Mediastinal hibernoma: An uncommon tumor.

Hibernoma is a rare tumor originating from fetal brown fat. Mediastinum is a very rare localization for the hibernoma. In this article, we present the clinical and radiological findings of a 46-year-old male patient with pleuritic chest pain.

The role of F-18 FDG PET/CT in differentiating benign from malignant pulmonary masses and accompanying lymph nodes.

INTRODUCTION: The aim of this study was to evaluate the usefulness of SUVmax and lesion size to differentiate benign and malignant lesions of the lung and accompanying mediastinal lymph node on F-18 FDG PET/CT imaging. MATERIALS AND METHODS: A retrospective analysis was carried out on 100 patients with suspected lung cancer who were recommended for PET/CT scans for diagnosis and staging. The results of the SUVmax, lesion size and patient's age were compared with histopathology which was considered to be the 'gold standard' and sensitivity and specificity were calculated respectively. Lymph nodes greater than 1 cm in patients with benign pathology were evaluated and the SUVmax values were recorded. RESULT: Of the 100 patients, 38 were found to have benign, whereas 62 had malignant on histopathology. The SUVmax was significantly more elevated in malign masses (13.1 ± 6.4) than in benign masses (8 ± 5.7) (p< 0.05). The dimensions of malignant masses (4.5 ± 2.5 cm) were larger than benign ones (3 ± 1.6 cm) (p< 0.05). SUVmax of 7.6 was determined as the cut-off value, while the sensitivity and specificity were 82% and 55% respectively. The sensitivity was 87% and specificity was 45% for the lesion sizes in differentiation of the malignant and benign lesions. CONCLUSIONS: There are significant overlaps between benign and malignant lesions and specialists must be aware of the various pathological conditions that can give false positives and negatives.

Rare congenital pulmonary malformation with diagnostic challenging: congenital pulmonary lymphangiectasia, report of four autopsy cases and review of literature.

Congenital pulmonary lymphangiectasia (CPL) is a rare congenital disorder that typically presents with intractable respiratory failure in the first few days of life. There is an association non-immun hydrops and CPL. In this study we reviewed four CPL cases between January 2006 and January 2014 among 684 fetal-pediatric autopsies. All cases were in the second trimester. In light microscopy there were marked dilatated channels in the subpleural -peribronchial-subseptal region of the lungs. The channels were lined with flattened cells which were expressing CD 31 and D2-40, negative for CD34. Although pulmonary interstitial emphysema (PIE) was considered an important differential diagnosis, a giant cell reaction surrounding the interstitial cystic lesions, a histological hallmark of PIE. CPL is characterized by dilatation of the pulmonary lymphatic vessels and occurs as a congenital anomaly. Noonan classified it into three groups. Primary developmental defect of pulmonary lymphatics is group 3. Group 3 is called also as CPL; normal regression of the connective tissue elements fails to occur after the 16th week of fetal life, associated with an aggressive clinical course, poor prognosis. In fetal autopsy examination CPL should be recognized if there is a fetus with pleural effusion, non-immune hydrops. There is no clinical evidence for CPL.

Spindle Cell Carcinoma of the Larynx: A Confusing Diagnosis for the Pathologist and Clinician.

Laryngeal spindle cell carcinoma (SpCC) is an uncommon subtype of squamous cell carcinoma which represents 0.5% of all laryngeal squamous cell carcinomas. It is a biphasic tumor consisting of the combination of a malignant mesenchymal spindle cell component and a squamous cell component that includes dysplasia, carcinoma in situ, or invasive carcinoma. Although it has aggressive biological features, the probability of making a diagnosis in the early stages is high as it often leads to obstructive symptoms in the early period. Due to its low incidence, there is no clear consensus on prognostic factors and optimal treatment strategies yet. In this paper, a 60-year-old laryngeal SpCC case that was effectively treated with wide local excision followed by adjuvant radiotherapy was presented with the literature.

Effects of high-dose intravenous immunoglobulin on lipopolysaccharide-induced acute lung injury.

