Metachronous Lung Metastases Research Articles

Laryngeal Small Cell Neuroendocrine Carcinoma: Case Report and Literature Review

Neuroendocrine malignancy of the larynx are rare but represents the first nonsquamous tumor in this localization. The World Health Organization (WHO) classifies these tumors into 3 groups: typical carcinoid, atypical carcinoid tumor, and small cell neuroendocrine carcinoma (SmCC). SmCC have an aggressive natural history characterized by widespread metastasis. Treatment is based on concomitant or sequential chemoradiation. We report herein the case of a 69 years old men, who presented with laryngeal small cell neuroendocrine carcinoma revealed by progressive dysphonia and cervical lymphadenopathy. The diagnosis was confirmed by biopsy and histopathological study. Pre-treatment workup was negative for metastatic disease. He has received chemotherapy based on etoposide and cisplatin followed by chemoradiation. The evolution was marked by the development of metachronous lung metastasis. Unfortunately, the patient passed away during a chemotherapy-induced myelosuppression after the first palliative chemotherapy cure.

Survival outcome following surgical versus non-surgical treatment of colorectal lung metastasis—a retrospective cohort study

PurposeThe optimal management of colorectal lung metastases (CRLM) is still controversial. The aim of this study was to compare surgical and non-surgical treatment for CRLM regarding the prognostic outcome.MethodsThis retrospective single-center cohort study included 418 patients, who were treated from January 2000 to December 2018 at a German University Hospital due to their colorectal carcinoma and had synchronous or metachronous lung metastases. Patients were stratified according the treatment of the CRLM into two groups: surgical resection of CRLM versus no surgical resection of CRLM. The survival from the time of diagnosis of lung metastasis was compared between the groups.ResultsTwo- and 5-year overall survival (OS) from the time of diagnosis of lung metastasis was 78.2% and 54.6%, respectively, in our cohort. Patients undergoing pulmonary metastasectomy showed a significantly better 2- and 5-year survival compared to patients with non-surgical treatment (2-year OS: 98.1% vs. 67.9%; 5-year OS: 81.2% vs. 28.8%; p < 0.001). Multivariate Cox regression revealed the surgical treatment (HR 4.51 (95% CI = 2.33–8.75, p < 0.001) and the absence of other metastases (HR 1.79 (95% CI = 1.05–3.04), p = 0.032) as independent prognostic factors in patients with CRLM.ConclusionOur data suggest that patients with CRLM, who qualify for surgery, benefit from surgical treatment. Randomized controlled trials are needed to confirm our findings.Clinical trial registry numberThe work has been retrospectively registrated at the German Clinical Trial Registry (DRKS00032938).

Impact of lateral cervical lymph node metastasis on lung metastasis in pediatric thyroid cancer: A correlation study

BackgroundThyroid cancer (TC) frequently manifests with lung metastases in the pediatric population, occurring at a significant rate of 30 %. This study aims to evaluate the impact of regional patterns of cervical lymph node metastases on lung metastases in pediatric TC. MethodsRetrospective analysis was conducted on data from pediatric TC patients spanning the years 2000 to 2018. We compared the rates of lymph node metastasis (LNR), the number of lymph node metastases, and the number of dissected lymph nodes in the central and lateral cervical regions between patients with and without lung metastases. Statistical methods were employed to adjust for confounders during hypothesis testing. ResultsA total of 227 pediatric patients, with a median age of 15.12 ± 2.84 years, were included in the study. Of these, 202 (89 %) exhibited LN metastasis, with 40(17.62 %) patients presenting with lung metastasis. Patients with lung metastases were found to be younger (13.40 ± 3.11 vs. 15.50 ± 2.64, p < 0.001), had larger primary tumor diameters (3.49 ± 1.98 vs. 2.31 ± 1.45, p < 0.001), and exhibited a higher number of lymph node metastases (23.40 ± 10.75 vs. 14.65 ± 13.16, p < 0.001). Notably, in patients with LN metastases, the presence of >12 lateral cervical lymph node metastases emerged as a significant risk factor for lung metastases. Among children with metachronous lung metastases, the median time to detection of lung metastases was 43 (12−132) months, and they appeared to receive a greater proportion of radioactive iodine (RAI) treatment compared to those with synchronous lung metastases. ConclusionLateral cervical lymph node metastasis independently predicts the likelihood of lung metastases in pediatric TC. Furthermore, our findings emphasize the importance of thorough examination of the lungs during follow-up, particularly when the number of metastatic lateral cervical lymph nodes exceeds 12.

