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Clinical Outcome and Morphology-Based Analysis of p53 Aberrant and Mismatch Repair Protein-Deficient Ovarian Clear Cell Carcinoma and Their Association With p16, HER2, and PD-L1 Expression

Wilkins, Reid; Lin, Lawrence Hsu; Xia, Rong; Shiomi, Tomoe; Zamuco, Ronaldo DeLeon; Shukla, Pratibha Sharma
OBJECTIVES/OBJECTIVE:We studied the prevalence and prognostic significance of mismatch repair deficient (MMRD) and p53 aberrant ovarian clear cell carcinoma (CCO) and their association with other prognostic and theranostic biomarkers (p16, HER2, PD-L1). We also aimed to identify morphologic features to serve as screening tools for immunohistochemical testing for these biomarkers. METHODS:Tissue microarrays with 3-mm cores from 71 pure CCOs were immunostained with PMS2, MSH6, p53, p16, HER2, and PD-L1. Expression status was correlated with tumor recurrence/disease progression and survival. It was also correlated with morphologic features (tumor size, nuclear grade, tumor architecture, mitotic activity, presence of endometriosis, tumor budding, and tumor inflammation). RESULTS:p53 aberrant tumors were associated with shorter overall and recurrence-free survivals (P = .002 and P = .01, respectively). In multivariate analysis, p53 aberrant status and tumor stage were independently associated with recurrence/disease progression (hazard ratio [HR] = 3.31, P = .037 and HR = 1.465, P = .004, respectively). p53 aberrant status was associated with tumor budding (P = .037). MMRD, p16, HER2, and PD-L1 expression had no prognostic significance. HER2 and PD-L1 were expressed in 56% and 35% of tumors, respectively. MMRD was associated with tumor expression of PD-L1 (P > .05) but not with tumor inflammation. CONCLUSIONS:Aberrant p53 in CCO is infrequent but associated with poor prognosis independent of stage. Presence of tumor budding could be a screening tool for p53 testing. High prevalence of HER2 and PD-L1 expression indicates the eligibility of patients with CCO for ongoing clinical trials using these therapeutic targets.
PMID: 37415414
ISSN: 1943-7722
CID: 5524402

DICER1 Mutation in Bethesda III Thyroid Nodules [Meeting Abstract]

Karimkhan, Afreen; Xia, Rong; Hindi, Issa; Belovarac, Brendan; Shafizadeh, Negin; Sun, Wei; Patel, Kepal; Givi, Babak; Hodak, Steven; Simsir, Aylin; Brandler, Tamar
ISI:000990969800344
ISSN: 0023-6837
CID: 5525462

Defining Quality Metrics in Thyroid FNA Cytology: A Comparison of Cytopathologists' TBS III, Molecular Positivity and TBS III:VI Rates in a Large Academic Institution [Meeting Abstract]

Brandler, Tamar; Xia, Rong; Shafizadeh, Negin; Hindi, Issa; Belovarac, Brendan; Karimkhan, Afreen; Sun, Wei; Simsir, Aylin
ISI:000990969803397
ISSN: 0023-6837
CID: 5525472

Biliary Duct Brushing Specimens: Fishing for the Right Combination [Meeting Abstract]

Xia, R; Mei, L; Antic, T; Reeves, W; Siddiqui, U; Setia, N; Yassan, L
Introduction: Biliary duct brushing (B
EMBASE:640494540
ISSN: 1938-2650
CID: 5512112

Cytomorphology of Low-Grade Urothelial Neoplasia (LGUN) in Urine Cytology [Meeting Abstract]

