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Context.--Human papillomavirus (HPV) is a wellknown cause of squamous cell carcinomas of anogenital and oropharyngeal regions, where treatment strategies and prognosis depend on HPV status. The significance of HPV status in tumors arising along the urinary tract is not well established. Objective.--To provide detailed clinical, morphologic, immunohistochemical, and molecular analysis of HPV1 urinary tract carcinomas (UTCs). Design.--We identified and retrospectively examined 12 HPV1 UTCs, confirmed by high-risk HPV in situ hybridization. Results.--The HPV1 UTCs originated from the urethra (9) and urinary bladder (3); 5 of 12 (42%) presented with nodal metastasis. On morphology, HPV1 UTCs were predominantly basaloid; well-differentiated squamous areas were focally seen. Available immunohistochemistry (IHC) showed strong staining for p16 (11 of 11), p63 (12 of 12), cytokeratin (CK) 903 (11 of 11), and CK5/6 (11 of 11); variable staining for GATA3 (8 of 12) and CK7 (4 of 11); and rare uroplakin II staining (1 of 12). Molecular analysis revealed the most frequently altered genes: KMT2C (42%), PIK3CA (42%), and KMT2D (25%). In contrast to published conventional urothelial and squamous cell carcinoma molecular data, TERTp mutation was rare (8%), and no TP53 or CDKN2A aberrations were identified. During available follow-up (11 of 12; median, 39 months), 6 patients required treatment for recurrence; ultimately, 1 died of disease, 2 were alive with disease, and 8 had no evidence of disease. Finally, we provide 11 HPV2 squamous predominant UTCs for IHC and molecular comparisons; notably, a subset of HPV2 UTCs was positive for p16 IHC (27%), making p16 IHC a less-specific surrogate marker for HPV status at this site. Conclusions.--HPV1 UTCs show distinct clinical, morphologic, and molecular characteristics, suggesting important roles for HPV in UTC. [ABSTRACT FROM AUTHOR]

An introduction to articles in the issue is presented on topics including one of the most frequent and important applications of diagnostic immunohistochemistry (IHC), ICH markers to address some of the frequently encountered diagnostic issues in the liver, gastrointestinal, and pancreatobiliary tract, and updates in IHC markers for salivary glands.

Context.--: Mesothelioma is an uncommon tumor that can be difficult to diagnose. Objective.--: To provide updated, practical guidelines for the pathologic diagnosis of mesothelioma. Data sources.--: Pathologists involved in the International Mesothelioma Interest Group and others with expertise in mesothelioma contributed to this update. Reference material includes peer-reviewed publications and textbooks. Conclusions.--: There was consensus opinion regarding guidelines for (1) histomorphologic diagnosis of mesothelial tumors, including distinction of epithelioid, biphasic, and sarcomatoid mesothelioma; recognition of morphologic variants and patterns; and recognition of common morphologic pitfalls; (2) molecular pathogenesis of mesothelioma; (3) application of immunohistochemical markers to establish mesothelial lineage and distinguish mesothelioma from common morphologic differentials; (4) application of ancillary studies to distinguish benign from malignant mesothelial proliferations, including BAP1 and MTAP immunostains; novel immunomarkers such as Merlin and p53; fluorescence in situ hybridization (FISH) for homozygous deletion of CDKN2A; and novel molecular assays; (5) practical recommendations for routine reporting of mesothelioma, including grading epithelioid mesothelioma and other prognostic parameters; (6) diagnosis of mesothelioma in situ; (7) cytologic diagnosis of mesothelioma, including use of immunostains and molecular assays; and (8) features of nonmalignant peritoneal mesothelial lesions. [ABSTRACT FROM AUTHOR]

Context.--Salivary gland tumors are rare tumor types for which the molecular understanding has resulted in a rapid expansion and shuffling of entities. These changes are reflected in the 5th edition World Health Organization Classification of Head and Neck Tumours (WHO 5th edition), although many nuances still remain. Objective.--To review how molecular alterations have helped recategorize, justify, and reinstate entities into our lexicon as well as defining interrelationships between categories, new entities, and subtypes. Furthermore, newer theranostic applications to molecular phenotype will be summarized. Data Sources.--World Health Organization Classification of Head and Neck Tumours (WHO 3rd through 5th editions), literature review, and personal and institutional experience. Conclusions.--Molecular alterations have helped reclassify, retain, and create new categories by augmenting rather than replacing standard criteria. Key entities that have emerged include sclerosing polycystic adenoma, microsecretory adenocarcinoma, and mucinous adenocarcinoma. Molecular phenotypes solidify the range of morphology in established entities such as mucoepidermoid carcinoma and facilitate connectivity between entities. Molecular characteristics now allow for targeted therapeutic approaches for secretory carcinoma and adenoid cystic carcinoma. [ABSTRACT FROM AUTHOR]

Context.--Oncocytic thyroid tumors displaying a papillary growth pattern are rare and may cause diagnostic problems. Objective.--To examine the clinicopathologic features of a series of 32 follicular cell-derived tumors composed of cells with oncocytic cytoplasm and displaying papillary architecture. Design.--Thirty-two cases were collected and studied to assess clinicopathologic features, including immunohistochemical and molecular testing for BRAF V600E. Results.--The patients were 26 women and 6 men, aged 17 to 77 years. The nodules ranged from 0.3 to 6.0 cm. Eighteen cases showed features of oncocytic hyper- plastic nodules and were identified against a background of thyroid follicular nodular disease; 4 cases showed features of oncocytic follicular adenoma; and 10 cases corresponded to carcinomas with oncocytic and papillary features. Nuclear features of papillary thyroid carcinoma were absent or exceedingly rare. All cases were negative for HBME-1 and cytokeratin 19 (CK19) and wild type for BRAF V600E. Follow-up in 25 patients showed that all patients with hyperplastic nodules and oncocytic follicular adenomas were alive and well and free of disease from 7 to 20 years. One patient with oncocytic follicular carcinoma showed metastases and died of tumor at 16 months; 2 patients with carcinoma had metastases and recurrence at 6 and 7 years; and 5 patients with invasive tumors were free of disease from 5 to 10 years. Conclusions.--Oncocytic thyroid tumors with papillary features can span a spectrum from benign hyperplastic, to encapsulated neoplastic, to invasive malignant lesions. Owing to their papillary features, it is important not to confuse them for other types of thyroid tumors, such as oncocytic papillary thyroid carcinoma. [ABSTRACT FROM AUTHOR]

* Context.--Recent molecular discoveries have led to improved understanding of tumor biology and the development of new diagnostic assays. Objective.--To review primarily 3 examples of liver tumors and to briefly illustrate how recent molecular discoveries have altered clinical liver pathology practice. Data Sources.--First, we will discuss fibrolamellar carcinoma, which will be the main focus of discussion, as an example for new diagnostic tests that have been developed as a result of molecular discoveries. Additional information on the role of molecular diagnostics in hepatocellular adenoma and hepatocellular carcinoma will be provided. Second, we will use the example of epithelioid hemangioendothelioma as an example of how new diagnostic tools, based on molecular discoveries, may support improved prognostication. Finally, we will use the example of intrahepatic cholangiocarcinoma as an example of a liver tumor where new molecular discoveries have identified tractable therapeutic targets and led to new effective therapies. This portion of the manuscript will also include a description of the anatomic and molecular differences between intrahepatic, hilar, and extrahepatic cholangiocarcinoma. Conclusions.--Fueled by molecular discoveries, new and better diagnostic tests and therapeutic targets have improved clinical care in patients affected by liver tumors. [ABSTRACT FROM AUTHOR]

