L1 Cell Adhesion Molecule (L1CAM) Expression and Molecular Alterations Distinguish Low-Grade Oncocytic Tumor From Eosinophilic Chromophobe Renal Cell Carcinoma.

Renal low-grade oncocytic tumor (LOT) is a recently recognized renal cell neoplasm designated within the "other oncocytic tumors" category in the 2022 World Health Organization classification system. Although the clinicopathologic, immunohistochemical, and molecular features reported for LOT have been largely consistent, the data are relatively limited. The morphologic overlap between LOT and other low-grade oncocytic neoplasms, particularly eosinophilic chromophobe renal cell carcinoma (E-chRCC), remains a controversial area in renal tumor classification. To address this uncertainty, we characterized and compared large cohorts of LOT (n = 67) and E-chRCC (n = 69) and revealed notable differences between the 2 entities. Clinically, LOT predominantly affected women, whereas E-chRCC showed a male predilection. Histologically, although almost all LOTs were dominated by a small-nested pattern, E-chRCC mainly showed solid and tubular architectures. Molecular analysis revealed that 87% of LOT cases harbored mutations in the tuberous sclerosis complex (TSC)-mTOR complex 1 (mTORC1) pathway, most frequently in MTOR and RHEB genes; a subset of LOT cases had chromosomal 7 and 19q gains. In contrast, E-chRCC lacked mTORC1 mutations, and 60% of cases displayed chromosomal losses characteristic of chRCC. We also explored the cell of origin for LOT and identified L1 cell adhesion molecule (L1CAM), a collecting duct and connecting tubule principal cell marker, as a highly sensitive and specific ancillary test for differentiating LOT from E-chRCC. This distinctive L1CAM immunohistochemical labeling suggests the principal cells as the cell of origin for LOT, unlike the intercalated cell origin of E-chRCC and oncocytoma. The ultrastructural analysis of LOT showed normal-appearing mitochondria and intracytoplasmic lumina with microvilli, different from what has been described for chRCC. Our study further supports LOT as a unique entity with a benign clinical course. Based on the likely cell of origin and its clinicopathologic characteristics, we propose that changing the nomenclature of LOT to "Oncocytic Principal Cell Adenoma of the Kidney" may be a better way to define and describe this entity.

Examining the role of diversity, equity, and inclusion in mitigating workforce burnout in laboratory medicine.

OBJECTIVES: The clinical laboratory workforce plays a crucial role in health care delivery, yet little is known about the unique pressures and challenges this workforce faces. The objective of this study was to identify factors that contribute to burnout, discrimination, exclusion, and inequity in pathology and laboratory medicine. METHODS: A nationwide survey was conducted in 2 phases. In phase 1, 2391 laboratory professionals were surveyed over a 1-week period about their experiences with burnout, discrimination, and work-related stress. In phase 2, the survey was extended to 1 month and questions were added to elicit more detailed information about diversity, equity, and inclusion (DEI) as well as wellness. RESULTS: Results showed a high prevalence of burnout, discrimination, and stress among laboratory professionals, with significant differences among certain demographic groups. Women, Black, indigenous, or people of color individuals and those with disabilities reported higher rates of discrimination. The study also showed a need for mentorship and resources to address educational barriers. CONCLUSIONS: Findings from this study highlight the urgent need for interventions to address burnout, discrimination, exclusion, and inequity in the laboratory workforce. Initiatives to increase workforce diversity, promote mentorship and diversity training programs, and improve recognition of the laboratory workforce are recommended. The results underscore the pressing need to addressing the challenges and apprehensions laboratory professionals face, including enhancing recognition of their role in patient care, tackling systemic problems related to discrimination and equity, and enhancing the provision of support and resources for managing burnout and fostering well-being.

Long-term Outcomes of Local and Metastatic Small Cell Carcinoma of the Urinary Bladder and Genomic Analysis of Patients Treated With Neoadjuvant Chemotherapy.

