Recent application of artificial intelligence on histopathologic image-based prediction of gene mutation in solid cancers.

PURPOSE: Evaluation of genetic mutations in cancers is important because distinct mutational profiles help determine individualized drug therapy. However, molecular analyses are not routinely performed in all cancers because they are expensive, time-consuming and not universally available. Artificial intelligence (AI) has shown the potential to determine a wide range of genetic mutations on histologic image analysis. Here, we assessed the status of mutation prediction AI models on histologic images by a systematic review. METHODS: A literature search using the MEDLINE, Embase and Cochrane databases was conducted in August 2021. The articles were shortlisted by titles and abstracts. After a full-text review, publication trends, study characteristic analysis and comparison of performance metrics were performed. RESULTS: Twenty-four studies were found mostly from developed countries, and their number is increasing. The major targets were gastrointestinal, genitourinary, gynecological, lung and head and neck cancers. Most studies used the Cancer Genome Atlas, with a few using an in-house dataset. The area under the curve of some of the cancer driver gene mutations in particular organs was satisfactory, such as 0.92 of BRAF in thyroid cancers and 0.79 of EGFR in lung cancers, whereas the average of all gene mutations was 0.64, which is still suboptimal. CONCLUSION: AI has the potential to predict gene mutations on histologic images with appropriate caution. Further validation with larger datasets is still required before AI models can be used in clinical practice to predict gene mutations.

Diagnostic implication of thyroid spherules for cytological diagnosis of thyroid nodules.

OBJECTIVE: Thyroid fine-needle aspiration (FNA) is a principal diagnostic procedure for thyroid nodules. A specific cytomorphological structure, known as the thyroid spherule, is often seen in FNA specimens. The clinical significance of these spherules in terms of diagnosis and prevalence remains largely unexplored. METHODS: We performed a retrospective study on 310 thyroid FNA specimens and categorized them according to the Bethesda System for Reporting Thyroid Cytopathology. The presence, size and number of thyroid spherules in each specimen were examined and these data were subsequently correlated with the clinicopathological features. RESULTS: Thyroid spherules were almost exclusively detected in benign cases, comprising 7.6% of all benign diagnoses. The average diameter of spherules in benign cases was 84.9 µm. Benign cases and cases with atypia of undetermined significance cases primarily exhibited low cellularity, while follicular neoplasms and malignant cases typically showed moderate to high cellularity. In the subgroup of FNA cases with moderate to high cellularity, spherules were identified in 12 (20%) of 59 benign FNA cases. Within this group, the sensitivity and specificity of thyroid spherules for detecting benign FNA cases were 20% and 100%, respectively. CONCLUSIONS: Our results suggest that the presence of thyroid spherules in FNA specimens can serve as a highly specific marker for benign thyroid conditions. The prevalence of spherule detection is strongly influenced by the cellularity. In cases with moderate to high cellularity, the identification of spherules can assist the cytopathologists in diagnosing thyroid FNA cases as benign.

Diagnosis of Marginal Infiltration in Soft Tissue Sarcoma by Radiomics Approach Using T2-Weighted Dixon Sequence.

BACKGROUND: Determination of preoperative soft tissue sarcoma (STS) margin is crucial for patient prognosis. PURPOSE: To evaluate diagnostic performance of radiomics model using T2-weighted Dixon sequence for infiltration degree of STS margin. STUDY TYPE: Retrospective. POPULATION: Seventy-two STS patients consisted of training (n = 58) and test (n = 14) sets. FIELD STRENGTH/SEQUENCE: A 3.0 T; T2-weighted Dixon images. ASSESSMENT: Pathologic result of marginal infiltration in STS (circumscribed margin; n = 27, group 1, focally infiltrative margin; n = 31, group 2-A, diffusely infiltrative margin; n = 14, group 2-B) was the reference standard. Radiomic volume and shape (VS) and other (T2) features were extracted from entire tumor volume and margin, respectively. Twelve radiomics models were generated using four combinations of classifier algorithms (R, SR, LR, LSR) and three different inputs (VS, T2, VS + T2 [VST2] features) to differentiate the three groups. Three radiologists (reader 1, 2, 3) analyzed the marginal infiltration with 6-scale confidence score. STATISTICAL TESTS: Area under the receiver operating characteristic curve (AUC) and concordance rate. RESULTS: Averaged AUCs of R, SR, LR, LSR models were 0.438, 0.466, 0.438, 0.466 using VS features, 0.596, 0.584, 0.814, 0.815 using T2 features, and 0.581, 0.587, 0.821, 0.821 using VST2 features, respectively. The LR and LSR models constructed with T2 or VST2 features showed higher AUC and concordance rate compared to radiologists' analysis (AUC; 0.730, 0.675, 0.706, concordance rate; 0.46, 0.43, 0.47 in reader 1, 2, 3). DATA CONCLUSION: Radiomics model constructed with features from tumor margin on T2-weighted Dixon sequence is a promising method for differentiating infiltration degree of STS margin. EVIDENCE LEVEL: 4 TECHNICAL EFFICACY: Stage 2.