PURPOSE: Intravenous immunoglobulin (IVIG) therapy is used in inflammatory diseases but the use of immunoglobulin as a treatment for acute lung injury (ALI) has not been previously studied. Transforming growth factor beta (TGF-ß) plays a critical role in the pathogenesis of of ALI. Therefore we examined the levels of TGF-ß and lung inflammation scores in IVIG treated ALI models. METHODS: Intratracheal lipopolysacccharide was given to rats. Groups 1 and 3 received saline, whereas group 2 received IVIG. 24h later saline was given to groups 1 and 2 and IVIG to group 3. Blood samples and bronchoalveolar lavage (BAL) fluids were obtained from each group and sacrificed for pathological evaluation. RESULTS: BAL TGF-ß levels of groups 2 and 3 on day 30, were lower compared to their levels of day 2 (p=0.01, p=0.01). BAL TGF-ß levels of groups 2 and 3 were lower than the levels of group 1 on day 30 (p=0.002, p=0.001). Pathological examination revealed that the inflammation scores of groups 2 and 3 on day 30, were lower than the scores of day 2 (p=0.02, p=0.01). Inflammation scores of group 2 were lower than group 1 on day 30 (p=0.02). Moderate fibrosis was seen in half of the rats from group 1 and one rat from group 2. CONCLUSION: High-dose IVIG decreased lung inflammation scores and BAL TGF-ß1 levels and this therapy would give even better results if it is given earlier.

Differential expression and activation of epidermal growth factor receptor 1 (EGFR1), ERK, AKT, STAT3, and TWIST1 in nonsmall cell lung cancer (NSCLC).

Lung cancer is the leading cause of death of both men and women across the world. Overexpression and activating mutations of the epidermal growth factor receptor-1 (EGFR1) are frequently observed and associated with poor prognosis. To inhibit the function of EGFR1, multiple antibodies and small-molecule tyrosine kinase inhibitors (TKI) that target EGFR1 have been developed. Even though some patients respond to these TKI, subsequent studies reveal that this is not the case for all nonsmall cell lung cancer (NSCLC) patients. In this study, we determine whether activation and expression levels of EGFR1, ERK, AKT, STAT3, and TWIST1 are dependent on the activating mutations of EGFR1. Protein lysates and DNA have been isolated from tumor and corresponding normal tissues of 16 NSCLC patients. Genomic-DNA is used to sequence the exons 18, 19, and 21 of EGFR1, and exon 2 of k-RAS. Protein lysates were used to determine the expression or phosphorylation levels of EGFR, STAT3, ERK, AKT, and TWIST1. Our results revealed that 16 tumor samples of NSCLC patients showed no mutation in any of the indicated exons of EGFR1 and k-RAS albeit significant levels of activation or expression of the above-mentined oncogenes. In NSCLC patients, the tumor micro-environment can be as important as the activating mutations of EGFR1. TK therapy may also be considered for patients who show high levels of activation of EGFR1 even in the absence of activating mutations.

Clinical and pathologic prognostic factors that are influential in the survival and prognosis of lung adenocarcinomas and invasive predominant subtypes.

Therapeutic approaches to lung adenocarcinomas differ because of their heterogeneous morphologies, prognoses, and clinical features. For this reason, new histopathologic classifications for lung adenocarcinomas were done by the International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society to form subtypes with homogeneous prognoses. There are limited clinical data in the literature on the prognosis of the subgroups formed according to the new classification. A total of 86 patients with adenocarcinoma who had undergone pathologic stages I and II curative resection and mediastinal lymph node dissection were retrospectively analyzed according to the seventh TNM staging system revised by the Union for International Cancer Control/American Joint Committee on Cancer. Histologic subtyping was reassessed according to the dominant histopathologic morphology. When survival rates of lung adenocarcinomas were compared according to their localizations, it was observed that adenocarcinomas localized to the right hemithorax had a longer survival than the ones with left hemithorax localization (P = 0.026). When necrosis was taken into account, it was seen that necrosis rate was higher in solid predominant type compared with other types, whereas it was lower in acinary type (P = 0.046). When peritumoral lymphovascular invasion data were assessed, it was observed that disease-free survival was influenced in a negative fashion (P = 0.018). New histopathologic classification of adenocarcinomas has been a step forward to attaining homogeneous groups, but when the biologic heterogeneity of the adenocarcinomas is taken into account, the authors believe that considering the peritumoral lymphatic vascular invasion, left hemithorax localization, and tumoral necrosis entities in the upcoming TNM classification will contribute to evaluating the prognosis.

