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Anaplastic thyroid cancer (ATC), a rare and highly aggressive malignancy, is characterized by an exceptionally poor prognosis, where the majority of patients present with extensive local invasion and/or distant metastases. 20-30% of ATCs harbor the BRAF-V600E mutation. Neoadjuvant BRAF-targeted therapy may have the potential to downstage and facilitate surgical resection for patients with locally advanced and unresectable primary tumors with BRAF mutation and may convey a survival advantage in those with metastatic disease. There is emerging evidence to support the use of other targeted agents, including multikinase inhibitors, as well as the incorporation of immunotherapy into the treatment regimen. Rapid molecular and pathological diagnosis and expert multidisciplinary discussion at specialized treatment centers are critical to expedite investigations and initiate treatment for this complex and rapidly progressive disease.
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Background: Papillary thyroid cancer (PTC) and lymphocytic thyroiditis (LT) co-occur with a prevalence of about 30%. PTC harboring BRAFV600E (PTC-BRAF) confers a worse prognosis, but it is unclear if LT alters prognostic features and recurrence of PTC. Objective: We compared the prevalence of PTC-BRAF with and without LT. The risk of adverse pathological features in (i) PTC in the presence and absence of BRAF mutation, irrespective of LT status, was compared to (ii) PTC in the presence and absence of LT, irrespective of BRAF status. Methods: We searched PubMed, Embase, and Web of Science Core Collection for observational studies published from 2010 to June 2023 on adult patients with PTC. The search strategy yielded 47 studies with relevant data. Data of baseline characteristics, clinicopathological features, and the quality assessment tool were extracted by two reviewers. The study was registered with PROSPERO (CRD42023437492). Results: Of the 47 studies, 39 studies with a total cohort of 28 143, demonstrated that the odds of PTC-BRAF were significantly lower in the presence of LT compared to its absence (odds ratio [OR] 0.53, 95% confidence interval [CI]: 0.48-0.58, p < 0.00001). In PTC-BRAF patients, there was a positive association of central neck nodal disease (CNND), PTC > 1 cm, extra-thyroidal extension, American Joint Committee on Cancer (AJCC) Stage 3-4, and multifocality with pooled ORs of 1.54 (95% CI: 1.16-2.04), 1.14 (95% CI: 0.82-1.58), 1.66 (95% CI: 1.40-1.97), 1.53 (95% CI: 1.35-1.75), and 1.24 (95% CI: 1.11-1.40) respectively, compared to wild-type PTC, irrespective of LT status. In the same studies, PTC with LT patients had lower pooled ORs of 0.64 (95% CI: 0.51-0.81) for CNND, 0.83 (95% CI: 0.73-0.95) for PTC > 1 cm, 0.71 (95% CI: 0.58-0.86) for ETE, 0.84 (95% CI: 0.75-0.94) for AJCC Stage 3-4 compared to PTC without LT, irrespective of BRAF status. PTC recurrence was not affected by BRAF or LT, with pooled ORs of 1.12 (95% CI: 0.66-1.90, p = 0.67) and 0.60 (95% CI: 0.28-1.30, p = 0.20) respectively. Similar results were seen with recurrence expressed as hazard ratio in this limited data-set. Conclusion: The odds of PTC-BRAF are significantly lower in the presence of LT than without. PTC with LT, irrespective of BRAF status, was significantly associated with better prognostic factors. Further studies are required to evaluate if LT inhibits PTC-BRAF, and whether this is relevant to the role of immunotherapy in advanced thyroid cancer.
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Summary: RET mutations are implicated in 60% of medullary thyroid cancer (MTC) cases. The RET-selective tyrosine kinase inhibitor selpercatinib is associated with unprecedented efficacy compared to previous multi-kinase treatments. Langerhans cell histiocytosis (LCH) is a clonal histiocytic neoplasm usually driven by somatic BRAF mutations, resulting in dysregulated MAPK signalling. We describe a 22-year-old woman with metastatic MTC to regional lymph nodes, lung and liver. Tumour tissue harboured a somatic pathogenic RET variant p.(M918T) and selpercatinib was commenced. She experienced sustained clinical, biochemical and radiological responses. Two years later, she developed rapidly progressive apical lung nodules, prompting biopsy. Histopathology demonstrated LCH with a rare BRAF variant p.(V600_K601>D). The lung nodules improved with inhaled corticosteroids. We hypothesize that selective pressure from RET blockade may have activated a downstream somatic BRAF mutation, resulting in pulmonary LCH. We recommend continued vigilance for neoplasms driven by dysregulated downstream MAPK signalling in patients undergoing selective RET inhibition. Learning points: Patients with RET-altered MTC can experience rapid disease improvement and sustained disease stability with selective RET blockade (selpercatinib). LCH is a clonal neoplasm driven by MAPK activation, for which the most common mechanism is BRAF mutation. Both MTC and pulmonary LCH are driven by dysregulated MAPK signalling pathway activation. We hypothesise that the RET-specific inhibitor selpercatinib may have caused the activation of dormant LCH secondary to selective pressure and clonal proliferation.
