Advances in Thyroid Pathology: High Grade Follicular Cell-derived Thyroid Carcinoma and Anaplastic Thyroid Carcinoma.

In the upcoming World Health Organization fifth edition classification of endocrine tumors, there were several major changes related to high grade follicular-derived thyroid carcinoma (HGFCTC) and anaplastic thyroid carcinoma (ATC) based on emerging evidence about the diagnostic criteria clinical behavior, prognostic factors, and molecular signatures of these tumors. In this review, we aim to summarize the major evolutions of HGFCTC and ATC. HGFCTC is a nonanaplastic carcinoma with high grade features (High mitotic count, tumor necrosis). It is subdivided into poorly differentiated thyroid carcinoma diagnosed using the Turin proposal and differentiated high grade thyroid carcinoma. The latter is defined by the presence of the cytoarchitectutal features of well-differentiated thyroid carcinoma (eg, papillae) but harbors elevated mitotic activity and/or tumor necrosis. Poorly differentiated thyroid carcinoma is predominantly RAS -driven and associated with RAI avidity and high propensity for distant metastasis, whereas differentiated high grade thyroid carcinoma is mostly BRAFV600E -driven. ATC may show a wide range of histologic features. Carcinoma of pure squamous phenotype is associated with a high frequency of BRAF V600E mutations and is now considered as a subtype of ATC. There is a stepwise molecular progression from well-differentiated carcinoma to HGFCTC to ATC manifested by 1) early and persistent driver alteration in the MAPK pathway, particularly BRAF V600E and RAS mutations, and 2) gain of secondary aggressive molecular signatures (such as TERT promoter and TP53 mutations) when tumors progress from well-differentiated to high grade to anaplastic carcinoma.

Whole-genome sequencing of synchronous thyroid carcinomas identifies aberrant DNA repair in thyroid cancer dedifferentiation.

The genetics underlying thyroid cancer dedifferentiation is only partly understood and has not yet been characterised using comprehensive pan-genomic analyses. We investigated a unique case with synchronous follicular thyroid carcinoma (FTC), poorly differentiated thyroid carcinoma (PDTC), and anaplastic thyroid carcinoma (ATC), as well as regional lymph node metastases from the PDTC and ATC from a single patient using whole-genome sequencing (WGS). The FTC displayed mutations in CALR, RB1, and MSH2, and the PDTC exhibited mutations in TP53, DROSHA, APC, TERT, and additional DNA repair genes - associated with an immense increase in sub-clonal somatic mutations. All components displayed an overrepresentation of C>T transitions with associated microsatellite instability (MSI) in the PDTC and ATC, with borderline MSI in the FTC. Clonality analyses pinpointed a shared ancestral clone enriched for mutations in TP53-associated regulation of DNA repair and identified important sub-clones for each tumour component already present in the corresponding preceding lesion. This genomic characterisation of the natural progression of thyroid cancer reveals several novel genes of interest for future studies. Moreover, the findings support the theory of a stepwise dedifferentiation process and suggest that defects in DNA repair could play an important role in the clonal evolution of thyroid cancer. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Unusual cutaneous metastatic carcinoma.

Most of metastatic tumors to the skin are from primary tumors of the breast, lung, or from melanoma; metastases to the skin from primary carcinomas at other sites are rare. Cutaneous metastases of visceral carcinomas most often occur in patients with advanced disease, and are associated with a poor prognosis. We report 6 cases of nonmammary, nonpulmonary carcinoma metastatic to the skin. Most patients were elderly with advanced disease at the time of diagnosis of skin metastasis. The primary tumor sites included the thyroid, esophagus, biliary tract, ovary, and prostate. Awareness of these rare cases of metastasis to the skin will help pathologists and clinicians make the correct diagnosis.

[Clinical characteristics and prognosis of anaplastic thyroid carcinoma].

