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1
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Keith RL, Miller YE, Ghosh M, Franklin WA, Nakachi I, Merrick DT. Lung cancer: Premalignant biology and medical prevention. Semin Oncol 2022; 49:254-260. [PMID: 35305831 DOI: 10.1053/j.seminoncol.2022.02.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/06/2022] [Accepted: 02/08/2022] [Indexed: 11/11/2022]
Abstract
Lung cancer (both adenocarcinoma and squamous cell) progress through a series of pre-malignant histologic changes before the development of invasive disease. Each of these carcinogenic cascades is defined by genetic and epigenetic alterations in pulmonary epithelial cells. Additionally, alterations in the immune response, progenitor cell function, mutational burden, and microenvironmental mediated survival of mutated clones contribute to the risk of pre-malignant lesions progressing to cancer. Medical preventions studies have been completed and current and future trials are informed by the improved understanding of pre-malignancy. This will lead to precision chemoprevention trials based on lesional biology and histologic characteristics.
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Affiliation(s)
- R L Keith
- Division of Pulmonary Sciences and Critical Care Medicine, Rocky Mountain Regional Veterans Affairs Medical Center, Aurora, CO; Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado, Anschutz Medical Campus, Aurora, CO.
| | - Y E Miller
- Division of Pulmonary Sciences and Critical Care Medicine, Rocky Mountain Regional Veterans Affairs Medical Center, Aurora, CO; Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado, Anschutz Medical Campus, Aurora, CO
| | - M Ghosh
- Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado, Anschutz Medical Campus, Aurora, CO
| | - Wilbur A Franklin
- Department of Pathology, University of Colorado, Anschutz Medical Campus, Aurora, CO
| | - I Nakachi
- Department of Pulmonary Medicine, Keio University, Tokyo, Japan
| | - D T Merrick
- Department of Pathology, University of Colorado, Anschutz Medical Campus, Aurora, CO
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2
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Updates in grading and invasion assessment in lung adenocarcinoma. Mod Pathol 2022; 35:28-35. [PMID: 34615984 DOI: 10.1038/s41379-021-00934-3] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2021] [Revised: 09/10/2021] [Accepted: 09/15/2021] [Indexed: 01/15/2023]
Abstract
The pathologic evaluation of lung adenocarcinoma, because of greater understanding of disease progression and prognosis, has become more complex. It is clear that histologic growth patterns reflect indolent and aggressive disease, resulting in clearer morphologic groups that can be the underpinning of a grading system. In addition, the progression of adenocarcinoma from a tumor that preserves alveolar architecture to one that remodels and effaces lung structure has led to criteria that reflect invasive rather than in-situ growth. While some of these are based on tumor cell growth pattern, aspects of this remodeling from desmoplasia to artifacts of lung collapse and sectioning, can lead to difficult to interpret patterns with lower reproducibility between observers. Such scenarios are examined to provide updates on new histologic concepts and to highlight ongoing problem areas.
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3
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Gene Expression Profiles of Multiple Synchronous Lesions in Lung Adenocarcinoma. Cells 2021; 10:cells10123484. [PMID: 34943992 PMCID: PMC8700398 DOI: 10.3390/cells10123484] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2021] [Revised: 12/05/2021] [Accepted: 12/06/2021] [Indexed: 11/24/2022] Open
Abstract
Many studies support a stepwise continuum of morphologic changes between atypical adenomatous hyperplasia (AAH) and lung adenocarcinoma (ADC). Here we characterized gene expression patterns and the association of differentially expressed genes and immune tumor microenvironment behaviors in AAH to ADC during ADC development. Tumor tissues from nine patients with ADC and synchronous multiple ground glass nodules/lesions (GGN/Ls) were analyzed using RNA sequencing. Using clustering, we identified genes differentially and sequentially expressed in AAH and ADC compared to normal tissues. Functional enrichment analysis using gene ontology terms was performed, and the fraction of immune cell types was estimated. We identified up-regulated genes (ACSL5 and SERINC2) with a stepwise change of expression from AAH to ADC and validated those expressions by quantitative PCR and immunohistochemistry. The immune cell profiles revealed increased B cell activities and decreased natural killer cell activities in AAH and ADC. A stepwise change of differential expression during ADC development revealed potential effects on immune function in synchronous precursors and in tumor lesions in patients with lung cancer.
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4
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Succony L, Rassl DM, Barker AP, McCaughan FM, Rintoul RC. Adenocarcinoma spectrum lesions of the lung: Detection, pathology and treatment strategies. Cancer Treat Rev 2021; 99:102237. [PMID: 34182217 DOI: 10.1016/j.ctrv.2021.102237] [Citation(s) in RCA: 150] [Impact Index Per Article: 37.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2021] [Revised: 05/24/2021] [Accepted: 05/26/2021] [Indexed: 02/07/2023]
Abstract
Adenocarcinoma has become the most prevalent lung cancer sub-type and its frequency is increasing. The earliest stages in the development of lung adenocarcinomas are visible using modern computed tomography (CT) as ground glass nodules. These pre-invasive nodules can progress over time to become invasive lung adenocarcinomas. Lesions in this developmental pathway are termed 'adenocarcinoma spectrum' lesions. With the introduction of lung cancer screening programs there has been an increase in the detection of these lesions raising questions about natural history, surveillance and treatment. Here we review how the radiological appearance of an adenocarcinoma spectrum lesion relates to its underlying pathology and explore the natural history and factors driving lesion progression. We examine the molecular changes that occur at each stage of adenocarcinoma spectrum lesion development, including the effects of the driver mutations, EGFR and KRAS, that are key to invasive adenocarcinoma pathology. A better understanding of the development of pre-invasive disease will create treatment targets. Our understanding of how tumours interact with the immune system has led to the development of new therapeutic strategies. We review the role of the immune system in the development of adenocarcinoma spectrum lesions. With a clear preinvasive phase there is an opportunity to treat early adenocarcinoma spectrum lesions before an invasive lung cancer develops. We review current management including surveillance, surgical resection and oncological therapy as well as exploring potential future treatment avenues.
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Affiliation(s)
- L Succony
- Department of Thoracic Oncology, Royal Papworth Hospital, Cambridge CB2 0AY, United Kingdom
| | - D M Rassl
- Department of Pathology, Royal Papworth Hospital NHS Foundation Trust, Cambridge CB2 0AY, United Kingdom
| | - A P Barker
- Department of Radiology, Royal Papworth Hospital NHS Foundation Trust, Cambridge CB2 0AY, United Kingdom
| | - F M McCaughan
- Department of Medicine, University of Cambridge, Addenbrookes Hospital, Cambridge CB2 0QQ, United Kingdom
| | - R C Rintoul
- Department of Thoracic Oncology, Royal Papworth Hospital, Cambridge CB2 0AY, United Kingdom; Department of Oncology, University of Cambridge, Cambridge CB2 0QQ United Kingdom.
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5
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Zhang H, Guo L, Chen J. Rationale for Lung Adenocarcinoma Prevention and Drug Development Based on Molecular Biology During Carcinogenesis. Onco Targets Ther 2020; 13:3085-3091. [PMID: 32341654 PMCID: PMC7166063 DOI: 10.2147/ott.s248436] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2020] [Accepted: 03/14/2020] [Indexed: 12/18/2022] Open
Abstract
Lung adenocarcinoma (LUAD) is the most common and aggressive subtype of lung cancer with the greatest heterogeneity and aggression. Inspite of recent years’ achievements in understanding the pathogenesis of this disease, as well as the development of new therapeutic approaches, our knowledge on crucial early molecular events during its development is still rudimentary. Recent classification and grading of LUAD has postulated that LUAD does not arise spontaneously, but through a stepwise process from lung adenomatous premalignancy atypical adenomatous hyperplasia to adenocarcinoma in situ, minimally invasive adenocarcinoma, and eventually frankly invasive predominant adenocarcinoma. In this review, we discuss the molecular processes that drive the evolutionary process that results in the formation of LUAD. We also describe how to handle lung premalignancy in clinical settings based on the most recent advances in genomic biology and our own understanding of lung cancer prevention.
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Affiliation(s)
- Hongming Zhang
- Department of Respiratory Medicine, Yancheng Third People's Hospital, Affiliated Yancheng Hospital of Southeast University Medical College, Yancheng, Jiangsu Province, People's Republic of China
| | - Liting Guo
- Department of Oncology, Ruijin Hospital,affiliated with Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
| | - Jibei Chen
- Department of Respiratory Medicine, Yancheng Third People's Hospital, Affiliated Yancheng Hospital of Southeast University Medical College, Yancheng, Jiangsu Province, People's Republic of China
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6
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Kimura K, Matsumoto S, Harada T, Morii E, Nagatomo I, Shintani Y, Kikuchi A. ARL4C is associated with initiation and progression of lung adenocarcinoma and represents a therapeutic target. Cancer Sci 2020; 111:951-961. [PMID: 31925985 PMCID: PMC7060486 DOI: 10.1111/cas.14303] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2019] [Revised: 11/26/2019] [Accepted: 12/23/2019] [Indexed: 02/06/2023] Open
Abstract
Lung adenocarcinoma is the most common histological type of lung cancer and is classified into adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA) and invasive adenocarcinoma (IA). Atypical adenomatous hyperplasia (AAH) lesions are possible precursors to adenocarcinoma. However, the mechanism underlying the stepwise continuum of lung adenocarcinoma is unclear. In this study, the involvement of ADP‐ribosylation factor (ARF)‐like (ARL) 4C (ARL4C), a member of the small GTP‐binding protein family, in the progression of lung adenocarcinoma and the possibility of ARL4C as a molecular target for lung cancer therapy were explored. ARL4C was frequently expressed in AAH and ARL4C expression in immortalized human small airway epithelial cells promoted cell proliferation and suppressed cell death. In addition, ARL4C was expressed with increased frequency in AIS, MIA and IA in a stage‐dependent manner, and the expression was correlated with histologic grade, fluorine‐18 fluorodeoxyglucose uptake and poor prognosis. An anti–sense oligonucleotide (ASO) against ARL4C (ARL4C ASO‐1316) inhibited RAS‐related C3 botulinum toxin substrate activity and nuclear import of Yes‐associated protein and transcriptional coactivator with PDZ‐binding motif, and suppressed in vitro proliferation and migration of lung cancer cells with KRAS or epidermal growth factor receptor (EGFR) mutations. In addition, transbronchial administration of ARL4C ASO‐1316 suppressed orthotopic tumor formation induced by these cancer cells. Thus, ARL4C is involved in the initiation of the premalignant stage and is associated with the stepwise continuum of lung adenocarcinoma. ARL4C ASO‐1316 would be useful for lung adenocarcinoma patients expressing ARL4C regardless of the KRAS or EGFR mutation.
