tumor that extends into pulmonary veins may cause the pulmonary vein flow stasis , and/or vascular injury results in thrombosis generation [ 25 ] .
pulmonary veins infiltration by tumors or compression by affected lymph nodes result in venous stasis is also a potential reason to develop thrombosis [ 25 ] .
impedance of blood flow from the pulmonary vein to the left atrium may cause pulmonary edema or pleural effusion . in the present prospective case series study
, we investigate the clinical significance of pulmonary vein obstruction in cancer patients and better characterize the syndrome that we term  pulmonary vein obstruction syndrome  ( pvos ) .
data collected from 1117 patients hospitalized in oncology wards of the chang - gung memorial hospital .
the urological cancer was our area of expertise ; most of these patients had urothelial carcinomas .
the criteria for pvos diagnosis inclusion / diagnosis are listed as symptoms , chest x - ray findings , and ct findings , and that all 3 were required .
the criteria for inclusion were ( 1 ) episodes of shortness of breath ; ( 2 ) chest x - ray showing unilateral or bilateral abnormal pulmonary hilum shadow with or without presence of pulmonary edema and/or pleural effusion ; ( 3 ) ct ( computed tomography ) scan demonstrating pulmonary vein thrombosis / tumor with or without lesions sticking to the outer vein surface .
when dyspnea occurred and chest x - ray shows abnormal hilum shadow , ct scan was traced to detect pulmonary vein thrombosis / tumor .
the characteristics of pvos included the presence of acute respiratory distress , combined with other thromboembolic complications and with other paraneoplastic syndromes .
acute respiratory distress was described as aggravated by chemotherapy , aggravated by medical / surgical procedures , and subject to diurnal fluctuation in intensity .
common thromboembolism - associated complications included consciousness loss / mental change [ 6 , 7 ] , paraneoplastic pain , and iliofemoral venous thrombosis symptoms .
paraneoplastic pain was defined as breakthrough pain occurring in the absence of an identifiable precipitating cause .
cerebral thromboembolic complication and/or paraneoplastic pain in most patients were clinically suspected because of difficulty in definite diagnosis .
paraneoplastic syndromes included neoplastic fever ( tumor - related fever with good response to naproxen test ) , cachexia syndrome ( simultaneous presence of weight loss > 5% within 6 months , reduced food intake , and muscle wasting ) . the d - dimer test , complete blood counts , liver function test , renal function test as checked in all patients with pvos , aptt ( active partial thromboplastin time ) and pt ( prothrombin time ) , calcium , c - reactive protein , blood gas , and pleural effusion study were checked in selected patients when diagnosing pvos .
the cutoff d - dimer value was 500  ng / ml . paraneoplastic syndromes included hypercalcemia ( serum calcium level more than 11  mg / dl ) , leukemoid reaction ( peripheral count to more than 20,000/l without evidence of infection or leukemia ) , and prerenal azotemia was defined as bun - to - creatinine ratio greater than 20 .
chest plain film findings included the location of abnormal pulmonary hilum shadows , presence of pulmonary edema , and presence of pleural effusion .
ct scan findings included pulmonary vein obstruction sites , presence of pulmonary embolism , and presence of pleural effusion .
echocardiography and lung ventilation / perfusion scan were performed in selected patients when diagnosing pvos .
treatment included subcutaneous injection of low molecular weight heparin ( lmwh ) either fraxiparin ( glaxosmithkline ) or enoxaparin ( sanofi - aventis ) , intravenous dexamethasone , and intravenous fluids with or without furosemide when pvos with acute respiratory distress occurred .
further use of chemotherapy or targeted therapy or hormone therapy depended on the patient 's condition .
ct scans were obtained from the hospital picture archiving and communication system ( pacs ) .
continuous data ( presented as mean  standard deviation ) were used for d - dimer , c - reactive protein , bun , creatinine , and bun - to - creatinine ratio analysis .
the data for 222 consecutive cancer patients ( 139 men and 83 women ; 2793 years old ; median age , 69 ) was collected for evaluation of pvos .
the patients ' characteristics and important laboratory and imaging findings of pvos were shown in table 1 .
one hundred and sixty - seven patients ( 75% ) had an eastern cooperative oncology group ( ecog ) performance status of 2 or greater .
common association with thromboembolic complications occurred in 146 patients ( 66% ) : consciousness disturbance ( n = 103 ) , paraneoplastic pain ( n = 53 ) , and iliofemoral venous thrombosis symptom ( n = 16 ) . of them , 62 associated with multiple thromboembolic presentations . of 103 patients with consciousness disturbance , 16 had ct scan- or magnetic resonance imaging- ( mri- ) evidence of cerebral infarction and/or their angiographic proven .
