Search

Renal manifestations in patients with tuberous sclerosis complex (TSC) include cysts, angiomyolipoma, and renal cell carcinoma. Unlike many hereditary predisposition syndromes, the spectrum of renal tumors in TSC patients (including both angiomyolipoma and renal cell carcinoma) is broad, with significant morphologic heterogeneity. An improved understanding of histopathologic findings in TSC patients and associated clinicopathologic correlates has significant implications not just in establishing a diagnosis of TSC, but also in the recognition of sporadic tumors occurring secondary to somatic alterations of TSC1/TSC2/MTOR pathway genes and accurate prognostication. In this review, we have discussed issues relevant to clinical management based on histopathologic findings in nephrectomy specimens from patients with TSC. This includes discussions related to screening for TSC, diagnosis of PKD1/TSC2 contiguous gene deletion syndrome, the morphologic spectrum of angiomyolipoma and renal epithelium-derived neoplasia, including the risk of disease progression.

Objectives Oil Red O (ORO) positivity in bronchoalveolar lavage (BAL) fluid macrophages in the setting of e-cigarette, or vaping, product use–associated acute lung injury (EVALI) has been frequently requested by clinicians based on rare reports and subsequent US Centers for Disease Control and Prevention guidelines. The aim of this study was to determine the specificity of ORO staining in BAL specimens with disease states other than EVALI. Methods Consecutive BAL specimens (October-December 2019) were stained with ORO. The lipid-laden macrophage index (LLMI) was calculated for each case. Results We studied BAL samples from 50 patients. Indications for BAL were surveillance bronchoscopy for lung transplantation (27/50), suspected infection (12/50), sarcoidosis/suspected sarcoidosis (3/50), nodules or ground-glass opacities (3/50), hemoptysis (2/50), asthma or eosinophilic pneumonia (2/50), and idiopathic pulmonary fibrosis (1/50). ORO staining was seen in BAL fluid macrophages in 45 of 50 cases (focal in 18, moderate in 23, diffuse in 4); LLMI ranged from 0 to 218. Using a threshold of LLMI of 85 or higher as positive, ORO was positive in 7 of 50 (14%) cases (range, 85-218). Conclusions ORO staining in BAL fluid macrophages is not specific for EVALI. Even when an LLMI of 85 or higher is used as a threshold for positivity, ORO positivity occurs in a significant subset of non–vaping-related cases.

New cytopreparatory technologies decrease the need for direct smears in favor of an increased use of liquid-based cytology methods. Despite these practice changes, Clinical Laboratory Improvement Amendments continue to require that cytopathology laboratories have procedures to prevent cross-contamination (CC). While the incidence of CC is not well documented, specific cytologic preparations and specimens with a high potential for CC have not been generally defined by professional guidelines or consensus. The American Society of Cytopathology Clinical Practice Committee surveyed cytology practitioners to better understand current practice related to CC in cytology.The survey focused on four topics: (1) practice settings and demographic data; (2) current practice for meeting CC requirements; (3) practice for rapid on-site evaluation; and (4) preparation types considered high risk for CC. The survey was sent to all American Society of Cytopathology and American Society for Cytotechnology members from July 1 to August 14, 2020.Ninety-eight percent of laboratories had a written CC policy, with 66.18% of the policies addressing rapid on-site evaluation CC procedures. Documented cases of CC were rare. Alcohol-fixed, direct smears of Pap-stained fluids were deemed the most likely to be impacted by CC. Cell block contamination during the histologic processing were reported by 56.20% of respondents.Changes in practice has resulted in decreased preparation types associated with a high potential for CC. Laboratories should follow a risk-based approach to define these cases. Knowledge of practice patterns among laboratories can guide the development and refinement of policy and procedures.

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.

Autoimmune pancreatitis (AIP) is a known mimicker of pancreatic ductal adenocarcinoma both clinically and radiologically. In this study, the authors present their institutional experience in diagnosing AIP on cytology and correlate results with the histologic findings.A 14-year computerized search for patients who had histologically confirmed AIP with concurrent or prior cytology was performed. Clinical data, cytology findings, and surgical pathology results were reviewed for analysis.Eighteen patients were identified. The patients showed a male predominance, with a mean age of 59 years. Jaundice, weight loss, and abdominal pain were the most common clinical presentation. Five of 12 patients who were tested for serum immunoglobulin G4 had elevated levels. Cytologic findings of 16 cases that were available for review showed markedly inflamed fibrous stroma (54%) and cytologic atypia (50%). The final cytologic diagnoses were suspicious for adenocarcinoma (n = 1), atypical (n = 8), and benign/negative (n = 9). The corresponding surgical pathology diagnoses were classified as type 1 (n = 10), type 2 (n = 6), and AIP, not otherwise specified (n = 2). All type 2 AIP cases had at least atypical cytologic diagnoses, with one called suspicious for adenocarcinoma and another called adenocarcinoma at the time of rapid on-site evaluation. In contrast, eight of 10 type 1 AIP cases were negative/benign, and two of 10 were atypical. In these two atypical cases, the possibility of AIP was raised because of the presence of inflamed stroma.

