Genetic profile characterization of histological micropapillary and solid components in lung adenocarcinoma: a systematic review

Introduction

Background

Micropapillary and solid components are histological features specific to adenocarcinoma in lung cancer and are morphologically identified; patients exhibiting these components show a worse prognosis. The latest International Association for the Study of Lung Cancer (IASLC) pathological classification defines the highest malignant grade (grade 3) as having 20% or higher micropapillary and/or solid patterns (1). These two components are handled equally in the pathological grading.

Rationale and knowledge gap

While numerous studies have focused on the prognostic impact of these components, only a few have explored the differences in genetic features between micropapillary and solid components. The prevalence of these cases and their genetic status have not been reviewed systematically.

Objective

The aim of this systematic review was to unveil the genetic background and refine the distinctions between these highly malignant components. We present this article in accordance with the PRISMA reporting checklist (available at https://jlpm.amegroups.org/article/view/10.21037/jlpm-23-88/rc).

Methods

Review process and eligibility criteria

Publications were searched through PubMed using two keywords: “lung adenocarcinoma micropapillary” or “lung adenocarcinoma solid”. A systematic review was performed according to the PRISMA guidelines (2). To determine current trends in evidence, the reviewed literature was limited to reports published in the last 5 years (publications between January 2019 and July 2023). The article type was limited to original research. There were no limitations in the inclusion criteria regarding the stage, treatment method, or methodology for genetic or protein examinations. The exclusion criteria were as follows: articles in non-English, case report(s), review, meta-analysis, letter to the editor, editorial, articles focusing on cases other than primary lung adenocarcinoma, and literature regarded as improper for this systematic review. “Books and documents”, “meta-analysis”, “review”, and “systematic review” articles were also searched using article-type filtering option in PubMed and were excluded. No other automation tool was used. Some articles published before January 2019 were included in the review via manual search or reference to citations in the literature if they were suitable for this review. Data collection was performed mainly by one author, and the decision to include the searched articles was discussed by authors.

Synthesis and assessment of results

Results are presented as median, range, and interquartile range (IQR). When an article included adenocarcinoma and other types of lung cancer, the incidence was calculated only from the adenocarcinoma data. As the review process had no limitations regarding clinical background (stage, treatment, and methodology of gene or protein detection), the appropriateness of the articles was evaluated individually. Owing to the heterogeneity of the research strategy and inclusion criteria reported in each article, a direct comparison of the reviewed literature was difficult. Results were not quantified using any unique tool, and the significance was not estimated by any statistical analysis.

This systematic review focused on the genetic background of micropapillary and solid components. Therefore, details of the results that were of little relevance to the genetic status were either described in a simple manner or omitted; the main notable results are summarized in table and figures. The possibilities of bias by searching or reporting and the certainty of outcomes are referred to in the discussion section.

Results

Systematic research and extraction of publications for review

Using two keywords for research, 1,320 and 320 candidate articles were respectively selected for review. Next, 213 and 361 articles were excluded owing to duplication and exclusion criteria, respectively. Unrelated 267 articles that included “solid” as a part of “solid tumor” or “solid appearance” as a radiological feature were also excluded. In addition, 478 articles that included little or no information on the micropapillary or solid component were excluded. After excluding duplicate articles for each keyword search, four articles were added by manually referring to the searched articles. Finally, 248 articles were reviewed (Figure 1). The reviewed articles can be mainly categorized mainly into three fields: 88, 37, and 97 articles on the prognosis, radiomics, or targetable genetic or programmed death-ligand 1 (PD-L1) features of adenocarcinoma with the micropapillary or solid components, respectively.

Figure 1 Consort diagram indicating the process of extracting articles for review. A publication search using the keywords “lung adenocarcinoma micropapillary” and “lung adenocarcinoma solid” was performed independently, and the results were combined.

Distribution of micropapillary and solid adenocarcinoma

Each study included cases with a wide range of tumor-node-metastasis (TNM) stages (early and/or advanced stages) and various histological adenocarcinoma subtypes (non-invasive and/or invasive, inclusion or exclusion of variant types of adenocarcinoma; some articles included non-adenocarcinoma cases). Some studies exclusively focused on micropapillary/solid predominant cases, while others analyzed micropapillary/solid component-positive cases even if the component was not predominant. Therefore, the definitions of micropapillary or solid adenocarcinoma cases vary, and it is difficult to compare literature without bias. In the reviewed literature, on direct comparison, the prevalence of solid predominant cases was higher than that of micropapillary predominant cases in most articles [micropapillary: median 2.65% (range: 0.0–25.22%, IQR: 1.29–6.28%) in 105 publications; solid: median 11.205% (range: 0.8–50.7%, IQR: 5.19–18.83%) in 112 publications]. A comparison of the prevalence between micropapillary component-positive and solid component-positive cases revealed that the frequency of micropapillary cases increased and became similar to those of solid cases [micropapillary: median 28.91% (range: 2.39–52.48%, IQR: 16.56–44.06%) in 20 publications; solid: median 26.32% (range: 9.0–79.44%, IQR: 15.69–29.93%) in 11 publications] (Figure 2). The prevalence of IASLC grade 3 widely varied from 7.75% to 64.9% (median 20.0%, IQR: 13.5–43.1%) in 9 publications.

