EGFR and ERBB2 Exon 20 Insertion Mutations in Chinese Non-small Cell Lung Cancer Patients: Pathological and Molecular Characterization, and First-Line Systemic Treatment Evaluation.

BACKGROUND: Data from studies looking at both EGFR and ERBB2 exon 20 insertion mutations (-20ins) in the same cohort of patients with non-small cell lung cancer (NSCLC) are limited. OBJECTIVE: The purpose of this study was to analyze EGFR/ERBB2-20ins in all-stage NSCLC patients to reveal their histological and molecular features, and to retrospectively evaluate the results of first-line real-world systemic treatments in patients with advanced-stage disease. PATIENTS AND METHODS: We collected 13,920 formalin-fixed paraffin-embedded NSCLC specimens. Clinicopathological features were recorded and DNA-based next-generation sequencing was performed. First-line systemic treatment data were obtained via chart review. RESULTS: In total, 414 (2.97%) EGFR-20ins cases and 666 (4.78%) ERBB2-20ins cases were identified. Both were more common in women, non-smokers, and patients with adenocarcinoma. The incidence of EGFR/ERBB2-20ins in adenocarcinoma is inversely proportional to the degree of invasion; 77 and 26 variants were detected in EGFR-20ins and ERBB2-20ins cases, respectively. The most common concurrently mutated genes were TP53 and RB1. In invasive adenocarcinoma, lepidic components were more common in EGFR/ERBB2-20ins-alone cases than in those with other concurrent mutated genes. In EGFR-/ERBB2-20ins patients, there was no significant difference in progression-free survival (PFS) or treatment response to first-line systemic treatments in this study. There was no significant difference in PFS or treatment response among patients with different EGFR/ERBB2-20ins variants and those with or without concurrent mutated genes. CONCLUSIONS: EGFR/ERBB2-20ins is more common in early lung adenocarcinoma. EGFR-20ins had more variants. In both cohorts, the results for first-line systemic treatments showed no significant difference.

Two-year outcomes of clinical N2-3 esophageal squamous cell carcinoma after neoadjuvant chemotherapy and immunotherapy from the phase 2 NICE study.

OBJECTIVE: This study aims to report the 2-year outcomes of patients with clinical stage N2-3 esophageal squamous cell carcinoma who received neoadjuvant chemotherapy and immunotherapy followed by surgery from a phase 2 NICE trial. METHODS: Eligible patients with clinical stage N2-3 esophageal squamous cell carcinoma were screened and enrolled, then treated with regimen of nab-paclitaxel (100 mg/m2, days 1, 8, 15), carboplatin (area under the curve = 5, day 1), camrelizumab (200 mg, day 1) of two 21-day cycles and esophagectomy 4 to 6 weeks after the last chemotherapy. Oncologic outcomes, recurrence patterns, overall survival (OS), and recurrence-free survival (RFS) were explored. RESULTS: From November 20, 2019, to December 22, 2020, 60 patients were recruited. After a median follow-up of 27.4 months, disease recurrence was observed in 19 (37.3%) patients, with 5 (9.8%) locoregional recurrence, 9 (17.6%) distant metastasis, and 5 (9.8%) combined recurrence. Lung was the most commonly involved metastatic site. The median time to recurrence was 10.8 months (interquartile range, 7.5-12.7 months). The 2-year OS and RFS rates were 78.1% and 67.9%, respectively. Patients who achieved major pathologic response (MPR) had a significantly greater 2-year OS rate (91.4% vs 47.7%; P < .001) and RFS rate (77.1% vs 45.9%; P = .003). On multivariable analysis, MPR was indicated as an independent prognostic factor for disease recurrence (hazard ratio, 0.39; 95% confidence interval, 0.21-0.82; P = .029). CONCLUSIONS: In patients receiving neoadjuvant chemotherapy and immunotherapy, distant metastasis remains the predominant recurrence pattern. MPR is associated with lower recurrence and better survival. Long-term results derived from randomized controlled trials are further required. TRIAL REGISTRATION NUMBER: ChiCTR1900026240.

