Hypersensitivity Pneumonitis A Perspective From Members of the Pulmonary Pathology Society.

CONTEXT: - Hypersensitivity pneumonitis (HP) is a lung disease that develops in susceptible individuals after inhalational exposure to an organic antigen or chemical compound. Pathogenesis is attributed to a combination of type III (immune complex-mediated) and type IV (delayed) hypersensitivity reactions to the inciting agent. OBJECTIVE: - To provide an overview of the current status of the medical literature regarding hypersensitivity pneumonitis. DATA SOURCES: - A literature search was performed using PubMed and Google search engines. The terms "hypersensitivity pneumonitis" and "extrinsic allergic alveolitis" were used, with the search starting on January 9, 2017, and concluding March 8, 2017. CONCLUSIONS: - As a pathologist, it is important to consider hypersensitivity pneumonitis when examining lung specimens because it is often clinically and pathologically overlooked. Recognizing the often subtle findings and correlating them with the patient's history or suggesting a thorough clinical investigation of potential exposures can be of help in identifying the underlying condition so that the patient can be appropriately managed.

Programmed Cell Death Ligand (PD-L1) Expression in Stage II and III Lung Adenocarcinomas and Nodal Metastases.

INTRODUCTION: Programmed death ligand 1 (PD-L1) expression determined by immunohistochemistry (IHC) may serve as a predictive biomarker for anti-PD-1/PD-L1 therapies; however, little is known about intertumoral heterogeneity of PD-L1 expression determined by IHC in lung adenocarcinomas (ADCs), and there have been conflicting results on the prognostic role of PD-L1 expression in ADCs. METHODS: PD-L1 expression was evaluated in resected stage II and III ADCs by using various cutoffs and correlated with clinicopathologic parameters and survival. PD-L1 expression was also compared between the primary tumor and lymph node metastases. RESULTS: There were 109 study cases. PD-L1 expression was seen in 56 (51%), 43 (39%), and 19 (17%) when cutoffs of at least 1%, at least 5%, and at least 50%, respectively, were used. Abundant intratumoral CD8-positive T cells were a significant predictor of the expression in the primary tumor, with cutoffs of 1% and 5% (p < 0.001 for both) by multivariate analysis, whereas they were a nonsignificant predictor of the expression with a 50% cutoff (p = 0.076). PD-L1 expression was concordant between the primary tumor and nodal metastasis in most of the cases, but it was discrepant in up to 38%. The discrepancy was attributed in part to different predominant histologic patterns between the primary and metastatic tumors. In the entire cohort, PD-L1 expression with all cutoffs had no bearing on 5-year recurrence-free survival. CONCLUSIONS: PD-L1 expression is associated with abundant intratumoral CD8-positive T cells in resected ADCs, suggesting a predictive role of PD-L1 expression in anti-PD-1/PD-L1 therapies; however, the possible intertumoral heterogeneity of PD-L1 expression raises a concern about selecting the most appropriate sample for PD-L1 IHC.

Programmed Cell Death Ligand 1 Expression in Resected Lung Adenocarcinomas: Association with Immune Microenvironment.

INTRODUCTION: Programmed cell death ligand 1 (PD-L1) expression on tumor cells can be upregulated via activation of CD8+ cytotoxic T lymphocytes (CTLs) or the T helper cell (Th1) pathway, counterbalancing the CTL/Th1 microenvironment. However, PD-L1 expression in association with subtypes of tumor-associated lymphocytes and molecular alterations has not been well characterized in lung adenocarcinomas. METHODS: PD-L1 expression was evaluated in 261 resected lung adenocarcinomas using tissue microarrays and various scoring systems, and was correlated with clinicopathologic/molecular features, including the extent/subtype of tumor-associated lymphocytes (i.e., CD8, T-bet [Th1 transcription factor], and GATA3 [Th2 transcription factor]), and patient outcomes. RESULTS: PD-L1 expression was present in 129 (49%), 95 (36.5%), and 62 (24%) cases using cutoffs of ≥1%, ≥5%, and ≥50%, respectively, 98 (38%) by H score and 72 (28%) by immune score. PD-L1 expression was associated with abundant CD8+ and/or T-bet+ tumor-infiltrating lymphocytes and EGFR wild-type, significant smoking history, and aggressive pathologic features. In addition, concurrent PD-L1 expression and abundant CD8+ tumor-associated lymphocytes were seen in 25% of KRAS mutants or cases with no alterations by clinical molecular testing as opposed to only 7.4% of EGFR mutants. PD-L1 expression was significantly associated with decreased progression-free and overall survival rates by univariate analysis, but not by multivariate analysis. CONCLUSION: PD-L1 expression in resected lung adenocarcinomas is frequently observed in the presence of CTL/Th1 microenvironment, in particular in those with KRAS mutations or no common molecular alterations, suggesting that blockade of the PD-1/PD-L1 axis may be a promising treatment strategy to reinstitute active immune response for at least a subset of such patient populations.

