Standardized Classification of Lung Adenocarcinoma Subtypes and Improvement of Grading Assessment Through Deep Learning.

The histopathologic distinction of lung adenocarcinoma (LADC) subtypes is subject to high interobserver variability, which can compromise the optimal assessment of patient prognosis. Therefore, this study developed convolutional neural networks capable of distinguishing LADC subtypes and predicting disease-specific survival, according to the recently established LADC tumor grades. Consensus LADC histopathologic images were obtained from 17 expert pulmonary pathologists and one pathologist in training. Two deep learning models (AI-1 and AI-2) were trained to predict eight different LADC classes. Furthermore, the trained models were tested on an independent cohort of 133 patients. The models achieved high precision, recall, and F1 scores exceeding 0.90 for most of the LADC classes. Clear stratification of the three LADC grades was reached in predicting the disease-specific survival by the two models, with both Kaplan-Meier curves showing significance (P = 0.0017 and 0.0003). Moreover, both trained models showed high stability in the segmentation of each pair of predicted grades with low variation in the hazard ratio across 200 bootstrapped samples. These findings indicate that the trained convolutional neural networks improve the diagnostic accuracy of the pathologist and refine LADC grade assessment. Thus, the trained models are promising tools that may assist in the routine evaluation of LADC subtypes and grades in clinical practice.

Nonspecific interstitial pneumonia pattern is a frequent finding in patients with post-acute COVID-19 syndrome treated with bilateral orthotopic lung transplantation: current best evidence.

Patients with post-acute COVID-19 (PA-COVID) syndrome or long COVID-19 syndrome develop persistent symptoms and complications that last beyond 4 weeks of the initial infection. There is limited information regarding the pulmonary pathology in PA-COVID patients who require bilateral orthotopic lung transplantation (BOLT). Our experience with 40 lung explants from 20 PA-COVID patients who underwent BOLT is described. Clinicopathologic findings are correlated with best evidence from literature. The lung parenchyma showed bronchiectasis (n = 20) and severe interstitial fibrosis with areas resembling the nonspecific interstitial pneumonia (NSIP) pattern of fibrosis (n = 20), interstitial fibrosis not otherwise specified (n = 20), and fibrotic cysts (n = 9). None of the explants exhibited a usual interstitial pneumonia pattern of fibrosis. Other parenchymal changes included multinucleated giant cells (n = 17), hemosiderosis (n = 16), peribronchiolar metaplasia (n = 19), obliterative bronchiolitis (n = 6), and microscopic honeycombing (n = 5). Vascular abnormalities included thrombosis of a lobar artery (n = 1) and microscopic thrombi in small vessels (n = 7). Systematic literature review identified 7 articles reporting the presence in 12 patients of interstitial fibrosis showing the NSIP pattern (n = 3), organizing pneumonia/diffuse alveolar damage (n = 4) and not otherwise specified (n = 3) patterns. All but one of these studies also reported the presence of multinucleated giant cells and none of the studies reported the presence of severe vascular abnormalities. PA-COVID patients undergoing BOLT show a pattern of fibrosis that resembles a mixed cellular-fibrotic NSIP pattern and generally lack severe vascular complications. As the NSIP pattern of fibrosis is often associated with autoimmune diseases, additional studies are needed to understand the mechanism of disease and learn whether this information can be used for therapeutic purposes.

Overcoming the Interobserver Variability in Lung Adenocarcinoma Subtyping: A Clustering Approach to Establish a Ground Truth for Downstream Applications.

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 17 international expert lung pathologists and 1 pathologist in training. 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.

Membranous HEG1 expression is a useful marker in the differential diagnosis of epithelioid and biphasic malignant mesothelioma versus carcinomas.

