[Show abstract][Hide abstract] ABSTRACT: Warthin-like variant of papillary thyroid carcinoma (WVPTC) is a rare entity recently characterized. We evaluated ultrasonographic (US) features and clinical characteristics of WVPTC. Nine patients were diagnosed with WVPTC through surgery in our institution from May 2005 to January 2015. Eight of nine patients had available preoperative US images. A retrospective review of the US and clinical characteristics was performed. WVPTC compromised of 0.06% of 14,071 PTCs surgically confirmed. A mean age of nine patients was 53.2 years (range, 32-75 years). The mean nodule size of nine WVPTCs was 0.9 cm (range, 0.5-1.5 cm). Two patients showed central nodal metastasis and one patient with conventional PTC as an index tumor underwent central and lateral neck dissection. No one showed recurrence or distant metastasis during the follow-up period (mean, 4.6 years; range, 0.6-10 years). The most common US features of WVPTCs were solid composition (62.5%), hypoechogenicity (75%), and wider-than-tall shape (100%), respectively. Four (50%) of eight nodules showed well-defined margin and three (37.5%) of them had cystic component. One of eight resembled focal thyroiditis. Three nodules were considered as probably benign with US. All nine cases demonstrated underlying heterogeneous parenchymal echogenicity and accompanied chronic lymphocytic thyroiditis in permanent sections. Thyroid function tests in all patients were normal except for one with subclinical hypothyroidism. WVPTC is an uncommon subtype of PTC and has favorable prognosis, which can be misdiagnosed as a probably benign nodule or focal thyroiditis with US. All cases are associated with heterogeneous parenchyma in the background.
[Show abstract][Hide abstract] ABSTRACT: The management of patients with thyroid cytopathologic diagnosis of atypia (or follicular lesion) of undetermined significance (AUS/FLUS) is a complex clinical problem. The purpose of this study was to develop a practical triage scheme based on multiple diagnostic tests in general use. We performed a retrospective cohort study involving 15,335 consecutive patients with a referral diagnosis of thyroid nodule between April 2011 and March 2015 using an institutional database. We obtained 904 patients with an initial cytopathologic diagnosis of AUS/FLUS who underwent repeat fine-needle aspiration or core needle biopsy, 388 of whom had a corresponding histopathological diagnosis for excised index lesions. The diagnostic performance of ultrasound (US) findings, repeat biopsy, and BRAF(V) (600E) mutation in cytopathologic specimens were evaluated individually or as a set. Of the 388 resected AUS/FLUS cases, 338 (87.1%) were thyroid cancer. The positive likelihood ratios (LRs) for BRAF(V) (600E) mutation and repeat biopsy result of suspicious for malignant cell (SMC) or worse were 11.6 (95% CI = 1.7-77.8) and 13.7 (95% CI = 4.6-41.0), respectively. The absence of suspicious findings on US combined with cytologic result of less than SMC or negative BRAF(V) (600E) mutation produced negative LRs ranging from 0.06 to 0.15, corresponding to negative predictive values of over 90% in both primary and referral settings. For patients with AUS/FLUS cytopathology, clinical decision making can be guided by a simple triage scheme based on US findings, repeat biopsy, or BRAF(V) (600E) mutation.
[Show abstract][Hide abstract] ABSTRACT: Aim:
Diffuse sclerosing variant of papillary thyroid carcinoma (DSV-PTC) is an uncommon variant of PTC, and its prognostic significance remains controversial. The aim of this study was to investigate the major genetic alterations of DSV-PTC and their prognostic implications.
