The aim of the present study was to verify the optimal method to obtain enough fine-needle aspira... more The aim of the present study was to verify the optimal method to obtain enough fine-needle aspiration (FNA) materials for detecting thyroid malignancy. A prospective study was performed by comparing two different regional standards of care. In one group a traditional FNA method mainly used in Asian countries, including China, was performed in which a single pass of a 22-G needle was applied with or without aspiration. In the other group, the method mainly used in Western countries was performed in which three passes of a 25-G needle with non-aspiration were undertaken for thyroid nodules. The study included 718 thyroid nodules from 695 patients. These nodules were allocated for three different methods of performing thyroid FNA. There were 332 thyroid nodules subjected to the traditional Asian FNA method using a 22-G needle with aspiration for 142 nodules and non-aspiration for 190 nodules. FNA using the Western method was performed with three passes of non-aspiration using 25 G for 386 nodules. All the FNAs were performed with the guidance of ultrasound. The components of the nodules were documented. All the samples were reported using the Bethesda System for Reporting Thyroid Cytopathology. Among the 22 G group, the non-diagnostic rate in the aspiration group was as high as 76.76%, which was significantly higher than 44.21% in the non-aspiration group (P<0.01). For the non-aspiration group, the non-diagnostic rate in the 25 G group was 34.97%, which was significantly lower than 44.21% in the 22 G group. In general, the non-diagnostic rate for the 25-G needle was 34.97%, which was significantly lower than 58.13% in all the 22 G groups. For the solid and mixed nodules, the non-diagnostic rate was lower in the 25-G needle group compared to the 22 G groups with statistical significance. The non-aspiration method using a 25-G needle with multiple passes can result in a higher diagnostic rate for thyroid FNA.
Fine-needle aspiration (FNA) is the crucial diagnostic test used for the evaluation of patients w... more Fine-needle aspiration (FNA) is the crucial diagnostic test used for the evaluation of patients with a thyroid nodule. The result of an FNA determines if a patient can be followed with repeated examinations or referred for surgery. The value of FNA can be enhanced by attention to technical details. Communication between operator and pathologist is essential. A pathologist's interpretation is aided if essential clinical information is provided on a requisition form. Although reporting terminology has been varied and confusing in the past, a proposal for a uniform reporting system provides 6 clearly defined and clinically relevant reporting categories and promises to standardize the reporting of thyroid FNA results.
Lung cancer is the leading cause of cancer-related deaths worldwide. Prognosis and survival are d... more Lung cancer is the leading cause of cancer-related deaths worldwide. Prognosis and survival are dependent on cell type, early detection, and surgical treatment. Hence, optimal screening strategies and new therapies are urgently required. Although surveillance with low-dose computed tomography can reduce lung cancer mortality by 20%, the number of false-positive detections is significant. Tissue diagnosis aids in the identification of benign nodules, reducing the number of false positive detections. To determine whether molecular testing of fine-needle aspirations (FNAs) can reduce false-positive detections, we developed a gene expressionebased test that distinguishes normal from cancerous lung tissues. The test first was applied to published microarray data, showing overall sensitivity and specificity values of 95% (95% CI, 90%e98%) and 100% (95% CI, 40%e100%), respectively. Subsequently, it was validated on 30 solid and ex vivo FNA lung cancer tumor samples and matched normal lung specimens using real-time PCR. The validation test was 93% (95% CI, 78%e99%) sensitive and 100% (95% CI, 88%e100%) specific for the detection of tumor versus normal lung on solid samples, whereas FNA specimens yielded a sensitivity of 91% (95% CI, 72%e99%) and a specificity of 94% (95% CI, 70%e100%). This study supports the hypothesis that the gene-ratio approach reliably distinguishes normal lung from cancerous tissues in FNA samples and can be optimized to diagnose benign nodules.
We compared the effectiveness of epithelial membrane antigen (EMA) with 2 newly described markers... more We compared the effectiveness of epithelial membrane antigen (EMA) with 2 newly described markers, X-linked inhibitor of apoptosis protein (XIAP) and an isoform of glucose transporter (GLUT-1), in the distinction between malignant mesothelioma (MM) and benign effusion (BE) in body cavity fluids. Immunohistochemical studies were performed on cell block sections from 35 cases of histologically confirmed MM and 38 BEs, using antibodies to EMA, XIAP, GLUT-1 (GLUT-1m, monoclonal; GLUT-1p, polyclonal). Results were graded based on the percentage of cells staining: negative (0%), 1+ (<25%), 2+ (25%–49%), 3+ (50%–74%), and 4+ (75%–100%). The performance of each marker was compared using receiver operating characteristic curve analysis. EMA demonstrated the best accuracy, with an area under the curve of 0.91 as compared with XIAP (0.67), GLUT-1m (0.74), and GLUT-1p (0.80). Based on these findings, EMA is a better marker than XIAP or GLUT-1 for the diagnosis of MM.
