10.14639/0392-100X-N1034
Objectives. PAX8/PPARG chromosomal rearrangement is frequently seen in thyroid cancer, and PPARG overexpression has been shown in the follicular variant of papillary thyroid carcinoma, but not in papillary thyroid carcinoma other than the follicular variant. The main aim of this study was to investigate the frequency of PPARG overexpression among papillary thyroid carcinoma and if there were any variants of papillary thyroid carcinoma with PPARG overexpression other than the follicular variant. Methods. Immunohistochemical analysis of PPARG overexpression was performed using a PPARG monoclonal antibody in a series of 111 paraffin-embedded blocks of thyroid tumours. Of the patients in our study, 100 were diagnosed with papillary thyroid carcinoma, 9 with follicular adenoma and 2 with follicular carcinoma. Results. PPARG staining was detected in 19 of the 111 cases. Sixteen patients with PPARG overexpression had papillary thyroid carcinoma and 3 had follicular adenoma. Conclusions. PPARG overexpression was detected mainly in follicular-variant papillary thyroid carcinoma. Vascular invasion, lymphatic invasion, thyroid capsule invasion and lymph node positivity were lower in patients with PPARG overexpression.
text/xml
1827-675X
1034
en
Orhan Asya
http://creativecommons.org/licenses/by-nc-nd/4.0
ACTA Otorhinolaryngologica Italica
pioglitazone
Relationship of PPARG overexpression with prognostic parameters in papillary thyroid carcinoma
Text.Serial.Journal
https://www.actaitalica.it/
42
Thyroid
2022-03-07
2020-07-30
2022-03-07
2022-03-07
34-40
1
Çağatay Oysu
2022/03/07
10.14639/0392-100X-N1034
34
Department of Otolaryngology, Marmara University Pendik Training and Research Hospital, Istanbul, Turkey
1827-675X
pioglitazone
40
Relationship of PPARG overexpression with prognostic parameters in papillary thyroid carcinoma
https://www.actaitalica.it/article/download/1034/738
42
ACTA OTORHINOLARYNGOLOGICA ITALICA 2022;42:34-40; doi: 10.14639/0392-100X-N1034




Thyroid


Relationship of PPARG overexpression with
prognostic parameters in papillary thyroid carcinoma
Correlazione fra iperespressione della proteina PPARG e parametri prognostici
nel carcinoma papillare della tiroide
Orhan Asya1, Ali Cemal Yumuşakhuylu1, Pelin Bağcı2, Handan Kaya2, Ayşegül Gönen1, Yavuz Gündoğdu1,
Tajaddın Muradov1, Akın Şahin1, Çağatay Oysu1
1
 Department of Otolaryngology, Marmara University Pendik Training and Research Hospital, Istanbul, Turkey; 2 Department of
Pathology, Marmara University Pendik Training and Research Hospital, Istanbul, Turkey