Context.-- Ankylosing spondylitis (AS) is an autoimmune disorder with a strong genetic risk, especially with HLA-B27. Clinical testing for HLA-B27 has been used to help diagnose patients with signs and symptoms of AS. Testing methods used by clinical laboratories for HLA-B27 fall into the broad categories of serologic/antibody- or molecular-based methods and have evolved over time. The College of American Pathologists (CAP) offers a proficiency testing survey for HLA-B27. Objective.-- To analyze HLA-B27 testing trends and their performance in the past decade, using the proficiency testing survey data submitted to CAP. Design.-- We analyzed the HLA-B27 CAP proficiency testing data from 2010 to 2020 for the method used, participant concordance, and error rates. Results from case scenarios to understand evolving scientific data around HLA-B27 risk alleles were also analyzed. Results.-- Antibody-based flow cytometry is the most common method, though it has decreased from 60% in 2010 to 52% in 2020, with a corresponding increase in molecular methods. Among the molecular methods, real-time polymerase chain reaction has increased from 2% to 15%. Flow cytometry had the highest error rate (5.33%), and sequence-specific oligonucleotide (0%) is the most accurate (0%). Results of case scenarios demonstrated that most participants understood that allele-level HLA-B27 typing results inform clinical interpretation, for example HLA-B*27:06 is not associated with AS. Conclusions.-- These data demonstrated the changing trends for HLA-B27 testing during the past decade. HLA-B27 allelic typing provides a better understanding of AS association. This is possible by testing for the second field with methods like next-generation sequencing. [ABSTRACT FROM AUTHOR]

Context.-- The Sustainable Predictive Oncology Therapeutics and Diagnostics quality assurance pilot study (SPOT/Dx pilot) on molecular oncology next-generation sequencing (NGS) reportedly demonstrated performance limitations of NGS laboratory-developed tests, including discrepancies with a US Food and Drug Administration-approved companion diagnostic. The SPOT/Dx pilot methods differ from those used in proficiency testing (PT) programs. Objective.-- To reanalyze SPOT/Dx pilot data using PT program methods and compare to PT program data.Also see p. 136. Design.-- The College of American Pathologists (CAP) Molecular Oncology Committee reanalyzed SPOT/Dx pilot data applying PT program methods, adjusting for confounding conditions, and compared them to CAP NGS PT program performance (2019-2022). Results.-- Overall detection rates of KRAS and NRAS single-nucleotide variants (SNVs) and multinucleotide variants (MNVs) by SPOT/Dx pilot laboratories were 96.8% (716 of 740) and 81.1% (129 of 159), respectively. In CAP PT programs, the overall detection rates for the same SNVs and MNVs were 97.2% (2671 of 2748) and 91.8% (1853 of 2019), respectively. In 2022, the overall detection rate for 5 KRAS and NRAS MNVs in CAP PT programs was 97.3% (1161 of 1193). Conclusions.-- CAP PT program data demonstrate that laboratories consistently have high detection rates for KRAS and NRAS variants. The SPOT/Dx pilot has multiple design and analytic differences with established PT programs. Reanalyzed pilot data that adjust for confounding conditions demonstrate that laboratories proficiently detect SNVs and less successfully detect rare to never-observed MNVs. The SPOT/Dx pilot results are not generalizable to all molecular oncology testing and should not be used to market products or change policy affecting all molecular oncology testing. [ABSTRACT FROM AUTHOR]

* Context.--Endometrial cancer is classified into 4 molecular subtypes: DNA polymerase epsilon ultramutated, mismatch repair deficient, p53 mutant, and nonspecific molecular profile (NSMP). Additional biomarkers are urgently needed to better characterize the NSMP subtype, the largest group with heterogeneous pathologic features and prognoses. Objective.--To investigate the expression of B7 homolog 3 (B7-H3), B7 homolog 4 (B7-H4), and V-set and immunoglobulin domain containing 3 (VSIG-3, a ligand for B7-H5) in 833 patients with endometrial cancer and determine their associations with clinicopathologic and molecular features as well as survival outcomes. Design.--Molecular classification was determined by polymerase epsilon sequencing and immunohistochemical staining for p53 and mismatch repair proteins. B7-H3, B7-H4, VSIG-3, and programmed death ligand-1 (PD-L1) were detected via immunohistochemistry. Results.--The positivity rates for B7-H3 in each of the tumor and immune cells, B7-H4 (exclusively in tumor cells), and VSIG-3 (exclusively in tumor cells) were 89.0%, 42.3%, 71.5%, and 99.8%, respectively. B7-H3 and B7-H4 positivity in tumor cells was associated with favorable pathologic features and prognosis. In contrast, B7-H3 expression in immune cells was frequent in samples with unfavorable pathologic features; those with p53-mutant subtype, PD-L1 positivity, and a high density of CD8+ T cells; and in patients with poor prognoses. Positive B7-H4 expression was a predictor of improved survival in patients with the NSMP subtype independent of tumor stage or pathologic features. Conclusions.--The NSMP subgroup of endometrial cancer can be further stratified by B7-H4 status. Incorporating B7-H4 status into the molecular classification of NSMP could improve the ability to predict disease relapse. [ABSTRACT FROM AUTHOR]

Context.--The World Health Organization classification of tumors of the breast recognizes several special type carcinomas and benign lesions with features comparable to those of salivary gland tumors. Objective.--To discuss the histologic, immunophenotypic, molecular, and clinical features of salivary gland--like carcinomas of the breast. These breast tumors are often negative for hormone receptors and human epidermal growth factor receptor 2 (HER2), that is, triple-negative, but they generally have a much better prognosis than triple-negative breast carcinomas of no special type. We compare the immunophenotypic, molecular, and clinical features of these breast tumors with their salivary gland counterparts, highlighting similarities and differences. We also discuss benign salivary gland--like breast tumors. Finally, we highlight recent developments in understanding the molecular pathogenesis of these breast tumors and novel ancillary studies that can be used to support their diagnosis. Data Sources.--A literature review was conducted, and papers were selected for further analysis and discussion by the authors of this review based on their novelty, applicability, and impact in the field. Conclusions.--Breast tumors that exhibit morphologic overlap with salivary gland tumors have been recognized by pathologists for decades, but the similarities and differences in their molecular pathogenesis have not been understood until more recently. These developments have led to novel diagnostic tools and further knowledge of these rare breast lesions. [ABSTRACT FROM AUTHOR]

Context.--Penile squamous cell carcinomas (PSCCs) are divided into tumors that are human papillomavirus (HPV) associated and those that are non-HPV associated. HPV and non-HPV PSCCs each display unique pathogenic mechanisms, histologic subtypes, and clinical behaviors. Treatment of localized PSCC tumors is linked to significant physical and psychological morbidity, and management of advanced disease is often treatment refractory. The identification of novel actionable mutations is of critical importance so that translational scientists and clinicians alike can pursue additional therapeutic options. Objective.--To provide an update on the molecular pathogenesis associated with PSCC. A special emphasis is placed on next-generation sequencing data and its role in identifying potential therapeutic targets. Data Sources.--A literature review using the PubMed search engine to access peer-reviewed literature published on PSCC. Conclusions.--Our understanding of the genetic and molecular mechanisms that underlie PSCC pathogenesis continues to evolve. PSCC tumorigenesis is mediated by multiple pathways, and mutations of oncogenic significance have been identified that may represent targets for personalized therapy. Preliminary results of treatment with immune checkpoint inhibition and tyrosine kinase inhibitors have produced variable clinical results. Further insight into the pathogenesis of PSCC will help guide clinical trials and develop additional precision medicine approaches. [ABSTRACT FROM AUTHOR]

Context.--In 2019, papillary renal neoplasm with reverse polarity (PRNRP) was defined as a new neoplasm because it has a predominately tubulopapillary pattern lined by a single layer of cuboidal and eosinophilic cells with apically located round nuclei. Immunohistochemically, this neoplasm showed expression of GATA-3 and L1CAM and had recurrent KRAS mutations. Objective.--To estimate the incidence of PRNRP and provide 8 additional cases with some variations in the morphology. Design.--We reviewed 1627 renal tumors from our hospital during a 21-year period (2000-2020). We reexamined 196 papillary renal cell carcinomas and selected those that met the diagnostic criteria for PRNRP. Results.--We found 8 cases consistent with PRNRP. The median age of the patients was 64.75 years; 7 patients were male, and 1 was female. Two patients had end-stage renal disease. No recurrence, metastasis, or tumor-related death occurred in a mean follow-up period of 67.62 months. Tumor size ranged from 1.6 to 3.7 cm. All cases were pT1. Seven cases (7 of 8; 87.5%) had predominantly cystic changes, and 1 had solid architecture. No foamy cells, clear cell change, or psammoma bodies were seen in any cases. All cases were positive for CK7, EMA, GATA3, and L1CAM. KRAS gene mutation was detected in 5 cases (5 of 8; 62.5%). Conclusions.--PRNRP represents 4.08% (8 of 196 cases) of papillary renal cell carcinomas and 0.49% (8 of 1627 cases) of all renal tumors in the 21-year period in our series. In our study, all cases exhibited an indolent clinical course. This supports that PRNRP has characteristic morphologic and molecular features. [ABSTRACT FROM AUTHOR]