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Affiliation(s)
- Kenji Kimura
- Department of Molecular Biology and Biochemistry, Graduate School of Medicine, Osaka University, Suita, Japan.,Department of General Thoracic Surgery, Graduate School of Medicine, Osaka University, Suita, Japan
| | - Shinji Matsumoto
- Department of Molecular Biology and Biochemistry, Graduate School of Medicine, Osaka University, Suita, Japan
| | - Takeshi Harada
- Department of Molecular Biology and Biochemistry, Graduate School of Medicine, Osaka University, Suita, Japan
| | - Eiichi Morii
- Department of Pathology, Graduate School of Medicine, Osaka University, Suita, Japan
| | - Izumi Nagatomo
- Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, Osaka University, Suita, Japan
| | - Yasushi Shintani
- Department of General Thoracic Surgery, Graduate School of Medicine, Osaka University, Suita, Japan
| | - Akira Kikuchi
- Department of Molecular Biology and Biochemistry, Graduate School of Medicine, Osaka University, Suita, Japan
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7
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Nguyen C, Larsen NK, Dietz N, Sirineni G, Balters M. Pulmonary Atypical Adenomatous Hyperplasia: Diagnostic and Therapeutic Implications. Cureus 2019; 11:e6079. [PMID: 31853430 PMCID: PMC6894895 DOI: 10.7759/cureus.6079] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
Lung cancer still remains one of the most common cancers throughout the world, especially in smokers. Adenocarcinoma is now the predominant histological type in many western countries. The etiology of adenocarcinoma is unknown, but evidence suggests that atypical adenomatous hyperplasia (AAH) may act as a precursor lesion. Here we present two case reports of patients diagnosed with AAH on biopsy, highlighting 1) available treatment strategies and 2) AAH’s progression to adenocarcinoma. A review of AAH is warranted as little literature is currently available regarding its treatment strategies, especially in light of its role as a precursor to adenocarcinoma. In this review, we will address the following topics: 1. What is the pathophysiology of AAH?
2. What is the natural history of AAH and its risk of malignant transformation?
3. When is surgery recommended?
4. What is the role of stereotactic body radiotherapy (SBRT) in the rare patient who refuses surgery?
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Affiliation(s)
- Cam Nguyen
- Radiation Oncology, Creighton University School of Medicine, Omaha, USA
| | | | - Nick Dietz
- Pathology, Creighton University School of Medicine, Omaha, USA
| | | | - Marcus Balters
- Surgery, Creighton University School of Medicine, Omaha, USA
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8
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Inamura K. Clinicopathological Characteristics and Mutations Driving Development of Early Lung Adenocarcinoma: Tumor Initiation and Progression. Int J Mol Sci 2018; 19:ijms19041259. [PMID: 29690599 PMCID: PMC5979290 DOI: 10.3390/ijms19041259] [Citation(s) in RCA: 93] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2018] [Revised: 04/19/2018] [Accepted: 04/20/2018] [Indexed: 01/01/2023] Open
Abstract
Lung cancer is the leading cause of cancer-related deaths worldwide, with lung adenocarcinoma representing the most common lung cancer subtype. Among all lung adenocarcinomas, the most prevalent subset develops via tumorigenesis and progression from atypical adenomatous hyperplasia (AAH) to adenocarcinoma in situ (AIS), to minimally invasive adenocarcinoma (MIA), to overt invasive adenocarcinoma with a lepidic pattern. This stepwise development is supported by the clinicopathological and molecular characteristics of these tumors. In the 2015 World Health Organization classification, AAH and AIS are both defined as preinvasive lesions, whereas MIA is identified as an early invasive adenocarcinoma that is not expected to recur if removed completely. Recent studies have examined the molecular features of lung adenocarcinoma tumorigenesis and progression. EGFR-mutated adenocarcinoma frequently develops via the multistep progression. Oncogene-induced senescence appears to decrease the frequency of the multistep progression in KRAS- or BRAF-mutated adenocarcinoma, whose tumor evolution may be associated with epigenetic alterations and kinase-inactive mutations. This review summarizes the current knowledge of tumorigenesis and tumor progression in early lung adenocarcinoma, with special focus on its clinicopathological characteristics and their associations with driver mutations (EGFR, KRAS, and BRAF) as well as on its molecular pathogenesis and progression.
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Affiliation(s)
- Kentaro Inamura
- Division of Pathology, The Cancer Institute, Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo 135-8550, Japan.
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9
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Lu L, Zhang C, Cheng Y. [Solitary AAH Arising from Extralobar Sequestration in A Less Than 3-year-old Boy: A Case Report]. ZHONGGUO FEI AI ZA ZHI = CHINESE JOURNAL OF LUNG CANCER 2017; 20:787-788. [PMID: 29167010 PMCID: PMC5973271 DOI: 10.3779/j.issn.1009-3419.2017.11.11] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
We present a case of two-year old boy with solitary atypical adenomatous hyperplasia (AAH) in extralobar sequestration (ELS), which was misdiagnosed as diaphragmatic hernia before surgery. Review of AAH and pulmonary sequestration (PS) revealed that the present case is the youngest of solitary AAH and also the first report of solitary AAH arising in ELS without a primary lung cancer. In a sense, the present case firstly supports the hypothesis that ELS may be an underlying cancer predisposition syndrome, so aggressive surgical therapy should be recommended for ELS.
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Affiliation(s)
- Liqing Lu
- Department of Thoracic Surgery, Xiangya Hospital, Central South University, Changsha 410008, China
| | - Chunfang Zhang
- Department of Thoracic Surgery, Xiangya Hospital, Central South University, Changsha 410008, China
| | - Yuanda Cheng
- Department of Thoracic Surgery, Xiangya Hospital, Central South University, Changsha 410008, China
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10
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Jin M, Lee YH, Kim B, Yoon YC, Wi JH. Solitary Atypical Adenomatous Hyperplasia in a 12-Year-Old Girl. THE KOREAN JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY 2016; 49:141-4. [PMID: 27065090 PMCID: PMC4825920 DOI: 10.5090/kjtcs.2016.49.2.141] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/01/2015] [Revised: 11/02/2015] [Accepted: 11/03/2015] [Indexed: 11/26/2022]
Abstract
Atypical adenomatous hyperplasia is a premalignant lesion reflecting a focal proliferation of atypical cells. These lesions are usually observed as incidental findings in lungs that have been resected due to other conditions, such as lung cancer. We report the youngest case of atypical adenomatous hyperplasia on record in a 12-year-old girl. In this patient, the lesion was found in association with pneumothorax.
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Affiliation(s)
- Moran Jin
- Department of Thoracic and Cardiovascular Surgery, Inje University Busan Paik Hospital, Inje University College of Medicine
| | - Yang-Haeng Lee
- Department of Thoracic and Cardiovascular Surgery, Inje University Busan Paik Hospital, Inje University College of Medicine
| | - Bomi Kim
- Department of Pathology, Inje University Busan Paik Hospital, Inje University College of Medicine
| | - Young Chul Yoon
- Department of Thoracic and Cardiovascular Surgery, Inje University Busan Paik Hospital, Inje University College of Medicine
| | - Jin Hong Wi
- Department of Thoracic and Cardiovascular Surgery, Inje University Busan Paik Hospital, Inje University College of Medicine
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11
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Veronesi G, Guerrieri-Gonzaga A, Infante M, Bonanni B. Chemoprevention studies within lung cancer screening programmes. Ecancermedicalscience 2015; 9:597. [PMID: 26635901 PMCID: PMC4664502 DOI: 10.3332/ecancer.2015.597] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2015] [Indexed: 12/21/2022] Open
Abstract
While aggressive tobacco control and help to stop smoking are essential weapons in the fight against lung cancer, screening with low-dose computed tomography (LDCT) in high-risk populations and chemoprevention may also contribute to reducing lung cancer deaths. Persons undergoing LDCT screening are an ideal population to be tested for agents potentially able to prevent the development of lung cancer by the regression of precancerous lesions, which are routinely monitored as part of the screening process. Peripheral subsolid nodules appear as particularly suitable targets, since many are adenocarcinoma precursors. A study on inhaled budesonide (a potential chemopreventive drug) for 1 year found that the mean size of non-solid lung nodules was significantly reduced over 5 years of follow-up, compared to inhaled placebo, in a population of high-risk individuals with indeterminate lung nodules not requiring immediate specific investigation for lung cancer and detected as part of a lung cancer screening program with LDCT. A new randomised placebo-controlled phase-II trial to test the ability of aspirin to induce the regression of non-solid and partially solid nodules detected by LDCT screening has been started. The effect of aspirin on a miRNA signature able to predict the presence of both cancer and precancerous lesions in high-risk asymptomatic individuals is also being monitored in the trial. This signature was previously shown to predict the presence of both lung cancer and non-solid lung nodules in asymptomatic individuals.
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Affiliation(s)
- G Veronesi
- Division of Thoracic Surgery, European Institute of Oncology, Via Ripamonti 435, Milan 20141, Italy
| | - A Guerrieri-Gonzaga
- Division of Cancer Prevention and Genetics, European Institute of Oncology, Via Ripamonti 435, Milan 20141, Italy
| | - M Infante
- Division of Thoracic Surgery, Humanitas Research Hospital, Via Manzoni 56, Rozzano 20100, Italy
| | - B Bonanni
- Division of Cancer Prevention and Genetics, European Institute of Oncology, Via Ripamonti 435, Milan 20141, Italy
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12
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Izumchenko E, Chang X, Brait M, Fertig E, Kagohara LT, Bedi A, Marchionni L, Agrawal N, Ravi R, Jones S, Hoque MO, Westra WH, Sidransky D. Targeted sequencing reveals clonal genetic changes in the progression of early lung neoplasms and paired circulating DNA. Nat Commun 2015; 6:8258. [PMID: 26374070 PMCID: PMC4595648 DOI: 10.1038/ncomms9258] [Citation(s) in RCA: 111] [Impact Index Per Article: 11.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2015] [Accepted: 08/03/2015] [Indexed: 01/01/2023] Open
Abstract
Lungs resected for adenocarcinomas often harbour minute discrete foci of cytologically atypical pneumocyte proliferations designated as atypical adenomatous hyperplasia (AAH). Evidence suggests that AAH represents an initial step in the progression to adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA) and fully invasive adenocarcinoma. Despite efforts to identify predictive markers of malignant transformation, alterations driving this progression are poorly understood. Here we perform targeted next-generation sequencing on multifocal AAHs and different zones of histologic progression within AISs and MIAs. Multiregion sequencing demonstrated different genetic drivers within the same tumour and reveal that clonal expansion is an early event of tumorigenesis. We find that KRAS, TP53 and EGFR mutations are indicators of malignant transition. Utilizing droplet digital PCR, we find alterations associated with early neoplasms in paired circulating DNA. This study provides insight into the heterogeneity of clonal events in the progression of early lung neoplasia and demonstrates that these events can be detected even before neoplasms have invaded and acquired malignant potential. Atypical adenomatous hyperplasia is thought to be a precursor lesion for lung adenocarcinoma. Here, using targeted deep sequencing, the authors demonstrate that hyperplastic lesions contain somatic mutations associated with malignant disease and that these can be detected in circulating tumour cells.