Thyroid Isthmusectomy with Prophylactic Central Compartment Neck Dissection is a Feasible Approach for Papillary Thyroid Cancer on the Isthmus.

BACKGROUND: The treatment for papillary thyroid cancer (PTC) has become more conservative, but still no specific guidelines exist for managing isthmic PTC. This study analyzed the outcomes from isthmusectomy in single isthmic PTC and compared it with those for patients who previously had undergone a total thyroidectomy. METHODS: An isthmusectomy with prophylactic central compartment neck dissection (pCCND) was planned for a single isthmic PTC between 2014 and 2018 (isthmusectomy group). For cases with gross extrathyroidal extension (ETE) or multiple nodal metastasis, the procedure was converted to a total thyroidectomy. The study analyzed the characteristics and outcomes of the isthmusectomy group. Additionally, the results were compared with those of the isthmusectomy-feasible group who met the eligibility criteria for isthmusectomy among total thyroidectomies performed between 2009 and 2013. RESULTS: Of the 90 patients in the isthmusectomy group, 81 received isthmusectomy and 9 had conversion to a total thyroidectomy. Microcarcinoma occurred in 72 cases and gross ETE in 3 cases. One patient showed occult satellite cancer, and seven patients showed more than five metastatic nodes. Transient hypocalcemia developed in five and patients and permanent hypocalcemia in one patient with total thyroidectomy. Of 46 patients who began hormone replacement postoperatively, 13 completely stopped taking medication during the follow-up period. Metachronous PTC was diagnosed for one patient 12 months after isthmusectomy. The isthmusectomy group and the isthmusectomy-feasible group showed similar clinicopathologic properties including multifocality, ETE, and nodal metastasis. However, the isthmusectomy group showed significantly less transient or permanent hypocalcemia and thyroid hormone dependency. CONCLUSIONS: Isthmusectomy with pCCND may be a feasible alternative for properly selected isthmic PTC, resulting in a better quality of life than total thyroidectomy.

The implications of clinical risk factors, CAR index, and compositional changes of immune cells on hyperprogressive disease in non-small cell lung cancer patients receiving immunotherapy.

BACKGROUND: Immune checkpoint blockades (ICBs) are characterized by a durable clinical response and better tolerability in patients with a variety of advanced solid tumors. However, we not infrequently encounter patients with hyperprogressive disease (HPD) exhibiting paradoxically accelerated tumor growth with poor clinical outcomes. This study aimed to investigate implications of clinical factors and immune cell composition on different tumor responses to immunotherapy in patients with non-small cell lung cancer (NSCLC). METHODS: This study evaluated 231 NSCLC patients receiving ICBs between January 2014 and May 2018. HPD was defined as a > 2-fold tumor growth kinetics ratio during ICB therapy and time-to-treatment failure of ≤2 months. We analyzed clinical data, imaging studies, periodic serologic indexes, and immune cell compositions in tumors and stromata using multiplex immunohistochemistry. RESULTS: Of 231 NSCLC patients, PR/CR and SD were observed in 50 (21.6%) and 79 (34.2%) patients, respectively and 26 (11.3%) patients met the criteria for HPD. Median overall survival in poor response groups (HPD and non-HPD PD) was extremely shorter than disease-controlled group (SD and PR/CR) (5.5 and 6.1 months vs. 16.2 and 18.3 months, respectively, P = 0.000). In multivariate analysis, HPD were significantly associated with heavy smoker (p = 0.0072), PD-L1 expression ≤1% (p = 0.0355), and number of metastatic site ≥3 (p = 0.0297). Among the serologic indexes including NLR, PLR, CAR, and LDH, only CAR had constantly significant correlations with HPD at the beginning of prior treatment and immunotherapy, and at the 1st tumor assessment. The number of CD4+ effector T cells and CD8+ cytotoxic T cells, and CD8+/PD-1+ tumor-infiltrating lymphocytes (TIL) tended to be smaller, especially in stromata of HPD group. More M2-type macrophages expressing CD14, CD68 and CD163 in the stromal area and markedly fewer CD56+ NK cells in the intratumoral area were observed in HPD group. CONCLUSIONS: Our study suggests that not only clinical factors including heavy smoker, very low PD-L1 expression, multiple metastasis, and CAR index, but also fewer CD8+/PD-1+ TIL and more M2 macrophages in the tumor microenvironment are significantly associated with the occurrence of HPD in the patients with advanced/metastatic NSCLC receiving immunotherapy.