INTRODUCTION: Small cell carcinoma of the bladder (SCCB) is a rare variant of bladder cancer with poor outcomes. We evaluated long-term outcomes of nonmetastatic (M0) and metastatic (M1) SCCB and correlated pathologic response with genomic alterations of patients treated with neoadjuvant chemotherapy (NAC). PATIENTS AND METHODS: Clinical history and pathology samples from SCCB patients diagnosed at our institution were reviewed. RESULTS: One hundred and ninety-nine SCCB patients were identified. (M0: 147 [74%]; M1: 52 [26%]). Among M0 patients, 108 underwent radical cystectomy (RC) (NAC: 71; RC only: 23; adjuvant chemotherapy: 14); 14 received chemoradiotherapy; the rest received chemotherapy alone or no cancer-directed therapy. RC-only patients had a median follow-up of 9.1 years, and median disease-free survival (DFS) and overall survival (OS) were 1.1 and 1.2 years, respectively. NAC patients had pathologic response (

Neuroendocrine differentiation in the setting of prostatic carcinoma: contemporary assessment of a consecutive series.

AIM: Clinicopathologic characterisation of a contemporary series of neuroendocrine (NE) differentiation in the setting of prostatic carcinoma (PCa) was examined. METHODS AND RESULTS: We reviewed institutional databases for in-house cases with a history of PCa and histopathologic evidence of NE differentiation during the disease course. In all, 79 cases were identified: 32 primary and 47 metastases. Metastatic lesions were in liver (n = 15), lymph node (n = 9), bone (n = 6), lung (n = 3), brain (n = 1), and other sites (n = 13). In all, 63 of 76 (82%) cases with NE differentiation and available history were posttherapy: six postradiation therapy (RT), 24 post- androgen-deprivation therapy (ADT), and 33 post-RT + ADT. Morphologic assessment (n = 79): (i) 23 pure small-cell/high-grade NE carcinoma (HGNEC): 20/23 metastatic; (ii) 10 combined high-grade PCa and small-cell/HGNEC: 9/10 primary; (iii) 15 PCa with diffuse NE immunohistochemistry (IHC) marker positivity/differentiation, associated with nested to sheet-like growth of cells with abundant cytoplasm and prominent nucleoli, yet diffuse positivity for at least one prostatic and one NE IHC marker: all metastatic; (iv) 11 PCa with patchy NE differentiation, displaying more than single-cell positivity for NE IHC: five primary / six metastatic; (v) nine PCa with focal NE marker positive cells: four primary / five metastatic; (vi) 11 PCa with 'Paneth cell-like' change: all primary. CONCLUSIONS: In this contemporary series, the majority of NE differentiation in the setting of PCa was seen posttherapy. We highlight the tendencies of small-cell/HGNEC and PCa with diffuse NE differentiation by IHC to occur in metastatic settings, while morphologically combined high-grade PCa + small-cell/HGNEC and 'Paneth cell-like' change occur in primary disease.

Using Technology to Enhance Cancer Clinical Trial Participation.

The COVID-19 pandemic presented many challenges to health care systems, including oncology clinical research programs. There were substantial negative effects on oncology clinical trial screening, enrollment, and study activities that forced institutions and regulatory bodies to develop innovative solutions to maintain robust and equitable participation in these trials. Digital pathology innovations at Memorial Sloan Kettering Cancer Center have streamlined the diagnostic life cycle for patients with cancer, and the seamless integration of digital pathology services with next-generation sequencing and other molecular pathology services have accelerated the time to diagnosis and receipt of molecular results. Timely access to these results, coupled with Memorial Sloan Kettering Cancer Center's knowledge engine OncoKB, enhances patient clinical trial coordination precisely and efficiently. At the Sarah Cannon Research Institute, centralized remote clinical trial matching and screening, virtual molecular tumor boards, and centralized molecular interpretation support services have empowered clinic staff to identify more efficiently potential participants in clinical research, despite the COVID-19 pandemic. In addition, the U.S. Food and Drug Administration Oncology Center of Excellence has been involved in several efforts to address challenges for patients with cancer during the COVID-19 pandemic, including writing guidance documents and participating in efforts to modernize clinical trials. The enclosed personal experience of a patient with cancer currently participating in an oncology clinical trial emphasizes the need for continued decreasing of barriers to study participation. Clinical trial advances that were accelerated by the pandemic will ultimately help patients with cancer and the greater oncology health care community.

Impact of Zone of Origin in Anterior Dominant Prostate Cancer: Long-Term Biochemical Recurrence-Free Survival in an Anatomically Well-Characterized Cohort.