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BACKGROUND: Experience with targeted neoadjuvant treatment for locoregionally advanced thyroid cancer is nascent. METHODS: Multicenter retrospective case series examining targeted neoadjuvant treatment for locoregionally advanced thyroid cancer. The primary outcome was change in surgical morbidity as measured by two metrics developed for use in clinical trials to characterize surgical complexity and morbidity. Secondary outcomes included percentage of patients proceeding to surgery and percentage receiving an R0/R1 resection. RESULTS: Seventeen patients with varied molecular alterations, pathologies, and treatment regimens were included. Mean surgical complexity scores decreased between time points for baseline and postneoadjuvant treatment, postneoadjuvant treatment and surgery, and between baseline and surgery. Eleven patients (64.7%) underwent surgical resection, with 10 (58.8%) receiving an R0/R1 resection. CONCLUSIONS: Neoadjuvant treatment of advanced thyroid cancer improves resectability and decreases the morbidity of required surgical procedures. However, treatment is not uniformly effective.
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AIMS: Recently, there have been attempts to improve prognostication and therefore better guide treatment for patients with medullary thyroid carcinoma (MTC). In 2022, the International MTC Grading System (IMTCGS) was developed and validated using a multi-institutional cohort of 327 patients. The aim of the current study was to build upon the findings of the IMTCGS to develop and validate a prognostic nomogram to predict recurrence-free survival (RFS) in MTC. METHODS AND RESULTS: Data from 300 patients with MTC from five centres across the USA, Europe, and Australia were used to develop a prognostic nomogram that included the following variables: age, sex, AJCC stage, tumour size, mitotic count, necrosis, Ki67 index, lymphovascular invasion, microscopic extrathyroidal extension, and margin status. A process of 10-fold cross-validation was used to optimize the model's performance. To assess discrimination and calibration, the area-under-the-curve (AUC) of a receiver operating characteristic (ROC) curve, concordance-index (C-index), and dissimilarity index (D-index) were calculated. Finally, the model was externally validated using a separate cohort of 87 MTC patients. The model demonstrated very strong performance, with an AUC of 0.94, a C-index of 0.876, and a D-index of 19.06. When applied to the external validation cohort, the model had an AUC of 0.9. CONCLUSIONS: Using well-established clinicopathological prognostic variables, we developed and externally validated a robust multivariate prediction model for RFS in patients with resected MTC. The model demonstrates excellent predictive capability and may help guide decisions on patient management. The nomogram is freely available online at https://nomograms.shinyapps.io/MTC_ML_DFS/.
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Carcinoma Neuroendócrino , Nomogramas , Neoplasias da Glândula Tireoide , Humanos , Área Sob a Curva , Prognóstico , Neoplasias da Glândula Tireoide/diagnósticoRESUMO
OBJECTIVE: Somatostatin receptor (SST) functional imaging with positron emission tomography (PET)/computed tomography (CT) has broadened the diagnostic and staging capabilities for medullary thyroid cancer (MTC). Gallium-68 (68Ga)-DOTA-conjugated peptide (Tyr3)-octreotate (DOTATATE) is a radiotracer with a high affinity for type 2 SSTs expressed in several, but not all, MTCs. The utility of 68Ga-DOTATATE PET/CT and 18fluorine-labeled fluoro-2-deoxy-D-glucose (18F-FDG)-PET/CT imaging in predicting MTC prognosis is also unknown. METHODS: In this single-center retrospective study, 103 of patients with MTC underwent assessment of SST2 and SST5 immunohistochemistry (IHC). A subgroup of 37 patients received 68Ga-DOTATATE PET/CT imaging, and 13 received contemporaneous 18F-FDG-PET/CT imaging. The maximum standardized uptake value (SUV), mean SUV, metabolic tumor volume, and total lesion activity (TLA) were assessed. RESULTS: Forty-two patients (41%) demonstrated positive expression of SST2, and 45 (44%) had a positive SST5 IHC result. Seventeen patients (17%) expressed both SST2 and SST5. No survival advantage was identified with SST2 or SST5 IHC positivity. No correlation was noted between the maximum SUV, mean SUV, metabolic tumor volume, or TLA and SST2 and/or SST5 expression by IHC. Shorter survival was associated with a TLA of >20 (P = .04). A RET-negative status also appeared to have shorter survival, although this may be because the small numbers did not reach statistical significance (P = .12). CONCLUSION: Assessment of TLA from 68Ga-DOTATATE PET/CT may predict survival. SST2 IHC was not correlated with 68Ga-DOTATATE avidity. Metastatic disease may be optimally assessed by concurrent 18F-FDG and 68Ga-DOTATATE imaging.
