Dynamic Analysis of the Impact of Micropapillary Component on Different Recurrence Patterns of Pathological Stage IA3 Lung Adenocarcinoma: A Multicenter, Retrospective Study.

BACKGROUND: This study aimed to evaluate the dynamic impact of the micropapillary (MIP) component on local recurrence (LR), distant metastasis (DM), and multiple recurrence (MR) of pathological stage IA3 lung adenocarcinoma. METHODS: Between July 2012 and July 2020, a total of 351 patients at two medical institutions were enrolled in this study. Cumulative incidence of curves, dynamic risk curves, and time-dependent multivariate analysis was performed to evaluate the effect of the MIP component on patients. RESULTS: The 5-year cumulative incidence of total recurrence with or without an MIP component was 34.2% and 12.3%, respectively (p = 0.001). In three recurrence patterns, our findings revealed that the 5-year cumulative incidence of LR (p = 0.048) and DM (p = 0.005) was higher in the 'MIP-present' group than in the 'MIP-absent' group. In the dynamic recurrence curve, the risk of the three recurrence patterns was different and varied over time between the two groups, especially in DM. Moreover, the dynamic cumulative event curve showed that after 1, 2, and 3 years of survival, the cumulative incidence of DM in the group with MIP continued to be higher than that in the group without MIP (all p < 0.05). Time-dependent Cox regression analysis indicated that the MIP component continued to be an independent risk factor for the cumulative incidence of DM in patients with 3-year survival. CONCLUSIONS: Of the three recurrence patterns, the MIP component mainly aggravated the risk of DM in patients with pathological stage IA3 lung adenocarcinoma, which persisted for 3 years.

Prognostic significance and survival benefits of postoperative adjuvant chemotherapy in patients with stage IA lung adenocarcinoma with non-predominant micropapillary components.

BACKGROUND: The prognostic significance of adjuvant chemotherapy (ACT) for patients with stage IA micropapillary non-predominant (MPNP) lung adenocarcinoma (LUAD) remains unknown. This study aimed to investigate the effects of postoperative ACT in patients with stage IA MPNP-LUAD. METHODS: A total of 149 patients with pathological stage IA MPNP-LUAD who underwent surgery at our center were retrospectively analyzed. Propensity score matching (PSM) analysis was conducted to reduce potential selection bias. Kaplan-Meier analyses were used to assess the impact of ACT on recurrence-free survival (RFS), overall survival (OS), and disease-specific survival (DSS). Subgroup analyses were performed for the survival outcomes based on the percentage of micropapillary components. Cox proportional hazards regression analyses were applied to identify risk factors associated with survival. RESULTS: The receipt or non-receipt of postoperative ACT had no significant effect on RFS, OS, and DSS among all enrolled patients with stage IA MPNP-LUAD (P > 0.05). For patients with a micropapillary component > 5%, the 5-year rates of RFS, OS, and DSS were significantly higher in the ACT group compared to the observation group, both before and after PSM (P < 0.05). However, the differences between the two groups were not significant for patients with a micropapillary component ≤ 5% (P > 0.05). The resection range (HR = 0.071; 95% CI: 0.020-0.251; P < 0.001), tumor size (HR = 2.929; 95% CI: 1.171-7.330; P = 0.022), and ACT (HR = 0.122; 95% CI: 0.037-0.403; P = 0.001) were identified as independent prognostic factors for RFS through Cox regression analysis. CONCLUSION: Patients with stage IA MPNP-LUAD who have a micropapillary component greater than 5% might benefit from postoperative ACT, while those with a micropapillary component ≤ 5% did not appear to derive the same benefit from postoperative ACT.

Association of frequent hypermethylation with high grade histological subtype in lung adenocarcinoma.