Figure 2 Comparison of the incidence of micropapillary and solid adenocarcinoma cases. Black dots represent the frequency, and the results from the same literature are connected in each figure. The white dot represents the median frequency. (A) Frequencies of micropapillary predominant and solid predominant cases. The median of reported incidence was 2.65% (range: 0.0–25.22%, IQR: 1.29–6.28%) and 11.205% (range: 0.8–50.7%, IQR: 5.19–18.83%), respectively. (B) Frequencies of micropapillary component-positive and solid component-positive cases. The frequency of solid component-positive cases was about two times higher than that of solid predominant cases. The frequency of micropapillary component-positive cases was approximately 11 times higher than that of micropapillary predominant cases and similar to that of solid component-positive cases. IQR, interquartile range.

Clinical characteristics of cases including micropapillary and solid components

Reported cases with micropapillary or solid components show worse prognosis, even if these components were not predominant (3-5). The searched literature suggests a higher incidence of local invasion (lymphovascular invasion or spread through the air space) (6-8) or metastasis in the lymph node/brain (9-11) in micropapillary or solid component-positive cases. Regarding clinical diagnosis, the usefulness of radiomics in detecting the existence of these components has been suggested (12-15).

Genetic characteristics and PD-L1 expression in micropapillary and solid component

Comprehensive genetic analysis has revealed a higher tumor mutation burden (TMB) (16-18) and a higher number of mutations in tumor suppression genes (19) in cases with micropapillary or solid components. Several studies have reported a higher frequency of actionable genetic alterations; furthermore, a high incidence of epidermal growth factor receptor (EGFR) mutation (10,20-26), v-Raf murine sarcoma viral oncogene homolog B (BRAF) mutation (27-29), or ROS proto-oncogene 1 (ROS1) rearrangement (27,30,31) has been reported in adenocarcinoma with a micropapillary component. A high level of Kirsten rat sarcoma (KRAS) mutation (23,24,32-34), anaplastic lymphoma kinase (ALK) rearrangement (3,35-44), or PD-L1 expression (25,45-63) and a low frequency of EGFR mutation was suggested in adenocarcinoma with a solid component (64-66) (Table 1). One study concluded ROS1 arrangement highly occurred in solid predominant adenocarcinoma (67). Some studies have suggested that the level of these targetable alterations is related to the prognosis (21,33,54).

Other crucial targetable variants [mesenchymal-epithelial transition (MET) factor amplification (68), wingless and Int-1 (Wnt) signaling activation (16,18,69), activation or mutation of tumor protein p53 (TP53) (16,18,70-72), and high antigen Kiel 67 (Ki-67) expression (73,74)] have been suggested to occur in micropapillary or solid adenocarcinoma. An erythroblastic oncogene B-2 (ERBB2) mutation has been detected in patients with (18,75) or without (69) micropapillary component (Figure 3). Only 21 articles described the incidence of micropapillary or solid-positive cases and their relationship with genetic alternation or PD-L1 expression.

Figure 3 Schema summarizing the genetic characteristics or PD-L1 expression in micropapillary and solid components. A high incidence of EGFR mutation, BRAF mutation, or ROS1 rearrangement in adenocarcinoma with micropapillary component. A high level KRAS mutation, ALK rearrangement, or PD-L1 expression in adenocarcinoma with solid component. TP53 is reported to be activated in both components. EGFR, epidermal growth factor receptor; Wnt, wingless and Int-1; ERBB2, erythroblastic oncogene B-2; PD-L1, programmed death-ligand 1; ROS1, ROS proto-oncogene 1; BRAF, v-Raf murine sarcoma viral oncogene homolog B; ALK, anaplastic lymphoma kinase; KRAS, Kirsten rat sarcoma; TP53, tumor protein p53.

