Faculty Bibliography

Introduction: Recent studies evaluating p16 immunohistochemistry (IHC) in cell blocks (CB) of fine needle aspirations (FNAs) in patients with oropharyngeal squamous cell carcinoma (OP-SCC) have shown good correlation between cytology and surgical pathology. Our study aimed to determine the reproducibility of p16 IHC scoring in CBs. Additionally, we evaluated whether interobserver variability would significantly affect the optimal threshold for p16 IHC positivity in CBs.
Material(s) and Method(s): 40 FNAs from 2014-2019 of head and neck squamous cell carcinoma with p16 IHC were obtained. Surgical pathology p16 IHC results were set as reference. p16 IHC stained CBs were scored independently by 5 cytopathologists and recorded as percentage of tumor cell positivity: 0%,0-1%,1-10%,10-50%,50-70%,70%. AgreeStat2015.6/Windows software was used to calculate the percent agreement (Pa) and Gwet's AC1 statistic to assess inter-rater reliability. ROC curves were examined to determine optimal cutoffs for each pathologist based on sensitivity and specificity values (IBM SPSS version 25).
Result(s): Overall performances of the raters were similar, with areas under the curve (AUCs) ranging from 0.88-0.95 (Figure 1). >10% appeared to be the optimal threshold for p16 positivity because this was the lowest threshold to reach 100% specificity with high sensitivity (55-84%) in all 5 raters. Using the >10% as threshold, the Pa was 86% (95% CI 0.78-0.94) and Gwet's AC1 coefficient was 0.72 (95% CI 0.56-0.89).
Conclusion(s): While the goal in developing guidelines for the interpretation of p16 IHC on cytology CBs is to provide generalizable standards for all cytopathologists, interobserver variability must be taken into account. Prior studies have shown optimal cutoffs ranging from >0% (any staining) to >70%, with sensitivity and specificity values ranging from 37%-100%. While our study did not show perfect agreement, all cytopathologists in our study displayed reproducible high sensitivity and specificity values at the >10% threshold with a percent agreement of 86%. [Formula presented]
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OBJECTIVES/OBJECTIVE:Recent investigations have shown strong correlations between cytology and surgical non-small cell lung carcinoma (NSCLC) specimens in programmed death-ligand 1 (PD-L1) immunohistochemical (IHC) evaluations. Our study aims to evaluate the reproducibility of PD-L1 IHC scoring in NSCLC cytology cell blocks (CBs) and to assess the impact of CB cellularity, method of sample collection, and observer subspecialty on scoring agreement. METHODS:PD-L1 IHC was performed on 54 NSCLC cytology CBs and was scored independently by seven cytopathologists (three of seven with expertise in pulmonary pathology). Three-tier scoring of negative (<1%), low positive (1%-49%), and high positive (≥50%) and interrater agreement were assessed. RESULTS:Total and majority agreement among cytopathologists was achieved in 48% and 98% of cases, respectively, with κ = 0.608 (substantial agreement; 95% confidence interval, 0.50-0.72). Cytopathologists with pulmonary pathology expertise agreed in 67% of cases (κ = 0.633, substantial agreement), whereas the remaining cytopathologists agreed in 56% of cases (κ = 0.62, substantial agreement). CB cellularity (P = .36) and sample collection type (P = .59) had no statistically significant difference between raters. CONCLUSIONS:There is substantial agreement in PD-L1 IHC scoring in cytology CB specimens among cytopathologists. Additional expertise in pulmonary pathology, sample collection type, and CB cellularity have no statistically significant impact on interobserver agreement.

Pathogenic variants in COCH, encoding cochlin, cause DFNA9 deafness disorder with characteristic histopathologic findings of cochlin deposits in the inner and middle ears. Here, we present the first case of deafness associated with bilateral external auditory canal (EAC) cochlin deposits, previously unreported evidence suggestive of cochlin-derived amyloid formation, and a novel COCH variant. A 54-year-old woman presented with progressive sensorineural hearing loss and bilateral EAC narrowing by subcutaneous thickening. Excision and histologic evaluation of tissue from both EACs showed paucicellular eosinophilic aggregates containing multiple Congo red-positive foci with yellow and green birefringence under crossed polarization light microscopy. Mass spectrometry performed on both the Congo red-positive and Congo red-negative areas identified cochlin as the most abundant protein, as well as a low abundance of universal amyloid signature peptides only in the Congo red-positive areas. Peptides indicative of a canonical amyloid type were not detected. Electron microscopy showed haphazard, branched microfibrils (3-7 nm in diameter) consistent with cochlin, as well as swirling fibrils (10-24 nm in diameter) reminiscent of amyloid fibrils. Cochlin immunohistochemical staining showed positivity throughout the aggregates. Sequencing of the entire COCH gene coding region from the patient's blood revealed a novel variant resulting in a non-conservative amino acid substitution of isoleucine to phenylalanine (c.1621A>T, p.I541F) in the vWFA2 domain at the protein's C-terminus. Our findings reveal a new pathologic manifestation of cochlin, raise the possibility of previously undescribed cochlin-derived amyloid formation, and highlight the importance of thoroughly investigating all aggregative tissue findings in the practice of diagnostic pathology.

