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The emergence of anaplastic lymphoma kinase (ALK) rearrangements in non-small cell lung cancer (NSCLC) has revolutionized targeted therapy. This dynamic landscape, featuring novel ALK inhibitors and combination therapies, necessitates a profound understanding of resistance mechanisms for effective treatment strategies. Recognizing two primary categories – on-target and off-target resistance – underscores the need for comprehensive assessment. This review delves into the intricacies of resistance to ALK inhibitors, exploring complexities in identification and management. Molecular testing, pivotal for early detection and accurate diagnosis, forms the foundation for patient stratification and resistance management. The literature search methodology involved comprehensive exploration of Pubmed and Embase. The multifaceted perspective encompasses new therapeutic horizons, ongoing clinical trials, and their clinical implications post the recent approval of lorlatinib. Our expert opinion encapsulates the critical importance of understanding resistance mechanisms in the context of ALK inhibitors for shaping successful treatment approaches. With a focus on molecular testing and comprehensive assessment, this review contributes valuable insights to the evolving landscape of NSCLC therapy. [ABSTRACT FROM AUTHOR]

The reporting of lung neuroendocrine neoplasms (NENs) according to the 2021 World Health Organisation (WHO) is based on mitotic count per 2 mm2, necrosis assessment and a constellation of cytological and immunohistochemical details. Accordingly, typical carcinoid and atypical carcinoid are low‐ to intermediate‐grade neuroendocrine tumours (NETs), while large‐cell neuroendocrine carcinoma (NEC) and small‐cell lung carcinoma are high‐grade NECs. In small‐sized diagnostic material (cytology and biopsy), the noncommittal term of carcinoid tumour/NET not otherwise specified (NOS) and metastatic carcinoid NOS have been introduced with regard to primary and metastatic diagnostic settings, respectively. Ki‐67 antigen, a well‐known marker of cell proliferation, has been included in the WHO classification as a non‐essential but desirable criterion, especially to distinguish NETs from high‐grade NECs and to delineate the provisional category of carcinoid tumours/NETs with elevated mitotic counts (> 10 mitoses per mm2) and/or Ki‐67 proliferation index (≥ 30%). However, a wider use of this marker in the spectrum of lung NENs continues to be highly reported and debated, thus witnessing a never‐subsided attention. Therefore, the arguments for and against incorporating Ki‐67 in the classification and clinical practice of these neoplasms are discussed herein in detail. [ABSTRACT FROM AUTHOR]

The 5th WHO classification of thoracic tumours includes thoracic SMARCA4-deficient undifferentiated tumour (SMARCA4-UT) among the "other epithelial tumours of the lung" chapter. Herein, we present a case of undifferentiated thoracic neoplasm with retention of SMARCA4 expression, lack of NUT fusion protein and loss of SMARCB1/INI1 expression. After presenting the clinical and pathological features of the tumour, we carried out a review of the literature on the same topic. Albeit very rare, we believe this entity should be included in the heterogeneous group of undifferentiated neoplasms of the thorax., (Copyright © 2024 Società Italiana di Anatomia Patologica e Citopatologia Diagnostica, Divisione Italiana della International Academy of Pathology.)

The WHO Classification of Tumors, Thoracic Tumors, 5th edition, has outlined the use of TTF-1 and ΔNP63/P40 to discriminate between adenocarcinoma and squamous cell carcinoma. In 2015, the first description of a rare non-small cell lung carcinoma featuring co-expression of glandular and squamous differentiation within most of the same individual tumor cells was reported on, with ultrastructural and molecular demonstration of such a biphenotypic differentiation. We herein describe an additional case of this rare tumor entity, which is confirmed to be an aggressive neoplasm despite potential targets of therapy., (Copyright © 2024 Società Italiana di Anatomia Patologica e Citopatologia Diagnostica, Divisione Italiana della International Academy of Pathology.)

The transcription factors TTF1/NKX2-1 and ΔNp63/p40 are the counterposed molecular markers associated with the main Non-Small Cell Lung Cancer subtypes: TTF1 for adenocarcinoma, p40 for squamous cell carcinoma. Although they generally display a mutually exclusive expression, some exceptions exist simultaneously lacking or (very rarely) expressing both markers, either pattern being associated to poor prognosis. Hence, we quantitatively analyzed the relationship between their coordinated activity and prognosis. By analyzing the respective downstream transcriptional programs of the two genes, we defined a simple quantitative index summarizing the amount of mutual exclusivity between their activities, called Mean Absolute Activity (MAA). Systematic analysis of the MAA index in a dataset of 1018 NSCLC samples replicated on a validation dataset of 275 showed that the loss of imbalance between TTF-1 and p40 corresponds to a steady, progressive reduction in both overall and recurrence-free survival. Coherently, samples correspondent to more balanced activities were enriched for pathways related to increased malignancy and invasiveness. Importantly, multivariate analysis showed that the prognostic significance of the proposed index MAA is independent of other clinical variables including stage, sex, age and smoke exposure. These results hold irrespectively of tumor morphology across NSCLC subtypes, providing a unifying description of different expression patterns., (© 2024. The Author(s).)