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Background A single center experience with sporadic pancreatic insulinoma was analyzed to develop an algorithm for modern surgical management. Methods Thirty-four patients undergoing surgery from 2001 to 2019 were reviewed. Results The majority underwent enucleation (10 laparoscopic, 15 open). Laparoscopy was performed in 22 patients with conversion to open in 11, mostly related to the proximity of the tumor to the pancreatic duct (n = 4). Tumors on the anterior and posterior surface of the pancreas in all anatomic locations were completed with laparoscopic enucleation. Overall, the clinically-relevant postoperative pancreatic fistula (CR-POPF) rate was 21%, with no difference between laparoscopic versus open enucleation (10% vs 20%, p = 0.50) or enucleation versus resection (16% vs 33%, p = 0.27). Laparoscopic enucleation had shorter median hospital length of stay (LOS) compared with open (4 vs 7 days, p = 0.02). Conclusions Laparoscopic enucleation does not increase the CR-POPF risk and provides an advantage with a shorter hospital LOS in select patients. Tumor location and relationship to the pancreatic duct guide surgical decision-making. These findings highlight tumor-specific criteria that would benefit from a minimally invasive approach.

Background:Patients with COVID-19 and ARDS on prolonged mechanical ventilation are at risk for developing endotracheal tube (ETT) obstruction that has not been previously described in patients with ARDS due to other causes. The purpose of this report is to describe a case series of patients with COVID-19 and ARDS in which ETT occlusion resulted in significant clinical consequences and to define the pathology of the obstructing material.Methods:Incidents of ETT occlusion during mechanical ventilation of COVID-19 patients were reported by clinicians and retrospective chart review was conducted. Statistical analysis was performed comparing event rates between COVID-19 and non-COVID 19 patients on mechanical ventilation over the predefined period. Specimens were collected and submitted for pathological examination.Findings:Eleven COVID-19 patients experienced endotracheal tube occlusion over a period of 2 months. Average age was 69 (14.3, range 33-85) years. Mean APACHE III score was 73.6 (17.3). All patients had AKI and cytokine storm. Nine exhibited biomarkers for hypercoagulability. Average days on mechanical ventilation before intervention for ETT occlusion was 14 (5.18) days (range of 9 to 23 days). Five patients were discharged from the ICU, and 4 expired. Average documented airway resistance on admission was 14.2 (3.0) cm H2O/L/sec. Airway resistance before tube exchange was 28.1 (8.0) cm H2O /L/sec. No similar events of endotracheal tube occlusion were identified in non-COVID patients on mechanical ventilation during the same time period. Microscopically, the material consisted of mucin admixed with necrotic cell debris, variable numbers of degenerated inflammatory cells, oral contaminants and red blood cells.Interpretation:Patients with COVID-19 and ARDS on prolonged mechanical ventilation are at risk for developing ETT obstruction due to deposition of a thick, tenacious material within the tube that consists primarily of mucin and cellular debris. Clinicians should be aware of this dangerous but treatable complication.

Introduction This study aims to improve understanding of the cytopathology community’s perspective regarding the value of rapid onsite evaluation (ROSE) in clinical practice. Materials and methods The American Society of Cytopathology membership was surveyed in 2019 to obtain subjective data on the cytopathology community’s perceptions regarding ROSE. Comments were categorized by major themes and attitudes and analyzed by respondent’s role in laboratory, practice size, and practice setting (Fisher’s exact and χ2 tests). Results A total of 541 responses were received from 255 cytopathologists/pathologists, 261 cytotechnologists, 19 trainees, and 6 others (as previously reported). Reasons for which cytopathology personnel provide this service aligned with their perceptions of why clinicians request ROSE. A minority of respondents, disproportionally from high volume centers, felt ROSE is unnecessary. Overall attitude regarding ROSE was generally positive. There were no significant differences in attitude regarding ROSE according to role in laboratory or practice size, but respondents from academic centers provided a significantly higher percentage of positive comments than those in private or community practice. Although survey respondents generally felt that ROSE is valuable to patient care, they also highlighted several challenges, including staffing, time commitment, and inadequate reimbursement. Implementation of telecytology was felt to potentially alleviate some of these challenges. Conclusions Survey results show that the cytology community views ROSE favorably, practices vary considerably, and there is a perceived need for improved reimbursement. Data from this study may be used to identify areas that warrant additional research to clarify the clinical value of ROSE.

Solitary fibrous tumour (SFT) is well-described in the urinary tract, but malignant examples are rare. We studied our experience with high grade malignant SFT of the prostate to address the degree of histological and immunophenotypical overlap with sarcomatoid carcinoma and prostatic stromal sarcoma. Four cases were identified from the surgical pathology consultation archives. All available H&E stained sections were reviewed. Immunostains for STAT6, CAM5.2, NKX3.1, PAX-8, GATA3, high molecular weight cytokeratin (34BE12), p40, and p63 were performed on available material. Each case was evaluated by three separate SFT prognostic risk models based on clinicopathological features, and for features of 'dedifferentiated SFT'. The patient's ages were 49, 55, 69, and 73 years. Three presented with symptoms of benign prostatic hyperplasia and one with haematuria. Tumour sizes were 5, 9, 13, and 13 cm. Mitotic rate ranged from 6 to 20 mitoses per 10 high power fields, and two cases showed abrupt transition from conventional SFT to areas with marked nuclear pleomorphism/anaplasia (i.e., 'de-differentiation'). Immunophenotypically, all four cases had strong and diffuse nuclear reactivity for STAT6. For other markers, three of three had both focal PR and GATA3 nuclear expression (up to 30% of cells). One case with 'dedifferentiated' features showed expression of multiple epithelial markers, including EMA (focal), high molecular weight cytokeratin (focal), p63, and p40. In summary, malignant SFT may rarely occur in the prostate and may closely mimic sarcomatoid carcinoma or prostatic stromal sarcoma, both histologically and immunophenotypically. Consideration of the diagnostic possibility of malignant SFT, recognition of unexpected GATA3 and PR expression, and utilisation of monoclonal STAT6 immunohistochemistry facilitate appropriate diagnosis at this unusual anatomical site.

Introduction ACGME Milestones describe 6 areas of proficiency, indicating readiness for practice. Each is divided into 5 levels of mastery; Level 1 (new trainees) through Levels 4 (graduation) and 5 (aspirational). Milestones reporting began Spring 2016. We used Milestones to assess graduated fellows. Materials and methods We conducted phone interviews with previous fellows and collected demographic information including practice setting. We asked graduates if they fulfilled each example of mastery and recorded their answers. Results A total of 22 fellows graduated from 2010 to 2017; 15 responded (10 academic, 5 private). Milestones in which nearly all respondents performed well (Level 4+) were: PC1, MK1, SBP2, SBP4, PROF1-4, ICS1-3. Some were more challenging (PC2, MK2, SBP1/3/5, PBL1). For PC2, 2 respondents achieved Level 1 (did not perform fine-needle aspirations). For MK2, 2 respondents achieved Level 1 (did not evaluate Papanicolaou). For SBP1, 80% in private practice achieved Level 5; 50% in academics achieved Level 3. For SBP3, 80% in private practice achieved Level 4+; 100% in academics achieved maximum Level 2. For SBP5, 60% of all respondents achieved maximum Level 3; only 1 achieved Level 5. Conclusions Many Milestones are attainable. Eleven of 18 yielded Level 4+ from most respondents. Three (PC2, MK1, MK2) yielded rare Level 1 due to scope of practice. Others (SBP1, SBP3) reflect more of an all-or-nothing phenomenon. For SBP5, most respondents achieved Level 3; only 1 achieved Level 5. Some Milestones are highly dependent on practice setting, and others remain aspirational.

Germ cell tumors in the mediastinum are rare and often occur in young patients but may occur in older patients. Seminoma, embryonal carcinoma, yolk sac tumor, choriocarcinoma and teratoma have distinct morphologic features with high grade nuclei. They are the primary diagnostic consideration in young males but may be lower on the list in older patients, where they may be misdiagnosed as carcinomas. Review of the history, use of immunohistochemistry stains and recognition of morphologic features will help to make the diagnosis of germ cell tumor of the mediastinum. These tumors have a good to intermediate prognosis, depending on when they are detected.