Napsin A/p40 antibody cocktail for subtyping non-small cell lung carcinoma on cytology and small biopsy specimens.

BACKGROUND: Subtyping non-small cell lung carcinomas (NSCLC) into adenocarcinoma (ACA) or squamous cell carcinoma (SQCC) is important for treatment and specimen triage for molecular studies. To preserve tissue for molecular studies in cytology/small biopsy specimens, a 2-antibody cocktail for NSCLC subtyping was developed. METHODS: Markers for lung ACA (thyroid transcription factor 1 and napsin A) and SQCC (cytokeratin 5/6 and p40) were evaluated on tissue microarrays (TMAs) with 143 ACA and 98 SQCC specimens. The napsin A/p40 combination was selected for NSCLC subtyping and validated on the TMA as well as on a cohort of cell block/small biopsy specimens from 80 poorly differentiated NSCLCs. RESULTS: Using TMA analysis, the napsin A-positive (+)/p40± immunophenotype identified ACA with 94% sensitivity and 100% specificity, whereas the napsin A (negative)-/p40+ immunophenotype identified SQCC with 100% sensitivity and specificity. On the validation cohort of 80 cell block and small biopsy specimens, the napsin A/p40 cocktail accurately subtyped 63 of 70 NSCLC (90%) as ACA or SQCC using the subsequent surgical resection as reference histology. Of the remaining 17 cases, 15 were classified as NSCLC-not otherwise specified based on a napsin A-/p40- immunophenotype; their corresponding resections were diagnosed as ACA (7 cases), large cell carcinoma (7 cases), or pleomorphic carcinoma (1 case). Two additional large cell carcinoma cases showed a napsin A-/p40+ or napsin A+/p40+ profile in the preoperative cell block/small biopsy sample. CONCLUSIONS: A napsin A/p40 cocktail can accurately subtype NSCLC into ACA and SQCC in most cell block/small biopsy specimens of poorly differentiated NSCLC. In the minority of cases in which the napsin A/p40 immunophenotype is indeterminate, additional stains may be necessary for precise classification. Cancer Cytopathol 2016;124:472-84. © 2016 American Cancer Society.

Mutually exclusive extracellular signal-regulated kinase pathway mutations are present in different stages of multi-focal pulmonary Langerhans cell histiocytosis supporting clonal nature of the disease.

AIMS: Pulmonary Langerhans cell histiocytosis (PLCH) is an idiopathic cigarette smoking-related disorder of the lung. Molecular changes in cellular or fibrotic stages of PLCH have not been investigated. We studied the prevalence of extracellular signal-regulated kinase (ERK) pathway mutations in different PLCH stages and other non-PLCH smoking-related lung diseases. METHODS AND RESULTS: The cohort included 28 PLCH with cellular (n = 10), mixed cellular/fibrotic (n = 4) and fibrotic histology (n = 14). Seven cases had concurrent multi-focal/multi-lobar tumours. Respiratory bronchiolitis interstitial lung disease (RB-ILD, n = 2), desquamative interstitial pneumonia (DIP, n = 4) and mixed RB-ILD/DIP (n = 2) were included for comparison. BRAF(V) (600E) immunohistochemistry, next-generation sequencing (NGS) and peptide nucleic acid (PNA) clamp polymerase chain reaction (PCR) with high analytical sensitivity (<0.1-0.2%) were used to analyse RAS, BRAF and MAP2K1 genes. Of 26 cases with gene mutation data, BRAF(V) (600E) was identified in eight of 12 (67%) cellular cases and in one of 14 (7%) fibrotic cases. MAP2K1 or KRAS mutations were observed in four of 14 (29%) fibrotic cases and three of the 12 (25%) cellular cases. Multi-focal/multi-lobar specimens carried identical BRAF (n = 5) or non-hotspot MAP2K1 (n = 2) mutations. The other smoking-related disorders were negative for mutations. Patients with cellular lesions or BRAF mutation were significantly younger than patients with fibrotic or BRAF wild-type PLCH. CONCLUSION: The presence of identical but mutually exclusive ERK pathway mutations in multi-focal PLCH supports a neoplastic/clonal origin for this disease. Patient age and mutation type differed between cellular and fibrotic histology and may indicate a natural progression or a mutation-specific pathogenicity.

