Lepidic Growth Research Articles

Clinicoradiological features associated with epidermal growth factor receptor exon 19 and 21 mutation in lung adenocarcinoma

To retrospectively identify clinicopathological and radiological characteristics that could be independent predictors of epidermal growth factor receptor (EGFR) exon 19 and 21 mutation in surgically resected lung adenocarcinomas in a cohort of Asian patients. Demographics, histopathology data, and preoperative chest computed tomography (CT) images were evaluated retrospectively in 471 surgically resected lung adenocarcinomas. A total of 24 CT descriptors were assessed. Univariate analyses and multivariate logistic regression analyses were performed to identify independent predicted factors of harbouring EGFR mutations. EGFR mutations were existed in 252 (53.5%) of 471 patients, and associated with 11 clinicoradiological features. For the model with both clinical and radiological features, the independent predictors of harbouring EGFR mutation were small maximum diameter (≤3.9 cm), non-smokers, micropapillary pattern, pleural retraction, vascular convergence, and absence of solid pattern. The area under the receiver operating characteristic (ROC) curve (AUC) was 0.784. Multivariable logistic regression analysis indicated that non-smokers, vascular convergence, and absence of solid pattern were important independent predictors of EGFR exon 19 mutation, while non-smokers and vascular convergence were independent predictors of EGFR exon 21 mutation. The AUCs were 0.807 and 0.794, respectively. A lepidic growth pattern appeared more frequently in exon 21 mutant tumours than in exon 19 mutant group (p<0.001). CT imaging features of lung adenocarcinomas in combination with clinical variables could be used to prognosticate EGFR mutation status. The separate analysis of EGFR exon 19 or 21 mutation could further improve diagnostic performance.

Ciliated Muconodular Papillary Tumors of the Lung.

Ciliated muconodular papillary tumor is a rare tumor of the lung with 38 cases reported to date in the English literature. It is typically found incidentally in older adults (average age, 67 years) as a small, peripheral, ground glass opacity or nodule on computed tomography. Microscopically, the tumor is composed of a mixture of ciliated columnar, mucous, and basal cells in a variety of architectural patterns including glandular, papillary, lepidic, and micropapillary growth patterns. Recently, studies have shown the tumor has several associated gene alterations, supporting that the lesion is indeed neoplastic. The tumor seemingly follows an indolent clinical course, as there have been no reported recurrences or metastases. In this article, we review the clinical, radiographic, pathologic, and molecular findings of ciliated muconodular papillary tumors. Diagnostic pitfalls and the diagnostic considerations are discussed.

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.

Nuisance Neighbors: Gut-Lung Cross Talk in a Case of Crohnʼs Disease

Crohn's disease (CD) is a systemic illness with a plethora of extra-intestinal manifestations (EIM) affecting various organs, of which lungs are relatively rare. The clinicopathological patterns of pulmonary involvement consist of subclinical alterations, airway diseases, lung parenchymal diseases, pleural diseases and drug-related diseases. Tracheobronchial involvement is the most common respiratory presentation, whereas CD-related interstitial lung disease (ILD) is seen less frequently. A 41-year-old woman with a past medical history of CD (s/p subtotal colectomy) presented to the hospital for an enlarging ground-glass opacity (GGO) in her right middle lobe (RML) detected on routine CT abdomen for a CD workup six months back. She was asymptomatic, HR- 62/min, BP- 90/70 mm Hg, FEV1-122%, DLCO 106% on PFT. Contrast-enhanced CT chest showed the GGO in RML had increased in size from 21 x 18 mm to 28 x 18 mm and another GGO in the right lower lobe (RLL) increased in size from 5 mm to 12.4 mm. A robotic RML lobectomy with lymph node dissection and bronchoscopy, to rule out adenocarcinoma with lepidic growth, showed benign nodular lymphoid hyperplasia and a single perivascular epithelioid granuloma. A year later, her relapsing episodes of a cough and shortness of breath were managed with prednisone 20 mg for a probable pulmonary manifestation of CD. A non-contrast CT (NCCT) chest showed interval resolution of RLL GGO. A year later, she presented to the hospital with increasing cough, shortness of breath and a new GGO RLL (14 x 14 mm) on NCCT chest and is being managed with steroids with consideration of immunosuppression. In conclusion, pulmonary manifestations of CD present in a myriad of varieties often representing confounding diagnostic problems necessitating an extensive work-up. Thus, CD should be kept in the differential list in the case of unusual clinical symptoms and radiological signs of a pulmonary presentation. These infrequent, and sometimes life-threatening, EIM need to be considered when dealing with CD, to avoid further impairment of health status and alleviate patient symptoms by prompt recognition and treatment.2082_A Figure 1. Initial CT Abdomen & CT Chest2082_B Figure 2. CT Chest six months later2082_C Figure 3. NCCT Chest s/p lobectomy and most recent one

