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Differentiating separate primary lung adenocarcinomas from intrapulmonary metastases with emphasis on pathological and molecular considerations: Recommendations from the IASLC Pathology Committee

Brooks V. Udelsman, MD MHS, Christina K. Bedrosian, BS, Eric S. Kawaguchi, PhD, Li Ding, MD, Williams D. Wallace, MD, Graeme Rosenberg, MD, Takashi Harano, MD, Sean Wightman, MD, Scott Atay, MD, Anthony W. Kim, MD, Gavitt Woodard, MD

26 October 2024

Introduction: With the implementation of low-dose computed tomography (LDCT) screening, multiple pulmonary tumor nodules (MPTN) are diagnosed with increasing frequency and the selection of surgical treatments versus systemic therapies has become challenging on a daily basis in clinical practice. In the presence of multiple carcinomas, especially adenocarcinomas, pathologically determined to be of pulmonary origin, the distinction between separate primary lung carcinomas (SPLCs) and intrapulmonary metastases (IPMs) is important for staging, management, and prognostication.

背景：随着低剂量计算机断层扫描（LDCT）筛查的实施，多发性肺肿瘤结节（MPTN）的诊断频率越来越高，手术治疗与全身治疗的选择在临床实践中变得每天都具有挑战性。在存在病理确定为肺源性的多种癌症（尤其是腺癌）时，单独的原性肺癌（SPL）和肺内转移（IPL）之间的区别对于分期、管理和预测非常重要。

Methods: We systemically reviewed various means that aid in the differentiation between SPLCs and IPMs explored by histopathologic evaluation and molecular profiling, the latter includes DNA microsatellite analysis, array comparative genomic hybridization, TP53 and oncogenic driver mutation testing and, more recently, with promising effectiveness, next-generation sequencing (NGS) comprising small- or large-scale multi-gene panels.

方法：我们系统地回顾了通过组织病理学评价和分子分析探索的帮助区分SPLCs和IPM的各种方法，后者包括DNA微卫星分析、基因组杂交比较、TP 53和致癌驱动突变检测，以及下一代测序（NGS），包括小规模或深度多基因组测序的有效性。

Results: Comprehensive histologic evaluation may suffice to differentiate between SPLCs and IPMs. However, molecular profiling using larger-scale NGS typically provides superior discriminatory power, allowing for more accurate classification. Based on the literature review and expert opinions, we proposed a combined 4-step histologic and molecular classification algorithm for addressing MPTN of adenocarcinoma histology that encourages a multidisciplinary approach. It is also noteworthy that new technologies combining machine learning and digital pathology may develop into valuable diagnostic tools for distinguishing SPLCs from IPMs in the future.

结果：系统的组织学评估可能足以区分SPL和IPL。然而，使用大panel NGS的分子检测通常提供更好的区分能力，从而实现更准确的分类。根据文献回顾和专家意见，我们提出了一种组合的4步组织学和分子分类算法，用于解决腺癌组织学的MPTN问题，该算法鼓励多学科方法。同样值得注意的是，将机器学习和数字病理学相结合的新技术可能会发展成为未来区分SPLCs和IPM的宝贵诊断工具。

Conclusions: Although histopathologic evaluation is often adequate to differentiate SPLCs from IPMs, molecular profiling should be performed when possible, especially in cases with tumors exhibiting similar morphology. This manuscript summarized the previous efforts in resolving the current challenges and highlighted the recent progress in the differentiation methods and algorithms used in categorizing multiple lung adenocarcinomas into SPLCs or IPMs, which are becoming more and more critical in precision lung cancer management.

结论：尽管组织病理学评估通常足以区分SPLCs和IPM，但在可能的情况下应进行分子分析，特别是在肿瘤表现出相似形态的情况下。这篇手稿总结了之前为解决当前挑战所做的努力，并强调了用于将多发性肺腺癌分类为SPLCs和IPM的分化方法和算法的最新进展，这些方法和算法在肺癌精准中变得越来越重要。

目录

1. INTRODUCTION

    1.1 Lung Cancer: Solitary versus multiple

    1.2 Multiple Pulmonary Tumor Nodules: Metachronous versus synchronous and separate primary lung carcinomas versus intrapulmonary metastases 

    1.3 Clinical Impacts of MPTN: Staging and management (Figure 1)

2. DIAGNOSIS OF MULTIPLE PULMONARY TUMOR NODULES 

    2.1 Clinical Aspects of Multiple Pulmonary Tumor Nodules (Figure 1)

        2.1.1 Second Primary Lung Cancers 

        2.1.2 Separate pulmonary non-ground-glass tumor nodules 

        2.1.3 Multifocal lung adenocarcinoma with ground-glass features 

        2.1.4 Pneumonic-type lung adenocarcinoma 

    2.2 Multiple Pulmonary Tumor Nodules: Radiologic diagnosis 

    2.3 Multiple Pulmonary Tumor Nodules: Histopathologic diagnosis (Figure 2) 

    2.4 Multiple Pulmonary Tumor Nodules: Invasive mucinous adenocarcinoma 

    2.5 Molecular Diagnosis of Multiple Pulmonary Tumor Nodules: Genomic breakpoint, TP53, driver gene mutation and next-generation sequencing 

