Indeterminate Diagnosis Research Articles

Elevations of novel cytokines in bacterial meningitis in infants.

BackgroundBacterial meningitis is challenging to diagnose in infants, especially in the common setting of antibiotic pre-treatment, which diminishes yield of cerebrospinal fluid (CSF) cultures. Prior studies of diagnostic markers have not demonstrated sufficient accuracy. Interleukin-23 (IL-23), interleukin-18 (IL-18) and soluble receptor for advanced glycation end products (sRAGE) possess biologic plausibility, and may be useful as diagnostic markers in bacterial meningitis.MethodsIn a prospective cohort study, we measured IL-23, IL-18 and sRAGE levels in CSF. We compared differences between infected and non-infected infants, and conducted receiver operating characteristic (ROC) analyses to identify individual markers and combinations of markers with the best diagnostic accuracy.Results189 infants <6 months, including 8 with bacterial meningitis, 30 without meningitis, and 151 with indeterminate diagnosis (due to antibiotic pretreatment) were included. CSF IL-23, IL-18 and sRAGE levels were significantly elevated in infants with culture proven meningitis. Among individual markers, IL-23 possessed the greatest accuracy for diagnosis of bacterial meningitis (area under the curve (AUC) 0.9698). The combination of all three markers had an AUC of 1.ConclusionsIL-23, alone and in combination with IL-18 and sRAGE, identified bacterial meningitis with excellent accuracy. Following validation, these markers could aid clinicians in diagnosis of bacterial meningitis and decision-making regarding prolongation of antibiotic therapy.

Performance of Roche cobas high-risk human papillomavirus (hrHPV) testing in the two most common liquid-based Papanicolaou test platforms

High-risk human papillomavirus (hrHPV) testing is important in cervical cancer screening and management algorithms. Roche (Pleasanton, Calif.) cobas hrHPV testing is commonly performed on both ThinPrep (TP) and SurePath (SP) samples, but performance of these platforms has not been fully investigated in the literature. Roche hrHPV testing was performed on 47,885 (TP = 18,295; SP = 29,590) out of 130,648 consecutive Papanicolaou tests, over 16 months; 1895 of those had interpretable biopsies. The overall hrHPV detection rates were similar in TP (13.5%) and SP (13.1%). The hrHPV positive rate was higher in SP (8.5%) than TP (7.3%, P < 0.0001) in women with negative cytology; the difference in other cytologic diagnosis categories was insignificant. TP samples had significantly fewer negative cytology diagnoses (7.3% versus 8.5%, P < 0.0001), more low-grade abnormalities in cytology and biopsies, and higher colposcopy referral rate (4.8% versus 2.7%, P < 0.0001) than SP. There were no differences between TP and SP in detecting ≥HSIL by hrHPV testing, cytology or biopsy. SP samples had a significantly higher rate of HPV 16/18 but a lower rate of non-16/18 hrHPV genotypes than TP. Roche cobas hrHPV testing was similar in both TP and SP platforms. The significantly lower hrHPV detection rate in cytological negative TP samples is likely related to higher cytology reporting rates for indeterminate and low-grade diagnoses in TP than SP samples. Significant differences were also observed in hrHPV genotyping results between TP and SP. Clinical risk stratification based on hrHPV testing may need to take testing platforms into consideration.

A Novel Host-protein Assay Accurately Distinguishes Bacterial From Viral Upper Respiratory Tract Infections

