CONTEXT.—: The American Board of Pathology (ABPath) publishes annual performance data for the anatomic pathology (AP) and clinical pathology (CP) board examinations, as well as for ABPath subspecialty examinations. Overall board pass rates for all AP and CP board examinees have increased during the past decade; however, no study has analyzed the board pass rates for pathology subspecialty examinations, and whether these follow the same trend. OBJECTIVE.—: To evaluate ABPath subspecialty examination pass rates to assess the trend in certification. DESIGN.—: We analyzed the total number of first-time test takers and board pass rates for 11 pathology subspecialties recognized by the ABPath from 2007 to 2021, acquired from annual reports published by the ABPath. We compared the pass rates in 5-year intervals (2007-2011, 2012-2016, 2017-2021) for each individual specialty. We also analyzed the pass rate of CP subspecialties compared with AP subspecialties. RESULTS.—: The overall mean pass rate for ABPath subspecialty examinations during the previous 15 years was 89% (range, 78.9%-100%), with the overall pass rate being significantly higher in 2017-2021 (P = .02). The contemporary overall rate of passing was significantly higher for AP subspecialty examinations (P < .001) and higher, though not significantly, for CP subspecialties (P = .13). There were significant differences between first-time test takers' mean pass rate (92.1%), repeat test takers' mean pass rate (54.5%), and the overall rate (P < .001). CONCLUSIONS.—: Contemporary pathology subspecialty board examination pass rates are significantly higher than historic rates, possibly reflecting continuously improving and readily available preparatory materials.

CONTEXT.—: Clear communication between pathologists and surgeons during intraoperative consultations is critical for optimal patient care. OBJECTIVE.—: To examine the concordance of intraoperative diagnoses recorded in pathology reports to surgeon-dictated operative notes and assess the impact of an intervention on the discrepancy rates. DESIGN.—: Discrepancies between the intended communication by pathologists and the interpretation by surgeons were characterized as minor with no crucial clinical impact, and major with the potential of altering patient management. After analysis, a corrective intervention was implemented with education, information sharing, and change in protocol, and a comparative analysis was conducted. RESULTS.—: We examined 223 surgical cases with 578 intraoperative consultations. In 23% (51) of the cases, the intraoperative diagnosis was not recorded in the operative reports. We found minor discrepancies in 34% (59) and major discrepancies in 2% (3) of the remaining cases. Deferrals accounted for 24% (14 of 59) of the minor and 33% (1 of 3) of the major discrepancies. Among the discrepant cases, 56% (35 of 62) were multipart cases, including all major discrepancies. Following intervention, no major discrepancies were found in 101 cases with 186 intraoperative interpretations. The cases with no operative documentation reports decreased from 23% to 16% (16 of 101). Minor discrepancies were found in 11% (9 of 85) of the cases, indicating significant improvement (P < .001). CONCLUSIONS.—: Intraoperative diagnoses can be miscommunicated and/or misinterpreted, possibly impacting intraoperative management, particularly in multipart cases and those involving deferrals. This study highlights the importance of auditing intraoperative communications and addressing the findings through a local intervention.

CONTEXT.—: The accurate identification of different lung adenocarcinoma histologic subtypes is important for determining prognosis but can be challenging because of overlaps in the diagnostic features, leading to considerable interobserver variability. OBJECTIVE.—: To provide an overview of the diagnostic agreement for lung adenocarcinoma subtypes among pathologists and to create a ground truth using the clustering approach for downstream computational applications. DESIGN.—: Three sets of lung adenocarcinoma histologic images with different evaluation levels (small patches, areas with relatively uniform histology, and whole slide images) were reviewed by 18 international expert lung pathologists. Each image was classified into one or several lung adenocarcinoma subtypes. RESULTS.—: Among the 4702 patches of the first set, 1742 (37%) had an overall consensus among all pathologists. The overall Fleiss κ score for the agreement of all subtypes was 0.58. Using cluster analysis, pathologists were hierarchically grouped into 2 clusters, with κ scores of 0.588 and 0.563 in clusters 1 and 2, respectively. Similar results were obtained for the second and third sets, with fair-to-moderate agreements. Patches from the first 2 sets that obtained the consensus of the 18 pathologists were retrieved to form consensus patches and were regarded as the ground truth of lung adenocarcinoma subtypes. CONCLUSIONS.—: Our observations highlight discrepancies among experts when assessing lung adenocarcinoma subtypes. However, a subsequent number of consensus patches could be retrieved from each cluster, which can be used as ground truth for the downstream computational pathology applications, with minimal influence from interobserver variability.

