Metastatic Follicular Carcinoma Research Articles

Palliative treatment of generalized metastatic follicular carcinoma of thyroid after operation: A case report and literature review.

Follicular carcinoma of thyroid is a rare pathological type of thyroid carcinoma, accounting for 4.5% of the total. At present, the main treatment methods include surgery, iodine therapy, thyroid hormone inhibitors, etc. Targeted drug therapy is very important for distant metastasis and iodine-refractory differentiated thyroid cancer. This clinical case is a 51-year-old male patient with follicular carcinoma of thyroid. After 7 years of total thyroidectomy, multiple distant metastasis occurred to bilateral lungs, bones, multiple lymph nodes, etc. After multidisciplinary consultation in the department of oncology, thoracic surgery, nuclear medicine and other departments, he received targeted drug therapy of Lenvatinib. After 3 months, his condition was partially relieved, and his quality of life was significantly improved. After 11 months of treatment, the evaluated efficacy was still in remission. Late metastatic thyroid cancer is faced with dilemma of radioiodine refractory after traditional treatment. This will provide further evidence for therapeutic intervention in similar patients in the future.

SAT541 Pleural Effusion As First Manifestation Of Recurrent Follicular Thyroid Cancer

Abstract Disclosure: N.S. Kadakia: None. C.A. Poku: None. Pleural effusions are a rare presentation of Follicular Thyroid Cancer (FTC). We portray a case of a patient with a remote history of FTC who presented with pleural effusion 57 years later as the first sign of recurrence. A 80 year old male presented to the hospital 8/2021 with shortness of breath and was found to have a pleural effusion. He had a history of FTC diagnosed at age 23 status post total thyroidectomy, external beam radiation and radioactive iodine. He was started on thyroid hormone replacement and was subsequently lost to follow up. Chart review showed unremarkable neck ultrasounds completed in 2004 and 2006. During admission 8/2021, a malignant pleural effusion was diagnosed after the effusion tested positive for TTF-1 and thyroglobulin (Tg). He was diagnosed with recurrent metastatic thyroid cancer. A CT scan of the neck showed a small paratracheal nodule while a PET scan revealed hypermetabolic activity in the left pleura. A neck ultrasound reported a 2 cm cervical lymph node on the right with preserved fatty hilum and an ovoid 1 cm isoechoic solid nodule in the left surgical bed. There was evidence of bulky calcified lymph nodes on CT. The pleural lesion was not accessible however biopsy of a supraclavicular lymph node was consistent with metastatic follicular carcinoma. After a delay due to iodine contrast exposure, a whole body scan with radioactive iodine was completed in 1/2022 and showed multiple foci of uptake in the right neck, right thyroid, left clavicular region, and lung bases. He was treated with 250 mCi I-131 sodium iodide in 1/2022 and levothyroxine dose was increased with a target TSH of less than 0.1. His Tg level was mildly increased. Thyroglobulin antibodies (Tg ab) were positive but have continued to trend down after treatment. A follow up CT chest done 7/2022 had persistent pleural thickening but significant improvement in pleural effusion and thus thyroxine kinase inhibitors (TKI) chemotherapy has not been initiated. Malignant pleural effusion is a rare presentation of FTC metastasis with a reported median survival of 11 months (Kazushige). Pleural effusion is a poor prognostic sign in patients with FTC and distant metastases (Broome). This affirms that prompt recognition is of essence however it also raises the question of how effective current therapies are. A retrospective study evaluated 20 patients who received RAI for pulmonary metastasis from FTC, and found the efficacy rate was relatively low (40%). There is insufficient data to determine the effectiveness of RAI as treatment for metastatic FTC to the pleura. This case adds to the limited literature on recurrence of FTC with pleural effusion and highlights limitations of current management. If the response to RAI is deemed inadequate then consideration should be given to the use of TKI. Presentation Date: Saturday, June 17, 2023

Unusual Presentation of Thyroid Storm in a Patient with Metastatic Follicular Carcinoma of Thyroid

Unusual Presentation of Thyroid Storm in a Patient with Metastatic Follicular Carcinoma of Thyroid

Synchronous Metastatic Follicular Carcinoma and BRAF Mutated Papillary Carcinoma Thyroid-a Rare Occurrence.