BackgroundBacterial and viral infections are often clinically indistinguishable, particularly in upper respiratory tract infections (URTI), which leads to antibiotic misuse. A novel assay (ImmunoXpert™) that integrates measurements of three host-response proteins (TRAIL, IP-10, CRP) was recently developed to assist in differentiation between bacterial and viral etiologies. We evaluated the assay performance in URTI patients and compared it with standard laboratory measures.MethodsWe performed a sub-analysis of 464 patients with clinical suspicion of URTI enrolled in three previously conducted multi-center clinical studies that evaluated the assay performance in patients with acute infections: ‘Curiosity’ study (NCT01917461), ‘Opportunity’ study (NCT01931254), and ‘Pathfinder’ study (NCT01911143). Comparator method was predetermined criteria combined with expert panel adjudication, which was blinded to the test results. Diagnostic performance was evaluated by comparing test and comparator method outcomes.ResultsA unanimous panel adjudication was attained for 61 bacterial (13%) and 241 viral (52%) patients (162 patients (35%) had an indeterminate diagnosis). The assay distinguished between bacterial and viral infected patients with a sensitivity of 92% (95% CI: 82%- 98%) and specificity of 93% (88%-96%) with 11% equivocal test results. Overall the assay outperformed other routine laboratory tests (FIG 1), including: white blood cell count (WBC; cutoff 15,000 cells/µL, sensitivity 48% (35%-60%), P < 10-−6; specificity 85% (80%-90%), P < 0.05); CRP (cutoff 40 mg/L, sensitivity 82% (72%–92%), P = 0.16, specificity 79% (74%–84%), P < 10-4); Procalcitonin (PCT; cutoff 0.5 ng/mL, sensitivity 22% (11%–32%), P < 10–14, specificity 80% (74%–85%), P < 0.001); absolute neutrophil count (ANC; cutoff 10,000 cells/µL, sensitivity 58% (45%–71%), P < 10-−4, specificity 94% (91%–97%), P = 0.7).ConclusionThe novel assay demonstrated superior performance compared with routine laboratory tests (WBC, ANC) and biomarkers (CRP, PCT), in distinguishing bacterial from viral etiologies in patients with URTI. It has the potential to help clinicians avoid missing bacterial infections or prescribing unwarranted antibiotics for viral URTIs.Disclosures K. Oved, MeMed Diagnostics: Board Member, Employee and Shareholder, Salary E. Eden, MeMed Diagnostics: Board Member, Employee and Shareholder, Salary T. Gottlieb, MeMed Diagnostics: Employee, Salary R. Navon, MeMed Diagnostics: Employee, Salary A. Cohen, MeMed Diagnostics: Employee, Salary O. Boico, MeMed Diagnostics: Employee, Salary M. Paz, MeMed Diagnostics: Employee, Salary L. Etshtein, MeMed Diagnostics: Employee, Salary G. Kronenfeld, MeMed Diagnostics: Employee, Salary T. Friedman, MeMed Diagnostics: Employee, Salary E. Bamberger, MeMed Diagnostics: Employee, Salary I. Chistyakov, MeMed Diagnostics: Consultant, Consulting fee I. Potasman, MeMed Diagnostics: Holding stock options, stock options

Suggesting the cytologic diagnosis of noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP): A retrospective analysis of atypical and suspicious nodules.

The term "noninvasive follicular thyroid neoplasm with papillary-like nuclear features" (NIFTP) has replaced a subset of follicular variant of papillary thyroid carcinoma due to the indolent behavior of such tumors. NIFTPs are most often classified in an "indeterminate" diagnostic category. In the current study, the authors sought to identify cytologic features helpful in distinguishing NIFTP from other entities in these categories, particularly benign nodules. The authors retrospectively evaluated a consecutive cohort of 130 thyroid fine-needle aspiration (FNA) specimens with an indeterminate diagnosis and available histopathologic follow-up. All FNA specimens were evaluated using the ThinPrep method. Each FNA was blindly reviewed by 2 board-certified cytopathologists, who assessed overall cellularity; architectural parameters; and nuclear features, including nuclear pallor and fine chromatin, distinct nucleoli, and irregular nuclear membranes. Each case received a score of 0 to 3, based on the presence or absence of these 3 nuclear features. Nuclear but not architectural features appeared to distinguish NIFTP from benign nodules. Ninety-one percent of the NIFTPs (32 of 35 NIFTPs) received a score of ≥2, compared with 35% of benign nodules (23 of 66 benign nodules) (P<.0001). In contrast, NIFTP could not be differentiated from the invasive/infiltrative follicular variant of papillary thyroid carcinoma using these criteria (P = 1.000). Nuclear scoring was found to be especially useful in atypia of undetermined significance/follicular lesion of undetermined significance (AUS); a score ≥2 enriched for NIFTP (39% vs 3% of AUS cases with a score <2), whereas a score <2 was more likely benign (85% vs 50% of AUS cases with a score ≥2). In indeterminate FNA specimens, the distinction of a possible NIFTP from a benign thyroid nodule can be suggested using a simple nuclear scoring system that is most valuable in AUS aspirates. Cancer Cytopathol 2018;126:86-93. © 2017 American Cancer Society.