Effect of atorvastatin on atherosclerotic plaque formation and platelet activation in hypercholesterolemic rats.

We aimed to investigate whether atorvastatin influenced the CD40-CD40L pathway in atherosclerosis formation in rats fed a high cholesterol diet. Thirty-six male Wistar rats were divided among 4 groups as follows: control (C), statin (S), 5% cholesterol fed (HC), and statin-administered hypercholesterolemic (HCS). Serum levels of lipids, soluble CD40L, platelet factor 4, and interleukin-6 were assayed with commercial kits. The number of platelets expressing surface P-selectin, CD40, and CD40L were determined by flow cytometry. Aortas were examined for fatty streaks. In the HC group, we observed a significant increase in serum lipid levels and platelet activation markers compared with the control group. Rats in the HCS group had a significant decrease in lipid levels and downregulation in the number of platelets expressing surface P-selectin, CD40, and CD40L compared with the HC group. We observed decreased fatty streak formations in aortas in HCS rats. A positive correlation was found for platelet activation markers and atherosclerotic fatty streak formations. Regression analysis revealed that the predictor of atherosclerosis was CD40L. Our study suggests that in a rat hypercholesterolemic model, statin treatment may influence the CD40-CD40L dyad, and that this effect is parallelled by a suppression of progression of atherosclerotic plaque formation.

Metachronous malignant mesothelioma and pulmonary adenocarcinoma.

The prevalence of multiple primary malignant neoplasms in a single patient is reported in a wide variation. The co-existence of malignant mesothelioma and pulmonary carcinoma is a rare entity. Herein, we reported a 60-year-old man who was a retired employee and heavy smoker. He had a suspicious history of asbestos exposure. He complained of chest pain and computerized tomography revealed a mass in the lower lobe of left lung. The patient underwent a left lower lobectomy and was diagnosed as pulmonary adenocarcinoma. During follow-up two years after surgery, the patient complained of dyspnea and chest computerized tomography scan revealed right pleural effusion and diffuse pleural thickening. For the differential diagnosis, the patient underwent wedge biopsy from the right lower lobe and was diagnosed as epithelial diffuse malignant mesothelioma. The development of malignant pleural mesothelioma and lung carcinoma could be associated with asbestos exposure. However, a history of asbestos exposure is not required for the diagnosis. The influence of effective anticancer therapies that improve the survival rates and increase the population ages could be related to the occurrence of a second malignancy.

Measurements of tumor size using CT and PET compared to histopathological size in non-small cell lung cancer.

PURPOSE: In this study, we aimed to compare the tumor sizes determined by maximum morphological computed tomography (CT) and functional positron emission tomography (PET) with the histopathological size to determine which method provides the best correlation with the histopathological size in lung carcinoma patients. MATERIALS AND METHODS: Forty lung carcinoma patients (39 males, one female) diagnosed histopathologically from surgical resection materials were included in this retrospective study. The mean age (±standard deviation, SD) of the patients was 67.8±10.3 years with a range of 44 to 81 years. The PET scans were performed within the same week as the CT scan. In the CT scans, the morphological tumor sizes were measured three-dimensionally by the longest transaxial section in the parenchymal and mediastinal screening window. The functional tumor sizes were also measured three-dimensionally in the PET scans. These two measurement values were compared with the histopathological size using Bland-Altman plotting. Bland-Altman plotting was also performed to define the 95% limits of agreement, which was presented as the bias ±1.96 SD. RESULTS: The histopathological sizes were measured in a range of 1.2 to 7.5 cm. The maximum measurement of the tumors on the CT scans showed a lower concordance (mean difference, -0.30) than that obtained from PET, and the SD was found to be larger than the PET (1.96 SD was 3.50 for CT and 2.50 for PET). CONCLUSION: The PET measurements of tumor size were more compatible with the histopathological sizes than the CT measurements in patients with non-small cell lung cancer.

Tbx3 represses PTEN and is over-expressed in head and neck squamous cell carcinoma.