How to identify indolent thyroid tumors unlikely to recur and cause cancer death immediately after surgery-Risk stratification of papillary thyroid carcinoma in young patients.

Current histopathological diagnosis methods cannot distinguish the two types of thyroid carcinoma: clinically significant carcinomas with a potential risk of recurrence, metastasis, and cancer death, and clinically insignificant carcinomas with a slow growth rate. Both thyroid tumors are diagnosed as "carcinoma" in current pathology practice. The clinician usually recommends surgery to the patient and the patient often accepts it because of cancer terminology. The treatment for these clinically insignificant carcinomas does not benefit the patient and negatively impacts society. The author proposed risk stratification of thyroid tumors using the growth rate (Ki-67 labeling index), which accurately differentiates four prognostically relevant risk groups based on the Ki-67 labeling index, ≥30%, ≥10 and <30%, >5 and <10%, and ≤5%. Indolent thyroid tumors with an excellent prognosis have the following four features: young age, early-stage (T1-2 M0), curatively treated, and low proliferation index (Ki-67 labeling index of ≤5%), and are unlikely to recur, metastasize, or cause cancer death. Accurate identification of these indolent tumors helps clinicians select more conservative treatments to avoid unnecessary aggressive (total thyroidectomy followed by radio-active iodine) treatments. Clinicians can alleviate the fears of patients by confirming these four features, including the low proliferation rate, in a pathology report immediately after surgery when patients are most concerned.

Differentiation of soft-tissue lymphoma from undifferentiated sarcoma: apparent diffusion coefficient histogram analysis.

BACKGROUND: Making the preoperative diagnosis of soft-tissue lymphoma is important because the treatments for lymphoma and sarcoma are different. PURPOSE: To determine the reliability and accuracy of single-slice and whole-tumor apparent diffusion coefficient (ADC) histogram analysis when differentiating soft-tissue lymphoma from undifferentiated sarcoma. MATERIAL AND METHODS: Patients with confirmed soft-tissue lymphoma or undifferentiated sarcoma who underwent 3-T magnetic resonance imaging (MRI), including diffusion-weighted imaging, were included. Single-slice and whole-tumor ADC histogram analyses were performed using software. Mean, standard deviation (SD), 5th and 95th percentiles, skewness, and kurtosis were compared between groups, and a receiver operating characteristic curve with area under the curve (AUC) was obtained. RESULTS: Thirteen patients with soft-tissue lymphoma and 12 patients with undifferentiated sarcoma were included. ADC histogram analysis of single-slice and whole-tumor, mean, SD, and 5th and 95th percentiles was significantly lower in lymphoma than in undifferentiated sarcoma. Whole-tumor analysis kurtosis was significantly higher in lymphoma than in undifferentiated sarcoma. All AUCs were high in single-slice and whole-tumor analysis: 0.987 vs. 1.000 in mean; 0.821 vs. 0.782 in SD; 0.949 vs. 0.949 in 5th percentile; and 1.000 vs. 1.000 in 95th percentile without significant difference. AUC of kurtosis in whole-tumor ADC histogram analysis was 0.750. CONCLUSION: Single-slice and whole-tumor ADC histogram analysis seems to be reliable and accurate for differentiating soft-tissue lymphoma from undifferentiated sarcoma.

Anti-tumor efficacy of CKD-516 in combination with radiation in xenograft mouse model of lung squamous cell carcinoma.