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Carcinoma Neuroendócrino , Tumores Neuroendócrinos , Compostos Organometálicos , Cintilografia , Neoplasias da Glândula Tireoide , Humanos , Radioisótopos de Gálio , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Fluordesoxiglucose F18/metabolismo , Estudos Retrospectivos , Tomografia Computadorizada por Raios X/métodos , Tomografia por Emissão de Pósitrons/métodos , Neoplasias da Glândula Tireoide/diagnóstico por imagem , Compostos Organometálicos/metabolismoRESUMO
Background: Active surveillance (AS) is an alternative to surgery in select patients with very low risk papillary thyroid cancer (PTC). Many clinicians feel ill-equipped in selecting appropriate patients. We aimed to 1) Develop an evidence-based web delivered decision support tool to assist clinicians in identifying patients appropriate for AS; and 2) Evaluate the prevalence of patients suitable for AS in a tertiary high volume thyroid cancer centre. Method: A REDCap web based clinical support tool was developed utilising evidence-based characteristics for AS suitability available to clinicals during initial assessment. A retrospective database was interrogated for patients who underwent hemithyroidectomy between 2012 - 2021 with final histopathology demonstrating PTC. Patients with PTCs>2cm, missing data, benign disease on surgical histopathology or incidental PTC were excluded. Results: Between 2012 - 2021, 763 patients underwent hemithyroidectomy with final histopathology confirming PTC. Of these, 316 patients were excluded (missing data, incidental PTC, concomitant hyperparathyroidism were most common reasons for exclusion) and 114/447 remaining patients had a pre-operative fine needle aspirate (FNA) of Bethesda V or VI (high likelihood of malignancy). Using the tool, 59/114 (52%) met criteria for AS. The majority of patients were female (85% vs 15% male); median age 36 years (range 19 - 78). Following initial surgery, 10/59 patients had a completion thyroidectomy, with 4/10 demonstrating malignancy in contralateral lobe and eight of those patients undergoing I131 ablation. During a median follow up of over 3 years, 49/59 (83%) did not require further surgery or intervention with no patients developing recurrence. A subgroup analysis with second radiology assessment excluded 4/59 patients as meeting criteria for AS based on presence of ETE on preoperative ultrasound. None of these 4 patients had completion thyroidectomy. Conclusion: Our clinical support tool identifies patients with PTC potentially suitable for AS which could be utilised during initial patient assessment. In a retrospective cohort of patients who had hemithyroidectomy for PTC with a pre-operative FNA diagnosis of Bethesda V or VI, 55/114 (48%) patients may have been suitable for AS. Prospective validation studies are required for implementation of the tool in clinical practice.
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Diffuse sclerosing variant papillary thyroid carcinoma (DS-PTC) is characterized clinically by a predilection for children and young adults, bulky neck nodes, and pulmonary metastases. Previous studies have suggested infrequent BRAFV600E mutation but common RET gene rearrangements. Using strict criteria, we studied 43 DS-PTCs (1.9% of unselected PTCs in our unit). Seventy-nine percent harbored pathogenic gene rearrangements involving RET, NTRK3, NTRK1, ALK, or BRAF; with the remainder driven by BRAFV600E mutations. All 10 pediatric cases were all gene rearranged (P = .02). Compared with BRAFV600E-mutated tumors, gene rearrangement was characterized by psammoma bodies involving the entire lobe (P = .038), follicular predominant or mixed follicular architecture (P = .003), pulmonary metastases (24% vs none, P = .04), and absent classical, so-called "BRAF-like" atypia (P = .014). There was no correlation between the presence of gene rearrangement and recurrence-free survival. Features associated with persistent/recurrent disease included pediatric population (P = .030), gene-rearranged tumors (P = .020), microscopic extrathyroidal extension (P = .009), metastases at presentation (P = .007), and stage II disease (P = .015). We conclude that DS-PTC represents 1.9% of papillary thyroid carcinomas and that actionable gene rearrangements are extremely common in DS-PTC. DS-PTC can be divided into 2 distinct molecular subtypes and all BRAFV600E-negative tumors (1.5% of papillary thyroid carcinomas) are driven by potentially actionable oncogenic fusions.