Objective The aim of this study was to analyze the incidence of and risk factors for adrenocortical carcinoma (ACC) in adrenal incidentaloma (AI). Summary of background data AI guidelines are based on data obtained with old-generation imaging and predominantly use tumor size to stratify risk for ACC. There is a need to analyze the incidence and risk factors from a contemporary series. Methods This is a retrospective review of 2219 AIs that were either surgically removed or nonoperatively monitored for ≥12 months between 2000 and 2017. Multivariate logistic regression was performed to define risk factors. ROC curves constructed to determine optimal size and attenuation cut-offs for ACC. Results 16.8% of AIs underwent upfront surgery and rest initial nonoperative management. Of conservatively managed patients, an additional 7.7% subsequently required adrenalectomy. Overall, ACC incidence in AI was 1.7%. ACC rates by size were 0.1%, 2.4%, and 19.5% for AIs of 6 cm, respectively. The optimal size cut-off for ACC in AI was 4.6 cm. ACC risks by Hounsfield density were 0%, 0.5%, and 6.3% for lesions of 20 HU, with an optimal cut-off of 20 HU to diagnose ACC. 15.5% of all AIs and 19.2% of ACCs were hormonally active. Male sex, large tumor size, high Hounsfield density, and >0.6 cm/year growth were independent risk factors for ACC. Conclusion This contemporary analysis demonstrates that ACC risk per size in AI is less than previously reported. Given these findings, modern management of AIs should not be based just on size, but a combination of thorough hormonal evaluation and imaging characteristics.

Since mid-2019, > 2,000 cases of e-cigarette or vaping product use-associated lung injury (EVALI) have been reported. Although initial reports suggested that this entity may be a form of inhalation-related lipoid pneumonia, subsequent studies indicate that EVALI represents various patterns of acute lung injury. Cases of EVALI continue to be reported, and public awareness of the epidemic is increasingly high. However, evidence surrounding optimal management of EVALI remains limited. In this case series, we report 15 cases of EVALI across a spectrum of severity, highlighting key radiologic, pathologic, and cytologic findings, and discuss management implications. In line with national findings, most patients with EVALI in the series vaped liquids containing tetrahydrocannabinol. Our imaging and pathologic findings support the notion that EVALI is a form of acute lung injury.

Introduction Abdominopelvic washing cytology is a common specimen evaluated for ovarian, fallopian tubal, and peritoneal cancer staging or other nongynecologic malignancies presented as metastases. We reviewed our experience in diagnosing abdominopelvic washing specimens and assessing the primary tumor types and origins of the positive abdominopelvic washings. Materials and methods A pathology archive database search was performed for abdominopelvic washing specimens from 2007 to 2018. The corresponding cytologic diagnoses, results of ancillary studies, clinical histories, and surgical follow-up were reviewed. The primary sites were determined based on the synoptic reports, when available. Results A total of 5.8% (350 of 6023) of cases were positive for malignancy or neoplasm. Additionally, 1.3% (78 of 6023) were diagnosed as atypical cells. Of the 350 positive cases, 93.4% were mullerian tumors. The frequency of primary sites for mullerian tumors in descending order were: ovary, uterus, fallopian tube, peritoneum, and uncertain mullerian sites. The common ovarian tumors identified in pelvic washing in descending order were: high-grade serous carcinoma, serous borderline tumor, clear cell carcinoma, low-grade serous carcinoma, and endometrioid carcinoma. Gastrointestinal, breast, bladder, and lymphoma primaries were the 23 nongynecologic tumors identified in pelvic washings. Conclusions Positive findings in abdominopelvic washing cytology is rare. The majority of the positive cases were from mullerian origins, with ovary and uterus as the most common sites. Endometrial adenocarcinoma, endometrioid type and ovarian high-grade serous carcinoma were the most common tumor types. Knowing prior history of malignancy, morphologic comparison with concurrent surgical cases, and performing ancillary studies are keys to improve diagnostic accuracy of abdominopelvic washings.

Papillary renal cell carcinoma (PRCC) is well-recognized as a morphologically and molecularly heterogenous group of kidney tumors with variable clinical behavior. Our goal was to analyze a unique histologic pattern of PRCC we have observed in routine practice to evaluate for potential clinical significance or distinct molecular signature. We identified 42 cases of PRCC showing a morphologically distinct architecture characterized by numerous epithelial-lined cysts containing the papillary tumor (herein called "microcysts"), which are typically separated by fibrous stroma. Of the initial 42 case test set with microcystic features, 23 (55%) were stage pT3a or higher. Most tumors had strong and diffuse cytoplasmic immunoreactivity for CK7 (93%, 37/40) and AMACR (100%, 40/40). Fumarate hydratase staining was retained in all cases tested (39/39). We performed next-generation sequencing on 15 of these cases with available tissue and identified chromosomal alterations commonly reported in historically "type 1" PRCC, notably multiple chromosomal gains, particularly of chromosomes 7 and 17, and MET alterations. However, alterations in pathways associated with more aggressive behavior (including SETD2, CDKN2A, and members of the NRF pathway) were also identified in 6 of 15 cases tested (40%). Given this molecular and immunophenotypic data, we subsequently reviewed an additional group of 60 consecutive pT2b-pT3 PRCCs to allow for comparisons between cases with and without microcysts, to assess for potential associations with other recently described histologic patterns (ie, "unfavorable architecture": micropapillary, solid, and hobnail), and to assess interobserver reproducibility for diagnosing architectural patterns and grade. Of the total combined 102 PRCCs, 67 (66%) had microcystic architecture within the intrarenal component but were commonly admixed with other patterns (39% had micropapillary, 31% solid, and 31% hobnail). Twenty-seven cases (26%) had metastatic disease, and 24 of these 27 (89%) had microcystic architecture in the intrarenal tumor. Within the pT3 subset, 21 of 22 cases with metastases (95%) had extrarenal invasion as either individual microcysts in renal sinus fat or aggregates of microcysts bulging beyond the confines of the capsule. Backward elimination and stepwise regression methods to detect features significantly associated with adverse outcome identified solid architecture (hazard ratio [HR]: 6.3; confidence interval [CI]: 2.1-18.8; P=0.001), hobnail architecture (HR: 5.3; CI: 1.7-16.7; P=0.004), and microcystic architecture at the tumor-stromal interface (HR: 4.2; CI: 1.1-16.7; P=0.036) as strongest. Of architectural patterns and grade, the microcystic pattern had a substantial interobserver agreement (κ score=0.795) that was highest among the 6 observers. In summary, PRCCs with microcystic architecture represents a subset of historically "type 1" PRCC with a predilection for morphologically distinctive extrarenal involvement and metastatic disease. Microcysts co-vary with other "unfavorable" architectural patterns also associated with higher risk for aggressive disease (ie, micropapillary, hobnail, and solid), but microcysts were more common and have superior interobserver reproducibility. These findings suggest that microcystic PRCC should be recognized as a potentially aggressive histologic pattern of growth in PRCC.

Introduction Rapid on-site evaluation (ROSE) is a service provided by cytologists that helps ensure specimen adequacy and appropriate triage for ancillary testing. However, data on the current usage patterns across different practice settings have been lacking. Materials and methods To obtain an accurate and timely assessment of the current state of practice of ROSE, a 14-question online survey was constructed by the Clinical Practice Committee of the American Society for Cytopathology. The survey was available to the membership of the American Society for Cytopathology for a 3-week period in early 2019. Results A total of 541 responses were received, including from 255 cytopathologists/pathologists, 261 cytotechnologists, 19 cytology resident/fellow trainees, and 6 others. ROSE was offered as a clinical service by 95.4% of the respondents, with telecytology for ROSE used in 21.9% of the practices. Endobronchial ultrasound-guided transbronchial needle aspiration was the procedure most frequently reported to use ROSE (mean, 59.1%; median, 70%). Cytotechnologists were involved in ROSE in most practices. The number of daily ROSE procedures correlated with the annual nongynecologic cytology volumes. Approximately 70% of ROSE procedures were reported to require >30 minutes, on average, for the cytologist. Conclusions The results from our survey of cytologists have shown that the reported practice patterns for the usage of ROSE vary considerably. The presented data can help inform future guideline recommendations and the implementation of ROSE in different clinical settings.