INTRODUCTION: Our goal was to determine whether zonal origin of anterior dominant prostate cancers is associated with clinical outcome among patients treated with radical prostatectomy. METHODS: We investigated the clinical outcomes of 197 patients with previously well-characterized anterior dominant prostatic tumors on radical prostatectomy. Univariable Cox proportional hazards models were used to test for an association between anterior peripheral zone (PZ) or transition zone (TZ) tumor location and clinical outcomes. RESULTS: Zonal origin of anterior dominant tumors: 97/197 (49%) anterior PZ, 70 (36%) TZ, 14 (7%) both zones and 16 (8%) indeterminate zone. Comparing anterior PZ and TZ tumors, there were no significant differences in Grade group, incidence of extraprostatic extension or surgical margin positivity rate. Overall, 19 (9.6%) patients experienced biochemical recurrence (BCR), including 10 with anterior PZ origin and 5 with TZ origin. Median followup time among those without BCR was 9.5 years (IQR 7.2, 12.7). BCR-free survival at 5 and 10 years was 91% and 89% for anterior PZ tumors, and 94% and 92% for TZ tumors, respectively. On univariate analysis, there was no evidence of a difference in time to BCR between anterior PZ and TZ tumor zone of origin (p=0.5). CONCLUSIONS: In this anatomically well-characterized cohort of anterior dominant prostate cancers, long-term BCR-free survival was not significantly associated with zone of origin. Future studies utilizing zone of origin as a parameter should consider separating anterior and posterior PZ localization, as outcomes may differ.

Papillary renal cell carcinoma: a single institutional study of 199 cases addressing classification, clinicopathologic and molecular features, and treatment outcome.

The morphologic spectrum of type 1 papillary renal cell carcinoma (PRCC) is not well-defined, since a significant proportion of cases have mixed type 1 and 2 histology. We analyzed 199 cases of PRCC with any (even if focal) type 1 features, with a median follow-up of 12 years, to identify clinicopathological features associated with outcome. Ninety-five tumors (48%) of the cohort contained some type 2 component (median amount: 25%; IQR: 10%, 70%). As a group they showed high rates of progression-free (PFS) and cancer-specific survival (CSS). Tumor size, mitotic rate, lymphovascular invasion, sarcomatoid differentiation, sheet-like architecture, and lack of tumor circumscription were significantly associated with CSS (p ≤ 0.015) on univariate analysis. While predominant WHO/ISUP nucleolar grade was associated with PFS (p = 0.013) and CSS (p = 0.030), the presence of non-predominant (<50%) nucleolar grade did not show association with outcome (p = 0.7). PFS and CSS showed no significant association with the presence or the amount of type 2 morphology. We compared the molecular alterations in paired type 1 and type 2 areas in a subset of 22 cases with mixed type 1 and 2 features and identified 12 recurrently mutated genes including TERT, ARID1A, KDM6A, KMT2D, NFE2L2, MET, APC, and TP53. Among 78 detected somatic mutations, 61 (78%) were shared between the paired type 1 and type 2 areas. Copy number alterations, including chromosome 7 and 17 gains, were similar between type 1 and 2 areas. These findings support that type 2 features in a PRCC with mixed histology represent either morphologic variance or clonal evolution. Our study underscores the notion that PRCC with any classic type 1 regions is best considered as type 1 PRCC and assigned the appropriate WHO/ISUP nucleolar grade. It provides additional evidence that type 2 PRCC as a separate category should be re-assessed and likely needs to be abandoned.

Integrated digital pathology at scale: A solution for clinical diagnostics and cancer research at a large academic medical center.

