Incidental lesions of the thyroid are increasingly discovered as the prevalence of medical imaging escalates. The likelihood of malignancy must be assessed for each of these incidentalomas. The utility of the metabolic data derived from the identification of these lesions on PET/CT imaging is unclear. The overall rate of detection of thyroid incidentalomas on PET/CT is estimated at 1.5％-4.2％. However, this rate varies by the pattern of uptake. Several studies have evaluated predictive measures such as maximal standardized uptake value (SUVmax) and radiomics. However, no definitive conclusion has been reached. Given that the majority of PET/CT scans are performed in the context of malignancy, we recommend first assessing the general condition and life expectancy of patients when PET-detected thyroid incidentalomas are unveiled. We also recommend considering observation versus diagnostic workup with further imaging and/or fine-needle aspiration and cytology.

We read with much interest the paper,[1] “Clinical significance of thyroid incidentalomas detected on fluorodeoxyglucose positron emission tomography scan (PETomas): An Indian experience” by Kumar et al. published in the July–September 2019 issue of your journal. In April 2011, our team published our findings on this topic, at which time we suggested that this thyroid entity should be called “PETomas.”[2] We are, therefore, extremely surprised that Kumar et al. did not cite our publication and acknowledge our role in initiating the use of the term “PETomas.”

Multifocal papillary thyroid carcinoma (PTC) is common and the number of tumor foci rarely exceeds ten. The mechanism of multifocal disease is debated, with the two main hypotheses consisting of either intrathyroidal metastatic spread from a single tumor or independent multicentric tumorigenesis from distinct progenitor cells. We report the case of a 46-year-old woman who underwent total thyroidectomy and left central neck lymph node dissection after fine-needle aspiration of bilateral thyroid nodules that yielded cytological findings consistent with PTC. Final pathology of the surgical specimen showed an isthmic dominant 1.5 cm classical PTC and over 30 foci of microcarcinoma, which displayed decreasing density with increasing distance from the central lesion. Furthermore, all malignant tumors and lymph nodes harbored the activating BRAF V600E mutation. The present case highlights various pathological features that support a mechanism of intraglandular spread, namely a strategic isthmic location of the primary tumor, radial pattern of distribution and extensive number of small malignant foci and BRAF mutational homogeneity.

Molecular profiling in thyroid cancer has made significant progress in part due to advances in somatic mutation profiling. Yet, differentiating benign from malignant thyroid nodules remains elusive. A unique set of DNA methylation signatures has the potential of improving thyroid cancer molecular diagnostics based on the DNA methylome. See related article by Yim et al., p. 544

Lugol’s solution is usually employed for a limited period for thyroidectomy preparation in patients with Graves’ disease and for the control of severe thyrotoxicosis and thyroid storm. We describe a rare case of Lugol’s solution-induced painless thyroiditis. In November 2014, a 59-year-old woman was prescribed Lugol’s solution four drops per day for the alleviation of menopausal symptoms. She was referred to our clinic in June 2015 for fatigue, hair loss, and a 20-lb weight loss without thyroid pain or discomfort. Physical examination revealed a normal thyroid gland. On 7 May 2015, laboratory tests revealed a suppressed thyroid-stimulating hormone (TSH) 0.01 U/L with elevated free T4 3.31 ng/dL (42.54 pmol/L). Repeat testing on 25 May 2015 showed spontaneous normalization of the free thyroid hormone levels with persistently low TSH 0.10 U/L. Following these results, a family physician prescribed methimazole 10 mg PO TID and very soon after, the TSH concentration rose to >100 U/L along with subnormal free T4 and T3 levels. Methimazole was promptly discontinued, namely within 18 days of its initiation. Over the course of the next few months, the patient spontaneously achieved clinical and biochemical euthyroidism. To our knowledge, this is a unique case of painless thyroiditis induced by Lugol’s solution, which has not been reported before. Lugol’s solution is a short-term medication given for the preparation of thyroidectomy in patients with Graves’ disease and for the control of severe thyrotoxicosis. Iodine excess can cause both hyperthyroidism and hypothyroidism. Rarely, Lugol’s solution can cause acute painless thyroiditis. Learning points: Lugol’s solution is used for thyroidectomy preparation in patients with Graves’ disease and for the control of severe thyrotoxicosis and thyroid storm. Iodine excess can cause both hypothyroidism and thyrotoxicosis. Thyroid glands with an underlying pathology are particularly susceptible to the adverse effect of iodine. The prolonged off-label use of Lugol’s solution can be harmful. Rarely, Lugol’s solution can cause acute painful thyroiditis.

