Impact of molecular testing on thyroid nodule neoplastic diagnosis, stratified by 4-cm size, in a surgical series.

Whether molecular testing adds diagnostic value to the evaluation of thyroid nodules 4-cm or larger is unknown. The impact of molecular testing on cytopathologic-histopathologic diagnosis of neoplasm (adenoma or malignant), stratified by nodule size

Systematic Review and Meta-analysis of the Impact of Noninvasive Follicular Thyroid Neoplasm with Papillary-Like Nuclear Features (NIFTP) on Cytological Diagnosis and Thyroid Cancer Prevalence.

A re-named diagnosis of noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) likely impacts the prevalence of thyroid cancer and risk of malignancy in populations based on the established Bethesda System of Reporting Thyroid Cytopathology (TBSRTC). This study was done to investigate the prevalence and cytological distribution of NIFTP. PRISMA guided systematic review was done from a database search of Pubmed, EMBASE, and Medline using the search terms "non-invasive follicular thyroid neoplasm with papillary-like nuclear features", "non-invasive follicular variant of papillary carcinoma", "niftp", and "Bethesda" until November 2018. Original articles with surgically proven diagnoses of NIFTP using strict NIFTP criteria were included. Twenty-nine studies with 1563 cases of NIFTP were included. The pooled prevalence of NIFTP in cases which would be classified previously as the follicular variant of papillary thyroid cancer (FVPTC) and papillary thyroid cancer (PTC) were 43.5% (95% CI 33.5-54.0%) and 4.4% (95% CI 2.0-9.0%) respectively. The pooled TBSRTC distribution of cases diagnosed as NIFTP was: from the non-diagnostic category 3.6% (95% CI 2.4-5.3%), benign 10.0% (95% CI 7.2-13.6%), AUS/FLUS 34.2% (95% CI 28.2-40.8%), FN/SFN 22.7% (95% CI 17.2-29.4%), suspicious for malignancy 22.4% (95% CI 17.7-27.9%), and malignant 7.5% (95% CI 4.2-12.9%). While a significant reduction in FVPTC prevalence is anticipated, a modest reduction of PTC prevalence is also expected with adoption of the NIFTP terminology that would be distributed mainly among lesions classified as indeterminate thyroid nodules. Further studies are needed to identify unique clinical characteristics of these lesions preoperatively.

Cytomorphology of Noninvasive Follicular Thyroid Neoplasm with Papillary-Like Nuclear Features and the Impact of New Nomenclature on Molecular Testing.

The re-naming of noninvasive follicular variant papillary thyroid cancer to the apparently non-malignant, noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) impacts the prevalence of malignancy rates, thereby affecting mutation frequency in papillary thyroid cancer. Preoperative assessment of such nodules could affect management in the future. The original publications following the designation of the new nomenclature have been extensively reviewed. With the adoption of NIFTP terminology, a reduction in the follicular variant of papillary thyroid cancer (FVPTC) prevalence is anticipated, as is a modest reduction of papillary thyroid cancer (PTC) prevalence that would be distributed mainly across indeterminate thyroid nodules. Identifying NIFTP preoperatively remains challenging. RAS mutations are predominant but the presence of BRAF V600E mutation has been observed and could indicate inclusion of the classical PTC. The histological diagnosis of NIFTP to designate low-risk encapsulated follicular variant papillary thyroid cancers (EFVPTCs) would impact malignancy rates, thereby altering the mutation prevalence. The histopathologic criteria have recently been refined with an exclusion of well-formed papillae. The preoperative identification of NIFTP using cytomorphology and gene testing remains challenging.

USE OF A CONTINUOUS GLUCOSE MONITOR FOR PREOPERATIVE MONITORING AND TREATMENT OF HYPOGLYCEMIA IN A CASE OF PANCREATIC NEUROENDOCRINE TUMOR.

OBJECTIVE: Pancreatic neuroendocrine tumors secreting proinsulin and insulin could lead to life-threatening hypoglycemia. We aim to show this can be avoided by utilizing continuous glucose monitoring. METHODS: We describe a case of a 55-year-old female with hypoglycemia unawareness and seizures diagnosed with proinsulinoma. She utilized an intermittently scanned continuous glucose monitor (isCGM) to monitor hypoglycemia preoperatively. RESULTS: The patient underwent biochemical and radiographic evaluation to confirm the diagnosis of proinsulinoma. Utilizing isCGM to monitor blood glucose, she was able to prevent hypoglycemia-related seizures prior to definitive surgery. CONCLUSION: In the time leading up to a definitive surgery, patients with proinsulinomas are at risk of hypoglycemic events leading to falls, seizures, and even death. isCGMs can be utilized for preoperative monitoring and treatment of hypoglycemia in these patients.

Role of Relative Malnutrition in Exercise Hypogonadal Male Condition.

