A Detailed Histologic and Molecular Assessment of the Diffuse Sclerosing Variant of Papillary Thyroid Carcinoma.

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.

Multimodality Treatment Improves Locoregional Control, Progression-Free and Overall Survival in Patients with Anaplastic Thyroid Cancer: A Retrospective Cohort Study Comparing Oncological Outcomes and Morbidity between Multimodality Treatment and Limited Treatment.

BACKGROUND: Patients with anaplastic thyroid cancer (ATC) have poor overall survival, and the optimal management approach remains unclear. The aim of this study is to evaluate our experience with multimodality (MMT) versus limited treatment (LT) for ATC. PATIENTS AND METHODS: A cohort study of patients with ATC managed in a tertiary referral center was undertaken. The outcomes of MMT were compared with those of LT. The primary outcome measures were locoregional control and progression-free and overall survival. Secondary outcome measures were treatment-related complications and factors associated with improved survival. RESULTS: In total, 59 patients (35 females) with a median age of 73 years (range 39-99 years) and ATC stage IVA (n = 2), IVB (n = 28), or IVC (n = 29) were included. LT was utilized in 25 patients (42%), and 34 cases had MMT. MMT patients had a longer time of locoregional control (18.5 versus 1.9 months; p < 0.001), progression-free survival (3.5 versus 1.2 months; p < 0.001), and overall survival (6.9 versus 2.0 months; p < 0.001) when compared with LT. For patients with stage IVC ATC, locoregional control (p = 0.03), progression-free survival (p < 0.001), and overall survival (p < 0.001) were superior in the MMT cohort compared with LT. MMT had more treatment-related complications than LT (p < 0.001). An Eastern Cooperative Oncology Group performance status < 2 (HR 0.30; p = 0.001) and MMT (HR 0.35; p = 0.008) were associated with improved overall survival. CONCLUSION: MMT is likely to improve locoregional control, progression-free survival, and overall survival in selected ATC patients including stage IVC tumors but comes with a greater complication risk.

Medullary Thyroid Cancer: Molecular Drivers and Immune Cellular Milieu of the Tumour Microenvironment-Implications for Systemic Treatment.

In this review, we explore the underlying molecular biology of medullary thyroid carcinoma (MTC) and its interplay with the host immune system. MTC is consistently driven by a small number of specific pathogenic variants, beyond which few additional genetic events are required for tumorigenesis. This explains the exceedingly low tumour mutational burden seen in most MTC, in contrast to other cancers. However, because of the low tumour mutational burden (TMB), there is a correspondingly low level of tumour-associated neoantigens that are presented to the host immune system. This reduces tumour visibility and vigour of the anti-tumour immune response and suggests the efficacy of immunotherapy in MTC is likely to be poor, acknowledging this inference is largely based on the extrapolation of data from other tumour types. The dominance of specific RET (REarranged during Transfection) pathogenic variants in MTC tumorigenesis rationalizes the observed efficacy of the targeted RET-specific tyrosine kinase inhibitors (TKIs) in comparison to multi-kinase inhibitors (MKIs). Therapeutic durability of pathway inhibitors is an ongoing research focus. It may be limited by the selection pressure TKI treatment creates, promoting survival of resistant tumour cell clones that can escape pathway inhibition through binding-site mutations, activation of alternate pathways, and modulation of the cellular and cytokine milieu of the tumour microenvironment (TME).

MicroRNA-222 and microRNA-146b are tissue and circulating biomarkers of recurrent papillary thyroid cancer.