A minority of metastatic well-differentiated thyroid cancer (WDTC) patients present with end-organ disease other than in the lung, bone or lymph nodes. These metastases tend to be overlooked because of their low incidence, and this results in delayed diagnosis. The purpose of this study was to perform a systematic review of the clinical and histologic features of unusual WDTC metastases.

In current clinical practice, fine-needle aspiration biopsy (FNAB) of thyroid nodules will result in indeterminate cytology (atypia of undetermined significance [AUS] or follicular lesion of undetermined significance [FLUS], follicular neoplasm [FN] or suspicious for FN, and suspicious for malignancy) in 15–30% of patients (1). Despite a low risk of malignancy, diagnostic surgery is often necessary in determining a final pathology. However, recent advances in molecular diagnostics may potentially aid clinicians by identifying certain patients in whom surgery can be safely avoided. Two novel molecular tests have become commercially available in the past several years. The gene-expression classifier (GEC) (Afirma; Veracyte, Inc) is based on an expression profile of 142 gene mRNA, which gained prominence after the large industry-sponsored multicenter validation study by Alexander et al (2) on a total study sample of 265 samples of indeterminate nodules from 49 participating centers. This study demonstrated high sensitivity (92%) and high negative predictive value (93%), but low specificity (52%) and positive predictive value (PPV; 47%) for the GEC. Subset analyses of nodules with AUS/FLUS and FN cytology demonstrate a similar diagnostic performance. Given these findings, the GEC has been proposed as a “rule-out” test; that is, nodules with indeterminate cytology and a benign GEC result could be managed by close observation, rather than proceeding to diagnostic surgery. However, diagnostic performance was less favorable for nodules with “suspicious for malignancy” cytology, and therefore these nodules should not undergo GEC testing and should rather proceed directly to surgery. Another molecular diagnostic test has been developed based on the presence of point mutations of BRAF and RAS, and rearrangements of RET/PTC and PAX8/PPAR . Contrary to the GEC, the gene mutation panel (miRInform; Asuragen Inc) was shown to have high specificity (96–99%) and PPV (87–95%), but low sensitivity (57–63%) and negative predictive value (72– 94%) for indeterminate nodules in a study of FNAB samples from 513 nodules at a single academic center (3). This mutation panel can be used as a “rule-in” approach; that is, indeterminate nodules with positive markers can proceed directly to a total thyroidectomy due to the high probability of malignancy, rather than a two-stage operation. The utility of these new tests is recognized because they have been included in the 2013–14 revisions of the National Comprehensive Cancer Network guidelines on thyroid carcinoma (4). In this issue of the JCEM, McIver et al (5) have reported their results on the use of a GEC in the management of patients with indeterminate thyroid nodules based on cytopathology at a large tertiary academic institution. Importantly, FNAB cytopathology was determined by their specialized thyroid cytopathologists, rather than undergoing an initial “screening” process by Thyroid Cytology Partners, as is otherwise required by Veracyte (the manufacturer of the GEC) in clinical practice. In their study, the GEC was offered to all patients with AUS/FLUS or FN cytology. Patients with a benign GEC classification were managed observantly (n 16), whereas those with a “suspicious” result were offered surgery (n 44). Among these 60 patients, only 36 (60%) underwent surgery (four with benign GEC, and 32 with suspicious GEC). The overall prevalence of malignancy in these patients was 16% (6 of

CONTEXT:Novel molecular diagnostics, such as the gene expression classifier (GEC) and gene mutation panel (GMP) testing, may improve the management for thyroid nodules with atypia of undetermined significance (AUS) cytology. The cost-effectiveness of an approach combining both tests in different practice settings in North America is unknown.OBJECTIVE:The aim of the study was to determine the cost-effectiveness of two diagnostic molecular tests, singly or in combination, for AUS thyroid nodules.DESIGN AND SETTING:We constructed a microsimulation model to investigate cost-effectiveness from US (Medicare) and Canadian healthcare system perspectives.PATIENTS:Low-risk patients with AUS thyroid nodules were simulated.INTERVENTIONS:We examined five management strategies: 1) routine GEC; 2) routine GEC + selective GMP; 3) routine GMP; 4) routine GMP + selective GEC; and 5) standard management.MAIN OUTCOME MEASURES:Lifetime costs and quality-adjusted life-years were measured.RESULTS:From the US perspective, the routine GEC + selective GMP strategy was the dominant strategy. From the Canadian perspective, routine GEC + selective GMP cost and additional CAN$24 030 per quality-adjusted life-year gained over standard management, and was dominant over the other strategies. Sensitivity analyses reported that the decisions from both perspectives were sensitive to variations in the probability of malignancy in the nodule and the costs of the GEC and GMP. The probability of cost-effectiveness for routine GEC + selective GMP was low.CONCLUSIONS:In the US setting, the most cost-effective strategy was routine GEC + selective GMP. In the Canadian setting, standard management was most likely to be cost effective. The cost of these molecular diagnostics will need to be reduced to increase their cost-effectiveness for practice settings outside the United States.

