Nazarena Nannini

Herpes Virus Infection Is Associated with Vascular Remodeling and Pulmonary Hypertension in Idiopathic Pulmonary Fibrosis

Background Pulmonary hypertension (PH) represents an important complication of idiopathic pulmonary fibrosis (IPF) with a negative impact on patient survival. Herpes viruses are thought to play an etiological role in the development and/or progression of IPF. The influence of viruses on PH associated with IPF is unknown. We aimed to investigate the influence of viruses in IPF patients focusing on aspects related to PH. A laboratory mouse model of gamma-herpesvirus (MHV-68) induced pulmonary fibrosis was also assessed. Methods Lung tissue samples from 55 IPF patients and 41 controls were studied by molecular analysis to detect various viral genomes. Viral molecular data obtained were correlated with mean pulmonary arterial pressure (mPAP) and arterial remodelling. Different clinical and morphological variables were studied by univariate and multivariate analyses at time of transplant and in the early post-transplant period. The same lung tissue analyses were performed in MHV-68 infected mice. Results A higher frequency of virus positive cases was found in IPF patients than in controls (p = 0.0003) and only herpes virus genomes were detected. Viral cases showed higher mPAP (p = 0.01), poorer performance in the six minute walking test (6MWT; p = 0.002) and higher frequency of primary graft (PGD) dysfunction after lung transplant (p = 0.02). Increased arterial thickening, particularly of the intimal layer (p = 0.002 and p = 0.004) and higher TGF-β expression (p = 0.002) were demonstrated in viral cases. The remodelled vessels showed increased vessel cell proliferation (Ki-67 positive cells) in the proximity to metaplastic epithelial cells and macrophages. Viral infection was associated with higher mPAP (p = 0.03), poorer performance in the 6MWT (p = 0.008) and PGD (p = 0.02) after adjusting for other covariates/intermediate factors. In MHV-68 infected mice, morphological features were similar to those of patients. Conclusion Herpesviral infections may contribute to the development of PH in IPF patients.

Serpin B4 isoform overexpression is associated with aberrant epithelial proliferation and lung cancer in idiopathic pulmonary fibrosis.

Aims: The aim of the study was to evaluate the role of Serpin B3/B4 in advanced idiopathic pulmonary fibrosis (IPF) patients, mainly focusing on epithelial proliferation. Methods: Lungs from 48 IPF patients (including cases with cancer or high-grade epithelial dysplasia) were studied and compared with other diffuse parenchymal diseases and normal lungs. Immunohistochemistry for Serpin B3/B4 and Ki-67 was quantified in all cases, distinguishing stained metaplastic cells. In IPF patients correlations between Serpin expression and several clinicopathological data, including fibrotic remodelling [fibrosis extension and transforming growth factor &bgr; expression (TGF-&bgr;)] were performed. Molecular analysis was used for Serpin isoform characterisation. Results: In IPF patients Serpin B3/B4 and Ki-67 were significantly overexpressed in many metaplastic cells (mainly squamous type) compared to control cases. Higher Serpin B3/B4 was found in older patients and cases with more impaired respiratory function. Serpin B3/B4 expression was related to both TGF-&bgr; and Ki-67 and was higher in patients with cancer/high-grade dysplasia. Serpin B3 was expressed in all cases, whereas Serpin B4 was expressed only in IPF. Conclusions: Serpin B3/B4, particularly Serpin B4, appears to play an important role in aberrant epithelial proliferation. Evaluation of Serpin B3/B4 could have prognostic value in predicting disease progression, especially in patients with increased susceptibility to lung cancer.

Localized pleuropulmonary crystal-storing histiocytosis: 5 cases of a rare histiocytic disorder with variable clinicoradiologic features