BACKGROUND: Papillary thyroid cancer (PTC) persistence or recurrence and the need for long-term surveillance can cause significant inconvenience and morbidity in patients. Currently, recurrence risk stratification is accomplished by using clinicopathologic factors, and serum thyroglobulin is the only commercially available marker for persistent or recurrent disease. The objective of this study was to determine microRNA (miRNA) expression in PTC and determine whether 1 or more miRNAs could be measured in plasma as a biomarker for recurrence. METHODS: Patients with recurrent PTC (Rc-PTC) and those without recurrence (NR-PTC) were retrospectively recruited for a comparison of their tumor miRNA profiles. Patients with either newly diagnosed PTC or multinodular goiter who were undergoing total thyroidectomy were prospectively recruited for an analysis of preoperative and postoperative circulating miRNA levels. Healthy volunteers were recruited as the control group. RESULTS: MicroRNA-222 and miR-146b were over-expressed 10.8-fold and 8.9-fold, respectively, in Rc-PTC tumors compared with NR-PTC tumors (P = .014 and P = .038, respectively). In plasma from preoperative PTC patients, levels of miR-222 and miR-146b were higher compared with the levels in plasma from healthy volunteers (P < .01 for both). Reductions of 2.7-fold and 5.1-fold were observed in the plasma levels of miR-222 and miR-146b, respectively, after total thyroidectomy (P = .03 for both). CONCLUSIONS: This study demonstrated that tumor levels of miR-222 and miR-146b are associated with PTC recurrence and that miR-222 and miR-146b levels in the circulation correspond to the presence of PTC. The potential of these miRNAs as tumor biomarkers to improve patient stratification according to the risk of recurrence and as circulating biomarkers for PTC surveillance warrants further study.

Level VII is an important component of central neck dissection for papillary thyroid cancer.

BACKGROUND: Therapeutic central neck dissection (CND) is an accepted part of the management of papillary thyroid carcinoma (PTC), while prophylactic CND remains controversial. Regardless of the indication for CND, the lower anatomic border of the central compartment, specifically the inclusion or otherwise of level VII, is not always clearly defined in the literature. This study aimed to determine if the routine inclusion of level VII lymph node dissection as part of CND confers increased utility in the detection of macrometastatic lymph nodes compared with level VI dissection alone. METHOD: This was a prospective cohort study of patients undergoing CND for PTC at a tertiary referral center. All patients received either a prophylactic or therapeutic CND. The CND specimens were divided by the surgeon into level VI and level VII at the level of the suprasternal notch and submitted separately for histopathology. Criteria for macroscopic lymph node disease were taken from the American Joint Committee on Cancer (AJCC) recommendations for breast cancer. RESULTS: A total of 45 patients with PTC underwent total thyroidectomy and routine CND, at a tertiary referral center; 77 % of the therapeutic CND group had positive level VI lymph nodes, and 38 % had positive level VII lymph nodes. Of the prophylactic CND group, 50 % of patients had positive level VI nodes and 16 % has positive level VII nodes detected. All patients with positive level VII lymph nodes in the prophylactic CND group had macrometastatic disease. Temporary hypocalcemia rate was 31 % in the therapeutic group and 6 % in the prophylactic CND group. One patient experienced permanent hypoparathyroidism. There was no vascular injury or recurrent laryngeal nerve palsy in either group. CONCLUSIONS: CND incorporating both level VI and level VII can be undertaken safely through a cervical incision with no increased risk of permanent complications of hypoparathyroidism or recurrent laryngeal nerve injury. Failure to include level VII as part of CND will leave significant macrometastatic nodal disease behind in both therapeutic and prophylactic dissections. As level VII is in direct anatomic continuity with the pretracheal level VI nodes, it should be routinely included as part of every CND.

Is focused minimally invasive parathyroidectomy appropriate for patients with familial primary hyperparathyroidism?

BACKGROUND: The aim of this study was to determine whether a focused minimally invasive parathyroidectomy (MIP) for patients with primary hyperparathyroidism and concordant pre-operative localization studies is appropriate for patients with a family history of the disease. Familial hyperparathyroidism may be seen as a chronic disease in which recurrence is inevitable. Patients frequently undergo subtotal or total parathyroidectomy for perceived 4-gland parathyroid hyperplasia in an attempt to reduce this risk. Controversy remains regarding whether a MIP is appropriate in this setting. METHODS: Patients undergoing an MIP were identified from prospectively maintained databases. Chart review confirmed the presence of a family history of hyperparathyroidism in a direct relative. Patients with and without a family history were compared regarding overall complications, recurrence, and cure rates. RESULTS: A total of 1,652 patients underwent a MIP. Of these, 34 patients had a positive family history. There was no statistically significant difference in age, gender, preoperative biochemistry, gland weight, or complication rates between the groups. The cure rate at 6 months from a single operation was equivalent between the 2 groups (97 vs. 98%). With a median of 39 months follow-up, the recurrence rate was higher in those with a family history compared with those without (8.8 vs 1.1%; P=0.002). Reoperation was successful in the small population of familial patients who did present with recurrent hyperparathyroidism. CONCLUSIONS: The vast majority of patients who underwent a MIP were surgically cured. Although recurrence rates remain higher in the familial hyperparathyroidism group, these data suggest that this alone should not be a contraindication to MIP.