Sialylated HEG1 has been reported as a highly specific and sensitive mesothelioma marker but a comprehensive evaluation of its expression in carcinomas in different organs, various sarcomas and reactive mesothelial proliferations has not been reported. The aim of this study was to evaluate the clinical applicability of HEG1 as a marker in the diagnosis of mesothelioma. HEG1 immunoreactivity was evaluated in whole sections of 122 mesotheliomas, 75 pulmonary carcinomas, 55 other carcinomas, 16 mesenchymal tumors, and 24 reactive mesothelial proliferations and in tissue microarrays containing 70 epithelioid (EM), 36 biphasic (BM), and 2 sarcomatoid mesotheliomas (SM). In whole sections and tissue microarrays, respectively, membranous HEG1 was expressed in 93.0% and 85.5% of EM, 81.3% and 69.4% of BM, 0% and 0% of SM. HEG1 was not expressed in pulmonary adenocarcinomas. HEG1 was expressed as cytoplasmic immunoreactivity in pulmonary squamous cell carcinomas (21.7%). Membranous HEG1 staining was seen in ovarian carcinomas (66.7%), thyroid carcinomas (100%), reactive conditions (16.7%), and mesenchymal tumors (18.8%). The sensitivity of membranous HEG1 expression to distinguish EM/BM from all carcinomas was 88.8%. The specificity for the differential diagnosis between EM/BM and all carcinomas and pulmonary carcinomas was 92.3% and 98.7%, respectively.

Comparison of Nuclear Grade, Necrosis, and Histologic Subtype Between Biopsy and Resection in Pleural Malignant Mesothelioma: An International Multi-Institutional Analysis.

OBJECTIVES: Numerous studies on malignant mesothelioma (MM) highlight the prognostic importance of histologic subtype, nuclear grade, and necrosis. This study compares these parameters in paired biopsy and resection specimens of pleural MM. METHODS: Histologic subtype, percentage of epithelioid morphology, nuclear grade, and the presence or absence of necrosis were compared in 429 paired biopsies and resection specimens of pleural MM from 19 institutions. RESULTS: Histologic subtype was concordant in 81% of cases (κ = 0.58). When compared with resection specimens, epithelioid morphology at biopsy had a positive predictive value (PPV) of 78.9% and a negative predictive value (NPV) of 93.5%; sarcomatoid morphology showed high PPV (92.9%) and NPV (99.3%), and biphasic morphology PPV was 89.7% and NPV was 79.7%. Agreement of the percentage of epithelioid morphology was fair (κ = 0.27). Nuclear grade and necrosis were concordant in 75% (κ = 0.59) and 81% (κ = 0.53) of cases, respectively. Nuclear grade showed moderate (κ = 0.53) and substantial (κ = 0.67) agreement from patients with and without neoadjuvant therapy, respectively, and necrosis showed moderate (κ = 0.47 and κ = 0.60) agreement, respectively, in the same subsets of paired specimens. CONCLUSIONS: Paired biopsy-resection specimens from pleural MM show overall moderate agreement in pathologic parameters. These findings may help guide postbiopsy management and triage of patients with MM.

Clinico-pathologic findings in patients with median arcuate ligament syndrome (celiac artery compression syndrome).

Median Arcuate Ligament Syndrome (MALS) is a rare entity characterized by severe post-prandial epigastric pain, nausea, vomiting, and/or weight loss. Symptoms have been attributed to vascular compression (celiac artery compression syndrome, CACS), but it remains controversial whether they could be secondary to neural compression. Literature review identified rare description of pathologic findings in surgery journals. The clinico-pathologic findings of four MALS patients who underwent robotic or laparoscopic surgery in our hospital are described. All our patients were female with a median age of 32.5 (range 25-55 years), and a median BMI of 23.5 kg/m2. They presented with chronic often post-prandial abdominal pain (4/4), nausea (3/4), emesis (2/4), anorexia (1/4), and weight loss (1/4). Two patients had a history of Crohn's disease. At intraoperative exploration, the celiac artery and adjacent nerves and ganglia were encased and partially compressed by fibrotic tissue in each patient. In each case laparoscopic excision of fibrotic tissue, celiac plexus and ligament division and was performed; celiac plexus nerve block was also performed in one patient. After surgical intervention, symptoms improved in three of the patients whose specimens show periganglionic and perineural fibrosis with proliferation of small nerve fibers. Our findings support neurogenic compression as a contributing factor in the development of pain and other MALS symptoms, and favor the use of MALS rather than CACS as diagnostic terminology. To further study the pathogenesis of this unusual syndrome, surgeons should submit all tissues excised during MALS procedures for histopathologic examination.

The concept of mesothelioma in situ, with consideration of its potential impact on cytology diagnosis.