Crystal-storing histiocytosis (CSH) localized to the thoracic region is a rare occurrence, often secondary to lymphoproliferative or plasma cell diseases. About 10 case reports have been previously published, and 3 of these have no relationship with clonal hematologic disorders. We collected here the first series of 5 consecutive cases of CSH involving lungs (4 cases) and pleura (1 case). There were 3 women and 2 men with a mean age at diagnosis of 65 years. All cases had an underlying hematologic disorder (2 B-cell marginal-zone lymphomas, 2 monoclonal gammopathy of undetermined significance and 1 pulmonary plasmacytoma). Despite a common morphology characterized by a dense and irregular growth of large eosinophilic histiocytes with intracytoplasmic refractile crystals, 2 cases presented with cystic changes at gross and imaging examinations, calcified amyloid was found in 2 cases, and 1 case showed an interstitial lung disease with nonspecific interstitial pneumonia pattern. Histiocytes were immunoreactive for CD68 (clones PGM-1 and KP-1) but were not for CD1a and S100; the associated lymphoplasmacellular disorder had a clonal profile on molecular analysis with &kgr; light-chain restriction. Two cases were originally misdiagnosed as cystic fibrohistiocytic tumor and carcinoid tumor, thus confirming that CSH localized to this site may result in a diagnostic challenge with a broad spectrum of differential diagnoses. The presence of intracytoplasmic crystals and a plasma cell infiltrate around a histiocytic proliferation should alert the pathologist to consider CSH and to carefully investigate the presence of clonal hematologic disease.

Necrotizing sarcoid granulomatosis with an uncommon manifestation: clinicopathological features and review of literature

We report a rare case of an incidental diagnosis of necrotizing sarcoid granulomatosis (NSG) in a 60-y-old non-smoking male. The patient was admitted to the hospital for sudden back pain. Chest x-ray revealed areas of parenchymal consolidation and high-resolution computed tomography demonstrated a pulmonary nodular pattern with no lymph node enlargement. All laboratory and pulmonary function tests were normal. Bronchoscopy with bronchoalveolar lavage showed no sign of infection or specific inflammation. The diagnosis of NSG was made by histopathological examination of a surgical lung biopsy and by excluding other causes of granulomatous disease. In paucisymptomatic/asymptomatic patients, as in our case, therapy is not necessary, with a good prognosis and complete recovery. NSG is a rare systemic disease similar to sarcoidosis and Wegeners granulomatosis with a benign clinical course and should always be considered for patients with nodular pulmonary lesions even with subclinical or uncommon features.

Conflicting or complementary role of computed tomography (CT) and positron emission tomography (PET)/CT in the assessment of thymic cancer and thymoma: our experience and literature review

To evaluate the role of computed tomography (CT) and positron emission tomography (PET)/CT in patients with thymic cancer and thymoma at initial staging.

Crystal‐storing histiocytosis presenting with pleural disease

accrued in part as referrals for expert opinion. However, the primary goal of the study was to determine whether there were histological features in these biopsy specimens that come from infants with unexplained suspected diffuse parenchymal lung disease that have coexistent vascular abnormalities and that might give prognostic and predictive data in relation to future management; to a limited degree, this is what we achieved. In relation to cases with overlapping features of ACD and CAD, we think it unwise to provide specific clinical criteria, as our view is that this is a spectrum of changes that reflect variable immaturity and disordered growth within the lung. We can only hypothesize that the extent of ACD in such cases reflects poor survival, and the presence of relatively better capillary development in biopsy specimens with CAD suggests an improved chance of survival in these critically ill neonates and infants. The number of cases is small and the evidence is weak, but our study should at least provide a template for accrual of more data.

COPD-related adenocarcinoma presents low aggressiveness morphological and molecular features compared to smoker tumours

OBJECTIVES Adenocarcinoma comprises a group of diseases with heterogeneous clinical and molecular characteristics. COPD and lung cancer are strictly related; to date it is unknown if COPD-associated cancers have different features from tumours arising in non-COPD patients. Our aim was to study COPD-associated adenocarcinoma phenotypes mainly focusing on morphological and molecular aspects, in comparison to smoke-related cancer without COPD. MATERIALS AND METHODS From 2010 to 2013, 54 patients with adenocarcinoma (20 COPD and 34 smokers) were prospectively studied. Each patient underwent a complete clinical and instrumental assessment. Morphological studies included analysis of growth pattern, cell proliferation (Ki-67/MIB1 expression) and parameters of intra- and peri-tumoral remodelling (inflammation, fibrosis and necrosis). Genetic analysis of EGFR and KRAS mutations was also performed. RESULTS The two groups were comparable for the main demographic and biohumoral parameters except for increased blood basophil cell count in the COPD group. Compared to COPD, tumours of smokers presented an increased percentage of solid component (median: 20% vs 5%, p=0.02), a reduced percentage of lepidic pattern (median: 0% vs 10%, p=0.06) and higher Ki-67/MIB1 median value (55% vs 30%, p=0.02). In multivariate analysis lepidic and solid histological pattern were significantly influenced by clinical group (p=0.03 and 0.05, respectively). Concerning EGFR mutation, no differences were found between groups while KRAS mutation presented a trend of higher percentage in smokers compared to COPD (41% vs 20%, p=NS). Adenocarcinoma with KRAS mutation showed a higher value of Ki-67/MIB1 (65% vs 35%, p=0.048) and prevalent solid pattern (35% vs 10%, p=0.019) in comparison to wild-type form. CONCLUSIONS COPD-related adenocarcinoma presents molecular and morphological features of lower aggressiveness (increased lepidic component, reduced solid pattern, lower cell proliferation and less frequent KRAS mutation) compared to smokers. Different molecular mechanisms could be associated with the development of COPD associated cancer.

