Lepidic Predominant Research Articles

Stepwise flowchart for decision making on sublobar resection through the estimation of spread through air space in early stage lung cancer1

ObjectivesThe sensitivity for tumor spread through air space (STAS), an independent risk factor for locoregional recurrence after sublobar resection for lung cancer, has been relatively low in frozen sections. We aimed to determine predictors with high negative predictive value for the presence of STAS and to provide the flowchart in combination with these predictors for the decision-making for sublobar resection. Materials and MethodsBetween July 2015 and December 2017, 387 patients who underwent surgery for non-small cell lung cancer (NSCLC) with pathologic findings of the total masses measuring ≤ 2 cm were enrolled. The lesions were divided into two groups according to presence of STAS. We compared the preoperative characteristics, operative data, and developed a flowchart for STAS prediction using receiver operator characteristic curve analysis and multivariable logistic regression. ResultsThe STAS-positive group (N = 111) had a significantly higher preoperative tumor size (1.70 [1.5] vs 1.50 [0.69], p < 0.001) and standardized uptake value tumor-to-liver (SUV T/L) ratio (1.40 [1.60] vs 0.60 [1.10], p < 0.001) and a significantly lower two-dimensional ground-glass opacity (GGO) percentage (35.86 [61.00] vs 78.14 [39.00], p < 0.001). Meanwhile, the STAS-negative group (N = 286) had higher lepidic predominance (41.6% vs. 1.8%, p < 0.001). We developed a flowchart for predicting STAS in combination with two-dimensional GGO percentage on computed tomography (CT), SUV T/L ratio on positron-emission CT, and lepidic predominant pattern. The sensitivity, specificity, and negative predictive value for STAS positivity were 79.3%, 68.5%, and 89.5%, respectively. ConclusionsThe stepwise flowchart using two-dimensional GGO percentage on CT, maximum SUV, and lepidic predominance might be helpful in selecting patients with early NSCLC for sublobar resection.

New T1 classification.

The IASLC staging and Prognostic Factor Committee proposed new changes to the descriptors for the 8th edition of the Tumour Node Metastasis Staging for Lung Cancer. The T1 descriptor changes include (1) T1 tumours are subclassified into T1a (< 1cm), T1b (> 1 to < 2cm), T1c (> 2 to < 3cm). The corresponding changes are introduced to the overall staging: T1aN0M0 = Stage IA1; T1bN0M0 = Stage IA2; T1cN0M0 = Stage IA3. (2) The introduction of the pathological entities Adenocarcinoma-In-Situ (AIS), Minimally Invasive Adenocarcinoma, and Lepidic Predominant Adenocarcinoma. The corresponding changes on the T descriptor are as follows: Adenocarcinoma-in situ is coded as Tis (AIS); Minimally Invasive Adenocarcinoma is coded as T1a(mi). In this review, the basis for these changes will be described, and the implications on clinical practice will be discussed.

JCES01.19 Clinicopathologic Characteristics, Genetic Variability and Therapeutic Options of RET Rearrangement Patients in Lung Adenocarcinoma

RET fusion gene is identified as a novel oncogene in a subset of non-small cell lung cancer (NSCLC). However, few data are available about the prevalence, clinicopathologic characteristics, genetic variability and therapeutic options in RET-positive lung adenocarcinoma patients. For 615 patients with lung adenocarcinoma, RET status was detected by reverse transcription-polymerase chain reaction (RT-PCR). Next-generation sequencing (NGS) and FISH were performed in positive cases. Thymidylate synthetase (TS) mRNA level was assayed by RT-PCR. Overall survival (OS) was evaluated by Kaplan-Meier method and compared with log-rank test. Twelve RET-positive patients were identified by RT-PCR. However, one patient failed the detection of RET arrangement by FISH and NGS. Totally, 11 patients (1.8%) confirmed with RET rearrangements by three methods, including six females and five males with a median age of 54 years. The presence of RET rearrangement was associated with lepidic predominant lung adenocarcinoma subtype in five of 11 patients. RET rearrangements comprised of nine KIF5B–RET and two CCDC6–RET fusions. Four patients had concurrent gene variability by NGS detection, including EGFR (n=1), MAP2K1 (n=1), CTNNB1 (n=1) and AKT1 (n=1). No survival difference existed between RET-positive and negative patients (58.1 vs. 52.0 months, P=0.504). The median progression-free survival of first-line pemetrexed/platinum regimen was 7.5 months for four recurrent cases, and longer than RET-negative patients (7.5 vs. 5.0 months, P=0.026). The level of TS mRNA was lower in RET-positive patients than that in those RET-negative counterparts (239±188×10-4 vs. 394±457×10-4, P=0.019). The prevalence of RET fusion is approximately 1.8% in Chinese patients with lung adenocarcinoma. RET arrangement is characterized by lepidic predominance and a lower TS level. RET-rearranged patients may benefit more from pemetrexed-based regimen.

