Proper Tweeting Etiquette Guidelines for Pathologists, Trainees, and Medical Students on #PathTwitter.

The use of social media in pathology has broadly had a positive impact on pathology education and outreach with the frequent posting of high-quality educational material of potential value to trainees, practicing pathologists, and other clinical and laboratory specialists. These posts are also of potential utility and interest to members of the public, who are now more than ever able to gain a window into the field and the role of pathologists in their medical care. There can be a lighthearted aspect to teaching material with the use of food items/analogies, emojis, or other descriptors, which may cross over into the classroom. However, when pathology discussion is taken to a public forum, such as on Twitter (parent company: X Corp.), there is the potential for posted material to be misunderstood, such as when certain emojis or adjectives may be used to describe a human disease state or patient sample. The authors present examples of potential areas of caution, suggestions of how to create a positive impact, and brief guidelines for social media etiquette on #PathTwitter that may apply to other social media platforms widely used by pathologists (including, but not limited to, Facebook, Instagram, YouTube, and KiKo). While the points discussed here may be common knowledge and well-known to pathologists who use social media for virtual medical education, the concerns mentioned here (such as using language like "beautiful" to describe abnormal mitotic figures and cancer cells) still exist and, henceforth, bear reinforcing.

#PathX: #PathTwitter's Transformation and a Discussion on Different Social Media Platforms Used by Pathologists in 2024.

#PathTwitter is a well-known virtual community that has historically been positive for pathologists, trainees, and medical students worldwide to communicate, collaborate, and connect for free. However, in 2023, the popular social media platform Twitter (parent company: X Corp.) transitioned to "X" and, with this, #PathTwitter evolved into #PathX. Although the overall user experience of X and Twitter has not changed significantly, this transition brought much anecdotal hesitancy from the online virtual pathology community early on. Thus, the purpose of this review is to discuss the background of Twitter's importance in pathology, the implications of this transition to the online pathology community, current views from this community regarding Twitter versus X, and to provide an overview of pertinent changes in the platform, as well as of different popular social media platforms that may be used by pathologists in 2024.

TLE3 Sustains Luminal Breast Cancer Lineage Fidelity to Suppress Metastasis.

Breast cancer subtypes and their phenotypes parallel different stages of the mammary epithelial cell developmental hierarchy. Discovering mechanisms that control lineage identity could provide novel avenues for mitigating disease progression. Here we report that the transcriptional corepressor TLE3 is a guardian of luminal cell fate in breast cancer and operates independently of the estrogen receptor. In luminal breast cancer, TLE3 actively repressed the gene-expression signature associated with highly aggressive basal-like breast cancers (BLBC). Moreover, maintenance of the luminal lineage depended on the appropriate localization of TLE3 to its transcriptional targets, a process mediated by interactions with FOXA1. By repressing genes that drive BLBC phenotypes, including SOX9 and TGFß2, TLE3 prevented the acquisition of a hybrid epithelial-mesenchymal state and reduced metastatic capacity and aggressive cellular behaviors. These results establish TLE3 as an essential transcriptional repressor that sustains the more differentiated and less metastatic nature of luminal breast cancers. Approaches to induce TLE3 expression could promote the acquisition of less aggressive, more treatable disease states to extend patient survival. SIGNIFICANCE: Transcriptional corepressor TLE3 actively suppresses SOX9 and TGFß transcriptional programs to sustain the luminal lineage identity of breast cancer cells and to inhibit metastatic progression.

Focal Adhesion Kinase Provides a Collateral Vulnerability That Can Be Leveraged to Improve mTORC1 Inhibitor Efficacy.