Incidence, survival, and associated factors estimation in osteosarcoma patients with lung metastasis: a single-center experience of 11 years in Tianjin, China

BackgroundOsteosarcoma is the most common primary malignant bone tumor. The current study was conducted to describe the general condition of patients with primary osteosarcoma in a single cancer center in Tianjin, China and to investigate the associated factors in osteosarcoma patients with lung metastasis.MethodsFrom February 2009 to October 2020, patients from Tianjin Medical University Cancer Institute and Hospital, China were retrospectively analyzed. The Kaplan–Meier method was used to evaluate the overall survival of osteosarcoma patients. The Cox proportional hazard regression analysis was performed to analyze the prognostic factors of all osteosarcoma patients and those patients with lung metastasis, respectively. Furthermore, risk factors for developing lung metastasis were identified in synchronous lung metastasis (SLM) and metachronous lung metastasis (MLM) patients.ResultsA total of 203 patients were involved and 150 patients were successfully followed up for survival status. The 5-year survival rate of osteosarcoma was 70.0% and the survival months for patients with SLM and MLM were 33.3 ± 12.6 and 45.8 ± 7.4 months, respectively. The presence of lung metastasis was one of the independent prognostic factors for prognosis of osteosarcoma. In patients with lung metastasis, twenty-one (10.3%) showed lung metastasis at the diagnosis of osteosarcoma and 67 (33%) were diagnosed with lung metastases during the later course. T3 stage (OR = 11.415, 95%CI 1.362–95.677, P = 0.025) and bone metastasis (OR = 6.437, 95%CI 1.69–24.51, P = 0.006) were risk factors of SLM occurrence. Bone metastasis (OR = 1.842, 95%CI 1.053–3.224, P = 0.032), good necrosis (≥ 90%, OR = 0.032, 95%CI 0.050–0.412, P < 0.001), elevated Ki-67 (OR = 2.958, 95%CI 1.098–7.969, P = 0.032) and elevated LDH (OR = 1.791, 95%CI 1.020–3.146, P = 0.043) were proved to be independent risk factors for developing MLM.ConclusionThe overall survival, prognostic factors and risk factors for lung metastasis in this single center provided insight about osteosarcoma management.

CT features of osteosarcoma lung metastasis: a retrospective study of 127 patients.

Osteosarcoma lung metastases have a wide variety of CT presentations, representing a challenge for radiologists. Knowledge of atypical CT patterns of lung metastasis is important to differentiate it from benign lung disease and synchronous lung cancer, as well as to determine the extent of primary disease. The objective of this study was to analyze CT features of osteosarcoma lung metastasis before and during chemotherapy. Two radiologists independently reviewed chest CT images of 127 patients with histopathologically confirmed osteosarcoma treated between May 10, 2012 and November 13, 2020. The images were divided into two groups for analysis: images obtained before chemotherapy and images obtained during chemotherapy (initial CT examination). Seventy-five patients were diagnosed with synchronous or metachronous lung metastases. The most common CT findings were nodules (in 95% of the patients), distributed bilaterally (in 86%), with no predominance regarding craniocaudal distribution (in 71%). Calcification was observed in 47%. Less common findings included intravascular lesions (in 16%), cavitation (in 7%), and the halo sign (in 5%). The primary tumor size was significantly greater (i.e., > 10 cm) in patients with lung metastasis. On CT scans, osteosarcoma lung metastases typically appear as bilateral solid nodules. However, they can have atypical presentations, with calcification being the most common. Knowledge of the typical and atypical CT features of osteosarcoma lung metastasis could play a key role in improving image interpretation in these cases.

