Lung cancer is the leading cause of cancer-related deaths worldwide. Patients with resectable NSCLC are often treated with surgery and adjuvant chemotherapy. However, these patients continue to have ...a high risk of recurrence and death. Unfortunately, there has been little progress in the treatment of resectable NSCLC over the past several decades. Neoadjuvant therapy, which has been considered as an approach to improve survival in patients with resectable NSCLC, is a hotly debated topic. A systematic review of 32 randomized trials involving 10,000 patients revealed that there was no difference in survival between preoperative and postoperative chemotherapy. Because of such results and the theoretical concern about resectable tumors progressing on relatively ineffective neoadjuvant chemotherapy, and thus becoming unresectable, neoadjuvant chemotherapy fell out of favor, and many clinicians preferred adjuvant chemotherapy after surgery. However, neoadjuvant therapy has been revived in the past couple of years, with emerging data from various ongoing trials suggesting that neoadjuvant immunotherapy may have significant efficacy and could potentially improve the survival of patients with resectable NSCLC. In this review article, we discuss the evidence supporting the role of neoadjuvant immunotherapy in the multimodal management of resectable NSCLC. We summarize early results of ongoing clinical trials and highlight the challenges in adopting a uniform definition of treatment “success.” We address hurdles to be overcome for seeking regulatory approval for neoadjuvant immunotherapy and establishing it as a standard of care. Finally, we provide some perspectives for the future.
Molecularly defined neoplasms are increasingly recognized, given the broader application and performance of molecular studies. These studies allow us to better characterize these neoplasms and learn ...about their pathogenesis. In the thorax, molecularly defined neoplasms include tumors such as NUT carcinoma, SMARCA4-deficient undifferentiated tumor (DUT), primary pulmonary myxoid sarcoma with EWSR1::CREB1 fusion, hyalinizing clear cell carcinoma, and SMARCB1-deficient neoplasms. Overall, these tumors are rare but are now more often recognized given more widely available immunostains such as NUT (NUT carcinoma), BRG1 (SMARCA4-DUT), and INI-1 (SMARCB1-deficient neoplasm). Furthermore, cytogenetic studies for EWSR1 to support a hyalinizing clear cell carcinoma or primary pulmonary myxoid sarcoma are, in general, easily accessible. This enables pathologists to recognize and diagnose these tumors. The diagnosis of these tumors is important for clinical management and treatment. For instance, clinical trials are available for patients with NUT carcinoma, SMARCA4-DUT, and SMACRB1-deficient neoplasms. Herein, our current knowledge of clinical, morphologic, immunophenotypic, and molecular features of NUT carcinomas, SMARCA4-DUT, primary pulmonary myxoid sarcomas, hyalinizing clear cell carcinoma, and SMARCB1-deficient neoplasms will be reviewed.
Thymic epithelial tumors (TET) are rare and large molecular studies are therefore difficult to perform. However, institutional case series and rare multi-institutional studies have identified a ...number of interesting molecular aberrations in TET, including gene fusions in a subset of these tumors. These gene fusions can aid in the diagnosis, shed light on the pathogenesis of a subset of tumors, and potentially may provide patients with the opportunity to undergo targeted therapy or participation in clinical trials. Gene fusions that have been identified in TET include
rearrangements in 50% to 56% of mucoepidermoid carcinomas (
), 77% to 100% of metaplastic thymomas (
), and 6% of B2 and B3 thymomas (
);
rearrangements in NUT carcinomas (most commonly
);
rearrangement in hyalinizing clear cell carcinoma (
); and
rearrangement in a thymoma (
). This review focuses on TET in which these fusion genes have been identified, their morphologic, immunophenotypic, and clinical characteristics and potential clinical implications of the fusion genes. Larger, multi-institutional, global studies are needed to further elucidate the molecular characteristics of these rare but sometimes very aggressive tumors in order to optimize patient management, provide patients with the opportunity to undergo targeted therapy and participate in clinical trials, and to elucidate the pathogenesis of these tumors.