Fine-needle aspiration (FNA) of liver masses is a minimally invasive means of evaluation, with diagnostic accuracy over 85%. Given that most of the recent literature on sampling hepatic tumors was published by radiologists and gastroenterologists, we herein conduct a 10-year retrospective review of a single institution's cytopathology experience with the diagnosis of liver lesions. Electronic record review of the cytopathology files (CoPathPlus; Cerner Corp) was conducted for the 10-year interval January 2007 through December 2016. All cytology specimens designated as "liver" and "FNA" were included. Associated concurrent and subsequent surgical pathology and cytopathology cases were identified. All FNA cases were organized into four diagnostic categories: positive for malignancy, atypical, negative for malignancy, and non-diagnostic. There were 713 hepatic FNAs that were categorized as follows: positive for malignancy 467 (65.5%), atypical 49 (6.9%), negative 171 (24.0%) and non-diagnostic 26 (3.6%). Metastatic tumors (95.7%) were more common that primary (4.3%). The top two metastatic primary sites were pancreas (30.1%) and colon (12.7%). A total of 166 (23.2%) cases had concurrent core needle biopsies (CNB). 111 (66.9%) were concordant with the FNA diagnosis. Of the 55 discordant cases, 43 (25.9%) had diagnostic material only on CNB and 12 (7.2%) had diagnostic material only on FNA. The sensitivity, specificity, positive predictive value, negative predictive value, and diagnostic accuracy were 93.4%, 96.7%, 98.2%, 84.3%, and 89.3% respectively. Irrespective of endoscopic versus percutaneous approach, hepatic FNA is a sensitive and specific means of identifying metastatic and primary malignancies of the liver.

Background Mutational status for KRAS, NRAS, and BRAF genes should be performed on all colorectal carcinoma (CRC) specimens in order to guide targeted therapy selection for metastatic disease. Mutations are typically assessed via polymerase chain reaction and/or next generation sequencing (NGS) on formalin-fixed paraffin-embedded tissues. With minimally invasive diagnostic methodologies, the cytology cell pellet obtained by fine-needle aspiration (FNA) can serve as an alternative source of tumor deoxyribonucleic acid. Methods An electronic record review of the cytopathology files (CoPathPlus, Cerner Corp., North Kansas City, Missouri) from September 1, 2015 through December 31, 2018 was conducted. All cytology specimens obtained via FNA and diagnosed as metastatic CRC on which NGS was performed were included. NGS for KRAS, NRAS, and BRAF mutations using the AmpliSeq Cancer Hotspot Panel v2.0 kit (Thermo Fisher Scientific, Waltham, Massachusetts) was performed on cytology cell pellets. Results Forty-eight cases were identified. Forty-six of 48 specimens (96%) were adequate for molecular testing. Of those adequate specimens, proportion of malignant cells in the sample ranged from 5% to 95% (mean 46%). Twenty-seven of 48 cases (56%) were positive for clinically relevant mutations. Twenty-four of 27 cases (89%) were positive for KRAS mutations, with exon 2 most frequently involved (22/24 cases, 92%). Two of 27 cases (7%) were positive for NRAS mutations and one case (1/27, 4%) was positive for a BRAF mutation involving codon 594. Conclusion Mutational analysis performed on cytology cell pellets serves as a useful means of gathering clinically actionable information on tumor mutation status in metastatic CRC.

Background Historically, sampling of adrenal lesions has been performed by percutaneous image-guided fine-needle aspiration (FNA) biopsy. Endoscopic ultrasound guided (EUS)-FNA of the adrenals was first employed at Cleveland Clinic ~10 years ago. We report a two-decade experience of adrenal FNA in our institution. Methods An electronic retrieval identified adrenal FNAs from 1997 to 2017. Data points from each case (diagnosis, method of FNA, age, sex, laterality, needle gauge, size of lesion, adequacy of sample, and histologic follow up) were analyzed. Results Our retrieval confirmed 198 adrenal FNAs performed over 20 years. Of these, 90% (179/198) were percutaneous, and the remaining 10% (19/198) were collected by EUS. Of the 179 CT guided FNAs, 93% (162/179) yielded an adequate specimen as compared with an adequacy rate of 89% (17/19) for EUS-FNAs, with no significant difference in adequacy rates by collection method, P = .64 (Fisher's exact). Of all adrenal FNAs, 53% (105/198) confirmed metastases, 33% (65/198) showed adrenal cells or primary adrenal neoplasms (85% cortical cells, 14% cortical neoplasia, 1% pheochromocytoma), 8% were inadequate (15/198), 3% were atypical (7/198), and 2% were suspicious for malignancy (5/198). Conclusion FNA of the adrenal glands can be useful in the diagnosis and staging of metastatic neoplasms, as well as in distinguishing primary adrenal cortical from medullary neoplasms and characterizing hematolymphoid and mesenchymal neoplasms. Overall adequacy rates for adrenal cytology are high (92%) with no statistically significant difference between CT-guided (93%) and EUS-FNA adequacy (89%). The majority of our procedures confirmed metastases, sparing patients unnecessary surgery.

Background The diagnosis of spindle cell neoplasms (SCN) of the upper gastrointestinal (GI) tract, hepatobiliary tract, and pancreas detected by fine needle aspiration (FNA) is challenging. We describe a single-center experience of these samples with follow-up data and characterization of the morphologic findings. Methods We retrospectively reviewed pathology records for all FNAs diagnostic for or suggestive of SCN on esophagus, stomach, small bowel, liver, and pancreas in a 15 year period. All cases with at least 6 month follow-up were included. Surgical material (biopsy or resection) was the diagnostic gold standard. All FNAs with subsequent surgical specimens were reviewed and assessed for cellularity, architectural features, and nuclear features. Results In 15 years, 5101 FNAs of the upper GI tract, hepatobiliary tract, and pancreas were performed. SCN was diagnosed in 98 (2%) patients. Seventy-two patients had definitive pathologic diagnoses: 68 were neoplastic and four were non-neoplastic. Cytomorphologic review in relationship to final diagnosis revealed three statistically significant features: low cellularity favors a benign process (P = .00544), epithelioid nuclear morphology favors malignancy (P = .00278), and identification of perinuclear vacuoles favors a diagnosis of GIST over non-GIST SCN (P = .04236). Conclusions Among cases with follow-up, final pathologic diagnoses were SCN in 94% of cases diagnosed as SCN on FNA of upper GI, hepatobiliary tract, and pancreas. Although some cytomorphologic criteria are more suggestive of malignancy, arriving at a specific diagnosis relies on collaboration of clinical, radiologic, cytomorphologic, and immunohistochemical data.

Objectives SMARCA4-deficient undifferentiated tumor has distinct clinicopathologic features. We describe our experience with primary diagnosis on adrenal sampling. Methods We collected six SMARCA4-deficient undifferentiated tumors diagnosed on adrenal sampling. Immunostains for SMARCA4, SF-1, inhibin, calretinin, S-100 protein, EMA, and TTF-1 were performed. A control group of 63 primary adrenocortical tumors was also immunostained. Results Patients included four men and two women (aged 52-77 years). Five had unilateral adrenal masses and one bilateral (range, 2.4-9.6 cm). Five had pulmonary masses, and one had a midline mediastinal mass. All cases had a monotonous epithelioid appearance and variable rhabdoid morphology. Immunophenotypically, all six cases had loss of nuclear SMARCA4 expression and no staining for SF-1, inhibin, calretinin, or S-100 protein. Variable EMA immunoreactivity was present in four of six cases and focal nuclear TTF-1 expression in one of six. All 63 adrenocortical neoplasms had retained nuclear SMARCA4 expression. Conclusions SMARCA4-deficient undifferentiated tumor may present in the adrenal gland, and this series likely represents metastases from thoracic primaries. Because of the frequent absence of lineage marker expression, knowledge of the characteristic clinical presentation, the rhabdoid morphology, and the typical immunophenotype (loss of SMARCA4/BRG1) allow for appropriate distinction from adrenocortical carcinoma.