Methods and results:
We included 37 patients with DSV-PTC who underwent thyroid surgery and had formalin-fixed paraffin-embedded samples. We tested for a panel of genetic alterations including BRAF(V) (600E) , NRAS codon 61, HRAS codon 12/13/61, and KRAS codon 12/13 point mutations as well as RET/PTC1, RET/PTC3, and PAX8/PPARγ rearrangements using reverse transcription real-time PCR. All genetic alterations found on PCR were confirmed by Sanger sequencing. Associations between the identified genetic alterations and clinicopathologic characteristics were evaluated. Among 37 cases of DSV-PTC, 17 were positive for RET/PTC1 (46%), 6 for RET/PTC3 (16%), and 9 for BRAF(V) (600E) (24%). All mutations/rearrangements were mutually exclusive. The remaining 5 cases had none of the above genetic alterations. DSV-PTC with RET/PTC3 rearrangement was associated with advanced-stage disease, including T4 and distant metastasis (P < 0.05). Patients with RET/PTC3 showed a higher frequency of persistent disease (P < 0.01). In contrast, DSV-PTC with RET/PTC1 was associated with a higher prevalence of disease remission (P < 0.05) and coexistent Hashimoto's thyroiditis (P < 0.01).
Taken together, RET/PTC rearrangement was the major genetic alteration seen in patients with DSV-PTC and RET/PTC3 rearrangement was associated with advanced stage at diagnosis and poor clinical outcomes. This article is protected by copyright. All rights reserved.
[Show abstract][Hide abstract] ABSTRACT: Objective:
The Bethesda System for Reporting Thyroid Cytopathology is now widely used as the standard reporting system for fine-needle aspiration cytology (FNAC). Recently, several studies have attempted to subcategorize the atypia of undetermined significance (AUS)/follicular lesion of undetermined significance (FLUS) category. We aimed to analyze the significance of a subcategory of AUS/FLUS showing both cytologic and architectural atypia (AUS/FLUS-C&A).
From April 2011 to May 2014, 18,091 patients underwent FNAC at Samsung Medical Center. For those patients we analyzed the clinical significance of the subcategory AUS/FLUS-C&A.
One hundred and sixty-three patients were diagnosed as AUS/FLUS-C&A. Of 71 cases with subsequent histologic confirmation, 47 (66.2%) were diagnosed with papillary thyroid carcinoma (PTC). Of the 47 PTC cases, 32 (68.1%) were follicular variant-PTC. A significant difference in the PTC rate (58.3 vs. 82.6%) and PTC size (average: 1.8 and 0.9 cm) was noted between circumscribed lesions and infiltrative lesions on ultrasonography.
We demonstrated that the subcategory of AUS/FLUS-C&A has considerable clinical implications and one should be aware of the cytological and ultrasonographic features.
[Show abstract][Hide abstract] ABSTRACT: A 31-year-old woman was referred to our hospital with symptoms of hypertension and bilateral adrenocortical masses with no feature of Cushing syndrome. The serum aldosterone/renin ratio was elevated and the saline loading test showed no suppression of the plasma aldosterone level, consistent with a diagnosis of primary hyperaldosteronism. Overnight and low-dose dexamethasone suppression tests showed no suppression of serum cortisol, indicating a secondary diagnosis of subclinical Cushing syndrome. Adrenal vein sampling during the low-dose dexamethasone suppression test demonstrated excess secretion of cortisol from the left adrenal mass. A partial right adrenalectomy was performed, resulting in normalization of blood pressure, hypokalemia, and high aldosterone level, implying that the right adrenal mass was the main cause of the hyperaldosteronism. A total adrenalectomy for the left adrenal mass was later performed, resulting in a normalization of cortisol level. The final diagnosis was bilateral adrenocortical adenomas, which were secreting aldosterone and cortisol independently. This case is the first report of a concurrent cortisol-producing left adrenal adenoma and an aldosterone-producing right adrenal adenoma in Korea, as demonstrated by adrenal vein sampling and sequential removal of adrenal masses.
