Re-evaluation of the methodology for estimating the US specialty physician workforce.

Increasing pursuit of subspecialized training has quietly revolutionized physician training, but the potential impact on physician workforce estimates has not previously been recognized. The Physicians Specialty Data Reports of the Association of American Medical Colleges, derived from specialty designations in the American Medical Association (AMA) Physician Professional Data (PPD), are the reference source for US physician workforce estimates; by 2020, the report for pathologists was an undercount of 39% when compared with the PPD. Most of the difference was due to the omission of pathology subspecialty designations. The rest resulted from reliance on only the first of the AMA PPD's 2 specialty data fields. Placement of specialty designation in these 2 fields is sensitive to sequence of training and is thus affected by multiple or intercalated (between years of residency training) fellowships. Both these phenomena have become progressively more common and are not unique to pathology. Our findings demonstrate the need to update definitions and methodology underlying estimates of the US physician workforce for pathology and suggest a like need in other specialties affected by similar trends.

Strong Job Market for Pathologists: Results From the 2021 College of American Pathologists Practice Leader Survey.

CONTEXT.­: There has long been debate about whether and when there may be a shortage of pathologists in the United States. One way to assess this is to survey the hiring experiences of pathology practices. A 2018 survey revealed a strong demand for pathologists, with expectations of continued strength. This study updates that prior analysis using data from a 2021 survey of pathology practice leaders. OBJECTIVE.­: To assess the US pathologist job market and examine implications. DESIGN.­: We analyzed data from the 2021 College of American Pathologists Practice Leader Survey. This survey queried practice leaders, including regarding the hiring of pathologists, the level of experience being sought, success in filling positions, and expectations for hiring in the next 3 years. RESULTS.­: Among the 375 surveyed practice leaders (about one-third of all US pathology practices), 282 provided information about pathologist hiring in 2021. A total of 157 of these 282 practices (55.7%) sought to hire at least 1 pathologist in 2021, up from 116 of 256 practices (45.3%) in 2017; the mean number of pathologists hired per practice also increased. In 2021, a total of 175 of 385 positions (45.5%) were to fill new positions, compared with 95 of 249 positions (38.2%) in 2017. Most practice leaders were comfortable hiring pathologists with less than 2 years of posttraining experience. Practice leaders anticipated continued strong demand for hiring pathologists during the next 3 years. CONCLUSIONS.­: Our analysis confirms that the demand in pathologist hiring is strong and much increased from 2017. We believe, in combination with other job market indicators, that demand may outstrip the supply of pathologists, which is limited by the number of trainees and has remained constant during the past 20 years.

Features of burnout amongst pathologists: A reassessment.

There has been little rigorous assessment of burnout among pathologists and pathology trainees. Given this relative dearth of relevant literature on pathologist burnout, this report aims to raise awareness of the issue among those working in and around this specialty. Our results are based on a survey given in conjunction with the American Board of Pathology's (ABPath) biennial Continuing Certification (CC) reporting of activities required of diplomates to maintain certification. The survey was voluntary, open to all diplomates participating in CC, and conducted over two consecutive years (2019 and 2020), with alternate years comprising different sets of diplomates. The data are based on 1256 respondents (820 from 2019 to 436 from 2020). The three highest aggregate reported rates of burnout (reported as experienced nearly all of the time, most of the time, or part of the time) occurred when respondents were in their first year of residency training (41.1%) and when they were in (47.6%) and beyond (46.6%) their first three years of practice. We considered this high-low-high, or U-shaped distribution in recollected burnout over time among pathologists a notable finding and investigated its distribution among respondents. Conversely at every point in their training and practice, from half to three-quarters of respondents reported never or infrequently experiencing burnout. This study represents the largest pathologist cohort survey to date about pathologists' burnout. Importantly, especially for those considering pathology as a career, these data are on the low end of the distribution of burnout among specialties for those in practice.

Therapeutic Targeting of Macrophage Plasticity Remodels the Tumor-Immune Microenvironment.