Synergistic Antitumor Activity of Recombinant Human Apo2L/Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand (TRAIL) in Combination with Carboplatin and Pemetrexed in Malignant Pleural Mesothelioma

Introduction: Malignant pleural mesothelioma (MPM) is an aggressive, currently incurable tumor with increasing incidence in industrialized countries. Tumor necrosis factor-related, apoptosis-inducing ligand (TRAIL) is a member of the TNF family, which induces cancer cell death through extrinsic apoptotic pathway, while sparing normal cells. The aim of this study was to investigate the antitumor activity of recombinant human Apo2L/TRAIL (dulanermin) in combination with chemotherapy in MPM in vitro and in vivo. Methods: In the present studies, we employed a panel of MPM cell lines to test the antitumor activity of recombinant human Apo2L/TRAIL (T) in combination with carboplatin and pemetrexed (CP) in vitro and SCID mice. Results: Results demonstrated a significant increase of apoptosis in cell lines treated with CPT compared with those receiving CP or T as single agents. This synergistic effect was dependent on the ability of CP to increase the expression of the TRAIL receptors DR4 and DR5 in a p53 manner. The CPT combination was also effective in blocking the growth of MPM cell lines in a SCID mice preclinical model. Conclusions: CPT increases MPM cell death in vitro and in vivo compared with CP. In vitro results suggest that chemotherapy sensitizes MPM to TRAIL-dependent apoptosis through p53 activation and subsequent upregulation of DRs.

Higher Risk of Acute Cellular Rejection in Lung Transplant Recipients with Cystic Fibrosis.

BACKGROUND Acute cellular rejection (ACR) affects up to 40% of recipients within the first year after lung transplant (LTx). The aim of this study was to determine the frequency of ACR and associated major risk factors in cystic fibrosis (CF) recipients. Bronchiolitis obliterans syndrome (BOS) and 1-year/long-term survival were also evaluated. MATERIAL AND METHODS ACR was reviewed in 643 scheduled biopsies from 44 CF (Group 1) versus 89 other recipients (Group 2). We performed univariate/multivariate analyses of risk factors for ACR and BOS, and survival analysis. RESULTS Group 1 showed higher ACR frequency, especially for ACR ≥ A2. Multivariable generalized linear models considering both native lung disease and age showed that higher values of ACR index were significantly related to the pretransplant diagnosis of CF. BOS and long-term survival were not influenced by the increased incidence of ACR. Poorer long-term survival was observed in Group 2. CONCLUSIONS CF recipients have a higher ACR risk, which may be due to enhanced immune activation related to a genetic disorder, and younger age.

Clear Cell Carcinoid of the Appendix: An Uncommon Variant of Lipid-Rich Neuroendocrine Tumor with a Broad Differential Diagnosis

The designation of clear cell/lipid-rich refers to an unusual variant of neuroendocrine tumor (“carcinoid”) described in several organs, but only recently observed in the appendix. In this study, we report the morphologic, immunohistochemical, and ultrastructural features of an incidentally discovered appendiceal clear cell/lipid-rich carcinoid in a 32-year-old man without any evidence of von Hippel–Lindau disease. Differential diagnosis with mimicking neoplastic and non-tumor lesions, epidemiology, and clinical behavior of this exceedingly rare variant of carcinoid of the appendix are also discussed.