Journal of Surgery
Multistep Progression from Atypical Adenomatous Hyperplasia to Lung Adenocarcinoma: Clinico-Pathologic, Epigenetic and Genetic Aspects
Hong Kwan Kim1,3, David M. Jablons1,2* and Il-Jin Kim1,2*
- 1Thoracic Oncology Laboratory, Department of Surgery, University of California San Francisco, San Francisco, CA, USA
- 2Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA
- 3Department of Thoracic and Cardiovascular Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
*Address for Correspondence: David M. Jablons, MD, Thoracic Oncology Laboratory, Department of Surgery, University of California San Francisco, San Francisco, CA, USA, E-mail: David.Jablons@ucsfmedctr.org
Il-Jin Kim, PhD, Thoracic Oncology Laboratory, Department of Surgery, University of California San Francisco, San Francisco, CA, USA, E-mail: kimij@cc.ucsf.edu
Citation: Kim HK, Jablons DM, Kim IJ. Multistep Progression from Atypical Adenomatous Hyperplasia to Lung Adenocarcinoma: Clinico-Pathologic, Epigenetic and Genetic Aspects. J Surgery. 2013;1(1): 10.
Copyright © 2013 Kim HK, et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Journal of Surgery | ISSN: 2332-4139 | Volume: 1, Issue: 1
Submission: 03 July 2013 | Accepted: 07 August 2013 | Published: 12 August 2013
Abstract
Detection of small peripheral ground-glass opacity nodules has increased due to the advances in imaging modalities and the widespread use of computed tomography screening. Pathologic examination of these nodules revealed that they have a pure lepidic or replacement growth pattern such as atypical adenomatous hyperplasia or adenocarcinoma in situ (formerly known as bronchioloalveolar carcinoma). When untreated, ground-glass opacity nodules gradually develop a solid component. The greater the solid component or the invasive component, the less favorable outcomes after treatment for patients with ground-glass opacity nodules. Based on the clinical, radiologic and pathologic findings, the concept of multistep progression from preinvasive atypical adenomatous hyperplasia through noninvasive adenocarcinoma in situ to invasive adenocarcinoma has been postulated. Recently, evidence has accumulated explaining this putative concept by molecular alterations, including activating mutation of oncogenes and inactivation of tumor suppressor genes by epigenetic changes or loss of heterozygosity. This review 1) comprehensively outlines the accumulated knowledge regarding radiologic and pathologic features of adenocarcinoma and its precursor which presents as ground-glass opacity and 2) summarizes the molecular basis of the multistep progression to lung adenocarcinoma. As a result, we believe identification of undiscovered molecular markers involved in the progression of lung adenocarcinoma is critical for early detection of lung cancer and the development of targeted therapeutic and chemoprevention strategies.Keywords
Atypical adenomatous hyperplasia; Adenocarcinoma in situ; Invasive adenocarcinoma; Ground-glass opacity; Molecular alterationsAbbreviations
AAH: Atypical Adenomatous Hyperplasia; ADC: Adenocarcinoma; AIS: Adenocarcinoma in situ; BAC: Bronchioloalveolar Carcinoma; CT: Computed Tomography; GGO: Ground-Glass Opacity; LOH: Loss of Heterozygosity; MIA: Minimally Invasive Adenocarcinoma; NGS: Next Generation Sequencing; NSCLC: Non-Small Cell Lung Cancer; PET: Positron Emission Tomography; WHO: World Health OrganizationIntroduction
Lung cancer is the leading cause of cancer deaths in the United States and worldwide with over 1.3 million deaths in 2008 [ 1-3]. Despite the fact that enormous resources have been spent on research involving molecular and therapeutic aspects of lung adenocarcinoma (ADC), there has been no significant improvement in the mortality associated with lung cancer for the past 25 years. This can be attributed in part to untimely diagnosis at advanced stages or recurrence occurring even after optimal treatment at early stages. About 70% of patients are diagnosed with lung cancer at advanced stages when there is little chance to cure [ 4]. Although patients diagnosed at early stages receive curative-intent complete resection by surgery, about 20% of them will not survive due to recurrence within 5 years [ 5-12]. One cause may be that patients already have microscopic systemic metastases in other distant organs at the time of surgery. In order to reduce the mortality and eventually to overcome lung cancer, understanding carcinogenesis and tumor progression is paramount.Radiologic and Pathologic Features
With recent advances in diagnostic imaging modalities, small indeterminate nodules such as GGO lesions have been increasingly detected on high-resolution computed tomography (CT) scans [ 22-25]. In addition, the introduction of low-dose helical CT scanning for lung cancer screening has further increased the detection rate of small GGO lesions. Recently, the observation from the National Lung Screening Trial that low-dose CT screening can reduce mortality from lung cancer obviously justified the use of CT screening in clinical practices and it is anticipated that GGO lesions will be detected more commonly [ 26].Concept of Multistep Progression