Context.-- The pathology residency program began in China in 2014. There has been no competency assessment on training programs in the Hubei province of China. Objective.-- To evaluate the current residency training curriculum and resident performance in Hubei Province. Design.-- A 37-question online questionnaire was designed to cover general demographic information, diagnostic competency, expectations of ideal caseload for gross and preview, teaching patterns, examinations, research activities, weak points, and other topics in pathology practice. Results.-- A total of 166 participants, including 62 postgraduate year (PGY) 2, 49 PGY3, and 55 new practicing pathologists, responded to the survey. PGY3 residents were found to be more competent than PGY2 in diagnostic competency. Forty-five of 55 new practicing pathologists (81.8%) reported that they could sign out cases independently, whereas 10 of 55 (18.2%) were found to still need transitional time for learning before working independently. Some residents could sign out cytopathology cases and gained knowledge in immunohistochemistry and histochemical staining, while some residents did not receive adequate training in molecular pathology. The ideal caseloads for gross and preview during residency were greater than 5000 and 7000, respectively. Nonneoplastic diseases, neuropathology, dermatopathology, hematopathology, and soft tissue pathology were considered difficult subspecialties in pathology practice. Conclusions.-- While residents trained in Hubei Province have met the basic requirements for qualified pathologists, more efforts need to be made in many areas, such as a well-structured training curriculum and better-designed proficiency examinations. The findings of this study are of great importance to prioritizing training in the future. [ABSTRACT FROM AUTHOR]

Context.--Anatomic pathology slide unknown conferences are usually limited to a microscopic slide, slide images, or a virtual slide that is previewed prior to a conference. The answer is provided at a conference along with the ancillary studies, such as immunohistochemical or molecular studies, that enabled the diagnosis. In this rigid system the learner never gains experience with an appropriate workup for cases that will enable the definitive diagnosis. Objective.--To develop an interactive system in which the user can work through a difficult case, ordering stains and other special studies, ideally leading to more involvement and retention. Design.--An online system was developed using HTML, PHP Hypertext Preprocessor, and JavaScript for ordering and result display. When the user selects a study, an image or text result is displayed. Studies include immunohistochemistry, cytogenetics, flow cytometry, molecular, and radiology. The user then selects the diagnosis and, if correct, is shown some additional didactics. Results.--Unknown conferences were held at 3 institutions using this novel teaching method that allowed residents to work up unknown cases. Conferences are available online (http://www.drdoubleb.com/unknowns/) and include general, soft tissue, and hematopathology cases. Evaluations were obtained that showed that residents enjoyed the system, considered it better than standard unknown sessions and lectures, and wanted more sessions. Conclusions.--This system was very highly received by the residents in all programs, who enjoyed getting immediate results and being able to work through interesting cases. More widespread use of this system could make for an effective learning tool. [ABSTRACT FROM AUTHOR]

* Context.--Laboratories of many medical college hospitals in India do not offer important diagnostic tests, most of which are routine in the West. This detracts from the service as well as the educational function of the college. Objectives.--To provide the background to pathology and laboratory medicine services and education in India, and to create a questionnaire that will put the lack of tertiary care laboratory services in perspective. This article will help illustrate the lacunae in laboratory medicine services and in the education of students. For this, we present information on the health services and pathology education facilities in India. We propose a questionnaire comprising 30 questions in various disciplines in pathology and laboratory medicine. These questions will help administrators and bureaucrats evaluate the status of the laboratories with respect to the services provided. Data Sources.--Sources include Web sites of the government of India, including that of the National Accreditation Board for Testing and Calibration Laboratories; indexed medical journal articles; and standard books and white papers on health care in India. We also used our personal experiences and interpretations of the laboratory and medical education sector in India. Conclusions.--Medical colleges in India need to offer specialized diagnostic services if they are to achieve the targets of universal health care as well as turning out competent doctors. The agencies responsible for health care in India should use the questionnaire as a first step toward improving laboratory services. Other low- and middle-income countries should also adopt this method. [ABSTRACT FROM AUTHOR]

* Context.--In 2016, the College of American Pathologists (CAP) launched the first next-generation sequencing (NGS) in silico bioinformatics proficiency testing survey to evaluate the performance of clinical laboratory bioinformatics pipelines for the detection of oncology-associated variants at varying allele fractions. This survey focused on 2 commonly used oncology panels, the Illumina TruSeq Amplicon Cancer Panel and the Thermo Fisher Ion AmpliSeq Cancer Hotspot v2 Panel. Objective.--To review the analytical performance of laboratories participating in the CAP NGS bioinformatics (NGSB) surveys, comprising NGSB1 for Illumina users and NGSB2 for Thermo Fisher Ion Torrent users, between 2016 and 2019. Design.--Responses from 78 laboratories were analyzed for accuracy and associated performance characteristics. Results.--The analytical sensitivity was 90.0% (1901 of 2112) for laboratories using the Illumina platform and 94.8% (2153 of 2272) for Thermo Fisher Ion Torrent users. Variant type and variant allele fraction were significantly associated with performance. False-negative results were seen mostly for multi-nucleotide variants and variants engineered at variant allele fractions of less than 25%. Analytical specificity for all participating laboratories was 99.8% (9303 of 9320). There was no statistically significant association between deletion-insertion length and detection rate. Conclusions.--These results demonstrated high analytical sensitivity and specificity, supporting the feasibility and utility of using in silico mutagenized NGS data sets as a supplemental challenge to CAP surveys for oncologyassociated variants based on physical samples. This program demonstrates the opportunity and challenges that can guide future surveys inclusive of customized in silico programs. [ABSTRACT FROM AUTHOR]

* Context.--A wide spectrum of mesenchymal tumors harboring ALK gene rearrangements has been identified outside the archetypal example of ALK-positive inflammatory myofibroblastic tumors. Objective.--To evaluate the molecular pathology of unusual ALK-positive mesenchymal tumors and their response to ALK-targeted treatments. Design.--Seven patients with ALK-positive mesenchymal tumors, including inflammatory epithelioid cell sarcoma, undifferentiated sarcoma, histiocytic neoplasm, smooth muscle tumor of uncertain malignant potential (STUMP), and atypical fibrohistiocytic tumor, were included on the basis of aberrant ALK immunoexpression. Patients with inflammatory myofibroblastic tumors were excluded from the study. ALK gene rearrangement was investigated either by fluorescence in situ hybridization or next-generation sequencing. Results.--ALK was immunolabeled in all patients, diffusely (≥50%) in 6 patients and partially (10%-50%) in 1 patient. ALK gene rearrangement was discovered in 5 of the 6 available patients. The 3'-partners of ALK fusion were identified in 3 of 4 investigated patients as follows: PRKAR1A-ALK (ALK-positive histiocytic neoplasm), TNS1-ALK (STUMP), and KIF5B-ALK (ALK-positive atypical fibrohistiocytic tumor). We failed to discover ALK translocation in 1 patient with ALK-positive inflammatory epithelioid cell sarcoma. However, transcriptomic investigation showed that this tumor was significantly enriched with ALK-related pathways, which suggested activation of ALK through a nontranslocation pathway, as a constitutive oncogenic mark in this tumor. ALK-targeted inhibitors, which were administered to 3 patients with metastatic diseases, achieved partial remission in 1 patient with ALK-positive inflammatory epithelioid cell sarcoma and stable disease in patients with ALK-positive undifferentiated sarcoma and STUMP. Conclusions.--Molecular investigation of ALK-positive mesenchymal neoplasms could allow for an accurate diagnosis and personalized treatment. [ABSTRACT FROM AUTHOR]