The PI3K/AKT/mTORC1 pathway is a major therapeutic target for many cancers, particularly breast cancer. Everolimus is an mTORC1 inhibitor used in metastatic estrogen receptor-positive (ER+) and epidermal growth factor receptor 2-negative (HER2-) breast cancer. However, mTORC1 inhibitors have limited efficacy in other breast cancer subtypes. We sought to discover collateral sensitivities to mTORC1 inhibition that could be exploited to improve therapeutic response. Using a mouse model of breast cancer that is intrinsically resistant to mTORC1 inhibition, we found that rapamycin alters the expression of numerous extracellular matrix genes, suggesting a potential role for integrins/FAK in controlling mTORC1-inhibitor efficacy. FAK activation was also inversely correlated with rapamycin response in breast cancer cell lines. Supporting its potential utility in patients, FAK activation was observed in >50% of human breast cancers. While blocking FAK in mouse models of breast cancer that are highly responsive to rapamycin had no impact on tumor growth, FAK inhibition sensitized rapamycin-resistant tumors to mTORC1 inhibition. These data reveal an innate dependency on FAK when mTORC1 signaling is lost in tumors that are resistant to mTORC1 inhibitors. They also suggest a precision medicine approach to improving mTORC1 inhibitor efficacy in resistant cancers by suppressing FAK signaling.

Immune cells and signatures characterize tumor microenvironment and predict outcome in ovarian and endometrial cancers.

Aims: We investigated immunogenomic signatures and correlated them with survival in ovarian cancer (OV) and endometrial cancer (EC). Materials & method: We used whole transcriptome sequencing data from uterine serous cancer and The Cancer Genome Atlas data of OV and EC (n = 719). Gene expression score was calculated. Population abundance of immune cells were estimated. Results: TGF-ß, myeloid cells, IFN-γ, T cells, B cells and endothelial cells predicted overall survival. Whereas CD47, neutrophils and endothelial cells predicted progression-free survival. In multivariate analyses, TGF-ß, CD47 and monocytic cells predicted survival in high levels of microsatellite instability (MSI-H) EC whereas high IFN-γ trended toward improved survival in the MSI-S EC. High IFN-γ/low TGF-ß and high IFN-γ/low CD47 signatures predicted longer overall survival. Low TGF-ß/low CD47 signature predicted longer overall survival only in the MSI-H EC. Conclusion: Our data support the role of immune markers in predicting survival in OV/EC.

Lay abstract We studied the association of immune markers and immune cells with survival outcome in ovarian and endometrial cancers. We performed gene expression analyses on tumor tissue of 719 patients. We generated signatures for the immune cells and markers and correlated them with survival outcome. We showed that specific immune cells and markers correlated strongly with survival even after we adjusted for other confounding factors. Further, we showed that these immune markers and immune cells have different correlation with survival when stratified in subtypes of endometrial cancer. Our data support the role of these immune markers in predicting survival outcome in ovarian and endometrial cancers.

Significance of atypical endometrial cells in women younger than 40 years of age.

INTRODUCTION: The presence of atypical endometrial cells in the Papanicolaou (Pap) test has been associated with an increased rate of endometrial malignancy, with reported rates ranging from 14% to 47%. However, most reported studies have focused on patients who were aged >40 years. The purpose of the present study was to investigate the clinical significance of identifying atypical endometrial cells in Pap test samples in women aged <40 years of age. MATERIALS AND METHODS: A search of the cytology Pap test database was performed from 2000 to 2014 using the keywords "atypical endometrial cells" or "atypical glandular cells favor endometrial origin" in women aged <40 years. The available ThinPrep slides were reviewed. The patients' clinical presentation, follow-up endometrial biopsy findings, treatment, and clinical follow-up data were recorded. Endometrial carcinoma tissue sections were screened for Lynch syndrome. RESULTS: The database search yielded 63 study cases. Of these 63 patients, 52 had subsequently undergone endometrial biopsy. Of the 52 patients with follow-up biopsy findings available, 9 (17.3%) had premalignant (5 with atypical hyperplasia) or malignant (4 with endometrioid adenocarcinoma) lesions. In addition, 16 patients (30.8%) had other endometrial pathologic features. The 9 patients with premalignant or malignant endometrial lesions (8 white, 1 black) were overweight or obese; 3 of the patients did not have any clinical symptoms. All 4 patients with endometrioid adenocarcinoma had negative Lynch syndrome screening findings. CONCLUSIONS: Our results suggest that it is important to recognize the presence of atypical endometrial cells in the Pap tests from young patients, given its association with the finding of premalignant and malignant pathologic features in subsequent endometrial biopsies.

