Lepidic Pattern Research Articles

Epstein-Barr Virus-Associated Pulmonary Carcinoma: Proposing an Alternative Term and Expanding the Histologic Spectrum of Lymphoepithelioma-like Carcinoma of the Lung.

Lymphoepithelioma-like carcinoma (LELC) of the lung is a rare Epstein-Barr virus (EBV)-associated carcinoma. It is histologically characterized by a syncytial growth pattern with marked lymphocytic infiltration that is indistinguishable from the histology observed in undifferentiated nasopharyngeal carcinomas. However, it has been noted that LELC can display nonclassic morphology and lack significant lymphocytic infiltration. In this study, we conducted a comprehensive clinicopathologic analysis of 61 patients with pulmonary LELC and performed automatic quantification of the lymphocytic infiltrate using the IHC Profiler software. We demonstrated that pulmonary LELCs have a morphologically continuous spectrum, ranging from classic poorly differentiated tumors with intense lymphocytic infiltration to nonclassic morphology with little lymphocytic infiltration. These EBV-associated tumors represent a distinct entity and usually occur in female and nonsmoking patients. Tumors with low lymphocytic infiltration can closely resemble nonkeratinizing squamous cell carcinoma and tend to be larger in size, have higher maximum standardized uptake values on radiography, and exhibit shorter times to recurrence than those with high lymphocytic infiltration. Through detailed pathologic examination, we observed several distinct morphologic features in pulmonary LELCs, including granulomatous inflammation, focal keratinization, spread through alveolar spaces, and lepidic spreading pattern. We also found that patients with tumors exhibiting granulomatous inflammation have favorable outcomes; however, spread through alveolar spaces did not significantly correlate with prognosis. As many of these "LELCs" do not resemble undifferentiated nasopharyngeal carcinoma or lymphoepithelioma, we propose using an alternative term, EBV-associated pulmonary carcinoma, to encompass the entire morphologic spectrum of this distinct disease entity.

Molecular signatures in IASLC/ATS/ERS classified growth patterns of lung adenocarcinoma.

BackgroundThe current classification of human lung adenocarcinoma defines five different histological growth patterns within the group of conventional invasive adenocarcinomas. The five growth patterns are characterised by their typical architecture, but also by variable tumor biological behaviour.AimsThe aim of this study was to identify specific gene signatures of the five adenocarcinoma growth patterns defined by the joint IASLC/ATS/ERS working group.MethodsTotal RNA from microdissected adenocarcinoma tissue samples of ten lepidic, ten acinar, ten solid, nine papillary, and nine micropapillary tumor portions was isolated and prepared for gene expression analysis. Differential expression of genes was determined using the R package “LIMMA”. The overall significance of each signature was assessed via global test. Gene ontology statistics were analysed using GOstat. For immunohistochemical validation, tissue specimens from 20 tumors with solid and 20 tumors with lepidic growth pattern were used.ResultsMicroarray analyses between the growth patterns resulted in numerous differentially expressed genes between the solid architecture and other patterns. The comparison of transcriptomic activity in the solid and lepidic patterns revealed 705 up- and 110 downregulated non-redundant genes. The pattern-specific protein expression of Inositol-1,4,5-trisphosphate-kinase-A (ITPKA) and angiogenin by immunohistochemistry confirmed the RNA levels. The strongest differences in protein expression between the two patterns were shown for ITPKA (p = 0.02) and angiogenin (p = 0.113).ConclusionsIn this study growth pattern-specific gene signatures in pulmonary adenocarcinoma were identified and distinct transcriptomic differences between lung adenocarcinoma growth patterns were defined. The study provides valuable new information about pulmonary adenocarcinoma and allows a better assessment of the five adenocarcinoma subgroups.

