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Predictive Value of a Genomic Classifier in Indeterminate Thyroid Nodules Based on Nodule Size

Dublin, Jared C; Papazian, Michael; Zan, Elcin; Oweity, Thaira; Sun, Wei; Jacobson, Adam; Patel, Kepal; Brandler, Tamar C; Givi, Babak
Importance/UNASSIGNED:Genomic classifiers were developed to better guide clinicians in the treatment of indeterminate thyroid nodules (ITNs). To our knowledge, whether there is variation in the diagnostic accuracy of these tests depending on ITN size has not been previously studied. Objective/UNASSIGNED:To analyze the diagnostic performance of a genomic classifier in relation to ITN size. Design, Setting, and Participants/UNASSIGNED:A case series study with medical records review was conducted including all patients with a cytologic diagnosis of ITN managed with genomic classifier testing and surgery from January 2015 to December 2018 at NYU Langone Health. Demographics, ITN characteristics, genomic profiles, treatment, and final pathologic findings were recorded. Data analysis was conducted from March to April 2021. Main Outcomes and Measures/UNASSIGNED:The primary aim was to assess the positive predictive value (PPV), negative predictive value (NPV), sensitivity, and specificity of a genomic classifier test (ThyroSeq) in relation to ITN size (<2, 2-4, and >4 cm). The secondary aim was to investigate the risk of cancer associated with genetic signatures. Results/UNASSIGNED:Of the 212 patients with 218 ITNs, 158 (74.5%) were women; median (SD) age was 49 (15.6) years. Genomic classifier results were positive in 173 ITNs (79.4%) treated with surgery. In this group of 173 positive ITNs, 46 (26.6%) were malignant on final pathologic testing. Overall, the observed cancer prevalence in the population was 23.9% (52 ITNs). In 45 ITNs that underwent surgery despite a negative genomic classifier interpretation, 6 (13.3%) were malignant. The PPV of a positive test was 27% and the NPV was 87%. The PPV and NPV findings improved as the ITN size increased (<2 cm [n = 98]: PPV, 25%; NPV, 79% vs >4 cm [n = 33]: PPV, 50%; NPV, 89%). Test specificity was higher in larger ITNs (<2 cm: 15% vs >4 cm: 40%; P = .01). Isolated RAS sequence variations were the most common variant identified in malignant nodules (11 [21.1%] of all ITNs), followed by BRAF variants (7 [13.5%] of all ITNs). Conclusions and Relevance/UNASSIGNED:In this case series, the performance of the ThyroSeq test improved for larger ITNs. The risk of cancer in large ITNs with negative test results was low. These data suggest that, in genomic classifier-negative ITNs larger than 4 cm, initial management of thyroid lobectomy may be sufficient.
PMID: 34734965
ISSN: 2168-619x
CID: 5038292

Follicular dendritic cell sarcoma of the cervical lymph node diagnosed on fine needle aspiration cytology [Case Report]

Xia, Rong; Shafizadeh, Negin; Brandler, Tamar; Liu, Cheng; Oweity, Thaira
Follicular dendritic cell sarcomas (FDCS) are rare tumours of lymph nodes and extranodal tissues which are grouped with the histiocytic and dendritic cell neoplasms. The diagnosis is usually made after thorough clinical and pathological examination with immunohistochemical analysis. Difficulties persist in diagnosing FDCS on cytological preparations. We report herein a case of a 57-year-old female who presented with a right neck mass of 5 months duration. Computed Tomography (CT) imaging of the neck reported a necrotic right level IIb lymph node and asymmetric fullness of the right palatine tonsil. Fine needle aspiration (FNA) biopsy revealed numerous spindle, oval and stellate neoplastic cells, arranged singly and in syncytia with moderate nuclear pleomorphism, vesicular chromatin pattern, and prominent nucleoli, sprinkled with small lymphocytes. The tumour cells were strongly diffusely positive for CD21, CD23, and D2-40 immunostaining on cell bock sections, but were negative for CD1a and CD34, supporting the diagnosis of FDCS. Follow-up surgical pathology on the resection showed histopathological features and an immunohistochemical profile consistent with FDCS.
PMID: 34351024
ISSN: 1365-2303
CID: 4988692