BACKGROUND: Hypoxic tumors are known to be highly resistant to radiotherapy and cause poor prognosis in non-small cell lung cancer (NSCLC) patients. CKD-516, a novel vascular disrupting agent (VDA), mainly affects blood vessels in the central area of the tumor and blocks tubulin polymerization, thereby destroying the aberrant tumor vasculature with a rapid decrease in blood, resulting in rapid tumor cell death. Therefore, we evaluated the anti-tumor efficacy of CKD-516 in combination with irradiation (IR) and examined tumor necrosis, delayed tumor growth, and expression of proteins involved in hypoxia and angiogenesis in this study. METHODS: A xenograft mouse model of lung squamous cell carcinoma was established, and the tumor was exposed to IR 5 days per week. CKD-516 was administered with two treatment schedules (day 1 or days 1 and 5) 1 h after IR. After treatment, tumor tissues were stained with hematoxylin and eosin, and pimonidazole. HIF-1α, Glut-1, VEGF, CD31, and Ki-67 expression levels were evaluated using immunohistochemical staining. RESULTS: Short-term treatment with IR alone and CKD-516 + IR (d1) significantly reduced tumor volume (p = 0.006 and p = 0.048, respectively). Treatment with CKD-516 + IR (d1 and d1, 5) resulted in a marked reduction in the number of blood vessels (p < 0.005). More specifically, CKD-516 + IR (d1) caused the most extensive tumor necrosis, which resulted in a significantly large hypoxic area (p = 0.02) and decreased HIF-1α, Glut-1, VEGF, and Ki-67 expression. Long-term administration of CKD-516 + IR reduced tumor volume and delayed tumor growth. This combination also greatly reduced the number of blood vessels (p = 0.0006) and significantly enhanced tumor necrosis (p = 0.004). CKD-516 + IR significantly increased HIF-1α expression (p = 0.0047), but significantly reduced VEGF expression (p = 0.0046). CONCLUSIONS: Taken together, our data show that when used in combination, CKD-516 and IR can significantly enhance anti-tumor efficacy compared to monotherapy in lung cancer xenograft mice.

Prevalence and diagnostic challenges of thyroid lymphoma: a multi-institutional study in non-Western countries.

Research on the primary thyroid lymphoma (PTL) diagnosis is limited, with only a few large sample size studies, reported from Asian countries. The aim of the present study was to clarify the current prevalence and challenges in PTL diagnosis, and recommended ancillary studies for PTL in non-Western countries. PTL (n = 153) cases were retrieved from 10 institutions in non-Western countries and analyzed. Ultrasound examination (UE) and fine needle aspiration cytology (FNAC) were used as main preoperative diagnostic tools in all participating institutions. Flow cytometry (FCM) was performed in the 5 institutions (50%). Lobectomy was the most common histological procedure to confirm the PTL diagnosis. All institutions routinely performed immuno-histochemical analysis. PTL was 0.54% of malignant thyroid tumor cases, with mucosa-associated lymphoid tissue lymphoma (MALTL) and diffuse large B-cell lymphoma (DLBCL) being 54.9% and 38.6%, respectively. Kuma Hospital, where the frequency of MALTL was highest (83.7%), routinely performed FCM using the materials obtained by FNAC. UE and FNAC sensitivities were 62.5% and 57.8%, respectively. In both UE and FNAC, sensitivity of MALTL was lower than of DLBCL. The study elucidated that the prevalence of PTL in non-Western countries was lower than previously reported. We propose that FCM should be more actively used to improve the preoperative diagnosis of MALTL. Our data predicted that the MALTL proportion will increase with improved diagnostic tools, while observation of PTL-suspected nodules without histological examination remains a viable option.

Evaluation of Human MSCs Treatment Frequency on Airway Inflammation in a Mouse Model of Acute Asthma.

BACKGROUND: Studies in experimental models of allergic asthma have shown that mesenchymal stem cells (MSCs) have therapeutic potential for T-helper 2 (TH2) cell-mediated inflammation. However, the mechanisms underlying these therapeutic effects are not fully understood and their safety has not been confirmed. METHODS: Using a mouse model of experimental allergic asthma, we investigated the efficacy of human adipose-derived mesenchymal stem cells (hADSCs) or human bone marrow-derived mesenchymal stem cells (hBMSCs) according to treatment frequency and timing. RESULTS: Ovalbumin (OVA)-sensitized and -challenged mice exhibited airway hyperresponsiveness (AHR), airway inflammation, and significant increases in TH2 cytokine levels. Both double and single human mesenchymal stem cell (hMSC) treatments significantly decreased AHR and bronchoalveolar lavage fluid counts. In addition, single treatment with hMSCs showed significant attenuation of allergic airway inflammation. However, double treatment with hMSCs during OVA -sensitization and -challenge further increased inflammatory cell infiltration, and TH2 cytokine levels. CONCLUSION: The results of treatment with hADSCs or hBMSCs suppresses AHR and airway inflammation. However, double hMSC treatment significantly induces eosinophilic airway inflammation and lung histological changes. Therefore, double hMSC treatment is ineffective against asthma and single injection frequency appears to be more important for the treatment of asthma. These results suggest that hMSC therapy can be used for treatment of asthma patients but that it should be used carefully.