BACKGROUND: Despite advances in diagnostic and treatment strategies, head and neck squamous cell cancer (HNSCC) constitutes one of the worst cancer types in terms of prognosis. PTEN is one of the tumour suppressors whose expression and/or activity have been found to be reduced in HNSCC, with rather low rates of mutations within the PTEN gene (6-8%). We reasoned that low expression levels of PTEN might be due to a transcriptional repression governed by an oncogene. Tbx2 and Tbx3, both of which are transcriptional repressors, have been found to be amplified or over-expressed in various cancer types. Thus, we hypothesize that Tbx3 may be over expressed in HNSCC and may repress PTEN, thus leading to cancer formation and/or progression. METHODS: Using immunohistochemistry and quantitative PCR (qPCR), protein and mRNA levels of PTEN and Tbx3 were identified in samples excised from cancerous and adjacent normal tissues from 33 patients who were diagnosed with HNSCC. In addition, HeLa and HEK cell lines were transfected with a Tbx3 expressing plasmid and endogenous PTEN mRNA and protein levels were determined via qPCR and flow cytometry. Transcription assays were performed to demonstrate effects of Tbx3 on PTEN promoter activity. Mann-Whitney, Spearman's Correlation and Wilcoxon signed-rank tests were used to analyze the data. RESULTS: We demonstrate that in HNSCC samples, Tbx3 mRNA levels are increased with respect to their normal tissue counterparts (p<0.001), whereas PTEN mRNA levels are significantly reduced in cancer tissues. Moreover, Tbx3 protein is also increased in HNSCC tissue sections. Over-expression of Tbx3 in HeLa and HEK cell lines causes reduction in endogenous PTEN mRNA and protein levels. In addition, transcription activity assays reveal that Tbx3 is capable of repressing both the basal and induced promoter activity of PTEN. CONCLUSIONS: We show that Tbx3 is up-regulated in tissue samples of HNSCC patients and that Tbx3 represses PTEN transcription. Thus, our data not only reveals a new mechanism that may be important in cancer formation, but also suggests that Tbx3 can be used as a potential biomarker in cancer.

Pulmonary alveolar microlithiasis with homozygous c.316G > C (p.G106R) mutation: a case report.

Pulmonary alveolar microlithiasis is characterized by the presence of calcospherites in alveolar spaces. Sporadic cases are more common, but the disease also presents in an inherited familial form. The greatest number of reported cases is from Europe and especially Turkey. We present a 43-year-old female with complaints of dyspnea for many years. She had a suspicious familial history of pulmonary alveolar microlithiasis. The surgical lung biopsy specimen appeared gritty and firm. Histological sections showed diffuse involvement of the lung parenchyma by innumerable tiny calcospherites. Genetic studies showed a homozygous c.316G > C (p.G106R) mutation in exon 4 and confirmed the diagnosis of pulmonary alveolar microlithiasis. The present report aims to contribute to the literature with a pathologically and genetically confirmed new case to add insight into the etiology of this rare disease. This case confirms an autosomal recessive inheritance and does not support the role of non-genetic and other factors in the pathogenesis of pulmonary alveolar microlithiasis.

Acute effects of vardenafil on pulmonary artery responsiveness in pulmonary hypertension.

Phosphodiesterase type-5 (PDE-5) inhibitors are novel and important options for the treatment of pulmonary arterial hypertension (PAH). Therefore, we aimed to examine effects of vardenafil, a PDE-5 inhibitor, on the pulmonary arteries isolated from rats with monocrotaline- (MCT-) induced pulmonary hypertension. MCT (60 mg/kg) or its vehicle was administered by a single intraperitoneal injection to 6-week-old male Sprague Dawley rats. Rats were sacrificed 21 days after MCT injection, and the main pulmonary arteries were isolated and then mounted in 20 mL organ baths. Concentration-response curves for vardenafil (10(-10)-10(-5) M) were constructed in phenylephrine- (Phe-) precontracted rings. PAH caused marked rightward shift in the curves to vardenafil whereas maximal responses were not affected. Inhibition of NO synthase (L-NAME, 10(-4) M) or guanylyl cyclase (ODQ, 10(-5) M) caused similar attenuation in responses evoked by vardenafil. Moreover, contraction responses induced by CaCl(2) (3 × 10(-5)-3 × 10(-2) M) were significantly reduced in concentration-dependent manner by vardenafil. In conclusion, vardenafil induced pulmonary vasodilatation via inhibition of extracellular calcium entry in addition to NO-cGMP pathway activation. These results provide evidence that impaired arterial relaxation in PAH can be prevented by vardenafil. Thus, vardenafil represents a valuable therapeutic approach in PAH besides other PDE-5 inhibitors.

