their incidence is rising due to improvements in survival and diagnosis ; nevertheless , our patient is the fourth case reported up to date .
therefore , treatment choice is made based on clinical experience and case reports ; notably , the largest case report series was prior to the approval for using tyrosine - kinase inhibitors in thyroid cancer .
a 73-year - old lady had dedifferentiated papillary thyroid cancer with ongoing sorafenib . after 9 months on this treatment
differential diagnosis included infection , progression of disease and cardiotoxicity . after a comprehensive assessment ( echocardiography , computed tomography , pet , magnetic resonance ) , we found progression of lung disease , and the appearance of heart metastases .
after recovering from the basal status , she started on second - line treatment with sunitinib , which was well - tolerated .
we should include cardiac metastases in the differential diagnosis of heart failure in cancer patients .
sorafenib is the mainstay of the first - line therapy in metastatic thyroid cancer , achieving long - term disease control with good tolerance .
sunitinib could be a safe second - line treatment option ( not cardiotoxicity related ) with promising results .
therefore , our report presents a sequence of treatment with tyrosine - kinase inhibitors in metastatic thyroid carcinoma with an encouraging outcome , which deserves further investigation .
cardiac metastases from thyroid cancer are a rare entity ; in fact , its frequency reported in historical series ranges from 0 to 2% .
the improvements in survival of thyroid cancer patients and current advances in imaging diagnoses have contributed to increase its incidence .
nevertheless , after a comprehensive literature review , we found only 15 case reports in the last 35 years [ 3 , 4 ] .
thyroid cancer histologic subtypes more prone to develop cardiac metastases are anaplastic thyroid cancer , follicular thyroid cancer , and hrthle cell cancer . to date
, there are only 3 case reports of cardiac metastases from papillary thyroid carcinoma , so our patient will be the fourth case .
a 73-year - old lady with a personal history of well - controlled high blood pressure and chronic atrial fibrillation on anticoagulant therapy , but with performance status 0 presented with a neck enlargement mass in may 2010 .
she underwent a total thyroidectomy and therapeutic lymph node neck dissection achieving a complete resection in june 2010 .
the initial diagnosis was a papillary thyroid carcinoma measuring 5.5  4  4 cm , with regional lymph node involvement ( 1/4 ; pathologic stage , pt4n1am0 ) .
no residual uptake was seen in the post - therapeutic radioiodine-131 whole - body scan .
three months after the first operation , the patient presented with a tender lump in the left supraclavicular fossa .
the lymph node was excised and the histopathology analysis showed features consistent with dedifferentiated papillary thyroid cancer with a solid , insular and trabecular growth pattern , frequent mitosis and pleomorphic nuclei .
immunohistochemical examination demonstrated that the cells stained positively for thyroglobulin , thyroid transcription factor ( ttf1 ) , bcl2 , e - cadherin , cyclin d1 , cd15 and ki-67 ( 10% ratio ) and were negative for calcitonin and hbm45 .
postoperative treatment with radioactive iodine-131 ( i-131 ) at a dose of 150 mci was advised . after a disease - free interval of 18 months
, in may 2011 , she had a new relapse in form of isolated cervical lymph node metastases , with a negative 18f - fluorodeoxyglucose - positron emission tomography elsewhere .
again , the pathology showed this to be a relapse of her poorly differentiated thyroid carcinoma ( pdtc ) , with papillary features .
she completed adjuvant treatment with external beam radiotherapy over the neck and mediastinum ( 60 gy for 30 fractions ) .
unfortunately , a year later , in may 2012 , in a follow - up visit , thyroglobulin level rose to 3,042 ng / ml ; an i-131 scan and a positron emission tomography and computed tomography ( pet / ct ) were requested ; metabolically active paratracheal lymph nodes and new lung metastases were observed .