Distinct Clinical Manifestations of Thyroid Cancer After Hematopoietic Stem Cell Transplantation.

BACKGROUND: The incidence of a secondary solid malignancy after hematopoietic cell transplantation (HCT) is increasing in long-term survivors. OBJECTIVE: The aim of this study was to compare the clinicopathological characteristics of HCT recipients with secondary thyroid cancer (STC), with those of non-HCT thyroid cancer patients. METHODS: We retrospectively investigated 5184 patients who received HCT between 1983 and 2016. Of these, 18 patients developed STC and underwent thyroidectomy due to differentiated thyroid cancer. We compared the clinicopathological characteristics of post-HCT thyroid cancer patients (post-HCT group) with those of a primary differentiated thyroid carcinoma cohort (cohort group) from Seoul St. Mary's Hospital. RESULTS: The mean ages at HCT and thyroidectomy after HCT were 22.0 and 31.8 years, respectively, and the median time interval between HCT and thyroidectomy was 5 years (range 1-16). Compared with the cohort group, the post-HCT group was younger at cancer onset and frequently had a palpable mass at initial diagnosis. The post-HCT group had more aggressive features, including larger tumor size, frequent extrathyroidal extension, lymphatic invasion, perineural invasion, and frequent lateral neck node metastasis and distant metastasis, relative to the cohort group; however, most patients (83.2%) in the post-HCT group were stage I or II. Additionally, BRAF V600E mutation was less frequent in the post-HCT group. CONCLUSIONS: We found that STC after HCT showed younger presentation and more aggressive clinical presentation. Therefore, a policy of regular screening, including neck ultrasound examination, may promote early detection and treatment in HCT recipients.

Soft tissue sarcoma: adding diffusion-weighted imaging improves MR imaging evaluation of tumor margin infiltration.

PURPOSE: To determine the added value of diffusion-weighted imaging (DWI) to conventional magnetic resonance (MR) imaging in assessment of tumor margin infiltration in soft tissue sarcoma (STS) at 3T. MATERIALS AND METHODS: The institutional review board approved this retrospective study. Forty-five patients who underwent 3T MR imaging including DWI and were pathologically confirmed were included in this study. Two readers retrospectively scored conventional MR imaging alone. Then, they assessed a combination of conventional MR imaging and DWI. At pathology, margin infiltration was retrospectively reviewed by one pathologist blinded to MR findings. Areas under the curve (AUCs) of the receiver-operating characteristic curve were obtained for diagnostic performance. Interobserver agreement for the scoring of margin infiltration of STS was assessed with kappa statistics. RESULTS: Among 45 cases of STS, 33 had infiltrative tumor margin at pathology. Sensitivity, specificity, and accuracy of each reader were 100%, 17%, and 78%; 97%, 25%, and 78% on conventional MR imaging alone and 94%, 67%, and 87%; 94%, 42%, and 80% on conventional MR imaging combined with DWI. AUCs of conventional MR imaging combined with DWI were significantly higher than those of conventional MR imaging alone: 0.890 vs 0.678 (p = .0123) and 0.846 vs 0.640 (p = .0305) for each reader. Interobserver agreements of conventional MR imaging alone and conventional MR imaging combined with DWI were moderate to substantial (κ = 0.646, κ = 0.496). CONCLUSION: The addition of DWI to conventional MR imaging may improve specificity for assessing tumor margin infiltration in STS at 3T. KEY POINTS: • DWI has added value for assessment of tumor margin infiltration in soft tissue sarcoma. • Addition of DWI to conventional MRI at 3T may improve specificity. • Addition of DWI to conventional MRI may help orthopedic surgeon determine the extent of the resection margin.

Comparison of efficacy and complications between radiofrequency ablation and repeat surgery in the treatment of locally recurrent thyroid cancers: a single-center propensity score matching study.