Objective: To investigate the clinical characteristics, treatment outcomes and prognostic factors in patients with anaplastic thyroid cancer. Methods: Clinical data of 56 patients with anaplastic thyroid cancer at Zhejiang Cancer Hospital from January 2006 to June 2016 were retrospectively reviewed and followed up. Results: Of the 56 patients, there were 24 male and 32 female. The median age was 65 years old. At diagnosis, 10 patients have different degrees of breathing difficulty; 8 patients have varying degrees of dysphagia, and 12 patients have hoarseness. Distant metastases were found in 23 patients at presentation. Patient staging was performed in accordance with the tumor-node-metastasis system as follows: stage ⅣA (n=19), stage ⅣB (n=14) and stage ⅣC (n=23). The median survival time of 56 patients was 4.5 months.The overall 1-year survival rate was 5.4%. Univariate analysis showed that radiotherapy and multimodality therapy were prognostic factors for 1-year overall survival (both of P<0.05). The overall 1-year survival rate of the patients who received precision radiotherapy was 16.7%, which was higher than who received the other radiation therapy (4.0%, P=0.040). Furthermore, the overall 1-year survival rate of the patients who received surgery combined with radiotherapy was 12.5%, which was higher than who received the other treatments(4.2%, P=0.040). Multivariate analysis indicated that radiotherapy was independently associated with improved survival (P=0.020). Conclusions: Patients with anaplastic thyroid cancer should receive multimodality therapies combining surgery with radiotherapy. Radiotherapy is independently associated with improved overall survival. Notably, the precision radiotherapy that based on image guidance has a significantly beneficial impact on the prognosis of patients.

E-cadherin/α-catenin deregulated co-expression in thyroid carcinoma based on tissue microarray digital image analysis.

PURPOSE: Deregulation of cell-to-cell adhesion molecules is a common and also critical genetic event in epithelial malignancies leading to an increasing metastatic potential. Among them, e-cadherin and catenins--especially α and ß--, act as oncogenes during the carcinogenetic process affecting specific signaling transduction pathways (i.e. Wnt/ b-catenin). Concerning thyroid carcinoma, decreased or loss of expression in these proteins seems to affect the biological behavior of the neoplasm increasing its aggressiveness. The aim of this study was to investigate the deregulation of e-cadherin/α-catenin complex in thyroid carcinomas. METHODS: Thirty-five paraffin-embedded tissue samples including thyroid carcinomas (N=20) and also 15 cases of benign follicular nodules were cored at 1 mm diameter and transferred to a microarray block. Immunohistochemistry (IHC) was performed using anti-e-cadherin/α-catenin antibodies. Digital image analysis was also implemented for measuring the corresponding protein expression levels. RESULTS: E-cadherin/α-catenin protein expression demonstrated a significant progressive decrease regarding benign and malignant lesions (p=0.001). Simultaneous e-cadherin/α-catenin reduced or loss of expression was observed in 10/20 (50%) cancer cases correlated to advanced stage (especially nodal metastasis) of the examined tumours (p=0.02). Concerning the histological type, combined loss of e-cadherin/α-catenin expression was predominantly associated with follicular and anaplastic histology (p=0.001). Interestingly, α-catenin protein expression pattern was significantly correlated with the grade of differentiation of the examined malignancies (p=0.01). CONCLUSIONS: Progressive loss of e-cadherin mainly and also α-catenin expression is associated with an aggressive phenotype (low differentiation, increased metastatic activity/advanced stage) in thyroid carcinomas. Based on their aberrant protein expression, novel agents have been developed for restoring their normal function.

Anaplastic Thyroid Carcinoma, Version 2.2015.

This selection from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Thyroid Carcinoma focuses on anaplastic carcinoma because substantial changes were made to the systemic therapy recommendations for the 2015 update. Dosages and frequency of administration are now provided, docetaxel/doxorubicin regimens were added, and single-agent cisplatin was deleted because it is not recommended for patients with advanced or metastatic anaplastic thyroid cancer.

Orbital Metastasis of Undifferentiated/Anaplastic Thyroid Carcinoma.

A 52-year-old woman presented with decreased vision, diplopia, esotropia, proptosis, and right orbital pain. Clinical examination was suspicious for an orbital mass and additionally revealed a thyroid gland mass. Imaging studies showed an enhancing mass within the right lateral rectus muscle and a heterogeneous mass in the left lobe of the thyroid gland. Excisional biopsies of the thyroid and orbital lesions were consistent with metastatic undifferentiated/anaplastic thyroid carcinoma. This represents the first reported case of undifferentiated/anaplastic thyroid carcinoma metastatic to the orbit.

Anaplastic thyroid carcinomas incidentally found on postoperative pathological examination.

