Pulmonary tumor thrombotic microangiopathy induced by gastric carcinoma: Morphometric and immunohistochemical analysis of six autopsy cases

Abstract

BackgroundPulmonary tumor thrombotic microangiopathy (PTTM) has been known as a rare and serious cancer-related pulmonary complication. However, the pathogenesis and pathophysiology of this debilitating condition still remains obscure and no effective management was recommended. The present study aims to elucidate the pathophysiology of PTTM.MethodsAutopsy records were searched to extract cases of pulmonary tumor embolism induced by metastasis of gastric carcinoma in the Toho University Omori Medical Center from 2000 to 2006. And then, tissue sections of extracted cases were prepared for not only light microscopic observation but morphometric analysis with the use of selected PTTM cases.ResultsSix autopsies involved PTTM and clinicopathological data of them were summarized. There was a significant negative association between pulmonary arterial diameter and stenosis rate in four cases. Although all cases showed an increase of stenosis rate to some degree, the degree of stenosis rate varied from case to case. Significant differences were found for average stenosis rate between the under 100 micrometer group or the 100 to 300 micrometer group and the 300 micrometer group in four cases. However, no significant differences were found for average stenosis rate between the under 100 micrometer group and the 100 to 300 micrometer group in all cases. Meanwhile, all cases showed positive reactivity for tissue factor (TF), five showed positive reactivity for vascular endothelial growth factor (VEGF), and three showed positive reactivity for osteopontin (OPN).ConclusionsIn the present study, we revealed that the degree of luminal narrowing of the pulmonary arteries varied from case to case, and our results suggested that pulmonary hypertension in PTTM occurs in selected cases which have a widespread pulmonary lesion with severe luminal narrowing in the smaller arteries. Furthermore, our immunohistochemical examination indicated that gastric carcinoma indicating PTTM shows a higher TF-positive rate than typical gastric carcinoma. However, it remains still obscuring whether gastric carcinoma indicating PTTM shows a higher VEGF or OPN-positive rate as determined by immunohistochemistry.

Pulmonary tumour thrombotic microangiopathy

“…Macrophage-derived factors, such as interleukin-6 (IL-6), as implicated in PAH [20], may also contribute to the fibrointimal proliferation in PTTM. Tumour cell nests are also evident in pulmonary veins and lymphatics [9,10,18], with evidence for lymphatic tumour invasion (Fig. 1c).…”

“…Most reported cases of PTTM have been described in Japan, which is likely to reflect the high prevalence of gastric carcinoma. PTTM occurs in 16-27% cases of gastric carcinoma [4,5,9], especially the mucinous, signet ring and poorly differentiated subtypes [3,5,9]. PTTM is less commonly associated with breast [10], bladder [11], ovarian clear cell [12], hepatocellular [13] and gallbladder carcinoma [14].…”

“…myofibroblastic) in origin [5]. Cancer cell attachment is postulated to cause intimal (endothelial cell) damage, activation of coagulation and initiation of proliferation through growth factors and cytokine release/ expression, including tissue factor, vascular endothelial growth factor (VEGF) [4,8,9] and plateletderived growth factor (PDGF) [9, Fig. 1b).…”

Subacute right heart failure revealing three simultaneous causes of post‐embolic pulmonary hypertension in metastatic dissemination of breast cancer

“…Previous studies have shown that tumour cells have the abilities to activate coagulation pathway and local thrombus formation and trigger fibroblastic intimal proliferation via production of cytokines such as tissue factor,2 vascular growth factor, or platelet‐derived growth factor 3. High VEGF expression associated with gastric cancer could explain the high incidence of PTTM.…”

Crosstalk between cancer and haemostasis

“…In fact, it has become clear from both earlier and more recent animal studies that formation of a fibrin(ogen) and platelets containing thrombus around circulating tumour cells is a critical step during the blood-borne phase of the metastatic cascade (1,27). Although direct in-vivo evidence for this hypothesis in cancer patients is still lacking, microscopic tumour emboli resembling a thrombotic microangiopathy may be detected on autopsy in patients with gastric or ovarian carcinomas (28)(29)(30)(31). Interestingly, immunohistochemistry in some of these patients revealed strong TF staining on tumour cells, suggesting that the expression of procoagulant activity was an important determinant for tumour cell embolization.…”