A severe combined immunodeficiency disease mouse model of human adenocarcinoma with lepidic-predominant growth

Severe combined immunodeficiency disease (SCID) mice with human lepidic adenocarcinoma were established by the intrabronchial implantation of fresh surgically resected specimens. Human pulmonary adenocarcinoma tissue from 16 different cases was transplanted into SCID mice, and SCID mouse tumors were established from four of these cases (25%). Among the four tumors, the tumor cells of two SCID mice showed replacement lepidic growth of mouse alveolar structures accompanied by multiple intrapulmonary lesions. Human lung carcinoma cell lines showing lepidic growth are rare and the xenograft models using the SCID mouse model developed in the current study will be useful for analyzing the growth and/or progression patterns and clinical behavior of lepidic adenocarcinoma, the major histological subtype of human carcinoma of the lung.

Predictive accuracy of lepidic growth subtypes in early-stage adenocarcinoma of the lung by quantitative CT histogram and FDG-PET

ObjectivesThe aim of this study was to analyze the accuracy of computed tomography (CT) and F-18 fluorodeoxyglucose-positron emission tomography/CT (FDG-PET/CT) to distinguish lepidic growth adenocarcinoma (LGA), including adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA), and lepidic-predominant adenocarcinoma, all of which have favorable survival outcomes, from the more aggressive and invasive non-LGA subtypes. Materials and MethodsWe identified 225 patients with c-0/I adenocarcinoma of the lung who underwent PET/CT and 3DCT followed by complete resection. Maximum standardized uptake values (SUVmax) of FDG and several histogram parameters were analyzed. Histological grades were classified according to the predominant subtype (G1: lepidic; G3: micropapillary or solid; and G2: subtypes other than G1/G3). ResultsThe proportion of pathological invasive factors (lymphatic vessel involvement/blood vessel invasion/pleural invasion/lymph node metastasis) of patients with preinvasive adenocarcinoma, G1, G2, and G3 tumors were 0%, 3.6%, 48.0%, and 100%, respectively; p < 0.001). Multivariate analysis with CT-related parameters demonstrated that 75th percentile CT attenuation value (75th%, p < 0.001) and maximum CT attenuation value (maxCT, p = 0.009) were associated with incidence of non-LGA, whereas the value of SUVmax demonstrated a significant correlation (p < 0.001). When all patients were dichotomized according to ground-glass opacities (GGO)/solid-dominancy for CT maximum diameter, a significant correlation with non-LGA was shown in patients with solid-dominant tumor on SUVmax (p < 0.001) and with GGO-dominant tumor on 75th% (p = 0.006) and maxCT (p = 0.007). The combination of one of the two significant histogram parameters and SUVmax revealed higher predictive performance for pathological high malignant features (positive pathological invasive factors, non-LGA, and the highly malignant subtype covering G2 with moderately or poorly-differentiated carcinoma and G3) than the individual use of either factor. ConclusionThe 75th%, maxCT, and SUVmax were highly useful in distinguishing LGA from non-LGA in c-0/I adenocarcinoma.

