Pulmonary pathologists were aware of cases of idiopathic interstitial pneumonia (IIP) that morphologically did not fit Liebow's classification scheme. These cases were labeled as "cellular ...interstitial pneumonia" or "chronic interstitial pneumonia not otherwise specified." The term nonspecific interstitial pneumonia (NSIP) was first used in relation to a pattern of lung interstitial inflammation seen in association with human immunodeficiency virus (HIV) infection. In 1994 NSIP was used to indicate a group of subacute or chronic interstitial pneumonias characterized morphologically by interstitial inflammation or fibrosis or both, with preservation of the lung architecture and the absence of typical findings for any of the other main categories of IIP (mainly usual interstitial pneumonia, desquamative interstitial pneumonia, and bronchiolitis obliterans organizing pneumonia). Although these patients presented with "nonspecific" lung histology (categorized as cellular and fibrotic variants), and with a broad spectrum of associated clinical conditions, such as connective tissue diseases (CTDs), environmental exposure, and previous acute lung injury, they showed some peculiar clinical aspects, including favorable response to corticosteroid treatment and overall good prognosis.The clinical and radiographic profiles were better defined in the last decade. The NSIP pattern is the histological background of a subacute/chronic interstitial pneumonitis that may be observed in many conditions, including CTD, drug-induced lung disease, hypersensitivity pneumonitis, slowly healing diffuse alveolar damage (DAD), relapsing organizing pneumonia, occupational exposure, immunodeficiency (mainly HIV infection), graft versus host disease (GVHD), familial pulmonary fibrosis, immunoglobulin G4 (IgG4)-related sclerosing disease, with or without overlap features with Rosai-Dorfman disease, multicentric Castleman disease, and myelodysplastic syndrome. Rarely, NSIP is the histology recognized in patients with idiopathic interstitial pneumonitis, in whom efforts to find potential causative exposures are futile. This entity occurs mostly in middle-aged, never-smoker women, with a likely association with an autoimmune background. High-resolution computed tomographic (HRCT) scans typically demonstrate ground-glass attenuation with a bibasilar distribution, or in the fibrotic variant, ground-glass attenuation along with reticular lines and traction bronchiectasis. The prognosis is good compared with idiopathic pulmonary fibrosis (IPF), and therapeutic options include mainly corticosteroids and immunosuppressive agents. Recently a more precise definition of clinical profiles and radiographic findings of idiopathic NSIP allows consideration of less invasive diagnostic procedures (bronchoalveolar lavage, transbronchial lung biopsy). Better understanding of pathogenetic mechanisms might widen the therapeutic horizon giving a role to new therapeutic options in more severe cases.
In B-cell chronic lymphocytic leukemia (B-CLL), defective apoptosis causes the accumulation of mature CD5+ B cells in lymphoid organs, bone marrow (BM), and peripheral blood (PB). These cells are the ...progeny of a proliferating pool that feeds the accumulating compartment. The authors sought to determine which molecular mechanisms govern the proliferating pool, how they relate to apoptosis, and what the role is of the microenvironment. To begin to resolve these problems, the expression and modulation of the family of inhibitor of apoptosis proteins (IAPs) were investigated, with consideration given to the possibility that physiological stimuli, such as CD40 ligand (CD40L), available to B cells in the microenvironment, might modulate IAP expression. The in vitro data on mononuclear cells from PB or BM of 30 patients demonstrate that B-CLL cells on CD40 stimulation express Survivin and that Survivin is the only IAP whose expression is induced by CD40L. Through immunohistochemistry, in vivo Survivin expression in lymph node (LN) and BM biopsies was evaluated. In reactive LN, Survivin was detected only in highly proliferating germinal center cells. In LN from patients with B-CLL, Survivin was detected only in pseudofollicles. Pseudofollicle Survivin+ cells were actively proliferating and, in contrast to Survivin+ B cells found in normal GC, were Bcl-2+. In B-CLL BM biopsies, CD5+, Survivin+ cells were observed in clusters interspersed with T cells. These findings establish that Survivin controls the B-CLL proliferative pool interfacing apoptosis and that its expression may be modulated by microenvironmental stimuli.
Follicular lymphoma is characterized by aberrant BCL2 expression, a feature that is exploited for diagnostic purposes. However, a certain percentage of follicular lymphomas might be BCL2-negative by ...immunohistochemistry, increasing the difficulties in differentiating them from follicular hyperplasia. The expression of TUBB3 has been recently reported as negative in a small series of follicular lymphomas. We have therefore tested a larger series, including 61 BCL2-positive and 25 BCL2-negative cases, and compared them with 61 reactive lymphoid tissues. First, a subjective score of TUBB3 staining was applied, showing that it was consistently positive in reactive germinal centers, while most follicular lymphomas were negative; in fact, only 10/61 (16%) BCL2-positive and 1/25 (4%) BCL2-negative cases showed a positive staining for TUBB3, while 58/61 (95%) of tissues with follicular hyperplasia were positive. The application of a standardized scoring system to a large number of follicles, based on virtual slides, demonstrated that reactive lymphoid tissues had a significantly higher number of TUBB3-positive follicles both compared with BCL2-positive cases and to BCL2-negative cases. Our data support the use of TUBB3 staining in differentiating follicular lymphoma, including BCL2-negative cases, from follicular hyperplasia.
