Faculty Bibliography

We report two cases of an uncommon benign lesion, retroperitoneal ganglioneuroma, first diagnosed on fine needle aspiration (FNA) cytology. Our first case presented with nausea, constipation, vomiting, and neutropenia after three cycles of chemotherapy for breast cancer treatment, while our second patient presented with seemingly unprovoked abdominal pain and progressive neuropathy. Both underwent computed tomography (CT) scans, in which a soft tissue mass was found in the retroperitoneal space in each patient. An endoscopic ultrasound guided (EUS) FNA was performed on both patients, and as a result, the masses were diagnosed as retroperitoneal ganglioneuromas. As retroperitoneal ganglioneuromas have low incidence of proliferation, invasive surgery was avoided in favor of routine follow-up imaging. Cytologically, both masses showed large, scattered ganglion cells with abundant cytoplasm and large nuclei against a background of wavy spindle cells with elongated nuclei. Histologically, both were positive for S-100. When an EUSFNA is performed and quality material is collected, a diagnosis of retroperitoneal ganglioneuroma may be established, preventing invasive surgery and its accompanying risks in favor of routine follow-up imaging.

Glomus tumors make up 1% of stromal tumors of the stomach. Radiologic diagnosis of glomus tumors can be challenging as they share imaging characteristics with other neuroendocrine tumors and gastrointestinal stromal tumors. Endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) has been reported as a useful method for the evaluation of gastrointestinal lesions. We report two cases of gastric glomus tumors in which EUS-FNA diagnosis was challenging. Cytologically, neoplastic cells were round to oval, uniform, bland appearing epithelioid cells with delicate chromatin and inconspicuous to vague nucleoli. Both samples lacked worrisome features such as high nuclear grade, high mitotic rate, and necrosis. Neoplastic cells were negative for Cam5.2 and AE1/AE3 with focal expression of synaptophysin in one of the cases. A definitive diagnosis was not made based on FNA. Familiarity with glomus tumors in the GI system and procurement of adequate material for cell block allowing the use of immunohistochemistry may allow an accurate preoperative diagnosis.

BACKGROUND:Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which is responsible for coronavirus disease 2019 (COVID-19), is known to cause severe respiratory infections with occasional accompanying pleural effusion (PE), pericardial effusion (PCE), or peritoneal effusion (PTE). The effect of COVID-19 on effusion cytology is not yet known. This study aimed to examine the cytomorphologic features and workup of effusion fluids in patients with active COVID-19 infection versus those in recovery. METHODS:PE (n = 15), PCE (n = 1), and PTE samples (n = 20) from hospitalized patients with a SARS-CoV-2 infection (from June 1, 2020, to December 30, 2020) were reviewed. Effusion fluids with metastatic carcinoma were excluded. Differential cell counts, cytomorphology, and relevant immunostains for effusion fluids were retrospectively evaluated and compared between patients with active infection (positive on a SARS-CoV-2 nucleic acid amplification test [NAAT] within 2 months; n = 23) and those in the recovery phase from COVID-19 (negative on a SARS-CoV-2 NAAT for >2 months; n = 13). RESULTS:The cytology diagnoses were negative for malignancy (n = 31), atypical (n = 4), and suspicious for malignancy (n = 1). Active infection cases showed more atypical mesothelial cells than recovery cases (P < .05); some had enlarged nuclei, prominent nucleoli, occasional multinucleation, and bizarre nuclei. Immunostains were performed more often in active infection cases than recovery cases (47.8% vs 7.7%; P < .05). Differential cell counts (available for 28 cases) showed no significant differences between the active infection and recovery groups. CONCLUSIONS:This study found atypical and bizarre mesothelial cells more often in effusions of cases with active COVID-19 infection in comparison with patients in recovery. It is important for cytopathologists to become familiar with the cytomorphologic effects of SARS-CoV-2 on effusion cytology so that these cases can be properly triaged.

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.