OBJECTIVE: Exercise hypogonadal male condition is a well-recognized condition in women but much less understood in men. The aim of this case report is to highlight exercise-induced hypogonadotropic hypogonadism in a male who recovered with lifestyle modifications. METHODS: We report a case of an adolescent male who developed hypogonadotropic hypogonadism secondary to excessive exercise and malnutrition that was followed up for a year without exogenous testosterone supplementation. Informed consent was obtained from the patient for his information to be used in a manuscript submitted to a journal. RESULTS: An 18-yr-old adolescent male presented to the clinic with symptoms of fatigue and low endurance, low libido, and lack of morning erections. At the time of his presentation, he was running about 60 miles per week for school cross-country team in addition to cross training with kickboxing. Physical examination was remarkable for low body mass index of 19 kg·m but was otherwise normal. Biochemical workup confirmed hypogonadotropic hypogonadism and a mild pancytopenia. Other pituitary laboratory values and MRI of the brain were unremarkable. Bone marrow biopsy performed for anemia showed features consistent with malnutrition. With a working diagnosis of exercise hypogonadal male condition, he was advised to reduce the frequency and intensity of his exercise and increase calorie intake. Cell counts and testosterone levels normalized, and his symptoms resolved without any further interventions. CONCLUSION: Significant reversible hypogonadism can develop after intensive and prolonged exercise. One of the mechanisms of hypogonadism in endurance athletes performing intensive exercise could be relative malnutrition. Further studies to evaluate the role of nutrition and body mass index in male endurance athletes presenting with hypogonadism are needed to identify the underlying mechanism of this condition.

Association of Biotin Ingestion With Performance of Hormone and Nonhormone Assays in Healthy Adults.

Importance: Biotinylated antibodies and analogues, with their strong binding to streptavidin, are used in many clinical laboratory tests. Excess biotin in blood due to supplemental biotin ingestion may affect biotin-streptavidin binding, leading to potential clinical misinterpretation. However, the degree of interference remains undefined in healthy adults. Objective: To assess performance of specific biotinylated immunoassays after 7 days of ingesting 10 mg/d of biotin, a dose common in over-the-counter supplements for healthy adults. Design, Setting, and Participants: Nonrandomized crossover trial involving 6 healthy adults who were treated at an academic medical center research laboratory. Exposure: Administration of 10 mg/d of biotin supplementation for 7 days. Main Outcomes and Measures: Analyte concentrations were compared with baseline (day 0) measures on the seventh day of biotin treatment and 7 days after treatment had stopped (day 14). The 11 analytes included 9 hormones (ie, thyroid-stimulating hormone, total thyroxine, total triiodothyronine, free thyroxine, free triiodothyronine, parathyroid hormone, prolactin, N-terminal pro-brain natriuretic peptide, 25-hydroxyvitamin D) and 2 nonhormones (prostate-specific antigen and ferritin). A total of 37 immunoassays for the 11 analytes were evaluated on 4 diagnostic systems, including 23 assays that incorporated biotin and streptavidin components and 14 assays that did not include biotin and streptavidin components and served as negative controls. Results: Among the 2 women and 4 men (mean age, 38 years [range, 31-45 years]) who took 10 mg/d of biotin for 7 days, biotin ingestion-associated interference was found in 9 of the 23 (39%) biotinylated assays compared with none of the 14 nonbiotinylated assays (P = .007). Results from 5 of 8 biotinylated (63%) competitive immunoassays tested falsely high and results from 4 out of 15 (27%) biotinylated sandwich immunoassays tested falsely low. Conclusions and Relevance: In this preliminary study of 6 healthy adult participants and 11 hormone and nonhormone analytes measured by 37 immunoassays, ingesting 10 mg/d of biotin for 1 week was associated with potentially clinically important assay interference in some but not all biotinylated assays studied. These findings should be considered for patients taking biotin supplements before ordering blood tests or when interpreting results. Trial Registration: clinicaltrials.gov Identifier: NCT03034707.

Correlation Between Histological Diagnosis and Mutational Panel Testing of Thyroid Nodules: A Two-Year Institutional Experience.