Single-cell profiling reveals the trajectory of FOLR2-expressing tumor-associated macrophages to regulatory T cells in the progression of lung adenocarcinoma.

An immunosuppressive microenvironment enriched with regulatory CD4+ T lymphocytes (Tregs) facilitates the progression of lung adenocarcinoma (LUAD). This study aims to investigate the cellular mechanism underlying the formation of the immunosuppressive microenvironment in LUAD. LUAD samples (n = 12) and normal lung samples (n = 3) were obtained from patients with different pathological stages of LUAD. Single-cell RNA sequencing was performed to classify cellular components and analyze the transcriptomes, including transcription factors/targets and chemokine ligands/receptors, followed by bioinformatics study such as pseudotime analysis. Myeloid cells and T cells were the most abundant cell types in tumors and normal lung tissues, while tumor-associated macrophage-folate receptor 2 (TAM-FOLR2) and CD4+ nuclear receptor subfamily 4 group A member 3 (NR4A3) exhibited sharp increases in invasive adenocarcinoma (IA). The enrichment of TAM-FOLR2 in IA might result from alveolar resident macrophage-resistin (ARM-RETN) transformation and recruitment of dendritic cells (DCs) and other TAMs, as evidenced by temporal trajectories and differential expression profiles of chemokine ligands/receptors versus those in the early stages of tumors. High expression of CCL17/19/22 was observed in IA as well as in DCs, along with the strong interaction of TAM-FOLR2 with DCs. The results of pseudotime analysis suggested that CD4+NR4A3 might potentially convert to CD4+FOXP3, further supported by the high expression of NR4A3 target genes in CD4+FOXP3 cells. This study provides a single-cell transcriptome atlas from preinvasive to invasive LUAD and reveals a potential ARM-RETN/TAM-FOLR2/DCs/CD4+NR4A3/CD4+FOXP3 trajectory in shaping the immune suppressive microenvironment along the pathogenesis of LUAD.

Patterns of Recurrence After Robot-Assisted Minimally Invasive Esophagectomy in Esophageal Squamous Cell Carcinoma.

Robot-assisted minimally invasive esophagectomy (RAMIE) has been proven to be a feasible surgical approach for esophageal squamous cell carcinoma (ESCC). This study aimed to investigate the recurrence pattern and potential risk factors after RAMIE. Consecutive patients with ESCC who received RAMIE with McKeown technique at a single Esophageal Cancer Institute from November 2015 to September 2018 were retrospectively reviewed. Patients with available data, radical resection (R0), and a minimum 2-year follow-up period were eligible for the recurrence analysis. Risk factors of recurrence were examined by logistic regression analysis. R0 resection was achieved in 95.1% of patients (310/326). Of the 298 eligible patients with a median follow-up period of 30.6 months, recurrence was recognized in 95 patients (31.9%), with 4 (1.3%) local-only, 40 (13.4%) regional-only, 44 (14.8%) hematogenous-only and 7 (2.3%) combined recurrences. Cervical lymph nodes and lungs were the most frequent sites of regional and hematogenous recurrence, respectively. The median disease-free interval until recurrence was 12.1 (range 1.7-37.6) months and 83.2% of relapses occurred within 2 years after surgery. Multivariable analysis indicated that tumor in the upper esophagus, larger tumor length and positive lymph nodes as independent risk factors for recurrence. Hematogenous recurrence is the prevailing pattern after RAMIE for ESCC. For patients with advanced disease, neoadjuvant therapy is a key factor in reducing recurrence rather than surgical approaches.

Identification and therapeutic evaluation of ALK rearrangements in non-small-cell lung cancer.

