Promising Therapeutic Targets for Recurrent/Metastatic Anaplastic Thyroid Cancer.

OPINION STATEMENT: Anaplastic thyroid cancer presents formidable challenges, particularly in cases of recurrence or metastasis. Timely BRAF V600E testing is imperative at diagnosis, initially through immunohistochemistry, followed by comprehensive genomic profiling encompassing genes such as NTRK, RET, ALK, and assessment of tumor mutation burden (TMB). FDA-approved treatment options include dabrafenib and trametinib for patients with BRAF mutations, while those exhibiting high TMB may benefit from pembrolizumab. Further therapeutic decisions hinge upon mutational profile, urgency of response required, airway integrity, and access to targeted therapies There is growing use of immunotherapy for ATC based on published reports of activity, but currently there is no FDA approved agent for ATC. The off-label utilization of "precision medicine" combinations imposes a considerable financial strain, underscoring the necessity for further clinical trials to elucidate promising therapeutic avenues for this orphan disease. There is a pressing need for the development and support of clinical trials investigating genomically driven and immune-based therapies for anaplastic thyroid cancer.

Cervical lymph node metastasis as the first symptom of combined anaplastic thyroid carcinoma (squamous cell carcinoma) and follicular carcinoma: a case report.

BACKGROUND: Anaplastic thyroid carcinoma(ATC) is a rare pathological type of thyroid malignancy. Primary squamous cell carcinoma of thyroid(PSCCT) is now considered as a subtype of ATC, hereinafter referred to as ATC-SCC subtype. ATC-SCC subtype combined with follicular thyroid carcinoma is exceedingly rare, with fewer cases reported. The ATC-SCC subtype is a highly invasive tumor with a poor prognosis for patients after metastasis occurs, and current treatment of this type of tumor is tricky. CASE PRESENTATION: A 68-year-old female patient presented with a gradually growing swelling of right cervical region. Comprehensive auxiliary examinations and postoperative pathology confirmed the diagnosis of ATC-SCC subtype with follicular thyroid carcinoma, and the metastasis squamous cell carcinoma of the right cervical lymph nodes originates from ATC-SCC subtype. The patient received chemoradiotherapy postoperative. However, the residual cervical lymph nodes metastasis with squamous cell carcinoma still infiltrated surrounding structures in the neck extensively after palliative resection. The patient died 7 months after surgery. CONCLUSION: Our case highlights that cervical lymph node metastasis may be a significant factor in the poor prognosis of ATC-SCC subtype. This malignancy should be detected and treated early.

Non-papillary thyroid carcinoma diagnoses in The Bethesda System for Reporting Thyroid Cytopathology categories V and VI: An institutional experience.

BACKGROUND: The non-papillary thyroid carcinoma (PTC) subgroups of The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) categories V (Suspicious for malignancy) and VI (Malignant) are rare, and specific tumor typing is difficult. We aimed to analyze histologic outcomes and to investigate the points of caution. METHODS: We reviewed the electronic database and identified 12,215 cases of thyroid fine-needle aspiration cytology between 2013 and 2022. In total, 2783 patients were diagnosed with TBSRTC V or VI. Of these, 51 patients with non-PTC diagnosis were identified. Histological outcomes were analyzed with the cytologic findings. RESULTS: The subgroups of non-PTC diagnoses in TBSRTC category V or VI consisted of medullary thyroid carcinoma (MTC) (13/51, 25.5 %), anaplastic thyroid carcinoma (3/51, 5.9 %), lymphoma (2/51, 3.9 %), metastatic tumor (4/51, 7.8 %), and malignant, not otherwise specified (NOS) (29/51, 56.9 %). The concordance rate of the histological outcomes was 30 % (12/40), predominantly comprising MTC cases. The obscuring factors for specific tumor typing in the suspicious for malignancy/malignant NOS cytology diagnosis group was mixed pattern of well differentiated thyroid carcinoma and less differentiated carcinoma cells (9/24, 37.5 %), low cellularity (7/24, 29.2 %) and a history of non-thyroid organ malignancy (6/24, 25 %). The less differentiated carcinoma component in mixed pattern consisted of 2 poorly differentiated thyroid carcinomas, 2 anaplastic thyroid carcinomas, 4 high-grade PTCs and 1 high-grade MTC. CONCLUSION: The high-grade feature of PTC or MTC cytology is a noteworthy obscuring factor in specific tumor typing of non-PTC cytology diagnosis.