Multfocal micronodular pneumocyte hyperplasia in a Chinese man masquerading as miliary tuberculosis.

Multifocal Micronodular Pneumocyte Hyperplasia (MMPH) is a rare and histologically, distinctive pulmonary manifestation of tuberous sclerosis complex (TSC) characterized by numerous and extensive proliferative lesions of type II pneumocytes similar to atypical adenomatous hyperplasia (AAH) or non-mucinous adenocarcinoma in situ (AIS). We reported MMPH in a 38-year-old Chinese man with TSC masquerading for 16 months as miliary tuberculosis and discussed the differential diagnosis.

Diagnosing lung carcinomas with optical coherence tomography.

RATIONALE: Lung carcinoma diagnosis on tissue biopsy can be challenging because of insufficient tumor and lack of architectural information. Optical coherence tomography (OCT) is a high-resolution imaging modality that visualizes tissue microarchitecture in volumes orders of magnitude larger than biopsy. It has been proposed that OCT could potentially replace tissue biopsy. OBJECTIVES: We aim to determine whether OCT could replace histology in diagnosing lung carcinomas. We develop and validate OCT interpretation criteria for common primary lung carcinomas: adenocarcinoma, squamous cell carcinoma (SCC), and poorly differentiated carcinoma. METHODS: A total of 82 ex vivo tumor samples were included in a blinded assessment with 3 independent readers. Readers were trained on the OCT criteria, and applied these criteria to diagnose adenocarcinoma, SCC, or poorly differentiated carcinoma in an OCT validation dataset. After a 7-month period, the readers repeated the training and validation dataset interpretation. An independent pathologist reviewed corresponding histology. MEASUREMENTS AND MAIN RESULTS: The average accuracy achieved by the readers was 82.6% (range, 73.7-94.7%). The sensitivity and specificity for adenocarcinoma were 80.3% (65.7-91.4%) and 88.6% (80.5-97.6%), respectively. The sensitivity and specificity for SCC were 83.3% (70.0-100.0%) and 87.0% (75.0-96.5%), respectively. The sensitivity and specificity for poorly differentiated carcinoma were 85.7% (81.0-95.2%) and 97.6% (92.9-100.0%), respectively. CONCLUSIONS: Although these results are encouraging, they indicate that OCT cannot replace histology in the diagnosis of lung carcinomas. However, OCT has potential to aid in diagnosing lung carcinomas as a complement to tissue biopsy, particularly when insufficient tissue is available for pathology assessment.

Interinstitutional whole slide imaging teleconsultation service development: assessment using internal training and clinical consultation cases.

CONTEXT: Assessment of accuracy and feasibility of whole slide imaging (WSI) for interinstitutional consultation in surgical pathology. OBJECTIVES: To train technical and pathologist staff in WSI technology, establish and evaluate a WSI workflow using training cases and second-opinion consultations, and assess diagnostic accuracy. DESIGN: First, WSI training and evaluation using selected subspecialty service cases were performed and compared with the clinical glass slide (GS) diagnosis. Second, WSI and GS diagnoses of consecutive, second-opinion consultation cases were compared. Discrepancies underwent adjudication to determine a reference diagnosis. Participant observations on WSI initiation to practice were gathered. RESULTS: There were 130 cases evaluated, with 123 correlations (94.6%) and 6 minor (4.6%) and 1 major (0.8%) discrepancies. The 74 consultation cases interpreted had 52 correlations (70.3%), and 18 minor (24.3%) and 4 major (5.4%) discrepancies. The WSI and GS adjusted major discrepancy rates in second-opinion consultations were 2.7% (2 of 74) and 4.1% (3 of 74), respectively. Statistical analysis showed that WSI was not inferior to GS interpretation. Pathologists agreed the software was easy to use and the images were adequate, but more time was spent rendering WSI interpretations. CONCLUSIONS: A significant learning curve was observed in the transition from the training set to clinical consultation cases associated both with WSI interpretation and adjustments to the digital analogs of routine GS workflow. Results from second-opinion consultations indicated that WSI interpretation was as accurate as GS interpretation among properly trained and experienced users. Overall, WSI-based practice appears feasible for second-opinion consultations.