The management of occult cervical lymph node metastasis in well-differentiated thyroid cancer (WDTC) is controversial. Given the risks of hypocalcemia, recurrent laryngeal nerve injury, and increased operative time with a central compartment neck dissection (CCND), a routine adoption of prophylactic lymph node dissection has not been accepted by many as a standard management for occult metastasis (Henry et al., 1998; Pereira et al., 2005; Shen et al., 2010). Conversely, other thyroid surgeons feel that the complication rate is low and that the benefits of CCND outweigh the risks (Anand et al., 2009; Haigh et al., 2000; Keleman et al., 1998; Pelizzo et al., 2001; Pitman et al., 2003; Rettenbacher et al., 2000). As a result, sentinel lymph node biopsy (SLNB) has gained an increase in popularity in recent years.

With the current trend of alarming rise in obesity rates, the health impacts of excess weight will become more apparent. While an increased incidence of cardiovascular disease and diabetes mellitus has been well documented, the association between obesity and carcinogenesis is just being appreciated and is receiving increasing attention. The current review focuses on the evidence linking thyroid cancer with obesity. We conclude that there is sufficient evidence that obesity can predispose to an increased risk of thyroid cancer in both men and women. This population-based association is mainly explained at a biological level through specific obesity-related endocrinopathies.

BACKGROUNDRecent series of incidental thyroid activity on fluorodeoxyglucose positron emission tomography (FDG-PET) in patients evaluated for nonthyroidal malignancy, which we refer to as a "PEToma," have suggested that such lesions are associated with a significant incidence of primary thyroid cancer.METHODSWe retrospectively reviewed 6457 FDG-PET scans performed on 4726 patients from May 2004 to March 2007. We reviewed the cases of patients whose PET or computed tomography (CT) radiology reports described PET uptake within the thyroid to identify incidence and malignant potential of PETomas and evaluate their clinical and histopathologic features.RESULTSWe found that 160 patients (3.4%) had incidental, abnormal FDG uptake in the thyroid gland, 103 of whom had focal uptake (the PEToma group). Of these patients, 50 (48%) underwent further investigations, including ultrasonography in 48, fine-needle aspiration cytology in 38 and computed tomography in 3. Ten patients underwent surgery, and papillary thyroid cancer was identified in 9. The remaining 53 patients with PETomas underwent no further investigation. Interestingly, 5 patients who had focal uptake within the thyroid showed either spontaneous resolution on repeat FDG-PET (self-resolving) or no focal lesion on subsequent ultrasonography (false-positive).CONCLUSIONThe incidence of papillary thyroid cancer in the present series is similar to that in the literature. Although some patients will show self-resolving or false-positive focal thyroid uptake on FDG-PET, we believe that, if the patient's clinical status permits, the evaluation of patients with incidental thyroid PEToma should include ultrasonographic confirmation and fine-needle aspiration cytology.

OBJECTIVE To report a case of life-threatening hyponatremia as a complication of a 4-week long low-iodine diet and highlight the risk factors for this complication by reviewing all previously reported cases. METHODS The clinical and biochemical data from the study patient are presented and the pertinent literature is reviewed. A risk analysis for this complication is highlighted. RESULTS A 66-year-old Vietnamese woman had a total thyroidectomy and bilateral neck lymph node dissection for papillary thyroid carcinoma. A whole body radioiodine scan demonstrated 2 foci of activity in the anterior neck. The patient received recombinant human thyrotropin (rhTSH) and was admitted for radioiodine therapy. She had strictly adhered to a low-iodine diet for 4 weeks in preparation for ablation. The patient was on a thiazide diuretic for her hypertension, which was discontinued on admission. On admission, the patient started feeling light-headed, dizzy, and nauseated. Blood tests revealed a critical serum sodium concentration of 107 mEq/L. Further investigations confirmed hypotonic hyponatremia, which had developed despite being euthyroid after receiving rhTSH. The patient was managed accordingly and made a full recovery. CONCLUSIONS This case, in addition to the reviewed cases, emphasizes the importance of preventing and managing this rare but relatively dangerous complication. Based on an analysis of the reviewed cases, the risk factors for developing this complication are a prolonged low-iodine diet, the elimination of salt from the diet, and the use of thiazide diuretics. All patients in the reported cases were older than 65 years of age.

