HPV Cotesting of Unsatisfactory Papanicolaou Tests: Implications for Follow-up Intervals
Chen, Fei; Hsu Lin, Lawrence; Hindi, Issa; Sun, Wei; Shafizadeh, Negin; Szeto, Oliver; Brandler, Tamar C; Simsir, Aylin
OBJECTIVES/OBJECTIVE:The 2019 American Society of Colposcopy and Cervical Pathology management guidelines recommend that patients with an unsatisfactory Papanicolaou (Pap) test (UPT) and negative human papillomavirus (HPV) cotest undergo repeat age-based screening in 2 to 4 months. The rationale is that a negative HPV test in the setting of an UPT may reflect an inadequate sample and therefore should not be interpreted as truly "negative." For patients 25 years and older who are cotested, if HPV is positive for the 16 or 18 genotypes, direct referral for colposcopy is recommended. Our study aimed to determine if a negative HPV cotest result is predictive of the absence of a high-grade squamous intraepithelial lesion (HSIL) and whether these patients may be called back for repeat testing at an interval longer than 2 to 4 months. METHODS:Follow-up cervical cytology and biopsy results in women with UPT and HPV cotests from January 2017 to December 2021 were collected. Original UPT and HPV cotest results were correlated with the follow-up Pap and biopsy results. RESULTS:There were 1,496 (2.28%) UPT cases out of 65,641 total Pap tests. Among the 1,496 UPT cases, 1,010 (67.5%) had HPV cotesting; 676 (45.1%) were followed by repeat Pap or biopsy within 4 months and 850 (56.8%) within 12 months. The total follow-up rate was 81%, with a range of 3 days to 36 months. The HSIL rate in HPV-positive cases was 5.7% (3/53) vs 0.4% (2/539) (P = .006) in HPV-negative cases. In UPT, HPV cotesting showed negative predictive values for low-grade and high-grade squamous intraepithelial lesion detection of 98.5% and 99.6%, respectively, while positive predictive values were 19% and 5.7%. CONCLUSIONS:A negative HPV cotest in individuals with UPT predicted the lack of HSIL in our study. Compliance with the recommended follow-up time of 2 to 4 months for women with UPT was low (45.1%). Our study suggests that women with UPT and negative HPV cotest may be safely called back at an interval longer than 4 months.
The Milan System for Reporting Salivary Gland Cytopathology
Hindi, Issa; Simsir, Aylin; Szeto, Oliver; Hernandez, Osvaldo; Sun, Wei; Zhou, Fang; Brandler, Tamar C
OBJECTIVES/OBJECTIVE:Our study assesses whether the Milan System for Reporting Salivary Gland Cytopathology (MSRSGC) offers any benefit over the original cytology classification, and measures interobserver agreement. METHODS:Four cytopathologists retrospectively blindly classified preoperative cytology by MSRSGC from 101 resected salivary tumors. Consensus MSRSGC diagnoses were correlated with surgical pathology diagnoses and compared with the original cytology classification. Diagnostic parameters were calculated for both systems. Interobserver variability was assessed. RESULTS:The original cytology classification vs MSRSGC had sensitivity, specificity, positive predictive value, and negative predictive value of 75.0% vs 78.3%, 97.1% vs 98.0%, 91.2% vs 94.7%, and 90.1% vs 90.0%, respectively. The original cytology classification risk of neoplasm (RON) was 91.7% for "negative for malignancy" and 100.0% for other categories. The MSRSGC RON was 71.4% in category II (nonneoplastic) and 100.0% in all other categories. The original cytology classification risk of malignancy (ROM) ranged from 0.0% for "atypical" to 100.0% for "positive for malignancy." The MSRSGC ROM ranged from 0.0% in categories I (nondiagnostic) and III (nonneoplastic) to 100.0% in category VI (malignant). Weighted agreement using the MSRSGC was 92% (Gwet AC1, 0.84); unweighted agreement was 69% (Gwet AC1, 0.64). MSRSGC category IVA (benign neoplasm) was most likely to show interobserver agreement, with complete agreement in 67% of cases. CONCLUSIONS:The MSRSGC performs similarly to the original cytology classification and shows relatively high interobserver agreement.
