The 2015 World Health Organization Classification of lung tumors: new entities since the 2004 Classification.

In the last few years different new pulmonary neoplastic lesions have been recognised and some of them, namely NUT carcinoma, PEComatous tumors, pneumocytic adenomyoepithelioma, pulmonary myxoid sarcoma, myoepithelial tumors/carcinomas entered in the last 2015-WHO classification of lung tumors. In addition angiomatoid fibrous histiocytoma and ciliated muconodular papillary tumor have been morphologically and genetically characterized albeit not yet included in the 2015-WHO classification.In the present paper we summarised the clinical, morphological, immunohistochemical and molecular features of these new entities. The knowledge of key histologic and molecular characteristics may help pathologists in achieving a correct diagnosis thus leading to an adequate therapeutic approach.

Rare diffuse diseases of the lung. Pulmonary alveolar proteinosis, lymphangioleiomyomatosis, amyloidosis.

Pulmonary alveolar proteinosis (PAP), lymphangioleyomiomatosis (LAM) and amyloidosis are three unrelated diseases of rare occurrence, with characteristic histopathological features. A pattern of alveolar filling with granular pink material accumulation is characteristic of PAP. This material can be recognized in lung biopsies, but also in bronchial lavage fluid. PAP is clinically related to the abnormal clearance of alveolar surfactant, most commonly due to the disruption of the granulocyte macrophage-colony stimulating factor signalling pathway. Whole lung lavage is the treatment of choice. LAM is characterized by cystic lung degeneration and interstitial proliferation of LAM cells, which express both melanocyte and smooth muscle cell markers, has a typical cystic pattern on CT scan, can be associated clinically with abdominal angiomyolipomas and limphangioleiomyomas, and occurs in female patients, either in isolation or as a manifestation of tuberous sclerosis. Sex hormone manipulation is the therapy of choice in this otherwise progressive disease. Diffuse interstitial or perivascular amyloid deposits in the lung can form in the context of systemic amyloidosis, usually associated with myeloma or monoclonal gammopathy, and less often with chronic inflammatory diseases. Nodular amyloid deposits, in contrast, are not associated with systemic lung disease, and present instrumentally as a coin lesion or lung mass. Isolated tracheobronchial amyloidosis is another rare form that is not related to systemic disease. In all conditions, amyloid has a typical waxy, amorphous, slightly eosinophilic stain, stains red with Congo red and presents a characteristic apple-green birefringence under polarized light, which is essential for diagnosis.

A rare case of pedunculated bronchial hemangioma.

We describe a rare case of pedunculated endobronchial hemangioma observed in a 60-years-old patient complaining of chronic productive cough and accessional dyspnea which had been progressively worsening over 20 years. The lesion was first noticed at fiberoptic bronchoscopy; then computed tomography scan was performed and integrated with tridimensional reconstruction techniques. Pathology showed the picture of a vascular neoplasm, compatible with capillary hemangioma. The lesion was submitted to laser-assisted endoscopic removal in order to relieve the obstruction, leading to remission of symptoms.

Rapidly progressive organising pneumonia associated with cytomegalovirus infection in a patient with psoriasis.

A 63-year-old woman experienced progressive respiratory distress and psoriatic plaques. The radiographic images showed diffuse interstitial infiltrates. The surgical open lung biopsy revealed an obliteration of the alveolar spaces by plugs of connective tissue distributed within the terminal bronchioles, alveolar ducts and spaces. No relevant cause was determined, and she was diagnosed with idiopathic organising pneumonia. The patient was discharged with oral glucocorticosteroid and supplemental oxygen therapy. One month later, the patient's pulmonary status had progressively worsened, and she was re-admitted. She required higher oxygen concentrations and mechanical ventilation. Pharmacological therapy included high-dose steroids and cyclophosphamide. Serological assays revealed high antibodies titers (both IgM and IgG) to cytomegalovirus. Therefore, ganciclovir was added to the regimen. Despite the therapy, she died as a result of the disease. The review of the current literature on the topic is also presented.

Upregulation of basic fibroblast growth factor in smokers with chronic bronchitis.