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Carcinoma Papilar , Neoplasias Pulmonares , Neoplasias da Glândula Tireoide , Adulto Jovem , Humanos , Criança , Câncer Papilífero da Tireoide/genética , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/patologia , Proteínas Proto-Oncogênicas B-raf/genética , Carcinoma Papilar/genética , Carcinoma Papilar/patologia , Mutação , Receptores Proteína Tirosina Quinases/genéticaRESUMO
Background: The 2015 American Thyroid Association (ATA) Guidelines permit thyroid lobectomy (TL) or total thyroidectomy in the management of low-risk papillary thyroid cancer (PTC). As definitive risk-stratification is only possible post-operatively, some patients may require completion thyroidectomy (CT) after final histopathological analysis. Methods: A retrospective cohort study of patients undergoing surgery for low-risk PTC in a tertiary referral centre was undertaken. Consecutive adult patients treated from January 2013 to March 2021 were divided into two groups (pre- and post-publication of ATA Guidelines on 01/01/2016). Only those eligible for lobectomy under rule 35(B) of the ATA Guidelines were included: Bethesda V/VI cytology, 1-4 cm post-operative size and without pre-operative evidence of extrathyroidal extension or nodal metastases. We examined rates of TL, CT, local recurrence and surgical complications. Results: There were 1488 primary surgical procedures performed for PTC on consecutive adult patients during the study period, of which 461 were eligible for TL. Mean tumour size (P = 0.20) and mean age (P = 0.78) were similar between time periods. The TL rate increased significantly from 4.5 to 18% in the post-publication period (P < 0.001). The proportion of TL patients requiring CT (43 vs 38%) was similar between groups (P = 1.0). There was no significant change in complications (P = 0.55) or local recurrence rates (P = 0.24). Conclusion: The introduction of the 2015 ATA Guidelines resulted in a modest but significant increase in the rate of lobectomy for eligible PTC patients. In the post-publication period, 38% of patients who underwent TL ultimately required CT after complete pathological analysis.
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A personalized approach to the management of medullary thyroid cancer (MTC) presents several challenges; however, in the past decade significant progress has been made in both diagnostic and treatment modalities. Germline rearranged in transfection (RET) testing in multiple endocrine neoplasia 2 and 3, and somatic RET testing in sporadic MTC have revolutionized the treatment options available to patients. Positron emission tomography imaging with novel radioligands has improved characterization of disease and a new international grading system can predict prognosis. Systemic therapy for persistent and metastatic disease has evolved significantly with targeted kinase therapy especially for those harboring germline or somatic RET variants. Selpercatinib and pralsetinib are highly selective RET kinase inhibitors that have shown improved progression-free survival with better tolerability than outcomes seen in earlier multikinase inhibitor studies. Here we discuss changes in paradigms for MTC patients: from determining RET alteration status upfront to novel techniques for the evaluation of this heterogenous disease. Successes and challenges with kinase inhibitor use will illustrate how managing this rare malignancy continues to evolve.
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Carcinoma Medular , Carcinoma Neuroendócrino , Neoplasias da Glândula Tireoide , Humanos , Carcinoma Medular/patologia , Proteínas Proto-Oncogênicas c-ret/genética , Carcinoma Neuroendócrino/diagnóstico , Carcinoma Neuroendócrino/genética , Carcinoma Neuroendócrino/terapia , Neoplasias da Glândula Tireoide/diagnóstico , Neoplasias da Glândula Tireoide/tratamento farmacológico , Neoplasias da Glândula Tireoide/genéticaRESUMO
Background: BRAFV600E and N/H/K RAS mutations and oncogenic kinase fusions involving neurotrophin tyrosine receptor kinase (NTRK), RET, anaplastic lymphoma kinase (ALK), and ROS1 have been identified as actionable targets in thyroid cancer. These driver alterations lead to oncogene addiction, which has been successfully exploited through tyrosine kinase inhibitors. Acquired resistance may develop following an initial response requiring a therapeutic pivot to new therapies. Summary: Several pathways for development of acquired resistance have been identified. These encompass acquired on-target gene mutation impeding drug activity and upregulation of bypass kinase signaling pathways leading to tumor progression. Biopsy of resistant lesions (liquid or tissue) and subsequent molecular analysis can assist with new therapeutic strategies. Conclusions: Progression-free survival is curtailed by developing acquired resistance. To minimize this therapeutic liability, clinicians must be anticipatory in identifying the drivers and characterizing mechanisms of on-target resistance.
