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

Imperatori A, Rotolo N, Dominioni L, Nardecchia E, Cattoni M, Cimetti L, Riva C, Sessa F, Furlan D - BMC Cancer (2015)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Center for Thoracic Surgery, Department of Surgical and Morphological Sciences, University of Insubria, Ospedale di Circolo, Via Guicciardini, 9, Varese, 21100, Italy. andrea.imperatori@uninsubria.it.

ABSTRACT

Background: 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.

Case presentation: 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.

Conclusion: 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.

No MeSH data available.


Related in: MedlinePlus

Chest CT details, histological and immunohystochemical studies. a Chest CT-scan axial view (lung window) showing a right hilar mass and post-obstructive collapse in the upper lobe anterior segment. b Close view of right pneumonectomy bronchial section margin (arrows); the main bronchus is obstructed by a polypoid tumor. c Lung metastatic adenocarcinomatous proliferation (hematoxylin & eosin staining, original magnification × 400); inset shows CDX-2 immunohistochemical staining (left), and CK20 positivity (right). d Chest CT-scan six months after right pneumonectomy, demonstrating enlarged left supraclavicular lymph nodes (arrow). e Lymph node metastasis with morphological features similar to Fig. 2c (hematoxylin & eosin staining, original magnification × 400); inset shows CDX-2 positivity
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Fig2: Chest CT details, histological and immunohystochemical studies. a Chest CT-scan axial view (lung window) showing a right hilar mass and post-obstructive collapse in the upper lobe anterior segment. b Close view of right pneumonectomy bronchial section margin (arrows); the main bronchus is obstructed by a polypoid tumor. c Lung metastatic adenocarcinomatous proliferation (hematoxylin & eosin staining, original magnification × 400); inset shows CDX-2 immunohistochemical staining (left), and CK20 positivity (right). d Chest CT-scan six months after right pneumonectomy, demonstrating enlarged left supraclavicular lymph nodes (arrow). e Lymph node metastasis with morphological features similar to Fig. 2c (hematoxylin & eosin staining, original magnification × 400); inset shows CDX-2 positivity

Mentions: In 1990, a 40-year-old male underwent anterior resection of rectal adenocarcinoma (Dukes B2; preoperative carcinoembryonic antigen (CEA) serum level: 35 ng/mL), that was diagnosed synchronously with a 9-cm metastasis in liver segments V-VIII. After postoperative 5-fluorouracil based chemotherapy, the CEA serum level was slightly decreased (22 ng/mL); liver metastasis was markedly downsized and was radically resected. Follow-up revealed no evidence of residual disease until 2002; follow-up was then intentionally interrupted because the patient was considered to be free of disease. On March 2007, the patient developed dyspnea and cough, and a chest computed tomography (CT) scan revealed a 5-cm right hilar mass bulging into the main bronchus and infiltrating the upper lobe (Figs. 1 and 2a). Bronchoscopy demonstrated a neoplastic growth that was obstructing the right main bronchus 2 cm distal to the carina; biopsy revealed moderately differentiated adenocarcinoma, compatible with rectal cancer recurrence. Colonoscopy and CT of the abdomen and pelvis showed no other evidence of neoplastic disease, and the CEA serum level was normal (1 ng/mL). On April 2007, the patient was aged 57 years and was fit for major thoracic surgery. He was treated by means of right pneumonectomy and regional lymphadenectomy to obtain complete resection (Fig. 2b). Histology of the excised lung metastasis (Fig. 2c) revealed an adenocarcinomatous proliferation with morphological features overlapping those of primary rectal cancer and of previously resected hepatic metastasis. The primary cancer and all of the metastatic sites were characterized by extensive complex tubular gland formation with sparse centroglandular necrotic foci. Nuclei were moderately or highly atypical, elongated and stratified. The mitotic index ranged from 17 (in rectal cancer) to 24 × 10 high power fields (in metastatic sites). A mild peritumoral lymphocytic infiltrate (cluster of differentiation 3 positive) was present. Budding was absent and there was no lymphovascular invasion. The immunophenotype included caudal-type homeobox protein 2 and cytokeratin (CK) 20 (CK 20) positivity (Fig. 2c, inset), whereas thyroid transcription factor-1 and CK 7 were negative. The main bronchus resection margin was tumor-free. Of the 18 lymph nodes excised, 4 (all peribronchial) were metastatic. The early postoperative course was complicated by empyema that was successfully treated with antibiotics and drainage. Follow-up with CT scans of the chest and abdomen at 6 months after pneumonectomy revealed enlarged left supraclavicular lymph nodes (Fig. 2d). Biopsy of the latter revealed a metastatic adenocarcinomatous growth with a high mitotic index (14 × 10 high-power fields) and a morphological and immunohistochemical profile identical to that previously described (Fig. 2e). There were no other signs of relapse. Systemic chemotherapy (leucovorin, 5-fluorouracil and oxaliplatin regimen) was then initiated and continued until July 2008, resulting in complete clinical remission. Subsequent follow-up with semi-annual assessments of CEA level and total body CT and/or a positron emission tomography scans revealed no evidence of recurrence. At the last examination, in February 2015, the patient was relapse-free and enjoyed a good quality of life, at 7 years after pneumonectomy for lung metastasis and at 24 years after rectal cancer resection. Genetic and epigenetic profiles of the primary tumor and the three matched metastases (pulmonary, hepatic and lymph nodal) were assessed to verify the clonal origin of the four tumor samples and to characterize key biological traits during the tumor evolution. Tables 1 and 2 summarize the molecular results. Methylation specific-multiplex ligation dependent probe amplification (MS-MLPA) was performed by using the ME001 MS-MLPA tumor suppressor-1 kit and the ME002 MS-MLPA tumor suppressor-2 Kit (MRC-Holland, Amsterdam, The Netherlands) to simultaneously analyze the methylation status of 33 tumor suppressor genes and copy number alterations (CNA) of 53 genes [11]. The primary rectal carcinoma showed a high frequency of CNAs at multiple chromosome regions suggesting an unstable karyotype in this tumor. Clonal CNAs including chromosome gains at 7q, 9pq, 11pq, 13q, 19p and 20q were recurrent in the primary tumor and in the matched metastases, demonstrating a common origin of the four tumor samples (Table 1). Similarly, clonal gene specific hypermethylation was observed at adenomatous polyposis coli (APC) and cadherin 13 (CDH13) loci, while additional hypermethylated genes, namely WT1, DAPK1, CHFR, PAX5 and GATA5, were found in the lung and in supraclavicular lymph node metastases (Table 2). Microsatellite instability (MSI) analysis, carried out using a pentaplex panel of monomorphic mononucleotide repeats (BAT25, BAT26, NR-21, NR-22 and NR-24) as previously reported [12], demonstrated the absence of MSI in all tumor samples. The Maldi-TOF mass spectrometry platform and the myriapod colon status kit (Diatech Pharmacogenetics, Jesi, Italy) were used to profile the patient’s four tumor samples, analyzing the 216 common hot-spot cancer mutations in the four major oncogenes involved in CRC pathogenesis (KRAS, BRAF, PIK3CA and NRAS). This analysis demonstrated no gene mutation in the primary rectal adenocarcinoma, and interestingly this genetic profile remained relatively well preserved in the three metastatic sites.Fig. 1


