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Vera Vukić

Kliničko-bolnički centar “Bežanijska kosa”, Beograd Odeljenje pulmologije sa bronhološkim odsekom
Klinike za internu medicinu; Odeljenje posebnih medicinskih usluga, Bežanijska kosa University Hospital, Belgrade, Serbia


The paper was received on 06.02.2017. /  Accepted on 20.02.2017.


Correspondence to

Dr Vera Vukić
11080 Zemun, Đorđa Pantelića 24,





Benign inflammatory lung diseases (bronchopneumonia, bronchiolitis, abscesses, tuberculosis, granulomatosis) are usually accompanied by biohumoral disorders. Similar or identical biochemical disturbances are also frequently present in lung cancers – in their occult, initial or developed stages. It is important to monitor their valuesuspicions of malignancy.
Many lung cancers of all histological types (adenocarcinomas being the leas in the clinical course of the disease in terms of prediction and prognosis. Regression or complete normalisation of the values of certain pathological biohumoral parameters after initial treatment (antibiotic or immunosuppressive) may indicate the benign nature of the disease, but their persistence must raise st frequent) are accompanied by secondary bacterial infections. The influence of certain pro-inflammatory cytokines and adhesion molecules is pronounced in some subacute and chronic lung diseases (tuberculosis, chronic obstructive pulmonary disease – COPD, granulomatosis). They may also be included in the list of pathogenic factors contributing to the development of lung cancers with their metabolic, haematological and inflammatory symptoms, as has often been proved in clinical practice.
In clinical practice, radiographic and biohumoral resolution of lung shadows is often inadequate since these are initially perceived and treated as pneumonic. Most cancers only show themselves to be suspect on X-rays taken during the period of typical or atypical symptoms. In their early stages, lung cancers may be occult or completely invisible on X-rays. These “hidden” cancers are usually centrally localised section the distal part of the trachea, on the main carina, or at the beginning of the main bronchi. Apart from radiographic “occult” tumours, different forms of “mimicked” lung cancers may appear on X-rays – these are chiefly pneumonias, lung abscesses, increased reticular-nodular patterns, unilateral laminar or partial atelectasis, spontaneous pneumothorax, pleural effusion, etc. All insufficiently clear X-ray images that show any discrepancy with the anticipated etiological factor or result of initial treatment must lead us to search for possible malignancy. Precisely because of these dilemmas in interpreting pathological radiographic findings, it is imperative that we monitor some other tumour “markers” – pathological biohumoral parameters. This is why we emphasise the possibility of etiopathogenetic links and radiographic similarities between some chronic benign lung diseases and lung cancers. Any “pneumonic shadow”that regresses slowly after antibiotic treatment or persists, especially persistent pathological biohumoral parameters, indicates the necessity for biopsy.
Regression or complete normalisation of the values of certain pathological biohumoral parameters after initial treatment (antibiotic and/or immunosuppressive) indicates the benign nature of a lung disease, while their persistence may suggest malignancy. This fact is particularly important in radiographically occult or “mimicked” lung tumours.
Medicine has long been aware of the link between hypercoagulation states and thrombotic signs in individual cancers, including lung cancer. The origin of thrombosis or subclinical coagulopathy is to be found in the many changes in the systems of coagulation and fibrinolysis. Thromboses partly reflect the hyperpermeable vascular system of the tumour, which allows the accumulation of plasma haemostatic factors in fairly high concentrations in the stroma of the tumour, as well as the production of pro-coagulating and tissue factors by the tumour cells themselves. In lung cancers, hypercoagulation states are most commonly caused by expression of the vascular endothelial growth factor (VEGF). A raised serum level of VEGF may be associated with a poor viable prognosis, especially in NSCLC, but need not be linked to histological type or disease stage. The activation of coagulation cascades may be induced by the malignant changes in the cells themselves or by tumour-associated inflammatory cells. Some thromboembolism accidents (pulmonary thromboembolism – PTE, cerebrovascular thrombosis, non-bacterial thrombotic endocarditis) may be precursors of more typical manifestations of lung cancer and represent the first clinical sign of occult neoplasm. Systemic hypoxemia likewise induces raised expression of VEGF in the lungs, which in turn causes much greater frequency of cerebrovascular accidents in hypoxemic patients as against patients with normal levels of partial oxygen pressure in the arterial blood (pO2).
Subclinical reflections of coagulation changes in lung cancer are far more frequent than clear clinical signs. This imposes the need to define prethrombic states as clinical markers of overt or occult neoplasm. To this end, it is essential the monitor the values of prothrombic time (PT), partial thromboplastin time (PTT), the platelet count, the fibrinogen level, the DD value and antithrombin III (AT-III). The most striking biohumoral coagulation parameters of greatest indications of the possibility of malignant lung disease are revealed by thrombocytosis, increased fibrinogen and DD levels. They can be significantly correlated with the clinical stage of the disease and performance status.
As a possible concomitant to lung tumours in their initial and advanced stages, thrombocytosis is one of the most striking haematological disorders. Thrombocytosis may be an early serological marker of an oligosymptomatic (sometimes even asymptomatic) lung neoplasm.