Lung adenocarcinoma is classified morphologically into five histological subtypes according to the WHO classification. While each histological subtype correlates with a distinct prognosis, the molecular basis has not been fully elucidated. Here we conducted DNA methylation analysis of 30 lung adenocarcinoma cases annotated with the predominant histological subtypes and three normal lung cases using the Infinium BeadChip. Unsupervised hierarchical clustering analysis revealed three subgroups with different methylation levels: high-, intermediate-, and low-methylation epigenotypes (HME, IME, and LME). Micropapillary pattern (MPP)-predominant cases and those with MPP components were significantly enriched in HME (p = 0.02 and p = 0.03, respectively). HME cases showed a significantly poor prognosis for recurrence-free survival (p < 0.001) and overall survival (p = 0.006). We identified 365 HME marker genes specifically hypermethylated in HME cases with enrichment of "cell morphogenesis" related genes; 305 IME marker genes hypermethylated in HME and IME, but not in LME, with enrichment "embryonic organ morphogenesis"-related genes; 257 Common marker genes hypermethylated commonly in all cancer cases, with enrichment of "regionalization"-related genes. We extracted surrogate markers for each epigenotype and designed pyrosequencing primers for five HME markers (TCERG1L, CXCL12, FAM181B, HOXA11, GAD2), three IME markers (TBX18, ZNF154, NWD2) and three Common markers (SCT, GJD2, BARHL2). DNA methylation profiling using Infinium data was validated by pyrosequencing, and HME cases defined by pyrosequencing results also showed the worse recurrence-free survival. In conclusion, lung adenocarcinomas are stratified into subtypes with distinct DNA methylation levels, and the high-methylation subtype correlated with MPP-predominant cases and those with MPP components and showed a poor prognosis.

Impact of minimal solid and micropapillary components on invasive lung adenocarcinoma recurrence.

BACKGROUND: The specific impacts of solid and micropapillary components on prognosis in lung adenocarcinoma remain unclear. Herein, we elucidated their distinct contributions to lung adenocarcinoma recurrence. MATERIALS AND METHODS: Lung adenocarcinoma was classified into solid and micropapillary absent (S-M-); solid absent, micropapillary present (S-M+); micropapillary absent, solid present (S + M-); and solid and micropapillary present (S + M+). Cumulative incidence of recurrence (CIR) was calculated using competing risk analysis. RESULTS: Of 994 adenocarcinomas, 650 (65.4%) were classified as S-M-; 152 (15.3%), S-M+; 148 (14.9%), S + M-; and 44 (4.4%), S + M+. In total, 168 (16.9%) patients had recurrence; 16 (1.6%) died from other causes. S-M- had significantly lower CIR than other groups (S-M- vs. S-M+: P < 0.001, S-M- vs. S + M-: P < 0.001, S-M- vs. S + M+: P < 0.001); S + M- had significantly higher CIR than S-M+ (P = 0.002). These differences remained significant in multivariable analysis. In stage IA, S-M- had significantly lower CIR than other groups (S-M- vs. S-M+: P = 0.006, S-M- vs. S + M-: P < 0.001, S-M- vs. S + M+: P < 0.001); S + M- and S + M+ had significantly higher CIR than S-M+ (P = 0.005, P = 0.008, respectively). These differences remained significant in multivariable analysis. CIR was not significantly different between S + M- and S-M+ subgroups. CONCLUSIONS: The presence of solid or micropapillary component (≥1%) was an independent risk factor for CIR; patients with solid component alone had a higher CIR than those with micropapillary component alone. In IA lung adenocarcinoma, patients with both solid and micropapillary components had a higher CIR than those with micropapillary component alone; the proportion of solid or micropapillary component was not associated with CIR.

Whole-Exome Sequencing and Experimental Validation Unveil the Roles of TMEM229A Q200del Mutation in Lung Adenocarcinoma.

INTRODUCTION: Lung adenocarcinoma (LUAD) is one of the major histopathological types of non-small cell lung cancer (NSCLC), including solid, acinar, lepidic, papillary and micropapillary subtypes. Increasing evidence has shown that micropapillary LUAD is positively associated with a higher percentage of driver gene mutations, a higher incidence of metastasis and a poorer prognosis, while lepidic LUAD has a relatively better prognosis. However, the novel genetic change and its underlying mechanism in the progression of micropapillary LUAD have not been exactly determined. METHODS: A total of 181 patients with LUAD who underwent surgery at the First Affiliated Hospital of Huzhou University from January 2020 to December 2022 were enrolled. Three predominant lepidic and three predominant micropapillary LUAD tissue samples were carried out using whole-exome sequencing. Comprehensive analysis of genomic variations and the difference between lepidic and micropapillary LUAD was performed. In addition, the TMEM229A Q200del mutation was verified using our cohort and TCGA-LUAD datasets. The correlations between the TMEM229A Q200del mutation and the clinicopathological characteristics of patients with LUAD were further analyzed. The functions and mechanisms of TMEM229A Q200del on NSCLC cell proliferation and migration were also determined. RESULTS: The frequency of genomic changes in patients with micropapillary LUAD was higher than that in patients with lepidic LUAD. Mutations in EGFR, ATXN2, C14orf180, MUC12, NOTCH1, and PKD1L2 were concomitantly detected in three predominant micropapillary and three predominant lepidic LUAD cases. The TMEM229A Q200del mutation was only mutated in lepidic LUAD. Additionally, the TMEM229A Q200del mutation had occurred in 16 (8.8%) patients, and not found TMEM229A R76H and M346T mutations in our cohort, while TMEM229A mutations (R76H, M346T, and Q200del) occurred only in 1.0% of the TCGA-LUAD cohort. Further correlation analysis between the TMEM229A Q200del mutation and clinicopathological characteristics suggested that a lower frequency of the Q200del mutation was significantly associated with positive lymph node metastasis, advanced TNM stage, positive cancer thrombus, and pathological features. Finally, overexpression of TMEM229A Q200del suppressed NSCLC cell proliferation and migration in vitro. Mechanistically, overexpression of TMEM229A and TMEM229A Q200del both reduced the expression level of phosphorylated (p)-ERK and p-AKT (Ser473), and the reduced protein level of p-ERK in the TMEM229A Q200del group was more pronounced compared to the TMEM229A group. CONCLUSION: Our results demonstrated that the TMEM229A Q200del mutant may play a protective role in the progression of LUAD via inactivating ERK pathway, providing a potential therapeutic target in LUAD.

