Measuring the margin distance in pulmonary wedge resection.

BACKGROUND: Margin distance contributes to survival and recurrence during wedge resections for early-stage non-small cell lung cancer. The Initiative for Early Lung Cancer Research on Treatment sought to standardize a surgeon-measured margin intraoperatively. METHODS: Lung cancer patients who underwent wedge resection were reviewed. Margins were measured by the surgeon twice as per a standardized protocol. Intraobserver variability as well as surgeon-pathologist variability were compared. RESULTS: Forty-five patients underwent wedge resection. Same-surgeon measurement analysis indicated good reliability with a small mean difference and narrow limit of agreement for the two measures. The median surgeon-measured margin was 18.0 mm, median pathologist-measured margin was 16.0 mm and the median difference between the surgeon-pathologist margin was -1.0 mm, ranging from -18.0 to 12.0 mm. Bland-Altman analysis for margin measurements demonstrated a mean difference of 0.65 mm. The limit of agreement for the two approaches were wide, with the difference lying between -16.25 and 14.96 mm. CONCLUSIONS: A novel protocol of surgeon-measured margin was evaluated and compared with pathologist-measured margin. High intraobserver agreement for repeat surgeon measurements yet low-to-moderate correlation or directionality between surgeon and pathologic measurements were found. DISCUSSION: A standardized protocol may reduce variability in pathologic assessment. These findings have critical implications considering the impact of margin distance on outcomes.

Micropapillary adenocarcinoma of lung: Morphological criteria and diagnostic reproducibility among pulmonary pathologists.

CONTEXT: Invasive micropapillary adenocarcinoma (MPC) is an aggressive variant of lung adenocarcinoma, frequently manifesting with advanced stage lymph node metastasis and decreased survival. OBJECTIVE: Identification of this morphology is important, as it is strongly correlated with poor prognosis regardless of the amount of MPC component. To date, no study has investigated the morphological criteria used to objectively diagnose it. DESIGN: Herein, we selected 30 cases of potential MPC of lung, and distributed 2 digital images per case among 15 pulmonary pathology experts. Reviewers were requested to diagnostically interpret, assign the percentage of MPC component, and record the morphological features they identified. The noted features included: columnar cells, elongated slender cell nests, extensive stromal retraction, lumen formation with internal epithelial tufting, epithelial signet ring-like forms, intracytoplasmic vacuolization, multiple nests in the same alveolar space, back-to-back lacunar spaces, epithelial nest anastomosis, marked pleomorphism, peripherally oriented nuclei, randomly distributed nuclei, small/medium/large tumor nest size, fibrovascular cores, and spread through air-spaces (STAS). RESULTS: Cluster analysis revealed three subgroups with the following diagnoses: "MPC", "combined papillary and MPC", and "others". The subgroups correlated with the reported median percentage of MPC. Intracytoplasmic vacuolization, epithelial nest anastomosis/confluence, multiple nests in the same alveolar space, and small/medium tumor nest size were the most common criteria identified in the cases diagnosed as MPC. Peripherally oriented nuclei and epithelial signet ring-like forms were frequently identified in both the "MPC" and "combined papillary and MPC" groups. CONCLUSIONS: Our study provides objective diagnostic criteria to diagnose MPC of lung.

Tertiary lymphoid neogenesis is a component of pulmonary lymphoid hyperplasia in patients with common variable immunodeficiency.

BACKGROUND: Despite reducing pneumonia and other infections, antibody replacement does not appear to treat pulmonary lymphoid hyperplasia (PLH) in patients with common variable immunodeficiency (CVID). The pathogenesis and optimal treatments remain to be clarified. OBJECTIVE: We aimed to better understand the pathology of CVID-associated lung disease. Tertiary lymphoneogenesis, although a component of interstitial lung disease associated with autoimmune diseases, has not previously been explored in patients with CVID. METHODS: We examined the clinical characteristics and pathologic findings of 6 patients with CVID with nodular/infiltrative lung disease who had biopsy specimens demonstrating PLH. RESULTS: In these subjects regions of PLH contained distinct B- and T-cell zones, with B-cell predominance in 1 patient and T-cell predominance in the others. Colocalization of Ki67, Bcl6, and CD23 within this ectopic lymphoid architecture demonstrated tertiary lymphoneogenesis with active centers of cellular proliferation. One patient received rituximab with improved pulmonary radiologic findings. CONCLUSION: Ectopic lymphoid tissue forming germinal centers suggest tertiary lymphoneogenesis in CVID-associated lung disease. B cell-targeted therapy might disrupt CVID-associated lymphoid hyperplasia.