OBJECTIVE: Broad adoption of digital pathology (DP) is still lacking, and examples for DP connecting diagnostic, research, and educational use cases are missing. We blueprint a holistic DP solution at a large academic medical center ubiquitously integrated into clinical workflows; researchapplications including molecular, genetic, and tissue databases; and educational processes. MATERIALS AND METHODS: We built a vendor-agnostic, integrated viewer for reviewing, annotating, sharing, and quality assurance of digital slides in a clinical or research context. It is the first homegrown viewer cleared by New York State provisional approval in 2020 for primary diagnosis and remote sign-out during the COVID-19 (coronavirus disease 2019) pandemic. We further introduce an interconnected Honest Broker for BioInformatics Technology (HoBBIT) to systematically compile and share large-scale DP research datasets including anonymized images, redacted pathology reports, and clinical data of patients with consent. RESULTS: The solution has been operationally used over 3 years by 926 pathologists and researchers evaluating 288 903 digital slides. A total of 51% of these were reviewed within 1 month after scanning. Seamless integration of the viewer into 4 hospital systems clearly increases the adoption of DP. HoBBIT directly impacts the translation of knowledge in pathology into effective new health measures, including artificial intelligence-driven detection models for prostate cancer, basal cell carcinoma, and breast cancer metastases, developed and validated on thousands of cases. CONCLUSIONS: We highlight major challenges and lessons learned when going digital to provide orientation for other pathologists. Building interconnected solutions will not only increase adoption of DP, but also facilitate next-generation computational pathology at scale for enhanced cancer research.

Pathology Informatics Education during the COVID-19 Pandemic at Memorial Sloan Kettering Cancer Center (MSKCC).

This review details the development and structure of a four-week rotation in pathology informatics for a resident trainee at Memorial Sloan Kettering Cancer Center (MSKCC) in New York City so that other programs interested in such a rotation can refer to. The role of pathology informatics is exponentially increasing in research and clinical practice. With an ever-expanding role, training in pathology informatics is paramount as pathology training programs and training accreditation bodies recognize the need for pathology informatics in training future pathologists. However, due to its novelty, many training programs are unfamiliar with implementing pathology informatics training. The rotation incorporates educational resources for pathology informatics, guidance in the development, and general topics relevant to pathology informatics training. Informatics topics include anatomic pathology related aspects such as whole slide imaging, laboratory information systems, image analysis, and molecular pathology associated issues such as the bioinformatics pipeline and data processing. Additionally, we highlight how the rotation pivoted to meet the department's informatics needs while still providing an educational experience during the onset of the COVID-19 pandemic. CONCLUSION: As pathology informatics continues to grow and integrate itself into practice, informatics education must also grow to meet the future needs of pathology. As informatics programs develop across institutions, such as the one detailed in this paper, these programs will better equip future pathologists with informatics to approach disease and pathology.

College of American Pathologists Cancer Protocols: From Optimizing Cancer Patient Care to Facilitating Interoperable Reporting and Downstream Data Use.

The College of American Pathologists Cancer Protocols have offered guidance to pathologists for standard cancer pathology reporting for more than 35 years. The adoption of computer readable versions of these protocols by electronic health record and laboratory information system (LIS) vendors has provided a mechanism for pathologists to report within their LIS workflow, in addition to enabling standardized structured data capture and reporting to downstream consumers of these data such as the cancer surveillance community. This paper reviews the history of the Cancer Protocols and electronic Cancer Checklists, outlines the current use of these critically important cancer case reporting tools, and examines future directions, including plans to help improve the integration of the Cancer Protocols into clinical, public health, research, and other workflows.

Adverse histology, homozygous loss of CDKN2A/B, and complex genomic alterations in locally advanced/metastatic renal mucinous tubular and spindle cell carcinoma.

Mucinous tubular and spindle cell carcinoma (MTSCC) is a rare subtype of renal cell carcinoma with characteristic histologic features and chromosomal alterations. Although typically indolent, a small subset of cases has been reported to exhibit aggressive clinical behavior. We retrospectively identified 33 patients with MTSCC, consisting of 10 cases of locally advanced/metastatic MTSCC (pT3 or N1 or M1) and 23 kidney-confined MTSCC (pT1/T2) without disease recurrence or progression. Utilizing a single-nucleotide polymorphism array and a targeted next-generation sequencing platform, we examined genome-wide molecular alterations in 24 cases, including 11 available samples from 8 patients with locally advanced/metastatic MTSCC. Ten patients with locally advanced/metastatic MTSCC were 8 females (80%) and 2 males (20%). At nephrectomy, 7 of these 10 cases (70%) were pT3 or pN1 while the remaining 3 (30%) were pT1/T2. Eight patients (80%) developed metastases and common sites included lymph node (4, 40%), bone (4, 40%), and retroperitoneum (3, 30%). Four patients died of disease (40%) during follow-up. Locally advanced/metastatic MTSCCs shared typical MTSCC genomic profiles with loss of chromosomes 1, 4, 6, 8, 9, 13, 14, 15, and 22, while some exhibited additional complex genomic alterations, most frequently a relative gain of 1q (7/8). Homozygous loss of CDKN2A/B was observed in 3 (38%) locally advanced/metastatic MTSCCs. Tumor necrosis, solid nested/sheet pattern, irregular trabecular/single-file infiltration in a desmoplastic stroma, lymphovascular space invasion, and increased mitotic activity were associated with locally advanced/metastatic MTSCCs (all p < 0.05). Our findings reveal that MTSCCs with aggressive clinical behavior have progressed through clonal evolution; CDKN2A/B deletion and additional complex genomic abnormalities may contribute to this process. Recognizing the morphologic presentation of high-grade MTSCC and evaluating adverse histologic features seen in these tumors can help establish a definitive diagnosis and stratify patients for treatment and prognostication.