common association with paraneoplastic syndromes occurred in 101 patients ( 45% ) : cachexia syndrome ( n = 79 ) , neoplastic fever ( n = 23 ) , leukemic - like reactions ( n = 18 ) , hypercalcemia ( n = 4 ) , and lactic acidosis ( n = 3 ) . of them
acute respiratory distress ( n = 222 ) was aggravated by chemotherapy ( n = 28 ; 13% ) and medical / surgical procedures ( n = 21 ; 9% ) and fluctuated diurnally in intensity ( n = 32 , 14% ) .
blood gas tests in 126 patients found acidity ( ph less than 7.3 ) in 24 ( 19% ) , paco2 > 50  mmhg in 23 ( 18% ) , pao2 < 60  mmhg in 36 ( 29% ) , hco3 < 18  meq / l in 35 ( 28% ) , and sao2 < 90% in 35 ( 28% ) .
pleural effusion tests in 32 patients found exudate in 28 ( 88% ) , erythrocyte count < 500 in 14 ( 44% ) , leukocyte count < 500 in 22 ( 69% ) , and lymphocytes predominant in 25 ( 78% ) .
d - dimer values 10013000  ng / ml in 35% of patients was the most common . there were 132 patients ( 59% ) with hemoglobin levels below 10  g / dl , 95 patients ( 43% ) with elevated white blood counts ( > 10,000/l ) , and 21 patients ( 9% ) with decreased platelet counts ( < 100,000/l ) .
aptt ( active partial thromboplastin time ) was checked in 100 patients and pt ( prothrombin time ) was checked in 109 patients ; of these , 34 ( 34% ) had aptt values above 36 seconds and 29 ( 27% ) had pt values above 15 seconds .
albumin values were below 3.0  g / dl in 78 ( 41% ) of the 189 patients .
mean c - reactive protein value was 114  96  mg / l ( 0.7 to 384  mg
of them mean bun value , creatinine value , and bun - to - creatinine ratio were 79.3  41.6  mg / dl ( 36.3 to 163  mg / dl ) , 3.7  2.7  mg / dl ( 0.65 to 12.3  mg / dl ) , and 21.4  15.5 ( 6.9 to 60.5 ) , respectively .
chest plain x - rays of 222 patients before and at the onset of pvos were shown in figures 1(a ) , 1(b ) , 2(a ) , 2(b ) , 3(a ) , 3(b ) , 4(a ) , and 4(b ) .
abnormal hilum shadows were bilateral in 175 ( 79% ) and unilateral in 47 ( 21% ) and present in both lobes in 186 ( 84% ) , upper lobes in 19 ( 9% ) , and lower lobes in 17 ( 8% ) .
chest plain x - rays showed pulmonary edema in 194 patients ( 87% ) and pleural effusion in 192 patients ( 86% ) ( figures 1(b ) , 2(b ) , 3(b ) , and 4(b ) ) .
ct scans that revealed tumor / thrombosis located in pulmonary veins were shown in figures 1(c ) , 1(d ) , 2(c ) , 2(d ) , 3(c ) , 3(d ) , 4(c ) , and 4(d ) .
the separate time between doing ct scan and detecting abnormal hilum shadows by chest films due to pvos was 149 patients ( 67% ) within 1 month , 46 ( 21% ) in 1 - 2 months , 20 ( 9% ) in 2 - 3 months , and 7 ( 3% ) more than 3 months .
tumor or atelectatic lesions surrounding the pulmonary vein ( figures 4(c ) and 4(d ) ) were seen in 140 ( 63% ) .
pulmonary vein obstructions were present bilaterally in 204 ( 92% ) and unilaterally in 18 ( 8% ) , in both the superior and inferior pulmonary vein in 203 ( 91% ) , in the superior pulmonary vein only in 11 ( 5% ) , and inferior pulmonary vein only in 8 ( 4% ) .
chest ct scan detected pleural effusion in 155 patients ( 70% ) , pulmonary artery embolism in 70 patients ( 32% ) , peripheral tumor / thrombi lesions ( figures 2(c ) and 2(d ) ) in 72 patients ( 32% ) , and cardiac tumor / thrombi lesions ( figures 3(c ) and 3(d ) ) in 7 patients ( 3% ) , and lung ventilation - perfusion scan in 5 patients found two ( 40% ) with a pulmonary embolism and echocardiography in 29 patients found 14 ( 48% ) with left atrium enlargement ( 38  mm ) .
