Pelosi G.,Italian National Cancer Institute |
Pelosi G.,University of Milan |
Fabbri A.,Italian National Cancer Institute |
Bianchi F.,Italian National Cancer Institute |
And 9 more authors.
Journal of Thoracic Oncology | Year: 2012
Introduction: Diagnosing non-small cell lung cancer on biopsy/cellblock samples by morphology may be demanding. As sparing material for molecular testing is mandatory, a minimalist immunohistochemistry (IHC)-based diagnostic approach is warranted by means of novel, reliable, and easy-to-assess biomarkers. Methods: Forty-six consecutive biopsy/cellblock samples and the corresponding resection specimens (as the gold standard for morphology and IHC) from 30 adenocarcinomas (AD), 10 squamous carcinomas (SQC), 5 adenosquamous carcinomas (ADSQC), and 1 sarcomatoid carcinoma (SC) were IHC-evaluated for p40 [corresponding to nontransactivating ΔNp63 isoforms] and thyroid transcription factor-1 (TTF1) by semiquantitative assessment. For p40, also immunodecoration intensity was taken into account and dichotomized as strong or low. Results: Nonrandom and overlapping distributions of the relevant markers were found in biopsy/cellblock and surgical specimens, which closely correlated with each other and the diverse tumor categories, with no differences in area under curve-receiver-operating-characteristic curves for each marker between any two samples, including p40 and p63. Diagnostic combinations were p40-/TTF1+ or TTF1- for AD (where p40 was negative, apart from 5/30 AD showing at the best 1-2% tumor cells with low intensity); p40+/TTF1- (p40 strong and by far higher than 50%) for SQC; and p40+/TTF1- or p40+/TTF1- (p40 strong and less than 50%) for ADSQC. The single SC case was p40-/TTF1-, suggesting glandular lineage. Practically, 41/46 (89%) tumors were correctly classified by IHC on small samples, including 30 AD, 10 SQC, 1/5 ADSQC, and no SC. Underdiagnosis of ADSQC was actually because of sampling error of biopsies/cellblocks rather than insufficient biomarker robustness, whereas underdiagnosis of SC was really because of the failure of either marker to highlight epithelialmesenchymal transition. Conclusions: This minimalist IHC-based model of p40 and TTF1 on biopsy/cellblock samples was effective to correctly subtype most cases of lung cancer. Copyright © 2012 by the International Association for the Study of Lung Cancer.
Recommendations for the analysis of ALK gene rearrangements in non-small-cell lung cancer: A consensus of the italian association of medical oncology and the Italian society of pathology and cytopathology
Marchetti A.,University of Chieti Pescara |
Ardizzoni A.,University of Parma |
Papotti M.,University of Turin |
Crino L.,Perugia Hospital |
And 9 more authors.
Journal of Thoracic Oncology | Year: 2013
INTRODUCTION: Recent clinical trials led to the approval of crizotinib (PF-02341066; Pfizer) by the U.S. Food and Drug Administration for the treatment of locally advanced or metastatic non-small-cell lung cancer (NSCLC) patients whose tumors are positive for anaplastic lymphoma kinase (ALK) alterations. The European Medicines Agency accepted the regulatory submission of crizotinib for the treatment of these patients. Therefore, ALK gene testing has become mandatory to choose the most appropriate therapy. METHODS: To help physicians, involved in the management of NSCLC patients to be treated with ALK inhibitors in Italy, the Italian Association of Medical Oncology and the Italian Society of Pathology and Cytopathology identified a large panel of Italian medical oncologists and pathologists that outlined recommendations for ALK testing in NSCLC patients. RESULTS: The guidelines produced include specific information on the target patient population, the biological material for molecular analysis, a section dedicated to the histocytopathologic diagnosis of NSCLC, and the methods for the assessment of ALK alterations that are summarized in this article. CONCLUSIONS: Clinicopathologic recommendations were produced to guide the management of NSCLC patients who need to be tested for ALK rearrangements before treatment with ALK inhibitors. Copyright © 2013 by the International Association for the Study of Lung Cancer.
Moch H.,University of Zürich |
Blank P.R.,University of Zürich |
Dietel M.,University Hospital Charite |
Elmberger G.,Karolinska University Hospital |
And 5 more authors.