Bilateral tonsillar and esophageal Kaposi sarcoma in an HIV-negative patient.

Tonsillar involvement in Kaposi sarcoma is extremely rare, as only a few such cases have been reported; all but 1 of these previously reported cases occurred in patients with human immunodeficiency virus (HIV) infection. We describe what to the best of our knowledge is the first reported case of concurrent bilateral tonsillar and esophageal Kaposi sarcoma in an HIV-negative patient. A 68-year-old man presented with sore throat and dysphagia. Clinical examination revealed the presence of bilateral and asymmetrical tonsillar masses, as well as generalized lymphadenopathy in the cervical chain. The masses were resected, and findings on histopathologic analysis were consistent with Kaposi sarcoma. In addition, human herpesvirus 8 was demonstrated on a tonsil specimen by polymerase chain reaction, and microinvasive squamous cell carcinoma was also detected. Later, another Kaposi sarcoma lesion was detected in the lower third of the esophagus. We recommend that clinicians not discount the possibility of oral classic Kaposi sarcoma in the workup of an immunocompetent patient with oral vascular lesions.

Diagnostic value of transbronchial needle aspiration cytology in sarcoidosis.

OBJECTIVE: Sarcoidosis is a systemic granulomatous inflammation that occurs as a result of disturbed immune regulation in individuals exposed to certain environmental agents. Although tissue sampling is considered the "gold standard" for the diagnosis of sarcoidosis, a medically treated disease, minimally invasive diagnostic methods are preferred instead of surgical tissue sampling. Transbronchial needle aspiration has been reported as an effective diagnostic method. MATERIAL AND METHOD: In this study, transbronchial needle aspiration cytology samples were assessed from 38 patients where sarcoidosis was suspected clinically and radiologically. The existence of epithelioid histiocytes and/or giant cells that formed granulomas was used as a cytological diagnostic criterion for chronic granulomatous inflammation. The presence of lymphocytes and/or germinal center cells, and of histiocytes in lymph nodes was regarded as adequate sampling criteria. RESULTS: A total of 31 out of the 38 patients were diagnosed as sarcoidosis with clinical, radiological and microbiological findings, after chronic granulomatous inflammation was considered by cytologic assessment. Cytologic diagnosis was achieved in: 4 of 7 patients with sampling from a single lymph node region, 25 of 28 patients with sampling from two different lymph node regions and 2 of 3 patients with sampling from three different lymph node regions. Two of the 7 patients who could not be diagnosed cytologically underwent a transbronchial parenchyma biopsy and the rest were diagnosed histologically from mediastinoscopic lymph node sampling. CONCLUSION: We would like to emphasize that transbronchial needle aspiration is a successful diagnostic method. We highlighted the adequacy criteria of cytological sampling and the encountered cytological findings of chronic granulomatous inflammation.

Inter-observer agreement in laryngeal pre-neoplastic lesions.

In this series, laryngeal preneoplastic lesions were evaluated by the classifications of the World Health Organization (WHOC), Ljubljana (LC) and squamous intraepithelial neoplasia (SINC) by multiple observers. The inter-observer agreement (IA) by WHOC for laryngeal lesions had been previously evaluated, but to the best of our knowledge, there are no data for LC and SINC. H&E stained slides from 42 laryngeal biopsies were evaluated by fourteen participants according to WHOC and LC, and SINC was additionally applied by 6. The results were analyzed statistically. The diagnoses which were favored by most participants for each case, according to WHOC, were as follows: squamous cell hyperplasia (n = 5; 12%), mild dysplasia (n = 11; 26.2%), moderate dysplasia (n = 12; 28.6%), severe dysplasia (n = 7; 16.7%), carcinoma in situ (n = 5; 12%), and invasive squamous cell carcinoma (n = 2; 4.8%). There was a significant difference between the participants for all three classifications; some participants gave lower or higher scores than the others. The mean correlation coefficients (MCC) of the participants were higher for WHOC compared to LC (0.55 ± 0.15 and 0.48 ± 0.14, respectively). The mean linear-weighted kappa (wKappa) values of participants were not significantly different (0.42 ± 0.10, 0.41 ± 0.12 and 0.37 ± 0.07 for WHOC, LC and SINC, respectively). The kappa values in this series are in agreement with those in previous literature for WHOC, and the similar results obtained for LC and SINC are novel findings. Although the MCC of WHOC was higher, as the wkappa was not significantly different, the findings in this series are not in favor of any of the classifications for better IA for pre-neoplastic laryngeal lesions.