SUMMARY
Objectives. PAX8/PPARG chromosomal rearrangement is frequently seen in thyroid can-
cer, and PPARG overexpression has been shown in the follicular variant of papillary thyroid
carcinoma, but not in papillary thyroid carcinoma other than the follicular variant. The main
aim of this study was to investigate the frequency of PPARG overexpression among papil-
lary thyroid carcinoma and if there were any variants of papillary thyroid carcinoma with
PPARG overexpression other than the follicular variant.
Methods. Immunohistochemical analysis of PPARG overexpression was performed using
a PPARG monoclonal antibody in a series of 111 paraffin-embedded blocks of thyroid tu-
mours. Of the patients in our study, 100 were diagnosed with papillary thyroid carcinoma,
9 with follicular adenoma and 2 with follicular carcinoma.
Results. PPARG staining was detected in 19 of the 111 cases. Sixteen patients with PPARG
overexpression had papillary thyroid carcinoma and 3 had follicular adenoma.
Conclusion. PPARG overexpression was detected mainly in follicular-variant papillary
thyroid carcinoma. Vascular invasion, lymphatic invasion, thyroid capsule invasion and
lymph node positivity were lower in patients with PPARG overexpression.
                                                                                                    Received: July 30, 2021
KEY WORDS: papillary thyroid carcinoma, PPARG overexpression, prognostic parameters,
                                                                                                    Accepted: October 11, 2021
PAX8/PPARG fusion protein (PPFP), pioglitazone
                                                                                                    Correspondence
RIASSUNTO                                                                                           Orhan Asya
Obiettivi. Il riarrangiamento cromosomico PAX8/PPARG è frequentemente osservato nel                 Marmara University Hospital, Muhsin Yazıcıoğlu
cancro della tiroide, la sovraespressione della proteina PPARG è stata già dimostrata nella         Street, 34899, Pendik, İstanbul, Turkey
                                                                                                    Tel. +90 5418125013
variante follicolare del carcinoma papillare della tiroide, ma non nelle varianti del carci-        E-mail: orhan4913@gmail.com
noma papillare della tiroide, diverse da quella follicolare. L’obiettivo principale di questo
studio è stato quello di indagare la sovraespressione di PPARG nel carcinoma papillare
della tiroide e se ci sia qualche variante del carcinoma papillare della tiroide, diversa da          How to cite this article: Asya O, Yumuşakhuylu
                                                                                                      AC, Bağcı P, et al. Relationship of PPARG
quella follicolare, con sovraespressione di PPARG.
                                                                                                      overexpression with prognostic parameters
Metodi. È stata eseguita una analisi immunoistochimica della sovraespressione di PPARG,               in papillary thyroid carcinoma. Acta Otorhi-
utilizzando un anticorpo monoclonale PPARG in una serie di 111 campioni di tumori ti-                 nolaryngol Ital 2022;42:34-40. https://doi.
roidei inclusi in paraffina. In 100 casi, è stato diagnosticato un carcinoma papillare della          org/10.14639/0392-100X-N1034
tiroide, in 9, adenoma follicolare e 2, carcinoma follicolare.
Risultati. La proteina PPARG è stata rilevata in 19 dei 111 casi. Sedici di quei pazienti con       © Società Italiana di Otorinolaringoiatria
sovraespressione di PPARG avevano carcinoma papillare della tiroide e 3 pazienti avevano            e Chirurgia Cervico-Facciale
adenoma follicolare.
Conclusione. La sovraespressione di PPARG è stata rilevata principalmente nella variante                           OPEN ACCESS

follicolare del carcinoma papillare della tiroide. L’invasione vascolare, l’invasione linfati-      This is an open access article distributed in accordance with
ca, l’invasione della capsula tiroidea e la positività dei linfonodi sono risultate inferiori nei   the CC-BY-NC-ND (Creative Commons Attribution-Non-
                                                                                                    Commercial-NoDerivatives 4.0 International) license. The
pazienti con sovraespressione di PPARG.                                                             article can be used by giving appropriate credit and mentio-
                                                                                                    ning the license, but only for non-commercial purposes and
PAROLE CHIAVE: carcinoma papillare della tiroide, sovraespressione di PPARG,                        only in the original version. For further information: https://
parametri prognostici, proteina di fusione PAX8/PPARG (PPFP), pioglitazone                          creativecommons.org/licenses/by-nc-nd/4.0/deed.en




34
                                                                                     Papillary thyroid carcinoma and PPARG overexpression