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Affiliation(s)
- Evgeny Izumchenko
- Department of Otolaryngology and Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA
| | - Xiaofei Chang
- Department of Otolaryngology and Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA
| | - Mariana Brait
- Department of Otolaryngology and Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA
| | - Elana Fertig
- Division of Biostatistics and Bioinformatics, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA
| | - Luciane T Kagohara
- Department of Otolaryngology and Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA
| | - Atul Bedi
- Department of Otolaryngology and Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA
| | - Luigi Marchionni
- Center for Computational Genomics, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA
| | - Nishant Agrawal
- Department of Otolaryngology and Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA
| | - Rajani Ravi
- Department of Otolaryngology and Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA
| | - Sian Jones
- Personal Genome Diagnostics, Inc., 2809 Boston Street, Suite 503, Baltimore, Maryland 21224, USA
| | - Mohammad O Hoque
- Department of Otolaryngology and Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA
| | - William H Westra
- Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, Maryland 21231, USA
| | - David Sidransky
- Department of Otolaryngology and Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA.,Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA
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13
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Truini A, Santos Pereira P, Cavazza A, Spagnolo P, Nosseir S, Longo L, Jukna A, Lococo F, Vincenzi G, Bogina G, Tiseo M, Rossi G. Classification of different patterns of pulmonary adenocarcinomas. Expert Rev Respir Med 2015; 9:571-86. [PMID: 26313326 DOI: 10.1586/17476348.2015.1083428] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The epidemic increase of adenocarcinoma histology accounting for more than 50% of primary lung malignancies and the advent of effective molecular targeted-therapies against specific gene alterations characterizing this tumor type have led to the reconsideration of the pathologic classification of lung cancer. The new 2015 WHO classification provided the basis for a multidisciplinary approach emphasizing the close correlation among clinical, radiologic and molecular characteristics and histopathologic pattern of lung adenocarcinoma. The terms 'bronchioloalveolar carcinoma' and 'mixed adenocarcinoma' have been eliminated, introducing the concepts of 'adenocarcinoma in situ', 'minimally invasive adenocarcinoma' and the use of descriptive predominant patterns in invasive adenocarcinomas (lepidic, acinar, papillary, solid and micropapillary patterns). 'Invasive mucinous adenocarcinoma' is the new definition for mucinous bronchioloalveolar carcinoma, and some variants of invasive adenocarcinoma have been included, namely colloid, enteric and fetal-type adenocarcinomas. A concise update of the immunomorphologic, radiological and molecular characteristics of the different histologic patterns of lung adenocarcinoma is reported here.
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Affiliation(s)
- Anna Truini
- a 1 Lung Cancer Unit, IRCCS AOU San Martino - IST and Dipartimento di Medicina Interna e Specialità Mediche (DIMI), Università di Genova, Genova, Italy
| | - Poliana Santos Pereira
- b 2 Operative Unit of Pathologic Anatomy Hospital "Maggiore della Carità" of Novara, Novara, Italy
| | - Alberto Cavazza
- c 3 Department of Oncology and Advanced Technologies, Operative Unit of Oncology, Arcispedale S. Maria Nuova/ I.R.C.C.S., Reggio Emilia, Reggio Emilia, Italy
| | - Paolo Spagnolo
- d 4 Medical University Clinic, Canton Hospital Baselland, and University of Basel, Basel, Switzerland
| | - Sofia Nosseir
- e 5 Section of Pathologic Anatomy, University Hospital Policlinico of Modena, Modena, Italy
| | - Lucia Longo
- f 6 Medical Oncology Unit, Civic Hospital "Ramazzini", Carpi, Carpi, Italy
| | - Agita Jukna
- g 7 Pathology Institute, Pauls Stradins Clinical University Hospital, Riga, Riga, Latvia
| | - Filippo Lococo
- h 8 Department of Surgery, Operative Unit of Thoracic Surgery, Arcispedale S. Maria Nuova/ I.R.C.C.S., Reggio Emilia, Reggio Emilia, Italy
| | - Giada Vincenzi
- i 9 Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy
| | - Giuseppe Bogina
- j 10 Section of Pathologic Anatomy, Hospital "Don Calabria", Negrar, Verona, Italy
| | - Marcello Tiseo
- k 11 Division of Medical Oncology University Hospital, Parma, Italy
| | - Giulio Rossi
- l 12 University Hospital of Modena, Modena, Italy
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14
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Liao JH, Amin VB, Kadoch MA, Beasley MB, Jacobi AH. Subsolid pulmonary nodules: CT–pathologic correlation using the 2011 IASLC/ATS/ERS classification. Clin Imaging 2015; 39:344-51. [DOI: 10.1016/j.clinimag.2014.12.009] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2014] [Revised: 12/02/2014] [Accepted: 12/08/2014] [Indexed: 11/30/2022]
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15
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Prognostic significance of promoter CpG island hypermethylation and repetitive DNA hypomethylation in stage I lung adenocarcinoma. Virchows Arch 2015; 466:675-83. [DOI: 10.1007/s00428-015-1749-0] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2014] [Revised: 01/15/2015] [Accepted: 02/24/2015] [Indexed: 12/15/2022]
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16
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Veronesi G, Lazzeroni M, Szabo E, Brown PH, DeCensi A, Guerrieri-Gonzaga A, Bellomi M, Radice D, Grimaldi MC, Spaggiari L, Bonanni B. Long-term effects of inhaled budesonide on screening-detected lung nodules. Ann Oncol 2015; 26:1025-1030. [PMID: 25672894 DOI: 10.1093/annonc/mdv064] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2014] [Accepted: 01/31/2015] [Indexed: 11/13/2022] Open
Abstract
BACKGROUND A previously carried out randomized phase IIb, placebo-controlled trial of 1 year of inhaled budesonide, which was nested in a lung cancer screening study, showed that non-solid and partially solid lung nodules detected by low-dose computed tomography (LDCT), and not immediately suspicious for lung cancer, tended to regress. Because some of these nodules may be slow-growing adenocarcinoma precursors, we evaluated long-term outcomes (after stopping the 1-year intervention) by annual LDCT. PATIENTS AND METHODS We analyzed the evolution of target and non-target trial nodules detected by LDCT in the budesonide and placebo arms up to 5 years after randomization. The numbers and characteristics of lung cancers diagnosed during follow-up were also analyzed. RESULTS The mean maximum diameter of non-solid nodules reduced significantly (from 5.03 mm at baseline to 2.61 mm after 5 years) in the budesonide arm; there was no significant size change in the placebo arm. The mean diameter of partially solid lesions also decreased significantly, but only by 0.69 mm. The size of solid nodules did not change. Neither the number of new lesions nor the number of lung cancers differed in the two arms. CONCLUSIONS Inhaled budesonide given for 1 year significantly decreased the size of non-solid nodules detected by screening LDCT after 5 years. This is of potential importance since some of these nodules may progress slowly to adenocarcinoma. However, further studies are required to assess clinical implications. CLINICAL TRIAL NUMBER NCT01540552.
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Affiliation(s)
| | - M Lazzeroni
- Cancer Prevention and Genetics, European Institute of Oncology, Milan, Italy
| | - E Szabo
- Division of Cancer Prevention, National Cancer Institute, National Institutes of Health, Bethesda
| | - P H Brown
- Department of Clinical Cancer Prevention, University of Texas MD Anderson Cancer Center, Houston, USA
| | - A DeCensi
- Cancer Prevention and Genetics, European Institute of Oncology, Milan, Italy; Division of Medical Oncology, Ospedali Galliera, Genoa
| | - A Guerrieri-Gonzaga
- Cancer Prevention and Genetics, European Institute of Oncology, Milan, Italy
| | - M Bellomi
- Division of Radiology, European Institute of Oncology, Milan; University of Milan, Milan
| | - D Radice
- Division of Epidemiology and Biostatistics, European Institute of Oncology, Milan, Italy
| | - M C Grimaldi
- Division of Radiology, European Institute of Oncology, Milan
| | - L Spaggiari
- Divisions of Thoracic Surgery; University of Milan, Milan
| | - B Bonanni
- Cancer Prevention and Genetics, European Institute of Oncology, Milan, Italy
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Jacobsen B, Kriegbaum MC, Santoni-Rugiu E, Ploug M. C4.4A as a biomarker in pulmonary adenocarcinoma and squamous cell carcinoma. World J Clin Oncol 2014; 5:621-632. [PMID: 25302166 PMCID: PMC4129527 DOI: 10.5306/wjco.v5.i4.621] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2014] [Revised: 03/10/2014] [Accepted: 06/16/2014] [Indexed: 02/06/2023] Open
Abstract
The high prevalence and mortality of lung cancer, together with a poor 5-year survival of only approximately 15%, emphasize the need for prognostic and predictive factors to improve patient treatment. C4.4A, a member of the Ly6/uPAR family of membrane proteins, qualifies as such a potential informative biomarker in non-small cell lung cancer. Under normal physiological conditions, it is primarily expressed in suprabasal layers of stratified squamous epithelia. Consequently, it is absent from healthy bronchial and alveolar tissue, but nevertheless appears at early stages in the progression to invasive carcinomas of the lung, i.e., in bronchial hyperplasia/metaplasia and atypical adenomatous hyperplasia. In the stages leading to pulmonary squamous cell carcinoma, expression is sustained in dysplasia, carcinoma in situ and invasive carcinomas, and this pertains to the normal presence of C4.4A in squamous epithelium. In pulmonary adenocarcinomas, a fraction of cases is positive for C4.4A, which is surprising, given the origin of these carcinomas from mucin-producing and not squamous epithelium. Interestingly, this correlates with a highly compromised patient survival and a predominant solid tumor growth pattern. Circumstantial evidence suggests an inverse relationship between C4.4A and the tumor suppressor LKB1. This might provide a link to the prognostic impact of C4.4A in patients with adenocarcinomas of the lung and could potentially be exploited for predicting the efficacy of treatment targeting components of the LKB1 pathway.