Diffuse malignant mesothelioma (MM) is an incurable tumour of the serosal membranes, which is often caused by exposure to asbestos and commonly diagnosed at advanced stage. Malignant mesothelioma in situ (MMIS) is now included as diagnostic category by the World Health Organization (WHO). However, our international survey of 34 pulmonary pathologists with an interest in MM diagnosis highlights inconsistency regarding how the diagnosis is being made by experts, despite published guidelines. Whilst the WHO restricts the diagnosis to surgical samples, the very concept has implication for cytological diagnosis, which is already regarded as controversial in itself by some. MMIS is currently only applicable as precursor to MM with an epithelioid component, and raises the possibility for different molecular pathways for different histological MM subtypes. The clinical implications of MMIS at this stage are uncertain, but aggressive therapies are being initiated in some instances. Based on the results of the survey we here present a critical appraisal of the concept, its clinical and conceptual implications and provide practice suggestions for diagnosis. A low threshold for ancillary testing is suggested. The designations of 'malignant mesothelioma, cannot exclude MMIS' or 'atypical mesothelial proliferation with molecular indicators of malignancy, so-called MMIS' could be used on cytology samples, adding 'no evidence of invasion in sample provided' for surgical samples. Clinical and radiological correlation are integral to diagnosis and best done at multidisciplinary meetings. Finally, collaborative studies are required to improve our understanding of MMIS.

Challenges in Ki-67 assessments in pulmonary large-cell neuroendocrine carcinomas.

AIMS: To gather the best available evidence regarding Ki-67% values in large-cell neuroendocrine carcinoma (LCNEC) and determine whether certain cut-off values could serve as a prognostic feature in LCNEC. METHODS AND RESULTS: Aperio ScanScope AT Turbo, eSlide Manager and ImageScope software (Leica Biosystems) were used to measure Ki-67% in 77 resected LCNEC diagnosed by World Health Organisation (WHO) criteria. Cases were stratified into six classes by 10% Ki-67 increments. Using the Kaplan-Meier method, overall (OS) and disease-free survivals (DFS) were compared by AJCC stage, by six Ki-67% classes and with Ki-67% cut-points ≥20% and ≥40%. Tumours were from 0.9 to 11.5 cm and pathological stages 1-3. The system measured Ki-67% positivity using 4072-44 533 tumour nuclei per case (mean 16610 ± 8039). Ki-67% ranged from 1 to 64% (mean = 26%; median = 26%). Only 16 (21%) tumours had Ki-67% ≥40%. OS ranged from 1 to 298 months (median follow-up = 25 months). DFS ranged from 1 to 276 months (median follow-up = 9 months). OS and DFS differed across AJCC stage (overall log-rank P = 0.038 and P = 0.037). However, neither OS nor DFS significantly correlated with Ki-67% when six or two classes were used with either ≥20% Ki-67 or ≥40% Ki-67 as cut-point. A literature review identified 14 reports meeting our inclusion criteria with ≥10 LCNEC. Reported Ki-67% ranged from 2% to 100%. Problems contributing to variability in Ki-67% measurements are discussed. CONCLUSION: Our findings caution against a blanket use of 20%, 40% or other Ki-67% cut-points for LCNEC diagnosis or prognostication.

Pathologists should probably forget about kappa. Percent agreement, diagnostic specificity and related metrics provide more clinically applicable measures of interobserver variability.

Kappa statistics have been widely used in the pathology literature to compare interobserver diagnostic variability (IOV) among different pathologists but there has been limited discussion about the clinical significance of kappa scores. Five representative and recent pathology papers were queried using clinically relevant specific questions to learn how IOV was evaluated and how the clinical applicability of results was interpreted. The papers supported our anecdotal impression that pathologists usually assess IOV using Cohen's or Fleiss' kappa statistics and interpret the results using some variation of the scale proposed by Landis and Koch. The papers did not cite or propose specific guidelines to comment on the clinical applicability of results. The solutions proposed to decrease IOV included the development of better diagnostic criteria and additional educational efforts, but the possibility that the entities themselves represented a continuum of morphologic findings rather than distinct diagnostic categories was not considered in any of the studies. A dataset from a previous study of IOV reported by Thunnissen et al. was recalculated to estimate percent agreement among 19 international lung pathologists for the diagnosis of 74 challenging lung neuroendocrine neoplasms. Kappa scores and diagnostic sensitivity, specificity, positive and negative predictive values were calculated using the majority consensus diagnosis for each case as the gold reference diagnosis for that case. Diagnostic specificity estimates among multiple pathologists were > 90%, although kappa scores were considerably more variable. We explain why kappa scores are of limited clinical applicability in pathology and propose the use of positive and negative percent agreement and diagnostic specificity against a gold reference diagnosis to evaluate IOV among two and multiple raters, respectively.

