Volume Doubling Times of Lung Adenocarcinomas: Correlation with Predominant Histologic Subtypes and Prognosis.

The Underlying Tumor Genomics of Predominant Histologic Subtypes in Lung Adenocarcinoma.

Objective: Solid and micropapillary pattern are highly invasive histologic subtypes in lung adenocarcinoma and are associated with poor prognosis while the biopsy sample is not enough for the accurate histological diagnosis. This study aims to assess the correlation and predictive efficacy between metabolic parameters in (18)F-fluorodeoxy glucose positron emission tomography/computed tomography ((18)F-FDG PET-CT), including the maximum SUV (SUV(max)), metabolic tumor volume (MTV), total lesion glycolysis (TLG) and solid and micropapillary histological subtypes in lung adenocarcinoma. Methods: A total of 145 resected lung adenocarcinomas were included. The clinical data and preoperative (18)F-FDG PET-CT data were retrospectively analyzed. Mann-Whitney U test was used for the comparison of the metabolic parameters between solid and micropapillary subtype group and other subtypes group. Receiver operating characteristic (ROC) curve and areas under curve (AUC) were used for evaluating the prediction efficacy of metabolic parameters for solid or micropapillary patterns. Univariate and multivariate analyses were conducted to determine the prediction factors of the presence of solid or micropapillary subtypes. Results: Median SUV(max) and TLG in solid and papillary predominant subtypes group (15.07 and 34.98, respectively) were significantly higher than those in other subtypes predominant group (6.03 and 10.16, respectively, P<0.05). ROC curve revealed that SUV(max) and TLG had good efficacy for prediction of solid and micropapillary predominant subtypes [AUC=0.811(95% CI: 0.715~0.907) and 0.725(95% CI: 0.610~0.840), P<0.05]. Median SUV(max) and TLG in lung adenocarcinoma with the solid or micropapillary patterns (11.58 and 22.81, respectively) were significantly higher than those in tumors without solid and micropapillary patterns (4.27 and 6.33, respectively, P<0.05). ROC curve revealed that SUV(max) and TLG had good efficacy for predicting the presence of solid or micropapillary patterns [AUC=0.757(95% CI: 0.679~0.834) and 0.681(95% CI: 0.595~0.768), P<0.005]. Multivariate logistic analysis showed that the clinical stage (Stage Ⅲ-Ⅳ), SUV(max) ≥10.27 and TLG≥7.12 were the independent predictive factors of the presence of solid or micropapillary patterns (P<0.05). Conclusions: Preoperative SUV(max) and TLG of lung adenocarcinoma have good prediction efficacy for the presence of solid or micropapillary patterns, especially for the solid and micropapillary predominant subtypes and are independent factors of the presence of solid or micropapillary patterns.

ObjectiveThis study aimed to evaluate the tumor doubling time of invasive lung adenocarcinoma according to the International Association of the Study for Lung Cancer (IASLC)/American Thoracic Society (ATS)/European Respiratory Society (ERS) histologic classification.Materials and MethodsAmong the 2905 patients with surgically resected lung adenocarcinoma, we retrospectively included 172 patients (mean age, 65.6 ± 9.0 years) who had paired thin-section non-contrast chest computed tomography (CT) scans at least 84 days apart with the same CT parameters, along with 10 patients with squamous cell carcinoma (mean age, 70.9 ± 7.4 years) for comparison. Three-dimensional semiautomatic segmentation of nodules was performed to calculate the volume doubling time (VDT), mass doubling time (MDT), and specific growth rate (SGR) of volume and mass. Multivariate linear regression, one-way analysis of variance, and receiver operating characteristic curve analyses were performed.ResultsThe median VDT and MDT of lung cancers were as follows: acinar, 603.2 and 639.5 days; lepidic, 1140.6 and 970.1 days; solid/micropapillary, 232.7 and 221.8 days; papillary, 599.0 and 624.3 days; invasive mucinous, 440.7 and 438.2 days; and squamous cell carcinoma, 149.1 and 146.1 days, respectively. The adjusted SGR of volume and mass of the solid-/micropapillary-predominant subtypes were significantly shorter than those of the acinar-, lepidic-, and papillary-predominant subtypes. The histologic subtype was independently associated with tumor doubling time. A VDT of 465.2 days and an MDT of 437.5 days yielded areas under the curve of 0.791 and 0.795, respectively, for distinguishing solid-/micropapillary-predominant subtypes from other subtypes of lung adenocarcinoma.ConclusionThe tumor doubling time of invasive lung adenocarcinoma differed according to the IASCL/ATS/ERS histologic classification.

