Grading system for medullary thyroid carcinoma; an institutional experience.

OBJECTIVE: Medullary thyroid carcinoma (MTC) is a rare type of thyroid malignancy. Recently, a two-tier grading system (GS) for MTC has been suggested. We conducted this study to evaluate the generalizability, as well as application of recently proposed GS to our cohort of Medullary thyroid carcinoma (MTC) cases. METHODS: We assigned grades to MTC cases and divided them into two groups by using morphologic criteria only as suggested by recent studies: low-grade (LG, <5 mitosis per 2 mm2, and no necrosis) and high-grade (HG, ≥5 mitosis per 2mm2 or necrosis). RESULTS: A total of 59 MTC cases were evaluated and of those 52 (88 %) were LG and 7 (12 %) were HG. Vascular invasion (VI) (p = 0.017), distant metastasis (DM) (p < 0.0001), nuclear pleomorphism (NP) (p = 0.017) and prominent nucleoli (p = 0.03) were prominently noted in the HG group. After controlling for demographics using multivariate cox regression, tumor grade and necrosis remained significantly associated with the overall survival (HR = 22.7, p < 0.01 and HR = 11.1, p = 0.008, respectively). Upon comparing the cases with and without nodal disease, we found that nodal disease is more strongly associated with NP (p = 0.029), tumor fibrosis (p = 0.0001), VI (p = 0.001) and DM (p = 0.005). CONCLUSIONS: We applied the two-tier GS for MTC to our cohort of cases and found statistically significant differences in the overall survival among the two groups. Adding the grading to the pathology report communicates additional information regarding risk stratification in MTC.

CONCENTRATED INSULINS: CLINICAL UPDATE OF THERAPEUTIC OPTIONS.

Improved glycemic control is associated with a reduced risk of diabetic complications. Optimal management of patients with type 2 diabetes includes nutritional therapy, physical activity, and pharmacotherapy for glycemic control. Most patients with type 2 diabetes are initially managed with oral antidiabetic agents, but as ß-cell function declines and the disease progresses, insulin therapy is frequently needed to maintain glycemic control. Insulin therapy given with multidose insulin injection regimen or by continuous insulin infusion is needed for patients with type 1 diabetes to achieve control. Obesity and its associated insulin resistance contribute to greater insulin requirements in patients with both type 1 and type 2 diabetes to achieve glycemic control, creating a need for concentrated insulin. Concentrated insulin formulations can be prescribed as an alternative to 100 unit/mL insulin and provide the advantage of low injection volume, leading to less pain and possibly fewer insulin injections. This review includes a stepwise analysis of all currently available concentrated insulin products, analyzes the most up-to-date evidence, and presents this in combination with expert guidance and commentary in an effort to provide clinicians with a thorough overview of the characteristics and benefits of concentrated insulins in patients with type 1 and type 2 diabetes-instilling confidence when recommending, prescribing, and adjusting these medications. Abbreviations: A1C = glycated hemoglobin; ß-cell = pancreatic betacell; BG = blood glucose; CI = confidence interval; CSII = continuous subcutaneous insulin infusion; MDI = multiple daily injections; NHANES = National Health and Nutrition Examination Survey; PD = pharmacodynamic; PK = pharmacokinetic; TDD = total daily dose; U100 = 100 units/mL; U200 = 200 units/mL; U300 = 300 units/mL; U500 = 500 units/mL; USD = United States dollars.

Performing Calcitonin Immunocytochemistry on an Additional ThinPrep Slide in Fine-Needle Aspiration Diagnosis of Medullary Thyroid Carcinoma.

OBJECTIVES: This study reviewed the institutional experience of performing calcitonin immunostain on an additional ThinPrep slide in fine-needle aspiration (FNA) diagnosis of medullary thyroid carcinoma (MTC). METHODS: Thyroid FNA cases with MTC suspected or included in the differential diagnosis during cytologic evaluation and calcitonin immunostain performed were retrieved and reviewed. RESULTS: Calcitonin immunostain was performed in 132 cases with 41 positive, 81 negative, and 10 indeterminate results. All calcitonin-positive cases had a cytologic diagnosis of MTC while all calcitonin-negative cases were cytologically classified as non-MTCs except for two cases suspicious for MTC. In 10 cases with an indeterminate calcitonin result, diagnoses of non-MTC and suspicious for MTC were rendered in 6 and 4 cases, respectively. Histopathologic follow-up was available in 85 (64%) cases. All cytologically diagnosed MTC cases were confirmed on histopathology. In 3 MTC cases with an indeterminate calcitonin result, 1 case was misclassified cytologically as follicular neoplasm. The calculated sensitivity, specificity, positive predictive value, and negative predictive value of calcitonin immunostain were all 100% for diagnosing MTC. CONCLUSIONS: Our study demonstrates the feasibility of performing calcitonin immunostain on an additional ThinPrep slide. Calcitonin immunocytochemistry is a valuable adjunct test for FNA diagnosis and differential diagnosis of MTC.