meeting was accompanied by a permanent informational web-site and several on-line discussions bet... more meeting was accompanied by a permanent informational web-site and several on-line discussions between May 1 and De-cember 15, 2007
The Journal of clinical endocrinology and metabolism, Dec 1, 2017
Thyroid nodule growth was once considered concerning for malignancy, but data showing that benign... more Thyroid nodule growth was once considered concerning for malignancy, but data showing that benign nodules grow questioned the use of this paradigm. To date, however, no studies have adequately evaluated whether growth rates differ in malignant vs. benign nodules. To sonographically evaluate growth rates in benign and malignant thyroid nodules ≥1 cm. Prospective, cohort study of patients with tissue diagnosis of benign or malignant disease, with repeated ultrasound evaluation six or more months apart. Growth rate in largest dimension of malignant compared with benign thyroid nodules. Regression models were used to evaluate predictors of growth. Malignant nodules (126) met inclusion criteria (≥6-month nonoperative followup) and were compared with 1363 benign nodules. Malignant nodules were not found to be uniquely selected or prospectively observed solely for low-risk phenotype. Median ultrasound intervals were similar (21.8 months for benign nodules; 20.9 months for malignant nodules...
Thyroid nodules with atypia of undetermined significance (AUS) on fine-needle aspiration (FNA) ha... more Thyroid nodules with atypia of undetermined significance (AUS) on fine-needle aspiration (FNA) have a low risk of malignancy that appears to vary based on specific features described in the AUS diagnosis. The Afirma gene expression classifier (GEC) is a molecular test designed to improve preoperative risk stratification of thyroid nodules, but its performance for different patterns of AUS has not been defined. The objective of this study was to assess GEC results and clinical outcomes in AUS nodules with architectural atypia (AUS-A), cytologic atypia (AUS-C) or both (AUS-C/A). This was a retrospective review of all thyroid nodules with AUS cytopathology that underwent GEC testing at the authors' institution over a period of >4 years. In 227 nodules that had AUS cytology results and Afirma GEC testing, the rate of benign GEC results was higher in AUS-A nodules (70 of 107; 65%) than in AUS-C/A nodules (25 of 65; 38%; P = .0008), and AUS-C nodules exhibited an intermediate rate ...
Thyroid : official journal of the American Thyroid Association, 2016
The term noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) has... more The term noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) has been proposed to replace noninvasive follicular variant of papillary thyroid carcinoma (FVPTC) in recognition of the indolent behavior of this tumor. The ability to differentiate NIFTP from classical papillary thyroid carcinoma (cPTC) by fine-needle aspiration (FNA) would facilitate conservative management for NIFTP. The aim of this study was to determine if NIFTP can be distinguished prospectively from cPTC. From June 2015 to January 2016, thyroid FNAs with a diagnosis of "malignant" or "suspicious for malignancy" were prospectively scored for features associated with NIFTP/FVPTC (microfollicular architecture) or cPTC (papillae, psammomatous calcifications, sheet-like architecture, and nuclear pseudoinclusions) and categorized as NIFTP/FVPTC, cPTC, or indeterminate. Results were correlated with subsequent histologic diagnoses. The study included 52 patients with 56 ...
The Journal of clinical endocrinology and metabolism, Jan 30, 2016
Mutations in the BRAF and RAS oncogenes are responsible for most well-differentiated thyroid canc... more Mutations in the BRAF and RAS oncogenes are responsible for most well-differentiated thyroid cancer. Yet, our clinical understanding of how BRAF-positive and RAS-positive thyroid cancers differ is incomplete. We correlated clinical, radiographic, and pathologic findings from patients with thyroid cancer harboring a BRAF or RAS mutation. Prospective cohort study Setting: Academic, tertiary care hospital Patients: 101 consecutive patients with well-differentiated thyroid cancer Main Outcome Measure: We compared the clinical, sonographic, and pathologic characteristics of patients with BRAF-positive cancer to those with RAS-positive cancer. Of 101 patients harboring these mutations, 71 were BRAF-positive, while 30 were RAS-positive. Upon sonographic evaluation, RAS-positive nodules were significantly larger (p=0.04), though BRAF-positive nodules were more likely to harbor concerning sonographic characteristics [hypoechogenicity (p<0.001); irregular margins (p=0.04)]. Cytologically, ...