Adenocarcinoma is the most common type of lung cancer, and pre-operative biopsy plays an important role to determine its major subtypes. As proposed by the International Association for the Study of Lung Cancer (IASLC), American Thoracic Society (ATS), and European Respiratory Society (ERS) in 2011, the predominant histological subtype of adenocarcinoma is an indicator of outcomes and recurrence rate. However, the value of CT-guided core biopsy in predicting the predominant subtype and detecting the presence of an aggressive subtype of adenocarcinoma, peripheral sub-solid nodule, has less been discussed. We retrospectively reviewed 318 consecutive peripheral sub-solid nodules that underwent percutaneous CT-guided lung biopsy and surgical resection, between October 2015 and December 2018 and were diagnosed as adenocarcinoma with histological subtype. The subtyping results from biopsy and surgical pathology were compared to evaluate the concordance rate. The overall concordance rate between biopsy and surgical pathology in determining the predominant histological subtype was 64%. Better concordance was found in small tumors (≤ 2cm), in predicting either predominant histology (χ2 = 7.091, P = 0.008) or high grade adenocarcinoma, micropapillary and/or solid subtype, MIP-SOL (χ2 = 22.301, P < 0.001). The analysis of ground glass opacity (GGO) component (C/T ratio) obtained significantly higher accuracy in the pure GGO group than in the other two groups in predicting predominant histology or high grade adenocarcinoma (χ2 = 17.560, P < 0.001 and χ2 = 61.938, P < 0.001, respectively). CT-guided core biopsies provide additional value in predicting the histological subtype of lung adenocarcinoma after surgical resection, especially in small tumors (≤ 2cm) or an initially pure GGO group.

Tumor cell proliferation (Ki-67) expression and its prognostic significance in histological subtypes of lung adenocarcinoma

Objective To evaluate volume doubling time (VDT) and net mass doubling time of tumor (nMDT) of pulmonary pure ground glass nodules (PGGN) of different pathological types and to investigate whether VDT and nMDT can help to differentiate invasive pulmonary adenocarcinomas from minimally invasive adenocarcinomas and preinvasive lesions. Methods Fifty-one pathologically confirmed pGGNs in 46 patients were retrospectively evaluated, in whom at least two HRCT scans were obtained preoperatively (median scan times, 3 times; range, 2—6 times) with 1-month or longer follow-up interval(median follow-up interval, 251 days; range, 30-1 552 days). According to the rechecked results of the postoperative pathological section, 51 pGGNs were divided into two groups: group A, invasive adenocarcinoma (IAC), 30 pGGNs (58.8%); group B, 21 pGGNs (41.2%), including 8 minimally invasive adenocarcinoma (MIA), 7 adenocarcinomas in situ (AIS) and 6 atypical adenomatous hyperplasia (AAH). The volume, cumulative percentage of volume growth and VDTs of pGGNs were automatically acquired by Lung VCAR (advantage windows 4.6, GE HealthCare). Subsequently, the mass, cumulative percentage of mass growth and nMDTs of pGGNs were calculated. The count data and measurement data between two groups were compared using Fisher exact probability and Mann-Whitney U test, respectively. A pairwise comparision were performed by using Wilcoxon signed-rank test. Subsequently, the receiver operating characteristic (ROC) curve was used to determine the optimal cut-off values of VDT and nMDT for the differential diagnosis of IAC and MIA/AIS/AAH, and calculated the area under the curve (AUC). Results The median VDT and nMDT of 51 pGGNs were 1 854.11 days (range, 165.22—+∞ days) and 1 138.45 days (range, 95.92—+∞ days), respectively. The median nMDT was shorter than the median VDT, and the difference was significant (Z=-2.444, P=0.015). The median VDTs of IAC and MIA/AIS/AAH were 847.07 days (165.22—+∞ days) and 4 460.09 days (691.14—+∞ days), respectively. The median nMDTs of IAC, MIA/AIS/AAH were 769.93 days (95.92—+∞ days) and 3814.77 days (611.56—+∞ days), respectively. The median VDT and nMDT of IAC were significantly shorter than those of MIA/AIS/AAH (Z=-3.443,-3.860, P<0.01, respectively). Differentiating IAC from MIA/AIS/AAH, the optimal cutoff value of VDT was 2095.86 days (sensitivity, 71.4%; specificity, 80.0%), the optimal cutoff value of nMDT was 1 169.77 days (sensitivity, 81.0%; specificity, 76.7%). Conclusions In pulmonary pGGNs, IAC showed significantly shorter VDT and nMDT than MIA/AIS/AAH. When VDT is shorter than 2 095.86 days or nMDT is shorter than 1 169.77 days, IAC is suggested. Key words: Lung neoplasms; Tomography, X-ray computed; Ground glass nodule; Volume doubling time; Mass doubling time