PURPOSE: To compare the efficacy and complication rates of radiofrequency ablation (RFA) and repeat surgery in the treatment of locally recurrent thyroid cancers. MATERIALS AND METHODS: A total of 221 patients with locally recurrent thyroid cancers who underwent either RFA (n = 96) or repeat surgery (n = 125) between March 2008 and March 2017 were retrospectively enrolled (range of follow-up, 1-10 years). Each cohort consisted of 70 patients after propensity score adjustment. Patients with more than three recurrent lesions were excluded. The primary and secondary end points were recurrence-free survival and complication rates, respectively. Recurrence-free survival curves were compared via the log-rank test. The complications-voice changes, hypocalcemia, and immediate procedural complications-were compared between the groups. In addition, pretreatment serum thyroglobulin (Tg) levels and those at the last follow-up were also compared between the two groups to examine therapeutic efficacy. RESULTS: After propensity score matching, both groups showed no significant differences in baseline characteristics. The recurrence-free survival rates were comparable between the RFA and surgery groups (p = .2). There were no significant differences in mean serum Tg levels and their mean decrease after treatment between the groups (p = .891 and p = .963, respectively). Immediate procedural complications and voice changes also showed no significant between-group differences (p = .316, p = .084, respectively). Hypocalcemia occurred only in the repeat surgery group (n = 18). Overall complications were significantly more frequent in the repeat surgery group (RFA, n = 7; surgery, n = 27; p < .001). CONCLUSION: RFA may be an effective and safe alternative to repeat surgery in the treatment of a small number of locally recurrent thyroid cancers.

Interobserver and intraobserver variation in the morphological evaluation of noninvasive follicular thyroid neoplasm with papillary-like nuclear features in Asian practice.

To evaluate the current diagnostic criteria in reporting nuclear features of noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP), nine Asian pathologists with expertise in thyroid reviewed virtual slides of 30 noninvasive follicular patterned thyroid lesions according to the nuclear scoring system originally proposed by an international expert and a more detailed scoring system proposed by the Asian Working Group. The interobserver agreement for nuclear grading score was generally moderate (kappa value = 0.452). The best consistency fell on the chromatin features (kappa value = 0.658-1.000). A fair to moderate interobserver agreement was demonstrated in the evaluation of nuclear elongation, nuclear overlapping, membrane irregularities and distribution of papillary thyroid carcinoma (PTC) type nuclear features. A slight agreement was rendered for the evaluation of the nuclear enlargement. Intraobserver agreement was substantial to perfect when comparing results of both scoring systems. However, both scoring systems were not able to reliably separate NIFTP from an encapsulated follicular variant PTC with minimal lymph node metastasis or BRAFV600E mutation. Although the three-point nuclear scoring system for the diagnosis of NIFTP is widely used in Asian practice, interobserver variation was considerable. Ancillary immunohistochemical or molecular testing might be helpful in differentiating NIFTP from true PTC.

CLINICAL IMPACT OF NON-INVASIVE FOLLICULAR THYROID NEOPLASM WITH PAPILLARY-LIKE NUCLEAR FEATURES ON THE RISK OF MALIGNANCY IN THE BETHESDA SYSTEM FOR REPORTING THYROID CYTOPATHOLOGY: A META-ANALYSIS OF 14,153 RESECTED THYROID NODULES.

Objective: It is still controversial as to how the reclassification of noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) affects the risk of malignancy (ROM) in The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC). This meta-analysis was aimed to investigate the impact of NIFTP on the ROM in each TBSRTC category. Methods: We accessed three electronic databases including PubMed, Web of Science, and Scopus to search for relevant data from January, 2016 to July, 2018. Relative risk and meta-analysis of proportions using the DerSimonian-Laird method, and each corresponding 95% confidence interval (CI) was pooled using a random-effect model. Results: A total of 14 studies consisting of 14,153 resected nodules were included for meta-analyses. Overall, there was a significant reduction in ROM in all TBSRTC categories following the NIFTP reclassification, except TBSRTC category I. The largest absolute and relative decrease in ROM was observed in TBSRTC category V (16%; 95% CI = 8 to 24) and category III (32%; 95% CI = 24 to 39), respectively. There was a positive correlation between the rate of NIFTP and resection rate (r = 0.83; P = .02). The decreases in ROM were more prominent in Western than in Asian cohorts. Conclusion: We confirmed the decrease in ROM due to the NIFTP reclassification for most of TBSRTC categories, which was more significant in Western than in Asian practice. The incidence of NIFTP was higher in institutions where surgical resection rates were high in patients with indeterminate cytology nodules. Abbreviations: AUS/FLUS = atypia of undetermined significance/follicular lesion of undetermined significance; CI = confidence interval; FNA = fine-needle aspiration; FN/SFN = follicular neoplasm/suspicious for follicular neoplasm; NIFTP = noninvasive follicular thyroid neoplasm with papillary-like nuclear features; NI-FVPTC = noninvasive follicular variant of papillary thyroid carcinoma; ROM = risk of malignancy; RR = relative risk; SM = suspicious for malignancy; TBSRTC = The Bethesda System for Reporting Thyroid Cytopathology.

