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.

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.

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.

Maintaining glycogen synthase kinase-3 activity is critical for mTOR kinase inhibitors to inhibit cancer cell growth.

mTOR kinase inhibitors that target both mTORC1 and mTORC2 are being evaluated in cancer clinical trials. Here, we report that glycogen synthase kinase-3 (GSK3) is a critical determinant for the therapeutic response to this class of experimental drugs. Pharmacologic inhibition of GSK3 antagonized their suppressive effects on the growth of cancer cells similarly to genetic attenuation of GSK3. Conversely, expression of a constitutively activated form of GSK3ß sensitized cancer cells to mTOR inhibition. Consistent with these findings, higher basal levels of GSK3 activity in a panel of human lung cancer cell lines correlated with more efficacious responses. Mechanistic investigations showed that mTOR kinase inhibitors reduced cyclin D1 levels in a GSK3ß-dependent manner, independent of their effects on suppressing mTORC1 signaling and cap binding. Notably, selective inhibition of mTORC2 triggered proteasome-mediated cyclin D1 degradation, suggesting that mTORC2 blockade is responsible for GSK3-dependent reduction of cyclin D1. Silencing expression of the ubiquitin E3 ligase FBX4 rescued this reduction, implicating FBX4 in mediating this effect of mTOR inhibition. Together, our findings define a novel mechanism by which mTORC2 promotes cell growth, with potential implications for understanding the clinical action of mTOR kinase inhibitors.

Phase II study of docetaxel in combination with everolimus for second- or third-line therapy of advanced non-small-cell lung cancer.

We conducted a phase II study of docetaxel in combination with everolimus, a mammalian target of rapamycin (mTOR) inhibitor, for salvage therapy of advanced non-small-cell lung cancer (NSCLC) based on promising preclinical and early-phase clinical data. Patients with advanced-stage NSCLC treated with one or two previous systemic therapy regimens were given docetaxel (60 mg/m) and everolimus (5 mg orally once daily on days 1-19) every 3 weeks. Archived tumor specimens were evaluated for markers of mTOR pathway activation (total and phosphorylated mTOR, Akt, S6, eIF4e, and 4EBP1). Twenty-eight patients were enrolled (median age: 62 years; male: 13; Caucasians: 19; adenocarcinoma: 20; performance status 0, 3; performance status 1, 23; 1 previous regimen, 16). A median of 3.5 cycles of therapy was administered. Two patients experienced partial response and 15 had stable disease (clinical benefit rate, 70%). The 6-month progression-free survival rate was 5%, and the median overall survival was 9.6 months. Low pAkt expression correlated with clinical benefit rate (p = 0.01) but not with progression-free survival or overall survival. The combination of everolimus and docetaxel was tolerated well, but the efficacy was relatively modest in an unselected population of patients with NSCLC.

Routine intraoperative frozen section analysis of bronchial margins is of limited utility in lung cancer resection.

BACKGROUND: Residual disease at the bronchial margin after resection of non-small cell lung cancer (NSCLC) adversely affects survival. To ensure an R0 resection, thoracic surgeons commonly use intraoperative frozen section analysis of the bronchial margin. We hypothesize that frozen section of the bronchial margin is rarely positive and seldom changes intraoperative management. METHODS: Our institutional Society of Thoracic Surgery database was queried for all patients undergoing planned lobectomy for NSCLC from 2009 to 2011. Clinical variables, intraoperative data, and postoperative outcomes were reviewed. Specifically, intraoperative frozen section and final pathology results of all bronchial margins were examined. The frequency that frozen section results affected intraoperative decision making was evaluated. RESULTS: A total of 287 lobectomies for NSCLC were performed. Frozen section of the bronchial margin was performed in 270 patients (94.1%). There were 6 (2.2%) true-positive bronchial margins and 1 (0.4%) false-negative margin. In no cases did a positive frozen section lead to a change in operative management; reasons included unable to tolerate further resection (n = 5) and advanced-stage disease (n = 1). Positive margins were more frequent with open techniques (7%) than in video-assisted thoracoscopic operations (0.05%; p < 0.01). Tumors with positive margins were closer to the bronchial margin (1.0 vs 2.5 cm; p = 0.04). Frozen section was not used in 17 patients (5.9%), and none had positive margins on final pathology. CONCLUSIONS: Frozen section analysis of the bronchial margin rarely yields a positive result and infrequently changes intraoperative management in patients undergoing NSCLC resection. These data support selective use of intraoperative frozen section of bronchial margins during lobectomy for NSCLC.