•Morphologic and immunophenotypic features resemble salivary gland tumors elsewhere.•Primary tumors are usually centrally located and associated with large airways.•MAML2 rearrangements are present ...in a subset of mucoepidermoid carcinoma.•MYB rearrangements are present in a subset of adenoid cystic carcinoma.•Metastatic disease needs to be excluded.
Salivary gland tumors are uncommon primary lesions in the lung. Their morphologic, immunophenotypic, and molecular characteristics resemble those of their counterparts in the head and neck or elsewhere. Most common primary pulmonary salivary gland tumors include mucoepidermoid carcinoma, adenoid cystic carcinoma, and epithelial-myoepithelial carcinoma. The study of these neoplasms is hampered by their paucity. Therefore, studies are in general small or restricted to individual cases. Despite this challenge recent advances have been made specifically at the molecular level. Molecular alterations such as MAML2 rearrangements in mucoepidermoid carcinoma, MYB rearrangements in adenoid cystic carcinomas, and EWSR1 rearrangements in hyalinizing clear cell carcinomas and myoepithelial tumors have been identified. These molecular alterations might be helpful in the distinction of these salivary gland tumors from other neoplasms in the lung. However, the distinction from metastatic disease remains challenging. Awareness of these tumors and knowledge of available ancillary studies to confirm the diagnosis is important to avoid misdiagnosis which might lead to differences in treatment, management, and prognosis. Further studies are needed to identify biomarkers to better predict patient's outcome and for individual management and treatment of patients.
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Interleukin (IL)-17 is a T helper 17 cytokine implicated in the pathogenesis of many autoimmune diseases, including rheumatoid arthritis (RA). Although IL-17A has a well-established role in murine ...pulmonary fibrosis models, its role in the tissue remodeling and fibrosis occurring in idiopathic pulmonary fibrosis (IPF) and RA-associated interstitial lung disease (RA-ILD) is not very well defined. To address this question, we utilized complimentary studies to determine responsiveness of human normal and pathogenic lung fibroblasts to IL-17A and used lung biopsies acquired from patients with IPF and RA-ILD to determine IL-17A receptor (IL-17RA) expression. Both normal and pathogenic IPF lung fibroblasts express functional IL-17RA and respond to IL-17A stimulation with cell proliferation, generation of extracellular matrix (ECM) proteins, and induction of myofibroblast transdifferentiation. Small interfering RNA (siRNA) silencing of IL-17RA attenuated this fibroblast response to IL-17A on ECM production. These fibroblast responses to IL-17A are dependent on NF-κB-mediated signaling. In addition, inhibiting Janus activated kinase (JAK) 2 by either siRNA or a selective pharmacological inhibitor, AZD1480-but not a JAK1/JAK3 selective inhibitor, tofacitinib-also significantly reduced this IL-17A-induced fibrogenic response. Lung biopsies of RA-ILD patients demonstrate significantly higher IL-17RA expression in areas of fibroblast accumulation and fibrosis, compared with either IPF or normal lung tissue. These observations support a direct role for IL-17A in lung fibrosis that may be particularly relevant in the context of RA-ILD.
Currently, there is no established guidance on how to process and evaluate resected lung cancer specimens after neoadjuvant therapy in the setting of clinical trials and clinical practice. There is ...also a lack of precise definitions on the degree of pathologic response, including major pathologic response or complete pathologic response. For other cancers such as osteosarcoma and colorectal, breast, and esophageal carcinomas, there have been multiple studies investigating pathologic assessment of the effects of neoadjuvant therapy, including some detailed recommendations on how to handle these specimens. A comprehensive mapping approach to gross and histologic processing of osteosarcomas after induction therapy has been used for over 40 years.
