The role of extensive lymph node dissection in the new grading system for lung adenocarcinoma.

OBJECTIVES: This study evaluates the prognostic impact of the new grading system for lung adenocarcinoma, stratified by lymphadenectomy extent. MATERIALS AND METHODS: We analyzed 1258 lung adenocarcinoma patients who underwent curative resections between 2006 and 2017. We analyzed overall survival (OS), cancer-specific survival (CSS), and recurrence-free survival (RFS) across tumor grades and lymphadenectomy extent, categorized as IASLC-R0 (complete resection) or R(un) (uncertain resection). RESULTS: The median age of cohort was 63 and 41.9 % were male. The majority had undergone lobectomy. The distribution of tumors was 274 grade 1, 558 grade 2, and 426 grade 3 cases. After a median follow-up time of 102 months, the 10-year OS/CSS/RFS rates worsened significantly across grade 1-3: 92.4/99.3/92.3 %, 77.8/87.5/71.7 %, and 63.6/70.2/52.0 %, respectively (p < 0.001). Multivariate Cox regression analysis identified grade 3, R(un) lymphadenectomy, higher Charlson Comorbidity Index, smoking history, thoracotomy, higher pathology stage, and angiolymphatic invasion as independent prognostic factors for lower OS, CSS, and RFS. Furthermore, grade 3 patients benefited significantly from IASLC-R0 lymphadenectomy, showing significantly better OS and RFS than those who underwent R(un) lymphadenectomy (p = 0.007 for OS, p = 0.001 for RFS, post-propensity score matching). Among grade 3 tumors underwent R0 or R(un) resections found the incidence rates of local, distant, and simultaneous local and distant recurrence were 8.5 % vs 13.7 %, 11.0 % vs 12.2 %, and 11.0 % vs 20.6 %, respectively. CONCLUSION: Surgical outcomes for lung adenocarcinoma have declined across grades 1-3. IASLC-R(un) treatment worsens OS and RFS in grade 3. Intensive monitoring and adjuvant therapy should be considered when patients with grade 3 lung adenocarcinoma undergo R(un) lymphadenectomy.

Prognostic Significance of the Highest Mediastinal Lymph Node Involvement in Patients with Stage III-N2 Non-small Cell Lung Cancer.

BACKGROUND: Highest mediastinal lymph node (HMLN) involvement is a category of uncertain resection, yet the prognostic significance of HMLN involvement remains controversial. METHODS: A total of 486 patients with pathological stage III-N2 disease who underwent radical resection were enrolled from January 2015 to December 2018. Patients were allocated into two groups-HMLN involvement (219 cases) and HMLN-negative (249 cases) groups. Kaplan-Meier analysis and Cox proportional hazard regression models were used to evaluate the impact of HMLN involvement on 5-year recurrence-free survival (RFS) and overall survival (OS). RESULTS: The proportion of patients with multiple N2 diseases (72.1% vs. 23.7%; p < 0.001) and stage IIIA (87.2% vs. 77.5%; p < 0.009) were greater in the HMLN-involvement group than in the HMLN-negative group, and the survival rates of the HMLN-involvement group were significantly lower than those of the HMLN-negative group (RFS: 27.2% vs. 49.8%, p < 0.001; OS: 42.1% vs. 59.2%, p = 0.001). HMLN status was an independent factor for OS only (RFS: adjusted hazard ratio [aHR] 1.26, 95% confidence interval CI 0.94-1.68; OS: aHR 1.45, 95% CI 1.07-1.99) in the entire stage III cohort. After stratification of patients according to stage, the involvement of HMLN decreased both RFS and OS in the stage IIIA group (RFS: aHR 1.46, 95% CI 1.06-2.02; OS: aHR 1.70, 95% CI 1.19-2.42); however, no such difference was observed within the stage IIIB group. CONCLUSIONS: HMLN involvement is a prognostic factor of deteriorating survival in highly advanced N2 disease only in patients with stage IIIA.

Prognostic significance of uncertain resection for metastasis in the highest mediastinal lymph node after surgery for clinical N0 non-small cell lung cancer.