P2.03b-046 Clinicopathologic Characteristics, Genetic Variability and Therapeutic Options of RET Rearrangement Patients in Lung Adenocarcinoma: Topic: Biomarkers

RET fusion gene is identified as a novel oncogene in a subset of non-small cell lung cancer (NSCLC). However, few data are available about the prevalence, clinicopathologic characteristics, genetic variability and therapeutic options in RET-positive lung adenocarcinoma patients. For 615 patients with lung adenocarcinoma, RET status was detected by reverse transcription-polymerase chain reaction (RT-PCR). Next-generation sequencing (NGS) and FISH were performed in positive cases. Thymidylate synthetase (TS) mRNA level was assayed by RT-PCR. Overall survival (OS) was evaluated by Kaplan-Meier method and compared with log-rank test. Twelve RET-positive patients were identified by RT-PCR. However, one patient failed the detection of RET arrangement by FISH and NGS. Totally, 11 patients (1.8%) confirmed with RET rearrangements by three methods, including six females and five males with a median age of 54 years. The presence of RET rearrangement was associated with lepidic predominant lung adenocarcinoma subtype in five of 11 patients. RET rearrangements comprised of nine KIF5B–RET and two CCDC6–RET fusions. Four patients had concurrent gene variability by NGS detection, including EGFR (n=1), MAP2K1 (n=1), CTNNB1 (n=1) and AKT1 (n=1). No survival difference existed between RET-positive and negative patients (58.1 vs. 52.0 months, P=0.504). The median progression-free survival of first-line pemetrexed/platinum regimen was 7.5 months for four recurrent cases, and longer than RET-negative patients (7.5 vs.5.0 months, P=0.026). The level of TS mRNA was lower in RET-positive patients than that in those RET-negative counterparts (239±188×10-4 vs. 394±457×10-4, P=0.019). The prevalence of RET fusion is approximately 1.8% in Chinese patients with lung adenocarcinoma. RET arrangement is characterized by lepidic predominance and a lower TS level. RET-rearranged patients may benefit more from pemetrexed-based regimen.

Clinicopathologic characteristics, genetic variability and therapeutic options of RET rearrangements patients in lung adenocarcinoma

BackgroundRET fusion gene is identified as a novel oncogene in a subset of non-small cell lung cancer (NSCLC). However, few data are available about the prevalence, clinicopathologic characteristics, genetic variability and therapeutic options in RET-positive lung adenocarcinoma patients. Patients and methodsFor 615 patients with lung adenocarcinoma, RET status was detected by reverse transcription-polymerase chain reaction (RT-PCR). Next-generation sequencing (NGS) and FISH were performed in positive cases. Thymidylate synthetase (TS) mRNA level was assayed by RT-PCR. Overall survival (OS) was evaluated by Kaplan-Meier method and compared with log-rank test. ResultsTwelve RET-positive patients were identified by RT-PCR. However, one patient failed the detection of RET rearrangement by FISH and NGS. Totally, 11 patients (1.8%) confirmed with RET rearrangements by three methods, including six females and five males with a median age of 54 years. The presence of RET rearrangements was associated with lepidic predominant lung adenocarcinoma subtype in five of 11 patients. RET rearrangements comprised of nine KIF5B–RET and two CCDC6–RET fusions. Four patients had concurrent gene variability by NGS detection,including EGFR(n=1),MAP2K1 (n=1), CTNNB1 (n=1) and AKT1 (n=1). No survival difference existed between RET-positive and negative patients (58.1 vs. 52.0 months, P=0.504). The median progression-free survival of first-line pemetrexed/platinum regimen was 7.5 months for four recurrent cases. And the level of TS mRNA was lower in RET-positive patients than that in those RET-negative counterparts (239±188×10−4 vs. 394±457×10−4, P=0.019). ConclusionThe prevalence of RET fusion is approximately 1.8% in Chinese patients with lung adenocarcinoma. RET rearrangements are characterized by lepidic predominance and a lower TS level. RET-rearranged patients may benefit more from pemetrexed-based regimen.