Evaluation of PTEN and Mcl-1 expressions in NSCLC expressing wild-type or mutated EGFR.

Signaling pathways activated by epidermal growth factor receptors (EGFRs) are important in lung carcinogenesis. New treatment strategies with EGFR-targeting drugs provided improvements in management of lung cancer. However, molecular mechanisms underlying resistance to these drugs need to be evaluated. Surgically resected samples were obtained from 50 patients with non-small-cell-lung cancer. PTEN, Mcl-1 and EGFR protein expression levels were evaluated by Western-blot. Direct sequencing was performed to investigate EGFR tyrosine kinase domain mutations. We detected c.2235-2249 (pGlu746-Ala750del) mutation in exon 19 in two patients with adenocarcinoma histology. Elevated expression levels of both Mcl-1 isoforms (Mcl-1S and Mcl-1XL) and EGFR proteins were found in 15 (30%) and 23 (46%) of the cases, respectively. Reduced PTEN protein expression levels were observed in 17 (34%) of the cases. PTEN expression level was reduced in 26% of cases that showed increased EGFR expression. Also, increased expression of Mcl-1 protein was observed in 26% of cases with EGFR overexpression. One of the cases harboring pGlu746-Ala750del mutation had increased levels of Mcl-1 and decreased PTEN expression levels. Our results indicate that, in addition to lack of PTEN expression, elevated levels of the Mcl-1 protein might be one of the important intrinsic mechanisms protecting non-small-cell-lung cancer cells from apoptosis induced by several compounds. Therefore, EGFR mutations in conjunction with evaluation of Mcl-1 and PTEN expression levels in large cohorts might provide important clues for improvements of new treatment strategies in non-small-cell-lung cancer management.

Vascular endothelial growth factor expression and neovascularization in non--small cell lung carcinoma.

The prognostic significance of microvascular density (MVD) and vascular endothelial growth factor (VEGF) expression were investigated in 15 patients with adenocarcinoma (AC) and 15 patients with squamous cell carcinoma (SCC). Immunohistochemically, VEGF and factor VIII were applied. The average microvessel counts were given as MVD, and VEGF expression was given as VEGF percentage area and VEGF staining degree. Higher values of MVD were obtained in patients with AC (11.47 +/- 3.48) when compared with patients with SCC (7.47 +/- 2.50; P = .001) and also in patients at early stages of disease (10.77 +/- 3.24) when compared with patients at advanced stages (8.47 +/- 3.64; P = .050). A significant correlation was shown between MVD and VEGF percentage area (P = .006) and between VEGF percentage area and VEGF staining degree (P = .000). No significant difference was found in VEGF percentage area between patients with SCC and AC and between patients at early and advanced stages. In conclusion, VEGF or MVD should not be regarded as a solitary prognostic factor but should be supported by other prognostic factors.

DNA gains and losses of chromosome in laryngeal squamous cell carcinoma using comparative genomic hybridization.

PURPOSE: A larynx squamous cell carcinoma (LSCC) is one of the most common forms of cancer and may exhibit various complex karyotypes. MATERIALS AND METHODS: We used comparative genomic hybridization (CGH) to analyze DNA gains and losses in 15 squamous cell carcinomas that consisted of 4 glottic, 10 supraglottic, and 1 transglottic localization samples. RESULTS: The majority of the chromosomal alterations detected were gains: 3 samples of LSCCs revealed high level amplification, while 6 samples displayed gains in various chromosomal regions (17p, 3p, 4p, 5p, 6q, 8p, 9p, 14q, 18p and Xq). One sample was found to have losses (chromosomes 15q and 22q) and 5 had normal CGH profiles. CONCLUSION: Many of these gained regions (4p, 5p, 8p, 10q, 18q and Xq) were novel sites, which may harbor oncogene(s) that potentially play an important role in squamous cell tumorigenesis and progression at supraglottic localizations.