This study aimed to present a comprehensive assessment of anaplastic lymphoma kinase (ALK) rearrangements evaluated by DNA/RNA-based next-generation sequencing (NGS) and Ventana immunohistochemistry (IHC) in patients with non-small-cell lung cancer (NSCLC) and to evaluate the therapeutic outcomes of ALK tyrosine kinase inhibitor (TKI) treatment. We investigated ALK gene fusions in 14,894 patients with NSCLC using Ventana IHC and NGS, including 12,533 cases detected via DNA-based NGS and 2,361 cases using RNA-based NGS. The overall percentage agreement (OPA), positive percentage agreement (PPA), and negative percentage agreement (NPA) were calculated when comparing the results between NGS and IHC. The therapeutic responses to ALK-TKIs were also evaluated. In total, 3.50% (439/12,533) of specimens were NGS ALK-positive (NGS-p) in the DNA-based NGS cohort and 3.63% (455/12,533) were IHC ALK-positive (IHC-p). The OPA of NGS was 99.60%, whereas its PPA and NPA were 92.75 and 99.86%, respectively. In the adenocarcinoma (ADC) subcohort, the PPA was 95.69%. In the RNA-based NGS cohort, 2.20% (52/2,361) of specimens were NGS-p and 2.63% (62/2,361) were IHC-p. The OPA of NGS was 99.49%; its PPA and NPA were 82.26 and 99.96%, respectively. Thirteen patients with discordant results received ALK-TKI treatment. In the seven NGS-p/IHC-negative (IHC-n) patients, the overall response rate (ORR) was 85.4% (6/7) and the disease control rate (DCR) was 100%. In the six NGS-negative/IHC-p patients, the ORR was 66.7% (4/6) and the DCR was 100%. In summary, a high concordance of ALK gene fusion detected via NGS and IHC was observed in this study. DNA-based NGS had a higher OPA, PPA, and PPA in the ADC subcohort, whereas RNA-based NGS had a higher NPA. Overall, the results suggest that the combination of NGS and IHC can improve the accuracy of ALK fusion detection; hence, a result determination algorithm for clinical detection of ALK gene fusion was also proposed.

Three-arm phase II trial comparing camrelizumab plus chemotherapy versus camrelizumab plus chemoradiation versus chemoradiation as preoperative treatment for locally advanced esophageal squamous cell carcinoma (NICE-2 Study).

BACKGROUND: Preoperative chemoradiotherapy (CRT) with CROSS regimen has been the recommended treatment for locally advanced esophageal squamous cell carcinoma (ESCC). The addition of programmed cell death protein 1 (PD-1) inhibitor to preoperative CRT may further improve oncologic results. Preoperative camrelizumab plus chemotherapy has been demonstrated as a promising treatment modality based on results of the phase II NICE study (ChiCTR1900026240). METHODS: The NICE-2 study is designed as a three-arm, multicenter, prospective, randomized, phase II clinical trial, comparing camrelizumab plus chemotherapy (IO-CT) and camrelizumab plus CRT (IO-CRT) versus CRT as preoperative treatment for locally advanced ESCC. A total of 204 patients will be recruited from 8 Chinese institutions within 1.5 years. The primary endpoint is pathological complete response (pCR) rate and secondary endpoints include event-free survival (EFS), R0 resection rate, and adverse events. DISCUSSION: This is the first prospective randomized controlled trial to explore commonly used neoadjuvant treatments in clinical practice, which will provide high-level evidence of neoadjuvant treatment for patients with locally advanced ESCC. The purpose of this study is to establish the optimal modality of IO-CT, IO-CRT and CRT as preoperative treatment for locally advanced ESCC. The Institution Review Committee approved this study protocol in August 2021 and patient enrollment was started in September 2021. TRIAL REGISTRATION: ClinicalTrial.gov: NCT05043688 (August 29, 2021). The trial was prospectively registered.

Multicenter, single-arm, phase II trial of camrelizumab and chemotherapy as neoadjuvant treatment for locally advanced esophageal squamous cell carcinoma.