Xia, R; Sun, W; Chen, F; Lin, L; Shafizadeh, N; Shi, Y; Deng, F -M; Simsir, A; Brandler, T
Introduction: The utility of The Paris System (TPS) in diagnosing low-grade urothelial neoplasm (LGUN) on urine cytology is controversial due to the strict requirement for fibrovascular cores, and low sensitivity/specificity. Many LGUNs are classified as atypical urothelial cells (AUC) on cytology, which compromises the performance and utility of TPS. Here, we studied cytomorphologic features of LGUN in urine samples to determine which features were commonly observed.
Material(s) and Method(s): Twenty-two urine cytology cases with corresponding (within 2 months) LGUN histologic diagnosis were retrieved for this pilot study and were evaluated by one cytopathologist for the presence of clusters, cercariform cells, hyperchromasia, irregular nuclear rim, papillary architecture +/-fibrovascular core, and nucleus:cytoplasm (N:C) ratio (Figure 1). Hierarchical cluster analysis (Ward's Method) was used to classify the features.
Result(s): Of the 22 urines, one was voided (4.5%) and 21 were instrumented (95.5%). Majority (77.3%) were diagnosed as AUC, 1 was suspicious for urothelial carcinoma (4.5%), 4 cases were graded as LGUN (18.2%, Table 1). Clustering analysis demonstrated that the morphologic features abundantly present in the urine specimen of LGUN included: clusters (77.3%), N:C ratio >50% (85.4%), and papillary architecture without a core (72.7%). The features that were mostly absent in LGUN specimens included: irregular nuclear rim (0%), papillary formation with a core (0%), hyperchromasia (9.1%), coarse chromatin (22.7%), and cercariform cells (36.3%). (Table 2).
Conclusion(s): Papillary formation with a fibrovascular core, the most convincing feature of LGUN, was not present in our pilot cohort of LGUN urines. However, our study describes additional cytomorphologic features that may be useful in identifying LGUN in urine cytology. Our research will continue with the evaluation of a larger cohort of LGUN cases with corresponding urine cytology in order to further investigate these findings
EMBASE:640494478
ISSN: 1938-2650
CID: 5512122

Isolated THADA-IGF2BP3 Gene Fusions in Fine-Needle Aspiration Cytology: An Indicator of Favorable Prognosis [Meeting Abstract]

Chen, F; Xia, R; Sun, W; Liu, C; Suh, I; Givi, B; Patel, K; Szeto, O; Simsir, A; Brandler, T
Introduction: Thyroid fine-needle aspiration (FNA) cytology combined with molecular testing guides individualized patient management by providing information regarding tumor biology and the risk of recurrence associated with specific mutations in the indeterminate groups (Bethesda group III-V). Thyroid adenomaassociated (THADA)-IGF2BP3 fusions have been identified as an oncogenic event in thyroid neoplasms, but the clinical-pathologic features and subsequent management are not well-established. Here we report the findings associated with thyroid nodules with THADA-IGFBP3 fusions in our institution.
Material(s) and Method(s): FNA cytology samples of thyroid nodules during 01/2015-12/2016 with the diagnosis of atypia of undetermined significance or follicular lesion of undetermined significance (AUS/FLUS; Bethesda III), follicular neoplasm/ suspicious for follicular neoplasm (FN/SFN; Bethesda IV) and suspicious for malignancy (Bethesda V) with corresponding ThyroSeqV2 data were assessed. Molecular test results yielding a THADA gene fusion were identified. In addition, follow-up surgical pathology and available radiology results were reviewed.
Result(s): 186 out of 558 (33.3%) thyroid nodules displayed molecular alterations; 7 out of 186 (3.8%) Bethesda category III-V nodules with ThyroSeq molecular alterations displayed isolated THADA-IGFBP2 fusions (Table 1). The median age was 45 years. The female to male ratio was 5:2. The nodule sizes ranged from 1.8 to 5.0 cm. Four (57%) patients had surgery; three cases displayed noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) on histology; one case was a follicular adenoma. No patients had recurrence or metastasis on follow-up.
Conclusion(s): Our pilot study shows that thyroid nodules with THADA-IGF2BP3 fusions display low-risk/indolent features. These findings may aid in clinical management decisions in patients presenting with thyroid nodules with isolated THADAIGF2BP3 fusions on molecular testing
EMBASE:640494779
ISSN: 1938-2650
CID: 5512142

Do ACR TI-RADS scores demonstrate unique thyroid molecular profiles?