BackgroundDistinction in the mutational profile between the common histological types, lung adenocarcinoma (LUAD) and squamous cell lung carcinoma (LUSC) has been well‐established. However, comprehensive mutation profiles of the predominant histological subtypes within LUAD and LUSC remains elusive.MethodsWe analyzed the mutational profile of 318 Chinese NSCLC patients of adenocarcinoma and squamous cell carcinoma predominant subtypes from seven hospitals using capture‐based ultra‐deep sequencing of 68 lung cancer‐related genes.ResultsOf the 318 NSCLC patients, 215 were diagnosed with LUAD and 103 with LUSC. Adenocarcinoma in situ and acinar adenocarcinoma were the most predominant subtypes of LUAD. On the other hand, keratinizing squamous cell carcinoma was the most predominant subtype of LUSC. Among the LUAD subtypes, EGFR sensitizing mutations were most prevalent in the invasive lepidic subtype. More than half of the patients with preinvasive adenocarcinoma in situ, minimally invasive, acinar, micropapillary and papillary subtypes were also EGFR‐mutants. Patients with colloidal, invasive mucinous, and fetal subtypes had the least number of EGFR mutations. Moreover, KRAS mutations were prevalent in patients with invasive mucinous, colloid, enteric and solid subtypes. A total of 90% of the LUSC patients harbor mutations in TP53, wherein all patients except five with nonkeratinizing were TP53 mutants. PIK3CA amplifications were most prevalent in keratinizing, followed by basaloid and nonkeratinizing subtypes.ConclusionThese data suggest that the mutational profiles among the predominant histological subtypes were very distinct, which provided a reliable tool to improve treatment decisions.

1552 Background: The frequencies of known driver mutation in lung adenocarcinoma from patients in the United States have been reported by the NCI’s Lung Cancer Mutation Consortium (LCMC), indicating driver mutations were detected in 54% (280/516) of tumors. In this report, mutations found: EGFR 17%, KRAS 22%, HER2 0.6%, PIK3CA 1.2%, BRAF 2%, MET amplification 0.6%, MAP2K1 0.4%, NRAS 0.4%, AKT 0%, ALK rearrangements 7%. However little is known about ethnic difference of driver mutation frequencies and correlations between driver mutations and histological subtypes in lung adenocarcinoma. Methods: Known driver mutations in tumors from 97 Japanese patients with lung adenocarcinoma who underwent surgical resection between 1999 and 2003 in National Cancer Center Hospital East were analyzed by next-generation sequencing and confirmed by Sanger sequencing. Correlations between driver mutations and histological subtypes were also assessed. Results: Driver mutations were detected in 72% of tumors. Mutations found: EGFR 57%, KRAS9%, HER2 2%, PIK3CA 2%, BRAF 1%, MET amplification 1%, MAP2K1 0%, NRAS 0%, AKT 0%. Due to the limitation of rearrangement detection by exon-sequencing, ALK rearrangements were not analyzed. Compared with the report by LCMC, the frequency of EGFR mutations was high and that of KRAS mutations was low in the present study. All mutations were mutually exclusive. The number of predominant histological subtypes of tumors harbored EGFR mutations were papillary 28, acinar 3, solid 5, lepidic 19. That with KRAS mutations showed papillary 2, acinar 2, solid 2, lepidic 3, and HER2 mutations showed papillary 1 and acinar 1. Two tumors harbored PIK3CA mutations showed both histological acinar pattern. Each of BRAF mutation and MET amplification showed lepidic and papillary pattern, respectively. Conclusions: It was suggested that there should be ethnic difference of driver mutation frequencies in lung adenocarcinoma between Asian and non-Asian patients, although the details of ethnic distribution included in LCMC study has not been opened. In addition, each driver mutations did not correspond to specific histological subtypes of lung adenocarcinoma.