Prediction of solid and micropapillary components in lung invasive adenocarcinoma: radiomics analysis from high-spatial-resolution CT data with 1024 matrix.

PURPOSE: To predict solid and micropapillary components in lung invasive adenocarcinoma using radiomic analyses based on high-spatial-resolution CT (HSR-CT). MATERIALS AND METHODS: For this retrospective study, 64 patients with lung invasive adenocarcinoma were enrolled. All patients were scanned by HSR-CT with 1024 matrix. A pathologist evaluated subtypes (lepidic, acinar, solid, micropapillary, or others). Total 61 radiomic features in the CT images were calculated using our modified texture analysis software, then filtered and minimized by least absolute shrinkage and selection operator (LASSO) regression to select optimal radiomic features for predicting solid and micropapillary components in lung invasive adenocarcinoma. Final data were obtained by repeating tenfold cross-validation 10 times. Two independent radiologists visually predicted solid or micropapillary components on each image of the 64 nodules with and without using the radiomics results. The quantitative values were analyzed with logistic regression models. The receiver operating characteristic curves were generated to predict of solid and micropapillary components. P values < 0.05 were considered significant. RESULTS: Two features (Coefficient Variation and Entropy) were independent indicators associated with solid and micropapillary components (odds ratio, 30.5 and 11.4; 95% confidence interval, 5.1-180.5 and 1.9-66.6; and P = 0.0002 and 0.0071, respectively). The area under the curve for predicting solid and micropapillary components was 0.902 (95% confidence interval, 0.802 to 0.962). The radiomics results significantly improved the accuracy and specificity of the prediction of the two radiologists. CONCLUSION: Two texture features (Coefficient Variation and Entropy) were significant indicators to predict solid and micropapillary components in lung invasive adenocarcinoma.

Evaluation of the preoperative neutrophil-to-lymphocyte ratio as a predictor of the micropapillary component of stage IA lung adenocarcinoma.

OBJECTIVE: To assess the ability of markers of inflammation to identify the solid or micropapillary components of stage IA lung adenocarcinoma and their effects on prognosis. METHODS: We performed a retrospective study of clinicopathologic data from 654 patients with stage IA lung adenocarcinoma collected between 2013 and 2019. Logistic regression analysis was used to identify independent predictors of these components, and we also evaluated the relationship between markers of inflammation and recurrence. RESULTS: Micropapillary-positive participants had high preoperative neutrophil-to-lymphocyte ratios. There were no significant differences in the levels of markers of systemic inflammation between the participants with or without a solid component. Multivariate analysis showed that preoperative neutrophil-to-lymphocyte ratio (odds ratio [OR] = 2.094; 95% confidence interval [CI], 1.668-2.628), tumor size (OR = 1.386; 95% CI, 1.044-1.842), and carcinoembryonic antigen concentration (OR = 1.067; 95% CI, 1.017-1.119) were independent predictors of a micropapillary component. There were no significant correlations between markers of systemic inflammation and the recurrence of stage IA lung adenocarcinoma. CONCLUSIONS: Preoperative neutrophil-to-lymphocyte ratio independently predicts a micropapillary component of stage IA lung adenocarcinoma. Therefore, the potential use of preoperative neutrophil-to-lymphocyte ratio in the optimization of surgical strategies for the treatment of stage IA lung adenocarcinoma should be further studied.