Prognostic Role of Subtype Classification in Small-Sized Pathologic N0 Invasive Lung Adenocarcinoma

The prognosis of patients with small, node-negative lung cancers, which the current indication for adjuvant chemotherapy never includes, is sometimes poor despite complete tumor resection. The present study aimed to identify independent prognostic factors and to clarify possible candidates for adjuvant chemotherapy among patients with small, node-negative invasive adenocarcinoma. This study involved 153 patients with completely resected small (≤20 mm) pathologic N0 invasive adenocarcinomas. Invasive adenocarcinoma was classified as lepidic predominant (LPA), papillary or acinar predominant (PA), or solid or micropapillary predominant (SM), according to the International Association for the Study of Lung Cancer, American Thoracic Society, and European Respiratory Society classification. Overall survival and recurrence-free survival were estimated from Kaplan-Meier curves. Prognostic factors for recurrence-free survival were determined using univariate and multivariate Cox proportional hazards models. Three-year overall survival and recurrence-free survival rates were 98% and 98%, 97% and 88%, and 85% and 64% for LPA, PA, and SM tumors, respectively. Prognosis was the worst for patients with SM tumors (overall survival LPA versus PA, p= 0.099; LPA versus SM, p < 0.001; and PA versus SM, p= 0.032; recurrence-free survival LPA versus PA, p= 0.014; LPA versus SM, p < 0.001; and PA versus SM, p < 0.001). Subtype was a significantly independent prognostic factor for recurrence-free survival in multivariate analysis (SM versus LPA hazard ratio 22, 95% confidence interval: 2.5 to 190, p= 0.0054). Patients with small (≤20 mm) pathologic N0 solid or micropapillary predominant invasive adenocarcinoma might be possible candidates for adjuvant chemotherapy.

Application of Lepidic Component Predominance to Adjuvant Chemotherapy with Oral Fluoropyrimidines for Stage I Lung Adenocarcinoma

BackgroundIn the present study we aimed to investigate whether the predominance of the lepidic component in tumors was associated with the outcome of postoperative adjuvant chemotherapy for stage I lung adenocarcinoma. Patients and MethodsCharts for patients with pathological stage I lung adenocarcinoma were retrospectively reviewed and then outcomes of adjuvant chemotherapy were assessed according to the lepidic component predominance in tumors. Prognostic factors were evaluated using a Cox proportional hazard model. Propensity scores were determined using the optimal matching method on the basis of Cox modeling and matched (1:1) analysis was applied after classification into lepidic and nonlepidic predominant tumors. ResultsAmong 798 patients with stage I lung adenocarcinoma, 168 received adjuvant chemotherapy. Although adjuvant chemotherapy conferred no disease-free survival (DFS) advantage upon patients with lepidic predominant tumors, it improved DFS in T1b and T2a nonlepidic predominant tumors (P = .045 and P = .029, respectively). Propensity score matched analysis revealed no survival benefits of adjuvant oral fluoropyrimidines in lepidic predominant tumors (DFS, P = .461 and overall survival, P = .983) and the positive survival advantages in nonlepidic predominant tumors (DFS, P = .015 and overall survival, P = .027). ConclusionAdjuvant oral fluoropyrimidines conferred a better survival advantage upon patients with nonlepidic predominant tumors than patients with lepidic predominant tumors. The predominance of a lepidic component could serve as an indicator of adjuvant chemotherapy with oral fluoropyrimidines in stage I lung adenocarcinoma.

Ground-Glass Nodule on Thin-Section CT: Differentiation among AdenocarcinomaIn Situ, Minimally Invasive Adenocarcinoma and Lepidic Predominant Invasive Adenocarcinoma

Poster: ECR 2014 / C-0423 / Nodular ground glass opacities on thin-section CT: differentiation among in situ, minimally invasive and lepidic predominant invasive adenocarcinoma by: M. H. Lee1, D. S. Ryu2, D. Y. Kim3, S.-J. Choi2, J.-H. Ahn2, D. G. Yoo1, J. Jo2, K. Gilhyun4, D. R. Shin2; 1Gangneung/KR, 2Gangneung-si/KR, 3Gangneung-si, Gangwon-do/KR, 4Gangnung/KR

Close association of IASLC/ATS/ERS lung adenocarcinoma subtypes with glucose-uptake in positron emission tomography