CONTEXT.—: The tissue diagnosis of amyloidosis is traditionally suggested by hematoxylin-eosin stain and confirmed by Congo red stain, both examined by routine light microscopy. Both false-positive and false-negative congophilia are well documented, limiting the sensitivity and specificity of the Congo red stain for the diagnosis of amyloidosis. Examination of Congo red-stained tissue by Texas Red-filtered fluorescence microscopy (TRFM) is known to enhance the amyloid-specific congophilia, thus increasing the diagnostic sensitivity. OBJECTIVE.—: To determine whether TRFM can mitigate the false positivity and thus improve the diagnostic specificity of the Congo red stain. DESIGN.—: Ninety-two tissue samples were categorized into 3 groups. Group I included 15 samples with tissue deposition of amyloid. Group II consisted of 63 samples in which amorphous eosinophilic structures reminiscent of amyloid were seen on hematoxylin-eosin-stained tissue sections. Group III included 14 samples in which amyloid and amyloid-like tissue were seen side by side. The final diagnosis of presence or absence of amyloidosis in each case was established by clinicopathologic correlation. The congophilic areas in each case were identified by light microscopy. The same areas were then examined by TRFM. RESULTS.—: TRFM enhanced congophilia, confirming the diagnosis of amyloidosis in all cases of group I. Enhancement was not seen in 52 of the 63 cases in group II. For group III cases, TRFM enhanced the amyloid-specific congophilia, but not the nonspecific congophilia, in all cases. CONCLUSIONS.—: TRFM increases the diagnostic yield and specificity of Congo red-stained tissue sections for detection of amyloid.

CONTEXT.—: Biliary atresia (BA) patients can have portal vein (PV) abnormalities. OBJECTIVE.—: To investigate the explant pathology of BA patients transplanted in adulthood with a focus on portal venous abnormalities. DESIGN.—: Adult BA liver explants were reviewed along with prior biopsies, Kasai portoenterostomy (KP), and relevant medical records. RESULTS.—: Three explants were identified; all patients were female, with age at diagnosis, KP, and liver transplantation (LT) as follows: (1) less than 1 week, 8 days, and 25 years; (2) 15 weeks, 16 weeks, and 32 years; and (3) 7 weeks, 8 weeks, and 33 years, respectively, with normalization of conjugated bilirubin within 6 months of KP and development of portal hypertension (PHTN) within 3 years of KP for all 3. The first 2 had recurrent cholangitis. Duration of pre-LT PHTN was 22, 29, and 30 years, and that of pre-LT cholangitis was 9, 3, and 0 years, respectively. All 3 explants showed hilar and extrahepatic fibromyxoid intimal hyperplasia of the PV with parenchymal hepatoportal sclerosis. Cholestasis was limited to those with history of cholangitis. Patient 3, without cholangitis, showed delicate septal fibrosis with peripheral accentuation without biliary cirrhosis. CONCLUSIONS.—: In the context of a functioning KP, cholestasis and biliary cirrhosis are likely related to recurrent cholangitis, which may or may not occur after KP. In the absence of biliary cirrhosis, PHTN may be secondary to obliterative venopathy. Adult BA explants should be sampled thoroughly with a focus on hilar/perihilar connective tissue to include PV branches. Explants may not show biliary cirrhosis and should be reported with appropriate clinicopathologic correlation.

CONTEXT.—: Glioma is the most common primary brain tumor in adults. The diagnosis and grading of different pathological subtypes of glioma is essential in treatment planning and prognosis. OBJECTIVE.—: To propose a deep learning-based approach for the automated classification of glioma histopathology images. Two classification methods, the ensemble method based on 2 binary classifiers and the multiclass method using a single multiclass classifier, were implemented to classify glioma images into astrocytoma, oligodendroglioma, and glioblastoma, according to the 5th edition of the World Health Organization classification of central nervous system tumors, published in 2021. DESIGN.—: We tested 2 different deep neural network architectures (VGG19 and ResNet50) and extensively validated the proposed approach based on The Cancer Genome Atlas data set (n = 700). We also studied the effects of stain normalization and data augmentation on the glioma classification task. RESULTS.—: With the binary classifiers, our model could distinguish astrocytoma and oligodendroglioma (combined) from glioblastoma with an accuracy of 0.917 (area under the curve [AUC] = 0.976) and astrocytoma from oligodendroglioma (accuracy = 0.821, AUC score = 0.865). The multiclass method (accuracy = 0.861, AUC score = 0.961) outperformed the ensemble method (accuracy = 0.847, AUC = 0.933) with the best performance displayed by the ResNet50 architecture. CONCLUSIONS.—: With the high performance of our model (>80%), the proposed method can assist pathologists and physicians to support examination and differential diagnosis of glioma histopathology images, with the aim to expedite personalized medical care.