Wnt pathway activation predicts increased risk of tumor recurrence in patients with stage I nonsmall cell lung cancer.

OBJECTIVE: To determine the incidence of Wnt pathway activation in patients with stage I NSCLC and its influence on lung cancer recurrence. BACKGROUND: Despite resection, the 5-year recurrence with localized stage I nonsmall cell lung cancer (NSCLC) is 18.4%-24%. Aberrant Wnt signaling activation plays an important role in a wide variety of tumor types. However, there is not much known about the role the Wnt pathway plays in patients with stage I lung cancer. METHODS: Tumor and normal lung tissues from 55 patients following resection for stage I NSCLC were subjected to glutathione S-transferase (GST) E-cadherin pulldown and immunoblot analysis to assess levels of uncomplexed ß-catenin, a reliable measure of Wnt signaling activation. The ß-catenin gene was also screened for oncogenic mutations in tumors with activated Wnt signaling. Cancer recurrence rates were correlated in a blinded manner in patients with Wnt pathway-positive and -negative tumors. RESULTS: Tumors in 20 patients (36.4%) scored as Wnt positive, with only 1 exhibiting a ß-catenin oncogenic mutation. Patients with Wnt-positive tumors experienced a significantly higher rate of overall cancer recurrence than those with Wnt-negative tumors (30.0% vs. 5.7%, P = 0.02), with 25.0% exhibiting distal tumor recurrence compared with 2.9% in the Wnt-negative group (P = 0.02). CONCLUSIONS: Wnt pathway activation occurred in a substantial fraction of Stage I NSCLCs, which was rarely due to mutations. Moreover, Wnt pathway activation was associated with a significantly higher rate of tumor recurrence. These findings suggest that Wnt pathway activation reflects a more aggressive tumor phenotype and identifies patients who may benefit from more aggressive therapy in addition to resection.

Thymomas diagnosed during pregnancy: two cases in young women without paraneoplastic or autoimmune disease.

We report 2 cases of thymomas diagnosed during pregnancy. Neither of these 2 patients had paraneoplastic autoimmune conditions or previous neoplasia. The first patient had a 7.3-cm lymphocyte-predominant thymoma with capsular invasion. The second patient was diagnosed through fine needle aspiration biopsy after computed tomography showed multiple mediastinal masses. Although cases of thymoma during pregnancy have been reported, the exact cause has yet to be elucidated. We review the clinical, radiologic, pathologic, and immunohistochemical findings-including those of podoplanin, estrogen receptor, and progesterone receptor-of 2 previously unreported cases, as well as discuss the relationship of malignancy and pregnancy and review the available literature regarding pregnancy and thymoma.

Pneumonectomy for Idiopathic Fibrosing Mediastinitis Mimicking Neoplasm in a Child.

The unique case of a child with idiopathic fibrosing mediastinitis mimicking neoplasm is presented. A 5-year-old boy presented with pneumonia and was found to have a complex, heterogeneous, and calcified mediastinal mass along the left hilum. Percutaneous and surgical biopsies, while suggesting a potential epithelial malignancy, were nonconclusive. Owing to worsening symptoms of airway obstruction and chest wall invasion, resection was performed for therapeutic and diagnostic purposes. This ultimately required pneumonectomy on cardiopulmonary bypass. Pathology revealed fibrosing mediastinitis with infiltration of lung parenchyma, and subsequent workup for infectious, neoplastic, granulomatous, and autoimmune etiologies was negative.

Diagnosis of Hypersensitivity Pneumonitis: Review and Summary of American College of Chest Physicians Statement.

Assessment of lung biopsies for the diagnosis of hypersensitivity pneumonitis (HP) is one of the most difficult diagnostic problems for surgical pathologists. It is a form of interstitial lung disease resulting from an immune reaction provoked by an inhaled antigen in susceptible individuals. Although this definition sounds simple, in practice, the diagnosis of HP can be challenging. To address these issues, the American College of Chest Physicians (CHEST) has recently published a guideline for the diagnosis of HP. In this review, we will explore the multidisciplinary diagnostic evaluation of HP with a focus on the pathologic features as outlined in the CHEST guidelines. The histologic criteria are divided into 4 diagnostic categories: (1) Typical nonfibrotic HP or fibrotic HP; (2) Compatible with nonfibrotic HP or fibrotic HP; (3) Indeterminate for nonfibrotic or fibrotic HP; and (4) Alternative Diagnosis. It is important to emphasize that patterns 1 to 3 do not represent discrete histologic entities or pathologic diagnoses. Rather, these categories are meant to serve as a practical guide for organizing a complex set of overlapping histologic patterns into an integrated diagnostic framework for facilitating multidisciplinary discussion. High-resolution computed tomography features are also summarized, emphasizing how the correlation of lung biopsies with computed tomography findings can help to favor the diagnosis, particularly in cases where biopsies are not typical for HP. This review highlights details of the histologic spectrum of HP as well as the utility of different types of biopsies and bronchoalveolar lavage. We also emphasize the importance of multidisciplinary discussion and the complex differential diagnosis.