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Du H, Chen D, Zhou Y, Han Z, Che G. Fibroblast phenotypes in different lung diseases. J Cardiothorac Surg 2014; 9:147. [PMID: 25189096 PMCID: PMC4173054 DOI: 10.1186/s13019-014-0147-z] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2014] [Accepted: 08/18/2014] [Indexed: 01/26/2023] Open
Abstract
Background The “seed and soil” hypothesis emphasizes the importance of interactions between tumor cells and their microenvironment. CAFs (Cancer associated fibroblasts) are important components of the tumor microenvironment. They were widely involved in cancer cells growth and metastasis. Fibroblasts may also play a role in inflammatory disease. The phenotype conversion of fibroblasts in lung diseases has not been investigated previously. We hypothesized that fibroblasts phenotypes may vary among different types of lung disease. Methods The study included six types of lung tissues, ranging from normal lung to lung adenocarcinoma with lymphatic metastasis. Para-carcinoma tissues which were 2-cm-away from the tumor focus were also included in the analysis. The expression of target proteins including alpha-SMA (smooth muscle actin), FAP (fibroblast activation protein), vimentin, E-cadherin, and CK-19 (cytokeratin-19) were examined by immunohistochemistry. TGF-beta(transforming growth factor) and Twist were detected simultaneously in all samples. Results A progressive increase in the levels of alpha-SMA, vimentin and CK-19 was observed in correlation to the degree of malignancy from normal lung tissue to lung adenocarcinoma with lymphatic metastasis, whereas E-cadherin expression showed the opposite trend. TGF-beta and Twist were detected in cancer tissues and inflammatory pseudotumors. None of the proteins were detected in para-carcinoma tissues. Conclusions Fibroblast phenotypes varied according to the type and degree of lung malignancy and fibroblasts phenotypic conversion occurs as a gradual process with specific spatiotemporal characteristics. Similar fibroblast phenotypes in inflammatory diseases and cancer tissues suggested a correlation between inflammation and cancer and implied a common mechanism underlying the formation of fibroblasts in inflammatory diseases and lung cancer. Electronic supplementary material The online version of this article (doi:10.1186/s13019-014-0147-z) contains supplementary material, which is available to authorized users.
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Zhang Y, Hu H, Wang R, Ye T, Pan Y, Wang L, Zhang Y, Li H, Li Y, Shen L, Yu Y, Sun Y, Chen H, Garfield D. Synchronous Non-small Cell Lung Cancers: Diagnostic Yield can be Improved by Histologic and Genetic Methods. Ann Surg Oncol 2014; 21:4369-74. [DOI: 10.1245/s10434-014-3840-1] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2014] [Indexed: 12/11/2022]
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Abstract
Lung cancer is now the leading cause of death from cancer in Australia. Most patients are diagnosed with late-stage disease. Although diagnosis at pre-invasive stages could theoretically improve outcomes, mooted precursor lesions are often asymptomatic and often undetectable by non-invasive investigations. Nonetheless, they merit study to identify early and essential molecular steps involved in lung carcinoma pathogenesis, with the aim of developing therapies targeted against one or more such steps. Some lung cancers appear to develop via a series of progressive morphological changes with correlating molecular alterations, but others seem to arise in histologically normal epithelium, and these differences may reflect anatomically and functionally distinct epithelial compartments of the respiratory tract. Pre-invasive precursor lesions recognised by the World Health Organization (WHO) include squamous metaplasia with dysplasia and carcinoma in situ, atypical adenomatous hyperplasia, and diffuse idiopathic pulmonary neuroendocrine cell hyperplasia. Other lesions that likely represent pre-invasive lesions, but which are not currently WHO-listed, include human papillomavirus (HPV)-related respiratory papillomatosis and mesothelioma in situ. No single cancer stem cell marker has been identified. Field cancerisation plays an important role in lung cancer development, and includes the spread of pre-invasive clones along the respiratory epithelium or the occurrence of multiple separate foci of pre-invasive abnormalities such as squamous dysplasia and carcinoma in situ.In addition to well-characterised step-wise progression in squamous cell carcinomas and some adenocarcinomas, alternative pathways exist, and are currently being investigated. In addition, molecular techniques, including miRNA screening on blood samples or cytology samples--such as sputum samples--may become clinically relevant and more accurate in predicting lung cancer progression.
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Abstract
INTRODUCTION Pulmonary ground-glass nodules are frequently encountered. The purpose of this study was to evaluate the natural history of them and to gain some insights on how to follow them up. METHODS We retrospectively studied patients with pulmonary nodules that met the following criteria: (1) tumor diameter of 3 cm or less, (2) ground-glass opacity proportion of 50% or more, and (3) observation without treatment for 6 months or more. Between 1999 and 2012, 108 pulmonary lesions in 61 patients fulfilled these criteria. We reevaluated their computed tomography images and analyzed changes in their size. RESULTS The tumors were 1 cm or lesser in size in 69 lesions, 1.1 cm to 2 cm in 34, and 2.1 cm to 3 cm in five. The proportion of solid lesions was 0% for 82 lesions, 1% to 25% for 19, and 26% to 50 % for seven. At the median observation period of 4.2 years, 29 lesions had become larger, whereas the remaining 79 had persisted without changing in size (±1 mm). The median size change in the nodules that grew was 7 mm (range, 2-32 mm). All 29 tumors began to grow within 3 years of their first observation: 1 year or lesser in 13 lesions, after 1.1 years to 2 years in 12, and after 2.1 years to 3 years in four. CONCLUSIONS Some small lung lesions exhibiting ground-glass opacity persisted without changes in size, whereas others grew gradually. The tendency to grow was clear within the first 3 years in all cases. Therefore, we conclude that these lesions should be followed for at least 3 years.
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Park BM, Cho MJ, Lee HS, Park DI, Park MR, Kim JO, Lee JE, Lee CS, Jung SS. A Case of Atypical Adenomatous Hyperplasia of Larger Than 2 cm. Tuberc Respir Dis (Seoul) 2013; 74:280-5. [PMID: 23814601 PMCID: PMC3695311 DOI: 10.4046/trd.2013.74.6.280] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2012] [Revised: 12/04/2012] [Accepted: 02/06/2013] [Indexed: 02/05/2023] Open
Abstract
Atypical adenomatous hyperplasia (AAH) has been considered to be a precursor lesion of bronchioloalveolar carcinoma (BAC) and pulmonary adenocarcinoma. It usually coexists with BAC and/or an adenocarcinoma. Chest computed tomography reveals multiple well-defined nodules with ground-glass opacity. Usually, AAH does not exceed 10 mm in size. AAH with extensive involvement on one side of the lung field or one that is larger than 2 cm has not been previously reported. We herein report a case of a 71-year-old nonsmoking female with lung AAH of larger than 2 cm.
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Affiliation(s)
- Bo Mi Park
- Department of Internal Medicine, Chungnam National University School of Medicine, Daejeon, Korea
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Park WY, Kim MH, Shin DH, Lee JH, Choi KU, Kim JY, Park DY, Lee CH, Sol MY. Ciliated adenocarcinomas of the lung: a tumor of non-terminal respiratory unit origin. Mod Pathol 2012; 25:1265-74. [PMID: 22555174 DOI: 10.1038/modpathol.2012.76] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Whereas most carcinomas occur through a sequential step, atypical adenomatous hyperplasia and bronchioloalveolar carcinoma pathway is known for pulmonary adenocarcinoma. This type is known as terminal respiratory unit adenocarcinoma. Based on our observation of transitions from normal ciliated columnar cells to adenocarcinoma via dysplastic mucous columnar cells, we reviewed our archive of pulmonary adenocarcinoma. Terminal respiratory unit type adenocarcinoma was defined as adenocarcinoma with type II pneumocyte, Clara cell, or bronchiolar cell morphology according to previous reports. Among 157 cases, 121 cases have been identified as terminal respiratory unit type adenocarcinoma and 36 cases as non-terminal respiratory unit type adenocarcinoma. Among non-terminal respiratory unit type adenocarcinoma, 24 cases revealed mucous columnar cell changes that were continuous with bronchial ciliated columnar cells. The mucous columnar cells became dysplastic showing loss of cilia, disorientation, and enlarged nuclei. Adenocarcinoma arose from these dysplastic mucous columnar cells and, characteristically, this type of adenocarcinoma showed acute inflammation, and honeycombing changes in the background. TTF1 immunostaining was consistently negative. In a case study with 14 males and 10 females, including 12 smokers or ex-smokers, EGFR and KRAS mutations were detected in 3 and 6 patients, respectively. We think that this kind of adenocarcinoma arising through mucous columnar cell change belongs to non-terminal respiratory unit type adenocarcinoma, and mucous columnar cell change is a precursor lesion of pulmonary adenocarcinoma.
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Affiliation(s)
- Won Young Park
- Department of Pathology, School of Medicine, Pusan National University, Yangsan, Korea
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Abstract
Lung cancer, of which non-small-cell lung cancer comprises the majority, is the leading cause of cancer-related deaths in the United States and worldwide. Lung adenocarcinomas are a major subtype of non-small-cell lung cancers, are increasing in incidence globally in both males and females and in smokers and non-smokers, and are the cause for almost 50% of deaths attributable to lung cancer. Lung adenocarcinoma is a tumour with complex biology that we have recently started to understand with the advent of various histological, transcriptomic, genomic and proteomic technologies. However, the histological and molecular pathogenesis of this malignancy is still largely unknown. This review will describe advances in the molecular pathology of lung adenocarcinoma with emphasis on genomics and DNA alterations of this disease. Moreover, the review will discuss recognized lung adenocarcinoma preneoplastic lesions and current concepts of the early pathogenesis and progression of the disease. We will also portray the field cancerization phenomenon and lineage-specific oncogene expression pattern in lung cancer and how both remerging concepts can be exploited to increase our understanding of lung adenocarcinoma pathogenesis for subsequent development of biomarkers for early detection of adenocarcinomas and possibly personalized prevention.