Interpretable multimodal deep learning for real-time pan-tissue pan-disease pathology search on social media.

Pathologists are responsible for rapidly providing a diagnosis on critical health issues. Challenging cases benefit from additional opinions of pathologist colleagues. In addition to on-site colleagues, there is an active worldwide community of pathologists on social media for complementary opinions. Such access to pathologists worldwide has the capacity to improve diagnostic accuracy and generate broader consensus on next steps in patient care. From Twitter we curate 13,626 images from 6,351 tweets from 25 pathologists from 13 countries. We supplement the Twitter data with 113,161 images from 1,074,484 PubMed articles. We develop machine learning and deep learning models to (i) accurately identify histopathology stains, (ii) discriminate between tissues, and (iii) differentiate disease states. Area Under Receiver Operating Characteristic (AUROC) is 0.805-0.996 for these tasks. We repurpose the disease classifier to search for similar disease states given an image and clinical covariates. We report precision@k = 1 = 0.7618 ± 0.0018 (chance 0.397 ± 0.004, mean ±stdev ). The classifiers find that texture and tissue are important clinico-visual features of disease. Deep features trained only on natural images (e.g., cats and dogs) substantially improved search performance, while pathology-specific deep features and cell nuclei features further improved search to a lesser extent. We implement a social media bot (@pathobot on Twitter) to use the trained classifiers to aid pathologists in obtaining real-time feedback on challenging cases. If a social media post containing pathology text and images mentions the bot, the bot generates quantitative predictions of disease state (normal/artifact/infection/injury/nontumor, preneoplastic/benign/low-grade-malignant-potential, or malignant) and lists similar cases across social media and PubMed. Our project has become a globally distributed expert system that facilitates pathological diagnosis and brings expertise to underserved regions or hospitals with less expertise in a particular disease. This is the first pan-tissue pan-disease (i.e., from infection to malignancy) method for prediction and search on social media, and the first pathology study prospectively tested in public on social media. We will share data through http://pathobotology.org . We expect our project to cultivate a more connected world of physicians and improve patient care worldwide.

Practice Patterns in Reporting Tertiary Grades at Radical Prostatectomy: Survey of a Large Group of Experienced Urologic Pathologists.

CONTEXT.­: In prostate cancer, "tertiary" higher-grade patterns (TPs) have been associated with biochemical recurrence after radical prostatectomy. OBJECTIVE.­: To determine variation regarding definition and application of TPs. DESIGN.­: Online survey regarding TPs in a range of grading scenarios circulated to 105 experienced urologic pathologists. RESULTS.­: Among 95 respondents, 40 of 95 (42%) defined TPs as "third most common pattern" and 55 (58%) as "minor pattern/less than 5% of tumor." In a tumor with pattern 3 and less than 5% pattern 4, of the 95 respondents, 35 (37%) assigned 3 + 3 = 6 with TP4, while 56 (59%) assigned 3 + 4 = 7. In a tumor with pattern 4 and less than 5% pattern 5, of the 95 respondents, 51 (54%) assigned 4 + 4 = 8 with TP5, while 43 (45%) assigned 4 + 5 = 9. Six scenarios were presented in which the order of most common patterns was 3, 4, and 5 (Group 1) or 4, 3, and 5 (Group 2) with varying percentages. In both groups, when pattern 5 was less than 5%, we found that 98% and 93% of respondents would assign 3 + 4 = 7 or 4 + 3 = 7 with TP5. In scenarios with 15% or 25% pattern 5, most respondents (70% and 80%, respectively) would include pattern 5 as the secondary grade, that is, 3 + 5 = 8 (Group 1) or 4 + 5 = 9 (Group 2). For 85 of 95 (89%), a TP would not impact Grade Group assignment. CONCLUSIONS.­: This survey highlights substantial variation in practice patterns regarding definition and application of "tertiary" grading in radical prostatectomy specimens. High consistency was observed in 3 + 4 = 7/4 + 3 = 7 scenarios with truly minor pattern 5. These findings should inform future studies assessing the standardization and predictive value of "tertiary" patterns.