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

Imperatori A, Rotolo N, Dominioni L, Nardecchia E, Cattoni M, Cimetti L, Riva C, Sessa F, Furlan D - BMC Cancer (2015)

Chest CT details, histological and immunohystochemical studies. a Chest CT-scan axial view (lung window) showing a right hilar mass and post-obstructive collapse in the upper lobe anterior segment. b Close view of right pneumonectomy bronchial section margin (arrows); the main bronchus is obstructed by a polypoid tumor. c Lung metastatic adenocarcinomatous proliferation (hematoxylin & eosin staining, original magnification × 400); inset shows CDX-2 immunohistochemical staining (left), and CK20 positivity (right). d Chest CT-scan six months after right pneumonectomy, demonstrating enlarged left supraclavicular lymph nodes (arrow). e Lymph node metastasis with morphological features similar to Fig. 2c (hematoxylin & eosin staining, original magnification × 400); inset shows CDX-2 positivity
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4522059&req=5

Fig2: Chest CT details, histological and immunohystochemical studies. a Chest CT-scan axial view (lung window) showing a right hilar mass and post-obstructive collapse in the upper lobe anterior segment. b Close view of right pneumonectomy bronchial section margin (arrows); the main bronchus is obstructed by a polypoid tumor. c Lung metastatic adenocarcinomatous proliferation (hematoxylin & eosin staining, original magnification × 400); inset shows CDX-2 immunohistochemical staining (left), and CK20 positivity (right). d Chest CT-scan six months after right pneumonectomy, demonstrating enlarged left supraclavicular lymph nodes (arrow). e Lymph node metastasis with morphological features similar to Fig. 2c (hematoxylin & eosin staining, original magnification × 400); inset shows CDX-2 positivity
Mentions: In 1990, a 40-year-old male underwent anterior resection of rectal adenocarcinoma (Dukes B2; preoperative carcinoembryonic antigen (CEA) serum level: 35 ng/mL), that was diagnosed synchronously with a 9-cm metastasis in liver segments V-VIII. After postoperative 5-fluorouracil based chemotherapy, the CEA serum level was slightly decreased (22 ng/mL); liver metastasis was markedly downsized and was radically resected. Follow-up revealed no evidence of residual disease until 2002; follow-up was then intentionally interrupted because the patient was considered to be free of disease. On March 2007, the patient developed dyspnea and cough, and a chest computed tomography (CT) scan revealed a 5-cm right hilar mass bulging into the main bronchus and infiltrating the upper lobe (Figs. 1 and 2a). Bronchoscopy demonstrated a neoplastic growth that was obstructing the right main bronchus 2 cm distal to the carina; biopsy revealed moderately differentiated adenocarcinoma, compatible with rectal cancer recurrence. Colonoscopy and CT of the abdomen and pelvis showed no other evidence of neoplastic disease, and the CEA serum level was normal (1 ng/mL). On April 2007, the patient was aged 57 years and was fit for major thoracic surgery. He was treated by means of right pneumonectomy and regional lymphadenectomy to obtain complete resection (Fig. 2b). Histology of the excised lung metastasis (Fig. 2c) revealed an adenocarcinomatous proliferation with morphological features overlapping those of primary rectal cancer and of previously resected hepatic metastasis. The primary cancer and all of the metastatic sites were characterized by extensive complex tubular gland formation with sparse centroglandular necrotic foci. Nuclei were moderately or highly atypical, elongated and stratified. The mitotic index ranged from 17 (in rectal cancer) to 24 × 10 high power fields (in metastatic sites). A mild peritumoral lymphocytic infiltrate (cluster of differentiation 3 positive) was present. Budding was absent and there was no lymphovascular invasion. The