, 5 and 4 patients, 
respectively. Graves’ disease was present in two 
patients with Hürthle cell carcinoma, one with 
papillary and one with poorly differentiated thy-
roid carcinoma (p = 0.28).
The mean age of patients without GD and with 
GD was 74 years and 71 years, respectively. Age of 
patients with and without GD was not statistically 
different (p = 0.36). There was a trend for male pre-
dominance in patients with GD (p = 0.06). Mean 
primary tumor size in patients without GD and 
with GD was 5.5 and 6.3 cm, respectively (p = 0.36). 
There was no statistical difference in pT stage (p = 
0.52) or pN stage (p = 1.00) between the group of 
patients without GD and with GD.
Initial sites of metastases were: lungs in 24 cas-
es, bones in 12 cases, mediastinum in eight cases, 
TABLE 2. Treatment of patients and their outcome
Factor Subgroup
All patients
(N = 28)
Without Graves’ disease
 (N = 24)
With Graves’ 
disease
(N = 4)
p-value
Thyroid surgery
No
Yes
8
20
7
17
1
3
1.00
Thyroid surgical
procedure
Total or near-total thyroidectomy
Lobectomy or less
18
10
15
9
3
1
1.00
Residual tumor
after surgery
No surgery
R0 (without residual tumor)
R1
R2
8
11
2
7
7
9
2
6
1
2
0
1
0.916
Neck dissection
No
Yes
24
4
21
3
3
1
0.481
Surgery of distant 
metastases
No
Yes
26
2
24
0
2
2
0.016
RAI ablation
after surgery
No
Yes
10
18
9
15
1
3
1.00
Therapy with
RAI
No
Yes
10
18
9
15
1
3
1.00
EBRT to the neck
No
Yes
21
7
17
7
4
0
0.545
EBRT (any site)
No
Yes
15
13
13
11
2
2
1.00
Preoperative 
chemotherapy
No
Yes
25
3
23
1
2
2
0.045
Chemotherapy
No
Yes
22
6
20
4
2
2
0.191
Targeted therapy
No
Yes
18
10
16
8
2
2
0.601
Outcome
Alive with disease
Dead of disease
Dead of other causes
9
15
4
7
14
3
2
1
1
0.461
RAI = radioiodine

Radiol Oncol 2023; 57(3): 380-388.
Besic N and Vidergar-Kralj B / Graves’ disease in metastatic differentiated thyroid cancer 385
liver in two cases and skin in one case. Single and 
multiple organ metastases were present in 14 and 
14 patients, respectively. Lung metastases only, 
bone metastases only and skin metastases only 
were present in eleven patients, two patients and 
one patient, respectively. There was no statistical 
difference in distribution of metastases between 
patients without GD and with GD.
Treatment
Palliative treatment was only applied in four cases: 
in one due to severe comorbidities, and in three 
due to very advanced cancer. The data on the type 
of surgery for primary tumors and treatment of 
distant metastasis are listed in Table 2. Total or 
near-total thyroidectomy is considered a proper 
surgical procedure for thyroid cancer; however, it 
was performed in only 18 of 28 patients. It was not 
performed because of inoperable tumors (N = 8), 
very advanced age of the patient, severe comorbid-
ities (N = 1), or if the patient refused surgical proce-
dure (N = 1). Initial treatment in three patients with 
a locally advanced tumor was neoadjuvant chemo-
therapy. Tumor size decreased in all patients: by 
more than 30% in two patients, and by less than 
30% in one patient. Metastases in regional lymph 
nodes were surgically treated as a part of primary 
surgical procedure by functional radical neck dis-
section in four patients. Surgical treatment of dis-
tant metastases was more common in patients with 
GD in comparison to those without GD (p = 0.016). 
Surgical therapy of bone metastases was conduct-
ed on two patients: a resection of the 8
th
 right rib 
with hormone active metastases in one patient and 
a resection of metastasis in the 2
nd
 thoracic vertebra 
due to pathological fracture and narrowing of the 
spinal canal in another patient.
RAI was used for the ablation of thyroid rem-
nant tissue in 18 (64%) patients. The ablation dose 
was 3.4–4.8 GBq (92–129 mCi) of RAI. RAI was 
used also for treatment of distant metastases with 
empiric dose of 3.7–7.4 GBq (100–200 mCi) in 14 
patients. These 18 patients received altogether 31 
therapies with RAI (range 1– 4; median 2) and a 
dose 11.47–24.72 GBq (310–668 mCi; median 535 
mCi).