Context.— Epithelioid angiomyolipomas (eAMLs) are rare tumors of the kidney that occur in patients with tuberous sclerosis complex or in a sporadic setting; a subset of these tumors exhibit metastatic behavior. Objective.— To analyze molecular profiling data to identify pathogenic alterations in rare cases of metastatic eAML, and to identify immunohistochemistry (IHC)-based surrogate markers. Design.— Molecular profiling data from the American Association for Cancer Research GENIE registry was accessed for 23 patients with angiomyolipomas, and 9 of 16 patients with eAMLs in our institutional registry were evaluated with next-generation sequencing. IHC was performed to screen for alterations of P53, RB, and ATRX for all 16 institutional cases. Results.— Combined alterations of 5 tumor-suppressor genes (TP53, ATRX, RB1, APC, and NF1) were identified using next-generation sequencing in 7 of 8 (88%) patients with metastatic disease compared to a single patient with nonmetastatic disease (RB1 variant of uncertain significance; 1 of 24, 4%). No cases with abnormal IHC results were identified in 11 patients with nonmetastatic disease compared to 3 of 5 patients with metastatic disease. Conclusions.— Our results show that the majority of metastatic eAMLs have mutations of 5 tumor-suppressor genes (TP53, ATRX, RB1, APC, and NF1), while these are rare in patients with nonmetastatic disease. Furthermore, IHC for P53, RB, and ATRX may serve as a screen for a subset of these alterations in resource-limited settings. These findings, if validated in larger data sets, have the potential to predict metastatic behavior in eAML.

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.

Adrenocortical Carcinoma (ACC) is a rare endocrine tumor with poor overall prognosis and 1.5-fold overrepresentation in females. In children, ACC is associated with inherited cancer syndromes with 50–80% of childhood-ACC associated with TP53 germline variants. ACC in adolescents and young adults (AYA) is rarely due to germline TP53, IGF2, PRKAR1A and MEN1 variants. We analyzed exome sequencing data from 21 children (39y) with ACC, and retained all pathogenic, likely pathogenic, and highly prioritized variants of uncertain significance. We engineered a stable lentiviral-mutant ACC cell line, harboring an EGFR variant (p.Asp1080Asn) from a 21-year-old female without germline-TP53-variant and with aggressive ACC. We found that 4.8% of the children (P = 0.004) and 6.2% of AYA (P

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.

The impact of implementing the Paris system (TPS) on the rate of discrepant cases in the negative for high-grade urothelial carcinoma (NHGUC) category that had a subsequent diagnosis of high-grade urothelial carcinoma (HGUC) on histology is not well studied.We adopted TPS in May 2019. We searched discrepant cases with negative urine cytology 2017-2019 in our cyto-histo correlation database. The urine cytology and follow-up biopsy/resection were reviewed by a cytopathologist who also did Genitourinary (GU) Pathology subspecialty sign-out. Voided urine and instrumented urine were included in this study.There were total of 70 discrepant cases with negative cytology interpretation but HGUC on the subsequent biopsy or resected specimen. Following the TPS criteria, the rate of discrepant negative cytology cases increased from 6 cases between January 2017 and May 2019 to 64 cases after May 2019 when we adopted TPS. There were 2 discrepant negative cases in 2017, 3 cases in 2018, and 65 cases in 2019. Out of 65 cases in 2019, 64 cases were identified after May 2019. Additional 55 urine cytology slides were reviewed according to the TPS criteria, of which, the diagnoses remained unchanged in 45 (82%) cases and 10 (19%) cases were reassigned to either atypical or suspicious categories. The discrepancy was noted more on the instrumented urine and the upper tract urine. However, the false-negative rate rose faster in voided urine and lower tract urine. The risk of HGUC with the category of NHGUC was 0.03% in 2017, 0.05% in 2018, and 1.06% in 2019 at our institution. The increase in false-negative rate could not be attributed to a single cytopathologist.After adopting TPS for reporting urine cytology, there was an increase in HGUC from negative urine cytology which was subsequently confirmed on histology as cases of HGUC. The quality control of negative urines could be important monitoring the process when implementing TPS.

