Identification of filigree pattern increases the diagnostic accuracy of micropapillary pattern on frozen section for lung adenocarcinoma.

AIMS: The presence of micropapillary (MIP) in early-stage lung adenocarcinoma is associated with a poorer prognosis, especially in patients undergoing sublobectomy. However, data on the sensitivity of frozen section (FS) evaluation of MIP is still limited. We included the concept of a filigree pattern on FS to assess its effect on the diagnostic sensitivity and specificity of MIP, and to verify its prognostic value in stage T1 lung adenocarcinoma. METHODS: A panel of five pathologists evaluated 125 patients with T1 lung adenocarcinoma from January to February 2014 as a study cohort, and 151 patients from January to February 2020 as a validation cohort. The diagnostic accuracy of the filigree and classical micropapillary (cMIP) pattern on FS was investigated. RESULTS: The diagnostic sensitivity of the MIP pattern on FS increased from 43.2% to 65.3% and 56.8% to 81.1% in the study cohort and validation cohort, respectively, and both with good specificity. Filigree not only increased the sensitivity of identifying MIP when there was an absence of cMIP, but also increased the sensitivity when the presence of a minor amount of cMIP. The almost perfect agreement among five pathologists was reached on cMIP and substantial agreement was reached on the filigree in the two cohorts. Moreover, the cMIP and filigree were both correlated with poorer recurrence-free survival (pcMIP = 0.003; pfiligree = 0.032) and overall survival (pcMIP = 0.004; pfiligree = 0.005). CONCLUSIONS: The identification of a filigree may improve the diagnostic sensitivity of the MIP pattern on FS. FS was feasible for the detection of filigree and cMIP patterns in stage T1 lung adenocarcinomas.

Morphological Subtypes of Tumor Spread Through Air Spaces in Non-Small Cell Lung Cancer: Prognostic Heterogeneity and Its Underlying Mechanism.

BACKGROUND: Tumor spread through air spaces (STAS) has three morphologic subtypes: single cells, micropapillary clusters, and solid nests. However, whether their respective clinical significance is similar remains unclear. METHODS: We retrospectively reviewed 803 patients with resected non-small cell lung cancer (NSCLC) from January to December 2009. Recurrence-free survival (RFS) and overall survival (OS) were compared among patients stratified by STAS subtypes. We also performed a prospective study of NSCLC resection specimens to evaluate the influence of a prosecting knife on the presence of STAS subtypes during specimen handling (83 cases). RESULTS: STAS was found in 370 NSCLCs (46%), including 47 single cell STAS (13%), 187 micropapillary cluster STAS (50%), and 136 solid nest STAS (37%). STAS-negative patients had significantly better survival than patients with micropapillary cluster STAS (RFS: P < 0.001; OS: P < 0.001) and solid nest STAS (RFS: P < 0.001; OS: P < 0.001), but similar survival compared with those with single cell STAS (RFS: P = 0.995; OS: P = 0.71). Multivariate analysis revealed micropapillary cluster (RFS: P < 0.001; OS: P < 0.001) and solid nest STAS (RFS: P = 0.001; OS: P = 0.003) to be an independent prognostic indicator, but not for single cell STAS (RFS: P = 0.989; OS: P = 0.68). Similar results were obtained in subgroup analysis of patients with adenocarcinoma. The prospective study of NSCLC specimens suggested that 18 cases were considered as STAS false-positive, and most were singe cell pattern (13/18, 72%). CONCLUSIONS: Single cell STAS was the common morphologic type of artifacts produced by a prosecting knife. A precise protocol of surgical specimen handling is required to minimize artifacts as much as possible.

Recognition of filigree pattern expands the concept of micropapillary subtype in patients with surgically resected lung adenocarcinoma.