Discussion

Adenocarcinoma is the dominant histological subtype of primary lung cancer and comprises several histological components. Adenocarcinoma is also likely to harbor various types of actionable genetic alterations. The prognosis of lung adenocarcinoma largely depends on TNM stage, histological subtype, and the use of targeted therapy drugs and/or immune checkpoint inhibitors (ICIs). In the clinical setting, all cases of adenocarcinoma are classified based on the TNM staging, and resected cases are additionally subdivided based on pathological features. Genetic status and PD-L1 expression levels are essential for deciding the therapeutic strategy in adjuvant settings or recurrent cases. However, TNM stage is defined independent of pathological features, and the relationship between histological subtype and genetic status has not been sufficiently revealed. The present review reveals that micropapillary and solid components can be related to different genetic features. Although the incidence of micropapillary predominant cases is low compared with that of solid predominant cases, the frequency of cases including micropapillary components has been confirmed to be similar to that of solid component-positive cases. Recent clinical trials have shown that adjuvant targeted therapy or ICI improves outcomes in resected lung cancer cases (76,77). Patients harboring KRAS mutation or wild-type EGFR show favorable response to ICIs (77,78). Hence, genetic profiling in cases with high malignant potential is important.

The micropapillary and solid components can be characterized by different genetic features or PD-L1 expression. Several studies have suggested that genetic features and PD-L1 are highly expressed in both micropapillary and solid adenocarcinomas (3,43,44,59-63). This finding might partially be due to the heterogeneity in histology or morphological diagnosis. Some studies have included cases with micropapillary or solid components in the same cohort. These components actually often appear in the same tumor; micropapillary predominant cases can include solid components, and vice versa. Regarding diagnosis, morphological decision depends on the pathologist. The distribution of the predominant subtypes varied widely among institutions (79). This diagnostic discordance may account for the migration of genetic profiles between micropapillary and solid adenocarcinomas.

Morphology seems less important in advanced non-resected cases and is not directly related to drug indications. However, morphology is fundamental for lung cancer diagnosis and is crucial for resected cases to predict the malignant potential. Cases with equal to or more than 20% micropapillary and solid components are treated as high risk in an ongoing adjuvant osimertinib clinical trial for resected stage IA2–IA3 EGFR-mutated non-small cell lung cancer (ADAURA2) (80).

When discussing genetic alternations, the regional difference in incidence should not be ignored. EGFR mutation is more common in Asia, and the majority of the reports on EGFR mutations in our review was also from Asia. However, a previous review on the incidence of EGFR mutations by distinguishing between Asian and non-Asian cohorts showed that the incidence of EGFR mutation was higher in micropapillary component-predominant cases even in non-Asians (81). The incidence of EGFR mutation seems to be higher in micropapillary cases regardless of geographic differences. The evidence regarding the relationship between the prevalence of PD-L1 expression or druggable genetic alterations and histological features needs to be gathered, particularly in cases with micropapillary or solid component.

This systematic review has some limitations. First, we only utilized PubMed as a source; despite the size and popularity of PubMed, the use of several sources is warranted. Second, although we searched articles published within 5 years to identify current trends in evidence, the methodology, sensitivity, and accuracy to detect the genetic alternations were quite different among studies. In addition, several studies did not primarily focus on the genetic background of the micropapillary and solid components, and genetic status or incidence data were obtained as secondary information from each article. The terms “high” and “low” regarding incidence are not absolutely quantified results; rather, they represent the conclusion of each reviewed article. The impact of results was not compared among studies, and the significance of genetic status was not analyzed statistically; thus, the heterogeneity, sensitivity, certainty, and risk of bias stemming from missing results in each study could not be evaluated in the synthesized data. Further reviews unifying patient background and performing statistical analysis are warranted. Third, we used simple search keywords to include a large selection of candidate studies. However, bias was inevitable because the information about the prevalence of adenocarcinoma subtypes and clinically targetable genetic alternations are generally included in studies on lung cancer, and evaluating articles not identified by simple keyword searches might not be practical.

Conclusions

Patients with micropapillary and solid components showed worse prognosis. They are handled equally for pathological grading, and the incidence of micropapillary- or solid-positive cases is similar. These two components can be distinguished based on their genetic features or PD-L1 expression level. Classification of cases with these poor prognostic components can be reasonably based on the genetic profile, which can indicate the prognostic status and is directly related to the treatment strategy.

Acknowledgments

We would like to thank Editage (https://www.editage.jp/) for English language editing.

Funding: None.

Footnote

Reporting Checklist: The authors have completed the PRISMA reporting checklist. Available at https://jlpm.amegroups.org/article/view/10.21037/jlpm-23-88/rc

Peer Review File: Available at https://jlpm.amegroups.org/article/view/10.21037/jlpm-23-88/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jlpm.amegroups.org/article/view/10.21037/jlpm-23-88/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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