Prediction factors in surgical treatment of intragrawn kidney cancer metastasis

Background . The incidence of distant metastases of intrathoracic localization in kidney cancer, including intrathoracic lymph nodes, makes the problem of identifying and introducing knowledge about prognostic factors into clinical practice when using the surgical treatment of this disease urgent. Aim . To identify prognostic factors in the surgical treatment of intrathoracic metastases of renal cancer. Materials and methods . In this work, a retrospective analysis was carried out of a group of 100 patients with intrathoracic cancer metastases, almost who underwent surgical treatment in the form of removal of distant metastases. We analyzed the clinically significant factors associated with the prevalence of the tumor process in the lungs, which could affect the long-term results of treatment, as well as the influence of various instrumental research methods on the frequency of detection of intrathoracic lesions. In addition, the influence of the choice of surgical approach and the volume of surgery on the long-term survival of this group of patients was analyzed. Results . 40 (40 %) patients had synchronous and 60 (60 %) had metachronous lung metastases. 63 (63 %) had open and 36 (36 %) – thoracoscopic surgery, 1 (1 %) patient underwent a transdiaphragmatic resection. 70 (70 %) patients had atypical lung resections. 5-year overall survival was 53.4 %, 5-year progression-free survival – 43.1 %. There was no postoperative mortality and no grade 3–4 morbidity. Following factors were associated with an overall survival during a single-factor analysis: bilateral lung lesions (р &lt;0.0001), R0 resection (р = 0.002), Munich scale (р = 0.007). Only bilateral lung lesion were associated with an overall survival during a multifactor analysis (р = 0.001). Conclusions . Removal of intrathoracic metastases of kidney cancer in the lung can lead to long-term survival in a significant number of patients. Achieving R0 resection is the main goal of surgical treatment.

Literature review of imaging, pathological diagnosis, and outcomes of metachronous lung and pancreatic metastasis of cecal cancer

BackgroundPancreatic metastasis from colorectal cancer is extremely rare. Here, we report a case of colorectal cancer with lung and pancreatic metastasis and analyze the histopathology, immunohistochemistry, and next-generation sequencing (NGS) to generate a differential diagnosis and treatment of metastatic colon cancer.Case presentationAC1A 78-year-old man was admitted because of a recently elevated carcinoembryonic antigen. This patient had undergone laparoscopic right hemicolectomy for cecal cancer IIA (T3N0M0) 5 years before admission, and thoracoscopic left upper lung wedge resection for primary colon cancer lung metastasis 2 years before admission. At that time, the patient was thought to have pancreatic metastasis from colon cancer. He underwent laparoscopic distal pancreatectomy (combined with splenectomy). Postoperative pathology revealed colon cancer metastasis. We performed NGS on tumor samples at three loci and found colon cancer's most common oncogenic driver genes (KRAS, APC, and TP53). One month after surgery, the patient was given capecitabine for six cycles of chemotherapy. At present, no high adverse reactions have been reported.DiscussionFor patients with pancreatic space-occupying, such as a previous history of colorectal cancer, and recent carcinoembryonic antigen elevation, we should highly suspect pancreatic metastatic colorectal cancer. NGS is an essential auxiliary for identifying metastatic tumors. Surgery combined with postoperative chemotherapy is an effective treatment.

Prognosis and tumor biology of pancreatic cancer patients with isolated lung metastases: translational results from the German multicenter AIO-YMO-PAK-0515 study

BackgroundPulmonary metastasis (M1-PUL) as first site of dissemination in pancreatic ductal adenocarcinoma (PDAC) is a rare event and may define a distinct biological subgroup.Patients and methodsArbeitsgemeinschaft Internistische Onkologie-Young Medical Oncologists-Pankreas-0515 study (AIO-YMO-PAK-0515) was a retrospective German multicenter study investigating clinical and molecular characteristics of M1-PUL PDAC patients; 115 M1-PUL PDAC patients from 7 participating centers were included. Clinical characteristics and potential prognostic factors were defined within the M1-PUL cohort. Archival tumor samples were analyzed for Her2/neu, HNF1A and KRT81 expression. Additionally, messenger RNA (mRNA) expression analysis (using a 770-gene immune profiling panel) was carried out in the M1-PUL and in a control cohort (M1-ANY).ResultsMedian overall survival in the entire M1-PUL cohort was 20 months; the most favorable prognosis (median survival: 28 months) was observed in the subgroup of 66 PDAC patients with metachronous lung metastases after previous curative-intent surgery. The number of metastatic lesions, uni- or bilateral lung involvement as well as metastasectomy were identified as potential prognostic factors. Her2/neu expression and PDAC subtyping (by HNF1A and KRT81) did not differ between the M1-PUL and the M1-ANY cohort. mRNA expression analysis revealed significant differentially expressed genes between both cohorts: CD63 and LAMP1 were among the top 20 differentially expressed genes and were identified as potential mediators of organotropism and favorable survival outcome of M1-PUL patients.ConclusionM1-PUL represents a clinically favorable cohort in PDAC patients. Site of relapse might already be predetermined at the time of surgery and could potentially be predicted by gene expression profiling.

