Pulmonary effects of synthetic marijuana: chest radiography and CT findings.

OBJECTIVE: The purpose of this article is to present the first chest radiographic and CT descriptions of organizing pneumonia in response to smoking synthetic marijuana. CONCLUSION: Chest radiographs showed a diffuse miliary-micronodular pattern. Chest CT images showed diffuse centrilobular nodules and tree-in-bud pattern and a histopathologic pattern of organizing pneumonia with or without patchy acute alveolar damage. This distinct imaging pattern should alert radiologists to include synthetic marijuana abuse in the differential diagnosis.

Lung cancer staging: pathology issues.

The previous, 6th, American Joint Committee on Cancer and International Union Against Cancer Staging Manual classification of lung cancer was largely unchanged from 5th edition. However, the most recent, 7th, edition has significantly updated the tumor, node, metastasis classification of lung cancer with regards to the inclusion of additional size criteria for T stages and revision of the staging for multiple tumor nodules, and represents the most dramatic change in 30 years. The recommendations for this most recent edition of tumor, node, metastasis classification are derived from a systematic retrospective review of data from a multi-international/institutional database of lung cancers and also incorporate expert opinion, to revise and clarify various staging factors. This review will primarily focus on the pathologically relevant aspects of 7th edition of American Joint Committee on Cancer/International Union Against Cancer classification of lung cancer as well as briefly reviewing the new staging guidelines.

Pathology and pathogenesis of fatal Bordetella pertussis infection in infants.

BACKGROUND: Each year, Bordetella pertussis infection causes an estimated 294,000 deaths worldwide, primarily among young, nonvaccinated children. Approximately 90% of all deaths due to pertussis in the Unites States occur in young infants. These children often develop intractable pulmonary hypertension; however, the pathophysiologic mechanism responsible for this complication has not been well characterized, and there have been no detailed descriptions of the pathology of this disease since the 1940s. METHODS: Respiratory tissue samples obtained at autopsy from 15 infants aged

Prognostic factors for hospital mortality and ICU admission in patients with ANCA-related pulmonary vasculitis.

BACKGROUND: The objective of this study was to evaluate the factors predictive of 28-day mortality and admission to Intensive Care Unit (ICU) in patients with ANCA-related pulmonary vasculitis. METHODS: We reviewed the medical records and imaging studies of 65 patients diagnosed with ANCA-related vasculitis hospitalized with pulmonary complications between February 1985 and November 2002. All patients underwent open or video-assisted thoracoscopic lung biopsy, had a positive ANCA serology, and were negative for glomerular basement membrane antibodies. RESULTS: At presentation, 72% had dyspnea, 68% fever, 47% cough, 45% elevated blood pressure, 32.3% hemoptysis, 26.1% sinus involvement, 15% renal failure, and 4.6% scleritis. Pathological findings included alveolar hemorrhage (60%), granulomatous inflammation (46%), and capillaritis (38%). A significant number required mechanical ventilation (27.7%), hemodialysis (24.6%), continuous renal replacement therapy (3.1%), and plasmapheresis (3.1%). The 28-day mortality was 16.9% (11/65). Mechanical ventilation (OR 68, P < 0.005), admission to ICU (OR 18.5, P < 0.01), and blood transfusion (OR 22.4, P < 0.004) were strong predictors of increased mortality within 28 days after admission. Respiratory failure (OR 31, P < 0.0007), hemoptysis (OR 2.9, P < 0.06), smoking (OR 5.9, P < 0.02), and acute renal failure (OR 7.8, P < 0.01) were also predictors for admission to the ICU. CONCLUSION: In patients with ANCA-related pulmonary vasculitis several clinical factors, but not pathologic findings or ANCA titers, are associated with ICU admission and/or 28-day mortality.

LKB1 mutation in large cell carcinoma of the lung.