Utilization of Direct Smears of Thyroid Fine-needle Aspirates for Ancillary Molecular Testing: A Comparison of Two Proprietary Testing Platforms

Background Ancillary molecular testing has been recommended for thyroid fine-needle aspirates (FNA) with indeterminate cytologic diagnoses. Rosetta Genomics and Interpace Diagnostics have developed assays that can utilize direct smears as the testing substrate. Methods A retrospective study of indeterminate thyroid FNAs with known histologic follow-up was performed. One Diff-Quik-stained smear and one Papanicolaou-stained smear with similar cellularity (at least 60-100 lesional cells) from each case were sent to Rosetta and Interpace, respectively, for analysis. The results were directly compared and correlated with the final histopathology. Neither company was aware of the follow-up histologic findings in these cases. Results A total of 10 thyroid FNAs were identified from our 2015 files. The cytologic diagnoses included follicular lesion of undetermined significance (FLUS, n = 5), follicular neoplasm/suspicious for follicular neoplasm (FN/SFN, n = 4), and suspicious for malignancy (SM, n = 1). Of the seven cases with benign histology, six smears were classified as benign by the RosettaGX microRNA classifier, and one case was designated as suspicious. Five cases were negative by both ThyGenX oncogene panel and ThyraMIR microRNA classifier. One case was negative by ThyGenX and positive on follow-up ThyraMIR, and one case was positive for KRAS mutation and positive on ThyraMIR. Both the RosettaGX and ThyGenX/ThyraMIR tests demonstrated positive results for the three histologically malignant cases. Conclusion This study demonstrates that two molecular testing platforms performed equally well using our stained direct smears. Both molecular tests revealed a 100% negative predictive rate. RosettaGX showed a 75% positive predictive value in comparison to 60% for ThyGenX/ThyraMIR.

Trends in diagnoses after implementation of the Chicago classification for esophageal motility disorders (V3.0) for high-resolution manometry studies

To determine trends in the diagnostic distribution of esophageal motility disorders after implementation of the Chicago Classification Version 3.0 (CC V3.0) for interpretation of high-resolution manometry (HRM) studies compared to non-Chicago Classification criteria. Retrospective trends analysis of patients with an HRM study conducted at a single center from January 1, 2013 to September 30, 2015. The implementation of the CC V3.0 for manometry interpretation occurred in September 2014. Patient charts were manually reviewed for data collection including demographics and HRM diagnoses. The prevalence and relative risks (RR) of CC V3.0 diagnostic categories (i.e. normal, indeterminate, achalasia, and EGJ outflow obstruction [EJGOO], and major and minor motility disorders) were calculated before and after CC V3.0 implementation. Four hundred sixty-five HRM studies were included in the study including 268 before and 179 after CC V3.0 implementation. The mean ± SD age was 54±15.4 years and 59.8% were female (n =278). The percentage with indeterminate diagnosis decreased from 35.3% before CC V3.0 implementation to 16.8% after implementation (adjusted RR 0.5, 95%CI 0.30-0.70, p <0.001). The percentage with a major motility disorders decreased from 13.9% to 7.3% (adjusted RR 0.5, 95%CI 0.2-1.0, p <0.001). The percentage with EJGOO and minor diagnoses increased from 1.4% to 14.5% and 11.9% to 22.9%, respectively. The percentage with achalasia and normal diagnosis did not change over the study period. Implementation of CCV3.0 was associated with changes in the distribution of esophageal motility diagnoses in clinical practice. The percentage of indeterminate and major diagnosis decreased and EGJOO and minor diagnoses increased. The decrease in the number of indeterminate studies suggests that the CC V3.0 may clarify the criteria for the interpreting physician. The increase in studies with a diagnosis of EGJ outflow obstruction may reflect the heterogeneity of disorders with clinically relevant outflow obstruction.

Wilms tumor screening in diffuse capillary malformation with overgrowth and macrocephaly–capillary malformation: A retrospective study

CLOVES (congenital lipomatous overgrowth, vascular malformations, epidermal nevi, and skeletal anomalies) syndrome is associated with regional bony and/or soft tissue overgrowth, capillary malformation, and an increased risk for Wilms tumor. To evaluate the frequency of Wilms tumor in patients with 2 similar conditions: diffuse capillary malformation with overgrowth (DCMO) and macrocephaly-capillary malformation (M-CM). Culling our Vascular Anomalies Center database, we retrospectively reviewed patients in whom DCMO and M-CM had been diagnosed and who were evaluated between 1998 and 2016 for possible development of Wilms tumor. Patients younger than 8years of age at their last visit and not seen in more than 2years were contacted for follow-up. The study comprised 89 patients: 67 with DCMO, 17 with M-CM, and 5 with an indeterminate diagnosis. No case of Wilms tumor was found in these groups. Some patients were younger than 8years of age at last follow-up visit and the sample size was small. Patients with DCMO do not appear to be at increased risk for Wilms tumor. Screening is probably unnecessary in DCMO unless there is associated hemihypertrophy. Although there were no cases in our cohort, there are 2 reports of M-CM associated with Wilms tumor in the literature.