Characteristics and Growth Rate of Lung Metastases in Patients With Primary Gastrointestinal Malignancies and Lung-dominant Metastatic Disease: A Retrospective Cohort Analysis.

There are no formal guidelines for the management of patients with primary gastrointestinal (GI) cancers who have lung-exclusive or lung-predominant metastases. We performed a retrospective analysis to evaluate host and tumor characteristics of this patient population, model patterns and rates of growth, and describe treatment approaches. Eligible patients had a GI cancer with either synchronous or metachronous lung metastases but no other visceral or peritoneal sites of involvement. In addition to collecting detailed patient-specific and tumor-specific information, all imaging studies (computed tomography±positron emission tomography scans) were reviewed by an independent radiologist. Up to 5 lung metastases were tracked through each patient's clinical course. Growth rate was estimated using a linear mixed model analysis. Forty patients met eligibility criteria (18 pancreatic, 15 colorectal, 6 hepatobiliary, 1 gastroesophageal; synchronous vs. metachronous, 13 and 27, respectively). Median time from original cancer diagnosis to onset of metachronous lung lesions was 16 months. Interval from first appearance of lung metastases to treatment initiation was 6.2 months. Average growth rate of the largest lesion was 0.21 mm/mo (95% confidence interval, 0.12-0.30), with substantial intrapatient and interpatient variability. Sixty percent of patients underwent locoregional interventions in addition to or in lieu of systemic therapy for their lung metastases. Median survival of the entire study cohort from first appearance of lung metastases was 54 months. Lung metastases from primary GI cancers have a variable but overall indolent natural history and are generally associated with prolonged survival outcomes. Further efforts to define patterns of growth of lung metastases, informed by size, number, and clinical/molecular features, are needed to guide appropriate timing and selection of therapy as well as surveillance strategies.

TNM classification for lung metastases

: Although extensively discussed in the field of oncology, lung metastases (LM) remains an important clinical dilemma full of uncertainty with many unresolved questions. The extensive literature shows that the level of evidence to perform LM is weak, and surgeons continue to operate on the basis of their own experience without formal guidelines. Furthermore, the recent results of the Pulmonary Metastasectomy colorectal (PulMiCC) trial showed no statistical differences on survival between operated and no-operated patients with lung metastases. It is obvious that we are caught in a dead-end, as it seems impossible to know whether or not surgery is indicated in pulmonary metastases or when other treatments should be preferred. The aim of this paper is to highlight the rationale, the possible advantages and future direction of the TNM classification for lung metastases. For these reasons, we re-propose a TNM classification for lung metastases which was published initially in 2016. The originally idea of the TNM classification of LM was born to explain how the number of metastases and nodal involvement interfere between each other to influence survival. We anticipate that in the amended classification the T will describe the number of metastases. We will also include the acronymous LM before the TNM (lmTNM) to differentiate it from the classical TNM classification for cancers. Time to metastasis (TM), defined as the time of appearance of lung metastasis, which is an important prognostic factor could also be added in the staging system to separate synchronous from metachronous lung metastases. Conclusion: We believe that the TNM classification for LM will simplify the indication for surgery and allow physicians, oncologist and surgeons to speak the “same language” in comparing their data and assessing the results of treatment of lung metastases.

Survival outcome of pulmonary metastasectomy among the patients with colorectal cancers.

