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Interact CardioVasc Thorac Surg 2008;7:613-615. doi:10.1510/icvts.2007.174391
© 2008 European Association of Cardio-Thoracic Surgery
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Institutional report - Thoracic general

Prognostic impact of thrombocytosis in resectable non-small cell lung cancer

Masaki Tomita*, Tetsuya Shimizu, Masaki Hara, Takanori Ayabe and Toshio Onitsuka

Department of Surgery II, Faculty of Medicine, University of Miyazaki, Kihara 5200, Kiyotake, Miyazaki, 889-1692, Japan

Received 27 December 2007; received in revised form 7 April 2008; accepted 13 May 2008

*Corresponding author. Tel.: +81-985-85-2291; fax: +81-985-85-5563.

E-mail address: mtomita{at}med.miyazaki-u.ac.jp (M. Tomita).


   Abstract
Top
 Abstract
1. Introduction
 2. Materials and methods
 3. Results
 4. Discussion
 References
 
Relationship between thrombocytosis and poor prognosis has been reported in lung cancer. However, the majority of previous studies included many advanced stage and small cell lung cancer patients. Few studies focused on resectable non-small cell lung cancer patients. In the present study, therefore, consecutive 240 non-small cell lung cancer patients who received surgical resection were reviewed retrospectively, and investigated the survival impact of preoperative platelet count. In our results, the frequency of preoperative thrombocytosis was only 5.83% (14/240). The 5-year survival of patients with and without thrombocytosis was 28.87% and 63.73%, respectively. Both univariate and multivariate analyses indicated the independent prognostic impact of thrombocytosis. The present study is the first evaluation of prognostic effect of thrombocytosis in patients with resectable non-small cell lung cancer. Preoperative platelet count was a prognostic factor for resectable non-small cell lung cancer patients.

Key Words: Prognosis; Platelet count; Thrombocytosis; Non-small cell lung cancer


   1. Introduction
Top
 Abstract
 1. Introduction
2. Materials and methods
 3. Results
 4. Discussion
 References
 
Thrombocytosis is observed frequently in patients with malignancies, and prognostic significance has been found in patients with lung cancer [1–5]. However, the majority of previous studies included many advanced stage and small cell lung cancer patients [1–5]. Among previous studies that assessed thrombocytosis and lung cancer, to our knowledge, there are few reports focused on resectable non-small cell lung cancer patients.

In the present study, therefore, we retrospectively investigated the prognostic impact of preoperative thrombocytosis in resected non-small cell lung cancer patients.


   2. Materials and methods
Top
 Abstract
 1. Introduction
 2. Materials and methods
3. Results
 4. Discussion
 References
 
The present study was conducted from 2000 through 2004, including all patients with lung cancer who had a thoracotomy for intended surgical resection. Consecutive 240 lung cancer patients who fulfilled the inclusion criteria and underwent surgical resection were included in this study. There were 157 men and 83 women, ages ranged from 26 to 85 years, with an average of 66.4 years.

The preoperative platelet count was obtained before invasive diagnostic procedures were performed. Thrombocytosis was defined as a platelet count of at least 40x 104/mm3, in agreement with other studies [1–5]. All patients underwent thoracotomy. Pathologic (p) TNM staging was recorded in all patients. Follow-up information, including cause of death, was ascertained through a review of clinic notes and direct or family contact.

Comparisons of data between the two groups were made by using Fisher's extract test. Survival curves were obtained according to the Kaplan–Meier method. Comparison of survival curves was carried out using the log rank test. Statistical calculations were conducted with JMP (SAS Institute Inc. Cary, NC, USA) and values of P<0.05 were accepted as significant.


   3. Results
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
4. Discussion
 References
 
We identified only 14 patients (5.83%) having thrombocytosis at the time of their admission to our hospital. The frequency of the thrombocytosis was 6.37% (10/157) in men and 4.82% (4/83) in women. Thrombocytosis was found in 4.74% (9/190) of stage I/II patients, whereas 12.20% (5/41) of stage III/IV patients had thrombocytosis.

The relationship between preoperative thrombocytosis and clinicopathological factors is shown in Table 1. Thrombocytosis did not correlate with gender, clinical stage, histological type and serum CEA level.


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  		Table 1 The relationship between preoperative thrombocytosis and clinicopathological factors

 
As shown in Fig. 1a, 5-year survival of patients with and without thrombocytosis was 28.87% and 63.73%, respectively (P<0.0001). The results of univariate analysis are summarized in Table 2. The gender, histology, pT status, pN status, preoperative serum CEA level and preoperative thrombocytosis were related to patients' prognosis. The results of multivariate analysis including all variables for which P<0.05 on univariate analysis are summarized in Table 3. Of the variables that were included in the multivariate analysis, histology, pT status, pN status and preoperative thrombocytosis were independent prognostic determinants.


Figure 1
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  		Fig. 1. Survival of patients according to the preoperative platelet counts. PLT: platelet count.

 

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  		Table 2 Univariate analysis

 

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  		Table 3 Multivariate analysis

 
Postoperative platelet counts remained relatively stably increased in 11 of 14 patients having thrombocytosis preoperatively, whereas those of three patients had returned to normal range within one month after surgery. Among patients with preoperative thrombocytosis, the 5-year survival of patients with normal and elevated postoperative platelet counts was 66.67% and 18.18%, respectively. There was a trend toward an association between postoperative normalization of platelet counts and patients' survival; however, it could not be examined statistically because of very the small number of patients.


