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The integration of whole slide imaging (WSI) and artificial intelligence (AI) with digital cytology has been growing gradually. Therefore, there is a need to evaluate the current state of digital cytology. This study aimed to determine the current landscape of digital cytology via a survey conducted as part of the American Society of Cytopathology (ASC) Digital Cytology White Paper Task Force. A survey with 43 questions pertaining to the current practices and experiences of WSI and AI in both surgical pathology and cytology was created. The survey was sent to members of the ASC, the International Academy of Cytology (IAC), and the Papanicolaou Society of Cytopathology (PSC). Responses were recorded and analyzed. In total, 327 individuals participated in the survey, spanning a diverse array of practice settings, roles, and experiences around the globe. The majority of responses indicated there was routine scanning of surgical pathology slides (n = 134; 61%) with fewer respondents scanning cytology slides (n = 150; 46%). The primary challenge for surgical WSI is the need for faster scanning and cost minimization, whereas image quality is the top issue for cytology WSI. AI tools are not widely utilized, with only 16% of participants using AI for surgical pathology samples and 13% for cytology practice. Utilization of digital pathology is limited in cytology laboratories as compared to surgical pathology. However, as more laboratories are willing to implement digital cytology in the near future, the establishment of practical clinical guidelines is needed. • To investigate the current landscape of digital cytology and artificial intelligence in cytology, the American Society of Cytopathology in conjunction with the International Academy of Cytology and the Papanicolaou Society of Cytopathology created a 43-question survey that was distributed to the global cytology community as a part of the American Society of Cytopathology Digital Cytology Task Force. • With a total of 327 responses, most participants report that they do not scan cytology slides routinely compared with surgical pathology slides. However, many who did not scan cytology slides indicated plans to do so in the near future. • The major challenges and areas of improvement for cytology whole slide images (WSI) were in the areas of poor image quality compared with surgical WSI where cost was the most cited challenge. • Areas of cytology practice participants would most like to see artificial intelligence development included screening cytology slides, biomarker quantification, and for quality assurance/quality control. [ABSTRACT FROM AUTHOR]

Digital cytology and artificial intelligence (AI) are gaining greater adoption in the cytology laboratory. However, peer-reviewed real-world data and literature are lacking in regard to the current clinical landscape. The American Society of Cytopathology in conjunction with the International Academy of Cytology and the Digital Pathology Association established a special task force comprising 20 members with expertise and/or interest in digital cytology. The aim of the group was to investigate the feasibility of incorporating digital cytology, specifically cytology whole slide scanning and AI applications, into the workflow of the laboratory. In turn, the impact on cytopathologists, cytologists (cytotechnologists), and cytology departments were also assessed. The task force reviewed existing literature on digital cytology, conducted a worldwide survey, and held a virtual roundtable discussion on digital cytology and AI with multiple industry corporate representatives. This white paper, presented in 2 parts, summarizes the current state of digital cytology and AI practice in global cytology practice. Part 1 of the white paper is presented as a separate paper which details a review and best practice recommendations for incorporating digital cytology into practice. Part 2 of the white paper presented here provides a comprehensive review of AI in cytology practice along with best practice recommendations and legal considerations. Additionally, the cytology global survey results highlighting current AI practices by various laboratories, as well as current attitudes, are reported. • The American Society of Cytopathology in conjunction with the International Academy of Cytology and the Digital Pathology Association established a special task force comprising 20 members with expertise and/or interest in digital cytology to investigate the feasibility of incorporating digital cytology and artificial intelligence applications into the workflow of the laboratory. • The task force reviewed existing literature on digital cytology, conducted a worldwide survey, and held a virtual roundtable discussion on digital cytology and artificial intelligence (AI) with multiple industry corporate representatives. • Part 2 of the white paper presented here provides a comprehensive review of artificial intelligence in cytology practice along with best practice recommendations and legal considerations. [ABSTRACT FROM AUTHOR]

Digital cytology and artificial intelligence (AI) are gaining greater adoption in the cytopathology laboratory. However, peer-reviewed real-world data and literature are lacking regarding the current clinical landscape. The American Society of Cytopathology in conjunction with the International Academy of Cytology and the Digital Pathology Association established a special task force comprising 20 members with expertise and/or interest in digital cytology. The aim of the group was to investigate the feasibility of incorporating digital cytology, specifically cytology whole slide scanning and AI applications, into the workflow of the laboratory. In turn, the impact on cytopathologists, cytologists (cytotechnologists), and cytology departments were also assessed. The task force reviewed existing literature on digital cytology, conducted a worldwide survey, and held a virtual roundtable discussion on digital cytology and AI with multiple industry corporate representatives. This white paper, presented in 2 parts, summarizes the current state of digital cytology and AI practice in global cytology practice. Part 1 of the white paper presented herein is a review and offers best practice recommendations for incorporating digital cytology into practice. Part 2 of the white paper provides a comprehensive review of AI in cytology practice along with best practice recommendations and legal considerations. Additionally, the results of a global survey regarding digital cytology are highlighted. • The American Society of Cytopathology in conjunction with the International Academy of Cytology and the Digital Pathology Association established a special task force comprising 20 members with expertise and/or interest in digital cytology to investigate the feasibility of incorporating digital cytology and artificial intelligence applications into the workflow of the laboratory. • The task force reviewed existing literature on digital cytology, conducted a worldwide survey, and held a virtual roundtable discussion on digital cytology and artificial intelligence with multiple industry corporate representatives. • Part 1 of the white paper presented herein is a review and offers best practice recommendations for incorporating digital cytology into practice. [ABSTRACT FROM AUTHOR]