Uterine Inflammatory Myofibroblastic Tumor Showing an Atypical ALK Signal Pattern by FISH and DES-ALK Fusion by RNA Sequencing: A Case Report.

Inflammatory myofibroblastic tumors (IMTs) are spindle cell neoplasms of intermediate (borderline) biologic potential with tendency for local recurrence but low risk of metastasis. They affect children more than adults. The most common sites of involvement are the lung, soft tissue, peritoneum, bladder, and less commonly the gynecologic tract. IMTs are characterized by spindle to epithelioid cells with myofibroblastic differentiation, some degree of smooth muscle differentiation, myxoid stroma and usually associated with brisk lymphoplasmacytic infiltrates. In about half of the cases, IMTs are associated with rearrangements of the anaplastic lymphoma kinase (ALK) gene located at chromosome 2p23. The ALK rearrangement can be detected by immunohistochemistry for ALK protein expression (mostly cytoplasmic with or without perinuclear accentuation) or by fluorescent in situ hybridization (FISH) using dual-color break-apart probes for which the typical pattern is seen as split 3' end (red) and 5' end (green) probe signals in addition to single normal, unsplit red-green signal pair (yellow). Herein we describe a case of uterine IMT initially misdiagnosed intraoperatively as leiomyoma which showed sparse lymphocytic infiltrates, positive ALK expression by immunohistochemistry, a predominantly atypical FISH signal pattern (1 yellow and 1 red signal only) and few typical signal patterns (1 yellow, 1 red, and 1 green signal) in a smaller population of tumor cells. The RNA sequencing showed a recently described DES-ALK fusion transcript in the tumor cells, suggesting an intrachromosomal inversion and deletion as the likely underlying mechanism for the atypical FISH pattern. Familiarity with the unusual morphology and atypical FISH pattern is crucial given that this tumor has an activating ALK rearrangement and may benefit from targeted tyrosine kinase inhibitors in the future.

P16 Expression in Primary Vulvar Extramammary Paget Disease.

P16 immunohistochemistry has been widely used in facilitating the diagnosis of human papillomavirus (HPV)-related usual type vulvar intraepithelial neoplasm. However, studies of p16 expression in primary vulvar extramammary Paget disease (EMPD) are limited. We assessed the p16 expression by immunohistochemistry in 40 cases of primary vulvar EMPD, including 34 cases of intraepithelial vulvar EMPD and 6 cases of invasive vulvar EMPD and correlated p16 expression patterns with disease progression. Overall, p16 expression was present in 36 cases (90%), including 20 cases (50%) with focal staining pattern and 16 cases (40%) with diffuse staining pattern. All 20 cases with focal p16 staining pattern were intraepithelial vulvar EMPD. Diffuse p16 staining pattern was present in 10/30 cases (33.3%) of intraepithelial EMPD and in 6/6 cases (100%) with invasive vulvar EMPD. Negative p16 staining was present in four intraepithelial EMPD cases. Using a highly sensitive RNA in situ hybridization method, we did not detect high-risk HPV in the selected 10 cases with diffuse p16 staining pattern, including 6 cases of intraepithelial EMPD and 4 cases of invasive EMPD. We also observed that intraepithelial EMPD had predominantly cytoplasmic p16 immunoreactivity, whereas nuclear p16 immunoreactivity was mainly seen in invasive EMPD components. Our study demonstrated that the p16 positive immunostaining was seen in the majority of primary vulvar EMPD which is not related to HPV infection. Therefore, knowing the overlapping p16 immunostaining patterns in vulvar EMPD and usual type vulvar intraepithelial neoplasm is important to render the correct diagnosis.

Thy-1 predicts poor prognosis and is associated with self-renewal in ovarian cancer.