Synchronous Metastatic Follicular Carcinoma and BRAF Mutated Papillary Carcinoma Thyroid-a Rare Occurrence.

Follicular Carcinoma of Thyroid Presented with Soft Tissue Metastasis: An Uncommon Fine Needle Aspiration Diagnosis

A-60-year-old elderly female presented with long standing swelling over the right shoulder. Thyroid was enlarged on examination and along with the routine work-up of patient, serum thyroid function test; Ultrasonography and Chest X-ray were performed. FNAC was performed from both the swellings i.e., thyroid gland and shoulder, and a provisional diagnosis of metastatic follicular carcinoma of thyroid was made A combination of proper history, along with serological markers, and fine needle aspiration cytology findings are necessary to make a provisional diagnosis of thyroid neoplasms. Also, a long term follow up is necessary to knock down the impact of metastases in previously diagnosed follicular thyroid carcinomas.

Metastatic Follicular Thyroid Carcinoma Presenting as Thoracic Cord Compression

Follicular thyroid carcinoma (FTC) is an uncommon cancer and the incidence of FTC is higher in endemic areas of iodine deficiency or endemic goiter. Up until the 1990s Fiji was listed as an iodine deficient country. We report a rare case of a 53-year-old native Fijian man who presented to our hospital with spinal cord compression due to a metastatic deposit of an undiagnosed FTC. He underwent emergent neurosurgical treatment for his cord compression, with histology of the lesion at the level of T5 identifying metastatic FTC. Despite the emergent surgery, he did not have any neurological recovery. Total thyroidectomy confirmed the presence of a large left-sided FTC and the patient was assessed for radioactive iodine treatment. Nuclear medicine imaging revealed extensive distant bony metastatic disease. Unfortunately due to his significant distant disease burden, he was unable to undergo radioactive iodine ablation therapy. After significant allied health input he was discharged home with community palliative care input. J Med Cases. 2021;12(5):177-180 doi: https://doi.org/10.14740/jmc3658

Unexpected Lung Metastasis After Left Hemithyroidectomy for Follicular Adenoma in a Young Adult Male: A Case Report

Follicular neoplasms of the thyroid gland are benign follicular adenoma and follicular carcinoma. To distinguish follicular carcinoma from a follicular adenoma based on cytologic, sonographic or clinical features alone is very difficult. As follicular adenoma of the thyroid is a benign tumor usually do not metastasize. Here, a case is presented with follicular variant of papillary thyroid carcinoma (FVPTC) with lung metastasis which was treated as follicular adenoma four years back. Patient had left hemithyroidectomy for follicular adenoma and ignored to have regular follow up. He suddenly developed fever, chest pain and dry cough. CT scan evaluated a fairly big lung mass which eventually came out as metastatic follicular carcinoma. From this reported case, it is evident that regular checkup of patient with follicular adenoma should be ensured for early diagnosis of further transformation of adenoma to malignancy.
 Bangladesh J. Nuclear Med. 22(2): 157-160, Jul 2019

Pure T3 thyrotoxicosis from a Struma Ovarii characterised by a paradoxical rise in thyroxine on treatment.