[Show abstract][Hide abstract] ABSTRACT: The genetic landscape of medullary thyroid cancer (MTC) is not yet fully understood, although some oncogenic mutations have been identified. To explore genetic profiles of MTCs, formalin-fixed, paraffin-embedded tumor tissues from MTC patients were assayed on the Ion AmpliSeq Cancer Panel v2. Eighty-four sporadic MTC samples and 36 paired normal thyroid tissues were successfully sequenced. We discovered 101 hotspot mutations in 18 genes in the 84 MTC tissue samples. The most common mutation was in the ret proto-oncogene, which occurred in 47 cases followed by mutations in genes encoding Harvey rat sarcoma viral oncogene homolog (N = 14), serine/threonine kinase 11 (N = 11), v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog (N = 6), mutL homolog 1 (N = 4), Kiesten rat sarcoma viral oncogene homolog (N = 3) and MET proto-oncogene (N = 3). We also evaluated anaplastic lymphoma kinase (ALK) rearrangement by immunohistochemistry and break-apart fluorescence in situ hybridization (FISH). Two of 98 screened cases were positive for ALK FISH. To identify the genomic breakpoint and 5' fusion partner of ALK, customized targeted cancer panel sequencing was performed using DNA from tumor samples of the two patients. Glutamine:fructose-6-phosphate transaminase 1 (GFPT1)-ALK and echinoderm microtubule-associated protein-like 4 (EML4)-ALK fusions were identified. Additional PCR analysis, followed by Sanger sequencing, confirmed the GFPT1-ALK fusion, indicating that the fusion is a result of intra-chromosomal translocation or deletion. Notably, a metastatic MTC case harboring the EML4-ALK fusion showed a dramatic response to an ALK inhibitor, crizotinib. In conclusion, we found several genetic mutations in MTC and are the first to identify ALK fusions in MTC. Our results suggest that the EML4-ALK fusion in MTC may be a potential driver mutation and a valid target of ALK inhibitors. Furthermore, the GFPT1-ALK fusion may be a potential candidate for molecular target therapy.
[Show abstract][Hide abstract] ABSTRACT: Background
The association of vascular invasion with tumor aggressiveness and poor prognosis in follicular thyroid carcinoma (FTC) remains controversial. Methods
We reviewed medical records of 204 patients with histologically confirmed FTC. ResultsThe disease-specific survival rates at 5 and 10 years were 94% and 85%, respectively. Using Cox proportional hazard model, the extent of invasiveness and the frequency of distant metastasis were found to be independent prognostic factors for survival in all patients with FTC. When we performed individual analyses stratified by the extent of invasiveness, vascular invasion was an independent predictor of disease-specific survival in minimally invasive FTC, but that did not independently affect survival in widely invasive FTC. Conclusion
This study suggests that vascular invasion is associated with aggressive features of FTC and independently influences outcomes in minimally invasive FTC. For patients aged <45 years with minimally invasive FTC without vascular invasion, thyroid lobectomy alone may be adequate. (c) 2014 Wiley Periodicals, Inc. Head Neck 36: 1695-1700, 2014
[Show abstract][Hide abstract] ABSTRACT: The purpose of this study is to assess the clinicopathologic features, treatment outcomes, and role of adjuvant radiation therapy (RT) in cervical thymic neoplasm involving the thyroid gland or neck.
The medical and pathologic records of eight patients with cervical thymic neoplasm were reviewed retrospectively. All patients underwent surgical resection, including thyroidectomy or mass excision. Adjuvant RT was added in five patients with adverse clinicopathologic features. The radiation doses ranged from 54 Gy/27 fractions to 66 Gy/30 fractions delivered to the primary tumor bed and pathologically involved regional lymphatics using a 3-dimensional conformal technique.
Eight cases of cervical thymic neoplasm included three patients with carcinoma showing thymus-like differentiation (CASTLE) and five with ectopic cervical thymoma. The histologic subtypes of ectopic cervical thymoma patients were World Health Organization (WHO) type B3 thymoma in one, WHO type B1 thymoma in two, WHO type AB thymoma in one, and metaplastic thymoma in one, respectively. The median age was 57 years (range, 40 to 76 years). Five patients received adjuvant RT: three with CASTLE; one with WHO type B3; and one with WHO type AB with local invasiveness. After a median follow-up period of 49 months (range, 11 to 203 months), no recurrence had been observed, regardless of adjuvant RT.
Adjuvant RT after surgical resection might be worthwhile in patients with CASTLE and ectopic cervical thymoma with WHO type B2-C and/or extraparenchymal extension, as similarly indicated for primary thymic epithelial tumors. A longer follow-up period may be needed in order to validate this strategy.