BACKGROUND: Ovarian cancer is the leading cause of gynecologic cancer death in the United States despite effective first-line systemic chemotherapy. Cancer stem cells (CSCs) retain the ability to self-renew and proliferate and may be a means of harboring disease that evades standard treatment strategies. We previously performed a high-throughput screen to assess differential protein expression in ovarian CSCs compared to non-CSCs and observed that Thy-1 was more highly expressed in CSCs. Our primary aim was to validate Thy-1 (CD90) as a cancer stem cell (CSC) marker in epithelial ovarian cancer (EOC), correlate with clinical outcomes, and assess as a potential therapeutic target. RESULTS: Kaplan Meier (KM) Plotter data were correlated with survival outcomes. Quantitative real-time PCR, flow cytometry, and immunoblots assessed RNA and protein expression. Limiting dilution assays assessed self-renewal capacity and proliferation assays assessed proliferative capacity. RNA in-situ hybridization was performed on patient specimens to assess feasibility. Thy-1 (CD90) is more highly expressed in ovarian CSCs than non-CSCs, in EOC compared to benign ovarian epithelium (P < 0.001), and is highest in serous EOC (P < 0.05). Serous ovarian cancers with high Thy-1 expression have poorer outcomes (median PFS 15.8 vs. 18.3 months, P = 0 < 0.001; median OS 40.1 v. 45.8 months, P = 0.036). Endometrioid ovarian cancers with high Thy-1 have poorer PFS, but no difference in OS (upper quartile PFS 34 v. 11 months, P = 0.013; quartile OS not reached, P = 0.69). In vitro, Thy-1 expression is higher in CSCs versus non-CSCs. EOC cells with high Thy-1 expression demonstrate increased proliferation and self-renewal. Thy-1 knockdown in EOC cells decreases proliferative capacity and self-renewal capacity, and knockdown is associated with decreased expression of stem cell transcription factors NANOG and SOX2. RNA in situ hybridization is feasible in ovarian cancer tissue specimens. CONCLUSIONS: Thy-1 is a marker of ovarian CSCs. Increased expression of Thy-1 in EOC predicts poor prognosis and is associated with increased proliferative and self-renewal capacity. Thy-1 knockdown decreases proliferative and self-renewal capacity, and represents a potential therapeutic target.

Role of ThinPrep liquid-based cytology in evaluation of the endocervical canal in patients with abnormal cervical screening.

INTRODUCTION: Endocervical sampling is frequently used as an adjunct to colposcopy. Few studies address the role of endocervical brushing (ECB) with liquid-based cytology (LBC) for evaluation of the endocervical canal. We assessed the roles of ThinPrep (TP) LBC of ECB specimens and cell blocks (CBs). MATERIALS AND METHODS: Pathology archives were searched for ECB specimens from 2010-2015. Preceding Papanicolaou test interpretation, human papillomavirus status, concurrent and follow-up surgical specimens, and ECB diagnoses were recorded. CB cellularity, when available, was scored on a scale of 0 to 4. The cellularity of the TP and CBs was compared. RESULTS: Of 365 ECB cases, 6 (1.6%) were insufficient for diagnosis, compared with a 5% rate for endocervical curettings. Eleven ECB cases (3%) showed low cellularity. Of the 241 (66%) cases with concurrent biopsies, the ECB diagnosis agreed with the biopsy diagnosis (within 1 grade) in 198 (82%) cases. In 9 (2.5%) cases, ECB was the only means of diagnosis of a high-grade squamous intraepithelial lesion / adenocarcinoma in situ confirmed on follow-up. Compared with TP LBC, the CBs (performed in 84 [23%] of cases) were of greater cellularity in 30 (42%) and of equal cellularity in 17 (24%). None of the CBs showed an additional epithelial abnormality missed in TP LBC. CONCLUSIONS: TP LBC is capable of detecting endocervical epithelial abnormalities and may be used as a substitute for endocervical curettings. Performing a CB did not lead to detection of additional abnormalities, although it complemented TP findings and facilitates the performance of ancillary studies.

Thickened Endometrium in Postmenopausal Women With an Initial Biopsy of Limited, Benign, Surface Endometrium: Clinical Outcome and Subsequent Pathologic Diagnosis.