Xia, Rong; Sun, Wei; Yee, Joseph; Sheth, Sheila; Slywotzky, Chrystia; Hodak, Steven; Brandler, Tamar C
PURPOSE/OBJECTIVE:The present study aimed to examine the molecular profiles of cytologically indeterminate thyroid nodules stratified by American College of Radiology Thyroid Imaging Reporting and Data System (TI-RADS) categories and to determine whether certain ultrasonographic features display particular molecular alterations. METHODS:A retrospective review was conducted of cases from January 1, 2016 to April 1, 2018. Cases with in-house ultrasonography, fine-needle aspiration Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) diagnoses, molecular testing, and surgery were included. All cases were diagnosed as TBSRTC indeterminate categories. The ultrasound studies were retrospectively reviewed and assigned TI-RADS scores (TR1-TR5) by board-certified radiologists. The final diagnoses were determined based on the surgical resection pathology. Binary logistic regression analysis was used to study whether demographic characteristics, TI-RADS levels, and TBSRTC diagnoses were associated with ThyroSeq molecular results. RESULTS:Eighty-one cases met the inclusion criteria. RAS mutations were the most common alteration across all TI-RADS categories (TR2 2/2; TR3 10/19, TR4 13/44, and TR5 8/16), and did not stratify with any particular TI-RADS category. Only TR4 and TR5 categories displayed more aggressive mutations such as BRAFV600E and TERT. ThyroSeq results were positively correlated with thyroid malignancy when non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) was categorized in the malignant category (odds ratio [OR], 6.859; P<0.01), but not when NIFTP was removed from the malignancy category. Echogenicity scores were found to be negatively correlated with ThyroSeq results in thyroid nodules (OR, 0.162; P<0.01). CONCLUSION/CONCLUSIONS:Higher-risk molecular alterations tended to stratify with the higher TI-RADS categories.
PMID: 35189676
ISSN: 2288-5919
CID: 5175032

Comparison of the clinicopathologic features of prostate cancer in US and Chinese populations

Zhang, Lei; Liu, Xiaoyan; Xia, Rong; Chen, Fei; Wang, Xin; Bao, Jia; Shao, Yongzhao; Lu, Xian; Wang, Yan; Wang, Jili; Tun, May Thu; Melamed, Jonathan; Lepor, Hebert; Deng, Fang-Ming; Wang, Dongwen; Ren, Guoping
BACKGROUND:Prostate cancer (PCa) is the most common malignant tumor found among men in the United States. Incidence rates of PCa have recently grown in Asian countries, partially due to the comprehensive implementation of early detection systems. Interestingly, a prospective cohort study showed that adopting a westernized dietary pattern was associated with a higher risk of being diagnosed with PCa among Korean and Japanese men. However, a comparison of current clinicopathological features of PCa between American and Chinese men is lacking. In this study, we report the current clinicopathological features of PCa in Chinese men and compare them to those of patients in the USA. MATERIALS AND METHODS/METHODS:Case cohorts included, in total, 871 PCa cases with prostatectomy sequentially treated since 2017, including 299 cases from USA and 572 cases from two different academic hospitals in China. The parameters, including patient's age, preoperative Prostate-Specific Antigen (PSA) level, Gleason score, Grade Group, stage and tumor focality, were collected, analyzed and compared using two sample t-test, Wilcoxon rank sum test, Pearson's Chi-squared test and Fisher's exact test. RESULTS:Significant differences were demonstrated in the mean age of patients, preoperative PSA levels, extra-prostatic extension, Gleason scores, and Grade Groups (p < 0.05). PCa patients in the Chinese group were older than patients in the USA group (67.81 vs. 63.53, p < 0.01). The preoperative PSA levels in the Chinese group were higher than those in the USA group (11.69 v.s 6.30, p < 0.01). A higher percentage of high Grade Groups (Groups 4 and 5) was observed in the Chinese group (25.7%) compared to the USA cohort (17.11%), while Grade Group 2 was more common in the USA group than in the Chinese group (51.68% vs. 32.52%, p < 0.01). CONCLUSIONS:All these data suggest that the clinicopathologic features of PCa are different between the USA and Chinese populations, which may be influenced by treatment strategies (including surgical case selection criteria).
PMID: 35525175
ISSN: 1618-0631
CID: 5216582