* Context.--The College of American Pathologists (CAP), a laboratory accreditation organization with deemed status under the Clinical Laboratories Improvement Amendments of 1988 administers accreditation checklists. Checklists are used by laboratories to ensure regulatory compliance. Peer-level laboratory professionals audit laboratory records during inspections to assess compliance. Objective.--To identify the most frequently cited deficiencies for molecular oncology laboratories undergoing CAP accreditation inspections and describe laboratory improvement opportunities. Design.--The CAP Molecular Oncology Committee (MOC), which is involved in maintaining the Molecular Pathology checklist, reviewed data and inspector comments associated with the most frequently observed citations related to molecular oncology testing from laboratories inspected by the CAP during a 2-year period (2018-2020). Results.--Of 422 molecular oncology laboratories that underwent accreditation inspections, 159 (37.7%) were not cited for any molecular oncology-related deficiencies. For the All Common (COM) and Molecular Pathology checklists, there were 364 and 305 deficiencies, corresponding to compliance rates of 98.8% and 99.6%, respectively. The most frequently cited deficiencies are described. The COM checklist deficiencies were associated most often with the analytic testing phase; the MOL checklist deficiencies were more evenly distributed across the preanalytic, analytic, and postanalytic phases of testing. Conclusions.--Molecular oncology laboratories demonstrated excellent compliance with practices that support high-quality results for patients and the health care providers who use those test results in patient management. This review includes a critical assessment of opportunities for laboratories to improve compliance and molecular oncology testing quality. [ABSTRACT FROM AUTHOR]

* Context.--This article is based on a talk given by the lead author at the Eigth Annual Princeton Integrated Pathology Symposium: Breast Pathology, on Sunday, April 11, 2021. Objective.--To show how the World Health Organization (WHO) Classification of Tumours links to the requirements for quality assurance in breast pathology, including both immunohistochemistry and molecular pathology. Data Sources.--The WHO Classification of Tumours 5th edition Breast Tumours entries formed the basis of the talk, together with guidance published by the International Quality Network for Pathology. Conclusions.--The WHO Classification of Tumours provides a definitive set of international standards for tumor diagnosis contributed by experts, based on available clinical and research evidence. Techniques used in pathology need internal and external quality assurance to ensure accurate reports for patient management. [ABSTRACT FROM AUTHOR]

Context.--: The US Food and Drug Administration (FDA) approved immune checkpoint inhibitor therapy for patients with advanced solid tumors that have DNA mismatch repair defects or high levels of microsatellite instability; however, the FDA provided no guidance on which specific clinical assays should be used to determine mismatch repair status. Objective.--: To develop an evidence-based guideline to identify the optimal clinical laboratory test to identify defects in DNA mismatch repair in patients with solid tumor malignancies who are being considered for immune checkpoint inhibitor therapy. Design.--: The College of American Pathologists convened an expert panel to perform a systematic review of the literature and develop recommendations. Using the National Academy of Medicine-endorsed Grading of Recommendations Assessment, Development and Evaluation approach, the recommendations were derived from available evidence, strength of that evidence, open comment feedback, and expert panel consensus. Mismatch repair immunohistochemistry, microsatellite instability derived from both polymerase chain reaction and next-generation sequencing, and tumor mutation burden derived from large panel next-generation sequencing were within scope. Results.--: Six recommendations and 3 good practice statements were developed. More evidence and evidence of higher quality were identified for colorectal cancer and other cancers of the gastrointestinal (GI) tract than for cancers arising outside the GI tract. Conclusions.--: An optimal assay depends on cancer type. For most cancer types outside of the GI tract and the endometrium, there was insufficient published evidence to recommend a specific clinical assay. Absent published evidence, immunohistochemistry is an acceptable approach readily available in most clinical laboratories. [ABSTRACT FROM AUTHOR]

Context.--Neoplastic cellularity assessment has become an essential component of molecular oncology testing; however, there are currently no best practice recommendations or guidelines for this potentially variable step in the testing process. Objective.--To describe the domestic and international practices of neoplastic cellularity assessment and to determine how variations in laboratory practices affect neoplastic cellularity assessment accuracy. Design.--Data were derived from 57 US and international laboratories that participated in the 2019 College of American Pathologists Neoplastic Cellularity Proficiency Testing Survey (NEO-B 2019). NEO-B 2019 included 29 laboratory practice questions and 5 images exhibiting challenging histologic features. Participants assessed the neoplastic cellularity of hematoxylin-eosin-stained digital images, and results were compared to a criterion standard derived from a manual cell count. Results.--The survey responses showed variations in the laboratory practices for the assessment of neoplastic cellularity, including the definition of neoplastic cellularity, assessment methodology, counting practices, and quality assurance practices. In some instances, variation in laboratory practice affected neoplastic cellularity assessment performance. Conclusions.--The results highlight the need for a consensus definition and improved standardization of the assessment of neoplastic cellularity. We put forth an initial set of best practice recommendations to begin the process of standardizing neoplastic cellularity assessment. [ABSTRACT FROM AUTHOR]

The entity known as thyroid follicular variant of papillary carcinoma has been a controversial one for many years. The controversy revolved around 2 features of the lesion: (1) the concept [...], Context.--This article presents a review of noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP), including its separation from follicular variant of papillary carcinoma of the thyroid, its evolution, and current definition and pathologic characteristics. Objectives.--To emphasize the understanding of the concept of NIFTP as a neoplasm based on molecular analyses, its critical histopathologic features, the microscopic findings that exclude the diagnosis, and the importance of complete sectioning of the tumor to exclude neoplasms that should be diagnosed as carcinomas. Important distinctions are discussed including difficulties with literature that shows NIFTP with metastases, inadequacy of sectioning of the tumor, and lack of descriptive histology of the surrounding thyroid and possible other lesions. Data Sources.--Review of articles in the English literature on NIFTP, as well as comparative papers showing differences and distinctions between this entity and papillary carcinomas. Conclusions.--This article concludes that with the current state of knowledge on NIFTP with studies from all over the world, this entity is a low-risk neoplasm that, when diagnosed using appropriate criteria, should not be associated with metastatic or recurrent disease, at least on intermediate length of follow-up. This review includes discussion of multifocal NIFTP, as well as the recently defined micro-NIFTP (1 cm or less), and describes features of the tumor that remain to be studied and correlated with outcome: oncocytic variants of NIFTP, percentage of allowable solid areas of growth in the lesions, and definitions of true neoplastic papillae and hyperplastic ones and how these should influence the diagnosis of NIFTP. (Arch Pathol Lab Med. 2021;145:659-663; doi: 10.5858/arpa.2019-0689-RA

Context.--Rhabdomyosarcoma, the most common soft tissue sarcoma of children, is currently classified into the following 4 subtypes: embryonal rhabdomyosarcoma, alveolar rhabdomyosarcoma, spindle cell/sclerosing rhabdomyosarcoma, and pleomorphic rhabdomyosarcoma, based on recent molecular genetic knowledge and morphologic features. Objective.--To highlight the most recent advances of molecular genetic alterations, and to familiarize pathologists with most recent genotype and phenotype correlation in rhabdomyosarcoma. Data Sources.--Data were derived from the World Health Organization Classification of Soft Tissue and Bone Tumors, fifth edition, recently published literature (PubMed), and clinical practice experience. Conclusions.--Current classification has been significantly impacted by genotype and phenotype correlation, especially with PAX-FOXO1 fusion-positive rhabdomyosarcoma versus fusion-negative rhabdomyosarcoma, and with the emergence of 3 distinct new subtypes of spindle cell/sclerosing rhabdomyosarcoma. Although all rhabdomyosarcomas were considered a single diagnostic entity in the past, they are now considered to be a group of histologically similar but biologically diverse entities because their clinical behavior and underlying molecular alterations dramatically differ. This review outlines recent molecular genetic developments, corresponding morphologic features, and current challenges faced by pathologists in daily practice. [ABSTRACT FROM AUTHOR]