Thyrocyte-specific deletion of insulin and IGF-1 receptors induces papillary thyroid carcinoma-like lesions through EGFR pathway activation.

Insulin and insulin-like growth factor (IGF)-1 signaling in the thyroid are thought to be permissive for the coordinated regulation by thyroid-stimulating hormone (TSH) of thyrocyte proliferation and hormone production. However, the integrated role of insulin receptor (IR) and IGF-1 receptor (IGF-1R) in thyroid development and function has not been explored. Here, we generated thyrocyte-specific IR and IGF-1R double knockout (DTIRKO) mice to precisely evaluate the coordinated functions of these receptors in the thyroid of neonates and adults. Neonatal DTIRKO mice displayed smaller thyroids, paralleling defective folliculogenesis associated with repression of the thyroid-specific transcription factor Foxe1. By contrast, at postnatal day 14, absence of IR and IGF-1R paradoxically induced thyrocyte proliferation, which was mediated by mTOR-dependent signaling pathways. Furthermore, we found elevated production of TSH during the development of follicular hyperplasia at 8 weeks of age. By 50 weeks, all DTIRKO mice developed papillary thyroid carcinoma (PTC)-like lesions that correlated with induction of the ErbB pathway. Taken together, these data define a critical role for IR and IGF-1R in neonatal thyroid folliculogenesis. They also reveal an important reciprocal relationship between IR/IGF-1R and TSH/ErbB signaling in the pathogenesis of thyroid follicular hyperplasia and, possibly, of papillary carcinoma.

Molecular correlates and rate of lymph node metastasis of non-invasive follicular thyroid neoplasm with papillary-like nuclear features and invasive follicular variant papillary thyroid carcinoma: the impact of rigid criteria to distinguish non-invasive follicular thyroid neoplasm with papillary-like nuclear features.

Thyroid tumors formerly classified as non-invasive encapsulated follicular variant of papillary thyroid carcinoma were recently renamed 'non-invasive follicular thyroid neoplasm with papillary-like nuclear features'. The current study investigated the frequency of lymph node metastasis and mutational profile of encapsulated follicular variant in the setting of a clinical practice where central neck dissection was the standard of practice. We defined the impact of rigid diagnostic criteria by regrouping such tumors based on the complete absence of papillae or presence of ≤1% papillae. Of a total of 6,269 papillary thyroid carcinomas, 152 tumors fulfilled the criteria for encapsulated follicular variant. The results were stratified according to two different diagnostic cutoff criteria with respect to the extent of papillae. When the cutoff of 1% papillae was used, the rates of lymph node metastasis and BRAFV600E mutation were 3% and 10% in non-invasive tumors and 9% and 4% in invasive tumors, respectively. Despite the lack of invasive growth, one patient with BRAFV600E mutant-tumor displaying predominant follicular growth and subtle papillae developed a bone metastasis. When absence of papillary structure was applied as rigid diagnostic criteria, no BRAFV600E mutation was found in all tumors. However, central lymph node micrometastasis still occurred in 3% of non-invasive tumors. Non-V600E BRAF and RAS mutations were detected in 4% and 47% of non-invasive tumors, respectively. Our findings suggest that non-invasive follicular thyroid neoplasm with papillary-like nuclear features should not be regarded as a benign thyroid neoplasm as it can present with lymph node micrometastasis and should not be diagnosed in the presence of even a single papillary structure. Our findings underscore the original American Thyroid Association recommendation that defined non-invasive encapsulated follicular variants as low risk thyroid cancers. Clinical surveillance similar to low risk differentiated thyroid cancers and capture of this diagnostic category by Cancer Registries should be considered.

Clinicopathological characteristics including BRAF V600E mutation status and PET/CT findings in papillary thyroid carcinoma.