Background: It is now recognized that noninvasive follicular variant of papillary thyroid carcino... more Background: It is now recognized that noninvasive follicular variant of papillary thyroid carcinoma (NFVPTC) is a distinct subset of FVPTC with an exceedingly indolent clinical course. The Afirma gene-expression classifier (GEC) helps guide clinicians in the management of thyroid nodules with indeterminate fine-needle aspiration (FNA) results. Thyroid surgery is recommended for nodules with a suspicious Afirma result, whereas observation is deemed reasonable for most nodules with a benign result. The aim of this study was to confirm that the Afirma test detects NFVPTCs and to determine how many carcinomas detected by the Afirma GEC represent NFVPTCs. Methods: From a database of 249 FNAs sent for Afirma testing between January 2012 and October 2014, a search was conducted for cases with a preceding FNA diagnosis of atypia/follicular lesion of undetermined significance (AUS/FLUS) or suspicious for a follicular neoplasm (SFN), a suspicious Afirma result, and a corresponding resection specimen reviewed at Brigham and Women's Hospital. The diagnoses of the prior FNAs and subsequent resection specimens were recorded. Slides for all resection specimens with a diagnosis of FVPTC were reviewed to identify NFVPTCs. Results: Sixty-three cases met the inclusion criteria. The preceding FNA diagnosis was AUS/FLUS in 34 (54%) cases and SFN in 29 (46%) cases. The surgical resection specimen demonstrated 16 (25%) FVPTCs, five (8%) follicular thyroid carcinomas, one (2%) classical type PTC, and 41 (65%) benign tumors/nodules. Of the 16 FVPTCs, 14 (88%) were NFVPTCs. Thus, NFVPTCs accounted for 64% of the carcinomas in the cohort. Conclusion: These results indicate that the Afirma GEC detects NFVPTCs and that many of the carcinomas detected by Afirma are NFVPTCs. While all care should be individualized and include clinical and sonographic assessment, these results suggest lobectomy as opposed to total thyroidectomy should be considered for nodules with a preceding AUS/FLUS or SFN on cytology and a suspicious Afirma result.
Background: Since its inception, the Bethesda System for Reporting Thyroid Cytopathology (TBS) ha... more Background: Since its inception, the Bethesda System for Reporting Thyroid Cytopathology (TBS) has been widely adopted. Each category conveys a risk of malignancy and recommended next steps, though it is unclear if each category also predicts the type and extent of malignancy. If so, this would greatly expand the utility of the TBS by providing prognostic information in addition to baseline cancer risk. Methods: All patients prospectively enrolled into the authors' thyroid nodule database from 1995 to 2013 with histologically proven malignancy were analyzed. The primary ultrasound-guided fine-needle aspiration cytology (AUS, atypia of unknown significance; FN, follicular neoplasm; SUSP, suspicious; M, malignant) was correlated with the type of thyroid cancer and histological features known to impact prognosis and recurrence, including lymph node metastasis (LNM), lymphovascular invasion, and extrathyroidal extension (ETE). Primary cytology was separately correlated with higher risk malignancy. Results: A total of 1291 malignancies were identified, with primary cytology AUS in 130 cases, FN in 241 cases, SUSP in 411 cases, and M in 509 cases. AUS, SUSP, and M cytology were progressively associated with an increasing risk of high-risk disease (p < 0.001), LNM (p < 0.001), ETE (p < 0.001), and margin positivity (p < 0.001). Notably, 71% of malignancies with AUS cytology were follicular variants of papillary thyroid cancer compared with 63% with SUSP cytology and only 20% with M cytology. In contrast, high-risk malignancies were diagnosed in only 4% with AUS cytology, but 9% and 27% with SUSP and M cytology, respectively. FN conveyed a significantly increased risk of follicular thyroid carcinoma compared with all other types (28% vs. 2%; p < 0.001). A composite endpoint of recurrence, distant metastases, and death similarly increased as cytology progressed from AUS to SUSP to M (p < 0.001). Conclusion: In addition to predicting cancer prevalence, the TBS also imparts important prognostic information about cancer type, variant, and risk of recurrence. These data extend the utility of TBS classification by fostering an improved understanding of the risk posed by any confirmed malignancy.