Idiopathic pulmonary fibrosis (IPF) is the most common type of idiopathic interstitial pneumonia and has a dismal prognosis. Median age at IPF onset is 60-70 years and it is mainly related to ...cigarette smoke exposure. Its clinical profile is heterogeneous and different clinical phenotypes are now better defined: familial IPF, slow and rapid progressors, combined pulmonary fibrosis and emphysema, anti-neutrophil cytoplasmic antibodies/microscopic polyangiitis and IPF, and IPF associated with lung cancer. Acute exacerbation associated with rapid functional decline is an event that does not happen infrequently and affects survival. Diagnosis requires a typical usual interstitial pneumonia (UIP) pattern on computed tomography in the appropriate clinical setting or morphological confirmation of the UIP pattern when imaging findings are not characteristic enough. Surgical lung biopsy is the gold standard to obtain valuable information for histological analysis. However, less invasive procedures (transbronchial lung biopsy or even improved transbronchial lung biopsy by cryoprobes) are now under consideration. Prognostic indicators are mainly derived by pulmonary function tests. Recently, staging systems have been proposed.
Fibroblast foci (FF) are considered a relevant morphologic marker of idiopathic pulmonary fibrosis/usual interstitial pneumonia (IPF/UIP), and are recognised as sites where fibrotic responses are ...initiated and/or perpetuated in this severe disease. Despite their relevance, the cellular and molecular mechanisms responsible for the formation of FF and their role in tissue remodelling are poorly defined. In previous studies we have provided evidence of abnormal activation of the wnt-signaling-pathway in IPF/UIP that is centred on FF and the overlying epithelium. This important morphogenetic pathway is able to trigger epithelial-mesenchymal-transition (EMT), a mechanism involved in developmental and metastatic processes, which is also potentially involved in pulmonary fibrosis.
Since EMT is characterised by enhancement of migratory potential of cells, we investigated the molecular profile of FF in 30 biopsies of IPF/UIP and a variety of control samples, focussing on the immunohistochemical expression of three molecules involved in cell motility and invasiveness, namely laminin-5-gamma2-chain, fascin, and heat-shock-protein-27.
We provide evidence that in UIP these three molecules are abnormally expressed in discrete clusters of bronchiolar basal cells precisely localised in FF. These cellular clusters expressed laminin-5-gamma2-chain and heat-shock-protein-27 at very high levels, forming characteristic three-layered lesions defined as "sandwich-foci" (SW-FF). Upon quantitative analysis SW-FF were present in 28/30 UIP samples, representing more than 50% of recognisable FF in 21/30, but were exceedingly rare in a wide variety of lung pathologies examined as controls. In UIP, SW-FF were often observed in areas of microscopic honeycombing, and were also found at the interface between normal lung tissue and areas of dense scarring.
These molecular abnormalities strongly suggest that SW-FF represent the leading edge of pulmonary remodelling, where abnormal migration and re-epithelialisation take place, and that abnormal proliferation and migration of bronchiolar basal cells have a major role in the remodelling process characterising IPF/UIP. Further investigations will assess their possible use as reliable markers for better defining the UIP-pattern in difficult cases.
Different anatomic and physiological changes occur in the lung of aging people that can affect pulmonary functions, and different pulmonary diseases, including deadly diseases such as chronic ...obstructive pulmonary disease (COPD)/emphysema and idiopathic pulmonary fibrosis (IPF), can be related to an acceleration of the aging process. The individual genetic background, as well as exposure to a variety of toxic substances (cigarette smoke in primis ) can contribute significantly to accelerating pulmonary senescence. Premature aging can impair lung function by different ways: by interfering specifically with tissue repair mechanisms after damage, thus perturbing the correct crosstalk between mesenchymal and epithelial components; by inducing systemic and/or local alteration of the immune system, thus impairing the complex mechanisms of lung defense against infections; and by stimulating a local and/or systemic inflammatory condition (inflammaging). According to recently proposed pathogenic models in COPD and IPF, premature cellular senescence likely affects distinct progenitors cells (mesenchymal stem cells in COPD, alveolar epithelial precursors in IPF), leading to stem cell exhaustion. In this review, the large amount of data supporting this pathogenic view are discussed, with emphasis on the possible molecular and cellular mechanisms leading to the severe parenchymal remodeling that characterizes, in different ways, these deadly diseases.