The Morphologic Profile of Inflammatory Bowel Disease and the Diagnostic Problem of Crohn’s Disease versus TB Colitis– A Case Series

The aim of this study is to describe the morphologic profile of the biopsy and resection specimen that were diagnosed with Crohn’s disease and ulcerative colitis in the University of the East Ramon Magsaysay Memorial Medical Center (UERMMMC) from 2008-2016. Features that classify the specimen as Inflammatory Bowel Disease – Indeterminate Type are also presented. Considerations for the definitive IBD classification after an initial indeterminate diagnosis by morphology are also briefly discussed. Biopsy and resection specimen that were diagnosed with Crohn’s disease, cannot exclude TB Colitis, are also presented; and the subsequent steps for a definitive classification are also discussed. All the patients included underwent an endoscopic biopsy, and are categorized by histopathologic diagnoses, age, sex, and GIT segment involved in the endoscopic procedure. Patients that underwent subsequent resection due to the disease condition are also identified. Comparison of the histologic findings observed in the patients, with the microscopic basis for the diagnosis recommended by the European consensus on the histopathology of inflammatory bowel disease (2013), and with the histologic features described by Patil et al. (2015) for the inflammatory disorders of the large intestine, is done. The histologic features described by Lamps (2015) for the gastrointestinal TB is used in the evaluation of the findings in the patients diagnosed with Crohn’s disease, cannot exclude TB Colitis. There are 5 Crohn’s disease patients, accounting for 0.8% of all patients with lower GIT inflammatory conditions, and 10 ulcerative colitis patients, accounting for 1.6% of all patients with lower GIT inflammatory conditions. Seven patients, which comprise 1.1% of all patients with lower GIT inflammatory conditions, have the diagnosis of indeterminate colitis. The histologic features of 6 out of 7 patients that had the initial diagnosis of indeterminate colitis presented with morphologic features that favored an ulcerative colitis, but with Crohn’s disease features. In comparison, one patient who had an initial diagnosis of indeterminate colitis presented with morphologic features that favored Crohn’s disease but with ulcerative colitis features. In these patients, correlation with chronology of symptoms and associated ancillary procedures that can classify the patients as CD or UC are recommended to the gastroenterologist attending such patients so that a more definitive classification can be done. Four patients, accounting for 0.6% of all lower GIT inflammatory conditions, were initially diagnosed as Crohn’s disease, cannot exclude TB Colitis. This is in contrast with 34 patients who were diagnosed with diagnosed with Chronic Granulomatous Inflammation, Tuberculosis which accounted for 5.7% of all patients that were diagnosed with inflammatory conditions of the lower GIT. The remaining 536 patients were composed of acute self-limited/infectious colitis, ischemic colitis, eosinophilic colitis, inflammatory polyp, and nonspecific inflammation. With the trend of increasing incidence of Inflammatory Bowel Disease in Asia, comparison of the more commonly seen causes of chronic inflammation of the gastrointestinal tract with a condition that appears to have a growing incidence in the region is necessary for optimal diagnostic protocol, management, and quality of care.

Prospective comparison of gadoxetic acid-enhanced liver MRI and contrast-enhanced CT with histopathological correlation for preoperative detection of colorectal liver metastases following chemotherapy and potential impact on surgical plan

ObjectiveTo prospectively compare the diagnostic performance of gadoxetic acid-enhanced MRI (EOB-MRI) and contrast-enhanced CT (CECT) for preoperative detection of colorectal liver metastases (CRLM) following chemotherapy and to evaluate the potential change in the hepatic resection plan. Methods51 patients with CRLM treated with preoperative chemotherapy underwent liver imaging by EOB-MRI and CECT prospectively. Two independent blinded readers characterized hepatic lesions on each imaging modality using a 5-point scoring system. 41 patients underwent hepatic resection and histopathological evaluation. Results151 CRLM were confirmed by histology. EOB-MRI, compared to CECT, had significantly higher sensitivity in detection of CRLM ≤1.0 cm (86% vs. 45.5%; p < 0.001), significantly lower indeterminate lesions diagnosis (7% vs. 33%; p < 0.001) and significantly higher interobserver concordance rate in characterizing the lesions ≤1.0 cm (72% vs. 51%; p = 0.041). The higher yield of EOB-MRI could have changed the surgical plan in 45% of patients. ConclusionFollowing preoperative chemotherapy, EOB-MRI is superior to CECT in detection of small CRLM (≤1 cm) with significantly higher sensitivity and diagnostic confidence and interobserver concordance in lesion characterization. This improved diagnostic performance can alter the surgical plan in almost half of patients scheduled for liver resection.