Establishment and visualization of a model based on high-resolution CT qualitative and quantitative features for prediction of micropapillary or solid components in invasive lung adenocarcinoma.

OBJECTIVE: To predict the existence of micropapillary or solid components in invasive adenocarcinoma, a model was constructed using qualitative and quantitative features in high-resolution computed tomography (HRCT). METHODS: Through pathological examinations, 176 lesions were divided into two groups depending on the presence or absence of micropapillary and/or solid components (MP/S): MP/S- group (n = 128) and MP/S + group (n = 48). Multivariate logistic regression analyses were used to identify independent predictors of the MP/S. Artificial intelligence (AI)-assisted diagnostic software was used to automatically identify the lesions and extract corresponding quantitative parameters on CT images. The qualitative, quantitative, and combined models were constructed according to the results of multivariate logistic regression analysis. The receiver operating characteristic (ROC) analysis was conducted to evaluate the discrimination capacity of the models with the area under the curve (AUC), sensitivity, and specificity calculated. The calibration and clinical utility of the three models were determined using the calibration curve and decision curve analysis (DCA), respectively. The combined model was visualized in a nomogram. RESULTS: The multivariate logistic regression analysis using both qualitative and quantitative features indicated that tumor shape (P = 0.029 OR = 4.89; 95% CI 1.175-20.379), pleural indentation (P = 0.039 OR = 1.91; 95% CI 0.791-4.631), and consolidation tumor ratios (CTR) (P < 0.001; OR = 1.05; 95% CI 1.036-1.070) were independent predictors for MP/S + . The areas under the curve (AUC) of the qualitative, quantitative, and combined models in predicting MP/S + were 0.844 (95% CI 0.778-0.909), 0.863 (95% CI 0.803-0.923), and 0.880 (95% CI 0.824-0.937). The combined model of AUC was the most superior and statistically better than qualitative model. CONCLUSION: The combined model could assist doctors to evaluate patient's prognoses and devise personalized diagnostic and treatment protocols for patients.

Does the presence of a micropapillary component predict worse prognosis in pathological stage IA lung adenocarcinoma?

Considerable evidence has verified that the micropapillary pattern is significantly associated with worse prognosis in pulmonary adenocarcinoma. However, whether the presence of a micropapillary component in pathological stage IA lung adenocarcinoma is also related to worse prognosis remains unclear up to now. The aim of this meta-analysis was to identify the prognostic role of presence of a micropapillary component in pathological stage IA lung adenocarcinoma patients. Relevant studies were searched from the PubMed, EMBASE, Web of Science and CNKI databases and reviewed. The primary and secondary outcomes were the recurrence risk and long-term survival including the overall survival (OS) and disease-free survival (DFS), respectively. All statistical analysis were conducted by STATA 12.0 software. A total of 5257 lung adenocarcinoma patients at the pathological stage IA from ten retrospective studies were enrolled. The recurrence rates in pathological stage IA lung adenocarcinoma patients with and without the a micropapillary component were 32% [95% confidence interval (CI): 20%- 44%] and 7% (95% CI: 4%-10%) separately and pooled results indicated that presence of a micropapillary component was an obvious risk factor for recurrence [odds ratio (OR)= 3.41, 95% CI: 2.80-4.16, P＜0.001]. Besides, the presence of a micropapillary component was significantly related to poorer OS [hazard ratio (HR)= 2.44, 95% CI: 1.28-4.68, P = 0.007] and DFS (HR=2.60, 95% CI: 1.63-4.16, P＜0.001). Subgroup analysis focusing on invasive adenocarcinoma manifested consistent results. In pathological stage IA lung adenocarcinoma, the presence of a micropapillary component predicts obviously higher recurrence risk and worse prognosis even after focusing on invasive adenocarcinoma. However, more prospective high-quality studies are still needed to verify our findings.

A clinical spectrum of resectable lung adenocarcinoma with micropapillary component (MPC) concurrently presenting as mixed ground-glass opacity nodules.