Germline inactivation of LKB1 is responsible for Peutz-Jeghers syndrome, an autosomal dominant disorder characterized by benign hamartomas of the GI tract and an increased predisposition to certain cancers, including lung. Acquired mutations in LKB1 are rarely observed in most sporadic tumor types except for adenocarcinomas of the lung where up to 50% harbor inactivating mutations. In this study, we focused on LKB1 mutations in lung cancer cell lines originating from large cell carcinomas. We identified a novel 1.5kb interstitial deletion within LKB1 gene in H157 cancer cells. Homozygosity mapping-of-deletion analysis (HOMOD) analysis showed that the deletion is accompanied by LOH of one parental allele, indicating biallelic inactivation of LKB1. This deletion results in an LKB1 transcript lacking exons 2 and 3 and a predicted in-frame deletion of 58 amino acids within the kinase domain of the LKB1 protein. The truncated transcript was expressed at relatively low levels, and the truncated LKB1 protein was virtually undetectable in this cell line. To determine the impact of LKB1 protein truncation on its function, we examined AMPK-alpha, a downstream target of LKB1 kinase activity triggered by low energy stress conditions. Phosphorylation of AMPK-alpha was attenuated in H157 cells treated with 2-deoxyglucose, and could be rescued by expression of an exogenous GFP-LKB1 fusion protein. Therefore, our data suggest that LKB1 function is compromised in H157. Of the four cell lines and six primary tumors of large cell lung carcinoma origin that have been evaluated in this and other studies, LKB1 mutations have been found in three cases. These results suggest that, in addition to adenocarcinomas, acquired loss of function mutations in LKB1 may also be frequently involved in the pathogenesis of large cell lung carcinomas.

Lung Adenocarcinoma Staging Using the 2011 IASLC/ATS/ERS Classification: A Pooled Analysis of Adenocarcinoma In Situ and Minimally Invasive Adenocarcinoma.

BACKGROUND: Lung adenocarcinoma accounts for almost 60% of non-small-cell lung cancer. According to the 2011 International Association for the Study of Lung Cancer (IASLC), American Thoracic Society (ATS), and European Respiratory Society (ERS) classification and 2015 World Health Organization classification of tumors of the lung, lepidic-predominant adenocarcinomas ≤ 3 cm in size can be classified as adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA), and invasive adenocarcinoma, lepidic predominant. AIS lesions, which are noninvasive, and MIA lesions, which show ≤ 0.5 cm of invasion, have been recommended to be considered stage pTis (adenocarcinoma) and pT1(mi), respectively. We conducted a systematic analysis of the published data to evaluate the prognostic differences between AIS and MIA. MATERIALS AND METHODS: A comprehensive search of published studies was conducted from the electronic databases using relevant search criteria. Studies that reported outcomes for ≥ 8 cases classified as AIS or MIA using the 2011 IASLC/ATS/ERS criteria were selected for the present analysis. A systematic analysis of the extracted data were performed using Comprehensive Meta-Analysis software, version 2.2. RESULTS: Nineteen studies published from 2011 to 2015 were eligible. A total of 972 patients were included (429 with AIS and 294 with MIA; 2 studies reported AIS and MIA together, n = 249). The median age was 65.5 years, 63% were female, and 40% were smokers. The 5-year disease-free survival rate for the whole population was 97.9%. The 5-year disease-free survival rate was 100% for AIS and MIA pooled from the studies that reported the 2 groups separately. The 5-year overall survival rate for the entire group was 97.5%, and the 5-year overall survival rate was 100% for AIS and 98.5% for MIA. CONCLUSION: No significant differences were found in the survival rates between patients with lung adenocarcinoma categorized as MIA or AIS. This finding raises questions regarding the evidence for TNM staging of AIS and MIA as recommended by the 2011 IASLC/ATS/ERS and 2015 World Health Organization classification of tumors of the lung and should be reevaluated with further studies.

Clinical Validation and Implementation of a Targeted Next-Generation Sequencing Assay to Detect Somatic Variants in Non-Small Cell Lung, Melanoma, and Gastrointestinal Malignancies.