Context.--Next-generation sequencing studies are increasingly used in the evaluation of suspected chronic myeloid neoplasms (CMNs), but there is wide variability among laboratories in the genes analyzed for this purpose. Recently, the Association for Molecular Pathology CMN working group recommended a core 34-gene set as a minimum target list for evaluation of CMNs. This list was recommended based on literature review, and its diagnostic yield in clinical practice is unknown. Objective.--To determine the diagnostic yield of the core 34 genes and assess the potential impact of including selected additional genes. Design.--We retrospectively reviewed 185 patients with known or suspected CMNs tested using a 62-gene next-generation sequencing panel that included all 34 core genes. Results.--The Association for Molecular Pathology's core 34 genes had a diagnostic yield of 158 of 185 (85.4%) to detect at least 1 variant with strong/potential clinical significance and 107 of 185 (57.8%) to detect at least 2 such variants. The 62-gene panel had a diagnostic yield of 160 of 185 (86.5%) and 112 of 185 (60.5%), respectively. Variants of unknown significance were identified in 49 of 185 (26.5%) using the core 34 genes versus 76 of 185 (41.1%) using the 62-gene panel. Conclusions.--This study demonstrates that the Association for Molecular Pathology--recommended core 34-gene set has a high diagnostic yield in CMNs. Inclusion of selected additional genes slightly increases the rate of abnormal results, while also increasing the detection of variants of unknown significance. We recommend inclusion of CUX1, DDX41, ETNK1, RIT1, and SUZ12 in addition to the Association for Molecular Pathology's 34-gene core set for routine evaluation of CMNs. [ABSTRACT FROM AUTHOR]

Context.--Nonalcoholic fatty liver disease (NAFLD) encompasses steatosis and steatohepatitis. The cause may be multifactorial, and diagnosis requires correlation with clinical information and laboratory results. Objective.--To provide an overview of the status of histology diagnosis of steatosis, steatohepatitis, and associated conditions. Data Sources.--A literature search was performed using the PubMed search engine. The terms ''steatosis,'' ''steatohepatitis,'' ''nonalcoholic fatty liver disease (NAFLD),'' ''nonalcoholic steatohepatitis (NASH),'' ''alcoholic steatohepatitis (ASH),'' ''type 2 diabetes (T2DM),'' ''cryptogenic cirrhosis,'' ''drug-induced liver injury (DILI),'' ''immune checkpoint inhibitor therapy,'' and ''COVID-19 and liver'' were used. Conclusions.--Nonalcoholic fatty liver disease has become the most common chronic liver disease in the United States. NASH is the progressive form of nonalcoholic fatty liver disease. The hallmarks of steatohepatitis are steatosis, ballooned hepatocytes, and lobular inflammation. NASH and alcoholic steatohepatitis share similar histologic features, but some subtle differences may help their distinction. NASH is commonly seen in patients with metabolic dysfunction but can also be caused by other etiologies. Examples are medications including newly developed immune checkpoint inhibitors and viral infections such as coronavirus disease 2019 (COVID-19). NASH is also a common cause of cryptogenic cirrhosis but can be reversed. The results from recent clinical trials for NASH treatment are promising in reducing the severity of steatosis, ballooning, and fibrosis. [ABSTRACT FROM AUTHOR]

* Context.--The diagnosis and clinical management of patients with diffuse gliomas (DGs) have evolved rapidly over the past decade with the emergence of molecular biomarkers that are used to classify, stratify risk, and predict treatment response for optimal clinical care. Objective.--To develop evidence-based recommendations for informing molecular biomarker testing for pediatric and adult patients with DGs and provide guidance for appropriate laboratory test and biomarker selection for optimal diagnosis, risk stratification, and prediction. Design.--The College of American Pathologists convened an expert panel to perform a systematic review of the literature and develop recommendations. A systematic review of literature was conducted to address the overarching question, "What ancillary tests are needed to classify DGs and sufficiently inform the clinical management of patients?" Recommendations were derived from quality of evidence, open comment feedback, and expert panel consensus. Results.--Thirteen recommendations and 3 good practice statements were established to guide pathologists and treating physicians on the most appropriate methods and molecular biomarkers to include in laboratory testing to inform clinical management of patients with DGs. Conclusions.--Evidence-based incorporation of laboratory results from molecular biomarker testing into integrated diagnoses of DGs provides reproducible and clinically meaningful information for patient management. [ABSTRACT FROM AUTHOR]

The article discusses the Cancer Biomarkers Conference (CBC) first held on March 22,2014 in Houston, Texas. Cited are the success and highlights of the CBC over the years, the uniqueness of the CBC boot camp, and an overview of the 4 articles originating from the authors' lectures at CBC V held September 10 and 11, 2022, in Jackson, Mississippi.

* Context.--Lesions in the genitourinary (GU) organs, both benign and malignant, can demonstrate overlapping morphology, and practicing surgical pathologists should be aware of these potential pitfalls and consider a broad differential diagnosis for each specific type of lesion involving the GU organs. The following summary of the contents presented at the 6th Annual Chinese American Pathologists Association (CAPA) Diagnostic Course (October 10-11, 2020), supplemented with relevant literature review, exemplifies the common diagnostic challenges and pitfalls for mass lesions of the GU system of adults, including adrenal gland, with emphasis on immunohistochemical and molecular updates when relevant. Objective.--To describe the common mass lesions in the GU system of adults, including adrenal gland, with emphasis on the diagnostic challenges and pitfalls that may arise in the pathologic assessment, and to highlight immunohistochemical workups and emerging molecular findings when relevant. Data Sources.--The contents presented at the course and literature search comprise our data sources. Conclusions.--The diagnostic challenges and pitfalls that arise in the pathologic assessment of the mass lesions in the GU system of adults, including adrenal gland, are common. We summarize the contents presented at the course, supplemented with relevant literature review, and hope to provide a diagnostic framework to evaluate these lesions in routine clinical practice. [ABSTRACT FROM AUTHOR]

* Context.--SARS-CoV-2 can undergo maternal--fetal transmission, heightening interest in the placental pathology findings from this infection. Transplacental SARS-CoV-2 transmission is typically accompanied by chronic histiocytic intervillositis together with necrosis and positivity of syncytiotrophoblast for SARS-CoV-2. Hofbauer cells are placental macrophages that have been involved in viral diseases, including HIV and Zika virus, but their involvement in SARS-CoV-2 is unknown. Objective.--To determine whether SARS-CoV-2 can extend beyond the syncytiotrophoblast to enter Hofbauer cells, endothelium, and other villous stromal cells in infected placentas of liveborn and stillborn infants. Design.--Case-based retrospective analysis by 29 perinatal and molecular pathology specialists of placental findings from a preselected cohort of 22 SARS-CoV-2--infected placentas delivered to pregnant women testing positive for SARS-CoV-2 from 7 countries. Molecular pathology methods were used to investigate viral involvement of Hofbauer cells, villous capillary endothelium, syncytiotrophoblast, and other fetal-derived cells. Results.--Chronic histiocytic intervillositis and trophoblast necrosis were present in all 22 placentas (100%). SARS-CoV-2 was identified in Hofbauer cells from 4 of 22 placentas (18.2%). Villous capillary endothelial staining was positive in 2 of 22 cases (9.1%), both of which also had viral positivity in Hofbauer cells. Syncytiotrophoblast staining occurred in 21 of 22 placentas (95.5%). Hofbauer cell hyperplasia was present in 3 of 22 placentas (13.6%). In the 7 cases having documented transplacental infection of the fetus, 2 (28.6%) occurred in placentas with Hofbauer cell staining positive for SARS-CoV-2. Conclusions.--SARS-CoV-2 can extend beyond the trophoblast into the villous stroma, involving Hofbauer cells and capillary endothelial cells, in a small number of infected placentas. Most cases of SARS-CoV-2 transplacental fetal infection occur without Hofbauer cell involvement. [ABSTRACT FROM AUTHOR]