Survival analysis of patients with stage I non-small-cell lung cancer using clinical and DNA repair pathway expression variables.

BACKGROUND: Lung cancer is the leading cause of cancer-related mortality. Understanding patient attributes that enhance survival and predict recurrence is necessary to individualize treatment options. METHODS: Patients (N = 162) were dichotomized into favorable (n = 101) and unfavorable (n = 61) groups based on survival characteristics. Ku86 and poly(ADP-ribose) polymerase (PARP) expression measures were incorporated into the analyses. LR, Kaplan-Meier analysis, and Cox regression were used to investigate intervariable relationships and survival. Odds ratios (ORs) and hazard ratios (HRs) with 95% confidence intervals (CIs) were used to assess associations. RESULTS: Sex (OR, 0.32; CI-0.14, 0.76), squamous cell carcinoma (SCC) (OR, 0.41; CI-0.17, 0.98), and recurrence (OR, 0.04; CI-0.01, 0.20) confer an unfavorable outcome with area under the receiver operating characteristic curve (Az) = 0.788. Patients with increased tumor grade (OR = 1.84; CI-1.06, 3.19) or increased Ku86 intensity (OR, 2.03; CI-1.08, 3.82) were more likely to be male individuals, and older patients (OR, 1.70; CI-(1.14, 2.52) were more likely to have SCC. Patients older than the median age (HR, 1.86; CI-1.11, 3.12), patients with SCC (HR, 1.78; CI-1.05, 3.01), patients with recurrence (HR, 4.16; CI-2.37, 7.31), and male patients (HR, 2.03; CI-1.20, 3.43) have a higher hazard. None of the DNA repair measures were associated with significant HRs. CONCLUSION: Clinical and pathologic factors that enhance and limit survival for patients with stage I NSCLC were quantified. The DNA repair measures showed little association. These findings are important given that certain clinical and pathologic features are related to better long-term survival outcome than others.

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.

Granulomatous lung disease: an approach to the differential diagnosis.

CONTEXT: Granulomas are among the most commonly encountered abnormalities in pulmonary pathology and often pose a diagnostic challenge. Although most pathologists are aware of the need to exclude an infection in this setting, there is less familiarity with the specific histologic features that aid in the differential diagnosis. OBJECTIVE: To review the differential diagnosis, suggest a practical diagnostic approach, and emphasize major diagnostically useful histologic features. This review is aimed at surgical pathologists who encounter granulomas in lung specimens. DATA SOURCES: Pertinent recent and classic peer-reviewed literature retrieved from PubMed (US National Library of Medicine) and primary material from the institutions of both authors. CONCLUSIONS: Most granulomas in the lung are caused by mycobacterial or fungal infection. The diagnosis requires familiarity with the tissue reaction as well as with the morphologic features of the organisms, including appropriate interpretation of special stains. The major noninfectious causes of granulomatous lung disease are sarcoidosis, Wegener granulomatosis, hypersensitivity pneumonitis, hot tub lung, aspiration pneumonia, and talc granulomatosis.

Dynamics of human regulatory T cells in lung lavages of lung transplant recipients.