Pulmonary metastasectomy for the treatment of metastatic colorectal cancer is essential, but high ranked evidence of survival benefit is lacking. Here, we aimed to examine the prognostic factors after pulmonary metastasectomy in patients with colorectal cancer. This is a single-center, retrospective hospital-based observational case series study. We reviewed data for 607 patients with metastatic colorectal cancer (mCRC) who were treated and observed from 2012 to 2019. Of the 607 patients with mCRC, 87 were with solitary lung metastases. Of the 87 patients, 39 were not appropriate for metastasectomy, while 15 patients recognized as suitable candidates by the multidisciplinary thoracic tumor board rejected metastasectomy. Consequently, only 33 patients were included in the final analysis. Rectum was detected as the primary site in 16 (48.5%) patients. Over 80% of patients had metachronous lung metastases, with a median of 29.0 months from initial diagnosis. Video-assisted thoracic surgery with wedge resection was performed in 20 (60.6%) patients. Over 90% of patients had solitary metastasis resected, with 97% of R0 resection. Median tumor size was 23.0 mm (min: 10; max: 90). Adjuvant treatment was given to 31 (93.9%) patients, while neoadjuvant treatment was given only to 8 (25%) patients. Of the 33 patients, there were 25 (75.7%) relapses. The most frequent site of relapse was lung in 15 (45.5%) patients. Interestingly, there were only 4 (12.2%) patients who had a relapse in the liver after lung metastasectomy. We found that median disease-free survival (DFS) and overall survival (OS) were 43.0 (13.0-73.0) and 55.0 (31.6-78.4) months, respectively. Pulmonary metastasectomy was associated with significantly long-time survival rates in mCRC (43 months of DFS and 55 months of OS). The second relapse occurred in 25 (75.7%) patients, with isolated lung metastases in nearly half of the patients (45.5%). Therefore, lung metastases in mCRC were unique and a multidisciplinary team including a thoracic surgeon should manage these patients.

Prognostic Factors Affecting Survival after Pulmonary Resection of Metastatic Renal Cell Carcinoma: A Multicenter Experience.

Simple SummaryThis multicentric paper aimed at evaluating the role of pulmonary metastasectomy in patients affected by metastatic renal cell carcinoma. The impact of pulmonary metastasectomy was analysed with respect to long-term survival and disease-free survival in a wide population of patients affected by pulmonary metastases from renal cell carcinoma. The prognostic value of factors affecting survival, disease-free interval and disease-free survival was evaluated. Our results aid clinicians in identifying those patients affected by pulmonary metastases from renal cell carcinoma who are more likely to benefit from pulmonary metastasectomy.In this paper we aimed to address the role of pulmonary metastasectomy (PM) in patients affected by Lung Metastases (LM) from Renal Cell Carcinoma (RCC) and to analyse prognostic factors affecting overall survival (OS), disease-free interval (DFI) between primary RCC and first LM, and disease-free survival (DFS) after PM and before lung recurrence. Medical records of 210 patients who underwent PM from RCC in 4 Italian Thoracic Centres, from January 2000 to September 2019, were collected and analysed. All patients underwent RCC resection before lung surgery. The main RCC histology was clear cells (188, 89.5%). The 5- and 10-year OS from the first lung operation were 60% and 34%, respectively. LM synchronous with RCC (p = 0.01) and (Karnofsky Performance Status Scale) KPSS < 80% (p < 0.001) negatively influenced OS. Five- and 10-year DFI were 54% and 28%, respectively. The main factors negatively influencing DFI were: male gender (p = 0.039), KPSS < 80% (p = 0.009) and lactate dehydrogenase > 1.5 times 140 U/L (p = 0.001). Five- and 10-year disease-free survival were 54% and 28%, respectively; multiple LM (p = 0.036), KPSS < 80% (p = 0.001) and histology of RCC other than clear cells negatively influenced disease-free survival. Conclusions: patients with KPSS > 80%, single metachronous LM with a long DFI from RCC diagnosis, and clear cell histology, benefit from pulmonary metastasectomy.

Impact of Driver Mutations on the Evolution of Isolated Metachronous Lung Metastasis of Pancreatic Ductal adenocarcinoma

The incidence of pancreatic ductal adenocarcinoma (PDAC) is increasing sharply. The survival of patients with metastases is usually about a year. However, the occurrence of isolated lung metastases after resection of the primary tumor, although rare, seems to indicate a better prognosis, with an average survival ranging from 40 to 80months. KRAS, TP53, CDK2NA, and SMAD4 are the most common driver genes in pancreatic adenocarcinoma. Our objectives were to determine whether a link exists between survival and mutations of driver genes in patients with isolated pulmonary metastases. All patients who underwent curative surgery in our institution between 2010 and 2018 were included in the study. From these, we identified patients for whom recurrence was only pulmonary and those with metastases at other sites. KRAS, TP53, CDK2NA, and SMAD4 were analyzed on the primary tumorof patients with pulmonary metastases. Among 233 patients diagnosed with PDAC in our institution over 8years, 41 (17.5%) underwent curative surgery. Of these, seven (3%) developed isolated pulmonary metastases, 32 developed other metastases, and two did not recur. Median survival was 59months for patients with isolated lung metastases and 25.3months for patients with metastases at other sites. An absence of mutations of two driver genes in primary tumors (CDK2NA and SMAD4) was observed in patients with isolated pulmonary metastases. The absence of mutations in the CDK2NA and SMAD4 tumor-suppressor genes in patients with isolated pulmonary metastases contrasts with the commonly observed high rates of driver gene mutations and suggests a link with overall survival.