P1.05-19 CT and PET/CT Parameters of Lepidic Predominant Pattern Lung Adenocarcinoma and Invasiveness on Pathology

P1.05-19 CT and PET/CT Parameters of Lepidic Predominant Pattern Lung Adenocarcinoma and Invasiveness on Pathology

P2.09-20 Minor Components of Solid Pattern is a Significant Poor Prognostic Factor in Pathological Stage I Lung Adenocarcinoma

Lung adenocarcinoma with solid pattern (SP) predominant subtype was reported to be associated with poor prognosis. However, whether minor components of SP predict poor prognosis remains unknown. The present study aimed to clarify the influence of different proportion of SP on the prognosis of pathological stage I lung adenocarcinoma. Tumors of 341 patients who underwent radical resections were classified according to the IASLC/ATS/ERS classification. Patient contained less than 5% SP in the tumor was determined SP negative and SP positive patients were reclassified to SP minor (5-50%) and SP major (≥50%) groups. Survival analyses were used to determine the association between each group with patient survival. 50 (15%) patients were SP positive and compared to SP negative group they showed a significantly lower five-year disease-free survival (DFS) rate (85.2 vs. 55.4%, p<0.001) and overall survival (OS) rate (97.3 vs. 66.7%, p<0.001). Multivariate analysis for DFS showed that SP positive, lepidic pattern negative, KRAS mutation and pathological stage IB were independent poor prognostic factors. In addition, higher proportions (<5%, 5–50% and ≥50%) of SP components were associated with a poorer prognosis (85.2, 76.6, and 40.0% of 5y-DFS, respectively; p<0.001). Solid pattern is a significant poor prognostic factor and an indicator of early recurrence after radical resection for early stage lung adenocarcinoma. Patients with tumors harboring a higher ratio of SP components have worse survival.

MS05.03 Tumor Heterogeneity in Lung Cancer

MS05.03 Tumor Heterogeneity in Lung Cancer

MS05.01 Staging and Pathology of Multiple Lung Nodules

MS05.01 Staging and Pathology of Multiple Lung Nodules

Successful resection of a slow-growing synchronous pulmonary metastasis from distal cholangiocarcinoma resected 3.5\xa0years after initial surgery: a case report

BackgroundA few reports have described the effectiveness of resection for recurrent cholangiocarcinoma. However, none have described resection of synchronous pulmonary metastasis from distal cholangiocarcinoma. We report the first case, to the best of our knowledge, of a slow-growing synchronous pulmonary metastasis from distal cholangiocarcinoma resected 3.5 years after the initial surgery.Case presentationA 67-year-old Japanese man with a diagnosis of distal cholangiocarcinoma was referred to our hospital. Thickening of the distal bile duct and an air-space pattern in the upper lobe of the left lung were detected by preoperative computed tomography. He underwent pancreaticoduodenectomy for the distal cholangiocarcinoma. Follow-up chest computed tomography demonstrated that the air-space pattern in the left lung had gradually enlarged. Thoracoscopic left S6 segmentectomy with lymph node dissection was performed 3.5 years after the initial surgery. Histopathology of the resected specimen revealed a solitary metastasis from distal cholangiocarcinoma with lepidic growth. We diagnosed the patient with a solitary synchronous pulmonary metastasis from distal cholangiocarcinoma.ConclusionsSurgical resection might offer better long-term survival to patients with synchronous pulmonary metastasis from distant cholangiocarcinoma than nonsurgical treatments. Pulmonary metastasis from distal cholangiocarcinoma may exhibit a lepidic pattern. Therefore, because of the possibility of synchronous pulmonary metastasis, pulmonary resection should be considered for patients with lepidic lesions who have been diagnosed with distal cholangiocarcinoma.

Comprehensive Assessment of PD-L1 Staining Heterogeneity in Pulmonary Adenocarcinomas Using Tissue Microarrays: Impact of the Architecture Pattern and the Number of Cores.

Checkpoint inhibitors directed against programmed death receptor 1 (PD-1) and its ligand (PD-L1) changed the treatment of advanced lung non-small cell carcinomas. The decision to treat patients is influenced by PD-L1 expression by tumor cells, but evidence indicates that this staining is heterogenous within a tumor. As PD-L1 staining is tested mostly on biopsies, false negative results can occur due to sampling issues. The clinical impact of this heterogeneity has not been established. We selected 241 patients who underwent pulmonary resection for adenocarcinoma. Tissue microarrays were constructed with five 1 mm cores representative of the histologic patterns observed in each tumor and stained for PD-L1. For each core, the histologic pattern and the percentage of PD-L1 positive tumor cells were noted. Staining heterogeneity was defined as cases with both positive and negative cores at positivity thresholds of 1%, 10%, and 50% of tumor cells. At the 50% cut-off, 37.8% of patients were PD-L1 positive, whereas 22.4% showed staining heterogeneity. Among patients with 1 negative core, 26.5% also had a positive core and could have been misclassified based on 1 biopsy. Mean staining of PD-L1 was higher in solid (47.9%) and micropapillary (24.2%) patterns and was lower in acinar (14.1%), papillary (3.4%), and lepidic (6.4%) architectures. A significant proportion of patients presented a heterogenous staining for PD-L1. A total of 26.5% of patients negative on 1 core turned out to be positive on another core, which raises the consideration of rebiopsy, in particular when lepidic, acinar, or papillary patterns are observed on a biopsy.

