Using molecular characteristics to distinguish multiple primary lung cancers and intrapulmonary metastases
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ABSTRACT:
SUBMITTER: Li Z
PROVIDER: S-EPMC10838092 | biostudies-literature | 2024 Jan
REPOSITORIES: biostudies-literature
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Project description:The effective differentiation between multiple primary lung tumors (MPs) and intrapulmonary metastases (IMs) in patients is imperative to discover the exact disease stage and to select the most appropriate treatment. In this study, the authors was to evaluate the efficacy and validity of large-scale targeted sequencing (LSTS) as a supplement to estimate whether multifocal lung cancers (MLCs) are primary or metastatic. Targeted sequencing of 520 cancer-related oncogenes was performed on 36 distinct tumors from 16 patients with MPs. Pairing analysis was performed to evaluate the somatic mutation pattern of MLCs in each patient. A total of 25 tumor pairs from 16 patients were sequenced, 88% (n = 22) of which were classified as MPs by LSTS, consistent with clinical diagnosis. One tumor pair from a patient with lymph node metastases had highly consistent somatic mutation profiles, thus predicted as a primary-metastatic pair. In addition, some matched mutations were observed in the remaining two paired ground-glass nodules (GGNs) and classified as high-probability IMs by LSTS. Our study revealed that LSTS can potentially facilitate the distinction of MPs from IMs. In addition, our results provide new genomic evidence of the presence of cancer invasion in GGNs, even pure GGNs.
| S-EPMC7606457 | biostudies-literature
Project description:BackgroundMultiple synchronous lung tumors (MSLT), particularly within a single lobe, represent a diagnostic and treatment challenge. While histologic assessment was once the only method to possibly distinguish multiple primary lung cancers, there is a growing interest in identifying unique genomic features or mutations to best characterize these processes.MethodsIn order to differentiate multiple primary lung malignancies from intrapulmonary metastases in patients with MSLT, we performed whole exome sequencing (WES) on 10 tumor samples from 4 patients with MSLT.ResultsShared mutations between tumors from the same patient varied from 0-91%. Patient 3 shared no common mutations; however, in Patients 2 and 4, identical mutations were identified among all tumors from each patient, suggesting that the three tumors identified in Patient 3 represent separate primary lung cancers, while those of Patients 1, 2 and 4 signify hematogenous and lymphatic spread.ConclusionsA high proportion of shared mutations between different lung tumors is likely indicative of intrapulmonary metastatic disease, while tumors with distinct genomic profiles likely represent multiple primary malignancies driven by distinct molecular events. Application of genomic profiling in the clinical setting may prove to be important to precise management of patients with MSLT.
| S-EPMC7330333 | biostudies-literature
Project description:BackgroundTo explore the genetic and immunophenotyping heterogeneities between patients with intrapulmonary metastasis (IPM) or multiple primary lung cancer (MPLC).MethodsWhole exome sequencing (WES) and transcriptome sequencing (RNA-seq) were performed on the tissue and blood samples of IPM and MPLC patients to comprehensively analyze the clonal evolution, molecular typing and immunophenotyping.ResultsThere was no significant difference in genetic mutation, tumor mutational burden (TMB) value and mutant allele tumor heterogeneity (MATH) value between IPM and MPLC patients. Notably, the loss of heterozygosity (LOH) of human leukocyte antigen (HLA) appeared in all IPM patients, while there was also no significant difference between the two groups. In addition, expression of immune checkpoint-related genes including CTLA-4, BTLA, TIGIT and HAVCR2 in the MPLC group was significantly higher than those in IPM group. At the same time, 86 differentially expressed genes (DEGs) were observed between IPM and MPLC patients with transcriptome sequencing, of which 56 DEGs were upregulated and 30 were downregulated in the IPM group compared with the MPLC group. The cluster analysis revealed that the 86 DEGs could be distinguished in IPM and MPLC samples. Moreover, only the infiltration levels of CD56dim natural killer cells in the IPM group was significantly higher than that in the MPLC group, and the infiltration levels of the remaining 27 immune cell subsets were similar in both groups.ConclusionsIPM and MPLC are roughly similar in genetic and immune characteristics indicating that genomics alone may not be able to effectively distinguish between IPM and MPLC, which still needs to be comprehensively evaluated with clinical manifestations, imaging, and pathological characteristics.
| S-EPMC8487821 | biostudies-literature
Project description:The presence of bilateral pulmonary nodules in lung cancer usually means distant metastases (M1a). We present an extraordinary example that challenges to look beyond this classification, and illustrates the potential benefits of a multidisciplinary re-evaluation in such a case.