ObjectivesCorrelations between maximum standardized uptake value (SUVmax) in fluorodeoxyglucose positron emission tomography (FDG-PET) and IASLC/ATS/ERS histopathologic subtypes of lung adenocarcinoma remain unclear. Therefore, the aim of this study was to retrospectively clarify associations between SUVmax and adenocarcinoma subtypes with postoperative outcomes. Materials and methodsAssociations of SUVmax measured in preoperative FDG-PET/CT and histologic subtypes of lung adenocarcinoma resected in our hospital were analyzed retrospectively. Overall and disease-free survival rates after surgery were calculated by the Kaplan–Meier method, and survival differences between patient groups were tested by the log-rank test. Multivariate analysis for survival was performed using the Cox regression model. ResultsA total of 255 patients (130 men and 125 women; mean age, 69 years; range, 22–88 years) were included in the study. Clinical stages included IA in 151 patients, IB in 79, IIA in 9, IIB in 10, and IIIA in 6. SUVmax was closely associated with histologic subtype in resected specimens (p<0.0001). Values were highest in micropapillary predominant invasive adenocarcinoma (MPA) followed by solid predominant (SPA), invasive mucinous (IMA), acinar predominant (APA), papillary predominant (PPA), lepidic predominant (LPA), minimally invasive adenocarcinoma (MIA), and adenocarcinoma in situ (AIS). When the subtypes were classified into three subgroups [group A, AIS+MIA+LPA (low risk); group B, APA+PPA+IMA (intermediate risk); and group C, SPA+MPP (high risk)] by expected postoperative prognoses, there were significant differences in SUVmax among the subgroups corresponding to recurrence risk (p=0.0001). ConclusionPreoperative SUVmax was closely associated with both adenocarcinoma subtype and aggregated subgroups, reflecting malignant grade of the tumor and prognosis.

Prognostic Significance of Adenocarcinoma In Situ, Minimally Invasive Adenocarcinoma, and Nonmucinous Lepidic Predominant Invasive Adenocarcinoma of the Lung in Patients With Stage I Disease

According to the IASLC/ATS/ERS classification, the lepidic predominant pattern consists of 3 subtypes: adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA), and nonmucinous lepidic predominant invasive adenocarcinoma. We reviewed tumor slides from 1038 patients with stage I lung adenocarcinoma, recording the percentage of each histologic pattern and measuring the invasive tumor size. Tumors were classified according to the IASLC/ATS/ERS classification: 2 were AIS, 34 MIA, and 103 lepidic predominant invasive. Cumulative incidence of recurrence (CIR) was used to estimate the probability of recurrence. Patients with AIS and MIA experienced no recurrences. Patients with lepidic predominant invasive tumors had a lower risk for recurrence (5-y CIR, 8%) than nonlepidic predominant tumors (n=899; 19%; P=0.003). Patients with >50% lepidic pattern tumors experienced no recurrences (n=84), those with >10% to 50% lepidic pattern tumors had an intermediate risk for recurrence (n=344; 5-y CIR, 12%), and those with ≤10% lepidic pattern tumors had the highest risk (n=610; 22%; P<0.001). CIR was lower for patients with ≤2 cm tumors than for those with >2 to 3 cm tumors (for both total and invasive tumor size), with the difference more pronounced for invasive tumor size (5-y CIR, 13% vs. 21% [total size; P=0.022] and 12% vs. 27% [invasive size; P<0.001]). Most patients with lepidic predominant adenocarcinoma who experienced a recurrence had potential risk factors, including sublobar resection with close margins (≤0.5 cm; n=2), 20% to 30% micropapillary component (n=2), and lymphatic or vascular invasion (n=2). It therefore may be possible to identify lepidic predominant adenocarcinomas that carry a low or high risk for recurrence.

多彩な画像所見が腫瘍進展形式を示唆した置換性増殖優位型浸潤性肺腺癌の1例

背景．置換性増殖優位型浸潤性腺癌は，以前は粘液非産生性細気管支肺胞上皮癌と呼ばれており，多彩な画像所見を呈する．症例．70歳の男性．7か月間の湿性咳嗽と1か月前からの労作時呼吸困難感を認めて受診した．胸部CTで広範囲に気管支透亮像を伴う浸潤影とメロンの皮様網目状陰影を認め，一部分に小葉中心性のすりガラス陰影を認めた．以上より経気道散布する病変が進行している状態が考えられ，経気管支肺生検の結果，置換性増殖優位型浸潤性腺癌，cT4N3M1a，IV期と診断した．気管支漏，低酸素血症を認めたが，エクソン21の点突然変異（L858R）を確認した後にゲフィチニブを投与したところ，症状は迅速に改善し酸素療法を離脱できた．一旦は改善したが，原病の悪化があり2次，3次治療を行ったが治療開始後26か月で死亡した．結論．胸部CT読影や病理学的検索の際，小葉単位における病変分布の推定を行うためには，病変の程度が軽い部分で行うことが重要である．また，気管支漏を呈する肺腺癌に対する上皮成長因子受容体チロシンキナーゼ阻害剤の有用性は，抗腫瘍効果に加え，同薬剤による直接的な粘液産生抑制が関与している可能性が考えられた．