BACKGROUND: In clinical practice, preoperative identification of mixed ground-glass opacity (mGGO) nodules with micropapillary component (MPC) to facilitate the implementation of individualized therapeutic strategies and avoid unnecessary surgery is increasingly importantOBJECTIVE: This study aimed to build a predictive model based on clinical and radiological variables for the early identification of MPC in lung adenocarcinoma presenting as mGGO nodules. METHODS: The enrolled 741 lung adenocarcinoma patients were randomly divided into a training cohort and a validation cohort (3:1 ratio). The pathological specimens and preoperative images of malignant mGGO nodules from the study subjects were retrospectively reviewed. Furthermore, in the training cohort, selected clinical and radiological variables were utilized to construct a predictive model for MPC prediction. RESULTS: The MPC was found in 228 (43.3%) patients in the training cohort and 72 (41.1%) patients in the validation cohort. Based on the predictive nomogram, the air bronchogram was defined as the most dominant independent risk factor for MPC of mGGO nodules, followed by the maximum computed tomography (CT) value (> 200), adjacent to pleura, gender (male), and vacuolar sign. The nomogram demonstrated good discriminative ability with a C-index of 0.783 (95%[CI] 0.744-0.822) in the training cohort and a C-index of 0.799 (95%[CI] 0.732-0.866) in the validation cohort Additionally, by using the bootstrapping method, this predictive model calculated a corrected AUC of 0.774 (95% CI: 0.770-0.779) in the training cohort. CONCLUSIONS: This study proposed a predictive model for preoperative identification of MPC in known lung adenocarcinomas presenting as mGGO nodules to facilitate individualized therapy. This nomogram model needs to be further externally validated by subsequent multicenter studies.

Genomic and clinicopathological features of lung adenocarcinomas with micropapillary component.

Background: Lung adenocarcinoma (LA) with a micropapillary component (LAMPC) is a histological subtype of lung cancer that has received increasing attention due to its correlation with poor prognosis, and its tendency to recur and metastasize. At present, comprehensive genomic profiles and clinicopathological features for LAMPC remain unclear and require further investigation. Methods: From September 2009 to October 2020, a total of 465 LAMPC patients were recruited and divided into four groups according to MPC proportions, and the correlations between varying proportions of MPCs and clinicopathological characteristics were analyzed. Twenty-nine (29) LAMPC patients and 89 LA patients without MPC (non-MPC) that had undergone NGS testing were selected for further study The comprehensively analyze genomic variations and the difference between LAMPC and MPC were determined. In addition, Gene alterations of LAMPC between Chinese and Western populations were also compared using cBioPortal data. Results: A higher proportion of MPCs, associated with higher tumor stage, pleural invasion, and vascular tumor thrombus formation, was determined in LA patients. Compared to non-MPC patients, LAMPC patients were determined to have a lower frequency of single nucleotide variants and a higher frequency of insertion-deletion mutations. Mutations in TP53, CTNNB1, and SMAD4, and ALK rearrangements/fusions were significantly more frequent in LAMPC patients. ERBB2 mutations were only detected in non-MPC patients. Gene mutations in the Wnt pathway were significantly more common in LAMPC patients as compared to non-MPC patients. ALK fusions were more prevalent in younger patients. Patients with KRAS or LBP1B mutations had significantly larger tumor diameters than patients with wild-type KRAS or LBP1B. Patients with KRAS mutations were more likely to develop vascular tumor thrombus. Using the cBioPortal public database, we determined that mutations in EGFR were significantly higher in Chinese patients than in a Memorial Sloan Kettering Cancer Center (MSKCC) Western cohort. ALK fusions were exclusively detected in the Chinese cohort, while mutations in KEAP1 and NOTCH4 were only detected in the MSKCC cohort. Our analysis of signaling pathways revealed that Wnt pathway gene mutations were significantly higher in the Chinese cohort. Conclusion: LA patients with higher proportions of MPCs were determined to have a higher tumor stage, pleural invasion, and vascular tumor thrombosis formation. We comprehensively analyzed the genomic mutation characteristics of LAMPC patients and identified multiple, novel MPC-related gene alterations and pathway changes. Our data provide further understanding of the nature of the LAMPC and potential drug-targeted gene alterations, which may lead to new therapeutic strategies.

The prognostic influence of histological subtypes of micropapillary tumors on patients with lung adenocarcinoma ≤ 2 cm.