Surgery for synchronous and metachronous single-organ metastasis of pancreatic cancer: a SEER database analysis and systematic literature review

Surgery for metastatic pancreatic cancer remains controversial as the survival benefit is questionable. The aim of the present study was to analyze the survival of these patients using data extracted from the surveillance, epidemiology, and end results (SEER) program database. Further, studies on resection for metastatic disease to the lung were systematically reviewed. A total of 11,541 cases with synchronous distant metastasis were analyzed. The median survival of single-organ metastasis was better than of multi-organ metastasis (single-organ 4.0 ± 0.07 months, two-organs 3.0 ± 0.13 months, three/four-organs 2.0 ± 0.19 months; p < 0.0001). Single organ lung metastasis had longer median survival times compared to the other sites (lung 6.0 ± 0.32 months, HR 0.87, 95% CI 0.78–0.97; p = 0.013). Resection of the primary tumor was associated with longer survival in synchronous single-organ metastasis to the lung compared to no resection (14.0 ± 1.93 months vs 6.0 ± 0.31 months, p < 0.0001). A systematic literature review identified 79 cases of metachronous lung metastasis with a survival of 120.0 ± 6.32 months and 83.0 ± 24.84 months following resection of the primary tumor and metastasis, respectively. Lower TNM staging, longer interval to metastasis, and single metastatic lesion correlated with better survival. Resection in highly selected pancreatic cancer patients with synchronous and metachronous lung only metastasis might confer a survival benefit and should be considered on an individual basis.

Surgical treatment of metastatic pancreatic ductal adenocarcinoma: A review of current literature

BackgroundThere is no international consensus concerning the role of surgical treatment of metastatic pancreatic ductal adenocarcinoma (mPDAC), but favorable prognoses can be expected for highly selected patients. MethodsA comprehensive literature search of the PubMed and Cochrane databases was conducted using combinations of keywords to 4 July 2018. Eligible studies were those reporting on patients with histologically confirmed mPDAC undergoing surgery with curative intent. We excluded case reports with fewer than five patients, insufficient descriptions of survival data, and palliative or cytoreductive surgery as well as studies that assessed para-aortic lymph node metastasis or peritoneal washing cytology. ResultsThirteen studies were deemed eligible, and six studies were identified from their references. The studies involved 428 patients who underwent surgical resection for liver metastases (n = 343), lung metastases (n = 57), and peritoneal dissemination (n = 28). Median overall survival (OS) in patients with synchronous liver metastases who underwent conversion surgery following favorable response to initial chemotherapy was 27 or 34 months, and peritoneum metastases was 28 months. Median OS after the initial treatment was varied from 51 to 121 months in metachronous lung metastasis and from 24 to 40 months in metachronous liver metastasis, respectively. ConclusionEncouraging OS was indicated in patients with synchronous mPDAC of liver and peritoneum who underwent conversion surgery. Metastasectomy for metachronous lung and liver oligometastases could be considered a practical treatment option.