Placental intervillous hematomas have not previously been reported to undergo any sort of change, maturation, or healing. In this article, we present the first 2 case reports of recanalization-like neovascularization within placental hematomas: a 0.15 cm focus in an intervillous fibrin thrombus and a 0.2 cm focus in a subchorionic hematoma. Increased recognition and further studies are needed to gain a better understanding of this seemingly rare phenomenon and the factors that govern the lack of typical organization in placental hematomas. This might lead to a deeper knowledge of the repair process in general and shed light on how to control it in diseases caused by excessive repair.

OBJECTIVES/OBJECTIVE:The 2014 Bethesda System (TBS 2014) guidelines for reporting cervical cytology revised the age for reporting benign endometrial cells (BECs) from 40 years or older to age 45 years or older. We evaluated this change and further investigated if extending the reporting age to 50 years or older may be acceptable. METHODS:We reviewed cases with BECs reported on Papanicolaou tests in women age 40 years or older and 45 years or older before and after implementation of TBS 2014. Follow-up endometrial biopsy/curettage results were categorized as benign, endometrial hyperplasia with or without atypia, or malignant. Hyperplasia and malignant follow-up were considered clinically significant. Clinical data were documented. Results were compared for women age 40 to 44, 45 to 49, and 50 years or older. RESULTS:Follow-up in 15 (100%) women age 40 to 44 years was benign. In women age 45 to 49 years, 61 (96.8%) had benign follow-up, one (1.6%) had atypical hyperplasia, and one (1.6%) had malignant follow-up. In women age 50 years or older, 57 (86.5%) had benign follow-up, four (6%) had malignant follow-up, and seven (7.5%) had atypical or nonatypical hyperplasia. There was a significant difference in follow-up between the age groups of 40 to 49 and 50 or older (P = .023). CONCLUSIONS:We conclude that the TBS 2014 revision was justified. Our data suggest that age 50 years or older rather than age 45 years or older may be an acceptable cutoff for reporting BECs.

BACKGROUND:Ultrasound has become the initial approach to evaluating thyroid nodules, facilitating the distinction between benign and malignant nodules based on composition, echogenicity, nodule border or margin, shape, the presence of calcifications, and nodule dimensions. The American College of Radiology (ACR) recommended the Thyroid Imaging Reporting and Data System (TI-RADS) as a classification system to standardize thyroid ultrasound reports and to predict the probability of malignancy in thyroid nodules using a scoring system (TR1-TR5) based on multiple ultrasound characteristics and nodule size. Fine-needle aspiration (FNA) is recommended as the next step for nodules that warrant further workup. The authors assessed the accuracy of the ACR TI-RADS based on the corresponding FNA cytology results (Bethesda system diagnoses I-VI). METHODS:ACR TI-RADS ultrasound reports and corresponding FNA cytology diagnoses from January 1, 2018 to August 30, 2018 were evaluated. RESULTS:From January 1, 2018 to August 30, 2018, 2306 thyroid ultrasound-guided FNAs were performed at our institution. Of 2306 cases, 361 had ACR TI-RADS reports available. The majority of FNAs were TR4 (180; 49.9%) or TR3 (108; 29.9%). No TR2 or TR3 nodules were associated with Bethesda category V or VI diagnoses. The majority of TR4 nodules (142 of 180; 78.9%) and TR5 nodules (42 of 65; 64.6%) exhibited benign (Bethesda category II) cytology. Fourteen TR5 cases (21.5%) had malignant (Bethesda category VI) cytology. CONCLUSIONS:Although there were no TR2 or TR3 malignant (Bethesda category VI) diagnoses, and there were only a few malignancies in the TR4 and TR5 categories, the current results reassert the notion that the ACR TI-RADS scoring system shows at least some correlation between benign or malignant cytology diagnoses, as illustrated by the greater number of malignant cases in the higher ACR TI-RADS categories.

A case is presented in which a preoperatively diagnosed hydatid cyst was found to be a mature cystic teratoma on pathological examination. Diagnostic dilemmas surrounding each disease are discussed.