i-131 rechallenge was indicated at a dose of 178 mci . a partial response and a decrease in thyroglobulin levels ( 2,580 ng / ml )
were obtained . in march 2013 , thyroglobulin level reached 9,946 ng / ml and a new pet / ct scan demonstrated progression of her pulmonary and ganglionic disease . at this point , treatment with sorafenib 400 mg orally twice daily was initiated .
her disease remained stable for 8 months ( thyroglobulin level : 8,298 ng / ml ) and the patient did not experience significant side effects ( except grade 1 mucositis and hand - foot syndrome ) . in october 2013 , the patient came to the emergency department at this hospital because of progressive dyspnea , irritative cough , pleuritic chest pain , orthopnea and oliguria . on examination ,
the temperature was 37c , the blood pressure 110/80 mm hg , the pulse 90 beats per minute , the respiratory rate 22 breaths per minute and the oxygen saturation 90% while the patient was breathing ambient air .
there were decreased lung sounds with expiratory wheezes bilaterally and crackles at the right base and there was 2 + edema of the legs .
hemogram and biochemistry showed mild anemia ( hemoglobin 11 g / dl ) without any other abnormalities .
chest radiography showed a sclerotic lesion in the sixth dorsal vertebra , alveolar diffuse infiltrate in the right lung base , right paratracheal lymph node enlargement , and cardiomegaly .
electrocardiogram ( ecg ) was reportedly normal with no changes compared with the previous one .
she was admitted to the hospital with depletive treatment , empirical antibiotics , and steroids , according to the initial diagnosis of acute heart failure , in the context of a likely respiratory infection .
symptoms were stabilized and the patient reported clinical improvement ; however , progression of disease could not be ruled out , so a diagnostic procedure was performed .
transthoracic echocardiography revealed minimal mitral and tricuspid regurgitation with an estimated left ventricular ejection fraction of 60% .
a moderate circumferential pericardial effusion was present without evidence of tamponade ; echodensities along the visceral pericardium were considered to be consistent with the deposition of fibrin or metastases .
the assessment was completed with a pet / ct scan and cardiac magnetic resonance imaging ( mri ) which demonstrated further significant progression in the lungs and confirmed the development of bone and cardiac metastases in the pericardium and the right atrium ( fig .
2 ) . due to the evolution after the discharge , and the lack of relevant toxicity at any time during the previous treatment with sorafenib , the patient was very keen on having further treatment . concern regarding morbidity and efficacy of this approach was raised , and sunitinib at a dose of 37.5 mg / day , daily , was initiated in november 2013 , with the approval of the committee for high impact drugs .
again , therapy was well tolerated with easily manageable adverse effects ; the patient experienced only grade 1 high blood pressure and fatigue . at the time of the last follow - up after 4 months of treatment , the patient 's tumor was stable with respect to size in the imaging assessment ; however , it demonstrated a marked reduction in thyroglobulin level ( 8,625 ng / ml ) , and the patient likewise was experiencing continued improvement of her symptoms and a benefit to her quality of life , although one dose reduction was required .
unfortunately , 1 month later her general condition started to deteriorate due to new exacerbation of heart failure ; then , palliative treatment for symptom control was decided , with home care support . finally she died in april 2014 due to cardiac congestive failure .
cardiac metastases have historically been considered an exceptional event , occurring less than 2% of the time .
the three main reasons could be : first , cancers whose route of spread could involve the heart are very scarce .
second , the majority of cardiac metastases have indolent behavior or unspecific symptoms that could be attributed to other causes , so its diagnosis has been challenging .
third , the availability and accuracy of imaging - based diagnostic systems used to be low compared to today . owing to the facts mentioned above ,
however , both improvement in cancer treatment with an increased longevity of cancer patients and the development of diagnosis techniques , like cardiac mri , have contributed to the current incidence of cardiac metastases which has increased to slightly above 10% .
we can distinguish three groups among cardiac metastases according to its primary tumor origin : uncommon primary tumors that have a high rate of metastasis to the heart ( malignant melanoma , malignant germ cell neoplasm , malignant thymoma ) ; common tumors that have an intermediate rate of cardiac metastases but account for the greatest number of cardiac metastasis ( carcinoma of the stomach , liver , ovary , colon , and rectum ) , and common tumors with rare metastases to the heart .