BACKGROUND. In lung adenocarcinomas manifesting as part-solid lesions, evidence supports greater prognostic importance for the volume of the solid component than that of the whole nodule. However, assessments of lesion growth rates have historically focused on the volume doubling time (VDT) of the whole lesion. OBJECTIVE. The purpose of the study was to compare the prognostic utility of the VDT of the solid component versus the VDT of the whole lesion for resected lung adenocarcinomas manifesting as part-solid lesions on chest CT. METHODS. This retrospective study included 122 patients (mean age, 64.0 ± 8.2 [SD] years; 53 men, 69 women) with resected lung adenocarcinoma manifesting as a part-solid lesion who underwent at least two preoperative chest CT examinations showing either solid-component growth or at least 2 years of stability. Semiautomated software was used to perform 3D segmentations of whole lesions and their solid components; these segmentations were used to derive corresponding whole-lesion and solid-component volumes. These volumes were used to compute for each patient VDT of the whole lesion (VDTw) and VDT of the solid component (VDTs). In 81 patients in whom the lesion's ground-glass component increased, VDT of the ground-glass component (VDTgg) was calculated, subtracting the solid-component volume from the whole-lesion volume to derive the ground-glass component volume. The prognostic utility of VDTw, VDTs, and VDTgg (each as continuous variables and as binary variables at 200- and 400-day cutoffs) for recurrence-free survival (RFS) and overall survival (OS) were evaluated using Cox proportional hazards models, adjusted for age, sex, and clinical variables associated with lung cancer survival. RESULTS. Median VDTw, VDTs, and VDTgg were 921, 455, and 1000 days, respectively. The only VDT metrics showing significant independent associations with RFS were VDTs as a continuous variable (HR = 0.999; p = .02), VDTs of less than 400 days (HR = 2.68; p = .03), and VDTs of less than 200 days (HR = 3.68; p = .003). The only VDT metrics showing significant independent associations with OS were VDTs of less than 200 days (HR = 3.27; p = .047) and VDTw of less than 200 days (HR = 4.86; p = .03). CONCLUSION. In lung adenocarcinomas manifesting as part-solid lesions, VDTs of less than 200 days was the only evaluated VDT metric that showed significant independent associations with both RFS and OS. CLINICAL IMPACT. The findings support a focus on lesions' solid components when assessing growth rates of part-solid lesions.

BACKGROUND. Pulmonary metastases of bone and soft-tissue sarcoma are common and have a high recurrence rate after metastasectomy. Factors associated with postmetastasectomy recurrence are not well studied. OBJECTIVE. The purpose of this study was to investigate the association of the volume doubling time (VDT) of pulmonary metastases with the subsequent development of new pulmonary nodules and survival after metastasectomy in patients with bone or soft-tissue sarcoma. METHODS. This retrospective study included patients with bone or soft-tissue sarcoma who, between January 2010 and December 2020, underwent first complete metastasectomy of pulmonary nodules visualized on two sequential preoperative CT scans. Semiautomatic volumetric segmentation of the pulmonary metastases was performed on the two CT scans, and VDTs were calculated. VDT was compared between patients with and without subsequent new metastases after metastasectomy. Cox proportional hazards regression analyses were performed to determine risk factors for recurrence-free survival (RFS) after metastasectomy and for postmetastasectomy overall survival (OS). RESULTS. Forty patients (21 women, 19 men; mean age, 51.1 ± 14.3 [SD] years) were included. Of these patients, 23 (57.5%) developed new metastatic nodules after metastasectomy, and 10 (25.0%) died during follow-up. Median VDT was shorter in patients with, versus those without, new metastases after metastasectomy (56 vs 140 days, p = .002). Only four of 23 patients with new metastases had VDT of 140 days or more. In multivariable analysis, older age (hazard ratio [HR], 1.06; p = .004), female sex (HR, 2.80; p = .03), and VDT less than 140 days (HR, 4.22; p = .01) were independent predictors of worse RFS. Also in multivariable analysis, only older age (HR, 1.17; p = .005) and VDT less than 50 days (HR, 8.60; p = .02) were independent predictors of worse OS. OS was significantly worse in patients with VDT less than 140 days (10 deaths among 27 patients) than in patients with VDT of 140 days or more (no deaths in 13 patients) (p = .01). CONCLUSION. In patients with bone and soft-tissue sarcoma, shorter VDT of pulmonary metastases is independently associated with subsequent new metastases after metastasectomy and worse OS. CLINICAL IMPACT. VDT of pulmonary nodules may be considered in patient selection for pulmonary metastasectomy and in postoperative patient management.