Our study aimed to validate the clinicopathological characteristics and prognosis of lung adenocarcinoma (ADC) with a filigree pattern and to further investigate the relationship between the filigree pattern and the classical micropapillary (MP) pattern. We retrospectively reviewed the clinical and pathologic characteristics of 461 Chinese patients with completely resected ADC (stage I, 310; stage II, 44; stage III, 107). The filigree pattern was more likely to be observed in ADC with a higher stage (p = 0.003) and the classical MP pattern (p < 0.001). Patients with filigree-predominant ADC showed poor survival, similar to those with classical MP-predominant ADC. Multivariate analysis confirmed that the presence of the filigree pattern was an independent prognostic factor for recurrence-free survival (hazard ratio (HR), 2.01; 95% confidence interval (CI), 1.50-2.68; p < 0.001) and overall survival (OS; HR, 1.83; 95% CI, 1.34-2.50; p < 0.001). Patients with both classical MP-positive and filigree-positive ADC had the worst survival compared with those with the filigree pattern or classical MP pattern alone. In stage I, ADC with both the filigree and classical MP patterns had a higher incidence of micrometastasis than ADC with the filigree pattern or classical MP pattern alone. Lymph node micrometastasis indicated poor survival in patients with ADC with the filigree pattern or classical MP pattern. Similar clinicopathologic features between patients with the filigree pattern and the classical MP pattern support the inclusion of the filigree pattern in the MP category. Recognition of the filigree pattern could provide helpful prognostic information, especially for stage I ADC.

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.

Lepidic component identifies a subgroup of lung adenocarcinoma with a distinctive prognosis: a multicenter propensity-matched analysis.

BACKGROUND: Our aim was to investigate the prognostic impact of the lepidic component on T stage in patients with lung adenocarcinoma (LUAD). METHODS: A retrospective data set including 863 cases of LUAD with lepidic component and 856 cases without lepidic component was used to identify matched lepidic-positive and lepidic-negative cohorts (n = 376 patients per group) using a propensity-score matching. Primary outcome variables included recurrence-free survival (RFS) and overall survival (OS). Prognostic factors were assessed by Cox regression analysis and Kaplan-Meier estimates. RESULTS: Multivariate analysis revealed that lepidic component presence was an independent prognostic factor for prolonged RFS (p < 0.001) and OS (p < 0.001). Furthermore, lepidic ratio (LR) >25% or ⩽25% were confirmed to be independent prolonged survival predictors. No survival differences were observed between patients with LUAD with LR >25% or ⩽25% (RFS p = 0.333; OS p = 0.078). The 5-year OS rates of patients with LUAD with a lepidic component were 90% regardless of the T stage, and these survival rates were significantly better than those of patients with LUAD without a lepidic component in the corresponding T stage. Multivariate analysis confirmed that T stage was associated with survival only in patients with LUAD without a lepidic component. CONCLUSIONS: Lepidic component presence identifies a LUAD subgroup with an excellent prognosis independent of the LR, pathological T classification. Considering the lepidic component presence may improve prognostic predictions for patients with LUAD.

Genome-Wide Analysis of Lung Adenocarcinoma Identifies Novel Prognostic Factors and a Prognostic Score.

BACKGROUND AND OBJECTIVE: Lung adenocarcinoma (LUAD) is the most common histological type of all lung cancers and is associated with genetic and epigenetic aberrations. The tumor, node, and metastasis (TNM) stage is the most authoritative indicator of the clinical outcome in LUAD patients in current clinical practice. In this study, we attempted to identify novel genetic and epigenetic modifications and integrate them as a predictor of the prognosis for LUAD, to supplement the TNM stage with additional information. METHODS: A dataset of 445 patients with LUAD was obtained from The Cancer Genome Atlas database. Both genetic and epigenetic aberrations were screened for their prognostic impact on overall survival (OS). A prognostic score (PS) integrating all the candidate prognostic factors was then developed and its prognostic value validated. RESULTS: A total of two micro-RNAs, two mRNAs and two DNA methylation sites were identified as prognostic factors associated with OS. The low- and high-risk patient groups, divided by their PS level, showed significantly different OS (p < 0.001) and recurrence-free survival (RFS; p = 0.005). Patients in the early stages (stages I/II) and advanced stages (stages III/IV) of LUAD could be further subdivided by PS into four subgroups. PS remained efficient in stratifying patients into different OS (p < 0.001) and RFS (p = 0.005) when the low- and high-risk subgroups were in the early stages of the disease. However, there was only a significant difference in OS (p = 0.04) but not RFS (p = 0.2), between the low-risk and high-risk subgroups when both were in advanced stages. CONCLUSION: PS, in combination with the TNM stage, provides additional precision in stratifying patients with significantly different OS and RFS prognoses. Further studies are warranted to assess the efficiency of PS and to explain the effects of the genetic and epigenetic aberrations observed in LUAD.