We tested and clinically validated a targeted next-generation sequencing (NGS) mutation panel using 80 formalin-fixed, paraffin-embedded (FFPE) tumor samples. Forty non-small cell lung carcinoma (NSCLC), 30 melanoma, and 30 gastrointestinal (12 colonic, 10 gastric, and 8 pancreatic adenocarcinoma) FFPE samples were selected from laboratory archives. After appropriate specimen and nucleic acid quality control, 80 NGS libraries were prepared using the Illumina TruSight tumor (TST) kit and sequenced on the Illumina MiSeq. Sequence alignment, variant calling, and sequencing quality control were performed using vendor software and laboratory-developed analysis workflows. TST generated ≥500× coverage for 98.4% of the 13,952 targeted bases. Reproducible and accurate variant calling was achieved at ≥5% variant allele frequency with 8 to 12 multiplexed samples per MiSeq flow cell. TST detected 112 variants overall, and confirmed all known single-nucleotide variants (n = 27), deletions (n = 5), insertions (n = 3), and multinucleotide variants (n = 3). TST detected at least one variant in 85.0% (68/80), and two or more variants in 36.2% (29/80), of samples. TP53 was the most frequently mutated gene in NSCLC (13 variants; 13/32 samples), gastrointestinal malignancies (15 variants; 13/25 samples), and overall (30 variants; 28/80 samples). BRAF mutations were most common in melanoma (nine variants; 9/23 samples). Clinically relevant NGS data can be obtained from routine clinical FFPE solid tumor specimens using TST, benchtop instruments, and vendor-supplied bioinformatics pipelines.

Current concepts in the classification of interstitial lung disease.

The diagnosis and classification of idiopathic interstitial pneumonias continue to be problematic areas for pathologists. The recently proposed American Thoracic Society/European Respiratory Society International Multidisciplinary Consensus Classification of the Idiopathic Interstitial Pneumonias defines specific clinical, radiologic, and pathologic criteria for each of the pulmonary disorders that encompass the idiopathic interstitial pneumonias. In this review, the highlights of this classification are presented, along with recommended guidelines for handling lung biopsy specimens and diagnosing interstitial lung diseases.

Epstein-Barr Virus-Associated Pulmonary Smooth Muscle Tumor After Lung Transplantation.

We report an Epstein-Barr virus (EBV)-associated pulmonary posttransplant smooth muscle tumor arising in the left lung of a 71-year-old bilateral lung transplant recipient nearly 3 years after transplantation, treated with thoracoscopic wedge resection. Four previous smooth muscle tumors have been reported following lung transplantation. To our knowledge, this is the first reported case of an EBV-positive posttransplant smooth muscle tumor within the transplanted lung. We describe the clinical, pathologic, and histologic diagnosis of this uncommon tumor.

A Translational, Pharmacodynamic, and Pharmacokinetic Phase IB Clinical Study of Everolimus in Resectable Non-Small Cell Lung Cancer.

PURPOSE: The altered PI3K/mTOR pathway is implicated in lung cancer, but mTOR inhibitors have failed to demonstrate efficacy in advanced lung cancer. We studied the pharmacodynamic effects of everolimus in resectable non-small cell lung cancer (NSCLC) to inform further development of these agents in lung cancer. EXPERIMENTAL DESIGN: We enrolled 33 patients and obtained baseline tumor biopsy and 2[18F]fluoro-2-deoxy-D-glucose-positron emission tomography/computed tomography (FDG-PET/CT) imaging followed by everolimus treatment (5 or 10 mg daily, up to 28 days), or without intervening treatment for controls. Target modulation by everolimus was quantified in vivo and ex vivo by comparing metabolic activity on paired PET scans and expression of active phosphorylated forms of mTOR, Akt, S6, eIF4e, p70S6K, 4EBP1, and total Bim protein between pretreatment and posttreatment tissue samples. RESULTS: There were 23 patients on the treatment arm and 10 controls; median age 64 years; 22 tumors (67%) were adenocarcinomas. There was a dose-dependent reduction in metabolic activity (SUVmax: 29.0%, -21%, -24%; P = 0.014), tumor size (10.1%, 5.8%, -11.6%; P = 0.047), and modulation of S6 (-36.1, -13.7, -77.0; P = 0.071) and pS6 (-41.25, -61.57, -47.21; P = 0.063) in patients treated in the control, 5-mg, and 10-mg cohorts, respectively. Targeted DNA sequencing in all patients along with exome and whole transcriptome RNA-seq in an index patient with hypersensitive tumor was employed to further elucidate the mechanism of everolimus activity. CONCLUSIONS: This "window-of-opportunity" study demonstrated measurable, dose-dependent, biologic, metabolic, and antitumor activity of everolimus in early-stage NSCLC.