the incidence and prevalence of thyroid cancer is rising ; actually , it has become the ninth cancer in frequency in the developed countries .
over 90% of cases are well - differentiated thyroid cancers ( wdtcs ) , originated from the follicular cells , encompassing papillary and follicular thyroid forms ( ptcs and ftcs ) .
the ptc is considered to be potentially curable by using a multimodal treatment , which combines surgery , radioactive iodine , and tsh - suppressive hormonal therapy .
nevertheless , 30% of ptcs have a relapse , and the recurrence can be associated to a cell dedifferentiation .
it implies a more aggressive biological behavior , characterized by a fast growth and metastatization , loss of the iodine uptake and radiotherapy resistance .
this situation was observed in our patient , who presented an early nodal recurrence , resectable , whose pathological report was confirmed as pdtc , with papillary features .
pdtc is a well - defined diagnosis entity since the turin experts meeting in 2006 , with features and prognosis in between wdtc and anaplastic thyroid carcinomas .
de novo , or like in our patient , can be developed from wdtc with the appearance of new genetic alterations , such as point mutations and translocations that increase mitogenesis and cell proliferation .
the carcinogenesis in thyroid carcinomas is preceded by unopposed activation of either the mitogen - activated protein kinase pathway ( controlled by the genes ret , ras braf ) or the phosphatidylinositol-3-kinase pathway .
pdtc presents several of these genetic alterations : ras mutations have been observed in 3035% and braf mutations have been found in 45% .
tp53 mutations in a range of 2030% and overexpression of tyrosine - kinase receptors , including epidermal growth factor receptor and vascular - endothelial growth factor receptor ( vegfr ) have been reported as well .
table 1 illustrates the prevalence of genetic alterations in regard to the different histological subtypes of thyroid cancer .
the current approach is to emphasize the use of new targeted therapies against these potential targets ; so , it supports the use of multikinase tyrosine - kinase inhibitors ( such as sorafenib , sunitinib , vandetanib ) , drugs which may act by blocking several targets ( vegfr , ret , braf ) instead of classic cytotoxic agents . the efficacy and safety of sorafenib , the first - line treatment for metastatic disease used in our patient , have been proved in three phase ii trials .
it has recently been approved by the us food and drug administration in october 2013 on the basis of the results of a phase iii double - blind , randomized , controlled trial , with 417 advanced thyroid cancer patients with iodine - refractory disease .
it demonstrated that patients on sorafenib obtained a benefit in median disease - free survival ( 10.58 vs. 5.8 months ) and improvement in overall response rate ( 12 vs. 1% ) , with good toxicity profile ( hand - foot syndrome and diarrhea ) . considering all of the above
, sorafenib should be the mainstay first - line treatment in metastatic thyroid carcinoma , due to its good results in efficacy and toxicity .
our patient presented with stable disease and excellent tolerance during the whole 9 months of treatment , which is consistent with the published data ; notably , our patient 's baseline characteristics were worse than the patients enrolled in the study ; in spite of that , improved clinical outcome persisted .
then , she needed to be hospitalized due to worsening dyspnea in the context of the first episode of congestive heart failure . although the chief symptom of dyspnea led us to think first of pulmonary disease , like concomitant respiratory infection which could trigger the congestive heart failure episode , the additional history of our patient demanded consideration of causes of dyspnea that are more likely in a patient with aggressive pdtc treated with radiotherapy and systemic treatment with tyrosine - kinase inhibitors
therefore , conditions like cardiotoxicity from sorafenib ( table 2 ) , radiation - related complications ( pneumonitis or radiation - associated constrictive pericarditis ) , progression of disease ( involving either lungs , heart or both ) , and malignant pericardial effusion should be ruled out .
radiation - related complications were unlikely , and neither the chronology ( pneumonitis usually appears 312 weeks after the ending of treatment ) nor the radiological findings were consistent with them .