* Context.--Errors in laboratory medicine could compromise patient safety. Good laboratory practice includes identifying and managing nonconformities in the total test process. Varying error percentages have been described in other fields but are lacking for molecular oncology. Objectives.--To gain insight into incident causes and frequency in the total test process from 8 European institutes routinely performing biomarker tests in nonsmall cell lung cancer and colorectal cancer. Design.--All incidents documented in 2018 were collected from all hospital services for pre-preanalytical entries before the biomarker test, as well as specific incidents for biomarker tests. Results.--There were 5185 incidents collected, of which 4363 (84.1%) occurred in the pre-preanalytical phase (all hospital services), 2796 of 4363 (64.1%) related to missing or incorrect request form information. From the other 822 specific incidents, 166 (20.2%) were recorded in the preanalytical phase, 275 (33.5%) in the analytical phase, and 194 (23.6%) in the postanalytical phase, mainly due to incorrect report content. Only 47 of 822 (5.7%) incidents were recorded in the post-postanalytical phase, and 123 (15.0%) in the complete total test process. For 17 of 822 (2.1%) incidents the time point was unknown. Pre- preanalytical incidents were resolved sooner than incidents on the complete process (mean 6 versus 60 days). For 1215 of 5168 (23.5%) incidents with known causes a specific action was undertaken besides documenting them, not limited to accredited institutes. Conclusions.--There was a large variety in the number and extent of documented incidents. Correct and complete information on the request forms and final reports are highly error prone and require additional focus. [ABSTRACT FROM AUTHOR]

* Context.--The 5th edition of the World Health Organization classification of digestive system tumors discusses several advancements and developments in understanding the etiology, pathogenesis, and diagnosis of several digestive tract tumors. Objective.--To provide a summary of the updates with a focus on neuroendocrine neoplasms, appendiceal tumors, and the molecular advances in tumors of the digestive system. Data Sources.--English literature and personal experiences. Conclusions.--Some of the particularly important updates in the 5th edition are the alterations made in the classification of neuroendocrine neoplasms, understanding of pathogenesis of appendiceal tumors and their precursor lesions, and the expanded role of molecular pathology in establishing an accurate diagnosis or predicting prognosis and response to treatment. [ABSTRACT FROM AUTHOR]

Context.--Controversies and uncertainty persist in prostate cancer grading. Objective.--To update grading recommendations. Data Sources.--Critical review of the literature along with pathology and clinician surveys. Conclusions.--Percent Gleason pattern 4 (%GP4) is as follows: (1) report %GP4 in needle biopsy with Grade Groups (GrGp) 2 and 3, and in needle biopsy on other parts (jars) of lower grade in cases with at least 1 part showing Gleason score (GS) 4 + 4 = 8; and (2) report %GP4: less than 5% or less than 10% and 10% increments thereafter. Tertiary grade patterns are as follows: (1) replace ''tertiary grade pattern'' in radical prostatectomy (RP) with ''minor tertiary pattern 5 (TP5),'' and only use in RP with GrGp 2 or 3 with less than 5% Gleason pattern 5; and (2) minor TP5 is noted along with the GS, with the GrGp based on the GS. Global score and magnetic resonance imaging (MRI)-targeted biopsies are as follows: (1) when multiple undesignated cores are taken from a single MRI-targeted lesion, an overall grade for that lesion is given as if all the involved cores were one long core; and (2) if providing a global score, when different scores are found in the standard and the MRI-targeted biopsy, give a single global score (factoring both the systematic standard and the MRI-targeted positive cores). Grade Groups are as follows: (1) Grade Groups (GrGp) is the terminology adopted by major world organizations; and (2) retain GS 3 + 5 = 8 in GrGp 4. Cribriform carcinoma is as follows: (1) report the presence or absence of cribriform glands in biopsy and RP with Gleason pattern 4 carcinoma. Intraductal carcinoma (IDCP) is as follows: (1) report IDC-P in biopsy and RP; (2) use criteria based on dense cribriform glands (> 50% of the gland is composed of epithelium relative to luminal spaces) and/or solid nests and/or marked pleomorphism/necrosis; (3) it is not necessary to perform basal cell immunostains on biopsy and RP to identify IDC-P if the results would not change the overall (highest) GS/GrGp part per case; (4) do not include IDC-P in determining the final GS/GrGp on biopsy and/or RP; and (5) ''atypical intraductal proliferation (AIP)'' is preferred for an intraductal proliferation of prostatic secretory cells which shows a greater degree of architectural complexity and/or cytological atypia than typical high-grade prostatic intraepithelial neoplasia, yet falling short of the strict diagnostic threshold for IDC-P. Molecular testing is as follows: (1) Ki67 is not ready for routine clinical use; (2) additional studies of active surveillance cohorts are needed to establish the utility of PTEN in this setting; and (3) dedicated studies of RNA-based assays in active surveillance populations are needed to substantiate the utility of these expensive tests in this setting. Artificial intelligence and novel grading schema are as follows: (1) incorporating reactive stromal grade, percent GP4, minor tertiary GP5, and cribriform/intraductal carcinoma are not ready for adoption in current practice. [ABSTRACT FROM AUTHOR]

Context.--An increasing number of molecular laboratories are implementing next-generation sequencing platforms to identify clinically actionable and relevant genomic alterations for precision oncology. Objective.--To describe the validation studies as per New York State--Department of Health (NYS-DOH) guidelines for the Oncomine Comprehensive Panel v2, which was originally tailored to the National Cancer Institute Molecular Analysis for Therapy Choice (NCIMATCH) trial. Design.--Accuracy, precision, and reproducibility were investigated by using 130 DNA and 18 RNA samples from cytology cell blocks; formalin-fixed, paraffin-embedded tissues; and frozen samples. Analytic sensitivity and specificity were tested by using ATCC and HapMap cell lines. Results.--High accuracy and precision/reproducibility were observed for single nucleotide variants and insertion/ deletions. We also share our experience in the detection of gene fusions and copy number alterations from an amplicon-based sequencing platform. After sequencing analysis, variant annotation and report generation were performed by using the institutional knowledgebase. Conclusions.--This study serves as an example for validating a comprehensive targeted next-generation sequencing assay with both DNASeq and RNASeq components for NYS-DOH. [ABSTRACT FROM AUTHOR]

Context.--The need for appropriate specimen use for ancillary testing has become more commonplace in the practice of pathology. This, coupled with improvements in technology, often provides less invasive methods of testing, but presents new challenges to appropriate specimen collection and handling of these small specimens, including thoracic small biopsy and cytology samples. Objective.--To develop a clinical practice guideline including recommendations on how to obtain, handle, and process thoracic small biopsy and cytology tissue specimens for diagnostic testing and ancillary studies. Methods.--The College of American Pathologists convened an expert panel to perform a systematic review of the literature and develop recommendations. Core needle biopsy, touch preparation, fine-needle aspiration, and effusion specimens with thoracic diseases including malignancy, granulomatous process/sarcoidosis, and infection (eg, tuberculosis) were deemed within scope. Ancillary studies included immunohistochemistry and immunocytochemistry, fluorescence in situ hybridization, mutational analysis, flow cytometry, cytogenetics, and microbiologic studies routinely performed in the clinical pathology laboratory. The use of rapid on-site evaluation was also covered. Results.--Sixteen guideline statements were developed to assist clinicians and pathologists in collecting and processing thoracic small biopsy and cytology tissue samples. Conclusions.--Based on the systematic review and expert panel consensus, thoracic small specimens can be handled and processed to perform downstream testing (eg, molecular markers, immunohistochemical biomarkers), core needle and fine-needle techniques can provide appropriate cytologic and histologic specimens for ancillary studies, and rapid on-site cytologic evaluation remains helpful in appropriate triage, handling, and processing of specimens. [ABSTRACT FROM AUTHOR]

