Loose Tumor Cells in Pulmonary Arteries of Lung Adenocarcinoma Resection Specimen: No Correlation With Survival, Despite High Prevalence.

CONTEXT.­: Loose tumor cells and tumor cell clusters can be recognized in the lumen of intratumoral pulmonary arteries of resected non-small cell lung cancer specimens. It is unclear whether these should be considered tumor-emboli, and as such could predict a worsened prognosis. OBJECTIVE.­: To investigate the nature and prognostic impact of pulmonary artery intraluminal tumor cells. DESIGN.­: This multicenter study involved an exploratory pilot study and a validation study from 3 institutions. For the exploratory pilot, a retrospective pulmonary resection cohort of primary adenocarcinomas, diagnosed between November 2007 and November 2010, were scored for the presence of tumor cells, as well as potentially other cells in the intravascular spaces using hematoxylin-eosin, and cytokeratin 7 (CK7) stains. In the validation part, 2 retrospective cohorts of resected pulmonary adenocarcinomas, between January 2011 and December 2016, were included. Recurrence-free survival (RFS) and overall survival (OS) data were collected. RESULTS.­: In the pilot study, CK7+ intravascular cells, mainly tumor cells, were present in 23 of 33 patients (69.7%). The 5-year OS for patients with intravascular tumor cells was 61%, compared with 40% for patients without intravascular tumor cells (P = .19). In the validation study, CK7+ intravascular tumor cells were present in 41 of 70 patients (58.6%). The 5-year RFS for patients with intravascular tumor cells was 80.0%, compared with 80.6% in patients without intravascular tumor cells (P = .52). The 5-year OS rates were, respectively, 82.8% and 71.6% (P = .16). CONCLUSIONS.­: Loose tumor cells in pulmonary arterial lumina were found in most non-small cell lung cancer resection specimens and were not associated with a worse RFS or OS. Therefore, most probably they represent an artifact.

Correction: Clonality analysis of pulmonary tumors by genome-wide copy number profiling.

[This corrects the article DOI: 10.1371/journal.pone.0223827.].

Clonality analysis of pulmonary tumors by genome-wide copy number profiling.

Multiple tumors in patients are frequently diagnosed, either synchronous or metachronous. The distinction between a second primary and a metastasis is important for treatment. Chromosomal DNA copy number aberrations (CNA) patterns are highly unique to specific tumors. The aim of this study was to assess genome-wide CNA-patterns as method to identify clonally related tumors in a prospective cohort of patients with synchronous or metachronous tumors, with at least one intrapulmonary tumor. In total, 139 tumor pairs from 90 patients were examined: 35 synchronous and 104 metachronous pairs. Results of CNA were compared to histological type, clinicopathological methods (Martini-Melamed-classification (MM) and ACCP-2013-criteria), and, if available, EGFR- and KRAS-mutation analysis. CNA-results were clonal in 74 pairs (53%), non-clonal in 33 pairs (24%), and inconclusive in 32 pairs (23%). Histological similarity was found in 130 pairs (94%). Concordance between histology and conclusive CNA-results was 69% (74 of 107 pairs: 72 clonal and two non-clonal). In 31 of 103 pairs with similar histology, genetics revealed non-clonality. In two out of four pairs with non-matching histology, genetics revealed clonality. The subgroups of synchronous and metachronous pairs showed similar outcome for the comparison of histological versus CNA-results. MM-classification and ACCP-2013-criteria, applicable on 34 pairs, and CNA-results were concordant in 50% and 62% respectively. Concordance between mutation matching and conclusive CNA-results was 89% (8 of 9 pairs: six clonal and two non-clonal). Interestingly, in one patient both tumors had the same KRAS mutation, but the CNA result was non-clonal. In conclusion, although some concordance between histological comparison and CNA profiling is present, arguments exist to prefer extensive molecular testing to determine whether a second tumor is a metastasis or a second primary.

Is the current diagnostic algorithm reliable for selecting cases for EGFR- and KRAS-mutation analysis in lung cancer?

OBJECTIVES: Adenocarcinoma (ADC) of the lung may harbor EGFR- or KRAS-mutations, which are relevant for treatment decisions. There is no consensus on the percentages of EGFR- and KRAS-mutations that are allowed to be missed by a diagnostic algorithm, although a percentage of less than 1% for EGFR-mutations has been suggested. The current guidelines do not advise to perform EGFR-mutation analysis in unequivocal squamous cell carcinoma (SqCC). For KRAS-mutations no threshold for missing cases is suggested yet. To improve segregation between ADC and SqCC in small samples, the classification of lung cancer was updated in 2011, adding immunohistochemistry (IHC) for p63 and TTF-1 to the diagnostic algorithm. In this study we examined how many cases with an EGFR- or KRAS-mutation in our database would have been missed, if the current guideline for selecting cases for mutation analysis would have been applied. MATERIALS AND METHODS: From an institutional lung cancer database of specimens analyzed for EGFR- and KRAS-mutations (n=816), cases harboring a mutation without being treated prior with an EGFR-TKI were selected (n=336). Corresponding original histological diagnoses and IHC for TTF-1, p63 and PAS-D were collected. Cases with SqCC on HE or with an IHC pattern favoring SqCC were reassessed according to the criteria of the 2011-classification. RESULTS: From the 336 cases 70% had a KRAS-mutation and 30% an EGFR-mutation. The number of cases with SqCC on HE and/or an IHC-profile favoring SqCC was 12. After the reassessment six specimens (1.8%) would not have been tested for EGFR-/KRAS-mutations, if the current diagnostic algorithm had been used: 2.0% of EGFR-mutations and 1.7% KRAS-mutations. All six cases were NSCLC with an IHC-profile favoring SqCC. CONCLUSION: Most NSCLC-cases with EGFR- and KRAS-mutations are selected by the current diagnostic algorithm. As a small but relevant fraction is missed, there is room for improvement.