Clinicopathological Characteristics and Mutations Driving Development of Early Lung Adenocarcinoma: Tumor Initiation and Progression.

Lung cancer is the leading cause of cancer-related deaths worldwide, with lung adenocarcinoma representing the most common lung cancer subtype. Among all lung adenocarcinomas, the most prevalent subset develops via tumorigenesis and progression from atypical adenomatous hyperplasia (AAH) to adenocarcinoma in situ (AIS), to minimally invasive adenocarcinoma (MIA), to overt invasive adenocarcinoma with a lepidic pattern. This stepwise development is supported by the clinicopathological and molecular characteristics of these tumors. In the 2015 World Health Organization classification, AAH and AIS are both defined as preinvasive lesions, whereas MIA is identified as an early invasive adenocarcinoma that is not expected to recur if removed completely. Recent studies have examined the molecular features of lung adenocarcinoma tumorigenesis and progression. EGFR-mutated adenocarcinoma frequently develops via the multistep progression. Oncogene-induced senescence appears to decrease the frequency of the multistep progression in KRAS- or BRAF-mutated adenocarcinoma, whose tumor evolution may be associated with epigenetic alterations and kinase-inactive mutations. This review summarizes the current knowledge of tumorigenesis and tumor progression in early lung adenocarcinoma, with special focus on its clinicopathological characteristics and their associations with driver mutations (EGFR, KRAS, and BRAF) as well as on its molecular pathogenesis and progression.

The more the micropapillary pattern in stage I lung adenocarcinoma, the worse the prognosis-a retrospective study on digitalized slides.

Although the majority of lung adenocarcinomas show mixed pattern, only the predominant component is taken into account according to the novel classification. We evaluated the proportion of different patterns and their impact on overall survival (OS) and disease-free survival (DFS). Patterns were recorded according to predominance and their proportions were rated and calculated by objective area measuring on digitalized, annotated slides of resected stage I lung adenocarcinomas. Spearman's rank correlation, Kaplan-Meier models and the log rank test were used for statistical evaluation. Two hundred forty-three stage I adenocarcinoma were included. Lepidic pattern is more frequent in tumours without recurrence (20 vs. 8%), and lepidic predominant tumours have favourable prognosis (OS 90.5%, DFS 89.4%), but proportions above 25% are not associated with improving outcome. Solid and micropapillary patterns are more frequent in patients with recurrence (48 vs. 5% and 13 vs. 4%) and predominance of each one is associated with unfavourable prognosis (OS 64.1%, DFS 56.3% and OS 28.1%, DFS 28.1%, respectively). Above 25%, a growing proportion of solid or micropapillary pattern is not associated with worsening prognosis. In contrast, tumours having micropapillary pattern as secondly predominant form a different intermediate group (OS 51.1%, DFS 57.8%). Our study was based on measured area of each growth pattern on all available slides digitalized. This is the most precise way of determining the size of each component from the material available. We propose using predominant and secondly predominant patterns for prognostic purposes, particularly in tumours having solid or micropapillary patterns.

Tumor histology predicts mediastinal nodal status and may be used to guide limited lymphadenectomy in patients with clinical stage I non–small cell lung cancer