Gastrointestinal stromal tumors (GISTs) arising in uncommon locations: clinicopathologic features and risk assessment of esophageal, colonic, and appendiceal GISTs

Hu, Shaomin; Alpert, Lindsay; Cates, Justin M M; Gonzalez, Raul S; Graham, Rondell; Goldblum, John R; Bakhshwin, Ahmed; Shetty, Sindhu; Wang, Hanlin L; Lollie, Trang; Ma, Changqing; Siddique, Ayesha; Karamchandani, Dipti M; Chen, Fengming; Yantiss, Rhonda K; Hissong, Erika; Chatterjee, Deyali; Chopra, Shefali; Chen, Wei; Vazzano, Jennifer; Wang, Wei-Lien; Ai, Di; Lin, Jingmei; Zheng, Lan; Davis, Jessica L; Brinkerhoff, Brian; Breitbarth, Amanda; Yang, Michelle; Madahian, Sepideh; Panarelli, Nicole; Kuan, Kevin; Pomper, Jonathan; Longacre, Teri; Raghavan, Shyam; Misdraji, Joseph; Cui, Min; Yang, Zhaohai; Savant, Deepika; Harpaz, Noam; Chen, Xiuxu; Resnick, Murray; Wu, Elizabeth Yiru; Klimstra, David; Shia, Jinru; Vyas, Monika; Kakar, Sanjay; Choi, Won-Tak; Robert, Marie E; Li, Hongjie; Lee, Michael; Clark, Ian; Li, Yongchao; Cao, Wenqing; Chang, Qing; Bronner, Mary P; Dong, Zachary; Zhang, Wei; Buehler, Darya; Swanson, Paul E; Mantilla, Jose G; Bellizzi, Andrew M; Feely, Michael; Cooper, Harry S; Nagarathinam, Rajeswari; Pai, Rish; Hammer, Suntrea; Hosseini, Mojgan; Hu, JingJing; Westerhoff, Maria; Cheng, Jerome; Agostini-Vulaj, Diana; Lauwers, Gregory; Ghayouri, Masoumeh; Pezhouh, Maryam K; Zeng, Jianying; Xia, Rong; Yin, Feng; Zhang, Tao; Gao, Zu-Hua; Demko, Nadine; Chen, Hannah H; Yu, Sanhong; Hart, John
Risk stratification of gastrointestinal stromal tumors (GISTs) is based on experience with tumors of the stomach, small bowel, and rectum, which are far more common than GISTs of other sites. In this study from 47 institutions, we analyzed GISTs of the esophagus (n = 102), colon (n = 136), and appendix (n = 27) for their size, mitotic rate, morphology, and outcome to determine which criteria predict their behavior. Esophageal GISTs were small (median: 2.5 cm) with spindle cell morphology and a low mitotic rate (mean: 3.6/5 mm2). Twelve (12%) tumors progressed, including 11 with a mitotic rate >5/5 mm2 and one large (6.8 cm) GIST with a mitotic rate of 2/5 mm2. Colonic GISTs were smaller (median: 1.4 cm) and presented with abdominal pain or bleeding in 29% of cases. Most (92%) were composed of spindle cells with a mean mitotic rate of 4.6/5 mm2. Sixteen (12%) tumors progressed: 14 had mitotic rates >5/5 mm2, and two were >5.0 cm with a mitotic rate <5/5 mm2. All but one appendiceal GIST measured <2.0 cm. These tumors were composed of spindle cells with low mitotic rates (<5/5 mm2), and none progressed. Our results suggest that progression risk among esophageal and colonic GISTs is associated with increased mitotic activity (>5/5 mm2) and size >5.0 cm. These findings support the use of size and mitotic rate for prognostication of GISTs in these locations, similar to tumors of the stomach, small bowel, and rectum.
PMID: 34702994
ISSN: 1530-0285
CID: 5486732

Effusion fluid cytology and COVID-19 infection

Xia, Rong; Hsu Lin, Lawrence; Sun, Wei; Moreira, Andre L; Simsir, Aylin; Brandler, Tamar C
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.
PMID: 34958719
ISSN: 1934-6638
CID: 5106332