BACKGROUND: Camrelizumab and chemotherapy demonstrated durable antitumor activity with a manageable safety profile as first-line treatment in patients with advanced esophageal squamous cell carcinoma (ESCC). This study aimed to evaluate the safety and efficacy of camrelizumab plus neoadjuvant chemotherapy, using pathologically complete response (pCR) as primary endpoint, in the treatment for locally advanced ESCC. METHODS: Patients with locally advanced but resectable thoracic ESCC, staged as T1b-4a, N2-3 (≥3 stations), and M0 or M1 lymph node metastasis (confined to the supraclavicular lymph nodes) were enrolled. Eligible patients received intravenous camrelizumab (200 mg, day 1) plus nab-paclitaxel (100 mg/m2, day 1, 8, 15) and carboplatin (area under curve of 5 mg/mL/min, day 1) of each 21-days cycle, for two cycles before surgery. The primary endpoint is pCR rate in the per-protocol population. Safety was assessed in the modified intention-to-treat population that was treated with at least one dose of camrelizumab. RESULTS: From November 20, 2019 to December 22, 2020, 60 patients were enrolled. 55 (91.7%) patients completed the full two-cycle treatment successfully. 51 patients underwent surgery and R0 resection was achieved in 50 (98.0%) patients. pCR (ypT0N0) was identified in 20 (39.2%) patients and 5 (9.8%) patients had complete response of the primary tumor but residual disease in lymph nodes alone (ypT0N+). 58 patients (96.7%) had any-grade treatment-related adverse events (TRAEs), with the most common being leukocytopenia (86.7%). 34 patients (56.7%) had adverse events of grade 3 or worse, and one patient (1.7%) occurred a grade 5 adverse event. There was no in-hospital and postoperative 30-day as well as 90-day mortality. CONCLUSIONS: The robust antitumor activity of camrelizumab and chemotherapy was confirmed and demonstrated without unexpected safety signals. Our findings established camrelizumab and chemotherapy as a promising neoadjuvant treatment for locally advanced ESCC. TRIAL REGISTRATION NUMBER: ChiCTR1900026240.

Occurrence and Prognostic Value of Perineural Invasion in Esophageal Squamous Cell Cancer: A Retrospective Study.

OBJECTIVE: The aim of this study was to explore the occurrence and prognostic value of perineural invasion (PNI) as a classic tumor pathological feature in esophageal squamous cell carcinoma (ESCC). METHODS: We retrospectively enrolled 794 ESCC patients who underwent radical esophagectomy at Shanghai Chest Hospital from 2017 to 2018. The incidence, associated factors, and prognosis of PNI were analyzed. RESULTS: PNI was identified in 15.7% (125/794) of patients. The presence of PNI was significantly associated with depth of invasion (p < 0.001), pN stage (p = 0.008), tumor stage (p < 0.001), and lymphovascular invasion (LVI; p < 0.001). Multivariate logistic regression analysis demonstrated that advanced pT stage and LVI were independently associated with the presence of PNI, while multivariate Cox regression analysis demonstrated that PNI was not an independent risk factor for poor overall survival (OS) or recurrence-free survival (RFS) in ESCC patients (OS hazard ratio [HR] 0.688, 95% confidence interval [CI] 0.448-1.056, p = 0.087; RFS HR 0.837, 95% CI 0.551-1.273, p = 0.406). In the PNI-positive patient subgroup, adjuvant therapy was associated with better OS and RFS. CONCLUSION: PNI correlates with, and may be a concomitant consequence of, LVI and advanced tumor invasion (T3-4) in ESCC patients. Although PNI was not identified as an independent prognostic indicator, our results suggest ESCC patients with PNI should be considered for adjuvant therapy.

YAP1-MAML2 Fusion as a Diagnostic Biomarker for Metaplastic Thymoma.

BACKGROUND: Metaplastic thymoma is a very rare tumor with only a few case reports documented in literature. Hence, its molecular features have not been well explored. MATERIAL AND METHODS: Seventeen specimens of metaplastic thymoma were sequenced and retrospectively analyzed by fluorescence in situ hybridization (FISH) and immunohistochemistry in the study. In addition, seven cases of micronodular thymoma with lymphoid stroma and nine cases of type A thymoma were also investigated. RESULTS: Among these metaplastic thymomas, fifteen cases showed classical histological features, and two cases displayed characteristic micronodular-like growth patterns. DNA and RNA based next-generation sequencing identified and confirmed highly recurrent Yes Associated Protein 1 (YAP1) - Mastermind Like Transcriptional Coactivator 2 (MAML2) translocation (13/17, 76.5%) in metaplastic thymoma but not in micronodular thymoma with lymphoid stroma (0/7, 0%) and type A thymoma (0/9, 0%). In addition, six nonsense mutations were also detected in the metaplastic thymoma. FISH in microdissection specimens indicated that both epithelioid and spindle cell components harbored YAP1-MAML2 gene rearrangements. CONCLUSIONS: Our study explored the genetic alterations in epithelioid and spindle cell components in metaplastic thymoma. Furthermore, YAP1-MAML2 gene rearrangements emerged as a potential diagnostic biomarker helpful for distinguishing metaplastic thymoma from type A and micronodular thymoma with lymphoid stroma.