Background: Increased recognition of the indolent nature of noninvasive follicular variant of pap... more Background: Increased recognition of the indolent nature of noninvasive follicular variant of papillary thyroid carcinoma (NFVPTC) along with greater insight into the molecular alterations of these tumors has prompted endocrine pathologists to question whether these tumors warrant a diagnosis of carcinoma. However, a change in terminology would affect the rates of malignancy of fine-needle aspiration (FNA) diagnostic categories. Therefore, the aim of this study was to determine the percentage decrease in associated risk of malignancy for each FNA diagnostic category if NFVPTCs were no longer termed carcinomas. Methods: We evaluated a cohort of 655 FNAs with subsequent resection specimens over a 22-month time period. The diagnoses of the preceding FNAs were recorded according to the Bethesda System for Reporting Thyroid Cytopathology. For cases with more than one preceding FNA, the FNA diagnosis associated with the highest risk of malignancy was identified. Slides for all resection specimens with a diagnosis of FVPTC were reviewed to identify noninvasive tumors. By definition, all of these tumors were encapsulated, partially encapsulated, or well circumscribed and lacked any indication of infiltrative growth, capsular penetration, or lymphovascular invasion. Results: Our cohort of 655 FNAs with subsequent resection specimens included 53 (8.1%) nondiagnostic (ND), 167 (25.5%) benign, 97 (14.8%) atypia/follicular lesion of undetermined significance (AUS/FLUS), 88 (13.4%) suspicious for follicular neoplasm (SFN), 94 (14.4%) suspicious for malignancy (SUS), and 156 (23.8%) malignant cases (POS). Surgical resections demonstrated benign findings in 309 (47.2%) and malignant tumors in 346 (52.8%), including 85 NFVPTCs accounting for 24.6% of malignancies. Our rates of malignancy for ND, benign, AUS/FLUS, SFN, SUS, and POS were 18.9%, 13.2%, 39.2%, 45.5%, 87.2%, and 98.7%, respectively. If NFVPTC were no longer termed carcinoma, these rates would drop to 17.0% (10% decrease), 5.4% (59% decrease), 21.6% (45% decrease), 37.5% (18% decrease), 45.7% (48% decrease), and 93.6% (5% decrease), respectively. Conclusion: Our findings demonstrate that if terminology were changed and NFVPTCs were not considered carcinomas, the rates of malignancy for FNA diagnostic categories would be substantially decreased, with the most clinically significant decrease seen in the SUS category, which demonstrated a relative decrease of nearly 50%.
Percutaneous fine-needle aspiration (FNA) cytology is an important diagnostic test for the evalua... more Percutaneous fine-needle aspiration (FNA) cytology is an important diagnostic test for the evaluation and management of selected renal masses. Cytogenetic analysis of cytology specimens can serve as an adjunct for precise classification because certain tumors are associated with specific chromosomal aberrations. This study summarizes our experience with the application of conventional cytogenetics and fluorescence in situ hybridization (FISH) to renal FNA specimens. All percutaneous renal FNAs performed during 2005 through 2008 were identified from the electronic pathology database. Results of cytogenetic and FISH analyses were correlated with the final diagnoses of the renal FNAs. A total of 303 renal FNAs were performed. During an onsite assessment, a portion of the cytology specimen was allocated for cytogenetic analysis in 74 cases. Karyotypic analysis or FISH was successful in 44 (59%) of these. Characteristic chromosomal abnormalities were observed in 27 cases. In 17 cases, a ...
Specific inhibitors can be designed to inactivate the molecular pathways involved in tumor growth... more Specific inhibitors can be designed to inactivate the molecular pathways involved in tumor growth. A compelling example is the use of small molecule drugs, such as imatinib (Gleevec), which inhibit the KIT tyrosine kinase in gastrointestinal stromal tumors (GIST). Assays are needed to determine which inhibitor is most effective at silencing the KIT kinase in each GIST patient. The aim of this study was to develop a robust, cytology-based assay to measure tumor susceptibility to target-specific small molecule inhibitors. We created an immortal GIST cell line (GIST882) that was treated in vitro with several inhibitors of the KIT-AKT-mTOR-S6 signaling pathway. KIT was inhibited with imatinib, and mTOR with RAD001. Treatment response was assessed in cytologic preparations by immunocytochemical staining with antibodies to KIT, phospho-KIT, phospho-AKT, and phospho-S6. Optimization was performed to maximize staining in the absence of inhibitor, and minimize staining in the presence of inhibitor. GIST882 cells demonstrated strong, robust phospho-S6 expression in the absence of inhibitor. This expression was completely inhibited by treatment with upstream signaling pathway inhibitors (imatinib and RAD001). Other phospho-specific antibodies had weaker baseline reactivity in the absence of inhibitor. The accuracy of the immunocytochemical results on the cytologic preparations was validated by immunoblotting studies. Our study demonstrates the feasibility of cytologic methods to monitor labile biochemical responses in tumor cells during drug therapy. Such approaches will be enhanced by the development of additional activation state-specific antibodies, particularly those optimized for use in cytologic preparations.