Prognosis in pathology: Are we "prognosticating" or only establishing correlations between independent variables and survival? A study with various analytics cautions about the overinterpretation of statistical results.

Survival data from 225 patients with resected pulmonary typical carcinoids were analyzed with Kaplan-Meier statistics (K-M) and "deep learning" methods to illustrate the difference between establishing "correlations" and "prognostications". Cases were stratified into G1 and G2 classes using a ≤5% Ki-67% cut-point. Overall survival, number of patients at risk and 95% confidence intervals (CI) were estimated for the two classes. Seven neural network models (NN) were developed with GMDH Shell 3.8.2 and Statgraphics Centurion 18.1 software, using variable prior probabilities and different numbers of training vs testing cases. The NNs used age, sex, and pTNM, G1 and G2 as input neurons and "alive" and "dead" as output neurons. Areas under the curve (AUC) and other performance measures were evaluated for all models. Log-rank test showed a significant difference in overall survival between G1 and G2 (p < 0.001). However, 95% CI estimates showed considerable variability in survival at different time intervals. Including the number of patients at risk at different time intervals showed that most G2 patients had been censored by 100 weeks. The NN models provided variable "prognostications", with AUC ranging from 0.5 to 1 and variability in the sensitivity, specificity, and other performance measures. The results illustrate the limitations of survival statistics and NNs in predicting the prognosis of individual patients. The need for pathologists not to overinterpret the finding of significant correlations as "prognostic" or "predictive" for individual patients is discussed.

Mediastinal tumors of peripheral nerve origin (so-called neurogenic tumors).

The mediastinum can be the site of origin of a variety of benign and malignant tumors of peripheral nerve sheath origin. Although schwannoma is one of the most common tumors found in the posterior mediastinum, peripheral nerve sheath tumors are reported in all compartments of the mediastinum. The majority of peripheral nerve sheath tumors in the mediastinum as in other anatomic sites occur sporadically, and a subset of them, most notably neurofibromas, and to a lesser extent, schwannomas and malignant peripheral nerve sheath tumors, occur in patients with syndromes such as neurofibromatosis 1 (NF1). In this review, the characteristics of mediastinal nerve sheath tumors along with the histologic differential diagnosis are summarized. Primary emphasis is placed upon the use of morphologic criteria for establishing a definitive diagnosis with reference to photomicrographs to illustrate the classic and sometimes unusual features of this varied group of tumors. The judicious application of ancillary testing, most frequently immunohistochemistry, for separating peripheral nerve sheath tumors from each other and from their morphologic mimics is reviewed. Included in the review are the clinicopathologic features, clinical management and prognostic implications of benign and malignant mediastinal peripheral nerve sheath tumors.

Localized malignant mesothelioma, an unusual and poorly characterized neoplasm of serosal origin: best current evidence from the literature and the International Mesothelioma Panel.

Localized malignant mesotheliomas (LMM) is an uncommon and poorly recognized neoplasm. Its pathologic diagnosis is often surprising in patients with serosal/subserosal based localized tumors that are clinically suspicious for metastatic lesions or primary sarcomas. Once a tumor is diagnosed as "mesothelioma", LMM is often mistaken for diffuse malignant mesothelioma (DMM). Best currently available evidence about LMM was collected from the literature and cases diagnosed by members of the International Mesothelioma Panel (IMP). One hundred and one (101) LMM have been reported in the English literature. Patients had localized tumors with identical histopathologic features to DMM. Patients ranged in age from 6 to 82 years; 75% were men. Most (82%) of the tumors were intrathoracic. Others presented as intrahepatic, mesenteric, gastric, pancreatic, umbilical, splenic, and abdominal wall lesions. Tumors varied in size from 0.6 to 15 cm. Most patients underwent surgical resection and/or chemotherapy or radiation therapy. Median survival in a subset of patients was 29 months. Seventy two additional LMM from IMP institutions ranged in age from 28 to 95 years; 58.3% were men. Sixty tumors (83.3%) were intrathoracic, others presented in intraabdominal sites. Tumors varied in size from 1.2 to 19 cm. Median survival for 51 cases was 134 months. Best evidence was used to formulate guidelines for the diagnosis of LMM. It is important to distinguish LMM from DMM as their treatment and prognosis is different. A multidisciplinary approach is needed for the diagnosis of LMM as it shows identical histopathology and immunophenotype to DMM.