Endometrial biopsy or curetting is indicated for postmenopausal women with abnormal uterine bleeding and/or thickened endometrium. Often, endometrial biopsy or curetting yields limited benign surface endometrium, which may indicate insufficient sampling. This study addresses the clinical outcome and subsequent pathologic diagnoses in postmenopausal women who received this initial diagnosis. Among a total of 370 endometrial biopsy or curetting between 2012 and 2015, 192 (52%) were diagnosed as limited benign surface endometrial epithelium. The women ranged in age from 55 to 91 yr old. Their clinical presentations mainly included postmenopausal bleeding, pelvic pain, and enlarged uterus. Primarily because the initial report was interpreted as "benign," 108 (57%) had no subsequent follow-up. Interestingly, women with an increased endometrial thickness were more likely to receive repeat evaluation. Among the 84 women who underwent follow-up endometrial sampling, 6 (7%) had hyperplasia with atypia or malignancy, 21 (25%) had a repeat diagnosis of limited surface sample, 4 (5%) had insufficient materials, and 53 (63%) had other benign findings. Among the subset of women who did receive subsequent follow-up, endometrial atypia or malignancies are more likely found in those with increased body mass index. In conclusion, a slight majority of women with postmenopausal bleeding and/or thickened endometrium had an initial limited surface endometrial sample. Most had no subsequent endometrial sampling. Among those with subsequent follow-up, the majority had benign findings. The study highlights the inconsistencies in adequacy criteria for endometrial sampling and the lack of standardization of subsequent management.

The membrane tethered matrix metalloproteinase MT1-MMP triggers an outside-in DNA damage response that impacts chemo- and radiotherapy responses of breast cancer.

Breast cancer is the second leading cause of death among women in the US. Targeted therapies exist, however resistance is common and patients resort to chemotherapy. Chemotherapy is also a main treatment for triple negative breast cancer (TNBC) patients; while radiation is delivered to patients with advanced disease to counteract metastasis. Yet, resistance to both chemo- and radiotherapy is still frequent, highlighting a need to provide novel sensitizers. We discovered that MT1-MMP modulates DNA damage responses (DDR) in breast cancer. MT1-MMP expression inversely correlates to chemotherapy response of breast cancer patients. Inhibition of MT1-MMP sensitizes TNBC cells to IR and doxorubicin in vitro, and in vivo in an orthotopic breast cancer model. Specifically, depletion of MT1-MMP causes stalling of replication forks and Double Strand Breaks (DBSs), leading to increased sensitivity to additional genotoxic stresses. These effects are mediated by integrinß1, as a constitutive active integrinß1 reverts replication defects and protects cells depleted of MT1-MMP from IR and chemotherapy. These data highlight a novel DNA damage response triggered by MT1-MMP-integrinß1 and provide a new point of therapeutic targeting that may improve breast cancer patient outcomes.

Expression of LC3B and FIP200/Atg17 in brain metastases of breast cancer.

BACKGROUND: Macroautophagy/autophagy is considered to play key roles in tumor cell evasion of therapy and establishment of metastases in breast cancer. High expression of LC3, a residual autophagy marker, in primary breast tumors has been associated with metastatic disease and poor outcome. FIP200/Atg17, a multi-functional pro-survival molecule required for autophagy, has been implicated in brain metastases in experimental models. However, expression of these proteins has not been examined in brain metastases from patients with breast cancer. METHODS: In this retrospective study, specimens from 44 patients with brain metastases of infiltrating ductal carcinoma of the breast (IDC), unpaired samples from 52 patients with primary IDC (primary-BC) and 16 matched-paired samples were analyzed for LC3 puncta, expression of FIP200/Atg17, and p62 staining. RESULTS: LC3-puncta+ tumor cells and FIP200/Atg17 expression were detected in greater than 90% of brain metastases but there were considerable intra- and inter-tumor differences in expression levels. High numbers of LC3-puncta+ tumor cells in brain metastases correlated with a significantly shorter survival time in triple-negative breast cancer. FIP200/Atg17 protein levels were significantly higher in metastases that subsequently recurred following therapy. The percentages of LC3 puncta+ tumor cells and FIP200/Atg17 protein expression levels, but not mRNA levels, were significantly higher in metastases than primary-BC. Meta-analysis of gene expression datasets revealed a significant correlation between higher FIP200(RB1CC1)/Atg17 mRNA levels in primary-BC tumors and shorter disease-free survival. CONCLUSIONS: These results support assessments of precision medicine-guided targeting of autophagy in treatment of brain metastases in breast cancer patients.