BACKGROUND: Anaplastic thyroid carcinoma (ATC) is occasionally found on postoperative pathological examination of patients with differentiated thyroid carcinoma (DTC). There is no general consensus on how we should treat these incidentally diagnosed ATC (incidental ATC). MATERIALS AND METHODS: A total of 675 patients with ATC were registered with the ATC Research Consortium of Japan. These patients were treated between 1995 and 2008 in 38 registered institutions. About 81 % of the ATC patients had common-type ATC and about 14 % had ATC co-existing with a metastatic DTC lesion. The remaining 5 % had incidental ATC. Among the patients with incidental ATC, we investigated 25 patients whose clinical data were fully available. We examined the clinical profile of incidental ATC, and the relationships between treatment and outcome in patients with incidental ATC. RESULTS: The tumor size was clearly smaller, and patients with extrathyroid invasion or distant metastasis were significantly fewer in incidental ATC than in common-type ATC. Most incidental ATC coexisted with papillary carcinoma. While the clinical course of incidental ATC was favorable compared with common-type ATC, half of the patients had disease-related deaths. The prognostic factors of incidental ATC were nearly the same as those of common-type ATC, but the tumor size alone was an independent factor on multivariate analysis. Regarding treatments, the outcome was more favorable in those who underwent curative resection, and the clinical course showed a slight improvement by the addition of external beam radiotherapy and/or chemotherapy after curative resection, but it did not reach statistical significance. CONCLUSION: Incidental ATC is the only curable type of ATC, and further studies are needed to establish the effectiveness of additional postoperative radiotherapy and/or chemotherapy in incidental ATC.

Anaplastic Transformation of Differentiated Thyroid Carcinoma.

OBJECTIVES: Anaplastic thyroid carcinoma (ATC) is a rare but highly aggressive form of thyroid cancer. Increasingly, patients with ATC present with concurrent foci of well-differentiated thyroid carcinoma (WDTC); however, the significance of these pathologic findings remains unclear. The objective of this study is to determine whether the presence of WDTC within anaplastic tumors is a prognosticator of survival. METHODS: A retrospective cohort study of all cases of biopsy-proven ATC managed at a tertiary care academic medical center from 2002 to 2020 was performed. Mean age at diagnosis, median survival time, and locations of distant metastases were assessed. The impact of clinical markers such as presence of differentiation, demographic variables, and oncologic information on overall survival was also determined via univariate and multivariate analysis. RESULTS: Forty-five patients were included in this study. The mean age at diagnosis was 69.1 years. Median survival time was 6.1 months after diagnosis. The most common location of distant metastases was the lung (40%). The presence of limited areas of WDTC in patients with predominantly anaplastic thyroid tumors was not significantly associated with improved outcomes (p = 0.509). Smaller tumor size and use of chemotherapy in ATC patients were significantly associated with prolonged survival (p = 0.026 and 0.010, respectively). CONCLUSIONS: Clinical outcomes for ATC remain poor. The presence of foci of differentiation within anaplastic thyroid tumors does not appear to improve overall survival-the anaplastic component evidently drives outcomes. Further studies into novel therapies are needed to improve survival in ATC. LEVEL OF EVIDENCE: 4 Laryngoscope, 133:437-442, 2023.

Primary Versus Secondary Anaplastic Thyroid Carcinoma: Perspectives from Multi-institutional and Population-Level Data.

Primary (or de novo) anaplastic thyroid carcinoma (ATC) is ATC without pre-existing history of differentiated thyroid carcinoma (DTC) and no co-existing DTC foci at the time of diagnosis. Secondary ATC is diagnosed if the patient had a history of DTC or co-existing DTC components at time of diagnosis. This study aimed to investigate the incidence, clinical presentations, outcomes, and genetic backgrounds of primary versus secondary ATCs. We searched for ATCs in our institutional databases and the Surveillance, Epidemiology, and End Result (SEER) database. We also performed a systematic review and meta-analysis to analyze the genetic alterations of primary and secondary ATCs. From our multi-institutional database, 22 primary and 23 secondary ATCs were retrieved. We also identified 620 and 24 primary and secondary ATCs in the SEER database, respectively. Compared to primary ATCs, secondary ATCs were not statistically different in terms of demographic, clinical manifestations, and patient survival. The only clinical discrepancy between the two groups was a significantly larger tumor diameter of the primary ATCs. The prevalence of TERT promoter, PIK3CA, and TP53 mutations was comparable between the two subtypes. In comparison to primary ATCs, however, BRAF mutations were more prevalent (OR = 4.70; 95% CI = 2.84-7.78) whereas RAS mutations were less frequent (OR = 0.43; 95% CI = 0.21-0.85) in secondary tumors. In summary, our results indicated that de novo and secondary ATCs might share many potential developmental steps, but there are other factors that suggest distinct developmental pathways.