p16ink4a status is an independent predictor of survival in PC. There is a strong concordance between p16ink4a and HPV ISH results. Also, there is a significant association between HPV positivity and the histology with 100% of the warty, basaloid, and mixed warty-basaloid subtypes being positive for HPV. p53 is a predictor of nodal metastasis irrespective of p16ink4a status. Dual positive tumors (p16ink4a and p53 positive) have a significantly better outcome in comparison to dual negative tumors (both markers negative). Thus, p53 and p16ink4a immunohistochemistry should be performed at the baseline in all patients of PC. Background: Human papilloma virus (HPV) infection is implicated in a proportion of invasive squamous cell carcinoma of the penis (PC). A subset of PC involves dysregulation of the p53 pathway. HPV in situ hybridization (ISH) and p16ink4a positivity are surrogate markers for HPV infection, and p53 immunohistochemistry (IHC) denotes abnormality in the p53 pathway. There remains an ambiguity with regard to the contribution of both the pathways in the prognosis of PC. We sought to analyze the clinicopathologic characteristics of a cohort of Indian PC patients with respect to p16 ink4a and p53 expression. Patients and Methods: A cohort of 123 PC patients was studied for p16 ink4a and p53IHC and HPVISH. The results of these biomarkers were correlated with various clinicopathologic parameters. Results: p16 ink4a and HPV ISH were positive in 47% and 53% of the tumors, respectively. The propor tion of war ty, basaloid, or mixed war ty-basaloid tumor subtypes showed significant p16 ink4a positivity (P < .0001) compared to other subt ypes. Twent y-eight patients were dual negative (p53- /p16 ink4a -), 32 were dual positive (p53 + /p16 ink4a + ), 38 were p53 + /p16 ink4a -, and 25 were p53- /p16 ink4a + . In patients where p16 ink4a was negative, a p53-positive phenotype had a higher propensity for lymph node metastases (OR, 5.42; 95% CI, 1.75-16.80; P = .003). Similarly, p53 positivity dictates nodal involvement in the p16 ink4a - positive subset of tumors (OR, 5.00; 95% CI, 1.23-20.17; P = .024). On multivariate analyses, pathologic subtypes (warty, warty-basaloid, and basaloid) (P < .0001), p16 ink4a expression (P < .0001), and absence of nodal metastasis (P < .0001) were significant predictors of improved overall (OS) and cancer specific survival (CSS). In Kaplan-Meier analysis, the OS was significantly longer in patients with p16 ink4a + tumors (P < .0001), as was the CSS (P < .0001). Patients with dual positive tumors had a significantly higher OS (P < .001) and CSS (P = .012), in the entire cohort. In the node positive patients, dual positivity was associated with significantly higher OS (P < .0001); however, the median CSS for p53 + /p16 ink4a + tumors were not significantly different compared to p53- /p16 ink4a - tumors (P = .064), although there was a trend towards improved CSS. Conclusions: There is a strong concordance between p16 ink4a IHC and HPV ISH results. p16 ink4a status is an independent predictor of survival (OS and CSS) in our cohort of PCs. p53 is a predictor of nodal metastasis irrespective of p16 status. Dual positive tumors have a significantly better outcome in comparison to dual negative tumors. [ABSTRACT FROM AUTHOR]

Amplification and overexpression of human epidermal growth factor receptor 2 (HER2) in breast cancer is associated with an adverse prognosis. The introduction of trastuzumab and lapatinib has substantially improved the clinical outcomes of patients with HER2-positive breast cancer. The key element of the successful application of anti-HER2 therapies in real-world has been the selection of candidates for treatment based on the level of HER2 positivity of the tumor. HER2 status of breast cancer is clinically assessed by HER2 protein expression with immunohistochemistry (IHC) or HER2 gene amplification with in situ hybridization (ISH). The 2018 American Society of Clinical Oncology and the College of American Pathologists (ASCO/CAP) HER2 guideline focused update revised the HER2 scoring criteria. Digital image analysis (DIA) has emerged as an objective and reproducible IHC scoring method and the ASCO/CAP HER2 guideline has acknowledged DIA as a diagnostic modality. In this article, we aim to review the assessment of HER2 status and its clinical application in breast cancer. [ABSTRACT FROM AUTHOR]

