ABSTRACT Objective: The treatment of patients with differentiated thyroid cancer (DTC) was modified in the last decade towards a more individualized approach according to the risk of recurrence (RR). We compared the outcomes of patients with low and intermediate RR (LRR and IRR) who received or did not receive radioiodine remnant ablation (RRA) after assessing the dynamic risk. Materials and methods: We included 307 DTC patients with LRR and IRR submitted to total thyroidectomy. All patients were reclassified according to the dynamic risk stratification (low or high). Patients with high dynamic risk received RRA (141 patients). Results: LRR patients who received RRA presented a frequency of structural incomplete response (SIR) of 5% at the end of the follow-up, compared to 2% in those who did not receive it (p=0.353). IRR patients treated with RRA had a frequency of SIR of 22%, compared to 5% in patients without RRA (p=0.008). Conclusions: This study demonstrates the usefulness of dynamic risk assessment to decide RRA in a cohort with a long-term follow-up. The lower prevalence of SIR at the end of the follow-up in patients who did not receive RRA highlights the adequate selection of those who would not benefit from RRA, even with an intermediate risk of recurrence.

SUMMARY Anaplastic thyroid carcinoma is the rarest tumor of the thyroid gland, representing less than 2% of clinically recognized thyroid cancers. Typically, it has an extremely rapid onset, fatal outcomes in most cases, and a median overall survival of 3 to 10 months despite aggressive multidisciplinary management. The presence of targetable mutations in anaplastic thyroid carcinoma patients is an opportunity for treatment when conventional therapeutics approaches are not effective, a frequent situation in the majority of patients. We present our experience in the management of a patient with unresectable anaplastic thyroid cancer who had a remarkable and rapid response to treatment with dabrafenib and trametinib during the COVID-19 pandemic. After four weeks of dabrafenib 150 mg twice daily plus trametinib 2 mg daily, he showed a dramatic reduction of the cervical mass around 90%. Nearly eight weeks under treatment with dabrafenib plus trametinib, the patient remains with minimal locoregional disease without distant metastases.

Abstract There are numerous reports of incidental findings of thyroglossal duct remnants (TGDR) after total thyroidectomy, but its implication on the outcome of patients with differentiated thyroid cancer (DTC) is unknown. The aim of this study was to determine the frequency of TGDR detected by ultrasonography after total thyroidectomy in patients with DTC and to evaluate the impact of this finding on the response to treatment. A total of 377 records of patients with DTC who received total thyroidectomy between January 1994 and January 2017 were reviewed. Patients with less than one year of follow-up after surgery were excluded. TGDR was diagnosed in 16 out of 377 (4.2%). Fifteen had a low risk of recurrence DTC and 13 of them were treated with radioactive iodine. All low risk patients had an excellent response to treatment. Only one with an intermediate risk of recurrence DTC had an initial structural incomplete response which changed to an indeterminate response after a modified central lymph node dissection. The median time of TGDR diagnosis after thyroidectomy was 5 years (1-16). Two patients underwent TGDR surgery due to the presence of a rapidly growing neck mass, 2.4 and 4 cm in size, detected 9 and 16 years after thyroidectomy, respectively. The prevalence of this condition seems to be rare. However, the appearance of a cystic mass during the follow-up of a patient with DTC cancer could be confused with metastatic disease. The diagnosis of TGDR seems not to have an impact on the response to treatment.