Introduction                                                    patients, FA in 9 patients and FTC in 2 patients. Pathology
                                                                reports and haematoxylin and eosin (H&E) slides of all
The majority of thyroid cancers are well-differentiated tu-
                                                                patients were obtained from the archives of the Depart-
mours that develop from thyroid follicular cells 1. These
                                                                ment of Pathology. The preoperative examination, intra-
tumours are histologically classified as papillary thyroid
                                                                operative surgical findings and postoperative follow-up
carcinoma (PTC), follicular thyroid carcinoma (FTC) and
                                                                findings of the patients were obtained by accessing medi-
Hurthle cell carcinoma 2. Of all thyroid cancers, 79% are
                                                                cal records.
PTC, 13% FTC and 3% Hurthle cell carcinoma 1. The prog-
nosis is excellent in most patients with well-differentiated
                                                                Pathological evaluation and immunohistochemistry
thyroid carcinomas who receive proper diagnosis and treat-
                                                                Haematoxylin-eosin stained slides of 111 patients with
ment. The 5-year relative survival in PTC is higher than
99% in women at age 15-55 years and higher than 96% in          PTC, FTC, or FA were re-examined by a pathologist expe-
men at age 15-55 years 3. Some subtypes of well-differ-         rienced on thyroid (P.B.), who was blinded to the patient’s
entiated thyroid cancers are known to be more aggressive,       clinical information and pathology results. In addition to
and clinical and pathological prognostic factors are helpful    the thyroid, slides of metastatic foci (neck metastases) were
in determining which patients will develop aggressive or        also examined. Tumour foci that were suitable for IHC
recurrent disease 4.                                            were marked and highlighted. Two distinct tumour foci
The PAX8/PPARG oncogene occurs as a result of stable            were marked for each patient on at least 2 separate slides.
translocation between PAX8, a transcription factor required     The paraffin blocks of the selected slides were pulled from
for thyroid differentiation, and peroxisome proliferator re-    the archives of pathology.
ceptor gamma (PPARG), a member of the steroid/thyroid           All IHC staining processes, including deparaffinisation
nuclear receptor family (t [2; 3] [q13; p25]) 5. The exist-     and antigen retrieval, were performed on a fully automated
ence of this translocation was detected only in FTC and         staining device (Ventana BenchMark Ultra, Ventana Medi-
follicular adenoma (FA) in one study 6, whereas in other        cal Systems, Tucson, AZ, USA). Cross-sections were incu-
studies the translocation was also detected in the follicular   bated for 30 minutes at 1/800 dilution with PPARG rabbit
variant of PTC (FVPTC) 5,7. In the study by Nikiforova et       monoclonal antibody (Cell Signaling, Danvers, MA, USA).
al., it was observed that FTCs with PAX8/PPARG translo-         Nuclear staining in omental adipose tissue of 3 patients
cation were associated with more aggressive pathological        without thyroid carcinoma was used as the external control
prognostic parameters 6. The translocation of PPARG has         as defined in the user manual by the manufacturer. Similar-
been shown with PCR-based methods with better clarity,          ly, nuclear staining of perithyroidal fat cells was observed
although the technique is too expensive to apply in all labo-   in some of the thyroid specimens and used as an internal
ratories and settings. Immunohistochemistry (IHC) is an         control.
easy and inexpensive method to reveal protein expression        PPARG monoclonal antibody staining was scored as weak
in tissues and cells.                                           (1+), moderate (2+), or strong (3+) and as focal (less than
In this study, we investigated the presence of PPARG            half of tumour cells were stained) or diffuse (more than half
overexpression in PTC, FTC and FA with IHC. We also             of tumour cells were stained) (Tab. I) 6.
evaluated the histologic subtypes of tumours with PPARG
overexpression and the relationship with prognostic param-      Statistical analysis
eters. The present study was performed to investigate the       IBM SPSS version 15 was used to perform the analysis.
frequency of PPARG overexpression among PTC and if              When descriptive analysis was presented, mean, stand-
there were any variants of PTC with PPARG overexpres-           ard deviation, median and 25-75 percentile values were
sion other than the follicular variant.

                                                                Table I. Immunohistochemical scoring of tumours stained with PPARG.
Materials and methods
                                                                             Staining and score of stained tumour cells
Patient selection                                               Strong staining                                    3+
Pathology specimens were examined from 124 patients             Moderate staining                                  2+
who had thyroid surgery during 2012-2017 at a single ter-
                                                                Weak staining                                      1+
tiary referral centre with a diagnoses of PTC, FTC, or FA.
                                                                                    Percentage of tumour cells stained
Thirteen patients were excluded because the tumour focus
was too small for IHC analysis, and thus a total of 111         Diffuse staining                      > 50% of tumour cells positive
patients were included. Of these, PTC was found in 100          Focal staining                        < 50% of tumour cells positive




