Lung Metastases - Diagnostic, Prognostic and Molecular Aspects with Focus on Colorectal Cancer

Abstract: In Sweden 4200 patients are diagnosed with lung cancer and 6500 patients with colorectal cancer (CRC) annually. The lungs are a common site for metastases. Immunohistochemistry (IHC) is a helpful aid in diagnostics of a pulmonary tumour. Selected patients with metastatic CRC undergo pulmonary metastasectomy and knowledge about which patients benefit from it is important. In this thesis IHC markers to distinguish between primary lung cancer and lung metastases, survival and prognostic factors of CRC patients treated with pulmonary metastasectomy and genetic profiles of paired primary CRC, lung and liver metastases are studied. I: Lung adenocarcinoma (AC) was TTF-1 positive in 89, 93 and 93% of cases with clones 8G7G3/1, SPT24 and SP141 respectively. None of the lung squamous cell carcinoma (SqCC) was positive with clone 8G7G3/1 but 6 and 8% with clone SPT24 and SP141, respectively. Equivalent numbers for CRC lung metastases were 2, 7 and 8%. II: Lung adenocarcinoma (AC) was TTF-1 positive in 90%, napsin A in 84%, and CK7 in 99% of cases. 68% were positive for all three markers and negative for other evaluated markers. None of the lung squamous cell carcinoma (SqCC) was expressed CK5, p40 and p63 in 94-97% of cases, while 64% were positive for all three markers, CK7+/-, and negative for other evaluated markers. CRC lung metastases were CK20+ in 83% and CDX2+ in 99% of cases, while 78% were positive for both and negative for other evaluated markers. III: In total 216 patients with primary tumour in the rectum (57%), left colon (34%) or right colon (9%) underwent pulmonary metastasectomy. The 5-year overall survival was 56%. Age >60 years, >1 lung metastasis, size of metastasis >3 cm, disease-free interval <24 months, N2 status of the primary tumour, low RBM3 expression in the lung metastasis, and no adjuvant chemotherapy following pulmonary metastasectomy were prognostic factors for shorter overall survival. IV: Mutations were most frequent in the TP53, APC and KRAS genes with rates of 81-85%, 70% and 41-48%, respectively in the primary tumours and corresponding lung and liver metastasis. With TST26, identical mutational profile was found in 59% of paired triplet tumours. The concordance was higher between primary tumour and lung metastasis (74%) vs. primary tumour and liver metastasis (63%). For seven (54%) of the 13 KRAS-mutated cases the KRAS mutations were concordant. With TSO500, discordant KRAS mutational profiles could be confirmed, sometimes with discrepancy compared to TST26. There was no significant difference in TMB between primary tumour and metastases.

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