Resumen Existen numerosas comunicaciones de hallazgo incidental de remanentes del conducto tirogloso (CTG) posteriores a una tiroidectomía total, pero se desconoce su implicancia en pacientes con cáncer diferenciado de tiroides (CDT). Nuestro objetivo fue determinar frecuencia de detección ecográfica de remanentes del CTG posterior a la tiroidectomía total en pacientes con CDT y evaluar el impacto del hallazgo en la respuesta al tratamiento. Se incluyeron 377 pacientes con CDT tratados con tiroidectomía total entre enero 1994 y enero 2017, con seguimiento de al menos un año posterior a la cirugía. Se detectó la presencia de remanente del CTG en 16/377 (4.2%): 15 de bajo riesgo de recurrencia y uno de riesgo intermedio. Trece recibieron radioyodo. Todos tuvieron un estado sin evidencia de enfermedad al final del seguimiento, excepto uno con riesgo intermedio que presentó una respuesta inicial estructural incompleta e indeterminada posterior al vaciamiento ganglionar. La mediana del tiempo de diagnóstico del remanente del CTG luego de la tiroidectomía fue de 5 años (rango 1-16). Dos pacientes con remanentes del CTG fueron intervenidos quirúrgicamente, ambos presentaron tumoraciones de aparición súbita en región suprahioidea, 2.4 y 4 cm, detectados a los 9 y 16 años luego de la tiroidectomía, respectivamente. La prevalencia de esta condición parece ser poco frecuente. Sin embargo, la aparición de una masa quística en el seguimiento de un paciente con CDT puede ser confundido con enfermedad metastásica y generar ansiedad. El hallazgo de remanentes del CTG parecería no tener ningún impacto en la respuesta al tratamiento.

ABSTRACT Objectives To determine the percentage of patients with papillary thyroid carcinoma (PTC) who accepted active surveillance as an alternative to surgery in our clinical practice and to describe the clinical characteristics and outcomes of patients with Bethesda category V and VI thyroid nodules who chose active surveillance. Subjects and methods We included 136 PTC patients from the Hospital de Clínicas, University of Buenos Aires without (i) US extrathyroidal extension, (ii) tumors adjacent to the recurrent laryngeal nerve or trachea, and/or (iii) US regional lymph-node metastasis or clinical distant metastasis. PTC progression was defined as the presence of i) a tumor larger than ≥ 3 mm, ii) novel appearance of lymph-node metastasis, and iii) serum thyroglobulin doubling time in less than one year. For patients with these features, surgery was recommended. Results Only 34 (25%) of 136 patients eligible for active surveillance accepted this approach, and around 10% of those who accepted abandoned it due to anxiety. The frequency of patients with tumor enlargement was 17% after a median of 4.6 years of follow-up without any evidence of nodal or distant metastases. Ten patients who underwent surgical treatment after a median time of 4 years of active surveillance (AS) had no evidence of disease after a median of 3.8 years of follow-up after surgery. Conclusion Although not easily accepted in our cohort of patients, AS would be safe and easily applicable in experienced centers.

ABSTRACT Objective: The advent of multikinase inhibitor (MKI) therapy has led to a radical change in the treatment of patients with advanced thyroid carcinoma. The aim of this manuscript is to communicate rare adverse events that occurred in less than 5% of patients in clinical trials in a subset of patients treated in our hospital. Subjects and methods: Out of 760 patients with thyroid cancer followed up with in our Division of Endocrinology, 29 (3.8%) received treatment with MKIs. The median age at diagnosis of these patients was 53 years (range 20-70), and 75.9% of them were women. Sorafenib was prescribed as first-line treatment to 23 patients with differentiated thyroid cancer and as second-line treatment to one patient with advanced medullary thyroid cancer (MTC). Vandetanib was indicated as first-line treatment in 6 patients with MTC and lenvatinib as second-line treatment in two patients with progressive disease under sorafenib treatment. Results: During the follow-up of treatment (mean 13.7 ± 7 months, median 12 months, range 6-32), 5/29 (17.2%) patients presented rare adverse events. These rare adverse effects were: heart failure, thrombocytopenia, and squamous cell carcinoma during sorafenib therapy and squamous cell carcinoma and oophoritis with intestinal perforation during vandetanib treatment. Conclusions: About 3 to 5 years after the approval of MKI therapy, we learned that MKIs usually lead to adverse effects in the majority of patients. Although most of them are manageable, we still need to be aware of potentially serious and rare or unreported adverse effects that can be life-threatening.

