Immunohistochemistry and next-generation sequencing for NTRK fusion detection in differentiated thyroid cancer of children, adolescents and young adults / Imunohistoquímica e sequenciamento nova geração para detecção de fusão NTRK em câncer diferenciado de tireoide em crianças, adolescentes e adultos jovens

INTRODUCTION: Pan-TRK immunohistochemistry staining can assess the protein expression from NTRK gene fusions. A little is known about its utility in differentiated thyroid cancer samples from children, adolescents, and young adults patients. Objective: Investigate pan-TRK immunohistochemistry sensitivity and specificity in differentiated thyroid cancer samples from children, adolescents, and young adults patients. METHODS: Tumor samples obtained from 79 children, adolescents, and young adults patients (age <21 years) diagnosed with differentiated thyroid cancer between January, 2010 and January, 2021 were retrospectively recruited from four health centers from state of Bahia e Paraíba, Brazil. NTRK gene fusion testing of all archival FFPE tumor samples: pan-TRK immunohistochemistry staining for TRKA, TRKB and TRKC protein expression were performed and then analyzed with RNA-based next-generation sequencing assay to confiC:\Users\yngrid.narciso\Desktop\CLIENTES\SITES\BJO\2024\5 - Maio\2024-05-02\siterm immunohistochemistry pan-TRK result and elucidate fusion partner. RESULTS: Pan-TRK immunohistochemistry: 3 of 79 cases had positive pan-TRK expression: next-generation sequencing; 4 were identified with NTRK gene fusion, pan-TRK immunohistochemistry was negative in all 4 NTRK next-generation sequencing-positive cases. 25 of 79 NTRK next-generation sequencing-negative control cases had concordant negative pan-TRK immunohistochemistry results. Therefore, our rate of false positive pan-TRK immunohistochemistry results was 3/25 (12%). The overall results for pan-TRK immunohistochemistry in our cohort of next-generation sequencing-negative cases was: (i) sensitivity (0%), (ii) specificity (96%), (iii) positive predictive value (94.7%), (iv) negative predictive value (91%). CONCLUSION: Pan-TRK immunohistochemistry was not a tissue-efficient screen for NTRK fusions in differentiated thyroid cancer from children, adolescents, and young adults patients. This is the largest cohort of from children, adolescents, and young adults differentiated thyroid cancer cases stained with pan-TRK immunohistochemistry, and it is the first to detail the sensitivity and specificity of pan-TRK immunohistochemistry regarding the data obtained by targeted RNA-based next-generation sequencing panel in differentiated thyroid cancer.

INTRODUÇÃO: A coloração imuno-histoquímica Pan-TRK pode avaliar a expressão proteica de fusões de genes NTRK. Pouco se sabe sobre sua utilidade em amostras diferenciadas de câncer de tireoide de crianças, adolescentes e adultos jovens. Objetivo: Investigar a sensibilidade e especificidade da imuno-histoquímica pan-TRK em amostras diferenciadas de câncer de tireoide de pacientes crianças, adolescentes e adultos jovens. MÉTODOS: Amostras tumorais obtidas de 79 pacientes crianças, adolescentes e adultos jovens (idade <21 anos) com diagnóstico de câncer diferenciado de tireoide entre janeiro de 2010 e janeiro de 2021 foram recrutadas, retrospectivamente, em quatro centros de saúde dos estados da Bahia e Paraíba, Brasil. Teste de fusão genética NTRK de todas as amostras de tumor FFPE arquivadas: coloração imuno-histoquímica pan-TRK para expressão da proteína TRKA, TRKB e TRKC foi realizada e depois analisada com ensaio de sequenciamento de próxima geração baseado em RNA, para confirmar o resultado imuno-histoquímico pan-TRK e elucidar o parceiro de fusão. RESULTADOS: Imunohistoquímica pan-TRK: 3 de 79 casos tiveram expressão pan-TRK positiva: sequenciamento de próxima geração; 4 foram identificados com fusão do gene NTRK, a imuno-histoquímica pan-TRK foi negativa em todos os 4 casos positivos para sequenciamento de próxima geração de NTRK. 25 dos 79 casos de controle negativo para sequenciamento de próxima geração de NTRK tiveram resultados de imuno-histoquímica pan-TRK negativos concordantes. Portanto, nossa taxa de resultados de imuno-histoquímica pan-TRK falsos positivos foi de 3/25 (12%). Os resultados gerais da imuno-histoquímica pan-TRK em nossa coorte de casos negativos para sequenciamento de próxima geração foram: (i) sensibilidade (0%), (ii) especificidade (96%), (iii) valor preditivo positivo (94,7%), (iv) valor preditivo negativo (91%). CONCLUSÃO: A imuno-histoquímica pan-TRK não foi uma triagem tecidualmente eficiente para fusões de NTRK em pacientes com câncer diferenciado de tireoide em crianças, adolescentes e adultos jovens. Esta é a maior coorte de casos de câncer diferenciado de tireoide de crianças, adolescentes e adultos jovens corados com imunohistoquímica pan-TRK, e é a primeira a detalhar a sensibilidade e especificidade da imunohistoquímica pan-TRK em relação aos dados obtidos por RNA direcionado baseado em um painel de sequenciamento de próxima geração no câncer diferenciado de tireoide.