Preview · Article · Nov 2014 · Cancer Research and Treatment
[Show abstract][Hide abstract] ABSTRACT: Soybean may be a promising ingredient for regulating UVB-induced inflammatory damage to the skin. We investigated the anti-inflammatory effects of diets supplemented with fermented soybean on UVB-induced skin photodamage and the effectiveness of soybean (S) and fermented soybean (FS) dietary supplementation. To investigate the effects of two major isoflavones-daidzein and genistein-from FS, we used co-cultures with keratinocytes and fibroblasts. Genistein treatment strongly inhibited the production of IL-6 and MAPK signaling. Forty hairless male mice divided into four groups were fed with a control diet (Group N: normal, Group C; +UVB) or diets with 2.5% S+UVB or 2.5% FS+UVB (Group S, Group FS) for 8 weeks. Macrophage infiltration to the dermis was reduced more in Groups S and FS than in Group C. The expression levels of iNOS and COX-2 were significantly decreased in Group FS (by 7.7% ± 0.4% and 21.2% ± 0.3%, respectively [p < 0.05]).
No preview · Article · Aug 2014 · Journal of Agricultural and Food Chemistry
[Show abstract][Hide abstract] ABSTRACT: Background
The objective of this study was to evaluate the validity of fine needle aspiration biopsy (FNAB) according to ultrasonography (US) characteristics in thyroid nodules 4 cm and larger.
We retrospectively reviewed the cases of 263 patients who underwent thyroid surgery for thyroid nodules larger than 4 cm between January 2001 and December 2010.
The sensitivity of US-FNAB was significantly higher in nodules with calcifications (micro- or macro-) than those without (97.9% vs. 87.% P<0.05). The accuracy of US-FNAB was higher in large thyroid nodules with US features suspicious of malignancy, such as a solid component, ill-defined margin, hypoechogenicity or marked hypoechogenicity, or any calcifications (micro- or macro-) compared to thyroid nodules with none of these features. Furthermore, the accuracy improved as the number of these features increased. The overall false negative rate (FNR) was 11.9%. The FNR of thyroid nodules that appeared benign on US, such as mixed nodules (7.7%) or nodules without calcification (9.8%), trended toward being lower than that of solid nodules (17.9%) or nodules with any microcalcification or macrocalcification (33.3%). In nodules without suspicious features of malignancy, the FNR of US-FNAB was 0% (0/15).
We suggest individualized strategies for large thyroid nodules according to US features. Patients with benign FNAB can be followed in the absence of any malignant features in US. However, if patients exhibit any suspicious features, potential false negative results of FNAB should be kept in mind and surgery may be considered.
[Show abstract][Hide abstract] ABSTRACT: Further management for thyroid nodules with cytological atypia of undetermined significance (AUS) has made controversial conclusions. The aim of this study was to evaluate the most reliable ultrasonography (US) findings to predict malignancy in thyroid nodules with AUS, and to compare inconclusive rates of repeat fine-needle aspiration (rFNA) and core needle biopsy (CNB) in nodules with AUS.
We retrospectively reviewed cases of thyroid nodules with AUS from 8,421 US-guided fine-needle aspirations in our institution between 2010 and 2012. Nodules were confirmed either surgically or followed-up for at least 1 year and were compared based on nodule size, US findings, and US diagnosis to predict malignancy. Inconclusive rates of rFNA and CNB after initial AUS were compared.
The incidence of AUS in all thyroid nodules was 3.2 % (273 of 8,421). Malignancies were identified in 42.1 % (64 of 152) nodules with surgery or sufficient follow-up. In univariate analysis, not-oval to round shape, irregular margin, taller-than-wide orientation, hypoechogenicity, marked hypoechogenicity, microcalcifications, and malignant US diagnosis were more frequent in actual malignancies (p < 0.05). In multivariate analysis, hypoechogenicity, marked hypoechogenicity, and malignant US diagnosis were significantly more frequent in malignancies (p < 0.05). With respect to further management of AUS, the inconclusive rate of CNB (17.6 %, 6/34) was significantly lower than that of rFNA (37.3 %; 44 of 118) (p = 0.032).