ObjectiveMethods to minimize surgical trauma from mediastinal lymphadenectomy in patients with early-stage lung cancer are still immature. This study aimed to identify predictors of negative pathologic N2, which may be used to select patients for limited mediastinal lymphadenectomy. MethodsClinicopathologic features of 1430 patients with resected clinical stage I non–small cell lung cancer and complete mediastinal lymphadenectomy were retrospectively analyzed for variables associated with negative N2 nodal metastasis (2008-2015). Overall and recurrence-free survival in patients after complete or limited mediastinal lymphadenectomy were assessed via Kaplan–Meier survival analysis and log-rank testing. The accuracy of frozen section diagnosis for predicting final pathology was retrospectively assessed in 126 randomly selected patients after the surgery. ResultsMultivariable analysis revealed that tumor size ≤2 cm, negative pN1, lymphovascular invasion, and lepidic adenocarcinoma were associated with negative mediastinal nodal metastasis. Notably, none of the patients with histology of adenocarcinoma in situ, minimally invasive adenocarcinoma, or lepidic pattern–predominant adenocarcinoma on final pathology had pN2 disease, and the 5-year overall and recurrence free-survival of these patients (99.3% and 99.3%, respectively) was not different from those after limited mediastinal lymphadenectomy (98.7% and 100%, P = .582 and .511, respectively). If these subtypes were classified together as the low-risk group, the concordance rate between frozen section and final pathology diagnosis was 88.9% in the retrospective test cohort. ConclusionsTumor histology may predict negative mediastinal metastasis in patients with early-stage lung cancer. Future prospective studies are merited to validate the feasibility of using frozen section to select patients for limited mediastinal lymphadenectomy.

What CT characteristics of lepidic predominant pattern lung adenocarcinomas correlate with invasiveness on pathology?

ObjectivesThe International Association for the Study of Lung Cancer, American Thoracic Society and European Respiratory Society lung adenocarcinoma classification in 2011 defined three lepidic predominant patterns including adenocarcinoma in situ, minimally invasive adenocarcinoma and lepidic predominant adenocarcinoma. We sought to correlate the radiology and pathology findings and identify any computed tomography (CT) features which can be associated with invasive growth. Materials and methodsAn institutional review board approved, retrospective study was conducted evaluating 63 patients with resected, pathologically confirmed, adenocarcinomas with predominant lepidic patterns. Preoperative CT images of the nodules were assessed using quantitative and qualitative radiographic descriptors while blinded to pathologic sub-classification and size. Maximum diameter was measured after evaluation of the axial, sagittal and coronal planes. Radiologic − pathologic associations were examined using Fisher’s exact test, the Kruskal-Wallis test and the Spearman correlation coefficient (ρ). Results and conclusionIncreasing maximum diameter of the whole lesion (ground glass and solid component) on CT was significantly associated with invasiveness (p = .003), as was the maximum pathologic specimen diameter (p = .008). Larger diameter of the solid component on CT was also found in lepidic predominant adenocarcinoma compared to minimally invasive adenocarcinoma (median 10.5 vs 2 mm, p = .005). More invasive tumors had higher visual estimated percentage solid component compared to whole lesion measurement on CT (p = .014). CT and pathologic measurements were positively correlated, although only moderately (ρ = .66) for the maximum whole lesion size and fair (ρ = .49) for solid/invasive component maximum measurements. Larger whole lesion size and solid component size of lepidic predominant pattern adenocarcinomas are associated with lesion invasiveness, although radiologic and pathologic lesion measurements are only fair-moderately positively correlated.

Presence of micropapillary and solid patterns are associated with nodal upstaging and unfavorable prognosis among patient with cT1N0M0 lung adenocarcinoma: a large-scale analysis.

To investigate whether the presence of micropapillary and solid patterns are associated with nodal upstaging and survival patterns in patients with cT1N0M0 lung adenocarcinoma. We retrospectively analyzed the clinicopathologic data of 2571 patients undergoing lobectomy and lymph node dissection or sampling. Logistic and Cox regression analysis were applied to determine the association between histological patterns and nodal upstaging and survival. Nodal upstaging was detected in 115 patients (4.5%) through postoperative pathologic examination. Tumors absent of lepidic pattern, and present with acinar, micropapillary and solid patterns had significantly higher nodal upstaging rate (all P < 0.001). Presence of micropapillary [odds ratios (ORs) = 3.51; 95% confidence intervals (CI) = 2.09-5.89; P < 0.001] and solid (OR 2.28; 95% CI 1.42-3.64; P = 0.001) patterns were independent predictors for nodal upstaging. Presence of micropapillary and solid patterns also significantly deteriorated the recurrence-free survival (RFS) (both log-rank P < 0.001), and were independently associated with unfavorable RFS in multivariable Cox analysis RFS [micropapillary: hazard ratios (HR) = 1.41; 95% CI 1.04-1.99; P = 0.041; solid: HR 2.05; 95% CI 1.56-2.70; P < 0.001]. The analysis of a large-scale cohort demonstrated that the presence of micropapillary and solid patterns significantly increase the risk of nodal upstaging and are independently associated with unfavorable prognosis.