Objective: This study aimed to explore the value of micropapillary histological subtypes in predicting the specific surgical specificity and lymph node metastasis prognosis of early lung adenocarcinoma. Methods: A total of 390 patients with lung adenocarcinoma were included who underwent surgery in the Department of Thoracic Surgery of the Affiliated Provincial Hospital of Anhui Medical University from January 2016 to December 2017. The data were analysed with SPSS 26.0 statistical software, and the clinicopathological data of the two groups were compared with the chi-square test. The survival rate was calculated by the Kaplan-Meier method, and the difference in survival rate between groups was analysed by the log-rank test. Multivariate survival analysis was performed using the Cox model. Results: Univariate analysis of the clinicopathological data of the patients showed that the micropapillary histological subtype was significantly associated with the survival rate of patients (p=0.007). The clinicopathological data of the patients were substituted into the Cox model for multivariate analysis, and the results showed that the micropapillary histological subtype was an independent prognostic factor affecting the survival rate of the patients (p=0.009).The average survival time of Group A (micronipple composition > 5%) was 66.7 months; the 1-year, 3-year, and 5-year survival rates were 98.8%, 93.0%, and 80.9%, respectively.The survival of the lobectomy group was better than that of the sublobectomy group and the survival of patients with systematic dissection was better than that of patients with limited lymph node dissection. The average survival time of Group B (micronipple composition ≤ 5%) was 70.5 months; the 1-year, 3-year, and 5-year survival rates were 99.3%, 95.4%, and 90.6%, respectively. There was no difference in the survival rate between the lobectomy group and sublobectomy group, and there was also no difference in survival between systematic lymph node dissection and limited lymph node dissection, The survival rate of Group B was significantly better than that of Group A. Conclusion: The micropapillary histological component is an independent risk factor after surgery in patients with ≤2 cm lung adenocarcinoma. When the proportion of micropapillary components is different, the prognosis of patients is different when different surgical methods and lymph node dissections are performed. Lobectomy and systematic lymph node dissection are recommended for patients with a micropapillary histological composition >5%; sublobar resection and limited lymph node dissection are recommended for patients with a micropapillary histological composition ≤5%.

Factors associated with lymph node metastasis upstage after resection for patients with micropapillary lung adenocarcinoma.

BACKGROUND: Micropapillary adenocarcinoma has a poor prognostic histological pattern. Additionally, preoperative detection of lymph node metastases by preoperative examination is difficult in some patients with micropapillary adenocarcinoma, and postoperative upstage may occur. However, clinicopathological features of patients with micropapillary adenocarcinoma with nodal upstage have not been established, therefore this study aimed to identify the factors associated with potential lymph node metastases during preoperative examination to ensure effective surgical procedures. METHODS: Between January 2011 and December 2020, 1029 patients received complete resection for primary non-small-cell lung cancer by lobectomy or more extensive resection with systematic lymph node dissection at this institution. One hundred and thirty-one patients diagnosed with adenocarcinoma with micropapillary component were included in this study. The clinicopathological features of patients with nodal upstage whose postoperative N stage was more advanced than the preoperative N stage were examined. RESULTS: Forty patients had nodal upstage after resection. 18 F-fluorodeoxyglucose (FDG) positron emission tomography-computed tomography (PET-CT) revealed that a maximum standardized uptake value (SUVmax) ≥5 for the primary lesion was significantly associated with postoperative nodal upstage. There were no significant differences in terms of sex, age, smoking history, surgical procedure, and diabetes. Among 38 patients with nodal upstage, 23 patients had no significant preoperative lymphadenopathy and showed no abnormal FDG uptake in the lymph nodes on 18 F-FDG-PET-CT, respectively. CONCLUSIONS: Lymph node metastases were suspected in patients preoperatively diagnosed with micropapillary adenocarcinoma with FDG SUVmax ≥5 for the primary tumor. Therefore, standard surgical resection and careful lymph node dissection should be performed for such patients.

Prognostic impact of micropapillary component in patients with node-negative subcentimeter lung adenocarcinoma: A Chinese cohort study.

BACKGROUND: In this study, we investigated the prognostic significance of a micropapillary (MP) component in patients with subcentimeter lung adenocarcinoma. METHODS: A total of 311 patients with subcentimeter lung adenocarcinoma who underwent surgical resection between January 2009 to December 2012 from seven medical centers were included. Recurrence-free survival (RFS) and overall survival (OS) were analyzed. RESULTS: The five-year RFS was 79.8% in 97 (97/311, 31%) cases of adenocarcinoma with a MP component and 93.5% in the 214 (214/311, 69%) cases without. In multivariate analysis, MP was an independent risk factor for worse RFS (hazard ratio [HR], 3.73; 95% confidence interval [CI]: 1.87-7.42; P < 0.001) and OS (HR, 5.84; 95% CI: 2.20-15.49; P < 0.001). There was no significant difference among wedge resection, segmentectomy and lobectomy on RFS (P = 0.256) and OS (P = 0.103) in patients without MP. Regarding patients with a MP component, lobectomy achieved equivalent prognosis than segmentectomy, and both were better than wedge resection (P = 0.001). CONCLUSIONS: A MP component still suggest a poor prognosis in subcentimeter lung adenocarcinoma. Patients with subcentimeter lung adenocarcinoma with a MP component of 5% or greater treated with wedge resection were at higher risk of recurrence than patients treated with anatomical resection.