2012-11-20 | GSE42377 | GEO
Project description:The presence of bilateral pulmonary nodules in lung cancer usually means distant metastases (M1a). We present an extraordinary example that challenges to look beyond this classification, and illustrates the potential benefits of a multidisciplinary re-evaluation in such a case. FFPE DNA from a patient with three primary tumors. Test samples were compared to normal tissue.
| S-ECPF-GEOD-42377 | biostudies-other
Project description:The presence of bilateral pulmonary nodules in lung cancer usually means distant metastases (M1a). We present an extraordinary example that challenges to look beyond this classification, and illustrates the potential benefits of a multidisciplinary re-evaluation in such a case. FFPE DNA from a patient with three primary tumors. Test samples were compared to normal tissue.
2012-11-20 | E-GEOD-42377 | biostudies-arrayexpress
Project description:It has been a big challenge to distinguish synchronous multiple primary lung cancer (sMPLC) from primary lung cancer with intrapulmonary metastases (IPM). We aimed to assess the clinical application of dynamic 18F-FDG PET/CT in patients with multiple lung cancer nodules. We enrolled patients with multiple pulmonary nodules who had undergone dynamic 18F-FDG PET/CT and divided them into sMPLC and IPM groups based on comprehensive features. The SUVmax, fitted K i value based on dynamic scanning, and corresponding maximum diameter (D max) from the two largest tumors were determined in each patient. We determined the absolute between-tumor difference of SUVmax/D max and K i /D max (ΔSUVmax/D max; ΔK i /D max) and assessed the between-group differences. Further, the diagnostic accuracy was evaluated by ROC analysis and the correlation between ΔSUVmax/D max and ΔK i /Dmax from all groups was determined. There was no significant difference for ΔSUVmax/D max between the IPM and sMPLC groups, while the IPM group had a significantly higher ΔK i /Dmax than the sMPLC group. The AUC of ΔK i /D max for differentiating sMPLC from IPM was 0.80 (cut-off value of K i = 0.0059, sensitivity 79%, specificity 75%, p < 0.001). There was a good correlation (Pearson r = 0.91, 95% CI: 0.79-0.96, p < 0.0001) between ΔSUVmax/D max and ΔK i /D max in the IPM group but not in the sMPLC group (Pearson r = 0.45, p > 0.05). Dynamic 18F-FDG PET/CT could be a useful tool for distinguishing sMPLC from IPM. K i calculation based on Patlak graphic analysis could be more sensitive than SUVmax in discriminating IPM from sMPLC in patients with multiple lung cancer nodules.
| S-EPMC9281433 | biostudies-literature
Project description:ImportanceMerkel cell carcinoma (MCC) is an aggressive cutaneous neuroendocrine carcinoma. In rare cases, the development of an additional cutaneous MCC tumor is clinically consistent with a second primary MCC tumor rather than a cutaneous metastasis, which has important treatment and prognostic implications.ObjectiveTo evaluate genetic relatedness in 4 cases with the clinical diagnosis of multiple primary MCCs.Design, setting, and participantsIn this case series, 7 cases of clinically designated multiple primary MCC were identified; 4 cases met inclusion criteria for next-generation sequencing (NGS) analysis. Mutations, copy number alterations, and Merkel cell polyomavirus (MCPyV) sequence were analyzed and compared between clinically designated multiple primary tumors to characterize genetic relatedness and hence assess clonality. Patients with clinically designated multiple primary MCC were identified from the multidisciplinary MCC Program at the University of Michigan, a tertiary care center.Main outcomes and measuresFour cases of clinically designated multiple primary MCC were characterized by tumor sequencing and targeted MCPyV sequencing to distinguish independent primary tumors from related metastases.ResultsOverall, 4 patients in their 70s or 80s were included and analyzed. Cases 1 and 4 were verified as genetically distinct primary tumors and did not harbor similar copy number alterations or demonstrate significant mutational overlap. Cases 2 and 3 were designated as clonally related based on overlapping copy number alterations. In clonally related tumors, chromosomal copy number changes were more reliable than mutations for demonstrating clonality. Regardless of clonality, we found that MCPyV status was concordant for all tumor pairs and MCPyV positive tumors harbored predominatly subclonal mutations.Conclusions and relevanceOur findings suggest that patients with MCC may develop a second genetically distinct primary tumor; in this case, the subsequent tumor is likely to develop through similar mechanisms of pathogenesis, either MCPyV-mediated or ultraviolet light-mediated. Next-generation sequencing analysis of chromosomal copy number changes and mutations is useful in distinguishing multiple primary MCCs from progression of MCC clinically resembling multiple primaries, allowing appropriate staging of the patient.