The aim of the study was to investigate the expression of basic fibroblast growth factor (bFGF) and its receptor, fibroblast growth factor receptor (FGFR)-1, in the central airways of smokers with chronic bronchitis. The lobar bronchi from 17 subjects undergoing thoracotomy for solitary nodules were examined. All had a history of cigarette smoking, nine had symptoms of chronic bronchitis and airflow limitation, and eight were asymptomatic with normal lung function. Using immunohistochemical methods, bFGF and FGFR-1 expression in the total airway wall and the different airway compartments, i.e. bronchial glands, submucosal vessels and smooth muscle, was quantified. Moreover, to investigate the role of bFGF in angiogenesis, the number of submucosal vessels was quantified. Smokers with chronic bronchitis had an increased bFGF expression in the total airway wall compared with asymptomatic smokers, which was mainly due to bFGF upregulation in bronchial glands. By contrast, the expression of FGFR-1 and the number of submucosal vessels was similar in the two groups of subjects examined. In conclusion, smokers with chronic bronchitis have an increased expression of basic fibroblast growth factor in the central airways, which is mainly due to an increased expression in bronchial glands, suggesting the involvement of this growth factor in the pathogenesis of chronic bronchitis.

c-erbB-2 and episialin challenge host immune response by HLA class I expression in human non-small-cell lung cancer.

The role of major histocompatibility complex expression in cancer prognosis and pathogenesis is contradictory. The aim of the current study was to compare the expression of HLA class I molecules and of oncoproteins that may be sources of peptides presented by HLA class I antigens in non-small-cell lung cancer. For this purpose, the expression of HLA class I antigen and TAP-1 molecule (a transporter in the antigen-processing 1 transport protein) were studied with epidermal growth factor, receptor; c-erbB-2; episialin; wild-type and mutant p53; bcl-2 oncoprotein expression; and angiogenic factor expression (vascular endothelial growth factor and thymidine phosphorylase). The degree of lymphocytic stromal infiltration and of platelet-endothelial cell adhesion molecule-expressing lymphocytes was also studied. A strong association of c-erbB-2 and MUC1 (episialin) expression with HLA class I expression was observed (p = 0.005 and 0.009, respectively). Intense CD31-positive lymphocytic infiltration was also more frequent in HLA class I-positive cases (p = 0.05). Although there was no association of HLA class I expression with survival, loss of the HLA class I expression in MUC1 or c-erbB-2 overexpressing cases conferred a poorer clinical outcome (p = 0.04). Both c-erbB-2 and MUC1 are well-known targets of T-cell-mediated cytotoxicity and cell-cell or cell-matrix adhesion-regulating proteins. The authors provide evidence that the sequence of cell adhesion-disrupting oncoprotein expression, HLA class I induction, and enhanced epitope presentation followed by lymphocytic response is an important pathogenetic three-step sequence of events that define, in part, the clinical outcome in non-small-cell lung cancer.

The expression of basic fibroblast growth factor (bFGF) in tumor-associated stromal cells and vessels is inversely correlated with non-small cell lung cancer progression.

Tumor progression results from complex interactions between tumor and tumor-associated host tissue. Basic fibroblast growth factor (bFGF), via activation of its receptor, FGFR-1, has been postulated to be an important inducer of host stromal response and angiogenesis. To assess the putative role of tumor-associated stromal cells and vessels in tumor progression, we studied non-small cell lung cancer (NSCLC) from 84 patients, including 51 squamous cell carcinomas and 33 nonsquamous cell carcinomas, by immunohistochemical detection. bFGF and FGFR-1 immunoreactivity was observed in tumor and in tumor-associated stromal cells and vessels. The expression of bFGF and FGFR-1 in stromal cells was higher in squamous than in non-squamous cell carcinomas (respectively, P = .007 and P = .0004). We found that bFGF and FGFR-1 expression in tumor and tumor-associated stromal cells and vessels was directly correlated with host stromal response, as assessed by intratumoral extension of stroma, but not with angiogenic response, as assessed by microvessel count. Although FGFR-1 expression of tumor cells was directly correlated with T-stage (P = .03), bFGF expressions of tumor-associated stromal cells and vessels were inversely correlated with lymph node metastasis (respectively, P = .0001 and P = .0002) and advanced pathological stage (respectively, P = .03 and P = .01). These findings suggest that bFGF might mediate host stromal response in NSCLC and that the expression of bFGF in tumor-associated stromal cells and vessels might have an inhibitory role in NSCLC progression.

