Applying Comprehensive Histologic Assessment and Genetic Testing to Synchronous Multifocal Lung Adenocarcinomas and Further Survival Analysis
The differentiation of multiple primary lung adenocarcinomas (MPLAs) from intrapulmonary metastases is a critical challenge in thoracic oncology, as it directly influences clinical management and prognostic outcomes. The revised diagnostic criteria proposed by the American College of Chest Physicians (ACCP) in 2003 have been widely adopted, but distinguishing between homologous and non-homologous tumors remains technically complex. This study presents a cohort of 45 patients with synchronous multifocal lung adenocarcinomas, utilizing comprehensive histologic assessment and genetic testing to differentiate MPLAs from metastases and to analyze survival outcomes.
Patient Cohort and Diagnostic Workup
The study included 45 patients diagnosed with synchronous multifocal lung adenocarcinomas through surgical resection between October 2012 and December 2017. Patients with multiple tumors in the same lobe were excluded due to their limited impact on treatment strategy. The cohort comprised 39 patients with double lung adenocarcinomas, 5 with triple tumors, and 1 with four tumors. Preoperative diagnostic evaluations included bronchoscopy, cranial computed tomography (CT) or magnetic resonance imaging (MRI), abdominal ultrasonography or CT, and nuclide bone scanning to rule out extrapulmonary metastasis. Positron emission tomography (PET)-CT was performed in 36 patients, and mediastinoscopy or endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) was conducted in 14 patients to exclude suspicious N2 cases. Pulmonary function tests (PFTs) and general condition assessments were routinely performed before surgery.
Surgical Procedures and Postoperative Outcomes
All 97 lung adenocarcinomas from the 45 patients were surgically removed. Thirty-seven patients underwent completely unilateral or bilateral video-assisted thoracic surgery (VATS), while 8 patients required or were converted to open thoracotomy. Among the 14 patients with bilateral disease, 6 underwent synchronous bilateral procedures, and 8 were operated on within a 6- to 12-week interval. Postoperative recovery was generally favorable, with only two patients (4.4%) experiencing complications: one with sustained pulmonary air leakage and another with postoperative atrial fibrillation, both of which resolved with appropriate treatment. There were no perioperative deaths.
Comprehensive Histologic Assessment
Comprehensive histologic assessment was employed to differentiate metastatic carcinomas from synchronous MPLAs. According to the updated ACCP criteria and the international multidisciplinary classification, lung adenocarcinomas were categorized as invasive adenocarcinoma or preinvasive lesions, including atypical adenomatous hyperplasia (AAH), adenocarcinoma in situ (AIS), and minimally invasive adenocarcinoma (MIA). For invasive adenocarcinomas, the relative percentage of each histologic subtype—lepidic, acinar, papillary, micropapillary, and solid components—was semiquantitatively evaluated in 10% increments. Two cases were diagnosed as multiple AIS/MIA and classified as synchronous MPLAs. Among the remaining 43 patients, 18 had only one invasive lung adenocarcinoma, while 25 had multiple invasive tumors. Tumor pairs from 8 of the 25 patients exhibited similar histologic subtypes and were considered possible intrapulmonary metastases. The remaining 35 patients, with different histologic subtypes or cytological features, were classified as synchronous MPLAs.
Genetic Testing and Mutation Analysis
The mutational status of EGFR in exons 18 to 21 was determined using amplification refractory mutation system real-time polymerase chain reaction technology. Next-generation sequencing (NGS) was applied to patients with similar EGFR mutation types to further differentiate synchronous MPLAs from intrapulmonary metastases. Semiconductor sequencing based on the Ion Personal Genome Machine (PGMTM) System was performed using the Ion AmpliSeq Cancer Hotspot Panel v2 to sequence over 2800 loci from 50 oncogenes and tumor suppressor genes. Among the 37 synchronous MPLA patients, EGFR mutation status was available for 64 tumors from 35 patients. EGFR mutations were identified in 29 tumors (28 invasive lung adenocarcinomas and 1 MIA) from 19 patients, including Exon 19 deletions, Exon 21 L858R mutations, Exon 20 insertions, and other rare mutations. The concordant frequency rate of EGFR mutation distribution was 31.6% (6/19). For the 8 patients with possible intrapulmonary metastases, EGFR mutation status was available for all 16 tumors, with 8 tumors from 5 patients testing positive. Discordant EGFR mutation status in 2 patients led to their reclassification as synchronous MPLAs. NGS was applied to 12 tumors from 6 patients with similar histologic subtypes and concordant EGFR mutation status, identifying one patient with discordant gene mutations as having synchronous MPLAs.