BACKGROUND Urine cytology is an important screening tool in the diagnosis of high-grade urothelial carcinoma. Diagnosis in urine samples follows criteria outlined by The Paris System for Reporting Urinary Cytology (TPS). However, cytologic characteristics of the recently described urothelial carcinoma in situ with plasmacytoid features (P-CIS) have not been described, and it is unknown whether they conform to TPS criteria for high-grade urothelial carcinoma. This study was aimed at better characterizing possibly unique cytologic features of P-CIS. METHODS The authors collected urine cytology specimens from patients with subsequent bladder biopsy-proven P-CIS. Specimens were re-reviewed according to the TPS criteria. The proposed cytologic features of P-CIS (eccentric, enlarged, and hyperchromatic nuclei) were evaluated; this included the reproducibility of 3 cytopathologists for the proposed cytologic features. RESULTS Seventy-four urine specimens from 18 patients with P-CIS-diagnosed bladder biopsies were identified. The TPS diagnoses of the 74 urine cytology specimens were as follows: negative for high-grade urothelial carcinoma (n = 26), atypical urothelial cells (n = 26), suspicious for high-grade urothelial carcinoma (n = 12), and high-grade urothelial carcinoma (n = 10). Only 7 urine specimens met the proposed cytologic criteria for P-CIS, and they had TPS diagnoses of negative for high-grade urothelial carcinoma (n = 1), atypical urothelial cells (n = 3), and high-grade urothelial carcinoma (n = 3). The κ interobserver agreement ranged from poor to fair. CONCLUSION The features of P-CIS on urine cytology are subtle and infrequently reproducible and often do not meet the TPS criteria for diagnosis as high-grade urothelial carcinoma. In specimens that do not meet TPS criteria for high-grade urothelial carcinoma, P-CIS cytology in isolation would be best classified as atypical urothelial cells.

Purpose: Transcriptomic profiling can shed light on the biology of small-cell bladder cancer (SCBC), nominating biomarkers, and novel therapeutic targets. Experimental Design: Sixty-three patients with SCBC had small-cell histology confirmed and quantified by a genitourinary pathologist. Gene expression profiling was performed for 39 primary tumor samples, 1 metastatic sample, and 6 adjacent normal urothelium samples (46 total) from the same cohort. Protein levels of differentially expressed therapeutic targets, DLL3 and PDL1, and also CD56 and ASCL1, were confirmed by IHC. A SCBC PDX model was utilized to assess in vivo efficacy of DLL3-targeting antibody–drug conjugate (ADC). Results: Unsupervised hierarchical clustering of 46 samples produced 4 clusters that correlated with clinical phenotypes. Patients whose tumors had the most “normal-like” pattern of gene expression had longer overall survival (OS) compared with the other 3 clusters while patients with the most “metastasis-like” pattern had the shortest OS (P = 0.047). Expression of DLL3, PDL1, ASCL1, and CD56 was confirmed by IHC in 68%, 30%, 52%, and 81% of tissue samples, respectively. In a multivariate analysis, DLL3 protein expression on >10% and CD56 expression on >30% of tumor cells were both prognostic of shorter OS (P = 0.03 each). A DLL3-targeting ADC showed durable antitumor efficacy in a SCBC PDX model. Conclusions: Gene expression patterns in SCBC are associated with distinct clinical phenotypes ranging from more indolent to aggressive disease. Overexpression of DLL3 mRNA and protein is common in SCBC and correlates with shorter OS. A DLL3-targeted ADC demonstrated in vivo efficacy superior to chemotherapy in a PDX model of SCBC.

Objectives: Signet-ring cells (SRCs) in effusion specimens represent a diagnostic challenge. In this study, a consecutive series of pleural and peritoneal effusions with benign SRCs are examined and compared with malignant SRCs. Material and Methods: We reviewed consecutive Wright-stained serous effusion slides and searched for cases with SRCs. Corresponding ThinPrep slides and clinical histories were reviewed. Cytology cases with known signet-ring adenocarcinoma were retrieved and reviewed. Results: Four hundred Wright-stained serous effusions were reviewed. Eighteen cases were identified with SRC-like cells. Thirteen patients had liver cirrhosis, three patients had end-stage renal disease, one patient had a history of pancreatic adenocarcinoma, and one patient had endometrioid carcinoma. For the latter two patients, the primary tumor showed no histologic findings of signet-ring features. In all cases, no SRCs were found on the corresponding ThinPrep slides. Five cytology cases with malignant SRCs were reviewed. Benign SRCs have a uniformly pale and markedly distended cytoplasm, and the nuclei are thin and curved. The malignant SRCs showed larger non-curved nuclei and bubbly mucin-containing cytoplasm. Conclusion: Mesothelial cells and histiocytes can mimic signet-ring adenocarcinoma cells on Wright-stained slides. Correlation with ThinPrep specimens is necessary before reporting, as the SRCs typically are not present in ThinPrep preparations.

The incidence of renal cell carcinoma (RCC) is known to be higher in patients with end-stage renal disease, including those with acquired cystic kidney disease due to dialysis. Acquired cystic disease (ACD)-associated RCC was recently incorporated into the 2016 WHO Classification of Tumors of the Urinary System and Male Genital Tract as a distinct entity and is reportedly the most common RCC arising in end-stage renal disease. In this study, we sought to further describe clinicopathologic findings in a large series of ACD-RCC, emphasizing histologic features, immunophenotype, clinical outcome, and patterns of disease spread. We collected 40 previously unpublished cases of ACD-RCC with mean clinical follow-up of 27 months (median, 19 mo; range, 1 to 126 mo). Mean tumor size was 2.7 cm (median, 2.4 cm), and 32 tumors (80%) were confined to the kidney (pT stage less than pT3a). International Society of Urological Pathology grade was 3 in 37 cases (92.5%), grade 2 in 1 case (2.5%), and grade 4 in 2 cases (5%). Architectural variability among ACD-RCC was common, as 39 cases (98%) showed varying combinations of tubular, cystic, solid, and/or papillary growth. ACD-RCC frequently occurred in association with other renal tumor subtypes within the same kidney, including papillary RCC (14 patients), papillary adenomas (7 cases), clear cell papillary RCC (5 cases), clear cell RCC (1 case), and RCC, unclassified type (1 case). A previously undescribed pattern of perinephric and renal sinus adipose tissue involvement by dilated epithelial cysts with minimal or absent intervening capsule or renal parenchyma was identified in 20 cases (50%); these cysts were part of the tumor itself in 5 cases (25%) and were part of the non-neoplastic acquired cystic change in the background kidney in the remaining 15 cases (75%). Of the 24 cases (60%) with tissue available for immunohistochemical stains, 19 (79%) were positive for PAX8, 20 (83%) showed negative to patchy expression of cytokeratin 7, and 24 (100%) were both positive for AMACR and negative for CD117. Fumarate hydratase expression was retained in all tumors, including those with nuclear features resembling fumarate hydratase-deficient RCCs. Of the 36 patients (90%) with available follow-up information, 4 (11%) experienced adverse events: 2 patients developed a local recurrence, 1 patient experienced multiple visceral metastases and subsequently died of disease, and 1 patient developed metastases to regional lymph nodes only. One local recurrence and the lymph node only metastasis both had an unusual, exclusively cystic pattern of growth. In summary, we present the largest clinicopathologic series of ACD-RCC to date and describe previously unreported cystic patterns of local soft tissue involvement and recurrence/metastases.

Most prior studies of primary diagnosis in surgical pathology using whole slide imaging (WSI) versus microscopy have focused on specific organ systems or included relatively few cases. The objective of this study was to demonstrate that WSI is noninferior to microscopy for primary diagnosis in surgical pathology. A blinded randomized noninferiority study was conducted across the entire range of surgical pathology cases (biopsies and resections, including hematoxylin and eosin, immunohistochemistry, and special stains) from 4 institutions using the original sign-out diagnosis (baseline diagnosis) as the reference standard. Cases were scanned, converted to WSI and randomized. Sixteen pathologists interpreted cases by microscopy or WSI, followed by a wash-out period of ≥4 weeks, after which cases were read by the same observers using the other modality. Major discordances were identified by an adjudication panel, and the differences between major discordance rates for both microscopy (against the reference standard) and WSI (against the reference standard) were calculated. A total of 1992 cases were included, resulting in 15,925 reads. The major discordance rate with the reference standard diagnosis was 4.9% for WSI and 4.6% for microscopy. The difference between major discordance rates for microscopy and WSI was 0.4% (95% confidence interval, -0.30% to 1.01%). The difference in major discordance rates for WSI and microscopy was highest in endocrine pathology (1.8%), neoplastic kidney pathology (1.5%), urinary bladder pathology (1.3%), and gynecologic pathology (1.2%). Detailed analysis of these cases revealed no instances where interpretation by WSI was consistently inaccurate compared with microscopy for multiple observers. We conclude that WSI is noninferior to microscopy for primary diagnosis in surgical pathology, including biopsies and resections stained with hematoxylin and eosin, immunohistochemistry and special stains. This conclusion is valid across a wide variety of organ systems and specimen types.