immunophenotype included caudal-type homeobox protein 2 and cytokeratin (CK) 20 (CK 20) positivity (Fig. 2c, inset), whereas thyroid transcription factor-1 and CK 7 were negative. The main bronchus resection margin was tumor-free. Of the 18 lymph nodes excised, 4 (all peribronchial) were metastatic. The early postoperative course was complicated by empyema that was successfully treated with antibiotics and drainage. Follow-up with CT scans of the chest and abdomen at 6 months after pneumonectomy revealed enlarged left supraclavicular lymph nodes (Fig. 2d). Biopsy of the latter revealed a metastatic adenocarcinomatous growth with a high mitotic index (14 × 10 high-power fields) and a morphological and immunohistochemical profile identical to that previously described (Fig. 2e). There were no other signs of relapse. Systemic chemotherapy (leucovorin, 5-fluorouracil and oxaliplatin regimen) was then initiated and continued until July 2008, resulting in complete clinical remission. Subsequent follow-up with semi-annual assessments of CEA level and total body CT and/or a positron emission tomography scans revealed no evidence of recurrence. At the last examination, in February 2015, the patient was relapse-free and enjoyed a good quality of life, at 7 years after pneumonectomy for lung metastasis and at 24 years after rectal cancer resection. Genetic and epigenetic profiles of the primary tumor and the three matched metastases (pulmonary, hepatic and lymph nodal) were assessed to verify the clonal origin of the four tumor samples and to characterize key biological traits during the tumor evolution. Tables 1 and 2 summarize the molecular results. Methylation specific-multiplex ligation dependent probe amplification (MS-MLPA) was performed by using the ME001 MS-MLPA tumor suppressor-1 kit and the ME002 MS-MLPA tumor suppressor-2 Kit (MRC-Holland, Amsterdam, The Netherlands) to simultaneously analyze the methylation status of 33 tumor suppressor genes and copy number alterations (CNA) of 53 genes [11]. The primary rectal carcinoma showed a high frequency of CNAs at multiple chromosome regions suggesting an unstable karyotype in this tumor. Clonal CNAs including chromosome gains at 7q, 9pq, 11pq, 13q, 19p and 20q were recurrent in the primary tumor and in the matched metastases, demonstrating a common origin of the four tumor samples (Table 1). Similarly, clonal gene specific hypermethylation was observed at adenomatous polyposis coli (APC) and cadherin 13 (CDH13) loci, while additional hypermethylated genes, namely WT1, DAPK1, CHFR, PAX5 and GATA5, were found in the lung and in supraclavicular lymph node metastases (Table 2). Microsatellite instability (MSI) analysis, carried out using a pentaplex panel of monomorphic mononucleotide repeats (BAT25, BAT26, NR-21, NR-22 and NR-24) as previously reported [12], demonstrated the absence of MSI in all tumor samples. The Maldi-TOF mass spectrometry platform and the myriapod colon status kit (Diatech Pharmacogenetics, Jesi, Italy) were used to profile the patient’s four tumor samples, analyzing the 216 common hot-spot cancer mutations in the four major oncogenes involved in CRC pathogenesis (KRAS, BRAF, PIK3CA and NRAS). This analysis demonstrated no gene mutation in the primary rectal adenocarcinoma, and interestingly this genetic profile remained relatively well preserved in the three metastatic sites.Fig. 1

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Center for Thoracic Surgery, Department of Surgical and Morphological Sciences, University of Insubria, Ospedale di Circolo, Via Guicciardini, 9, Varese, 21100, Italy. andrea.imperatori@uninsubria.it.

ABSTRACT

Background: 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.

Case presentation: 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.

Conclusion: 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.

No MeSH data available.


Related in: MedlinePlus