A 51-Year-Old Woman With Interstitial Lung Disease and Subsequent COVID-19 Presenting With Worsening Dyspnea.

CASE PRESENTATION: A 51-year-old Puerto Rican woman, with a known but inconclusive diagnosis of interstitial lung disease (ILD) since 2002 and recent moderate COVID-19, is now presenting with subacute worsening dyspnea on exertion. The patient had sporadic medical care over the years for her ILD (Table 1). Prior workup included chest CT imaging with a "crazy-paving" pattern of lung disease, as defined by ground-glass opacity with superimposed interlobular septal thickening and visible intralobular lines. Bronchoscopy showed normal airway examination, and BAL revealed clear fluid with foamy macrophages and negative cultures. Video-assisted thoracoscopic surgery and transbronchial biopsy specimens both showed foamy macrophages. Results of pulmonary function testing (PFT) revealed an isolated gas transfer defect on diffusing capacity of the lungs for carbon monoxide (Dlco). She had lived with mild yet nonprogressive functional impairment and stable exercise intolerance over these years. She was then hospitalized for COVID-19 in August 2020 and for recurrent shortness of breath in September 2020. She now presented 4 months following her September 2020 hospitalization.

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.

Human Papillomavirus (HPV69/HPV73) Coinfection associated with Simultaneous Squamous Cell Carcinoma of the Anus and Presumed Lung Metastasis.

BACKGROUND: Human papillomaviruses (HPVs) have been linked to a variety of human cancers. As the landscape of HPV-related neoplasia continues to expand, uncommon and rare HPV genotypes have also started to emerge. Host-virus interplay is recognized as a key driver in HPV carcinogenesis, with host immune status, virus genetic variants and coinfection highly influencing the dynamics of malignant transformation. Immunosuppression and tissue tropism are also known to influence HPV pathogenesis. METHODS: Herein, we present a case of a patient who, in the setting of HIV positivity, developed anal squamous cell carcinoma associated with HPV69 and later developed squamous cell carcinoma in the lungs, clinically presumed to be metastatic disease, associated with HPV73. Consensus PCR screening for HPV was performed by real-time PCR amplification of the L1 gene region, amplification of the E6 regions with High-Resolution Melting Curve Analysis followed by Sanger sequencing confirmation and phylogenetic analysis. RESULTS: Sanger sequencing of the consensus PCR amplification product determined that the anal tissue sample was positive for HPV 69, and the lung tissue sample was positive for HPV 73. CONCLUSIONS: This case underscores the importance of recognizing the emerging role of these rare "possibly carcinogenic" HPV types in human carcinogenesis.

E-Cigarette or Vaping Product Use-Associated Lung Injury: A Review for Pathologists.

CONTEXT.­: Vaping is the inhalation of heated aerosol from a small battery-powered device as a method to deliver nicotine or other substances. A recent outbreak of severe respiratory illness primarily in the United States has put a spotlight on vaping and its potential risks. OBJECTIVE.­: To familiarize pathologists with vaping, the cytologic and histopathologic features of vaping-associated acute lung injury, and the role of pathology in this diagnosis. DATA SOURCES.­: A targeted literature review was performed. CONCLUSIONS.­: Most cases of vaping-associated lung injury have been linked to vaping products containing tetrahydrocannabinol or other cannabinoids. Lung biopsies show a spectrum of nonspecific acute lung injury patterns (organizing pneumonia, diffuse alveolar damage, acute fibrinous, and organizing pneumonia, or combinations of the above), accompanied by prominent, foamy macrophage accumulation. Injury is usually accentuated around small airways. Lipid-laden macrophages can be identified in bronchioloalveolar lavage fluid in most patients and these can be highlighted using lipid stains, such as oil red O, but the clinical utility of this finding remains unclear, as lipid-laden macrophages can be seen in a wide variety of processes and should not be relied upon to make the diagnosis. Classic histologic features of exogenous lipoid pneumonia have not been identified in tissue samples. Lightly pigmented macrophages, similar to those seen with traditional cigarette smoking, are present in some cases but are usually a minor feature. To date, no specific pathologic features for vaping-related injury have been identified, and it remains a diagnosis of exclusion that requires clinicopathologic correlation.

