Faculty Bibliography

OBJECTIVE:To analyze clinical outcomes in a series of indeterminate thyroid nodules (ITNs) with repeat fine-needle aspiration (FNA) biopsy and results of genomic classifier. STUDY DESIGN/METHODS:Historical chart review. SETTING/METHODS:Tertiary care center. METHODS:We reviewed FNA samples from subjects with Bethesda III or IV diagnoses from January 2015 to December 2018 at a single institution and selected those with repeat FNA and ThyroSeq testing of the same nodule. Patient demographics, Bethesda classifications, ThyroSeq results, treatment detail, and surgical pathology, when available, were analyzed. RESULTS:< .0001). In excised nodules, the prevalence of malignancy and noninvasive follicular thyroid neoplasm with papillary-like nuclear features was 28% (n = 10) and 22% (n = 8), respectively, and all malignancies were low risk. CONCLUSION/CONCLUSIONS:In this case series, repeat FNA helped patients with ITNs avoid diagnostic surgery through reclassification to benign cytology. The risk of high-risk malignancy in ThyroSeq-positive nodules with repeat indeterminate cytology was low.

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.

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.

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.
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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.
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Introduction: Our study aimed to assess the sensitivity (SN) and specificity (SP) of fluorescence-in-situ-hybridization (FISH) alone and as an adjunct to routine cytology for the detection of malignancy in biliary tract lesions.
Material(s) and Method(s): Bile duct brush specimens with FISH results from 1/2013-1/2020 were tabulated yielding 55 cases. Cases were classified as "Benign" where surgical resection showed benign findings or follow-up was uneventful >18 months and as "Malignant" where surgical pathology or clinical follow up identified malignancy in the pancreatobillary system (40 cases). Cases not falling under these categories were excluded. Cytologically suspicious and positive cases were designated as "positive." FISH positive and "equivocal" results were also designated as "positive." When examining the combined cytology-FISH results, cases were designated as "positive" if either cytology or FISH test was "positive." Atypical cytology cases were excluded.
Result(s): 21/40 cases fell under benign or malignant categories. 5/21 cases had malignant surgical follow-up: 4 pancreaticobiliary ductal adenocarcinoma and 1 Hodgkin lymphoma. FISH showed high SP (100%) and low SN (33.3%) in diagnosing malignancy in bile brush cytology. In cytology alone, FISH alone and the combined cytology-FISH testing, there was a statistically significant difference in risk-of-malignancy between Positive and Negative diagnostic categories, p<0.05(Table 1). Accuracy improved using combined cytology-FISH results over either test alone, area under the curve (AUC: Cytology=0.8; FISH=0.717; Combined test=0.85) (Figure1).
Conclusion(s): Cytology, FISH and combined cytology-FISH results all showed higher risk-of-malignancy values in positive compared to negative categories. The FISH-cytology combination may improve the SN of detecting malignancy in biliary tract lesions. Sample size may have been too small to detect a significant difference between combined cytology-FISH results versus either test alone. However, due to the potential clinical impact of improving bile duct brush cytology accuracy, our results should be evaluated further in larger samples. [Formula presented] [Formula presented]
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The majority of malignancies identified in indeterminate thyroid nodules (ITN) are low risk. Therefore, the need for total thyroidectomy or adjuvant treatment such as completion thyroidectomy or radioactive iodine (RAI) therapy in the treatment of ITNs is uncertain. This study aimed to analyze the likelihood of a need for total thyroidectomy and RAI therapy in the management of ITNs. All ITNs diagnosed on FNA cytology from 2014-2018 at NYU Langone Health were reviewed. ITNs managed with surgery were selected. Demographics, nodule characteristics, final pathology, treatment detail, and clinical outcomes were recorded. During the study period, 218 patients with surgically excised ITNs were identified. One hundred forty-two (65.1%) patients underwent thyroid lobectomy (TL), and 76 (34.9%) had total thyroidectomy (TT) upfront. In the lobectomy group, 26 (18.3%) had a malignant nodule on final surgical pathology, 8 (5.6%) underwent completion thyroidectomy, and 5 (3.5%) received RAI. In the total thyroidectomy group, 26 (34.2%) were diagnosed as malignant, and 14 (18.4%) received RAI. Follicular variant of papillary thyroid carcinoma (FVPTC) was the most common malignant diagnosis in both groups (TL: 20, 76.9%; TT: 12, 46.2%). Adenomatous nodule was the most common benign diagnosis (TL: 55, 72.5%; TT: 15, 51.2%). NIFTP accounted for 28.2% (40) of nodules treated with lobectomy and 27.6% (21) of nodules treated with upfront total thyroidectomy. In the entire cohort, only two (1%) patients had significant pathology in the contralateral lobe (1 [0.5%] with papillary thyroid carcinoma [PTC] and 1 [0.5%] with multifocal micro-PTC). Of all 218 ITNs, only 19 patients (8.7%) received RAI. With a median follow-up of 31.5 months (interquartile range = 21-39.5), no recurrences or progression was seen. The need for completion thyroidectomy or adjuvant RAI therapy in the treatment of ITN was low in our series. These data suggest that initial management of ITNs with lobectomy might be sufficient in the majority of cases

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

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.

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.