OBJECTIVE:To assess the efficacy of ultrasound-guided thyroid fine-needle aspiration biopsies (USFNABs) performed in the office setting by an otolaryngologist and to evaluate the specimen adequacy of USFNABs performed in patients whose initial palpation-guided fine-needle aspiration biopsies (PGFNABs) were nondiagnostic.DESIGN:Retrospective chart review.SETTING:Royal Victoria Hospital-McGill University Health Centre, Montreal.METHODS:This is a retrospective analysis of 76 USFNABs performed by an otolaryngologist on consecutive patients over a 6-month period. Each patient had a previous nondiagnostic PGFNAB. Biopsies were performed using a 20-gauge fine needle with a Mylab25 Biosound Esoate ultrasound machine. Samples were then classified according to the adequacy of sample and pathologic findings.MAIN OUTCOME MEASURE:Specimen adequacy rate.RESULTS:Sixty-six patients underwent 76 USFNABs. The sample included 57 females and 9 males (mean age 51.1 and 55.4 years, respectively). The specimen adequacy rate was 90.8% (69 of 76). Among the adequate specimens, 2 (2.6%) were malignant, 6 (7.9%) were suspicious for malignancy, 43 (56.6%) were benign, and 18 (23.7%) were follicular or Hürthle cell lesions (indeterminate).CONCLUSION:Our experience demonstrates that USFNAB performed in the clinic by an otolaryngologist is a promising tool for improving specimen adequacy for nodules initially classified as nondiagnostic. USFNAB also avoids the need for radiologic consultation, thus improving efficacy in the workup of nodules.

OBJECTIVE To determine whether sentinel lymph node (SLN) biopsy can accurately predict central compartment metastasis in patients with differentiated thyroid carcinoma. DESIGN Prospective clinical study. SETTING Academic tertiary care center. PATIENTS Ninety-eight patients (82 women and 16 men; mean age, 48.3 years) underwent a total thyroidectomy and central compartment dissection. INTERVENTION Peritumoral injection of methylene blue dye, 1%, followed by SLN biopsy. MAIN OUTCOME MEASURES The final pathology report established the presence of metastasis among SLNs and lymph nodes that did not stain blue (non-SLNs [NSLNs]). RESULTS Differentiated thyroid carcinoma was found in 75 of 98 patients (77%). Seventy of 75 patients with differentiated thyroid carcinoma presented with SLNs and/or NSLNs within the central compartment. Fifteen of 70 patients had metastasis-positive SLNs, while 55 had metastasis-negative SLNs. Six of 15 patients with positive SLNs also had positive NSLNs. No patients with negative SLNs were found to have positive NSLNs. Sentinal lymph node status was a highly significant predictor of NSLN result (Fisher exact test, P < .001). The accuracy, sensitivity, specificity, and positive and negative predictive values of SLN biopsy were 87%, 100%, 86%, 40%, and 100%, respectively. CONCLUSIONS To our knowledge, this is the largest series of SLN biopsy in patients with differentiated thyroid carcinoma. Our experience suggests that this is an accurate and noninvasive means to identify subclinical lymph node metastasis. Because negative SLNs correlate strongly with a negative central compartment (100% in this study, P < .001), this technique can be used as an intraoperative guide when determining the extent of surgery necessary in cervical level VI.

BACKGROUND:Obesity has been linked to numerous diseases including thyroid cancer, but the exact nature of the relationship, especially with respect to patients with thyroid nodules, remains unclear. The objective of this study was to evaluate the impact of body mass index (BMI) on thyroid cancer risk in a population of patients with indeterminate cytology on fine-needle aspiration biopsy (FNAB).METHODS:A total of 253 consecutive patients with indeterminate thyroid nodule FNABs who underwent total thyroidectomy in a tertiary care teaching hospital between 2002 and 2007 were reviewed. Height and weight reported on the anesthesia summary were recorded for each patient. Malignancy rates were calculated for the underweight, normal, overweight, and obese groups stratified according to their BMI. Subanalyses according to age and sex were also performed.RESULTS:The risk of malignancy tended to be lower in obese patients compared to patients with BMIs in the underweight, normal, and overweight ranges (52% vs. 61%, p = 0.195). In men, a BMI classified as obese was associated with a significantly lower rate of malignancy (36% vs. 72%, p = 0.003). Women older than 45 years were a subgroup in which higher malignancy rates were associated with obesity (65% vs. 54%, p = 0.293). Conversely, in men over the age of 45 years and women under 45 years, a BMI in the obesity range was linked to a lower incidence of malignancy (20% vs. 68% p = 0.009 and 36% vs. 68% p = 0.043, respectively). When older women were excluded from the population studied, the rate of malignancy in obese patients was 36% versus 70% in nonobese patients (p = 0.002) with an associated reduction of 5% in the risk of malignancy per increased unit of BMI.CONCLUSIONS:For patients with FNAB results of indeterminate significance, a higher BMI correlates with lower rates of thyroid malignancy for all patients except women over the age of 45 years.