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.

To describe the clinical, histologic, immunophenotypic, and genetic characteristics of myeloid sarcoma (MS) diagnosed in the testes of adults, 3 cases were identified, and information on their presentation, clinical features, treatment, and outcome was retrieved from the medical records. In addition, histologic, immunophenotypic, and molecular characteristics were reviewed. This showed that all patients had a previous history of acute myeloid leukemia (AML), in 2 cases diagnosed10 years before the testicular lesions. In 1 case, there was bilateral involvement, while in 2, involvement was unilateral. The neoplastic cells showed evidence of cytogenetic/molecular clonal evolution in all cases, 1 of which also had significant immunophenotypic changes. A mutational profile including NPM1 p.Trp288Cysfs*12, IDH1 p.Arg132His NRAS p.Gly12Asp was seen in 2 of the 3 cases. Concurrent bone marrow involvement by a myeloid neoplasm was diagnosed in 2 patients, in 1, there was AML in the second 8% blasts. These patients progressed rapidly after MS and had a dismal outcome. The patient with no concurrent bone marrow disease had a favorable outcome. In conclusion, MS involving the testes of adults is a rare event, and it may represent the clonal evolution of AML.

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.

Epithelioid hemangioendothelioma (EHE) is a genetically homogenous vascular sarcoma that is a paradigm for TAZ dysregulation in cancer. EHE harbors a WWTR1(TAZ)-CAMTA1 gene fusion in >90% of cases, 45% of which have no other genetic alterations. In this study, we used a first of its kind approach to target the Wwtr1-Camta1 gene fusion to the Wwtr1 locus, to develop a conditional EHE mouse model whereby Wwtr1-Camta1 is controlled by the endogenous transcriptional regulators upon Cre activation. These mice develop EHE tumors that are indistinguishable from human EHE clinically, histologically, immunohistochemically, and genetically. Overall, these results demonstrate unequivocally that TAZ-CAMTA1 is sufficient to drive EHE formation with exquisite specificity, as no other tumor types were observed. Furthermore, we fully credential this unique EHE mouse model as a valid preclinical model for understanding the role of TAZ dysregulation in cancer formation and for testing therapies directed at TAZ-CAMTA1, TAZ, and YAP/TAZ signaling.

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.

The Paris System (TPS) for Reporting Urinary Cytology is a standardized, evidence-based reporting system, comprising seven diagnostic categories: nondiagnostic, negative for high-grade urothelial carcinoma (NHGUC), atypical urothelial cells (AUC), suspicious for high-grade urothelial carcinoma (SHGUC), HGUC, low-grade urothelial neoplasm (LGUN), and other malignancies. This study aimed to calculate the pooled risk of high-grade malignancy (ROHM) of each category and demonstrate the diagnostic accuracy of urine cytology reported with TPS. Four databases (PubMed, Embase, Scopus, Web of Science) were searched. Specific inclusion and exclusion criteria were applied, while data were extracted and analyzed both qualitatively and quantitatively. The pooled ROHM was 17.70% for the nondiagnostic category (95% CI, 0.0650; 0.3997), 13.04% for the NHGUC (95% CI, 0.0932; 0.1796), 38.65% for the AUC (95% CI, 0.3042; 0.4759), 12.45% for the LGUN (95% CI, 0.0431; 0.3101), 76.89 for the SHGUC (95% CI, 0.7063; 0.8216), and 91.79% for the HGUC and other malignancies (95% CI, 0.8722; 0.9482). A summary ROC curve was created and the Area Under the Curve (AUC) was 0.849, while the pooled sensitivity was 0.669 (95% CI, 0.589; 0.741) and false-positive rate was 0.101 (95% CI, 0.063; 0.158). In addition, the pooled DOR of the included studies was 21.258 (95% CI, 14.336; 31.522). TPS assigns each sample into a diagnostic category linked with a specific ROHM, guiding clinical management.

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.