                                                                                                                                       35
O. Asya et al.




Table II. Number of cases stained with PPARG antibody in IHC and degree
of staining.
                                                     n          %
 PPARG staining                   Positive          19        (17.1)
                                 Negative           92        (82.9)
 Degree of PPARG staining   1 + diffuse staining     5         (4.5)
                            2 + diffuse staining    10         (9.0)
                            3 + diffuse staining     3         (2.7)
                            3 + focal staining       1         (0.9)
                                No staining         92        (82.9)



used. The normal distribution of variables was examined
by histogram graphs and the Kolmogorov-Smirnov test.
When normally distributed (parametrical) variables were                   Figure 1. Nuclear staining of omental adipose tissue cells with PPARG mon-
compared between groups, the one-way analysis of vari-                    oclonal antibody (external control), X40.
ance (ANOVA) test was used. Post hoc analysis was done
according to PPARG staining of tumour cells between the
PTC classical and follicular variants. Chi-square and Fish-
er’s exact tests were used to compare categorical data. For
statistical significance, p < 0.05 was accepted.

Results
The study included 111 patients, of whom 33 were men
(29.7%) and 78 women (70.3%). The mean age of patients
was 42.0 ± 15.3 years. Nineteen of the 111 cases were
stained with PPARG monoclonal antibody (Tab. II). Among
these 19 cases, nuclear staining was found in only one case
with PTC classical variant, and in all other 18 cases there
was cytoplasmic staining of tumour cells (Figs. 1-3).
The pathological prognostic parameters of patients were
examined according to PPARG monoclonal antibody stain-                    Figure 2. Diffuse 3+ cytoplasmic staining of tumour cells with PPARG mono-
                                                                          clonal antibody, X20.
ing. According to a post-hoc analysis, PPARG staining was
higher in FVPTC than in the classical variant. Vascular in-
vasion (p = 0.039), lymphatic invasion (p = 0.019) and thy-
roid capsule invasion (p = 0.002) were found to be lower in
patients with PPARG staining (Tab. III).
There was no lymph node metastasis in any tumour that
stained with PPARG monoclonal antibody in our case se-
ries (p = 0.012). Lymph node metastasis was detected in 22
of 111 patients. Nuclear or cytoplasmic PPARG immuno-
reactivity was not observed in any of these 22 cases. There-
fore, we could not examine whether there is a relationship
between PPARG and lymph node positive or negative cases
in terms of recurrence. There was no relationship between
tumour size and positive staining of tumours (p = 0.654)
(Tab. IV).
There was also no relationship between PPARG positive
tumours and stage, postoperative need of radioactive iodine               Figure 3. Focal nuclear staining of tumour cells with PPARG monoclonal
(RAI), or recurrence (p > 0.05). There was no statistically               antibody, X40.



36
                                                                                                                  Papillary thyroid carcinoma and PPARG overexpression




Table III. Histological types of tumours stained with PPARG and relationship with pathological prognostic parameters.
                                                                                                            PPARG staining                                    p
                                                                                                              Positive                  Negative
                                                                                                          n              %          n              %
    Histopathology                                                    Classical variant of PTC            2           10.5         48           52.2        0.004b
                                                                              FVPTC                      9           47.4          19           20.7
                                                                       Other variants of PTC             5           26.3          17           18.5
                                                                                 FA                      3           15.8           6            6.5
                                                                                FTC                      0            0.0           2            2.2
    Vascular invasion                                                         Positive                   1            5.3          26           28.3        0.039b
                                                                             Negative                    18          94.7          66           71.7
    Lymphatic invasion                                                        Positive                   1            5.3          29           31.5        0.019a
                                                                             Negative                    18          94.7          63           68.5
    Perineural invasion                                                       Positive                   0            0.0          13           14.1        0.120b
                                                                             Negative                    19          100.0         79           85.9
    Thyroid capsule invasion                                                  Positive                   3           15.8          51           55.4        0.002a
                                                                             Negative                    16          84.2          41           44.6
    Extrathyroidal soft tissue invasion                                       Positive                   3           15.8          26           28.3        0.391b
                                                                             Negative                    16          84.2          66           71.7
a
    Chi-square test, b Fisher’s exact test (n: number of patients; %: percentage of patients).