Prognostic Significance of Singular RAS Mutations in Cytologically Indeterminate Thyroid Nodules [Meeting Abstract]

Dublin, J C; Papazian, M; Zan, E; Oweity, T; Sun, W; Hodak, S; Baldwin, C K; Patel, K N; Brandler, T C; Givi, B
Introduction: The prognostic significance of a singular RAS mutation in cytologically indeterminate thyroid nodules (ITN) is unclear. This study aimed to analyze the incidence of malignancy and clinical outcomes of ITNs diagnosed on fine needle aspiration (FNA) cytology with RAS mutations.
Method(s): All FNA ITNs that underwent ThyroSeq testing and thyroidectomy from 2014-2018 were reviewed. ITNs with RAS (N-, H-, or K-RAS) mutations identified on ThyroSeq testing were selected. Demographics, Bethesda classifications, genomic profiles, treatment, final pathology, and clinical outcomes were recorded.
Result(s): During the study period, 93 patients with cytologic diagnosis of ITN and RAS mutations were identified. The mean nodule size was 2.2 cm (range: 0.5-6.6 cm). Most nodules were classified as Bethesda III (77, 82.8%). NRAS mutations were the most common (53, 57%), followed by HRAS (24, 25.8%), and KRAS (16, 17.2%). The majority of patients were treated with thyroid lobectomy (67, 72%). On final pathology, 9 (10%) were diagnosed as malignant (follicular variant of papillary thyroid carcinoma [FVPTC]) and were distributed among all 3 RAS variants (NRAS: 4 [7.5%]; HRAS: 4 [16.7%]; KRAS: 1 [6.3%]; p=0.4). Most FVPTCs were encapsulated (8, 88.9%). With a median follow up of 19 months (interquartile range = 8-35), no recurrences or progression was seen.
Conclusion(s): The risk of malignancy in ITNs with singular RAS mutations is low. All malignancies were low-risk. Our findings demonstrate a low incidence of high-risk malignancy in ITNs with RAS mutations, suggesting that initial management with conservative approaches such as thyroid lobectomy may be justified.
ISSN: 1879-1190
CID: 5024622

Concordance of Initial and Repeat Molecular Analysis in Cytologically Indeterminate Thyroid Nodules [Meeting Abstract]

Papazian, M; Dublin, J C; Zan, E; Oweity, T; Baldwin, C; Jacobson, A S; Hodak, S; Patel, K N; Brandler, T C; Givi, B
Introduction: Molecular tests such as ThyroSeq are recommended in the workup of cytologically indeterminate thyroid nodules (ITN). While repeat molecular testing is often performed after repeat fine needle aspiration (FNA) yields persistently indeterminate cytology, ThyroSeq's inter-test reliability is unclear. We assessed consistency of initial and repeat ThyroSeq analyses performed on samples from the same thyroid nodules.
Method(s): All thyroid nodules diagnosed as ITN on consecutive FNAs that received ThyroSeq with both biopsies from 2014-2018 at our institution, were reviewed. Initial analysis was ThyroSeq v2 while repeat was v2 or v3. Nodules with gene mutations, fusions, or copy number alterations (CNA) were considered ThyroSeq-positive.
Result(s): During the study period, 30 patients underwent ThyroSeq analysis on initial and repeat FNA samples (median interval=21 months). On initial testing, 27 (90%) nodules were ThyroSeq-negative and 3 (10%) low-risk mutations (RAS, EIF1AX, TSHR) were identified. Repeat ThyroSeq re-identified these 3 nodules and also interpreted 9 initially ThyroSeq-negative nodules as positive (kappa=0.286). All 9 molecular alterations were low-risk, most were identified on v3 (7, 77.8%), and CNA was the most common change (6, 66.7%). Of 12 patients with ThyroSeq-positive nodules, 8 underwent lobectomy. Final pathology identified low-risk malignancy in 3 nodules; the remainder were benign.
Conclusion(s): New findings on repeat ThyroSeq are possible. Whether these findings were detected by expanded panel or are the result of de-novo changes is unknown. The risk of missing high-risk changes appears to be low. More studies are needed to characterize the concordance of ThyroSeq analyses and natural evolution of ITNs.
ISSN: 1879-1190
CID: 5024612