The aim of the present study was to verify the optimal method to obtain enough fine-needle aspira... more The aim of the present study was to verify the optimal method to obtain enough fine-needle aspiration (FNA) materials for detecting thyroid malignancy. A prospective study was performed by comparing two different regional standards of care. In one group a traditional FNA method mainly used in Asian countries, including China, was performed in which a single pass of a 22-G needle was applied with or without aspiration. In the other group, the method mainly used in Western countries was performed in which three passes of a 25-G needle with non-aspiration were undertaken for thyroid nodules. The study included 718 thyroid nodules from 695 patients. These nodules were allocated for three different methods of performing thyroid FNA. There were 332 thyroid nodules subjected to the traditional Asian FNA method using a 22-G needle with aspiration for 142 nodules and non-aspiration for 190 nodules. FNA using the Western method was performed with three passes of non-aspiration using 25 G for 386 nodules. All the FNAs were performed with the guidance of ultrasound. The components of the nodules were documented. All the samples were reported using the Bethesda System for Reporting Thyroid Cytopathology. Among the 22 G group, the non-diagnostic rate in the aspiration group was as high as 76.76%, which was significantly higher than 44.21% in the non-aspiration group (P<0.01). For the non-aspiration group, the non-diagnostic rate in the 25 G group was 34.97%, which was significantly lower than 44.21% in the 22 G group. In general, the non-diagnostic rate for the 25-G needle was 34.97%, which was significantly lower than 58.13% in all the 22 G groups. For the solid and mixed nodules, the non-diagnostic rate was lower in the 25-G needle group compared to the 22 G groups with statistical significance. The non-aspiration method using a 25-G needle with multiple passes can result in a higher diagnostic rate for thyroid FNA.
Fine-needle aspiration (FNA) is the crucial diagnostic test used for the evaluation of patients w... more Fine-needle aspiration (FNA) is the crucial diagnostic test used for the evaluation of patients with a thyroid nodule. The result of an FNA determines if a patient can be followed with repeated examinations or referred for surgery. The value of FNA can be enhanced by attention to technical details. Communication between operator and pathologist is essential. A pathologist's interpretation is aided if essential clinical information is provided on a requisition form. Although reporting terminology has been varied and confusing in the past, a proposal for a uniform reporting system provides 6 clearly defined and clinically relevant reporting categories and promises to standardize the reporting of thyroid FNA results.
Lung cancer is the leading cause of cancer-related deaths worldwide. Prognosis and survival are d... more Lung cancer is the leading cause of cancer-related deaths worldwide. Prognosis and survival are dependent on cell type, early detection, and surgical treatment. Hence, optimal screening strategies and new therapies are urgently required. Although surveillance with low-dose computed tomography can reduce lung cancer mortality by 20%, the number of false-positive detections is significant. Tissue diagnosis aids in the identification of benign nodules, reducing the number of false positive detections. To determine whether molecular testing of fine-needle aspirations (FNAs) can reduce false-positive detections, we developed a gene expressionebased test that distinguishes normal from cancerous lung tissues. The test first was applied to published microarray data, showing overall sensitivity and specificity values of 95% (95% CI, 90%e98%) and 100% (95% CI, 40%e100%), respectively. Subsequently, it was validated on 30 solid and ex vivo FNA lung cancer tumor samples and matched normal lung specimens using real-time PCR. The validation test was 93% (95% CI, 78%e99%) sensitive and 100% (95% CI, 88%e100%) specific for the detection of tumor versus normal lung on solid samples, whereas FNA specimens yielded a sensitivity of 91% (95% CI, 72%e99%) and a specificity of 94% (95% CI, 70%e100%). This study supports the hypothesis that the gene-ratio approach reliably distinguishes normal lung from cancerous tissues in FNA samples and can be optimized to diagnose benign nodules.
We compared the effectiveness of epithelial membrane antigen (EMA) with 2 newly described markers... more We compared the effectiveness of epithelial membrane antigen (EMA) with 2 newly described markers, X-linked inhibitor of apoptosis protein (XIAP) and an isoform of glucose transporter (GLUT-1), in the distinction between malignant mesothelioma (MM) and benign effusion (BE) in body cavity fluids. Immunohistochemical studies were performed on cell block sections from 35 cases of histologically confirmed MM and 38 BEs, using antibodies to EMA, XIAP, GLUT-1 (GLUT-1m, monoclonal; GLUT-1p, polyclonal). Results were graded based on the percentage of cells staining: negative (0%), 1+ (<25%), 2+ (25%–49%), 3+ (50%–74%), and 4+ (75%–100%). The performance of each marker was compared using receiver operating characteristic curve analysis. EMA demonstrated the best accuracy, with an area under the curve of 0.91 as compared with XIAP (0.67), GLUT-1m (0.74), and GLUT-1p (0.80). Based on these findings, EMA is a better marker than XIAP or GLUT-1 for the diagnosis of MM.