ABSTRACT Objective To compare the historic risk of recurrence (RR) and response to therapy to risk stratification estimated with historical pathology reports (HPRs) and contemporary re-review of the pathological slides in patients with differentiated thyroid cancer (DTC). Subjects and methods Out of 210 DTC patients with low and intermediate RR who underwent total thyroidectomy and remnant ablation in our hospital, 63 available historic pathologic samples (HPS) were reviewed. The RR and the response to therapy were evaluated considering historical histological features (histological type, tumor size, capsular invasion, number of lymph node metastases) and then, reassessed after observing additional histological features (vascular invasion, extrathyroidal extension, size of lymph node metastases, presence of extranodal extension, and/or status of the resection margins). Results A change in the RR category was observed in 16 of 63 cases (25.4%). Out of 46 patients initially classified as low RR, 2 patients were reclassified as intermediate RR, 4 as high RR, and 1 as noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP). Out of 17 patients initially classified as intermediate RR, 3 were reassigned to the low RR group, 5 as high RR, and 1 as NIFTP. The percentages of structural incomplete response at final follow-up changed from 2.2 to 0% (p = 1) in patients with low RR and from 6.3 to 20% (p = 0.53) in patients with intermediate RR. Conclusion A detailed report of specific features in the HPR of patients with DTC might give a more accurate RR classification and a better estimation of the response to treatment.

ABSTRACT Objective Bone metastases (BM) from differentiated thyroid cancer (DTC) are associated with poor survival rates. Due to the low frequency of this entity, we performed a multicentric retrospective study that aimed to evaluate the presentation, outcome and causes of death in this population. Subjects and methods We reviewed file records from 10 databases. BM were diagnosed by: i) biopsy and/or ii) radioiodine (RAI) bone uptake + elevated thyroglobulin (Tg) levels and/or c) bone uptake of 18-FDG in the PET-CT scan + elevated Tg levels. Results Fifty-two patients with DTC were included (44% male, mean age 54 years); 58% had papillary histology. BM were synchronous with DTC diagnosis in 46% of the participating cases. BM were symptomatic in 65% of the cases. Multiple BM were present in 65% of patients, while simultaneous metastatic disease in additional sites was found in 69%. Ninety-eight percent of patients received treatment for the BM, which included RAI therapy in 42 patients; 30 of them received cumulative RAI doses that were larger than 600 mCi 131I. The mean follow-up after a BM diagnosis was 34 months. The 2- and 5-year survival rates after diagnosis of the first BM were 64% and 38%, respectively. The status on the last evaluation was DTC-related death in 52% of the patients; 26% of them died from direct complications of BM or their treatments. Conclusion BM are usually radioiodine-refractory and are associated with a short overall survival, although most of the patients died of causes not directly related to the BM.

The therapeutic approach and the follow-up of patients with differentiated thyroid cancer (DTC) is currently individualised according to the risk of recurrence, with a lower tendency to perform remnant ablation (RA) in patients with low risk of recurrence. While response to therapy assessment has been validated for DTC patients treated by total thyroidectomy (TT) and RA, it has not been widely confirmed in patients treated with TT without RA. The aims of this study were to describe the characteristics of the population of patients treated with TT without RA, and to validate the response to therapy. The study included 88 patients followed-up for at least 12 months after surgery. In the entire cohort, 87.9% were female and the mean age was 47.5 years old. Based on the Argentine Intersociety Consensus, 97.7% and 2.3% were classified as low risk and intermediate risk of recurrence, respectively. Patients had an initial excellent response to treatment in 73% of cases, with a disease-free status at the end of follow-up of 85.5%. A minority of patients (1%) presented with an initial structural incomplete response, which was similar at the end of follow-up (1%). On the other hand, 26% of the patients had an initial indeterminate response, although only 13.5% remained with this response at the end of follow-up. These results validate the responses to treatment in DTC patients treated with TT without RA as an effective tool for the dynamic risk stratification. Patients appropriately selected who did not receive RA have an excellent outcome, with a low frequency of structural incomplete response, even lower than that observed in low risk ablated patients.