Basal or stimulated thyroglobulin in evaluating response to treatment in papillary thyroid carcinoma? A retrospective cohort study.

OBJECTIVE: It is not clear whether response to initial treatment in papillary thyroid carcinoma (PTC) patients is best evaluated by measuring thyroglobulin (Tg) in the presence of levothyroxine (BTg) or when stimulated by elevated TSH (STg). The aim of this study was to evaluate whether response to therapy 1 year after initial treatment changes with the use of STg in relation to BTg in PTC patients treated with total thyroidectomy (TT) and radioiodine (131I), and, if observed, to assess which response is better associated with clinical course. SUBJECTS AND METHODS: This is a retrospective study of 148 PTC patients submitted to TT and 131I. We analyzed the response to therapy (excellent, biochemical incomplete, or indeterminate) at 1 year after initial treatment, using BTg or STg, and compared which method was better associated with "excellent response at final evaluation." RESULTS: Twenty-eight patients (20.4%) presented change in response to therapy, with 17 of these (60.7%) presenting a worse response. Response using STg was 1.6 times better associated with proposed outcome [odds ratio (OR) = 4.61; confidence interval 95% (IC95%): 2.13-9.98] than with BTg (OR = 2.84; IC95%: 1.33-6.06). CONCLUSION: Response to therapy at 1 year using STg was altered in approximately 20% of cases and therefore proved to be a better predictor of excellent response in the last evaluation.

Physicians' preferences for radioiodine treatment of differentiated thyroid cancer in Brazil: an observational study

ABSTRACT Objective The aim of this observational, cross-sectional study was to investigate physicians' preferences for radioiodine (RAI) treatment in patients with differentiated thyroid cancer (DTC) in Brazil and the factors influencing RAI indications. Materials and methods A survey was distributed to physicians potentially involved in DTC care in Brazil to understand the factors influencing RAI indications. The survey collected information on the profiles of the physicians, along with the characteristics of their workplaces and their preferences regarding RAI indications in three hypothetical clinical cases. Cases 1, 2, and 3 described the cases of patients with DTC and variations to the case that included different scenarios to assess how the respondents would change their RAI recommendations. The analysis included the RAI indications across different medical specialties. Results A total of 175 physicians answered the survey. There was considerable variability in RAI recommendations in all three cases. The training background influenced the respondents' preferences for RAI indications and their approaches to preparing patients for RAI treatment. Conclusion The findings of this study reaffirm the need for a Brazilian consensus among physicians across multiple specialties to help guide health care professionals treating patients with DTC in Brazil.

Rehabilitación del nervio recurrente laríngeo postiroidectomía / Recurrent laryngeal nerve rehabilitation after thyroidectomy

El carcinoma papilar tiroideo es el tipo de cáncer más común de esta glándula, y su tratamiento de elección es la tiroidectomía. Entre las complicaciones asociadas resalta la parálisis de las cuerdas vocales, la cual ocurre por una lesión directa del nervio laríngeo recurrente durante la cirugía. Se presenta una paciente de 22 años de edad con este diagnóstico, a la cual se le realizó una tiroidectomía total; en el postoperatorio inmediato la paciente comenzó con estridor laríngeo intenso que requirió una traqueotomía de urgencia. En el examen físico se constató una parálisis bilateral de las cuerdas vocales y se decidió comenzar un tratamiento de rehabilitación del nervio recurrente laríngeo con laserterapia y HIVAMAT-200 como modalidades combinadas. Los resultados alcanzados con la fisioterapia fueron satisfactorios y la paciente se reintegró rápidamente a su ámbito familiar, escolar y social.