Table IV. Relationship of PPARG positive tumours with tumour size, lymph node metastasis and distant metastasis.
                                                                                                         PPARG staining                                       p
                                                                                                              Positive                  Negative
                                                                                                          n              %          n              %
    T (tumour size)                                                             T1a                       4           21.1         18           19.6        0.654a
                                                                                T1b                       9           47.4         35           38.0
                                                                                 T2                       2           10.5         22           23.9
                                                                                T3a                       1           5.3           8            8.7
                                                                                T3b                       0           0.0           2            2.2
                                                                                T4a                       0           0.0           1            1.1
                                                                                 FA                       3          15.8           6            6.5
    N (lymph node)                                                               Nx                      16          84.2          64           69.5        0.166a
                                                                                N0a                       3           15.8          6            6.5
                                                                                N0b                       0           0.0           0            0.0
                                                                                N1a                       0           0.0           8            8.7
                                                                                N1b                       0           0.0          14           15.3
    M (metastasis)                                                              M0                       19          100.0         88           95.7       > 0.999a
                                                                                M1                        0            0.0          4            4.3
    Lymph node positivity                                                     Negative                   19          100.0         70           76.1        0.012a
                                                                              Positive                    0            0.0         22           23.9
a
    Fisher’s exact test.




significant difference between PPARG staining and multi-                                         sociation (ATA) Guideline for thyroid nodule sonographic
focality or multicentricity (p > 0.05).                                                          patterns and estimated risk of malignancy. PPARG-positive
The ultrasonographic characteristics of tumour nodules                                           tumours were found to be more related with low-to-moder-
were investigated according to the American Thyroid As-                                          ate risk nodules (p = 0.009) (Fig. 4).