CD55 regulates self-renewal and cisplatin resistance in endometrioid tumors.

Effective targeting of cancer stem cells (CSCs) requires neutralization of self-renewal and chemoresistance, but these phenotypes are often regulated by distinct molecular mechanisms. Here we report the ability to target both of these phenotypes via CD55, an intrinsic cell surface complement inhibitor, which was identified in a comparative analysis between CSCs and non-CSCs in endometrioid cancer models. In this context, CD55 functions in a complement-independent manner and required lipid raft localization for CSC maintenance and cisplatin resistance. CD55 regulated self-renewal and core pluripotency genes via ROR2/JNK signaling and in parallel cisplatin resistance via lymphocyte-specific protein tyrosine kinase (LCK) signaling, which induced DNA repair genes. Targeting LCK signaling via saracatinib, an inhibitor currently undergoing clinical evaluation, sensitized chemoresistant cells to cisplatin. Collectively, our findings identify CD55 as a unique signaling node that drives self-renewal and therapeutic resistance through a bifurcating signaling axis and provides an opportunity to target both signaling pathways in endometrioid tumors.

Cytologic-Histologic Discrepancies in Pathology of the Uterine Cervix: Analysis of the Clinical and Pathologic Factors.

Cytologic-histologic correlation (CHC) represents a documented effort to obtain and compare, when available, gynecologic cytology reports with an interpretation of high-grade squamous intraepithelial lesion or malignancy, with the subsequent histopathology report, and to determine the possible cause of any discrepancy. The correlation is influenced by multiple closely interdependent clinical and pathologic factors. Many of these factors including the sensitivity and accuracy of colposcopy-directed biopsy, the diligence of the colposcopist, and the attributes of the cervical lesion represent "preanalytical" factors which can significantly affect the CHC outcome, but are often less emphasized during CHC process. The status of "gold standard" of cervical biopsy histology will be less "golden" if clinicians miss, during colposcopy, the lesion which had been flagged by cytology. CHC also serves as one of the important assurance tools to monitor and improve the pathology laboratory overall quality, and the ability of the pathologists to enhance their diagnostic interpretation. As pathologists, we should make every effort to improve on CHC, by applying systematic approaches, both in technical laboratory and interpretive diagnosis, which increase yield and reduce diagnostic discrepancies. The widespread use of Human Papilloma Virus testing and p16 immunohistochemistry have significantly enhanced diagnostic accuracy both in cytology and in histology. Herein, we review the intimate relationships and factors that may govern discrepancies between cytology, colposcopy-directed biopsies, and biopsies with subsequent Loop Electroexcision Procedure for cervical squamous intraepithelial lesions. Ultimately the projected risk for high-grade squamous intraepithelial lesion and cancer and the suggested management guidelines are directly tied in with effective CHC.

Follistatin is a metastasis suppressor in a mouse model of HER2-positive breast cancer.

BACKGROUND: Follistatin (FST) is an intrinsic inhibitor of activin, a member of the transforming growth factor-ß superfamily of ligands. The prognostic value of FST and its family members, the follistatin-like (FSTL) proteins, have been studied in various cancers. However, these studies, as well as limited functional analyses of the FSTL proteins, have yielded conflicting results on the role of these proteins in disease progression. Furthermore, very few have been focused on FST itself. We assessed whether FST may be a suppressor of tumorigenesis and/or metastatic progression in breast cancer. METHODS: Using publicly available gene expression data, we examined the expression patterns of FST and INHBA, a subunit of activin, in normal and cancerous breast tissue and the prognostic value of FST in breast cancer metastases, recurrence-free survival, and overall survival. The functional effects of activin and FST on in vitro proliferation, migration, and invasion of breast cancer cells were also examined. FST overexpression in an autochthonous mouse model of breast cancer was then used to assess the in vivo impact of FST on metastatic progression. RESULTS: Examination of multiple breast cancer datasets revealed that FST expression is reduced in breast cancers compared with normal tissue and that low FST expression predicts increased metastasis and reduced overall survival. FST expression was also reduced in a mouse model of HER2/Neu-induced metastatic breast cancer. We found that FST blocks activin-induced breast epithelial cell migration in vitro, suggesting that its loss may promote breast cancer aggressiveness. To directly determine if FST restoration could inhibit metastatic progression, we transgenically expressed FST in the HER2/Neu model. Although FST had no impact on tumor initiation or growth, it completely blocked the formation of lung metastases. CONCLUSIONS: These data indicate that FST is a bona fide metastasis suppressor in this mouse model and support future efforts to develop an FST mimetic to suppress metastatic progression.

