Identification of EGFR R776H germline mutations in a patient with multifocal lung adenocarcinoma: A case report and literature review.

The advancement of molecular pathology techniques has led to the discovery of rare EGFR mutations for targeted therapy in lung cancer. Additionally, a substantial body of evidence indicates a connection between the development of lung cancer and genetic variations in the EGFR gene. Here, we present a case report of a patient with multifocal lung adenocarcinoma who possessed a rare germline mutation, EGFR R776H. An investigation into the family history of the patient exposed the notable incidence of lung adenocarcinoma, indicating a plausible genetic vulnerability to the ailment. To be specific, the patient's older brother and sister both suffered from lung cancer, which underlines the hereditary predisposition. Furthermore, it should be noted that the patient's daughter has inherited the germline mutation and also presented with multiple lung ground-glass nodules, emphasizing the clinical importance of this genetic variation. Following the lobectomy, the patient received treatment with almonertinib, a third-generation EGFR tyrosine kinase inhibitor (TKI), and at the latest follow-up, the patient has achieved partial remission. This case highlights the significance of taking into account germline possibilities when multiple lesions carry the same mutation. It stresses the importance of acquiring a comprehensive family history and performing genetic testing on leukocytes. Moreover, for the infrequent EGFR R776H mutation, third generation EGFR-TKIs may be a viable option.

A novel NGS-based diagnostic algorithm for classifying multifocal lung adenocarcinomas in pN0M0 patients.

The classification of multifocal lung adenocarcinomas (MLAs), including multiple primary lung adenocarcinomas (MPLAs) and intrapulmonary metastases (IPMs), has great clinical significance in staging and treatment determination. However, the application of molecular approaches in pN0M0 MLA diagnosis has not been well investigated. Here, we performed next-generation sequencing (NGS) analysis in 45 pN0M0 MLA patients (101 lesion pairs) who were initially diagnosed as having MPLA by comprehensive histologic assessment (CHA). Five additional patients with intrathoracic metastases were used as positive controls, while 197 patients with unifocal lung adenocarcinomas (425 random lesion pairs) were used as negative controls. By utilizing a predefined NGS criterion, all IPMs in the positive control group could be accurately classified, whereas 13 lesion pairs (3.1%) in the negative control cohort were misdiagnosed as IPMs. Additionally, 14 IPM lesion pairs were diagnosed in the study group, with at least 7 misdiagnoses. We thus developed a refined algorithm, incorporating both NGS and histologic results, that could correctly diagnose all the known MPLAs and IPMs. In particular, all IPMs identified by the refined algorithm were diagnosed to be IPMs or suspected IPMs by CHA reassessment. The refined algorithm-diagnosed MPLAs patients also had significantly better progression-free survival than the refined algorithm-diagnosed IPMs (p < 0.0001), which is superior to conventional NGS or CHA diagnoses. Overall, we developed an NGS-based algorithm that could accurately distinguish IPMs from MPLAs in MLA patients. Our results demonstrate a promising clinical utility of NGS to complement traditional CHA-based MLA diagnosis and help determine patient staging and treatment.

Concomitant EGFR mutation and ALK rearrangement in multifocal lung adenocarcinoma: a case report.

BACKGROUND: The prevalence of EGFR/ALK co-alterations in patients with NSCLC was low. The several previous studies focused on the simultaneous occurrence of EGFR mutations and ALK rearrangements in a unifocal lung cancer. However, the incidence of multifocal pulmonary adenocarcinomas was increasingly encountered in clinical practice, due to the increased availability and improvement of the thoracic imaging. The clinical relevance of EGFR/ALK co-alterations in multifocal adenocarcinomas required detailed investigation as well. CASE PRESENTATION: We present the case of a 57-year-old woman with solid nodule in the left upper lung and a ground glass nodule in the left lower lobe, who underwent radical operation. Pathological examination confirmed multifocal adenocarcinoma, molecular tests revealed that the left upper lung lesion was positive for ALK rearrangement but the left lower lobe displayed EGFR mutation positive separately. The patient pulmonary lesions were well controlled by adjuvant chemotherapy and radiation therapy. When brain metastases occurred, EGFR-TKI was not effective after firstly administration, while subsequent ALK inhibitors were efficient. We retrospective evaluated the oncogenic status of metastatic lymph nodes and found that the driver gene was ALK rearrangement rather than EGFR mutation. CONCLUSIONS: The status of the oncogenic mutations in lymph node metastasis may provide some effective hints for metastasis lesion in other organ or tissue. Therefore, it is recommended to fully evaluate the driver genes in lymph node metastasis after radical resection.

Clonality assessment of multifocal lung adenocarcinoma by pathology evaluation and molecular analysis.

The aim of this study was to explore morphologic and molecular features distinguishing between multifocal lung adenocarcinoma (MLA) and intrapulmonary metastases (IMs). Sixteen patients with MLAs, a total of 34 tumors, were reviewed. Four approaches were used: (1) array-comparative genomic hybridization (CGH) as a standard clonality assessment; (2) EGFR and KRAS mutational profiles as a supplementary method; (3) comprehensive histologic assessment (CHA) was method I in pathology evaluation; and (4) CHA combined with lepidic component analysis was method II. The lepidic component was divided into low grade and high grade according to extent of atypia; tumors with low-grade lepidic component were defined as primary. Eight patients were found to have IMs and 8 to have multiple primaries (MPs) by array-CGH; 7 had MPs and 9 had IMs by method I; 5 had MPs and 11 had IMs by method II. Compared with array-CGH, method I had a lower coincidence rate (65%) than method II (85%). Univariate analysis revealed that patients with MP had a better clinical outcome than those with IM only if the MPs were diagnosed by array-CGH (P = .034) or method II (P = .027) but not EGFR/KRAS mutation (P = .843) or method I (P = .493). Our results suggest that a low-grade lepidic component is a sign of a primary tumor. CHA combined with a low-grade lepidic component (method II) is more accurate clinically and more cost-effective in distinguishing MLAs from IMs. Also, EGFR mutation is not an appropriate molecular marker for clonality assessment.

Significance of nonmucinous lepidic component with mild nuclear atypia in the discrimination of multiple primary lung cancers from intrapulmonary metastases.

The distinguishing of intrapulmonary metastases from multiple primaries is of great clinical importance. Although comprehensive histological assessment (CHA) was recommended for addressing this problem, the limitations of CHA have been addressed. We hypothesized that a nonmucinous lepidic component with mild nuclear atypia (NLCMA) may be one of the important sign suggesting primary lesions. In this study, we measured the value of NLCMA in distinguishing multiple primaries from intrapulmonary metastases. We retrospectively analyzed a cohort of 54 patients with 116 lesions (70 comparisons). Intrapulmonary metastases and multiple primaries were differentiated on the basis of CHA (Method I) and CHA combined with the assessment of NLCMA (Method II), respectively. Then, the results of two methods were compared with survival analysis. 33 cases were defined as multiple primaries and 21 cases as metastases by Method I, while 41 cases as multiple primaries and 13 cases as metastases by Method II. On univariate analysis, there was a better DFS in patients with a tumor ≤ 3 cm (P=0.012), female gender (P=0.011), highest N0 (P=0.002), absent micropapillary (P=0.013), multiple primaries (P=0.008 by method I, P < 0.001 by method II). A multivariate analysis adjusting for gender, tumor size, micropapillary and multiple primaries/metastases (by methodI and method II, respectively) indicated that multiple primaries (by method II) was an independent predictors for DFS. The presence of NLCMA may indicate that a lesion should be defined as primary in multifocal adenocarcinoma.