Papillary thyroid carcinoma in pregnancy: a variant of the disease?

BACKGROUND: There are conflicting reports in the literature regarding the prognostic influence of pregnancy on patients with papillary thyroid carcinoma (PTC), and there is no literature on specific microRNA (miRNA) profiles of PTC in the context of pregnancy. We aim to examine clinically if pregnancy is an adverse factor in PTC, and if pregnancy-associated PTC are biologically different from those in nonpregnant women in terms of their miRNA profiles. METHODS: Women diagnosed with PTC during or soon after pregnancy were recruited into the pregnancy group. Age-matched nonpregnant females were recruited into the nonpregnancy group. MiRNA microarray was performed on PTC tissue of pregnant patients (10), nonpregnant patients (10), and normal thyroids (5). There were 6 differentially expressed miRNAs from the microarray comparisons validated with RT-PCR. RESULTS: There were 24 patients in the clinical pregnancy group and 30 in the nonpregnancy group. Tumors from the pregnancy group were significantly larger and showed more regional lymph node metastases. The microarray data showed a total of 27 miRNAs that were potential differentiators of PTC tissue samples from pregnant and nonpregnant patients. Of the 6 selected for validation, no significant difference in expression was found. CONCLUSIONS: Our clinical data suggests that PTC during pregnancy may be more locoregionally aggressive. However, no difference in survival or recurrence is demonstrated. The miRNA profiles of the pregnancy-associated PTC have not been shown to be different to the nonpregnancy counterparts. This likely suggests that the differences seen clinically are related to patient factors rather than the disease itself.

Surgery alone for papillary thyroid microcarcinoma is less costly and more effective than long term active surveillance.

BACKGROUND: Papillary thyroid microcarcinoma is a subtype of thyroid cancer that may be managed with active surveillance rather than immediate surgery. Active surveillance decreases complication rates and may decrease health care costs. This study aims to analyze complication rates of thyroid surgery, papillary thyroid microcarcinoma recurrence, and survival rates. Additionally, the costs of surgery versus hypothetic active surveillance for papillary thyroid microcarcinoma are compared in an Australian cohort. METHODS: Papillary thyroid microcarcinoma patients were included from a prospectively collected surgical cohort of patients treated for papillary thyroid cancer between 1985 and 2017. The primary outcomes were the complications of thyroid surgery, recurrence-free survival, overall survival, and cost of surgical treatment and active surveillance. RESULTS: In a total of 349 patients with papillary microcarcinoma with a median age of 48 years (range, 18-90 years), the permanent operative complications rate was 3.7%. Postoperative radioactive iodine did not decrease recurrence-free survival (P = .3). The total cost of surgical treatment was $10,226 Australian dollars, whereas hypothetic active surveillance was at a yearly cost of $756 Australian dollars. Estimated cost of surgical papillary thyroid microcarcinoma treatment was equivalent to the cost of 16.2 years of active surveillance. CONCLUSION: Surgery may have a long-term economic advantage for younger Australian patients with papillary thyroid microcarcinoma who are likely to require more than 16.2 years of follow-up in an active surveillance scheme.

Parafibromin-deficient (HPT-JT Type, CDC73 Mutated) Parathyroid Tumors Demonstrate Distinctive Morphologic Features.

