Anthony A. Gal

Survival Analysis of 200 Pulmonary Neuroendocrine Tumors With Clarification of Criteria for Atypical Carcinoid and Its Separation From Typical Carcinoid

Neuroendocrine tumors of the lung embrace a spectrum from low-grade typical carcinoid (TC), intermediate-grade atypical carcinoid (AC), and high-grade categories of large cell neuroendocrine carcinoma (LCNEC) and small cell carcinoma (SCLC). We studied 200 neuroendocrine lung tumors to critically evaluate the Arrigoni histologic criteria for AC using statistical analysis to delimit more rigorously an intermediate survival for AC between TC and the high-grade tumors of LCNEC and SCLC. Histologic features that might predict prognosis were used for Kaplan-Meier and Cox proportional hazards survival analysis, and an optimal mitotic range for AC was calculated. The optimal mitotic range for AC was 2 to 10 mitoses per 2 mm2 of viable tumor (10 high-power fields). Based on this finding, we collapsed mitoses into three categories (< 2; 2-10; > or = 11) and performed Cox multivariate analysis for all 200 neuroendocrine tumors. Mitotic counts were the only independent predictor of prognosis. Based on this analysis, we propose that AC be defined as a tumor with neuroendocrine morphology, mitotic counts between 2-10 per 2 mm2 of viable tumor (10 high-power fields), or coagulative necrosis. Using these criteria, the 200 neuroendocrine tumors were classified as 51 TC, 62 AC, 37 LCNEC, and 50 SCLC. The 5- and 10-year survival was 87% and 87% for TC, 56% and 35% for AC, 27% and 9% for LCNEC, and 9% and 5% for SCLC, respectively. After stratification for stage, survival for AC was significantly worse than for TC (p < 0.001); for LCNEC and SCLC it was significantly worse than for AC; but the survival for LCNEC was no different than that for SCLC.

Reproducibility of neuroendocrine lung tumor classification

For a tumor classification scheme to be useful, it must be reproducible and it must show clinical significance. Classification of neuroendocrine lung tumors is a difficult problem with little information about interobserver reproducibility. We sought to evaluate the classification of typical carcinoid (TC), atypical carcinoid (AC), large-cell neuroendocrine carcinoma (LCNEC), and small-cell carcinoma (SCC) tumors as proposed by W.D. Travis et al (Am J Surg Pathol 15:529, 1991). Forty neuroendocrine tumors were retrieved from the Armed Forces Institute of Pathology (AFIP) files and independently evaluated by five lung pathologists and classified as TC, AC, LCNEC, or SCC (pure SCC, mixed small cell/large cell, and combined SCC). A single hematoxylin and eosin-stained slide from each case was reviewed. Each participant was provided a set of tables summarizing the criteria for separation of the four major categories. Agreement was regarded as unanimous if all five pathologists agreed, a majority if four agreed, and a consensus if three or more pathologists agreed. The kappa statistic was calculated to measure the degree of agreement between two observers. A consensus diagnosis was achieved in all 40 cases (100%), a majority agreement in 31 of 40 (78%), and unanimous agreement in 22 of 40 (55%) of cases. Unanimous agreement occurred in seven of SCC (70%), seven of TC (58%), four of AC (50%), and four of LCNEC (40%). A majority diagnosis was achieved in 11 of 12 (92%) of TC, 9 of 10 (90%) of SCC, 6 of 8 (75%) of AC, and 5 of 10 (50%) of LCNEC. Most of the kappa values were 0.70 or greater, falling into the substantial agreement category. The most common disagreements fell between LCNEC and SCC, followed by TC and AC, and AC and LCNEC. The highest reproducibility occurred for SCC and TC, with disagreement in 8% and 10% of the diagnoses, respectively. For TC, 10% of the diagnoses rendered were AC. For AC, 15% of the diagnoses were rendered as TC, with 2.5% called LCNEC and 2.5% called SCC. For LCNEC, 18% and 4% of the diagnoses were called SCC and AC, respectively. For SCC, 4% of the diagnoses were called AC and 4% were called LCNEC. Thus, using the classification scheme tested, a consensus diagnosis can be achieved for virtually all neuroendocrine lung tumors with substantial agreement between experienced lung pathologists. Classification of NE tumors is most reproducible for classification of TC and SCC but less reproducible for AC and LCNEC. These results indicate a need for more careful definition and application of criteria for TC versus AC and SCC versus LCNEC.

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.

Predictors of outcome in thymectomy for myasthenia gravis

BACKGROUND Factors determining predictability of response to thymectomy for myasthenia gravis (MG) vary in the literature. METHODS A 25-year retrospective review (1974 to 1999) of all thymectomies performed at a single institution was undertaken. RESULTS In 113 consecutive thymectomies for MG, women comprised 79% (89 of 113 patients), and mean age was 40+/-15 years. Complications occurred in 14% of patients (16 of 113). In-hospital mortality was 0, but 90-day hospital mortality was 0.88% (1 of 113 patients). Follow-up was obtained in 81% (92 of 113 patients) at a mean of 51+/-59 months postoperatively. Complete remission was achieved in 21% of patients (19 of 92), and marked improvement of MG in 54% (50 of 92), for a total benefit rate of 75%. Fourteen percent (13 of 92) were unchanged, and 11% (10 of 92) were worse. Using univariate analysis, sex, age, and pathology correlated significantly with outcome (p < 0.05): 80% of women (57 of 70) benefited from the procedure, versus 57% of men (12 of 21). Eighty percent (57 of 70) of patients less than 51 years of age were improved or in remission, versus 57% (12 of 22) older than 50. Twenty-three percent (5 of 22) of patients with thymoma deteriorated, versus 7.1% (5 of 70) without thymoma. Sex did not significantly correlate in the multivariate model. CONCLUSIONS Sex, age, and thymic pathology are potential predictors of outcome in thymectomy for MG, and may shape treatment decisions and target higher-risk patients.