Metformin Reduces Thyroid Cancer Tumor Growth in the Metastatic Niche of Bone by Inhibiting Osteoblastic RANKL Productions.

Background: Metformin has antitumoral actions in human cancers, including the thyroid, while its effects on metastatic lesions are unclear. Patients with bone metastasis (BM) from thyroid cancers have poor survival. Because metformin inhibits the activation of osteoclasts, which has essential roles in BM, the aim of this study was to investigate the therapeutic effects of metformin on thyroid cancer BM and osteoclast activation in the bone microenvironment. Methods: The anaplastic thyroid cancer (ATC) cell lines FRO and SW1736 were used to test the antitumoral effect of metformin in vitro and in vivo. A murine model of BM was established by intratibial injection of cancer cells. To mimic the BM microenvironment, osteoblasts were treated with conditioned media from the FRO (FRO-CM) and SW1736 (SW1736-CM) cells. Thyroid cancer patients with or without BM were recruited, and the serum receptor activator of nuclear factor kappa-B ligand (RANKL) levels was measured. Results: Metformin treatment significantly reduced the viabilities of the FRO and SW1736 cells in vitro and the tumor growth of SW1736 in vivo. In the murine model of BM, metformin delayed tumor growth in the bone and decreased the numbers of tartrate-resistant acid phosphatase-positive osteoclasts on the bone surface with reduced RANKL in the bone marrow. Furthermore, FRO- or SW1736-CM significantly increased the osteoblastic RANKL productions and activated osteoclast differentiation in whole marrow cultures, which were blocked by metformin treatment. Among 67 thyroid cancer patients, the serum RANKL levels were significantly increased in BM patients compared with patients with lung-only metastasis or no distant metastasis. In addition, the interleukin-6 superfamily in the FRO- or SW1736-CM stimulated STAT3 phosphorylation, which was inhibited by gp130 blocking. Metformin treatment decreased the FRO- or SW1736-CM-induced STAT3 phosphorylation by AMPK phosphorylation. Metformin also inhibited the FRO- or SW1736-CM-induced osteoclastic differentiation of bone marrow-derived monocyte/macrophage by RANK/c-Fos/NFATC1 signaling. Conclusions: In the microenvironment of BM, metformin effectively reduced ATC tumor growth by inhibiting cancer cell viability, blocking cancer cell-induced osteoblastic RANKL production, which further activated osteoclastogenesis, and directly reduced osteoclast differentiation. These multifactorial actions of metformin suggest that it has potential therapeutic effects in thyroid cancer BM.

Dietary iodine intake, therapy with radioiodine, and anaplastic thyroid carcinoma.

Background Anaplastic thyroid cancer (ATC) is one of the most aggressive tumors. The aim of the study was to determine the correlation between a higher dietary intake of iodine, frequency of ATC and the characteristics of ATC, and to find out how often patients with ATC had a history of radioiodine (RAI) therapy. Patients and methods This retrospective study included 220 patients (152 females, 68 males; mean age 68 years) with ATC who were treated in our country from 1972 to 2017. The salt was iodinated with 10 mg of potassium iodide/ kg before 1999, and with 25 mg of potassium iodide/kg thereafter. The patients were assorted into 15-year periods: 1972-1986, 1987-2001, and 2002-2017. Results The incidence of ATC decreased after a higher iodination of salt (p = 0.04). Patients are nowadays older (p = 0.013) and have less frequent lymph node metastases (p = 0.012). The frequency of distant metastases did not change over time. The median survival of patients in the first, second, and third periods was 3, 4, and 3 months, respectively (p < 0.05). The history of RAI therapy was present in 7.7% of patients. Conclusions The number of patients with a history of RAI therapy did not change statistically over time. The incidence of ATC in Slovenia decreased probably because of higher salt iodination.

miR-199a-5p suppresses epithelial- mesenchymal-transition in anaplastic thyroid carcinoma cells via targeting Snail signals.