SummaryA 33-year-old female presented with a right 11.6 cm ovarian cyst. Routine pre-operative thyroid function tests showed thyroid stimulating hormone (TSH) of less than 0.02 mU/L (0.3–3.05) and a free thyroxine (FT4) of 5.5 pmol/L (10–28.2) suggesting either assay interference, triiodothyronine (T3) ingestion or hypopituitary hypothyroidism. A free triiodothyronine (FT3) level was requested which was high normal 6.9 pmol/L (3.1–8.1). Parallel assays on a different platform were similar but with a raised FT3 of 7.2 pmol/L (3.1–6.8). TSH receptor stimulating antibody (TSHAb) and thyroid peroxidase antibodies (TPO) were negative. Antithyroglobulin antibody (TgAb) was positive at 155.6 IU/mL (0–115). She was clinically euthyroid. Thyroid ultrasound showed a normal sized mildly heterogeneous gland with low blood flow and a solitary 1.5 cm U3 (BTA) nodule with higher blood flow. Thyroid Tc99m uptake was very low 0.2% (0.6–3.0) with no nodule uptake. These results demonstrated an extrathyroidal source of excessive autonomous T3 production resulting in the low thyroxine (T4). With carbimazole her TSH rose to 11.9 mU/L, FT4 rose to 7.7 pmol/L and FT3 reduced to 3.6 pmol/L. Histological diagnosis was Struma Ovarii. Her TSH, FT4 and FT3 remained normal thereafter. In conclusion, an extrathyroidal source of high T3 secretion was diagnosed using routine thyroid tests and scans. We believe this is the first description of a Struma Ovarii exclusively secreting T3 hormone characterised by the paradoxical rise of a low FT4 to normal with treatment. Two years later she developed non-secreting peritoneal deposits of highly differentiated follicular carcinoma.Learning points:Abnormally low TSH and FT4 levels suggestive of possible T3 ingestion, or less likely, hypopituitary hypothyroidism should always be followed by an assay of FT3.The diagnosis of an extrathyroidal source of T3 can be made using conventional thyroid tests, thyroid ultrasound scanning and technetium thyroid uptake and scan imaging. In a pre-menopausal patient this avoids a radiation dose to the pelvis.Pelvic radioisotope scanning of a suspected Struma Ovarii causing thyrotoxicosis can be reserved for patients whose thyroid function remains abnormal after initial surgery.Carbimazole is effective in the treatment of extrathyroidal autonomous T3 hormone production from a Struma Ovarii.The pathological appearance of a Struma Ovarii is not a guide to its malignancy. Even with a benign appearance they can disseminate to peritoneum, as highly differentiated follicular carcinoma (previously known as peritoneal strumosis).Hyperthyroid secretion by a Struma Ovarii may not be replicated in the metastatic follicular carcinoma in the peritoneum.

Follicular carcinoma of thyroid - scalp secondaries

Follicular thyroid carcinoma is the second most common thyroid cancer after papillary carcinoma but it is ranked first in producing distant metastasis among thyroid carcinomas. It accounts for 20 of all thyroid malignancies and is most often seen in patients over 40 years of age. There have been less than 30 reported cases of cutaneous metastases from follicular thyroid carcinoma in the literature. Majority of them have affected the head and neck region. We present a 60-year old lady with a swelling in the right fronto-parietal region since 9 months . FNAC revealed metastatic follicular carcinoma. Past history revealed patient undergoing total thyroidectomy one year back and was prescribed thyroxine 100mcg which she had discontinued after one month. Thyroid function test revealed hypothyroidism. Metastatic tumors are TSH dependent and strict TSH suppression is mandatory. Patient was treated with radioactive iodine at a dose of 400 mCi.

Follicular Carcinoma of Thyroid with the First Presentation as Vertebral Column Metastasis: A Case-report

Follicular carcinoma of thyroid is the second most common type of thyroid cancer that its incidence has increased in recent years. Herein, the study reported a 64-year male case of follicular carcinoma of thyroid that his first presentation was vertebral column metastasis. His chief complaint was back pain. In the past medical history, the patient had hypothyroidism and was opium inhalation addict since 15 years ago. Thoraco-lumbar magnetic resonance imaging (MRI) demonstrated spinal tumor of T10. The pathology report showed metastatic follicular carcinoma of thyroid with Thyroid transcription factor-1 (TTF-1), Thyroglobulin (TG), and Cytokeratin-7 (CK-7) positivity. Then thyroidectomy confirmed the diagnosis. In conclusion, follicular carcinoma of thyroid may be presented with spinal column metastasis. Pathologist should consider this diagnosis in the differential diagnosis of metastatic carcinoma in vertebral column and use Thyroglobulin with TTF-1 in immunohistochemistry panel for definite diagnosis and identification of origin.