Background: The International Association for the Study of Lung Cancer defined types of surgical resection and considered the positivity of the highest mediastinal lymph node resected a parameter of "uncertain resection" (R-u). We investigated the metastases in the highest mediastinal lymph node, defined as the lowest numerically numbered station among those resected. We aimed to evaluate the prognostic value of R-u compared with R0. Materials and methods: We selected 550 patients with non-small cell lung cancer at clinical Stage I, IIA, IIB (T3N0M0), or IIIA (T4N0M0) undergoing lobectomy and systematic lymphadenectomy between 2015 and 2020. The R-u group included patients with positive highest mediastinal resected lymph node. Results: In the groups of patients with mediastinal lymph node metastasis, we defined 31 as R-u (45.6%, 31/68). The incidence of metastases in the highest lymph node was related to the pN2 subgroups (p < 0.001) and the type of lymphadenectomy performed (p < 0.001). The survival analysis compared R0 and R-u: 3-year disease-free survival was 69.0% and 20.0%, respectively, and 3-year overall survival was 78.0% and 40.0%, respectively. The recurrence rate was 29.7% in R0 and 71.0% in R-u (p-value < 0.001), and the mortality rate was 18.9% and 51.6%, respectively (p-value < 0.001). R-u variable showed a tendency to be a significant prognostic factor for disease-free survival and overall survival (hazard ratio: 4.6 and 4.5, respectively, p-value < 0.001). Conclusions: The presence of metastasis in the highest mediastinal lymph node removed seems to be an independent prognostic factor for mortality and recurrence. The finding of these metastases represents the margin of cancer dissemination at the time of surgery, so it could imply metastasis into the N3 node or distant metastasis.

Uncertain resection of highest mediastinal lymph node positive among pN2 non-small cell lung cancer patients: survival analysis of postoperative radiotherapy and driver gene mutations.

BACKGROUND AND PURPOSE: The role of postoperative radiotherapy (PORT) in uncertain resection of pN2 non-small cell lung cancer (NSCLC) with highest mediastinal lymph node positive has not been determined. We aim to evaluate the effect of PORT and driver gene mutation status (DGMS) on survival in such patients. METHODS: 140 selected patients were grouped according to whether they received PORT and their DGMS. Locoregional recurrence-free survival (LRFS), distant metastasis-free survival (DMFS), disease-free survival (DFS), and overall survival (OS) of each group were evaluated by Kaplan-Meier analyses. COX regression was used to evaluate the effects of various factors on DFS and OS. RESULTS: Of 140 patients, thirty-four patients (24.3%) received PORT, and forty (28.6%) had positive driver gene mutation status (DGp). PORT significantly prolonged LRFS (p = 0.002), DFS (p = 0.019) and OS (p = 0.02), but not DMFS (p = 0.062). By subgroup analysis, in patients with negative driver gene mutation status (DGn), those receiving PORT had notably longer LRFS (p = 0.022) and DFS (p = 0.033), but not DMFS (p = 0.060) or OS (p = 0.215), compared to those not receiving PORT. Cox analysis showed that the number of positive lymph nodes (PLNs) and administration of PORT were independent prognostic factors of DFS, and pathology, PLNs, and DGMS may be prognostic factors of OS (all p < 0.05). CONCLUSION: Postoperative radiotherapy may improve locoregional recurrence-free and disease-free survival in patients with pN2 NSCLC with positive highest mediastinal lymph nodes, while driver gene mutation status impacted OS significantly. Only patients with positive driver gene mutations experienced significant overall survival benefits from postoperative radiotherapy.

Reclassifying the International Association for the Study of Lung Cancer Residual Tumor Classification According to the Extent of Nodal Dissection for NSCLC: One Size Does Not Fit All.

INTRODUCTION: The extent of nodal assessment may require risk-based adjustments in NSCLC. We reclassified the International Association for the Study of Lung Cancer Residual tumor classification according to the extent of nodal dissection and evaluated its long-term prognosis by tumor stage and histologic subtype. METHODS: We reclassified 5117 patients who underwent resection for clinical stages I to III NSCLC and had complete or uncertain resection by International Association for the Study of Lung Cancer classification into the following 3 groups according to compliance with three components (N1, N2, and subcarinal node) of systematic nodal dissection criteria: fully compliant group (FCG), partially compliant group (PCG), and noncompliant group (NCG). Recurrence-free survival (RFS) and overall survival (OS) were compared. RESULTS: Of the 5117 patients, 2806 (55%), 1959 (38%), and 359 (7%) were FCG, PCG, and NCG, respectively. PCG and NCG were more likely to be of lower clinical stage and adenocarcinoma with lepidic component than FCG. The 5-year RFS and OS were significantly better in NCG than in FCG or PCG (RFS, 86% versus 70% or 74%, p < 0.001; OS, 90% versus 80% or 83%, p < 0.001). In particular, NCG had better RFS and OS than FCG or PCG in clinical stage I and in lepidic-type adenocarcinoma. CONCLUSIONS: In early stage NSCLC with low-risk histologic subtype, a less rigorous nodal assessment was not associated with a worse prognosis. Although surgeons should continue to aim for complete resection and thorough nodal assessment, a uniform approach to the extent and invasiveness of nodal assessment may need to be reconsidered.

Prognostic evaluation of the proposed residual tumor classification in a Chinese non-small cell lung cancer population.

