No abstract

IHC scoring correlates with FISH and may be a useful algorithm in testing ALK+ by FISH in non-small cell lung carcinoma, similar to human epidermal growth factor-2 testing in breast cancer. Further study is needed to validate this approach.

A distinct subset of thoracic sarcomas with undifferentiated rhabdoid morphology and SMARCA4 inactivation has recently been described, and potential targeted therapy for SMARC-deficient tumors is emerging. We sought to validate the clinicopathological features of SMARCA4-deficient thoracic sarcomas. Clinicopathological information was gathered for 40 undifferentiated thoracic tumors with rhabdoid morphology (mediastinum (n=18), lung (n=14), pleura (n=8)). Thymic carcinomas (n=11) were used as a comparison group. Immunohistochemistry included BRG1 (SMARCA4), BRM (SMARCA2), INI-1 (SMARCB1), pan-cytokeratin, desmin, NUT, S-100 protein, TTF1, CD34, and SOX2. BRG1 loss was present in 12 of 40 rhabdoid thoracic tumors (30%): 7 of 18 in mediastinum (39%), 2 of 8 in pleura (25%), and 3 of 14 in lung (21%). All BRG1-deficient tumors tested for BRM (n=8) showed concomitant loss. All thymic carcinomas showed retained BRG1 and INI-1. Morphologically, tumors with BRG1 loss showed sheets of monotonous ovoid cells with indistinct cell borders, abundant eosinophilic cytoplasm, and prominent nucleoli. Scattered areas with rhabdoid morphology (ie, eccentric nuclei, dense eosinophilic cytoplasm, discohesion) were present in all the cases. SMARCA4/BRG1-deficient sarcomas showed rare cells positive for cytokeratin in 10 cases (83%). One showed rare TTF1-positive cells. All were negative for desmin, NUT, and S-100 protein. CD34 was positive in three of five (60%) BRG1-deficient tumors tested. SOX2 was positive in all four BRG1-deficient tumors tested, and negative in all seven tested cases with retained BRG1. SMARCA4/BRG1-deficient sarcomas occurred at median age of 59 years (range 44-76) with male predominance (9:3) and had worse 2-year survival compared with BRG1-retained tumors (12.5% vs 64.4%, P=0.02). SMARCA4-deficient thoracic sarcomas can be identified based on their distinctive high-grade rhabdoid morphology, and the diagnosis can be confirmed by immunohistochemistry. Identification of these tumors is clinically relevant due to their aggressive behavior, poor prognosis, and potential targeted therapy.

No abstract

No abstract

Ciliated muconodular papillary tumors (CMPTs) are rare peripheral lung lesions, characterized by papillary architecture and ciliated columnar cells admixed with mucinous cells and basal cells. They often have prominent surrounding intra-alveolar mucin, which can lead to diagnostic confusion with mucinous adenocarcinoma. Recognition of the ciliated component is the key to diagnosis of CMPT. The literature contains few reported cases to date, all occurring in East-Asian patients. Although follow-up data are limited, CMPT seems to be an indolent tumor with very good prognosis, leading some to question whether it is a reactive or hamartomatous lesion. However, a very recent molecular study has identified BRAF (40%) and EGFR (30%) alterations in CMPT, supporting a truly neoplastic process. Here for the first time, we report 4 cases of morphologically typical CMPT in western patients, occurring in 1 man (60 y) and 3 women (71 to 83 y). Interestingly, 1 case occurred in background of pronounced small airway disease with necrotizing bronchiolitis and multiple carcinoid tumorlets. We further analyzed 1 tumor using a 50 gene next-generation sequencing oncology panel that identified 2 pathogenic mutations (BRAF V600E and AKT1 E17K). Our study is the first to describe that CMPT can occur in western (non-Asian) patients. Our data confirm BRAF V600E mutation as a probable driver in a subset of these tumors, along with AKT1 mutation, which further supports that CMPT are indolent pulmonary neoplasms.

No abstract

Introduction The EML4–anaplastic lymphoma kinase (ALK) translocation is a recognized oncogenic driver in non-small cell lung cancer. We investigated immunohistochemistry (IHC) screening with fluorescence in-situ hybridization (FISH) confirmation for ALK detection and estimated the prevalence of ALK-positivity in our patient cohort of never smokers, together with differences in clinical outcomes and prognostic factors for patients with ALK-positive and ALK-negative tumors. Methods We designed a three-phase study (training, validation, and testing) in 300 never-smokers with lung adenocarcinoma from the observational Mayo Clinic Lung Cancer Cohort. Tumor samples were tested using IHC and FISH, and concordance between the methods was assessed. Clinical outcomes were assessed via 5-year progression or recurrence-free survival from diagnosis. Prognostic factors for ALK-positive tumors and metastases were also investigated. Results ALK-positive patients were significantly (p<0·05) younger and had higher-grade tumors than ALK-negative patients. ALK-positivity was 12.2% by IHC and confirmed at 8.2% of tumors by FISH, with complete concordance between IHC 3+/0 and FISH+/− assessments, respectively. Five-year risk of progression or recurrence was doubled for patients with ALK-positive compared with ALK-negative tumors; ALK-positive tumors also appeared to be associated with a higher risk of brain and liver metastases. Conclusions Our findings suggest that ALK-positivity is associated with a significantly poor outcome in non-smoking-related adenocarcinoma, and that ALK-positive tumors may be associated with an increased risk of brain and liver metastases compared with ALK-negative disease. Consequently, an unmet medical need exists in ALK-positive lung cancer patients, and effective ALK-specific therapies are needed now.