SIGNIFICANCE: Comprehensive single-cell proteomics analyses of lung adenocarcinoma progression reveal the role of tumor-associated macrophages in resistance to PD-1 blockade therapy. See related commentary by Lee et al., p. 2515.

ISUP Consensus Definition of Cribriform Pattern Prostate Cancer.

The presence of a cribriform pattern is now recognized as a clinically important, independent adverse prognostic indicator for prostate cancer. For this reason the International Society of Urological Pathology (ISUP) recently recommended its inclusion in standard reporting. In order to improve interobserver agreement as to the diagnosis of cribriform patterns, the ISUP assembled an international panel of 12 expert urogenital pathologists for the purpose of drafting a consensus definition of cribriform pattern in prostate cancer, and provide their opinions on a set of 32 images and on potential diagnostic criteria. These images were selected by the 2 nonvoting convenors of the study and included the main categories where disagreement was anticipated. The Delphi method was applied to promote consensus among the 12 panelists in their review of the images during 2 initial rounds of the study. Following a virtual meeting, convened to discuss selected images and diagnostic criteria, the following definition for cribriform pattern in prostate cancer was approved: "A confluent sheet of contiguous malignant epithelial cells with multiple glandular lumina that are easily visible at low power (objective magnification ×10). There should be no intervening stroma or mucin separating individual or fused glandular structures" together with a set of explanatory notes. We believe this consensus definition to be practical and that it will facilitate reproducible recognition and reporting of this clinically important pattern commonly seen in prostate cancer. The images and the results of the final Delphi round are available at the ISUP website as an educational slide set (https://isupweb.org/isup/blog/slideshow/cribriform-slide-deck/).

Aspiration fluid cytology during single operator cholangioscopy with targeted biopsy to improves the diagnostic yield in indeterminate biliary strictures.

INTRODUCTION: Sensitivities of various sampling methods to detect malignant biliary strictures remain suboptimal. Irrigation during digital single operator cholangioscopy (dSOC) is done routinely for visualization of the duct. The aim of this study was to evaluate improvement of the sensitivity for detecting malignant biliary strictures when adding aspiration fluid cytology (AFC) from the irrigated fluid during cholangioscopy to cholangioscopic biopsy (CBx). METHODS: We conducted a retrospective analysis of patients at a tertiary medical center who underwent CBx for evaluation of their biliary strictures. We included patients who had aspiration of fluid from the bile duct after CBx and were sent for cytology from January 2017 to October 2017. Diagnosis was made on the basis of final pathology or follow-up over 9 months. RESULTS: Fifty-six patients had CBx obtained, out of which 35 patients had AFC in conjunction. Twenty-two (62%) patients were male and the average age was 65 years. Considering atypical cells as benign, the sensitivity, specificity, positive and negative predictive values (PPV, NPV) for CBx were 62.5%, 100%, 100%, and 76% respectively. When CBx combined with AFC, the above statistics went up to 81.25%, 100%, 100%, and 86.36% respectively. When atypical cells were considered malignant, the sensitivity, specificity, PPV and NPV for CBx were 81.25%, 84.21%, 81.25%, 84.21% and increased to 93.75%, 78.94%, 78.94%, and 93.75% respectively after adding AFC results. CONCLUSION: For patients with biliary stricture, addition of AFC dSOC guided biopsies, significantly improves the sensitivity for detecting malignancy.

Cribriform prostate cancer: Morphologic criteria enabling a diagnosis, based on survey of experts.