Challenging of frozen diagnoses of small sclerosing pneumocytoma.

AIMS: An increasing number of small pulmonary nodules are being screened by CT, and an intraoperative diagnosis is necessary for preventing excessive treatment. However, there is limited literature on the frozen diagnosis of small sclerosing pneumocytomas (SPs). In particular, tumours smaller than 1 cm are challenging for pathologists performing intraoperative frozen diagnosis. METHODS: In total, 230 cases of SP were surgically resected between January 2015 and March 2019 at Shanghai Chest Hospital, and of them, 76 cases were smaller than 1 cm. The histology and clinical information of these 76 cases (33.0%, 76/230) were reviewed retrospectively, 54 cases of which were diagnosed intraoperatively, and the pitfalls were summarised. All diagnoses were confirmed on permanent sections and immunohistochemical sections. RESULTS: Histologically, 78.9% (60/76) of the small SP was dominated by one growth pattern, and solid and papillary growth pattern were the most commonly misdiagnosed circumstances. The rate of intraoperative misdiagnosis of these SP smaller than 1 cm was 11.1% (6/54). CONCLUSIONS: The main reason for misdiagnosis was failure to recognise the dual cell populations and the cellular atypia. Diagnostic clues include the gross morphology, the presence of dual-cell populations and a hypercellular papillary core, foam cell accumulation in glandular spaces and haemorrhage and haemosiderin on the periphery. In spite of awareness of pitfalls some cases may still be essentially impossible to diagnose on frozen section.

Identification of NTRK gene fusions in lung adenocarcinomas in the Chinese population.

The molecular profile of neurotrophic tyrosine kinase receptor (NTRK) gene fusions in lung adenocarcinoma (LUAD) is not fully understood. Next-generation sequencing (NGS) and pan-tyrosine kinase receptor (TRK) immunohistochemistry (IHC) are powerful tools for NTRK fusion detection. In this study, a total of 4,619 LUAD formalin-fixed, paraffin-embedded tissues were collected from patients who underwent biopsy or resection at the Shanghai Chest Hospital during 2017-2019. All specimens were screened for NTRK1 rearrangements using DNA-based NGS. Thereafter, the cases with NTRK1 rearrangements and cases negative for common driver mutations were analyzed for NTRK1/2/3 fusions using total nucleic acid (TNA)-based NGS and pan-TRK IHC. Overall, four NTRK1/2 fusion events were identified, representing 0.087% of the original sample set. At the DNA level, seven NTRK1 rearrangements were identified, while only two TPM3-NTRK1 fusions were confirmed on TNA-based NGS as functional. In addition, two NTRK2 fusions (SQSTM1-NTRK2 and KIF5B-NTRK2) were identified by TNA-based NGS in 350 'pan-negative' cases. Two patients harboring NTRK1/2 fusions were diagnosed with invasive adenocarcinoma, while the other two were diagnosed with adenocarcinoma in situ and minimally invasive adenocarcinoma. All four samples with NTRK fusions were positive for the expression of pan-TRK. The two samples with NTRK2 fusions showed cytoplasmic staining alone, while the other two samples with NTRK1 fusions exhibited both cytoplasmic and membranous staining. In summary, functional NTRK fusions are found in early-stage LUAD; however, they are extremely rare. According to this study's results, they are independent oncogenic drivers, mutually exclusive with other driver mutations. We demonstrated that NTRK rearrangement analysis using a DNA-based approach should be verified with an RNA-based assay.

Morphological, immunohistochemical, and genetic analyses of bronchiolar adenoma and its putative variants.