BACKGROUND: Indeterminate thyroid fine-needle aspiration (FNA) cytology, including atypia of undetermined significance (AUS/FLUS) and suspicious for follicular neoplasm (SFN), continues to generate uncertainty about the presence of malignancy, resulting in repeated follow-up, repeat FNA, or diagnostic surgery. Mutational panel testing may improve the malignancy risk prediction in indeterminate nodules, but the general application of such testing has not been investigated extensively. METHODS: A retrospective review was performed of all patients undergoing thyroidectomy at a tertiary care facility over a two-year period. Mutational panel test results, when present, were analyzed relative to FNA cytologic result and surgical histopathologic diagnosis. Malignancy rates, sensitivity, specificity, positive predictive values (PPV), negative predictive values (NPV) and positive and negative likelihood ratios (LR) were calculated. RESULTS: A total of 261 operated thyroid nodules had the following initial FNA cytology results: 2% non-diagnostic, 23% benign, 28% AUS/FLUS, 11% SFN, 9% suspicious for malignancy (SUSP), and 27% malignant. The histopathologic malignancy rate was 48%, subcategorized by cytology into benign 7%, AUS/FLUS 30%, SFN 38%, and SUSP 83%. Mutations were more frequent in indeterminate nodules that were histologically malignant versus benign (p < 0.0001) or versus adenoma (p = 0.001). Mutational analysis in 44 AUS/FLUS nodules resulted in a malignancy detection sensitivity of 85%, a specificity of 65%, a PPV of 50%, a NPV of 91%, and a positive LR of 2.4. In 12 SFN nodules analyzed with ThyroSeq(®) testing, sensitivity was 100%, specificity 57%, PPV 63%, NPV 100%, and LR 2.3. Performance of the seven-gene mutational panel was not significantly different from the ThyroSeq(®) panel in the AUS/FLUS group. The malignancy yield, comparing the mutation positive AUS/FLUS group with the untested AUS/FLUS surgical cohort, did not reach statistical significance (p = 0.17). CONCLUSIONS: In a surgical cohort, a similar NPV but a lower PPV was found with the use of mutational panel testing compared to the published literature. Following the identification of a mutation, the prevalence of malignancy in the AUS/FLUS or SFN category was increased by nearly 15% to 45% and 53%, respectively. Further study is needed to confirm these results and to analyze clinical outcome subcategories relative to the utility of mutational testing.

Cytologic subclassification of atypia of undetermined significance may predict thyroid nodules more likely to be malignant at surgery.

BACKGROUND: The atypia of undetermined significance or follicular lesion of undetermined significance (AUS/FLUS) category in the Bethesda System of reporting thyroid fine-needle aspiration (FNA) includes various cytological findings considered to have a low risk of malignancy. It is still unclear if any particular subset of the cytological findings within this category carries a higher risk for malignancy requiring a more aggressive treatment plan. METHODS: We reviewed 221 AUS/FLUS FNAs performed between January of 2006 and May of 2012. Histopathological data from surgery was available in 101 nodules and characteristics of these nodules were analyzed. We reviewed the initial cytology report and subclassified the nodules into one of four groups: architectural atypia (AA, includes abnormal follicular arrangement but no cellular abnormalities), cellular atypia (CA, atypical cellular findings) with or without AA, Hurthle cells Predominant and Others that included otherwise unspecified AUS categories. The surgical pathology confirmed malignancy rate for each group was calculated. RESULT: Papillary thyroid carcinoma was the most common malignancy identified (26 of 29 or 90%). We found that in the AA only category, 2/21 (10%) nodules were malignant, whereas when CA with or without AA was present, 23/66 (35%) were malignant, significantly higher than the former group (P values of 0.025). CONCLUSION: CA seen on initial AUS/FLUS had a higher malignancy rate compared to AA group. Further research is required to consider subclassification of this category to assign appropriate risk of malignancy for AUS nodules. Diagn. Cytopathol. 2016;44:492-498. © 2016 Wiley Periodicals, Inc.

Multiple Mutations Detected Preoperatively May Predict Aggressive Behavior of Papillary Thyroid Cancer and Guide Management--A Case Report.

BACKGROUND: Multiple gene mutations in thyroid nodules are rare. The presence of several oncogenic mutations could be associated with aggressive biological behavior of tumors. PATIENT FINDINGS: A 60-year-old female presented to her physician after she felt a lump in her neck. On ultrasound, she was found to have a 1.4 cm × 0.8 cm × 1.3 cm nodule in the isthmus and a 0.5 cm × 0.6 cm × 0.6 cm nodule with irregular margins and hypoechogenicity in the right thyroid lobe, warranting fine-needle aspiration (FNA). Cytological examination of the smaller nodule yielded a diagnosis of atypia of undetermined significance (AUS/FLUS, Bethesda Category III). The aspirate was submitted for molecular testing using the next-generation sequencing ThyroSeq(®) v2 panel. The test revealed four distinct mutations: BRAF (p.V600E), TERT (C228T), PIK3CA (p.H1047R), and AKT1 (p.E17K). Presence of multiple oncogenic mutations in the FNA specimen was highly indicative of cancer, and suggestive of a cancer with propensity toward more aggressive biological behavior. Four weeks after the FNA results were available, the patient underwent total thyroidectomy. This was followed by radioactive iodine ablation after the final pathology revealed a 0.5 cm papillary thyroid carcinoma (PTC) with extrathyroidal extension and positive resection margins (pT3 stage). SUMMARY: Herein, the first case of four mutations preoperatively detected in a subcentimeter thyroid nodule that was confirmed to be a PTC with aggressive biological behavior is reported. CONCLUSIONS: The judicious indication of FNA and use of molecular screening can potentially help in predicting aggressive behavior of small-sized thyroid cancers and in identifying patients who may benefit from early and more extensive therapy.