MicroRNAs (miRNAs) have been validated to play prominent roles in the occurrence and development of anaplastic thyroid carcinoma (ATC). miR-199a-5p was previously reported to act as a tumor suppressor or oncomiRNA in various types of cancer. However, its accurate expression, function, and mechanism in ATC remain unclear. Here, we find that miR-199a-5p is significantly downregulated in ATC tissues compared with adjacent non-cancerous tissues. Overexpression of miR-199a-5p significantly inhibits migration and invasion of ATC cells in vitro, and lung metastasis in vivo. Importantly, miR-199a-5p suppresses epithelial-mesenchymal transition (EMT) both in vitro and in vivo by targeting Snail. Taken together, this study reveals that miR-199a-5p is critical to the EMT progression in ATC cells. Targeting the pathway described here may be a novel approach for inhibiting metastasis of ATC.

Metastasis to Stomach in a Patient with Anaplastic Thyroid Carcinoma: A Clinical Challenge.

BACKGROUND Anaplastic thyroid carcinoma (ATC) is an uncommon and aggressive form of human cancer. Despite advancement in multimodal therapy for patients with ATC, the prognosis remains poor. Most patients presenting with ATC have metastasis to the lungs and regional lymph nodes. Gastrointestinal tract metastasis is a rare entity observed among patients with ATC. We report a case of ATC with gastrointestinal metastasis. CASE REPORT A 72-year-old euthyroid female with hypertension presented to the clinic with swelling of the neck and breathlessness. Fine needle aspiration cytology revealed colloid goiter. Positron emission tomography and computed tomography revealed hypermetabolic, lobulated mass in left hemi-thyroid, displacing trachea, and hypermetabolic lymph nodes on the left side. The patient underwent total thyroidectomy along with left modified radical neck dissection. Histopathology and immunochemistry were suggestive of ATC with thyroid transcription factor 1 (TTF-1), cytokeratin, Pax8, and C53 positive while calcitonin and thyroglobulin were negative. The patient presented with persistent nausea and vomiting during adjuvant radiation therapy. After radiation therapy, the patient underwent upper gastrointestinal endoscopy that revealed large polypoidal lesions in the stomach. No active bleeding was observed. Biopsy results confirmed it to be metastasis from ATC. CONCLUSIONS ATC can spread to distant sites including the gastrointestinal tract. Patients with ATC metastasis have a poor prognosis despite multimodal therapy. This is the first case of ATC with gastrointestinal metastasis reported in India.

Case Report: 84-Month Disease-Free Survival after Surgery for Anaplastic Thyroid Carcinoma.

We present a rare case of a patient with anaplastic thyroid carcinoma (ATC) who survived for 87 months after surgery. The patient was a 71-year-old man who presented with a painful enlarged mass in the right side of his neck that rapidly enlarged over 2 months. He was diagnosed with T4a, stage IVA ATC with no distant metastasis and underwent total thyroidectomy with modified neck dissection. Although only radiation and radioactive iodine therapy were administered after surgery, he remained disease-free for 84 months. Bone metastasis occurred after 84 months, and he was treated with Lenvatinib, but he died from a decline in his general condition 3 months later. We suggest that surgery is effective for stage IVA ATC, but adjuvant therapy is necessary for long-term disease-free survival in this patient population.

LncRNA NEAT1 enhances the resistance of anaplastic thyroid carcinoma cells to cisplatin by sponging miR­9­5p and regulating SPAG9 expression.