Metástases Cutâneas de Carcinoma de Células de Hürthle da Tiróide

Metástases cutâneas de neoplasias internas constituem um evento raro, ocorrendo em 0,9% a 4,4% em grandes estudos necrópsicos e atingindo 9% em grandes séries de doentes neoplásicos. Metástases cutâneas de carcinomas da tiróide são ainda mais raros e, entre eles, os de carcinomas foliculares foram mais raramente reportados, mais escassamente do que os de carcinomas papilares ou medulares. Um Eurocaucasiano de 57 A de idade recorreu à consulta por pápula angiomatoide na área parietal do couro cabeludo, com cerca de 4 meses de evolução. O doente tinha sido submetido, 2 anos antes, a tiroidectomia total, complementada com radioterapia e diversos esquemas quimioterapêuticos por um carcinoma metastático de células de Hürthle da tiróide. A biópsia excisional da pápula permitiu estabelecer, com recurso a estudos imuno-histoquímicos, o diagnóstico de metástase cutânea de carcinoma folicular da tiróide. Os gânglios linfáticos, pulmões e os ossos constituem as mais prevalentes localizações à distância das metástases do carcinoma folicular da tiróide. Embora estas neoplasias representem até 12% das neoplasias malignas da tiróide, metástases cutâneas destes tumores têm sido muito raramente reportadas. Estes tumores são habitualmente carcinomas bem diferenciados, com prognóstico favorável a longo termo e caracterizados histologicamente por estruturas foliculares com material colóide e variáveis anaplasia e distorção arquitectural. No caso apresentado merecem destaque a morfologia angiomatoide da lesão metastática, classicamente associada a metástases de tumores de células renais e a alguns casos já relatados de tumores de células de Hürthle, bem como o comportamento agressivo e a evolução fatal verificados. O caso é ilustrado iconograficamente e uma breve revisão da literatura é efectuada.

Abstract 330: SGK1 activation is essential for PI3K-dependent tumor development

Abstract The PI3K signaling cascade is frequently activated in human cancer, with AKT being commonly considered its major transforming conduit. Conditional deletion of Pten in the mouse thyroid epithelium induces constitutive activation of the PI3K pathway, which causes thyroid hyperplasia at birth that progresses to invasive and metastatic follicular carcinoma. Concomitant loss of p53 or activation of KRAS dramatically accelerates the development of aggressive and lethal tumors. The PDK1 kinase plays a key role in the PI3K signaling cascade, directly activating, in a PI3K-dependent manner, not only AKT but also a set of additional AGC kinases, including, S6K, PKC, and SGK. Using in vivo, ex vivo, and in vitro genetic and pharmacological approaches, we now show that AKT activation is not sufficient to transform thyroid epithelial cells. Concomitant activation of additional PDK1-dependent pathways is absolutely required to develop neoplastic lesions in vivo, and to induce cell proliferation ex vivo, in mouse models based on Pten loss, alone and in combination with additional genetic alterations. In particular, we show that one member of the SGK family, SGK1, is an essential mediator of the transformation process downstream of PI3K. Genetic and pharmacological SGK1 inhibition strongly reduces cell proliferation in Pten-/-and PIK3CA-mutant cell lines. Moreover we show that concomitant SGK inhibition significantly increases the efficacy of inhibitors targeting AKT or PI3K. Taken together, our data identify an essential and druggable signaling cascade that critically cooperates with AKT activation to transform thyroid epithelial cells. Citation Format: Arturo Orlacchio, Antonio Di Cristofano. SGK1 activation is essential for PI3K-dependent tumor development [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 330. doi:10.1158/1538-7445.AM2017-330

Metastatic follicular thyroid carcinoma of the proximal humerus 20 years after subtotal thyroidectomy: A Case report and literature review

Though rare, metastatic thyroid carcinoma may present as thyrotoxicosis. We present a case of thyrotoxicosis caused by metastatic follicular thyroid carcinoma in the right proximal humerus. A 75-year-old female presented with pain and movement restriction of her right proximal upper arm for 1 month. She received a bilateral subtotal thyroidectomy 20 years ago for thyroid cancer. Images from roentgenogram and magnetic resonance (MR) studies revealed a lobulated mass arising from the proximal humerus. Her thyroid stimulating hormone (TSH) level was non-detectable, and free T4 was 0.8 ng/dl. A bilateral radical thyroidectomy was performed, and the histopathological diagnosis was nodular goiter. Wide excision of the tumor and right proximal humerus was also performed, and the histopathological diagnosis was metastatic follicular thyroid carcinoma. Her TSH and free T4 levels began to normalize after surgery. Postoperatively, she was treated with ^(131)I and has remained free from thyroid cancer recurrence or metastasis. Functioning metastatic lesions from thyroid cancer can present many years after the initial treatment for thyroid cancer, and surgical removal of the metastatic lesions can lead to normalization of thyroid function. Treatment with ^(131)I should be administered to eliminate the possibility of residual tumor.