The contemporary utility of intraoperative frozen sections in thyroid surgery

PurposeTo determine the accuracy of intraoperative frozen section analysis on thyroidectomy specimens stratified by the Bethesda classification scheme and its utility for intraoperative decision-making. Study designRetrospective chart review. MethodsA retrospective review was performed on all patients who underwent thyroidectomy or thyroid lobectomy with intraoperative frozen sections at a tertiary care academic center from 2009 to 2015. ResultsThere were 74 total patients who underwent partial or total thyroidectomy with intraoperative frozen section analysis of a thyroid nodule whom had previously undergone a thyroid fine needle aspiration of the nodule. The sensitivity, specificity, positive predictive value, and negative predictive value for a thyroid frozen section with respect to its prediction for malignancy was 81%, 95%, 98%, and 66%, respectively, with a diagnostic accuracy of 85%. For 37 patients with an indeterminate cytologic diagnosis on fine needle aspiration (Bethesda categories III–V), the sensitivity, specificity, positive predictive value, and negative predictive value for a thyroid frozen section was 81%, 91%, 95%, and 67%, respectively, with a diagnostic accuracy of 84%. False positives and false negatives resulted in 1 completion thyroidectomy for benign pathology and 3 reoperations for malignancy not discovered on frozen section. ConclusionWhile intraoperative frozen sections on thyroid specimens may be helpful if positive, the false negative rate remains high. There appears to be limited value in routine frozen sections to guide clinical management and decision-making in the era of the Bethesda system.

Galectin-1 is a diagnostic marker involved in thyroid cancer progression.

Fine-needle aspiration (FNA) is the most commonly used pre-operative technique for diagnosis of malignant thyroid tumor. However, many benign lesions, with indeterminate diagnosis following FNA, are referred to surgery. Based on multifunctionality of the endogenous galectin-1, we aimed to assess its status for early diagnosis of thyroid cancer. Immunohistochemistry for galectin-1 and -3 was performed on a clinical series of 69 cases of thyroid lesions. Galectin-1 expression was further examined in two additional tissue microarrays (TMA) composed of 66 follicular adenomas and 66 papillary carcinomas in comparison to galectin-3 and cytokeratin-19 (CK19). In addition, a knockdown of galectin-1 in papillary (TPC-1) and anaplastic (8505C) thyroid cancer cell lines was achieved by lentiviral transduction for in vitro experiments. A murine orthotopic thyroid cancer model was used to investigate tumor growth and metastatic ability. Immunohistochemical analyses of galectin-1 and -3 in the series of 69 cases of thyroid lesions revealed that galectin-1 was completely absent in the epithelial compartment of all benign thyroid lesions. Levels of both galectins significantly increased in the cytoplasmic compartment of malignant thyroid cells. Galectin-1 expression in the TMA yielded an excellent specificity (97%), while galectin-3 and CK19 presented a higher sensitivity (>97%) in discriminating benign from malignant thyroid lesions. In vitro experiments revealed that migration was negatively affected in TPC-1 galectin-1 knockdown (KD) cells, and that proliferation and invasion capacity of 8505C cells decreased after galectin-1 KD. Moreover, an orthotopic mouse model displayed a lower rate of tumor development with galectin-1 KD thyroid anaplastic cancer cells than in the control. Our findings support the introduction of galectin-1 as a reliable diagnostic marker for thyroid carcinomas. Its involvement in cell proliferation, migration, invasion and tumor growth also intimate functional involvement of galectin-1 in the progression of thyroid carcinoma, suggesting its potential as a therapeutic target.