We collected 26 cases of bronchiolar adenoma (BA) and its variants, and performed a comprehensive characterization using a combination of morphological, immunohistochemical, and genetic assessments. Of these 26, 13 were classic bilayered cases, including 10 proximal and 3 distal-type BAs. Of note, we also identified 13 cases that lacked a continuous basal cell layer. In five cases, the adenomas were partially classic bilayered, leaving a single layer of columnar or cuboidal epithelial cells in some areas of the lesion (BA with monolayered cell lesions). In the other eight cases, the glandular or papillary structures were entirely composed of monolayered columnar or cuboidal epithelial cells, which were morphologically identical to the luminal epithelial cells of classic BA (monolayered BA-like lesions). Immunohistochemical analysis revealed thyroid transcription factor 1 expression by ciliated columnar epithelial cells, basal cells, and nonciliated columnar and cuboidal epithelial cells. Basal cells also expressed p40 and p63. Twenty-five cases underwent next-generation sequencing using a 422-cancer-gene panel (GeneseeqPrime). Oncogenic driver mutations were detected in 23 cases, including 13 (52%) with EGFR mutations, 4 (16%) with KRAS G12D/V mutations, 3 (12%) with BRAF V600E mutations, 2 (8%) with ERBB2 exon 20 insertions, and 1 (4%) with a RET fusion. EGFR exon 20 insertions were present in 100% of BAs with monolayered cell lesions, 37.5% of monolayered BA-like lesions, and 8% of classic BA (Fisher's exact test, p = 0.002, false discovery rate = 0.014). Collectively, our study revealed a gradual morphological transition between BA and its variants. The genetic composition of BAs with monolayered structures differed significantly from those of classic BAs or lung adenocarcinoma.

An effective inflation treatment for frozen section diagnosis of small-sized lesions of the lung.

BACKGROUND: The accuracy of intraoperative pathological diagnosis of small-sized pulmonary nodules including ground-glass opacity (GGO) is important for the surgeon to choose a suitable surgical procedure. Diagnosis of the small-sized lesions of the lung by frozen section (FS) is very difficult for the pathologist because of limited FS technology. Here we tested an effective inflation treatment for FS to improve the diagnostic accuracy of small-sized lung lesions. METHODS: The lung specimens were derived from 113 patients who underwent the surgery at Shanghai Chest Hospital in 2018-2019. The specimens were randomly divided into two groups-uninflated or inflated with diluted embedding medium (Tissue-Tek OCT; Sakura Finetek-USA, CA). The qualities of the FSs were compared with that of corresponding permanent paraffin sections. The FS diagnoses were compared with the final pathologic diagnoses of corresponding permanent sections. RESULTS: Our results showed that the quality of FS of lung tissue was excellent after inflation with diluted embedding medium (1:1). The total consistency between diagnosis of inflated FS and final pathological diagnosis was 85.7%. In control group, however, the consistency was only 70.2%. When the lesions were less than 1cm, the consistency between diagnosis of inflated FS and final pathological diagnosis was 90.3%, compared to 64.9% consistency in uninflated group (P=0.014, <0.05). When the lesions' computed tomography (CT) measurement threshold ≤-350 HU, the consistency between diagnosis of inflated FS and final pathological diagnosis was 88% compared to 73.2% consistency in uninflated group (P=0.071, >0.05). Accuracy, sensitivity and specificity were observed about 90% for adenocarcinoma in situ (AIS), whereas it is drop to more than 80% for minimally invasive adenocarcinoma (MIA) in inflated FS. CONCLUSIONS: Inflation with diluted embedding medium (1:1) could make lung tissue expand well during FS. By using this method, small-sized lesions (especially less than 1 cm) could be correctly diagnosed to enable adequate surgical procedure, and evaluation of which can be easily based on the intraoperative pathological diagnosis. The small lesions especially AIS could be readily identified on FS. Therefore, this method improves the diagnostic accuracy of FSs for small-sized lung lesions, and has important practical consequences for further therapy.

Thoracic solitary fibrous tumors: an analysis of 70 patients who underwent surgical resection in a single institution.