Abstract 4376: Beyond AKT: Critical pathways for PI3K-dependent transformation

Abstract Genetic alterations activating the PI3K/AKT pathway have been identified in most human cancers, including those originating in the thyroid gland, particularly follicular thyroid cancer (FTC) and anaplastic thyroid cancer (ATC). However, although PI3K and AKT represent relevant targets for therapeutic purposes, the number of essential roles played by this pathway in normal cells poses the problem of reaching therapeutic efficacy without harming healthy tissues. Ideally, the toxicity associated with wide-range inhibitors could be reduced by targeting only molecules directly involved in the transformation process. The PDK1 kinase is a master regulator of PI3K downstream effectors belonging to the AGC kinases family, such as AKT and S6K1. Additional AGC kinases are controlled by PDK1 independently of PI3K activity. If PDK1-controlled AGC kinases contribute to PI3K-dependent transformation, they would clearly represent novel important therapeutic targets. PDK1 possesses a substrate-docking site, the “PIF pocket”, required for the phosphorylation of most AGC kinases (including S6K, PKC, SGK, and RSK) but not of AKT. The L155E mutation in PDK1disrupts the PIF pocket, without affecting AKT activation. This differential mechanism of substrate selection allows us to clearly define the relative contribution of AKT and other PDK1 targets to the neoplastic transformation process. Using in vivo as well as ex vivo and in vitro genetic and pharmacological approaches, we have shown that Akt activation is not sufficient to transform thyroid epithelial cells. Mice in which the PI3K pathway is constitutively activated in the thyroid epithelium through loss of Pten show thyroid hyperplasia at birth that progresses to invasive and metastatic follicular carcinoma. While Pdk1 deletion, as expected, completely rescue the phenotype observed in Pten−/- thyroids, we found that the simple impairment of the PIF-pocket is able to completely abrogate neoplastic transformation, despite AKT and mTOR being constitutively activated. We show that members of two families of AGC kinases, SGK (1and 3) and RSK (1-3) are essential components of this PDK1-dependent pathway required for PI3K-dependent transformation. Genetic and pharmacological SGK and RSK inhibition strongly reduces cell proliferation in Pten−/− as well as Pik3ca mutant cell lines, both in 2d and in 3D systems, with SGK1 and RSK3 being the most critical isoforms. Furthermore, genetic inhibition of SGK and RSK drastically impairs tumor growth in syngeneic allograft and metastasis models. Taken together, our data identify two new signaling cascades that are essential for neoplastic transformation of thyroid epithelial cells, and thus novel strong candidates for drug development. Citation Format: Arturo Orlacchio, Antonio Di Cristofano. Beyond AKT: Critical pathways for PI3K-dependent transformation. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4376.

Follicular thyroid carcinoma with NRAS Q61K and GNAS R201H mutations that had a good (131)I treatment response.

SummaryWe report a case of follicular thyroid carcinoma with concomitant NRAS p.Q61K and GNAS p.R201H mutations, which manifested as a 13.5 cm thyroid mass with lung, humerus and T9 spine metastases, and exhibited good response to radioactive iodine treatment.Learning points GNAS p.R201H somatic mutation is an activating or gain-of-function mutation resulting in constitutively activated Gs-alpha protein and downstream cAMP cascade, independent of TSH signaling, causing autonomously functioning thyroid nodules. NRAS p.Q61K mutations with GNAS p.R201H mutations are known for a good radioactive iodine treatment response.Further exploration of the GNAS-activating pathway may provide therapeutic insights into the treatment of metastatic follicular carcinoma.

Cytodiagnosis of distant metastases from follicular thyroid carcinoma.