Insight into utility and impact of immunohistochemistry in evaluating microinvasion in breast core needle biopsies [Meeting Abstract]

Roychoudhury, S; Ozerdem, U; Warfield, D; Oweity, T; Levine, P; Hernandez, O; Darvishian, F
Background: Diagnosis of microinvasion (MI) in breast core needle biopsy (CNB) can be challenging particularly in a background of carcinoma in situ (CIS) involving sclerosing lesion with periductal fibrosis and lymphocytic infiltrate. Immunohistochemical stains (IHC) for myoepithelial cells aid in confirming MI. Surgical management of MI deviates from CIS as the former includes sentinel lymph node biopsy (SLNB) while the latter typically includes SLNB only when total mastectomy (TM) is planned. We investigated the utility of IHC in diagnosing MI in our CNBs and its impact on final histopathology on surgical excision.
Design(s): We conducted a search for cases of CIS with foci suspicious for MI, in which IHC for calponin and p63 was used to confirm MI (defined as invasive carcinoma <=1 mm) between January 2010 and June 2019. CIS included ductal carcinoma in situ (DCIS) and lobular carcinoma in situ (LCIS). MI cases diagnosed based on routine histology were also collected for the same time period. Only cases with follow up excision data were included. Cases with synchronous invasive carcinoma were excluded. Clinicopathologic data including age, size, laterality, resection type, SLNB status and biomarker profiles were compared. Graphpad Prism software was used for statistical analysis.
Result(s): We identified 106 cases of CIS (102 DCIS, 4 LCIS), where IHC was used to confirm MI (MI-IHC hereafter). Mean age was 58 years. Of the 106 cases MI-IHC was identified in 24 cases (23%). See table. All 24 MI-IHC cases had SLNB (100%). Of the 82 CIS cases, 39 had SLNB (48%). Relative risk of finding invasive carcinoma/MI on resection in MI-IHC was 1.8 (p=0.03) compared to CIS. There was no correlation between the biomarker profile with the resection outcome in either CIS (p=0.5, Fisher's exact test) or MI-IHC cases (p=3.4, Chi-square test). We identified 7 cases of MI, diagnosed on routine histology without IHC, of which 5 (71%) had invasive carcinoma/MI and 2 (29%) had CIS or no residual carcinoma on resection. Mean size of invasive carcinoma and CIS on resection in this group was 11 mm and 25 mm, respectively. The resection outcome between MI-IHC and MI based on routine histology was not significant (p=0.6). (Table presented)
Conclusion(s): IHC helped diagnose MI in CNB for CIS in 23% of cases. Compared to CIS, the diagnosis of MI-IHC carried a relative risk of 1.8 in finding invasive carcinoma/MI on resection. There was no difference in the significance of the method used for the diagnosis of MI
ISSN: 1530-0285
CID: 4471202

Hurthle cell lesions on thyroid fine needle aspiration cytology: Molecular and histologic correlation