   4. Discussion
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
 4. Discussion
References
 
We found patients with thrombocytosis in 14/240 patients (5.83%). However, the frequency of thrombocytosis reported in previous studies had varied between 16% and 46% [1–5]. The frequency of thrombocytosis in the present study was lower than that in previous studies. In our result, thrombocytosis was found in 4.74% (9/190) of stage I/II patients, whereas it was 12.20% (5/41) of stage III/IV patients. Although the number of patients with advanced stage in the present series is small, this result indicates that thrombocytosis is more common among patients with advanced stage disease. Previous studies [1–5] included patients with advanced stage and small cell lung cancer. For example, the study population of Pedersen and Milman [4] had 64% of stage III/IV diseases and 22% of small cell lung cancers, and Aoe's series [5] had 82.65% of stage III/IV diseases and 32.08% of small cell lung cancers. Therefore, the reason for the difference in the frequency of thrombocytosis might be due to differences in stage and histological distribution of patients' population. In other words, the present study focused on resectable non-small cell lung cancer patients, whereas previous studies included many advanced stage and small cell lung cancer patients. Our result showed the prognostic impact of thrombocytosis in resectable non-small cell lung cancer patients. To our knowledge, the present study is the first evaluation of prognostic effect of thrombocytosis in patients with resectable non-small cell lung cancer.

Although the mechanism underlying development of thrombocytosis in lung cancer patients remains unclear, tumor-associated elevation of bone marrow-stimulating cytokines such as interleukin (IL)-6 [6–8], IL-1 [6, 8] and macrophage colony-stimulating factor (M-CSF) [9] might be one of possible mechanisms [4, 5]. These cytokines could exhibit thrombocytosis.

It has been also unknown whether thrombocytosis is an end result of growth factors secreted by tumor cells and the host response, or an event that directly increases the risk of disease spread and worsened prognosis. Several previous studies demonstrated that thrombocytosis might adversely affect survival by facilitating cell invasion and metastasis [10–12]. Platelets have been reported to promote metastasis by releasing certain tumor growth factors and by shielding tumor cells from immune surveillance, and also promote deposition of tumor cells to the vascular surface [10–12]. Moreover, platelets have been reported to play an important role in the process of tumor angiogenesis [13]. Taken together, prognostic impact of thrombocytosis in the present and previous results [1–5] might be due to direct effect of platelets that accelerate malignant process, at least in part.

Although the number of patients with thrombocytosis is small, our result showed a trend toward an association between postoperative normalization of platelet counts and patients' survival. Therefore, there is a possibility that postoperative normalization of platelet counts might be a prognostic indicator for patients with thrombocytosis, and patients without postoperative normalization of platelet counts might be suitable population for adjuvant chemotherapy. Further studies in this area are warranted.

In conclusion, the frequency of thrombocytosis in patients with resectable non-small cell lung cancer was 5.83%. Although the frequency of thrombocytosis is low compared to patients with advanced stage or small cell lung cancer, thrombocytosis was found to be an independent prognostic factor for patients with resectable non-small cell lung cancer.


   References
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
 4. Discussion
 References
 

  1. Costantini V, Zacharski LR, Moritz TE, Edwards RL. The platelet count in carcinoma of the lung and colon. Thromb Haemost 1990;64:501–505.[Medline]
  2. Gislason T, Nou E. Sedimentation rate, leucocytes, platelet count and haemoglobin in bronchial carcinoma: an epidemiological study. Eur J Respir Dis 1985;66:141–146.[Medline]
  3. Engan T, Hannisdal E. Blood analyses as prognostic factors in primary lung cancer. Acta Oncol 1990;29:151–154.[Medline]
  4. Pedersen LM, Milman N. Prognostic significance of thrombocytosis in patients with primary lung cancer. Eur Respir J 1996;9:1826–1830.[Abstract]
  5. Aoe K, Hiraki A, Ueoka H, Kiura K, Tabata M, Tanaka M, Tanimoto M. Thrombocytosis as a useful prognostic indicator in patients with lung cancer. Respiration 2004;71:170–173.[CrossRef][Medline]
  6. Suzuki A, Takahashi T, Nakamura K, Tsuyuoka R, Okuno Y, Enomoto T, Fukumoto M, Imaru H. Thrombocytosis in patients with tumors producing colony-stimulating factor. Blood 1993;80:2052–2059.
  7. Tefferi A, Ho TC, Ahmann GJ, Katzmann JA, Greipp PR. Plasma interleukin-6 and C-reactive protein levels in reactive versus clonal thrombocytosis. Am J Med 1994;97:374–378.[CrossRef][Medline]
  8. Alexandrakis MG, Passam FH, Perisinakis K, Ganotakis E, Margantinis G, Kyriakou DS, Bouros D. Serum proinflammatory cytokines and its relationship to clinical parameters in lung cancer patients with reactive thrombocytosis. Respir Med 2002;96:553–558.[CrossRef][Medline]
  9. Lidor YJ, Xu FJ, Martinez-Maza O, Olt GJ, Marks JR, Berchuck A, Ramakrishnan S, Berek JS, Bast RC Jr. Constitutive production of macrophage colony-stimulating factor and interleukin-6 by human ovarian surface epithelial cells. Exp Cell Res 1993;207:332–339.[CrossRef][Medline]
  10. Mehta P. Potential role of platelets in the pathogenesis of tumor metastasis. Blood 1984;63:55–63.[Abstract/Free Full Text]
  11. Karpatkin S, Pearlstein E. Role of platelets in tumor cell metastases. Ann Intern Med 1981;95:636–641.[Medline]
  12. Gastpar H, Ambrus JL, Ambrus CM. Platelet cancer cell interaction in metastasis formation. Platelet aggregation inhibitors: a possible approach to metastasis prevention. Prog Clin Biol Res 1982;89:63–82.[Medline]
  13. Sierko E, Wojtukiewicz MZ. Platelets and angiogenesis in malignancy. Semin Thromb Hemost 2004;30:95–108.[CrossRef][Medline]




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