Among four sub-patterns of Gleason grade 4 prostate cancer, voluminous evidence supports that the cribriform pattern holds an unfavorable prognostic impact, as compared with poorly-formed, fused, or glomeruloid. The International Society of Urological Pathology (ISUP) recommends specifying whether invasive grade 4 cancer is cribriform. Recently, ISUP experts published a consensus definition of cribriform pattern highlighting criteria that distinguish it from mimickers. The current study aimed to analyze morphologic features separately to identify those that define the essence of the cribriform pattern. Thirty-two selected photomicrographs were classified by 12 urologic pathologists as: definitely cribriform cancer, probably cribriform, unsure, probably not cribriform, or definitely not cribriform. Consensus was defined as 9/12 agree or disagree, with ≤1 strongly supporting the opposite choice. Final consensus was achieved in 21 of 32 cases. Generalized estimating equation (GEE) model with logit link was fitted to estimate effect of multiple morphologic predictors. Fisher exact test was used for categorical findings. Presence of intervening stroma precluded calling cribriform cancer (p = 0.006). Mucin presence detracted (p = 0.003) from willingness to call cribriform cancer (only 3 cases had mucin). Lumen number was associated with cribriform consensus (p = 0.0006), and all consensus cases had ≥9 lumens. Predominant papillary pattern or an irregular outer boundary detracted (p = NS). Invasive cribriform carcinoma should have absence of intervening stroma, and usually neither papillary pattern, irregular outer boundary, nor very few lumens. Setting the criteria for cribriform will help prevent over- or undercalling this important finding.

Intraductal Carcinoma of the Prostate: Pathogenesis and Molecular Perspectives.

Intraductal carcinoma of the prostate (IDC-P), a clinicopathological entity characterized by malignant prostatic epithelial cells growing within ducts and/or acini, has a distinct architectural pattern, cytological features, and biological behavior. Whereas most IDC-P tumors could be derived from adjacent high-grade invasive cancer via retrograde spreading of cancer cells along benign ducts and acini, a small subset of IDC-P may arise from the transformation and intraductal proliferation of precancerous cells induced by various oncogenic events. These isolated IDC-P tumors possess a distinct mutational profile and may function as a carcinoma in situ lesion with de novo intraductal outgrowth of malignant cells. Further molecular characterization of these two types of IDC-P and better understanding of the mechanisms underlying IDC-P formation and progression could be translated into valuable biomarkers for differential diagnosis and actionable targets for therapeutic interventions. PATIENT SUMMARY: Intraductal carcinoma of the prostate is an aggressive type of prostate cancer associated with high risk for local recurrence and distant metastasis. In this review, we discussed pathogenesis, biomarkers, differential diagnoses, and therapeutic strategies for this tumor.

ORIGIN AND DEVELOPMENT OF AMERICAN SURGICAL PATHOLOGY.

Although the discipline of pathology had its very beginnings in the earliest development and evolution of what became "modern medicine," the subset of pathology known as "surgical pathology" had its origins only in the last two centuries. Surgical pathology began as a clinico-pathologic analysis of gross morphologic findings with clinical outcomes, beginning with findings at autopsy. With the advent of microscopy, which enabled a higher level of morphologic classification and disease understanding, along with advances in surgery (anesthesia, antisepsis, and then antibiotics), the need for accurate pathologic classification in the living patient became of paramount importance. This review chronicles the evolution of surgical pathology in the United States in the context of advances in the science and practice of medicine generally and surgery specifically.

The 2019 International Society of Urological Pathology (ISUP) Consensus Conference on Grading of Prostatic Carcinoma.

Five years after the last prostatic carcinoma grading consensus conference of the International Society of Urological Pathology (ISUP), accrual of new data and modification of clinical practice require an update of current pathologic grading guidelines. This manuscript summarizes the proceedings of the ISUP consensus meeting for grading of prostatic carcinoma held in September 2019, in Nice, France. Topics brought to consensus included the following: (1) approaches to reporting of Gleason patterns 4 and 5 quantities, and minor/tertiary patterns, (2) an agreement to report the presence of invasive cribriform carcinoma, (3) an agreement to incorporate intraductal carcinoma into grading, and (4) individual versus aggregate grading of systematic and multiparametric magnetic resonance imaging-targeted biopsies. Finally, developments in the field of artificial intelligence in the grading of prostatic carcinoma and future research perspectives were discussed.