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Affiliation(s)
- Humam Kadara
- Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
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Abstract
Lung cancer classification is of paramount importance in determining the treatment for oncologic patients. Most lung cancers are non-small cell lung carcinomas (NSCLC), which are further subclassified into squamous cell carcinoma, adenocarcinoma, and large cell carcinoma. Lung neuroendocrine tumors are subclassified into typical carcinoid, atypical carcinoid, small cell carcinoma, and large cell neuroendocrine carcinoma. In NSCLC in particular, the histologic classification and tumor mutation analysis are central to today's targeted therapy and personalized treatment. This article discusses the current diagnostic criteria for classification of NSCLC and lung neuroendocrine tumors and implications for oncologic treatment.
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Affiliation(s)
- Zhen Fan
- Department of Pathology, St Joseph Pathology Associates, St Joseph Medical Center, 7601 Osler Drive, Towson, MD 21204, USA.
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Yatabe Y, Borczuk AC, Powell CA. Do all lung adenocarcinomas follow a stepwise progression? Lung Cancer 2011; 74:7-11. [PMID: 21705107 DOI: 10.1016/j.lungcan.2011.05.021] [Citation(s) in RCA: 97] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2011] [Revised: 05/19/2011] [Accepted: 05/23/2011] [Indexed: 01/15/2023]
Abstract
Similar to the adenoma-carcinoma sequence of colorectal cancer, lung adenocarcinoma is thought to follow a linear multistep progression, in which a precursor lesion progresses to adenocarcinoma in situ, which is followed by invasive adenocarcinoma. However, lung adenocarcinoma can no longer be considered as a single type of tumor but rather a group of distinct subsets of tumors that arise from different molecular pathways. Consistent with this concept, recent findings revealed that this linear progression might not occur in all lung adenocarcinomas. First, according to the molecular classification based on expression profiling, lung cancer can be divided into at least two subsets; precancerous and in situ lesions share characteristics of molecular expression and clinical features with only one of the two subsets, suggesting that the linear progression is only applicable to the subset in the molecular classification. Second, when EGFR and KRAS were examined based on the progression steps, the mutation rate of KRAS was disproportionally distributed; however, according to the progression schema, gene alterations should be evenly accumulated along the entire progression. Third, by means of comparative genomic hybridization analysis, some adenocarcinoma in situ revealed gene alterations discontinuous to invasive adenocarcinoma. Finally, there were some clinical observations that support that some lesions escape from the progression. In this review, we hypothesize a novel scenario for the progression of lung adenocarcinoma, which does not support a linear progression schema.
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Affiliation(s)
- Yasushi Yatabe
- Department of Pathology and Molecular Diagnostics, Aichi Cancer Center, 1-1 Kanokoden, Chikusa-ku, Nagoya 464-8681, Japan.
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Selamat SA, Galler JS, Joshi AD, Fyfe MN, Campan M, Siegmund KD, Kerr KM, Laird-Offringa IA. DNA methylation changes in atypical adenomatous hyperplasia, adenocarcinoma in situ, and lung adenocarcinoma. PLoS One 2011; 6:e21443. [PMID: 21731750 PMCID: PMC3121768 DOI: 10.1371/journal.pone.0021443] [Citation(s) in RCA: 85] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2011] [Accepted: 05/28/2011] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Aberrant DNA methylation is common in lung adenocarcinoma, but its timing in the phases of tumor development is largely unknown. Delineating when abnormal DNA methylation arises may provide insight into the natural history of lung adenocarcinoma and the role that DNA methylation alterations play in tumor formation. METHODOLOGY/PRINCIPAL FINDINGS We used MethyLight, a sensitive real-time PCR-based quantitative method, to analyze DNA methylation levels at 15 CpG islands that are frequently methylated in lung adenocarcinoma and that we had flagged as potential markers for non-invasive detection. We also used two repeat probes as indicators of global DNA hypomethylation. We examined DNA methylation in 249 tissue samples from 93 subjects, spanning the putative spectrum of peripheral lung adenocarcinoma development: histologically normal adjacent non-tumor lung, atypical adenomatous hyperplasia (AAH), adenocarcinoma in situ (AIS, formerly known as bronchioloalveolar carcinoma), and invasive lung adenocarcinoma. Comparison of DNA methylation levels between the lesion types suggests that DNA hypermethylation of distinct loci occurs at different time points during the development of lung adenocarcinoma. DNA methylation at CDKN2A ex2 and PTPRN2 is already significantly elevated in AAH, while CpG islands at 2C35, EYA4, HOXA1, HOXA11, NEUROD1, NEUROD2 and TMEFF2 are significantly hypermethylated in AIS. In contrast, hypermethylation at CDH13, CDX2, OPCML, RASSF1, SFRP1 and TWIST1 and global DNA hypomethylation appear to be present predominantly in invasive cancer. CONCLUSIONS/SIGNIFICANCE The gradual increase in DNA methylation seen for numerous loci in progressively more transformed lesions supports the model in which AAH and AIS are sequential stages in the development of lung adenocarcinoma. The demarcation of DNA methylation changes characteristic for AAH, AIS and adenocarcinoma begins to lay out a possible roadmap for aberrant DNA methylation events in tumor development. In addition, it identifies which DNA methylation changes might be used as molecular markers for the detection of preinvasive lesions.
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Affiliation(s)
- Suhaida A. Selamat
- Departments of Surgery and of Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America
| | - Janice S. Galler
- Departments of Surgery and of Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America
| | - Amit D. Joshi
- Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America
| | - M. Nicky Fyfe
- Department of Pathology, Aberdeen Royal Infirmary, University of Aberdeen, Aberdeen, United Kingdom
| | - Mihaela Campan
- Departments of Surgery and of Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America
| | - Kimberly D. Siegmund
- Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America
| | - Keith M. Kerr
- Department of Pathology, Aberdeen Royal Infirmary, University of Aberdeen, Aberdeen, United Kingdom
| | - Ite A. Laird-Offringa
- Departments of Surgery and of Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America
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Wong AS, Seto KY, Ang B, Wong E, Chin TM, Nga ME, Soo RA. How many adenocarcinoma lung cancers come from bronchioloalveolar carcinoma? Thorac Cancer 2011; 2:54-60. [PMID: 27755811 DOI: 10.1111/j.1759-7714.2011.00041.x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
Abstract
BACKGROUND There is emerging evidence that bronchioloalveolar carcinoma (BAC) is the forerunner of peripheral adenocarcinoma lung cancers (ALC). Since advanced stage ALC is often diagnosed on cytology alone, we hypothesized that the incidence of BAC is underreported and that a large proportion of ALC in our population are part of the BAC-adenocarcinoma sequence. METHODS We reviewed the pretreatment computed tomographic (CT) scans of 69 patients with ALC and looked for characteristic features of BAC. RESULTS The median patient age was 63, and the majority were of Chinese descent (75.4%). Women comprised 43.5% of the patients (30 patients) and never-smokers comprised 47.8% (33 patients). Only 15 patients (21.7%) had surgical specimens. The presence of BAC components was reported in the pathology of 16 patients (23.2%). CT features classically associated with BAC were found in 35 patients (50.7%). These included air bronchograms or bubble-like lucencies in 24 patients (34.8%), ground-glass opacities in 19 (27.5%), consolidation or pneumonic picture in 11 (15.9%), diffuse small or miliary nodules in 10 (14.5%), and the CT angiogram sign in 4 (5.8%). CONCLUSIONS We found provocative radiologic evidence that a large proportion of our ALC cases arise from BAC. The CT findings are consistent with current understanding of the likely pathogenesis of peripheral ALC.
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Affiliation(s)
- Alvin S Wong
- Department of Hematology-Oncology, National University Hospital, National University Health System, Singapore Department of Diagnostic Imaging, National University Hospital, National University Health System, Singapore Cancer Science Institute of Singapore, National University of Singapore, Singapore Department of Pathology, National University Hospital, National University Health System, Singapore
| | - Kar-Yin Seto
- Department of Hematology-Oncology, National University Hospital, National University Health System, Singapore Department of Diagnostic Imaging, National University Hospital, National University Health System, Singapore Cancer Science Institute of Singapore, National University of Singapore, Singapore Department of Pathology, National University Hospital, National University Health System, Singapore
| | - Bertrand Ang
- Department of Hematology-Oncology, National University Hospital, National University Health System, Singapore Department of Diagnostic Imaging, National University Hospital, National University Health System, Singapore Cancer Science Institute of Singapore, National University of Singapore, Singapore Department of Pathology, National University Hospital, National University Health System, Singapore
| | - Eunice Wong
- Department of Hematology-Oncology, National University Hospital, National University Health System, Singapore Department of Diagnostic Imaging, National University Hospital, National University Health System, Singapore Cancer Science Institute of Singapore, National University of Singapore, Singapore Department of Pathology, National University Hospital, National University Health System, Singapore
| | - Tan-Min Chin
- Department of Hematology-Oncology, National University Hospital, National University Health System, Singapore Department of Diagnostic Imaging, National University Hospital, National University Health System, Singapore Cancer Science Institute of Singapore, National University of Singapore, Singapore Department of Pathology, National University Hospital, National University Health System, Singapore
| | - Min-En Nga
- Department of Hematology-Oncology, National University Hospital, National University Health System, Singapore Department of Diagnostic Imaging, National University Hospital, National University Health System, Singapore Cancer Science Institute of Singapore, National University of Singapore, Singapore Department of Pathology, National University Hospital, National University Health System, Singapore
| | - Ross A Soo
- Department of Hematology-Oncology, National University Hospital, National University Health System, Singapore Department of Diagnostic Imaging, National University Hospital, National University Health System, Singapore Cancer Science Institute of Singapore, National University of Singapore, Singapore Department of Pathology, National University Hospital, National University Health System, Singapore
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Cagle PT, Allen TC, Dacic S, Beasley MB, Borczuk AC, Chirieac LR, Laucirica R, Ro JY, Kerr KM. Revolution in lung cancer: new challenges for the surgical pathologist. Arch Pathol Lab Med 2011; 135:110-6. [PMID: 21204716 DOI: 10.5858/2010-0567-ra.1] [Citation(s) in RCA: 64] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
CONTEXT Traditionally, lung cancer has been viewed as an aggressive, relentlessly progressive disease with few treatment options and poor survival. The traditional role of the pathologist has been primarily to differentiate small cell carcinoma from non-small cell carcinoma on biopsy and cytology specimens and to stage non-small cell carcinomas that underwent resection. In recent years, our concepts of lung cancer have undergone a revolution, including (1) the advent of successful, new, molecular-targeted therapies for lung cancer, many of which are associated with specific histologic cell types and subtypes; (2) new observations on the natural history of lung cancer derived from ongoing high-resolution computed tomography screening studies and recent histologic findings; and (3) proposals to revise the classification of lung cancers, particularly adenocarcinomas, in part because of the first 2 developments. OBJECTIVE To summarize the important, new developments in lung cancer, emphasizing the role of the surgical pathologist in personalized care for patients with lung cancer. DATA SOURCES Information about the new developments in lung cancer was obtained from the peer-review medical literature and the authors' experiences. CONCLUSIONS For decades, we have perceived lung cancer as a relentlessly aggressive and mostly incurable disease for which the surgical pathologist had a limited role. Today, surgical pathologists have an important and expanding role in the diagnosis and treatment of lung cancer, and it is essential to keep informed of new advances.