Altogether, six patients were treated with chem-
otherapy, while kinase inhibitors were used in ten 
patients. EBRT was done in a total of 13 patients, of 
whom seven received EBRT to the neck and supe-
rior mediastinum.
Survival
Patients were followed for 0.04–7.83 (median 3.33) 
years. Disease-specific survival of our 28 patients 
ranged from 0.04 to 7.83 years. The 5-year disease-
specific and overall survival was 51% and 44%, 
respectively. The 3-year disease-specific survival 
of patients with and without Graves’ disease were 
67% and 57%, respectively (Figure 2). The length of 
disease-specific survival in patients with and with-
out Graves’ disease was not statistically different 
(p = 0.59). The 3-year overall survival of patients 
with and without Graves’ disease were 50% and 
54%, respectively (Figure 3). The length of overall 
survival in patients with and without Graves’ dis-
ease was not statistically different (p=0.99).
In 18 patients who had total thyroidectomy and 
RAI therapy, the 5-year disease-specific and over-
all survival was 70% and 61%, respectively. The 
3-year disease-specific survival of patients with 
and without Graves’ disease were 66% and 81%, 
respectively. The length of disease-specific sur-
FIGURE 2. Disease-specific survival of patients with Graves’ disease (GD) and 
without GD.
FIGURE 3. Overall survival of patients with Graves’ disease (GD) and without GD.

Radiol Oncol 2023; 57(3): 380-388.
Besic N and Vidergar-Kralj B / Graves’ disease in metastatic differentiated thyroid cancer 386
vival in patients with and without Graves’ disease 
was not statistically different (p = 0.66). In these 
18 patients, the 3-year overall survival of patients 
with and without Graves’ disease were 66% and 
76%, respectively. The length of overall survival in 
patients with and without Graves’ disease was not 
statistically different (p = 0.91).
By the end of the study, nine patients were still 
alive (2.3-7.83 years, median 4.42 years), four pa-
tients died of causes unrelated to primary disease, 
while 15 patients died of thyroid carcinoma. Of the 
latter, eleven patients died of distant metastases, 
one of uncontrolled locoregional disease, and the 
remaining three patients died of distant and lo-
coregional progression of the disease. Two of four 
patients with Graves’ disease are alive, at the time 
of writing for 34 and 52 months. Both have slow 
progression of RAI non-avid metastases; one is on 
systemic multikinase inhibitor therapy, while the 
other is still asymptomatic and on active surveil-
lance before initiation of systemic therapy.
Discussion
The aim of our study was to report on our experi-
ence about the treatment and outcome of patients 
with Graves’ disease and metastatic thyroid can-
cer in comparison to those without Graves’ disease 
and metastatic thyroid cancer in our country. In 
our country, 14% of patients with metastatic dif-
ferentiated thyroid carcinoma at the time of diag-
nosis had Graves’ disease. There were no signifi-
cant differences in the oncological treatment of pa-
tients with GD in comparison to those without GD. 
Cancer-specific and overall survival of patients 
with GD was not significantly shorter in compari-
son to those without GD. 
Functioning metastatic thyroid carcinoma is a 
rare disease.
10
 Qiu et al.
10
 reported that the preva-
lence of hyperfunctioning metastases in patients 
with follicular thyroid carcinoma was 5/38 (13%). 
However, hyperfunctioning metastatic thyroid 
carcinoma with concomitant Graves’ disease is an 
even rarer condition. Our data show that it was 
present in 7% of patients with distant metastases 
at the time of diagnosis.
Treatment of patients with hyperfunctioning 
metastases of thyroid cancer and GD is a challeng-
ing task. For the treatment of patients with hy-
perfunctioning thyroid carcinoma, there are two 
aims: to control hyperthyroidism, as well as the 
cancer.
11
 Unfortunately, the current management 
guidelines for differentiated thyroid cancer does 
not recommend any specific management for pa-
tients with metastatic cancer and GD.
4,5
Liu et al.
11
 reported that total thyroidectomy 
may be the optimal primary treatment option for 
patients with functional primary tumor and me-
tastases which are not hyperfunctioning. In such 
cases a total thyroidectomy reduces the dose of 
RAI required to treat the metastatic lesions. But in 
patients with hyperfunctioning metastatic lesions 
with non-functioning primary thyroid carcinoma, 
a total thyroidectomy may lead to deterioration 
of hyperthyroidism, as the majority of hormones 
are produced by metastatic lesions.
11
 Such was 
the case in one of two of our patients with hyper-
functioning metastases. In a systematic review of 
the literature, Liu et al.