Besides the well-known hepatal synthesis of fibrinogen, recent years have also revealed expression of fibrinogen (FBG) , and of gene chains in the epithelial cells of the lungs. Local lung inflammation results in increased transcription of the -FBG gene, in answer to the pro-inflammatory mediators. Apart from acting as a very frequent serological marker of lung neoplasm, FBG can also have a predictive value in chemotherapy, especially in SCLC. A raised FBG level in lung cancer is in correlation with the values of fibrin-degradation products (FDP), CRP and Interleukin-6 (IL-6). To be sure in diagnosing hypercoagulability, the following are used as molecular markers: fibrinopeptide A (FPA), FPB, DD, the soluble fibrin monomer-fibrinogen complex (FM), FDP, and the thrombin-antithrombin complex (TAT). These are valuable parameters in the early diagnosis of thrombosis and disseminated intravascular coagulopathy (DIC) that may also accompany lung neoplasms. FM levels are also very useful in differentiating between pneumonia associated with the systemic inflammatory response syndrome (SIRS) and coagulopathy (most common in malignancy) on the one hand, and other forms of pneumonia, on the other.
In the literature, thrombocytosis, increased fibrinogen values and DD (as markers indicating prethrombic states) point to less viable carcinoma prognosis and are sometimes independent of the clinical stage of the disease and the histological type and size of the tumour. The clinical course of tumour coagulopathy, after the resection of lung tumours, can act as a useful indicator of the success of the resection, as well as a predictor of disease recurrence.
Fibrin-degradation products (FDP) are formed as fibrin is broken down under the influence of enzymes (e.g. plasmin), and the smallest degradation product is DD. This is present in the blood after the disintegration of a blood clot through fibrinolysis. A high DD plasma level reflects the activation of the coagulation and fibrinolytic system, which is of major importance in subclinical forms. A consistently high DD value indicates poor prognosis in malignant lung disease, and its determination may help in deciding on the use of adjuvant chemotherapy in resectable tumours.
The reason I chose this subject for my paper derives from our clinical experience in detecting “occult” or “mimicked” lung cancers on the basis of radiography or exhibited symptoms. The persistence of some pathological biochemical parameters after initial antibiotic treatment led us to expand our diagnostic procedures, in some cases repeating biopsies. Major parameters of our interesting are: platelet count, fibrinogen and D-dimers (DD) level.
All 70 subjects in our study showed pathological findings in their lung X-rays. The average time gap that elapsed between the first symptoms and hospitalisation was 2.19 months and there was a significant difference here between the two groups – in the working group (benign inflammatory lung diseases) this was most often 3 months (42.9%) and in the control group (lung cancer) 1 month (85.7%). This difference can be explained by the very nature of the diagnosed disease. Benign diseases had a sudden onset of symptoms that was more violent than the frequently occult lung cancers.
All the results obtained in our study were analysed using descriptive and differential statistics. We analysed the dynamics of certain biohumoral parameters in order to differentiate between benign and potentially malignant lung diseases: the link between pathological biohumoral parameters and the clinical stages of lung cancer; the link between pathological biohumoral parameters and PH types of cancer (Non-small cell lung cancers – NSCLC) and Small cell lung cancers (SCLC); and the dynamics of pathological biohumoral parameters in these two PH-type cancers at different clinical stages. The post-treatment decrease in all biohumoral parameters was much more striking in benign lung diseases.
In our study, patients in the working group had extremely high levels of fibrinogen before therapy and only medium levels after it. The therapy resulted in partial reduction of the fibrinogen level. In the control group, medium to high fibrinogen values were noticed before treatment, which completely returned to normal after it. Thrombocytosis persisted in the same percentage (17.1%) of patients in the working group (lung cancer) before and after treatment.
When investigating DD values, it was noticed that high values (in varying percentages) persisted in the working group both before and after treatment. In the control group, initially high values were far less common and these reverted to normal in 90% of the patients after treatment.
To sum up, our study produced the following conclusions: The acute rise in the DD value was more specific to NSCLC than to SCLC, as well as the change in the fibrinogen value.
It is our view that this study goes part of the way towards illuminating and explaining the importance of continuously monitoring these biohumoral parameters when trying to differentiate between benign and malignant lung disease during diagnosis, for initial PH findings are not always sufficiently convincing or conclusive.
This paper is aimed primarily at doctors in smaller medical establishments in Serbia, which do not have the technical facilities for detailed diagnosis of lung cancer, such as immuno-histochemical analysis, the designation of tumour markers, often not even the wherewithal to conduct bronchological investigation and HRCT thorax. If our labours have contributed to the speedier and more accurate illumination of diagnostic problems associated with lung cancer, then the purpose of this study will have been all the better served.