Histologic Features Associated With Metastatic Potential in Invasive Adenocarcinomas of the Lung

The International Association for the Study of Lung Cancer (IASLC) recently reclassified adenocarcinomas of the lung on the basis of histologic patterns. However, there is lack of consensus about a grading system for these tumors. We studied a series of invasive lung adenocarcinomas and correlated histologic features with lymph node and distant metastases. A series of invasive lung carcinomas resected over a 5-year period were retrospectively reviewed and classified by the IASLC system. The proportion of each histologic subtype was estimated at 5% increments, and cytologic features were blindly recorded and subsequently correlated with lymph node and distant metastases. The 125 tumors were classified on the basis of the predominant pattern as lepidic predominant (LPA) (n=9), acinar (n=71), solid (n=23), papillary (n=11), and mucinous (n=11). The acinar pattern was heterogeneous, in that a cribriform subgroup (n=34) was significantly more likely to demonstrate lymph node metastases compared with a tubular subgroup (n=37) and had a higher mitotic rate, rate of necrosis, vascular invasion, and prominent nucleoli. Mucinous tumors were LPA (n=3), tubular (n=4), and cribriform predominant (n=4). The rate of lymph node metastasis was greatest in the solid type (P=0.02). The rate of distant metastasis was greatest in the mucinous and solid groups (P<0.02). Mitotic activity (≥ 1/HPF), desmoplasia >20% of the tumor, prominent nucleoli, and vascular invasion, along with a solid growth pattern ≥ 20%, were independently associated with metastatic potential and considered poor prognostic histologic features. A 3-tiered grading system separated tumors into well differentiated (predominantly LPA, papillary, and tubular patterns), moderately differentiated (predominantly cribriform tumors), and poorly differentiated (≥ 20% solid growth pattern). Tumors in the well-differentiated group were elevated to moderately differentiated if there were poor prognostic histologic features. Using this system, there was a stepwise increase in the rate of lymph node metastasis (P<0.0001) and distant metastasis (P=0.0004) from well-differentiated, moderately differentiated, to poorly differentiated tumors, the rate being 40, 46, and 39, respectively. Application of the IASLC classification in this series resulted in a predominance of acinar adenocarcinomas. To stratify tumors into clinically relevant grades, grading by pattern (tubular, cribriform, solid), mitotic activity, and nuclear features is useful.

Erratum to: High Expression of Sonic Hedgehog Signaling Proteins Is Related to the Favorable Outcome, EGFR Mutation, and Lepidic Predominant Subtype in Primary Lung Adenocarcinoma

Erratum to: High Expression of Sonic Hedgehog Signaling Proteins Is Related to the Favorable Outcome, EGFR Mutation, and Lepidic Predominant Subtype in Primary Lung Adenocarcinoma

High Expression of Sonic Hedgehog Signaling Proteins Is Related to the Favorable Outcome, EGFR Mutation, and Lepidic Predominant Subtype in Primary Lung Adenocarcinoma

Dysregulation of the Sonic hedgehog (SHH) signaling pathway has been identified in many human malignancies. However, it remains unclear whether this pathway is activated in human lung adenocarcinoma. We investigated the expression of the SHH ligand and its downstream molecules, such as glioma-associated oncogene homologue (GLI)-1, GLI-2, GLI-3, and ATP-binding cassette G2 (ABCG2), in 166 cases of surgically resected lung adenocarcinoma by immunohistochemistry. Correlations between the expression of SHH-related proteins and clinicopathologic parameters, histologic subtypes, and prognostic significance were statistically analyzed. SHH was highly expressed in the 36.1 % (60/166), GLI-1, GLI-2, and ABCG2 were found in 90/164 (54.9 %), 26/166 (15.7 %), and 139/165 (84.2 %), respectively, and GLI-3 was positive in all cases. SHH was more frequently highly expressed in nonsmokers, patients with no recurrences, lepidic predominant subtype, and with EGFR mutation (p < 0.05, respectively). The high expression of SHH and GLI-1 was related to better overall survival and progression-free survival (p < 0.05). The SHH signaling pathway is frequently up-regulated in a subset of lung adenocarcinoma and is significantly associated with EGFR mutation and lepidic subtype. Although SHH signaling protein expression is not an independent prognostic marker, the expression of these proteins can predict a better prognostic outcome.