Nodule echogenicity and US diagnosis can be predictive factors of malignancies for the thyroid nodules with cytological AUS. The CNB is more useful than rFNA for reducing the frequency of inconclusive results after initial AUS.
No preview · Article · Feb 2014 · Annals of Surgical Oncology
[Show abstract][Hide abstract] ABSTRACT: Objective:
The aim of this study was to evaluate the diagnostic accuracy of fine needle aspiration (FNA) cytology of benign salivary gland tumors with myoepithelial cell participation, namely, pleomorphic adenoma, basal cell adenoma and myoepithelioma, at a single institution over a period of 10 years.
This study was based on 575 cytologic and matching histological samples (534 pleomorphic adenomas, 26 basal cell adenomas and 15 myoepitheliomas).
In most cases (393/534) of pleomorphic adenoma, a precise diagnosis was given. However, only 2 cases of basal cell adenoma and 1 case of myoepithelioma were diagnosed definitively. Descriptive diagnosis, instead of a definite diagnosis, was rendered in 16.9% of pleomorphic adenomas, 53.8% of basal cell adenomas and 40.0% of myoepitheliomas. Among all cases, the possibility of malignancy was raised in 5.2% of pleomorphic adenomas, 15.4% of basal cell adenomas and 20.0% of myoepitheliomas with a variable degree of suspicion.
In some cases, the distinction between these three neoplasms remains difficult in that all exhibit some degree of myoepithelial participation. However, FNA showed a high diagnostic accuracy in diagnosing benign salivary tumors with myoepithelial differentiation, and triage into this category provides sufficient information for clinicians to make treatment decisions.
[Show abstract][Hide abstract] ABSTRACT: Recently, BRAF inhibitors showed dramatic treatment outcomes in BRAF V600 mutant melanoma. Therefore, the accuracy of BRAF mutation test is critical.
BRAF mutations were tested by dual-priming oligonucleotide-polymerase chain reaction (DPO-PCR), direct sequencing and subsequently retested with a real-time PCR assay, cobas 4800 V600 mutation test. In total, 64 tumors including 34 malignant melanomas and 16 papillary thyroid carcinomas were analyzed. DNA was extracted from formalin-fixed paraffin embedded tissue samples and the results of cobas test were directly compared with those of DPO-PCR and direct sequencing.
BRAF mutations were found in 23 of 64 (35.9%) tumors. There was 9.4% discordance among 3 methods. Out of 6 discordant cases, 4 cases were melanomas; 3 cases were BRAF V600E detected only by cobas test, but were not detected by DPO-PCR and direct sequencing. One melanoma patient with BRAF mutation detected only by cobas test has been on vemurafenib treatment for 6 months and showed a dramatic response to vemurafenib. DPO-PCR failed to detect V600K mutation in one case identified by both direct sequencing and cobas test.
In direct comparison of the currently available DPO-PCR, direct sequencing and real-time cobas test for BRAF mutation, real-time PCR assay is the most sensitive method.
Preview · Article · Aug 2013 · The Korean Journal of Pathology
[Show abstract][Hide abstract] ABSTRACT: Our aim was to evaluate predictive factors of malignancy in patients with cytologically suspicious for Hurthle cell neoplasm (HCN) of thyroid nodules.
We searched cases with cytologically suspicious for HCN from 11,569 ultrasound-guided fine-needle aspirations (US-FNA) performed at our institution. Nodules that were confirmed surgically or followed-up for at least 2 years were compared with respect to age, gender, tumor size, US diagnosis, and US findings to predict malignancy.