Abstract 3683: Reciprocal expressions of TFF-1 and TTF-1 in lung adenocarcinomas

Abstract The molecular targeted therapies against EGFR, ALK etc. have improved progression-free survival of patients with lung adenocarcinomas. However, targetable driver mutations have mainly been found in TTF-1-positive terminal respiratory unit (TRU)-type, but have yet been undiscovered in non-TRU type despite the advances in genomics technologies. In order to find the molecular candidate characterizing major subtype of non-TRU type adenocarcinomas, we compared TTF-1-positive/CDH1-positive adenocarcinoma cell lines (“TRU-type” cell lines) (n=11) and TTF-1-negative/CDH1-positive adenocarcinoma cell lines (“non-TRU-type” cell lines) (n=8), and found that TFF-1 (trefoil factor family-1), a gastric mucosal protective factor, was characteristically highly expressed in “non-TRU-type” cell lines. Immunohistochemical analysis of primary lung adenocarcinomas (n=70) revealed that TFF-1 expression was inversely correlated with TTF-1 expression (p=0.0116) and was very rare in primary lung adenocarcinoma cases (5.7%:4/70). So we focused on the non-TRU type adenocarcinomas on the basis of histologic pattern (acinar, solid or mucinous morphology predominant tumors without non-mucinous lepidic growth components) (n=43). Among them, TFF-1 was frequently expressed (62%:27/43), and significantly correlated with the expressions of MUC5AC, HNF4A and CK20 (p&amp;lt;0.0001, p=0.0001, and p=0.0007, respectively), and inversely correlated with TTF-1 expression (p=00039). Next generation sequencing analysis of the 43 cases revealed that KRAS gene mutations and Inactivating mutations and hypermethylation of the TTF-1 gene were frequent in TFF-1 positive cases. The analysis of publicly available data of 442 lung adenocarcinoma cases revealed that high expression of TFF-1 correlated with low expression of TTF-1 and worse prognosis. We confirmed that shRNA against TFF-1 inhibited the cell proliferation and the colony formation, and induced the apoptosis, in the TFF-1 positive “non-TRU-type” cell lines. These results indicate that TFF-1 is not only the marker but also can possibly be the molecular target of a subset of non-TRU-type lung adenocarcinomas. Citation Format: Daisuke Matsubara, Manabu Soda, Taichiro Yoshimoto, Yusuke Amano, Atsushi Kihara, Yuji Sakuma, Shunsuke Endo, Koichi Hagiwara, Masashi Fukayama, Hiroyuki Mano, Toshiro Niki. Reciprocal expressions of TFF-1 and TTF-1 in lung adenocarcinomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3683.

Thin-Walled Cavitary Lung Adenocarcinoma: A Rare Unusual Case

: Thin-walled cavitary lung adenocarcinoma is not common. When cavitary lung cancer was classified as a histologic subtype, squamous cell carcinoma was the most common, followed by adenocarcinoma and finally large cell carcinoma. Cavitation was not found in small cell lung cancer. Some cases of thin-walled cavitary lung adenocarcinoma have been reported. Thin-walled cavitary lung cancer can be detected by the following radiological signs: irregular thickening of the cavity wall, wall nodule formation, the presence of compartments in the cavity, increased standard uptake values (SUVs) on positron emission tomography (PET). A thin‑walled cavity accompanied by mediastinal lymph node or distant metastasis, or enlargement of the lesion on long term follow-up. We report on a case of thin walled cavitary lung cancer whose cavity tended to enlarge during a 10-month follow-up, but no other evidence of imaging finding indicated potential lung cancer. It suggests that the unidirectional check-valve mechanism could make enlarging thin walled cavitary lesion due to lepidic growth pattern.

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.