[Interpretation of the pathological diagnostic criteria and characteristics of high-grade thyroid follicular-derived carcinoma in the 5th edition WHO classification].

The 5th edition WHO classification of thyroid tumors proposed high-grade non-anaplastic thyroid carcinoma, which includes traditional poorly differentiated thyroid carcinoma (PDTC) and differentiated high-grade thyroid carcinoma (DHGTC), with a prognosis between highly differentiated thyroid carcinoma and anaplastic thyroid carcinoma (ATC), in which about 50% of patients do not take radioactive iodine. Therefore, this classification is of great clinical significance. This article interprets the diagnostic criteria and genetic features of high-grade non-anaplastic thyroid carcinoma in 5th edition WHO classification, comparing with ATC.

Molecular targets of tyrosine kinase inhibitors in thyroid cancer.

Thyroid cancer (TC) is the eighth most frequently diagnosed cancer worldwide with a rising incidence in the past 20 years. Surgery is the primary strategy of therapy for patients with medullary TC (MTC) and differentiated TC (DTC). In DTC patients, radioactive iodine (RAI) is administered after thyroidectomy. Neck ultrasound, basal and thyroid-stimulating hormone-stimulated thyroglobulin are generally performed every three to six months for the first year, with subsequent intervals depending on initial risk assessment, for the detection of possible persistent/recurrent disease during the follow up. Distant metastases are present at the diagnosis in ∼5 % of DTC patients; up to 15 % of patients have recurrences during the follow up, with a survival reduction (70 %-50 %) at 10-year. During tumor progression, the iodide uptake capability of DTC cancer cells can be lost, making them refractory to RAI, with a negative impact on the prognosis. Significant advances have been done recently in our understanding of the molecular pathways implicated in the progression of TCs. Several drugs have been developed, which inhibit signaling kinases or oncogenic kinases (BRAFV600E, RET/PTC), such as those associated with Platelet-Derived Growth Factor Receptor and Vascular Endothelial Growth Factor Receptor. Tyrosine kinase receptors are involved in cancer cell proliferation, angiogenesis, and lymphangiogenesis. Several tyrosine kinase inhibitors (TKIs) are emerging as new treatments for DTC, MTC and anaplastic TC (ATC), and can induce a clinical response and stabilize the disease. Lenvatinib and sorafenib reached the approval for RAI-refractory DTC, whereas cabozantinib and vandetanib for MTC. These TKIs extend median progression-free survival, but do not increase the overall survival. Severe side effects and drug resistance can develop in TC patients treated with TKIs. Additional studies are needed to identify a potential effective targeted therapy for aggressive TCs, according to their molecular characterization.

Identification of novel characteristic biomarkers and immune infiltration profile for the anaplastic thyroid cancer via machine learning algorithms.

PURPOSE: Anaplastic thyroid cancer (ATC) is a rare and lethal malignant cancer. In recent years, the application of molecular-driven targeted therapy and immunotherapy has markedly improved the prognosis of ATC. This study aimed to identify characteristic genes for ATC diagnosis and revealed the role of ATC characteristic genes in drug sensitivity and immune cell infiltration. METHODS: We downloaded ATC RNA-sequencing data from the GEO database. Following the combination and normalization of the dataset, we first divided the combined datasets into the training cohort and the validation cohort. We identified differentially expressed genes (DEGs) in ATC by differential expression analysis in the training cohort. We used two machine learning algorithms, least absolute shrinkage and selection operator (LASSO) and support vector machine-recursive feature elimination (SVM-RFE) to identify ATC characteristic genes. The CIBERSORT algorithm was performed to calculate the abundance of various immune cells in ATC. Finally, we validated the expression of ATC characteristic genes by quantitative RT-PCR (RT-qPCR) in ATC cell lines and immunohistochemistry (IHC). RESULTS: A total of 425 DEGs were identified in the training cohort, including 240 upregulated genes and 185 downregulated genes. Four ATC characteristic genes (ADM, PXDN, MMP1, and TFF3) were identified, and their diagnostic value was validated in the validation cohort (AUC in ROC analysis > 0.75). We established a practical gene expression-based nomogram to accurately predict the probability of ATC. We also found that ATC characteristic biomarkers are associated with the tumor immune microenvironment and drug sensitivity. CONCLUSION: ADM, PXDN, MMP1, and TFF3 might serve as potential ATC diagnostic biomarkers and may be helpful for ATC molecular targeted therapy and immunotherapy.