Current Evaluation of Thyroid Nodules.

Thyroid nodules may be discovered in a variety of settings. Familiarity with their management is important for medical specialists. Workup should start with history and physical examination, proceed to laboratory studies, and then to imaging. Nodules are selected for fine needle aspiration (FNA) biopsy based on imaging criteria. Most nodules can be accurately diagnosed on cytopathology, but some may require additional molecular testing to evaluate risk of malignancy. Patients with malignant lesions require additional investigation before referral to an experienced thyroid surgeon. Those who have benign lesions may require monitoring by periodic ultrasound to identify nodules requiring reevaluation.

Changes in Population-Level and Institutional-Level Prescribing Habits of Radioiodine Therapy for Papillary Thyroid Cancer.

Background: In the past two decades, new evidence and guidelines have emerged to refine recommendations for the use of radioactive iodine (RAI) therapy after thyroidectomy for cancer. We aim to describe national trends in RAI utilization, assess the impact of individual hospitals on RAI utilization, and examine whether variation in prescribing habits has declined over time. Methods: The National Cancer Database (NCDB) was queried from 2004 to 2016 for patients with papillary thyroid cancer (PTC) who received total thyroidectomy. Trends were analyzed using Joinpoint analysis. Hospital-specific effects and variation in prescribing habits were assessed through a hierarchical, mixed regression model. Results: RAI utilization declined from 61.0% in 2004 to 43.9% in 2016. RAI use declined most profoundly in patients with T1a, N0/X, M0 PTC without extrathyroidal extension (34.8% in 2004 to 9.5% in 2015), but continues to be used commonly in patients with advanced disease for whom it is routinely recommended (73.4% in 2004 to 72.0% in 2015). Furthermore, ∼80% of hospitals in 2016 utilized at or below the median utilization rate in 2006. Variation in RAI utilization across hospitals decreased by ∼50% from 2004 to 2016 (Levene's test p < 0.001), with a significant decline (p = 0.002) in the variation after 2012 (confidence interval: 2010 to 2014). Conclusions: Recommendations for whom to prescribe RAI appear to have impacted both the number of patients receiving RAI and the variation in prescribing habits across hospitals. Hospital selection has contributed less to the probability of receiving RAI over time.

Care of the pregnant thyroid cancer patient.

PURPOSE OF REVIEW: Thyroid cancer is the fastest rising type of cancer among women in North America. Care of the pregnant patient with thyroid cancer is, therefore, of concern to obstetricians, internists and endocrine specialists. Guidelines for the care of the pregnant patient with thyroid disease were released by the Endocrine Society in late 2007, and a symposium on thyroid dysfunction and pregnancy was hosted by the American Thyroid Association in April 2009. With this increasing interest in thyroid disease and pregnancy, a variety of important studies have been published recently. RECENT FINDINGS: In addition to guidelines published by the Endocrine Society, recent research has focused on detection and management of hypothyroidism in pregnancy, and consequences of hypothyroidism for the fetus and child. Impact of radioactive iodine therapy on subsequent fertility has been described. The risk of adverse outcomes due to thyroid surgery during pregnancy was evaluated in analysis of a large inpatient database. SUMMARY: Identification of hypothyroidism during pregnancy continues to be challenging due to the need for well established trimester-specific normal ranges. Physicians may reassure patients about the effects of radioactive iodine therapy on fertility, although men may wish to cryopreserve sperm prior to treatment. Thyroid surgery during pregnancy was associated with a two-fold increased risk of surgical complications.

Adjuvant external beam radiotherapy for surgically resected, nonmetastatic anaplastic thyroid cancer.

