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. 2023 May;18(5):608-619.
doi: 10.1016/j.jtho.2023.01.002. Epub 2023 Jan 18.

Micropapillary and Solid Histologic Patterns in N1 and N2 Lymph Node Metastases Are Independent Factors of Poor Prognosis in Patients With Stages II to III Lung Adenocarcinoma

Yan Li  1 , Alexander J Byun  2 , Jennie K Choe  2 , Shaohua Lu  3 , David Restle  2 , Takashi Eguchi  4 , Kay See Tan  5 , Jasmeen Saini  2 , James Huang  2 , Gaetano Rocco  2 , David R Jones  2 , William D Travis  6 , Prasad S Adusumilli  7
Affiliations

Micropapillary and Solid Histologic Patterns in N1 and N2 Lymph Node Metastases Are Independent Factors of Poor Prognosis in Patients With Stages II to III Lung Adenocarcinoma

Yan Li et al. J Thorac Oncol. 2023 May.

Abstract

Introduction: High-grade histologic patterns are associated with poor prognosis in patients with primary nonmucinous lung adenocarcinoma (ADC). We investigated whether the presence of micropapillary (MIP), solid (SOL), or both patterns in lymph node (LN) metastases has prognostic value.

Methods: Patients who underwent lobectomy for pathologic stages II to III lung ADC with N1 or N2 LN metastases (N = 360; 2000-2012) were analyzed. We assessed overall survival (OS), lung cancer-specific cumulative incidence of death (LC-CID), and cumulative incidence of recurrence (CIR) between patients with and without MIP/SOL patterns in LN metastases. Multivariable Cox regression analysis was used to quantify the association between MIP/SOL patterns and outcomes.

Results: MIP and SOL in LN metastases were associated with a higher incidence of smoking history (p = 0.004), tumor necrosis (p = 0.013), and spread of tumor through air spaces (p < 0.0001), a higher prevalence of MIP or SOL in the primary tumor (p < 0.0001), shorter OS (5-y OS, 40% [95% confidence interval or CI: 29%-56%] versus 63% [48%-83%] for no MIP/SOL in LNs, p = 0.03), higher LC-CID (5-y, 43% [29%-56%] versus 14% [4%-29%], p = 0.013), and higher CIR (5-y, 65% [50%-77%] versus 43% [25%-60%], p = 0.057). MIP and SOL in LN metastases were independently associated with poor outcomes: OS (hazard ratio [HR] = 1.81 [95% CI: 1.00-3.29], p = 0.05), LC-CID (HR = 3.10 [1.30-7.37], p = 0.01), and CIR (HR = 2.06 [1.09-3.90], p = 0.026).

Conclusions: MIP/SOL histologic patterns in N1 or N2 LN metastases are associated with worse outcomes in patients with stages II to III lung ADC. MIP/SOL histologic patterns in LN metastases can stratify patients with high-risk stages II to III lung ADC.

Keywords: Micropapillary adenocarcinoma; N classification; Nodal metastasis; Non–small cell lung cancer; Solid adenocarcinoma.

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Conflict of interest statement

Conflict of Interest Statement: D.R.J. is a member of the Advisory Council for Astra Zeneca and a member of a Clinical Trial Steering Committee for Merck. P.S.A. declares research funding from ATARA Biotherapeutics; Scientific Advisory Board Member and Consultant for ATARA Biotherapeutics, Bayer, Carisma Therapeutics, Imugene, ImmPactBio, Johnson & Johnson, Orion Pharma, Outpace Bio; Patents, royalties, and intellectual property on mesothelin-targeted CAR and other T-cell therapies, which have been licensed to ATARA Biotherapeutics, issued patent method for detection of cancer cells using virus, and pending patent applications on PD-1 dominant negative receptor, on a wireless pulse-oximetry device, and on an ex vivo malignant pleural effusion culture system.

Memorial Sloan Kettering Cancer Center has licensed intellectual property related to mesothelin-targeted CARs and T-cell therapies to ATARA Biotherapeutics and has associated financial interests.

Figures

Figure 1.
Figure 1.
Patient flowchart. ADC, adenocarcinoma; IMA, invasive mucinous adenocarcinoma; LN, lymph node.
Figure 2.
Figure 2.
Prevalence of micropapillary (MIP) and solid (SOL) pattern in lymph nodes (LNs) and primary tumors. (A) Violin plot describing the distribution of MIP and SOL pattern in LN from patients with N1 versus N2 staging. (B) Violin plot describing the distribution of MIP and SOL pattern in LN from patients with single versus multiple involved LNs. (C) Violin plot describing the distribution of MIP and SOL pattern in primary tumors of which corresponding LNs had MIP and/or SOL pattern present. (D) Violin plot describing the distribution of MIP and SOL pattern in primary tumors of which corresponding LNs were either acinar (ACI), papillary (PAP), MIP, or SOL predominant. (E) Alluvial plot describing the proportion of patients with each predominant histologic subtype in the primary tumor and in the corresponding LNs. (F) Correlation of the percentage of histologic patterns between primary tumors and LNs. For each histological subtype (ACI, PAP, MIP and SOL), the mean percentage of the pattern in the LN across patients is calculated within four groups of increasing percentages (0–4%, 5–24%, 25–49%, 50–100%) of the pattern in the primary tumor. #, p>0.05; *p<0.05; ***p<0.0001.
Figure 3.
Figure 3.
Overall survival, lung cancer–specific cumulative incidence of death, and cumulative incidence of recurrence for patients stratified by N1 versus N2 staging (A-C) or micropapillary (MIP) and/or solid (SOL) patterns in lymph nodes (LNs) (D-F).
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