Interstitial lung abnormalities detected incidentally on CT: a Position Paper from the Fleischner Society.

The term interstitial lung abnormalities refers to specific CT findings that are potentially compatible with interstitial lung disease in patients without clinical suspicion of the disease. Interstitial lung abnormalities are increasingly recognised as a common feature on CT of the lung in older individuals, occurring in 4-9% of smokers and 2-7% of non-smokers. Identification of interstitial lung abnormalities will increase with implementation of lung cancer screening, along with increased use of CT for other diagnostic purposes. These abnormalities are associated with radiological progression, increased mortality, and the risk of complications from medical interventions, such as chemotherapy and surgery. Management requires distinguishing interstitial lung abnormalities that represent clinically significant interstitial lung disease from those that are subclinical. In particular, it is important to identify the subpleural fibrotic subtype, which is more likely to progress and to be associated with mortality. This multidisciplinary Position Paper by the Fleischner Society addresses important issues regarding interstitial lung abnormalities, including standardisation of the definition and terminology; predisposing risk factors; clinical outcomes; options for initial evaluation, monitoring, and management; the role of quantitative evaluation; and future research needs.

Concomitant Interstitial Lung Disease with Psoriasis.

Background: We encounter interstitial lung disease (ILD) patients with psoriasis. The aim of this case series was to examine clinical and radiographic characteristics of patients with concomitant psoriasis and ILD. Methods: This is a retrospective review of our institutional experience of ILD concomitant with psoriasis, from the database in the Advanced Lung/Interstitial Lung Disease Program at the Mount Sinai Hospital. Out of 447 ILD patients, we identified 21 (4.7%) with antecedent or concomitant diagnosis of psoriasis. Clinical, radiographic, pathological, and outcome data were abstracted from our medical records. Results: Median age was 66 years (range, 46-86) and 14 (66.7%) were male. Thirteen (61.9%) had not previously or concomitantly been exposed to immunosuppressive therapy directed against psoriasis. Two (9.5%) ultimately died. Clinical diagnosis of ILD included idiopathic pulmonary fibrosis, 11 (52.4%); nonspecific interstitial pneumonia (NSIP), 2 (9.5%); cryptogenic organizing pneumonia, 2 (9.5%); chronic hypersensitivity pneumonitis, 2 (9.5%); and the others, while radiographic diagnosis included usual interstitial pneumonia pattern, 9 (42.9%); NSIP pattern, 6 (28.6%); organizing pneumonia pattern, 4 (19.0%); hypersensitivity pneumonitis pattern, 2 (9.5%); and the others. Conclusions: We report 21 ILD cases with antecedent or concomitant diagnosis of psoriasis. Further prospective studies are required to determine the association between ILD and psoriasis.

Updating the role of FDG PET/CT for evaluation of lung cancer manifesting in nonsolid nodules.

PURPOSE: To assess the feasibility of using CT to correct specific uptake values (SUVs) for fluorodeoxyglucose (FDG) in patients with nonsolid nodules. METHODS: Patients with FDG-PET/CT and thin-section CT were included in this pilot study. Thirty-five adenocarcinomas manifesting as nonsolid nodules were classified into two groups; 90-100% and 1-89% lepidic component. SUVmax was corrected based on the CT determination of the proportion of soft tissue component within the cancer (SUVatt). RESULTS: Both SUVmax and SUVatt increased as the percentage of the lepidic component decreased. SUVmax and SUVatt were significantly different between the groups. CONCLUSION: Extent of invasiveness of nonsolid cancers (as a marker of aggressiveness) can potentially be quantified by PET/CT using a correction method that accounts for the proportion of soft tissue within the tumor.

Integrin alpha 11 in the regulation of the myofibroblast phenotype: implications for fibrotic diseases.