        2.5.1 Historical perspective 

        2.5.2 Loss of heterozygosity 

        2.5.3 Comparative genomic hybridization 

        2.5.4 Genomic breakpoint

        2.5.5 Mutation analysis (Table 1-2)

        2.5.6. Correlation between histologic and molecular analyses  (Table 3)

        2.5.7. Classification algorithm combining histologic and molecular analyses (Figure 3)

    2.6 Application of Machine and Deep Learning in Diagnosing Multiple Pulmonary Tumor Nodules 

3. METACHRONOUS AND SYNCHRONOUS PRIMARY LUNG CANCERS: THERAPEUTIC CONSIDERATIONS 

4. CONCLUSION AND FUTURE PERSPECTIVES 

— 图表汇总—

    2.1 Clinical Aspects of Multiple Pulmonary Tumor Nodules

Figure 1. Diagrammatic representations to illustrate multiple pulmonary tumor nodules in the setting of (a) metachronous tumors, (b) synchronous tumors, (c) intrapulmonary metastases, (d) metastases from other organ, (e) intrapulmonary metastases with tumor metastasizing to the same lobe where the primary tumor is located (T3-stage, 8th edition, AJCC), (f) intrapulmonary metastases with tumor metastasizing to an ipsilateral lobe different from the lobe where the primary tumor is located (T4-stage, 8th edition, AJCC), (g) intrapulmonary metastases with tumor metastasizing to a contralateral lobe different from the lobe where the primary tumor is located (M1a-stage, 8th edition, AJCC), (h) multifocal lung adenocarcinoma with ground-glass features and (i) pneumonic-type lung adenocarcinoma. MPTN, multiple pulmonary tumor nodules 

    2.3 Multiple Pulmonary Tumor Nodules: Histopathologic diagnosis

Figure 2. Histologic classification algorithm for determining clonality of multiple lung adenocarcinomas.

(Adapted from Figure 1A, in Yang CY, Yeh YC, Wang LC, et al. Genomic Profiling with Large-Scale Next-Generation Sequencing Panels Distinguishes Separate Primary Lung Adenocarcinomas from Intrapulmonary Metastases. Modern Pathology. 2023;36(3):10004739) 

    2.4 Multiple Pulmonary Tumor Nodules: Invasive mucinous adenocarcinoma 

    2.5 Molecular Diagnosis of Multiple Pulmonary Tumor Nodules: Genomic breakpoint, TP53, driver gene mutation and next-generation sequencing 

        2.5.1 Historical perspective 

        2.5.2 Loss of heterozygosity 

        2.5.3 Comparative genomic hybridization 

        2.5.4 Genomic breakpoint

        2.5.5 Mutation analysis

Table 1. Summary of studies examining multiple primary lung tumors with mutation analysis for number of cases, genes, clonality (Clonal) and non-clonality (Non-Cl) at patient level, non-informative number of cases (Non-I), and lastly, number of cases with same histological type and different mutation (SHDM).

N, number of cases; max, maximal; CNV, copy number variation, ADC, adenocarcinoma, SqCC, squamous cell carcinoma, LCC, large cell carcinoma, SCLC, small cell lung carcinoma. 

Table 2. Studies presenting individual cases with the same driver mutation found in two pulmonary tumors and additional different molecular findings detected by another technique.

WES, whole exome sequencing; WGS, whole genome sequencing; cn del, copy number deletion; cn amp, copy number amplification 

        2.5.6. Correlation between histologic and molecular analyses 

Table 3. Recent studies with comparison of predictive histology and molecular analysis for establishing the diagnosis of SPLC and IPM.

N, number of cases; IPM, intrapulmonary metastases; SPLC, separate primary lung carcinoma; max, maximal; CNV, copy number variation. 

        2.5.7. Classification algorithm combining histologic and molecular analyses

Figure 3. Flowchart for classifying multiple lung adenocarcinomas with a 4-step combined histologic and molecular classification algorithm.

(Adapted from Figures 1A and 6, in Yang CY, Yeh YC, Wang LC, et al. Genomic Profiling with Large-Scale Next-Generation Sequencing Panels Distinguishes Separate Primary Lung Adenocarcinomas from Intrapulmonary Metastases. Modern Pathology. 2023;36(3):10004739) AIS, adenocarcinoma in situ; MIA, minimally invasive adenocarcinoma; LPA, lepidic predominant adenocarcinoma; NGS, next generation sequencing 

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