An exceptionally rare case of metastatic osteoclast-like giant cell-rich variant of anaplastic thyroid carcinoma: A diagnostic challenge.

Osteoclast-like giant cell-rich variant of anaplastic thyroid carcinoma is extremely uncommon. In this paper we describe one such case in a 50 year-old male. The patient presented with enlarged cervical lymph node after initial total thyroidectomy. The fine needle aspiration cytology (FNAC) smear showed abundant multinucleated osteoclastic-like giant cells and scattered large bizarre tumour cells. FNAC of such cases may often be mistaken as osteoclast-like giant cell-rich lesions.

Evaluation of anaplastic thyroid carcinoma in the Kurdistan region of Iraq.

BACKGROUND: Anaplastic thyroid carcinoma is a rare and lethal disease that accounts for 1-2% of thyroid malignancies. It is an aggressive locoregional disease with a high rate of distant metastasis, a poor prognosis, and a mean survival rate of 3-6 months after diagnosis. This retrospective study aimed to analyse the clinical and pathological features of ATC to assess treatment procedures and its outcome. METHODS: We analysed data from 22 patients diagnosed with ATC from 2018 to 2021, using the Kaplan-Meier method and log-rank test to determine overall survival. RESULTS: Patients' median age was 64.3 ± 17.1 years. Females were more affected (male/female ratio: 1:1.7); 14 cases occurred in females (63.6.4%), and eight in males (36.4%). The most common manifestations were neck enlargement (81.8%) and dyspnoea (72.27%), and the tumour size was > 4 cm in 17 (77.3%) patients. The percentage of cases that presented in clinical-stage IVA was 36.4%, with 31.8% presenting in clinical-stage IVB and 31.8% presenting in clinical-stage VIB. Among 22 cases, 14 (63.6%) were operable, and 8 (36.4) were inoperable (p = 0.015). Multimodal therapies were associated with better survival (surgery plus radiotherapy without systemic treatment, P = 0.063). The median overall survival was three months (IC 95%, 0.078-5.922). One-year and two-year survival rates were 9% and 4.5%, respectively. CONCLUSION: ATC is a rapidly growing cancer that, fortunately, is rare. Early diagnosis and multimodality treatment may provide a better quality of life and survival time for this group of patients.

IGF2BP1 is the first positive marker for anaplastic thyroid carcinoma diagnosis.

Anaplastic thyroid carcinomas (ATC) are rare, but represent the most lethal malignancy of the thyroid. Selective molecular markers and drivers distinguishing ATC from other thyroid carcinomas of follicular origin remain largely unknown, limiting advances in diagnosis and treatment. In a retrospective study, we analyzed gene expression in 36 ATC, 18 poorly differentiated, 132 papillary, and 55 follicular thyroid carcinoma, as well as 124 paired and unpaired normal thyroid tissues in three independent cohorts by RNA-sequencing and immunohistochemistry. RNA-sequencing data in the test cohort suggested selective ATC protein biomarkers. Evaluation of these revealed that ATCs are characterized by the de novo expression of various testis antigens, including melanoma-associated antigen A3 (MAGEA3), but most importantly the oncofetal IGF2 mRNA binding protein 1 (IGF2BP1). Shallow whole genome sequencing essentially excluded that IGF2BP1 upregulation results from gene copy number alterations. Immunohistochemical analyses in all three tumor cohorts confirmed the selective de novo expression of IGF2BP1 protein in ATC. In sum, 75% (27/36) of all tested ATC and 0.5% (1/204) of poorly and well-differentiated thyroid carcinoma tissue samples were positive for IGF2BP1 protein. This indicates that IGF2BP1 protein expression identifies ATC with a diagnostic odds ratio of 612 (95% CI: 74.6-5021). In addition, we found that MAGEA3 is exclusively, although less consistently upregulated in ATC, presenting with an odds ratio of 411 (95% CI: 23.8-7098.7). Importantly, we provide confirmatory evidence that IGF2BP1 and MAGEA3 expression distinguishes ATC from poorly differentiated thyroid carcinoma. IGF2BP1 furthermore identified ATC foci within low-grade follicular thyroid carcinoma. In conclusion, IGF2BP1 represents the most promising single-gene marker available for ATC, followed by MAGEA3, improving on current techniques. Robust markers are essential to help distinguish this high-grade malignancy from other thyroid carcinomas, to guide surgical decision making, therapy and post-resection/therapy monitoring strategies.