Potential explanations for the increasing incidence of papillary thyroid carcinoma• Increased incidence of small, subclinical papillary thyroid carcinoma • Changes in medical practice such as increased use of neck

ifferentiated thyroid cancer (DTC), in which histologic examination often reveals evidence of lymphocytic infiltration at the edges of the tumour, is a good model for the interaction between human cancer and the immunocompetent host immune system. Materials and Methods: We tested sera from patients with DTC for cytotoxicity against cultured human thyroid, eye muscle and K562 cells in antibody-dependent cell mediated cytotoxicity (ADCC) and natural killer (NK) cell cytotoxicity assays. Results: When cultured thyroid cells were used as targets in ADCC assay, specific cytotoxicity was increased (% specific lysis > mean + 2SD for normals) in only 2 out of 30 patients with DTC but decreased (% specific lysis < mean + 2SD for normals) in 19 patients and mean for the group was significantly less than that for the normals. The same effect was observed using human eye muscle cells as targets in an ADCC assay. Serum from patients with DTC, but not those from normal subjects, inhibited the ADCC activity against normal thyroid cells in serum from patients with Graves’ disease, in a dose dependent manner. Serum from patients with thyroid cancer inhibited natural cytotoxicity against human K562 cells while normal serum did not. Pretreatment of normal PBMC with pooled serum from patients with DTC abolished natural cytotoxicity against K562 cells whereas pooled normal serum had no significant effect. Conclusion: This phenomenon reflected inhibition of the natural cytotoxicity mediated by (NK) cells in the mixed peripheral blood mononuclear cells (PBMC) population by an unknown serum factor or factors. We confirmed this by performing experiments using sera from patients with DTC, human K562 cells as targets in NK cell assay and PBMC from normal subjects as source of NK cells. The inhibitory factor, which probably works at the level of the NK cells and is called natural cytotoxicity blocking factor (NKBF), may be a marker for invasive thyroid cancer, although this needs to be addressed in further studies.

Background. An alternative to completion thyroidectomy for well-differentiated thyroid carcinoma is to ablate the remnant lobe with I-131. The purpose of this study is to review our own experience with large remnant ablation.Methods. A retrospective review of 169 patients with well-differentiated thyroid cancer treated at one institution over a 14-year period was undertaken. Seventy-one patients who underwent partial thyroidectomy (PT)followed by I-131 ablation were identified. This group was compared to 98 patients treated with total thyroidectomy (TT).Results. Mean follow-up was 6.2 years for the 71 PT+ I-131 versus 4.7 years for the 98 TT patients (P = .184). Recurrence occurred in 4 of 71 PT+ I-131 patients (5.6%) versus 9 of 98 TT patients (9.2%) (P = .393). Other than a tendency for the size of the primary to be slightly larger and for the histology to be follicular carcinoma in the PT + I-131 patients, the 2 groups were nearly identical in age, gender, and other prognostic factors such as capsular invasion and metastases.Conclusions. Large-dose ablation with I-131 is a viable alternative to completion thyroidectomy. Recurrence rates over an average 6-year period are similar to TT. Long term monitoring of these cohorts is required.

Clinical practice guidelines provide a means to enhance physician performance. This investigation was undertaken in an attempt to understand the nature of impact of guideline use on physician performance. We investigated the impact of (a) algorithmic-based and (b) text-based practice guidelines on clinical decision-making by physicians at varying levels of expertise. Data were collected using clinical scenarios and a think-aloud paradigm, both with (primed) and without (spontaneous) the use of the guidelines. The two guidelines used in the study were management of diabetes and screening for thyroid disease. The results show that guidelines were used as reminders for both experts and non-experts. Guidelines acted as an educational tool for non-experts by assisting in knowledge reorganization, particularly for the non-experts. Text and algorithmic guideline formats were both useful to physician performance depending on the purpose of use: solving clinical problems or learning. These results provide insights into how guidelines can be fine-tuned for different users and for different purposes. Empirical research, coupled with design principles from the cognitive sciences, can form an essential component of guideline design and development.