Lung Metastases in Patients with Well-Differentiated Gastroenteropancreatic Neuroendocrine Neoplasms: An Appraisal of the Validity of Thoracic Imaging Surveillance

Background/Aims: To evaluate the impact of lung metastases (LM) on overall survival (OS) in well-differentiated (WD) stage IV gastroenteropancreatic neuroendocrine neoplasms (GEP-NEN) patients along with developing surveillance strategies for thoracic imaging. Methods: Thirty-four patients with LM, from 3 centres, were identified (22 small intestine/12 pancreatic; 17 grade 1/15 grade 2/2 of unknown grade). For comparison, we used 106 stage IV WD, grade 1 and 2 GEP-NEN patients with metastatic disease confined in the abdomen. Results: LM prevalence was 4.9% (34/692). Eleven patients (32%) presented with synchronous LM whereas 23 (68%) developed metachronous LM at a median of 25 months (range 1–150 months). Patients with metachronous LM had already established liver and/or para-aortic lymph node metastases. Eighteen of 23 patients (78%) with metachronous LM exhibited concomitant progression in the abdomen. Median OS of WD GEP-NEN patients with LM was shorter than for those with stage IV disease without extra-abdominal metastases (56 [95% CI 40.6–71.6] vs. 122.7 [95% CI 70.7–174.8] months; log-rank p = 0.001). Among patients with progressive stage IV disease, the subset of patients with LM exhibited shorter OS (log-rank p = 0.005). LM were also confirmed as an independent prognostic factor for survival in multivariable analysis (HR 0.18; 95% CI 0.07–0.45; p < 0.0001). Conclusion: LM, although relatively rare in patients with WD stage IV GEP-NENs, may impact patients’ outcome. The development of metachronous LM is associated with concomitant disease progression in established abdominal metastases in most patients. These patient-related parameters could be utilized for a stratified surveillance approach, mainly reserving thoracic imaging for GEP-NEN patients with progressive disease in the abdomen.

Einfluss des primären Lymphknotenstatus kolorektaler Karzinome auf die Entwicklung von Lungenmetastasen und thorakalen Lymphknotenmetastasen

The lungs are the second most common organ site for metastases in patients with colorectal cancer (CRC). Lymph node metastasis of CRC represents aprognostic factor for survival. The present study investigated the influence of CRC lymph node metastasis on lung metastasis, in particular thoracic lymph node metastasis. A retrospective analysis of 88patients (n = 56male) with curative resection of lung metastases of CRC was performed. Primary endpoint: influence of lymph node status of CRC on lung metastases. Secondary endpoints: disease-free survival and overall survival. Statistical evaluation was carried out with SPSS. In 48patients apositive lymph node status of CRC and in 9patients an N+ status of lung metastases were determined. The lymph node status of the CRC significantly affected the incidence of synchronous metastases (p = 0.03), disease-free interval until formation of metachronous lung metastases (p = 0.012) and the overall survival of patients with CRC (p = 0.048). The 5‑year survival rate for CRC patients with lung metastases was 48.7% after pulmonary metastasectomy. Thoracic lymph node involvement also significantly affected survival (p = 0.001). Screening for pulmonary metastases should be included in the staging and follow-up of all patients with CRC, especially in patients with apositive lymph node status of the CRC.

Novel Indications for Surgical Resection of Metachronous Lung Metastases From Pancreatic Cancer After Curative Resection.

Few reports exist regarding surgical resection of metachronous lung metastases (MLM) from pancreatic ductal adenocarcinoma (PDA) after curative resection. To elucidate the indications for surgical resection of MLM and long-term survival, we analyzed Japanese case reports of MLM from PDA. Between 1983 and 2014, 17 Japanese case reports concerning surgical resection of MLM from PDA were published. We determined long-term survival in 16 patients (considering the published data of 15 patients and 1 of our own) by using a questionnaire survey and analyzing the relationships between background factors and long-term survival. In 16 patients with long-term survival, 4 patients were still alive without recurrence. The remaining 12 patients died of disease after recurrence. The median survival after the initial lobectomy was 37 months and the 3- and 5-year survival for all patients after lobectomy was 50% and 41%, respectively. Fourteen patients had a disease-free interval after initial resection of the primary pancreatic tumor of >20 months. These patients had a longer median survival period after lobectomy (46 vs. 25.5 mo, P=0.19). Seven patients had MLM of <16 mm. These patients had a statistically longer overall survival after lobectomy (83 vs. 16 mo, P=0.04). Three of 4 patients with primary stage I tumors were still alive without recurrence. We found that the conventional criteria for surgical resection of MLM from PDA (first disease-free interval of >20 mo with no other metastatic lesions) were appropriate. In addition, it is possible that MLM of <16 mm or primary stage I tumors are novel criteria.