En la actualidad, el enfoque terapéutico y el seguimiento de los pacientes con carcinoma diferenciado de tiroides (CDT) es individualizado de acuerdo con el riesgo de recurrencia de la enfermedad, con una menor tendencia a ablacionar a pacientes de bajo riesgo de recurrencia. Por otro lado, la evaluación de las respuestas al tratamiento se validó en pacientes tratados con tiroidectomía total (TT) y ablación con radioyodo (RAI), pero son escasos los estudios en pacientes no ablacionados. Los objetivos de este estudio fueron describir las características de una población de pacientes con CDT no ablacionados y validar las respuestas al tratamiento durante el seguimiento. Se incluyó a 88 pacientes con un seguimiento mínimo de 12 meses. El 87,6% eran mujeres y la edad promedio en el momento del diagnóstico fue de 47,5 años. Basados en el Consenso Intersocietario Argentino, el 97,7% de la cohorte fue clasificada como de bajo riesgo y el 2,3% como de riesgo intermedio de recurrencia. Los pacientes presentaron una respuesta inicial excelente en el 73% de los casos, con un estado sin evidencia de enfermedad al final del seguimiento en el 85,5%. Una minoría de los pacientes (1%) presentó una respuesta inicial estructural incompleta, la cual fue similar al final del seguimiento (1%). Por otro lado, el 26% de los pacientes presentó una respuesta inicial indeterminada, aunque solo el 13,5% permaneció con esta respuesta al final del seguimiento. Nuestros datos validan las respuestas al tratamiento en pacientes con CDT que recibieron TT no ablacionados como una herramienta efectiva para la estratificación del riesgo dinámico. Los pacientes apropiadamente seleccionados tratados sin RAI tienen un excelente pronóstico, con una baja frecuencia de respuesta estructural incompleta en el seguimiento, inclusive menor que la de los pacientes de bajo riesgo ablacionados.

Distant metastases occur in less than 10% of patients with differentiated thyroid carcinoma. In these patients, overall survival at 10 years is considerably reduced. Whereas cure is the initial goal of treatment, stabilisation of the disease and management of symptoms have become the primary objective in many patients with persistent radio-iodine refractory progressive disease. In the last decade, several targeted therapies have shown encouraging results in patients with advanced disease. The objective of this review is to describe the characteristics, diagnosis, overall survival, and the local and systemic available treatments for patients with distant metastases from differentiated thyroid cancer.

La presencia de metástasis a distancia en el cáncer diferenciado de tiroides es un hecho infrecuente que ocurre en menos del 10% de los pacientes. Cuando sucede, la supervivencia a 10 años disminuye significativamente. La curación es el objetivo primario, pero dado que 2 tercios de los tumores metastásicos se volverán radiorrefractarios en su evolución, la finalidad terapéutica es estabilizar la enfermedad y tratar sus síntomas. En la última década, el manejo de estos pacientes cambió radicalmente con el advenimiento de las terapias con blancos moleculares. El objetivo de esta revisión es describir las características de los pacientes con cáncer diferenciado de tiroides que presenten metástasis a distancia, la supervivencia global, los métodos diagnósticos utilizados, y los tratamientos locales y sistémicos disponibles.

The advent of multikinase inhibitors therapy has led to a radical change in the treatment of patients with advanced thyroid carcinoma. The ANMAT (the Argentinian regulatory health agency) has currently approved sorafenib for patients with radioiodine resistant differentiated thyroid carcinoma, and vandetanib for patients with medullary thyroid carcinoma (progressive and/or symptomatic disease). It has been demonstrated by phase III clinical trials that these drugs improve progression free survival in this group of patients. Although they have a precise indication, an interdisciplinary team in close contact with a committed patient, are required for their effective management. The adverse events of these drugs are common, but many of them may ameliorate over time, and most of them are manageable, even without the need for dose reduction or drug withdrawal. Knowledge of the correct management of the adverse events is a fundamental tool for the medical team and for the patient to prevent or minimise them, to avoid serious complications and to obtain better patient compliance. The primary objective of this article is to provide a guideline for the diagnosis and treatment of the adverse events produced by the multikinase inhibitors, and to present the initiative of the Hospital de Clinicas in order to implement these guidelines.

