Durable recurrence-free survival after pneumonectomy for late lung metastasis from rectal cancer: case report with genetic and epigenetic analyses

Andrea Imperatori, Nicola Rotolo, Lorenzo Dominioni, Elisa Nardecchia, Maria Cattoni, Laura Cimetti, Cristina Riva, Fausto Sessa, Daniela Furlan

Treatment of pulmonary recurrence from colorectal cancer involving the main bronchus usually entails palliation using interventional bronchoscopy, because the prognosis is generally very poor. Surgical experience has clarified that in this setting pneumonectomy should only be performed in carefully selected patients showing favorable prognostic profiles (defined by low carcinoembryonic antigen serum levels pre-thoracotomy), solitary and completely resectable pulmonary metastasis, and long disease-free intervals. In the few long-term survivors after pneumonectomy for late-recurrent colorectal cancer, the disease has a relatively indolent metastatic course and genetic and epigenetic profiling may provide further insight regarding tumor evolution. We describe a rare case of late hilar-endobronchial and lymph nodal recurrence of rectal cancer, sequential to hepatic metastasectomy, that we successfully treated with pneumonectomy and chemotherapy (leucovorin, 5-fluorouracil and oxaliplatin regimen); the patient achieved 7-year relapse-free survival after lung metastasectomy and 24-year overall survival after primary rectal cancer resection. To our knowledge, this is the longest survival reported after sequential liver resection and pneumonectomy for recurrent colorectal cancer. In our case the primary rectal cancer and its recurrences showed identical immunohistochemical patterns. The primary rectal cancer and the matched metastases (hepatic, pulmonary and lymph nodal) demonstrated no KRAS, NRAS, BRAF and PIK3CA mutations, a microsatellite stable phenotype, and no tumor protein p53 alterations or recurrent copy number alterations on chromosome 8. High genetic concordances between the paired primary tumor and metastases suggest that the key tumor biological traits remained relatively conserved in the three metastatic sites. Minor differences in gene specific hypermethylation were observed between the primary tumor and lung and nodal metastases. These differences suggest that epigenetic mechanisms may be causally involved in the microenvironmental regulation of cancer metastasis. The exceptionally long survival of the patient in our case study involving favorable clinical features was related to an excellent response to surgery and adjuvant chemotherapy; however, genetic or epigenetic factors that remain unidentified cannot be excluded as contributory factors. Our findings support the concept of a common clonal origin of the primary cancer and synchronous and late metastases, and suggest that aberrant DNA methylation may regulate tumor dormancy mechanisms.