Comparison between nasal and bronchial inflammation in asthmatic and control subjects.

Although asthma and rhinitis often coexist, it is still unknown whether they are characterized by a similar inflammatory profile. We studied eosinophilic infiltration, epithelial shedding and reticular basement membrane thickness in nasal and bronchial biopsies of six control subjects, 15 untreated allergic asthmatics with perennial rhinitis, and six corticosteroid-dependent (CSD) asthmatics. In nasal and bronchial biopsies, eosinophils were greater in untreated asthmatics than in control subjects and CSD asthmatics (p = 0.001). In untreated asthmatics, eosinophils were higher in bronchial than in nasal biopsies (p = 0.002). In nasal and bronchial biopsies, reticular basement membrane thickness was greater in untreated and CSD asthmatics than in control subjects (nasal: p < 0.008 and p < 0. 004; bronchial: p < 0.001 and p < 0.008). In untreated and CSD asthmatics, reticular basement membrane thickness was greater in bronchial than in nasal biopsies (p = 0.001; Wilcoxon's W test). Nasal epithelium was not shed in all the study groups. In untreated asthmatics, bronchial epithelium shedding was greater than in control subjects or CSD asthmatics (p < 0.005), and it was greater than nasal epithelium shedding (p < 0.006). This study has shown that, although concomitant, the extent of eosinophilic inflammation of reticular basement membrane thickness and of the epithelium shedding is greater in bronchial than in nasal mucosa of asthmatic patients with perennial rhinitis.

Depolarized expression of episialin (EMA, MUC1) in lung adenocarcinoma is associated with tumor progression.

Carcinoma cell detachment is an important step in tumor progression and metastasis. Episialin (EMA), if expressed throughout the entire cell surface, may inhibit cell-cell and cell-matrix adhesion. We investigated whether the cellular distribution of episialin in non-small cell lung cancer (NSCLC) is associated with tumor progression. We evaluated the expression of episialin by immunohistochemical staining, in surgical specimens from 122 adenocarcinomas and 99 squamous cell carcinomas. Episialin was present in most NSCLC, with a higher percentage of immunoreactive neoplastic cells in adenocarcinoma than in squamous cell carcinoma (p = 0.0001). In adenocarcinoma the depolarized pattern was significantly associated with nodal metastasis (p = 0.005) and with advanced stage (p = 0.007). In conclusion, nodal metastasis and advanced pathological stage in adenocarcinoma are associated with a depolarized cellular distribution of episialin, suggesting a possible involvement of the molecule in cancer metastasis.

MUC1 (episialin) expression in non-small cell lung cancer is independent of EGFR and c-erbB-2 expression and correlates with poor survival in node positive patients.

AIM: To examine tumour samples immunohistochemically for MUC1 (episialin), epidermal growth factor receptor (EGFR), and c-erbB-2, since the disruption of the cell-cell adhesion system by MUC1 and the c-erbB oncoprotein family is known to be important in the development of metastasis in human cancers. METHODS: 93 tumour samples from patients with early stage non-small cell lung cancer treated with surgery alone were examined for episialin, EGFR, and c-erbB-2. RESULTS: Episialin depolarised expression did not correlate with any of the histopathological variables examined (T,N stage, grade, histology, Ki67 proliferation index). No correlation was observed between episialin and EGFR or c-erbB-2 expression. Survival analysis showed that episialin depolarised expression correlated with poor prognosis (p = 0.003), especially in squamous cell cases (p = 0.0003). Episialin expression defined a group of patients with poor prognosis in the node positive category (p = 0.003). In multivariate analysis episialin was the most significant independent prognostic factor (p = 0.007), followed by N stage (p = 0.04). CONCLUSIONS: Depolarised expression of episialin is associated with poor outcome in early stage non-small cell lung cancer. Despite the similar activity on the cadherin cell-cell adhesion system, the expression of episialin and c-erbB oncoproteins is likely to be activated within different pathogenic pathways.