Twist: a regulator of epithelial-mesenchymal transition in lung fibrosis.

Background Several studies have implicated viral infection as an important factor in the pathogenesis of IPF and related fibrotic lung disorders. Viruses are thought to cause epithelial cell injury and promote epithelial-mesenchymal transition (EMT), a process whereby differentiated epithelial cells undergo transition to a mesenchymal phenotype, and considered a source of fibroblasts in the setting of lung injury. We have demonstrated an association between the epithelial injury caused by chronic herpes virus infection with the murine γ-herpes virus, MHV68, and lung fibrosis. We hypothesize that EMT in this model of virus-induced pulmonary fibrosis is driven by the expression of the transcription factor Twist. Methods/Findings In vitro MHV68 infection of murine lung epithelial cells induced expression of Twist, and mesenchymal markers. Stable overexpression of Twist promoted EMT in MLE15 lung epithelial cells. Transient knockdown expression of Twist resulted in preservation of epithelial phenotype after in vitro MHV68 infection. In concordance, high expression of Twist was found in lung epithelial cells of MHV68 infected mice, but not in mock infected mice. Alveolar epithelial cells from lung tissue of idiopathic pulmonary fibrosis (IPF) patients were strongly positive for Twist. These cells demonstrated features of EMT with low expression of E-cadherin and upregulation of the mesenchymal marker N-cadherin. Finally, IPF tissue with high Twist protein levels was also positive for the herpesvirus, EBV. Conclusions/Significance We conclude that Twist contributes to EMT in the model of virus-induced pulmonary fibrosis. We speculate that in some IPF cases, γ-herpes virus infection with EBV might be a source of injury precipitating EMT through the expression of Twist.

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

Angiogenesis As A Predictor Of Survival After Surgical Resection For Stage I Non-Small-Cell Lung Cancer

700 compared with

Neuroendocrine tumors of the thymus: a clinicopathological and prognostic study

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.

The pathology of sarcoidosis.

OBJECTIVES Some patients with surgically resected stage I non-small-cell lung cancer eventually have metastatic disease. A histologic marker of metastatic potential and diminished survival for stage I non-small-cell lung cancer may distinguish this patient population. This study evaluates the degree of angiogenesis as a predictor of cancer-related death after operation for stage I non-small-cell lung cancer. METHODS Demographic, surgical, and histopathologic data, including presence of vascular invasion, were reviewed for 106 patients with stage I non-small-cell lung cancer from 1985 through 1990. Visual quantitation of microvessels immunostained with factor VIII-related antigen and CD31 in 5 microm sections from the paraffin blocks of tissue defined rumor angiogenesis. RESULTS Follow-up was 95.1% complete, mean 5.2 +/- 3.0 years. Lung cancer-related mortality rate was 24.4% at 5 years. Mean microvessel counts were 20.7 +/- 11.2 for FVIII and 29.6 +/- 18.1 for CD31. Univariate analysis revealed an FVIII count of at least 20 (p = 0.025) and blood vessel invasion (p = 0.017) to be significant predictors of disease-related death. After adjustment for other patient and tumor characteristics, multivariate Cox regression analysis found an FVIII count of at least 20 (hazard ratio 2.9) and blood vessel invasion (hazard ratio 3.7) to be significant independent correlates of lung cancer death (p = 0.018 and p = 0.011, respectively). CD31 quantitation did not predict survival on univariate or multivariate analyses and did not correlate strongly with FVIII quantitation (Spearmans rank correlation r = 0.19). CONCLUSIONS This analysis reveals a significant association between tumor neovascularization and cancer-related mortality rate among patients with stage I non-small-cell lung cancer. Microvessel quantitation of FVIII, as an indicator of tumor angiogenesis and metastatic potential, may define a subset of patients with stage I non-small-cell lung cancer who could benefit from adjuvant therapy after surgical resection.

Distribution of Extracellular Matrices, Matrix Receptors, and Transforming Growth Factor-β1 in Human and Experimental Lung Granulomatous Inflammation

BACKGROUND Neuroendocrine tumors of the thymus are rare, histologically diverse neoplasms with an unpredictable clinical behavior. This study provides a useful clinicopathological classification and determines the relevance of specific prognostic factors. METHODS Ten neuroendocrine tumors of the thymus were analyzed for specific clinical and pathological features. Prognostic factors of these cases and 71 previously published cases were evaluated by Kaplan-Meier survival curves and Cox multivariate hazard model. RESULTS There were 7 males and 3 females, with ages ranging from 26 to 77 years. Cases were classified as carcinoid tumor (2), atypical carcinoid tumor (6), and small cell carcinoma (2). An advanced clinical stage was evident in all instances with frequent recurrence (4) and metastases (8), and a short disease-free survival. Overall mortality was 60%. Statistical analysis of current and previously published cases (n = 81 total) revealed that unresectability (p = 0.0001), extent of surgical resection (p = 0.0002), and advanced clinical stage at presentation (p = 0.03) were associated with higher mortality. By multivariate Cox regression analysis, unresectability (p = 0.02) and advanced clinical stage (p = 0.03) were associated with decreased survival. CONCLUSIONS Neuroendocrine tumors of the thymus can be classified into distinct clinicopathological entities, and specific factors have prognostic relevance.