Schatz-Siemers, Nina; Brandler, Tamar C; Oweity, Thaira; Sun, Wei; Hernandez, Andrea; Levine, Pascale
BACKGROUND:Hurthle cell lesions often pose diagnostic challenges, despite their common occurrence on thyroid fine-needle aspiration cytology (FNAC). The associated molecular alterations are also not well understood. Therefore, our study aimed to delineate the molecular profile of Hürthle cell lesions classified as Bethesda Categories III or IV (atypia of undetermined significance (AUS) or suspicious for follicular neoplasm (SFN)) on FNAC and to correlate this molecular profile with surgical resection findings. METHODS:This study consisted of 188 Hürthle cell lesions with indeterminate cytology and ThyroSeq® v2/v3 molecular testing results. Surgical follow-up was available for 33 cases. RESULTS:The majority of indeterminate Hürthle cell lesions had negative ThyroSeq® results (61%) and were benign on available surgical follow-up. The most prevalent mutations involved the RAS gene (21%), which were associated with benign lesions, non-invasive follicular thyroid neoplasms with papillary-like nuclear features (NIFTP), and malignancy. The remaining mutations involved less than 18% of the cases, including PAX8/PPARG (3.7%), TSHR (3.7%), EIF1AX (2.7%), MET (2.1%), PTEN (1.6%), clonal copy number alteration (1.6%), TERT (1.1%), and 0.5% each of GNAS, PIK3CA, and TP53 mutations. On follow-up, 45% were benign, 24% were NIFTP, and 30% were malignant. The malignant cases had different molecular alterations. CONCLUSION/CONCLUSIONS:No single molecular alteration defines cytologically indeterminate Hürthle cell lesions; the majority of cases have low-risk or no molecular alterations and are benign on follow-up. These findings suggest that molecular testing may be useful, but is not definitive, in determining which cases may be managed conservatively; additional studies are needed to fully determine the negative predictive value in ruling out malignancy.
PMID: 31293091
ISSN: 1097-0339
CID: 3976702

Noninvasive Follicular Thyroid Neoplasm with Papillary-Like Nuclear Features (NIFTP); An Interobserver Study of Key Cytomorphologic Features From a Large Academic Medical Center

Brandler, Tamar C; Cho, Margaret; Wei, Xiao-Jun; Simms, Anthony; Levine, Pascale; Hernandez, Osvaldo; Oweity, Thaira; Zhou, Fang; Simsir, Aylin; Rosen, Lisa; Sun, Wei
OBJECTIVE:Because of the indolent nature of Noninvasive Follicular Thyroid Neoplasm with Papillary-Like Nuclear Features (NIFTP) and potential requisite for conservative treatment, it is crucial to identify features of this entity pre-operatively. Our group recently published our findings that there are several cytomorphologic features that may be used as clues to distinguish NIFTP, PTC and follicular adenoma (FA) on fine-needle aspiration (FNA). Therefore, we aimed to determine the interobserver reproducibility of these findings. METHODS:Pre-surgical FNA slides from NIFTP (n=30), classic PTC (n=30) and FA (n=30) collected from 1/2013-8/2016 were reviewed by 7 cytopathologists blindly. Presence of selected cytomorphologic features was recorded and compared to determine percent agreement and inter-rater reliability among study cytopathologists using Gwet's AC1 statistics. RESULTS:For all the cytomorphologic features, the overall percent agreement amongst the pathologists ranged between 65.1% and 86.8% (Gwet's AC1 0.30 to 0.80). There was substantial or almost perfect agreement (Gwet's AC1 >0.60) in seven cytomorphologic features in the classic PTC group, in six features in the NIFTP group, and in five features in the FA group. There were no features with poor agreement (Gwet's AC1<0.0). CONCLUSIONS:The current study supports the reproducibility of our previous findings. The high level of agreement amongst pathologists for these groups, and particularly the NIFTP group, supports the notion that when viewed in combination as a cytologic profile, these cytomorphologic features may assist the cytopathologist in raising the possibility of NIFTP pre-operatively. This can potentially aid clinicians in deciding whether more conservative treatment may be appropriate.
PMID: 30230094
ISSN: 1365-2303
CID: 3300612

Molecular and Histologic Correlation of Hurthle Cell Lesions on Thyroid Fine Needle Aspiration Biopsies [Meeting Abstract]

Schatz-Siemers, Nina; Oweity, Thaira; Sun, Wei; Brandler, Tamar; Hernandez, Andrea; Levine, Pascale
ISSN: 0893-3952
CID: 3049062