CONTEXT.—: In the last 2 decades there has been significant progress in typing and recognition of pancreatitis, a necroinflammatory and fibroinflammatory process of multifactorial origin. OBJECTIVE.—: To present the current state of pathology and pathogenesis of alcohol-associated pancreatitis, including paraduodenal pancreatitis. In the context of the most important epidemiologic, clinical, and radiologic features, the related macroscopic changes and histopathologic characteristics are addressed. DATA SOURCES.—: In acute pancreatitis we discuss the pathologic findings that distinguish mild from severe pancreatitis and highlight autodigestive fat necrosis as the initial morphologic damage. In chronic pancreatitis we present a histologic staging system that describes the damage patterns as a necrosis-fibrosis sequence that takes place during the development of early to advanced and end-stage chronic pancreatitis. In paraduodenal pancreatitis the anatomic peculiarities are related to the sequence of morphologic changes that are correlated to the most important imaging findings. Pathogenetically, we discuss the role of alcohol overconsumption in triggering autodigestive fat necrosis in the pancreas, the repair of which results in a pancreas-transforming fibroinflammatory process. CONCLUSIONS—: Whereas in acute pancreatitis there are no lesions that are diagnostic for alcohol overconsumption and that exclude other etiologies such as gallstone disease or drugs, the sequence of damage patterns in chronic pancreatitis are strongly related to the effect of alcohol overconsumption and allow in many cases the distinction from hereditary, autoimmune, or obstructive pancreatitis. Paraduodenal pancreatitis can be considered a special manifestation of alcoholic pancreatitis.

CONTEXT.—: The tumor-host interaction in the tumor microenvironment (TME) affects the prognosis of patients with malignant tumors. TME assessed via tumor budding (BD) and tumor-infiltrating lymphocyte (TIL) had a prognostic impact in patients with nonampullary small intestinal and colorectal carcinomas. In ampullary carcinoma (AC), MUC5AC was recently revealed as a significant prognosticator, but studies about the TME have not been conducted. OBJECTIVE.—: To assess TME-based prognostic risk in AC. DESIGN.—: We generated a collective TME risk index based on high-grade BD at the invasive front (BD3) and high density of stromal-TIL (>5%) in 64 surgically resected ACs. We evaluated its predictive values for overall survival (OS) and recurrence-free survival (RFS). We also investigated the relationship of TME to MUC5AC expression. RESULTS.—: TME prognostic risk index was classified into low-risk (BDLow/TILHigh; 26 of 64; 41%), intermediate-risk (BDLow/TILLow or BDHigh/TILHigh; 23; 36%), and high-risk (BDHigh/TILLow; 15; 23%) groups. Higher TME prognostic risk was associated with higher tumor grade (P = .03), lymphovascular invasion (P = .05), and MUC5AC immunopositivity (P = .02). TME prognostic risk index displayed better predictive ability for both OS (53.9 versus 46.1 versus 42.2) and RFS (24.8 versus 16.9 versus 15.3) than BD or TIL alone. In multivariate analysis, TME prognostic risk index was an independent prognosticator for OS (P = .003) and RFS (P = .03). CONCLUSIONS.—: TME risk index in combination with BD and TIL was a stronger predictor of prognostic risk stratification than either BD or TIL alone for both OS and RFS in patients with AC. MUC5AC may modulate the interaction between tumor cells and immunity toward enhancing invasiveness in TME.

CONTEXT.—: Evidence of T-cell clonality is often critical in supporting a T-cell lymphoma. OBJECTIVES.—: To retrospectively explore the significance of copy number losses at the 14q11.2 T-cell receptor α locus in relation to the presence of a T-cell neoplasm and proportion of T cells by targeted next-generation sequencing. DESIGN.—: Targeted next-generation sequencing data from 139 tissue biopsies including T-cell lymphomas, B-cell lymphomas, classic Hodgkin lymphomas, nonhematopoietic malignancies, and normal samples were reviewed for copy number losses involving the T-cell receptor α gene segments at chr14q11.2. RESULTS.—: We found that biallelic or homozygous deletion of 14q11.2 was found in most (28 of 33, 84.8%) T-cell lymphomas. The magnitude of 14q11.2 loss showed a statistically significant correlation with the proportion of T cells in lymphoma tissue samples. Copy number losses could also be detected in other lymphomas with high number of T cells (8 of 32, 25% of B-cell lymphomas, 4 of 4 classical Hodgkin lymphomas), though biallelic/homozygous deletion of 14q11.2 was not significantly observed outside of T-cell lymphomas. Most nonhematopoietic neoplasms and normal tissues (59 of 64, 92.2%) showed no significant copy number losses involving the T-cell receptor α locus at chr14q11.2. CONCLUSIONS.—: Analysis of copy number losses at the T-cell receptor α locus chr14q11.2 with targeted next-generation sequencing can potentially be used to estimate the proportion of T cells and detect T-cell neoplasms.