The morphological changes of bronchovascular bundles within subsolid nodules on HRCT correlate with the new IASLC classification of adenocarcinoma

To observe the morphological changes of bronchovascular bundles within subsolid nodules on high-resolution (HR) computed tomography (CT) and analyse the correlation with the new adenocarcinoma classification. Two hundred and sixteen lesions (absent consolidation on mediastinal window) were reviewed retrospectively. CT features including dimensions, contour, morphological changes of the blood vessels, and bronchi/bronchioles, vacuole signs, and their correlation with histopathology were evaluated. Excluding nine non-cancerous lesions, 34 pre-invasive lesions (PILs) including 15 atypical adenomatous hyperplasias (AAHs) and 19 adenocarcinomas in situ (AISs), 21 minimally invasive adenocarcinomas (MIAs), and 152 invasive adenocarcinomas (IACs) were analysed. Lepidic, acinar, and papillary patterns were identified in this cohort of adenocarcinomas. IACs were grouped into three types: type I (lepidic pattern ≥80%, n=47), type II (lepidic pattern ≥50%, <80%, n=67), and type III (lepidic pattern <50%, n=38). The contour of lesions, and morphological changes in vessels and bronchi/bronchioles significantly correlated with the classification of PIL, MIA, and IACs (p=0.000, p=0.000, and p=0.017, respectively). In IACs, the prevalence of vascular abnormalities on HRCT significantly correlated with (p=0.000) the proportion of non-lepidic pattern (23.40% in type I, 58.21% in type II, and 76.32% in type III); the prevalence of bronchial/bronchiolar abnormalities was higher (p=0.008) in type II/III (20.95%) compared with type I (6.38%). The morphological changes of vessels and bronchi/bronchioles within the subsolid nodules on HRCT help to differentiate IAC from PIL and MIA, and are more common in non-lepidic predominant adenocarcinomas.

The utility of KRAS mutation analysis in differentiating a lung primary mucinous carcinoma from a metastatic colorectal mucinous carcinoma

A 58-year old male has a past medical history of a rectal low-grade mucinous adenocarcinoma with a KRAS codon 12/13 mutation (GGT&gt;GAT), for which he received neoadjuvant chemotherapy and radiation. Five months after diagnosis, the patient underwent a low anterior resection showing persistent tumor with the pathological staging being (ypT3, ypN0, ypMx). Six months after surgery, follow-up PET scan showed two right upper lung nodules measuring 1.0 and 1.8 cm. Subsequent video-assisted thoracic surgery with a lung wedge resection revealed two tumors: a mucinous adenocarcinoma and an acinar-predominant adenocarcinoma. The mucinous adenocarcinoma showed similar cytologic features as the rectal tumor; however, it showed more of a lepidic pattern. The immunohictochemical profile of the lung mucinous adenocarcinoma was positive CK7 (cytoplasmic), negative CK20, TTF1, napsin-A, and CDX2. KRAS codon 12/13 analysis also showed a mutation in the lung, however it was different compared to the previous rectal tumor and showed a GGT&gt;AGT mutation. The acinar adenocarcinoma had a wild-type KRAS. In this case, we favored a primary lung mucinous carcinoma over a metastasis from the rectum based on the lepidic morphology, CK20 negativity and differing KRAS codon 12 mutations. A year after the resection of the lung adenocarcinomas, the patient presented with dyspnea and abnormal liver functions. Abdominal US and MRI revealed multiple liver lesions (up to 1.9 cm). Core liver biopsies showed a poorly-differentiated mucinous adenocarcinoma with positive CK7 (cytoplasmic) and negative CK20, TTF-1, napsin-A, CDX2 and HSA. KRAS codon 12/13 analysis also showed a mutation GGT&gt;AGT, similar to that of the lung mucinous adenocarcinoma. The immunohistochemical profile and the KRAS mutation sequence of the hepatic tumor suggests a metastasis from the lung primary and corroborates the earlier premise that the lung tumor is distinct from the rectal one. In conclusion, in the unusual circumstance of a lung mucinous adenocarcinoma in a patient with established gastrointestinal mucinous primary, KRAS mutation analysis sequencing could help distinguish whether the lung mucinous is a primary tumor or metastasis from colorectal origin.