Background: Little is known about Warthin-like variant of papillary thyroid carcinoma (WL-PTC). Its clinicopathologic features are thought to be similar to the classic variant of papillary thyroid carcinoma (PTC). Our aim was to evaluate clinical histories, laboratory findings, cytologic (FNA) and histopathologic features to better understand and characterize WL-PTC.
Design(s): We performed a retrospective review of PTC resection cases from 2013-2019 in our pathology database. Cases with a predominant WL-PTC pattern were chosen for further review. Corresponding clinical histories, laboratory results, and FNA cases were assessed.
Result(s): Of 3,731 thyroid surgical resection cases, 1,671 were diagnosed with PTC. 25/1,671 were reported to have Warthin-like features, but only 15/25 cases displayed Warthin-like features in >50% of tumor cells and were included in our study (Table 1). 80% were white, 6.7% Asian/Pacific Islander and 13.3% did not report race. 3/15 FNA cases were Bethesda III due to few follicular cells with nuclear atypia in a background of lymphocytes, making it difficult to distinguish atypia from PTC (Figs 1a-d). On resection, all cases had concomitant Hashimoto thyroiditis (HT). All cases tested for BRAF V600E immunohistochemistry were positive (4/4). All 5/15 cases with lymph node metastases had coexisting classic or tall cell features, though not all cases with classic or tall cell features metastasized. 46.7% required post-operative radioactive iodine therapy. To date, the median survival is 100% (range 1 to 6 years). (Table presented)
Conclusion(s): Of all PTC resections at our institution 0.9% were WL-PTC. WL-PTC cases had a prominent lymphocytic infiltrate within papillary fronds and oncocytic cytoplasm (Fig 2a). The unique histologic features of WL-PTC add unique challenges to its diagnosis. Due to its strong association with HT, WL-PTC, particularly microcarcinomas, may be overlooked as endocrine atypia (Fig 2c). As WL-PTC possesses oncocytic features, it can resemble tall cell variant PTC which has a poorer prognosis (Fig 2b). Moreover, minor co-existing tall cell components can actually occur in some WL-PTCs. Foci with tall cell features should be distinguished from WL-PTC by lack of lymphocytic infiltrate within long papillae, and taller than wide cells with distinct cell borders. Like the classic variant, WL-PTC has a favorable prognosis. Metastasis seems to be associated with the presence of classic or tall cell features. More studies are needed to further elucidate this association

Background: When the first diagnosis of a well-differentiated neuroendocrine neoplasm (WDNEN) is made on a biopsy, crush artifact may impede mitotic counting, and the Ki-67 proliferative index (KPI) plays a more important role in grading. Few studies have examined the reliability of KPI in the grading of metastatic (met) WDNEN.
Design(s): Cases were retrieved from 2008-19. For each primary (1degree) and met, a 40x hotspot image of a Ki-67 stained slide was taken. KPI was analyzed by the ImmunoRatio Plugin using ImageJ software. All were validated by independent manual counting. In 1 case, crush artifact precluded use of ImageJ. If multiple mets were present, the largest was selected. Cytology and cases with fewer than 100 cells were omitted. Tumors were graded as G1(KPI<3%), G2(KPI 3-20%), or G3(KPI>20%). Grade and KPI were compared between each 1degree and met.
Result(s): 67 cases, including 38 mets from 29 1degree WDNEN, were evaluated. There were 12, 2, 2, 1, 17, and 4 mets from lung, thymus, middle ear, pancreas, small bowel, & colon respectively. The greatest variations in KPI from 1degree to met were seen in lung compared to all other sites. In 24/38(63%) of all mets, the grade was the same as 1degree. In 14/38(37%) of all mets, the grade was different: 4/14(29%) were lower while 10/14(71%) were higher than 1degree. In mets from lung, 2 had lower, 6 had the same, & 4 had higher grade. In mets from middle ear, the grades increased. In mets from small bowel 2 had lower, 12 had the same, and 3 had higher grade. In mets from colon 3 had the same and 1 had higher grade. And in mets from thymus & pancreas, the grades remained the same. See Fig 1. 3 mets were diagnosed before 1degree (2 days to 2 months). Mets with higher grade than 1degree tended to have longer time interval between 1degree and met, but this was not significant at the 95% confidence level (Kruskal-Wallis test, p=0.08). 28 mets were regional and 10 were distant. There was no correlation between met site and grade change (Person Chi-square, p=0.33). Also see Table 1. (Table presented)
Conclusion(s): Our study showed that in most met WDNEN (63%), the grade remained the same as the 1degree. The grade was higher in 10/38(26%) and lower in 4/38(11%). There was a trend toward higher grade in mets that occurred at a longer time interval after the 1degree. Fig 2 shows a potential diagnostic pitfall when the met shows much higher KPI than 1degree. In conclusion, if a met WDNEN is suspected as a firsttime diagnosis, KPI must be used cautiously for classification of WDNEN since over/under-grading may occur