11
 reported that, after total 
or subtotal thyroidectomy, a transient improve-
ment of hyperthyroidism was obtained in only 
one of five patients, while in four patients, hyper-
thyroidism persisted. Furthermore, one of four 
patients succumbed to thyroid crisis 12 days af-
ter surgery. Likewise, Girelli et al.
12
 reported on a 
case of extremely severe hyperthyroidism due to 
pelvic bone metastasis in which hyperthyroidism 
worsened after total thyroidectomy and after the 
first dose of RAI. But in their case, the adminis-
tration of methimazole, prednisone and multiple, 
fractioned and small doses of radioiodine cured 
the hyperthyroidism and stabilized the neoplastic 
growth.
12
 Our experience is similar to the report by 
Liu et al.
11
, because after total thyroidectomy, hy-
perthyroidism persisted in both our patients with 
hyperfunctioning metastases. In one of them, ther-
apy with thiamazole, RAI therapy, a combination 
of EBRT and concomitant doxorubicin chemother-
apy cured hyperthyroidism caused by functional 
metastasis in bone metastasis in the sternum and 
pelvis. In the other patient, on the other hand, a 
surgical resection of the 8
th
 right rib in which func-
tional metastasis caused a T3 hyperthyroidism 
was needed in order to cure hyperthyroidism.
8
 
Our second case confirm the opinion, that in cases 
with a metastatic lesion which is resistant to RAI 
and the functioning lesion is resectable, surgery is 
a good treatment option.
11
RAI is an essential part of the treatment of hy-
perfunctioning metastatic lesions.
10
 But therapy 
with RAI in patients with functioning metastases 
may result in thyroid storm and death.
11,13
 To avoid 
a possible thyroid storm, antithyroid medication is 
required before treatment with RAI.
11
 In the litera-
ture review, Fu et al.
14
 reported that activity of RAI 
to treat hyperfunctioning metastases varied from 
13 mCi to 200 mCi.
14-17
 Severe hyperthyroidism can 

Radiol Oncol 2023; 57(3): 380-388.
Besic N and Vidergar-Kralj B / Graves’ disease in metastatic differentiated thyroid cancer 387
be improved with repeated low-dose radioiodine 
therapy.
16
 High doses of RAI could cause a large 
amount of tumor cell destruction, releasing a burst 
of thyroid hormones and causing thyrotoxic storm 
if the patients are not adequately prepared before 
and treated after RAI.
14
 Glucocorticoids and an-
tithyroid medications should be used prior to sur-
gery and RAI treatment to avoid the occurrence of 
thyrotoxic storm, as well as during RAI treatment 
in order to inhibit thyroid hormone synthesis and 
peripheral conversion of T4 to T3.
13
Another effective evolving treatment modality 
for progressive metastatic thyroid cancer is sys-
temic therapy.
8,18
 Systemic therapy with a multi-
kinase inhibitor, sorafenib, was effective in two of 
our patients. The effect before cancer progression 
lasted eight and 24 months. Furthermore, hyper-
thyroidism was also prevented after therapy with 
sorafenib in both cases. In one of them, sorafenib 
was stopped due to side effects after four months. 
After progression of the disease and recurrence of 
hyperthyroidism, lenvatinib effectively prevented 
disease progression and cured hyperthyroidism. 
Also, Danilovic et al.
18
 described that targeted ther-
apy with lenvatinib is an option for the control of 
hyperfunctioning metastases.
External beam radiotherapy is the treatment of 
choice for inoperable distant metastases and/or 
large functional metastases. Unfortunately, it does 
not always prevent hyperthyroidism.
16
Premoli et al.
19
 reported that there was no as-
sociation between baseline anti-TSH-R levels and 
outcome in patients with differentiated thyroid 
carcinoma associated with GD. But, Valenta et al.
20
 
reported that in one of three patients with meta-
static follicular thyroid cancer-causing hyperthy-
roidism associated with elevated anti-TSH-R, level 
of anti-TSH-R declined after two RAI treatments 
with improvement in thyrotoxicosis. Also, Basaria 
et al.
21
 reported in a patient with functional metas-
tases of papillary thyroid cancer and GD, a decline 
in the level of anti-TSH-R to 87% of normal range 
after three RAI therapies. The effect of RAI thera-
py was confirmed with CT investigation and with 
decrease of thyroglobulin level which on TSH sup-
pression declined from 2280 ng/dL to 55 ng/dL.
21
 In 
three of our patients with GD, levels of anti-TSH-R 
have not declined after therapy with RAI or with 
sorafenib. However, three months after initiation 
of therapy with lenvatinib, the level of anti-TSH-R 
declined dramatically in the patient.