Radiografske, kliničke i biohemijske manifestacije pojedinih subakutnih i hroničnih benignih inflamatornih plućnih oboljenja mogu često predstavljati diferencijalno dijagnostički problem u odnosu na karcinom pluća. Plućni karcinomi, u svojim okultnim, inicijalnim ili razvijenim fazama, često mogu biti asocirani sa poremećajem pojedinih biohemijskih parametara, neretko uzrokovanih i sekundarnim bakterijskim infekcijama. Praćenje vrednosti ovih parametara, uključujući i koagulacione, u kliničkom toku bolesti može biti značajno u prediktivnom i prognostičkom smislu. Mnogi citokini i adhezioni molekuli patogenetski su povezani sa brojnim manifestacijama plućnih karcinoma, ali i pojedinih hroničnih benignih inflmtornih plućnih oboljenja. Kod bolesnika sa nedovoljnom postterapijskom radiografskom i biohemijskom regresijom pneumoničnih senki, retikularnih i nodularnih zasenčenja, slike plućnog apscesa, fibroznih promena, parcijalne atelektaze, spontanog parcijalnog pneumotoraksa, ponekad smo i više puta ponavljali biopsiju bronha, kada inicijalni patohistološki (PH) nalaz nije sa sigurnošću mogao potvrditi prirodu bolesti. U našoj studiji, najmarkantniji koagulacioni poremećaji kod karcinoma pluća bili su: trombocitoza, povišenje vrednosti fibrinogena i D-dimera. Kod benignih inflamatornih plućnih oboljenja je, posle inicijalne antibiotske i/ili imunosupresivne terapije, bila znatno izraženija regresija svih navedenih poremećaja nego kod karcinoma pluća.