BACKGROUND: Thoracic solitary fibrous tumors (TSFTs) are uncommon mesenchymal tumors. The data regarding surgical outcomes and prognostic factors are scarce. This retrospective paper is to analyze surgical outcomes, clinical characteristics and prognosis of TSFT. METHODS: A single-center retrospective study of the data of 70 patients with TSFT who underwent surgical resection in our department between August 2008 and October 2014 was conducted. RESULTS: A total of 70 TSFTs (58 benign, 12 malignant) were included and all patients underwent complete surgical resection except one recurrent patient with initial treatment. TSFTs originated from the pleura (n = 43), lung (n = 9), mediastinum (n = 16), esophagus (n = 1) and diaphragm (n = 1), respectively. Mass excision was only performed in 29 patients, en bloc excision including surrounding structures was performed in 41 patients. During follow-up, no tumor recurrence occurred in benign TSFT patients. All recurrences occurred in 6 malignant patients, and 5 of them died because of local recurrence and distant metastasis. Median follow-up was 95 months (range, 3-133 months). The 5-year overall survival (OS) of TSFT patients was 94.3%. The 5-year relapse-free survival and OS of malignant TSFT patients were 58.3% and 66.7%, respectively. CONCLUSION: The gold standard of TSFT treatment is complete surgical resection. VATS is safe and reliable for treating selected TSFT patients. Aggressive surgical resection could be underwent in such patients of local recurrence or solitary metastatic tumor. A long-term follow-up is necessary due to the risk of recurrence.

Micropapillary pattern is associated with the development of brain metastases and the reduction of survival time in EGFR-mutation lung adenocarcinoma patients with surgery.

OBJECTIVE: The role of micropapillary pattern (MIP) in EGFR-mutated NSCLC patients with brain metastases (BM) after complete surgical resection still remains unclear. Therefore, a retrospective study was conducted to evaluate the role of MIP in those patients. METHODS: This study included 332 stage I-III patients with EGFR-mutant lung adenocarcinoma and complete resection. Patients were classified in four groups: the MIP-positive patients without BM development, the MIP-negative patients without BM development, the MIP-positive patients with BM development and the MIP-negative patients with BM development. Intracranial disease-free survival (iDFS), systemic disease-free survival (DFS) and overall survival (OS) were evaluated. RESULTS: The median OS in the whole group was 70 months. The patients with MIP show inferior DFS (13 months vs. 22 months; P < 0.001) and OS (56 months vs. 74 months; P < 0.001). Furthermore, BM development was more likely to be found in patients with MIP (P = 0.001). In addition, the MIP-positive patients showed a significantly shorter iDFS compared with MIP-negative patients (14.5 months vs. 26 months; P < 0.001). Furthermore, the MIP-positive patients had significantly inferior iDFS in both BM as first line development groups (13 months vs. 19 months; P < 0.001) and BM as non-first line development groups (18 months vs. 33 months; P = 0.007). CONCLUSIONS: MIP was related to the earlier recurrence and shortened survival time. In addition, MIP was an independent poor prognostic factor for the increase of BM rate and the shortened time of BM development after surgery.

Clinicopathological Features of ALK Expression in 9889 Cases of Non-small-Cell Lung Cancer and Genomic Rearrangements Identified by Capture-Based Next-Generation Sequencing: A Chinese Retrospective Analysis.