lmwh therapy was given to 170 patients with pvos , including 113 on fraxiparin ( 3800  iu or 5700  iu daily ) and 57 on enoxaparin ( 6000  iu daily ) . and intravenous dexamethasone was also used in 133 patients .
symptoms and/or image improvement in 113 ( 66% ) including 99 of those treated with dexamethasone . of them
, 37 patients continued their lmwh for secondary prevention . of 69 patients who received therapy , including chemotherapy in 59 , targeted therapy in 9 , and hormone therapy in one , 46 ( 68% ) had disease control .
pvos developed again after disease progression in 32 patients ( 74% ) , including 20 with their lmwh for secondary prevention .
follow - up periods ranged from 1 day to 267 weeks . besides the fact that 12 patients were lost to follow - up , 210 patients could be followed until death or up to the present .
three - month , 6-month , 1-year , and 2-year - survival probabilities were 30% , 13% , 9% , and 1% , respectively .
for 52 patients not receiving lmwh therapy patients , median overall survival time was 4 weeks .
for 170 patients receiving lmwh  dexamethasone therapy showed clinical / image improvement in 114 patients . the composite survival rate for those with clinical / image improvement was superior to those without clinical / image improvement .
the median survival rate was 11 weeks versus 2 weeks by log - rank test ( p = 0.001 ) .
the predeath status could be identified in 198 patients as respiratory failure ( n = 90 ; 45% ) and consciousness loss ( n = 108 ; 55% ) .
sixty - three patients ( 32% ) died of septicemia and/or febrile neutropenia , including 34 with respiratory failure and 28 with consciousness loss .
trouseau 's syndromein is characterixed by spontaneous , multiple , recurrent , and migratory venous thrombosis , and arterial emboli [ 1113 ] .
a few patients also exhibit other paraneoplastic syndromes related to cytokine production [ 810 ] .
virchow describes the three elements , including venous stasis , endothelial injury , and hypercoagulability that are thought to contribute to venous thromboembolism ( vte ) [ 14 , 15 ] .
cancer cells can activate the hemostatic system through the expression of adhesion molecules , release of inflammatory cytokines , and production of hemostatic factors [ 1620 ] .
activation of blood coagulation results in thrombin generation and intravascular fibrin formation [ 1620 ] .
thrombin - activated tumor cell adhesion to host cells also enhances tumor cell growth , tumor cell seeding , and spontaneous metastasis and stimulates tumor angiogenesis [ 1619 ] .
once cancer cells enter into and/or approach to the pulmonary vein , they result in blood flow stasis and vascular injury .
the increase cytokine production among cancer patients have been well recognized in sepsis , surgery / medical procedures and chemotherapy [ 2022 ] .
three lines of evidence are presented in the study to indicate that pvos is a real model of the thromboembolic complication [ 16 , 17 ] .
second , acute respiratory distress is aggravated by chemotherapy and medical / surgical procedures and fluctuates diurnally in intensity .
cancer itself , its treatments , and its complications can activate cytokine signaling pathways including those of nuclear factor kappa b ( nfb ) and p38 mitogen - activated protein kinase ( mapk ) .
third , d - dimer and crp levels were elevated in 89% and 95% , respectively , of our patients , as occurs in cases of vte and pe [ 25 , 26 ] . elevated d - dimer or crp
a rise in hydrostatic pressure occurs due to blood flow through the pulmonary vein to the left atrium stasis .
a few patients already had an oncological emergency ( i.e. , respiratory failure with hypoxemia , hypercapnia , decreased ph , or low sao2 ) .
a complex cause of pleural effusion noted in pvos patients , and 69% had leukocyte count less than 500 on the pleural fluids .
the reason in part for the low leukocyte count is that , in pvos ( like heart failure ) , hydrostatic pressure is also increased .
cancer can induce pulmonary embolism ( pe ) formation and thrombotic formation and can invade large veins [ 2830 ] .
extensive tumor - associated thromboemboli in the pulmonary microvasculature have been reported in a cancer patient with dyspnea [ 2830 ] . however , microscopic tumor embolism is rarely recognized before death .
pvos can combined with pulmonary artery embolism ; tumor / thrombi from pulmonary veins can extend peripherally [ 28 , 29 ] or enter left atrium .
pulmonary artery embolism , peripheral pulmonary tumor / thrombi lesion , and cardiac tumor / thrombi lesions were 32% , 32% , and 3% of our patients , respectively .
the appearance of abnormal pulmonary hilum shadows on chest plain x - ray films ( which are due to pulmonary hypertension ) is essential for raising suspicion of pvos .
pulmonary edema and/or pleural effusion on chest plain films indicate severe blockade of pulmonary veins .