Solid component proportion is an important predictor of tumor invasiveness in clinical stage T1N0M0 (cT1N0M0) lung adenocarcinoma

BackgroundPreoperative tumor invasiveness in clinical stage T1N0M0 lung adenocarcinoma is critical for optimal surgical procedure. The aim of the present study was to evaluate the relationship between the ground-glass opacity component (GGOc) / solid component (Sc) proportion measured using three-dimensional (3D) computer-quantified computer tomography (CT) number analysis to explore radiographic features for invasiveness prediction in cT1N0M0 lung adenocarcinomas.MethodsA total of 375 surgically resected cT1N0M0 lung adenocarcinoma patients were included. The relativity between the GGOc/Sc proportion and lepidic growth pattern percentage was assessed using Spearman’s rank analysis. Multiple logistic regression analysis was used to determine independent factors from radiographic features for tumor invasiveness. Prediction probability for tumor invasiveness was analysed using a receiver operating characteristic curve (ROC).ResultsWe found that the GGOc proportion was positively correlated with lepidic growth pattern percentage (r = 0.67, P < 0.01), while the Sc proportion was negatively correlated with it (r = − 0.74, P < 0.01). Multivariate analysis showed that tumor size and Sc proportion were identified as independent predictors for tumor invasiveness. The area under the ROC curve (AUC) of Sc proportion was 0.875, which was higher than that of tumor size (0.750) (P < 0.001), and had no significant difference with that of combination of these two factors (0.884) (P = 0.28).ConclusionsThe GGOc/Sc proportion measured using 3D computer-quantified CT number analysis reflects the lepidic growth pattern percentage in tumors, and the Sc proportion may be an important factor for the prediction of tumor invasiveness in cT1N0M0 lung adenocarcinoma.

A genomic and clinicopathological study of non‐small‐cell lung cancers with discordant ROS1 gene status by fluorescence in‐situ hybridisation and immunohistochemical analysis

ROS1 immunohistochemistry (IHC) using D4D6 antibody is a useful tool for screening patients with non-small-cell lung cancer (NSCLC) who may be suitable for targeted therapy. Many studies and our data have identified cases that express the ROS1 protein strongly but are negative for ROS1 by fluorescence in-situ hybridisation (FISH). The present study investigated the driver mutation and clinicopathological characteristics of 26 discordant cases (ROS1 IHC-positive but FISH-negative) to find new clues for distinguishing real ROS1-rearranged cases. Tumours from 26 discordant cases were analysed for clinicopathological characteristics, mutations in EGFR, KRAS, ERBB2, BRAF and PIK3CA; fusions in ALK and RET; and amplifications in MET, ERBB2 and ROS1. ROS1-rearranged NSCLCs were significantly more likely to be found in younger patients and at an advanced stage; they showed cribriform features, extracellular mucus and psammoma bodies, whereas ROS1-discordant cases were found in older patients at a relatively early tumour-node-metastasis (TNM) stage and showed a lepidic growth pattern (all P < 0.001). Most ROS1-rearranged NSCLCs had no concurrent mutation, whereas 73% of discordant cases harboured genetic aberrations, including EGFR and ERBB2. Compared with general lung adenocarcinomas, ERBB-2 abnormality was disproportionately high in ROS1-discordant cases. Moreover, we optimised the scoring criteria for ROS1 IHC as 'H score > 150 and no concurrent mutations'; the specificity was then increased to 81.6%. Compared with ROS1-rearranged cases, ROS1-discordant patients showed distinct clinical and morphological features and often harboured another oncogenic driver alteration. The use of optimised screening criteria will increase the specificity of ROS1 antibody.

Air bronchogram in pleomorphic carcinoma of the lung is associated with favorable prognosis.

BackgroundPleomorphic carcinoma (PC) of the lung is a rare histological type of lung carcinoma. The association between computed tomography (CT) findings and histology with outcome remains unclear. We examined the relationships between CT features and histopathologic findings, and evaluated the impact of CT features and other clinicopathologic factors on survival.MethodsThirty‐five consecutive patients with PC of the lung who underwent surgery between October 2010 and December 2015 were enrolled in this study. The 35 tumors were classified with or without air bronchogram in the tumors, and with or without intratumoral ground glass opacity (GGO) on CT.ResultsAir bronchogram and GGO were detected in 12 (34.3%) and 5 (14.3%) tumors, respectively. Multivariate analysis revealed that air bronchogram was significantly associated with the presence of adenocarcinoma components with lepidic growth patterns (P = 0.005), and predominance of adenocarcinomas (P = 0.026). GGO was significantly associated with the presence of adenocarcinoma component with lepidic growth pattern (P = 0.010). Air bronchogram was an independent favorable prognostic factor for overall survival, whereas GGO did not have a significant effect on survival.ConclusionAir bronchogram observed in PCs of the lung is strongly related with histological components of the tumor and favorable outcome.