cardiotoxicity was ruled out with the preliminary results ( ecg without abnormalities and echocardiography with conserved left ventricular ejection fraction ) as well .
furthermore , the final diagnosis was suggested with some suspicious findings in the initial echocardiography , which were suggesting the existence of metastases in the pericardium and the right atrium , but inconclusive to state it . to achieve the diagnosis confirmation
we completed the diagnosis procedure with a pet / ct scan , the optimal imaging technique to evaluate undifferentiated thyroid cancer with loss of radioiodine uptake ability .
the mri showed two new sites of disease in the pericardium and the right atrium which were associated with abnormal metabolic activity in the pet / ct .
in addition , the pet / ct showed further progression of the disease with new hypermetabolic foci in the lungs and in the thoracic vertebras . in the last comprehensive literature review published in 2011 that covers the last 130 years
, 54 patients with cardiac metastases from thyroid cancer were identified , all with poor outcome ( survival since cardiac metastasis presentation < 5 months ) . elective treatment for cardiac metastases
the main goal in the majority of cardiac metastasis case reports published to date was to control cardiologic symptoms because of its life - threatening condition and its complex management .
contrary to the facts mentioned above , our patient experienced cardiologic clinical improvement just with medical treatment adjustment .
therefore , due to the new symptomatic systemic progression , without requiring locoregional control maneuver , systemic second - line therapeutic options were considered for our patient .
sunitinib , an anti - vegfr , platelet - derived growth factor receptor , multikinase drug , has shown successful results in three phase ii trials for iodine - refractory thyroid carcinoma in second - line treatment [ 13 , 14 , 15 ] , achieving partial responses or stabilization of disease , without relevant side effects . owing to its proved activity and its low cardiotoxicity rate ,
finally we decided to start sunitinib ; a stabilization of the disease with a lack of relevant toxicity was observed in our case after 4 months of treatment .
therefore , our case report presents a sequence of treatment with tyrosine - kinase inhibitors in metastatic thyroid carcinoma with an encouraging outcome ; we achieved long - term disease stabilization ( over 13 months ) with clinical benefit and good toxicity profile , without increasing cardiotoxicity , in spite of the development of heart metastases .
there is a need to confirm our experience in prospective studies ; further investigations to establish the optimal sequence therapy in this setting are required .
 backgroundcardiac metastases from papillary thyroid carcinoma are very uncommon . 
 their incidence is rising due to improvements in survival and diagnosis ; nevertheless , our patient is the fourth case reported up to date . 
 there are no clinical trials available in this scenario . 
 therefore , treatment choice is made based on clinical experience and case reports ; notably , the largest case report series was prior to the approval for using tyrosine - kinase inhibitors in thyroid cancer.patienta 73-year - old lady had dedifferentiated papillary thyroid cancer with ongoing sorafenib . after 9 months on this treatment 
 , she presented with dyspnea and heart failure . 
 differential diagnosis included infection , progression of disease and cardiotoxicity . after a comprehensive assessment ( echocardiography , computed tomography , pet , magnetic resonance ) , we found progression of lung disease , and the appearance of heart metastases.resultsafter recovering from the basal status , she started on second - line treatment with sunitinib , which was well - tolerated . 
 she achieved stable disease with a decrease in tumor marker levels.conclusionswe should include cardiac metastases in the differential diagnosis of heart failure in cancer patients . 
 magnetic resonance imaging is the gold standard for assessment . 
 sorafenib is the mainstay of the first - line therapy in metastatic thyroid cancer , achieving long - term disease control with good tolerance . 
 sunitinib could be a safe second - line treatment option ( not cardiotoxicity related ) with promising results . 
 therefore , our report presents a sequence of treatment with tyrosine - kinase inhibitors in metastatic thyroid carcinoma with an encouraging outcome , which deserves further investigation . 
Background
Patient
Results
Conclusions
Introduction
Case Report
Discussion
Disclosure Statement