Faculty Bibliography

OBJECTIVES/OBJECTIVE:To describe the histologic features that are helpful in the diagnosis of the rare bronchiolar adenomas/ciliated muconodular papillary tumors (BAs/CMPTs) during intraoperative consultation. METHODS:Multi-institutional retrospective review of frozen sections of 18 BAs/CMPTs. RESULTS:In 14 of 18 cases, BA/CMPT was the primary reason for sublobar lung resection, and in 4 cases, BA/CMPT was an incidental finding intraoperatively for resections performed for carcinoma in other lobes. There were 11 proximal-type/classic BAs/CMPTs and 7 distal-type/nonclassic BAs/CMPTs. Only 3 (16.7%) of 18 were correctly diagnosed at the time of frozen section, all of which were proximal type/classic. The remainder were diagnosed as adenocarcinoma (n = 7); invasive mucinous adenocarcinoma (n = 1); non-small cell lung carcinoma (n = 1); cystic mucinous neoplasm, favor adenocarcinoma (either mucinous or colloid type) (n = 1); favor adenocarcinoma, cannot exclude CMPT (n = 1); atypical proliferation (n = 2); mucinous epithelial proliferation (n = 1); and mucous gland adenoma (n = 1). CONCLUSIONS:BA/CMPT can potentially be misdiagnosed as carcinoma during intraoperative consultation. On retrospective review of the frozen sections, the presence of the following may help to avoid misdiagnosis: a mixture of bland ciliated columnar cells, mucinous cells, and, most important, a basal cell layer, as well as a lack of necrosis, significant atypia, and mitoses.

The COVID-19 pandemic has presented countless new challenges for healthcare providers including the challenge of differentiating COVID-19 infection from other diseases. COVID-19 infection and acute endocarditis may present similarly, both with shortness of breath and vital sign abnormalities, yet they require very different treatments. Here, we present two cases in which life-threatening acute endocarditis was initially misdiagnosed as COVID-19 infection during the height of the pandemic in New York City. The first was a case of Klebsiella pneumoniae mitral valve endocarditis leading to papillary muscle rupture and severe mitral regurgitation, and the second a case of Streptococcus mitis aortic valve endocarditis with heart failure due to severe aortic regurgitation. These cases highlight the importance of careful clinical reasoning and demonstrate how cognitive errors may impact clinical reasoning. They also underscore the limitations of real-time reverse transcription-polymerase chain reaction (RT-PCR) for SARS-CoV-2 testing and illustrate the ways in which difficulty interpreting results may also influence clinical reasoning. Accurate diagnosis of acute endocarditis is critical given that surgical intervention can be lifesaving in unstable patients.

Background: Thyroseq next-generation sequencing assay and Afirma gene expression classifier (GEC) are used to risk-stratify thyroid nodules with indeterminate cytology: Bethesda III (atypia of undetermined significance, AUS/FLUS) and IV (suspicious for follicular neoplasm, SFN). In this study, we performed a paired comparison of both tests on the same group of indeterminate thyroid nodules with surgical followup.
Design(s): Of 645 AUS/FLUS/SFN cases with both molecular testing and surgical resection in 2014-2017, 40 cases had both Thyroseq (v2) and Afirma GEC performed on the same specimen. Cross-tabulations and ROC curves were created. McNemar tests were done to compare the performance of Thyroseq versus Afirma. The diagnostic performance of combined results were also examined: the combined result was called positive only if both Thyroseq and Afirma were positive/suspicious. Non-invasive follicular thyroid with papillary like nuclear features (NIFTP) on surgical resections was defined as ?positive.? Results: 20/40 (50%) cases were ?positive? on surgical pathology: 8 papillary thyroid carcinoma (PTC), 11 NIFTP, and 1 follicular carcinoma. Thyroseq and Afirma both showed high sensitivity and low specificity in diagnosing malignancy in indeterminate thyroid nodules. Next, the results of both tests were combined. The overall accuracy of combined testing was higher than either test alone (Figure 1). Compared to Afirma alone, the combined test had significantly higher specificity (30% vs 70%, p<0.05, Table 1), while the sensitivity declined from 90% to 75% (p=0.25, Table 1). Compared to Thyroseq alone, there was no significant difference in specificity (45% vs 70% p=0.06) or sensitivity (80% vs 75%, p=1.00, Table 1). Positive predictive value (PPV) improved compared to either test alone. Negative predictive value (NPV) improved compared to Thyroseq alone, and declined only slightly compared to Afirma alone.
Conclusion(s): Molecular testing of cytologically indeterminate thyroid nodules helps determine the extent of surgery. Low diagnostic performance metrics may limit the utility of molecular studies in distinguishing benign from malignant thyroid lesions. Our results show that the combined results of Thyroseq and Afirma improved the specificity and overall accuracy of molecular testing, and provided additional value in the surgical management of patients with indeterminate thyroid nodules. To the best of our knowledge, this is the first study that compares the performance of these two molecular tests on the same thyroid nodules