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Neoplasias Pulmonares , Neoplasias da Glândula Tireoide , Humanos , Proteínas Tirosina Quinases/genética , Neoplasias Pulmonares/tratamento farmacológico , Proteínas Proto-Oncogênicas/genética , Receptores Proteína Tirosina Quinases/genética , Neoplasias da Glândula Tireoide/genética , Mutação , Inibidores de Proteínas Quinases/uso terapêuticoRESUMO
CONTEXT: Management of sporadic medullary thyroid microcarcinoma smaller than 1 cm (micro-MTC) is controversial because of conflicting reports of prognosis. As these cancers are often diagnosed incidentally, they pose a management challenge when deciding on further treatment and follow-up. OBJECTIVE: We report the outcomes of surgically managed sporadic micro-MTC in a specialist endocrine surgery and endocrinology unit and identify associations for recurrence and disease-specific survival in this population. METHODS: Micro-MTCs were identified from a prospectively maintained surgery database, and slides were reviewed to determine pathological grade. The primary end points were recurrence, time to recurrence and disease-specific survival. Prognostic factors assessed included size, grade, lymph node metastasis (LNM), and postoperative calcitonin. RESULTS: From 1995 to 2022, 64 patients were diagnosed with micro-MTC with 22 excluded because of hereditary disease. The included patients had a median age of 60 years, tumor size of 4 mm, and 28 (67%) were female. The diagnosis was incidental in 36 (86%) with 4 (10%) being high grade, 5 (12%) having LNM and 9 (21%) having elevated postoperative calcitonin. Over a 6.6-year median follow-up, 5 (12%) developed recurrence and 3 (7%) died of MTC. High grade and LNM were associated with 10-year survival estimates of 75% vs 100% for low grade and no LNM (hazard ratio = 831; P < .01). High grade, LNM, and increased calcitonin were associated with recurrence (P < .01). Tumor size and type of surgery were not statistically significantly associated with recurrence or survival. No patients with low grade micro-MTC and normal postoperative calcitonin developed recurrence. CONCLUSION: Most sporadic micro-MTCs are detected incidentally and are generally associated with good outcomes. Size is not significantly associated with outcomes. Using grade, LNM, and postoperative calcitonin allows for the identification of patients at risk of recurrence to personalize management.
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Conservadores da Densidade Óssea , Carcinoma Medular , Hormônios Peptídicos , Neoplasias da Glândula Tireoide , Humanos , Feminino , Pessoa de Meia-Idade , Masculino , Calcitonina , Neoplasias da Glândula Tireoide/diagnóstico , Neoplasias da Glândula Tireoide/cirurgia , Neoplasias da Glândula Tireoide/patologia , Tireoidectomia , Excisão de Linfonodo , Carcinoma Medular/cirurgia , Prognóstico , Hormônios e Agentes Reguladores de Cálcio , Estudos RetrospectivosRESUMO
Diffuse sclerosing variant (DSV) of papillary thyroid carcinomais a rare form of thyroid cancer that demonstrates more aggressive histopathology than classical papillary thyroid carcinoma (c-PTC); however, if this leads to worse survival is debated. Many DSVs are driven by fusion events which are of recent clinical importance due to the advent of targeted RET inhibitors. A systematic search and meta-analysis of the literature was performed to compare outcomes of disease-specific mortality (DSM), metastatic and recurrent disease and the incidence of fusion events between DSV and c-PTC to July 2022. The Newcastle-Ottawa Quality Assessment studies was used to assess quality. An odds ratio (OR) was utilised to measure outcomes with 95% CIs. The Preferred Reporting Items for Systematic Reviews and Meta-analysis guideline was followed. Seventeen studies were included with 874 DSV patients compared to 76,013 c-PTC patients. DSV patients had worse DSM (OR=2.50, 95% CI 1.39-4.51) and presented with a higher rate of metastatic lymph nodes (OR = 5.85, 95% CI 2.73-12.53) and more distant metastases (OR = 3.83, 95% CI 2.17-6.77). DSV patients had higher odds of recurrent disease (OR = 3.23, 95% CI 2.00-5.23) and overall distant metastasis (OR = 2.70, 95% CI 1.74-4.17). Rates of RET fusion alterations for DSV ranged from 25 to 83%. DSV has a worse prognosis than c-PTC with higher rates of recurrent disease and distant metastasis. The high prevalence of RET fusions offers the potential to improve outcomes for patients with DSV.