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Affiliation(s)
- Philip T Cagle
- Department of Pathology and Laboratory Medicine, 6565 Fannin Street, The Methodist Hospital, Houston, Texas 77030, USA.
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Clinicopathologic analysis of multiple (five or more) atypical adenomatous hyperplasias (AAHs) of the lung: evidence for the AAH-adenocarcinoma sequence. J Thorac Oncol 2010; 5:466-71. [PMID: 20357616 DOI: 10.1097/jto.0b013e3181ce3b73] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
OBJECTIVE Clarification of the clinicopathologic characteristics of patients with multiple atypical adenomatous hyperplasias (AAHs). MATERIALS AND METHODS The subjects were 1,639 patients who underwent lobectomy or pneumonectomy for lung tumors. The clinicopathologic features of the AAHs in the lung background and the main tumors were examined with regard to the number and the size of the AAHs, the incidence and histology of adenocarcinomas (ADs), and the outcome. RESULTS Thirty-two patients (2.0%) had 5 or more AAHs (ranging from 5 to 171), being present predominantly in the upper lobe (86%) and in women (75%). Among the 794 AAHs, 495 (62%) measured less than 1 mm, 170 (22%) measured 1 to less than 2 mm, 118 (15%) measured 2 to less than 5 mm, and 11 (1%) measured 5 to less than 10 mm. Twenty-eight patients (88%) had AD (1 in 18 patients and 2 to 6 in 10 patients). Thirty-two of the 51 patients with ADs (63%) had an AAH component. The incidence of ADs among the total of both AAHs and ADs was 6.0% (51 of 845). The 5-year cancer-free survival rate was 71.4%. CONCLUSION Five or more AAHs were seen in the background in 2.0% of lung tumors. Most of the AAHs were small, measuring less than 2 mm, and few exceeded 5 mm. Most of the patients had ADs, which were histologically suggested to be derived from AAH. However, the incidence of the AAH-AD sequence was considered to be low at the tumor basis, and the outcome of ADs was not very favorable.
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Distribution of Basal/Myoepithelial Markers in Benign and Malignant Bronchioloalveolar Proliferations of the Lung. Appl Immunohistochem Mol Morphol 2010; 18:219-25. [DOI: 10.1097/pai.0b013e3181c6feec] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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Chirieac LR, Flieder DB. High-resolution computed tomography screening for lung cancer: unexpected findings and new controversies regarding adenocarcinogenesis. Arch Pathol Lab Med 2010; 134:41-8. [PMID: 20073604 DOI: 10.5858/134.1.41] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
CONTEXT Recent advances in human imaging technologies reawakened interest in lung cancer screening. Although historic and current preliminary and noncontrolled studies have not shown a decrease in lung cancer mortality in screened populations, many explanations have been proffered while the lung cancer community awaits the results of several large controlled population studies. OBJECTIVE To critically review the current model of adenocarcinoma development against the background of lung cancer screening results combined with observational pathologic and radiographic studies. DATA SOURCES Published articles pertaining to lung cancer screening, lung adenocarcinoma pathology, and radiology accessible through PubMed form the basis for this review. CONCLUSIONS The current adenocarcinogenesis model is probably valid for many but not all lung adenocarcinomas. Screening data combined with radiographic and pathologic studies suggest that not all lung adenocarcinomas are clinically aggressive, and it is uncertain whether all aggressive adenocarcinomas arise from identified precursors.
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Affiliation(s)
- Lucian R Chirieac
- Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA
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Chilosi M, Murer B. Mixed Adenocarcinomas of the Lung: Place in New Proposals in Classification, Mandatory for Target Therapy. Arch Pathol Lab Med 2010; 134:55-65. [DOI: 10.5858/134.1.55] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
Abstract
Context.—Lung cancer is one of the most frequent and lethal malignant neoplasms, but knowledge regarding the molecular basis of its pathogenesis is far from complete due to the striking diversity of different forms. The current lung cancer classification (World Health Organization 2004) can efficiently distinguish clinically relevant major subtypes (small cell and non–small cell carcinomas), but its results are partly inadequate when facing prognostic and therapeutic decisions for non–small cell carcinomas, especially for the group of tumors classified as adenocarcinoma. Lung adenocarcinoma comprises a heterogeneous group of tumors characterized by diverse morphologic features and molecular pathogenesis. The category of mixed adenocarcinomas includes most adenocarcinomas (approximately 80%) and, according to World Health Organization criteria, is defined by the occurrence of a mixed array of different patterns (acinar, papillary, bronchioloalveolar, solid with mucin). The histologic recognition of mixed adenocarcinoma is subjective and cannot consistently discriminate between responders and nonresponders to new targeted therapies (eg, tyrosine kinase inhibitors). Diagnostic problems are mainly related to the poor reproducibility of histologic criteria, especially when applied in small biopsies and cytology, and to the difficulty in assigning each form to a precisely defined entity, as needed by updated therapeutic approaches. In this evolving scenario, pathologists face new challenging diagnostic roles that include not only the precise morphologic definition of carcinoma subtypes but also their molecular characterization.
Objective.—To use a comprehensive critical analysis reconciling the overwhelming variety of biologic, morphologic, molecular, and clinical data to define new classification schemes for lung adenocarcinoma.
Data Sources.—Scientific literature and personal data were used.
Conclusions.—A new classification approach should redefine lung adenocarcinoma heterogeneity reconciling classic morphology, immunophenotypic and molecular features of neoplastic cells, and also relevant information provided by stem cell biology. This approach, which has been already successfully applied in World Health Organization classification of other tumors, could improve the recognition of new reproducible profiles for adenocarcinomas, more closely and reproducibly related to clinical features and response to specific therapies, limiting the use of “wastebasket” categories such as mixed adenocarcinoma.
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Affiliation(s)
- Marco Chilosi
- From the Department of Pathology, University of Verona, Italy (Dr Chilosi); and the Anatomic Pathology Unit, Ospedale dell'Angelo, Mestre, Italy (Dr Murer)
| | - Bruno Murer
- From the Department of Pathology, University of Verona, Italy (Dr Chilosi); and the Anatomic Pathology Unit, Ospedale dell'Angelo, Mestre, Italy (Dr Murer)
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Lantuéjoul S, Salameire D, Salon C, Brambilla E. Pulmonary preneoplasia--sequential molecular carcinogenetic events. Histopathology 2009; 54:43-54. [PMID: 19187179 DOI: 10.1111/j.1365-2559.2008.03182.x] [Citation(s) in RCA: 72] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2022]
Abstract
Bronchial and bronchioloalveolar carcinogenesis is a multicentric and multistep process, leading to a sequential accumulation of molecular and genetic abnormalities, mainly due to exposure to tobacco carcinogens. Concomitantly, a series of morphological alterations of normal bronchial or bronchioloalveolar epithelium occur, resulting in preneoplastic and then neoplastic lesions. The three pulmonary preneoplastic changes recognized to date in the lung include bronchial squamous dysplasia and in situ carcinoma, preceding invasive squamous cell carcinoma and basaloid carcinoma, atypical adenomatous hyperplasia, a preneoplastic condition of bronchioloalveolar carcinoma, and diffuse idiopathic pulmonary neuroendocrine cell hyperplasia, a proposed precursor for carcinoid tumours. Although the gradual accumulation of molecular alterations has been widely investigated in bronchial carcinogenesis, with the aim of determining new biomarkers for early lung cancer detection in high-risk patients and targeted chemoprevention, lung adenocarcinoma pathogenesis has been only recently highlighted, with the recent discovery of epidermal growth factor receptor mutation pathway in non-smokers. This review focuses on the current status of molecular pathology in lung cancer and pulmonary preneoplastic conditions.
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Affiliation(s)
- Sylvie Lantuéjoul
- Department of Pathology and Lung Cancer Research Group, INSERM U578, CHU A Michallon, Université J Fourier, Grenoble, France.
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Lee HS, Choi JS, Seo KH, Na JO, Kim YH, Oh MH, Jou SS. A Case of Congenital Cystic Adenomatoid Malformation of the Lng with Atypical Adenomatous Hyperplasia in Adult. Tuberc Respir Dis (Seoul) 2009. [DOI: 10.4046/trd.2009.66.5.385] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Affiliation(s)
- Ho Sung Lee
- Department of Internal Medicine, Soonchunhyang University Cheonan Hospital, College of Medicine, Cheonan, Korea
| | - Jae Sung Choi
- Department of Internal Medicine, Soonchunhyang University Cheonan Hospital, College of Medicine, Cheonan, Korea
| | - Ki Hyun Seo
- Department of Internal Medicine, Soonchunhyang University Cheonan Hospital, College of Medicine, Cheonan, Korea
| | - Ju Ock Na
- Department of Internal Medicine, Soonchunhyang University Cheonan Hospital, College of Medicine, Cheonan, Korea
| | - Yong Hoon Kim
- Department of Internal Medicine, Soonchunhyang University Cheonan Hospital, College of Medicine, Cheonan, Korea
| | - Mi Hye Oh
- Department of Diagnostic Pathology, Soonchunhyang University Cheonan Hospital, College of Medicine, Cheonan, Korea
| | - Sung Shick Jou
- Department of Radiology, Soonchunhyang University Cheonan Hospital, College of Medicine, Cheonan, Korea
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Expression profile of early lung adenocarcinoma: identification ofMRP3as a molecular marker for early progression. J Pathol 2008; 216:75-82. [DOI: 10.1002/path.2383] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
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Holm N, Byrnes K, Johnson L, Abreo F, Sehon K, Alley J, Meschonat C, Md QC, Li BDL. A prospective trial on initiation factor 4E (eIF4E) overexpression and cancer recurrence in node-negative breast cancer. Ann Surg Oncol 2008; 15:3207-15. [PMID: 18719964 DOI: 10.1245/s10434-008-0086-9] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2008] [Revised: 07/01/2008] [Accepted: 07/02/2008] [Indexed: 12/27/2022]
Abstract
BACKGROUND Eukaryotic Initiation Factor 4E (eIF4E) plays a crucial role in translation control. High eIF4E increase in tumor specimens independently predicted recurrence by multivariate analysis. This prospective trial of node-negative only breast cancer patients was initiated to test the hypothesis that high eIF4E increase predicts cancer recurrence and death, independent of nodal status. METHODS The trial was powered to detect a 2.4-fold increase in relative risk for cancer recurrence in 240 node-negative patients on the basis of high versus low eIF4E increase in tumor specimens (type I error = .05, statistical power = .08). eIF4E level was quantified by using Western blot test. Treatment and surveillance regimens were standardized. Primary endpoints were cancer recurrence and cancer-related death. RESULTS Of the 242 patients accrued, 112 were in the low eIF4E group (<7.5-fold), 82 were in the intermediate eIF4E group (7.5- to 15-fold), and 48 were in the high eIF4E group (>15-fold). Patients in the high eIF4E group had a statistically significant higher rate of cancer recurrence and cancer-related death (P = .0001 and P < or = .0001, log rank test). The relative risk for cancer recurrence was 2.2-fold higher in the high eIF4E group (P = .001, Cox model), and 3.7-fold higher for cancer-related death (P = .0009). CONCLUSIONS In node-negative breast cancer, high eIF4E increase predicted a higher rate of cancer recurrence and death. High eIF4E patients had a >2-fold increase in relative risk for cancer recurrence and nearly a 4-fold increase in relative risk for death. This supports our hypothesis that high eIF4E is an independent predictor for breast cancer outcome independent of nodal status.