CONTEXT.—: It is important to recognize high-grade foamy gland prostatic adenocarcinoma with desmoplastic stroma given its aggressive clinical course with frequent metastases and death. OBJECTIVE.—: To review the morphology, immunohistochemistry, and prognosis for this rare subtype of prostate adenocarcinoma. DESIGN.—: Twenty-four cases received for consultation from 2010 to 2021 were analyzed including needle biopsy (n = 21), transurethral resection (n = 2), and a cytostoprostatectomy (n = 1). RESULTS.—: Patients ranged in age from 40 to 89 years (mean, 67 years). On average, 8 cores per case were involved (mean 67% core involvement). Extraprostatic extension and seminal vesicle invasion were observed in 6 of 21 (29%) and 3 of 21 (14%) needle biopsy cases, respectively. Twenty of the 24 cases (83%) were Grade Group (GG) 5 with 4 of 24 (17%), GG4. Tumor necrosis as a component of Gleason pattern 5 was observed in 21 of 24 cases (87%). Associated intraductal adenocarcinoma (IDC) was observed in 22 of 24 cases (92%), with 4 of 24 cases (17%) demonstrating extensive IDC. Diagnostic challenges were as follows: (1) sparse isolated cancer glands embedded in the dense desmoplastic stroma; (2) fragmented glands; and (3) aberrant staining for high-molecular-weight cytokeratin in a nonbasal cell pattern in all cases. PTEN loss was observed in 9 cases, and p53 nuclear accumulation was observed in 8 cases. Three patients were lost to follow-up. Overall, of the 16 patients with meaningful follow-up, 12 (75%) either had metastases or died from prostate cancer. CONCLUSIONS.—: High-grade desmoplastic foamy gland adenocarcinoma is difficult to diagnose and grade and has a poor prognosis.

CONTEXT.—: Eosinophilic diseases of the gastrointestinal tract (EGIDs), eosinophilic gastritis (EoG), and eosinophilic duodenitis (EoD) are rarely suspected clinically and infrequently detected by pathologists. OBJECTIVE.—: To determine whether histories of allergic or eosinophilic disorders and requests to rule out EoG and EoD affect pathologists' awareness of eosinophils in gastrointestinal biopsies. DESIGN.—: Thirty-one community-based pathologists were given 16 sets of biopsies from gastric and duodenal mucosa with elevated eosinophils, Helicobacter pylori gastritis, atrophic gastritis, normal stomach and duodenum, lymphocytosis, and celiac disease. Participants were assigned to 3 groups: group A did not receive histories of allergic or eosinophilic conditions; group B received similar histories plus a clue of possible allergic or eosinophilic conditions; and group C received the same histories as B and was asked to rule out EoG/EoD. A list of gastric and duodenal diagnoses and a space for comments were provided. Results were analyzed descriptively. RESULTS.—: Pathologists correctly diagnosed most noneosinophilic gastrointestinal disorders, indicating competence in gastrointestinal pathology. With respect to EoG and EoD, pathologists in group C performed significantly better that those in groups A and B. The combined odds ratio with 95% CI was 12.34 (2.87-53.04), P < .001, for A versus C and 4.02 (1.60-10.09), P < .02, for B versus C. CONCLUSIONS.—: Most pathologists neither reported gastric/duodenal eosinophilia nor diagnosed EoG/EoD, even when provided histories of eosinophilic disorders. Requests to rule out EoG/EoD resulted in only 4 of 11 participants evaluating and counting eosinophils in some cases. Simple evidence-based histopathologic criteria are needed before pathologists can be expected to consider and diagnose EGIDs.

CONTEXT.—: Despite their stromal origin, follicular dendritic cells (FDCs) share many functions with hematopoietic system cells. FDC neoplasms are currently classified by the World Health Organization along with those of a histiocytic nature. However, the molecular alterations driving oncogenesis in FDC sarcomas (FDCSs) are beginning to be unveiled, and do not seem to concur with those described in histiocytic neoplasms, namely MAPK pathway activation. OBJECTIVE.—: To identify molecular alterations driving tumorigenesis in FDCS. DESIGN.—: We investigated the role of MYC and TP53 in FDC-derived tumor oncogenesis and assessed comprehensively the status of the MAPK pathway in 16 FDCSs, 6 inflammatory pseudotumor (IPT)-like FDCSs, and 8 IPTs. RESULTS.—: MYC structural alterations (both amplifications and rearrangements) were identified in 5 of 14 FDCSs (35.7%), all associated with MYC overexpression. TP53 mutations were identified in 4 of 14 FDCSs (28.6%), all of which displayed intense and diffuse p53 expression. None of these alterations were identified in any IPT-like FDCS or in IPT cases. No MAPK pathway gene alterations were identified in any of the cases studied. CONCLUSIONS.—: The presence of MYC and TP53 alterations and the lack of association with Epstein-Barr virus segregate classical FDCS from IPT-like FDCS, pointing at different oncogenic mechanisms in both entities. Our results suggest a possible oncogenic role of MYC and TP53 alterations in FDCS. The absence of MAPK pathway alterations confirms the lack of a significant role of this pathway in the oncogenesis of FDC-derived neoplasms.