MTE 19.02 Ablative Therapy for Early Stage Lung Cancer

The fact that an early cancer is early in its nature implies that a curative therapy should be offered. However, radical treatments such as surgery and radiotherapy might not be the best options for various reasons. Firstly, the amount of normal tissue that has to be removed or denaturalized can contraindicate the treatment, secondly the unresectability for some central tumors, and finally the concern that metachronous lesions can occur and might need further intervention. Thus, the use of bronchoscopic therapies in the management of lung cancer limited to the airways has brought light to the management of early lung cancer. Several techniques are available to treat endoluminal superficial lesions, including laser, electrocautery, argon-plasma coagulation, photodynamic therapy, cryotherapy and brachytherapy. The curative potential of all these therapies has been demonstrated, as all of them are able to effectively destroy the depth of an early lung central cancer, which counts no more than 5 mm of malignant tissue. The definition of early lung cancer used in the studies of bronchoscopic therapies does not exactly correspond with the actual definitions of the TNM classification and differs among authors. Nagamoto et al. observed that squamous cell carcinoma (SCC) ≤ 3 mm thick and with longitudinal extension ˂ 20 mm was associated with no nodal involvement.1 Konaka et al. suggested that hypertrophic lesions of ˂ 1 cm are either carcinoma in-situ (CIS) or micro-invasive tumor within the muscle layer, while nodular and polypoid lesions ≥ 1 cm are more likely invasive beyond the cartilaginous layer.2 According to these, Mathur et al. defined early stage cancer as radiographically occult SCC that is endoscopically superficial, ˂ 2 cm in surface area with clearly visible margins and not invading beyond the bronchial cartilage.3 Later, the Japan Lung Cancer Society defined the bronchoscopic criteria of central type early stage lung cancer as that located subsegmental or more proximal, ˂ 2 cm with bronchoscopically recognizable margin and proven SCC.4 The new 8th edition of the TNM classification incorporates new definitions in the early stages including some special situations. Superficial spreading tumors in the central airways are those confined to the tracheal or bronchial wall regardless of size and location, and are labeled T1a ss. Carcinoma in situ (classified as Tis) now includes both squamous cell carcinoma in situ (SCIS, or squamous dysplasia) and adenocarcinoma in situ (AIS, which is localized, ≤ 3 cm and shows pure lepidic growth, lacking stromal, vascular, alveolar space or pleural invasion). Minimally invasive adenocarcinoma is classified as T1a(mi) and corresponds to solitary adenocarcinoma ≤ 3 cm with a predominantly lepidic pattern and ≤ 0.5 cm invasion. The invasive component is defined as histologic type other than lepidic or tumor cells infiltrating myofibroblastic stroma. In our setting, it is important to remark that examination of small biopsy specimens cannot exclude or quantify invasive components for AIS and T1a(mi) respectively. Although AIS can be highly suspected from biopsies with pure lepidic pattern together with a CT correlation of the ground glass component, AIS and T1a(mi) require examination of the entire resection specimen. The accuracy of the diagnostic techniques for early lung cancer represents the first step for defining the lesions suitable for endobronchial therapy. High definition bronchoscopy, autofluorescence bronchoscopy (AFB) and narrow band imaging (NBI) have been used for defining the margins of the lesion, the latter having a higher specificity. To evaluate the shallowness of the tumor, radial endobronchial ultrasound (rEBUS) and optical coherence tomography (OCT) have been used.6 Also, the combination of AFB and OCT have shown good results for both detection and characterization of premalignant lesions of the centrals airways.7 Thin-section CT (≤ 1 mm) and PET-CT might also be useful in the evaluation of premalignant lesions.8,9 Treatment success is directly dependent on lesion accessibility and the capability to correctly delineate the margins and shallowness of the lesions (10). Once the boundaries of the lesion are defined, choosing a technique over another depends mainly on the expertise of the bronchoscopist and availability of the therapy.

ES 01.02 New Histological Classification

ES 01.02 New Histological Classification

P3.04-011 A Prospective Study to Optimize the Extent of Pulmonary Resection According to Decision-Making Algorithm in cStage IA NSCLC

Recent advances in imaging technology and the widespread use of low-dose computed tomography screening have greatly increased the chance of detecting small-sized non-small cell lung cancer (NSCLC) with indolent features (radiologically ground-glass opacity and histopathologically lepidic pattern adenocarcinoma). This change in the disease pattern of NSCLC has led to a resurgence of interest in sublobar resection. The purpose of this study is to determine the outcome of patients with clinical stage IA NSCLC treated by 3 types of surgical resection (wide wedge resection, segmentectomy, or lobectomy) according to the institutional decision-making algorithm.