BACKGROUND: The clinicopathological features and genomic rearrangements of anaplastic lymphoma kinase (ALK) fusion cases have not been fully identified. OBJECTIVE: Our objective was to explore the status of ALK in non-small-cell lung cancer (NSCLC) specimens, to explore the relationships between ALK status and clinicopathological features and to identify genomic rearrangements via capture-based next-generation sequencing (NGS). METHODS: We tested 9889 NSCLC specimens for ALK status using the Ventana anti-ALK (D5F3) antibody. Clinicopathological features were analyzed and genomic rearrangements identified using capture-based NGS in 76 ALK-positive cases. RESULTS: In total, 485 specimens (4.90%) tested positive for ALK. The positivity rate was higher for adenocarcinoma samples than for non-adenocarcinoma samples (6.03 vs. 1.47%; p < 0.001) and for biopsies/cell blocks than for surgical specimens (7.00 vs. 4.16%; p < 0.001). Patient age, patient sex, specimen type, specimen histotype, and patient smoking history were all significantly correlated with ALK status. Genomic rearrangements were detected in 98.68% (75/76) of the ALK-positive samples; 89.33% (67/75) carried the canonical EML4-ALK, and the remaining samples carried only noncanonical ALK rearrangements. Four of these noncanonical ALK fusion samples were identified as carrying EML4-ALK transcripts at the RNA level. A novel fusion variant, SRD5A2-ALK, was revealed. CONCLUSIONS: Younger patients with NSCLC, especially those aged < 30 years, were more likely to test positive for ALK. Positive ALK test results were more common in patients with invasive mucinous adenocarcinoma and solid-predominant invasive adenocarcinoma than in patients with other histotypes. Samples that carried only noncanonical ALK rearrangements may also have carried the canonical EML4-ALK, which was not detected by capture-based NGS. EML4-ALK transcripts might result from rare splicing mechanisms without genomic rearrangements.

Differential diagnosis of pulmonary enteric adenocarcinoma and metastatic colorectal carcinoma with the assistance of next-generation sequencing and immunohistochemistry.

PURPOSE: Pulmonary enteric adenocarcinoma (PEAC), defined as tumors with an enteric component exceeding 50% and a histological morphology similar to colorectal cancer (CRC) and metastatic colorectal carcinoma (MCC), is an extremely rare primary lung adenocarcinoma, which was recently recognized by World Health Organization (WHO). Adenocarcinomas with intestinal differentiation have also been described in other anatomic sites, including paranasal sinuses, extrahepatic biliary tree, uterine and cervix, ovary. The morphologic spectrum and immunohistochemical profiles of PEAC overlap with those of colonic adenocarcinomas, the diagnosis of PEAC remains challenging. Currently, colonoscopy has to be performed to confirm the diagnosis, resulting in low compliance due to its invasiveness. Due to the rareness of PEAC, its molecular signature has not been comprehensively examined. METHODS: In this study, we investigated the molecular signatures associated with PEAC and its histological counterparts, CRC and MCC using capture-based targeted sequencing. RESULTS: We revealed that 12/13 (92.31%) PEAC patients harbored mutations in well-established driver genes for non-small cell lung cancer and none of them had mutations unique to CRC. Furthermore, 13/15 (86.7%) of MCC harbored mutations that are frequently seen in CRC. CONCLUSION: Collectively, our study showed that PEAC, exhibiting a similar mutational profile with NSCLC, showed a distinctive signature from CRC and MCC. Furthermore, we derived a classification model, intergrading both IHC markers and genetic signature, to accurately diagnose PEAC.

Analysis of the Clinicopathologic Characteristics of Lung Adenocarcinoma With CTNNB1 Mutation.

INTRODUCTION: Lung adenocarcinoma with CTNNB1 mutation is relatively uncommon, and its clinicopathologic characteristics, disease course, and prognosis have not been well-studied. METHODS: A total of 564 lung adenocarcinoma patients were enrolled in this study. The relationship between CTTNB1 mutational status and clinicopathologic parameters, the rates of relapse-free survival (RFS) and overall survival (OS), and the mutational status of other genes commonly mutated in lung adenocarcinoma were analyzed. RESULTS: Of 564 lung adenocarcinoma patients, 30 (5.3%) harbored CTNNB1 mutations. Univariate analyses revealed that gender, smoking history, pleural invasion, and histological subtype were all significant predictors of RFS and OS. Pleural invasion and histological subtype remained significant predictors of RFS and OS in a multivariate analysis. There were no significant differences in RFS (p = 0.504) or OS (p = 0.054) between lung adenocarcinoma patients with CTNNB1 mutation and those without CTNNB1 mutation. However, patients with CTNNB1 mutation tended to have a worse OS. CONCLUSIONS: Female patients and nonsmokers are likely to harbor CTNNB1 mutation and primary lung adenocarcinoma with mutated CTNNB1 has a poor prognosis.