Follicular carcinoma of the thyroid is second most common primary malignancy of the thyroid gland after papillary carcinoma and metastasis is uncommonly seen in these patients. To describe the cytomorphologic features for the accurate diagnosis of distant metastases from follicular carcinoma of thyroid. A total of 10 aspirates reported as metastatic follicular carcinoma of thyroid were reviewed for the available clinical and radiological details. All the patients were females. Six of these patients presented with subcutaneous and soft tissue swellings, one presented with a lung mass, one with right breast swelling, one with lumbar vertebral lesion and one with left iliac bone involvement. The cytology smears revealed tumour cells predominantly arranged in a repetitive microfollicular pattern with some scattered individually and in sheets. The tumour cells were small, had mild nuclear pleomorphism, round nuclei, low nuclear-cytoplasmic ratio, fine chromatin, inconspicuous nucleoli, and scanty to moderate amount of cytoplasm with some showing marginal vacuoles with "fire-flare" appearance. Occasional microfollicles showed scanty eosinophilic colloid in the center. Identification and establishment of a correct clinical diagnosis of a distant metastasis from a follicular thyroid carcinoma is a challenging task. We believe that with prior knowledge of characteristic cytologic features, such metastases can be rapidly and accurately diagnosed by fine needle aspiration cytology.

Abstract 2158: PDK1-dependent activation of RSK is an absolute requirement for PI3K oncogenic activity in the thyroid gland

Abstract Aberrant activation of the phosphatidylinositol-3 kinase (PI3K)/Akt pathway plays a key role in thyroid tumorigenesis, particularly in follicular thyroid cancer (FTC) and anaplastic thyroid cancer (ATC). Accordingly, conditional deletion of Pten in the mouse thyroid epithelium induces constitutive activation of the PI3K/AKT pathway, and causes thyroid hyperplasia at birth that progresses to invasive and metastatic follicular carcinoma. This phenotype is dramatically accelerated by simultaneous deletion of Trp53, leading to the development of ATC, or activation of Kras, leading to poorly differentiated carcinomas. The PDK1 kinase plays a central role in the PI3K signaling cascade, acting as a master regulator of PI3K downstream effectors belonging to the AGC kinases family, such as AKT and S6K1. Additional AGC kinases are controlled by PDK1 independent of PI3K activity. PDK1 possesses a substrate docking site, the “PIF pocket”, required for the phosphorylation of most AGC kinases (including S6K, PKC, SGK, and RSK) but not of AKT. The L155E PDK1 mutant disrupts the PIF pocket and impairs AGC kinase activation, without any effect on AKT activation. Thanks to this differential mechanism of substrate activation, we are defining the relative contribution of AKT and other PDK1 targets to the neoplastic transformation process in Pten-/- thyrocytes. Surprisingly, in vivo disruption of the PIF-pocket completely abrogates neoplastic transformation of Pten-/- thyroids, even in the face of AKT constitutive activation. This finding supports the hypothesis that the linear PI3K-AKT pathway is not sufficient to drive thyroid transformation and that concomitant activation of additional PDK1-dependent pathways is absolutely required. We now show that RSK family members (RSK1-3) are essential components of this PDK1-dependent accessory pathway. Remarkably, RSK3 levels in the thyroid are increased in the absence of Pten, and RSK activity in thyroid cells is abrogated when PDK1 PIF-pocket is mutated. Genetic and pharmacological inhibition of RSK drastically impairs [Pten,Trp53]-/- ATC cell proliferation both in vitro and in vivo, in syngeneic allograft models. Taken together, our data identify a new signaling cascade that is essential for neoplastic transformation of thyroid epithelial cells, and thus a new critical candidate for drug development. Citation Format: Arturo Orlacchio, Antonio Di Cristofano. PDK1-dependent activation of RSK is an absolute requirement for PI3K oncogenic activity in the thyroid gland. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2158. doi:10.1158/1538-7445.AM2015-2158

Adrenal Mass: An Unusual Presentation of Metastatic Follicular Carcinoma of Thyroid