Dataset for the reporting of prostate carcinoma in radical prostatectomy specimens: updated recommendations from the International Collaboration on Cancer Reporting.

The International Collaboration on Cancer Reporting (ICCR) was formed in 2011 to harmonise the datasets, protocols and checklists for pathological reporting of various cancers and develop internationally agreed upon, evidence-based datasets. A dataset for prostate cancer in radical prostatectomy specimens was developed in 2011-2012 as part of a pilot project; however, it required substantial revision following the ISUP Consensus Conference on Gleason Grading in 2014, the publication of the World Health Organisation (WHO) Classification of Tumours of the Urinary System and Male Genital Organs in 2016, and the 8th edition of the Tumour-Node-Metastasis (TNM) staging system in late 2016. This article presents the up-to-date, evidence-based ICCR dataset and associated commentary for reporting prostate cancer in radical prostatectomy specimens. PubMed and Google search engines were used to review the published literature on the subject, and the dataset was developed in line with the previously published ICCR framework for the development of cancer datasets. Substantial changes have been incorporated into the second edition of the ICCR prostate cancer (radical prostatectomy) dataset. These include revisions to prostate cancer grading, reporting of intraductal carcinoma of prostate and surgical margins, among others. Up-to-date cancer datasets underpin structured reporting and facilitate the production of consistent and accurate pathological data for patient care as well as comparisons between different cohorts and populations internationally.

Dataset for the reporting of prostate carcinoma in core needle biopsy and transurethral resection and enucleation specimens: recommendations from the International Collaboration on Cancer Reporting (ICCR).

The International Collaboration on Cancer Reporting (ICCR) is a project which issues datasets and guidelines for international standardisation of cancer reporting. This review summarises the required and recommended elements of the datasets for prostate core needle biopsies and transurethral resection (TURP) and enucleation specimens of the prostate. To obtain as much information as possible from needle biopsies there should be only one core in each specimen jar with the exception of saturation biopsies. The gross description of the specimens should include core lengths of needle biopsies and weight of resection specimens. The tumours should be classified according to the 4th World Health Organization (WHO) classification and graded both by Gleason scores and the grouping of these in International Society of Urological Pathology (ISUP) grades (Grade groups). Percent high-grade cancer is an optional component of the report. Tumour extent in needle biopsies should be reported both by number of cores positive for cancer and the linear extent measured in either millimetre or percent core involvement by tumour. In needle biopsies where low-grade cancer is discontinuous and seen in few cores, it is recommended that the tumour extent should be reported both by including and subtracting intervening benign tissue. For resection specimens, the percentage of the tissue area (or percentage of number of TURP chips) involved with cancer should be estimated. Extraprostatic extension should be reported when seen, while the reporting of perineural, seminal vesicle/ejaculatory duct and lymphovascular invasion is only recommended. Intraductal carcinoma of the prostate (IDC-P) should be reported when present, because of its strong link with aggressive cancer. The current recommendation is that the IDC-P component should not be graded. The structured and standardised reporting of prostate cancer contributes to safer and more efficient patient care and facilitates the compilation and understanding of multiparametric diagnostic and prognostic data.

Comprehensive immunoproteogenomic analyses of malignant pleural mesothelioma.

We generated a comprehensive atlas of the immunologic cellular networks within human malignant pleural mesothelioma (MPM) using mass cytometry. Data-driven analyses of these high-resolution single-cell data identified 2 distinct immunologic subtypes of MPM with vastly different cellular composition, activation states, and immunologic function; mass spectrometry demonstrated differential abundance of MHC-I and -II neopeptides directly identified between these subtypes. The clinical relevance of this immunologic subtyping was investigated with a discriminatory molecular signature derived through comparison of the proteomes and transcriptomes of these 2 immunologic MPM subtypes. This molecular signature, representative of a favorable intratumoral cell network, was independently associated with improved survival in MPM and predicted response to immune checkpoint inhibitors in patients with MPM and melanoma. These data additionally suggest a potentially novel mechanism of response to checkpoint blockade: requirement for high measured abundance of neopeptides in the presence of high expression of MHC proteins specific for these neopeptides.