BACKGROUND: This study aimed to validate the R classification including uncertain resection (R-un) proposed by the International Association for the Study of Lung Cancer (IASLC) in a Chinese non-small cell lung cancer (NSCLC) population. METHODS: The study retrospectively investigated a 2009-2013 single-institutional NSCLC resection cohort in China. After reclassification, recurrence-free survival (RFS) and overall survival (OS) were calculated using survival analyses and compared with those using the 2005 version IASLC R classification. RESULTS: Under the proposed stratification, 3819 (72.1%) individuals were classified as R0, 1371 (25.9%) as R-un, 71 (1.3%) as R1, and 32 (0.6%) as R2. The 5-year OS probabilities for the R0, R-un, and R1/R2 groups were 71%, 46%, and 34%, respectively. The prognostic stratification remained significant in the fully adjusted Cox models (p < 0.001). Compared with the original classification, Harrell's concordance index of reclassification improved significantly, from 0.508 to 0.679 for RFS and from 0.510 to 0.692 for OS (RFS: p = 0.007; OS: p = 0.001). The survival analysis showed that R-un patients with highest mediastinal lymph node station metastasis had significantly worse survival than R0 patients with mediastinal nodal metastasis (RFS: 44 vs. 36 months, hazard ratio [HR]: 1.29, p < 0.001; OS: 59 vs. 50 months, HR: 1.34, p < 0.001). Cox proportional hazards regression analysis showed that highest mediastinal lymph node station metastasis was an independent risk factor for RFS (HR: 1.22) and OS (HR: 1.25). CONCLUSIONS: The proposed R classification showed valid prognostic stratification, including highest mediastinal nodal station metastasis.

The Evolving Concept of Complete Resection in Lung Cancer Surgery.

Different definitions of complete resection were formulated to complement the residual tumor (R) descriptor proposed by the American Joint Committee on Cancer in 1977. The definitions went beyond resection margins to include the status of the visceral pleura, the most distant nodes and the nodal capsule and the performance of a complete mediastinal lymphadenectomy. In 2005, the International Association for the Study of Lung Cancer (IASLC) proposed definitions for complete, incomplete and uncertain resections for international implementation. Central to the IASLC definition of complete resection is an adequate nodal evaluation either by systematic nodal dissection or lobe-specific systematic nodal dissection, as well as the integrity of the highest mediastinal node, the nodal capsule and the resection margins. When there is evidence of cancer remaining after treatment, the resection is incomplete, and when all margins are free of tumor, but the conditions for complete resection are not fulfilled, the resection is defined as uncertain. The prognostic relevance of the definitions has been validated by four studies. The definitions can be improved in the future by considering the cells spread through air spaces, the residual tumor cells, DNA or RNA in the blood, and the determination of the adequate margins and lymphadenectomy in sublobar resections.

Clinical implications of uncertain resection in scenarios of metastasis of the highest or most distant mediastinal lymph node station following surgical treatment of non-small-cell lung cancer.

OBJECTIVES: The positive highest nodal station after operation is one of the definitions of "uncertain resection" proposed by the International Association for the Study of Lung Cancer. This study was performed to determine the prognostic value of positive highest or the most distant nodal station in patients with N2 non-small-cell lung cancer (NSCLC). MATERIALS AND METHODS: Three hundred thirty-nine patients who underwent complete anatomical resection and mediastinal lymph node (LN) dissection for N2 NSCLC between 2000 and 2015 were reviewed. Cases of operative mortality, extracapsular invasion of LN and incomplete resection were excluded from analysis. RESULTS: The mean age was 61.58 ±â€¯9.43 years, and 235(69.3%) patients were male. The numbers of total dissected LNs and positive LNs were 29.90 ±â€¯11.92 and 5.49 ±â€¯5.90, respectively. The subcategory of N stage was divided as follows: N2a1, 91(26.8%); N2a2, 132(38.9%); and N2b, 116(34.2%). One hundred forty-two (41.9%) patients showed highest LN metastasis, and 162(47.8%) patients showed most distant LN metastasis. Kaplan-Meier analysis revealed no differences between distant LN negative and positive patients regarding 5-year overall survival (43.1% vs. 39.2%; p = 0.428) and between highest LN negative and positive patients regarding 5-year overall survival (42.1% vs. 40.0%; p = 0.539). On multivariable analysis, metastasis to the most distant mediastinal LN (hazard ratio (HR): 1.050; p = 0.755) and metastasis to the highest mediastinal LN (HR: 1.015; p = 0.924) were not related to overall survival. CONCLUSION: The current definition of uncertain resection based on metastasis of the highest or most distant LNs did not show survival differences in completely resected N2 NSCLC.