S. B. Sidhu

A multicenter cohort study of total thyroidectomy and routine central lymph node dissection for cN0 papillary thyroid cancer

BACKGROUND The role of routine central lymph node dissection (CLND) for papillary thyroid cancer (PTC) remains controversial. The aim of this study was to evaluate the impact of routine CLND after total thyroidectomy (TTx) in the management of patients with PTC who were clinically node negative at presentation with emphasis on stimulated thyroglobulin (Tg) levels and reoperation rates. METHODS This retrospective, multicenter, cohort study used pooled data from 3 international Endocrine Surgery units in Australia, the United States, and England. All study participants had PTC >1 cm without preoperative evidence of lymph node disease (cN0). Group A patients had TTx alone and group B had TTx with the addition of CLND. RESULTS There were 606 patients included in the study. Group A had 347 patients and group B 259 patients. Stimulated Tg values were lower in group B before initial radioiodine ablation (15.0 vs 6.6 ng/mL; P = .025). There was a trend toward a lower Tg at final follow-up in group B (1.9 vs 7.2 ng/mL; P = .11). The rate of reoperation in the central compartment was lower in group B (1.5 vs 6.1%; P = .004). The number of CLND procedures required to prevent 1 central compartment reoperation was calculated at 20. CONCLUSION The addition of routine CLND in cN0 papillary thyroid carcinoma is associated with lower postoperative Tg levels and reduces the need for reoperation in the central compartment.

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

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.

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.

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 BRAFV600E 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 Glucocorticoid Receptor Is Overexpressed in Malignant Adrenocortical Tumors

CONTEXT Adrenocortical carcinoma (ACC) is a rare tumor with a poor prognosis. The Weiss score is the most widely accepted method for distinguishing an ACC from an adrenocortical adenoma (ACA); however, in borderline cases, accurate diagnosis remains problematic. We recently discovered that the glucocorticoid receptor (GR) gene NR3C1 is significantly up-regulated in ACCs compared with ACAs in global gene expression studies. OBJECTIVE Our objective was to study GR expression in adrenocortical tumors (ACTs) and to assess its utility as an adjunct to the Weiss score. DESIGN Microarray analysis, real-time quantitative RT-PCR (qPCR), immunohistochemistry, Western blot, and direct sequencing were performed. RESULTS Analysis of 28 ACTs by microarray and 49 ACTs by qPCR found NR3C1 expression to be up-regulated in ACCs compared with ACAs (P < 0.001). Western blotting and RT-PCR confirmed the presence of the GRalpha isoform in ACCs, and no mutations were detected on direct sequencing. Immunohistochemistry for GR in an overlapping cohort of ACTs demonstrated strongly positive nuclear staining in 31 of 33 ACCs (94%), with negative staining in 40 of 41 ACAs (98%) (P < 0.001). This finding was validated in an external cohort of ACTs, such that 14 of 18 ACCs (78%) demonstrated positive nuclear staining whereas 32 of 33 ACAs (94%) were negative (P < 0.001). CONCLUSIONS The immunohistochemical finding of nuclear GR staining identified ACCs with high diagnostic accuracy. We propose that GR immunohistochemistry may complement the Weiss score in the diagnosis of ACC in cases that display borderline histology. The possibility that GR is transcriptionally active in these tumors, and may therefore be a therapeutic target, requires further study.

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

ObjectiveThis study aims to compare dual tracer, dual phase pinhole technetium-99m labelled 2-methoxyisobutylisonitrile (99mTc-MIBI) imaging (including oblique imaging), with single photon emission computed tomography (SPECT) and dual phase planar 99mTc-MIBI images, and combined SPECT, dual phase planar 99mTc-MIBI images and anterior pinhole thyroid images for the localization of parathyroid adenomas in the neck in primary hyperparathyroidism. MethodsSixty-two patients underwent 99mTc-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 [99mTc] pertechnetate anterior and anterior oblique pinhole thyroid images. Images were reviewed by consensus in three combinations – dual phase anterior and anterior oblique pinhole 99mTc-MIBI images and pinhole thyroid images; SPECT and dual phase planar 99mTc-MIBI images and combined SPECT, dual phase planar 99mTc-MIBI images and anterior pinhole thyroid images. ResultsFor 52 parathyroid adenomas in 50 patients, the sensitivity of dual phase anterior and anterior oblique pinhole 99mTc-images and pinhole thyroid images was 81%. Significantly lower sensitivities were observed with SPECT and dual phase planar 99mTc-MIBI images (54%, P=0.0005) and combined SPECT, dual phase planar 99mTc-MIBI images and anterior pinhole thyroid images (65%, P=0.0209). The positive predictive value for all imaging combinations was 88–92%. ConclusionDual phase anterior and anterior oblique pinhole 99mTc-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.

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

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.

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.

ES12 CAN GIANT PARATHYROID ADENOMAS BE SAFELY REMOVED BY MINIMALLY INVASIVE PARATHYROIDECTOMY

Purpose  Minimally invasive parathyroidectomy (MIP) has become the procedure of choice for the surgical management of a parathyroid adenoma (PA) which localizes on preoperative imaging. The removal of giant PA (weighing greater than two grams) by the minimally invasive technique has not previously been described. Our aim was to determine the safety and efficacy of the removal of giant parathyroid adenomas at MIP.

Papillary Thyroid Carcinoma in Pregnancy: A Variant of the Disease?

BackgroundThere 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.MethodsWomen 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.ResultsThere 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.ConclusionsOur 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.