In modern clinical practice, digital pathology has a crucial role and is increasingly a technological requirement in the scientific laboratory environment. The advent of whole-slide imaging, availability of faster networks, and cheaper storage solutions has made it easier for pathologists to manage digital slide images and share them for clinical use. In parallel, unprecedented advances in machine learning have enabled the synergy of artificial intelligence and digital pathology, which offers image-based diagnosis possibilities that were once limited only to radiology and cardiology. Integration of digital slides into the pathology workflow, advanced algorithms, and computer-aided diagnostic techniques extend the frontiers of the pathologist's view beyond a microscopic slide and enable true utilisation and integration of knowledge that is beyond human limits and boundaries, and we believe there is clear potential for artificial intelligence breakthroughs in the pathology setting. In this Review, we discuss advancements in digital slide-based image diagnosis for cancer along with some challenges and opportunities for artificial intelligence in digital pathology. [ABSTRACT FROM AUTHOR]

Osteoclast-type giant cell-rich carcinomas (OGCRCs) of urinary bladder are extremely rare, aggressive tumors that are often diagnosed as undifferentiated carcinomas. The morphology overlaps with other giant cell-rich benign and malignant bladder lesions. Little is known about the pathogenesis and clinical management of this aggressive variant. The aim of this study was to review clinico-pathologic features, and survival characteristics in a series of OGCRCs. Five cases of OGCRCs of bladder were retrospectively reviewed. Clinical presentation, histomorphology, ancillary tests, treatment and follow-up data were retrieved and analyzed. All patients were adult males (age range 63–86 years) and presented with painless gross hematuria. All cases showed biphasic morphology with polygonal to epithelioid to spindle mononuclear cells (MCs) and scattered multinucleated osteoclast-like giant cells (OGCs). Background urothelium showed urothelial carcinoma in-situ (CIS) (4/5) and/or invasive urothelial carcinoma (UC) (2/5) and invasive high-grade papillary urothelial carcinoma (PUC) (2/5). MCs showed focal expression of at least one epithelial marker and focal/diffuse expression of urothelial markers. OGCs were positive only for histiocytic markers. Oncomine test showed presence of p53 mutation (p.R282W) in case 3. Pathologic stage was T1 (n = 3), T2b (n = 1) and T3a (n = 1). 2/5 patients died of disease within 3 years of diagnosis. OGCRC is an extremely rare and potentially aggressive malignant neoplasm of bladder. Most cases have associated conventional in-situ or invasive UC supporting undifferentiated or de-differentiated nature of this neoplasm. Surgery should be considered given the potential for aggressive behavior. However optimal treatment for OGCRCs remains unknown. [ABSTRACT FROM AUTHOR]

Summary: Primary renal carcinoid tumors are rare neoplasms. Because of the rarity of these neoplasms, clinicopathologic and immunohistochemical characteristics have not been fully characterized. Immunohistochemistry for renal cell lineage transcription factors, such as paired box gene 2 and paired box gene 8, has not been studied in renal carcinoid tumors and may be useful in demonstrating nephrogenic differentiation. We studied the clinical, morphological, and immunohistochemical features in 9 primary renal carcinoid tumors from multiple institutions with particular emphasis on immunohistochemical findings, in particular, expression of paired box gene 2 and paired box gene 8. All 9 cases expressed at least 1 neuroendocrine marker (CD56, synaptophysin, chromogranin). The renal-associated (paired box gene 2/paired box gene 8), gastrointestinal (caudal-related homeobox–2), and pulmonary/thyroid (thyroid transcription factor–1) transcription factors were not expressed in renal carcinoids (0/9). Of interest, CD99 was expressed in 8 of 9 cases, with the one negative case representing an atypical carcinoid. Perinephric extension and nodal and distant metastases are common. The absence of expression of paired box gene 2 and paired box gene 8, although not conclusive, supports the theory that these are derived from nonnephrogenic elements. CD99 was expressed in almost all cases (8/9); recognition of this could prevent misdiagnosis of a renal primitive neuroectodermal tumor. [ABSTRACT FROM AUTHOR]

Abstract: Vitamin D has been shown to have anti-proliferative effects in a wide variety of cancers including lung cancer. The anticancer effects of vitamin D are mediated primarily by its active metabolite, 1,25-dihydroxyvitamin D (calcitriol), through vitamin D receptor (VDR) signaling. However, thus far there have been no studies evaluating the association between VDR expression and survival outcome in lung cancer. Using immunohistochemical analysis, we evaluated VDR expression, separately in the nucleus and cytoplasm, in lung cancer samples from 73 non-small cell lung carcinoma (NSCLC) patients with no prior therapy, and investigated the association between VDR expression and overall survival (OS). Cox proportional hazard models were used for our primary analyses. There were 44 deaths during a median follow-up of 51 months (range 13–93 months). High nuclear VDR expression was associated with improved OS after adjusting for age, gender, stage, smoking status, and histology (adjusted hazard ratio, 0.36; 95% confidence interval, 0.17–0.79). There was no association between cytoplasmic VDR expression and OS. Our results suggest that nuclear VDR status may be a prognostic marker in NSCLC. Future large studies to replicate our findings and to assess the impact of VDR gene polymorphisms on VDR expression are required as therapies targeting the vitamin D signaling pathway may be influenced by VDR status in the target lung cancer tissue. [ABSTRACT FROM AUTHOR]