Introduction/Objective The cytopathology laboratory is one of the most highly regulated clinical laboratories. The Accreditation Council for Graduate Medical Education (ACGME) milestones include competencies in laboratory management. Additionally, many cytology fellows will be involved in laboratory management after finishing training. Therefore, it is imperative to incorporate formal laboratory management training for cytology fellows. Our cytopathology department implemented a formal laboratory management curriculum this year, with emphasis placed on the milestones (1.0 and 2.0) provided by the ACGME. Methods/Case Report The curriculum is divided into seven modules extending throughout the fellowship year (August-April). The modules include hand-off communication, process improvement, laboratory accreditation (introduction, intermediate, advanced) and error management (introduction, intermediate). Each module has two components: self-study of assigned reading materials and online courses, followed by an interactive session with faculty and/or laboratory personnel. Several engaging, high-quality resources are used including Institute for Healthcare Improvement Open School, modules from professional organizations, PubMed articles, National Quality Forum, departmental committees and mock inspections. Each module is followed by an interactive session to review policies, procedures and/or checklists. The fellows also spend time in the cytology laboratory preparation area and participate in Quality Improvement meetings. Results (if a Case Study enter NA) The fellowship director discusses the educational expectations at the start of each module. Evidence of compliance is demonstrated by uploading all of the completed assignments to MedHub (a web- based training management system) at the end of the module. All of the modules include self-assessment questions that are reviewed by the fellowship director. Conclusion Our cytopathology laboratory introduced a structured laboratory management curriculum. This curriculum fulfills some of the laboratory management competencies put forth in the ACGME milestones. This curriculum will also help to prepare fellows to confidently participate in cytology laboratory management as they enter the workforce.

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.

BACKGROUND The detection of mutated epidermal growth factor receptor (EGFR) in non–small cell lung cancer (NSCLC) with residual cell pellets derived from liquid-based cytology (LBC) samples (eg, endoscopic ultrasound–guided fine-needle aspiration) has been validated with allele-specific polymerase chain reaction. The aim of this study was to validate next-generation sequencing (NGS) technology for detecting gene mutations with residual cell pellets from LBC. METHODS Archived DNA extracted from LBC samples of adenocarcinoma stored in PreservCyt with a known EGFR mutation status was retrieved. Genomic DNA was multiplex-amplified and enriched with Ion AmpliSeq Cancer Hotspot Panel v2 chemistry and the OneTouch 2 instrument; this was followed by semiconductor sequencing on the Ion Personal Genome Machine platform. The mutation hotspots of 6 NSCLC-related genes (BRAF, EGFR, ERBB2, KRAS, MET, and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit α [PIK3CA]) were analyzed with NextGENe and Torrent Suite bioinformatics tools. RESULTS The commonly identified EGFR sequence changes, including 4 L858R mutations, 3 exon 19 deletions, and 1 exon 20 insertion, were in 100% concordance between the assay platforms. Less common NSCLC variants were also found in the mutation hotspots of ERBB2, KRAS, MET, and PIK3CA genes. CONCLUSIONS NSCLC mutation analysis using NGS can be successfully performed on residual cell pellets derived from LBC samples. This approach allows the simultaneous examination of multiple mutation hotspots in a timely manner to improve patient care. Cancer Cytopathol 2017;125:178–187. © 2016 American Cancer Society.

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.

Although ERG and SPINK1 molecular alterations have been studied in acinar and ductal adenocarcinoma of the prostate, EZH2 expression has not been previously evaluated in ductal adenocarcinoma.We collected cases of pure and mixed ductal adenocarcinoma of the prostate and evaluated clinical significance and EZH2, ERG, and SPINK1 protein expression.We investigated 61 ductal adenocarcinomas, 22 pure and 39 mixed ductal/acinar. Except for tumor growth pattern, none of the clinical parameters studied significantly differed between pure and mixed tumors. Thirty-five percent of ductal adenocarcinomas were organ confined, 15% displayed seminal vesicle invasion. Lymph node and distal metastasis occurred in 13% and 24% of cases, respectively; 34% of patients experienced biochemical failure, 7% died of disease. Ninety-eight percent of tumors expressed EZH2; in 80% of cases50% of tumor cells were positive. ERG and SPINK1 were expressed in 20% and 36% of cases, respectively. There was no difference in protein expression between pure and mixed ductal adenocarcinomas. ERG expression tended to be lower, and SPINK1 higher than reported for acinar tumors. Biochemical failure, metastasis and death did not differ between EZH2, ERG, and SPINK1 positive and negative patients, nor between50% versus50% expression of SPINK1 and EZH2, respectively.Pure and mixed ductal adenocarcinomas have similar clinical behavior and molecular alterations. Higher EZH2 and SPINK1 protein expression, compared to acinar prostatic adenocarcinoma, might account for the more aggressive clinical course of ductal adenocarcinoma.

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.