The incidence of cases with cytologically suspicious for HCN was 1.2% (143 of 11,569). Of 75 nodules that underwent sufficient follow-up or surgery, malignancies were found in 11 (14.7%). Malignant histological examination revealed oncocytic variants of papillary thyroid carcinoma (PTC) in 3 cases, classic PTC in 1, Hurthle cell carcinoma in 3, follicular carcinoma in 3 and an unclassified carcinoma in 1. In univariate analysis, tumor size was significantly larger in malignant nodules compared to benign nodules (p = 0.026). The best cut-off value of tumor size in predicting malignancy was 2.5 cm. (p = 0.006, sensitivity: 63.6%, specificity: 79.7%). The incidences of hypoechogenicity and malignant US diagnoses were higher in malignant nodules than in benign nodules (p < 0.001). In multivariate analysis, tumor size was an independent factor in predicting malignancies. (p = 0.037, odd ratio: 2.09, confidence interval: 1.046-4.161).
Preoperative US provides predictive factors of malignancy in thyroid nodules with cytologically suspicious for HCN. Predictive factors include tumor size of 2.5 cm or greater, hypoechoic nodule and malignant US diagnosis.
No preview · Article · Jul 2013 · International Journal of Surgery (London, England)
[Show abstract][Hide abstract] ABSTRACT: BRAF mutation is an important diagnostic and prognostic marker in patient s with papillary thyroid carcinoma (PTC). To be applicable in clinical laboratories with limited equipment, diverse testing methods are required to detect BRAF mutation.
A shifted termination assay (STA) fragment analysis was used to detect common V600 BRAF mutations in 159 PTCs with DNAs extracted from formalin-fixed paraffin-embedded tumor tissue. The results of STA fragment analysis were compared to those of direct sequencing. Serial dilutions of BRAF mutant cell line (SNU-790) were used to calculate limit of detection (LOD).
BRAF mutations were detected in 119 (74.8 %) PTCs by STA fragment analysis. In direct sequencing, BRAF mutations were observed in 118 (74.2 %) cases. The results of STA fragment analysis had high correlation with those of direct sequencing (p < 0.00001, kappa = 0.98). The LOD of STA fragment analysis and direct sequencing was 6 % and 12.5 %, respectively. In PTCs with pT3/T4 stages, BRAF mutation was observed in 83.8 % of cases. In pT1/T2 carcinomas, BRAF mutation was detected in 65.9 % and this difference was statistically significant (p = 0.007). Moreover, BRAF mutation was more frequent in PTCs with extrathyroidal invasion than tumors without extrathyroidal invasion (84.7 % versus 62.2 %, p = 0.001). To prepare and run the reactions, direct sequencing required 450 minutes while STA fragment analysis needed 290 minutes.
STA fragment analysis is a simple and sensitive method to detect BRAF V600 mutations in formalin-fixed paraffin-embedded clinical samples.Virtual Slides: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/5684057089135749.
[Show abstract][Hide abstract] ABSTRACT: To evaluate telomerase activity as an adjunct in the cytologic diagnosis of malignant ascites.
Malignant ascites collected from 19 gastrointestinal or liver cancer patients with clinical or pathologic evidence of peritoneal metastasis were tested for routine cytology with a liquid-based preparation, and telomerase activity was measured by telomere-repeat amplification protocol (TRAP) and real-time quantitative TRAP (RTQ-TRAP) assays. For comparison, controls from peritoneal washings from 8 early gastric cancer patients were used.
Cytological examination detected cancer cells in 8 patients (42%), and 3 cases (16%) were diagnosed as "atypia." With TRAP and RTQ-TRAP assays 16 (84%) and 15 (78%) cases, respectively, were positive for telomerase activity. The sensitivity of telomerase activity by TRAP, RTQ-TRAP assays, and cytology was 84%, 78%, and 58%, respectively. All cases with "atypia" by cytological examination were positive for both TRAP and RTQ-PCR assays. In all negative controls, cytology, TRAP and RTQ-TRAP assays were negative.
Based on our findings telomerase activity is a more sensitive method than ascitic fluid cytology and therefore can be considered as a useful diagnostic adjunct to current standard diagnostic methods. However, further large cohort studies with clinical correlation are needed to confirm our findings.
No preview · Article · Jun 2013 · Analytical and quantitative cytology and histology / the International Academy of Cytology [and] American Society of Cytology