Key words

Karcinom pluća, koagulacioni poremećaji, benigna inflamatorna plućna oboljenja





  1. Antoniou D, Pavlakou G, Stathopoulos G et al. Predictive value of D-dimer plasma levels in response and progressive disease in patients with lung cancer. Lung Cancer 2006 Aug;53(2):205-10
  2. Muraoka M, Tagawa T, Akamine S et al. Acute interstitial pneumonia following surgery for primary lung cancer. Eur J Cardiothorac Surg 2006 Oct;30(4):657-62
  3. Unsal E, Atalay F, Atikcan S, Yilmaz A. Prognostic significance of hemostatic parameters in patients with lung cancer. Respir Med 2004 Feb;98(2):93-8
  4. Ferrigno D, Buccheri G. Hematologic counts and clinical correlates in 1201 newly diagnosed lung cancer patients. Monaldi Arch Chest Dis. 2003 Jul-Sep;59(3):193-8
  5. Czerny M, Fleck T, SalatA et al. Sealing of the mediastinum with a local hemostyptic agent reduces chest tube duration after complete mediastinal lymh node dissection for stage I and II non-small cell lung carcinoma. Ann Thorac Surg 2004 Mar:77(3):1028-32
  6. Zacharski L, Wojtukiewicz M. Pathways of coagulation/fibrinolysis activation in malignancy. Sem Thromb Hemost 1992;18:104-196
  7. Pasqualini M, Mohn C, Patiti J et al. COX and LOX eicosanoids modulate platelet activation and procoagulation induced by two murine cancer cells. Prostaglandins Leukot Essent Fatty Acids 2000 Dec;63(6):377-83
  8. Gouin-Thibault I, Samama MM. Laboratory diagnosis of the thrombofilic state in cancer patients. Sem Thromb Hemost 1999;25:167-172
  9. Unsal E, Atalay F, Atikcan S, Yilmaz A. Prognostic significance of hemostatic parameters in patients with lung cancer. Respir Med 2004 Feb;98(2):93-8
  10. Pedersen LM, Milman N. Prognostic significance of thrombocytosis in patients with primary lung cancer. Eur Respir J 1996 Sep; 9(9):1826-1830
  11. Pedersen L, Milman N. Diagnostic significance of platelet count and other blood analyses in patients with lung cancer. Oncol Rep 2003 Jan-Feb,10(1):213-6
  12. Janowska-Wieczorek A, Wysoczynski M, Kijowski J et al. Microvesicles derived from activated platelets induce metastasis and angiogenesis in lung cancer. Int J Cancer 2005 Feb20;113(5):752-60
  13. Aoe K, Hiraki A, Ueoka H et al. Thrombocytosis as a useful prognostic indicator in patients with lung cancer. Respiration 2004 Mar-Apr;71(2):170-3
  14. Alexandrakis M, Passam F, Perisinakis K et al. Serum proinflammatory cytokines and its relationship to clinical parameters in lung cancer patients with reactive thrombocytosis. Respir Med 2002 Aug;96(8):553-8
  15. Leon-Mateos A, Ginarte M, Leon L, Toribio J. Reticular erythematous mucinosis (REM) with teleangiectasis associated with essential thrombocytosis and lung carcinoma. Eur J Dermatol 2005 May-Jun;15(3):179-81
  16. Altiay G, Ciftci A, Demir m et al. High plasma D-dimer levels is associated with decreased survival in patients with lung cancer. Clin Oncol (R Coll Radiol) 2007 Sep; 19(7):494-8
  17. Kaya A, Ciledag A, Gulbay BE et al. The prognostic significance of vascular endothelial growth factor levels in sera of non-small cell lung cancer patients. Respir Med 2004 Jul; 98(7): 632-6
  18. Takigawa N, Segawa Y, Fujimoto N et al. Elevated vascular endothelial growth factor levels in sera of patients with lung cancer. Anticancer Res 1998 Mar-Apr; 18(2B): 1251-4
  19. Pavey SJ, Hawson GA, Marsh NA. Impact of the fibrinolytic enzyme system on prognosis and survival associated with non-small cell lung carcinoma. Blood Coagul Fibrinolysis 2001 Jan; 12(1):51-8
  20. Marti HH, Risau W. Systemic hypoxia changes the organ-specific distribution of vascular endothelial growth factor and receptors. Proc Natl Acad Sci USA 1998; 95: 15809-15814
  21. Buccheri G, Torchio P, Ferrigno D. Plasma levels of D-dimer in lung carcinoma: clinical and prognostic significance. Cancer 2003 Jun 15; 97(12):3044-52

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PDF Vukić V. • MD-Medical Data 2017;9(1): 007-015




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