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Affiliation(s)
- Neal Holm
- Louisiana State University Health Sciences Center and Feist-Weiller Cancer Center, 1501 Kings Highway, Shreveport, LA 71130, USA
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Butnor KJ. Avoiding underdiagnosis, overdiagnosis, and misdiagnosis of lung carcinoma. Arch Pathol Lab Med 2008; 132:1118-32. [PMID: 18605766 DOI: 10.5858/2008-132-1118-auoamo] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/07/2007] [Indexed: 11/06/2022]
Abstract
CONTEXT Given the magnitude of the therapeutic and prognostic implications, it is critical that pathologists diagnose lung cancer accurately. This can sometimes be a formidable challenge, as a number of benign entities mimic lung carcinoma and vice versa. OBJECTIVE To present strategies for recognizing benign entities likely to be confused with lung carcinoma, malignancies of the lung prone to misinterpretation as benign, and commonly misclassified pulmonary neoplasms. DATA SOURCES The medical literature and experience from consultative and surgical practice. CONCLUSIONS In addition to understanding the clinical context in which a lung biopsy is procured and the radiographic findings, appreciating the histologic distribution of disease and what, if any, pathologic features are present in the background can go a long way toward averting a misdiagnosis of lung cancer. Recognizing the limitations posed by small samples and communicating clearly to clinicians the level of diagnostic uncertainty are equally as important for establishing an accurate diagnosis of lung cancer.
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Affiliation(s)
- Kelly J Butnor
- Department of Pathology, University of Vermont/Fletcher Allen Health Care, Burlington, VT 05401, USA.
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Abstract
Abstract
Context.—Improved screening techniques for lung cancer have resulted in detection of lesions that are considered to represent precursors of invasive lung carcinomas. These lesions may cause a diagnostic dilemma particularly on small biopsy or cytology specimens. Ancillary studies are usually not helpful, and diagnosis is based on morphology alone. Recognition of these lesions is very important to prevent potential diagnostic mistakes that may result in inadequate patient management. Future molecular studies may provide clinically useful diagnostic and prognostic gene markers.
Objective.—To review currently proposed morphologic criteria for precursor lesions of non–small cell lung carcinomas including squamous dysplasias, atypical adenomatous hyperplasia, and diffuse idiopathic neuroendocrine cell hyperplasia. Major molecular abnormalities are briefly discussed.
Data Sources.—Published literature and recent World Health Organization classification of lung tumors.
Conclusions.—Practicing surgical pathologists must be familiar with morphology of recognized pulmonary preneoplastic lesions that are more frequently detected radiographically and subjected to diagnostic procedures. Future understanding of underlying molecular abnormalities associated with progression of these lesions into invasive lung carcinoma may result in a development of molecular assays with potential diagnostic and prognostic importance.
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Affiliation(s)
- Sanja Dacic
- From the Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, Pa
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Immunoexpression of P16INK4a, Rb and TP53 proteins in bronchiolar columnar cell dysplasia (BCCD) in lungs resected due to primary non-small cell lung cancer. Folia Histochem Cytobiol 2008; 46:89-96. [DOI: 10.2478/v10042-008-0013-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
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Abstract
From histological and biological perspectives, lung cancer is a complex neoplasm. Although the sequential preneoplastic changes have been defined for centrally arising squamous carcinomas of the lung, they have been poorly documented for the other major forms of lung cancers, including small cell lung carcinoma and adenocarcinomas. There are three main morphologic forms of preneoplastic lesions recognized in the lung: squamous dysplasias, atypical adenomatous hyperplasia, and diffuse idiopathic pulmonary neuroendocrine cell hyperplasia. However, these lesions account for the development of only a subset of lung cancers. Several studies have provided information regarding the molecular characterization of lung preneoplastic changes, especially for squamous cell carcinoma. These molecular changes have been detected in the histologically normal and abnormal respiratory epithelium of smokers. Two different molecular pathways have been detected in lung adenocarcinoma pathogenesis: smoking-associated activation of RAS signaling, and nonsmoking-associated activation of EGFR signaling; the latter is detected in histologically normal respiratory epithelium.
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Affiliation(s)
- Ignacio I Wistuba
- Department of Pathology, M.D. Anderson Cancer Center, University of Texas, Houston, Texas 77030, USA.
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Mun M, Kohno T. Efficacy of thoracoscopic resection for multifocal bronchioloalveolar carcinoma showing pure ground-glass opacities of 20 mm or less in diameter. J Thorac Cardiovasc Surg 2007; 134:877-82. [PMID: 17903500 DOI: 10.1016/j.jtcvs.2007.06.010] [Citation(s) in RCA: 62] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/05/2007] [Revised: 06/07/2007] [Accepted: 06/15/2007] [Indexed: 10/22/2022]
Abstract
OBJECTIVE Small bronchioloalveolar carcinoma showing pure ground-glass opacity on high-resolution computed tomographic scans is commonly multifocal. Surgical treatment for these lesions is controversial. We discuss the efficacy of video-assisted thoracic surgery for multifocal bronchioloalveolar carcinoma in patients at our institution. METHODS Twenty-seven patients with multifocal bronchioloalveolar carcinoma lesions less than or equal to 20 mm in diameter (105 lesions) underwent video-assisted thoracic surgery pulmonary resection between 2000 and 2006. Their clinicopathologic features were investigated retrospectively. RESULTS Twenty-seven patients (10 male and 17 female) with a median age of 64 years (range, 41-78 years) had 91 ground-glass opacity lesions on high-resolution computed tomography. Sixteen patients (59%) were women with no history of smoking. The distribution of bronchioloalveolar carcinoma lesions was unilateral in 14 patients and bilateral in 13 patients. Ten patients underwent wedge resection. Seventeen patients underwent single-stage segmentectomy or lobectomy (alone or with wedge resection) for technical reasons. All lesions were completely resected. One patient underwent conversion to thoracotomy for bleeding. Histologic diagnoses showed 62 bronchioloalveolar carcinoma type A lesions, 28 type B lesions, and 15 type C lesions according to Noguchi's classification, and atypical adenomatous hyperplasia in 43 lesions (13 patients). All patients had N0 disease. The median postoperative observation period was 46 months. All patients have survived to date, but new lesions have developed in 7 (26%). Patients with new lesions had a higher incidence of bronchioloalveolar carcinoma lesions of 3 mm or less in diameter (P = .0254) and atypical adenomatous hyperplasia (P = .011). CONCLUSION Video-assisted thoracic surgery management of multifocal bronchioloalveolar carcinoma yielded satisfactory results. However, the appearance of new lesions remains a problem.
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Affiliation(s)
- Mingyon Mun
- Department of Thoracic Surgery, Toranomon Hospital, Tokyo, Japan.
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45
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van den Berg RM, Teertstra HJ, van Zandwijk N, van Tinteren H, Visser C, Pasic A, Sutedja TG, Baas P, Golding RP, Postmus PE, Smit EF. CT detected indeterminate pulmonary nodules in a chemoprevention trial of fluticasone. Lung Cancer 2007; 60:57-61. [PMID: 17983686 DOI: 10.1016/j.lungcan.2007.09.007] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2007] [Revised: 09/10/2007] [Accepted: 09/12/2007] [Indexed: 10/22/2022]
Abstract
INTRODUCTION In animal models of lung carcinogenesis, inhaled corticosteroids appear to reduce the number of new lung tumors. In a trial of budesonide in smokers with bronchial dysplasia, the proportion of indeterminate CT detected pulmonary nodules that resolved was larger in the treatment group. We performed a secondary analysis of CT data of subjects at risk of lung cancer enrolled in a chemoprevention trial of fluticasone. METHODS Subjects with bronchial squamous metaplasia or dysplasia had a baseline chest CT scan. They were randomized to fluticasone or a placebo. After 6 months a repeat CT was performed and the change in number and size of nodules was evaluated. RESULTS Two hundred and one subjects were screened. Of the 108 volunteers included in the study, 74 were male, mean age was 53 years and mean number of pack years 48. Baseline: 35 subjects had 91 nodules in total, 62% <4mm. In the fluticasone arm more subjects had a decrease and fewer had an increase in number of nodules, however this trend did not reach statistical significance. CONCLUSION In this preliminary study there was a tendency of nodules to resolve, however, studies with CT detected nodules as inclusion criterion are needed.
