Faculty Bibliography

The landscape of care for early stage non-small cell lung cancer continues to evolve. While some of the developments do not seem as dramatic as what has occurred in advanced disease in recent years, there is a continuous improvement in our ability to diagnose disease earlier and more accurately. We have an increased understanding of the diversity of early stage disease and how to better tailor treatments to make them more tolerable without impacting efficacy. The International Association for the Study of Lung Cancer and the Journal of Thoracic Oncology publishes this annual update to help readers keep pace with these important developments. Experts in the care of early stage lung cancer patients have provided focused updates across multiple areas including screening, pathology, staging, surgical techniques and novel technologies, adjuvant therapy, radiotherapy, surveillance, disparities, and quality of life. The source for information includes large academic meetings, the published literature, or novel unpublished data from other international oncology assemblies.

Biospecimen quality can vary depending on many pre- and post-collection variables. In this study, we consider a natural disaster as a post-collection variable that may have compromised the quality of frozen tissue specimens. To investigate this possible link, we compared the quality of nucleic acids, the level of antigenicity, and the preservation of histology from frozen specimens collected before and after the power outage caused by Hurricane Sandy. To analyze nucleic acid quality, we extracted both DNA and RNA and performed capillary electrophoresis to compare the quality and concentrations of the nucleic acids. To compare antigenicity, frozen sections were cut and immunostained for thyroid transcription factor 1 (TTF-1), a nuclear transcription protein commonly used as a diagnostic biomarker for multiple cancer types, including thyroid and lung cancers. Positive expression of TTF-1, as noted by homogenous nuclear staining, would demonstrate that the TTF-1 proteins could still bind antibodies and, therefore, that these proteins were not significantly degraded. Furthermore, representative frozen sections stained with hematoxylin and eosin were also assessed qualitatively by a trained pathologist to examine any possible histologic aberrations. Due to the similar quality of the tissue samples collected before and after the storm, Hurricane Sandy had no discernable effect on the quality of frozen specimens, and these specimens exposed to the natural disaster are still valuable research tools.

Multiple tumor nodules (MTNs) are seen with increasing frequency in clinical practice. Based on the 2015 WHO classification of lung tumors, we assessed the reproducibility of the comprehensive histologic assessment (CHA) to distinguish second primary lung cancers (SPLC) from intrapulmonary metastases (IPM), looking for the most distinctive histological features. An international panel of lung pathologists reviewed a scanned sequential cohort of 126 tumors from 48 patients, 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. Cohen's Kappa statistics of 0.60 on overall assessment of SPLC or IPM indicated a good agreement. Likewise, there was good agreement (0.64 Kappa score, p<0.0001) between WHO histological pattern in individual cases and SPLC or IPM status but proportions diversified for histology and SPLC or IPM status (McNemar's test, p<0.0001). The strongest associations for distinguishing between SPLC and IM were observed for nuclear pleomorphism, cell size, acinus formation, nucleolar size, mitotic rate, nuclear inclusions, intra-alveolar clusters and necrosis. Conversely, lymphocytosis, mucin content, lepidic growth, vascular invasion, macrophage response, clear cell change, acute inflammation keratinization and emperipolesis did not reach significance with tumor extent. CHA 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 p staging status.

CONTEXT/BACKGROUND:- Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) has emerged as a very useful tool in the field of diagnostic respiratory cytology. Rapid on-site evaluation (ROSE) of EBUS-TBNA not only has the potential to improve diagnostic yield of the procedure but also to triage samples for predictive molecular testing to guide personalized treatments for lung cancer. OBJECTIVE:- To provide an overview of the current status of the literature regarding ROSE of EBUS-TBNA in the diagnosis of lung cancer. DATA SOURCES/METHODS:- An electronic literature search in PubMed and Google databases was performed using the following key words: cytology, lung cancer, on-site evaluation, rapid on-site evaluation, and ROSE EBUS-TBNA. Only articles published in English were included in this review. CONCLUSIONS:- Rapid on-site evaluation can ensure that the targeted lesion is being sampled and can enable appropriate specimen triage. If available, it should be used with EBUS-TBNA in the diagnosis of lung cancer because it can minimize repeat procedures for additional desired testing (ie, molecular studies). Some studies have shown that ROSE does not adversely affect the number of aspirations, total procedure time of EBUS-TBNA, or the rate of postprocedure complications; it is also helpful in providing a preliminary diagnosis that can reduce the number of additional invasive procedures, such as mediastinoscopy. As EBUS technology continues to evolve, our knowledge of the role of ROSE in EBUS-TBNA for the diagnosis of lung cancer will also continue to grow and evolve.

In this review, we outline the biology and management of patients with carcinosarcomas and related malignancies, which are often included under the broader concept of sarcomatoid carcinomas. Carcinosarcomas are unusual tumors that are commonly gynecologic in origin, where they are referred to as malignant mixed Müllerian tumors, but may appear in any anatomic site. Although a variety of hypotheses have been presented as to the biphasic nature of these tumors, carcinosarcomas seem to represent the best example in human cancers of the concept of epithelial-mesenchymal transition (EMT), in which the two parts of the tumor are genomically related to one another, as opposed to the mesenchymal component that represents a second neoplasm or (benign) reactive process. In general, patients with carcinosarcomas fare worse than patients with carcinomas of the same anatomic site. Treatment paradigms for carcinosarcomas generally follow those of carcinomas of the same organ site, except where clinical trials provide more specific options. Agents that block or reverse EMT are worth examination in patients with carcinosarcoma and arguably may be even more effective in carcinomas, given evidence of dependence on EMT to generate successful metastases. Information about EMT may also inform other phase transitions in cancer, such as those between prostate or lung carcinoma and more aggressive tumors with neuroendocrine differentiation.

BACKGROUND: Two recent observations regarding the Warburg effect are that (i) the metabolism of stem cells is constitutive ('aerobic') glycolysis while normal cellular differentiation involves a transition to oxidative phosphorylation and (ii) the degree of glucose uptake of a malignancy as imaged by 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) is associated with histologic measures of tumor differentiation. Combining these observations, we hypothesized that the high levels of glucose uptake observed in poorly differentiated cancers may reflect persistence of the glycolytic metabolism of stem cells in malignant cells that fail to fully differentiate. PATIENTS AND METHODS: Tumor glucose uptake was measured by FDG-PET in 552 patients with histologically diverse cancers. We used normal mixture modeling to explore FDG-PET standardized uptake value (SUV) distributions and tested for associations between glucose uptake and histological differentiation, risk of lymph node metastasis, and survival. Using RNA-seq data, we performed pathway and transcription factor analyses to compare tumors with high and low levels of glucose uptake. RESULTS: We found that well-differentiated tumors had low FDG uptake, while moderately and poorly differentiated tumors had higher uptake. The distribution of SUV for each histology was bimodal, with a low peak around SUV 2-5 and a high peak at SUV 8-14. The cancers in the two modes were clinically distinct in terms of the risk of nodal metastases and death. Carbohydrate metabolism and the pentose-related pathway were elevated in the poorly differentiated/high SUV clusters. Embryonic stem cell-related signatures were activated in poorly differentiated/high SUV clusters. CONCLUSIONS: Our findings support the hypothesis that the biological basis for the Warburg effect is a persistence of stem cell metabolism (i.e. aerobic glycolysis) in cancers as a failure to transition from glycolysis-utilizing undifferentiated cells to oxidative phosphorylation-utilizing differentiated cells. We found that cancers cluster along the differentiation pathway into two groups, utilizing either glycolysis or oxidative phosphorylation. Our results have implications for multiple areas of clinical oncology.