OBJECTIVE: We assessed the associations between FDG uptake in primary papillary thyroid carcinomas (PTCs) and clinicopathological features, including the BRAF V600E mutation, using quantitative and qualitative analyses of preoperative PET/CT data. DESIGN AND PATIENTS: This was a retrospective review of 106 patients with PTC who underwent PET/CT scans between February 2009 and January 2011 before undergoing total thyroidectomy. Data collected from surgical specimens were compared with FDG uptake in the primary tumour using quantitative and qualitative analyses of preoperative PET/CT data. Clinicopathological data included the primary tumour size, subtype, capsular invasion, extrathyroid extension, multifocality, BRAF V600E mutation status, lymph node metastasis and distant metastasis. RESULTS: The SUVmax of the primary tumour was significantly higher in patients with a primary tumour >1 cm, extrathyroid extension or the BRAF V600E mutation than in patients without these features (P<.001, .049 and <.001). Univariate analyses showed that primary tumour size, extrathyroid extension and BRAF V600E mutation status were associated with the SUVmax of the PTC. Multivariate analysis indicated that primary tumour size and the BRAF V600E mutation were associated with the SUVmax of the PTC. In a visual assessment, the primary tumour size was larger in FDG-avid than in non-FDG-avid PTCs (P<.001). There was no significant difference in the presence of multifocality, thyroid capsular invasion, extrathyroid extension, BRAF V600E mutation, lymph node metastasis or distant metastasis between FDG-avid and non-FDG-avid PTCs. CONCLUSIONS: Primary tumour size and the BRAF V600E mutation are significant factors associated with the SUVmax on preoperative PET/CT in patients with PTC.

Prognostic value of preoperative anti-thyroglobulin antibody in differentiated thyroid cancer.

CONTEXT: The coexistence of differentiated thyroid cancer (DTC) and thyroid autoimmune disease could represent a better or worse prognosis. This study investigated the prognostic importance of preoperative anti-thyroglobulin antibody (TgAb) in DTC patients. DESIGN AND PATIENTS: This retrospective hospital-cohort study enrolled 1171 consecutive DTC patients with preoperative TgAb data, who underwent total thyroidectomy between January 2006 and December 2011. Clinical parameters studied included demographics, primary tumour characteristics, radioiodine therapy, thyroid function tests, preoperative thyroglobulin (Tg) and TgAb levels, and cancer persistence/recurrence. RESULTS: A total of 254 (21.7%) patients were preoperatively TgAb positive. The percentage positive for thyroid peroxidase (TPO) antibody and lymphocytic thyroiditis was significantly higher in the TgAb-positive group. The TgAb-positive group had a significantly higher rate of lymphatic invasion and lymph node metastasis both overall and in patients without TPOAb and lymphocytic thyroiditis (non-HT group). The mean number of total and central lymph nodes dissected and rate of lateral lymph node dissection were significantly higher in the TgAb-positive group, both overall and in non-HT patients. In regression analysis, preoperative TgAb was an independent risk factor for lateral lymph node metastasis. Over 50.2±14.5 months of follow-up, disease persistence/recurrence was not significantly different between patients with and without TgAb, both overall and in non-HT patients. Preoperative TgAb showed no significant correlation with final disease status. CONCLUSION: Positive preoperative serum TgAb is associated with worse primary tumour characteristics but rarely showed poor prognosis, probably due to more aggressive treatment of these subjects.

Preoperative differentiation between noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) and non-NIFTP.

BACKGROUND: A recent concept was proposed that the noninvasive encapsulated follicular variant of papillary thyroid carcinoma reclassified as "noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP)" is benign. Our aim was to identify the differences between NIFTP and non-NIFTP preoperatively. METHODS: This retrospective study included a total of 208 patients with 208 follicular variant of papillary thyroid carcinomas (FVPTC) that were surgically confirmed at three university hospitals from 2008 to 2014. Clinical factors, the biopsy techniques and ultrasonography (US) imaging characteristics were compared between the NIFTP and non-NIFTP groups. RESULTS: A total of 34 NIFTP (16·3%) and 174 non-NIFTP (83·7%) were observed. For NIFTPs, the need for surgery was indicated by ultrasonography-guided fine needle aspiration (US-FNA) in 54·3% and by ultrasonography-guided core needle biopsy (US-CNB) in 100% (P = 0·008). For non-NIFTP, no significant difference was noted in the rates of surgical indication between US-FNA and US-CNB (62·6% vs 78·9%, P = 0·054). The most common biopsy diagnosis of NIFTP was Bethesda category V (28·6%) in the US-FNA group and category IV (45·5%) in the US-CNB group. US diagnosis of NIFTP had a significantly lower rate of the high suspicion of malignancy than that of non-NIFTP (14·7% vs 37·9%, P = 0·024). Central nodal metastasis was found in only one case (2·9%) of NIFTP patients, but none had distance metastasis or recurrence. CONCLUSION: Noninvasive follicular thyroid neoplasm with papillary-like nuclear features lacks malignant US features and is better triaged using US-CNB than using US-FNA to facilitate the surgical management. US evaluation is pivotal in determining the next step of FVPTC management.