Based on clinical implications and pathologic findings, many researchers proposed a hypothesis of multistep carcinogenesis in which some lung ADCs arise from preneoplastic lesions called AAH, which progress to AIS, eventually developing into invasive ADC [ 15-18]. This concept was initially proposed in the field of colorectal cancer, in which colorectal carcinogenesis involves a multistep process from normal mucosa and inflammation, through early and late adenomas to invasive carcinoma [ 64,65]. If specimens for histologic analysis could easily be obtained repeatedly over time in the same patient, it would be an ideal method to elucidate the natural history of cancer. In colon cancer, this longitudinal study can be performed because it is relatively easy to obtain colon cancer specimens via an endoscopic approach. However, in lung cancer, such a procedure is more challenging especially in peripheral lung cancer, because it is rarely accessible via an endoscopic approach. Furthermore, it is much more difficult to obtain specimens if the lesion of interest is at an early stage such as AAH [ 66]. Although serial morphologic changes in imaging tests such as CT or positron emission tomography (PET) can be an alternative way to demonstrate the multistep progression of lung ADC [ 20,21], it cannot be guaranteed that radiographic features are equivalent to pathologic findings. Otherwise, it cannot help but compare individual lesions from different patients and a temporal assumption is inevitable in this cross-sectional method, which should be interpreted with caution. It should also be noted that the time point at which genetic or epigenetic alterations occur might differ from patient to patient, since it is still difficult to tell exactly when these alterations first occur. In addition, genes affected in a specific pathway might vary from tumor to tumor, because not all molecular changes will be fully penetrant and only a portion of tumors will gain a specific molecular change [ 67]. Furthermore, since lung ADC can no longer be considered a single type of tumor but rather a group of distinct subsets that arise from different molecular pathways, the concept of multistep progression carcinogenesis is not necessarily applicable to all ADCs [ 68].Genetic Alteration
Lung ADC arises from the accumulation of enormous genetic and epigenetic changes, giving advantages to neoplastic cells in cellular growth and/or survival with progression depending mainly on the balance between oncogene activation and tumor suppressor gene inactivation [ 89]. To date, over 100 oncogenes have been identified such as ras and tyrosine kinase receptors (EGFR, c-erb-B2 (HER-2/neu)). Many of these behave dominatly in that only one allele needs to be overexpressed to have effect [ 77]. In contrast, tumor suppressor genes behave as recessive genes and thus both alleles need to be inactivated either by epigenetic modifications (predominantly by promoter methylation), allelic deletion or mutation [ 71].Epigenetic Alteration
Silencing of various tumor suppressor genes by epigenetic alteration is also an important mechanism in human carcinogenesis [ 148]. Epigenetic changes in one allele and LOH or another epigenetic changes of the remaining allele can also result in biallelic inactivation of tumor suppressor genes [ 149-152]. Aberrant DNA methylation is a typical epigenetic change that has been extensively detected in nearly all types of cancer [ 153-158], including lung cancer [ 156-158]. DNA hypermethylation mainly occurs in the CpG islands located in the promoter regions of tumor suppressor genes, effectively silencing the gene without any accompanying alterations in the DNA sequence [ 153]. This phenomenon is very widely observed in lung ADC, which suggests that DNA hypermethylation plays a critical role in the pathogenesis of lung ADC.Future Direction
Since the concept of multistep development and progression of lung ADC was postulated, supporting evidence has been accumulating in clinical, radiologic, pathologic and molecular studies. As mentioned earlier, however, a critical challenge that researchers are still facing in studying the molecular basis of this concept is limited availability of tissue samples. This is mainly due to the limited size of these early lesions like AAH, which are by definition smaller than 5 mm and contain few cells from their alveolar structure [ 17]. Another reason is related to the fact that clinicians are reluctant to perform a surgery for early indolent nodules with GGO features. A possible solution to overcome this limitation is to find an alternative way of obtaining tissue samples by AAH or AIS-derived cell lines. This interesting approach was done by Shimada and coworkers, who compared a cell line derived from an AAH lesion (PL16T) with its normal counterpart (PL16B) [ 163]. Although there is still concern whether these cells maintain their AAH or AIS characteristics [ 66], this alternative method will potentially shed light on how to study the molecular alterations occurring during the development and progression from AAH to AIS and ADC. Another way to solve the limited specimen issue is to make better use of it by high-throughput technologies such as next generation sequencing (NGS) and tissue microarray. Data generated by high-throughput experiments need to be further analyzed by bioinformatics methods.Acknowledgements
This work as supported by the Barbara Isackson Lung Cancer Research Fund (DJ), The Eileen D. Ludwig Endowed Fund for Thoracic Oncology Research (DJ), Uniting Against Lung Cancer (UALC) (IJK), and Mesothelioma Applied Research Foundation (MARF) (IJK).References
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