Abstract: Nephrogenic adenoma is an uncommon benign lesion. Its pathogenesis is as yet unclear although various theories have been proposed, including the embryological and inflammatory theory. The proposal that nephrogenic adenoma originates from the implantation of exfoliated renal tubular cells is lately gaining wider acceptance. Careful histological examination is essential to accurately identify this lesion and to differentiate it from other locally arising malignant lesions. The role of immunohistochemistry cannot be undermined in the diagnosis of nephrogenic adenoma, although histological diagnosis is usually conclusive. The possibility of nephrogenic adenoma should always be in the differential diagnosis when evaluating patients with predisposed urinary tract symptoms. [Copyright &y& Elsevier]

Abstract: Micropapillary carcinoma is a rare distinct variant of high grade urothelial carcinoma, which has specific morphological characteristics and is almost always associated with muscularis propria and vascular invasion. No currently defined imaging techniques can reliably diagnose some types of deeply invasive urothelial carcinoma of urinary bladder, in particular its micropapillary variant. Therefore, the pathological findings are crucial in making the diagnosis. Micropapillary carcinoma (MPC) is a tumor with an aggressive clinical course, an advanced stage of disease at the time of presentation, and usually a poor outcome. Metastatic micropapillary carcinoma to bladder should always be included in the differential diagnosis. Correct histological diagnosis of this aggressive neoplasm would allow timely, albeit intense, radical treatment of the disease. The current most generally favored treatment option for all patients who present with MPC is immediate radical cystectomy. [Copyright &y& Elsevier]

Abstract: Primary osteosarcoma of the heart is an extremely rare entity. In this report, we describe a case of primary osteosarcoma of the heart that recurred and metastasized. The patient is a 50-year-old woman who presented with an abrupt onset of dyspnea, dizziness, and palpitations. Echocardiography results showed a left atrial tumor that was resected and had histological features of high-grade osteosarcoma. The patient was treated with adjuvant chemotherapy. The tumor recurred in the same location 4 years later and was resected. Three years later, the patient presented with a 4-cm polypoid mass in the stomach that was consistent with metastatic osteosarcoma. One year later, the patient presented with recurrent high-grade sarcoma in the soft tissue of the left chest wall. We herein present the spectrum of histological findings and molecular genotyping data. [Copyright &y& Elsevier]

Summary: Whole slide images (WSIs), also known as virtual slides, can support electronic distribution of immunohistochemistry (IHC) stains to pathologists that rely on remote sites for these services. This may lead to improvement in turnaround times, reduction of courier costs, fewer errors in slide distribution, and automated image analyses. Although this approach is practiced de facto today in some large laboratories, there are no clinical validation studies on this approach. Our retrospective study evaluated the interpretation of IHC stains performed in difficult prostate biopsies using WSIs. The study included 30 foci with IHC stains identified by the original pathologist as both difficult and pivotal to the final diagnosis. WSIs were created from the glass slides using a scanning robot (T2, Aperio Technologies, Vista, CA). An evaluation form was designed to capture data in 2 phases: (1) interpretation of WSIs and (2) interpretation of glass slides. Data included stain interpretations, diagnoses, and other parameters such as time required to diagnose and image/slide quality. Data were also collected from an expert prostate pathologist, consensus meetings, and a poststudy focus group. WSI diagnostic validity (intraobserver pairwise κ statistics) was “almost perfect” for 1 pathologist, “substantial” for 3 pathologists, and “moderate” for 1 pathologist. Diagnostic agreement between the final/consensus diagnoses of the group and those of the domain expert was “almost perfect” (κ = 0.817). Except for one instance, WSI technology was not felt to be the cause of disagreements. These results are encouraging and compare favorably with other efforts to quantify diagnostic variability in surgical pathology. With thorough training, careful validation of specific applications, and regular postsignout review of glass IHC slides (eg, quality assurance review), WSI technology can be used for IHC stain interpretation. [Copyright &y& Elsevier]

Summary: Morphological discrimination of urothelial carcinoma (UC) in situ, a precursor of high-grade invasive carcinoma, from severe reactive atypia is essential, but can be challenging at times. Mutations of the cell cycle regulatory gene INK4a (located at 9p21) that encodes p16INK4 are one of the critical early events in carcinogenesis of UC. The purpose of this study was to investigate p16INK4 expression in different urothelial lesions and assess its possible utility in distinguishing reactive versus neoplastic changes. Immunoreactivity of p16INK4 was investigated using paraffin sections from 8 different sample groups (n = 80), including organ donor bladders with normal and/or reactive urothelium; bladder biopsies with reactive atypia; isolated carcinoma in situ; high-grade UC with concurrent carcinoma in situ; low-grade papillary urothelial neoplasms; high-grade stage T1 UC; and high-grade stage T2-T4 UC without concomitant carcinoma in situ. A composite staining score was calculated (Σ% positive cells × intensity) for each case. Fluorescence in situ hybridization analysis was performed in selected cases. A uniform and weak cytoplasmic p16INK4 expression was observed in normal urothelium and urothelium with reactive atypia from organ donors. Bladder biopsies with reactive atypia showed lower scores and loss of p16INK4 expression in 38% of cases. Strong p16INK4 staining was found in 100% of carcinoma in situ with no loss of p16INK4 expression. The strong p16INK4 immunoreactivity in foci of carcinoma in situ clearly demarcated the neoplastic cells from adjacent nonneoplastic cells, which showed either normal or focal loss of p16INK4 staining. Fluorescence in situ hybridization study revealed abundant deletion of chromosome 9p21 or polysomy of chromosome 9 in malignant cells of carcinoma in situ. Increased p16INK4 expression was also seen in most high-grade invasive UC with concurrent carcinoma in situ, but the intensity of p16INK4 staining did not correlate with the cancer grade or stage. We conclude that the 16INK4 immunoreactivity seems to be most useful in distinguishing carcinoma in situ from severe reactive atypia. Alterations of 9p21/chromosome 9 detected by fluorescence in situ hybridization can also be used for diagnostic confirmation and prognostic prediction. [Copyright &y& Elsevier]