Patients with follicular carcinoma of thyroid may have asymptomatic involvement of adrenal gland and associated metastases to other organs, which may remain undetected for long time if not diagnosed, treated and followed up properly. A very rare case of adrenal metastasis from follicular carcinoma of thyroid, five years after total thyroidectomy is presented. The patient also had synchronous involvement of bones including an unusual site in upper end of left tibia. Here, emphasis is given on awareness of the possibility of unique metastatic deposits of follicular carcinoma of thyroid at unexpected sites as this has a significant impact on clinical decision-making and prognosis of the patients. DOI: http://dx.doi.org/10.3329/bjnm.v17i1.22499 Bangladesh J. Nuclear Med. 17(1): 97-103, January 2014

Métastases uvéales des carcinomes thyroïdiens. À propos de 3 cas

To study the characteristics of ocular metastases of thyroid carcinomas through three observations of patients. Three patients aged respectively 41, 55 and 66 years were followed for thyroid carcinoma. All patients were treated by surgery followed by IRA therapy. They developed ocular metastases after a mean period of 10 years after thyroidectomy. They presented in addition multiple secondary sites such as bone, lungs and cerebrum. The uveal lesion was unilateral and localized at the choroid or iris. The predominant symptomatology was decreased visual acuity. The diagnosis was based on ophthalmoscopic examination and post-IRA therapy scan and was confirmed by anatomopathological study. Treatment options were respectively IRA therapy, sectoral iridectomy and enucleation. Evolution was fatal in 2 cases and towards aggravation for one case. Uveal metastases of thyroid cancer are associated with a pejorative prognosis. Ophthalmologic follow-up is necessary when patient presents warning sign mainly with metastatic follicular carcinoma. Conversely, thyroid carcinoma should be considered in the differential diagnosis of a uveal mass of unknown origin.

Abstract 4776: PDK1-dependent activation of AGC kinases is an absolute requirement for AKT oncogenic activity

Abstract The PI3K signaling cascade is frequently activated in human cancer, and AKT is commonly considered its major transforming conduit. Thus, PI3K and AKT represent relevant targets for therapeutic purposes. However, the many essential of roles played by this pathway in normal cells poses the problem of reaching therapeutic efficacy without harming healthy tissues. In principle, it would be ideal to target only molecules directly involved in the transformation process, thus reducing the toxicity associated with wide-range inhibitors. PDK1 plays a key role in the PI3K cascade, directly activating AKT. In addition, PDK1 possesses a substrate docking site named “PIF pocket” that is required to phosphorylate and activate members of the AGC kinase family, including S6K, PKC, SGK, and RSK. Mice in which the PI3K pathway is constitutively activated in the thyroid epithelium through loss of Pten are born with thyroid hyperplasia that progresses to invasive and metastatic follicular carcinoma, a process that is accelerated by the simultaneous loss of p27 or p53, and by Ras or Braf activation. Using in vivo as well as ex vivo and in vitro genetic and pharmacological approaches, we now show that although Akt activation is necessary, it is not sufficient to transform thyroid epithelial cells. Concomitant activation of Pdk1-dependent pathways is absolutely required to develop neoplastic lesions in vivo, and to induce cell proliferation ex vivo. Pten mutants develop adenomas and carcinomas by one year of age. Strikingly, complete rescue of this phenotype is observed in compound mutants in which, in addition to thyroid-specific Pten loss, the PIF-pocket of Pdk1 has been genetically disrupted, maintaining constitutive activation of Akt and mTor, but not of PIF-pocket dependent AGC kinases. We also show that the transcription factor STAT3 represents a key mediator of this essential Pdk1-dependent pathway: STAT3 phosphorylation is increased in Pten mutants, and abolished in compound mutants. Furthermore, genetic and pharmacological inhibition of STAT3 drastically impairs cell proliferation in vitro and rescues the hyperplastic phenotype of Pten mutant mice in vivo. Thus, we have identified an essential and druggable signaling cascade that critically cooperates with AKT activation to transform thyroid epithelial cells. Citation Format: Arturo Orlacchio, Valeria Antico Arciuch, Antonio Di Cristofano. PDK1-dependent activation of AGC kinases is an absolute requirement for AKT oncogenic activity. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4776. doi:10.1158/1538-7445.AM2014-4776