| S-EPMC5540059 | biostudies-literature
Project description:PurposeIn patients with >1 non-small cell lung carcinoma (NSCLC), the distinction between separate primary lung carcinomas (SPLCs) and intrapulmonary metastases (IPMs) is a common diagnostic dilemma with critical staging implications. Here, we compared the performance of comprehensive next-generation sequencing (NGS) with standard histopathologic approaches for distinguishing NSCLC clonal relationships in clinical practice.Experimental designWe queried 4,119 NSCLCs analyzed by 341-468 gene MSK-IMPACT NGS assay for patients with >1 surgically resected tumor profiled by NGS. Tumor relatedness predicted by prospective histopathologic assessment was contrasted with comparative genomic profiling by subsequent NGS.ResultsSixty patients with NGS performed on >1 NSCLCs were identified, yielding 76 tumor pairs. NGS classified tumor pairs into 51 definite SPLCs (median, 14; up to 72 unique somatic mutations per pair), and 25 IPMs (24 definite, one high probability; median, 5; up to 16 shared somatic mutations per pair). Prospective histologic prediction was discordant with NGS in 17 cases (22%), particularly in the prediction of IPMs (44% discordant). Retrospective review highlighted several histologic challenges, including morphologic progression in some IPMs. We subsampled MSK-IMPACT data to model the performance of less comprehensive assays, and identified several clinicopathologic differences between NGS-defined tumor pairs, including increased risk of subsequent recurrence for IPMs.ConclusionsComprehensive NGS allows unambiguous delineation of clonal relationship among NSCLCs. In comparison, standard histopathologic approach is adequate in most cases, but has notable limitations in the recognition of IPMs. Our results support the adoption of broad panel NGS to supplement histology for robust discrimination of NSCLC clonal relationships in clinical practice.
| S-EPMC7713586 | biostudies-literature
Project description:BackgroundIn lung cancer management, differential diagnosis between multiple primary lung cancer (MPLC) and intrapulmonary metastasis (IMP) is a critical point that is of direct therapeutic and clinical importance. However, this process often suffers from absence of a gold standard, resulting in equivocal cases. Herein, we present a series of three cases, in which genomic alteration patterns revealed by next-generation sequencing (NGS) facilitated the differential diagnosis between MPLC and IMP.Case presentationCase 1 was a 57-year-old female with two separate lesions in the upper lobe and the lower lobe of left lung, which were both histopathologically determined as T2aN0M0 adenocarcinomas. NGS identified an EGFR L858R in one lesion and an EGFR 20 exon insertion in the other one, suggestive of double primary malignancies. The patient underwent wedge resections and received an adjuvant treatment of icotinib and chemotherapy. She had a disease-free survival (DFS) of 19 months and counting. Case 2 was a 55-year-old female with multiple small lesions in both lungs. Histopathological examinations of resected lesions from right upper lobe revealed three subtypes: atypical adenomatous hyperplasia of alveolar epithelium, adenocarcinomas in situ and minimally invasive adenocarcinoma. NGS identified two different BRAF driver mutations G466E and V600_K601delinsE in two lesions of adenocarcinoma in situ, and a BRAF K601E in a lesion of minimally invasive adenocarcinoma. Case 3, a 68-year-old male, had the right upper lobe lesion histophathologically classified as a stage T3NxM0 mixed adenoneuroendocrine carcinoma and the left upper lobe lesion as a stage T1aN0M0 adenocarcinoma. NGS performed with different loci of surgical tissues revealed a rare sensitizing EGFR mutation G719A shared by the right upper lobe lesion and lymph node, and two EGFR mutations L861Q and G719S in left upper lobe lesion. The patient received icotinib treatment postoperatively and achieved a stable disease with a progression-free survival of 5 months.ConclusionOur cases provide evidence for utility of NGS in facilitating diagnosis and treatment decisions.
| S-EPMC7953741 | biostudies-literature