Papillary thyroid carcinoma is the most common type of cancer of this gland, and its treatment of choice is thyroidectomy. Vocal cord paralysis stands out among the associated complications, in which a direct injury to the recurrent laryngeal nerve occurs during surgery. We present a 22-year-old female patient with this diagnosis, who underwent a total thyroidectomy; in the immediate postoperative period the patient began with intense laryngeal stridor requiring an emergency tracheotomy. Physical examination revealed bilateral vocal cord paralysis and it was decided to begin rehabilitation treatment of the recurrent laryngeal nerve with laser therapy and HIVAMAT-200 as combined modalities. The results achieved with physiotherapy were satisfactory and the patient was quickly reintegrated into her family, school and social environment.

Metastatic diffuse follicular variant papillary thyroid cancer without cervical lymph node metastasis presenting with symptoms related to hypopituitarism

ABSTRACT In this article, we present a case of diffuse follicular variant papillary thyroid carcinoma with pituitary metastasis, which is a rare cause of pituitary metastasis. The follicular variant of papillary thyroid carcinoma is an uncommon variant of papillary carcinoma. A 74-year-old male was presented with weakness, fatigue, and a decreased appetite. The patient was diagnosed with secondary adrenal and thyroid insufficiencies. Imaging revealed a pituitary mass with suprasellar extension, right cavernous sinus invasion, and optic chiasm compression. Thyroid ultrasonography revealed a nodule with a maximum size of 7.2cm in the right lobe. Cytological examination via fine-needle aspiration suggested papillary thyroid cancer. Total thyroidectomy with central and right lateral neck dissection confirmed the diagnosis of diffuse follicular variant of papillary thyroid carcinoma. Owing to visual field defects, the patient underwent transsphenoidal surgery. Histological and immunohistochemical evaluations confirmed pituitary metastasis from the papillary thyroid cancer. Radioactive iodine treatment and gamma knife radiotherapy of the pituitary gland were performed. The initiation of sorafenib treatment was deemed appropriate during the follow-up. A significant decrease in the thyroglobulin levels was observed after sorafenib treatment. Pituitary metastasis should be considered in patients diagnosed with hypopituitarism and pituitary lesions at initial evaluation. The presence of visual field defects may be an indication for neurosurgical intervention and guide both diagnosis and treatment. The management of papillary thyroid cancer and the role of treatment modalities in prognosis depend on the biological behavior of the tumor. Early diagnosis and multidisciplinary management are crucial for the treatment of these patients.

Papillary thyroid carcinoma with nodular fasciitis-like stroma: a rare variant.

Papillary thyroid carcinoma with desmoid-type fibromatosis (PTC-DTF) or nodular fasciitis-like stroma (PTC-NFS) is a rare morphological variant of PTC with a favorable prognosis. There is a paucity of molecular data regarding this entity. We present the case of a 20-year-old female who presented with a palpable mass over the anterior aspect of the neck for the past 3-4 months, which was diagnosed as PTC-NFS. Ultrasonogram of the neck revealed a bulky left lobe of thyroid that contained a well-defined heterogenous lesion measuring around 24 × 26 × 36 mm with involvement of the adjacent isthmus. She underwent a total thyroidectomy with central compartment lymph node dissection. Histological examination revealed a biphasic tumor with epithelial and stromal components resembling nodular fasciitis. Two dissected lymph nodes showed metastasis of the epithelial component only. On immunohistochemistry, BRAF mutant protein expression was evident in the epithelial component only, while ß-catenin was negative in both the components. The histopathological diagnosis of papillary thyroid carcinoma with nodular fasciitis-like stroma was offered. Sanger sequencing revealed a BRAFV600E (c.1799T>A, Val600Glu) mutation. Post-operatively, no residual tumor was detected on ultrasound and radioiodine scans. The patient was doing well at follow-up of 9 months. PTC-NFS/DTF is a histological variant of PTC with a favorable prognosis. Our index case was associated with the BRAF mutation, which was restricted to the epithelial component. Thorough sampling of the excised specimen is essential in order not to miss the epithelial component, which, in most reported cases (including ours) appears to be small.