Virchows Archiv | Year: 2012
In February 2011, a group of pathologists from different departments in Europe met in Zurich, Switzerland, to discuss opportunities and challenges for pathology in the era of personalized medicine. The major topics of the meeting were assessment of the role of pathology in personalized medicine, its future profile among other biomedical disciplines with an interest in personalized medicine as well as the evolution of companion diagnostics. The relevance of novel technologies for genome analysis in clinical practice was discussed. The participants recognize that there should bemore initiatives taken by the pathology community in companion diagnostics and in the emerging field of next-generation sequencing and whole genome analysis. The common view of the participants was that the pathology community has to be mobilized for stronger engagement in the future of personalized medicine. Pathologists should be aware of the challenges and the analytical opportunities of the new technologies. Challenges of clinical trial design as well as insurance and reimbursement questions were addressed. The pathology community has the responsibility to lead medical colleagues into embracing this new area of genomic medicine. Without this effort, the discipline of pathology risks losing its key position in molecular tissue diagnostics. © Springer-Verlag 2011.
A single institution-based retrospective study of surgically treated bronchioloalveolar adenocarcinoma of the lung: Clinicopathologic analysis, molecular features, and possible pitfalls in routine practice
Casali C.,Policlinico di Modena |
Rossi G.,Section of Pathologic Anatomy |
Marchioni A.,University of Modena and Reggio Emilia |
Sartori G.,Section of Pathologic Anatomy |
And 4 more authors.
Journal of Thoracic Oncology | Year: 2010
INTRODUCTION:: Prognostic evaluation of bronchioloalveolar carcinoma (BAC) from a homogenous population of Caucasian patients. METHODS:: Retrospective analysis of resected BAC reclassified according to the 2004 World Health Organization classification of lung tumors. Analyzed variables are clinicoradiologic presentation, histologic subtypes, stage, epidermal growth factor receptor (EGFR) and HER2/neu immunohistochemical expression, EGFR exons 18, 19, and 21 mutations, K-RAS exon 2 mutation. Univariate and multivariate analyses of survival were performed. RESULTS:: Of 40 patients analyzed, EGFR and HER2/neu expression were detected in 72% and 20%, respectively. HER2/neu expression significantly characterized mucinous BAC (46% versus 7%; p = 0.014). EGFR mutations were identified in 17% (30% in nonmucinous BAC and none in mucinous BAC; p = 0.083). K-RAS mutations were found in 42.5% (92% in mucinous BAC versus 18% in other types; p < 0.0001). Early stages (IA+IB) nonmucinous BAC had excellent prognosis: 5 years overall survival of 91% (100% for stage IA). Sixty six percent (4 of 6) of patients with multifocal disease died (two mucinous BAC and one nonmucinous BAC with recurrent disease). Seventy one percent (5 of 7) of patients with pneumonic-like tumor (all mucinous BAC) died of recurrent/progressive disease. Stage (p = 0.004) and histologic classifications (p = 0.035) resulted as independent prognostic factors at multivariate analysis. CONCLUSIONS:: Early stage nonmucinous BAC has excellent prognosis, whereas mucinous BAC presents a poor prognosis. Locally advanced nonmucinous BAC has a poor prognosis: the diagnosis of nonmucinous BAC in large tumors should be interpreted with caution given the possible presence of invasive areas in incompletely sampled tumor. Coexpression of EGFR and HER2/neu in mucinous BAC could be considered for future trials on target therapies even in Caucasian population. Copyright © 2010 by the International Association for the Study of Lung Cancer.
Rossi M.,Siena Biotech S.p.A. |
Magnoni L.,Siena Biotech S.p.A. |
Miracco C.,Section of Pathologic Anatomy |
Mori E.,Siena Biotech S.p.A. |
And 6 more authors.
Cancer Biology and Therapy | Year: 2011
Glioblastomas (GBMs), the most common primary malignancies of the central nervous system, are highly aggressive and heterogeneous, and remain a dramatic therapeutic challenge. Markers mirroring the complex molecular profile of GBMs that are predictive of patient outcomes are needed to define novel multi-targeted treatment strategies. Resistance to current GBM therapies is partly due to a subpopulation of stem-like and other self-renewing cells (hereafter called glioma stem-like cancer cells, GSCC), which are therefore of key interest as therapeutic entry points. Wnt and Hedgehog are among the main pathways involved in GSCC renewal. β-catenin and Gli1 are markers of Wnt and Hedgehog activation respectively and both pathways are known to be altered in gliomas. To date, there are no investigations of Gli1 protein expression in GBM tissue, and recently a high expression of β-catenin has been found to have a poor prognostic impact in GBM patients in a study. We have therefore quantified the positivity for β-catenin, Gli1, as well as Ki-67, p53 and EGFR proteins on immunohistochemically-stained GBM sections from 106 patients in an investigation for potential predictive biomarkers. Correlation between these markers and survival was evaluated by pair-wise Pearson correlation coefficient and by bi-dimensional hierarchical clustering, followed by survival estimations using linear regression models and classification trees. We demonstrated that both β-catenin and, for the first time, Gli1 proteins are highly predictive markers of short survival, being found in 75 and 90% of the highly predictive trees, respectively, whereas Ki-67, p53 and EGFR were under 30% and thus, not considered as predictive. Our results indicate a role of β-catenin and Gli1 in GBM malignant behavior, and suggest that inhibiting members of Wnt and Hedgehog pathways could be a valuable therapeutic strategy for GBM patients. © 2011 Landes Bioscience.