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Affiliation(s)
- Remco M van den Berg
- Department of Pulmonology, VU University Medical Center, Boelelaan 1117, 1081HV Amsterdam, The Netherlands
| | - H Jelle Teertstra
- Department of Radiology, The Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, Plesmanlaan 121, 1066CX Amsterdam, The Netherlands
| | - Nico van Zandwijk
- Department of Thoracic Oncology, The Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, Plesmanlaan 121, 1066CX Amsterdam, The Netherlands
| | - Harm van Tinteren
- Department of Biometrics, The Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, Plesmanlaan 121, 1066CX Amsterdam, The Netherlands
| | - Christien Visser
- Department of Thoracic Oncology, The Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, Plesmanlaan 121, 1066CX Amsterdam, The Netherlands
| | - Arifa Pasic
- Department of Pulmonology, VU University Medical Center, Boelelaan 1117, 1081HV Amsterdam, The Netherlands
| | - Thomas G Sutedja
- Department of Pulmonology, VU University Medical Center, Boelelaan 1117, 1081HV Amsterdam, The Netherlands
| | - Paul Baas
- Department of Thoracic Oncology, The Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, Plesmanlaan 121, 1066CX Amsterdam, The Netherlands
| | - Richard P Golding
- Department of Radiology, VU University Medical Center, Boelelaan 1117, 1081HV Amsterdam, The Netherlands
| | - Pieter E Postmus
- Department of Pulmonology, VU University Medical Center, Boelelaan 1117, 1081HV Amsterdam, The Netherlands
| | - Egbert F Smit
- Department of Pulmonology, VU University Medical Center, Boelelaan 1117, 1081HV Amsterdam, The Netherlands.
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Thumma SC, Kratzke RA. Translational control: a target for cancer therapy. Cancer Lett 2007; 258:1-8. [PMID: 17923280 DOI: 10.1016/j.canlet.2007.08.022] [Citation(s) in RCA: 35] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2007] [Revised: 08/21/2007] [Accepted: 08/31/2007] [Indexed: 12/22/2022]
Abstract
Cap-mediated translation is the default mechanism for the synthesis of proteins in eukaryotic cells. Increasingly, malignant cells have been found to have deregulation of this process. Return of normal translational control is associated with loss of tumorigenic potential in pre-clinical models. Currently, a variety of novel therapeutics are in development targeting this mechanism as a treatment for cancer.
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Affiliation(s)
- Saritha C Thumma
- The Division of Hematology-Oncology-Transplant, Department of Medicine, The University of Minnesota Medical School, Minneapolis, MN 55455, USA
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Sakamoto H, Shimizu J, Horio Y, Ueda R, Takahashi T, Mitsudomi T, Yatabe Y. Disproportionate representation of KRAS gene mutation in atypical adenomatous hyperplasia, but even distribution of EGFR gene mutation from preinvasive to invasive adenocarcinomas. J Pathol 2007; 212:287-94. [PMID: 17534846 DOI: 10.1002/path.2165] [Citation(s) in RCA: 91] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
In the resected lung, additional small lesions are occasionally found incidentally, and include the full spectrum of preinvasive to invasive lesions under the current putative schema of the sequential development of lung cancer. In this study, we examined EGFR and KRAS gene mutations in 119 synchronous pulmonary lesions, including 40 precursor lesions (atypical adenomatous hyperplasia, AAH), 26 carcinomas in situ (non-mucinous bronchioloalveolar carcinoma, BAC), 14 minimally invasive adenocarcinomas, 34 overt invasive adenocarcinomas, and five of other subtypes of cancer. Although the mutually exclusive nature of KRAS and EGFR gene mutations was maintained even in preinvasive lesions, the incidences of the lesions along the putative progression schema were quite different. The KRAS gene was mutated in 33% of AAH, 12% of carcinomas in situ, 8% of minimally invasive adenocarcinomas and 0% of well-differentiated adenocarcinomas, whereas the frequencies of EGFR mutation did not fluctuate greatly, at 25%, 51%, 36%, 86% and 67%, respectively. These results are consistent with the findings of a published gene-targeted mouse model; the mice expressing oncogenic KRAS developed AAH but not invasive adenocarcinoma, whereas a spectrum of preinvasive to invasive adenocarcinomas was observed in the mice expressing mutant EGFR. Taking these factors together, it is suggested that AAH could develop by either KRAS or EGFR gene mutation, but AAH harbouring a KRAS gene mutation might not progress further to an invasive cancer.
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Affiliation(s)
- H Sakamoto
- Department of Pathology and Molecular Diagnostics, Aichi Cancer Center, Nagoya, Japan
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Gradowski JF, Mantha GS, Hunt JL, Dacic S. Molecular Alterations in Atypical Adenomatous Hyperplasia Occurring in Benign and Cancer-bearing Lungs. ACTA ACUST UNITED AC 2007; 16:87-90. [PMID: 17525677 DOI: 10.1097/pdm.0b013e318030afde] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
Atypical adenomatous hyperplasia (AAH) is considered to be a precursor lesion of the lung adenocarcinoma. Several genetic abnormalities have been reported in AAH associated with adenocarcinoma, but little is known about AAH associated with benign lung lesions. To address this we compared the molecular characteristics of AAH present in benign conditions to those coexisting with carcinoma. Seven cases of AAH from resected non-neoplastic lungs (AAH-B) and 12 cases from lungs resected for primary lung carcinoma (AAH-M) were analyzed for loss of heterozygosity (LOH) using 21 polymorphic microsatellite markers situated in proximity to known tumor suppressor genes on chromosomes 3p, 5q, 7p, 9p, 10q, and 17p. Direct DNA sequencing for K-ras mutation was also performed. There was a broad range of LOH in both groups. No LOH was identified in 3 cases (25%) of AAH-M, but all cases of AAH-B showed LOH (P=0.26). Six cases (50%) of AAH-M and 3 cases (43%) of AAH-B showed loss at 1 marker (P=0.99). LOH at 2 or more markers was identified in 3 (25%) cases of AAH-M and 4 (57%) cases of AAH-B (P=0.32). LOH was most frequently detected on chromosomes 3p and 10q in both groups. The difference in overall fractional allelic loss between the 2 groups did not reach statistical significance. K-ras mutations were not identified in either group. Our results showed a significant overlap in LOH patterns between AAH with or without coexistent lung malignancy. Therefore, AAH may represent a smoking induced low-grade neoplastic lesion that may be a precursor lesion of only a subset of invasive lung adenocarcinoma.
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Affiliation(s)
- Joel F Gradowski
- Department of Pathology, Division of Anatomic Pathology, University of Pittsburgh Medical Center, Presbyterian University Hospital, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA
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Dacic S. Molecular profiling of lung carcinoma: identifying clinically useful tumor markers for diagnosis and prognosis. Expert Rev Mol Diagn 2007; 7:77-86. [PMID: 17187486 DOI: 10.1586/14737159.7.1.77] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
The overall survival of patients with lung cancer is dismal despite extensive effort in improvement of diagnosis and treatment. A better understanding of the multistep genetic and epigenetic alterations in lung cancer pathogenesis and progression is necessary for development of improved diagnostic approaches and new targeted therapies. Identification of molecular alterations in the early lung carcinogenesis, together with advanced molecular techniques, may facilitate development of rapid and effective methods for early diagnosis and prognosis of lung carcinoma. In this review, we discuss current understanding of lung carcinogenesis and prospective molecular markers in lung cancer diagnosis. Although the impact of translating new technologies into clinical practice on survival has not been completely determined, they offer a new avenue of exciting novel approaches to early diagnosis of this deadly disease.
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MESH Headings
- Biomarkers, Tumor/genetics
- Carcinoma, Non-Small-Cell Lung/diagnosis
- Carcinoma, Non-Small-Cell Lung/genetics
- Carcinoma, Non-Small-Cell Lung/pathology
- Carcinoma, Non-Small-Cell Lung/therapy
- Carcinoma, Small Cell/diagnosis
- Carcinoma, Small Cell/genetics
- Carcinoma, Squamous Cell/diagnosis
- Carcinoma, Squamous Cell/genetics
- Carcinoma, Squamous Cell/pathology
- Carcinoma, Squamous Cell/therapy
- Chromosome Mapping
- Gene Expression Profiling
- Genes, ras
- Humans
- Lung Neoplasms/diagnosis
- Lung Neoplasms/genetics
- Lung Neoplasms/pathology
- Lung Neoplasms/therapy
- Multigene Family
- Prognosis
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Affiliation(s)
- Sanja Dacic
- University of Pittsburgh Medical Center, Department of Pathology, PUH A610, Pittsburgh, PA 15213, USA.
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Morandi L, Asioli S, Cavazza A, Pession A, Damiani S. Genetic relationship among atypical adenomatous hyperplasia, bronchioloalveolar carcinoma and adenocarcinoma of the lung. Lung Cancer 2007; 56:35-42. [PMID: 17241687 DOI: 10.1016/j.lungcan.2006.11.022] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2006] [Revised: 11/02/2006] [Accepted: 11/27/2006] [Indexed: 10/23/2022]
Abstract
Atypical adenomatous hyperplasia (AAH) has been recently defined by WHO as a small lesion, not exceeding 5mm in major axis, composed of slightly enlarged alveolar septa lined by pneumocytes with plump, atypical nuclei. AAH is frequently found in tissue surrounding lung adenocarcinoma and is considered a precursor of this subtype of lung cancer by many Authors. However, the genetic relationship between adenocarcinoma and the associated foci of AAH is not well defined. In particular, it is not clear whether multiple foci of AAH and of adenocarcinoma in the same patients are clonally related to each other or represent independent neoplastic foci. To clarify if AAH and the associated cancer are clonally related, we evaluated the genetic distance between these two lesions in 16 patients, using direct sequencing of mitochondrial DNA (D-loop region). Furthermore, LOH analysis for 7 microsatellites (D3S1478 at 3p21, D3S1300 at 3p14.2, D9S942 at 9p21, D5S346 at 5q21, D17S261 at 17p13.1, D18S46 at 18q21, D19S246 at 19q13.2) was also performed. Our results indicate that, in at least 9 out of 13 informative cases (69.2%), AAH and the associated cancer were not clonally related as they showed a different mutation pattern in the mitochondrial D-loop region. These findings were also in agreement with the LOH data which showed losses in different loci in at least three cases. On the contrary an identical LOH pattern between BAC and AAH was found in one case. Similar but not identical LOH pattern between AAH and related tumors was found in other three cases. Therefore, our results suggest that AAH and the associated cancer are genetically independent in agreement with the concept of cancerization field. Less frequently AAH foci could represent an early spread of cells from the main tumor, rather than a precursor lesion.
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Affiliation(s)
- Luca Morandi
- Department of Oncology, Section of Anatomic Pathology "M. Malpighi", University of Bologna, Bellaria Hospital, Via Altura no. 3, 40139 Bologna, Italy
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