meeting was accompanied by a permanent informational web-site and several on-line discussions bet... more meeting was accompanied by a permanent informational web-site and several on-line discussions between May 1 and De-cember 15, 2007
The Journal of clinical endocrinology and metabolism, Dec 1, 2017
Thyroid nodule growth was once considered concerning for malignancy, but data showing that benign... more Thyroid nodule growth was once considered concerning for malignancy, but data showing that benign nodules grow questioned the use of this paradigm. To date, however, no studies have adequately evaluated whether growth rates differ in malignant vs. benign nodules. To sonographically evaluate growth rates in benign and malignant thyroid nodules ≥1 cm. Prospective, cohort study of patients with tissue diagnosis of benign or malignant disease, with repeated ultrasound evaluation six or more months apart. Growth rate in largest dimension of malignant compared with benign thyroid nodules. Regression models were used to evaluate predictors of growth. Malignant nodules (126) met inclusion criteria (≥6-month nonoperative followup) and were compared with 1363 benign nodules. Malignant nodules were not found to be uniquely selected or prospectively observed solely for low-risk phenotype. Median ultrasound intervals were similar (21.8 months for benign nodules; 20.9 months for malignant nodules...
Thyroid nodules with atypia of undetermined significance (AUS) on fine-needle aspiration (FNA) ha... more Thyroid nodules with atypia of undetermined significance (AUS) on fine-needle aspiration (FNA) have a low risk of malignancy that appears to vary based on specific features described in the AUS diagnosis. The Afirma gene expression classifier (GEC) is a molecular test designed to improve preoperative risk stratification of thyroid nodules, but its performance for different patterns of AUS has not been defined. The objective of this study was to assess GEC results and clinical outcomes in AUS nodules with architectural atypia (AUS-A), cytologic atypia (AUS-C) or both (AUS-C/A). This was a retrospective review of all thyroid nodules with AUS cytopathology that underwent GEC testing at the authors' institution over a period of >4 years. In 227 nodules that had AUS cytology results and Afirma GEC testing, the rate of benign GEC results was higher in AUS-A nodules (70 of 107; 65%) than in AUS-C/A nodules (25 of 65; 38%; P = .0008), and AUS-C nodules exhibited an intermediate rate ...
Thyroid : official journal of the American Thyroid Association, 2016
The term noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) has... more The term noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) has been proposed to replace noninvasive follicular variant of papillary thyroid carcinoma (FVPTC) in recognition of the indolent behavior of this tumor. The ability to differentiate NIFTP from classical papillary thyroid carcinoma (cPTC) by fine-needle aspiration (FNA) would facilitate conservative management for NIFTP. The aim of this study was to determine if NIFTP can be distinguished prospectively from cPTC. From June 2015 to January 2016, thyroid FNAs with a diagnosis of "malignant" or "suspicious for malignancy" were prospectively scored for features associated with NIFTP/FVPTC (microfollicular architecture) or cPTC (papillae, psammomatous calcifications, sheet-like architecture, and nuclear pseudoinclusions) and categorized as NIFTP/FVPTC, cPTC, or indeterminate. Results were correlated with subsequent histologic diagnoses. The study included 52 patients with 56 ...
The Journal of clinical endocrinology and metabolism, Jan 30, 2016
Mutations in the BRAF and RAS oncogenes are responsible for most well-differentiated thyroid canc... more Mutations in the BRAF and RAS oncogenes are responsible for most well-differentiated thyroid cancer. Yet, our clinical understanding of how BRAF-positive and RAS-positive thyroid cancers differ is incomplete. We correlated clinical, radiographic, and pathologic findings from patients with thyroid cancer harboring a BRAF or RAS mutation. Prospective cohort study Setting: Academic, tertiary care hospital Patients: 101 consecutive patients with well-differentiated thyroid cancer Main Outcome Measure: We compared the clinical, sonographic, and pathologic characteristics of patients with BRAF-positive cancer to those with RAS-positive cancer. Of 101 patients harboring these mutations, 71 were BRAF-positive, while 30 were RAS-positive. Upon sonographic evaluation, RAS-positive nodules were significantly larger (p=0.04), though BRAF-positive nodules were more likely to harbor concerning sonographic characteristics [hypoechogenicity (p<0.001); irregular margins (p=0.04)]. Cytologically, ...