TNM Staging and Adjuvant Therapy
According to the 8th edition of TNM staging for non-small cell lung cancer (NSCLC), tumor pairs from 40 synchronous MPLA patients were staged separately. The largest tumor or main lesion determined the highest pT stage, with 27 cases classified as pT1, 11 as pT2, and 2 as pT3. Twenty-nine patients were confirmed as pN0, while 11 had at least one pN1 lesion. The 5 patients with intrapulmonary metastases were staged as pT4N1M0 due to their location in different lobes of the same side and positive hilar, interlobular, or intrapulmonary lymph nodes. No positive N2 lymph nodes were identified in the cohort. Postoperative adjuvant chemotherapy was administered to 2 of 4 synchronous MPLA patients with stage IB disease, all 11 synchronous MPLA patients with at least one pN1 lesion, and the 5 patients with intrapulmonary metastases. A pemetrexed and platinum combination chemotherapy regimen was routinely adopted.
Survival Analysis
The median follow-up time was 45 months (range: 10–83 months). Chest CT was performed every 3 months for the first year, every 6 months for the second year, and annually thereafter. Serum tumor markers, cranial CT/MRI, abdominal ultrasonography/CT, and nuclide bone scans were conducted annually or as needed. Kaplan-Meier survival curves were generated for progression-free survival (PFS) and overall survival (OS). The median PFS for the 40 synchronous MPLA patients was 51 months, with 3-year and 5-year PFS rates of 72.8% and 42.4%, respectively. These rates were significantly better than those for the 5 patients with intrapulmonary metastases (P=0.001). The median OS for synchronous MPLA patients was 64 months, with 3-year and 5-year OS rates of 86.7% and 52.7%, respectively, also significantly higher than those for intrapulmonary metastasis patients (P<0.001).
Risk Factor Analysis
Univariate analysis identified several candidate variables for PFS and OS risk factors. For PFS, these included larger maximal tumor dimension, ECOG performance status, the use of a minimally invasive approach, operational option, highest pT stage, pN stage, the number of invasive adenocarcinomas, and the use of postoperative chemotherapy. For OS, candidate variables included larger maximal tumor dimension, ECOG performance status, the use of a minimally invasive approach, highest pT stage, pN stage, the number of invasive adenocarcinomas, and the use of postoperative chemotherapy. Multivariate analysis identified ECOG performance status, highest pT stage, and pN stage as independent risk factors for PFS. For OS, ECOG performance status, the use of a minimally invasive approach, and highest pT stage were independent risk factors. Interestingly, pN stage did not significantly affect OS, possibly due to advancements in chemotherapy and targeted therapy.
Discussion
This study underscores the importance of comprehensive histologic assessment and genetic testing in differentiating synchronous MPLAs from intrapulmonary metastases. Histologic assessment remains a cornerstone, but a subset of patients with similar histologic subtypes requires further genetic analysis. EGFR mutation status provided additional differentiation in 2 of 8 patients with similar histologic features, while NGS further refined the diagnosis in one patient. Surgical treatment, particularly minimally invasive approaches, demonstrated favorable outcomes for synchronous MPLA patients, with significantly better PFS and OS compared to intrapulmonary metastasis patients. The study also highlights the prognostic significance of ECOG performance status, highest pT stage, and pN stage.
Limitations and Future Directions
The retrospective nature of this study and the limited cohort size introduce potential selection bias. Future multicenter studies with larger sample sizes are needed to validate these findings and further elucidate the diagnostic and prognostic nuances of synchronous multifocal lung adenocarcinomas.
doi.org/10.1097/CM9.0000000000000055
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