Fine-needle aspirates of thyroid microcarcinoma

Widespread use of ultrasound allows for detection of smaller thyroid nodules and preoperative evaluation with fine-needle aspiration (FNA). Both incidental and non-incidental microcarcinoma can be found, leading to uncertainty with clinical management. A retrospective analysis of thyroid FNAs performed at our institution was conducted for the 5-year period from 2010 to 2014. Aspirates were categorized using the Bethesda System for Reporting Thyroid Cytopathology. Cytologic diagnoses were then correlated with final histopathology. Among samples with malignancy on surgical resection, nodules were stratified by size. A total of 2531 thyroid FNAs were identified; 587 samples had histologic correlation, and 259 malignancies were reported. They were separated into nodules >1 cm (n = 144, 56%) and ≤1 cm (n = 115, 44%). Microcarcinoma was further subdivided into incidental (size ≤0.5 cm, n = 55, 48%) and non-incidental (size >0.5 cm and ≤1 cm, n = 60, 52%). The preoperative cytologic diagnoses for incidental microcarcinoma were: benign (B, n = 11, 20%), follicular lesion of undetermined significance (FLUS, n = 15, 27%), follicular neoplasm (FN, n = 11, 20%), suspicious for malignancy (SM, n = 7, 13%), malignant (M, n = 8, 15%), and nondiagnostic (ND, n = 3, 5%). The FNA categories for non-incidental microcarcinoma were: B (n = 13, 22%), FLUS (n = 3, 5%), FN (n = 3, 5%), SM (n = 10, 17%), M (n = 29, 48%), and ND (n = 2, 3%). Incidental microcarcinoma is not an uncommon entity, making up 21% (55 of 259) of malignant nodules on thyroidectomy. Indeterminate diagnoses (FLUS + FN + SM) accounted for the majority (60%) of preoperative FNAs for incidental microcarcinoma, compared with 27% for those of non-incidental microcarcinoma (P < 0.05, χ2 test).

Urinary tract washing specimens containing atypical urothelial tissue fragments are significantly associated with urothelial neoplasia.

We previously found that the presence of atypical urothelial tissue fragments (AUTF) was associated with an increased risk of high-grade urothelial carcinoma (HGUC) but not low-grade urothelial neoplasia (LGUN) in voided urine (VU) specimens. However, we subsequently found that patients with LGUN were more likely to have cytologic atypia in urinary washing (UW) specimens, suggesting that cytologic atypia found in UW specimens might be associated with both LGUN and HGUC. In this study, we retrospectively examined UW specimens containing AUTF to determine whether they were associated with HGUC, LGUN, or both HGUC and LGUN. 1173 UW specimens and any follow up biopsies were identified over a 10-year period and the presence of AUTF was recorded based on the original clinical diagnosis. The presence of AUTF in UW specimens was significantly associated with high-risk indeterminate diagnosis or definitive diagnosis of HGUC (P < .001). In addition, AUTF specimens were significantly associated with a neoplastic diagnosis of low-grade urothelial carcinoma (LGUC) or HGUC on subsequent biopsies when compared to specimens lacking AUTF (P = .047). The overall rate of CIS/HGUC in specimens with AUTF was 33.0 vs. 13.5% for specimens without AUTF (P = .051). Urothelial tissue fragments (UTF) found in UW specimens should be examined for the presence of cytomorphological atypia, as the presence of AUTF almost triples the risk of HGUC. As opposed to what has been found in VU specimens, AUTF in UW specimens is also associated with an increased risk of LGUN.

Next-Generation Sequencing Identifies Gene Mutations That Are Predictive of Malignancy in Residual Needle Rinses Collected From Fine-Needle Aspirations of Thyroid Nodules.

- Thyroid nodules have a prevalence of approximately 70% in adults. Fine-needle aspiration (FNA) is a minimally invasive, cost-effective, standard method to collect tissue from thyroid nodules for cytologic examination. However, approximately 15% of thyroid FNA specimens cannot be unambiguously diagnosed as benign or malignant. - To investigate whether clinically actionable data can be obtained using next-generation sequencing of residual needle rinse material. - A total of 24 residual needle rinse specimens with malignant (n = 6), indeterminate (n = 9), or benign (n = 9) thyroid FNA diagnoses were analyzed in our clinical molecular diagnostics laboratory using next-generation sequencing assays designed to detect gene mutations and translocations that commonly occur in thyroid cancer. Results were correlated with surgical diagnoses and clinical outcomes. - Interpretable data were generated from 23 of 24 residual needle rinse specimens. Consistent with its well-known role in thyroid malignancy, BRAF V600E mutations were detected in 4 malignant cases. An NRAS mutation was detected in 1 benign case. No mutations were detected from specimens with indeterminate diagnoses. - Our data demonstrate that residual thyroid FNA needle rinses are an adequate source of material for molecular diagnostic testing. Importantly, detection of a mutation implicated in thyroid malignancy was predictive of the final surgical diagnosis and clinical outcome. Our strategy to triage thyroid nodules with indeterminate cytology with molecular testing eliminates the need to perform additional FNA passes into dedicated media or to schedule additional invasive procedures. Further investigation with a larger sample size to confirm the clinical utility of our proposed strategy is underway.