Tumor Spread Through Air Spaces in Non-Small Cell Lung Cancer: A Systematic Review and Meta-Analysis.

BACKGROUND: A series of studies have assessed the clinicopathological features and prognostic impact of spread through air spaces (STAS) in non-small cell lung cancer (NSCLC) bringing conflicting findings so far. We performed a systematic review and meta-analysis to synthesize the available evidence regarding to the prognostic value of STAS in NSCLCs. METHODS: Studies were identified by searching databases including PubMed, EMBASE, Web of Science, and Cochrane Library up to August 2018 without language restrictions. Results of these searches were filtered according to a set of eligibility criteria and analyzed in line with PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. RESULTS: A total of 3,754 patients from 14 studies were selected for the present study. The pooled results suggested that presence of STAS was associated with worse recurrence-free survival (hazard ratio [HR], 1.975; 95% confidence interval [CI], 1.691 to 2.307; p < 0.001) and overall survival (HR, 1.75; 95% CI, 1.375 to 2.227; p < 0.001) in NSCLCs. Subgroup analysis by histology type indicated the presence of STAS was significantly associated with inferior recurrence-free survival in resected lung adenocarcinoma (n = 7; HR, 2.288; 95% CI, 1.843 to 2.840; I2 = 7.80%), lung squamous cell carcinoma (n = 3; HR, 1.622; 95% CI, 1.279 to 2.056; I2 = 0%), and lung pleomorphic carcinoma (n = 1; HR, 4.76; 95% CI, 1.168 to 19.398). Additionally, a number of clinicopathological characteristics indicating STAS in NSCLCs are summarized. CONCLUSIONS: Our study indicates that tumor STAS was a potentially significant prognostic predictor for surgical patients with NSCLCs. The prognostic impact of STAS present in the resection margin remains undetermined. Further large-scale prospective studies are warranted to confirm the prognostic significance of STAS in patients with NSCLCs.

A Proposal for Restaging of Invasive Lung Adenocarcinoma Manifesting as Pure Ground Glass Opacity.

BACKGROUND: Invasive lung adenocarcinoma (IAC) occurs in 22.8% to 40.4% of pure ground-glass opacity (GGO) cases. This study assessed the malignancy and survival outcomes of IAC manifesting as pure GGO with the aim of providing suggestions on T staging of these tumors. METHODS: From January 2010 to December 2012, the study focused on 109 cases of IAC that radiologically manifested as pure GGO. For comparison, 305 clinical stage IA part-solid IACs were also included. Clinicopathological characteristics, managements, and prognoses were evaluated. RESULTS: As compared with part-solid nodules, pure GGOs showed lower T stage, lower N stage, smaller invasive size, less invasive predominant components, and better survival. Long-term outcomes were independently influenced by whether the tumors presented as pure GGO. For the pure GGO group, the 5-year overall and disease-free survival rates were 100% and 99.1%, respectively. The pT stage, invasive size, and predominant component type did not influence survival. CONCLUSIONS: IAC radiologically manifesting as pure GGO is a group of tumors with low-grade malignancies and excellent prognosis. External validation is needed to assess whether it should be restaged in the TNM classification of non-small lung cancers.

Video-assisted thoracic surgery is an optimal alternative to conventional thoracotomy for reoperations for ipsilateral pulmonary lesions.