El advenimiento de la terapia con inhibidores multicinasas (IMK) representó un cambio radical en el tratamiento de pacientes con carcinoma avanzado de tiroides. Hasta la fecha, 2 fármacos se encuentran aprobados por la Asociación Nacional de Medicamentos, Alimentos y Tecnología Médica (ANMAT) en Argentina: sorafenib, para pacientes con carcinoma diferenciado de tiroides radiorresistente, y vandetanib, para aquellos con carcinoma medular de tiroides (enfermedad progresiva y/o sintomática). Los estudios de fase III han demostrado que estos fármacos aumentan significativamente la supervivencia libre de progresión en este grupo de pacientes. Si bien tienen una indicación precisa, su manejo requiere de un equipo multidisciplinario en contacto estrecho con un paciente involucrado en su tratamiento. Los efectos adversos de sorafenib y vandetanib son frecuentes, sin embargo, muchos de ellos disminuyen con el tiempo y la mayoría puede manejarse a menudo sin disminuir la dosis ni suspender el fármaco. El conocimiento del correcto manejo de los efectos adversos por parte del equipo tratante constituye una herramienta fundamental para poder educar al paciente y, consecuentemente, poder prevenirlos o minimizarlos, y de esta manera evitar complicaciones severas. El objetivo de esta publicación es brindar una guía para el diagnóstico y tratamiento de los efectos adversos de estos IMK y, por otro lado, presentar la iniciativa del Hospital de Clínicas de la Universidad de Buenos Aires en cuanto a la implementación de la misma.

ABSTRACT Radioiodine (RAI)-refractory thyroid cancer is an uncommon entity, occurring with an estimated incidence of 4-5 cases/year/million people. RAI refractoriness is more frequent in older patients, in those with large metastases, in poorly differentiated thyroid cancer, and in those tumors with high 18-fluordeoxyglucose uptake on PET/CT. These patients have a 10-year survival rate of less than 10%. In recent years, new therapeutic agents with molecular targets have become available, with multikinase inhibitors (MKIs) being the most investigated drugs. Two of these compounds, sorafenib and lenvatinib, have shown significant objective response rates and have significantly improved the progression-free survival in the two largest published prospective trials on MKI use. However, no overall survival benefit has been achieved yet. This is probably related to the crossover that occurs in most patients who progress on placebo treatment to the open treatment of these studies. In consequence, the challenge is to correctly identify which patients will benefit from these treatments. It is also crucial to understand the appropriate timing to initiate MKI treatment and when to stop it. The purpose of this article is to define RAI refractoriness, to summarize which therapies are available for this condition, and to review how to select patients who are suitable for them.

ABSTRACT Objective The reclassification of the risk according to the response to the initial treatment makes the treatment of differentiated thyroid cancer (DTC) vary in each individual. As the influence of age on this diagnostic strategy is unknown, we have decided to assess it in adults who are over 60 years of age. Subjects and methods Ninety patients with DTC above 60 years old were enrolled, with total thyroidectomy plus radioiodine ablation, negative anti-thyroglobulin antibodies, follow-up ≥ 2 years and with clinical and pathological information to classify the risk of recurrence according to ATA (American Thyroid Association) and reclassify based on the response to initial therapy according to MSKCC (Memorial Sloan Kettering Cancer Center). The structural persistence at the end of the follow-up was the gold standard of our analysis. Results The structural persistence in ATA low, intermediate and high risk categories was 0, 38, and 100%, respectively. In the intermediate group, none of those with an excellent response to the initial treatment showed structural persistence, whereas 39% of those with an incomplete/indeterminate response showed structural persistence (p < 0.01). Conclusions The re-stratification according to the response to the initial treatment in patients over 60 years of age with an ATA intermediate risk of recurrence allowed for the distinction of disease-free patients at the end of the follow-up from those with structural persistence and a worse clinical progression.