Blocked expression of key genes of the angiogenic pathway in JSRV-induced pulmonary adenocarcinomas

JSRV (Jaagsiekte Sheep Retrovirus) is a retrovirus inducing a transmissible lung adenocarcinoma in sheep and goats with predominantly lepidic and papillary lesions. This naturally occurring lung cancer in large animals shares many features with human pneumonic-type lung adenocarcinomas with predominant lepidic growth. The metastatic spread is rare in both human and animal cancers. This unique feature prompted us to decipher the angiogenesis pathway in these cancers. We focused on the levels of mRNA and proteins of genes implicated in the extension of JSRV-induced lung adenocarcinomas by studying their expression in lung cancers (n = 10) and normal lungs (n = 10) and in primary epithelial alveolar type II cells derived from cancers (n = 10) or normal lungs (n = 6). In parallel, we evaluated the levels of expression of key genes in lung tissues collected from lepidic (n = 13) or papillary (n = 5) human adenocarcinomas and, when available, adjacent normal lungs (n = 11). We measured the expression of the same key genes implicated in angiogenesis, lymphangiogenesis and degradation of the extracellular matrix. In ovine adenocarcinomas, VEGFR2 and VEGFD mRNA were downregulated in cancers; MMP9, TIMP1 and FGFR2 mRNA were overexpressed as compared to normal lungs. Importantly, VEGFA and VEGFR2 proteins were not expressed in JSRV-induced cancers. In human lepidic adenocarcinomas, VEGFA and VEGFR2 mRNA were weakly expressed and no VEGFR2 protein was detectable. Downregulation of key angiogenic players may contribute to the control of extra thoracic invasion of cancer cells in human and ovine pneumonic-type adenocarcinoma with predominant lepidic growth.

Interobserver Variation among Pathologists and Refinement of Criteria in Distinguishing Separate Primary Tumors from Intrapulmonary Metastases in Lung

Multiple tumor nodules are seen with increasing frequency in clinical practice. On the basis of the 2015 WHO classification of lung tumors, we assessed the reproducibility of the comprehensive histologic assessment to distinguish second primary lung cancers (SPLCs) from intrapulmonary metastases (IPMs), looking for the most distinctive histologic features. An international panel of lung pathologists reviewed a scanned sequential cohort of 126 tumors from 48 patients and recorded an agreed set of histologic features, including tumor typing and predominant pattern of adenocarcinoma, thereby opining whether the case was SPLC, IPM, or a combination thereof. Cohen κ statistics of 0.60 on overall assessment of SPLC or IPM indicated a good agreement. Likewise, there was good agreement (κ score 0.64, p < 0.0001) between WHO histologic pattern in individual cases and SPLC or IPM status, but the proportions diversified for histologic pattern and SPLC or IPM status (McNemar test, p < 0.0001). The strongest associations for distinguishing between SPLC and IPM were observed for nuclear pleomorphism, cell size, acinus formation, nucleolar size, mitotic rate, nuclear inclusions, intraalveolar clusters, and necrosis. Conversely, the associations for lymphocytosis, mucin content, lepidic growth, vascular invasion, macrophage response, clear cell change, acute inflammation keratinization, and emperipolesis did not reach significance with tumor extent. Comprehensive histologic assessment is recommended for distinguishing SPLC from IPM with good reproducibility among lung pathologists. In addition to main histologic type and predominant patterns of histologic subtypes, nuclear pleomorphism, cell size, acinus formation, nucleolar size, and mitotic rate strongly correlate with pathologic staging status.