One of the aims of our study was to compare 
outcome of patients with and without GD. Median 
survival of our patients with differentiated thyroid 
cancer with GD was 31 months. The 3-year disease-
specific survival of patients with and without GD 
were 67% and 57%, respectively. The length of dis-
ease-specific survival in patients with and with-
out GD was not statistically different (p = 0.59). 
Similar survival was reported by Als et al.
22
 who 
treated five patients with functional metastatic 
differentiated carcinoma with median survival of 
39 months. Our results are also in agreement with 
a systematic review and meta-analysis of 25 stud-
ies which included 987 patients with differentiated 
thyroid cancer with GD and 2,064 patients with 
differentiated thyroid cancer without GD, which 
showed no difference in cancer related mortality 
and recurrence/persistence during follow-up.
4
Our study has several limitations. The first limi-
tation is the retrospective nature. Another limita-
tion is a low number of all cases with metastatic 
thyroid cancer. Furthermore, only two of four pa-
tients with GD had hyperfunctioning metastases. 
However, to our knowledge, there are no data in 
the literature about the national incidence of pa-
tients with metastatic thyroid cancer and concomi-
tant GD. Furthermore, notification of cancer has 
been compulsory in Slovenia since the foundation 
of the Cancer Registry of Republic of Slovenia in 
1950 and prescribed by law
23
, so our data about in-
cidences represent reliable population-based data. 
Additionally, all patients with thyroid cancer are 
treated at the Institute of Oncology in Ljubljana, so 
our data represent a population-based incidence of 
GD among patients with metastatic differentiated 
thyroid cancer.
Conclusions
In our country, 14% of patients with metastatic dif-
ferentiated thyroid carcinoma at the time of diag-
nosis had GD. There was a trend for male predomi-
nance in patients with GD. Treatment of patients 
with metastatic differentiated thyroid carcinoma at 
the time of diagnosis who have GD is multidisci-
plinary and includes surgical therapy, RAI thera-
py, systemic therapy and/or EBRT. There were no 
significant differences in the oncological treatment 
of patients with GD in comparison to those with-
out GD. Cancer-specific and overall survival of 
patients with GD was not significantly shorter in 
comparison to those without GD.

Radiol Oncol 2023; 57(3): 380-388.
Besic N and Vidergar-Kralj B / Graves’ disease in metastatic differentiated thyroid cancer 388
Acknowledgements
This research was funded by the Ministry of 
Education, Science and Sport of the Republic of 
Slovenia. Grant P3-0289. Principal investigator: 
Nikola Besic.
We are grateful to all our colleagues from the 
Institute of Oncology Ljubljana and Department of 
Nuclear Medicine from University Clinical Centre 
Ljubljana for their advice on treating patients and 
technical assistance. 
References
1. Kahaly GJ. Management of Graves thyroidal and extrathyroidal disease: an 
update. J Clin Endocrinol Metab 2020; 105: 3704-20. doi: 10.1210/clinem/
dgaa646
2. Smith TJ, Hegedüs L. Graves’ disease. N Engl J Med 2016; 375: 1552-65. doi: 
10.1056/NEJMra1510030
3. Mazzaferri EL. Thyroid cancer and Graves’ disease. J Clin Endocrinol Metab 
1990; 70: 826-9. doi: 10.1210/jcem-70-4-826
4. Mekraksakit P, Rattanawong P, Karnchanasorn R, Kanitsoraphan C, 
Leelaviwat N, Poonsombudlert K, et al. Prognosis of differentiated thyroid 
carcinoma in patients with Graves’ disease: a systematic review and meta-
analysis. Endocr Pract 2019; 25: 1323-37. doi: 10.4158/EP-2019-0201
5. Haugen BR, Alexander EK, Bible KC, Doherty GM, Mandel SJ, Nikiforov 
YE, et al. 2015 American Thyroid Association Management Guidelines for 
adult patients with thyroid nodules and differentiated thyroid cancer: The 
American Thyroid Association Guidelines Task Force on Thyroid Nodules 
and Differentiated Thyroid Cancer. Thyroid 2016; 26: 1-133. doi: 10.1089/
thy.2015.0020
6. Filetti S, Durante C, Hartl D, Leboulleux S, Locati LD, Newbold K, et al. 
Thyroid cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment 
and follow-up. Ann Oncol 2019; 30: 1856-83. doi: 10.1093/annonc/mdz400
7. Pellegriti G, Mannarino C, Russo M, Leboulleux S, Locati LD, Newbold K, et 
al. Increased mortality in patients with differentiated thyroid cancer associ-
ated with Graves’ disease. J Clin Endocrinol Metab 2013; 98: 1014-21. doi: 
10.1210/jc.2012-2843
8. Besic N, Vidergar-Kralj B, Zaletel K, Grasic-Kuhar C. Graves’ disease and met-
astatic hormonal-active Hürthle cell thyroid cancer: a case report. Medicine 
2021; 100: e26384. doi: 10.1097/MD.0000000000026384
9. Sobin L, Gospodarowicz MK, Wittekind C. TNM Classification of Malignant 
Tumours. 7th edition. Hoboken, USA: John Wiley & Sons; 2009.