The incidence and mortality of prostate cancer (PCa) vary greatly in different geographic regions, for which lifestyle factors, such as dietary fat intake, have been implicated. Human 15-lipoxygenase-1 (h15-LO-1), which metabolizes polyunsaturated fatty acids, is a highly regulated, tissue-specific, lipid-peroxidating enzyme that functions in physiological membrane remodeling and in the pathogenesis of atherosclerosis, inflammation, and carcinogenesis. We have shown that aberrant overexpression of 15-LO-1 occurs in human PCa, particularly high-grade PCa, and in high-grade prostatic intraepithelial neoplasia (HGPIN), and that the murine orthologue is increased in SV40-based genetically engineered mouse (GEM) models of PCa, such as LADY and TRansgenic Adenocarcinoma of Mouse Prostate. To further define the role of 15-LO-1 in prostate carcinogenesis, we established a novel GEM model with targeted overexpression of h15-LO-1 in the prostate [human fifteen lipoxygenase-1 in mouse prostate (FLiMP)]. We used a Cre- mediated and a loxP-mediated recombination strategy to target h15-LO-1 specifically to the prostate of C57BL/6 mice. Wild-type (wt), FLiMP+/-, and FLiMP+/+ mice aged 7 to 21, 24 to 28, and 35 weeks were characterized by histopathology, immunohistochemistry (IHC), and DNA/RNA and enzyme analyses. Compared to wt mice, h15-LO-1 enzyme activity was increased similarly in both homozygous FLiMP+/+ and hemizygous FLiMP+/- prostates. Dorsolateral and ventral prostates of FLiMP mice showed focal and progressive epithelial hyperplasia with nuclear atypia, indicative of the definition of mouse prostatic intraepithelial neoplasia (mPIN) according to the National Cancer Institute. These foci showed increased proliferation by Ki-67 IHC. No progression to invasive PCa was noted up to 35 weeks. By IHC, h15-LO-1 expression was limited to luminal epithelial cells, with increased expression in mPIN foci (similar to human HGPIN). In summary, targeted overexpression of h15-LO-1 (a gene overexpressed in human PCa and HGPIN) to mouse prostate is sufficient to promote epithelial proliferation and mPIN development. These results support 15-LO-1 as having a role in prostate tumor initiation and as an early target for dietary or other prevention strategies. The FLiMP mouse model should also be useful in crosses with other GEM models to further define the combinations of molecular alterations necessary for PCa progression. [ABSTRACT FROM AUTHOR]

Summary: By imaging large numbers of slides automatically at high resolution, modern automated whole slide imaging (WSI) systems have the potential to become useful tools in pathology practice. This article describes a pilot validation study for use of automated high-speed WSI systems for surgical pathology quality assurance (QA). This was a retrospective comparative study in which 24 full genitourinary cases (including 47 surgical parts and 391 slides) were independently reviewed with traditional microscopy and whole slide digital images. Approximately half the cases had neoplasia in the diagnostic line. At the end of the study, diagnostic discrepancies were evaluated by a pathology consensus committee. The study pathologists felt that the traditional and WSI methods were comparable for case review. They reported no difference in perceived case complexity or diagnostic confidence between the methods. There were 4 clinically insignificant discrepancies with the signed-out cases: 2 from glass slide and 2 with WSI review. Of the 2 discrepancies reported by the WSI method, the committee agreed with the reviewer once and the original report once. At the end of the study, the participants agreed that automated WSI is a viable potential modality for surgical pathology QA, especially in multifacility health systems that would like to establish interfacility QA. The participants felt that major issues limiting the implementation of WSI-based QA did not involve image acquisition or quality but rather image management issues such as the pathologist''s interface, the hospital''s network, and integration with the laboratory information system. [Copyright &y& Elsevier]