Impact of the micropapillary component on the timing of recurrence in patients with resected lung adenocarcinoma.

OBJECTIVES: A micropapillary (MIP) component is reported to be associated with a poor prognosis in patients with completely resected lung adenocarcinoma. The purpose of this study was to investigate the impact of an MIP component on the timing of postoperative recurrence using hazard curves. METHODS: A total of 1289 patients with lung adenocarcinoma who underwent complete pulmonary resection from 2008 to 2015 were studied. Hazard curves representing the changes in hazard over time were evaluated. RESULTS: The hazard curve displayed an initial wide, high peak within 1 year after surgery in patients with an MIP component, whereas some gentle peaks around the second year were noted in patients without an MIP component. The presence of an MIP component was associated with a worse recurrence-free survival and an early recurrence in stage I patients but not in advanced-stage patients. In multivariable Cox regression, the presence of an MIP component and lymph node metastasis, pleural invasion and gender were associated with a poor prognosis. CONCLUSIONS: Patients with an MIP component retained a high risk of early recurrence after surgery, and the risk for recurrence persisted over the long term. Even after complete resection in stage I lung adenocarcinoma patients, an MIP component remains correlated with a poor prognosis.

Both the presence of a micropapillary component and the micropapillary predominant subtype predict poor prognosis after lung adenocarcinoma resection: a meta-analysis.

OBJECTIVE: It has been confirmed that the micropapillary (MP) pattern is a poor prognostic factor after resection of lung adenocarcinoma (ADC), but the proportion of the MP component as a prognostic criterion is still controversial. Hence, a meta-analysis was performed to evaluate whether the presence of an MP component has equal prognostic power as the MP predominant subtype. METHODS: Literature retrieval was performed in the MEDLINE, EMBASE, and Cochrane databases until December 23, 2019. Eligible studies were selected based on the inclusion and exclusion criteria. The included studies were divided into two subgroups, the MP component subgroup and the MP predominant subgroup, according to the proportion of the MP pattern to analyse the effect of this pattern on disease-free survival (DFS) and overall survival (OS). The hazard ratio (HR) and 95% confidence interval (CI) were extracted from each study. Review Manager 5.3 was used for statistical analyses. RESULTS: Finally, 10 studies, including a total of 4934 lung ADC patients, were included in this meta-analysis. Our results indicated a significantly worse pooled DFS (HR 1.62, 95% CI 1.20-2.21) and OS (HR 1.53, 95% CI 1.19-1.96) in the subgroup of MP predominant subtype patients. The pooled DFS (HR 1.80, 95% CI 1.45-2.85) and OS (HR 2.26, 95% CI 1.46-3.52) were also poor in the subgroup of patients with the presence of an MP component. CONCLUSIONS: Both the presence of an MP component and the MP predominant subtype are related to poor DFS and OS after lung ADC resection and represent adverse prognostic factor for lung ADC patients. However, there are some limitations in this meta-analysis, and quantitative stratification based on the proportion of the MP component is needed to explore its effect on prognosis of lung ADC patients in the future.

CT-Based Deep Learning Model for Invasiveness Classification and Micropapillary Pattern Prediction Within Lung Adenocarcinoma.

Objective: Identification of tumor invasiveness of pulmonary adenocarcinomas before surgery is one of the most important guides to surgical planning. Additionally, preoperative diagnosis of lung adenocarcinoma with micropapillary patterns is also critical for clinical decision making. We aimed to evaluate the accuracy of deep learning models on classifying invasiveness degree and attempted to predict the micropapillary pattern in lung adenocarcinoma. Methods: The records of 291 histopathologically confirmed lung adenocarcinoma patients were retrospectively analyzed and consisted of 61 adenocarcinoma in situ, 80 minimally invasive adenocarcinoma, 117 invasive adenocarcinoma, and 33 invasive adenocarcinoma with micropapillary components (>5%). We constructed two diagnostic models, the Lung-DL model and the Dense model, based on the LeNet and the DenseNet architecture, respectively. Results: For distinguishing the nodule invasiveness degree, the area under the curve (AUC) value of the diagnosis with the Lung-DL model is 0.88 and that with the Dense model is 0.86. In the prediction of the micropapillary pattern, overall accuracies of 92 and 72.91% were obtained for the Lung-DL model and the Dense model, respectively. Conclusion: Deep learning was successfully used for the invasiveness classification of pulmonary adenocarcinomas. This is also the first time that deep learning techniques have been used to predict micropapillary patterns. Both tasks can increase efficiency and assist in the creation of precise individualized treatment plans.