Tissue fibrosis, characterized by excessive accumulation of aberrant extracellular matrix (ECM) produced by myofibroblasts, is a growing cause of mortality worldwide. Understanding the factors that induce myofibroblastic differentiation is paramount to prevent or reverse the fibrogenic process. Integrin-mediated interaction between the ECM and cytoskeleton promotes myofibroblast differentiation. In the present study, we explored the significance of integrin alpha 11 (ITGA11), the integrin alpha subunit that selectively binds to type I collagen during tissue fibrosis in the liver, lungs and kidneys. We showed that ITGA11 was co-localized with α-smooth muscle actin-positive myofibroblasts and was correlatively induced with increasing fibrogenesis in mouse models and human fibrotic organs. Furthermore, transcriptome and protein expression analysis revealed that ITGA11 knockdown in hepatic stellate cells (liver-specific myofibroblasts) markedly reduced transforming growth factor ß-induced differentiation and fibrotic parameters. Moreover, ITGA11 knockdown dramatically altered the myofibroblast phenotype, as indicated by the loss of protrusions, attenuated adhesion and migration, and impaired contractility of collagen I matrices. Furthermore, we demonstrated that ITGA11 was regulated by the hedgehog signaling pathway, and inhibition of the hedgehog pathway reduced ITGA11 expression and fibrotic parameters in human hepatic stellate cells in vitro, in liver fibrosis mouse model in vivo and in human liver slices ex vivo. Therefore, we speculated that ITGA11 might be involved in fibrogenic signaling and might act downstream of the hedgehog signaling pathway. These findings highlight the significance of the ITGA11 receptor as a highly promising therapeutic target in organ fibrosis.

Diagnosis of Acute Cellular Rejection and Antibody-Mediated Rejection on Lung Transplant Biopsies: A Perspective From Members of the Pulmonary Pathology Society.

CONTEXT: - The diagnosis and grading of acute cellular and antibody-mediated rejection (AMR) in lung allograft biopsies is important because rejection can lead to acute graft dysfunction and/or failure and may contribute to chronic graft failure. While acute cellular rejection is well defined histologically, no reproducible specific features of AMR are currently identified. Therefore, a combination of clinical features, serology, histopathology, and immunologic findings is suggested for the diagnosis of AMR. OBJECTIVE: - To describe the perspective of members of the Pulmonary Pathology Society (PPS) on the workup of lung allograft transbronchial biopsy and the diagnosis of acute cellular rejection and AMR in lung transplant. DATA SOURCES: - Reports by the International Society for Heart and Lung Transplantation (ISHLT), experience of members of PPS who routinely review lung allograft biopsies, and search of literature database (PubMed). CONCLUSIONS: - Acute cellular rejection should be assessed and graded according to the 2007 working formulation of the ISHLT. As currently no specific features are known for AMR in lung allografts, the triple test (clinical allograft dysfunction, donor-specific antibodies, pathologic findings) should be used for its diagnosis. C4d staining might be performed when morphologic, clinical, and/or serologic features suggestive of AMR are identified.

Lung Disease in Primary Antibody Deficiencies.

Primary antibody deficiencies (PADs) are the most common form of primary immunodeficiency and predispose to severe and recurrent pulmonary infections, which can result in chronic lung disease including bronchiectasis. Chronic lung disease is among the most common complications of PAD and a significant source of morbidity and mortality for these patients. However, the development of lung disease in PAD may not be solely the result of recurrent bacterial infection or a consequence of bronchiectasis. Recent characterization of monogenic immune dysregulation disorders and more extensive study of common variable immunodeficiency have demonstrated that interstitial lung disease (ILD) in PAD can result from generalized immune dysregulation and frequently occurs in the absence of pneumonia history or bronchiectasis. This distinction between bronchiectasis and ILD has important consequences in the evaluation and management of lung disease in PAD. For example, treatment of ILD in PAD typically uses immunomodulatory approaches in addition to immunoglobulin replacement and antibiotic prophylaxis, which are the stalwarts of bronchiectasis management in these patients. Although all antibody-deficient patients are at risk of developing bronchiectasis, ILD occurs in some forms of PAD much more commonly than in others, suggesting that distinct but poorly understood immunological factors underlie the development of this complication. Importantly, ILD can have earlier onset and may worsen survival more than bronchiectasis. Further efforts to understand the pathogenesis of lung disease in PAD will provide vital information for the most effective methods of diagnosis, surveillance, and treatment of these patients.

Subsolid pulmonary nodules: CT-pathologic correlation using the 2011 IASLC/ATS/ERS classification.

Adenocarcinoma is the most common histologic subtype of lung cancer. Recent advances in oncology, molecular biology, pathology, imaging, and treatment have led to an increased understanding of this disease. In 2011, the International Association for the Study of Lung Cancer, the American Thoracic Society, and the European Respiratory Society published a new international multidisciplinary classification. Using this taxonomy, we review the spectrum of subsolid pulmonary nodules seen on computed tomography together with their histopathologic correlates and current management guidelines.