Pathology in the era of "Personalized Medicine": The need to learn how to integrate multivariate immunohistochemical and "omics" data with clinicopathologic information in a clinically relevant way".

"Personalized medicine" has been proposed as a new paradigm for patient care that, based on the integration of genomics and other "omics" data with clinical and other multidisciplinary information, promises early disease detection, improved outcomes and reduced side effects to therapies. Pathologists have become important participants in this new approach as the guardians of tissues and experts in the performance of molecular and other laboratory tests. Large amounts of new laboratory data in multiple neoplasms and other entities are being reported but there has been limited discussion about how best to evaluate the clinical significance of this information and how to integrate it into currently available diagnostic and therapeutic modalities. This article introduces a variety of epistemological problems presented by the "personalized medicine" paradigm and briefly discusses various topics that will be evaluated in further detail in future articles of this new series on Evidence-Based Pathology.

Carcinoid tumors of the thymus and Cushing's syndrome: Clinicopathologic features and current best evidence regarding the cell of origin of these unusual neoplasms.

It is uncertain whether thymic neuroendocrine tumors (NET) associated with Cushing's syndrome (CS) produce corticotropin-releasing hormone (CRH) and adrenocorticotropin hormone (ACTH) and whether the thymus contains ACTH and/or CRH cells that could originate NET. The clinicopathologic features of 5 typical (TC) and 6 atypical carcinoids (ATC), 10 additional non-neoplastic thymi, 6 adrenal glands with bilateral nodular hyperplasia and 8 adrenal cortical adenomas were reviewed. Representative slides were immunostained for ACTH and CRH. Four (36.4%) of the 11 patients had CS. The incidence of Masaoka stage IV was higher (p < 0.0001) in patients with ATC than TC. Only 2 (18.1%) of the 11 patients were alive at follow-up. Ten NET were CRH immunoreactive and 6 were ACTH immunoreactive. Thymic NET with CS exhibited stronger immunoreactivity for ACTH and CRH than those without CS. Non-neoplastic thymi exhibited scattered ACTH and CRH immunoreactive cells. Normal adrenal cortex and glands with bilateral nodular hyperplasia showed diffuse CRH immunoreactivity while adrenal adenomas showed no or only focal CRH immunoreactivity. Literature review showed no association between thymic NET and adrenal adenomas. The thymus contains CRH and ACTH immunoreactive cells that are probably the origin of thymic NET. Neoplasms associated with CS exhibit strong immunoreactivity for both hormones, suggesting that CRH probably plays a role in the pathogenesis of CS. As adrenals with bilateral nodular hyperplasia exhibit diffuse CRH immunoreactivity and adrenal cortical adenomas either lack this finding or show few immunoreactive cells, this marker may be useful to distinguish these lesions.

Procurement and Storage of Pleural and Peritoneal Fluids for Biobanking.

There is limited information regarding the biobanking of pleural and peritoneal fluids that might supplement storage of pulmonary and thoracic tissue biospecimens. Such fluids are sometimes collected for clinical analyses and may have uses that obviate or supplement tissue samples. There has been a growing interest in using liquid biopsies as they are less invasive and may be amenable to analyses that guide targeted therapies. Integrating cytology and biobanking approaches, we describe techniques that may be used for collecting and banking pleural and peritoneal fluids.

The use of Ki-67 labeling index to grade pulmonary well-differentiated neuroendocrine neoplasms: current best evidence.

Although Ki-67 labeling index (Ki-67%) is not a diagnostic or grading criterion in the World Health Organization classification of pulmonary carcinoid tumor, oncologists often request this test. A survey was administered at a North American Society for Neuroendocrine Tumors meeting to understand how Ki-67% is used in oncologic practices. A systematic literature review was performed to gather best evidence regarding the use of Ki-67%. Consecutive pulmonary carcinoids were stratified into pulmonary typical carcinoids with Ki-67% <5% (group A, n = 187), typical carcinoids with Ki-67% ≥5% (group B, n = 38) and atypical carcinoids irrespective of Ki-67% (group C, n = 31). Overall survival, progression-free survival, recurrence proportions and time to recurrence were compared, by group, using the log-rank test, chi-square statistics and ANOVA, respectively. Our survey confirmed that Ki-67% is frequently used by specialists caring for these patients. Ki-67% of 1-7% significantly correlated with overall survival in the literature but we found no information about Ki-67% cut-off values that would accurately distinguish pulmonary typical from atypical carcinoids or estimate the prognosis of patients stratified by World Health Organization diagnosis and Ki-67% cut-off. Overall survival was significantly different in our 3 patient groups (p < 0.001), with survival probabilities decreasing from groups A to C. Progression-free survival was significantly longer in group A than B (p < 0.007). Our results support the concept that by combining World Health Organization diagnosis and Ki-67%, pulmonary carcinoids can be stratified into 3 grades: G1 (typical carcinoids with Ki-67% <5), G2 (typical carcinoids with Ki-67% ≥5%) and G3 (atypical carcinoids) with different prognoses.