CONTEXT.—: Cholestasis within bile ductules is touted as a key histologic finding in septic patients but is not entirely sensitive or specific. The spectrum of other histopathologic findings in septic patients has not been thoroughly studied. OBJECTIVE.—: To evaluate histologic features in liver biopsies from septic patients, as well as mimics. DESIGN.—: For 121 liver samples where sepsis was mentioned in provided clinical information or in the pathologic differential diagnosis, we compiled patient outcome, clinical impression (sepsis or not), and blood culture results. We evaluated each case for inflammatory and cholestatic histologic findings, comparing them between patients with and without clinical sepsis, and between patients with gram-positive versus gram-negative results on blood culture. RESULTS.—: Cases from clinically septic patients (n = 77) showed portal mononuclear inflammation (52 cases, 68%), lobular neutrophilic inflammation (45, 58%), ductular reaction (58, 75%), lobular cholestasis (68, 88%), ductular cholestasis (52, 68%), and acidophil bodies (36, 47%). Findings between clinically septic and nonseptic patients were similar, though the latter more often had lobular mononuclear inflammation (19% versus 45%, P = .004). Ductular cholestasis rates were similar in both groups (68% versus 55%, P = .17). Ductular cholestasis had a sensitivity of 68%, a specificity of 45%, a positive predictive value of 68%, and an accuracy of 60% for the diagnosis of sepsis. Gram-positive and gram-negative sepsis caused comparable findings. CONCLUSIONS.—: Ductular cholestasis can be present in septic and nonseptic liver samples, though its presence does suggest the possibility of sepsis. Other common findings in sepsis include lobular cholestasis, ductular reaction, portal mononuclear inflammation, and lobular neutrophilic inflammation.

CONTEXT.—: The pathologic nodal staging of prostatic adenocarcinoma is binary for regional lymph nodes. Stages pN0 and pN1 indicate the absence or presence of regional nodal metastasis, respectively, whereas patients with metastasis to nonregional lymph nodes are staged as pM1a. OBJECTIVE.—: To determine the risk of recurrence of pN1 prostatic adenocarcinoma patients based on the extent of nodal tumor burden. DESIGN.—: We retrospectively reviewed pN1 patients with prostatic adenocarcinoma managed with radical prostatectomy seen between 2011 and 2019. Kaplan-Meier and Cox regression analyses were performed to compare disease-free survival. RESULTS.—: Ninety-six patients were included (median [interquartile range] age, 62 years [57-67 years]; 70 of 96 [73%] White). On univariate analysis, age >65 years (P = .008), ≥2 positive regional lymph nodes (P < .001), and a maximum size of the tumor deposit ≥2 mm (P = .004) were significantly associated with an unfavorable outcome. Controlling for age, stage, metastatic deposit size, margin status, and the presence of extranodal extension, patients with ≥2 positive regional lymph nodes were 3.03 times more likely (95% confidence interval, 1.39-6.60; P = .005) to have an unfavorable outcome. Patients with pN1M1a stage showed a disease-free survival similar to that of pN1M0 patients, after controlling for the number of positive regional lymph nodes (P = .36). CONCLUSIONS.—: Overall, pN1 patients with ≥2 positive regional lymph nodes are 3 times more likely to have an unfavorable outcome. The results suggest a benefit in further stratifying patients with metastatic prostatic adenocarcinoma to the lymph nodes into prognostically significant risk categories that could help the treating clinicians tailor subsequent patient follow-up and therapy.

CONTEXT.—: Primary breast carcinomas constitute a divergent group of neoplasms. The classification of breast tumors has been evolving. Recent advances in molecular genetic techniques have enhanced our understanding of these diseases. Integration of state-of-the-art knowledge from research and practice has resulted in the recognition of novel entities as primary carcinomas of the breast with therapeutic and prognostic significance. OBJECTIVE.—: To provide an overview of current concepts in the classification and diagnosis of selective salivary-type carcinomas of the breast, focusing on their salient histologic and immunophenotypic characteristics and recent molecular genetic advancements. DATA SOURCES.—: Data were obtained from review of pertinent English-language literature and firsthand experience of the authors as practicing breast pathologists. CONCLUSIONS.—: The cutting-edge knowledge has led us to further understand a growing number of uncommon types of breast carcinoma that demonstrate morphologic and immunophenotypic resemblance to those more frequently encountered in other organ systems, particularly salivary glands. Some of them also harbor identical molecular genetic alterations to those in their salivary gland counterparts. Yet they typically have diverse prognostic outcomes, thus warranting different clinical management. Accurate diagnosis of these tumors necessitates recognition of salient histologic features and judicious assessment of ancillary studies in the pursuit of precision medicine.