Objective: Postmenopausal squamous atypia (PSA) mimics squamous intraepithelial lesion (SIL). We investigate the PSA contribution to the atypical squamous cells of undetermined significance (ASCUS) pool, its cytologic features and Hybrid Capture 2 (HC2) relative light unit/cutoff (RLU/CO) values. Study Design: 658 ASCUS Pap tests in women ≥55 years were reviewed to select those with koilocyte-like cells and/or atypical parakeratosis. Follow-up was positive when a biopsy showed SIL or carcinoma or a later HC2 test was positive. Results: Sixty-nine cases (10.5%) were selected. Forty-two (60.9%) were HC2 negative, and 27 (39.1%) were HC2 positive. Follow-up was available for 23 (54.7%) HC2-negative and 19 (70.3%) HC2-positive cases. No HC2-negative (0%) and 8 HC2-positive (42.1%) cases were positive on follow-up. Within cases negative on follow-up, 3 were PSA on biopsy. PSA was characterized by perinuclear halos, mild nuclear enlargement, smooth nuclear contours, and smooth chromatin. PSA-associated RLU/CO values were 0.25–2.95. Cases with SIL or carcinoma had RLU/CO values from 3.78 to 1,241.59. Conclusions: PSA contributes 0.5–2.3% to the ASCUS pool in women ≥55 years old. HC2 testing with RLU/CO of ≥1 may result in PSA occasionally testing positive. A different cutoff is not recommended but awareness of this caveat is important.

Objectives Fine-needle aspiration (FNA) of head and neck lymph nodes (LNs) is useful in diagnosing metastatic papillary thyroid carcinoma (PTC) and most commonly shows classic cytologic features of PTC. Metastatic PTC, however, may occasionally present with a pattern unfamiliar to most pathologists: atypical histiocytoid cells (AHCs). Methods All PTC thyroidectomy specimens with associated FNA of LNs were retrieved from our files for 2007 to 2013. We aimed to assess cytologic features of metastatic PTC, as well as the presence of AHCs and their morphology. Results Fifty-six FNAs from LNs with metastatic PTC were reviewed. AHCs were identified in 38 (68%) cases, while only PTC with classic cytologic features was seen in 18 (32%) cases. AHCs did not show diagnostic nuclear features of PTC and presented as large cells with abundant cytoplasm either vacuolated or dense. Nuclei varied from vesicular with prominent nucleoli to dark and smudgy. Thirty-one cases showed mixed AHCs and classic PTC, but seven cases (13% of all metastatic PTCs in LNs) consisted only of AHCs. Conclusions AHCs are an often unrecognized metastatic morphologic pattern of cystic PTC, as it does not show diagnostic classic nuclear features of PTC. AHCs are the predominant cytologic finding in approximately 13% of metastatic PTCs to neck LNs.

Pancreatic neuroendocrine neoplasms (PanNENs) are uncommon tumors. Fine needle aspiration (FNA) samples from PanNENs are typically of high cellularity and lack necrosis. In cytology slides from these tumors, dyscohesive cells are usually reported with variably round to oval to plasmacytoid forms exhibiting coarsely granular chromatin and showing immunoreactivity for synaptophysin. We present an unusual, and to our knowledge not previously described, example of an FNA of a PanNEN with large extracellular fibrous spheroids containing intrinsic fibroblasts and rimmed by small to intermediate sized neoplastic epithelial cells with high nuclear cytoplasmic ratios. The cytomorphology of the PanNEN in this case was in some ways reminiscent of that expected in adenoid cystic carcinomas of the salivary glands that most often contain large extracellular globules of basement membrane material and a somewhat biphasic population of lesional cells. The cytomorphology in this case was found to correlate well with the resection specimen histomorphology of an exaggerated gyriform pattern of growth resulting in a unique cobblestone-pavement like microscopic appearance. Knowledge of this potential cytomorphology will aid the cytology community through recognition and reporting of this previously undescribed pattern in an uncommon disease.

Aims Intraductal proliferations of the prostate with more complexity and/or cytological atypia than high-grade prostate intra-epithelial neoplasia (HGPIN), but falling short of intraductal carcinoma (IDC-P), are described as 'atypical intraductal proliferation' (AIP). When present in needle biopsy (NBX) without IDC-P, the clinical significance is not known. Methods and results Sixty-two NBX cases were diagnosed as AIP over 7 years with estimated incidence of 1%. AIP was characterised by loose cribriform architecture (90%) or non-cribriform architecture exhibiting significant nuclear atypia that fell short of IDC-P. Fifty patients had concomitant PCa (20% grade group (GG) 1, 48% GG2, 14% GG3, 8% GG4 and 10% GG 5), and 12 had AIP alone. Of 40 patients who were candidates for no therapy (AIP alone) or active surveillance (AIP with GG1 or GG2 PCa without cribriform pattern 4), 20 had subsequent follow-up pathology [seven NBXs and 13 radical prostatectomy (RP)]. Of the 12 AIP only patients, six had a subsequent biopsy diagnosis of: benign prostate (two), IDC-P with PCa (one) and PCa (three). One or more adverse pathological features at subsequent RP were present in 93% of patients with AIP and GG1 or GG2 PCa, defined as: GG ≥ 3 (15%), IDC-P (77%), cribriform Gleason pattern 4 (69%), pT3a (77%) or pT3b (8%). Conclusions AIP in NBX may be a marker of unsampled IDC-P and/or other adverse pathological features in suspected low- to intermediate-risk PCa. AIP should be considered distinct from HGPIN for risk assessment and warrant consideration for further work-up to detect unsampled high-risk PCa.

Polyomavirus-associated nephropathy (PVAN) is one of the most common disease affecting transplant patients, mainly caused by BK polyomavirus (BKV) and with5% of the cases caused by JC polyomavirus (JCV). Screening and early intervention, including appropriate reduction in immunosuppressive therapy, are critical to reduce allograft loss. The presence of decoy cells in the urine is a characteristic cytopathic effect of polyomavirus. The goal of this study was to investigate the significance of decoy cells in urine cytology in transplant patients, comparing with the plasma viral replication level detected by the real-time quantitative BK virus polymerase chain reaction test (Qt-BK PCR).A cohort of post-transplantation patients with serum BKV level monitored by Qt-BK PCR from 2008 to 2013 was studied. Among them, 35 patients had both urine cytology (UC) analysis and Qt-BK PCR performed. The clinical presentation along with the available UC slides were retrieved and reviewed.Compared with Qt-BK PCR, the sensitivity, specificity, positive predictive value, and negative predictive value of urine cytology analyzed within one week apart were 92%, 71%, 85%, and 83%, respectively. The accuracy of the UC was 84%. More interestingly, UC played a key role in identifying a case of JCV associated PVAN whereas Qt-BK PCR from both urine and plasma failed to detect this virus.Our data suggests that urine cytology is a sensitive surveillance test for early detection of polyomavirus in transplant patients, and it is particularly useful to screen for rare JC polyomavirus.