Summary: Extrarenal rhabdoid tumors have been described in a variety of primary sites with only rare case reports of urothelial carcinomas with rhabdoid features in the literature. In this report, we describe the clinicopathologic characteristics, including clinical follow-up on 6 cases of urothelial carcinoma with prominent rhabdoid features. Four cases were retrieved from the consultation files of one of the authors and 2 were retrieved from the surgical pathology files at our institution. The patients were all men, with ages ranging from 53 to 86 years (mean, 66.5 years). Patients initially presented with hematuria or obstructive symptoms. The sites included bladder (n = 4) and renal pelvis (n = 2). All cases had a prominent rhabdoid component (mean, 60%), ranging from 40% to 80%. In addition to the rhabdoid component, multiple coexistent histological components were seen, including in situ urothelial carcinoma (carcinoma in situ) and high-grade papillary urothelial carcinoma (n = 2), poorly differentiated carcinoma with small-cell features (n = 1), sarcomatoid (n = 2), and a myxoid component (n = 2). All cases in this series had focal or diffuse positive staining with one or more cytokeratin markers (epithelial membrane antigen, CAM 5.2, AE1/AE3). Of the 6 patients, 4 were treated initially with surgery (radical cystoprostatectomy, n = 2; radical nephrectomy, n = 2). Of 6 patients, 2 died within 1 month, whereas a third patient died within 4 months. The remaining 3 patients were alive at 3, 3, and 9 months after diagnosis. The histological and immunohistochemical findings in this study serve to broaden the morphological spectrum of urothelial carcinomas with prominent rhabdoid features and add further evidence as to their poor prognosis. [Copyright &y& Elsevier]

A 61-year-old man presented with gross hematuria and a polypoid right lateral bladder mass. The tumor was composed of conventional urothelial carcinoma with sarcomatoid and choriocarcinomatous features, both positive for epithelial markers (pancytokeratin, AE1/AE3, and CAM 5.2). In addition, choriocarcinomatous tumor cells were positive for beta human chorionic gonadotropin and placental alkaline phosphatase. Treatments included surgery, chemotherapy, and radiation therapy. The clinical course was aggressive, with liver, lung, and distant lymph node metastases and a postdiagnosis survival of 6 months. This is the first report, to our knowledge, indicating both sarcomatoid and choriocarcinomatous features in a conventional urothelial carcinoma of the bladder. [Copyright &y& Elsevier]

Abstract: Idiopathic granulomatous orchitis is a rare inflammatory process of the testis of unknown etiology. It is characterized by presence of non-specific granulomatous inflammation and admixed multinucleated giant cells. It usually presents as a testicular mass which is highly suspicious of malignancy. Histologically, there is extensive destruction of seminiferous tubules with tubular or interstitial pattern of granulomatous inflammation and prominent collagen fibrosis. Trauma and possible auto-antibodies against sperms have been postulated to be the underlying mechanism. Differential diagnoses include intratubular germ-cell neoplasia, malignant lymphomas, and malakoplakia. Orchiectomy is currently the most appropriate therapy for this condition. [Copyright &y& Elsevier]

• Light chain deposition disease (LCDD) is due to the deposition of immunoglobulin in multiple organs due to the abnormal clonal proliferation of B lymphocytes and plasma cells • Renal involvement is the most common with cardiac manifestations being the most common extra renal presentation of the disease • Cardiac involvement of light chain deposition disease is also known as cardiac nonamyloidotic immunoglobulin deposition disease (CIDD) which can present as: congestive heart failure, restrictive cardiomyopathy, and arrhythmia. • Isolated cardiac involvement, presenting as an atrial mass is a very unique finding Light chain deposition disease (LCDD) also known as nonamyloidotic immunoglobulin deposition disease is a rare systemic disorder due to the abnormal deposition of immunoglobulin in multiple organs caused by the clonal proliferation of B lymphocytes and plasma cells. Renal involvement is the most common with cardiac manifestations being the most common extra renal presentation of the disease. Renal involvement is not always associated with LCDD. Isolated cardiac involvement can manifest in a wide variety of ways: heart failure, cardiomyopathy, arrhythmias, angina, myocardial infarction, etc. We hereby present an unusual case of 59-year-old female who presented to clinic for routine follow up. A murmur on physical exam was evaluated with echocardiogram which led to the discovery of an incidental right atrial mass. Cardiac magnetic resonance imaging was completed 6 months later for follow up which showed increasing size of the mass. The mass was excised and found to be consistent with LCDD. To the best of our knowledge, this is the first reported case of LCDD manifesting as an atrial mass. Through this case report and review of literature we would like to generate awareness among our fellow pathologists and clinicians to maintain a high level of suspicion for LCDD as it can manifest in many unusual ways, with or without kidney involvement. [ABSTRACT FROM AUTHOR]

The establishment of minimum standards for display selection for the whole slide image (WSI) interpretation has not been fully defined. Recently, pathologists have increasingly preferred using remote displays for clinical diagnostics. Our study aims to assess and compare the performance of three fixed work displays and one remote personal display in accurately identifying ten selected pathologic features integrated into WSIs. Hematoxylin and eosin-stained glass slides were digitized using Philips scanners. Seven practicing pathologists and three residents reviewed ninety WSIs to identify ten pathologic features using the LG, Dell, and Samsung and an optional consumer-grade display. Ten pathologic features included eosinophils, neutrophils, plasma cells, granulomas, necrosis, mucin, hemosiderin, crystals, nucleoli, and mitoses. The accuracy of the identification of ten features on different types of displays did not significantly differ among the three types of "fixed" workplace displays. The highest accuracy was observed for the identification of neutrophils, eosinophils, plasma cells, granuloma, and mucin. On the other hand, a lower accuracy was observed for the identification of crystals, mitoses, necrosis, hemosiderin, and nucleoli. Participant pathologists and residents preferred the use of larger displays (>30″) with a higher pixel count, resolution, and luminance. Most features can be identified using any display. However, certain features posed more challenges across the three fixed display types. Furthermore, the use of a remote personal consumer-grade display chosen according to the pathologists' preference showed similar feature identification accuracy. Several factors of display characteristics seemed to influence pathologists' display preferences such as the display size, color, contrast ratio, pixel count, and luminance calibration. This study supports the use of standard "unlocked" vendor-agnostic displays for clinical digital pathology workflow rather than purchasing "locked" and more expensive displays that are part of a digital pathology system. [ABSTRACT FROM AUTHOR]