Asthma as a consequence of bone marrow transplantation.

Atopy, allergy, or asthma rarely can complicate organ transplantation. We identified two patients who developed asthma following bone marrow transplantation. Neither patient had a documented history of allergy, atopy, or asthma, but their donors were human leukocyte antigen-identical siblings who had a history of asthma. Pulmonary function testing revealed decreased airflow. Investigation of the bronchial biopsy specimens revealed eosinophilia and histologic features that were compatible with asthma. No infectious pathogens were identified. Both patients received therapy with bronchodilators and inhaled corticosteroids with symptomatic improvement. A diagnosis of asthma should be entertained in the differential diagnosis of pulmonary complications in bone marrow transplant recipients.

Thoracic presentations of posttransplant lymphoproliferative disorders.

BACKGROUND: Posttransplant lymphoproliferative disorders (PTLDs) are rare complications following transplantation. Although organ-specific cases have been reported, primary presentation in the thoracic cavity has not been fully characterized. METHODS: Eleven cases of PTLD with a primary thoracic presentation were identified among 3,085 solid-organ transplant patients and 1,662 bone marrow transplant patients from 1990 to 2001. RESULTS: There were eight men and three women with a mean age of 49 years. Transplanted organs included lungs (three patients), kidneys (three patients), kidney/pancreas (two patients), allogeneic bone marrow (two patients), and heart (one patient). The time to presentation ranged from 1 to 97 months (median time, 8 months). Six patients developed PTLD within 1 year of undergoing transplantation. Pretransplant serology for Epstein-Barr virus (EBV) and cytomegalovirus was negative in 80% and 78% of cases, respectively. Radiographic evaluation revealed mediastinal adenopathy in 45% of patients, and pulmonary parenchymal lesions in 55%. Fifty-five percent of patients also had extrathoracic involvement. Diagnosis was achieved by CT-guided transthoracic needle biopsy in eight patients, and by open biopsy in three patients. Pathologic analysis revealed monomorphic PTLD (ie, diffuse large B-cell lymphoma) in seven patients, polymorphic PTLD in two patients, anaplastic large cell lymphoma in one patient, and Hodgkin lymphoma in one patient. Eighty-four percent of the specimens evaluated for EBV were determined to be positive by in situ hybridization and/or immunohistochemistry. All patients were initially treated with a reduction in immunosuppression therapy, and six patients (55%) received adjuvant chemotherapy. The overall mortality rate was 64%. Four patients died from complications of PTLD (kidney, two patients; heart, one patient; bone marrow, one patient), and three patients (all lung transplant recipients) died from rejection or infectious complications. The median interval from diagnosis to death was 13 months (range, 1 to 42 months). CONCLUSIONS: Thoracic PTLD can occur in any transplant patient and must be regarded as a potentially fatal complication in the immunosuppressed patient. Heart and lung allograft recipients have the worst prognosis because of the mortality that accompanies rejection with subtherapeutic immunosuppression therapy. Earlier diagnosis and improvements in immunosuppression and chemotherapy may improve survival for these inherently high-risk patients.

Saprophytic fungal infections and complications involving the bronchial anastomosis following human lung transplantation.