The impact of noninvasive follicular thyroid neoplasm with papillary-like nuclear features on the performance of the Afirma gene expression classifier.

A recent revision in thyroid tumor nomenclature has resulted in a change from a malignant diagnosis (noninvasive follicular variant of papillary thyroid carcinoma) to one that is nonmalignant (noninvasive follicular thyroid neoplasm with papillary-like nuclear features [NIFTP]). The objective of the current study was to evaluate the impact of this change on the performance of the Afirma gene expression classifier (GEC). The authors retrospectively analyzed consecutive thyroid fine-needle aspiration specimens with indeterminate diagnoses on which GEC was performed. Surgical pathology material was reviewed with the reclassification of nodules into NIFTP. GEC testing was performed on 384 fine-needle aspiration specimens diagnosed as atypia of undetermined significance (AUS) (304 cases) and suspicious for a follicular neoplasm (SFN) (80 cases) and yielded a suspicious result in 152 of the AUS cases (50%) and 50 of the SFN cases (63%). Thyroidectomy was performed on 177 patients. After reclassifying NIFTP, the positive predictive value of GEC decreased from 42% (95% confidence interval [95% CI], 39%-45%) to 24% (95% CI, 22%-26%) in the AUS group and from 23% (95% CI, 19%-27%) to 13% (95% CI, 9%-18%) in the SFN group. Total thyroidectomy was performed more frequently than a partial thyroidectomy in patients with AUS with a suspicious GEC result compared with pre-GEC controls (68% vs 49%; P = .037). Reclassification of NIFTP significantly decreases the positive predictive value of GEC in indeterminate thyroid nodules. Nevertheless, the majority of patients with indeterminate thyroid nodules with a suspicious GEC result in the study institution have undergone total thyroidectomy. This finding raises concerns over reliance on a suspicious GEC result by clinicians to justify total thyroidectomy. Cancer Cytopathol 2017;125:683-91. © 2017 American Cancer Society.

Intra-institutional second opinion diagnosis can reduce unnecessary surgery for indeterminate thyroid FNA: A preliminary report on 34 cases.

Indeterminate diagnoses are rendered on 15%-30% of thyroid fine-needle aspirates (FNA). Thus, a second diagnostic opinion given by an outside expert pathologist is a common practice that facilitates a more appropriate clinical management. Conversely, the role of an intra-institutional second opinion diagnosis (iSOD), which is usually informally performed in-house, has not been well established. To assess the contribution of iSOD, a retrospective series of 34 thyroid FNA diagnosed as follicular neoplasm/suspicious follicular neoplasm (FN/SFN) with matched histological follow-up and a malignancy rate of 17.6% was selected and independently reviewed by two cytopathologists (CYT1 and 2). Cases with discrepant diagnoses were referred to a third in-house senior cytopathologist for the iSOD. The malignancy rates (MR) obtained after single independent reviews and iSOD were compared. MR obtained after CYT1 and CYT2 re-screening was similar (14.28% and 19.04%, respectively) and did not improve the original MR (17.64%). Conversely, after the iSOD of discrepant diagnoses, the overall malignancy rate increased up to the 27.27%, potentially sparing unnecessary surgical procedures. Intra-institutional second opinion practice for "indeterminate" thyroid FNA avoids unnecessary surgeries and maximises the detection of malignant cases diagnosed as FN/SFN.

496a - Serum IL-2 and IL-8 are Elevated within 4 h after Gluten Ingestion in Celiac Disease (CED) Patients on Gluten-Free Diet (GFD) and Potential to Resolve Indeterminate Diagnoses for Patients on GFD

496a - Serum IL-2 and IL-8 are Elevated within 4 h after Gluten Ingestion in Celiac Disease (CED) Patients on Gluten-Free Diet (GFD) and Potential to Resolve Indeterminate Diagnoses for Patients on GFD

