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Reggio nell'Emilia, Italy

Pelosi G.,University of Milan | Gasparini P.,Tumor Genomics Unit | Conte D.,Tumor Genomics Unit | Pupa S.M.,Molecular Targets Unit | And 9 more authors.
Journal of Thoracic Oncology | Year: 2016

Introduction: Genetic alterations suitable for targeted therapy are poorly known issues in pulmonary sarcomatoid carcinoma (PSC), an uncommon and life-threatening family of non-small cell lung cancers. Methods: Ninety-eight PSCs were assessed for MNNG HOS Transforming gene (MET) and anaplastic lymphoma receptor tyrosine kinase gene (ALK) status by fluorescence in situ hybridization (FISH) and for relevant protein expression by immunohistochemical analysis, also taking advantage of phosphorylated (p-) antibodies. Moreover, levels of ALK and MET mRNA were also determined by real-time polymerase chain reaction and Western blot analysis for downstream activation pathways involving p-MET, p-protein kinase B, p-mitogen-activated protein kinase, p-SRC proto-oncogene tyrosine-protein kinase, and p-focal adhesion kinase (p-FAK). Results: MET amplification was detected by FISH in 25 of 98 PSCs (25.6%) and ALK amplification (but not the relevant rearrangement) was found in 16 of 98 (16.3%), with all ALKamplified tumors also showing MET amplification (p < 0.0001). Nine PSCs, however, showed MET amplification without any ALK gene alteration. ALK protein expression was always lacking, whereas MET and p-MET were confined to the relevant amplified tumors only. Increased levels of ALK and MET mRNA were detectable in tumors with no direct relationship between mRNA content, protein expression, or alterations detected by FISH. Western blot assays showed complete activation of downstream signal pathways up to p-SRC proto-oncogene tyrosine-protein kinase, and p-focal adhesion kinase recruitment in MET and ALK-coamplified tumors only, whereas isolated MET amplification, MET and ALK borderline amplification (5%-10% of tumor cells with 15 copies of the relevant gene), or negative tumors showing eusomy or chromosome polysomy were confined to p-mitogen-activated protein kinase, p-protein kinase B, and/or p-MET activation. Multivariate survival analysis pushed a higher percentage of MET altered cells or a higher value of MET copy gain per cell to marginally emerge for overall survival (p = 0.140) and disease-free survival (p = 0.060), respectively. Conclusions: ALK and MET seemed to act as synergistic, nonrandom coactivators of downstream signal when coamplified in a subset of patients with PSC, thus likely suggesting a combined mechanism of oncogene addiction. These alterations could be a suitable target for therapy based on specific inhibitors. © 2016 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.

Rossi G.,University of Modena and Reggio Emilia | Cavazza A.,Operative Unit of Pathologic Anatomy
Clinical Reviews in Allergy and Immunology | Year: 2015

Pathologists are frequently involved in the diagnosis of sarcoidosis on conventional biopsies or examining bronchoalveolar lavage fluid and assisting bronchoscopists when performing bronchial or transbronchial biopsies or transbronchial needle aspiration (TBNA)/endobronchial ultrasound (EBUS)-guided biopsies of enlarged lymph nodes. Histology generally does not pose difficult tasks in the correct clinical and imaging scenario, but atypical forms of sarcoidosis exist, and in these cases, the diagnosis may become difficult. When faced with granulomas in the lung, the evaluation of their qualitative features, anatomic distribution, and accompanying findings usually allows the pathologist to narrow considerably the differential diagnosis. The final diagnosis always requires the careful integration of the histology with the clinical, laboratory, and radiologic findings. How robust is the histologic component of the diagnosis varies from case to case, and the pathologist should always clearly discuss this point with the clinician; in general, the weaker the histology is, the stronger should be the clinical–radiologic findings, and vice versa. The differential diagnosis of sarcoidosis includes granulomatous infections, hypersensitivity pneumonitis, pneumoconiosis, autoimmune diseases (e.g., inflammatory bowel disease, primary biliary cirrhosis, several collagen vascular diseases (particularly Sjögren), drug reactions, chronic aspiration, and even diffuse fibrosing diseases. In this review, conventional and unusual histologic findings of pulmonary sarcoidosis are presented, highlighting the role of the pathologist and discussing the main differential diagnoses. © 2015, Springer Science+Business Media New York.

Pelosi G.,University of Milan | Papotti M.,University of Turin | Rossi G.,Pathologic Anatomy | Cavazza A.,Operative Unit of Pathologic Anatomy | And 5 more authors.
Journal of Thoracic Oncology | Year: 2015