CONTEXT.—: Appendiceal goblet cell adenocarcinoma is an uncommon appendiceal neoplasm that is typically diagnosed incidentally to a presentation of acute appendicitis. Over the years, there have been many changes to the histologic evaluation and classification of this neoplasm, culminating in the most recent (2019) World Health Organization recommendations. OBJECTIVE.—: To understand the evolution of the concept of "goblet cell" neoplasia in the appendix, we explore a series of cases of goblet cell adenocarcinoma encountered at a county hospital over a 20-year period. We performed a historically informed review of these cases to highlight the significance and blind spots of our current definition and approach to this disease entity. DATA SOURCES.—: The cases were recovered from the archives of a county hospital (1999-2019). The literature was assembled through PubMed searches on the various names given to "goblet cell" neoplasms since the 1970s. We also refer to standard reference books of gastrointestinal pathology. CONCLUSIONS.—: Frequent and numerous changes in the nomenclature of "goblet cell" lesions of the appendix resulted in considerable confusion regarding the approach to this rare entity, especially pertaining to its grade, as well as to its management in the clinical setting. The newest approach, recommended by the World Health Organization, provides clarity to its pathologic and clinical management. Adherence to these recommendations will improve communication between pathologists, surgeons, and oncologists about the natural history and prognosis of this malignant neoplasm.

CONTEXT.—: A prolonged activated partial thromboplastin time (APTT), a vital screening test for coagulation, can be due to deficiencies in coagulation factors and the existence of factor inhibitors or antiphospholipid antibodies. APTT mixing studies are being optimized to help find the cause. OBJECTIVE.—: To optimize APTT mixing studies, we evaluated existing standards and explored when and how to combine 1:1 and 4:1 mixing. DESIGN.—: Patients with a prolonged APTT but otherwise normal prothrombin time and thrombin time were enrolled in our hospital from January 1, 2018, to December 31, 2019. All samples were subjected to 1:1 mixing studies, while 134 were subjected to 4:1. RESULTS.—: A total of 251 samples were involved, including 116 with factor deficiencies, 75 with FVIII inhibitors, and 60 with antiphospholipid antibodies. A Rosner index less than 11% or an extended incubation time of more than 3 seconds was better than other existing standards in differentiating factor deficiencies from inhibitors and in differentiating time-dependent inhibitors from time-independent inhibitors, but the approach presented here improves upon those. For the best diagnostic accuracy, samples with a Rosner index between 5.0% and 9.1% need a 4:1 mixing study, while others need 1:1. A combination of Rosner index and percent-extended incubation time-P seemed to offer objective and effective criteria for interpreting the results. CONCLUSIONS.—: APTT mixing studies had overall good sensitivity and specificity in differentiating factor deficiencies from inhibitors, or time-dependent from time-independent inhibitors. The combination of 1:1 and 4:1 mixing studies can improve the diagnostic ability compared with 1:1 alone.

CONTEXT.—: The rapid recognition of fetal nucleated red blood cells (fNRBCs) presents considerable challenges. OBJECTIVE.—: To establish a computer-aided diagnosis system for rapid recognition of fNRBCs by convolutional neural network. DESIGN.—: We adopted density gradient centrifugation and magnetic-activated cell sorting to extract fNRBCs from umbilical cord blood samples. The cell-block method was used to embed fNRBCs for routine formalin-fixed paraffin sectioning and hematoxylin-eosin staining. Then, we proposed a convolutional neural network-based, computer-aided diagnosis system to automatically discriminate features and recognize fNRBCs. Extracting methods of interested region were used to automatically segment individual cells in cell slices. The discriminant information from cellular-level regions of interest was encoded into a feature vector. Pathologic diagnoses were also provided by the network. RESULTS.—: In total, 4760 pictures of fNRBCs from 260 cell-slides of 4 umbilical cord blood samples were collected. On the premise of 100% accuracy in the training set (3720 pictures), the sensitivity, specificity, and accuracy of cellular intelligent recognition were 96.5%, 100%, and 98.5%, respectively, in the test set (1040 pictures). CONCLUSIONS.—: We established a computer-aided diagnosis system for effective and accurate fNRBC recognition based on a convolutional neural network.

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.

CONTEXT.—: Although pathology is essential to almost every practice in medicine, laboratory medicine professionals do not routinely volunteer in global health practice. OBJECTIVE.—: To gather information about the experience and interest levels of the pathology community in global health work. DESIGN.—: Data were analyzed from an 8-question, online, anonymous survey directed toward anyone working in the field of pathology and laboratory medicine. The survey collected data from respondents on their interest level in participating in global health pathology, potential barriers to participation, and the types of volunteer opportunities that would be of interest. RESULTS.—: A total of 267 people participated in the survey, of whom 142 (53%) were American citizens. One hundred seventy (64%) indicated that they had never volunteered in a low-resource setting. The majority of respondents (237; 89%) indicated interest in global pathology opportunities. More than half of the 267 respondents indicated interest in short-term trips (136; 51%), digital education opportunities (138; 52%), and reviewing slides/cases digitally (160; 60%). Lack of time to travel and lack of financial support were the 2 most cited reasons for lack of participation. One hundred nine respondents (41%) indicated that they were "willing and able, but do not know where to start." CONCLUSIONS.—: Our data demonstrate that laboratory medicine professionals are highly interested in global pathology efforts, but factors such as lack of time, lack of funding, and lack of knowledge of potential volunteer opportunities are barriers to participation. A significant number of respondents were willing and able to participate, indicating that pathology and laboratory medicine professionals may be an untapped resource for global health volunteers.