Anaplastic thyroid carcinoma (ATC) has a poor prognosis due to its resistance to all conventional treatments. The long non­coding RNA (lncRNA) nuclear paraspeckle assembly transcript 1 (NEAT1) serves a critical role in cancer chemoresistance; however, whether NEAT1 is associated with chemoresistance of ATC remains unclear. In the present study, reverse transcription­quantitative PCR assays were performed to detect the expression levels of NEAT1, microRNA (miR)­9­5p and sperm­associated antigen 9 (SPAG9). Western blot analysis was conducted to assess the protein expression levels of p62, microtubule­associated proteins 1A/1B light chain 3B and SPAG9. Cell proliferation was detected using the Cell Counting kit­8 assay, and cell apoptosis was determined by flow cytometry. Dual­luciferase reporter and RNA immunoprecipitation assays were performed to verify the interaction between NEAT1 and miR­9­5p, or miR­9­5p and SPAG9. Furthermore, an animal model was used to investigate the regulatory effects of NEAT1 on cisplatin (DDP)­resistance in tumors in vivo. The present results demonstrated that NEAT1 was upregulated in ATC tissues and cell lines, and NEAT1 silencing resulted in decreased DDP­resistance of ATC cells. In addition, NEAT1 suppressed miR­9­5p expression by binding to miR­9­5p and SPAG9 was a direct target of miR­9­5p. miR­9­5p overexpression sensitized ATC cells to DDP. Notably, NEAT1 silencing exerted its inhibitory effect on DDP­resistance of ATC via the miR­9­5p/SPAG9 axis in vitro and in vivo. In conclusion, the present study demonstrated that NEAT1 silencing ameliorated DDP­resistance of ATC, at least in part by reducing miR­9­5p sponging and regulating SPAG5 expression; therefore, NEAT1 may be considered a potential therapeutic target of ATC.

Anaplastic thyroid carcinoma: an epidemiologic, histologic, immunohistochemical, and molecular single-institution study.

Anaplastic thyroid carcinoma (ATC) is a highly aggressive form of thyroid cancer. A single-institution thyroid cancer cohort of ATC was identified within the last 10 years at our institution. Retrospective analysis revealed that the frequency of ATC was 0.5% (11/2106 thyroid carcinomas). The average age at diagnosis of ATC was 74 years, and the female-to-male ratio was 1.2:1. ATC presented as a rapidly enlarging neck mass involving predominantly the left thyroid lobe (7/11; 64%). Cervical adenopathy was present in 7 (64%) of 11 cases. Fifty-five percent (6/11) of patients had distant metastases at the time of diagnosis. Histologically, ATC closely simulated a large variety of soft tissue sarcomas; osteoclast-like giant cell-rich tumors; squamous cell, spindle cell, and small cell carcinomas; and anaplastic/large cell lymphomas. Four tumors (4/11; 36%) showed heterologous elements, including rhabdoid and chondroid differentiation. Immunohistochemical studies showed that all ATCs lost TTF-1 and thyroglobulin expression, whereas PAX-8 expression was identified in 36% (4/11) of tumors. Intense and extensive nuclear staining of p53 (>50%) and high Ki-67 proliferative rate (>30%) were seen in all ATCs (11/11; 100%). Next-generation sequencing revealed recurrent BRAF V600E and TP53 gene mutations. Individual examples of a BRAF G469A mutation in ATC with follicular carcinoma component, EGFR, PTEN, PIK3CA, and FGFR3 mutations, were also identified, whereas 1 case of ATC showed wild-type sequencing with no identifiable alterations.

Thyroglobulin Determination in Fine Needle Aspiration Biopsy Washout of Suspicious Lymph Nodes in Thyroid Carcinoma Follow up.

BACKGROUND: Differentiated thyroid carcinomas (DTCs) account for about 1% of all human malignancies. Cervical lymph nodes metastases and recurrences in the thyroid bed frequently occur. Furthermore, about 10-15% of patients develop distant metastases. Therefore, patients must undergo life-long follow-up. OBJECTIVE: The aim of this study was to evaluate the usefulness of Thyroglobulin measurement in FNAB washout (FNAB-Tg) in the detection of local metastasis in patients affected by or evaluated for thyroid cancer. MATERIALS AND METHODS: In a 3-year period, a total of 83 consecutive patients coming to our attention at the Ear-Nose-Throat (ENT) Outpatients Service of the National Cancer Research Center &quot;Istituto Tumori Giovanni Paolo II&quot; of Bari, Italy, because of the finding of one or more cervical lymph node(s), were enrolled in the study. After collection of the cytological specimen, the needle used for performing FNAB was then washed in 1 ml of normal saline. 89 FNAB washouts were collected from the same number of lymph nodes and subsequently investigated for Thyroglobulin levels using a sequential chemiluminescent-immunometric assay. RESULTS: Comparing the cytological or, when performed, histological diagnoses with the results of FNAB-Tg, we found that in 24 cases of lymph node metastases from PTC (19 lymph nodes from patients at the first diagnoses and 5 lymph nodes from PTC patients in follow up) the mean level of Thyroglobulin was 1840.11 ng/ml; range: <0,2 to 11440 ng/ml. In the group of PTC patients (27 lymph nodes) with lymph nodes negative for metastatic involvement at cytology (i.e. no lymph node recurrence at follow-up), as well as in the cases of subjects without PTC and submitted to FNAB because of the appearance of lymph node(s) classified as reactive at cytology (37 lymph nodes), FNAB-Tg was lower than or equal to 0.2 ng/ml. As expected, the Thyroglobulin level was not detectable (< 0.2 ng/ml) also in a lymph node FNAB from a case of anaplastic thyroid carcinoma. CONCLUSION: In our study, FNAB-Tg was not detectable in all node negative patients showing, when considering together all the lymph node metastases, a 96% sensitivity and 100% specificity.