Tumor necrosis has been shown to be an independent predictor of adverse outcome in renal cell carcinoma. A modification of the International Society of Urological Pathology (ISUP) grading system for renal cell carcinomas has recently been proposed, which incorporates the presence of tumor necrosis into grade. The investigators proposing this system found that necrosis added significant prognostic information to ISUP grade. We attempted to describe our experience with the effect of tumor necrosis in relationship to nuclear grade by reviewing the slides from a large consecutive series of localized clear cell renal cell carcinomas from our institution and obtaining long-term clinical follow-up information (overall survival). Of the 842 clear cell renal cell carcinomas reviewed, 265 (31.5%) were ISUP grade 1 or 2, 437 (51.9%) were ISUP grade 3, and 140 (16.6%) were ISUP grade 4. Tumor necrosis was present in 177 (21%) cases. Five hundred and forty-seven (64.9%) cases were stage pT1, 83 (9.9%) were stage pT2, 193 (22.9%) were stage pT3a, and 19 (2.3%) were pT3b or higher. Median follow-up was 73.2 months (range 0.12 to 273.6), and 310 (36.8%) patients died. On univariable analysis, there was no significant difference in outcome for tumors of ISUP grades 1 to 3. After adjustment for age, tumor stage, and tumor size, ISUP grade 4 and necrosis were significant predictors of overall survival on multivariable analysis. When the recently proposed modified grading system incorporating tumor necrosis was applied to our data, there was no significant difference in overall survival between patients with modified grade 1 tumors and those with modified grade 2 tumors (P=0.31); however, there was a statistically significant difference between patients with modified grade 1 or 2 tumors and those with modified grade 3 tumors (P=0.04),and a substantial difference in outcome between those with modified grade 3 and modified grade 4 tumors (P0.001). When a recursive partitioning approach was applied to our data, patients of a given ISUP grade could be further prognostically separated according to the presence or absence of necrosis and could be divided into 3 statistically significant prognostic groups: (1) non-necrotic ISUP grade 1 to 3 tumors, (2) ISUP grade 1 to 3 tumors with necrosis and ISUP grade 4 tumors with10% necrosis, and (3) ISUP grade 4 tumors with10% necrosis. In conclusion, our study shows that tumor necrosis adds additional prognostic information to ISUP grade and that quantification of necrosis can further stratify patients with ISUP grade 4 tumors.

Introduction Endobronchial ultrasound transbronchial needle aspiration (EBUS-TBNA) is a safe, cost-effective, and accurate diagnostic modality for the lung/mediastinum. Although some studies have been published on EBUS-TBNA of isolated mediastinal lesions, none have been reported from the United States. This study examines EBUS-TBNA for diagnosis of isolated mediastinal lesions. Materials and methods All cases of mediastinal EBUS-TBNA (defined in radioanatomic terms) during a 7-year period (July 2007-September 2014) were obtained from the anatomic pathology database. Pathologic reports, clinical notes, bronchoscopy notes, and imaging studies were reviewed. Only patients with a mediastinal lesion or non-pulmonary parenchyma-based lesions sampled by EBUS-TBNA without a prior or synchronous lung carcinoma were included in this study. Results Of the 3005 EBUS-TBNA cases accessioned during this time period at our institute, 47 fulfilled the inclusion criteria. The median patient age was 61 years (range: 27-84 years). Both genders were nearly equally represented. A definitive cytologic interpretation was rendered in 40 out of 47 cases (85.1%). Malignancies included non-pulmonary carcinomas (8), sarcomas (5), hematolymphoid malignancies (5), neuroendocrine neoplasm (1), melanoma (1), and undifferentiated malignancy (1). Surgical follow-up was available in 18 of 47 cases (38.3%). There was cytologic-histologic correlation in 16 of 18 cases (88.9%). Surgical follow-up of all cysts diagnosed by cytology were benign cysts. Over the 7-year period, an increasing proportion of all EBUS-TBNAs performed were for mediastinal lesions unassociated with lung carcinoma. Conclusions EBUS-TBNA has a high accuracy rate when used to diagnose mediastinal lesions unassociated with lung carcinoma. Its utility as a primary diagnostic modality in this setting needs to be explored further.

Introduction Although frequently used as an adjunct to cytology in patients with differentiated thyroid cancers, interpretation of thyroglobulin washout remains unclear. We aim to compare the utility of different analytic tools to develop recommendations for use in post-total thyroidectomy follow-up. Methods This is an institutional review board-approved retrospective study of patients who underwent lymph node fine needle aspiration biopsy with thyroglobulin washout between 2012 and 2018, during the post-total thyroidectomy follow-up of differentiated thyroid cancer. The utilities of thyroglobulin washout concentration, thyroglobulin washout/serum thyroglobulin ratio, and absolute thyroglobulin content were compared. Results Sixty-four patients underwent 79 fine needle aspirations with thyroglobulin washout of cervical lymph nodes. Fifty-two lymph nodes were found to be metastatic and 27 benign. One patient had a pathologically confirmed lymph node metastasis despite a thyroglobulin washout of 0. The optimal cutoffs of thyroglobulin washout, thyroglobulin washout/serum thyroglobulin ratio, and absolute thyroglobulin content to predict metastatic involvement were 2.5 ng/ml (94% sensitive, 100% specific), 0.1 (100% sensitive and specific), and 12.5 (94% sensitive, 100% specific), respectively. The second measure lacked utility in patients with undetectable serum thyroglobulin. Conclusion The use of thyroglobulin washout concentration or thyroglobulin washout/serum thyroglobulin ratio has drawbacks based on variations in technique and clinical scenario. Absolute thyroglobulin content is an alternative that may be a more objective expression of thyroglobulin washout.

The utility of urine cytology has shifted from the identification of red blood cells, crystals, or parasites to its currently used role of detection of cancer cells exfoliated in urine samples. A variety of ancillary tests have been developed to complement the diagnostic ability of urine cytology. Furthermore, urine testing will continue to evolve as the pathogenesis of genitourinary tract diseases in depth is understood. This article focuses on the diagnostic advances in urine cytology from the cytomorphological perspective, past and current reporting schemes, and the application of ancillary testing in urine samples.

The value of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) in the mediastinal staging of lung cancer has been well established. However, data regarding its utility in the diagnosis of intrapulmonary lesions has been sparse. This study assesses the sampling utility of convex probe EBUS-visible intrapulmonary lesions not visualized by the white-light bronchoscopy.A retrospective analysis of EBUS-TBNA of EBUS-visible intrapulmonary lesions was performed between January 2010 and March 2015. Patients with visible endobronchial lesions by white-light bronchoscopy were excluded from analysis.Among 108 procedures, the diagnostic yield of EBUS-TBNA for EBUS-visible intrapulmonary lesions was 87%. Following diagnoses were established: lung cancer (73/67.6%), lung metastases (10/9.2%), infection (5/4.6%), lymphoma (1/1%), sarcoma/spindle cell sarcoma or neoplasm (3/2.8%), unspecified malignancy (11%), and hamartoma (1/1%). EBUS-TBNA was nondiagnostic in 14 (13%); among these, 9 turned out to have benign disease based on additional bronchoscopy samples or other testing and/or follow-up imaging. Five were ultimately diagnosed with a malignant condition: lymphoma (1), epithelioid hemangioendothelioma (1), and non-small cell lung cancer (3). The sensitivity and the negative predicted value of EBUS-TBNA for differentiating malignancy from benign disease was 94.7% and 75%, respectively, while the accuracy for diagnosing the neoplastic disease was 95.3%. There was one major bleeding requiring bronchial artery embolization and 1 pneumothorax requiring chest tube drainage.EBUS-TBNA is safe and effective in the diagnosis of EBUS-visible intrapulmonary lesions. It should be considered as the diagnostic test of choice in patients with these lesions undergoing EBUS-TBNA for the staging of suspected lung cancer.

Background Choroidal and ciliary body melanomas divide into two approximately equal groups. Local therapy cures one group while the other metastasizes and proves lethal. Monosomy 3 strongly associates with aggressive behavior. We analyzed a series of choroidal and ciliary body melanomas to describe the cellular features and to compare them to monosomy 3 status using the latter as a surrogate for survival. Methods One hundred eleven specimens met the study's inclusion criteria. Following ThinPrep processing, samples were analyzed for cellular features including: cell type, nuclear grade, tumor infiltrating lymphocytes, and the presence of necrosis and melanin. FISH analysis for monosomy 3 was performed on ThinPrep slides using a threshold of 20% monosomic cells per 200 melanoma cells. Results Seventy-two tumors (65%) had a mixed cell type while spindle cell type and epithelioid cell type occurred in 37 (33%) and 2 (1.8%), respectively. Seventy-five tumors (68%) had Grade 2 nuclear atypia. Monosomy 3 occurred in 57 tumors (51%). Significantly more tumors with Grade 3 nuclei had monosomy 3 (79% vs.43%, P = 0.002) and metastases (29% vs. 8%, P = 0.01). None of the 11 pure spindle cell tumors with Grade 1 nuclei metastasized or had monosomy 3. Conclusions Uveal melanoma has a relatively consistent cellular appearance, characterized by a mixed cell pattern and no more than moderate nuclear atypia. This consistent appearance aids in the cellular diagnosis but limits prognostication using cellular features. Cellular features significantly associate with monosomy 3 status only in the minority of tumors at the extremes of the morphologic spectrum. Diagn. Cytopathol. 2016. © 2016 Wiley Periodicals, Inc.