Molecular and histologic correlation of hurthle cell lesions on thyroid fine needle aspiration biopsies [Meeting Abstract]

Schatz-Siemers, N; Oweity, T; Sun, W; Brandler, T; Hernandez, A; Levine, P
Background: Despite their common occurrence on fine-needle aspiration (FNA) biopsies, Hurthle cell lesions often pose diagnostic challenges. The associated molecular alterations are also not well understood. The goal of this study was to delineate the molecular profile of Hurthle cell lesions classified as Bethesda categories III or IV (atypia of undetermined significance (AUS) or suspicious for follicular neoplasm (SFN)) on FNA and to correlate this molecular profile with surgical resection findings. Design: 140 of 575 FNA's diagnosed as AUS or SFN were Hurthle cell lesions, of which 130 had Thyroseq molecular tests; 21/130 had surgical follow-up and the remaining 109/130 cases were lost to follow-up or considered clinically benign. Results: A majority of the Hurthle cell AUS or SFN had negative Thyroseq results (65%). The most prevalent mutations involved the RAS gene (19%). The remaining mutations each involved fewer than 4% of the cases. On surgical follow-up, 29% (6/21) were benign follicular neoplasms (5/6 were Hurthle type) with a variety of associated mutations. 24% (5/21) were non-neoplastic on surgical excision, including Hashimoto's thyroiditis with no mutations and nodular hyperplasia with KRAS or NRAS mutation. Another 24% (5/21) had non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) with different associated mutations. Finally, 24% (5/21) were malignant on surgical excision including Hurthle variant of follicular carcinoma with a variety of associated mutations, invasive follicular-variant of papillary thyroid carcinoma with NRAS mutation and an incidental papillary thyroid microcarcinoma (micro PTC) with KRAS mutations (Table 1). One micro PTC and three NIFTP cases had marked associated Hashimoto's thyroiditis in the surgical specimens. Conclusions: Our study shows the majority of Hurthle cell lesions diagnosed as AUS or SFN on thyroid FNA biopsies have no molecular alterations. Among the molecular alteration identified in Hurthle cell lesions, RAS mutations were the most prevalent; however, they were equally associated with benign lesions, NIFTP and malignant tumors. Therefore, they may not be useful in pre-surgical management decisions. The number of remaining molecular alterations was too small for significant analysis. Interestingly, almost half of the NIFTP and micro PTC cases had a background of Hashimoto's thyroiditis which may have masked the true nature of the lesions during FNA evaluation. (Table Presented)
ISSN: 1530-0307
CID: 3046412

Peripancreatic paraganglioma mimics pancreatic/gastrointestinal neuroendocrine tumor on fine needle aspiration: report of two cases and review of the literature

Zeng, Jennifer; Simsir, Aylin; Oweity, Thaira; Hajdu, Cristina; Cohen, Steven; Shi, Yan
Cytologic diagnosis of extra-adrenal paraganglioma presenting as a peripancreatic mass is challenging with a high error rate due to its rarity. We report two cases of peripancreatic masses identified by radiology. Endoscopic ultrasound-guided fine needle aspiration (FNA) of the masses showed a moderately cellular tumor composed of small to medium sized neoplastic cells with round to oval nuclei, arranged singly and in loose clusters. Focal rosette-like structures were present. The cells were positive for neuroendocrine markers (synaptophysin and chromogranin). A diagnosis of a neoplasm with neuroendocrine differentiation and neuroendocrine tumor was made respectively on FNA for each case. The subsequent surgical resection of the tumors revealed peripancreatic paraganglioma. Although paraganglioma has been reported in the literature, the detailed comparison of perpancreatic paraganglioma versus pancreatic/gastrointestinal neuroendocrine tumor is still lacking. Therefore using these two cases with literature review, we wish to illustrate the differential diagnosis between these two entities based on cytomorphology and immunohistochemical study.
PMID: 28560856
ISSN: 1097-0339
CID: 2591722