ct scans are vital for the diagnosis of pvos and can show pulmonary vein thrombosis , tumor , and pulmonary vein stricture especially from their abnormal pulmonary hilum shadows .
pulmonary edema and/or pleural effusion may be unilateral or bilateral and may arise from the superior pulmonary vein , inferior pulmonary vein , or both .
bilateral lung and pulmonary veins involvement are seen in most of our patients . in the present study ,
pleural effusion was detected in 86% of our cases on plain chest x - ray films but in only 70% on ct scans .
the discrepancy may be due to the timing of the ct scan , which was usually performed before the pvos attack .
echocardiography found left atrium enlargement ( thought to be due to stenosis of the pulmonary vein distal to the left atrium ) in approximately 48% of our cases . in cancer patients , it is important to recognize that early appearance on chest x - ray of abnormal pulmonary shadows can result in a misdiagnosis of lung infection and acute respiratory distress syndrome .
cytokine and nfb inhibitors , such as dexamethasone , are used to suppress cytokine formation in acute stage .
stress related to cytokines can influence the course of neoplastic diseases . preventing unnecessary procedures and calming the patients can reduce cytokine overproduction . knowing aggravated factors can cause pvos .
adequate fluids supplement is necessary for maintaining good perfusion of vital organ ( brain , coronary artery , and kidney ) [ 6 , 7 , 37 , 38 ] .
the importance of cancer - associated hyper - coagulation is an etiology of acute ischemic stroke [ 6 , 7 ] and probably a leading death in our patients .
renal insufficiency had been linked to increased mortality from the literature   and prerenal azotemia pattern in our 16% patients .
furosemide for preload reduction can provide immediate symptom relief when acute respiratory distress with pulmonary edema occurs .
maintenance of lmwh is suggested for secondary prevention [ 39 , 40 ] and probably a survival benefit [ 4143 ] .
clinical / image improved in 66% of our patients after lmwh with or without combination with dexamethasone .
the survival rate for those with clinical / image improvement was superior to those without clinical / image improvement .
the cause of death was either respiratory failure or consciousness disturbance and related to thromboembolic complications .
two - thirds patients died of septicemia and/or febrile neutropenia . in the pathogenesis of sepsis , inflammation and coagulation
sepsis increases cytokine production and is considered to be an aggravating factor of thromboembolic complications .
first , the data was collected from prospective case cohort study in a single center mainly from a single physician .
secondary , image study included chest plain film and ct scan was probably not done simultaneously .
third , pulmonary vein thrombosis , tumor , or mixed type was difficult judge from ct scan .
fourth , consciousness / mental change related to thromboembolic complication seldom proven by image study .
physicians should be alert to pvos when shortness of breath occurs and chest x - ray reveals abnormal pulmonary hilum shadows .
symptoms can be relieved by the administration of lmwh , dexamethasone , prevent unnecessary procedures , calm the patients , adequate fluids , furosemide given when there is acute respiratory distress , and antibiotics given immediately when there is an infection .
 
 background . we study the clinical significance and management of pulmonary venous obstruction in cancer patients . 
 methods . 
 we conducted a prospective cohort study to characterize the syndrome that we term  pulmonary vein obstruction syndrome  
 ( pvos ) between january 2005 and march 2014 . 
 the criteria for inclusion were ( 1 ) episodes of shortness of breath ; ( 2 ) chest x - ray showing abnormal pulmonary hilum shadow with or without presence of pulmonary edema and/or pleural effusion ; ( 3 ) ct scan demonstrating pulmonary vein thrombosis / tumor with or without tumor around the vein . results . 
 two hundred and twenty - two patients developed pvos . 
 shortness of breath was the main symptom , which was aggravated by chemotherapy in 28 ( 13% ) , and medical / surgical procedures in 21 ( 9% ) and showed diurnal change in intensity in 32 ( 14% ) . 
 chest x - rays all revealed abnormal pulmonary hilum shadows and presence of pulmonary edema in 194 ( 87% ) and pleural effusion in 192 ( 86% ) . 
 ct scans all showed pulmonary vein thrombosis / tumor ( 100% ) and surrounding the pulmonary veins by tumor lesions in 140 patients ( 63% ) . 
 pvos was treated with low molecular weight heparin in combination with dexamethasone , and 66% of patients got clinical / image improvement . 
 conclusion . 
 physicians should be alert to pvos when shortness of breath occurs and chest x - ray reveals abnormal pulmonary hilum shadows . 
1. Introduction
2. Materials and Methods
3. Results
4. Discussion
5. Conclusion