Implementation of Digital Pathology Offers Clinical and Operational Increase in Efficiency and Cost Savings.

CONTEXT.­: Digital pathology (DP) implementations vary in scale, based on aims of intended operation. Few laboratories have completed a full-scale DP implementation, which may be due to high overhead costs that disrupt the traditional pathology workflow. Neither standardized criteria nor benchmark data have yet been published showing practical return on investment after implementing a DP platform. OBJECTIVE.­: To provide benchmark data and practical metrics to support operational efficiency and cost savings in a large academic center. DESIGN.­: Metrics reviewed include archived pathology asset retrieval; ancillary test request for recurrent/metastatic disease; cost analysis and turnaround time (TAT); and DP experience survey. RESULTS.­: Glass slide requests from the department slide archive and an off-site surgery center showed a 93% and 97% decrease, respectively. Ancillary immunohistochemical orders, compared in 2014 (52%)-before whole slide images (WSIs) were available in the laboratory information system-and 2017 (21%) showed $114 000/y in anticipated savings. Comprehensive comparative cost analysis showed a 5-year $1.3 million savings. Surgical resection cases with prior WSIs showed a 1-day decrease in TAT. A DP experience survey showed 80% of respondents agreed WSIs improved their clinical sign-out experience. CONCLUSIONS.­: Implementing a DP operation showed a noteworthy increase in efficiency and operational utility. Digital pathology deployments and operations may be gauged by the following metrics: number of glass slide requests as WSIs become available, decrease in confirmatory testing for patients with metastatic/recurrent disease, long-term decrease in off-site pathology asset costs, and faster TAT. Other departments may use our benchmark data and metrics to enhance patient care and demonstrate return on investment to justify adoption of DP.

Distinctive mechanisms underlie the loss of SMARCB1 protein expression in renal medullary carcinoma: morphologic and molecular analysis of 20 cases.

Renal medullary carcinoma is a rare but highly aggressive type of renal cancer occurring in patients with sickle cell trait or rarely with other hemoglobinopathies. Loss of SMARCB1 protein expression, a core subunit of the switch/sucrose nonfermentable (SWI/SNF) chromatin remodeling complex, has emerged as a key diagnostic feature of these tumors. However, the molecular mechanism underlying this loss remains unclear. We retrospectively identified 20 patients diagnosed with renal medullary carcinoma at two institutions from 1996 to 2017. All patients were confirmed to have sickle cell trait, and all tumors exhibited a loss of SMARCB1 protein expression by immunohistochemistry. The status of SMARCB1 locus was examined by fluorescence in situ hybridization (FISH) using 3-color probes, and somatic alterations were detected by targeted next-generation sequencing platforms. FISH analysis of all 20 cases revealed 11 (55%) with concurrent hemizygous loss and translocation of SMARCB1, 6 (30%) with homozygous loss of SMARCB1, and 3 (15%) without structural or copy number alterations of SMARCB1 despite protein loss. Targeted sequencing revealed a pathogenic somatic mutation of SMARCB1 in one of these 3 cases that were negative by FISH. Tumors in the 3 subsets with different FISH findings largely exhibited similar clinicopathologic features, however, homozygous SMARCB1 deletion was found to show a significant association with the solid growth pattern, whereas tumors dominated by reticular/cribriform growth were enriched for SMARCB1 translocation. Taken together, we demonstrate that different molecular mechanisms underlie the loss of SMARCB1 expression in renal medullary carcinoma. Biallelic inactivation of SMARCB1 occurs in a large majority of cases either via concurrent hemizygous loss and translocation disrupting SMARCB1 or by homozygous loss.