FNA diagnosis of deep-seated lymphoma: an institutional experience

Controversy remains as to whether image-guided fine-needle aspiration (FNA) biopsy coupled with appropriate ancillary techniques has clinical utility in the diagnosis of deep-seated lymphomas. A retrospective search (20 years) was performed to identify FNA cases with a definitive or indeterminate lymphoma diagnosis for deep-seated locations. The FNA diagnosis was compared with corresponding surgical pathology (SP) and clinical follow-up. The application of ancillary tests was also evaluated. A total of 121 cases from 118 patients were recovered. Among 95 of 121 (79%) aspirates that had a definitive lymphoma diagnosis, 50 lacked SP follow-up. Most (82%) represented possible recurrent lymphoma, and thus therapy proceeded based on the FNA results alone. Additionally, 44 of 95 (46%) had an FNA diagnosis concordant with corresponding SP and 1 case was discordant. Of 44 with concordant SP diagnosis, 25 had further lymphoma subtyping that was concordant with SP. There were 26 of 121 (21%) with indeterminate diagnosis on FNAs. Of these, SP confirmed a diagnosis of lymphoma in 81%. Indeterminate cytologic diagnoses were due either to absent/inconclusive flow cytometry (FC) (11 of 21) or Hodgkin lymphoma (10 of 21). Of 121 cases, 93 utilized FC, 53 utilized cell-block immunohistochemical stains, and 29 utilized molecular testing as part of FNA work-up. FNA plays an important role in the diagnosis/clinical management of deep-seated non-Hodgkin B cell lymphoma (NHL), particularly for recurrence. The addition of ancillary techniques, particularly FC, markedly increases NHL diagnostic accuracy and subclassification. Our study is one of the few large series examining the clinical utility of FNA in the setting of deep-seated lymphomas.

Design considerations for identifying breast cancer risk factors in a population-based study in Africa.

Although breast cancer is becoming more prevalent in Africa, few epidemiologic studies have been undertaken and appropriate methodologic approaches remain uncertain. We therefore conducted a population-based case-control study in Accra and Kumasi, Ghana, enrolling 2,202 women with lesions suspicious for breast cancer and 2,161 population controls. Biopsy tissue for cases prior to neoadjuvant therapy (if given), blood, saliva and fecal samples were sought for study subjects. Response rates, risk factor prevalences and odds ratios for established breast cancer risk factors were calculated. A total of 54.5% of the recruited cases were diagnosed with malignancies, 36.0% with benign conditions and 9.5% with indeterminate diagnoses. Response rates to interviews were 99.2% in cases and 91.9% in controls, with the vast majority of interviewed subjects providing saliva (97.9% in cases vs. 98.8% in controls) and blood (91.8% vs. 82.5%) samples; lower proportions (58.1% vs. 46.1%) provided fecal samples. While risk factor prevalences were unique as compared to women in other countries (e.g., less education, higher parity), cancer risk factors resembled patterns identified elsewhere (elevated risks associated with higher levels of education, familial histories of breast cancer, low parity and larger body sizes). Subjects with benign conditions were younger and exhibited higher socioeconomic profiles (e.g., higher education and lower parity) than those with malignancies, suggesting selective referral influences. While further defining breast cancer risk factors in Africa, this study showed that successful population-based interdisciplinary studies of cancer in Africa are possible but require close attention to diagnostic referral biases and standardized and documented approaches for high-quality data collection, including biospecimens.

Diagnostic Accuracy of Fine Needle Aspiration in Thyroid Nodules Arising in Patients with Graves Disease

Objective: Cytopathologic interpretation in Graves disease (GD) is considered challenging due to significant cellular atypia. Study Design: We retrospectively identified 55 fine needle aspirations (FNAs) from 43 patients with GD that subsequently underwent thyroidectomy from 1995 to 2016. Results: There were 5 patients with papillary thyroid carcinoma (PTC) and 4 with follicular adenoma (FA). Of the 5 patients with PTC, FNA was interpreted as PTC in 3, atypia of undetermined significance (AUS) in 1, and adenomatoid nodule (AN) in 1 (with a 0.5-cm incidental microcarcinoma). Of the 4 patients with FA, FNA was interpreted as follicular neoplasm (FN) in 2, AUS in 1, and AN in 1. Of the 46 nonneoplastic nodules, FNA was interpreted as nondiagnostic in 2, benign in 26, AUS in 15, FN in 1, and suspicious for PTC in 2. None was diagnosed as malignant. The sensitivity, specificity, positive predictive value, and negative predictive value of PTC diagnosis in FNA were 60, 100, 100, and 96.2%, respectively. Conclusion: FNA is a useful tool for identifying neoplastic nodules arising in GD. However, cytologic atypia often leads to indeterminate diagnoses (18/46, 39.1%). Awareness of clinical information regarding prior treatment for GD may be helpful to avoid overinterpretation.