Warthin-like and classic papillary thyroid cancer have similar clinical presentation and prognosis.

OBJECTIVE: Warthin-like papillary thyroid cancer (WL-PTC) is an uncommon variant of PTC, usually associated with lymphocytic thyroiditis. Scarce evidence suggests that WL-PTC has similar clinical presentation to classic PTC (C-PTC), with no studies comparing risks of recurrence and response to treatment between both variants. Our objective was to describe the clinical presentation and prognosis of WL-PTC and compare it to C-PTC. METHODS: Retrospective analysis of a prospective cohort, including 370 (96%) patients with C-PTC and 17 (4%) with WL-PTC, consecutively treated with total thyroidectomy with or without RAI, followed for at least 6 months. We compared clinical presentation, risk of mortality and recurrence, as well as response to treatment between both variants. RESULTS: Of the total cohort: 317 (82%) female, 38 ± 13.5 years, median follow-up 4 years (0.5-28.5); most of them stage I and low/intermediate risk of recurrence. We found no differences regarding clinical-pathological data and risk of recurrence. WL-PTC was associated with a higher rate of anti-thyroglobulin antibodies (TgAb) (65% vs. 36%, p = 0.016) and lymphocytic thyroiditis (59% vs. 34%, p = 0.03). The rates of biochemical and structural incomplete responses were similar in both variants. WL-PTC had a lower rate of excellent response (23% vs. 54%, p = 0.01), which became non-significant when performing analysis by TgAb presence (50% vs. 67%, p = NS). CONCLUSION: WL-CPT and C-CPT have similar clinical presentation and rate of recurrence. The lower rate of excellent response to treatment in WL-PTC is due to a higher frequency of TgAb. WL-PCT should not be considered an aggressive variant of PTC.

Papillary thyroid carcinoma with nodular fasciitis-like stroma: a rare variant

Papillary thyroid carcinoma with desmoid-type fibromatosis (PTC-DTF) or nodular fasciitis-like stroma (PTC-NFS) is a rare morphological variant of PTC with a favorable prognosis. There is a paucity of molecular data regarding this entity. We present the case of a 20-year-old female who presented with a palpable mass over the anterior aspect of the neck for the past 3-4 months, which was diagnosed as PTC-NFS. Ultrasonogram of the neck revealed a bulky left lobe of thyroid that contained a well-defined heterogenous lesion measuring around 24 × 26 × 36 mm with involvement of the adjacent isthmus. She underwent a total thyroidectomy with central compartment lymph node dissection. Histological examination revealed a biphasic tumor with epithelial and stromal components resembling nodular fasciitis. Two dissected lymph nodes showed metastasis of the epithelial component only. On immunohistochemistry, BRAF mutant protein expression was evident in the epithelial component only, while β-catenin was negative in both the components. The histopathological diagnosis of papillary thyroid carcinoma with nodular fasciitis-like stroma was offered. Sanger sequencing revealed a BRAFV600E (c.1799T>A, Val600Glu) mutation. Post-operatively, no residual tumor was detected on ultrasound and radioiodine scans. The patient was doing well at follow-up of 9 months. PTC-NFS/DTF is a histological variant of PTC with a favorable prognosis. Our index case was associated with the BRAF mutation, which was restricted to the epithelial component. Thorough sampling of the excised specimen is essential in order not to miss the epithelial component, which, in most reported cases (including ours) appears to be small.