P1.08-005 Stratification of pStage I Lung Adenocarcinoma by the Scoring System Based on Prognostic Factors

Objective: To analyze the clinical features and prognostic factors of different histological subtypes of lung adenocarcinoma. Methods: Data from 370 lung adenocarcinoma patients who underwent surgical resection for pathologically supported adenocarcinoma in our hospital between 2000 and 2003 were retro- spectively reviewed. The Kaplan-Meier method was used to estimate patient survival, and Cox’s proportional hazards model was performed for multivariate analysis. Results: The 5-year overall survival rate was 25.26%, and the mean survival time was 3.89 years. In multivariate analysis, histological subtype, incised margin residual, TNM stage, tumor size, and adjuvant chemotherapy were identified as independent survival predictors. The 5-year survival rate in bronchioloalveolar adenocarcinoma (BAC) patients was 41.30%, higher than in patients with other subtypes of lung adenocarcinoma (P=0.002). No significant difference was found in the prognosis among patients with different subtypes of adenocarcinoma without a BAC component. Conclusion: Ade-nocarcinoma with a BAC component is an independent subtype of lung adenocarcinoma. Its prognosis lies between those of BAC and adenocarcinoma without BAC. Histological subtype, incised margin residual, TNM stage, tumor size, and adjuvant chemotherapy are independent survival predictors.

Invasive adenocarcinoma subtypes are known to be associated with prognosis; however, the underlying reason remains unclear. To find out the reason, we investigated the possible influence of lymph node (LN) involvement by the constituent histologic subtypes in the tumor and clarified the different prognosis according to the predominant histologic subtypes in the tumor and LN. A total of 97 consecutive patients who underwent surgical resection for lung invasive adenocarcinoma between February 2009 and December 2015 were included. We analyzed the associations of the histologic subtypes between the tumor and LN and disease-free survival (DFS) according to the histologic subtypes and predicted the histologic subtype in LN involvement using the component ratio of the predominant histologic subtype in the tumor. A P value <0.05 was considered statistically significant. Acinar and papillary subtypes occupied the majority of the predominant histological subtypes (tumor 73.2%, LN 71.1%). The tumor showed significantly more constituent histologic subtypes than LN (P<0.001). Micropapillary and solid predominant subtype were more common in poorer differentiation (tumor P<0.001, LN P=0.001). The predominant histologic subtype in the tumor was not the same as that in LN and micropapillary and solid predominant subtypes were significantly more prone to LN involvement than other subtypes (P<0.001). Regarding the predominant histologic subtypes in the tumor, there was no significant difference in DFS between micropapillary and solid predominant subtypes and other subtypes. However, regarding the predominant histologic subtypes in LN, micropapillary and solid predominant subtypes had significantly lower DFS than other subtypes (P=0.010). Solid predominant subtype had a significant cutoff value for prediction of the predominant histologic subtype in LN using the component ratio of the predominant histologic subtype in the tumor (cutoff value 12.5%, sensitivity 70.0%, specificity 82.4%, area 0.775, P<0.001). The present study presented a possible reason of discrepancies in outcomes according to the lung adenocarcinoma constituent subtypes. Micropapillary and solid predominant subtypes had poorer prognosis than other subtypes, which might be explained by being more prone to LN involvement.

P1.02-035 Concomitant Driver Mutation Determines Tumor Growth in EGFR Mutation-Positive Lung Adenocarcinoma

High tumor mutation burden predicts favorable outcome among patients with aggressive histological subtypes of lung adenocarcinoma: A population-based single-institution study