10. Qiu ZL, Shen CT , Luo QY . Clinical management and outcomes in patients with 
hyperfunctioning distant metastases from differentiated thyroid cancer 
after total thyroidectomy and radioactive iodine therapy. Thyroid 2015; 25: 
229-37. doi: 10.1089/thy.2014.0233
11. Liu J, Wang Y , Da D, Zheng M. Hyperfunctioning thyroid carcinoma: a system-
atic review. Mol Clin Oncol 2019; 11: 535-50. doi: 10.3892/mco.2019.1927
12. Girelli ME, Casara D, Rubello D, Pelizzo MR, Busnardo B, Ziliotto D. Severe 
hyperthyroidism due to metastatic papillary thyroid carcinoma with favora-
ble outcome. J Endocrinol Invest 1990; 13: 333-7. doi: 10.1007/BF03349573
13. Cerletty JM, Listwan WJ. Hyperthyroidism due to functioning metastatic thy-
roid carcinoma. Precipitation of thyroid storm with therapeutic radioactive 
iodine. JAMA 1979; 242: 269-70. doi: 10.1001/jama.1979.03300030041020
14. Fu H, Cheng L, Jin Y , Chen L. Thyrotoxicosis with concomitant thyroid cancer. 
Endocr Relat Cancer 2019; 26: R395-413. doi: 10.1530/ERC-19-0129
15. Tan J, Zhang G, Xu W, Meng Z, Dong F, Zhang F, et al. Thyrotoxicosis due to 
functioning metastatic follicular thyroid carcinoma after twelve I-131 thera-
pies. Clin Nucl Med 2009; 34: 615-9. doi: 10.1097/RLU.0b013e3181b06b2d
16. Nishihara E, Amino N, Miyauchi A. Fractionated radioiodine therapy for 
hyperthyroidism caused by widespread metastatic follicular thyroid carci-
noma. Thyroid 2010; 20: 569-70. doi: 10.1089/thy.2009.0460
17. Kunawudhi A, Promteangtrong C, Chotipanich C. A case report of hyper-
functioning metastatic thyroid cancer and rare I-131 avid liver metastasis. 
Indian J Nucl Med 2016; 31: 210-14. doi: 10.4103/0972-3919.183616.
18. Danilovic DL, de Camargo RY , Castro G Jr, Papadia C, Marui S, Hoff AO, et al. 
Rapid control of T3 thyrotoxicosis in patients with metastatic follicular thy-
roid cancer treated with lenvatinib. Thyroid 2015; 25: 1262-4. doi: 10.1089/
thy.2015.0167. 
19. Premoli P, Tanda ML, Piantanida E, Veronesi G, Gallo D, Masiello E, et al. 
Features and outcome of differentiated thyroid carcinoma associated 
with Graves’ disease: results of a large, retrospective, multicenter study. 
J Endocrinol Invest 2020; 43: 109-16. doi: 10.1007/s40618-019-01088-5
20. Valenta L, Lemarchand-Béraud T, Nĕmec J, Griessen M, Bednár J. Metastatic 
thyroid carcinoma provoking hyperthyroidism, with elevated circulating thy-
rostimulators. Am J Med 1970; 48: 72-6. doi: 10.1016/0002-9343(70)90100-2
21. Basaria S, Salvatori R. Thyrotoxicosis due to metastatic papillary thyroid can-
cer in a patient with Graves’ disease. J Endocrinol Invest 2002; 25: 639-42. 
doi: 10.1007/BF03345090
22. Als C, Gedeon P, Rösler H, Minder C, Netzer P, Laissue JA, et al. Survival 
analysis of 19 patients with toxic thyroid carcinoma. J Clin Endocrinol Metab 
2002; 87: 4122-7. doi: 10.1210/jc.2001-011147
23. Epidemiology and Cancer Registry. Ljubljana: Institute of Oncology 
Ljubljana. [cited 2019 Aug 28]. Available at: https:// www.onko-i.si/eng/
sectors/epidemiology-and-cancer-registry