126 Chapter 10 Secondly, tumor cells in smaller branches with or without occlusive fibro-intimal remodeling in small pulmonary arteries, which are usually a sign of metastases from other organs in the form of pulmonary tumor micro-embolism and pulmonary tumor thrombotic microangiopathy. In the pilot study, only 4 of the patients had a history of cancer, of which only 1 had a colonic carcinoma (Table 1), which is a tumor type that is infrequently CK7+. In the validation cohort, the presence of a previous malignancy was an exclusion criterion. Additionally, none of the cases with luminal tumor cells showed intimal fibro-remodeling. Thirdly, the morphological features in our study differ from tumor emboli in larger vessels from metastases of other organs in several ways. (1) In our cases, the alveolar walls surrounding the pulmonary artery were covered with tumor cells extending from the adjacent tumor, with a similar cytonuclear appearance as in the lumen of the artery. In metastatic emboli, the adjacent alveolar walls do not contain tumor, and the cytonuclear details of the metastases have a similarity with the primary tumor, which is usually different from a primary lung adenocarcinoma. (2) The amount of tumor cells was small (i.e., isolated tumor cells or small clusters) and without surrounding fibrin or other blood components, as discussed above in point 2. In cases of metastasis, the lumen of the larger pulmonary artery is usually slightly extended by the filling of the tumor embolus, while in our study, a large part of the occasionally indented lumen was ‘empty’. In patients with clinical suspicion of pulmonary emboli on preoperative imaging, the differential diagnosis includes sarcoma of the pulmonary artery 183, which was not present in our patients. Furthermore, hydrophilic coats on medical interventional devices may dissociate from the device surface during endovascular manipulation and give rise to hydrophilic polymer embolism184–186. These are morphologically characterized by intraluminal foreign body material surrounded by thrombosis, with or without inflammatory response, and are usually located in smaller arteries. Foreign body material was not present in our study. A last distinction can be made from circulating tumor cells that may appear similar, but these cells in the pulmonary artery of the resection specimen should then be derived from a primary source elsewhere in the body and flow via the heart to the lung. Morphologically, the circulating tumor cells should be surrounded by blood components, while in our study, the arterial lumen looked ‘empty’ with occasional tumor cells without a lot of blood components. Moreover, in most patients, a primary tumor of other origin than the lungs was not present at the time of resection and during follow-up (median time > 5 years). In addition, circulating tumor cells are rare in the bloodstream. For analysis of circulating tumor cells, enrichment and isolation methods have been developed 187, while in our study, there was a relatively high frequency in histological sections of both the pilot study and the validations cohorts. In the lung, a pilot study of blood sampling from tumor-draining pulmonary veins at the time of tumor resection was previously performed with the hypothesis that patients with detectable circulating tumor cells in the pulmonary vein would have a higher risk
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