Treatment of anaplastic thyroid cancer with tyrosine kinase inhibitors targeted on the tumor vasculature: initial experience in clinical practice.

Anaplastic thyroid cancer (ATC) is a rarely occurring refractory disease. While recent clinical trials have demonstrated the efficacy of tyrosine kinase inhibitor (TKI) therapy for ATC, evidence is scarce in clinical practice. In this study, we reviewed our initial experiences with TKI treatment in ATC patients with the aim of revealing the efficacy and safety of the same in clinical practice. We retrospectively reviewed our experiences with TKI treatment use in ATC patients diagnosed at our institute from 2014 to 2019. Changes in the patients' neutrophil-to-lymphocyte ratio (NLR) by TKI therapy introduction as well as their clinical factors to indicate the efficacy were examined. Seven patients showed no indication for TKI treatment, while 13 (65%) received treatment. The median duration of TKI treatment was 1.9 months. All patients died, and the overall survival period from diagnosis was 4.7 (95% confidence interval: 2.0-11.5) months. Adverse events ≥Grade 3 were observed commonly (92.3%), and resulted in the termination of TKI treatment in six cases (46.1%). Existence of multiple unfavorable characteristics (higher Prognostic Index) was associated with poor survival. The NLR decreased after the introduction of TKIs and increased again when treatment failed. The response rate to TKI among the ATC patients were approximately 30% in practice. Although the duration of the response was short, several patients demonstrated long survival durations when TKI treatment was provided after successful multidisciplinary treatment to control local disease. Decreases in high NLR values during treatment may suggest the continued effect of TKIs.

[Anaplastic thyroid carcinoma : new therapeutic approaches]. / Carcinome anaplasique de la thyroïde : nouvelles approches thérapeutiques.

Anaplastic thyroid cancer (ATC) is among the most aggressive cancers with a median overall survival of 4 months and a disease-specific mortality of close to 100%. As soon as the diagnosis is suspected or established, urgent referral to an experienced multidisciplinary center is imperative. Chemotherapy has limited efficacy. Molecular analyses, together with the availability of novel targeted therapies and immunotherapies, now permit to improve outcomes. In particular, targeted therapy with dabrafenib and trametinib is indicated as first-line therapy for BRAF V600E-mutated ATC.

Le cancer anaplasique de la thyroïde (CAT) compte parmi les cancers les plus agressifs avec une survie médiane de 4 mois et une mortalité spécifique à la maladie proche de 100 %. Dès que le diagnostic est suspecté ou établi, une orientation urgente vers un centre multidisciplinaire expérimenté est essentielle. La chimiothérapie a une efficacité limitée. Les analyses moléculaires, ainsi que la disponibilité de nouvelles thérapies ciblées et d'immunothérapies, permettent désormais d'améliorer les résultats. En particulier, le CAT avec mutation BRAF V600E bénéficie d'une combinaison de thérapies ciblées par dabrafénib et tramétinib en traitement de première ligne.

Histological features of BRAF V600E-mutant anaplastic thyroid carcinoma.

AIMS: Treatment with a BRAF inhibitor, alone or in combination with a MEK inhibitor, may be considered for BRAF-mutant anaplastic thyroid carcinoma (ATC). The purpose of this study was to characterise the histology of BRAF V600E-mutant ATC. METHODS AND RESULTS: We identified 28 ATC that were consecutively resected between 2003 and 2019. All tumour slides for each case were evaluated for the presence of a precursor tumour and for ATC morphology (sarcomatoid, pleomorphic giant cell, epithelioid or squamous). BRAF V600E mutation status was determined by BRAF V600E IHC or molecular analysis (OncoPanel NGS). Eighteen (64%) ATC had an associated well-differentiated precursor, including 10 (36%) with associated papillary thyroid carcinoma (PTC) and eight (29%) with associated follicular thyroid carcinoma (FTC) or Hürthle cell carcinoma (HCC). Most ATC (19 cases, 68%) demonstrated a mixed anaplastic morphology. Squamous morphology was present in four cases. Ten (36%) ATC had a BRAF V600E mutation. All ATC that had a PTC precursor had a BRAF V600E mutation (and all ATC with a BRAF V600E mutation had a PTC precursor), whereas no ATC with an FTC or HCC precursor had a BRAF V600E mutation. All four cases of ATC with a squamous morphology had a PTC precursor and a BRAF V600E mutation. CONCLUSION: In our cohort, the presence of a PTC precursor predicted the presence of the BRAF V600E mutation, whereas ATC with an FTC or HCC precursor lacked a BRAF V600E mutation. A squamous morphology was associated with the presence of a PTC precursor and a BRAF V600E mutation.