The purpose of this article is to outline detailed recommendations on how to process lung cancer resection specimens and to define pathologic response, including major pathologic response or complete pathologic response after neoadjuvant therapy. A standardized approach is recommended to assess the percentages of (1) viable tumor, (2) necrosis, and (3) stroma (including inflammation and fibrosis) with a total adding up to 100%. This is recommended for all systemic therapies, including chemotherapy, chemoradiation, molecular-targeted therapy, immunotherapy, or any future novel therapies yet to be discovered, whether administered alone or in combination. Specific issues may differ for certain therapies such as immunotherapy, but the grossing process should be similar, and the histologic evaluation should contain these basic elements. Standard pathologic response assessment should allow for comparisons between different therapies and correlations with disease-free survival and overall survival in ongoing and future trials. The International Association for the Study of Lung Cancer has an effort to collect such data from existing and future clinical trials. These recommendations are intended as guidance for clinical trials, although it is hoped they can be viewed as suggestion for good clinical practice outside of clinical trials, to improve consistency of pathologic assessment of treatment response.
The recent development of immune checkpoint inhibitors (ICIs) has led to promising advances in the treatment of patients with NSCLC and SCLC with advanced or metastatic disease. Most ICIs target ...programmed cell death protein 1 (PD-1) or programmed death ligand 1 (PD-L1) axis with the aim of restoring antitumor immunity. Multiple clinical trials for ICIs have evaluated a predictive value of PD-L1 protein expression in tumor cells and tumor-infiltrating immune cells (ICs) by immunohistochemistry (IHC), for which different assays with specific IHC platforms were applied. Of those, some PD-L1 IHC assays have been validated for the prescription of the corresponding agent for first- or second-line treatment. However, not all laboratories are equipped with the dedicated platforms, and many laboratories have set up in-house or laboratory-developed tests that are more affordable than the generally expensive clinical trial–validated assays. Although PD-L1 IHC test is now deployed in most pathology laboratories, its appropriate implementation and interpretation are critical as a predictive biomarker and can be challenging owing to the multiple antibody clones and platforms or assays available and given the typically small size of samples provided. Because many articles have been published since the issue of the IASLC Atlas of PD-L1 Immunohistochemistry Testing in Lung Cancer, this review by the IASLC Pathology Committee provides updates on the indications of ICIs for lung cancer in 2019 and discusses important considerations on preanalytical, analytical, and postanalytical aspects of PD-L1 IHC testing, including specimen type, validation of assays, external quality assurance, and training.
Immune checkpoint inhibitor (ICI) therapies have revolutionized the management of patients with NSCLC and have led to unprecedented improvements in response rates and survival in a subset of patients ...with this fatal disease. However, the available therapies work only for a minority of patients, are associated with substantial societal cost, and may lead to considerable immune-related adverse events. Therefore, patient selection must be optimized through the use of relevant biomarkers. Programmed death-ligand 1 protein expression by immunohistochemistry is widely used today for the selection of programmed cell death protein 1 inhibitor therapy in patients with NSCLC; however, this approach lacks robust sensitivity and specificity for predicting response. Tumor mutation burden (TMB), or the number of somatic mutations derived from next-generation sequencing techniques, has been widely explored as an alternative or complementary biomarker for response to ICIs. In theory, a higher TMB increases the probability of tumor neoantigen production and therefore, the likelihood of immune recognition and tumor cell killing. Although TMB alone is a simplistic surrogate of this complex interplay, it is a quantitative variable that can be relatively readily measured using currently available sequencing techniques. A large number of clinical trials and retrospective analyses, employing both tumor and blood-based sequencing tools, have evaluated the performance of TMB as a predictive biomarker, and in many cases reveal a correlation between high TMB and ICI response rates and progression-free survival. Many challenges remain before the implementation of TMB as a biomarker in clinical practice. These include the following: (1) identification of therapies whose response is best informed by TMB status; (2) robust definition of a predictive TMB cut point; (3) acceptable sequencing panel size and design; and (4) the need for robust technical and informatic rigor to generate precise and accurate TMB measurements across different laboratories. Finally, effective prediction of response to ICI therapy will likely require integration of TMB with a host of other potential biomarkers, including tumor genomic driver alterations, tumor-immune milieu, and other features of the host immune system. This perspective piece will review the current clinical evidence for TMB as a biomarker and address the technical sequencing considerations and ongoing challenges in the use of TMB in routine practice.