Introduction: TERT promoter mutations in thyroid carcinoma suggest worse prognosis based on findings of a small number of studies. Additionally, pathologic features and clinical behavior of indeterminate thyroid nodules (ITN) with TERT promoter mutations remain less studied. Our study aims to explore the clinicopathologic features of ITN with TERT promoter mutations.
Material(s) and Method(s): A search conducted in our electronic medical record between 2015-2018 identified 18 cases with indeterminate thyroid fine-needle aspiration (FNA) cytology (Bethesda Class III, IV, and V) and a TERT mutation on molecular testing. 17 patients underwent thyroidectomy and were the subjects of this study.
Result(s): The mean age was 65 (range 38-83) with a female to male ratio of 9:8. The FNA Bethesda diagnoses were Class III in 9, IV in 8, and V in 1. Majority of patients who underwent thyroidectomy had malignant nodules (14,78%). Thyroidectomy diagnoses included classic PTC (5,29%), FVPTC (5,29%), follicular variant of papillary carcinoma (3,17%), poorly differentiated thyroid carcinoma (1, 6%), follicular adenoma (2,11%) and NIFTP (1,6%). Additional alterations were present in 11 cases, including NRAS(6), KRAS(2), and BRAF V600E (3). Of three cases with concurrent BRAF V600E mutation, two were metastatic, and one had tall cell features. Of two follicular adenoma cases, one had a concomitant NRAS mutation, and the other displayed negative results on Afirma testing. Malignant cases tended to occur in older patients, the majority exhibited follicular architecture, frequent oncocytic morphology, and higher pathologic stage (pT3 in 92%, pT2 in 8%).
Conclusion(s): Most TERT promoter mutations in ITN cytology are associated with high risk of malignancy and these malignancies are associated with unfavorable features such as advanced stage, capsular/vascular invasion, and metastatic disease. Few TERT promoter mutations have a benign outcome. Further studies on ITNs with TERT mutations are needed to determine the optimal management of these nodules.
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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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Introduction: Pancreatic neuroendocrine tumors (PNET) are relatively uncommon neoplasms. Endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) has been shown to be an efficient method for preoperative assessment of pancreatic tumors; however, the role of cytologic grading of PNETs is unclear. We aim to evaluate cytologic diagnosis and grading of PNETs by correlating with histopathology.
Material(s) and Method(s): Cytopathology cases with a diagnosis of PNET from 6/2011-6/2020 were tabulated and compared with their corresponding surgical pathology to evaluate the diagnostic accuracy of EUS-FNA. In addition, tumor grading based on Ki-67 immunohistochemistry was correlated between cytologic and histologic specimens (Cohen's kappa coefficient).
Result(s): Thirty-nine cases of EUS-FNAs with PNET diagnosis and concomitant histologic evaluation were included. EUS-FNA showed a positive predictive value of 85% for PNET diagnosis. There were 6 discrepant cases (15%), including: 1 mixed ductal-neuroendocrine carcinoma, 1 PNET with concomitant high-grade carcinoma, 1 metastatic renal cell carcinoma, 1 solid pseudopapillary neoplasm, and 2 cases of chronic pancreatitis, potentially explained by under-sampling, scant cellularity and/or absence of adequate cell block for immunostaining (Table 1).Nineteen cases had Ki-67 immunostaining on both cytologic and histologic specimens with a concordance of 58% (Table 2). All discrepancies in Ki-67 evaluation were due to underscoring in cytologic samples. Cyto-histologic grading correlation was fair (Cohen's Kappa coefficient=0.24).
Conclusion(s): EUS-FNA is a valuable minimally invasive diagnostic tool in the preoperative diagnosis of PNETs with a positive predictive value of 85% in this cohort. Cyto-histologic grading correlation was fair, which suggests that applying surgical pathology ki-67 grading cut-off points to cytology sample evaluations may not be appropriate. All cyto-histologic grading discrepancies in our study were due to underscoring in cytologic samples, which might be related to sampling issues or tumor heterogeneity.
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Introduction: SARS-CoV-2 (COVID-19) is known to cause severe respiratory infections with occasional accompanying pleural (PE), pericardial (PCE) or peritoneal effusion (PTE). The effect of COVID-19 disease on effusion cytology is not yet known. Therefore, our study aims to examine the cytomorphologic features and work-up of effusion fluid in patients in recovery from COVID-19 infection versus those with active disease.
Material(s) and Method(s): PE (n=15), PCE (n=1), PTE (n=19) samples from hospitalized patients with COVID-19 infection (6/1/2020-12/30/2020) were reviewed. EFs with metastatic carcinoma were excluded. Differential cell count (DCC), cytomorphology, and immunostains of EFs were retrospectively evaluated by a board-certified cytopathologist and compared between patients with active infection (AI, n=22, positive COVID-19 nucleic acid amplification test (NAAT) within 2 months) and recovery phase from COVID-19 (RC, n=13, negative COVID-19 NAAT for >2 months).