BACKGROUND: Ipsilateral pulmonary reoperation is empirically considered a contraindication of video-assisted thoracic surgery (VATS) because of intrapleural adhesion and the destruction of anatomical structures caused by previous surgery. The purpose of this study was to present our experience of the use of VATS for ipsilateral reoperations. METHODS: The medical records of patients who underwent VATS reoperation or re-thoracotomy between January 2006 and March 2017 were retrospectively reviewed. Data were compared to assess the feasibility and safety of VATS for ipsilateral reoperations. RESULTS: The study enrolled 64 patients, including 36 patients who underwent attempted ipsilateral VATS reoperations (VATS group) and 28 who underwent conventional re-thoracotomy as a control with clinicopathological characteristics similar to those in the VATS group. Intrapleural severe adhesions were detected in 28 (77.8%) and 22 (78.6%) patients in the VATS and re-thoracotomy groups, respectively (P = 0.906), and their dissection required a longer period in the VATS group (P = 0.014). VATS reoperations were converted to re-thoracotomy or video-assisted mini re-thoracotomy in three patients because of bleeding or difficulty in dissecting hilar structures. There were no significant differences in resection methods, time to reoperation, intraoperative blood loss, or drainage time between the two groups. However, patients in the VATS group had a shorter hospital stay (P < 0.01) and fewer complications (P = 0.042). CONCLUSION: VATS is an optimal alternative to re-thoracotomy for ipsilateral pulmonary lesions, regardless of intrapleural adhesions and the destruction of anatomical structures caused by former operations in selected patients.

Intraoperatively measured tumor size and frozen section results should be considered jointly to predict the final pathology for lung adenocarcinoma.

Invasive adenocarcinoma intraoperatively misdiagnosed as adenocarcinoma in situ or minimally invasive adenocarcinoma is more likely to undergo potentially insufficient resection. The purpose of our study was to evaluate the diagnostic accuracy of frozen section. We retrospectively reviewed 1,111 lung adenocarcinomas from January to March 2016 to evaluate the diagnostic performance of frozen section. A derivation cohort consisting of 436 cases of adenocarcinoma in situ or minimally invasive adenocarcinoma diagnosed by frozen section in the same period were analyzed to find predictive factors for invasive adenocarcinoma as the final diagnosis. Validation cohorts (first: April to June 2016, second: January to March 2015) were included to confirm the results. The overall concordance rate between frozen section and final diagnosis was 92%. Most frozen section errors were underestimation. The sensitivity of frozen section diagnosis for minimally invasive adenocarcinoma (74%) was significantly lower than others. Intraoperatively measured tumor size was the only independent factor for invasive adenocarcinoma as the final diagnosis (<1 cm: 2%, reference; 1-1.4 cm: 15%, odds ratio, 5.678; > 1.5 cm: 18%, odds ratio, 5.878; P = 0.001) in the derivation cohort, and was confirmed by validation cohorts. Fifty-nine misdiagnosed invasive adenocarcinomas in the three cohorts consisted of 54 lepidic predominant type, 1 papillary and 4 acinar predominant type. There were no positive N1, N2 node, pleural, lymphatic and vascular invasion cases found. Thirty-seven (37/59, 63%) cases of misdiagnosis were attributed to sampling error, which was the main reason. Our study suggests that adenocarcinoma in situ or minimally invasive adenocarcinoma ≥1 cm by frozen section were more likely to be invasive adenocarcinoma because of sampling error. Frozen section diagnosis of adenocarcinoma in situ or minimally invasive adenocarcinoma should be considered cautiously for tumors ≥1 cm to avoid potentially insufficient resection.

Relationship of Lymph Node Micrometastasis and Micropapillary Component and Their Joint Influence on Prognosis of Patients With Stage I Lung Adenocarcinoma.