                                                                                                                                                                     37
O. Asya et al.




                                                                           forov et al., PPARG overexpression was found in FTC and
                                                                           FA, but not detected in PTC 6. In that study, the authors
                                                                           pointed out that PAX8/PPARG translocation may be spe-
                                                                           cific to follicular lesions of the thyroid gland and may be
                                                                           used as a molecular marker. In addition, it was reported that
                                                                           FTC cases with this translocation showed a more aggres-
                                                                           sive growth pattern and more vascular invasion 6. In a study
                                                                           by Wreesmann et al., PPARG overexpression was detected
                                                                           in FVPTC as well as in FTC and FA 10. In that study, an
                                                                           immunohistochemical analysis of PPARG monoclonal an-
                                                                           tibody was performed, and PPARG overexpression was de-
                                                                           tected in 2 of 3 patients with FTC, in 8 of 11 patients with
Figure 4. Relationship between PPARG staining and ATA nodule sonographic
                                                                           FA and in 3 of 17 cases with FVPTC, but not detected in
patterns and risk of malignancy.                                           any of the 25 cases with the classical variant of PTC. In our
                                                                           study, PPARG overexpression was detected in some cases
                                                                           with FA, as in the literature, but, in contrast, there was no
Discussion                                                                 overexpression in the 2 FTC cases in our database. PPARG
                                                                           overexpression in FVPTC has been shown in some studies
PPARG staining was detected in 19 of 111 cases studied                     but not in others, while it was observed in 9 of 28 patients
herein. Sixteen of the patients with PPARG overexpression                  with FVPTC in our study. In contrast to what is known in
had PTC (9 follicular variant, 3 oncocytic variant, 2 classi-              the literature, PPARG overexpression was also found in
cal variant, 1 solid variant and 1 Warthin-like variant), and              PTC variants other than the follicular variant in our series.
3 patients had FA.                                                         Although the immunohistochemical detection of PPARG
Even though nuclear staining of PPARG has been found to                    overexpression in tumour cells may be a sign of PAX8/
be meaningful in recent studies 6,8, 18 of our cases showed                PPARG translocation, a definitive diagnosis is established
cytoplasmic staining as well. The antibody used in the im-                 by RT-PCR or FISH. In addition, Nikiforova et al. reported
munohistochemistry was a monoclonal antibody which                         that they detected PAX8/PPARG rearrangement in all tu-
means it has less background staining and higher specific-                 mours that stained diffuse and strong with PPARG mon-
ity for the target compared to polyclonal antibodies. Omen-                oclonal antibody, but not in patients with focal or weak
tal tissues of non-PTC cases were used as external controls,               staining 6. In the context of that study, we detected diffuse
and perithyroidal fat tissues were used as internal controls               and strong cytoplasmic staining with PPARG monoclo-
to compare and adjust the staining (Figs. 1-3). Despite these              nal antibody in three cases, which may be a sign with the
calibrations and adjustments, the difference in the brands                 translocation being found in 1 patient with FA, 1 patient
and clones of the antibodies might have affected these re-                 with the PTC oncocytic variant, and 1 patient with the PTC
sults. This might also explain the confusing results in the                solid variant. In contrast, Lacroix et al. found that in the 17
current literature. One might consider that mitochondrial                  FTCs in which no PAX8/PPARG translocation was found,
rich cells can show background staining as their organelle                 nuclear staining with PPARG monoclonal antibody was
burden is too high, but only 3 of the positive cases were                  diffusely positive and intense in five samples 11.
oncocytic PTCs, so this cannot explain the cytoplasmic                     Vascular invasion (p = 0.039), lymphatic invasion
staining (Figs. 1-3). According to the Human Protein At-                   (p = 0.019), thyroid capsule invasion (p = 0.002) and
las 9 results, PPARG immunohistochemical staining is seen                  lymph node positivity (p = 0.012) were found to be lower
in the nucleus as well as in cytoplasmic/membranous parts                  in PTC patients with PPARG overexpression than in PTC
of thyroid cancer cells. As a result, cytoplasmic staining                 patients without overexpression. This suggests that PTCs
in our cases might be interpreted as a verification or new                 with PPARG overexpression may be associated with less
contribution to the literature.                                            aggressive behaviour in terms of the pathological prog-
As far as we can determine from the literature, PPARG                      nostic parameters. In the study by Nikiforova et al., it was
overexpression has been detected in FTC, FVPTC and FA,                     found that thyroid capsule invasion, extrathyroidal soft tis-
but there is no study showing PPARG overexpression in                      sue invasion and vascular invasion were more common in
PTC other than in the follicular variant. Thus, in our study               FTC cases with PPARG overexpression 6. However, in our
we demonstrated PPARG overexpression in both FVPTC                         study we had only two cases of FTC and there was no stain-
and other variants of PTC with IHC. In a study by Niki-                    ing with these two cases. Galusca et al. reported that PTCs



38
                                                                                  Papillary thyroid carcinoma and PPARG overexpression