Result(s): Cytology diagnoses were: negative for malignancy (n=30), atypical (n=4), suspicious for malignancy (n=1). AI cases showed more atypical mesothelial cells than RC cases (Table 1, p<0.05), some with enlarged nuclei with prominent nucleoli and occasional multi-nucleation (Figure 1), and some with bizarre nuclei (Table 1, p<0.01). Immunostains were performed more often in AI than RC cases (50.0% vs 7.7%, p<0.05). DCC (available in 28 cases) showed no significant difference amongst AI and RC cases (Figure 1, p>0.05).
Conclusion(s): Our study found atypical and bizarre mesothelial cells to be present more often in effusions of cases with active COVID-19 infection than in samples from patients in recovery, though DCCs did not show significant difference. Diagnosis of malignancy may be considered in cases with such nuclear atypia, which explains increased immunostain work-up in AI cases. It is important for cytopathologists to consider the patients' COVID-19 infection status when evaluating effusion cytology cases. [Formula presented] [Formula presented] [Formula presented]
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Introduction: Preoperative diagnosis of pancreas ductal adenocarcinoma (PDAC) on endoscopic ultrasound guided fine needle aspiration (FNA) cytology is often required to determine proper therapy. Accurate cytopathology diagnosis on FNA may be challenging due to limited/suboptimal cellularity and gastrointestinal contamination with accurate diagnoses necessitating consideration of the full clinical and radiologic picture in evaluating the pancreatic lesions. In this study, we investigated predictive value of integrating cytology diagnosis, radiologic and clinical features in diagnosing pancreatic adenocarcinoma.
Material(s) and Method(s): Pancreatic FNA cases from 1/2016-12/2018 with >18 months of follow-up or histopathology diagnosis on surgical resection were retrieved (n=203). Cases were categorized as "Adenocarcinoma" or "Benign" according to the surgical resection pathology or clinical follow-up. Their documented serum CA19-9 level, and in-house radiologic reports were studied (n=177, Table 1). A multiplayer perceptron neural network (MNN) was trained and tested for the ability of using the integrated clinical and radiologic features and cytologic diagnosis to distinguish between benign and malignant cases.
Result(s): The sensitivity, specificity, and accuracy for pancreatic FNA cytology alone was 77.5%, 97.6%, and 88.4%, respectively. There were significant correlations between malignant outcome and cytology diagnosis, CA19-9 level and involvement of common bile duct (CBD), pancreatic duct (PD), superior mesenteric artery (SMA) or superior mesenteric vein (SMV) (Table 1, p<0.001). Integration of the cytology diagnosis and CA19-9 level showed 92% accuracy in predicting surgical outcome. The MNN highlighted cytopathology to be the most important factor in predicting pancreatic lesion outcomes, followed by the serum CA19-9 level and involvement of the SMA (Figure 1).
Conclusion(s): Integration of the clinical and radiologic information with cytology diagnosis can improve accuracy in evaluating pancreatic adenocarcinomas, especially in suboptimal FNA cytology specimens. [Formula presented] [Formula presented]
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Introduction: The Paris System classifies polyoma virus cytopathic effect (P-CPE) as "negative for high grade urothelial carcinoma (HGUC)". However, P-CPE may raise false suspicion for HGUC. Conversely, HGUC cells may display considerable degenerative nuclear changes mimicking P-CPE. Thus, P-CPE remains a known source of "atypia" in urine cytology. The aim of our study was to determine the frequency of P-CPE cases reported as atypical urothelial cells (AUC) in our laboratory, and to assess the diagnostic utility of SV40 immunostaining (IHC) in this setting.
Material(s) and Method(s): Urine cytology cases, all processed as single Thin prep (TP) slides, were searched for P-CPE diagnosis from 2018 to 2020. An additional slide was prepared for a subset of 40 randomly selected cases (19 P-CPEs, 21 negative controls) for SV40 IHC validation on TP slides.
Result(s): There were 111 urines with P-CPE. 51% were included in this study (Figure 1). Of these, 25% were diagnosed as negative for HGUC, 72% as AUC, and 3% as suspicious for HGUC. Follow-up histology showed HGUC in 3 (5%) cases (2 with AUC and 1 with suspicious for HGUC presurgical cytology). SV40 IHC was positive in 61.5% of cases in the P-CPE group and negative in 38.5% including one with confirmed HGUC on biopsy (Figure 2). In the control group, SV40 IHC was negative in 88% and equivocal in 12% (Figure 3). The difference in SV40 IHC between the P-CPE and control group was statistically significant (p<0.001).
Conclusion(s): Majority of urine samples with P-CPE were reported as AUC with a very low incidence of confirmed HGUC. SV40 IHC aided in the confirmation of viral infection. Our study shows that once the source of atypia is confirmed as polyoma virus with SV40 IHC, downgrading atypia to negative can safely be accomplished without the concern for missing a high-grade lesion. [Formula presented] [Formula presented] [Formula presented]
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