Soluble Mesothelin-Related Peptides to Monitor Recurrence After Resection of Pleural Mesothelioma.

BACKGROUND: Most patients undergoing surgical resection of malignant pleural mesothelioma (MPM) will experience recurrence, and radiographic diagnosis of recurrence can be difficult in the postoperative chest. Our objective was to determine the utility of the serum biomarker soluble mesothelin-related peptide (SMRP; or mesothelin) in monitoring of the postoperative MPM patient. METHODS: We retrospectively evaluated a prospectively maintained single institution clinical database. SMRP levels were evaluated preoperatively and postoperatively in patients undergoing surgical resection of MPM. RESULTS: One hundred two patients underwent pleurectomy/decortication (58%), extrapleural pneumonectomy (20%), chest wall resection (2%), or exploratory thoracotomy (20%) for MPM of 81% epithelial histology. Sixty percent received heated intraoperative chemotherapy and 57% received perioperative systemic chemotherapy. Patients with epithelial histology had substantially greater mean (± SD) preoperative SMRP levels (4.5 ± 7.3 nmol/L) than did patients with biphasic (1.9 ± 2.5 nmol/L) or sarcomatoid (1.2 ± 1.0 nmol/L) histology. Radiologic 3-dimensional tumor volume and tumor mesothelin gene (MSLN) expression correlated with preoperative SMRP. In patients with epithelial histology undergoing complete resection (n = 66), preoperative SMRP (3.4 ± 4.9 nmol/L) dramatically decreased immediately after operation (0.8 ± 0.5 nmol/L), and preoperative SMRP was independently associated with poor disease-free survival. Percentage of change in serial postoperative SMRP values at the best statistical cutoff at 48% revealed high predictive capability of disease recurrence with 90% sensitivity and 93% specificity (area under the curve = 0.96, p < 0.001). CONCLUSIONS: SMRP is a promising serum biomarker for the detection of recurrence after resection of epithelial MPM that may have value in clinical practice and should be studied in a prospective cohort.

Progression of EGFR-Mutant Lung Adenocarcinoma is Driven By Alveolar Macrophages.

PURPOSE: Lung adenocarcinomas with mutations in the EGFR have unprecedented initial responses to targeted therapy against the EGFR. Over time, however, these tumors invariably develop resistance to these drugs. We set out to investigate alternative treatment approaches for these tumors. EXPERIMENTAL DESIGN: To investigate the immunologic underpinnings of EGFR-mutant lung adenocarcinoma, we utilized a bitransgenic mouse model in which a mutant human EGFR gene is selectively expressed in the lungs. RESULTS: EGFR oncogene-dependent progression and remission of lung adenocarcinoma was respectively dependent upon the expansion and contraction of alveolar macrophages, and the mechanism underlying macrophage expansion was local proliferation. In tumor-bearing mice, alveolar macrophages downregulated surface expression of MHC-II and costimulatory molecules; increased production of CXCL1, CXCL2, IL1 receptor antagonist; and increased phagocytosis. Depletion of alveolar macrophages in tumor-bearing mice resulted in reduction of tumor burden, indicating a critical role for these cells in the development of EGFR-mutant adenocarcinoma. Treatment of mice with EGFR-targeting clinical drugs (erlotinib and cetuximab) resulted in a significant decrease in alveolar macrophages in these mice. An activated alveolar macrophage mRNA signature was dominant in human EGFR-mutant lung adenocarcinomas, and the presence of this alveolar macrophage activation signature was associated with unfavorable survival among patients undergoing resection for EGFR-mutant lung adenocarcinoma. CONCLUSIONS: Because of the inevitability of failure of targeted therapy in EGFR-mutant non-small cell lung cancer (NSCLC), these data suggest that therapeutic strategies targeting alveolar macrophages in EGFR-mutant NSCLC have the potential to mitigate progression and survival in this disease. Clin Cancer Res; 23(3); 778-88. ©2016 AACR.