Thyroid cancer surgical indication during pregnancy: systematic literature review and series of illustrative cases

Introduction: Thyroid papillary carcinoma is the second most frequent type of cancer during pregnancy. Its diagnosis is related to patient fear and anxiety. There is little consensus on when to perform surgery in those cases. Objective: To evaluate and discuss timing possibilities for surgical treatment in thyroid cancer in pregnant women. Methods: Systematic literature review based on online search at the Literatura Latino-Americana e do Caribe em Ciências da Saúde (LILACS) and National Center for Biotechnology Information (NCBI) databases. Retrospective analysis of thyroidectomies performed in the second trimester of pregnancy by the authors between 1999 and 2019. Results: The systematic review included nine articles. Their conclusions diverge with respect to the optimal timing of thyroid surgery. The medical literature considers thyroidectomy after safe delivery. The most recent studies are more flexible regarding carrying out this surgery during the second trimester of pregnancy. In the authors' experience (n=5), surgical treatment during the second trimester of pregnancy is a good option for more aggressive tumors. Conclusion: More aggressive cases of thyroid papillary carcinoma can be treated with surgery during the second trimester of pregnancy. Performing the surgery after delivery is safer in the case of less aggressive cancer cases. The decision should consider hospital costs, surgery risks, and patient anxiety in relation to cancer.

Tumores de colisión en tiroides: carcinoma papilar y metástasis de carcinoma renal a células claras / Collision tumors in the thyroid: papillary carcinoma and metastases of clear cell renal cell carcinoma

RESUMEN Los tumores de colisión son neoplasias poco comunes, requieren terapias combinadas tratando independientemente cada tumor. La presentación en la glándula tiroides es rara. Reportamos el caso de un paciente de 55 años con diagnóstico de carcinoma renal a células claras; la tomografía corporal reportó nódulos pulmonares y hepáticos sugestivos de metástasis. Oncología indicó tratamiento con sunitinib. Once meses después, la tomografía de control reportó múltiples nódulos tiroideos. Se realizó tiroidectomía total, con informe anatomopatológico: carcinoma papilar de tiroides y metástasis de carcinoma renal a células claras. Recibió ablación con 80 mCi de iodo 131; luego hormonosupresión con levotiroxina.

ABSTRACT Collision tumors are rare neoplasms, they require combination therapy for the treatment of each tumor independently. We describe the case of a 55 year old patient diagnosed with clear cell renal cell carcinoma; whole body computed tomography reported pulmonary and hepatic nodules suggestive of metastatic disease. Oncology indicated sunitib therapy. Eleven months later, evaluation with computed tomography reported multiple thyroid nodules. Total thyroidectomy was performed, with anatomo-pathological report: papillary thyroid carcinoma and metastases of clear cell renal cell carcinoma. He received ablation with 80 mCi of radioactive iodine (I-131); then thyroid hormone suppressive therapy with levothyroxine.

Warthin-like and classic papillary thyroid cancer have similar clinical presentation and prognosis

ABSTRACT Objective Warthin-like papillary thyroid cancer (WL-PTC) is an uncommon variant of PTC, usually associated with lymphocytic thyroiditis. Scarce evidence suggests that WL-PTC has similar clinical presentation to classic PTC (C-PTC), with no studies comparing risks of recurrence and response to treatment between both variants. Our objective was to describe the clinical presentation and prognosis of WL-PTC and compare it to C-PTC. Subjects and methods Retrospective analysis of a prospective cohort, including 370 (96%) patients with C-PTC and 17 (4%) with WL-PTC, consecutively treated with total thyroidectomy with or without RAI, followed for at least 6 months. We compared clinical presentation, risk of mortality and recurrence, as well as response to treatment between both variants. Results Of the total cohort: 317 (82%) female, 38 ± 13.5 years, median follow-up 4 years (0.5-28.5); most of them stage I and low/intermediate risk of recurrence. We found no differences regarding clinical-pathological data and risk of recurrence. WL-PTC was associated with a higher rate of anti-thyroglobulin antibodies (TgAb) (65% vs. 36%, p = 0.016) and lymphocytic thyroiditis (59% vs. 34%, p = 0.03). The rates of biochemical and structural incomplete responses were similar in both variants. WL-PTC had a lower rate of excellent response (23% vs. 54%, p = 0.01), which became non-significant when performing analysis by TgAb presence (50% vs. 67%, p = NS). Conclusions WL-CPT and C-CPT have similar clinical presentation and rate of recurrence. The lower rate of excellent response to treatment in WL-PTC is due to a higher frequency of TgAb. WL-PCT should not be considered an aggressive variant of PTC.