Evaluation of ACR TI-RADS cytologically indeterminate thyroid nodules and molecular profiles: a single-institutional experience
Belovarac, Brendan; Zhou, Fang; Modi, Lopa; Sun, Wei; Shafizadeh, Negin; Negron, Raquel; Yee-Chang, Melissa; Szeto, Oliver; Simsir, Aylin; Sheth, Sheila; Brandler, Tamar C
INTRODUCTION/BACKGROUND:The American College of Radiology (ACR) Thyroid Imaging Reporting and Data Systems (TI-RADS) was developed to standardize thyroid ultrasound reports and predict the likelihood of malignancy. In our study, we aimed to correlate indeterminate thyroid fine needle aspiration cytology cases with preceding ultrasound (US) ACR TI-RADS scores and concurrent molecular testing results to examine how well the use of the ACR TI-RADS in our institution predicted which patients with indeterminate cytology might harbor molecular alterations. MATERIALS AND METHODS/METHODS:We performed a retrospective review of thyroid nodules. Patients with US reports that included TI-RADS scores, fine needle aspiration specimens with indeterminate cytology (Bethesda class III-V), and molecular testing results were included. RESULTS:A total of 46 indeterminate cytology cases had had preceding US reports with TI-RADS scores and molecular testing (Bethesda class III, n = 37; Bethesda class IV, n = 6; Bethesda class V, n = 3). Most of the indeterminate cases had had a TI-RADS score of TR4 (31 of 46; 67.39%) or TR5 (9 of 46; 19.57%). RAS mutations were the most common alteration (n = 12). Of the 46 cases, 22 (47.85%) showed no alterations. Ten cases proceeded to surgery, of which seven displayed malignancies. CONCLUSIONS:Molecular testing in cytologically indeterminate thyroid nodules provided valuable information for TR4 and TR5 lesions; however, the TR2 and TR3 lesions often had no molecular alterations. These findings highlight the potential value of including US imaging features when assessing the significance of indeterminate cytology findings.
Utility of EZH2 Immunostaining for Atypical Bile Duct Brush Cytology [Meeting Abstract]
Chen, F; Wang, Q; Hajdu, C; Szeto, O; Simsir, A; Brandler, T
Background: Bile duct brush cytology (B
p16 immunostaining in fine-needle aspirations of the head and neck: determining the optimal positivity threshold in HPV-related squamous cell cancer
Wang, Qian; Zhou, Fang; Snow, Justin T; Simsir, Aylin; Hernandez, Osvaldo; Levine, Pascale; Szeto, Oliver; Sun, Wei; Givi, Babak; Brandler, Tamar C
INTRODUCTION/BACKGROUND:There is no consensus for interpretation of p16 immunohistochemistry (IHC) in cytology preparations. Our study aims to assess p16 IHC staining in formalin-fixed cytology cell blocks (CBs) from head and neck squamous cell carcinoma (HNSCC) fine-needle aspiration (FNA) specimens in comparison with surgical pathology p16 staining and to determine the reproducibility of p16 IHC scoring in CBs. METHODS:) was calculated to assess inter-rater reliability. RESULTS:= 0.79 (95% CI: 0.61-0.98). CONCLUSION/CONCLUSIONS:p16 IHC performed on cytology CBs can serve as a surrogate marker for the detection of HPV with high sensitivity and specificity levels. Using a threshold lower than that recommended for surgical pathology for the interpretation of p16 positivity may be appropriate for FNA cytology CB preparations. All cytopathologists in our study displayed reproducible high sensitivity and specificity values at the >10% threshold.
Integration of Cytologic, Clinical and Radiologic Information Improves Diagnostic Efficacy in Pancreatic Ductal Adenocarcinoma FNA Cytology [Meeting Abstract]
Xia, R; Sun, W; Brandler, T; Shafizadeh, N; Szeto, O; Noori-Koloori, M; Gutierrez-Amezcua, J -M; Simsir, A
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]
Pancreatic Neuroendocrine Tumor Diagnosis and Grading on Fine Needle Aspiration Cytology [Meeting Abstract]
Lin, L; Xia, R; Sun, W; Szeto, O; Cho, M; Simsir, A; Brandler, T
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.
Bile Brush Cytology Fluorescence in Situ Hybridization and the Detection of Malignancy [Meeting Abstract]
Xia, R; Sun, W; Chen, F; Negron, R; Noori-Koloori, M; Oweity, T; Szeto, O; Simsir, A; Brandler, T
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]
Implementation of the milan system for reporting salivary gland cytopathology (MSRSGC): An interobserver reproducibility study from a large academic medical center [Meeting Abstract]
Hindi, I; Simsir, A; Brandler, T; Sun, W; Szeto, O; Zhou, F; Hernandez, O
Background: Fine needle aspiration (FNA) of salivary gland lesions is a fast, minimally invasive and cost-effective procedure that aids in early patient management decisions. Recently, the Milan System for reporting Salivary Gland cytopathology (MSRSGC) was published in order to establish diagnostic categories with implied malignancy risks and recommended clinical follow-up. Our study aims to assess the interobserver reproducibility of salivary gland cytology diagnoses using the MSRSGC.