Background: It is now recognized that noninvasive follicular variant of papillary thyroid carcino... more Background: It is now recognized that noninvasive follicular variant of papillary thyroid carcinoma (NFVPTC) is a distinct subset of FVPTC with an exceedingly indolent clinical course. The Afirma gene-expression classifier (GEC) helps guide clinicians in the management of thyroid nodules with indeterminate fine-needle aspiration (FNA) results. Thyroid surgery is recommended for nodules with a suspicious Afirma result, whereas observation is deemed reasonable for most nodules with a benign result. The aim of this study was to confirm that the Afirma test detects NFVPTCs and to determine how many carcinomas detected by the Afirma GEC represent NFVPTCs. Methods: From a database of 249 FNAs sent for Afirma testing between January 2012 and October 2014, a search was conducted for cases with a preceding FNA diagnosis of atypia/follicular lesion of undetermined significance (AUS/FLUS) or suspicious for a follicular neoplasm (SFN), a suspicious Afirma result, and a corresponding resection specimen reviewed at Brigham and Women's Hospital. The diagnoses of the prior FNAs and subsequent resection specimens were recorded. Slides for all resection specimens with a diagnosis of FVPTC were reviewed to identify NFVPTCs. Results: Sixty-three cases met the inclusion criteria. The preceding FNA diagnosis was AUS/FLUS in 34 (54%) cases and SFN in 29 (46%) cases. The surgical resection specimen demonstrated 16 (25%) FVPTCs, five (8%) follicular thyroid carcinomas, one (2%) classical type PTC, and 41 (65%) benign tumors/nodules. Of the 16 FVPTCs, 14 (88%) were NFVPTCs. Thus, NFVPTCs accounted for 64% of the carcinomas in the cohort. Conclusion: These results indicate that the Afirma GEC detects NFVPTCs and that many of the carcinomas detected by Afirma are NFVPTCs. While all care should be individualized and include clinical and sonographic assessment, these results suggest lobectomy as opposed to total thyroidectomy should be considered for nodules with a preceding AUS/FLUS or SFN on cytology and a suspicious Afirma result.
Background: Since its inception, the Bethesda System for Reporting Thyroid Cytopathology (TBS) ha... more Background: Since its inception, the Bethesda System for Reporting Thyroid Cytopathology (TBS) has been widely adopted. Each category conveys a risk of malignancy and recommended next steps, though it is unclear if each category also predicts the type and extent of malignancy. If so, this would greatly expand the utility of the TBS by providing prognostic information in addition to baseline cancer risk. Methods: All patients prospectively enrolled into the authors' thyroid nodule database from 1995 to 2013 with histologically proven malignancy were analyzed. The primary ultrasound-guided fine-needle aspiration cytology (AUS, atypia of unknown significance; FN, follicular neoplasm; SUSP, suspicious; M, malignant) was correlated with the type of thyroid cancer and histological features known to impact prognosis and recurrence, including lymph node metastasis (LNM), lymphovascular invasion, and extrathyroidal extension (ETE). Primary cytology was separately correlated with higher risk malignancy. Results: A total of 1291 malignancies were identified, with primary cytology AUS in 130 cases, FN in 241 cases, SUSP in 411 cases, and M in 509 cases. AUS, SUSP, and M cytology were progressively associated with an increasing risk of high-risk disease (p < 0.001), LNM (p < 0.001), ETE (p < 0.001), and margin positivity (p < 0.001). Notably, 71% of malignancies with AUS cytology were follicular variants of papillary thyroid cancer compared with 63% with SUSP cytology and only 20% with M cytology. In contrast, high-risk malignancies were diagnosed in only 4% with AUS cytology, but 9% and 27% with SUSP and M cytology, respectively. FN conveyed a significantly increased risk of follicular thyroid carcinoma compared with all other types (28% vs. 2%; p < 0.001). A composite endpoint of recurrence, distant metastases, and death similarly increased as cytology progressed from AUS to SUSP to M (p < 0.001). Conclusion: In addition to predicting cancer prevalence, the TBS also imparts important prognostic information about cancer type, variant, and risk of recurrence. These data extend the utility of TBS classification by fostering an improved understanding of the risk posed by any confirmed malignancy.