Indicadores morfométricos del carcinoma papilar de tiroides diagnosticado por biopsia escisional / Morphometric indicators of thyroid papillary carcinoma diagnosed by escisional biopsy

RESUMEN Fundamento: la tiroides es donde con más frecuencia se originan enfermedades tumorales de naturaleza endocrina maligna. A este antecedente se suman las múltiples variantes histológicas que posee la enfermedad, que en ocasiones son motivo de importantes dudas diagnósticas. Por esta razón, se desarrollan estudios en los que cada vez más se añaden procedimientos morfométricos. Se reconoce que el éxito de un tratamiento individualizado depende de un diagnóstico preciso, donde la morfometría, al descartar la subjetividad en el diagnóstico se convierte en una herramienta de mucho valor. Objetivo: caracterización morfométrica del carcinoma papilar de tiroides diagnosticado por biopsias escisionales. Métodos: se realizó un estudio morfométrico de serie de casos en 12 pacientes con este diagnóstico histopatológico, atendidos en el Hospital Provincial Universitario Vladimir Ilich Lenin. Se seleccionaron 340 campos y se midieron 10 465 núcleos celulares, lo que constituyó la muestra. Se caracterizaron indicadores morfométricos nucleares del carcinoma papilar de tiroides como el área, el volumen y el factor de forma. Resultados: el área y volumen nuclear mostraron valores aumentados comparados con los valores de enfermedades nodulares benignas de otros estudios. El valor del factor de forma nuclear se acercó a uno por lo que los núcleos tienden a ser redondos y se pudo observar que a mayores valores del área nuclear mayores valores del factor de forma nuclear. Conclusiones: se caracterizaron indicadores morfométricos del carcinoma papilar de tiroides en los casos estudiados como el área, el volumen y el factor de forma que contribuyen a su diagnóstico histopatológico.

ABSTRACT Background: thyroid is where malignant endocrine tumor diseases originate more frequently. This entity possesses multiple histological variants added to this antecedent, which are usually the cause of important diagnostic doubts. For this reason, studies in which more and more morphometric procedures are added have been developed. The success of an individualized treatment depends on an accurate diagnosis, in which morphometry is recognized by ruling out subjectivity in diagnosis, becomes a valuable tool. Objective: morphometric characterization of papillary thyroid carcinoma diagnosed by excisional biopsies. Morphometric. Methods: a morphometric study of a series of cases was carried out with 12 patients with this histopathological diagnosis, attended at the Vladimir Ilich Lenin University Provincial Hospital. 340 fields were selected and 10 465 cell nuclei were measured, which was our sample. Nuclear morphometric indicators were characterized, such as area, volume and shape factor. Results: nuclear area and volume showed increased values compared to benign nodular disease values from other studies. The value of the nuclear form factor approached one, so the nuclei tend to be round and it was observed that the higher the values of the nuclear area, the higher the values of the nuclear form factor. Conclusions: morphometric indicators of papillary thyroid carcinoma were characterized in the studied cases that may contribute to histopathological diagnosis.

Metástasis pancreática como debut de carcinoma papilar de tiroides: caso clínico y revisión del perfil clínico patológico y molecular / Papillary thyroid carcinoma presenting with pancreatic metastases: report of one case

Pancreatic metastases of papillary thyroid carcinoma (PTC) are exceptional. We report a 80-year-old man consulting for obstructive jaundice and dysphonia. Abdominal ultrasonography showed biliary dilation and abdominal magnetic resonance imaging (MRI) showed a pancreatic head mass of 36 mm. A left vocal cord paralysis was confirmed and cervical computed tomography (CT) showed multiple thyroid nodules of up to 35 mm associated with bilateral cervical lymph nodes (LN). Positron emission tomography ( 18 F-FDG PET/CT) evidenced hyper-metabolic activity in bilateral cervical LN, lungs, pancreas and left intercostal soft tissue, as well as left gluteus. Thyroid biopsy reported a tall-cell variant of PTC, and endoscopic ultrasound guided fine needle aspiration (EUS-FNA) of pancreatic mass confirmed PTC metastasis. The molecular study was positive for BRAFV600E. Pancreatic metastasis from PTC can be accurately diagnosed with 18 F-FDG PET/CT and EUS-FNA, which is consistent with a predominant expression of BRAFV600E mutation and, thus, an aggressive presentation with poor short-term survival.