The gene CDC73 (previously known as HRPT2) encodes the protein parafibromin. Biallelic mutation of CDC73 is strongly associated with malignancy in parathyroid tumors. Heterozygous germline mutations cause hyperparathyroidism jaw tumor syndrome,which is associated with a high life-time risk of parathyroid carcinoma. Therefore loss of parafibromin expression by immunohistochemistry may triage genetic testing for hyperparathyroidism jaw tumor syndrome and be associated with malignant behavior in atypical parathyroid tumors. We share our experience that parafibromin-negative parathyroid tumors show distinctive morphology. We searched our institutional database for parathyroid tumors demonstrating complete loss of nuclear expression of parafibromin with internal positive controls. Forty-three parafibromin-negative tumors from 40 (5.1%) of 789 patients undergoing immunohistochemistry were identified. Thirty-three (77%) were external consultation cases; the estimated incidence in unselected tumors was 0.19%. Sixteen (37.2%) fulfilled World Health Organization 2017 criteria for parathyroid carcinoma and 63% had serum calcium greater than 3mmol/L. One of 27 (3.7%) noninvasive but parafibromin-negative tumors subsequently metastasized. Parafibromin-negative patients were younger (mean, 36 vs. 63 y; P<0.001) and had larger tumors (mean, 3.04 vs. 0.62 g; P<0.001). Not all patients had full testing, but 26 patients had pathogenic CDC73 mutation/deletions confirmed in tumor (n=23) and/or germline (n=16). Parafibromin-negative tumors demonstrated distinctive morphology including extensive sheet-like rather than acinar growth, eosinophilic cytoplasm, nuclear enlargement with distinctive coarse chromatin, perinuclear cytoplasmic clearing, a prominent arborizing vasculature, and, frequently, a thick capsule. Microcystic change was found in 21 (48.8%). In conclusion, there are previously unrecognized morphologic clues to parafibromin loss/CDC73 mutation in parathyroid tumors which, given the association with malignancy and syndromic disease, are important to recognize.

Comparison of pinhole and SPECT 99mTc-MIBI imaging in primary hyperparathyroidism.

OBJECTIVE: This study aims to compare dual tracer, dual phase pinhole technetium-99m labelled 2-methoxyisobutylisonitrile (Tc-MIBI) imaging (including oblique imaging), with single photon emission computed tomography (SPECT) and dual phase planar Tc-MIBI images, and combined SPECT, dual phase planar Tc-MIBI images and anterior pinhole thyroid images for the localization of parathyroid adenomas in the neck in primary hyperparathyroidism. METHODS: Sixty-two patients underwent Tc-MIBI dual phase, anterior and anterior oblique pinhole images of the neck, anterior planar images of the neck and chest and early phase neck/chest SPECT followed by [Tc] pertechnetate anterior and anterior oblique pinhole thyroid images. Images were reviewed by consensus in three combinations - dual phase anterior and anterior oblique pinhole Tc-MIBI images and pinhole thyroid images; SPECT and dual phase planar Tc-MIBI images and combined SPECT, dual phase planar Tc-MIBI images and anterior pinhole thyroid images. RESULTS: For 52 parathyroid adenomas in 50 patients, the sensitivity of dual phase anterior and anterior oblique pinhole Tc-images and pinhole thyroid images was 81%. Significantly lower sensitivities were observed with SPECT and dual phase planar Tc-MIBI images (54%, P=0.0005) and combined SPECT, dual phase planar Tc-MIBI images and anterior pinhole thyroid images (65%, P=0.0209). The positive predictive value for all imaging combinations was 88-92%. CONCLUSION: Dual phase anterior and anterior oblique pinhole Tc-MIBI images and pinhole thyroid images are significantly more sensitive than imaging combinations that included SPECT and remains the optimal imaging protocol for the localization of parathyroid adenomas in the neck in primary hyperparathyroidism.

Predicting malignancy in adrenal incidentaloma and evaluation of a novel risk stratification algorithm.

BACKGROUND: Incidentally discovered adrenal lesions known as adrenal incidentalomas (AI) are being encountered with increasing frequency due to the widespread use of abdominal computed tomography (CT). The aim of this study was to identify the clinical predictors of malignancy in AI and to evaluate the accuracy of a recently proposed risk stratification algorithm. METHODS: A retrospective analysis of 96 patients presenting with AI between 2004 and 2014 was undertaken; 66 patients underwent adrenalectomy, and 30 were managed non-operatively. Univariate analysis including patient demographics, CT features of tumour size, density and heterogeneity was performed. Hormonal parameters including 24-h urinary-free cortisol and serum dehydroepiandrosterone sulphate (DHEAS) were also included. A Cleveland Clinic risk stratification model utilizing adrenal size and density was evaluated. RESULTS: The overall rate of malignancy was 8%. On univariate analysis, the following preoperative variables were predictive of malignancy - tumour size on pathology (P = 0.0031) and CT (P = 0.0016), heterogeneity on CT imaging (P = 0.0036), a relative percentage washout of less than 40% (P = 0.0178), elevated 24-h urinary-free cortisol levels (P = 0.0176), elevated DHEAs (P = 0.0061) and younger age at presentation (P < 0.0001). Evaluation of the Cleveland Clinic algorithm found an area under the receiver operating characteristic curve of 0.81 (95% confidence interval 0.52-1.00). CONCLUSION: CT characteristics of tumour size, density and heterogeneity are significantly associated with malignancy in AI and applied together reliably exclude malignancy. The risk stratification algorithm utilizing size and density alone may fail to identify some smaller adrenal cancers.