Lobular breast carcinoma usually shows poor responsiveness to chemotherapies and often lacks targeted therapies. Since FGFR1 expression has been shown to play pivotal roles in primary breast cancer ...tumorigenesis, we sought to analyze the status of FGFR1 gene in a metastatic setting of lobular breast carcinoma, since promising FGFR1 inhibitors has been recently developed.
Fifteen tissue metastases from lobular breast carcinomas with matched primary infiltrative lobular breast carcinoma were recruited. Eleven cases showed loco-regional lymph-nodal and four haematogenous metastases.FGFR-1 gene (8p12) amplification was evaluated by chromogenic in situ hybridization (CISH) analysis. Her-2/neu and topoisomerase-IIα gene status was assessed. E-cadherin and Hercept Test were also performed. We distinguished amplification (>6 or cluster of signals) versus gains (3-6 signals) of the locus specific FGFR-1 gene.
Three (20%) primary lobular breast carcinomas showed >6 or cluster of FGFR1 signals (amplification), six cases (40%) had a mean of three (range 3-6) chromogenic signals (gains) whereas in 6 (40%) was not observed any abnormality. Three of 15 metastasis (20%) were amplified, 2/15 (13,4%) did not. The ten remaining cases (66,6%) showed three chromogenic signals.The three cases with FGFR-1 amplification matched with those primary breast carcinomas showing FGFR-1 amplification. The six cases showing FGFR-1 gains in the primary tumour again showed FGFR-1 gains in the metastases. Four cases showed gains of FGFR-1 gene signals in the metastases and not in the primary tumours. Her-2/neu gene amplification was not observed in all cases but one (6%) case. Topoisomerase-IIα was not amplified in all cases.
1) a subset of metastatic lobular breast carcinoma harbors FGFR-1 gene amplification or gains of chromogenic signals; 2) a minor heterogeneity has been observed after matching primary and metastatic carcinomas; 3) in the era of tailored therapies, patients affected by the lobular subtype of breast carcinoma with FGFR1 amplification could be approached to the new target biological therapy such as emerging FGFR-1 inhibitors.
The discovery of specific molecular alterations (i.e. EGFR activating mutations, EML4/ALK translocation, ROS1 rearrangements) in a selected population of patients affected by non small cell lung ...cancer (NSCLC) translated into effective treatments for this small but well defined fraction of patients, driven by the use of predictive biomarkers of efficacy for targeted agents. Unfortunately, the same reliable predictive biomarkers are lacking for anti-angiogenic drugs. Angiogenesis plays a major role in the progression of NSCLC, however, anti-angiogenic agents provided a minimal, although significant, clinical benefit in unselected populations, burdened by a not negligible toxicities. In this context, no validated angiogenic factor or other molecular biomarker of angiogenesis can reliably predict clinical outcome, sensitivity, early response or resistance to any of the investigated anti-angiogenic therapies currently used. Moreover, the available clinical data are prevalently retrospective, underpowered, and, in many cases, contradictory, thus underscoring that the understanding of the complex architecture of angiogenic signaling is still incomplete. We here review the currently available studies on the effect of anti-angiogenic drugs in NSCLC, with a particular focus on bio-molecular factors that are regarded as potential predictors of treatment efficacy.
Hepatocellular carcinoma is one leading cause of cancer-related death and surgical resection is still one of the major curative therapies. Recently, there has been a major effort to find mechanisms ...involved in carcinogenesis and early relapse. c-myc gene abnormality is found in hepatocarcinogenesis. Our aim was to analyze the role of c-myc as prognostic factor in terms of overall survival and disease-free survival and to investigate if c-myc may be an important target for therapy. We studied sixty-five hepatocellular carcinomas submitted to surgical resection with curative intent. Size, macro-microvascular invasion, necrosis, number of nodules, grading and serum alfa-fetoprotein level were registered for all cases. We evaluated the c-myc aberrations by using break-apart FISH probes. Probes specific for the centromeric part of chromosome 8 and for the locus specific c-myc gene (8q24) were used to assess disomy, gains of chromosomes (polysomy due to polyploidy) and amplification. c-myc gene amplification was scored as 8q24/CEP8 > 2. Statistical analysis for disease-free survival and overall survival were performed. At molecular level, c-myc was amplified in 19% of hepatocellular carcinoma, whereas showed gains in 55% and set wild in 26% of cases. The 1- and 3-year disease-free survival and overall survival for disomic, polysomic and amplified groups were significantly different (p=0.020 and p=.018 respectively). Multivariate analysis verified that the AFP and c-myc status (amplified vs. not amplified) were significant prognostic factors for overall patients survival. c-myc gene amplification is significantly correlated with disease-free survival and overall survival in patients with hepatocellular carcinoma after surgical resection and this model identifies patients with risk of early relapse (≤12 months). We suggest that c-myc assessment may be introduced in the clinical practice for improving prognostication (high and low risk of relapse) routinely and may have be proposed as biomarker of efficacy to anti-c-myc targeted drugs in clinical trials.
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