BACKGROUND: EBRT in resected, nonmetastatic anaplastic thyroid cancer (ATC) remains undefined. We evaluated patterns/outcomes with EBRT and chemotherapy in this setting. METHODS: This retrospective analysis included patients identified from the National Cancer Database with nonmetastatic ATC from 2004 to 2014 who underwent non-palliative resection. RESULTS: Our analysis included 496 patients, including 375 who underwent adjuvant EBRT (among whom 198 received concurrent chemotherapy). The median age was 68 years. On MVA, EBRT was associated with sex (OR 0.5, 95% CI 0.3-0.8, P = .002) and income (OR 2.2, 95% CI 1.4-3.3, P < .001). EBRT was associated with longer OS on UVA (12.3 vs 9.1 months, P = .004) and MVA (HR 0.7 [CI 0.6-0.9], P = .004). Concurrent chemoradiation was associated with longer OS on UVA (14.0 vs 9.1 months, P = .003) and MVA (HR 0.6 [CI 0.5-0.8], P < .001). CONCLUSION: Adjuvant EBRT is associated with longer OS in resected, nonmetastatic ATC, with additional improved survival with concurrent chemotherapy.

Differential Clinicopathological Risk and Prognosis of Major Papillary Thyroid Cancer Variants.

CONTEXT: Individualized management, incorporating papillary thyroid cancer (PTC) variant-specific risk, is conceivably a useful treatment strategy for PTC, which awaits comprehensive data demonstrating differential risks of PTC variants to support. OBJECTIVE: This study sought to establish the differential clinicopathological risk of major PTC variants: conventional PTC (CPTC), follicular-variant PTC (FVPTC), and tall-cell PTC (TCPTC). METHODS: This was a retrospective study of clinicopathological outcomes of 6282 PTC patients (4799 females and 1483 males) from 26 centers and The Cancer Genome Atlas in 14 countries with a median age of 44 years (interquartile range, 33-56 y) and median follow-up time of 37 months (interquartile range, 15-82 mo). RESULTS: The cohort consisted of 4702 (74.8%) patients with CPTC, 1126 (17.9%) with FVPTC, and 239 (3.8%) with TCPTC. The prevalence of high-risk parameters was significantly different among the three variants, including extrathyroidal invasion, lymph node metastasis, stages III/IV, disease recurrence, mortality, and the use (need) of radioiodine treatment (all P < .001), being highest in TCPTC, lowest in FVPTC, and intermediate in CPTC, following an order of TCPTC > CPTC ≫ FVPTC. Recurrence and mortality in TCPTC, CPTC, and FVPTC were 27.3 and 6.7%, 16.1 and 2.5%, and 9.1 and 0.6%, corresponding to events per 1000 person-years (95% confidence interval [CI]) of 92.47 (64.66-132.26) and 24.61 (12.31-49.21), 34.46 (30.71-38.66), and 5.87 (4.37-7.88), and 24.73 (18.34-33.35) and 1.68 (0.54-5.21), respectively. Mortality hazard ratios of CPTC and TCPTC over FVPTC were 3.44 (95% CI, 1.07-11.11) and 14.96 (95% CI, 3.93-56.89), respectively. Kaplan-Meier survival analyses showed the best prognosis in FVPTC, worst in TCPTC, and intermediate in CPTC in disease recurrence-free probability and disease-specific patient survival. This was particularly the case in patients at least 45 years old. CONCLUSION: This large multicenter study demonstrates differential prognostic risks of the three major PTC variants and establishes a unique risk order of TCPTC > CPTC ≫ FVPTC, providing important clinical implications for specific variant-based management of PTC.

BRAF mutation predicts a poorer clinical prognosis for papillary thyroid cancer.

CONTEXT: Use of BRAF mutation in papillary thyroid cancer (PTC) has the potential to improve risk stratification of this cancer. OBJECTIVE: The objective of the study was to investigate the prognostic value of BRAF mutation in patients with PTC. DESIGN, SETTING, AND SUBJECTS: In a multicenter study of 219 PTC patients, data on their clinicopathological characteristics and clinical courses between 1990 and 2004 were retrospectively collected, and their tumor BRAF mutation status was determined. Associations of BRAF mutation with initial tumor characteristics and subsequent recurrence were analyzed. MAIN OUTCOME MEASURE: Relationships between the BRAF mutation status and clinicopathological outcomes, including recurrence, were measured. RESULTS: We found a significant association between BRAF mutation and extrathyroidal invasion (P < 0.001), lymph node metastasis (P < 0.001), and advanced tumor stage III/IV (P = 0.007) at initial surgery. This association remained significant on multivariate analysis, adjusting for conventional clinicopathological predictors of recurrence excluding the histological PTC subtype, but was lost when the tumor subtype was included in the model. BRAF mutation was also significantly associated with tumor recurrence, 25 vs. 9% with and without mutation, respectively (P = 0.004), during a median of 15 (interquartile range, 3-29) months of follow-up. This association remained significant on multivariate analysis adjusting for conventional clinicopathological predictors of recurrence, even including the PTC subtype (odds ratio, 4.0; 95% confidence interval, 1.1-14.1; P = 0.03). BRAF mutation was even an independent predictor of recurrence in patients with stage I/II disease, 22 vs. 5% with and without BRAF mutation, respectively (P = 0.002). BRAF mutation was also more frequently associated with absence of tumor I-131 avidity and treatment failure of recurrent disease. CONCLUSIONS: In patients with PTC, BRAF mutation is associated with poorer clinicopathological outcomes and independently predicts recurrence. Therefore, BRAF mutation may be a useful molecular marker to assist in risk stratification for patients with PTC.