Interobserver agreement in the cytologic grading of atypia in neoplastic pancreatic mucinous cysts with the 2-tiered approach.

BACKGROUND: The accurate cytologic grading of epithelial atypia in fine-needle aspirates of pancreatic mucinous cysts has important implications for clinical management. The Papanicolaou Society of Cytopathology has recommended a 2-tiered system of low-grade (LG) and high-grade (HG) for grading this atypia. Using this approach, this study examined the interobserver agreement within a group of cytopathologists at the Cleveland Clinic. METHODS: Twenty cases of fine-needle aspiration of pancreatic neoplastic mucinous cysts with documented histologic follow-up and representative lesional cells were selected. Blinded to the histologic outcome, 4 cytopathologists were independently asked to assign the highest grade of atypia with the 2-tiered system of LG and HG atypia for these cases. The interobserver agreement was calculated with the κ statistic. RESULTS: The overall raw agreement in the grading of atypia was 60%. The overall chance-adjusted agreement was fair (κ = 0.28). On the basis of the histologic outcomes, the cases were stratified into group A (HG dysplasia or worse) and group B (LG or intermediate-grade [IG] dysplasia on follow-up). Group A (n = 12) showed good chance-adjusted agreement (κ = 0.65). For group B, the chance-adjusted agreement among the observers was poor (κ = 0.03). CONCLUSIONS: This study shows that the cytologic recognition of HG dysplasia or worse as HG atypia in pancreatic mucinous cysts has a good degree of interobserver reproducibility among cytopathologists. In contrast, a problematic area with a lack of agreement appears to be the cytologic recognition of LG and IG dysplasia as LG atypia. Additional studies with the development of reproducible criteria and educational tools may help with this challenging distinction. Cancer Cytopathol 2016;124:909-916. © 2016 American Cancer Society.

Racial disparity in survival of patients with uterine serous carcinoma: Changes in clinical characteristics, patterns of care and outcomes over time from 1988 to 2011.

OBJECTIVES: To determine if the disparities in the outcome between white (W) and African American (AA) patients with uterine serous carcinoma (USC) have changed over time. METHODS: Women with USC were identified using the SEER database from 1988 to 2011 (N=7667). Years of the study were divided into three periods (1988-1997, 1998-2004 and 2005-2011). Overall (OS) and disease-specific survivals (DSS) was estimated. RESULTS: Over the three time periods, African American patients continued to be younger and less likely to have cancer directed surgery and extensive lymphadenectomy when compared to white patients. In multivariable analysis adjusting for age, race, marital status, stage, cancer-directed surgery, extent of lymphadenectomy, adjuvant radiation, and geographic location, AA was significantly associated with worse DSS and OS in the three time periods compared to white race. African American patients were 29% (95% CI 1.03-1.62, p=0.027) in 1988-1997, 40% in 1998-2004 (95% CI 1.21-1.63, p<0.0001) and 34% in 2005-2011 (95% CI 1.13-1.59, p=0.0008) more likely to die from uterine cancer compared to their white counterparts. A slight improvement in the difference in OS over time was noted comparing African American and white patients. African American patients were 46% (95% CI 1.23-1.73, p<0.0001) in 1988-1997, 39% in 1998-2004 (95% CI 1.23-1.56, p<0.0001) and 26% in 2005-2011 (95% CI 1.10-1.45, p<0.0001) more likely to die from any cause compared to their white counterparts. CONCLUSIONS: Significant improvement in outcome was noted in both racial groups over time. However, African American patients continued to have worse outcome than white patients over time.