Salvage Lenvatinib Therapy in Metastatic Anaplastic Thyroid Cancer.

BACKGROUND: Historical anaplastic thyroid cancer (ATC) outcomes have been terrible, with a median survival of only five months and <20% one-year survival. Improved outcomes are now achieved with aggressive initial therapy in stages IVA and IVB disease, but patients with distant metastatic disease (stage IVC) still do poorly; improved therapies are sorely needed. Kinase inhibitors have emerged as promising agents in the therapy of advanced medullary and differentiated thyroid cancer, but there are limited data regarding the use of lenvatinib in ATC. The aim of this study was to delineate clinical outcomes in a series of patients with advanced ATC in response to lenvatinib therapy. METHODS: A retrospective analysis was conducted involving all lenvatinib-treated Mayo Clinic ATC patients in 2015. RESULTS: Of 28 distinct ATC patients seen in 2015, three (11%) with metastatic disease of ECOG performance status 2-3 were treated with lenvatinib. Two patients were male; age range at ATC diagnosis was 57-84 years. All three patients attained successful local control of their disease with surgery and/or combined chemoradiotherapy. Lenvatinib was offered as the second, third, or fourth line of therapy at the time of metastatic disease progression. Two patients incurred minor responses to therapy, with structural regression of distant metastatic tumor disease soon after starting lenvatinib treatment (at one to two months), while one patient achieved stable disease, but no Response Evaluation Criteria In Solid Tumors partial responses resulted. Overall survival after starting lenvatinib was two, six, and seven months. Fatigue and hypertension were prominent, and one patient developed pulmonary emboli while on lenvatinib. CONCLUSION: This initial single-institution experience suggests that lenvatinib may have some disease-modifying activity in metastatic ATC that is otherwise refractory to cytotoxic chemotherapy. Unfortunately, observed benefits were transient, and toxicities were prominent. Clinical trials are required to ascertain better the utility of lenvatinib in the management of advanced ATC.

Metastatic thyroid carcinoma without identifiable primary tumor within the thyroid gland: a retrospective study of a rare phenomenon.

Metastatic papillary thyroid carcinoma (PTC) without an identifiable primary tumor despite extensive microscopic examination of the thyroid gland is a rare but true phenomenon.We retrieved 7 of such cases and described in detail the clinical and pathologic features of these tumors. BRAF V600E immunohistochemistry and Sequenom molecular profile were conducted in selected cases. All patients harbored metastatic disease in the central (n=3), lateral (n=3), or both neck compartments (n=1). The histotype of the metastatic disease was PTC (n=5), poorly differentiated thyroid carcinoma in association with a PTC columnar variant (n=1), and anaplastic thyroid carcinoma in association with a PTC tall cell variant (n=1). Fibrosis was present in the thyroid of 5 patients. All patients with PTC were alive without evidence of recurrence. The 76-year-old patient with poorly differentiated thyroid carcinoma did not recur and died of unknown causes. Finally, the patient with anaplastic thyroid carcinoma was alive with distant metastasis at last follow-up. The median follow-up for this cohort was 2.2years (range, 0.8-17). BRAF V600E was detected in 4 of 6 cases by immunohistochemistry. In conclusion, metastatic nodal disease without identifiable thyroid primary is a rare but real phenomenon of unknown mechanisms. Although most tumors are low grade and well differentiated, aggressive behavior due to poorly differentiated or anaplastic carcinoma can happen. Most cases are BRAFV600E-positive thyroid tumors. A papillary carcinoma phenotype is found in all reported cases.