The Covidien LigaSure Maryland Jaw Device.

Since its invention nearly 20 years ago, the Covidien LigaSure device along with its ForceTriad generator has dominated the Electrothermal Bipolar Vessel Sealing market. The LigaSure was used for surgical procedures, both open and laparoscopic. The purpose of this review is to provide evidence of the safety and utility of the LigaSure device compared to more traditional means of hemostasis and its ultrasonic competitor, particularly in laparoscopic applications. We will provide evidence related to electrothermal bipolar vessel sealing in general and look specifically at Covidien's newest product, the LigaSure Maryland Jaw Device.

Adenomas of cervical maldescended parathyroid glands: pearls and pitfalls.

BACKGROUND: Missed parathyroid adenoma (PTA) is the commonest cause of persistent hyperparathyroidism. Although many are subsequently found in well-described locations, some are found in unusual regions of the neck. This paper presents the combined experience of three large tertiary endocrine surgery centres with maldescended PTA (MD-PTA). METHODS: Patients were recruited from the endocrine surgical databases of three tertiary endocrine surgery units. Patients with PTA found >1 cm above the superior thyroid pole or other cervical locations as a result of abnormal or incomplete descent were included for analysis. RESULTS: MD-PTA was identified in 16 patients out of a total of 5241 patients who had undergone parathyroidectomies in the 7-year study period (incidence 0.3%). Seven (44%) patients had minimally invasive parathyroidectomy, while nine (56%) had bilateral neck exploration. The mean excised gland weight was 750 + 170 mg. Cure was achieved in all patients with a minimum follow-up of 6 months. The locations of MD-PTA in this study included submandibular triangle, retropharyngeal space, carotid sheath (at carotid bifurcation and intravagal), parapharyngeal space (superior to thyroid cartilage or superior thyroid pole) and cricothyroid space. CONCLUSIONS: Despite their rare occurrence, incompletely or abnormally descended PTAs can be encountered by any surgeon who performs parathyroidectomies. It is important to develop a strategy to systematically locate these glands. High cure rates can still be achieved with minimally invasive parathyroidectomy if confident preoperative localization is available. A sound knowledge of embryology and a thorough exploration also facilitate an overall high success rate with open exploration.

Four-dimensional computed tomography for parathyroid localization: a new imaging modality.

INTRODUCTION: Four-dimensional computed tomography (4DCT) is a new parathyroid localization technique not previously reported in Australia. It provides both functional and anatomical imaging in a single test, with superior sensitivity compared with sestamibi scintigraphy (SeS). This study examines the utility of 4DCT in defined clinical situations. METHODS: This is a retrospective cohort study in a tertiary referral hospital setting. One hundred consecutive operative cases of primary hyperparathyroidism (99 patients) undergoing both preoperative 4DCT and SeS. Localization studies were correlated with operative findings, histopathology and clinical outcomes. The utility of 4DCT was analysed in three common clinical settings: primary cases with positive SeS (Group A, n = 68), primary cases with negative SeS (Group B, n = 21) and re-operative cases (Group C, n = 11). RESULTS: The overall sensitivity of 4DCT was 92% compared with 70% for SeS. The sensitivity of 4DCT was superior to SeS in Groups B and C (76% versus 0% and 91% versus 46%, respectively). The overall cure rate was 98%, with 94% of cases completed as minimally invasive procedures. Up to 62% of Group B cases potentially avoided a bilateral neck exploration owing to a positive 4DCT. CONCLUSIONS: 4DCT is an accurate technique providing both functional and anatomical localization of abnormal parathyroid glands. However, the advantage of speed and simplicity in image acquisition needs to be balanced against the small risk of increased radiation exposure in the younger patient group.