The impact of combined radiation and chemotherapy on outcome in uterine papillary serous carcinoma compared to chemotherapy alone.

OBJECTIVE: To investigate the impact of pelvic radiation on survival in patients with uterine serous carcinoma (USC) who received adjuvant chemotherapy. METHODS: Patients with stage I-IV USC were identified from the Surveillance, Epidemiology, and End Results program 2000 to 2009. Patients were included if treated with surgery and chemotherapy. Patients were divided into two groups: those who received chemotherapy and pelvic radiation therapy (CT_RT) and those who received chemotherapy only (CT). Kaplan-Meier curves and Cox regression proportional hazard models were used. RESULTS: Of the 1,838 included patients, 1,272 (69%) were CT and 566 (31%) were CT_RT. Adjuvant radiation was associated with significant improvement in overall survival (OS; p<0.001) and disease-specific survival (DSS; p<0.001) for entire cohort. These findings were consistent for the impact of radiation on OS (p<0.001) and DSS (p<0.001) in advanced stage (III-IV) disease but not for early stage (I?II) disease (p=0.21 for OS and p=0.82 for DSS). In multivariable analysis adjusting for age, stage, race and extent of lymphadenectomy, adjuvant radiation was a significant predictor of OS and DSS for entire cohort (p=0.003 and p=0.05) and in subset of patients with stage III (p=0.02 and p=0.07) but not for patients with stage I (p=0.59 and p=0.49), II (p=0.83 and p=0.82), and IV USC (p=0.50 and p=0.96). Other predictors were stage, positive cytology, African American race and extent of lymphadenectomy. CONCLUSION: In USC patients who received adjuvant chemotherapy, adjuvant radiation was associated with significantly improved outcome in stage III disease but not for other stages. Positive cytology, extent of lymphadenectomy and African race were significant predictors of outcome.

Cytologic categorization of pancreatic neoplastic mucinous cysts with an assessment of the risk of malignancy: A retrospective study based on the Papanicolaou Society of Cytopathology guidelines.

BACKGROUND: Cytology plays a pivotal role in the preoperative diagnosis of pancreatic cysts. Here the Papanicolaou Society of Cytopathology (Pap Society) guidelines were used to reclassify and assess the malignancy risk of cytology diagnoses of histologically proven pancreatic neoplastic mucinous cysts. METHODS: A database search (January 2000 to June 2014) was performed for pancreatic neoplastic mucinous cyst resections with endoscopic ultrasound-guided fine-needle aspiration within the preceding year. Histologic diagnoses were reclassified according to the 2010 Word Health Organization criteria. For atypical/suspicious/positive cytology diagnoses, the cytology slides were reviewed, blinded to the histologic diagnoses. The cysts were reclassified according to the Pap Society guidelines, and the findings were correlated with the histology. RESULTS: One hundred thirty-eight cases of pancreatic neoplastic mucinous cysts were retrieved. Eleven cases with atypical/suspicious cytology diagnoses with unavailable slides were excluded. The remaining 127 cases included 81 intraductal papillary mucinous neoplasms and 46 mucinous cystic neoplasms. The sensitivity of cytology for the diagnosis of neoplastic mucinous cysts was 76.4%. The sensitivity, specificity, and accuracy of cytology for the diagnosis of malignancy (high-grade dysplasia or worse) were 48.3%, 94.9%, and 84.3%, respectively. The risk of malignancy was 17.4% for the nondiagnostic category, 0% for the negative category, 13% for the neoplastic category, 63.6% for the atypical category, 80% for the suspicious category, and 100% for a positive diagnosis. CONCLUSIONS: This study reveals that the Pap Society guidelines allow the accurate categorization of pancreatic neoplastic mucinous cysts with cytology. The diagnostic categories (from negative to positive) are associated with an increasing risk of malignancy, and this can further aid in patient management and risk stratification.