with lymph node metastasis showed a significantly higher          radiotherapy in 10 fractions, the patient showed no improve-
percentage of PPARG-positive cases than those without,            ment 17. In that study, pioglitazone decreased the size of the
and they highlighted that PPARG expression might be re-           metastatic lesion, decreased the level of thyroglobulin in the
lated to tumour progression 8. Contrary to the two afore-         patient with PPARG overexpression and decreased pain re-
mentioned studies, Lacroix et al. found no relationship be-       lated to metastatic disease.
tween PAX8-PPARG rearrangement and the clinical status            Well-differentiated thyroid cancers respond well to sur-
of patients such as age, TNM stage and radioactive iodine         gical treatment. Radioactive iodine treatment is very ef-
uptake 11.                                                        fective in treating both local and distant metastases after
In 12 of the 111 patients in our study, variable degrees of       surgical treatment and in relapses. Although well-dif-
immunoreactivity were observed with PPARG in the non-             ferentiated thyroid cancers respond superbly to surgical
tumoural thyroid parenchyma. In 2 of those cases, immu-           treatment and radioactive iodine therapy, new treatment
noreactivity together with non-tumour thyroid parenchyma          modalities are needed in patients with progressive disease
was observed in tumour cells, while in other cases im-            refractory to radioactive iodine. The response to pioglita-
munoreactivity was observed only in non-tumour thyroid            zone of the patient with a radioactive iodine refractory
tissue. Among the cases with varying degrees of immuno-           progressive thyroid carcinoma harbouring PPFP 24 shows
reactivity in the non-tumoural areas, 6 had lymphocytic           the importance of molecular pathways in thyroid cancers
thyroiditis, 1 had nodular hyperplasia, 1 had Hashimoto’s         and suggests possible new treatment modalities in select-
thyroiditis and 1 had Graves’ disease, while 3 had stain-         ed cases.
ing in normal thyroid tissue. Similarly, in the study by Ni-
kiforova et al. moderate or strong immunoreactivity with
                                                                  Conclusions
PPARG was observed in some cases with Hashimoto’s thy-
roiditis. This condition was attributed to the probability of     In our study, PPARG overexpression was detected with
wild-type PPARG expression in these areas 6.                      IHC in FA and in some variants of PTC, including the folli-
Well-differentiated thyroid cancer is usually treated sur-        cular, classical, solid, oncocytic and Warthin-like variants.
gically, with radioactive iodine therapy as needed, as well       PPARG overexpression in PTC was found to be associated
as thyroid stimulating hormone suppression 12-14. In case         with less lymphovascular invasion, less thyroid capsule in-
of recurrence, repeated radioiodine administration may be         vasion and less lymph node metastasis. PTC cases with cy-
beneficial when the tumour takes radioiodine 15,16. In cases      toplasmic or nuclear immunohistochemical overexpression
refractory to radioiodine therapy, palliation of local symp-      of PPARG monoclonal antibody might be good candidates
toms can be achieved by external beam radiotherapy with or        to further analyse PAX8/PPARG translocations with PCR-
without a multikinase inhibitor 17-20. Because thyroid cancer     based methods, if necessary.
is a chemotherapy refractory disease 21, new agents or new
treatment modalities are necessary to treat patients with ra-     Conflict of interest statement
dioiodine refractory metastatic disease in thyroid carcinoma.     The authors declare no conflict of interest.
Pioglitazone is an antidiabetic agent used to treat type 2 dia-
betes through PPARG 22. A study investigating the efficacy        Funding
of pioglitazone in thyroid carcinoma in a transgenic mouse        This study was funded by the project committee of Mar-
model with PAX8/PPARG translocation was conducted by              mara University Scientific Research Project Unit. Project
Dobson et al. 23. In that study, it was reported that piogl-      number is SAG-C-TUP-120917.
itazone transdifferentiated thyroid tumour cells containing
PAX8/PPARG fusion protein (PPFP) to adipocyte-like cells,         Authors’ contributions
decreased tumour size and prevented metastatic disease. In        All authors contributed in design, data collection and pro-
light of the possible effect of pioglitazone in animal mod-       cessing, analysis, literature review, writing and critical re-
els, it was thought that pioglitazone might have an effect on     view.
human thyroid tumour cells harboring PPFP. In a phase 2
multicentre study investigating the efficacy of pioglitazone      Ethical consideration
in patients with progressive thyroid cancer refractory to RAI     The study was approved by Marmara University Medical
treatment, PPFP was detected in only 1 patient 24. That pa-       Faculty Ethics Committee for Clinical Research (Approval
tient had a 6 cm painful metastatic focus at the right acetabu-   number 09.2017.489 on 14/07/2017).
lum, had thyroglobulin levels above the thousands and had         The research was conducted ethically, with all study pro-
to use a wheelchair. Despite receiving 30 Gy external beam        cedures being performed in accordance with the require-



                                                                                                                                  39
O. Asya et al.




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Helsinki.                                                                          thy.2015.0020
                                                                              13
                                                                                   Haymart MR, Esfandiari NH, Stang MT, et al. Controversies in the
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