A detailed clinicopathologic study of ALK-translocated papillary thyroid carcinoma.

Pathogenic ALK translocations have been reported in papillary thyroid carcinoma (PTC). We developed and validated a screening algorithm based on immunohistochemistry (IHC), followed by fluorescence in situ hybridization (FISH) in IHC-positive cases to identify ALK-rearranged PTC. IHC and FISH were performed in a cohort of 259 thyroid carcinomas enriched for aggressive variants. IHC was positive in 8 cases, 6 confirmed translocated by FISH (specificity 75%). All 251 IHC-negative cases were FISH negative (sensitivity 100%). Having validated this approach, we performed screening IHC, followed by FISH in IHC-positive cases in an expanded cohort. ALK translocations were identified in 11 of 498 (2.2%) of all consecutive unselected PTCs and 3 of 23 (13%) patients with diffuse sclerosing variant PTCs. No ALK translocations were identified in 36 PTCs with distant metastases, 28 poorly differentiated (insular) carcinomas, and 20 anaplastic carcinomas. All 14 patients with ALK translocations were female (P=0.0425), and translocations occurred at a younger age (mean 38 vs. 48 y, P=0.0289 in unselected patients). ALK translocation was an early clonal event present in all neoplastic cells and mutually exclusive with BRAF mutation. ALK translocation was not associated with aggressive clinicopathologic features (size, stage, metastasis, vascular invasion, extrathyroidal extension, multifocality, risk for recurrence, radioiodine resistance). We conclude that 2.2% of PTCs are ALK-translocated and can be identified by screening IHC followed by FISH. ALK translocations may be more common in young females and diffuse sclerosing variant PTC but do not connote more aggressive disease.

The role of Cdk5 in neuroendocrine thyroid cancer.

Medullary thyroid carcinoma (MTC) is a neuroendocrine cancer that originates from calcitonin-secreting parafollicular cells, or C cells. We found that Cdk5 and its cofactors p35 and p25 are highly expressed in human MTC and that Cdk5 activity promotes MTC proliferation. A conditional MTC mouse model was generated and corroborated the role of aberrant Cdk5 activation in MTC. C cell-specific overexpression of p25 caused rapid C cell hyperplasia leading to lethal MTC, which was arrested by repressing p25 overexpression. A comparative phosphoproteomic screen between proliferating and arrested MTC identified the retinoblastoma protein (Rb) as a crucial Cdk5 downstream target. Prevention of Rb phosphorylation at Ser807/Ser811 attenuated MTC proliferation. These findings implicate Cdk5 signaling via Rb as critical to MTC tumorigenesis and progression.

Mucoepidermoid carcinoma of the thyroid: a report of three cases and postulated histogenesis.

BACKGROUND: Primary mucoepidermoid carcinoma (MEC) of the thyroid is a rare clinical and pathological entity that accounts for <0.5% of all thyroid malignancies. Although the histogenesis has been controversial, most investigators now favor it as arising from either metaplasia of thyroid follicular epithelium or heterologous de-differentiation from papillary thyroid carcinoma (PTC). We report three cases of thyroid MEC found in continuity with, and clearly arising from de-differentiation of, well-differentiated thyroid carcinomas (WDTCs). PATIENT FINDINGS AND SUMMARY: The cases presented here included two women (aged 22 and 52) and one man (aged 58). One of these cases arose in conjunction with PTC, one with follicular thyroid carcinoma (FTC), and one with Hurthle cell carcinoma (HCC). In all three cases, there was a gradual transition in morphology between the areas of typical WDTC and the areas showing MEC differentiation. In addition, immunohistochemistry demonstrated a gradual loss of thyroid specific markers (thyroid transcription factor-1, thyroglobulin) mirroring the change in morphology. CONCLUSION: We conclude that thyroid MEC can arise from metaplastic de-differentiation of WDTC, including FTC or HCC in addition to PTC. Currently, we recommend that after excision, each of the WDTC and MEC components of these tumors be treated with targeted adjuvant therapies, which may involve radioactive-iodine ablation, thyrotropin suppression, and external beam radiotherapy.