STUDY OBJECTIVE: To demonstrate an association between saprophytic fungal infections occurring at the bronchial anastomosis (BA) and the development of additional complications arising at this site. DESIGN: Retrospective review. SETTING: University lung transplant center. MATERIALS AND METHODS: Review of all single-lung and double-lung transplant (LTX) recipients who underwent transplantation between June 1993 and December 2000. All recipients were subjected to surveillance bronchoscopy with biopsy at predetermined intervals and when clinically indicated. Bronchial wash fluid and biopsy material were examined using appropriate fungal stains and culture techniques. An infection was defined when fungal organisms were identified in tissue specimens. RESULTS: Fifteen saprophytic fungal infections involving the BA were identified in 61 LTX recipients (24.6%) who survived a minimum of 75 days post-transplantation. Infections were attributed to Aspergillus sp (n = 9), Candida sp (n = 2), Torulopsis sp (n = 1), and mixed flora (ie, Penicillium + Candida, two patients; and Aspergillus + Candida, one patient). Saprophytic fungal infections occurred by a median of postoperative day 35 (range, 13 to 159 days). Airway complications involving the BA ultimately developed in 11 of 61 recipients (18%). These complications included symptomatic bronchial stenosis (nine patients), bronchomalacia (one patient), and fatal hemorrhage (one patient). Bronchial complications arose in 7 of 15 recipients (46.7%) with saprophytic fungal infections of the BA in contrast to 4 of 46 (8.7%) without infections (p = 0.003, Fisher exact test). Also demonstrated was a positive correlation between anastomotic infections and bronchial complications (Phi coefficient = 0.43; p = 0.001), while logistic regression analysis revealed that the absence of anastomotic infections predicted the absence of such complications (p = 0.002). The risk of developing an additional complication following an anastomotic infection in patients with infections was five times that of those recipients without an infection (relative risk, 5.36; 95% confidence interval [CI], 1.82 to 15.79). The odds in favor of a bronchial complication following an infection were eight times greater than in those recipients without infection (odds ratio, 8.31; 95% CI, 1.96 to 35.16). CONCLUSIONS: Following LTX, saprophytic fungal infections of the BA are associated with serious airway complications.

Cytopathology of pulmonary alveolar proteinosis complicating lung transplantation.

Pulmonary alveolar proteinosis is a disorder of unknown origin that occurs rarely after lung transplantation. We identified a patient with pulmonary alveolar proteinosis 66 days after undergoing single lung transplantation for idiopathic pulmonary fibrosis. We based the diagnosis on the presence of amorphous clumps or globules of acellular and finely granular material in bronchoalveolar lavage fluid (BALF). This material persisted for an 18.5-month period and was present in 9 of 14 lavage specimens. However, despite its presence in the native lung at autopsy, the material was seen in only 1 of 14 transbronchial lung biopsy specimens. Although uncommon, pulmonary alveolar proteinosis can be diagnosed readily in BALF by its distinctive cytopathologic features and should be considered in the differential diagnosis of pulmonary disease in lung transplant recipients.

The morphologic spectrum of metastatic prostatic adenocarcinoma to the lung: special emphasis on histologic features overlapping with other pulmonary neoplasms.

We undertook a detailed histologic study to identify specific morphologic features that may aid in distinguishing prostatic adenocarcinoma with lung metastases (PALM) from other pulmonary tumors with similar histologic features. In 16 cases, we found 3 predominant architectural patterns: microacinar (n = 10), tubulopapillary (ductal; n = 4), and carcinoid-like (n = 2). Characteristic features of PALM included small acinar and/or cribriform growth, frequent lymphangitic permeation, lack of stromal response, uniform round nuclei with prominent nucleoli, intraluminal blue mucin, and prominent cell borders. By immunohistochemical staining, prostate-specific antigen and prostate-specific acid phosphatase were present in 13 of 14 and 13 of 13 cases, respectively. Metastatic prostatic duct adenocarcinoma exhibited morphologic features similar to metastatic colonic adenocarcinoma. Two cases had a carcinoid-like appearance with nested or solid architecture, parachromatin clearing, and prominent nucleoli, but lacked the finely stippled chromatin pattern of carcinoid tumors. Several features that may result in misinterpretation or lack of association of the neoplasm in the lung with a prostatic primary include lung metastasis preceding the detection of a prostatic primary tumor, solitary pulmonary nodule, tubulopapillary (ductal) or carcinoid-like pattern, scant material in which histologic features of metastatic prostate carcinoma are not fully appreciated, and frequent necrosis. Attention to specific discriminating histologic features, supported by immunohistochemical staining, may be useful in the differential diagnosis, which is therapeutically and prognostically critical.