Tracking the origin of simultaneous endometrial and ovarian cancer by next-generation sequencing \u2013 a case report

BackgroundEndometrioid adenocarcinoma of the uterus and ovarian endometrioid carcinoma share many morphological and molecular features. Differentiation between simultaneous primary carcinomas and ovarian metastases of an endometrial cancer may be very challenging but is essential for prognostic and therapeutic considerations.Case PresentationIn the present case study of a 33 year-old patient we used targeted amplicon next-generation re-sequencing for clarifying the origin of synchronous endometrioid cancer of the corpus uteri and the left ovary. The patient developed a metachronous lung metastasis of an endometrioid adenocarcinoma four years after hyster- and adnexectomy, vaginal brachytherapy and treatment with the synthetic steroid tibolone. Removal of the metastasis and megestrol treatment for seven years led to a complete remission.A total of 409 genes from the Ampliseq Comprehensive Cancer Panel (Ion Torrent, Thermo Fisher) were analysed by next generation sequencing and mutations in 10 genes, including ARID1A, CTNNB1, PIK3CA and PTEN were identified and confirmed by Sanger sequencing. Primary endometrial as well as ovarian cancer showed an identical mutational profile, suggesting the presence of an ovarian metastasis of the endometrial cancer, rather than a simultaneous endometrial and ovarian cancer. The metachronous lung metastasis showed a different mutational profile compared to the primary cancer. Immunohistochemical staining of the corresponding proteins suggested that the tumour development was driven by alterations in the protein function rather than by changes of the protein abundance in the cell.ConclusionsOur results have demonstrated next generation sequencing as a valuable tool in the differentiation of synchronous primary tumours and metastases, which has an important impact on the clinical decision making process. Similar to breast cancer, targeted therapies based on mutational tumour profiling will become increasingly important in endometrial and ovarian cancer. In summary, our results support the usage of next generation sequencing as a supplementary diagnostic tool, assisting in personalized precision medicine.

Spatio-temporal mutation profiles of case-matched colorectal carcinomas and their metastases reveal unique de novo mutations in metachronous lung metastases by targeted next generation sequencing.

BackgroundTargeted next generation sequencing (tNGS) has become part of molecular pathology diagnostics for determining RAS mutation status in colorectal cancer (CRC) patients as predictive tool for decision on EGFR-targeted therapy. Here, we investigated mutation profiles of case-matched tissue specimens throughout the disease course of CRC, to further specify RAS-status dynamics and to identify de novo mutations associated with distant metastases.MethodsCase-matched formalin-fixed and paraffin-embedded (FFPE) resection specimens (n = 70; primary tumours, synchronous and/or metachronous liver and/or lung metastases) of 14 CRC cases were subjected to microdissection of normal colonic epithelial, primary and metastatic tumour cells, their DNA extraction and an adapted library protocol for limited DNA using the 48 gene TruSeq Amplicon Cancer PanelTM, MiSeq sequencing and data analyses (Illumina).ResultsBy tNGS primary tumours were RAS wildtype in 5/14 and mutated in 9/14 (8/9 KRAS exon 2; 1/9 NRAS Exon 3) of cases. RAS mutation status was maintained in case-matched metastases throughout the disease course, albeit with altered allele frequencies. Case-matched analyses further identified a maximum of three sequence variants (mainly in APC, KRAS, NRAS, TP53) shared by all tumour specimens throughout the disease course per individual case. In addition, further case-matched de novo mutations were detected in synchronous and/or metachronous liver and/or lung metastases (e.g. in APC, ATM, FBXW7, FGFR3, GNAQ, KIT, PIK3CA, PTEN, SMAD4, SMO, STK11, TP53, VHL). Moreover, several de novo mutations were more frequent in synchronous (e.g. ATM, KIT, PIK3CA, SMAD4) or metachronous (e.g. FBXW7, SMO, STK11) lung metastases. Finally, some de novo mutations occurred only in metachronous lung metastases (CDKN2A, FGFR2, GNAS, JAK3, SRC).ConclusionTogether, this study employs an adapted FFPE-based tNGS approach to confirm conservation of RAS mutation status in primary and metastatic tissue specimens of CRC patients. Moreover, it identifies genes preferentially mutated de novo in late disease stages of metachronous CRC lung metastases, several of which might be actionable by targeted therapies.Electronic supplementary materialThe online version of this article (doi:10.1186/s12943-016-0549-8) contains supplementary material, which is available to authorized users.