Adenocarcinoma of the lung: an exploration of the relationships between histopathology, molecular pathology and inflammatory markers and their relationship to patient outcomes

© 2017 Dr. Timothy Dudley ClayLung cancer remains the most common cause of cancer related death worldwide, with nearly 1.4 million deaths in 2008 globally. Adenocarcinoma is the most common type of lung cancer, and its frequency compared to other histologic subtypes is increasing. The simplicity of the label “adenocarcinoma” hides its significant pathologic and clinical heterogeneity. This thesis explores a number of clinicopathologic correlates in lung adenocarcinoma specimens obtained from patients treated at St Vincent’s Hospital in Melbourne, Australia. In 2011 the International Association for the Study of Lung Cancer (IASLC), the American Thoracic Society (ATS) and the European Respiratory Society (ERS) proposed a new classification system for pulmonary adenocarcinoma. This was subsequently adopted in the 2015 edition of the World Health Organisation Classification of Tumours of the Lung, Pleura, Thymus and Heart. Multiple groups demonstrated that the new classification had prognostic significance following resection of pulmonary adenocarcinoma independent of stage. The impact of the classification in metastatic disease was not known. This thesis found that it was possible to identify the adenocarcinoma patterns of solid with mucin, papillary, micropapillary and acinar in each specimen taken from a metastatic site and semi-quantitatively assess each component. Further, the identification of a major pattern was not prognostic, but did predict for differences in survival time for patients treated with systemic therapy. The worst outcomes were observed for patients with tumours with a major solid pattern. The major solid pattern was also found to have infrequent occurrence of activating epidermal growth factor receptor (EGFR) mutations. As this is the first time that this novel finding has been reported. Validation from other groups is required. The presence of the IASLC/ATS/ERS classification as a robust new tool with clinical relevance has led to further research to define other clinicopathologic correlates. Oncogene driver mutations in genes such as EGFR and Kirsten RAS (KRAS) are critical in selection of therapy in advanced disease. This thesis examined relationships between adenocarcinoma subtype and mutation status for patients who had resected lung adenocarcinoma. Patients with solid predominant adenocarcinoma were significantly less likely to have EGFR mutations, while KRAS mutation was a frequent event in invasive mucinous adenocarcinoma. No other significant associations were found. The findings were consistent with those recently reported by other groups from centres located in predominantly Caucasian countries. EGFR inhibition and the discovery of EGFR mutations was the starting point for a major change in the approach to treatment of advanced lung adenocarcinoma, however resistant to treatment occurs. It had been suggested that upregulation of phosphorylated STAT3 (pSTAT3) via interleukin 6 (IL6) and Janus Kinase (JAK) may be linked to EGFR mutation status in the absence of treatment with EGFR tyrosine kinase inhibitors and therefore may offer a rational target to delay resistance to such therapies. In the patient cohort studied the presence of EGFR or KRAS mutation status did not enrich for activation of IL6, JAK1 or pSTAT3 as determined by immunohistochemistry. Further, there was no clinicopathologic or prognostic correlates of note found by the IL6, JAK1 or pSTAT3 activation state. The assessment of IL6, JAK1 and pSTAT3 in the same samples and by two methods to assess positivity was a unique feature of this study. In conclusion this contributes new knowledge on the relevance of pathologic subtyping in advanced lung adenocarcinoma. It confirms and consolidates recent reports oncogene mutation status and adenocarcinoma subtype following surgical resection. It examines the IL6 / JAK1 / pSTAT3 pathway in detail in resected pulmonary adenocarcinoma. Translational research that explores why adenocarcinoma subtypes have different outcomes by treatment may allow clinicians to direct therapies differently or unlock new pathways for targeting lung adenocarcinoma with therapeutic effect