Clinical Evidence that Coagulation Activation Drives Cancer Progression--a Report of 2 Cases.

BACKGROUND: Tissue factor (TF), the principal initiator of the extrinsic coagulation pathway, is expressed by many tumors and can be released into the bloodstream on plasma microparticles (MPs). Experimental studies indicate that TF may facilitate hematogenous metastasis by promoting tumor cell-induced microvascular thrombosis, but clinical data supporting this hypothesis is sparse. CASE REPORTS: Here, we report 2 unusual cases of rapidly progressive solid malignancies (gastric and urothelial carcinoma). In both patients, cancer cell dissemination with diffuse bone marrow involvement was either strongly suggested by leukoerythroblastic changes on peripheral blood smear or directly proven by positive findings on aspiration cytology. Furthermore, laboratory evidence of thrombotic microangiopathy (TMA) and disseminated intravascular coagulation was accompanied by new-onset severe pulmonary hypertension and a hemolytic uremic syndrome-like disorder in the gastric and the urothelial carcinoma patient, respectively. TF-specific procoagulant activity of isolated plasma MPs, as assessed by single-stage clotting assay, was dramatically increased in both patients compared to healthy controls (21- and 55-fold), and primary tumor samples stained strongly positive for TF by immunohistochemistry. CONCLUSION: TMA was likely caused by TF-triggered tumor cell embolization in both patients. Further clinical evidence is thus provided that TF directly links coagulation activation to cancer cell dissemination.

Plasma tissue factor antigen in localized prostate cancer: distribution, clinical significance and correlation with haemostatic activation markers.

Tissue factor (TF) is involved in cancer growth and metastasis, and haemostatic abnormalities are found in most patients with advanced malignancies, including prostate cancer (PC). Because anti-haemostatic agents are increasingly screened for their potential to prolong survival in tumor patients, a detailed characterization of haemostatic markers in selected cancer subtypes and clinical stages is warranted. In this study, we measured preoperative plasma TF antigen in a large cohort of patients with localized PC and correlated its levels with markers of coagulation and platelet activation, prostate-specific antigen (PSA), and histopathological findings to explore its potential as a prognostic marker in this tumor entity. Out of 140 patients, 19% and 23% had plasma TF antigen levels of <40 pg/ml (low-TF) and >200 pg/ml (high-TF), respectively, which was substantially higher than in 42 healthy male controls. Patients also had low-grade systemic coagulation activation as evidenced by elevated D-dimer, F1 + 2, and PAP plasma levels. Furthermore, similar to sP-selectin and sCD40L antigen, flow cytometric analysis of platelet-derived microparticles in plasma revealed significantly increased numbers in high-TF as compared to low-TF patients and controls. Whereas elevated D-dimer was associated with larger and less differentiated tumors, preoperative plasma TF antigen levels (median [IQR]) were higher in patients with (161 pg/ml [100-236]) than in those without recurrent PC (105 pg/ml [52-182]), as indicated by a serum PSA of >0.1 ng/ml during ambulatory follow-up. In patients with localized PC, preoperative plasma TF antigen levels correlate with platelet activation in vivo and may indicate an increased risk for recurrent disease.

Detection of human telomerase RNA in the tumour-surrounding mucosa of bladder carcinomas as a marker for premalignant transformation.

OBJECTIVES: To investigate tumour tissue and non-malignant tumour-surrounding bladder mucosa (NTSBM) for expression of human telomerase RNA (hTR) as a possible marker for premalignant transformation of urothelial cells. MATERIAL AND METHODS: From 67 patients with superficial transitional cell carcinoma (TCC), sections with representative tumour tissue and NTSBM were selected for evaluation. Sections with moderate or severe dysplasia were omitted from evaluation. hTR expression was detected with in situ hybridization using a 35S-UTP-labelled riboprobe, and analysed semiquantitatively by counting the hybridization signals. RESULTS: In 45 of the 67 patients hTR expression was moderate or strong in tumour tissue, and in 20 hTR expression was moderate or strong in NTSBM. Moderate or strong hTR expression was detected in the NTSBM from 19 of 60 patients with pTa/pT1 tumours. Of the 56 patients who were treated conservatively, eight had tumour recurrence, of whom five had moderate or strong hTR expression in the TSBM, compared with only 14 of 48 patients without tumour recurrence. CONCLUSION: Detecting hTR expression and the morphological distribution of hTR hybridization signals in NTSBM by in situ hybridization might indicate premalignant alterations involved in tumour recurrence.