The tumor suppressor genes EAF2 and p53 are frequently dysregulated in prostate cancers. Recently, we reported that concurrent p53 nuclear staining and EAF2 downregulationwere associatedwith highGleason score. Combined loss of EAF2 and p53 in a murine model induced prostate tumors, and concurrent knockdown of EAF2 and p53 in prostate cancer cells enhanced proliferation and migration, further suggesting that EAF2 and p53 could functionally interact in the suppression of prostate tumorigenesis. Here, RNA-seq analyses identified differentially regulated genes in response to concurrent knockdown of p53 and EAF2. Several of these genes were associated with the STAT3 signaling pathway, and this was verified by significantly increased p-STAT3 immunostaining in the Eaf2-/-p53-/- mouse prostate. STAT3 knockdown abrogated the stimulation of C4-2 cell proliferation by concurrent knockdownofEAF2andp53. Furthermore, immunostaining of p-STAT3was increased in human prostate cancer specimenswithEAF2downregulationand/or p53 nuclear staining.Our findings suggest that simultaneous inactivation of EAF2 and p53 can act to activate STAT3 and drive prostate tumorigenesis. [ABSTRACT FROM AUTHOR]

Background Despite revisions in 2005 and 2014, the Gleason prostate cancer (PCa) grading system still has major deficiencies. Combining of Gleason scores into a three-tiered grouping (6, 7, 8–10) is used most frequently for prognostic and therapeutic purposes. The lowest score, assigned 6, may be misunderstood as a cancer in the middle of the grading scale, and 3 + 4 = 7 and 4 + 3 = 7 are often considered the same prognostic group. Objective To verify that a new grading system accurately produces a smaller number of grades with the most significant prognostic differences, using multi-institutional and multimodal therapy data. Design, setting, and participants Between 2005 and 2014, 20 845 consecutive men were treated by radical prostatectomy at five academic institutions; 5501 men were treated with radiotherapy at two academic institutions. Outcome measurements and statistical analysis Outcome was based on biochemical recurrence (BCR). The log-rank test assessed univariable differences in BCR by Gleason score. Separate univariable and multivariable Cox proportional hazards used four possible categorizations of Gleason scores. Results and limitations In the surgery cohort, we found large differences in recurrence rates between both Gleason 3 + 4 versus 4 + 3 and Gleason 8 versus 9. The hazard ratios relative to Gleason score 6 were 1.9, 5.1, 8.0, and 11.7 for Gleason scores 3 + 4, 4 + 3, 8, and 9–10, respectively. These differences were attenuated in the radiotherapy cohort as a whole due to increased adjuvant or neoadjuvant hormones for patients with high-grade disease but were clearly seen in patients undergoing radiotherapy only. A five–grade group system had the highest prognostic discrimination for all cohorts on both univariable and multivariable analysis. The major limitation was the unavoidable use of prostate-specific antigen BCR as an end point as opposed to cancer-related death. Conclusions The new PCa grading system has these benefits: more accurate grade stratification than current systems, simplified grading system of five grades, and lowest grade is 1, as opposed to 6, with the potential to reduce overtreatment of PCa. Patient summary We looked at outcomes for prostate cancer (PCa) treated with radical prostatectomy or radiation therapy and validated a new grading system with more accurate grade stratification than current systems, including a simplified grading system of five grades and a lowest grade is 1, as opposed to 6, with the potential to reduce overtreatment of PCa. [ABSTRACT FROM AUTHOR]

Abstract: Collision tumors, characterized by the coexistence of phenotypically and genotypically distinct tumors at the same site, are distinctly rare in the genitourinary tract and pose a diagnostic challenge. The goal of this study is to present a series of such cases from a single institution highlighting the unusual clinicopathologic features of these tumors. Six cases were retrospectively identified from our surgical pathology files and included internal and consultation cases (2006–2012). All tumors were identified by H&E and selected immunohistochemistry. There were 5 males and 1 female patients ranging in age from 57 to 84 years (average 73 years). The sites of these collision tumors were located in the kidney (3 cases), bladder (2 cases), and prostate. All collision tumors involved at least one malignant neoplasm. The diagnosis of collision tumors in the genitourinary tract is a perplexing task. Awareness of these rare entities, thorough sampling of the tumor mass, and appropriate use of ancillary techniques to demonstrate the different tumor components can help avoid an incorrect diagnosis, as well as with pathologic staging. [Copyright &y& Elsevier]