Morphometric analysis of calcification and fibrous layer thickness in carotid endarterectomy tissues.

BACKGROUND: Advanced atherosclerotic lesions are commonly characterized by the presence of calcification. Several studies indicate that extensive calcification is associated with plaque stability, yet recent studies suggest that calcification morphology and location may adversely affect the mechanical stability of atherosclerotic plaques. The underlying cause of atherosclerotic calcification and the importance of intra-plaque calcium distribution remains poorly understood. METHOD: The goal of this study was the characterization of calcification morphology based on histological features in 20 human carotid endarterectomy (CEA) specimens. Representative frozen sections (10µm thick) were cut from the common, bulb, internal and external segments of CEA tissues and stained with von Kossa׳s reagent for calcium phosphate. The morphology of calcification (calcified patches) and fibrous layer thickness were quantified in 135 histological sections. RESULTS: Intra-plaque calcification was distributed heterogeneously (calcification %-area: bulb segment: 14.2±2.1%; internal segment: 12.9±2.8%; common segment: 4.6±1.1%; p=0.001). Calcified patches were found in 20 CEAs (patch size: <0.1mm(2) to >1.0mm(2)). Calcified patches were most abundant in the bulb and least in the common segment (bulb n=7.30±1.08; internal n=4.81±1.17; common n=2.56±0.56; p=0.0007). Calcified patch circularity decreased with increasing size (<0.1mm(2): 0.77±0.01, 0.1-1mm(2): 0.62±0.01, >1.0mm(2): 0.51±0.02; p=0.0001). A reduced fibrous layer thickness was associated with increased calcium patch size (p<0.0001). CONCLUSIONS: In advanced carotid atherosclerosis, calcification appears to be a heterogeneous and dynamic atherosclerotic plaque component, as indicated by the simultaneous presence of few large stabilizing calcified patches and numerous small calcific patches. Future studies are needed to elucidate the associations of intra-plaque calcification size and distribution with atherothrombotic events.

Usefulness of transurethral biopsy for staging the prostatic urethra before radical cystectomy.

PURPOSE: We determined the likelihood that transurethral resection biopsy of the prostatic urethra adjacent to the verumontanum would detect prostatic involvement of urothelial carcinoma in patients with bladder carcinoma. MATERIALS AND METHODS: We compared precystectomy transurethral resection biopsy specimens of the prostatic urethra with those of the matched radical cystoprostatectomy in 272 patients with urothelial carcinoma of the bladder. All prostates were evaluated by whole mount step sections. RESULTS: Prostatic involvement by urothelial carcinoma was detected by transurethral resection biopsy or radical cystoprostatectomy in 101 patients (37.1%). Transurethral resection biopsy detected urothelial carcinoma in 72 cases with 71.3% sensitivity and 100% specificity. The overall accuracy of transurethral resection biopsy to detect urothelial carcinoma of the prostate was 89% (positive and negative predictive values 100% and 86%, respectively). Invasive prostatic urothelial carcinoma arising from the prostatic urethra was detected by transurethral resection biopsy in 21 of 26 patients (81%) while prostatic carcinoma in situ was detected in 39 of 52 (75%). Transurethral resection biopsy detected prostatic invasive urothelial carcinoma resulting from transmural invasion of a bladder tumor in 4 of 15 patients. CONCLUSIONS: Prostatic involvement by urothelial carcinoma of the bladder was found in 37.1% of patients. Transurethral resection biopsy missed most tumors resulting from transmural invasion of the bladder primary lesion. Carcinoma in situ and invasive urothelial carcinoma arising from the prostatic urethra were detected in most cases. Transurethral resection biopsy of the prostatic urethra can complement staging and support clinical decision making with respect to neoadjuvant chemotherapy and planning for an orthotopic neobladder.