Background: Increased recognition of the indolent nature of noninvasive follicular variant of pap... more Background: Increased recognition of the indolent nature of noninvasive follicular variant of papillary thyroid carcinoma (NFVPTC) along with greater insight into the molecular alterations of these tumors has prompted endocrine pathologists to question whether these tumors warrant a diagnosis of carcinoma. However, a change in terminology would affect the rates of malignancy of fine-needle aspiration (FNA) diagnostic categories. Therefore, the aim of this study was to determine the percentage decrease in associated risk of malignancy for each FNA diagnostic category if NFVPTCs were no longer termed carcinomas. Methods: We evaluated a cohort of 655 FNAs with subsequent resection specimens over a 22-month time period. The diagnoses of the preceding FNAs were recorded according to the Bethesda System for Reporting Thyroid Cytopathology. For cases with more than one preceding FNA, the FNA diagnosis associated with the highest risk of malignancy was identified. Slides for all resection specimens with a diagnosis of FVPTC were reviewed to identify noninvasive tumors. By definition, all of these tumors were encapsulated, partially encapsulated, or well circumscribed and lacked any indication of infiltrative growth, capsular penetration, or lymphovascular invasion. Results: Our cohort of 655 FNAs with subsequent resection specimens included 53 (8.1%) nondiagnostic (ND), 167 (25.5%) benign, 97 (14.8%) atypia/follicular lesion of undetermined significance (AUS/FLUS), 88 (13.4%) suspicious for follicular neoplasm (SFN), 94 (14.4%) suspicious for malignancy (SUS), and 156 (23.8%) malignant cases (POS). Surgical resections demonstrated benign findings in 309 (47.2%) and malignant tumors in 346 (52.8%), including 85 NFVPTCs accounting for 24.6% of malignancies. Our rates of malignancy for ND, benign, AUS/FLUS, SFN, SUS, and POS were 18.9%, 13.2%, 39.2%, 45.5%, 87.2%, and 98.7%, respectively. If NFVPTC were no longer termed carcinoma, these rates would drop to 17.0% (10% decrease), 5.4% (59% decrease), 21.6% (45% decrease), 37.5% (18% decrease), 45.7% (48% decrease), and 93.6% (5% decrease), respectively. Conclusion: Our findings demonstrate that if terminology were changed and NFVPTCs were not considered carcinomas, the rates of malignancy for FNA diagnostic categories would be substantially decreased, with the most clinically significant decrease seen in the SUS category, which demonstrated a relative decrease of nearly 50%.
Percutaneous fine-needle aspiration (FNA) cytology is an important diagnostic test for the evalua... more Percutaneous fine-needle aspiration (FNA) cytology is an important diagnostic test for the evaluation and management of selected renal masses. Cytogenetic analysis of cytology specimens can serve as an adjunct for precise classification because certain tumors are associated with specific chromosomal aberrations. This study summarizes our experience with the application of conventional cytogenetics and fluorescence in situ hybridization (FISH) to renal FNA specimens. All percutaneous renal FNAs performed during 2005 through 2008 were identified from the electronic pathology database. Results of cytogenetic and FISH analyses were correlated with the final diagnoses of the renal FNAs. A total of 303 renal FNAs were performed. During an onsite assessment, a portion of the cytology specimen was allocated for cytogenetic analysis in 74 cases. Karyotypic analysis or FISH was successful in 44 (59%) of these. Characteristic chromosomal abnormalities were observed in 27 cases. In 17 cases, a ...
Specific inhibitors can be designed to inactivate the molecular pathways involved in tumor growth... more Specific inhibitors can be designed to inactivate the molecular pathways involved in tumor growth. A compelling example is the use of small molecule drugs, such as imatinib (Gleevec), which inhibit the KIT tyrosine kinase in gastrointestinal stromal tumors (GIST). Assays are needed to determine which inhibitor is most effective at silencing the KIT kinase in each GIST patient. The aim of this study was to develop a robust, cytology-based assay to measure tumor susceptibility to target-specific small molecule inhibitors. We created an immortal GIST cell line (GIST882) that was treated in vitro with several inhibitors of the KIT-AKT-mTOR-S6 signaling pathway. KIT was inhibited with imatinib, and mTOR with RAD001. Treatment response was assessed in cytologic preparations by immunocytochemical staining with antibodies to KIT, phospho-KIT, phospho-AKT, and phospho-S6. Optimization was performed to maximize staining in the absence of inhibitor, and minimize staining in the presence of inhibitor. GIST882 cells demonstrated strong, robust phospho-S6 expression in the absence of inhibitor. This expression was completely inhibited by treatment with upstream signaling pathway inhibitors (imatinib and RAD001). Other phospho-specific antibodies had weaker baseline reactivity in the absence of inhibitor. The accuracy of the immunocytochemical results on the cytologic preparations was validated by immunoblotting studies. Our study demonstrates the feasibility of cytologic methods to monitor labile biochemical responses in tumor cells during drug therapy. Such approaches will be enhanced by the development of additional activation state-specific antibodies, particularly those optimized for use in cytologic preparations.
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Papers by Edmund Cibas