Background: Growing evidence suggests the prognostic significance of SATS in patients with early-stage lung adenocarcinoma, in particular, those with sublobar resection. However, published studies used various definitions for STAS; the diagnosis of STAS may be subject to interobserver variability that, in turn, may result in the difference in prevalence and prognostic significance of STAS across institutions.
Design(s): The study cohort consisted of stage 1 lung adenocarcinomas resected at two institutions (cohort A: n=283; cohort B: n=198) during similar time periods with similarly decent follow-up. Both institutions had applied similar grossing/processing protocols. The prevalence of STAS and its association with clinicopathologic variables, recurrence free survival (RFS), and overall survival (OS) were compared between the cohorts. The variables included type of operation, AJCC 8th stage, histologic grade, as well as the presence of lepidic, micropapillary (mPAP), or solid (SOL) patterns (5% cut-off for presence).
Result(s): The prevalence of STAS was 7% in cohort A and 39% in cohort B (p<0.0001). The tumor histologic grade (high grade: 21% in A vs. 37% in B, p=0.0001) and AJCC stage (Stage 1B: 19% in A vs. 13% in B, p=0.048) also differed between the cohorts, while no difference was seen in the other variables. STAS was associated with high grade histology, the absence of lepidic and the presence of mPAP and SOL patterns (p<0.01 for all) in both cohorts, while it was also associated with stage 1B in cohort A (p=0.016). In multivariate analysis, STAS was associated with high grade histology (p<0.0001) and marginally with the presence of mPAP (p=0.065) in cohort A, and lobectomy (p=0.016), the presence of mPAP (p<0.0001) and SOL (p=0.027) in cohort B. Regarding survival, STAS was associated with shorter RFS (p=0.030) and OS (p=0.048) in cohort B and with shorter OS (p=0.040) and marginally with shorter RFS (p=0.060) in the sublobar resection subset of cohort B by univariate analysis, while STAS had no bearing on survival in the lobectomy subset or cohort A. Of note, no difference in RFS and OS was seen as a whole between the cohorts.
Conclusion(s): The prevalence and prognostic significance of STAS differ between the two institutional cohorts. While this may be explained in part by the difference in patient populations, subjectivity to the diagnosis of STAS may potentially contribute. Additional multi-institutional studies to better define and improve reproducibility of STAS are warranted

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

Immunohistochemical (IHC) stain for PD-L1 as a biomarker for immunotherapy is recommended in non-small cell lung cancer (NSCLC). Under the FDA, the selection of patients for pembrolizumab requires companion diagnostic testing using the Dako Agilent PD-L1 IHC 22C3 pharmDx kit performed on the Dako Autostainer Link 48 platform. However, because it is not widely available, there is need for cross-platform validation. Existing studies provide incomplete protocol detail. In our study, 73 lung tumors were stained using the FDA-approved test ('gold standard'). The same blocks were stained using two different models of the Ventana DISCOVERY platform (ULTRA, n = 73 and XT, n = 70) using different parameters, and interpreted by three pathologists. The ULTRA group met College of American Pathologists (CAP) validation criteria (concordance 91.8%) while the XT group did not (concordance 67.1%). Using tumor proportion score (TPS) ≥1% and TPS ≥50% as cut-offs, the ULTRA protocol had higher sensitivity (97.8% and 91.7%) than XT (73.3% and 60.9%) and similar specificity (ULTRA 88.9% and 100%, XT 88% and 100%). Discordance between ULTRA and XT was 27%, and in all these cases ULTRA was concordant with gold standard. Interobserver reliability was substantial for ULTRA and almost perfect for XT, providing evidence that staining rather than observer variability accounts for XT's inferior performance. Cross-validation of the clinically used 22C3 anti PD-L1 antibody test with substantial interobserver agreement is possible on the commonly used the Ventana DISCOVERY ULTRA automated instrument, while the validation failed on the XT. Cautious attention to detail must be paid when choosing cross-validation parameters.