CONTEXT.—: Critically ill patients with acute kidney injury (AKI) requiring renal replacement therapy (RRT) have a poor prognosis. Several urinary AKI biomarkers have been proposed to predict renal recovery, but with limited discriminatory ability. OBJECTIVE.—: To validate the predictive performances of novel biomarkers to identify which critical patients with AKI may successfully wean from RRT. DESIGN.—: We prospectively recorded and analyzed clinical variables at several time points: (1) before starting RRT, (2) at the time of weaning off RRT, and (3) 24 hours after stopping RRT. A total of 140 critically ill patients who received RRT at a multicenter referral hospital from August 2016 to January 2019 were enrolled. The outcomes of interest were the ability to wean from RRT and 90-day mortality. RESULTS.—: The 90-day mortality rate was 13.6% (19 of 140), and 47.9% (67 of 140) of the patients were successfully weaned from RRT. Cluster analysis showed that the following biomarkers were correlated with estimated glomerular filtration rate at the time of weaning off RRT: urinary neutrophil gelatinase-associated lipocalin, kidney injury molecule 1, hemojuvelin, C-C motif chemokine ligand 14, interleukin 18, and liver-type fatty acid-binding protein (L-FABP). Among these, urinary L-FABP/creatinine (uL-FABP/Cr) at the time of weaning off RRT showed the best predictive performance for mortality (area under the receiver operating characteristic curve = 0.79). Taking mortality as a competing risk, Cox proportional hazards analysis indicated that a low uL-FABP/Cr (log) level was an independent prognostic factor for weaning from RRT (subdistribution hazard ratio, 0.35; P = .01). CONCLUSIONS.—: uL-FABP/Cr at the time of weaning off RRT could predict weaning from RRT and 90-day mortality.

CONTEXT.—: The histopathology reporting practice in rural areas is largely variable. To ensure the adequacy of histopathology reports (HPRs), the College of American Pathologists (CAP) has developed cancer reporting checklists. OBJECTIVE.—: To assess the adequacy of resection specimen HPRs received from outside centers for a second opinion. Further, the adequacy of breast resection HPRs from these centers was compared with that of our center. Additionally, the reports representing endometrial carcinoma were assessed for impact on the treatment decision. DESIGN.—: This was a retrospective study conducted from June 2015 to December 2019. HPRs from outside centers and our institute were analyzed for mandatory reporting elements as per CAP 2013 checklists. RESULTS.—: A total of 730 HPRs (558 outside HPRs and 172 in-house breast HPRs) were reviewed for completeness. The outside HPRs were complete in 42 of 558 cases (7.5%). Only 11 of 143 reports (7.7%) from the academic centers were complete. Seventeen of 249 outside breast HPRs (6.8%) were complete, whereas predominant (n = 123 of 172; 71.5%) in-house breast HPRs were adequate. Most outside endometrial carcinoma reports (60.8%; n = 28 of 46) were inadequate with potential impact on the adjuvant treatment, whereas 10 of 46 reports (21.7%) were inadequate and had an actual impact on the adjuvant treatment decision. CONCLUSIONS.—: Minimal data set reporting using checklists is not yet widely operational in most rural laboratories. We call for continuous education and sensitization of the practicing pathologists, oncopathology education of the trainees, and regulatory standards for signing out an oncopathology report.

CONTEXT.—: The International Collaboration on Cancer Reporting (ICCR), supported by major pathology and cancer organizations, aims at the standardization of evidence-based pathology reporting of different types of cancers, with the inclusion of all parameters deemed to be relevant for best patient care and future data collection. Lymph node metastasis is one of the most important prognostic factors in breast cancer. OBJECTIVE.—: To produce a histopathology reporting guide by a panel of recognized experts from the fields of pathology and surgery with elements deemed to be core (required) and noncore (recommended) to report when assessing regional lymph nodes of patients with breast cancer. DATA SOURCES.—: Published literature, previous guidelines/recommendations, and current cancer staging principles were the basis of the data set drafted by the expert panel. This was discussed in a series of teleconferences and email communications. The draft data set was then made available for public consultation through the ICCR Web site. After this consultation and ICCR ratification, the data set was finalized. CONCLUSIONS.—: The ICCR has published a data set for the reporting of surgically removed lymph nodes (including sentinel lymph node biopsy, axillary lymph node dissection, targeted axillary surgery, and lymph node sampling specimens) for breast tumors. This is part of a series of 4 ICCR breast cancer-related data sets. It includes 10 core elements along with 2 noncore elements. This should allow for synoptic reporting, which is more precise, uniform, and complete than nonsynoptic reporting, and leads to improved patient outcomes.