This study aimed to investigate the relationship between lymph node micrometastasis and histologic patterns of adenocarcinoma, with a particular focus on their joint effect on prognosis. We retrospectively reviewed 235 patients with stage I adenocarcinoma from January 2009 to December 2009. Lymph node micrometastasis was evaluated by immunohistochemical staining for cytokeratin (AE1/AE3) and thyroid transcription factor-1. A logistic regression model was applied to confirm the predictive factors of micrometastasis. Survival analysis was performed to evaluate the effect of micrometastasis on prognosis. Lymph node micrometastasis was observed in 35 patients (15%). Patients with micrometastasis had significantly worse recurrence-free survival (P<0.001) and overall survival (P<0.001) compared with those without micrometastasis. Micropapillary component was confirmed as an independent predictor of increased frequency of micrometastasis (P<0.001). Among 62 patients with adenocarcinoma with a micropapillary component, 23 (37%) had lymph node micrometastasis. Micropapillary-positive/micrometastasis-positive patients had significantly worse survival compared with micropapillary-positive/micrometastasis-negative patients (RFS, P=0.039; OS, P=0.002) and micropapillary-negative patients (recurrence-free survival, P<0.001; overall survival, P<0.001). Moreover, the presence of micrometastasis correlated with a higher risk of locoregional recurrence (P=0.031) rather than distant recurrence (P=0.456) in micropapillary-positive patients. In summary, lymph node micrometastasis was more frequently observed in adenocarcinoma with a micropapillary component. Moreover, lymph node micrometastasis could provide helpful prognostic information in patients with resected stage I lung adenocarcinoma with a micropapillary component; thus, immunohistochemical detection of micrometastatic tumor cells in lymph nodes should be recommended.

Tumor Spread through Air Spaces Affects the Recurrence and Overall Survival in Patients with Lung Adenocarcinoma >2 to 3 cm.

OBJECTIVES: Tumor spread through air spaces (STAS) is a novel invasive pattern in lung adenocarcinoma (ADC). The effects of the combination of STAS and tumor size on survival have not been well studied. METHODS: A total of 383 patients with ADC 3 cm or smaller (stage IA) and 161 patients with stage IB ADC were identified from 2009 to 2010. Recurrence-free survival (RFS) and overall survival (OS) were compared between patients as stratified by STAS and tumor size. A validation cohort was included in this study. RESULTS: STAS was observed in 116 ADCs 3 cm or smaller (30.3%). In cases involving ADCs 3 cm or smaller, patients with STAS had worse RFS (p = 0.006) and OS rates (p < 0.001) than those without STAS. Furthermore, comparable RFS (p = 0.091) and OS (p = 0.443) rates were observed in patients with ADCs 3 cm or smaller with STAS present and those with stage IB ADC. Multivariate analysis revealed STAS to be an independent prognostic factor in ADCs 3 cm or smaller (RFS, p = 0.043; OS, p = 0.009). Among patients with ADCs larger than 2 to 3 cm, STAS still stratified the prognosis. Moreover, the unfavorable prognosis of patients with ADCs larger than 2 to 3 cm with STAS present was similar to that of patients with stage IB ADC. Among patients with ADCs 2 cm or smaller, STAS failed to stratify the prognosis significantly. Similar results were obtained in the validation cohort. CONCLUSIONS: These results provide preliminary evidence that STAS could be considered as a factor in a staging system to predict prognosis more precisely, especially in ADCs larger than 2 to 3 cm.

3-(4-Hy-droxy-3-meth-oxy-phen-yl)acrylic acid-2,3,5,6-tetra-methyl-pyrazine (2/1).

The asymmetric unit of the title compound, C(8)H(12)N(2)·2C(10)H(10)O(4), contains a tetra-methyl-pyrazine mol-ecule, situated about an inversion center, and two substituted acrylic acid derivatives. The dihedral angle between the phenyl and pyrazine rings is 69.45 (9)°. In the crystal, inter-molecular O-H⋯O, O-H⋯N hydrogen bonds and weak C-H⋯O inter-actions lead to the formation of a supra-molecular network. The acrylic acid side chain is positionally disordered [occupancy ratio 0.852 (7):0.148 (7)].

(3aRS,4SR,7RS,7aSR)-2-(Tricyclo-[3.3.1.1]decan-1-yl)-4,5,6,7-tetra-hydro-4,7-epoxy-isoindoline-1,3-dione.

The title compound, C(18)H(23)NO(3), the adamantane derivative of norcantharidin, which is itself derived from cantharidin, crystallized with three independent mol-ecules in the asymmetric unit. In the crystal, mol-ecules are linked by inter-molecular C-H⋯O inter-actions, leading to the formation of a supra-molecular two-dimensional network.