Context.-- In routine clinical practice, tumor tissue is stored in formalin-fixed, paraffin-embedded blocks. However, the use of formalin-fixed, paraffin-embedded tissue for genome analysis is challenged by poorer DNA quality and quantity. Although several studies have reported genome-wide massive parallel sequencing applied on formalin-fixed, paraffin-embedded samples for mutation analysis, copy number analysis is not yet commonly performed. Objective.-- To evaluate the use of formalin-fixed, paraffin-embedded tissue for copy number alteration detection using shallow whole-genome sequencing, more generally referred to as copy number variation sequencing. Design.-- We selected samples from 21 patients, covering a range of different tumor entities. The performance of copy number detection was compared across 3 setups: array comparative genomic hybridization in combination with fresh material; copy number variation sequencing on fresh material; and copy number variation sequencing on formalin-fixed, paraffin-embedded material. Results.-- Very similar copy number profiles between paired samples were obtained. Although formalin-fixed, paraffin-embedded profiles often displayed more noise, detected copy numbers seemed equally reliable if the tumor fraction was at least 20%. Conclusions.-- Copy number variation sequencing of formalin-fixed, paraffin-embedded material represents a trustworthy method. It is very likely that copy number variation sequencing of routinely obtained biopsy material will become important for individual patient care and research. Moreover, the basic technology needed for copy number variation sequencing is present in most molecular diagnostics laboratories. [ABSTRACT FROM AUTHOR]

* Context.--Pancreatic acinar lesions encompass a broad spectrum of malignant tumors and benign reactive processes affecting both adults and children, with clinical, pathologic, and molecular features that are distinct from more common ductal neoplasms. Accurate morphologic diagnosis and molecular assessment of these uncommon neoplasms is critical for effective patient care. Objective.--To review the clinical, pathologic, and molecular features of pancreatic neoplasms with acinar differentiation, the most common of which is acinar cell carcinoma but which also includes mixed carcinomas with acinar components, cystic acinar lesions, and pancreatoblastoma. Data Sources.--We assessed the current primary literature, as well as recently updated diagnostic manuals. Conclusions.--Pancreatic acinar neoplasms are a morphologically and molecularly heterogeneous group of diseases that are characterized by acinar differentiation of at least a subset of the neoplastic cells, defined either morphologically (granular cytoplasm, single prominent nucleoli) or immunohistochemically. Squamoid nests are a key morphologic feature of pancreatoblastoma. Alterations in WNT signaling and chromosomal 11p loss are common molecular features of both acinar cell carcinoma and pancreatoblastoma. Targetable molecular alterations in acinar carcinoma include BRAF rearrangements and DNA repair defects, including mismatch repair deficiency and BRCA pathway defects. For practicing pathologists, morphologic recognition of such acinar neoplasms is critical, and in the future, molecular diagnostics to identify lesions susceptible to targeted therapy will likely form an important component of patient care. [ABSTRACT FROM AUTHOR]

An introduction is presented in which the author discusses the various topics published within the special section, including molecular pathology, cancer biomarkers, and lobular neoplasm.

Context.-- Standards for pathology reporting of cancer are foundational to national and international benchmarking, epidemiology, and clinical trials, with international standards for pathology reporting of cancer being undertaken through the International Collaboration on Cancer Reporting (ICCR). Objective.-- To develop standardized templates for brain tumor diagnostic pathology reporting. Design.-- As a response to the 2016 updated 4th edition of the WHO (World Health Organization) Classification of Tumours of the Central Nervous System (2016 CNS WHO), an expert ICCR committee developed data sets to facilitate reporting of brain tumors that are classified histologically and molecularly by the 2016 CNS WHO; as such, this represents the first combined histologic and molecular ICCR data set, and required a novel approach with 3 highly related data sets that should be used in an integrated manner. Results.-- The current article and accompanying ICCR Web site describe reporting data sets for central nervous system tumors in the hope that they provide easy-to-use and highly reproducible means to issue diagnostic reports in consort with the 2016 CNS WHO. Conclusions.-- The consistent use of these templates will undoubtedly prove useful for patient care, clinical trials, epidemiologic studies, and monitoring of neuro-oncologic care around the world. [ABSTRACT FROM AUTHOR]

Context.--Female adnexal tumor of probable Wolffian origin (FATWO) is an extremely rare gynecologic neoplasm of low malignant potential. Fewer than 90 cases of this entity have been described in the English-language literature. It is presumed to be derived from mesonephric (Wolffian) duct remnants in the upper female genital tract. We provide a literature review to increase awareness of this extremely uncommon entity. Objectives.--To review the clinical and pathologic findings of FATWO and to discuss common entities in the differential diagnosis. Data Sources.--The study involved PubMed (National Center for Biotechnology Information, Bethesda, Maryland) searches, including multiple review articles, case reports, retrospective studies, selected book chapters, and University of Mississippi Medical Center cases. Conclusions.--FATWO can affect patients from a wide age range and present with a nonspecific clinical presentation. It typically presents as solid tumors with occasional nodular, lobulated, or cystic appearances. FATWO can show a variety of histologic patterns which may result in diagnostic difficulties for pathologists. There is no single specific immunohistochemical stain for FATWO, and the pathogenesis and molecular alterations are not yet well understood. Although it is generally considered a benign entity, recurrent and metastatic cases have been reported. There are no current recommendations regarding the optimal clinical management of FATWO. [ABSTRACT FROM AUTHOR]

Context.--Renal tumor classification has evolved in recent decades, as evidenced by the comparable complexity of the 2016 revision to the World Health Organization Classification of Tumours of the Urinary System and Male Genital Organs. A recent expansion of the knowledge base surrounding the cells of origin and evolutionary genomic characteristics of renal tumors has led to molecular characterization of novel entities and enriched understanding of established entities. This pace of research and its implementation into clinical practice has again begun to surpass that of our own classification schemata, with significant discoveries having been made since the introduction of the 2016 revision to the World Health Organization classification. In particular, biomarkers for renal tumor diagnosis and prognosis are in translation for future clinical application. Objectives.--To provide a brief framework for clinical characterization of renal tumors rooted in morphologic assessment, to briefly review the current and future status of renal tumor biomarkers with an emphasis on practical use of these ancillary tools for accurate diagnosis, and to discuss the impact of emerging technologies and clinical trials relevant to renal cell carcinoma classification and biomarker development. Data Sources.--We review recent literature relevant to renal tumor classification (including established and proposed entities), focusing on molecular characterization and biomarker assessment. Conclusions.--Accurate renal tumor diagnosis requires an up-to-date understanding of renal tumor classification, including an awareness of morphologic clues that should stimulate consideration of molecularly defined entities, as well as the ancillary biomarker testing required to confirm diagnoses. [ABSTRACT FROM AUTHOR]

Context--Metaplastic carcinoma is a rare, triple-negative carcinoma of the breast that exhibits transformation of part or all of its glandular carcinomatous component into a nonglandular, or metaplastic, component. The World Health Organization currently recognizes 5 variants of metaplastic carcinoma based on their histologic appearance. Objective--To review the histologic classifications, differential diagnosis, prognosis, and recent laboratory studies of metaplastic breast carcinoma. Data Sources.--We reviewed recently published studies that collectively examine metaplastic carcinomas, including results from our own research. Conclusions.--Metaplastic breast carcinoma has a broad spectrum of histologic patterns, often leading to a broad differential diagnosis. Diagnosis can typically be rendered by a combination of morphology and immunohistochemical staining for high-molecular-weight cytokeratins and p63. Recent studies elucidate new genes and pathways involved in the pathogenesis of metaplastic carcinoma, including the downregulation of CCN6 and WNT pathway gene mutations, and provide a novel MMTV-Cre;Ccn6f'/f' knockout disease-relevant mouse model to test new therapies. [ABSTRACT FROM AUTHOR]