Association between BRAF V600E mutation and recurrence of papillary thyroid cancer.

PURPOSE: To investigate the prognostic value of BRAF V600E mutation for the recurrence of papillary thyroid cancer (PTC). PATIENTS AND METHODS: This was a retrospective multicenter study of the relationship between BRAF V600E mutation and recurrence of PTC in 2,099 patients (1,615 women and 484 men), with a median age of 45 years (interquartile range [IQR], 34 to 58 years) and a median follow-up time of 36 months (IQR, 14 to 75 months). RESULTS: The overall BRAF V600E mutation prevalence was 48.5% (1,017 of 2,099). PTC recurrence occurred in 20.9% (213 of 1,017) of BRAF V600E mutation-positive and 11.6% (125 of 1,082) of BRAF V600E mutation-negative patients. Recurrence rates were 47.71 (95% CI, 41.72 to 54.57) versus 26.03 (95% CI, 21.85 to 31.02) per 1,000 person-years in BRAF mutation-positive versus -negative patients (P < .001), with a hazard ratio (HR) of 1.82 (95% CI, 1.46 to 2.28), which remained significant in a multivariable model adjusting for patient sex and age at diagnosis, medical center, and various conventional pathologic factors. Significant association between BRAF mutation and PTC recurrence was also found in patients with conventionally low-risk disease stage I or II and micro-PTC and within various subtypes of PTC. For example, in BRAF mutation-positive versus -negative follicular-variant PTC, recurrence occurred in 21.3% (19 of 89) and 7.0% (24 of 342) of patients, respectively, with recurrence rates of 53.84 (95% CI, 34.34 to 84.40) versus 19.47 (95% CI, 13.05 to 29.04) per 1,000 person-years (P < .001) and an HR of 3.20 (95% CI, 1.46 to 7.02) after adjustment for clinicopathologic factors. BRAF mutation was associated with poorer recurrence-free probability in Kaplan-Meier survival analyses in various clinicopathologic categories. CONCLUSION: This large multicenter study demonstrates an independent prognostic value of BRAF V600E mutation for PTC recurrence in various clinicopathologic categories.

Association of aberrant methylation of tumor suppressor genes with tumor aggressiveness and BRAF mutation in papillary thyroid cancer.

The role of aberrant tumor suppressor gene methylation in the aggressiveness of papillary thyroid cancer (PTC) has not been documented. By showing promoter methylation-induced gene silencing in PTC-derived cell lines, we first demonstrated the functional consequence of methylation of several recently identified tumor suppressor genes, including those for tissue inhibitor of metalloproteinase-3 (TIMP3), SLC5A8, death-associated protein kinase (DAPK) and retinoic acid receptor beta2 (RARbeta2). We then investigated the role of methylation of these genes in the aggressiveness of PTC by examining the relationship of their aberrant methylation to clinicopathological characteristics and BRAF mutation in 231 primary PTC tumors. Methylation of TIMP3, SLC5A8 and DAPK was significantly associated with several aggressive features of PTC, including extrathyroidal invasion, lymph node metastasis, multifocality and advanced tumor stages. Methylation of these genes was also significantly associated with BRAF mutation in PTC, either individually or collectively in various combinations. Methylation of these genes, either individually or collectively, occurred more frequently in more aggressive classical and tall-cell PTC subtypes than in less aggressive follicular-variant PTC, with the latter known to infrequently harbor BRAF mutation. Several other tumor suppressor genes investigated were not methylated. These results suggest that aberrant methylation and hence silencing of TIMP3, SLC5A8, DAPK and RARbeta2, in association with BRAF mutation, may be an important step in PTC tumorigenesis and progression.