Introduction Pericardial effusion can be a consequence of various diseased states, including infection, autoimmune disease, renal failure, myocardial disease, and neoplasms. Although multiple case reports of malignancy-associated pericardial effusion have been published, few database analyses are available in these published reports. In this study, we retrospectively reviewed 1022 cytology cases and assessed malignancy-associated pericardial effusion. Materials and methods We reviewed our cytology reports for pericardial effusion cases from January 1, 1983 to July 31, 2013. These cases were classified as benign, atypical, malignant, and nondiagnostic. The malignant cases were further characterized based on either immunohistochemical staining results or patients' history. Results We identified 1022 cases and grouped them as follows: 824 benign (80.6%), 38 atypical (3.7%), 158 malignant (15.4%), and 2 unsatisfactory (0.1%). Malignant cases included 131 adenocarcinoma (82.9%), 12 lymphoma (7.9%), 6 poorly differentiated carcinoma (3.8%), 4 mesothelioma (2.5%), 2 squamous cell carcinoma (1.3%), 1 melanoma (0.6%), 1 sarcoma (0.6%), and 1 small cell carcinoma (0.6%). Of these 131 adenocarcinomas, 83 cases had clinical history and/or immunohistochemical study available for further classification, which included 44 lung, 18 breast, 7 esophagogastric adenocarcinomas, 6 adenocarcinomas of unknown primary sites, 5 ovarian, and 2 rectal adenocarcinomas. The clinical presentation, prognosis, and cytopathologic features for malignant pericardial effusions are summarized. Conclusions In this study, 15.4% of pericardial effusion cases were caused by metastatic malignancy, with lung adenocarcinoma being the most common primary site, followed by breast and lymphoma. Relatively young patients are affected, with average age being 56 years. Prognosis is poor for patients with malignant pericardial effusion. However, targeted therapy showed improved survival.

Background Peritoneal carcinomatosis (PC) greatly affects cancer staging and resectability. Objective To compare the PC detection rate by using EUS and noninvasive imaging and to determine the impact on staging and resectability. Design Retrospective study. Setting Single tertiary-care referral center. Patients A prospectively maintained EUS database was reviewed to identify patients who underwent EUS-guided FNA (EUS-FNA) of a peritoneal anomaly. Findings were compared with a strict criterion standard that incorporated cytohistologic, radiologic, and clinical data. Intervention EUS-FNA of a peritoneal anomaly. Main Outcome Measurements Safety and diagnostic yield. Results Of 106 patients, a criterion standard was available in 98 (39 female patients; median age, 65 years). The sensitivity, specificity, and accuracy of EUS-FNA versus CT/magnetic resonance imaging (MRI) was 91% versus 28%, 100% versus 85%, and 94% versus 47%, respectively. In newly diagnosed cancer patients, peritoneal FNA upstaged 17 patients (23.6%). Of 32 patients deemed resectable by pre-EUS CT/MRI, 15 (46.9%) were deemed unresectable based solely on peritoneal FNA. The odds of FNA changing the resectability status remained highly significant after adjustment for cancer type, time between CT/MRI and EUS-FNA, and the quality of CT/MRI. The malignant appearance of the peritoneal anomaly but not the presence of ascites on EUS predicted a positive FNA finding (odds ratio 2.56; 95% confidence interval, 1.23-5.4 and odds ratio 0.83; 95% confidence interval, 0.4-1.8, respectively). There were 3 adverse events among 4 patients. Two of the patients developed abdominal pain and one each hypertensive urgency and pancreatitis. Limitations Retrospective design, single-center, bias toward EUS as a diagnostic test. Conclusion Peritoneal EUS-FNA appears to safely detect radiographically occult PC and improve cancer staging and patient care.

BACKGROUND Pancreatic fine-needle aspiration (FNA) is useful for diagnosing pancreatic masses. This article describes the experience of a single institution with metastases to the pancreas sampled by FNA and provides a review of the literature. METHODS Medical records were retrospectively searched for pancreatic FNA that showed metastatic disease. Data were gathered for the tumor size, focality, and time period between the primary tumor and the metastasis. A literature search using PubMed was performed. RESULTS Pancreatic FNA was performed 2327 times in 14 years at the authors’ institution. Twenty-two cases showed metastatic disease. The average size of the metastatic lesions in their greatest dimension was 3.7 cm (range, 1.5-6.5 cm). The majority of the tumors were unifocal (16 of 22 or 73%). A rapid onsite adequacy evaluation was performed for 13 patients (4 were diagnostic of metastasis, 3 were positive for malignant cells, 6 were atypical, and none were negative). There were 14 renal cell carcinomas, 2 colonic adenocarcinomas, 1 urothelial carcinoma, 1 non–small cell lung carcinoma, 1 ovarian serous carcinoma, 1 prostatic adenocarcinoma, 1 papillary thyroid carcinoma, and 1 mesenchymal chondrosarcoma. The median time between the diagnosis of the primary tumor and the initial pancreatic metastasis was 9 years (range, concurrent diagnosis to 21 years). A literature review yielded 12 case series with a variety of metastases to the pancreas diagnosed by FNA and surgical pathology specimens. CONCLUSIONS In agreement with prior series, the most common metastasis to the pancreas was renal cell carcinoma. A variety of other primary malignancies were also documented in this study and in the literature. Also, this article reports the first case of metastatic mesenchymal chondrosarcoma to the pancreas diagnosed by FNA. Cancer (Cancer Cytopathol) 2015;123:347–55. © 2015 American Cancer Society.

Introduction Studies investigating histologic follow-up of The 2001 Bethesda System diagnosis of atypical glandular cells (AGC) have focused on various screening methods, patient populations, and Papanicolaou preparations. Our aim was to report the histologic follow-up of AGC diagnoses from ThinPrep slides and evaluate specific cytologic features predicting benign or malignant follow-up results. Materials and methods A retrospective search identified liquid-based cervical cytology results interpreted as AGC. AGC diagnoses were stratified into four groups: atypical endometrial cells (AGC-EM); atypical endocervical cells (AGC-EC); AGC, favor neoplastic (AGC-FN); and AGC not otherwise specified (AGC-NOS). Evidence of disease was based on histologic follow-up (biopsy or resection specimen) with a diagnosis of cancer, complex endometrial hyperplasia, or high-grade squamous dysplasia. Available slides were blindly reviewed for specific cytologic features. Statistical analysis compared cytologic factors that would predict benign or malignant follow-up. Results We interpreted 264 samples as AGC from 2005 through 2009. Of the 246 (93.2%) with follow-up histologic material, 60 (24.4%) were AGC-EM; 36 (14.6%) were AGC-EC; 28 (11.4%) were AGC-FN; and 122 (49.6%) were AGC-NOS. Neoplasia was diagnosed in 80 (32.5%). Neoplastic cases showed significantly increased numbers of single cells, cells in 3-dimensional clusters, engulfed neutrophils, nuclear enlargement, increased nuclear-to-cytoplasmic ratio, irregular nuclear borders, reniform nuclei, loss of polarity, and macronucleoli. Conclusions Cytologic parameters can be used to predict benign from neoplastic glandular lesions. Biopsy follow-up is necessary to correlate cytologic findings when AGC is diagnosed on a Papanicolaou smear.

