Conventional tumor grading systems based on the degree of tumor differentiation may not always be optimal because of difficulty in objective assessment and insufficient prognostic value for decision making in colorectal cancer (CRC) treatment. This study aimed to determine the importance of assessing the number of poorly differentiated clusters as the primary criterion for histologic grading of CRC. Five hundred consecutive patients with curatively resected stage II and III CRCs (2000 to 2005) were pathologically reviewed. Cancer clusters of ≥5 cancer cells and lacking a gland-like structure were counted under a ×20 objective lens in a field containing the highest number of clusters. Tumors with <5, 5 to 9, and ≥10 clusters were classified as grade (G)1, G2, and G3, respectively (n=156, 198, and 146 tumors, respectively). Five-year disease-free survival rates were 96%, 85%, and 59% for G1, G2, and G3, respectively (P<0.0001). Poorly differentiated clusters affected survival outcome independent of T and N stages and could help in more effective stratification of patients by survival outcome compared with tumor staging (Akaike information criterion, 1086.7 vs. 1117.0; Harrell concordance index, 0.73 vs. 0.67). The poorly differentiated cluster-based grading system showed a higher weighted κ coefficient for interobserver variability (5 observers) compared with conventional grading systems (mean, 0.66 vs. 0.52; range, 0.55 to 0.73 vs. 0.39 to 0.68). Our novel histologic grading system is expected to be less subjective and more informative for prognostic prediction compared with conventional tumor grading systems and TNM staging. It could be valuable in determining individualized postoperative CRC treatment.

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Background: Cancer-associated venous thromboembolism (VTE) is a critical complication in patients with cancer. However, the pathological findings of VTE are limited. Here, we investigated the histopathological features of cancer-associated VTE in human autopsy cases. Methods: We clinically examined the autopsy cases of VTE with (n=114) and without cancer (n=66) and immunohistochemically analyzed the expression of prothrombotic factors in intrathrombus cancer cells, the thrombus contents of erythrocytes, fibrin, platelets, citrullinated histone H3, and degree of organization. Results: Vascular wall invasion or small cell clusters of cancer cells was observed in thrombi in 27.5% of deep vein thrombosis and 25.9% of pulmonary embolism cases. The majority of the cancer cells in deep vein thrombi appeared to be invading the vessel wall, whereas the majority of pulmonary thrombi had cancer cell clusters, consistent with embolization via blood flow. These cancer cells were immunohistochemically positive for TF (tissue factors) or podoplanin in up to 88% of VTE cases. The frequency of TF-positive monocyte/macrophages in thrombi was higher in cancer-associated VTE than that in VTE without cancer. Citrullinated histone H3 was predominantly observed in the early stages of organizing thrombi. There was no significant difference in thrombus components between VTE with cancer and without cancer groups. Conclusions: Vascular wall invasion or cancer cell clusters in thrombi might influence thrombogenesis of cancer-associated VTE. TF and podoplanin in cancer cells and in monocyte/macrophages may induce coagulation reactions and platelet aggregation. Neutrophil extracellular traps may play a role in the early stages of VTE, regardless of cancer status.

Aims: Patients with peripheral artery disease (PAD) have a high prevalence of cardiovascular morbidity and mortality; however, majority of patients with PAD are asymptomatic. This study aimed to histologically evaluate whether asymptomatic, lower extremity artery plaques are associated with systemic atherosclerosis and the onset of cardiovascular disease (CVD) events using autopsy cases.Methods: We histologically investigated the atherosclerotic plaques of the common iliac, common carotid, coronary, and renal arteries from 121 autopsy cases without symptoms of PAD (mean age: 67.6 years; 63% men; 83% non-CVD death). We evaluated the relationship between the degree of iliac artery atherosclerosis and that of other arteries, and also the presence of any CVD, myocardial infarction, stroke, and renal failure.Results: Advanced atherosclerotic plaques (American Heart Association ≥ 4) were present in 86 (72%) common iliac arteries in these cases. These arteries also showed high frequencies of calcification (66%), intraplaque hemorrhage (42%), and plaque disruption (24%). These advanced lesions were associated with age (≥ 60 years), sex (male), hypertension, diabetes, and smoking habit (all P < 0.05). Additionally, it was significantly associated with CVD (odds ratio, 95% confidence interval; 6.2, 2.2–22), myocardial infarction (6.4, 1.2– 19), stroke (8.7, 1.7 –16), and renal failure/hemodialysis (5.8, 1.1 – 11). Cases with advanced iliac artery plaques had advanced coronary and carotid atherosclerosis.Conclusion: These results indicate that asymptomatic advanced plaques are frequently observed in common iliac arteries, and are associated with generalized atherosclerosis and CVD events.