Diagnostic and prognostic value of preoperative systemic inflammatory markers in anaplastic thyroid cancer.

BACKGROUND: Easily accessible, generalized, and inexpensive methods are expected to differentiate anaplastic thyroid carcinoma (ATC) from advanced differentiated thyroid cancer (aDTC). We aimed to explore potential diagnostic and prognostic value of systematic inflammatory markers (SIMs) in ATC and aDTC. METHODS: About 22 ATC, 101 aDTC, and 100 matched early DTC patients were analyzed retrospectively. SIMs included the comprehensive index, neutrophil-monocyte-platelet-to-lymphocyte ratio (NMPLR) and the previously reported ones. Receiver operating characteristic, Kaplan-Meier, and COX regression analyses were mainly conducted. RESULTS: NMPLR exhibited the highest area under the curve value 0.806 (P < .0001) to diagnose ATC from aDTC. NMPLR was identified as an independent risk factor for overall survival (OS) (hazard ratio [HR]: 47.821, 95% confidence interval [CI], 2.863-798.765, P = .007) in ATC, as well as for OS (HR: 7.360, 95% CI, 1.620-33.430, P = .010) and recurrence-free survival (HR: 4.172, 95% CI, 1.139-15.286, P = .031) in aDTC. Taken both refractory types (ATC and aDTC) together, NMPLR could independently predict OS (HR: 6.470; 95% CI, 2.134-19.616; P = .001). CONCLUSION: NMPLR is a generalized index. It showed excellent potential in differential diagnosis and survival prediction in refractory thyroid cancer. However, it needs to be validated in larger cohort and clinical practice.

Hanging Up the Gloves.

Despite the availability of cancer treatments, the best decision may be to facilitate quality time at the end of life. Through the story of a boxer diagnosed with anaplastic thyroid cancer, this narrative considers the question of when to stop cancer treatment when the road is coming to an end.

Mutational profiling of poorly differentiated and anaplastic thyroid carcinoma by the use of targeted next-generation sequencing.

AIMS: To characterise the mutational profiles of poorly differentiated thyroid carcinoma (PDTC) and anaplastic thyroid carcinoma (ATC) and to identify markers with potential diagnostic, prognostic and therapeutic significance. METHODS AND RESULTS: Targeted next-generation sequencing with a panel of 18 thyroid carcinoma-related genes was performed on tissue samples from 41 PDTC and 25 ATC patients. Genetic alterations and their correlations with clinicopathological factors, including survival outcomes, were also analysed. Our results showed that ATC had significantly higher mutation rates of BRAF, TP53, TERT and PIK3CA than PDTC (P = 0.005, P = 0.007, P = 0.005, and P = 0.033, respectively). Nine (69%) ATC cases with papillary thyroid carcinoma (PTC) components harboured BRAF mutations, all of which coexisted with a late mutation event (TP53, TERT, or PIK3CA). Nine cases with oncogenic fusion (six RET cases, one NTRK1 case, one ALK case, and one PPARG case) were identified in 41 PDTCs, whereas only one case with oncogenic fusion (NTRK1) was found among 25 ATCs. Moreover, all six cases of RET fusion were found in PDTC with PTC components, accounting for 33%. In PDTC/ATC patients, concurrent TERT and PIK3CA mutations were associated with poor overall survival after adjustment for TNM stage (P = 0.001). CONCLUSIONS: ATC with PTC components is typically characterised by a BRAF mutation with a late mutation event, whereas PDTC with PTC components is more closely correlated with RET fusion. TERT and concurrent PIK3CA mutations predict worse overall survival in PDTC/ATC patients.

Anaplastic Thyroid Cancer: A Rare Entity Presented Clinically Only with Fever and Elevated CRP.