Primary glandular tumors of the urachus and urinary bladder are an intriguing group of clinically and morphologically diverse neoplasms for which there have been recent refinements in diagnostic subclassification and advances in molecular pathology. In addition, the urachus and urinary bladder may be secondarily involved by tumors with glandular differentiation that demonstrate remarkable morphologic, immunophenotypic, and molecular overlap. Thus, surgical pathologists need to be aware of the broad differential diagnosis of glandular tumors that involve the urachus and urinary bladder and have a practical diagnostic framework to evaluate these lesions in routine clinical practice. In this review, we summarize the salient clinical, morphologic, immunohistochemical, and molecular features of glandular tumors of the urachus and urinary bladder, including mucinous cystic tumors of the urachus, noncystic urachal adenocarcinomas, urothelial carcinomas with glandular or pseudoglandular features, primary urinary bladder adenocarcinomas, and Müllerian-type carcinomas, highlighting the strengths and limitations of various diagnostic features and ancillary tests, as well as the need for close clinical and radiographic correlation. [ABSTRACT FROM AUTHOR]

Context.--Liposarcoma is divided into myxoid, pleomorphic, well-differentiated, and dedifferentiated subtypes. Dedifferentiated liposarcoma displays the greatest histomorphologic diversity, including a subset with myofibroblastic differentiation that shares similarities with a spectrum of reactive, benign, and malignant soft tissue lesions. Misdiagnosis may lead to deleterious consequences, as dedifferentiated liposarcoma differs significantly in its prognosis and treatment from its mimics. Objective.--To review the clinicopathologic, immunohistochemical, and molecular features of the myofibroblastic variant of dedifferentiated liposarcoma as well as the key distinguishing features from its mimics. Data Sources.--Review of pertinent literature on major features and current understanding of dedifferentiated liposarcoma with myofibroblastic differentiation. Conclusions.--The myofibroblastic variant of dedifferentiated liposarcoma is an uncommon and underrecognized sarcoma with several important differential diagnoses, and likely represents the major subset of aggressive retroperitoneal tumors that may have been misdiagnosed as desmoid-type fibromatosis, inflammatory myofibroblastic tumor, or another type of sarcoma in the past. [ABSTRACT FROM AUTHOR]

Context.--Cancer registrars should work closely with pathologists to ensure compliance with reporting standards. Many registrars, however, have little contact with pathologists, resulting in a lack of "real-time" interaction that is essential for their professional activities and development. Objective.--To facilitate registrars' case management, as cancer biology becomes more complex, we developed the ATP (Ask the Pathologist) forum as a place to ask pathology-related questions about neoplasms, such as terminology, biology, histologic classification, extent of disease, molecular markers, and prognostic factors. Design.--Questions posted are reviewed by the ATP multidisciplinary oversight committee, which consists of 3 pathologists, 4 cancer registrars, 1 internal medicine physician, the pathology resident member of the College of American Pathologists Cancer Committee, and 2 medical technologists. The oversight committee may answer the question. Alternatively, the committee may forward the question to a content expert pathologist, determine that the question is better suited for another reference Web site, or both. Results.--Since September 2013, when the ATP forum became available, users have posted 284 questions, of which 48 (17%) related to gastrointestinal tumors, 43 (15%) to breast tumors, and 37 (13%) to general pathology. The average turnaround time, from question posted to response, is 11.1 days. Conclusions.--The ATP forum has had a positive impact in the daily activities of cancer registrars. Of 440 registrars surveyed, more than 90% considered that questions were answered satisfactorily, and one-third reported that ATP answers affected how they managed a given case. [ABSTRACT FROM AUTHOR]

Context.--There has been a paradigm shift in the understanding of molecular pathogenesis of lung cancer. A number of oncogenic drivers have been identified in non--small cell lung carcinoma, such as the epidermal growth factor receptor (EGFR) mutation and anaplastic lymphoma kinase (ALK) gene rearrangement. Because of the clinical presentation at an advanced stage of disease in non-small cell lung carcinoma patients, the use of minimally invasive techniques is preferred to obtain a tumor sample for diagnosis. These techniques include image-guided biopsies and fine-needle aspirations, and frequently the cytology specimen may be the only tissue sample available for the diagnosis and molecular testing for these patients. Objective.--To review the current literature and evaluate the role of cytology specimens in lung cancer mutation testing. We reviewed the types of specimens received in the laboratory, specimen processing, the effect of preanalytic factors on downstream molecular studies, and the commonly used molecular techniques for biomarker testing in lung cancer. Data Sources.--PubMed and Google search engines were used to review the published literature on the topic. Conclusions.--Mutation testing is feasible on a variety of cytologic specimen types and preparations. However, a thorough understanding of the cytology workflow for the processing of samples and appropriate background knowledge of the molecular tests are necessary for triaging, and optimum use of these specimens is necessary to guide patient management. [ABSTRACT FROM AUTHOR]

Context.--Lung tumors are histologically heterogeneous, but classification of lung carcinoma has prognostic impact and increasingly, specific molecular correlates. Objective.--To update the gross, microscopic, and molecular pathology of unusual lung carcinomas to assure accurate classification. In entities with mixed histology, the recognition of specific features or rare patterns is critical to diagnosis. These diagnoses can identify tumors with aggressive clinical behavior, and diagnostic pitfalls can therefore result in underdiagnosis of these already rare entities. Incorrect classification of more indolent tumors into the more aggressive categories can also occur. In the area of molecular pathology, these unusual tumors have a specific spectrum of molecular alterations. Data Sources.--PubMed searches for lung and sarcomatoid carcinoma, pleomorphic carcinoma, blastoma, carcinosarcoma, and adenosquamous and mucoepidermoid carcinoma were undertaken and this information was integrated with clinical experience of the author. Conclusions.--These uncommon carcinomas have specific clinicopathologic features, and attention to their gross and microscopic pathology leads to classification with important associated molecular findings. [ABSTRACT FROM AUTHOR]

Context.--Comprehensive molecular investigations of mainstream carcinogenic processes have led to the use of effective molecular targeted agents in most cases of solid tumors in clinical settings. Objective.--To update readers regarding the evolving role of the pathologist in the therapeutic decision-making process and the introduction of next-generation technologies into pathology practice. Data Sources.--Current literature on the topic, primarily sourced from the PubMed (National Center for Biotechnology Information, Bethesda, Maryland) database, were reviewed. Conclusions.--Adequate evaluation of cytologic-based and tissue-based predictive diagnostic biomarkers largely depends on both proper pathologic characterization and customized processing of biospecimens. Moreover, increased requests for molecular testing have paralleled the recent, sharp decrease in tumor material to be analyzed--material that currently comprises cytology specimens or, at minimum, small biopsies in most cases of metastatic/advanced disease. Traditional diagnostic pathology has been completely revolutionized by the introduction of next-generation technologies, which provide multigene, targeted mutational profiling, even in the most complex of clinical cases. Combining traditional and molecular knowledge, pathologists integrate the morphological, clinical, and molecular dimensions of a disease, leading to a proper diagnosis and, therefore, the most-appropriate tailored therapy. [ABSTRACT FROM AUTHOR]

Context.--The critical role of pathology in diagnosis, prognosis, and prediction demands high-quality subspecialty diagnostics that integrates information from multiple laboratories. Objective.--To identify key requirements and to establish a systematic approach to providing high-quality pathology in a health care system that is responsible for services across a large geographic area. Design.--This report focuses on the development of a multisite pathology informatics platform to support high-quality surgical pathology and hematopathology using a sophisticated laboratory information system and whole slide imaging for histology and immunohistochemistry, integrated with ancillary tools, including electron microscopy, flow cytometry, cytogenetics, and molecular diagnostics. Results.--These tools enable patients in numerous geographic locations access to a model of subspecialty pathology that allows reporting of every specimen by the right pathologist at the right time. The use of whole slide imaging for multidisciplinary case conferences enables better communication among members of patient care teams. The system encourages data collection using a discrete data synoptic reporting module, has implemented documentation of quality assurance activities, and allows workload measurement, providing examples of additional benefits that can be gained by this electronic approach to pathology. Conclusion.--This approach builds the foundation for accurate big data collection and high-quality personalized and precision medicine. [ABSTRACT FROM AUTHOR]

An introduction is presented in which the authors discuss articles within the issue on topics including characteristic histology, immunophenotypes and molecular genetic alterations of salivary-type carcinomas, differential diagnoses of mucinous breast lesions and a three-tier diagnostic algorithm for classifying spindle cell lesions of the breast.