Design(s): Salivary gland cytology slides from 101 cases with surgical pathology follow-up from 11/2016-06/2019 were blindly and independently reviewed and classified according to the MSRSGC by four cytopathologists. Unweighted and linearly weighted percent agreement and Gwet's AC1 coefficients were calculated in AgreeStat 2015.6/Windows (AgreeStat Analytics).
Result(s): Unweighted percent agreement was 0.69 (substantial agreement) and weighted percent agreement was 0.92 (almost perfect agreement). Unweighted Gwet's AC1 was 0.64 (substantial agreement), and weighted Gwet's AC1 was 0.84 (almost perfect agreement) (Table 1). 50 of 101 (49%) cases had complete agreement among all 4 observers, 77 (76%) had at least 3 observers agreeing on the same diagnosis, and 99 (98%) had at least 2 observers agreeing on the same diagnosis. Category IVA (benign neoplasm) was the most likely to show interobserver agreement: among the 51 cases in which at least 2 cytopathologists agreed on a diagnosis of category IVA, 34 (67%) showed complete agreement among all 4 cytopathologists. Two cases showed no agreement among any observers. One low-grade mucoepidermoid carcinoma had MSRSGC diagnoses ranging from I to IVB, and one secretory carcinoma had MSRSGC diagnoses ranging from III to VI. Low-grade mucoepidermoid carcinoma is reportedly the most common malignant salivary gland tumor associated with false-negative diagnoses on cytology and is often misdiagnosed as a pleomorphic adenoma, due to the presence of bland-appearing intermediate cells as well as confusion between mucin and chondromyxoid stroma (Figure 1). The case of secretory carcinoma showed scant cellularity on cytology, confounding an accurate diagnosis (Figure 2).
Conclusion(s): Interobserver reliability analyses using the MSRSGC showed substantial to almost perfect agreement among the four observers in our study. Only two cases showed no agreement. Category IVA (benign neoplasm) is the most likely to show complete agreement among all observers
Hpv co-testing of unsatisfactory papanicolaou tests: Implications for follow-up intervals [Meeting Abstract]
Chen, F; Hindi, I; Sun, W; Shafizadeh, N; Szeto, O; Brandler, T; Simsir, A
Background: The ASCCP management guidelines recommend that women with an unsatisfactory Pap test (UPT) and negative HPV co-test undergo repeat age-based screening in 2 to 4 months. The rationale is that a negative HPV test in the setting of an UPT may reflect an inadequate sample and therefore should not be interpreted as truly ?negative?. For patients 25 years and older who are co-tested, if HPV is positive for the 16 or 18 genotypes, direct referral for colposcopy is recommended. Our study aimed to determine if a negative HPV co-test result is predictive of the absence of a high grade squamous intraepithelial lesion (HGSIL) and whether these patients may be called back for repeat testing at an interval longer than 2-4 months.
Design(s): Follow up cervical cytology and biopsy results in women with UPT and HPV co-tests between 2017-2019 were collected. Original UPT and HPV co-test results were correlated with follow up Pap and biopsy results.
Result(s): There were 708 UPT cases out of 30,647 total Pap tests (2.3%). Among the 708 UPT cases, 407 had HPV co-testing (57%); 260 (37%) were followed by repeat Pap or biopsy within 2-4 months and 317 (45%) within 12 months. The total follow-up rate was 81%, with a range of 10 days to 18 months. Table 1 depicts follow up information for women with UPT and HPV co-testing. Negative predict values of HPV co-testing for LGSIL and HGSIL detection were 98% and 100%, respectively, while positive predictive values were 43% and 4.7%.
Conclusion(s): A negative HPV co-test in women with an UPT predicted the lack of HGSIL in our study. Compliance with the recommended follow up time of 2-4 months for women with UPT was low at 37%. This may be due to multiple factors, one presumably being the women's reluctance to undergo a repeat pelvic exam due to its uncomfortable nature. Even with a longer follow up time of up to 12 months, there were no HGSILs in the HPV negative group. Our study suggests that women with an UPT and a negative HPV co-test may be safely called back at an interval longer than 2-4 months