Abstract: The National Mesothelioma Virtual Bank (NMVB) was established to provide annotated biospecimens to the mesothelioma research community. The resource provides tissue microarrays (TMA) to evaluate the biomarkers along with a variety of other resected mesothelioma specimens. In this manuscript, we describe the immunohistochemical evaluation of the mesothelioma TMA with three key antibodies that are used in making the diagnosis of mesothelioma, and compared the immunohistochemical assessment between manual scoring and image analysis. The TMA was assessed for the immunohistochemical expression of calretinin (N =39), cytokeratin (CK) 5/6 (N =33), and D2-40 (N =37). Immunohistochemistry was evaluated by semi-quantitative (manual) scoring using light microscope (MS) and by automated image analysis (AS). Calretinin staining was seen in both cytoplasmic and nuclear locations. CK5/6 stain was localized to the cytoplasm. D2-40 stain showed only membranous expression in our cases. [•] Based on the pathologist's scores, calretinin was positive in 31 of the 39 cases (80%), CK 5/6 in 15 of the 33 cases (46%) and D2-40 in 18 of the 37 cases (49%). [•] The percent-positive agreement between manual scores and image analysis was 90% (35/39), 94% (31/33), and 95% (35/37) for calretinin, CK 5/6, and D2-40, respectively. There was a substantial agreement between manual and automated scores for calretinin (kappa=0.614) and an almost perfect agreement for CK5/6 (kappa=0.879) and D2-40 (kappa=0.892). Our study confirms that the immunohistochemical staining pattern of mesotheliomas in the NMVB UPMC TMA is similar to other studies. Our findings also show that automated image analysis provides similar results to manual scoring by pathologists, and provides a reproducible, objective, and accurate platform for immunohistochemical assessment of biomarker expression. [Copyright &y& Elsevier]

Teratomas with malignant transformation occur in approximately 3 to 6% of patients with metastatic germ cell tumors treated with platinum-based chemotherapy. The histology of the nongerm cell (somatic) malignant elements most commonly includes carcinoma and various types of sarcomas; however, so far as the primitive neuroectodermal tumors (PNETs) are concerned the experience is quite limited. There are only seven documented case reports and occasional series of PNET in association with testicular teratoma either in the primary site or in the metastatic location. We report a relatively unusual case of PNET arising in a malignant mixed germ cell tumor in a 35-year-old man. [Copyright &y& Elsevier]

Abstract: The lipid-peroxidating enzyme, 15-lipoxygenase (LO)-1 and its metabolite, 13-S-hydroxyoctadecadienoic acid (13-S-HODE), likely contribute to prostate tumorigenesis. Thus, this study evaluated adenovirus-mediated overexpression of 15-LO-1 on normal mouse prostate. Adenovirus expressing either human 15-LO-1 tagged with green fluorescent protein (GFP) or GFP alone was orthotopically injected into the dorsolateral prostates of C57BL/6 mice, three times over the course of 60 days. On day 90, pathological changes in prostate tissue were assessed by hematoxylin and eosin (H&E) staining. Expression of the proliferation marker Ki-67 was evaluated by immunohistochemistry and expression of angiogenesis markers were analyzed by an antibody array. Based on the latter study, immunoprecipitation analysis was used to measure the effect of 13-S-HODE, with or without conditioned media, on fibroblast growth factor-a and b (FGF-a and FGF-b) expression in human PrEC (normal prostate epithelial), PrSMC (normal prostate smooth muscle) and PrSC (normal prostate stromal) lines. Expression of viral 15-LO-1-GFP, but not GFP alone, resulted in the development of a prostate intraepithelial neoplasia (PIN)-like phenotype with increased expression of Ki-67. Aberrant 15-LO-1 expression also induced the angiogenic markers FGF-a and FGF-b. Human PrEC, PrSMC and PrSC lines demonstrated an increase in FGF-b expression upon stimulation with 13-S-HODE, which was further increased by the addition of conditioned media from the epithelial or smooth muscle cells. Using adenoviral mediated 15-LO-1 gene delivery, this study suggests that aberrant 15-LO-1 overexpression in normal prostate can trigger events leading to prostate epithelial and stromal cell proliferation. Thus, our findings demonstrate the effectiveness of this viral system for 15-LO-1 expression studies in tissues. [Copyright &y& Elsevier]

Abstract: Tumor-to-tumor metastasis is a very rare event. The recipient tumor may be benign or malignant. Renal cell carcinoma is the most common tumor recipient of metastasis while lung carcinoma is the most common donor tumor. We report a 57-year-old Caucasian male who presented with chest pain. On PET CT Scan, he was also found to have a large renal mass for which he underwent left nephrectomy. On histology of the renal mass, the tumor was a conventional renal cell carcinoma with areas of metastatic non-small cell lung carcinoma. The two components had a distinctive morphology which was confirmed on subsequent immunohistochemistry. The physiopathological mechanisms making clear cell renal cell carcinoma an avid recipient of a metastatic carcinoma have been speculated upon, but are still unknown. [Copyright &y& Elsevier]