Pelosi G.,Instituto Nazionale Tumori |
Pelosi G.,University of Milan |
Barbareschi M.,Hospital S Chiara |
Cavazza A.,Arcispedale S. Maria Nuova I.R.C.C.S. |
And 3 more authors.
Lung Cancer | Year: 2015
Large cell carcinoma (LCC) is a merely descriptive term indicating a subtype of lung cancer with no specific features of small-cell lung cancer (SCLC), adenocarcinoma (ADC) or squamous cell carcinoma (SQC). This diagnosis is allowed on surgical specimens only, whereas its counterpart in biopsy/cytology samples is non-small-cell lung carcinoma (NSCLC), not otherwise specified (NOS). Although these two terms do not fulfill the same concept, they can be interchangeable synonyms at the clinical level, reflecting, in different ways, the inability to define a specific subtype. Immunohistochemistry (IHC), next generation sequencing (NGS) analysis and, historically, electron microscopy have been unveiling diverse cell differentiation lineages in LCC, resulting in LCC-favor ADC, LCC-favor SQC and LCC-favor large-cell neuroendocrine carcinoma (LCNEC), the latter hopefully to be included into the neuroendocrine tumor (NET) group in the future. Paradoxically, however, the interpretation issues of LCC/NSCLC-NOS are not diminishing, but even increasing albeight an accurate diagnosis is oncologically required and crucial. Also, rare LCC/NSCLC-NOS cases exhibiting null/unclear phenotype, are difficult to classify, and this terminology could be maintained for the sake of classification (basically these tumors are serendipitous ADC, as also confirmed by the lack of p40). In this review article, seven relevant issues to LCC have been addressed by using a question-answer methodology, with final key points discussing major interpretation issues. In conclusion, most LCC/NSCLC-NOS may be eventually re-classified and addressed by exploiting IHC and/or molecular testing to satisfy the criteria of precision medicine (the right drug, to the right patient, at the right time). © 2015 Elsevier Ireland Ltd.
Diazzi C.,University of Modena and Reggio Emilia |
Brigante G.,University of Modena and Reggio Emilia |
Rossi G.,Section of Pathologic Anatomy |
Rochira V.,University of Modena and Reggio Emilia
Thyroid | Year: 2012
Background: Propylthiouracil (PTU) therapy is associated with a variety of adverse reactions, among the most rare being interstitial pneumonia. To date, this has been reported in four Asian patients with autoimmune hyperthyroidism. Here we describe a Caucasian woman who developed a bronchiolitis obliterans organizing pneumonia (BOOP)-like interstitial pneumonia after PTU administration for amiodarone-induced thyrotoxicosis. Patient Findings: The patient was a 68-year-old woman who had been treated with amiodarone for chronic atrial fibrillation starting in May 2004. She had been a heavy smoker with a history of hypertension but no dust exposures. In October 2006, amiodarone was stopped after she developed thyrotoxicosis. In January 2007 serum thyroid-stimulating hormone (TSH) was 0.01mIU/L (0.35-4.94) and free T4 was 17.5pg/mL (7 to 15). She was initially started on methimazole and then changed to PTU after she developed pruritus. She developed severe dyspnea 9 months after starting PTU. At the time she was also taking warfarin, enalapril, and sotalol. Chest X-ray showed diffuse interstitial peripheral opacities and transbronchial lung biopsy revealed subacute lung injury with organizing pneumonia with hyperplasia of the alveolar type 2 pneumocytes, and characteristics of BOOP-like interstitial pneumonia. Signs and symptoms progressively improved after PTU discontinuation as confirmed at X-ray and computed tomography (CT) scan of the chest and by respiratory function tests. She has been recurrence free for 4 years after stopping PTU. Summary: This woman of Caucasian ancestral origin developed BOOP-like interstitial pneumonia after PTU treatment for apparent amiodarone-induced thyrotoxicosis, with resolution of her lung disease after stopping PTU. Tests for TSH receptor antibodies, thyroid peroxidase antibodies, and antinuclear cytoplasmic autoantibody were negative. Thyroid ultrasound was consistent with thyroiditis without nodules. Conclusions: PTU-associated interstitial pneumonia is not limited to patients of Asian origin or those with autoimmune thyroid disease. PTU must be withdrawn in the presence of respiratory symptoms and documented interstitial pneumonia. X-ray films, CT-scan, respiratory function tests, and lung biopsy are needed to diagnose PTU-induced interstitial pneumonia with certainty and to monitor the evolution of the disease after PTU discontinuation. © 2012, Mary Ann Liebert, Inc.