BACKGROUND: Despite advances in the field of lung transplantation, the median survival after lung transplant remains below 5 years. Early rejection is a risk factor for the development of chronic rejection. In animal models of transplant tolerance, regulatory T cells (Tregs) can prevent the establishment of rejection. METHODS: This study was designed to explore the dynamics of Tregs focally and systemically in lung transplant recipients. Sequential surveillance bronchoscopy results were available in 51 patients with at least four sequential samples recovered from each patient at defined times posttransplant. In 36 individuals, a complete year of follow-up data for BAL was analyzed. In 33 of these individuals had a complete year of follow-up data for peripheral blood monocyte cell specimens were also analyzed. Lung lavage cells were recovered from each bronchoscopy and corresponding blood draw and subjected to polychromatic flow cytometry. The percentage of CD4 lymphocytes, which expressed the intracellular transcription factor FoxP3 was recorded at each point. At each time point, lung biopsy specimens were scored for rejection. RESULTS: Lung Treg frequency was significantly more variable than blood Treg frequency. Treg frequency in the lung was increased in the aftermath of acute rejection. In contrast, lung Treg frequency declined sequentially in patients demonstrating continued quiescence. Mean BAL Treg level integrated over the first transplant year correlated inversely with the degree of acute cellular rejection. In contrast, blood Treg levels demonstrated no correlation with lung pathology. CONCLUSIONS: Lung Tregs increase in the setting of acute cellular rejection, whereas declining levels of BAL Tregs correlates with immunologic quiescence.

Primary yolk sac tumor of the lung.

Yolk-sac tumor mimics the yolk sac of the embryo, and the presence of alpha fetoprotein in the tumor cells is highly characteristic. We present an 18-year-old boy with primary pulmonary yolk-sac tumor diagnosed postoperatively. A computed tomographic scan revealed a huge intrathoracic soft tissue mass 20 x 25 cm occupying most of the left hemithorax. Two trials of computed tomographic-guided needle biopsy were nonconclusive. A left upper lobectomy was performed with a complete tumor resection. Postoperatively, the patient's alpha fetoprotein (AFP) was 10,512 IU/mL with gradual decline under chemotherapy. The patient is alive 10 months after surgery and is disease free.

Efficacy of oral ribavirin in lung transplant patients with respiratory syncytial virus lower respiratory tract infection.

BACKGROUND: Respiratory syncytial virus (RSV) can cause severe lower respiratory tract infection (LRI) and is a risk factor for the development of bronchiolitis obliterans syndrome (BOS) after lung transplantation (LTx). Currently, the most widely used therapy for RSV is inhaled ribavirin. However, this therapy is costly and cumbersome. We investigated the utility of using oral ribavirin for the treatment of RSV infection after LTx. METHODS: RSV was identified in nasopharyngeal swabs (NPS) or bronchoalveolar lavage (BAL) using direct fluorescent antibody (DFA) in 5 symptomatic LTx patients diagnosed with LRI. Data were collected from December 2005 and August 2007 and included: age; gender; type of LTx; underlying disease; date of RSV; pulmonary function prior to, during and up to 565 days post-RSV infection; need for mechanical ventilation; concurrent infections; and radiographic features. Patients received oral ribavirin for 10 days with solumedrol (10 to 15 mg/kg/day intravenously) for 3 days, until repeat NPS were negative. RESULTS: Five patients had their RSV-LRI diagnosis made at a median of 300 days post-LTx. Mean forced expiratory volume in 1 second (FEV(1)) fell 21% (p < 0.012) during infection. After treatment, FEV(1) returned to baseline and was maintained at follow-up of 565 days. There were no complications and no deaths with oral therapy. A 10-day course of oral ribavirin cost $700 compared with $14,000 for nebulized ribavirin at 6 g/day. CONCLUSIONS: Treatment of RSV after LTx with oral ribavirin and corticosteroids is well tolerated, effective and less costly than inhaled ribavirin. Further studies are needed to directly compare the long-term efficacy of oral vs nebulized therapy for RSV.

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.

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

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.

The centennial anniversary of the frozen section technique at the Mayo Clinic.

The frozen section technique has become an invaluable tool to assist the surgeon with intraoperative diagnosis. Although there were various descriptions of frozen section technique before and after the turn of the 20th century, the publication by Louis B. Wilson, MD, at the Mayo Clinic in 1905 heralded the beginning of a new era in intraoperative diagnosis. This historical review traces the circumstances that led to this landmark publication 100 years ago.