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Carcinoma Papilar , Neoplasias da Glândula Tireoide , Humanos , Câncer Papilífero da Tireoide , Carcinoma Papilar/patologia , Neoplasias da Glândula Tireoide/patologia , PrognósticoRESUMO
Background: Genomic deletions in medullary thyroid cancer (MTC) are rare. Selpercatinib is a highly selective RET inhibitor for treatment of metastatic RET-altered MTC. We report a 35-year-old male with an aggressive metastatic MTC harboring p.632_633del RET that was poorly responsive to RET kinase inhibitor selpercatinib. Objective: Our objective was to understand the clinical phenotype of p.632_633del RET in MTC in the context of novel RET kinase inhibitor treatment. Methods: Wild-type and p.632_633del RET sequences were modeled using a lighter version of the AlphaFold2 (AF2) software. Functional studies were performed on transfected HEK 293 cells (pCMV6-Entry, pCMV6-RET, or pCMV6-RET(p.632_633del) treated with inhibitors for 24 hours and analyzed on luciferase assays. Results: Structural modeling revealed a paucity of disulfide bridge between Cys630-Cys634 in p.632_633del RET sequences, apparent in wild-type, while forming an intermolecular disulfide bridge between two Cys656. Proximity of juxtamembrane segments of each dimer may impede Tyr687 phosphorylation and stable conformation of intracellular RET that hosts selpercatinib. In vitro experiments confirmed a reduction in efficacy of selpercatinib upon p.632_633del RET compared with wild-type RET control. Conclusion: Clinical presentation together with structural modeling and functional studies suggests that p.632_633del RET results in poor response to selpercatinib.
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Carcinoma Neuroendócrino , Neoplasias da Glândula Tireoide , Masculino , Humanos , Proteínas Proto-Oncogênicas c-ret/genética , Células HEK293 , Carcinoma Neuroendócrino/genética , Neoplasias da Glândula Tireoide/tratamento farmacológico , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/patologia , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/farmacologiaRESUMO
OBJECTIVE: We propose a new scoring system (I-PET) combining whole body scan (WBS) and FDG findings to identify patients who have or are likely to become refractory to radioactive iodine. DESIGN: Retrospective analysis of 142 patients age >18 with differentiated thyroid cancer who had a F-18 labelled fluoro-2-deoxyglucose (18 F-FDG) positron emission tomography (PET) and WBS within a 6-month period between 2010 and 2020. Pairs of 18 F-FDG PET and WBS were reviewed by three independent nuclear medicine physicians and an I-PET score was assigned: I-PET [0]: Iodine -ve/FDG -ve, I-PET [1]: Iodine +ve/FDG -ve, I-PET [2]: Iodine +ve/FDG +ve and I-PET [3]: Iodine -ve/FDG +ve. Patients with FDG +ve lesions (I-PET [2] and I-PET [3]) were further classified into groups A and B if SUVmax was ≤5 or >5, respectively. Follow-up data were obtained by chart review. Progression was defined as structural progression as per RECIST 1.1 or further surgical intervention; or biochemical progression as unstimulated thyroglobulin increasing >20% from baseline. RESULTS: Of 142 patients included in the study 121 patients had follow-up data available for review. At baseline, 49 patients were classified as I-PET [0], 10 as I-PET [1], 16 as I-PET [2] and 46 as I-PET [3]. Progression was seen in 11/49 (22%) of I-PET [0], 4/10 (40%) of I-PET [1], 10/16 (63%) of I-PET [2] and 34/46 (74%) of I-PET [3] (p < 0.001). I-PET [2B] and I-PET [3B] had a progression rate of 88% (7/8) and 78% (25/32), respectively. I-PET [3B] were 9.6 times more likely to commence multikinase inhibitor therapy (p = 0.001) and had 8 times greater mortality (p = 0.003) than patients in other I-PET groups combined. CONCLUSION: I-PET is a simple readily acquired imaging biomarker that potentially enhances the dynamic risk stratification and guide treatment in thyroid cancer.