Objectives To evaluate if cumulative prostate cancer length (CCL) on prostate needle biopsy divided by the number of biopsy cores (CCL/core) could improve prediction of insignificant cancer on radical prostatectomy (RP) in patients with prostate cancer eligible for active surveillance (AS). Patients and Methods Patients diagnosed with prostate cancer on extended (≥10 cores) biopsy with an initial prostate-specific antigen (iPSA) level of

Objectives Epidermal growth factor receptor ( EGFR ) gene mutation status should be determined in all patients with advanced, non-squamous non-small cell lung carcinoma (NSCLC) to guide targeted therapy with EGFR tyrosine kinase inhibitors. EGFR mutations are commonly tested by Sanger sequencing or allele specific polymerase chain reaction (ASPCR) on formalin-fixed paraffin-embedded (FFPE) samples including cell blocks (CB) that may fail due to absence of tumor cells. The cell pellet from cytology specimens obtained at the time of endobronchial guided ultrasound fine needle aspiration (EBUS FNA) (EBUS-TBNA, transbronchial needle aspiration) represents an alternative resource for additional tissue. Here we demonstrate the utility of using the FNA cell pellet versus for the detection of EGFR mutations in NSCLC. Materials and methods For internal validation, 39 cytology samples from patients with NSCLC referred for EGFR testing were analyzed using the EGFR rotor-gene Q (RGQ) PCR assay (Qiagen). Thereafter, a consecutive series of 228 EBUS FNA samples were tested. Results The ASPCR assay demonstrated acceptable intra-assay, inter-assay and inter-lot reproducibility, sensitivity, and specificity. For the consecutive series, only 6/228 (2.6%) failed analysis (5 due to insufficient DNA yield). Of 228 EBUS FNA cell pellets tested 32 (14.0%) demonstrated clinically relevant mutations. Results and conclusion ASPCR can reliably detect EGFR gene mutations in FNA preparations from patients with NSCLC obtained at EBUS.

BACKGROUND Previous studies have provided cytologic criteria that aid in the recognition of parathyroid tissue on aspirate smears, including high cellularity, the presence of naked nuclei, loose 2-dimensional clusters, and papillary architecture. However, to the authors knowledge, the cytomorphologic features of parathyroid fine-needle aspiration (FNA) on liquid-based preparations have not been previously described. METHODS The authors retrospectively reviewed all parathyroid FNAs that had aspirate smears and a ThinPrep preparation performed over 10 years at 1 institution. The FNA smears and ThinPrep preparations from each case were deidentified and independently reviewed for cellularity, naked nuclei, architecture, and colloid-like material. RESULTS Forty patients were included in the current study. When individual cases were compared, the ThinPrep preparation was more likely to have lower cellularity, lack papillary architecture, lack naked nuclei, and have areas with a microfollicular pattern compared with the FNA smear. CONCLUSIONS The cytologic features of parathyroid tissue vary depending on preparation. Many of the common features of parathyroid aspirates are lost on ThinPrep preparations, and an increased percentage of parathyroid FNA specimens have a microfollicular pattern on ThinPrep. This may lead to difficulty in recognizing parathyroid origin on FNA. Cancer (Cancer Cytopathol) 2014;122:678–684. © 2014 American Cancer Society.

Introduction: Oncogenic anaplastic lymphoma kinase ( ALK ) gene rearrangements in non–small-cell lung carcinomas (NSCLC) provide the basis for targeted therapy with crizotinib and other specific ALK inhibitors. Treatment eligibility is conventionally determined by the Food and Drug Administration–approved companion diagnostic fluorescence in situ hybridization (FISH) assay on paraffin-embedded tissue (PET). On limited samples such as fine needle aspiration–derived cytoblocks, FISH for ALK is often uninformative. FISH performed on liquid-based ThinPrep slides (ThinPrep-FISH) may represent a robust alternative. Methods: Two hundred thirty cytology samples from 217 patients with advanced NSCLC, including a consecutive series of 179 specimens, were used to generate matched ThinPrep slides and paraffin cytoblocks. The same ThinPrep slides used for cytologic diagnosis were assessed by standard ALK break-apart two-color probe FISH, after etching of tumor areas. Ultrasensitive ALK immunohistochemistry (IHC) on corresponding cytoblocks [D5F3 antibody, OptiView signal amplification] served as the reference data set. Results: ThinPrep-FISH ALK signals were robust in 228 of 230 cases and not compromised by nuclear truncation inherent in paraffin-embedded tissue–FISH; only two samples displayed no signals. Nine of 178 informative cases (5%) in the consecutive series and 18 of 228 informative cases (7.8%) overall were ALK rearranged by ThinPrep-FISH. In 154 informative matched ThinPrep-FISH and cytoblock-IHC samples, 152 were concordant (10, 6.5% ALK status positive; 142, 92.2% ALK status negative), and two (1.3%) were ThinPrep-FISH positive but IHC negative (sensitivity 100%, specificity 98.6%, overall agreement 98.7%). Conclusion: Detection of ALK gene rearrangements in liquid cytology ThinPrep slides derived from patients with NSCLC can be confidently used for clinical ALK molecular testing.

BACKGROUND The cytologic diagnosis of urothelial carcinoma (UC) of the upper urothelial tract (UT) is challenging. Using the UroVysion probe set adds diagnostic value for the detection of bladder cancer in voided urine. In instrumented UT specimens, the authors encountered positive UT cytology and fluorescence in situ hybridization (FISH) cases that did not demonstrate subsequent UT carcinoma. METHODS The performance of cytology and FISH in the presence or absence of concomitant bladder cancer within 2 years was compared in 61 patients (112 samples) from 2003 through 2009. The mean follow-up was 3.2 years. The authors also compared the performance of near-tetrasomy versus hypertetrasomy. Biopsy confirmation of UTUC in 21 patients was considered the gold standard. RESULTS Cytology alone was found to be poorly sensitive (38%) but highly specific (89%) for the detection of UTUC. FISH was found to increase the sensitivity of cytology and decrease specificity. Tetrasomy FISH resulted in many false-positive cases. Other false-positive FISH results were likely due to the presence of bladder cancer cells contaminating the UT specimen. CONCLUSIONS Caution should be used when evaluating instrumented urine specimens of the UT from patients with a previous history of bladder carcinoma, and tetrasomy FISH results should not be interpreted as abnormal because it significantly lowers the specificity of the test. The combination of cytology and FISH appears to have good specificity while maintaining good sensitivity in evaluating UTUC when using modified scoring criteria for the appropriate patient population. Cancer (Cancer Cytopathol) 2014;122:459–467. © 2014 American Cancer Society.

Monitoring changes in the thyroid bed (TB) is one of the clinical mainstays for surveillance of recurrent thyroid carcinoma. Fine-needle aspiration (FNA) is a diagnostic tool that is commonly used to aid in the identification of residual or recurrent disease. The aim of our study was to evaluate the efficacy of ultrasound-guided FNA of the TB in detecting recurrent thyroid cancer and to correlate the findings with clinicopathologic parameters to identify predictors of TB recurrence.We retrieved cases of soft tissue masses within the TB that were evaluated for recurrence between January 1, 2006, and February 1, 2011. All ultrasound-guided FNA biopsies clinically suspected to indicate a lymph node metastasis and specimens with lymphocytes were excluded from the data.Of the 291 patients identified for evaluation of recurrence, 250 had papillary thyroid carcinoma (PTC), 10 had follicular carcinoma, 22 had medullary carcinoma, 7 had Hürthle cell carcinoma, and 2 had a previous thyroidectomy for an unknown type of thyroid carcinoma. For all FNAs that were clinically suspicious or intermediate for recurrence, the rate of positivity was 71.8% (209 patients). All cases diagnosed as "positive for PTC" or "suspicious for PTC" on TB FNA were found to have soft tissue metastasis on follow-up surgical resection. This resulted in a negative predictive value of 88.4% and a positive predictive value of 100%. The average time between thyroidectomy and TB FNA was 73.5 months. Of the patients with a previous diagnosis of PTC, those with suspicious/positive cytology were more likely to be women, to be older at thyroidectomy, to have documented metastasis to other sites as well as extrathyroidal extension and multifocal primary disease as compared with nondiagnostic/negative cytology cases. Patient age ≥45 years, primary tumor size at thyroidectomy, and surgical resection margin status had no statistical significance for predicting risk of TB recurrence.TB recurrence of PTC is most likely to occur in patients who have the following clinicopathologic parameters: documented metastasis to any site, extrathyroidal extension, and increased number of primary cancer foci.

4546Background: SCBC is a rare malignancy with poorly understood biology. TCGA data in BC underscores the presence of a neuronal subtype possibly misclassified by conventional histopathology. Incre...