Driver mutation profiles and clinicopathological correlation in pulmonary adenocarcinoma with a micropapillary component.

Pulmonary adenocarcinoma (PA) with a micropapillary component (PA-MPC) is considered a highly aggressive neoplasm. The molecular profile of PA-MPC has not yet been clearly elucidated. Based on these, we performed next-generation sequencing and quantitative real-time polymerase chain reaction (qPCR) to detect the driver mutation profiles of 50 PA-MPC cases and confirmed the results by Sanger sequencing. In addition, in 10 selected MPC-predominant cases, we captured the MPC and non-MPC by laser-capture microdissection and sequenced them separately to investigate the differences in driver mutation profiles between MPC and non-MPC. In 50 PA-MPC cases, the prevalence rates of EGFR, KRAS, and PIK3CA somatic mutations were 76.0%, 6.0%, and 2.0%, respectively; no BRAF, NRAS, ALK, PDGFRA, or other mutations were found. With regard to the MPC, EGFR mutation was more frequent in MPC-predominant cases (18/20; 90%) than in non-MPC-predominant cases (20/30; 66.7%). The overall survival of the MPC-predominant group was significantly worse than that of the non-MPC-predominant group. In the 10 microdissected MPC-predominant cases, the EGFR mutation was identical in both components and was consistent with previous results without microdissection. In conclusion, our study indicated that EGFR mutations were frequent in PA-MPC. Paired MPC and non-MPC from the same cases had the same driver mutation profiles.

Study of Histopatological Parameters of Gastric Carcinomas with Micropapillary Component.

Micropapillary carcinoma was recently identified as a carcinoma variant characterized by the presence of small clusters of tumor cells located in optically empty spaces. The study included a number of 14 cases represented by surgical excision specimens diagnosed with gastric carcinoma (tubular, papillary and signet-ring) which associated the micropapillary component in variable proportions. Regarding the low-grade tubular carcinomas, the micropapillary component represented less than 25% of the tumor, while in the high-grade tubular carcinomas and papillary carcinomas it represented 25-50%. Among signet-ring carcinomas, the micropapillary component had a percentage of over 50. The depth of invasion was frequently associated with T3 and T4 categories. Lymph nodes metastasis were found in ten cases and distant metastasis were present in three cases. Recognition of the micropapillary component associated with gastric carcinoma represents an aspect of great importance because it is frequently correlated with unfavorable prognosis parameters.

Clinicopathological Characteristics of Lung Adenocarcinoma with Unexpected Lymph Node Metastasis.

PURPOSE: The objective is to demonstrate the clinicopathological characteristics of patients with unexpected node-positive lung adenocarcinoma and to analyze predictive factors of unexpected disease. METHODS: We reviewed 225 patients with lung adenocarcinoma who underwent curative-intent operation between January 2008 and December 2014. Unexpected node-positive diseases were defined as cases with hilar or mediastinal lymph nodes metastasis in spite of both negative significant enlargement of lymph nodes on preoperative chest computed tomography (CT) and negative fluorodeoxyglucose (FDG) uptake in lymph nodes on preoperative positron emission tomography (PET)/CT. We retrospectively analyzed clinical features of these patients and evaluated associated factors for unexpected diseases. RESULTS: There were 41 patients (18%) with unexpected node-positive disease, consisting of 16 (39%) unexpected pN1 and 25 (61%) unexpected pN2 diseases. The most common predominant subtype was papillary (22 patients; 54%), and 17 patients (41%) had micropapillary component in the tumors. Younger age (p <0.01), left side (p <0.01), larger tumor size (p <0.01), and having a micropapillary component (p <0.01) were significant associated factors of unexpected diseases in multivariate analysis. CONCLUSION: Histological findings of the primary tumor are often important because they can provide predictive information for lymph nodes status. Having a micropapillary component was one of the significant predictors of unexpected node-positive diseases.