MS 24.02 What Type of Surgery Should be Selected for GGO-Containing Tumors?

A ground glass opacity (GGO) is a radiographic finding defined as hazy, increased attenuation of the lung with preservation of bronchial vascular margin. A subsolid nodule (SSN) includes pure ground glass nodules and partsolid nodules in which both solid and ground glass components are present. These nodules are nowadays more commonly found with the introduction of CT screening programs. The optimal management of patients with SSN is of growing clinical concern. The newly1 introduced adenocarcinoma classification makes a clear distinction between pre-invasive lesions (atypical adenomatous hyperplasia), adenocarcinoma in situ (AIS: ≤ 3cm pure lepidic growth without invasion), minimally invasive adenocarcinoma (MIA: ≤ 3cm lepidic growth with ≤ 5mm invasion) and invasive adenocarcinoma (IA) of different subtypes.

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

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.

Squamous cell carcinoma of the lung showing a ground glass nodule on high-resolution computed tomography associated with pneumoconiosis: a case report

BackgroundAdenocarcinoma with lepidic growth pattern presents as a ground glass nodule (GGN) on high resolution computed tomography (CT), whereas peripheral pulmonary squamous cell carcinoma (SCC) usually presents as a solid nodule. We herein report a rare case of pulmonary SCC extending along the alveolar lumen representing as a GGN on a CT scan in a patient with pneumoconiosis.Case presentationA 77-year-old man with pneumoconiosis was found to have a gradually enlarging GGN in the right lower lobe of the lung on CT. An adenocarcinoma of the lung was suspected. The GGN was successfully resected by thoracoscopic segmentectomy. Pathological examination of the resected specimen was pathologically diagnosed as a stage IA SCC extending along the alveolar lumen. The patient had no evidence of recurrence 19 months after surgery.ConclusionsSCC should be included in the differential diagnosis of peripherally located GGNs, especially in patients at high risk of SCC of the lung such as those with pneumoconiosis.

Pulmonary invasive mucinous adenocarcinoma and mixed invasive mucinous/nonmucinous adenocarcinoma—a clinicopathological and molecular genetic study with survival analysis

Invasive mucinous adenocarcinoma is a variant of lung adenocarcinoma, which may be mixed with nonmucinous adenocarcinoma. KRAS mutations are common, but other clinical and genetic features are not clearly established. Lung adenocarcinomas (n=760) with ≥5 years of follow-up comprised 3 nonoverlapping cohorts for survival analysis. Mucinous tumors were evaluated with Ion AmpliSeq Cancer Hotspot Panel v2. Cases without detected mutations were tested for ALK and ROS1 and by OncoScan array. Fifty-seven invasive mucinous adenocarcinomas and 54 mixed mucinous/nonmucinous adenocarcinomas were identified. Mucinous tumors constituted 27 of 218 nonselected patients (12.4%), 23 of 268 never-smokers (8.6%), and 61 of 274 in a smokers cohort enriched for lepidic growth (22.3%). In the lepidic-enriched smokers, patients with mucinous tumors experienced worse overall survival (P=.006) and progression-free survival (P=.024), which persisted on multivariable analysis. No survival differences were observed in the other cohorts. KRAS mutations were common (76% of invasive mucinous adenocarcinomas, 68% of mixed mucinous/nonmucinous), and 38% of KRAS mutations occurred with other mutations, especially STK11. Six cases had potentially targetable mutations (3 ALK, 2 EGFR, 1 BRAF V600E). All ALK-rearranged tumors were mixed mucinous/nonmucinous. Four of 6 cases without hotspot mutations showed complex copy number/structural abnormalities. Pulmonary invasive mucinous adenocarcinomas and mixed nonmucinous/mucinous adenocarcinomas are clinically and genetically similar, except for a higher rate of ALK rearrangement in mixed tumors. Survival for mucinous tumors is similar to that for nonmucinous tumors in a nonselected cohort, although worse survival was seen in a cohort of smokers enriched for lepidic growth.