CONTEXT.—: Endoscopic mucosal resection (EMR) has made it possible for Barrett esophagus patients with superficial cancers to be treated without esophagectomy. Recent guidelines recommend measuring depth of invasion (DOI) in submucosal cancers based on reports that in low-risk cancers, submucosal invasion 500 μm or less is associated with low nodal metastasis rates. However, pathologists face challenges in reproducibly measuring DOI. OBJECTIVE.—: To determine how often DOI measurements could impact treatment and to evaluate reproducibility in measuring submucosal DOI in EMR specimens. DESIGN.—: Consecutive adenocarcinoma EMR cases were identified, including cases of "low histologic risk" submucosal cancer, as follows: those with negative deep margins, no high-grade histology (G3), and no lymphovascular invasion. Submucosal DOI was measured by 7 pathologists according to guidelines. RESULTS.—: Of 213 cancer EMR cases, 46 were submucosa invasive and 6 cases were low histologic risk submucosal cancers for which measurement could impact decision-making. Of these low histologic risk cases, 3 were categorized as superficial, indicating that measurement would be a clinically actionable decision point in only 1.4% of adenocarcinoma EMRs. Interobserver agreement for in-depth categorization between 7 pathologists was moderate (κ = 0.42), and the range of measurements spanned the 500-μm relevant threshold in 40 of 55 measured samples (72.7%). CONCLUSIONS.—: While therapeutic decisions would rarely have depended on DOI measurements alone in our cohort, interobserver variability raises concerns about their use as a sole factor on which to offer patients conservative therapy. Responsibly reporting and clinically using submucosal DOI measurements will require practical experience troubleshooting common histologic artifacts, as well as multidisciplinary awareness of the impact of variable specimen-handling practices.

CONTEXT.—: Breast carcinoma grade, as determined by the Nottingham Grading System (NGS), is an important criterion for determining prognosis. The NGS is based on 3 parameters: tubule formation (TF), nuclear pleomorphism (NP), and mitotic count (MC). The advent of digital pathology and artificial intelligence (AI) have increased interest in virtual microscopy using digital whole slide imaging (WSI) more broadly. OBJECTIVE.—: To compare concordance in breast carcinoma grading between AI and a multi-institutional group of breast pathologists using digital WSI. DESIGN.—: We have developed an automated NGS framework using deep learning. Six pathologists and AI independently reviewed a digitally scanned slide from 137 invasive carcinomas and assigned a grade based on scoring of the TF, NP, and MC. RESULTS.—: Interobserver agreement for the pathologists and AI for overall grade was moderate (κ = 0.471). Agreement was good (κ = 0.681), moderate (κ = 0.442), and fair (κ = 0.368) for grades 1, 3, and 2, respectively. Observer pair concordance for AI and individual pathologists ranged from fair to good (κ = 0.313-0.606). Perfect agreement was observed in 25 cases (27.4%). Interobserver agreement for the individual components was best for TF (κ = 0.471 each) followed by NP (κ = 0.342) and was worst for MC (κ = 0.233). There were no observed differences in concordance amongst pathologists alone versus pathologists + AI. CONCLUSIONS.—: Ours is the first study comparing concordance in breast carcinoma grading between a multi-institutional group of pathologists using virtual microscopy to a newly developed WSI AI methodology. Using explainable methods, AI demonstrated similar concordance to pathologists alone.

CONTEXT.—: In 1954, Benjamin Castleman, MD, described what was then believed to be a new entity in lymph node pathology. Initially labeled "Hyperplasia of the mediastinal node" and then "Localized mediastinal lymph node hyperplasia resembling thymoma," we now recognize the condition with the eponym "Castleman disease." We document a paper that describes the same condition, a half century before Castleman did. OBJECTIVE.—: To report the striking resemblance between Castleman disease and the lymph node reported in the paper published by Edwin R. LeCount, MD, titled "Lymphoma, a benign tumor representing a lymph gland in structure," published in Journal of Experimental Medicine in 1899. We also provide an overview of the remarkable achievements of LeCount. DESIGN.—: We compared the elucidation in the original paper by LeCount with the morphologic details in the papers published by Castleman et al. Material on the life of LeCount was compiled from the scientific literature, the Internet, and the files of the University of Chicago. RESULTS.—: LeCount's description and illustrations of the lymph node are uncannily similar to the onion-skinning and vascularity that Castleman documented. CONCLUSIONS.—: LeCount deserves credit for his depiction of a hitherto-unreported entity.