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Iodo , Neoplasias da Glândula Tireoide , Humanos , Neoplasias da Glândula Tireoide/patologia , Fluordesoxiglucose F18 , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Estudos Retrospectivos , Radioisótopos do Iodo , Tomografia por Emissão de Pósitrons , Tireoglobulina , Imagem Corporal TotalRESUMO
Thyroid cancer is the most common endocrine cancer, with papillary thyroid carcinoma (PTC) accounting for the majority of these cases. Cerebellar metastasis is rarely the presenting feature and confers poor prognosis. Genetic mutations in this setting are most commonly TERTp, in contrast to BRAF V600E in the majority of PTC. We report the case of an 82 year-old male who presented with a symptomatic right cerebellar lesion and underwent surgical resection to demonstrate metastatic PTC. Extensive workup with computed tomography, neck ultrasound and FDG-PET was suggestive of a left thyroid primary lesion, with FNA confirming PTC. However, total thyroidectomy demonstrated incidental microMTC (medullary thyroid microcarcinoma, defined as tumour <10mm) without any evidence of PTC, whereas the left level VI neck dissection demonstrated a 30mm nodule of PTC without identifiable normal thyroid or lymph node tissue.
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CONTEXT: Metastatic medullary thyroid carcinoma (MTC) and radioactive iodine-refractory differentiated thyroid carcinoma (RAI-R DTC) have poor prognosis and limited treatment options. Selpercatinib (LOXO-292), a selective kinase inhibitor targeting the RET gene, has shown a 69% to 79% objective response rate in this cohort with benefits in other tumors including lung cancer harboring the same oncogenic driver. Published reports describe only 17% of patients experiencing gastrointestinal (GI) adverse effects (AEs), which is in contrast to our local experience. OBJECTIVE: Here we characterize the AEs and correlate them with radiological and histopathological findings. METHODS: Sequential patients enrolled in LIBRETTO-001 at Royal North Shore Hospital, Sydney, Australia, with available imaging (nâ =â 22) were recruited. Patients had regular visits with AEs documented and computed tomography (CT) scans every 3 months. CT at screening, at time of GI AE, and at most recent follow-up were reviewed and scored. Endoscopic examination was performed in 5 patients. RESULTS: Of 22 patients in this cohort, the majority had somatic RET alterations (nâ =â 18), most commonly p.Met918Thr (nâ =â 14). Ten patients (50%) developed GI AEs. Dose reduction was required in 8 of the 10 patients, but none discontinued therapy. The majority had stable disease (nâ =â 17). Gastric and small-bowel edema was evident in symptomatic patients after a median time of 67 weeks' treatment. Histological correlation in 5 patients revealed mucosal edema correlating with radiological evidence of congestion and edema. CONCLUSION: GI AEs with selpercatinib may be more common than previously described. Most are self-limiting but often require dose adjustments. Histological evidence of mucosal edema observed in conjunction with the radiological findings of congestion and wall thickening suggest bowel-wall edema is a predominant mechanism of abdominal pain in these patients.
Assuntos
Neoplasias da Glândula Tireoide , Trato Gastrointestinal/efeitos dos fármacos , Humanos , Radioisótopos do Iodo/uso terapêutico , Proteínas Proto-Oncogênicas c-ret/genética , Pirazóis/efeitos adversos , Pirazóis/uso terapêutico , Piridinas/efeitos adversos , Piridinas/uso terapêutico , Neoplasias da Glândula Tireoide/tratamento farmacológico , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/patologiaRESUMO
Purpose: Papillary thyroid microcarcinoma (PTMC) is typically indolent in nature, allowing management with active surveillance protocols. Occasionally, a more aggressive phenotype can present and may lead to poor outcomes such as patients presenting with clinically significant lateral lymphadenopathy (cN1b). Prior analysis of the outcomes of this cohort is largely from papillary thyroid cancer (PTC) (>1 cm) or from institutions where use of radioactive iodine (RAI) is limited. Hence, we aim to describe the outcomes of patients with PTMC who presented with palpable cN1b disease, treated with total thyroidectomy and RAI. Methodology: We performed a retrospective cohort study. Outcomes of patients with PTMC who presented with palpable lateral lymph node (LN) metastases (microPTC cN1b) treated between 1997 and 2020 at Royal North Shore Hospital were compared with two control groups' outcomes: patients with clinically detected PTMC without evidence of involved LNs (microPTC cN0) and with larger PTC (>10 mm) who presented with palpable lateral lymphadenopathy (larger PTC cN1b). We assessed clinicopathological variables, postoperative risk stratification, rates of disease recurrence, reoperative surgery, and structural disease-free survival (DFS). Results: In total, 1534 PTMCs were diagnosed following thyroid surgery in the study period; of these, 157 (10%) were clinically detected microPTC cN0 and 26 microPTC cN1b (1.7%). There were 138 patients in the larger PTC cN1b control group. All cN1b patients were treated with total thyroidectomy and adjuvant RAI. Mean size of the largest LN deposit was similar between the microPTC cN1b and larger PTC cN1b groups (23 vs. 27 mm, p = 0.11). Patients with microPTC cN1b were more likely to have biochemical or structural persistence or recurrence compared with microPTC cN0 (19%, 5/26 vs. 3.8%, 6/157, p = 0.002) but less likely than larger PTC cN1b patients (19%, 5/26 vs. 42%, 58/138, p = 0.04). All patients in the microPTC cN1b group who had an excellent response to initial therapy (85%, 22/26) were disease free at last follow-up. The rate of reoperation was similar for the microPTC cN1b and microPTC cN0 groups (4%, 1/26 vs. 2%, 3/157, p = 0.461) and significantly lower than the larger PTC cN1b group (4%, 1/26 vs. 26%, 36/138, p = 0.002). Five-year DFS estimates were significantly better for microPTC cN1b patients than for larger PTC cN1b patients (94% vs. 59%, p = 0.001). Conclusions: MicroPTC cN1b patients treated with thyroidectomy and adjuvant RAI have inferior clinical outcomes compared with microPTC cN0 patients but have better outcomes than their larger PTC cN1b counterparts with respect to disease persistence and recurrence. Response to initial therapy provides valuable prognostication in microPTC cN1b patients: if these patients had an excellent response to initial treatment, they achieved long-term DFS in this series.
Assuntos
Linfadenopatia , Neoplasias da Glândula Tireoide , Carcinoma Papilar , Humanos , Radioisótopos do Iodo/uso terapêutico , Linfadenopatia/tratamento farmacológico , Linfadenopatia/cirurgia , Metástase Linfática , Recidiva Local de Neoplasia/epidemiologia , Estudos Retrospectivos , Câncer Papilífero da Tireoide/tratamento farmacológico , Câncer Papilífero da Tireoide/cirurgia , Neoplasias da Glândula Tireoide/patologia , Tireoidectomia/métodosRESUMO
Background: The goal of radioactive iodine (RAI) in differentiated thyroid cancer (DTC) is to treat metastasis and reduce recurrence risk. International guidelines provide broad risk stratification to aid treatment decisions, but a more nuanced approach to individualize care is warranted. We developed a predictive risk model for DTC. Methods: We performed a retrospective multivariable analysis of 899 patients who received RAI after thyroidectomy at a quaternary center in Australia between 2008 and 2016. Collected data included age, gender, histology, stimulated thyroglobulin (sTg), and 8th American Joint Committee Cancer (AJCC) staging. The ATA Modified Initial Risk (ATA) was calculated retrospectively. Recurrence was defined as clinically significant progression requiring either surgical intervention or administration of a second activity of RAI. Synchronous metastasis was defined as distant metastasis (i.e., outside of the neck) that was present at the time of diagnosis on structural imaging or initial post-iodine treatment scan. The features significantly associated with synchronous metastasis or recurrence were employed in the generation of a predictive risk model. A separate cohort of 393 patients who received RAI in 2017-2021 was used for validation. Results: On multivariate analysis, sTg ≥10 µg/L, extrathyroidal extension (ETE) and lymph node involvement predicted recurrence. Independent of ATA, patients with sTg ≥10 µg/L had a shorter disease-free survival (DFS) than those with sTg <10 µg/L (p < 0.001). The ETE stratified by four histological categories was significantly associated with worse DFS (p < 0.001). In a subset of patients, the presence of thyroglobulin antibody (TgAb) did not influence recurrence in patients with sTg <10 µg/L. On multivariate analysis, widespread ETE, sTg ≥10 µg/L, multifocal papillary thyroid cancer and follicular thyroid cancer were positively associated with synchronous metastasis. A predictive risk model was developed to estimate synchronous metastasis/recurrence risk and validated successfully in the second cohort. Conclusions: Our novel predictive risk model modifies and extends ATA stratification by including sTg and ETE, which we found to be independent predictors of both recurrence and synchronous metastasis in DTC.