Introduction: Little is known about genotypic and phenotypic correlations in undifferentiated large-cell carcinoma (LCC) of the lung. Methods: Thirty LCC were dissected by unsupervised targeted next generation sequencing analysis for 50 cancer-associated oncogenes and tumor suppressor genes. Cell differentiation lineages were unveiled by using thyroid transcription factor-1 (TTF1) for adenocarcinoma (ADC) and p40 for squamous cell carcinoma (SQC), dichotomizing immunohistochemistry (IHC) results for TTF1 as negative or positive (whatever its extent) and for p40 as negative, positive, or focal (if <10% of reactive tumor cells). Results: Three LCC were wild type (all TTF1+/p40-), whereas the remaining 27 (90%) tumors had at least one gene mutation. Twenty-four cases featuring TTF1+/p40-, TTF1+/p40±, TTF1-/p40±, or TTF1-/p40- phenotypes comprised ATM, BRAF, CDKN2A, EGFR, ERBB4, FBXW7, FLT3, KRAS, NRAS, PIK3CA, PTPN11, RET, SMAD4, SMO, STK11, or TP53 mutations in keeping with ADC lineage, whereas three tumors showing TTF1-/p40+ phenotype harbored TP53 only and no ADC-related mutations in keeping with SQC lineage. Single, double, triple, quadruple, and quintuple mutations occurred in 16, 6, 2, 2, and 1 patient, respectively. The occurrence of three mutations or more but not any immunohistochemistry categorization predicted shorter overall survival (OS, p = 0.001) and disease-free survival (DFS, p = 0.007), independent of age, sex, and tumor stage. Conclusions: Albeit preliminary also because of the relatively small number of LCC under evaluation, this targeted next generation sequencing study, however, revealed gene mutation heterogeneity in LCC with some genotypic-phenotypic correlations. Negativity or focal occurrence of p40 made SQC diagnosis unlikely on molecular grounds, but suggested ADC confirming validity of the axiom "no p40, no squamous.". © 2015 by the International Association for the Study of Lung Cancer.

Rossi G.,Section of Pathologic Anatomy | Cavazza A.,Operative Unit of Pathologic Anatomy | Gennari W.,Laboratory of Virology | Marchioni A.,Respiratory Diseases Clinic | And 4 more authors.
American Journal of Surgical Pathology | Year: 2012

Pulmonary granulomas represent a common inflammatory reaction to several lung infective or noninfective diseases. However, little is known about the histology and clinical presentation of chickenpox-related granulomas in immunocompetent subjects. We collected a series of 8 adult patients (mean age, 40 y; range, 33 to 53 y) with several bilateral pulmonary granulomas incidentally discovered after imaging studies. All patients were asymptomatic and had experienced a varicella-zoster virus (VZV) infection as adults but were clinically suspected to have a metastatic neoplasm of unknown origin. Chest computed tomography scan revealed numerous, tiny (few millimeters to 1 cm in size) nodules randomly dispersed through the lungs. Positron emission tomography scan performed in 4 patients was negative. All patients underwent video-assisted thoracoscopic surgical resection and were still alive and well. At histology, granulomas consisted of well-defined, rounded, small nodules centered by a deeply eosinophilic, acellular necrosis rimmed by lamellar dense collagen and a chronic inflammatory infiltrate with or without multinucleated giant cells. Chickenpox-related granulomas were included in the differential diagnosis along with several other granulomatous diseases. Polymerase chain reaction-based molecular analysis for VZV performed on paraffin sections detected VZV DNA in all 8 cases. By contrast, 85 cases of pulmonary granulomas of different etiologies were simultaneously studied by molecular analysis with negative results. Pathologists should be familiar with the peculiar morphologic appearance of chickenpox-related granulomas. A careful search for a history of VZV infection in adulthood and molecular studies may be very helpful in confirming the diagnosis. Copyright © 2012 by Lippincott Williams &Wilkins.

Cadioli A.,University of Modena and Reggio Emilia | Rossi G.,Operative Unit of Pathologic Anatomy | Costantini M.,Operative Unit of Pathologic Anatomy | Cavazza A.,Operative Unit of Pathologic Anatomy | Migaldi M.,University of Modena and Reggio Emilia
American Journal of Surgical Pathology | Year: 2014

On the basis of seminal studies in the 1980s, appreciable histologic heterogeneity, ranging from 45% to 70% of cases, may be encountered in lung cancer. However, the epidemiologic and histologic landscape of lung cancer in the last 3 decades has radically changed. In this study, 172 consecutive surgically resected primary lung carcinomas evaluated from 2010 to 2012 were entirely sampled and examined according to current histologic classifications. In 129 cases, a positive preoperative biopsy was also available. Major histologic heterogeneity (a single tumor showing at least 2 different histologic types) and minor histologic heterogeneity (a single tumor showing just 1 histologic type but at least 2 different growth patterns) were evaluated in all cases. Immunohistochemical heterogeneity (ie, "aberrant" staining) was also assessed using a panel of markers of adenocarcinoma (TTF-1, napsin, and CK7), squamous cell carcinoma (p63, CK5/6), and neuroendocrine differentiation (chromogranin and synaptophysin), both on positive biopsies and surgical specimens. Overall, major and minor histologic heterogeneity on resections were disclosed in 4% (7 cases) and 50.6% (87 cases), respectively, whereas just 1 case of minor heterogeneity (pleomorphic carcinoma) was observed on biopsies. Minor heterogeneity was limited to adenocarcinomas (82.6%, 81/98 cases) and sarcomatoid carcinomas (6 pleomorphic types among 8 sarcomatoid carcinomas). Immunohistochemical heterogeneity was recorded in 22.6% of the cases, with expression of p63 and CK5/6 in a subset of adenocarcinomas (25 cases, 25.5%), CK7 in 17.4% of squamous cell carcinomas, and synaptophysin in 6 cases of non-neuroendocrine tumors (4%, 6/155). The high rate of adenocarcinomas, accounting for 57% (98 cases) of 172 consecutively resected lung cancers, reflects the new scenario of thoracic oncology and may explain the significant lower rate of major histologic heterogeneity (4%) and the higher frequency of different architectural patterns (minor heterogeneity) that we found in lung cancer compared with previous studies. © 2014 by Lippincott Williams & Wilkins.

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