Advanced radioactive refractory and progressive or symptomatic differentiated thyroid carcinoma (DTC) is a rare condition. Sorafenib was recently approved for the treatment of these patients. We present the case of a 67 year old woman diagnosed with DTC who underwent a total thyroidectomy with central, lateral-compartment neck dissection and shaving of the trachea and esophagus due to tumor infiltration. A local recurrence was detected 14 months later requiring, additionally, two tracheal rings resection. The patient received a cumulative 131I dose of 650 mCi and developed dysphagia and dyspnea 63 months after initial surgery. A 18FGD-PET/CT showed progression of the local mass associated to hypermetabolic pulmonary nodules. Sorafenib 800 mg/day was then prescribed. A dose reduction to 400 mg/day was necessary due to grade 3 thrombocytopenia that appeared four months after drug prescription. Platelet count went to normal after this dose reduction. Five months after initiation of sorafenib, a partial response of the local mass with significant intra-tumoral necrosis was observed. We conclude that sorafenib is a valid option for locally advanced DTC and that the platelet count should be evaluated regularly because it seems that thrombocytopenia might be more frequently observed in DTC than in other types of tumors.

Medullary thyroid carcinoma (MTC) may rarely present with paraneoplastic syndromes. Among the most frequent ones are the appearance of diarrhea and ectopic Cushing syndrome (ECS). The ECS in the context of MTC is usually present in patients with distant metastatic disease. The use of drugs such as ketoconazole, metyrapone, somatostatin analogs and etomidate have been ineffective alternatives to control hypercortisolism in these patients. Bilateral adrenalectomy is often required to manage this situation. Recently, the use of tyrosine kinase inhibitors has been shown to be a useful tool to achieve eucortisolism in patients with metastatic MTC and ECS. We present a patient with sporadic advanced persistent and progressive MTC with lymph node and liver metastases, which after 16 years of follow-up developed an ECS. After one month of 300 mg/day vandetanib treatment, a biochemical and clinical response of the ECS was achieved but it did not result in significant reduction of tumor burden. However the patient reached criteria for stable disease according to response evaluation criteria in solid tumors (RECIST 1.1) after 8 months of follow-up.

Patients infected with human immunodeficiency virus (HIV) have a higher prevalence of thyroid dysfunction when compared with the general population. The most frequently observed manifestations are euthyroid sick syndrome, Graves´ disease and subclinical hypothyroidism. The relationship between the use of highly active antiretroviral therapy and the increased prevalence of thyroid dysfunction has been demonstrated in several series of patients. Grave’s disease is recognized as a consequence of immune restitution syndrome. Besides, several studies have suggested an association between hypothyroidism and the use of nucleoside reverse transcriptase inhibitors, particularly stavudine and non-nucleoside reverse transcriptase inhibitors such as efavirenz. Further studies could provide additional evidence of the need for routine assessment of thyroid function in HIV-infected patients.

Los pacientes con infección por el virus de inmunodeficiencia humana (HIV) tienen una mayor prevalencia de disfunción tiroidea cuando se los compara con la población general. Las manifestaciones más frecuentemente observadas son: el síndrome del eutiroideo enfermo, la enfermedad de Graves y el hipotiroidismo subclínico. La relación entre el uso de la terapia antirretroviral y el incremento en la prevalencia de alteraciones tiroideas fue demostrada en varias series de pacientes. La enfermedad de Graves se reconoce claramente como una consecuencia del síndrome de restitución inmune. Además, existen estudios que sugieren una relación entre hipotiroidismo y el uso de inhibidores nucleósidos de la transcriptasa reversa, en particular estavudina y el inhibidor no nucleósido de la transcriptasa reversa efavirenz. Nuevos estudios podrán aportar evidencia adicional sobre la necesidad de evaluaciones rutinarias de la función tiroidea en pacientes infectados por HIV.