This overview of the fifth edition of the WHO classification of thymic epithelial tumors (including thymomas, thymic carcinomas, and thymic neuroendocrine tumors NETs), mediastinal germ cell tumors, ...and mesenchymal neoplasms aims to (1) list established and new tumor entities and subtypes and (2) focus on diagnostic, molecular, and conceptual advances since publication of the fourth edition in 2015. Diagnostic advances are best exemplified by the immunohistochemical characterization of adenocarcinomas and the recognition of genetic translocations in metaplastic thymomas, rare B2 and B3 thymomas, and hyalinizing clear cell carcinomas. Advancements at the molecular and tumor biological levels of utmost oncological relevance are the findings that thymomas and most thymic carcinomas lack currently targetable mutations, have an extraordinarily low tumor mutational burden, but typically have a programmed death-ligand 1high phenotype. Finally, data underpinning a conceptual advance are illustrated for the future classification of thymic NETs that may fit into the classification scheme of extrathoracic NETs. Endowed with updated clinical information and state-of-the-art positron emission tomography and computed tomography images, the fifth edition of the WHO classification of thymic epithelial tumors, germ cell tumors, and mesenchymal neoplasms with its wealth of new diagnostic and molecular insights will be a valuable source for pathologists, radiologists, surgeons, and oncologists alike. Therapeutic perspectives and research challenges will be addressed as well.
Background Diagnostic evaluation of patients with diffuse parenchymal lung disease (DPLD) is best achieved by a multidisciplinary team correlating clinical, radiological, and pathologic features. ...Surgical lung biopsy remains the gold standard for histopathologic diagnosis of idiopathic interstitial pneumonias. Emerging data suggest an increasing role for transbronchial cryobiopsy (TBC) in DPLD evaluation. We describe our experience with TBC in patients with DPLD. Methods We retrospectively reviewed medical records of patients with radiographic features of DPLD who underwent TBC at Mayo Clinic in Rochester, Minnesota from June 2013 to September 2015. Results Seventy-four patients (33 women 45%) with a mean age of 63 years (SD, 13.8) were included. The mean maximal diameter of the samples was 9.2 mm (range, 2-20 mm SD, 3.9). The median number of samples per procedure was three (range, one to seven). Diagnostic yield was 51% (38 of 74 specimens). The most frequent histopathologic patterns were granulomatous inflammation (12 patients) and organizing pneumonia (OP) (11 patients), resulting in the final diagnoses of hypersensitivity pneumonitis (six patients), cryptogenic OP (six patients), connective tissue disease-associated OP (three patients), drug toxicity (three patients), infection-related OP (two patients), sarcoidosis (two patients), and aspiration (one patient). Other histopathologic patterns included respiratory bronchiolitis (three patients), acute fibrinous and organizing pneumonia (two patients), desquamative interstitial pneumonia (1 patient), diffuse alveolar damage (one patient), pulmonary alveolar proteinosis (one patient), amyloidosis (one patient), eosinophilic pneumonia (one patient), necrotizing vasculitis (one patient), bronchiolitis with food particles (one patient), and malignancy (three patients). Pneumothorax developed in one patient (1.4%), and bleeding occurred in 16 patients (22%). Conclusions Our single-center cohort demonstrated a 51% diagnostic yield from TBC; the rates of pneumothorax and bleeding were 1.4% and 22%, respectively. The optimal use of TBC needs to be determined.
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