The Use of Screencasts with Embedded Whole-Slide Scans and Hyperlinks to Teach Anatomic Pathology in a Supervised Digital Environment.

BACKGROUND: There is an increasing interest in using digitized whole-slide imaging (WSI) for routine surgical pathology diagnoses. Screencasts are digital recordings of computer screen output with advanced interactive features that allow for the preparation of videos. Screencasts that include hyperlinks to WSIs could help teach pathology residents how to become familiar with technologies that they are likely to use in their future career. MATERIALS AND METHODS: Twenty screencasts were prepared with Camtasia 2.0 software (TechSmith, Okemos, MI, USA). They included clinical history, videos of chest X-rays and/or chest computed tomography images, links to WSI digitized with an Aperio Turbo AT scanner (Leica Biosystems, Buffalo Grove, IL, USA), pre- and posttests, and faculty-narrated videos of the WSI in a manner closely resembling a slide seminar and other educational materials. Screencasts were saved in a hospital network, Screencast.com, YouTube.com, and Vimeo.com. The screencasts were viewed by 12 pathology residents and fellows who made diagnoses, answered the quizzes, and took a survey with questions designed to evaluate their perception of the quality of this technology. Quiz results were automatically e-mailed to faculty. Pre- and posttest results were compared using a paired t-test. RESULTS: Screencasts can be viewed with Windows PC and Mac operating systems and mobile devices; only videos saved in our network and screencast.com could be used to generate quizzes. Participants' feedback was very favorable with average scores ranging from 4.5 to 4.8 (on a scale of 5). Mean posttest scores (87.0% [±21.6%]) were significantly improved over those in the pretest quizzes (48.5% [±31.2%]) (P < 0.0001). CONCLUSION: Screencasts with WSI that allow residents and fellows to diagnose cases using digital microscopy may prove to be a useful technology to enhance the pathology education. Future studies with larger numbers of screencasts and participants are needed to optimize various teaching strategies.

Current Evidence Does Not Warrant Frozen Section Evaluation for the Presence of Tumor Spread Through Alveolar Spaces.

CONTEXT: - Tumor spread through alveolar spaces (STAS) has been correlated with unfavorable prognosis in lung adenocarcinomas treated with sublobar resection, but it is unknown whether STAS can be reliably identified in frozen section (FS) to help stratify patients for lobectomy or sublobar resection. OBJECTIVE: - To evaluate STAS in FS. DESIGN: - Tumor spread through alveolar spaces was evaluated in hematoxylin-eosin-stained FS, FS control slides, and all additional slides with lung tissue adjacent to tumor (AdLT) from 48 pT1-2 adenocarcinomas operated on using video-assisted thoracotomy (n = 25) or open thoracotomy (n = 23). The samples included lobectomies (n = 27) and sublobar resections (n = 21). The STAS incidences were compared by FS versus FS control versus AdLT, video-assisted thoracotomy versus open thoracotomy, and lobectomy versus sublobar resection. Sensitivity, specificity, and positive and negative predictive values of STAS+ findings were calculated. The literature was queried for best evidence regarding incidence and predictive value of STAS in FS. RESULTS: - Tumor spread through alveolar spaces positivity was identified in 46 of 48 cases (95.8%), including 23 FS (47.9%), 32 FS control (66.7%), and 43 AdLT (89.6%). The STAS incidence was significantly higher in AdLT than in FS or FS control. Only 2 of the 25 cases that were STAS- in FS were true negatives. Frozen section sensitivity to detect STAS positivity was 50%, with a 100% positive predictive value and 8% negative predictive value. Systematic literature review identified no evidence regarding STAS identification in FS. CONCLUSIONS: - The sensitivity and negative predictive value of FS for STAS detection are unacceptably low. There are insufficient data to support intraoperative detection of STAS as a useful predictive feature to help stratify patients for lobectomy or sublobar resections.