Mengoli M.C.,Section of Pathologic Anatomy |
Jukna A.,Riga Stradins University |
Cesinaro A.M.,Section of Pathologic Anatomy
American Journal of Dermatopathology | Year: 2016
Rhabdomyoma (RM) is a rare benign mesenchymal tumor associated with skeletal muscle differentiation. We report a case of adult-type RM occurring in the lower lip of a 48-year-old man, clinically suspicious for squamous cell carcinoma. Only 3 cases of adult-type RM have been described in the literature in this anatomical site. The histologic differential diagnoses with other lesions are presented, with emphasis on immunohistochemical aspects. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Rossi G.,Section of Pathologic Anatomy |
Gasser B.,Service de Pathologie |
Sartori G.,Section of Pathologic Anatomy |
Migaldi M.,Section of Pathologic Anatomy |
And 5 more authors.
Histopathology | Year: 2012
Aims: To analyse the expression of several mucins (MUC1, MUC2, MUC3, MUC5AC and MUC6), epidermal growth factor receptor (EGFR), v-erb-b2 erythroblastic leukaemia viral oncogene homologue 2 (HER2), thyroid transcription factor-1 (TTF-1), caudal type homeobox 2 (CDX2) and cytokeratin 20 (CK20), and the presence of mutations of EGFR, KRAS and HER2 in congenital pulmonary airway malformations (CPAM). Methods and results: Forty-one cases of CPAM and six pulmonary sequestrations were included. TTF-1 expression was observed in all cases but was not seen in mucinogenic growths in CPAM. CDX2 expression was completely negative. MUC1 expression was noted in 12 (29%) CPAM and in 33% sequestrations. MUC5AC was noted in only five cases (26%) by immunohistochemistry and was found in the mucinogenic proliferations of type 1 CPAM. No immunolabelling was noted for the other mucins. EGFR was expressed variably in almost all cases, while HER2 and CK20 was seen exclusively in the mucinogenic proliferations. All mucinous growths were characterized by KRAS mutations. No EGFR and HER2 gene alterations were identified. Conclusions: KRAS mutations and MUC5AC, CK20 and HER2 expression was seen in all mucinogenic proliferations, supporting the neoplastic nature of these cytologically bland growths. These findings emphasize the importance of complete surgical resection of such lesions. © 2012 Blackwell Publishing Ltd.
Pantaleo M.A.,University of Bologna |
Astolfi A.,University of Bologna |
Urbini M.,University of Bologna |
Nannini M.,University of Bologna |
And 13 more authors.
European Journal of Human Genetics | Year: 2014
Mutations of genes encoding the subunits of the succinate dehydrogenase (SDH) complex were described in KIT/PDGFRA wild-type GIST separately in different reports. In this study, we simultaneously sequenced the genome of all subunits, SDHA, SDHB, SDHC, and SDHD in a larger series of KIT/PDGFRA wild-type GIST in order to evaluate the frequency of the mutations and explore their biological role. SDHA, SDHB, SDHC, and SDHD were sequenced on the available samples obtained from 34 KIT/PDGFRA wild-type GISTs. Of these, in 10 cases, both tumor and peripheral blood (PB) were available, in 19 cases only tumor, and in 5 cases only PB. Overall, 9 of the 34 patients with KIT/PDGFRA wild-type GIST carried mutations in one of the four subunits of the SDH complex (six patients in SDHA, two in SDHB, one in SDHC). WB and immunohistochemistry analysis showed that patients with KIT/PDGFRA wild-type GIST who harbored SDHA mutations exhibited a significant downregulation of both SDHA and SDHB protein expression, with respect to the other GIST lacking SDH mutations and to KIT/PDGFRA-mutated GIST. Clinically, four out of six patients with SDHA mutations presented with metastatic disease at diagnosis with a very slow, indolent course. Patients with KIT/PDGFRA wild-type GIST may harbor germline and/or de novo mutations of SDH complex with prevalence for mutations within SDHA, which is associated with a downregulation of SDHA and SDHB protein expression. The presence of germline mutations may suggest that these patients should be followed up for the risk of development of other cancers. © 2014 Macmillan Publishers Limited.