Anaplastic thyroid carcinoma (ATC) is a rare but almost invariably lethal disease. In this manuscript, we present a case where the dominant manifestation of ATC beside the goitre was elevated CRP values and a persistent low-grade fever. The patient underwent surgical removal of the tumour, chemotherapy and radiotherapy treatment. She is still alive and healthy 11 months after the surgery. We aim to demonstrate that ATC can be present with no specific symptoms or findings and to raise awareness towards an earlier diagnosis.

Therapeutic advances in anaplastic thyroid cancer: a current perspective.

Thyroid cancer incidence is increasing at an alarming rate, almost tripling every decade. In 2017, it was the fifth most common cancer in women. Although the majority of thyroid tumors are curable, about 2-3% of thyroid cancers are refractory to standard treatments. These undifferentiated, highly aggressive and mostly chemo-resistant tumors are phenotypically-termed anaplastic thyroid cancer (ATC). ATCs are resistant to standard therapies and are extremely difficult to manage. In this review, we provide the information related to current and recently emerged first-line systemic therapy (Dabrafenib and Trametinib) along with promising therapeutics which are in clinical trials and may be incorporated into clinical practice in the future. Different categories of promising therapeutics such as Aurora kinase inhibitors, multi-kinase inhibitors, epigenetic modulators, gene therapy using oncolytic viruses, apoptosis-inducing agents, and immunotherapy are reviewed. Combination treatment options that showed synergistic and antagonistic effects are also discussed. We highlight ongoing clinical trials in ATC and discuss how personalized medicine is crucial to design the second line of treatment. Besides using conventional combination therapy, embracing a personalized approach based on advanced genomics and proteomics assessment will be crucial to developing a tailored treatment plan to improve the chances of clinical success.

Anaplastic Carcinoma Thyroid in a Young Child - an Extremely Rare Occurrence.

Anaplastic thyroid carcinoma (ATC), one of the most aggressive malignancies, is extremely rare in childhood. We present a case of 5-yearold child who presented with rapidly progressing thyroid swelling and stridor, for which she underwent emergency tracheostomy and biopsy. Histopathological features were suggestive of ATC and the patient died within two months after diagnosis. ATC, though very rare in childhood, should be kept in the differential diagnoses of rapidly enlarging neck masses in children. To the best of our knowledge, this is the youngest case of ATC reported in literature.

Nodular thyroid disease in the elderly: novel molecular approaches for the diagnosis of malignancy.

Epithelial thyroid cancers (TC) comprise two differentiated histotypes (DTC), the papillary (PTC) and the follicular (FTC) thyroid carcinomas which, following dedifferentiation, are assumed to give rise to the poorly differentiated thyroid carcinomas and the rare, but highly aggressive and invariably fatal, anaplastic thyroid carcinomas. Although thyroid cancer mortality has not been changed, its annual incidence has increased over the last two decades, mainly because of the improved ability to diagnose malignant transformation in small non-palpable thyroid nodules. Despite DTC patients have a favorable prognosis, aggressive disease is more frequently observed in the elderly showing a higher disease-specific mortality. Of relevance is the high prevalence of nodular thyroid disease in aged patients being higher than 90%, in women older than 60 year, and 60% in men older than 80 year. This implies a careful evaluation of thyroid nodules in this group of patients in order to exclude malignancy. In fact, despite the tremendous progress in the comprehension of the underlying molecular mechanisms deregulated in DTC progression, several aspects of their clinical management remain to be solved and novel diagnostic strategies are sorely needed. Here, we will attempt to review new molecular approaches, which are currently being exploited in order to ameliorate the diagnosis of thyroid nodules.

Rare Manifestations of Anaplastic Thyroid Carcinoma: the Role of BRAF Mutation Analysis.

Anaplastic thyroid carcinoma (ATC) is difficult to distinguish from other cancers, especially when its pathological features are atypical for ATC or when the tumor is totally undifferentiated and occurs after a considerable lapse of time, in an area remote from the original site of the tumor. Here, we present two patients (68-year-old man and 56-year-old woman) with rare manifestations of ATC, which were initially thought to be other malignancies. Immunohistochemical tests, using various markers, failed to provide information about the origin of these tumors. However, both patients had a history of papillary thyroid carcinoma (PTC) from several years ago and BRAF mutations were observed in the undifferentiated tumors, as well as in the previous PTCs. Therefore, we could make a diagnosis of ATC derived from PTC. As such, BRAF mutation analysis may serve as a useful tool for ATC diagnosis in challenging ATC cases.