Polysialylated N-CAM, chromogranin A and B, and secretogranin II in neuroendocrine tumours of the lung.

Highly alpha 2-8-sialylated N-CAM (neural cell adhesion molecule) impairs N-CAM-mediated cell adhesion. We investigated polysiaN-CAM immunoreactivity in a range of neuroendocrine lung tumours: 15 typical carcinoids, 21 atypical carcinoids, 2 large cell neuroendocrine carcinomas and 12 small cell lung carcinomas were selected on a morphological basis and by their immunoreactivity for chromogranin A and B and secretogranin II. A progressive loss of chromogranin expression, particularly of chromogranin B, was paralleled by the up-regulation of polysiaN-CAM in histologically more aggressive tumours (P = 0.001). These data support the hypothesis that loss of cell-cell adhesion properties might be a relevant factor in the origin of the aggressivity of lung neuroendocrine tumours.

Extracellular matrix proteins, integrin receptors (VLA-beta 1, VLA-alpha 2 and VLA-alpha 5) and growth fraction in atypical macroregenerative nodules of the liver: an immunocytochemical case study.

A case of cirrhotic liver harbouring three atypical macroregenerative nodules and an hepatocellular carcinoma was immunocytochemically investigated for the expression of VLA-beta 1, VLA-alpha 2 and VLA-alpha 5 integrins and for different extracellular matrix (ECM) components (collagen I, collagen IV, laminin, fibronectin and tenascin). In addition, the proliferative activity within the nodules was evaluated, using the MIB 1 monoclonal antibody (MAb). The cirrhotic liver disclosed a continuous staining pattern of the ECM proteins investigated, as well as a "sinusoidal" immunostaining of VLA-beta 1, VLA-alpha 2 and VLA-alpha 5. The macroregenerative nodules showed a discontinued immunoreactivity for ECM proteins while maintaining a VLA-beta 1 sinusoidal immunostaining, coupled with intercellular immunostaining. VLA-alpha 2 and VLA-alpha 5 expression was lacking. The growth fraction was low in both the above pathological conditions. The hepatocellular carcinoma was devoid of any ECM immunostaining. VLA-beta 1 immunoreactivity exhibited a honeycomb pattern of staining, whereas VLA alpha subunits were absent. MIB1 expression was high, being present in 30% of neoplastic nuclei. A possible relationship between atypical macroregenerative nodules and hepatocellular carcinoma is discussed.

[Collagenous colitis. Morphologic and immunohistochemical study]. / Colite collagena. Studio morfologico ed immunoistochimico.

Collagenous colitis is a clinico-pathological entity characterized by chronic diarrhoeas and deposition of collagen beneath the epithelium surface of large bowel. We revised 265 endoscopy biopsy specimens of the large bowel from 198 consecutive patients with "aspecific chronic colitis". Morphometric study showed that were not significant differences among various tracts in the same patients regarding to the thickness of basament membrane. It was more than 11.9 +/- 0.49 mu only in 13 pts (6.6%), while it was 3.96 +/- 1.4 mu in the others. Immunohistochemistry study confirmed the normality of subepithelial basement membrane and the below deposition of the large quantity of collagen IV.

[Argyrophilic nucleoproteins of the cervical epithelium in HPV infection and intraepithelial neoplasia]. / Studio delle nucleoproteine argirofile dell'epitelio cervicale nelle infezioni da HPV e nelle neoplasie intraepiteliali.

50 colposcopic biopsies of cervical epithelium were studied, using a silver colloid technique. These comprised 28 cases of human papillomavirus infection of the cervix, 8 cases of cervical intraepithelial neoplasia (CIN) I, 8 cases of CIN II, 6 cases of CIN III. The AgNOR mean number of the basal and parabasal cells of the cervical epithelium was significantly different in virus infected cells and in CIN. Different patterns of AgNOR distribution were observed: they were single and compact in virus infection without dysplasia whereas they appeared small and often loosely arranged in dysplastic lesions. Our data suggest that this simple technique is diagnostically useful in the evaluation of borderline lesions.