Extraskeletal osteosarcoma of the diaphragm presenting as a chest mass.

Extraskeletal osteosarcoma is a rare malignancy that has not been previously reported to arise from the diaphragm. We describe the case of a 47-year-old woman who had a large thoracic mass found at operation to be an extraskeletal osteosarcoma arising from the diaphragm. The tumor was completely resected en bloc with a margin of surrounding diaphragm, which necessitated a diaphragmatic reconstruction. The literature concerning this rare tumor is reviewed.

Galanin immunoreactivity in paragangliomas but not in carcinoid tumors.

Galanin is a 29 to 30-amino acid neuropeptide involved in diverse regulatory effects in the central and peripheral nervous systems. Although galanin has been found in paragangliomas and other tumors, its expression has not been studied in carcinoid tumors arising in various locations. Galanin was detected in 62% (15/24) of adrenal pheochromocytomas, 40% (2/5) of jugulotympanic paragangliomas, and 18% (2/11) of carotid body paragangliomas, but was absent in 4 extra-adrenal pheochromocytomas and 3 metastatic or recurrent paragangliomas. All 26 carcinoid tumors were negative. Galanin may have limited utility as a diagnostic marker alone but would be most useful in conjunction with other immunohistochemical markers for the differential diagnosis of neuroendocrine tumors.

Granulomatous Pneumocystis carinii pneumonia complicating hematopoietic cell transplantation.

Pneumocystis carinii pneunonia (PCP) is associated with a wide spectrum of clinical and histopathological presentations. While granulomatous PCP uncommonly occurs in AIDS patients, it is extremely rare in other non-AIDS immunocompromised patients. We identified three patients who developed granulomatous PCP after bone marrow or blood stem cell transplantation. In all cases, fiberoptic bronchoscopy with bronchoalveolar lavage was non-diagnostic, and an open lung biopsy was required for diagnosis. All patients were successfully treated with trimethoprim-sulfamethoxazole. The histological appearance varied from an ill-defined granulomatous pneumonia to well-formed necrotizing granulomas. The typical intraalveolar eosinophilic frothy exudate was absent. Often sparsely distributed, the organisms were detected by GMS and immunohistochemical stains for P. carinii. No other pathogens were identified by additional histochemical stains or by microbiological cultures. Awareness of this unusual granulomatous tissue response to P. carinii and initiation of specific treatment can lead to successful resolution of this potentially lethal infection.

High-resolution computed tomography appearance of pulmonary Mycobacterium avium complex infection after exposure to hot tub: case of hot-tub lung.

Reports detailing Mycobacterium avium complex (MAC) infection in an immunocompetent host after exposure to hot tub (hot-tub lung) are few and have not focused on the radiographic presentation. On high-resolution computed tomography (HRCT), hot-tub lung caused by MAC infection closely resembles subacute hypersensitivity pneumonitis and is difficult to distinguish based on imaging parameters alone. Centrilobular nodules of ground-glass attenuation with beading of the interlobular septae are prominent features on HRCT. Correlation of clinical history with radiographic, pathologic, and microbiologic findings are necessary to establish a diagnosis of hot-tub lung.

Cytopathologic diagnosis of pulmonary sclerosing hemangioma.

There are many reports of sclerosing hemangioma from the perspective of its histopathologic features, but its cytopathologic characteristics are less well known. In this report we present the case of a patient in which the cytologic features firmly established a definitive diagnosis; surgical intervention was warranted only after the lesion had grown over the course of 7 yr of close observation. The cytologic diagnosis requires the identification of a dual cell population. Both populations of tumor cell nuclei are immunoreactive for thyroid transcription factor-1, but caution is warranted because this marker may be present in other tumors. Recognition of its distinctive cytologic features can lead to proper diagnosis and conservative management.