Histopathologic and molecular approach to staging of multiple lung nodules.

Distinguishing multiple primary lung cancers from intrapulmonary metastases in patients with synchronous multifocal lung adenocarcinomas can be challenging. The most recent 8th edition American Joint Committee on Cancer staging manual (AJCC staging manual) distinguishes four disease patterns in patients with multiple lung nodules: (I) two or more distinct and histologically different masses (considered unrelated and staged as individual cancers); (II) multiple ground-glass or part-solid nodules, histologically of with lepidic growth pattern (considered separate tumors, T staged based on highest T stage lesion); (III) patchy areas of ground-glass and consolidations, histologically often invasive mucinous adenocarcinomas (considered single tumor with diffuse "pneumonic-type" involvement); and (IV) separate nodules with the same histologic features based on comprehensive histologic subtyping (considered intrapulmonary metastases). Histologic and molecular features, in conjunction with clinical and radiological information, can all be tools to assist with staging of multiple nodules. Histologic features of adenocarcinomas are best characterized using comprehensive histologic subtyping (percentage of lepidic, acinar, solid, papillary and micropapillary pattern). Genomic alterations are commonly assessed using fluorescence in-situ hybridization and next generation sequencing (NGS). The AJCC considers exactly matching breakpoints by comparative genomic hybridization (CGH) as the only evidence for intrapulmonary metastases, and clearly different histologic types or subtypes as the only evidence for separate primary tumors. Similar histologic subtypes or the same biomarker pattern are considered merely relative arguments in favor of a single tumor source. When assessing multifocal lung cancer, pathologists should consider, and carefully weigh the importance of, molecular testing results in addition to the tumor's histologic features. For many cases encountered in routine clinical practice, absolute certainty cannot be reached as to whether they represent multiple primary cancers or intrapulmonary metastases. Classification of difficult cases often benefits from multidisciplinary discussion.

Inactivating mutations and hypermethylation of the NKX2-1/TTF-1 gene in non-terminal respiratory unit-type lung adenocarcinomas.

The major driver mutations of lung cancer, EGFR mutations and EML4‐ALK fusion, are mainly detected in terminal respiratory unit (TRU)‐type lung adenocarcinomas, which typically show lepidic and/or papillary patterns, but are rarely associated with a solid or invasive mucinous morphology. In order to elucidate the key genetic events in non‐TRU‐type lung cancer, we carried out whole‐exome sequencing on 43 non‐TRU‐type lung adenocarcinomas based on morphology (17 acinar, nine solid, and two enteric adenocarcinomas, and 15 adenocarcinomas with a mucinous morphology). Our analysis identified mutations in TP53 (16/43, 37.2%), KRAS (13/43, 30.2%), and NKX2‐1/TTF‐1 (7/43; 16.3%) as the top three significantly mutated genes, while the EGFR mutation was rare (1/43, 2.3%) in this cohort. Eight NKX2‐1/TTF‐1 mutations (five frameshift, two nonsense, and one missense) were identified, with one case harboring two distinct NKX2‐1/TTF‐1 mutations (one missense and one frameshift). Functional assays with the NK2 homeobox 1 (NKX2‐1)/thyroid transcription factor 1 (TTF‐1) mutants revealed that none of them retain the activity as a transcriptional factor. Histologically, invasive mucinous adenocarcinomas accounted for most of the NKX2‐1/TTF‐1 mutations (five cases), as well as one enteric and one acinar adenocarcinoma. Immunohistochemistry showed that the cohort was largely divided into TTF‐1‐postive/hepatocyte nuclear factor 4‐α (HNF4‐α)‐negative and TTF‐1‐negative/HNF4‐α‐positive groups. NKX2‐1/TTF‐1 mutations were exclusively found in the latter, in which the gastrointestinal markers, mucin 5AC and cytokeratin 20, were frequently expressed. Bisulfite sequencing revealed that the NKX2‐1/TTF‐1 gene body was highly methylated in NKX2‐1/TTF‐1‐negative cases, including those without the NKX2‐1/TTF‐1 mutations. The genetic or epigenetic inactivation of NKX2‐1/TTF‐1 may play an essential role in the development and aberrant differentiation of non‐TRU‐type lung adenocarcinomas.